Organic compounds of sulphur, selenium, and tellurium vol 2

A Specialist Periodical Report Organic Compounds of Sulphur, Selenium, and Tellurium Volume 2 A Review of the Literat...

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A Specialist Periodical Report

Organic Compounds of Sulphur, Selenium, and Tellurium Volume 2

A Review of the Literature Published between April 1970 and March 1972

Senior Reporter D m HI Reid, Department of Chemistry, The University, St. Andrews Reporters G. C. Barrett, Oxford Polytechnic R. J. S. Beer, The University of Liverpool F. DUUS,Odense University, Denmark S. Gronowitz, University of Lund, Sweden A. Wm. Johnson, University of North Dakota, U.S.A. D. N. Jones, The University, Shefleld F. Kurzer, Royal Free Hospital School of Medicine, University of London G. Prota, University of Naples, Italy

@ Copyright 1973

The Chemical Society Burlington House, London, W I V OBN

ISBN : 0 85186 269 1 Library of Congress Catalog Card No. 77-23818

Organic formulae composed by Wright's Symbolset method

PRINTED IN GREAT BRITAIN BY JOHN WRIGHT AND SONS LTD., AT THE STONEBRIDGE PRESS, BRISTOL

Preface

The aims and structure of this second Volume of ‘Organic Compounds of Sulphur, Selenium, and Tellurium’ remain those set out in the Preface to Volume 1. Two changes in the coverage are announced. First, a review of the Theoretical Aspects of Organosulphur, Organoselenium, and Organotellurium Compounds has been omitted from this volume. A review of the subject, covering the four-year period beginning April 1970, will appear in Volume 3. Secondly, an extended chapter on the chemistry of Thiophen and Related Compounds, which could not be reviewed in time for inclusion in Volume 1, takes its place in this volume, and covers the three-year period April 1969 to March 1972. Reviewing of all other material covered in this volume is for the two-year period April 1970 to March 1972. D. H. R.

Contents

Chapter 1 Aliphatic Organo-sulphur Compounds, Compounds with Exocyciic Sulphur Functional Groups, and their Selenium and Tellurium Analogues By G. C.Barreff 1 1 General 1 Text-books and Reviews 2 Thiols Preparation Spectroscopic and Related Properties of Thiols Thiols as Nucleophiles Reactions of Thiols with Organoboron, Organophosphorus, and Organotin Compounds Addition of Thiols to Multiple Bonds Protection of SH Groups in Synthesis Thiols in Biochemistry

3 3 6

7 8 9 12

12

3 Sulphides Preparation Preparation of Sulphides using Organomagnesium, Organoboron, or Organophosphorus Reagents Heteroaryl Sulphides Properties of Sulphides Reactions of Sulphides a-Substituted Sulphides a-Chloro-sulphides p-Ket o-sulphides Unsaturated Sulphides Reactions of Unsaturated Sulphides Skeletal Rearrangements of Unsaturated Sulphides Naturally Occurring Organo-sulphur Compounds

27 28 30

4 Thioacetals and Related Compounds Preparation Reactions Tetrathioethylenes and Related Compounds

31 31 31 34

14

14 16 17 18

21 24 25 25 26

Contents

vi

5 Sulphoxides Preparation Spectroscopic Properties of Sulphoxides Resolution and Racemization of Sulphoxides Reactions of Sulphoxides StereochemicalFeatures of Reactions of Sulphoxides Dimethyl Sulphoxide as a Reagent

35 35 37 39 41 45 50

6 Sulphones Preparation Properties of Sulphones Reactions of Sulphones Addition Reactions of Unsaturated Sulphones Smiles Rearrangement Ramberg-Backlund Rearrangement

57 57 59 59 62 64 64

7 Sulphenic Acids and their Derivatives Sulphenic Acids and Sulphenate Esters Sulphenamides Sulphenyl Halides Sulphenyl Protecting Groups

65 65 67 69 71

8 Thiocyanates and Isothiocyanates Preparation of Thiocyanates Preparation of Isothiocyanates Reactions of Thiocyanates and Isothiocyanates

72 72 73 74

9 Sulphinic acids Preparation Reactions of Sulphinic Acids Sulphinate Esters Sulphinamides

76 76 77 78 78

10 Sulphonic Acids Preparation Sulphonyl Peroxides Sulphonate Esters Vinyl Sulphonates Sulphonyl Halides and Sulphenes Sulphonyl Cyanides Sulphonamides and Related Compounds 11 Disulphides, Trisulphides, and their Oxy-sulphur Analogues Preparation of Disulphides, Hydrodisulphides, and Oligosulphides

80 80 82 82 84 85 87 87

90 90

vii

Contents

Properties of Disulphides Reactions of Disulphides and Polysulphides Thiolsulphinates Thiolsulphonates Sulphinyl Sulphones and a-Disulphones

Chapter 2 Small Ring Compounds of Sulphur and Selenium By D. N. Jones 1 Thiirans Formation Spectroscopic and Conformational Aspects Reactions

93 94 97 98 99

100 100 102 103

2 Thiiran 1-Oxides Format ion N.M.R. Characteristics Reactions

104 104 105 105

3 Thiiran 1,l-Dioxides

107

4 Thiiren 1-Oxides and Thiiren 1,l-Dioxides Formation Reactions

108 108 1 09

5 Thiiranium and Thiirenium Ions

109

6 Thiaziridines

111

7 Thietans Formation By Intramolecular Displacement Reactions By Cycloadditions involving Thiocarbonyl Compounds Photolysis Other Reactions involving Ring Fission Thietanium Ions

111 111 111

113 114 114 114

8 Thietan 1-Oxides, Thietan 1,l-Dioxides, and Thiet 1,lDioxides Formation By Oxidation of Thietans By Cycloadditions involving Sulphenes BYCvcloadditions involving Thiet 1.1-Dioxides

116 116 116 116 118

...

Contents

Vlll

Reactions Thermolysis and PhotoIysis of Thietan 1,l-Dioxides Thermolysis of Thiet 1,l-Dioxides Reactions of Thietan 1,l-Oxides, Thietan 1,lDioxides, and Thiet 1,l-Dioxides involving Sulphur-stabilized Carbanions 9 Structure and N.M.R. Properties of Thietan Derivatives

119 120 121

122 124

10 1,3=Dithietansand 1,3-Diselenetans

128

11 1,ZThiazetidines

131

12 1,3-Thiazetidines and 1,2,3-0xathiazetidines

132

13 1,2-Oxathietansand 1,2,3-Dioxathietans

133

Chapter 3 Saturated Cyclic Compounds of Sulphur and Selenium By D. N. Jones 1 Thiolans, Thians, Thiepans, Thiocans, their Oxides and Dioxides, and their Selenium Analogues Formation Properties and Reactions Oxides and Dioxides Sulphimides and Sulphoximides

2 Compounds with Two Sulphur or Selenium Atoms in the Ring; their Oxy-sulphur Analogues Cyclic Disulphides and Cyclic Diselenides Formation Properties and Reactions 1,3-Dithiolans, 1,3-Dithians, and their Selenium Analogues Formation Properties and Reactions 1,4-Dithians, 1,4-Diselenans, 1,4-Dithiepans, and 1,5-Dithiocans Formation Pronerties and Reactions

135 135 141 149 158

160 160 160 160 163 163 166 173 173 174

ix

Contents 3 Compounds containing Three or More Sulphur Atoms 1,2,4-Trithiolans 1,3,5-Trithians, 1,2,4-Trithians, and 1,2,4,5-Tetrathians Macrocyclic Polysulphides

4 Compounds containing Sulphur or Selenium and other Heteroatoms Cyclic Sulphonates, Cyclic Sulphinates, and Related Systems 1,3-0xathiolans, 1,3-0xathians, 1,3-Oxaselenans, 1,4-0xathians, and Related Systems Cyclic Sulphites, Cyclic Selenites, Cyclic Sulphates, and Related Systems Penicillins, Cephalosporins, and Related Compounds

176 176 177 179 180 180

182 187 191

Chapter 4 Thiocarbonyl, Selenocarbonyl, and Tellurocarbonyl

Compounds By F. Duus 1 Introduction Reviews The Thiocarbonyl Group in General Thioaldehydes and Thioketones Thioketens Sulphines Sulphenes Thioamides Derivatives of Thioamides Thioureas Thiono- and Dithio-acids and Derivatives Selenocarbonyl Compounds

200 200 200 200 201 201 201 201 201 201 201 201

2 Thioaldehydes Synthesis Transient Species Metal Complexes

201 202 204

3 Thioketones Synthesis Transient Species The Thio-Claisen Rearrangement Metal Complexes Reactions

204 204 209 210 212 214

201

Contents

X

4 Thioketens

220

5 Thiocarbonyl Ylides

222

6 Sulphines

223

7 Sulphenes

225

8 Thioamides Synthesis Reactions

228 228 233

9 Thioureas Synthesis Reactions

236 236 239

10 Thiosemicarbazides and Derivatives Synthesis Reactions

243 243 246

11 Thionocarboxylic and Dithiocarboxylic Acids and Derivatives Synthesis Reactions

250 250 254

12 Thionocarbonates, Thionodithiocarbonates, and Trithiocarbonates Synthesis Reactions

258 258 260

13 Thionocarbamic Derivatives Synthesis Reactions

263 263 267

and

Dithiocarbamic

Acids

and

14 Selenocarbonyl Compounds Synthesis Reactions

271 271 271

15 Physical Properties Structure Tautomerism Ring-Chain Isomerism Polarization Effects and Restricted Rotation Crystal and Molecular Structures

273 273 273 276 277 279

xi

Contents Spectra Ultraviolet Spectra Infrared Spectra N.M.R. Spectra E.S.R. Spectra Mass Spectra 0ther Physical Properties Electrochemistry Dipole Moments Acidity and Basicity Measurements

Chapter 5 Ylides of Sulphur, Selenium, Tellurium, and Related Structures By A. William Johnson 1 Introduction

279 279 28 1 282 284 285

286 286 286 286

288

2 Sulphonium Ylides Methods of Synthesis Physical Properties Chemical Stability Reactions of Sulphonium Ylides Sulphonium Ylides as Reaction Intermediates

289 289 289 29 1 296 306

3 Oxysulphonium Ylides Synthesis and Properties Reactions of Oxysulphonium Ylides

307 307

4 Sulphinyl Ylides

312

5 Sulphonyl Ylides

315

6 Sulphenes

317

7 Sulphines

320

8 Sulphur Imines Iminosulphuranes Sulphurdi-imines Imino-oxysulphuranes Sulphonedi-imines

322 322 328 329 334

9 Sulphonyl- and Sulphinyl-amines

336

10 Ylides of Selenium and Tellurium

339

308

xii

Contents

Chapter 6 Heterocyclic Compounds of Quadricovalent Sulphur By D. H. Reid 1 Introduction

341

2 Thiabenzenes

34 1

3 Thiabenzene 1-Oxides

345

4 Azathiabenzenes

347

5 Four- and Five-membered Ring Compounds

349

Chapter 7 Thiophens and their Selenium and Tellurium Analogues By S. Gronowitz 1 General

352

2 Monocyclic Thiophens Syntheses of Thiophens by Ring-closure Reactions MO Calculations Electronic Spectra Molecular Geometry 1.r. Spectra and Dipole Moments N.M.R. Spectra E.S.R. Spectra Mass Spectra Electrophilic Substitution Electrophilic Ring-closure Reactions Radical Reactions Nucleophilic Substitution Metallation and Halogen-Metal Exchange Photochemistry of Thiophens Application of the Hammett Equation The Structures and Reactions of Hydroxy- and Mercapto-thiophens and their Simple Derivatives Side-chain Reactivities Rearrangement Reactions Biheterocyclics Thiophen Analogues of Porphyrins Reactions at the Thiophenic Sulphur Diels-Alder Reactions Raney-nickel Desulphurization 0t her Ring-opening React ions

353 353 361 362 363 363 365 369 370 371 378 38 1 384 386 392 395 396 401 409 410 414 41 7 417 417 420 ~-

...

Contents

xi11

Polymers from Thiophen Derivatives Naturally Occurring Thiophens Thiophens of Pharmacological Interest Thiophen Derivatives of Analytical Interest

3 Thienothiophens, their Benzo-derivatives, and Analogous Compounds Synthesis Theoretical Studies and Physical Properties Substitution Reactions Non-classical Thienothiophens 4 Benzothiophens and their Benzoannelated Derivatives Synthesis of Benzothiophens by Ring-closure Reactions Theoretical Studies and Physical Properties Electrophilic Substitution Electrophilic Ring-closure Radical Substitution Metallation and Halogen-Metal Exchange Side-chain Reactions Photochemistry The 2- and 3-Hydroxybenzo[b]thiophen Systems and their Derivatives Reaction at Sulphur Pharmacologically Active Compounds

5 Thiophen Analogues of Polycyclic Aromatic Hydrocarbons Thiophen Analogues of Anthracene Thiophen Analogues of Phenanthrene Thiophen Analogues of Helicenes Thiophen Analogues of Fluorene Thiophen Analogues of Tropylium Ions and Related Compounds Miscellaneous Thiophen Analogues of Polycyclic Hydrocarbons 6 Thiophen Analogues of Indole, Quinoline, Isoquinoline, and Similar Systems Thiophen Analogues of Indole and Related Compounds Thiophen Analogues of Quinoline and Related Compounds

42 1 422 423 427

428 428 430 430 433 435 435 441 442 445 447 447 449

449 45 1 452 452

455 455 458 460 462

467 470

472 472 473

xiv

Contents

Thiophen Analogues of Isoquinoline and Related Compounds 0ther Pyridine-fused Thiophen-cont aining Systerns

475 478

7 Thiophens Fused to Rings containing Two Nitrogens Pyrazole- and Imidazole-fused Systems Pyridazine-fused Systems Pyrimidine-fused Systems Miscellaneous Rings containing Several Nitrogens

480 480 480 483 485

8 Miscellaneous Fused Systems Thiazole-fused Systems Pyrylium-fused Systems Thiapyrylium-fused Systems Other Fused Systems

487 487 487 488 489

9 Selenophens and Tellurophens Monocyclic Selenophens Benzo[blselenophens Miscellaneous Fused Selenophens Tellurophens

490 490 49 1 495 495

Chapter 8 6a-Thiathiophthens and Related Compounds By R. J. S. Beer 1 Introduction

497

2 Structural and Theoretical Studies

497

3 Synthesis, Properties, and Reactions of 6a-Thiathiophthens

500

4 Compounds Structurally Related to 6a-Thiathiophthen

505

Chapter 9 1,2- and 1,3-Dithioles By R. J. S. Beer 1 Introduction

51 1

2 1,2-Dithioles and Related Compounds Synthesis Reactions

51 1 51 1 512

xv

Contents

3 1,ZDithiolium Salts

515

4 1,3-Dithioles and Related Systems

519

Chapter 10 Thiopyrans and Related Compounds By R. J. S. Beer 1 Introduction

526

2 Dihydrothiopyrans

526

3 2H-Thiopyrans and Related Compounds

529

4 4H-Thiopyran Derivatives

530

5 Thiopyrylium Salts

532

6 Thiochromans and Related Compounds

535

7 Thio- and Seleno-coumarins

537

8 2-Thioisocoumarins, Dithioisocoumarins, and Related Compounds

538

9 Thioxanthones, Selenoxanthones, and Related Compounds

541

10 Peri-Fused Naphthothiopyrans

542

11 Complex Thiopyran and Selenopyran Derivatives

543

Chapter 11 Thiepins and Dithiins By D. H. Reid 1 Thiepins

545

2 Dithiins 1,ZDithiins 1,4-Dithiins and 1,4-Diselenins Benzo- and Dibenzo-l,4-dithiins

551 55 1 552

554

xvi

Contents

Chapter 12 lsothiazoles By F. Kurzer 1 Introduction

556

2 Synthesis From a-Amino-ketones or fl-Cyano-enamines and Sulphur Chlorides (Type A)

556

From Oxathiazolones (Type B) From Chlorosulphonyl Isothiocyanates and Olefins (Type B) From 3,3’-Dithiodipropionamides (Type C) From Phenylcysteine (Type C) From Vilsmeier Salts (Type C) From 1,2-Dithiolans (Type C) From Thiazoles

558

556

559 560 560 561 563 563

3 Physical Properties

564

4 Chemical Properties Free-radical and Photolytic Reactions Nitration and Halogenation Diazo tization Conversion into 1,2,3-Thiadiazoles Metallation Miscellaneous Substitution Reactions (mostly Nucleophilic) Nucleophilic Ring Cleavage Base-catalysed Dimerization S-Oxides and -Dioxides Complexes Some Biological Properties

567 567 567 568 569 569

5 Condensed Ring Systems 2,l -Benzisothiazoles Synthesis Electrophilic Substitution 1,ZBenzisothiazoles Synthesis Mass Spectra Chemical Properties Nucleophilic Substitution and Ring Fission Complexing Isothiazolo[5, 1-e]isothiazoles Isothiazolo[2,3-b]quinazolines

576 576 576 577 577 577 579 579 582

570 574 574 575 575 576

585

585 585

xvii

Contents

Chapter 13 Thiazoles By F. Kurzer 587

1 Introduction

2 Synthesis Hantzsch’s Synthesis (Type A, S-C-N C-C) Other Type A (S-C-N C-C) Syntheses + C) Synthesis Type E (N-C-C-S Type F (C-N-C-S + C) Synthesis Type G (N-C-S-C-C) Synthesis Fission of Thiamine

587 587 589 590 59 1 591 592

3 Physical Properties

594

4 Chemical Properties Deuterium and Tritium Exchange Free-radical Reactions Alkylation Electrophilic Substitution Miscellaneous Substitutions Reactions of Aminothiazoles Ring Cleavage Ring Expansion to 1,4-Thiazines Dimerization Azines and Dyes Metal Complexes

595 595 596 597 598 599 600 603 605 606 607 609

5 Biochemical Aspects Thiamine (Vitamin B,) Miscellaneous Biochemical Contributions Biological Activity Mesionic Thiazoles Formation from Mesionic Oxazoles

610 610 612 613 614 614

6 2-Thiazolines Synthesis From (Thio)carbamoyl Isothiocyanates From Thioamides and Acetylenedicarboxylic Acid Further Syntheses from Thioamides (Linear and Cyclic) From Aziridines 2-Thiazoline Pept ides Physical Properties

616 616 616

+

+

617 618 620 622 624

Contents

xviii Chemical Properties Alkylation Acylat ion Action of Isocyanate Esters Hydrolysis and Aminolysis Conversion into Triazoles

625 625 625 627 628 629

7 4-Thiazolines Synthesis Properties

630 630 632

8 Thiazolidines Synthesis Hantzsch’s Synthesis and Related Cyclizations From 2-Aminoethanethiol and Related Compounds From Aziridines From Thiirans From 1,4-Thiazines by Ring Contraction From Thiocarbonylamino-acid Silyl Esters From Enamines and Mercaptocarboxylic Acids From Keten, Carbodi-imide, and Sulphur Dioxide Physical Properties Chemical Properties Thiazolidines in Peptide Synthesis Rhodanines

632 632 632 634 636 639 640

640 641 641 642 642 645 648

Chapter 14 Condensed Ring Systems incorporating Thiazole By F. Kurzer 1 Benzothiazole Synthesis Synthesis from o-Aminothiophenols Synthesis from Thioamides and Related Compounds Synthesis from Quinones and Thioureas Synthesis from Benzothiazines Physical Properties X-Ray Analysis Chemical Properties Oxidation Benzothiazolin-Zone Hydrazones Benzothiazole 3-Oxides

653 653 653 656 658 658 659 664 664 665 665 665

Contents

xix Diazotization Alkylation and Related Reactions Aminomethylation Michael Reaction Azidobenzothiazoles Acylation Alkylation and Acylation by Free-radical Reactions Alkylation and Arylation Acylation Heterocyclic Carbenes Nucleophilic Substitution Silylbenzothiazoles Polymethine Dyes Polymers Metal Complexes Biochemical Aspects Physiological Activity Benzoselenazoles Condensed Ring Systems

670 670 67 1 67 1 67 1 672 673 676 677 679 680 680 68 1

2 Structures Comprising Two Five-membered Rings (5,5) Thiazolo[2,3-c or 3,2-b]-s-triazoles Thiazolo [2,3-b]t hiazoles Thiazolo [5,4-d]thiazoles Pyrrolo[2,1-b]thiazole

682 682 683 683 684

3 Structures Comprising One Five-membered and One Six-membered Ring (5,6) Thiazolo [3,Za]-s-triazines Thiazolo[3,2-b]- and Thiazolo[2,3-c]-ns-triazines

Thiazolo[4,5-d]pyridazines Thiazolo[3,2-a]pyrimidines Synthesis from 2-Mercapt opyrimidines Synthesis from 2-Aminothiazoles Thiazolo[3,2-c]pyrimidines Thiazolo[4,5-d]pyrimidines Thiazolo [3,2-a]pyrazines Thiazolo [3,2-a]pyridines Synthesis from L-Cysteine Synthesis from Penicillamine Synthesis from Substituted 2-Mercaptopyridines Thiazolo[3,2-a]pyridinium 3-Oxides Thiazolo [5,4-b(and c)]pyridines

667 668 668 669 669 669

684 684 685 686 688 688 689 692 694 695 695 696 697 697 699 700

xx

Contents

4 Structures Comprising One Five-membered and One Seven-membered Ring ( 5 7 ) Thiazolo[5,4-f]- 1,4-diazepines Thiazolo [5,4-c]azepines

700 700 70 1

5 Structures Comprising Two Five-membered and One Six-membered Ring (5,5,6) Bisthiazolo[3,2-a; 4’,5’-d]pyrimidines Thiazolo [2,3-b]benzothiazoles Thiazolo[3,2-f]xanthine Thiazolo [3,2-a]benzimidazoles Thiazolo [3,4-a]benzimidazole Thiazolo[4,3-b] benzot hiazoles Thiazolo [3,2-a]pyrrolo[2,3-d]pyrimidines

701 70 1 702 703 703 706 707 707

6 Structures Comprising One Five-membered and Two Six-membered Rings (5,6,6) [ 1,3]Thiazino [2,3-b]benzo thiazoles Pyrimido [2,1-b]benzot hiazoles Thiazolo [3,2-a]quinazolines Thiazolo[4,5-b]quinoxalines Thiazolo [2,3-a]isoquinolines Thiazolo[ 3,2-b]isoquinolines Pyrano [3,2-g]benzothiazoles Thiazolo [5,4-~]benzo(thio)pyrans Naphtho[ 1,2-d]thiazoles Selenazolo [5,4-f]quinolines

707 707 707 708 709 709 710 710 710 71 1 71 1

7 Structures Comprising One Five-membered, One Sixmembered, and One Seven-membered Ring (5,6,7) Thiazolo [3,2-b][2,4]benzodiazepines

712 712

8 Structures Comprising Two Five-membered and Two Six-membered Rings (5,5,6,6) Thiazolo [3’,4’- 1,2]pyrazino[7,8-a]benzimidazoles Benzimidazo [2,1-b]benzothiazole Naphth[ 1,2-d]imidazo[3,2-b]thiazole Thiazolo [S ,4-a]carbazoles Isoindolo[1,2-b]benzothiazoles

712 712 712 713 713 71 3

9 Structures Comprising Two Five-membered, One Sixmembered, and One Seven-membered Ring (5,5,6,7) Thiazolo [3’,4’-1,2] [1,4]diazepin0[8,9-a]benzimidazoles

714 714

Contents

xxi

10 Structures Comprising One Five-membered and Three Six-membered Rings (5,6,6,7) Thiazolo[5,4-b]- and Thiazol0[4,5-~]-phenothiazine Thiazolo [4,5-c]acridines Isoquinolino[3,2-b]benzothiazole 11 Structures Comprising One Five-membered and Four Six-membered Rings (5,6,6,6,6) Quinoxalino [2’,3’-4,5]t hiazolo [3,2-a(and b)]quinazolines

714 714 716 716

716 716

Chapter 15 Thiadiazoles and Selenadiazoles By F. Kurzer 1 Introduction

71 7

2 1,2,3-ThiadiazoIes Synthesis Pechmann’s Synthesis Synthesis from Sulphonyl Azides 0ther React ions Properties 1,2,3-SeIenadiazoles Benzo-1,2,3-t hiadiazoles

717 717 717 718 718 718 719 72 1

3 1,2,4-Thiadiazoles Synthesis Chemical Properties

72 1 72 1 723 724

1,2,4-ThiadiazoIo[4,3-a]pyridines 4 1,3,4-Thiadiazoles Synthesis From Thiosemicarbazides Cyclization of Acylthiosemicarbazides From Aminoguanidines and Diaminoguanidines From Carbonohydrazide From Thiocarbonohydrazide From Thiosemicarbazides and (Thio)phosgene Oxidation of Thiosemicarbazones Syntheses from Dithiocarbazates Synthesis from Acylhydrazines Synthesis from 1-Thiocyanato-2,3-diazabuta1,3dienes

725 725 725 725 725 727 727 730

731 732 733 733

xxii

Contents Synthesis from 1,2-Dithiole-3-thiones Synthesis from Oxadiazolium Salts Chemical Properties Ring Expansion to Thiazines Miscellaneous Reactions Biological Properties Mesionic 1,3,4-Thiadiazoles Synthesis Properties Condensed Ring Systems 1,3,4-Thiadiazoio[3,2-a]pyridines 1,3,4-Thiadiazolo[3,Za]pyrimidines 1,3,4-Thiadiazol0[2,3-c]-1,2,4-triazines 1,3,4-Thiadiazolo[2,3-c]quinazolines

734 734 736 741 741 743 745 745 746 749 749 749 749 749

5 1,3,4-Selenadiazoles

751

6 1,2,5-Thiadiazoles Condensed Systems incorporating 1,2,SThiadiazole Benz0-2,1,3-thiadiazoles 1,2,5-Thiadiazolo[3,4-b(and c)]pyridines 1,2,5-Thiadiazolo[3,4-d]pyridazines

752 753 753 755 756

7 1,2,5-Selenadiazoleand Condensed Ring Systems 1,2,5-SeIenadiazolo[3,4,-b(and c)]pyridines Naph tho [2,3-d]-2,1,3-selenadiazole

756 756 757

Chapter 16 Thiazines By G. Profa 1 1,2-Thiazines Simple 1,2-Thiazines Benzo-l,2-thiazines

758 758 759

2 1,3-Thiazines Simple 1,3-Thiazines Benzo-l,3-thiazines

760 760 765

3 1,4-Thiazines Monocyclic 1,4-Thiazines Benzo- 1,4-thiazines and Related Compounds Phenothiazines (Dibenzo- 1,4-thiazines) and Related Compounds

769 769 77 1 779

xxiii

Contents

Chapter 17 Thiazepines and Thiadiazepines By D. H. Reid 1 1,4-Thiazepines

785

2 Benzothiazepines

788

3 Dibenzothiazepines

793

4 Thiadiazepines

795

Errata

797

Author Index

798

Introductory Review

Important general principles concerning the structure of aliphatic organosulphur compounds have been surveyed (I, 18-20).* The essentials of d-p, d-sp3, and d-d interactions have been set out, providing a background of experimental data on bivalent sulphur compounds (I, 18). Structural consequences of interactions between lone pairs or between lone pairs and polar bonds have been outlined. Preferred conformations for a-sulphonyl, a-sulphinyl, and m-sulphenyl carbanions are those involving maximum gauche interactions of the pyramidal carbanion with the lone pairs on sulphur or with S-0 polar bonds. The skew conformation of the disulphide grouping is an example of gauche lone pair-lone pair interactions. General reinforcement is given to the idea that the disposition of d-orbitals does not determine conformational preferences. Understanding of these interactions will assist the interpretation of physical and chemical properties of organosulphur compounds and their oxygen and nitrogen analogues. Stereochemical reaction cycles involving sulphoxides, sulphimides, and sulphoximides (I, 317, 318) and for sulphinimides and related compounds (I, 527) have filled gaps in sulphur functional group chemistry and provided new knowledge of the stereochemical aspects of reactions at a sulphur atom in general. The high affinity of both phosphorus and boron for sulphur can result in extrusion of sulphur from a variety of compounds on treatment with tervalent phosphorus and boron compounds. The oxathiolan-5-one obtained by treatment of thiobenzilic acid with benzaldehyde or a ketone loses carbon dioxide and sulphur when warmed with tris(diethy1amino)phosphine to give 1,l -diphenylalkenes ( I , 60). The same reagent converts cystine derivatives into lanthionines (I, 123), while triethylphosphine converts disulphides (R-S-S-But) into sulphides (R-S-Et) (I, 124). Trialkylboranes show synthetic possibilities, converting disulphides into sulphides in free-radical chain reactions (I, 120). Thioboranes have been used to transform a sulphenate ester into an unsymmetrical sulphide (I, 122), and aldehydes and ketones into the corresponding thioacetals and thioketals (I, 217, 218). Interest in small-ring organosulphur compounds has in the past received much impetus from the synthetic potential attending the loss of sulphur or its oxides from compounds to furnish olefins, acetylenes, or cycloalkanes, and a recent, elegantly conceived, potential synthesis of highly hindered

* Italicized numerals in brackets refer to chapter numbers, ordinary numerals to reference numbers.

xxvi

Introductory Review

olefins involves the desulphurization by tervalent phosphorus compounds of thiirans formed in situ from dihydrothiadiazoles (2, 4, 5 ) or 1,3-oxathiolan-5-ones (2, 5). Thermal loss of sulphur dioxide from thiiran 1,l-dioxides to give olefins, well documented and exploited synthetically, did not occur in some exceptional cases (2, 36, 38), fission of the thiiran carbon-carbon bond occurring instead. The recently synthesized phenyland alkyl-substituted thiiren 1,l-dioxides (2, 40, 41) and diphenylthiiren 1-oxide (2, 42) displayed remarkable thermal stability when compared with their saturated analogues, and diphenylthiiren 1-oxide was more stable than the corresponding dioxide. Interest in the reactions and electronic structure of these interesting heterocycles will doubtless develop rapidly. The carefully investigated thermolysis and photolysis of thietan 1,l-dioxides (2, 62, 63, 82, 84, 89, 90) and thiet 1,l-dioxides (2, 82) occurs non-stereoselectively and gives mixtures of products, but the stereospecificity of butyl-lithium-induced fragmentation of thietanium salts (2, 63) and of the base-catalysed isomerizations of 2,4-diphenylthietan 1-oxide (2, 96) and the corresponding dioxide (2, 96, 98) are interesting developments which should receive stimulation from the ready availability of thietan systems by a variety of synthetic routes. Stereochemical aspects of organosulphur chemistry are investigated most conveniently with saturated cyclic compounds, and in this area the role of sulphinyl oxygen in thian 1-oxides (3, 90), cyclic thiolsulphinates (3, 125, 126), cyclic sulphinates (3, 125, 221), and cyclic sulphites (3, 177, 258-270) in determining the conformational behaviour of compounds containing these groups has been elucidated. Investigations of the configurational integrity of sulphur-stabilized carbanions in cyclic sulphonium salts (3, 63, 64), 1,3-dithians (3, 146), lY3,5-trithians(3, 205), cyclic sulphoxides (3, 108), cyclic sulphones (3, 107), and cyclic sulphonates (3, 228) have made important contributions to this developing area, the salient features of which have been discussed in a significant paper (3, 191). The exploitation of the synthetic versatility of substituted 1,3-dithians should receive further impetus from the recent availability of methods for their formation (3, 130), utilization (3, 147-152), and hydrolysis (3, 157-161), whilst the cheletropic loss of sulphur dioxide on heating 3-thiabicyclo[3,1 ,O]hexane 3,3-dioxide derivatives and related 6-oxa- and 6-azaanalogues leads stereospecifically to 1,5-dienes, substituted divinyl ethers, and substituted divinyl carbamates (3, 36, 110). The intermediacy of sulphenic acid derivatives in the rearrangement of penicillin sulphoxides to deacetylcephalosporins, and in the thermal stereomutation of penicillin sulphoxides, has been elegantly demonstrated (3, 283-286) and skilfully exploited (3, 286-293). Although thioaldehydes belonging to certain classes of heterocyclic compounds have been isolated and characterized (Volume 1, p. 184), all attempts to prepare aliphatic thioaldehydes have so far proved unsuccessful. However, monomeric thioformaldehyde has recently been generated at low

Introductory Review

xxvii

pressure in a radiofrequency discharge tube by the reaction of methane with small sulphur-containing molecules, such as carbon disulphide and hydrogen sulphide (4, 25), or by the reaction of dimethyl sulphide with sulphur hexafluoride (4, 26). Thioformaldehyde thus produced has a half-life of a few minutes. Cleavage of a/3-unsaturated sulphides with alkali metals in liquid ammonia produces enethiols, the tautomeric forms of aliphatic thioaldehydes and thioketones (4, 2, 21). The enethiol tautomers of thioaldehydes are stable and show no tendency to tautomerize spontaneously, but with base they form high-boiling polymers. Thioketone enethiols equilibrate spontaneously with the thiocarbonyl form. Metal complexes of thiocarbonyl compounds are the subject of growing interest. Two of the more interesting reactions involve the trapping of unstable thioaldehydes as their nickel(rz) complexes (4, 32, 33). Theoretically and mechanistically significant is the reaction of thiobenzophenone with Grignard and organolithium reagents (4, 84). The direction of addition is the opposite to that taken by benzophenone. Thus phenyl-lithium gives benzhydryl phenyl sulphide. Monomeric thioketens are unstable compounds, and most of the literature has been concerned with these compounds as transient intermediates. Raasch (4, 6) now describes the stable bis(trifluoromethyl)thioketen, an orange-red liquid obtained by thermolysis of its dimer. It undergoes a variety of cycloaddition reactions involving the thiocarbonyl function. The first stable thiocarbonyl ylides have been isolated (4, 126) from the reaction of 1,2-dithiole-3-thiones with bis(toluene-psulphony1)diazomethane. The intermediacy of thiocarbonyl ylides had previously been deduced (4, 124, 125) from the formation of cycloaddition products during the thermal decomposition of 1,3,4-thiadiazolines in the presence of diethyl azodicarboxylate and dimethyl acetylenedicarboxylate. Sulphenes are very reactive species and have hitherto escaped detection. Flash thermolysis of chlorosulphonylacetic acid has now been shown to give sulphene, which was trapped at - 196 "C (4, 132) and characterized by its i.r. spectrum and by its reaction with hydrogen chloride to form methyl sulphonyl chloride. Application of the sulphonium salt ligand-exchange reaction to sulphonium ylide synthesis provides a route (5, 13-17) to diphenylsulphonium ylides which possess some advantages over the more readily available dialkylsulphonium ylides. A major limitation in the use of oxysulphonium ylides is the scarcity of ylides other than methylides. Johnson (5, 72) has now devised a high-yield synthesis of phenyldimethylamino-oxysulphonium methylide potentially expandable for the preparation of higher alkylides. Data on the structure of iminosulphuranes come from X-ray crystallographic structure determinations of N-(toluene-psulphonyl)iminodiphenylsulphurane, the corresponding dimethyl compound, and related structures (5, 146-149). A study of the reactions of sulphoximine ylides (5, 145-147) suggests that these compounds have considerable potential for reactions requiring stereochemical control.

xxviii

Introductory Review

The key step in a new approach to thiabenzenes (6, 5 ) involves the reduction of the readily available thiabenzene 1-oxides (6, 6, 7) with trichlorosilane. In contrast to earlier views on the structure of thiabenzenes and their 1-oxides (Volume 1, p. 309), the results of recent lH n.m.r. spectroscopic studies and studies of the basicity of thiabenzenes and their 1-oxides are interpreted in terms of ylide.structures in which two orthogonal and non-conducting hybrid d-orbitals on positively charged sulphonium or oxysulphonium sulphur overlap weakly with the ends of the n-system of a pentadienyl carbanion (6, 5, 9). Cram (5, 10) has developed an elegant general synthesis of heterocyclic compounds containing the sulphoximine function as part of a ring, including 2,4-diazathiabenzene 1-oxides. lH n.m.r. spectral studies indicate that ring-current effects do not operate significantly in these compounds. A large amount of work continues to be carried out on thiophen and its derivatives. Considerable progress has been made in the past few years on the quantitative aspects of electrophilic substitution reactions of thiophens and benzothiophens, increasing our knowledge of the differences in reactivity of five-membered heterocyclic compounds (7, 88, 362). The mechanism of the now celebrated photochemical rearrangement of monoand di-substituted thiophens has been elucidated by Wynberg (7, 146, 146a) in terms of valence-bond isomerizations. Thienyl-lithium derivatives continue to find use in the synthesis of otherwise inaccessible compounds, for example fluorothiophens (7, 59e, 96a), and the rings of 3-lithio-2methyl-thiophen and -selenophen open spontaneously in boiling ether to give vinylacetylenes (7, 129-13 1). A detailed description of the synthesis and physical and chemical properties of tellurophen has been published (7, 584). It is now becoming evident that 6a-thiathiophthens comprise only one of a potentially large number of structurally related heterocyclic systems. Members of several of these systems have recently been synthesized and, in some cases, their structures determined by X-ray crystallography. These include the 6a-selenathiophthens (8, 3l), the 6a-selenaselenophthens(8, 33), isothiazolo[5,1-e]isothiazoles (8, 40), dibenzo derivatives of 1,6-dioxa-6athiapentalene (8, 41, 42), 3,4-diaza-6a-thiathiophthens(8, 34, 3 9 , 1,6dioxa-6a-thia-2,5-diazapentalenes(8, 49), 1,6a-dioxa-6a-selena-2,5-diazapentalenes (8, 46-48), 1,6-dioxa-6a-tellura-2,5-diazapentalenes (8, 46), and 6a-selena-1,2,5,6-tetra-azapentalenes (8, 46). Of especial interest theoretically are two ‘extended’ 6a-thiathiophthens containing five sulphur atoms (8, 28). The array of sulphur atoms in these compounds is nearly linear, and the S - S distances fall into the range normal for 6a-thiathiophthens (8, 16, 17). From the limited information available, position 3 in 6athiathiophthen is more reactive than position 2 towards electrophiles; the results of theoretical studies agree with these experimental results. New, long-lived, sulphur-containing radicals based on the 1,3-dithiole system have been characterized spectroscopically (9, 29, 54), and in one

Introductory Review

xxix

case (9,55) a cation-radical salt was isolated. Bis-thiopyrylium salts have also been obtained and reduced to stable cation-radical salts (10, 43). Thiepins are predicted to be antiaromatic (11, 2), and previous studies have shown that annelated thiepins extrude sulphur readily, doubtless by valence isomerization into benzene sulphides and cheletropic elimination of sulphur. Attempts to isolate simple thiepins not stabilized by conjugation have been unsuccessful. A stable thiepin has now been synthesized by employing steric effects to prevent valence isomerization (If, 3). Interesting cycloaddition and electrocyclic reactions of thiepin derivatives are reported. Thermal cycloaddition of sulphur monoxide to cyclo-octatetraene leads to a 2,7-sulphur-bridged-2,7-dihydrothiepinwhich, when irradiated, produces thiabarbaralene (11, 5, 6). Addition of sulphur dioxide to vinyldiazomethane gives initially a thiiran 1,l-dioxide which undergoes a Cope rearrangement into a 4,Sdihydrothiepin 1,I-dioxide (11, 7, 8). The exploration of novel preparative routes commands much attention in isothiazole chemistry. Especially interesting are the reactions of 3-phenyl1,2,4-oxathiazol-5-one with acetylenic esters which afford isothiazoles in high yield (12, 7). The reaction is envisaged as a 1,3-dipolar addition of benzonitrile N-sulphide, produced as a transient intermediate, to the dipolarophilic dimethyl acetylenedicarboxylate or propiolic ester. Isothiazoles are also produced by photoisomerization of thiazoles (12, 19). Nitrenes may be implicated in the thermal decomposition of 2-azidoaryl thioketones into benzoisothiazoles (12, 51). A large volume of work continues to be published in the area of thiazole chemistry. Physicochemical aspects continue to receive their share of attention, and interest in meso-ionic compounds has been sustained. Asinger and Offerman’s versatile synthesis provides routes to reduced thiazoles (13, 212-217). Other notable methods employ thiirans (13, 218, 219), thiocarbonylamino-acid silyl esters (13, 220), and enamines (13, 221) as starting materials. Reduced thiazoles play an important role in peptide and protein studies (13, 234-239), and generate interest because of their occurrence as structural units in compounds of physiological interest, such as the antibiotics bacitracin A (23, 147 - 149) and thiostrepton. Benzothiazole derivatives have been employed to separate amidines for the first time into their syn- and anti-isomers (14, 49). The reaction of citric acid with penicillamine provides an interesting entry into the thiazolo[3,2-a]pyridine system (14, 152). In the field of thiadiazole chemistry the study of meso-ionic compounds stimulates interest (15, 98-1 13). The parent thiadiazoles have been obtained for the first time only in recent years; they have now been joined by 1,3,4-~elenadiazole (15, 120), whose physical properties have been compared with those of relevant analogues in studies of bonding in these systems. The nature of the products formed in the photolysis of 1,2,3thiadiazoles is accounted for in terms of a transient thiocarbene intermediate (15, 10).

xxx

Introductory Review

A number of mechanistically important papers have appeared which deal with the deoxygenation of 2-nitrophenyl aryl suIphides with triethyl phosphite and the thermolysis of aryl 2-azidophenyl sulphides. These reactions involve a novel molecular rearrangement and lead to phenothiazines via nitrene intermediates. Studies have now been made of sulphides in which the essential ortho-positions are blocked (16, 66, 67); hydroaromatic intermediates are involved. In certain cases 1,sthiazepines result (17,8, 9). The group of amphoteric pigments from red mammalian hair and bird feathers that are known as trichosiderins have recently been shown to contain the hitherto unknown 2,2’-bi-(2W-l,bbenzothiazine) chromophore, which arises biogenetically by a new metabolic pathway involving as the key step the 1,6-addition of cysteine to dopaquinone, produced by enzymic oxidation of tyrosine (17, 46-50). G . C. B. R.J. S. B. F. D. S. G . A. W. J. D. N. J. F. K. G . P. D. H. R.

Abbreviations

The following abbreviations have been used: circular dichroism c.d. CIDNP chemically induced dynamic nuclear polarization dicyclohexylcarbodi-imide DCC NN-dimethylformamide DMF DMSO dimethyl sulphoxide electron nuclear double resonance endor electron spin resonance e.s.r. gas-liquid chromatography g.1.c. infrared i.r. lithium aluminium hydride LAH megaHertz MHz molecular orbital MO N-bromosuccinimide NBS nanometre nm n.m.r. nuclear magnetic resonance 0.r.d. optical rotatory dispersion parts per million P.Pp ' Pariser-Parr-Pople PPP pyri dine PY self-consistent field SCF tetrahydrofuran THF t hin-layer chromatography t.1.c. toluene-p-sulphonyl Tos ultraviolet U.V.

A I ip hati c Organo-s uI phur Co mpo u nds, Compounds with Exocyclic Sulphur Functional Groups, and their Selenium and Tellurium Analogues BY G. C. BARRETT

1 General For every literature report, describing a new detail of the properties of sulphur functional groups, there now appears a matching publication in which an implication of new knowledge is followed through, enriching broad areas of organic synthesis and reaction mechanism. This process, the putting to use of knowledge acquired for its own sake, is well illustrated in the literature from which this Chapter is built. Text-books and Reviews.-Volumes 1-111 of a detailed coverage of sulphur chemistry augment the sparse textbook coverage in this field; analytical aspects are exhaustively covered.2 Reviews cover the topics :alkynethiolates in synthesis ;aa oxygen-exchange reactions of sulphoxides;3b sulphonyldiazomethanes ;3c C- S bond ~leavage;~"acyl isothio~yanates;~~ radical reactions of sulphur compounds;3f addition of sulphenyl halides to 01efins;~"s~lphenarnidcs;~~ mercaptoethylation of amines ;4c sulphur as a chiral centre ;6a stereochemistry of SVand Svl compounds ;5b reductive cleavage of sulphides, synthetic uses of alkene- and alkyne-thiolates, and thio-Claisen rearrangements;6Cnucleophilic displacements at sulphur in disulphides ; 6 a aromatic

'

'Sulphur in Organic and Inorganic Chemistry', ed. A. Senning, Marcel Dekker, New York, 1971. e.g. 'The Analytical Chemistry of Sulphur and its Compounds', ed. J. H. Karchmer, Wiley, New York, 1972; 'Instrumental Methods of Organic Functional Group Analysis', ed. S. Siggia, Wiley, New York, 1972. Quart. Reports Surfur Chem., 1970, 5 ; (a) p. 1, J. F. Arcns, L. Brandsma, P. J. W. Schuijl, and H. E. Wijers; (b) p. 53, S. Oae; (c) p. 67, A. M. Van Leusen and J. Strating; ( d ) p. 125, R. Mayer; (e) p. 175, J. Goerdeler; (f)p. 305, W. A. Pryor, J. P. Stanley, and T.-H. Liu. Mech. Reactions SuZfur Compounds, 1970,5; (a) p. 87, D. R. Hogg; (b) p. 93, C. Brown and B. T. Grayson; (c) p. 103, D. L. Johnson and D. D. Reynolds. Internat. J. Sulfur Chem., B, 1971,6; (a) p. 65, C. K. Ingold; (b) p. 69, K. K. Andersen; (c) p. 85, L. Brandsma, P. J. W. Schuijl, D. Schuijl-Laros, J. Meijer, and H. E. Wijers; (d) p. 103, J. P. Danehy; (e) p. 123, H. Cerfontain and C. W. F. Kort; (f)p. 137, F. Montanari; (g) p. 149, S. Braverman; (h) p. 159, J. P. Danehy; (i) p. 177, I. B. Douglass.

2

1

Organic Compounds of Sulphur, Selenium, and Tellurium

2

sulphonation ;5e neighbouring-group participation by sulphinyl oxygen rearrangement of allylic sulphinates to sulphones, and related sigmatropic rearrangements ;58 conversion of thiols into disulphides via sulphenyl iodides ;sh methanesulphenyl chloride as an electrophile;si nucleophilic attack at 6 b elimination and addition reactions of sulphur compounds;6c~ynthesis,~" oxidation, reduction, and addition reactions of sulphenyl halides ; 7 b s 7c sulphonylnitrenes ;* protonation of sulphur functional groups ;9 synthesis of sulphinyl chlorides, solvolysis of organosulphur trichlorides, chlorinolysis of disulphides in AcOH or Ac20;lo insertion of SO2 and SO, into metal-carbon bonds;ll free-radical addition of thiols to unsaturated compounds ;12,l3 stereochemistry of polysulphides;l* modification of -SH and - S - S groupings in proteins;l6 broad possibilities of the use of organic sulphur compounds in synthesis.16 Spectroscopic studies (n.m.r., i.r., u.v., m.s.) of o-hydroxyphenyl alkyl sulphides, sulphoxides, and sulphones l7 have been reported, bringing together basic correlations, including hydrogen-bonding effects, into one review. Important general principles of structure have been surveyed,18-20 based on molecular orbital considerations. The essentials of d-p, d-sp3, and d-d interactions have been set out, providing a background for the interpretation of experimental data on bivalent sulphur compounds.18 Wolfe and co-workers l9, 2o have collected data from the literature concerning the conformations adopted by groupings in which lone pairlone pair or lone pair-polar bond interactions may occur. Preferred conformations for a-sulphonyl-, -sulphinyl-, and -sulphenyl-carbanions, R1-X- CH-R2, are those involving maximum gauche interactions of the pyramidal carbanion with the S - 0 polar bond(s) or lone pairs on sulphur; the skew conformation of the disulphide grouping is an example of gauche lone pair-lone pair interactions. There is a satisfying generality to the principle (the stabilization of an axial l-hydroxy-group in a pyranose ;sf

' lo

l1 l2 l3

l4 l6 l7

Internat. J. Sulfur Chem., C, 1971, 6; (a) p. 3, J. L. Kice; (b) p. 17, D. R. Hogg and P. W. Vipond; (c) p. 41, C. J. M. Stirling. E. Kuehle, Synthesis; (a) 1970, 561; (b) 1971, 563; (c) 1971, 617. R. A. Abramovitch and R. G. Sutherland, Fortschr. Chem. Forsch., 1970, 16, 1. G. A. Olah, A. M. White, and D. H. O'Brien, Chem. Rev., 1970,70,561; G. A. Olah, A. T. Ku, and J. A. Olah, J . Org. Chem., 1970,35, 3904, 3908. M.-L. Kee and I. B. Douglas, Org. Prep. Procedures, 1970, 2, 235. W. Kitching and C. W. Fong, Organometallic Chem. Rev., 1970, AS, 281 ;A. Wojcicki, Accounts Chem. Res., 1971,4, 344. K. Griesbaum, Angew. Chem. Internat. Edn., 1970, 9, 273. D. I. Davies, Chem. SOC.Special Publ., No. 24, 1970, p. 201. R. Rahman, S. Safe, and A. Taylor, Quart. Rev., 1970, 24, 208. A. N. Glazer, Ann. Rev. Biochem., 1970,39, 101. E. Block, J. Chem. Educ., 1971, 48, 814. A. 0. Pedersen, G . Schroll, S. 0.Lawesson, W. A. Laurie, and R. I. Reed, Tetrahedron, 1970,26,4449.

la

l9 2o

D. L. Coffen, Records Chem. Progress, 1969,30, 275. S. Wolfe, A. Rauk, L. M. Tel, and I. Z . Csizmadia, J . Chem. SOC.(B), 1971, 136. S. Wolfe, Accounts Chem. Res., 1972, 5 , 102.

. 3 sugar - the ‘anomeric effect’ - is a further example), and for sulphur compounds it gives general reinforcement to the idea that the disposition of d-orbitals does not determine conformational preferences. A lipha t ic 0rgano-sulphur Compounds e t c

2 Thiols Methods employed for the synthesis of new thiols RSH are mainly those which have already proved themselves. The properties and reactions of compounds of this class are well documented, and although new data do not upset existing foundations, there are many points of interest. Preparation.-For those interested in the past, the report,21that irradiation (185 and/or 254 nm) of mixtures of CH,, C2H6, NHS, HaO, and H2S gives cysteine and cystine, among other products, will give a basis for speculation on developments in pre-biotic Earth history. Among well-tried procedures, the preparation of naphthalene-2-thiol from 2-naphthol is notable; the thionocarbamate RO.CS.NMe,, obtained from the reaction of the phenol with Me,N. CS-C1, gives the thiol on pyrolysis.22 Routes of widest applicability involve nucleophilic displacement of halide or toluene-p-sulphonate, or disulphide cleavage, or the less widely used reduction of thione to thiol. 2-Benzamido-2-mercaptopropionicacid (1) has been prepared 23 from 2-phenyl-4-methyloxazol-5(4H)-one(2), Me

SH (2)

(1)

though the corresponding route from the thiazolone failed at the last stepe4 The trifunctional grouping -NH-CR(S-)CO- is a feature of the structure of gliotoxin and related natural products (see Vol. 1, p. 104). p-Chlorolactic acid serves as starting material for the synthesis of a-hydroxy-analogues of S-benzylcysteine;reaction 25 with benzylmercaptan is followed by debenzylation with Na-NH, in an efficient route to the mercapto-acid (3),26 and D- and L-isomers are available in this way.2s CH,-Cl

CHd-SH

CH-OH

CH-OH

I

I COzH

I I

CO,H (3)

a1

ra 23 l4

B. N. Khare and C. Sagan, Natrire, 1971, 232, 577. M. S. Newman and F. W. Hetzel, Org. Synthesis, 1971, 51, 139. 1. D. Rae and P. M. Pojer, Tetrahedron Letters, 1971, 3077. I. D. Rae and B. N. Umbrasas, Austral. J. Chem., 1971, 24, 2729. D. B. Hope and M. WBlti, J. Chem. SOC.(C), 1970,2475. M. Wsilti and D. B. Hope, J . Chem. SOC.(C), 1971,2326.

Organic Compounds of Sulphur, Selenium, and Tellurium 3-Mercapto-4-phenylcyclobutene-1,2-dione (4) is even more acidic than its oxygen analogue (the latter has pK' = 0.37 k 0.04) but can be liberated from its pyridinium salt with conc. hydrochloric as pale yellow crystals.

4

Ph pyridine

'

0

Nucleophilic replacement reactions (by AcS-, Ph- CO. S-, MeS-, and PhCH,S-) with methyl 0-toluene-p-sulphonyl-L-lactateand sodium L-2-chloropropionate give 2-acylthio- and 2-alkylthio-~-propionic acids and esters.28 Extensive racemization accompanies the use of excess thioacetate or thiobenzoate, due to further S N replacement ~ reactions, as observed for LiAlH, reduction of ~-(2-methylthio)propionic acid or its methyl ester. Diborane reduction gives optically pure ~-(2-methylthio)propanol, however.28 This work28 includes a new synthesis of (+)-2mercaptopropionic acid, though by known methods, and establishes the D configuration for this isomer. Adamantanone with PzS5 gives the corresponding thione, which can be reduced to the thiol with sodium b o r ~ h y d r i d e success ;~~ in this example should not be taken as an indication of a similar result in other cases, in genera1. A simple method for reducing diselenides to alkylselenols RSeH by warming with aq. H3P02at 80-100 "C gives high yieldsao Other cleavage reactions, exposing as a thiol group a sulphur atom that was present in some other form, include further details on the ring-opening of 4Hthiopyran-4-thiones by sulphide or hydroxide ions,31 the demonstration of the existence of equal amounts of thiol and thiazoline isomers in solutions of S-(2-aminoethyl)isothiowea at pH 4.2 [i.e. (9,(6), and (7) in equilibr i ~ m ] ,and ~ ~ some novel reactions of penicillin d e r i ~ a t i v e s . ~ ~The -~~ epimerization at C(6) in penicillins (8) may be accounted for by /3-elimination, giving (9), which gives back the epimer mixture in the reverse step,33 though enethiolate or enolate intermediates are alternative pos~ibilities,~~ with the enethiolate (10) as a likely intermediate in the conversion of a A. H. Schmidt, W. Reid, P. Pustolemsek, and H. Dietschmann, Angew. Chem. Znternat. Edn., 1972, 11, 142. as L. N. Owen and M. B. Rahman, J. Chem. SOC.(C), 1971, 2432. J. W. Griedanus, Canad. J . Chem., 1970, 48, 3530, 3593. ao M. Schmidt and H. D. Block, Chem. Ber., 1970, 103, 3348. a1 J. G. Dingwall, D. H. Reid, and J. D. Symon, J . Chem. SOC.( C ) , 1971, 2412. 32 M. D. Hallas, P. B. Reed, and R. B. Martin, Chem. Comm., 1971, 1506. ss S. Wolfe, W. S. Lee, and R. Misra, Chem. Comm., 1970, 1067. 34 J. R. Jackson and R. J. Stoodley, J.C.S. Perkin Z, 1972, 895. 3LI B. G. Ramsay and R. J. Stoodley, J. Chem. SOC.(C), 1971, 3859.

O7

5

Aliphatic Organa-sulphur Compounds etc. HZC-CH, I \ S, NH, + /G,

H,N.'*+ '.NH2 (5)

-H+ \L

-+H+

H2C--CHz I +\ S, /NHz C H ~ N " 'NH,

I-

7

IIZC-CH, +\ ,NH HS H,N/ 'NH,

d

(6)

or

H2C-CHz I \ S, ,,NH" C I NH2 (7)

penicillin chloromethyl ketone into the cepham (1 1) by treatment with NEt3.35 Monosaccharides with OH groups replaced by SH are being studied systematically; their synthesis requires carefully planned multi-step routes. gives Addition of PhCH2S- Na+ to 1,6:2,3-dianhydr0-/3-~-mannopyranose 1,6-anhydro-3-deoxy-3-benzyl thio-p-~-al tropyranose (major product) and 1,6-anhydro-2-deoxy-2-benzylthio-/3-~-glucopyranose, the latter giving 2-thio-/3-~-glucopyranosethrough further reactions 36 (the benzylthiosugars result from di-equatorial and di-axial epoxide ring-opening of a 2,3-epoxide, respectively). Complementary routes to 2-thio-~-glucoseand -mannose3' involve addition of PhCH,SH to the olefinic double bond in ~-arabino-3,4,5,6-tetra-acetoxy-l -nitrohex- 1-ene, in the presence of pyridine ; elaboration of S-benzyl-1,2-O-isopropylidene-5-thio-~-xylose into I-thioL-xylitol 38 illustrates the satisfactory removal of protecting groups, just the aspect of any synthesis of a multi-functional compound which must go well to justify the route. The use of N-(benzoylthiomethy1)piperidine hydrochloride (12) as a reagent for introducing a mercaptomethyl group into an active-methylene ~~ gives (1 3). N-Methylation of position has been d e m ~ n s t r a t e d ;dimedone sulphonamides is the net result of mercaptomethylation in this way followed by reductive desulphurization using Raney nickeL3@ 36

37 38 3a

E. Hardegger and W. Schuep, Helv. Chim. Acta, 1970, 53, 951. P. Wirz and E. Hardegger, Helv. Chim. Acta, 1971, 54, 2017. P. Wirz, J. Stanek, and E. Hardegger, Helv. Chim. Acta, 1971, 54, 2027. E. E. Smissman, J. R. J. Sorenson, W. A. Albrecht, and M. W. Creese, J. Org. Chenr., 1970,35, 1357.

6


A convenient synthesis 40 of benzene-l,2-dithiol (14), and another involving replacement of the NH2 group by SH to give the biologically important 4-thiouridine and its analogues from cytidines (but in low yield)41 [e.g. (1 5 ) + (16)] illustrate additional synthetic methods.

--+

I

KOH glyme

Spectroscopicand Related Properties of Thio1s.-The n.m.r. absorption of the thiol proton moves to lower field in the order PhCH2-SH, Ph,CH-SH, Ph&* SH;42corresponding hydrotrisulphides RSS- SH show the opposite sequence,42due to over-riding inductive and anisotropic effects within the cumulative sulphur chain. The ultraviolet c.d. of 2-(R)-mercaptopropionicacid is dominated by the n -+ v* Cotton effect (near 220 nm) of the carboxy-group, while the S-methyl homologue shows, in addition to the positive n + (T*thioether Cotton effect at 238 nm, a weak negative c.d. maximum at 271 nm, ascribed to electrostatic coupling of the carboxyl and thioether t r a n ~ i t i o n s . ~ ~ 40 41

42 43

S. Huenig and E. Fleckenstein, Annalen, 1970, 738, 192. T. Ueda, M. Imazawa, K. Miura, R. Iwata, and K. Odajima, Tetrahedron Letters, 1971, 2507. S. Kawamura, T. Horii, and J. Tsurugi, Bull. Chem. SOC.Japan, 1971, 44, 2878. P. M. Scopes, R. N. Thomas, and M. €3. Rahman, J. Chem. SOC.((3, 1971, 1671.

Aliphatic Organo-sulphur Compounds etc. 7 Pulse radiolysis of penicillamine in aqueous solution gives thiyl radicals RS', A,, 330 nm, and the radical anion RSSR-, AmX 450 nm, formed from RS' and RS-.44 Photolysis of propanethiol tritiated at SH, in the presence of a hydrogen donor, results45in tritium scrambling in the propyl group and in the hydrogen donor, suggesting that such a system is a useful source of H atoms in Increased yields of the products of sensitized photodecarboxylation of R * X * C H 2 - C 0 2 H (X = 0, S, or NH) are obtained in the presence of thiophenol as hydrogen Butanethiol quenches triplet acetophenone only slowly (k = 1.4 x lo71mol-1 s-l), and it can be included in the reaction systems of ketone photo-reactions as a radical trap without interfering with the photo-excited Thiols as Nuc1eophiles.-Rates of nucleophilic substitution and addition reactions of thiols vary over several orders of magnitude, and studies of structure-reactivity relationships are now being supplemented by studies of other factors influencing transition-state energy. Isotope effects on the ionization of arenethiols (Ph, 4-N02-Ph, pentafluoro-Ph), AcSH, HSCH,CO,H and its methyl ester, and HSCH,. CH,OH, in D 2 0and HzO, range from K R ~ H / K R=~2.0-2.5, D the isotope effect increasing with decreasing These data are discussed in terms of isotope effects on the interaction of the thiolate anion with solvent. Copper@ thiobutoxide and thiophenoxide show unusual solvent and ligand effects in displacement of Br from pentafluorobromobenzene,60aor of I from trans-l,2-di-iodoethylene.60bS-Alkylation of pentafluorothiophenol in the presence of base gives low yields, due to polymerization (nucleophilic displacement of the para-substituent), but the yields may be increased by addition of the thiol to the alkyl halide in DMF.51 Substituent effects on the proton and carbon basicities of thiophenol have been studied thiopicrate anion is an exceedingly poor leaving group,63while its oxygen analogue has uses in synthesis. Second-order rate constants have been reported for reactions of thiolates with l-aryl-2-hal0geno-alkynes,~~ and with 3-bromo-2(or 4)-nitro-4(or 2)substituted thiophens, showing in the latter case that the conjugative effect from C(2) is greater than that from C(4) in t h i o ~ h e n .These ~ ~ examples illustrate the study of structure-reactivity relationships in organic halides, 44

45 46 47

48 4D 60

61 62

63 64 55

J. W. Purdie, H. A. Gillis, and N. V. Klassen, Chem. Comm., 1971, 1163. W. A. Pryor and M. G. Griffith, J. Amer. Chem. SOC.,1971,93, 1408. W. A. Pryor and J. P. Stanley, J. Amer. Chem. SOC.,1971, 93, 1412. R. S. Davidson and P. R. Steiner, J. Chem. SOC.(C), 1971, 1682; R. S. Davidson, S. Korkut, and P. R. Steiner, Chem. Comm.,1971, 1052. R. G. Zepp and R. J. Wagner, J.C.S. Chem. Comm., 1972, 167. W. P. Jencks and K. Salvesen, J. Amer. Chem. SOC.,1971, 93, 4433. J. Burdon, P. L. Coe, C. R. Marsh, and J. C. Tatlow, J.C.S. Perkin I, 1972, (a) 763, (b) 639. R. T. Wragg, Tetrahedron Letters, 1971, 2475. M. R. Crampton, J. Chem. SOC.(B), 1971, 2112. M. L. Sinnott and M. C. Whiting, J . Chem. SOC.(B), 1971, 965. M. C. Verploegh, L. Donk, H. J. T. Bos, W. Drenth, Rec. Truu. chim.,1971, 90, 765. D. Spinelli, G. Guanti, and C. Dell'Erba, J.C.S. Perkin ZI, 1972, 441.

8


the choice of a thiolate as reactant for this purpose being based on the considerations that reaction rates may be measured conveniently and monitoring of the progress of the reaction is simple. Preparative uses of thiolates, quite apart from syntheses of other sulphur functional groups discussed elsewhere in this Volume, include the demethylation of aryl methyl ethers with EtS- in hot DMF,6s and a similar use of thiophenol for demethylating aza-heterocyclic O-methyl ethers, of type =N-C(OMe)= .67 2-Methylthio-l-methylbenzimidazoledoes not react with thiophen01,~~ though an alternative reaction path is available for certain hetero-aryl methyl sulphides (1 7).68 MeS-?

/$

Miyn--RN

MeSSMe i- R - i sN’- R

Equilibrium constants for the reactions of cysteine derivatives with formaldehyde, and proton dissociation constants for the eight species of cysteine which exist in solution within the pH range 0-14, provide essential background information for evaluating the complex pH-rate profile for the formation of ~-thiazolidine-4-carboxylic acid (1 8) from L-cysteine and f~rmaldehyde.~~

A

HS\

FH2 NHZ--C---H LO2H

+

H2C\ FHz HCHO + HN-C---H kO,H

Reactions of Thiols with Organoboron, Organophosphorus, and Organotin Compounds.-The high affinity for sulphur that is shown by both boron and phosphorus can result in excision of a sulphur atom from a variety of compounds on treatment with trivalent boron and phosphorus compounds. This may be exploited in a number of ways in synthesis; the reagents used are easily available and the immediate appeal and implications of some recent work are certain to stimulate further studies. Thiobenzilic acid, Ph,C(SH)C02H, has been used as a source of 1,l-diphenyl-alkenes through its condensation with benzaldehyde or a ketone, followed by treatment of the resulting oxathiolan-5-one (1 9) with warm tris(diethylamino)phosphine.60 Trialkylboranes react with butanethiol giving the corresponding thioboronite R,BSBun, through a free-radical mechanism (e.s.r. of the displaced 56

57

58 5s 6o

G, I. Feutrill and R. N. Mirrington, Tetrahedron Letters, 1970, 1327. P. Dembech, A. Ricci, G. Seconi, and P. Vivarelli, J. Chem. SOC.(B), 1971, 2299. M. Begtrup, Acta Chem. Scund., 1971, 25, 3500. R. G. Kallen, J. Amer. Chem. SOC.,1971, 93, 6227. D. H. R. Barton and B. J. Willis, Chem. Comm., 1970, 1225.

Aliphatic Organo-sulphur Compounds etc.

9

R1 R2 \ /

sYcb I

PhzC-CO

I

Ph (Et,N),P

~

\

R'

/

alkyl radical), and disulphides react to give the same product.61 The reaction of benzaldehyde, keten, and Bu,BSBu leads to PhCH(0H). CH2CO SBU.~, Preparation of tris(organose1eno)boranes from a boron trihalide and selenols, and their reactions with representative nucleophiles and electrophiles, have been reported.63 The use of ethylthio-groups as protecting groups facilitates the preparation of mono-alkyl phosphates

-

(201.64

PCI,

+ 2EtSH

PPOH

--

(EtS),PCl-(EtS),P-OPr"

-e" 1

+

Pr"0-PO,H,

Photochemical addition of arenethiols to allyltrialkyltin compounds gives 3-(trial kylstanny1)propyl aryl sulphides R,Sn( CH,),S Ar . Di splacement of the ally1 group as propene, with the formation of Bu,SnSPh, was observed in one case,66providing an interesting analogy to boron-carbon bond cleavage.61 Addition of Thiols to Multiple Bonds.-The optical purity of (,S')-( -)-phenylethyl vinyl sulphide, prepared in good yield from acetylene and (,S)-lphenylethanethiol in alkaline solution, was assessed by hydride reduction back to the thiol followed by esterification with (A)-( +)-a-methoxy-atrifluoromethylphenylacetic acid, the resulting diastereoisomer mixture being analysed by n.m.r. spectrometry.66 Further examples of basecatalysed addition include the formation of 2-benzylthiocycloalkane-lcarboxylic acids by interaction of benzylmercaptan and 4-, 5-, or 6membered cycloalkene-1-carboxylicacids, giving mixtures of geometrical isomers, then diastereoisomer mixtures after oxidation to the sulphoxides (stereochemical assignments from n.m.r. data and reaction rates) ;67 and also Michael addition of thiols to ap-unsaturated lactones.68 A method for the protection of the conjugated olefinic double bond in a-methylene-ylactones has emerged from such studies,6Billustrated by the formation of 63 64

6s

B6 67

Bs

A. G. Davies and B. P. Roberts, J . Chem. SOC.(B), 1971, 1830. T. Mukaiyama and K. Inomata, Bull. Chem. SOC.Japan, 1971, 44, 3215. M. Schmidt and H. D. Block, J. Organometallic Chem., 1970, 25, 17. H. Takaku and Y. Shimada, Tetrahedron Letters, 1972, 41 1 . G. Ayrey, R. D. Brassington, and R. C. Poller, J. Organometallic. Chem., 1972, 35, 105. E. Chiellini, M. Marchetti, and G. Ceccarelli, Znternat. J. Sulfur Chem., A, 1971, 1 , 73. S. Allenmark and H. Johnson, Acta Chem. Scand., 1971, 25, 1860. S. M. Kupchan, T. J. Giacobbe, I. S. Krull, A. M. Thomas, M. A. Eakin, and D. C. Fessler, J. Org. Chem., 1970, 35, 3539. S. M. Kupchan, T. J. Giacobbe, and I. S. Krull, Tetrahedron Letters, 1970, 2859.

10


(21) by addition of propanethiol to the corresponding naturally occurring tri-olefin. Reduction of the vinyl group located at the ring junction, and removal of the two protecting groups with MeI, was shown to be feasible.sB CH=CH, I

The more common free-radical addition path provides the antiMarkownikov adduct predominantly with terminal olefins, though isomer ratios depend to some extent on the structures of the reactant^.^^ Increasing tendency towards Markownikov addition through a series has been linked70 with increasing dipolar character in the double bond, from one compound to the next in the series. A number of free-radical thiol addition reactions reported during the period under review show unusual features. a-Pinene gives (22) and p-pinene gives (23), on treatment with thiols in the presence of di-t-butyl peroxide,71 while unsaturated epoxides (24) give

ct)”

GSR

CH2=CH-CH-CR’R2

\0/

MeSCH2*CH=CH*O*CHR1R2 (R1 = Ph, R2 = H; or R1 = R2 = Me) and MeS*CH,-CH=CH*O*CH=CH-Me (R1= H, R2 = CH=CH,), through conjugate addition with homolytic C- C bond cleavage.72 Concurrent studies 73 with (24; R1 = R2 = H) have been reported, continuing earlier work (see Vol. 1, p. 54), while the reaction of styrene epoxide with ethyl thioglycollate, giving PhCH(0H)-CH2SCH2 C02Et, illustrates a straightforward epoxide-opening path whose direction is little influenced by substituents in the phenyl Addition of ethane-1,Zdithiol to furan gives the 1,2- and 1,4-adducts (overall yield 55%) in the ratio 18 : 82 under BF3 catalysis,76while free-radical addition of ethanethiol to ethoxyacetylene involves an intermediate cis-1-ethoxyvinyl radical, which proceeds 70 71

72

73 74 76

K. Boustany, J . Chem. and Eng. Data, 1972, 17, 104. A. Gaiffe and J. Castenet, Compt. rend., 1970, 271, C, 1012. F. L. Stogryn and M. H. Gianni, Tetrahedron Letters, 1970, 3025. R. S. Razina and V. M. Albitskaya, Zhur. org. Khim., 1971, 7 , 1637. C. Berse and R. Coulombe, Canad. J . Chem., 1971, 49, 3051. B. Rindone and C. Scolastico, J . Chem. SOC.(C), 1971, 3339.

11


to trans- 1-ethoxy-2-ethylthioethene under kinetic contr 01, with concurrent equilibration to give the reaction product, a mixture of cis- and transi s o m e r ~ .Reversibility ~~ of addition of ethyl thioglycollate to acrolein and the cyclization of the adduct to a tetrahydrofuran has been studied.?? A careful study of the formation of thiolesters R1R2CH*CO-SR3,by the addition of a thiol to a keten, suggests that a radical path is followed. At least this accounts for the very irreproducible rates.'$ Photochemical reactions of 2-aminothiophenol (25) with carboxylic acids 7g or cyclohexene 8o provide a challenge from a mechanistic point of view ;the S-methyl

primary alc. l1v

1 0

compound (26) was formed, whatever aliphatic carboxylic acid was while the methyl group in (27) may originate in the olefin rather than the There is an implication that the thiol may be efficient both for inducing the photolysis of an alcohol and for capturing the resulting fragments. Addition of thiols to the azomethine grouping in a Schiff base in non-aqueous media involves an equilibrium [ArCH=NAr + RSH + ArCH(SR)*NHAr] analogous to that leading to a hemimercaptal; the equilibrium lies to the right when there are electron-withdrawing groups in the aryl residues.81 On raising the temperature of the reaction mixture, C-N bond cleavage ensues, giving a dithioacetal ArCH(SR), and the aniline, or the disulphide RSSR and the secondary amine ArCH,-NHAr, again depending on structure.81 An isocyanide reacts with a thiol either (a) uiu a,a-addition of thiyl radicals to the carbon atom to give a thioformimidate, or (6) to give an isothiocyanate and the alkane corresponding '13

D. K. Wedegaertner, R. M. Kopchik, and J. A. Karnpmeier, J. Amer. Chem. SOC., 1971,93, 6890.

'I7 'I8

H. Esterbauer, Monafsh., 1970, 101, 782. P. J. Lillford and D. P. N. Satchell, J . Chem. SOC.(B), 1970, 1303; Chem. and Znd., 1970, 157.

'O

Y. Maki and M. Suzuki, Chem. Comm., 1971, 117. Y. Maki, M. Suzuki, Y. Masada, and K. Hashimoto, J.C.S. Chem. Comm., 1972, 209,

T. R. Oakes and G . W. Stacy, J . Amer. Chern. SOC.,1972, 94, 1594.

12


to the thioLe2 The route followed depends upon the structure and experimental conditions, the more useful route (a) being determined by catalysis by copper salts. Alkylthioaluminium compounds provide a range of products with simple olefins and ketones.83 For R2AIMe (R = MeS, PriS, or Buts), initiation of aldol condensation occurs with methyl ketones, but other ketones or aldehydes give a mixture of thioacetal and enol thioether. Olefins add two RS groups, with some side product arising from allylic substitution, while a conjugated ketone gives the /3-alkylthio-ketone. Protection of -SH Groups in Synthesis.-The requirements of peptide synthesis are particularly demanding as far as cysteine is concerned, since reversible S-protection must involve chemical operations which do not affect N-or C-protection methods, quite apart from the need to manipulate one cysteine residue in a polypeptide containing other cysteine residues, which must therefore remain protected. A large number of alternative protecting methods are necessary, though the recent literature includes only development of known methods. An improved method for preparing S-triphenylmethyl- and S-diphenylmethyl-cysteine derivatives 84 involves carbonium ion formation from the aralkylcarbinols in the presence of trifluoroacetic acid or a hydrogen halide in AcOH. S-p-Methoxybenzyloxycarbonyl-protection of cysteine is reversed by methanolysis or by treatment with a hydrogen halide in ACOH,*~and is claimed to be compatible with N-protection using the o-nitrophenylsulphenyl group. S-Alkylthio-cysteine derivatives are cleaved under mild conditions (oxidative sulphitolysis or 2-rnercaptoethanol) and the derivatives are suitable for peptide synthesis by the Merrifield (solid-phase) method.86 S-Picolyl-L-cysteine, prepared by the addition of picolyl chloride to a solution of L-cystine in liquid ammonia to which 1 equivalent of Na had been added, has been employed in representative peptide syntheses. The protecting group is compatible with N-t-butoxycarbonyl-protectionand dicyclohexylcarbodi-imide coupling methods in peptide synthesis, and it may be removed by electrolytic reduction (A. Gosden, D. Stevenson, and G. T. Young, personal communication). Thiols in Biochemistry.-Monoterpene keto-thiols (28, and the cis-isomer) are the first of their type to appear in Nature.87 The major interest in biosynthesized thiols remains within the polypeptide field, and the identification, reactivity, and function of cysteine residues in polypeptides and proteins feature prominently in the literature. 82 88

84

85 86

87

T. Saegusa, S. Kobayashi, and Y. Ito, J. Org. Chem., 1970, 35, 2118. J. M. Lalancette, Y. Beauregard, and M. Bhereur, Cunad. J. Chem., 1971, 49, 2983. I. Photaki, J. Taylor-Papadimitriou, C. Sakarellos, P. Mazatakis, and L. Zervas, J . Chem. Soc. (C), 1970, 2683. I. Photaki, J. Chem. Soc. ( C ) , 1970, 2687. U. Weber and P. Hartter, 2. physiol. Chem., 1970, 351, 1384; U. Weber, P. Hartter, and L. Flohe, ibid., p. 1389. E. Sundt, B. Willhalm, R. Chappaz, and G. Ohloff, Helu. Chim. Acta, 1971, 54, 1801.


13

Me

The reactivity of the -SH group of the cysteine residue at position 93 in the /%chain of human haemoglobin is dependent upon conformation,ss as indicated by rates and activation energies of reactions with p-hydroxymercuribenzoate (stopped-flow analysis). This illustrates one widely used analytical technique in this field; another is the use of N-ethylmaleimide for the estimation of -SH groups, which is 10-100 times more sensitive when polarographic methods are used, rather than spectrophotometry, for following the reaction.89 Fluorescence-quenching of fluorescein mercury acetate at 520 nm provides a basis for determining -SH and -S-Sgroups in proteins at levels down to 10-l’ m ~ l . ~ O 2-Vinylquinoline has been suggested 91 as a reagent for locating thiols giving the S-2-(2-quinolylethyl)cysteine analogue, hmar318 nm, E 10 OOO; like corresponding 4-pyridylethyl derivative^,^^ the products are stable to acid. The increased reactivity of the -SH group in mercaptomethyl-imidazole is demonstrated by thc use of Ellman’s reagent (2,2’-dinitro-5,5’-dithiodibenzoic acid) ; the thiol reacts ten times faster than glutathione (a cysteinyl tripeptide), and thirty times faster than N-acetylcysteine, suggesting 93 that it reacts as the thiolate under neutral conditions. A review of side-reactions available to Ellman’s reagent, and pyridine analogues, in alkaline solution, has been published.9a Specific S-methylation of -SH groups with methyl p-nitrobenzenesulphonate, without affecting other residues, proceeds at pH 8.6, at 37 “C, and has been demonstrated for mercaptoethanol-reduced l y s o ~ y r n e . ~ ~ Speculations on the function of -SH groups in biological systems have been reviewed for membranes 96 and for oxidative phosphorylation The experimental basis to this is usually inhibition studies with the thiol-group-specific reagents of the types mentioned in the preceding paragraph. Incorporation of amino-acids into protein biosynthesis

95

G. Geraci and L. J. Parkhurst, Atti Accad. naz. Lincei, Rend. Classe Sci. j s . , mat., nat., 1971, 50, 12. P. D. J. Weitzman and H. J. Tyler, Anulyt. Biochem., 1971, 43, 321. G. P. Mironov, Y . G. Kaminskii, and M. N. Kondrashova, Voprosy. med. Khim., 1971, 17, 83 (Chem. A h . , 1971,74, 136 219). L. H.Krull, D. E. Gibbs, and M. Friedman, Anulyt. Biochem., 1971, 40, 80. M. Friedman, L. H. Krull, and J. F. Cavins, J . Biol. Chem., 1970, 245, 3868. H. Wenck and F. Schneider, Experientia, 1971, 27, 20. J. P. Danehy, V. J. Elia, and C. J. Lavelle, J . Org. Chem., 1971, 36, 1003. R. L. Heinrickson, Biochem. Biophys. Res. Comm., 1970, 41, 962; J. Biol. Chem., 1971, 246,4090.

O6

97

A. Rothstein, in ‘Current Topics in Membranes and Transport’, ed. F. Bronner and A. Kleinzeller, Academic Press, New York, 1970, vol. 1, p. 135. D. Gautheron, Bull. SOC.chim. biol., 1970, 52, 499.

14


by rabbit reticulocytes was immediately halted by Me,N. COO N=N. COONMe,, a thiol-oxidizing agent, implicating -SH groups at various stages in protein s y n t h e s i ~ .The ~ ~ effect of dithiothreitol and dithioerythritol, in mimicking uridine incorporation into rat bone cells in vitro as stimulated by insulin, has been related to the environment of the -SH groups in these compounds; a number of other thiols did not behave in this way.Q9

3 Sulphides Preparation.-In addition to a number of reactions of thiols, discussed in the preceding section, a variety of other routes have been explored for the preparation of sulphides. U.V. irradiation of thiolesters gives mixtures (CH,. CO. SPh gives PhSH, PhSMe, o- and p-AcPhSH, and disulphides as major products),100while addition of an alkyl halide to a thiolester in the presence of strong base (LiH, Ph,CLi, etc.) provides a one-step route.lol A novel /3-keto-sulphide synthesis from a 1,2-diketone is illustrated by the conversion of (29) into (3O).lo2 Alternative routes to /3-keto-sulphides often

- R1

R1*COCO-R1

EtJ'

\

C=C

I

0, (29)

R1

1

\

/o PEt,

R2SCI

c1 I R1-CO*CR1 I SR2

CI,SiH-Bu,N

1

followed by NaOH

R1*COCHR1SR2

give only low yields. Tellurium reacts with an aromatic organolithium compound, to give either a mono- or a di-telluride, depending on the mode of formation of the lithium substrate.lo3 The migration of methyl to sulphur observed in reactions of o-mercaptobenzoic acid methyl ester with primary aliphatic amines, possibly via an SNi mechanism, contributes another example to an extensive list of interactions of aromatic ortho-substituents.104More conventional nucleophilic substitution processes include syntheses of L-selenomethionine, MeSeCH, CH,' CH(NH,). CO,H, and its Se-ethyl and Se-benzyl analogues by treatment of O-toluene-p-sulphonyl-L-homoserine with appropriate organoselenium nucleophiles;lo5 also, analogous reactions of hydroxy-acid T. Zehavi-Willner, E. M. Kosower, T. Hunt, and N. S. Kosower, Biochim. Biophys. Acta, 1971, 228, 245. OB W. A. Peck, K. Messinger, and J. Carpenter, J . Biol. Chem., 1971, 246, 4439. l o o J. S. Bradshaw, E. L. Loveridge, and B. R. Beck, J . Org. Chem., 1971, 36, 221. lol G.E. Wilson and J. G. Riley, Tetrahedron Letters, 1972, 379. lo2 D. N. Harpp and P. Mathiaparanam, J. Org. Chem., 1971, 36,2540. lo8 J. L. Piette and M. Renson, Bull. SOC.chim. belges, 1970, 79, 353, 367. lo4 J. C. Grivas and K. C. Navada, J . Org. Chem., 1971, 36, 1520. loo C. S. Pande, J. Rudick, and R. Walter, J. Org. Chem., 1970, 35, 1440. Ba


15

toluene-p-sulphonates, or of halogeno-acids, have continued to provide satisfactory routes to sulphides.28 Thiobenzophenone adds phenyl-lithium (a ‘thiophilic addition’ lo6) to give PhzCHSPh after work-up,loBwhile carbonyl sulphide provides the singlet sulphur atom which inserts into a C-H bond, when in solution with an olefin and cyclohexane under 254 nm irradiation. The product is a cyclohexyl alkyl su1phide,lo7though disulphides are also formed by concurrent coupling of alkanethiyl radicals. The reaction of fulminic acid with H,S, giving HO*N=CHSCH=N.OH, has been known for many decades, and is shown to be applicable to thiols generally, giving anti-Sbenzylthioformhydroximate when benzyl mercaptan is used;lo8the thermodynamically more-stable isomer of S-cyanoethyl acetothiohydroximate has the syn-(alkylthio) configuration (3 l).lo9 NCCH2-CH2-S,

,OH

Me’C=N

Sulphenyl reagents are capable of introducing alkyl- or aryl-thio-groups into substrates which, if not activated, are stable to the relatively drastic electrophilic substitution conditions; MeS S0,R-AlC1, has been used to methylthiolate aromatic hydrocarbons and is said to be more convenient than MeSCl-AICl,.l10 Secondary sulphenamides, e.g. PhSNEtz, react similarly but under mild conditions with active-methylene compounds,111 and aryl thiocyanates react with alcohols in the presence of CN- to give aryl alkyl sulphides.l12 The intermediate O-alkyl-S-aryl thioiminocarbonate was isolable in one case in this study from a reaction mixture at 0 OC,l12 and it gave p-tolyl methyl sulphide in high yield on treatment with cyanide. Compounds of the type ArCH,SR are available through a number of novel routes, the simplest example being base-catalysed rearrangement of an N-aryl-SS-dimethylsulphimide(32),113 a reaction which has an analogy with the pyrolysis of the ylide (33) formed from the N-chloro-amine and dimethyl s ~ 1 p h i d e . l ~Mannich ~ bases, e.g. (34), give corresponding aryl sulphides with ArSH, via an Elcb-type mechanism, as deduced from an isotope effect inconsistent with the alternative concerted mechanism.l16 Reactions which might be categorized as sulphide interchange include the conversion of a sulphide into its N-toluene-p-sulphonylimine, P. Beak and J. W. Worley, J . Amer. Chem. SOC.,1970, 92, 4142; 1972,94, 597. E. Leppin and K. Gollnick, Chem. Ber., 1970, 103, 2571. lo8 D. Kjersgaard and A, Kjaer, Acta Chem. Scand., 1970, 24, 1367. log M. G. Waite and G. A. Sim, J . Chem. SOC.(B), 1971, 752, 1102. J. K. Bosscher, E. W. A. Kraak, and H. Kloosterziel, Chem. Comm., 1971, 1365. ll1 T. Mukaiyama, S . Kobayashi, and T. Kumamoto, Tetrahedron Letters, 1970, 5715. 11* K. Tanaka, J. Hayami, and A. Kaji, Bull. Chem. Soc. Japan, 1971, 44, 3815. 11% P. Claus, W. Vycudilik, and W. Rieder, Monatsh., 1971, 102, 1571. n4 P. G. Gassman, G. Gruetzmacher, and R. H. Smith, Tetrahedron Letters, 1972, 497. R. Andrisano, C. Della Casa, and M. Tramontini, J. Chem. SOC.(C), 1970, 1866. lo6 lo‘


16

R CH,SMe Et,N toluene

&N=SMe2

(32)

'

A

/

-CH2

(33) NR,

I

&-mH

-

&OH \

CH,SMe

CH,SAr

7 Slow

/

\

ArSH

/

\

/

(34) R1R2S=N*Ts, followed by reaction with a potassium thiolate ArSK to give ArSRl R2S*fi*Ts K+, an example of 5"2 attack by ArS- at the carbon atom alpha to sulphur.116 Novel routes to methyl polyfluoroalkyl sulphides involve photochemically induced reaction of Me,S with a polyfluoro-mono-iodo-alkane.117A novel alkylation procedure in the penicillin series, (35) to (36), uses methyl iodide in the presence of NaH or

+

ButOK in THF.ll* Further studies of the formation of sulphides from rearrangements of sulphonium salts provide more details of the repression of the rearrangement by adjacent substituents capable of causing delocalization of charge from the intermediate ylide.

Preparation of Sulphides using Organomagnesium, Organoboron, or Organophosphorus Reagents.-Trialkylboranes readily participate in freeradical chain reactions with disulphides (initiated by light or by O2 but 116 117

11s

T. Aida, N. Furukawa, and S. Oae, Tetrahedron Letters, 1971,4255. R. N. Haszeldine, B. Hewitson, B. Higginbottom, R. B. Rigby, and A. E. Tipping, J.C.S. Chem. Comm., 1972, 249; R. N. Haszeldine, B. Higginbottom, R. B. Rigby, and A. E. Tipping, J.C.S. Perkin I , 1972, 155. J. P. Clayton, J. H. C. Nayler, R. Southgate, and P. Tolliday, Chem. Comm., 1971, 590.

119

J. E. Baldwin and W. F. Erickson, Chem. Comm., 1971,359.

-

17

Aliphtaic Organo-sulphur Compounds etc.

strongly inhibited by 12), providing a convenient new route to sulphides : I z 0 R1,B

+ R2*S*S*R2

R1*S.R2+ R1,B*S*R2

Grignard reagents behave similarly,121 and a thioborane gives an unsymmetrical sulphide with a sulphenate ester.lZ2 Tris(diethy1amino)phosphine converts cystine derivatives into corresponding lanthionines [NH,. CH(CO,H)* CH,]2S,12Sand the disulphide formed between penicillin sulphoxide and ButSH (36;Buts in place of Me at S ) forms the ethyl sulphide (36; Et in place of Me at S) by treatment with triethy1pho~phine.l~~ Heteroaryl Su1phides.-Oxidation of thiols in the presence of pyrrole, using 12-K1, gives 2-pyrrolyl sulphides, via the sulphenyl iodide;126analogous 2-methylthio-indoles are obtained directly from the indole and MeSC1,lZ6 while isatin (37) gives the thioketal (38) through the route shown, from

I

reflux, tolucnc

which 2-methylthio-3-0x0-indole is obtained via a somewhat reluctant is formed elimination of MeSH.12' 2-Mercapto-7-methyl-8-azapurin-6-one from the reaction of 4-amino-l-methyl-lH-l,2,3-triazole-5-carboxamide with thiourea; it gives the S-methyl derivative with Mel, and the bis-2,6methylthio-homologue (39) by further treatment with P,S, and MeI.12*

120 lZ1

122 lZs lZ4 lZ5

lZ6 lZ7 lZ8

H. C. Brown and M. M. Midland, J. Amer. Chem. SOC.,1971, 93, 3291. A. W. P. Jarvie and D. Skelton, J . Organometailic Chem., 1971, 30, 145. R. H. Cragg, J. P. N. Husband, and A. F. Weston, Chem. Comm., 1971, 1701. D. N. Harpp and J. G. Gleason, J . Org. Chem., 1971, 36, 73. D. H. R. Barton, P. G. Sammes, M. V. Taylor, C. M. Cooper, G. Hewitt, B. E. Looker, and W. G. E. Underwood, Chem. Comm., 1971, 1137. S. Beveridge and R. L. N. Harris, Austral. J . Chem., 1971, 24, 1229. B. W. Bycroft and W. Landon, Chem. Comm., 1970, 967. J. T. Baker and C. C. Duke, Tetrahedron Letters, 1972, 307. A. Albert and H. Taguchi, J.C.S. Perkin I , 1972, 449.

18 Organic Compounds of Sulphur, Selenium, and Tellurium Properties of Sulpbides.-An a-alkylthio-group increases the enol content of /3-dicarbonyl compounds,12gand causes a shift in carbonyl stretching frequency to lower values, in a-(alkylthio) thioesters, ketones, and amides ;130 the C-N stretching frequency in corresponding nitriles is similarly a1tered.lS1 S-Alkyl-L-cysteinesdisplay a positive c.d. maximum at 220 nm, assigned to the n + u* transition on sulphur, since it is not shown by ~-methionine.l~~ L-Djenkolic acid, NH2*CH(C0,H). CH2SCH,SCH2*CH(C0,H)- NH, displays large he values, suggesting that the -S-CH,-Sgrouping is ~ h i r a 1 ,al ~conclusion ~ reached also for lanthionine as far as its single sulphur atom and neighbouring methylene groups are ~ 0 n c e r n e d . lThe ~ ~ proton dissociation constants of lanthionine are unusually low, implicating 133 the sulphur atom and possibly related to a cyclic conformation in aqueous solution. ortho-Substituted thioanisoles show coupling between the S-methyl protons and the ortho-H, through sulphur, but corresponding sulphoxides and sulphones do not, indicating an anti configuration for the sulphide, with respect to the ortho-substituent, but syn for the sulphoxides and ~ u l p h o n e s . ~Long-range ~~ coupling in CH3*COOCHzSR causes nonequivalence of the methylene protons ;136 ButCH,SBut should reflect in its n.m.r. spectrum the effect of lone-pairs on S on Jgemas a function of the dihedral angle with the adjacent methylene protons, and preliminary studies are r e ~ 0 r t e d . l ~ ~ Photolytic decarboxylation of (nitroary1thio)acetic acids is facilitated by sulphur 3d-orbital resonance,13' and anchimeric assistance in the proton abstraction by di-t-butyl peroxide from 3-(methylthio)butan-2-01 is consideredlS8 to be demonstrated in the fact that the threo-isomer is more reactive than the erythro-analogue. The effect of an alkylthio-group in complexing an adjacent lithium atom is shown in two studies; an alkene will add an alkyl-lithium due to assistance of this kind by a suitably placed thioether grouping (40),13*while a new alkylation reaction depends on the same principle,140illustrated in a new squalene synthesis starting from the 2-farnesylthio-thiazoline(41). A similar reaction sequence, constituting a lZ9

lSo 131

Z. Yoshida, H. Ogoshi, and T. Tokumitsu, Tetrahedron, 1970, 26, 2987. B. Wladislaw, R. Rittner, and H. Viertler, J . Chem. SOC.(B), 1971, 1859; B. Wladislaw, H. Viertler, and E. B. Demant, ibid., p. 565. B. Wladislaw, R. Rittner, P. R. Olivato, and C. C. Saucho, J.C.S. Chem. Comm., 1972,236.

L. Fowden, P. M. Scopes, and R. N. Thomas, J . Chem. SOC.( C ) , 1971, 833. I. W. Stapleton and A. 0. Weber, Internat. J . Protein Res., 1971, 3, 243. 134 L. Lunazzi and D. Macciantelli, Chem. Comm., 1971, 933. 13,5 M. Brink, Tetrahedron Letters, 1971, 2753. 136 R. Davies and J. Hudec, J.C.S. Chem. Comm., 1972, 124. 13' R. S. Goudie and P. N. Preston, J . Chem. SOC.( C ) , 1971, 3081. laB E. S. Huyser and R. H. C. Feng, J. Org. Chem., 1971,36, 731. 139 A. H. Veefkind, J. Van der Schaaf, F. Bickelhaupt, and G. W. Klumpp, Chem. Comm.,

lS2 lS3

1971, 722.

140

K. Hirai, H. Matsuda, and Y . Kishida, Tetrahedron Letters, 1971, 4359.

19


squalene

useful C-C bond formation procedure, has been illustrated 141with ally1 2-pyridyl sulphide, which gives py- SCH(CH,Ph) CH= CH2 with successive treatment with PhLi and PhCH,Br, and finally PhCH,CH2*CH: CH, and pyridine on treatment with CuCI, and LiAIH4. The entropy of activation AS* for the homolytic cleavage of azo-bis(w-ethylthio-t-butane) (42; transition state depicted) is higher (13.6 e.u.) than that (9.6 e.u.) of the analogue with CH, in place of S, indicating no anchimeric participation by the sulphur atoms in (42); in other words, a Me Me E t SCH,. CI -- -- - - - -N=N-- - -- -...C1 CH, SEt

.

I

I

Me

Me (42)

sulphur atom does not stabilize a p-radical centre.l4,1 14' Displacement of methanesulphonate with concurrent 1,2-shift of a neighbouring ary1thi0-l~~ or a l k y l t h i ~ -group ~ ~ ~ follows a well-understood path; its stereospecific nature is illustrated by the conversion of S-alkyl-l-thio-a-D-arabinoside 2-O-mesylates into 2-thio-?-ribose n u c l e o s i d e ~ . ~ ~ ~ a-Alkylthio-radicals R1CHSR2 are the subject of continuing studies, with clear indications recently of greater delocalization of the unpaired electron in comparison with the oxygen analogues,1u and severely hindered internal rotation,145* 146 as deduced from e.s.r. spectra. Radicals with a /3-alkylthio-s~bstituent,~~~* 14* produced in Tia+-H,02-olefin-RSH mixtures, T. Mukaiyama, K. Narasaka, K. Maekawa, and M. Furusato, Bull. Chem. SOC. Japan, 1971, 44,2285. 142 A. Ohno and Y . Ohnishi, Tetrahedron Letters, 1972, 339; Internat. J . Surfur Chem., A, 1972, 2, in the press. 148 M. S. Khan and L. N. Owen, J . Chem. SOC. (C), 1971, 1442, 1448. 144 K. J. Ryan, E. M. Acton, and L. Goodman, J . Org. Chem., 1971, 36,2646. 146 I. Biddles, A. Hudson, and J. T. Wiffen, Tetrahedron, 1972, 28, 867. u6 J. Q. Adams, J . Amer. Chem. SOC.,1970, 92, 4535. 14' T. Kawamura, M. Ushio, T. Fujimoto, andT. Yonezawa, J . Amer. Chem. SOC.,1971, 141

93, 908. lP8

P. J. Krusic and J. C. Kochi, J. Amer. Chem. SOC.,1971, 93, 846.

Organic Compounds of SuIphur, Selenium, and Tellurium

20

show hindered rotation about the Ca-Cp bond, and adopt a conformation in which the sulphur atom eclipses the p-orbital at the trigonal Thiophenyl radical cations, produced by electrochemical oxidation 149 or by the use of manganic acetate150with aryl alkyl sulphides, respectively, ~ ~they ~ retain the bivalent either yield disulphides and s u l p h o ~ i d e s ,or sulphur grouping, with acetoxylation or oxidation occurring elsewhere in the molecule.150 Organic sulphides have a number of uses as incidental additives - the partial poisoning of catalysts, and uses to quench photo-excited states 152 and an interesting new example has appeared, in which the oxidation of N-aminophthalimide to trans-l,4-diphthalyltetrazene with lead tetraacetate is modified in the presence of diphenyl sulphide to give the same product but predominantly (more than 70%) in the cis-isomeric form.153 Possibly,153 the nitrene formed by oxidation gives a sulphidimine (43a; R = N-phthalimidoyl) whose pyramidal structure directs an incoming nitrene into a cis-configuration with respect to the phthalimido-imide residue (43). R

R

/

ph-/S=N Ph (43a)

R

'N

R

+ II

__j

\

R

\

R

N,

R

A methylthio-substituent activates a benzene ring to further substitution,ll0 and a recent report details the electrophilic substitution of thioanisole, with partial rate factors for 0- and p-bromination and acetylation.15* The inductive effect of a methylthio-substituent is increased by replacing hydrogen atoms by fluorine, as shown by a 19Fn.m.r. evaluation of Hammett-Taft a constants for rn- and p-fluorothioanisole and their mono- and difluoro-methylanalogues.166Conversion of a peptide 4-(methylthio)phenyl ester into its 4-(methylsulphony1)phenyl analogue greatly increases the electrophilic reactivity of the ester carbonyl group, and therefore speeds up aminolysis reactions; a recent example exploiting this property describes the polymerization of a tetrapeptide 4-(methylsulphony1)phenyl 140

lSo 161 lSa 168

16'

lS6

K. Uneyama and S. Torii, Tetrahedron Letters, 1971, 329. J. R. Gilmore and J. M. Mellor, Tetrahedron Letters, 1971, 3977. H. E. Ganther, Biochemistry, 1971, 10, 4089. J. Guttenplan and S. G. Cohen, Chem. Comm., 1969, 247. D. W. Jones, Chem. Comm., 1970, 1084. S. Clementi and P. Linda, Tetrahedron, 1970, 26, 2869. G. P. Syrova, L. N. Sedova, L. Z. Gandelsman, L. A. Alekseeva, and L. M. Yagupolskii, Zhur. org. Khim., 1970, 6, 2285. B. J. Johnson and D. S. Rea, Cunad. J . Chem., 1970,48,2509.


21

Benzyl methyl sulphide acts as a source of PhCH,+ in the presence of CuF12-ZnC12 mixtures, and the dithioacetal PhCH(SEt)2 similarly provides PhCHSEt, as shown by the use of such systems to prepare substituted anis01es.~~~ Mixtures of rearrangement products are produced by treating aryl sulphides with A1c13,15*via the triphenylsulphonium ion as primary intermediate in the case of diphenyl s ~ l p h i d e , whose l ~ ~ [1-14C]variant has been treated with AICl, to examine the possibility of PhS- migration during the reacfion.lsa At high temperatures, 14C-activity is completely scrambled by exposing the substrate to AlCl,. Reactions of Sulphides.-Reactions involving the displacement of an alkylthio- or arylthio-substituent from a sulphide are well represented in the recent literature, some of the reactions providing new syntheses. The usefulness of RS- groups in activating the adjacent centre for metallation can only be exploited in general synthetic methods if the groups can be removed without difficulty after they have fulfilled their purpose [cf. (41)].140,141,160, 161 A scheme for converting a ketone into a terminal olefin (cf. Wittig synthesis) accommodates this feature (44).160 The use of

+

(44)

(R300),P(0)SPh

1,3-bis(methylthi0)-2-methoxypropane, easily available in two steps from epichlorhydrin, for introducing a formylvinyl group at carbon, has been demonstrated.ls2 The effective reagent is the bis(methy1thio)allyl anion, formed from the methoxy-compound by treatment with lithium diisopropylamine ; a representative synthesis of an $-unsaturated aldehyde (45) starting from cyclohexene oxide (46) illustrates the methylthiodisplacement step. The first examples of thermal alkyl exchange between alkyl sulphides and methyl esters of carboxylic acids have been reported.le3 A sulphoxonium carboxylate is a likely intermediate. R3C02Me

+ R1SR2

_I_,

R3C02R1

+ R2SMe

The net result of dissolving /3-(1 -adamantylthio)-ethyl- or -pentyl-amine in boiling hydrochloric acid is the displacement of the exocyclic group by T. Mukaiyama, K. Maekawa, and K. Narasaka, Tetrahedron Letters, 1970, 4669. T. Fujisawa, N . Ohtsuka, and G . Tsuchihashi, Bull. Chem. Soc. Japan, 1970,43, 1189. lse S. Oae, M. Nakai, and N. Furukawa, Chem. and Znd., 1970, 1438. lE0 I. Kuwajima, S. Sato, and Y . Kurata, Tetrahedron Letters, 1972, 737. lE1 K.Ogura and G . Tsuchihashi, Tetrahedron Lerters, 1971, 3151, la* E. J. Corey, B. W. Erickson, and R. Noyori, J. Amer. Chem. SOC.,1971, 93, 1724. lE3 T. Migita, H. Matsuyama, and W. Ando, Internat. J. Sulfur Chem., A , 1971, 1, 47. lS7 168

22

Organic Compounds of Sulphur, Selenium,and Tellurium

SMe

chloride.ls4 Analogous C-S bond cleavage is observed for the isothiouronium salt also,ls4 but not in adamantane-1-thiol or in simple alkyl adamantyl sulphides. Reactions of the novel meso-ionic pyrazine (47), including displacement of PhS-, have been reported,ls5 in continuation of SPh

I

co-c @ >-Ph

Ph-N, /

co-c

I

SPh

(47)

work reported in Volume 1 (p. 89). Oxidation of 1,Zseco-penicillins (36) with lead tetra-acetate gives the expected sulphoxide, and a-acetoxymethyl sulphide, but also two structures in which the MeS group has been displaced by acetoxyl.lgs Interestingly, the allylic methyl groups are unaffected by the oxidant. a-Alkylthio- or a-arylthio-carbonyl compounds are smoothly reduced to the parent compound (RCH2*COOX) by treatment with thiolate anions,lS7 while alkoxide anions fail to bring about C-S bond cleavage (cf. ref. 58). a-Halogeno- and aa-dihalogeno-carbonyl compounds are also reductively dehalogenated with thi01ates.l~~3-Thienyl alkyl selenides react with BuLi without loss of the selenium substituent, with lithiation of both apositions.ls8 This is in contrast to the displacement of RSe groups from the 2-position on thiophen. Olefin-forming elimination of thiol from an alkyl L. Bauer and K. K. Khullar, J . Org. Chem., 1971, 36, 3038. J. Honzl, M. Sorm, and V. Hanus, Tetrahedron, 1970, 26,2305. lo6 E. G. Brain, A. J. Eglington, J. H. C. Nayler, M. J. Pearson, and R. Southgate, J.C.S. Chem. Comm., 1972,229. lE7 M. Oki,W. Funakoshi, and A. Nakamura, Bull. Chem. SOC. Japan, 1971,44,828,832. lE8 Y . L. Goldfarb, V. P. Litvinov, and A. N. Sukiasyan, Izvest. Akad. Nauk. S.S.S.R.. Ser. khim., 1971, 1296.


23

sulphide offers an alternative C- S bond-cleavage route of some importance in biochemistry. The pyridoxal-Fe"'-catalysed elimination of MeSH from methionine is slower than that from S-methylcysteine at pH 5.8-6.2,1se a result illustrating the continuing collection of simple data on methionine as a particularly important amino-acid in metabolism. Generalizations concerning the reactions of sulphides with organometallic reagents are usually unreliable; at least, sulphides can be reliably stated to be less reactive than disulphides since sulphides are the products of treating disulphides with organo-magnesium or the rather more reactive organo-lithium reagents.121 2-Methoxy-l-(ethylthio)cyclohexane with MeMgI in xylene gives the 2-methylcyclohexyl sulphide by displacement of m e t h o ~ y lwhile , ~ ~ ~treatment with MeHgI in the absence of solvent causes cleavage of the thioether substituent from the ring. Arc-generated carbon atoms can abstract sulphur from CS, or from sulphides, Et2Sgiving ethane, ethylene, and n-butane as major Further studies of carbene insertion into the C-S bond are the authors' earlier work on alkyl ally1 sulphides, using bis(methoxycarbonyl)carbene, now being supplemented by a study of the relative tendencies towards C-S insertion and C=C addition for the same substrates with carbethoxycarbene (from ethyl diazoacetate). 1,2-Diphenylethyl phenyl sulphide, PhCH(CH,Ph)SPh, is formed by the action of benzyne on dibenzyl sulphide, via the sulphonium ~ 1 i d e . lAlkylation ~~ at sulphur is one of the best-known reactions of sulphides, and novel syntheses of this type have been reported in which the formation of hydroquinone sulphonium salts, from quinone and a sulphide in 70% H2S04at - 5 to + 5 0C,174and Markownikov addition of a sulphide to an alkene under similar conditions 175 are discussed. Derivatives of the hypothetical molecule SH4, which would be named sulphurane by analogy with p h o ~ p h o r a n e ,have ~ ~ ~been described, of the general formula Rl2S(0R2),; these might be named sulphoxals, though compounds of this type are too rare to have developed a common usage of this name. aa-Bis(trifluoromethy1)benzyl hypochlorite (48) and the diary1 sulphide (49) give an alkoxysulphonium chloride (50), which can be converted into the sulphoxal ( 5 l), a colourless crystalline The use of diphenyl di-[O-bis(trifluoromethyI)benzyl] sulphoxal as an efficient reagent for dehydrating alcohols 17' opens up new possibilities; as an 169

170

171 172

173

174

176 17% 177

D. W. Gruenwedel and R. K. Patnaik, J. Agric. Food Chem., 1971, 19, 775. S. Cabiddu, A. Maccioni, and M. Secci, Gazzetta, 1970, 100, 939. K. J. Klabunde and P. S. Skell, J . Amer. Chem. SOC.,1971, 93, 3807. W. Ando, T. Yagihara, S. Kondo, K. Nakayama, H. Yamato, S. Nakaido, and T. Migita, J . Org. Chem., 1971, 36, 1732. H. Iwamura, M. Iwamura, T. Nishida, M. Yoshida, and J. Nakayama, Tetrahedron Letters, 1971, 63. H. Bosshard, Helu. Chim. Acta, 1972, 55, 32. H. Bosshard, Helu. Chim. A d a , 1972, 55, 37. J. C. Martin and R. J. Arhart, J. Amer. Chem. SOC.,1971, 93, 2339, 2341. J. C. Martin and R. J. Arhart, J. Amer. Chem. SOC.,1971, 93, 4327.

24


a:o a Ph

CF3 I Ph-C-0-C1 I CF3

(48)

Ph OC(CF,),Ph

\s/.

I

+

-78 'C

co

-EE-+

I

I

OC (CF,),P h

OC (C F3)pPh (49)

(50)

1 Ph OC(CF,),Ph \/

a s ' o c ( c F3),Ph co I

OC (CF,) J'h

(51)

example, t-butyl alcohol gives isobutene within a few seconds at - 50 "C, via Ph2S(OBut)[OCPh(CF,),], with diphenyl sulphoxide and PhC(CF3)20H as by-products.

a-Substituted Sulphides.-Several instances of the activation of an a-position by sulphenyl sulphur have been mentioned in the preceding section. Benzoyl peroxide reacts with aryl methyl sulphides to give corresponding arylthiomethyl benzoates ArSCH,O* CO Ph, with no side-products indicative of free-radical intermediates ;178 this stands in contrast with the formation of products from radical dimerization when di-t-butyl peroxide reacts with thioanis~le.~'~ Asymmetric syntheses based upon the a-sulphenyl carbanion formed from benzyl phenyl sulphide have been studied, threo(52) and erythro-isomers (53) being formed by reaction with benzaldehyde, in relative proportions 60 : 40, respecfively.lso The formulae (52) and (53)

depict the preferred conformations of the products, but are not intended to imply that these enantiomers are formed in greater amounts than their mirror-image forms. 17* 178

180

D. I. Davies, D. H. Hey and B. Summers, J. Chem. SOC. (C), 1970, 2653. H. B. Henbest, J. A. W. Reid, and C. J. M. Stirling, J. Chem. SOC., 1964, 1220. C. A. Kingsbury, J . Org. Chem., 1972,37, 102.

25


a-Chloro-sulphides.-Aliphatic sulphides are converted into a-chloroderivatives in ca. 80% yield by treatment with 3-dichloroiodo-pyridine 181 or with N-chlorosuccinimide.182 Extreme mechanisms for the chlorination of sulphides are Elcb-like, in which a weak base (Cl-) is implicated, or E2-type, in which a stronger base (e.g. succinimidoyl in an N-chlorosuccinimide chlorination procedure) is inv01ved.l~~In either case, the chlorosulphonium ion (54) is the primary reaction intermediate? but steric CI

y / x+(54) \

CI

HX

I + RS-CHR +-

I

RS.CH,R

HX

+ R:=cCHR CI -

-

CI

I

RS=CHR

-

/

KS$HR

effects could be route-determining and although a broad study shows them to be important,ls3 electronic effects are also significant? especially in unsaturated sulphides. aa-Dichloromethyl sulphides RSCHC12, prepared in high yields from thiolformates RSCHO and PC16,184can be further chlorinated to give trichloromethyl phenyl sulphide (when R = Ph) using excess PC15, or can be converted into dithioacetals (RS),CHCl and orthothioformates (RS)&H with excess thiolformate in the presence of HgC1,.lR4 Chlorophenylthiocarbene ( 5 5 ) is formed in anhydrous media by treating dichloromethyl phenyl sulphide with ButOK, and also in aqueous media (50% aq. NaOH with a quaternary ammonium chloride), where traces of the dimer (56) are formed in addition to a cyclopropane (57) when an olefin is added.185

R,

PhSCHCla

I PhseCr (55)

,R CH-CH

\ /

+

PhS,

,CI

,C=C,

CI

SPtl

C

RCH=CIlR

/ \

PhS Cl (57)

(56)

f3-Keto-su1phides.-The activated methylene group in Ph CO CH,SMe undergoes typical substitution reactions, e.g. hydrazone formation with a diazonium cation (58).lS6Phenacyl sulphides give the corresponding ketone E. Vilsmaier and W. Spruegel, Annalen, 1971, 749, 62. E. Vilsmaier and W. Spruegel, Annalen, 1971, 747, 151. lS3 L. A. Paquette, R. E. Wingard, J. C. Philips, G. L. Thompson, L. K. Read, and J. Clardy, J . Amer. Chem. Soc., 1971, 93, 4508. l n 4 D. H. Holsboer and A. P. M. Van der Veek, Rec. Trav. chim., 1972, 91, 349. l n 6 M. Makosza and E. Bialecka, Tetrahedron Letters, 1971, 4517. lS6 K. Hirai, H. Matsuda, and Y . Kishida, Chem. andPharm. Bull. (Japan), 1971,19,2207.

lnl

lS2

26

Organic Compounds of Sulphur, Selenium, and Tellurium Ph *COCSMe

and thione under irradiation (Ph-COOCH2SCHR1R2-+ Ph. COOCH, R1R2C= S).lE7

+

Unsaturated Su1phides.-Well-established preparative methods are illustrated in recent work, particularly the use of acetylenes and simple sulphur halides, or thiols, or disulphides. Dialkylacetylenes give trans-divinyl sulphides in high yields with SCl, through the vinylsulphenyl chloride, isolable in some cases.188 The addition proceeds in an anti-Markownikov manner. Diphenylacetylene gives (PhCCl=CPh),S or 3-chloro-2-phenylbenzo[b]thiophen, depending on reaction conditions.188 Diselenium dichloride gives benzoselenopheno[2,3-b]benzoselenophens with 1,l -diarylethylene~,l~~ and seleninyl chloride behaves in the same way. The vinyl selenide Ar,C=CHSeCH=CAr, is obtained, where Ar = 2,4-dimethylphenyl. Selenium tetrachloride and TeCl, form adducts with diarylethylenes, and only 2,2-diarylvinyl chlorides are obtained . Acetylene reacts with di-isobutyl disulphide at 170-180 "C and at 12-1 9 atm pressure to give BuiSCH= CH, (38%), trans-BuiSCH= CHSBui (1 1.6%) and its cis-isomer (3.8%), MeCH(SBui), (10.6%), and (Bu'SCH,), (2.5%).lS0 Excess disulphide increases overall yields, and lower temperatures increase the proportions of the two major 1,4-Nucleophilic addition of RlSH to R2*COOC=CH in alcoholic solution containing Triton B is stereoselective, giving predominantly cis-R2*COOCH=CH* SR1 even at low temperatures.lQ2 Photochemical (589 nm) addition of thiobenzophenone at 40 "C to tetramethylallene (59) gives 2,4,4-trimet hyl-3-(diphenylmethylthi 0)but adiene (60) as major product, with the cyclo-adduct (61).lQ3 The stepwise approaches used for the syntheses of acetylenic sulphides (62) illustrate some general methods.lg4 The elimination of MeSH from an 187 188 188

iga 181

192

193

194

M. C. Caserio, W. Lauer, and T. Novinson, J. Amer. Chem. SOC.,1970, 92, 6082. T. J. Barton and R. G. Zika, J. Org. Chem., 1970, 35, 1729. D. Elmaleh, S. Patai, and Z. Rappoport, J. Chem. SOC.( C ) , 1971, 2637; Israel J . Chem., 1971,9, 155. A. S. Atavin, N. K. Gusarova, S. V. Amosova, B. A. Trofimov, and G. A. Kalabin, Zhur. org. Khim., 1970, 6, 2386. N. K. Gusarova, B. A. Trofimov, A. S. Atavin, S. V. Amosova, and A. V. Gusarov, Zhur. org. Khim., 1971, 7, 1780. E. N. Prilezhaeva, G. S. Vasilev, I. L. Mikhelashvili, and V. S . Bogdanov, Zhur. org. Khim., 1971,7, 1349. H. Gotthardt, Tetrahedron Letters, 1971, 2343, 2345. L. A. Krichevskii and A. V. Shchelkunov, Zhur. org. Khim., 1971,7, 1888.


-

27

Pl1,CIIS

Ph

\

C=S 4- Me,C=C=CMe, / Ph

RMgBr

-t

-

\

/C=CMe,

CH2=C

\

Mc

S ---+ RS-MgBr OMgBt

Me&-C=CMgBr I

(i) S *

4 Me$-C=C-SR (ii) R X I

OH i-OH

Me,CO

-j-

HCEC-SR (62)

alkyl dimethyl thioacetal [e.g. PrnCH(SMe), -+ EtCH=CH*SMe] lo5can be achieved using HJPOQ.

Reactions of Unsaturated Sulphides.-lY3-Alkenynyl alkyl sulphides have been the subject of continuing study by Russian workers, and recent results include isomerization during addition of an aryl-lithium (RSC=C* CH=CH2 + RSCH=C=CH.CH2Ar),log or with an alkyl calcium iodide;lo7 diethylamine in the presence of cuprous chloride gives RSCH=C=CH* CH2NEt2.108 A Pd catalyst prepared by NaBH, reduction of PdCI, was found lo5to be suitable for the partial hydrogenation of cis-1-(methylthio)but-1-en-3-yne to 1-methylthiobuta- 1,3-diene. Cleavage of alkenyl sulphides into alkenethiolates loo$6c with sodium in liquid ammonia, and further studies (see Vol. 1, p. 53) of the conversion of an alkynyl sulphide RIS. C=C*R2 into the thioamide R2CH2* CSoNRa2by heating with a secondary amine to 150 0C,200 have been reported. Sulphide cleavage into (R2*C=C-S- ++ R2*c=C=S) precedes addition of the amine, and the reaction product is R2C(NR3,)=CH. SR for primary alkyl substrates, for which the reaction conditions are too mild to cause C-S bond cleavage. lE5

Ie7 le8

G. S. Vasilev, E. P. Mikos, V. N. Petrov, B. D. Polovnikov, R. I. Shekhtman, and E. N. Prilezhaeva, Izvest. Akad. Nuuk S.S.S.R., Ser. khim., 1971, 1079. S . I. Radchenko, L. N. Cherkasov, B. S. Kupin, and A. N. Krivosheya, Zhur. org. Khim., 1971, 7, 104. L. N. Cherkasov, S. 1. Radchenko, G. I. Pismennaya, and K. V. Balyan, Zhur. org. Khim., 1971,7, 1111. M. L. Petrov, S. I. Radchenko, B. S. Kupin, and A. A. Petrov, Zhur. org. Khim., 1971, 7, 1123.

lee 2oo

L. Brandsma, Rec. Trav. chim., 1970, 89, 593. M.L.Petrov, B. S. Kupin, and A. A. Petrov, Zhur. org. Khim., 1971, 7 , 1120.

28


Skeletal Rearrangements of Unsaturated Sulphides.-Thermal rearrangement of allyl aryl sulphides gives mixtures resulting from the cyclization of the initial allyl-transfer intermediate. yy-Dimethylallyl phenyl sulphide (63) gives mainly (85%) 2-isopropyl-1-thiacoumarin (64),201illustrating the general features of the thio-Claisen rearrangement.

Important variants of procedure have been tested, providing wider possibilities for thio-Claisen rearrangements in synthesis; like any other method for forming carbon-carbon bonds whose scope exceeds its limitations, there is the likelihood of studies of the type described in this Section being taken up in many more laboratories. Lithiation of allyl sulphides is followed by 203 providing a very efficient method for the synthesis of thiols, alkyl sulphides, and hydrocarbons of the squalene type, or based upon the artemisyl skeleton.202 Typically, benzyl yy-dimethylallyl sulphide (65) gives (66) with four equivalents of

BunLi at - 30 "C,followed by treatment with MeLZo2A diallyl sulphide behaves similarly in that one of the two S-substituents is lithiated, and this centre is the point at which the y-carbon of the other S-substituent is are formed in approxiattached in the product.203 Compounds (67)-(69) mately equal amounts by the photolysis of the /l-alkylthioalkyl-carbene derived from 3-crotyl-3-methylbutyrophenone tosylhydrazone sodium salt.204 An a-ally1thioalkyl-carbene (70) behaves differently on irradiation at - 70 oC,204giving an intermediate (71) which rearranges, without the need for irradiation, to give the violet thione (72);this last step is the first

202 203

204

J. Tanaka, T. Katagiri, K. Tanabe, and S. Takeshita, Yuki Gosei Kagaku Kyokai Shi, 1971,29, 7 8 8 (Chem. Abs., 1971, 75, 140636). V. Rautenstrauch, Helv. Chim. Acta, 1971, 54, 739. J. F. Biellmann and J. B. Ducep, Tetrahedron Letters, 1971, 33. K. Kondo and 1. Ojima, J.C.S. Chem. Comm., 1972, 62.


29

Ph

P11

example of a thio-Claisen rearrangement of a simple ally1 vinyl sulphide, an earlier study205 suggesting that such compounds fail to rearrange at 160-180 "C but require HgO catalysis to achieve this result. a-Allylthioalkyl-carbenes, e.g. (70), undergo intramolecular cycloaddition without rearrangement when irradiated at elevated temperatures in the presence of NaOMe.206 The related [2,3]sigmatropic rearrangement of S-methy1-S'(3,3-dimethylallyl)carbene (73) to a dithiocarboxylic ester constitutes another new carbon-carbon bond synthesis based upon the thio-Claisen rearrangement.207 New dithio-ester and thioamide syntheses are reported,208based upon the reaction of chloropropiolonitrile CIC=C- CN with two equivalents of allenethiol in the presence of NaOMe, to give (74), and of NN-diethylaminopropiolonitrile with allenethiol in the presence of NaOMe, to give (75).208 206

2oo 207 208

E. J. Corey and J. I. Shulman, J. Amer. Chem. SOC.,1970, 92, 5522. K. Kondo and I. Ojima, J.C.S. Chem. Comm., 1972, 63. J. E. Baldwin and J. A. Walker, J.C.S. Chem. Comm., 1972, 354. T. Sasaki, A. Kojima, and M. Ohta, J . Chem. SOC.(0,1971, 196.

30


S CH,-CH=CH,

I

NC-CH-CS-S-CH,-CH=CH2 (74)

CH,-CH=CH,

I

NC- CH- CSNEt2 (75)

Naturally occurring Organo-sulphur Compounds.-Simple sulphur-containing functional groups are represented in a variety of natural products, in addition to the sulphur-containing a-amino-acids cysteine and methionine which are constituents of proteins. Quinolizidine alkaloids carrying methylthiomethyl groups have been model compounds showing that an axial MeSCH2- substituent suffers a larger downfield shift of the methylene protons in its n.m.r. spectrum than the equatorial isomer. The antibiotics sparsomycin (76)210and lincomycin (see Vol. 1, p. 69) carry

methylthio-substituents ; a new synthesis of lincomycin from D-galactose differs from the first-published route in introducing the glycosidic methylthio-group during a late stage, involving ring-closure of a dimethyldithioacetaL211 Arabis hirsuta has provided new isothiocyanates ; MeS(CH,), NCS and MeS(CH,),. COO(CH,),. NCS have been isolated from enzymic hydrolysates.212 Hawaiian Dictopteris produces various 3-acetoxy-undec-5-enyl ao8

211 21s

R. T. LaLonde, C. F. Wong, and H. G. Howell, J. Org. Chem., 1971,36, 3703. P. F. Wiley and F. A. MacKellar, J. Amer. Chem. Soc., 1970, 92, 417. G. B. Howarth, W. A. Szarek, and J. K. N. Jones, J. Chem. SOC.( C ) , 1970, 2218. A. Kjaer and A. Schuster, Acta Chem. Scand., 1972, 26, 8.


31

thiolacetates RSAc and di-, tri-, and tetra-sulphides RS,R, which may be precursors of the undeca-l,3,5-trienes found in the essential oil of this s~ecies.~l~-~l~ 4 Thioacetals and Related Compounds

Preparation.-Thioacetals are best regarded as masked forms of aldehydes and ketones, from which they may be prepared by relatively straightforward methods ; for example, methyldithiohemiacetal MeCH(SH)SMe is obtained by a one-step method from acetaldehyde, methanethiol, and H2S via the monothiohemiacetal, at pH 5.216 Previous workers have favoured a roundabout route in which a 1-alkylthio-l-chloro-alkaneis treated with thiourea and the resulting isothiouronium salt is hydrolysed. Pyruvaldehyde gives the corresponding product Me. COOCH(SH)SEt but further reactions lead to Me. COOCHaSSEt.21eThioacetals are formed in moderate yields by treating aldehydes with t h i o b ~ r a n e s ; ~ while ~ ' ethyl isopropyl ketone gives the ethylthioketal with (EtS)8B, further reaction leads to the thio-enol ether Me,C=C(SEt)* CH2*CH,.218 Treatment of acetals with thiols in excess produces an equilibrium mixture from which the corresponding dithioacetal may be obtained; a favourable case from this point of view is the conversion of formamide acetals R,NCH(OMe), into corresponding m e r ~ a p t a l s . ~Vinyl ~~ sulphides CH,=CHSR give acetaldehyde dithioacetals CH3- CH(SR),, in 40% yield, and acetylene, on being heated at 170-180 "C in the presence of KOH,220through synchronous intramolecular transfer of hydride and thiolate. Reactions.-Rate constants for the acid-catalysed hydrolysis of benzaldehyde methyl S-aryl thioacetals at 30 "C in 20% dioxan-water have established C-S bond-breaking in the rate-determining step to follow an A 1 mechanism; overall, there is no evidence of general-acid catalysis,221 and the S-o-carboxyphenyl compound does not show the marked rate enhancement (lo4-lo6 depending on solvent) associated with the presence of the carboxyl substituent in the oxygen analogue.222 a-Keto-aldehydes with thiols give a-ketohemimercaptals (77), which rearrange to give the corresponding a-hydroxy-thiolester (78) in the presence of various salts or a tertiary amine.223This is an observation which als 214

216

217

a18

alo 220

p2a

ma

P. Roller, K. Au, and R. E. Moore, Chem. Cornm., 1971, 503. R. E. Moore, Chem. Comm., 1971, 1168. R. E. Moore, J. Mistysyn, and J. A. Pettus, J.C.S. Chem. Comm., 1972, 326. L. Schutte, Tetrahedron Letters, 1971, 2321. R. H. Cragg and J. P. N. Husband, Inorg. Nuclear Chem. Letters, 1970, 6, 773. R. H. Cragg and J. P. N. Husband, Inorg. Nuclear Chem. Letters, 1971, 7 , 221. F. M. Stoyanovich, I. A. Ivanova, and B. P. Federov, BuN. Soc. chim. France, 1970, 2013. B. A. Trofimov, A. S. Atavin, N. R. Gusarova, and S. V. Amosova, Zhur. obshchei. Khim., 1970, 40, 1428. T. H. Fife and E. Anderson, J. Amer. Chem. Soc., 1970, 92, 5464. T. H. Fife and E. Anderson, J. Amer. Chem. Soc., 1971, 93, 6610. S. S. Hall and A. Poet, Tetrahedron Letters, 1970, 2867.

32


K' - CO .CH(OH)SR?

- -+R'CH(0H).

(77)

CO .SR"

(78)

might be useful in the field of carbohydrate synthesis, though the different course of the reaction reported for pyruvaldehyde with EtSH and H2S,,16 leading to MeCO-CH2SSEt,may suggest that reaction conditions must be carefully studied and selected if one is to obtain optimum yields in any particular case. Keten reacts with dithioacetals R1R2C(SR3), to give the 'insertion' product R1R2C(SR3)CH,-CO. SR3, which may readily lose R3SH to give an a/3-unsaturated thiolester R1R2C=CH- CO SR3.224The orthothioformate CH(SR)3 gives both single- and double-insertion products ; all these reactions are known in the oxygen series. Elimination of thiol from a dithioacetal, providing a useful route for vinyl thioether synthesis,lBsis matched by the formation of 1,l-bis(alky1thio)ethylenes (RS),C=CHMe from 1,1,2-tris(alkylthio)propanes by heating to 175 "C with ButOKB u ~ O H . ~These ,~ reactions are perhaps less successful with the oxygen analogues. Dithioacetals and related compounds have a number of uses in synthesis, both in Friedel-Crafts-type reactions and in reactions which exploit the high reactivity of carbanions stabilized by two or more sulphur atoms bonded at the carbanion centre. Benzyl orthothioformate, CH(SCH,Ph),, may be used to introduce a -CH(SCH,Ph), group into 2- and 3-positions of an indole, with Tic& as catalyst at - 5 "C in CHC13, and has been used in this way for 2-substitution of (79), giving (80) and (81), with further elaboration of (80) into 2-methyl-lysergic acid.22s Studies of ethyl dithio-

-

Q-V HN

HN

(79)

224 225

226

CH( SCH,Ph)?

(80)

H. Eck and H. Prigge, Annalen, 1972, 755, 177. A. S. Atavin, A. I. Mikhaleva, B. A. Trofimov, G. A. Kalabin, and N. P. Vasilev, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1971, 614. P. Stutz and P. A. Stadler, Helv. Chim. Acta, 1972, 55, 75.

Aliphatic Organo-sulphur Compounds etc. 33 acetals, orthothioformates, or methyl benzyl sulphide as reagents for substitution of active methylene compounds, or anisole, have also been Bis(methylthio)methane, (MeS),CH,, in the presence of BuLi, provides the stabilized carbanion which reacts with epoxide (82) to give the corresponding cyclopropane (83), from which (84) and (85) can be

obtained.228Since the epoxide itself is obtained from an olefin, the reagent offers a means of inserting a C=O group between the carbon atoms of an olefinic double bond [cf. (85)].228 Reactions of monosaccharide dithioacetals reported recently show the consequences of participation by the sulphur functional group. 5 - 0 Toluene-p-sulphonyl-L-arabinose dibenzyl di thioacetal (86) gives the furanoside (87) but no pyranoside, on heating, and the thiopyranoside (88) RS,

acetone NaT

,SR CH

H HO

O CH20Ts

(88)

(86)

-% ~

rC:: T H~ O+

CH2SK (8 7)

on treatment with NaI in acetone.22B 3,4,5,6-Tetra-O-benzoyl-~-glucose diethyl dithioacetal undergoes substitution of the unprotected 2-hydroxygroup by EtSH-ZnCl,-HCl, with inversion of configuration, giving the z-thio-~-mannose derivative, by way of the 1,2-episulphoniurn intermediate;230 the 1-ethylthio-group assists epimerization, at pH 8 in the 227

228 229

230

3

T. Mukaiyama, N. Narasaka, K. Maekawa, and H. Hokonoki, Bull. Chem. SOC. Japan, 1970, 43, 2549. D. Seebach and M. Braun, Angew. Chem. Internat. Edn., 1972, 11, 49. J. Harness and N. A. Hughes, Chem. Comm., 1971, 811. B. Berrang and D. Horton, Chem. Comm., 1970, 1038.

34


presence of HgC12, at the adjacent asymmetric centre.230 D-Arabinose diethyl dithioacetal on peracid oxidation gives the corresponding d i ~ u l p h o n e which , ~ ~ ~ on treatment with dilute AcOH gives 1,l-bis(ethy1sulphonyl)-~-erythro-3,4,5-trihydroxypent-l-ene, in equilibrium with the furanosyl isomer in solution. This constitutes a facile elimination reaction. The preparation of monosaccharide dithioacetals is a high-yield procedure in general, but low yields are common for their oxidation at This may be accounted for by the ease with which a 1,l-bis(alkylsulphiny1) compound R1R2C(SOMe)2is reduced to the monosulphinyl analogue (it oxidizes HCl to C12), and the ease with which the monosulphinyl compound is hydrolysed to the corresponding ketone R1R2C0 and MeSSMe MeS02*SMe.232 1.r. and Raman spectra of aryl mono- and di-thioacetals have been studied in comparison with those of analogous s ~ l p h i d e sshowing , ~ ~ ~ some characteristic band patterns in the 1000-1 650 cm-l region.

+

Tetrathioethylenesand Related Compounds.-These compounds, (RS),C= C(SR),, are obtained from the pyrolysis in mesitylene solution of (PhS),C, or of (PhS),C. C(SPh),, for example [giving(PhS),CH, PhSSPh, Ph- CS. SPh, (PhS),C=C(SPh),, and (89)],234or from (PhS)3CLi.235In part, interest in

them is based upon their formation by dimerization of carbenes [e.g. (PhS),C: 235 or MeSENMe, 236]. Other preparative methods include orthothio-oxalate pyrolysis,237and triethyl phosphite coupling of trithiocarbonates RS. CS SR.238 Compounds with hetero-atoms as substituents at an olefinic double bond have particularly interesting properties, for example the cycloaddition of tetramethoxyethylene to tetracyanoethylene ;237 tetrathioethylenes, however, do not behave like electron-rich olefins, as do their oxygen and nitrogen counterparts. They can be recovered unchanged from conc. H2S04, and merely form a green charge-transfer complex with tetra~yanoethylene.~,~ Photo-oxidation of tetrathioethylenes gives dithioloxalates RS.CO CO. SR,238considered to arise via a 1 : 1 adduct with 02,together with the disulphide RSSR.

-

231

235

2s4 2s6

238 237

238

A. Farrington and L. Hough, Carbohydrate Res., 1971, 16, 59. H. Nieuwenhuyse and R. Louw, Tetrahedron Letters, 1971, 4141. B. Wladislaw, P. R. Olivato, and 0. Sala, J. Chem. Sac. (B), 1971, 2037. D. Seebach, A. K. Bech, and H. B. Stegmann, Tetrahedron Letters, 1970, 1933. D. Seebach, Chem. Ber., 1972, 105, 487. T. Nakai and M. Okawara, Chem. Comm., 1970, 907. D. L. Coffen, J. Q. Chambers, D. R. Williams, P. E. Garrett, and N. D. Canfield, J. Amer. Chem. Soc., 1971, 93, 2258. W. Adam and J.-C. Liu, J.C.S. Chem. Comm., 1972, 73.


35

Tetra(ethylthio)allene, (EtS),C=C=C(SEt),, undergoes a cycloaddition reaction with ArSO,. NCO or with an aryl i s o t h i o ~ y a n a t e . However, ~~~ though allenes are not directly comparable with ethylenes in many respects, further studies are likely to clarify the structural requirements for tetrathioethylenes to show minimal electrophilic and dienophilic reactivity. Mono-, bis-, and tris-(pheny1seleno)methyl-lithium compounds have been prepared.240They are the first representatives of their class, and early results suggest that the PhSe group stabilizes an adjacent carbanion centre nearly as well as PhS. 5 Sulphoxides

Preparation.-Oxidation of sulphides remains the method almost invariably chosen for the preparation of sulphoxides. There are variations in procedure, mainly concerned with avoiding over-oxidation to the sulphone, which are represented in the recent literature. The four isomeric 2-phenylsulphinylindanols, isolated from the oxidative addition of PhSH to indene using O2 as oxidant, have been properly ~ h a r a c t e r i z e d .Cumene ~~~ hydroperoxide, in the presence of alkali,242oxidizes sulphides or sulphoxides to sulphones, though t-pentyl hydroperoxide in the presence of MoCl, gives good yields of sulphoxides from sulphides when used on a strictly molar two moles of the hydroperoxide give good yields of sulphones. The use of 2,4,4,6-tetrabromocyclohexadienonein aq. dioxan or THF 244 is advocated for oxidizing sulphides to sulphoxides without sulphone contamination. The sensitized photo-oxidation of sulphides is te+ntativelyinterpreted as proceeding via the corresponding persulphoxide R2SOO-,246while a kinetic study of the oxidation of diary1 sulphides by nitric acid indicates that protonated N204is an important species in the reaction.246 Interesting complications appear in the persulphate oxidation of phenyl o-carboxyphenyl sulphide since, in addition to the expected sulphoxide, the corresponding disulphide and thiolsulphonate, formed with oxidative migration of the phenyl group from S to 0, are obtained.247 The oxidation of the methionine residue in a protected hexapeptide to the sulphoxide has been reported to occur merely by aerial oxidation when AcOH is used as Methionine itself, and other sulphides of R. Gompper and D. Lach, Angew. Chem. Internat. Edn., 1971, 10, 70. D. Seebach and N. Peleties, Chem. Ber., 1972, 105, 511. 241 H. H. Szmant and J. J. Rigau, J . Org. Chem., 1972, 37, 447. ara Y. Ogata and S. Suyama, Chem. and Ind., 1971, 707. ars G. A. Tolstikov, U. M. Dzhemilev, N. N. Novitskaya, V. P. Yurev, and R. G. Kantyukova, Zhur. obshchei Khim., 1971,41, 1883. 244 V. Cato, F. Ciminale, G. Lopez, and P. E. Todesco, Internat. J . Sulfur Chem., A , 280

e40

a46

a40

2413

1971, 1, 130. C. S. Foote and J. W. Peters, J . Amer. Chem. Soc., 1971, 93, 3795. Y. Ogata and T. Kamei, Tetrahedron, 1970, 26, 5667. P. M. Brown, P. S. Dewar, A. R. Forrester, A, S. Ingram, and R. H. Thomson, Chem. Comm.,1970, 849. K. Norris, J. Halstroem, and K. Brunfeldt, Acra Chem. Scand., 1971, 25, 945.

36


biological interest, are rapidly and efficiently oxidized to sulphoxides by a Mn2+-02-S0,2N-Benzyloxycarbonyl-m-selenomethionine diphenylmethyl ester gives the corresponding selenoxide with NaIO, or Hz02, widely used oxidants for the analogous sulphide-sulphoxide conversion.25oThe selenoxide slowly becomes deoxygenated on storage ; the attempted oxidation of the Se-diphenylmethyl analogue or the diselenide gave the corresponding dehydroalanine diphenylmethyl ester, PhCH20.-

CO*NH*C(=CHz)*CO*OCHPh2.250 An intermediate (90) has been identified in the oxidation of a sulphide to a sulphoxide by l-chlorobenzotriazole.251This contributes a further example to the growing number of putative quadricovalent sulphur intermediates involved in reactions of divalent sulphur compounds. Reaction of (90) with an alcohol in the presence of AgBF, gives an alkoxysulphonium salt, while a secondary amine similarly gives an amino-

sulphonium Reactions of sulphur-nitrogen compounds which may be mentioned in the context of sulphoxide formation include the pyrolysis of N-phthalimido-diphenylsulphoximide, (Phth)N- N= S(= O)R,, which gives 70% benzocyclobutenedione, nitrogen, and RzSO in 80% yield.252 A versatile asymmetric synthesis of acyclic sulphoxides is illustrated by the treatment of (91), obtained from L-ephedrine and SOC1, in the presence of NEt,, with a Grignard reagent at - 33 "C(inversion of configuration at S), or with an a l k y l - l i t h i ~ m .The ~ ~ ~diastereoisomers of the oxathiazolidine2-oxide (91) are formed in 80 : 20 ratio, and the less-soluble isomer is depicted as (91); treatment of the other diastereoisomer in solution with HC1 provides more (91). The chiral hydroxysulphinamide (92) is further treated with an alkyl-lithium, where a Grignard reagent was used in the first step, or conversely with a Grignard reagent, to provide either enantiomer of a s ~ l p h o x i d e . ~ ~ ~ Further studies of the formation of sulphoxides from sulphenates have been reported, by a [2,3]sigmatropic rearrangement (93) to (94),254and unexpectedly from the reaction of cyclohexen-1-01 with phenylsulphenyl 260

251 a6a

263

S. F. Yang, Biochemistry, 1970, 9, 5008. R. Walter and J. Roy, J. Org. Chern., 1971, 36, 2561. C. R. Johnson, C. C. Bacon, and W. D. Kingsbury, Tetrahedron Letters, 1972, 501. T. L. Gilchrist, C. W. Rees, and E. Stanton, Chern. Comm., 1971, 801. F. Wudl and T. B. K. Lee, J.C.S. Chern. Cornm., 1972, 61. D. A. Evans, G. C. Andrews, and C. L. Sims, J . Amer. Chem. Soc., 1971,93, 4956.


PhI:), (i)o R'MgBr,

-

..o

PhCH(0H) CH(Me)NMeS, I R1 (92)

33 "C+

(ii) H,O+

Me

I Me

?: & :

:;7

37

at - 70 "C,in THF

I.0

R1-

R2

Ar (93)

(94)

(95)

chloride, giving (95) by way of the s ~ l p h e n a t e .Reactions ~~~ of sulphines with organolithium compounds (Vol. 1, p. 72) give sulphoxides through nucleophilic addition at S;25s one useful feature of this route lies in the facility with which it gives highly hindered sulphoxides. Spectroscopic Properties of Su1phoxides.-New data in the n.m.r. and c.d. fields are collected with the purpose of gaining further knowledge of preferred conformations and particularly of the influence of the sulphinyl group on the reactivity of an adjacent centre; as such, spectroscopic data are mcntioned also in the later sections of this Chapter, dealing with properties and reactions of sulphinyl compounds. The n.m.r. spectra of the four isomers of PhCH(0H). CHPh- SO*Ph in comparison with corresponding sulphides and sulphones give an indication of the much larger space requirements of the sulphinyl oxygen atom compared with a sulphur lone pair.257 Available 13C n.m.r. data on penicillin sulphoxides, in which the y-carbon shifts show anomalies, are interpreted as indicating that a sizeable steric effcct is exerted by the sulphoxide The methylene protons in dibenzyl sulphoxide are magnetically equivalent in solvents of low dielectric constant, but non-equivalent in polar This behaviour is reversed for diphenacyl sulphoxide ; the non-equivalence arises, on changing solvent, from the downfield shift of one of the methylene protons with increasing polarity. Solvent effects on the deuteriation of

258

N. S. Zefirov and F. A. Abdulvaleeva, Zhur. org. Khim., 1971, 7 , 947. A. G. Schultz and R. H. Schlessinger, Chem. Comm., 1970, 747, 748. C. A. Kingsbury and R. A. Auerbach, J . Org. Chem., 1971, 36, 1737. R. A. Archer, R. D. G. Cooper, P. V. DeMarco, and L. F. Johnson. Chem. Comm.,

259

I. Sataty, Org. Magn. Resonance, 1971. 3, 429.

255 256 257

1970, 1291.

38


(S)-benzyl methyl sulphoxide have been studied by n.m.r. spectroscopy.2s0 Rates of exchange of the two diastereotopic protons in D,O, using NaOD as base, are in the ratio 14 : 1, while the corresponding ratio in ButOD with ButO- Na+ is 0.5 : 1. When a-lithiobenzyl methyl sulphoxide is quenched with D20, the diastereoisomer ratio is 1.7 : 1, but when the quenching is performed in THF, the diastereoisomer ratio is 0.065 : 1. These observations are all due to the adoption of different conformations by the a-sulphinyl carbanion in different solvents.2so Pseudo-contact chemical-shift n.m.r. studies have involved sulphoxides from the points of view of configurational assignment at sulphur and determination of optical purity of chiral sulphoxides. Tris(dipivaloy1methanato)europium enhances the magnetic non-equivalence of methylene protons in meso-Ph*SO- CH,. SO. Ph; the racemate is identified readily by n.m.r., since its methylene protons are equivalent.261 The europium complex of 3-heptafluorobutanoyl-( + )-camphor is capable of differentiating the contributions of the enantiomers of benzyl methyl sulphoxide in a partly resolved mixture, through producing n.m.r. non-equivalence of methylene protons.262 This may be used to determine optical purity in such cases (and more generally); by way of illustration,262a 0.13 mol 1-1 solution of (S)-benzyl methyl sulphoxide, [aID + 86 (c = 0.8, EtOH) in CC14, in the presence of the Eu complex (0.45 equivalents) showed two singlet methyl peaks (W,= 2.0 Hz), which were sharpened (W4= 1.7 Hz) on warming the sample to 66 "C;the non-equivalence was 5.2 Hz. Integration showed that the major enantiomer comprised 94.5 k 0.5% of the mixture, i.e. optical purity was 89%, while the use of optical rotation data indicated an optical purity of 90%. Assignment of configuration at sulphur is illustrated for a steroidal sulphoxide, based upon 100 MHz studies with E~(dpm),.~~~ A novel method for determining protonation equilibria for sulphoxides is based upon the reduction in intensity of the 210nm c.d. maximum of a chiral sulphoxide as a result of 0-protonation. (+)-t-Butyl phenyl sulphoxide, which shows a positive c.d. band at 240nm and a negative band at 210nm, was used to show that a plot of ellipticity, [el, against HA of the medium, is ~ i g m o i d . ,The ~ ~ standard method for determining the R2SOH+: R,SO ratio, using U.V. extinction coefficients, has some limitations, though even the c.d. method advocated here 264 may require broader assessment before adoption, since the dependence of the parameters of the 210 nm c.d. band on structure is not yet known, and solvent effects, perhaps comparable with those found in c.d. studies of a-chlorosulphoxides,286may need to be considered. The 0.r.d. curves of (R)- and O,

260

261

262 26s 264

266

T. Durst, R. R. Fraser, M. R. McClory, R. B. Swingle, R. Viau, and Y.-Y. Wigfield, Canad. J . Chem., 1970, 48, 2148. J. L. Greene and P. B. Shevlin, Chem. Comm., 1971, 1092. R. R. Fraser, M. A. Petit, and J. K. Saunders, Chem. Comm., 1971, 1450. M. Kishi, K. Tori, and T. Komeno, Tetrahedron Letters, 1971, 3525. U. Quintily and G. Scorrano, Chem. Comm., 1971, 260. M. Cinquini, S. Colonna, I. Moretti, and G. Torre, Tetrahedron Letters, 1970, 2773.

39 (S)-isomers of 6/3-allylsulphinyl-5a-cholestane are almost perfect mirrorimages about the wavelength axis; although these isomers are enantiomeric at sulphur, they carry the same steroidal moiety and the dominant effect of sulphur chirality is not expected.266The U.V. spectrum indicates coupling of the 7~ -+ T* transition of the py-double bond to the sulphoxide n -+ d transition, and the 0.r.d. characteristics are determined by the relative spatial orientation of the sulphoxide lone pair and the olefinic double bond, reversal of chirality at sulphur setting up the mirror-image relationship of these groupings and therefore the observed 0.r.d. behaviour. Resolution and Racemization of Su1phoxides.-Resolution of sulphoxides into enantiomers usually requires the presence of an acidic or basic grouping that can be used for diastereoisorneric salt formation with a chiral acid or base; sulphoxides without such ‘handles’ may be partially resolved (4.414.5% optical purity) by stereospecific inclusion into ~ - c y ~ l o d e x t r i n . ~ ~ ~ Racemization mechanisms unique to sulphoxides have been studied in detail, since they can give considerable insight into the reactions at a sulphinyl centre. Photostereomutation of cyclohexyl methylsulphinylmethyl ketones C6Hll. CO. CR1R2*SO Me by U.V. irradiation probably involves internal energy transfer from the carbonyl group to sulphoxide;2s8 prolonged photolysis of the parent compound (R1 = R2 = H) gives primarily cyclohexyl methyl ketone by cleavage of the C-S bond, while with different R1 and R2 groups, a-cleavage into R1-C0.R2 and C6Hll*COOSMe is observed.268 The mechanism of the racemization of sulphoxides by halide ions in acid solution, and the concurrent reduction to the sulphide, is established by rate studies 269 to involve the conversion of the O-protonated sulphoxide into the halogenosulphonium ion in the rate-determining step. Chlorinolysis of a sulphoxide in AcOH gives the products obtained by chlorinolysis of the corresponding sulphide ArSR, where R is a group capable of independent carbonium ion stability, together with products of the Pummerer reaction (e.g. PhCHO, PhSH):270 Albhatic Organo-sulphur Compounds etc.

OAc

ArSR i- C1,

+ AcOH

Ar-k-R

I

C1

OAc

I Ar-S-R

-+ArCl

+ ROAc

C1-

Corresponding C-S bond cleavage in aqueous HCl does not feature in the currently accepted mechanism 2 6 9 ~271 for sulphoxide racernization, in which D. N. Jones, E. E. Helmy, R. J. K. Taylor, and A. C. F. Edmonds, Chem. Comm., z67

2R8 268

270 271

1971, 1401. M. Mikolajczyk, J. Drabowicz, and F. Cramer, Chem. Comm., 1971, 317. C. Ganter and J. F. Moser, Helv. Chim. Acta, 1971, 54, 2228. G. Modena, D. Landini, F. Montanari, and G. Scorrano, J . Amer. Chem. SOC.,1970, 92, 7168. H. Kwart and H. Omura, J. Amer. Chem. SOC.,1971, 93, 7250. J. H. Kreuger, Znorg. Chem., 1966, 5 , 132.


40

the chlorosulphonium cation formed by nucleophilic displacement of OH by C1- can revert to the protonated racemic sulphoxide by reversal of this reaction; however, recent work with ( +)-But*SO*Phshows that in losing its optical activity in solution, isolable products are PhSSPh, PhS- S02Ph, and (+)-sulphoxide, thus reviving the idea of reversible C-S bond cleavage to account for the racemization of s u l p h o ~ i d e s . The ~ ~ ~ alkyl residue in a-phenylethyl phenyl sulphoxide (chiral centres at C and at S ) retains 6&65% of its optical activity while the sulphur centre is completely racemized in aq. HCI04, and a reversible alkyl to oxygen shift, or an equivalent ArSOH :R+ ion-molecule pair, is suggested to account for Quadricovalent sulphur intermediates should also be considered eligible to account for the racemization of sulphoxides 273 :2709

Ar.SO.R

-

OH

_ - _ _ - _ _- _ 1 7

ArSR

I

OH (96)

Here,270the formation of (96) and reversal of the path by which it is formed results in racemization. Treatment of a methyl sulphoxide R. SO. Me with HCI in CH2C12gives RSCH2Cl when the water formed in this reaction is removed by molecular sieves;273since this seems to be accounted for in terms of a quadricovalent intermediate R2SCI2,the suggestion that sulphoxide racemization by HCI involves the same intermediate is The halide-catalysed racemization of ( )-2-methylsulphinylbenzoicacid follows complex kinetics in acid possibly indicating anchimeric assistance by carboxyl. Iodide ion reduction and chloride ion racemization of isopropyl phenyl sulphoxide have been studied in H2S04in comparison with HCIOp,275and the greater relative rate of racemization in H2S04 suggests a shift towards general-acid catalysis. Both reactions involve the same intermediate R2S-X (X = C1 or I), but the reduction process is known 276 to be a specific-acid-catalysed reaction. 180-Exchange studies provide support for the mechanism of the racemization of diary1 sulphoxides by hydrochloric acid, in which nucleophilic attack by C1- at S is followed by rate-determining S - 0 bond cleavage, giving an unstable chloro-sulphonium ion which can either give a sulphonium dichloride or suffer hydrolysis back to the racemic s ~ l p h o x i d e . Also, ~~~ participation by the carboxy-group in (- )-2-phenylsulphinylbenzoic acid

+

272

273 274 276

276

G. Modena, U. Quintily, and G . Scorrano, J . Amer. Chem. SOC.,1972, 94, 202; Chimica e Industria, 1971, 53, 155. R. H. Rynbrandt, Tetrahedron Letters, 1971, 3553. S. Allenmark and C. E. Hagberg. Acta Chem. Scand., 1970, 24, 2225. D. Landini, G . Modena, U. Quintily, and G . Scorrano, J . Chem. SOC.(B), 1971,2041. D. Landini, G . Modena, F. Montanari, and G . Scorrano, J. Amer. Chem. SOC.,1970, 92, 7168.

2a7

H. Yoshida, T. Numata, and S. Oae, Bull. Chem. SOC.Japan, 1971, 44, 2875.


41

(97) is indicated since O-exchange occurs some lo4 times faster than r a ~ e m i z a t i o n while , ~ ~ ~ for the alkylthio-analogue (97; RS- in place of Ph

-C02H) the rate of O-migration to RS- is identical with the rate of r a c e m i z a t i ~ n .Extensive ~~~ studies of the racemization of lRO-labelled diary1 sulphoxides by Ac,O have been reported, showing that the rate of racemization is twice that of O-exchange, with rate-enhancement by added AcOH. Mechanistic (evidence for a Walden inversion in the ratedetermining step) and product analysis (use of 180-labelledAc,O for studies of the course of the Pummerer reaction) is fully discussed.280

Reactions of Sulphoxides.-The general features of the reactions of sulphoxides can be illustrated by reference to the simplest structural types, without regard for stereochemical details. A minority of the new work published within the period under review falls within this category when the well-defineduses of dimethyl sulphoxide as a reagent are considered separately (p. 50), but interpretation of the reactions of sulphinyl compounds with chirality at sulphur fully in view is the outstanding feature of recent work. Quantitative reduction of sulphoxides to sulphides is brought about using NaBH,-CoCl, for a number of representative compounds; tetramethylene sulphoxide is an exception, while dibenzyl sulphoxide gives only a low yield.281 Cleland‘s reagent, threo-2,3-dihydroxybutane-ly4-dithiol (dithiothreitol) reduces methionine sulphoxide quantitatively to the sulphide, and is-useful for preventing adventitious oxidation of methioninecontaining pep tides during column-chromat ographic purification. QB p,p’Ditolyl sulphoxide on treatment withp-tolyl-lithiumin ether gives mainly the corresponding sulphide, but also p,p’-ditolyl and m,p’-di tolyl ;283 4-methylbenzyne and (tol),S- OLi are involved. Iodide ion reduction of sulphoxides has been discussed in the preceding section, and independent kinetic studies (I-, aq. HCIOJ have been reported.284 The methylsulphinyl substituent is para-directing in the electrophilic bromination of Ph. SO. Me,285while the appearance of p-bromophenyl 278

2’9 280

2s1

283 284 285

T. Numata, K. Sakai, M. Kise, N. Kunieda, and S . Oae, Chem. and Ind., 1971, 576; Internat. J. Sulfur Chem., A, 1971, 1, 1. T. Numata and S . Oae, Internat. J. Surfur Chem., A , 1971, 1, 6. M. Kise and S. Oae, Bull. Chem. SOC.Japan, 1970, 43, 1421, 1416, 1426, 1804. D. W. Chaser, J . Org. Chem., 1971, 36, 613. K. P. Polzhofer and K. H. Ney, Tetrahedron, 1971, 27, 1997. K. K. Andersen, S . A. Yeager, and N. B. Peynircioglu, Tetrahedron Letters, 1970,2485. L. Cermakova and J. Hamplova, Analyt. Letters, 1971, 4, 631. C. Carpanelli, G. Gaiani, and G . Leandri, Gazzetta, 1970, 100, 618.

42


methyl sulphide in the reaction mixture is due to reduction by HBr. met?-Nitration of diphenyl sulphoxide involves mainly the conjugate acid Ph,S.OH, while the para-isomer is formed by nitration of the nonprotonated substrate.288 a-Halogenation of alkyl or aralkyl sulphoxides is observed with a number of standard halogenating agents, though the complexities associated with the direct interaction of Br, or Cl, and a sulphoxide have been emphasized (Me,SO + C1,-NEt, + Me-SO*CH,Cl; this gives Me-SO-CCl, with C1,-py; Me,SO Br, -+ Me,S+ Br- + MeS0,H + Me,S).287 a-Chlorosulphoxides are conveniently prepared by the use of SOzC1,-py,288~ 280 or N-chlorosuccinimide,200or iodobenzene dichloride and pyridine.201# A 90% yield of Me- SO- CH,Cl is obtained from dimethyl sulphoxide and N-chlorosuccinimide in CH,Cl, in the presence of K2C03,200and PhCHCl-SO-Me is obtained similarly using KOAc as base, but with pyridine some PhCH,* SO- CH,Cl is also formed, possibly indicating concurrent ionic and radical mechanisms.20oa-Chlorination with PhICl, involves a-chlorosulphoxonium salts,202and (+ )-methyl p-tolyl sulphoxide gives either (- )- or (+ )-a-chloromethyl p-tolyl sulphoxide in the presence or absence, respectively, of AgN03.201 Inversion of configuration at S therefore takes place in one of these reactions, probably the reaction in the presence of AgNO,, through the a-halogeno-sulphoxonium salt by migration of Cl to the a-position,201without bond breakage. a-Bromo-sulphoxides may be prepared by the use of N-bromosuccinimide together with Br,, in pyridine, or by use of Br, alone (but cJ: ref. 287).,03 In addition to broader uses in synthesis, a-halogeno-alkyl sulphoxides are of interest as substrates for studies of nucleophilic substitution at carbon. While chloromethyl methyl sulphoxide reacts via the SN2 route, as would be expected for a primary alkyl halide, the corresponding sulphide undergoes nucleophilic substitution by RO-, PhO-, PhS-, or MeS-, following the S N ~ path.,04 Bromomethyl p-tolyl sulphoxide similarly gives sN2 replacement products with RS- and RO-, but secondary amines attack preferentially at sulphur, giving t oluene-p-sulphenamides.205 1,2-Dichlorovinyl p-tolyl sulphoxide R *SO- CCl: CHCl gives the chloromethyl sulphoxide R*SO*CH,Cl, in 80% yield, on treatment with 5% NaOH;,08 the t-butyl analogue gives a lower yield but the reaction is shown to be general for sulphoxides and sulphones.

+

28e

287 288

289

290 291 292

293 294 296

2B6

N. C. Marziano, E. Maccarone, and R. C. Passerini, J . Chem. SOC.(B), 1971, 745. D. Martin, A. Berger, and R. Peschel, J. prakt. Chem., 1970, 312, 683. K. C. Tin and T. Durst, Tetrahedron Letters, 1970, 4643. G. Tsuchihashi, K. Ogura, S. Iriuchijima, and S. Tomisawa, Synthesis, 1971, 89. G. Tsuchihashi and K. Ogura, Bull. Chem. SOC.Japan, 1971, 44, 1726. M. Cinquini, S. Colonna, and F. Montanari, Chem. Comm., 1970, 1441. M. Cinquini, S. Colonna, and D. Landini, J.C.S. Perkin ZZ, 1972, 296. S. Iriuchijima and G. Tsuchihashi, Synthesis, 1970, 588. K. Ogura and G. Tsuchihashi, Chem. Comm., 1971, 1689. T. Numata and S. Oae, Internat. J. Sulfur Chem., A , 1971, 1, 215. M. S. Brown, J. Org. Chem., 1970, 35, 2831.


43

Phenyl methyl sulphoxide oxidizes triphenyl phosphite and (PhO),P(OMe) to corresponding phosphates in quantitative yields, illustrating the oxidant reactivity of a sulphoxide ; trimethyl phosphite, however, undergoes Michaelis-Arbuzov rearrangement under the same conditions, the novel function of the sulphoxide as a catalyst being rationalized in terms Ph*SO-R + of a+n alkylsulphoxonium salt intermediate [P(OR), PhRS-OR -OP(OR)2 +- Me,P(O)P(OMe), Ph- SO- R].2D7Sulphoxides are capable of initiating the oxidation of a substrate by a hydroperoxide, radical formation with the hydroperoxide accounting for the ‘pro-oxidant’ effect of the sulphoxide since thermal decomposition of an aliphatic sulphoxide, e.g. (MeO,C*CH,. CH2),S0, does not produce radicals capable of initiating oxidation.2D8A mixture of dimethyl sulphoxide and H,O, provides methyl radicals capable of substituting various heteroaromatic compounds ; typically,2DD2-nitrothiophen gives 3-methyl-2nitrothiophen, though a furan analogue undergoes a novel substitution of NO, by methyl in this + + Dimethyl sulphoxide gives the radical anion Me2S- 0.(or Me,S&O), capable of initiating acrylonitrile polymerization, on treatment with a one-electron oxidant (Mn3+).300Pulse radiolysis of dimethyl sulphoxide produces a reaction mixture showing absorption features at 925 nm (solvated electron), 625 nm (the dimethyl sulphoxide cation radical), and at 300 nm ( ~ n i d e n t i f i e d ) . Photolysis ~~~ of dimethyl sulphoxide (254 nm) in H 2 0 or in MeCN gives mixtures of CH,, MeS03H, Me& Me,SO,, MeS.SO,Me, and Me2Sz;302 in H 2 0 the stable primary products are CH, and MeS02H, while in MeCN they are CH4 and MeSOH. Me2S and Me2S02arise by photo-induced disproportionation of the substrate, and the acquisition of hydrogen represented by these products is at the expense of the /3-Keto-sulphoxides have valuable applications in synthesis, associated mainly with their active methylene group. The synthesis of simple representatives is straightforward, e.g. RCOgEt Na+ -CH2.SO- Me + R*CO-CH2.SO* 304 and a quite different new route has been reported, using alkylsulphinyl epoxides (98).3059306 New applications include a 1,2-diketone shown in Scheme 1, and a synthesis of acetylenic sulphides via vinyl sulphides RCH=CHSMe, the latter being obtained in two steps from the ~ - k e t o - s u l p h ~ x i d eThe . ~ ~ ~bromination-dehydro-

+

+

+

297

aes 2ee 300 302

*03 304

3os 307

S. Oae, A. Nakanishi, and S. Kozuka, Tetrahedron, 1972, 28, 549. C. Armstrong and G. Scott, J . Chem. SOC.(B), 1971, 1747. U. Rudqvist and K. Torssell, Acta Chem. Scand., 1971, 25, 2183. N. G. Devi and V. Mahadevan, Chem. Comm., 1970, 797. A. M. Koulkes-Pujo, L. Gilles, B. Lesigne and J. Sutton, Chem. Comm., 1971, 749. K. Gollnick and H. U. Stracke, Tetrahedron Letters, 1971, 203, 207. G. A. Russell and G . Hamprecht, J. Org. Chem., 1970, 35, 3007. Y . Otsuji, Y. Tsujii, A. Toshida, and E. Imoto, Bull. Chem. SOC.Japan, 1971,44, 219. D. F. Tavares, R. E. Estep, and M. Blezard, Tetrahedron Letters, 1970, 2373. T. Durst and K. C. Tin, Tetrahedron Letters, 1970, 2369. G. A. Russell and L. A. Ochrymowycz, J . Org. Chem., 1970, 35, 2106.

44


R1 M c o S O - c H - c /o, RIRZ

BF3*Et20

M c o S O - Y - C IH O

R2 (98)

bromination route for converting a vinyl sulphide into an acetylenic sulphide gives only ca. 13% yield, while the sequence vinyl sulphoxide (from the sulphide and NaIO,), jS-chlorovinyl sulphoxide (using SOCI,), acetylenic sulphide (dehydrochlorination using KOH-EtOH) is advocated as an improved laboratory method. Me R*CO.CH,*CH,

I

6 R-COCH.SO.Me

.I . I..I

R.CO-CH,.SO.Me

R COC=CH, I SMe I< = cycloalkyl Reagents: i, base; ii, MeI; iii, H+; iv, SOCI,; v, Zn-H+; vi, Zn-H+-EtOH. Scheme 1 RCO-CHOEt

The synthesis of ketones from /l-keto-sulphoxidesshows the comparability of these compounds with /l-dicarbonyl Other synthetic uses include the formation of a-chloro-oximes RC(Cl)=NOH on nitrosation Naf

BuiCH,.CO.CH.SO-Me+ CH,=CH.CO.Me

aQ. THF%

Bui-C0.(CH,)3.CO*Me

with NaN0,-aq. HCl, and diketone mono-oximes R1.CO- C(R2)=NOH from R1*CO-CHR2.SO. Me (R2 = H or alkyl, respectively);304acidcatalysed rearrangement and a synthesis of the naphthalene (99),309 starting from a hydrocinnamate ester, have been reported. Electrolytic reductive cleavage of p-methoxy-2-(methylsulphinyl)acetophenone gives Ar.CO.(CH,),-CO.Ar at pH 12 in aq. DMF, as a result of C-S cleavage followed by attack of the carbon fragment on solvent; in other words, the central methylene group in the product originates in DMF.310 Acetophenone, 1,Zdibenzoylethane, and MeS. S0,Me are formed by irradiation of Ph*CO CH2 SO Me in benzene, via jS-cleavage

-

308

0. M. Vig, K. L. Matta, J. M. Sehgal, and S. D. Sharma, J . Indian Chem. SOC.,1970, 47, 894.

30s 310

Y. Oikawa and 0. Yonemitsu, Chem. Comm., 1971, 555. B. Samuelsson and B. L a m , J.C.S. Perkin I, 1972, 652.


45

J. Mc OEt

MeoaSM M e O m O E t

Me0 \

+

MeO\

+

M c O m O H

McO

'--.

(99)

or cleavage into Ph-CO-Me and sulphine, CH,=SO, as a result of y-H abstraction by the photo-excited carbonyl Stereochemical Features of Reactions of Sulphoxides.-The pyramidal configuration of sulphinyl compounds, seen at its simplest in a sulphoxide R1* SO- R2(e.g. Scheme 2), determines the existence of enantiomeric forms. While the resolution and absolute configurational assignment aspects pose only routine problems, and while the stereochemical features are conceptually the same as those for the tetrahedral carbon atom, there are various properties of compounds containing a chiral sulphur centre which cannot be related to the organic chemist's basic grounding in carbon stereochemistry. The most obvious of these properties specific to sulphur as a chiral centre relate to racemization mechanisms (covered in a preceding section), concurrent activation of an adjacent carbon centre to asymmetric carbanion reactivity, and the stabilization of the asymmetric carbanion. The conversion of the sulphur pyramid in a sulphinyl compound into a sulphur tetrahedron by dative bonding of the lone pair, preserving chirality, also has no parallel in carbon chemistry. Considerable advances in sulphur stereochemistry are represented in the recent literature, particularly in the influence of the sulphinyl centre on the stereochemistry of reactions conducted at the a-carbon atom in alkyl sulphoxides. The confused position and contradictory interpretations of data of the late 1960's on the latter point bring to mind the indictment (Joyce) : 'Thus the unfacts, did we possess them, are too imprecisely few to warrant our certitudes.' The opportunities which exist for performing simple, yet still novel, transformations at a sulphinyl centre are illustrated in the conversion of 311

S. Majeti, Tetrahedron Letters, 1971, 2523.

46


optically active sulphoxides into optically active sulphonium salts by , ~ ~ ~treatment alkylation, e.g. with triethyloxonium t e t r a f l u o r ~ b o r a t e then with an alkyl-cadmium. There is some racemization, and the independent study 313 of the decomposition of dimethyl sulphoxide with a catalytic amount of triethyloxonium tetrafluoroborate (giving S , Me,SO,, MeSOMe, Me,O, and Me,SO,) provides a warning that side-reactions might be expected in general. The sulphoxide formed252in good yield by the pyrolysis of an N-phthalimido-sulphoximideis recovered with its original chirality 314 [ 95% optical purity when the sulphoximide (100) is treated with NaOEt

=-

The formation of the sulphoximide (100) involves a nucleophilic substitution at sulphinyl sulphur, which may be considered to proceed either with retention of configuration or with inversion; if inversion, then the breakdown of (100) must also involve inversion since the sulphoxide is recovered with its original chirality; if retention, then similarly the breakdown of (100) must involve retention of configuration. On balance,314 the double-retention mechanism is preferred. These results, and their interpretation, are matched by a number of independent studies of the stereochemistry of reactions at a sulphinyl centre. An earlier report establishing the retention of configuration during the conversion of methionine sulphoxide into a sulphimide (Vol. 1, p. 76) is not considered definitive since anchimeric assistance from substituents at the carbon asymmetric centre may have been involved, and no distinction between retention and double inversion was made. This work was therefore followed up with structurally simpler compounds, viz. methyl p-tolyl sulphoxide and methyl n-butyl sulphoxide, again indicating retention of configuration on conversion into the sulphimide by treatment in benzene solution with NN’-bis(to1uene-psulphony1)sulphur di-imide, but inversion in the case of the butyl compound when pyridine was used as The retention mechanism may involve a four-centre transition state, or an intermediate (101) analogous to that of the Wittig Studies of this type may be broadened to establish stereochemical cycles, with the challenge of getting back to the starting point in some way 31a

313

314 316 316

K. Andersen, Chem. Comm., 1971, 1051, M. Kobayashi, H. Minato, and K. Shimada, Internat. J. Sulfur Chem., A , 1971, 1, 105. S. Colonna and C. J. M. Stirling, Chem. Comm., 1971, 1591. B. W. Christensen and A. Kjaer, Chem. Comm., 1969, 934. B. W. Christensen, Chern. Comm.,1971, 597.

Aliphatic Organo-sulphur Compoirnds etc. :. I

47

I

R1;S--N-Ts R2 (101)

other than retracing one's steps; this has been met successfuIly,317~ 318 at the same time establishing a number of new organosulphur reactions. Scheme 2 illustrates the stereochemical changes which accompany interconversions

TsNMe \

TEPl

MeN

\

HCHO

C

\\

To1. - - s=o /

Me

of sulphoxides, sulphimides, and sulphoximides, while closely related studies of sulphinamides (p. 79) should be compared with those in Scheme 2 by readers seeking the overall current position. Noteworthy points illustrated in Scheme 2 include the novel alkylation of a sulphoximide with formalin and formic acid,s1s the reaction of the N-methyl compound, obtained in this way, with toluene-p-sulphonyl chloride and pyridine, des. Overall, providing a route to N-t oluene-p-sulphonyl-N-alkylsulphinami the Scheme is an example of a stereochemical reaction cycle in which only one ligand (the tolyl group) is common to all members of the cycle.318 s17

D. J. Cram, J. Day, D. R. Rayner, D. M. Von Schriltz, D. J. Duchamp, and D. C. Garwood, J. Amer. Chem. SOC.,1970,92, 7369. T. R. Williams, R. E. Booms, and D. J. Cram, J . Amer. Chem. SOC.,1971,93,7338.


48

New terminology 319 is helpful in such cases, and the members of the cycle, the ‘chiromers’, participate in a monoligostatic stereochemical cycle if a single ligand at a chiral tetrahedron is common to all c h i r o m e r ~ . ~ ~ * determines The chirality at sulphur in 3a-t-butylsulphinyl-5a-cholestanes the proportions of olefins formed on pyrolysis,320while n-butyl isomers with (R)-or (S)-chirality at sulphur give the identical product mixture. It would seem that the steric requirements of n-butyl are too small to influence the disposition of groupings that are involved in the transition state leading to elimination products. In addition to cholestenes, the 3a-t-butyl sulphoxides give sulphur-containing steroids, including the disulphide (102).

(yq

-Ios”. H

/-u

‘C H

CMe,

H

+ Me,C=CH2

+R.SO.SR

I

Reactions of a-lithio-sulphoxides have been studied, in an attempt to exploit the synthetic possibilities based upon different exchange rates of the a-methylene protons in an alkyl sulphoxide R1CH2.SO-R2and the effects of solvent upon the exchange rates.2so ( S ) - (+)-Benzyl methyl sulphoxide (103) gives the (S,S)-a-lithio-derivative (104) with MeLi-THF at - 60 “C;quenching with D 2 0 and oxidation to the sulphone (105) with m-chloroperbenzoic acid gives laevorotatory material, while (R)-(+ )phenylethyl methyl sulphone (106) is obtained by successive methylation (MeI) and With benzyl t-butyl sulphoxide (103 ; But in place of Me), the (R,S)-a-lithio-derivative is formed, which gives the (S)-( - )phenylethyl t-butyl sulphone by successive methylation and oxidation.32’ The possibilities of using this process in asymmetric syntheses are certain 319

320

321

D. C. Garwood and D. J. Cram, J. Amer. Chem. SOC.,1970, 92,4575. D. N. Jones, E. E. Helmy, and A. C. F. Edmonds, J. Chem. SOC.(C), 1970, 833. T. Durst, R. Viau, and M. R. McClory, J. Amer. Chem. Soc., 1971, 93, 3077.


49

to be studied further; since H-D exchange via the a-lithio-derivative is known 321 to proceed with retention, then the methylation step must However, the opposite conclusion concerning the involve i n v e r s i ~ ns22 .~~ ~~ stereochemistry of these steps has been reached.323The (+)-sulphone (106) was synthesized from (S)-( - )-a-phenylethyl chloride by treatment with MeS- Na+, followed by oxidation. The laevorotatory enantiomer of (106) 260p

(S)-(103)

(S,S)-(104)

*.:

p0

P h S, \ /

c,

Mc

H ?Me,

HO

(106)

(S)-(105)

Ph S0,Mc

--+

\ /

c, H CMc,!

Hd

U was obtained 323 on successive lithiation (1 equiv. BunLi at - 70 "C,in dry THF, under N,), treatment with MeI, storage during 1 h at - 70 "C, and oxidation (H,O,-hot AcOH), showing that methylation occurred with retention of onf figuration.^^^ Methylation of (S,S)-a-deuteriosulphoxide (104; D in place of Li) resulted in replacement of a-H rather than a-D, supporting the retention mechanism for m e t h y l a t i ~ n . ~ ~ ~ The reaction of (104) with acetone gives (107), from which the (R)sulphone (108) is obtained on oxidation, indicating that the steric course of hydroxyalkylation through this procedure is the same as that of deuteriation, but opposite to that of m e t h y l a t i ~ n .Cyclohexanone ~~~ gives (log), in the 322 323

T. Durst, R. Viau, R. Van den Elzen, and C. H. Nguyen, Chem. Comm., 1971, 1334. K.Nishihata and M. Nishio. Chem. Comm., 1971, 958.

50


same way, from which the chiral epoxide (110) may be prepared, establishing a novel stereospecific Assignment of configuration to diastereoisomeric sulphoxides of type (107) through interpretation of n.m.r. solvent effects (see Vol. 1, p. 74) has been shown to be This required model compounds of carefully established absolute configuration; reaction of (S)-(- )-menthy1 p-tolylsulphinate and ( & )-a-phenylethylmagnesium chloride involves inversion of configuration at sulphur, giving (S)-a-phenylethyl p-tolyl (R)-sulphoxide and its (R,R)-isomer. These were separated by crystallization, the (S,R)-diastereoisomer being recognized by oxidation to the sulphone and comparison with authentic (S)-a-phenylethyl p-tolyl sulphone. Configurational assignments to these diastereoisomers were incorrect when based upon n.m.r. solvent shifts, and since these were interpreted on the basis of preferred conformations predicted on the usual arguments, it must be concluded that the most important conformations of these compounds are not those in which eclipsing of bulky groups is avoided.324 Asymmetric syntheses with chiral ap-unsaturated sulphoxides have been reported, (R)-( - )-cis-propenyl p-tolyl sulphoxide giving a mixture of diastereoisomers with piperidine ; the mixture gives the laevorotatory sulphide (pip)CHMe CH2S(p-tol) on reduction, consistent with asymmetric induction of (S)-configuration at carbon with 74% optical yield.325Addition of bromine to (S)-(+)-p-tolyl vinyl sulphoxide occurs with induction of (S)-configuration at carbon.326

-

Dimethyl Sulphoxide as a Reagent.-Dimethyl sulphoxide revealed itself as a useful reagent partly through participation in reactions for which it was intended to act as a passive polar solvent. It functions as an oxidant, a methylthiolating agent, a methylthiomethylating agent, and a methylsulphinylmethylating agent, and recent work is divided approximately into these categories in this Chapter. Dimethyl sulphoxide has interesting physiological properties, and a recent two-volume treatise 327 is devoted mainly to this aspect; a report of a violent explosion which occurred when one drop of 70% HClO, solution was added to 10 ml of dimethyl sulphoxide at room temperature should be Methylthiolation of 2-bromoanisole, giving (11l), is brought about with dimethyl sulphoxide and NaH at 60-65 0C.32B4-Bromoanisole gives a mixture of the corresponding 3- and 4-methylthio-isomers. Monohalogenonaphthalenes on treatment with dimethyl sulphoxide, ButOK, and ButOH at 140 "C give naphthols, t-butyl ethers, and l-methylthio-2324

3z6

327

s28

329

M. Nishio and K. Nishihata, Chem. Comm., 1970, 1485. D. J. Abbott, S. Colonna, and C. J. M. Stirling, Chem. Comm., 1971, 471. D. J. Abbott and C. J. M. Stirling, Chem. Cornm., 1971, 472. 'Dimethyl Sulfoxide', ed. S. W. Jacob, E. Rosenbaum, and D. C. Wood, Marcel Dekker, New York, 1970. S. Uemura, Y. Ikeda, 0. Itoh, and K. Ichikawa, Bull. Chem. SOC.Japan, 1971, 44, 2571. A. J. Birch, K. B. Chamberlain, and S. S. Oloyede, Austral. J. Chem., 1971, 24, 2179.

51


naphthol.330 These reactions exemplify the intervention of aryne interm e d i a t e ~ ,330 ~ ~1,2-dehydronaphthalene ~, acting as precursor to the isomeric 1- and 2-methylthio-naphthols which are obtained as major products when ButOK is added to a solution of a halogenonaphthalene in dimethyl s~lphoxide.~~~ OMe

(111)

OH

(1 12)

(1 13)

The Fe3+-H,O,-dimethyl sulphoxide system is a source of methyl radicals, but in addition to mono-, di-, and tri-methylated benzoquinones, (1 12), (1 13), and isomers of (1 13) are formed from b e n ~ o q u i n o n e . ~ ~ ~ Methylthiomethylation of phenols is brought about in the simplest cases by boiling in dimethyl sulphoxide solution; substitution ortho to the phenolic hydroxy-group is generally and in the case of vanillin as substrate 333 (see Vol. 1, p. 81) the other products detected were Me,S, Me,&, and (MeS),CH,. Studies of the reaction using dimethyl sulphoxide pyridine-NEt3-S03,334 or using dimethyl sulphoxide-dicyclohexylcarbodiimide in the presence of acids and bases,336show that a variety of products is obtained, including 0- and p-methylthiomethyl-substituted phenols, 0-methylthiomethyl phenols, a1kylated dienones, and 5,6-benzo-1 ,3oxathians, all of which are derived from the aryloxysulphonium cation formed between the phenol and dimethyl s ~ l p h o x i d e . ~ Phthalimide ~~ refluxed with dimethyl sulphoxide gives a 43% yield of N-(methylthiomethy1)phthalimide and a similar yield of N-hydro~ymethylphthalimide.~~~ N-Methylthiomethyl-saccharin was prepared in the same way, but tetrachlorophthalimide gives the N-methyl compound and imide cleavage The sodium salt of the methylsulphinyl carbanion, Me*SO- CH,- Na+, has simple uses in synthesis, such as converting alcohols into alkoxides, for the synthesis of ethers by alkylation with an alkyl halide,337or for synthesis of xanthates by successive treatment with CS, and an alkyl halide.338 The method is useful for reactions with tertiary alcohols. 330 331

332 333 33* 336 336

337 338

R. H. Hales, J. S. Bradshaw, and D. R. Pratt, J . Org. Chem., 1971, 36, 314; J. S. Bradshaw and R. H. Hales, J . Org. Chem., 1971, 36,318. K.Torssell, Angew. Chem. Infernat. Edn., 1972, 11, 241. P. Claus, N. Vavra, and P. Schilling, Monatsh., 1971, 102, 1072. J. Doucet and A. Robert, Compt. rend., 1971, 272, C, 1562. P. Claus, Monatsh., 1971, 102, 913. J. P. Marino, K. E. Pfitzner, and R. A. Olofson, Tetrahedron, 1971, 27, 4181. C.-T. Chen and C.-H. Wang, Bull. Inst. Chem., Acud. Sinica, 1970, 30 (through Chem. Abs., 1971,75, 20 166). B. Sjoberg and K. Sjoberg, Acta Chem. Scand., 1972, 26,275. P. Meurling, K. Sjoberg, and B. Sjoberg, Acfa Chem. Scand., 1972, 26, 279.

52


p-Chlorobenzotrifluoride provides an example of nucleophilic aromatic substitution with Me*SO- CH2-,330 and o-aminobenzophenone gives 3-phenylindole through nucleophilic addition to the carbonyl group followed by c y c l i ~ a t i o n . ~Methylation ~~ of 2-methylstilbene with Me*SO-CH,- can be controlled to produce either 01- or a'-methyl homologue, while the more hindered 2,6-dimethylstilbene produces the @)-form of the a-methyl homologue (114).341 The course of the ,Me

methylation reaction is best represented as a nucIeophilic addition of Me. SO. CH,- followed by a prototropic shift, then elimination of methyl~ulphinate.~~~ Carbanions derived from dimethyl sulphoxide and dimethyl sulphone give p-thioamido-sulphoxides and mlphones, respectively, with isothiocyan ate^.^^^ With isocyanates, Me-SO*CH,- gives mixtures of /I-amidosulphoxides and methylsulphinylmalonamides, while Me SO,. CH2- gives methylsulphonylmalonamides.342Reaction with dimethyl sulphoxide and NaH converts the N-(toluene-psulphony1)sulphoximide (1 15) into the methylenation reagent (1 16).343Its propensity for acting as a nucleophilic 0

II

Ph.SO,.Me -+ Ph-S=N-Ts

1

Me

0 II ---+Ph-S=N-Ts I CH2- Na'

(115)

33g 340

s41

s42

343

J, A. Meschino and J. N. PIampin, J. Org. Chem., 1971, 36, 3636. P. Bravo, G. Gaudiano, and P. P. Ponti, Chem. and Ind., 1971, 253. B. G. James and G. Pattenden, Chem. Comm., 1971, 1015, M. Von Strandtmann, S Klutchko, D. Connor, and J. Shavel, J . Org. Chem., 1971, 36, 1742. C. R. Johnson and G. F. Katekar, J . Amer. Chem. Suc., 1970,92, 5753.

AlQhatic Organo-sulphur Compounds etc.

53

methylene transfer reagent, shown in its reaction with ketones to give epoxides reg. (1 17)], derives from the formation of the highly stabilized anion Ph. SO-FTs after reaction.343 While dimethyloxosulphonium methylide, Me,SO*CH2-, acts as a powerful methylenation reagent, converting 9-methylenefluorene into (118) by methylenation of a C=C bond (in 100% yield) and fluorenone azine into (118) in 70% yield, by methylenation of a C=N bond and subsequent steps, the methylsulphinyl carbanion does not react.344

Conversion of the N-methylamide of linoleic acid into a mixture of conjugated 9,ll- and 10,12-N-methyloctadecadienarnides(&,trans- after short reaction, trans,trans- after prolonged treatment),346and reduction of &unsaturated ketones and lactones to their radical anions ( k e t y l ~ ) , ~ ~ ~ are brought about by an alkali-metal methylsulphinylmethylide. Use of dimethyl sulphoxide as an oxidizing agent for alcohols, and limitations due to side-reactions, are illustrated in the formation of a /l-keto-sulphide from a /l-hydroxy-sulphi de (methyl 4,6-O-benzylidene-2S-phenyl-2-thio-a - ~ - atropyranoside) l with inversion of configuration at C(2); when dimethyl sulphoxide-acetic anhydride is used as the isomeric 3-phenylthio-2-hydroxy-compoundgives the enol acetate -C(SPh)=C(OAc)in 40% yield, together with the 2-methylthiomethyl ether, under the same conditions, but gives the 2-keto-compound when a dimethyl sulphoxide-dicyclohexylcarbodi-imide(DCCI)-pyridinium trifluoroacetate mixture is used as Methyl thiomethyl ether formation is observed in attempted DMSO-Ac,O oxidation of a hexosylpurine, protected at all sites except the 2’-OH This appears to be the first case of ether formation in the nucleoside series. The alternative reaction paths leading to ketone or ether, starting from a secondary alcohol, are shown in Scheme 3. Efficient oxidation of N4-acetyl-2’,5’- or -3’,5’-bis(trity1ated) cytidines to 2’- or 3’-oxocytidines using DMSODCCI or D M S O - A C , ~ ,the ~ ~ ~oxidation of cyclo-oct-S-en-trans-1,2-diol 344 345 346 3p7

348 348

B. C. Elmes, Tetrahedron Letters, 1971, 4139. S. Glily-Terry and J. Klein, J . Chem. SOC.( C ) , 1971, 3821. G. A. Russell and R. L. Blankespoor, Tetrahedron Letters, 1971, 4573. S. Hanessian and A. P. A. Staub, Chem. and Ind., 1970, 1436. K. Antonakis and F. Leclercq, BUN. SOC.chim. France, 1971, 4309. U.Brodbeck and J. G. Moffatt, J . Org. Chem., 1970, 35, 3552.

54

Organic Compounds of Sulphur, Selenium, and Tellurium Me,SO

R CHOH

R,CH-0-CH,SMe

Me,SOAc

++

A CH,=S-Me

R,CHOH

+

+ R,CH-0-SMe,

R,C=O

Scheme 3

to the 1,Zdione with DMSO-AC~O,~~O and the oxidation of (119) to a tetrahydrofuran while the trans-isomer gives the expected keto-aldehyde (using DMSO-DCCI, the Pfitzner-Moffatt reagent) 351 provide further examples.

Various alternative systems for oxidizing steroidal alcohols have been reported, where diphenylketen-p-tolylimine, NN-diethylaminopropl-yne, or NN-dimethylaminophenylacetyleneare added to mixtures of DMSO and Dimethyl sulphoxide acts as a nucleophile, rather than an oxidant, in the conversion of epoxides into glycols, in the presence of BF, 353 or trinitrobenzenesulphonic but the conversion of cyclohexane 1,4dioxide into pyrocatechol with DMSO-BF3,Et20 implies Lead tetra-acetate in DMSO oxidizes N-amino-pyridones and -phenanthridones to nitrenes, which can be trapped as sulphoximides R2N* N=S(0)Me2.35s Diphenylacetylene gives benzil, Ph. C O . COOPh, on treatment with N-bromosuccinimide (more than 2 equiv.) in anhydrous DMSO, while stilbene gives the dibromo-adduct under the same cond i t i o n ~ ; ~further ~' studies may show this to be a very useful method for preparing 1,2-diketones from acetylenes. DMSO with proton acids or BF3 oxidizes thiocarbonyl compounds to carbonyl analogues; Me$ and sulphur are the other products, and are 360

ssl s6a

860

357

P. Yates and E. G. Lewars, Chem. Cumm., 1971, 1537. E. G. Brain, F. Cassidy, M. F. Constantine, J. C. Hanson, and D. J. D. Tidy, J. Chem. SOC.(0,1971, 3846. R. E. Harmon, C. V. Zenarosa, and S. K. Gupta, J. Org. Chem., 1970, 35, 1936. D. N. Kirk and F. J. Rowell, J. Chem. SOC.(C), 1970, 1498. M. A. Khuddus and D. Swern, Tetrahedron Letters, 1971, 411. B. McKague, Canad. J. Chem., 1971,49, 2447. C. W. Rees and M. Yelland, J.C.S. Perkin I, 1972, 77. S. Wolfe, W. R. Pilgrim, T. F. Garrard, and P. Chamberlain, Canad. J . Chem., 1971, 49, 1099.


55

suggested to arise from the decomposition of a thiosulphoxide Me,S=S, e ~ )not yet been sought in support. though evidence (e.g. 3 5 S - ~ t ~ d ihas Further studies (see Vol. 1, pp. 81, 82) of the ring-opening of l-carbethoxy2-methyl-3-phenylaziridinewith DMSO show that the cis-isomer is cleaved at 1,2- and 1,3-bonds in 1 : 1 ratio, while the trans-isomer reacts almost exclusively at the 1 , 3 - b 0 n d ; ~under ~ ~ acid conditions, 1,3-bdnd cleavage predominates for both isomers. A DMSO-NaHCO, mixture oxidizes primary or secondary alkyl toluene-p-sulphonates to aldehydes, i.e. RCH,OTs + DMSO + RCH,OiMe, HC03- -+ RCHO H20 C 0 2 + Me2S,360though exceptionally it gives the cyclic carbonate (120), indicating that bicarbonate anion is a better nucleophile than DMSO.

+

+

+

New evidence concerning the mechanism of DMSO-DCCI oxidation of alcohols has been obtained using (CD,),SO ; the dicyclohexylurea formed in the reaction carries one D showing that the previously adopted mechanism should be modified; abstraction of a proton from the intermediate oxysulphonium ion is now depicted as in (121).

/

L

H/

6

'CHR2

Oxidation of nitrogen-containing organic compounds with dimethyl sulphoxide is being explored, providing a second generation of oxidative conversions for this reagent. Benzylamine salts PhCHRNH,+ X- give carbonyl compounds and/or olefins in Me,SO at 160-180 "C during 20 h.362 Alkyl phenyl ketones formed in this way react in situ with formaldehyde (originating from DMSO or X) and with NH4CI similarly 368 36B

360

381

M. Mikolajczyk and J. Luczak, Chem. and Znd., 1972, 76. S. Fujita, T. Hiyama, and H. Nozaki, Tetrahedron, 1970, 26, 4347. N. Bosworth and P. D. Magnus, J.C.S. Chem. Comm., 1972, 257. J. G. Moffatt, J. Org. Chem., 1971, 36, 1909. V. J. Traynelis and R. H. Ode, J . Org. Chem., 1970, 35, 2207.


56

formed during the oxidation. Methylthiomethyl esters are formed, with N-acylureas, when carboxylic or hydroxamic acids are treated with DMSO-DCCI in the presence of a proton source.3s3 N-Methoxy-pnitrobenzamide gives the N-( 1,3-dicyclohexyl-1-ureidomethyl) derivative and a small amount of methylthiomethyl N-methoxy-p-nitrobenzimidate, while primafy amides give nitriles and N-acylsulphilimines ; replacement of DCCI by P205or Ac20reduces the amount of N-acyl~ulphilimine.~~~ Nitroanilines give N-aryl-SS-dimethylsulphilimines,and 2,4-dinitrophenylhydrazines gives a variety of products from an initially formed mixture of aryldiazonium salt and aryl di-imide, when treated with DMSO-DCCI.3s4 DMSO-P205converts acylhydrazides into diacylhydrazines, and sulphonylhydrazides into thiolsulphonates, presumably via cleavage into the ~ u l p h i n a t e .Benzil ~ ~ ~ bis(hydrazone) gives diphenylacetylene when treated with this reagent.364 Sulphonamides give SS-dimethyl-N-sulphonylsulphilimines with DMSO-DCCI ; N-alkylsulphonamides cannot give such products, but give N-alkyl-N-(dicyclohexyl-1-ureidomethy1)sulphonamides;366ortho-methylthiomethylationwas noticed in some cases in these Reactions of oximes with DMSO-DCCI and a proton source, either H,PO, 367 or trifluoroacetic have been studied as a logical extension of studies with alcohols. The first-formed ylide (122) from benzophenone oxime gives benzanilide or N-(dipheny1methylene)methylthiomethylamine N-oxide (123) and the oxime methylthiomethyl ether (124), the latter accumulating in the reaction mixture with prolonged reaction 368 Aliphatic ketoximes give more complex and the Beckmann rearrangement illustrated by the formation of benzanilide has been shown to be more general, in reactions with steroid 1 7 - k e t o ~ i m e s . ~ ~ ~ 3669

Ar2C=N-O-S,

. -

CH,-

+

+H +

+,Me

~

+ Ar,C=N-0-SMe,

I

-H+

-1

Ar. CO-NHPh

Ar,C=N-CH,SMe I

Ar,C=N- 0 -CH,SMe (124) 363 364

3e5

366 38’ 368

J. G. Moffatt and U. Lerch, J . Org. Chem., 1971, 36,3391. J. G . Moffatt and U. Lerch, J . Org. Chem., 1971, 36, 3861. J. G. Moffatt and U. Lerch, J . Org. Chem., 1971, 36, 3686. D.A. Kerr and D. A. Wilson, J. Chem. SOC.(C), 1970, 1718. I. W. Jones, D. A. Kerr, and D. A. Wilson, J . Chem. SOC.( C ) , 1971, 2591. A. H. Fenselau, E. H. Hamamura, and J. G. Moffatt, J. Org. Chem., 1970, 35, 3546.

57


The methylthiomethyl ether (124) is formed thermally from the nitrone (123), together with Ph,CO, Ph,C=NOH, (MeS),, (MeS),CH,, and (Ph2C=N0)2CH2.367 a-Chloro-oximes could react with DMSO either through analogous nucleophilic attack of the oxime oxygen on sulphinyl sulphur (125) or through nucleophilic displacement of Cl by sulphinyl

n

Ar-C=N-0-H

Id

Ar.CO.NO

+

-

ArC0,H

Me$

(126) oxygen (126). In fact, both paths are probably represented, since p-nitrobenzaldehyde a-chloro-oxime gives 80% p-nitrobenzoic acid, Me,S, p-nitrobenzonitrile ($9, and N'" oxides36ewhen heated in DMSO at 150 "C. 6 Sulphones

Preparation.-Sulphones are readily available from sulphides and sulphoxides through oxidation; e.g. KMn04 converts O-acetyl-l-alkylthio-ldeoxy-alditols into the 1-alkylsulphonyl analogues,37oand related monothioacetals are sources of s ~ l p h o n e s . A ~ ~reaction ~ mixture in which di-imide is generated by oxidation of hydrazine with HzOzor ferricyanide is capable of oxidizing sulphides to sulphones while reducing olefinic 266 However, hydrazine with a milder oxidizing agent double (NalO,) produced di-imide, but this system did not affect s ~ l p h i d e s . ~ ~ ~ Sulphides formed by the addition of EtSH or PhSH to a series of chloronorbornadienes are converted into sulphones by oxidation, with no skeletal or stereochemical change in most cases; conversion of (128) into the 2-exo-sulphone, and of (127) into the epimeric mixture of 7-syn- and 7-anti-sulphone~,~~~ were exceptions. A further instance (see Vol. 1, p. 78) of an explosion during work-up of the products from oxidation of a sulphide to a sulphone with HP02-acetone has been reported.480 370 371 372

M. E. C. Biffin and D. B. Paul, Tetrahedron Letters, 1971, 3849. H. Zinner, R. Kleeschaetzky, and M. Schlutt, Carbohydrate Res., 1971, 19, 71. J. M. Hoffmann and R. H. Schlessinger, Chem. Comm., 1971, 1245. D. I. Davies and P. J. Rowley, J . Chcm. SOC.( C ) , 1971, 446.

58

Organic Compounds of'Sulphur, Selenium, and Tellurium C1 H

c1 H

Cl

c1 61 (127)

Alkenes and alkynes are starting points in a number of sulphone syntheses; addition of SO, to olefins in the presence of formic acid-tertiary amine adducts gives sulphones in a novel one-step ~ynthesis.~'SThe method seems to be limited to monosubstituted olefins in which the substituent is electron-withdrawing; disulphides are formed too, sometimes in major amounts, probably from thiols formed by disproportionation of the sulphinic acid, which itself is formed from sulphoxylic acid H2SOz as reagent. The essential feature of the method is the involvement of formate as a reducing agent, creating reactive sulphur species. Addition reactions of arenesulphonyl chlorides to olefins in the presence of CuCl, have been 376 the intermediate p-chloro-sulphone giving the trans-vinyl sulphone on treatment with Et3N (ArCHCl. CHRS0,Ar' gives transArCH=+CRSO,Ar'). Similar addition reactions of HOCH,SO,- Na+, H,N(H,N=)CSO,-, S(SO,Na)O,Na, and (H,N),C(SO,K), have been trans-Addition of arylsulphonyl iodides to alkynes has been reported, the /3-iodo-alkenyl sulphones being useful synthons for enyne sulphones, for example.377 Copper-catalysed addition of PhS0,Cl to phenylacetylene is a stereoselective free-radical process, giving cis-adducts preferentially in solvents of low polarity (e.g. CS,).378 Alternative general methods are illustrated by the ZnC1,-catalysed reaction of ROCH,Cl with ethylene sulphone, giving ROCH,SO,CH, CHaC1,37Q by diary1 sulphone synthesis from treatment of an aromatic compound with an amino-sulphonic acid in the presence of trifluoroacetic anhydride,380or by the pyrolysis of hydrazonium ylides ArSO,*N*&Me,R (giving ArS02R).381 A simplified route to dihalogenomethyl sulphones, involving reaction of a sulphinate with the appropriate haloform in aq. KOH,382has been studied: RSOZ- + CHX3 RSO2CHXz + X___+

373 374 375

376

377 378

378

380

381 382

H. W. Gibson and D. A. McKenzie, J . Org. Chem., 1970, 35, 2994. W. E. Truce and C. T. Goralski, J . Org. Chem., 1970, 35, 4220. W. E. Truce and C. T. Goralski, J . Org. Chem., 1971, 36,2536. R. Kerber and J. Starnick, Chem. Ber., 1971, 104, 2035. W. E. Truce and G. C. Wolf, J. Org. Chem., 1971, 36, 1727. Y.Amiel, J. Org. Chem., 1971, 36, 3691, 3697. E. Vilsmaier and B. Hloch, Synthesis, 1971, 428. E. E. Gilbert, Synthesis, 1971, 372. J. E. Baldwin and J. E. Brown, J. Org. Chem., 1971, 36, 3642. W. Middlebos, J. Strating, and B. Zwanenburg, Tetrahedron Letters, 1971, 351.


59

For R = But and X = Br, the monobromomethyl sulphone is the major product, while for R = PhCH2 and X = C1 the major product is PhCH= CHS03H, resulting from Ramberg-Backlund rearrangement of the dichloromethyl ~ u l p h o n e . ~ * ~ Properties of Su1phones.-The pronounced electron-withdrawing power of the sulphonyl group is most easily demonstrated by the acidity of the a-methylene protons ; bis(methanesulphonyl)methane, for which the finer details of proton donation to solvent have been has pK, 12.54 in water at 25 "C. Sulphones PhSO,CHMeBut, ButSO,CH Me(n-C,H,,), and PhS02CHMePh are included in a broad study of racemization rates and H-D exchange rates, in continuing attempts to relate properties of a-sulphonyl carbanions to Electric moment measurements indicate conformations (129) for bis(methanesulphonyl)methane, and (130) for the But analogue, in which eclipsing of a sulphonyl oxygen atom with a bridge hydrogen occurs.386

Transannular interaction between the 4-substituent and the intermediate betaine formed between 4-phenylsulphonylcyclohexanone and diazomethane in methanolic KOH is inferred from the greater relative proportion of epoxides accompanying ring-enlarged ketones in the reaction mixture; the 4-phenylthio-analogue forms epoxides in only small Reactions of Su1phones.-The first report of pyrolytic elimination of arylsulphinic acid from an aryl alkyl sulphone3*' has appeared, for 2-pentyl compounds; these give pent-1-ene in constant proportion with cis- and trans-pent-2-ene, with exceptions for mesityl and p-nitrophenyl 2-pentyl sulphones. Base-catalysed elimination reactions leading to vinyl sulphones are well known, amine-promoted elimination from PhS02CH2 CHF-SPh following a syn-stereospecific course through an El cb mechanism involving i o n - p a i r ~ .A ~ ~mild ~ decarbomethoxylative elimination is the last step in a synthesis of ( ? )-versimide (131).38B 383

386

386

J. Hine, J. C. Philips, and J. I. Maxwell, J . Org. Chem., 1970, 35, 3943. L. A. Paquette, J. P. Freeman, and M. J. Wyvratt, J. Amer. Chem. SOC.,1971,93, 3216. C. Pigenet, G. Jeminet, and H. Lumbroso, Compt. rend., 1971, 272, C, 2023. H. Favre, D. Gravel, Z . Hamlet, M. Menard, and J. Temler, Canad. J. Chem., 1971,49, 3097.

387 388 388

A. K. Colter and R. E. Miller, J . Org. Chem., 1971, 36, 1898. V. Fiandanese, G. Marchese, and F. Naso, J.C.S. Chem. Comm., 1972, 250. P. R. Atkins and I. T. Kay, Chem. Comm., 1971, 430.

60


Synthetic uses of a-sulphonyl carbanions remain a major preoccupation. While NaBH, reduction of /3-keto-sulphones gives threo-/3-hydroxysulphones in good yields, mixtures of erythro- and threo-isomers result from condensation of a-sulphonyl carbanions with aldehydes ; configurational assignments rest upon n.m.r. data.390 Substitution of OH by C1, using SOCI,, proceeds with epimerization for threo-isomers, but with retention with erythro-is~rners.~~~ Corresponding stereochemical features have been considered in the bromination of ( f )- and meso-bis-(a-methylbenzyl) sulphone by N-bromosuccinimide;3g1 both erythro- and threoisomers were obtained, the erythro-configuration (132) being assigned through X-ray crystal analysis. The Ramberg-Backlund rearrangement of (132) gives cis-aa-dimethylstilbene (133) with NaOMe in MeOH, through

inversion at both asymmetric centres, while Na2S03 or Ph3P reduction gives back the meso-isomer of the starting material, i.e. with retention of configurati~n.~~~ Alkylation of /3-keto-sulphones in the presence of base gives a-substitution products, typical of active-methylene PhSO2CH2acts as a methylating agent towards anthracene or diphenylacetylene, and converts 1,l-diphenylethylene into the corresponding c y c l ~ p r o p a n e . ~ ~ ~ Like the methylsulphinyl c a ~ b a n i o nit, ~converts ~~ o-aminobenzophenone into 3-phenylind0le.~~~ Cyclopropane formation is also observed with vinyldimethylsulphonium salts as substrates for sulphonyl and bis(alky1sulphonyl) car bani on^.^^* A novel reaction involving a sulphonyl carbanion R1CHSOzR2and CS, with MeI, giving R2SO2C(R1)=C(SMe),,is the basis for a-methylation, since NaBH, reduction causes reductive cleavage into R2S02CHMeR1.3e5 3s0 3s1 8s2

393 3s4

396

W. 8. Truce and T. C. Klingler, J. Org. Chem., 1970,35, 1834. F. G. Bordwell, E. Doomes, and P. W. R. Corfield,J. Amer. Chem. SOC.,1970,92,2581. B. Samuelsson and B. Lamm, Acta Chem. Scand., 1971,25, 1555. Y. Yamamoto, T. Nisimura, and H. Nozaki, Bull. Chem. SOC.Japan, 1971, 44, 541. G. Becker and J. Gosselck, Tetrahedron Letrers, 1971, 4081. M. L. Gorbaty, W. E. Truce, and J. E. Tracy, J . Org. Chem., 1971,36, 237.


61

a-Lithiation of ClCH2S02R1with BunLi, followed by treatment with a chloromethyl-amine, gives R2,NCH2.CHCISO,R1, readily converted into the a-chlorovinyl sulphone H2C= CClS02R1.3@6 In fact, gern-dilithio-derivatives, e.g. PhS02C(Li)2Ph, may be formed using BunLi, and these can be di-alkylated or d i - a ~ y l a t e d . ~ This ~ ~ indicates the high degree of d,-p, resonance stabilization in such sulphonyl bis-carbanions, the canonical forms ArC-SO,R t)ArC=S&R * ArCeS6,R illustrating the delocalization of charge.3v7 Attempted di-ionization of (PhSO,),CH, gave only mono-lithio a result that is ascribed merely to the low solubility of the mono-anion, though it is possible that the considerable space requirement of the sulphonyl group is partly respynsible. Sulpho+nyl-stabilizedphosphonium ylides RSO,EH. PPhs are prepared from Ph,P* CH,- and a sulphonyl fluoride, or from bromomethyl sulphones with Ph,P, followed by treatment with base.,@*They are useful in synthesis, e.g. of sulphonyl cyanides. Aryl a-diazo-sulphones similarly show interesting reactions, giving arylsulphonylmethyl arenesulphonates by reaction with an arenesulphonic acid,,@@ and arylsulphonylmethyl nitrates general-base-catalysed hydrolysis of the nitrates involves an with HNO, intermediate a-keto-sulphone, with products HNO,, HC02H, and arenesulphinic acid.400a-Diazo-sulphones give a-t-butyloxy-a-chloro-sulphones with B U ~ O C ~and , ~ ~the ' formation of an a-alkoxy-a-chloro-sulphonecan be brought about with SO,Cl, and an ether.402 Differences in halogenation patterns between EtaSO2and EtS02Bunare found when S02C1, is used, Et,SO, giving 18-, p/3'-, and a-chloro-derivatives in 69.2, 25.1, and 5.7% yields respectively, while no attack at Et occurs with the Bun analogue, which suffers p-, y-, and S - s u b s t i t ~ t i o n .Sub~~~ stitution of an arylthio-group at the p-position is observed on treatment of a /3-amino-alkyl alkyl sulphone hydrochloride or methiodide with thiophenols, through an elimination-addition mechanism.404 Continuation of studies aimed at preparing sulphenes by pyrolysis of sulphonyl derivatives has involved the ally1 vinyl sulphone (134), which on heating at 170 "C in the liquid phase, or at 800 "C in the gas phase, gives products derived from the sulphene, itself arising through a 'sulpho-Cope' [3,3]sigmatropic rearrangement.405 3e8

8e7

3e*

H. Bohme and W. Stammberger, Annalen, 1971,754, 56. E. M. Kaiser, L. E. Solter, R. A. Schwarz, R. D. Beard, and C. R. Hauser, J. Amer. Chem. SOC.,1971, 93,4237. A. M. Van Leusen, B. A. Reith, A. J. W. Iedema, and J. Strating, Rec. Trav. chim., 1972, 91, 37.

3ee 400 401

A. Bruggink, B. Zwanenburg, and J. B. F. N. Engberts, Tetrahedron, 1970, 26, 4995. A. Bruggink, B. Zwanenburg, and J. B. F. N. Engberts, Tetrahedron, 1971, 27, 4571. B. Zwanenburg, W. Middelbos, G. J. K. Hemke, and J. Strating, Rec. Trav. chim., 1971, 90, 429.

'02 403

404 40G

W. Middlebos, B. Zwanenburg, and J. Strating, Rec. Trav. chim., 1971, 90, 435. I. Tabushi, Y. Tamaru, and Z. Yoshida, Tetrahedron Letters, 1971, 3893. A. S. Angeloni, P. De Maria, A. Fini, and G. Salvadori, Tetrahedron, 1970, 26, 5601. J. F. King and D . R. K. Harding, Chem. Comrn., 1971, 959.

62


R=HorD

Sulphone cleavage is involved in a number of otherwise unrelated observations; 2-(hydroxyamino)aryl phenyl sulphones or bis-(Zhydroxyamino)aryl sulphones disproportionate into arylsulphinate and 2-hydroxy2’-(arylsulphonyl)azoxybenzene (135) in aq. NaOH at 20 0C,406while

SOzPh

R2

NHOH

-OH

___+

&;?\ + PhSOII

R2

NvR2

PhSO,

\

R1

(135j

phenylazo p-tolyl sulphone gives products of free-radical decomposition, e.g. biphenyl on photolysis in benzene.407 Selective reduction of aryl

methyl sulphones at a Hg cathode in DMF solution gives arylsulphinic acids, though there are complications when the aryl moiety carries halogen s ~ b s t i t u e n t s .Electrolysis ~~~ of 8-keto-sulphones gives mono-ketones as major products, via R *CO. kHz and R -COOCH2-, but also y-diketones through dimerization of the initially formed radicals.409 The methanesulphonyl substituent in 5-methanesulphonyl-isothiazoles and 3,5-bis(methanesulphonyl) analogues suffers nucleophilic displacement by OH-, RO-, and NH2-.410 Addition Reactions of Unsaturated Sulphones.-Mechanistic and synthetic aspects of the addition reactions undergone by ap-unsaturated sulphones reflect interaction of the sulphone grouping with incoming addenda, through some unusual stereochemical results, and the powerful activating effect of the sulphone grouping, in the ease with which addition reactions may be brought about. Addition of ethyleneimine to non-terminal acetylenic sulphones RIC= CSOzR2or sulphoxides gives mixtures of cisand trans-vinyl sulphones, while allenic analogues give trans-adducts under Io6 Io7

M. F. Grundon, D. J. Maitland, and W. L. Matier, J. Chem. SOC.(C), 1971, 654. M. Kobayashi, H. Minato, M. Kojima, and N. Kamigata, Bull. Chem. SOC.Japan, 1971,44,2501.

Oo8

Oo9 010

J. Simonet and G. Jeminet, Bull. SOC. chim. France, 1971, 2754. B. L a m and B. Samuelsson, Chem. Comm., 1970, 1010. M. Davis and J. A. Gordon, J.C.S. Perkin I, 1972, 638.

63


kinetic control and ethynyl sulphones HC==C.S02Ar give cis-adducts (CH&N*CH=CH- S02Ar.411 Nucleophilic addition of ArSH to aryl vinyl sulphones in 50% EtOH at 25 "C shows kinetic features indicating a carbanionic transition state, discounting to some extent 412 the concerted mechanism proposed earlier ;413 ethynyl ethyl sulphone gives cis- 1-(ethylsulphonyl)-2-alkylthioethylenes exclusively,414 with alkanethiols under mild conditions, and vinyl ally1 sulphones add alkanethiols only at the vinyl group under conditions promoting nucleophilic addition."16 Thebaine acts as diene component in Diels-Alder reactions with methyl vinyl sulphone or divinyl ~ u l p h o n e .1~:~1~Adducts are formed in both cases. The analgesic properties of some elaboration products of these adducts, e.g. (136), equal the potency of codeine.416Cyclopentadiene adds Me0

\

Jr---

H 0. @\NMe .--

.

Me0

H 'S0,R

(136)

a-bromovinyl methyl sulphone, giving 5-bromo-S-methanesulphonylbicycl0[2,2,l]hept-Zenes [(137) and configurational for which a high-yield Ramberg-Backlund rearrangement [giving (138)] and a product of homolytic C-Br bond cleavage (139) have been de~cribed.~"

\

NaOMe-.DMSO

Br ( 1 38)

(139)

$l4

W.E. Truce and L. D. Markley, J. Org. Chem., 1970, 35, 3275. P. De Maria and A. Fini, J. Chem. SOC.(B), 1971, 2335. S. T. McDowell and C. J. M. Stirling, J . Chem. SOC.(B), 1967, 343. E. N. Prilezhaeva, V. I. Laba, V. I. Shegotskii, and R. I. Shekhtman, Izvest. Akad.

416

E. N. Prilezhaeva and E. S. Shapiro, Izvest. Akad. Nauk S.S.S.R.,Ser. khim., 1970,

r17

K. W. Bentley, J. W. Lewis, and A. C. B. Smith, J.C.S. Perkin I, 1972, 870. J. C.Philips and M. Oku, J. Amer. Chem. SOC.,1972, 94, 1012.

411 4la

413

Nauk S.S.S.R., Ser. khim., 1970, 1602. 1608.


64

Reactions at a py-alkynyl function in an acetylenic sulphone (140) give products indicating the influence of the sulphonyl group, e.g. the formation of the vinyl sulphone (141),418 which gives p-keto-sulphones through cleavage of the oxetan ring at different points on acid hydrolysis.

PhSO,CH,.C=C.Me (140)

+

I

U

Acylation of ethyl carbamate with MeS02CH2* C0,H gives MeS0,CH2 COONHCO,Et, used for the synthesis of 5-methanesulphonyluridine by ethoxymethylenation followed by condensation with 2,3,5-tri-O-benzoyl ribofurano~ylamine.~~~ Smiles Rearrangement.-Rearrangement of mesityl 1-naphthyl sulphone to 2-( l’-naphthylmethyl)-4,6-dimethylbenzenesulphinicacid (BuLi in ether) or to the 2’-naphthylmethyl isomer (with ButOK in DMSO) exemplifies the Smiles reaction.420 In contrast with the naphthyl compound, mesityl p-tolyl sulphone and its o- and m-isomers give normal Smiles products regardless of variations in reaction conditions.420 Kinetics of the Smiles rearrangement of o-methyl diary1 sulphones to the corresponding o-benzylarenesulphinic acids with BuLi reveal that the rearrangement is first-order in sulphone, with increased rates with meta- and especially orthosubstituents in the migrating aryl moiety.421 Ramberg-Backlund Rearrangement.-a-Halogeno-sulphones give olefins on treatment with base, with loss of Hhal and extrusion of SO,; this valuable carbon-carbon bond formation technique has been illustrated earlier in 417 and conversion of R1CH,S02CHBr*CO- R2 into this RICH= CH- CO R2, and a-bromo-a-carbethoxy sulphones into apunsaturated esters, are simpler examples.422Conversion of p-disulphones into ap-unsaturated sulphones through this general route is a novel Chlorination of di-(2-picolyl)sulphone, prepared from 2-chloromethylpyridine via the sulphide, and treatment with base gives 1,2-di-(2-pyridyl)ethylene, py- CH= CH-PY.~,~Anomalous behaviour of the a-chlorocyclopropyl sulphone (142) with ButOK is 382s

418

M. Yoshimoto, N . Ishida, and Y. Kishida, Chem. andPharm. Bull. (Japan), 1971, 19, 1409.

419

4ao 421

422 433

424

J. M. Carpenter and G. Shaw, J . Chem. SOC.(C), 1970,2016. W. E. Truce and W. W. Brand, J . Org. Chem., 1970,35, 1828. V. N. Drozd and 0. I. Trifanova, Zhur. org. Khim., 1971,7, 1926,2388; V. N. Drozd and K. A. Pak, ibid., 1970,6,818; V. N. Drozd, L. A. Nikonova, and M. A. Tseleva, ibid., p. 825. I. Shahak and E. D. Bergmann, Israel J. Chem., 1970, 8, 589. H. J. J.-B. Martel and M. Rasmussen, Tetrahedron Letters, 1971, 3843. L. A. Paquette and R. W. Houser, J. Org. Chem., 1971, 36, 1015

A l i phat ic 0rgano-sulph ur Compounds etc.

65 OBut

7 Sulphenic Acids and their Derivatives Sulphenic Acids and Sulphenate Esters.-Sulphenic acids have been implicated in mild thermally induced isomerization reactions of sulphoxides. One aspect of the revitalized penicillin chemistry features the equilibrium between a penicillin 8-sulphoxide, e.g. from penicillin V methyl and the corresponding sulphenic acid, revealed by the incorporation of one D atom in the /%methyl group in D,O as reaction medium.425 With ButOD at 80 "Cduring 3 h,426the sulphoxide with (R)-chirality at sulphur epirnerizes at sulphur with 60% incorporation of D into the 2P-methyl group, while the (S)-isomer has greater configurational stability and does not show D incorporation under these conditions.426 Sulphenic acids produced thermally from penicillin sulphoxides can be trapped by olefins, (143) being formed with norbornadiene in the presence of NEt3,427giving ring-opened penicillin derivatives which can be stripped down further [e.g. removal of the isopentenoyl residue via 1,3-dipolar addition of diazomethane followed by Zn--AcOH gives (144)].428

I

P h CH2- CO (or norbornenyl cpimer)

Allylic sulphenic acids are transient intermediates in the rearrangement of episulphoxides carrying a suitably located H atom;429trans-but-2-ene episulphoxide gives diallyl thiolsulphinate via HaC= CH CHMeSOH, the product (145) existing in equilibrium with the butenyl thiosulphoxylate (146).

428

R. D. G . Cooper, J . Amer. Chem. Soc., 1970, 92, 5010. D. H. R. Barton, F. Corner, D. G. T. Greig, G. Lucente, P. G . Sammes, and W. G. E. Underwood, Chem. Comm., 1970, 1059. D. H. R. Barton, D. G. T. Greig, G . Lucente, P. G . Sammes, M. V. Taylor, C. M. Cooper, G . Hewitt, and W. G. E. Underwood, Chem. Comm., 1970, 1683. D. H. R. Barton, D. G. T. Greig, P. G. Sammes, and M. V. Taylor, Chem. Comm.,

428

J. E. Baldwin, G . Hofle, and S. C. Choi, J. Amer. Chem. SOC., 1971, 93, 2810.

42s 426

427

1971, 845.

4

66


bs-,

-

Sulphenate esters, prepared through an improved method involving N-t-butylthio-phthalimide (148;R1 = But) and alkoxides, give quantitative yields of the corresponding ethers in toluene, at 35 "C (48 h, in the dark), with tri-n-butylphosphine, providing yet another example of efficient sulphur-abstraction by tervalent phosphorus A new ortho-Claisen rearrangement 431 involves an allenic sulphenate (147).

ZH2R I

CHZR I

I

CCI, reflux

' CI

61

-*= 61

Mechanistic studies with sulphenates have included chlorinolysis of 2H-labelled cycloalkyl 2,4-dinitrobenzenesulphenates in AcO+H, giving cycloalkyl chlorides from intimate sulphoxonium ion pairs ROSClAr C1and acetates from solvent-separated ion pairs.432Base-catalysed hydrolysis of 2-nitrobenzenesulphenateesters gives the sulphenate anion, recognized by an absorption maximum at 588 the concentration of this species passes through two maxima during the course of the reaction before decreasing to zero, and it is suggested 433 that sulphenate is involved in an unexpected way in the middle stage of the reaction (ArSO- + ArSOH --+ ArSOSAr + -OH). Isomerization of 3-hydroxy-l-methylpropyl-2-nitrobenzenesulphenate with NaH-dioxan gives the 3-hydroxybutyl analogue, providing an example of a trans-sulphenylation reaction which is best interpreted in terms of an intermolecular substitution at sulphenyl sulphur rather than the apparently attractive intramolecular process.434 Aryl triphenylmethyl sulphenates react with amines in 45% aqueous dioxan, showing a large influence of amine basicity on rate, a feature that is

432

434

D. H. R. Barton, G. Page, and D. A. Widdowson, Chem. Comm., 1970, 1466. K. C. Majumdar and B. S. Thyagarajan, J.C.S. Chem. Comm., 1972, 83. J. G. Traynham and A. W. Foster, J. Amer. Chem. SOC.,1971,93, 6216. D. R. Hogg and P. W. Vipond, J . Chem. SOC.(B), 1970, 1242. D. R. Hogg and P. W. Vipond, J . Chem. SOC.(C), 1971,2142.

Aliphatic Organo-sulphur Compounds etc. 67 interpreted in terms of some degree of bond formation in the transition Su1phenamides.-A variety of bivalent sulphur compounds act as sulphenylating reagents towards amines, giving sulphenamides, and most routes to these compounds are of this type. The copper(1)-catalysed reaction of azides with alkanethiols gives sulphenamides, in addition to the corresponding primary amine and disulphide ;43e arenethiols give only amine and disulphide, the sulphenamide being entirely converted into these products. The best route to sulphenamides uses a sulphenyl chloride with an amine or ~ l m i d e ; ~ it ~is' exemplified in the formation of C6F,SNH, in 55% yield at 0 "C, with concomitant formation of (C6F5S)2NH(2179, which can further react to give (C6FbS)BN.438 Methanesulphenyl chloride gives low yields of sulphenamides when it reacts with amines, gem-diamines [CH,(NR),],MeSSMe, and MeS3Me being isolated as probably arising from the elimination product of MeSCl, viz. thioformaldehyde CH,=S. A mechanistic study of the reaction between p-nitrobenzenesulphenyl chloride and aniline using stopped-flow spectrophotometry indicates a two-stage Transamination reactions of sulphenamides provide convenient access to particular derivatives; a useful source of sulphenyl compounds is 430 whose use is advocated 4 4 1 ~ 402 for a thiophthalimide (148),441s 4428

a:)-S-F 0Z 1

,R2 R3 + 0 f ) l0- I

+ HN,

+ R'-S-N,

, R2 R3

the general preparation of sulphenamides. Simple examples of transamination have been reported (e.g. MeSNMe, + Prn,NH -+MeSNPP, + Me,NH) 443 and examined mechanistically as examples of nucleophilic substitution at bivalent sulphur (2,ddichloroaniline and X.C6H4.SNHPh).444 Substantial substituent effects are observed for the latter system and also a correlation with enhanced U-values for the X = p-NOz case, with negative p, incompatible with a truly synchronous 5"2 mechanism. 4389

436

436 430

488 440

441 44a

~4

E. Ciuffarin, L. Senatore, and M. Isola, J . Chem. SOC. (B), 1971, 2187. T. Saegusa, Y . Ito, and T. Shimizu, J. Org. Chem., 1970, 35, 2979. N. E. Heimer and L. Field, J . Org. Chem., 1970, 35, 3012. P. Sartori and A. Golloch, Chem. Ber., 1971, 104, 967. D. A. Armitage and M. J. Clark, J. Chem. SOC.( C ) , 1971, 2840. E. Ciuffarin and F. Griselli, J. Amer. Chem. Soc., 1970, 92, 6015. K. S. Boustany, Chimia (Switz.), 1970, 24, 396. D. N. Harpp and T. G. Back, Tetrahedron Letters, 1971, 4953. D. A. Armitage, M. J. Clark, and A. M. White, J . Chem. SOC.( C ) , 1971, 3141. F. A. Davis, S. Divald, and A. H. Confer, Chem. Comm., 1971, 294.

68


Alternative sulphenylation routes involve disulphides, which give sulphenamides with amines in MeOH as solvent, in the presence of AgN03;446disulphide bond cleavage is facilitated by the assistance of Ag+, a powerful electrophile capable of assisting disulphide cleavage reactions both in this specific example and more generally. O-Methyl benzenesulphenate has been advocated as a reagent for preparing sulphenamides using primary or secondary amines, or NN'-di(alkylamino)si1anes.44s N-Alkylaminosilanes give mixtures of N-alkyl- and N-alkyl-N-trimethylsilyl-sulphenamides, while disilazanes give N-silylsulphenamides. Structural features of the sulphenamide grouping have been studied intensively by n.m.r. spectroscopy, c.d., and X-ray crystallographic analysis. Chemical shift non-equivalence is observed at low temperatures, through n.m.r. studies of N-isopropyl-N-arenesulphonylarenesulphena m i d e ~ . ~The ~ ' implied dissymmetry of the sulphenamide grouping is identified as a chirality axis along the S-N bond, rather than a centre of chirality (i.e. the N atom). X-Ray diffraction shows the substituents to be nearly coplanar with the nitrogen atom.448 N-(l-a-Naphthylethyl)-N-(benzenesulphonyl) trichloromethanesulphenamide(149) contains

I

CCI, ( 149)

CCI, Newman projection of (149): (R)-configuration of the sulphenamide helix

an appreciably shorter bond between sulphonyl sulphur and nitrogen than between the sulphenamide sulphur and This is consistent with p,,-d,, bonding, not normally considered significant for bivalent sulphur compounds, but which is facilitated in (149) by electron-withdrawal by the trichloromethyl group. Interactions between the nitrogen lone pairs and the sulphonyl oxygen atoms do not seem to determine the torsion angle in the sulphonamide bond, though the conformation of a-sulphonyl carbanions has been assumed, until recently, to be determined by such a factor. Substituents in the arene groupings influence the torsion barrier about the sulphenamide S-N bond, with para-substituents showing a greater effect than meta-substituents; conjugation with the aromatic rr-system is therefore important. Electron-withdrawing substituents in both arene groups M. D. Bentley, I. B. Douglass, J. A. Lacadie, D. C. Weaver, F. A. Davis, and S. J. Eitelman, Chem. Comm., 1971, 1625. 446 D. A. Annitage, M. J. Clark, and A. C. Kinsey, J . Chem. SOC.( C ) , 1971, 3867. 447 M. Raban and F. B. Jones, J . Amer. Chem. SOC.,1971,93, 2692. u8 J. Kay, M. D. Glick, and M. Raban, J. Amer. Chem. SOC.,1971, 93, 5224. 446

Aliphatic Orguno-sulphur Compounds etc, 69 reduce the torsion barrier. The c.d. of (149)in MeCN shows a number of Cotton effectsin the 195-255 nm wavelength range; the chirality at carbon favours the (Qconfiguration of the sulphenamide helix, and the intense Cotton effect at 226 nm is assigned to the sulphenamidc c h r ~ m o p h o r e . ~ ~ ~ Reactions of sulphenamides include applications in synthesis, e,g. of primary amines from alkyl halides or toluene-p-sulphonates, reminiscent of the Gabriel synthesis: (PhS),NH + (PhS),NLi RBr -+ (PhS),NR + RNH, on treatment with PhSH or 3N-HC1;460and a novel amide synthesis, in which a sulphenamide reacts with a Cu" salt of a carboxylic acid in the presence of Ph3P (RlC0,- + R2SNHRS3 R1*CO-NHR3).4s1 A closely similar procedure 462 employs the carboxylic acid itself, a sulphenamide, and P(OEt)3. o-Nitrobenzenesulphenanilidesgive Q- and p-aminophenyl-o-nitrophenyl sulphides, phenothiazines, and 2-aminobenzenesulphonanilides as a result of an unusual thermal rearrangement which is specific for ~rtho-nitro-compounds.~~~ Reactions of sulphenamides with N-acylpyridinium b e t a i n e ~ and , ~ ~ an ~ interesting dimerization with rearrangement (1 50) + (15 1),466 have been reported.

+

c NEt,

benzene

ArSo~NHSCC13

' A r SO,r-(>u

p SO,A I-

Sulphenyl Halides.-Illustrative procedures for the synthesis of sulphenyl halides reported during the period under review employ well-established methods, Tetrachloropyridine-4-sulphenylchloride is obtained from the corresponding disulphide by c h l o r i n o l y s i ~ , while ~ ~ ~ the corresponding sulphonyl chloride is formed in AcOH or hydroxylic media. 2-Methyl-2propanesulphenyl iodide is obtained from the thiol with I,, or from the sulphenamide with HI ;4s7 addition reactions of selenium dichloride, or seleninyl chloride, to acetylene are specific examples of generally applicable reactions 4s9 (HC=CH SeCI, ClCH=CH* Se- Cl).488 The chlorination of CS,under activated charcoal catalysis 460 has been developed as a continuous process, giving trichloromethanesulphenyl chloride. 468p

448 45O

45l 462 463

+

M. Raban and S. K. Lauderback, J. Amer. Chem. SOC.,1971,93, 2781. T. Mukaiyama and T. Taguchi, Tetrahedron Letters, 1970, 341 1. M. Ueki, H. Maruyama, and T. Mukaiyama, Bull. Chem. SOC.Japan, 1971,44, 1108. Y. V. Mitin and G. P. Vlasov, Zhur. obshchei Khim., 1971, 41, 427. F. A. Davis, R. B. Wetzel, T. J. Devon, and J. F. Stackhouse, J . Org. Chem., 1971, 36, 799.

T. Mukaiyama and K. Saigo, Bull. Chem. SOC.Japan, 1971,44, 3077. 455 M. M. Kremlev, A. D. Biba, N. A. Kirsanova, G. I. Derkach, E. V. Bryukhova, and G. K. Semin, Ukrain. khim. Zhur., 1971, 37, 1026. 456 E. Ager, B. Iddon, and H. Suschitzky, J. Chem. SOC. (0,1970, 1530. 457 L. Field, J. L. Vanhorne, and L. W. Cunningham, J. Org. Chem., 1970, 35, 3267. 466 C. D. Hurd and 0. Fancher, Internat. J. Sulfur Chern., A , 1971, 1, 18. I D gN. Schindler, Synthesis, 1971, 656. 460 H. Maegerlein, G. Meyer, and H. D. Rupp, Synthesis, 1971, 478. 464

70 Organic Compounds of Sulphur, Selenium, and Tellurium Electrophilic cleavage of sulphides is rarely employed as a route to sulphenyl halides, though penicillin esters give corresponding sulphenyl chlorides by cleavage of the S-C(5) bond, without affecting the azetidinone ring, on treatment with one equivalent of C1, or S2C12,461 in CC14 at room temperature. N-Phthaloyl 6-aminopenicillanic acid methyl ester gives 80% (152) and 20% of its C(5)-epimer through this reaction; reconstitution of the penicillin nucleus is brought about by treating (152) with stannous chloride dihydrate in hot d i ~ x a n . ~ ~ , 0

(152)

Organoselenium trichlorides and corresponding tellurium compounds are more stable than their sulphur analogues, though with tetramethylthiourea (tmtu), MeSeC1, gives SeCl, that is complexed with tmtu, and thereby stabilized.463 Sulphenyl halides, like sulphenate e ~ t e r s , ~444 ~~~ are susceptible to nucleophilic attack at sulphur, and kinetic studies encompassing the effects of substituents and the basicities of entering and leaving groups at sulphur indicate a synchronous S N displacement ~ at S,464(but see ref. 444) with d-orbital participation, in the butylaminolysis of tritylsulphenyl chloride 486 or in the reactions of para-substituted anilines with para-substituted phenylsulphenyl indicated by solvent-dependence of reaction rates and the large effect of nucleophile basicity. The characteristic reaction behaviour of sulphenyl halides is exemplified in a wide range of alkyl- or aryl-thiolation processes. 2,3-Dimethylindole gives (153) with 2,4-dinitrophenylsulphenyl and wphenylthiolation of ketones (PhSCl + R1*CO CHR2R3-+ R1CO. CR2R3SPh)468 4369

I H (153) Kukolja, J. Amer. Chem. SOC.,1971, 93, 6267. rea S. Kukolja, J. Amer. Chem. SOC.,1971, 93, 6269. 463 K. J. Wynne and P. S. Pearson, Chem. Comm., 1971, 293. 464 L. Senatore, E. CiuEarin, and A. Fava, J . Amer. Chem. SOC.,1970, 92, 3035. 466 E. Ciuffarin and G. Guaraldi, J . Org. Chem., 1970, 35, 2006. lB6 E. Ciuffarin and L. Senatore, J. Chem. SOC.(B), 1970, 1680. 487 0. Hutzinger and R. K. Raj, Terrahedron Letters, 1970, 1703. 468 P. Held, M. Gross, and A. Jumar, Z . Chem., 1970, 10, 187. u1 S.

71 and comparable 5-alkylthiolation of pyrimidines 48B are representative of related substitution processes. Reactions in which methanesulphenyl chloride acts as an electrophile 5 i include the formation of 2-octyl or 2-butyl chloride with predominant inversion of configuration when optically active octan-2-01 or butan-2-01, or their xanthate or methanesulphinate esters, are treated with MeSCl.P70 MeSCI, reacts in the same way as MeSCl with these compounds, but shows a greater degree of inversion, while Cl, gives the same products with considerable r a ~ e m i z a t i o n . ~ ~ ~ A simple sulphinate ester Me- SO*OMe is attacked predominantly at alkoxide 0 by MeSCl, but sulphinate esters with more bulky groups are attacked predominantly at S.470 Addition reactions of sulphenyl halides to olefins provide /%halogenosulphides in their normal course. 7,7-Dimethylnorbornene adds PhSCI, and steric control by the 7,7-dimethyl grouping directs the formation of the endo-2-(phenylthio)-exo-3-chloro-adduct,471not em-2-phenylthio-isomer as earlier claimed. A useful incidental chemical feature of this work471 is the use of Ph,SnH to replace the 3-chloro-substituent by H; in the addition of an arylsulphenyl chloride to a-methylthio-styrenes, dehydrochlorination occurs readily, and a-methylthio-/I-arylthio-styrenesare The addition of 2,4-dinitrobenzenesulphenyl chloride to alkenes in AcOH is less selective that that of Br, or Clz, attributable to steric effects and to the greater participation by sulphur as a neighbouring group, reducing the control exerted by electron-releasing groups in the a1kene.473The /I-chloro-alkyl sulphides formed between 4-chlorobenzenesulphenyl chloride and olefins have been shown474to react with excess oct-1-ene in sym-tetrachloroethylene solution in an ‘exchange’ process. An episulphonium ion is Aliphatic Organa-sulphur Compounds etc.

Sulphenyl Protecting Groups.-N-Protection of amino-acids for use in peptide synthesis is satisfactorily accomplished by N-(0-nitrophenylsulphenyl)ation, normally using the sulphenyl chloride to introduce the group ; o-nitrophenylsulphenyl thiocyanate is more stable than the and gives N-(o-nitrophenylsulpheny1)-amino-acidsin good yield in the presence of AgNO,. o-Nitrophenylsulphenyl p-nitrophenolate converts L-phenylalanine into its N-(o-nitrophenylsulphenyl)p-nitrophenyl ester in moderate yield, a two-in-one procedure which may be welcomed by peptide chemists.476Deprotection of N-(o-nitrophenylsulpheny1)-peptides normally involves treatment with hydrochloric acid, though the use of -SCN for the purpose has been 4eo 470 471

472 47s 474 476

476

E. A. Gray, R. M. Hulley, and B. K. Snell, J. Chem. SOC.( C ) , 1970, 986. I. B. Douglass, R. V. Norton, P. M. Cocanour, D. A. Koop, and M. L. Kee, J . Org. Chem., 1970,35, 2131. H. C. Brown and K.-T. Liu, J . Amer. Chem. SOC.,1970, 92, 3502. M. Oki and K. Kobayashi, Bull. Chem. SOC.Japan, 1970, 43, 1234. G. M. Beverly and D. R. Hogg, J. Chem. SOC.(B), 1971, 175. G. H. Schmid and P. H. Fitzgerald, J. Amer. Chem. SOC.,1971, 93, 2547. J. Savrda and D. H. Veyrat, J. Chem. SOC.(C), 1970, 2180. E. Wunsch and R. Spangenberg, Chem. Ber., 1972,105, 740.


72

Protection of carbohydrate hydroxyl functions by 0-(2,4-dinitrobenzenesulpheny1)ation has been studied;477the group is introduced in better than 70% yield for (154; R = H), and the 5,6-isopropylidene grouping of (154;

R = 2,4-dinitrobenzenesulphenyl) can be selectively removed by acid hydrolysis ; the sulphenate is cleaved by Al-HgOAc-MeOH reduction or by hydrogenation over Raney 8 Thiocyanates and Isothiocyanates Preparation of Thiocyanates.-As in other sections of this Chapter, wellestablished preparative procedures have not been superseded, nor even tilted at, by new methods. Potassium thiocyanate gives (155) with 1,4-diphenyl-l-chloro-2,3-diazabuta-l,3-dienein high yield;478treatment PhCHO, while thermal rearrangement with acid in EtOH gives (156) gives (157).

+

(157)

Thiocyanogen has been used for thiocyanation of porphyrin (as its copper complex),47Qand for the conversion of 2-bromothiophen into 5-bromo-2-thiocyanatothiophen 480 in the presence of AlCl,, a procedure which results in conversion of 2-(methy1thio)thiophen into 3,5-di(thiocyanato)-2-(methylthio)thiophen.480 Continuation of studies of the 477

478

K. Takiura, S. Honda, and T. Endo, Carbohydrate Res., 1972, 21, 301. W. T. Flowers, D. R. Taylor, A. E. Tipping, and C. N. Wright, J . Chem. SOC.( C ) , 1971, 3097.

478 480

P. S. Clezy and C. J. R. Fookes, Chem. Comm., 1971, 1268. F. M. Stoyanovich, G. I. Gonishkina, and Y.L. Goldfarb, Zzvest. Akad. Nauk S.S.S.R., Ser. khim., 1970, 1151.


73

homolytic addition of thiocyanogen to olefins, giving mixtures of thiocyanates and isothiocyanates, and their stereoisomers, is reported.481 Cyanogen bromide has been used for conversion of 4-thiouridine (16) into uridine, in phosphate buffer, at pH 8.5 and 100 "C, during 3 min, via the disulphide (resulting from Br + oxidation) and 4-thio~yanatouridine.~~~ In a synthesis of thiocyanates from disulphides by cyanolysis (RSSR -CN -+ RSCN RS-), only half the available sulphur is bound up as thiocyanate in the product; the use of cyanogen bromide for converting the thiolate RS- into RSCN in the reaction mixture offers a simple alternative 483 to converting the thiolate into disulphide for further cyanolysis, and has been exemplified with the synthesis of 2-nitro-5-thiocyanatobenzoic Attack by cyanide at sulphur in 3-chloro-1,2-benzoisothiazoleis implied by the production of o-cyanophenyl thiocyanate and of bis-(o-cyanophenyl) disulphide;484other nucleophiles (BunLi, PhS-) also attack at sulphur, but EtO- causes replacement of C1 without cleaving the isothiazole ring. Aryl thiocyanates are formed in high yields through pyrolysis of N-aryl-dithiocarbamates. 4R6

+

+

Preparation of 1sothiocyanates.-A conventional synthetic method is illustrated in the preparation of N-(isothiocyanato-acy1)-amino-acids, c.g. S: C:N*(CH,); CO-NHCHR-C02H, starting from the peptide trimethylsilyl ester; treatment with CS, and an alkyl chloroformate480 gives an alkoxycarbonyl dithiocarbamate which readily cyclo-eliminates COS and alkanol. Acylation of an amino-acid trimethylsilyl ester with SCN. (CH,),. CO*Cl provides an alternative route; cyclization of an a-isothiocyanato-acid (158) to a 2-thio-oxazolidone (1 59) occurs readily in R

I SCN-CH-CO,SiMe,,

R ROt I

I

o,,c SCN-CH-C02H

HN-CII-R

I

I

s4c\ 0/c,o though apparently their polymerization to poly-(a-amino-acids) is less favoured. These interesting bifunctional compounds (1 58) have been postulated only as reaction intermediates prior to the present The reaction of an a-chloro-/I-keto-sulphide with KSCN gives a 2-thiooxazoline (1 60), which is formed through phenyl migration within an intermediate i s o t h i o ~ y a n a t e . ~ ~ ~ 481

482 483 484

485 486

4*' 488

R. G. Guy and J. J. Thompson, Chem. and Znd., 1970, 1499. R. T. Walker, Tetrahedron Letters, 1971, 2145. A. Patchornik and Y . Degani, J. Org. Chem., 1971, 36, 2727. D. E. L. Carrington, K. Clarke, and R. M. Scrowston, J. Chem. SOC.( C ) , 1971, 3262. R. M. Ottenbrite, J.C.S. Perkin Z, 1972, 88. H. R. Kricheldorf, Angew. Chem. Znternat. Edn., 1971, 10, 507. H. R. Kricheldorf, Chem. Ber., 1971, 104, 3146, 3156. D. N. Harpp and P. Mathiaparanam, J . Org. Chem., 1971, 36, 2886.

74

Organic Compounds of Sulphur, Selenium, and Tellurium Ph

c1 I

I

PhCOCPh

I SR

Ph-C -C-SR

+ KSCN

I

0,

II

,N

C

II

S (160)

A novel pyrolysis sequence (161) -+ (162) + MeNCS has been studied;48g the overall reaction is brought about at lower temperature (100 "C) with the N-phenyl analogue of (161). Me

I

A~CO-N-C

I

A~.CO.N-C'

+S

2oo"c+MeNCS

+ ArCS,Me

Reactions of Thiocyanates and 1sothiocyanates.-Although these functional groups are structurally dissimilar from many points of view, a thiocyanate behaving as a sulphenyl cyanide, while an isothiocyanate shows the reactions expected of it on the basis of its heterocumulene structure, there are several examples now of isomerization reactions -S-C=N -+ -N= C= S, partly justifying a unified treatment of their reactions. S-Cyanylation of thiols (2-mercaptoethanol, cysteine, or papain) can be achieved with 2-nitro-5-thiocyanatobenzoic acid 483 at pH 7-8, at room Addition reactions of isothiocyanates are perhaps most widely represented in their reactions with amines. The Edman stepwise degradation of polypeptides depends upon the conversion of the amine terminus into a phenylthiocarbamoyl derivative with phenyl i s o t h i o ~ y a n a t ethe , ~ ~adducts ~ formed between a-amino-acids and MeNCS showing a Cotton effect centred near 270 nm whose sign is an indication of absolute configuration (positive c.d. maximum near 270 nm being associated with the ~ - c o n f i g ~ r a t i o n ) . ~ ~ ~ Thiols also form corresponding adducts MeNH- CS. SR with MeNCS, that from N-acetyl-L-cysteine showing similarly characteristic c.d. b e h a v i o ~ r . ~ ~ , The addition of an isothiocyanate to a carbodi-imide gives (163);403the products of decomposition of MeNCS in neutral aqueous solution are MeNHCS,H and (164),404and the decomposition is catalysed by trace metals. 490 491

482

498

494

Y. Ueno, T. Nakai, and M. Okawara, Bull. Chem. SOC.Japan, 1971, 44, 841. A. Patchornik, Y. Degani, and H. Neumann, J . Amer. Chem. SOC.,1970, 92, 6969. P. Edman in 'Protein Sequence Determination', ed. S. B. Needleman, Chapman & Hall, London, 1970, p. 211. C. Toniolo, Tetrahedron, 1970, 26, 5479. I. Ojima and N. Inamoto, Chem. Comm., 1970, 1629. G. J. Bridgart and I. R. Wilson, Austral. J. Chem., 1971, 24, 2695.

75

Aliphatic Organa-sulphur Compounds etc.

Similar addition reactions are undergone by hydrazides and aminoguanidines with aroyl isothiocyanates Ar- CO NCS,4DSthe products being useful intermediates for heterocyclic syntheses. Chlorosulphonyl isothiocyanate is ‘an exceptionally reactive h e t e r ~ ~ ~ r n ~ l ean ‘particularly e’,~~~ useful uniparticulate electrophile’ (i.s. a reagent incapable of fragment a t i ~ n ) ,giving ~ ~ ~ cyclic adducts with olejins comparable with those obtained from analogous isocyanates (p. 89). E m . spectra of isothiocyanato-alkyl radicals, e.g. MeeH. NCS from Et .NCS, produced by X-irradiation in adamantane, are interpreted somewhat inconclusively in terms of structure, but are consistent with rapid interconversion of bent planar and linear structures for the -CH2-NN=C- S Thermal isomerization of thiocyanates accompanies olefin formation (Et-SCN -+ CH2=CH2 + HNCS -j Et-NCS) in a gas-phase reaction involving a cyclic transition state with very little charge ~ e p a r a t i o n49D .~~~~ More complex systems have been studied, seeking primarily some indication of the tightness of the transitiw state through identification of reaction products ; thermal isomerization of anti-7-norbornenyl and 7-norbornadienyl thiocyanates gives isothiocyanates with no skeletal changes.600 Allylic rearrangement of thiocyanates to isothiocyanates has been demonstrated for monosaccharide derivatives,sol~ opening up methods for sugar transformations but especially for synthesizing amino-sugars.602 For example, (165) gives (166) by way of the isothiocyanate resulting from thermal isomerization.602 The allylic 0-methanesulphonyl substituent in

-

406

F. Kurzer, J. Chem. SOC.(C), 1971,2927,2932. L. A. Paquette, G. R. Allen, and M. J. Broadhurst, J. Amer. Chem. Soc., 1971, 93, 4503.

407

4ng

D. E. Wood, R. V. Lloyd, and W. A. Lathan, J . Amer. Chem. Soc., 1971, 93,4145. N. Barroeta and A. Maccoll, J . Amer. Chem. Soc., 1971, 93, 5787. N. Barroeta, A. Maccoll, M. Cavazza, L. Congiu, and A. Fava, J. Chem. Sac. (B), 1971, 1264, 1267.

L. A. Spurlock and Y. Mikuriya, J. Org. Chem., 1971, 36, 1549. R. J. Ferrier and N. Vethaviyasar, Chem. Comm., 1970, 1385; J. Chem. SOC.(C), 1971, 1907.

R. D. Guthrie and G. J. Williams, Chem. Comm., 1971, 923.

76


I

CH,NHAc (166)

ethyl 2,3-dideoxy-4,6-di-O-methanesulphonyl-~-~-eryt~oand -three-hex2-enepyranoside is selectively substituted by -SCN with inversion, to provide substrates for the allylic rearrangement the 4-azido-compounds were obtained by analogous substitution by N3-. 9 Sulphinic acids Preparation.-Arenesulphinic acids are products of the Smilesrearrangement and have appeared as incidental reaction products in mechanistic studies discussed elsewhere in this Chapter (e.g. ref. 387). The attractive possibilities of using sulphur dioxide as a reagent, not only specifically for the synthesis of sulphinic acids but more for the artefacts produced from these in reaction mixtures, are becoming apparent. U.V. irradiation of EtOH in liquid SO, gives MeCH(OH)S02H,503and similar treatment of trialkyl orthoformates, or benzaldehyde dimethyl acetal, gives the sulphinic acid as C-H insertion product, which provides a+ source of carbonium ions [X- CH(OR), -+ (RO),CX- S0,H + (R0)2CX].604 Biradical formation from a t-butyl-quinone (167) on irradiation in liquid SO, ( A 3 435 nm,

6But -Rq OH

R

dH,

R

R

=

0 H or But

(167)

0'

OH (168) and cyclic analogues

Oo3

J. R. Nooi, P. C. Van der Hoeven, and W. P. Haslinghuis, Tetrahedron Letters,

Oo6

J. R. Nooi, P. C. Van der Hoeven, and W. P. Haslinghuis, Rec. Trav. chirn., 1972,

1970, 2531. 91, 161.


77

at - 50 "C) precedes conversion into the sulphinic acid (168) and sulphone (169).505 Radicals HOiO,, Mego,, and Butgo, have been identified by e.s.r. spectroscopy in mixtures of alkyl hydroperoxides and Insertion of sulphur dioxide into transition-metal alkyls and aryls l1 gives an alkyl-S-sulphinate, via M-OSOR or M-S(0)OR (M = metal), probably the former 607 (see also refs. 508, 509). Corresponding products are obtained from alkyl and aryl dicyclopentadienyltitanium compounds, giving (~-C,H,)~Ti(0~SMe),,610 and from cyclopentadienyl iron carbonyls (.rr-C6H6)Fe(CO)2R,611 including conservation of optical activity when R = (R)-phenylethyL612 Kinetic studies of the insertion of SO2 into ArSnMe, have been made.51s Reduction of arenesulphonamides in tetraethylammonium bromideMeCN at a Hg cathode gives arenesulphinate and amine in high yields through a two-electron process, confirming earlier work (see Vol. 1, p. 91).514 The Friedel-Crafts reaction of benzenesulphonyl chloride with cyclohexene gives benzenesulphinic acid and trans-1,2-dichlorocyclohexane,61K correcting an earlier report claiming that there was p-chloro-sulphone formation by analogy with the course of the reaction with an acyl chloride. Reactions of Suiphinic Acids.-Sulphinic acids undergo Mannich-type reactions with aldehydes and a large excess of formamide (RISO,H + R2CH0 H2NCH0 -+ R1S0,CHR2NHCHO), exemplifying an efficient, general route.616 Benzenesulphinic acid undergoes Michael-type addition to acrylonitrile in aqueous buffers, following second-order kinetics, with rates independent of pH.617 Further examples of nucleophilic reactivity are shown in the formation of MeS0,CS. S0,Me from methanesulphinate and t h i o p h o ~ g e n e and , ~ ~ ~of the related oxygen analogue of a trithiocarbonate, viz. MeSO,. CS.SR, formed from methanesulphinate and a chlorodithioformate C1. CS*SR,,l9 accompanied by MeSO,CH(SPh)SSPh and diphenyl trithiocarbonate when R = Ph.51a The reaction RSOa- + CS2 + RS02CSS- was found not to occur,61ebut addition to a thiocarbonyl group, uiz. MeSO,. CS. S02Me + MeS0,H + (MeSO,),CHSSO,Me, has been d e m ~ n s t r a t e d , oxidation ~~~ (using HaOa) of the product providing

+

50*

608 509

blo 611 512 b19 514 515

S. Farid, Chem. Comm., 1971, 73. B. D. Flockhart, K. J. Ivin, R. C. Pink, and B. D. Sharma, Chem. Comm., 1971, 339. S . E. Jacobsen, P. Reich-Rohrwig, and A. Wojcicki, Chem. Comm., 1971, 1526. C. A. Reed and W. R. Roper, Chem. Comm., 1971, 1556. G. Vitzthum and E. Lindner, Angew. Chem. Internat. Edn., 1971, 10, 315. P. C. Wailes, H. Weigold, and A. P . Bell, J. Organometallic Chem., 1971, 33, 181. S. E. Jacobsen and A. Wojcicki, J. Amer. Chem. SOC.,1971, 93, 2535. J. J. Alexander and A. Wojcicki, Inorg. Chim. A d a , 1971, 5 , 655. C. W. Fong and W. Kitching, J. Amer. Chem. SOC.,1971, 93, 3791. P. T. Cottrell and C. K. Mann, J. Amer. Chem. SOC.,1971, 93, 3579. G . Holt, K. D. Jeffreys, P. D. Jeffreys, and S. E. Tonietti, J. Chem. SOC.(0,197 361 1.

G16

517 G18 619

T. Olijusma, J. B. F. N. Engberts, and J. Strating, Rec. Trau. chim., 1972, 91, 209. Y. Ogata, Y. Sawaki, and M. Isono, Tetrahedron, 1970, 26, 3045. N. H. Nilsson, C. Jacobsen, and A. Senning, Chem. Comm., 1970, 658. N. H. Nilsson, C. Jacobsen, and A. Senning, Chem. Comm., 1971, 314.

78 Organic Compounds of Sulphur, Selenium, and Tellurium (MeSO,),CH, and establishing a novel route to bis(sulphony1)methanes. 1-Chloroethanesulphinic acid, MeCHClSO,H, gives products derived from methylsulphene, MeCH=SO,, in basic media, e.g. (170) -+ (171).6eo

(171)

(170)

Reduction of a series of para- and meta-substituted benzeneseleninic acids to diselenides, using iodide in acidic aqueous EtOH, has been studied;521three equivalents of I- are required per mole of substrate. Sulphinate Esters.-Acetate-catalysed exchange between methyl toluene-psulphinate and CD30H involves as rate-determining step the reaction of CD30- with a hydrogen-bonded complex formed between the sulphinate ester and AcOH; the overall process follows the rate law k, = K[-OAc]/ [AcOH] ~ - o A ~ [ - O A CHydrogen-bonding ].~~~ of sulphinate esters and sulphinyl chlorides through sulphinyl oxygen to phenols has been studied by i.r. spectroscopy, as a sensitive measure of S - 0 bond polarity.523 The first aryl alkanesulphinate, Me. SO. OPh, arises from this study, which shows that inductive effects have a much greater effect in determining S - 0 bond polarity than resonance effects. Thermal rearrangement of aryl prop-Zynyl sulphinates Ar SO OCH2-C=CH to allenyl sulphones ArS02CH=C=CH2, in chlorobenzene at 130 "C, and the corresponding sulphenate-sulphoxide rearrangement, probably involve a cyclic intramolecular mechanism;S24the evidence favouring this is the conversion of (R)-( )-l-methylprop-2-ynyl toluenep-sulphonate into ( - )-buta-l,2-dienyl p-tolyl ~ u l p h o n e . ~The ~ ~ bissulphinate of but-2-yne-1,4-diol rearranges at 200 "C into H,C=C(SO,Ar) C(SO,Ar)= CH,, a butadiene which does not undergo Diels-Alder addition (e.g. with acrylonitrile).624

+

+

-

Sulphinamides.-Aluminium amalgam, an excellent reagent for the hydrogenolysis of /3-keto-sulphoxides, sulphones, and sulphonamides, is also shown 625 to be useful for converting sulphoximines into sulphinamides, with retention of configuration (see also Scheme 2 318). The reduction, which is carried out in 90% aq. THF, involves cleavage of a sulphur-alkyl bond [(172) -+(173)l; S-OPh and S-NMe, analogues of (172) are similarly converted into (173), and with deference to independent this represents the first synthesis of optically active sulphinamides. Chlorination 620 521 528 sa3

5%'

m 5

J. F. King and R. P. Beatson, Chem. Comm., 1970, 663. F. Ferranti and D. De Filippo, J. Chem. SOC.(B), 1971, 1925. J. L. Kice and C. A. Walters, J. Amer. Chem. SOC.,1972, 94, 590. J. B. F. N. Engberts and G. Zuidema, Rec. Truv. chim., 1970, 89, 1202. G. Smith and C. J. M. Stirling, J. Chem. SOC.( C ) , 1971, 1530. C. W. Schroeck and C. R. Johnson, J. Amer. Chem. SOC.,1971,93, 5305.

79


of sulphinamides gives sulphonimidoyl chlorides, Cl,-ether at - 78 0C,626 1-chlorobenzotriazole,K28 or C12-py 627 proving suitable reaction conditions and reagents. The sulphonimidoyl chlorides [e.g. (174)] give nucleophilic substitution products [e.g. (1 75)], including a sulphanilamide analogue in which the -S(O)(NR)group replaces -SOa-, which will doubtless set off an interest in their pharmacological properties. A new cycle of asymmetric transformations at sulphur is based upon these reactions (Scheme 4).627Sulphinamides are reported to react with l-chlorobenzo-

Me,NH

MeN \\

ph--;s=o

triazole, in CH2CIz,in the presence of PhC0,- Naf, to give sulphonamidines (1 76),628rather than the compounds (174), which are formed 626 in the same system but omitting sodium benzoate. 0

II

Ar-S=NR

Alkylation of sulphinamides at nitrogen can be achieved through the N-lithio-derivative by treatment with an alkyl halide.529 N.m.r. spectroscopy of para-substituted Ph- SO NHPh shows that there is no variation in the chemical shift of aromatic protons in the phenyl

-

m6 627

E. E. F. E.

U. Jonsson, C. C. Bacon, and C. R. Johnson, J. Amer. Chem. Soc., 1971,93,5306. U. Jonsson and C. R. Johnson, J . Amer. Chem. Soc., 1971, 93, 5309. Wudl, C. K. Brush, and T. B. K. Lee, J.C.S. Chem. Comm., 1972, 151. Wenschuh and B. Fritzsche, J . prukr. Chem., 1970, 312, 129.

80


ring adjacent to sulphur when the N-phenyl group carries various parasubstituents, but the N-proton shift was affected, suggesting that there is little double-bond character in the S-N bond but significant double-bond character between sulphur and its phenyl ~ u b s t i t u e n t . ~ ~ ~ 10 Sulphonic Acids

Preparation.-Few examples of insertion of SO, into organometallic compounds have been reported,llv 531 in contrast with corresponding reactions of sulphur dioxide; recent examples are the formation of RSO,Re(CO), (R = Me, Ph, or p-toly1)532and MeHgS0,Me from HgMe, and SO, at - 70 0C,531further reaction giving methylmercuric methanedisulphonate, MeHgS,06Me.531 Oxidation of heterocyclic thiones to corresponding sulphonic acids is easily brought about where there is no risk of oxidation elsewhere in the molecule, e.g. pyrimidine-Zthiones give 2-sulphonic acids with aq. KMn04,533and sulphonyl fluorides, RSO,F, with KHF,; the latter give sulphonamides with NH,. Chloramine gives the corresponding sulphengive correspondamides and d i s ~ l p h i d e s . ~1,2,4-Triazoline-3-thiones ~~ ing sulphonic acids with Cl, or Br, followed by hydrolysis.534 The alternative route to pyrimidine-2-sulphonic acids, treatment of the 2-chloropyrimidines with aqueous potassium s ~ l p h i t eillustrates , ~ ~ ~ a general reaction of organic halides susceptible to nucleophilic substitution. Extensive studies adding to those reported in Volume 1 (p. 94) illustrate the scope of sulphonic acid formation by addition of bisulphite to pyrimidine nucleosides, again with the warning of the possible genetic hazards associated with the interaction between SO, and nucleic acids. Bisulphite adds quantitatively to uracil (1 5 ;R = H ; OH in place of NH,) and cytosine (1 5 ; R = H) in hot aqueous solution at pH ca. 6.536 5,6-Addition of bisulphite [(l5) --f (177)] offers a

method for deuterium-labelling at C(5) in cytidine (15; R = p-D-ribofuranosidyl) under conditions avoiding deamination, since the 5,6-addition reac530

531

532 533 534 535

K. Mori and Y. Ueda, Yukugaku Zasshi, 1971,91,940 (Chem. A h . , 1971,75,150 938). K. A. R. Salib and J. B. Senior, Chem. Comm., 1970, 1259. E. Liiidner and R. Grimmer, Chem. Ber., 1971, 104, 544. D. J. Brown and J. A. Hoskins, J.C.S. Perkin I, 1972, 522. A. J. Blackman and J. B. Polya, J. Chem. SOC.( C ) , 1970, 2403. D. J. Brown and J. A. Hoskins, J. Chem. SOC.(B), 1971, 2214. H. Hayatsu, Y. Wataya, K. Kai, and S. Iida, Biochemistry, 1970, 9, 2858.

Al@hatic Organo-sulphur Compounds etc.

81

tion is reversible in this case.s37 Additional points of attack on substituted pyrimidines are the thione grouping in l-methyl-4-thiouracil (16; R = Me) 638 and participation in the deamination of the 5,6-dihydrocytosine-6sulphonate intermediate in the overall conversion of cytosine nucleotidss into u r i d i n e ~ . l-Methyluracil ~~~ 4-thiosulphonate can be isolated in the former example,B38 the reaction leading to this intermediate (established by Y3 studies) being mediated by oxygen at pH 7 and inhibited by hydroquinone, suggesting that the sulphite radical is involved; the ultimate reaction product is l-methyluracil-4-sulphonate."s8Adrenochrome gives the unusual bisulphite addition product (178).640

M C

Studies in aromatic sulphonation Kc include full details of the rearrangement of sodium 1-naphthylsulphamate into the 4-sulphonate in dioxansulphuric acid, where YGstudies show that the reaction is partly intramolecular.s41 There are few syntheses of natural products offering an opportunity for employing aromatic sulphonation as an essential step, though a recent synthesis of the demethyl derivative establishes the structure of aeruginosin B as 2-amino-6-carboxy-l0-rnethylphenaziniurn-8-~~1phonate.542 Ionization of aromatic sulphonic acids in aqueous sulphuric showing that the benzoacid has been studied by U.V. phenone H t and the HA acidity functions are followed; substituent effects are small (Hammett p-value 0.7 4 0.2). Formation of acetophenone in benzene-Ac,O-H,SO, mixtures is a known procedure, though the demonstration by Raman spectroscopic measurements that H0,C. CH,SO,- is also formed (by rearrangement of AcOS0,-) is a novel result.644The acetylating agent in Ac,O-MeS0,H or Ac,O-HO,C- CH,SO,H mixtures is shown by i.r., Raman, and n.m.r. data to be AcOS0,Me or AcOSO,CH,- C02H, Sulphonic anhydrides are involved in continuing mechanistic studies of their hydrolysis pathways ;546 methanesulphonic anhydride is prepared by distillation from 537

63R 5s9

540 G41 542 543 544 545 546

K. Kai, Y. Wataya, and H. Hayatsu, J. Amer. Chem. SOC.,1971, 93, 2089. H. Hayatsu and M. Inoue, J. Amer. Chem. SOC.,1971,93,2301. H. Hayatsu and M. Sono, Chem. Comm., 1971, 1178. R. A. Heacock, R. Marchelli, and W. S. Powell, Chem. and Ind., 1971, 1021. W. J. Spillane, F. L. Scott, and C. B. Goggin, J. Chem. Sac. (B), 1971, 2409. R. K. Bentley and F. G. Holliman, J. Chem. SOC.( C ) , 1970, 2447. H. Cerfontain and B. W. Schnitger, Rec. Trav. chim., 1972, 91, 199. A. Casadevall and A. Commeyras, Bull. SOC.chim. France, 1970, 1850. A. Casadevall and A. Commeyras, Bull. SOC.chim. France, 1970, 1856. R. M. Laird and M. J. Spence, J . Chem. SOC.(B), 1971,454, 1434.

82


Mixed sulphonic-carboxylic a mixture of the sulphonic acid and P,0&.547 anhydrides disproportionate into sulphonic anhydrides, and form sulphonates by keten extrusion;648a broad study of their use for cleaving ethers (see Vol. 1, p. 95) has been Sulphonyl Peroxides.-Benzoyl toluene-p-sulphonyl peroxide, formed by the addition of aqueous Ba(OH), to toluene-p-sulphonyl chloride and perbenzoic acid in CH2C12at - 15 “C, undergoes autocatalysed decomposition in inert solvents to give biphenyl (in benzene) or to give chlorobenzene and hexachloroethane when CCl, is m-Nitrobenzenesulphonyl peroxide in PhNO, gives m-nitrophenyl m-nitrobenzenesulphonate and rn-nitrobenzenesulphonic acid through electrophilic substitution by the peroxide, whereas in CHCl:, solution homolytic cleavage of the peroxide bond takes place, giving hexachloroethane and rn-nitrobenzenesulphonic acid.660 Addition reactions of arylsulphonyl peroxides to norbornadiene give (179), and norbornene gives (180) and (181), through

electrophilic attack;661this is in contrast with results for phthaloyl peroxide, which gives the 2,3-exo-cis-diol phthalate, with no substitution product.662 Sulphonate Esters.-Simple methods based upon sulphonyl halides are entirely satisfactory for the synthesis of sulphonate esters in general, and a variety of methanesulphonate esters have been prepared in this ~ a y . ~ 6 3 Trifluoromethanesulphonatesare of interest because of the rapid rates of solvolysis, and 1-(trifluoromethanesulphonyl)imidazole, from the anhydride and imidazole, is useful for introducing the ‘triflate’ ~ I - O U P . ~The ~~ ‘tresylate’ leaving group (2,2,2-trifluoroethanesulphonate)has been advocated666to fill the gap in solvolysis rates shown between triflates and tosylates ; it is introduced using the sulphonyl chloride, prepared from 647

R. C. Paul, S. K. Sharma, R. D. Sharma, and K. C. Malhotra, Chem. and Ind., 1971, 702.

648 640

550

M. H. Karger and Y. Mazur, J. Org. Chem., 1971,36, 528, 532, 540. R. Hisada, H. Minato, and M. Kobayashi, Bull. Chem. SOC.Japan, 1971,44, 2541. Y. Tokoyama, H. Wade, M. Kobayashi, and H. Minato, Bull. Chem. SOC.Japan, 1971,44,2479.

651

Wa 663 654

666

J. Bolte, A. Kergomard, and S. Vincent, Bull. SOC.chim. France, 1972, 301. F. D. Greene and W. Rees, J. Amer. Chem. SOC.,1960, 82, 890. R. K. Crossland and K. L. Servis, J . Org. Chem., 1970, 35, 3195. F. Effenberger and K. E. Mack, Tetrahedron Letters, 1970, 3947. R. K. Crossland, W. E. Wells, and V. J. Shiner, J. Amer. Chem. SOC.,1971, 93, 4217.


83

methyl 2,2,2-trifluoroethanesulphonate by conversion into CFsCH2.SCN, which on chlorination in aqueous trifluoroaceticacid gives CF3CH2S02Cl.sss Dimethyl sulphite can be isomerized into methyl methanesulphonate in 49% yield, catalysed by tertiary amines, or by methanesulphonate anion, the sulphite acting as a methylating agent.666 Alkyl alkanesulphonates react with Na naphthalene to form first the radical anion, which splits into R1'+ - 0 . S 0 2 * R 2 ,from which alkanols, alkanes, and alkanesulphinicacids are formed, depending on Photochemical cleavage of tosylated sterols and terpene alcohols at 254 nm proceeds in moderate yield within 3 h, in ether, to give back the alcohol via RSO2* + RO'; sulphonamides similarly give a m i n e ~ . ~ ~ ~ Claisen-type condensation reactions of aralkanesulphonate esters, ArCH,SO,OAr' -+ ArCH(SO,CH,Ar)SO,OAr', have been exemplified further (see also Vol. 1, p. 72), sulphonylation being brought about in the presence of a strong base (e.g. ButO- K+-THF).55g Routine use is made in synthesis of the tendency of the sulphonyloxygroup to facilitate nucleophilic substitution at a centre to which it is attached, but this does not extend to hydroxylamine toluene-psulphonates, e.g. TsONMe, does not act as a dimethylaminating agent,6e0 but formaldehyde is formed by its reaction with diethylamine, suggesting an elimination of TsOH to form CH,=NMe, and it undergoes Mannichtype reactions with e n a ~ n i n e s . ~Carbohydrate ~~ toluene-p-sulphonates continue to provide interesting results in terms of products from nucleophilic displacement reactions, since both conformation and configuration determine the course of the reaction. While the 2-0-toluene-p-sulphonyl group in (182) is displaced by benzoate with inversion, the 4-0-methanesulphonyl group is eliminated with the H at C(3).661Related results are reported in refs. 562-564.

LS* 657 6s8

660

A. J. W. Brook and R. K. Robertson, J , Chem. SOC.(B), 1971, 1161. J. R. Ganson, S. Schulenberg, and W. D. Closson, Tetrahedron Letters, 1970, 4397. A. Abad, D. Mellier, J. P. Pete, and C. Portella, Tetrahedron Letters, 1971, 4555, 4559. W. E. Truce and L. W. Christensen, J. Org. Chem., 1970,35, 3968. D. H. R. Barton, L. Bould, D. L. J. Clive, P. D. Magnus, and T. Hase, J. Chem. SOC.

(0,1971, 2204. A. K. Al-Radhi, J. S. Brimacornbe, and L. C. N. Tucker, J . Chem. SOC.(C), 1971, 2305. 68a

663

664

E. J. Reist and M. Tan, Carbohydrate Res., 1971, 18, 446. C. Bullock, L. Hough, and A. C. Richardson, Chem. Comm., 1971, 1276. A. Dmytraczenko, W. A. Szarek, and J. K. N. Jones, Chem. Comm., 1971, 1220.

84


Vinyl Sulphonates.-Addition of a sulphonic acid to an alkyne gives a vinyl ~ u l p h o n a t e a, ~particular ~ ~ ~ ~ ~ variant ~ of this being the addition of a sulphenyl 2,4,6-trinitrobenzenesulphonate to an alkyne, giving a trans/3-alkyl- or -aryl-thiovinyl sulphonate RISCR= CR20S02Ar.567Aldehydes and ketones give vinyl trifluoromethanesulphonates with trifluoromethanesulphonic anhydride,56athe use of an aryl sulphonyl halide with an enolized acylmalonate giving poor yields because of competing halogenation reactions.56ss Poor yields result from the reaction of an a-halogenoacylmalonate with arenesulphinate salts in dry B u ~ O H570 . ~ Triphenyl~~~ vinyl sulphonates may be prepared using Ph,C= C(Ph)N= N-N(Ac)Ph with a sulphonic acid.666 Thermal or photo-isomerization of trans-PhCH= C(0Ts)Ph in MeCN gives the cis-isomer, but also PhCH(Ts)*C O -Ph through a free-radical illustrated also by a steroidal vinylogue, TsOC(3)= C(4)- C(5)=C(6) -+O= C(3)- C(4)= C(5)- C(6)Ts. Decarboxylative elimination from enol sulphonates ArSO, OC(Ar)= C(CO,H), gives acetylenic acids ArC=C- C0,H under exceptionally mild conditions,572via a more or less concerted fragmentation (sic) in which a vinyl carbon atom is appreciably cationic. Interest in solvolysis of vinyl sulphonates has been sustained, with a general consensus in support of a simple SN1 mechanism, i.e. 573 liberation of vinyl Studies of /3-alkyl- and -aryl-thio-vinyl sulphonates, mainly from a mechanistic point of view but with implications in synthesis, have been reported in a series of papers.567,574-679 /3-Arylthio-compounds (183) give benzo[b]thiophens (1 84) by cyclization, spontaneously or by BF3 5767

565 566

667 568

588

670 571 672 573

574 575

L76 577

57s 578

R. J. Hargrove, T. E. Dueber, and P. J. Stang, Chem. Comm., 1971, 1614. W. M. Jones and D. D. Maness, J. Amer. Chem. SOC.,1970, 92, 5457. G. Capozzi, G. Melloni, and G. Modena, J. Chem. SOC.( C ) , 1970, 2617, 2621, 2625. T. E. Dueber, P. J. Stang, W. D. Pfeifer, R. H. Summerville, M. A. Imhoff, P. von R. Schleyer, K. Hummel, S. Bocher, C. E. Harding, and M. Hanack, Angew. Chem. Znternat. Edn., 1970, 9, 521. I. Fleming and C. R. Owen, J. Chem. SOC.( C ) , 1971, 2013. I. Fleming and C. R. Owen, Chem. Comm., 1970, 1402. N. Frydman and Y. Mazur, J . Amer. Chem. SOC.,1970, 92, 3203. I. Fleming and C. R. Owen, J. Chem. SOC.(B), 1971, 1293. M. A. Imhoff, R. H. Summerville, P. von R. Schleyer, A. G. Martinez, M. Hanack, T. E. Dueber, and P. J. Stang, J . Amer. Chem. SOC.,1970, 92, 3802. G. Melloni and G. Modena, J.C.S. Perkin I, 1972, 218. G. Capozzi, G. Melloni, and G. Modena, J. Chem. SOC.( C ) , 1971, 3018. G. Capozzi, G. Melloni, and G. Modena, J. Org. Chem., 1970, 35, 1217. G. Modena and U. Tonellato, J . Chem. SOC.(B), 1971, 374, 387, 1569. G. Capozzi, G. Modena, and U. Tonellato, J. Chem. SOC.(B), 1971, 1700. A. Burighel, G. Modena, and U. Tonellato, Chem. Comm., 1971, 1325.

AlQhatic Organo-sulphur Compounds etc.

85

c a t a l y ~ i s , ~ 575 ~ ~ by ~ way of a sulphur-bridged intermediate since the a - 1 4 C - ~ ~ m p ~(183; ~ n d R1 = Ph) gives a benzothiophen in which the isotope distribution indicates substantial equilibration of the two ethylenic carbon With a para-substituent in the arylthio-residue, a rearranged benzo[b]thiophen is though for (183; R2 = mor p-substituted phenyl) the unrearranged benzothiophen is obtained when a para-substituent is present in the arylthio-residue, while the metasubstituted analogue cyclizes to a rearranged b e n z ~ t h i o p h e n ,con~~~ stituting a 1,Zsulphur shift via (187; S in place of SO,). Nucleophilic substitution of the sulphonate grouping in (183) is brought about with weak nucleophiles (e.g. MeOH, HCl, or PhSH), but more powerful nucleophiles (e.g. ArS- or piperidine) may react at the R2-SO, bond if R2 is a phenyl group carrying electron-withdrawing ~ u b s t i t u e n t s576 .~~~~ The /?-sulphur atom provides anchimeric assistance in S,l reactions of /%phenylthiovinyl sulphonates (183), a filled orbital overlapping the developing empty p-orbital of the a-vinylic carbon atom;"' products indicating migration of the arylthio-group, with retention of configuration, may be obtained. If the substituents are varied, products of the two extreme transition states (185) and (186) may be Rates for S N processes ~ with MeSC(Me)=C(Me)O. SO& are lo4-lo5 times larger K749

, ' R

c=c \+/

,Ar

S

I

Ar

(186)

than those for Me,C=C(Me)O* SO,Ar, confirming that the bridged sulphonium ion (186) can be more stable than the open vinyl cation (185).67s Oxygen analogues cyclize to benzofurans s80 with BF3-CH2C12, though participation by oxygen is less marked [i.e. bridged oxonium ions analogous to (186) are less BF,-Catalysed cyclization of trans-l,2-diphenyl2-arylsulphonylvinyl p-bromobenzenesulphonates (183 ; SO, in place of -S-; R1 = Ph; R2 = p-Br.CuH4) gives 5-, 6-, or 7-substituted benzo[b]thiophen-1,1-dioxides for X = p-Me and similar analogues, via (187), constituting a 1,2-sulphonyl shift.681 Sulphonyl Halides and Sulphenes.-It is becoming clear that reactions of alkanesulphonyl chlorides in the presence of a tertiary amine are likely to give poor yields of simple sulphonation products, due to the formation of sulphenes (RCH,SO,Cl + RCH= SO,) and artefacts resulting from them. Electron-withdrawing groups in the substituent facilitate sulphene 680 681

G. Capozzi and G. Modena, J.C.S. Perkin I, 1972,216. G. Melloni and G. Modena, Internat. J. Sulfur Chem., A , 1971, 1, 125.

86


formation, e.g. CF,CH,S0,C1.66S The first direct observation on sulphene itself, CH2=S02, produced by flash thermolysis of HO2C-CH2S02Clat 650 "C, is its i.r. spectrum at - 196 "C; the reaction mixture shows absorption at 3170, 3040, 1330, 1230, and 950 cm-1 and these bands disappear, to be replaced by bands due to MeSO,Cl, on warming.682 Vinylsulphene, CH2= CH- CH= SO,, intervenes in reactions of prop-2ene-l-sulphonyl chloride with enamines since 3-amin0-2-vinylthietan-1,ldioxides, i.e. 1,2-cyclo-adducts, are formed together with ally1 aminovinyl ~ u l p h o n e s .Benzoylsulphene ~~~ is responsible for the products of DielsAlder-adduct type from Ph. CO CH2S02Cl,NEt,, and anils ArCH=NR,684 and cinnamylidene-amines.686 Azibenzil, PhCN,. COOPh, and SO, give the 21 cyclo-adducts are formed with sulphene O,S=CPh-CO.Ph, since [4 diphenylketen.S86 a-Halogenation of alkanesulphonyl chlorides in the presence of a tertiary amine gives moderate yields, using the halogen itself as reagent,687presumably not via the sulphene judging by the observation MeS0,Cl + BrCH,SO,Cl. that Br, Mechanistic studies of the solvolysis of arenesulphonyl halides are being conducted in a number of laboratories; while p-OMe-, o- or p-NH2-, or p-NHAc-substituted benzenesulphonyl fluorides are hydrolysed immeasurably slowly in 40% aqueous dioxan, the o-NHAc-substituted compound is hydrolysed relatively rapidly, with loss of the N-acetyl substituent, suggesting that there is neighbouring-group participation.688 Further data to support the contention that 2,4,6-trimethylbenzenesulphonylchloride is hydrolysed via a S N path, ~ while unhindered analogues follow SN2 kinetics, have been published;689 a useful property of this sulphonyl chloride is its ability to sulphonylate primary hydroxy-groups while leaving secondary hydroxy-groups unprotected, and therefore it may have applications in carbohydrate Extensive studies of aminolysis of (substituted-Ph)SO,Cl with ortho-substituted anilines indicate a rateslowing steric effect but particularly an effect of electron release through the sulphonyl group in 'loosening' the transition state;591the leaving-group mobility of the halogen in sulphonyl halides is much more dependent on the pK, of the nucleophile for sulphonyl fluorides than for chlorides, bromides, or iodides, and intermediate complex formation is indicated.6D2

+

+

J. F. King, R. A. Marty, P. De Mayo, and D. L. Verdun, J. Amer. Chem. SOC.,1971, 93, 6304. S. Bradamante, S. Maiorana, and G. Pagani, J.C.S. Perkin Z, 1972, 282. 684 0. Tsuge and S. Iwanami, Bull. Chem. Soc. Japan, 1970,43,3543. 686 0. Tsuge and S. Iwanami, Bull. Chem. SOC. Japan, 1971, 44, 2750. J. B. Stothers, L. J. Danks, and J. F. King, Tetrahedron Letters, 1971, 2551. 687 G. A. Sokolskii, L. I. Ragulin, G. P. Ovsyannikov, and I. L. Knunyants, Zzuest. Akad. Nauk S.S.S.R., Ser. khim., 1971, 1270. 688 M. E. Aberlin and C. A. Bunton, J. Org. Chem., 1970, 35, 1825. s80 M. L. Tonnet and A. N. Hambly, Austral. J . Chem., 1971, 24, 703. OB0 S. E. Creasey and R. D. Guthrie, Chem. Comm., 1971, 801. m1 0. Rogne, J.C.S. Perkin ZZ, 1972, 472; J. Chem. SOC.(B), 1971, 1855. 683 E. Ciuffarin, L. Senatore, and M. Isola, J.C.S. Perkin ZZ, 1972, 468. 68a

87 Sulphonyl Cyanides.-Arylsulphonyl cyanides are more reactive than aroyl cyanides in cycloaddition reactions, because of delocalization of CN v-charge density; this is illustrated by their cycloaddition to 5,5-dimethoxytetrahalogeno-cyclopentadienes.60S Olefins give /I-cyano-sulphones under irradiation (254 nm), e.g. ArSOaCHa*CH(CN)*(CH,),Me from he~-l-ene.~Od Aliphatic Organa-sulphur Compounds etc.

Sulphonamides and Related Compounds.-Standard

preparative methods,

e.g. arninolysis of sulphonate esters or sulphonyl halides, are unsuccessful

with t-alkanesulphonamides, though these may be made by oxidation of corresponding sulphinamides or through a novel route RtSOCl + R1R2NOH.+ RtS02NR1R2.60s Sulphonimidoyl chlorides, e.g. (174), react rapidly with alcohols at 0 "C in the presence of NEt8, possibly via iminosulphenes R;C= S(O)= NR2 where the presence of an a-hydrogen allows these to form, to give sulphonamides.606 Cyanomethanesulphonamides have been prepared from the sulphonyl chloride, and shown to be useful in synthesis through reactions at their active methylene group. O7 N-Alkylation of toluene-p-sulphonamide is a well-known reaction, making use of the acidic character of the NH, protons, and a novel use is made of this in an iso-indole synthesis;698 1,2-bis(bromornethyl)naphthalene gives (188), from which (189) and toluene-p-sulphinic acid are

formed in good yield. N-Methylation of NN-disubstituted aryl sulphonamides with dimethoxycarbonium hexachloroantimonate gives crystalline sulphonamidium salts, which give methylamines on acid hydrolysis, offering a new route to pure tertiary amines.6QB Aliphatic sulphonamides are activated also at the a-carbon atom, and treatment of chloromethanesulphonylmorpholide, ClCH,. S02N(CH2-CH,),O, with BunLi-THF at - 75 "C gives the first discovered a-chloro-dicarbanion, the CICLi,SO,derivative, stabilized by the adjacent sulphonyl group.s00 Attempted hydroxyethylation of N-(0-hydroxypheny1)methanesulphonamide with

588

R. G . Pews, E. B. Nyquist, and F. P. Corson, J. Org. Chem., 1970, 35, 4096. R. G. PewsandT. E. Evans, Chem. Comm., 1971, 1397. K. Hovius and J. B. F. N. Engberts, Tetrahedron Letters, 1972, 181. C . R. Johnson and E. U. Jonsson, J . Amer. Chem. SOC.,1970, 92, 3825. M. P. Sammes, C. M. Wylie, and J. G. Hoggett, J . Chem. SOC.(0,1971, 2151. J. Bornstein, D. A. McGowan, A. L. Di Salvo, J. E. Shields, and J. Kopecky, Chem.

6oo

Comm., 1971, 1503. T. Oishi, K. Kamata, and Y. Bau, Chem. Comm., 1970, 777. W. E. Truce and L. W. Christensen, Chem. Comm., 1971, 588

595

88


epichlorhydrin gave (1 N-Acylsulphonamides R CO NHSO,(p), derived from a sulphonated polystyrene (p), resist alkaline hydrolysis due to the low pK, (ca. 2.5) of the NH group, but the N-methyl analogues, prepared using diazomethane, are rapidly cleaved with one equivalent of

S0,Mc

O.5M-NaOH, or NH,, or hydrazine, opening up the possibilities of peptide synthesis with satisfactory cleavage of the completed peptide from the polystyrene support. 602 Contrary to statements in some textbooks, aliphatic sulphonamides react readily with NaOCl or NaOBr to give N-halogeno-N-sodio-alkane~ u l p h o n a m i d e scharacterized ,~~~ by conversion into crystalline SS-dimethylsulphimides RSO,. N=SMe, by reaction with Me,S. The -SO,NCl grouping is a powerful nucleophile, comparable with azide ion, and this is exploited in the synthesis of N-chloro-N-(2-hydroxyethyl)benzenesulphonamides by reaction of the N-sodio-derivative with ethylene oxide; corresponding reactions with propane sultone and ethylene sulphate are successful.6o4Side-chain substitution of tolyl halides with PhSO,NCI, or PhS0,NHNa gives ArCH,NHSO,Ph, but also ArCH=NSO,Ph in the presence of excess sulphonamide, from which the corresponding aldehyde is obtained by hydrolysis. This provides an alternative route for transformations ArCH, -+ A I - C H O . ~ Reaction ~~ of an arylseleno-trimethylsilane, e.g. PhSeSiMe,, with an NN-dichloro-arenesulphonamidegives the corresponding sulphonyliminoseleninyl chloride PhSe(CI)=N. S02Ar.606 Sulphonyl cumulenes, i.e. sulphonyl azides, isocyanates, and sulphinylamides, continue to provide novel possibilities in synthesis. A sulphonyl azide RS02N3 reacts (- 20 "C, 24 h) with keten diethyl acetal, CH2= C(OEt),, to give an NN-disulphonylated diketopiperazine (1 91), essentially a new route to a-amino-acids, though yet to be explored fully.607 o-Amino- or o-phenylthio-phenylsulphonylazide reacts via the sulphonyl nitrene to give cyclization products [e.g. (192)], while analogous carbonyl 601

602

603 604 605

607

C. J. Coulson, K. R. H. Wooldridge, J. Memel, and B. J. Millard, J. Chem. SOC.( C ) , 1971, 1164. G. W. Kenner, J. R. McDermott, and R. C. Sheppard, Chem. Comm., 1971, 636. F. E. Hardy, J. Chem. SOC.(C), 1970, 2087. F. E. Hardy, J . Chem. SOC.(B), 1971, 1899. M. M. Kremlev, S. A. Boiko, M. S. Rovinskii, and S. Kandabarova, Zhur. org. Khim., 1971, 7 , 1700. N. Y.Derkach, N. A. Pasmurtseva, and E. S. Levchenko, Zhur. org. Khim., 1971, 7 , 1543. G. J. Koves and I. G. Csizmadia, Tetrahedron Letters, 1971, 2599.


89

azides give the expected isocyanate.608Decomposition of the nitrene from ferrocenylsulphonyl azide is metal-catalysed, implying complex formation in thermolysis reactions leading to sulphonamides, possibly also in corresponding photochemical reactions.609 Toluene-p-sulphonyl azide gives 3-toluene-p-sulphonylamino-derivatives of indoles,slobut no corresponding analogues with alkyl-indolizines;611 N-methyltctrahydrocarbazole gives several products with toluene-p-sulphonyl azide,gloone of which is (193), Ts-NH

H

shown by X-ray crystallographic analysiss12 to possess a very short (1.553 A) S-N bond. This can be rationalized in terms of resonance 4

-

1

hybrids MeN=C-N=S(O-)(=O)-

I

+

I

and MeN=C----SO,-

I

together

with (193). Benzenesulphonyl isocyanate, ThSO,NCO, gives the 1,.l-dipolar compound PhSO,.&*CO*CH2*C(=SMe)NMe2 when it reacts with the electron-rich keten S,N-acetal CH2= C(SMe)NMe2.e13Toluene-p-sulphonyl isocyanate gives (1 94) with d i a ~ o r n e t h a n e ,and ~ ~ ~the six-membered ring relative (195) is obtained from FS0,NCO and PhC==CH.61S Related reactions include those of PhS0,- NCS with H,C=C(SMe)NMe, 613 and ArSO,. N=S=O with H,C=C(H)OR.616 ao8 609

610 611

613 614 615

J. Martin, 0. Meth-Cohn, and H. Suschitzky, Chem. Comm., 1971, 1319. R. A. Abramovitch, C. 1. Azogu, and R. G. Sutherland, Tetrahedron Letters, 1971, 1632. A. S. Bailey, R. Scattergood, and W. A. Warr, J . Chern. SOC.( C ) , 1971, 2479, 3769. A. S. Bailey, B. R. Brown, and M. C. Churn, J. Chem. SOC.( C ) , 1971, 1590. I. J. Tickle and C. K. Prout, J . Chem. Sac. ( C ) , 1971, 3401. R. Gompper and B. Wetzel, Tetrahedron Letters, 1971, 529. D. Kobelt, E. F. Paulus, and G. Lohaus, Tetrahedron Letters, 1971, 4243. D. Kobelt, E. F. Paulus, and K.-D. Kampe, Tetrahedron Letters, 1971, 1211. W. Wucherpfennig, Tetrahedron Letters, 1971, 1891.

90

Organic Compounds of Sulphur, Selenium, and Tellurium F

The predominance of the amino-tautomer of an arylsulphonylamidine ArSO,N=C(Me)NH, has been demonstrated by lH n.m.r. studies 617 (see also ref. 618), and synthetic uses of these compounds include the ringclosure of iodomethanesulphonyl benzamidines to thiadiazolines, by treatment with illustrating nucleophilic displacement of iodide from a severely hindered position. Such a displacement is rarely successful. 11 Disulphides, Trisulphides, and their Oxy-sulphur Analogues Preparation of Disulphides, Hydrodisulphides, and 0ligosulphides.-A variety of mild oxidative and nucleophilic displacement reactions at a sulphenyl centre are available for disulphide synthesis. The controlled synthesis of inter- and intra-chain disulphide linkages in peptide synthesis demands the use of distinctly different methods of disulphide formation under conditions that avoid disulphide interchange, for the not uncommon synthetic objective of linking chains through several disulphide groupings. If for no other reason, continuing refinement of existing methods is a recognized aim of recent work. Oxidation of thiols to disulphides can be brought about by using 12,620 K2Fe(CN)s,26FeC13,231,3-dihydro-1-hydroxy-3-oxo-1,2-benziodo~ole,~~~ or manganic tris(acetylacetonate).622 Unsymmetrical disulphides are prepared by the reaction of thiols with sulphenyl compounds, a new synthesis of this type623involving first the conversion of a thiol RlSH into R1SSC02R3 by its reaction with ClSC0,R3 in MeOH at 0 "C,followed by room-temperature reaction of the intermediate with a second thiol R2SH to give R1SSR2 and HO*CS-OR3. Acetyl sulphenyl chlorides AcSCl similarly yield AcSSR with RSH,624-626 though the product is susceptible to attack by the thiol, resulting in the formation of symmetrical d i s ~ l p h i d e s . ~ Acyl ~ ~ alkyl J. C. Danilewicz, M. J. Sewell, and J. C. Thurman, J. Chem. SOC. (C), 1971, 1704.

61*

618 620

621 622

823 624 626 826

R. B. Tinkler, J. Chem. SOC.(B), 1970, 1052. A. Lawson and R. B. Tinkler, J. Chem. SOC.(C), 1970, 1429. R. K. Olsen and A. J. Kolar, J . Org. Chem., 1971, 36, 591. J . Leslie, Canad. J . Chem., 1970, 48, 3104. T. Nakaya, H. Arabori, and M. Imoto, Bull. Chem. SOC.Japan, 1970, 43, 1888. S. J. Brois, J. F. Pilot, and H. W. Barnum, J . Amer. Chem. SOC.,1970, 92, 7629. L. Field, W. S. Hanley, and I. McVeigh, J. Org. Chem., 1971, 36, 2735. J. Tsurugi, Y.Abe, and S. Kawamura, Bull. Chem. SOC.Japan, 1970,43, 1890. T. Fujisawa and N. Kobayashi, J. Org. Chem., 1971, 36, 3546.


91

disulphides are formed from thiolacids by reaction with alkanesulphenyl chlorides or thiol~ulphonates.~~~ Thiolysis of sulphenamides has been established as a serviceable route 629 and N-(alkyl- or aryl-sulpheny1)to unsymmetrical disulphides,62E~ phthalimides are particularly suitable for the purpose. The reaction is conducted at room temperature with arenethiols,62Ethough still with the risk of contamination of the product with symmetrical disulphides formed by interchange. A specific example of relevance to peptide synthesis, methyl ester by thiolysis of N-trifluoroacetyl-S-phthalimido-L-cysteine PhCH,SH, L-cysteine, or glutathione, has been investigated 630 and shown to give the corresponding unsymmetrical disulphides. The use of an alkyl- or aryl-thiosilane in place of the thiol, for cleavage of sulphenamides or sulphenate esters, also gives unsymmetrical disulphides, though the tendency to form mixtures of disulphides by disproportionation under reaction conditions has been confirmed.631 Sulphenamides probably intervene when chloramine or Me,NCl are used to convert thiols into d i s ~ l p h i d e s or , ~ ~to~ convert mixtures of thiols and selenols into selenosulphides, diselenides, and d i s ~ l p h i d e s . ~ ~ ~ 2-Naphthylsulphenyl thiocyanate, Z-C10H7S SCN, is readily converted into di-(2-naphthyl) disulphide with Fe(CO),-THF at - 70 0C,634 and has been used for the conversion of N-benzyloxycarbonyl-selenocysteine diphenylmethyl ester into the Se-(2-naphthylsulphenyl) derivative, the seleno-sulphide R1SSeR2,636 though this disproportionates readily, especially in basic media, and diselenides and disulphides appear in the product mixture for this reason.635 The Bunt6 salt, PhCH2.S*S03-Na+, gives similar results when used in place of the sulphenyl thiocyanate in these and this general route to disulphides 637 and d i ~ e l e n i d e s ,and ~ ~ ~its variant BuS.S03- Na+ TolSCl -+ BuSSBu TolSSTol,638have been explored more widely. Incidental reference has been made to disulphide formation elsewhere in this Chapter, and a number of alternative methods have been explored: /3-dimethylaminoethyl and y-dimethylaminopropyl diselenides have been prepared from the corresponding alkyl chloride and Na,Se, ;639 cyanolysis

+

627 02*

030 Oal 632

633 634

OaS Oa6

687

636p

+

L. Field, W. S. Hanley, I. McVeigh, and 2. Evans, J . Medicin. Chem., 1971, 14, 202. A. B. Sullivan and K. Boustany, Internat. J . Sulfur Chem., A , 1971, 1, 121; Tetruhedron Letters, 1970, 3547. D. N. Harpp, D. K. Ash, T. G. Back, J. G. Gleason, B. A. Orwig, W. F. Van Horn, and J. P. Snyder, Tetrahedron Letters, 1970, 3551. D. N. Harpp and T. G. Back, J. Org. Chem., 1971, 36, 3828. D. A. Armitage, M. J. Clark, and C. C. Tso, J.C.S. Perkin I, 1972, 680. H. H. Sisler, N. K. Kotia, and R. E. Highsmith, J. Org. Chem., 1970, 35, 1742. H. H. Sisler and N. K. Kotia, J. Org. Chem., 1971, 36, 1700. J. Roy, Z . Naturforsch., 1970, 25b, 1063. J. Roy, 1. L. Schwartz, and R. Walter, J. Org. Chem., 1970, 35, 2840. S. Hayashi, M. Furukawa, Y . Fujino, T. Nakao, and S. Inoue, Chem. and Pharm. Bull. (Japan), 1971, 19, 1557. D. L. Klayman, D. Kenny, R. B. Silverman, J. E. Tomaszewski, and R. J. Shine, J. Org. Chem., 1971, 36, 3681. F. Klivenyi, E. Vinkler, and A. E. Szabo, Actu Chim. Acad. Sci. Hung.,1970,63,437. A. Fredga, Actu Chem. Scund., 1971, 25, 1896.


92

of thiolsulphinates gives first the disulphide (+ CNO-), which reacts further to give the sulphide (+ SCN-);640an interesting reaction between an aryl N-toluene-p-sulphonylsulphimide ArS(R)=NTs (see also Scheme 2) and DMSO at 180 "C results in the formation of aryl methyl disulphide ArSSMe, with formaldehyde (and also benzene when R = PhCH2);641 organotin sulphides R,SnSR and R,Sn(SR), (cf. ref. 65) give disulphides with sulphenyl compounds, while (R,Sn),S gives trisulphides with sulphenyl compounds and tetrasulphides with S2C12;642 and reduction of representative sulphenyl, sulphinyl, and sulphonyl chlorides and esters with Pr,NHSiC1, gives Symmetrical d i s ~ l p h i d e s . ~ ~ ~ In addition to work referred to above,630concerning unsymmetrical disulphide formation from cysteine, thiolysis of a thiolsulphinate (R1*SO.SR1 R2SH R1SSR2 RlSOH) has been employed,26using the thiolsulphinate derived from L- or D-cystine, and 2-hydroxy-3-mercaptopropionic acid as the thiol component. The least sophisticated level at which the problem of controlled synthesis of a molecule with more than one disulphide linkage can be visualized is illustrated for the peptide NH2...Cys(A). ..Cys(B). ..C02H.644An intra-chain link could be formed, or the parallel dimer [Cys(A) in one chain linked to Cys(A) in the other, and Cys(B) likewise linked to Cys(B)], or the anti-parallel dimer, as well as many more possibilities for trimers and oligomers. Continuing earlier in which factors determining the tendency for dimerization in competition with cyclization were explored, the synthesis of parallel bis-cystine dimers using selective protection methods (A = S-trityl- or S-benzoyl-cysteine; B = S-benzhydryl-cysteine)has been Insulin carries one intra-chain disulphide linkage and two inter-chain disulphide linkages, creating formidable synthetic problems; syntheses of insulin fragments carrying the link between Cys(20) in the A-chain and Cys(l9) in the B-chain are by I2 oxidation of mixtures of S-trityl-L-cysteine peptides, for which N-t-butyloxycarbonyl- and C-t-but ylprotection methods are compatible. Butyl chloride, sulphur, and a diamine NH2(CH2)nNH2(n = 2 or 6) in D M F provide dibutyl disulphide together with the trisulphide, while dibutyl polysulphides are formed when the diamine hydrotrisulphide salt (NH2CH2.CH,. NH,. H2S3) or hydropentasulphide analogue is used with BuCl and S.647 A symmetrical trisulphide is formed from trans-2-hydroxy-

+

040

641 642

1 3

644

646

646 647

--f

+

V. N. Fedoseeva and V. E. Petrunkin, Ukruin. khim. Zhur., 1970, 36, 71. K. Tsujihara, T. Aida, N. Furukawa, and S. Oae, Tetrahedron Letters, 1970, 3415. J. L. Wardell and P. L. Clarke, J . Orgunometullic Chem., 1971, 26, 345. ~ T.-H. ~ Chan, J. P. Montillier, W. F. Van Horn, and D . N. Harpp, J . Amer. Chem. SOC.,1970, 92, 7224. R. G. Hiskey, G. W. Davis, M. E. Safdy, T. Inui, R. A. Upham, and W. C. Jones, J . Org. Chem., 1970, 35, 4148. P. M. Hardy, B. Ridge, H. N. Rydon, and F. 0. dos S. P. Serrao, J. Chem. SOC.( C ) , 1971, 1722; and earlier papers in this series. B. Kamber, Helv. Chim. Acfu, 1971, 54, 398. K. Mori and Y. Nakamura, J. Org. Chem., 1971,36, 3041.


93

cyclohexanethiol, sulphur, and BuNH, ;s20 this compound had been wrongly assigned the disulphide structure some years ago. Aralkyl hydrodisulphides ArSSH react with amines to give symmetrical di- and poly-sulphides, but S-S bond cleavage into the thiol predominates in some case^.^^*^ 64B Unsymmetrical trisulphides are formed from Ph,CSSCI and thiols, or analogously from the N-phthalimido-disulphide.660The arylthio-sulphenyl chloride is obtained by treating a thiol with SCl, at - 80 0C,s61 but practical difficulties often prevent isolation of the arylthio-sulphenamide formed by its reaction with phthalimide or succinimide in D M F in the presence of a tertiary amine, viz. RlSSCl + HNR2z-+ R1SSNR22. From a broad study, the only successful examplewas the t-butylthio-sulphenylation of succinimide.s6 The use of sulphur halides in di- and poly-sulphide syntheses is illustrated by the formation of bis(fluoreny1) hexasulphides by heating fluorene with powdered Sn and S2C12,652and similar results with xylenes and an aluminium-SZC1, mixture;663thiols react with S,-2C1, to give polysulphides RS,R (n = 3-7),654 exemplified for alkenethiols. A known reaction 36S0,)suggested the study of the reaction (Ph36S02Ph S -+ PhSPh between bromobenzene and S;sss within 2-3 h at 230-250 "C, PhS,Ph mixtures (n 2 2) are formed together with S,Br2. Chlorobenzene is slower-reacting, and gives some chlorothiophenol and thiophenol in addition to polysulphides.

+

+

Properties of Disulphides.-Structural features of the disulphide bond that have recently been examined by physical methods concern both electron distribution and stereochemistry. Bond energy data for the S-S bond have been reviewed,s56emphasizing the considerable influence of substituents (e.g. the bond energy of the S-S bond in dialkyl disulphides is some three times greater than that of PhSSPh). U.V. spectra reveal considerable conjugation through the polysulphide linkage in di-alkenyl polysulphides, RS,R,664while the electron-withdrawing effect of the polysulphide linkage in ArS,Ar is shown by the shift of the ortho-proton resonance in the n.m.r spectrum to lower field with increasing n.e67 Barriers to rotation in acyclic disulphides of general formula PhCH,SSR are small, ca. 7 kcal mo1-1 or less, in the absence of a steric effect, and the low-temperature n.m.r, spectrum ( A B quartet) further indicates that the cis-form is actually of 64B 649 650

OL1 852

J. Tsurugi, Y. Abe, T. Nakabayashi, S. Kawamura, T. Kitao, and M. Niwa, J. Org. Chem., 1970,35, 3263. J. Tsurugi, S. Kawamura, and T. Horii, J . Org. Chem., 1971, 36, 3677. D. N. Harpp and D. K. Ash, Internal. J. Surfur Chem., A , 1971, 1, 211. M. Behforouz, H. Firouzabadi, and A. A. Ardakani, J . Chem. SOC.( C ) , 1971, 3550. Z. Binenfeld, A. Sakic, D. Rakin, and A. Damanski, Bull. SOC.chim. France, 1971, 2722.

653 664

666

OS7

A. Sakic, D. Rakin, M. Orlov, and Z. Binenfeld, Compt. rend., 1971, 273, C, 364. F. Feher and E. Kiewert, 2.anorg. Chem., 1970,377, 152. S. Oae and Y. Tsuchida, Tetrahedron Letters, 1972, 1283. E. N. Guryanova, Quart. Reports Sulfur Chem., 1970,5, 113. T. Fujisawa and G. Tsuchihashi, Bull. Chem. SOC.Japan, 1970, 43, 3615.

94


lower energy, the chirality axis through the sulphur-sulphur bond being the origin of the magnetic non-equivalence of the CH2 protons (196);658when R is electron-withdrawing (e.8. -CCl,), AG* for the S-S rotation is enhanced, and increasing bulk in R also increases the barrier.668 The

/S-R

S

disulphide linkage in [2,7-~ystine]-gramicidin S , a cyclic decapeptide bridged by a disulphide bond, has P-helical chirality with dihedral angle for -S-Sgreater than go", shown by n.m.r. and by c.d. data ([O],,,., - 7550 in EtOH).659 The Te-Te stretching band in diary1 ditellurides is at 167-187 cm-1; this result arises from a broad study of i.r. and Raman spectra below 400 cm-l for these compounds.660

Reactions of Disulphides and Polysu1phides.-Disulphide interchange reactions show clearly the ease with which S-S bond cleavage occurs, particularly through nucleophilic attack. Kinetic studies of exchange equilibria involving cysteine and diphenyl or dibenzyl disulphide show that high rates are associated with a high pKa of the attacking thiol and low pK' for the displaced thio1.661 The rapidly achieved equilibrium between Me,$-SMe BF4- and MeSSMe explains the catalytic effect of the fiuoroborate on disulphide interchange+reactions ;662 the intermediate cation Me,S=S(Me)-&(Me)SMe f-) Me,S-S(Me)=S(Me)SMe represents delocalization of positive charge over three sulphur atoms via (3p-3d) 7 ~ bonding.662 Benzophenone-sensitized photolysis of t-butyl disulphide in deoxygenated benzene gives a mixture of isobutane, isobutene, and t-butyl tri- and tetra-sulphides, indicating both C-S and S-S bond c l e a ~ a g e ; ~ ~ 3 the photochemical deactivation of enzymes may be associated with this process. An o-sulphenic-carboxylic anhydride intermediate is proposed to account for the faster disproportionation shown by salts of o-(pheny1dithio)benzoic acid, into diphenyl disulphide and di-(0-carboxyphenyl)disulphide, compared with the free acid.66*Cleavage of disulphide bonds in proteins by 658

E59 660 661

6u2

663

OB4

R. R. Fraser, G. Boussard, J. K. Saunders, J. B. Lambert, and C. E. Mixan, J. Amer. Chem. SOC.,1971,93, 3822. U. Ludescher and R. Schwyzer, Helv. Chim. Acta, 1971, 54, 1637. W. R. McWhinnie and P. Thavornyutikam, J. Organometallic Chem., 1972, 35, 149. H. Nogami, J. Hasegawa, N . Ikari, K. Takeuchi, and K. Ando, Chem. and Pharm. Bull. (Japan), 1970, 18, 1091. S. H. Smallcornbe and M. C. Caserio, J. Amer. Chem. SOC.,1971, 93, 5826. G. W. Byers, H. Gruen, H. G. Giles, H. N. Schott, and J. Kampmeier, f, Amer. Chem. Soc., 1972,94, 1016. L. Field, P. M. Giles, and D. L. Tuleen, J. Org. Chem., 1971, 36, 623.

Aliphatic Organo-subhur Compoiinds etc.

95

dithiothreitol may be conducted efficiently in liquid ammonia where the more usual employment of aqueous media results in poor yields. First-order thermolysis of the disulphide (197) parallels the spontaneous PhN-N

I

RHC,

S

II ,C-S-S-C,

N-NPh

II

I ,CHR

S

+

PhN-N

I;+ :I

RC+.>C=S S

PhN-N

+ RHC,I

I1

S

,C-SH

(1 97)

decomposition of the disulphide formed from dithizone [PhNHN=C(SH)-N=NPh] by SeIV-H+ oxidation, into dithizone and a meso-ionic tetrazolinethione ; the overall conversion is of a symmetrical disulphide into products of dissimilar oxidation level.666 Treatment of diphenyl disulphide with triethyloxonium tetrafluoroborate under reflux during 6 h, then hydrolysis to dealkylate the resulting sulphonium salts, gives mainly PhSEt (51%), and its p-PhS-analogue (30%) and o-isomer (473, also p-phenylthio-p'-ethylthio-diphenyl sulphide (15%) and thianthrene (8%).667 The essential feature of this reaction is S-ethylation followed by nucleophilic attack at the adjacent sulphur atom by a disulphide, but the rearrangement products are formed by an intermolecular path with some points of similarity with that of the semidine rearrangement. Formation of sulphides from disulphides is easily brought about by treatment with aminophosphines, in contrast with the lack of reactivity of simple disulphides with alkylphosphines or the necessity for photochemical activation to achieve desulphurization by phosphites.668 Aliphatic trisulphides are similarly converted into disulphides ;ssa points of mechanistic interest are the inversion of configuration at one of the carbon atoms alpha to sulphur,668and the discrimination of different phosphines between the constituent atoms of the trisulphide bond. Using PhCH2S-36S- SCH2Ph, predominant (90%) excision of the central sulphur atom is brought about with Ph3P, but only non-labelled sulphur is excised with (Et,N),P, while Bun3P causes random mono-desulphuriati ion.^^^ It would be interesting to see the outcome of reactions of these phosphines with selenotrisulphides RSSeSR, formed from thiols by treatment with selenious acid H2Se03.1s1The general equation R1- S-XX-R~ + (Et,N),P +- R1-X-R2 (Et,N),P=S now applies to di- and trisulphides, sulphenimides, thiolsulphonates, and sulphenate esters. Di-(2-pyridyl) disulphide has found a novel use as oxidant in peptide synthesis: N-benzoyl-L-leucine is coupled to glycine ethyl ester to give the protected dipeptide, when triphenylphosphine and the disulphide are added, formation of triphenyl phosphite and pyridine-2(1H)-thione balancing the

+

6os

667

Oo8 669

070

J. Meienhofer, J. Czombos, and H. Maeda, J . Amer. Chem. SOC.,1971, 93, 3080. A. M. Kiwan and H. M. N. H. Irving, Chem. Comm., 1970, 928. B. Miller and C.-H. Han, Chem. Comm., 1970,623; J . Org. Chem., 1971, 36, 1513. D. N. Harpp and J. G. Gleason, J. Amer. Chem. Soc., 1971, 93, 2437. D. N. Harpp and D. K. Ash, Chem. Comm., 1970, 811. T. Mukaiyama, R. Matsueda, and M. Suzuki, Tetrahedron Letters, 1970, 1901.

96 Organic Compounds of Sulphur, Selenium, and Tellurium Homolysis of the disulphide bond determines the addition to olefins of CF3SSCF3, on irradiation in Pyrex 1 : 1 Adducts are formed in simple cases, with some olefin oligomerization [e.g. CF2= CF2 gives CF,S(CF,- CF2),SCF3, where n is 2 or a large value].671Free-radical substitution of a perfluoroalkyl iodide with methylthio-radicals produced thermally or photolytically from MeSSMe gives perfluoroalkyl methyl sulphides as major product, with lH-perfluoroalkane~.~~~ Diphenyl disulphide reacts with diphenyl sulphoxide or diphenyl sulphone to give diphenyl sulphide and SOz, through radical intermediates, studies involving 35S- and 14C-labellingshowing that the sulphoxide cleaves at the S-0 bond at an early stage in the process, while the sulphone cleaves at C-S.673 Radical substitution at sulphur in a disulphide appears to follow &2 kinetics, but the uncertainties of conclusions drawn from rate data for these processes have been The alternative addition-elimination sequence may account for both nucleophilic and radical substitution at sulphur in a disulphide, although the accompanying Walden inversion is normally taken as conclusive support for synchronous Rearrangement of diallyl disulphides (198) occurs at room temperature through a thiosulphoxide intermediate (199); this intermediate may be

intercepted by Ph3P, leading to the m o n o ~ u l p h i d e .This ~ ~ ~is not conclusive evidence since disulphides themselves are desulphurized by phosphines, although only under relatively more drastic conditions, but facilitation of Ph,P desulphurization of (198) remains a possibility which has not been excluded. Di-( l-alkenyl) disulphides give 3,4-dialkyl-thiophens on heating with KHSOl at 15&200 "C, whereas alkyl l-propenyl disulphides give mixtures of disproport ionation products, together with 3,4-dimethylt hi ophen ;6 76 [3,3]sigmatropic rearrangement mechanisms are discussed. Insertion reactions are particularly unprofitable for disulphides and diazomethane, though under irradiation moderate yields may be obtained N2).677Diselenides give quantitative (RSSR + CHzN2-+ RSCH,SR yields under these conditions, and ditellurides are easily inserted, in a dark

+

671

672 673 674

676 676

677

G. Haran and D. W. A. Sharp, J.C.S. Perkin I, 1972, 34. R. N. Haszeldine, R. B. Rigby, and A. E. Tipping, J.C.S. Perkin I, 1972, 159. S. Oae, Y. Tsuchida, and M. Nakai, Bull. Chem. SOC.Japan, 1971, 44, 451. W. A. Pryor and K. Smith, J. Amer. Chem. SOC.,1970, 92,2731. G. Hofle and J. E. Baldwin, J. Amer. Chem. SOC.,1971, 93,6307. H. Boelens and L. Brandsma, Rec. Trau. chim., 1972, 91, 141. N . Petragnani and G. Schill, Chem. Ber., 1970, 103,2271.


97

reaction. Disulphides are readily converted into RSP(S)SR by treatment with PhP(S)C12in the presence of Mg, the effective reagent being Phy=S.s78 Thiolsu1phinates.-Acid- and nucleophile-catalysed i80-exchange rates of (+ )-180-labelled diphenyl thiolsulphinate are considerably slower than that of r a c e r n i ~ a t i o nidentifying ,~~~ O-protonation as the first step, followed by nucleophilic cleavage and recombination. The rapid final step has a PhSSPh

+ HC

II 0

PhSSPh

I OH

PhSNu

+ PhSOH

+

\

( )-PhS- SO*Ph

bearing on the chemistry of sulphenic acids, explaining why they are not isolable from such reaction mixtures. Thiolsulphinates are invariably the primary products from reactions of reactive sulphenyl compounds in water, because of the high reactivity of the sulphenic acid (PhSOH is lo5 times f more nucleophilic than H 2 0 towards P ~ S S B U ~ ~ ) . ~ ~ ~ Triphenyl phosphite ozonide, a source of singlet oxygen, gives a mixture of thiolsulphinate (90%) and thiolsulphonate RSO,.SR (10%)with simple disulphides,6s0and offers a useful preparative route to But derivatives of these types, for which the usual process using oxidation by peracetic acid is inefficient. The isolation of a thiolsulphinate from such reaction mixtures is usually complicated by its disproportionation into a mixture of the corresponding disulphide and thiolsulphonate,680a first-order process in inert solvents, interpreted through the effects of additives on reaction rates as a radical process involving homolysis of the -SO-Sbond.681 A dialkyl thiolsulphinate has two routes open to it for alternative thermolytic cleavage, one involving an a-hydrogen (200) to provide a sulphenic

(2W acid and a thione, verified by a metastable peak in the mass spectrum of the thiolsulphinate and by trapping the sulphenic acid by its addition to alkenes or alkynes.682 In fact, the alkyne adducts are formed efficiently, and this may constitute the best available method for the synthesis of +unsaturated sulphoxides. Further points of interest from this work (cf. ref. 320) are the formation of polythioformaldehyde as a white solid 67a 678 680

O8l

5

S. Nakayama, M. Yoshifuji, R. Okazaki, and N. Inamoto, Chem. Comm., 1971, 1186. J. L. Kice and J. P. Cleveland, J. Amer. Chem. SOC.,1970, 92, 4757. R. W. Murray, R. D. Smetana, and E. Block, Tetrahedron Letters, 1971, 299. P. Koch, E. Ciuffarin, and A. Fava, J . Amer. Chem. SOC.,1970, 92, 5971. E. Block, J. Amer. Chem. SOC.,1972, 94, 642.

98


by heating methyl alkanethiolsulphinates, and the formation of scrambled products when two different thiolsulphinates of this type (i.e. carrying a-hydrogens) are heated together.s82 The alternative thermolysis route (201) provides the first example of a thiosulphoxylic acid ButSSOH, and

(20 11

occurs when there is no a-hydrogen atom in the sulphenyl substituent (201).683Like sulphenic acids, the thiosulphoxylic acid can be trapped by olefins or alkynes; But*SO*SButheated with a tenfold excess of phenylacetylene at 96 "C during 6 - 8 h gives ButS*SO*C(Ph)=CH2, while pyrolysis of the thiolsulphinate alone gives isobutene, butyl polysulphides, and ButS02SSBut, a further example of thiolsulphinate disproportionati~n.~~, Thiolsulphonates.-These are the most readily available of the oxy-sulphur analogues of disulphides, for reasons touched upon in the preceding paragraph. Cleavage of dialkyl disulphides with alkanesulphinate salts, e.g. MeS0,- Na+, in the presence of AgN03 gives thiolsulphonates in high yield, in aqueous acetone, with the exception of B U ~ S S B UTrichloro~.~~~ methanesulphenyl chloride C1,CSCl provides a surprising variety of products in its reactions in aqueous media (see Vol. 1, p. 87), and the formation of the thiolsulphonate C12CHS0,SCCl,, m.p. 76 "C, from 0.5M-NaOH is a new example,o8sprobably passing through the sulphine C12C= S= O.SSs Regarded as sulphenylsulphonates, the reactions of thiolsulphonates as sulphenylating reagents are readily understood.llo Their primary interest lies in this property, both in synthesis and as substrates for the study of nucleophilic displacements at sulphur. o-Carboxyphenyl o-carboxybenzenethiolsulphonate reacts with thiols in ethanol or in pH 7 buffers, to 627 and the reagent can be used for give unsymmetrical disulphides,686p reactions with protein thiols, but it wouldnot appear to offer real advantages over standard methods, e.g. use of Ellman's reagent (p. 13). 1,3-Bis(toluene-p-sulphonylthio)propane, prepared from Br(CH,),Br and TsS- Kf, has been advocated for use in synthesis as a blocking reagent for active methylene groups, giving (202),687which is susceptible to the usual thioacetal cleavage methods. Substitution of PhSO2CH2SO2Phat its active methylene group, using a thiolsulphonate in the presence of NEt,, proceeds through a two-stage mechanism.s88 E. Block, J . Amer. Chem. Soc., 1972, 94, 644. M. D . Bentley, I. B. Douglass, and J. A. Lacadie, J . Org. Chem., 1972, 37, 333. la6 E. Dykman, Chem. Comm., 1971, 1400. .sEa L. Field and P. M. Giles, J . Org. Chem., 1971, 36, 309. 687 R. B. Woodward, I. J. Pachter, and M. L. Scheinbaum, J. Org. Chern., 1971,'36, 1137. J. K. Basscher and H. Kloosterziel, Rec. Trau. chim., 1970, 89, 402. ws w4


99

An alternative route to trichloromethyl sulphides uses thiolsulphonates as substrates for nucleophilic attack by ClsC-.66g Aminolysis reactions are not always as simple as this, benzyl p-tolyl thiolsulphinate giving dibenzyl trisulphide by aminolysis in aqueous media, with PhCH(SCH2Ph)SS02CH2Ph as minor product in some cases.6go Methanolysis of 2,4-dinitrophenyl benzenethiolsulphonate in the presence of KOH gives the expected methyl sulphenate and benzenesulphinic acid, while p-acetylaminobenzenethiolsulphinates give mainly disulphide (85%) and the two possible sulphinic acids, but no sulphenate ester, under identical conditions.*g1 Sulphonyl disulphides ArSSS0,R have been prepared by treatment of pyridinium alkane- and arene-thiolsulphonates with an arenesulphenyl chloride (ArSC1 + R1S02SR2), the products giving thiolsulphonates by PhsP d e s u l p h u r i z a t i ~ nstudies ; ~ ~ ~ using 36Sshow that the central sulphur atom is excised.692 Aminophosphine desulphurization of thiolsulphonates gives sulphones and sulphinate esters through nucleophilic attack at sulphenyl sulphur,ges~ 668 while Ph,P gives products of deoxygenation; both Ph,P and (Et,N),P attack sulphenyl sulphur in sulphenylthiolsulphonates.~g~ Sulphinyl Sulphones and a-Disulphones.-A kinetic study of the thiolysis of p-tolylsulphinyl p-tolyl sulphone, R *SO- S02R, in 60% dioxan, in the presence of HCIOl (0.001-0.4 moll-l) reveals a change-over point at lower acidities where the thiolate ion, e.g. Buns-, is detectable as a reagent, attacking sulphinyl The reaction of the unionized thiol at the same centre is not acid-catalysed, in contrast to attack by a sulphide, s.g. B U ~ S . ~General-base ~* catalysis is demonstrated for the hydrolysis of p-anisylsulphinyl p-methoxyphenyl sulphone in aqueous dioxan in the presence of a tertiary amine, the first example of general-base catalysis of nucleophilic substitution at sulphinyl s ~ l p h u r . ~The @ ~structural requirement in the amine, so that it shall show nucleophilic catalytic activity, appears to be low steric barriers around the nitrogen atom.6ga General-base catalysis is demonstrated for aryl a-disulphones ArS0,Soakthrough kinetic studies using various Et,N-Et,NH+ buffers in 60% dioxan or 60% glyme.6e6 (8s 890

H. Kloosterziel and S. Van der Ven, Rec. Trav. chim., 1970, 89, 1017. S. Hayashi, M. Furukawa, Y. Fujino, and H. Okabe, Chem. and Pharm. Bull. (Japan), 1971,19,2252.

691 692 698

696

B. G. Boldyrev and L. V. Vid, Zhur. org. Khim., 1971, 7 , 1990. Y.Abe, T. Nakabayashi, and J. Tsurugi, Bull. Chem. SOC.Japan, 1971,44,2744. D. N. Harpp, J. G. Gleason, and D. K. Ash, J. Org. Chem., 1971, 36, 322. J. L. Kice and J. D. Campbell, J. Org. Chem., 1971, 36, 2288. J. L. Kice and J. D. Campbell, J. Org. Chem., 1971, 36, 2291. J. L. Kice and G. J. Kasperek, J. Amer. Chem. SOC.,1970, 92, 3393.

2 Small-ring Compounds of Sulphur and Selenium BY D. N. JONES

1 Thiirans Formation.-The intermediacy of dihydrothiadiazoles in the formation of thiirans from aliphatic thiones by reaction with diazoalkanes is now well established. Diazomethane reacted with adamantanethione to give a mixture of the two possible dihydrothiadiazole derivatives, but with tetramethyl-l,3-cyclobutanedithione it gave only (l), suggesting that steric factors are important in determining the regioselectivity of cycloadditi0n.l The ease of thermolysis of the dihydrothiadiazoles depends markedly upon their structure, (1) decomposing to a mixture of the dithiirans (2) [diastereoisomericat C(2)] in boiling chloroform,l whilst (3), /-N

N=N

(5)

(6)

R1 = Et, R2 = Et, R3 = H (b) R1 = Et, R2 = H, R3 = Et (c) R1 = But, R2 = H,R3 = But (a)

(7)

obtained from 2-keto-l,1,3,3-tetramethylcyclobutanethione and diazomethaneY2lost nitrogen readily at room temperature to give the thiiran (4). The compound (9, obtained indirectly from cycl~hexanone,~-~ was stable

4

A. P. Krapcho, D. R. Rao, M. P. Silvon, and B. Abegaz, J . Org. Chem., 1971,36,3885. C . E. Diebert, J. Org. Chem., 1970,35, 1501. R. M. Kellog and S. Wassenaar, Tetrahedron Letters, 1970 1987. D. H. R. Barton, E. H. Smith, and B. J. Willis, Chem. Comm., 1970, 1226. D. H. R. Barton and B. J. Willis, J. C. S. Perkin I, 1972, 305.

100

Small-ring Compounds of Sulphur and Selenium

101 at its melting point (82 "C) and decomposed to (6) only at 90-100 "C, whereas the diethyl-dihydrothiadiazoles (7a) and (7b) decomposed readily above 10 "C to the corresponding 2,3-dieth~lthiirans.~ These reactions involve loss of nitrogen to give thiocarbonyl ylides, which have been tra~ped,~ and orbital symmetry considerations predict that these ylides

Ar, ,C=S Ar

RM

Ar2c-S---R

M+

Ar,C-S

Ar I Ar,c-S-C-S-R

I

M'

Ar

S

*YkAr Ar Ar Scheme 1

(8) Scheme 2

Scheme 3

102


should ring-close in a conrotatory manner. Accordingly, the transdiethyl compound (7b) and trans-di-t-butyl derivatives (7c) gave only cis-2,3-diethylthiiran and cis-2,3-di-t-butylthiiran, respectively.6 The reaction of substituted thiobenzophenones with Grignard reagents to give tetra-arylthiirans appears to involve initial thiophilic attack by the Grignard reagent (Scheme l), whereas in the reaction of trimethyl phosphite with a-chlor othioacetone * to give 2-methylphosphono-2-methyl thiiran (8) initial nucleophilic attack occurred at the thione carbon atom, with subsequent ring closure (Scheme 2). Measurement of the Arrhenius parameters for the addition of atomic sulphur, generated by gas-phase photolysis of carbon oxysulphide, to olefins to give thiirans confirmed the electrophilic nature of sulphur in this r e a ~ t i o n . In ~ an exploration of the synthetic utility of such reactions, sulphur atoms generated in solution by the photolysis of S-phenyl- and 5-amino-l,2,3,4-thiatriazoles were found to react with cyclohexene to give the corresponding thiirans, but the yields were not high.1° The epimeric forms of cholest-4-ene 2,3-episulphides and cholest-Sene 2,3-episulphides have been prepared by established methods,ll but in a more unusual reaction deoxybenzoin reacted with thionyl chloride to give 1,2-dibenzoyl-l,2-diphenylthiiran.12 The thiiran derivative (9) was formed photocatalytically from (10) as shown in Scheme 3,13 and in a more remarkable photochemical reaction (12) and (13) were both converted into

H’“ (12) (13)

R1 = Et, R2 = H R1 = H, R2 = Et

(14) (15)

R1 = Et, R2 = H R1 = H, R2 = Et

a mixture of the unstable thiiran derivatives (14) and (15).14 Existing theory does not readily account for the stereoselectivity of these transformati~ns.~~ Spectroscopic and Conformational Aspects.-According to SCF (CND0/2) theory, the U.V. spectrum of thiiran can be accounted for only if d-orbitals are in~1uded.l~ Precise signal assignments and coupling constants are now a

lo l1 la la l4

l5

R. M. Kellog, S. Wassenaar, and J. Buter, Tetrahedron Letters, 1970, 4689. P. Beak and J. W. Worley, J. Amer. Chem. SOC.,1972, 94, 597. E. Gaydou, G. Peiffer, and A. Guillemonat, Tetrahedron Letters, 1971, 239. 0 . P. Strausz, W. B. O’Callaghan, E. M. Lown, and H. Gunning, J. Amer. Chem. SOC., 1971, 93, 559. R. Okazaki, K. Okawa, S. Wajiki, and N. Inamoto, Bull. Chem. SOC.Japan, 1971, 44, 3 167. T. Komeno and H. Itani, Chem. and Pharm. Bull. (Japan), 1970, 18, 608. C. J. Ireland and J. S . Pizey, J. C . S. Chem. Comm., 1972, 4. A. G. Anastassiou and B. Y.-H. Chao, Chem. Comm., 1971, 979. R. M. Kellog, J. Amer. Chem. SOC.,1971, 93, 2344. D. R. Williams and L. T. Kontnik, J. Chem. SOC.(B), 1971, 312.

Small-ring Compounds of Sulphur and Selenium 103 available for the n.m.r. spectra of thiiran and 2-methylthiiran,l6 whilst a detailed n.m.r. and i.r. study of /3-hydroxy-thiirans indicated transannular intramolecular hydrogen-bonding between sulphur and hydroxy-group, and it was suggested that benzene formed a collision complex with these molecules in which the planes of the benzene ring and the thiiran ring were approximately perpendi~u1ar.l~Dipole moment data for cyclohexanespirothiiran and l-t-butylpiperidine-4-spiro-2’-thiiranshowed that the conformer (16a) with an axial C-S bond was more stable than the conformer (16b) by 0.42 kcal mol-l, a value which is appreciably smaller than

(16b)

the difference in the conformational free-energies of the methyl- and methylthio-groups.l8 This diminished conformational preference is due, at least in part, to the effect of the angles in the thiiran ring in reducing the syn-axial interactions in the cyclohexane ring. Reactions.-The apparent lack of uniformity in the mode of reaction of thiirans with amines is readily explained in terms of the relative nucleophilicity of the nitrogen and sulphur atoms in the #3-amino-thiols formed initially by cleavage of the thiiran ring.18 With amines of high basicity, and in polar solvents, the /3-amino-thiols form thiolate anions which react further with the thiiran to give 2-mercaptoethyl 2’-(alky1amino)ethyl sulphides, and associated oligomers and polymers, but with weakly basic amines, in solvents of low polarity where the thiol group does not ionize, the amino-group is the more nucleophilic and attacks a further molecule of the thiiran. Hence thiiran reacted with aniline in the absence of catalysts and solvents to give, first, (2-mercaptoethy1)aniline and subsequently di-(2-mer~aptoethyl)aniline,~~ and glycine reacted similarly. The thiolate anions derived from a-mercaptoketones attacked thiirans to give alkyl 2-thia-4-mercaptoalkyl ketones, which on acid-catalysed cyclization gave substituted 2,3-dihydro-1,4-dithiins.2o The reactions described above 199 2o involve nucleophilic attack on a thiiran-ring carbon atom, but the cleavage of thiiran to give 1,6-dichloro3,4-dithiahexane on treatment with 3-dichloroiodopyridine 21a and the cleavage of thiiran derivatives by a-chloro-ethers to give S-(/%chloro-aIkyl)monothioacetals 21b almost certainly involve nucleophilic attack by chloride 16

17

M. Ohtsuru, K. Tori, and M. Fukuyama, Tetrahedron Letters, 1970, 2877. K. D. Carlson, D. Weisleder, and M. E. Daxenbichler, J . Amer. Chem. Soc., 1970,92, 6232.

18

19

ao 21

R. A. Y. Jones, A. R. Katritzky, P. G. Lehman, A. C. Richards, and R. Scattergood, J. C. S. Perkin ZZ, 1972, 41. L. G. Bulavin, J. Org. Chem. (U.S.S.R.), 1971, 7, 2703. F. Asinger, A. Saus, H. Offermans, and P. Scherberich, Annalen, 1971, 753, 151. (a) E. Vilsmaier and W. Sprugel, Annalen, 1971,749,62; (b) E. Vilsmaier and W. Schalk, ibid., 1971, 750, 104.

104


ion on an initially formed thiiranium ion. 2-Methylthiiran, for example, with chloromethyl methyl ether gave a mixture of 6-chloro-2-oxa-4in the ratio 1 : 4, thiaheptane and 6-chloro-5-methyl-2-oxa-4-thiahexane a result consistent with the expected modes of cleavage of l-methoxymethyl2-methyl thiiranium ion with chloride ion.21bLithium alkyls attack thiirans solely at sulphur, 1-methylthiiran, for example, giving propylene and lithium ethanethiolate, which reacts further with 2-methylthiiran to give polymeric products.22 According to e.p.r. spectroscopy, photolysis of thiiran (adsorbed on porous Vycor glass) results predominantly in homolysis of a C-S bond,23a phenomenon implicated 24 in the photolytic conversion of the thiiran derivative (9) into the fluxional 9-thiabarbaralene (1 1) (Scheme 3); heating alone converted (9) into (lO).I3 The synthetic potential of the easy loss of sulphur from suitable thiirans to give olefins continues to attract attention. A valuable method of alkylative coupling leading to the synthesis of secondary vinologous amides and enolizable /3-dicarbonylcompounds takes advantage of the rapid abstraction of sulphur from thiirans, formed onIy as transient intermediates, by tervalent phosphorus An elegantly conceived potential synthesis of highly hindered olefins involved the desulphurization by tervalent phosphorus compounds of thiirans formed in situ by thermolysis of dihydrothiadiazoles 4 * or 1,3-0xathiolan-5-ones.~ Where particularly stable unsaturated compounds may result, loss of sulphur occurs thermally, as in the conversion of 3,4-dibromo-7-thiabicyclo[4,1 ,O]heptane and bis-endo-2,5-dichloro-7-thiabicyclo[2,2, llheptane into benzene and sulphur on treatment with non-nucleophilic bases,26the reactive intermediate being thianorcaradiene (17). The conversion of active-methylene compounds

into tetrasubstituted ethylene derivatives on treatment with thionyl chloride also probably involves the ready thermal loss of sulphur from intermediate thiirans.12 Thiiran was also postulated as an intermediate in the formation of a complex mixture of products formed by subjecting ethylene and hydrogen sulphide to an electric di~charge.~'

2 Thiiran 1-Oxides Formation.-Thiiran 1-oxides are conveniently prepared by the oxidation of thiirans with peroxybenzoic acid or rn-chloroperoxybenzoic acid in 22

23

24

25 26 27

M. Morton and R. F. Kammereck, J. Amer. Chem. SOC.,1970, 92, 3217. P. S. H. Bolman, I. Safarik, D. A. Stiles, W. J. R. Tyerman, and 0. P. Strausz, Canad. J. Chem., 1970, 48, 3872. A. G. Anastassiou and B. Y.-H. Chao, J. C. S. Chem. Comm., 1972, 277. M. Roth, P. Dubs, E. Gotschi, and A. Eschenmoser, Helv. Chim. Acta, 1971,54,710. T. J. Barton, M. D. Martz, and R. G. Zika, J. Org. Chem., 1972, 37, 552. Y . Nishimura and K. Kawarnoto, Bull. Chem. SOC.Japan, 1972, 45, 274.


105

methylene chloride at 0 "C,followed by precipitation of the aromatic acid as its sodium salt.2s This procedure minimizes acid-catalyscd ring opening. Oxidation of thiirans with peroxy-acids proceeds from the lcast hindered side of the 2D 1,3-Elimination of bromine from the meso-dibromide (18) by treatment with tris(dimethy1amino)phosphine gave only cis-2,3diphenylthiiran trans-1-oxide (19), revealing that the elimination occurred Ph

PI1

with inversion of configuration at each reacting centre.29 Similarly, ( k )-a,a'-di bromobenzyl sulphoxide gave only trans-2,3-diphenylthiiran l-oxide.29 N.m.r. Characteristics.-Full details of the n.m.r. characteristics of a number of 2,2-disubstituted- and 2,3-disubstituted-thiiran1-oxides are now available ;2s solvent-induced shifts were particularly useful for assigning configuration. The geminal coupling constants in thiiran 1-oxide (- 6.4Hz) and 2-methylthiiran 1-oxide (- 6.0 Hz) were appreciably more negative than those in thiiran (- 0.7 Hz) and 2-methylthiiran (- 0.8 Hz), respectively;16 the trend to greater negative value of J,,, with increasing group electronegativity of the heteroatom is the converse of the usual n.m.r. behaviour of three-membered heterocycles.16 The vicinal coupling constants for the syn-protons, namely 11.5 and 11.7 Hz, in thiiran 1-oxide were also abnormal.16

Reactions.-Thiiran 1-oxides bearing alkyl groups cis to sulphinyl oxygen are unstable at ambient temperature, trans-2,3-dimethylthiiran 1-oxidc (20), for example, decomposing very readily into a sulphenic acid (21), probably by way of an intramolecular /%eliminationfacilitated by relief of strain in the ring of thiiran l-oxide.28s30 The sulphenic acid undergoes rapid dehydrative dimerization to a mixture of diastereoisomeric allylic thiolsulphinates (22),28s30 which are themselves in equilibrium with allylic sulphoxylates (23) by way of [2,3]sigmatropic rearrangement^.^^ In the presence of triethyl phosphite the sulphenic acid (21) is trapped, being converted into 2-mer~aptobut-3-ene.~~ However, rapid thermolysis of trans-2,3-dimethylthiiran1-oxide (20) at 200-340 "C gave a mixture of cis- and trans-but-2-enes in which the latter slightly predominated. At these temperatures cis-2,3-dimethylthiiran trans-1-oxide, which was stable at room temperature, also extruded sulphur monoxide to give cis- and 28

30

K. Kondo and A. Negishi, Tetrahedron, 1971, 27, 4821. B. B. Jarvis, S. D. Duthey, and H. L. Ammon, J. Amer. Chem. SOC.,1972, 94, 2136. J. F. Baldwin, G . Hofle, and S. C . Choi, J. Amer. Chem. SOC.,1971, 93, 2810.

106


-

H Me

H (20)

(21)

trans-but-2-enes, but with much higher stereoselectivity (95 : 5 cis : trans at 200 "C)and yields than for the trans-isomer (20).30Biradical intermediates (Scheme 4) in which bond rotation may occur were invoked in order to

+ M e F H +SO H Scheme 4

account for the lack of complete stereospe~ificity.~~ The thermolysis of thiiran l-oxide has been utilized as a convenient method for preparing sulphur monoxide for addition to cyclo-0~tatetraene.l~ 2,3-Dibenzoyl-2,3-diphenylthiiran1-oxides (24) behaved very differently to the 2,3-dimethylthiiran l-oxides on heating, giving mainly benzil and thiobenzil together with a little cis- and trans-dibenz~ylstilbene.~~ The stereochemistry at sulphur had no effect upon the mode of decomposition. Similar results were obtained on photolysis, and a common intermediate for thermolysis and photolysis was p o s t ~ l a t e d ,possibly ~~ a vibrationally D. C. Dittmer, G. E. Kuhlmann, and G . C.Levy, J . Org. Chem., 1970,35, 3676.

Small-ring Compounds af Sulphur and Selenium 107 excited molecule, which rearranged to a transient 1,Zoxathietan (25) and subsequently fragmented (Scheme 5). 0 II Pli..&'h

c=o

o=c

I Ph

t Ph

s-0 Ph.. I I .Ph J-%

o=c I

Ph

(24)

-~

CEO

I Ph

(25)

o=c 1

-

-

s o

It II Ph-C-C-Ph

+

0 0 II II Ph- C-C-Ph

c=o 1

Ph Scheme 5 Ph

Alkyl chloromethyl ethers react with thiiran l-oxide to give sulphenic esters (26), probably by way of an intermediate sulphoxonium salt (27).92 Thiiran oxide in FS03H-SbF, at - 78 "Cwas protonated at sulphur and not at oxygen, according to n.m.r. studiesea3 CICH,CH,SOCH,OR

1>8-OCH20R

3 Thiiran 1,l-Dioxides The synthesis of thiiran 1,l-dioxides and their decomposition to olefins has been reviewed.34 The thermal decomposition of many thiiran 1,I-dioxides at 25-50 "C to give sulphur dioxide and alkenes continues to be exploited for synthetic purposes, especially in the Ramburg-Backlund rearrangement, where a transient thiiran 1,l-dioxide is generated by baser catalysed dehydrohalogenation of an a-halogeno-sulphone.a6s In the Ramburg-Backlund rearrangement of threo-2-bromo-2,4-diphenyl-3-thiapentane 3,3-dioxide to trans-2,3 -diphenylbut-2-ene, decomposition of the intermediate trans-2,3-dimethyl-2,3-diphenylthiiran1,l-dioxide was the rate-limiting whereas usually loss of halide ion is rate-limiting. The 32

33 3Q 35 s6

3'

E. Vilsmaier and B. Hloch, Synthesis, 1971, 590. G. A. Olah and P. J. Szilagyi, J. Org. Chern., 1971, 36, 1121. N. H. Fischer, Synthesis, 1970, 393. L. A. Paquette, J. C. Philips, and R. E. Wingard, J. Amer. Chem. SOC.,1971,93,4516. L. A. Paquette and R. A. Homer, J. Amer. Chem. SOC.,1971, 93, 4522. F. G. Bordwell, E. Doomes, and P. W. R. Corfield, J. Amer. Chem. Soc., 1970,92,2581.


108

reaction apparently proceeded with inversion at both chiral centres, although the possibility of double retention was not excluded by the data. In the thermolysis of some thiiran 1,l-dioxides it appears that the sulphur dioxide moiety is retained, and C-C bond fission occurs instead. For example, the chloro-sulphone (28) on treatment with potassium t-butoxide in THF gave only the t-butyl ether (29), and no [4,2,2]propella3,7-diene, which would be the product of Ramburg-Backlund rearrangement.36 This unusual displacement with retention of configuration was

$3 (28) R = CI (29) R = Bu'O

ASO2 p&so2 -

H

H

(30) (31)

rationalized in terms of the addition of t-butyl alcohol to the dipolar species (30), arising from the C-C bond fission of an intermediate thiiran 1,l-dioxide (31), a process which is facilitated by considerable release of angle In another example, vinyldiazomethane on treatment with sulphur dioxide furnished 4,5-dihydrothiepin 1, l - d i o ~ i d e undoubtedly ,~~ by way of a rapid sigmatropic rearrangement of the initially formed cis-2,3-divinylthiiran 1,l-dioxide. cis-2-Phenyl-3-vinylthiiran1,l-dioxide, formed by reaction of vinyldiazomethane with benzylidene sulphone, also rearranged spontaneously in an analogous manner.38 Thiiran 1,l-dioxide reacts with alkyl chloromethyl ethers in the presence of zinc chloride to give a1koxymethyl 2-chloroet hyl sulphones.30

4 Thiiren 1-Oxides and Thiiren 1,l-Dioxides Formation.-Experimental details are now available for the synthesis of diphenylthiiren 1,l-dioxide (32) from a,a'-dibromodibenzyl sulphone by treatment with triethylamine.*O It is also formed by base-catalysed dehydrohalogenation of a,a-dichlorobenzyl benzyl s ~ l p h o n e , whilst ~~ similar treatment of a,a'-dibromobenzyl sulphoxide (18) afforded diphenylthiiren 1-0xide.~~ Alkyl-substituted thiiren 1,l-dioxides (33), (34), and (35), which could not be synthesized by this method, were obtained by dehydrobromination of the appropriate bromothiiran 1,l-dioxides (36), (37), and (38), catalysed by triethylamine or 1,5-diazabicyclo[4,3,0]non-5-ene.40 The bromothiiran 1,l-dioxides were synthesized from the appropriate L. A. Paquette and S. Maiorana, Chem. Comm., 1971, 313. E. Vilsmaier and B. Hloch, Synthesis, 1971, 428. 4 0 L. A. Carpino, L. V. McAdams, R. H. Rynbrandt, and J. W. Spiewak, J. Amer. Chem. SOC.,1971, 93,476. J. C. Philips, J. V. Swisher, D. Haidukewych, and 0. Morales, Chem. Comm., 1971,22. ra L. A. Carpino and H.-W. Chen, J. Amer. Chem. SOC.,1971, 93, 785.

38

as


R1

R2

w S

0 2

(32) R1 = ( 3 3 ) R1 = (34) R' = ( 3 5 ) R1 =

R2 = Ph R2 = Me H , R2 = Me

Me, R2 = Ph

109 H Br

R l Y R 2 0, (36) R1 = R2 = Me (37) R1 = H, R2 = Me (38) R1 = Ph, R2 = Me

diazoalkanes, which were treated with a-bromoethanesulphonyl bromide and trieth~lamine.~~ Reactions.-Diphenylthiiren 1-oxide, which is unique in being both potentially aromatic (assuming the possibility of d-orbital conjugation effects) and potentially antiaromatic because of the presence of an unshared electron-pair on the heteroatom, is more stable thermally than diphenylthiiren 1,l-dioxide (32).42 This is surprising in view of the fact that conjugative effects in sulphoxides are generally greater than those in sulphones. Diphenylthiiren 1,l-dioxide (32) is itself more stable than 2,3-diphenylthiiran 1,l-dioxide, a phenomenon not solely attributable to conjugation effects since dimethylthiiren 1,l-dioxide (33) is even more stable thermally.40 From the data yet available no clear picture emerges of the electronic nature of these new heterocycles. In refluxing benzene, diphenylthiiren 1,l-dioxide (32) gave diphenylacetylene and sulphur 41 a phenomenon also observed for the strong complexes of thiiren 1,l-dioxides with zerovalent Diphenylthiiren 1,l-dioxide behaved conventionally in being reduced by aluminium amalgam to 2,3-diphenylthiiran 1,l -dioxide, and in undergoing cycloaddition with diphenyldiazomethane to give, after rearrangement, a-diazobenzyl 1,l-diphenylvinyl sulphone, and, after loss of sulphur dioxide and prot otropy, 3,4,5-triphenylpysa~ole.~~ Similarly, hydrazine and hydroxylamine underwent nucleophilic addition to (32) to give sulphur dioxide, and deoxybenzoin and deoxybenzoin oxime, respectively, whilst with hydroxide ion 1,2-diphenylethylene-l-sulphonic acid was formed. Lithium aluminium hydride and phenylmagnesium bromide reacted anomalously with (32), giving respectively diphenylacetylene and, after acidification, benzenesulphinic acid.40 5 Thiiranium and Thiirenium Ions Protonated 2-methylthiiran exists as cis- and trans-isomers in FS03H-SbF6 at - 78 "Caccording to n.m.r. data.33 Data pertinent to the relative rates of nucleophilic attack at carbon and sulphur in thiiranium ions were provided by an investigation concerned primarily with the exchange of 4-chlorobenzenesulphenyl chloride between cyclic chloroalkyl 4-chlorophenyl 4s

J. P. Visser, C. G. Leliveld, and D. N. Reinhoudt, J. C. S. Chem. Comrn., 1972, 178.


110

sulphides and oct- 1-ene,44 exemplified for the cyclo-octyl derivative in Scheme 6. The order of rates of exchange for the cyclic derivatives was 9 fi: 8 > 7 z 5 > 6-membered ring, in accord with the expected ease of sp2 hybridization in the ring systems. It was estimated that attack at carbon in

Ar=

0

Ar SCH,CHC,H,, I CI

Cl Scheme 6

the thiiranium ions occurred appreciably faster than at in contrast to the reported behaviour of cyclo-octene-S-methylthiiranium 2,4,6-trinitrobenzoate. Uncommon bridgehead thiiranium ions have been proposed as reactive intermediate^,^^ and the thiiranium ylide (40) is

probably an intermediate in the formation of the diene (41) from the carbene (39) produced by photolysis of a-allylthioacetophenone toluene-psulphonylhydrazone.4e Calculations 47 have indicated that thiirenium ions, invoked as intermediates in the solvolysis of /3-arylthiovinyl sulphonic 44 45

4e

47

G. H. Schmid and P. H. Fitzgerald, J. Amer. Chem. SOC.,1971,93,2541. (a) F. H. Deckers, W. N. Speckamp, and H. 0. Huisman, Chem. Comm., 1970, 1521 ; (b) E. R. de Waard, W. J. Vloon, and H. 0. Huisman, Chem. Comm., 1970, 541. K. Kondo and I. Ojima, J. C . S. Chem. Comm., 1972, 62. A. S. Denes, I. G. Csizmadia, and G. Modena, J. C. S. Chem. Comm., 1972, 8.


111

esters 48 and in the addition of sulphur dichloride to substituted acetylene^,^^ are substantially more stable than the acyclic #I-thiovinylcationic alternative. 6 Thiaziridines Thiaziridines have been postulated as reactive intermediates in the photochemical rearrangement of t h i a z o l e ~ ,isothiazoles,61~~ 62 and 4-aryl-l,3,2oxathiazolium 5-0xide,~~ and in the conversion of oxaziridines into imines and elemental sulphur on treatment with thiourea, potassium thiocyanate, or potassium ethyl ant hate.^^ Irradiation of a mixture of N-sulphinylaniline and diphenyldiazomethane gave N-diphenylmethyleneaniline,which was probably formed by extrusion of sulphur monoxide from 2,3,3-triphenylthiaziridine l-oxide formed as an i n t e r ~ e d i a t e . ~ ~

7 Thietans Formation-By Intramolecular Displacement Reactions. Syntheses that use the intramolecular nucleophilic displacement of a suitable leaving group by a thiolate anion have been exemplified by the preparation of (S)-2-methylthietan from (R)-(-)-1,3-dibromob~tane,~~ of 2-phenylthietan from 1-phenyl-1-chlor0-3-bromopropane,~~ and of 2-methyl-3-alkylthietansfrom l-methyl-2-alkyl-l,3-dibromopropane 58 by reaction with thiourea in aqueous sodium hydroxide. Base-catalysed cyclization of a mixture of the diastereoisomeric forms of 1,3-diphenyl-3-chloropropanethiol gave a mixture of cis- and trans-2,4-diphenylthietanYfrom which only the transisomer was obtained pure by crystallizati~n.~~ Even strained thietans have been formed by this method, trans-3-chlorocyclopentylthioacetate on treatment with aqueous ethanolic potassium hydroxide furnishing 5-thiabicyclo[2,l,l]he~ane.~~ This general mechanism also pertains in the partial desulphurization by tris(diethy1amino)phosphine of 4-phenyl-1,2dithiolan to 3-phen~lthietan.~~ Esters and amides of a-lipoic acid were converted into the corresponding 2-substituted thietan derivatives by this 48

49

6o

I1 6a

63 64

G. Capozzi, G. Melloni, and G.Modena, J. Chem. SOC.(C), 1970,2621,2625; J . Org. Chem., 1970, 35, 1217; J. Chem. SOC.(C), 1971, 3018; G. Capozzi, G. Modena, and U. Tonellato, J . Chem. SOC.(B), 1971,1700; G. Modena and U. Tonellato, ibid., p. 381 ; A. Burighel, G. Modena, and U. Tonellato, Chem. Comm.,1971, 1325. T. J. Barton and R. G. Zika, J. Org. Chem., 1970, 35, 1729. M. Kojima and M. Maeda, Chem. Comm., 1970, 386. M. Ohashi, A. Lio, and T. Yonezawa, Chem. Comm., 1970, 1148. J. P. Catteau, A. Lablanche-Combier, and A. Pollet, Chem. Comm., 1969, 1018. H. Gotthardt, Tetrahedron Letters, 1971, 1277. D. St. Clair Black and K. G. Watson, Angew. Chem. Internat. Edn., 1971, 10, 327.

66 66

67 68

6e

J. 0. Stoffer and H. R. Musser, Chem. Comm., 1970,481. L. A. Paquette and J. P. Freeman, J . Org. Chem., 1970, 35, 2249. C. Schaal, Compt. rend., 1970, 271, C, 1015. A. V. Bogatskii and T. I. Davidenko, J. Org. Chem. (U.S.S.R.), 1971, 7, 1608. R. M. Dodson, E. H. Jancis, and G. Klose, J. Org. Chem., 1970,35,2520. I. Tabushi, Y. Tamaru, and Z. Yoshida, Tetruhedron Letters, 1970, 2931. D. N. Harpp and J. G. Gleason, J. Org. Chem., 1970,35, 3259.


112

n

Scheme 7

method,s1 and trans-3-phenyl-4-benzoyl-1,2-dithiolan into trans-2-phenyl3-ben~oylthietan.~~ Pyrolysis of the sodium salts of a diastereoisomeric mixture of 2-hydroxy-4-thiocyanatopentanesgave a mixture of cis- and trans-2,4-dimethylthietan,which were separated chr~matographically.~~ This reaction is related to the conversion of 1,3-dioxan-2-ones into thietans by treatment with potassium thiocyanate, the stereochemical and mechanistic course of which was revealed56by the transformation of the 0 II

c1 0

SOCI?

PhCH2CHZCCH3

___f

I II PhCHZC-C-CH, I

J

0

PhCH

S-J Scheme 8

Padwa and R. Gruber, J. Org. Chem., 1970,35, 1781. B. M. Trost, W. L. Schinski, F. Chen, and I. B. Mantz, J . Amer. Chem. SOC.,1971,93, 676.

e3 A. 63

- HCl

f-------


113

cyclic carbonate (42) derived from (R)-(-)-1,3-butanediol into (S)-( -)-2methylthietan (43) (Scheme 7). The nucleophilic displacement of chloride from a sulphenyl chloride by an enolate anion is apparently involved in the formation of 3-thietanone derivatives from alkyl methyl ketones, such as 4-phenylbutan-2-0ne,~~ on treatment with thionyl chloride in pyridine (Scheme 8). The reaction of 2,2-dimethyl-1,3-dibromopropane with potassium selenocyanate in ethanol, followed by treatment with sodium ethoxide, gave 3,3-dimethyl~elenetan.~~ By Cycloadditions involving Thiocarbonyl Compounds. The photocatalysed cycloaddition of thiocarbonyl compounds to olefins to form thietans has been reviewed.66 The photo-addition of thiobenzophenone to cis- and trans-dichloroethylene and to cis-dicyanoethyleneapparently proceeds with retention of configuration in the olefin moiety.87 Allenes participate in such reactions, thiobenzophenone with tetramethylallene 68* 6g and methoxyallene,sg for example, giving the thietan derivatives (44) and (45). Thiobenzophenone in its triplet excited state apparently attacks the central

(44) R1 (45)

R1

= R2 = R3 = = = =

R2 R3

= Mc, R6 = R' = Ph H, R4 = OMe, R5 = RC = Ph

R4

carbon atom of the allene to form a biradical species, which cyclizes to a thietan after spin-inversi~n.~~ Photochemical cycloadditions of nonaromatic thiones have been described for the first time, adamantanethione and a-methylstyrene on irradiation giving (46), whilst (47) and (48) were

(46) R1 = Me, R2 = Ph (47) R1 = H, R2 = OEt

(48)

R1

=

R2 = Ph

formed with ethyl vinyl ether and with l,l-diphenylethylene.70 The intermediacy of biradicals in these reactions was established. Bis(trifluor0methyl)thioketen, a versatile reagent for the synthesis of many cyclic 64 6c

67 68 6s

70

A. J. Krubsack, T. Higa, and W. E. Slack. J. Amer. Chem. SOC., 1970, 92, 5258. A. Geens and M. Anteunis, Bull. Soc. chim. belges, 1971, 80, 639. A. Ohno, Znternat. J. Surfur Chem. (B), 1971, 6, 183. S. Kumakura, T. Shimozawa, Y. Ohnishi, and A. Ohno, Tetrahedron, 1971, 27, 767. H. Gotthardt, Tetrahedron Letters, 1971, 2345. H. J. T. Bos, H. Schinkel, and Th. C. M. Wijsman, Tetrahedron Letters, 1971, 3905. C. C. Lido and P. de Mayo, Chem. Comm., 1971, 1525.

114 Organic Compounds of Sulphur, Selenium, and Tellurium sulphur compounds, also reacted regioselectively with a large variety of olefins, including keten, to give t h i e t a n ~ . ~ ~ Photo1ysis.-Photochemical transformations of thietan derivatives have not received much attention, but it appears that the initial process is homolysis of a C-S bond,23,62 and that extrusion of sulphur is not 62, 72 in contrast to the case for thiirans. A reversed [2 2lcycloaddition may occur via initial homolysis of the C-S bond, 2,2-diphenyl-3,3-dimethyl-4isopropylidenethietan, for example, giving 1 ,1diphenyl-2,Zdimethylethy1eneyseand trans-2-phenyl-3-benzoylthiiranbeing converted into a mixture of cis- and trans-benzalacetophenoney62 probably by way of its triplet excited state. Thietan vapour on photolysis gave mixtures containing ethylene, propylene, and polymer, and on prolonged irradiation, 2-1nethylthiiran.~~

+

chloromethyl ether Other Reactions involving Ring Fission.-Methyl reacted with thietan to give 2-oxa-4-thia-7-chloroheptaneand with 2-methylthietan to give a mixture of 5-methyl- and 7-methyl-7-chloro-20xa-4-thiaheptane.~~ 3-Dichloroiodopyridine chlorinated thietan with fission of the ring to give 1,8-dichloro-4,5-dithiaoctane,z1u and ring-opened products were obtained when thietans were treated with lithium alkyls, e.g. 2-methylthietan with ethyl-lithium gave l-lithio-3-methyl-4-thiahexaneY which reacted further with 2-methylthietan to give polymeric products.22 2,2-Diphenyl-3,3-dimethyl-4-isopropylidenethietanwith concentrated sulphuric acid gave a mixture of benzophenone, di-isopropyl ketone, and hydrogen sulphide.g8 Reactions of the thietan ring in thiamine anhydride have received further attention, treatment with hydrogen sulphide in DMF converting it into a 1,Zdithiolan ring,74whilst it is cleaved by thiophenols to give acyclic disulphides7s and by thiolacetic acid to give, by intramolecular recycliza t ion, a thiazolinethi one. trans-2,4-Diphenylthietanwith potassium t-butoxide in DMF gave nine products, four of which were identified as 2,3,5-triphenylthiophenY1,2,4,5tetraphenylbenzene, 1,3-diphenyl-l-propanone, and, tentatively, 1,4,5,7tetraphenyl-2,3-dithiabicycl0[2,2,2]0ctane.~~ The 1,2-diphenylcyclopropylthiolate anion was considered to be an intermediate in these reactions. Thietanium Ions.-Methylation of ~is-2~4-dimethylthietanwith trimethyloxonium fluoroborate gave the cis-S-methylthietanium ion (49) stereospecifically, but 2,2,4-trimethylthietan gave a mixture of the sulphonium salts (50) and (51) isomeric at sulphur.63 In the ion (49) and that (52) derived from trans-2,4-dimethylthietanYthe S- Me group adopted the 71

7s 7'

76 76

M. S. Raasch, J. Org. Chem., 1970, 35, 3470. H. A. Wiebe and J. Heicklen, J. Amer. Chem. SOC.,1970, 92, 7031. E. Vilsmaier and W. Schalk, Synthesis, 1971, 429. A. Takamizawa, K. Hirai, and T. Ishiba, Chem. andPharm. Bull. (Japan), 1971,19,1022. A. Takamizawa, K. Hirai, and T. Ishiba, Chem. andPharm. Bull. (Japan), 1971,19,2009. A. Takamizawa, K. Hirai, and T. Ishiba, Chem. andPharm. Bull. (Japan), 1971,19,2222. R. M. Dodson and J. Y. Fan, J. Org. Chem., 1971,36,2708.


115

equatorial orientation according to the n.m.r. spectra of these ions, and the invariance up to 80 "Cof the n.m.r. spectra of (50) and (51) suggested that inversion at sulphur was considerably slower than in acyclic sulphonium salts. The butyl-lithium-induced stereospecific fragmentation Me Mc MeG - M e

R2

Bu

Me

(49) R1 = Me, R2 = H (50) R1 = R2 = Me (52) R1 = H, R2 = Me

(51)

(53) cis-2,4 (54) trans-2,4

of (49) and (52) to trans- and cis-1,2-dimethylcyclopropane has now been described more fully.63 The proposed mechanism involved stereospecific fragmentation (with retention of configuration) of the intermediate sulphuranes (53) and (54) to methyl butyl sulphide and 1,3-biradicals, which underwent conrotatory ring closure to the 1,2-dimethylcyclopro pane^.^^ A sulphwane intermediate was also implicated in the formation of oxaspiropentanes from cyclopropylsulphonium salts and carbonyl compounds (Scheme 9).78 The carbene (55) formed by photolysis of the BF4PhzSf

A

Ph I

0

+

II

C

/ \

R1 K2

Ph

Scheme 9

sodium salt of 3-crotylthio-3-methylbutyrophenonetoluene-p-sulphonylhydrazone apparently cyclized (Scheme 10) to the thietanonium ylide (56), which subsequently underwent a [2,3]sigmatropic rearrangement to give (57) or else a Stevens-type rearrangement to produce the thiolan (58).46 In both cases diastereoisomeric mixtures of the products were formed. The base-catalysed exchange of deuterium with the hydrogen atoms of the M. J. Bogdanowicz and B. M. Trost, Tetrahedron Letrers, 1972, 887.

116


(55)

h

e

(56)

(58)

Scheme 10

S-methyl group in the S-methylthietanium ion occurred very much faster than exchange with the a-methylene protons in the ring, a phenomenon attributed to the difference in hybridization in the exocyclic and endocyclic 8 Thietan 1-Oxides, Thietan 1,l-Dioxides, and Thiet 1,l-Dioxides Formation.-By Oxidation of Thietans. The stereoselectivity of the oxidation of 3-alkylthietans to their cis- and trans-1-oxides was less sensitive to the nature of the oxidant than in the 4-alkylthian system, although the pattern of results was roughly comparable.8o The ratio of cis- to trans-1-oxide was greatest (3 : 1) with dinitrogen tetroxide as oxidant, and least (1 : 2) when N-chlorotriazole was used, hydrogen peroxide and peroxy-acids giving a 46 : 54 ratio.80 With cis-2,4-diphenylthiiran, however, hydrogen peroxide in formic acid gave only cis-2,4diphenylthietan trans-l-o~ide,~~ consistent with ‘steric approach control’. The possible hazards associated with the oxidation of 3-hydroxythietan to its dioxide,81which is used in the synthesis of thiet l,l-dioxide,82have been outlined. By Cycloadditions involving Sulphenes. The cycloaddition of sulphenes to electron-rich olefins remains a convenient method of preparing compounds with the thietan ring system. In their preparation of 3-substituted thietans, 79

81

8a

G. Barbarella, A. Garbesi, and A. Fava, Helv. Chim. Acta, 1971, 54, 2297. W. 0. Siegl and C. R. Johnson, J. Org. Chem., 1970, 35,3657. D. C. Dittmer, M. F. Christy, N. Takashina, R. S. Henion, and J. M. Balquist, J . Org. Chem., 1971, 36, 1324. J. F. King. P. de Mayo, C. L. McIntosh, K. Piers, and D. J. H. Smith, Canad. J . Chem., 1970, 48, 3704.


117

Siegl and Johnson 8o formed 3-substituted-3-N-morpholinothietan1,ldioxides by cycloaddition of sulphene to the appropriate 1-substituted1-N-morpholinoethylene, and then eliminated the morpholino moiety by oxidation to the N-oxide and thermolysis at 65 "Cto give the 3-substitutedthiet 1,l-dioxides. These compounds were then reduced sequentially to 3-substituted-thietan 1,l-dioxides (by sodium borohydride) and 3-substituted-thietans (by lithium aluminium hydride). Full details are now provided 66 for the synthesis of (R)-( -)-4-methylthiet 1,I-dioxide, starting with the addition of sulphene to N-propenylpiperidine to give trans-2methyl-3-piperidinothietan 1,l-dioxide. After resolution and quaternization with methyl iodide, the dextrorotatory methiodide was subjected to Hofmann elimination, dry silver oxide and calcium sulphate in THF giving mainly (R)-(-)-4-methylthiet 1,l -dioxide, whilst silver oxide in aqueous solution gave predominantly 2-methylthiet 1,l-dioxide. Catalytic reduction of (R)-( -)-4-methylthiet 1,l-dioxide gave (R)-( +)-Zmethylthietan 1,ldioxide.66 Asymmetric induction in the cycloaddition of sulphene to optically active enamines has been discussed in terms of a concerted 2 ,, + 1r2,process in which the transition state is more like product than reactant,83addition taking place preferentially from the more hindered side of the enamine to give a transition state such as (59) for the enamine from propionaldehyde and (R)-(- )-2-methylpy1-rolidine.*~ However, the configurations of the products (60) and (61) arising from addition of chlorosulphene to 4-rnethyl-2-methylene-1,3-dioxolan were assigned on the assumption that addition occurred specifically from the least hindered side of the ~ l e f i n .Chlorosulphene ~~ and sulphene respectively reacted with 2-methylenedioxolan to give (62) and (63).8a Vinylsulphene reportedly undergoes 1,4-~ycloadditionwith 1,1-diethoxyethylene, but with 1-morpholinocyclopentene and its cyclohexene and cycloheptene analogues it gave 1,Zcycloadducts (64) together with acyclic sulphones (65), which were primary products and not derived from (64) under the reaction condition^.^^ The ratio of cycloaddition to acylation depended strongly on the nature of the enamine, 1-morpholinocyclo-octene and 1-morpholino2-methylpropene giving only thietan 1,1-dioxide derivatives, whereas with a-morpholinostyrene only an acyclic sulphone was formed.ss Similarly benzoylsulphene gave no [2 2]cycloadducts with 1-pyrrolidinocyclohexene.86 Sulphenes are normally formed for these cycloadditions by the eaction of the appropriate alkenesulphonyl chloride with triethylamine, but methylsulphene has also been prepared by treatment of l-chloroethanesulphonic acid with triethylamine, and then allowed to react with 1-(2-rnethylpropenyl)pyrrolidine to give trans-2,2,4-trimethyl-3-pyrrolidino-

+

83

85

86

L. A. Paquette, J. P. Freeman, and S. Maiorana, Tetrahedron, 1971, 27, 2599. L. A. Paquette and R. W. Houser, J. Amer. Chem. SOC.,1971, 93,944. S. Bradamente, S. Maiorana, and G. Pagani, J. C . S. Perkin I, 1972, 282. 0. Tsuge, S. Iwanami, and S. Hagio, Bull. Chem. SOC.Japan, 1972, 45, 237.

118


Me

x

(59)

(60) X = CI, R1 = Me, R2 = H (61) X = CI, R1 = H, R2 = Me (62) X = C1, R1 = R2 = H (63) X = R1 = R2 = H

n = 0, 1,2,or3 (64)

n = 0,1,2,or3 (65)

0

thietan 1 , l - d i o ~ i d e .In ~ ~an ~ interesting extension of this type of cycloaddition, the sulphoximide (66) was synthesized from 1, l-dimethoxyethylene and the iminosulphene (67).87b By Cycloadditions involving Thiet 1,l -Dioxides. The 2-thiabicyclo[2,2,0]hexane system is accessible by cycloaddition of thiet 1,l-dioxide to suitable enamines,88 2-methyl-l-dimethylaminoprop-l-ene,for example, giving (68), and diethylaminoprop-1-yne providing (69) after hydrolysis. The

*Mm:

H2N

H o 4 % e

(71)

H (68)

*'

R1 = R2 = H (70) R1 = R2 = M e

(69)

(a) J. F. King and R. P. Beatson, Chem. Comm., 1970, 663; (b) C. R. Johnson and E. U. Jonsson, J . Amer. Chem. Soc., 1970,92, 3815.


119

0

@

R1R2

NH,so, Ph

(74)

(73)

H

phas NPo2 NPo2 Ph

R1 R 2

(75)

COZEt

(77)

(76)

keto-sulphone (70) obtained similarly from 2,4-dimethylthiet 1,l -dioxide readily underwent reductive cleavage in the presence of diborane to give (71).68 The reaction of l-dimethylamino-l,3-butadiene with thiet 1,l -dioxide gave 7-thiabicyclo[4,2,0]oct-3-ene 7,7-dioxide (72), and 4substituted-thiet 1,l-dioxides gave analogous products. However, the reaction is not entirely general, some enamines failing to react 3-phenylthiet 1,l-dioxide is also less reactive than thiet 1,l-dioxide in addition reactions.80 The dienophilicity of thiet 1,l-dioxide was utilized to synthesize (73) from tetracy~lone,~~ whilst it acted also as a good dipolarophile towards diazoalkanesYe0giving mixtures of 1-pyrazoline derivatives (74) and (75) in which the isomers (74) predominated, except in the cases of diazomethane and diazoethane, where (75) was the major isomer.eo Ethyl diazoacetate on the other hand gave the 2-pyrazoline (76). These compounds are potentially useful for the synthesis of bicyclobutanes by sequential expulsion of nitrogen and sulphur, and thermolysis or photolysis of (74; R1 = R2 = Ph) did in fact give 5,5-diphenyl-2-thiabicyclo [2,1,O]pentane 2,2-dioxide (77).90 Reactions.-Thietan 1-oxide is reduced more readily than thiolan 1-oxide by aqueous sodium hydrogen sulphite or iodide ion.e2 This observation was rationalized in terms of mechanisms involving nucleophilic displacement of a hydroxy-group (formed by protonation at sulphinyl oxygen) at 92 sulphur by bisulphite or iodide 89

B2

L. A. Paquette, R. W. Houser, and M. Rosen, J. Org. Chem., 1970, 35,905. D. C. Dittmer, K. Ikura, J. M. Balquist, andN. Takashina, J. Org. Chem., 1972,37,225. D. C. Dittmer and R. Glassman, J . Org. Chem., 1970, 35, 999. C. R. Johnson, C. C. Bacon, and J. J. Rigau, J. Org. Chem., 1972,37,919. S. Tamagaki, M. Mizuno, H. Yoshida, H. Hirota, and S. Oae, Bull. Chem. SOC.Japan, 1971,44,2456.

120


Thermolysis and Photolysis of Thietan 1,l-Dioxides. These reactions frequently lead non-stereospecifically to cyclopropanes and olefins, the relative yields of which vary markedly with the constitution of the thietan 1,l-dioxides. Thietan 1,l-dioxide at 960 "C gave a mixture of cyclopropane and propene in roughly equivalent amounts,82 accompanied by a little 1,2-oxathiolan 2-oxide when the thermolysis was performed at 800 "C. 2,2-Dimethylthietan 1,l-dioxide gave only mixtures of methyl-butenes at these temperatures,82 whilst at 350 "C both cis- and trans-2,bdimethylthietan 1,l-dioxide gave mixtures of cis- and trans-l,2-dimethylcyclopropane, cis- and trans-pent-2-enes, C3 hydrocarbons, and sulphurcontaining Attempted photolysis of these compounds was unsuccessful, but 2-phenyl-3-benzoylthietan1,l-dioxide underwent both thermolytic (at 230 "C) and photolytic expulsion of sulphur dioxide in a non-stereospecific manner to give a mixture of cis- and trans-1-phenyl-2benzoylcyclopropane.82These reactions probably involve initial homolysis of a C-S bond, followed by formation of a 1,3-biradical by loss of sulphur dioxide, and subsequent ring closure or hydrogen migration. 3-Oxothietan 1,1-dioxide, and its 2,2-dimethyl and 2,2-diphenyl derivatives, lost both sulphur dioxide and carbon monoxide on heating to give ethylene, 2-methylpropene, and 1,l-diphenylethylene, respectively.82 3-Hydroxythietan 1,l-dioxide on the other hand was thermolysed to a complex mixture of products, including acrolein, formaldehyde, acetaldehyde, propionaldehyde, and acetone, which apparently arose by three distinct mechanisms.82 The first involved dehydration to thiet 1,l-dioxide, which subsequently decomposed to acrolein. Sulphur dioxide was extruded in the second mechanism to give, ultimately, acetone and propionaldehyde, whilst the third process, to give acetaldehyde, involved the reversed cycloaddition of enolic acetaldehyde and sulphene. The formation of formaldehyde was rationalized in terms of rearrangement of sulphene to its cyclic isomer, oxathiiran 1-oxide, which underwent loss of sulphur monoxide at the high temperatures employed.82 Thermolysis of (74; R1 = Ph, R2 = H) at 150 "C led to the expulsion of sulphur dioxide to give 3-methyl-5-phenylpyrazole,whereas the diphenyl compound (74 ; R1 = R2 = Ph), either on heating to 130 "C or on photolysis with benzophenone as sensitizer, lost nitrogen and not sulphur dioxide to give (77).90 At higher temperatures (74; R1 = R2 = Ph) lost sulphur dioxide, but the products were not identified. Both sulphur dioxide and carbon monoxide were expelled from (73) in boiling xylene, to give, after isoAt 230-250 "C the merization, 1,2,6,7-tetraphenyl~ycloheptatriene.~~ compound (62) gave 2-chloroethyl acetate in high yield, together with sulphur dioxide and carbon, the non-concerted nature of this thermal decomposition being revealed by the thermolysis of (60) and (61) to give identical mixtures of 2-chloropropyl acetate and 2-acetoxy-1-chloropropane.84 Furthermore, when (62) was heated in ethanol or propanol, no 2-chloroethyl acetate was produced, the only products being the ethyl or


121

propyl esters of (chloromethanesulphony1)acetic acid, (78) or (79). These observations were accommodated 84 by a mechanism which required the intermediacy of an a-sulphonylcarbene (Scheme 11). 0

1

1

(62)

CICH, S02CH,COR II

0 (78) R = Et (79) R = Pr

CH3COCH,CH2CI I1

0

Scheme 11

Thermolysis of Thiet 1,l-Dioxides. In the vapour phase at 400 "C or in solution at 220 "C, thiet 1,l-dioxide (80) gave the cyclic sulphinate (Sl), the intermediate vinylsulphene in this rearrangement (Scheme 12) being

g""' (80) R = H (83) R = Ph

S0,Ph

"Q

Rc. II

(81) R = I3 (84) R = Ph Scheme 12

trapped by phenol to give the sulphonate ester (82).82 2-Phenylthiet 1,I-dioxide (83) behaved similarly, giving the cyclic sulphinate (84), but no analogous cyclic sulphinate was obtained by thermolysis of 4,4-dimethylthiet l,l-dioxide.s2 At 800 "C thiet 1,l-dioxide was thermolysed

122 Organic Compounds of Sulphur, Selenium, and Tellurium predominantly to acrolein.82 2-Oxobenzothiet (85), formed by lowtemperature photolysis of (86), decomposed at - 40 "C to give (87),83 and not (88) g4 as previously reported. 0

0

w Ph

\

/

so,

Ph (89)

Reactions of Thietan 1-Oxides, Thietan 1,l-Dioxides, and Thiet 1,l -Dioxides involving Sulphur-stabilized Carbanions. Current interest in the stereochemistry of sulphur-stabilized carbanions has extended to thietan derivatives. Determination of the relative rate of base-catalysed racemization and of deuterium exchange for the thiet 1,l-dioxide derivative (89) in t-butyl alcohol-benzene indicated exchange with complete racemization, in accord with the enforced planar configuration (Figure 1)

Figure 1

of the a-sulphonyl ~ a r b a n i o n .Although ~~ this spatial disposition (Figure 1) of the a-carbanion is energetically unfavourable according to currently accepted theoretical conclusions and experimental results, (89) exchanged deuterium and racemized considerably faster than (R)-(- )-Zmethylthietan 1,l-dioxide, in which a favourable pyramidal configuration of the carbanion is attainable. The rate acceleration was attributed to the stabilization associated with the benzylic nature of the carbanion, and 93 94

0. L. Chapman and C. L. McIntosh, J. Amer. Chem. SOC.,1970,92,7007. A. 0. Pedersen, S.-0. Lawesson, P. D. Klemmensen, and J. Kolc, Tetrahedron, 1970, 26, 1157.

S6

L. A. Paquette, J. P. Freeman, and M. J. Wyvratt,J. Amer. Chem. Soc., 1971,93, 3216.

Small-ring Compounds of Sulphur and Selenium 123 possibly to some relief of steric compression of the methyl group in attaining the transition state. Racemization occurred faster than exchange for (R)-(- )-Zmethylthietan 1,1-dioxide, a phenomenon interpreted in terms of most of the racemization occurring with exchange, and some racemization without exchange (isoracemi~ation).~~ Whereas 4-substitutedthietan 1,l -dioxides underwent complete exchange of hydrogen for deuterium at the 2- and 4-positions with sodium deuteroxide in deuterium oxide, the corresponding thietan 1-oxides did not undergo exchange.80 However, trans-2,4-diphenylthietan 1-oxide was converted into cis-2,4diphenylthietan trans-1 -oxide in hot methanolic sodium e t h o ~ i d e , ~ * indicating that an a-sulphinyl carbanion was formed in that case. Both cis- and trans-2,4-diphenylthietan1-oxide, (90) and (91), treated separately with potassium t-butoxide in DMF, gave a mixture of cis-1,2diphenylcyclopropanethiol (92) and cis-l,2-diphenylcyclopropanesulphinic acid (93), which apparently arose by disproportionation of the intermediate sulphenate anion (94) and subsequent p r o t o n a t i ~ n . ~In~ other highly stereoselective reactions both cis- and trans-2,4-diphenylthietan1,1-dioxide Y

(90) R1 = Ph, R2 = H, X = (91) R1 = 14, R = Ph, X = (95) R1 = Ph, R2 = H, X = (96) R1 H, R2 = Ph, X --5

0, Y = lonc electron pair 0, Y = lone clcctron pair Y =0 Y =0

RDh R2 X

R' = Ph, R2 = H,X R1 = Ph, R2 = H, X (94) R1 = Ph, R2 = H,X (97) R1 = H, R2 = Ph, X

(92) (93)

= = = =

SH SOzH SOH SO,H

I

I1 (98) (99)

I

Ph

R1 = Ph, R2 = H Rl = H, R2 Ph =L

(95) and (96), on separate treatment with ethylmagnesium bromide,B7 rearranged to trans-l,2-diphenylcyclopropanesulphinicacid (97), but with t-butoxymagnesium bromide 98 they were converted into cis-3,5-diphenyl1,2-0xathiolan cis-2-oxide (98) and trans-3,5-diphenyl-1,2-0xathiolan-(2,3) cis-2-oxide (99), respectively. The latter reaction proceeded stereospecifically 98 97

98

R. M. Dodson, P. D. Hammen, and J. Y. Fan, J. Org. Chem., 1971, 36, 2703.

R. M. Dodson, P. D. Hammen, E. H. Jancis, and E. Klose, J . Org. Chem., 1971, 36, 2698. R. M.Dodson, R. D. Hammen, and R. A. Davies, J . Org. Chem., 1971, 36, 2693.

124


with regard to the phenyl groups, and stereoselectively with respect to sulphinyl oxygen. The reactions catalysed by potassium t-butoxide and ethylmagnesium bromide were considered as modified Stevens rearrangem e n t ~the , ~ stereoselectivity ~ of which was controlled by the configurational stability of the intermediate carbanions from the sulphones (Figure 2a) nPh

T.

Figure 2b

Figure 2a

..

p$pk Figure 3

Ph

Figure 4

and sulphoxides (Figure 3). The most stable conformation of the anion derived from the sulphones (95) and (96) was assumed to be that in which the orbital carrying the negative charge bisected the projected 0 - S - 0 angle, whilst in the case of the carbanion from the sulphoxides (90) and (91) the negative charge was assumed to be trans to the lone electron pair on sulphur. These anions were then stabilized by migration of a C-S bond (via an intermediate radical pair) to the rear lobe of the orbital associated with the negative charge, hence providing an explanation for the observed stereoselectivity.g6 However, according to current views the more likely configuration of the a-sulphinyl carbanion is that indicated in Figure 2b, the rearrangement of which should also lead to the observed stereoselectivity. The different course of the rearrangement of the 2,4-diphenylthietan 1,l-dioxides in the presence of t-butoxymagnesium bromide was attributed to the proximity of the nascent t-butyl alcohol to the carbanions, which were consequently reprotonated rapidly before or after rearrangement ; steric effects apparently controlled the stereospecificity of rearrangement, the migration of the C-S bond being directed to the oxygen nearer to the catalyst (Figure 4). However, an alternative concerted 1,2-anionic rearrangement, symmetry-allowed in this case, could not be ruled out.

9 Structure and N.M.R. Properties of Thietan Derivatives Aspects of the configuration, conformation, and n.m.r. properties of thietan derivatives are so closely interwoven that they are reviewed


125

together (see also pp. 115 and 132). A pattern is emerging in the accumulating n.m.r. data which is sufficiently coherent to provide valuable criteria for the elucidation of configurational and conformational problems. Protons or methyl groups syn-axially orientated with respect to an axial lone electron pair on sulphur in thietans, thietan l-oxides,60p thietanium ions,03* and thietan 1-toluene-p-sulphonylimides are invariably more shielded than protons or methyl groups equatorial at C(3) (Figure 5). This 639

more shieldcd than R2 = R2 = H, or R1 = R2 = Me X = 0, NTs, Me, OMe, or lone electron R1

R1

pair (charges omitted)

Figure 5

is most pronounced in thietan 1-oxides and thietanium ions. An axial lone electron pair is usually more effective than an axial S-0 bond in shielding the syn-axial proton at C(3), the signal due to the axial C(3)proton moving upfield in the sequence of compounds (loo), (101), (102), and (103).0° This did not hold for cis-4-acetoxythietan 1-oxide (103;

R1 = p-CI.C6€-14,C6H5, or Bu‘, R3 = H (100) X = Y = lone electron pair (101) X = 0,Y = lone electron pair (102) =Y = 0 (103) X = lonc electron pair, Y = 0

x

R1

=

R2

=

Me

(105) X

=

lone electron pair, Y

=

NTs

R1 = OAc, R2 = H), where the C(3)-proton was more shielded than that in the corresponding 3-acetoxythietan (100; R1 = OAc, R2 = H),nor in the case of cis-2,4-diphenylthietan 1,l -dioxide (95).69 There was also some disparity in the relative deshielding of the axial and equatorial protons at C(3) in the sulphones (95) and (104), the axial C(3)-proton being the more shielded in (95) 59 and the less shielded in (104).63 In thietans and thietan 1,l-dioxides, equatorial methyl groups or protons at C(2) are more shielded than geminal axial methyl group^,^^^ 6s but, as in other cyclic sulphur compounds, the axial lone electron pair in thietan 9g and thietanium salts exerts a marked shielding effect on l-oxides 69p

eB

63p

039

W.0.Si,egl and C. R. Johnson, Tetrahedron, 1971,27, 341.

126

Organic Compounds of Sulphur, Seleniunr, and Tellurium

(104)

R1 =

(106) R1 =

H R2 = Me,X = Y = 0 R2 = Ph, X = Y = lone electron pair

H (107) R = Ph (109) R = Me

(108) R = Ph (110) R = Me

trans-diaxial substituents, so that axial methyl groups or protons at C(2) become more shielded than their equatorial counterparts. However, this does not hold for 2,2-dimethylthietan-1-toluene-p-sulphonylimide (105), where the axial C(2)-protons are the more d e ~ h i e l d e d . ~ ~ The predominant conformation of a thietan ring is normally determined by the propensity of substituents to adopt the equatorial o r i e n t a t i ~ n , ~99~ ~ so that 3-substituted thietans and cis-2,4-disubstituted thietans favour the conformations depicted by (100) and (106), respectively. The two equienergetic conformations (107) and (108) of tran~-2,4-diphenylthietan,~~ and (109) and (110) of trans-2,4-dimethylthietan63 rapidly equilibrate at room temperature. With polar substituents, electrostatic interactions may play a role in determining the preferred conformation, since the favoured according to dipoleconformation of 2,2-diphenyl-cis-3,4-dichlorothietan, moment data,67is that with the 3-chlorine equatorial and 2-chlorine axial (11l), although steric repulsive non-bonded interactions appear to be less severe in the alternative conformation (112). 2,2-Diphenyl-cis-3,4dichlorothietan 1,l-dioxide also adopted a conformation similar to that of (111). In the 2-chlorothietan 1,l-dioxide derivatives (60)-(62) the chlorine also prefers to adopt an axial orientation, as revealed by a long-range coupling between H(2) and H(4) in the n.m.r. spectra, which requires a W arrangement of the intervening sigma-bond~.~~ In 2,2-diphenyl-trans3,4-dichlorothietan (113) and its dioxide, both chlorines adopted the equatorial ~ r i e n t a t i o nso , ~ it ~ appears that a syn-axial disposition of a C-Cl bond and a lone electron pair or S - 0 bond in all these compounds is energetically unfavourable. The ligands at sulphur in thietan l - o ~ i d e s , ~ ~ loo ~ thietan-l-toluenep-s~lphonylimides,~~ S-methylthietanium ions,63and S-methoxythietanium 639

67e

loo

K. N.Slessor and A. S. Tracy, Canad. J. Chem., 1971, 49, 2874.


127

(111) X = H , Y = C1 (113) X = C1,Y = H

0

I Ph H ionso0preferentially adopt the equatorial orientation. In the case of the sulphoximide (114), however, it was not possible to assign the preferred conformation unambiguously from n.m.r. data, nor to rule out the possibility of a planar ring.Oo The preference for the equatorial orientation of sulphinyl oxygen is noteworthy in (115), where the orientations of the chlorine atoms are the converse of those found in the corresponding deoxy-compound (11l).67 The assignments of n.m.r. signals and conformations were substantiated in the case of thietan 1-oxides and thietan-1-toluene-p-sulphonylimidesby the determination of benzeneinduced shifts in the n.m.r. the benzene complexing preferentially on the face of the ring trans to the oxygen or toluene-p-sulphonyliminogroup, causing greater upfield shifts in the signals of protons on that side of the ring. Analyses 6Bs looof the n.m.r. spectra of cis-2,4-diphenylthietan (106), its 1-oxide, and its 1,l-dioxide indicated that the angles of pucker in the rings were 37.7", 39.7", and 35", respectively. According to one method of analysis,69trans-2,4-diphenylthietan1,l-dioxide was severely distorted as well as puckered, but anotherloo suggested that the ring was somewhat flattened in order to allow both phenyl groups to become more nearly equatorial. The rings in cis- and trans-2,4-dimethylthietan l,l -dioxide also appeared to be somewhat flatter than in the corresponding thietans and thietanium ions, according to n.m.r. data,63whilst the dipole moments of both 2,2-diphenyl-cis- and -trans-3,4-dichlorothietan1,l -dioxide indicated that they were puckered to a much smaller extent than in the parent substituted thietans (111) and (1 13).67 X-Ray analysis showed that the high-melting isomer of thietan-3carboxylic acid 1-oxide has the trans configuration,101the puckered ring lol

S. Abrahamson and G . Rehnberg, Acra Chem. Scand., 1972, 26, 494.

128


having a dihedral angle of 153". The structures of N,S-cis- and N,S-trans-N(p-bromophenylcarbamoy1)thiamineanhydride have been determined by the X-ray method,lo2and gas-phase electron-diffraction data indicated that the C-S bond distance (1.865 A) in 5-thiabicyclo[2,1,1]hexane was much bond angle longer than in 7-thiabicyclo[2,2,1]heptane,whilst the C-S-C (69.7') was appreciably smaller.1o3The high-resolution 13Cn.m.r. spectrum of thiet 1,l -dioxide indicated that ring strain and rehybridization were significant.lo4 A theoretical interpretation of the U.V. spectrum of thietan required the participation of &orbitals on and the 70 eV mass spectrum of thietan has been

10 1,3-Dithietans and 1,3-Diselenetans The base-catalysed reaction of carbon disulphide with active-methylene compounds has provided a convenient route to the desaurins (116), the likely mechanism lo6 for derivatives of 2,4-bismethylene-l,3-dithietan, the formation of which is presented in Scheme 13. The selenium analogue (117) was formed from dimethyl malonate and carbon di~e1enide.l~~ An alternative method of preparation involves the treatment of sodium salts of activated-methylene compounds such as deoxybenzoin or diethyl malonate 71 with thiophosgene. These desaurins, and those derived from ethyl acetoacetate and phenyl ethyl ketone, have been known since the last century, but their structures have now been established unambiguously by chemical methods.lo6 The desaurin (116; R1 = But, R2 = H) was also prepared from pinacolone by conversion into the dithiolate anion (118; R1 = But, R2 = H) and subsequent treatment with oxalyl chloride.l0* The compound (119) was formed from bis(trifluoromethy1)keten on heating with triphenylphosphine sulphide, and from the desaurin (1 16; R1 = OEt, R2 = C0,Et) by its reaction with sulphur tetrafluoride in the presence of hydrogen fluoride.'l N-Alkyl-3-isothiazolineswith a free 5-position readily dimerized in the presence of base to give 2,4-bismethylene1,3-dithietans [e.g. (120)], for which the mechanism indicated in Scheme 14 was proposed.1oBN-Acyl-3-isothiazolines gave only polymers. The desaurin (116; R1 = Ph, R2 = H) from acetophenone was shown by X-ray analysis to have the depicted trans-structure, the two sulphur atoms and the unsaturated carbonyl moiety being coplanar and the phenyl rings making an angle of 11" with this plane.lo6 Infrared spectroscopy H. Nakai and H. Koyama, J. C. S . Perkin 11, 1972,248; H. Nakai and H. Koyama, J. Chem. SOC.(B), 1971, 1525. 103 T. Fukuyama, K. Kuchitzu, Y.Tamaru, Z.Yoshida, and I. Tabushi, J. Amer. Chem. Soc., 1971, 93, 2799. 1 0 4 G. C . Levy and D. C. Dittmer, Org. Magn. Resonance, 1972, 4, 107. lo6 J. R. Gilbert and A. J. Stace, Org. Mass Spectrometry, 1971, 5 , 1119. 1 0 6 P. Yates, D. R. Moore, and T. R. Lynch, Canad. J. Chem., 1971,49, 1456. l o 7 K. A. Jenson and L. Henriksen, Acta Chem. Scand., 1970, 24, 3213. lo8 P. Yates, T. R. Lynch, and D. R. Moore, Canad. J. Chem., 1971, 49, 1467. A. W. K. Chan, W. D. Crow, and I. Gosney, Tetrahedron, 1970, 26, 1493. 102

Small-ring Compounds of Sulphur and Selenium R1-C

0 4

'CH,

/ R2

-

129 0

0

R1-C

4 \

/

/

\

c=c

R2

R1-C

S-

4 \

/c=c=s

I__j.

S'

R2

(118)

R' _I__,

-R1

i also suggested that (1 16; R1 = Me, R2 = Ph) and (1 16; R1 = R2 = Me) also had the sym-cis conformation of the ap-unsaturated ketone,lo8which requires considerable twisting of the phenyl ring in (116; R1 = Me, R2 = Ph) out of the plane of the conjugated carbonyl system. In the MeOzCHSeHCOzMe Me0,C

Se (117)

C02Me

F3cxsxcF3 F,C

S

CFS

(1 19)

desaurins derived from dialkyl ketones there was strong through-bond conjugative interaction between the sulphur atoms and the carbonyl groups, according to U.V. and i.r. spectroscopy.1o* The 2,4-bismethylene1,3-dithietan system was characteristically inert to acids and bases,106vlo9 although it was susceptible to oxidation and reduction.lo6 Bromination of 6

130

Organic Compounds of Sulphur, Selenium, and Tellurium YR

(120) (121)

R1 = H R1 = Br

R Scheme 14

(120) gave (121), presumably by an addition-eliminatia mechanism.loB On heating, the desaurins gave thioketens, the dissociation of (119) in this manner being particularly fruitful ~ynthetically.~~ Alkylation of appropriate dithiolate anions with methylene bromide is a useful route to dithietan derivatives, (122) being formed in this way from (118; R1 = Ph, R2 = H),lo8 whilst potassium diethoxyphosphinyldithiocarbamate gave (123) and ammonium isopropyldithiocarbamate afforded (124).llo Hydrolysis of (123) provided 2-imino-1,3-dithietan (125) as its hydrochloride. The sulphonium ylide (126) reacted with carbon disulphide in aprotic solvents to give the 1,3-dithietan derivative (12 7 ) F 0

4

ph-cXs) H S

Me,S=CH-C-Ar

R N 4S7 0

(122)

II

II 0 (126)

(123) R = (EtO)2-P(124)

R

=

Pri

(125) R = H

(127) ll1

R. W. Addor, J . Heterocyclic Chem., 1970, 7 , 381. Y. Hayashi, T. Akazawa, K. Yamamoto, and R. Oda, TetrahedronLetters, 1971,1781.


131 Dimerization and analogous cycloadditions of thiocarbonyl compounds also lead to 1,3-dithietans. Adamantanethione on irradiation 70 or on treatment with methanesulphonic acid 112 gave the dimer, containing a 1,3-dithietan ring, and 2-isopropylidene-5,5-dimethyl-6-oxo-l,3-oxathian4-thione also dimerized on irradiation.l13 Bis(trifluoromethy1)thioketen reacted with a variety of thiocarbonyl compounds, including isothiocyanates, to give 2-(hexafluoroisopropylidene)-l,3-dithietanderivative~.~~ 11 1,2-Thiazetidines 1,2-Thiazetidine 1,l-dioxide, prepared by the cyclization of 2-aminoethanesulphonyl chloride hydrochloride under dry basic conditions,114 reverted to starting material on treatment with hydrogen chloride in dry solvents, but with water it hydrolysed slowly to taurine. Benzoylsulphene, generated by treatment of benzoylmethanesulphonyl chloride with 2lcycloaddition with anils to give 1,2triethylamine, underwent [2 thiazetidine 1,l -dioxide derivatives.lls With benzylidene-alkylamines the only products in the presence of triethylamine were those of [4 + 21cycloaddition, but, unexpectedly, in the absence of triethylarnine, 1,Zthiazetidine 1,l-dioxide derivatives were also formed ;benzylideneaniline gave only 4-benzoyl-2,3-diphenyl-l,2-thiazetidine1,1-dioxide, and other Schiff-bases reacted similarly.l15 N-Sulphinyltoluene-p-sulphonamideunderwent reversible cycloaddition to ethyl vinyl ether at - 30 "C to give an approximately equimolecular ,Zthiazetidine cis- and transmixture of N-toluene-p-sulphonyl-3-ethoxy-1 1-oxides (128) and (129), the trans-oxide (129) reverting to starting materials at 0 "C whilst the cis-isomer (128) did so above room temperature.'ls Phenyl vinyl ether gave (130) and (131) slowly at 24 "C; these oxides, which were formed in the ratio 2.5 to 1, did not revert to starting materials. The adducts (132)-(135) formed from cis- and trans-methyl 1-hexenyl ether

+

I

R3 (128) Rf = Et, R2 = R3 = H (130) R1 = Ph, R2 = R3 = H (132) R1 = Me, R2 = H, R3 = C,H, (134) R1 = Me, R2 = C,H,, R3 = H

(129) Rf = Et, R2 = RS = H (131) R1 = Ph, R2 = RS = H (133) R1 = Me, R2 = H, Rs = C4H9 (135) R1 = Me, R2 = C,H,, R3 = H

113

J. W. Greidanus, Canad. J. Chem., 1970, 48, 3530. J. C. Martin, R. D. Burpitt, P. G. Gott, M. Harris, and R. H. Meen, J. Org. Cliem.,

11*

A. Le Berne and J. Pettit, Tetrahedron Letters, 1972, 213.

112

1971,36,2205.

116

0. Tsuge and S . Iwanami, Bull. Chem. SOC.Japan, 1970, 43, 3543.

W. Wucherpfennig, Tetrahedron Letters, 1971, 1891.

132


reverted to starting materials on heating, with retention of configuration in the olefin moiety. The configuration and conformation of the adducts were established by n.m.r. spectroscopy.ll6 NN'-Bis-(p-tolylsulphonyl) sulphur di-imide reacted with diphenylketen at - 15 "C to give (136), which rearranged at 70 "C to (137).l17 Although 1,2-thiazetidine l-oxide and 1,l-dioxide systems are well characterized, the parent 1,2-thiazetidines Ts

TsN'

+Ph Ph (136)

'

N

Ts Ph (137)

are apparently unknown. Attempts to prepare N-toluene-p-sulphonyl1,2-thiazetidine by treatment of 2-toluene-p-sulphonylaminoethanesulphonyl chloride with triethylamine gave only 1,5-di(toluene-p-sulphonyl)2,6-dithia-1,5-diazocine.lls The first synthesis of a benzo-fused fourmembered ring containing two heteroatoms has been achieved, 2-(2,6-dimethylphenyl)-2H-1,2,3,4-benzothiatriazine1,l-dioxide giving (138) on p h o t o l y s i ~ .Compound ~~~ (138) reacted readily with water and aniline to give, respectively, o-arylaminobenzenesulphonic acid and o-(NNdiary1amino)benzenesulphonamide. The ortho-methyl groups in (138) apparently stabilize the molecule, since the phenyl analogue was much less stable, decomposing to phenothiazine dioxide, undoubtedly via the valence tautomer (139).ll9 The novel compound (140) was obtained by treatment 0

of an aryl methyl sulphoximide sequentially with butyl-lithium, carbon dioxide, and acid.120 12 1,3=Thiazetidinesand 1,2,3-Oxathiazetidines Carbodi-imides undergo 1,2-cycloaddition to diphenylphosphinothioyl isothiocyanate and p-tolyl isothiocyanate across the C=S bond to give 1,3-thiazetidine derivatives,l2' and not across the C=N bond as previously 11'

118

119 120

H. Grill and G. Kresze, Tetrahedron Letters, 1970, 1427.

N. E.Heimer and L. Field, J . Org. Chem., 1970, 35, 1668. M.S. Ao and E. M. Burgess, J. Amer. Chem. Suc., 1971, 93, 5298. T. R. Williams and D. J. Cram, J. Amer. Chem. Suc., 1971, 93, 7333. I. Ojima and N. Inamoto, Chem. Curnm., 1970, 1629.

lZ1


133

reported. For example, p-tolylsulphinyl isothiocyanate reacted with dicyclohexylcarbodi-imide to give (141).l2l The photocatalysed reaction of thiobenzophenone with benzaldehyde N-methylimine to give a mixture of 2,4,6-triphenyl-5-methyl-1,3,5-dithiazineY 2,2,4,6-tetraphenyl-5-methyl1,3,5-dithiazine, and benzophenone was rationalized in terms of fission of

+

the initial [2 2]cycloadduct, 2,2,4-triphenyl-3-methylthiazetidine, in two ways, to give starting materials, or to give benzophenone N-methylimine and thiobenzaldehyde, which reacted further to give the observed products.122 1,3-Thiazetidine derivatives have been invoked as intermediates in other reactions.x2s Aryl sulphinylamines reacted with aryl aldehydes to give crystalline 1 : 1 adducts formulated as 3,4-diaryloxathiazetidine 2-oxides, which decomposed on heating to give Schiff-bases and sulphur d i 0 ~ i d e . l ~ ~ Analogous adducts were formed with aliphatic aldehydes and ketones, but they were extremely unstable. 1,2,3-0xathiazetidine intermediates have 126 been postulated in other

13 1,2-0xathietansand 1,2,3-Dioxathietans During the period under review these systems have been reported or postulated only as transient intermediates. The conversion of phenyl 2-hydroxyethyl sulphoxide into phenyl2-chloroethyl sulphone on treatment with sulphuryl chloride proceeded via 2-phenyl-l,2-oxathietan 2-oxide as intermediate,12' and 1,2-0xathietan 2-oxides have been postulated as intermediates in the reactions of sulphur dioxide with olefins.128s129 1,2-0xathiet derivatives have also been proposed as reactive intermediate^,^^^ and although the U.V. and i.r. properties of monothiobenzil are not consistent with its formulation as 3,4-diphenyl-l,2-oxathiet,its mass Ira

lZ8 lZ4 lZ6 126

lZ7 12*

lZo

A. Ohno, N. Kito, and T. Koizumi, Tetrahedron Letters, 1971, 2421. R. Okazaki, K. Okawa, and N. Inamoto, Chem. Comm., 1971, 843. N. S. Zefirov and T. M. Pozdnyakova, J. Org. Chem. (U.S.S.R.),1971,7,966. F. Yamada, T. Nishiyama, and T. Emi, Bull. Chem. SOC.Japan, 1972,45, 271. R.A. Abramovitch, R. G. Sutherland, and A. K. V. Unni, Tetrahedron Letters, 1972, 1065. T. Durst and K.-C. Tin, Canad. J. Chem., 1971, 49, 2374.

H. W. Sidebottom, C. C. Badcock, 5. G. Calvert, B. R. Rabe, and E. K. Damon, J . Amer. Chem. SOC.,1971, 93, 3121. D.Sianesi, G. C. Bernardi, and G. Moggi, Tetrahedron Letters, 1970, 1313. J. S. Bradshaw and R. H. Hales, J. Org. Chem., 1971, 36, 318.

134


spectral behaviour, in which the sulphur and oxygen atoms are lost concurrently, may indicate that this structure is important in the molecular The photosensitized oxygenation of thiones 132 and sulphines 133 apparently results in the transient formation of 1,2,3-dioxathietans and 1,2,3-dioxathietan 3-oxides, respectively. D. C. Dittmer and G. E. Kuhlmann, J. Org. Chem., 1970, 35, 4224. N. Ishibe, M. Odani, and M. Sunami, Chem. Comm.,1971, 118. la3 B. Zwanenburg, A. Wagenaar, and J. Strating. Tetrahedron Letters, 1970, 4683. 131

18%

3 Saturated Cyclic Compounds of Sulphur and Selenium

A review of recent developments in synthetic organic sulphur chemistry included much valuable material pertinent to cyclic sulphur compounds,l and another review covered photocycloaddition reactions of thiocarbonyl compounds with olefins to give 1,4-dithians and cycloadditions with dienes to give thian derivatives.2 Macrocyclic polythioethers and their complexes have been r e ~ i e w e d and , ~ in other articles the conformational aspects of multisulphur heterocycles,* sulphur-containing [2,2]metacy~lophanes,~ and other cyclic sulphur compounds have been discussed. Other reviews mention configurational aspects of cyclic sulphur compounds.' 1 Thiolans, Thians, Thiepans, Thiocans, their Oxides and Dioxides, and their Selenium Analogues Formation.-Conventional methods of constructing thian and thiolan ring systems involving the intramolecular nucleophilic displacement of a suitable leaving group (halide or sulphonate ester) by a thiolate anion (frequently generated in situ from the halide or sulphonate ester) located on a y- or 8-carbon atom have been utilized to synthesize thiolan specifically labelled with 13C at the 2- and S-position~,~ cis- and trans-2,S-dimethylt h i ~ l a n , 3,3-dimethylthiolan-4-one ~ and its selenium analogue,1° and 2-thia-Sar-chole~tane.~~ Bicyclic compounds have also been prepared by this method, including the strained 5-thiabicycl0[2,1,1]hexane,l2N-toluenep-sulphonyl-2-thia-5-azabicyclo[2,2,1 Iheptane (1),13 3-oxa-7-thiabicycloa

lo l1

l2 l3

L. Field, Synthesis, 1972, 101. A. Ohno, Internat. J . Sulfur Chem. (B), 1971, 6, 183. C. J. Pedersen and H. K. Frensdorff, Angew. Chem. Internat. Edn., 1972, 1 1 , 16. C. H. Bushweller, Mechanism Reactions Sulfur Compounds, 1970, 5, 75. F. Vogtle and P. Neumann, Angew. Chem. Internat. Edn., 1972, 11, 73. J. B. Lambert, Accounts Chem. Res., 1971,4,87; I. 0.Sutherland,Ann. Reports N.M.R. Spectroscopy, 1971, 4, 71. A. Nudelman, Internat. J. Surfur Chem. (B), 1971, 6, 1; K. K. Anderson, ibid., p. 69. A. S. Siegel, Tetrahedron Letters, 1970, 41 13. A. R. Jones, Chem. Comm., 1971, 1042. L. Fitjer and W. Luttke, Chem. Ber., 1972, 105, 907. Y. Kashman and E. D. Kaufman, Tetrahedron, 1971,27, 3437. I. Tabushi, Y.Tamaru, and Z. Yoshida, Tetrahedron Letters, 1970, 2931. P. S. Portoghese and V. G. Telang, Tetrahedron, 1971, 27, 1823.

135


136

(a) x = s, n = 1 (b) X = S , n = 2 (c) x = 0, n = 2 (d) X = S, t~ = 3 (e) X = 0,n = 3

\I

S (3) X = Br (4) X = H

[3,3,0]octane and the propellane derivatives (2),l4 3-thiabicyclo[3,3,1]nonane and the corresponding As-olefin,ls and 2-bromo-7-thiabicyclo[3,2,lloctane (3).16 Reduction of (3) with triphenyltin hydride gave (4), but the bromide (3) was very resistant to nucleophilic displacement and elimination, a phenomenon ascribed to severe steric compression in the relevant transition states.le The partial desulphurization of cyclic disulphides to cyclic sulphur compounds presented another useful, but less conventional, example of this method of synthesis.17 It was used to convert dimethyl 1,2-dithian-cis-and -trans-3,6-dicarboxylateinto dimethyl thiolantrans- and -cis-2,5-dicarboxylate,re~pective1y.l~ A number of examples have also been provided of the formation of thiolan and thian rings by intramolecular electrophilic or radical additions of sulphur functions to double bonds. The methylthio-group in 4-methylthiocyclohexene participated in the addition of hydrogen iodide to the double bond to give mainly the known 7-methyl-7-thiabicyclo[2,2,1]heptanesulphonium iodide, together with a mixture of the isomeric formed from 4-methylthiocyclohexyl iodides.ls The sulphonium salt (9, (6) on treatment with hydrogen bromide, was reduced by lithium aluminium hydride to give a mixture of (7) and @),la whilst the bromoderivative (9), obtained from (6) by reaction with bromine, reacted with a

(5) X (9) X

=

=

H Br

(6)

(8) 2,3-dihydro

(7) Y (10)

Y

= =

H

Br, OPh, SPh,

or OAc l4 l6

l6

l7 lo

K. Weinges and A. Wiesenhutter, Annalen, 1971, 746,70. N. S. Zefirov and S. V. Rogozina, J. Org. Chem. (U.S.S.R.), 1971, 7, 2730. C. R. Johnson and F. L. Billman, J . Org. Chem., 1971, 36, 855. D. N. Harpp and J. G. Gleason, J . Amer. Chem. Soc., 1971, 93,2437. M. B. Dines and W. Mueller, J. Org. Chem., 1970,35, 1720. P. Wilder and R. F. Gratz, J , Org. Chem., 1970, 35, 3295.

Saturated CycIic Compounds of Sulphur and Selenium

137 variety of nucleophiles to give the derivatives (lo), probably by way of an intermediate thiiranium ion (Scheme l).19 Initial nucleophilic attack at C(8) or C(10) appears to be favoured sterically over attack at C(6). 2,7Dithiaisotwistane (1 1) has been prepared from endu-2-mercapto-9-thiabicyclo[3,3,l]non-6-ene, by treatment with bromine to give the bromoderivative (12)and subsequent reduction with lithium aluminium hydride.20

Scheme 1

In an analogous case, 5a-mercaptocholest-2-ene with bromine gave 3~-bromo-2ol,5a-epithiocholestane (1 3a),21 probably by way of an intermediate thiiranium ion, whilst treatment of 5a-mercaptocholcst-2-ene with lead tetra-acetate gave the 3/3-acetoxy-derivative(14a), the formation of which may involve homolytic cleavage of a sulphur-lead bond in an

(11) R = H (12) R = Br

(a) X

(b) X

= =

Br, Y = H H, Y = Br or OMS (1 3)

(a) X = OAc, Y = H

(b) X = OH, Y = H = H, Y = OH

(c) X

(14)

intermediate triacetoxyalkylthio-lead compound, and subsequent cyclization of the thiyl radical. 2/3-Mercaptocholest-4-enegave only the corresponding disulphide with lead tetra-acetate,21suggesting that the generation of the endu-acetoxy-7-thiabicyclo[2,2,l]heptanesystem by this method is limited to homoallylic thiols of suitable rigid conformation in which the thiol group is resistant to oxidation to the disulphide. The ratio of 2-methylthian to thiepan obtained by photocatalysed cyclization of 6-mercapto2o

21

C. Ganter and N. Wigger, Helv. Chim. Acta, 1972, 55, 481. T. Komeno, M. Kishi, and K. Nabeyama, Tetrahedron, 1971, 27, 1503.

138


hexene was remarkably sensitive to temperature,22 2-methylthian preponderating at 80 "C and thiepan being the major product at - 65 "C.At a given temperature the proportion of thiepan formed increased with increasing concentration of starting thiol; it appeared that thiepan was the kinetically controlled product, but cyclization of the thiyl radicals was reversible and the formation of 2-methylthian was favoured for thermodynamic reasons at the higher temperatures.22 In another remarkably regioselective cyclization involving a thiyl radical, irradiation of 4-mercaptomethylcyclohexene gave only 2-thiabicyclo[2,2,2]octane, whereas irradiation of 1-methyl-4-mercaptomethylcyc1ohexene gave a 3 : 1 mixture of 4-methyl-6-thiabicyclo[3,2,l]octaneand l-methyl-2-thiabicyclo[2,2,2]The overall yields in the photocatalysed cyclizations of these mercapto-olefins were quite good, which augurs well for the synthetic potential of the method. Returning now to heterolytic intramolecular cyclizations, sulphur dichloride on addition to dilute solutions of cis,transhexa-2,4-diene and trans,trans-hexa-2,4-dienegave 3,4-dichlorothiolan derivatives which were reduced by the ethylenediamine complex of chromous acetate to give respectively a 9 : 1 and 3 : 1 mixture of trans- and ~is-2,5-dimethyl-A~-thiolen.~~ With N-toluene-p-sulphonyl-9-azabicyclo[3,3,l]nona-2,6-diene, sulphur dichloride gave N-toluene-p-sulphony1-4,8dichlor0-2-aza-6-thia-adamantane.~~ Among the products of the liquidphase oxidation of butadiene with selenium dioxide in acetic acid were 3,4-diacetoxyselenolan and 3-hydroxy-4-acetoxyselenolan,26supposedly formed by a mechanism involving electrophilic attack of selenium dioxide or its conjugate acid upon the diene to give a carbonium ion which subsequently cyclized. The thian ring system has also been formed by Michaelwith hydrogen sulphide type additions, 3-0~0-2,4-dimethylpenta-l,4-diene and cx-bromogiving a mixture of cis- and truns-3,5-dimethylthian-4-0ne,~~ methylchalcone with sodium hydrosulphide affording, as a minor product, 2,6-dipheny1-3,5-diben~oylthian.~* An intramolecular nucleophilic addition of a thiolate ion to an acetylenic bond to form a thiolan derivative was exemplified by the conversion of 5-chloro-l-phenyl-l-pentyne into 2-benzylidenethiolan on successive treatment with thiourea and hydroxide ions.29 The easily made methylcyanodithioformate promises to be a useful dienophile for the synthesis of cyclic sulphur With cyclopentadiene it gave a mixture of the adducts (15) and (16) in which the 22

23 24 26

26

27 28 28

so

J. M. Surmr, M.-P. Crozet, and C. Dupuy, Tetrahedron Letters, 1971, 2025. J. M. Surzur, R. Nougier, M.-P. Crozet, and C. Dupuy, TetrahedronLetters, 1971,2035. B. M. Trost and S. D. Ziman, J. Amer. Chem. Soc., 1971, 93, 3825. H. Stetter and K. Heckel, Tetrahedron Letters, 1972, 801. K. A. Javaid, N. Sonada, and S. Tsutsumi, Ind. and Eng. Chem. (Product Res. and Development), 1970, 9, 87. M. D. Brown, M. J. Cook, and A. R. Katritzky, J. Chem. SOC.(B), 1971, 2358. A. Padwa and R. Gruber, J . Org. Chem., 1970, 35, 1781. W. E. Truce and T. C. Klinger, J. Org. Chem., 1970, 35, 1834. D. M. Vyas and G. W. Hay, Chem. Comm., 1971, 1411; Canad. J . Chem., 1971, 49, 3755.

Saturated Cyclic Compounds of Sulphur and Selenium

139

former predominated, whilst with appropriate butadiene derivatives it gave the adducts (17)-(19); the regioselectivity of addition to methoxybutadiene is noteworthy. Bis(trifluoromethy1)thioketen is also a good dienophile, adding to 2,3-dimethylbutadiene to give an unsaturated thian derivative and to norbornadiene to give the adduct (20).31

kX b&: @ Y

(15) X = C N , Y = SMe (16) X = SMe, Y = CN

Y

(17) X = Y = H (18) X = H, Y z= OMe (19) X = Y = OAC

F3C CF3

(20)

A number of interesting cyclizations not directly involving the sulphur function have been described. 1-Methylcyclohexene oxide with sodium 2-chloroallylthiolate gave (21), which underwent acid-catalysed cyclization to (22), whilst 2,4-diphenylthiepan-6-onewas formed from benzalacetophenone on sequential treatment with 2-chloroallylthiolate ions, lithium

aluminium hydride, and formic acid.s2 Whereas allylthioglycollic acid chloride and but-2-enylthioglycollic acid chloride cyclized on treatment with aluminium chloride to give 5,6-dihydr0-2H-thiopyran-S-one and its 4-methyl derivative, respectively, 3’-methylbut-2-enylthioglycollic acid chloride under these conditions gave only 3-isopropylidenethiolan-4-0ne,~~ an outcome rational in terms of the relative stabilities of the intermediate carbonium ions. 4-Allylthio-4-methylpentan-2-onetoluene-p-sulphonylhydrazone on thermal decomposition in the presence of sodium methoxide gave (23), which on irradiation lost nitrogen to give 1,3,3-trimethyl-4thiabicyclo[4,1,O]heptane (24).34 This compound was also formed by irradiation of the sodium salt of the toluene-p-sulphonylhydrazone,and similar treatment of the sodium salt of the toluene-p-sulphonylhydrazone of wall ylthioacetophenone gave 1-phenyl-3-thiabicyclo[3,1,O] hexane (25).34 The unusually high efficiency of these intramolecular cycloadditions to the 32

33 34

M. S. Raasch, J . Org. Chem., 1970, 35, 3470. P. T. Lansbury, E. J. Nienhouse, D. J. Scharf, and F. R. Hilfiker, J . Amer. Chem. Soc., 1970,92, 5649. K. Sato, S. Inoue, and K. Kondo, J. Org. Chem., 1971, 36, 2077. K. Kondo and I. Ojima, Chem. Comm.,1972, 63.

140


isolated double bonds was tentatively attributed to an unspecified activating effect of the sulphur atom in the allylthio-groups. A number of thiolan-3one derivatives (26) were prepared by routes involving Dieckmann cy~lization.~~ Cycloadditions involving unsaturated five- and six-membered rings containing sulphur have offered convenient routes to thiolan and thian derivatives. 3-Thiabicyclo[3,1,0]hexane 3,3-dioxide (27a) and its 2-methyland cis-2,4-dimethyl-derivatives(27b) and (27c) have been synthesized from the appropriate thiolen 1,l-dioxides by cycloaddition of diazomethane

ZiO2 R1frc02R

R2

H

R1 = R2 = C02Et, R3 = Et (b) R' =. C02Et, R' H, R3 = Et (c) R' = C02H, R2 = R3 = H (a)

7

(d) R' = R'

= R3 =

H

(36)

R 2

(a) R1 = R2 = H (b) R1 = Me, R2 = H (c) R1 = R2 = Me

(27)

(a) R = H (b) R = Me (28)

followed by photocatalysed expulsion of nitrogen,3s and the anhydride of 3-thiabicyclo[3,2,0]heptane-6,7-dicarboxylic acid 3,3-dioxide was formed by photocatalysed cycloaddition of maleic anhydride to thiolen 1,l-dio~ide.~' 4H-Thiapyran-4-one and its 2,6-dimethyl derivative underwent photodimerization in a head-to-tail manner to give the compounds (28).38 Full 36 38

88

A. J. Poole and F. L. Rose, J. Chem. SOC.(C), 1971, 1285. W. L. Mock, J . Amer. Chem. SOC.,1970, 92, 6918. V. Sh. Shaikhrazleva, R. S. Enikeev, and G. A. Tolsikov, J. Org. Chem. (U.S.S.R.), 1971, 7 , 1831. N. Ishibe and M. Odani, J. Org. Chem., 1971, 36, 4132; N. Sugiyama, Y. Sato, N. Kashima, and K. Yamada, Bull. Chem. SOC.Japan, 1970,43, 3205.

Saturated Cyclic Compouqds of Sulphur and Selenium

141

details have now appeared of the phosphoric-acid-catalysedpolymerization of thiophen to give the cis- and trans-isomers of 2,4-di-2’-thien~lthiolan.~~ Many fluorinated thiolan derivatives have been formed by fluorination of thiophen or thiolan over potassium tetrafluorocobaltate(rrr) or manganic t r i f l ~ o r i d e ,and ~ ~ from various fluorinated thiolen derivative^,^^ whilst irradiation of a mixture of bis-trifluoromethyl disulphide and chlorotrifluoroethylene gave, amongst other products, 2,4-dichloroperfluorothi01an.~~ Treatment of 3-(3’-methyl-2-oxobutyl)-3-hydroxyindole with thionyl chloride gave, unexpectedly, the thiolan derivative (29),43and reduction of trans-4-phenyl-but-3-en-2-one with sulphurated sodium borohydride gave 3-acetyl-2,6-diphenyl-4-hydroxy-4-methylthian, of unknown conf i g ~ r a t i o n . The ~ ~ cis- and trans-isomers of 2-mercaptothiolan-2,5-dicarboxylic acid were formed by base-catalysed rearrangement of 1,2-dithian3,6-dicarboxylic acid.45 Unexceptional methods were used to synthesize various thiosugar derivative^,^^ and the synthesis of a-methylbiotin, a new natural product, by a modification of the Hofman-LaRoche method has been de~cribed.~’ Properties and Reactions.-An important discussion of the ‘gauche effect’ the stereochemical consequences of adjacent electron pairs and polar bonds - contains material pertinent to five- and six-membered rings containing The preferred conformation of 2-alkoxy- and 2-alkylthio-thian is that with the 2-substituent axially orientated in a chair-like thian ring, according to n.m.r. data.49 The magnitude of this ‘anomeric effect’ was greater for 2-methoxythian, for which it had values of 1.8 kcal mol-1 in carbon tetrachloride and 1.5 kcal mol-l in acetonitrile, than for 2-methylthiotetrahydropyran, presumably because the greater C-S bond distances in the ring of the former reduced the 1,3-diaxial non-bonded interactions. cis-3,5-Dimethylthian-4-onewas more stable than the trans-isomer, the difference in enthalpy, according to n.m.r. spectroscopy, being 1.16 kcal mol-1 in carbon tetrachloride and 1.01 kcal mol-l in ~yridine.~’These values were much smaller than for the isomeric 2,4-dimethylcyclohexanones,a phenomenon attributed to the larger C- S R. F. Curtis, D. M. Jones, and W. A. Thomas, J. Chem. SOC.( C ) , 1971, 234. J. Burdon, I. W. Parsons, and J. C. Tatlow, J. Chem. Soc. ( C ) , 1971, 346. I1 J. Burdon, J. G. Cambell, I. W. Parsons, and J. C. Tatlow, J. Chem. SOC.( C ) , 1971,352. G. Haran and D. W. A. Sharp, J.C.S. Perkin I, 1972, 34. 43 J. Bergman, S. Abrahamsson, and B. Dahlen, Tetrahedron, 1971, 27, 6143. 44 J. M. Lalancette and A. Freche, Canad. J. Chem., 1970, 48, 2366. 46 J. P. Danehy and V. J. Elia, J. Org. Chem., 1971, 36, 1394. 48 M. Bobek, R. L. Whistler, and A. Bloch, J. Medicin. Chem., 1972, 15, 168; M. H. Halford, D. H. Ball, and L. Long, J. Org. Chern., 1971, 36, 3714; U. G. Nayak and R. L. Whistler, Annalen, 1970,741, 131; J. Harness and N. A. Hughcs, Chem. Comrn., 40

1971, 811.

47 48 @ ‘

W. C. Fong, R. Thomas, and K.V. Scherer, Tetrahedron Letters, 1971, 3789. S. Wolfe, Accounts Chem. Res., 1972, 3, 102. N. S. Zefirov, V. S. Blagoveshchenskii, I. V. Kazimirchik, and 0.P. Yakovleva, J. Org. Chem. (U.S.S.R.), 1971, 7 , 599.

142


bond distances and the smaller steric requirements of the lone electron pair on sulphur. It is interesting that cis-3,5-dimethyl-4-oxothian1 , l dioxide was more stable than the trans-isomer to an extent ( A H o = 1.05 kcal mol-l) very similar to that observed in the parent thians, despite the 1,3-diaxial interactions between methyl group and sulphonyl oxygen which are supposedly present in the trans-isomer of the dioxide.27 Lanthanide shift reagents complexed preferentially at sulphur in thian-4-0ne,~~ as indicated by the greater downfield shift in the signals due to the C(2)than C(3)-protons in the presence of Eu(dpm),. The U.V. spectra of thiolan and thian were satisfactorily accounted for by SCF (CND0/2) theory only if d-orbitals were included on the sulphur atoms.s1 The photolysis of thiolan vapour gave mainly ethylene, together with numerous other hydrocarbons, hydrogen, thiols, and thiiran, all in minor amounts.62 No sulphur atoms were formed, and the results were interpreted in terms of the intermediacy of two excited states, and the initial homolysis of a C-S bond,52 a conclusion supported by other spectroscopic data.63 The photochemical rearrangement of 9-thiabicyclo[3,3,l]non-6-ene (30) proceeded via a charge-transfer intermediate (31), since photolysis in deuteriomethanol gave mainly (32) together with a little D

(33), the main product of photolysis in benzene.64 Deuterium would have been incorporated next to the carbonyl group in (32) if Norrish Type I cleavage were involved. This pathway appeared to be general, and did not depend upon the presence of the double bond, in contrast to earlier so 61 62

63

64

H. Hart and G. M. Love, Tetrahedron Letters, 1971, 625. D. R. Williams and L. T. Kontnik, J. Chem. SUC.(B), 1971, 312. S. Braslavsky and J. Heicklen, Canad, J. Chem., 1971, 49, 1316. P. S. H. Bolman, I. Safarik, D. A. Stiles, W. J. R. Tyerman, and O.P. Strausz, Canad. J . Chem., 1970,48, 3872. A. Padwa and A. Battisti, J . Amer. Chem. Suc., 1971, 93, 1304.


143

conclusions, since the saturated analogue of (30) on irradiation in deuteriomethanol gave the saturated analogue of (32) together with the ketone (34), the formation of which was accounted for in terms of scission of the C-S bond, internal hydrogen abstraction to give 6-mercaptocyclo-oct-2-en-1one, and subsequent intramolecular cyclization. The influence of the hetero-atom was critical in these photolyses, since irradiation of the oxaanalogues of (30) and dihydro-(30) in deuteriomethanol gave respectively the oxa-analogues of (32) and dihydro-(32), differing only in the important respect that they were deuteriated adjacent to the carbonyl function, and

not adjacent to the ring oxygen.K4 Features of the electronic spectra of (30) 64 and of thiocan-5-one 55 were indicative of intramolecular chargetransfer involving the sulphur atom and the carbonyl group, and photoelectron spectroscopy suggested that there was effective transfer of charge from the sulphur atom to the unsaturated chromophores in the dione (35).56 This compound underwent photorearrangement rapidly to (36), probably by way of a concerted [1,3]sigmatropic process. The photorearrangement of (35), which was not solvent-dependent, contrasted sharply with that of its carbocyclic analogue, bicyclo[3,3,l]nona-3,7-diene-2,6dione, which underwent [1,2]- and [1,5]-rearrangement; the presence of the sulphur atom apparently controlled the direction of Irradiation of 1-methyl-3-oxothianium tetrafluoroborate gave 6-0x0-2thiaheptane in very low yield, as sole monomeric The 1 : 1 adduct of thiolan with bromine was shown by X-ray malysis to have a pyramidal configuration at sulphur, whilst rapid pseudorotation in the ring rendered it apparently planar.68 N.m.r. data were consistent with rapid inversion of pyramidal co-ordination at sulphur, and with the presence of a highly charged sulphur atom.68 N.m.r. data have also been recordedK9for protonated thiolan and thian in FS03H-SbF6 at - 78 "C. Thiolan acted as a very efficient trap for carbonium ions; with protonated alkenes it gave alkylsulphonium salts,6o and with the carbonium ions derived from acidified pinacol it gave the sulphonium salts (37) and (38).61 K,

's 67

s8

H. Yamabe, H. Kato, and T. Yonezawa, Bull. Chem. Soc. Japan, 1971,44, 611. J. M. Mellor and C. F. Webb, J.C.S. Perkin Z, 1972, 211. A. L. Maycock and G. A. Berchtold, J. Org. Chem., 1970, 35, 2532. G. Allegra, G . E. Wilson, E. Benedetti, C. Pedone, and R. Albert, J. Amer. Chem. Sac.,

1970, 92, 4002. G. A. Olah and P. J. Szilagyi, J. Org. Chem., 1971, 36, 1121. uo H. Bosshard, Helv. Chim. Acta, 1972, 55, 37.

H. Bosshard, M. F. Baumann, and G. Schetty, Helv. Chim. Acta, 1970, 53, 1271.

144


1,2-Dimethylthiolanium perchlorate, 1,3,3-trimethylthiolanium perchlorate, and 1,3,3-trimethylthianiurn perchlorate, partially resolved but of unknown optical purity, racemized at sulphur about a thousand times more slowly than acyclic sulphonium cations.62 Epimerization took place by pyramidal inversion at sulphur and not by a C-S heterolysis-recombination mechanism, since the 1,3,3-trimethylthiolanium cation and 1,3,3-trimethylthianium cation racemized at the same rate, and 1,2-dimethylthiolanium perchlorate retained some optical activity even after racemization was complete.62 The hydrogens of the 1-methyl group in 1-methylthiolanium iodide exchanged with deuterium 23 times faster than the C(2)-hydrogens trans-orientated to the lone electron pair on For the second pair of C(2)-hydrogens there was no detectable exchange under the reaction conditions, indicating that reprotonation occurred exclusively with retention of config~ration.~~ By contrast, no stereoselectivity in hydrogen-deuterium exchange was exhibited by the ring protons in the 1-methylthianiurn and 1-methylthiepanium ions,64 a phenomenon attributable either to small inherent differences in the rates of exchange or to highly stereoselective proton abstraction followed by reprotonation with inversion of configuration. The relative rates of exchange of the a-methylene ring protons in the five-, six-, and seven-membered-ring cations were 17 : 1 : 10, and the effects of various structural changes on the kinetic acidity of these hydrogens were consistent with the formation of a transition state closely resembling a c a r b a n i ~ n . ~ ~ Intramolecular interactions involving the sulphur atom in cyclic sulphur compounds, sometimes with the formation of discrete sulphonium ion intermediates, have played an important role in determining the rate and stereochemical outcome of many reactions. Both steric and electronic factors were important in controlling the stereochemistry of the chlorination of various thiapropellanes by N-chlorosuccinimide.65~ For example, the ratio (65 : 35) of (39) to (40) obtained by chlorination of (41) was greater than the ratio (56 : 44) of (42) to (43) obtained from (44), although consideration of steric effects alone would have predicted the converse G2

63 64 66

66

A. Garbesi, N. Corsi, and A. Fava, Helv. Chim. Acta, 1970, 53, 1499. G. Barbarella, A. Garbesi, and A. Fava, Helv. Chim. Acta, 1971, 54, 341. G. Barbarella, A. Garbesi, and A. Fava, Helo. Chim. Acta, 1971, 54, 2297. L. A. Paquette, R. E. Wingard, J. C. Philips, G. L. Thompson, L. K. Read, and J. Clardy, J. Amer. Chem. Soc., 1971, 93, 4508. L. A. Paquette and R. A. Houser, J . Amer. Chem. Soc., 1971, 93, 4522.


(39) X = H,Y = CI (40)X = CI, Y = H (41) X = Y = H

(42) X (43) X (44) X

= = =

145

H, Y = CI CI, Y = H Y =H

This was rationalized in terms of greater electronic stabilization of the initially formed chlorosulphonium ion derived from (41) (Figure 1) than that derived from (44), with the further assumption that subsequent migration of chlorine from sulphur to carbon proceeded stereospecifically

Figure 1

under the continuing stabilizing effect of the double bonds upon the intervening sulphonium or ylide species.65 A clear example of the influence of molecular geometry upon the ability of sulphur to participate in nucleophilic displacements was provided by the observation that suitable 3p-substituted derivatives, such as (13a), of 2a,5-epithio-5a-cholestaneunderwent solvolysis in aqueous dioxan containing sodium acetate about 10 l1 times faster than the 3a-epimers (13b), and also much faster than its 2a,S-oxaanalogue.67 These marked rate differences, together with the formation of compounds (14a) and (14b) with retention of configuration as sole products, were consistent with participation by sulphur in the heterolysis of the 3P-oriented function and the intermediate formation of the sulphonium ion (45). The predominant product from the solvolysis of (13b) was the hemithioacetal(46), which arose from participation by the C(l)-C(2) bond in the heterolysis of the 3 a - f ~ n c t i o n . ~ In~ the reactions of isotwistane

RW} +

(45) 67

H-

HO

(46)

T. Tsuji, T. Komeno, H. Itad, and H. Tanida, J. Org. Chem., 1971, 36, 1648.

146 Organic Compounds of Sulphur, Selenium, and Tellurium halides [e.g. (12)] with nucleophiles, however, there was no evidence for the intervention of episulphonium ions arising by intramolecular participation by sulphur; in particular, no twistane derivatives were obtained as products.20 Treatment of 3@-hydroxy-2a,5-epithio-5a-cholestane(14b) with lead tetra-acetate resulted predominantly in homolysis of the C(2)- C(3) bond to give the thiolan derivatives (47) and (48), with some C(3)-C(4) bond fission to give (49).ss Since the oxygen analogue of (14b) cleaved exclusively at C(2)-C(3) under these conditions, it appeared that the sulphur in this system is capable of stabilizing a radical both on an a- and

(47) X = OAC,Y = H,Z = CHO (48) X = H, Y = OAC, Z = CHO (49) X, Y = H, OAC, Z = OAC

@-carbonatom. Similarly, in thian derivatives it has been postulated that the sulphur atom facilitates the formation of free radicals at C(3) and at C(4).6B The relative geometry of sulphur and the developing free-radical centre appeared to be important in these cases, since stabilization by sulphur of non-adjacent radicals did not appear to occur in comparable acyclic The 3a-hydroxy-compound (14c) with lead tetra-acetate gave predominantly the ketone (50), together with some (47), an observation rationalized in terms of nucleophilic attack by sulphur on the lead atom of an intermediate alkoxy-lead acetate (Figure 2), instead of the usual homolysis of the lead-oxygen bond leading to fragmentation.6s The role of sulphur in this process is important, since the oxygen analogue of (14c) gave the same products as its 38-isomer. Steric effects associated with the sulphur atom in bicyclic compounds also controlled some reactions. Whereas reduction of (5 1) with lithium aluminium hydride gave exclusively the 3fl-alcohol, the corresponding sulphur compound (50) gave predominantly the 3a-alcohol (14c), which was consistent with the increased steric requirements of the sulphur bridge.21 The unreactivity of 2-bromo-7thiabicyclo[3,2,lloctane (3) towards nucleophilic displacement and elimination reactions was also ascribed to steric effects associated with the sulphur bridge.ls Thiolan was desulphurized to ethylene and cyclobutane in the ratio 10 : 1 on treatment with atomic carbon generated in an electric arc.'O The e9 'O

M. Kishi and T. Komeno, Tetrahedron, 1971, 27, 1527. A. Ohno and Y. Ohnishi, Tetrahedron Letters, 1972, 339. K. 5. Klabunde and P. S. Skell, J. Amer. Chem. SOC.,1971, 93, 3807.


147

photocatalysed reaction of diazomethane with thiolan gave an almost statistical mixture of 2- and 3-methylthiolan, and thian similarly gave a statistical mixture of 2-, 3-, and 4-meth~lthian.~~ Base-catalysed cleavage of (50) with methanolic potassium hydroxide gave 2ar-mercaptocholest-4en-3-0ne,'~ whilst the sodium-hydride-catalysed condensation of 3-oxothiolan with ethyl acetate gave mostly the 2-acetyl derivative, with a little

/ \ OAc

AcO

AcO OAc

J (50) X = S (51) X = 0 Figure 2

4-acetyl-3-0xothiolan.~~ This behaviour is consistent with additional stabilization of the carbanion at C(2) by participation of the 3d orbitals on sulphur. Clemmenson reduction of 2-benzoylthiolan gave 2-phenylthian in a type of rearrangement apparently new for keto-~ulphides.~~ 2-Thia-adamantane-4,8-dione has been and its optical purity and absolute configuration were determined. The carbonyl groups in some derived optically active compounds, such as 2-thia-adamantan-4-one, showed very intense Cotton effects which obeyed a rule analogous to the a-halogenoketone rule. Chiroptical data have been recorded for biotin, its methyl ester, and t h i ~ b i o t i n .Biotin ~ ~ gave two positive Cotton effects, the first, centred at 239 nm, being attributed essentially to the thiolan ring, and the second, below 200 nm, to a superimposition of effects due to the thiolan and ureido chromophores. The chiroptical properties of thiobiotin, however, bore no simple relationship to the properties of the two constituent rings. The n.m.r. properties of the thiolan derivatives (52) and (53) 71 72

73 7s 70

G. N. Gordadze, J . Org. Chem. (U.S.S.R.), 1971, 7 , 2076. T. Komeno and M. Kishi, Tetrahedron, 1971, 27, 1517. G. Buchi, P. Degen, F. Gautschi, and B. Willhalm, J . Org. Chem., 1971, 36, 199. N . A. Nesmeyanov and V. A. Kalyavin, J. Org. Chem. (U.S.S.R.), 1971, 7 , 612. G. Snatzke and B. Wolfram, Tetrahedron, 1972, 28, 655. N. M. Green, W. P. Mose, and P. M. Scopes, J . Chem. SOC.(C), 1970, 1331.

148

(52) R (54) R (63) R (65) R (90) R (91) R


Me, X = Y = lone electron pair H,X = Y = lone electron pair Me, X = 0, Y = lone electron pair = H,X = 0, Y = lone electron pair = H, Y = 0, X = lone electron pair = Me, Y = 0, X = lone electron pair = = =

(53) X (64) X

= =

Y

= lone electron pair 0,Y = lone electron pair

H

(55) X (66) X

= =

Y

lone electron pair 0, Y = lone electron pair =

were consistent with the assumption that the methyl substituents, because of their preference for the equatorial orientation, forced the thiolan rings into the depicted envelope c o n f ~ r m a t i o n .By ~ ~comparison of n.m.r. data, the depicted conformation was assigned to (54) and to biotin ( 5 9 , which according to X-ray analysis also adopts this conformation in the solid state. The C-S bond distances and sulphur valence angles in 5-thiabicyclo[2,1,1Ihexane and 7-thiabicyclo[2,2,llheptane have been determined by gas-phase electron d i f f r a c t i ~ n . ~The ~ structure and stereochemistry originally proposed for dimethyl 1,3-dimethyl-2-aza-8-thiabicyclo[3,2,1 Ioct3-ene-4,7-dicarboxylatehave been confirmed by X-ray analysis, but n.m.r. studies of deuteriated derivatives reversed some original n.m.r. signal assignment^.^^

Determination of the relative basicities of the carbonyl oxygens in thiolan-2-one and its oxygen and selenium analogues, by studying their interaction with phenylacetylene by i.r. methods, coupled with dipolemoment measurements, suggested that resonance forms in which a fractional negative charge was located on the heteroatom vicinal to the carbonyl group were of increasing importance in passing from oxygen to sulphur to selenium.8o Thiolan-Zone was alkylated both at sulphur and oxygen on 77

78

7B

R. Lett and A. Marquet, Tetrahedron Letters, 1971, 2851. T. Fukuyama, K. Kuchitzu, Y. Tamaru, Z. Yoshida, and I. Tabushi, J . Amer. Chern. SOC.,1971, 93, 2799. U. Eisner, M. Z. Haq, J. Flippen, and I. Karte, J.C.S. Perkin I, 1972, 357. I. Wallmark, M. H. Krakov, S.h. Chu, and H. G . Mautner, J . Amer. Chem. SOC.,1970, 92, 4447.


149

treatment with triethyloxonium tetrafluoroborate, since hydrolysis of the alkylated compound gave a mixture of thiolan-2-one with ethyl 4-mercaptobutanoate and its diethylsulphonium tetrafluoroborate derivative.81 3-Amino- and 3-acylamino-thiolan-2-onereacted with hydroxylamine to give homocystinedihydroxamic acids less readily than their oxygen analogues.82 At high temperatures and very high pressures thiolan-2-one gave a mixture of compounds which included (56) and (57).83 The compounds ( 5 8 ) and (59) underwent acid-catalysed rearrangement in alcoholic solvents to give a1kyl 4,5-dihydro-2-methyl thiophen-3-carboxylate and

x

s

(56) = CH,, Y = (57) X = S, Y = CH2

(58) n = 1 (59) n = 2

alkyl 5,6-dihydro-2-methyl-4H-thiopyran-3-carboxylate, re~pectively.~~ A probable mechanism for these rearrangements involved ring-opening of the thiolactones by alcoholysis, followed by recyclization by intramolecular nucleophilic attack of the newly formed thiol function upon the thione carbon, and subsequent elimination of hydrogen s ~ l p h i d e . *The ~ strained triple bond in 2,2,6,6-tetramethyl-4-thiacycloheptyne reacted with aryl and alkyl isocyanides to give 8-alkylimino-4-thiabicyclo[5,1,O]oct-l(7)-ene derivatives.8s Oxides and Dioxides.-Oxidation of thiolans and thians remains the foremost method for the preparation of the oxides and dioxides, and stereochemical data on these transformations are accumulating. Oxidation of 2-methylthiolan with a variety of oxidizing agents was less stereoselective than for 4-t-butylthian, although significant differences in the ratio of cis- to trans-Zmethylthiolan 1-oxide were observed according to the nature of the oxidizing agent.8a Thiolan was autoxidized about five times faster than thian, in reactions which involved the formation and subsequent decomposition of a-peroxido~ulphides.*~It is generally assumed that oxidation of cyclic sulphides to their oxides by peroxy reagents proceeds preferentially on the less sterically hindered side of the sulphur atom, and that with t-butyl hypochlorite a predominance of the more-hindered sulphoxide is obtained. Accordingly, oxidation of 2a,5-epithio-5a-cholestane (60) with peroxy-acids gave the sulphoxide (61) with very little of the 81

M. Mori, M. Shizawa, Y. Ban, and T. Oishi, Chem. and Pharm. Bull. (Japan), 1971,19, 2033.

84

8.s 86

Y. Knobler, S. Bittner, and M. Frankel, Israel J. Chem., 1970, 639. R. Proetzsh, D. Bieniek, and K. Korte, Tetrahedron Letters, 1972, 543. F. Duus and S . - 0 . Lawesson, Tetrahedron, 1971, 27, 387. A. Krebs and H. Kimling, Angew. Chem. Internut. Edn., 1971,409. J. J. Rigau, C. C. Bacon, and C. R. Johnson, J. Org. Chem., 1970,35, 3655. J. A. Howard and S. Korcek, Cunad. J. Chem., 1971, 49, 2178.

150


(60) X (61) X (62) Y

X Y Y = lone electron pair

= = =

0, Y = lone electron pair 0, X = lone electron pair

isomer (62), and t-butyl hypochlorite gave (62) with very little (61).88 On the other hand, oxidation of 2-methylthiolan with both m-chloroperbenzoic acid in dichloromethane and with t-butyl hypochlorite in propan-2-01 gave mainly cis-2-methylthiolan l-oxide,86 whilst m-chloroperbenzoic acid in aqueous dioxan at pH 12, and isopropyl hypochlorite in methylene chloride, both gave predominantly trans-2-methylthiolan 1-oxide.86 Furthermore, oxidation of the thiolan derivatives (52), (53), (54), and biotin ( 5 5 ) with hydrogen peroxide, peroxy-acids, t-butyl hypochlorite, or sodium metaperiodate gave, in each case, predominantly the sulphoxides (63), (64), (65), and (66) (see formulae on p. 148), in which the sulphinyl oxygens were trans-orientated to the dioxolan ring oxygen^.^^ Oxidation of cyclic sulphides with sodium metaperiodate is generally assumed to provide the thermodynamically more stable sulphoxide as major product, but the biotin sulphoxide (66) is the less stable of the two isomers at sulphur, and oxidation of 2-methylthiolan with sodium metaperiodate gave a 43 : 57 mixture of the sulphoxides in which the less thermodynamically stable trans-isomer predominated.86 However, oxidation of (1) with sodium metaperiodate gave only the more stable exo-s~lphoxide.~~ The common assumptions relating stereoselectivity with the nature of the oxidizing agent used to convert cyclic sulphides into their sulphoxides are clearly not universally valid, and their use for the allocation of configuration to cyclic sulphoxides is particularly hazardous. Configurations at sulphur in the above sulphoxides were reliably allocated by interpretation of their n.m.r. spectra, utilizing the following criteria. Protons syn-axially orientated with respect to sulphinyl oxygen were relatively deshielded,l3# and J,,, for the a-methylene protons was smaller when the lone electron pair was axial than when it was e q ~ a t o r i a lO0. ~ Chemical-shift ~~ differences between the a-methylene protons were usually larger when the lone electron pair on sulphur was axial than when it was equatorial, but the sensitivity of these chemical-shift differences to substitution pattern in the cyclic sulphur compounds rendered the coupling-constant criterion more useful.9o The solvent-dependence of the n.m.r. spectra also provided useful information, the addition of benzene causing an upfield shift of the signals due to a8

M. Kishi and T. Komeno, Tetrahedron Letters, 1971, 2641. R. Lett and A. Marquet, Tetrahedron Letters, 1971, 2855. J. B. Lambert, D. S. Bailey, and C. E. Mixan, J . Org. Chem., 1972, 37, 377.


151

protons on the side of the thiolan or thian ring opposite to that of the sulphinyl 89 whilst addition of methanol appeared to produce the opposite effect.7g Lanthanide shifts also proved useful.e1 Chromatographic properties were also utilized to allocate configuration, the sulphoxide isomer with the less sterically hindered sulphinyl oxygen being assumed to have the larger The mass spectral characteristics of thiolan 1-oxide, thian 1-oxide, and thiepan 1-oxide have been inve~tigated.~~ According to n.m.r. data, 4,4-&methylthian 1-oxide showed a greater preference for the chair conformation with an axially orientated sulphinyl oxygen than was exhibited by thian 1-oxide, presumably because the greater puckering at C(4) increased the syn-axial distances, so decreasing the syn-axial interaction^.^^ I n 3,3-dimethylthian 1-oxide the chair conformation with an equatorially orientated sulphinyl oxygen was overwhelmingly preferred,g0 evidently because the attractive 1,3-syn-axial interaction involving the sulphinyl oxygen in thian 1-oxide and the C(5)hydrogen was outweighed by repulsive interaction involving the 3-methyl group. The sulphinyl oxygen was equatorial in the preferred conformations of (63), (65), and (66) and axial in the preferred conformation of (64).8D The greater thermodynamic stability of cis-Zmethylthiolan 1-oxide than its trans-isomer was attributed to attractive interactions between the sulphinyl oxygen and 2-methyl group in the cis-isomer.86 The stereomutation of sulphoxides continues to excite interest. The thermal interconversion of the isomeric sulphoxides (67) and (68) was attributed to homolytic scission-recombination of a C-S bond,7e a conclusion supported by the partial decomposition of the sulphoxides on continued heating at 80 "C. Sulphur, sulphur dioxide, and 2-methylpyrrole-3-carboxylate appeared among the products, which were presumably formed via a sulphenic acid intermediate (Scheme 2), and not by direct extrusion of sulphur monoxide. Oxidation of (67) with m-chloroperbenzoic acid gave complex mixtures, but the sulphoxide (68) gave the corresponding epoxysulphoxide and not the ~ u l p h o n e .The ~ ~ sulphoxides derived from (1) also equilibrated in boiling de~a1in.l~Photoinduced stereomutation at sulphur, a common phenomenon in diary1 and aryl alkyl sulphoxides, has now been encountered in dialkyl sulphoxides.88s93 On irradiation, the sulphoxides (61) and (62) interconverted, although a true equilibrium mixture could not be attained, presumably because of concomitant decomposition.8s The stereomutation of the sulphoxides (69) and (70) was tentatively attributed to intramolecular energy transfer from the carbonyl group, since in its absence stereornutation did not occur.g3 However, there was some decomposition of the sulphoxides during irradiation, and a C-S homolysis-recombination mechanism for inversion at 86p

91 92

93

M. Kishi, K. Tori, and T. Komeno, Tetrahedron Letters, 1971, 3525. R. Smakman and T. J. De Boer, Org. Muss Spectrometry, 1970, 3, 1561. C. Ganter and J.-F.Moser, Helo. Chim. Actu, 1971, 54, 2228.

152


Me02Cm-C0,Me

__+

Me0,C Me

Me

N Me H ( 6 7 ) X = 0, Y = lone electron pair (68) Y = 0, X = lone electron pair

\

\

Me

m

MeO,C,

Me

&/

’C0,Me

I

Me

Scheme 2

sulphur was not ruled out. Prolonged irradiation of both (69) and (70) gave l-hydroxy-9-oxabicyclo[3,3,l]nonan-4-one,probably by initial C-S bond homolysis and intramolecular hydrogen shift to give a sulphine, a species known to desulphurize readily to ketones.g3 The relative rates for

oe

0-

“OH

(69) X = 0, Y = lone electron pair = 0, X = lone electron pair

(70) Y

U (71)

the hydrogen-chloride-catalysedstereomutation of 2-methylthiolan 1 -oxide, 2-methylthian 1-oxide, 2-methylthiepan 1-oxide, and ( + )-methyl 2-butyl sulphoxide g4 were 390 : 1 :31 : 19. Since the critical step in these reactions involved nucleophilic displacement at the sulphur atom, and the relative rates closely matched those established for nucleophilic displacement at carbon in the carbocyclic analogues, it appeared that the geometries of the transition states for nucleophilic displacement at carbon and sulphur were closely similar. The sulphoxides (61) and (62) were very resistant to equilibration in hydrochloric acid-dioxan,88 probably because of the sterically hindered environment of the sulphur atom. Aqueous sodium hydrogen sulphite Ds and iodide ions O6 reduced thiolan 1-oxide to thiolan much faster than they reduced the six- and sevenmembered analogues to the corresponding sulphides. The reactions O4 s5

06

L. Sagramora, A. Garbesi, and A. Fava, Helv. Chim. Acta, 1972, 55, 675. C. R. Johnson, C. C. Bacon, and J. J. Rigau, J. Org. Chem., 1972, 37, 919. S. Tamagaki, M. Mimno, H. Yoshida, H. Hirota, and S. Oae, Bull. Chem. SOC.Japan, 1971,44,2456.

Saturated Cyclic Compounds of Sulphur and Selenium 153 apparently involved initial protonation of the sulphinyl oxygen followed by nucleophilic displacement at sulphur by bisulphite ion or iodide ion with inversion of configuration. Accordingly, sulphate ions were detected in the reaction mixture from the reaction with bisulphite, and cis-Zmethylthiolan l-oxide was reduced much faster than the trans-isomer, leading to a useful preparation of this Similarly, cis-4-t-butylthian l-oxide was reduced somewhat faster than its trans-i~omer.~~ The differences in the rates of reduction of thiolan l-oxide and its six- and seven-membered-ring analogues by iodide ion were attributed largely to differences in the entropy of activation term, which reflected the degree of conformational distortion required in acquiring the transition-state Little distortion was required in the case of thiolan l-oxide, but for thian l-oxide the adoption of transition-state geometry involved twisting into a half-chair conformation. This postulate was substantiated by the immeasurably slow reduction of 9-thiabicyclo[3,3,1]nonane 9-oxide, in which adoption of the favourable half-chair conformation was irnpo~sible.~~ Thiolan 1-oxide reacted with phenol in the presence of hydrochloric acid to give the zwittcrion (71), which on heating at 170 "C produced a tough crystalline Chlorination of thiolan l-oxide with sulphuryl chloride in the presence of pyridine g* gave predominantly trans-Zchlorothiolan 1-oxide together with some of the cis-isomer, which was the predominant isomer when chlorine, t-butyl hypochlorite, or N-chlorosuccinimide was For chlorination with sulphuryl chloride an intermediate similar to that of the Pummerer rearrangement was tentatively proposed.Os Thian l-oxide was converted into a 1 : 1 mixture of cis- and trans-2-chlorothian l-oxide on treatment loo with sulphuryl chloride in methylene chloride at - 78 "C.The isomers did not interconvert under the reaction conditions, and hence appeared to be products of kinetic control. Thiolan 1,l-dioxide with sulphuryl chloride surprisingly gave only 3-chlorothiolan 1,l-dioxide.lol Some interesting chemistry has been encountered in investigations directed towards the formation of cyclobutene derivatives by RamburgBacklund rearrangement of 2-chlorothiolan 1,l-dioxide derivatives. A detailed discussion of the synthesis of the unsaturated propellane derivatives (72), (73), and (74) by Ramburg-Backlund rearrangement of (75), (76), and (77) has now appeared.lo2 These transformations proceeded on treatment with potassium t-butoxide in THF, but similar treatment of the more strained (78) gave only the t-butyl ether (79), whilst the isomeric chlorocompound (80) gave a mixture of (79) and the parent sulphone (81).ss The mechanism proposed for the unusual conversion of (78) into (79) with g7

M. J. Hatch, M. Yoshimine, D. L. Schmidt, and H. B. Smith, J. Amer. Chem. Soc.,

1971,93, 4617. G. Tsuchihashi, K. Ogura, S. Iriuchijima, and S. Tomisawa, Synrhesis, 1971, 2, 89. g9 G. Tsuchihashi and S. Iriuchijima, Bull. Chem. Soc. Jupun, 1970, 43, 2271. loo K . 4 . Tin and T. Durst, Tetrahedron Letters, 1970, 4643. lol I. Tabushi, Y. Tamaru, and 2.Yoshida, Tetrahedron Lerrers, 1971, 3893. lo2 L. A. Paquette, J. C. Philips, and R. E. Wingard, J . Amer. Chem. Soc., 1971,93,4516. 98


154

c1

5

(72)

(73) 3,4-dihydro

(75) (76) 3,4-dihydro

(78) (79) (80) (81)

X

X X X

= = = =

CI, Y = H BuQ, Y = H H, Y = C1 Y =H

retention of configuration has been discussed in Chapter 2, Section 3. The reduction of (80) to (81) under these conditions was attributed to the diminished importance of the competing reaction pathway leading to a thiiran 1,l-dioxide intermediate, which was a probable precursor of (79), because of unfavourable stereoelectronic factors.6s On treatment with butyl-lithium, both (78) and (80) gave the highly strained [4,2,2]propella3,7-diene in very low yield. Compounds with a diene system suitably disposed with respect to the 2-chlorothiolan 1,l-dioxide ring did not undergo the usual Ramburg-Backlund rearrangement on treatment with potassium t-butoxide, but instead underwent a rearrangement which provided a useful method for the synthesis of polyunsaturated bridged sulphones and substituted cyclo-o~tatetraenes.~~~ For example, (82) gave (83), and (84)

c1

&j+QJ -

(82)

(83)

(86)

gave (85), and further heating or irradiation gave (86) and (87). Among the possible mechanisms advanced for this new rearrangement were bishomoconjugative 1,8-dispIacement of chloride ion from the initially formed carbanion to give annelated dicyclopropyl sulphones, which subsequently underwent [02s ,2, + ,2,] bond reorganization to give the products (Scheme 3). Alternatively, the zwitterion (88) formed directly from the carbanion or by cleavage of an intermediate thiiran 1,l-dioxide may have been trapped by the diene moiety more rapidly than sulphur dioxide was 10~t.103

+

lo3

L. A. Paquette, R. E. Wingard, and R. H. Meisinger, J . Amer. Chern. Soc., 1971, 93, 1047.


4

___,

155

me Me

Me

Scheme 3

cis-2-Chlorothiolan 1-oxide reacted with methanethiolate anion with inversion of configuration to give trans-2-methylthiothiolan 1-oxide, but trans-2-chlorothiolan 1-oxide did not react, presumably because of electrostatic repulsion between sulphinyl oxygen and the approaching nucleophile.loa Bis-endo-1,5-dichloro-7-thiabicyclo [2,2,1Iheptane 7-oxide reacted with non-nucleophilic bases to give mainly benzene,los which may have arisen by extrusion of sulphur monoxide from the intermediate 7-thiabicyclo[2,2,l]hepta-2,5-diene 7-oxide. A potentially useful method for the enlargement of sulphur-containing rings was provided by the acid-catalysed or thermal rearrangement of ap-epoxy-sulphoxides and -sulphones, which proceeded in a manner analogous to enlargement reactions of other negatively substituted epoxides.lo6 For example, 2-(diphenylmethylene)thiolan 1,l -dioxide and 2-(diphenylmethy1ene)thian 1,1-dioxide were converted respectively into 3-oxo-2,2-diphenylthian 1,l-dioxide and 3-0~0-2,2-diphenylthiepan1,I-dioxide on treatment with nz-chloroperbenzoic acid and subsequent heating.lo6 The configurations of the diastereoisomeric #I-hydroxy-sulphones formed by the reaction of 1,l-dioxo-2thiolanylmagnesium bromide with benzaldehyde have been deduced from their n.m.r. characteristics.2g Whereas the thveo-isomer gave a 1 : 1 mixture of threo- and erythro-chlorides on treatment with thionyl chloride, the loo

lo6 Io6

K. Ogura and G . Tsuchihashi, Chem. Cornrn., 1970, 1689. T. J. Barton, M. D. Martz, and R. G. Zika, J. Org. Chem., 1972, 37, 552. T. Durst and K.-C. Tin, Tetrahedron Letters, 1970, 2369.

156


erythro-isomer gave only the erythro-chloride, which was rationalized in terms of participation by one of the sulphonyl oxygens of the erythrochloride in the heterolysis of the intermediate chlorosulphite (Figure 3), so that one side of the incipient carbonium ion was protected against subsequent attack. Steric factors inhibited such participation in the threoisomer, so that epimerization at the reacting centre ensued. Dehydrohalogenation of the erythro-chloride with triethylamine at 25 "C gave

Figure 3

2-benzylidenethiolan 1,l -dioxide, but the threo-isomer was inert under these and more drastic conditions, presumably because trans-elimination of the elements of hydrogen chloride was inhibited by steric interactions between the sulphonyl and phenyl groups in the transition state, as in analogous acyclic The equatorial protons at C(2) in (89) exchanged with deuterium 1.6 times faster than did their geminal axial protons, in [2H,]dimethyl sulphoxide-2H,0-Na02H This was in accord with recent MO

(89)

calculations which indicated that the carbanionic charge was most stable when it was located in the bisector of the 0 - S - 0 angle. However, this study did not preclude the intermediacy of planar carbanionic species. In 2H20-Na02H,hydrogen-deuterium exchange took place between two and three times faster for the protons H, in (90) (see formula on p. 148) than for the geminal protons (R = H).Io8 Hydrogen-deuterium exchange at C(2) took place with retention of configuration in (64) and (91) (see p. 148), but with inversion of configuration in (63). The results were complicated somewhat by reactions involving the acetonide moiety, (90) giving rise to (92), and (63) being transformed into (93) under the conditions employed. Pummerer rearrangements of the thiolan l-oxide derivatives (94) consisting of a mixture of isomers at sulphur gave the thiophen derivatives (95) and (96), which apparently arose by addition of acetic anhydride to ylide intermediate^.^^^ lo'

M. D. Brown, M. J. Cook, B. J. Hutchinson, and A. R. Katritzky, Tetrahedron, 1971, 27, 593.

lo8

loQ

R. Lett, S. Bory, B. Moreau, and A. Marquet, Tetrahedron Letters, 1971, 3255. J. Kusmann, P. Sohar, and G . Horvath, Tetrahedron, 1971, 27, 5055.

Saturated Cyclic Compounds of Sulphur and Selenirirn

157

P'

ATEe Me

i

0

(92) R1 =

'jD

H,R2 = OD

(93)R1 = OD, Rz

=

(95) R (96) R

= OAC =:

H

(94)

H

The thermolytic decomposition of the cyclic sulphones (97) and (98) to sulphur dioxide and the 1,5-dienes (99) and (loo), respectively, occurred readily, and was apparently concerted and stereospecific, their formulation as fully concerted [2 + 2 + 21 retrogressions being substantiated by the thermal stability of (101), in which the concerted chelotropic loss of sulphur dioxide would lead to the impossibly strained trans,trans-1,dcycloheptadiene.as These reactions were potentially useful for the synthesis of 1,5-dienes. The epoxy-sulphones (102) and (1 03) also thermolysed stereospecifically to trans,trans-dipropenyl ether (104) and cis,trans-dipropenyl ether (105), respectively, confirming the concerted nature of the reaction, but these reactions were not significant synthetically because of technical difficultie~.~~ Rearrangement of the epoxy-sulphones competed with loss

HO Q0)

R (101)

(110) R = H

(111) R

=

Me

158


of sulphur dioxide. The compounds (106) and (107) eliminated sulphur dioxide to give (108) and (109) on rapid heating at 250 "C, but on gradually increasing the temperature from room temperature up to 250 "C they isomerized to (1 10) and (11l).l10 N-Ethoxycarbonylaziridinothiolan 1,l-dioxides also decomposed on rapid heating to 250 "C, to give divinyl carbamates,l1° the compound (112) for example giving (1 13); the stereochemistry of the reaction again indicated concerted ring-opening in a disrotatory manner. In an investigation directed towards finding new and efficient means of converting bis-carboxylic acids into olefins, the decompositions of cyclic thioanhydrides such as (114) to olefins such as (115) were found to be promoted by transition-metal catalysts such as triphenylphosphinenickel dicarbonyl, di-iron nonacarbonyl, and tris(tripheny1ph0sphine)rhodium chloride.lll However, the method did not appear to be practical for compounds with abstractable /%hydrogens since disproportionation of the resulting olefin occurred, 8-thiabicyclo[4,3,0]nonane7,g-dione giving a mixture of cyclohexene, cyclohexane, and benzene. Further more, both cis- and trans-3,4-dimethylthiolan-2,5-dione gave a mixture of cis- and trans-but-2-ene and but-1-ene, although these olefins did not interconvert under the reaction conditions.lfl Sulphimides and Su1phoximides.-N.m.r. investigations revealed that the toluene-p-sulphonylimideand N-benzenesulphonylimide groups in (1 16) and (117) had a slight preference for the axial orientation, by 145 cal mol-1 and 70 cal mol-l, respectively, and so behaved conformationally like the related thian l-oxide.l12 However, the parent sulphimide (1 18) displayed a slight preference for the equatorial orientation. The toluene-p-sulphonylimido-group in the 4,4-dimethyl derivative of (1 16) showed a slightly increased preference for the axial orientation, probably because of the increased puckering at C(4), but the 3,3-dimethyl derivative of (1 16)

(116) K = TS (117) R = SOz-C,H4 (118) R = H

(120) n = 1 (121) n = 2 (122) M = 3

existed only in the chair conformation with the toluene-p-sulphonylimidogroup e q u a t ~ r i a l .The ~ ~ sulphoximide (119) existed in two distinct conformations in the ratio 2 : 1 at low temperature, the more highly populated 110

111

A. I. Meyers and T. Takaya, Tetrahedron Letters, 1971, 2609.

B. M. Trost and F. Chen, Tetrahedron Letters, 1971, 2603. J. B.Lambert, C. E. Mixan, and D. S. Bailey, Chem. Comm., 1971,316; J. Amer. Chem.

lla

Sac., 1972, 94, 208.

Saturated Cyclic Compounds of Sulphur and Selenium 159 of which was tentatively regarded as being that with the sulphinyl oxygen axially orientated,112 and a similar conclusion was drawn for the 4,4dimethyl derivative of (1 19).90 Barriers to ring-inversion, determined by the complete lineshape method, were consistently larger by about 3 kcal mol-l for these sulphimides and sulphoximides than those in cyclohexane and thian.l12 The criteria used for assigning conformation in the sulphirnides and sulphoxides were the same as those successfully used for thian 1-oxides, the chemical-shift difference between the geminal protons at C(2) being larger, and the geminal coupling constant being smaller, when 112 The couplingthe lone electron pair on sulphur was axially constant criterion was the more reliable because the chemical-shift differences were sometimes strongly affected by the presence of remote groups.9oAn X-ray examination of trans-4-t-butyl-1-(N-ethyl-N-toluene-psulphony1amino)-l-thioniacyclohexane fluoroborate indicated that the thian ring adopted a chair conformation with the substituents at C(l) and C(4) equatorial, confirming earlier stereochemical assignments made to the 4-t-butylthian 1-0xides.l~~The sulphimides (120), (121), and (122), on treatment with methanolic potassium hydroxide, gave respectively 2-methoxythiolan, 2-methoxythian, and 2-methoxythiepan, and not the thiolan l-oxide, thian l-oxide, and thiepan 1-oxide expected by analogy with previous results.114 The relative rates of reaction for these cyclic sulphur compounds were (122) > (120) % (121), and deuterium isotope effects, together with a kinetic study of the effect of varying the parasubstituent in the leaving group, were consistent with the operation of a mechanism similar to that of the Pummerer reurangement.ll4 The use of oxosulphonium ylides derived from salts of sulphoximides for the synthesis of epoxides and cyclopropanes has been extended to the cyclic ylides (123)-(125).l15 With benzalacetophenone the ylide (123) gave (126),

c1

(127) H = I (128) n = 2 (129) i? = 3

whilst with p-chlorobenzaldehyde the three homologous ylides stereoselectively gave the homologous trans-epoxysulphinamides (127)(12 9 ) F R. E. Cook, M. D. Glick, J. J. Rigau, and C. R. Johnson, J . Amer. Chem. Soc., 1971, 93, 924. n4 H. Kobayashi, N. Furukawa, T. Aida, K. Tsujihara, and S. Oae, Tetrahedron Letters,

llS

1971, 3109. n6 C. R. Johnson and L. J. Pepoy, J . Org. Chern., 1972,37, 671.


160

2 Compounds with Two Sulphur or Selenium Atoms in the Ring; their Oxy-sulphur Analogues Cyclic Disulphides and Cyclic Dise1enides.-Formation. No fundamentally new methods of synthesis of this class of compounds have been reported in the past two years. For 1,Zdithiolan the oxidation of 1,3-dithiolsremains a favoured method, the use of iodine in the presence of triethylamine leading smoothly to 1,2-dithiolans without attendant polymerization.116 cis- and trans-l,2-Dithiolan-3,5-dicarboxylic acids were prepared from a diastereoisomeric mixture of dimethyl 2,4-dibromoglutarates by sequential treatment with potassium thioacetate and potassium hydroxide in the presence of iodine,l17 and syn-2,3-dithiabicyclo[3,2,l]octan-8-olwas formed from 2,6-dibromocyclohexanone by successive treatment with potassium thiocyanate, lithium aluminium hydride, and iodine.l18 The stereoselective formation of the less thermodynamically stable alcohol in this case was attributed partly to the formation of chelates with sulphur-aluminium bonds.l18 2,2-Dimethyl-l,3-dibromopropanewas converted into 4,4dimethyl-1,Zdiselenolan on treatment with potassium selenocyanate at 175 "C,but at 140 "Cthe product was 3,3-dimethyl~elenetan.~~~ Reductive debenzylation of 2-alkylamino-1,3-bis(benzylthio)propaneswith lithium in liquid ammonia and oxidation of the resultant dithiols with air afforded 4-dialkylamino-l,2-dithiolans,120 whilst treatment of a-bromomethylchalcone with sodium hydrosulphide gave, as minor product, trans-3pheny1-4-ben~oyl-l,2-dithiolan.~~ Among the many products of thermal decomposition of trans-2,4-diphenylthietanwas 1,4,5,7-tetraphenyl-2,3dithiabicyclo[2,2,2]0ctane.l~~ Properties and Reactions. The desulphurization of a variety of cyclic disulphides to the corresponding sulphides on treatment with aminophosphines followed second-order kinetics, and was attended by inversion of configuration at one of the carbon atoms adjacent to the disulphide g r 0 ~ p . lFor ~ example, cis-3,6-di(methoxycarbonyl)-1,2-dithian (130) gave trans-2,5-di(methoxycarbonyl)thiolan(13 l), most probably by the depicted mechanism, whilst the trans-isomer of (130) gave the cis-isomer of (131). R 0 2 C o C 0 2 R

s-s

(130) trans, R = Me (130a) trans, R = H (130b) cis, R = H lI8 118 ll@ lao

lal

+Me02C--&0,Me S

(131)

D. N. Harpp and J. G. Gleason, J. Org. Chem., 1970,35, 3259. M.-0. Hedblom, Tetrahedron Letters, 1970, 5159. R. M.Wilson, D. N. Buchanan, and J. E. Davis, TetrahedronLetters, 1971, 3919. A. Geens and M. Anteunis, Bull. SOC.chim. belges, 1971, 80, 639. R. M. Pinder, K. Brewster, and D. W. Swanston, Synthesis, 1971, 669. R. M.Dodson and J. Y. Fan, J. Org. Chem., 1971,36, 2708.


161

The partial desulphurization occurred successfully in the presence of many common functional groups, and was accelerated in polar solvents; the rate-controlling step was probably the nucleophilic cleavage of the sulphursulphur b0nd.l' In accord with these mechanistic conclusions, desulphurization of (132) did not give the thietan derivative (133) but gave (134),

probably by the depicted pathway.lls In the oxy-analogues of cyclic disulphides the sulphonyl oxygens also took part in the intramolecular nucleophilic displacements, so that 1,Zdithiolan 1,l-dioxide (135) with tris-diethylamino-phosphine gave only 1,Zoxathiolan 2-oxide (136), whilst

(135) n (137) n

=

1

=

2

(136) n = 1 (138) II = 2

1,Zdithian 1,l-dioxide (137) gave mostly 1,Zoxathian 2-oxide (138) together with some thiolan 1,l-dioxide (139).122 With acyclic thiolsulphonates the predominant products were sulphones, not sulphinates, and the behaviour of the cyclic thiolsulphonates (135) and (137) was consistent with the depicted mechanism, and with the expected effect of ring size upon lza

7

D. N.Harpp, J. G . Gleason, and D. K.Ash, J. Org. Chem., 1971, 36, 322.

162


the course of the reactions.122 trans-l,2-Dithian-3,6-dicarboxylicacid (130a) decomposed in aqueous base 100 times more slowly than its cisisomer (130b), to give mixtures of cis- and trans-2-mercaptothiolan-2,5dicarboxylic acid (140) and (141).45The reaction occurred stereoselectively, Ho2cQ-co2H HS (140) cis (141) trans

the trans-isomer (130a) giving predominantly the cis-thiolan derivative (140), and vice versa. However, cis- and trans-1,2-dithiolan-3,5-&carboxylic acids decomposed in aqueous alkali at the same rate, to give 2-mercapto-2-pentenedioic whilst 1,2-dithiolan-4-carboxylicacid gave a-(mercaptomethy1)acrylic A number of mechanisms were discussed for these rearrangements. 1,2-Dithian 1,l-dioxide reacted with sodium sulphide in methanol to give disodium 4,4'-dithiobis(butanesu1phinate), although it was not cleaved by sodium hydride or sodium iodide.12* As expected, the presence of the second heteroatom in 1,Zdithian 1,ldioxide lowered the barrier to chair-chair interconversioncompared to that in thian 1,l-dioxide, according to low-temperature n.m.r.12K However, 1,2-dithian 1-oxide did not undergo chair-chair interconversion, according to the invariance of its n.m.r. spectrum in the temperature range - 90 to + 150 "C.The orientation of the sulphinyl oxygen in the preferred conformation could not be deduced from the n.m.r. data.126 Similarly, there was no conformational inversion in cis- and trans-4-hydroxy-1,Zdithiolan l-oxide, according to n.m.r. data.126In both these compounds, which occur naturally, the hydroxy-group adopted the equatorial orientation, and the trans-isomer, in which the sulphinyl oxygen was axial, was thermodynamically more stable than the cis-isomer, where sulphinyl oxygen was equatoria1.126 Accordingly, acetylation of cis-4-hydroxy-l,2-dithiolanl -oxide was accompanied by much epimerization at sulphur,126although trans-3phenyl-4-benzoyl-l,2-dithiolan2-oxide apparently did not isomerize at sulphur on heating.28 Pyrolysis of trans-3-phenyl-4-benoyl-1,2-dithiolan 2,2-dioxide in dilute benzene solution at 230 "C gave trans-2-phenyl-3benzoylthietan together with trans-benzalacetophenone,but in the absence of solvent at 225 "C no thietan derivative was formed, the products being trans-3-phenyl-4-benzoyl-1,2-dithiolan and trans-a-methylchalcone.28 It appeared likely that a biradical formed from trans-3-phenyl-4-benzoyl1,Zdithiolan 2,2-dioxide by initial homolysis of the sulphur-sulphur bond and subsequent loss of sulphur dioxide cyclized in dilute solution, but in the absence of solvent it attacked another molecule of thiolsulphonate by an lZs lZ4

lZ6 lZ8

J. P. Danehy and V. J. Elia, J. Org. Chem., 1972, 37, 369. L. Field and Y. H. Khim, J. Medicin. Chem., 1972, 15, 312. D. N. Harpp and J. G. Gleason, J. Org. Chem., 1971, 38, 1314. A. Kato and M. Numata, Tetrahedron Letters, 1972, 203.


163

sH2 process with further elimination of sulphur dioxide to give the observed products.28 The electronic structure and transitions of cyclic disulphides have been calculated by a semi-empirical method, which indicated that absorption at 250-3OOnm was due to n -+ u* transitions, and that the positions of the absorption maxima were related to the dihedral angles about the sulphursulphur bond.127 The optical properties of 1,Zdithiolans and 1,2-dithians have also been accounted for in a theoretical treatment,128and the photocatalysed homolytic scission of the sulphur-sulphur bond in cyclic disulphides has been investigated spectroscopically.s3 Spectrophotometry indicated that there was particularly strong interaction between ethylene chloride and l,Zdithian, compared to that observed for acyclic disulphide~.l~~ 1,3-Dithiolans, 1,3-Dithians, and Their Selenium Analogues.--Formation. Precise experimental conditions have now been published for the preparation of 2-substituted 1,3-dithians and 2-substituted 1,3-dithiolans by the reaction of trimethylenedi(toluenepthiosu1phonate) and ethylenedi(toluene-p-thiosulphonate), respectively, with compounds having activated methylene groups, such as esters of malonic, benzoylacetic, and acetonedicarboxylic acid.lao Disodium ethylenebisthiosulphate and disodium trirnethylenebisthiosulphate similarly reacted with malondiamide and cyanoacetamide to give 1,3-dithiolan and 1,3-dithian derivatives.131 Less reactive methylene groups in compounds such as cyclohexanone and 501cholestan-3-one were activated by conversion into enamine or hydroxymethylene derivatives prior to their reaction with the toluene-p-thiosulphonates.13* However, 1,2-disulphenyI chlorides appeared to be more reactive, converting aldehydes into 2-alkyl-1,3-dithian-2-aldehyde~.~~~ No useful products were obtained with acetophenone or acetone, but ethyl acetoacetate with 1,2-ethanedisulphenyl chloride gave 2-ethoxycarbonyl2-a~etyl-l,3-dithiolan.~~~ In contrast, trimethylenedi(to1uene-p-thiosulphonate) reacted with the pyrrolidine enamine of ethyl acetoacetate by condensation at the methyl, and not the methylene cis- and trans-l,3-Dithian-4,6-dicarboxylicacids and their 2,2-dimethyl analogues were prepared by condensation of 2,4-dimercaptopentane-l,5dioic acid with formaldehyde or acetone, and the trans-isomer was resolved into its enantiomeric forms.117 Similar conventional methods were used to prepare many disubstituted 1,3-diselenansand 4,6-dialkyl-1,3-thia~elenafls.~~~ Ketones are usually regarded to be less reactive than aldehydes towards 12' la*

lZ9

130 131 132

H. Yamabe, H. Kato, and T. Yonezawa, Bull. Chem. SOC.Japan, 1971, 44, 604. J. Linderberg and J. Michl, J . Amer. Chem. SOC.,1970, 92, 2619. B. Nelander and I. Noren, Actu Chem. Scund., 1972, 26, 809. R. B. Woodward, I. J. Pachter, and M. L. Scheinbaum, J. Org. Chem., 1971, 36, 1137. S. Hayashi, M. Furukawa, Y.Fujino, T. Nakao, and S . Inoue, Chem. and Pharm. Bull. (Japan), 1971, 19, 1557. C. M. Leir, J . Org. Chem., 1972, 37, 887

164


condensation with thiols and dithiols, but many keto-aldehydes condense with 1,2-dithiolsmorereadily at the keto-group than at the aldehyde carbonyl For example, pyruvaldehyde with propane-l,2-dithiol gave only 2,4-dimethyl-l,3-dithiolan-2-carboxaldehyde, and even t-butylglyoxal gave mostly 2-t-butyl-4-methyl-l,3-dithiolan-2-carboxaldehyde, the product of condensation at the aldehyde group being formed only in minor Condensation of some gem-dichloro-compounds with 1,2- and 1,3-dithiols gave 1,3-dithiolan and 1,3-dithian derivatives, re~pective1y.l~~ The conversion of active-methylene compounds into 2-alkylidene derivatives of 1,3-dithiolans by base-catalysed condensation with carbon disulphide followed by treatment with 1,2-dihalogenoalkanes has been further exemplified,136and extended to the synthesis of substituted alkylidene derivatives of 1,3-diselenolans and 1,3-di~elenans.l~~ With dimethyl malonate, carbon diselenide, and either 1,2-dibromoethane or 1,3-dibromopropane, for example, the compounds (142) and (143), respectively, were formed.136 Analogously, the dithiolate anion obtained from deoxybenzoin Ph I

Meo2cxco2Me Se

kCHa)n (142) n = I (143) n = 2

Ph (144)

and carbon disulphide under strongly basic conditions was converted into (144) on treatment with a-chlorodiphenylacetyl chloride and pyridine.13' This synthesis established that (144) was the true structure of the product obtained from the reaction of azibenzil with carbon disulphide, a conclusion later corroborated by X-ray data.13' In a related process, 1,3-dithiolan2,4-dione and its 5-methyl and 5-ethyl derivatives were synthesized by treatment of sodium ethyl xanthate successively with the appropriate 2-halogenocarboxylic acid, trimethylsilyl chloride in triethylamine, and finally thionyl chloride.13* These hitherto unknown compounds polymerized in the presence of bases, or on heating above 100 "C. Methods for the preparation of tetrathioethylenes, including cyclic derivatives of general structure (145), have been and the T. L. Fridinger and K. R. Henery-Logan, J . Heterocyclic Chem., 1971, 8, 469. G. Zinner and R. Vollrath, Chern. Ber., 1970, 103, 766. 13ti P. Yates, T. R. Lynch, and D. R. Moore, Canad. J . Chem., 1971, 49, 1467. lS6 K. A. Jensen and L. Henrikson, Acta Chem. Scand., 1970, 24, 3213. lS7 P. Yates, B. G. Christensen, and L. L. Williams, Canad. J . Chem., 1971, 49, 1691; K. Dichmann, D. Bichan, S. C. Nyberg, and P. Yates, TetrahedronLetters, 1971, 3649. H. R. Kricheldorf, Angew. Chem. Internat. Edn., 1971, 10, 726. lag D. L. Coffen, J. Q. Chambers, D. R. Williams, P. E. Garrett, and N. D. Canfield, J. Amer. Chem. SOC.,1971, 93, 2258.

lS3

134


165

intermediacy of carbenes in the formation of such compounds from the reactions of orthothioformates with organolithium reagents was substantiated by the conversion of (146) into (145b) on treatment with butyl1 i t h i ~ m . lUnder ~ ~ the same conditions, however, (147) gave only ethylene

(a) n = 1

(b) n

=

2

(146) n = 2, wz = 3 (147) n = I , TI = 2

(145)

and 1,3-dithiolan-2-thione, probably because the intermediate 1,3-dithiolanoid-2-carbene fragmented readily to ethylene and carbon disulphide, which subsequently took part in secondary reactions. A highly efficient new method of making compounds such as (145), involving the pyrolysis of orthothio-oxalates, was exemplified by the conversion of 1,3-dithiolan-2thione into (148) on treatment with diazomethane, followed by pyrolysis of (148) to (145a).13g This method worked also with 1,3-dithian-2-thione, but 1,3-dithietan-2-thione failed to react with diazomethane. An alternative method of preparing orthothio-oxalates was exemplified by the reaction of ethane-l,2-dithiol with oxalyl chloride to give (149), the alternative propellane structure for the product being ruled out on the basis of its 13C n.m.r. when irradiated Olefins reacted with 5-phenyl-l,2,4-dithiazole-3-thiones to give 1,3-dithiolan derivatives, cyclohexene for example giving (150), which on acid hydrolysis unexpectedly gave (151).140 The cis-fusion of the rings in (151) was established by its conversion into cyclohexene on treatment with triethyl phosphite. Olefins with electron-withdrawing subsuggesting stituents did not react with 5-phenyl-l,2,4-dithiazole-3-thioneY that free-radical intermediates, and not 1,3-dipolar intermediates, were involved in the initial addition.140 The hitherto unknown lY3-dithiolan-4thione system has been synthesized;141 cyclohexane-1,1-dithiol reacted I4O 141

R. Okazaki, K. Okawa, and N. Inamoto, Chem. Comm., 1971, 843. D. H. R. Barton and B. J. Willis, J.C.S. Perkin I, 1972, 305; D. H. R. Barton and B. J. Willis, Chem. Comm., 1970, 1225; D. H. R. Barton, E. H. Smith, and B. J. Willis, ibid., p. 1226.

166

Organic Compounds of Sulphur, Selenium, and Tellurium H

(isij x = s with potassium cyanide in dioxan-water to give a mixture of 4-imino-2spirocyclohexane-5-spirocyclohexane1,3-dithiolan and 2-spirocyclohexaneS-spirocyclohexane-l,3-dithiolan-4-thione, the former compound giving the latter on treatment with hydrogen s ~ 1 p h i d e . lCarbon ~~ disulphide reacted with bicycloheptene derivatives at very high pressures to give thiolan derivatives, bicyclo[2,2,l]hept-2-ene itself giving (152) and its exo,endoisomer,142whilst retro-diene cleavage of 2,3-di(methoxycarbonyl)bicyclo[2,2,2]octa-2,5-dieneunder these conditions led to (145a). The reaction of epoxides with alkali-metal xanthates is a well-used method of preparing 1,3-dithiolan-2-thionederivatives, but it has now been established that they may be formed from epoxides and carbon disulphide in the presence of only a trace of potassium hydroxide or potassium m e t h 0 ~ i d e . l ~ ~ Sodium hydrosulphide reacted with a-bromomethylchalcone to give which according to n.m.r. mainly 2,4-diphenyl-5-benzoyl-1,3-dithian, spectroscopy adopted the chair conformation with all the substituents equatorially orientated.28 Bis(trifluoromethy1)thioketen reacted with sulphur at 200 "C to give perfluoro-2-isopropylidene-5,5-dimethyl-l,3-dithi0lan-4-thione,~lwhilst other 1,3-dithiolan derivatives were isolated from the decomposition of dihydrothiadiazoles in the presence of t h i ~ n e s , ~ ~ ~ reactions for which there is ample precedent. Thermal degradation of a polyethylene sulphide prepared using metal thiolates as initiators gave 2-methyl-I ,3-dithiolan as major product, probably by cyclization of 2-mercaptoethyl vinyl sulphide formed as a transient intermediate, whilst polypropylene sulphide on thermal degradation gave a mixture of products which included 2-ethyl-4-methyl-l,3-dithiolanand 2,2,4-trimethyl-1,3dithi01an.l~~ Properties and Reactions. There have been interesting further developments in the synthetic utility of 1,3-dithians. Deuteriation or methylation of the lithium salts of conformationally fixed 1,3-dithian derivatives occurred with high stereospecificity to give the deuterio or methyl derivative equatorially orientated at C(2).146 For example, cis-4,6-dimethyl-l,3-dithian 14a

143 114

146

H. Plieninger, C. C. Henck, and R. Buhler, Tetrahedron, 1972, 28, 73. S. Hayashi, M. Furukawa, Y . Fujino, T. Nakao, and K. Nagato, Chem. and Pharm. Buff. (Japan), 1971, 19, 1594. C. E. Diebert, J. Org. Chem., 1970, 35, 1501. R. T. Wragg, J. Chem. Soc. (B), 1970, 404. A. A. Hartmann and E. L. Eliel, J. Amer. Chem. Soc., 1971, 93, 2572.


167

(1 53), on successive treatment with butyl-lithium and deuterium chloride, gave only (154), whilst methylation of the lithio-derivative gave only (155). Deuteriation of the lithio-derivatives of the trans-2-methyl derivatives (156) gave only (157), whereas deuteriation of the lithium salt of the all-ciscompound (158) proceeded much more slowly to give only (157), with

(153) R' = R2 = H (154) (155) (156) (157) (158)

R' = H, R2 = D R1 = H, R2 = Me R 1 = Me, R2 = H R1 = Me, R2 = D R* = H, R2 = M e

inversion of configuration at C(2).146 This provided a potential method of synthesis of otherwise poorly accessible 1,3-dithians in which the C(2)substituent was axially orientated. The reaction of 2-lithio-l,3-dithians with epoxides has been usefully exploited for the introduction of methyl groups 14' and of corticoid-like C(17) functions 14* into steroids, whilst ethyl 1,3-dithian-2-carboxylate,which was readily prepared from ethyl diethoxyacetate and 1,3-propanedithiol, was shown to be a convenient intermediate for the synthesis of a-keto-esters and of alkylated acetic acids.14@It was sufficiently acidic to be alkylated by alkyl halides with sodium hydride in DMF-benzene as base, instead of the more usual but less convenient alkyl-lithium reagents. A new method for selective fission of carbon-carbon bonds under non-oxidative conditions was exemplified by the conversion of (159) into (160) on treatment with sodium methoxide P

14'

S

J. B. Jones and R. Grayshan, Cunud. J. Chem., 1972, 50, 810. J. B. Jones and R. Grayshan, Chem. Comm., 1970, 741. E. L. Eliel and A. A. Hartmann, J . Org. Chem., 1972, 37, 505.

168

Organic Compounds of Sulphur, Selenium, arid Tellurium

in dimethyl sulphoxide.lS0 It had the additional advantage that it led directly to the synthetically versatile dithian moiety, which was capable of further transformations. The isolation of the acid (160) rather than the corresponding methyl ester was unexpected, and may be due to the presence of traces of moisture. The synthetic versatility of 1,3-dithian anions was further illustrated by their use as electrofugal groups in fragmentation reactions, the compound (161) for example fragmenting to (162) on treatment with phenyl-lithium, further hydrolysis leading to hept-6-enoic acid.151 A method for the homologation of aldehydes involved the reaction of aldehydes with the ylide obtained from 1,3-dithian-2-thioneand trimethyl phosphite, to give keten thioacetals which were subsequently reduced and hydrolysed (Scheme 4).152 This homologation depended upon the ability

I

E f:,SiH

RCH,CHO +---

s T R

U

Scheme 4

of sulphur to stabilize adjacent carbonium ions, whilst an important cyclization in a synthesis of the tetracycline skeleton took advantage of the ability of sulphur in 1,3-dithiolans to stabilize radicals at C(2).153 2-aStyryl-l,3-dithian (163a) formed an ambident anion on treatment with bases, as indicated by its deuteriation to give a mixture of (163b) and (164b), and by its methylation to give a mixture of (163c) and (164c).15* Calculations by the CNDO method did not provide clear-cut supporting evidence for the role of 3d-orbital conjugation in the stabilization of these ambident underwent oxidative dimeriza~ a r b a n i 0 n s . l2-Phenyl-2-lithio-l,3-dithian ~~ tion in the presence of nitrobenzene derivatives, but it reacted with 2-bromopyridine to give 2-phenyl-2-(2’-pyridyl)-l,3-dithian,providing, after hydrolysis, a useful route to 2-aryl pyridyl ketones.155 2-Lithio-l,3-dithian, like J. A. Marshall and H. Roebke, Tetrahedron Letters, 1970, 1555. J. A. Marshall and J. L. Belletire, Tetrahedron Letters, 1970, 871. lS2 F. A. Carey and J. R. Neergaard, J. Org. Chem., 1971, 36, 2731. 153 D.H.R. Barton, D. L. Clive, P. D. Magnus, and G. Smith, J. Chem. Suc. ( C ) , 1971, 2193. 164 D.L. Coffen, T. E. McEntee, and D. R. Williams, Chem. Cumm., 1970, 913. 155 W. H.Baarschers and T. L. Loh, Tetrahedron Letters, 1971, 3483. 150

161


dR1

R2

sU

S

s-s

U

t3

p

U

169

d":

S

U

stronger nucleophiles, reacted with O-alkylaziridine carbamates by attack at carbonyl carbon, without fission of the aziridine ring.156 Efficient methods have been described for the hydrolysis of 2-substituted 1,3-dithians to carbonyl a transformation which is important if the full synthetic potential of the versatile 1,3-dithian reagents is to be realized, but which many workers found troublesome. The mercury(rr)promoted hydrolysis of 2,2-dialkyl-1,3-dithianswas more rapid than that of 2-monosubstituted derivatives, whilst 2-acyl-1,3-dithians were fairly unreactive and were best converted into carbonyl compounds by oxidative cleavage either with N-bromosuccinimide or by N-chlorosuccinimide in the presence of silver ions.lS7 The latter reagent was particularly useful for the hydrolysis of unsaturated 1,3-dithian derivatives since it did not affect unsaturated 1ink~tges.l~'Mercuric oxide and boron trifluoride etherate in aqueous THF hydrolysed 2-substituted-l,3-di thians eficiently to carbonyl compounds, but these conditions gave disappointing yields of carbonyl compounds from 2-spiroalkane derivatives of 1,3-dithians, whilst 2-benzoyl1,3-dithian was converted into benzoic acid.15* Other methods of converting 2,2-disubstituted-l,3-dithiolansand -1,3-dithians into the corresponding ketones have involved oxidation to the 1,3-disulphoxidesby peroxy-acids,15* or conversion into the 1,3-bis-sulphonium salts by treatment with triethyloxonium tetrafluoroborate,lso followed by hydrolysis of the disulphoxides or bis-sulphonium salts to ketones under mild basic conditions. 2,2-Disubstituted-l,3-dithiolans were also converted directly into carbonyl compounds on treatment with Chloramine T.lS1 The reduction of substituted 1,3dithiolans and 1,3-dithians by calcium in liquid ammonia to ,k?- and y-alkylthioalkanethiols, respectively, occurred readily and in high yield, the ready 1156

15'

159 180

A. Hassner and A. Kascheres, Tetrahedron Letters, 1970, 4623. E. J. Corey and B. W. Erickson, J. Org. Chem., 1971, 36, 3553. E. Vedejs and P. L. Fuchs, J. Org. Chem., 1971, 36, 366. P. R. Heaton, J. M. Midgley, and W. B. Whalley, Chem. Comm.,1971, 750. T. Oishi, K. Kamemoto, and Y . Ban, Tetrahedron Letters, 1972, 1085. W. E. J. Huurdeman, H. Wynberg, and D. W. Emerson, Tetrahedron Letters, 1971, 3449.

170


accessibility of the starting materials making the reaction synthetically useful.lS2 Further reduction occurred readily when the substituents at C(2) were capable of stabilizing carbanions, in accord with the proposition that the reactions involved a two-stage electron transfer (Scheme 5). Such

Scheme 5

'over-reduction' was avoided by careful control of reaction conditions,162 and in a further example 2,2-diphenyl- 1,3-dithiolan was reduced to diphenyImethane by four equivalents of alkali metal in ammonia, and to 2-(diphenylmethylthio)ethanet hiol when two equivalents of a1kali met a1 were used.ls3 2,2-Diphenyl-l,3-dithiolanwas also reduced to diphenylmethane by lithium aluminium hydride in the presence of cupric chloride and zinc ch10ride.l~~ 1,3-Dithiolan-2-thione reacted with dimethyl acetylenedicarboxylate at 140 "C to give ethylene and dimethyl 2-thioxo-l,3-dithiole-4,5-dicarboxylate.ls5*lS6 Such reactions occurred only with acetylenes bearing electronwithdrawing substituents (except for acetylene itself, which reacted under forcing conditions),166and the transfer of a trithiocarbonate grouping from an olefin to an acetylene probably involved a concerted cis-elimination via a bicyclic transition state (Scheme 6), since cis- and trans-4,5-diphenylR1

R2 H~ , : > S H

-

R1

C02Me

--+

€3

+

Scheme 6 le2

le4 lo6

le6

B. C. Newman and E. L. Eliel, J. Org. Chem., 1970, 35, 3641. E. M. Kaiser, C. G. Edmomds, S. D. Grubb, J. W. Smith, and D. Tramp, J. Org. Chem., 1971, 36, 330. T. Mukaiyania, K. Narasaka, K. Maekawa, and M. Furusato, Bull. Chem. SOC. Japan, 1971, 44, 2285. D. B. J. Easton, D. Leaver, and T. J. Rawlings, J.C.S. Perkin I, 1972, 41. B. R. O'Connor and F. N. Jones, J. Org. Chern., 1970,35,2002.


171

1,3-dithiolan-2-thiones gave cis- and trans-stilbene, respectively, whilst the trans-bicyclic thione (165) did not react with dimethyl acetylenedicarboxylate.166 Benzyne took part in an analogous reaction,ls5 but bromocyanoacetylene converted 1,3-dithiolan-2-thione into the adduct (166), the first

example of a stable thioacyl bromide.lS6 2-Dialkylamino-l,3-dithiolanium perchlorates (167) behaved as ambident electrophiles, the reactive sites being C(2) and C(4).16' The nature of the attacking nucleophile determined the course of the reaction, basic nucleophiles attacking at C(2), bulky basic nucleophiles abstracting a proton from C(4) and thus causing elimination, whilst polarizable nucleophiles performed nucleophilic displacements at C(4). Examples are provided in Scheme 7. Nucleophilic displacement at

[)=&Me2

CN-

Scheme 7 C(2) and C(4) occurred progressively more readily in the six- and sevenmembered-ring analogues of (167), suggesting a progressive decrease in the stability of the cations with increasing ring size.lB8 Photo-oxygenation of the tetrathioethylene (145b), a process involving singlet oxygen, gave the twelve-membered heterocycle (1 68), and not the expected 1,3-dithian-2-0ne; it was proposed that fission of carbon-sulphur bonds in an intermediate dioxetan occurred in preference to the fission of a carbon-carbon bond.169 167

lB8

lo8

T. Nakai and M. Okawara, Bull. Chem. SOC.Japan, 1970, 43, 1864. T. Nakai, Y. Ueno, and M. Okawara, Bull. Chem. SOC.Japan, 1970, 43, 3175. W. Adam and J.-C. Liu, J. Amer. Chem. Soc., 1972, 94, 1206; Chem. Comm., 1972, 73.

172


H (169) X (1701 X

= =

Br H

C

The bromide (169), obtained from tetramethyltetrathia-adamantane (170) on treatment with bromine, was moderately stable despite the antiperiplanar arrangement of the carbon-sulphur and carbon-bromine bonds that should be ideal for sulphur-assisted ionization of the Solvolysis gave (171), presumably by way of the indicated pathway. The formation of a dianion from tetramethyltetrathia-adamantane (170) in THF on stirring with sodium-potassium alloy has been refuted by electrochemical evidence,171the previously observed behaviour that suggested the presence of anions being attributed to the presence of impurities. 2,4Dioxa-6,8-dithia-, oxatrithia-, pentathia-, and hexathia-analogues of (170) were also apparently incapable of forming dianions.171 Bis-sulphonium salts derived from 1,3-dithiolans and 1,3-dithians by treatment with triethyloxonium fluoroborate were successfully converted into the corresponding ylide whilst 1,3-dithian was converted into a carbonylstabilized ylide by successive treatment with phenacyl bromide and sodium hydr0~ide.l~ Keten ~ inserted into the carbon-sulphur bonds of 2-substituted-l,3-dithiolans to give polythio-ethers.174 The relationship between spectroscopic properties and conformation and configuration of 1,3-dithians and 1,3-dithiolans continues to attract interest, and some recent reviews contain relevant inf~rmation.~,Anteunis and his associates have shown that the geminal coupling constant at C(2) in 1,3dithians and 1,3-diselenans can be predicted by an equation which takes into account the electronegativity of the heteroatoms, the bond lengths 170 171

172 173 174

D. L. Coffen and M. L. Lee, J . Org. Chem., 1970,35, 2077. K. Olssen and S.-0. Almqvist, Acta Chem. Scand., 1970, 24, 3777. I. Stahl, M. Hetschko, and J. Gosselk, Tetrahedron Letters, 1971, 4077. I. Stahl and J. Gosselk, Tetrahedron Letters, 1972, 989. H. Eck and H. Prigge, Annalen, 1972, 755, 177.


173 terminating at the heteroatoms, and the mutual spatial orientation of the adjacent p-orbitals on the heteroatoms and the carbon-hydrogen bonds at C(2).175This leads to quantitative information about the conformations of the systems. I n many, but not all, 2-alkyl-l,3-dithians the vicinal exocyclic coupling constants were larger when the substituent at C(2) was axially than when equatorially orientated, providing an additional method for the assignment of structure for such The high degree of puckering in 2-phenyl-1,3-dithian was confirmed by an examination of its 220 MHz n.m.r. spectrum, which furnished all the relevant coupling constants,177and the ring torsional angles were determined by n.m.r. using the ‘R-value’ method.178 This method appeared to be valid even for anancomeric conformational eq~i1ibria.l~~ The n.m.r. spectrum of 1,3-dithian-trans-4,6-dicarboxylicacid indicated that it existed either as rapidly equilibrating chair forms or in a conformationally homogeneous twist form.l17 Calculation of the U.V. spectra of 1,3-dithiolan and 1,3-dithian indicated that d-orbitals played an important part.51 According to an n.m.r. study involving the analysis of the AA’BB’ spin systems of the methylene protons of some 1,3-dithiolans, the rings were more puckered than those in their oxygen analogues, having an approximate ring torsion angle of f 49”. The evidence, however, could not distinguish between a C, and C, conformation of the 13ng.l~~ The shielding effects of the 1,3dithiolan moiety in the thioketal derivatives of monoketoandrostanes upon the methyl groups C(18) and C(19) have been determined experimentally for a number of solvents and compared with calculated values.lao In other steroidal ethylene thioketals no useful additional n.m.r. spectral information was provided if lanthanide shift reagents were added.le1 The mass spectra of 1,3-dithian, 2-methyl-l,3-dithian, and 2,2-dimethyl-l,3dithian,la2and the negative-ion mass spectra of 2-aryl-l,3-dithians la3have been studied in detail, and full details have now appeared of the mass spectral behaviour of 2-spiro-2’-(1’,3’-dithian) derivatives of 3-0x0steroids, which provides a simple method for differentiating between 19-methyl- and 19-nor-ster0ids.~~~ 1,4-Dithians,1,4-Diselenans,1,4-Dithiepans,and 1,5-Dithiocans.-Forrnation. The ratio of 2-methyl-1,4-dithian (172) to 1,4-dithiepan (173) obtained on photocatalysed cyclization of the unsaturated thiol (174) was sensitive to M. Anteunis, G. Swaelens, and J. Gelan, Tetrahedron, 1971, 27, 1917. M. Anteunis, Bull. SOC.chim. belges, 1971, 80, 3. 177 H. R. Buys, Rec. Trav. chim., 1970, 89, 1244. 178 H. R. Buys, Rec. Trav. chim., 1970, 89, 1253. 178 L. A. Sternson, D. A. Coviallo, and R. S . Egan, J. Amer. Chem. Soc., 1971,93, 6529. l80 J. W. ApSimon, H. Beierbeck, D. K. Todd, P. V. DeMarco, and W. G. Craig, Cunud. J. Chem., 1971, 49, 1335. lE1 5. E. Herz, V. M. Rodriguez, and P. Joseph-Nathan, Tetrahedron Letters, 1971, 2949. lE2 J. H. Bowie and P. Y. White, Org. Mass Spectrometry, 1972, 6, 317. lS3 J. H. Bowie and P. Y. White, Org. Mass Spectrometry, 1972, 6, 75. J. M. Midgley, B. J. Millard, W. B. Whalley, and C. J. Smith, J. Chem. SOC.( C ) , 1971, 176

176

19.

174


/?/

4

) 5 3 -7

R

R2 R1 = R' = H (175) R1 = Me, R2 = H (176) R1 = H, R2 = M e

(174)

R2 (172) R' = R2 = H (177) R1 = H, RZ = Me

(179) R* = Me, R2 = H

\ R2 (173) R' = R2 = H (178) R' = Me, R2 = H

temperature, being approximately 2 : 1 at 80 "C, and 1 : 7 at - 65 "C, apparently because the cyclization of the thiyl radicals was reversible, and because the cyclized radicals leading to 2-methyl-l,4-dithian were thermodynamically the more stable.22 The role of reversibility of radical cyclization, and of the relative stability of the cyclized radicals, was clearly indicated by the observation that the unsaturated thiols (175) and (176) gave the same products, 2-ethyl-l,4-dithian (177) and 5-methyl-l,4-dithiepan (178), in the same ratio (95 : 5 ) on photolysis at 80 "C, no 2,3-dimethyl1,4-dithian (179) being isolated in either case.185 At - 65 "C the predominant photocatalysed cyclization product was 5-methyl-1,ddithiepan (178).lE6 In an intermolecular example, 3-methyl-but-2-enethiol photodimerized to a mixture of cis- and trans-2,5-di-isopropyl-l,4-dithian in good yield.lss Divinyl sulphone reacted with sulphur dioxide in the presence of a mixture of formic acid and formaldehyde as catalyst to give 1,4-dithian1,l ,4,4-tetroxide,ls7 and 1,4-dithian derivatives were also formed in the reactions of 1,2-di-immonium salts with sodium ethanedithiolate,188and in the pyrolysis of polyethylene and polypropylene s ~ 1 p h i d e . lThe ~ ~ formation of 1,4-dithians by photocycloaddition of thiocarbonyl compounds to olefins has been reviewed.2 Properties and Reactions. The products of photo-oxidation of 1,4-dithian, which involved singlet oxygen and presumably the intermediacy of persulphoxides, depended critically upon the solvent, temperature, and concentration of substrate, low temperature and aprotic solvents favouring the M.-P. Crozet, J.-M. Surzur, and C. Dupuy, Tetrahedron Letters, 1971, 2031. K. Takabe, T. Katagiri, and J. Tanaka, Tetrahedron Letters, 1970, 4805. lE7 H. W. Gibson and D. A. McKenzie, J . Org. Chem., 1970,35,2994. lE8 L. Duhamel, P. Duhamel, and G . Ple, Tetrahedron Letters, 1972, 85. lE6

188


175

formation of sulphone, whilst high temperature and protic solvents favoured the formation of sulphoxides, which occurred stereospecifically to give the c i ~ - i ~ ~ r n eExtensive r ~ . ~ * ~rearrangement accompanied the fluorination of 1,4-dithian with potassium tetrafluorocobaltate, the main products of 1,4-dithians being polyfluoro-2-methyl-1, 3 - d i t h i o l a n ~ rearrangements ;~~~ to 2-methyl-l,3-dithiolans were previously unknown. Potassium tetrafluorocobaltate was a much milder fluorinating agent than the commonly used cobalt trifluoride, and sulphur-containing compounds were fluorinated An unusual example of the fragmentation with little extrusion of of a 1,4-dithian tetroxide derivative was encountered in the oxidation of (149) by hydrogen peroxide in acetic acid, to give 1,3-dithiolan 1,1,3,3t e t r 0 ~ i d e . lThe ~ ~ ready fragmentation of the supposed intermediate (180) to

n

"'02sUs02 ">c;"' (1 81) was possibly accelerated by repulsive interactions among the accumulated sulphone groups, and was probably not concerted. The rapid conversion of (181) into 1,3-dithiolan 1,1,3,3-tetroxide was confirmed by the 1,4-Dithian has been converted into a behaviour of (145a) on carbonyl-stabilized ylide by treatment with phenacyl bromide and sodium and some of the reactions of these ylides were explored. The stereochemical requirements of adjacent lone electron pairs and polar bonds have been discussed in an important paper which analysed the considerable volume of available data, including those pertaining to 1,ddithians and similar The 'Edwards-Lemieux' effect in substituted 1,6dithians was accounted for satisfactorily by calculations using fluoromethanol as a model compound.lQ1 The temperature-dependence of the lSF n.m.r. spectrum of perfluoro-1,4-dithian indicated a barrier to ring-inversion of 10.05 f 0.10 kcal mo1-l.lD2 The fluorine chemical-shift differences at - 90 "C appeared to be consistent with a preferred chair conformation, possibly strongly puckered as in 1,4-dithian. The i.r. and Raman spectra of 1,4-dithian lQ3and 1,4-diselenan 194 have received detailed attention, and the crystal and molecular structures of lag 180 lol

lQ2 lQ3

194

C. S. Foote and J. W. Peters, J. Amer. Chem. SOC.,1971, 93, 3795. J. Burdon and I. W. Parsons, J. Chem. SOC.( C ) , 1971, 355. S. Wolfe, A. Rauk, L. M. Tel, and I. G. Csizmadia, J. Chem. Soc. (B), 1971, 136. J. E. Anderson, D. R. Davis, and J. D. Roberts, J. Org. Chem., 1970, 35, 1195. 0. H. Ellestad, P. Klaboe, and G. Hagen, Spectrochim. Acta, 1972, 28A, 137. 0. H. Ellestad, P. Klaboe, G. Hagen, and T. Stroyer-Hanson, Spectrochim. Acta, 1972,28A, 149.

176


1 -acetonyl-1-thionia-5-thiacyclo-octaneperchlorate were established by X-ray analysis.1g6 The eight-membered ring was in the boat-chair conformation, which in solution underwent rapid conformational equilibration, according to n.m.r. spectroscopy. 3 Compounds containing Three or more Sulphur Atoms 1,2,4-Trithiolans.-Oxidation of the /3-keto-dithio-acids prepared by the reaction of active-methylene compounds with carbon disulphide under basic conditions gave 3,5-bis(acylmethylene)-1,2,4-trithiolan derivat i v e ~lg7 . ~For ~ ~example, ~ pinacolone gave the trithiolan (182) on sequential

(182) (183) (184)

R R R

= = =

H,X = 0 C1,X = 0 H,X = S

base-catalysed reaction with carbon disulphide and oxidation with ammonium peroxydisulphate. The depicted structure and configuration were established by X-ray analysis.1as The reaction of (182) with phosphorus pentasulphide gave 5-t-butyl-l,2-dithiole-3-thione, for which the mechanism indicated in Scheme 8 was proposed, whilst with phosphorus pentachloride

Scheme 8

the chloro-derivative (183) was obtained in a reaction analogous to that found between desaurins and bromine (see Chapter 2, Section 10). The i.r. and U.V. spectra of these trithiolans indicated strong conjugative interaction between the sulphur atoms and the carbonyl groups, as in the desaurins. Three stereoisomeric forms of these trithiolan derivatives are S. M. Johnson, C. A. Maier, and I. C. Paul, J. Chem. SOC.(B), 1970, 1603. P. Yates and T. R. Lynch, Cunad. J. Chem., 1971,49, 1477. lU7 F. M. Dean, D. B. Frankham, N. Hatam, and A. W. Hil1,J. Chem. SOC.(C), 1971,218. lg6

lU6

Saturated Cyclic Compounds of Sulphur and Selenium 177 possible, but from pinacolone only the depicted cis-isomer (182) was obtained.las Acetophenone, p-methylacetophenone, and deoxybenzoin, however, gave mixtures of two diastereoisomers in which the trans-isomer predominated.ls6 Trithiolans such as the above were converted into desaurins on treatment with triethyl phosphite, but in contrast dispiro-3cyclohexane-1,2,4-trithiolan-5-cyclohexaneresisted attack by tervalent phosphorus reagents.lQ1 Oxidation of phenyldithiocarbazic acid with hydrogen peroxide gave the diphenylhydrazone of 1,2,4-trithiolan-3,5dione, the structure of which was established by X-ray analysis.1e* The trithiolan ring adopted a puckered conformation, and the diphenylhydrazone moieties were cis to S(4) of the trithiolan ring.lg8 Elemental sulphur reacted with bis(trifluoromethy1)thioketen at 200 "C to give perfluoro3,5-di-isopropylidene-1,2,4-trithi0lan,~~ whilst thiobenzophenone on trcatment with Chloramine T gave 3,3,5,S-tetraphenyl-l,2,4-trithi0lan;~~~ amines, especially primary amines, also catalysed the latter reaction, but somewhat inefficiently, and the reaction did not appear to involve radical intermediates. 1,3,5-Trithians, 1,2,4-Trithians, and 1,2,4,5-Tetrathians.-A convenient new synthesis of 2-substituted 1,3,5-trithians involved the acid-catalysed condensation of di(rnercaptomethy1) sulphide with aldehydes.200Adamantanethione, unlike most dialkyl and alkyl aryl thioketones,201 did not spontaneously trimerize to the 1,3,5-trithiolan derivative, but the tri-, merization was catalysed by methanesulphonic acid.202Thioacetophenone trimer (2,4,6-trimethyl-2,4,6-triphenyl1,3,5-trithian), on irradiation in cyclohexane, gave the blue monomeric thioacetophenone, which underwent Diels-Alder addition to cyclopentadiene.20s Prolonged irradiation gave 2,4-diphenylthiophen and 9,lO-dimethylphenanthrene.In an unusual reaction, cyclohexane-1,l-dithiol reacted with 1,Zdibromopropane under alkaline conditions to give either 5- or 6-methyl-1,2,4-trithian-3-spirocyclohexane (the precise structure was not established), instead of the expected 1,3-dithiolan An n.m.r. investigation of the rate of hydrogen-deuterium exchange in trans-2,4,6-trimethyl-1,3,5-trithian(185) catalysed by t-butoxide ions in deuteriated t-butyl alcohol revealed that the equatorial proton exchanged 40 times faster than the axial protons, and that under comparable conditions there was negligible exchange in the cis-isomer (186).206 Under more severe conditions the axial protons in (186) exchanged with deuterium 550 lea

19@ *01 202

203 204

2os

G. Casalone and A. Magnoli, J. Chem. SOC.(B), 1971,415. M. M. Campbell and D. M. Evignos, Chem. Comm., 1971, 179. P. Y. Johnson, Chem. Comm., 1971, 1083. J. Ashby and H. Suschitsky, Tetrahedron Letters, 1971, 1315. J. W. Greidanus, Canad. J. Chem., 1970, 48, 3530. N. Sugiyama, M. Yoshioka, H. Aoyama, and T. Nishio, Chem. Comm., 1971, 1063. J. V. Burakevich, A. M. Lore, and G. P. Volpp, J. Org. Chem., 1970, 35, 2102. M. Fukunaga, K. Arai, H. Iwamura, and M. Oki, Bull. Chem. SOC.Japan, 1972,45, 302.

178


times more slowly than the axial protons in (185). In both cases hydrogendeuterium exchange proceeded with retention of configuration, but treatment of (185) and (186) sequentially with butyl-lithium and water gave the same mixture of (185) and (186) in the ratio 96 : 4, whilst quenching the lithio-derivatives of both (185) and (186) with carbon dioxide gave only

R* = H, R2 = Me (186) R1 = Me, R2 = H (187) R1 = C 0 2 H , R2 = Me (188) R1 = Me, R2 = C0,Me (185)

the equatorial carboxylic acid (187).205 The acid (187) was less thermodynamically stable than its diastereoisomer (188), the equilibration of these isomers being catalysed by boron trifluoride etherate. The barrier to ring inversion in 1,3,5-trithian, 11.1 k 0.2 kcal mol-1 according to n.m.r. data,206was only slightly higher than that in cyclohexane; the data suggested that the preferred conformation of 1,3,5-trithian was chair-like. The i.r. and Raman spectra of 1,3,5-triselenan have been investigated.lg4 The temperature-dependence of the n.m.r. spectrum of deuteriated dispiro-3-cyclohexane-l,2,4,5-tetrathian-6-cyclohexanerevealed that at - 12 "Cthe twist conformation (189) was more stable than the chair (190)

by 0.6 kcal mol-l, and that at - 90 "Cin carbon disulphide the twist form was slowly pseudorotating with an estimated energy barrier of at least 10 kcal m ~ l - ~ .The ~ ~much ' greater magnitude of this barrier than that in cyclohexane (0.8 kcal mol-I) was attributed to repulsive interactions between 208 207

J. E. Anderson, J . Chem. SOC.(B), 1971, 2030. C. H. Bushweller, G. V. Rao, and F. H. Bissett, J. Amer. Chem. Soc., 1971, 93, 3058.


179

vicinal lone electron pairs in the transition state for pseudorotation, coupled with large prow-prow non-bonded repulsions in this boat-like transition state. The derivation of activation parameters for the chairtwist-form equilibration of 3,3,6,6-tetramethyl-1,2,4,5-tetrathianby direct thermal stereomutation and total n.m.r. lineshape analysis has been described in full.2oMSulphurated sodium borohydride, NaBH,S,, in THF at 65 “C converted cyclohexanone into the tetrathian (1go), and cyclopentanone into the cyclopentane analogue of (1 whilst benzylidenetriphenylphosphorane reacted with sulphur to give a compound tentatively formulated as 5,7-diphenyl-l,2,3,4,6-pentathiepan.20@ Macrocyclic Polysu1phides.-Macrocyclic polysulphides were much poorer complexing agents for alkali-metal and alkaline-earth cations than were the corresponding macrocyclic polyethers, probably because of the influence of the larger size of the sulphur atom, its lower electronegativity, and the different bond angles at sulphur upon the distribution of negative charge about the ‘hole’ in the molecules.210~ 211 However, the macrocyclic polysulphides were more effective than their oxygen analogues in complexing with silver ions.211Among the interesting new macrocyclic ligands that have been synthesized, 1,4,8,11,15,18,22,25-octathiacyclo-octacosane was remarkable in that it circumscribed completely two metal ions such as whilst 1,4,7,10,13,16-hexathiaoctadecanewas the first sexidentate ligand which formed octahedral complexes of the type ML(picrate), with cobalt and nickel.213 Thiacyclophanes have aitracted interest not only as useful intermediates in the synthesis of cyclophanes214 and annulenes,215but also for their stereochemical 216 and mass spectral 217 behaviour. The synthesis of new thiacyclophanes 214-218 utilized established methods, and X-ray analysis provided a convenient method of determining their crystal and molecular 6v

808

C. H. Bushweller, J. Golini, G. V. Rao, and J. W. O’Neil, J . Amer. Chem. Soc., 1970, 92, 3055.

208 210

tll 21a

213

a14

H. Tokunaga, K. Akiba, and N. Inamoto, Bull. Chem. Sac. Japan, 1972,45, 506. C. J. Pederson, J. Org. Chem., 1971, 36, 254. H. K. Frensdorff, J . Amer. Chern. Soc., 1971, 93, 600. K. Travis and D. M. Busch, Chem. Comm., 1970, 1041. D. St. C. Black and I. A. McLean, Austral. J. Chem., 1971, 24, 1401. R. H. Mitchell and V. Boekelheide,J. Amer. Chem. SOC.,1970,92,3510; V. Boekelheide and R. A. Hollins, ibid., 1970, 92, 3512; R. H. Mitchell and V. Boekelheide, Chem. Comm., 1970, 1555; H. J. J.-B. Martel and M. Rasmussen, Tetrahedron Letters, 1971, 3843.

21s

Ple 217

218 210

P. G. Garratt, A. B. Holmes, F. Sondheimer, and K. P. C. Vollhardt, Chem. Comm., 1971, 947. S. Akabori, K. Shiomi, and T. Sato, Bull. Chem. SOC.Japan, 1971, 44, 1346. D. W. Allen, P. N. Braunton, I. T. Millar, and J. C. Tebby, J. Chem. SOC.(C), 1971, 3454. F. Vogtle, Annalen, 1970, 735, 193; Chem.-Ztg., 1970, 94, 313. J. S. Ricci and I. Bernal, J. Chem. SOC.(B), 1971, 1928; B. R. Davies and I. Bernal, ihid., p. 2307.

Organic Compounds of Sulphur, Selenium, and Tellurium 4 Compounds containing Sulphur or Selenium and other Heteroatoms Cyclic Sulphonates, Cyclic Sulphinates, and Related Systems.-A valuable new method of synthesizing 1,Zoxathiolan 2,2-dioxides and 1,2-0xathian 2,2-dioxides involved treatment of suitable alkanesulphonate esters of 1,2- and 1,3-diols, respectively, with one equivalent of butyl-lithium.220 The formation of 6-methyl-l,2-oxathian 2,2-dioxide in good yield from 1,3-dimethanesulphonyloxybutane was in accord with the expected mechanism involving intramolecular nucleophilic displacement of the primary methanesulphonate group by a sulphonyl-stabilized carbanion generated by butyl-lithium from the secondary methanesulphonate group ; none of the isomeric 4-methyl-1,Zoxathian 2,2-dioxide was apparently produced. The alkanesulphonate esters of 1,2-brornohydrins also underwent the reaction, but less efficiently. However, the ready availability of such substrates rendered the method synthetically attractive, and the methanesulphonate of trans-l-bromo-2-hydroxycyclohexane,for example, gave (191) in useful yield.220Attempts at synthesizing seven- and eightmembered-ring analogues by this method failed. Both cis- and trans-2,4diphenylthietan 1,l -dioxides rearranged stereospecifically to cis-3,5diphenyl-l,2-oxathiolan cis-2-oxide and trans-3,5-diphenyl-l,2-oxathiolan (2,3)-cis-2-oxide respectively on treatment with t-butoxymagnesium 180

bromide 221 (see Chapter 2, Section 8). These 1,Zoxathiolan 2-oxide derivatives were synthesized independently by oxidation of 1,3-diphenyl3-hydroxypropanethiol with chlorine in acetic acid. Other cyclizations in which sulphinate ions are at least formally involved include the conversion of 1,2-dithiolan 1,l-dioxide into 1,2-0xathiolan 2-oxide, and of 1,Zdithian 1, l-dioxide into 1,Zoxathian 2-oxide by its reaction with tris-diethylaminophosphine,122 the cycloaddition of diphenyl-N-toluene-p-sulphonylimine with the keten-sulphur dioxide adduct to give 4-oxo-5,5-diphenyl-6t oluene-p-sulphonylimino-1,2-oxathian 2-oxideY 222 and the thermol y t ic conversion of thietan 1,l-dioxide into 1,2-0xathiolan 2-oxide in poor 220

229

T. Durst and K. C. Tin, Cunad. J. Chem., 1970, 48, 845. R. M. Dodson, P. D. Hammen, and R. A. Davies, J. Org. Chem., 1971, 36, 2693; R. M. Dobson, P. D. Hammen, and J. Y.Fan, ibid., p. 2703. J. M. Bohen and M. M. Joullie, Tetrahedron Letters, 1971, 1815.

Saturated Cyclic Compounds of Sulphur and Selenium 181 yield.223 The intermediacy of 1,Zoxathiolan 2-oxide derivatives and 1,Zoxathian 2-oxide derivatives in the formation of y- and 6-chlorosulphones from y- and 8-hydroxysulphoxides, respectively, on treatment with sulphuryl chloride has been 2,2'-Thiodibenzoic acid reacted with dry Chloramine T to give (192), which was also formed by heating the sulphoxide derived from 2,2'-thiodibenzoic Similarly, oxidation of 3,3'-selenodipropionic acid gave (193) by spontaneous cyclization of the intermediate selenoxides;226the homologous selenodibutyric and selenodivaleric acids under the same conditions gave only the corresponding selenoxides. Configurational assignments to cis-3,5-diphenyl-l,Zoxathiolancis-2oxide and trans-3,5-diphenyl-l,Zoxathiolan (2,3)-cis-2-oxide based on the observed greater thermodynamic stability of the former isomer were substantiated by complete n.m.r. analysis, which also revealed that the cisdiphenyl isomer adopted the half-chair conformation (194) with the phenyl group at C(5) pseudoequatorial, and that the trans-diphenyl isomer favoured a conformation more like an envelope than a half-chair, with the phenyl group at C(5) pseudoaxially orientated.221 These differences in preferred conformation were attributed not only to the general minimization of non-bonded interactions, but also to the strong preference of the sulphinyl oxygen for an axial orientation,221a phenomenon established in 1,Zoxathian 2-oxide systems by n.m.r.222 and dipole-moment data.227 Oxidation of the 3,5-diphenyI-l,Z-oxathiolan2-oxides to the 2,2-dioxides was attended by a slight flattening of the ring and a considerable enhancement of conformational mobility.221 In an analogous case, 1,Zoxathian 2,2-dioxide underwent rapid chair-chair interconversion at - 90 "C according to n.m.r. data, but 1,Zoxathian 2-oxide appeared to be locked in the chair conformation with sulphinyl oxygen axial in the temperature range - 90 to + 150 "C, illustrating further the strong preference for the axial orientation of sulphinyl oxygen.12s The lithium in 3-lithio-5-t-butyl-l,2-oxathian 2,2-dioxide (195) apparently exerted a strong preference for the equatorial orientation, since treatment of 5-t-butyl-1,2-oxathian 2,2-dioxide with butyl-lithium at - 78 "C and then with methyl iodide, acetone, or deuterium oxide gave respectively (196), (197), or (198);228it was assumed that the lithium was replaced with retention of configuration. The marked equatorial preference of the lithium was strikingly demonstrated by the conversion of cis-5-t-butyl-3-methyl1,2-0xathian 2,2-dioxide (196) into the trans-isomer (199), in which the methyl group was axially orientated, on successive treatment with butyl223

J. F. King, P. de Mayo, C. L. McIntosh, K. Piers, and D. J. H. Smith, Canad.J . Chem., 1970,48, 3704.

224

2ab 226

a27 228

T. Durst and K.-C. Tin, Canad. J. Chem., 1971, 49, 2374. I. Kapovits and A. Kalman, Chem. Comm., 1971, 649. L.-B. Agenas and B. Lindgren, Acta Chem. Scand., 1970, 24,3301. 0. Exner, D. N. Harpp, and J. G. Gleason, Canad. J . Chem., 1972, 50, 548. T. Durst, Tetrahedron Letters, 1971,4171.

182

Organic Compounds of Sulphur, Selenium, and Tellurium 0

(195) R1 = Li, R2 = H (196) R1 = Me, R2 = H (197) R1 = Me,COH, R2 = H (198) R' = D, R' = H (199) R1 = H, R2 = Me

lithium and water.228 Hydrolysis of 1,2-0xathiolan 2,2-dioxide and 1,2oxathian 2,2-dioxide in water and water-acetone mixtures occurred predominantly by scission of the carbon-oxygen and not the sulphur-oxygen bond, but in strongly alkaline solutions and in aprotic solvent-water mixtures some hydrolysis involving nucleophilic attack at sulphur Five-membered cyclic sulphonates hydrolysed appreciably faster than their six-membered analogues, the difference being attributed to entropy and not enthalpy (strain) effects.2291,2-0xathiolan 2-oxide and 1,Zoxathian 2-oxide were cleaved and reduced on treatment with the tri-n-propylamine-trichlorosilane system to give di-(2-hydroxyethyl) disulphide and di-(3-hydroxypropyl) disulphide, respectively.230 1,3-Oxathiolans, 1,3-Oxathians, 1,3-Oxaselenans, 1,4-0xathians, and Related Systems.-The condensation of cyclic ketones or their enamines with a-mercaptocarboxylic acids to give 1,3-0xathiolan-5-one derivatives proceeded in good yield even in the absence of additional acid although acid catalysts were employed in the synthesis of hindered 1,3oxathiolan-5-one derivatives (200) by the condensation of thiobenzilic acid with alkylated c y c l o h e ~ a n o n e s .Such ~ ~ ~ compounds (200) were converted into the corresponding olefins (201) in excellent yield on heating with tris-diethylamino-phosphine,providing a viable method for the synthesis of highly hindered olefins. However, the method was useful only if aryl groups

R1'R2 Ph phQ

R3

230

A. Mori, M. Nagayama, and H. Mandai, Bull. Chem. SOC.Japan, 1971, 44, 1669. T. H. Chen, J. P. Montillier, W. F. Van Horn, and D. N. Harpp, J . Amer. Chern. SOC.,

231

P. D:Klemmensen, J. Z. Mortensen, and S . - 0 . Lawesson, Tetrahedron, 1970, 26,

22B

1970, 92, 7224.

4641.


183

were present to facilitate the loss of carbon dioxide, cyclohexane-2-spiro1,3-oxathiolan-5-one on heating with triphenylphosphine giving only 1-methylthiocyclohexene.141As expected, pyrolysis of (200a) gave a mixture of (201a), 2,2-diphenylthiiran-3-spirocyclohexane,and triphenylmethane. 141 2-Alkyl- and 2,2-dialkyl-4,4-diphenyl1,3-0xathiolan-5-ones similarly lost both sulphur and carbon dioxide on pyrolysis to give the relevant tri- or tetra-substituted ~ l e f i n s but , ~ ~the ~ predominant mode of fragmentation in the mass spectrometer was expulsion of carbon dioxide, direct expulsion of thiobenzophenone being important for the 2,2-dialkyl The acetic-anhydride-induced Pummerer rearrangements of 5-oxo-2,2-dialkyl- 1,3-0xathiolan 3-oxides such as (202) to 4-acetoxy2,2-dialkyl-1,3-oxathiolan-5-ones such as (203) apparently proceeded with

(203)

a high degree of stereo~electivity.~~~ However, the methods used to assign configuration to (202) and (203) were not unequivocal, and the reaction merits further attention. The n.m.r. properties of 2,2-disubstituted 1,3oxat hi olan-5-ones have been investigated.234 The carbon-sulphur bond in 1,3-0xathiolans and 1,3-oxathians was selectively cleaved by alkali metals in liquid ammonia to give 18- and y-alkoxy-thiols, r e s p e c t i ~ e l y .The ~ ~ ~reaction was of preparative significance in the case of 2,2-disubstituted lY3-oxathiolansand 1,3-oxathians, but only poor yields were obtained with monosubstituted 1,3-oxathiolans, and 1,3-0xathiolans bearing 2-phenyl substituents were completely reduced. The mechanism presumably involved a stepwise two-electron reduction (Scheme 9), and it appeared that the intermediate carbanions rapidly lost stereochemical integrity, since (204a) and (204b) gave predominantly (205), whilst (206a) and (206b) gave mainly (207). The low yields of selective carbon-sulphur bond fission observed for 2-monosubstituted 1,3-oxathiolans were attributed to the greater importance of pathway B depicted in Scheme 9, and this was supported by the nature of the products isolated from such reactions.236 Photolysis of 2-alkyl-l,3-oxathiolans in trichlorofluoromethane in the presence of benzophenone gave only 2-chloroethyl thioesters, for which the mechanism indicated in Scheme 10 was 2-Substituted-l,3-oxathiolansand 2,2-disubstituted-l,3-oxathiolanswere a32

238 234

236 236

C. T. Pedcrson, Actu Chem. Scund., 1970, 24, 2489. S. Glue, I. T. Kay, and M. R. Kipps, Cham. Comm.,1970, 1158. M. Brink, Org. Mugn. Resonance, 1972, 4, 195. E. L. Eliel and T. W. Doyle, J . Org. Chem., 1970, 35, 2716. J. W. Hartgerink, L. C. J. van der Laan, J. B. F. N. Engbcrts, and T. J. de Boer, Tetrahedron, 1971, 27, 4323.


184

I

M + NH,

"%?.!I

R2

Rl >CHOH*

R'\

R3

GS/'

,C=O

+

MS-

+ CH,=CH2

R2

Scheme 9

(204a) (204b) (206a) (206b)

X X X X

0, Y = S , n = 1 S, Y = 0,n = I = 0, Y = S, n = 2 = S, Y = 0,11 = 2

(205) 117 = 2 (207) ni = 3

= =

converted in high yield into the corresponding carbonyl compounds on treatment with Chloramine T in aqueous and insertion into a carbon-sulphur bond occurred to give polythioethers on treatment with keten.174

I t

Scheme 10 987

D. W. Emerson and H. Wynberg, Tetrahedron Letters, 1971, 3445.


185

The condensation of aldehydes with thiocyanoacetic esters, catalysed by potassium fluoride or potassium carbonate, gave as minor products N-carbamoyl-2-imino-5-alkyl(or ary1)-1,3-oxathiolan-4-carboxylicesters,23L) in which the 4,5-cis-isomers predominated according to n.m.r. spectros c ~ p y 1,3-0xathiolan-2-thione .~~~ was converted into dimethyl 1,3-dithiol2-0ne-4~5-dicarboxylateand ethylene on treatment with dimethyl acetylenedicarboxylate,ls6 and the transformation of methyl 2-methoxycarbonylmethyl-1,3-oxathiolan-2-carboxylate into &methy1-5,6-dihydro-1,4-oxathiin-2,3-dicarboxylate by chlorination at low temperatures found analogy in the reactions of 2,2-dialkyl-1,3-0xathiolans.~~~ Thiomethoxymethyl hexachloroantimonate reacted with potassium t-butoxide to give mainly 3,5,5-trimethyl- 1,3-0xathiolanium hexachloroantimonate ; the mechanism of this remarkable reaction was not The oxygen atoms in 1,3-0xathiolans apparently associate more readily than the sulphur atoms with lanthanide shift reagents, providing a method for the analysis of mixtures isomeric at C(2); it was shown that two isomeric 1,3-dithiolans were formed in equal amounts by condensation of 5a-cholestan-3-one and fi-mercaptoethano1.le1 Base-catalysed equilibration at C(5) of the C(3)-isomers of 4-oxocho1estane-3-spiro-2’-(1’,3’oxathiolan) (208) revealed that the oxathiolan oxygen exerted a strong

preference for the equatorial Under conditions where an equilibrium mixture of 5a- and 5p-cholestan-4-one contained 83% of the 5a-isomer, an equilibrium mixture of (208a) and (208c) contained 87% of the 5b-isomer ( 2 0 8 ~ and ) ~ equilibration of (208b) and (208d) gave only the 5a-isomer (208b).242In other 1,3-oxathiolan-2-spiroalkylderivatives the efficiency of intramolecular catalysis of the hydrolysis of an ester group associated with the spiroalkyl moiety depended upon the stereochemistry 238

S. Kambe, T. Hayashi, H. Yasuda, and H. Midorikawa, Bull. Chem. SOC.Japan, 1971, 44, 1357.

239 a40 241

242

T. Hayashi, M. Akano, T. Yokono, J. Uzawa, S. Kambe, and H. Midorikawa, Bull. Chem. SOC.Japan, 1972, 45, 578. P. ten Haken, J . Heterocyclic Chem., 1970, 7 , 1211. R. A. Olofson and D. W. Hansen, Tetrahedron, 1971, 27, 4209. C. H. Robinson and L. Milewich, J. Org. Chem., 1971, 36, 1812.

186


at C(2).153 An n.m.r. investigation of 2-substituted and 2,2-disubstituted1,3-0xathiolans suggested that rapid pseudorotation of the ring was occurring, but that an incompletely specified envelope conformation was preferred.243 Improved procedures for the synthesis of derivatives of 1,3-oxatluans 244-246 and 1,3-0xaselenans have been described, all of which involve the intermediacy of j5-hydroxythiols or /I-hydroxyselenols. The conformation and n.m.r. behaviour of these compounds have been extensively investigated. The 220 MHz spectrum of 2-phenyl-l,3-oxathian furnished all the relevant coupling constants, and confirmed its chair c ~ n f o r m a t i o n , whilst ~ ~ ~ the geminal, vicinal, and long-range coupling constants in 4-phenyl- and 6-methyl-l,3-oxathian have been In many 2-alkyl derivatives of 1,3-0xathians the vicinal exocyclic coupling constants were larger when the substituent was axial then when equat0ria1,l~~ and quantitative information about the conformations of l ,3oxathians and 1,3-0xaselenans unsubstituted at C(2) could be obtained from their geminal C(2) coupling constants, which depended upon the electronegativity of the heteroatoms, the bond lengths involving the heteroatoms, and the mutual spatial orientation of the adjacent lone electron pairs on the heteroatoms and the carbon-hydrogen bonds at C(2).176 The Lambert-Buys criterion for determining the shape of nonaromatic heterocycles applied not only to rapidly inverting equi-energetic conformations, as originally stated, but also to anancomeric systems, provided that the necessary coupling parameters could be extracted from the n.m.r. spectrum. This could be done for non-symmetric anancomeric ring systems if two independent model compounds were available for the provision of the coupling By this method it was shown that the preferred conformation of the 1,3-oxathian ring was that in which the sulphur side of the ring was flattened, and the oxygen side puckered (and not the converse, which is possible from models) although this appeared to involve appreciable repulsive non-bonded interactions between syn-axial In trans-4-methyl-6-alkyl-1,3-oxathians 246 and trans-4-methyl-6-alkyl-1,3-oxaselenans 248 the chair-like conformation with the 4-methyl group axial was preferred in every case, and the preferred axial orientation of the substituent adjacent to sulphur was also manifest in the equilibration of the isomers at C(2) of 2,4,6-trimethyl-1,3-oxathian, in which the 4,6-dimethyl groups were trans-~rientated.~~~ The mass spectral characteristics of 1,3-0xathian and some alkyl derivatives have been

248

G. E. Wilson, M. G. Huang, and F. A. Bovey, J. Amer. Chem. SOC.,1970, 92, 5906. P. Pasanen and K. Pihlaja, Acta Chem. Scand., 1971, 25, 1908. Y . Allingham, T. A. Crabb, and R. F. Newton, Org. Magn. Resonance, 1971, 3, 37. J. Gelan and M. Anteunis, Bull. SOC.chim. belges, 1970, 79, 313. J. Gelan, G. Swaelens, and M. Anteunis, Bull. SOC.chim. belges, 1970, 79, 321. A. Geens, M. Anteunis, F. de Pessemier, J. Fransen, and G. Verhegge, Tetrahedron,

249

P. Pasanen and K. Pihlaja, Tetrahedron Letters, 1971, 4515.

243 244 246

a46

*"

1972,28, 1097.


187

examined.260 Carbon disulphide and dimethylketen, with triphenylphosphine as catalyst, formed a 1 : 2 adduct, 6-oxo-2-isopropylidene-5,5dimethyl-1,3-oxathian-4-thione,which dimerized on photolysis, and decomposed on heating to give 2-mercapto-3-methyl-5-isopropylthiophen. 261 Photocatalysed cyclization of ally1 2-mercaptoethyl ether gave a mixture of 3-methyl 1,4-0xathian, and 1,4-0xathiepan,~~ the former predominating at 80 "C and the latter at - 65 "C. Acid-catalysed condensation of chloroacetone with 2,3-dihydroxypropanethiolgave l-methyl-2,8-dioxa-6thiabicyclo[3,2,l]octane, which was reduced by lithium aluminium hydride to 2-methyl-6-hydroxyrnethyl-1,4-0xathian.~~~ Fluorination of 1'doxathian over potassium tetrafluorocobaltate gave a complex mixture of products, mainly polyfluoro-l,4-oxathians,the structures of which were deduced from their leF n.m.r. In these compounds fluorine apparently exerted a strong preference for the axial orientation, and if this was not attainable in chair conformations of the ring, flexible conformations were adopted. Details of the determination of the molecular structure of (2R,4S,6S)-2-hydroxymethyl-6-methoxy-l,4-oxathian 4-oxide have been furnished,254and the degree of ring pucker in the isomeric 4-oxides of cis-2acetoxy-6-methyl-l,4-oxathianhas been determined by a new n.m.r. method.256 The stereochemical requirements of lone electron pairs and adjacent polar bonds in 1,4-0xathian derivatives have been discussed,lB1 and the preference of a polar substituent at C(2) in 1,4-oxathians for the axial orientation - the 'Edwards-Lemieux effect' - was satisfactorily accounted for in a theoretical treatment.lsl According to n.m.r. studies of 2-substituted l74-oxathians,the relative population of chair conformations with the C(2)-substituent axial was markedly lower than in the analogous 2-substituted 1 , 4 - d i o ~ a n s and , ~ ~ ~the barrier to ring inversion in 1,4-oxathian-Zone was considerably lower than those in its 5- and 6-phenyl derivatives.2s7The i.r. and Raman spectra of 1,4-oxathian lo3and the n.m.r. behaviour of its complexes with lanthanide shift reagents have been studied. Cyclic Sulphites, Cyclic Selenites, Cyclic Sulphates, and Related Compounds. Interest in cyclic sulphites has centred mostly on their conformational behaviour. Thorough reinvestigations of the n.m.r. and i.r. properties of 1,3,2-dioxathian 2-oxide confirmed the general conclusion that it existed 250 251

K. Pihlaja and P. Pasanen, Org. Mass Spectrometry, 1971, 5, 763. J. C. Martin, R. D. Burpitt, P. G. Gott, M. Harris, and R. H. Meen, J. Org. Chem., 1971,36,2205.

25a

aS3

S. Gelas, Tetrahedron Letters, 1971, 509. J. Burdon and I. W.Parson, Tetrahedron, 1971, 27, 4533, 4553.

256

D. J. Watkin and T. A. Harnor, J. Chem. SOC.(B), 1971, 1692. K. N. Slessor and A. S. Tracy, Canad. J. Chem., 1971, 49, 2874. N. S. Zefirov, V. S. Blagoveshchensky, I. V. Kazimirchik, and N. S. Surova, Tetrahedron,

357

K. Jankowski and R. Coulombe, Tetrahedron Letters, 1971, 991.

264 255

1971,27, 31 11.


188

predominantly if not exclusively in a chair conformation (A in Scheme 11) with an axial sulphinyl bond.l7'9 258-280 The compound did not undergo ring-inversion on the n.m.r. time-scale,2S8 contrary to previous conclusions based on acoustic measurements, and it appeared that the i.r. band at

R6

B

A

C

(209) R2 = Me [unspecified substituents are hydrogen]

(210) R3 = (211) R2 = (212) R1 = (213) R4 =

But

R6 = Me R5 = Me But

(214) R1 = R6 = Me (215) R2 = R' = R6 = Me

(216) R2 = R3 = R" = Me (217) R1 = R4 = R6 = M e (218) R1 = R3 = R6 = Me

Scheme 11

1234 cm-l in 1,3,2-dioxathian 2-oxide and some of its substituted derivatives may not have been due only to conformers with an equatorial sulphinyl bond, or to a sulphinyl bond in flexible conformers as is generally assumed,26oand other unknown factors may be involved. A chair conformation with an axial seleninyl bond was also suggested for 1,3,2dioxaselenan 2-oxide from electron-diffraction data.261 Conformations of type A in Scheme 11 were, not unexpectedly, preferred for trans-4-methyl1,3,2-dioxathian 2-oxide (209),262cis-5-t-butyl-l,3,2-dioxathian2-oxide (210),262and 2r,4t,6t-dialkyl-1,3,2-dioxathian2-oxides [as (21 1)],262-266 where the substituents could adopt equatorial orientations, but 2r,4c,6cdimethyl-l,3,2-dioxathian2-oxide (212) existed only in conformation C (Scheme 1l), in which sulphinyl oxygen was e q ~ a t o r i a l . ~The ~ ~ dipole -~~~ moment of trans-5-t-butyl-l,3,2-dioxathian 2-oxide (213) varied with solvent, indicating the interconversion of conformers of appreciably different dipole moment,262whilst i.r., n.m.r., and dipole-moment data for ZS8 25D

260

261

P. Albriktsen, Acta Chem. Scand., 1971, 25, 478. G. Wood, G. W. Buchanan, and M. H. Miskow, Canad. J. Chem., 1972,50, 521. C. H. Green and D. G. Hellier, J.C.S. Perkin II, 1972, 458. B. A. Arbuzov, V. A. Naumov, and I. V. Anonimova, Dolkudy Chemistry, 1970, 192, 336.

z6s

264 26s

G. Wood, J. M. McIntosh, and M. H. Miskow, Canad. J . Chem., 1971, 49, 1202. W. Wucherpfennig, Annalen, 1970, 737, 144. L. Casaw and P. Maroni, Bull. SOC.chim. France, 1972, 773. P. Maroni and L. Casaw, Compt. rend., 1971,272, C, 2065; 1971, 273, C, 156.

Saturated Cyclic Compounds of Sulphur and Selenium 189 2r,4~,6t-dimethyl-l,3,2-dioxathian 2-oxide (2 14) a63, 264* 266 and other 4,6dialkyl analogues indicated the presence of a conformational equilibrium involving the conformations A, B, and C in Scheme 11, the relative populations of which depended upon the solvent and the nature of the alkyl groups.266The presence of a gern-dimethyl group at C(5) did not materially affect the conformational behaviour of these systems,262, 263 except for trans-4,6-dialkyl derivatives, for which the populations of the flexible conformations were increased.266* 267 The trimethyl derivatives (2 15) and (216) both adopted conformation A, but the trimethyl derivatives (217) and (218) existed as solvent-dependent equilibrium mixtures of the conformations A, B, and C.268Vapour-phase osmometry indicated that ~ i s - 4 ~ 6 dimethyl-l,3,2-dioxathian2-oxide (2 12) was associated in solution even at very low concentrations,26Bso that it was unnecessary to assume a twelvemembered-ring dimeric structure for the compound, previously proposed to account for the cryoscopically determined molecular weight. Changes in the i.r. absorption of such compounds with solvent, previously attributed to conformational changes, may therefore have reflected a change in the degree of association.26s The conformational energy of the sulphinyl bond in the cyclic sulphites (219) and (220), determined directly by acidcatalysed equilibration and analysis of the mixture, was 1.57 kcal mol-1 in X

(219) X (220) Y

= =

0,Y = lone electron pair 0,X = lone electron pair

acetonitrile and 1.9 kcal mol-1 in carbon tetrachloride at 40 "C,the axial isomer (219) being the more The solvent-dependence of the equilibrium was consistent with the stabilization of the axial isomer relative to the equatorial isomer by intramolecular dipolar forces. The conformations of isomeric cyclic sulphites derived by the reaction of thionyl chloride with 1,3-dihydroxy-groupsin more complicated molecules depended critically upon the intramolecular environment. The isomeric sulphites derived from dihydrofukinolidol differed in the conformations of the 1,3,2-dioxathian ring, being respectively chair and boat, with the sulphinyl group axial in each case,271whereas the isomeric sulphites derived from 3/3,5/3-dihydroxycholestan-6-one both had the 1,3,2-dioxathian ring in the boat conformation, with the sulphinyl group axial in one case 267 268 260

271

P. Maroni and L. Casaux, Compt. rend., 1971, 272, C, 1660. L. Casaw and P. Maroni, Bull. SOC.chim. France, 1972, 780. P. Maroni and P. Times, Bull. SOC.chim. France, 1972, 794. G. Wood and M, H. Miskow, Tetrahedron Letters, 1970, 1775. H. F. van Woerden and A. T. de Vries-Miedema, Tetrahedron Letters, 1971, 1687. K. Naya, I. Takagi, and T. Kasai, Bull. Chem. SOC.Japan, 1971,44,3204.

190


and equatorial in the Boat conformations were encountered in other cases. 273 The barrier to chair-chair interconversion in 5,5-dimethyl-l,3,2-dioxathian 2,2-dioxide was between 8.1 and 8.4 kcal mol-l, according to variabletemperature n.m.r. It was therefore suggested 274 that the energy barrier obtained earlier for 4-methyl-l,3,2-dioxathian2,2-dioxide by the ultrasonic relaxation technique 275 referred to the interconversion of a chair and a flexible conformation, and not to a chair-chair interconversion. However, Wyn-Jones27s pointed out that the two sets of figures are in excellent agreement if temperature differences and entropy terms were taken into account. Variable-temperature n.m.r. data also indicated that the barrier to ring inversion in 5,5-dimethyl-l,3,2-dioxathian was ca. 12.4 kcal mol-l, i.e. slightly higher than that in c y ~ l o h e x a n e The .~~~ sulphur-oxygen rotational barrier was apparently sufficiently high to overcome the low barrier to rotation about the carbon-oxygen bond. Configurations at sulphur influence the relative reactivity of some cyclic s ~ l p h i t e s278, . ~ 279 ~~~ For example, cis-4,5-diphenyl-l,3,2-dioxathiolan trans-2-oxide thermolysed to a 1 : 2 mixture of diphenylacetaldehyde and deoxybenzoin, whereas the isomer at sulphur gave the same two products in the ratio 2 : l.279 The greater yield of deoxybenzoin from the trans-oxide was attributed to intramolecular proton capture from C(4) and C(5) by sulphinyl oxygen to give the ketone via an enol intermediate.279 The decomposition of 4,5-dichloro-4,5-di(trifluoromethyl)1,3,Zdioxathiolan 2,2-dioxide into perfluorobiacetyl and sulphuryl chloride was catalysed by tervalent nitrogen and phosphorus compounds.28o 4-0xo-1,3,2-dioxathiolan 2-oxide and various 5-substituted and 5,5-disubstituted derivatives have been prepared by improved methods, and their polymerization and reaction with alcohols and amines were investigated.2s1 Treatment of divinyl sulphone with alkaline hydrogen peroxide gave 1,2,5-dioxathiepan 5,5-dio~ide.~~~ 272

278

274 27b

A. T. Rowland, T. B. Adams, H. W. Attland, W. S. Creasy, S. A. Dressner, and T. M. Dyott, Tetrahedron Letters, 1970, 4405; A. T. Rowland, H. W. Attland, W. S. Creasy, and T. M. Dyott, ibid., 1970, 4409. M. E. Herr, R. A. Johnson, W. C. Kreuger, H. C. Murray, and L. M. Pschigoda, J. Org. Chem., 1970, 35, 3607. G. Wood, J. M. McIntosh, and M. Miskow, Tetrahedron Letters, 1970, 4895. R. A. Pethrick, E. Wyn-Jones, P. C. Hamblin, and R. F. M. White, J . Chem. SOC.(A), 1969,2552.

273 277 278 279

E. Wyn-Jones, Tetrahedron Letters, 1971, 907. G . Wood and R. M. Srivastava, Tetrahedron Letters, 1971, 2937. G. Schumacher, W. Klein, and F. Korte, Tetrahedron Letters, 1971, 2229. J. M. Coxon, M. P. Hartshorn, G. R. Little, and S. G. Maister, Chem. Comm., 1971, 271.

280

L. 0. Moore, J . Org. Chem., 1970, 35, 3999.

281

M. D. Thomas and B. J. Tighe, J . Chem. SOC.(B), 1970, 1039; D. J. Fenn, M. D. Thomas, and B. J. Tighe, ibid., p. 1044; B. W. Evans, D. 5. Fenn, and B. J. Tighe, ibid., p. 1049; G . P. Blackbourn and B. J. Tighe, ibid., 1971, 1384; J. Chem. SOC.(C),

282

H. Kropf and C.-R. Bernet, Annalen, 1971,743, 151.

1971, 257.

191

Sarurated Cyclic Compounds of Sulphur and Selenium

Penicillins, Cephalosporins, and Related Compounds.-Much current research is directed towards the conversion of penicillins into more active and more 19-lactamase-resistant antibiotics, an object stimulated by the fact that the presence of a 1,3-thiazolidine ring is not a prerequisite for antibiotic activity. Many investigations have been concerned with the conversion of penam systems into cepham and cephem systems, and the two main avenues of approach involve cleavage of the S(l)-C(2) and C(3)-"(4) bonds, respectively. The general method first discovered in 1963, the acid-catalysed rearrangement of penicillin sulphoxide esters into deacetylcephalosporins, has received the most attention, and the generally accepted intermediacy of sulphenic acid derivatives in this rearrangement, and in the thermal stereomutation of penicillin sulphoxides, has been established unambiguously. Thermal isomerization of the penam (R)sulphoxide (221; a, y) to the more stable (,!?)-isomer (222; a, y) in ButOD

-N-..

(a) Ph-CH2.CO*NH

(v) COaNHBut (w)CO2H

(b) PhO CH2*C0NH (c) phthalimido (d) ButO*CO*NH

(x) C0,Me

(e) MeoCOeNH

(2)

(223)

R2

R2

R1

(y) C0,.CH2*CCI,

p-02N*C,H,*CH,*C0,

(224)

at 80 "C was attended by incorporation of only one deuterium atom stereospecifically into the 2p-methyl group, a process rational in terms of a six-electron sigmatropic transformation of the (R)-sulphoxide into the corresponding sulphenic acid, which after deuterium exchange recyclized to give the thermodynamically more stable (S)-sulphoxide (Scheme 12).2*3 D. H. R. Barton, F. Comer, D. G. T. Greig, P. G. Sammes, C. M. Cooper, G. Hewitt, and W. G. E. Underwood, J. Chem. SOC.(C), 1971,3540; D. H. R. Barton, F. Comer, D. G. T. Greig, G. Lucente, P. G. Sammes, and W. G. E. Underwood, Chem. Comm., 1970, 1059.

192


0

Scheme 12*

The (S)-isomer (222; a, y) incorporated little deuterium after 3 hours under these conditions, but after 24 hours in boiling benzene-D,O the analogous (27)-sulphoxide(222 ;b, x) was monodeuteriated in the 2P-methyl group, and the (R)-sulphoxide (221 ;c, x) (which is the more stable isomer at sulphur in this case) was monodeuteriated in the 2a-methyl Further evidence for this mechanism was elegantly provided by the thermal isomerization of the (R)-sulphoxide (223; a, y) to the (S)-sulphoxide (224; a, y),285and of (223; e, x) into (224; e, the concomitant inversion of configuration at C(2) clearly revealing the rotation about the C(2)-C(3) bond required by the above mechanism.28s Irradiation of the C(2)-isomer of (224; e, x), on the other hand, gave a mixture of all four possible diastereoisomers at S( l) and C(2), indicative of photocatalysed homolysisrecombination of the S(l)-C(2) bond.286Sulphenic acids (225; X = OH)* produced from penam sulphoxides in boiling benzene were trapped in the presence of trimethyl phosphite by reduction to the thiols (225; X = H),287which were not isolated since under the reaction conditions they underwent intramolecular cyclization to give thiazole derivatives (226). However, if acetic anhydride was also present, the thiols (225; X = H) R. D. G. Cooper, J. Amer. Chem. SOC.,1970, 92, 5010. D. H. R. Barton, D. G. T. Greig, G . Lucente, P. G. Sammes, M. V. Taylor, C. M. Cooper, G. Hewitt, and W. G. E. Underwood, Chem. Comm., 1970, 1683. 288 D. 0. Spry, J . Amer. Chem. SOC.,1970, 92, 5006. R. D. G . Cooper and F. L. Jose, J . Amer. Chem. SOC.,1970,92, 2575. * For key to R1and R2see p. 191. 284 285


193

R I

R 2

(23 1)

were themselves trapped as their thioacetates (225; X = A c ) . ~ *Sulphenic ~ acids produced by thermolysis of penam sulphoxidcs were also trapped by thiols to give disulphides,28B and by their reaction with suitable olefins such as norbornadiene and dihydropyran 286 to give adducts which were important intermediates in the isolation of the p-lactam function in penicillins.2e0 In the presence of dehydrating agents, such as acetic anhydride, the sulphenic acids could form mixed anhydrides such as (225; X = OAc), which could either rearrange to the less reactive uncyclized a/&double-bond isomer, or cyclize to intermediate thiiranium ions (227). These thiiranium ions were quenched by external nucleophiles such as acetate ions to give penam derivatives (228) or cepham derivatives (229), the penam derivatives being kinetically favoured, and the cepham derivatives being the products of thermodynamic catalysis of the rearrangement with weak acids, which have strong conjugate anions, therefore favoured the formation of penams, whilst strong acids, with weak conjugate anions, favoured the formation of cephams. For example, the acetic-anhydride-catalysed L. D. Hatfield, J. Fisher, F. L. Jose, and R. D. G. Cooper, Tetrahedron Letters, 1970, 4897.

D. H. R. Barton, P. G. Sammes, M. V. Taylor, C. M. Cooper, G. Hewitt, B. E. Looker, and W. G. E. Underwood, Chern. Comm., 1971, 1137. D. H. R. Barton, D. G. T. Grieg, P. G. Sammes, and M. V. Taylor, Chem. Comm., 1971, 845.

8

194


rearrangement of (222 ; a, z) gave predominantly the penam derivative (228; a, z, R3 = OAc) with a little of the cepham derivative (229; a, z, R3 = OAc), but with chloroacetic anhydride as catalyst the cepham derivative (229; a, z, R3 = 02C*CC13)was the sole With sulphuric acid, sulphamic acid, sulphate esters, or metal bisulphate salts as catalysts, (222 ; b, z) gave predominantly the 3#?-hydroxy-cephamderivative (229; b, z, R3 = OH), whereas alkyl- or aryl-sulphonic acids promoted the formation of the cephem derivative (230; b, The p-configuration of the hydroxy-group in the related compound (229; b, y, R3 = OH) was revealed by spectroscopic data, and by the formation of the lactone (231; b, y) on chromatography over silica Minor products in the aceticanhydride-catalysed rearrangement of (222 ; a, x) were the isothiazolinone (232; a, x) and the cephem derivative (230; a, x), which were formed in greater amounts in the presence of added acetate Cephem derivatives [e.g. (230)] were useful intermediates in the conversion of the penicillins into deacetoxycephalosporin antibiotics, and the transformation of (222; a, y) and (222; b, y) into (230; a, y) and (230; b, y) respectively was most efficient when either acetic anhydride or 12-oxathiolan 2,2-dioxide was used as catalyst, with dimethylformamide or dimethylacetamide as solvent, at temperatures below 135 0C.2Q3The formation of cephem derivatives [e.g. (230)], which involved the enolization of the 3p-proton in the thiiranium intermediate (227), was suppressed if the less electron-withdrawing 3a-t-butylamide group was present, so that (222; a, v) with acetic anhydride gave good yields of the acetoxypenam (228; a, v, R3 = OAc) and the acetoxycepham (229; a, v, R3 = OAc), with very little isothiazolinone formation.283The structures of the acetoxycepham derivatives were elucidated spectroscopically and confirmed by X-ray data.2Q4The cephalosporin derivative (233 ; c, x)* was synthesized from the penam sulphoxide (221 ; c, x) by treatment with acetic anhydride, followed by re-oxidation to give (223; c, x), followed in turn by a second sulphoxide rearrangement under conditions leading predominantly to ring expansion.288The major product, accompanying (233 ;c, x), was (234; c, x). A key step in a synthesis of cephalosporins is the transformation of a A2-cepheminto a A3-cephem. This was efficiently performed by oxidation of a A2-cephem such as (235; b, z) to its sulphoxide, which isomerized to the A3-sulphoxide on dissolution in hydroxylic solvents. The A3-su1phoxides, previously known to be quite resistant to reduction, were readily reduced to the corresponding sulphides (230; b, z) by a variety of reducing

29a

G. E. Gutowski, B. 5. Foster, C. J. Daniels, L. D. Hatfield, and J. W. Fisher, Tetrahedron Letters, 1971, 3433. G. E. Gutowski, C. M. Daniels, and R. D. G. Cooper, Tetrahedron Letters, 1971, 3429.

R. R. Chauvette, P. A. Pennington, C. W. Ryan, R. D. G. Cooper, F. L. Jose, I. G. Wright, E. M. Van Heyningen, and G. W. Huffman, J. Org. Chem., 1971, 36, 1259. 204 M. L. Smart and D. Rogers, Chem. Comm., 1970, 1060. * For key to R1 and R2see p. 191.

29s

2 95


R2

(234)

(233)

(232)

Rz (235)

(236)

agents if a reactive acid halide were This reduction probably involved conversion of the sulphoxide.by an acylating agent into a more readily reduced sulphoxonium salt. The oxidation of penarn derivatives by peroxy-acids usually proceeds stereospecifically to one sulphoxide, but this restriction was overcome by using iodobenzene d i c h l ~ r i d e t-butyl , ~ ~ ~ h y p o ~ h l o r i t eor , ~ ozone ~ ~ in protic which gave mixtures of the sulphoxides diastereoisomeric at sulphur. With ozone in water or acetone the ratio of diastereoisomcric sulphoxides obtained from penams appeared to be controlled by steric factors associated with the nitrogen function at C(6), and no sulphones were formed; the double bond in the A3-cephem system was more readily oxidized than sulphur, but cepham derivatives were oxidized to mixtures of s ~ l p h o x i d e s .The ~ ~ ~conversion of penicillin G (228; a, w, R3 = H)* and penicillin V (228; b, w, R3 = H) into their dethio-derivatives (236; a, w) and (236; b, w) with deuteriated Raney nickel proceeded with retention of configuration at C(5) and with extensive incorporation of deuterium into the gem-dimethyl groups,297suggesting that intermediates such as (225 ;a, w, X = Ni) were formed by a /%elimination, and that radical intermediates were In another selective cleavage of the S( 1)-C(2) bond, treatment of p-methoxybenzyl-6~-(triphenylmethylamino)penicillanate (228; R1 = Ph,CNH, R2 = p-MeO. C6H4* CH2*02C,RS = H) with methyl iodide and strong anhydrous base gave (225; R1 = Ph,CNH, R2 = p-MeO. C6H4* CH2*02C, X = Me), although with 6-acylamino-derivatives fission of the 8-lactam ring occurred.2g8 This base-catalysed fission of the S(l)-C(2) bond found analogy in the rearrangement of 3a-acid G. V. Kaiser, R. D. G. Cooper, R. E. Koehler, C. E. Murphy, J. A. Webber, I. G. Wright, and E. M. Van Heyningen, J . Org. Chem., 1970, 35, 2430. 298 D. 0.Spry, J. Org. Chem., 1972, 37, 793. S. Wolfe and S. K. Hasan, Chem. Comm., 1970, 833. z98 3. P. Clayton, J. H. C. Nayler, R. Southgate, and P. Tolliday, Chem. Comm., 1971,590. * For key to R1and R2see p. 191. 286

196 Organic Compounds of Sulphur, Selenium, and Tellurium chlorides or 3a-mixed anhydrides of penams into anhydropenicillins, which also inspired the synthesis of the cepham (237; c)* from the penam derivative (238; c, X = Cl or OTs) by tertiary-amine-induced ring expansion, for which the mechanism in Scheme 13 appeared appropriate,2s9the

(238) Scheme 13

abstraction of the 3-proton being rate-determining for (238; c, X = Cl). The rearrangement was accompanied by much epimerization at C(6), which occurred in the starting material and not in the product, but the rearrangement of (238; b, X = C1) and (238; Rf = NH2, X = Cl) catdysed by DBN gave the cepham derivatives (237; b) and (237; R1 = NH2) without epimerization at C(6).300 The failure of penicillins bearing 6/?-secondary amide side-chains to undergo base-catalysed epimerization at C(6) was overcome if the amide function was first ~ i l y l a t e d , 302 ~ ~and l ~ the sulphoxides derived from the 6a-isomers were converted into C(7)-epicephem derivatives by acid-catalysed ring-expansion.so2 The mechanism of epimerization at C(6) in penicillins has attracted attention.303,304 Wolfe et aL303 showed that a common intermediate (239; c, x)* was involved in the triethylamine-catalysed conversion of

(228; c, x, R3 = H) into the 6a-epimer (240; c, x) and the thiazepin (241; c, x), and they suggested that it was formed by a p-elimination rather than an Elcb mechanism, since (240; c, x) gave no (241 ;c, x) under the reaction conditions, and because no deuterium was incorporated at C(6) into (240; c, x) when the reaction was performed in deuteriated solvents. 289

so0 so1

B. G. Ramsay and R. J. Stoodley, J. Chem. SOC.(C), 1971,3859; Chem. Comm., 1970, 1517.

B. G. Ramsay and R. J. Stoodley, J. Chem. SOC.(C), 1971, 3864. A. Vlietinck, E. Roets, P. Class, and H. Vanderhaeghe, TetrahedronLetters, 1972,285. aos G. E . Gutowski, Tetrahedron Letters, 1970, 1779. S . Wolfe, W. S. Lee, and R. Misra, Chem. Comm., 1970, 1067. 804 B. G. Ramsay and R. J. Stoodley, Chem. Comm., 1971, 450. * For key to R1and R2see p. 191.


197

However, Ramsay and Stoodley a04 showed that deuterium was incorporated into the homologous compound (240; c, R2 = CH,*CO,Me) when (228; c, R2 = CH,.CO,Me, RS = H) was converted into (240; c, R2 = CH2*C0,Me) and (241 ;c, R2 = CH2-C0,Me) on treatment with l-methylpiperidine in [2H,]dimethyl sulphoxide, and these authors considered that an Elcb process more probably operated, The transformation of (228; c, x, Rs = H) into (241; c, x) and of methyl penicillanate and methyl 6ar-chloropenicillanate into analogous thiazepins was also catalysed by antimony pentachloride.sOs With sulphuryl chloride, however, (228 ; c, x, Rs = H) gave a mixture of the sulphenyl chlorides (242; c, x) and (243;

(242) X = CI, Y = H (243) X = H,Y = C1

c, x), possibly by the depicted mechanism,ao6and treatment of (242; c, x) with stannous chloride in dioxan 307 gave a mixture of (228; c, x, R3 = H) and its 5p-epimer in the ratio 5 : 1. Imidazole strongly catalysed the isomerization of penicillin 0 into benzylpenicillenic acid.308 An elegant procedure for the degradation of the thiazolidine ring in the penicillins involved the transformation of the carboxy-group into a 2,2,2trichlorourethane group [as in (228; b, Ra = NH-COa*CH2*CCla, R3 = H)]* via the acyl azides (228; b, Ra = CON3, Ra = H) and isocyanates (228; b, R2 = NCO, R3 = H), followed by reductive removal of the trichloroethoxycarbonyl group in an aqueous medium to give the 3-hydroxypenam derivatives (228; R1 = a, b, or d, R2 = OH, R3 = H).309 Scission of the /I-lactam ring in the carbinolamides occurred with piperidine benzoate or with trimethyl orthoformate in the presence of acetic acid, but 305

J. P. Clayton, R. Southgate, B. G. Ramsay, and R. J. Stoodley, J . Chem. SOC.( C ) , 1970,2089.

a07

S. Kukolja, J . Amer. Chem. SOC.,1971, 93, 6268. S. Kukolja, J . Amer. Chem. SOC.,1971, 93, 6269. H. Bundegaard, Tetrahedron Letters, 1971, 4613. K. Heusler, Helv. Chim. Acta, 1972, 55, 388. * For key to R' and Re see p. 191.

198


Rt JV

NH

0

CHO

(345)

(234)

0' (236)

when it reacted with lead tetra-acetate (228; d, R2 = OH, R3 = H)gave (244; d), which on decarbonylation and elimination of acetic acid furnished (245 ; d). Acid-catalysed intramolecular cyclization of (245 ; d) afforded the thiazolidine (246; R3 = R4 = Me), which was transformed by established methods into an intermediate in Woodwards synthesis of cephalos p o r i n ~ .The ~ ~ ~carbinolamide (228; a, R2 = OH, R3 = H) was transformed (Scheme 14) into the cephem derivative (247; a), which was con-

I

o=c,

OBut iii

(228a) R2 = OH, R3 = H

N

CHO

I C 0 2But

Reagents: i, Sodium borohydride, 2,2,2-trichloroethyl chloroformate, t-butylglyoxylic acid; ii, thionyl chloride, triphenylphosphine and pyridine, zinc in aqueous acetic acid; iii, dimethyl sulphoxide and acetic anhydride Scheme 14

verted into '7-aminocephalocillanic acid' by known Reduction of the urethanes (228; b, R2 = NH*CO,.CH,-CCl,, R3 = H) and (228; R1 = NH2, R2 = NH*COz-CH2.CC13,R3 = H) with zinc in acetic acid gave (246; R3,R4 = H, Pri), a useful intermediate for the synthesis of new p-lactam antibiofi~s,~~' and oxidation of (246; R3, R4 = H, 310

sll

R. Scartazzini, H. Peter, H. Bickel, K. Heusler, and R. B. Woodward, Helu. Chirn. Acta, 1972, 55, 408. B. Fechtig, H. Bickel, and K. Heusler, Helu. Chim. Acta, 1972, 55, 417.


199

Pri) with iodine, followed sequentially by acylation and reductive a1kylation with ethylene oxide and zinc in acetic acid, afforded (248; a),a12which was transformed (in a similar manner to that shown in Scheme 14) into 7-aminoceph-3-em-4-carboxylic acid (249).

RFs) pJ H2N

0

N

H H

N3-a

N/

CH,OH

Et

N

CO,H (249)

(248)

Et

0 (250)

The compounds (250) and (251), synthesized by addition of azidoacetyl chloride to the appropriate thiazoline derivatives in the presence of triethylamine, were converted by conventional procedures into structural isomers of peni~illins,~~~1 314 whilst the t-butoxide-catalysed condensation of C02But

N3-~sy 1

Br Br PLHgT J-N-..N

L S d

k N 0

f

0

s . C0,Me

+

phenylmercuric chloride and ( )-methyl-N-(dibromoacetyl)-5,5-di methylthiazolidine-4-carboxylateafforded (252), which on thermal decomposition in refluxing bromobenzene gave (240; R1 = Br, R2 = C0,Me) stereospecifically, but in low yield.31s

a14 a16

R. Scartazzini and H. Bickel, Helv. Chim. Acta, 1972, 55, 423. A. K. Bose, G. Spiegelman, and M. S. Manhas, J . Chem. SOC.(C), 1971, 188. A. K. Bose, G. Spiegelman, and M. S. Manhas, J. Chem. Sac. ( C ) , 1971, 2468. N. G. Johansson and B. Akermark, Tetrahedron Letters, 1971, 4785.

4 Thiocarbonyl, Selenocarbonyl, and Tellurocarbonyl Compounds BY

F. DUUS

1 Introduction As in the preceding volume, this chapter reports on progress in all aspects of the chemistry of organic compounds formally containing the C=S, the C=Se, or the C=Te linkage. Whereas the extensive output of papers in the two-year period under review documents solid advances within the field of thio- and seleno-carbonyl compounds, no paper reporting progress in the chemistry of the analogous tellurocarbonyl compounds seems to have appeared. It is considered likely that this fact does not reflect a lack of interest in the latter compounds, but rather that there are experimental difficulties connected with their preparation and handling because they are more unstable than sulphur and selenium compounds. With respect to structure and coverage, the present chapter follows quite closely Chapter 5 in Volume 1, which also serves as a natural background to the material of this review. The introductory comments in the previous review are still valid, and only one additional remark should be made, namely that several important papers which have appeared during the period presently under review have in fact already been reviewed (often in detail) in Volume 1 on the basis of preliminary short communications. Such papers will here be subjected to a more detailed treatment only if additional information has been given or if important corrections have been made. Reviews.-A list of relevant, more or less comprehensive, and specialized reviews that have appeared during the period under consideration is given below. The Thiocarbonyl Group in General. Synthesis, and physical and chemical pr0perties.l Thioaldehydes and Thioketones. Ci) Synthesis of simple aliphatic thioaldehydes and thioketones by reductive cleavage reactions of unsaturated sulphides.2 (ii) Photochemistry of t h i ~ k e t o n e s . ~ ~(iii) Synthesis of M. Fukuyama and A. Ohno, Kagaku No Ryoiki, 1968,22, 977, 1091. L. Brandsma, P. J. W. Schuijl, D. Schuijl-Laros, J. Meijer, and H. E. Wijers, Internal. J. Sulfur Chem. (B), 1971, 6, 85. G. Tsuchihashi, Kagaku No Ryoiki, Zokan, 1970, 125. A. Ohno, Internat. J. Sulfur Chem. (E), 1971, 6, 183.

200

Thiocarbonyl, Selenocarbonyl, and Tellurocarbonyl Compounds

201

thioanalogues of p-diketones and their metal complexes.J (iv) The t hio-Claisen Thioketens. Synthesis and properties.6 Sulphines. Synthesis and properties.‘ Sulphenes. Synthesis of episulphones and olefins via sulphenes.s Thioamides. (i) Synthesis and chemical proper tie^.^^ lo (ii) Physical properties 11-13 (electronic s t r u c t ~ r e ,l1~ , topomerizati~n,~* l2# l3 n.m.r. spectra l2,13). Derivatives of Thioamides. (i) Syntheses,14 reactions,14 and physical properties 13, l4 of thiohydrazides. (ii) Syntheses and reactions of thiohydroxamic acids.lb (iii) Syntheses, dimerization, trimerization, and reactions of thioacyl isocyanates.le Thioureas. Topomeri~ation.~~ Thiono- and Dithio-acids and Derivatives. (i) Syntheses, properties, and reaction^.^' (ii) Rearrangements of thiono-esters.lR (iii) Reactions of carbon di~u1phide.l~ Selenocarbonyl Compounds. Ref. 20. gs

2 Thioaldehydes Synthesis.-All attempts to prepare simple aliphatic thioaldehydes have until now been unsuccessful, as only the cyclic trimers or less well-defined polymeric substances have been obtained. However, Brandsma has now reported 2* 21 that +-unsaturated sulphides (1) are cleaved by alkali metals in liquid ammonia to produce the corresponding enethiols (2) in high yields. For R1 = H, the products (2) represent the simple aliphatic thioaldehydes (3) in what is evidently their more stable tautomeric enethiol form. Apparently the pure enethiols (2; R1 = H) showed no tendency to 6

6

7 6

lo l1 la

lS 14

16 16

l7

*O

21

(a) M. Cox and J. Darken, Co-ordination Chem. Rev., 1971,7,29; (b)S . E. Livingstone, ibid., p. 59. M. S. Raasch, J . Org. Chem., 1970, 35, 3470. B. Zwanenburg and J. Strating, Quart. Reports Sulfur Chem., 1970, 5 , 79. N. H. Fischer, Synthesis, 1970, 2, 393. W. Walter and J, Voss, ‘The Chemistry of the Amide Group’, ed. J. Zabicky, Interscience, London, 1970, p. 383. K. A. Petrov and L. P. Andreev, Uspekhi Khim., 1971, 40, 1014. K. V. Ramiah and V. V. Chalapathi, Current Sci., 1971, 40, 363. W. E. Stewart and T. H. Siddall, tert, Chem. Rev., 1970, 70, 517. W. Walter, 2. Chem., 1970, 10, 371. W. Walter and K. J. Reubke, ref. 9, p. 477. W. Walter and E. Schaumann, Synthesis, 1971, 1 1 1. 0. Tsuge, Kugaku To Kogyo (Tokyo), 1969, 22, 770. M. J. Janssen, ‘The Chemistry of Carboxylic Acids and Esters’, ed. S. Patai, Interscience, New York, 1969, p. 705. T. Oishi, Yuki Gosei Kagak Kyokai Shi, 1971, 29, 953. W. 0. Foye, J. Chem. Educ., 1969,46, 841. K. A. Jensen, Quart. Reports Sulfur Chem., 1970 5 , 45 L. Brandsma, Rec. Trav. chim., 1970, 89, 593.

202


R', R2, R3 = H or alkyl R4 = Et or Bu

R2\ ,CH-C--H R3 II S

(3)

tautomerize, but when a trace of triethylamine was added, an exothermic reaction took place, forming higher-boiling liquids, probably cyclic trimers or polymers of the initially produced thioaldehydes.21 The cycloaddition reaction between 1,2-dithiole-3-thiones that are not substituted in the 5-position and acetylene derivatives has been found to give the thioaldehydes (4) as brown solids or p a s t e ~ . ~The ~ - ~products ~ could not be obtained analytically pure, but were characterized spectroscopically. The yields of the thioaldehydes were rather dependent on the

reaction conditions. For example, prolonged reaction times afforded mainly the partly desulphurized coupling products (5),23e 24 which were also obtained by refluxing (4) in benzene for a longer time.23 Transient Species.-Pioneering studies by Johnson and co-workers 25 have shown that monomeric thioformaldehyde is generated when methane reacts with small sulphur-containing molecules, such as carbon disulphide, carbonyl sulphide, or hydrogen sulphide, at low pressure in a radiofrequency discharge tube. On the basis of these results, Johns and Olson 28 prepared thioformaldehyde, under slightly different conditions, from dimethyl disulphide in the presence of sulphur hexafluoride. The reaction path suggested was : Me$,

MeS. 22

23 24

26

26

+ F (from SF,)

___+

2 MeS. CH,S + HF*

M. Ahmed, J. M. Buchshriber, and D. M. McKinnon, Canad. J. Chem., 1970,48, 1991. D. M. McKinnon and J. M. Buchshriber, Canad. J . Chem., 1971, 49, 3299. D. B. J. Easton, D. Leaver, and T. J. Rawlins, J . C. S . Perkin I, 1972,41. (a) D. R. Johnson and F. X. Powell, Science, 1970,169, 679; (b) D. R. Johnson, F. X. Powell, and W. H. Kirchhoff, J . Mol. Spectroscopy, 1971,39, 136. J. W. C. Johns and W. B. Olson, J. Mol. Spectroscopy, 1971,39, 479.


203

Accordingly, the formation of hydrogen fluoride could be verified spectroscopically. The thioformaldehyde generated in this way was unambigously identified by means of its microwave 25 and i.r. spectra,26and its half-life was determined to be a few minutes. The thermal decomposition of 1,3-dithiacyclobutanethione27 and 2-vinylmercaptotetrahydropyran 28 gives products which suggest the formation of transient monomeric thioformaldehyde and thioacetaldehyde, respectively. In the latter case, the isomeric a- and p-trithioacetaldehydes were isolated.28 Transient monomeric thiobenzaldehyde is regarded as being responsible for the formation of a polymeric material during the photolysis of w-benzylmercaptoa~etophenones.~@ The same thioaldehyde also plays an important part in the mechanism outlined by Ohno and his co-workersa0 for the formation of the products (7), (8), and benzophenone N-methylimine by the reaction of photo-excited thiobenzophenone with benzaldehyde N-methylirnine. The thioaldehyde is most probably generated by the cleavage (b) of the intermediate cyclo-adduci 6). Although the formation

Ph,C= NMe b

+

__j

[PhCHSJ

H [PhCHSl

T!T

Ph-)'"''f-Ph

+

sxs H Ph (7)

Me ' H F%-)-"'fPh

H

H

sYs Ph Ph (8)

of (7) and (8) was not discussed further,30 the fact that the elements of thiobenzaldehyde are present in these molecules also lends support to the suggestion of the transient existence of the thioaldehyde. The formation of 1,4-dianthronylidenebut-2-ene (13) by the photolysis of diazoanthrone in thiophen has been explained by a mechanism involving the thioaldehyde (1la) as an intermediate.31 It was considered likely that the initially formed carbene (9) reacts with the solvent to give (lo), which then undergoes valence isomerization to the thioaldehyde (1 1a). The two 27 28

28

30

31

J. Wortmann, G. Kiel, and G. Gattow, Z . anorg. Chem., 1970, 376, 73. D. T. Witiak and M. C . Lu, J. Org. Chem., 1970, 35, 4209. A. Padwa and D. Pashayan, J. Org. Chem., 1971,36, 3550. A. Ohno, N. Kito, and T. Koizumi, Tetrahedron Letters, 1971, 2421. G. Cauquis, B. Divisia, and G. Reverdy, Bull. Soc. chim. France, 1971, 3027.

204


(lla) X (llb) X

(13)

=

=

S 0

(12)

subsequent steps, the formation of the thiiran (12) by the reaction of (1 la) with another carbene species, and the elimination of sulphur from (12), constitute a reaction sequence that is well known in principle. The proposed mechanism was supported by the fact that the photolysis of diazoanthrone in furan yielded the isolable aldehyde (11b).31 Metal Complexes.-Two interesting thioaldehydes, unknown as free ligands, have been characterized as their nickel@) complexes. Thus (14) was obtained as a black partially crystalline mixture by treatment of H I

Ph I

(15a) X (15b) X

= =

S 0

3-acetylmercaptoacroleinwith nickel(@ acetate in ethanolic and (15a) was obtained as green crystals from the reaction of the corresponding aldehyde (15b) with hydrogen s ~ l p h i d e . ~ ~ 3 Thioketones Synthesis.-Simple aliphatic and alicyclic thioketones are prepared easily and in high yields by the same method 2s 21 as described in the preceding section for the preparation of the enethiol tautomers of simple aliphatic a2

L. Beyer and G. Schone, Tetrahedron Letters, 1970, 1959. E. Uhlemann, G. Hinsche, H. Braunschweig, and M. Weissenfels, 2. anorg. Chern., 1970,377, 321.

205 thioaldehydes, i.e. by the cleavage of a/I-unsaturated sulphides (1) by lithium or sodium metal in liquid ammonia. The products (2; R1 = alkyl) and [2; R1R2 = -(CH&-, n = 3 or 41 are enethiol tautomers of aliphatic and alicyclic thioketones, and in agreement with the present knowledge of the latter compounds, these enethiols spontaneously undergo partial tautomerization to the thioketones, as evidenced by their being pink. Another recently described based on the reaction of enamines with thiolacetic acid in refluxing benzene, seems to be usable only in those cases where the generated thioketone is sufficiently stable to survive under the rather forcing reaction conditions. The yields of the diaryl thioketones, formed by the reaction of diaryl ketimine anions with carbon disulphide, have been found to depend strongly on the base used to generate the imine anions.35 The action of sulphur on ethyl 5-ary1-2-cyano-2,Qpentadienoates [method (a)] or on mixtures of 3-arylacroleins and ethyl cyanoacetate [method (b)] was found to give the thioaroylthiophens (16) in moderate Thiocarbonyl, Selenocarbonyl, and Tellurocarbonyl Compounds

+

A , + ~ ~ ~CH2-C02Et I

CN

to good yields.as Some 2-amino-3-aroyl-5-thioaroylthiophens were synthesized in a similar manner.36 Several papers reporting the further application of well-established techniques have appeared. Thus the interesting thioketones (1 7)-(20) were synthesized by thionation of the corresponding ketones using phosphorus penta~ulphide.~~ A series of aliphatic enamino-thioketones (21) were prepared by the same method, although in relatively low yields.a8 The n.m.r. spectra of the latter compounds suggested a cis configuration in the cases where R1 = H, presumably due to the presence of a hydrogenbond as shown in (22), and a trans configuration in all other investigated cases (R1,R2 = a l k ~ l ) .Other ~ ~ thiones prepared by the above-mentioned method include adamantanethioneY3@ a 4-~yridthione,~O some dibenzo [b,e]P. D. Klemmensen, J. Z. Mortensen, and S.-0. Lawesson, Tetrahedron, 1970,26,4641. R. Ahmed and W. Lwowski, Org. Prep. Procedures, 1971, 135. 36 N. K. Son and Y. Mollier, Compt. rend., 1971, 273, C, 278. 87 E. I. G. Brown, D. Leaver, and D. M. McKinnon, J. Chem. Soc. (0, 1970, 1202. ss K. Kamienska-Trela, U. Dabrowska, and J. Dabrowska, Bull. Acad. polon. Sci., St+. Sci. chim., 1971, 19, 549. 9B J. W. Greidanus, Canad. J . Chem., 1970,48, 3540. M. J. Robins, B. L. Currie, R. K.Robins, and A. D. Broom, Canad. J. Chem., 1971, 49, 3037. s4

s6


206

P 1-1

P 11

(19)

(20)

X

=

0

x=s

(23) R X

= =

H or Me S or SO,

thiepin-1 l-thiones (23),41and a series of anthyridine-thiones and - d i t h i o n e ~ . ~ ~ Another standard method, the thionation of ketones by hydrogen sulphide in the presence of hydrogen chloride as catalyst, has been used in the synthesis of a series of alicyclic ap-unsaturated t h i ~ n e s The . ~ ~same method, when applied to some 2-azidoaryI ketones (24) at lower temperatures, afforded the corresponding thioketones only in the case R = Ph (25), whereas for R = Me the isolated product was the cyclic trimer (26).44

acx-,

Me

N3

(24) X (25) X

= =

0, R

=

S. R

=

Me or Ph Ph

(26) Ar =

PI;

E:

0

(29)

41 42

G . Vasiliu and C. Vladescu, An. Uniu. Bucuresti, Chirn., 1970, 19, 21. S. Carboni, A. DaSettimo, D. Bertini, C. Mori, and I. Tonetti, J. Heterocyclic Chem., 1971, 8, 637.

43 44

P. Metzner and J. Vialle, Bull. SOC.chim. France, 1970, 3739. J. Ashby and H. Suschitzky, Tetrahedron Letters, 1971, 1315.


207

On the other hand, the action of hydrogen sulphide on 2-acetylcyclopentanone and 1-acetylindan-2-oneyrespectively, gave products that were tentatively formulated by the authors as (27) and (28), respecti~ely.~~ However, the reaction is known to be quite susceptible to temperature effects, and the possibility cannot be excluded that the formation and isolation of the latter products instead of the immediately expected monothio-/3-diketones, which according to experience with similar compounds should possess reasonable stabilities, is merely a consequence of the relatively high reaction temperature (- 10 "C). The use of the reaction of vinylic chlorides with hydrogen sulphide, or its anion, as a suitable route to thioketones has been further demonstrated by the syntheses of (29) 4e and (30).47 New examples of thioacylation of active-methylene compounds with thiono- or dithio-esters have been r e p ~ r t e d . ~Some ~-~~ new 1,3-dithiol-2ylidene-thioketones have been prepared by the cycloaddition reaction between acetylenes and 1,2-dithioIe-3-thione~.~~~ 24 The latter compounds and their imino-analogues yielded related cycloadducts (31) on treatment with ketens.sl The reaction of 1,2-dithiole-3-thiones with a-chlorobenzylidenephenylhydrazinein basic medium gave the thioketones (32) by

sulphur and (33) appeared as a rearrangement product when 4-substituted 2-aryl-5-isopropyl-6a-thiathiophthens were treated with methyl iodide in the presence of a base.63 The well-known synthesis of enamino-thioketones (21) using the reaction of 1,Zdithiolium salts with primary or secondary amines has been the ~ - ~ ~ and Quiniou observed 68 that subject of renewed i n ~ e s t i g a t i o n . ~Duguay the action of p-methylaniline on unsymmetrical 3,5-diaryl-l,2-dithiolium 45 46

47

48 49

6o

61

W. Uhde and K. Hartke, Arch. Pharm., 1971, 304, 42. A. H. Schmidt, W. Ried, P. Pustoslemsek, and H. Dietschmann, Angew. Chem. Infernat. Edn., 1972, 11, 142. E. Bayer and H.-P. Miiller, Tetrahedron Letters, 1971, 533. K. Hartke and B. Seib, Pharmazie, 1970, 25, 517. K. Hartke and F. Meissner, Tetrahedron, 1972, 28, 875. E. Uhlemann and U. Eckelmann, 2. anorg. Chem., 1971,383, 321. G. Hervieu, P. Rioult, and J. Vialle, Bull. SOC.chim. France, 1971, (a) p. 3480; (h) p. 4375.

sz 53 64 5s 66

M. Maguet, Y . Poirier, and J. Teste, Bull. SOC.chim. France, 1970, 1503. A. Josse and M. Stavaux, Compt. rend., 1971, 272, C, 1374. F. Clesse, A. Reliquet, and H. Quiniou, Compt. rend., 1971, 272, C, 1049. C. M6tayer and G. Duguay, Compt. rend., 1971,273, C, 1457. G. Duguay and H. Quiniou, Bull. SOC.chim. France, 1970, 1918.

208


ions (34) in most cases afforded only one of the two possible isomeric thiones (35) and (36). Moreover, the same workers found 56 that treatment of the ketone corresponding to either of the thioketones (35) and (36) with phosphorus pentasulphide always resulted in the formation of mixtures of (35) and (36) in accordance with the product distribution found in the firstmentioned reaction. On the basis of these findings the authors assumed the formation of (34) as an intermediate in the latter reaction (Scheme 1).

Ar2-CS-CH=C, (35) and/or

RNH,

Ar’-CS-CH=C,

(34)

A?-CO-CH=C,

,Ar2 NHR

, Ar * NHR

~

Ar’-CO-CH=C(

NHR

Ar

NHR

Scheme 1

This assumption was confirmed by the fact that (34) could be trapped as a perchlorate in the latter reaction66 and, further, that none of the thioketones (35) and (36), in those cases where both of them were obtainable, was able to rearrange thermally into its isomer.56 The reaction product obtained on treatment of tetrabromodibenzyl ketone with potassium xanthate was earlier assigned the structure (37), but renewed investigations by the same group of workers 57 have now led to the conclusion that the product is better described as a meso-ionic compound (38). However, in order to explain the formation of the quinone (39) as the main product of the pyrolysis of the compound in question, the authors simultaneously suggested 57 the existence of a temperature-dependent equilibrium between (37) and (38), favouring (37) at elevated temperatures. The photolysis 58 of 2,3-dibenzoyl-2,3-diphenylthiiranl-oxide afforded a compound which, on the basis of its i.r. and U.V. spectra, was found to be best represented by the monothiobenzil structure (40),69 although its mass spectrum revealed the importance of the oxathiet configuration (41) in its molecular Thioacridone is reported as the product from the reaction 67

s8

A. Schonberg and E. Frese, Chem. Ber., 1970,103, 3885. D. C. Dittmer, G . E. Kuhlmann, and G. C. Levy, J . Org. Chem., 1970,35,3676. D.C. Dittmer and G . E. Kuhlmann, J. Org. Chem., 1970,35, 4224.

;loph 209

Thiocarbonyl, Selenocarbonyl, and Telturocarbonyl Compounds 0

&$LPh

Ph-C-C-C-Ph sII oII sII

Ph

(37)

Ph

0-

0

0 s

II il Ph-C-C-Ph (40)

Ph

Ph (41)

of acridine N-oxide with acetyl sulphide60and as the major product from the reaction of 9-aminoacridine with butyl isothiocyanate.61 Transient Species.-The formation of the same two products (42) and (43) by the self-condensation reactions of 4-chloro-5-mercapto-3(2H)-pyridazinones and their 5-chloro-4-mercapto-isomerswas interpreted in terms of the existence of a reversible interconversion between the intermediate thioketocarbene species (44)and (45).8a Similar reactions 63 were interpreted

(44) 6o

61

63

(45)

J. H. Markgraf, M.-K. Ahn, C. G. Carson, and G. A. Lee, J. Org. Chem., 1970, 35, 3983. A. DeLeenheer, Y. Y. Shum, J. E. Sinsheimer, and J. H. Burckhalter, J . Pharm. Sci., 1971, 60, 1238. K. Kaji, M. Kuzuya, and R. N. Castle, Chem. and Pharm. Bull. (Japan), 1970,18, 147. (a) K. Kaji and M. Kuzuya, Chem. and Pharm. Bull. (Japan), 1970, 18, 970; (6) M. Kuzuya and K. Kaji, ibid., p. 2420.

210


in the same way, and evidence for the transient existence of the thioketocarbenes was obtained by trapping experiments.62 The base-promoted dimerization of trans-2,4-diphenylthietan was considered to involve the thione anion (46) as a key intermediate.s4 The existence of a pink reaction mixture lends support to the suggestion that the initially formed cyclohexanethione is the reactive species in the reaction of 1,l-dimercaptocyclohexane with cyanide ions, resulting in the formation of (47).g6 The dithione (48) was postulated as an intermediate in the phosphorus-pentasulphide-promoted cleavage of (49) leading to the product (50),6sand the

(47)

But B+C-CH~

II

X

S

(48) X (49)

x

).=cH-c-B~~ It X

= =

(50)

S

R2

0

I

\

(51)

X

=

R3 0 or S

\

(52) X

=

R3

0 or S

thiones (51) were considered to be the reactive intermediates in the reactions of 2-thio- or 1,2-dithio-coumarins with amines that result in the final isolation of the enamines (52).67 Thiones (and thials) appeared to be the primary photoproducts together with enolic acetophenone in the photochemical fragmentation of phenacyl alkyl sulphides.68 The formation of (56) by the photodecarbonylation of the thiolactone (53) was explained by the mechanism outlined in Scheme 2. The thioketone intermediate (54) is postulated, but the authors claim to have U.V. spectroscopic evidence for the transient existence of (55). The Thio-Claisen Rearrangement.-The thermal [3,3]sigmatropicrearrangement of aP-py'-unsaturated sulphides, resulting in the formation of ~3' e6

ee 67

O9

R. M. Dodson and J. Y. Fan, J. Org. Chem., 1971, 36,2708. D. H. R. Barton and B. J. Willis, J. C. S. Perkin I, 1972, 305. P. Yates and T. R. Lynch, Canad. J. Chem., 1971,49, 1477. L. Legrand and N. Lozac'h, Bull. SOC.chim. France, 1970, 2233. M. C. Caserio, W. Lauer, andT. Novinson, J . Amer. Chem. SOC.,1970,92,6082. J. Nasielski and G. Jacqmin, Tetrahedron, 1972, 28, 597.


21 1

Scheme 2

thiocarbonyl compounds as the primary products, is now relatively well understood. However, owing to the high reactivity of the thiocarbonyl group, the primary products generally spontaneously undergo further rearrangements or reactions, and their isolation or at least the demonstration of their transient existence is still an important subject of research. Two recent papers 71 appear to be of especial interest in this connection. Kondo and Ojima have reported‘O that the sulphide (57), generated by photolysis of the sodium salt of a-allylthio-acetophenone toluene-psulphonylhydrazone, is quite stable at - 70 “C,but undergoes the thioClaisen rearrangement spontaneously at room temperature. The rearrangement conditions only allowed isolation of the ketone (59), but n.m.r. monitoring and the appearance of an intense violet colour during this process gave clear evidence for the transient existence of (58). Corey and Shulman have described71 a similar reaction sequencc, in which the last 70e

70

K. Kondo and I. Ojima, J . C. S. Chem. Comm., 1972, 62. E. J. Corey and J. I. Shulman, J. Amer. Chem. SOC.,1970, 92, 5522,

212


step was promoted by added mercuric oxide. In the example given here, the aldehyde (60) was obtained in a yield of 82%, whereas in the absence of the oxidizing agent only less well-defined polymeric material was formed.71 As stated by the a ~ t h o r s , ~this ’ new oxidative technique doubtless broadens the scope and utility of the thio-Claisen rearrangement. The thio-Claisen rearrangements of allylic phenyl s u l p h i d e ~ ,allyl ~~ thienyl s ~ l p h i d e s ,addition ~~ products of acetylene derivatives and allyl r n e r ~ a p t a n and , ~ ~ dimethylallyl 2-indolyl sulphonium salts 75 have been described. Of particular interest is a recent paper 78 reporting the quantitative formation of (62) by the thermal rearrangement of the sulphoxide (61). The second step in the mechanism (Scheme 3) proposed for this reaction

b

x~s’CH2-C~C-CH2R

Scheme 3

constitutes the first reported example of the thio-Claisen rearrangement of the bond system C=C-S-0-C=C=C. Metal Complexes.-The metal complexes of thioketones appear to be the subject of growing interest, and recent progress in this field should deserve notice. Thiobenzophenones were found to react with di-iron enneacarbonyl, Fe,(CO)@,at room temperature to form ortho-metallated products (63), whereas adamantanethione by a similar treatment gave a quite different product (64).77 Monothiothenoyltrifluoracetone has been found to act both as a mono- and a bi-dentate ligand towards certain zerovalent metal carbonyls of Group VIA.78 Thus the thallium(1) salt of the monothio-/?diketone in question reacted with Et4N+ [M(CO),CI]- (where M = Cr, 72

J. Tanaka, T. Katagiri, K. Takabe, and S. Takeshita, Yuki Gosei Kagaku Kyokai Shi, 1971, 29, 788.

7s ‘I4 76 76

78

J. Z. Mortensen, B. Hedegaard, and S . - 0 . Lawesson, Tetrahedron, 1971,27, 3831. T. Sasaki, A. Kojima, and M. Ohta, J. Chem. SOC.(C), 1971, 196. B. W. Bycroft and W. Landon, Chem. Comm., 1970,967. K. C. Majumdar and B. S. Thyagarajan, J. C. S. Chem. Comm., 1972,83. H. Alper and A. S. K. Chan, Chem. Comm., 1971, 1203. G. H. Barnett and M. K. Cooper, Chem. Comm., 1971, 1082.

Thiocarbonyl, Selenocarbonyl, and Teilurocarbonyi Compounds

213

Mo, or W) at room temperature to give solely the product (65), which at elevated temperatures was converted completely into (66) by release of carbon monoxide.78 The chelating behaviour of a-alkylated monothio-8diketones has also been investigated,b0and the conclusion has been drawn

that the metal complexes of these ligands, presumably due to steric crowding effects, are best characterized as mercaptides. A relationship between

the enethiolization tendency and the metal-chelating activity of monothio8-diketones has been suggested.a3,6o Further recent papers concerning metal complexes of thio-analogues of /?-diketones deal with the preparation of the cobalt(@ complex of 1,3diacetylthioa~etone,~~ the synthesis and properties of a series of metal complexes of dithioacetylacetone,sOthe synthesis of the nickel(n) complexes of monothio- and dithio-dibenzoylmethane (67) by the nucleophilic cleavage of 1,2-dithiolium salts by hydroxide or mercaptide ions in the presence of nickel(I1) ions,81the bromination of the cobalt(m) complex of monothioacetylacetone (68) with N-bromosuccinimideto yield (69),82and the application of monothiodibenzoylmethane as an analytical reagent for quantitative determination of copper.83 7B

82

A. Furuhashi, Bull. Chem. SOC.Japan, 1970,43, 3604. G. A. Heath and R. L. Martin, Austral. J. Chem., 1970, 23, 1721, 2297. E. Uhlemann and K.-H. Uteg, 2. Chem., 1970, 10,468. A. Yokoyama, S. Kawanishi, and H. Tanaka, Chem. and Pharm. Bull. (Japan), 1970, 18, 356.

E. Uhlemann, B. Schuknecht, K. D. Busse, and V. Pohl, Analyt Chim. Acra, 1971, 56, 185.

214


v (67) X = 0 or S

Y

(68) Y = H (69) Y

=

Br

Reactions.-Beak and Worley 84 have studied the reactions of thiobenzophenones with a series of organometallic compounds, viz. PhMgBr, PhNa, BuLi, and PhLi, and they concluded that these reactions in general proceed by the same thiophilic addition mechanism, i.e. by an initial attack of, for example, phenyl-lithium on the sulphur atom of thiobenzophenone to give the intermediate adduct (70). Addition of water to the decolorized reaction solution then gives benzhydryl phenyl sulphide (71). The existence of (70) as an intermediate was suggested by the results of two quenching experiments, in which [hydro~y-~Hlmethanol or trimethylsilyl chloride was added instead of water, thus giving (72) and (73), respectively, as the reaction products. The possibility that thiobenzophenone and phenyl-lithium react by initial Ph

Phk=S Ph’

I + PhLi + Ph-G-SPh Li+ (70)

Ar Ar>C=!j

Al-

+ Li+

Ar

Ph,C-S-

(74) (a) P.

597.

I 1

-C-SAr

Ph I

+ Ph-C-SPh

I

X (71) X = H (72) X = D (73) X = SiMe, Ar

Ar

Ar

Ar

I I + Li+ -C-S-C-SAr I I

S Ar*Ar Ar Ar (75)

Beak and J. W. Worley, J . Anrer. Chem. SOC.,1970, 92,4142;(6) ibid., 1972, 94,


215

addition to carbon to give the anion (74), which then rearranges to (70), was discounted by the observation that [2Hlo]thiobenz~phen~ne reacts with phenyl-lithium to give [2H,,]benzhydryl phenyl sulphide containing less than 3% of S-[2H,]phenyl material. The formation of tetra-arylthiirans (75) by the reaction of arylthioketones with organometallics, as stressed in earlier papers, is fully consistent with a thiophilic reaction mechanism. The possibility that the general thiophilic addition reaction involves radicals was discussed.84b Recent studies 86 on the reactions with diazomethane of those thioketones that cannot exist in the enethiol form yielded conclusive evidence for the occurrence of a 1,3-cycloaddition reaction, because the nitrogencontaining cycloadducts (76) and/or (77) could be isolated under appropriate reaction conditions. Diebert 86 formulated the unstable compound 8sp

. .

.nrvvv\r

(78) derived from tetramethyl-3-thio-l,3-cyclobutanedioneas (76), and Krapcho and his co-workersB6 made a similar assignment to the cycloadducts obtained from some tetrasubstituted 1,3-cyclobutanedithiones. However, adamantanethione apparently gave both (76) and (77) on treatment with diazomethane.86 In all cases the thermal conversion of the cycloadducts into the normally observed reaction products, the thiirans (78), occurred readily. Whether the cycloaddition mechanism has general validity is still an open question, but it appears likely that the carbene mechanism may play a part in those cases where the carbene possesses some relative stability. The reactions of thiobenzophenone and tetramethyl-l,3-~yclobutanedithione with diazoanthrone 31 and diphenyldiazoniethane,*6respectively, yielded only the thiirans. Huisgen and his co-workers *' allowed thiobenzophenone to react with the meso-ionic compound (79), and they obtained as product the thiobenzamide (81), formed by what is probably an electrocyclic ring-opening 86

C. E. Diebert, J. Org. Chem., 1970, 35, 1501. A. P. Krapcho, D. R. Rao, M. P. Silvon, and B. Abegaz, J . Org. Chem., 1971, 36, 3885. E. Funke, R. Huisgen, and F. C. Schaefer, Chem. Ber., 1971, 104, 1550.

216


I

Me (79)

L O

1-

Ph COZ

Me I

PhrNyph Ph Ph

of the cyclic ylide (80). New examples of the 1,3-cycloaddition reaction of nitrile N-oxides with aromatic thioketones yielding 1,4,2-oxathiazoleshave been r e p ~ r t e d . ~80~ ~A mechanistic study 89 characterized this reaction as a one-step concerted process, obeying second-order kinetics. The positive Hammett p value for this reaction was taken as an indication of the electrophilic behaviour of the thiocarbonyl compound towards the nitrile Diphenylcyclopropenethione has been reported to undergo cycloaddition reactions with enamines O0 and certain nitrogen-containing heterocycle^,^^ but the thiocarbonyl function, in accordance with earlier observations, is not involved in the cyclization reactions, and exists as such in the products. A variety of thioketones have found applicability in the synthesis of heterocyclic compounds. Chloro-thioacetone reacted with trialkoxyphosphines to give thiirans.02 Thiophens have been prepared from monothio-fl-diket~nes,~~ /3-thioketo-ester~,~~~ g4 and from c~-thioketo-acids.~~ a-Thioacyl-7-lactones and -thiolactones rearrange in acid alcoholic solution to give dihydrofurans and dihydrothiophens, respecti~ely.~~ The simultaneous action of carbon disulphide, sulphur, and triethylamine on aliphatic thioketones gave mixtures of 1,2-dithiole-3-thiones and 1,3dithiole-2-thi0nes.O' The formation of thio-ozonides (1,2,4-trithioIans) by A. Battaglia, A, Dondoni, and G. Mazzanti, Synthesis, 1971, 378. A. Battaglia, A. Dondoni, G . Maccagnani, and G. Mazzanti, J . Chem. SOC.(B), 1971, 2096. 90

s1 s2

Bs @*

B6 g6

s7

J. W. Lown and T. W. Maloney, Chem. and Ind., 1970, 870. J. W. Lown and K. Matsumoto, Canad. J. Chem., 1971,49,3119. E. Gaydou, G. Peiffer, and A. Guillemonat, Tetrahedron Letters, 1971, 239. M. Takaku, Y . Hayasi, and H. Nozaki, Bull. Chem. SOC.Japan, 1970,43, 1917. B. Hedegaard, J. Z. Mortensen, and S.-0.Lawesson, Tetrahedron, 1971,27, 3853. N. B. Chapmann, C. G. Hughes, and R. M. Scrowston, J. Chem. SOC.(C), 1970,2431. F. Duus and S . - 0 . Lawesson, Tetrahedron, 1971, 27, 387. R. Couturier, D. Paquer, and A. Thuillier, Compt. rend., 1970, 270, C, 1878.

Thiocarbonyl, Selenocarbonyl, and Tellurocarbonyl Compounds 217 the treatment of thiobenzophenones with amines was investigated recently,08 and the utility of 4H-thiopyran-4-thiones in the syntheses of 6a-thia thi ophthens and 3-acylmethylene-3H-1,2-dithioles has been further e s t a b l i ~ h e d .A ~ ~novel route to benzoisothiazoles was exemplified by the thermal decomposition of o-azido-thiobenzophenone (25) to give Trimeric o-azido-thioacetophenone(26) behaved similarly, yielding R

CH3-C=CH-C02Et

1

S (82) R = Ph (83) R = Me

Ethyl thioacetoacetate, or more probably its predominating enethiol tautomer, reacted with p-benzoquinone in the presence of zinc chloride to give the 1,6adduct (84).lo0 The action of methyl iodide on enamino-thioketones of the type (21 ; R = Ar) resulted exclusively in S-methylation.lol The reduction of adamantanethione to the corresponding thiol by sodium borohydride has been described,lo2 and the usefulness of thioketones as scavengers of carbon radicals was demonstrated Several papers dealing with the oxidation of thioketones also deserve some attention. The oxidation of thiobenzophenones with peroxybenzoic acid has been the subject of a detailed kinetic study.lo4 By means of U.V. spectroscopy it was shown that the first stage in the reaction sequence:

is so much faster than the second stage that the latter does not interfere with the kinetics of the former. The first stage was found to be a secondorder process, characterized by a Hammett p value of - 0.88. The correlation of reaction rates for the formation of diphenylsulphine in a series of solvents with similar data reported earlier for the oxidation of a sulphide with the same peracid in the same series of solvents suggested to the authors lo4 that both oxidation processes proceed by the same mechanism although thiones are more reactive than sulphides by a factor of ca. 10. M. M. Campbell and D. M. Evgenios, Chem. Comm., 1971, 179. J. G. Dingwall, D. H. Reid, and J. D. Symon, J. Chern. SOC.( C ) , 1970, 2412. loo A. N. Grinev, G. Ya. Uretskaya, E. S. Krichevskii, and T. F. Vlasova, Zhur. org. Khim., 1971, 7 , 851. lol F. Clesse and H. Quiniou, Compt. rend., 1971, 272, C, 326. Io2 J. W.Greidanus, Canad. J. Chem., 1970, 48, 3593. lo3 G.Tsuchihashi, M. Yamauchi, and A. Ohno, Biill. Chem. SOC.Japan, 1970, 43, 968. lo4 A. Battaglia, A. Dondoni, P. Giorgianni, G. Maccagnani, and G. Mazzanti, J . Chem. SOC.(B), 1971, 1547. OB

218


The oxidation of diphenylcyclopropenethione using lead tetra-acetate led to the formation of the corresponding ketone as the only product.lo5 On the other hand, monoperphthalic acid afforded an almost quantitative yield of the salt (85), from which the less stable diphenylcyclopropenethione S-oxide (86) was obtained by addition of sodium hydrogen carbonate.lo5 The hydrogen peroxide oxidation of the thione (87) in acid medium yielded

Ph

Ph

the inner salt (88), which, however, was easily reconverted into (87) by treatment with boiling aqueous sodium sulphide.lo6 The methylene-bluesensitized photo-oxygenation of 4H-pyran- and 4H-thiopyran-4-thiones to yield the corresponding ketones was suggested to proceed through the intermediate (89).lo7 The oxygenation was quenched efficiently by /3-carotene, which led the authors to consider singlet oxygen as the reactive

(89) X

=

0 or S

The thiocarbonyl chromophore has attracted much attention among photochemists in the past, as is clearly demonstrated by several recent papers. Kemp and de Mayo observed108 the formation of short-lived transient species by laser photolysis of thiobenzophenone and Michler’s thione and, based on their U.V. absorptions, these species were assigned to J. W. Lown and T. W. Maloney, J. Org. Chem., 1970, 35, 1716. M. Maguet, Y. Pokier, and J. Teste, Compt. rend., 1970, 271, C, 204. (a) N. Ishibe, M. Odani, and M. Sunami, Chem. Comm., 1971, 118; (b)J. Chem. SOC. (B), 1971, 1837. lo* D. R. Kemp and P. de Mayo, J . C. S. Chem. Comm., 1972,233. lo6

lo6

lo’


219

the triplet state of the thioketones. In both cases the transient U.V. absorption decayed by first-order kinetics and was dependent on the concentration of the thione.lo8 The formation of the enethiol (90) by the photolysis of

o-benzylthiobenzophenone led Kito and Ohno looto the conclusion that photoreduction of thiobenzophenone i?volves initial formation of the radical PhzC-SH rather than PhzCH-S, as proposed earlier. Photocycloaddition reactions of thiones with compounds containing multiple bonds have, however, commanded especial attention and have been the subject of a recent re vie^.^ The photoaddition reaction of adamantanethione with olefins R1R2C:CH, was reported to give thietans (91) as the main products,ll* in accordance with the results of similar reactions of thiobenzophenone. The formation of sulphides of type (92)

as by-products when R2 = Me 110 is presumably connected with the special steric properties of the adamantyl group. The photoreaction of thiobenzophenone with imines 30 is described in Section 2, as thioaldehydes are the primary products when aldimines participate in the reaction. The photolysis of thiones in the presence of an alleiie has been studied by two research 112 The mechanism was considered to involve the initial attack of the photo-excited thione on the central carbon atom of the allene, forming the intermediate (93), which subsequently undergoes cyclization to the product(s). Gotthardt reported ll1 thietans of the type (94) as the main products and explained the formation of by-products either by the occurrence of a simultaneous thermal reaction,ll1, 113 or by isomerization of the allene.lll However, the photoreaction of thiobenzophenone with methoxyallene gave,112besides the thietan (95), the thiopyran log 111 113

N. Kito and A. Ohno, Chem. Cornrn., 1971, 1338. C. C. Liao and P. de Mayo, Chem. Cornrn.,1971, 1525. H. Gotthardt, Tetrahedron Letters, 1971, 2345. H. J. T. Bos, H. Schinkel, and Th. C. M . Wijsman, Tetrahedron Letters, 1971, 3905. H. Gotthardt, Tetrahedron Letters, 1971, 2343.

220


Ar

(94) (95)

Rf = R2 = Me R1 = OMe, R2 = H

derivative (96), a phenomenon that is presumably connected with the unsymmetrical nature of the allene and differences in reactivity of the two possible biradical intermediates. In this connection, attention should be drawn to the recently studied photo-cycloaddition reaction of thiobenzophenone with a ~ e t y l e n e slls , ~ leading ~ ~ ~ to products (97) closely related to (96), suggesting that there are similar mechanisms of formation. The photolysis of trimeric thioacetophenone gave 116 2,ddiphenylthiophen and 9,lO-dimethylphenanthreneas identified products ; a bicyclic compound (98) was obtained 116 when the photolysis was carried out in the presence of

Ph (99)

cyclopentadiene, suggesting the intermediacy of monomeric thioacetop henone. The p hot o-dimerization of diphenylcyclopropenethi one, yielding (99), has also been described 4 Thioketens

Monomeric thioketens are very unstable compounds and have been isolated and characterized only in very few cases. Not surprisingly, therefore, most of the relevant literature published within the past two years reports on these compounds as transient species or postulated intermediates. 114

ll5 lI6 11’

A. Ohno, T. Koizumi, Y. Ohnishi, and G. Tsuchihashi, Tetrahedron Letters, 1970, 2025. A. Ohno, T. Koizumi, and Y . Ohnishi, Bull. Chem. SOC.Japan, 1971,44,2511. N. Sugiyama, M. Yoshioka, H. Aoyama, and T. Nishio, Chem. Comm., 1971, 1063. A. Schonberg and M. Mamluk, Tetrahedron Letters, 1971, 4993.


22 1

However, the comprehensive paper of Raasch6 is exceptional in that it describes the preparation and properties of the stable bis(trifluoromethy1)thioketen (100). The thioketen in question appeared as a reddish orange liquid by cracking its dirner, the desaurin (101). Besides its ability to dimerize and tetramerize, its reactivity and synthetic utility were demonstrated6 by a long series of cycloaddition reactions. Thus it reacts with thiocarbonyl compounds to yield 1,3-dithietans, with certain electron-rich carbonyl compounds to yield also 1,3-dithietans (by cleavage of the initially formed lY3-oxathietanand further reaction with the liberated thiocarbonyl compound), with electron-rich olefins, forming thietans, and with carbodi-imides to form 1,3-thiazetidines(102). Its addition reactions with quadricyclene, 2,5-norbornadiene, and 2,3-dimethylbutadieneY yielding

R

Me

the interesting compounds (103), (104), and the Diels-Alder adduct (105), should also be mentioned. Compound (100) reacts with diazomethane, without loss of nitrogen, in both directions to yield two isomeric thiadiazoles. The lY3-dipolaraddition reactions with hydrogen azide, nitrile oxides, nitrones, and oximes were reported6 to give the expected heterocyclic compounds, i.e. 1,2,3,4-thiatriazoles, 1,4,2-0xathiazoles, and 1,4,2oxathiazolidines, respectively. It is interesting to observe that only the thiocarbonyl function of (100) is involved in all the cycloaddition reactions that have been performed. This is in contrast to experience with ketens and is probably a consequence of the generally greater reactivity of the thiocarbonyl function as compared to the carbonyl function. The spontaneous thio-Claisen rearrangement of the sulphide (1 06) yielded the thioketen (107), which, however, could not be isolated because Et-CSC-S I Me-CEC-CH, (106)

E t-C=C=S

I

Me-C=C=CH, ( 107)


222

of its tendency to undergo polymerization, but was trapped with a secondary amine to yield a thioamide or an aminothiophen, depending on the reaction conditions.2 The intermediacy of thioketens has been discussed in connection with the photo-reaction of 1,2,3-thiadiazoIes118*11° and the decomposition of l,l-dimercapto-2-cyanoalkenes.120 The mechanism for the formation of desaurins by the action of base and carbon disulphide on active-methylene compounds has been discussed by Yates and his coworkers,121but although the products are formally dimers of thioketens, the authors consider the participation of thioketen intermediates in this reaction to be unlikely. Thioketen radical cations have been proposed in the electron-impact-inducedfragmentation pathways of 1,2,3-thiadiazoles 122 and tetra-a1kylmercapt oeth ~ 1 e n e s . l ~ ~ 5 Thiocarbonyl Ylides

Thiocarbonyl ylides constitute a new class of compounds, conveniently represented by the general structure (108a). However, resonance structures such as the 1,3-dipolar structure (108b), the neutral structure (108c) \

,c=s-c, f

(10th)

-/

-

>d-s-c,- /

S I Me

X-SO,

0 \

NH-C0,Mc

(186) X = CI (187) X = NH*CS.'NH',

(185)

(1 84) with carbon disulphide. Russian workers found 241 that successive treatment of the sulphonyl chloride (186) with (i) sodium hydroxide at pH 8.5-9 and (ii) sodium thiosulphate at pH 2 in the presence of cyanamide affords the thiourea (1 87). Phenetidine hydrochloride was practically quantitatively converted into NN'-di-(p-ethoxypheny1)thiourea on treatment with ammonium r h ~ d a n i d e . Rhodanide ~~~ ions also played an important part in the synthesis of the cyclic thioureas (188) by the simultaneous action of a primary amine and trimethylsilyl isothiocyanate on The reaction ketones containing an unsubstituted a-methylene was shown to proceed via the ketiminium rhodanides (189), which were the

237 238

23s 240

M. Chaturvedi and A. C. Jain, Current Sci., 1971,40, 156. K. Nagarajan, V. R. Rao, and A. Venkateswarlu, Indian J. Chem., 1970, 8, 126. G. Kempter, M.-J. Ziegner, and G. Moser, Z . Chem., 1971, 11, 12. S. Sakai, Y. Asai, Y Kiyohara, K. Itoh, and Y. Ishii, Organometal. Chem. Synth., 1970-1971,

1,45.

241

V. A. Zasosov, L. S. Blinova, V. N. Sycheva, and G. N. Sokolava, Khim.-Farm. Zhur.,

242

1971, 5 , 42. B. N. Chetverikov and I. V. Bannykh, Khim.-Furm. Zhur., 1969,3,43. J. Burkhardt, Chem. Ber., 1970, 103, 1589.

248

23 8


isolable products under more gentle reaction conditions.243Goerdeler and Ludke have prepared a series of thiocarbamoyl isothiocyanates (190) by the reaction of thiocarbamic acid chlorides with sodium thiocyanate ; the authors reported i.r. spectroscopic evidence for the intermediacy of thiocarbamoyl t h i ~ c y a n a t e s . ~ ~ ~ The most common method for the preparation of thioureas is, however, based on the reaction of isothiocyanateswith amines, and, not unexpectedly, the majority of papers deal with this particular reaction.238,245-261 Among the N-substituent groups thus introduced into thiourea are 3-cyclo~ e n t e n y l l, -~a~d~a m a n t ~ l ,f~u~r ~ f ~ r y l diphenylpho~phinoyl,~~~ ,~~~ diphenylpho~phinothioyl,~~~ NN-9,1 O-diacetyldihydr0-2-phenaziny1,~~~ and variously substituted ary1s.261-264If the isothiocyanate or the amine contains other reactive groups, cyclization to heterocyclic compounds containing the thiourea grouping may occur, either spontaneously or promoted by external influence, as recently demonstrated in the synthesis of thiones derived from imida~oline,~~~e 263 and s - t ~ i a z i n e . ~ ~ ~ - ~ ~ ~ 244 246 240 247 248

249

250

251

J. Goerdeler and H. Ludke, Chem. Ber., 1970, 103, 3393. I. V. Smolanka and N. P. Man’o, Ukrain. khim. Zhur., 1970, 36, 589; 1971, 37, 182. A. Kreutzberger and H.-H. Schroders, Tetrahedron Letters, 1970, 4921. P. Krkoska, A. Martvon, M. Uher, and J. Kohut, Chem. Zvesti, 1971,25,59. G. Tomaschewski and D. Zanke, 2 . Chem., 1970, 10, 117. I. Ojima, T. Onishi, T. Iwamoto, N. Inamoto, and K. Tamaru, Bull. Chem. SOC. Japan, 1971,44,2150. S . B. Serebryanyi and A. P. Terent’ev, Ukrain. khim. Zhur., 1971,37,469. N. B. Galstukhova, I. M.Berzina, and M. N. Shchukina, Zhur. org. Khim., 1970, 6, 1870.

251

263 264 266

E. Vanags, A. Sausins, and V. Grinsteins, Latu. P.S.R. Zinat. Akad. Vestis, khim. Ser., 1970, 581 (Chem. Abs., 1970, 74, 53312); E. Vanags and V. Grinsteins, ibid., 1971, 456 (Chem. Abs., 1972,76, 14057). B. Singh and D. N. Chaudhury, J. Indian Chem. Soc., 1971,48,443. G. Vasilev, Khim. Ind. (Sofia), 1971, 43, 210. V. V. Dunina, E. G. Rukhadze, and A. P. Terent’ev, Zhur. obshchei Khim., 1970,40, 2278.

260

267

268

269

aao 261 202

20s

an4

S . N. Lewis, G. A. Miller, E. C. Szamborski, and M. Hausman, J. Heterocyclic Chem., 1971, 8, 587. F. Fujikawa, K. Hirai, T. Hirayama, T. Matsunashi, Y. Nakanishi, K. Kumoto, T. Shimizu, C. Sakaki, and Y . Hamuro, Yakugaku Zasshi, 1971,91, 159. A. C. Veronese, C. DiBello, F. Filira, and F. D’Angeli, Gazzetta, 1971, 101, 569. M. Dembecki and T. Pyl, 2. Chem., 1970, 10, 390. A. Kjaer and A. Schuster, Acta Chem. Scand., 1970,24, 1631; R. Gmelin, A. Kjaer, and A. Schuster, ibid., p. 3031 ;E. Bach and A. Kjaer, ibid., 1971,25,2629. G. S . Johar, U. Agarwala, and P. B. Rao, Indian J. Chem., 1970,8,759. B. Dash and S. K. Mahapatra, Current Sci., 1970, 39, 559. T. Kinoshita, S. Sato, and C. Tamura, Tetrahedron Letters, 1971, 3695. R. M. Khachatryan, S. K. Pirenyan, and S . A. Vartanyan, Armyan. khim. Zhur., 1970, 23, 645.

206

206

A. C. Glasser and J. Triplett, J. Pharm. Sci., 1971,60,122; A. C . Glasser, L.Diamond, and G. Combs, ibid., p. 127. B. V. Unkovskii, L. A. Ignatova, and M. G. Saitseva, Khim. geterotsikl. Soedinenii, 1969, 889.

P. Spacu and C. Marculescu, Rev. Roumaine Chim., 1971, 16, 513. L. Capuano and M. J. Schrepfer, Chem. Ber., 1971,104, 3039. 209 A. Schoberl and K.-H. Magosch, Annalen, 1970, 742, 85. a70 J. Goerdeler and J. Neuffer, Chem. Ber., 1971, 104, 1580, 1606. a n J. Neuffer and J. Goerdeler, Chem. Ber., 1971, 104, 3498. 207 268


239

The reaction between isothiocyanates containing an electron-withdrawing group and amines has been found 272 to give 1,3-thiazetidine derivatives (191) rather than 1,3-diazetidine-2-thiones (192), as earlier postulated. Among several other papers 273-278 dealing with the syntheses of a variety of heterocycles with incorporated thiourea groupings is an interesting S

(192)

(193) X (194) X

= =I

SR2 NR'R'

paper 278 describing the formation of 2-thioxo-h3-imidazoline-3-oxides by the ring-closure reaction of anti-a-amino-ketoximes with thiophosgene. Dahl and Larsen obtained phosphorus analogues of thiourea (194) from the reactions of esters of thiophosphinoyldithioformic acids (1 93) with ammonia or a r n i n e ~ . ~ ~ ~ Reactions.-The utility of thioureas in synthesis is well documented and depends in most cases on the nucleophilic reactivity of the thiocarbonyl sulphur atom. The reaction of thioureas with simple alkyl halides leads normally to S-alkylisothiouronium salts, but when the latter reactants contain additional reactive centres a subsequent reaction may occur, resulting overall in the formation of a heterocyclic compound. A new route to 2-arylthietans is based on the reaction of l-aryl-l-chloro-3bromopropanes with thiourea in the presence of sodium carbonate, the latter reagent being responsible for the subsequent ring-closure reaction of the primarily formed S-(1-aryl-1-chloropropyl)isothiouronium bromide.280 Russian workers have studied 281 the reaction of a-halogenoacylcarbamates with thiourea, and found it to be very sensitive towards alterations in reaction conditions. Thus, at 20 "Cin acetone, the products were the expected S-alkylisothiouronium salts; in boiling acetone the compounds (195) were the only products, and in boiling ethanol (196) were formed in high yields.281Several further examples of the synthesis of thiazoles or thiazolines by the reaction of thioureas with different types of a-halogenocarbonyls 272

273 274

276 277

278 27* 280

2*l

I. Ojima and N . Inamoto, Chem. Comm., 1970, 1629. J. Clark and Z. Munawar, J. Chem. SOC.(C), 1971, 1945; J. Clark and F. S. Yates, ibid., p. 2278. B. C. Pal, J. Org. Chem., 1971, 36, 3026. A. Mustafa, A. H. Harhash, M. H. Elnagdi, and F. A. E1-All, Annalen, 1971, 748, 70. Yu. I. Mushkin and M. V. Rozhnova, Zhur. org. Khim., 1971,7,842. P. Nuhn and G. Wagner, J. prakt. Chem., 1970,312, 90. H. Gnichtel, S. Exner, H. Bierbiisse, and M. Alterdinger, Chem. Ber., 1971, 104, 1512. 0. Dahl and 0. Larsen, Acta Chem. Scand., 1970, 24, 1094. C. Schaal, Compt. rend., 1970, 271, C, 1015. K. A. Nuridzhanyan and G. V. Kuznetsova, Khim. geterotsikl. Soedinenii, 1970, 908.

240


7-iY VNH

bs)-NHR

Y+ H

X

(195) X = NH2+C1-, Y =

Br-

N-CO,Me

(196) X = 0 , Y = NH

(197)

have 282-288 N-(Cyclopent-Zeny1)thioureas were found to react with bromine to form thiazolium bromides (197), apparently via intermediate N-(2,3-dibromocyclopentyl)thioureas,245and thiazoles were formed by the reaction of a/3-unsaturated ketones with thiourea, using bromine or iodine as condensing agent.28DThe treatment of N-allylthioureas with 96% sulphuric acid afforded S-protonated compounds, which, either spontaneously or on warming, cyclized to thiazolium cations.2D0The nucleophilic reactivity of the thiocarbonyl sulphur atom in thioureas has been further used in syntheses of heterocycles derived from lY3-thiazane2D1 and 1,3,5-thiadia~ine.~~~~ 2D3 S-Pyrrolylisothiouronium salts (198) were obtained in high yields when thioureas were treated with halogens in the presence of pyrr01es.~~~ This E

t

o

c

f~H P

s-c:+

Me I

H (198)

\'*

x-

NHZ

reaction was, however, explained on the basis of an electrophilic substitution mechanism involving an oxidatively generated sulphenyl halide as the reactive electrophilic species towards the p y r r ~ l e . ~ ~ ~ The acylation of thioureas with acyl halides may give S-acylisothiouronium halides as well as N-acylthioureas, the formation of the latter compounds being normally favoured at higher temperatures as a result of the rearrangement of the former compounds. Janssen and Spoelstra have studied 2D5 this rearrangement and the compounds involved therein using n.m.r. and U.V. spectroscopy, and they were able to show that S-benzoyl282

283 284 285 286

287 288

289 2Bo

281 282

2B3 284

296

R. S. Shadbolt, J. Chem. SOC.(C), 1971, 1667. S. Rajappa and B. G . Advani, Indian J. Chem., 1970, 8, 1145. F. W. Short, B. C. Littleton, and J. L. Johnson, Chem. andInd., 1971,705. G. Kempter, H. Schafer, and G . Sarodnick, 2. Chem., 1970, 10,460. H. Patel, T. C. Sharma, and M. M. Bokadia, Indian J. Chem., 1970, 8, 376. H. Bohme and R. Braun, Annalen, 1971,744,27. A. Taurins and A. Blaga, J. Heterocyclic Chem., 1970,7, 1137. H. Tripathy, B. C. Dash, and G. N. Mahapatra, Indian J. Chem., 1970, 8, 586. S. P. McManus, J. T. Carroll, and C. U. Pittman, J . Org. Chem., 1970, 35, 3768. A. P. Grishuk and G . I. Roslaya, Khim. geterotsikl. Soedinenii, 1971,7, 1053. J. P. Chupp, J . Heterocyclic Chem., 1971, 8, 677. J. E. Oliver and A. B. De Milo, J. Heterocyclic Chem., 1971, 8, 1087. R. L. N. Harris, Austral. J. Chem., 1970, 23, 1199. M. 5. Janssen and 5. Spoelstra, 2. Chem., 1970, 10, 391.


241

isothiouronium chlorides in solution are partially dissociated into benzoyl chloride and the thiourea, thus further confirming the occurrence of an intermolecular rearrangement.296 Lau and Gornpf have described 2Q6 a novel route to 2-amino-6-hydroxybenzothiazoles that depends on the reaction of thioureas with quinones in the presence of concentrated hydrochloric acid. It was shown 2Q6 that the reaction proceeds through the adduct (199), which is isolable when the reaction is performed with excess thiourea. Mattson and Sundstrom allowed the dispiro-compound (200) to react with thiourea and obtained

OH (1 99) J

as product the internal thiouronium salt (201), which on distillation at reduced pressure was converted into (202).297 The reaction of 2-thiazolyldiazonium tetrafluoroborates with equivalent amounts of thiourea afforded the salts (203), which were easily converted into 2-thiazolinethiones on further reaction with a three-fold excess of thiourea.208 Several examples of the utility of thiourea as a thionation agent for heterocyclic halides have appeared.185-187, 209-301 286 297

2B8 2@@

so* 801

P. T. S. Lau and T. E. Gompf, J. Org. Chem., 1970,35, 4103. 0. H. Mattson and G. Sundstrom, Acta Chem. Scand., 1970, 24, 1454. K. Grunert and K. Wiechert, 2.Chern., 1970, 10, 396. I. A. Mazur, P. M. Kochergin, and 0.S. Tkachenko, Khim. geterotsikl. Soedinenii, 1970, 824; A. N. Krasovskii, P. M. Kochergin, and L. V. Samoilenko, ibid., 1970, 827. C. L. Schmidt and L. B. Townsend, J. Heterocyclic Chem., 1970, 7, 715. F. Boberg and R. Wiedermann, Annulen, 1970,734, 164.

242


Japanese workers have investigated302 the reaction between thioureas and diethyl azodicarboxylate, which in the presence of triphenylphosphine has been found to give carbodi-imides. They have now shown that the reaction in question involves (204) as an intermediate, which in the absence of triphenylphosphine could be isolated and characterized for R1 = R2 = Ph. Compound (204) is easily converted into the carbodi-imide by treatment with triphenylphosphine or by refluxing in benzene. Moreover, the same workers were able to demonstrate30athat the formation of carbodiimide under the first-mentioned conditions does not involve the oxidatively

generated disulphide (205) as an intermediate. Goerdeler and his coworkers have reported that carbodi-imides (206) containing conjugated polar double bonds are formed in high yields by the action of cyanogen chloride and triethylamine on the appropriate t h i o u r e a ~ .Unsubstituted, ~~~ N-mono-, and NN-di-substituted thioureas have been converted into the corresponding cyanamides by treatment with carbodi-imide~.~~~ In the case of NN'-disubstituted thioureas, the same reaction resulted in the formation of new carbodi-imides, derived from the reacting The nucleophilic reactivity of the nitrogen atoms in thioureas towards carbonyl compounds has been further exemplified by some recently described addition 305 and addition-elimination306 reactions of thioureas with aldehydes. The same reactivity also played an important part in recent syntheses of heterocyclic compounds containing the thioureidog~ouping.~O~-~~~ 0. Mitsunobu, K. Kato, and M. Tomari, Tetrahedron, 1970,26,5731. J. Goerdeler, H. Lohmann, R. Losch, and S. Raddatz, Tetrahedron Letters, 1971, 2765.

308

slo

R. T. Wragg, Tetrahedron Letters, 1970, 3931. V. Mozolis and S. Jokubaityte, Liet. T.S.R. Mokslu Akad. Darb., Ser. B, 1969, 125 (Chem. Abs., 1970,72, 90 008x). F. Eiden and U. Schaffer, Arch. Pharm., 1971,304,445. A.-M. A. Samour, A. Marei, and M. H. M. Hussein, J. Chem. U.A.R., 1969,12,451; A.-M. A. Samour, M. M. N. El-Deen, and M. Abd-El-Halim, ibid., 1970,13, 7. F. I. Carroll and A. Philip, J . Medicin. Chem., 1971,14, 394. M. Draminski and B. Fiszer, Roczniki Chem., 1971, 45, 19. E. G. Mesropyan, Yu. A. Buniatyan, and M. T. Dangyan, Armyan. khim. Zhur., 1970, 23, 844.

311

N. A. Baranova, V. G. Beilin, and L. B. Dashkevich, Zhur. org. Khim., 1970,6, 1734.

Thiocarbonyl,Selenocarbonyl, and Tellurocarbonyl Compounds

243 The reaction of thioureas with nucleophiles has been only sparsely studied in the past. Guanidines have been prepared by treatment of corresponding thioureas with propylamine in the presence of lead and thioureas with a hydroxy-group at the 8-position of the N-substituent have been cyclized to oxazolines by refluxing in ethanol in the presence of cupric acetate.a13 The latter reaction was shown to proceed uia an intermediate copper complex.313 The photosensitized oxidation of allylthiourea with erythrosin or eosin gave three products, the sulphinic acid (207), ally1 cyanamide, and sulphuric

acid.314 The authors considered314(207) to be the primary product, the other two products being generated from it by a secondary oxidation process. A miscellany of papers dealing with the potency of the thioureido neighbouring group in nucleophilic substitution processes,316the complexing ability of thioureas towards macrocyclic pol yet her^,^^^ and the cycloaddition reactions of thiocarbamoyl isothiocyanates (190) with ketens, ketenimines, imines, isocyanates, carbodi-imides, and isonitriles 244 also deserve attention. Lack of space precludes a fuller presentation of the many papers reporting on the reactivity of relevant heterocyclic thiones derived from imidazole,226, 317-319 pyrimidine,22%320-325 and x-friazine.326

10 Thiosemicarbazides and Derivatives Synthesis.-One of the most commonly used methods for the preparation of thiosemicarbazides, perhaps the most important, depends on the reaction V. N. Choubey, Current Sci., 1971, 40, 322. Y.Iwakura, T. Kaya, and K. Kurita, Bull. Chem. SOC.Japan, 1970,43, 2531. J.-P. Dubosc, C. Mercier, and J. Bourdon, Bull. SOC.chim. France, 1971, 3286. 315 F. L. Scott and C. V. Murphy, Tetrahedron Letters, 1970, 1731. *lo C. J. Pedersen, J. Org. Chem., 1971, 36, 1690. 317 E. Kynchev and D. Nikolov, Khim. Ind. (Sofia), 1971, 43, 107. A. Kobayashi, S. Umemoto, and M. Kato, Yakugaku Zasshi, 1970,90, 1377. H. Zinner and K. Peseke, J. prakt. Chem., 1970, 312, 185. s20 G. Zigeuner, A. Frank, H. Dujmovits, and W. Adam, Monatsh., 1970, 101, 1415; G. Zigeuner, H. Brunetti, H. Ziegler, and M. Bayer, ibid., p. 1767; G . Zigeuner, A. Frank, and W. Adam, ibid., p. 1788; G. Zigeuner, G. Duesberg, E. Fuchs, and F. Paltauf, ibid., p. 1794; G . Zigeuner, H. Schmidt, and D. Volpe, ibid., p. 1824; G . Zigeuner, C. Knopp, and A. Fuchsgruber, ibid., p. 1827. K. Lempert and P. Gyulai, Tetrahedron, 1970, 26, 3443. T. Ueda and S. Shibuya, Chem. andPhmm. Bull. (Japan), 1970,18,1076; T . Ueda and H. Tanaka, ibid., p. 1491. 323 B. V. Unkovskii and L. A. Ignatova, Khim. geterotsikl. Soedinenii, 1969, 896; B. V. Unkovskii, L. A. Ignatova, P, L. Ovechkin, and A. I. Vinogradova, ibid., 1970, 1690. 824 M. Calligaris, S. Fabrissin, M. de Nardo, and C. Nisi, J. Org. Chem., 1971,36, 602. a25 A. W. Spassow and Z. D. Raikow, Z. Chem., 1971,11,260. 82e M. S. Chande, Indian J. Chem., 1970, 8, 697. 318

244 Organic Compounds of Sulphur, Selenium, and Tellurium between isothiocyanates and hydrazines. Well known in principle, this reaction has nevertheless been the subject of much recent research, mainly because the products constitute valuable starting material for the synthesis of a variety of heterocyclic compounds. On this basis, Kurzer prepared the thiosemicarbazides (208) by the reaction of aroyl isothiocyanates with carbonohydra~ides,~~~" thiocarbon~hydrazides,~~~~ a ~ n i n o g u a n i d i n e sand ,~~~~ Ar-CO-NH-CS-NH-NH-X (208) X = CO-NHR, CS*NHR, C(:NH)-NH,, or C(: NH) *NH NH2

X-NH-CS-NH-NH-Y (209) X = Ph2P0, Y = R (210) X = R, Y = Ph2PO

d i a m i n o g ~ a n i d i n e s . ~Jahns ~ ~ ~ prepared 328 isomeric diphenylphosphinyl thiosemicarbazides (209) and (210) using diphenylphosphinyl isothiocyanate and diphenylphosphinylhydrazine,respectively, as the appropriate reactants. The same author also found32Qthat the reaction between diphenylphosphinylhydrazine and acyl isothiocyanates affords the desired thiosemicarbazides only when the electrophilicity of the carbonyl group of the acyl isothiocyanate is adequately reduced as, for example, is effected by conjugation with other multiple bonds present in the acyl group. The utility of the method in question has been demonstrated further by the successful syntheses of thiosemicarbazides containing at their 1-position the 2-hydroxy-4-alkoxybenzoy1,330 the 0xamy1,~~l the 2-(benzoy1amino)~ i n n a r n o y lor , ~ the ~ ~ 1-naphthylacetyl gr0up.~3~ Thiosemicarbazides that are not substituted at the 4-position have been obtained by the action of ammonium r h ~ d a n i d e ,334 ~ ~ or ~ * potassium rhodanide in the presence of hydrochloric on hydrazines. A thiosemicarbazide of the type (210) was the only product obtained by the treatment of a 4-substituted thiosemicarbazide with diphenylphosphinyl chloride.328 The acid-catalysed reaction of phenyl isothiocyanate with butyraldazine has been reported33s to give the compound (211). The reaction was interpreted in terms of a two-stage process, the first stage being the ringclosure isomerization of butyraldazine to (212) which then, in the second stage, reacts with the isothiocyanate in a normal manner.33s The action of salicyloylhydrazide on 2-(o-hydroxypheny1)-A2-1,3,4-0xadiazoline-5-thione 83'

F. Kurzer, J. Chem. SOC.(C), (a) 1971,2927; (b) 1971,2932; (c) 1970, 1805; ( d ) 1970, 1813.

828 a2s

8tl

ssa 3ss

H.-J. Jahns, 2.Chem., 1970, la, 435. H.-J. Jahns, 2. Chem., 1970, 10, 465. J. Soare and V. Zotta, Farmaciu (Bucharest), 1970, 18, 461. M, Pesson and M. Antoine, Bull. SOC.chim. France, 1970, 1590. C. Demetresco and V. Manu, Chim. Ther., 1971, 6, 18. E. Comanita and M. Tutoveanu, Bul. Znst. Politeh. Zasi, 1969, 15, 89. H. Reimlinger, J. J. M. VandewaUe, and W. R. F. Lingier, Chem. Ber., 1970, 103, 1960.

as6 386

I. S. Ioffe, A. B. Tomchin, and E. N. Zhukova, Zhur. org. Khim., 1971,7, 173. L. Zirngibl and S. W. Tam, Helv. Chim. Acta, 1970, 53, 1927.


245

(213) afforded 337 the open-chain thiocarbohydrazide (214), alternatively synthesized by the reaction of salicyloylhydrazidewith carbon d i s ~ l p h i d e . ~ ~ ~ 3,SDisubstituted 2-imino-l,3,4-oxadiazolines (215 ) yielded 1,2,4-triazoline3-thiones (216) on treatment with ammonium hydrogen s ~ l p h i d e .The ~~~ K2

R

/

/

N-N. Et (211) R = CS*NHPh (212) R = H

(213) R1 = o-HO*C6H4;

R2 = H ;

x=s

(215) X = NH

(O-HO C6H4*C 0 . N H.N H *)&S

K2

I

N-N

/

assumption concerning the thiosemicarbazide (217) as an intermediate in this reaction was supported by the fact that l-benzoyl-2-phenylthiosemicarbazide (217; R1 = R2 = Ph), obtained by benzoylation of 2-phenylthiosemicarba~ide,~~~ easily cyclized in basic medium to (216; R1 = R2 = Ph).338 Several recent papers deal with the synthesis of heterocyclic thiones containing the thiosemicarbazide or the thiocarbohydrazide r n ~ i e t y . ~ 33g-343 ~~~ Among these are two interesting papers describing the acid-promoted rearrangement of 2-hydrazino-l,3,4-thiadiazolesto 4-amino-l,2,4-triazoline-3(2N)-thiones 342 and the synthesis of 1-amino-3,4-dihydro2(1H)-pyrimidinethiones (188; R3 = NR1R2) by the reaction of ketones containing an unsubstituted a-methylene group with hydrazines and trimethylsilyl isothiocyanate (compare ref. 243),343respectively. Kiwan and Irving have recently described 344 the heterolytic scission of bis-l,5-diphenylformazan-3-yl disulphide (218), resulting in the formation of the compounds (219) and (220). Two papers 345, 846 dealing with metal complexes of thiosemicarbazides may be of interest to workers in this field. 3363

ss7 338

340

s41 342

s43

34d

Z. Brzozowski, Roczniki Chem., 1970,44, 1309. H. Gehlen and P. Demin, 2.Chern., 1970,10, 189. J. Daunis, K. Diebel, R. Jacquier, and P. Viallefont, Bull. SOC.chim. France, 1970,1606. A. Mustafa, A. H. Harhash, M. H. Elnagdi, and F. A. EI-All, Annalen, 1971,748, 79. G. Wagner and S. Leistner, 2.Chem., 1971, 11, 65. J. Sandstrom, 2.Chem., 1970, 10, 406. R. Neidlein and H. G. Hege, Tetrahedron Letters, 1971, 1299. A. M. Kiwan and H. M. N. H. Irving, Chem. Comm., 1970, 928; J. Chem. SOC.(B), 1971, 901. S. 0. Ajayi and D. R. Goddard, J. Chem. SOC.(A), 1971,2673. S . N. Poddar, K. Dey, and N. G. Podder, Indian J. Chem., 1970, 8, 364.

246

Organic Compounds of Sulphur, Selenium, and Tellurium N=N Ph PhN=N, /

k- s - s -c’\\

PhNH-N

4

N-NHPh

(218)

PhN=N

\

FSH PhNH-N

-s EtOZC-NH-SO2-OCHMe2

Et02C-N-Sb2

0 2

as the triethylamine complex of N-sulphonyl ethyl carbamate. The zwitterion reacted with aniline, isopropyl alcohol, and with tetramethylallene. The mechanism of these reactions may be accounted for on the basis of the zwitterion or the N-sulphonylamine. N-Sulphinyl-amines were briefly mentioned in the review by Roesky.g The conversion of sulphinyl-amines into sulphurdi-imides with the extrusion of sulphur dioxide in the presence of base has been fully documented as a useful synthetic procedure.lQs High-temperature pyrolysis of thionylaniline afforded products which appeared to arise from phenylnitrene.lQ7 Sulphinyl-amines can be prepared by an exchange reaction with the readily available N-sulphinyl-tosylamide, the sulphinyl group moving to the most basic amine function.lQs Thus, (124a) afforded the sulphinylaniline, whereas (124b) gave the sulphinylhydrazide. Sulphinyl-amines undergo addition with acidic substances, HA, to afford 1 : 1 adducts of the type R-NH-S02-A. Thus, reaction with ethanol, which was observed to be catalysed by CuCl,, afforded lB4 lg5 lg6

M. Haake, Angew. Chem. Internat. Edn., 1970, 9, 373. G. M. Atkins and E. M. Burgess, J. Amer. Chem. SOC.,1968, 90, 4744. H. H. Horhold and J. Beck, J. prakt. Chem., 1969,311, 621. C. Wentrup, Tetrahedron, 1971, 27, 1027. H. Grill and G. Kresze, Annalen, 1971, 749, 171.

YIides of Sulphur, Selenium, and Tellurium, and Related Structures

aNH2am, X-NH2

+ TsN=S=O

337

N=S=O

+ (a)

X = -CO(124b) X = -CONH-

(124a)

R-NH-S02Et.1aa When the acidic reagent carries a functional group with an oxygen atom which can be lost, SO2 generally is extruded during the reaction. Thus, a reaction with carboxylic acids afforded carboxyl sulphonyl imides,200probably via an intermediate such as (1 25).

H

R2SOZ-N=S=0

+ R'C02H

--+ R2S0,NHCORl

+

S%

Thionylaniline reacted with diphenyldiazomethane under photochemical conditions to afford triphenylketimine via, it was proposed, addition of diphenylcarbene to the sulphinyl group and then extrusion of SO (Scheme 4).201The presence of tetraphenylethylene and other fragments Ph,CNz

Arc=

+ PhNSO

-

PhN=CPh,

&- 6 3- PhNSO

ArN=C=NPh

+

SQ2

Scheme 4

lent support to the carbene proposal. Aryl nitrile oxides also added to sulphinyl-amines, again across the N=S bond, eventually to afford a carbodi-imide (Scheme 4).202 A kinetic study of this reaction showed that it was first-order in each component, the rates of reactant consumption and product formation were equal, there was no major solvent effect, electron-withdrawing groups on the sulphinyl amine accelerated the reaction, the energy of activation was 11-14 kcal mol-l, and the entropy of activation was - 28 to - 37 e.u. It was concluded that the reaction lgS 201 202

N. C. Collins and W. K. Glass, J . Chem. Soc. (B), 1971,2156. F. Bentz and G. E. Nischk, Angew. Chem. Internat. Edn., 1970,9,66. J. 0. Stoffer and H. R. Musser, Chem. Comm., 1970, 481. P. Beltrame and C. Vintani, J. Chem. Soc. (B), 1970, 873.

338 Organic Compounds of Sulphur, Selenium, and Tellurium was a concerted cycloaddition but with a somewhat uneven development of charge at the four bonding sites. At - 30°C N-sulphinyltosyl amide adds to ethoxyethylene to give a 1 : 1 mixture of the cis- and trans-adducts (126).203The cis-isomer appeared to be the more stable because at 20°C, in the presence of 2,3-dimethylbutadiene to trap any released sulphinylamide, the mixture of the two Ts

EtOCH=CH,

+

TsN= S=O

isomers afforded 62% of the cis-isomer and 38% of the adduct between N-sulphinyltosylamide and 2,3-dimeth ylbutadiene. When cis-1-ethoxypropene was used in the initial addition and the adduct allowed to reverse, > 90% of the olefin isolated had the same stereochemistry as the starting material. The adduct from phenoxyethylene, formed in a cis : trans ratio of 2.5, would not undergo reversaL203 N-Sulphinylacetamide added to 2,3-dimethylbutadiene using the N= S bond, but with norbornene a 1,4-addition occurred; normal additions occurred with N-sulphinylcyanamide and with disulphinyloxamide (Scheme 5).204 MeCONSO

+

\

-

J-$fCOMe

kO

MeCONSO

Me

CO-NSO I CO-NSO

Scheme 5 203 204

W. Wucherpfennig, Tetrahedron Letters, 1971, 1891. 0. J. Scherer and R. Schmitt, Chem. Ber., 1968, 101, 3302.

Ylides of Sulphur, Selenium, and Tellurium, and Related Structures

339 Thionylaniline reacted with ethylene oxide at low temperatures to afford the oxathiazolidine (127), which was converted into a piperazine (128) at 160 0C.20sThe same workers also studied the stereochemistry of the products formed in a similar reaction using propylene oxide.2o6A similar 0

t

W

H2C-CH2

PhNSO

-

+ PhT

k

Ph-NwN-Ph

+

Ph-N 5

- m

v

Ph reaction with styrene oxide afforded only the two piperazines, probably because the reaction temperature was 120 O C 2 0 7 The mechanism of these reactions was proposed to involve first the attack of the sulphinyl group on the oxiran oxygen atom, resulting in the formation of a zwitterion which closed to form an oxathiazolidine, the isolated first product in some instances. Heating was proposed to result in the loss of SO2, with the new zwitterion undergoing dimerization (head-to-head or head-to-tail) to form the pipera~ine(s).~~~ Thionylbenzamide reacted with styrene oxide to afford different products, but they could be accounted for by the same overall mechanism, any differences being due to the presence of the reactive benzoyl group.2o8 Using the same CND0/2 calculations as applied to the sulphurdi-imides, Grunwell and Danison170have carried out calculations of the geometry of sulphinyl-amines,including 3d orbitals in the basis set. They concluded that the trans conformation about the N=S bond was the more stable. Ph

10 Ylides of Selenium and Tellurium Freeman and Lloyd applied their now standard method to prepare diphenyltelluronium-2,3,4,5-tetraphenylcyclopentadienide(1 29).209 This first tellurium ylide was very weakly basic and would not undergo the typical ylide reactions with p-nitrobenzaldehyde or nitrosobenzene. By application of the Horner method,210developed originally for the preparation of stabilized phosphonium ylides, Ernstbrunner and Lloyd %06

206

208

210

211

F. Yamada, T. Nishiyama, M. Kinugasa, and M. Nakatani, Bull. Chem. SOC.Japan, 1970, 43, 3611. T. Nishiyama and F. Yamada, Bull. Chem. SOC.Japan, 1971, 44, 3073. 0. Tsuge and S. Mataka, Bull. Chem. SOC.Japan, 1971, 44, 1896. 0. Tsuge and S. Mataka, Bull. Chem. SOC.Japan, 1971, 44, 2836. B. H. Freeman and D. Lloyd, Chem. Comm., 1970,924. L. Horner and H. Oediger, Chem. Ber., 1958,91,437. E . Ernstbrunner and D. Lloyd, Annalen, 1971,753, 196.

340

Organic Compounds of Sulphur, Selenium, and Tellurium Ph Ph

PhTe

f

D N z

Ph Ph

Ph Ph p T e P h 2

Ph Ph (129)

prepared the highly stabilized selenium ylide (130) from Meldrum’s acid. Delocalization of the negative charge of the ylide carbanion through the two carbonyl groups was evidenced by the virtual identity of the i.r. absorption for the ylide carbonyl groups and that for the sodium salt of Meldrum’s acid. The ylide was insoluble in water but dissolved upon the addition of dilute acid. The ylide did not react with p-nitrobenzaldehyde, but this experiment cannot be taken as conclusive evidence for the absence of normal ylide characteristics.

6 Heterocyclic Compounds of Quad ticovalent Sulphur BY D. H. REID

1 Introduction Less work has been reported in this area during the past two years. The majority of papers have been concerned with thiabenzenes and nitrogencontaining derivatives. 6a-Thiathiophthens and related compounds are accorded separate treatment (Chapter 8) in view of the volume of published work on this subject. 2 Thiabenzenes Further attempts have been made to prepare stable l-substituted 2,4,6triarylthiabenzenes. Previously it had been shown l, that 1,2,4,6-tetraphenylthiabenzene (1) is unstable to heat, light, and oxygen, this instability being attributed to steric effects arising from overcrowding of substituents at positions 2, 1, and 6 (see ref. 2). In order to alleviate the Ph

Ph

PhQPh

I

I

C

Ph

111 C

(1)

I

steric problem but retain the conjugation of the l-substituent which is apparently necessary for the stability of the thiabenzene system, 2,4,6triphenylthiapyrylium perchlorate was allowed to react with phenylethynyll i t h i ~ m .It ~ was inferred from the colour of the solution that l-phenylethynyl-2,4,6-triphenylthiabenzene(2) had been formed but attempted isolation gave a mixture (n.m.r.) of the thiopyrans (3) and (4), from which G. Suld and C. C. Price, J. Arner. Chem. Soc., 1961, 83, 1770; 1962, 84,2094. ‘Organic Compounds of Sulphur, Selenium, and Tellurium’, ed. D. H. Reid (Specialist Periodical Reports), The Chemical Society, London, 1970, Vol. 1, p. 309. C. C. Price, J. Follweiler, H. Pirelahi, and M. Siskin, J. Org. Chem., 1971, 36, 791.

341

342 Organic Compounds of Sulphur, Selenium, and Tellurium the former compound was isolated. The rearrangement of the presumed intermediate (2) into compounds (3) and (4) recalls2 the behaviour of the thiabenzene (1). The isomeric thiabenzenes ( 5 ) and (6), prepared by established procedures, have properties and show chemical behaviour

similar to that of 1,2,4,6-tetraphenylthiabenzene(1). Reaction of 2,4,6triphenylthiapyrylium perchlorate with p-dimethylaminophenyl-lithium gave the considerably more stable thiabenzene (7). This compound Ph

+? p

Phn

0 NMe,

NMe,

Ph

Ph

h

Heterocyclic Compounds of Quadricovalent Sulphur

343

reacted slowly with oxygen and subsequently with acid to give a mixture of the zwitterion (8) and the thiol(9) (isolated as its disulphide). Formation of the thiol (9) establishes that p-dimethylaminophenyl-lithiumhad reacted SH

+

v

NMe, (9)

at the sulphur atom in the thiapyrylium salt. It had earlier been suggested that 1,2,4,6-tetraphenylthiabenzene(1) is best represented by a model (Figure 1) involving bent geometry at the sulphur atom, which uses its 3d,, orbital for cyclic conjugation. The relatively high dipole moment for

V

Figure 1 Proposed bonding model for 1,2,4,6-tetraphenyIthiabenzene. SuZphur atom uses d,, orbital for conjugation

thiabenzene (1) was taken as indicative of greater ylide character for this compound compared with other thiabenzenes, for example l-phenyl-lthianaphthalene. The greater stability of the thiabenzene (7) then comes from delocalization of the positive charge on sulphur, as depicted by structures (7a)-(7c). A novel approach to thiabenzenes has been developed in the course of attempts to synthesize l-alkylthiabenzenes. Reduction of the known thiabenzene 1-oxide (10) with trichlorosilane gave a mixture of the thiopyrans (11) and (12), from which the 2H-isomer (11) was isolated and methylated with MeI-AgBF,. Deprotonation of the resulting sulphonium salt (13) with t-butyl-lithium in pentane-DMSO gave an orange solution of the thiabenzene (14), which regenerated the salt (13) when treated with fluoroboric acid. The thiabenzene decomposed upon attempted isolation. 6v

a

7

C. C. Price, M. Hori, T. Parasaran, and M. Polk, J. Amer. Chem. Soc., 1963,85,2278. A. G. Hortmann and R. L. Harris, J. Amer. Chem. SOC., 1970,92, 1803. A. G. Hortmann, J. Amer. Chem. SOC.,1965, 87,4972. T. M. Harris, C. M. Harris, and J. C. Cleary, Tetrahedron Letters, 1968, 1427.

344


86.18

I Me 8t73

(14)

A notable feature of the lH n.m.r. spectrum of the thiabenzene (14), prepared in situ in [2H6]DMS0,is the high-field resonance of 2-H, 4-H, and 6-H. Addition of CD,COOD to the thiabenzene in [2HB]DMS0 caused rapid H-D exchange at positions 2, 4, and 6, giving the deuteriated salt (15). Addition of a limited amount of deuterium oxide to a solution

D Me

x-

83.00

(1 5 )

of the thiabenzene in [2H6]DMS0 resulted in slow H-D exchange at positions 2, 4, and 6, and 2-H and 6-H exchanged more rapidly than 4-H. The pronounced carbanionic character of positions 2, 4, and 6 and the high shielding of protons at these positions led to the conclusion that ylide-type bonding occurs in thiabenzenes. These results were also taken to cast doubt on the recent claim to the synthesis of l-phenylthiabenzene, for which all ring protons resonate at 67.2 p.p.m. A significant observation was that base-catalysed exchange of the S-methyl protons occurs before reaction of the salt (13) with base, leading to the thiabenzene (14), is complete. The lack of evidence for a ring-current in the thiabenzene (14) is regarded as supporting a bonding scheme of the type suggested by Dewar for the phosphonitrilic halides. Thus in thiabenzenes two orthogonal and non-conducting hybrid d-orbitals on positively charged sulphonium sulphur overlap weakly with the ends of the n-system of the remaining pentadienyl carbanion. M. Polk, M. Siskin, and C. C. Price, J. Amer. Chem. SOC.,1969, 91, 1206.


345

3 Thiabenzene l-Oxides Full details have appearede of the synthesis of thiabenzene l-oxides from the reaction of acetylenic ketones with dimethyloxosulphonium methylide (Scheme 1), following a preliminary account.6 By working at low temperatures with THF-DMSO solutions, intermediate allylides (22)-(24) could

CH2=SMe2

It

0 (16) R' = R2 = Ph (17) R1 = Me, R2 = Ph

(18) R1 = Ph, R2 = But (19) R1 = R2 = Me (20) R1 = R2 = Et (21) K1 = Ph, Ra = Me Reagent: i, DMSO, room temperature

Scheme 1

R1 COR2

Yx

Me-S=CH

I

H

Me (22) R1 = R2 = Ph (23) R1 = Me, R2 = Ph (24) R1 = Ph, R2 = But

be isolated. Compounds (23) and (24) were subsequently cyclized to the thiabenzene 1-oxides (17) and (18) on being heated in chloroform or ethanolic sodium ethoxide. Thiabenzene l-oxides are stable to oxygen and do not react with methyl iodide or acetyl chloride. The oxide (16) decomposed when treated with lithium aluminium hydride, and when hydrogenated over palladium gave a product believed to have structure (25). The S-methyl group is acidic, however, and base-catalysed H-D

(25)

exchange is complete in MeOD-D,O-NaOD solution. The acidity of the S-methyl group allows other S-alkylthiabenzene l-oxides to be prepared (Scheme 2). In contrast to the S-alkyl protons, which undergo bases A. G. Hortmann and R. L. Harris, J. Amer. Chem. SOC.,1971,93,2471.

346


>

>

/N

I\

Et 0

Me 0 Reagents: i, BuLi; ii, Me1

Scheme 2

catalysed H-D exchange but are stable to acid, the ring protons of thiabenzene 1-oxides are immobile in the presence of base but undergo acid-catalysed exchange. Exchange is sufficiently slow in CDCI3-CD3COOD solution to allow the process to be followed by lH n.m.r. spectroscopy. A study of compound (16) reveals that 2-H and 6-H exchange more rapidly than 4-H, recalling the behaviour of the thiabenzene (14).5 These results suggest that in acid solution thiabenzene 1-oxides are in equilibrium with protonated species, the latter in low concentration (Scheme 3). The

Scheme 3

proton resonances of 2-H and 6-H in the thiabenzene 1-oxides (16)--(20) (see Table) are well outside the aromatic region and are markedly upfield of Table Chemical shuts (8) in the lH n.m.r. spectra of the thiabenzene 1oxides (16)-(20). Solutions in CDCls; TMS as internal reference Compound (16) (17) (1 8) (19) (20)

2-H,6-H 5.83 5.28, 5.47 5.23, 5.79 5.30 5.18

CH,=CH.SMe CH,=CH.SO,Me PhCH=CH.SOMe"

4-H 6.26 5.67 5.91 5.47 5.32

S-Me 3.50 3.33 3.44 3.45 3.32

86.43 86.70 86.91 or 7.20

Neat liquid.

the range for olefinic protons on sp2 carbon adjacent to a sulphur atom, The 4-H proton resonances, although in the olefinic region, have shifts sufficiently far upfield to suggest that no ring-current effects are operative in thiabenzene 1-oxides. The combined H-D exchange and lH n.m.r. spectral studies indicate that C-2, C-6, and C-4 have high electron densities

347


and are carbanionic in character. The greater shielding at C-2 and (2-6 indicates more carbanionic character at these sites than at C-4. Thiabenzene 1-oxides are accordingly viewed as cyclic sulphonium ylides in which the carbons at the termini of a pentadienyl carbanion form weak 2pv-3dv bonds with the a-bonded sulphur. The results of lSCn.m.r. studies provide evidence for the presence of a pentadienyl carbanionic system. S Values, exemplified by those in formula (26) for compound (16) (CHC13 solution;

+

relative to CS2, based on Sm, = ~ C H C I , 115.2 p.p.m.), indicate high shielding of C-2 and C-6 and moderate shielding of (2-4. (For comparison, 13C shifts for olefinic compounds occur in the range 647-70p.p.m. and for benzenoid compounds at ca. 665p.p.m.) It is concluded that the ylide-type bonding system in thiabenzene 1-oxides is best represented by Dewar’s scheme for pv-dm bonding in which six .rr-electronsare distributed in a seven-orbital system. Two of these are orthogonal hybrid orbitals on sulphur which do not permit through conjugation at the sulphur atom. There is thus no possibility of a significant ring-current effect. The U.V. spectra of thiabenzene 1-oxides moreover do not resemble those of heteroaromatic systems. 4 Azathiabenzenes Cram and his co-workers1° have developed a new general synthesis of heterocyclic systems containing the sulphoximine function as part of a ring. Compounds described include 2-aza- and 2,4-diaza-thiabenzenes (1,2thiazines and 1,2,dthiadiazines, respectively). The synthesis of the 2-azathiabenzene 1-oxides (29) and (30) (Scheme 4) resembles that of

(27) R = p-MeC,H, (28) R = Me Reagent: i, NaH-DMSO

(29) R (30) R

= p-MeC,H,; = Me; 4-H at

4-H at 85.90 p.p.m. 66.10 p.p.m.

Scheme 4 lo

T. R. Williams and D. J. Cram, J. Amer. Chem. SOC.,1971, 93, 7333.

OSM'

Me\

0"""

i, ii

CH2C02H

Me\

COMe

iv

Me\ O S OCH2C02H M e (3 1) Reagents: i, S-morpholine; ii, HaO+ or OH-; iii, NaIO,; iv, NaNS-H,S06 Scheme 5

i

OoMe

Me\

COMe

(34) Reagents: i, NaIO4; ii, NaNa-H$04; iii, 10% NaOH; iv, HC1-MeC0,H; v, (COaMe),, 170 "C;vi, H,O+; vii, Di-NN'-imidazolyl ketone; viii, HCOaH

Scheme 6


349

thiabenzene 1-oxides from dimethyloxosulphonium methylides and acetylenic ketones, the sulphoximines (27) and (28) replacing dimethyloxosulphonium methylide. The 2-azathiabenzene derivative (31) was obtained by the sequence of reactions in Scheme 5. Several 2,4-diazathiabenzene 1oxides (32)-(36) were synthesized by the reactions shown in Scheme 6. Although heterocycles (29), (30), and (36) formally contain a T-electron sextet, the lH n.m.r. chemical shifts (CDCl,) show that their ring protons are much more shielded than the corresponding protons of configurationally similar heteroaromatic compounds. For comparison, 2-H of quinazoline resonates ( C D Q ) at 89.29 p.p.m. It appears therefore that ring-curren effects do not operate significantly in 2-aza- and 2,4-diaza-thiabenzene 1 oxides. An X-ray diffraction study l1 of the tricyclic 4-azathiabenzene (37) shows that the zwitterionic structure depicted (Figure 2) is the main

-

Me

contributor. The sulphur atom has a pyramidal configuration. The C-S length of 1.765 A agrees well with the average value (1.76 A) for C(sp2)-S bonds. The shorter C-S distance (1.72 A) compares satisfactorily with the analogous polarized C=S bond in ethylenethiourea.

o1.2101

Me

I1.803

I

Me Figure 2 Molecular dimensions of the 1,4-thiazine (37)

5 Four- and Five-membered Ring Compounds Sulphoximines have also been employed for the synthesislo of four- and five-membered ring structures containing the sulphoximine unit (Scheme 7). The /3-lactam (38) shows an abnormally low C=O stretching frequency (1690 cm-l), attributed to the contribution of a dipolar structure +S-N=C-0-, or to an expanded N-C-C bond angle, or both. The isothiazole derivative (39) exists in the enolic form; its U.V. spectrum is l1

1. P. Schaefer and L. R. Reed, J. Amer. Chem. SOC.,1972, 94, 908.


3 50

1

vii

(40) Reagents: i, BuLi; ii, COz; iii, H90+;iv, NaH; v, BrCH,C02Et; vi, NaH; vii, CH,N,MeOH

Scheme 7

0""'

Me\

i, ii,

COMe

0"""'

Me\

COaH

1 iii

Reagents: i, Br,-KOH; ii, H90+;iii, NaNB-HBSO,

Scheme 8


351 similar to that of the ether (40). A synthesis similar to that employed for the preparation of the 2-azathiabenzene 1-oxide (31) was employed lo for the synthesis of the isothiazole (41) (Scheme 8). Independently, in a similar approach, other workers l2 converted the sulphinobenzoates (42)-(44) into the corresponding isothiazoles (45)-(47) by reaction with sodium azide in polyphosphoric acid.

eN R1 0

R2\ O S OC0,Me R 1 (42) Rf = Me, R2 = R3 = H (43) R1 = Me, R2 = C1, R3 = H (44) R1 = Me,R2 = R3 = CI l2

R2\

0

(45) R1 = Me,R2 = R3 = H (46) R1 = Me, R2 = CI, RZ = H (47) R1 = Me, R2 R.3 = C1

P. Stoss and G . Satzinger, Angew. Chem., 1971, 83, 83.

5

7 Thiophens and their Selenium and Tellurium Analogues BY S. GRONOWITZ

1 General This Report covers the period April 1969-March 1972. Attempts have been made to make it as comprehensive as possible. However, Russian papers have been read in their English translations, which means that some older work has also been included. Finally, the English translation of Khim. geterotsikl. Soedinenii for the past two years has not been available to the present author, and thus thiophen work published in this journal is treated somewhat summarily, for which the author apologizes. Certain trends in the development of the chemistry of thiophens are clearly noticeable during this period of time and important results have been achieved. Quantitative studies on the rates of electrophilic substitution of thiophens and the other five-membered heterocyclics with one heteroatom, mainly by Marino and co-workers in Perugia, have greatly increased our knowledge of the differences in reactivity of the five-membered heterocyclics. The relative rates of attack at the a- and /I-positions, the effect of benzo-fusion, and the effects of substituents in general on isomer distribution in thiophens are now better understood. Successful attempts have been made to put substituent effects on chemical and physical properties on a more quantitative basis in the thiophen series by the application of Hammett-type equations. Through work at Lund during this period and the years before, the tautomeric properties of the hydroxythiophen systems have been elucidated and the chemical reactions of these systems have been studied. Thienyl-lithium derivatives have maintained their position as key intermediates for the synthesis of thiophen derivatives. Their synthetic usefulness has been increased by conversion into thienylcopper compounds, and ring-opening of certain 3-thienyl-lithium derivatives has given a completely new synthetic aspect to these intermediates. The usefulness of the thiophen derivatives as ideal models for the study of n.m.r. spectral properties was further demonstrated by l9F n.m.r. investigations of fluorothiophens, a class of compounds which became easily available during the review period. Through the excellent work of Wynberg and his co-workers the interesting photochemical rearrangements of thiophens have been elucidated. 352

Thiophens and their Selenium and Tellurium Analogues

353

Gol’dfarb’s group in Moscow is continuing to demonstrate the usefulness of Raney-nickel desulphurization of thiophens for the synthesis of aliphatic and, especially, macrocyclic compounds. The isosteric properties of benzene and thiophen are, to an increasing extent, attracting the interest of medicinal chemists, and some marked successes have occurred during the period of this review. In the selenophen field, research has somewhat slackened, owing to the death of Yur’ev at Moscow University, whose group for many years carried out extensive work in this field. However, it has become evident that the differences between thiophen and selenophen are in many respects greater than hitherto believed, although it is still true that selenophen is the fivemembered heterocycle most similar to thiophen. Detailed reports on the synthesis of tellurophen and simple derivatives and on their spectroscopic properties have appeared. The progress in the field of fused thiophens has perhaps been even larger than with the monocyclic systems. British research groups especially have extensively contributed to an increase in our understanding of the electrophilic substitution of benzo[b]thiophen and its substituted derivatives. There has been great interest in the effect of annelation of different aromatic rings on the b-side and c-side of thiophens. Thus the synthesis, chemistry, and spectroscopic properties of all thiophen analogues of fluorene have attracted the interest of Wynberg’s, MacDowell’s, and the author’s research groups. Another example is the work on the thiophen analogues of isoquinoline, which during the past 3-4 years has been carried out in two different laboratories in the United States, and in Belgium and Sweden. Much interesting work has also been carried out on analogues of phenanthrene and anthracene. Especially important is Wynberg’s stereochemical work on the heterohelicenes, which again illustratcs the fact that thiophen offers many advantages over benzene for the study of chemical or physical properties of theoretical interest, owing to more facile synthesis and simpler interpretation. 2 Monocyclic Thiophens Syntheses of Thiophens by Ring-closure Reactions.-The base-catalysed reaction between 3-amino-substituted dithioacrylate esters or amides (l), which are easily available from trithione, and a-halogenocarbonyl compounds yields 2,5-disubstituted thiophens (2).l The same is true for

l

E. J. Smutny, J. Amer. Chem. SOC.,1969, 91, 208. 13

354


vinylogous thi0amides.l" It is suggested that the reaction proceeds via the sulphur ylide (3). It has been found that 2-nitroethylenedithiolates(4) react with a-halogeno-aldehydesand -ketones to form (5), which at pH > 7 yields the 3-nitrothiophen-2-thiol (6), isolated as the disulphide or the

(4)

(5)

(6)

methylthio-derivative.2 The cyclization can be visualized as an electrophilic attack of the carbonyl carbon atom on the C-2 atom of the nitroethylene1,l-dithiolate. Under alkaline conditions, ethylene-1,l-dithiolates with electron-attracting groups such as cyano on C-2, easily obtained from active methylene compounds and carbon disulphide, yield 2-acylthiophens by the reaction between the active methylene group situated between the sulphur and the oxo-group and one of the electron-attracting 2-substituents in the original dithi~late.~,The base-catalysed reaction between isothiocyanates and derivatives of cyanoacetic acids yields (7),which with a-halogenomethyl ketones, via the assumed intermediate (8), gives 5-acyl-2,4-diaminothiophen-3-carboxylic acid derivatives (9) or thiazoline-A2u-aceticacid Z-R2

0 II

/

OC, ,NHR1 NC/C=C'S-

Z=NHorO

NC,

,C-Z-R2

C II

0 II R3-C-CHz,

,C,

S

NHRl

derivatives 6 a Reaction temperature and substituents have a pronounced influence on the course of the reaction. A somewhat similar thiophen synthesis was discovered in the reaction between the 1 : 1 adducts (1 1) of p-iminocarbonyl derivatives with organic isothiocyanates and phenacyl bromide, in which base-catalysis is not necessary, yielding the tetrasubstituted thiophen (13),6 via the assumed intermediate (12). The la

*

J.-C. Meslin and H. Quiniou, Compt. rend., 1971, 273, C, 148. L. Henriksen and H. Autrup, Acta Chem. Scand., 1970, 24,2629. R. Gompper, E. Kutter, and W. Topfl, Annulen, 1962, 659, 90. (a) K. A. Jensen and L. Henriksen, Acta Chem. Scand., 1968,22, 1107; (b) T. Liljefors and J. Sandstrom, ibid., 1970, 24, 3109. R. LalibertC and G. MCdawar, Canad. J. Chem., 1970, 48, 2709. R. LalibertC and G. Medawar, Canad. J. Chem., 1971, 49, 1372. S. Rajappa and B. G. Advani, Tetrahedron Letters, 1969, 5067.


355

NIIB

NHZ

1 ,CO,R Me-C=C, C-NHCOPh

/I , C a R Mc-C-C Ph,,C=HC, ,&-NHCOPh HO

S

adduct (14), on the other hand, yielded the thiazolone derivative (15). Another new thiophen synthesis based on the same principles as described above starts from monothio-/3-diketones (16), which recently have become easily available. The triethylamine-catalysed reaction with a-halogenocarbonyl compounds such as phenacyl bromide yields (17), which upon treatment with a stronger base such as sodium ethoxide gives the thiophen

(18).' The reaction of dithio-esters (19) with bromoalkynes in the presence of potassium amide in liquid ammonia yields the keten dithioacetal (20), which upon heating undergoes an electrocyclic rearrangement to the allenic dithio-esters (21). Acid-catalysed or strongly base-catalysed cyclization yields the thiophen derivatives (22), whereas weak bases yield the 2Hthiopyran (23). The Gewald synthesis of 2-aminothiophen-3-carboxylicacid derivatives has been extended to cyanoacetic acid hydrazides. In the base-catalysed reaction with cyclohexanone and sulphur, the hydrazides yielded the thienopyrimidone derivative (24), which could be hydrolysed to the 2-aminothiophen-3-carboxylicacid hydrazide (24a).lo A series of substituted 2-aminothiophen-3-carboxylicesters have been prepared by a a lo

M. Takaku, Y. Hayasi, and H. Nozaki, Bull. Chem. SOC.Japan, 1970,43, 1917. P. J. W. Schuijl, H. J. T. Bos, and L. Brandsma, Rec. Trav. chim., 1969, 88, 597. D. Schuijl-Laros, P. J. W. Schuijl, and L. Brandsma, Rec. Trav. chim.,1969,88,1343. K. Gewald and I. Hofmann, J. prakt. Chem., 1969, 311,402.

356

Organic Compounds of Sulphur, Selenium, and Tellurium ,S-CH,-C-CR' R*CH=C, SEt

R CH2- C,4 s SEt

(19) R2 R1

I

I

H,C=C=C-CH-C< (21)

,s SEt

EtS J f 1 R

modification of the Gewald method, the alkylidene esters derived from ketones and cyanoacetic esters reacting with sulphur in the presence of catalytic amounts of diethylamine.ll From the reaction of (25) with sulphur and diethylamine (Gewald reaction), the thiophen derivative (25a)

(25)

(25a)

was obtained.lla A deamination procedure via diazotization provides a new method for the synthesis of 5- and 4,5-substituted thiophen-3-carboxylic acids.12 From the reaction of ethyl 5-aryl-2-cyano-2,4-pentadienoates (25 b) with sulphur, ethyl 2-amino-5-thioaroylthiophen-3-carboxyates (25c) were obtained in 30-65% yield.12a Upon reaction with thionyl chloride or triethyloxonium fluoborate, (25c) yields the reactive salts (25d) and (25e), respectively. V. I. Shvedov, V. K. Ryzhkova, and A. N. Grinev, Khim. geterotsikl. Soedinenii, 1967, 3, 239. V. P. Arya and S. P. Ghate, Indian J. Chem., 1971, 9, 904. l a V. I. Shvedov, V. K. Ryzhkova, and A. N. Grinev, Khim. geterotsikl. Soedinenii, 1967, 3, 1010. 12a N. Kim Son and Y. Mollier, Compt. rend., 1971, 273, C, 278. l1

Thiophens and their Selenium and Tellurium AnaIogues C0,Et

357

nCO2Et

Ar+sJNH2

The reaction between esters of arylpropiolic acids and esters of thioglycollic acids, using sodium methoxide in benzene as basic catalyst, leads to a mixture of the hydroxythiophencarboxylic acid esters (26) and (26a),I3 in contrast to what had been reported earlier. Only (26), however, is Ar

obtained when the thioglycollate is condensed with an ethyl aroylacetate with sodium hydroxide in methanol. With 2-chlorovinyl ketones, thioglycollate yields a variety of substituted thiophen-2-carboxylic acids.14 An apparently new synthesis of thiophen derivatives starts with the addition of hydrogen sulphide to 2-cyclohexenones,yielding 3-mercaptocyclohexanones (27), which upon condensation with glyoxal or other a-dicarbonyl compounds yield (27a).14a

Tilak and co-workers l6 have continued their investigations on the synthesis of 2-ethoxycarbonyl-3-hydroxythiophanes,through the basecatalysed condensation of methyl vinyl ketone, chalcones, ethyl 2-benzoylacrylate, and Mannich bases with ethyl thioglycollate. Dehydration of the thiophanes with polyphosphoric acid followed by dehydrogenation using chloranil or diphenyl disulphide affords thiophens. A new synthesis of 2-aminothiophen has been found in the cyclization of cis-y-benzylthiocrotononitrilewith anhydrous hydrogen chloride in a l3

l6

J. Brelivet, P. Appriou, and J. Teste, Compt. rend., 1969, 269, C,398. S. Hauptmann, M. Weissenfels, E. Werner, and J. Weisflog, 2.Chem., 1969, 9, 22. R. P. Napier and C. Chu, Internat. J. Surfur Chem. (A), 1971, 1, 62. B. D. Tilak and S. S. Gupte, Indian J. Chem., 1969, 7, 9.

358


dipolar aprotic so1vent.l6 The reaction of a-chloro-thioacetanilides(28) in refluxing methanol provides a new route to N-substituted thiophen-2,4diamines (29).17 The detailed mechanism is not known, but the intermediate (30) is probably involved in the reaction.

R I

4s CICH,C,

R S I II Ph-N-C c\H,Cl cs,C=N< /R C T

Ph-N

N-Ph

i R

QN-Ph R = alkyl

I R

Ph

(29)

(28)

Buta-l,3-diene-l -thiols such as a-mercapto-/%styrylacrylic acid (31) are ring-closed to thiophen derivatives (3 la) in better yield and higher purity, and above all much more rapidly, by the use of chlorine in anhydrous carbon tetrachloride, instead of iodine.l* The mechanism of this oxidative ringclosure has been studied in detail and good evidence has been presented

SH (31)

that sulphenyl halides are intermediates in the ring-closure in aprotic A series of 4-phenylbutylthio-derivativeshas been shown to cyclize by treatment with iodine or acid to form 2-phenylhydrothi0phens.~~~ In this paper evidence was found for the presence of a sulphenyl iodide intermediate, since in the treatment of bis-(4-phenyl-3-butenyl)disulphide with iodine, 2-phenyl-3-iodothiolan was formed in high yield. In connection with an investigation of the mass spectra of di-(l-alkenyl) sulphides (32), a convenient synthesis of 3,4-dialkylthiophens was discovered by heating the former compounds to 150-200 "C in the presence of potassium hydrogen sulphate.lgb The 3,4-dialkylthiophen could have

R

H R

R

\

$CjcVH

II HC,p.,S S

I

/R

HC-cH I I HC HC

\=. $

\

HA, 1

aS

R

R R

R

HC-CH

/

,A S H

/

\

HC-CH

&,, S H

I ,C\H

S

sm

D. L. Eck and G. W. Stacy, J. Heterocyclic Chem., 1969, 6, 147. J. P. Chupp, J. Heterocyclic Chem., 1970, 7 , 285. l 8 P. M. Chakrabarti, N. P. Chapman, and K. Clarke, Tetrahedron, 1969, 25, 2781. IS P. M. Chakrabarti and N. P. Chapman, J. Chem. SOC.(0, 1970, 914. l e a E. Campaigne, R. L. White, and B. G. Heaton, Internat. J. Surfur Chem. (A), 1971,1, l6

l7

39.

H. Boelens and L. Brandsma, Rec. Trav. chim., 1972, 91, 141.

lBb

Thiophens and their Selenium and Tellurium Analogues 359 been formed through a sequence of a [3,3]-sigmatropic rearrangement of (32) to the dithial(32a) followed by polymerization to (32b) and elimination of hydrogen sulphide from the polymer. A very promising new route to substituted thiophens has recently been developed by Hartmann. The reaction of 2-aryl-ly3-oxathiolium salts such as (33) with malononitrile in the presence of base yields 3-amino-4cyanothiophens (34), with ethyl malonate or ethyl cyanoacetate 3-hydroxythiophens (34a), and finally with nitromethane 3-nitrothiophens (34b).lacThe

MeOkCQC02Me / \

reactions proceed most probably via addition compounds of the type (34c). The reaction of the mesoionic compound (35) with dimethyl acetylenedicarboxylate yields the thiophen derivative (35a).led The treatment of aliphatic acids such as (36), (36a), (36b) with thionyl chloride leads to the formation of the thiophen derivatives (37), (37a), (37b).20 In particular, the formation of thiophen-2,5-dicarboxylicacid chloride in 63% yield from adipic acid is almost sensational. Through the CH2-C Hz

I HOOC-CH, CH2-COOH

CH-CH, II I CHZ CHZ-COOH

(36)

(3W

I

CH-CH

II HOOC-CH

II

CH-COOH

(36b) IgC Igd 2o

H. Hartmann, Z . Chem., 1971, 11, 421. K. T. Potts and U. P. Singh, Chem. Comm., 1969, 569. S. Nakagawa, J. Okumura, F. Sakai, H. Hoshi, and T. Naito, Tetrahedron Letters, 1970, 3719.

360


reaction of exohalogeno-derivativesof ethylbenzeneand styrenewith sulphur at 200-220 "C,methods for the synthesis of 2,4- and 2,5-diphenylthiophen have been developed.21 The classical Paal-Knorr synthesis was applied to the macrocyclic y-diketone 1,4-cyclododecanedione(38) in order to obtain the (8)-2,5-heterocyclophane (39).22 The conformations of (39) and its

(381

(39)

furan and pyrrole analogues are discussed on the basis of U.V. and n.m.r. spectra.22 The (9)-heterophane (41) was obtained in 10% yield by a classical thiophen synthesis, heating the sodium salt of the keto-acid (40) with PpS10,23 and the (6)-heterophane (41a), with the shortest methylene bridge hitherto reported, was prepared from (41b). U.V.data are taken as evidence for the non-planarity of the thiophen ring in (41a).23a

The reaction of the y-diketone (42) with P,S,, did not lead to the expected thiophen derivative, but gave instead the furan (43).24 The Paal-Knorr synthesis has been used for the synthesis of the cyclopenta[b]thiophen derivative (43a) from (43b).24a In another variant of the Paal-Knorr synthesis, the bicycloheterenes (45) and (45a) have been obtainedfromthey-diketones(44) and (44a), through 21

M. G. Voronkov, V. E. Udre, and E. P. Popova, Khim. geterotsikl. Soedinenii, 1967, 3, 1003.

H. Nozaki, T. Koyama, and T. Mori, Tetrahedron, 1969, 25, 5357. S. Bradamante, R. FUSCO, A. Marchesini, and G. Pagani, Tetrahedron Letters, 1970, 11. S. Fujita, T. Kawaguti, and H. Nozaki, Tetrahedron Letters, 1971, 1119. 24 C. Trebaul and J. Teste, Bull. SOC.chim. France, 1970, 2272. 2m A. Ermili and L. Salamon, Ann. Chim. (Italy), 1969, 59, 375. 22

23


361

S II

CH2-CH-CO2Et I I R2-CII CII-R'

0

0 (42)

R2

Q :;

OE

(43)

COOH

reaction with hydrogen sulphide in the presence of hydrogen chloride.2h A convenient modification (use of sodium hydride in DMSO) has been introduced for the synthesis of 3,4-dimethylthiophen-2,5-dicarboxylicacid monomethyl ester through a Stobbe-type condensation of biacetyl and

dimethyl thiodiacetate.26 Thermodynamic calculations have been performed on the commercial thiophen synthesis from n-butane, butylenes, and 173-butadieneand sulphur dioxide or hydrogen disulphide.26a The mechanism of the thermal decomposition of 2,s-dihydrothiophen to thiophen and hydrogen has been discussed.26b MO Calculations.-An increasing interest in theoretical calculations on sulphur-containing heterocycles can be noted. Dewar 27 has used his H. Wynberg and A. J. H. Klunder, Rec. Trav. chim., 1969, 88, 328. D. J. Zwanenburg and H. Wynberg, Rec. Trav. chim., 1969, 88, 321. 280 Yu. A. Afanas'eva, M. A. Ryashentseva, Kh. M. Minachev, and I. I. Levitskii, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1970, 2012. 26a C. A. Wellington, T. L. James, and A. C. Thomas, J. Chem. SOC.(A), 1969, 2897. 27 M. J. S. Dewar and N. Trinajstid, J. Amer. Chem. SOC.,1970, 92, 1453. 26 26

362


semi-empirical SCF MO .rr-approximation for the calculation of groundstate properties of thiophen, the two benzothiophens and the four thienothiophens, as well as the bithienyls. Participation of the 3d A 0 of sulphur is neglected. This is also the case in the modified Pariser-Parr-Pople method used by Skancke and Skancke 28 and Momicchioli and Del Re.2s All authors claim satisfactory agreement between predicted values and experimental results. Although the numerical values of the calculated parameters differ, the overall agreement between the three sets of calculation seems rather good. The PPP approximation has also been applied in an SCF study of the barrier to internal rotation in 2,2'- and 3,3'-bithien~l.~OFor the latter isomer energy minima were found at about 30" and 150" from the planar form whereas no distinct minima were found for 2,2'-bithienyl. A study of the reactivity of thiophen and related compounds using a HMO delocalized core binding energies have been model has been ~ n d e r t a k e n . Molecular ~~ measured for thiophen and are interpreted in terms of non-empirical calculated energy levels assuming Koopman's Electronic Spectra.-The electronic spectra of thiophens and furans which bear an ethylene, butadiene, or hexatriene group at the 2- and 5-positions 32 With respect to the first electronic transition, the have been excitation energies appear to be independent of the presence or nature of the heteroatom, which was confirmed by LCAO SCF MO calculation~.33 Orbital diagrams show that a fundamental difference is expected between compounds in which five-membered rings are conjugated with a n-electron system and compounds in which these rings are part of a larger condensed ring system. The electronic spectra of 2-thienyl methyl ketones are interpreted by analogy with those of acetophenones. The conformation of 2-thienyl phenyl ketone was determined from its electronic structure by a study of 2,6-disubstituted-phenyl2-thienyl ketones. The carbonyl group is coplanar with the thiophen ring and not with the benzene ring, confirming earlier evidence that 2-thienyl-carbonyl conjugation is more effective than phenyl-carbonyl c ~ n j u g a t i o n .In ~ ~connection with MO LCAO calculations of the U.V. absorption of aryldithiocarboxylic esters, thiophen-Zdithiocarboxylate was studied.36 The charge-transfer (CT) interactions of thiophen and other five-membered heterocycles with tetracyanoethylene, chloranil, and maleic anhydride have been investigated by electron spectroscopy. In some cases two CT bands were observed. The association A. Skancke and P. N. Skancke, Acta Chem. Scand., 1970,24,23. F. Momicchioli and G. Del Re, J. Chem. SOC.(B), 1969,674. 30 A. Skancke, Acta Chem. Scand., 1970,24,1389. 31 C. Decoret and B. Tinland, Austral. J. Chem., 1971,24, 2679. 31a D. T. Clark, Chem. Comm., 1971,230. 3 1 b J. W.van Reijendam, G. J. Heeres, and M. J. Janssen, Tetrahedron, 1970, 26, 1291. 33 M. J. Janssen and J. W. van Reijendam, 2. Chem., 1970,10,261. 33 J. W.van Reijendam and M. 5. Janssen, Tetrahedron, 1970,26, 1303. L. Kaper and Th. J. de Boer, Spectrochim. Acta, 1970,26A,2161. 35 J. Fabian, S. Scheithauer, and R. Mayer, J. prakt. Chem., 1969,311,45. 28 28

niophens and their Selenium and Tellurium Analogues

363 constants of these CT complexes were compared with those of the hydrogenbonding of these heterocyclics with phenol.3sa The effect of a cyclopropyl group on the U.V. spectra of cyclopropylthiophens was found to be similar to that of a phenyl group and quite different from the effect of the cyclopropyl group in cyclopropyl-substituted aryl systems, where only modest bathochromic shifts are found.36b The larger effect in thiophens was attributed to a relatively larger decrease in electron density upon excitation at the carbon to which cyclopropyl is attached, thereby making a greater demand upon the conjugative abilities of cyclopropyl. A detailed photoelectron-spectroscopic study of the vibrations of thiophen and other five-membered heterocycles has been undertaken 36 and was found to be of considerable value in the interpretation of Raman and i .r. spectra. Molecular Geometry.-The structures of thiophen, 2-chlorothiophen, and 2-bromothiophen have been determined by gas-phase electron diffra~tion.~~ Least-squares analyses of the molecular intensity functions indicated that two significantly different structures fitted the data equally well for the two halogenothiophens. However, other physical and chemical evidence favours models for these compounds, in which the bonds adjacent to the halogen atom are lengthened and the bonds across the ring are shortened relative to the corresponding bond lengths in thiophen. Some of the conclusions have been criticized by other An X-ray investigation of 2-acetyl-S-bromothiophenconfirms n.m.r. predictions that the conformation of the thiophen ring with respect to the carbonyl group is trans.s8 The crystal and molecular structures of the semicarbazone of t hi ophen-2-aldehyde have been determined.385 1.r. Spectra and Dipole Moments.-Complete sets of harmonic symmetry force constants have been developed for several heterocyclics, including thi~phen.~@ The calculations were based on observed vibrational frequencies from the literature. Calculated frequencies for [2H,]thiophen, [2,5-2H,]thiophen, and [3,4-2H,]thiophen are given. The i.r. (365050 cm-I) and Raman spectra of 2-chloro- and 2-bromo-thiophen, 2,5dimethyl-, 2,5-dichloro-, and 2,5-dibromo-thiophen, in the liquid state, have been interpreted. The spectroscopic thermodynamic functions have been calculated and the values for 298 K have been reported.89q The Z. Yoshida and T. Kobayashi, Tetrahedron, 1970,26,267. R. M.Kellogg and J. Buter, J. Org. Chem., 1971,36,2236. 36 P. J. Derrick, L. Asbrink, 0. Edqvist, and E. Lindholm, Spectrochim. Ada, 1971, 27A,2525. 37 W. R. Harshbarger and S. H. Bauer, Acta Cryst., 1970,B26, 1010. 37a J. L. Derissen, J. W. M. Kocken, and R. H. van Weelden, Acta Cryst., 1971, 827, 1692. 38 H.J. Streurman and H. Schenk, Rec. Trav. chim.,1970,89,392. M.Mathew and G. J. Palenik, Acta Cryst., 1971,B27, 59. 38 B. N.Cyvin and S. J. Cyvin, Acta Chem. Scand., 1969, 23, 3139. 3*a J. H.S. Green, Spectrochim. Acta, 1971,27A, 2015. 3w

35b

364


carbonyl doublets of esters of furan-2- and thiophen-2-carboxylic acids have been used for an analysis of rotational The spectra of the v ( C 0 ) region of thiophen-Zaldehyde and some 5-substituted derivatives have been studied in 13 different solvents.39cThe i.r. spectra of 45 thiophen analogues of chalcones and their vinylogues were determined in the 1700-650 cm-l region and frequency assignments The results indicate that the carbonyl group and the aliphatic double bond are approximately in the S-cis form. An indication of the larger electron-donating effect of the 2-thienyl group compared with the 2-fury1 group is also obtained. The dipole moments of 25 of these a@unsaturated ketones have been measured in benzene at 25 "C and their most probable coplanar conformation has been e~tablished.~~ Linear correlations of the shifts of the carbonyl group frequency*O and of the dipole moments41with Hammett U-values have been attempted. The i.r. spectra of the chalcone-related compounds (46) and (46a) have been studied

(46)

in the 500-700 cm-l region.42 Hammett relations for C=O and C-Br frequencies were found and substituent constants of the 2-thienyl group were determined.4a The i.r. spectra and dipole moments of a large number of aroylthiophens, the corresponding thiocarbonyl derivatives, and di-2thienyl ketone have been studied.4s Similarly, a detailed i.r. investigation of the C=O stretching region of l*O-enriched 2-formyl- and 2-deuterioformyl-thiophen was carried out in order to determine the preferred conformation of the formyl From the integrated intensity of the carbonyl and thiocarbonyl stretching frequencies and the dipole moments, conclusions regarding the conformations of these compounds were drawn. The dipole moments of thiophen-Zthiol, 2,5-dimethyl-thiophen-3-thiol, 2methylthiophen, and also of some carbonyl derivatives such as 2-acetylthiophen, 2-benzoyl- and 2-thiobenzoyl-thiophen, and some cyclic derivatives have been studied in order to determine the precise conformations of these The C=O stretching frequencies aeb

D. J. Chadwick, J. Chambers, G. D. Meakins, and R. L. Snowden, Chem. Comm., 1971, 625.

40

I1 4a 43

430

44

B. Antoine, J.-J. Peron, P. Saumagne, and R. Guilard, J. Chim. phys., 1970, 232. S. V. Tsukerman, V. M. Nikitchenko, Yu. S. Rozum, and V. F. Lavrushin, Khim. geterotsikl. Soedinenii, 1967, 3, 452. S. V. Tsukerman, V. M. Nikitchenko, V. D. Orlov, and V. F. Lavrushin, Khim. geterotsikl. Soedinenii, 1967, 3, 232. F. G. Weber, Tetrahedron, 1970, 26, 2507. C. Andrieu and Y. Mollier, Bull. SOC.chim. France, 1969, 831. C. Andrieu, R. Pinel, and Y.Mollier, Bull. SOC.chim. France, 1971, 1314. H. Lumbroso, D. M. Berth, and P. Cagniant, Bull. SOC.chim. France, 1970, 1720.

Thiophens and their Selenium and Tellurium Analogues 365 offer a convenient way for the identification of thiophenocapro- and thiophenoenantho-lactams of type (47) and (47a), respectively, both of which, depending upon experimental conditions, can be formed from the oxime (48).46

N.M.R. Spectra.-Active interest in the n.m.r. spectra of thiophen and its derivatives is still strong. The new technique of determining interprotonic distances by analysing n.m.r. spectra in a nematic solvent has been applied to thiophen 46a and thi0phen-2,5-dialdehyde.*~~N.m.r. methods have also been used to study molecular motion in solid t h i ~ p h e n .The ~ ~ solvent ~ and concentration effectson the n.m.r. parameters of thiophen and related systems have been investigated in detail.46d The stereospecific long-range coupling constants between the aldehydic and heterocyclic protons have been used for conformational studies of thiophen aldehydes.47# 47a# 47b Examination by variable-temperature n.m.r. indicates the cis-form (49) to be preponderant, which is in agreement with 465

the planar crystalline structure found by X-ray analyses. Especially interesting is 3-hydroxythiophen-2-aldehyde,which in carbon tetrachloride solution exists in the trans-form (50) owing to intramolecular hydrogenbonding and therefore shows a long-range coupling to the 4-hydrogen, whereas in solvents like acetone, hydrogen-bonding is intermolecular and Ya. L. Gol’dfarb, I. P. Yakovlev, and 0. S. Chizhov, Izvest. Akad. Nuuk S.S.S.R., Ser. khim., 1970, 1011. P. Diehl, C. L. Khetrapal, and U. Lienhard, Cunad. J. Chem., 1968,46, 2645. 460 J.-M. Dereppe, J.-P. Morisse, and M. van Meerssche, Org. Magn. Resonance, 1971, 3, 583. 46b T. N. Huckerby, Tetrahedron Letters, 1971, 3497. 40e J. E. Anderson, Mol. Crystals and Liquid Crystals, 1970, 11, 343. D. F. Ewing and R. M. Scrowston, Org. Magn. Resonance, 1971,3,40S. 47 B. Roques, S. Combrisson, C. Riche, and C. Pascard-Billy, Tetrahedron, 1970, 26, 3555. M. L. Martin, J.-C. Roze, G. J. Martin, and P. Fournari, Tetrahedron Letters, 1970, 46

46

3407. 47b B.

Roques and M. C. FourniC-Zaluski, Org. Magn. Resonance, 1971, 3, 305.

366


the molecule exists in the normal trans-conformation (5 l), with long-range coupling to the 5-proton. Similar studies of the long-range couplings of thiophen-2,3-dialdehyde are interpreted as indicating a conformational equilibrium of about 65% of the cis,cis-form (52) and 35% of the trans,transform (53).48 A similar technique has been applied in order to determine the 0 II

H I

d-0

F-0

GdH

I

II

H (53)

0 (52)

preferred conformation of tran~-2-(2-thienyl)ethylenes.~~” N.m.r. spectroscopy and also i.r. and U.V. have been applied in a study of the conformation of 2-thienylglyoxylic acid, those of some of its derivatives, and that of the NN-diethylamide of 3-thienylglyoxylic It is suggested that the S-cis,trans-conformation(54) is predominant for 2-thienylglyoxylic acid. 0

The anisotropy of the second carbonyl group increases the downfield shift of the 3-hydrogen by more than 0.5 p.p.m. compared with simple carbonyl derivatives such as thiophen-2-aldehyde. Magnetically non-equivalent thiophenic protons have been observed in thienylglycollic acid esters of certain asymmetric alcohols.60 A useful method for structure determination of symmetrically substituted 3,3’-bithienyls has been found in the chemical shifts of the methoxycarbonyl protons.61 The OCH,-resonance in 2- and 3-methoxycarbonylthiophensas well as in 5,5’-dimethoxycarbonyl-3,3’-bithienylsoccurred within the small 45

40a

4B 6o 61

B. Roques and M. C. FourniB-Zaluski, Tetrahedron Letters, 1971, 145. T. N. Huckerby, Tetrahedron Letters, 1971, 353. B. Roques and M. Robba, Bull. SOC.chim. France, 1969, 4032. K. Nyberg, B. Ostman, and G. Wallerberg, Acta Chem. Scand., 1970, 24, 1590. R. HAkansson, Acta Chem. Scand., 1969,23, 952.


interval of 6.10-6.20

T,

367

but was shifted 0.2-0.3 p.p.m. upfield in 2,2'- and

4,4'-dimethoxycarbonyl-3,3'-bithienyls. This is also true for unsymmetrically substituted 3,3'-bithienyls with only one methoxycarbonyl group in the 2- or 4 - p o ~ i t i o n .N.m.r. ~~ spectral parameters for 38 chlorornethylthiophens and seven dithienylrnethanes have been obtained.62u N.m.r. spectral studies prove that 2-thienylcarbonyl derivatives are monoprotonated at the oxygen in SO2-SbF6-HFSOs at - 80 "C,forming the antiisomer.6s Both mono- and di-protonation are observed for Smethylthiophen-2-carboxylic acid, the second proton entering the 4-position. In the n.rn.r. spectrum of 5-methoxythiophen-2-carboxylicacid only the diprotonated form (55) is observed. The second protonation in 2-thienyl mesityl

ketone occurs in the mesityl ring. The n.m.r. spectra of the carbonium ions derived from methyl 2,2'-dithienylglycollate as well as the 3,3'-isomer 66 (56) have been observed on dissolution in chlorosulphonic acid-methylene chloride at low temperature. The ring-closure of the latter to (56a) could be

observed. The n.m.r. spectra of the isomeric trithienylcarbonium ions have also been The low-field shifts, relative to the corresponding carbinols, were discussed in relation to the delocalization of the positive charge into the thiophen ring bonded at position 2 or 3. A linear correlation was found between chemical shifts and r-charge densities, and the proportionality constant was higher than that previously found for benzene derivatives. Vicinal coupling constants in these systems agreed satisfactorily with the corresponding calculated r-bond orders. The n.m.r. spectra of a series of thiophens with 2-substituents ranging in electronegativity from lithium to fluorine have been analysed, and the 52

62a 63

s4 56

66

R. HAkansson and E. Wiklund, Acta Chem. Scand., 1970,24,2667. T. Sone and K. Takahashi, Org. Magn. Resonance, 1971, 3, 527. L. Kaper and Th. 5. de Boer, Spectrochim. Acta, 1970, 26A, 2125. G. P. Nilles and R. D. Schuetz, Tetrahedron Letters, 1969, 4313. B. ustman and S. Sjoberg, TetrahedronLetters, 1970, 3137. F. Taddei, P. Spagnolo, and M. Tiecco, Org. Mugn. Resonance, 1970, 2, 159.


368

three proton-proton coupling constants were found to vary linearly with the electronegativity of the ~ubstituent.~'An attempt has been made to correlate the proton chemical shifts of monosubstituted thiophens, using the EIP model within the HMO method.58 A detailed investigation of the n.m.r. spectra of fluorothiophens has been carried out during recent The lH and 19Fmagnetic resonance spectra of the four difluorothiophens, 5-bromo-2,3-difluorothiophen, 3-bromo-2,5-difluorothiophen, and 2,3,5-trifluorothiophen have been analy~ed.~~g The magnitudes of H-F and F-F couplings differed markedly from the corresponding couplings in fluorobenzenes. The ranges for the H-F spin couplings were found to be (in Hz): J2F-3 1.29-3.40, J3F-2 1.23-2.92, J3l7-4 - 0.33 to -I- 0.88, J2~--43.08-3.66, J3F-5 3.17-4.61, and J2F-5 3.40-4.47. The magnitudes of the different F-F spin couplings are: &-3F 0.224.85, J ~ F - 9.23-15.26, ~F J 3 ~ - 12.88, 4 ~ and J ~ F - ~ 22.91F 27.76Hz. The coupling J3F-4F was found to be of opposite sign to the proton-proton spin coupling J2-5. The isotope shift of the fluorine resonance of 2-fluorothiophen due to 34Swas The lH and 19Fspectra of a large number of 5- and 4-substituted 2-fluorothiophens and 5-substituted 3-fluorothiophens have been analysed in detail.5QbThe relative signs of the spin couplings between the fluorine nucleus and the ring-protons have been determined by double resonance, The lQFchemical shifts and coupling constants of the fluorinated thiophens and of fluorobenzenes and the proton shifts of monosubstituted thiophens have been successfully correlated with the reactivity constants F and R of Swain and Lupton by means of linear two-parameter equat i o n ~ .Molecular ~~~ orbital calculation of the l9Fchemical shifts has been carried The lQFand lH spectroscopic parameters for 2-thienylcarbonylfluoride have been determined. Carbon-13 resonances for twelve monosubstituted thiophen derivatives have been observed at 15.085 MHz. In 2-substituted thiophens the C-4 shifts fall into a narrow range of 5.2 p.p.m. (as do the C-5 shifts of 3-substituted compounds), whereas the C-5 shifts are spread over a range of 21.1 p.p.m., indicating the sensitivity of the chemical shifts to resonance effects.60 There has been active interest in the n.m.r. spectra of thienylsubstituted phosphorus and silicon derivatives. The IH n.m.r. spectra of 57

O8

M. J. Bulman, Tetrahedron, 1969, 25, 1433. B. KamiCnski and T. M. Krygowski, Tetrahedron Letters, 1971, 103. S . Rodmar, B. Rodmar, M. K. Sharma, S. Gronowitz, H. Christiansen, and U. Roskn, Acta Chem. Scand., 1968, 22, 907. S. Rodmar, L. Moraga, S. Gronowitz, and U. RosCn, Acta Chem. Scand., 1971, 25, 3309.

me S.

Rodmar, S. Gronowitz, and U. RosCn, Acta Chem. Scand., 1971, 25, 3841.

69d

S. Rodmar, Mol. Phys., 1971, 22, 123.

6Bf

R. D. Schuetz and G. P. Nilles, J. Org. Chem., 1971, 36, 2188. J. Burdon, J. G. Campbell, I. W. Parsons, and J. C. Tatlow, J . Chem. SOC.( C ) , 1971, 352.

Christiansen, S. Gronowitz, B. Rodmar, S. Rodmar, U. RosCn, and M. K. Sharma, Arkiv Kemi, 1969, 30, 561. seh K. Schaumburg, Canad. J. Chem., 1971,49, 1146. eo K. Takahashi, T. Sone, and K. Fujieda, J. Phys. Chem., 1970,74,2765. 69u H.


369

tri-2-thienylphosphine and tri-3-thienylphosphine and some of their derivatives, such as the oxides, the sulphides, the selenides, and phosphonium salts, have been carefully analysed in order to determine the magnitudes and relative signs of the 1H-31Pspin coupling constants.61-6Sa The effects of phosphorus-containing substituents on the chemical shifts are discussed in terms of d,,-p,,-b~nding.~~The chemical shifts of about twenty organosilicon derivatives of thiophen have been determined.s4 Attempts are made to correlate the H-3 chemical shifts of such compounds with adsorption energies from gas-chromatographic data.66 The lH n.m.r. spectra and the la9Hgsatellite bands of 2,2'- and 3,3'-dithienylmercury have been analysed completely, giving Jzmda70.73, Jz~g-414.44, 35.80, 14.56 Hz. JH-Hand J ~ - were H found 68.71, J3Hg-4 45.29, and to have the same relative sign, and a linear relationship between J ~ - and H the corresponding JH-Hwas established.6e The n.m.r. spectral parameters of tetra-(2-thienyl)lead have been compared with those of the corresponding mercury compounds.e6a A study of the lH n.m.r. spectra of a number of selenides of the thiophen series with electron-attracting substituents has been carried out. Spin-spin coupling to "Se was observed.66b

E.S.R. Spectra.-The e.s.r. spectra of some thienylphenyl and trithienylmethyl radicals have been analy~ed.~'The complex e.s.r. spectrum that arises on treatment of 2,2'-bithienyl with potassium at - 80 "C is interpreted as due to two rotamers of the radical anion of 2,2'-bithien~l.~~ It is believed that the two aromatic rings are held in a planar or nearly planar conformation, where the sulphur atoms are in a cis- or trans-position, for a sufficient time for each rotamer to give an individual spectrum. 2-Phenylthiophen is claimed to behave similarly. The ketyls from thiophen-2aldehyde and 2-acetylthiophen also give overlapping spectra, assigned to the O-cis- and O-trans-isomers present in unequal amounts.69 Well-resolved e.s.r. spectra of the 2- and 3-thenyl and 5-methyl-2-thenyl radicals, produced by the reaction of t-butoxyl radicals with the methylthiophens, were also obtained, and the spin distributions in the radicals studied were compared 8a 6s

H. J. Jakobsen and J. A. Nielsen, Acta Chem. Scand., 1969, 23, 1070. H. J. Jakobsen and J. A. Nielsen, J. Mol. Spectroscopy, 1970, 33, 474. R. H. Kemp, W. A. Thomas, M. Gordon, and C. E. Griffin, J. Chem. SOC. (B), 1969, 527.

H. J. Jakobsen and 0. Manscher, Acta Chem. Scand., 1971, 25, 680. 84 A. N. Egorochkin, A. I. Burov, N. S. Vyazankin, V. I. Savushkina, V. Z . Anisimova, and E. A. Chernyshev, Doklady Akad. Nauk S.S.S.R., 1969,184, 351. 66 G. N. Bortnikov, A. N. Egorochkin, N. S. Vyazankin, E. A. Chernyshev, and Ya. I. Yashin, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1970, 1402. 66 L. Lunazzi, M. Tiecco, C. A. Boicelli, and F. Taddei, J. Mol. Spectroscopy, 1970, 35, 190. A. P. Ebdon, T. N. Huckerby, and F. G. Thorpe, Tetrahedron Letters, 1971,2921. 6 6 b V. S. Bogdanov, V. P. Litvinov, A. N. Sukiasyan, and Ya. L. Gol'dfarb, Zhur. org. Khim., 1970, 7 , 1257. A. Mangini, G. F. Pedulli, and M. Tiecco, J. Heterocyclic Chem., 1969, 6, 271. P. Cavalieri d'Oro, A. Mangini, G. F. Pedulli, P. Spagnolo, and M. Tiecco, Tetrahedron Letters, 1969, 4179. 6s A. Hudson and J. W. E. Lewis, Tetrahedron, 1970, 26, 4413. 6SCr

370 Organic Compounds of Sulphur, Selenium, and Tellurium with the results of semi-empirical molecular orbital calculations.s0 Alkalimetal reduction of some thienylethylene derivatives at - 80 "C gave the corresponding radical anions, whose e.s.r. spectra have been interpreted by the use of deuteriated The work on the e.s.r. spectra of thiophen derivatives by the Bologna school has recently been reviewed.89b

M a s s Spectra.-Detailed investigation of the fragmentation of thiophen upon electron impact has been carried out using deuterium- and I3C-labelling.70-73The hydrogen randomization in the [HCS]+-precursoris largely due to rearrangement of the carbon skeleton, hydrogen migration being of minor importance. The hydrogen randomization in the [C2H2S]+-precursor on the other hand is largely caused by hydrogen migration. The rearrangement of the carbon skeleton is not a random reaction, and the specificity of this reaction can be explained if the precursor is represented by the 'Ladenburg' structure of thiophen. Convenient methods for the synthesis of [2-13C]thiophen and [2,5-13C2]thiophenare given.72Through the use of partially deuteriated 2- and 3-phenylthiophens, it has been shown that under electron impact a rearrangement from 3- to 2-phenylthiophen occurs, which thus differs from the irreversible photochemical rearrangement of 2-phenyl- to 3-phen~l-thiophen.~~ The results of a detailed investigation of the label distribution in the parent ions from 2-phenylthiophens and 2,5-diphenylthiophens were interpreted in terms of both carbon skeletal rearrangement in the thiophen ring and migration of the phenyl sub~tituent.?~" By the use of thep-fluoro-labellingtechnique, it has been shown that carbon skeletal rearrangements occur in tetraphenylthiophen ions.7s This technique was also used in a study of the mass-spectral fragmentation of tetraphenylthiophen 1,l -dioxide, which loses SO2 to give (C8HJ4CP+-, with a nearly tetrahedral symmetry.76 An extensive investigation on the fragmentation of 1-(2-thienyl)alkylalkanones has been carried out.?? A prominent process is cleavage of the bond 18 to the carbonyl group with the concurrent rearrangement of a hydrogen atom. Another important process is cleavage (11 to the carbonyl group to produce thenoylium ions. Mass spectra of some selenides, sulphides, and ethers of furan, thiophen, and L. Lunazzi, A. Mangini, G. Placucci, P. Spagnolo, and M. Tiecco, J. C. S. Perkin 11, 1972, 192. ssb 7O

7l 78

73 7' 7M

L. Lunazzi, A. Mangini, G. F. Pedulli, and M. Tiecco, Gazzetta, 1971, 101, 10. S. Meyerson and E. K. Fields, Org. Mass Spectrometry, 1969, 2, 241. F. de Jong, H. J. M. Sinnige, and M. J. Janssen, Rec. Trav. chim., 1970, 89, 225. F. de Jong, H. J. M. Sinnige, and M. J. Janssen, Org. Mass Spectrometry, 1970, 3, 1539. A. S. Siegel, Tetrahedron Letters, 1970, 4113. M. J. Janssen and F. de Jong, 2.Chem., 1970, 10,216.

W. D. Weringa, H. J. M. Sinnige, and M. J. Janssen, Org. Mass Spectrometry, 1971, 5, 1399.

76

7e 77

T. A. Elwood, P. F. Rogerson, and M. M. Bursey, J . Org. Chem., 1969, 34, 1138. M. M. Bursey, T. A. Elwood, and P. F. Rogerson, Tetrahedron, 1969, 25, 605. N. G. Foster and R. W. Higgins, Org. Mass Spectrometry, 1969, 2, 1005.

37 1 selenophen are described and the influence of the three heteroatoms on the fragmentation is An apparently new fragmentation reaction consisting of splitting of alkyl, insertion of the side-chain heteroatom into the ring, and loss of one of the heteroatoms as C=X, is discussed in detail. The mass spectra of the thiophenoenantho- and thiophenocapro-lactams (47c and d) contain characteristic fragments, which permit a determination of the dimensions of the lactam ring and the relative positions of the thiophen ring and the carbonyl and imino-gro~ps.~~ In connection with negative-ion mass spectra of organosulphur compounds, a few thiophen derivatives have been studied.8o The molecularionizationpotentials, obtainedby a mass-spectraltechnique, of a number of substituted furans, thiophens, selenophens, and pyrroles have been determined. Hammett-type equations were obtained, which indicated that the sensitivity to substituent effects varies in the order furan > pyrrole > thiophen > benzene. The p-values obtained are more negative than those for the most selective electrophilic substitution.80Q Thiophens and their Selenium and Tellurium Analogues

Electrophilic Substitution.-An excellent review on electrophilic substitution of five-membered rings has recently been published.s1 During the past two years progress has been made in the quantitative study of electrophilic substitution reactions of thiophen. A study of salt effects and activation parameters indicates that the mechanism of bromination of thiophen in aqueous acetic acid is the same as that of benzene compounds.81QThere is an isotope effect k ~ / ofk 1.3, ~ which is shown to be secondary and does not represent slow proton loss. The effect of substituents at the 5-position upon the rate of chlorination and bromination of thiophen at the 2-position in glacial and 15% aqueous acetic acid, respectively, has been studied and found to exhibit a po+ relationship with p-values of - 6.5 and The p-value reported for the chlorination of substituted benzenes is - 9.80, thus indicating a smaller positive charge on the thiophen ring in the transition state. Brornination of deactivated thiophens has been analysed in terms of simultaneous second- and third-order processes and the activation parameters for various substituted thiophens indicate that the rate of reaction is affected more by changes in A H * than AS*. A detailed study of the mechanism and kinetics of the nitration of thiophen and some substituted thiophens in sulphuric acid and perchloric acid has been undertaken. A linear relationship between log k2 (observed) and - (HR + log aw)(where w = H20)was found, and the reaction mechanism

7B

*la 82

0.S. Chizhov, B. M. Zolotarev, A. N. Sukiasian, V. P. Litvinov, and Ya.L. Gol’dfarb, Org. Mass Spectrometry, 1970, 3, 1379. Ya. L. Gol’dfarb, B. M. Zolotarev, V. I. Kadentsev, and 0 . S . Chizhov, Izoest. Akad. Nauk S.S.S.R., Ser. khim., 1970, 1014. C. Nolde, J. 0. Madsen, S.-0. Lawesson, and J. H. IBowie, Arkiu Kemi, 1969,31,481. P. Linda, G. Marino, and S . Pignataro, J. Chern. SOC.(B), 1971, 1585. G. Marino, Adv. Heterocyclic Chem., 1971, 13, 235. A. R. Butler and J. B. Hendry, J. Chem. SOC.(B), 1970, 170. A. R. Butler and J. B. Hendry, J. Chem. SOC.(B), 1970, 848.

312


appears to be the same as for benzene compounds.82a The explosive violence of the nitration of thiophen with nitric acid in acetic acid is ascribed to facile autocatalytic nitrosation. The well-known successful practical nitration with nitric acid in acetic anhydride appears to be due to the removal of complications caused by nitrosation. The influence of the acidity of the medium on the direction of the nitration of thiophen-2aldehyde and 2-acetothienone in HzS04 by potassium nitrate has been studied. The ratio of 4-nitro- to 5-nitro-thiophen increased with increasing concentration (70-100%) of sulphuric acid, which was explained by assuming the participation of protonated forms of the carbonyl derivatives.82bNitration of thiophen-Zaldehyde with nitronium fluoroborate in 100% sulphuric acid gave the same ratio (4 : 1) as with potassium nitrate. However, when N-nitropicolinium fluoroborate in acetonitrile was used as nitrating agent, equal amounts of the 4- and 5-isomers were obtained.s2b The protodetritiation of 2- and 3-tritiothiophen in aqueous sulphuric and perchloric acids has been studied as a function of acidity and f e m p e r a t ~ r e . ~ ~ A linear relation was observed between log k and the Hammett acidity function - H,, but the activation parameters are independent of acidity. General acid catalysis has been demonstrated in the protodetritiation of 5-methoxy-2-tritiothophen. The relative reactivity of the 2- and 3-positions of thiophen appears to be a function of acidity. The conclusion was that the mechanism of aromatic hydrogen exchange in thiophen is the same as that in benzene. The kinetics and mechanism of the Vilsmeyer formylation of thiophen derivatives have been studied.84 Reactions of thiophen and 2-methylthiophen followed third-order kinetics, first-order in heterocycle, NN-di methylformamide, and PO Cl, . Isomer distributions have been determined for several electrophilic substitutions of thiophen, such as bromination by Br, and Br+, chlorination by tin tetrachloride, or iodine-catalysed acetylation by acetic anhydride, trifluoroacetylation, and Vilsmeyer formylation.86 The a :fi ratios vary from 100 to over 1000, according to the ‘selectivity’ of the electrophilic agent. The results obtained, together with other data from the literature, permit a test of the applicability of linear free-energy treatments to electrophilic substitution at the a- and p-positions of thiophen.86s86Plots of log q and log fif against p for nine reactions were linear, and from the slopes values of a,+ = - 0.79 and as+ = - 0.52 were obtained. Serious deviations were observed for mercuration and protodemercuration, while nitration and protodeboronation were not taken into account, as deviation could be expected for various reasons. The linearity was taken as evidence 82b

84 85 88

A. R. Butler and J. B. Hendry, J . Chem. SOC.(B), 1971, 102. Ya. L. Gol’dfarb, E. I. Novikova, and L. I. Belen’kii, Izvest. Akad. Nuuk S.S.S.R., Ser. khim., 1971, 1233. A. R. Butler and J. B. Hendry, J. Chem. SOC.(B), 1970, 852. P. Linda, G. Marino, and S. Santini, Tetrahedron Letters, 1970, 4223. S. Clementi, P. Linda, and G. Marino, J . Chem. SOC.(B), 1970, 1153. S. Clementi, P. Linda, and G. Marino, Tetrahedron Letters, 1970, 1389.


373 for the similar character of the transition states for substitution at thiophen and benzene rings. A comparison of the protodesilylation of 3-methylsilylfuran with that of 3-methylsilylthiophenshowed that the /3-position is only slightly more reactive in furan (up+ = 0.45) than in thiophen (up+ = - 0.43), whereas the difference in a-reactivity is much larger (au+= - 0.905 and a,+ = - 0.785 for the furan and thiophen, respect i ~ e l y ) .This ~ ~ is in agreement with the well-known greater &-selectivityin furans than in thiophens. The reactivity of thiophen has also been compared with that of selenophen and the relative reactivities in five electrophilic substitutions have been determined by kinetic or competitive procedures.8s The results have been compared with those available in the literature for furan. In all the reactions examined, selenophen exhibited a reactivity intermediate between those of furan and thiophen. p-Constants for electrophilic substitution of substituted thiophens are usually smaller than in the benzene series. A comparison of the trifluoroacetylation of a series of substituted thiophens and furans yielded p-values of - 7.4 and - 10.7 r e s p e c t i ~ e l y . The ~~~ observed order of substrate selectivity in the trifluoroacetylation (furan > thiophen) thus parallels the positional selectivity in electrophilic substitution, the a :/3 ratio always being larger in furans than in thiophens. The relative importance of primary steric effects in benzene and thiophen has been investigated by determination of the isomer distributionsin the acetylations of 2- and 3-methylthiophen72- and 3-t-butylthiophen, and toluene and t-butylbenzene. Steric hindrance is less significant in the thiophen series owing to the more favourable Thallation of thiophens in the 2-position with thallium(m) trifluoroacetate in trifluoroacetic acid is complete within a few minutes at room ternperat~re.~~ The thallium derivativereacts in situ with aqueous potassium iodide solution to give a convenient and high-yield synthesis of iodothiophens.gOA mixture of thallium(m) acetate has been shown to be a mild and efficient reagent for electrophilic aromatic bromination, Thiophen yields 2-bromothiophen in 82% yield and very little dibromothiophen. 3-Methylthiophen appears to be selectively brominated in the 2-position and 2-methylthiophen in the 5-position in 70-75% yield.0°5 The direct thiocyanation of thiophen and some alkylthiophens with thiocyanogen under various conditions using a variety of Friedel-Crafts catalysts has

-

87

88

88c

R. Taylor, J. Chem. SOC.(B), 1970, 1364. P. Linda and G. Marino, J. Chem. Soc. (B), 1970,43. S. Clementi and G. Marino, J . C. S. Perkin 11, 1972, 71. S. Clementi, P. Linda and M. Vergoni, Tetrahedron Letters, 1971, 611. S . Clementi, P. Linda and M. Vergoni, Tetrahedron, 1971, 27, 4667. A. McKillop, J. S. Fowler, M. J. Zelesko, J. D. Hunt, E. C. Taylor, and G. McGillivray, Tetrahedron Letters, 1969, 2423. A. McKillop, J. S. Fowler, M. J. Zelesko, J. D. Hunt, E. C. Taylor, and G. McGillivray, Tetrahedron Letters, 1969, 2427. A. McKillop, D. Bromley, and E. C. Taylor, J. Org. Chem., 1972, 37, 88.

374


been studied in order to optimize yields.g1 Aluminium tribromide cannot be used as catalyst, since 2,5-&bromothiophen becomes the main product. Bromo-, alkylthio-, and alkylsulphonyl-thiophens were also thiocyanated by this procedure.g1a 2-Methylselenothiophen is formylated selectively in the 5-position, whereas in the less selective SnC1,-catalysed acetylation with acetyl chloride, 85% of the 5-isomer and 15% of the 3-isomer are formed.92 The methylseleno-group is more strongly o,p-directing, since in the formylation and acetylation of 2-methyl-5-methylselenothiophenonly the 4-isomer is obtained. Competitive acetylation experiments indicate 2-methylthiothiophen to be somewhat more reactive than 2-methylselenot hi ophen. 2-Acetylthiophen can be acetylated or chloroacetylated at 100 “C, using the swamping-catalyst method (AlC13 as solvent).g3 Approximately 90% of the 4-isomer and 10% of the 5-isomer are formed. It was found that only relatively unreactive aromatics react faster with chloroacetyl chloride than acetyl chloride in the AlC1,-catalysed Friedel-Crafts reaction. For thiophens and activated benzene derivatives such as mesitylene, the opposite is as demonstrated by competitive experiments. Competitive acetylation of thiophen and derivatives such as 2-methylthiophen and 2,5-dimethylthiophen, and mesitylene leads to different results, depending upon the order of mixing of the reagents.g3bPossible reasons for this are discussed. The same reactions with 3-acetylthiophen give exclusively the 3,5-isomer. A series of aroylthiophens was prepared by SnC1,-catalysed acylation of thiophen and 2-ethylthiophen with aromatic acid chlorides, and the ketones were converted into thioketones through the reaction with PISloin x ~ l e n e . ~ ~ ~ Monobromination of (57) in aqueous acetic acid or ether gives mainly the 2- or the 5-bromo-derivative, respe~tively.~~ The 2-bromo-derivative reacts further with bromine in acetic acid to give the 2,3-dibromo-derivative

(57) s1

Dm 92

O3

(574

F. M. Stoyanovich, G. I. Gorushkina, and Ya. L. Gol’dfarb, Zzuest. Akad. Nauk S.S.S.R., Ser. khim., 1969, 387. F. M. Stoyanovich, G. I. Gorushkina, and Ya. L. Gol’dfarb, Zzuest. Akad. Nauk S.S.S.R., Ser. khim., 1970, 1851. A. N. Sukiasyan, V. P. Litvinov, and Ya. L. Gol’dfarb, Zzoest. Akad. Nauk S.S.S.R., Ser. khim., 1970, 1345. Ya. L. Gol’dfarb, A. P. Yakubov, and L. I. Belen’kii, Doklady Akad. Nauk S.S.S.R., 1969, 185, 91.

I. Belen’kii, A. P. Yakubov, and Ya. L. Gol’dfarb, Zhur. org. Khim., 1970, 6, 2518. L. I. Belen’kii, A. P. Yakubov, and Ya. L. Gol’dfarb, Zhur. org. Khim., 1970, 6, 2524. C. Andrieu, Y. Mollier, and N. Lozac’h, Bull. SOC.chim. France, 1969, 827. D. T. Drewry and R. M. Scrowston, J. Chem. SOC.( C ) , 1969,2750.

BwL. 93b B3c

B4


375

and in ether to give the 2,5-dibromo-derivative, which in turn with excess bromine in acetic acid gives 2,3,5,7-tetrabrorno-4-hydroxybenzo[b]thiophen. Vilsmeyer formylation of (57) yields a complex mixture of aldehydes, (57a) being the main product.04 The bromination of 2-benzoylthiophen in the presence of excess AICls without solvent yields a mixture of 4- and 5-bromo-2-benzoylthiophens (in a 6 : 1 ratio), and also 4,5-dibromo-2benzoylthiophen. In the presence of catalytic amounts of AICls in CHC1, only 5-bromo-2-benzoylthiophenis Competitive experiments on the bromination of 2-acetylthiophen and acetophenone using the swamping-catalystmethod showed the 4-position of 2-acetylthiophen to be 50 times more reactive than the meta-position of a c e t o p h e n ~ n e .t-Butyl ~~~ 2-thienyl ketone is also brominated almost exclusively in the 4-position using the swamping-catalyst method, and the bromination of 2-carbonylsubstituted thiophens occurs in this position regardless of whether the reaction is run in the absence of solvent in excess AlCI, or in chloroform. Use of the swamping-catalystmethod in the bromination of ethyl 2-thienyl sulphone gives predominantly the 4-isomer, although appreciable amounts of the 5-isomer and the 4,5-dibromo-substituted sulphone are formed.OPb Through addition of amines such as 2-thenylamine or 2-(NN-dimethylaminomethy1)thiophen to excess AICls, N-acylation or cleavage is prevented owing to complex formation, and acetylation occurs in the 5-positi0n.O~~ Acetylation of 5-NN-dimethylaminomethyl-2-methylthiophentakes place at the @-positionadjacent to the methyl group. The AlC1,-catalysed alkylation of 2-methylthiophen with t-butyl chloride in carbon disulphide yields a mixture of 80% 2-methyl-5-t-butylthiophen and 20% 2-methyl-4-t-butylthiophenin 40% yield, and about 30% of 3,5-di-t-butyl-2-methyIthi0phen.~~ During the AIC1,-catalysed acylation of 2-methyl-5-t-butylthiophenwith acetyl chloride, cleavage of the t-butyl occurred, yielding 3,5-diacetyl-2-methylthiophenas the main product. However, when succinic acid monomethyl ester chloride was used, the acylation proceeded normally, yielding (58). A new method of synthesizing COCH2CH2C0,Me

Me&Q.Us

thiophen analogues of chalcone based on the Friedel-Crafts reaction (SnCI,) of thiophen with aryl p-chlorovinyl ketones has been extended.OB Also, the reaction of acid chlorides from ap-unsaturated acids with thioYu. B. Vol’kenshtein, I. B. Karmanova, and Ya. L. Gol’dfarb, Izuest. Akad. Nauk S.S.S.R., Ser. khim., 1970, 2757. 9 4 b L. I. Belen’kii, G. P. Gromova, and Ya. L. Gol’dfarb, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1971, 1228. e4c A. P. Yakubov, L. I. Belen’kii, and Ya. L. Gol’dfarb, Zhur. org. Khim.,1971, 7 , 525. e5 P. Cagniant, A. Reisse, and D. Cagniant, Bull. Soc. chim. France, 1969, 991. e6 V. F. Belyaev and A. I. Abrazhevich, Khim. geterotsikl. Soedinenii, 1967, 3, 228. 94a

376


phen using SnCl, in equimolar amounts has been applied to the synthesis of c h a l c o n e ~ . ~ ~ ~ The isomer distributions in some electrophilic substitution reactions of g6b 2- and 3-fluorothiophen have been The chloromethylation reaction maintains its position as a preparatively very useful reaction in the thiophen series. The chloromethylation of 2,5-dimethylthiophen97 and 2,5-dichlorothiophen g8 with chloromethyl methyl ether has been improved. The same reagent has also been used for the chloromethylation of di-(2-thienyl)methaneY 1,1-di-(2-thienyl)ethaneY 2,2-di-(2-thienyl)propaneY 2,5-bis(dimethyl-2-thienylmethyl)thiophen and 1,l,l-tri-(2-thien~l)ethane.~~ The chloromethylation of 2-acetothienone and thiophen-Zaldehyde by monochloromethyl ether using the swampingcatalyst method (AlCl,) is directed almost exclusively in the 4-position of the thiophen ring (98% and 93% respectively). The product of chloromethylation of 2-acetothienone by paraformaldehyde and HCl in chloroform, described in the literature as 5-chloromethyl-2-acetothienone,was found to be an almost equimolar mixture of the 4- and 5-chloromethyl derivat i v e ~ .aI-Chloro-/3/3-dithieny1alkanes ~~~ (58a) have been prepared in good

yields by acid-catalysed condensation of a-chloro-substituted aldehydes and ketones with thiophen, alkylthiophens, and 2-chlorothi0phen.~~~ Electrophilic substitution reactions of 2,5-dialkylmercaptothiophens have been studied. Both dibromination with bromine water and dichloromethylation with chloromethyl methyl ether proceeds smoothly in the 3,4-position~.~~~ Vilsmeyer formylation, however, gave a mixture of the monoformylated product and, interestingly enough, 5-alkylmercaptothiophen-2-aldehydeY formed by electrophilic displacement of an alkylmercaptogroup. The desired 2,5-dialkylmercaptothiophen-3,4-dialdehydecould not be obtained from the dibromo-derivative through halogen-metal exchange, V. F. Belyaev and A. I. Abrazhevich, Khim. geterotsikl. Soedinenii, 1967, 3, 827. S. Gronowitz and U. Roskn, Chemica Scripta, 1971, 1, 33. P. Cagniant, G. Merle, and D. Cagniant, Bull. SOC.chim. France, 1970, 302. D. J. Zwanenburg and H. Wynberg, J. Org. Chem., 1969,34, 333. P. A. Konstantinov, L. V. Semerenko, K. M. Suvorova, E. N. Bondar, and Ya. L. Gol'dfarb, Khim. geterotsikl. Soedinenii, 1968, 4, 230. Oe5 L. I. Belen'kii, I. B. Karmanova, Yu. B. Vol'kenshtein, and Ya. L. Gol'df'arb, Izuest. Akad. Nauk S.S.S.R., Ser. khim., 1971, 956. OQb R. H. Sieber and P. Hornig, Annalen, 1971, 743, 144. OBC Ya. L. Gol'dfarb, M. A. Kalik, and M. L. Kirmalova, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1969, 1769. Ow

Oeb O7


377

but was prepared by oxidation of 3,4-bis(hydroxymethyl)-2,5-bis(alkylmercapto)thiophens, obtained from the bischloromethyl derivative, with active manganese dioxide in boiling benzene.Qsd As a by-product, a 2- alkylsulphinyl-5 - alkylmercapto -formylthiophen-carboxylic acid was formed, At room temperature the principal oxidation products are 4-hydroxymethyl-2,5-bis(alkylmercapto)thiophen-3-aldehydes. Alkyl 3thienyl selenides, as well as alkyl 3-thienyl sulphides, are acylated in the 2-posit i ~ n . ~ ~ ~ The Vilsmeyer formylation of 3-phenylthiophen yields a 94 : 6 mixture of 3-phenylthiophen-2-aldehyde and 3-phenylthiophen-5-aldehyde, whereas Friedel-Crafts acetylation with SnCl, as catalyst is less selective and yields a 7 : 3 mixture of 2-acetyl-3-phenyl- and 5-a~etyl-3-phenyl-thiophen.~~~ In connection with an investigation of the conjugative abilities of the cyclopropyl group, electrophilic bromination, deuteriation, formylation, iodination, and nitration of 2- and 3-cyclopropylthiophenhave been carried Except for nitration, in which 60% 5-isomer and 40% 3-isomer are obtained, substitution of the 2-isomer occurs only in the 5-position. This behaviour is thus similar to that of 2-phenylthiophen. Similarly, except for nitration, electrophilic substitution of 3-cyclopropylthiophen occurs exclusively in the 2-position. The high selectivity is rather interesting, as, for instance in the formylation reaction, 3-methylthiophen gives a 4 : 1 mixture of 2- and 5-formylated products and 34sopropylthiophen gives a 1 : 1 mixture of 1,4-Di-(2-thienyl)benzene(59)has been diacetylated and monoformylated in the free a-positions.lO1

Nitration of decafluoro-l,S-di-(2-thienyl)pentane (60) gave a mixture of isomeric dinitro-derivatives. N.m.r. analysis indicates that competitive substitution had occurred in the 4- and 5-positions in the proportions 1 :3.102 In the presence of iron powder, thiophen reacted with sulphuryl chloride to give a mixture of chlorinated bithienyls as the main product in yields of up to 42%, whereas the reaction without a catalyst gave chlorothiophens.lo3 The reaction was also catalysed by Friedel-Crafts-type catalysts with the usual order of efficiency. It is suggested that the reaction is electrophilic in nature, the electrophilic reagent being thiophen, proYa. L. Gol'dfarb, M. A. Kalik, and M. L. Kirmalova, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1969, 2254. OBs Ya. L. Gol'dfarb, V. P. Litvinov, and A. N. Sukiasyan, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1971, 1296. l o o N. Gjers and S. Gronowitz, Acta Chem. Scand., 1970, 24, 99. lol P. Ribereau and P. Pastour, Bull. SOC.chim. France, 1969, 2076. loa E. Jones and I. M. Moodie, J. Chern. SOC.(C), 1969, 2051. lo8 T. Sone, K. Sakai, and K. Kuroda, Bull. Chem. SOC. Japan, 1970,43, 1411. *sd

378


tonated in the 2-position. This intermediate could also be involved in the polymerization of thiophen with 100% orthophosphoric acid. It has been confirmed recently that the trimer formed has the structure (61), and it was unambiguously established by X-ray analysis that the so-called pentamer had the structure and stereochemistry shown in (62).lo4,loto# It thus contains three sulphur atoms and is derived from four molecules of thiophen.

Activated thiophens, such as the diamines (29), are so reactive that they undergo electrophilic hydrogen exchange with water in carbon tetrachloride solution, which could be followed by n.m.r.17 2-Amino-3-ethoxycarbonyl4-arylthiophens are easily aminomethylatedwith bisdimethyl- or bisdiethylaminomethane to give Mannich bases.104c The bromodecarboxylation of some sodium salts of thiophencarboxylic acid with bromine in water has been shown to have some interesting aspects and furnishes a convenient route to 2,5-dibrom0-3,4-dimethylthiophen.~~ Attempted Vilsmeyer formylation of j3-(3-thienyl)nitromethane led to the discovery of a new reaction, as an 80% yield of a mixture consisting of 85% 2-thenylcyanide and 15% o-thenylchloride was obtained.lo5 It has been found that tris[l-(2-thienyl)butane-l,3-dionato]-cobalt(111)chelate and -chromium(In) chelate, as well as their 2-fury1 analogues, are nitrated and brominated in the chelate rings and not in the five-membered heterocycles.10s Deuteriation of thiophen-2carboxylic acid in the 5-position has been achieved by heating at 165 "C in a deuterium oxide-carbonate buffer, whereas heating the dry acid containing the COOD group at 250 "C yields the 3,5-dideuteriated acid.loBa The mechanism of this deuteriation is not known. Electrophilic Ring-closure Reactions.-During recent years an increasing interest in the study of annelation effects on the b-side and c-side of thiophen may be noticed. One way of preparing such systems is through electrophilic ring-closure reactions. Cagniant and c o - w ~ r k e r s ,starting ~~~ R. F. Curtis, D. M. Jones, G. Ferguson, D. M. Hawley, J. G . Sime, K. K. Cheung, and G. Germain, Chem. Comm., 1969, 165. D. M. Hawley and G . Ferguson, J. Chem. SOC.(B), 1971, 843. l o P bR. F. Curtis, D. M. Jones, and W. A. Thomas, J. Chem. SOC.(C), 1971,234. l o PCV. I. Shvedov, V. K. Ryzhkova, and A. N. Grinev, Khim. geterotsikl. Soedinenii, lo4

1967, 3, 450.

J. Skramstad, Acta Chem. Scand., 1970, 24, 3424. Io6 T. Sasaki, K. Kanematsu, and G. Kinoshita, J. Chem. SOC. (C), 1969, 951. l o w J. A. Zoltewicz and H. L. Jacobson, J. Heterocyclic Chem., 1971, 8, 331. lo' P. Cagniant, G . Merle, and D. Cagniant, Bull. Suc. chim. France, 1970, 308. Io5


379 from 3-bromomethylthiophen and using conventional, malonic ester synthesis and chain-lengthening via Amdt-Eistert synthesis and the cyanide route, have prepared the acids (63)-(64) and some of the corresponding 2-substituted acids. Use of the same synthetic approach, but starting from Mc

R = HorMe n = 2, 3, 4, or 5

R = HorMe n = 2, 3, 4, 5 , or 6

(634

(63)

CHZ-CCH-CHZ

R Q R

R

=

de

LOOH

HorMe

(64)

2,5-dimethyl-3-thenyl chloride and also applying Friedel-Crafts acylations with dicarboxylic ester chlorides followed by Wolff-Kishner reduction, gave the 2,S-dimethyl-substituted acids (63)-(64).lo8 It was then possible to study ring-closure of a 3-positioned side-chain to the 2- or 4-position and of a 2-positioned side-chain to the 3-position by FriedelCrafts catalysed ring-closure of the acid chlorides using SnCl, in CS2,or by polyphosphoric acid directly on the acids.loQIt was shown that for the preparation of (65) and (66) the PPA method was superior, since only traces of the ketones were obtained in the traditional Friedel-Crafts reaction. Interestingly, ring-closure to (67) could not be achieved with

O

R

R=HorMe

R=HorMe

R == H o r M e

(65)

(66)

(67)

either reagent. Ring-closure to the six- and seven-membered ketones was achieved in high yields by the Friedel-Crafts method. The ketones were reduced to the hydrocarbon and alcohol states, and the latter compounds were dehydrated to olefins. Ring-closure of the acid chloride (68) with SnCl, in carbon disulphide proceeds normally to the ketone (69).95 However, when the reaction is carried out in benzene using AlCl:, as catalyst, lo* log

P. Cagniant, G. Merle, and D. Cagniant, Bull. SOC.chim. France, 1970, 316. P. Cagniant, G. Merle, and D. Cagniant, Bull. SOC.chim. France, 1970, 322.


380

\(CH2)3C0C1

Me3CQI M c (68)

(70)

(69) O R II I CIC-C-H

/s r ; ? C - R I CIC

R

=

HorMe (71)

II 0 R = HorMe

& Q S

R=HorMe

O

(72)

R = HorMe

R

(7W

(73)

(744

(74)

eoCCi

R I

SCHCOCl

S

R = HorMe

R = HorMe

(75)

(76)


381

cleavage of the t-butyl group occurs and the ketone (70) and t-butylbenzene are obtained. Ring-closure of 2,5-di-t-butyl-3-alkanoic acid to the 4-position was also accompanied by cyclization to the 2-position owing to d e - t - b u t y l a t i ~ n . Ring-closure ~~~~ of the sulphido-acid chlorides (71) and (71a) to the ketones (72) and (72a) was achieved with SnCl, in CS2.110 From the acid chlorides (73) and (73a), seven-membered sulphur-containing rings were annelated on the thiophenic c-side to yield the ketones (74) and (74a), respectively.lloa The ketones (72), (72a), (74), and (74a) were transformed to alcohols, hydrocarbons, and olefins. Similarly, from the acid chlorides (75), prepared in the conventional manner from the chloromethyl derivative via the thiouronium salt and the thiol, the six-rnembered sulphide ketones (76) were obtained.lll The composition of intramolecular acylation products of w-(5-methyl-2-thienyl)alkanoic acids having sidechains containing nine to eleven CH,-groups has been studied. Ringclosure was observed only to the 3-position with the acid chloride containing nine CH,-groups, whereas mixtures of 3- and 4-ring-closed compounds were obtained with the other two.111a* Electrophilic ring-closure of the methylene derivatives of /?-(thienyl)ethylamines, catalysed by hydrochloric acid, gave high yields of tetrahydrothienopyridinium chlorides such as (77).11'C &NH+ S

c1-

(77)

A useful route to cyclized 2-thienyl ketones has been found by Gol'dfarb and co-workers. Starting from 2,5-dichlorothiophen, they obtained the keto-acids (78) by conventional Friedel-Crafts reaction with ester chlorides of succinic and glutaric acid followed by hydrolysis.l12 By treatment with copper in refluxing propionic acid the 2-chlorine could selectively be reduced and Wolff-Kishner reduction then yielded (78a), which in turn could be ring-closed to (78b) by conventional means. Some other dechlorination methods have also been used.112a Radical Reactions.-The phenylation of thiophen with several phenylating agents has been reinvestigated using modern analytical techniques. In G.Muraro, D.Cagniant, and P. Cagniant, Compt. rend., 1972, 274, C, 201. P. Cagniant, Compt. rend., 1970, 271, C, 375. llW P. Cagniant and G. Kirsch, Compt. rend., 1971, 272, C, 92. 111 P. Cagniant, Compt. rend., 1970, 271, C, 852. llla S. Z.Taits, 0. A. Kalinovskii, and Ya. L. Gol'dfarb, Khim. geterotsikl. Soedinenii,

low

ll0

1970, 6, 1467. 0. A. Kalinovskii, S. Z. Taits, and Ya. L. Gol'dfarb, Izuest. Akad. Nauk S.S.S.R., Ser. khim., 1970, 2331. l1lS. C Gronowitz and E. Sandberg, Arkiv Kemi, 1970,32,217. 118 B. P. Fabrichnyi, I. F. Shalavina, S. E. Zurabyan, Ya. L. Gol'dfarb, and S. M. Kostrova, Zhur. org. Khim., 1968, 4, 680. lracr G. Muraro and D. Cagniant, Compt. rend., 1971,273, C, 1362. lnb

382


n = 2or3

each case a mixture of 2- and 3-phenylthiophens consisting of 90-95% 2-isomer and l0-5% 3-isomer was obtained.l15 The rates of substitution of thiophen relative to benzene by substituted phenyl radicals, generated by the aprotic diazotization of the anilines with pentyl nitrite, have been found to follow, qualitatively, the order expected on the basis of the theory of polarized aryl radicals, i.e. those containing electron-attracting substituents being more reactive. The partial rate factors for the 2- and 3-positions of thiophen were found to be 7.25 and 0.5 respectively, while the or-position of furan, which reacts selectively with phenyl radicals, is 4.4 times more reactive than thiophen.l14 A linear relation has been found to hold between the partial rate factors for the 2-position of thiophen and the u+ constants of the substituent in the phenyl radicals.ll3 The only phenylation reaction in which appreciably larger amounts of 3-phenylthiophen are formed is the reaction with phenylazotriphenylmethane, the ratio of 2- to 3-isomer being 80 : 20 and highly dependent on the experimental conditions as well as on the working-up of the reaction This is attributed to the trapping of the a-complex (79),

leading to the 2-phenylthiophenYby the triphenylmethyl radical to give two &,trans-isomeric 2,5-dihydro-2-phenyl-5-triphenylmethylthiophens.E.s.r. investigations indicated that the formation of (80) was reversible. On chromatography of the reaction mixture on alumina, (80) was dehydrogenated to (81). The reaction of furan with phenylazotriphenylmethane led only to the formation of a cis,trans-isomeric dihydro-compound 11*

C. M. Camaggi, R. Leardini, M. Tiecco, and A. Tundo, J. Chem. SOC.(B), 1970, 1683.

L. Benati, N. La Barba, M. Tiecco, and A. Tundo,J. Chem. SOC.(B), 1969, 1253. n6 C. M. Camaggi, R. Leardini, M. Tiecco, and A. Tundo, J. Chem. SOC.(B), 1969, 1251.

114


383

analogous to (80).lI6 The reaction between nitrobenzene and thiophen in various proportions at 600 "C has been investigated. The reaction is relatively clean, and at a 1 : 20 molar ratio of nitrobenzene to thiophen, phenylthiophens and bithienyl in the ratio 3 : 1 are the main products. Minor amounts of aniline, phenol, biphenyl, and diphenylthiophen are also formed. 2- and 3-phenylthiophen are formed in a 3 : 1 ratio.117 Isomer distributions of phenylthiophens and phenylpyridines are almost identical in the reaction of thiophen and pyridine with phenyl radicals from nitrobenzene and benzyne from phthalic anhydride. Competitive arylations at 600 "Cindicated the following order of reactivity: benzene 1; pyridine 2.3; thiophen 5. The distribution of isomers in the radical methylation of 2- and 3-nitrothiophen and thiophen-2-carboxylic acid has been investigated. The nitro-group exhibits strong ortho-directing properties.f17u It has been suggested that the fluorination of thiophen with high-valency metal fluorides (e.g. AgF2, CoF,) involves initial oxidation by the metal ion to a radical The electrolytic oxidation of 2,5-dibromothiophen leading to methyl fumarate, and that of 3-bromothiophen to give the bis(dimethy1)acetal of bromobutendial, is also assumed to proceed via radical cations.1170The products from the anodic oxidation of 2- and 3-methylthiophen and 2,5-dimethyIthiophen have been identified.l17& A detailed study of the electrochemical oxidation of 2,5-dimethylthiophen in methanol showed that three types of reactions could occur depending upon the electrolytes used. 3-Bromo-2,5-dimethylthiophenwas the sole product when ammonium bromide was used. With non-halide electrolytes the formation of 2-methoxymethyl-5-methyl thi ophen was observed. Finally, with sodium cyanide the products were cis- and trans-2-cyano-5methoxy-2,5-dimethyldihydr othi ophens (cis/trans = 2.3). lnS The radical products of low-temperature reactions of hydrogen atoms with a number of thiophen derivatives in the solid phase have been studied.ll* In the case of 2-methylthiophen, thiophen-Zaldehyde, and 2-acetothienone, e.s.r. studies indicate that the hydrogen atoms are added to the ring at the C=C bonds, forming radicals with an unpaired electron on the carbon atom. In the interaction of 3-methylthiophen with hydrogen L. Benati, M. Tiecco, A. Tundo, and F. Taddei, J. Chem. SOC.(B), 1970, 1443. E. K. Fields and S. Meyerson, J. Org. Chem., 1970, 35, 67. 117= U. Rudqvist and K. Torssell, Acta Chem. Scand., 1971, 25, 2183. J. Burdon, I. W. Parsons, and J. C. Tatlow, Tetrahedron, 1972, 28, 43. ~7~ M. Janda, J. Srogl, A. JanouSovB, V. Kubelka, and M. Holfk, Coll. Czech. Chem. Comm., 1970,35,2635. 117d J. Srogl, M. Janda, and M. Valentovh, Coll. Czech. Chem. Comm., 1970, 35, 148. 1176 K. Yoshida, T. Saeki, and T. Fueno, J. Org. Chem., 1971, 36, 3673. 118 V. D. Shatrov, L. I. Belen'kii, and I. I. Chkeidze, Izuest. Akad. Nauk S.S.S.R., Ser. khim., 1969, 1497. 115 117

384

Organic Compounds of Sulphur, Selenium, and Tellurium atoms, the 3-thenyl radical is formed as a result of stripping a hydrogen atom from the methyl group. The reaction of hydrogen atoms with 2-chloro- and 2,5-dichlorothiophen or complexes between 2-nitrothiophen and carbonyl derivatives with AlC13 or H2S04is claimed to lead to radicals in which the unpaired electron is localized chiefly on the sulphur atom. The gas-phase reaction at room temperature between hydrogen atoms and 2-chlorothiophen and 2- and 3-methylthiophen leads to the stripping of chlorine and a side-chain hydrogen, respectively. E.s.r. has also been used for the investigation of the radicals formed from thiophen and some simple substituted derivatives upon r a d i o l y s i ~ . ~The ~ ~ primary radiochemical event was splitting of C-H bonds both in the ring and in side-chains. However, the formation of secondary radicals similar to those mentioned above was characteristic, by addition of hydrogen atoms to a ring-carbon. The radical addition of certain thiols to 2-allylthiophen has been investigated.120 An authoritative review article on homolytic arylation of heterocyclic compounds, including thiophen, has recently been published.lZoa Nucleophilic Substitution.-Quantitative studies of mechanistic aspects have not been as pronounced as for electrophilic substitution during recent years. However, Dell’Erba and co-workers have studied the kinetics of the reaction of a series of 5-substituted 2-nitro-3-bromothiophens with sodium thiophenoxide.121 The plot of logk against U-values gave a p-value of + 4.51 at 20 “C, indicating that the Hamrnett relationship can be used for reactions at the /%position of the thiophen ring. The effect of the leaving group (Cl, Br, I, OC6H4No2-p,SO,C,H,) on the reactivity of 3- and 5-substituted 2-nitrothiophens and 2-substituted 3-nitrothiophens with sodium thiophenoxide has been studied.lZla The reactivity ratio between 5- and 3-substituted 2-nitrothiophens is always greater than unity and is relatively uninfluenced by changing leaving groups, compared with the reactivity ratio between 3-substituted 2-nitrothiophens and 2-substituted 3-nitrothiophens, which in addition could be greater or smaller than unity depending upon the leaving group. As in most aromatic nucleophilic substitutions, the absence of ‘element effect’ was observed. Meisenheimer-type adducts have been obtained from the reaction of 2-methoxy-3-nitrothiophenand 2-metho~y-3~5-dinitrothiophen with sodium methoxide.121b-d An interesting adduct in which the methoxy-group is attached to the 5-carbon was observed with 2-nitro-3-methoxythiophen.121d The n.m.r. spectra of the complexes were analysed.121d The specific rate 119

V. I. Trofimov, I. I. Chkeidze, L. I. Belen’kii, and N. Ya. Buben, Khim. geferotsikl.

Soedinenii, 1967, 3, 606. A. Gaiffe and J.-L. ZCnou, Compt. rend., 1970, 271, C, 1382. l Z o aG. Vernin, H. J.-M. DOU,and J. Metzger, Bull. Soc. chim. France, 1972, 1173. lZ1 G. Guanti, C.Dell’Erba, and D. Spinelli, J. Heterocyclic Chem., 1970, 7 , 1333. 121a G.Guanti, C.Dell’Erba, and P. Macera, J . Heterocyclic Chem., 1971, 8, 537. lald G. Doddi, G.Illuminati, and F. Stegel, Chem. Comm., 1969, 953. l2lC G. Doddi, G.Illuminati, and F. Stegel, J. Org. Chem., 1971, 36, 1918, lZldD. Spinelli, V. Armanino, and A. Corrao, J. Heterocyclic Chem., 1970, 7 , 1441. lZo


385

and in particular the equilibrium constants at 25 "C for the adduct from 2-methoxy-3,5-dinitrothiophen,the 2,2'-dimethoxy-3,5-dinitrothiacyclopentenate ion, are larger than the corresponding values for the formation of the adduct between 2,4,6-trinitroanisole and methoxide ion at the same temperature.121c 3,4-Dinitrothiophen reacted with sodium arylthiolates with rearrangement, giving 2-aryl-(4-nitrothienyl) sulphide through a cinesubstitution reaction,121ealthough the experimental results are compatible with A& and with hetaryne intermediate mechanisms. The latter appears improbable and has been excluded for the cine-substitution occurring in the treatment of halogenothiophens with metal amides 121f in liquid ammonia, which has been developed into a useful method for the synthesis of /3-bromothiophens from the a-isomers.121g Besides cine-amination and halogen rearrangement and disproportionation, side-chain amination has been observed with methylthiophens. Thus, with potassium amide, 3,5dibromo-2-methylthiophen gives 4-bromo-2-methylthiophenand 4-bromo2-aminomethylthiophen3isolated as the acetamide. The complex nature of the reactions of halogenothiophens with metal amides is evident from the fact that 3,5-dibromo-2-methylthiophen yields 3,4-dibromo-2-methylthiophen with sodium amide.121h In the reaction of 3,4-dinitrothiophen with piperidine in methanol at room temperature an interesting ringopening reaction occurred, leading to 1,4-dipiperidin0-2,3-dinitrobutadiene and hydrogen sulphide.121i Of great preparative importance, however, is the discovery that 2- and 3-thiophenthiols react with secondary amines to give dialkylaminothiophens.122 The reaction between 2,5-di-iodothiophen, 2-iodo-5-propionylthiophen, and 2-iodothiophen-5-aldehydeacetal with one equivalent of copper(1) propynide yielded the corresponding acetylenic derivatives, which were used as intermediates in the synthesis of naturally occurring thiophens.122u Monosubstituted acetylenes cannot be prepared by this general method since monocopper(1) acetylide is unknown, but using a substituted copper(1) acetylide, such as copper(1) 3,3-diethoxyprop-1-ynide or copper(1) tetrahydropyranyloxy-prop- 1-ynide, substitution with 2-iodothiophen, 2,5-diiodothiophen, or 2-iodobithienyl could be achieved, The aldehydes and alcohols obtained upon hydrolysis could be decarbonylated (the latter after oxidation with nickel peroxide) by treatment of the thienyl-substituted acetylene with 4M sodium h ~ d r 0 x i d e . l ~ ~ The preparative usefulness of the copper-catalysed nucleophilic substitution in the thiophen series is evident from the preparation of the four C. Dell'Erba, D. Spinelli, and G. Leandri, Guzzetta, 1969, 99, 535. M. G . Reinecke and H. W. Adickes, J. Amer. Chem. Soc., 1968, 90, 51 1. lz18 M. G. Reinecke, H. W. Adickes, and Ch. Pyun, J . Org. Chem., 1971, 36, 2690. 121h M. G. Reinecke, H. W. Adickes, and Ch. Pyun, J. Org. Chem., 1971, 36, 3820. lZli C. Dell'Erba, D. Spinelli, and G. Leandri, Chem. Comm., 1969, 549. 123 H. Hartmann and S. Scheithauer, J. prakt. Chem., 1969, 311, 827. lZu) R. F. Curtis and J. A. Taylor, J. Chem. SOC.(C), 1969, 1813. R. E. Atkinson, R. F. Curtis, D. M. Jones, and J. A. Taylor, J. Chem. SOC.(C), 1969, lzlf

2173.

14

386


isomeric dicyanothiophens from the corresponding dibromothiophens and CuCN in quinoline 124 and the preparation of 2-benzoyl-3-cyanothiophen from 2-benzoyl-3-bromothiophen in the same way.126 The reaction of 2-iodothiophen or 5-chloro-2-iodothiophen with substituted thiophenols in the presence of potassium carbonate and copper yields substituted thienyl phenyl sulphides in good yields.126 The Ullmann coupling has been extensively used in connection with work on phenylthiophens, bithienyls, and thiophen analogues of fluorene from dihalogenodithienyl ketones.128a-c An elegant use of nucleophilic substitution is provided by the synthesis of dithieno-1,4-thiazines,12' A classical nucleophilic substitution between potassium t hiophen-3-thiolate and methyl 2-bromo-3-nitrothiophen-5carboxylate in DMSO yields the sulphide (82), which is reduced, acetylated, and brominated to (83). A copper-catalysed intramolecular nucleophilic

COMe

(84)

substitution then yields the desired ring system (84). The compound (85) was prepared analogously. The reaction of potassium 3-bromothiophen-4thiolate in the presence of Cu20 in NN-dimethylformamide gave the ring system (86) through two nucleophilic substitutions in 40% yield.127a

Metalation and Halogen-Metal Exchange.-The direct metalation of thiophens with organolithium compounds and the halogen-metal exchange reaction between halogenothiophens and organolithium derivatives have C. Paulmier, J. Morel, and P. Pastour, Bull. SOC.chim. France, 1969, 2511. P. Pirson, A. Schonne, and L. Christiaens, Bull. SOC.chim. belges, 1970, 79, 575. lZ6 M. RajSner, J. MetySovb, and M. Protiva, CON.Czech. Chem. Comm., 1970, 35, 378. 12Bo P. Jordens, G. Rawson, and H. Wynberg, J. Chem. SOC. (C), 1970, 273. l Z s bA. K. Wiersema and S. Gronowitz, Acta Chem. Scand., 1970, 24, 2593. lZoc D. W. H. MacDowell and A. T. Jeffries, J. Org. Chem., 1970, 35, 871. C. J. Grol and J. S. Faber, Rec. Trav. chim., 1970, 89, 68. 127a M. J. Janssen and J. BOS,Angew. Chem., 1969, 81, 570. lZ4

lZ5

Thiophens and their Selenium and Tellurium Analogues 387 maintained their positions as the most important synthetic reactions for the preparation of a variety of substituted thiophens. The complexing of organolithium compounds with NNN'N'-tetramethylethylenediamine (TMEDA) has been found to have a specific rate-enhancing effect on the metalation reaction compared with halogen-metal exchange. Thus, whereas reaction between phenyl-lithium and 2-iodothiophen in ether exclusively gives halogen-metal exchange to yield 2-thienyl-lithium and iodobenzene, the presence of one equivalent of TMEDA gives metalation, leading to 5-iodo-2-thienyl-lithium and benzene.128 Of fundamental importance is the recent discovery that 3-thienyl-lithium derivatives, such as 2,5-dimethyl-3-thienyl-lithium 120 (87) or the three undergo a ring-opening reaction in isomeric methyl-3-thienyl-lithi~ms,~~~ refluxing ether to acetylenic derivatives such as (88), which are alkylated HC-CECMe

HC-CzCMe

R

4 S-Alk R = HorMe

4SR

=

HorMe (87)

=

HorMe (88)

(89)

by the alkyl halide formed in the halogen-metal exchange reaction to give (89) in high yield. N.m.r. spectra indicated that from 2-methyl-3-thienyllithium (87; R = H) the cis-isomer is selectively forrned.130 In the absence of alkylating agents, (88) ring-closes to the methylthiophen upon hydro1ysi s.1Z0 As demonstrated earlier, 3-thieny1-lithium derivatives are stable at - 70 "C, which makes them very useful preparative intermediates. The selenophen analogue 2,5-dimethyl-3-selenienyl-lithiumring-opens, however, even at - 70 0C.120t131 3-Thienyl-lithium intermediates prepared by halogen-metal exchange at - 70 "C have been used for the synthesis of 3,3'-dithienylmercury,e6 tri-3-thienylphosphine~,l~~ 3,3'-theni1,133 4-acetyl3-phenylthiophen,lo0 4-phenylthiophen-3-aldehyde,lo0 and 3,3'-dithienyl ketone through the reaction of 3-thienyl-lithium with NN-disubstituted carbamates.lS4 These are useful reagents in general for the preparation of ketones. The reaction of thienyl-lithium derivatives with dithienyl disulphides has been extensively used for the preparation of unsymmetrically substituted dithienyl sulphides, whereas symmetrically substituted dithienyl sulphides have been obtained by the reaction of thienyl-lithium derivatives with bis(phenylsulphony1) s ~ l p h i d e . l ~ ~Conversion "@ of 3-thienyl-lithium N. Gjas and S. Gronowitz, Acta Chem. Scand., 1971, 25, 2596. S. Gronowitz and T. Frejd, Acta Chem. Scand., 1970, 24, 2656. lS0 H. J. Jakobsen, Acta Chem. Scand., 1970, 24, 2663. S. Gronowitz and T. Frejd, Acta Chem. Scand., 1969, 23, 2540. Is2 H. J. Jakobsen, Acta Chem. Scand., 1970, 24, 2661. 133 K. Nyberg, Acta Chem. Scand., 1969, 23, 1087. lS4 U. Michael and A.-B. Hornfeldt, Tetrahedron Letters, 1970, 5219. F. de Jong and M. J. Janssen, J. Org. Chem., 1971, 36, 1645. 181b F. de Jong and M. J. Janssen, J. Org. Chem., 1971, 36, 1998. lZ8 128

388


into 3-thienylmagnesium bromide followed by reaction with methyl 3-thienylglyoxylate was used for the synthesis of methyl 3,3-dithienylglycollate.60 Dithienyl diketones (thenils) have been obtained by the reaction of thienyl-lithiums with dimethyl oxalate and by oxidation of the thenoins resulting from the reaction of thienyl Grignards with t h i e n y l g l y ~ x a l s . ~ ~ ~ ~ The reaction of substituted thienyl-lithium derivatives, obtained by direct metalation or through halogen-metal exchange, with perchloryl fluoride has been utilized in the preparation of a large number of fluorot h i o p h e n ~ .98b ~ ~ ~Tetrafluorothiophen , has been prepared by dehydrofluorination of 3H/4H-hexafluorothiolan by molten alkali, and its reaction It reacted with sodium methoxide to yield 2-methoxy-3,4,5trifluorothiophen, which rapidly polymerized. Reaction of tetrachlorothiophen with cobalt trifluoride gave mainly polychloropolyfluorobutanes In connection and only small amounts of cyclic sulphur with attempts to prepare 2-fluorothiophen from 2-iodothiophen in dimethyl sulphoxide, disproportionation of the latter to 2,5-di-iodothiophen was observed. In addition, the interesting formation of small amounts of 5-iodothiophen-2-aldehydewas 0 b s e r ~ e d . l ~ ~ ~ The metalation of 3-benzylthiophen with ethereal butyl-lithium occurs to 88% in the 5-position and to 12% in the 2-po~ition.l~~ The isomer distribution obtained on metalation of 3-phenylthiophen was determined by conventional reactions of the lithium reagents 138 and by direct equal amounts of 3-phenyl-2-thienyln.m.r. a n a 1 y ~ i s . l Approximately ~~~ lithium and 3-phenyl-5-thienyl-lithiumwere formed. The reaction of 3-(p-bromophenyl)thiophen with butyl-lithium has been studied.lS6 Both halogen-metal exchange and metalation occurred as 3-(p-carboxyphenyl)thiophen, 3-p-bromophenyl-2-carboxythiophen,and 4-(p-bromophenyl)-2carboxythiophen were obtained in the relative proportions 1 :3 : 2. Interestingly, in the same reaction with 3-(o-bromophenyl)thiophen, both halogen-metal exchange and metalation of the 2-position of the same molecule were observed, as 3-(o-~arboxyphenyl)thiophen, 2-carboxy-3phenylthiophen, and 2-carboxy-3-(o-carboxyphenyl)thiophenwere obtained in the relative proportions 1 : 2 : 3. As demonstrated earlier, acetals of 3-thienylcarbonyl derivatives are metalated selectively in the 2-position, and this was utilized in the preparation of 3-benzoylthiophen-Zcarboxylic acid from the ethylene acetal of 3-benzoylthiophen, 3-acetyl-2-benzoylthiophen from the acetal of 3-acetylthiophen, and 2-benzoyl-3-formylthiophen from the acetal of thiophen-3-aldeh~de.l~~ t-Butyl 2-thienyl sulphone is easily dimetalated with butyl-lithium in the 3- and 5-positions, yielding the dialdehyde (90) upon reaction with NN-dimethy1f0rrnamide.l~~ 136a9

13&

134d

R. D. Schuetz and G. P. Nilles, J. Org. Chem., 1971, 36,2486. J. Burdon, I. W. Parsons, and J. C. Tatlow, J. Chem. SOC.(C), 1971, 346.

13M

A. G. Giwnanini and D. Savoia, J. Org. Chem., 1972, 37, 514. D. W. H. MacDowell and A. T. Jeffries, J. Org. Chem., 1971, 36, 1053. N. Gjas and S. Gronowitz, Arkiv Kemi, 1968, 30,225.

lS8

R. Leardini, G. Martelli, P. Spagnolo, and M. Tiecco, J. Chem. SOC.(C), 1970, 1464.

lS7

F. M. Stoyanovich and B. P. Fedorov, Khim. geterotsikl. Soedinenii, 1967, 3, 823.

13& 136


389

Yo

O H C1Q S O , B U t (90)

The t-butylsulphonyl group readily undergoes nucleophilic displacement by RS and RO groups, making this a preparatively useful route. t-Butyl 3-thienyl sulphone is also easily dimetalated in the 2- and 5-positions. The dialdehyde formed upon reaction with D M F does not, however, undergo nucleophilic substitution. NN-Dimethyl-Zthenylamine has been metalated with butyl-lithium in the 5-position; the product reacted with benzaldehyde and benzophenone to give (91).laa When the 5-position is blocked, metalation occurs in the

3-po~ition.l~~" In contrast to 3-alkylthiophensYNN-dimethyl-3-thenylamine and 3-thenyl methyl ether are metalated by butyl-lithium exclusively in the 2-position, probably owing to the co-ordination of the alkyl-lithium to the (59) has been metalside-chain h e t e r ~ a t o m .lY4-Di-(2-thienyl)benene ~~~~ ated in its free a-positions and converted into the dialdehyde.lo1 A very interesting discovery is that the alkylseleno-group in alkyl 2-thienyl selenides is very easily cleaved by alkyl-lithium reagent. This group is more reactive than /%bromine, as 4-bromo-2-methylseleno-5-methylthiophen even at - 70 "C with butyl-lithium yields 4-bromo-5-methyl-2thienyl-lithium and methyl butyl ~ e l e n i d e . ~5-Bromo-2-methylseleno~ thiophen gives bromine exchange, yielding 2-methylseleno-5-thienyllithium. In contrast to the alkyl-2-thienyl selenides, the corresponding 3-isomers are metalated in the a-positions. 3-Methylselenothiophen thus gives 56% metalation in the 2-position and 44% in the 3-positi0n.~~~ In order to determine whether a-bromine or p-iodine is more reactive in the halogen-metal exchange reaction, 3-iodo-2-bromothiophen was studied.la9 At - 100 "C 2-bromo-3-thienyl-lithium could be trapped. Even at - 70 "C a series of rapid halogen-metal exchange reactions occurred, leading to thermodynamically more stable'lithium derivatives, predominantly 3-bromo-2-thienyl-lit hium. Also with 2-bromo-3 thienyllithium, the most unstable ortho-halogenothienyl-lithium hitherto studied, no evidence for the splitting of lithium bromide and the formation of thiophyne could be obtained. Starting from the isomeric dibromothiophens and using two halogen-metal exchanges, many disubstituted thiophens have been prepared. For instance, starting from 3,4-dibromothiophen,

-

lS8 lSa4 lS8

R. T. Hawkins and D. B. Stroup, J. Org. Chem., 1969,34, 1173. D. W. Slocum and P. L. Gierer, Chem. Comm., 1971, 305. S. Gronowitz and B. Holm, Act0 Chem. Scund., 1969,23, 2207.

390


3-bromo-4-fluorothiophen was obtained by the reaction of 3-bromo-4thienyl-lithium with perchloryl fluoride. Renewed halogen-metal exchange followed by reaction with perchloryl fluoride yielded 3,4-difl~orothiophen.~~g Other br omofluorot hiophens and difluorothiophen were obtained similarly. In this connection it should perhaps be mentioned that tetrafluorothiophen was prepared by the reaction of thiophen with potassium tetrafluorocobaltate(m), followed by dehydrofluorination of the addition product by molten potassium hydroxide at 250 OC.140 Double halogen-metal exchange between 2,3,5-tribromothiophen and butyl-lithium gave 3-bromo-2,5dilithiothiophen, which upon reaction yielded 3-bromothiophen-2,Sdialdehyde. Protection of the formyl groups by acetal formation and renewed halogen-metal exchange and reaction with DMF gave thiophen2,3,5-trialdehyde after hydr01ysis.l~~The other isomeric thiophen trialdehyde was prepared by metalation of thiophen-3,4-dialdehyde ethylene acetal followed by reaction with DMF.124 Finally, the acetal of thiophen2,3,4-trialdehyde upon metalation and reaction with DMF gave thiophen tetra-aldehyde.lP1 Halogen-me ta1 exchange between 3-phenyl-5 -br om0t hiophen and butyl-lithium followed by reaction with DMF and NN-dimethylacetamide yielded 4-phenylthiophen-2-aldehyde and 2-acetyl-4-phen ylthiophen.loo Trichloro-2-thienyl-lithium has been prepared through halogen-metal exchange between tetrachlorothiophen and t-butyl-lithium in THF at - 70 0C.1422-t-Butoxy-3-thienylmethanols were prepared by the reaction of 2-t-butoxy-3-thienyl-lithium with ketones.142a 2-Thienyl-lithium reacts with perfluoroalkyl halides to give 70-80% yields of 2-halogen0thiophens.~~~ Thus, in order to prepare (60), perfluoroglutaric acid was treated with a large excess of 2-thienylmagnesium bromide, yielding (92), which through reaction with sulphur tetrafluoride was converted into (60).

(92)

The coupling of thienyl-lithium derivatives with cupric chloride to yield symmetrically substituted bithienyls has during recent years been extensively used in connection with work on optically active bithienyl derivatives and in connection with the synthesis of thiophen analogues of fluorene,126a-c and d i t h i e n o t h i ~ p h e n s . ~ ~Thus ~ ~ ~ 3,3’-bi thienyl and 4,4’-di bromo-3,3’bithienyl prepared in this way were brominated to form hexabromo-3,3’bithienyl. Halogen-metal exchange occurred selectively in the 53’positions, yielding the acid (93) upon (93) was resolved into 140 141 142

142a 143

J. Burdon, J. G. Campbell, I. W. Parsons, and J. C. Tatlow, Chem. Comm., 1969, 27. J. Morel, C. Paulmier, and P. Pastour, Compt. rend., 1969, 269, C, 37. I. Haiduc and H. Gilman, Rev. Roumaine Chem., 1971, 16, 305. E. B. Pedersen and S.-0. Lawesson, Tetrahedron, 1970, 26, 2959. R. HAkansson and E. Wiklund, Arkiu Kemi, 1969, 31, 101.

Thiophens and their Selenium and Tellurium Analogues 39 1 optical antipodes, and decarboxylation yielded the symmetrically substituted opticallyactive2,2’,4,4’-tetrabromo-3,3’-bithienyl. By transforming optically active (93) and optically active 4,4’-dibromo-2,2’-dicarboxy-3,3’-bithienyl (93a) to optically active hexabromo-3,3’-bithienyl(93b), it was found that (-)-(93), (+)-(93a), and (-)-(93b) have the same absolute configuration with respect to the bithienyl ~ k e 1 e t o n . l The ~ ~ ~reaction of optically active

(93) with excess ethyl-lithium for 2 min at - 70 “C,followed by carbonation, gave completely racemic (93a). On using instead one equivalent of butyl-lithium, active 2,4,4’-tribromo-2’-carboxy-3,3’-bithienyl(93c) was obtained. The outcome of halogen-metal exchange has been found to be dependent on the alkyl-lithium Thus 2,2’-dibromo-3,3’-bithienyl with one equivalent of butyl-lithium at - 70 “C yields mainly monocarboxylic acid upon reaction with COa, whereas ethyl-lithium yielded mixtures consisting of 60% dicarboxylic acid and 40% monocarboxylic acid. 4,4’-Dibromo3,3’-bithienyl was metalated at one of the 5-positions, and, when they were blocked by methyl groups, a mixture of a 4’-monocarboxylic acid and a 2,4’-dicarboxylic acid was obtained with both lithium reagents. The formation of dicarboxylic acids is suggested to be a consequence of the aggregated structure of organolithium 2-Thienylcopper preparations have been obtained by the reaction between 2-thienyl-lithium and copper(r) iodide or copper(1) bromide, which upon reaction with a number of iodoarenes and some bromoarenes in pyridine or quinoline yielded the corresponding 2-arylthiophens selectively in reasonable yields.ld4 The effect of substituents in the halogenoarenes has been studied. Strongly electron-attracting groups ortho to the iodine increase the reaction rate significantly. Meisenheimer complexes have been obtained in the reaction of 2-thienylcopper with 1,3,5-trinitroben~ene.~~~~ 3,4,5-Trichloro-2-thienylcopperwas prepared from trichloro-2-thienyllithium and copper@ bromide, and with 4-iodoanisole in pyridine 143b lr14

14@

R. Hitkansson and E. Wiklund, Acta Chem. Scand., 1971, 25, 2109. R. Hitkansson, Acta Chem. Scad., 1971, 25, 1313. M. Nilsson and C. Ullenius, Actu Chem. Scand., 1970, 24, 2379. M. Nilsson, C. Ullenius, and 0. Wennerstrom, Tetrahedron Letters, 1971, 2713.

392


gave the corresponding 2-(4-methoxyphenyl)trichlorothiophen selectively and in good yield.144b The decarboxylative coupling of copper(1) 3,4,5trichloro-Zthenoate with 4-iodoanisole was also studied, and proceeds via trichlor0-2-thienylcopper.~~~* Arylcopper reagents have also proved useful for the synthesis of biheterocyclics. The reaction of 1 -methyl-2pyrrolylcopper, prepared via the lithium derivative, gave with 2- and 3-iodothiophen preparatively useful yields of 1 -methyl-243-thienyl)pyrrole and 1-methyl-2-(3-thienyl)pyrr0le.~~*The Ullmann reaction of 1,3-di-iodohexafluoropropanewith 2-iodothiophen and copper in pyridine gives (94) in 25% 2-Iodothiophens react with iodoboranes to form mono-, di-, and tri-thienylboranes and elemental iodine.145 The thienylborane (94a) yields upon distillation the tricyclic derivative (95).

(94)

(94 4 I

I

I (95)

Photochemistry of Thiophens.-Wynberg and co-workers have continued their investigations on the photochemistry of t h i ~ p h e n sand , ~ ~an ~ excellent essay by Wynberg on the photochemistry and other aspects of thiophen chemistry has recently been p~b1ished.l~~" The photoisomerizations of thiophens are also discussed in a detailed review article on the photoisomerization of five-membered Irradiation of 2-methyl-, 2-benzyl-, 2-neopentyl-, and 2-t-butyl-thiophens leads to their irreversible transformation to the corresponding 3-substituted derivatives in 8-27% yields. 2,5-Di-t-but ylthiophen rearranges irreversibly to the 2,4-isomer, which is remarkably stable under the reaction conditions. Irradiation of 2,2'-bithienyl leads to 2,3'-bithienyl and a small amount of benzo[b]thiophen. 2,3'-Bithienyl affords 3,3'-bithienyl and benzo[b]thiophen as major products. 5,5'-Di deuterio-2,2'- bithienyl gives 5,S-di deut erio-2,3'-bit hienyl M. Nilsson and C. Ullenius, Acta Chem. Scund., 1971, 25, 2428. J. P. Critchley, V. C. R. McLoughlin, J. Thrower, and I. M. White, Chern. and Ind., 1969, 934. 14* V. C. R. McLoughlin and J. Thrower, Tetrahedron, 1969, 25, 5921. W. Siebert, Chem. Ber., 1970, 103, 2308. 116 R. M. Kellogg, J. K. Dik, H. van Driel, and H. Wynberg, J . Org. Chem., 1970, 35, 2737. lPW H. Wynberg, Accounts Chem. Res., 1971, 4, 65. lP8* A. Lablache-Combier and M.-A. Remy, Bull. Soc. chim, France, 1971, 679. lPlb l44e


393 upon irradiation, whereas 2,5'-dideuterio-2,3'-bi thienyl gives 2,5'-dideuterio3,3'-bi thienyl and 4,7'-dideuteri obenzo [blthiophen. A valence-bond isomerization reaction is proposed to account for the r e s ~ 1 t s . lIrradiation ~~ of thiophen and the methylthiophens in primary amines yields N-substituted pyrr01es.~~~ Thus 2-methylthiophen in propylamine gave a 5 : 1 mixture of N-propyl-2-methylpyrrole and N-propyl-3-methylpyrrole. In cyclohexylamine only N-cyclohexyl-2-methylpyrrolcwas formed. It is assumed that the cyclopropenylthioaldehyde, which has been suggested as an intermediate in the photochemical rearrangements of thiophens, is trapped by the amine. Irradiation of furan and 2,4- and 2,5-dimethylfuran in propylamine leads to the same N-propylpyrrole as obtained from the corrcsponding t h i ~ p h e n s . ~ ~Photodimerization ~"~ of the two thiophen analogues of the chalcones (96) and (97) yielded the cyclobutane derivatives (98) and

FOCdH3S

COPh

sH3c4

0 C4H3S

Q-COCH=CHO

(1 02)

(99), respectively, whereas the chalcone analogue (100) gave a mixture of (101) and (102). The yields varied from 4-10% and the structures were determined by n.m.r. and mass spe~trometry.l*~ A. Couture and A. Lablache-Combier, Chem. Comm., 1969, 524. A. Couture and A. Lablache-Combier, Chem. Comm., 1971, 891. 147b A. Couture and A. Lablache-Combier, Tetrahedron, 1971, 27, 1059. H. Wynberg, M. B. Groen, and R. M. Kellogg, J. Org. Chem., 1970,35, 2828. 14'

14'0

394 Organic Compounds of Sulphur, Selenium, and Tellurium In an investigation on the benzophenone-sensitized photoaddition of citraconic anhydride and 2,3-dimethylmaleicanhydride to several thiophen and benzo[b]thiophen derivatives, it was found that, when 2,5-dimethylthiophen was used as substrate, only small amounts of the expected adduct (103) were formed, the main product being (104).149 Using only benzophenone in the photoaddition, the yield of (104) was 62%. The reaction R1

,o

(103)

Ph

(104)

failed with other thiophen derivatives such as 2- and 3-methylthiophen. The mass spectra of the 1,2-~ycloadditionproducts have been The reaction of singlet oxygen with simple thiophens has recently been studied. 2,5-Dimethylthiophen yields the sulphine (105) as the main product, and the ketone (106) as b y - p r o d ~ c t . ~151 ~ *From ~ the thiophen Me-C-C-Me

'AI+

JoMe

(J

0(105)

(108)

(108a)

(107) the compound (108) was obtained in methanol solution.lsl It is supposed that (108) is formed by methanol addition to the sulphine (108a). The mechanism of sulphine formation was discussed. U.V. irradiation of 3,4-diformylthiophen in CCl, yields the lactone (log), whereas 2,3-diformylthiophen gives a mixture of (109a) and (109b).l5Ia Upon irradiation, many 2-acylthiophens undergo 2 + 2 cycloaddition to simple olefins at the 2,3-position of the ring in the same way as carbocyclic ketones. A n -+ n* lowest triplet is implicated as the reactive excited state.151b C. Rivas, M. VClez, and 0. Crescente, Chem. Comm., 1970, 1474. S. E. Flores, M. VClez, and C. Rivas, Org. Mass Spectrometry, 1971, 5, 1049. C. N. Skold and R. H. Schlessinger, Tetrahedron Letters, 1970, 791. lS1 H. H. Wasserman and W. Strehlow, Tetrahedron Letters, 1970, 795. lsl0 C. Paulmier, J. Bourguignon, J. Morel, and P. Pastour, Compt. rend., 1970, 270, C, 14*

1400 160

494. T. S. Cantrell, Chem. Coinm., 1972, 155.

395


( 1094

(109)

(109h)

The photoconversion of some iodophenyl(thieny1)ethylenes and iodothienyl(thieny1)ethylenes into naphthothiophens and benzodithiophens, respectively, has been carried The results suggest that the intermediate in these cyclizations is most probably a dihydro-derivative, which suffers dehydrogenation, rather than an aryl radical which effects an intramolecular substitution.

Application of the Hammett Quation.-There has been great interest during the past two years in the application of Hammett-like relations to reactivity data or physical data in the thiophen series. One approach has been to determine a+-values for the 2-thienyl and 3-thienyl groups, which would make it possible, for instance, to predict the reactivity of thiophen if the p-value for the reaction was known from investigations of substituted benzenes. Such o+-values have been obtained, as mentioned before, from , ~such ~ ~ as a recent extensive study studies on electrophilic s ~ b s t i t u t i o n s87 of detritiation in trifluoroacetic acid at different temperatures. This provides a set of air, including those for 2- and 3-thienyl, applicable to electrophilic aromatic substitution in a large range of aromatic systems,162aand to homolytic ary1ati0n.l~~a+-values for the 2-thienyl and 3-thienyl groups have also been obtained for side-chain carbonium-ion reactions such as the solvolysis of l-(thieny1)ethyl p-nitrobenzoates and the isornerization of ~is-2-styrylthiophen.~~~ It seems clear that, in general, satisfactory correlation of a wide variety of reactions involving electron-deficient intermediates may be achieved with a of-constant for the 2-thienyl group of about - 0.80 and for the 3-thienyl group of about - 0.47. A marked exception was obtained in a study of the vapour-phase thermolyses of heteroaromatic l-arylethyl acetates to an arylethylene and acetic acid, which gave a+-values of - 0.68 and -0.24 for the 2- and 3-thienyl group, respectively. Some explanations for this are given.153a Another approach has been to relate the reactivities and properties of substituted thiophens to thiophen itself, using the same 0- and a+-values 82 As only few substituents have been included as in the benzene in the treatment, the general applicability is still somewhat doubtful. Attempts have been made to obtain a set of U-values for substituents on thiophen from dissociation constants for a number of substituted thiophen2-carboxylic The values obtained do not differ very much from 419

lsa 15za

153

15m

G. De Luca, G. Martelli, P. Spagnolo, and M. Tiecco, J. Chem. SOC.(C), 1970, 2504. R. Baker, C. Eaborn, and R. Taylor, J. C. S. Perkin 11, 1972, 97. D. S. Noyce, C. A. Lipinski, and G. M. Loudon, J. Org. Chem., 1970, 35, 1718. G. G. Smith and J. A. Kirby, J. Heterocyclic Chem., 1971, 8, 1101. A. R. Butler, J. Chem. SOC.(B), 1970, 867.

396


those in the benzene series, and were in excellent agreement with those calculated by the method of Dewar and Grisdale. However, results obtained by other workers indicate that only for electron-donating groups was it possible to use the same U-values as in the benzene series; larger values had to be used for electron-withdrawing Using this set of a-values for the substituents, a good Hammett correlation could be obtained for the rate constants for the rearrangement of thenils to thenilic acids.154uHammett-type treatments have also been applied to nucleophilic substitution of 2-nitro-3-bromothiophens 121 and the gas-phase ionization of 5-substituted t h i 0 ~ h e n s . lA ~ ~two-parameter ~ equation, using the reactivity constants of Swain and Lupton, was successfully applied to the correlation of n.m.r. spectral Finally, different types of a-constants for the 2-thienyl and 3-thienyl groups as substituents in the para- and meta-positions of benzene have been determined by measuring the ionization constants of p- and rn- (2- and 3-thieny1)benzoic acids and phenols 155 and the rates of solvolysis of 2-chloro-2-rn(orp)-2(or 3)-thienylpropanes in 90% aqueous acetone.155a The :a and of constants for the 2- and 3-thienyl groups have been calculated using the Brown-Okamoto equation. However, later studies of the solvolyses of 1-(Zthienylpheny1)ethyl acetates in aqueous 30% ethanol and of the carbonyl stretching frequencies of 2-thienyl-substituted acetophenones yielded a;t-values of - 0.33 and 0.38 for the 2-thienyl whereas the solvolyses of 1-arylethyl acetates gave a value of - 0.43,155aand an earlier value derived from the rate constants of the protodetritiation of 2,2'-[5-3H]bithienyl and [2-3H]thiophenis - 0.23.155c It is thus obvious that the electronic effects of a thienyl group as substituent at thepara-position of benzenes are variable and cannot be represented by a single a+,-value. Marino indicates that a two-parameter equation of the Yukawa-Tsuno type would give better correlations, which seems reasonable in the light of experience with the correlation of n.m.r. data.6g0 The Structures and Reactions of Hydroxy- and Mercapto-thiophens and their Simple Derivatives.-2-Hydroxythiophens can in principle exist in three tautomeric forms, the hydroxy-form (110) and the 3- (111) and 4-thiolen-2-one (1 1la) forms. During recent years a series of derivatives of the 2-hydroxythiophen system, substituted with halogen, methoxy, aryl, and R OS O H

" H

0

0

G. P. Nilles and R. D. Schuetz, J. Org. Chem., 1971, 36, 2489. P. Linda, G. Marino, and S. Pignataro, J. Chem. SOC.(B), 1971, 1585. lSs F. Fringuelli, G. Marino, and A. Taticchi, J. Chem. SOC.(B), 1970, 1595. F. Fringuelli, G. Marino, and A. Taticchi, J. Chem. Sac. (B), 1971, 2302. l m b F. Fringuelli, G. Marino, and A. Taticchi, J . C. S. Perkin ZZ, 1972, 158. 16se A. R. Butler and C. Eaborn, J. Chem. SOC. (B), 1968, 370. lSM.

lsob


397 alkyl groups, has been prepared, and the tautomeric structures and thermodynamic equilibria have been determined by means of n.m.r. spectroscopy (for a review cf. Refs. 156 and 157). The rates of tautomerization of 5-methyl- and 5-t-butyl-thiolen-Zone have been studied in methanolic solutions, pyridine serving as base,15*and also compared with those of the oxygen analogues, the /3,y-butenolide~.~~~ Deuterium exchange in 5-methyl4-thiolen-2-one 180 as well as the influence of various bases on its rearrangement has been studied.lal Dissociation constants and U.V. spectra of the 5-methyl- and 5-t-but ylthiolen-Zones have been determined.la2 The 5-alkyl-substituted thiolen-Zones undergo Michael-type d i m e r i ~ a t i o n s . ~ ~ ~ The sodium salt of the 5-methyl-2-hydroxythiophen system has been alkylated with methyl iodide, ally1 bromide, benzyl bromide, and dimethyl sulphate. The 3-position was found to be most reactive, whereas O-alkylation was obtained in the reaction with dimethyl s ~ 1 p h a t e . l ~ ~ ~ A more convenient method of alkylation is through an ion-pair extraction method using the tetrabutylammonium which is better than the alkylation of thallium(1) Also, in these cases dimethyl sulphate gives predominantly O - m e t h y l a t i ~ n . ~ ~ Oxidative ~~, coupling of the 2,5-dimethyl-3-hydroxythiophensystem with potassium ferricyanide yields a mixture of the racemic and meso-forms of (112). 2,5-Di-t-butyl-3hydroxythiophen, on the other hand, gives (1 12a).1S3BTreatment of 2-tbutoxy-3-thienylmethanols(113) with toluene-p-sulphonic acid at elevated

Mc

""QO

B u t rSJ B u '

(112)

(112a)

temperature causes both dehydration and dealkylation, producing a mixture of (1 14) and (115).142a(115) smoothly undergoes Diels-Alder reactions with dienophiles ;for instance (116) yields (1 17) with ethyl vinyl ether. The four isomeric di-t-butoxythiophens, as well as some substituted di-t-butoxythiophens, have been prepared via organometallic reagents. A.-B. Hornfeldt, Svensk kem. Tidskr., 1968, 80, 343. S. Gronowitz, 'The Jerusalem Symposia on Quantum Chemistry and Biochemistry II', The Israel Academy of Sciences and Humanities, Jerusalem, 1970. 16* A.-B. Homfeldt, Actu Chem. Scund., 1967, 21, 673. 15B A.-B. Hornfeldt, Arkiv Kemi, 1968, 29, 229. le0 A,-B. Hornfeldt, Arkiv Kemi, 1968, 29, 455. lol A.-B. Hornfeldt, Arkiv Kemi, 1968, 29, 461. lea A.-B. Hornfeldt, Arkiv Kemi, 1968, 29, 247. le3 A.-B. Hornfeldt, Arkiv Kemi, 1968, 28, 363. B. Cederlund and A.-B. Hornfeldt, Actu Chem. Scund., 1971, 25, 3324. l s s b B. Cederlund, A. Jesperson, and A.-B. Hornfeldt, Acta Chem. Scund., 1971,25, 3656. l9Sc B. Cederlund and A. B.-Hornfeldt, Actu Chem. Scund., 1971, 25, 3546. loSdE. B. Pedersen and S . - 0 . Lawesson, Tetrahedron, 1971, 27, 3861. los* A.-B. Hornfeldt and P.-0. Sundberg, Acta Chem. Scand., 1972, 26, 31. 156

lS7

398

Organic Compounds of Sulphur, Selenium, and Tellurium R1

R1 I C-R2

K2

K2

I C=CHR3

\ /

$ ::

6 0

(1 13)

0

(1 14)

0

(115)

Ph

Acid-catalysed dealkylation gave the corresponding dihydroxythiophen systems. The predominant tautomeric structure was determined by spectroscopic methods.laa 5-Substituted 2-cyano-3-hydroxythiophens,prepared through ring-closure reactions, were shown to exist as intramolecularly hydrogen-bonded hydro~y-forms.l~4~ During recent years Gol’dfarb and his co-workers in Moscow have carried out interesting work on the synthesis and properties of 2-mercapto5-alkyl-3-thenylideneimines(118),165 which were obtained through the H I

CH(0Et)Z

(118)

(1 19)

action of sodium in liquid ammonia on the diethylacetals of 2-alkylmercaptothiophen-3-aldehydes (1 19). The unusual stability of these imines was explained by intramolecular hydrogen-bonding. On the other hand, attempts to prepare similar derivatives from analogously constituted benzene derivatives failed.1s5a This was explained by the different geometries of thiophen and benzene rings. In order to study the effect of the mode of annelation on the stability of the mercapto-aldimines, a study of the reduction of (120) and (121) with sodium in liquid ammonia has been undertaken.lse However, the reaction was more complex and proceeded differently. Treating (120) and (121) with two equivalents of sodium yielded the corresponding mercapto-acetals (122) and (123) as the main 16& 16s

16*

lE6

B. Hedegaard, J. Z . Mortensen, and S.-0.Lawesson, Tetrahedron, 1971, 27, 3853. J. Z. Mortensen, B. Hedegaard, and S.-0.Lawesson, Tetrahedron, 1971, 27, 3839. Ya. L. Gol’dfarb and M. A. Kirmalova, Zzvest. Akad. Nauk S.S.S.R., Ser. khim., 1962, 70. Ya. L. Gol‘dfarb, A. E. Skorova, and M. L. Kirmalova, Zzvest. Akad. Nauk S.S.S.R., Ser. khim., 1966, 1421. Ya. L. Gol’dfarb, M. A. Kalik, and M. L. Kirmalova, Khim. geterotsikl. Soedinenii, 1967, 3, 62.


399 products. Reaction of an alkaline solution of (122) with ammonia and HCl at pH 8 led to the formation of the tautomeric system (124) + (125).lSaa 1.r. and n.m.r. spectroscopic investigation indicated the predominance of (124). The reaction of (124) with methyl iodide in methanolic potassium hydroxide led to the interesting formation of (126). The action of primary MeS

SEt

R

RQCH(OEt)2

CHNH-CH

SMc

CH(0Et)z

Q

CH-N=CH

MeS

O C HI - N = = C H G

amines on (124) gives N-substituted 3-mercapto-2-thenylideneimides (127), which with nickel acetate form an intramolecular complex. Treatment of (120) and (121) with six equivalents of sodium led to the reduction of the acetal groups to methyl, yielding 2- and 4-methylthiophen-3-thi0ls.~~~ Derivatives of (127) and of the 2-mercapto-derivative (127a) have been shown by n.m.r. and i.r. to exist predominantly as (127b).166bAlso, the oxygen analogue exists predominantly in the similar tautomeric form (127c).lS7 H

I

H

H I

I

R(-j:N-R qfJR

EtQ-R s

(1 27a) leas

(127b)

' .+.H

(1 27c)

Ya. L. Gol'dfarb, M. A. Kalik, and M. L. Kirmalova, Khim. geterotsikl. Soedinenii, 1967, 3, 71.

V. S. Bogdanov, M. A. Kalik, I. P. Yakovlev, and Ya. L. Gol'dfarb, Zhur. obshchei Khim., 1970,40, 2102. lE7 V. S. Bogdanov, M. A. Kalik, and Ya. L. Gol'dfarb, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1970, 2413. lBEb

400


The sodium reduction has been extended to esters. Thus, methyl 2-ethylmercapto-5-ethyl thiophen-3-carboxylate (128) yielded the amide (129) as the main product upon treatment with four equivalents of sodium in liquid ammonia.168 Reduction of aldimines such as (1 18) with LiAlH4 gives thenylamines such as (130) in high yield, which can be condensed

(130)

(131)

(1 32)

with aromatic aldehydes or carbon disulphide to give 2-substituted 3,4dihydro-6-ethylthieno[3,2-e]173-thiazines (13 1) and (132), respectively.lss The bromination of the metal complexes (133) and (134) with bromine and N-bromosuccinimide leads to cleavage of the chelate ring and formation of the corresponding thieno[3,2-d]- (135) and thieno[2,3-d]- (136) isothiazolium Related to the above-mentioned work is an e.s.r. study of the copper(I1) complex (137).171 The reaction of 3-hydroxythiophen-2-carboxylateswith P,Sl, leads to thieno[3,2-c]l72-dithio1an-3-thione(138) and the phosphorus-containing

a l z Br-

R"'b Et

Ya. L. Gol'dfarb, M. A. Kalik, and M. L. Kirmalova, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1969, 2260. Ya. L. Gol'dfarb, M. A. Kalik, and M. L. Kirmalova, Khim. geterotsikl. Soedinenii, 1967, 3, 59. Ya. L. Gol'dfarb and M. A. Kalik, Khim. geterotsikl. Soedinenii, 1967, 3, 1022. I. V. Miroshnichenko, Ya. L. Gol'dfarb, M. A. Kalik, and G. M. Larin, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1969, 1494.

lBB

169

171

Et


401

ring system (138a).172e172a Compounds of the type (138) have also been prepared through the reaction of 5-vinyl-1,2-dithiolan-3-thiones with sulphur.173 The imino-form (139) has been found to be the stable tautomeric form.6a In connection with a u.v., i.r., and n.ni.r. spectral investigation of

p-enamino-esters it was confirmed that simple ethyl 2-aminothiophen-3carboxylates exist in the a m i n o - f ~ r m . ~ ~ ~ ~ Side-chain Reactivities.-The influence of the thiophen ring on the reactivity of functional groups bound to it has not been studied extensively in a quantitative way. However, carbonyl derivatives in particular and also halogenomethyl derivatives have been extensively utilized for the synthesis of various types of derivatives, and especially for the annelation of saturated and aromatic rings on to the b- and c-sides of thiophen. The interest in the effect of the mode of annelation on chemical and physical properties of the systems is still very strong. Specially interesting are the attempts to put obviously very strained four-membered rings on to thiophen, which recently have been successful. Thus, the reaction of the diketone (140) with the bis-ylide (140a) gave the 2-thianorbiphenylene (140b).173b The diketone (140c), with the ylide (140a) at - 78 "C, gave the bright-red thienocyclobutadiene (140d) in low yield. On heating under nitrogen to 160 "C, (140d) dirnerized to (140e). The reaction of (140e) with tetracyanoethylene has been Cyclization of (141) with potassium t-butoxide yielded (142a), which could be dechlorinated catalytically to the parent It has been shown that the true structure of a compound claimed to be (142c) is the J. Brelivet, P. Appriou, and J. Teste, Compt. rend., 1969, 268, C, 2231. J. Brelivet, P. Appriou, and J. Teste, Bull. SOC.chim. France, 1971, 1344. P. Appriou, J. Brelivet, and J. Teste, Bull. SOC.chim. France, 1970, 1497. 17s4 H. Wamhoff, H. W. Diirbeck, and P. Sohhr, Tetrahedron, 1971, 27, 5873. 17Sb P. J. Garratt and K. P. C. Vollhardt, Chem. Comm., 1970, 109. 173c P. J. Garratt and K. P. C. Vollhardt, J. Amer. Chem. SOC.,1972, 94, 1022. 174 D. J. Zwanenburg and H. Wynberg, J. Org. Chem., 1969,34,340. 17*a 173


402

Ph,P--\ S

Ph,P=/

Ph ( 140b)

(140a)

(140)

(140d)

Ph

Ph

Ph

Ph

0

(140c)

(140e)

(a)

R

H

=

(b) R = Cl (c) R = But

(142)

dimeric (143).174Steric inhibition of intramolecular cyclizations by orthosubstituentshas been observed and e~p1ained.O~ Thus, whereas the reaction of (144) with sodium sulphide furnished (145),(144a) did not form a thienopyrrole derivative with ethylamine in acetonitrile, but cyclization to (146) was successful when the chlorine atoms of (144)were removed prior to the reaction with ethylan~ine.~* Et

(a) X = C1

(b) X

=

(144)

Br

X = C1 (b) X = Br (a)

(145)

Ring-closure of the bischloromethyl derivative (1 47)with several primary amines gave a series of 5,6-dihydro-4H-thieno[2,3-c]pyrroles(148), which were oxidized to the corresponding N-oxides (149).175When the group on nitrogen was aromatic and the oxidation was carried out with aqueous hydrogen peroxide in formic acid, the Meisenheimerrearrangement product (150) was obtained instead of the iV-0~ide.l~~ 3,4-Biscyanomethylthiophens 176

J. Feijen and H. Wynberg, Rec. Trav. chim., 1970, 89, 639.


403

have been used in the synthesis of derivatives of a new condensed heterocyclic system, 4H-thien0[3,4-d]azepine,~~~~ and also transformed to the bismethoxycarbonylmethylthiophens,which react normally in the Dieckmann cyclization, yielding after hydrolysis and decarboxylation the c-annelated indanone ana10gue.l~~~ It has earlier been shown that ortho-formylthiophencarboxylicacid exists in the open form, in contrast to ortho-formylbenzoic acid. The lesser tendency for ring-closure of a five-membered ring on to thiophen, most probably due to angle-strain, is also illustrated in the low yields of lactones obtained from ortho-hydroxymethylthiophencarboxylic acids by conventional rnethods.l5la For a study of ring-chain tautomerism, a number of ortho-benzoyl- and ortho-acetyl-thiophencarboxylic acids, as well as chlorides and esters derived from them, have been synthesized.125 Methyl-substituted thienothiophens have been obtained by condensation of methyl esters of ortho-formyl- or -acetyl-thienylthioacetic acids.176 2,3-Diformylthiophen reacts with nitromethane in the presence of alkali to give the nitronate salt (151), which upon acidification with strong acid gives a mixture of (152) and (153), which in turn can easily be transformed to the 2-indanone analogue (154).177 OH

OH

OH (151)

OH

( 152)

(1 54)

(153)

The condensation of thiophen aldehydes with nitromethane to o-nitrovinylthiophens has been extensively used in connection with the synthesis of thiophen analogues of isoquinoline.l1lC The liquid-phase hydrogenation of w-nitro-2-vinylthiophen over Pd-black to 2-thienylacetaldoxime has Hoogzand, J. Nielsen, and E. H. Braye, Chem. Cumm., 1971, 1520. R. Helmers, J. prukt. Chem., 1971, 313, 31. A. Bugge, Acta Chem. Scand., 1971, 25, 27. J. Skramstad, Acta Chem. Scand., 1971, 25, 1287.

17mC. 176b 176

17'

404


been studied in detail.178 The Cannizzaro reaction has been applied to the various diformylthiophen~.~~~ 5-Acetylaminothiophen-2-aldehydehas been condensed with some active methylene The benzoin condensation has been used for the synthesis of substituted thenoins from thiophen-2-aldehyde~,l~~~ which have also been obtained through the reaction of 2-thienylglyoxal with thienylmagnesium reagent~.~~~~ An intramolecular benzoin condensation with 2,2'-diformyl-3,3'-bi thienyl has been utilized for the synthesis of a dithienobenzoquinone.le0 The Wittig reaction and its modifications have been shown to be useful in the thiophen lol especially in connection with the synthesis of heterohelicenes and dithienotropylium ions.lez Predominantly cisisomers could be obtained from certain bromothiophen aldehydes and bromothenyl trip henylphosphonium halides.lE2 Important quantitative information on the ability of thienyl and fury1 to leave as carbanions has been obtained from kinetic investigations of the alkaline hydrolyses of methyltri-(2-thienyl)phosphonium iodide to methyl di-(2-thieny1)phosphine oxide and thiophen, which proceeds ca. lo8 times more rapidly than the analogous reaction of methyltriphenylphosphonium iodide.ls2" Tri-(2-furyl)methylphosphonium iodide in turn is hydrolysed lo2-lo3 times faster than the 2-thienyl analogue.18zbThe greater rate of hydrolysis of the heteroarylphosphonium salts compared with the phenyl analogues is attributed to the greater electron-withdrawing character of the heteroaryl substituent. It is thus interesting to note that the reactivity order between the thiophen and furan derivatives is reversed compared with that of the metalation of thiophen and furan with organolithium compounds, to which reaction there is a formal resemblance. 31P chemical shifts of these compounds are taken as support for this conclusion. It was also possible with 31P n.m.r. techniques to study the equilibria between phosphonium salts and methoxide ion to form the quinquecovalent methoxyphosphoranes.lEzbThe ease with which 2-thienyl and 2-fury1 leave as anions from the quinquecovalent phosphorane intermediate is also evident from the hydrolyses of benzyltri-(2-thienyl)phosphonium bromide and benzyl tri-(2-fury1)phosphonium bromide, which lose 2-thienyl and 2-furyl, respectively, to give benzyl di-(2-thienyl)phosphine oxide and benzyl di-(2-furyl)phosphine oxide respectively, in contrast to benzyltriphenylphosphine oxide which loses benzyl to give triphenylphosphine oxide.182bThe preferential cleavage of furan and thiophen from the benzyl 178

179

180 18*

L. Kh. Freidlin, E. F. Litvin, and V. M. Chursina, Khim. geterotsikl. Soedinenii, 1967, 3, 22. C. Paulmier, J. Morel, D. Semard, and P. Pastour, Compt. rend., 1970, 271, C, 1252. B. Miche de Malleray, Helu. Chim. Acta, 1971, 54, 343. H. Wynberg and H. J. M. Sinnige, Rec. Trav. chim., 1969, 88, 1244. H. Wynberg and M. B. Groen, J. Amer. Chem. SOC., 1968, 90, 5339. S. Gronowitz and B. Yom-Tov, Z . Chem., 1970, 10, 389. D. W. Allen, J. Chem. SOC.(B), 1970, 1490. D. W. Allen, B. G. Hutley, and M. T. J. Mellor, J. C. S. Perkin 11, 1972, 63.

miophens and their Selenium and Tellurium Analogues

405

tri(heteroary1)phosphonium salts would suggest that the heteroaryl carbanions are more stable than the benzyl carbanion. This investigation has been extended to a series of (heteroarylmethy1)triphenylphosphonium bromides. It has been found that the rate of hydrolysis decreases in the series 2-furylmethyl > 2-thenyl > benzyl > 3-thenyl > 3 - f ~ r y l r n e t h y l . ~ ~ ~ ~ The rate data were again discussed in terms of the electron-withdrawing nature of the heteroaryl substituent and the reactive stability of the heteroarylmethyl carbanions. New organophosphorus compounds were synthesized by the reactions of 2-thienylphosphorus dichloride with phenol and a1kylphenols.182d Russian workers have continued their studies on the synthesis of chalcones from thiophen aldehydes, using 2-formylthiophen-5-aldehydelsS and 5-formyl-2,2'-bithienyl la4 and methyl ketones. Similarly, thiophennaphthalene analogues of chalcones have been synthesized,186and spectra and halochroism of some thiophen analogues of chalcones have been studied.las Chalcones derived from 2,5-diformylthiophen have also been prepared.la7 Condensation of thiophen-Zaldehyde and 5-nitrothiophen-2-aldehyde with p-aminobenzoic acid and barbituric acid leads to the corresponding thenylidene-p-aminobenzoicacids and thenylidenebarbituric acids.18a Thiophen-2-aldehyde has been used in a preparatively useful modification of the Knoevenagel reaction in which TiC14 and a tertiary amine in tetrahydrofuran were used in order to achieve facile condensation with ethyl acetoacetate and ethyl nitroacetate.ls9 The reaction of the dibromoderivative (155) obtained from the corresponding chalcone with cyclohexylamine gave the 2-(2-thienyl)aziridine (1 56).leo The reaction of (156)

'N I

D. W. Allen and B. G. Hutley, J. C.S. Perkin ZI, 1972, 67. D. A. Akhmedzade, V. D. Yasnopol'skii, and M. M. Guseinova, Zhur. obshchei Khim., 1971, 41, 1701. A. E. Lipkin, N. I. Putokhin, and S. I. Borisov, Khim. geterotsikl. Soedinenii, 1967, 3,

lBac

lezd 188

1020. 184 186

188

A. E. Lipkin and N. I. Putokhin, Khim. geterotsikl. Soedinenii, 1967, 3, 243. Yu. D. Churkin and V. I. Savin, Khim. geterotsikl. Soedinenii, 1968, 4, 369. S. V. Tsukerman, V. M. Nikitchenko, and V. F. Lavrushin, Ukrain. khim. Zhur., 1968,34, 1048.

187

188

S . V. Tsukerman, L. N. Thiem, V. M. Nikitchenko, and V. F. Lavrushin, Khim. geterotsikl. Soedinenii, 1967, 3, 1015. V. S. Egorova, V. N. Ivanova, and N. I. Putokhin, Khirn. geterotsikl. Soedinenii, 1967,3, 829.

189

ieo

W. Lehnert, Tetrahedron, 1972, 28, 663. J. W. Lown and K. Matsumoto, Canad. J. Chem., 1970,48,2215.

406


oJ-$ 1

COP11

MeO,C,

C0,Me

c 6 Hll

(159)

with olefinic and acetylenic dipolarophiles gave 2-pyrrolidines such as (157) with maleic anhydride and (1 58) with dimethyl acetylenedicarboxylate, which could easily be aromatized to the thienylpyrrole (159).lgo3lQ1 The reactions of (156) with other dipolarophiles such as chloral, aryl isothiocyanates, sulphonylimines, and methyl azodicarboxylate have also been studied.lB1 The dibromide (155; Ar = 2-hydroxyphenyl) reacts with base in a manner similar to that of its p-methoxyphenyl analogue, yielding mixtures of chromone and c o ~ m a r o n e . ~ ~ ~ The Stobbe condensation between 5-methylthiophen-2-aldehydeand dimethyl succinate has been studied.lQ3Through reduction of a mixture of thiophen-2-aldehyde and acrolein the vinylthienyl glycol (1 60) was obtained R'

COMe (160a)

\

COMe (160b)

in 50% yield, which upon treatment with palladium or copper catalysts was transformed to a mixture of hydroxy-ketones and dikefones.lB4 The gas-phase condensation of aldehydes R1CH2CH=CR2- CHO (R1, R2 = H, Me, or Et) with 1-(2-thienyl)but-3-en-l-oneover a magnesia catalyst yielded compounds (1 60a) and (160b).1g4a 2-Acetylthiophen has been condensed with 1 -nitro-2-dimethylaminoethylene to form the potassium salt of the acid nitro-compound (161), which is a useful intermediate for the synthesis of thienylpyrr01e.l~~The Ie1 lQ2

Ie3

le4 19*

lS5

J. W. Lown and K. Matsumoto, Canad. J . Chem., 1970,48, 3399. D. J. Donnelly, J. A. Donnelly, and E. M. Philbin, Tetrahedron, 1972, 28, 53. S. M. Abdel-Wahhab and N. R. El-Rayyes, J. prakt. Chem., 1971,313,247. A. Marbach and Y. L. Pascal, Compt. rend., 1969, 268, C, 540. G. Lasnier and J. Wiemann, Compt. rend., 1969, 268, C , 1891. T. Severin, P. Adhikary, and I. Schnabel, Chem. Ber., 1969, 102, 1325.


407

QcocH=cHcH=No;K+ (161) Mc

pyrolysis of 2-acetylthiophen ketazine (162) at 270 "C leads to the condensed compound (163) in 50% yield. Small amounts of 2-cyanothiophen and 2-acetylthiophen are also formed.lQ6 A reasonable pathway for the formation of (163) is given. Optically active ( )-methyl-2-thienylmethanol has been obtained through reduction of 2-acetylthiophen with a lithium aluminium hydridequinine The 2-thienyl analogues of ephedrine and #-ephedrine have been synthesized from 2-propionylthiophen via the a-bromo-derivative and the methylamino-ketone, followed by borohydride reduction. The amines were resolved into optical antipodes.lD8 Through the Claisen condensation between 2-acetylthiophen and ethyl formate, followed by the reaction with secondary amines, compounds of type (164) were obtained,

+

R' @cocH=CLI-N:

R2

which by treatment with hydrogen sulphide or PzS5were transformed to the corresponding thioketones. The n.m.r. spectra of these compounds were studied, and used to determine cis-trans Condensation of 2-acetylthiophen with glyoxylic acid in the presence of a secondary amine gave compounds of the type (164a).1*DaProducts from the reductive electrochemical dimerization of 2-acetylthiophens, such as 2,3-di-(2-thieny1)butane-2,3-diolyhave been isolated and identified.lgDb

(164a) 0. Tsuge, H. Watanabe, and K. Hokama, Bull. Chem. SOC.Japan, 1971,44, 505. 0. Cervinka, 0. BBlovskf, and L. KorAIovb, Z . Chem., 1969, 9, 448. J. M. Barker, D. J. Byron, and P. R. Huddleston, J. Chem. SOC.(C), 1969, 2183. lee F. Clesse and H. Quiniou, Bull. SOC.chim. France, 1969, 1940. lgga J. Couquelet, P. Tronche, and J. Couquelet, Bull. SOC.chim. France, 1971, 3196. l g s b M. Hebert and C. Caullet, Compt. rend., 1971, 273, C, 825. led

le7

408 Organic Compounds of Sulphur, Selenium, and Tellurium Thiophen-3-aldehyde has been obtained through the reduction of 3-cyanothiophen with sodium bis-(2-methoxyethoxy)aluminium hydride.200 This method can hardly compete with the preparation from 3-thienyllithium and NN-dimethylformamide. Nor does the reduction of thiophen-3-carboxylic acid with trichlorosilane in acetonitrile appear to be of preparative value.2o1 The course of transcarboxylation reactions of the salts of heterocyclic carboxylic acids, including thiophen-2-carboxylic acid and thiophen-2,5dicarboxylic acid, have been studied in detail using 14C02. An intermolecular ionic mechanism was proposed.202 3-Thienylglyoxylic acid has been obtained through the treatment of a-azido-3-thienylacetic acid with 3M methanolic sodium The method is essentially of no preparative use, as the azido-acid is the less easily available of the two starting materials. The 2-thienylethynyl thioether (1 65), prepared through the reaction of (166) with butyl-lithium followed by reaction of the resulting lithium 2-thienylethynethiolate with methyl iodide, was a key intermediate in the synthesis of 5-aminomethyl-2-thienylaceticacid (167).204

(166)

The different acidity of a- and /I-methylene groups was nicely illustrated in the different behaviour of the quaternary ammonium salts (168) and (169). The 3-isomer (168) gave p-elimination to (170), whereas the 2-isomer yielded 2-cyclopropylthiophen (171).35b The methyl group in 2-nitro-3-

methylthiophen is acidic enough to allow a facile condensation with formaldehyde to 2-nitro-3-vinylthiophen, using 40% formalin solution containing small amounts of pyrrolidine and acetic

202 203 204

I. Stibor, M. Janda, and J. Srogl, Z . Chem., 1970, 10, 342. J. Srogl, M. Janda, I. Stibor, and H. Prochazkova, Z . Chem., 1971, 11, 421. J. Ratuskq, Coll. Czech. Chem. Comm., 1971, 36, 2831. R. Raap, Tetrahedron Letters, 1969, 3493. R. Raap, Canad. J. Chem., 1971,49, 2155. K. Srinivasan, K. K. Balasubramanian, and S. Swaminathan, Chern. and Ind., 1971, 398.


409

Rearrangement Reactions.-The kinetic and thermodynamic parameters for the thenilic acid rearrangement have been followed as a function of substituent effect in the temperature range 15-80 0C.164u Acids of the thenilic acid type (or their methyl esters), such as 3,3’-dithienylglycollic acid 66 or 3-thienylmandelic acid,ls5 ring-close in the presence of Lewis acids to thiophen analogues of fluorene. The Beckmann rearrangement has been extensively used by Gol’dfarb et al. for the preparation of thiophenannelated lactams. Thus the oxime (172) gave directly with polyphosphoric acid or via the benzenesulphonate the lactam (173), which could also be

obtained through a Schmidt reaction with the ketone corresponding to (172). Interestingly, the homologous oxime (174) gave a mixture of lactams (175) and (176).Il2 The thio-Claisen rearrangement has attracted interest during recent years. SH-Thieno[3,2-b]thiin (179) and 6H-thieno[2,3-b]thiin

410


(182) are formed in high yields, when 3- (177) and 2- (180) propargylthiothiophen are heated to 170-1 80 "C in hexamethylphosphoric triamide.206 (178) and (181) are assumed to be intermediates. If (177) and (180) are heated in dimethyl sulphoxide in the presence of catalytic amounts of di-isopropylamine, the thio-Claisen rearrangement leads to the thienothiophens (183) and (184), respectively.207 Reaction conditions for the thioClaisen rearrangement of allylic sulphides are more critical. However, by using quinoline as solvent at 170-180 "C,Lawesson et al. successfully demonstrated rearrangements of allyl 2-thienyl sulphide (1 85), allyl 3-thienyl sulphide, allyl 2-methyl-3-thienyl sulphide, and crotyl-2-thienyl sulphide.208 The product distribution, however, is more complex than in the propargyl case, as compounds (186), (187), and (188) are obtained from (185). The

(188)

intermediates in the thio-Claisen rearrangements have been isolated or trapped as S-benzoyl derivatives. The reaction of 2-thienylmethanol with l-ethoxy-2-methylbuta-1,3-diene yielded the aldehyde (1 89) in low yield.20B This was taken as evidence that the formal double bond in thiophen can be induced to participate in a Claisen-Cope-type rearrangement. In contrast

to the benzene analogue, the quaternary ammonium salt (190) does not undergo the Sommelet-Hauser rearrangement upon treatment with butyllithium.210 Instead, NN-dimethylaniline (64%), 1,2-di-(2-thienyl)hexane (1 5%), and lY2-di-(2-thienyl)ethane(2%) were formed. Biheterocyc1ics.-During recent years increasing interest in biheterocyclics containing thiophen rings and phenylthiophens may be noted. This is due *08

eo7 208

210

L. Brandsma and H. J. T. Bos, Rec. Trau. chim., 1969, 88,732. L. Bransdma and D. Schuijl-Laros, Rec. Truo. chim.,1970, 89, 110. J. Z. Mortensen, B. Hedegaard, and S.-0. Lawesson, Tetrahedron, 1971, 27, 3831. A. F. Thomas and M. Ozainne, J. Chem. SOC.(0,1970,220. A. G. Giumanini and S. Grassi, Chem. undInd., 1970, 1567.


41 1

to the previously mentioned interest in optically active biheterocyclics of 143a;$b in the study of the directing effects of aromatic the biphenyl rings on substitution in thiophen,loo1128 and in connection with the synthesis of compounds of pharmaceutical interest.211The nitration and brornination of 2-(4-pyrimidyl)thiophen (191) and 3-(4-pyrimidyl)thiophen (192) have

(191)

(192)

been studied. The 4-pyrimidyl group, as well as its protonated form, acts as a strongly ‘meta’ directing group upon substitution in the thiophen nucleus. The compound (192) thus gives the 5-isomer on nitration and bromination, whereas a mixture of the 4- and 5-nitro-isomers is obtained upon nitration of (191). Also the chemical shifts of the thiophenic hydrogen resonances of (191) and (192) bear evidence for the electron-attracting properties of the 4-pyrimidyl group.212Derivatives of (191) have also been prepared through the reaction of thienyl-substituted p-diketones and guanidine or urea.213 Nitration of 3-(2-thienyI)pyrazole (193) with concentrated nitric acid gave 3-(5-nitro-2-thienyl)pyrazole, whereas nitration with fuming nitric acid in addition gave 3-(3,5-dinitro-2-thienyl)pyrazole. Finally, (193) with excess furning nitric acid yielded 3-(3,5-dinitro-2thienyl)-4-nitropyrazole. Nitration of 3-(3-thienyl)pyrazole (194) gave

3-(5-nitro-3-thienyl)pyrazole as the main product, and 3-(2-nitro-3thieny1)pyrazole and 3-(2,5-dinitro-3-thienyl)pyrazole as minor.211 Cornpounds (193) and (1 94) were obtained from the a-hydroxymethyleneacetylthiophens prepared from the acetylthiophens and ethyl formate by reaction with hydrazine. The 5-nitro : 3-nitro ratios obtained in the nitration of 2,2’-bithienyl have been determined under different conditions and an explanation for the ratios obtained has been attempted.214 T h e synthesis of the six isomeric pyridylthiophens has been carried out.216However, the yields obtained were low. The 3-thienyl isomers were 211

2la

*l*

21s

S. Gronowitz, A. Hallberg, S. Liljefors, U. Forsgren, B. Sjoberg, and S.-E. Westerbergh, Acta Pharm. Suecica, 1968, 5, 163. S. Gronowitz and J. Boler, Arkiv Kemi, 1968, 25, 587. T. Nishiwaki, Bull. Chem. SOC.Japan, 1970, 43, 937. C. Dell’Erba, G. Garbarino, and G. Guanti, J. Heterocyclic Chem., 1971, 8, 849. H. Wynberg, T. J. van Bergen, and R. M. Kellogg, J. Org. Chem., 1969, 34, 3175.

412


prepared in 2-1 0% yields from the appropriate pyridyl-lithium derivatives and 3-ketotetrahydrothiophen, with subsequent aromatization of the substituted methanols. 2-(4’-Pyridy1)thiophen was obtained from the 2-thienyl Grignard reagent and 1 -benzoyl-4-chloro-l,4-dihydropyridinein 2% yield, whereas reaction with pyridine gave 2-(2’-pyridy1)thiophen in low yield; this was later obtained by other workers in 48% yield through the reaction of 2-thienyl-lithium with 2-fl~oropyridine.~~~ Finally, 2-(3’pyridy1)thiophen was obtained from the isomer mixture formed in the reaction of 3-pyridyl radicals with thiophen. The n.m.r., mass, and U.V. spectra of these compounds,21Sas well as their basicities in the ground state and the S1excited state and the stability constants of the corresponding copper(n) 1 : 1 complexes, have been d e t e ~ m i n e d218 . ~ ~There ~ ~ was no evidence that the aromatic bonded sulphur of 2-(2’-pyridy1)thiophen participates in complex formation with Cu2+, in opposition to an earlier claim.218 Using the reaction between 2-thienyl-lithium with 2-fluoro- or chloro-pyridines or the coupling of lithium derivatives with copper halides as synthetic routes, polybiheterocyclics such as (195)-(198) have been

prepared.21s 3-(ZThienyl)-Zpyridone has been prepared by thermal cyclization of properly substituted vinyl isocyanates.21a In connection with an investigation of the fluorescent characteristics of derivatives of 2,2’-bithien~ls,~~O a number of heterocyclic substituted thiophen derivatives, such as (1 99)-(204) and their formyl derivatives, have been 222 The quinoline derivatives were obtained from the appropriate 2-lithiobithienyl and quinoline, whereas the benzimidazolyl, benzoxazolyl, and benzothiazolyl derivatives were prepared by the condensation of a cyanothiophen or 5-cyano-2,2’-bithienyl with the appropriate aniline derivative. (204) was prepared through a Fischer indole synthesis.2a2 als 217 218

T. KauRmann, E. Wienhofer, and A. Woltermann, Angew. Chem., 1971, 83, 796. E. Bouwhuis and M. J. Janssen, Tetrahedron Letters, 1972, 233. H. Sigel, H. Wynberg, T. J. van Bergen, and K. Kahmann, Helv. Chim. Acta, 1972, 55, 610.

220 222

F. Eloy and A. Deryckere, J . Heterocyclic Chem., 1970, 7 , 1191. R. E. Atkinson and F. E. Hardy, J. Chem. SOC.(B), 1971, 357. R. E. Atkinson and P. R. H. Speakman, J . Chem. SOC.(B), 1971, 2077. R. E. Atkinson and F. E. Hardy, J. C. S. Perkin ZZ, 1972, 27.

413


S

X

=

N H

S

NH, 0, or S

(203)

Cyanine dyes containing thiophen rings having the structure (205) have been prepared.223 In connection with studies on 1,3-dipolar cycloadditions, (206) has been prepared.224 Thienyl-substituted 3-alkylthio-1,2-dithiolium perchlorate

Q;J-i?-9cHm-j3 c1-

I

NI

R

R

(-g-J .? ';

I Me (206)

SMc

c101(207)

(207) has been obtained.226The effect of metal carbonyl carbene groups as electron-withdrawing substituents in thiophens has been studied.z25a In connection with a study of the reactions, structure, and properties of triarylimidazoyl radicals, some thienyl-substituted derivatives (207a and b) have been prepared from the appropriate benzil and aldehyde. Oxidation of these compounds gave deeply coloured substances possessing paramagnetic susceptibility.226b A. A. Shulezhko, I. T. Rozhdestvenskaya, and A. I. Kiprianov, Zhur. org. Khirn., 1970, 6, 2118. **' E. Brunn, E. Funke, H. Gotthardt, and R. Huisgen, Chem. Ber., 1971, 104, 1562. G. Duguay and H. Quiniou, Bull. SOC.chim. France, 1972, 637. J. A. Connor, E. M. Jones, and J. P. Lloyd, J. Organometallic Chem., 1970, 24, C20. m25b B. S. Tanaseichuk and S. Y. Yartseva, Zhur. org. Khim., 1971, 7 , 1260.


414

(207b)

(207a)

H

H (208)

The structure suggested by Steinkopf for the indophenine pigment formed by reaction between thiophen and isatin has been confirmed as (208) by n.m.r. and mass spectra and by chemical degradations such as desulphurization.226 In connection with a study of the transannular interaction between nonbonded aromatic rings, the cyclophanes (209) and (209a) were prepared by pyrolysis of suitable mixtures of quaternary ammonium

(209a)

(20%

Thiophen Analogues of Porphyrins.-During recent years several groups have become interested in thiophen analogues of porphyrins and related compounds. The 2 2 principle was used in the reaction of the 5,5'-dilithiodi-2-thienylmethane derivative (21Oa) with the corresponding diformyl

+

'2' aa7

J. A. Ballantine and R. G. Fenwick, J. Chem. SOC.(C), 1970,2264. S. Mizogami, T. Otsubo, Y. Sakata, and S. Misumi, Tetrahedron Letters, 1971, 2791.


415

Me R ( g 2Me - J RS

Me MeQ

\

(a) R = Li (b) R = CHO

I

R1 R2

R = Ac (210)

(c)

Me

(21 1)

(210b) or diacetyl (210c) derivative, which in low yield gave compounds (21l).2as,229 Attempts to cyclize derivatives of (212) failed. However, this compound showed high inertness towards many electrophilic substitutions, which is very unexpected in view of the reactivity of the a-positions of a l k y l t h i ~ p h e n s ,Under ~ ~ ~ forced acetylation of (212), ring-closure to (213) ~

S

S

S

S

Me Ac

Ac (213) Me

occurs,22B which led the authors to a direct Bradsher synthesis of benzodit h i o p h e n ~ Thus, . ~ ~ ~ treatment of (214) with acetic acid and polyphosphoric acid led to (215). The 3 + 1 principle has been applied to the synthesis of porphyrin analogues containing one thiophen ring. Thus, acid-catalysed condensation of the di(pyrroly1met hy1)pyrrole diacid (216) with 2,5-dif ormylthiophen gave the macrocycle (217) in 12%yield.231 A porphyrin analogue containing two thiophen rings (219) was similarly obtained from (218) and 2,5-diformyl229

aso 281

M. Ahmed and 0. Meth-Cohn, Tetrahedron Letters, 1969, 1493. M. Ahmed and 0. Meth-Cohn, J. Chem. SOC.(C), 1971,2104. M. Ahmed, J. Ashby, and 0. Meth-Cohn, Chem. Comm., 1970, 1094. M.J. Broadhurst, R. Grigg, and A. W. Johnson, Chem. Comm., 1969, 1480.


416

Me

Et

Et

Me

Me

Et

HO,C

h

H

H

(216)

Me Et H

O NO H

Et Me C S ~

(2 18)

CN O

O

H

H

t h i ~ p h e n .The ~ ~ ~enol acetate of the oxoporphyrin analogue (222) was obtained in low yield by the condensation of (221) with the thienyl pyrrolylmethane (220) in trifluoroacetic acid and acetic anhydride.233Spectroscopic properties and deuterium exchange have been studied in these systems.

RO2CCH2 I CH, X

CH2CO2R

M

M

e

m

I

CH2

e

OHC NH CHO (a) X = 0, R = M e (b) X = H2, R = Me (c) X = 0, R = Et (22 1)

R20,CCH2

CH2C02R2 (a) R1 = Ac, R2 = Et (b) R1 = H, R2 = Me (c) R1 = H, R2 = Et (222)

232

M. J. Broadhurst, R. Grigg, and A. W. Johnson, Chem. Comm., 1970, 807. P. S. Clezy and V. Diakiw, Austral. J. Chem., 1971, 24, 2665.

Thiophens and their Selenium and Tellurium Analogues 417 Reactions at the Thiophenic Sulphur.-By treating thiophens and condensed thiophens with alkyl halides in the presence of silver tetrafluoroborate or similar reagents, it has become possible to alkylate at the thiophenic sulphur and obtain S-alkylthiophenium s a l t ~235. ~ These ~~~ salts are powerful alkylating agents and their U.V. spectra resemble those of the corresponding sulphoxides and sulphones. It is concluded from n.m.r. data that the S-alkyl groups are not coplanar with the sulphurcontaining ring. Semi-empirical calculation of barriers to pyramidal inversion in the S-alkylated thiophenium ions and in thiophen S-oxides has been carried Recently, stable thiophen S-oxides and sulphones have been prepared from sterically hindered thiophens such as 2,5-di-tbutylthiophen through oxidation with rn-chloroperbenzoic Sterically non-hindered sulphoxides and sulphones of the thiophen series are not stable but dimerize in Diels-Alder-like reactions. Spectroscopic evidence suggests that the stable sulphoxide is tetrahedrally hybridized. This was especially evident from the non-equivalence of the geminal methylene protons in the side-chain of 2,5-bis-(l',l '-dimethylhexy1)thiophen l-oxide. From n.m.r. coalescence studies a value of 14.8 kcal mol-l for the energy of activation of the pyramidal inversion at 26 "Cwas Diels-Alder Reactions.-Thiophens normally do not undergo the DielsAlder reaction. However, Wynberg has recently found that simple thiophens react with dicyanoacetylenes in a Diels-Alder fashion.23s The intermediate adduct (223) is unstable and extrudes sulphur to give phthalonitriles (224). The yields with thiophen itself and with 2-methylthiophen

are low. A molecular orbital and mapping study of the allowed DielsAlder reaction of thiophen has been carried out and a comparison with furan and thiophen dioxide has been made.239 Raney-nickel Desulphurizati0n.-Many publications have appeared which illustrate the importance of Raney-nickel desulphurization for the synthesis of aliphatic compounds and for the structure determination of complex t hiophen derivatives. 234

*35 238

R. M. Acheson and D. R. Harrison, Chem. Comm., 1969,724. R. M. Acheson and D. R. Harrison, J. Chem. SOC.(C), 1970, 1764. J. D. Andose, A. Rauk, R. Tang, and K. Mislow, Znternat. J. SuZfur Chem. (A), 1971, 1, 66.

287

238

W. L. Mock, J. Amer. Chem. Soc., 1970, 92, 7610. R. Helder and H. Wynberg, Tetrahedron Letters, 1972, 605. P. W. Lert and C. Trindle, J. Amer. Chem. Soc., 1971, 93, 6392.

15


418

R

Me I

o (CH2),-C-CCH2C02H I Me

Me I Me(CHJS- C-CH2COzH

I

Me

(225)

(226)

pp-Dimethyl-fatty acids (226) of biological interest have been prepared through desulphurization of (225), obtained by Friedel-Crafts acylation of thiophen or its homologues with #l-dimethylglutaric anhydride, followed by Wolff-Kishner reduction.240 Desulphurization of (175) and (176) has been used for the preparation of C-alkyl derivatives of caprolactam and enantholactam (227) and (228).l12 Lactams of diamino-carboxylicacids, e.g.

To

Etc-? CH2NH

EtcY

/NH CH,CO

O,N

(230), have been obtained through desulphurization of the corresponding nitro-compound, e.g. (229).241 Various lactams, such as (230) and similar structures, were then used for the preparation of 2-imidazolidone derivatives (23 l), in connection with a study of biotin-related Diaminocarboxylic acids such as (233) have been obtained by desulphurization

followed by [e.g. (232) -t (233)l. Desulphurization of the acetamides of (234) gave the aliphatic diamine derivative (235) in 3 5 4 0 % yield.gQGol'dfarb and co-workers have also continued their work on the synthesis of macrocyclic compounds from thiophen derivatives. Thus, from (236), the 13- and 14-membered rings (237) were obtained.lllb 240

N.P. Buu-Hoi, 0. PQin-Roussel, and P. Jacquignon, J. Chem. Soc. (C), 1969, 942. B. P. Fabrichnyi, I. F. Shalavina, and Ya. L. Gol'dfarb, Zhur. org. Khirn., 1969, 5, 316.

242

B. P. Fabrichnyi, I. F. Shalavina, S. M. Kostrova, and Ya. L. Gol'dfarb, Zhur. obshchei Khim., 1970, 6, 1091.


419

R

Me R I I ACN+(CH~)~-C - (CH2)SNAc

I

I

Mc R = HorMe

Me (235)

(234)

n = 9 or 10

n = 11 or 12

(236)

(237)

5-n-Alkylresorcinol dimethyl ethers (239) have been obtained by desulphurization of (238).243 The desulphurization of 4-pyrimidylthiophens offers a new route to 4-substituted pyrimidines. Thus, (240) gives (241) in 28% yield.21a Carbon-boron bonds are not broken during reductive desulphurization. Thus 2,5-thiophendiboronicacid gave tetramethylenediboronic

The thiophen ring constitutes a convenient ‘cis-handle’, allowing annelation of other rings, and this technique offers a convenient route to other ring systems. Desulphurization of the thienoborazaropyridines(242)-(244) leads to the 3,2-borazaropyridine system (245), a stable, aromatic ring isoelectronic with p y ~ i d i n e .In ~ ~connection ~ with attempts to determine the absolute configuration of 2,6-disubstituted spiro[3,3]heptane derivatives, 243

D. Buddhasukh, J. R. Cannon, B. W. Metcalf, and A. 5. Power, Austral. J. Chem.,

244

I. G. C. Coutts, H. R. Goldschmid, and 0. C. Musgrave, J. Chern. SOC.(C), 1970,

2p5

488. S. Gronowitz and A. Maltesson, Acta Chem. Scand., 1971, 25, 2435.

1971,24,2655.

420


R1 I

a

-

R

.

(246)

(246a)

@Me

NHBz

(246) was desulphurized to (246a).246Desulphurization has been used to relate optically active (247) to (248).lg7 Examples of the usefulness of Raney-nickel desulphurization for the structure determination of more complicated thiophen derivatives can be found in Refs. 166a, 173c, and 196. Other Ring-opening Reactions.-The ring-opening of 3-thienyl-lithium derivatives 129 and that occurring upon anodic oxidation of thiophen derivahave been mentioned earlier in this Report. The cleavage of w-thienylalkanoic acids (249) with sodium in liquid ammonia offers a

method for obtaining aliphatic 0x0-acids (250).246aA very interesting ringopening-ring-closure reaction was discovered when methyl a-cyano-p-2thienylacrylate (251) was allowed to stand overnight in morpholine or piperidine at room temperature. Through the reaction path illustrated by formulae (252)-(255), the compound (256) and methyl cyanoacetate are formed, which then condense to (257), which is isolated in 5 6 6 9 % yield. artw

H. Wynberg and J. P. M. Houbiers, J. Org. Chem., 1971, 36, 834. Ya. L. Gol’dfarb and E. P. Zakharov, Zhur. org. Khim., 1970, 6, 1757.


42 1 n

HN H

(254)

(253) MeO,C,

HJ.

(255)

MeO$

\\

H

H P K S+=c< ,C=C(CN)CO,Me H H

The compound (257) was also obtained in 29-51% yield when methyl cyanoacetate and thiophen-Zaldehyde were mixed directly in morpholine or ~ i p e r i d i n e . ~ ~ ' Polymers from Thiophen Derivatives.-The bifunctionality of thiophen and its potential availability in large quantities at a low price has for many years attracted the interest of polymer chemists. However, progress has been slow. 2,5-Dichlorothiophen has been polymerized to a solid in 93% yield on treatment with aluminium chloride and cupric chloride in carbon disulphide. The product is believed to be poly-5-chlor0-2,3-thienylene.~~~ Thiophen-2,5-dicarboxylichydrazide was prepared by the reaction of thiophen-2,5-dicarbonyl chloride with the corresponding dihydrazide and then cyclodehydrated to poly-(thienylene-[2,5]-alt-1,3,4-oxadiazolylene[2,5]-amer) (258) by polyphosphoric This polymer could also be obtained directly from thiophen-2,5-dicarboxylicacid and hydrazine in oleum. The polymers produced were investigated in view of their thermal stability and as polymeric organic ~ e r n i c o n d ~ c t o r The s . ~ ~same ~ research z41 24@

H. Yasuda and H. Midorikawa, J. Org. Chem., 1971,36, 2196. J. S. Ramsey and P. Kovacic, J. Polymer Sci.,Part A-1, Polymer Chem., 1969, 7 , 127. G.Kossmehl and G. Manecke, Makromol. Chem., 1969, 123,233.

422


group has also prepared poly(thienylene[2,5]ethenamer) (259) via the Wittig reaction between 2,5-bis(triphenylphosphonomethyl)thiophen dichloride and 2,5-diformylthi0phen.~~~ The structures of the oligomers and polymers was confirmed by spectral data and further characterized by X-ray diffraction. The electrical conductivity of the oligomers and the polymers was investigated.250Instead of 2,5-diformylthiophen the 3-isomeric phthalaldehydes were used for the preparation of poly(thieny1ene[2,5]-et henamer-a1t-phenylene-(p,m,o)ethenamer s) (260). 25 Thi ophen analogues of polystyrene have also been studied. 2-Vinylthiophen was found

(260)

to undergo thermal polymerization. A kinetic investigation suggested that the thermal initiation is a termolecular process.252 The photochemical sulphochlorination of poly(viny1thiophen) has been studied and the optimum conditions for the introduction of the chlorosulphonyl group have been determined.253 Naturally Occurring Thiophens.-Bohlmann and co-workers are continuing their extensive investigation of naturally occurring thiophens. From the Indian Compositae Blumea Zacera, the acetylenic derivative (261) was Me-C=C

'' Q

(C=C),CH=CH,

(261)

260

262

263

G. Kossmehl, M. Hartel, and G. Manecke, Makromol. Chem., 1970,131, 15. G.Kossmehl, M. Hartel, and G. Manecke, Makromol. Chem., 1970, 131, 37. C. Aso, T. Kunitake, M. Shinsenji, and H. Miyazaki, J. Polymer Sci., Part A-1, Polymer Chem., 1969,7 , 1497. A. S. Nakhmanovich, G. G. Skvortsova, L. A. Shulyak, and G. V. Parshakova, Khim. geterotsikl. Soedinenii, 1967,3, 446.


423

No less than 16 new biogenetically closely related thiophen derivatives, besides known ones, were found in the Heliantheae EcZipta erecta L., and structures were proposed, based on spectral data.266Besides 2,5-disubstituted thiophens containing acetylenic groups, such as (262) and (263), bithienyl derivatives such as (264) and terthienyls such as (265) were present.265From the roots and aerial parts of Coreopsis uerticilfata L. the new thiophenic acetylene (266) has been isolated and the structure elucidated by spectroscopic methods.266Thiophen derivatives previously found H,C=CH-HC=HC

H I C=C-C=C-CH,OCH,CMc, I I OH H (266)

in Nature are also present in Tridax trilobata H e r n ~ l . ~and ~ ' in Anthernix fuscata Brot.268Indian workers have isolated 2-formyl-a-terthienyl from Eclipta aZba.26DThe compound was also found in Eclipta erecta by Bohlmann.266 The compounds (267) and (268) have been found in Daedalea juniperina Murr., and (268) was synthesized.12a Thiophens of Pharmacological Interest.-Since the beginning of the 1950's, when thiophen became commercially available at a reasonable price, there has been continued interest in the preparation of pharmacologically active thiophen derivatives. Attempts were often made to prepare analogues of pharmacologically active benzene derivatives, applying the principle of isosterism. This approach has only had limited success. During recent years, however, thiophen derivatives with superior activity have been found, and increased activity may be noted in this field. New anthelmintic agents which are already in use in veterinary medicine have been found in two cyclic amidine derivatives, pyrantel tartrate (Banminth, Strongid) (269) and morantel tartrate (Banminth 11) (270).260 For references concerning their evaluation in sheep, cattle, pigs, horses, dogs, and man see Ref. 260. These compounds are most probably prepared by condensation of the appropriate thiophen aldehyde with I ,4,5,6-tetrahydro-lY2-dimethylpyrimidine. Extensive investigations on structure2s4

F. Bohlmann and C. Zdero, Tetrahedron Letters, 1969, 69. Bohlmann and C. Zdero, Chem. Ber., 1970, 103, 834. F. Bohlmann and C. Zdero, Chem. Ber., 1970, 103,2095. F. Bohlmann, C. Zdero, and G. Weickgenannt, Annalen, 1970,739, 135. F. Bohlmann and C. Zdero, Chem. Ber., 1970, 103, 2856. N. R. Krishnaswamy and S. Prasanna, Indian J. Chem., 1970, 8, 761. W. C. Austin, R. L. Cornwell, R. M. Jones, and M. Robinson, J . Medicin. Chem.,

*s6 F. 2s0 267

258

1972, 15, 281.

424


activity relationships have been carried out. 2-Thiazoline (271) and 5,6dihydro-4H-l,3-thiazine analogues (272) of pyrantel and related compounds have been synthesized and tested.261 Also, compounds such as (271) and (272) were prepared by condensation of an appropriate aromatic aldehyde with the active methyl group of 2-methyl-2-thiazoline or 5,6-dihydro-2methyl-4H-l,3-thiazine. Compounds of types (273) and (274) were prepared by the reaction of an appropriate nitrile with cysteamine or 3-amino1-propanethiol. The dihydrothiazines (274) were also obtained through the

condensation of carboxylic acids or esters with 3-amino-1-propanol to form the amides, followed by reaction with P2S, at 110 "C. These compounds, as well as compounds with longer chains between the rings, were synthesized in order to evaluate their effect on anthelmintic activity.2e1 The effect of changing the cyclic amidine ring of pyrantel to open amidines has also been studied in a series of NN-disubstituted thiophen propionamidines (275) and thiophen acrylamidines (276). These compounds

(275)

were obtained from the nitriles by the Pinner reaction, or via ethyl N-alkylimidates formed through the action of triethyloxonium fluoroborate on an N-alkylamide. Some unsaturated nitriles reacted too slowly in the Pinner zel

J. W. McFarland, H. L. Howes, jun., L. H. Conover, J. E. Lynch, W. C. Austin, and D. H. Morgan, J . Medicin. Chem., 1970, 13, 113.

Thiophens and their Selenium and Tellurium Analogues 425 reaction, In such cases the corresponding amides were converted into the imidate salt by reaction with 1,3-propane sultone.2sa The effect of the number and kind of substituents on the nitrogen atoms is discussed. Anthelmintic activity has also been found in compounds of the general structure (277).283 These compounds are synthesized from 5-nitrothiophen-2aldehyde through condensation with a substituted ortho-aminobenzamide to form (278), followed by dehydrogenation by benzoquinone and transformation of the C=O group in the usual manner. The intermediate (278)

R1, ,R2 N

0

has significant activity against organisms implicated in bacterial ~aginitis.~~4 Antibacterial activity is also shown by 2-(5-nitro-2-thienyl)cinchoninic acids (279), prepared through nitration of the 2-(2-thienyl)cinchoninicacid obtained from 2-acetylthiophen and the appropriate isatin.266 Another group of nitrofuran-type antibacterial compounds are nitrones of structure (280), prepared from 5-nitro-2-thienylacroleinand N-alkylhydroxylamine

hydrochloride.2ss Some simple amides of 2-thiophencarboxylic acid with substituted anilines or heterocyclic amines show antimicrobial Thiosemicarbazones of 2-formyl-5-phenylthiophen268 and hydrazones (isoniazones) from some thiophen aldehydes and pyridine-4carboxylic hydrazide 2f19 have been tested for antitubercular activity. Antifungal activity has been observed in thiosemicarbazones of some 262

263

26a 266 266

267

268 269

J. W. McFarland and H. L. Howes, jun., J. Medicin. Chem., 1970, 13, 109. R. J. Alaimo and C. J. Hatton, J. Medicin. Chem., 1972, 15, 108. R. J. Alaimo and H. E. Russel, J. Medicin. Chem., 1972, 15, 335. I. Lalezari, F. Ghabgharan, and R. Maghsoudi, J. Medicin. Chem., 1971, 14, 465. H. K. Kim and R. E. Bambury, J . Medicin. Chem., 1971, 14, 366. M. Likar, P. Schauer, M. Japelj, M. Globokar, M. Oklobd?ija, A. PovSe, and V. SunjiL, J. Medicin. Chem., 1970, 13, 159. V. S. Misra and A. Khare, J. prakt. Chem., 1970, 312, 1188. L. N. Pavlov, 0. 0. Makeeva, Ya. L. Danyushevskii, Yu. B. Vol'kenshtein, N. E. Danilina, and Ya. L. Gol'df'arb, Khim. geterotsikl. Soedinenii, 1967, 3, 176.

426


heterocyclic aldehydes, including thiophen aldehydes.27o In connection with an extensive investigation of the fungicidal and phytotoxic properties of heterocyclic sulphonyl, sulphinyl, and thiomethyl thiocyanates, the corresponding 2-thienyl derivatives were synthesized and Substituted thiocyanothiophens are claimed to show considerable activity as herbicides.91

p

X

Thiophen derivatives (281) are also of interest as antithrombotic agents.272The compound (282) was fibrinolytic at 3 x 10-3mo11-1 and inhibited aggregation at 5 x mol l-1.273 l-Methyl-4-(2[and 31-thieny1)pyridinium iodide lowers the blood glucose concentration of normal mice on oral administration.274 A series of quinoline derivatives containing a 2-thienyl or 5-bromo-2-thienyl ring in the 2-position and different types of side-chains in the 4-position have been synthesized and tested as potential antimalarial^.^^^ In connection with studies of antispasmodic properties, tolylhydrazides of 2-thienylglyoxylic acid were treated with Grignard reagent to give compounds (283).278 N-Methyl-3-piperidyl esters of O R

thenilic acid have been synthesized for studies of their anticholinergic and psychotomimetic effects.277 In connection with studies related to the biological activity of folic acid, N-[4-(2-thienyl)methylaminobenzoyl]-dZa70

a71

D. M. Wiles and T. Suprunchuk, J. Medicin. Chem., 1971, 14, 252. A. G. M. Willems, A. Tempel, D. Hamminga, and B. Stork, Rec. Truv. chim., 1971, 90, 97.

a7a

273 a74

276

E. F. Elslager, J. R. McLean, S. C. Perricone, D. Potoczak, H. Veloso, D. F. Worth, and R. H. Wheelock, J. Medicin. Chem., 1971, 14, 397. D. Thilo and K. N. von Kaulla, J. Medicin. Chem., 1970, 13, 503. G. E. Wiegand, V. J. Bauer, S. R. Safir, D. A. Blickens, and S. J. Riggi, J. Medicin. Chem., 1971,14,214. J. P. Schaefer, K. S. Kulkarni, R. Costin, J. Higgins, and L. M. Honig, J . Heterocyclic Chem., 1970,7, 607. I. S. Berdinski and 0. P. Pilipenko, Khim. geterotsikl. Soedinenii, 1967, 3, 611. G. P. Nilles and R. D. Schuetz, J . Medicin. Chem., 1970, 13, 1249.


427

glutamic acid has been synthesized.278The pharmacological evaluation of the 2-thienyl analogues of ephedrine and #-ephedrine has been described.lQ8 In connection with studies on the synthesis and chemistry of cephalosporin antibiotics, 2-thiophenacetic acid and other thiophenic acids are used as ~ide-chains.~~~-~~~

Thiophen Derivatives of Analytical Interest.-2-Thenoyltrifluoroacetone has maintained its position as a chelating agent in analytical chemistry. Papers describing its use in the extraction or determination of copper,288europium,280thallium,2Q0niobium,201and molybdenum 202 have appeared. The effect of copper(1r) on the formation of monothenoyltrifluoroacetonatoiron(II1) has been The stability constants of some bivalent metal chelates of di-(2-thenoy1)methane have been determined.204 3-Thianaphthenoyltrifluoroacetone has been proposed as a reagent for the spectrophotometric determination of iron(1Ir) 205 and c e r i u m ( ~ v ) .The ~ ~ ~stabilities of metal chelates formed from derivatives of thiophen-Zaldehyde 2Q7 and of rare-earth carboxylates of thiophen-2carboxylate 208 have been studied. The separation of thiophen from benzene by solvent extraction has been studied.2Q0In connection with gas-chromatographic studies of donoracceptor complexes, the association between aromatic heterocyclic derivatives, including thiophens, and dibutyl tetrachlorophthalate has been 27R

279

281 282

284

286

286

287 288

290

281 202 2g3

294 295

S. L. Gurina, R. Kh. Batulina, L. Y.Alekseeva, and Z. V. Pushkareva, Khim. geterotsikl. Soedinenii, 1968, 4, 431. G. L. Biagi, M. C. Guerra, A. M. Barbaro, and M. F. Gamba, J. Medicin. Chern., 1970, 13, 511. S. L. Neidleman, S. C. Pan, J. A. Last, and J. E. Dolfini, J. Medicin. Chem., 1970, 13, 386. S. Kukolja, J. Medicin. Chem., 1970, 13, 1114. J. A. Webber, G. W. Huffman, R. E. Koehler, C. F. Murphy, C. W. Ryan, E. M. van Heyningen, and R. T. Vasileff, J. Medicin. Chem., 1971, 14, 113. I. G . Wright, C. W. Ashbrook, T. Goodson, G. W. Kaiser, and E. M. van Heyningen, J. Medicin. Chem., 1971, 14, 420. G. V. Kaiser, C. W. Ashbrook, T. Goodson, I. G. Wright, and E. M. van Heyningen, J . Medicin. Chem., 1971, 14, 426. J. A. Webber and R. T. Vasileff, J. Medicin. Chem., 1971, 14, 1136. R. A. Firestone, N. Schelechow, D. B. R. Johnston, and B. G. Christensen, Tetrahedron Letters, 1972, 375. L. Genov and G. Kassabov, Monatsh., 1969, 100, 594. H. Akaiwa, H. Kawamoto, and M. Abe, Bull. Chem. Soc. Japan, 1971, 44, 117. M. A. Carey and C. V. Banks, J. Inorg. Nuclear Chem., 1969,31, 533. H. Koch and H. Kupsch, 2. Naturforsch., 1969, 24b, 398. R. L. Deutscher and D. L. Kepert, Chem. Comm.,1969, 121. H. E. Pence and J. Selbin, Znorg. Chem., 1969, 8, 353. D. P. Fay, A. R. Nichols, jun., and N. Sutin, Inorg. Chem., 1971, 10, 2096. H. J. Harries and G. Wright, J. Znorg. Nuclear Chem., 1969, 31, 3149. J. Gerrard, W. J. Holland, A. E. Veel, and J. Bozic, Mikrochim. Acta, 1969, 724.

298

287

298

W. J. Holland, A. E. Veel, and J. Gerrard, Mikrochim. Acta, 1970, 297. M. P. Coakley, L. H. Young, and R. A. Gallagher, J. Inorg. Nuclear Chem., 1969, 31, 1449. R. Roulet, J. Few, and T. Vu Duc, Helu. Chim. Acta, 1969, 52, 2154. C. Hanson, A. N. Patel, and D. K. Chang-Kakoti, J. Appl. Chem., 1970, 20, 42.

428


investigated.300 References 301 from Khim. geterotsikl. Soedinenii treat different aspects of the chemistry of simple thiophens.

3 Thienothiophens, their Benzo-derivatives, and Analogous Compounds Synthesis.-Rearrangement of 2- and 3-(propargy1thio)thiophen leads to 2-methylthieno[2,3-b]thiophen (1 8 3) and 2-methylthieno[3,241thi ophen (1 84).207 A number of mono- and di-methylthieno[2,3-b]thiophensand thieno[3,2-b]thiophens, such as (284)-(286), were prepared by condensation

(284)

(285)

(286)

of methyl esters of formyl- or acetyl-thienylthioacetic The dithienothiophens (287)-(290) have been prepared using oxidative ringclosure of the appropriate dilithiodithienyl~ u l p h i d e s , ~ ~except ~ " , for (291),

C. Eon, C. Pommier, and G. Guiochon, Chrumatographiu, 1971, 4, 241. (a) R. I. Pogonina, N. S. Pivnenko, V. P. Izvekov, and V. F. Lavrushin, Khim. geterutsikl. Suedinenii, 1971, 7 , 21; (b) A. S. Nakhmanovich and E. N. Deryagina, ibid., p. 33; (c) V. I. Shedov, V. K. Vasilyeva, and A. N. Grinev, ibid., 1970, 6, 1602; ( d ) V. F. Lavrushin, R. I. Pogonina, N. S. Pivnenko, and V. P. Izvekov, ibid., p. 1605; (e) G. N. Dorofeenko, S. V. Krivun, E. I. Sadekova, and V. I. Beletskaya, ibid., p. 1003; (f)L. V. Cherkesova and A. A. Ponomarev, ibid., p. 1452; ( g ) S. Z. Taits, 0. A. Kalinovskii, V. S. Bogdanov, and Ya. L. Gol'dfarb, ibid., p. 1467; (h) Ya. L. Gol'dfarb and M. A. Kalik, ibid., p. 1323; (i) I. I . Lapkin and L. D. Orlova, ibid., p. 1181; ( j ) M. G. Voronkov, A. N. Pereferkovich, M. P. Gavar, and G. V. Ozolin, ibid., p. 1183 ;(k)E. N. Deryagina, A. S. Nakhmanovich, V. N. Yelokhina, and 0. G. Yarosh, ibid., p. 891; ( I ) A. S. Nakhmanovich, V. I. Knutov, and L. G. Klochkova, ibid., p. 894; (m) S. S. Novikov, L. I. Khmelnitskii, T. S. Novikova, and 0. V. Lebedev, ibid., p. 590; (n) Ya. L. Gol'dfarb, M. A. Kalik, and M. L. Kirmalova, ibid., 1969,5, 483; ( 0 ) Ya. L. Gol'dfarb and M. A. Kalik, ibid., p. 475; ( p ) V. I. Shvedov, V. K. Vasileva, and A. N. Grinev, ibid., p. 567; (4)A. E. Lipkin, ibid., 1968, 4, 984; ( r ) S. V. Tsukerman, L. N. Thiem, V. M. Nikitchenko, and V. F. Lavrushin, ibid., p. 980; (s) A. E. Lipkin and S. I. Borisov, ibid., p. 952; ( t ) V. S. Bogdanov, M. A. Kalik, A. V. Kessenikh, and Ya. L. Gol'dfarb, ibid., p. 793; (u) Ya. L. Gol'dfarb and M. A. Kalik, ibid., p. 788; (0) I. I. Lapkin, Y. P. Dormidontov, and T. A. Bidman, ibid., p. 801; ( w ) 0. G. Yarosh, A. S. Nakhmanovich, and N. V. Komarov, ibid., p. 642; ( x ) P. A. Konstantinov, L. V. Semerenko, K. M. Suvorova, E. N. Bondar, and Ya. L. Gol'dfarb, ibid., p. 230; (y) I. I. Lapkin and N. W. Bogoslowskii, ibid., p. 53; ( z ) Y. D. Churkin and V. I. Savin, ibid., p. 369.


429

which was obtained through an intramolecular copper-catalysed ringclosure of (292).134b The peroxide oxidation that occurs at the central sulphur atom is the only reaction of these interesting systems which has hitherto been studied. Thieno[2,3-b][1Ibenzothiophens (293), including the parent compound, were prepared from substituted 2-benzo[b]thiophenthiols, obtained from the corresponding lithium derivative followed by condensation with chloroacetaldehyde diethylacetal, chloroacetone, or 3-chlorobutan-2-one, and finally cyclization with hot polyphosphoric acid,30a For the synthesis of thieno[3,2-b][llbenzothiophens (294), the necessary thiol was

obtained by sulphonation of the benzo[b]thiophen, followed by reduction of the resulting sulphonyl chloride with lithium aluminium hydride. Reduction of the sulphonic acid with zinc in sulphuric acid failed, probably owing to rapid hydrolysis of the sulphonic acid. Alternatively, (293) and (294) were prepared from 3- and 2-formylbenzo[b]thiophen, using the convenient benzo[b]thiophen synthesis of Campaigne through condensation with rhodanine, followed by iodine cyclization of the a-mercaptoacrylic acid obtained upon alkaline hydrolysis of the condensation product.S02 The compound (294) has also been obtained by Italian workers through nucleophilic substitution of 2-formyl3-chlorobenzo[b]thiophen with thioglycollicacid to yield (295), followed by ring-closure under alkaline conditions and decarboxylation of the 2-carboxylic acid formed.302aThe compounds (294) and (295) were oxidized to S S - d i o ~ i d e s .Although ~~~ the position of oxidation was not demonstrated with certainty, the suggestion that the sulphur atom adjacent to the benzene ring is oxidized is strengthened by the results obtained with the dithienot h i ~ p h e n s . ~ ~The ~ " ~reaction of 1,l-diphenylethylenewith sulphur yields [l]benzothieno[2,3-b][l]benzothiophen(295a).302bp The structure of (295a) was established by chemical reactions, electronic and n.m.r. spectra, and

(295a) aoa

N. B. Chapman, C. G. Hughes, and R. M. Scrowston,J. Chem. SOC.(C), 1970,2431 Ricci, D. Balucani, and M. Bettelli, Gazzerta, 1971, 101, 774. M. G. Voronkov and V. E. Udre, Khim. geterotsikl. Soedinenii, 1968, 4, 43. S. Dayagi, I. Goldberg, and U. Shmueli, Tetrahedron, 1970, 26, 41 1.

soas A.

roac

(295b)

430


finally by X-ray analyses of (295a) 302d and its d i s u l p h ~ n e .The ~ ~ ~isomeric ~ compound (295b) has been obtained in low yield through the reaction of o-bromotoluene with sulphur and o-dichlorobenzene at 230 0C.30v Theoretical Studies and Physical Properties.-A CND0/2 study of the electronic spectra of the isomeric thienothiophens has been carried out .303 The cross-ring coupling constants in thieno[2,3-b]thiophen and a number of bromo-substituted thieno[2,3-b]thiophens and thieno[3,2-b]thiophens have been determined. The largest couplings (+ 1.2-1.5 Hz) are observed between protons separated by six bonds placed in a planar zig-zag path.304The coupling via five bonds in thieno[3,2-b]thiophen is + 0.7 Hz. The radical anions of thieno[2,3-b]thiophen and thieno[3,Zb]thiophen and some thiophen analogues of phenanthrene have been produced by reduction with Na-K alloy and their e.s.r. spectra have been investigated. The spin-density distribution has been interpreted in terms of sulphurp and d models.306The U.V. spectra of the compounds (287)-(291) are claimed to be in excellent agreement with those calculated by SCF MO Substitution Reactions.-In contrast to benzo [blthiophen, the t hienothiophens undergo electrophilic aromatic substitution predominantly in the 2-positions. Electrophilic hydrogen exchange has been studied by kinetic investigation of the dedeuteriation of thieno[2,3-b]thiophen, thieno[3,2-b]thiophen, their 2,5-diethyl derivatives, and benzo[b]thiophen with trifluoroacetic acid in a mixture with acetic acid or carbon tetrachloride at 25 "C. The electrophilic deuterium-hydrogen exchange rate in the a-position of the thienothiophens was found to be essentially the same and was 7-8 times greater than in thiophen. However, 2,5-diethylthieno[2,3-b]thiophen exchanged in the &position four times faster than the [3,2-b] analogue and at a rate similar to that of 2,5-diethylthi0phen.~~~ The isomer distribution in the Vilsmeyer formylation of the thienothiophens has been determined by V.P.C. ana1y~is.l~~ Whereas the [2,3-b]-compound gave 0.1% of the 3-isomer, less than 0.04%, if any, was formed from the [3,2-b]-isomer. The thienothiophens appear to be more sensitive to acid than thiophen. Much polymerization, besides dibromination, was obtained earlier upon bromination with bromine in acetic acid. Bugge has, however, found that both thienothiophens are conveniently monobrominated by N-bromosuccinimide (NBS) in acetic acid. Besides the 2-bromo-derivative, smaller amounts (9-15 mole %) of the 2,5-dibromo-derivativewere obtained when equimolar amounts were With two equivalents of NBS, the d02d 302s 302f

I. Goldberg and U. Shmueli, Actu Cryst., 1971, B27, 2173. I. Goldberg and U. Shmueli, Actu Cryst., 1971, B27,2164. M. G. Voronkov and A. N. Pereferkovich, Angew. Chem., 1969, 81, 257. A. Tajiri, T. Asano, and T. Nakajima, Tetrahedron Letters, 1971, 1785. A. Bugge, B. Gestblom, and 0. Hartmann, Actu Chem. Scund., 1970, 24, 105. L. Lunazzi, G. Placucci, M. Tiecco, and G. Martelli, J. Chem. SOC.(B), 1971, 1820. T. A. Yakushina, E. N. Zvyagintseva, V. P. Litvinov, S. A. Ozolin, Ya. L. Gol'dfarb, and A. I. Shatenshtein, Zhur. obshchei Khim., 1970, 40, 1622. A. Bugge, Actu Chem. Scund., 1969, 23,2704.


43 1

2,5-dibromo-compounds were obtained in good yield. The crystalline monobromo-derivatives are unstable, in contrast to 2-bromothiophen, and decompose in a few hours at room temperature, but can be stored for weeks at - 15 "C. The tribromothiophens, which have been prepared before, could be reduced to the 3-bromo-derivativesby excess zinc in acetic acid.807 By the use of smaller amounts of zinc, 2,4-di bromothieno[2,3-bJthiophen could be obtained. Some substitution reactions of the third classical thienothiophen, thieno[3,4-b]thiophen (296), have been carried Formylation of

(296) gives a mixture of the 4- and 6-formyl derivatives in a ratio of 70 : 30, whereas formylation of the 2-methoxycarbonyl derivative of (296) gives a 1 : 1 mixture of the 4- and 6-formyl derivatives. The n.m.r. spectra have been studied, and, together with Raney-nickel desulphurization, used for structure determination. The electrophilic substitution reactions of (293) and (294) and their simple derivatives have been extensively s t ~ d i e d . ~310~ ~Both ~ ~ parent compounds readily undergo bromination, Vilsmeyer formylation, Friedel-Crafts acetylation, and nitration in the 2 - p 0 s i t i o n . ~30B ~ ~ ~Owing * to its high reactivity, (293) gives upon attempted chloromethylation the bisarylmethane derivative. However, it does not undergo the Mannich reaction. Interestingly, the 2-bromo-derivative of (293) gives the 2,3-dibromo-compound upon further bromination, whereas the other 2-bromo-derivative is substituted in the benzene ring, probably in the 6 - p o ~ i t i o n .The ~ ~ ~3-methyl derivatives of (293) and (294) undergo, as expected, electrophilic substitution in the 3 - p o ~ i t i o n .The ~ ~ ~corresponding 2-methyl compounds are brominated in the 3-position, whereas acetylation of the 2-methyl derivative of (293) gives either the 3- or 6-acetyl compound as the major product, depending upon conditions. The 3-methyl derivative of (294), however, yields under two different conditions a mixture of the 3- and 6-acetyl and 3,6-diacetyl compounds.310 If both thiophenic positions are blocked with methyl groups, acetylation occurs in the 6-position, whereas bromination occurs in the 3-methyl side-chain. The next bromine enters the 6-position. Bromination of the 3-formyl derivatives of (293) and (294) occurs in the 2-position, whereas nitration or bromination of the 2-formyl compound causes replacement of the formyl g r o ~ p .The ~ ~side-chains ~ introduced 30Bv

H. Wynberg and J. Feijen, Rec. Trav. chim., 1970, 89, 77. N. B. Chapman, C. G. Hughes, and R. M. Scrowston, J. Chem. SOC.(C), 1971, 463. *lo N. B. Chapman, C. G. Hughes, and R. M. Scrowston, J. Chem. SOC. (C), 1971, 1308. SO*

432


showed the expected reactions. Thus, the 2-nitro-derivative was reduced with SnCl, to the amino-compound, which gave an acetylamino-derivative identical to the product of Beckmann rearrangement of the 2-acetyl compound.3o2a The carbonyl derivatives underwent Wolff-Kishner reduction. The acid (297) obtained by Wolff-Kishner reduction of the succinoylation product could be ring-closed to (298).302aA surprise was the fact that the

2-acetyl derivatives of (293) and (294), upon Schmidt reaction with hydrazoic acid, gave the N-methylcarboxamide and not the expected 2-aceta~~lide.~O@ The thienothiophens, like thiophen, are smoothly metalated by ethereal butyl-lithium in the a-positions. By means of competitive metalation experiments, both thieno [2,3-b]thiophen and thieno [3,241thi ophen were found to be about six times more reactive.311 The unsymmetrical thienothiophen (296) gives the 4-lithio- and 2-lithio-derivatives in a 1 :4 ratio.308 Also, (293) and (294) are smoothly metalated in the a - p ~ ~ i t i o Halogenn~.~~~ metal exchange between 2,3,5-tribromo thieno [3,2-b]thiophen and but yllithium at - 70 "Cfollowed by hydrolysis could be used for the synthesis of the 2,6-dibromo-compound.307However, the same reaction with 2,3,5-tribromothieno[2,3-b]thiophen led to ring-opening. The kinetics of the protophilic dedeuteriation of thien0[2,34]-[2-~H]-and -[3-2H]-thiophen,thien0[3,2-b]-[2-~H]-and -[3-2H]-thiophen,and benzo[b][2-2H]- and -[3-2H]-thiophen have been The activation parameters for the deuterium-exchange reactions of the isomeric thienothiophens with t-butyl alcohol catalysed by potassium t-butoxide were determined. The relative deuterium-exchange rate constants for the 2-position in thiophen, the isomeric thienothiophens, and benzo[b]thiophen were found to be 1 : 10 : 9 : 4, whereas the corresponding relative values for the 3-positions are 1 : 94 : lo4 : 65. These partial rate factors were compared with those obtained upon acidic exchange 308 and interpretation was attempted.312, Thieno [3,2-b]thi ophen and thieno [2,3-b]thiophen have been p henylated with phenyl radicals derived from the thermal decomposition of N-nitrosoacetanilide and from the reaction of aniline and pentyl nitrite.313 Radical substitution occurs predominantly in the 2-position in the [3,2-b]-compound, whereas about equal amounts of 2- and 3-substitution are obtained for the 311 s12

313

A. Bugge, Acta Chem. Scand., 1968, 22, 63. T. A. Yakushina, I. 0. Shapiro, E. N. Zvyagintseva, V. P. Litvinov, S. A. Ozolin, Ya. L. Gol'dfarb, and A. 1. Shatenshtein, Zhur. obshchei Khim., 1971, 41, 1930. P. Spagnolo, L. Testaferri, M. Tiecco, and G. Martelli, J . C. S. Perkin I, 1972, 93.


433

[2,3-b]-compound. For homolytic phenylation, the order of decreasing reactivity is t hieno [3,2-b]thiophen thiophen > thieno [2,3-Z1]thiophen.~~~ Authentic 2-phenyl derivatives were synthesized through photolysis of the corresponding iodo-compounds in benzene. 3-Phenylthieno[2,3-b]thiophen was obtained through the reaction of l-phenyl-l-(3-thienyl)ethanol with sulphur at 200 "C,whereas 3-phenylthieno[3,2-b]thiophenwas obtained by benzoylation of methyl 3-thienylthioacetate followed by base-catalysed ring-closure and d e c a r b ~ x y l a t i o n . ~ In~ ~connection with work on periannelated systems, it was found possible to obtain the strained system (300) through the reaction of (299) with sodium s ~ l p h i d e .In ~~ connection ~ with

=-

(299)

work on polymethine dyes, derivatives of thienothienothiazoles such as (301) and thienothienopyridines 316 and related compounds have been prepared. 3160

Non-classical Thienothiophens.-Having previously reported the transient existence of 1,3-methylthien0[3,4-c]thiophen (302),316for which the only uncharged resonance contributors are structures containing quadrivalent sulphur, Cava has now succeeded in preparing the stable non-classical ten-7r-electron heterocycle tetraphenylthieno [3,4-c]thiophen (303).317 The compound (303)was obtained in the following way. Tetrabenzoylethane was treated with phosphorus pentasulphide in xylene to form (304), which was oxidized with periodate to the sulphoxide (305), which in turn in 87% yield was dehydrated to (303) by acetic anhydride. The compound (303) could also be obtained in a single operation in 3% yield from tetrabenzoylethane and phosphorus pentasulphide. It reacts with N-phenylmaleimide to give a mixture of the exo- (306) and endo- (307) adducts in a 3 : 1 ratio. Another stable non-classical thiophen (308) was obtained in a similar way from 3,4-dibenzoyl-l,2,5-thiadiazole(309) and phosphorus S. H. Wilen, G . J. Douma, and H. Wynberg, Rec. Trau. chim., 1970, 89, 980. V. G. Zhiryakov and P. I. Abramenko, Khim. geterotsikl. Soedinenii, 1969, 5, 491. =160 V. G. Zhiryakov and P. I. Abramenko, Khim. geterotsikl. Soedinenii, 1969, 5, 488. M. P. Cava and N. M. Pollack, J. Amer. Chem. SOC.,1967, 89, 3639. 917 M. P. Cava and G . E. M. Husbands, J. Amer. Chem. SOC.,1969,91, 3952. 91p

*l6

434


pentasulphide as brilliant purple needles.31e It reacts slowly in the DielsAlder reaction with N-phenylmaleimide to yield a 2 : 1 mixture of the exo(310) and endo- (311) adducts, and in contrast to other stable quadrivalent sulphur systems it gives a dimer, probably with structure (312), on photolysis.318 Finally, the more complicated system (313) has also been synt hesized.

PhOC

COPh

n N N ‘S’

s18

J. D. Bower and R. H.Schlessinger, J . Amer. Chem. SOC.,1969, 91, 6891.


435

4 Benzothiophens and their Benzoannelated Derivatives Synthesis of Benzothiophens by Ring-closure Reactions.-A review of the

chemistry of benzothiophens, covering the period 1952-1 968, has appeared.31Q The mechanism of the oxidative coupling of 8-arylmercaptoacrylic acids, obtained by alkaline hydrolysis of 5-arylidenerhodanines (3 14), to yield

ArC=C-s

I 'c=s o=c, / NH

benzo[b]thiophen has been studied.le Improvements in the preparative procedures have been found,ls and this method maintains its position as a useful route to benzo[b]thiophens and similar systems, as illustrated in the synthesis of (293) and (294).302 A new simple benzo[b]thiophen synthesis consists of the reaction of cinnamic acid derivatives with thionyl chloride and pyridine, which leads to 3-chlorobenzo[b]thiophen-2-carbonyl 320 The disadvantage of the method is that activating substituents in the cinnamic acid cause chlorination in the benzene ring.s2o A synthesis of 2-alkyl- or 2-aryl-substituted benzo[b]thiophens consists of the cyclization of an aryl thioether with an acetonyl or phenacyl group in the ortho-position (315) with 48% hydrobromic In order to obtain (315; R2 = Ph), 2-methylthiobenzyl cyanide is treated with phenylmagnesium bromide. The reaction of ortho-methylthiostyrene derivatives, especially cinnamic acids (316), with sulphuryl chloride followed by pyridine, probably gives the benzo[b]thiophens (3 18) via the sulphenyl chloride (317).322 a19 a20

821

B. Iddon and R. M. Scrowston, Adv. Heterocyclic Chem., 1970, 11, 178. W. B. Wright, jun., and H. J. Brabander, J. Heterocyclic Chem., 1971, 8, 711. L. Christiaens and M. Renson, Bull. SOC.chim. belges, 1970, 79, 235. A. Ruwet and M. Renson, Bull. SOC.chim. belges, 1970, 79, 593.

436


Upon oxidation of l-thiocoumarins (319) with selenium dioxide in NN-dimethylformamide, ring-contraction occurs, yielding benzo[b]thiophen-Zaldehyde in 80% yield.323Possible reaction paths are discussed. A related ring-contraction to 2-bromomethylbenzo[b]thiophenoccurs when

&Rl \

'

s

(320), obtained through NaBH, reduction of the corresponding bromoketone, is heated in d i ~ x a n .Pyrylium ~ ~ ~ salts such as (321) give, upon treatment with alkali, the benzo[b]thiophen (323), probably through (322).326 In the abnormal Reformatsky reaction of o-methylthioacetophenonewith

ethyl bromoacetate, the sulphur atom is f2st attacked, and an intermediate such as (324) is assumed which condenses to (325).326 Ethyl a-bromopropionate gives the expected cinnamic acids, which are also formed with ethyl bromoacetate if the organozinc reagent is preformed.326 A. Ruwet, J. Meessen, and M. Renson, Bull. SOC.chim. belges, 1969, 78, 459. H. Hofmann and G. Salbeck, Angew. Chem., 1969, 81,424. sZs V. I. Dulenko, S. N. Baranov, G. N. Dorofeenko, I. G. Katts, and L. V. Dulenko, Doklady Akad. Nauk S.S.S.R., 1970, 195, 607. 326 A. Ruwet and M. Renson, Bull. SOC.chim. belges, 1970, 79, 75. 323 924


437

0 II @C02Et

S-CH2-COZE t I Me Br-

(325)

(324)

R I CH-CN S-CCHzPh

The cyclization of o-benzylthiobenzyl cyanides (326) with aluminium bromide gives 2-aminobenzo[b]thiophens (327).le A new synthesis of benzothiophens is based upon the reaction of o-mercapto-aromatic ketones or their xanthates (328) with dimethylsulphonium m e t h ~ l i d e . ~The ~~

reaction is assumed to proceed through (329) and is reminiscent of the Krollpfeiffer synthesis of benzo [blthiophens, which has recently been used for the synthesis of 3-phenylbenzo[b]thiophen-2-carboxylicacid and 2,3-diphenylbenzo[b]thiophen,through the reaction of 2-methylthiobenzophenone with chloroacetic acid and a-chlorophenylacetic acid, respecti~ely.~~'~ 2-Arylthio-l,2-diarylvinylarenesulphonates (330)cyclize upon treatment with boron trifluoride etherate in methylene chloride to yield benzo[b]thiophens (331).328-330 When the substituent X (Me, MeO, C1, or Br) in (330) was para to the vinylthio-group, rearrangement occurred, as the substituent was found in the 6-position of (331) and not in the expected 5-position. No rearrangement was observed when such substituents were in the rneta-position. Through the use of deuterium-labelled compound it was suggested that the carbonium-type species (332) can in principle react either through a normal Friedel-Crafts-type ring-closure (333) or through

3270

s2# s8O

P. Bravo, G. Gaudiano, and M. G. Zubiani, J. Heterocyclic Chem., 1970, 7 , 967. F. Sauter and A. Dzerovicz, Monatsh., 1969, 100, 905. G. Capozzi, G. Melloni, and G. Modena, J. Org. Chem., 1970,35, 1217. G. Capozzi, G. Melloni, and G. Modena, J . Chem. SOC. (C), 1970, 2621. G. Melloni and G. Modena, J. C.S. Perkin I, 1972, 218.

438

Organic Compounds of Sulphur Selenium, and Tellurium Ph,

+

,c=c,

S

Ph

X Ph

(332)

X X (335)

(3 34)

attack at the sulphur-bearing carbon (334) followed by a 1,2-sulphur shift (335).328,329 Depending upon the position and electronic properties of the substituent, the one or the other of these paths dominates. For instance, with phenylsulphonyl as substituent, it is in the cyclization of the metasubstituted derivative that rearrangement occurs.33o The l ,2-shift has also been observed with the corresponding trans-l,2-diphenyl-2-arylsulphonylvinyl p-bromobenzenesulphonates, which upon cyclization yield 2,3diphenylbenzo[b]thiophen 1,l - d i o ~ i d e s . ~Such ~ ~ " 1,2-sulphur shifts have previously been suggested to explain the rearrangements occurring in the ring-closures of 2-pyrrolylthioacetic acid and 2-thienylthioacetic 332 A convenient synthesis of 4-hydroxybenzo[b]thiophen consists of the addition of mercaptoacetaldehyde diethyl acetal to 2-cyclohexenone to form (336), followed by an intramolecular aldol condensation to (337) and

(336)

(337)

aromatization with sulphur.333The product (338), from the Stobbe condensation of 5-methylthiophen-2-aldehyde with dimethyl succinate, was cyclized by treatment with sodium acetate in acetic anhydride to yield 331

G. Melloni and G. Modena, Internat. J. Sulfur Chem. (A), 1971, 1, 125. S. Gronowitz, A.-B. Hornfeldt, B. Gestblom, and R. A. Hoffman, Arkiu Kemi, 1961,

s32

18, 151. S. Gronowitz and P. Moses, Acta Chem. Scand., 1962, 16, 155.

s30a

3a3

R. P. Napier, H. A. Kaufman, P. R. Driscoll, L. A. Glick, C. Chu, and H. M. Foster, J. Heterocyclic Chem., 1970, 7 , 393.


439

OAc

H

(338)

(339)

(339).'93 The ring-closure of 3-methoxyphenyl thioacetate in concentrated sulphuric acid gives 3-methyl-6-methoxybenzo[b]thiophenin good yield.Ss4 2-Phenylbenzo[b]thiophen-3-carboxylicacids have been synthesized by the reaction of thianaphthenquinones (340) with a-chlorophenylacetic acid, followed by cyclization of the o-(carboxybenzy1thio)phenylglyoxylic acid (341) isolated as an 338 These benzo[b]thiophencarboxylic

acids were used for the syntheses of amides and of basically substituted esters. Through the reaction of sulphur with em-halogen derivatives of ethyl-, isopropyl-, and n-propyl-benzenesand of di- and tri-phenyl-ethanes and -ethenes, a number of benzo[b]thiophen derivatives have been obtained.al, 338 Thus the reaction of 1,l -dichloro-2,2-diphenylethanewith sulphur provides a simple method for the synthesis of 3-phenylbenzo[b]t h i ~ p h e n .A~ convenient ~~ method for the synthesis of benzo[c]thiophen, consisting of heating 1,3-dihydrobenzo[c]thiophen 2-oxide (342) with 337s

neutral alumina to 120-130 "C, has been worked The instability and high reactivity of this system have been confirmed. With maleic anhydride the exo- and endo-isomers of (343) were formed in a 1 : 1.25 ratio. Using the same method, the benzo-analogue (344) could be prepared, which also easily underwent Diels-Alder reactions. The linear analogue 830 88K

336 887

E. Campaigne, A. Dinner, and E. S. Neiss, J. Heterocyclic Chem., 1970, 7 , 695. F. Sauter and A. Dzerovicz, Monatsh., 1969, 100, 899. F. Sauter and A. Dzerovicz, Monatsh., 1970, 101, 1806. M. G. Voronkov, T. V. Lapina, and E. P. Popova, Khim. geterotsikl. Soedinenii, 1968, 4, 49.

s30

M. G. Voronkov and V. E. Udre, Khim. geterotsikl. Soedinenii, 1968, 4, 43. M. P. Cava, N. M. Pollack, 0. A. Mamer, and M. J. Mitchell, J. Org. Chem., 1971, 36, 3932.

440


(345)could not be prepared by the alumina pyrolysis of the sulphoxide, as it was too unstable to be isolated. Its existence as intermediate could be demonstrated by a trapping experiment with N-phenylmaleimide. Three adducts were isolated, the two major ones resulting from dienophile addition to the thiophen ring of (345), and the minor product from addition to the central ring.339 Substituted benzo[c]thiophens (347) have been

prepared through reaction of the Diels-Alder adducts of dibenzoylacetylene and butadiene, isoprene, 2,3-dimethylbutadiene, and other dienes (346), with phosphorus pentasulphide and U.V., n.m.r., and massspectral data are discussed. The SnC1,-catalysed reaction of 2-allylbenzo[b]thiophen with a,a-dichloromethyl methyl ether yields dibenzothiophen in high yield.341 Through the use of ethyl dichloroethoxyacetate, 3-substituted dibenzothiophens have become available. Dibenzothiophen was also obtained in 79% yield through the reaction of biphenyl with sulphur at 110 "Cin the presence of anhydrous aluminium Starting from 5,6-dichlorobenzoquinone, the dibenzothiophen derivative (349) was obtained by treating (348) with hydrogen peroxide in acetic In connection with work on nucleophilic substitution of perfluorodibenzothiophen, an unambiguous synthesis

"mie

Me

0 (348) 3p0

841

848

0 (349)

J. D. White, M. E. Mann, H. D. Kirshenbaum, and A. Mitra, J. Org. Chem., 1971, 36, 1048. J. Ashby, M. Ayad, and 0. Meth-Cohn, Chem. Comm., 1971, 1251. M. G. Voronkov and F. D. Faitel'son, Khim. geterotsikl. Soedinenii, 1967, 3, 245. K. Fickentscher, Chem. Ber., 1969, 102, 1739.

441


of heptafluoro-2-rnethoxybenzothiophenhas been worked The benzoyl derivatives (350) underwent the Elbs reaction with rearrangement to give mainly (351), whereas (352) reacted without rearrangement to give (353).346 The parent system corresponding to (353) has been prepared by

Q--yaR 0

Mc

OM'

(3 50)

(CH,),COOH

(3 54)

0

(355)

cyclization of the butyric acid (354)to the ketone (355) followed by WolffKishner reduction and aromatization with selenium.346Through reaction of (355) with Grignard reagents, followed by aromatization, a number of 7-substituted derivatives of benzo[b]naphtho[2,3-d]thiophen were obtained. orders for Theoretical Studies and Physical Properties.-HMO-n-bond C-S bonds in benzo[b]thiophen and other derivatives have been related to experimental bond lengths.347 A detailed rotational analysis of the 0 - 0 The effects of band of benzo[b]thiophen at 2936 has been carried substituents in the 3-position of benzo[b]thiophens on U.V. and i.r. spectra and on the charge-transfer spectra with tetracyanoethylene have been A linear correlation of the wavenumber of the first maximum 344 346 340

347 348

340

R. D. Chambers and D. J. Spring, Tetrahedron, 1971, 27, 669. C1. Marie, N. P. Buu-Hol, and P. Jacquignon, J. Chem. SOC.(C), 1971, 431. D. D. Gverdtsiteli and V. P. Litvinov, Izuest. Akad. Nauk S.S.S.R., Ser. khim.,1970, 1340. 0. Hafelinger, Tetrahedron, 1971, 27, 1635. A. Hartford, jun., A. R. Muirhead, and J. R. Lombardi, J. Mol. Spectroscopy, 1970, 35, 199. N. Kucharczyk, B. KakBE, and V. Horbk, Coll. Czech. Chem. Comm., 1969,34,2959.

442 Organic Compounds of Sulphur, Selenium, and Tellurium of the charge-transfer spectra with :a constants is found. The U.V. spectra of a great number of acetyl- and aroyl-benzo[b]thiophens have been studied, and characteristic differences depending upon the position of the acyl group have been The polarized absorption spectrum of dibenzothiophen near 330nm has been measured in the pure crystalline state and in host lattices of fluorene, hexamethylbenzene, and some other compounds.361 From dipole-moment measurements and i.r. spectra it has been concluded that benzo[b]thiophen-Zaldehyde exists exclusively in the cis conformat i ~ n 1.r. . ~ spectra ~ ~ polarized along three orthogonal directions in single crystals of dibenzothiophen and [2H8]dibenz~thiophen have been recorded from 50 to 35OOcm-l. Also, the polarized Raman spectra of the single crystals have been The i.r. spectra of thioindogenides have been determined.354 Complete iterative analyses of the n.m.r. spectra of benzo[b]thi~phen,~~~~ 356 d i b e n z ~ t h i o p h e n357 , ~ ~and ~ ~ the S-oxides of the latter 358 have been carried out. Inter-ring long-range coupling constants and their signs have been determined. The n.m.r. spectra of acetyl- and aroyl-substituted benzo [blthiophens have been studied, especially the influence of the substituents on the chemical shifts of the ring-hydrogens, through which all monoacetylbenzo[b]thiophens can be identified.35g In order to facilitate structure determination, the n.m.r. spectra of substituted dibenzothiophens have been studied.36o U.V., n.m.r., and other physical properties as well as chemical reactivity and MO calculations have been discussed in a comparison of benzo[b]thiophen and b e n z ~ [ b ] f u r a n .leF ~~~ n.m.r. data for polyfluorodibenzothiophens have been Electrophilic Substitution.-The isomer distributions and the rates relative to those of the parent heterocyclic compounds for acetylation, benzoylation, chlorination, and bromination of benzo [blthiophen and benzo [blfuran have been determined.362It was found that although the orientation of substitution in the two bicyclic systems is different, the effect caused by annelation on the reactivity of the a- and /%positions is substantially the same in the two rings: the reactivity of the a-position is always decreased by a similar factor, and the reactivity of the #3-position is increased (with some exceptions) in both systems. The different orientation observed in the 350 351 352

353

35p

P. Faller, Bull. SOC.chim. France, 1969, 941. A. Bree and R. Zwarich, Spectrochim. Acta, 1971, 27A,621. C. G . Andrieu and A. Ruwet, Bull. SOC.chim. France, 1972, 1008. A. Bree and R. Zwarich, Spectrochim. Acta, 1971, 27A,599. M. A. Mostoslavskii, M. D. Kravchenko, and I. N. Shevchuk, Russ. J. Phys. Chem., 1970,44, 560.

356

F. Balkau and M. L. Heffernan, Austral. J. Chem., 1972, 25, 327.

s56

K.D. Bartle, D. W. Jones, and R. S. Mathews, Tetrahedron, 1971, 27,5177.

357 358

35Q 360

381 36a

F. Balkau, M. W. Fuller, and M. L. Heffernan, Austral. J. Chem., 1971,24,2293. F. Balkau and M. L. Heffernan, Austral. J. Chem., 1971, 24, 2305. P. Faller, Bull. SOC.chim. France, 1969, 934. E. Campaigne and J. Ashby, J. Heterocyclic Chem., 1969, 6, 517. 0. Chalvet, R. Royer, and P. Demerseman, Bull. SOC.chim. France, 1960, 1483. S. Clementi, P. Linda, and G. Marino, J . Chem. SOC.(B), 1971, 79.


443 bicyclic systems, therefore, is not a consequence of a different effect of benzo-fusion, but must be attributed to the different a : 18 ratios in the two monocyclic systems. The electrophilic deuterium-hydrogen exchange in the p-position of benzo[b]thiophen was found to be about 1000 times slower than that in the a-position of the thienothiophens.SO6 Benzo[b]thiophen is formylated in the 3-position more conveniently and in higher yield by dichloromethyl butyl ether in the presence of titanium tetrachloride than by conventional Vilsmeyer formylation ;the 3-methyl derivative reacts in the 2-positi0n.~~~ Contrary to previous reports, it has been found that t-butylation of benzo[b]thiophen with isobutylene in the presence of polyphosphoric acid gives a mixture consisting of 71% of 3-t-butylbenzo[b]thiophen, 22% of 2-t-butylbenzo[b]thiophen, and 7% of an unidentified compound. Upon alkylation with t-butyl alcohol and concentrated sulphuric acid, 89% of the 3-isomer and 6% of the 2-isomer are obtained.8e4 The isomer distribution obtained upon nitration of benzo[bJthiophen with nitric acid in acetic acid has been reinvestigated in an excellent study. The absence of the 5-nitro-isomer was confirmed and the approximate proportions of the 3-, 4-, 2-, 7-, and 6-nitrobenzo[b]thiophenswere found to be 56 : 13 : 12 : 11 : 10.s66Detailed n.m.r. data for all isomeric nitrobenzo[b]thiophens are given. The development of chromatographic separation techniques such as V.P.C. and the use of n.m.r. and mass spectrometry for structure determination has led to rapid progress in the study of isomer distributions obtained upon electrophilic substitution of complex heterocyclic systems. A number of investigations on substitution reactions of benzo[b]thiophens bearing an electron-withdrawing group in the 3-position have been carried O U ~ . ~ 3-Nitrobenzo[b]thiophen, ~ ~ - ~ ~ ~ which is not nitrated with fuming nitric acid in glacial acetic acid at elevated temperature, reacts with potassium nitrate in concentrated sulphuric acid or with a mixture of nitric acid, acetic acid, and acetic anhydride. All benzenic positions react, the reactivity order being 6 > 5 > 4 =- 7. The observed preference of substitution is discussed in terms of electron-density calculations for 3-nitrobenzo[b]thiophen, and in terms of the influence of peri interactions in the 3,4dinitro-derivati~e.~~~ The structure of a trinitro-derivative has been corrected to 3,4,6-trinitrobenzo[b]thiophen. Nitration of benzo[b]thiophen-3-carboxylic acid with nitric acid in acetic acid containing 10% sulphuric acid at 60 "C gave nitration in all four available positions in the benzene ring, the 4-nitro-isomer being the predominant If nitration 3 ~ sN. P. Buu-HoI, A. Croisy, and P. Jacquignon, J. Chem. SOC.(0,1969, 339. s64

s65

3e7

J. Cooper and R. M. Scrowston, J. C. S. Perkin I, 1972, 414. K. J. Armstrong, M. Martin-Smith, N. M. D. Brown, G. C. Brophy, and S. Sternhell, J. Chem. SOC.(C), 1969, 1766. I. Brown, S. T. Reid, N. M. D. Brown, K. J. Armstrong, M. Martin-Smith, W. E. Sneader, G. C. Brophy, and S. Sternhell, J. Chem. SOC.(C), 1969, 2755. G. C. Brophy, S. Sternhell, N. M. D. Brown, I. Brown, K. J. Armstrong, and M. Martin-Smith, J. Chem. SOC.(C), 1970, 933.

444


was carried out with potassium nitrate in sulphuric acid at 0 "C, the 6and/or 5-nitro-isomers became the major nitro-products. This is also true, in contrast to previous results, when fuming nitric acid-acetic anhydride is used. A minor reaction path involves replacement of the carboxy-group by a nitro-group, but under none of the conditions employed does substitution occur in the 2-position. 3-Acetyl- and 3-formylbenzo[b]thiophen have been nitrated under conditions similar to those used for the Although treatment of the 3-acetyl derivative with concentrated nitric acid in acetic acid containing 10% of sulphuric acid led to furoxan formation, reaction with potassium nitrate in concentrated sulphuric acid at 0 "C, or with a cold mixture of fuming nitric acid and acetic anhydride, gave rise to substitution at all four available positions in the benzene ring. Similar results were obtained with the 3-formyl derivative. In addition, with the last-mentioned method, appreciable amounts of deacetylation and deformylation, leading to the 3-nitro-derivative, were observed. Attempted bromination of both 3-acetyl- and 3-formyl-benzo[b]thiophen by means of bromine in acetic acid failed.367 The nitration of benzo[b]thiophen-2-carboxylic acid in sulphuric acid and acetic acid at 60 "C and in acetic acid-acetic anhydride at 0 "C has been A mixture of the 4- (27%), 7- (26%), 6- (llz),and 3- (3%) substitution products together with 2-nitrobenzo[b]thiophen (4%) and starting material (11%) was obtained with the latter method. The same isomers were obtained in sulphuric acid, although the amount of 3-isomer was greater (16%). Under similar conditions, the nitration of 3-methylbenzo[b]thiophen-2-carboxylicacid took place in all positions of the benzene ring apart from the Sposition, and the replacement of the carboxy-group by a nitro-group became more significant.368Bromination of 2-phenylbenzo[b]thiophen with N-bromosuccinimide in acetic acid occurs in the thiophenic 3 - p o ~ i t i o n . ~Nitration ~~ of 3-t-butylbenzo[b]thiophen-2-carboxylic acid with the above-mentioned nitrating agents is very complex, giving different proportions of the following acidic products in each case : benzo[b]thiophen-2-carboxylicacid, 3-, 4-, 6-, and 7-nitrobenzo[b]thiophen2-carboxylic acid, and 3-t-butyl-4-, 3-t-butyl-6-, and 3-t-butyl-7-nitrobenzo[b]thiophen-2-carboxylic Neutral material from the nitration reactions contains 3-t-butyl-2-nitro- and 2-nitro-benzo[b]thiophen. Nitration of 3-bromo-2-methylbenzo[b]thiophenin a mixture of sulphuric acid and acetic acid gives 2-methyl-3-nitrobenzo[b]thiophen(44%) and 3-bromo-2methyl-6-nitro- (31%), and 3-bromo-2-methyl-4-nitro-benzo[b]thiophen (22%).369 The nitration of 2,3-dimethylbenzo[b]thiophen in acetic acid yields 2,3-dimethyl-6-nitrobenzo[b]thiophen, 3-methyl-2-nitromethylbenzo[b]thi ophen, 3-methyl-2-formylbenzo [b]t hi ophen, and 2,3-dimethyl-4-nitrobenzo[b]thiophen as major Nitration of 2,3-dibromobenzo36B

J. Cooper and R. M. Scrowston, J . Chem. Soc. (C), 1971, 3405. J. Cooper and R. M. Scrowston, J. C. S. Perkin I, 1972, 265.


445 [blthiophen gives a mixture of 2,3,6-tribromo- (25%), 2,3,4-tribromo(3%), 2,3-dibromo-6-nitro- (32%), and 2,3-dibromo-4-nitro-benzo [b1thiophen (36%). Bromination of 2,3-dibromobenzo[b]thiophen in chloroform or acetic acid gives the 2,3,6-tribromo-deri~ative.~~~ Analogous results were obtained in the bromination and nitration of 2,3-dibromo-5methylbenzo[b]thiophen, except that the presence of the 5-methyl group increased the proportion of the 4-substituted product in each case. It is obvious that attempts to determine partial rate factors for different positions in substituted benzo[b]thiophens are seriously hampered by elimination of substituents and/or side-chain substitution, Bromination, acetylation, formylation, and nitration have been carried out with 4-methoxybenzo [b]thi ophen and 4-benzyloxybenzo[b]thi ophen.371 Substi tu tion occurs predominantly in the 7-position, except in the bromination of the benzyloxyderivative, which occurs in the 3-position. Bromination of 4-hydroxybenzo[b]thiophen occurs in the 5-position. Formylation of 5-hydroxybenzo[b]thiophen by a modified Gatterman procedure gave the 4-formyl derivative in high yield.372Similarly, nitration, formylation, and bromination of 5-hydroxy-3-methylbenzo[b]thiophenoccur in the 4-position, whereas dibromination and dinitration occur in the 4- and 6-po~ition.s.~~~ Nitration of 4-bromo-5-hydroxy-3-methylbenzo[b]thiophenalso occurred in the 6-position. Bromination and acetylation of 6-methoxy-3-methylbenzo[b]thiophen occur in the 2 - p o ~ i t i o n . ~ ~ ~ Succinoylation, acetylation, and nitration of 4-methyldibenzothiophen yield 2-substituted products. Bromination, on the other hand, gives the 3-bromo-derivative as the main product together with small amounts of the 2-i somer.37 Electrophilic Ring-closure.-Cagniant and co-workers have extended their studies on the synthesis and properties of thiophens with annelated saturated rings to benzo[b]t hiophen. The 3-benzo[blthienylthio-acids (356), S(CH,),COOH \ 11

= 2, Or

o

3

(356)

iJ

(357a)

(357)

Et i)

0

(358)

0

(360)

(359)

J. Cooper, D. F. Ewing, R. M. Scrowston, and R. Westwood, J . Chem. SOC.(C), 1970, 1949.

871 a7a 87a

E. Campaigne, A. Dinner, and M. Haseman, J. Heterocyclic Chem., 1971, 8, 755. P. M. Chakrabarti, N. B. Chapman, and K. Clarke, J. Chem. SOC.( C ) , 1969, 1. E. Campaigne, L. Hewitt, and J. Ashby, J. Heterocyclic Chem., 1969, 6, 553.

446


prepared from the thiol obtained from the Grignaxd reagent and sulphur and the appropriate halogeno-esters, were ring-closed uiu acid chlorides to (357) and (358) in the usual manner and reduced and transformed to other The u.v., i.r., and n.m.r. spectra of (357) and (358) have been A theoretically interesting observation is that (358a) is acetylated in position 7 (the 6-position in benzo[b]thiophen), whereas (359) as well as the open analogue (360) quite unexpectedly react in the 5-position of benzo[b]thiophen [9-position of (359)].37s Benzo[b]thiophens with annelated six- (361) and seven- (362), (363) 0

membered rings, with the sulphur atom in other positions, and derivatives obtained by modifying the carbonyl group, have been obtained from (364), (365), and (366), respectively, by Friedel-Crafts r i n g - c l ~ s u r e378 . ~ ~The ~~ compounds (364)-(366) were obtained by conventional methods from the

0

I1 Ho-c-c?-R Q(CH2l

thiols. The compounds with six- (367) and seven- (368) membered annelated carbocyclic rings and their derivatives have been prepared by ring-closure of the appropriate acid By starting from thio-acids (369), in which the 2-position is blocked by methyl, ring-closure to the peri374 375

376 377 378

P. Cagniant and J. Trierweiler, Bull. SOC.chim. France, 1969, 596. D. Cagniant, P. Cagniant, and J. Trierweiler, Bull. SOC.chim. France, 1969, 601. P. Cagniant, D. Cagniant, and J. Trierweiler, Bull. SOC.chim. France, 1969, 607. P. Cagniant and G. Kirsch, Compt. rend., 1971,272, C, 406. P. Cagniant, Compt. rend., 1970, 271, C, 1086. P. Cagniant and G. Kirsch, Compt. rend., 1971, 272, C, 948.

447


0 &Me \ n

=

1 or 2

(371)

(369)

(372)

(373)

position could be achieved with PPA to yield (370) and (371), which by NaBH, reduction and dehydration were transformed to (372) and (373).360 Radical Substitution.-The reactions of 3-benzo[b]thienylradicals generated by the photolysis of 3-iodobenzo[b]thiophen have been studied in a variety of monosubstituted benzenes as Isomer ratios were determined, and the results indicate that the 3-benzo[b]thienyl radical has a reactivity intermediate between those of 2- and 3-thienyl radicals. The honiolytic phenylations of benzo[b]thiophen and benzo[b]furan have been compared.382,363 Thermal decomposition of N-nitrosoacetanilide was the source of phenyl radicals. Whereas homolytic substitution in benzo[b]furan occurs almost exclusively in the heterocyclic ring, benzo[b]thiophen shows comparable reactivity in all positions. The synthesis of all six isomeric phenyl benzo[b]thiophens is given.s8s Metalation and Halogen-Metal Exchange.-Metalation of benzo[blthiophen with organolithium compounds occurs in the a?-positionand is therefore of great synthetic importance, as electrophilic substitution predominantly occurs in the p-position. Preparation of 2-benzo[b]thienyl-lithium followed by its reaction with butyl borate and oxidation of the intermediate boronic acid derivative has been used for the synthesis of the 2-hydroxybenzo[b]thiophensystem (thio380

s81 882

s8s

J. F. Muller, D. Cagniant, and P. Cagniant, Tetrahedron Letters, 1972, 81. L. Benati, G . Martelli, P. Spagnolo, and M. Tiecco, J . Chem. SOC.(B), 1969, 472. C. M. Camaggi, R. Leardini, M. Tiecco, and A. Tundo, J. Chem. SOC.(B), 1970, 1683. P. Spagnolo, M. Tiecco, A. Tundo, and G . Martelli, J. C.S. Perkin I, 1972, 556.

448 Organic Compounds of Sulphur, Selenium, and Tellurium indoxyl), which exists in the more stable tautomeric thiolactone 385 From 3-methylbenzo [b]thiophen the corresponding 3-methylbenzo [b]thiophen-2-(3H)-one was The reaction of 2-benzo[b]thienyl-lithium with chloral gave trichloromethyl-2-benzo[b]thienylmethanol,which could rearrange to a-methoxy-2benzo [b]thienylacetic acid.386 5-ChIoro- and 5-methyl-benzo[blthiophen were metalated with butyl-lithium, and the product reacted with carbon dioxide, dimethyl sulphate, and dimethyl disulphide to give the corresponding 2-substituted carboxy-, methyl-, and thiomethyl-deri~atives.~~~ The rates of protophilic dedeuteriation of ben~o[b]-[2-~H]and -[3-2H]-thiophen by potassium t-butoxide in t-butyl alcohol were found to be 4 and 2 x times that of [2-2H]thiophen. The exchange in the 3-position was 65 times faster than that of [3-2H]thiophen.312As in thiophen, halogen-metal exchange is more rapid in the 2- than the 3-positionYand the reaction between 2,3-dibromo-5-methyl- and 2,3-dibromo-5-chloro-benzo [b]thiophen and butyl-lithium at - 70 "C yields 3-bromo-5-methyl- and 3-bromo-5-chloro2-benzo[b]-thienyl-lithiumYwhich gave the 2-carboxylic acids with carbon dioxide and the corresponding hydrogen derivatives upon hydrolysis. At - 70 "C,3-benzo[b]thienyl-lithium 386s and substituted derivatives, such as 2-phenyl-, 5-methyl-2-phenyl-, 5-chloro-2-phenyl-, and 5-bromo-2phenyl - 3 - benzo[b]thienyl 2 -methyl- 2 - methylthio - 3 - benzo[b] thienyl-lithium, and their 5-methyl- and 5-chloro-deri~atives,~~~ as well as 5-methyl- and 5-chloro-3-benzo[b]thienyl-lithium,3g0 are obtained through halogen-metal exchange between the corresponding 3-bromo-derivatives and alkyl-lithium, and are stable enough to be very useful for the synthesis of many 3-substituted derivatives. At higher temperatures 3-benzo[b]thienyl-lithium ring-opens to form (374), which can be trapped as (375) by

(374)

(375)

reaction with dimethyl s ~ l p h a f e .This ~ ~ ~ring-opening has been studied in detail, and is partly complicated by transmetalations leading to 3-bromo-2benzo[b]thienyl-lithium, especially if tetrahydrofuran is used as solvent. The same ring-cleavage also occurs when 2 - m e t h ~ l - ,2-rnethylthi0-,~~~ ~~~ and 2-phenyl-3-benzo[b]thienyl-lithium38g and their derivatives are allowed to stand at room temperature, and thus provides a route to substituted 384

38s 388 387 a88 38g

3g0

R. P. Dickinson and B. Iddon, J. Chem. SOC.(C), 1970, 1926. W. C. Lumma, jun., G . A. Dutra, and C. A. Voeker, J. Org. Chem., 1970, 35, 3442. S. Gronowitz, J. Rehno, and J. Sandstrom, Acta Chem. Scand., 1970, 24, 304. R. P. Dickinson and B. Iddon, J. Chem. SOC.(C), 1971, 182. R. P. Dickinson and B. Iddon, J. Chem. SOC.(C), 1971, 3447. R. P. Dickinson and B. Iddon, J. Chem. SOC.(C), 1970, 2592. R. P. Dickinson and B. Iddon, J. Chem. SOC.( C ) , 1971, 2504.

Thiophens and their Selenium and TeIIurium Analogues

449

phenylacetylenes of preparative interest. Halogen-metal exchange with bromodibenzothiophens has been used for the preparation of substituted derivatives.373 Side-chain Reactions.-The rates of alkaline hydrolysis of carboxylic acid methyl esters in ‘70% dioxan’ solution followed the sequence 3-benzo[b]fury1 > 2-benzo[b]furyl 2-benzo[b]thienyl > indol-2-yl > indol-3-yl > phenyl > 3-benzo[b]thienyl. The effect of benzo-annelation on the rates of hydrolysis has been determined for furan, thiophen, and pyrrole esters. It is a rate increase of about 3 for 2-benzo[bJthienyland a 70% rate reduction for 3-ben~o[b]thienyl.~~~ The rates of detritiation of 2- and 3-[3H]methylbenzo[b]thiophen and [2-Me-3H]-2,3-dimethylbenzo[b]thiophen have been found to be 14.1 x lo-’, 2.6 x lo-’, and 1.1 x s-l, respectively. The results were interpreted in terms of a mechanism involving reversible attachment of a proton to the ring-carbon ortho to the [3H]methyl group followed by loss of a proton from the latter to give an olefinic species.3g2An allylic rearrangement occurred when a-methoxy-2-benzo[b]thienylacetic acid was treated with 30% hydrogen bromide in acetic acid to give 3-bromo-2-benzo[b]thienylacetic acid, whereas the 3-isomer reacted normally to give a-bromo-3-benzo[b]thienylacetic No rearrangement occurred on treating 3- or 2-hydroxymethylbenzo[b]thiophenwith the same reagent. When 3-alkyl-3-aryl- or 3-aralkylbenzo[b]thiophens, as well as the corresponding benzo[b]furans and indoles, are treated with polyphosphoric acid, isomerization to the corresponding 2-isomer occurs.3B3 It is believed that isomerization occurs through protonation of the heterocycle with subsequent intramolecular migration of the substituent. The cationic polymerization of benzo[b]thiophen and 4,7-dimethylbenzo[b]thiophen has been

=-

Photochemistry.-The photochemical addition of dimethyl acetylenedicarboxylate, methyl propiolate, or methyl phenylpropiolate to benzo[b]thiophen and its 2- and 3-methyl and 2,3-dimethyl derivatives leads to cyclobutene derivatives of unexpected structure^.^^^^ 396 From benzo[b]thiophen and dimethyl acetylenedicarboxylate (376) is obtained. Methyl propiolate adds in a direction opposite to that of methyl phenylpropiolate, suggesting that the excited state of benzo [blthiophen is highly polarized. The mechanism of the addition is discussed, and several mechanistic alternatives are ~ u g g e ~ t e dOnly . ~ ~ with ~ diphenylacetylene, which reacts slowly, can the normal addition product (377) be 397 Thc aB1 382

394

396

388 *07

A. Feinstein, P. H. Gore, and G. L. Reed, J. Chem. SOC.(B), 1969, 205. C. Eaborn and G. J. Wright, J. Chem. SOC.(B), 1971,2262. A. N. Kost, V. A. Budylin, E. D. Matveeva, and D. 0. Sterligov, Zhur. org. Khim., 1970, 6, 1503. C. Zaffran and E. Mardchal, Bull. SOC.chim. France, 1970, 3523. D. C. Neckers, 5. H. Dopper, and H. Wynberg, Tetrahedron Letters, 1969,2913. J. H. Dopper and D. C. Neckers, J. Org. Chem., 1971, 36, 3755. W. F. Sasse, P. J. Collin, and D. B. Roberts, Tetrahedron Letters, 1969, 4791.

16


450

- ‘S’k2H

-‘s’\

R2

cyclobutenes of type (376) are thermally unstable and rearrange with sulphur extrusion to naphthalenes, (378) being obtained from (376). Halogeno-olefins such as cis- and trans-1,Zdichloroethylene react normally with benzo[b]thiophen and its alkyl derivatives in a photosensitized reaction to give adducts of the type (379). Several stereoisomers are formed, and have in several cases been separated and their structures determined.3B8 The adducts are easily transformed to the cyclobutenes (380) on heating with methanolic sodium hydroxide and are smoothly oxidized to the sulphones (381) with perbenzoic acid. Benzo[b]thiophen 1,l-dioxide forms two isomeric dimers, (382) and (383), on U.V. irradiation.sBBReduction to the corresponding benzo[b]thiophen dimers and Raney-nickel desulphurization proved the structures,

and the assignment of dimer (383) was confirmed by Raman and i.r. specfro~copy.~~~ The U.V. irradiation of (384) gives (386) in high yields, probably through an electrocyclization of the ortho-quinoid structure (385) followed by a

398 899

D. C. Neckers, J. H. Dopper, and H. Wynberg, J. Org. Chem., 1970, 35, 1582. D. N. Harpp and C. Heitner, J . Org. Chem., 1970,35, 3256.

Thiophens and their Selenium and Tellurium Analogues 45 1 sigmatropic rearrangement.400 3-Methylbenzo[b]thiophen 1,l-dioxide adds chlorine, as well as methanol, upon irradiation by U.V. light to give four products where the nucleophilic group is in the 3 - p o ~ i t i o n . ~ ~ ~ The 2- and 3-Hydroxybenzo[b]thphen Systems and their Derivatives.The 2-hydroxybenzo[b]thiophen system exists in the thiolactone form (387), but gives upon dimethyl sulphate methylation of its sodium salt

(prepared with sodium hydride in hexamethylphosphoramide)Z-methoxybenzo[b]thiophen in high yield.384 Small amounts of 3-methyl-2-methoxybenzo[b]thiophen were also formed. The 3-hydroxybenzo[b]thiophen system, which can exist in the two tautomeric forms (388) and (389), has been prepared by heating an ethanolic solution of o-methylthio-w-diazoacetophenone in the presence of thiourea.402 The tautomerism of the 3-hydroxybenzo[b]thiophen system has recently been studied by a u.v.spectroscopic technique.*03 It is claimed that freshly sublimed material is practically pure ketone, whereas on acidifying an alkaIine solution pure

(392) 400 401

402 403

,--I

J. Nasielski and G . Jacqmin, Tetrahedron, 1972, 28, 597. V. I. Dronov, G. M. Prokhorov, and V. S. Fal'ko, Zhur. org. Khim., 1971, 7 , 162. W. Hampel and J. Friedrich, 2.Chem., 1970, 10, 343. W. Rubaszewska and 2.R. Grabowski, Tetrahedron, 1969, 25, 2807.

452


enol is first formed. The tautomeric equilibrium constant [enol]/[ketone] was found to be 0.18 in water and 2.02 in ethanol. The rate constants for tautomerization were determined.*03 The properties of some metal complexes derived from (390) have been described.404The reaction of substituted derivatives of (389) with aryl diazonium salts yields hydrazones (391) and condensation with aryl isothiocyanates in tetrahydrofuran in the presence of sodium yields (392), which can be cyclized to (393) by reaction with o - b r ~ m ~ a c e t o p h e n ~ n e . ~ ~ ~ Cyanine dyes derived from (389) have been described,40sand spectra and cis-trans-isomerization rates of some thioindigoids have been disc ~ s s e d408 .~~~~ Reaction at Sulphur.-The kinetics of the oxidation of benzo[b]thiophen and its 3-substituted derivatives by perbenzoic acid in dichloromethane at 30 "C have been The rate constants obtained for the first step, the oxidation to the sulphoxide, have been correlated with a : values, whereas the rate constants for the second step, of oxidation to the sulphone, have been correlated with values. A number of benzo[b]thiophen and dibenzothiophen derivatives and their sulphoxides have been S- and O-alkylated, respectively, with silver perchlorate and alkyl halides.410 5-Methoxydibenzothiophenium perchlorate reacted with amines to give 5-aminosulphonium salts, and with certain carbanions to give zwitterionic compounds such as (394).

Pharmacologically Active Compounds.-Much of the synthetic and pharmacological effort in the benzo[b]thiophen series is directed towards the study of analogues of the active indole derivatives. The benzo[b]thiophen analogues of tryptophan and a-methyltryptophan, as well as their 5-bromo-, 5-chloro-, 5-methyl-, and 5-nitro-derivatives, have been synthesized by conventional methods, starting from 3-~hlorornethylbenzo[b]thiophensand Io4

L. A. Smurova, T. V. Sirota, A. B. Gagarina, V. P. Litvinov, 8. G. Ostapenko, Ya. L. Gol'dfarb, and N. M. fimanukl, Doklady Akad. Nauk S.S.S.R., 1971, 198, 1378.

Ie6

M. 0. Lozinskii, S. N. Sanova, and P. S. Pel'kis, Khim. geterotsikl. Soedinenii, 1967,

Io6

3, 461. S. V. Lepikhova and G. T. Pilyugin, Zhur. obshchei Khim., 1969, 39, 1829.

407

A. Mostoslavskii, M. M. Shapkina, and S. I. Saenko, Khim. geterotsikl. Soedinenii, 1967, 3, 465.

M. A. Mostoslavskii and M. M. Shapkina, Russ. J. Phys. Chem., 1970, 44, 1542. Io9 N. Kucharczyk and V. Horik, Coll. Czech. Chem. Comm., 1969,34, 2417. 'lo R. M. Acheson and J. K. Stubbs, J. C. S. Perkin I, 1972, 899. 408


453

diethyl a~etamidomalonate.~~~ The synthesis of the benzo[b]thiophen analogues of 5-hydroxytryptophan, of melatonine (395) and bufotenine (396), and some closely related compounds has been described, and some H

preliminary pharmacological results are given.412 The pharmacology of 5-hydroxytryptamine and of its benzo[b]thiophen, benzo[b]furan, and indene isosteres has been compared.413 A series of 2-(5’-substituted)-3’benzo[b]thienylethylamines, which are analogous to tryptamine, has been prepared by reduction of the corresponding 3-benzo[b]thienylacetonitriles with lithium aluminium hydride and aluminium chloride, which also upon hydrolysis gave acetic acids isosteric with heteroauxine (indolylacetic 4- and 5-mono-substituted and 4,5-disubstituted amines (397) and

(397)

(398)

thiouronium salts (398) have been prepared for pharmacological evaluat i ~ n The . ~ ~key ~ intermediates in the synthesis were the corresponding 3-methyl derivatives, which were brominated in the side-chain and then treated with amines or with thioureas, or with N-alkylethanolamines, to give substituted 2-hydroxyethylamines, which gave the 2-chlor oethylamines when treated with thionyl chloride in chloroform. Substituted diary1 derivatives of benzo[b]thiophens appear to be promising as antifertility The highest activity was observed in compound (399). Compounds of this type were synthesized by ring-closure of the appropriate fhulphido-ketones (400) with polyphosphoric acid. In connection with an extensive study of /3-adrenergic blocking agents related to propanolol (401), heterocyclic analogues, including the benzo[b]thiophens (402), have been prepared 411

N. B. Chapman, R. M. Scrowston, and R. Westwood, J. Chem. SOC.(C), 1969, 1855. Campaigne and A. Dinner, J. Medicin. Chern., 1970, 13, 1205. R. M. Pinder, D. M. Green, and P. B. J. Thompson, J. Medicin. Chem., 1971,14,626. N. B. Chapman, K. Clarke, A. J. Humphries, and S. U.-D.Saraf, J. Chem. SOC.( C ) ,

ria E. 413 414

1969, 1612. 416

N. B. Chapman, K. Clarke, B. A. Gore, and K. S. Sharma, J. Chern. SOC.(C), 1971, 915.

416

R. R. Crenshaw, A. T. Jeffries, G. M. Luke, L. C. Cheney, and G. Bialy, J. Medicin. Chem., 1971, 14, 1185.

454


(399) OCH,CH(OH)CH,NHPr* R3HNH2CHCCH20 (401)

(402)

from the corresponding hydroxy-derivati~es.~~'Compounds with the side-chain in the 4-position showed the highest activity. The hydroxybenzo[b]thiophens have also been used for the synthesis of carbamates with insecticidal effects. One of them, 4-benzo[b]thienyl methylcarbamate, (mobam) (403), exhibited a favourable combination of

broad-spectrum insecticidal activity, coupled with low mammalian toxicity.418 2-Arylbenzo [b]thiophen-3(2H)-one 1,l-dioxides (404) exhibit both anticoagulant and anti-inflammatory activity. The compounds were prepared by cyclizing (405) by refluxing in acetic anhydride containing potassium acetate.41s Dibenzothiophen analogues of p-dimethylaminoazobenzene show carcinogenic Interest in the synthesis of analogues of steroids containing thiophen rings is still active, and benzo[b]thiophen derivatives are often used as starting materials. Thus starting from (406a), 3-desoxy-~-nor-6-thiaisoequilenin (407a) has been synthesized, using a modified Bachmann equilenin Similarly, starting from the methoxy-derivative (406b), *17

418

w0 421

A. F. Crowther, R. Howe, B. J. McLoughlin, K. B. Mallion, B. S. Rao, L. H. Smith, and R. W. Turner, J. Medicin. Chem., 1972, 15,260. J. R. Kilsheimer, H. A. Kaufman, H. M. Foster, P. R. Driscoll, L. A. Glick, and R. P. Napier, J. Agric. Food Chem., 1969, 17,91. J. G.Lombardino and E. H. Wiseman, J. Medicin. Chem., 1970, 13, 206. E. V. Brown and R. Isbrandt, J. Medicin. Chem., 1971, 14,84. B. D. Tilak, V. N. Gogte, A. S. Jhina, and G. R. N. Sastry, Indian J . Chem., 1969, 7, 31.


455 ~-nor-6-thiaisoequilenin(407b) was These compounds thus have the ‘wrong’stereochemistry in the annelation between the C and 0 rings. However, by starting from the hydrindene (408), converting it into

(a)

R

(b) R

= =

(a) R = H (b) R = OH

H OMe

(409), and cyclodehydrating to (410) with AICI, in methylene chloride, ~-nor-6-thiaequileninand related compounds were obtained upon further transformation^.^^^

5 Thiophen Analogues of Polycyciic Aromatic Hydrocarbons Thiophen Analogues of Anthracene.-The reaction of 5,5’-blocked 2,2’dithienylmethanes such as (214) with acylating agents such as acetic acid in polyphosphoric acid yields thiophen analogues of anthracene (215).230 Through electrochemical or chemical reduction of 2-acetylthiophen the anthracene analogue (411) has been obtained.laebThe methyl groups have Me

I

Me (411)

by conventional methods been modified to bromomethyl, formyl, and carboxylic acid groups.424 422 d23 4y4

B. D. Tilak and M. K. Bhattacharjee, Indian J . Chem., 1969, 7 , 36. R. R. Crenshaw and G. M. Luke, Tetrahedron Letters, 1969, 4495. M. Hebert and C. Caullct, Compt. rend., 1971, 273, C, 1451.

456

Organic Coinpounds af Sulphur, Selenium, and Tellurium

0

II

(413)

0

(415)

i OH

1

OH


457

In order to study the keto-enol tautomerism of thiophen analogues of anthrone, three of the monothieno-analogues (412)-(414) 425 and five of the six dithieno-analogues (415)-(419) have been prepared.426 These compounds are generally prepared by ring-closure of the acid chloride of the appropriate phenylthienylmethanecarboxylic acid or dithienylmethanecarboxylic acid in the presence of SnCl,. The compound (412) was obtained from (420), which was obtained through reduction of the keto-acid obtained from Friedel-Crafts acylation of thiophen with phthalic anhydride. The acid (421), precursor of (419, was prepared through the reaction of 3-thienyllithium with o-bromobenzaldehyde, followed by reduction of the intermediate alcohol with LiAlH,-AlCl, and carbonation of the Grignard reagent. By the same steps the alcohol derived from 4-bromo-3-thienyllithium and benzaldehyde was transformed to (422), except that halogenmetal exchange was used in the last step. The same synthetic principle was used for the synthesis of (423) starting from 4-bromo-3-thienyl-lithium and thiophen-3-aldehyde, of (424) starting from 4-bromo-3-thienyl-lithium and thiophen-2-aldehyde, and of (425) starting from 3-bromo-2-thienyl-lithium

.

,

(426)

and thiophen-3-aldehyde. The route to (426) was somewhat different, as 3,3’-di thienylmethane, obtained through the reaction of 3-thienyl-lithium with ethyl formate followed by reduction, was monobrominated and converted into the acid. Finally, (427) was obtained via the alkylation of 3-bromothiophen with 2-chloromethylthiophen, followed by halogenmetal exchange and carbonation. By the n.m.r. technique the positions of the tautomeric equilibria in (412)-(419) were determined and found to be dependent on the mode of fusion. Thus for (417), (418), and (419) only the 425

D. W. H. MacDowell and J. C. Wisowaty, J. Org. Chem., 1971, 36, 3999. D. W. H. MacDowell and J. C. Wisowaty, J. Org. Chem., 1971, 36, 4004.


458

hydroxy-form could be detected, whereas (412) and (413) exist as mixtures of enol and keto-forms, and for (414), (415), and (416) only the keto-form was detected by the n.m.r. technique. The observed result is inexcellent agreement with MO calculations of rr-delocalization-energy differences between the two forms. The anthracene analogue (428) has been prepared through reduction of the acetate of (412), and (428a) by treating 2,2’dithienylmethane-3-carboxaldehyde,obtained similarly to (427), with 48% hydrobromic By the reaction of (428) with (429), the unsubstituted heterocyclic asymmetric triptycene (431) was obtained via a mixture of stereoisomers of (430).

O-yJ s ’ /

(428)

s ’ s

\

(428a)

(429)

Dewar para localization energies for some anthracene analogues have been Another route to heterocyclic analogues of triptycene (433) is through the reaction of (432) with phosphorus pentasulphide. The starting material (432) was prepared by the Diels-Alder reaction of anthracenes with dibenzoyl- or diacetyl-ethylenes.428

\

R1

/

\

/

‘

R6

R5 (432)

(433)

Thiophen Analogues of Phenanthrene.-Electrophilic substitutions of naphtho[2, l-blthiophen (434) such as nitration, formylation, and acylation occur, in contrast to those in benzo[b]thiophen, in the thiophenic a-position (2-position). Bromination gives a mixture of the 2-bromo- and 2,5dibromo-derivative~.~~~ That the 5-position is the second most reactive 427 428

42g

H. Wynberg, J. de Wit, and H. J. M. Sinnige, J . Org. Chem., 1970, 35, 711. D. M. McKinnon and J. Y. Wong, Canad. J. Chem., 1971,49,3178. K. Clarke, G . Rawson, and R. M. Scrowston, J. Chem. SOC.(C), 1969, 537.


459 position was also shown by nitration and bromination of the 2-methyl derivative and by bromination of the 1,2-dimethyl and 2-formyl comp o u n d ~ The . ~ ~lack ~ of reactivity of the l-position of (434)is most probably

due to steric interaction with the nearby 9-position. As expected, bromination, formylation, and Friedel-Crafts acylation of the 1-methyl derivative occur in the 2-position, whereas nitration yields a mixture of the 2- and 5-nitro-isomers. When a deactivating substituent is in the 1-position, such as the formyl group, bromination occurs in the 5 - p o ~ i t i o n .Metalation ~~~ of (434) and its 1-methyl derivative with organolithium compounds occurs in the 2-position. Through Robinson annelation between (435)and (436),

R

the compound (437) was obtained, which by standard operations could be transformed to the phenanthrene analogue (438). One of the missing dithiophen analogues (439) was prepared from 4,4’-diformyl-3,3’-bithienyl by slowly distilling a mixture of this dialdehyde,

hydrazine, water, and sulphuric The U.V. and n.m.r. spectra of (439) indicate more formal resemblance to cis-l,2-di-(3-thienyl)ethylene than to phenanthrene. Metalation of (439) with organolithium compounds 430 K. Clarke, G. Rawson, and R. M.Scrowston, J. Chem. Sac. (C), 1969, 1274. 431 4:J2

G. Jacob and P. Cagniant, Compt. rend., 1969, 268, C, 194. D. W. H. MacDowell and M. H. Maxwell, J . Org. Chem., 1970,35, 799.

460


occurs in the 1- and 3-positions in a 64 : 36 ratio. The radical anions of three other dithiophen analogues (440)-(442), which have previously been prepared by photocyclization of di(thienyl)ethylene~,~~~ have been investigated.306The long-range couplings in the n.m.r. spectra of (440) have been

The 7-chloro-derivative of (440) was prepared by photocyclization of 1-(5-chloro-2-thienyl)-2-(2-thienyl)ethylene.Attempts to prepare the 7-bromo-analogue in the same way failed, owing to cleavage of the carbon-bromine bond.434 Thiophen Analogues of He1icenes.-The photocyclization with iodine as oxidant of 1,2-di(diheteroaryl)ethenes, in whichthe heteroarylgroup is derived from benzo[b]thienyl or from tricyclic systems such as (434) or (440), is the key step in the synthesis of heterohelicenes. The ethylenes in turn are prepared from the aldehydes and the chloromethyl derivatives via phosphonium salts or phosphonates through the Wittig r e a ~ t i o n . "436~ ~The ~ Bestmann method was also used for the synthesis of symmetrically substituted ethylenes from phosphonium period ate^.^^^ Thus from (443) the heterohexahelicene (444) was obtained, (445) gave (446), and the heteroheptahelicene (448) was obtained from (447). The undecahelicene (450) was prepared from (449).436s437 These syntheses illustrate the fact that heterohelicenes are more easily available than helicenes, as the necessary aldehyde is prepared by metalation of (448) with butyl-lithium followed by reaction with N-rnethylf~rmanilide.~~~ The heptahelicene (452) was obtained by a double photocyclization of (451). Several of the helicenes have been resolved by manual crystal separation, and in one case resolution was also achieved by recrystallization from an optically active solvent. The n.m.r. and mass spectra of these compounds have been studied in The electronic spectra of a number of heterohelicenes have been discussed. The optical rotatory dispersion and circular dichroism spectra of the resolved one were measured. Calculation on a model compound was performed to establish the absolute configuration. The right-hand chirality was assigned to the (+)-heteroheli~enes.~~~ An X-ray analysis of (444) 439

4s4 4s6 436

437

R. M. Kellogg, M. B. Groen, and H. Wynberg, J. Org. Chem., 1967, 32, 3093. E. V. Blackburn, T. J. Cholerton, and C. J. Timmons, J. C . S. Perkin 11, 1972, 101. M. B. Groen, H. Schadenberg, and H. Wynberg, J . Org. Chem., 1971, 36,2797. P. G. Lehman and H. Wynberg, Rec. Trav. chim., 1971,90, 1113. H. Wynberg and M. B. Groen, J. Amer. Chem. SOC.,1970, 92, 6664. M. B. Groen and H. Wynberg, J. Amer. Chem. Soc., 1971, 93,2968.


46 I

(444)

CH=CH (450)

(449)

cH=cHw

Q-

C H = C H SO


462

confirms this absolute onf figuration.^^^^ 440 The activation parameters for the racemization of the heterohexahelicenes (444) and (446) have been determined.441Wynberg has recently given an autoreview of his work on het erohelicenes.148 a The heterohelicenes can be used for the synthesis of a new class of polycyclic aromatic compounds, similar to coronene or corannulene, for which Wynberg suggests the name heterocirculenes. Thus the heterohexahelicene (446) gives (453) in 95% yield upon heating for several minutes at 140 with an AlC1,-NaCI melt, and upon reaction with maleic anhydride and chloranil (453) yields (454). Decarboxylation of the latter or the corresponding acid with copper powder in quinoline furnishes the heterocirculene (455).442 O

Thiophen Analogues of F1uorene.-During recent years several groups have been interested in the synthesis and chemistry of thiophen analogues of fluorene. MacDowell and co-workers have now synthesized the remaining two monothiophen analogues (456) and (457). The former compound was

obtained in the following way. Unsymmetrical Ullmann-coupling of 2-iodothiophen and methyl o-iodobenzoate was followed by hydrolysis to 0-(2-thienyl)benzoic acid (458). The latter was ring-closed via the acid chloride to the fluorenone analogue, which upon Wolff-Kishner reduction gave (456). The other isomer was obtained in an analogous way from the acid (459), which was prepared through the reaction of 4-bromo-3-thienyllithium with cyclohexanone, aromatization, halogen-metal exchange, and carboxylation.12sc 43B 440

G. Stulen and G. J. Visser, Chem. Comm., 1969, 965. M. B. Groen, G. Stulen, G. J. Visser, and H. Wynberg, J . Amer. Chem. Soc., 1970, 92, 7218.

441

H. Wynberg and M. B. Groen, Chem. Comm., 1969,964. J. H. Dopper and H. Wynberg, Tetrahedron Letters, 1972, 763.

463


The effect of the mode of annelation on the acidity of the fluorenic hydrogens is clearly noticeable. (456) is metalated by butyl-lithium only at the 4-position, whereas (457) gives upon metalation and carbonation a mixture consisting of 38% of the %acid, 14% of the l-acid, and 48% of the 3-acid of (457).12sc Treatment of 3-thienylmandelic acid (460) with AlCl, in benzene gave the 4-acid of (456).lB6 A similar ring-closure to (461) was obtained upon treatment of methyl 3,3’-dithienylglycollate with chlorosulphonic acid in methylene chloride

.

The nitration of (462)yields 10% of the 6-nitro-derivative and 30% of a mixture of the 2-nitro- and 2,6-dinitro-derivative~.~~~ Two alternative routes to (463) starting from (464)have been A very interesting synthetic route to the fluorene analogue series was found in the reaction of

Q-p WMe 0 0

\

MeQMe

0 (462)

0 (463)

(464)

(465) with SC12, which gave (466) in 90% yield; this, in 50% yield, was hydrolysed by potassium hydroxide in triethylene glycol to (467). The structure was proved by X-ray analysis, and the mechanisms of the reactions were The similar systems (468) and (469) were prepared by

AlCl,-catalysed ring-closure of the acid chlorides of 3-phenylbenzo[b]thiophen-2-carboxylic acid and 2-phenylbenzo[b]thiophen-3-carboxylicacid, respectively.446Interestingly, direct ring-closure of 3-phenylbenzo[b]thiophen-Zcarboxylic acid with PPA yields (470). The reaction proceeds most R. Dabard and J.-Y. Le Bihan, Compt. rend., 1970, 271, C, 31 1. J.-Y. Le Bihan and R. Dabard, Compt. rend., 1972, 274, C, 726. 445 T. J. Barton, A. J. Nelson, and J. Clardy, J . Org. Chem., 1971, 36, 3995. u6 F. Sauter and A. Dzerovicz, Monatsh., 1969, 100, 913. 443

4bb


464

probably via (468), which ring-opens between the keto-group and the thiophen ring and then recloses to the 4-position of the benzo[b]thiophen part .447 Wynberg and co-workers have previously prepared all six dithiophen analogues of f l u ~ r e n e .Recently ~~~ all fluorenone analogues (471)-(476)

(471)

(472)

(473)

v

(475)

C02H

OH

0

‘S‘

(474)

0 (476)

3

M-e

(477)

MC

(475)

have been prepared.126aThe key step in the synthetic scheme is an Ullmann ring-closure of the appropriate dihalogenodithienyl ketone, which in turn is obtained by oxidation of an alcohol obtained by reaction of a bromothienyl-lithium derivative with a bromothiophen aldehyde. The synthesis of (474), as an example, starts with the reaction of 4-bromo-3-thienyl-lithium with 2-bromothiophen-3-aldehydeto give the alcohol (477), which is oxidized by CrO, in pyridine to the ketone, which is then treated with copper in dimethylformamide.126uA similar approach was used for the synthesis of the four tetramethyl analogues, with methyl groups in the thiophenic positions, corresponding to (471), (472), (474), and (476). Only for the synthesis of the tetramethyl derivative of (476) was it possible to use a simpler approach, analogous to the classical fluorenone synthesis, namely electrophilic ring-closure of (478).449The mode of annelation had a marked influence on the reduction of the tetramethylcyclopentadithiophenones with lithium aluminium hydride and aluminium chloride. Whereas the ‘cyclopentanic’ (476) and the ‘cyclopentenic’ (474) are easily reduced in high yields, forcing conditions have to be used with the cyclopentadienic 447

44a 449

F. Sauter and W. Deinhammer, Munatsh., 1970, 101, 544. A. Kraak, A. K. Wiersema, P. Jordens, and H. Wynberg, Tetrahedron, 1968,24,3381. A. K. Wiersema and S. Gronowitz, Acta Chem. Scand., 1970, 24, 2593.


465

analogues (471) and (472). However, this route to the cyclopentadithiophens is to be preferred to the shorter route consisting of ring-closure of appropriate dilithiated dithienylmethane derivatives with cupric The compounds (479) and (480) show interesting behaviour in reactions with dienophiles. With dimethyl acetylenedicarboxylate or phenylacetylene the middle ring reacts with CO extrusion to give compounds such as (481) and (482).450,451 However, with maleic anhydride, (479) and (480) reacted

Me

Me

with different ‘dienic’ systems, giving (483) and (484), respectively. The compound (480) reacts analogously with N-phenylmaleimide. (484) is obviously formed by 1,4-addition to the formal diene system of a thiophen ring followed by aromatization through the subsequent loss of hydrogen ~ u l p h i d e .Non-methylated ~~~ and non-‘cyclopentadienic’ systems do not react. Not only treatment with but also the reaction with potassium t-butoxide in t-butyl alcohol causes ready cleavage of the ketones (462) and (471) to (476), rapidly giving carboxylic acids in high yield at room temperature. The thiophen-carbon bond is preferentially cleaved in (462), giving o-(3-thienyl)benzoic acid. In the unsymmetrical cyclopent adit hi ophenones (473) and (474), the 2-thienyl-C=O bond is preferentially cleaved, yielding 3-carboxy-2,3’-bithienyl and 4-carboxy-3,3’-bithienyl, respect i ~ e l y . *Also, ~ ~ oxidation of the isomeric cyclopentadithiophens by oxygen in the presence of potassium t-butoxide in t-butyl alcohol-dimethyl sulphoxide or Triton B in pyridine caused cleavage to give the corresponding bithienylcarboxylic In contrast, the dithienylmethanes gave the corresponding dit hienyl ketones. 460

451 452

458

A. K. Wiersema and S. Gronowitz, Acta Chem. Scand., 1969, 23, 2923. A. K. Wiersema and S. Gronowitz, Acta Chem. Scand., 1970, 24, 2653. G. Rawson and H. Wynberg, Rec. Trav. chim., 1971, 90,46. G. Rawson and H. Wynberg, Rec. Trav. chim., 1971, 90, 39.

466


In order to study spiroconjugation by the U.V. technique, the spirofluorene derivatives (485)-(488) have been prepared. They were prepared by the reaction of fluorenone with 2-lithio-3,3’-bithienyl,4,4’-dilithio3,3’-bithienyl, 3-lithio-2,3’-bithienyl, and 3,3’-dilithio-2,2’-bithienyl,respectively, followed by electrophilic ring-closure of the intermediate triarylcarbonium ions by the addition of a drop of hydrochloric

(487) (488) Attempts to use a cyclopentabithiophenone as starting material instead of fluorenone failed, as the intermediate alcohol decomposed prior to ring-closure. The competitive metalation of compounds (489)-(493) with ethyl-lithium has been The tetramethyl derivatives were chosen in order to avoid metalation in thiophenic positions. It has been shown that the parent compound of (489) is only metalated in the two thiophenic positions in a 6 :4 The relative rates of metalation of (489) : (490) : (491) : (492) :

M i a e

M& ; Mc

Me

Me

Me

M

e

m

M

e

Me

M -e (492) 464

466 458

(493)

NCHZCHZC CHZCHZCN

(494) H. Wynberg, G. J. Heeres, P. Jordens, and H. J. M. Sinnige, Rec. Trav. chim., 1970, 89, 545. A. K. Wiersema and S. Gronowitz, Actu Chem. Scund., 1971, 25, 1195. D. W. H. MacDowell, R. A. Jourdenais, R. Naylor, and G. E. Paulovicks, J . Org. Chem., 1971, 36, 2683.


467 (493) were found to be 1 : 168 : 371 : 754 : 1360. Factors determining the relative metalation rates and acidities were discussed. The parent compound corresponding to (491) takes part in a Michael addition with acrylonitrile to yield (494).463The less acidic parent compound of (489)does not react. The crystal structure and dimensions of (495) have been determined by X-ray analysis.467

Thiophen Analogues of Tropylium Ions and Related Compounds.-Condensation of 3,4-diformyl-2,5-dimethylthiophenwith acetone or diethyl ketone yields the tropone (496). The reaction with acetone differs from that of phthalaldehyde, which only yields i n d a n o n e ~469 .~~ The ~ ~reduction of (496) with LiAIH4, and also the reaction with Grignard reagents, gave ethereal solutions of alcohols, which with HClO, gave the deep-blue tropylium-type 469 The carbonium ion perchlorates (497),which are stable in acetic (497;R = Me) is less stable than the tropylium ion itself, as a mixture of (498;R = Me) and (499;R = Me) is obtained upon reaction with cyclo-

R = HorMe

R1 = H or Me

(496)

(497)

R

R

=

HorMe (498)

gR

Me'

'Me

R = HorMe (499)

467 458

468

P. B. Koster, F. van Bolhuis, and G. J. Visser, A d a Crysf., 1970, B26, 1932. A. V. El'tsov, A. A. Ginesina, and L. N. Kivokurtseva, Tetrahedron Letters, 1968, 735. A. A. Ginesina, L. N. Kivokurtseva, and A. V. El'tsov, Zhur. org. Khim., 1969, 5, 570.

468


h e ~ t a t r i e n ein , ~contrast ~~ to the [blannelated ion (500).481Besides hydride transfer, Grignard reagents and nucleophiles such as methoxide and cyanide add to the 4- and 6-positions of (497).462,463 The isomeric composition of the 4- and 6-hydrogen derivatives obtained upon reduction depends upon the reduction method.462 This was found to be due to equilibration of (498) and (499) in the presence of the corresponding carbonium ions under certain conditions. At equilibrium in acetonitrile or methylene chloride about 85% of the 4H- and 15% of the 6H-isomer are In connection with the elucidation of the structures of the products obtained upon reaction of the tropone (496) with perchloric acid, the 6-methoxy-substituted derivatives have been prepared by reaction of (496) with methyl iodide and silver f l u o r ~ b o r a t e . 465 ~ ~ ~Comparison , of U.V. spectra indicated that the salts between the tropones (496) and perchloric acid were 6-hydroxy-derivatives of the perchlorate of (497).465U.V. and n.m.r. spectra of the systems (496)-(499) are discussed 458, 459 and their properties and reactivities compared with the corresponding N-phenylpyrrole analogue.466 A preliminary report of the polarographic, i.r., and U.V. spectroscopic as well as the dipole of both the C-annelated systems (496) and (497) without methyl groups in the thiophen ring and also the ion (500) with alkyl, hydroxy, and methoxygroups in the seven-membered ring has been Values of p&+ between 6 and 7 have been obtained for this system. The spectroscopic properties of metallocene derivatives such as (501)-(503) have also

+ c104-

been studied.467The stable dithienotropylium perchlorates (504) and (505), with pKR+-values of 5.40 and 6.65, have been prepared through ring-closure of (506) and (507) to the corresponding ketones followed by reduction with LiAlH4 to the hydrocarbon and hydride exchange with trityl p e r ~ h l o r a t e . ~ ~ ~ A. V. El'tsov and A. A. Ginesina, Zhur. org. Khim., 1967, 3, 191. Sullivan and R. Pettit, Tetrahedron Letters, 1963, 401. r6a A. A. Ginesina and A. V. El'tsov, Zhur. org. Khim., 1968, 4, 1096. 463 A. V. El'tsov and A. A. Ginesina, Zhur. org. Khim., 1969, 5 , 1135. lS4 A. A. Ginesina and A. V. El'tsov, Zhur. org. Khim., 1968, 4, 1115. l E SA. V. El'tsov, A. A. Ginesina, and L. N. Kivokurtseva, Zhur. org. Khim., 1969, 5, 460

u1 D.

me. 467

468 489

961. A. V. El'tsov, L. N. Kivokurtseva, and A. A. Ginesina, Zhur. urg. Khim., 1968,4,907. R. Guilard and P. Fournari, Compt. rend., 1971, 273, C, 160. H. Lumbroso, C. Pigenet, and R. Guilard, Compt. rend., 1970, 270, C,1905. S. Gronowitz and B. Yom-Tov, Z . Chem., 1970,10, 389.


469

c10,-

Q -

H

H

0 H

H

CO,H

The ketone (496; R = H) was condensed with tetrachlorocyclopentadiene to the potentially dipolar system (508), and also with 4,5-dichlorocyclopentene-l,3-dione and malononitrile to give corresponding Derivatives from tricyclic systems with a central seven-membered ring have

interesting psychopharmacological effects, and a great number of derivatives containing one thiophen ring, such as (509) and (510), have been prepared.471 The stereochemistry at the double bond of (510), with an acyclic side-chain, has been determined by X-ray analysis of the h y d r ~ c h l o r i d e .The ~ ~ ~oxime

fy--$ S

\

R

0 1

R (510)

(509) R = O

R 470 471

M

e

= =CHCH2CH,NMe,

G. Seitz and H. Monnighoff, Angew. Chem., 1970, 82, 938. J. M. Bastian, A. Ebnother, E. Jucker, E. Rissi, and A. P. Stoll, Helu. Chim. Acta, 1971, 54, 277. J. M. Bastian and H. P. Weber, Helu. Chim. Acra, 1971, 54, 293.

470


of the ketone from which (510) is derived gives the azocines (51 1) and (512) upon Beckmann ~earrangement.~'~ Miscellaneous Thiophen Analogues of Polycyclic Hydrocarbons.-St arting from compound (51 3), the annelated acenaphthylene (514) and derivatives The thereof were prepared via condensation with ethyl thiogly~ollate.~~~ analogous c-annelated system (515) was obtained by the reaction of (516a)

( 5 13)

(a)

(b)

R R

= C1 =

SCH&'OOH

(5 16)

with thioglycollic acid to form (516b), followedby c y c l i ~ a t i o n A . ~detailed ~~ study of the electronic and n.m.r. spectra of (514) and (515) has been undertaken, and HMO calculations have been carried Treatment of phenanthrene with hydrogen sulphide and an alumina catalyst at 630 "C gives the compound (517). Its spectral properties and those of its sulphoxide and sulphone were Other examples of the direct insertion of a sulphur bridging atom into an aromatic molecule are reviewed. 473 474

475 47e

477

J. M. Bastian, A. Ebnother, and E. Jucker, Helv. Chim. Acta, 1971, 54, 283. S. Hauptmann, M. Scholz, H.-J. Kohler, and H.-J. Hofmann, J. prakt. Chem., 1969, 311, 614. S. Hauptmann, A. Hantschmann, and M. Scholz,2. Chem., 1969,9,22. K. D. Bartle, D. W. Jones, R. S. Matthews, A. Birch, and D. A. Crombie, J. Chem. SOC.(B), 1971,2092. L. H. Klemm, D. R. McCoy, and D. R. Olson, J. Heterocyclic Chem., 1970, 7 , 1347.


47 1

In connection with work on the synthesis of the sulphur isostere of lysergic acid, a number of derivatives of naphtho[l,8-bc]thiophen (518) have been prepared.478The ketone (519) is noticeably basic and dissolves in concentrated hydrochloric acid, presumably forming the aromatic ion (520).478

& & \

/

& \

0

47n

S

\

& s

\

/

0

E. Campaigne and D. R. Knapp, J. Heterocyclic Chem., 1970, 7, 107.


472

Three phenalenothiophens (521)-(523) have been synthesized by unambiguous methods from the corresponding phenalenothiophenones (524)(526), which in turn were prepared by electrophilic ring-closure of the corresponding 3-(au-naphthyl)thiophen-2-carboxylicacid, 2-(a-naphthyl)thiophen-3-carboxylic acid, and 3-(a-naphthyl)thiophen-4-carboxylic The reaction of (527) with glycerol, sulphuric acid, and iron leads to the

formation of a mixture of (524) and (525), in contrast to earlier claims in the literature. Fusion of 2-(1-naphthoyl)thiophen with an aluminium chloridesodium chloride-potassium chloride mixture has been shown to produce (524) as the main product, in contrast to literature statements which claim that (525) is the main product. Metalation of (522) and (523) with butyllithium occurs exclusively at the methylene bridge.45s

6 Thiophen Analogues of Indole, Quinoline, Isoquinoline, and Similar Systems Thiophen Analogues of Indole and Related Compounds.-SH-Thien0[2,3-c]pyrroles (528) have been prepared by dehydration of N-oxides, autooxidation of the dihydrothieno[2,3-~]pyrroles,and by dehydrogenation of

the dihydro-compounds with ~ h l o r o a n i l . SCF ~ ~ ~ MO calculations have been carried out on the isomeric thienopyrroles in the ground and excited states. The main result is that (529) and (530) are more stable than (528) while the non-classical (531) is claimed to have a triplet state of lower energy than the ground H I

a (529)

479

QQ I

H (530)

L. Klasinc and N. Trinajstid, Tetrahedron, 1971, 27, 4045.


473

Thieno[2,3-b]indoles (532) have been prepared through the reaction of (533) with phosphorus pentasulphide. The system (532) underwent an interesting Diels-Alder reaction, i.e. to (534), with dimethyl acetylenedi~arboxylate.~~~

I

I

R2

R2

(532)

(533)

n

(534)

m M e (535)

Mc Me (537)

The compounds (535) and (536) have been prepared through the condensation of 3-bromo-3-methyl-2-butanone with 2- and 3-thienylammonium hexachlorostannates in the presence of zinc Benzo[b]thieno[3,2-b]indoles (537) have been prepared by reductive cyclization of 2-aryl3-nitrobenzo[b]thiophens with triethyl p h ~ s p h i t e The . ~ ~parent ~ heterocycle was also obtained from 2-(o-nitrophenyl)benzo[b]thiophen with triethyl phosphite and by heating 3-azido-2-phenyl- or 2-(o-azidophenyl)-benzo[b]thiophen in d i g l ~ m e . ~ ~ ~ Thiophen Analogues of Quinoline and Related Compounds.-Convenien t methods for the synthesis of the thiophen analogues of quinoline have been worked out. By the condensation of 2- and 3-thienylammonium hexachlorostannates with malonic aldehyde tetraethyl acctal, thieno[2,3-b]pyridine (538) and thieno[3,2-b]pyridine (539) were obtained in 44% and 77% yields.483 With other /3-dicarbonyi compounds, substituted derivatives were obtained. Thus, acetoacet aldehyde dimeth yl aceta1 gave

480 481

4sa 483

G. Kobayashi, S. Furukawa, Y. Matsuda, and R. Natsuki, Yakugaku Zusshi, 1969, 89, 58. V. G. Zhiryakov and P. J. Abramenko, Khim. geterotsikl. Soedinenii, 1969, 5, 228. K. E. Chippendale, B. Iddon, and H. Suschitzky, Chem. Comm., 1971, 203. L. H. Klemm, C. E. Klopfenstein, R. Zell, D. R. McCoy, and R. A. Klemm, J. Org. Chem., 1969,34, 347.

474 Organic Compounds of Sulphur, Selenium, and Tellurium the 5-acetyl derivative of (538). Pyridines with vinyl, ethyl, a-hydroxyethyl, or acetyl groups in the 3-position react with hydrogen sulphide at 630 "C to give low yields of (538) and the isoquinoline analogue thieno[3,2-c]~ y r i d i n e .The ~ ~ ~third isomeric thiophen analogue of quinoline, thieno[3,4-b]pyridine (540), has been prepared from 2,3-dimethylpyridine.

(540)

Side-chain chlorination to 2,3-dichloromethylpyridine with N-chlorosuccinimide followed by ring-closure with sodium sulphide, oxidation to the sulphoxide with phenyliodonium chloride, and dehydration on Al,O, according to the method of Cava gave (540).486 Curiously, attempts to prepare the benzo-analogue (541) by the same method were unsuccessful. However, the transient existence of (541) could be demonstrated by trapping with N-phenylmaleimide.486 Electrophilic substitution reactions of (538) and (539) have been studied. Bromination of (538) gave the 2,3-dibromo-derivative, whereas reaction with deuteriosulphuric acid gave fastest D-H exchange at C-3 and slower exchange at C-2.483 Both (538) and (539) were nitrated in the 3-position in 50% yield by means of nitric acid in sulphuric acid.4s7 The nitro-derivatives were reduced to acetylamino-compounds. The results of electrophilic substitution were in agreement with simple MO calculations, and detailed n.m.r. data for (538)-(540) are 487 The reaction of (538) with methyllithium led to the products expected for metalation in the 2-position and from addition across the azomethine bond.483 The 5-acetyl derivative of (538) has been converted into the 5-NHz, 5-C02H, and 5-CHzC02H From the amino-compound the 5-bromo-derivative was obtained upon diazotization, which upon treatment with potassium amide in liquid ammonia gave a mixture of the 4-amino(major) and 5-amino-isomers. The compound (538) was converted into the N-oxide, which upon nitration in sulphuric acid gave 4-nitrothieno[2,3-b]pyridine 7 - 0 x i d e . ~Nitration ~~ in acetic acid, on the other hand, gave the isomeric 5-nitro-derivative. Several reactions were carried out with these nitro-compounds. In a manner similar to that described for (538) and (539), the compounds (542)-(544) were prepared from 3-aminobenzo[b]thiophen, 2-aminothieno[2,3-b]thiophen, and 5-aminobenzo[b]thiophen 4851

484

OBb 488

018

L. H. Klemm and D. R. McCoy, J. Heterocyclic Chem., 1969, 6, 73. L. H. Klemm, W. 0. Johnson, and D. V. White, J. Heterocyclic Chem., 1970, 7 , 463. D. W. H. MacDowell, A. T. Jeffries, and M. B. Meyers, J. Org. Chem., 1971,36, 1416. L. H. Klemm, R. Zell, I. T. Barnish, R. A. Klemm, C. E. Klopfenstein, and D. R. McCoy, J . Heterocyclic Chem., 1970, 7 , 373. L. H. Klemm and R. Zell, J . Heterocyclic Chem., 1968, 5 , 773. L. H. Klemm, I. T. Barnish, and R. Zell, J . Heterocyclic Chern., 1970, 7 , 81.


475

through condensation with a c e t y l a c e t ~ n eand , ~ ~were ~ used for the preparation of new polymethine dyes of the cyanine and merocyanine p92 Sulphur bridging into the phenylpyridines, 2- and 3-phenylquinolines, and the symmetric pyridines was accomplished by means of hydrogen sulphide and an alumina catalyst at 630 "C. 1-Benzothienopyridines,such as (549, l-benzothienoquinolines,and thienodipyridines such as (546) and (547) were obtained.493Structures of products were assigned on the basis of

spectral and chromatographic studies as well as separate synthesis. Relative yields of various products were rationalized in terms of a model for interaction between a chemisorbed sulphur atom and the substrate molecule. The compounds (545)-(547) could be converted into their sulphoxides by treatment with an equimolar quantity of iodosobenzene dichloride in aqueous acetonitrile. With excess chlorine gas in carbon tetrachloride the corresponding sulphones were obtained. Hydrogen peroxide in glacial acetic acid, on the other hand, converted (546) and (547) into their NN'-dioxides and (545) into its N-oxide. Spectral and chemical means for distinguishing between the oxide functions are Thiophen Analogues of Isoquinoline and Related Compounds.-During the past three years, interest in the synthesis, reactions, and physical properties of these compounds has been noticeable, and four different research groups have made important contributions to this field. Both thieno[2,3-c]pyridine (548) and thieno[3,2-c]pyridine (549) have been prepared in a

P. I. Abramenko, Khim. geterotsikl. Soedinenii, 1967, 3, 368. V. G. Zhiryakov and P. I. Abramenko, Khim. geterotsikl. Soedirtenii, 1967, 3, 621. V. G. Zhiryakov and P. I. Abramenko, Khim. geterotsikl. Soedinenii, 1967, 3, 830. 483 L. H. Klemm, D. R. McCoy, and C. E. Klopfenstein, J. Heterocyclic Chem., 1971, 8, 383. a4 L. H. Klemm, S. B. Mathur, R. Zell, and R. E. Merrill, J . Heterocyclic Chem., 1971, 8, 931. 4BO

491

48a

416


preparatively useful route by applying the Pictet-Spengler reaction to the thiophen series. p-Thienylethylamines were condensed with formaldehyde, followed by cyclization of the amines in 20% hydrochloric acid to the tetrahydro-derivatives in high yield. Aromatization was achieved in good yields by the use of alkaline potassium ferricyanide.ll1c Klemm et al. converted 4-vinylpyridine into benzyl 2-(4-pyridyl)ethyl sulphide by the reaction with benzyl mercaptan. Thermolysis at 605 "C gave (549) in 58% yield.4e6As mentioned above, (549) was also obtained in low yield together with (538) in the reaction of pyridines with vinyl and similar groups in the 3-position and hydrogen sulphides at 630 0C.484Another new route was developed by Eloy and Deryckere, which starts with the thermal cyclization of the unsaturated isocyanate (550), prepared from the thienylacrylic acid

azide, to the oxo-derivative (551). Upon treatment with POCl, this derivative gives the chloro-derivative (552), which by zinc in acetic acid is reduced to (549).21Q9498, 4Q7 Starting from 3-thienylacrylic acid, (548) was obtained in a similar way. Finally, Dressler and JoulliC used the low-yield methods developed by Herz in the 1950's for the synthesis of (548) and (549) and some methyl-substituted derivatives of these The c-annelated system (553) has been prepared from 3,4-dimethylpyridine in an analogous

(553)

way to that described earlier for the quinoline analogue (540).485Electro499 philic substitution of (548) and (549) has been extensively Nitration of both (548) and (549) with fuming nitric acid in concentrated sulphuric acid gave the 3-nitro-derivativesexclusively and in high yield.498,bQ9 Bromination of (548) and (549) was most conveniently carried out by bromine in 48% hydrobromic acid or in thionyl chloride, as bromination with these reagents occurred only in the 3-position and no dibromination took place. With more aggressive reagents, such as bromine in sulphuric 495

IB6 4B7 498

dBB

L. H. Klemm, J. Shabtai, D. R. McCoy, and W. K. T. Kiang, J. Heterocyclic Chem., 1968, 5, 883. F. Eloy and A. Deryckere, Helv. Chim. Acta, 1970, 53, 645. F. Eloy and A. Deryckere, Bull. SOC.chim. belges, 1970,79, 301. M. L. Dressler and M. M. Joullie, J. Heterocyclic Chem., 1970,7 , 1257. S. Gronowitz and E. Sandberg, Arkiu Kemi, 1970,32,249.


477 acid-silver sulphate or dibromoisocyanuric acid in sulphuric acid, (549) gave appreciable amounts ( 10%) of the 2,3-dibromo-derivative, even when only one equivalent of brominating agent was used. Deuteriodeprotonation occurs smoothly in the 3-position of (548) and (549), and the rates were determined.490 Sulphonation of (548) and Friedel-Crafts acetylation of the 7-methyl derivative of (548) also occur in the 3 - p o ~ i t i o n . ~ ~ ~ MO calculations have been carried Peracid oxidation of (548) and (549) yields the N-oxides. The compound (551), on the other hand, is brominated, chlorinated, and nitrated in the 7 - p o ~ i t i o n . ~ ~ ~ From (552) a number of compounds with basic side-chains in the 4-position have been prepared, as well as compounds of papaverine-like structure.SOO,solThe 7-methyl derivative of (548) can be condensed with benzaldehyde to give the styryl derivative.40s Halogen-metal exchange with the 3-bromo-derivative of (548) and ethyl-lithium can be carried out at - 70 "C without complications from addition to the azomethine bond.*O9 The compounds (548) and (549) can be reduced to the tetrahydroderivatives by reductive formylation or by sodium boxohydride reduction of the quaternized compounds.602 The pK, values,111c,4v8 dipole moments,111cand mass spectra 4v8-4g* of (548) and (549) have been reported and detailed studies of the n.m.r. spectra 498, 6oo, have been undertaken. The effect of protonation on chemical shifts and coupling constants has been discussed, and correlations between calculated r-electron densities and the observed chemical shifts were attempted.s0a The benzo-fused compound (553a) was prepared by Bischler-Napieralski cyclization of the N

X

(553a)

N-acetyl or N-benzoyl derivative of the appropriate 2-(5-substituted-3benzo[b]thienyl)ethylamine, followed by aromatization of the dihydroderivative with palladized The tetrahydro-derivative was prepared by the Pictet-Spengler reaction or by sodium borohydride reduction of the dihydro-derivative. Interestingly, Bischler-Napieralski cyclization of the N-acetyl or N-benzoyl derivatives of some 2-benzo[b]thienylethylamines gave directly the aromatized system (554). Interest in ring systems such as (553) and (554) is aroused by attempts to prepare polycyclic systems that are sulphur analogues of indole alkaloids. The 500

602

F. Eloy and A. Deryckere, BUN. SOC.chim. belges, 1970, 79, 407. F. Eloy and A. Deryckere, Bull. chim. therap., 1969, 466. F. Eloy and A. Deryckere, Bull. SOC.chim. belges, 1970, 79, 415. S. Gronowitz and E. Sandberg, Arkiv. Kemi, 1970, 32, 269. K. Clarke, C. G. Hughes, A. J. Humphries, and R. M. Scrowston, J. Chem. SOC. (C), 1970, 1013.


478

Qgp 0

(554)

(555)

compound (555) was used for the synthesis of (556), which is a sulphur analogue of rutecarpine. O6 Other Pyridine-fused Thiophen-containing Systems.-A number of thienoquinolines such as (557) and (558) have been prepared by applying the

Skraup and Conrad-Limpach reactions to appropriate benzo[b]thiophen derivatives.606Substitution reactions of thieno[3,2-f]quinoline (559), which was prepared by a Skraup synthesis from 5-aminobenzo[b]thiophen,have been The same method has also been used earlier for the synthesis of the 7-and 9-methyl derivatives of (559).508 Nitration, bromination, and acylation of (559) occur in the 2 - p o ~ i t i o n .Some ~ ~ ~ reactions of

the pyridine ring have also been studied. 5-Aminobenzo[blthiophen has also been used for the synthesis of derivatives of thieno[3,2-b]acridine(560), dithieno [3,2-b][3,2-f]quinoline (56 l), and thieno [3,2-a]phenarsazine (562). These systems were of interest in connection with a study of potential carcinogens.6oeIn connection with work on antithrombotic agents, an efficent inhibitor of platelet aggregation was found in (563), which was prepared via (564) and (565). The compound (565) was prepared through 506

606

507 50u 609

N. B. Chapman, C. G. Hughes, and R. M. Scrowston, 1. Chem. SOC.( C ) , 1970,2269. J.-P. Lechartier, P. Demerseman, J.-P. Buisson, A. Cheutin, M.-L. Desvoye, and R. Royer, Bull. SOC.chim. France, 1969, 797. N. B. Chapman, K. Clarke, and K. S. Sharma, J . Chem. SOC.(C), 1970, 2334. V. G. Zhiryakov and P. I. Abramenko, Khim. geterotsikl. Soedinenii, 1967, 3, 166. N. P. Buu-HOT,M. Dufour, P. Jacquignon, and A. Martani, J. Chem. SOC.( C ) , 1971, 2428.


N (560)

479

(561)

copper-catalysed nucleophilic substitution of 3 -bromobenzo[blthiophen with potassium anthranilate.K1O The thio-Claisen rearrangement of propargyl 4-quinolyl sulphide (566) gives 2-methylthieno[3,2-c]quinoline(567) in high yield.611 By allowing (552) to react with hydrazine, followed by treatment with ethyl orthoformate, (568) was obtained, which upon treatment with base in ethylene

SCHzCrCH

510

611

E. F. Elslager, N. F. Haley, J. R. McLean, D. Potoczak, H. Veloso, and R. H. Wheelock, J . Medicin. Chem., 1972, 15, 61. Y. Makisumi and A. Murabayashi, Tetrahedron Letters, 1969, 1971.

480


glycol-water was isomerized to (569).512 The mechanism of the isomerization and the spectral properties of these systems were discussed. Derivatives of the novel heterocyclic system (570) have been prepared by cyclization of 3,4-biscyanomethylthiophenswith hydrogen bromide in acetic acid,175a

7 Thiophens Fused to Rings containing Two Nitrogens Pyrazole- and Imidazole-fused System.-The thieno[2,3-b]pyrazole system has been obtained through the ring-closure of (571) to (572). The carboxygroup of (572) could be removed or transformed to other functional

I Ph (571)

(573)

N I Ph (572)

(574)

groups.513, 514 The thionaphtheno[2,3-d]imidazole system (573) has been synthesized from (574).615 Pyridazine-fused Systems.-Robba and co-workers have extended their earlier work on thienopyrazines 516, 617 to more heavily fused systems. From benzo[b]thiophen derivativessuch as (575)-(577), the benzo[b]thieno[2,3-d]pyridazines (578)-(580) have been prepared by reaction with hydra~ i n e . ~Compounds l~ (579) and (580) could by standard methods be transformed to the chloro-derivatives, which easily undergo nucleophilic substitution, whereby different substituents were introduced at the pyridazinic

612

614

618

617

C. Hoogzand, Rec. Trav. chim., 1971, 90, 1225. I. Ya. Kvitko and T. M. Galkina, Zhur. org. Khim., 1969, 5, 1498. I. Ya. Kvitko, Khim. geterotsikl. Soedinenii, 1969, 5 , 760. P. I. Abramenko, Khim. geterotsikl. Soedinenii, 1970, 6, 1473. M. Robba, B. Roques, and M. Bonhomme, Bull. SOC.chim. France, 1967, 2495. M. Robba, B. Roques, and Y. Le Guen, Bull. SOC.chim. France, 1967, 4220. M. Robba, G. Dore, and M. Bonhomme, Compt. rend., 1969, 268, C, 256.


48 1

0

carbon.61Q Also, some electrophilic substitution reactions of (578) and (579) have been studied.a1QThe hydrazino-derivative (581) was used for the synthesis of more complex ring systems such as (582) by refluxing with formic acid or acetic acid, or (583) by reaction with sodium nitrite in acetic acid. Via the hydrazones (584; R1 = C02H)the system (585) was obtained

NHNH,

by refluxing in acetic anhydride.520Analogous ring systems were obtained from the isomeric hydrazino-derivative (586).621 The reactions of the tautomeric systems (587) and (588) have been studied and both N- and S-alkyl derivatives prepared.622 From both (589) and (590) the aldehyde (591) was obtained upon reaction with hydrazine. The formyl derivatives (592) and (593) both gave a 1 : 1 mixture of (594) and (595).62a From (596), the diannelated compound (597) was obtained. 61B 620

621

623

M. Robba, G. Dor6, and M. Bonhomme, Compt. rend., 1969,269, C, 245. M. Robba, G. DorC, and M. Bonhomme, Compt. rend., 1970,271, C, 1090. M. Robba, G . DorC, and M. Bonhomme, Compt. rend., 1970, 271, C, 1328. M. Robba, G. DorC, and M. Bonhomme, Compt. rend., 1970, 271, C, 1008. B. Decroix, J. Morel, C. Paulmier, and P. Pastour, Bull. Soc. chim.France, 1971,4187.

17

482


SH

(596)

(597)

A third isomeric thienopyridazine (598) has been prepared. It was synthesized by sequential reduction and oxidation of the corresponding thienopyridazin-3-one (599), which itself was obtained from (600). This compound was made by stepwise oxidation with N-bromosuccinimide of the corresponding tetrahydro-derivative (601) which had resulted from a


483

reaction series requiring the condensation of hydrazine with (602), the product of a Dieckmann 626 Various functional derivatives of (S98), including oxidation products, have been prepared. Pyrimidine-fused Systems.-The Gewald synthesis of thiophen analogues of anthranilic acid has opened the synthetic route to pyrimidine-fused thiophens. The interest in this field is mainly due to the potential pharmacological properties of these systems. Condensation of (603) with formamide at 200 "Cyields (604).626Similarly, (605) was prepared from 3-amino2-methoxycarbonylthiophenor from its formamide derivative.627Derivatives of (604) were also obtained by cyclizationof the 2-amino-3-carboxamide 0

(605)

derivative with triethyl orthoformate in acetic anhydride.628 Another synthetic approach consists in treating amino-esters such as (603) with methyl or phenyl isocyanates in the presence of triethylamine to form the corresponding ureas, which on heating in aqueous sodium hydroxide ringclose to (604).628u An alternative synthesis under much milder conditions consists of the reaction of (603) with dimethylformamide chloride, yielding (606), which

(606)

reacts at room temperature with ammonia or amines in alcohol to form the system (604).629The thiophen analogues (607) and (608) of the sedative and hypnotic drug methaqualone have been prepared by the condensation of methyl 3-acetylaminothiophen-2-carboxylateand methyl 2-acetylaminothiophen-3-carboxylate with anilines.6s0 The n.m.r. and U.V. spectra of these systems were discussed. Very closely related compounds (609) have A. J. Poole and F. L. Rose, Chem. Comm., 1969, 281. A. J. Poole and F. L. Rose, J . Chem. SOC.( C ) , 1971, 1285. me V. I. Shvedov, V. K. Ryzhkova, and A. N. Grinev, Khim. geterotsikl. Soedinenii, 1967, 3, 459. s27 M. Robba, J.-M. Lecomte, and M. Cugnon de Sevricourt, Bull. SOC.chim. France, G24 526

1970, 3630. 628

680

V. P. Arya and S. P. Ghate, Indian J . Chem., 1971, 9, 1209. L. Capuano, M. Welter, and R. Zander, Chem. Ber., 1969, 102, 3698. Z. Csiiros, R. Sobs, J. PBlinkbs, and I. Bitter, Acta Chim. Acad. Sci. Hung., 1971, 68, 397. S. Gronowitz, J. Fortea-Laguna, S. Ross, B. Sjoberg, and N. E. Stjernstrom, Acta Pharm. Suecica, 1968, 5, 563.

484


R

(608)

(607)

been found to show anti-inflammatory 632 The compound (609a) has been synthesized as part of a programme of synthesis of new heterocycles for biological evaluation.lfa Nitration and bromination of (605) occurs in the thiophenic /%position, whereas chlorination gives the 6,7-dichloro-derivative.6z7 By conventional methods, (605) was transformed to the 4-chloro-derivative (610) and its nucleophilic substitution 633 From (610) the parent thien0[3,2d]pyrimidine (61 1) was

prepared via catalytic reduction or via oxidation of the 4-hydrazinoderivative. Electrophilic substitution, such as bromination, chlorination, and nitration, occurred in the 7-position. N.m.r. spectral data are 633 Additional-fused N-containing rings were obtained via the hydrazino-derivatives, as mentioned above for the thienopyridazine A quite different approach to the thieno[2,3-d]pyrimidine system is exemplified by the reaction of the pyrimidine derivative (612) with ethyl

M. S. Manhas, S. D. Sharma, and S. G. Amin, J. Medicin. Chem., 1972, 15, 106. F. Sauter, Monufsh., 1970, 101, 535. M. Robba, J.-M. Lecomte, and M. Cugnon de Skvvricourt, Tetrahedron, 1971, 27, 487.


485

mercaptoacetate in refluxing ethanol containing sodium carbonate to give (61 3).634 The amino-ester functionality on the thiophen ring then allows the fusion of an additional pyrimidinic ring, as illustrated by the synthesis of (614). Some nucleophilic substitution reactions of (615 ) have been

c1

(615 )

carried With phenyl-lithium the 4-phenyl derivative, and with dimsylsodium the 4-methylsulphinylmethyl derivative, was obtained. The benzoannelated system (616) has been prepared in the usual way and transformed to (61 7), which easily undergoes nucleophilic s u b s t i t ~ t i o n .From ~~~

S

(618)

(619)

(618), pyrimidinethiones (619) have been obtained in 30-70% condensation with thioamide~.~~'

yields by

Miscellaneous Rings containing Several Nitrogem.-From 4,5-diarninobenzo[b]thiophen and its 3-methyl derivative, the ring system (620) was obtained by condensation with 9,1O-phenanthrenequinone,and the system 2

634

636 636 537

A. A. Santilli, D. H. Kim, and S. V. Wanser, J. Heterocyclic Chem., 1971, 8, 445. M. S. Manhas and S. D. Sharma, J. Heterocyclic Chem., 1971, 8, 1051. A. I. Travin and 0 . Yu. Magidson, Khim. geterotsikl. Soedinenii, 1967, 3, 77. M. S. Manhas, V. V. Rao, P. A. Seetharaman, D. Succardi, and J. Pazdera, J. Chem. SOC.( C ) , 1969, 1937.

486


(621) with b~tane-2,3-dione.~~~ Treatment of the diamines with thionyl chloride yielded (622), whereas reaction with boiling formic acid gave (623). Nitration of (622) occurs in the 7 - p o ~ i t i o n . Oxidation ~~~ of (624) with Me

(624)

(625)

copper sulphate in pyridine furnishes (625).639In connection with work on compounds with anti-inflammatory properties, 4,5-dihydrothieno[3,2-e]benzothiazoles (626) showing good activity were prepared by the reaction of (627) with thiourea~.~*O From the reaction of (628) with hydroxylamine

Ho*c&

5

S

540

S

N. B. Chapman, K. Clarke, and K. S. Sharma, J. Chem. SOC.( C ) , 1971,919. M. Kamel, I. B. Hannout, M. A. Allam, A. T. A1 Aref, and A. Z. Morsi, J. prakt. Chem., 1970,312, 737. W. A. Remers, G. J. Gibs, J. F. Poletto, and M. T.: Weiss, J. Medicin. Chem., 1971, 14, 1127.

Thiophens and their Selenium and Tellurium Analogues 487 and hydrazine, (629) and (630) were obtained, which were aromatized by DDQ to (631) and (632), respectively.s40 8 Miscellaneous Fused Systems Thiazole-fused Systems.-S tart i ng from the hydroxynit rosot hi ophen (633), reduction and acetylation gave (634), which upon treatment with PzS5 yielded the thienothiazole (635).541 The structure of (636), previously

obtained by potassium ferricyanide oxidation of 5-thioacetylaminobeno[blthiophen in alkaline solution, has been An alternative synthesis of (636) consists of heating (637) with zinc dust in acetic acidacetic anhydride.

Ac

Ac

(637)

Pyrylium-fused Systems.-An extensive study on the condensation of ortho-hydroxy- and ortho-alkoxy-thiophen aldehydes with methyl ketones has been carried out. Upon treatment with a hydrochloric acid-perchloric acid mixture, ring-closure to pyrylium salts Thus (638) gave (639), which upon treatment with trifluoroacetic acid was dealkylated to (640), which finally, upon treatment with perchloric acid-hydrochloric acid,

541 642

P. I. Abramenko and V. G. Zhiryakov, Khim. geterotsikl. Soedinenii, 1970, 6, 1624. 2. I. Moskalenko and M. A. Al’perovich, Khim. geterotsikl. Soedinenii, 1967, 3, 626. J.-M. Meunier and P. Fournari, BUN.Soc. chim. France, 1971, 3343.

488


ring-closed to (641). The latter compound was also formed directly from (639)by treatment with the acid mixture. Attempts to prepare the isomeric thienopyrylium salts in the same way from (642) and (643) failed.543 7-Hydroxybenzo[b]thiophens (644) are formed on treatment of thienopyrylium salts (645)with alkali.s44

QQMRe

Thiapyrylium-fused Systems.-Thieno[b]thiapyrylium salts (646) and (647) have been prepared by the reaction of thiophen-2- and -3-thiol with acetylacetone.54s The benzo[b]thiophen analogues were prepared similarly. The parent compounds (648) and (649) were prepared from the benzo[b]thiophenthiols with /3-bromopropionic acid followed by cyclization of the acid chlorides to (650) and (651). Reduction with sodium borohydride to the +

clod-

alcohol, followed by treatment with triphenylmethyl perchlorate, led to dehydration and hydride abstraction to give (648)and (649).546From the reaction of 2- and 3-halogenomethylbenzo[b]thiophenwith mercaptoacetic acid, followed by the same steps as mentioned above, the thiapyrylium systems (652) and (653) were obtained. This approach was also used for the

5~

V. I. Dulenko, I. G. Katts, L. V. Dulenko, and G. N. Dorofeenko, Khim. geterotsikl. Soedinenii, 1970, 6, 134. J. Fabian and H. Hartmann, Tetrahedron Letters, 1969, 239. T. E. Young and C. R. Hamel, J. Org. Chem., 1970, 35, 816.


489

synthesis of the parent systems (654) and (655).647 N.m.r. and U.V. spectra of these stable salts have been studied and MO calculations have been carried O U ~ . ~ ~ ~ - ~ ~ ~ Other Fused Systems.-The nitration of the aromatic borazarothienopyridines, such as (656) and (657), has been studied in detail.648Through Raney-nickel desulphurization of (656) and (657), borazaro-analogues of

R1 I

pyridine have been The reaction of 2-formylthiophen-3boronic acids and 3-formylthiophen-2-boronicacids with arylsulphonylhydrazines give the systems (658) and (659) in high 660 Derivatives of (659) in particular showed high antibacterial activity in vitro against Gram-negative bacteria. A study of the influence of changes in the sulphonyl hydrazide moiety and of substituents on the rings, as well as of more

OH

I OH (659) 647 648

660

T. E. Young and C. R. Hamel, J. Org. Chem., 1970, 35, 821. J. Namtvedt, Acta Chem. Scund., 1968, 22, 1611. S. Gronowitz, T. Dahlgren, J. Namtvedt, C. Roos, B. Sjoberg, and U. Forsgren, Acta Pharm. Suecica, 1971, 8, 377. S. Gronowitz, T. Dahlgren, J. Namtvedt, C. ROOS, G. R o s h , B. Sjoberg, and U. Forsgren, Acta Pharm. Suecica, 1971, 8, 623.

490


radical structural changes, on antibacterial activity has been undertaken.649s660 The reaction of the amide (660) with ethyl phenylboronate gave the novel boron heterocycle (661).628 0 0

The acetylation of thienocymantrene has been studied.661In connection with work on neurotropic and psychotropic substances, derivatives of (662) have been synthesized.12s,662

9 Selenophens and Tellurophens Monocyclic Se1enophens.-A review article, covering research in selenophen chemistry carried out during the 1960’s, mainly at Moscow State University, has recently been The dipole moments of some simple halogeno-, cyano-, and formylselenophens have been measured and the conformations of these compounds have been Through a study of the n.m.r. spectrum of selenophen in lyotropic mesophase, the ratios of the interproton distances were calculated from the direct couplings and found to be in good agreement with the corresponding values calculated from microwave data.666 The n.m.r. spectra of a number of mono- and di-substituted selenophens have been analysed and the chemical shifts discussed in additivity terms.66s An X-ray analysis of racemic 4,4’-dicarboxy-2,2’,5,5’-tetramethyl-3-3,’biselenienyl has been carried Dipole moments 658 and U.V. spectra 6 6 9 of chalcone analogues containing a selenophen ring have been studied. 651 65a

H. Egger and A. Nikiforov, Monatsh., 1969, 100, 1069. K. Sindelhf, J. MetySovQ, and M. Protiva, Coll. Czech. Chem. Comm., 1971, 36, 3404.

66a 554

N. N. Magdesieva, Adu. Heterocyclic Chem., 1970, 12, 1. H. Lumbroso, D. Mazet, J. Morel, and C. Paulmier, Compt. rend., 1970, 271, C, 1481.

666

666

K.-I. Dahlqvist and A.-B. Hornfeldt, Chemicu Scrbtu, 1971, 1, 125. J. Morel, C. Paulmier, M. Garreau, and G. Martin, Bull. SOC.chim. France, 1971, 4497.

657

B. Aurivillius, Chemicu Scripta, 1971, 1, 25.

658

S. V. Tsukerman, V. D. Orlov, L. N. Thiem, and V. F. Lavrushin, Khim. geterotsikl.

659

Soedinenii, 1969, 5, 974. S. V. Tsukerman, V. D. Orlov, and V. F. Lavrushin, Khim. geterotsikl. Soedinenii, 1969, 5, 67.


49 1

Although some 3-selenienyl-lithium derivatives ring-open even at are still very useful for the synthesis of selenophen derivatives. They have been used in connection with the syntheses of diformyl- and triformyl-selenophens 124 and tetraformyl~elenophen.~~~ The six isomeric hydroxymethylselenophencarboxylic acids have been synthesized.161a The copper-promoted reaction between bromoselenophens and cuprous cyanide has been used for the synthesis of cyan~selenophens.~~~ The reactivity of 3-bromo-2-nitroselenophen towards nucleophilic reagents has been studied.S60It was found that both in the reaction with thiophenoxide and selenophenoxide ions the selenophen derivative was four times more reactive than the thiophen analogue. The reactivity of selenophen has been compared with that of thiophen and the relative reactivities in five different electrophilic substitutions have been determined by kinetic or competitive procedures.88 Selenophen was found to be 1 . 5 4 7 . 5 times more reactive than thiophen. Selenophen has been chloromethylated to 2,5-dichloromethylselenophen, which has been used for the syntheses of other 2,5-substituted derivatives such as the diacetic acid.661 Different 5-alkyl-2-formyl- and 5-a1kyl-2-acetyl-selenophenshave been synthesized as well as semicarbazones derived from them.S6a From 2-acetylselenophen, 2-vinylselenophen epoxide has been prepared uia the bromoacetyl In connection with investigations on the direction of enolization in /3-diketones of the selenophen series, compounds such as (663) and (664) have been K64 In connection

- 70 0C,129s131they

0

II

C -CHz-C Se

(663)

with this work, a number of simple 3-substituted selenophens like the chloromethyl, the cyano, the methoxycarbonyl, and the formyl derivatives were synthesized. The #3-dicarbonyl derivatives were also ring-closed to pyrazole~.~~~ Benzo[b]selenophens.-The mass spectra of benzo[b]selenophen, its 2- and 3-methyl homologues, and 2-formylbenzo[b]selenophen have been studied. Although the fragmentation of these compounds followed the pattern of 500

561 562

G. Guanti, C. Dell'Erba, and G. Garbarino, J . Heterocyclic Chem., 1970, 7 , 1425. M. Y. Kornilov and E. M. Ruban, Ukrain. khim. Zhur., 1969, 35, 824. N. N. Alekseeva, S. N. Baranov, and V. I. Dulenko, Khim. geterotsikl. Soedinenii, 1971,7, 31.

568

564

N. N. Magdesieva and T. A. Balashova, Khim. geterotsikl. Soedinenii, 1970, 6, 716. Yu. K. Yur'ev, N. N. Magdesieva, and A. T. Monakhova, Khim. geterotsikl. Soedinenii, 1968, 4, 645.

565

Yu. K. Yur'ev, N. N. Magdesieva, and A. T. Monakohva, Khim. geterotsikl. Soedinenii, 1968, 4, 650.


492

the corresponding benzo[b]thiophens, the benzo[b]selenophens proved relatively more fragile, selenium being easily split off .666 The conformation of 2-formylbenzo[b]selenophen had been studied by i.r. and n.m.r. spectroscopic techniques and by dipole-moment rneasurement~.~~~ The U.V. spectra of benzylidene derivatives of 5-methylbenzo[b]selenophen-3(2H)one (665) have been

(665)

The reaction of selenium with phenylacetylene yields benzo[b]selenophen among other products.668 A synthesis of 2-alkyl- or 2-aryl-substituted benzo[b]selenophens consists of the cyclization of an aryl selenoether having an acetonyl or phenacyl group in the ortho position with 48% hydrobromic Bromine addition to ortho-methylselenocinnamicacid followed by treatment with pyridine gives benzo[b]selenophen-2-carboxylic This reaction has been generalized to other styrenes having a selenoether group in the ortho position. Upon oxidation of l-selenocoumarins (666) with selenium dioxide in NN-dimethylformamide, ring-contraction occurs Another route to the benzoyielding benzo[b]~elenophen-2-aldehydes.~~~ [blselenophen series proceeds via the conversion of ortho-halogeno-acetals (667) into the lithium derivative, followed by reaction with selenium and alkylation of the selenolate with chloroacetic acid to (668), which in the

R2

0

usual way is ring-closed to benzo[b]selenophen-2-carboxylic acid.6ss The quaternization of (669) with bromoacetic acid followed by reaction with N. P. Buu-HoI, M. Mangane, M. Renson, and L. Christiaens, J. Chem. SOC.(B),

588

6es

1969,971. G. A. Yugai, M. A. Mostoslavskii,and T. V. Denisova, Khim. geterotsikl. Soedinenii, 1970, 6, 1326. E. G. Kataev, L. M. Kataeva, and Z. S. Titova, Khim. geterotsikl. Soedinenii, 1968, 4, 172. L. Christiaens and M. Renson, Bull. SOC.chim. belges, 1970, 79, 133.

Thiophens and their Selenium and Tellurium Analogues 493 acetic anhydride and pyridine yields (670).588 In the reaction of O-methylselenoacetophenone with ethyl bromoacetate and zinc, the selenium atom is first attacked, resulting in the formation of (671).326 The reaction of the 3-oxo-derivative (672) with methylmagnesium iodide yields 3-methylbenzo [blselenophen. O 0

The bromination, acetylation, and mercuration of benzo[b]selenophen have been studied by Russian s72 2-Methylbenzo[b]selenophen is acylated and brominated in the 3-position, whereas the 3-methyl isomer reacts in the 3 - p o ~ i t i o n .The ~~~ nitrosation of (672) is claimed to yield (673), which was reduced and acetylated to (674).674 From this compound, the

= O r M Se e

R

(677)

=

CH20H, (CH,),OH, (CH,),OH, CH,CI, (CH,),CI, (C H 2)3C1, CHzCH(CO,Et),, (CH,),COZH, CH,CMe(CO,Et),, CH,CHMeCO,H, (CH2),CH(C02Et)2, (CH &202H, (CH2),CMe(CO,Et),, (CH ,),CH McCO,H, (CH,),CH(CO,Et),, (CH2)4C0,H, (CH,),CMe(CO,Et),, or (CH,),CHMeCO,H.

fused heterocyclic systems (675) and (676) were obtained. A large number of 2-substituted benzo [blselenophens having longer side-chains (677) have been prepared from 2-ben~o[b]selenienyl-lithium.~~~ Through ringclosure reactions, (678)-(680) and functionally modified derivatives were prepared. Similarly, starting from the 2-lithio-derivative, 2-benzo[b]selenophenthiol was prepared, from which the thioacid derivatives (681) 670

67a

6'9

5T4 576

N. N. Magdesieva and V. A. Vdovin, Khim. geterotsikl. Soedinenii, 1970, 6, 1475. N. N. Magdesieva and V. A. Vdovin, Khim. geterotsikl. Soedinenii, 1972, 8, 15. N. N. Magdesieva, V. A. Vdovin, and L. D. Konyushkin, Khim. geterotsikl. Soedinenii, 1972, 8, 20. L. Christiaens, R. Dufour, and M. Renson, Bull. SOC.chim. beiges, 1970, 79, 143. P. I. Abramenko and V. G. Zhiryakov, Khim. geterotsikl. Soedinenii, 1971, 7 , 37. P. Cagniant and G. Kirsch, Compt. rend., 1971, 272, C, 1978.

494


R

=

HorMe

(679)

R

=

Li, Me, CH,CO,Et, CH,CO,H, CHMeCO,Et, CH MeCO,H, (CH ,),CO,Et , (CH ,) ,C02H, (CH,),CO,Et , or (CH,)3C02H.

(681)

were which were ring-closed to compounds such as (682) and (683). The chemistry of (672) has been studied. It gives upon acetylation 3-acetoxybenzo[b]selenophen and reacts with aldehydes to form (684). The compounds (685) were obtained from mercapto-acid Again,

some of these derivatives were ring-closed to compounds such as (686) and (687). Attempts to prepare benzo[c]selenophen from (688) have been made.678 The reaction of (688) with peracetic acid gave (689), and this reacted with bromine to give (690).

P. Cagniant, G. Kirsch, and M. Renson, Compt. rend., 1971, 272, C,1363. P. Cagniant, G. Kirsch, and D. Cagniant, Compt. rend., 1972, 274, C,711. 67~1 N. N. Magdesieva and V. A. Vdovin, Khim. geterotsikl. Soedinenii, 1972, 8, 24. 678

67'

Thiophens and their Selenium and Tellurium Analogues 49s Miscellaneous Fused Selenophens.-Selenolo[2,3-b]thiophen (691) has been prepared by metalation of thiophen-3-aldehyde diethyl acetal with butyllithium followed by reaction with selenium and methyl chloroacetoacetate. The intermediate (692) was, without isolation, hydrolysed and ring-closed to (693), which upon decarboxylation gave (691).678 Another isomeric

(692)

(691)

(693)

selenolothiophen (694) was prepared by quaternization of (695) with methyl bromoacetate and ring-closure to (696). Hydrolysis and decarboxylation then gave (694).680 Starting from derivatives of (68 l), compounds (697)(699) have been ~ y n t h e s i z e d .The ~ ~ ~n.m.r. and mass spectra of (700) have

R

R

(697)

(698)

(699)

been studied in detail.s82 The crystal and molecular structures of dibenzoselenophen have been determined by X-ray analyses.s83 Tellurophens.-A detailed description of the synthesis of tellurophen (701) from sodium telluride and butadiyne has been published.K8*Its chemical properties are similar to those of thiophen and selenophen. It can be

(700)

metalated by butyl-lithium, formylated, and acetylated. It is, however, more sensitive to mineral acids and gives addition products at the tellurium 679

680 681 682

683 684

A. Bugge, Actu Chem. Scand., 1969, 23, 1823. V. P. Litvinov, A. N. Sukiasyan, Ya. L. Gol'dfarb, and L. V. Bogacheva, Izuest. Akad. Nauk S.S.S.R., Ser. khim., 1971, 1592. G. Kirsch and P. Cagniant, Compt. rend., 1971, 273, C,902. D. Elmaleh, S. Patai, and Z . Rappoport, J. Chem. SOC.(C), 1970, 939. H. Hope, C. Knobler, and J. D. McCullough, Actu Cryst., 1970, B26,628. F. Fringuelli and A. Taticchi, J. C . S. Perkin I, 1972, 199.

496


atom with halogen. It cannot be nitrated with nitric acid-acetic acid under the usual conditions. Physical and spectroscopic properties, especially n.m.r. data, are very similar to those of thiophen and selenohen.^^* Benzo[b]tellurophen (702) has been prepared in a similar way to its sulphur and selenium analogues through quaternization of (703) with

'

Te

bromoacetic acid followed by ring-closure to the 2-acid and decarboxylit gives addition products at the heteroatom a t i ~ n .Like ~ ~ tellurophen, ~ when it reacts with halogens. Its i.r., u.v., and n.m.r. as well as its mass spectra,686have been compared with those of the sulphur and selenium analogues. The benzo[b]tellurophen derivatives (704)-(706) have also been prepared.587

CI, (705) s*s

J. L. Piette and M. Renson, Bull. SOC.chim. belges, 1971, 80, 521. N. P. Buu-Holy M. Mangane, M. Renson, and J. L. Piette, J. Heterocyclic Chem.,

687

I. D. Sadekov and V. I. Minkin, Khim. geterotsikl. Soedinenii, 1971, 7 , 138.

sB6

1970, 7, 219.

8 6a-Thiathiophthens and Related Compounds BY R. J. S. BEER

1 Introduction As in Volume 1, structure (l), with the numbering shown, will be adopted as the most convenient representation of 6a-thiathiophthen.

6s-s-s1 6a

A comprehensive review has appeared,l covering the literature up to 1969 and including a number of references to work reported in 1970.. 2 Structural and Theoretical Studies The popularity of 6a-thiathiophthens and related structures as targets for X-ray crystallography continues. Among the new studies is one on the parent compound of the series, which is shown to be symmetrical with S-S distances of 2.351 A.2 The molecular dimensions are generally except that the C-S similar to those of 2,5-dimeth~l-6a-thiathiophthen,~ distances are appreciably shorter in the unsubsti tuted compound. 2,3,4-Triphenyl-6a-thiathiophthen(2) has been compared structurally (3).3 The difference with 3,4-diphenyl- and 2,4-diphenyl-6a-thiathiophthen between the S - S distances in the triphenyl compound is less than in the two disubstituted derivatives. An example of a molecule with a completely unsymmetrical substitution pattern, and yet almost exactly equal S - S bond lengths, is provided by 2-p-dimethylaminophenyl-4-phenyl-6a-thiathiophthen(4).6 Comparison with structure (3) indicates that the effect of the dimethylamino-group is to shorten considerably the nearer S - S bond. The shortening effect is discussed in terms of the reduced electronegativity of one of the terminal N. Lozac’h, Adu. Heterocyclic Chem., 1971, 13, 161. L. K. Hansen and A. Hordvik, Acta Chem. Scand., 1970,24,2246. See ‘Organic Compounds of Sulphur, Selenium, and Tellurium’, ed. D. H. Reid (Specialist Periodical Reports), The Chemical Society, London, 1970, Vol. 1. A. Hordvik, Acta Chem. Scand., 1971, 25, 1822. A. Hordvik and L. J. Saethre, Acta Chem. Scand., 1970, 24, 2261.

497

498


-s

2.375 2 270

sPh*

Ph

Ph

2.222 s-s-s

W Ph

2.504

P

h

sulphur atoms through the contribution of the form (5). The angle of 'twist' of the 2-phenyl group is 14", with the plane of the dimethylaminogroup at 5" with respect to the benzene ring. Full details have appeared of X-ray studies on 2,5-diphenyL6 and 2-1nethy1-4-phenyl-6a-thiathiophthen,~ previously reported b r i e f l ~ . ~ It is noteworthy that the replacement of the 2-phenyl group in the 2,4-diphenyl compound (3) by a methyl group has only minor effects on the S-S distances and other bond lengths. The variations in S-S bond lengths found in those 6a-thiathiophthens which may be presumed to be free from distortion due to intramolecular strain are discussed in a recent communication a describing CND0/2 MO calculations on the parent compound, its 2- and 3-methyl, and 2- and 3phenyl derivatives. For each of these, total energies are calculated (with inclusion of sulphur d-orbitals) as a function of the lateral displacement of the central sulphur atom, the geometry of the rest of the bicyclic nucleus being kept constant and assumed to be the same as that found experimentally in the parent system. The energy curves show minima, which indicate the preferred disposition of the sulphur atoms in the linear S-S-S systems. The calculations suggest that a 2-methyl group should cause lengthening of the nearer S-S bond, whereas a 3-methyl group should have a shortening effect, as should a 3-phenyl group. A 2-phenyl group should lengthen the adjacent S-S bond, provided that the phenyl group is twisted out of the plane of the heterocyclic system; the greater the angle of twist, the greater is the lengthening effect. These theoretical results could explain the similarity in dimensions between 2,4-diphenyl-6a-thi athi ophthen and 2-met hyl-4-phenyl-6a-thiathiophthen which has been noted above. The inequality of the S-S lengths in the symmetrically substituted 2,5-diphenyl compound may be due, at least in part, to the differing angles of twist of the two phenyl groups (3" and 45"). 7

*

A. Hordvik, Acta Chem. Scand., 1971,25, 1583. A. Hordvik and K. Julshamn, Acra Chem. Scand., 1971,25, 1835. L. K. Hansen, A. Hordvik, and L. J. Saethre, Chem. Comm., 1972, 222.

6a-Thiathiophtheris and Related Compounds

499

The total energy calculated for 6a-thiathiophthen by Hordvik and his co-workers is in good agreement with the value obtained earlier by Clark and K i l c a ~ t . ~These authors have estimated w-populations, and hence charge densities, for 6a-thiathiophthen and its methyl derivatives; since their results are related to the chemical reactivity of 6a-thiathiophthens, they are discussed later in this chapter. All-valence-electron calculations on 2,5-dimethyl-6a-thiathiophthen and the corresponding dithiolylidene ketone have been reported by Japanese workers,1° but the calculated electronic transition energies do not appear to match observed values particularly well. X-Ray photoelectron spectroscopy has been applied l1 to the 6a-thiathiophthen structural problem, For the parent compound, the 2s core-binding energies of the two external sulphur atoms are reported to be the same but differ from the value for the central sulphur atom, the electrons of which are more tightly bound. The symmetrically substituted 2,Sdimethyl derivative gives very similar results but, in 2-methyl-6athiathiophthen, all three sulphur atoms give different binding energies, probably indicating unsymmetrical geometry for the bicyclic nucleus. Using the stretched film technique, the electronic spectrum of 2,5dimethyl-6a-thiathiophthen has been measured with polarized light parallel and perpendicular to the long axis of the The resulting data are compared with those predicted (by SCF-PPP calculations) for different models of the system. It is claimed that the experimental results are best understood in terms of an unsymmetrical model (6), although this conclusion seems to conflict with the crystallographic data.

(6)

The discrepancy is discussed briefly in a recent communication,l* which deals primarily with the formation of short-lived valence tautomers from 1,Z-dithiolylidene ketones and related compounds. The e x . spectra of radical ions generated from several symmetrically substituted thiathiophthens, either by electrolytic reduction or by reaction with metallic potassium, suggest that these species have symmetric A detailed account has appeared of structural work on the S , compound (7).16 Sulphur atoms S(1), S(Z), and S(3) clearly form part of a thia-

thiophthen system, with markedly unequal S-S bond lengths, and it is lo l1 la lS l4

D. T. Clark and D. Kilcast, Tetrahedron, 1971, 27, 4367. H. Yamabe, H. Kato, and T. Yonezawa, Bull. Chem. SOC.Japan, 1970,43,3154. D. T. Clark and D. Kilcast, Chem. Comm., 1971, 638. R. Gleiter, D. Schmidt, and H. Behringer, Chem. Comm., 1971, 525. R. Gleiter, D. Werthemann, and H. Behringer, J. Amer. Chem. SOC.,1972, 94, 651. F. Gerson, R. Gleiter, J. Heinzer, and H. Behringer, Angew. Chem. Internat. Edn., 1970, 9, 306. J. Sletten, Acta Chem. Scand., 1971, 25, 3577.


500

2.965

2.209

s(4)- -- s(3)L

W

2.482

(2) -s (1)

B

u

t

(7) 200

3-S

2.93

SEs

r

Ph (8)

presumed that bonding between S(3) and S(4) (separated by 2.965 A) must be very weak. The results are compared with those for the methine salt (8), in which the 2.93 A 'contact' between the central sulphur atoms does not produce any lengthening of the terminal S-S bonds beyond the normal value for simple 1,Zdithiolium salts. Among the most interesting of all the structures which have been reported in the period under review are those of the S5 compounds (9)16 and (10)l7 in which the array of five sulphur atoms is nearly linear. The

"d";"... 2 14

Ph

2.62

2.55

2 16

s2.183

2.580

2.583

2 172s

t uB- -

bond lengths suggest that here two thiathiophthen systems are fused together, producing in the symmetrically substituted example (10) a molecule with almost mirror symmetry. 3 Synthesis, Properties, and Reactions of 6a-Thiathiophthens The synthesis of the thiathiophthens (13) from 4H-thiopyran-4-thiones (ll), involving ring opening with sodium sulphide and oxidation of the resulting dianion (12) with ferricyanide, has been described in detail.I8 The method provides a convenient route to the parent compound and succeeds with the symmetrically substituted thiopyrans (1 1; R1 = Ph, R2 = H) and (11; R1 = H, R2 = Me), but gives negligible yields in some other cases tried. 1,2-Dithiolylidene aldehydes (14) are obtained in a similar way, by opening the thiopyran ring with hydroxide ion and subsequent oxidation. l6 l7 l8

J. Sletten, Acta Chem. Scand., 1970, 24, 1464. R. Kristensen and J. Sletten, Acta Chem. Scand., 1971, 25, 2366. J. G. Dingwall, D. H. Reid, and J. D. Symon,J . Chem. SOC.(C), 1970, 2412.

6a-Thiathiophthensand ReIated Compounds

501

S

Numerous routes to 1,2-dithiolylideneketones (see p. 507), and hence to thiathiophthens, are described in a paper which is chiefly concerned with comparisons, particularly in relation to their electronic spectra, of 6a-thiathiophthens, the corresponding dithiolylidene ketones, and certain other structurally similar systems, for example (15; X = 0 or S), (16; X = 0 or S), and (17; X = 0 or S). From their survey of an extensive collection of spectroscopic data, the authors conclude that varying degrees

Ph

of bonding interaction between sulphur and adjacent sulphur or oxygen atoms are possible, and that the 6a-thiathiophthen system represents an extreme case where the interaction leads to bicyclic structures with S-S bonds of almost equal length. In the same paper,le the conversion of 6a-thiathiophthens into 1,2-dithiolylidene ketones is discussed. The use of sulphuric acid as a reagent for this purpose, with unsymmetrically substituted compounds, may lead to only one or both of the possible isomeric ketones. With 2-methyl-5phenyl-6a-thiathiophthen, treatment with sulphuric acid gives the ketone (18), confirming an earlier report which had been questioned.

s-s

0

Ph

l9

E. I. G . Brown, D. Leaver, and D. M. McKinnon, J. Chern. Soc. ( C ) , 1970, 1202.

502

Organic Compounds of’Sulphur, Selenium, and Tellurium

Further and more definitive examples of electrophilic substitution reactions in the thiathiophthen series have been described.20 In the parent compound, in which both 2- and 3-positions are available for attack, formylation has been proved to occur at the 3-position, as would be anticipated from earlier experimental and theoretical work.21 2-t-Butyl-6athiathiophthen formylates in the 4-position. The thiathiophthen aldehydes show characteristic absorption bands in the i.r. at ca. 1670 cm-l, analogous to that shown by thiophen-Zaldehyde (1673 cm-l), implying electronreleasing properties at the 3- (or 4-) position. Vilsmeier-Haack formylation of 2,5-diaryl-6a-thiathiophthensleads to the 3-formyl compounds, which are also obtainable from 3-aryl-l,2dithiolium salts by treatment with triethylamine,22and details have been given 23 for the bromination of 2,5-disubstituted thiathiophthens. Nitration of 2-methylthio-5-phenyl-6a-thiathiophthen gives the 3-nitr o-compound in poor yield,23 and attempted nitrosation experiments lead, in several examples, to rearranged structures of type (19),3although the first stage of these reactions is presumed to be electrophilic attack on the 3-position.

What may be a more elaborate example of electrophilic substitution is provided by the observation 24 that methine salts of type (20) are converted into thienothiathiophthens (21) in boiling pyridine. The reaction appears to be analogous to one described p r e v i o ~ s l y ,which ~ ~ leads to the related structure (22)..

20

G. Duguay, D. H. Reid, K. 0. Wade, and R. G. Webster, J . Chem. SOC.( C ) , 1971, 2829.

21 22

23 24 25

R. J. S. Beer, D. Cartwright, R. J. Gait, R. A. W. Johnstone, and S. D. Ward, Chem. Comm., 1968, 688. J. Bignebat and H. Quiniou, Bull. SOC.chim. France, 1972, 645. R. J. S. Beer, D. Cartwright, R. J. Gait, and D. Harris, J. Chem. SOC.(C), 1971, 963. C. Retour, M. Stavaw, and N. Lozac’h, Bull. SOC.chim. France, 1971, 3360. D. B. J. Easton, D. Leaver, and D. M. McKinnon, J. Chem. SOC.( C ) , 1968,642.

6a-Thiathiophthensand Related Compounds

503

As noted earlier in this chapter, charge densities have been calculated for 6a-thiathiophthen and some of its derivatives ;O localization energies for Wheland-type intermediates in substitution reactions have also been estimated. The results indicate, as has been inferred previously, that the 3-position should be attacked by electrophiles. The localization energies for attack at sulphur are very similar to those for attack at C(3); thus, attack at sulphur may become competitive, and indeed examples of this mode of reaction are known.26 The theoretical treatment further predicts that attack by nucleophiles should occur at the 2- (or 5-) position, in agreement with the experimental evidence. These calculations have been extended to cover the relative acidities of methyl groups attacked at the 2- and 3-positions. Comparison of the calculated energies for the two methyl compounds, and for the corresponding anions, indicates that the 2-methyl group should be the more acidic, a result which is again in accord with the earlier experimental data. The formation of carbanions is involved in the rearrangement of 2-isopropyl-6a-thiathiophthens (23) to reduced thiophen derivatives (24; R = H, Me, or Ph), isolated as the methylated compounds (25),27

and carbanions (26) also play an essential role in the preparation, now fully described in an important series of papers,2s of systems containing a linear array of five sulphur atoms. Reference has already been made in this chapter to complete structure determinations on two compounds,

27

E. Klingsberg, J. Org. Chem., 1968,33,2915; H. Behringer and J. Falkenberg, Chem. Ber., 1969, 102, 1580. A. Jose and M. Stavaw, Compt. rend., 1971,212, C, 1374.

504


(9) and (lo), of this series. The main synthetical route proceeds by way of intermediates of type (28) which are best prepared by acidification of the dianions (27) ; the necessary oxidation step occurs spontaneously. The 5-(1’,2’-dithiolylidenemethylene)-1,2-dithiole-3-thiones(28) are converted into the extended ketones (29) by reaction with diazoketones, and the sequence to (30) is completed by sulphurization with phosphorus pentasulphide.

With symmetrical substitution, e.g. (lo), the n.m.r. and X-ray data indicate a symmetric structure. Even with the different substituents of compound (9) the crystallographic study shows that the S-S bond lengths approximate to a symmetrical pattern. The conclusion seems inescapable that in these molecules partial bonding exists between each adjacent pair of sulphur atoms in the extended system. The thiones (28) show some interesting similarities in behaviour to their simpler analogues, the 1,2-dit hiole-3-t hi ones. Thus, methylation converts them into salts (3 1),2sband cycloaddition reactions with acetylenes yield 1,3-dithiole derivatives (32),28canalogous to the ‘isothiathiophthens’ (33), the formation of which, from 1,2-dithiole-3-thiones,is discussed in a recent paper, elaborating an earlier report 29 (see also Chapter 10, p. 532).

29

(a) M. Stavaux, Bull. Soc. chim. France, 1971, 4418; M. Stavaux and N. Lozac’h, ibid., p. 4419; M. Stavaux, ibid., p. 4429; (6) M. Stavaux and N. Lozac’h, ibid., p. 4423; (c) M. Stavaux, ibid., p. 4426. D. B. J. Easton, D. Leaver, and T. J. Rawlings, J.C.S. Perkin I , 1972, 41.

6a-Thiathiophthens and Related Compounds

505

The conversion of ‘isothiathiophthens’ into 6a-thiathiophthens has been i n ~ e s t i g a t e d . ~The ~ rearrangement of compound (33; R1 = Rs = Ph, R2 = H) occurs smoothly in boiling xylene, in the presence of sulphur. The suggested mechanism involves formation of a spiro-compound (34) as an intermediate. When sulphur is replaced by selenium, the normal product, 2,5-diphenyl-6a-thiathiophthen,is accompanied by the 6aselenathiophthen (35; R1 = Ph, R2 = H). The possible intervention of a

.s s-s

Y r

S-Se-S

f 2 1

(37) carbenoid intermediate (36), in the direct formation of thiathiophthens from 1,2-dithiole-3-thiones and acetylenes, has suggested new routes to 6a-thiathiophthens, e.g. the reaction between the 1,2,3-thiadiazole (37) and 5-phenyl-1,2-dithiole-3-thione yields 2,5-diphenyl-6a-thiat hiopht hen. 4 Compounds Structurally Related to 6a-Thiathiophthen The 4H-thiapyran-4-thione route to thiathiophthens has been modified so as to yield 6a-selenahthiopthens (35).31 The intermediate selenoketones (38) are unstable, but react satisfactorily with sodium sulphide in aqueous dimethyl sulphoxide to give dianions which are oxidized, as in the original synthesis, with ferricyanide. N.m.r. data on 6a-selenathiophthen, and on its 3,ddimethyl and 2,5-diphenyl derivatives, indicate real or time-averaged 80

31

S. Davidson and D. Leaver, J.C.S. Chem. Comm., 1972, 540. D. H. Reid, J. Chem. SOC.( C ) , 1971, 3187.

506

Organic Compounds of Sulphur, Selenium, and Tellurium S

2446 L

S2446L

S

1.66

1.66 J.s'/

(38)

4

5

(39)

Czesymmetry. An X-ray study 32 on the parent compound gives the bond lengths shown (39). The Se-S bonds, like the S-S bonds in 6a-thiathiophthen, are longer (by ca. 10%) than would be expected for a normal covalent bond. This is also true for the Se-Se bonds in '6a-selenaselenophthen' (40). 33 Two 3,4-diaza-6a-thiathiophthens,(41) 34 and (42),35have been studied by the crystallographic method. The slightly differing values for the S-S bond lengths (2.319 and 2.328 A) in the 2,5-diphenyl compound may result from different degrees of 'twist' (2.9 and 7.0") of the phenyl groups. The 2,5-bisanilino-compound is of interest because of the possibility of

intermolecular hydrogen bonding. In the crystal, the molecules are arranged in pairs with hydrogen bonds as shown (42). The amino-groups are nearly coplanar with the central ring system, but the phenyl groups are twisted, to differing degrees (51 and 11") about the C-N bonds. Thus the marked difference in the S-S bond lengths in this compound may be partly due to the effect of hydrogen bonding and, partly, to the differing s2 33 s4

35

A. Hordvik and K. Julshamn, Acta Chem. Scand., 1971, 25, 1895. A. Hordvik and K. Julshamn, Acta Chem. Scand., 1971, 25, 2507. A. Hordvik and L. Milje, J.C.S. Chem. Comm., 1972, 182. A. Hordvik and P. Oftedal, J.C.S. Chem. Comm., 1972, 543.

6a-Thiathiophthensand Related Compounds

507 'twists' of the phenyl groups which could affect rr-overlap between the nitrogen atoms and the nucleus. Various routes to 1,Zdithiolylidene ketones (45) have been described. These include the reaction of 3-methylthio-1,Zdithiolium salts with sodium benz~ylacetate,~~ the treatment of 3-phenacylthio-l,2-dithioliurnsalts (43; R1 = Ra = Ph, R2 = H) with triethylamine and decomposition of the resulting disulphide (44) with sodium hydroxide,le and, similarly,

thermal decomposition of 4-aryl-3-acylmethylenethio-l,2-dithiolium salts (43;R1 = H,RZ = Ar, R3 = Me or Ph).36 Ferricyanide oxidation of the dianions obtained by the action of hydroxide ions on 4H-thiapyran-4thiones yields 1,Zdithiolylidene aldehydes.18 Studies of the i.r. spectra of dithiolylidene ketones in which the oxygen is enriched in l80have identified the carbonyl stretching bands which appear in the region 1550-1595 cm-I, depending on the substitution pattern and the conditions of rneas~remenf.~~ Structural data have been provided 38 for the ketone (46)and a correlation has been suggested between S 00distances and i.r. absorption frequencies. The S * * - Ocontact in (46) is the shortest so far reported for this type of structure.

-

36 37

38

G . Caillaud and Y. Mollier, Bull. SOC.chim.France, 1970, 2018; 1971, 331. D. Festal, 0. Coulibaly, R. Pinel, C. Andrieu, and Y . Mollier, Bull. SOC.chim. France, 1970, 2943; D. Festal and Y. Mollier, Tetrahedron Letters, 1970, 1259. R. Pinel, Y. Mollier, E. C. Llaguno, and I. C. Paul, Chem. Comm.,1971, 1352.


508

Compounds in which one (47) 30 or two (48) 40 of the sulphur atoms of the 6a-thiathiophthen system have been replaced by nitrogen atoms have been studied by the X-ray method. In the isothiazolo[5,l-elisothiazole derivative (48), the molecule shows some departure from mirror symmetry, 2364

1

.

Ph 4&

7

0

- quinolyl

1887

S -N-3 ~

\.& + ",

1

.

3

2

1

Me-N-

I 901

1.948

1.338

6 Ph

(47) (48) the significant differences being between the N-S distances (1.901 and 1.948 A) and between the central C-C bond lengths (1.421 and 1.374 A). The average length of the N-S bonds is 1.925 A, approximately 10% longer than the value for a normal N-S bond. In compound (47) the N-S distance (1.887 A) also indicates a 'stretched' bond; the S-S distance here has a typical 6a-thiathiophthen value (2.364 A). In the methylated derivative (49), on the other hand, the S-N distance is normal and the structural data accord reasonably well with the classical structure. MeS

2.814

1.717

S-N-3-

quinolyl

Ph (49) Long S - 0 bonds appear in the symmetrical structure (50).41 This interesting compound is obtained 42 by methylation of a fusion product of captan and resorcinol. The S - 0 bond lengths (1.88 A), which should be compared with the sum of the covalent radii of oxygen and sulphur (1.70 A) and with the sum of the van der Waals radii (3.25 A), approximate to the values found (1.89 and 1.92 A) for the apical S - 0 bonds in the sulphurane (5 1).43 Full descriptions have been given of X-ray crystallographic studies on the 3-nitrosomethylene-l,2-dithioles (52; R = COPh) and (52; R = N02),44 and on the nitromethylene compound (53),46the structures of which were 39 40

41 42 43 44

46

F. Leung and S. C. Nyburg, Chem. Comm., 1970,707; Canad.J . Chem., 1971,49, 167. A. Hordvik and K. Julshamn, Actu Chern. Scand., 1972, 26, 343. R. D. Gilardi and I. L. Karle, Actu Cryst., 1971, B27, 1073. I. Pomerantz, L. Miller, E. Lustig, D. Mastbrook, E. Hansen, R. Barron, N. Oates, and J.-Y. Chen, Tetrahedron Letters, 1969, 5307. I. C. Paul, J. C. Martin, and E. F. Perozzi, J . Amer. Chem. Soc., 1971, 93, 6674. P. L. Johnson, K. I. G. Reid, and I. C. Paul, J . Chem. SOC. (B), 1971, 946. K. I. G. Reid and I. C. Paul, J . Chem. Sac. (B), 1971, 952.

6a-Thiathiophthens and Related Compounds 509 discussed in Volume 1. Analogous structures, containing two 'nitroso' groups and selenium in place of sulphur, have been recognized 47 in a series of compounds first described in 1949.48 The original method of preparation involved treatment of the dioximes of 1,3-diketones with selenium dioxide, and it has now been extended46 to yield the parent compound of the series (54). N.m.r. studies suggest that the molecules are symmetric, and this view is supported by an X-ray study 47 on the product ( 5 9 , from dimedone dioxime, which gives the bond lengths shown. 46p

OC(CF&Ph

Ph ...I

,s:

Ph I OC(CFJ2Ph

O-Se----O

(54)

Me Me (55)

.a' 47

M. Perrier and J. Vialle, Bull. SOC.chim. France, 1971, 4591; D. Paquer, M. Perrier, and J. Vialle, ibid., 1970, 4517. R. J. S. Beer, J. R. Hatton, E. C. Llaguno, and I. C. Paul, Chem. Comm., 1971, 594. F. E. King and D. G. I. Felton, J. Chern. SOC.,1949, 274.

510


Tellurium analogues have been prepared, and the reaction of the bis(2,4-dinitrophenylhydrazone) (56) with selenium dioxide produces the interesting variant (57).46 Very recently a gap has been filled49by the preparation of the sulphur compound ( 5 8 ; X = 0),obtained by the action of sulphur dichloride on dimedone dioxime. A minor product isolated from the same reaction appears to be the related structure ( 5 8 ; X = S). 49

R.J.

S. Beer and A. J. Poole, Tetrahedron Letters, 1972, 1835.

9 1,2= and 1,3-Dithioles BY R. J. S. BEER

1 Introduction Reviews have appeared on structure and bonding in unsaturated fivemembered cyclic disulphides,l" and on the chemistry of 1,3-dithioliurn salts.lb Although published in 1970, these reviews contain few references to work published after 1966. 2 1,ZDithioles and Related Compounds Synthesis.-Thioketones (or enethiols) react with sulphur and carbon disulphide in D M F in the presence of triethylamine to give both 1,2dithiole-3-thiones and 1,3-dithiole-Zthiones; thus heptane-4-thione yields 4-ethyl-5-propyl-1,2-dithiole-3-thione (1) and 4-ethyl-5-propyl-1,3-dithiole2-thione (2). 5-Phenyl-4-styryl-l,2-dithiole-3-thione has been prepared * by application of the well-known keten mercaptal synthesis, and some aryl1,2-dithiole-3-thiones have been obtained, conventionally, by hightemperature reactions of arylalkanes with ~ u l p h u r . ~

s-s

C3H7\

,c=s

Pr

C3H7

""#"R

'S

-

s-s

H+

The reactions which ensue when dithiolate anions of type (3; R

=

CO*NHIor C0,Et) are protonated have interested several groups of workers.6 The formation of the S-amin0-1,2-dithiole-3-thione (4; R a

S .

=

(a) A. Hordvik, Quart. Reports SuIfur Chem., 1970, 5, 21 ; (b) E. Campaigne and R. D. Hamilton, ibid., p. 275. R. Couturier, D. Paquer, and A. Thuillier, Compr. rend., 1970, 270, C, 1878. J.-P. Pradkre and H. Quiniou, Compt. rend., 1971, 273, C,1013. M. G. Voronkov, T. Lapina, and Zh. Z. Minkina, Khim. geterotsikl. Soedinenii, 1971, 7, 999 (Chem. Abs., 1972,76, 3730). (a) E. Soderbiick, Actu Chem. Scand., 1970,24,228; (6) T . Takeshima, M. Yokoyama, N. Fukada, and M. Akano, J . Org. Chem., 1970, 35, 2438; (c) M. Yokoyama, Bull. Chem. SOC.Japan, 1970,43, 2938.

51 1

512


CO-NH,) may involve addition of hydrogen sulphide to the cyano-group and then oxidative ring-closure. In support of this mechanism, it is claimed6cthat the product (4; R = CO-NH2)is obtained in high yield if hydrogen sulphide is passed into the mixture, and if bromine is used to facilitate the oxidation step. Dithioloindoles (6; R = H or Me) have been prepared6 from thiooxindoles ( 5 ) by base-catalysed condensation with carbon disulphide, and

details have been published of syntheses of thieno-1,2-dithiole-3-thiones (8) from ‘trithione’ precursors of type (7) and also from thiophen derivatives (9)* as shown. Reactions.-Several interesting new developments in the chemistry of 1,2-dithiole-3-thiones have been reported. 5-Aryl derivatives are converted, by anodic oxidation in acetonitrile, into dimeric dications, for example (lo), which can be isolated as the insoluble perchl~rate.~With keten in benzene solution, the 5-aryl compounds give unstable green products which are formulated as thiolactones (l1);lo treatment of these with acid

G. Kobayashi, S. Furukawa, Y. Matsuda, and R. Natsuki, J. Pharm. Soc. Japan, 1970, 90, 132.

lo

P. Appriou, J. Brelivet, and J. Teste, Bull. Soc. chim. France, 1970, 1497. J. Brelivet, P. Appriou, and J. Teste, Bull. SOC.chim. France, 1971, 1344. C . Th. Pedersen and V. 0. Parker, Tetrahedron Letters, 1972, 771. G. Hervieu, P. Rioult, and J, Vialle, Bull. Soc. chim. France, 1971, 4375.

1,2- and 1,3-Dithioles

513

chlorides, in the presence of triethylamine, yields 4-acyloxy-l,3-dithiol-2ylidene thioketones (12). Generation of a carbene, by the copper-catalysed decomposition of bis-toluene-p-sulphonyldiazomethane,in the presence of 4-phenyl-l,2dithiole-3-thione results in the quantitative formation of the stable, red, thiocarbonyl ylide (1 3); with Chloramine T in methanol, the analogous nitrogen compound (14) is f0rrned.l' Similar reactions occur with benzo1,2-dithiole-3-thione; the nitrogen-containing product (1 5 ) undergoes loss of sulphur on being heated, yielding the N-tosylimine (16).

+ S-N Tos

s-s e

j.&-NTos Ph

NTos

s

The reaction between 5-aryl-l,2-dithiole-3-thiones and the hydrazine derivative (17), which has been reported previously, has now been described in detail,12 the mechanism suggested being that shown. 4-Aryl-l,2dithiole-3-thiones give analogous products. PhC=N*NHPh

I

c1

xylene

(17)

-1.

c1-

Ph

H

. 0

Ph

In an extension of the familiar addition reaction of 1,2-dithiole-3-thiones and acetylenes, dibenzoylacetylene has been shown to yield products of the expected type (18; X = CH). An attempt to utilize the adjacent carbonyl groups to generate the fused thieno-system (19; X = CH) failed, although the reaction succeeded with the nitrogen analogue (18; X = N), which, on l1 la

S. Tamagaki and S. Oae, Tetrahedron Letters, 1972, 1 1 59. M. Maguet, Y.Pokier, and J. Teste, Bull. SOC.chim. France, 1970,1503

18

514


treatment with phosphorus pentasulphide, gave the thieno-1,3-dithiole derivative (19; X = N).13 The dibenzoylacetylene addition product (18; X = CH, R = H) of 1,2-dithiole-3-thione loses sulphur when heated in benzene and gives a product formulated as the triene (20). A simil-ax structure is assigned to a minor product obtained in the addition reaction between 1,2-dithiole-3thione and dimethyl acetylenedi~arboxylate.~~

Studies on chlorinated dithiole derivatives have continued. 4-Chloro1,2-dithiol-3-ones of type (21) are converted by the action of oxalyl chloride into dichloro-1,2-dithiolium salts (22), which react at the 3-position with aromatic amines to give 3-arylimino-1,2-dithioles(23 ; R = Ar).16 Related structures (23; R = PhSO,, MeSO,, or EtO'CO) are obtained from

4,5-dichloro-3-imino-1,2-dithioles (24) by treatment with primary or secondary amines. The reaction of the dichloro-compound (24; R = EtO. CO) with thiourea in methanol gives the 'trithione' (25), the anion of which reacts with the dichlorodithiole to produce the bisdithiolyl sulphide (26).lS Further examples have been provided1' of the action of Grignard reagents on 1,2-dithiol-3-ones l8 and a detailed study has been presented of the mass spectra of 1,2-dithiol-3-onesand lY2-dithiole-3-thiones. lS

M. Ahmed, J. M. Buchshriber, and D. M. McKinnon, Canad. J. Chem., 1970, 48, 1991.

D. M. McKinnon and J. M. Buchshriber, Canad. J. Chem., 1971,49, 3299. R. Wiedermann, W. von Gentzkow and F. Boberg, Annalen, 1970, 742, 103. l8 F. Boberg and R. Wiedermann, Annalen, 1970, 734, 164. l7 F. Boberg and R. Schardt, Annalen, 1970,734, 173. See 'Organic Compounds of Sulphur, Selenium, and Tellurium', ed. D. H. Reid (Specialist Periodical Reports), The Chemical Society, London, 1970, Vol. 1, Ch. 9. l@ C. Th. Pedersen and J. Msller, Acta Chem. Scand., 1972, 26, 250.

l4

l6


The hydrochlorides of 5-aryl-3-imino-l,2-dithioles (27; R = H, X = C1) react with hydrazine to give known aminopyrazoles (28), and with benzoyl chloride and pyridine to give N-benzoylimino-1,Zdithioles (29). The latter are sulphurized with phosphorus pentasulphide to yield 3-aza-6athiathiophthens.20

Ar u

N

*CO Ph

(29)

3 1,2-DithioliumSalts The synthesis of 1,2-dithiolium salts from p-diketones has been modified by the use of diacetyl disulphide in place of hydrogen disulphide.21 Precursors of the general type (30),where Y = 0, S, (OEt),, or N+Me,, and Z = OH, CI, or OEt, are treated with the diacyl disulphide and a strong acid. This versatile synthesis has been applied to the preparation of a wide range of alkyl- and aryl-substituted dithiolium salts. 3-Methylthio-l,2-dithioliurn perchlorates may be obtained directly from keten mercaptals, for example (31), by the action of phosphorus pentasulphide and subsequent treatment of the insoluble residue with perchloric acid. Similar treatment of /?-keto-amides (32) yields 3-arylimino-l,2dithiole perchlorates (27; R = Ar, X = C10,).2z The method succeeds with amides (32; R = alkyl) and thus serves as a route to the previously inaccessible 5-a1kyl- 1,2-dithi ol-3-imines. Demethylation of 3-methylthio-5phenyl-1,Zdithiolium cation, to give 3-phenyl-l,2-dithiole-3-thione, occurs when the iodide is heated in xylene. 80 21 22

A. Grandin and J. Vialle, Bull. SOC.chim. France, 1971, 4002. H. Hartmann, K. Fabian, B. Bartho, and J. Faust, J. prakt. Chem., 1970, 312, 1197. G. Duguay and H. Quiniou, Bull. SOC.chim. France, 1972, 637.


516

Ac*S*S-AC HX

R' JJR3 R2 (30)

R

yR3 x'

_____3 f

R2

Ph.CO*CH=C(SMe)2

RCO.CH,*COSNHAr

(31)

(32)

a-Bromo-ketones react normally with 1,2-dithiole-3-thiones to give the corresponding dithiolium salts (33; R1 = Me or Ph), which show interesting 24 For example, treatment of the phenacyl compound (33; R1 = R2 = Ph) with triethylamine and acetic acid gives the red crystalline disulphide (34; R1 = R2 = Ph), which decomposes in the presence of alkali to yield the 1,2-dithiolylidene ketone (35; R1 = R2 = Ph).23 When the salt (33; R1 = R2 = Ph) is heated in ethanol containing pyridine, three products are 5-phenyl-l,2-dithiole-3-thione, the dithiolylidene ketone (35; R1 = R2 = Ph), and the disulphide (34; BrR2

@ S

o

CH2* CO R1

(33)

- (R2 &/

(34)

R1 = R2 = Ph). 4-Aryl-1,Zdithiolium salts of type (36; R1 = Me or Ph, R2 = H) yield 1,Zdithiolylidene ketones (37) when heated in but this reaction fails when the dithiolium salt has a 5-amino-substituent (36; R2 = NR2).26 The 5-amino-compounds have been found to give 1,3-dithiole derivatives on treatment with phosphorus pentasulphide in pyridine. The structure of one of the products (38) was established by conversion into the 6a-thiathiophthen (39), which was also prepared by sulphurization of the dithiolylidene ketone (37; R1 = Ar = Ph, R2 = Me2N) obtained by the triethylamine-acetic acid route. The unstable yellow salt obtained 28 by the action of hydrogen sulphide and hydrogen chloride on the triketone (40) has been assigned the dithiolium salt structure (41). On treatment with bases it yields the intensely coloured meso-ionic compound (42), which is also obtained 27 by the 23 24

a5 28 27

E. I. G. Brown, D. Leaver, and D. M. McKinnon, J. Chem. SOC.(0,1970, 1202. G. Caillaud and Y. Mollier, Bull. SOC.chim. France, 1970, 2018; 1971, 331. G. Caillaud and Y. Mollier, Bull. SOC.chim. France, 1971, 2326. K. Inouye, S. Sato, and M. Ohta, Bull. Chem. SOC.Japan, 1970, 43, 1911. A. Schonberg and E. Frese, Chem. Ber., 1970, 103, 3885.


517 Br'

R2p

*CH,.co .R1

s

s-s

A

+ EtOH

0

R2 Ar (37)

At

(36)

Ph

Ph (38)

(39)

reaction between potassium ethylxanthate and 1,1,3,3-tetrabromo-l,3diphenylacetone. The effect of varying degrees of alkyl substitution (mono-, di-, and tri-) in 1,2- and 1,3-dithiolium salts on electronic spectra, charge-transfer spectra with iodide anion as donor, and n.m.r. spectra, has been studied, and the data have been compared with the results of SCF MO calculations.28

The chemical shifts of ring protons and attached methyl groups have been correlated with calculated charge densities. The n.m.r. data confirm the non-uniform distribution of charges suggested by the simple resonance picture. Thus in 1,2-dithiolium cations, protons attached to the 3- and 5-positions have signals at lower field (between T = - 0.6 and T = 0.1) than those attached to the 4-position (ca. T = 1.5) and methyl groups are similarly affected. Cathodic reduction of 1,2-dithiolium cations in acetonitrile solution yields dimeric products (43).29 With 3,Sdiaryl compounds, evidence has been obtained, by measurement of e m . spectra, for the existence of free radicals (44) which are stable at room temperature in the absence of oxygen but probably dimerize at lower temperatures to bis-dithioles similar to (43). With 3,4-diaryl-1,2-dithiolium salts, the products are the dimers (43; R1 = R2 = Ar), which do not appear to dissociate into radicals.

s-s

s-s

Ar (43) 28

29

ZAr (44)

K. Fabian, H. Hartmann, J. Fabian, and R. Mayer, Tetrahedron, 1971, 27, 4705. C. Th. Pedersen and V. D. Parker, Tetrahedron Letters, 1972, 767; C . Th. Pedersen, K. Bechgaard, and V. D. Parker, J. C. S. Chem. Comm., 1972, 430.


518

Further examples have been given of the reaction of 1,Zdithiolium salts (both 3,4-dialkyl and 3,5-dialkyl) with ammonia to give isothiaz~les,~~ and the formation of ring-opened products, (45) and (46), from 3-aryl-1,2dithiolium perchlorates and excess of dimethylamine has been The reactions of 3-methylthio-l,2-dithioliumsalts with amines continue to be of interest. With primary aliphatic amines, 5-aryl-3-methylthio-1,2dithiolium iodides give /3-alkylaminodithioacrylates (47) and isothiazoline3-thiones (48) as well as the demethylated compounds (1,2-dithiole-3thiones).32 Similar products are obtained 33 with secondary amines, except that the isothiazole derivatives are replaced by 3-dialkylamino-1,2-dithiolium iodides (49), the n.m.r. spectra of which indicate 34 restricted rotation

s-s Ar

H N , R 2 I

f---------,

Ar -ANR2

1

R1

(494

about the C-N bonds [i.e. a substantial contribution from the immonium forms (49b)l. The formation of dithioacrylates in these reactions is of interest since it implies attack by the nucleophilic amine at the position occupied by the aryl group. /3-Aminodithioacrylates (51) become the major products when 4-aryl-3-methylthio-l,2-dithiolium cations (50) react with primary 32 and secondary a m i n e ~ . ~ ~ The formation of pyrazoles from 3-aryl- or 3,Sdiaryl-1 ,Zdithiolium salts and phenylhydrazine has been investigated in some 3-Chloro-

s4

J.-C. Poite, A. Perichaut, and J. Roggero, Compt. rend., 1970, 270, C, 1677; J.-C. Poite, S. Coen, and J. Roggero, Bull. SOC.chim. France, 1970, 4373. F. Clesse, A. Reliquet, and H. Quiniou, Compt. rend., 1971, 272, C, 1049. G. Le Coustumer and Y. Mollier, Bull. SOC.chim. France, 1970, 3076; Compt. rend., 1970, 270, C,433. G. Le Coustumer and Y. Mollier, Bull. SOC.chim. France, 1971, 499. M.-L. Filleux-Blanchard, G. Le Coustumer, and Y. Mollier, Bull. SOC.chim. France,

s6

1971, 2607. G. Le Coustumer and Y.Mollier, Bull. SOC.chim. France, 1971, 2958.

36

M.-T. Bergeou, C. Metayer, and H. Quiniou, Bull. SOC.chim. France, 1971, 917.

so s1

sa as

1,2- and 1,3-DithioZes

519

5-phenyl-l,2-dithiolium perchlorate, treated with a-naphthol in acetic acid, yields the 4-naphthyl derivative (52; R1 = OH, R2 = H), but with p-naphthol the products are of type (52; R1 = H, R2 = OH).37 Other papers on 1,2-dithiolium salts deal with reactions of 3-aryl and 3,5-diaryl compounds with cyanothioacetamide, yielding thiopyran

Ar ~10,- RZ-R~ (52)

d e r i v a t i ~ e s , ~the ~ ~ formation of dithio-@-diketonesstabilized as chelates by the action of hydrosulphide ion in the presence of suitable metal and the ring-opening reaction of 3,5-diamino-l,2-dithioliumperchlorates to dithiomalonami de~.~O Earlier work on the crystal structures of dithiolium salts has been continued by a study of 4-phenyl-1,Zdithiolium chloride m~nohydrate.~l 4 1,5Dithioles and Related Systems When 4-phenyl-l,3-dithiol-2-one is heated with mercuric acetate, a substitution reaction occurs leading to 4-acetoxymercuri-5-phenyl-l,3-dithiol2-one. Treatment of this product with iodine in chloroform solution brings about displacement of the acetoxymercuri-group by iodine.42 4-Bromo1,3-dithiol-2-one (54) is conveniently prepared from 1,3-dithiolan-2-0ne (53) by the sequence A detailed analysis has been made of the n.m.r. spectra of 1,3-dithio1-2-one and the corresponding 2-thi0ne.~~ 37 38

39 40

41 42 4s 44

N. Lozac'h and C. Th. Pedersen, Acta Chem. Scand., 1970, 24, 3189. R. Pinel, K. S. N'Guyen, and Y. Mollier, Compt. rend., 1970, 271, C, 955. E. Uhlemann, K.-H. Uteg, and B. Zollner, 2. Chem., 1970, 10, 468. M. B. Kolesova, L. I. Maksimova, and A. V. El'tsov, Zhur. org. Khim., 1970, 6, 610 (Chem. A h . , 1970, 72, 132 587). F. Grundtvig and A. Hordvik, Acta Chem. Scand., 1971, 25, 1567. I. D. Rae, Internat. J. Sulfur Chem., Sect. A , 1971, 1, 59. H.-D. Scharf, W.-D. Busse, and W. Pinske, Chem. Ber., 1970, 103, 3949. D. M. McKinnon and T. Schaefer, Canad. J. Chem., 1971, 49, 89.

520

Organic Compounds of Sulphur, Selenium, and Tellurium N-bromosuccinirnide hv

Br

Br Rr

(53)

As already noted in this Chapter, 4,5-dialkyl-1,3-dithiole-2-thiones are formed, with 1,2-dithiole-3-thiones, when thioketones are treated with sulphur and carbon disulphide in the presence of a base.2 An interesting series of compounds of general structure (56; X or Y = S or Se) has been prepared45 from phenylacetylene by the route shown, via the anions ( 5 5 ; X = S or Se). The four possible products all react with

Ph (58)

methyl iodide to give the N-methylated iodides (57) and, from these, compounds of type ( 5 8 ) are produced by the action of hydrogen sulphide or hydrogen selenide in pyridine. Examples are 4-phenyl-l,3-dithiole-2thione (58; X = Y = Z = S ) , the corresponding selenocarbonyl compound (58; X = Y = S , Z = Se), and the 1,3-thiaselenole-2-thione(58; X = Se, Y = S , Z = S). Reduction of 1,3-dithiole-2-thione and its benzo-derivative with lithium aluminium hydride gives ethanedithiol and thiocatechol respectively, but similar reduction of the cyclohexene compound (59) replaces the thiocarbonyl group by a methylene

Irradiation of 1,2,3-thiadiazoles (60; X = S , R1 = H or Me, R2 = C02Et or Ph) yields dithiafulvenes (61; X = S , R1 = H or Me, R2 = C02Et or Ph).47a Similarly, photochemical decomposition of the 1,2,3selenadiazole (60; X = Se, R1 = H, R2 = C02Et) gives the diselenafulvene (61; X = Se, R1 = H, R2 = C02Et)and its geometrical is0mer.~7~ 45

*’

40

H. Spies, K. Gewald, and R. Mayer, J. prakt. Chem., 1971, 313, 804.

J. R. Grunwell and J. D. Willett, Znternat. J . Sulfur Chem., Sect. A, 1971, 1, 60. (a) K. P. Zeller, H. Meier, and E. Muller, Tetrahedron Letters, 1971, 537; (b) H. Meier and I. Menzel, Tetrahedron Letters, 1972, 445.


521

Related structures, for example (62), are prepared by condensation of 2-piperidino-l,3-dithiolium salts with active-methylene A new synthesis of 1,3-dithioliurn salts (64) has been developed,49 involving the reaction of halogenated or other substituted ketones of type (63; Y = halogen, OH, or SH) with an excess of a thioacid in the presence

of a strong acid. With a series of alkyl derivatives available, the spectroscopic properties of 1,3-dithiolium salts have been compared 28 with those of the 1,2-series. Effects similar to those already discussed (for 1,2-dithiolium salts) are noticeable in the n.rn.r. spectra, with the signals for protons and methyl groups attached to the 2-position at lower fields than those for groups attached to the 4- and 5-positions, reflecting the positive character of the position between the two sulphur atoms. The relative stabilities of a series of 4-(p-substituted phenyl)-1,3-dithiolium cations in water have been studied q~antitatively.~~ Electrondonating groups in the para-position of the 4-phenyl group reduce the reactivity of the positive 2-position of the 1,3-dithiolium cation towards attack by water, whereas electron-attracting groups destabilize it. The equilibrium data correlate with calculated charge densities. In a related the effect of attaching para-substituted phenyl groups directly to the 2-position of the Q-phenyl-l,3-dithiolium cation has been examined. As expected, electron-rich aryl groups tend to stabilize the cations in water. The methods used for the preparation of the 2-ar~l-1~3dithiolium salts (66) are of interest. These include the action of Grignard reagents on 2-methoxy-4-phenyl-1,3-dithiole(65) followed by hydride abstraction with triphenylmethyl perchlorate, and the reaction of 4-phenyl1,3-dithiolium perchlorate (67) with appropriately activated benzene derivatives (e.g. phenol, anisole, and aniline). Treatment of 2-p-hydroxyphenyl-4-phenyl-l,3-dithioliumperchlorate with triethylamine yields the red quinonoid compound (68). 4,5-Diphenyl-l,3-dithioliumperchlorate, which with tertiary aliphatic amines yields the bis-1,3-dithiole derivative (69), gives 2-dialkylamino-l,3dithioles (70) on treatment with secondary amines.62 Reaction with primary amines can give similar products (70; R1 = H) but normally leads to the bis-1,3-dithiolylamines (71). With primary alcohols the perchlorate is converted into 2-alkoxy-l,3-dithioles; the reaction fails with 4a

49 60 61 62

K. Hirai, Tetrahedron Letters, 1971, 1137. K. Fabian and H. Hartmann, J. prakt. Chem., 1971, 313, 722. A. Takamizawa and K. Hirai, Chem. and Pharm. Bull. (Japan), 1970, 18, 865. K. Hirai, Tetrahedron, 1971, 27, 4003. K. M. Pazdro and W. Polaczkowa, Roczniki Chem., 1970, 44, 1823; 1971, 45, 811, 1249.

522


I

Ph,C+ Cl0,-

Ph

(68)

isopropyl alcohol, but the 2-isopropoxy-derivative can be prepared from 4,5-diphenyl-2-piperidino-l,3-dithiole by the action of isopropyl alcohol in benzene and acetic acid. Treatment of the perchlorate with sodium alkoxides yields only the bis-compound (69).

The analogous benzo-derivative (72) is obtained from benzo-l,3-dithiolium perchlorate by the action of triethylarnine in acetonitrile; in dimethylforrnamide as solvent, a second product (73) was isolated, whereas the action of water on the perchlorate yields the benzodithiole derivative (74).53 Earlier polarographic studies 54 indicated that the bis-compound (72) is reversibly oxidized to the radical cation (75) and the dication (76). It has now been shown55 that the simpler bis-dithiole (77), obtained by deprotonation of lY3-dithiolium hydrogen sulphate, reacts with chlorine in carbon tetrachloride to give a deep purple crystalline salt (78); further 63

64 55

D. Buza, A. Gryff-Keller, and S. Szymanski, Roczniki Chem., 1970, 44, 2319; 1971, 45, 501. S. Hiinig, H. Schlaf, G. Kiesslick, and D. Schentzow, Tetrahedron Letters, 1969, 2271. F. Wudl, G. M. Smith, and E. J. Hufnagel, Chem. Comm.,1970, 1453.

1,2- and 1,3- Dithioles

523

(74)

reaction with chlorine yields the yellow dichloride of the dication (79). Ethanolic solutions of the radical cation chloride (78) are stable at room temperature, but in aqueous solution decomposition occurs (tt is ca. 6 h). Reduction with sodium hydrogen sulphite reverses the oxidation and gives the starting material.

(77) (78) (79) An X-ray studyb6on the dithiole (77) furnishes the dimensions shown (80). The molecule is slightly distorted into a chair-type conformation, i.e. the central two carbon atoms and the four sulphur atoms lie in a plane with the terminal pairs of carbon atoms canted in opposite directions. It is of interest that the central C-C and C-S bonds are longer than the comparable bonds in the remainder of the molecule. In further studies, it has recently been showns7 that the bis-dithiole (77) and the radical cation chloride (78) are effective semiconductors. The bis-dithiole (77)is included 1.729

s

(80)

67

W. F. Cooper, N . C. Kenny, J. W. Edmonds, A. Nagel, F. Wudl, and P. Coppens, Chem. Comm., 1971, 889. F. Wudl, D. Wobschall, and E. J. Hufnagel, J . Amer. Chem. Soc., 1972, 94, 670.

524


in a detailed study of the spectral and electrochemical properties of t etrat hioethylene~.~' The syntheses of bis-l,3-dithiolylidene compounds noted above, involving treatment of 1,3-dithiolium salts with bases, are thought to proceed through carbene intermediates. These may be generated in other ways,58 for example, by the action of carbon disulphide on acetylenes (81; R = CF,) and by the action of triphenylphosphine on the 173-dithiole-2-thione (83; R = CF,). In the first of these two methods, more complex products,

R 1 C

R = CF,), can result, especially when the acetylene is treated with an excess of carbon disulphide at elevated temperatures, and in the absence of trifluoroacetic acid which, when present, favours the formation of the bis-compound (82). Dimethyl acetylenedicarboxylate, with excess of carbon disulphide, also gives a complex product with the probable structure (85; R = C0,Me).69

e.g. (84; R = CF,) and (85;

CO-Ph

67a 6* 59

D. L. Coffen, J. Q. Chambers, D. R. Williams, P. E. Garrett, and N. D. Canfield, J . Amer. Chem. SOC.,1971. 93, 2258. H. D. Hartzler, J. Amer. Chem. SOC.,1970, 92, 1412. D. L. Coffen, Tetrahedron Letters, 1970, 2633.

1,2- and 1,3-Dithioles 525 The carbene formed from the acetylene (81; R = CF,) and carbon disulphide brings about insertion reactions with ketones;6o with acetophenone, the product (86) is obtained in high yield. In an interesting extension of these studies, the adduct (87) of tributylphosphine and carbon disulphide is allowed to react at - 30°C with acetylenes which carry at least one electron-withdrawing group. Rather poor yields of bis-dithioles (82) are obtained, but if the reaction is carried out in the presence of an aromatic aldehyde, the products, isolated in good yield, are 2-arylidene-l,3-dithioles(89). It is suggested that a reactive Wittig reagent (88) is first formed which rapidly reacts with the aldehyde in the normal way. Bu~P-CS, +

RCcCR,

(87)

/ (82)

R ( R 1 ; ~ p B u 3 )

T

O

R

(88)

R

IS>,,*, S

(89)

Photolysis of the rneso-ionic 1,3-dithiolium compound (90) leads to diphenylacetylene, sulphur, and tetraphenyl-l,4-dithiin (92).g2 The formation of diphenylacetylene suggests the possible intermediacy of diphenylthiiren (91). Irradiation of the related dithiole (93) causes reorganization of the structure into the 1,2-dithiol-3-imine derivative (94).63

(93) eo 62

e3

(94)

H. D. Hartzler, J . Amer. Chem. SOC., 1970, 92, 1413. H. D. Hartzler, J . Amer. Chem. SOC.,1971, 93, 4961. H. Kato, M. Kawamura, and T. Shiba, Chem. Comm., 1970, 959. H. Kato, T. Shiba, H. Yoshida, and S. Fujimori, Chem. Comm., 1970, 1591.

10 Thiopyrans and Related Compounds BY R. J. S. BEER

1 Introduction For convenience, monocyclic thiopyran derivatives (Sections 2-5) have been separated from benzothiopyran derivatives (Sections 6-10). Section 11 deals briefly with fused-ring compounds containing other heterocyclic nuclei in addition to the thiopyran system. References to the patent literature have not been included. 2 Dihydrothiopyrans 2-Bromomethyl-he-dihydrothiopyrans(1 ; R = CH,Br), prepared by

bromination of the 2-methyl compounds, react with primary amines to give unstable 2-aminomethyl-A2-dihydrothiopyrans(1 ; R = CHaNHR4), which readily cyclize to pyrrolinones (2).l The bromo-compound (1 ; R1 = R2 = RS = H, R = CH,Br) cyclizes when heated to give the lactone (3).2

Ethyl 2-amino-A2-dihydrothiopyran-3-carboxylate has been included in a spectroscopic study of the protonation of heterocyclic enarnines, and the acid-catalysed addition of alcohols and thiols to A2-dihydrothiopyranhas been inve~tigated.~ Thiobenzophenone undergoes an addition reaction with dienes to yield A3-dihydrothiopyrans (4; R = H or Me).s The butadiene adduct (4; R = H) is methylated by treatment with butyl-lithium-methyl iodide in THF at - 80 "C to give the 2-methyl derivative, but similar methylation M. Baues, U. Kraatz, and F. Korte, Chem. Ber., 1972, 105, 1345. W. Ehrenstein and F. Korte, Chem. Ber., 1971, 104, 734. H. Wamhoff, Tetrahedron, 1970, 26, 3849. V. S. Blagoveshchenskii, I. V. Kazimirchik, M. I. Ivanova, and N. S. Zefirov, Zhur. org. Khim., 1970, 6, 877 (Chem. Abs., 1970,73, 14632). A. Ohno, Y.Ohnishi, and G. Tsuchihashi, Tetrahedron, 1969, 25, 871.

526

Thiopyrans and Related Compounds

527

R R I I

Ph,C=S

CH,=C-C-CM,

R

at - 15 "C yields the cyclopropane (7), apparently as the result of the rearrangement of the expected anion ( 5 ) to the cis-ethylenethiolate (6).6 The acid chloride of allylthioglycollic acid has been cyclized, with aluminium chloride, to a mixture of ketones which yield the known tetrahydrothiopyran-3-one on catalytic reduction. Similar cyclizations lead to 3-methyl- and 4-methyl-hs-dihydro thiopyran-5-ones. The products obtained by condensation of carbon disulphide with dienamines of type (8) have been shown to be 5,6-dihydro-2H-thiopyran-2thiones (9).8 RfCH2

S R1 (8)

R1

Rf (9)

Methyl dithiocyanoformate adds to butadiene, l-methoxybutadiene, and trans,trans-l,4-diacetoxybutadiene to give the A3-dihydrothiopyrans (lo; R1 = R2 = H), (10; R1 = OMe, R2 = H), and (10; R1 = R2 = OAC).~ With cyclopentadiene, a mixture of the two isomers (11; R1 = CN, R2 = MeS) and (11; R1 = MeS, R2 = CN) is obtained.1° Thioacetophenone, generated photochemically from the trimer, adds to cyclopentadiene to give related structures of type (1 l).ll The sulphur-bridged diketone (12), synthesized by oxidation of the previously known diol, shows some anomalous spectroscopic properties

@

lo

l1

J. F. Biellmann and J. B. Ducep, Tetrahedron Letters, 1970, 2899. K. Sato, S. Inoue, and K. Kondo, J . Org. Chem., 1971, 36, 2077. J. P. Sauvt and N. Lozac'h, Bull. SOC.chim. France, 1970, 2016. D. M. Vyas and G. W. Hay, Chem. Cornrn., 1971, 1411. D. M. Vyas and G. W. Hay, Canad. J. Chem., 1971,49, 3755. N. Sugiyama, M. Yoshioka, H. Aoyama, and T. Nishio, Chem. Cornrn., 1971, 1063.

528


R2

R2

which are attributed to intramolecular interactions. The dione is extremely sensitive to light and rearranges to an isomer which is assigned structure (13).12

Interactions between sulphur and carbonyl groups also appear to be important in the photochemistry of the ketone (14) and its dihydroderivative.13 Irradiation of compound (14) in methanol gives mainly the

6 0

A3-dihydrothiopyran (15; R = H) with a small amount of the ketone (16), which is the main product under other conditions. In deuterio-methanol, the product (15; R = D) has deuterium incorporated in the position shown. l2 l3

J. M. Mellor and C. F. Webb, J . C. S. Perkin I , 1972, 211. A. Padwa, A. Battisti, and E. Shefter, J. Amer. Chem. SOC.,1969, 91, 4000; A. Padwa and A. Battisti, ibid., 1971, 93, 1304.

Thiopyrans and Related Compounds 529 3 2H-Thiopyrans and Related Compounds 13-Dialkylaminodithioacrylates (1 7) react with rnaleic anhydride to give high yields of 1 : 1 adducts which have now becn shown, by X-ray crystallography, to be 2H-thiopyran derivatives (1 8).14

H

S

K;NJyLMe R' (17)

___,

K1

,

CO,H

MeS QCO*NRi (1 8)

Further evidence has been presented for cyclic delocalization of the r-electron sextet in the anions (21) derived from 2H-thiopyran 1,l-dioxides (19) and (20).169l6 The n.m.r. spectra of the anions show a shift to lower field for protons at the 2- (or 6-)position, compared with the methylene protons in the precursors. Methyl groups at the 2- or 6-position are similarly affected.

A study of kinetic acidities (which rcflect equilibrium acidities) has shown l8, l7 that the anions from cyclic sulphones of type (22) and (23) are relatively much more stable than those derived from open-chain analogues.

l4

l6 lC

l7

R. Kalish, A. E. Smith, and E. J. Smutny, Tetrahedron Letters, 1971, 2241. S. Bradamante, A. Mangia, and G . Pagani, Tetrahedron Letters, 1970, 3381. S. Bradamante, S. Maiorana, A. Mangia, and G . Pagani, J. Chem. SOC.(B), 1971, 74. S. Bradamante, A. Mangia, and G . Pagani, J. Chem. SOC.(B), 1971, 545.


530

A recent paper l8 describes syntheses of 2H-thiopyran 1,l-dioxides, for example (25), starting with enamines (24). This reaction sequence has also been applied to enamines prepared from cyclic ketones. Condensation of malononitrile with carbon disulphide in the presence of aqueous alkali leads to 4,6-diamino-3,5-dicyano-2H-thiopyran-2-thione in good yield,le and 6-aryl-3-cyano-2H-thiopyran-2-thiones (27 ; R = H or

ZR

Ar

c104-

S

NC*CH,-CS-NH,

Ar

R

Ph) may be obtained from 3-aryl-l,2-dithiolium perchlorates (26) by the action of cyanothioacetamide in boiling The thiones (27) are converted into the oxygen analogues in good yield by the action of mercuric acetate. 3,6-Diaryl-2H-thiopyan-2-ones (28), and hence 3,6-diaryl-2H-thiopyran2-thiones, have been prepared by the route shown.21

4 4H-Thiopyran Derivatives In a reinvestigation of earlier work, it has been shown22that alkaline hydrolysis of the 2,6-bismethylthio-4H-thiopyran-4-one (29) gives the 2-hydroxy-compound (30) as the main product. Methylation with diazomethane yields the ethers, i.e. (31) and its isomer, 2-methoxy-6-methylthio3,5-diphenyl-4H-thiopyran-4-one.Treatment of compound (31) with phosphorus pentasulphide gives the thione (32), which reverts to the starting material (29) at its melting point. The preparation has been described of stable sesquifulvalene analogues, (33) 23 and (34),24by condensations between the appropriate 4H-thiopyran$-one and either 1,2,3,4-tetrachlorocyclopentadiene or 4,5-dichlorocycloS. Bradamante, S. Maiorana, and G. Pagani, J. C . S. Perkin I, 1972, 282. T. Takeshima, M. Yokoyama, N. Fukada, and M. Akano, J. Org. Chem., 1970, 35, 2438.

R. Pinel, N'G. K. Son, and Y. Mollier, Compt. rend., 1970, 271, C, 955. J.-C. Medin and H. Quiniou, Compt. rend,, 1971, 273, C, 148. H. J. Teague and W. P. Tucker, J . Org. Chem., 1970,35, 1968. 23 G. Seitz, Arch. Pharm., 1969, 302, 886. ar G. Seitz and H. Monnighoff, Arch. Phurm., 1971, 304, 518. *O

a1

ph&rH ph&r -

Thiopyrans and Related Compounds ph&ph

I

OMe

CH,N,,

I

I

SMe

MeS

x,

I

MeS

MeS

MeS ph&ph

phs

S

(32)

3$

CI

53 1

Me

Ph

(33)

0, (35) pentene-l,3-dione. The synthesis of the formally similar but, in electron distribution, quite different structure (35) has also been reported.2s Details have been given for the synthesis of 6a-thiathiophthens (see Chapter 8) from 4H-thiopyran-4-thi0nes.~~ Analogous reactions with 4H-thiopyran-4-selenones lead to 6a-selenathio~hthens.~' Studies on the photochemistry of 4H-thiopyran derivatives have continued. 2,6-Dimethyl-4H-thiopyran-4-one (36; R = Me, X = 0) differs from the analogous 2,6-diphenyl compoundz8 in giving a cage dimer on irradiation.2B 2,6-Diphenyl-4H-thiopyrand-thione(36; R = Ph, X = S) is converted into the corresponding thiopyran-4-one on irradiation in the presence of oxygen and methylene blue, and similarly, QH-thiopyran-4thione gives 4H-thiopyran-4-0ne.~~A cage dimer has been obtained from

RJ?J R

26

(34)

phfiph

2+RS

ph)(-f;

S (36)

RS

(37)

SR

+s

(38)

G. Pagani and S. Maiorana, Chimica e Industria, 1971,53, 259 (Chem. Abs., 1971, 74, 125 342).

O6

*'

z8

J. G. Dingwall, D. H. Reid, and J. D. Symon,J. Chem. SOC.(C), 1970, 2412. D. H. Reid, J. Chem. Soc. (C), 1971, 3187. See 'Organic Compounds of Sulphur, Selenium, and Tellurium', ed. D. H. Reid, (Specialist Periodical Reports), The Chemical Society, London, 1970, Vol. 1, ch. 10. N. Sugiyama, Y.Sato, and C. Kashima, Bull. Chem. Soc. Japan, 1970, 43, 3205. N. Ishibe, M. Odani, and M. Sunami, Chern. Comm., 1971, 118.

532 Organic Compounds of Sulphur, Selenium, and Tellurium 4H-thiopyran-4-one by irradiation in acetonitrile (in the absence of oxygen).31 2,6-Bisalkylthio-3,5-diphenyl-4H-thiopyran-4-ones (37) are converted photochemically into cyclopentadienones (38) and 2,6-Diphenyl-4H-thiopyransundergo a disproportionation reaction in the presence of strong acids analogous to those previously reported for 2H-thiop~rans.~~ The products are thiopyrylium salts and tetrahydrothi opyrans.33 Adducts of type (39; X = CO-Ph or C02Me), containing the 4Hthiopyran structure, are formed from 1,2-dithiole-3-thionesand acetylenes 34

(see also Chapter 8). Some further references to 4H-thiopyran derivatives are included in the next section. 5 Thiopyrylium Salts

2H-Thiopyran-2-ones and 4H-thiopyran-4-ones are reduced with lithium aluminium hydride to give the corresponding thiopyranols which, with perchloric acid, generate thiopyrylium perchlorates. Peracetic acid oxidation of 2H-thiopyran-2-thiones also yields thiopyrylium 1,5-Diketones can be converted directly into thiopyrylium salts, by the action of hydrogen sulphide in the presence of a strong A disproportionation reaction is again involved, and the corresponding fully reduced thiopyrans are obtained as by-products; thus, diketones of type (40) give both the salts (41) and the tetrahydrothiopyrans (42). The preparation of 2,3,5,6-tetraphenylthiopyryliumsalts, using phosphorus pentasulphide and the appropriate lY5-diketone,has been rep~rted.~' a1

sa aa 34

96

9%

37

N. Ishibe and M. Odani, J. Org. Chem., 1971,36, 4132. N. Ishibe and M. Odani, Chem. Comm., 1971,702. V . G . Kharchenko, M. E. Stankevich, A. R. Yakoreva, and E. G. Lilienfel'd, Khim. geterotsikl. Soedinenii, 1971, 7 , 422 (Chem. Abs., 1972, 76, 14 262). M. Ahmed, J. M. Buchshriber, and D. M. McKinnon, Canad. J. Chem., 1970, 48, 1991; D. B. J. Easton, D. Leaver, and T. J. Rawlings, J. C . S. Perkin I, 1972, 41. D. M. McKinnon, Canad. J. Chem., 1970,48, 3388. ( a ) V . G. Kharchenko, N. M. Kupranets, V . I. Kleimenova, A. A. Rassudova, M. E. Stankevich, N. M. Yartseva, and A. R. Yakoreva, Zhur. org. Khim., 1970, 6 , 1119 (Chem. A h . , 1970, 73, 35 164); V . G. Kharchenko, V . I. Kleimenova, and A. R. Yakoreva, Khim. geterotsikl. Soedinenii, 1970, 900 (Chem. Abs., 1971, 74, 76 272); V . G. Kharchenko and N. M. Kupranets, Zhur. org. Khim., 1970,6, 193 (Chem. Abs., 1970, 72, 90212). ( b ) V . G. Kharchenko, A. A. Rassudova, T. I. Krupina, S. K. Klimenko, and T. P. Chepurnenkova, Khim. geterotsikl. Soedinenii, 1970, 338 (Chem. Abs., 1970, 73, 66 393); V . G. Kharchenko, N. M. Yartseva, and A. A. Rassudova, Zhur. org. Khim., 1970, 6, 1513 (Chem. Abs., 1970, 73, 87 734). V . G . Kharchenko and V . I. Kleimenova, Zhur. org. Khim., 1971, 7 , 613 (Chem. Abs., 1971, 75, 5634).

& h \& r

x-

H,S, HX

*

(41)

(40)

(43)

Me (44)

y&re Ph

Ph

CN

Ph (45)

(46) Two groups of workers 40 have observed that triphenylthiopyrylium salts (43)react with active-methylene compounds, in the presence of bases, to give tetrasubstituted benzenes, for example, triphenylbenzonitrile (46). 38 s8

U. Eisner and T. Krishnamurthy, J. Org. Chem., 1972, 37, 150. C. C. Price, J. Follweiler, H. Pirelahi, and M. Siskin, J. Org. Chem., 1971, 36, 791. Z. Yoshida, S. Yoneda, H. Sugimoto, and T. Sugimoto, Tetrahedron, 1971, 27, 6083; G. A. Reynolds and J. A. VanAllan, J . Heterocyclic Chem., 1971, 8, 301.

534


These evidently complicated reactions must involve initial attack by a carbanion at the 2-position of the thiopyrylium ring, followed by ringopening and elimination steps. The condensation of 2-methylthio- and 4-methylthio-thiopyrylium iodides (47; R1 = MeS, R2 = Ph) and (47; R1 = Ph, R2 = MeS) with sodium benzoylacetate yields the extended ketones (48) and (49).,' Condensations between 2-dialkylamino-thiopyrylium salts and active-methylene compounds have also been described.42 Ph

(47)

&

Ph

(49)

Ph

Reduction of thiopyrylium iodide with zinc, and treatment of the product with triphenylmethyl fluoroborate, perchlorate, or iodide, yields the bisthiopyrylium salts (50; X = BF,, Clop, or I), which are relatively stable in air but decompose rapidly in contact with 4-4-Coupling in the dication is indicated by the very simple n.m.r. spectrum. The dication is reduced with zinc in acetonitrile to the radical cation (51), the e.s.r.

s

m (50)

2x(51)

spectrum of which implies a symmetrical structure with the odd electron distributed equally between both rings.44 Charge-transfer spectra of 2,4,6-triarylthiopyrylium cations in the presence of stable carbanions, for example [C(CN),]-, have been rnea~ured.,~Irradiation of the thiopyrylium perchlorate (43 ; X = CIO,) in methanol, in the presence of oxygen, leads to a mixture of products, including thiophenol, benzaldehyde, benzoic acid, and methyl benzoate. Methylene blue inhibits the ~ x i d a t i o n . ~ ~ 41

4p 48

E. I. G. Brown, D. Leaver, and D. M. McKinnon, J. Chem. SOC.( C ) , 1970, 1202. H. Hartmann, J. prakt. Chem., 1971, 313, 1113. Z. Yoshida, S. Yoneda, T. Sugimoto, and 0. Kikukawa, Tetrahedron Letters, 1971, 3999.

44

46

Z. Yoshida, T. Sugimoto, and S. Yoneda, J. C. S. Chem. Comm., 1972, 60. H. Yasuba, T. Imai, K. Okamoto, S. Kusabayashi, and H. Mikawa, Bull. Chem. Suc. Japan, 1970,43, 3101. Z. Yoshida, T. Sugimoto, and S. Yoneda, Tetrahedron Letters, 1971, 4259.


535

6 Thiochromans and Related Compounds Catalytic reduction of 2,2-dimethylthiochroman-4-onein the presence of sulphuric acid gives the corresponding thiochroman in high yield, but in the absence of the acid a mixture of products is formed.47 The reduction of thiochroman-4-one oximes to 4-aminothiochromans has also been reported.48 The detailed structure of the clathrate compound formed between 2,5,5-trimethylhex-3-yn-2-01 and 4-p-hydroxyphenyl-2,2,4-trimethylthiochroman has been determined by X-ray cry~tallography.~~ trans-3,4-Dibromothiochromanand analogous dibromo-naphthothiopyrans, prepared by addition of bromine to the appropriate Aa-thiochromenes, may exist in 'sofa' conformations.6o The dibromo-compounds undergo ring-contraction reactions with alkalis, yielding benzo[b]thiophen derivatives.60# s1 A3-Thiochromenes(53; R = H or Me) have been prepared by the action of heat on the acetylenes (52; R = H or Me),62 and the cyclization of nitriles of type (54; X = CN or C0,Et) with aluminium bromide leads to A2-thiochromenederivatives (55).63 R C A

,CH,

(54)

(quinoline)

'

"J

P S H

(55)

Various reactions have been reported for thiochroman-4-ones : the Schmidt reaction brings about ring expansion to lactams of the 1,4- and 1,5-benzothiazepine series;54 the stereochemistry of bromination of 6-methyl-2-phenylthiochroman-4-one and its 1,l-dioxide has been investigated ;55 treatment of thiochroman-4-ones with dimethyloxosulphonium 47

48

so s1 62

E.S 54 65

J. B. Campbell, E. R. Lavagnino, R. B. Morin, and D. 0. Spry, Ann. New York Acad. Sci., 1970, 172, 261 (Chem. Abs., 1971, 74, 76267). V. A, Zagorevskii, N. V. Dudykina, and L. M. Meshcheryakova, Khim. geterotsikl. Soedinenii, 1970, 302 (Chem. A h . , 1970, 73, 66 390). D. D. MacNicol and F. B. Wilson, Chem. Comm., 1971, 786. W. D. Cotterill, C. J. France, R. Livingstone, J. R. Atkinson, and J. Cottam, J. C. S. Perkin I , 1972, 787. H. Hofmann and G . Salbeck, Angew. Chem. Internat. Edn., 1969, 8, 456. H. Kwart and T. J. George, Chem. Comm., 1970,433. G . W. Stacy, D. L. Eck, and T. E. Wollner, J. Org. Chem., 1970, 35, 3495. K.-H. Wunsch, K.-H. Stahnke, and A. Ehlers, Chem. Ber., 1970, 103, 2302. G . F. Katekar, J. Heterocyclic Chem., 1970, 7 , 187.


536

methylide can give benzo[b]thiophens (56) and o-mercaptoaroylcyclopropanes (57);56 3-bromo-2-methylthiochroman-4-one reacts with formaldehyde in the presence of base to produce the spiro-epoxide (58) and 3-hydroxymet hyl-2-methylthiochromone (5 9).57

R2mR2 0

CH,.SO.Me,+

. R1

R1

Cyclization of the thiochroman (60)with sulphuric acid yields a mixture of the tricyclic ketone (61) and its dihydro- and dehydro- derivative^.^^ Irradiation of the sulphoxide (62) gives the products shown; mono-3substituted analogues of (62) behave similarly, but 2-phenyl- and 2,2dimethylthiochroman-4-one sulphoxides are converted into ring-contracted products and much polymeric 56

57 68

6B

W. N. Speckamp, J. Dijkink, J. A. Maassen, and H. 0. Huisman, Tetrahedron Letters, 1970, 2743. H. Hofmann, G . Salbeck, and B. Meyer, Chem. Ber., 1970, 103, 2084. E. Campaigne, H. R. Burton, C. D. Blanton, and S. W. Schneller, J. HeterocycIic Chem., 1971, 8, 65. I. W. J. Still and M. T. Thomas, Tetrahedron Letters, 1970, 4225.


537

The synthesis of selenochromans, by reduction of selenochromanones, has been studied; the Wolff-Kischner-Minlon procedure can lead to byproducts, notably benzo[b]selen~phens.~~ Cyclization of p-phenylmercaptocinnamic acid (63) to 3-methyl-2phenylthiochromone is best conducted with phosphorus pentoxide; with polyphosphoric acid, isomerization of the acid can occur, resulting in the formation of mixed products.61 Thio- and seleno-chromones of type (64; X = S or Se) are obtained from thio- or seleno-phenols and ethyl

malonate by the action of polyphosphoric acid; the reactions do not apparently involve 4-hydroxythiocoumarin or the selenocoumarin as intermediates.62 Polyphosphoric acid has also been used to bring about condensations between 2,4-disubstituted thiophenols and a-acetamido-/?keto-esters, which yield 3-acetamidothiochromones. The products are hydrolysed with ethanolic hydrochloric acid to 3-aminothiochromone hydrochlorides.63 Rates of hydrogen exchange at various positions in the thiochromone ring have been compared with those for chromone and other 7 Thio- and Seleno-coumarins The original method for the preparation of thiocoumarin, from o-mercaptocinnamic acid, has been improved by the use of polyphosphoric acid as cyclizing agentYe5 and new routes to thio- and seleno-coumarins have been eo

a

N. Bellinger, P. Cagniant, D. Cagniant, and M. Renson, Bull. SOC.chim. France, 1971, 2689; P. Cagniant, N. Bellinger, and D. Cagniant, ibid., p. 2699; Tetrahedron Letters, 1971, 49. K. Buggle, J. J. Delahunty, E. M. Philbin, and N. D. Ryan, J. Chem. SOC.( C ) , 1971, 3168.

62

O3 O4

B5

A. Ruwet, A. Pourveur, and M. Renson, Bull. SOC.chim. belgcs, 1970, 79, 631. F. Bossert, Tetrahedron Letters, 1971, 555. U. Bressel, A. R. Katritzky, and J. R. Lea, J. Chem. SOC.(B), 1971, 11. W. D. Cotterill, C. J. France, R. Livingstone, and J. R. Atkinson, J. C. S. Perkin I, 1972, 817.

538

Organic Compounds af Sulphur, Selenium, and Tellurium

devised, for example, by the oxidation of thio- and seleno-chromenes with chromic oxide in pyridine.6s Known routes to 4-hydroxythiocoumarins and their selenium analogues involve inaccessible starting materials. It has now been shown that these compounds are directly available from thio- or seleno-phenols by condensation with malonic acid, brought about by polyphosphoric Thiocoumarin reacts with phenylmagnesium bromide to give a mixture of 2-phenyl-A2-thiochromeneand thioflavone, the latter product being presumed to arise by oxidation of 4-hydroxy-2-phenyl-A2-chromene, formed via a thiopyrylium cation.66 4-Hydroxythiocoumarin has been acetylated at the 3-position, by treatment with acetic acid and phosphorus oxychloride;reactions of the product with amines and with phenylhydrazine have been studied.68 Merocyanine dyes and g-dimethylaminobenzylidenecompounds derived from 4-hydroxythiocoumarins have been evaluated as optical sensitizer^.^^ 8 2-Thioisocoumarins, Dithioisocoumarins, and Related Compounds An effective synthesis of 3-aryl-l,2-dithioisocoumarinshas been described.'O 3-Aryl-l-thioisocoumarins(65) react with secondary amines to give thioamides (66) which, on treatment with phosphorus pentasulphide, give high yields of the dithioisocoumarins (67). The reactions of these

wAr R,NH

'

\

S (65)

COSAr

PA,,

pA

CS-NR, (66) '

S (67)

products with secondary amines 71 and with h y d r a ~ i n ehave ~ ~ been reviewed.73 3,4-Dihydrodithioisocournarin(68; X = S ) has been prepared, by the action of phosphorus pentasulphide on the isocoumarin (68; X = 0),and its reaction with diazomethane has been

(68) 66

67 68

6s 70 72

73

A. Ruwet, J. Meessen, and M. Renson, Bull. SOC.chim. belges, 1969,78, 459; A. Ruwet and M. Renson, ibid., p. 449. A. Ruwet, C. Dragnet, and M. Renson, Bull. SOC.chim. belges, 1970, 79, 639. W. Asker, M. H. Elnagdi, and S. M. Fahmy, J. prakt. Chem., 1971,313, 715. P. C. Rath and K. Rajagopal, Indian J. Chem., 1971, 9, 91. L. Legrand and N. Lozac'h, Bull. SOC.chim. France, 1970, 2227. L. Legrand and N. Lozac'h, Bull. SOC.chim. France, 1970, 2233. L. Legrand and N. Lozac'h, Bull. SOC.chim. France, 1970, 2237, 2244. L. Legrand and N. Lozac'h, Znternat. J. Surfur Chem., C, 1971, 6, 65. M. Ebel and L. Legrand, Bull. SOC.chim. France, 1971, 176.


539

Several papers deal with the chemistry of benzo-2H-thiopyrans of general type (69). The photoaddition reaction between thiobenzophenone and methoxyallene gives a mixture of a thietan derivative and the thiopyran (70), which rapidly isomerizes at 140 "C to the 2H-thiopyran (71).76 In a similar way, acetylenes add to thiobenzophenone to give products formulated as (72; R = Ph, C02H, or CH20H).7s Enamines of type (73) are converted thermally into benzo[c]thiophens (isothionaphthenes) (74), which form adducts with N-phenylmaleimide,77 H

I

PhzC=S

MeOCH=C=CH, hu

>

Ph

Ph

K

The 2H-thiopyran (75) undergoes a disproportionation reaction, when treated with perchloric acid, to give a mixture of the corresponding thiopyrylium salt (76) and the reduced compound (77) with a cis ring junction,'8 the reaction being similar to those described previously for ha-thiochromenes 28 and possibly involving a bridged sulphonium ion. 76 76

H. J. T. Bos, H. Schinkel, and Th. C. M. Wijsman, Tetrahedron Letters, 1971, 3905. A. Ohno, T. Koizumi, Y. Ohnishi, and G. Tsuchihashi, Tetrahedron Letters, 1970, 2025.

77 78

F. H. M. Deckers, W. N. Speckamp, and H. 0. Huisman, Chem. Comm.,1970, 1521. E. R. de Waard, W. J. Vloon, and H. 0. Huisman, Chem. Comm., 1970 841.

Organic Compounds of Sulphur, Selenium, and Tellurium Intermediates of type (69) are formed in a synthesis of benzothiopyrylium salts (79) via the cyclic ketones (78),79 and a similar route has been used in the preparation of the 2H-thiopyrans (80; R1 = H, R2 = Me) and (80; R1 = Me, R2 = H), which are reduced stereospecifically to the 540

n

HCI04

c104-

Me0

Me0 (75)

Me0 (77)

Yc+

c'04-

R=s+\

ClO,

cis-compounds (81).s0 Studies of the epimerization reactions (at C-1) in the corresponding sulphones suggested that the heterocyclic rings in these compounds exist in boat forms, a conclusion that was shown to be correct for one of the sulphones by an X-ray-crystallographic study. The cyano-compound (82; R = H) condenses with formaldehyde to give the alcohol (82; R = CH,OH), from which a series of acyl and other derivatives has been made.81 79

81

G. Canalini, I. Degani, and R. Fochi, Ann. Chim. (Italy), 1971, 61, 504 (Chem. A h . , 1972, 76, 25 002). D. A. Pulman and D. A. Whiting, Chem. Comm., 1971, 831. H. Bohme and K. Lindenberg, Arch. Pharm., 1970,303, 229.

541

Thiopyruns and Related Compounds

Q s R CN 9 Thioxanthones, Selenoxanthones, and Related Compounds Thioxanthones (83; X = S, R = CO*Meor NH2) have been synthesized by cyclization of appropriate thiosalicylic acid derivatives.82 Selenoxanthone (83; X = Se, R = H), prepared from the acid chloride (84) by 0

(83)

(84)

reaction with benzene in the presence of aluminium chloride, reacts normally with sodium borohydride and with Grignard reagents; the products can be converted into variously substituted selenoxanthylium salts and selenoxanthenes.8a Thioxanthenes with basic side-chains have been prepared for pharmacological e v a l ~ a t i o n85, ~and ~ ~ a series of O-alkyl, O-acyl, and O-carbamoyl derivatives of thioxanthydrol have been described.8s It has been shown that the product obtained by the action of phosphorus pentachloride on thioxanthone is the thioxanthylium salt (85).87 Reduction of thioxanthylium perchlorate with zinc (in the absence of oxygen) gives the bimolecular product (86), but with 9-phenylthioxanthyliumperchlorate

orcr 4

82

N. Raseanu, Rev. Chim. (Roumania), 1969, 20, 659 (Chem. Abs., 1970, 73, 3752); G. Vasiliu and N. Raseanu, An. Univ. Bucuresti Chim., 1970,19,87 (Chem. Abs., 1971, 75, 140638).

88

M. Renson and L. Christiaens, Bull. SOC.chim. belges, 1970, 79, 511.

84

K.Pelz, E. Svatek, J. Metysova, F. Hradil, and M. Protiva, CON.Czech. Chem. Comm.,

86

I. D. Tsvetkova, E. K. Orlova, and V. A. Zagorevskii, Khim. Farm. Zhur., 1969, 3, 17 (Chem. Abs., 1970,72, 10 435). L. Capuano and R. Zander, Chem. Ber., 1971,104,2212; L. Capuano, R. Zander, and A. Bolourtschi, ibid., p. 3750. R. C. Duty and R. E. Hallstein, J. Org. Chem., 1970, 35, 4226.

1970,35, 2623.

87

542


a dimeric product is obtained which is believed to be linked through the two sulphur atoms.88 Other papers on thioxanthene derivatives deal with the methylation, on sulphur and sulphoxide-oxygen respectively, of thioxanthene and thioxanthone s ~ l p h o x i d e ,the ~ ~ Beckmann rearrangement of thioxanthone o~ime,~O and the quantitative reduction of thioxanthene sulphoxide to thioxanthene with sodium borohydride-cobalt chloride, a reagent which appears to be of fairly general appli~ability.~~ 10 peri-Fused Naphthothiopyrans The preparation of the thiopyran (87; X = S) and the selenopyran (87; X = Se), from 1,8-bisbromornethylnaphthalene and sodium sulphide or selenide, requires strictly anhydrous conditions. Since the hetero-rings in 0

CHO CH,.R I

I

(89)

these compounds are presumably non-planar, the appearance of the methylene proton signals as singlets in the n.m.r. spectra implies rapid oscillation of the hetero-atom about the plane of the naphthalene ring.g2 Sensitized photolysis of a mixture of the stereoisomers represented by structure (88; R = OMe) leads to the desulphurized product (89; R = OMe), and similar ring-opening reactions have been observed with compounds (88; R = Et or Ph). The action of acetyl chloride on the thiopyran sulphoxide (87; X = SO) gives an unstable a-chloro-sulphide,which reacts with methanol to give the precursor of compounds (88; R = OMe).Q3The sulphone (87; X = SO2) is thermally and photochemically stable but the corresponding a,d-diphenyl derivative readily loses sulphur dioxide on irradiation, giving compound (90); in the presence of oxygen, the dehydrocompound is also

(90) C. C. Price, M. Siskin, and C. K. Miao, J. Org. Chim., 1971, 36, 794. R. M. Acheson and J. K. Stubbs, J. C. S. Perkin I, 1972, 899. P. Catsoulacos, Chim. Ther., 1970, 5,401 (Chem. A h . , 1971,74, 125341). D. W. Chasar, J. Org. Chem., 1971,36, 613. A. Biezais-Zirnis and A. Fredga, Acta Chem. Scund., 1971, 25, 1171. A. G. Schultz and R. H. Schlessinger, Chem. Comm., 1970, 1051. P. M. Weintraub, Chem. and Ind., 1970, 1296.


543

11 Complex Thiopyran and Selenopyran Derivatives

Work on thienothiopyransof various types continues. Syntheses have been reported for the following compounds: (91),”*28 (92; R = H or Me) and dihydro- derivative^,^^ (93) and (94),g7(95; X = S or Se),08 (96; R = H or Me),00 (97),loo (98) and (99),lo1 and the bisbenzothienothiopyrylium salt (100).102

Me

& ‘s s

1

Me Me (9.7)

(94)

L. Brandsma and D. Schuijl-Laros, Rec. Truu. chim., 1970, 89, 110. P. Cagniant, Compt. rend., 1970, 271, C, 852. B7 J. F. Muller, D. Cagniant, and P. Cagniant, Tetrahedron Letters, 1972, 81. P. Cagniant, G. Kirsch, and M. Renson, Compt. rend., 1971, 272, C, 1363. O D P. Cagniant, Compt. rend., 1970, 271, C, 1086. l o o S. H. Wilen, G. J. Douma, and H. Wynberg, Rec. Trau. chim., 1970, 89, 980. l o r A. Ricci, D. Balucani, C. Rossi, and A. Croisy, Boll. x i . Fac. Chirn. ind. Bologna, 1969,27, 279 (Chem. Abs., 1970, 72, 111 328). lo* M. Ahmed, J. Ashby, and 0. Meth-Cohn, Chem. Comm., 1970, 1094. OK

544


Some thiopyrano[4,3-b]benzofuranshave been described lo3and numerous systems with nitrogen-containingfused rings have been reported, including the indole derivatives (101) and (102),lo4(103) and (1O4),lo5and (105),lo6 other structures incorporating dihydropyridone (106) lo‘ and pyrazole (107) lo8rings, and more complex systems, for example (1O8).lo9

R3

@ J-f c1 ;-

0

H

Yh

0

109

104 106

106 107

108

L. M. Sharkova, L. A. Aksanova, N. F. Kucherova, and V. A. Zagorevskii, Khim. geterotsikl. Soedinenii, 1971, 7, 762 (Chem. Abs., 1972, 76, 25 138). J. Bourdais, Tetrahedron Letters, 1970, 2895. L. N. Borisova, N. F. Kucherova, and V. A. Zagorevskii, Khim. geterotsikl. Soedinenii, 1970, 935 (Chem. Abs., 1971,74, 13035). N. P. Buu-Hoi, A. Croisy, P. Jacquignon, M. Renson, and A. Ruwet, J. Chem. SOC. ( C ) , 1970, 1058. J. L. Huppatz and R. M. J. Moore, Austral. J . Chem., 1971, 24, 405. G. Pagani and S. Maiorana, Chimica e Industria, 1971,53, 469 (Chem. Abs., 1971,75, 48 829).

109

J. A. VanAllan, C. C. Petropoulos, G. A. Reynolds, and D. P. Maier, J. Heterocyclic Chem., 1970, 7, 1363.

Thiepins and Dithiins BY D. H. REID

1 Thiepins A comprehensive review of thiepins and thiepin oxides has appeared recent1y.l Recent calculations predict thiepin to be antiaromatic and, indeed, this compound has not yet been synthesized. Previous studies have shown that CH,CO,Me CH,C02Mc \i

\ iii

/i

L

Reagents: i, NaH-glyme; ii, N-phenylmaleimide, 120 "C; iii, MeMgBr; iv, N-phenyImaleimideCH&l,, 25 "C

Scheme 1 (4) a

U. Eisner and T. Krishnamurthy, Internat. J . Sulfur Chem., 1971, 6, 267. M. J. S. Dewar and N. Trinajstic, J. Amer. Chem. SOC.,1970, 92, 1453.

19

545

546


annelated thiepins extrude sulphur readily, presumably by valence isomerization into a benzene sulphide followed by cheletropic elimination of sulphur. A stable thiepin (4), not owing its stability to conjugation, has now been synthesized by employing steric effects to prevent valence isomerization (Scheme 1). The thiepin (1) suffers ready sulphur extrusion during reaction with N-phenylmaleimide giving a mixture of the exo-adduct (2) (shown) and the corresponding endo-adduct. In contrast, reaction of the ditertiary alcohol (3) with the same dienophile gave the thiepin endo-adduct (4) alone, which was stable up to 180 "C. The thiepin ring proton of the adduct (4) resonates at higher field (66.50 p.p.m.) than that of its precursor

0

.,...(

.. 0-

--..-,{ 0

0

(7) ex0

+ endo

+

Reagents : i, Maleic anhydride-C,H,, iii, MeOH; iv, CH,N,

(9) exo endo 25 "C; ii, DDQ-benzene, room temperature;

Scheme 2 3

J. M. Hoffmann and R. H. Schlessinger,J . Amer. Chem. SOC.,1970, 92, 5263.

Thiepins and Dit hiins 547 (3) (86.80p.p.m.); this was taken as indicative of the presence of a paramagnetic ring-current. The thia[l llannulene ( 5 ) reacts with maleic anhydride at room temperature to give the dihydrothiepin (7) as a 2 : 1 mixture of the exo- and endoadducts (Scheme 2).* The intermediate adduct (6) (exo- and endo-mixture) was not isolated but its presence was demonstrated by lH n.m.1. spectroscopy. Dehydrogenation of the dihydrothiepin (7) was accompanied by sulphur extrusion and led eventually to the ester (9). The presence of the thiepin (8) as an intermediate was presumed on the basis of indirect evidence. The synthesis of a 2,7-bridged 2,7-dihydrothiepin (11) and some of its transformations are reported briefly (Scheme 3). Thermal cycloaddition

(=J +

(=so

(13) Reagents: i, xylene, 140 O C ; ii, hv; iii, LiAlH,; ivyhv, visible, ether; v, heat

Scheme 3

of sulphur monoxide, produced in situ by thermolysis of ethylene sulphoxide, to cyclo-octatetraene gives the sulphoxide (10) which reverts to cyclooctatetraene when irradiated. Benzophenone-sensitized irradiation of the 4 8 6

A. B. Holmes and F. Sondheimer, Chem. Comm., 1971, 1434. A. G. Anastassiou and B. Y. Chao, Chem. Comm., 1971,979. A. G. Anastassiou and B. Y. Chao, Chem. Comm., 1972,277.

548 Organic Compounds of Sulphur, Selenium, and Tellurium thiepin (1 1) leads to 9-thiabarbaralene (13) via cyclo-octatetraene sulphide (12). Two preliminary communications describe the reaction of sulphur dioxide with vinyldiazomethane, which gives 4,s-dihydrothiepin 1,l-dioxide (16) (Scheme 4). Initial formation of the sulphone (14) is postulated. 79

Reagents: i, KOBd; ii, Et,N; iii, NBS

Scheme 4

Further reaction with vinyldiazomethane gives the thiiran 1,1-dioxide (15 ) which undergoes a rapid Cope rearrangement leading to the product (16). Base-catalysed rearrangement of the sulphone (16) gives the isomer (1 whereas bromination-dehydrobromination leads to thiepin 1,l-dioxide (1 8). Carbon-carbon bond cleavage in the Cope rearrangement of the intermediate (15) competes successfully with the customarily observed fragmentation (C-S bond rupture) of thiiran 1,l -dioxides, which 7),79

W. L. Mock, Chem. Comm.,1970, 1254. L. A. Paquette and S. Maiorano, Chem. Comm.,1971,313.

549

Thiepins and D it hiins

Me

Me Me

Me

(24)

7 f‘JyJ -s

-m +

FHO

CH=NH2

/

‘

s

’

550


normally occurs readily at 25-50 "C with expulsion of sulphur dioxide and alkene formation. In a similar manner 1-diazobut-Zene gaves the sulphone (19) and thence by base-catalysed isomerization the isomer (20). Extension* of this work to the reaction of vinyldiazomethane with preformed benzylidene sulphone led to the benzothiepin 1,l-dioxide derivative (21). The aziridine (23), which results from reduction of the oxime (22) with LiAlH4, gives dibenzo[b,f]thiepin (24) when treated with nitrous acid or when reduced catalytically (Pd-C), and with aqueous acid undergoes ringcontraction to the aldehyde (25) as shown.@ A large number of dibenzo[b,f]thiepins, exemplified by structures (26)-(29), and a dibenzoselenepin (29; Se for S), have been prepared by

(26) R = H,n = 2 R = C1,n = 3

NMe,. (27) R = H , n = 2 RE:C1,n == 3

g Me

R = Me (32) R = HO(CH& (31) J. Fauchk, Bull. SOC.chim. France, 1970, 1376.

Thiep ins and D ithiins

55 1

standard procedures.l0P l1 The benzo[b]thieno[f]thiepin derivatives (3 1) and (32) were obtained by reaction of the thiepinone (30) with the appropriate amines in benzene in the presence of titanium tetrachloride.12 2 Dithiins calculations support the 1,Zdithiin structure 1,2-Dithiins.-PPP-HMO (33) rather than the valence-tautomeric bis-thioaldehyde structure (34).13 The calculated ~ - 7 r * transition for 1,Zdithiin (439nm) compares well with the experimental value (451 nm, cyclohexane). Transitions calculated for structure (34)are 376 (n-n*)and 762 (weak, n-n*) nm.

J. 0. Jilek, K. Sindeliif, J. MetySova, J. MetyS, J. PomykiEek, and M. Protiva, Coll. Czech. Chem. Comm., 1970,35, 3721. J. 0. Jflek, J. PornykBZek, J. MetySova, and M. Protiva, Coll. Czech. Chem. Comm. 1971,36,2226.

K. SindelaE, J. MetySova, and M. Protiva, Coll. Czech. Chem. Comm., 1971, 36, 3404. J. Fabian, R. Borsdorf, H. Hofmann, H. Kohler, and M. Scholz, Tetrahedron, 1970, 26, 3227.

552 Organic Compounds of Sulphur, Selenium, and Tellurium 1,4-Dithiins and l,CDiselenins.-1,4-Dithiins (36) are among the photolysis products of biaryl- and benzo-1,2,3-thiadiazoles.14 The postulated intermediate biradicals (35) dimerize in the direction shown. Thermolysis of cycloalkeno-l,2,3-~elenadiazoles produces 1,4-diselenins (37) together with cycloalkynes.l5 A structure determination l6$ l7 of 2,5-diphenyl-l,4-dithiin 1-oxide reveals a boat-shaped configuration (Figure) with the sulphur 1.476 1

Ph Figure Bond lengths (A) in 2,S-d@henyZ-l,Cdithiin l-oxide

atom at the apex of a slightly distorted pyramid. The two bonds to unoxidized sulphur are distinctly shorter than those to the sulphoxide grOUP. 1,4-Dithiin (38) and its 2,3-dihydro-derivative (39) undergo S-ethylation with triethyloxonium fluoroborate giving the sulphonium salts (40) and

(38) (39) (41), respectively.l* An alternative representation of the 1-ethyl-l,4dithiinium cation is structure (42) involving drr-p.rr overlap and valenceshell expansion at sulphur with formation of a welectron sextet. Comparison + J = 10H~ J = 10H~

..

g"> y:

68.03

(43) l4 15

l6 l7

(44)

K. Zeller, H. Meier, and E. Muller, Tetrahedron Letters, 1971, 537. H. Meier and E. Voight, Tetrahedron, 1972, 28, 187. G. Bandoli, D. A. Clemente, C. Panattoni, A. Dondoni, and A. Mangini, Chem. Comm., 1970, 1143. G. Bandoli, C. Panattoni, D. A. Clemente, E. Tondello, A. Dondoni, and A. Mangini, J. Chem. SOC.(B), 1971, 1407. W. Schroth and M. Hassfeld, 2.Chem., 1970, 10, 296.

553

Thiepins and Dithiins

of the lH n.m.r. spectra of the salts (40) and (41) reveals insignificant differences in chemical shifts of corresponding protons [chemical shifts (8 p.p.m.) and coupling constants are appended to formulae (40) and (41)], whence it is concluded that there is no diamagnetic ring-current and hence no aromaticity in the l-ethyl-1,4-dithiiniurn cation. S-Ethylation of the ring homologues (43) and (44) was also carried out. The highest occupied MO of 1,4-dithiins is only weakly bonding and these compounds accordingly undergo ready oxidation to cation-radicals. In spite of charge repulsion it appeared possible to prepare dications by loss of two electrons by virtue of the resulting six-.rr-electron aromaticity. Electrochemical oxidation studies bear this 0 ~ t . l ~ Current-potential curves show two steps corresponding to the successive loss of two electrons. Half-wave potentials for the two steps are given for a series of compounds. For example, Ei (V) for 1,4-dithiin (38) are + 0.69 (1 electron) and + 1.16 (2 electrons). In agreement with the results of electrochemical studies, tetraphenyl- 1,4-dithiin reacted with antimony pentachloride by electron transfer to form violet salts. Depending on the molar ratio of the reactants, both the cation-radical (45) and the dication salt (46) could be isolated.

+*

SbClo-

+

2SbC1,

Empirical resonance-integral parameters have been derived for C-S n-bonds in tetracyano-l,4-di thiin (47) and thianthrene.20 Dithiin (47) undergoes ready aminolysis with secondary amines giving salts (48) which,

CN

CN

(47)

l9 SO

W. Schroth, R. Borsdorf, R. Herzschuh, and J. Seidler, Z . Chem., 1970, 10, 147. G. Haefliger, Tetrahedron, 1971, 27, 1635.

554 Organic Compounds of Sulphur, Selenium, and Tellurium when methylated, afford compounds (49) and, when oxidized with hydrogen peroxide, are partially desulphurized to the sulphides (50).21 Benzo- and Dibenzo-1,Cdithiins.-The benzo-l,4-dithiins (51) and (52), when oxidized with hydrogen peroxide, give mono-S-oxides (53) and (54) which on further oxidation are partially desulpburized to compound (55).22

.&t,.. 0

Me \

CN

RO (53) R = H

RO (51) (52)

R R

= =

CN

H Me

(54)

R

0

CN 0 (55)

1 0

R = Me or OMe

osyJ \

6

/

R

21

22

(58) K. Fickentscher and H. Fehlhaber, Annulen, 1970, 736, 176. K. Fickentscher, Chern. Ber., 1970, 103, 3000.

=

Me

Thiepins and Dithiins 555 The thianthrene cation-radical (56) shows enhanced stability in trifluoroacetic acid, which is recommended generally as a solvent in which to prepare cation-radical~.~~ Thianthrenium perchlorate (56; Clod as counter-ion) reacts 24 with substituted benzenes PhR at the para position, rapidly where R = MeO, more slowly where R = Me. The product is a sulphonium salt (58). Kinetic studies show that the reaction is secondorder in the thianthrene cation-radical (56). The suggested mechanism features the thianthrene dication (57) as the reactive species, formed in low concentration by disproportionation of the thianthrene cation-radical. Is

0. Hammerich, N. S. Moe, and V. D . Parker, Chem. Comm.,1972, 156. J. J. Silber and H.J. Shine, J. Org. Chem., 1971, 36, 2923.

12 lsothiazoles BY

F. KURZER

1 Introduction The increasing interest in the chemistry of isothiazoles is reflected in the considerable and diverse progress reported in this field during the past two years. Several new or modified syntheses of this ring system have been described, physical properties have been determined in considerable detail, and several novel reactions have been encountered. Careful studies of the fragmentation pattern of this system and of its i.r. spectra have appeared. An increasing variety of condensed polycyclic ring systems incorporating isothiazole are being reported.

2 Synthesis A sufficient number of syntheses of isothiazoles have now been described to make their formal classification desirable. They may be conveniently arranged, as in the case of other heterocyclics, according to the nature of the fragments from which the ring system is constructed. Although the isothiazole nucleus may be built up in numerous ways, the syntheses reported in the present section fall into the following three categories:

c-c I N

S

I C

Type A

c c I 'N--S c Type B

c-c I N

I

Type c

When the isothiazole arises from another ring system, the synthesis is classified according to the linear intermediates that are most likely concerned in the final ring closure. It will be noticed that the majority of syntheses reported are of Type C, i.e. the route by which isothiazole was first obtained. From a-Amino-ketones or P-Cyano-enamines and Sulphur Chlorides (Type A).-a-Amino-ketones, readily accessible from amino-acids and acid anhydrides by the method of Dakin and West,l are a convenient source of isothiazoles.2 l-Amino-l-phenylbutan-2-one (l), for example, is converted a

H. D. Dakin and R. West, J. Biol. Chem., 1928,78,91; R. H. Wiley and 0. H. Borum, Org. Synth., Coll. Vol. IVYWiley, New York, 1963, p. 5 . T. Naito, S. Nakagawa, J. Okumura, K. Takahashi, and K. Kasai, Bull. Chem. SOC. Japan, 1968, 41, 959.

556

557

lsothiazoles

by the action of thionyl chloride in pyridine or of sulphur monochloride at low temperatures into the heterocyclics (2; R = Me). At higher temperatures, the 5-formyl compound (3) becomes the main product (34%). The action of sulphur monochloride on the acetylated a-aminoketone (4) produces the same isothiazole (2; R = Me, 17%), with Ph-CH-C=O

I

Ph

Ph-CH-C=O

I I McCONH Et

I

\

OH

NQHO

r(

p"l'?JR "S

(3)

(2)

/

R

(4)

\

y-iJPh

Me 0 Et

= H or Me

(5)

SOCI,

S2CI2

p;g;;

Ph-CH-C=O

Ph-CK-C=O 1 1 NHZ CH,

(6)

S,ClS

I

I

MeCONH CH3

(7)

(8)

simultaneous deacylation, but thionyl chloride gives rise to 5-ethyl-2methyl-4-phenyloxazole (5). The latter cyclization (to 2,4,5-trimethyloxazole) has previously been r e p ~ r t e d . ~ 1-Amino-1-phenylpropan-Zone (6) and its N-acetyl derivative (8) produce the expected 4-halogeno- (7) or 4-hydroxy-isothiazoles [e.g. (2; R = H)].2 The comparable cyclization of p-cyano-enamines provides 3- and/or 5-alkyl-(or aryl-)substituted 4-cyanoisothia~oles.~ The starting materials (9) are synthesized by the condensation6 of the appropriate nitriles and form equilibrium mixtures of p-cyano-enamine (9a) and 13-iminonitrile (9b). Their interaction with thionyl chloride or sulphur monochloride in non-polar solvents affords a selection of 4-cyanoisothiazoles [e.g. (1 O)] analogous to the above 4-hydroxy-compounds, though generally in lower yields. They are readily hydrolysed to the corresponding carboxylic acids (1 l).4 The spectral data of all new compounds contributed substantially to the assignment of the s t r ~ c t u r e s . ~ In a further extension of this work,6 benzylidenemalononitriles (12) are condensed with sulphur chlorides or thionyl chloride to 5-aryl-3-chloro-4isothiazolecarbonitriles (13). Acrylonitrile and crotononitrile yield 3,4,5trichloro- and 3,4-dichloro-5-methylisothiazole, respectively, whereas ethyl 8

6

A. Treibs and W. Suter, Chem. Ber., 1951, 84, 96. T. Naito, S. Nakagawa, J. Okumura, K. Takahashi, K. Masuko, and Y. Narita, Bull, Chem. SOC.Japan, 1968, 41, 965. H. Baron, F. G. P. Pemery, and J. F. Thorpe, J. Chem. SOC.,1904,1726; G . A. Reynolds, W. H. Humphlett, F. W. Swamer, and C. R. Hauser, J. Org. Chem., 1951, 16, 165. S. Nakagawa, J. Okumura, F. Sakai, H. Hoshi, and T. Naito, Tetrahedron Letters, 1970, 3719.


558

Rl-C=C--CN

I

I

HZN CHzR2

R’CN

+R1li; “s

(94

+ R2CHzCHzCN

(10)

CN

/

ArCH=C,

or SOCI,

CN

’

(16)

(1 5)

(14)

benzylidenecyanoacetate (15) produces 3-chlorobenzo[b]thiophen-2-carbonitrile (14) in addition to the expected isothiazole (16).

From Oxathiazolones (Type B).-3-Phenyl- 1,2,4-oxathiazol-5-one (17) is decomposed thermally to benzonitrile and sulphur, but condenses with activated dipolarophiles to yield 1,3-dipolar adducts that may arise from the intermediate benzonitrile sulphide (18). Thus, interaction of the oxathiazolone (17) and dimethyl acetylenedicarboxylate in chlorobenzene at 130 “C produces dimethyl 3-phenylisothiazole-4,5-dicarboxylate(19) in excellent yield. The use of ethyl propiolate (HC=CCO,Et) similarly affords the expected isomeric esters (20) and (21), each in 35% yield.’ The C.CO,Me

*.,

(17)

I

COz 3- S

,=**

s (18)

Y.=*=*

+ PhCN

N,

(20) 7

J. E. Franz and L. L.Black, Tetrahedron Letters, 1970, 1381.

(21)

Zso thiazoles

559

reaction resembles the formation of the analogous isoxazoles from benzonitrile oxide * and promises to be of wide applicability.

From Chlorosulphonyl Isothiocyanates and Olefins (Type B).-The interaction of chlorosulphonyl isothiocyanate and olefins may yield either linear products Bs lo or isothiazolidine derivatives.B Both arise in homolytic reactions, the course of which may be controlled by a proper choice of conditions.# Thus, introduction of ethylene, together with catalytic quantities of a peroxide, into the isothiocyanate (22) results in high yields of the appropriate chloroalkanesulphonyl isocyanate (25) by the freeradical mechanism outlined in Scheme 1 [(22)-(25)]. In contrast, the use of an excess of olefin, preferably in an inert solvent, in the presence of U.V. light, results in N-(/3-chloroalkyl) derivatives (28) of 3-oxoisothiazolidine 1,l-dioxide. The essential processes involved are 1,3-~ycloadditionof the olefin to (22), bridging the two electrophilic centres (C and S) of the sulphonylisocyanate group, and addition of a second molecule of olefin at the nitrogen of the radical (26). The proposed mechanism (see Scheme 1) is supported by the demonstrated existence of the intermediate nitrogen

lo

R. Huisgen, J. Org. Chem., 1968, 33, 2291. D. Gunther and F. Soldan, Chem. Ber., 1970, 103, 663. R. Graf, Angew. Chem., 1968, 80, 179, (Angew. Chem. Internat. Edn, 1968,7, 172).


560

radical (26) which may be trapped, in the presence of cyclohexane, as (29) [and isolated as (30)]. The use of higher olefins affords substituted heterocycles (31) of this seriesg

From 3,3’-Dithiodipropionamides (Type C).-3-Hydroxyisothiazole (34; R1 = R2 = H), its 4-methyl homologue (34; R1 = H, R2 = Me), and an extensive series of 2-substituted 4-isothiazolin-3-ones (34; R1 # H) are R2

-f SCH2CH.C .NHR1)2

II 0 (32)

(35)

-

R2 c1, C1 R2 - HCI R2 CIS *CH2CHC*NHR1+CIS.CHCHC*NHR1 CIS-CH=C.C*NHRI II II II 0 0 0

I

J (33)

(34)

obtained in high yield by a simple and convenient synthesis involving the cyclization of the readily accessible 3,3’-dithiodipropionamides (32) by chlorine or sulphuryl chloride.ll If the well-established chlorinolysis of dialkyl disulphides to sulphenyl halides be accepted as the initial step of the synthesis, a probable mechanism is indicated in the reaction scheme. 5-Chloro-4-isothiazolin-3-ones (33, formed as by-product in a number of examples, may become the main products under appropriate conditions.ll Detailed experiments carried out with 3,3’-di thi odipropionami de (32 ; R2 = H) and mercaptopropionamide (HSCH,CH,CONH,) have established the precise conditions (temperature, concentration, molar proportion of chlorine, etc.) for the preferential formation of 3-hydroxyisothiazole or its 5-chloro- or 4,5-dichloro-deri~atives.~~ The use of 3,3’-dithiopropionamidine or the corresponding methyl imidate hydrochlorides as starting material similarly furnishes 3-amino- or 3-metho~y-isothiazole.~~

From Phenylcysteine (Type C).-4-Amino-3-isothiazolidinone 1 , l -dioxides l3 are of interest because they may be looked upon as a-amino-acids in which 11

S. N. Lewis, G. A. Miller, M. Hausman, and E. C. Szamborski, J. Heterocyclic Chem.,

l*

1971, 8, 571; G. A. Miller and M. Hausman, ibid., p. 657. G. A. Miller, E. D. Weiler, and M. Hausman, J. Hererocyclic Chem., 1971, 8, 581. J. C. Howard, J. Org. Chem., 1971, 36, 1073.

l3

Is0thiazoles

561

the acdic function is the N-sulphonylcarboxamide group. The parent compcund (36) has been known for some time.ld Further examples have now been synthesized l3 from NS-diacetyl-evythro-3-phenylcysteineethyl ester (37) by successive chlorination, ammonolysis of the resulting crude sulphonyl chloride, and acidification. This reaction sequence produces a mixiure of the trans- (38) and cis- (39) isomers of 4-acetamido-5-phenyl3-isothiazolidinone 1, l-dioxide, which may be separated by fractional cry~tal1ization.l~ Onattempted acetylation, either isomer [(38) or (39)] reacts with extrusion of the elements of aminosulphurous acid (NH,S02H), yielding 4-benzylidene~2-methyl-2-oxazolin-5-one (42). Since acetylation is a demonstrably necessary step in this elimination-rearrangement process, the latter is interpreted to involve acetylation of the ring-nitrogen, followed by nucleophilic attack by the oxygen of the 4-acetamido-group and a base-catalysed elimination of acetamidosulphurous acid (Scheme 2) [(40) + (41) + (42)].13

SCOMe

- ~5 NHCOMe

Ph

I

PhCH-CH-NHCOMc I COOEt

threc stages

0

2

\N

0

H (39)

(37) erylhro

H

d

C'$O,NHCOM~ PhCH

0

HI Ph-C

0

COMe

(40)

(41)

(42)

Scheme 2

From Vilsmeier Salts (Type C).-The Vilsmeier-Haak reaction has been applied to the synthesis of 2- (or 5-)substituted 4-cyanoisothiazoles (45). Thus, condensation of a Vilsmeier salt prepared from phosphorus oxyl4

H. Baganz and G.Dransch, Chem. Ber., 1960,93,784.

Organic Compounds of Sulphur, Selenium, and Tedurium

562

R2-C=CH-CN I

H2N

(43)

R1 = H,Me,or Ph R2 = Me or 3h

(44a)

X

=

NMe,

(44b) X = SH

(451

Isothimoles 563 chloride and dimethylformamide with an enaminonitrile [e.g.(43 ;R2= Ph)] results in intermediates, which, though not isolated, are regarded as dichlorophosphoric acid salts of (44a). Subsequent treatment, in situ, with sodium hydrosulphide, followed by oxidation of the thioaldehyde (44b) with iodine, affords the isothiazole (45; R1 = H, R2 = Ph; 14%). By adding the phosphorus oxychloride directly to a mixture of the enamine and dimethylformamide, yields are greatly improved (60%). Dimethylacetamide or -benzamide similarly give rise to the 3-substituted analogues (45; R1 = Me or Ph). In the latter example, however, preferential acylation of the enamine by the Vilsmeier reagent at the nitrogen rather than at carbon yields the intermediate salt (46), which cyclizes to the pyrimidine (47), and the expected isothiazole becomes the minor product.lS From 1,2-Dithiolans (Type C).-Primary aliphatic amines cleave the heterocyclic ring of 4-aryl-3-methylthio-1,Zdithiolylium iodides (48) by nucleophilic attack at the 5-positionY yielding methyl 3-alkylamino-2arylpropenedithioates (49) exclusively. In the same reaction, their 5-aryl analogues (50) produce, in addition to methyl 3-alkylamino-3-arylpropenedithioates ( 5 l), moderate yields of 2-alkyl-5-aryl-3-isothiazolinethiones (52). Owing to the basicity of the environment, appreciable quantities of 5-aryllY2-dithiolan-3-thione(54) are regenerated in each case.lS The synthesis resembles the conversion of 3-phenyl-1,2-dithiolyliumperchlorate (55) into 5-phenylisothiazole (56) by the action of amm0nia.l' This reaction was in fact used for confirming the structure of (52) by an alternative synthesis comprising the sequence (55) -+ (56) -+ (57) + (52a). Isothiazoliurn salts of type (53) are obtainable by further alkylation.le Another example of this reaction is the action of ammonia on 4 3 dimethyl-3-thiono-dithiolyliumperchlorate in anhydrous ethanol, which yields a mixture of 3,4- and (mainly) 4,5-dimethylisothiazole, possibly by the mechanism shown in Scheme 3.lS

From Thiazo1es.-Isothiazoles are formed in the photoisomerization of thiazoles. Irradiation of 2,5-diphenylthiazole in benzene affords 3,4diphenylisothiazole (32%), together with 4,5-diphenylthiazole (8%) and phenanthro[9,10-dJthiazole (8%). 2,4-Diphenylisothiazole similarly produces minor quantities (3%) of 3,5-diphenylisothiazole.1eAmongst possible mechanisms of this photorearrangement, the formation of bicyclic intermediates such as (58) or (59), or tricyclic sulphonium cations [(60) or (61)J, was ~0nsidered.l~ l6

l6 l7

l8 l9

R. R. Crenshaw and R. A. Partyka, J. Heterocyclic Chem., 1970, 7 , 871. G. Le Coustumer and Y. Mollier, Compt. rend., 1970, 270, C, 433; BUZZ. SOC.chim. France, 1970, 3076. R. A. Olofson, J. M. Landesberg, R. 0. Berry, D. Leaver, W. A. H. Robertson, and D. M. McKinnon, Tetrahedron, 1966, 22, 2119. J. C. Poite, A. Perichaut, and J. Roggero, Compt. rend., 1970, 270, C,1677. M. Kojima and M. Maeda, Chem. Comm., 1970, 386.

Organic Compounds of Sulphur, Selenium, and Teluriurn

*-

Me

'Me

Me,\

.Me NHp

'

394

Scheme 3

3 Physical Properties The determination of spectral properties of new and known compounds arising in investigations is performed almost invariably as a matter of course, and is often accompanied by detailed discussion. In the present section only substantial studies devoted exclusively to the determination and interpretation of physical properties are included. Numerical values have been computedz0 for the net charges, free valencies, and radical localization energies of isothiazole and its 3-, 4-, and 5-methyl homologues, employing the HMO method,z1 the procedure of J. C. Poite, G. Vernin, G. Loridan, H. J. M. Dou, and J. Metzger, Bull. SOC.chim. 21

France, 1969, 3912. A. Adams and R. Slack, J. Chem. Soc., 1959, 3061.

Is0 thimoles

565

Pariser, Pople, and Parr, and the w* method.2a As in the case of thiazole, discrepancies are encountered in the comparison of the theoretical and experimental values, when available. The HMO method gives too high figures for the free valency of the position adjacent to nitrogen (i.e. 2- in thiazale and 3- in isothiazole) in comparison with position 5, whereas the morerefined w* method gives values too high for the position adjacent to the sdphur. A very detailed study of the i.r. and Raman spectra of isothiazole has appeared,23 providing reasoned assignments of the observed spectral features. The work included the preparation of 4- and 5-monodeuterioand 4,5-dideuterio-isothiazoles,and their study from this point of view. The analysis of the Raman spectrum of isothiazole required the modification of the assignment of two of the fundamental modes previously given for this parent compound. Not the least useful aspect of this paper is the extensive list of references to the subject which it The mass spectra of a number of isothiazoles have been m a p ~ e d . ~ 4 The fragmentation pattern of the parent compound, shown in Scheme 4,

$4 lflle

58

/ CSH+ m/e 45

\ - C,H,

p? ($

mle 85

-

CS+'

mle 44

CH'

11

Nf 1 I

S

"M"

+S H mle 59 Scheme 4

resembles that of thiazole.26 The base peak is due to the molecular ion, reflecting the general stability of aromatic compounds. Loss of hydrogen cyanide therefrom, a process typical of heterocyclic compounds that are not highly substituted, produces the second most intense peak (m/e 58). Detailed fragmentation patterns were also described for 3-, 4-, and 5-methylisothiazole, 3-methylisothiazole-4-carboxylicacid, and isothiazole3(4, or 5)-carboxamide, as well as some bromo- and amino-derivatives. The accumulated data provide sufficient information to deduce the position of substituents in isothiazoles from their mass 3,4- and 43Dimethylisothiazole show different fragmentation patterns, a methyl group being lost more readily from the latter isomer.18 aa

R. P. T. Luu, L. Boucasse, E. Vincent, and J. Metzger, Bull. SOC.chim. France, 1967, 3274.

as

J. L. Meyer, G. Davidovics, J. Chouteau, J. C. Poite, and J. Roggero, Canad.J. Chem., 1971,49,2256.

a4

B. J. Millard, J . Chem. SOC.(0,1969, 1231. G. M. Clarke, R. Grigg, and D. H. Williams, J. Chem. Soc. (B), 1966, 339.

566

Organic Compounds of Sulphur, Selenium, and Tdluriurn

In another significant investigation 26 the fragmentation of tweny-four substituted 3-phenylisothiazoles and three 3-(halogenophenyl)isothhzoles, including several deuteriated examples, was studied. All spectra indude a prominent molecular ion, as well as diagnostic fragment ions arising from cleavage of the N-S or S-C(5) bonds, elimination of the side-chains, and scission of the phenyl ring. The predominating modes of fission are summarized in Scheme 5. A full discussion and interpretation cf the extensive data are provided.26

(iii)

(iv)

(ii)

M-

(iii)

(ivy

v)

115

103

+ R1

44+R2

Ph-C

II\ N-S+

135

C6H5+C4H3+C4H2+C,H3+ etc. 77 M

51

- R1,M - R2

50

39

etc.

Scheme 5

The occurrence of lactam-lactim tautomerism in 3-hydroxyisothiazoles is revealed by both physico-chemical and chemical methods.27 3-Hydroxyisothiazoles exist as such in non-polar solvents, but the tautorneric isothiazol-3-one predominates in solvents of increasing dielectric constant. This is shown by a comparison of the U.V. spectra of the parent compound (62) and its 5-methyl derivative with those of 3-ethoxyisothiazole (63 ;

7

S /OH

7

S,

/OR

sw T o R

R = Et) and 2-ethylisothiazol-3-one (64; R = Et) in the appropriate The findings are supplemented by acylation and alkylation studies : 3-hydroxyisothiazoleis very rapidly acylated in non-polar solvents by acyl halides in the presence of tertiary bases; the ratio of the products depends on the relative rates of reaction of the two tautomers rather than on their relative proportions. The size of the acyl group and the steric requirements of the catalyst are the critical factors in determining the site of a~ylation.~? 26

T . Naito, Tetrahedron, 1968, 24, 6237. A. W. K.Chan, W. D. Crow, and I. Gosney, Tetrahedron, 1970,26,2497.

Isothia:oIes

567

Of tie potential tautomeric forms of 5-hydroxyisothiazole, the ketonic tautoners predominate in the solid state, as shown by spectral data; the hydroxy-form makes but a small contribution in solution (see ref. 38, below1

4 Chemical Properties

A substantial proportion of recent studies of the chemical behaviour of isothirzoles deals with electrophilic substitutions in this ring system and the further displacement of the groups so introduced by a variety of reactions. The nucleophilic ring-cleavage of isothiazole at its N-S bond has also been further studied, Much of the work described consolidates and extends existing knowledge, but some fresh ground has been broken. Free-radical and Photolytic Reactions.-In the course of their systematic study of the free-radical phenylation in the heterocyclic series, Metzger et d . t 0 have examined the behaviour of isothiazole and its 3-, 4-, and 5-methyl homologues from this point of view. The reaction is induced by benzoyl peroxide in the presence of traces of copper at 110 "C,and the proportion of the resulting phenylated isomers was estimated by gas chromatography. Analysis of the extensive numerical results shows that the radical activity of isothiazole and its homologues exceeds that of thiazole. The observed free-valency distribution and the radical localization energies are similar for the 3- and Spositions in isothiazole; the observations conflict with the theoretical calculations, and are rationalized by introducing suitable corrections. Preliminary observations on the photochemical behaviour of isothiazoles have been briefly reported. The parent base is partially converted into thiazole on irradiation (7% in propylamine, 1% in ether), several unidentified products being formed (15%) side by side.28 3-Phenyl- and 3,5-diphenyl-isothiazole are converted into 4-phenyl- (12%) and 2,4diphenyl-thiazole (48%), respectively, but 5-phenylisothiazole preserves its ring system, merely producing small quantities (2.3%) of the 3-phenyl isomer.2B The reactions are believed20 to proceed by way of tricyclic sulphonium cations of the type previously postulated by Kojima and Maeda.lo It is recalled that the reverse photoisomerization is also on record lo (see syntheses, above). Nitration and Halogenation.4-Phenylisothiazole undergoes electrophilic substitution under mild conditions, predominantly in the benzene ring. a*

J. P. Catteau, A. Lablanche-Combier, and A. Pollet, Chem. Cornm., 1969, 1018. M. Ohashi, A. Iio, and T. Yonezawa, Chem. Comm., 1970, 1148.

568 Organic Compounds of Sulphur, Selenium, and Tdlurium Nitration at 0 "C yields 4-(p-nitrophenyl)isothiazole and its o-iscmer in 85 and 15% yields, respectively; further action produces the 2,4-dinitrophenyl compound. Bromination and chlorosulphonation sinilarly afford chiefly p-substituted products (65; R1 = Br or S0,Cl; R2 = H). Halogenation in glacial acetic acid at 25 "C yields 4-(p-bromophmyl)-5bromoisothiazole as a by-product (up to 20%). The substituent: thus introduced display their usual properties in aromatic Firther examples of halogenations are reported below (see p. 573). In contrast, nitration of 4-substituted 3-phenylisothiazoles (66) a 0 "C yields exclusively 3-(rn-nitrophenyl) derivatives (67). 3-Phenylisothazole itself (66; R1 = R2 = H) produces, under these conditions, 3-(p [and rn-]ni tropheny1)isothiazole (68). The nitro-compounds show the expected behaviour, being reducible to the corresponding amines [e.g. (69)], which

(68) R1 = R2 = H

(66)

(67) R1 = Rr, CN, or CO,.i, R2 = H or Me

in their turn undergo diazotization and the Gatterman-Sandmeyer rea~tion.~' Diazotization.-Goerdeler and Roegler 32 have described diazoniurn salts derived from 3-, 4-, and 5-aminoisothiazoles. By conventional procedures, 3-amino-5-phenylisothiazoleand 4-arninoisothiazole give labile diazonium salts in solution; isolable solid tetrafluoroborates are obtainable by the use of nitrosyl tetrafluoroborate (NOBF,) in glacial acetic-propionic acids at - 40 "C. 5-Amino-3-methyl(or pheny1)-isothiazoles behave similarly, but analogues bearing electron-attracting groups (e.g. CN, CO,Et, or COMe) in their 4-position produce stable nitrosamines. Typical reactions of both diazonium salts and nitrosamines thus obtained were performed, including their conversion into azo-dyes and t r i a z e n e ~ . ~ ~ Additional examples of reactions of this type axe the following:33 80

81

J. H. Finley and G. P. Volpp, J. Heterocyclic Chem., 1969, 6, 841. T. Naito, S. Nakagawa, and K. Takahashi, Chem. and Pharm. Bull. (Japan), 1968, 16, 160.

82

88

J. Goerdeler and M. Roegler, Chem. Ber., 1970, 103, 112. Z. Machon, Diss. Pharm. Pharmacol., 1969,21, 135 (Chem. Abs., 1969, 71, 61 276).

Isothiazoles

Me

569

C0,Et

NYKH,

X

= C1 or

Br

Conversion into 1,2,3-Thiadiazole~.~~ Diazotization of 5-amino-3-methylisothiazole, followed by treatment with aqueous thiourea and oxidation of the intermediate thiol, yields the expected 36 bis-(3-methylisothiazol-5-y1) disulphide. In contrast, 4-amino-3-methylisothiazole (70; R1 = Me, R2 = H) is converted by the same sequence of reactions into 4-acetyl1,2,3-thiadiazole(71), possibly by the mechanism outlined in the reaction 4-Aminoisothiazoles lacking the 3-methyl group [e.g. (70; R1 = R2 = H ; R1 = H, R2 = Me)] afford the corresponding 4-forinyl1,2,3-thiadiazoles (71; R1 = H). The structure of the products, suggested H

on the basis of their composition and spectral data, was confirmed by the oxidation of (71; R1 = R2 = H) to authentic 1,2,3-thiadiazole-4carboxylic acid.34

Metallation.-In the course of a wider research programme on the metallation of five-membered heteroaromatic systems, Micetich s6 has extended the work of Caton et aL3' on the lithiation of isothiazoles. Unlike 3,5dimethylisoxazole, which undergoes chiefly lateral lithiation to the 5-lithiomethyl derivative capable of furnishing heteroaryiacetic acids (HetCH, -+HetCH,Li -+ HetCH2C02H), 3,5-dimethylisothiazole (72) is 34

36

36 37

F. T. Lee and G. P. Volpp, J . Heterocyclic Chern., 1970, 7 , 415. K. H. Saunders, 'The Aromatic Diazo-compounds and their Technical Applications', Edward Arnold and Co., London, 1949, pp. 324-9; D. Kealy and H. Freiser, Talanta, 1966,13, 1381. R. G. Micetich, Canad. J . Chem., 1970, 48, 2006. M. P. L. Caton, D . H. Jones, R. Slack, and K. R. H. Wooldridge, J. Chern. Soc., 1964, 446.

570

Organic Compounds of Sulphur, Selenium, and Tdluriurn

(72)

(73)

(74)

(75)

I p;-q++

p(H

Me NC

SBuR

(76) cleaved by n-butyl-lithium, affording, after treatment with carbon dioxide (73). and water, 25% yields of 2-n-butylthiopent-2-en-4-one 4-Methylisothiazole (74), on the other hand, is lithiated predominantly in its Sposition, giving 69% yields of 4-methyl-5-iodoisothiazole (75) on successive treatment with n-butyl-lithium and iodine. In a parallel reaction, the ring system is cleaved to furnish small quantities of l-n-butylthio-2cyanoprop-1-ene (8%) (76). Miscellaneous SubstitutionReactions (mostly Nucleophilic).-The 5-halogensubstituent in isothiazoles is readily replaced by nucleophilic substitution with alkoxy- or hydroxy-groups; this provides a route to 5-alkoxy-3methyl-4-nitroisothiazolesand 5-hydroxy-4-nitroisothiazoles.4,5-Dibromo3-methylisothiazole affords the 5-butoxy-compound on treatment with sodium butoxide in butanol, and the 5-hydroxy-compound with methanolic sodium hydroxide, but fails to react with sodium m e t h ~ x i d e . ~ ~ Hydrazinolysis of 4-ethoxycarbonyl-3-methyl-5-benzamidoisothiazole (77) is attended by ring expansion to pyrimidines (these Reports, Vol. 1, p. 374). In contrast, its chlorobenzamido-analogues(78) are converted merely into the hydrazides (79), which are also accessible from the lactams (80). The difference in the course of the reaction must be ascribed to the effect of the halogen s u b s t i t ~ e n t s . ~ ~ 5-Bromo-3-methylisothiazole(81; X = H) and its 4-nitro- and 4acetamido-derivatives are convertible into the di-isothiazolyl sulphides (82) 38 89

I. D. H. Stocks, J. A. Waite, and K. R. H. Wooldridge, J. Chern. SOC.(C), 1971, 1314. Z. Machon, Roczniki Chem., 1970,44,2155.

Is0 thiazoles

571

R2 (78) R1 = C1, Rz = H R1 = H, Rz = C1

J

NHaNHa

c=o R2

R2

(79)

(80)

and thence into the sulphones (83) by conventional procedures. Sulphones are also accessible by the interaction of halides and sulphinates. 5-Bromo3-methyl-4-nitroisothiazole and sodium 3-rnethylisothiazole-4-sulphinate, for example, give the sulphone (84).

MJTJjs7 -T-pMclSJN4H O N F 9 s , A T l e Me

so2

(84)

Me

N\

NOz 02N

NHNHZ

(85)

(86)

One of the two isothiazole rings of (82; X = NO,) is opened by alkali, giving (86); the sulphide link of the same compound is cleaved by hydrazine hydrate, resulting in 5-hydrazino-3-methyld-nitroisothiazole(85). Unlike 4,4‘-diaminodiphenylsulphone (‘Dapsone’), which is active against leprosy and malaria, the diaminodi-isothiazolyl-sulphonesare devoid of useful biological proper tie^.^^ The thiocarbonyl group in isothiazolinethiones [e.g. (87)] is replaceable by the action of benzonitrile oxide, producing the corresponding isothiazolinone (88) in 45% yield.ls 3-Hydroxyisothiazoles (89) are converted by numerous alkyl or aryl isocyanates exclusively into the N-carbamoyl derivatives (90; X = 0),41 40

41

M. P. L. Caton, G. C. Martin, and D. L. Pain, J . Chem. Soc. (C), 1971, 776. S. N. Lewis, G. A. Miller, E. C. Szamborski, and M. Hausman, J . Heterocyclic Chem., 1971, 8, 587.

Organic Compounds of Sulphur, Selenium, and Ttllurium

572

S-N

R

- PhNCS

S-N

R

____+

A r s g S

A r u o

the structure of which is confirmed by their unequivocal synthesis, by the halogenative cyclization of 3,3'-dithiodipropionimides (92) l1 (see p, 560). The action of isothiocyanate esters, on the other hand, produce: 2 : 1 mixtures of the isomers (90 and 91; R1 = Br, R2 = H, X = S). These observations may be rationalized if initial exocyclic attack of the rzagent R1

OH

R3NC0

R2TL

-fSCHzCHzCNHCNHEt), I1 0

8

SO,Cl,

at the hydroxy-group be assumed, followed by migration of the carbamoyl grouping to the nitrogen of the hetero-ring. In the case of the thiocarbamoyl compounds, the latter stage reaches an equilibrium and does not go to completion (cf. ref. 42). The above, as well as other substitution reactions, both electrophilic and nucleophilic, has been taken advantage of in studies of penicillin analogues, particularly in an exploration 43 of possible synthetic routes to 5-methyl-3phenylisothiazole-4-carboxylicacid (100) (Scheme 6). 5-Amino-4-bromo-3-phenylisothiazole(96), obtained by bromination of (95) or directly from 3-phenyl-3-iminothiopropionamide(94), was deaminated to 3-phenyl-4-bromoisothiazole (97) and converted into the 4-cyano-analogue (98) by the action of cuprous cyanide in boiling picoline. Methylation of 3-phenyl-4-cyanoisothiazole(98) with butyl-lithium and methyl iodide3' gave low yields of the 5-methyl homologue (101); the alternative route (97) -+ (102) + (101) proved to be more advantageous. Each nitrile, (98) and (101), gave the desired carboxylic acid, (99) and (loo), respectively, on hydrolysis. The same series of reactions was carried out with the 3-(pmethoxyphenyl) ana10gues.~~ 42

43

A. W. K. Chan and W. D. Crow, Austral. J. Chem., 1968, 21, 2967; see also these Reports, Vol. 1, p. 372. T. Naito, S. Nakagawa, and K. Takahashi, Chem. and Pharm. Bull. (Japan), 1968, 16, 148.

Isothiazeles

573

ph7c02H - ph7cN K

N,

1

Bu Li-Me1

Ph

CuCN

Br

Scheme 6

A formyl group may be introduced into the 5-position of (97) by successive treatment with butyl-lithium and dimethylformamide; the resulting aldehyde (103) (39%) shows the expected behaviour on oxidation and reduction.48 In agreement with established experience,37,44 3-arylisothiazoles are brominated 43 in their 4-position, provided this is unsubstituted. Continued halogenation affects the aromatic moiety, giving products such as (104).

(103)

(104)

(105)

R

=

H or Me

Chlorination of both (98) and (101) similarly occurs in their phenyl nuclei, yielding consecutively mixtures of 0- and p-chloro-, 2,4-dichloro-, and eventually 2,4,5-trichloro-phenyl derivatives of type (105). U.V., i.r., and n.m.r. spectra were given for most of the new compounds and briefly discussed; the last proved instrumental in assigning the site of substitution in the halogeno-deri~atives.~~ D. Buttimore, D. H. Jones, R. Slack, and K. R. H. Wooldridge, J . Chem. Soc., 1963, 2032.

574

Organic Compounds of Sulphur, Selenium, and Tdlurium

Nucleophilic Ring Cleavage.-Crow and Gosney 4s have extended their studies (cf. these Reports, Vol. 1, p. 373) of the attack of nucleopiiles on the S-N bond of isothiazoles to that of 1,3-dicarbonyl compomds on N-ethylisothiazol-3-ones. Interaction of ethyl 2-methylacetoacetale (107) and N-ethylisothiazol-3-one (106) yields the linear ethyl 2-methyl.3-0x04-(N-ethyl-cis-3-acrylamido)mercaptobutanoate (108) (65%) and small quantities of the corresponding disubstituted product (109). 3-Methylpentane-2,4-dione (110) gives rise, with simultaneous deacetylation, to (1 11) Me

Et0,C. CHMe. COCHj-

I

CH,COCH. COMe

(107)

CH,COCHMe

1.

NHEt

0

EtO,C*CHMe*COCH

J

CHZ-CO-CHMe I

(ll1) I

PhCHR1COCH,R2

(113) R1 = R2= H (114) R1 = H,R2 = Me (115) R1 = R2 = Me as the major and (112) as the minor product. Analogous reactions also occur between the isothiazolone (106) and 2-methyl- and 2,6-dimethyl-cyclohexanone, 2-methylpentan-3-one, and the aromatic ketones (113), (1 14), and (115). In a detailed analysis of the extensive data, the mechanism of these reactions was discussed, and the conclusions were further tested experimentally. Broadly speaking, the electrophilic attack by N-ethylisothiazol-3-one generally results in the product from reaction at the less acidic site in a dibasic carbon Base-catalysed Dimerization. N-Alkyl-3-isothiazolones(116) having a free 5-position are readily dimerized by base to 2,4-bismethylene-l,3-dithietans W. D. Crow and I. Gosney, Tetrahedron, 1970, 26, 1463.

Isothiazoles

575

(1 17).46 The structure of these high-melting, insoluble, unreactive products was deduced by their fragmentation patterns and spectral properties. The dimerization process involves the attack by the 5-anion (1 16) on the S-N bond of a second molecule of the isothiazolone and may proceed by one of the pathways (a)-(c). The attempted extension of the reaction to N-acyl3-isothiazolones was unsuccessful, affording only intractable, dark, polymeric

RNHcRXH H

S

It

K

NI-IR

CONHR

S-Oxides and -Dioxides.-Isothiazol-4-in-3-ones (1 18) are convertible into the l-oxides and 1,l-dioxides by the action of the correct proportions of rn-chloroperbenzoic acid. Other oxidizing agents, including nitric acid, dinitrogen tetroxide, and chromic acid, are effective in forming l-oxides from 3-hydroxyisothiazoles(1 18; R2 = H).47

Complexes.-Isothiazole (L) forms complexes 48 of types CoL,X2, CoLaXa, and CoL,(ClO,), with COX, (X = Cl, Br, or I) and Co(ClO,),. They are all octahedral in the solid state, except the tetrahedral CoL212. Apart from CoL,(ClO,),, which remains octahedral, the complexes give solutions in which Co" has a tetrahedral environment. The similarity of the electronic and i.r. spectra of the complexes to those of comparable N-co-ordinated heterocyclicligands suggests that isothiazole is bonded to cobalt(I1) through nitrogen rather than through sulphur; its complexing behaviour thus resembles that of thiazole, benzothiazole, and their derivatives, all of which form N-co-ordinated complexes with C O I ~ . ~ * 46 47

46

A. W. K. Chan, W. D. Crow, and I. Gosney, Tetrahedron, 1970, 26, 1493. S. N. Lewis, G. A. Miller, M. Hausman, and E. C. Szamborski, J . Heterocyclic Chem., 1971, 8, 591. R. Rivest and A. Weisz, Canad. J. Chem., 1971, 49, 1750.

Organic Compounds .of Sulphur, Selenium, and Tellurium

576

Some Biological Properties.-Isothiazole-3(or 5)-carboxaldoximes and their 2-N-methylated derivatives are therapeutically active against poisoning by organophosphorus compounds (e.g. Sarin, Paraoxon), comparing favourably with ‘Pas’ (i.e. 2-hydroxyiminomethyl-l-methylpyridinium methanesulphonate), a generally accepted antidote for this purpose.4B Compounds (119)-(122) possess potent, though short-lasting, hypotensive action; (1 19) has also pronounced parasympaticolytic properties, but simultaneously depresses the respiratory centre.33 Me

COR (119) R

= O(CH21zNMe2 (120) R = O(CH,),NMe,CI (121) R = O(CH2),NEt2 (122) R = morpholino

‘ycl

Nb

5 Condensed Ring Systems There can be but few closely related pairs of isomers like 1,:- and 2,l-benzisothiazoles where so much is known about the one and SD little about the The reason here is the fact that the former is the parent compound of saccharin, whereas the latter has not been very xeadily accessible. However, a few contributions to the chemistry of 2, l-benzisothiazole have recently appeared.

2,l-Benzisothiazoles.-Synthesis. A novel route to 2,l -benzisothiazoles by the thermal decomposition of 2-azidoaryl thioketones has been briefly reported. I t proceeds by loss of nitrogen due to a nucleophilic attack of the thiono-group on the azide function.61 Another simple one-step synthesis, involving an oxidation-reduction process, is the action of thionyl chloride on o-toluidine. The reaction is carried out in boiling p-xylene and affords the heterocycle in 30% yield.62

R

R

7-Acetyl-3-methyl-2,l -benzisoxazole (123) is converted (75%) into the corresponding 2, l-benzisothiazole (125) by the action of phosphorus pentasulphide in boiling pyridine. Its production is rationalized in terms of the initial formation of the thioacyl compound (124), which undergoes valence tautomerism to (125).63

O0

61 Oa

O8

H. P. Benschop, A. M. van Oosten, D. H. J. M. Platenburg, and C. Van Hooidonk, J. Medicin. Chem., 1970, 13, 1208. L. L. Bambas, ‘The Chemistry of Heterocyclic Compounds’, Interscience, New York, 1952, devotes one page to 2,l- and some 120 pages to 1,2-benzisothiazoles. J. Ashby and H. Suschitzky, Tetrahedron Letters, 1971, 1315. M. Davis and A. W. White, Chem. Comm., 1968, 1547. D. M. McKinnon and J. Y . Wong, Canad. J. Chem., 1971,49,2018.

ZsothiaroIes

577

EZectrophiZic Substitution. Bromhation of 2,l -benzisothiazole under conditions where Brf is the electrophilic species gives a mixture of 5- and 7-bromo-2,l-benzisothiazole, together with a little of the 4,7-dibromocompound. The bromination products differ in basicity and may be separated by taking advantage of this fact. The orientation of the substituents may be deduced from n.m.r. Nitration of 2, l-benzisothiazole affords mainly 5-nitro-2, l-benzisothiazole, with smaller quantities of the 7-nitro- and 4-nitro-isomers. Monosubstituted 2,l-benzisothiazoles give nitro-derivatives, the orientation of which indicates that the substituent in the benzenoid ring is the decisive directing influence. 2,l-Benzisothiazole is clearly a stable heteroaromatic system, reacting with bromine only by substitution, and not, as can occur with 2,l-benzisoxazoles, by addition across the C(4)-C(5) bond. There is no evidence so far for scission of the heterocyclic ring during nitration. The sum total of the observations suggests that the perturbing effect of the heterocyclic ring on the benzenoid ring is relatively slight, and that the quadricovalentsulphur structure (126) provides a more acceptable representation of the properties of 2,l-benzisothiazoles so far

1,2-Benzisothiazoles.-Synthesis. A number of 1,2-benzisot hiazole-3-acet ic acids (128) have been prepared with the aim of studying their potential activity as plant hormones.K6 They were produced, usually in nearquantitative yields, by the action of hydroxylarnine on substituted 4-hydroxy-1-thiocoumarins (127) (cf. ref. 56). 5-Chloro-l,2-benzisothiazole3-acetic acid proved very potent, possessing an activity about three times that of of heteroauxin.6K p-Chloromethylbenzenesulphonyl chloride (129) is converted by the Willgerodt reaction into p-sulphonamidobenzoic acid (130). The use of 64

6s s6

M. Davis and A. W. White, J . Chem. Sac. (C), 1969, 2189. M. Gianella, F. Gualtieri, and C. Melchiorre, Phytochemistry, 1971, 10, 539. G. Casini, F. Gualtieri, and M. L. Stein, J. Heterocyclic Chem., 1969, 6, 279. 20

578


the o-isomer (131) yields, in the first place, the ammonium salt of the ortho-analogue of (130), which is cyclized to 1,2-benzisothiazolin-3-0ne 1,l-dioxide (132) in acid media.67 ortho-Lithiation of N-substituted benzenesulphonamides, followed by carbonation and cyclization, produces N-substituted 1,2-benzisothiazolin3-one 1,l-dioxides in moderate 6Q The presence of the N-substituent is essential for successful ortho-metalation with butyl-lithium :

primary sulphonamides do not undergo this reaction. A t-butyl group is readily removed from the N-position of the heterocyclic products, e.g. by the action of polyphosphoric acid, thus making the parent 1,2-benzisothiazolin-3-one 1,l-dioxide (132) accessible.68 Pyrolysis at 360 "C in a vacuum of the lithium salts of the substituted sulphonic acids (133) yields 5-substituted 3,3-difluorobenzyl sultones (134),

67 68

69

( 133) (134) H. Feichtinger, Chem. Ber., 1971, 104, 1697. J. G. Lombardino, J . Org. Chem., 1971,36, 1843. H. Watanabe, R. Gay, and C. R. Hauser, J. Org. Chem., 1968,33,900.

IsothiazoIes

579

which are convertible, by the action of aqueous ammonia, into the corresponding 5-substituted 1,2-benzisothiazolin-3-one1,l-dioxides (135).60 The interaction of sulphoxides and hydrazoic acid yields sulphoximines. Applied to 2-sulphinylbenzoic acid esters (136), it proceeds with simultaneous cyclization to 3-oxo-1,2-benzisothiazole l-oxides (137). The new ring system is remarkably stable, being unaffected by hot concentrated sulphuric acid or prolonged treatment with alkali.61 0

X

N

+ N2 + RIOH

0 (137)

Mass Spectra. The mass spectra of a large number of derivatives of 1,Zbenzisothiazole 1,l-dioxide have been studied and discussed.*2 A fragmentation pattern typical for this class of compounds is apparent, but is strongly influenced by the substituents present. When energetically favourable, fragmentation of the substituents occurs, frequently followed by expulsion of sulphur dioxide; in other cases the heteroaromatic ring is cleaved, sometimes after the occurrence of a rearrangement involving the SOa group. There appears to be no correlation between thermal and electron-impact-induced rearrangements in this group of substances. The fragmentation of 3-hydroxy-1,2-benzisothiazole1, l-dioxide is outlined in Scheme 7.62 Chemical Properties. The chemical behaviour of amino-derivatives of 1,Zbenzisothiazoles has been the subject of detailed studies. 3-Alkylamino1,Zbenzisothiazoles (138) are oxidized selectively to l-oxides (139) or 1,l-dioxides (140) by the action of potassium nitrate in concentrated sulphuric acid, or hydrogen peroxide in glacial acetic acid, respectively. The l-oxides are bases forming salts with mineral acids, whereas the 1,l-dioxides, being cyclic sulphonamides, are sufficiently acidic to be soluble in alkalis and reprecipitated by The isomeric 2-substituted 3-imino-l,2-benzisothiazolines(142) yield, on mild chlorination, N-chloro-compounds (144) (predominantly as the E configuration, as shown). These are in turn convertible, on treatment with thiophenol and isopropyl alcohol, into 3-imino-2-alkyl-1,2-benzisothiazoline l-oxide hydrochlorides (145); they are stable as salts only, and are rapidly isomerized to (139) on being heated in 60

L. M.Yagupolskii, R. V. Belinskaya, and N. G. Avramenko, Zhur. org. Khim.,

1970,

6, 1689 (Chem. A h . , 1970,73, 109 441~). 61

P. Stoss and G. Satzinger, Angew. Chem., 1971, 83, 83. H. Hettler, H. M. Schiebel, and H. Budzikiewicz, Org. Mass. Spectrometry, 1969, 2, 1117.

H. Boshagen, W. Geiger, and H. Medenwald, Chem. Ber., 1970, 103, 3166.

580


m/e 103 (104) Scheme 7

Treatment of the N-chloro-compounds (144) with boiling isopropyl alcohol causes oxidation to the sulphone (143), also directly obtainable by the oxidation of the parent thiazoline (142) with chromic acid. In contrast to the sulphoxides (145), the sulphones (143) are stable, isolable The action of hydroxylamine on 3-chloro-l,2-benzisothiazoliumchlorides (146) in ethanol affords sparingly soluble 3-alkylamino-1,2-benzisothiazole 2-oxide hydrochlorides (147). Their parent bases, formulated as N-oxides (148), are water soluble, but their stability is limited. With formic acid, the salts (147) yield the sulphoxides (139a); they are reconverted into the parent 3-alkylamino-1,Zbenzisothiazoles (138) by phosphorus trichloride, thus resembling pyridine N-oxides 64 in this respect. Paper electrophoresis was employed for separating and identifying some of the oxidation The ammonolysis 65 of 2-substituted 3-chloro-l,2-benzisothiazolium chlorides (146) yields, instead of the expected 3-imino-l,2-benzisothiazolines (15l), the isomeric 3-amino-1,Zbenzisothiazoles (150)? The structures of these compounds were confirmed by their spectral properties, and their isomerization was studied in detail.65 In suitable solvents, the hydrochlorides (152) of 3-amino-l,2-benzisothiazoles(150) rearrange to the 64

65

g6

M. Katadu, J. Pharm. SOC. Japan, 1947, 67, 51; M. Hamana, ibid., 1951, 71, 203; 1955, 75, 121, 123, 127, 135, 139; J. F. Vozza, J . Org. Chem., 1962, 27, 3856. W. Geiger, H. Boshagen, and H. Medenwald, Chem. Ber., 1969,102, 1961. H. Boshagen, Chem. Ber., 1966,99,2566.

Is0thiazoles

NH 142)

58 1

N ,

c1

Y

- (PhS),


582

hydrochlorides (153) of the isomeric 3-imino-l,2-benzisothiazolines (151). An equilibrium mixture of the two salts is formed, the composition of which depends on the nature of the substituents and on the solvents employed. The rate of equilibration is pH-dependent, suggesting that it occurs by way of the bases (150) and (151), by transient opening of the S-N bond, 'flipping over' of the -C(: NH)NHR group, and recyclization [to (151)]. Treatment of both (152) and (153) with alkali yields (150) exclusively; the imino-base (151) has not been isolated. The suggested formulations are further supported by the behaviour of alkyl and acyl derivative^.^^ Nucleophilic Substitution and Ring Fission. Although 3-chloro-l,2benzisothiazole (154) is convertible into the corresponding 3-ethoxy- 67 and 3-alkylamino- 68 compounds by nucleophilic substitution, its reaction with sodium cyanide in acetone 67 does not yield the expected 3-nitrile, but produces, with simultaneous ring fission, a mixture of bis-(o-cyanophenyl) disulphide (155) (2279, o-cyanophenyl thiocyanate (156) (62%), and

dN 0 10 ocN ' ' NaCN-Me,COt

CN NC

s-s

s'

+

\

\

CNS

(154)

aCN SBu

(1 58)

(1 59)

2-acetyl-3-aminobenzo[b]thiophen (157) (6%). The last product is obviously formed by participation of the carbanion derived from acetone.67 Action of copper(1) cyanide 67 on (154) yields the disulphide (155) almost exclusively, whereas its successive treatment with ethereal n-butyl-lithium and dimethylformamide at - 70 "C (aimed at the synthesis of the 3-carbaldehyde) gives merely o-(n-buty1thio)benzonitrile (158)?' The action of thiophenols yields disulphides of type (159).6* More detailed experiments 67 employing sodium thiophenoxide showed that a mixture of diphenyl disulphide (46-50%), bis-(a-cyanophenyl) disulphide (15 5 ) (5067 68

D. E. L. Carrington, K. Clarke, and R. M. Scrowston, J. Chem. SOC.(C), 1971, 3262. G.P. 1 174 783/1964, (Chem. Abs., 1964, 61, 12 008). S. Watanabe, Bull. Chem. SOC.Japan, 1969,42, 1152.

Is0thiazoles

583

55%), and o-cyanophenyl phenyl disulphide (159; X = H) (5%) is formed.

Several possible reaction mechanisms of these ring fissions were discussed. In further work 'O on nucleophilic replacements involving (154), the action of pentane-2,4-dione, ethyl aceto-(or cyano-)acetate, and diethyl malonate, each of which produce carbanions under basic conditions, was studied. These reagents produce either 3-substituted 1,2-benzisothiazoles or ring-cleaved products.'o Pentane-2,4-dione reacts with 3-chloro-1,Zbenzisothiazolein the presence of sodium ethoxide to form 2-acetyl-3-aminobenzo[b]thiophen (71%). Under similar conditions, ethyl acetoacetate and diethyl malonate each give mainly ethyl 3-aminobenzo[b]thiophen-2-carboxylate(160). Under modified conditions diethyl malonate gives, in addition, some of the expected diethyl (1,2-benzisothiazol-3-yl)malonate,whereas ethyl cyanoacetate forms only ethyl (1,2-benzisothiazol-3-yl)cyanoacetate,irrespective of conditions. Mechanisms were considered involving S-substituted o-cyanothiophenols as possible intermediates in the reactions leading to benzo[b]thiophen (see Scheme 8). The reactions constitute a useful

Scheme 8

synthesis of 3-aminobenzo[b]thiophens,which are otherwise not readily available.'O The action of zinc and hydrochloric acid cleaves the hetero-ring of 3-chloro-1,2-benzisothiazole(154) with formation of 2,2'-dicyanodiphenyl 'O

D. E. L. Carrington, K. Clarke, and R. M. Scrowston, J. Chem. SOC.(C), 1971, 3903; Tetrahedron Letters, 1971, 1075.

584


disulphide (155) (75%). The same product results from the action of hydrazine or on treatment of 3-amino-1,2-benzisothiazolewith nitrous acid.?l The results correct previous 72 erroneous formulations of these products. The reduction of 2-methyl-1,2-benzisothiazol-3-one(161) proceeds analogously, yielding (162).?l NHMe NHMe

The action of diethyl ethoxymethylenemalonate on 3-amino-l,2benzisothiazole 1,l-dioxide affords low yields of the 3-aminomethylenemalonate derivative (163), which is converted into (164) by the action of morpholine. The reaction may proceed by the addition of the base to the C=N bond, followed by elimination of diethyl aminornethylenemal0nate.~3

PI 0-( 1,2-Benzisothiazol-3-yl)oximinoalkane1,l-dioxides (166) are accessible from 3-chloro-1,2-benzisothiazole 1,l-dioxide ['pseudosaccharin chloride', (165)] and syn-aldoximes. Aromatic aldoximes afford yields usually in excess of 90%, but aliphatic analogues are less readily formed; anti-aldoximes fail to react. Ammonolysis of the condensation products (166) yields 3-amino-1,Zbenzisothiazole 1,l-dioxide (167) and regenerates the ~ x i r n e . ~ ~ Beckmann rearrangement of (166) under the influence of trihoroacetic acid yields, in addition to saccharin (132), N-substituted formamides (169) and nitriles (168) in competing reactions. The yields of (169) show a remarkably close correlation with the values of the Hammett constants. Thermal rearrangement in acetonitrile of (166) (R = p-Me,N-C,H, or p-Et2N C,H, ; i.e. examples incorporating substituents having the highest 71

73 74

S. Hiinig, G . Kiesslich, and H. Quast, Annalen, 1971, 748, 201. R. Stolle and M. Merkle, J. prakt. Chem., 1933,138, 221. S. Rajappa, K. Nagarajan, and A. S. Akerkar, Indian J. Chem., 1970, 8, 499. H. Hettler and H. Neyenfind, Chem. Ber., 1970,103, 1397.

585

Is0thiazoles

u

0 0 (165)

v

(166)

- RCmN - RNHaCHO

(168) (169)

cF3co~H

Hammett constants) produces 3-oxo-2-(4-dimethylaminophenyliminomethyl)-1 ,Zbenzisothiazoline1,l-dioxide(170) (79%) and 4-dimethylaminobenzonitrile (180/,).74 Complexing. 3-(2-Diethylammoniumethoxy)-l,Zbenzisothiazole chloride (171) forms complexes of type (LH)2MCI, with Cu", Co", and MnI1

chlorides. Their physical properties reveal the presence of tetrahedral metal halide anions and heteryl cations, without co-ordinate interactions between the metal and organic m~ieties.'~ Isothiazolo[5,1-e]isothiazoles.-A multi-stage synthesis of 1,3,4,6-tetramethylisothiazolo[S, 1-e]isothiazole (173) from 3-ethyl-4-methyl-1,2-dithiolium perchlorate (172) has been briefly menti~ned.'~The product is of especial interest in that it may be formulated as the bicyclic structure (173), or as a system of rapidly interconverting valence isomers (174) and (175). Isothiazolo[2,3-b]quinazolines.-The condensation of 3-hydroxyisothiazole (176) and isatoic anhydride (177) atI80-95 "Cproceeds with loss of carbon '5

'8

G.C. Pelizzi and C. Pelizzi, Guzzeffa, 1970, 100, 1160. D.H. Reid and J. D. Symon, Chem. Comm., 1969, 1314.

586

Organic Compounds of Sulphur, Selenium, and Tellurium Me

Me

A C H 2 M e

s-s

4-

2 f i 5

MeN-S

c104-

-NMe

1

Me Me

Me

m - m NMe

MeN-S

MeN

(174)

6

0s

Me

S-NMe

(175)

dioxide, yielding 3-anthranoyloxyisothiazole (179) and the isothiazolo[2,3-b]quinazolin-9-one(180) side by side. Since the latter is not obtainable from the former under identical conditions, it probably arises by dehydration of the initial N-acylation product (178), the normally favoured N + 0 acyl migration occurring in competition with this cy~lization.~~ 0

A. W. K. Chan and W. D. Crow, Austral. J. Chem., 1969,22, 2497.

I3 Thiazoles BY F. KURZER

1 Introduction A survey of recent contributions to the chemistry of thiazoles conveys an impression of steady progress over a wide front. Physicochemical aspects are increasingly receiving their due attention, and interest in mesionic compounds has been well sustained. Reduced thiazoles serve in the study of polypeptides and proteins, and occur as structural units in compounds of biological significance, e.g. firefly luciferins, and in the antibiotics bacitracin A and thiostrepton ; their investigation continues to provide interesting and significant results. The list of secondary sources reviewing the chemistry of thiazoles previously given is supplemented by the following publications. Prijs’ Card Index of Thiazole Compounds a provides swift access to information on individual compounds, but its appearance has unfortunately not continued. Asinger and Offermanns have reviewed the chemistry of A8-thiazolines, within the framework of a full account of their versatile synthesis of heterocyclic compounds by the simultaneous action of sulphur and amines on ketones. Ohta and Kate's* comprehensive survey on sydnones includes a section on mesionic thiazoles. 2 Synthesis Hantzsch’s Synthesis (Type A, S-C-N C-0.-Various forms of Hantzsch’s synthesis continue to be widely employed for producing both old and new types of thiazole derivatives (see Table 1). In a useful procedural variationy6a thioamide is generated from the corresponding amide by the action of phosphorus pentasulphide in dioxan, and condensed in situ with the a-halogenocarbonyl compound. The effectiveness of the

+

F. Kurzer, in ‘Organic Compounds of Sulphur, Selenium, and Tellurium’, ed. D. H. a

a

Reid (Specialist Periodical Reports), The Chemical Society, London, 1970, vol. 1, ch. 13, p. 378. B. Prijs, ‘Kartothek der Thiazolverbindungen’, Karger, Basel and New York, 1952, 4 vols. F. Asinger and H. Offermanns, Angew. Chem., 1967, 79, 953 (Internat. Edn., 1967, 6, 907).

4

M. Ohta and H. Kato, in ‘Nonbenzenoid Aromatics’, ed. J. P. Snyder, Academic Press, London and New York, 1969, vol. 1, pp. 117, 201. R. Vivaldi, H. J. M. Dou, G. Vernin, and J. Metzger, Bull. SOC.chim. France, 1969, 4014.

587


588

thiation determines the yield of thiazole since oxazole formation occurs when thioamide production is incomplete.s The thiazolylcarboxylic esters (3; Alk = Et, R = Ph) and (4; Alk = Et, R = Ph) are accessible by the condensation of benzoylchloropyruvic (1) or benzoylchloroacetic ester (2) with thioacetamide (Scheme 1).6 3-ArylRCO*CHCl* COC0,Alk

N C0,Alk MekJLOR

RCO * CHCl COzAlk .

(3)

Me+=?-

Me-C=C-C0,Et

(4)

C0,Et

(7) Scheme 1

amino-2-chloroprop-2-enoicesters (6), obtained from 2-chloroacetoacetic ester ( 5 ) and arylarnines, react with thiourea to yield substituted 2-arninothiazoles (7), probably by initial nucleophilic substitution of the chloroatom [of (5)], followed by cyclization with loss of aniline.' and steroids lo incorporating a thiazole ring in Monosaccharides their structure have also been produced by this method. Thus, pentaacetyl-D-galactonic acid thioamide [(8) or analogues] are condensed with chloroacetone or phenacyl bromide to give 4-substituted 2-(~-galacto-penta*9

K. A. Maier and 0. Hromatka, Monatsh., 1971, 102, 102. H. Bohme and R. Braun, Annalen, 1971,744,20, 27. R. Bognar, I. Farkas, L. Szilagyi, M. Menyhart, E. N. Nemes, and I. F. Szabo, Acta Chim. Acad. Sci. Hung., 1969,62, 179. H. Beyer and U. Schultz, Chem. Ber., 1954,87,78. H. Singh, R. B. Mathur, N. J. Doorenbos, A. K. Bose, and S. D. Sharma, Tetrahedron, 1971,27, 3993.

Thiazoles 589 acetoxypenty1)thiazoles [(9) or analogue^].^ The products may be deacetylated in the usual way. Comparable thiazolidines have also been described (see this volume, p. 635).8 2’-Phenylaminothiazolo[3,2-c]-6aza-~-homo-5a-cholest-3-en-7-one (1 1) is accessible (45%) from the homosterol (10) as shown,lo

+

Other Type A (S-C-N C-C) Syntheses.ll-Aminothiocyanogen l2 (12) reacts with a variety of ketones in ether to afford satisfactory yields of 4,5-disubstituted 2-aminothiazoles (13).13 N-Methylthiazolines, e.g. (1 5 ) , are similarly accessible from N-methylaminothiocyanogen (14). The reaction appears to proceed by way of intermediate enamines: in the R1-CO

I R2-CHz

Me-CO

I

Ph-CHz

Me-CO

.

+ +

NHMe

I

SCN

WH2

example employing acetoacetic ester (16), the enarnine (17) is isolated in good yield and is isomerized to (18) either thermally or by alkali.13 A novel approach to thiazoles is the condensation of thioacetamide or thiourea with jS-acylvinylphosphonium salts (1 9).14 If these salts reacted l1

For system of classification, see J. M. Sprague and H. Land, in ‘Heterocyclic Compounds’, ed. R. C. Eiderfield, Wiley, New York, 1957, vol. 5, pp. 484, 496. E. Schmitz, R. Ohme, and S. Schramm, Annalen, 1967,702, 131. E. Schmitz and H. Striegler, J. prukt. Chem., 1970, 312, 359. E. Zbiral, Tetrahedron Letters, 1970, 5 107.

Organic Compounds of Sulphur, Selenium, and Tellurium as ap-unsaturated carbonyl compounds they would be attacked by nucleophiles at the carbon atom adjacent to the phosphorus, i.e. /3 to the carbonyl group; reacting as vinylphosphonium salts they would be attacked at the carbon a to the CO group. The reaction proceeds in fact exclusively by the latter mechanism, thioamides and azide ions producing thiazoles and triazoles, respectively (Scheme 2). The initial nucleophilic attack by the 590

X- (Ph&CH=CHCOR1

(19)

+ HS-C=NH I R2

+ -

hSP- CH- CH-COR1 "s' &H2X'

R2

1

sulphur, yielding (20), is rapidly followed by a prototropic rearrangement, to (21), and by cyclization to the thiazolylmethylphosphonium salt (22) (isolable as an adduct with 1 mole of thiourea in 75--80% yields). Final alkaline hydrolysis furnishes the aminothiazoles (23).14

+

Type E (N-C-C-S C ) Synthesis.-In this group of syntheses, an N-C-C-S system is condensed with a one-carbon fragment, so that the latter reappears as C-2 in the thiazole ring. The interaction of enamines with sulphur in conjunction with carbon disulphide, isocyanates, or isothiocyanates results in the production of sulphur-containing heterocyclics. Cyanamide has now been shown to participate in this reaction.ls Treatment of enamines of type (24) with sulphur and cyanamide at room temperature in ethanol produces a range of 2-aminothiazoles (27) in 30-70% yield; no catalyst is required. Initial formation of the thiolated intermediate (25) is probably followed by addition of cyanamide, yielding (26) ; elimination of amine finally produces the observed thiazoles (27). Since NN-dialkylcyanamides do not undergo this reaction, cyanamide may react as the tautomeric carbodi-imide. An actual example of the reaction employing the enamine derived from cyclohexanone and morpholine is also shown [(28) --+ (29)].15 5-Formamidothiazole-4-carboxamides(3 1) are accessible by the cyclization of 2-acylamino-2-thiocarbamoylacetamides(30) with acetic formic I(. Gewald, H. Spies, and R. Mayer, J.prakt. Chem., 1970, 312, 776.

Thiazoles

59 1

R.,

anhydride; subsequent hydrolysis yields 5-aminothiazoles (32). Polyphosphoric acid cyclodehydrates (30) directly to (32) in excellent yield.ls

+

Type F (C-N-C-S C) Synthesis.-In this type of synthesis, one of the reactants supplies only the carbon at position 5 of the resultant thiazole. The route is exemplified by the production of 2-substituted 4-amino-5cyanothiazoles by the following sequence of reactions :17 S II

Type G (N-C-S-C-C) Synthesis.-N-(5-Aryl-1,3-oxathiol-2-ylidene) tertiary iminium salts (33) l8yield a variety of heterocyclic compounds upon reaction with nucleophiles containing an amino-group. The action of ammonia on (33; R2N = piperidino, morpholino, or dimethylamino), for la

Y.Tamura, T. Miyamoto, K. Shimooka, and T. Masui, Chem. andInd., 1970, 1470;

l7

Chem. and Pharm. Bull. (Japan), 1971, 19, 119. H. Hartke and B. Seib, Arch. Pharm., 1970,303, 625. K. Hirai, Tetrahedron Letters, 1971, 1137.


592

example, affords linear intermediates (34) which cyclize to 2-amino-5phenylthiazoles (35) on crystallization from acetic acid.l@ Fission of Thiamine.-Oka et aL20have described a novel fission of thiamine (36), by the action of two moles of triethylamine and an excess of benzaldehyde, chiefly into 4-amino-2,5-dimethylpyrimidine (38) and 2-benzoyl5-(2-hydroxyethyl)-4-methylthiazole (39) (Scheme 3). The thiazole was

(41)

Ph \

co

NH2 Me

+

hs

N\I

Me

CHZCHZOH

/ (39)

(37)

(40)

Scheme 3

identified by its spectral properties and by its reduction to the known 2-(a-hydroxybenzyl)-5-(2-hydroxyethyl)-4-methylthiazole(40). Since the cleavage does not occur in the absence of triethylamine, the benzaldehyde is believed to react at the 2-position of the thiazole-ring, producing the a-hydroxybenzylthiamine (37) as intermediate. The reaction is applicable to homologues of thiamine and other aromatic (but not aliphatic) aldehydes, and is claimed to afford a variety of new 2-acylthiazoles (39) which are not l9

eo

K. Hirai and T. Ishiba, Chern. Comm., 1971, 1318. Y. OkayS. Kishimoto, and H. Hirano, Chern. andPharm. Bull. (Japan), 1970, 18, 527.

Thiazoles

593

readily accessible by other routes. However, in view of the limitations of its applicability, the complexity of the starting materials, and the relatively low yields obtained (20-40%), its synthetic usefulness may be somewhat circumscribed.20 The main cleavage is attended by the formation of very small quantities (4%) of a by-product formulated as 2-[a-(4-amino-2-methyl-5-pyrimidinylmethyl)-cu-hydroxybenzyl]-5-(2-hydroxyethyl)-4-methylthiazole (41), on the basis of its spectral properties and chemical behaviour.21 The production of numerous thiazoles, particularly amino-derivatives, by the well-tried routes continues to be reported and is briefly listed in Table 1. In this type of work, a variation of Hantzsch‘s synthesis is almost

Table 1 Synthesis of thiazoles by conventional routes Thiazole Ref. 22 4,5-DiaIkylthiazoles 23 2,4-Dialkyl- and 2,5-dimethyl-4-alkylthiazoles 24 4-Adamant yl t hiazole and derivatives 5-(2-Chloroethyl)-4-methylthiazole (‘Clomethiazole’) and analogues 25 26 2-Aryl-4-chloromethylthiazoles 27 4-Methyl-S-(p-hydroxyethyl)t hiazole 2-Phenyl-4-(substituted)arylthiazoles and Schiffs bases derived therefrom 28 2-Substituted 4-(2,4-dimethoxyphenyl- or 2,4,6-trimethoxyphenyl)29 thiazoles 4-(p-Aminophenyl)-2-substitutedthiazoles; nitrogen mustards derived 30 therefrom 31 4-(2‘-Thienyl or 2’-fury1)thiazoles 32 2-Substituted 4-(indol-3-yl)thiazoles 33 Multiheteryl-substituted thiazoles 34 4-(Carboranylmethyl)thiazole 35 4-Substituted 2-aminothiazoles a1 22

24

26

27

28

81 52

84

Y.OkayS. Kishimoto, and H. Hirano, Chem. and Pharm. Bull. (Japan), 1970, 18, 534. U. H. Lindberg, G. Bexell, J. Pedersen, and S. Ross, Acta Pharm. Suecica, 1970, 7, 423 (Chem. Abs., 1970,73, 118 624s). C. Roussel, A. Babadjamian, M. Chanon, and J. Metzger, Bull. SOC.chim. France, 1971, 1087. F. N. Stepanov and S. D. Isaev, Zhur. org. Khim., 1970, 6, 1189 (Chem. Abs., 1970, 73, 66 488d). U. H. Lindberg, Acta Pharm. Suecica, 1971, 8, 39; U. H. Lindberg, G. Bexell, and B. Ulff, Acta Pharm. Suecica, 1971, 8, 49. I. Simiti and M. Farkas, Bull. SOC.chim. France, 1968, 3862. I. A. Rubtsov and B. I. Shapira, Khim. Farm, Zhur., 1970, 4, 49 (Chem. Abs., 1970, 73,56 015h). J. D. Modi, S. S. Sabnis, and C.V. Deliwala, J. Medicin. Chem., 1971, 14, 450. A. Boucherle, G. Carraz, M. I. Hicter, and H. Beriel, Chim. Therupeut., 1968, 3, 360 (Chem. Abs., 1969, 70, 106 424b). J. D. Modi, S. S. Sabnis, and C. V. Deliwala, J . Medicin. Chem., 1971, 14, 887. S. P. Misra and P. K. Jesthi, Current Sci., 1970, 39, 417. Y.I. Smushkevich, T. M. Babuyeva, and N. N. Suvorov, Khim. geterotsikl. Soedinenii, 1969, 91 (Chem. Abs., 1969,70, 115 049k). G. Kempter, H. Schtifer, and G. Sarodnick, 2. Chem., 1970, 10,462. L. I. Zakharkin, A. V. Grebennikov, and A. I. Lvov, Zzoest. Akad. Nauk S.S.S.R., Ser. khim., 1970, 106 (Chem. Abs., 1970,72, 111 544m). H. Tripathy, B. C. Dash, and G. N. Mahapatra, Indian J. Chem., 1970, 8, 586.

594

Organic Compoundr of Sulphur, Selenium, and Tellurium

Table 1 (con?). 4-(~-AryIethyl)-2-aminothiazoles 2-A mino-5-ethoxycarbon yl-4-met hy 1t hi azole and derivatives Acylated 2-amino-5-nitrothiazoles 2-Amino(or hydrazino)-5-nitrothiazoles; 2-acyl derivatives thereof, and related compounds 2-Amino-4-methyl(or p-toly1)arylazothiazoles S-2-{[2-(2-Thiazolylcarbamoyl)e~hyl]amino}ethyIhydrogen thiosulphate (thiazol-2-yl~NHC0CH,CH,NH,CHaCH,SSO,-), and analogous internal Bunte salts 2-(N4-Maleylsulphanilamido)thiazole 2-Hydrazino-4-methylthiazolesand aroyl derivatives 2-Substituted thiazol-4-yl arylhydrazones of glyoxylic acid 2-Amino-4-(2-furyl)thiazolesand bromo-derivatives 2-Amino-4-[2-(5-nitro-2-furyl)vinyI]t hiazoles 2-Arylamino-4-(3'-coumarinyl)t hiazoles 2-Amino-4-coumarinylthiazoles and sulphonamido-derivatives Pyridyl- and quinolyl-2-aminothiazoles 2-Amino-l-(thiazol-2-yl)imidazoles

Ref. 36 37 38

39 40

41 42 43 44 45 46 47 48 49 50

invariably employed, or a preformed thiazole structure is suitably modified. Much of this effort is occasioned by the search for biologically or chernotherapeutically active compounds; more than two-thirds of this work originates from Russian and Indian laboratories.

3 PhysicaI Properties The dipole moments of thiazole and its mono-, di-, and tri-phenyl derivatives have been determined at 20 "Cand compared with the theoretical values calculated by an LCAO method. Except for triphenylthiazole, the figures are in fair agreement; discrepancies are ascribed to imperfect values

40

a

4e 47

re 6o

B. C. Dash and G. N. Mahapatra, J. Indian Chem. SOC.,1970,47,98. F. Gagiu, C. Draghici, E. Banu, G. Csavassy, G. Vrejoiu, and M. Theodorescu, Chim. Therapeut., 1970,5, 194 (Chem. Abs., 1970,73,75 363m). I. Nabih and M. Abbasi, J. Pharm. Sci., 1971,60,1411. L. M. Werbel and J. R. Battaglia, J. Medicin. Chem., 1971, 14, 10. H. G. Garg and R. A. Sharma, Canad. J. Pharm. Sci., 1971,6,45. R. D. Westland, L. M.Werbel, J. R. Dice, J. L. Holmes, and B. Zahm, J. Medicin. Chem., 1971,14,916. L. Rylski, I. Kozakiewicz, B. Dekarz, J. Lewicka, and H. Polkowska-Krajewska, Acta Pol. Pharm., 1970,27,349 (Chem. Abs., 1971,74,12 779b). A. A. Aroyan and N. S . Bolshakova, Armyan. khim. Zhur., 1969,22,601(Chem. Abs., 1969,71,112 588v). M. 0.Lozinskii, T. N. Kudrya, S. N. Kukota, and P. S . Pelkis, Khim. geterotsikl. Soedinenii, 1969, 757 (Chem. Abs., 1970,72, 43 54711.) A. Perkone, N. Saldabols, and S . Hillers, Khim. geterotsikl. Soedinenii, 1969, 498 (Chem. Abs., 1970,72,31 670j). N. Saldabols and V. V. Krylova, Khim. geterotsikl. Soedinenii, 1969,555 (Chem. Abs., 1970,72, 21 633k). A. K. Panigrahi and M. K. Rout, J. Indian Chem. SOC.,1971,48, 665. K. A. Thakar and N. R. Manjaramkar, J. Indian Chem. Soc., 1971,48, 621. A. Taurins and A. Blaga, J . Heterocyclic Chem., 1970,7 , 1137. H. Beyer and S. Schmidt, Annalen, 1971,748,109.

Thiazoles 595 for the molecular dimensions on which the theoretical calculations are based.61 Friedmann et al.62-54have studied the U.V. spectra of numerous thiazoles. The absorption properties of derivatives bearing halogen,62 ethoxy,62 63 or dimethylamino-substituents6 2 in water, ethanol, and 0.08N-HCl have been compared, and the effect of the solvents and of the substituents on the position and intensity of the absorption maximum discussed. Regardless of the nature, number, and position of the substituents, a bathochromic effect with respect to thiazole is observed in the n-n* transition, which is maximal for groups having the greatest conjugation (nitro and dimethylamino).62 A Pariser-Pam calculation of the electron-distribution in 2-, 4-, and 5-nitrothiazole confirms that the transitions observed are all of the TIT* type.6s The U.V. spectra (in water, ethanol, or chloroform) of a range of 2-substituted thiazolium iodides have also been studied in detail and their significance The lsF and lH n.m.r. spectra of 2-thiazolylcarbonyl fluoride (42) have been compared with those of the related structures [(43)-(45)]. Theoretical values have been computed for the coupling constants and compared with those obtained experimentally.66

(43)

(44)

(45)

The natural abundance 13Cchemical shifts for thiazole (and its 2-, 4-, 2,4-, and 4,5-methyl derivatives) have been measured at 25.15 MHz against 50% enriched l3CS,. The results confirm the accuracy of the

13C-H coupling constants, and show that the methyl groups exert an appreciable substituent effect on the carbon atoms to which they are attached.56 2-Thiazoline (and its 2-methyl, 5-methyl, and 5-methyl-2ethyl homologues) have also been studied from this point of view.67 4 Chemical Properties Deuterium and Tritium Exchange.-Thiazole is readily ionized by deuteroxide in D20 or alkoxide in ROD, being deprotonated at C-2 and C-5 at about the same rate; deprotonation at C-5 of isothiazole is slightly faster; the other hydrogen atoms in either compound (H-4 in thiazole, H-3 and H-4 in isothiazole) do not exchange even under drastic conditions.68 The J. M. Bonnier and R. Arnaud, Compt. rend., 1970,270, C, 885. A. Friedmann, A. Cormons, and J. Metzger, Compt. rend., 1970, 271, C,17. D. Bouin and A. Friedmann, Compt. rend., 1969,269, C,1343. A. Cormons, D. Bouin, and A. Friedmann, Compt. rend., 1971,272, C,5. K. Schaumburg, Canad. J. Chem., 1971,49, 1146. E. J. Vincent, R. Phan-Tan-Luu, and J. Metzger, Compt. rend., 1970, 270, C, 666. E. J. Vincent, R. Phan-Tan-Luu, J. Roggero, and J. Metzger, Compt. rend., 1970, 270, C, 1688. R. A. Olofson, J. M. Landesberg, and K. N. Houk, J . Amer. Chem. SOC.,1966, 88,

I1

Ia Ia

.w 66

67

68

4265.

596


substitution of hydrogen by deuterium at C-2 in thiazole may occur by two mechanisms. At high pH, a simple base-induced proton abstraction is operative (Scheme A). At intermediate pH, the main exchange route is an equilibrium protonation on nitrogen, followed by a rate-determining C-H ionization (Scheme B).69

Scheme A

I

D

Scheme B

D

Measurements of the rate of detritiation in (46)-(48) have provided data concerning the base-catalysed hydrogen exchange in thiazolium salts. The results may have some bearing on the interpretation of enzymatic reactions involving thiamine.60

Free-radical Reactions.-2-Thiazolylhydrazine and the three isomeric thiazolecarbonyl peroxides may serve as thiazolyl radical precursors, the free radicals being generated by oxidation with silver oxide or by thermal deomposition :61 RNHNH,

+ Ag,O (RCO),O

-&-Ha0

>

RN=NH

RC02*

R*+H*+Nz

+ R* + COz

The generation of 2-thiazolyl radicals (49) in benzene, bromobenzene, or cumene affords thiazole, together with fair yields of 2-arylthiazoles, but negligible amounts of esters. The use of thiazole-4-carbonyl peroxide in benzene produces, in addition to thiazole, both 4-arylthiazoles and the phenyl ester as main products, indicative of the participation of both 4-thiazolyl radicals (50) and thiazole-4-carboxyl radicals. The 5-peroxide R. A. Coburn, J. M. Landesberg, D. S. Kemp, and R. A. Olofson, Tetrahedron, 1970, 26, 685. O 0 D. S. Kemp and J. T. O'Brien, J. Amer. Chem. SOC.,1970, 92, 2554. a A. Lee, D. Mackay, and E. L. Manery, Canad. J. Chem., 1970,48, 3554.

Thiazoles

597

(49)

(50)

(51)

appears to give radicals of low reactivity, no products diagnostic of either 5-thiazolyl (51) or thiazole-5-carboxyl radicals being obtained.61 The 4and 5-carbonyl peroxides required in this work are obtainable61 by an ingenious variation of an existing mefhodyp2taking advantage of the solubility of the parent acids and of l-cyclohexyl-3-(2-morpholinoethyl)carbodi-imide in water, Addition of 50% hydrogen peroxide to a solution in aqueous acetone of the acid and the di-imide precipitates the carbonyl peroxide directly. The procedure avoids the use of the hazardous ethereal hydrogen peroxide.61 The action of cyclohexyl radicals on thiazole, its three methyl, and three dimethyl homologues introduces cyclohexyl residues into the heterocyclic nucleus, preferably in the 2-position if this is available. Thiazole itself yields 2-, 4-, and 5-cyclohexylthiazolesin 73, 14, and 13%yield, respectively. Hydrogen abstraction from the side-chain of alkylthiazoles produces, in addition, compounds formed by the following sequence

The photolytic rearrangement of thiazole compounds to isothiazole derivatives is dealt with in Chapter 12 (see p. 563). Alky1ation.-Under the appropriate conditions 2-amino-4-methylthiazole may be alkylated in its 5-position yielding, for example, the 5-t-butyl homologue (52). Further methylation occurs at the ring nitrogen, affording (53).64 Nitrogen heterocyclics undergo perfluoroalkylation on being heated with perfluoroalkyl iodides.e6 The reaction has provided 2,4-dimethyl-5perfluoro-n-propylthiazole (54) in 50% yield.6s The compound is conF. D. Greene and J. Kazan, J. Org. Chem., 1963,28, 2168. G. Vernin, H. J. M. DOU,and J. Metzger, Compt. rend., 1971, 272, C, 854. 64

66

66

V. A. Krasovskii and S. I. Burmistrov, Khim. geterotsikl. Soedinenii, 1969, 56 (Chem. A h . , 1969, 70, 115 051e). L. M. Yagupol’skii, A. G. Galushko, and M. A. Rzhavinskaya, Zhur. obshchei Khim., 1968,38,668; L. M. Yagupol’skii, A. G. Galushko, and V. I. Troitskaya, ibid., p. 1736. L. M. Yagupol’skii and A. G. Galushko, Zhur. obshchei Khim., 1969,39,2087 [J. Org. Chem. (U.S.S.R.), 1969, 39, 20411.

598


vertible, after quaternization, into the carbocyanine (55) and merocyanine (56) dyes by conventional methods. The perfluoropropyl group causes opposite displacements of the absorption maximum in the two dyes: in the carbocyanine the peak is shifted by 13 nm towards the longer wavelengths, in the merocyanine by 15 nm towards the shorter wavelengths.6s

2-(4’-Thiazolyl)benzimidazole (57; R = H) (widely used as an anthelmintic and fungicide under the name ‘Thiabendazole’) is preferentially N-alkylated in the benzimidazole moiety, giving (57; R = Me, CH2Ph, or n-CaHls).67 The site of the alkylation is confirmed by the absence of the N-H stretching frequency in the i.r. spectra of the products, and by the characteristically large chemical shift of the aliphatic protons adjacent to nitrogen (cf. ref. 68). The use of dihalogenoalkanes in this reaction affords the appropriate a,w-bisbenzimidazolylalkanes(58).67

(57)

Electrophilic Substitution.-The ring nitrogen in thiazole deactivates the heterocyclic nucleus towards electrophilic substitution : its promotion requires the presence of electron-releasing groups. It is of interest that bromination of 2-amino(or acetylamino)-4-(2’-furyl)thiazole(59; X = Y = H) occurs successively in the furan and thiazole rings, giving rise to the mono- (59; X = Br, Y = H) and di-bromo-derivatives(59; X = Y = Br) in excellent yield.45 J. A. Maynard, I. D. Rae, D. Rash, and J. M. Swan, Austral. J. Chem., 1971,24, 1873. Pecher, R. H. Martin, N. Defay, M. Kaisin, J. Peeters, G. van Biust, N. Verzele, and F. Alderweireldt, Tetrahedron Letters, 1961, 270.

a P.

599

Thiazoles

Nitration by mixed acid of 4-(or 5-)alkylthiazoles yields 5-(or 4-)mononitro-derivatives in variable yields. 5-Nitration is in accord with the highest electron density of this position in the structure.6B Similarly, nitration of 2-methoxythiazole produces a mixture of the 5-nitro- (75%) and 4-nitro- (25%) derivatives, separable by chromatography. 5-Methoxythiazole is nitrated at its 4-position (75%).70 Mercuration of 2,4-dimethylthiazole by mercuric acetate in acetic acid yields the 5-mercuriacetyl compound (60), which is reconverted into the starting material by hydrochloric acid, and into the 5-bromo-analogue by halogenation in carbon tetrachloride. In 2-phenyl-4,5-dimethylthiazole, the phenyl nucleus is mercurated preferentially, resulting in Z-(p-mercuriacetylphenyl)-4,5-dimethylthiazole(61)in low yield (9%).'l -N

Miscellaneous Substitutions.-The enhanced reactivity of the 2-methyl group in thiazole is illustrated by the hydroxyalkylation of 2,ddimethylthiazole to the alcohols (62), on successive treatment with lithium amide in liquid ammonia, and with a carbonyl compound; the products are readily dehydrated to the ethylenes (63).7a

2-Aryl-4-chlorornethylthiazoles (64)undergo the Sommelet reaction with hexamethylenetetramine, affording the aldehydes (66) by way of intermediate quaternary salts (65).26 In their continued study of thiazole derivatives suitable as precursors of thiazolo[4,5-d]pyridazines, e.g. (69) (cf. Volume 1, p. 381), Robba and 70

71

72

A. Friedmann, D. Bouin, and J. Metzger, Bull. SOC.chim. France, 1970, 3155. A. Friedmann, Compt. rend., 1969,269,C, 1560. S. L. Gusinskaya, V. Y.Telly, and T. P. Makagonova, Khim. geterotsikl. Saedinenii, 1970,345 (Chem. A h . , 1970,73,66 486b). C. Ivanov, V. Dryanska, and I. Arnaudova, Doklady Bolgar. Akad. Nauk, 1969, 22,

891 (Chem. A h . , 1970,72, 31 674p).

600

'

'

Organic Compounds of Sulphur, Selenium, and Tellurium C1' C 6 H 1 2 N 4 H , C -)Ar ~Y

]

OHCLN JAr

LeGuen 73 have prepared 4,5-dicyanothiazoles (68) by the dehydration of the corresponding dicarboxamides (67). The dinitriles are convertible, by conventional methods, into cyano-aldehydes, dialdehydes, and cyanoketones.73 Reactions of Aminothiazo1es.-Aminothiazoles are obtained most conveniently by direct cyclizations (see Table l), but are also accessible from the preformed heterocycle by appropriate modification of other substituents. The reactivity of 2-halogeno-groups in thiazoles towards nucleophilic reagents (see Volume 1, p. 389) is enhanced by the activating influence of 5-nitro- or 5-carboxy-groups. Accordingly, 2-bromo-5-nitrothiazole reacts readily with dimethylamine, piperidine, or hydrazine (as well as thioureas, sodium methoxide, or hydrochloric acid) to yield the appropriate 2-substituted 5-nitrothiazoles (70; R = NMe,, )N(CH2)5, NHNH2, SH,

OMe, or OH).74 A more efficient approach to these 2-amino-heterocycles is the nitration of 2-dimethylamino(piperidino or morpholino)thiazoles, which proceeds in 70-75% Diazotization of 2-aminothiazoles (71) in borofluoric-phosphoric acids affords high yields of thiazolyl-2-diazonium tetrafluoroborates (72) as yellow crystalline fairly stable solids.76 These afford 2-fluorothiazoles (73;X = F) on being carefully heated under reduced pressure in admixture with sand and potassium fluoride, or on being warmed to 60-80 "C in 7s 74 76

76

M. Robba and Y.Le Guen, Bull. SOC.chim.France, 1970, 4026. A. Friedmann and J. Metzger, Compt. rend., 1970, 270, C, 502. A. Friedmann and J. Metzger, Compt. rend., 1969,269, C, 1000. C. Grunert, H. Schellong, and K. Wiechert, 2.Chem., 1970.10. 116.

Thiazoles

601

toluene (Balz-Schiemann reaction 77). The 2-fluorothiazoles are generally steam-volatile liquids and resemble their chloro-analoguesin their chemical proper tie^.^^ Other well-established exchange reactions convert thiazolyl-2-diazonium tetrafluoroborates (72) into a range of 2-substituted thiazoles (Scheme 4).

Scheme 4

The action of the appropriate alkali-metal salts yields 2-halogeno- (73) or 2-thiocyanato-derivatives (74) [and thence thiazoline-Zthiones (75)]. Sodium azide at - 5 "C produces thiazolo[3,2-d]tetrazoles(76). Thiourea in acetonitrile at - 5 "C reacts additively, affording yellow crystalline thiazol-2-yldiazo-isothiuronium tetrafluoroborates (77), but action of an excess of the reagent on either (72) or (77) caues loss of nitrogen and formation of the thiones (75),78 2,3-Diphenyl-4-aminothiazol~umchloride (78) reacts with aniline at room temperature to give a product formulated as 2-phenyl-4-anilinothiazole (80). Since the same product arises under the influence of o-toluidine, the 4-anilino-group is apparently not derived from the arylamine used as the reagent, but is formed by rearrangement of cyanomethyl N-phenylbenzthioimidate(79), which is also found to yield (80) on treatment with aniline. However, the action of other amines is not entirely consistent with this interpretati~n.~~ The amino-group in thiazoles undergoes the expected condensation reactions with activated methylene and related groupings. 2-Amino-4(3-methyl-4-isothiazolyl)thiazole(8 1) is convertible, by means of diethyl

cl-

ph$yNHz PA, (78)

7' 78 70

--HCI_, -

, ,

PhN CN PhC,s,CH2

- TJNHPh

(79)

G. Balz and G. Schiemann, Berichre, 1927, 60, 1186. C. Griinert and K. Wiechert, 2. Chem., 1970,10, 396. S. Sat0 and M. Ohta, Bull. Chem. SOC.Japan, 1968, 41, 2801.

PAs

(80)

602


ethoxymethylenemalonate, into the aminomethylenemalonate (82). Further action of morpholine yields a mixture of the original amine (81) and the condensation product (84), possibly via the intermediate (83) formed by an initial Michael addition.80

The condensation of substituted 2-aminothiazoles with paraformaldehyde and acetophenone in boiling ethanol affords 40-50% yields of 2-@-benzoylethylamino)thiazoles (85).*l Schiff's bases (86), derived from 2-amino-4-phenylthiazole,are readily prepared and are reduced catalytically to (87).82 CH,O CH,COAr

R,:cJN

HcH,cH,coAr (85)

(86)

(87)

2-Aminothiazole and 3-methylacrylophenone react in boiling ethano in the proportion 2 : 1 with loss of ammonia to yield a yellow condensation product to which structure (90) has been assigned, chiefly on the basis of its spectroscopic porperties. Its formation is thought to involve conjugate addition of the nitrogen of the heterocycle to the a/3-unsaturated ketone, 81

S. Rajappa, K. Nagarajan, and A. S. Akerkar, Indian J. Chem., 1970,8,499. J. M. Singh and B. N. Tripathi, J. Indian Chem. SOC.,1970, 47, 23. P. Bessin, 0. Tetu, and M. Selim, Chim. Therapeut., 1969, 4, 220 (Chem. Abs., 1969, 71, 101 762w.)

Thiazoles 603 producing the resonance-stabilized cation (88). Abstraction of the hydrogen a to the carbonyl group in (88) allows condensation of a second molecule of 3-methylacrylophenone, affording the ionic species (89) ; the latter ring-closes with elimination of ammonia to give the final product Yellow adducts resulting from the condensation of 2-aminothiazole or 2-aminobenzothiazole with /l-diethylaminopropiophenone that have previously been described 84 can now be formulated analogo~sly.~~

-

PhCO

1

CI-I=CHMe

I

PhCO

Diamines incorporating the thiazole ring-system, e.g. (91), are useful components of high-polymer structures.8K Ring Cleavage.-The ring cleavage of thiazoles in alkaline media, studied with model thiazolium ions by a combination of kinetic and spectral methods, appears to be initiated by the following stages:B6

The thiazole nucleus can also be cleaved by photosensitized oxidation : 2,4,5-triphenylthiazole consumes 0.45 mole of oxygen in methanol in the presence of a sensitizer, to form benzil and benzamide (11 and 18%), presumably via the cyclic peroxide (92) and the Schiff's base (93).*' In 88 84

86 87

J. A. Findlay, R.,F. Langler, C. Podesva, and K. Vagi, Canad.J. Chem., 1968,46,3659. C. Podesva and K. Vagi, Canad. J. Chem., 1966,44, 1872. H.E. Kunzel, G. D. Wolf, F. Bern, G. Blankenstein, and G. E. Nischk, Makromol. Chem., 1969,130, 103. P. Haake and J. M. Duclos, Tetrahedron Letters, 1970, 461. T. Matsuura and I. Saito, Bull. Chem. SOC.Japan, 1969, 42, 2973.


604

-

::CJpl1

Ph -N p]~&&Ph 0-0

J

(92)

(93)

non-polar solvents, e.g. chloroform, consumption of 0.9 mole of oxygen results in a red compound (30%) formulated as (97), which is degraded to thiobenzamide (50%) by boiling methanol, or to tribenzamide (10%) by aqueous silver nitrate (Scheme 5). One of the proposed pathways of this

;!c)fPh

-[

-

. F j P h

*;'&JPh

0I (94a)

PhCSNH,

(PhCO),N

O-O(94V

PhC-N-CSPh I1 I 0 CO I Ph (97) Scheme 5

1

t-

Ph 0 ' Z J P h Ph (95)

0 PhC-N ll

J

PhC,-,CPh I' II s 0

(96)

photo-oxidation involves an intermediate zwitterionic peroxide [(94a) or (94b)l. Its rearrangement to a four-membered cyclic peroxide (93,followed by ring-cleavage to N-benzoyl-S-benzoylisothiobenzamide(96) and final intramolecular rearrangement, would account for the observed production of (97).8' 2-Phenyloxazol-5(4H)-ones are effective acylating agents, useful in the preparation of N-terminal N-benzoyl-di- or oligo-peptides. The sulphur analogues (98) of these reagents have proved to react similarly.88 Terminal N-thiobenzoyloligopeptides (99; X = OH or amino-acid residue) are generally readily accessible by treatment of amino-acids or peptides with

.&sR; 3. H2NCHR2COX

PhCS*NH*CHR**CONH*CHR2COX (99)

(98) G . C. Barrett, J. Chem. SOC.(C),1971, 1380.

Thiazoles 605 an excess of 4-substituted 2-phenylthiazol-5(4H)-onesin acetic acid. The removal of the thiobenzoyl grouping from the derivatives (99) thus obtained is being studied.88 Conversely, optically active 4-substituted 2-phenylthiazol-5(4H)-ones are obtainable by cyclization of N-thiobenzoyl-L-aamino-acids, using dicyclohexylcarbodi-imide; they are more susceptible to racemization than the corresponding optically active oxazolones.88 Ring Expansion to 1,4-Thiazines.-In recent years, Takamizawa and his co-workers have developed a general ring-expansion reaction of wide scope in the heterocyclic field. Applied to thiazolium it provides a synthesis of 1,4-thiazines, an important example of which is the conversion of thiamine (100)into the thiazine (101);90it is effected by the successive action of dialkyl acylphosphonates and alkali.

(101)

Amongst several cases studied, the action of diethyl benzoyl(or acety1)phosphonates (102; R = Ph or Me) on 3-benzyl-4-methyl-5-(2-benzoyloxy)ethylthiazolium halides (103) is found to give adducts (104), which are converted into the substituted 3-oxo-l,4-thiazines (105) by alkali, or into the corresponding 3-(alkyl)imino-l,4-thiazines (106) by ammonia or primary amines (Scheme 6).89 The structure of the adducts (104) follows chiefly from their spectral properties, and from their degradation, by successive hydrogenation [to (107) and (lOS)] and ozonolysis to the simpler thiazol-2-one (109) and benzaldehyde. The rate of the rearrangement of the intermediate (104) to the final thiazine (105) was measured by observing changes in the U.V. A detailed mechanism, both of the phosphonate addition and the ring-expansion process, was Further application of this reaction to yet simpler starting materials, viz. 3,4-dimethylthiazolium bromide (1 lo), has given entirely comparable results [(llo) + (111) -+(112; R = Me or Ph)].gl The use of additional 89

O1

A. Takamizawa, Y. Hamashima, and H. Sato, J. Org. Chem., 1968,33,4038. A. Takamizawa, Y. Hamashima, Y. Sato, H. Sato, S. Tanaka, H. Ito, and Y . Mori, J. Org. Chem., 1966,31, 2951; Chem. and Pharm. Bull. (Japan), 1967, 15, 1178, 1183. A. Takamizawa, Y. Hamashima, H. Sato, and S. Sakai, Chem. and Pharm. BUN. (Japan), 1969,17, 1356.

606


-PhCHO

PhCHzA S

f---

L/

PhCHzN

Me CH2CH20COPh

LA

Me CH2CHzOCOPh

CHtPh

PhCH2GA,S

X-

\--I

Me CHzCH20COPh (107)

t

R

(Et0)gPOCOR (102)

' X PhCHzfibs

Li

Me CH,CH,OCOPh (103)

PhCH,N

L f

Me X

(W

p-

O

H

phcH2N Me CH2CH20COPh

S

\=/

Me X -#

I CH '0*PO(OEt)z > PhCH,N+b S

(105)

(106) Scheme 6

examples too numerous to detail in this present account clearly shows the general nature of this ring enlargement. The analogous ring expansion of 1,3,4-thiadiazoliumsalts to thiadiazines is reported in Chapter 15 of this volume (see p. 741).

Dimerization.-Quaternary thiazolium salts are ring-opened in aqueous, but dimerized in anhydrous, alkaline media. Preliminary results (Scheme 7) show that anhydro-bases of N-phenacyl-4-methylthiazoliumsalts (113) are dimerized by methanolic sodium methoxide to yellow labile products that

Thiazoles

607

are provisionally formulated as (115). The primary formation of the betaines (1 14) is confirmed by their conversion, in situ, into (1 16) by acrylonitrile, and into (1 17) by phenyl isothi~cyanate.~~ Azines and Dyes.-In their wider investigation of two-etage redox systems, Hiinig and Sauer 93 have studied the reversible oxidation of thiazol-Zone azines (121) to (122) and (123). The required rnodel-compounds (121) are

92

J. Frohlich, U.Habermalz, and F. Krohnke, Tetrahedron Letters, 1970, 271.

Organic Compounds of Sulphur, Selenium,and Tellurium 608 synthesized from thiazole-Zthiones (1 18) which are quaternized to (119) and converted, by the action of hydrazine under the appropriate conditions, to the hydrazones (120) or the azines (121), in yields up to 50%. The yellow azines (121) are oxidized to the red azo-dications (123) by concentrated nitric acid, or by perchloric acid-sodium perchlorate-lead(Iv) acetate in glacial acetic acid. The intermediate radical cations (122) ('Violenes') are obtainable, with some difficulty, from equivalent quantities of (121) and (123). They form dark green-blue crystals, which decompose on attempted purification, but may be stored at - 50 "C. The U.V. spectra of the three oxidation states of the azines were described and An extensive polarographic examination of this redox system [(121) t-) (122) t-) (123)] reveals two reversible one-electron exchanges (El,E2), involving the very stable radical cation (122), with a K value of 107-1010. The pK values of the azines (121), estimated by the variation of El with the pH in aqueous acetonitrile, are found in the range 2.8-3.8, depending on the nature of the s u b s t i t ~ e n t s . ~ ~ A series of p-dialkylaminostyryl dyes (124), their aza- (125), and diazaanalogues (126), all derived from 4,5-diarylthiazoles, have been prepared Q6 by existing methods 96 and their light absorption examined. The replacement

+

x-

of -CH=CHby -CH=Nor -N=Nis attended by a bathochromic displacement of their U.V. absorption maxima. The p-dialkylaminostyryl dyes possess sensitizing action in regions higher than their absorption maxima, but this is lost in the aza- and diaza-analog~es.~~ S. Hiinig and G. Sauer, Annalen, 1971, 748, 173. Q* S. Hiinig and G. Sauer, Annalen, 1971,748, 189. O6 K. Mukherjee, S. Misra, C. S. Panda, G. B. Behera, and M. K. Rout, J. Indian Chem. SOC.,1970, 47, 323. O6 M. K. Rout, P. K. Misra, P. K. Jesthi, and P. C. Rath, Indian J. Chem., 1966, 4, 24. O3

Thiazoles 609 Thiazolocyanines of type (127) and (128), derived from 3,s-diarylthiazolium salts, have been de~cribed.~'Further examples are given in the section dealing with the alkylation of thiazoles (p. 597).

(127)

(128)

Metal Complexes.-In an extensive study of the complexing power of thiazoles, numerous zinc@), cobalt(@, copper(ir), nickel@), and platinum(n) complexes of the parent compound, and of 4-alkyl- or 2,4-dialkyl-thiazoles, usually of the general type MX2L2,have been prepared.Da A consideration of their spectral and magnetic properties reveals that the zinc and cobalt complexes are tetrahedral, the 4-methyl copper and nickel complexes a r t octahedral, and the dialkyl complexes of copper and nickel and the platinum complexes are square planar. The four-co-ordinate dialkyl complexes follow the crystal field stabilization energy predictions as to the relative tendency to form tetrahedral or square-planar forms, i.e. Zn > Co > Cu > Ni. The complexes are invariably metal-nitrogen, and not metal-sulphur, co-ordina ted.D8 2-Methylthiazol-4-yl phenyl ketoxime forms a chloroform-soluble green complex with copper(@ salts. Spectrophotornetric measurements show that each metal ion binds two molecules of ligand.Da 3,4-Dialkylthiazolium halides and thiamine yield solid adducts with zinc(x1) and cobalt(u) halides. According to their spectra and magnetic susceptibilities they appear to be complex salts without metal-sulphur or metal-nitrogen interaction.loO 2-(2-Thiazolylazo)-1,8-dihydroxynaphthalene-3,6-disulphonic acid derivatives, e.g. (129), and their benzothiazolyl analogues, s.g. (130), give complexes of contrasting colours with Al, Zn, Zr, Th, and Ga, and are therefore useful reagents in the photometric analysis of these and other elements. Aluminium, for example, forms a green complex, having an absorption peak at 630nm ( E = 45 x 103).101s102Palladium(@ forms green 1:1 complexes with the comparable azothiazole derivatives (131; X = H or Br). Their characteristic absorption in the U.V. region provides the basis of a procedure for estimating Pa" in the presence of other mefals.lo3 n7

Y.D. Sych and 0. V. Moreyko, Khim. geterotsikl. Soedinenii, 1970, 1034 (Index

Chemicus, 1970,39, 170 823). J. A. Weaver, P. Hambright, P. T. Talbert, E. Kang, and A. N. Thorpe, Znorg. Chem., 1970, 9, 268. nn V. S. Bhagwat, S. W. Dhawale, and G. M. Pandit, J. Indian Chem. SOC.,1971,48, 337. loo P. T. Talbert, J. A. Weaver, and P. Hambright, J. Inorg. Nuclear Chem., 1970,32,2147. lol S . B. Savvin and Y . G. Rozovskii, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1968,2666 (Chem. Abs., 1969,70, 68 239k). lox S. B. Savvin, Y . G. Rozovskii, R. F. Propistsova, and E. A. Likhonina, Zhur. analit. Khim., 1970,25,423 (Chem. Abs., 1970,73, 10338n). loSA. I. Busev, L. S. Krysina, T. N. Zholondkovskaya, G. A. Pribylova, and E. P. Krysin, Zhur. analit. Khim., 1970, 25, 1575 (Index Chemicus, 1970, 39, 166 567).

21

610


-N=N HQ

OH

R - H03S

l-(2-Thiazolylazo)-2-hydroxy-3-naphthoicacid [‘TAHN’ (1 32)] is used as complexing indicator in alkaline solution (PH < 9): it forms pinkviolet chelates with various metals and gives a sharp end-point in the titration of Cu or Ni with H,edta.lo4 1-(2-Thiazolylaz0)-2-naphthol (‘TAN’) is similarly used in the spectrophotometric determination of nickel.lo5 The use of azo-derivatives of thiazoles in inorganic analysis has been reviewed.lo6 5 Biochemical Aspects Thiamine (Vitamin Bd.-The structure and stability of the thiazolium ion are of particular interest because of its possible role as the active site in thiamine. In considering the function of sulphur in the mechanism of action of this vitamin, Breslowlo7 was led to discuss the structure of thiazolium ylides: he suggested an overlap of a sulphur d,, orbital with the filled sp,p, orbital at C-2. d-a Overlap as a possible stabilizing factor in thiazolium ylides, suggested by Olofson and his co-workers,lo*has found support from quantitative comparisons of oxazolium and thiazolium ions.lo@Thus, the relative second-order rate-constant for the exchange of lo‘

H. Wada and G. Nakagawa, Nippon Kagaku Zasshi, 1968, 89, 951 (Chem. Abs.,

lo6

H. Wada and G. Nakagawa, Analyt. Letters, 1968, 1, 687 (Chem. Abs., 1968, 69,

1969, 70, 16 854n). 83 148c).

I. Busev, V. M. Ivanov, and L. S . Krysina, Sourem. Metody Analit. Muter., 1969, 135 (Chem. Abs., 1970,73, 136940~).

loo A. lo’

R. Breslow, in ‘The Mechanism of Action of Water-soluble Vitamins’, Ciba Study Group No. 11, Little, Brown and Co., Boston, p. 65; Ann. New York Acad. Sci.,

1962, 98, 445. A. Olofson, W. R. Thompson, and J. S . Michelman, J. Amer. Chem. SOC.,1964, 86, 1865; 1966, 88,4265. loo P. Haake and W. B. Miller, J. Amer. Chem. Soc., 1963, 85,4044; P. Haake and L. P. Bauscher, J. Phys. Chem., 1968,72,2213.

lo8 R.

Thiazoles 611 H-2 in 3,4-dimethyl-oxazolium, -thiazolium (1 33), and 1,3,4-trimethylimidazolium ion are respectively 106J: 103a5: 1. On the other hand, the 13C-H coupling constants at the 2-position in homologous imidazolium and thiazolium ions do not differ appreciably from one another, indicating

that these C-H bonds are similar in the ground state.llo The greatly enhanced exchange rate in thiazolium compared with imidazolium ion suggests that, in the sulphur heterocycle, the transition state for ylide formation is considerably stabilized. This indicates a special effect of the sulphur and underlines the importance of the thiazolium ion in the biological function of thiamine.ll0 Thiamine pyrophosphate is the essential coenzyme in the enzymatic decarboxylation of pyruvate to acetaldehyde. It has been proposed ll1 that the decarboxylation proceeds by way of 24l-carboxy-l-hydroxyethy1)thiamine pyrophosphate [(134a)arising from pyruvic acid and the coenzyme],

CH,-

R2= 0,P,0*CH2CH,3'

NHa

b; R1 = Me

..

R2= H

which is decarboxylated to 2-( 1-hydroxyethyl)thiamine pyrophosphate (1 35a) ; subsequent loss of acetaldehyde regenerates the thiamine pyrophosphate. The intermediate (135a) has in fact been isolated under suitable conditions. These views have prompted model experiments 112 involving 2 41-carboxy-1-hydroxyethyl)-3,4-dimethylthiazolium [CHDT (134b)l chloride, a greatly simplified analogue of the postulated coenzyme intermediate, and an examination of the kinetics of its (non-enzymatic) ll1

lla

P. Haake, L. P. Bauscher, and W. B. Miller, J. Amer. Chem. SOC.,1969, 91, 1113. R. Breslow, Chem. and Ind., 1957, 893. J. Crosby, R. Stone, and G. E. Lienhard, J. Amer. Chern. SOC.,1970, 92, 2891.


612

decarboxylation [to (135b)].l12 The synthesis of this model compound was described in detail. The observed first-order rate constants for the decarboxylation of CHDT (134b) to (135b) in water at 67 "Cis found to be pH dependent; the reactive species is therefore considered to be the one in which the carboxy-group is ionized. The most likely mechanism of the reaction involves the zwitterion (136) and the planar neutral enamine (137), which is protonated [to (138)] in a subsequent rapid reaction.l12 The rate of decarboxylation is greatly increased in solvents less polar than water (half times: in water at 45.6 "C, 24 h ; in ethanol at 26 "C, 3.2 min). Comparison of this model with the pyruvate decarboxylase reaction shows that the enzyme accelerates the decarboxylation of (134a) in water by a factor of at least lo5. It is proposed that the enzymatic catalysis is effected through binding of the thiazolium H

q

i

-%c,q s II Me 0

(136)

g -co,,

HOJ---

-Y

3

I + Me H-B (137)

1-

\+

HO'?T

/\cAs

Me \CO,Et

I

CO,Et

H

(139)

(140)

moiety of (134a) in a region of the enzyme less polar than water, and that an enzymic solvent effect of this type is a major cause of catalysis in other thiamine pyrophosphate-dependent enzymatic reactions.l12 These conclusions are in agreement with the results of further detailed studies of the kinetics of the remainder of the stages [(138) -+ (139) -+ (140)] of the enzymatic decarboxylation, or models thereof.l13 For the wealth of experimental data and the extensive discussion, the reader is referred to the original papers.112, 113 Thiamine is rapidly cleaved hydrolytically to 5-hydroxyethyl-4-methylthiazole and 4-amino-5-hydroxyethyl-2-methylpyrimidinein Tyrode's solution, but is stabilized by the addition of L-histidine. Possible mechanisms of this stabilization have been examined; the effect of the histidine appears to be due to its complexing power with metal ions which initiate the destruction of the thiamine.l14 Miscellaneous Biochemical Contributions.-The enzymatic bromination of the thiazole ring has been described.l15 2-Acetamidothiazole or 2-aceto113 114 115

J. Crosby and G. E. Lienhard, J. Amer. Chem. Soc., 1970, 92, 5707. J. R. Boissier and J. P. Tillement, Ann. pharm. franc, 1969, 27, 743. S. L. Neidleman, A. I. Cohen, and L. Dean, Biotechnol. and Bioeng., 1969, 11, 1227.

Thiazoles

61 3

caetamido-4-methylthiazoleare halogenated in their 5-position by bromidehydrogen peroxide in 0.06 mol 1-1 phosphate buffer (pH 3) in the presence of chloroperoxidase, but not in the absence of the enzyme.ll5 The structure of aeruginoic acid, which is isolated from the culture medium of Pseudomonas aeruginosa, has been recognized as 2-o-hydroxyphenylthiazole-4-carboxylicacid, and confirmed by an unequivocal synthesis of the Hantzsch type.ll6 Thiazol-4-ylmethoxyaminehydrochloride acts as a histidine decarboxylase inhibitor, lowering brain histamine levels in Full details have now appeared concerning the metabolic fate of 2-(p-chlorophenyl)thiazol-4-ylaceticacid (‘Myalex’, see Volume 1, p. 392). Except for the formation of the acylglucuronide, the drug is not metabolized in monkeys. In dogs and rats, the metabolic process involves hydroxylation at the para-position, attended by loss or ortho-migration of the original p-chloro-substituent. The metabolites, as well as the unchanged drug, are excreted as glucuronide conjugates in urine, and in the unconjugated form in faeces.l18 2-(6’-Hydroxybenzothiazol-2’-yl)-4-hydroxythiazole(141) and some of its derivatives, which appear to be concerned in the bioluminescence of the firefly, have been prepared and their spectral properties examined.l19

Biological Activity.-2-Amino-4-ethoxycarbonylthiazoIe and its 2-acyl derivatives possess mitodepressive and mitostatic properties; 2-dichloroacetylamino-4-ethoxycarbonylthiazoleis the most effective compound of a series of analogues examined.120 Certain Schiff’s bases derived from 2-amino-5-phenylthiazoleand their reduction products show diuretic properties.8a A large range of 2-amino(and hydrazino)-5-nitrothiazoles are devoid of schistosomicidal activity, thus emphasizing the specificity of the highly active 1-(5-nitro-2-thiazolyl)-2-imidazolidinone[“iridazole’ (142)J that has been introduced ~ l i n i c a l l y .However, ~~ some related thiazole derivatives do exhibit moderate, e.g. (143),121 or promising activity against schistosomiasis. The internal Bunte salt S-2-{[2-(2-thiazolylcarbamoyl)ethyl]amino} hydrogen thiosulphate is highly active, and would seem to merit 116 117

11*

ll@ lZo

l2I

Y. Yamada, N. Seki, T. Kitahari, M. Takahashi, and M. Matsui, Agric. and Biol. Chem. (Japan), 1970, 35, 780 (Chem. Abs., 1970, 73, 35 2652). M. K. Menon, W. G. Clark, and D. Aures, Life Sci., Physiol. Pharmacol., 1971, 10, 1097. D. M. Foulkes, J. Pharmacol., 1970, 172, 115; Nature, 1969, 221, 582. N. Suzuki, M. Sato, K. Nishikawa, and T. Goto, Tetrahedron Letters, 1969, 4683. F. Gagiu, T.Suciu, 0. Henegaru, and Z. Gyorfi, Arch. Pharrn., 1970, 303, 102. I. Nabih and H. Zoroob, Experientia, 1971, 27, 143.


614

clinical evaluation in man, because of the benign nature of its known ~ide-effects.~~

Mesionic Thiazo1es.-A summary and discussion of the chemistry of mesionic thiazoles has been provided by experts in this field.4 Mesionic 5-aminothiazoles are accessible from N-thiobenzoylmethylaminoacetonitriles (145).122The starting materials (145) are produced by the thiobenzoylation of acetonitriles (144), and are converted into 5-aminothiazolium hydrochlorides (146) on treatment with hydrogen chloride in aprotic solvents (Scheme 8). Subsequent action of acyl chloride produces

R1

I MeNH-C-CN

I H

(145)

(147) Scheme 8

(149)

the corresponding N-acetyl- or N-benzoyl-aminothiazoliumchlorides (147), whence the free bases are liberated by basification.122 The formation of these mesionic compounds resembles that of sydnone i m i n e ~ . ' ~ ~ The thiazolium chlorides (146) are convertible into the rnesionic phenyl(thio)carbamoyl derivatives (148) by phenyl iso(thio)cyanate, and into the mesionic 5-benzenesulphonyliminothiazole (149) by benzenesulphonyl chloride in alkaline media (Scheme 8). Detailed spectral data for each of the new types of compound were provided.122 Formation from Mesionic Oxazoles. In the course of their compreheiisive researches on 1,3-dicycloadditions, Huisgen and his group 124 have developed 122 la8 124

T. Shiba and H. Kato, Bull. Chem. SOC.Japan, 1971, 44, 1864. H. Kato, M. Hashimoto, and M. Ohta, Nippon Kagaku Zasshi, 1957,78, 707. E. Funke, R. Huisgen, and F. C. Schaefer, Chem. Ber., 1971, 104, 1550.

615

Thiuzoles

a synthesis of mesionic thiazolium compounds by the cycloaddition of N-substituted oxazolium 5-olates to suitable thiocarbonyl compounds. Thus, the action of carbon oxysulphide on 3-methyl-2,4-diphenyloxazolium 5-olate (1 50) yields the corresponding thiazolium 5-olate (151), the structure of which is confirmed by its independent synthesis from thiobenzoylated N-methylphenylglycine (152) by cyclization with acetic anhydride.124 The action of carbon disulphide on (150) similarly yields the thiazolium 5-thiolate (154), possibly by way of the primary adduct (153).

Me

s ( 153)

Me

(154)

C02H S I II PhH(+CPh Me

(155)

S

PhLJPh (156)

The reaction is performed most advantageously by generating the required starting material (150) in situ: thus a stirred mixture of N-methyl-Nbenzoylphenylglycine, acetic anhydride, and carbon disulphide evolves carbon dioxide, affording (154) in 96% yield. The procedure is particularly useful when the oxazolium 5-olate is not i ~ o l a b l e . ~ ~ ~ The deep-orange 3-methyl-2,4-diphenylthiazolium5-thiolate (154) forms yellow solutions in acids, presumably owing to protonation of the exocyclic sulphur. Its oxidation by hydrogen peroxide in acetic-formic acids produces the 5-sulphonate (155) (91%); subsequent treatment with concentrated hydrochloric acid yields 2,4-diphenylthiazole (156).124 Anhydro-5-hydroxy-3-methyl-2-phenylthiazolium hydroxide (157) resists alkylation by conventional reagents, but is readily O-alkylated by triethyloxonium fluoroborate,lZSyielding 5-ethoxy-3-methyl-2-phenylthiazolium fluoroborate (158).126 In this respect, it resembles related mesionic systems based on 1,3,4- and 1,2,3-thiadiazoles (cf. Chapter 15). H. Meerwein, Org. Synth., 1966, 46, 113. 126

K.T.Potts, E. Houghton, and S. Husain, Chem. Comm., 1970, 1025.

616


6 2-Thiazolines Synthesis.-From (Thio)carbamoyZ Isothiocyanates. Carbamoyl isothiocyanates and thiocarbamoyl isocyanates are thermally interconvertible : X-CS-NCO =: X*CO*NCS.127In an extensive study of the preparation and chemical behaviour of these reagents, their use in heterocyclic synthesis was evaluated.lZ8 The course of their cycloaddition to isocyanides depends on the nature of their substituents giving, as main products, either the oxazolines (159) or the analogous 2-dialkylamino-5-iminothiazolin-4-ones(160), the structure of which is established by the two independent syntheses (b) and (c) (Scheme 9).12*

s N=C=O

I

--I-

CGN-RZ

N-C=O

-5-It R1,N

,C,

S

I

,C-NR3

t

TH2+

R ~ ~ N / ~ " Sci

+

C=O

I

,C=NR2

+

In an extension of this work, analogous [4 21 and [4 11 cycloadditions of thiocarbamoyl isothiocyanates (161) have been examined.129 Their interaction with isocyanides under restrained conditions yields 2-amino-5-imino-2-thiazoline-4-thiones (1 62) as deeply coloured stable R1,NCSCl PaSCN

(161) la' 128 lzS

(162)

(163)

J. Goerdeler and H. Schenk, Chem. Ber., 1965, 98, 2956; H. Schenk, ibid., 1966, 99, 1258; J. Goerdeler and K. Jonas, ibid., p. 3572. J. Goerdeler and D. Wobig, Annalen, 1970, 731, 120. J. Goerdeler and H. Ludke, Chem. Ber., 1970, 103, 3393.

Thiazoles

617

solids. According to their spectral properties the resonance form (163) contributes significantly to their ground state.lZ9 From Thioamides and AcetyZenedicarboxyZic Acid. The interaction of o-aminobenzenethioarnides and dimethyl acetylenedicarboxylatelSo does not yield the quinazoline-4(lH)-thione (164) as might be expected from the behaviour of the corresponding o-aminoben~amides,~~~ but produces 2-(o-aminophenyl)-5-methoxycarbonylmethylidene-2-thiazolin-4-one (165) in high yield.lS0

sI -C=CHCO,Me I

(165)

The structure of the condensation products of thioureas and dimethyl acetylenedicarboxylatehad not been assigned with certainty. This problem has now been resolved, in one case, by X-ray analysis.1s2 Thus the addition of N-thiocarbamoylpiperidine to the acetylenic reagent, which may theoretically give rise to six isomeric products, yields in fact 5-methoxycarbonylmethylene-2-piperidino-2-thiazolin-4-one, having the geometrical configuration shown in (166).lS2 Confirmation has also been provided that the reaction of thiourea with brornosuccinic, maleic, fumaric, or acetylenedicarboxylic acids yields, in each case, a 2-thiazoline, e.g. (167).lSs

H02CCH, CHBr I COzH

130 131

lSa 133

N. D. Heindel and M. C. Chun, J. Heterocyclic Chem., 1971, 8, 685. N. D. Heindel, V. B. Fish, and T. F. Lemke, J. Org. Chem., 1968, 33, 3997. A. F. Cameron, N. J. Hair, N. F. Elmore, and P. J. Taylor, Chem. Comm., 1970,890. F. W. Short, B. C. Littleton, and J. L. Johnson, Chem. andlnd., 1971, 705.


618

The results exclude possible alternative thiazine structures that have been considered from time to time. Further Syntheses from Thioamides (Linear and Cyclic). The acid-catalysed cyclization of N-allylthioureas provides a synthetic route to 2-thiazolines. The reaction, performed in 60-90% sulphuric acid, is initiated by protonation, producing the highly resonance-stabilized thiazolinium cations (168), and is completed by hydrolysis to (169). It is an example of Me

Me

Me

a group of analogous acid-catalysed ring-closures, including the conversion of N-allylamides, urethanes, or ureas to the corresponding oxazolinium cations and thence 2-0xazolines.~~~ Undheim and his co-workers136 have applied their extensive experience of the chemistry of thiazolo-[3,2-a]pyridinesand -[3,2-c]pyrimidines to a synthesis of 2-thiazolinium salts. Thus, thioamides and a-bromo-a,% unsaturated acids (170) react in boiling ethyl acetate to afford 2-substituted 4-carboxy-2-thiazolinium salts (172), generally in very good yield. The reaction proceeds via the intermediate adducts (171), which assume a cis configuration with respect to the double bond, so that the lone pair of electrons of the nitrogen can displace the bromine. This cis configuration is less favoured as the size of the substituents R1and R2increases, resulting in reduced reaction rates and diminished yields of (172). There is also considerable steric interaction between the substituents R1and R2in (172) : the resulting high-energy state confers instability on the molecule, which is R1

R1

As

R2' N H

HO,C ..H$z

Br

R2NH SH I I HO,C-CH -CHR3

la' ls6

.1

R2NH S-COR' I I H0,C-CH-CHR3

S. P. McManus, J. T. Carroll, and C. U. Pittman, J. Org. Chem., 1970,35, 3768. A. Eidem, K. Undheim, and K. R. Reistad, Acta Chem. Scad., 1971, 25, 1.

Thiazoles

619

reflected by the ease with which it is attacked hydrolytically at C-2. This sequence of reactions is therefore suitable for the preparation of the cysteine derivatives (1 74).135 The condensation of NN-disubstituted thioureas and iminochlorides of oxalic acid (175) [including bis-sulphonyliminochlorides (1 75 ; RS = S02Ph)] in tetrahydrofuran affords 2-dialkyl(or ary1)aminothiazolidine2,4-dione bisimides (176). Thiobenzamide generally yields linear adducts, e.g. PhCSNHC(: NPh)C(: NPh)Cl, but affords 2-thiazolines (177) under suitable THz R1R2N-C, S

+

CI-C=NR3 I CI-C =NR3 ?X2N

N NRJ ( 7 N R 3

phN4;j.NS0,Ph NS0,Ph

The reaction of 3-benzenesulphonyl-5,5-diphenyl-2-thiohydantoin (1 78) with two moles of piperidine yields 2-piperidino-4,4-diphenyl-2-thiazolin5-one (179),lS7the structure of which was confirmed by an alternative synthesis. Its heterocyclic ring is cleaved, to (180), by the action of toluenep-sulphonic acid, and re-formed under the influence of trifluoroacetic acid.

I

PhS0,CI

11

The synthesis appears to be a generally applicable route to 2-thiazolinones of this type.138 Conventional syntheses of the Hantzsch type have been employed for the production of 2-amino-4-(3-indolylmethyl)-2-thiazoline139 and 2,4,5trialkyl-4-hydroxy-2-thiazolines.140 J. Goerdeler and K.Briining, Tetrahedron Letters, 1970, 3781. A. Kobayashi, S. Umemoto, and A. Kagemoto, Yakugaku Zasshi, 1970, 90, 1372 (Chem. A h . , 197lY74,31712r). laa A. Kobayashi, S. Umemoto, and M. Kato, Yakugaku Zasshi, 1970, 90, 1377 (Chem. Abs., 1971, 74, 31 713s). laD T. Hino, K. Uoji, and S. Akaboshi, Chem. and Pharm. Bull. (Japan), 1970, 18, 384. I4O C. Roussel, A. Babadjamian, M. Chanon, and J. Metzger, Bull. Soc. chim. France, 1971, 1087. la'

620


2-Aminoethylisothiuronium salts (18 1) have been the object of special interest ever since their pronounced radioprotective activity was realized. In aqueous solution they undergo trans-guanylation to 2-mercaptoethylguanidine (1 82) or cyclization to 2-amino-2-thiazoline (1 83).141 The NH2CH2CH2S*C(:NH)NH2+ (181)

1

(183)

NH,(NH :)C*NHCH,CH,SH (1 82)

kinetics of these reactions have now been studied by a potentiometric titration technique, but the mechanism of the cyclization requires further e1u~idation.l~~ Linear macromolecules incorporating 2-amino-2-thiazoline have been produced with the aim of improving the thermal stability and other properties of the resulting polymers. Model experiments performed with 1-(3-phenoxy-2-hydroxypropyl)-3-phenylthiourea (1 84) provided information on the relative ease of formation of thiazoline or oxazoline rings under the influence of a variety of cyclizing agents.143 N PhOCH,CHCH,NHCNHPh +P h O C H 2 L J N H P h

I

OH

II

S

X=OorS

(184)

In the polymer synthesis, bisamino-alcohols and phenylene di-isothiocyanates (SCN-R2-NCS) yield polythioureas (185) which are ring-closed to the polythiazolines (186) by polyphosphoric acid. The use of other cyclizing reagents is liable to produce polymers containing both thiazoline and the more readily hydrolysable oxazoline rings in the main chain.143 From Aziridines. The well-known synthesis of 2-thiazolines (see Volume 1, p. 397) and thiazolidines (see this Volume, p. 636) by the ring expansion of aziridines has been further studied and utilized. 2-Thiazolium salts (1 87) are produced from 1-substituted aziridines and thioacetamide in the presence of perchloric acid. Thioformamide affords 141 142

143

J. X. Khym, R. Shapira, and D. G. Doherty, J. Amer. Chem. SOC.,1957, 79, 5663; 1958, 80, 3342. A. Hanaki, Chem. and Pharm. Bull. (Japan), 1970, 18, 1653, and previous papers quoted therein. Y. Iwakura, K. Kurita, and F. Hayano, J. Polymer Sci.,Part A-1, Polymer Chem., 1969, 7 , 3075.

621

Thiazoles OH

S

S

(185)

(1 86)

2-unsubstituted analogues that are not readily accessible by other methods. The extension to 1-substituted aziridines of reactions previously applied to ethyleneimine gives the expected products [(188) and (189)] when thiocyanate ion or thiourea is the n u ~ l e o p h i l e . ~ ~ ~

R1,+

XJ

R2

x-

Treatment of N-aroylaziridines with phosphorus pentasulphide in boiling toluene affords good yields of 2-thiazolines rapidly in one stage:

Reaction occurs either by a one-step concerted mechanism, or via aziridine1-thiones which isomerize to the 2-thiazolines under the reaction conditions. However, direct evidence for the formation of these intermediates has yet to be p r 0 d u ~ e d . l ~ ~ Bis-(2-chlorotetrafluoroethyl) disulphide (190), prepared from tetrafluoroethylene and sulphur monochloride, reacts with aziridine at - 20 to - 60 "C to yield mainly l,l,l-chlorodifluorotriaziridinylethane(191 ; 144

us

R. Westland, M. H. Lin, and J. M. Vandenbelt, J. Heterocyclic Chem., 1971, 8, 405. F. A. Vingiello, M. P. Rorer, and M. A. Ogliaruso, Chem. Comm., 1971, 329.

622

Organic Compounds of Sulphur, Selenium, and Tellurium m F2C=CF,

+

-

S,CI,

F2C1CCF,S

I

F?

\

I

N

H

F2CICCF2S

1

H N -s ~

40%), together with smaller quantities of 1 -chlorodifluoromethyl-2thiazoline (193 ; up to 16%). The substituted aziridinylthioamide (192) probably acts as an intermediate. 2,ZDimethylaziridine similarly yields the homologous 2-thiazoline (194), isolable by gas c h r ~ m a t o g r a p h y . ~ ~ ~ 2-Thiazoline Peptides. Hirotsu et al.l4' have continued their studies of model compounds and reactions designed to provide the basic information for a projected total synthesis of bacitracin A. This object requires a route to unprotected thiazoline peptides. Their synthesis has now been achieved by taking advantage of readily detachable protecting groups on the N-terminus of the peptide. Specifically, di- and tri-peptides incorporating 2-thiazoline were synthesized either by the imino-ether coupling method, or by the dehydration method previously described by the same authors 14* using benzyloxycarbonyl or benzyl ester residues as the protecting groups. Compounds (195) and (196) were synthesized in this way.147

s-7Hz I HBr,NH2CH2C+ ,CHCOX N HBr (195) X = NH2 or OH

S-CHZ I I HBr,NH,CH,C* ,CHCO-Leu- OH N HBr

The synthesis displays interesting stereochemical

(196)

Thus, ethyl

2-( 1-benzyloxycarbonylaminoethyl)-(R)-2-thiazoline-4-carboxylate (1 97)

was obtained (i) by the 'imino-ether route', by condensing L-2-benzyloxycarbonylaminopropioimino ethyl ether (198) and ethyl L-cysteinate hydrochloride (route A) and (ii) by the dehydration of benzyloxycarbony1-Lalanyl-L-cysteine ethyl ester (199) (route B).14* Acidic hydrolysis of the 14( 14'

14@

F. Lautenschlager, J. Heterocyclic Chem., 1970, 7 , 1413. Y. Hirotsu, T. Shiba, and T. Kaneko, Bull. Chem. SOC.Japan, 1970,43, 1564. Y . Hirotsu, T. Shiba, and T. Kaneko, Bull. Chem. SOC.Japan, 1967,40,2945,2950, Y . Hirotsu, T. Shiba, and T. Kaneko, Bull. Chem. SOC.Japan, 1970,43, 1870.

Thiazoles 623 resulting 2-thiazoline peptide (197) prepared by either method gives completely racemized DL-alanine and L-cystine, but hydrolysis of the starting material (198) gives optically pure L-alanine (Scheme 10). This Me I

ZNH-CH-C,

OEt HSCHZ I I 3. ,CHCOzEt NH li,N

A _I_,

s-YH2

Me 1 1 ZNHCH-C+N,CHC02Et

(198) Z = PhCHzOCO

I

J

DL-Alanine L-Cys t ine

L-Alanine

My

(19’)

\

\

Me I O II ZNHCH-C,

,Et YH F-YH,

SH

ZNH-CH-~&HCONH,

YHz

,CHCO,Et N H (199)

(2001 Scheme 10

implies that the N-terminal amino-acid of the 2-thiazoline peptide (197) is completely racemized in both thiazoline syntheses during the cyclization stage. The cysteine residue is unaffected sterically at this stage, but is racemized under basic conditions. Analogous thiazoline peptides, e.g. (200), behave similarly, but may undergo epimerization as well.lP0 The results are of significance in connection with the chemistry of bacitracin A, providing a better understanding of its racemization and loss of activity in acidic media, Furthermore, in a projected total synthesis of this material, racemization of the N-terminal isoleucine residue cannot presumably be avoided during the thiazoline-ring closure, and pure bacitracin A must be isolated by a final fractionation of the diastereoThe hypothesis that cysteine residues in polypeptides may give rise to thiazoline rings has been advanced many years ago.lSo According to its NH,

I

HS-CH2

I

H0,CCHCH2CH,C0 * N HCHCO *NHCH,CO,H

lli0

K. Linderstrorn-Lang and C. F. Jacobson, Compt. rend. Trav. Lab. Carlsberg, 1940, 23, 289; J. Biol. Chem., 1941, 137, 443.

624


spectrum, glutathione (201) incorporates these hetero-residues in its structure, but attempts to isolate this form have been unsuccessful. By using the ‘imino-ether method’,148Hirotsu et t11.l~~have succeeded in synthesizing glutathione incorporating the 2-thiazoline moiety (202) as an unstable hygroscopic product, and have reported some of its physical properfies.l6l U.V.

Physical Properties.-The pK, values of 2-methyl- and 2-phenyl-2thiazoline, determined potentiometrically,are 5.37 and 4.00, respectively.lK2 The optical stability of 2-thiazolines of type (203) has been estimated by measuring their rate of racemization in 0.1N methanolic triethylamine. 2-Methyl-~-4-carboxymethyl-2-thiazoline (203 ; R = Me) is more stable

than the phenyl analogue, but the presence of electron-releasing groups in the p-position of the phenyl ring increases the optical stability. The 2-methyl homologue (203; R = Me) is sufficiently stable to be purified by distillation under conditions which racemize the phenyl analogue.163 According to their spectral properties, 5-phenyl-2-thiazolin-5-ones (204) show a pronounced tendency to tautomerize to 5-hydroxythiazoles (205). The 4-methyl homologue assumes the thiazolinone configuration (204; R = Me) in chloroform, but shows the 5-hydroxythiazole structure (205; R = Me) in DMF and in the crystalline state. The extent of enolization is influenced by the basicity of the solvent. The 4-benzyl and 4-isobutyl homologues behave analogously, but enol formation is inhibited by 4-isopropyl and 4-s-butyl substituents (incorporating a-branching in their carbon chain).ls4 H

(206) 151

Y.Hirotsu, T. Shiba, and T. Kaneko, Biochim. Biophys. Acta, 1970, 222, 540.

162

J. Elguero, E. Gonzalez, J. L. Imbach, and R. Jacquier, Bull. SOC.chim. France, 1969, 4075.

15s

164

K. Undheim and A. Eidem, Acta Chem. Scand., 1970,24,3129. W. Steglich, G. Hofle, L. Wilschowitz, and G. C. Barrett, Tetrahedron Letters, 1970, 169.

Thiazoles

625

Solutions of these thiazolinones in polar solvents show a distinct yellow colour (Arnx 428 nm), which is accounted for by neither (204) nor (205), and is attributed, in agreement with precedent,15Sto the presence of small quantities of the mesionic thiazolinone (206),164 Toldy et al. have examined the applicability and limitations of n.m.r. and mass spectrometry in assigning tautomeric structures (207) or (208) to 2-arylamino-Zthiazolines 166 and to their sulphonyl (209) and (210) lK7

and benzoyl and have correlated the conclusions with the results of U.V. absorption The sum of the spectral evidence suggests that the parent compound, 2-phenylarnino-Zthiazoline, exists in the amino-form (207). Chemical Properties.-AlkyZation. 3-Alkyl-2-thiazolinium salts are readily accessible by direct quaternization of the appropriate 2-thiazoIine~.~~O 4Methoxycarbonyl-2-methyl-2-thiazoline, obtainable from L-cysteine methyl ester, is rapidly N-alkylated by methyl iodide and other reagents (Scheme 1 1).

R1

R1

R1

MeNH SH

EtO'C"*H

4-

HZN SH \ / HC-CH, I C02Me

C0,Me

C0,Me

CO2H

Scheme 11

Subsequent acidic hydrolysis of the quaternary salt proceeds with retention of configuration and provides an improved method of preparation of N-alkylcysteins, N-Methylation of the 2-phenyl analogue, on the other hand, is accompanied by hydrolytic ring opening and complete ra~emization.~~~ Acylation. The action of acid chlorides or anhydrides on 2-thiazolines produces, depending on the conditions, a variety of products including (a)compounds arising by cycloaddition to the imino-function, (b) derivatives 166

lS6 lS7

lS8 lSD

160

(a,

G. C. Barrett and A. R. Khokhar, J. Chem. SOC. 1969, 1117. L. Toldy, P. Sohar, K. Farago, I. Toth, and L. Bartalis, TetrahedronLetters, 1970,2167; J. Tamas and L. Toldy, ibid., p. 2173. L. Toldy, P. Sohar, K. Farago, I. Toth, and L. Bartalis, Tetrahedron Letters, 1970, 2177. L. Toldy, P. Sohar, and K. Farago, Tetrahedron Letters, 1970, 2183. L. Toldy and J. Liptak, Tetrahedron Letters, 1970, 4319. A. D. Clark and P. Sykes, J. Chem. SOC.(C), 1971, 103.

626 Organic Compounds of Sulphur, Selenium, and Tellurium of cysteamine, formed by ring-cleavage, (c) products of substitution of an exocyclic 2-methyl function, and ( d ) products arising by substitution at the ring nitrogen, attended by migration of the double bond.lsl The acylation of 2-methyl-2-thiazoline (211) with p-nitrobenzoyl chloride or phthaloylglycyl chloride in benzene yields initially 2-chloro-N-acylthiazolidines (212), which are dehydrohalogenated by triethylamine to 2-methylene-N-acylthiazolidines (214) or converted into 2-hydroxy(or

cJMe- LF1- G y NCORl

(21 1)

(2 12)

(213)

LXcZ (214)

methoxy)-N-acylthiazolidines (213; R2 = H or Me) by addition of water or methanol. Acylation of 2-methyl-3-thiazoline affords the isomeric 3-acyl-2-methyl-4-thiazolines.16z The results correct previous interpretations ls3 that were proposed before n.m.r. studies were possible. The acylation of 2-methyl-2-thiazoline (21 1) with acetyl chloride in acetonitrile containing a little water yields NS-diacetylcysteamine (216) exclusively (Scheme 12). In anhydrous acetonitrile the yields of this

&xzr+

N

k O R

fCH,CHz.NAr.CS-S3T;-

HZC-CHZ I I ArN, / S C II S

(277)

N-Arylaziridines (275) react with carbon disulphide to yield 8-1 5% of 3-substituted thiazolidine-2-thiones (277), together with 60--80% of the polymeric products (276). The latter are depolymerized to (277) in a vacuum at 200-300 "C, or in improved yields in boiling toluene. The interaction of the aziridines (275) with phenyl isothiocyanate gives excellent yields (85-95%) of 3-aryl-2-phenyliminothiazolidines(278).202 The cycloaddition of aziridines to heteromultiple bonds resulting in fivemembered heterocycles has recently been studied extensively by Huisgen and his co-workers.211 l-(p-Methoxyphenyl)-2,3-diphenylaziridine (279)

210

S . Gabriel and R. Stelzner, Berichte, 1895, 28, 2929; S. Gabriel and C. F. von Hirsch, ibid., 1896, 29, 2747. T. A. Foglia, L. M. Gregory, G. Maerker, and S. F. Osman, J. Org. Chem., 1971, 36,

211

R. Huisgen, V. Martin-Ramos, and W. Scheer, Tetrahedron Letters, 1971, 477.

2oB

1068.

Thiazoles 637 was used as model compound to establish the steric course and the kinetics of the ring-cleavage to the intermediate azomethine ylides. The aziridine reacts with methyl dithiobenzoate (24 h at 120 "C)to yield (63%) a mixture of the substituted thiazolidines (280)-(283) in the relative proportions 40 : 12 : 34 : 14. The cycloaddition thus furnishes all four theoretically possible racemates of a thiazolidine having three asymmetric centres.211

g

N H.p\.CO,M MeO,C H (279)

H

e

C,H40Me -p I

C,H,OMe-p H p 1I O i h l C Mc0,C

M e 0 2 C.: < ~s~ ( % MC (280) (281)

s

Rr,'

R' R:

KZ

R1 = Ph, R2 = SMe (282) R1 = SMe, R2 = Ph (283)

The production of substituted thiazolines from ketones, sulphur, and ammonia under restrained conditions is well documented.3s*12 Asinger et aLZ13have successfully employed ethyleneimine as one of the reactants in this versatile synthesis. Thus, slow addition of sulphur to a mixture of ethyleneimine and diethyl ketone, heptan-4-one, or an alicyclic ketone at ca. 20 "C yields 5,6-dihydro-4H-l,4-thiazines(284) as main products (60-90%) and 2,2-dialkylthiazolidines (285) as by-products (1 0-23%).214

zc,

S

, k ~ ~ R~-F,~,-CH,.

(284)

R2H,C

(285)

The products may be isolated by fractional distillation 214 but, on occasion, separation of the mixtures presents formidable difficulties, even by gas chromatography,216and the relative proportions of the products can only be computed indirectly after having been subjected to further reactions.216 Phenyl isopropyl ketone yields the thiazolidine almost exclusively (55%)."'4 The observed cyclizations may be accounted for by several mechanisms, but the experimental evidence does not as yet allow of a final choice.214 Under the usual conditions, ethyleneimines and aldehydes yield merely adducts, uiz. l-(hydroxyalky1)aziridines (286), which fail to react with 212 *18 *14 215

F. Asinger, M. Thiel, and I. Kalzendorf, Annalen, 1957, 610, 25, and subsequent papers; see also F. Kurzer in this Report, 1970, vol. 1, p. 440. F. Asinger, H. Offermanns, W. Piirschel, K. H. Lim, and D. Neuray, Monatsh., 1968,99,2090. F. Asinger, H. Offermanns, K. H. Lim, and D. Neuray, Monatsh., 1970, 101, 1281. F. Asinger, A. Saus, H. Offermanns, D. Neuray, and K. H. Lim, Monarsh., 1971, 102, 321.

638 Organic Compoundi of Sulphur, Selenium, and Tellurium sulphur, even on heating. In DMF, or in the presence of anhydrous potassium carbonate, however, the sulphur is rapidly consumed exothermally (Scheme 16): 5,6-dihydro-l,4-thiazines(290) are formed side by

RC,

S

--+ +,CH2

RCH-CH=N, I

S

,CH2

,CH2 RC=CH-N,) 1 CH2 SH (289)

CH2 (287)

Scheme 16

side with thiazolidines (288), the latter as main products.21s The reaction is regarded to proceed by dehydration of the initial adduct (286) to the enamine (287), followed by thiolation to the mercapto-compound (289); the thiol group of the latter cleaves the aziridine-ring nucleophilically, providing the entity suitable for iinal cyclization to (290). The action of hydrogen sulphide, which arises in the course of the reaction, on either (286) or (287) accounts for the production of the thiazolidines (288).,ls This last conclusion is fully confirmed experimentally, and, incidentally, provides a synthesis of thiazolidines from 5,6-dihydro-l,4-thia~ines.~~~ The action of hydrogen sulphide on 2,3-disubstituted (291) and 2,2,3trisubstituted 5,6-dihydro-l,4-thiazines(293) in chloroform, catalysed by n-butylamine, results in their simultaneous hydrogenation and ring contraction to 2,Z-disubstituted thiazolidines [(292) and (294)l. The more fully substituted examples (293) react slowly, but excellent yields are *la 917

F. Asinger, H. Offermanns, D. Neuray, and P. Miiller, Monarsh., 1970, 101, 1295. F. Asinger, H. Offermanns, and D. Neuray, Annalen, 1970,739, 32.

Thiazoles

639

(294)

(293)

invariably Conversely, the thiazolidines (292) and (294) are dehydrogenated and ring-expanded by sulphur, with evolution of hydrogen sulphide, to yield once again the initial 1,4-thiazines (291) and (293), albeit in lower yields. The evidence suggests that ring expansion is initiated by thiolatioii at C-1 in the side-chain of the thiazolidine ring.217 From Thiirans. The synthesis of oxazolidinium salts from oxirans 21* has been supplemented by that of thiazolidinium salts from thiirans (Scheme 17).21BThus, thiiran (295) reacts with dimethylchloromethylamine (296;

ClCH2CH,S H

[CICH2CH2.S.CH2NR2]

(297)

R = Me) in acetonitrile, presumably by way of the episulphonium salts (297), to afford NN-dimethylthiazolidiniumchloride (298) nearly quantitatively. In a parallel route to the same compounds, 8-chloroethylmercaptan (299) replaces the thiiran. The thiazolidinium salts are convertible into the stable cyclic sulphones (300) by peracetic acid. The use of styryl sulphide (301) similarly yields the expected 3,3-dimethyl4-phenylthiazolidinium chloride (302; 85%) ; its 5-phenyl isomer (303), 218

810

H. Bohme and P. Wagner, Chern. Ber., 1969, 102, 2651. H. Bohme and G . Dahler, Chern. Ber., 1970, 103, 3058.


640

S

PhCHCH,NH, I SH

- HCHO

SANH

u Ph

s , M e 2 } APh

(303)

(304)

required for comparison, was accessible by the condensation of 2-amino- 1phenylethanethiol (304) and formaldehyde, followed by m e t h y l a t i ~ n . ~ ~ ~ From 1,4-Thiazines by Ring Contraction. See syntheses from aziridines, above. From Thiocarbonylamino-acid Silyl Esters. Thiazolidine-2,5-diones (306) are accessible in high yield and purity by the cyclization of N-(alkoxythiocarbony1)amino-acid trimethylsilyl esters (305) by phosphorus tribromide. The reaction proceeds by an electrophilic attack of the acyl group on the sulphur atom, presumably involving intermediates of type (307). The HN-CHR2

R10C*NHCHR2-C02SiMe,- POBr,

II

S (306)

(305)

[Rloy-Jj

1

Br-

Me3SiN-CHR2

o+o

(307)

(308) R2 = Me or CH,CHMe,

method offers considerable advantages over previous analogous routes, employing other N-alkoxythiocarbonylamino-acidderivatives, e.g. RlOCS NHCHR2-COBr, chiefly because of the ready accessibility of the silyl esters (305), and the restrained conditions of their cyclization, resulting in products of greatly improved purity.220 Further treatment of (306) with trimethylchlorosilane-triethylamine at 0 "C causes substitution at the ring-nitrogen, yielding (308). The stability of the thiazolidine system prevents the occurrence of an equilibrium with the isomeric linear trimethylsilyl a-isothiocyanatoesters of the kind that is observed with the less stable N-(trimethylsily1)oxazolidinediones [(309) f (3 lo)]. The greater stability of the thiazolidine-2,5-diones is also reflected by their higher resistance to thermal decomposition and polymerization.220 220

H. R. Kricheldorf, Chem. Ber., 1971, 104, 3146.

641

Thiazoles R2CH -COzSiMe, I N=C=O

Mc3SiN-CIIR2 7

(309)

From Enamines and Mercaptocarboxylic Acids. In the course of their wider study of the reaction between enamines and thiol acids, Klemmensen et aZ.22fhave described a smooth condensation of enamines (312) derived from ethyl acetoacetate and ammonia or methylamine (i.e. ethyl /%aminocrotonates) with a-mercaptocarboxylic acids (311) to thiazolidinones (313). The cyclization involves the addition of the thiol group, of (311), to the double bond, and amide formation between the amine and acid.221 CO,H I

CH

( R ‘SH

HOiC I

c\H2 SH

+

N HR2 ,Me C, CHC0,Et

I

NMe 3. II + CHAr

(3 14)

_ I

H02C NHMe I I H,C, ,CHAr S

+

OC-NMe I I H,C, ,CHAr S (316)

(3 15)

OC-NMe I I H,C, ,CHAr

S 0.)

(31 7)

A synthesis formally not unrelated is the cyclization of adducts of type (315), which arise by the addition of mercaptoacetic acid to Schiff’s bases (314); they are ring-closed to 2,3-&substituted thiazolidin-4-ones (316) and subsequently oxidized to the 1,l-dioxides (317).222 From Keten, Carbodi-imide, and Sulphur Dioxide. The 1,2-cycloaddition of diphenylketen to di-isopropylcarbodi-hide in benzene at room temperature yields the azetidine (3 19) in 90% yield (Scheme 18). The same reaction, carried out in liquid sulphur dioxide, affords 2-(N-isopropylimino)-3isopropyl-1,1-dioxo-5,5-diphenylthiazolidin-4-one (320) nearly quantit atively. The reaction appears to proceed by way of the dipolar species zal zz2

P. D. Klemmensen, J. 2. Mortensen, and S. 0. Lawesson, Tetrahedron, 1970, 26, 4641; see also P. D. Klemmensen and S. 0. Lawesson, Chem. Comm., 1968,205. J. C. Wilson, R. N. Downer, and H. E. Sheffer, J . Heterocyclic Chem., 1970, 7 , 955; compare also A. R. Surrey, W. G. Webb, and R. M. Gesler, J . Amer. Chem. Soc., 1958,80, 3469.

22


642

Ph?C=C=O

+ RN=C=NR

[RN=6-I’!JR

Ph.,C-C=O

I

I

‘I

Ph,C-C=O

Ph ,C-C=O t----f

RNSC-NR +-

Ph ?C-C= 0 \

/

RN=C-NR

O,SyNR

(319)

NR (320) Scheme 18

-so,

II

PhZCHCO

I

RNCONHR

(318). Hydrolysis cleaves the thiazolidine (320) to the acylurea (321) and sulphur dioxide.223 Physical Properties.-In a comparative study of the i.r. and Raman spectra of oxazolidine- (322; X = 0), thiazolidine- (322; X = S) and selenazolidine-2,4-diones (322; X = Se), the observations are interpreted in terms of coupling between the carbonyl groups, identical to that shown by cyclic imides such as hydantoins (323). The carbonyl band of low frequency

R1kx 0

R3

(323)

corresponds to the out-of-phase vibration, the other band to the in-phase vibration of the carbonyl Chemical Properties.-The chemical behaviour of thiazolidine-2,4-diones has been the subject of several studies. Bromination of 3-phenylthiazolidine-2,4-dione (324) yields the 5-mOnO- and 5,5-di-bromo-derivatives, successively, in excellent yield. The halogen in (325) is readily replaced by primary and secondary amines, resulting in a variety of heterocyclic bases.226 The action of alkali-metal amides in liquid ammonia on thiazolidine2,4-dione (327) and its 5-alkyl derivatives (329) produces the dianions 224

22b

W. T. Brady and E. D. Dorsey, J . Org. Chem., 1970,352732. C . Fayat and A. Foucaud, Bull. Soc. chim. France, 1971, 987. S. N.Baranov, and R. 0. Kochkanyan, Khim. Farm. Zhur., 1970,4,25 (Chem. Abs., 1970,73, 3 837w).

Thiazoles

643

(325)

(326)

(328) and (33 1), which are of considerable synthetic usefulness.226 Thus, further treatment with alkyl halides results in exclusive alkylation at their highly nucleophilic carbanion centre to yield 5-alkyl- (329) or 5,5-dialkylthia~olidine-2~4-diones(332). The action of acetophenone on (328) furnishes the carbinol (330; 45%) as a mixture of diastereoisomers.226 0

0

0

i, RX

R

H

(330)

The hydrazinolysis of thiazolidine-2,4-dione (327) and its sulphur analogues generally yields 1,2,4-triazolones (3 36) by a trans-cyclization process.227 The isolation of intermediates of type (333) supports the mechanism outlined in the reaction scheme. These intermediates, which are capable of undergoing ring-chain tautomerism [(333) (335)], may be isomerized to (334) or dehydrated by acids to (336). The presence of 5-alkyl substituents favours rearrangement, but that of 3-substituents promotes the cleavage of the ring to semicarbazide and the appropriate glycollic acid.228 The hydrazinolysis of the thio-analogues of (327) (i.e. rhodanine, isorhodanine, and thiorhodanine, see p. 648) yields, by a comparable series of reactions, analogues 1,2,4-triazolones as ultimate main

-

226 Zz7

J. D. Taylor and J. F. Wore, Synthesis, 1971, 310. 0. P. Shvaika, S. N. Baranov, and V. N. Artemov, Doklady Akad. Nauk S.S.S.R., 1969,186, 1102 (Dokludy Chern., 1969, 186,483). S. 0. Yurzhenko and M. M. Turkevich, Dopov. Akad. Nauk Ukrain. R.S. R., Ser. B, 1968,30, 743 (Chem. A h . , 1969, 70, 47 351a).


644

NH2

(327) (333)

HN-NH H S A N A O

-

I

(334)

0 S-NR

Ho&NrO SH NH

5-Arylazothiazolidin-4-onesof type (337) 229 and analogues 230 are obtained by coupling diazonium salts with the preformed heterocyclics; their spectral properties have been 2,3-Diaryl-4-thionothiazolidine 1,l-dioxides (338) are produced from the corresponding 4-oxo-compounds by the action of phosphorus pentasulphide

(338)

in x~lene.~~O Conversely, the thiono-compounds are convertible into their oxo-analogues by a novel general procedure,231 by being heated with propylene oxide at 170-180 “C in sealed vessels, in the presence of small quantities of triethylamine or boron trifluoride etherate (Scheme 19).

Scheme 19

N-Methyl-l,3-thiazolidine-2-thione (339) affords the cyclic ketone (340) in 81% yield in this way.231 229

230

I. I. Chizhevskaya, M. I. Zavadskaya, and N. N. Khovratovich, Khim. geterotsikl. Soedinenii, 1969, 52 (Chern. A h . , 1969,71, 13 045j). B. E. Zhitar and S. N . Baranov, Khim. Farm. Zhur., 1969, 3, 10 (Chem. Abs., 1970, 72, 1005782).

231

Y. Ueno, T. Nakai, and M. Okawara, Bull. Chem. SOC.Japan, 1970, 43, 168.

645

Thiazoles

3,4-Disubstituted 2-iminothiazolidines (342) are oxidized by potassium chlorate in hydrochloric acid to the linear cyanamido-derivatives, e.g. (343), which are once again cyclized thermally to the 1,2,4-thiadiazine 1,l-dioxides (344). The results of this degradation, and the spectral data, serve to exclude the alternative formulation of the starting materials (342) as (341).232

xJMe

ArNH

(341)

(343)

(344)

Thiazolidine-2-thione (L) forms pseudotetrahedral complexes (ML,X2) with cobalt(rx) chloride, bromide, or iodide, or nickel(@ iodide, but gives rise to (distorted) octahedral complexes (ML,X,) with nickel@) chloride or bromide. The usual physical measurements show that thiazolidine-2thione co-ordinates through the sulphur hetero-atom in tetrahedral complexes, and through both sulphur atoms in octahedral Thiazolidines in Peptide Synthesis.-The use of thiazolidine-2,S-diones (347) in peptide synthesis 234 provides certain advantages over that of a-amino-acid N-carboxyanhydrides (345) and 2-thionothiazolidin-5-ones (346) previously employed for the same purpose. The reagents (347), i.e. N-thiocarboxyamino-acid anhydrides, are accessible in good optical purity by three similar routes, based on existing methods (Scheme 20). The most convenient procedure is the cyclization of alkoxythiocarbonyl-L-amino-acids(348) with phosphorus tribromide at 0 "C (route A). Alternatively, treatment of amino-acid thiocarbamates (349) with phosphorus pentachloride gives a mixture of the desired thiazolidine (347) and the anhydride (345). Only the latter is cleaved by hydrogen sulphide and may thus be removed (route B). Thirdly, the potassium salt of thioleucine thiocarbamate (350; R = Bui) is cyclized directly to (347) in aqueous solution by Woodward's reagent K (route C). The application of the reagents is illustrated by the sequence (347) -+ (351) + (352). Their interaction with amino-acids or peptides in aqueous solution at pH 9.+9.5 at 0 - 4"C yields (351); acidification detaches the protective carbonyl sulphide moiety, which is swept from the reaction mixture with nitrogen. The sum of the experimental evidence appears to suggest that the usefulness of the thiazolidine-2,5-dione reagents (347) in controlled peptide synthesis is restricted to examples derived from glycine and alanine, which afford products of good optical purity, and from a3a

233 234

L. Toldy and P. Sohar, Tetrahedron Letters, 1970, 181. D. De Filippo and C. Preti, J. Chem. SOC.( A ) , 1970, 1904. R. S. Dewey, E. F. Schoenewaldt, H. Joshua, W. J. Paleveda, jun., H. Schwam, H. Barkemeyer, B. H. Arison, D. F. Veber, R. G . Strachan, J. Milkowski, R. G . Denkewalter, and R. Hirschmann, J. Org. Chern., 1971, 36, 49.


646

+-----I route

R'CH-CO,H HN-COSK

'0 (345)

RiCH-C02H

R'CH-COSK

HN-CSOR2

HN-COSK

I

/ " I

(350)

0

(353)

4- H,NCHCO.NH-*

~ ~ ~ I~ L H E H C O . w. N

J

X Hg S-CH2

I

R NH-CHCONHCHCO*NH.-* I CHO (355)

CHO (354)

647

ThiazoZes

insulin. The reaction is of additional interest because of its potential application to the preparation of covalent heavy-atom derivatives of proteins, such as (355).2a6 Goodman et uZ.a3es237 have proposed a detailed three-dimensional helical structure, based on theoretical calculations, for poly-(S)-thiazolidine-4carboxylic acid. This peptide is of particular interest because of its close structural analogy to poly-L-proline (containing sulphur atoms in place of y-methylene groups). The results of n.m.r. studies show that the monomeric N-acetyl-(S)-thiazoIidine-4-carboxylic acid methyl ester, which serves as a model compound for poly-(S)-thiazolidine-4-carboxylic acid, occurs in two stereoisomeric forms [(356) and (357)]. The polymer, however, is a

Me I

H'

0

H (357)

single stereoisomer (358); it is formulated as the trans-compound on the basis of conformational energy calculations which suggest that the all-trans poly-(S)-thiazolidine-4-carboxylic acid is more stable that the all-cis polypeptide by 5 kcal mol-l of peptide nit.^^^^ 2a7 The chloroacetyl residue has proved a suitable protective entity for amino-groups, being removable by thiourea under mild conditions.238 Applied to peptides, however, the reaction proceeds in unsatisfactory yields, because further condensation occurs between the liberated aminoacids and thiazolidinone (359). The use of an NN-disubstituted thiourea, e.g. NN-pentamethylenethiourea,removes this difficulty, since the reaction now terminates with the production of 2-piperidino-4-thiazolin-5-one(360) aa5

238 a37

238

D. G. Lindsey and S. Shall, European J . Biochem., 1970, 15, 547. M. Goodman, G. C . C. Niu, and K.C . Su,J. Amer. Chem. SOC.,1970, 92, 5219. M. Goodman, K. C . Su, and G. C. C. Niu,J. Amer. Chem. SOC.,1970,92, 5220. M. Masaki, T. Kitahari, H. Kurita, and M. Ohata, J. Amer. Chem. SUC.,1968, 90, 4508; A. Fontana and E. Scoffone, Gazzetta, 1968,98, 1261.

648


(Scheme 21). The procedure is therefore suitable for protecting the aminoterminus of peptides.29n

r

CICH,CONHCHRCOMe

NHZCSNHZ

Condensation products

+ LZ>NH O

+ NHnCHRCOMe + 0

H (359)

Scheme 21

Rhodanines.-The 2,4-oxothiones and 2,4-dithiones of thiazolidine, generally known by their trivial names rhodanine (361), isorhodanine (362), and thiorhodanine (363), have been the subject of continued studies, particularly by Russian research workers, with the ultimate aim of their incorporation into cyanine and other dye structures. They resemble one another in their general properties and are here dealt with together.

Isorhodanines (364) are readily accessible from thiazolidine-2,4-diones (371) by the action of phosphorus pentasulphide in dioxan. Aminolysis by aniline, phenylhydrazine, or isonicotinoyl hydrazide produces the corresponding 4-imino-derivatives (372; X = PhN, PhNHN, or NCIH4CONHN).240 The action of hydrazine on isorhodanine (364; R = H) or its 5-ethyl homologue (364; R = Et) proceeds in three stages (Scheme 22):241The hydrazine addition compound (365) is isolable at 0 "C but is converted at ambient temperatures, with loss of hydrogen sulphide, into the 4-hydrazonothiazolidin-2-one(366) ; at higher temperatures, 5-mercaptomethyl(or mercaptopropyl)-l,2,4-triazolin-3-ones(367) are formed as the final products by rearrangement. The action of aromatic aldehydes on (366) yields the expected 4-N-arylidenehydrazono- (368) and 4-arylidenehydrazono-5-arylidene analogues (369) successively. Dimerization of (366) to (370) is effected by 239 240

W. Steglich and H. G. Batz, Angew. Chem., 1971,83, 83. N. E. Plevachuk and I. D. Komaritsa, Khim. gererotsikl. Soedinenii, 1970, 159 (Chem. A h . , 1970, 72, 121 422j). 0. P. Shvaika, V. N. Artemov, and S. N. Baranov, Zhur. org. Khim., 1970, 6, 2353 (Chern. A h . , 1971,74,42 308q).

Thiazoles

TI0 -

ArCH=N-N

ArCH=N-N ArCH

649

(369)

N-N

c x o (368)

O g R R . @ O (370)

Hydrazinolysis of (364) using thiosemicarbazide produces thiazolidine2,4-dione 4-thiosemicarbazone (372; R = H, X = NH,CSNHN), which is converted, on condensation with chloroacetic acid, into the asymmetric 2,4'-azine (3 73).242 The alkylation 243 of rhodanine and its 5-benzylidene derivatives by diazomethane in a variety of solvents, or by alcohols containing three moles of sodium methoxide (i.e. under conditions in which rhodanine is ionized) produces a mixture of the S- and N-methyl derivatives. In contrast, un-ionized rhodanine (e.g. in ethanol acidified to pH 3 4 . 5 ) resists alkylation entirely.244 Substituted rhodanines readily undergo the Mannich reaction on treatment with formaldehyde and amines in ethanol (Scheme 23). Aliphatic amines give products incorporating one mole of amine and two moles each a42

244

N. M. Turkevich and 0. L. Grom, Dopovidi Akad. Nauk Ukrain. R.S.R., Set. B., 1970, 544 (Chem. A h . , 1970,73, 87 8302). A. I. Ginak, V. V. Barmina, K. A. Vyunov, and E. G. Sochilin, Zhur. obshchei Khim., 1970, 40, 942 [J. Gen. Chern. (U.S.S.R.), 1970, 40, 9261; see also F. Kurzer in this Report, 1970, vol. 1, p. 408, ref. 118. A. I. Ginak, K. A. Vyunov, and E. G. Sochilin, Zhur. org. Khim., 1970, 6, 1744 [J. Org. Chem. (U.S.S.R.),1970, 6, 17471.

650

0

Organic Compounds of Sulphur, Selenium, and Tellurium 0 0

XQSMe

x

CIS

+

(374)

X ~ X ;

(375) Scheme 23

of formaldehyde and rhodanine and are formulated as (375). The aromatic analogues arise from equimolar quantities of the components and are represented as (374). Alternative formulations derived from the thiol configuration of (361) are excluded by the resemblance of the U.V. spectra of the products and those of the starting materials of established thione structure. The aminomethyl compounds thus obtained are crystalline solids that are cleaved to the starting components on vigorous Rhodanine in the form of its sodium or triethylammonium salt is converted by phosphoryl chloride under mild conditions into SS-bis(4-0~0-2-thiazolin-2-yl) phosphochloridodithioate (376 ; X = Cl) and

thence, by sodium alkoxide, into the 0-alkyl triester (376; X = OAlk).246 A kinetic study of the base-catalysed solvolysis of 3-benzyl-5-phenylazorhodanine in a variety of solvents has revealed the formation of an anionic transition complex as the rate-determining stage (Scheme 24).247 Merocyanine dyes containing the thiorhodanine nucleus are obtainable directly from their rhodanine analogues by the action of phorphorus p e n t a s ~ l p h i d e . ~When ~~ this approach fails, the 5-anilinomethylenerhodanine (377; R1 = H or Et) is first thiated to (378; R1= H or Et) and

247

M. A. Borisova, A. I. Ginak, and E. G. Sochilin, Zhur. org. Khim., 1970, 6, 1738 [J. Org. Chem. (U.S.S.R.),1970, 6, 17411. A. I. Ginak, K. A. Vyunov, and E. G. Sochilin, Zhur. obshchei Khim., 1970,40, 1423 [J. Gen. Chem. (U.S.S.R.), 1970, 40, 14101. P. B. Talukdar, S. Banerjee, and A. Chakraborty, J . Indian Chem. Soc., 1968,45, 775;

240

M. Holger, Svensk kem. Tidskr., 1961, 73, 389.

245

2rs

1970, 47, 58, 1099.

65 1

Thiazoles 0

n-

Products Scheme 24

subsequently condensed with quinaldinium or lepidinium quaternary salts; this condensation occurs in fact more readily in this than in the rhodanine series. The thiorhodanine dyes (379) are deeper in colour than their rhodanine analogues and their absorption bands are displaced bathochromically in the visible and U.V. region.24B PhNIICH

PhNHCH

--,

0Q S R1

S

tJL R1

(377)

R' (379)

Isorhodanine (362) is convertible, by way of S-anilinomethyleneisorhodanine, into a variety of quinomerocyanine dyes, e.g. (380) and (381). 4-Phenyliminothiazolidin-2-one,obtainable from isorhodanine by the action of aniline, gives rise to a comparable series of dyes. Their electronic spectra and solvatochromic properties were recorded and discussed.26o 249

260

S. V. Lepikhova and G. T. Pilyugin, Zhur. obshchei Khim., 1969, 39, 2116 [J. Cen. Chem. (U.S.S.R.), 1969, 39, 20691. S. V. Lepikhova and G. T. Pilyugin, Zhur. obshchei Khim., 1970, 40, 863 [J. Gen. Chem. (U.S.S.R.),1970, 40, 8421.

652


R'

Rhodanine possesses antiviral properties, inhibiting the multiplication of echooirus 12, and the development of virus-induced morphological changes. Eighteen rhodanine derivatives proved to be considerably less active or inactive in this respect, and some were more toxic than the parent 251

H. J. Eggers, M.A. Koch, A. Furst, G. D. Daves, J. Wilczynski, and K. Folkers, Science, 1970, 167, 294.

14 Condensed Ring Systems Incorporating Thiazole BY F. KURZER

The fused polycyclic structures described in this chapter are arranged, as before,’ in their order of increasing ring complexity.2 Benzothiazole, however, is dealt with first in a separate section, because of the exceptionally large volume of work that is being reported in this field. The general remarks that introduced the previous Report are again applicable. It is an invidious task to single out work of special merit, but there is no doubt that the first separation of amidines into their syn- and anti-isomers, using benzothiazole derivatives (see p. 662), is of much interest. Considerable activity continues in the investigation of thiazolo[3,2-a]pyridines and closely related diheterocyclics, both by the original and by new groups of investigators (see p. 695); this ring system is of special interest in being the basis of several compounds of potential biological significance. 1 Benzothiazole Synthesis.-In following the practice adopted in Elderfield’s treatises on heterocyclic compounds the syntheses of benzothiazoles and benzothiazolines are again classified according to the nature of the fragments from which the ring system is built up. The letters designating the type of synthesis correspond to previous usage l, as closely as practicable. Synthesis from o-Aminothiophenols. (Type A , S-C,H,-N i- C.) The old-established synthesis of benzothiazoles by the condensation of o-aminothiophenols with compounds incorporating a carbonyl function continues to furnish both known and novel variations of this ring system. A few simple examples are the following. The interaction of o-aminothiophenol and o-methoxybenzoic acid in polyphosphoric acid yields the expected benzothiazole (1; R = Me) at 160 “C, but results in the demethylated 2-(2-hydroxyphenyl)benzothiazole (1 ; R = H) at higher temperat~res.~ Isatoic anhydride or the anhydride of an NN-(dicarboxy-

a

F. Kurzer, ‘Organic Compounds of Sulphur, Selenium, and Tellurium’, ed. D. H. Reid (Specialist Periodical Reports), The Chemical Society, London, 1970, Vol. 1, Ch. 14 and 15. A. M. Patterson, L. T. Capell, and D. F. Walker, ‘The Ring Index’, American Chemical Society, 2nd edn., Washington, 1960. ‘Heterocyclic Compounds’, ed. R. C. Elderfield, Wiley, New York, 1957, Vol. 5. C. M. Orlando, J. G. Wirth, and D. R. Heath, J. Org. Chern., 1970, 35, 3147.

653

654 Organic Compounds of Sulphur, Selenium, and Tellurium methy1)arylamine (2) give rise to the appropriate 2-substituted benzothiazoles (3) or (4). The use of Se(CH,COOH), makes 2-benzothiazolylmethylselenoacetic acid accessible.6 The lactone of homogentisic (2,5dihydroxyphenylacetic) acid produces 2-(2-benzothiazoIylmethyl)hydroquinone (9, and 2,5-dihydroxy-p-phenylenediaceticacid similarly affords 2,5-bis(benzothiazolylmethyl)hydroquinone.s H&-CO /

ArN

\

COOH

0

I

SH

Ar (4) hv

Irradiation of solutions of 2-aminothiophenol in the presence of aliphatic carboxylic acid produces, in addition to 2-methylthioaniline, very small yields of mixtures of 2,2-dialkylbenzothiazolines (6), which are separable by gas chromatography. The 2-alkyl groups in (6) correspond not only to the acids employed, but also to lower alkyl units arising therefrom by fragmentation.' The condensation of o-aminothiophenol and 2,5-bis(cyanomethyl)selenophen affords the expected benzothiazole incorporating a selenophen ring.* 2

+

6

6

V. P. Khilya and G. A. Lezenko, Khim. geterotsikl. Soedinenii, 1970, 1697 (Chem. Abs., 1971, 74, 99 93311). F. S. Babichev and L. G. Rudchenko, Ukrain. khim. Zhur., 1968,,34, 1269 (Chem. Abs., 1969, 70, 115 062j). Y.Maki and M. Suzuki, Chem. Comm., 1971, 117. M. Y.Kornilov and E. M. Ruban, Ukrain. khim. Zhur., 1969, 35, 824 (Chem. Abs., 1970, 72, 55 310t).

655 Condensed Ring Systems Incorporating Thiazole o-Aminothiophenol and /3-keto-esters such as ethyl acetoacetate react in boiling xylene to yield approximately equal quantities of 2-ethoxycarbonylmethyl-2methyl benzothiazoline (7) and 2-acetonylbenzothiazole (8; R = Me). Ethyl benzoylacetate produces the phenacyl compound (8; R = Ph) exclusively; the intermediate (9) is isolable when the reaction

(8) time is reduced. a-Ketonic esters, such as ethyl phenylglyoxalate and methyl pyruvate, react analogously, giving products (lo), (1l), and (12).B The results supplement and correct previous work in this field. The condensation of a-aminothiophenol and epoxy-ketones of type (13) yields benzothiazolines (14). Cyclic epoxy-ketones form the spirans (1 5 ) analogously.1° (12)

lo

(15) (13) (14) A. Buzas, F. Cossais, and J. P. Jacquet, Compt. rend., 1971, 272, C,403. L. G. Kovalenko, L. K. Mushkalo, and V. A. Chuiguk, Ukrain. khim. Zhur., 1970, 36, 369 (Chem. Abs., 1970, 73,454351).

656


Bognar et a2.l1 have employed this general synthesis for the preparation of monosaccharides incorporating benzothiazole. Thus, the condensation of o-aminothiophenol with acetylated aldonic acid chlorides (16 ) or nitriles (17) readily affords the benzothiazole derivatives (1 S), which may be deacetylated to the parent monosaccharides by treatment with alkali.

1,4-Bis-(2'-benzothiazolyl)-~-galactotetra-acetoxybutane(19) is similarly accessible from tetra-acetyl-D-galactaric acid dichloride.ll The corresponding benzothiazolines arise by the condensation of o-aminothiophenol with aldoses.12 D-Glucose or D-galactose yield, under various conditions, 2-(~-gluco- or D-galacto-)pentahydroxypentylbenzothiazoline (e.g. 20). Acetylation with acetic anhydride in pyridine yields penta-O-acetyl derivatives, whereas more drastic acylation produces hexa-ON-acetates (e.g. 21). These derivatives are also accessible directly from the appropriate acetylated aldohexoses.12 Synthesis from Thioamides and Related Compounds. (Type B, C6HS-N-C-S.) The action of a large excess of thionyl chloride on substituted thioureas of type (22) (incorporating a p-hydroxy-group in their N-alkyl group) produces 2-aminobenzothiazole derivatives (23) preferentially, rather than thiazolines (24) or oxazolines. Thionyl chloride, like sulphuryl l1 la

R. Bognar, I. Farkas, L. Szilagyi, M. Menyhart, E. N. Nemes, and I. F. Szabo, Acra Chim. Acad. Sci. Hung., 1969, 62, 179. R. Bognar, Z. Kolodynska, L. Somogyi, Z. Gyorydeak, L. Szilagyi, and E. N . Nemes, Acta Chim. Acad. Sci. Hung., 1969, 62, 65; see also L. Sattler, F. W. Zerban, G. L. Clark, and C. Chia-Chen, J. Amer. Chem. SOC.,1951, 73, 5908.

(24)

chloride and sulphur monochloride, is therefore a suitable cyclizing agent in Hugershoff's benzothiazole synthesis.13 Diadducts (25) of thiocarbonohydrazide and aryl isothiocyanates are cyclized by alkaline potassium ferricyanide to the rnercaptoformazans (26) 2 ArNCS

+ NH,NH*CS*NHNH2

ArN HCSNHN H - C S .N HNHCSN HAr

(27)

(28)

incorporating benzothiazole residues. Their central mercapto-group may be alkylated in the normal way.14 2-Picoline and its l-oxide react with aniline in the presence of sulphur at 160 "Cto yield the thioanilide (27) and the substituted benzothiazole (28) in proportions depending on the reaction tirne.l6 l4 l6

Y . Iwakura and K. Kurita, Bull. Chem. SOC.Japan, 1970, 43, 2535. R. G . Dubenko, I. M. Bazavova, and P. Pelkis, Khim. geterotsikl. Soedinenii, 1970, 598 (Chem. Abs., 1970,73, 77 122f). T. Hisano and H. Koga, Yakugaku Zasshi, 1970, 90, 552 (Chem. Abs., 1970, 73, 45 267r).


658

Synthesis from Quinones and Thioureas. (Type G, C,H,-S-C-N.) Benzoquinone reacts with excess of thiourea in the presence of mineral acids to yield S-(2,5-dihydroxyaryl)thiouronium chlorides (29), which are cyclized, under the influence of a further mole of benzoquinone, to 2-amino6-hydroxybenzothiazoles (e.g. 30). The end-products (30) arise directly in one stage by the use of an excess of benzoquinone. The reaction is a general one, gives excellent yields, and is applicable equally to naphthoquinones, 1,2-d]thiazoles (3 l), as well as thus furnishing 2-amino-5-hydroxynaphtho[ to substituted thioureas.l6 Extension of the synthesis to monosubstituted benzoquinones such as toluquinones gives the two expected benzothiazole derivatives (32) and (33), the former predominating. Thymoquinone yields

NHJSNH,

/

0

OH

OH

(31)

only one of two possible isomers, uiz. 2-amino-6-hydroxy-4-isopropyl-7methylbenzothiazole (80%).l6 Synthesis from Benzothiazines. (See Volume 1, p. 412.) A preliminary communication has briefly reported the ring-contraction of 3-phenyl2H- 1,4-benzothiazin-2-0ne (34) to 2-carboxy-2-phenylbenzothiazoline(35) by the action of potassium methoxide, and to 2-phenylbenzothiazole (36) on pyr01ysis.l~

(34)

(35)

(36)

Numerous benzothiazoles continue to be produced by well established routes; they are briefly listed in the Table. l6 l7

P. T. S. Lau and T. E. Gompf, J. Org. Chern., 1970,35,4103. G. Rabilloud, B. Sillion, and G. de Gaudemaris, Compt. rend., 1970, 270, C, 2019.

Condensed Ring Systems Incorporating Thiazole

659

Table Synthesis of Benzothiuzoles and Benzothiazolines Type of compound 2-Substituted benzo-thiazoles (and -thiazolines) 2-Arylbenzothiazoles 2-Aryl (and heteroary1)benzothiazolines and derivatives 3-Alk yl benzot hiazoline-2-thiones

Alkyl-4,5,6,7-tetrahydrobenzothiazole-2-thiols 2-(Hydroxybenzy1)benzothiazoles A1 koxy (and phenoxy)ethylbenzothiazolium toluene-p-sulphonates 2- Met hyl-6-(trifluoromet hylse1eno)benzot hiazole (and cyanine dyes therefrom) 2-Aminobenzothiazoles 2-Amino-5,6 (and 6,7)-dichlorobenzothiazole 2-Aminobenzothiazole-5-sulphonamides 2-Alkylaminobenzothiazoles 2-Pol ynitrophenylaminobenzothiazoles 2-Pyridylaminoacetamidobenzothiazoles 2- M orpholinoacetamidobenzot hiazoles 1-(Benzothiazol-2-y1)pyrazoles 1-(Benzothiazol-2-yl)-3-methyl-l,2-di hydropyrazol-5-one 2-(uic-Triazol-1-yl)benzothiazole

Benzothiazol-2-sulphenamides

Ref. 17 18 19 20 21 22 23

24 25 26 27 28 29 30

31 32 33 34 35

solubility (6.0-6.3 x mol 1-1 at 20 "C) and acid dissociation constant (pK, 6.8-7.2) of 2-mercaptobenzothiazole have been determined by several Physical Properties.-The

l8 l9

ao z1 a2

28

ar 26

20

27

28

29

31

32

33 34 35

J0

T. Prot and J. Parol, Roczniki Chem., 1971, 45, 1301. P. J. Palmer, R. B. Trigg, and J. V . Warrington, J. Medicin. Chem., 1971, 14, 248. A. F. Halasa and E. P. Smith, J. Org. Chem., 1971, 36, 636. Y. Usui, Yukuguku Zusshi, 1968, 88, 1535 (Chem. Abs., 1969, 71,49 830a). F. Gualtiere, G. Brody, A. H. Fieldstecl, and W. A. Skinncr, J. Medicin. Chem., 1971, 14, 546. A. D. Gavaghan and A. J. Nunn, Pharm. Acra Helu., 1971, 46, 413. L. M. Yagupolskii and V. G . Voloshchuk, Ukrain. khim. Zhur., 1970, 36, 66 (Chetn. Abs., 1970, 73, 16 251a). K. C. Tweit, J. Heterocyclic Chem., 1970, 7, 687. R. J. Alaimo, J. Heterocyclic Chem., 1971, 8, 309. D. Simov and A. Antonova, Compt. rend. Acad. bulg. Sci., 1969, 22, 1027 (Chem. A h . , 1970, 73, 120 552k). H. Ogura, S. Sugimoto, and K. Shimura, Yakugaku Zusshi, 1970, 90, 796 (Chem. Abs., 1970, 73, 77 121e). G. di Modica and L. Falletti, Boll. sci. Fac. Chim. ind. Bologna, 1969, 27, 95 (Chem. Abs., 1970, 72, 134 113j). P. K. Srivastava and P. N. Srivastava, J. Medicin. Chem., 1970, 13, 977. P. K. Srivastava and P. N. Srivastava, J. Medicin. Chetn., 1970, 13, 304. A. D. Garnovskii, Y. V. Kolodyazhnyi, I. I. Grandberg, S. A. Alieva, N. F. Krokhina, and N. P. Bednyagina, Khim. geterotsikl. Soedinenii, 1970, 660 (Chem. Abs., 1970, 73, 56 026n). P. Catsoulacos and A. Hassner, Chim. Ther., 1969,4,479 (Chem.Abs., 1970,72,111357~). A. J. Hubert and H. Reimlinger, Chem. Ber., 1970, 103,3811. V. Ignatov and P. A. Pirogov, Khim. geterotsikl. Soedinenii, 1970, 89 (Chem. Abs., 1970, 72, 100 584y). L. N. Lomakina and E. K. Yakovskaya, Vestnik Moskov. Univ., 1969,24, 73 (Chem. Abs., 1970, 72, 36 378e).

660


The dipole-moment method has provided information concerning the conformation of 2-formylbenzothiazole (37). The compound appears to assume a predominantly planar structure, the carbonyl group being

trans to the N-3 atom. This observation agrees with the results of quantummechanical calculations which predict a higher stability for the trans- over that of the cis-conformer by 1.2 kcal m ~ l - ~ . ~ ' The vapour absorption spectrum of benzothiazole near 2850 A, with origins at the wavenumber 34 327 cm-l, has been described and compared with those of benzoxazole and benzimidazole. In each case the origin is the strongest band, and excited-state fundamentals at ca. 700, 950, and 1225 cm-l are prominent. There is no evidence for a (T* -+ n) t r a n s i t i ~ n . ~ ~ The photoconductivity of layers obtained by suspending a variety of benzothiazole derivatives in cyclohexanone-formaldehyde resin or polyN-vinylcarbazole has been determined by electrophotographic methods, and various factors that exert an influence on this property have been studied. The photoconductivity, S (lx-l s-l), of the best examples ranges and 0.5 x these are suitable in the production between 0.1 x of xerographic images.18 Metzger and his co-workers39 have made a detailed study of the i.r. spectra of benzothiazole and of 29 of its mono-, di-, and tri-substituted derivatives. The extensive data have provided the basis for the assignment of v(CH) stretching and y(CH) out-of-plane deformation frequencies, as well as the other fundamental vibrations of the benzothiazole system. The Raman spectra of benzothiazole and its 2-methyl and 2-chloro-derivatives were also studied. The paper includes a useful literature survey of previous work on the vibrational spectra of benzothiaz~les.~~ The fluorine-19 n.m.r. spectra of the benzothiazol-2-ylperfluoroalkenes listed below have been recorded. The influence of the benzothiazol-2-yl group on the chemical shift of fluorine in the a- and 8-position indicates that benzothiazol-2-yl and phenyl groups possess comparable effective electronegati~ities.~~ cis-F,C=CFX cis-F,C- FC=CFX

cis-F,C=CF* CF,X cis-F,C= CF- CF,CF,X

cis-FXC=CF* COOMe cis-F,C. FC=CF- CF,X ~HULS-F,C* FC=CF* CFZX

X = benzothiazol-2-yl 37

38

40

A. D. Garnovskii, Yu. V. Kolodyazhnyi, S. A. Alieva, K. M. Yunusov, I. I. Popov, 0. A. Osipov, V. I. Minkin, A. M. Simonov, and I. I. Grandberg, Zhur. obshchei Khim., 1971, 41, 352 [J. Gen. Chem. (U.S.S.R.),1971,41, 3471. R. D. Gordon and R. F. Yang, Canad. J . Chem., 1970,48, 1722. J. C. Panizzi, G. Davidovics, R. Guglielmetti, G. Mille, J. Metzger, and J. Chouteau, Canad. J . Chem., 1971, 49, 956. N. M. Sergeev, N. A. Malichenko, and L. M. Yagupolskii, Zhur. strukt. Khim., 1969, 10,934 (Chem. Abs., 1970, 72, 37538~).


66 1 A study of the mass spectra of 2-methyl-5-chlorobenzothiazole and its 3-ethyl quaternary salt, as well as their deuteriated analogues, has provided data that support the fragmentation pattern shown in Scheme l.41

mfp 183

mle 148 Scheme 1

rnle 107

The loss of ethylene proceeds by a McLafferty rearrangement, i.e. the transfer of a y-hydrogen to a radical site uia a six-membered transition state. The evidence favours the view that this occurs by a stepwise, and not by a concerted mechanism, two alternatives that have recently been considered. The fragmentation patterns of 2-aminobenzothiazole (and its 2-alkaminohomologues) resemble those of the corresponding benzoxa~oles.~~ The suggested fragmentation mechanism is similar to that proposed by previous investigators in this field.43 Careful studies of physical properties have been instrumental in revealing the existence of tautomerism and geometrical isomerism in suitable compounds of the benzothiazole series. According to their spectral proper tie^,^^ 2-amino- and 2-methylaminobenzothiazoles exist chiefly in the enamino-forms (38a and 39a). Their dissociation constants indicate that the amino-forms (38a and 39a) predominate over the imino-forms (38b and 39b) by factors of the order of 2-3 x lo3 in 80% methyl cellosolve and 50% methanol. The freeenergy difference between the tautomers of both (38) and (39) is found, from the relation AG = - RTln kbut, to be approximately 4.4 kcal mol-l, which is indicative of the loss of aromatic energy in passing from the amino- into the imino-form. As expected, this energy loss is smaller than 42

Is

P. R. Briggs, T. W. Shannon, and P. Vouros, Org. Mass Spectrometry, 1971, 5 , 545. H. Ogura, S. Sugimoto, and T. Itoh, Org. Mass Spectrometry, 1970, 3, 1341. B. J. Millard and A. F. Temple, Org. Mass Spectrometry, 1968, 1, 285. K. Nagarajan and V. R. Rao, Indian J. Chem., 1969,7,964.

662


that associated with 2-aminopyridine (7.3 kcal mol-l) or 2-aminothiazole (6 kcal m ~ l - l ) . ~ ~ A comparison 44 of the U.V. spectra of the compounds concerned [(38) and (39)], and thoseofmodelsincapable of tautomerism [(40), (41),and (42)]agrees with the amino-structure of the former. Furthermore, both U.V. and n.m.r. spectra show that protonation occurs on the nuclear nitrogen of (38)-(40),

(38a) R = H (39a) R = Me

(38b) R = H (39b) R = Me

but on the extra-annular nitrogen of (41) and (42). No useful conclusions concerning the tautomeric structures of (38) and (39) in the solid state could be drawn from the i.r. spectra. The results are in agreement with previous formulations based on studies using n . m ~ . p, ~ o l~a r o g r a p h i ~ , ~ ~ and spectral 47 techniques. The tautomeric amido- and imido-forms of chloroacetyl- or a-chloropropionyl-2-aminobenzothiazoles(43) (and of more highly substituted

examples) may be isolated and interconverted into one another by the use of appropriate solvents under carefully controlled conditions. The assigned structures are again supported by spectral data.48 Geometrical isomerism of amidines of type R1-C(=NR2)NH2 has not been observed previously because of the occurrence of tautomeric changes (Scheme 2). In order to demonstrate the existence of geometrical isomerism in this series, a pair of tautomers, AA’ or BB’, must be suitably stabilized. A study 49 of i.r. spectra has indicated that monoarylamidines tend to exist 46 46

47

Q8

A. Mathias, Mol. Phys., 1967, 12, 381. F. von Sturm and W. Hans, Angew. Chem., 1955, 67, 743. G. Costa, Ann. Chim. (Italy), 1953, 43, 585. E. Costakis, P. Canonne, and G. Tsakas, Cunud. J . Chem., 1969,47,4483. D. C. Prevorsek, J. Phys. Chem., 1962, 66, 769.


R1 R2 \ / /C=N H,N

-

663 /R2 R1 N,

\dII N

/

(A) ~nti-(NH,)

H-

(B) unti-(NHR2)

N

\

H

(B') sy/1-(NHR2)

Scheme 2

as (44), whereas monoalkylamidines favour the alternative structure (45), irrespective of the nature of the group R1. In an extensive investigation, Baudet and Rao60 have prepared 2-amidinobenzothiazoles, which appear to exist in one tautomeric form only, their tricyclic planar structure being stabilized by hydrogen bonding : /H Rf N, CH2R1 1 I N / H

\c/

(44)

(45)

(46) R1 = H,CH,CHMe,, or CH,Ph R2 = H, Et, or CMe,

R1 I

(50) .sJ~~-(NH,) e nol-trans - (0R2)

P. Baudet and D. Rao, Helu. Chim. A d a , 1970, 53, 1011.

H

664


this permits a study of the possible existence of geometrical isomers (47) and (48). The examples actually studied (46) are accessible by the condensation of benzothiazole-2-iminocarboxylateand a-aminoacetic esters, and have been isolated and characterized in their syn- and anti-forms. The anti-isomers are formed at low temperatures, and the syn-isomers at more elevated temperatures (e.g. in refluxing methanol) ; the former assume the normal carboxylic ester structure (49),whereas the latter display properties consistent with an enolized structure (50). The reality of the existence of the isomers is supported by their i.r., u.v., andn.m.r. spectra, by thephotolytic inversion of their configuration, and by the formation of cyclic derivatives. Thus, the syn-(NH,)-enol (0Et)-isomers (50;R2 = Et) are readily ringclosed to 2-(benzothiazol-2-yl)-imidazol-5-ones (51), proving their configuration. The more stable anti-(NH,)-isomers (49) melt without change of configuration, but cyclize at higher temperatures. For the wealth of experimental data, and their extensive discussion, the reader is referred to the original memoir.6o Analogous heterocyclic substituted amidines should clearly be suitable for similar stereochemical studies. X-Ray Analysis.-A crystallographic study of the anhydro-base of 2,3dimethylbenzothiazole has confirmed the second of the two structures (52) and (53) that had previously been discussed (see Volume 1, p. 416).

The configuration is that of an asymmetrical dimer of 2-methylene-Nmethylbenzothiazoline with the sulphur atoms in trans positions. The stability of the benzothiazoline moiety of the molecule is impaired by the presence of the methyl group in position 2. The abnormally long S-l-C-2 bond (1.86 %.) explains the ready hydrolytic cleaving of the thiazoline ring. The planes of the benzothiazole and benzothiazoline rings subtend an angle of 91°.51 The structure of 2-(o-hydroxyphenyl)benzothiazole, a compound forming insoluble chelates with bivalent metal ions, has also been determined by X-ray analysis. The observed bond distances and angles deviate little from the expected values. The figures reveal a strong intramolecular chelating hydrogen bond O-H-N, with an O-N distance of 2.605 Chemical Properties.-The examination of the chemical behaviour of benzothiazoles continues steadily along generally predictable lines. The 62

E. Milerspenger, Bull. SOC.chim. France, 1969, 3970. P. Stenson, Acta Chem. Scand., 1970,24,3729.


665

technical importance of these heterocyclics is reflected in the preoccupation of several groups of workers in the study of numerous further examples of polymethine dyes and polymers incorporating this ring system. Increasingly detailed investigations are being undertaken of the metal-complexing power of benzothiazole derivatives. Oxidation. The copper(I1) acetate-catalysed oxidation of 6-hydroxybenzothiazoles by molecular oxygen in the presence of a secondary amine proceeds exothermally and is attended by simultaneous amination, yielding (54). The presence of a 2-aryl group inhibits the amination, possibly owing to steric

HO

Benzothiazolin-Zone hydrazones. The oxidation of 3-methylbenzothiazolin-Zone hydrazone (55) by potassium ferricyanide produces, apart from nitrogen, the compounds (56), (57), and (58) in relative proportions which vary with the prevailing pH and the order of the addition of the reagents; yields of (58) are consistently minute. Oxidation, under various conditions, of the 2-16N-labelledreactant yields di-labelled nitrogen, monolabelled 3-methyl-2-benzothiazoline azine (56), and unlabelled 2-imino-3rnethylbenzothiazoline (57). The formation of the individual products and the results of the labelling studies are consistent with the mechanism shown in Scheme 3.64 The action of lead tetra-acetate on benzothiazolylhydrazones (59) produces, by an acetoxylation process, N-aroyl-N’-acetylhydrazines (60) as main products, the structure of which is confirmed by their alternative synthesis from the aroylhydrazides (61). Substituted triazolo[4,3-h]benzothiazoles (62) which arise as by-products in this oxidation are accessible in 60% yield by heating the diacylhydrazines (60) in phenol.55 The results correct previous erroneous formulations.66 Benzothiazole 3-oxides. Benzothiazole 3-oxide 57 (64), unlike its 2-methyl homologue (63), is not obtainable by direct oxidation with permaleic acid.s8 It has now been prepared s7 from (63) by a seven-stage degradation, 63 64 55

57

A. V. Lukyanov, V. G. Voronin, and Y. S. Tsizin, Zhur. Vsesoyuz. Khim. obshch. im. D . I . Mendeleeua, 1970,15,238 (Chem. Abs., 1970,73, 25 345m). R. A. Bartsch, S. Hunig, and H. Quast, J . Amer. Chem. SOC., 1970, 92, 6007. R. N. Butler, P. O’Sullivan, and F. L. Scott, J. Chem. SOC.( C ) , 1971, 2265. J. D. Bower and F. P. Doyle, J. Chem. SOC.,1957, 727. S. Takahashi, S. Hashimoto, and H. Kano, Chem. and Pharm. Bull. (Japan), 1970, 18, 1176.


666

(55)

I

. H + f(S5)

Ar

(59)

the main steps of which are as shown. The chemical behaviour of the parent (64) has been examined in considerable detail and compared with that of benzimidazole N-oxide. Amongst reactions involving the N-oxide grouping, the following interactions with dipolarophiles are of special intere~t.~’

Condensed Ring Systems Incorporating Thiazole 0

667 0

0

t

?

163) 0

J

[ExNp1’?To

(64)

+

PhN=C=O +

(64)

+

NcxcN -+ NC

V ) N SH P h

CN

Diazotization. Diazonium salts of benzothiazoles have been useful in interconversions involving amino-derivatives of this ring system. 2-Fluorobenzothiazoles are accessible by the diazotization of the corresponding 2-amino-compounds, followed by cautious pyrolysis of the isolated diazonium fluoroborate with potassium fluoride and sand under reduced The four isomeric sulphonic acids of 2-rnethylbenzothiazoles are obtainable from the amino-compounds by diazotization, followed by treatment with acetic acid saturated with sulphur dioxide in the presence of cupric chloride; the resulting sulphonyl chlorides serve as source of the S. Takahashi and H. Kano, Chem. and Pharm. Bull. (Japan), 1969, 17, 1598; see also Vol. 1 of these Reports, p. 415. C. Griinert and K. Wiechert, Z . Chem., 1970, 10, 188.


668

desired functional derivatives.60 The benzothiazolesulphonic acids have been used for the production of carbocyanine dyes, the electronic spectra of which were studied. The results correct inaccuracies of previous work.61 A series of brilliant-red halogenobenzothiazolyl azo-dyes of general formula (65) (suitable as disperse dyes for synthetic polymer fibres) is

(65)

accessible by the diazotization of halogeno-2-aminobenzothiazoles, followed by coupling to N-p-hydroxyethyl-N-/3-cyanoethyl-m-toluidine. The dyes containing 4-halogeno-substituents have the highest fastness to sublimation on polyester fibres.s2 Alkylation and Related Reactions. Benzothiazolin-2-one is alkylated by benzyl chloride and analogous halides in sodium ethoxide to 3-benzylbenzothiazolin-2-ones (e.g. 66).63 Aminomethylation. Mannich bases (67) have been synthesized 2o in high yield by the interaction of the amine salts of 2-mercaptobenzothiazole with aqueous formaldehyde at ambient temperature. In contrast to certain earlier formulations, these products are invariably N- (and not S-) substituted 3-alkylbenzothiazoline-2-thiones.The concept of the oxibase AIk

I

CH,NR2 I

scale6*was employed in predicting the conditions for the formation of N- or S-substituted products from the ambident 2-mercaptobenzothiazole anion. 2o The aminomethylation of 2-aminobenzothiazoles with formaldehyde and morpholine affords methylenediamines of type (68) nearly quantitatively. The exocyclic 2-amino-group was established with certainty as the site of aminomethylation by n.m.r. measurements.66 so

E9

64

J. Libeer, H. Depoorter, and J. Nys, Bull. SOC.chim. belges, 1971, 80, 43. A. I. Kiprianov and I. Ushenko, Zhur. obshchei Khim., 1945, 15, 207 (Chem. A h . , 1946, 40, 2309). A. T. Peters, J. SOC.Dyers and Colourists, 1969, 85, 507. F. Yoneda and T. Otaka, Yukuguku Zusshi, 1968, 88, 1638 (Chem. Abs., 1969, 70, 77 897a). R. E. Davis in ‘Survey of Progress in Chemistry’, ed. A. Scott, Academic Press, New York, 1964, pp. 189-238; R. E. Davis, R. Nehring, W. J. Blume, and C. R. Chuang, J . Amer. Chem. SOC.,1969, 91, 91; R. E. Davis, S. P. Molnar, and R. Nehring, ibid., p. 97. J. Paris, J, Couquelet, and P. Tronche, Compt. rend., 1971, 272, C,679.

669


Michael reaction. 2-Mercaptobenzothiazole undergoes the Michael addition with activated unsaturated compounds such as methyl vinyl ketone, 2- (or 4-) vinylpyridine, divinyl sulphone, and 2-nitrobut-1-ene yielding N-substituted benzothiazoline-2-thiones [e.g. (70) or (71)]. The CH,CH,COMe I

E h (70)

(69) (CHZ=CH),SO,

reaction proceeds in excellent yield at ambient temperature in tetrahydrofuran in the presence of catalytic amounts of sodium hydride.2O The results correct the previous erroneous formulation of the acrylonitrile adduct [of (69)] as an S-substituted benzothiazole-2-thiol derivative.66 Azidobenzothiazoles. The reaction of 2-methyl-6-azidobenzothiazole(72) with lithium alkyls yields 3-N-alkyl derivatives (73) of 1-(2-methylbenzot hi azol-6-y l)tr iazene

.

(72)

(73)

Acylation. Quaternary salts of 2-methylbenzothiazole (74) yield 2-monoor 2,2-di-benzoylmethylene derivatives(75) and (76)with equimolar quantities or excess of benzoyl chloride. 2-Methylbenzoselenazole yields analogous derivatives. The spectral and photochemical properties of the compounds, particularly their sensitizing power, were evaluated and discussed.6s The mono-acyl compounds (75) are further convertible into O-acyl derivatives (77), which are once again deacylated on pyrolysis. When the groups R1and R2(in 78) are non-identical, the elimination occurs in such 66

M. W. Harman, Ind. Eng. Chem., 1937,29,205; U.S.P. 1 951.052/1934; 2 010.000/1935; 2 049.22911935.

67

L. I. Skripnik and V. Y. Pochinok, Khim. geterotsikl. Soedinenii, 1968, 1007 (Chem. Abs., 1969, 70, 68 229g. A. Mistr, V. Laznicka, and M. Vavra, Coll. Czech. Chem. Comm., 1971, 36, 150.

670


a way that the resulting product retains the more electronegative radical, culminating effectively in a transacylation 3-Methyl-2-@(p-nitrobenzoyloxy)propenyl]benzothiazoliumiodide (78 ; R1 = Me, R2 = p-N02C,H4), for example, is converted at 180 "C into 3-methyl-2(pnitrobenzoy1)methylenebenzothiazoline (79 ; R2 = p-NO,C,H,). The mechanism of the reaction is likely to involve a four-centred cyclic transition state (77).69

Alkylation and Acylation by Free-radical Reactions. Heteroaromatic bases, being electron-deficient compounds, readily react with nucleophilicreagents, particularly when protonation enhances their electron-deficient nature. Because of the nucleophilic character of the wide range of available alkyl radicals, homolytic alkylation of heteroaromatics is of interest comparable to that of electrophilic alkylation in the homocyclic series. Homolytic acylation is of no less importance because of the wide applicability of this general reaction in the heterocyclic field. Alkylation and arylation. The homolytic a-oxyalkylation of heteroaromatic bases using alcohols and ethers as radical sources has been studied. Although detailed experiments were chiefly concerned with quinoline and quinoxaline, benzothiazole was shown to yield 2-dioxanylbenzothiazole (40%) under the standard conditions. O The reactivity of benzothiazole (and its 2-methyl and 2-chloro-derivatives) towards phenyl radicals has been studied by the decomposition of benzoyl 69

70

V. I. Denes and G. Giurdaru, Chem. Comm., 1970, 510. W. Buratti, 0 . P. Gardini, F. Minisci, F. Bertini, R. Galli, and M. Perchinunno, Tetrahedron, 1971, 27, 3668.


67 1

peroxide at 110-120 "C in the presence of these heterocycles, followed by the chromatographic analysis of the mixture of phenylated compounds. The 4-position is the most reactive site in the ring system, followed by the 7-, 5-, and 6-positions. The observations are in good agreement with the results of theoretical calculations of the free valencies and radical localization energies by the o* method.71 Acylation. Benzothiazole is acylated selectively in the 2-position by acyl radicals, which are generated from a variety of aldehydes under the influence of the redox-system t-butyl hydroperoxide-ferrous ~ u l p h a t e . ~ ~ Because of the high reactivity and selectivity of the acylating agent, the reaction appears to be an advantageous route to 2-acylbenzothiazoles: thus, the use of a large excess of aromatic substrate (usually essential in homolytic aromatic substitutions) is not required, secondary products are not formed, and yields of the desired products are high (60430%). The reaction is also suitable for demonstrating the presence of acyl radicals, previously only surmised, in the oxidation of aldehydes by a variety of other oxidizing agents 72 (e.g. 02,CeIV, Crvl, or MnV1). Heterocyclic carbenes. 3-Methyl-2-benzothiazolylidene (80), obtained from 3-methylbenzothiazolium iodide and trieth~lamine,~~ condenses as a reactive carbene with acenaphthaquinone to yield the compound (8 1).74

+

Nucleophilic Substitution. Several nucleophilic replacements in benzothiazolium salts (82) and (83) have been r e p ~ r t e d .The ~ ~ reactions (see Scheme 4) were studied chiefly for the purpose of comparison with those of the analogous thiazolo[2,3-b]benzothiazoles (see p. 702). The results agree with the general experience that quaternization of benzothiazole enhances its susceptibility towards nucleophilic ~eagents.'~ The action of aqueous ammonia on benzothiazol-2-ylperfluoroalkenes and analogous compounds proceeds as Replacement appears to be accelerated by the presence of the heterocyclic moiety, since 71

G. Vernin, H. J. M. Dou, G. Loridan, and J. Metzger, Bull. SOC.chin?. France, 1970, 2705.

72

78 74

76

76

T. Caronna, R. Galli, V. Malatesta, and F. Minisci, J , Chem. Soc. (C), 1971, 1747. H.W. Wanzlick, H. J. Keiner, J. Lasch, and H. U. Fulder, Annalen, 1967, 708, 155. S. I. Burmistrov and S. F. Kondrateva, Zhur. org. Khim., 1971, 7 , 616 [J. Org. Chem. (U.S.S.R.), 1971, 7, 6211. P. Sohar, G. H. Denny, and R. D. Babson, J . Heterocyclic Chem., 1970, 7 , 1369. N. A. Malichenko, L. M. Yagupolskii, and V. F. Kulik, Zhur. org. Chem., 1970, 6, 389 (Chem. A h . , 1970,72, 111 3472).


672

+Me I-

(82)

I

I NH,

NHZOH

H*S

NaOH

Scheme 4

H(CF,),CF= CF, requires more stringent conditions to give H(CF2)aC(NHJ=CFCN. RCF,CF=CF,

NH,OH

zo"c

RCF=CFCN

NH,OH

so"c >

RC=CFCN

I NH2

(R = benzothiazol-2-yl)

Silylbenzothiazoles. 2-Trimethylsilylbenzothiazole (84) is accessible in 75-80% yields by the addition of trimethylchlorosilane to 2-benzothiazolyl-lithium at - 75 "C. The silicon-heterocyclic bond is unusually labile: it is cleaved smoothly by benzaldehyde, with formation of the silyl-ether (85) which is hydrolysable to the alcohol (86). The cleavage by benzoyl chloride or ethyl chloroformate produces the corresponding ketone (87; R = Ph) or ester (87; R = OEt); trimethylchlorosilane is evolved from the mixture during the reaction. Phthalic anhydride yields the keto-ester (88).77

1

RCOCl

77

F. H. Pinkerton and S. F. Thames, J. Heterocyclic Chem., 1971, 8, 257.

Page No. 673-704 Missing

Condensed Ring Systems Incorporating Thiazole 705 hydrobroinic 170 or polyphosphoric acid.I7l The ring-closure probably involves the initial protonation of the carbonyl group, enhancing its electrophilic nature: if so, other groups capable of forming a carbonium ion (at the &carbon atom) attached to the sulphur atom should participate in analogous cyclizations. This is realized in the conversion by polyphosphoric acid of 2-allylthiobenzimidazole (28 1) into 3-methyldihydrothiazolo[3,2-a]benzimidazole(282) (35%).l7I Numerous substituted thiazolo[3,2-a]benzimidazoles (274) arise similarly in the ring-closure of 2-(~-oxoalkylthio)benzimidazolesby phosphorus oxych10ride.l~~ Examples of ring-chain tautomerism in this ring system have been observed by spectral met hods. 173 Thus, 3"hydroxy-2,3-dihydrothiazolo[3,2-a]benzimidazole and its 3-trifluoromethyl analogue exist exclusively as the cyclic carbinolamines (283a; R = H or CF,) in both the solid and dissolved states. The 3-methyl homologue (283; R = Me) exists as (283a) in the solid state, but as a 1 :2-mixture of (283a) and the open-chain

(283a)

(283b)

aminoketone (283b) in solution. Increase of the size of R [of (283)] to t-butyl displaces the cquilibrium towards the chain-tautomcr (283b). When the 3-substituent is capable of conjugating with the carbonyl group [e.g. when R = cyclopropyl or ethoxycarbonyl in (283)], the compound exists solely as the linear tautomer (283b) both in the solid state and in solution, conjugation being the driving force for chain-tautomer stabili~ation.~7~ These and other observations lead to the following conclusions: (i) when R [in (283)] is a group of small bulk (up to t-butyl), ring-chain tautomerism is controlled by the inductive effects of the substituents : thus, if R is electron-releasing, the carbonyl carbon of (283b) becomes more negative and is therefore less susceptible to ring formation by reaction with the amino-group; if R is electron-attracting, the opposite tendency predominates ; (ii) for bulky groups, steric effects become significant ; (iii) any group having conjugative properties tends to stabilize the tautomer (283b).173 Some aspects of the chemical behaviour of 2,3-dihydrothiazolo[3,2-a]benzimidazol-3-ones have been studied.17* The interaction of the A. E. Alper and A. Taurin, Canad. J . Chem., 1967, 45, 2903. S. Singh, H. Singh, M. Singh, and K. S. Narang, Indian J. Chern., 1970, 8, 230. A. N. Krasovskii and P. M. Kochergin, Khim. geterotsikl. Soedinenii, 1969, 321 (Chem. A h . , 1969,71, 22 067v). n3 H. Alper, Chem. Comm., 1970, 3 8 3 ; H. Alper, E. C. H. Keung, and R. A. Partis, J . Org. Chem., 1971, 36, 1352. 174 A. Mustafa, M. I. Ali, and A. Abou-State, Annalen, 1970, 740, 132. 170 171

24

706


2-benzylidene derivatives (284) with Grignard reagents resembles that of Sbenzylidenerhodanine 176 in occurring at the arylidene group without cleaving the hetero-ring, yielding (285). The 2-g-dimethylaminophenylimino-compound (286) is attacked at the 3-carbonyl group, affording the carbinols (287). In the case of 2-arylazo-compounds (288), on the other hand, the thiazole nucleus is cleaved in the process, producing (289).17*

Oxidation of (284) with hydrogen peroxide does not yield the expected sulphone, but causes fission of the hetero-ring, with formation of benzimidazolinone (290). Further ring-cleavages of this type occur under the influence of amines and h y d r a ~ i n e . ~ ' ~

Thiazolo[3,4-a]benzimidazole.-[C,NS-C3N2-C,]. The synthesis of the 1-imino-1H,3H-thiazolo[3,4-a]benzimidazolering system (293) from 2-

176

A. Mustafa, W. Asker, A. F. A. Shalaby, and M. E. Sobhy, J. Org. Chem., 1958, 23, 1992.


707 chloromethylbenzimidazole (291) by the action of ammonium thiocyanate, followed by thermal cyclization, has been briefly ~ e p 0 r t e d . l ~ ~ Thiazolo[4,3-b]benzothiazoles.-[C,NS-C,N3-C6]. For a synthesis sli of examples of this ring system, cf. p. 665. Thiazolo[3,2-a]pyrrolo[2,3-d] pyrimidines.-[C,NS-C,M-CpNol. The use of 3,4-dihydro-2-mercapto-6-methylpyrrolo[2,3-d]pyrimidin-4-one (295) in the modified Hantzsch thiazole synthesis has made compounds of the above

(295)

(296)

tricyclic ring system available. Condensation with bromoacetaldehyde diethylacetal, for example, produces 3-ethoxy-2,3-dihydr0-7-methyl-SH,8Hthiazolo[3,2-a]pyrrolo[2,3-d]pyrimid-5-one(296).134

6 Structures Comprising One Five-membered and Two Sixmembered Rings (5,6,6) [l,3]Thiazino[2,3-b]benzothiazoles.-[C3NS-C~NS-C~]. For a synthesis of 2H-[1,3]-thiazino[2,3-b]benzothiazoliumsalts 163 see p. 702. Pyrimido [2,1-b]benzothiazoles.-[C,"-C,N,-C6]. 1,2,3,4-Tetrahydro-2oxopyrimido[2,1-b]benzothiazol-5-ium chloride (298) is readily formed on fusion of 2-(3-chloropropionylamino)benzothiazole (297) at 190 "C. Subsequent treatment with anhydrous diethylamine affords 3,4-dihydro2H-pyrimido[2,1-b]benzothiazol-2-one (299). The pyrimidine ring of (298) is opened with unusual ease on treatment with water or alcohol, with

170

R. D. Haugwitz, B. V. Maurer, and V. L. Narayanan, Chem. Comm., 1971, 1100.

708


production of the novel amino-acids (300). This facile ring-cleavage may be due to the enhanced electrophilic nature of the amide carbonyl group [position 2 in (298)], caused by resonance stabilization of a positive charge on the amide nitrogen and on the bridgehead nitr0gen.l''

A number of thiazolo[3,2-a]quinazolones have been obtained by the application of conventional cyclization reactions. Thus, the condensation of 2-mercapto-3phenylquinazolin-4(3H)-one (301) and phenacyl bromide yields the S-alkylated derivatives (302) which are reduced by sodium borohydride 3H)to 1,2-dihydro-2-(~-hydroxyphenetkyl)mercapto-3-phenylquinazolin-4( one (303). Cyclodehydration by acetic anhydride or toluene-p-sulphonic

Thiazolo[3,2-a]quinazolines.-[C,NS-C,N2-C,].

ArCH--dK, I OH

I

(303)

3. 0

0

u

Ph

(307)

0

(304)

(309) 177

K. K. Weinhardt and J. L. Neumeyer, J . Org. Chem., 1970,35, 1176; Chem. Comm., 1968, 1423.


709

acid yields the 1,4-diarylthiazolido[3,2-a]quinazolin-5(4H)-one(304).178 The use of monochloroacetic acid in the same reaction sequence [(301) + (305) + (306)] affords the analogous 4-phenylthiazolido[3,2-a]quinazolin1,5(4H)-dione (307) 178 or the 6,7-disubstituted hornologues thereof.179 Cyclodehydration of the mercaptoacetic acid (305)with acetic anhydridepyridine produces the mesoionic anhydro-base (308) as dark-blue crystals with a bronze 1 u ~ t r e . l ~ ~ Several 4-benzenesulphonyl-1-phenylthi azolido [3,2-a]quinazolin-5(4H)ones (309) 18* and thiazolo[3,2-a]quinazoloniurn salts (3 10) have been prepared by similar cyclizations.ls1

Thiazolo[4,5-6]quinoxalines.-[C,NS-C4N,-C6]. 2-Arylimino(and 2-imino3-aryl)-2,3-dihydrothiazolo[4,5-b]quinoxalines (3 11) are accessible by the

condensation of 2,3-dichloroquinoxalineswith thiourea derivatives. They yield the corresponding 2-keto-compounds on hydrolysis.ls2

Thiazolo[2,3-a]isoquinolines.-[C3NS-C5N-C6]. The conversion of Nbenzylisoquinoliniuni bromides (312) into rnesoionic 3-phenylthiazolo[2,3-a]isoquinolinium-2-thione betaines (313) lE3by carbon disulphide in alkaline aqueous dioxan has been re-investigated.le4~lE5 N-Benzylisoquinolinium 4-dithiocarboxylates (3 14) are formed as by-products.le4

The yields of the two products derived from seven benzyl-substituted salts have been determined lS5 by an isotopic-dilution technique using 35S.The molar ratio of adducts is correlated satisfactorily by a Hammett plot: 178

17e

180 l*l

lS2 lR3

B. D. Singh and D. N. Chaudhury, J. Indian Chem. SOC.,1970, 47, 759. S. K. P. Sinha and D. N. Chaudhury, J. Indian Chem. SOC.,1970, 47, 1095. B. Singh and D. N. Chaudhury, J. Indian Chem. SOC.,1971, 48, 443. B. Singh and D. N. Chaudhury, J. Indian Chem. Soc., 1971, 48, 395. S. Singh, H. Singh, R. S. Narang, S. Singh, and M. L. Mahajan, J . Indian Chem. Soc., 1970, 47, 859. F. Krohnke and H. H. Steuernagel, Angew. Cliem., 1961, 73, 26; Chem. Ber., 1964, 97, 1118.

J. E. Baldwin and J. A. Duncan, J. Org. Chem., 1971, 36, 627.

710


log [betaine/dithiocarboxylate] = 2.320 - 0.12 ( R = 0.971). The relevance of this electronic effect to the mechanism of the two competing addition processes has been

Thiazolo[3,2-b]isoquinolines.-[C3NS-C,N-C,]. In continuation of their investigation of cyclizations involving the loss of nitrous acid, Krohnke et have described a synthesis of thiazolo[3,2-b]isoquinolines.2-Methyl3-phenacylbenzothiazolium bromide (315; R = Ph) is found to react with picryl chloride to form (316). In common with picryl-substituted ylides,ls7 this is cyclizable, involving its nitroaryl and N-methylene groups, to yield

(317) with loss of the elements of nitrous acid. Thiazolium salts react analogously, affording products such as 7,9-dinitro-3-methyl-5-ethoxycarbonyl-5H-thiazolo[3,2-b]isoquinoline(318) in two stages.lse

Pyrano[3,2-g]benzothiazoles.-[C3NS-C60-C6]. Five isomeric thiazolochromones (320)-(324) have been synthesized from the appropriately substituted acetylhydroxybenzothiazoles by their base-catalysed condensation with diethyl oxalate, followed by acid-catalysed cyclization and hydrolysis of the resulting diketone esters [e.g. (319) -+ (320)l. The mass spectra of the resulting thiazolochromone carboxylic acids display a common fragmentation pattern, the base peak (m/e 191) being due to the fragment (325) arising from the molecular ion by a retro-Diels-Alder fission. Thiazolo[5,4-c]benzo(thio)pyrans.-[c3NS-C5X-C,]. Heterocyclic a-bromoketones (326) react with thioureas or thiosemicarbazides in alcoholic acetate-buffered solution to produce 2-substituted 4H-thiazolo[5,4-c]benzo(thi0)pyrans (327; X = 0 or S ) in 30-55% yield.18B J. E. Baldwin and J. A. Duncan, J. Org. Chem., 1971, 36, 3156. D. B. Reuschling and F. Krohnke, Chern. Ber., 1971, 104, 2110. W. Augstein and F. Krohnke, Annalen, 1966, 697, 158; D. B. Reuschling and F. Krohnke, Chem. Ber., 1971, 104, 2103. lg8 A. 0. Fitton, B. T. Hatton, M. P. Ward, and R. Lewis, J. Chem. SOC.(0,1970, 1553. lgS G. Kempter, H. Schiifer, and G. Sarodnick, Z. Chem., 1970, 10, 462.

lB6

lg8

71 1

Condensed Ring Systems Incorporating Thiazole 0

(323)

(326)

(327)

Naphtho[l,2-d]thiazoles.-[C3NS-C&,]. Examples of this ring system have been synthesized by an adaptation of conventional methods lo (see p. 658).

Selenazolo[5,4-f]quinolines.-[[C3NSe-C,N-C,].

wM

2,7,9-Trimethylselenazolo-

[5,4-f]quinoline (328) is accessible by a Doebner-Miller type of synthesis from 2-methyl-6-aminobenzoselenazoleand pent-3-en-2-one. Successive R

CH II

Me quaternization and treatment with p-dimethylaminobenzaldehyde affords the trinuclear styryl derivative (329), showing the superior reactivity of the 7- and 9-methyl groups.19o lS0

E. Barni and G . di Modica, J . Heterocyclic Chern., 1971, 8, 693.

712

Organic Compounds of Sulphur, Selenium, and Tellurium 7 Structures Comprising One Five-membered, One Sixmembered, and One Seven-membered Ring (5,6,7) Thiazolo [3,2-6][2,4]benzodiazepines.- [C,NS-C,-C,N,]. The extended Hantzsch synthesis has been applied to the preparation of a wide range of thiazolo[3,2-b][2,4]benzodiazepinederivatives and related compounds lgl (see also Volume 1, p. 442). Thus, the condeiisation of 1,2,4,5-tetrahydro3H-2,4-benzodiazepine-3-thione(330) with the appropriate 2-halogenoacetophenone in 2-methoxyethanol yields 5,10-dihydr0-3-phenylthiazolo[3,2-b][2,4]benzodiazepines (331 ; R = Ph); analogues (331 ; R = thienyl,

-K N b

Q f > S

\

H N

NJ R

(330) (331) furyl, or naphthyl) are similarly accessible. The compounds are effective inhibitors of ADP-induced platelet aggregation and represent a new class of antithrombic agents.l9

8 Structures Comprising Two Five-membered and Two Sixmembered Rings (5,5,6,6) Thiazolo [3',4'-1,2] pyrazino[7,8-a]benzimidazo1es.-[ C3NS-C3N2-C4N2-C6]. In connection with their more detailed work on thiazolodiazepinobenzimidazoles (see p. 714), Maynard et al.lg2have condensed 2-(4'thiazoly1)benzimidazole and 1,2-dibromoethane to produce 5,6-dihydrothiazolio [3',4'- 1,2]pyrazino[7,8-a]benzimidazole bromide, and described several of its reactions, notably the cleaving of its thiazolium ring.lg2

Benzi~dazo[2,l-b]benzoth~azole.-[C3NS-C3N2-C6-C~].The condensation of 2-chlorocyclohexanone and 2-mercaptobenzimidazole at 150 "C yields (72%) 1,2,3,4-tetrahydrobenzimidaz0[2,1-b]benz~thiazole.l~~

Q & H +

,gr3

- @-J--o

E. F. Elslager, J. R. McLean, S. C. Perricone, D. Potoczak, H. Veloso, D. F. Worth, and R. H. Wheelock, J. Medicin. Chem., 1971, 14, 397. lQP J. A. Maynard, I. D. Rae, D. Rash, and J. M. Swan, Austral. J . Chem., 1971, 24, 1873.

lo1


713

Naphth [1,Zd]imidazo [3,2-l)]thiazole.-[C,NS-C,N,-C,-C6].Examples of this ring system have been synthesized 164 by adaptations of known methods.

Thiazolo[5,4-a]carbazoles.---[C,NS-C4”C,-N-C6-C6]. 4,5-Dihydro-2-methylbenzothiazol-7(6H)-one (332), on being converted into the phenylhydrazone and subjected to the Fischer indole synthesis, yields (333), which affords 2-methyl-lOH-thiazolo[5,4-a]carbazolc(334) on dehydrogenation; the naphthylhydrazones give rise to the corresponding structures

_3

(333).

(332)

(334)

(335)

comprising five fused rings. The dehydration of the oximc of (332) with polyphosphoric acid furnishes 7-amino-2-methylbenzothiazole,together with 4,5-dihydro-2-methyl-8H-thiazolo[5,4-b]azepin-7(6H)-one (335) as a by-product. lo3

Isoindolo[1,2-b]benzothiazoles.-[C,NS-C4N-C6--C6]. Salts derived from isoindolo[l ,2-blbenzothiazoles (336) lg4readily undergo condensation with aromatic aldehydes at their 1 1-methylene group, furnishing the violet-blue

(335) lg3

(337)

N. P. Buu-Hoi, A. Croisy, P. Jacquignon, and A. Martani, J. Chem. SOC.(C), 1971, 1109.

m4 F. S. Babichev and V. K. Kibirev, J. Gen. Chem. (U.S.S.R.), 1963, 33, 1946.

714


methine dyes (337). These are decolourized in aqueous alkali to their pseudobases (338), but the change is reversed by mineral acids.135 9 Structures Comprising Two Five-membered, One Sixmembered, and One Seven-membered Ring (5,5,6,7)

Thiazolo[3’,4’-1,2][1,4]diazepino[8,9-a]benzimidsazoles. - [C,NS-C,N,-C,CnN,]. 1-(3’-Bromopropyl)-2-(4’’-thiazolyl)benzimida~ole (339) isomerizes above 100 “C to 6,7-dihydro-5H-thi azolio [3’,4’- 1,2][1,4]diazepino[8,9-a]benzimidazole bromide (340), the structure of which is established by its spectral properties and chemical behaviour. Treatment with alkali cleaves its thiazolium ring: the resulting thiol (341; R = SH) is isolable as the S-methyl derivative (341 ; R = SMe) and is oxidized by hydrogen peroxide CH2CH,CH,Br

(339)

Br-

\

(340)

H

(342)

(343)

(344)

(341)

to the monosulphide (342) with extrusion of sulphur, instead of the expected disulphide. Desulphurization of the anion derived from (340) by Raney nickel in akaline medium yields the formamide (343) as the major, and the tertiary amine (344; R = Me) as the minor product. Further interesting reactions of (340) and of its 13-methyl-quaternized derivatives were described.192 10 Structures Comprising One Five-membered and Three Six-membered Rings (5,6,6,6)

Thiazolo[5,4-6]- and Th~azo~o[4,5-c]-phenothiazine.-[~,NS-C,~S-C,-C,]. The action of alkaline potassium ferricyanide on the phenothiazine derivative (345) yields the two isomeric dimethylthiazolophenothiazines (346) and (347), separable by chromatography, in the approximate ratio 1 : 8. Their formulation is based on their spectral properties.lg6 IB6 lB6

G . Irick, J. Heterocyclic Chem., 1970, 7 , 3 3 . S . G . Fridman and D. K. Golub, Khim. geterotsikl. Soedirtenii, 1969, 247 (Chern. .4bs., 1969, 71, 30 430y).

716


Thiazolo[$,5-c]acridines.-[C,NS-C5N-C,-C,].

4,5-Dihydro-2-methylbenzothiazol-7(6H)-one (348), readily obtainable by the condensation of thioacetamide with 2-bromocyclohexane-1,3-dione, undergoes the Friedlander acridine synthesis. Its reaction with o-aminobenzaldehyde yields the 4,5-dihydro-compound (349), which is dehydrogenated by palladiumcharcoal to 2-methylthiazolo[4,5-c]acridine(350).

~soquinolino[~,~-b]benz0thiaz0~e.-[~,~~-~,~-~,-~,]. The condensation of homophthalic anhydride and o-mercaptoaniline yields the benzothiazole derivative (35l), which is convertible, by the route shown, into 6,ll -dihydroisoquinolino[3,2-6]benzothiazoliumbromide (352; X = Br). The quaternary salt loses a proton from C-6 to form the free base. A number of derivatives of type (353) and (354) are readily accessible by the action of the appropriate aldehyde.lQ7 11 Structures Comprising One Five-membered and Four Six-membered Rings (5,6,6,6,6) Quinoxalino[2’,3’-4,5]thiazolo[3,2-a(and b)]quinazolines.-[C,NS-C,N,-C,N&&,]. The condensation of 2,3-dichloroquinoxaline (355) and 2-mercapto-4-(3H)quinazolinone (356) yields a mixture, separable by preparative thin-layer chromatography, of SH-quinoxaIino[2’,3’-4,5]thiazolo[3,2-a]quinazolin-5-one(357) and its [3,2-b] isomer (358). The 0

assigned structures are supported by chemical evidence. In particular, (358) is obtainable by an alternative synthesis, involving the action of carbon disulphide on 2-chloro-3-(2’-aminobenzoyl)aminoquinoxaline (359), which is itself accessible from isatoic anhydride and 2-chloro-3-aminoquinoxaline.lS8 le7

19*

F. S. Babichev, V. N. Bubnovskaya, and N. M. Martyshko, Ukrain. khim. Zhur., 1969, 35, 817 (Chem. Abs., 1970, 72, 45003f). S. Singh, H. Singh, C. Singh, and K. S. Narang, Indian J. Chem., 1970, 8, 130.

I5 Thiadiazoles and Selenadiazoles BY F. KURZER

1 Introduction Progress in the investigation of thiadiazoles has been well sustained, much of the total effort being concerned, as usual, with the 1,3,4-isomers of this ring system. More than three times as much work on 1,3,4-thiadiazoles has been published as on the remaining three classes of isomer put together. In an old-established and well-documented field such as this, results of great novelty are hardly to be expected; however, there is still room for work of merit, as is exemplified by the appearance of interesting papers on mesionic compounds, ring-chain tautomerism, and novel synthetic aspects. The chemistry of the S-oxides of all four isomeric thiadiazoles has been reviewed in detai1.l The properties of these compounds are best accounted for by regarding their structures as cyclic sulphonylhydrazines (l), a- and /l-aniinosulphonamides (2), sulphamides (3), and hydrazinosulphones (4).

2 1,2,3-Thiadiazoles Synthesis. The 1,3-dipolar cycloaddition of Synthesis.-Peckmann’s diphenyl(or methy1)phosphinic i so thiocyanates to diazomethane or phenyldiazomethane affords low yields (7-29%) of the appropriate substituted 1,2,3-thiadiazoles (5).2 The method is an extension of Pechmann’s oldestablished synthesis (see Volume 1, p. 444). Carbamoyl isothiocyanates (6) similarly afford 40-60% yields of substituted 1,2,3-thiadiazoles of type (7),* the structure of which is confirmed by an independent synthesis s from the appropriate urethane (8). a

A. Lawson and R. B. Tinkler, Chern. Reo., 1970,70, 593. G. Tomaschewski and D. Zanke, 2. Chem., 1970, 10, 145. H. von Pechmann and A. Nold, Ber., 1896,29,2588. J. Goerdeler and D. Wobig, Annulen, 1970, 731, 120. J. Goerdeler and G. Gnad, Chem. Ber., 1966, 99, 1618.

717


718

Rr,{

RTH=N+

II

C

R ~ P O - N ~+s

N- >-

R;PONH

s

R1 = Me or Ph; R2 = H or Ph (5)

cy

CH2=N+ II

N‘ +R,NCO*NH S,N

C

R,NCO.N~

*R,NH

%

(6)

(7)

(8)

The carbamoyl isothiocyanates (6) thus react without isomerizing to the corresponding thiocarbamoyl isocyanates (compare thiazoles, p. 616). Synthesis from Sulphonyl Azides. The conversion of arylsulphonyl azides into 1,2,3-thiadiazole dioxides has been briefly reported.6 Highly purified arylsulphonyl azides incorporating secondary amino-groups in the ortho position (e.g. 9) are pyrolysed in chlorobenzene to give the heterocyclics in good yields. The thiadiazole dioxides thus obtained are either mesionic (10) or dealkylated products (ll), depending on the nature of the starting material.6 R

R

\ /

&02N3 \

NO2

(9)

R

I

R-N+-N-

(-yo2

640; RN-NH

\

NO2 (10)

NO2

(1 1)

Other Reactions. The conversion of 4-aminoisothiazoles into 4-acyl-l,2,3thiadiazoles is described in the chapter dealing with the former ring system’ (see p. 569). The oxidation of 2-hydrazono-NNN’N’-tetramethylthio-oxamide(12) by various reagents does not yield the expected 4,5-bis(dimethylamino)1,2,3-thiadiazole (14), but produces the azines (13).8 Properties.-The mass spectra of a number of mono- and di-substituted 1,2,34hiadiazoles have been discussed in detail.B The elimination of a molecule of nitrogen from the molecular ion usually precedes any fragmentation involving substituents. The behaviour of 1,2,3-thiadiazoles under J. Martin, 0. Meth-Cohn, and H. Suschitzky, Chem. Comm., 1971, 1319.

’ F. T. Lee and G . P. Volpp, J . Heterocyclic Chem., 1970, 7 , 415. @

J. E. Oliver and J. B. Stokes, Canad. J . Chem., 1971, 49, 2898. B. J. Millard and D. L. Pain, J . Chem. SOC.( C ) , 1970, 2043.

Thiadiazoles and Selenadiazoles

719 S

II

Me,N-C-$-X S".N

HNMe2 Me,N

MeCS-NHNHCOAr

N-N Me( )Ar 0

NHNHz I IIS/c',S 42

4s

44

46 40

+ BrCN

N-N

MeaS4Ar

N-N ___f

RSA S l r N i H 2

S. Kubota, T. Okitsu, and Y. Koida, Yakugaku Zasshi, 1970, 90, 841 (Chem. Abs., 1970, 73, 77 147t). S. Kubota, Y. Koida, T. Kosaka, and 0. Kirino, Chem. and Pharm. Bull. (Japan), 1970, 18, 1696. D. G. Neilson, R. Roger, J. W. M. Heatlie, and L. R. Newlands, Chem. Rev., 1970, 70, 151. K. H. Uteg, Z . Chern., 1969, 9,450. R. Clarkson and J. K. Landquist, J . Chem. Soc. ( C ) , 1967, 2700.


733

The reaction between hydrazinium dithiocarbazates and aliphatic aldehydes or ketones yields 5,5-disubstituted 1,3,4-thiadiazolidine-2-thiones (111). Treatment of (111) with potassium hydroxide or methyl iodide leads, in some cases, to ring fission, with formation of the salts or methyl esters of alkylidenedithiocarbazic acids (1 12). Lr., n.m.r., and mass spectra H,N-NR3 I R1R2C0 CSS-

OH-

HN-NR3

R1R2C=N-NR3-CSSH R&AS

(112) ( I 11)

support the structural assignments, 3,4,5,5-tetramethyl-1,3,4-thiadiazolidine-2-thione being used as a reference Synthesis from Acylhydrazines. The condensation of acylhydrazines and ethyl dithioacetate in boiling ethanol furnishes 5-aryl-2-methyl-173,4thiadiazoles, but 1,3,4-0xadiazoles are formed as main products in some cases. Under suitable conditions, the intermediate thioacetylacylhydrazines may be Synthesis from 1-Thiocyanato-2,3-diazabuta-l,3-dienes.l-Chloro- 1,4-diphenyl-2,3-diazabuta-1,3-diene(1 13) is readily converted by potassium thiocyanate into the corresponding 1-thiocyanato-compound (1 14) from which 1,3,4-thiadiazoles may be obtained. Thus, thermolysis of (1 14) in boiling toluene produces, in addition to much polymeric material (5379, N-N=CHPh PhC=N-N=CHPh

c1I

KSCN PhC,4 S-CEN

“i

N-N-CHPh

-%

y,l

[PhP ‘S-C=N

]

I

2-benzylideneamino-5-phenyl-l,3,4-thiadiazole (1 16) (47%) by a mechanism possibly involving the intermediate (115). Acid hydrolysis of (114) produces benzaldehyde and 2-amino-5-phenyl-l,3,4-thiadiazole (117)directly (94%).48 47 4a

49

U. Anthoni, C. Larsen, and P. H. Nielsen, Acta Chem. Scand., 1970, 24, 179. N. Nikeda, A. Yada, and K. Takase, J. Pharm. SOC.Japan, 1970,90,95 (Chem. Abs., 1970,72, 90 374p). W. T. Flowers, D. R. Taylor, A. E. Tipping, and C. N. Wright, J. Chem SOC(C). 1971, 3097.


734

Synthesis from 1,2-Dithiole-3-thiones. 5-Aryl-l,2-dithiole-3-thiones (1 18) react with a-chlorobenzylidenephenylhydrazine (1 19), with simultaneous dithiole-ring opening and formation of (A4-1,3,4-thiadiazolin-2-ylidine)thioacetophenones (120).50 The use of ethyl bromo(pheny1hydrazono)acetate similarly affords (5-ethoxycarbonyl-3-phenyl-A4-1 ,3,4-tkiadiazolin2-ylidene)thioacetophenone, which is saponifiable to the corresponding 5-carboxylic acid. The reactions resemble Huisgen's 51 synthesis of N-(3, 5-diphenyl-A4-1,3,4-thiadiazolin-2-ylidene) benzamide from (119). Oxidation of (120) with mercuric acetate yields the corresponding acetophenones (121), which are reconvertible into the sulphur analogues Ph

s-s

/

A r U S -k I'-

\ NNHPh

P,S,

0

T-l

Hg(OOCMe),

s-CPh

0

4.-

Ph

Ar

Ph

Ph

S

~

ACHN,! -I- s A N , N Ar

P

h

P 11

(120) by phosphorus pentasulphide. The structure of (121) is confirmed by their independent synthesis from diazoacetophenone and 3,5-diphenylA4-1,3,4-thiadiazoline-2-thione (1 22). Several additional reactions of the heterocyclic thioacetophenones (120) were described, including their successive methylation to 2-(2-vinylmethylthio)-3,5-diphenyl-1,3,4-thiadiazolium iodides (123) and aminolysis to (1 24).60 Synthesis from Oxadiazolium Salts. N-Aryl- 1,3,4-0xadiazolium salts (125)52may serve as starting materials for the preparation of the corresponding 1,3,4-thiadia~oles.~~ Their reaction with sodium sulphide yields 61 6a

5s

M. Maguet, Y. Poirier, and J. Teste, Bull. SOC.chim. France, 1970, 1503. R. Huisgen, R. Grashey, M. Seidel, H. Knupfer, and R. Schmidt, Annalen, 1962, 658, 169. G. V. Boyd and S. R. Dando, J . Chem. SOC.(C), 1970, 1397. G. V. Boyd and A. J. H. Summers, J . Chem. SOC.(C), 1971,2311.


735

N'-acyl-N-aryl-N-thioacylhydrazines(126) which are cyclized by acetic anhydride, in the presence of perchloric acid to N-aryl- 1,3,4-thiadiazolium perchlorates (127; up to 8873, or to the original oxadiazolium salts (125) or mixtures of both. The observations are accounted for by the mechanism shown in Scheme 2, the two processes being initiated by S- or U-acylation, controlled by electron release or withdrawal due to the s u b ~ t i t u e n t s . ~ ~

(1 27)

Scheme 2

The same sequence of reactions furnishes 2,5,7-trisubstituted 8-cyano-

1,3,4-thiadiazol0[3,2-a]pyridinium salts (1 29), by way of intermediate substituted acylaminopyridine thiones (1 28).63

Me

I

NHCOR

Numerous 1,3,4-thiadiazoles have been produced by known routes, mostly in the course of biological screening programmes. They are listed in Table 1, as are derivatives obtained by simple methods from the preformed heterocyclic system. Existing syntheses of 2-amino-5-(l-methyl-5-nitro-2-imidazolyl)-l,3,4thiadiazole (140), an outstandingly powerful antimicrobial and antiprotozoal agent, have been supplemented by a route in which the imidazole ring is built upon a preformed thiadiazole nucleus. For this purpose, a suitable cyano-1,3,4-thiadiazole (e.g. 136) is required; since this appeared to be accessible from the corresponding aldehyde, the was studied in some detail. synthesis of halogenomethyl-l,3,4-thiadiazoles Thus, thiosemicarbazide (133), on being condensed with dichloroacetyl chloride (or anhydride, 2 moles) under various conditions, affords up to (134). 53% yields of 2-dichloroacetamido-5-dichloromethyl-l,3,4-thiadiazole

736 Organic Compounds of Sulphur, Selenium, and Tellurium Table 1 Synthesis of 1,3,4-thiadiazoles Type of compound

2-Amino-5-aryl-l,3,4-thiadiazoles 2-Amino-5-(3-oxocyclopentyl)-1,3,4-thiadiazole thiosemicarbazones 2-Aniino-5-(5-methylthio-2-furyl)-l,3,4-thiadiazole and sulphone 5-Substituted-2-acylamino-l,3,4-thiadiazoles a 2-Amino-5-t-butyl-l,3,4-thiadiazole, ureido-derivatives a 1,3,4-Thiadiazolylureas a 1,3,4-Thiadiazolyl-ureasand -thioureas a 3-Aryl(or pyridyl)-5-aryl(or alkyl)amino-l,3,4-thiadiazoles 5-Acetamido-l,3,4-thiadiazole-2-sulphonamide and Mannich bases derived therefrom a [5-(5-Nitro-2-furyl)1,3,4-thiadiazol-2-yl]amides a 2-(5-Amino-l,3,4-thiadiazol-2-yl)quinoxaline1,4-dioxide and analogues

Ref. 54 55

56 57 58 59

60

61 62 63

64

Derivatives obtained from the pre-formed heterocyclic system.

The use of trichloro-, trifluoro-, or difluoro-acetic acids in conjunction with phosphorus oxychloride similarly affords tri(or di)halogenomethyl1,3,4-thiadiazoles(130)-(132). However, the condensation of chloroacetyl chloride with thiosemicarbazide did not yield the expected heterocyclic product, but gave merely 1,l -bis(chloroacetyl)thiosemicarbazide, (C1CH2CO)2NNHCSNH2.65 Of these compounds, the dichloromethylthiadiazole (1 34) is the key intermediate in the synthesis of the desired compound (140). It is hydrolysed to the 2-carboxyaldehyde, which is isolated as the oxime (135). This is next simultaneously acetylated and dehydrated by acetic anhydride to (1 36). Application of Pinner’s yield 5-acetamido-2-cyano-1,3,4-thiadiazole synthesis affords the amidine (138), which is dehydrated and cyclized by sulphuric acid to the imidazole (139); niethylation and nitration under carefully controlled conditions complete the synthesis.65 Chemical Properties.-Complete sets of harmonic symmetry force constants have been calculated 66 for 1,3,4-thiadiazole, based on observed vibrational 64 66 66

O7 b8

6o

64 6~

68

V. R. Rao and V. R. Srinivasan, Indian J. Chem., 1970, 8, 509. A. Ermili and G. Roma, Farmaco (Puuia), Ed. sci., 1971, 26, 19. S. Toyoshima, K. Shimada, K. Kawabe, and T. Kanazawa, Yakugaku Zasshi, 1969, 89, 779 (Chem. Abs., 1969,71, 81 05511). I. Lalezari and A. Vahdat, J. Medicin. Chem., 1971, 14, 59. M. Uchiyama and R. Sato, J. Agric. Chem. SOC.Japan, 1971, 45, 429. K. Ishizuka, I. N. Lee,T. Tatsuno, and Y. Kubota, Agric. and Biol. Chem. (Jupan), 1971, 35, 964. H. Kubo, R. Sato, I. Hamura, and T. Ohi, J. Agric. Food Chem., 1970, 18, 60. M. Y. Mhasalkar, M. H. Shah, P. D. Pilankar, S. T. Nikam, K. G. Anantanarayanan, and C. V. Deliwala, J. Medicin. Chem., 1971, 14, 1000. G. M. Sieger, W. C. Barringer, and J. E. Krueger, J. Medicin. Chem., 1971, 14, 458. P. J. Islip and M. D. Closier, J. Medicin. Chem., 1971, 14, 449. P. H. Gund and G. Berkelhammer, J . Medicin. Chem., 1971,14,992. W. A. Remers, G. J. Gibbs, and M. J. Weiss, J. Heterocyclic Chem., 1969, 6, 8 3 5 ; see also these Reports, vol. 1, p. 444. B. N. Cyvin and S. J. Cyvin, Acta Chem. Scand., 1969, 23, 3139.

737

Thiadiazoles and Selenadiazoles N -N H,N‘!,~IICHF~

N-N H,N(S,!J~F,

(1 30)

N -N CI~C.CONHLC~)CCI, ( 132)

(131)

NHNH? H,NAS

N-N CI,CHCONH(

(133)

JCHCI, *-+

N-N

H,N(

(1 34)

S I ] ~ ~ =

(1 35)

c1-

NHCH,CH(OMe),

(138) N-N

N

N-N

HtN(SMN]NO,

MeCONH

N

Me

H

( 139)

(140)

frequencies taken from the literatures7 (see also p. 752). Mass spectra of 5-alkylthio-1,3,4-thiadiazolyl-2-amines have provided data for suggested fragmentation patterns, but no unifying conclusions appear to have emerged so far.68 A careful analysis of n.m.r. spectra measured in various solvents has revealed the occurrence of ring-chain tautomerism in 1,3,4-thiadiazoIidine2-thiones (141). In solution, these compounds exist in equilibrium with their open-chain ‘hydrazone’-tautorners (1 42); the equilibrium is displaced entirely to the ‘hydrazone salt’ form (143) in alkaline media.6g The discovery was made with 5-(pyrid-2-yl)-1,3,4-thiadiazolidine-2-thione (141;R1 = R3 = H; R2 = 2-C,H4N), the alkali and amine salts of which show chemical shifts resembling those of the methine protons of hydrazones and azines of type (144). N-3-Substituted 1,3,4-thiadiazolidine-2-thiones (145)exhibit the same effect: here the ring-chain tautomerism incidentally 67 68

G. Sbrana and M. Ginanneschi, Spectrochim. Acta, 1966, 22, 517. C. S. Barnes, R. J. Goldsack, and R. P. Rao, Org. Mass Spectrometry, 1971, 5, 317. K. H. Mayer and D. Lauerer, Annulen, 1970, 731, 142.

25


738

accounts for their solubility in alkali that had previously remained unexplained.'O N-4-Substituted analogues (147), however, lack the N-4proton required for ring-cleavage : their chemical shifts in alkaline media show no anomaly, and their alkali-solubility is explicable by the conventional thione-thiol tautomerism (147 + 148). N-3,N-4-Disubstituted 1,3,4-thiadiazolidin-2-thiones (146) cannot, of course, undergo either tautomeric change and are alkali-ins~luble.~~

R'N-NH R'XSrS H

-

RlN-N

HN-NMe

R~&)JsH H

O S ' - S

(1 48)

(149)

(147)

N-NMe-CSSMe

+--

0-NMe-C-SH

(150)

II

S

These conclusions, derived entirely from spectral data, are supported by chemical evidence. Alkylation of 1,3,4-thiadiazolidine-2-thiones(149), for example, affords good yields of the hydrazones of the appropriate alkyl 2-alkyldithiocarbazates (1 50). Other reactions provided further confirmati~n.~~ The realization of this new type of ring-chain tautomerism suggested the existence of reverse changes, so that compounds of type (151), hitherto considered linear, might assume the tautomeric A2-1,3,4-thiadiazoline structure (153) in acidic media (e.g. in F3CC02D). N.m.r. measurements made with thiosemicarbazones (151 ;R3 = NH2 or NHMe) and hydrazones of alkyl dithiocarbazates (151; R3 = SMe) fully confirmed these expectation^.^^

A suggested mechanism for the facile cyclization and ring cleavage now described involves the electron displacements shown (154) + (155).6g 'O

F. C. Heugebaert and J. F. Willems, Tetrahedron, 1966,22,913.

739


H

V The majority of chemical reactions of 1,3,4-thiadiazoIesthat have recently been studied concern interactions with nucleophiles. Halogenation and nitration of 2-arylamino-5-methyl-1,3,4-thiadiazoles significantly occurs in the aryl nucleus, in accordance with the electron-attracting character of the 1,3,4-thiadiazoIe nucleus.71 Nucleophilic attack on 2-bromo-5-nitro-l,3,4-thiadiazole(156) may occur at either the bromo- or the nitro-substituent, depending on the nature of the reagent.72 Ammonia and amines exclusively yield the products of bromide-ion displacement (1 57). In contrast, sodium thiophenolate gives 2-bromo-5-phenylthio-1,3,4-thiadiazole (1 5 8 ) as the sole mono-substitution product (39%), as well as 2,5-bis(phenylthio)-1,3,4-tliiadiazole (159; 40%). N-N

~ ~ )kSP~, A

N-N

",R

R,NH

>NO% (157)

'

P

h

N-N +

P h S t ,kPh

(158)

(159)

N-N Br [IS)jN02 (156)

N-N PhS(SJN02

3- (158)

+ (159)

t 160)

Under the same conditions, silver thiophenolate affords mostly 2-nitro-5phenylthio-l,3,4-thiadiazole(160), together with minor amounts of (158) and (159). The observations indicate a dependence of the leaving-group potential upon the cation associated with the anionic nucleophile; an interpretation has been proposed 7 2 in terms of Pearson's 7 3 acid-base concept.

73

I. Simiti, L. Proinov, and H. Demian, Rev. Roumaine Chim., 1969, 14, 1285. H. Newman, E. L. Evans, and B. Angier, Tetrahedron Letters, 1968, 5829. R. G. Pearson, J . Arner. Chem. SOC.,1963, 85, 3533; Science, 1966, 151, 172.


740

The interaction of 2-imino-5-thiono-l,3,4-thiadiazolidines (161) with arylamines at 185 "C does not only yield 4-aryl-3-imino-5-thiono-l,2,4triazolidines (162) as previously but also 2,5-diarylimino-l,3,4thiadiazole (163), each in 20-50% yield.75 Evidence was adduced purporting to show that (162) are not isomerization products of (163), as might S T S N R Ar ( 162)

-

HN-NH

S A S k N R

-

HN-NH

A rN

4 A NR (163)

(161)

be expected (see Volume 1, p. 451), but that both isomers are formed by independent reaction mechanism^.^^ The Delkpine reaction 76 appears to be the most favourable procedure for into the correconverting 2-arylamino-5-chloromethyl-1,3,4-thiadiazoles sponding 5-aminomethyl compounds. Thus, treatment of (I 64) with urotropine produces the hexamethylenetetramino-salts(165) which afford (166) under the influence of ethanolic hydrochloric acid at room temperature. 77

165)

J.+ N-N A r N H C s k H 2 N H 2 , HCI (166)

The sensitivity of 1,3,4-thiadiazoles to nucleophilic attack is illustrated by the direct nuclear amination of certain 2-aryl-l,3,4-thiadiazoles(167; Ar = Ph, p-MeOC,H,, or 3,4-Cl2C,&) by hydroxylamine in presence of alkali. The products (168) arise in 45-72% yields, but the reaction failed in several examples, including 2-anilino-l,3,4-thiadiazole.A possible mechanism is outlined (169) with The reaction of 4,5-diphenyl-l,3,4-thiadiazolium-2-thiolate dimethyl azodicarboxylate does not yield a six-membered rnesionic system (172) as previously claimed.78 The orange product, formed in 30% yield in 74 75 76

Y.R. R. Rao and M. V. Konher, Indian J. Chem., 1969,7, 20. M. V. Konher, Indian J . Chem., 1970, 8, 391. M. Delepine, Compt. rend., 1895, 120, 501; 1897, 124, 292; Bull. SOC.chim. France, 1895, 3, 13, 358.

I. Simiti and L. Proinov, Arch. Pharm., 1970, 303, 134. R. M. Moriarty, J. M. Kliegeman, and R. B. Desai, Chem. Comm., 1967, 1045.

74 1


(169)

N=N I I MeOOC COOMe

N-N

I MeOOC

I COOMe

(171)

( 170)

boiling toluene, possibly via (170), is in fact 2-phenyl-5-phenylazo-1,3,4thiadiazole (1 71), as shown by its unequivocal synthesis from 2-arnino-5p henyl-1,3,4-thiadiazole and ni tro~obenzene.~~ Ring Expansion to Thiazines. In continuation of their extensive work on the ring expansion of thiazoles to 1,dthiazines (see p. 605), Takamizawa et aL80 have extended their studies to the comparable reaction of the 1,3,4thiadiazole ring system. Thus, treatment of 4-substituted 1,3,4-thiadiazolium iodides (173) with dialkylbenzoylphosphonates in dirnethylformamide yields products identified by their spectral properties as 5,6dihydro-4-substituted-5-0~0-2,6-diphenyl-4H1,3,4-thiadiazines (174). The course of this reaction is explained, in line with the one prcviously proposed for thiazolium salts, by the mechanism shown in Scheme 3. An analogue of thiamine, 3-(4-amino-2-meth yl-5-p yrimidy1)methyl1,3,4-thiadiazoIium bromide hydrobromide (179, undergoes the same ring expansion [to (176)]. The original paper 8o contains a wealth of details, to which the reader is referred. Miscellaneous Reactions. The thermal conversion of 2-nitrosamino-Sphenyl-1,3,4-thiadiazole into 2,5-diphenyl-1,3,4-thiadiazole in boiling benzene has been briefly reported.s1 The phenylation is regarded as an 7s 8o

W. L. Mosby and M. L. Vega, Chem. Comm., 1971, 837. A. Takamizawa and H. Sato, Chem. and Pharm. Bull. (Japan), 1970,18, 1201. T. M. Lambe, J. C. Tobin, and F. L. Scott, Chem. Comm., 1971,411.

(175)

(176)

example of the Gomberg-Bachman reaction,82the nitrosamine reacting in the tautomeric diazohydroxy-form, RN,OH, and undergoing preliminary homolysis to Re, *OH, and nitrogen. In a study of the non-catalytic exchange of a diazo- by a nitro-group in heterocyclic systems, a number of Ssubstituted 2-nitro-l,3,4-thiadiazoles have been obtained in 25-76% yield.s3 N-N

____,

N-N

(R

NaNO,

JNzX

'

45-50 "C

N-N

(R

)NO*

The synthesis of 5-~tro-l,3,4-thiadiazole-2-carboxaldehyde has involved further typical reactions of this ring system; they are briefly summarized as follows: 84 82

**

W. E. Bachmann and R. A. Hoffman, Org. Reactions, 1944,2, 224. L. I. Bagal, M. S. Pevzner, A. N. Frolov, and N. 1. Sheludyakova, Khim. geterotsikl. Soedinenii, 1970, 259 (Chem. A h . , 1970,72, 111 383h). G. Asato, G. Berkelhammer, and E. L. Moon, J. Medicin. Chern., 1970, 13, 1015.

743


Diamines of type (177) or (178) undergo the expected copolymerization with aromatic acid dichlorides (e.g. terephthaloyl d i c h l ~ r i d e ) . ~The ~ resulting thiadiazolyl polymers possess useful mechanical properties, but do not display greater stability to light than their analogues based on triazole or oxadiazoIe;s6their thermal stability is inferior.

(178)

2-Thiono-5-mercapto-1,3,4-thiadiazoline, the thiono-thiol structure of which is supported by its i.r. and U.V. spectra, forms a 1 : 1 molar complex with mercurous ion?' The dissociation constant of this adduct has been determined spectrophotometrically (k = 7 x at 20 "C)by the method of Job.ss A study of the chromatographic separation from animal-feed mixtures, and estimation of 1-methyl-6-(1-methylallyl)-2,5-dithiobiurea ('Methallibure', a veterinary oestrus regulator) has provided data for its distinction from its oxidation product, 2-methylamino-5-(l-methylallylamino)-1,3,4th i a d i a z ~ l e . ~ ~ Biological Properties.-2-(Halogenoacetylamino)-5-rnethyl- 1,3,4-thiadiazoles possess antitumour activity against Walker tumours, but are ineffective against Crooker sarcoma.9o 86

86

Bo

H. E. Kunzel, G. D. Wolf, F. Bentz, G. Blankenstein, and G. E. Nischk, Mukromol. Chem., 1969,130, 103. J. Preston and W. B. Black, J . Polymer. Sci., Part C: Polymer Symposia,1967, 19, 17. Z. Gregorowicz and Z . Klima, Roczniki Chem., 1970, 44, 503. P. Job, Compt. rend., 1925, 180, 928; Ann. chim., 1928, 9, 113. G. J. Krol, J. F. Carney, and B. T. Kho, J. Pharm. Sci., 1970, 59, 835. F. Gagiu, C. Daicoviciu, C. Draghici, E. Banu, and U. Binder, Chim. Ther., 1969, 4, 450.

744


2-p- Methoxybenzenesulphonamido-540 butyl- 1,3,4-thiadiazole (179) has hypoglycaemic properties, but produces neoplasms of the urinary bladder in rats, though not in dogs.91 This differencemay possibly be due to the nature of the metabolites produced in the two species. These were isolated from urines by preparative t.1.c. and identified by their mass and n.m.r. spectra. Three metabolites are common to both dog and rat, viz. 2-p-hydroxybenzenesulphonamido-5-isobutyl-1,3,4-thiadiazole, (1 SO), and (182), derived Me I R-CH2- CH I Me

Me I R-CH,-C-OH I Me

t 179)

CH,OH I R-C H,- C H

I

Me (181)

(180)

Me I R-CH-CH I I OH M e

COOH I R-CH,-CH I Me

N-N

R = Me0

(183)

(1 82)

by side-chain hydroxylation of the parent compound (179). Two additional metabolites, viz. (181) and (183), occur in rat urine only, and arise by hydroxylation or oxidation of one of the methyl groups of the isobutyl ~ide-chain.~~ Information is available concerning the cytostatic properties of 2-amino1,3,4-thiadiazole and its acyl d e r i v a t i ~ e s ,and ~ ~ its 5-isopropyl 93 and 5-butyl hom01ogues.~~ Certain 1,3,4-thiadiazoles, particularly 2-ureido-derivatives, possess herbicidal activity.59* 95 l-Methyl-3-(5-t-butyl-l,3,4-thiadiazol-2-yl)urea controls a broad range of weeds when sprayed on the foliage of the seedlings or the surface of the soil at a dosage of 1-2 kg/hm2.95The 1,3,4-thiadiazole nucleus appears to play an essential part in the activity, since analogous thiazoles are ineffe~tive.~~ The urea derivatives (184) and (185) (previous N-N

N -NCONMe,

B u t ( s ) ~ H ~ ~ ~ ~ e But ~ ~shNCONMe, (184) R = H or Me 91 92

93 g4

95

(185)

H. W. Ruelius, C. de Jongh, and S. R. Shrader, Arzneim-Forsch., 1970,20, 115. F. Gagiu, T. Suciu, 0. Henegaru, and M. Onisor, Arch. Pharm., 1970, 303, 97. T. Suciu, F. Gagiu, 0. Henegaru, and E. Bebesel, Arch. Pharm., 1970, 303, 641. T. Suciu, F. Gagiu, 0. Henegaru, and M. Maniu, Arch. Pharm., 1970, 303, 646. H. Kubo, R. Sato, I. Hamura, and T. Ohi, J . Agric. Food Chern., 1970, 18, 60.


745

formulations of which have incidentally now been modified) also possess promising herbicidal proper tie^.^^ 5-(2-Nitrofuryl-1-furylvinyl)-2-amino-l,3,4-thiadiazoles and related com28 pounds (59) and (60) exhibit significant activity against staphylo~occus.~~~ The rate of release of sulphaethylthiadiazole from tablet preparations in acid pepsin and alkaline pancreatin media has been measured.D6 The rate of photosynthesis of the alga Chlorellu pyrenoidosa is par tially inhibited by 2-acetylamino-1,3,4-thiadiazolesulphonamide (‘Diamox’)

Mesionic 1,3,4-Thiadiazoies.-Synthesis. The fission of disulphides (186 ; R = H) into the parent thiol (187; R = H) and the mesionic 1,3,4thiadiazole (188; R = H), first observed by B u s c ~ has , ~ ~been studied kinetically in various solvents.0e It is a fh-st-order reaction with respect to the reactant (1 86). The rate constant increases with increasing polarity of the solvent, with a good linear correlation between log k and the polarity parameter 2 of the solvent. Values of AH are found to lie within the range 3.3-4.2 kJ mol-l, and those of AS in the range 4.0---7.5 J deg-l. PhN-N

I RHC,

II S

,C-S-S--C,

N-NPh

II

S

I

,CHR

>-

PhN-N I RHC,

i-

II

S

/c, SH

+

PhN-N

I1

RC,

II

s,c, s-

A series of mesionic 4-phenyl-5-aryl-1,3,4-thiadiazoles(1 88) bearing substituents in their 5-aryl group have been preparedlooby Stewart and Kier’s method,lol in 15-20% yield, by the action of aroyl halides on potassium phenyl dithiocarbazinate. The spectra of these compounds indicate appreciable internuclear conjugation between the planar mesionic heterocycle and the 5-aryl ring, comparable with that in the biphenyl system. The observed U.V. absorption maxima near 275 and 250nm are assigned to the 4-phenyl and 5-aryl group, respectively, and a long-wave peak at ca. 400 nm is assigned to the mesionic thiadiazole nucleus. In the i.r. spectra, a band invariably appearing near 1330 cm-l is ascribed to the C-S stretch.loO The interaction of l-methyl-l-thiobenzoylhydrazine(1 89) and carbon disulphide produces the mesionic 5-phenyl-4-methyl-l,3,4-thiadiazole-2thione (191), which is convertible by aniline into the mesionic 1,2,4-triazole (192). The condensation of (189) with methyl isothiocyanate also yields I. S. Hamid and C. H. Becker, J. Pharm. Sci., 1970, 59, 511. (The structure of the compound concerned is not precisely specified.) O7 H. Budzikiewicz and H. Eckau, Z . Naturforsch., 1970, 25b, 610. O8 M. Busch, Ber., 1895, 28, 2635; J . prakt. Chem., 1899, 60, 25. O9 A. M. Kiwan and H. M. N. Irving, Chem. Comm., 1970,928. loo P. B. Talukdar and S. K. Sengupta, J . Indian Chem. SOC.,1970, 47, 50. lol T. G. Stewart and L. B. Kier, J. Pharm. Sci., 1965, 54, 731.

746


(191), together with mesionic 1,4-dimethyl-5-phenyl-1,2,4-triazole-2-thione (193), presumably via the common intermediate (190) by loss of methylamine or hydrogen sulphide, respectively.lo2 A further general route to mesionic 1,3,4-thiadiazoIesby a condensation involving thioacylhydrazines has been briefly d e ~ c r i b e d . ~The ~ ~ -inter~~~ action of 2-substituted thiohydrazides (194) with 3,3-dichloroacrylonitriles Me-N-NH,

MeNCS

( 189)

MeN-N 1 + 1 ph/C' As- PhNH,

____f

(191)

Me-N-NH-C-NHMe

' [Ph-LS /

Ph-C=S I

SII (190)

MeN-N 1 + 1 ph/C' /c, SN Ph

(192)

1 MeN-N

l + l

Ph'cY' c's-

Me (193)

(195) or with 3,3-bis(methylthio)acrylonitrile [(MeS),C= C(CN)Z] produces the mesionic heterocyclics (196), generally as yellow to orange crystalline s01ids.l~~~ lo4 Pyrolysis at 250 "C converts (196; R1 = Ph, R2 = Me, Z = CN) into the 2-dicyanomethylene derivative (197) in good yield.lo3,lo4 The scope of the synthesis is further extended lo5by the use of isocyanide dichlorides (199) : their condensation with N-methyl-N-thiobenzoylhydrazine (198) in boiling chloroform yields crystalline thiadiazolium chlorides (200), which are converted by ammonia in chloroform into the mesionic 1,3,4-thiadiazoles (201) (e.g. anhydro-4-methyl-5-phenyl-2phenylamino-l,3,4-thiadiazoliumhydroxide). Isomerization to mesionic 1,2,4-triazoles (202) occurs in hot ethanol, or under the influence of phenyl isocyanate in benzene. The two mesionic systems (201) and (202) may be distinguished by their mass spectra. Both isomers show a molecular ion, and a common fragyent ion, MeN=CPh, but they are diffezentiated by the fragments Ph-CGNR arising from (202) and by Ph-C=S from (201).lo5 Properties. Following extensive and detailed measurements on isosydnones,lo6Sutton et aI.lo7have determined the electric dipole moments of loa

A. Y.Lazaris and A. N. Egorochkin, Zhur. org. Khim., 1970, 6, 2342 (Chem. Abs., 1971, 74,42 317s).

108

104

106 101

10'

R. Grashey and M. Baumann, Angew. Chem., 1969, 81,r115. R. Grashey, M. Baumann, and R. Hamprecht, Tetrahedron Letters, 1970, 5083. W. D. Ollis and C. A. Ramsden, Chem. Comm., 1971, 1222. A. R. McCarthy, W. D. Ollis, A. N. M. Barnes, L. E. Sutton, and C. Ainsworth, J . Chem. SOC.(B), 1969, 1185. C. W. Atkin, A. N. M. Barnes, P. G. Edgerley, and L. E. Sutton, J . Chem. SOC.(B), 1969, 1194.

747


anhydr0-4~5-disu bstitu ted 2-mercapto(and hydroxy)-1,3,4-thiadiazolium hydroxides (203 and 204), and have analysed the results to compute the magnitude and direction of the moment of the thiadiazole ring. The data support the mesionic representation of the compounds concerned, and show KIN-N I

K’C,

-1

s

I

,c,

s-

KIN-N I -t I K’C, ,C,

s

0-

that exocyclic sulphur carries a larger negative charge than does exocyclic oxygen.lo7 Because of their large charge separations and dipole moments, mesionic thiadiazoles are suitable for examination by X-ray photoelectron spectroscopy. Measurements performed on (205) and (206) (as well as on phenylsydnone) confirm the view that a betaine structure predominates in the

ground-state of mesionic 1,3,4-thiadiazoIethiones and agree with the conventional charge distributions [e.g. in (205)].108 The photolysis of anhydro-5-mercapto-3-methyl-2-phenylthiadiazolium hydroxide (207) (0.11M in acetonitrile at 2537 A for 72 h) yields N-methylthiobenzamide (208; 21%) and sulphur (40%). The isomeric mesionic compound (209) similarly affords N-phenylthioacetamide (210; 20%) and sulphur (3579, whereas the 2,3-diphenyl analogue (211) produces N-phenylthiobenzamide (212; 27%).lo9 Photolysis of the last compound (211) by radiation of longer wavelength (> 3000 A), however, causes oxidative 108

M. Patsch and P. Thieme, Angew. Chem., 1971,83, 588 (Angew. Chem. Internat. Edn., 1971, 10, 569).

log R.

M. Moriarty and R. Mukherjee, Tetrahedron Letters, 1969, 4627.


748

K4-N

K'-NH

2537~

I

c____,

R1(s&-

R'-C=S

+ s

(208) (210) (212)

(207) R1 = Ph, R2 = Me (209) R1 = Me, R2 = Ph (211) R' = Ph, R2 = Ph

T I

R? ,N=C=S N ' I

R2,

-+

N'

I

IIV

' 1 R

C

+ 'NCS

-+ S

+S

(213)

cyclization to (213).110 The reaction is regarded to involve an initial valence tautomerization to the N-isothiocyanatothioamide(214), which is cleaved at the N-N bond to yield the radical precursor (215)of the thioamide and the isothiocyanate radical; the latter decomposes with liberation of sulphur. The interpretation is supported by the results of a trapping experiment log and by i.r. measurements111 carried out during the photolytic process in acetonitrile, in Nujol mull or in the pure melt. The 5-hydroxy-analogues of (207)show similar fragmentation patterns.lll The hydrolysis of the mesionic 4,5-diphenyl-l,3,dthiadiazole(21 1) has been studied kinetically in aqueous ethanol over a wide pH range, by measuring the decreasing intensity of its absorption maximum at 382 nm. The rate, which is first order with respect to the hydroxide-ion concentration, increases with the polarity of the medium. The reaction is characterized by its small entropy. A proposed mechanism consistent with the observed results accounts for the formation of N-benzoyl-N-phenylhydrazine as the final product of the hydro1ysis.ll2 Anhydro-5-hydroxy-3-methyl-2-phenyl-l,3,4-thiadiazolium hydroxide, in common with related mesionic systems (see pp. 615 and 719), may be 0-alkylated by triethyloxonium fluoroborate to yield the quaternary salt (216); this is reconverted into the mesionic starting material above its melting ~ 0 i n t . l ' ~

+

McN-N

-

+

McN-N

A

PhC $0S

PhQS))OEt (216)

R. M. Moriarty, J. M. Kliegeman, and R. B. Desai, Chem. Comm., 1967, 1255. n1 R. M. Moriarty, R. Mukherjee, 0. L. Chapman, and D. R. Eckroth, Tetrahedron Letters, 1971, 397. P. B. Talukdar, S. Banerjee, and A. Chakraborty, Bull. Chem. SOC.Japan, 1970, 43, 125.

113

K. T. Potts, E. Houghton, and S. Husain, Chem. Comm.,1970, 1025.


749

Condensed Ring Systems.-l,3,4-Thiadiazolo[3,2-a]pyridines. For a synthesis 5 3 of this ring system from the corresponding oxadiazole analogues, see p. 735. 1,3,4-Thiadiazulo[3,2-a]pyrimidines. 2,5-Diamino-1,3,4-thiadiazole (2 17) 1,3,4reacts with ethyl acetoacetate, yielding 2-amino-5-0~0-7-methyl-5Hthiadiazolo[3,2-a]pyrimidine(219) (19% after boiling for 80 h in ethanol, 90% in the absence of solvent), presumably by way of the /%aminocrotonic ester (218).l14 The action of diketen on (217) in aqueous solution at room temperature affords a rnonoacetoacetyl derivative (221) which is ring-closed quantitatively to the same bicyclic product (219). The intermediate (221) is

( 2 19)

smoothly deacetylated into its components in boiling ethanol, an observation which supports its formulation as an N-acyl heterocyc1e.ll6 Under more vigorous conditions, 2,5-diamino-l,3,4-thiadiazoleyields diacyl derivatives which, being stable towards alcoholysis, are formulated as (220); they show no tendency to c y ~ l i z a t i o n . ~ ~ ~ 1,3,4-Thiadiazolo[2,3-c]1,2,4-triazines. 7-Amino-4H-1,3,4-thiadiazolo[2,3c]-l,2,4-triazin-4-ones (223) are formed by the condensation of 4-amino-3thioxo-2,3,4,5-tetrahydro-1,2,4-triazin-5-ones (222) with bromocyanogen in aqueous potassium carbonate.l16 1,3,4-Thiadiazol0[2,3-b]quinazolines.2-Substituted 5H- 1,3,4-thiadiazoIo[2,3-b]quinazolin-5-ones(228) are accessible in good yield by the multistage synthesis outlined in Scheme 4.11' The starting materials (225), obtained H. Paul and A. Sitte, Monatsh., 1971, 102, 550. H. A. Staab, Angew. Chem., 1962, 74,407. 116 K. Zauer, J. Puskas, J. Nyitrai, G. Hornyak, A. Wolfner, G. Doleschall, and K. Lempert, Periodica Polytech., 1968, 12, 259 (Chem. Abs., 1969, 71, 124 385). n7 S. K. Modi, V. Kumar, and K. S . Narang, Indian. J. Chem., 1970, 8, 710. 114

lls

Organic Compounds of Sulphur, Selenium, and TelIurium

750

0

0

from isatoic anhydrides (224) and acylhydrazines, yield the tricyclic products by two successive ring-clo~ures.~~~ A similar reaction sequence, employing arylidenehydrazines, provides the corresponding 2,3-dihydro-analogues (229). Their thiadiazole nucleus is cleaved by alkali, with formation of (23O).ll8 0 II

0 II

0 II

\

0

0

(229) 11*

(230)

S. K. Modi, H. K. Gakhar, and K. S. Narang, Indian J . Chem., 1970, 8, 389.

Thiadiazoles and Sdenadiazoles

75 1

In yet another variation of this synthesis, 2,6-dithioxo-2,3-dihydro-4,5benzo-l,3-thiazine ('trithioisatoic anhydride') (231) is condensed with hydrazine at room temperature to form the intermediate (232). This is cyclized, by hot formic acid, to 1,3,4-thiadiazolo[2,3-b]-3,4-dihydroquinazoline-4-thione (233). The proposed structures are supported by spectral data.ll@ S

S'

S

5 1,3,CSelenadiazoles 1,3,4-Selenadiazole, the parent compound of this ring system, was first of synthesized 120 in 1970 by a method based on Fohlisch's synthesis 1,3,4-thiadiazoIe.Thus, the interaction of the readily available NN-dimethylformamide azine (234) and hydrogen selenide in methanol in the presence of 0.08 equivalents of pyridine affords 1,3,4-~elenadiazole(236) in ca. 25% yield. NN-Dimethylselenoformamide (237) is formed simultaneously in comparable yield and is isolable chromatographically. It may arise from the presumed intermediate (235) by the elimination of the amidrazone (238). Deuteriated 1,3,4-~elenadiazolewas also prepared.120

MezN-CH=N-N=CH-NMe2

Me,N-CH

II Se

+ NHzN=CHNMc2 (238)

(237)

N-N _ I I +

[,el]

+ 2Me2NH

1,3,4-Selenadiazoleis a colourless liquid, b.p. 58 "C (0.5 mmHg), which is stable at 0 "C in the absence of light, but decomposes slowly in air. Its n.m.r. spectrum features a single peak at very low field (7 -0.89); the W-H coupling constant is 214.3 Ilz. Other physical constants are as follows: m.p. 22.5-23.5 "C,dZ52.05; nD 1.5933; A,, 232, 204 nm ( E 2350, 1850); dipole moment 3.4 D.120 An analysis of its microwave spectrum has provided values for the bond angles and lengths (see Figure) and has occasioned their comparison with those of related heterocyclics. It is

lal

G. Wagner and S. Leistner, Z.Chem., 1971, 11, 65. R. V. Kendall and R. A. Olofson, J . Org. Chem., 1970, 35, 806. B. Fohlisch, R. Braun, and K. W. Schultze, Angew. Chem. Znternat. Edn., 1967, 6,361.

752


noteworthy that the C-Se-C angle of 81.8" is the smallest known angle in a planar five-membered ring.122 1.371 A

1.868 A 81.8"

Figure

6 1,2,5-Thiadiazoles Only relatively little recent work concerns the parent monocyclic system ; by far the greater part is devoted to fused ring systems incorporating 1,2,5t hiadiazole. 1,2,5-Thiadiazole (240; R1 = R2 = H) or its substitution products (240) and (242) are accessible by the action of tetrasulphur tetranitride (S,N,) in boiling xylene on aliphatic vicinal diamines (239) or monoamines (241)

RCH- CH, Ar

I

NHZ

S,N,

-s,-NH:

RIIIAr N,~,N

incorporating an arylmethylene group.123 They are isolated as cadmium chloride complexes, from which the free bases are liberated by steamdistillation. The product of the interaction of diphenylketen and diphenylsulphur di-imide, originally formulated 124 as the four-membered l-phenylimino2,4,4-triphenyl-1,2-thiazetidin-3-one has been shown to be in fact 2,3,3,5tetraphenyl-l,2,5-thiadiazolidin-4-one, by chemical 125 and X-ray-crystallographic lZ6 evidence. Sets of harmonic symmetry force constants have been calculated for 1,2,5-thiadia~ole,~~ based on its known vibrational frequencies taken from the 1iterat~re.l~' la2 lZs lZ4

D. M. Levine, W. E. Krugh, and L. P. Gold, J. Mol. Spectroscopy, 1969, 30, 459. V. Bertini and A. de Munno, Gazzetta, 1971, 101, 259. T. Minami, 0. Aoki, H. Miki, Y. Ohshiro, and T. Agawa, Tetrahedron Letters, 1969, 447.

lZ6

lZ6 la'

H. H. Horhold and H. Eibisch, Tetrahedron, 1969, 25, 4277 (cf. these Reports, vol. 1, p. 453). N. Yasuoka, N. Kasai, T. Minami, Y. Ohshiro, T. Agawa, and M. Kakudo, Bull. Chem. SOC.Japan, 1970,43, 1905. E. Benedetti and V. Bertini, Spectrochim. Acta, 1968, 24A,57.

753


Condensed Systems incorporating 1,2,5-Thiadiazole.-Benzo-2,1 ,3-thiadiazoles. The synthesis of benzo-2,1,3-thiadiazolesby the interaction of o-benzoquinone dioxime and sulphur dichloride 128 has been reinvestigated.120 The two products, formed in approximately equal proportions, are benzo-2,l93-thiadiazo1e (243) and its N-oxide (244). 9,1O-Phenanthrenequinone dioxime (245) analogously yields phenanthro[9,10-~]-1,2,5-thiadiazole (246) (and the corresponding N-oxide), the 0

(245)

(246)

(247)

structure of which is established by its alternative synthesis from 9,lOdiaminophenanthrene (247). That of the N-oxide is supported by its nonidentity with the known S-oxide which is readily reducible to the parent thiadiazole (246), whereas the N-oxide is not.120 The reaction is applicable to other suitable oximes, with the results summarized in Table 2. Thc possible mechanism of the hetero-ring formation was discussed.

Table 2 Synthesis of 1,2,5-thiadiazoles12' Reactant Dichlorogly oxime Diphenylglyoxime Acenaphthoquinone dioxime

3,4,6-Trichloro-o-benzoquinone dioxime

Product (including N-oxides) 3,4-Dichloro-l,2,5-thiadiazole 3,4-Diphenyl- 1,2,5-thiadiazole Acenaphtho[l,2-c]-1,2,5thiadiazole (248) 4,5,7-Trichloro-2,1,3benzothiadiazole

Pesin and his group have continued their investigation of benzo-2,1,3thiadiazoles and have provided a summary 130 of their recent work. In their opinion, the quinoid structure of benzo-2,1,3-thiadiazole and its selenium analogue is excluded by the sum of their physical and chemical properties, especially i.r. spectra. However, their preferred heteroaroniatic structure la* la9

130

V. G.Pesin, A. M. Khaletskii, and Chou-Chin, J. Gen. Chem. (U.S.S.R.),1958,28,2131. K. Pilgrim, J. Org. Chem., 1970, 35, 1165. V. G. Pesin, Khim. geterotsikl. Soedinenii, 1969, 235 (Chem. Abs., 1969, 71, 22 076x).

754


(249) incorporating quadrivalent sulphur has not been adopted elsewhere so far. Anion radicals of benz0-2,1,3-thia(and se1ena)diazolehave been produced by metal reduction in several solvents at low temperatures, and their electron spin resonance has been studied.131 The reductive desulphurization of substituted benz0-2,1,3-thiadiazolesby stannous chloride in concentrated hydrochloric acid gives o-phenylenediamines in 8 6 9 0 % yields. The stability of the heterocyclics against reduction increases with the number of chlorine s u b ~ t i t u e n t s . ~ ~ ~ Nitr0-2,1,3-benzothiadiazoles are reduced to the amines by ferrous sulphate in Mixtures of 4- and 5-aminobenzo-2,1,3-thiadiazole also arise in the amination of the parent compound (243) with hydroxylamine sulphate in concentrated sulphuric The oxidative degradation of benzo-2,1,3-thiadiazole by chromic acid produces 4,5-dicarboxy-l,2,5-thiadiazole(250) (up to 78%), which is decarboxylated in nitrobenzene at 160 "C to the 4-monocarboxylic acid (251). The acids give the usual salts and

(249)

(250)

(25 1)

The bromination of benzo-2,1,3-thiadiazole (243) in boiling 47% hydrobromic acid 136 or nitric acid produces successively the 4-bromo- (252) and 4,7-dibromo-derivatives (253), followed by more highly brominated species. The previously reported 138 addition product is not formed under these conditions, which favour electrophilic attack of Br+ at C-4 (or 7) involving a a-bond intermediate. When a substituent blocks the 4-position,

lS1 lSa

M. Kamiya and Y. Akahori, Bull. Chem. SOC.Japan, 1970, 43,268. V. G . Pesin and V. A. Sergeev, Khim. geterotsikl. Soedinenii, 1968, 1001 (Chem. Abs., 1969, 70, 77 875s).

V. G. Pesin and V. A. Sergeev, Khim. geterotsikl. Soedinenii, 1969, 65 (Chem. Abs., 1969,70, 106 473s).

V. G . Pesin, V. A. Sergeev, and E. V. Barkalaya, Khim. geterotsikl. Soedinenii, 1968, 812 (Chem. A h . , 1969,71, 3332m). la6 V. G. Pesin, V. A. Sergeev, B. S. Mirkin, and L. P. Mikheeva, Khim. geterotsikl. Soedinenii, 1969, 243 (Chem. Abs., 1969, 71, 22 077y). lS6 K. Pilgrim, M. Zupan, and R. Skiles, J . Heterocyclic Chem., 1970, 7, 629. la' K. Pilgrim and M. Zupan, J. Org. Chem., 1971, 36, 207. lS8 V. G. Pesin, A. M. Khaletskii, and C. Chi-Chzhun, J . Gem Chem. (U.S.S.R.), 1957, 27, 1648. la'

Thiadiazoles and Selenadiazoles 755 selective bromination occurs at C-7. 5-Bromo- and 5-rnethyl-benzo-2,1,3thiadiazoles react analogously. This direct halogenation provides a useful route to brominated benzo-2,1,3-thiadiazoles,particularly when the corresponding o-phenylenediamine is not readily available for ring-closure with thionyl chloride.136 Benzo-2,1,3-thiadiazole-5-aceticacid (255) yields, by conventional (256). methods, N-(2-phenylisopropyl)benzo-2,1,3-thiadiazole-5-acetamide Reduction with stannous chloride in concentrated hydrochloric acid opens the hetero-ring, yielding N-(2-phenylisopropyl)-3,4-diaminophenylacetamide (257).la9

(255)

(256)

i -

5,7-Dichloro -4-(ethoxycarbony1)methoxybenzo-2,1,3 thiadiazole (258; X = C1) and its analogues (258; X = Me; 259) are powerful selective plant-growth OCH,COOE t

61 (258)

(259)

1,2,5-Thiudinzolo[3,4-b(and c)]pyridines. The action of thionyl chloride on the appropriate diaminopyridines yields 1,2,5-thiadiazol0[3,4-b(or c)]pyridines (260) or (261); the products are of special interest in that they are structural analogues of 8-thiapurines (262). The selenium analogues are similarly produced by the action of selenious acid. 1,2,5-Selenadiazolo[3,4-c]pyridine [corresponding to (261)] is the most unstable l39

V. G.Pesin, S. A. Dyachenko, and R. Y. Ravdina, Khim.-Farm. Zhur., 1969, 3, 20

l40 l4l

(Chem. Abs., 1970, 72, 89 992g). J. J. van Daalen and J. Daams, Naturwiss., 1970, 57, 395. G. H. Harts, K. B. de ROOS,and C. A. Salemink, Rec. Trau. chim., 1970, 89, 5 .

756


1,2,5-Thiadiazol0[3,4- d]pyriduzines. 1,2,5- Thiadiazolo[3,4-d]pyridazines have been synthesized from either of their constituent monoheterocycles, by the routes 1,2,5-Thiadiazolo[3,4-dJpyridazine-4,7-dionehas been subjected to several conventional reaction sequences, but since they concern the pyridazine moiety they need not be detailed here.

7 1,2,5-SeIenadiazole and Condensed Ring Systems

Sets of harmonic symmetry force constants have been providedss for 1,2,5-~elenadiazole,the calculations being based on observed vibrational frequencies taken from the

1,2,5-SelenadiazoIo[3,4-6(and c)]pyridines.-The old-established synthesis of benzo-2,1,3-selenadiazole143 has been extended to the production of 1,2,5-selenadiazo10[3,4-b(andc)]pyridines(263) and (264). They are obtained as intensely yellow and red solids, in 36 and 11% yield respectively, by the reaction of 2,3- or 3,4-diaminopyridine with selenium dioxide in benzene,144 or with selenious acid at room temperature141r145by the procedure of car^.^^^ Both isomers are potentially ten-rr-electron systems, the structure of which may be considered in terms of various canonical forms; those of (263) are shown. The i.r., u.v., and n.m.r. spectra of the isomers were determined and discussed in detail.144 The products are of particular interest because of their close relationship to 8-selenapurine (265). l44 143 144

146

D. Pichler and R. N. Castle, J . Heterocyclic Chem., 1971, 8, 441. 0. Hinsberg, Chem. Ber., 1889, 22, 862; L. S. Efros, Uspekhi Khim., 1960, 29, 162. N. M. D. Brown and P. Bladen, Tetrahedron, 1968, 24, 6577. A. Carr, E. Sawicki, and F. E. Ray, J. Org. Chem., 1958, 23, 1940.

Thiudiuzoles and Selenadiuzoles

757

Naphtho[2,3-d] -2,1,3-~elenadiazole.-Naphtho[2,3 - d ]- 2,1,3 - selenadiazole (‘DanSe’) forms complexes with palladium(n) chloride, of probable structure (266) and (267). A highly selective procedure for determining macro- to submicro-amounts of palladium is based on their

146

H. K. Y . Lau and P. F. Lott, Talunta, 1970, 17, 717.

I6 T hiazines ~~~

BY G. PROTA

1 1,2-Thiazines Simple 1,ZThiazines.-In marked contrast to the increasing attention given to the chemistry of 1,3- and 1,4-thiazinesduring this period, the ring system of 1,2-thiazines continues to be relatively unexplored. Various 2-unsubstituted 3,6-dihydro-2H-1,2-thiazinel-oxides (3) have been prepared from their 2-trichloroethoxycarbonyl derivatives (2) which are readily available by [4 21 cycloaddition of the corresponding dienes and N-sulphinylurethane (1) (Scheme 1). Unlike other N-acyl groups (e.g. C02Et or C02But), the trichloroethoxycarbonyl residue in (2) can be removed without appreciable ring-cleavage by the action of zinc dust in boiling t-butyl alcohol. The electrophilic character of the sulphur atom in compounds of type (2) is markedly enhanced by the inductive effect of the

+

R1x

0

0 It COCHZCCI,

II

COCHZCCIS

+ NII/

R2

so

so

N-acyl group with the consequence that the sulphinamide N-S bond is easily attacked by various nucleophiles. In the case of 2-alkyl(or ary1)sulphonylthiazines it has been shown that the ring-opening process with the nucleophiles HO-, RO-, or RS- results in the formation of derivatives of 4-sulphonylamino-cis-but-2-ene sulphinates [e.g. (4) + (5)], whereas with

L. Wald and W. Wucherpfennig, Annalen, 1971, 746, 28. W. Wucherpfennig, Annalen. 1971, 746, 16.

758

Thirrzines 759 amines a more complex reaction takes place, the course of which has not yet been investigated. Benzoylsulphene, generated in situ by the action of triethylamine on benzoylmethanesulphonyl chloride, reacts with cinnamylidenamines (Scheme 2) to gives the corresponding [4 3- 21 adducts (6), in which the

R

= alkyl or

(6)

aryl

H

PhC0,H

3-

H Oz

N-R

iii

Ph P h

w

-

R

Ph H (8)

H

(7)

Reagents: i, NEt,; ii, MeONa-MeOH; iii, NaOH(aq)-MeOH Scheme 2

phenyl and the benzoyl groups are quasi-equatorial and quasi-axial, respecUhely, as indicated by spectral studies and chemical transformations. On treatment with sodium methoxide in methanol or with silica gel in chloroform, the cycloadducts undergo inversion to the corresponding epimers (7), with both the phenyl and benzoyl groups in quasi-equatorial positions. In dilute sodium hydroxide solution both (6) and (7) are converted into ( 8 ) with concomitant formation of benzoic acid.

Benzo-1,2-thiazines.-Syntheses of new 1,2-benzothiazines of pharmacological interest continue to attract most of the attention in this area. Sianesi et aL4 now report some convenient procedures for preparing the three isomeric dihydrobenzothiazine dioxides (9)-( 11) and their N-substitution products. For instance, (10) is obtained in 54% yield by dehydration of o-(2-aminoethyl)benzenesulphonic acid with POCl,, and also by hydrogenation in acidic medium of the corresponding cyanosulphonamide (77% yield) or by alkaline treatment of 0-(2-chloroethyl)benzenesulphonarnide (83% yield). Several 3,4-dihydro-lH-2,3-benzothiazin-4-0ne 2,2-dioxides and 3,4-dihydro-lH-1,2-benzothiazin-4-one 2,2-dioxides," as well as 3,40. Tsuge and S. Iwanami, Bull. Chem. Sac. Japan, 1971,44, 2730.

' E. Sianesi, G . Bonola, R. Pozzi, and P. Da Re, Chem. Ber., 1971, 104, 1880. E.Sianesi, R. Redaelli, M. Bertani, and P. Da Re, Chem. Ber., 1970, 103, 1922. J. G.Lombardino and N. W. Treadway, Org.Prep. Procedures, 1971,3,33; M. Nakanishi and R. Kobayashi, Jap. P, 22 150/197l,22 152/1971 (Chern. Abs., 1971, 75, 76 818s, 76 820m).

760


0,

dihydro-2H-l,2-benzothiazin-3-one 1,l-dioxides,5 have been prepared and some of them [e.g. (12)] * are claimed to exhibit interesting therapeutic proper ties. 9

2 1,3-Thiazines

Simple 1,3-Thiazines.-The reported formation of 1,3-thiazines (1 3) by the addition of thioureas to dimethyl acetylenedicarboxylate has been re-examined independently by two groups l o ,l1 who have unequivocally confirmed earlier studies l2 indicating the five-membered 1,3-thiazoline structures (14) for all condensation products (cf. Chapter 13) in this series. Sequential treatment of the condensation product (15 ) of dimethyl malonate and ally1 isothiocyanate with hydrazine, hydrochloric acid, and H, 0

lo

l1

l2

C

,CO,R~

P. Catsoulacos, J. Heterocyclic Chem., 1971, 8, 947; G. Hasegawa, T. Munakata, T. Yoshida, and T. Tsumagari, Jap. P. 00 029/1971 (Chem. Abs., 1971, 74, 141 828r); G. Hasegawa, T. Munakata, T. Furuta, and T. Tsuda, Jap. P. 22 027/1971 (Chem. Abs., 1971, 75, 76 815p). J. G. Lombardino and E. H. Wiseman, J . Medicin. Chem., 1971, 14, 973. J. W. Lown and J. C. N. Ma, Canad. J. Chem., 1967,45,939; E. Winterfeldt and J. M. Nelke, Chem. Ber., 1967, 100, 3671; Y. Kishida and A. Terada, Chem. and Pharm. Bull. (Japan), 1968, 16, 1351. A. F. Cameron, N. J. Hair, N, F. Elmore, and P. J. Taylor, Chem. Comm., 1970, 890. R. N. Warrener and E. N. Cain, Austral. J. Chem., 1970, 23, 51; ibid., 1971, 24, 785; J. F. B. Mercer, G. M. Priestley, R. N. Warrener, E. Adman, and L. H. Jensen, Synthetic Comm., 1972, 2, 35. L. K. Mushkalo and G. Y. Yangol, Ukrain. khim. Zhur., 1955, 21, 732 (Chem. Abs., 1956, 50, 16 751a); J. B. Hendrickson, R. Rees, and J. F. Templeton, J. Amer. Chem. SOC.,1964,86,107; H. Sasaki, H. Sakata, and Y. Iwanami, J. Chem. SOC.Japan, 1964, 85, 704 (Chem. Abs., 1965, 62, 14678f).

761

Thiazines

iodine was reportedI3 to give the thiazine (17) via (16), but new work14 now shows that the process follows a quite different pathway (Scheme 3), which leads to (19) via (18). The ring-closure of (15) by the action of iodine proceeded as for (18), giving the thiazine derivative (20), in which the double bond is exocyclic (n.m.r. evidence) and not endocyclic (Le. between C-2 and N), as had been suggested.13

X

New evidenceI5 obtained by i.r. and n.m,r. spectroscopy has led to the conclusion that the compounds described as 2-arylamino-4H-5,6-dihydro1,3-thiazines (21), which are formed in the reaction of l-arylthioureas with l,3-dihalogenopropanes,lahave in fact the tautomeric structures (22), i.e. 3-aryl-2-imino-perhydro-1,3-thiazines.In addition to the spectroscopic data, the structural revision rests on the fact that on oxidation with potassium chlorate in hydrochloric acid solution these compounds behave lS l4 l6

l6

D. E. Worrell, J. Amer. Chem. Soc., 1932, 54, 2061. G. Just and P. Rossy, J . Org. Chem., 1972, 37, 318. L. Toldy and P. Sohar, Tetrahedron Letters, 1970, 181 ; L. Toldy, P. Sohar, K. Farago, I. Toth, and L. Bartalits, ibid., p. 2167. A. C. Glasser and R. M. Doughty, J. Phurm. Sci., 1965, 54, 1055.

cx:i


762

'NHAr

CH2CH2CH,S0,C1 Ar, / +Ar-N \ +-

C/H2-CH

c1

CGN

N-SO,

similarly to their 2-iminothiazolidine analogues, yielding ring-cleavage products of the type (23) which by heating at 110 "C are converted into 1,2,4-thiadiazepine derivatives (24) by intramolecular addition of the sulphochloride group to the nitrile triple-bond (Scheme 4). A novel synthetic route to 4H-1,3-thiazin-4-ones (26) is reported l 7 to involve condensation of a 3-alkylthio-2-cyano-3-mercapto-acrylamide [e.g. (25)] with ketones or aldehydes in the presence of sulphuric acid (Scheme 5 ) . The reaction is considered to proceed by initial attack of the

0 NC,

0

II

C

-

,C-NH,

R < ,R2

II +

C

L

MeSJLI

MeS

S

S

0

(27) Scheme 5

strong nucleophilic thiol group of (25) on the carbonyl reagent, followed by dehydration of the resulting intermediate to give (26). The method is quite general and has also been adapted to the preparation of the 4H-1,3thiazine-4-thiones (27), using a thioamide [e.g. (28)] in place of (25). The coupling of carbonyl compounds with 2-iminocyclopentanedithiocarboxylic acid (29), available from the action of carbon disulphide and ammonia on cyclopentanone, has been further investigated.l* In the presence of a catalyst, aIiphatic and alicyclic ketones, as well as aldehydes l7

M. Yokayama, Bull. Chem. SOC.Japan, 1971,44, 1610; J. Org. Chem., 1971,36,2009. T. Takeshima, M. Yokoyama, T. Imamoto, M. Akano, and H. Asaba, J. Org. Chem., 1969, 34, 730; Bull. Chem. SOC. Japan, 1970, 43, 2134.

763

Thiazines

and acetophenones, react readily with (29) to give the corresponding 1,3-thiazine derivatives (3l), presumably via intermediate compounds of the type (30) (Scheme 6). In some cases the postulated intermediates were indeed isolated and, on heating in acidic medium, were converted into the corresponding thiazines in excellent yield.

(30) Scheme 6

Another example of 1,3-thiazine formation is afforded l9 by the acidcatalysed ring-opening and ring-closure of a 3,6-dihydro-2(1H)-pyrimidinethione to the isomeric 2-amino-4H-1,3-thiazine; thus, in hydrochloric acid solution the thione (32) is smoothly converted into (33), which appears to exist predominantly in the amino tautomeric form (u.v.and i.r. evidence). The sequence of reactions in Scheme 7 is suggested to account for the formation of (33).

SH

MMee n M e

-

Y

HO -

N

/ \

H

Me

\

H+

Me

(33) Scheme 7 1@

L. A. Ignatova, P. L. Ovechkin, and B. V. Unkovskii, Zhur. Vsesoyuz. Khim. obshch. im. D.I. Mendeleeoa, 1970, 15, 238 (Chem. Abs., 1970, 73, 25408j); B. V. Unkovskii, L. A. Ignatova, P. L. Ovechkin, and A. I. Vinogradova, Khim. geterotsilcl. Soedinenii, 1970, 1690 (Chem. A h . , 1971,74,99 962c); P. L. Ovechkin, L. A. Tgnatova and B. V. Unkovskii, ibid., 1971, 946 (Chem. Abs., 1971,75, 151 129y).

764


Following their work on the chemistry of sulphur analogues of certain naturally occurring pyrimidines, Warrener and his colleagues 2o have investigated the photochemistry of l-thiauracil (34) and the crystal structure of its photodimer ( 3 3 , obtained by irradiation with U.V. light. The

(34)

(35)

results indicate that the molecule of (35) is the same isomeric form as the cis-syn photodimer of uracil 21 with essentially the same structural features, including a puckered cyclobutane ring and non-planar heterocyclic rings. The chemistry of the dihydrothiazine ring system in the cephalosporins, as well as the synthesis, the structure, properties, and biological activity of this group of antibiotics, has been reviewed.22 A discussion of theoretical and practical relationships between cephalosporins and penicillins, and the chemical conversion of the latter into the former, is also available.23Particularly pertinent to this second review are recent at the Lilly Research Laboratories, which further aid the elucidation of the course of the thiazolidine ring-enlargement of penicillin sulphoxides to deacetoxycephalosporins, discovered by Morin et aZ.,25and emphasize the crucial role of the catalyst in determining the product. Another approach to the chemical conversion of the penam into the cepham system is reported,26and it stems from the work of Wolfe et aL2' who found that, in the presence of triethylamine, penicillinoyl chlorides, e.g. (36), rearrange to anhydropenicillins (38) via the thiolate anion (37). Hence, a base-promoted 8-elimination of the chloroketone (39) was expected to give an analogous anion (40), which would likely ring-close to the more stable dihydrothiazine ring of the cepham system, i.e. (41). In fact, the rearrangement of (39) with a tertiary amine in dichloromethane leads, in addition to the 2o 21

23 2s 2p

27

J. B. Bremner, R. N. Warrener, E. Adman, and L. H. Jensen, J. Amer. Chem. SOC., 1971, 93,4574. E. Adman and L. H. Jensen, Acta Cryst., 1970, B 26, 1326; E. Adman, M. P. Gordon, andL. H. Jensen, Chem. Comm., 1968,1019. R. B. Morin and B. G. Jackson, Fortschr. Chem. org. Naturstoffe, 1970, 28, 343. D. H. R. Barton and P. G. Sammes, Proc. Roy. SOC.,1971, B179, 1971. G. E. Gutowski, C. J. Daniels, and R. D. G. Cooper, Tetrahedron Letters, 1971, 3429; G. E. Gutowski, B. J. Foster, C. J. Daniels, L. D. Hatfield, and 5. W. Fischer, ibid.. p. 3433; R. D. G. Cooper, J . Amer. Chem. SOC.,1972, 94, 1018. R. B. Morin, B. G. Jackson, R. A. Mueller, E. R. Lavagnino, W. B. Scanlon, and S. L. Andrews, J. Amer. Chem. SOC.,1969,91, 1401. B. G. Ramsey and R. J. Stoodley, Chem. Comm., 1970, 1517; J. Chem. SOC.(C), 1971, 3859; ibid., p. 3864. S. Wolfe, J. C. Godfrey, C. T. Holdrege, and Y . G . Perron, Canad. J. Chem., 1968, 46, 2549.

Thiazines

(36) X (39) X

765

= =

C1, Y = RCONH CH,Cl, Y = phthalimido

y2/ Me

0

(37) X (40) X

= =

0

CI, Y = RCONH CH,CI, Y = phthalirnido

0

0

Me

(38) Y

=

RCONH

(41) Y = phthalimido

(42)

expected cepham (41), also to its 7-epimer (42);the latter is formed because of a competing reaction which results in a partial epimerization of the starting product at position 6. Experiments are reported 2 6 which indicate that this side-reaction can be minimized or even suppressed by an appropriate choice of the leaving group, solvent, and base.

Benzo-l,34hlazines.-A simple and novel route to 2H-1,3-benzothiazines is reported 28 to involve condensation of the NS-dimagnesium dibromide of a 2-mercaptobenzylamine with gem-polyhalogeno-compounds. The synthetic utility of the method is exemplified in the preparation of the hitherto-unknown parent heterocycle (Scheme 8). Treatment of 3-chloro1,2-benzisothiazolium chlorides [e.g. (43)] with formamides results 2 9 in ring-expansion and formation of 3,4-dihydro-2-imino-2H-1,3-benzothiazin-4-ones and/or 3,4-dihydro-4-imino-2H-1,3-benzothiazin-2-ones. The product ratio is influenced by the formamide used and the reaction conditions. For instance, (43) reacts with N-methylformamide to give predominantly (44) in pyridine at 35-40 "C,and (45) in 1,2-dichlorobenzene at 100 "C; using N-phenylformamide in place of N-methylformamide, the analogue of (45) is obtained under both reaction conditions. N.m.r. data indicate that, with one exception, compounds of the type (44)

Scheme 8 28 28

D. Bourgoin-Legay and R. Boudet, Compt. rend., 1971, 273, C, 372. H. Boshagen, W. Geiger, H. Hulpke, and C. Wunsche, Chem. Ber., 1971,104, 3757.

766 Organic Compounds of Sulphur, Selenium,and Tellurium exist only in the ( E ) form, whereas (45) and its analogues have always the (Z)-configuration. The C=N double bond in 4H-1,3-benzothiazines is reduced,30without appreciable secondary reactions, with zinc dust in ethanol containing hydrochloric acid, but not with either complex metal hydrides or with the aluminium-amalgam method developed 31 for the reduction of 4H-1,3benzothiazin-4-ones. Alkylation of the ring nitrogen in 2-aryl-4H-1,3benzothiazines is reported 32 to occur in excellent yield by heating with a large excess of the appropriate alkyl bromide for 12 h at 120 "C in a sealed tube. The resulting quaternary salts [e.g. (46)] are rather unstable, and in aqueous7solution readily undergo C-N bond fission to give an S-acyl-Nalkyl-2-mercaptobenzylammonium bromide (47) in the first step, which is ,Me

M e o ~ s c ~ p ~ E t

M e o Bra : 2 M eE 0 ; CH& H ? r l Me0 COPh (48) (49) subsequently transformed by intermolecular transacylation into a mixture of (48) and (49). In alkaline medium the ring-opening of (46) proceeds similarly, but the primary product (47) undergoes an intramolecular S -+ N acyl migration to give the corresponding N-benzoyl derivative. Treatment of 2-thioalkyl-4H-l,3-benzothiazines with two equivalents of potassium amide in liquid ammonia has been shown 33 to cause extrusion of the ring-sulphur atom to give the corresponding 2-thioalkylindoles in excellent yield [e.g. (50) -+ (52)]. The base-promoted loss of sulphur is so 31

32

J. Szab6, I. Varga, and E. Vinkler, Acta Chim. Acad. Sci. Hung., 1972,71, 363. H. Bohme and W. Schmidt, Arch. Pharm., 1953, 286, 437. J. Szab6, I. Verga, and E. Vinkler, Actu Chim. Acad. Sci. Hung., 1971,69,459 (Chem. Abs., 1971,75, 140 778h); ibid., 1971,70,71 (Chem. Abs., 1971,75, 151 745w). D.Lednicer and D. E. Emmert, J . Heterocyclic Chem., 1971,8,903.

Thiazines

767

(50) (51) (52) considered to proceed via decomposition of an episulphide intermediate (51), which is destabilized by the close proximity of the anionic nitrogen. The reaction appears to be quite general and permits considerable variation in the substituents of both the aromatic ring and the exocyclic sulphur atom. In connection with their studies on the chemical behaviour of thiocarbonyl derivatives of some heterocyclic systems, Ebel and co-workers 34

Ph

I

iii

(57) Reagents: i, PhCOCHNf; ii, CH2N,; iii, Raney Ni

Scheme 9 34

M. Ebel and N. Lozach, Bull. SOC.chim. France, 1971,180; M. Ebel, ibid., pp. 183,187.

768


with diazoacetohave examined the reaction of 1,3-benzothiazin-4-thiones phenones and diazomethane. Typically, the thione (53) reacts with diazoacetophenone at ca. 150 "C to give the 4-aroylmethylene derivative (54) (2-form), whereas with diazomethane at room temperature it forms two isomeric 1,3-dithiolans [(55) and (56)] having two spiro junctions with the benzothiazine systems (cf. Scheme 9). Elimination of the dithiolan sulphur atoms with Raney nickel in boiling benzene converts stereospecifically the cis-spiran (55) into the olefin (57), and the trans-spiran (56) into the corresponding olefin (58). These two isomeric olefins can also be obtained by direct desulphurization of (53) with Raney nickel or with copper at 215220 "C.Under the latter reaction conditions, interconversion of the cisinto the trans-olefin takes place and, hence, only (58) is obtained. The new dihydro-l,3-thiazino[3,2-a]pyridinium 9-oxide system [e.g. (59)] has been prepared 35 by condensation of 3-hydroxypyrid-2-thiones with 1,3-difunctional propane derivatives (Scheme 10). Acid-catalysed dehydration of (59) in warm orthophosphoric acid or in cold sulphuric acid leads to the 1,3-thiazine (61) and to the isomeric thiazole (62) in the

H

Scheme 10 st,

K. Undheim and K. R. Reistad, Acta Chem. Scand., 1970, 24, 2949.

Thiazines

769

ratio 1 : 1 or 3 : 1, respectively. The formation of (62) is envisaged as a rearrangement of the resonance-stabilized carbonium ion (60), which may well be sufficiently long-lived for extensive rearrangement to occur in competition with simple proton climination.

3 1,4-Thiazines Monocyclic 1,4-Thiazines.-Rernarkably little has been published recently on the chemistry of simple 1,4-thiazines. As an extension of early Carson and co-workers now report the isolation and structure of the new isomeric 3-carboxyl-1,4-thiazine S-oxides (63) and (64) from the oxidation

(64) R = M C

(63) R = Me or Et

of the corresponding sulphides with hydrogen peroxide in acetic acid.37 N.m.r. and i.r. data are generally consistent with conformations in which the sulphoxide bond is equatorial, but abnormally high gauche coupling constants in (63) indicate a probable highly puckered chair-form for these compounds. The action of sulphuryl chloride on 2-substituted 3-oxoperhydro-2H-l,4-thiazine-5-carboxylic acids, prepared by the route in Scheme 11, has been inve~tigated.~~ Treatment of the 2-phenyl derivative (65) with

Scheme 11

sulphuryl chloride at room temperature gives, in addition to the expected acid chloride, the lactone (68), presumably via (69); an analogous intermediate is postulated also in the reaction of (66) with sulphuryl chloride, leading to the 2-isopropylidene derivative (70). In the case of 2,2-dialkylthiazines [e.g. (67)] chlorination probably takes place at position 6, since the reaction gives both (71) and its decarboxylation product. Like their l-alkenyl analogues,s6 2-alkynylcysteine S-oxides and SSdioxides in the presence of base undergo an internal addition of the aminofunction to the triple bond to yield cyclic sulphoxides and ~ u l p h o n e s . ~ ~

37

8a

39

J. F. Carson and L. E. Boggs, J. Org. Chem., 1966, 31, 2862; J. F. Carson and R. E. Lundin, ibid., 1969, 34, 1996. J. F. Carson, L. M. Boggs, and R. E. Lundin, J. Org. Chem., 1970, 35, 1594. M. Nakanishi and T. Muro, J. Pharm. SOC.Japan, 1970, 90, 570 (Chem. Abs., 1970, 73, 25 383x); ibid., 1971, 91, 166 (Chem. Abs., 1971,74, 125 595g). J. F. Carson and L. E. Boggs, J. Org. Chem., 1971, 36, 611.

26

770


H NH,OH

HC~CCH~SO~CH~-CC-CO,H I H

NH,+ H

(72)

Thus S-(2-propynyl)-~-cysteineSS-dioxide ring-closes in dilute ammonium hydroxide solution to the ammonium salt of (72), which on the basis of n.m.r. data appears to exist in a half-chair ~ ~ n f o r m a t i o nUnder . ~ ~ more controlled conditions, ( )-S-(2-propynyl)-~-cysteine S-oxide behaves similarly, giving the corresponding cyclic sulphoxide, but the cyclization of the (-)-isomer was unsuccessful. The concomitant action of elemental sulphur and ethyleneimine upon aldehydes in the presence of dimethylformamide or potassium carbonate results 40 in the formation of 2-alkyl-5,6-dihydro-4H-1,4-thiazines and, as by-products, 2-alkylthiazolidines. The use of ketones in place of aldehydes, in addition to giving 2,2-dialkylthiazolidines, leads to a mixture of structurally isomeric 3-alkyl- and 2,3-dialkyl-5,6-dihydro-l,4-thiazines in a relative ratio depending mainly upon the ketone used (Scheme 12). In further studies 41 of this system, 5,6-dihydro-1,4-thiazines[e.g. (73) or (74)] were observed to undergo a hydrogenating ring-contraction to 2,2-dialkylthiazolidines (75) by the action of hydrogen sulphide. Moreover, in a reversal of the ring-contraction, 2,2-disubstituted thiazolidines were found to rearrange to 5,6-dihydro-l,4-thiazinesin a dehydrogenation reaction

+

40

F. Asinger, H. Offermanns, D. Neuray, and P. Mueller, Monutsh., 1970, 101, 1295; F. Asinger, H. Offermanns, K. H. Lim, and D. Neuray ibid., p. 1281; F . Asinger, A. Saus, H. Offermanns, D. Neuay, and K. H. Lim, ibid., 1971,102, 321. F. Asinger, H. Offermanns, and D. Neuray, Annulen, 1970,739,32.

77 1

Thiazines 0

II

('IMe ('1 +

S

+

N Me H (73) 75%

N

H

+

[ : > M e

EX

(74) 8%

Et

H (75) 17%

with elementary sulphur in boiling chloroform containing triethylamine or n-butylamine [e.g. (75) gives (74) and (73)]. Benzo-l,4-thiazines and Related Compounds.-The condensation of 2-aminothiols with simple o-benzoquinones has been studied as a model

(81)

(82)

Reagents: i, excess [Fe(CN),]3--NaHC0,(aq); ii, [Fe(CN),I3--NaHC0,(aq); Ag,0-Et20; iv, 0. IN-HCl-EtOH; v, 0,-NaHCO,(aq)

iii,

Scheme 13 42

G. Prota, 0. Petrillo, C. Santacroce, and D. Sica, J. HeterocycZic Chem., 1970, 7, 555.

772


reaction of formation of the 1,4-benzothiazine structures found in phaeomelanins,43a generic term used to designate the amphoteric pigments from red hair and feathers arising biogenetically from 3,4-dihydroxyphenylalanine (dopa) and cysteine. Co-oxidation of 4-methylcatechol and 2-aminoethanethiol with potassium ferricyanide in aqueous sodium bicarbonate results in the formation of two heterocyclic quinones, (79) and (80), the former probably deriving from the latter by hydrolysis of the enol-ether group during the work-up procedure. Under carefully controlled conditions the oxidation produces mainly the intermediate dihydrobenzothiazine (82), which in turn was shown to derive by intramolecular cyclization of the catecholamine (8 1) which results from the 1,6-additionof 2-aminoethanethiol to nascent 4-methyl-o-benzoquinone (Scheme 13). Subsequent studies 44 have revealed that an analogous sequence of reactions indeed occurs during the first stages of the enzymic (mushroom polyphenoloxidase) co-oxidation of dopa and cysteine to phae~melanins.~~ The spectrophotometric course of the reaction and the identification of the u.v.-detectable intermediates indicate that the process is initiated by the 1,6-addition of cysteine to dopaquinone to give the two isomeric amino-acids (83) and (84) (in the ratio 95 : 5), which are rapidly converted into the corresponding dihydrobenzothiazines (85) and (86), probably by a self-catalysed reaction involving oxidation and reduction steps (Scheme 14) : an initial oxidation of the catechol A produces the corresponding quinone B which undergoes an intramolecular condensation to the quinonimine C. Reduction of this by the original catechol A then gives the dihydrobenzothiazine D and a further molecule of the o-quinone B, so that the reaction may continue spontaneously, Considerable recycling is indicated by the high overall conversion and by separate studies 44 of the reaction (83) -+ (85), which is almost quantitative (> 95% yield). Confirming evidence for the intermediacy of both dihydrobenzothiazines (85) and (86) in the biosynthesis of phaeomelanins comes also from concurrent studies on the structure of a most characteristic group of phaeomelanic pigments known as the ‘trichosiderins’, the name deriving from early studies46indicating the presence of iron in the pigments from red human-hair as well as from other sources. A detailed re-examination 4 7 of the trichosiderins from the feathers of New Hampshire chickens has led to the isolation of four homogeneous members of this family, trichosiderins B, C,E, and F, which were assigned structures (87)-(go), respectively, by 44

4~

R. A. Nicolaus, ‘Melanins’, Hermann, Paris, 1968, pp. 107-123. G. Prota, S. Crescenzi, G . Misuraca, and R. A. Nicolaus, Experientia, 1970, 26, 1058. G. Prota and R. A. Nicolaus, Guzzetta, 1967, 97, 665; E. Fattorusso, L. Minale, S. De Stefano, G. Cimino, and R. A. Nicolaus, ibid., 1969,99,969. S. Rothman and P. Flesch, Proc. SOC. Exp. Biol. Med., 1943, 53, 134; P. Flesch and S. Rothman, J. Znuest. Dermutol., 1945, 6, 257; P. Flesch, Nature, 1968, 217, 1056; P. Flesch, J . Invest. Dermutol., 1968,51, 337. R. A. Nicolaus, G. Prota, C. Santacroce, G. Scherillo, and D. Sica, Gazzetta, 1969,99, 323; G. Prota, G. Scherillo, 0. Petrillo, and R. A. Nicolaus, ibid., p. 1193; G . Prota, A. Suarato, and R. A. Nicolaus, Experientiu, 1971, 27, 1381.

Thiazines

773

HC

HC k02H

H2d

H2N/I COzH

H2NYo2H HS

aH NH2

I

SCHzCCozH I

Rf

R2

NHa

I

(83) and (85) R1 = CH,CHC02H

R A

=

(84) and (86) R1

=

H H

NH2

H

I R2 = CPI,CHCO,H

A (83) and (84)

R1 R2

\

phaeomelanins

D ( 8 5 ) and (86)

SCH,qCO,H

R1

B Scheme 14

functional group analyses, degradative studies, and comparison of their spectral properties with those of synthetic model compounds. The most interesting feature of the proposed structures is the hitherto unknown A2J’-bi-(2H-1,4-benzothiazine) chromophore, which is formally derived by oxidative coupling of two 1,4-benzothiazine units related biogenetically to (85) or (86), as indicated by the relative positions of the substituents in the benzene rings. The two trichosiderins B and C are very sensitive to acids and on brief heating with O.1N-HCl undergo a selective decarboxylation at position 3 to give the corresponding decarboxy-derivatives (91) and

774


CH2

I

CH H2N C02H (87) R

/ \

HZN CO2H

/I

(91)

R

= CO,H

=

H

CH

HC H 2 dk02H

/\

H2N CO2H (88) R = COzH (92) R = H

OH

HC

/ \

HzN C02H

OH

CH / \ HZN CO2H

(92), which are also obtained 4 8 from red human-hair by extraction with boiling dilute acids. Unlike the parent trichosiderins, (91) and (92) exhibit characteristic pH-dependent colours, being reversibly yellow-orange ( 458-460 nm) in alkaline and red-violet ( 525 nm) in aqueous acidic solution as a result of protonation of the chromophoric system

-

-

‘!IG. Prota and R. A. Nicolaus, in ‘Advances in Biology of Skin’, ed. W. Montagna and F. Hu, Pergamon Press, New York, vol. VIII, 1967, pp. 323-328.

Thiazines

..

I

I

775

..

*.

-N=CH-C=C-S-, which gives rise to a mesomeric ammoniumthionium cation. An analogous, albeit larger, bathochromic shift on acidification is observed also in the visible spectra of the two acid-stable trichosiderins E and I; ()crnax(OH-), 482 nm; 587 nm) which possess the same chromophore as the model compounds (93) and (94), obtained 4 9 by the biogenetic-type syntheses shown in Schemes 15 and 16. 0

(93) Scheme 15

H? Me

Me OR

Reagents: i, [Fe(CN),]”-NaHCO,(aq);

OR

ii, 2N-HC1-EtOH, 4 *C

Scheme 16

As yet the stereochemistry of the A2pa’-bi-(benzothiazine)skeleton in the trichosiderins and in (93) and (94) has not been defined, although indirect evidence indicates that the isolated products may well be an equilibrium mixture of both geometrical isomers. Support for this view derives also from a recent study on the stereochemistry of some A2s2’-bi-(2H-1,4benzothiazine) derivatives (96), which have been obtained in good yield by oxidation of the corresponding 2H-1,4-benzothiazines (95) with chloranil 40

50

G. Prota, in ‘Pigmentation:Its Genesis and Biological Control’, ed. V. Riley, AppletonCentury-Crofts, New York, 1972, in the press. F. Giordano, L. Mazzarella, G. Prota, C. Santacroce, and D. Sica, J. Chern. SOC.(C), 1971, 2610.

776


(Scheme 17). In all cases examined, the reaction afforded both cis- and irans-isomers of (96) which were found to be surprisingly easily interconvertible, even at room temperature.

(95)

R1 (a) p-C,H,Br

(b) p-C,H,Me (C) p-C6H,Cl (d) p-C6H,Me Scheme 17

R2 H H H OMe

Moreover, a study of the thermal interconversion of the pure geometrical isomers into equilibrium mixtures revealed that, despite the presence of bulky substituents at the 3- and 3’-positions, at ordinary temperatures the cis-isomer is the more stable of the two. The relative stability of the geometrical isomers has been partly explained in terms of the molecular structures of the cis- and trans- forms of the 3-p-bromophenyl derivative (96a), which were determined by three-dimensional X-ray analyses by the heavy-metal method. The results indicate that both configurations are achieved through a considerable puckering of the heterocyclic rings, with a large deviation from planarity of the grouping of the atoms -N=C(3)C(2)=C(2’)-C(3’)=N-, resulting in some loss of resonance of the conjugated double-bond system, particularly in the case of the cis-isomer. However, a preference for this latter configuration may be associated with the Van der Waals forces which maintain the two phenyl groups, at the 3- and 3’-positions, in an almost fixed conformation, whereas the transisomer, with its more open structure, allows a larger oscillation of the phenyl groups around their bond axes. As the temperature increases, the effects of thermal motion destabilize the cis-configuration, and the lessstrained trans-molecule becomes energetically favoured. On treatment with mild oxidizing agents, 2H-1,4-benzothiazines7 as well as 2H-1,4-thiazines, undergo self-coupling at the 2-position to yield the corresponding 2,2’-dehydro-dimer~.~lIn addition to picric acid and nitrobenzene, molecular oxygen is also effective as a dehydrogenating agent, particularly when the reaction is performed in ethanol containing hydrochloric acid; thus, for instance, (97) gives (98) (45% yield), which by X-ray analysis is shown to be the meso-isomer.61 In ethanolic solution, 2-ethoxycarbonyl-4H-1,4-benzothiazine(99), available from o-aminothiophenol and ethyl bromopyruvate,62undergoes aerial oxidation, but the s1 62

D. Sica, C. Santacroce, and G. Prota, J . Heterocyclic Chern., 1970,7, 1143. C. Santacroce, D. Sica, and R. A. Nicolaus, Gazzerta, 1968, 98, 85; G. Pappalardo, P. Condorelli, and M. Raspagliesi, ibid., 1966, 96, 1147.

Thiazinw

777

(100)

(99)

(101)

two isomeric dehydro-dimers (100) and (101) are formed in the relative ratio 3 : 2.63 On the other hand, use of ethyl azodicarboxylate as dehydrogenating agent converts (99) specifically into (101), presumably via a radical mechanism similar to that proposed by Colonna and co-workers 64 for the dehydrogenation of enamines and enamine-like systems. Various aspects of the chemistry of some 2H-1,4-benzothiazinehydroxamic acids have been investigated.66 When refluxed in aqueous sodium hydroxide the hydroxamic acid (102) gives three products, two of which correspond to the lactam acid (103) and the unsaturated acid (104). The 6-methyl and 6-bromo-derivatives of (101) behave similarly, whereas the R*

R' (102) OH

(103) H (105) OH (106) H (107) OH (108) H 68

ci4 65

R'

RS

H H H CI

CHZCOZH CHzCOzH H H

Me Me

H H

F. Duro, P. Condorelli, G. Scapini, and G . Pappalardo, Ann. Chim. (Italy), 1971, 7, 351. M. Colonna and L. Marchetti, Guzzerta, 1969,99, 14, and refs. therein. R. T. Coutts, S. J. Matthias, E. Mah, and N. J. Pound, Canud. J . Chem., 1970, 48, 3727; R. T. Coutts and N. J. Pound, ibid., p. 1859.

778


simpler hydroxamic acid (105) undergoes mainly ring-opening to give a mixture of sodium o-aminophenylthioacetate and 2,2'-diaminophenyl disulphide. Like aromatic hydroxylamines, benzothiazinehydroxamic acids on treatment with hydrochloric acid undergo nucleophilic attack by chloride ion at position 7 and displacement of water from the protonated hydroxamic group to give s6 7-chlorobenzothiazines in good yield [e.g. (105) gives (106) in 81% yield]. The introduction of a chlorine atom is not observed with the 7-methyl derivative (107), which when refluxed in boiling hydrochloric acid gives the corresponding lactam (108) and, as by-product, its dehydro-dimer (109). Treatment of the 4-acetoxylactam (110) with acetic acid leads to the isomeric 2-acetoxylactam (11l), presumably according to the mechanism in Scheme 1KS6This also explains the formation of rOAc

OAc

(1 11)

Scheme 18

(111) from the acylation of the hydroxamic acid (105) with acetic anhydride and acetic acid.s6 Similar reactions are also described for 4-hydroxy1,4-benzo~azin-3(4H)-ones.~ Several papers have been published on the synthesis and properties of fused-ring systems incorporating the 1,4-thiazine structure, mainly pyrido[2,3-b]- 1,4-thia~ines,~'pyrazino[2,3-b]- 1,4-thiazine~,~~ and pyrimido[4,54]-1,4-thia~ines,~ including some sulphur isosteres of dihydropteridines [e.g. (1 12)].60 A detailed account of ring-chain tautomerism in 6-hydroxy@

b6 s7

68

6s 6o

R. T. Coutts and N. J. Pound, J. Chem. SOC.(C), 1971,2696. T. S. Safonova and L. G. Levkovskaya, Khim. geterotsikl. Soedinenii, 1971, 68 (Chem. Abs., 1971, 75, 35 637p); ibid., p. 78 (Chem. Abs., 1971, 75, 20 321g); L. G. Levkovskaya and T. S. Safonova, ibid., p. 1502. T. S. Safonova and L. A. Myshkina, Khim. geterotsikl. Soedinenii, 1970, 1101 (Chem. Abs., 1971,74,53 742c); ibid., p. 1092 (Clzem. Abs., 1971,74, 53 744e); T. S. Safonova, L. A. Mishkina, V. A. Chernov, and A. S. Sokolova, ibid., 1971, 1498; S . Kawano, S. Zoga, H. Watanabe, and T. Sato, Jap. P. 32 670/1971, 32 671/1971 (Chem. Abs., 1971, 75, 140 888u, 140 890p). M. P. Nemeryuk and T. S. Safonova, Khim. geterotsikl. Soedinenii, 1971, 73 (Chem. Abs., 1971, 75, 35 917e). H. Fenner and H. Motschall, Tetrahedron Letters, 1971, 4185, 4333.

Thiazines

779

pyrirnido[4,5-21]-1,4-thiazines(1 13) has also appeared,61 in which spectral methods (u.v., i.r., and n.m.r.) have been used in detecting both tautomeric forms-the cyclic carbinolamine A and the open aminocarbonyl form Band observing their mutual transformation. The results shows that the position of the tautomeric equilibrium in these compounds is influenced

B

A

R* R2 Me

(113) (a) H (b) H

CH,CI (c) H CH,C02Et (d) Me Me (e) Me CH2CI (f) Me CH2C0,Et

not only by the nature of the substituent at C-6, but also by steric factors which involve interaction between the chlorine atom at C-4 and the substituents at N-5.Thus, compounds (1 13a-c) exist as cyclic carbinolamines either in the solid state or in solution, whereas compounds (113d-f) can adopt both forms A and B, which in solution interconvert reversibly. Moreover, the n.m.r. data indicate that the tautomeric equilibrium A + B in CDCls for the 6-methyl derivative (113d) is shifted to the open form B, and for 6-chloromethyl and 6-ethoxycarbonylmethyl derivatives (1 13e and 113f) to the cyclic form A. Phenothiazines (Dibenzo-l,4-thiazines) and Related Compounds.-Further studies (LCAO-MO) on the electronic structure of phenothiazine and mono- and di-benzophenothiazines are reported, 62 in which the total 7r-electron energy of the highest occupied MOs and the lowest five vacant MOs, wavelength of the longest-wave transition, and the charge of the N atom are calculated, assuming a non-planar molecule in the H-intra configuration. The crystal structure of Methylene Blue hydrochloride pentahydrate has been successfully determined.63 The bond lengths are consistent with a partial quinonoid structure in which the charge is mainly localized on the dimethylamino-groups. The molecules are packed in sheets associated with chloride ions on the terminal nitrogen with a dl

63

T. S. Safonova, J. N. Sheinker, M. P. Nemerjuch, E. M. Peresleni, and G. P. Syrova, Tetrahedron, 1971, 27, 5453. N. Tyutyulkov, D. Simov, and S . Stoyanov, Compt. rend. Acad. bulg. Sci., 1970, 23, 1095 (Chem. Abs., 1971,74, 41 728q). H. E. Marr and J. M. Stewart, Chem. Comm., 1971, 131.

780


clathrate-like network of water molecules perpendicular to the planes formed by the phenazathionium units. In the past two years there has been a further increase in the number of papers on syntheses in the phenothiazine series, However, a large number of these are concerned with the preparation of side-chain modified analogues of chloropromazine 64 and related phenothiazines 65 of potential pharmacological interest ; for reasons of space these cannot be discussed here. In view of the recent demonstration 6 6 that triethyl phosphite deoxygenation of 2-nitrophenyl aryl sulphides and thermolysis of their 2-azidoanalogues proceed via a molecular rearrangement involving a free orthoposition in the aryl moiety to give phenothiazines, the corresponding reactions of nitro-compounds and azides in which the essential ortho-positions are substituted have been in~estigated.~'As expected, the structure of the reaction products was found to be strongly dependent upon the nature of the ortha-blocking groups. An interesting case is offered by the deoxygenation of the nitro-compound (114) and thermolysis of the azide analogue (115) both leading, at 150 "C, to 1-methoxyphenothiazine (116) (12 and 20%, respectively) and 1,2-dimethoxyphenothiazine (117) (52 and 39%, respectively) via a novel nitrene-induced demethoxylation and a most unusual 1,4-methoxy-group shift (Scheme 19). The ring-closure of 2,6dichlorophenyl 2-nitrophenyl sulphide and its 2-azido-analogue proceed similarly to give 1-chlorophenothiazine (37 and 40%, respectively), but differ in the formation of 4-chlorophenothiazine (52 and 5%, respectively). In addition, the marked dependence of the product ratio on the reagent suggests the participation in the former case of an additional intermediate, e.g. a nitrene precursor Ar%O-$(OEt),, which leads to the 4-isomer. Another course of reaction is observed in the triethyl phosphite deoxygenation of the nitro-compound (1 18), which leads to diethyl 4aH-phenothiazine-l,4a-dicarboxylate(120). Its isolation is good evidence in support of the mechanism proposed 6 6 for this new series of aromatic rearrangements involving spiro-intermediates of the type (1 19) which are converted, 64

66

67

E. A. Nordiff, H. L. Sharma, T. Kohno, F. Schnierle, M. Mori, and A. A. Manian, J . Heterocyclic Chem., 1971,8, 321; E. A. Nordiff, T. Hayazaki, T. Ito, H. L. Sharma, T. Kohno, T. Ueda, S. Morosawa, and A. A. Manian, ibid., p. 1075; V. N. Sharma, N. S. Pancholi, H. L. Sharma, R. L. Mital, and D. Chandra, J . Pharm. Sci., 1971, 60, 1262; C. L. Huang and C. T. Chang, ibid., p. 1895; C. Kaiser, D. H. Tedeschi, P. J. Fowler, A. M. Pavloff, B. M. Lester, and C. L. Zirkle, J. Medicin. Chem., 1971, 14, 179. K. P. Bogeso and N. A. Klitgaard, Acta Chem. Scand., 1971,25, 1889; C. Casagrande, A. Galli, R. Ferrini, and G. Miragoli, Arzneim.-Forsch., 1971,21,808; A. N. Gritsenko, Z. I. Ermakova, S. V. Zhuravlev, Y. I. Vikhlyaev, T. A. Klygul, and 0. V. Ulyanova, Khim. Farm. Zhur., 1971,5, 18 (Chem. Abs., 1971,75, 140 776f); V. S. Karpinskii and L. V. Konovalova, Khim. geterotsikl. Soedinenii, 1971, 950; K. A. Petrov, L. V. Khorkhoyanu, Z. Beishekeev, and D. Dzhundubaev, Zhur. obshchei. Khim., 1971, 41, 110 (Chem. Abs., 1971, 75, 36 244v); H. Shirai, T. Hayazaki, and T. Aoyama, Chem. and Pharm. Bull. (Japan), 1971, 19, 892 (Chem. Abs., 1971, 75, 49 004s). J. I. G. Cadogan, S. Kulik, and M. J. Todd, Chem. Comm., 1968,736; J. I. G . Cadogan, S. Kulik, C. Thomson, and M. J. Todd,J. Chem. SOC. (C), 1970,2437; J. I. G . Cadogan, R. Marshall, D. M. Smith, and M. J. Todd, ibid., p. 2441 ;see also vol. 1, pp. 4 7 0 - 4 7 2 . J. I. G. Cadogan and S. Kulik, J . Chem. SOC.( C ) , 1971, 2621.

781

Thiazines

OMe

Me0 (114) X = NO, (115) X = N3

- c H,O OMe

( 1 17) Scheme 19

782


via a 1,Zsigmatropic shift, into hydroaromatic intermediates [e.g.(120)] and thence by prototropy to the 'rearranged' phenothiazines. A possible route to 2- and 3-t-aminophenothiazines is afforded 6 8 by the reaction of chloro-10-alkylphenothiazineswith sodium or lithium derivatives of secondary amines. Thus, treatment of l-chloro- or 2-chloro-10methylphenothiazine with sodium amide-morpholine leads to the same product, i.e. 2-morpholino-lO-methylphenothiazine,presumably by way of the same phenothiazyne intermediate (121). 3-Chloro- and 4-chloro-10methylphenothiazine react similarly giving, as expected, the same 3-morpholino-derivative uia an analogous phenothiazyne intermediate. The phenazathionium cation (122), generated oxidatively in situ with ferric chloride, reacts readily with toluene-p-sulphinic acid, nitrite, or thiourea to

(123) X = p-S02C,H,Me (124) X = NO2 (125) X = S-C-NH2

II

*NH, Cl-

(126) X = SH

give the corresponding addition products (123)-( 126). Dimedone, as well as other reactive methylene compounds, reacts with (122) similarly, but the primary adduct is subsequently oxidized to give the quinonoid dye (127). As a result of this study, Danek and co-workers 6 B have also succeeded in preparing the very sensitive 3-mercaptophenothiazine (126) by alkaline fission of the isothiuronium chloride derivative (125) in anaerobic conditions, and also by reduction of phenothiazinyl 3-thiocyanate with LiAlH4. A facile chlorination of phenothiazines results from the action of hydrogen chloride in DMSO at 40 O C . ' O Under these mild conditions, phenoIJ*

G8

'O

D. H. Jones, J. Chem. Sac. (C), 1971, 132. J. Daneke, U. Jahnke, B. Pankov, and H. W. Wanzlich, Tetrahedron Letters, 1970, 1271; J. Daneke and H. W. Wanzlich, Annulen, 1970, 740, 52. Y. Tsujino, T. Naito, and J. Sugita, J. Chem. SOC.Japan, 1970, 91, 1075 (Chem. Abs., 1971,74, 141 663h).

783

Thiazines

thiazine itself gives the 3,7-dichloro-derivative in excellent yield (84%). Addition of thiocyanates, e.g. NH,SCN, to the above reaction system causes thiocyanation of the phenothiazines, again at the 3,7-positions, rather than chlorination. The seven possible monomethyl-3H-phenothiazin-3-one isomers have been prepared 71 by the following pathways: (a) oxidation of methylphenothiazines with FeCI, (for the 2-, 4-, 6-, and 8-methyl isomers) ; (b) thionation of 4-hydroxymethyldiphenylamines (for the 6-, 7-, 8-, and 9-methyl isomers); (c) condensation of zinc o-aminobenzenethiolate with methyl- or halogenomethyl-p-benzoquinones(for the 1- and 2-methyl isomers). The use of chloranil or bromanil in the last reaction is reported to give 6,13-dichloro- or 6,13-dibromo-triphenodithiazine (129) via the corresponding 1,2,4-trihalogenophenothiazines (128), which can be isolated when the condensation is performed in the presence of one molar equivalent of zinc o-aminobenzenethiolate (Scheme 20).

X ( 129)

Scheme 20

In connection with his studies on bridge syn-metacyclophanes, Boekelheide now describes 73 the properties of N-methyl-l,9-ethenophenothiazine (130), which has been prepared according to a route similar to that employed for the synthesis of 8,16-imino[2,2]metacyclophane-l ,9-diene.', The U.V. and n.m.r. spectra of this new bridged syn-metacyclophane are fully consistent with the expected structure (130), and indicate that valence tautomerization to (131) is not occurring to any significant degree at ordinary temperatures. On heating at 203 "C in benzene, (130) undergoes l' 72

74

M. Terdic, Annalen, 1971, 746, 200. R. L. Mital and S. K. Jain, J. Chem. SOC.( C ) , 1971, 1878. V. Boekelheide and R. A. Hollins, J. Org. Chern., 1971, 36, 2437. B. A. Hess and V. Boekelheide, J. Amer. Chem, SOC.,1969, 91, 1665.


784

expulsion of the bridging NMe group to give, in addition to other products, (1 32) via, it is suggested, decomposition of the valence tautomer (1 3 1). A synthesis of furo[2,3-b]phenothiazines[e.g. (133)], members of a novel heterocyclic system, involves 75 condensation of phenacyl bromide with 2-formyl-3-hydroxy-phenothiazine.The chemistry and pharmacological properties of azaphenothiazine systems have been recently reviewed, 7 6

s@

/

N H

H

Other work in this field includes the synthesis of 2,3-diazaphenothiazine (134),77and the chemical behaviour of some new derivatives of 2,4-7 8 and 3,4-diazaphenothiazines. @

76

'*

78

7B

B. Lobert, G. Saint-Ruf, and N. P. Buu-Hoi, BUN. SOC.chim. France, 1971, 3251. C. 0. Okafor, Internat. J. SuIfur Chem. (B), 1971, 6, 237. G. Pappalardo, F. Duro, and G. Scapini, Ann. Chem. (Italy), 1971,58, 280. V. G. Granik and R. G. Glushkov, Khim. Farm. Zhur., 1971,5, 10 (Chem. Abs., 1971, 75, 63 723g). D. E. Ames and N. D. Griffiths, J. Chem. SOC.(C), 1971, 2672.

17 Th iazepi nes and Th iadiazepines BY

D. H. REID

1 1,4-Thiazepines Aspects of the chemistry of 1,6thiazepines arising from work on the penicillins and related compounds are reviewed in Chapter 3. The present chapter covers all other work in this area. A comprehensive review of thiazepines and their benzo- and dibenzoderivatives has appeared.l The 2,3-dihydro-1,4-thiazepine(1) has been synthesized (Scheme 1) and its photochemistry studied.2 Irradiation in aprotic solvents (hexane, ether ;

CH2

U

Me-CO,Et

+

i

HZN

1,

0

iii

(1) Reagents: i, Base; ii, SO2Cl2-CH2CI2,30 "C; iii, 25 "C, - HCI; iv, Et,O+ BF,-

Scheme I U.V. light) gives a mixture of unidentified dimers via a triplet excited state. In protic solvents (methanol), however, the singlet excited state of thiazepine (1) is trapped and leads to the 1,4-thiazine (2) by the pathway suggested in Scheme 2. A different and more efficient addition of methanol occurs with the hydrochloride (3) of the thiazepine (1) to give a mixture of epimers tentatively assigned structures (4)and (5). l

a

K. Wunsch and A. Ehlers, Z. Chem., 1970, 10, 361. M. F. Semmelhack, S. Kunkes, and C. S. Lee, Chem. Comm., 1971, 698.

785

786


Etd

'

H

H+

Me

Etd

-N EtO

Scheme 2

hv ____+

EtO

EtO

C1-

Me

Na,CO,

M e O C - Me M e

Me*'- -N

Etd (4)

EtO H

+

M e O C T Me M e

Me

-N

Etd (5)

787 An unusual, thermally reversible, 1,3-hydrogen shift has been encountered upon irradiation of 6-benzyloxycarbonylamino-2,3-di hydro- 1,4thiazepines (6) and (7), which were synthesized as shown in Scheme 3. Thiazepines and Thiadiazepines

R = PhCH,OCO

(7) Reagents: i, SOzCIz-CH2CI2,-30 "C;ii, 25 "C,- HCI; iii, Et,O+ BF4-

Scheme 3

Irradiation of thiazepine (7) gives the isomeric imine (8) which is thermodynamically unstable, returning to the starting compound (7) by a thermal shift (dark reaction) which is dependent upon concentration, solvent, and acid and base catalysis. The sequence (7) + (9) -+ (10) -+(8) is proposed hv

(7)

c,

dark

EtO

(8 in which a polar singlet excited state (9) is formed and undergoes a 1,3hydrogen shift to give the product (8) via the intermediate (10). This mechanism is supported by the observation that the N-deuteriated form (1l), when irradiated, gives a photo-product formulated as compound (12) which reverts thermally to a mixture of nearly equal amounts of starting compound (11) and the isomer (13). The sulphoxide and sulphone derived from the thiazepine (7) show similar behaviour, as does the amide (6), which is transformed reversibly into the isomer (14). M. F. Semmelhack and B. F. Gilman, Chem. Comm., 1971, 988.

788


2 Benzothiazepines Application of the Schmidt reaction to a series of l-thiochroman-4-ones (15) gives benzo-l,4- (16) or benzo-l,5-thiazepines (17), depending on the nature of the substituents in the benzene ring (Scheme 4).4 Oxidation with hydrogen peroxide affords the corresponding sulphones (18) and (19). Ring expansion of the 1-thiochroman4-one sulphones (20) yields benzo1,5-thiazepines (19) alone.

' K. Wunsch, K. Stahnke, and A. Ehlers, Chem. Ber., 1970, 103,2302.

789

Thiazepines and Thiadiazepines

0

N H

0

(20) Reagents: i, HN3-H2SOa,benzenc; ii, H,O,

Scheme 4

Sulphur extrusion occurs when 2-phenyl-4-methylthiobenzo[b]-l,4thiazepine (21) is refluxed in propan-2-01 containing morpholine.s Formation of the product (23) is accounted for by the sequence (21) --f (22) --f (23) in which the postulated valence isomer (22) suffers cheletropic elimination of sulphur. The thioamide (24) similarly gives the quinolinethione (25). The 2,3-dihydrothiazepine (26), however, rearranges to 2-styrylbenzothiazole (28) via a suggested intermediate (27). Acid-catalysed rearrangement of 2,7-diphenyl-hexahydo-l,4-thiazepin-5-one (29) gave 5-phenyl-2styryl-4,5-dihydrothiazole (30), for which the alternative sequences in ti

M. Wilhelm and P. Schmidt, Helv. Chim.Acta, 1970, 53, 1697.

790


SMe

Scheme 5 are suggested. Benzothiazepine derivatives (33) and (34) result when the acids (3 1) are cyclized with dicyclohexylcarbodi-imide or the nitriles (32) with ethanolic hydrogen chloride. A series of 5-dialkylaminoethyl-benzo-l,5-thiazepin-4-ones (36) has been obtained by reaction of the known benzo-1,5-thiazepin-4-ones(35) with dialkylaminoethyl chlorides and sodium hydride in dioxan or, better, DMSO. The acetoxy-compounds (37) are converted by standard procedures into benzo-1,5-thiazepine derivatives such as (38) and (39). J. B. Carr, J. Heterocyclic Chem., 1971, 8, 511.


79 1

Phf.-ph N

(30) Scheme 5

(31) R = COOH (32) R = CN

(34) X = H, 7-CI, or 8-C1

(33)


792

(37)

(40) (41)

X X

=

NO,: (EtO),P-cumene, boil

= N3:Decalin, 150-160 "C

N Et

I

I

O=P-OEt \ OEt

a;&

&/

(44) Me Scheme 6

H (43)

Thiazep ines and Thiadiazepines

793

3 Dibenzothiazepines Full details have appeared of the behaviour, inter aka, of 2,6-disubstituted aryl2-nitrophenyl sulphides with triethyl phosphite and of 2,6-disubstituted aryl2-azidophenyl sulphides on thermolysis, following preliminary reports (see Volume 1, p. 470). In both cases the reaction involves a novel heteroaromatic rearrangement that is interpreted in terms of the intervention of nitrene intermediates. The process is exemplified by the behaviour of 2-nitrophenyl 2,6-dimethylphenyl sulphide (40) and 2-azidophenyl 2,6dimethylphenyl sulphide (41)(Scheme 6). The sigmatropic rearrangement of the postulated intermediate (42), which is necessary to produce the [b,e]azepine (44), is not allowed in the suprafacial sense: hence the intervention of a biradical species (43)is considered to be more likely. N-Formylanilines (45)-(47) when heated in polyphosphoric acid give dibenzo[b,f]-1,4-thiazepines (48)-(50) in a Bischler-Napieralski-type

kHO (45)

R1 = R2 = H

(46) R1 = R2 = OMe (47) R1 = Me, R2 = H

(48)

R1 = R2 = H

(49) R1 = R2 = OMe

(50) R1 = Mc,R2 = H

synthesis.1° Heating the sulphide (51; X = S) or its sulphoxide (51; X = SO) at 220 "C gives the dibenzothiazepinone (52; X = S) or its sulphoxide (52; X = SO), respectively. Reduction (LiAIH4)of the dibenzothiazepines (48)-(50) produces the corresponding dihydro-derivatives (53), one of which (53; R1 = R2 = H) is also obtained by reduction of compound (52; X = S ) with LiAlH4. Diastereoisomeric sulphoxides, formulated on spectroscopic grounds as (55a) and (55b), are obtained in proportions depending on the reaction conditions by oxidation (H202,CF3C03H,or HJO,) of the sulphide (54).11

lo

l1

H. Kugita, H. Inoue, M. Ikezaki, M. Konda, and S . Takeo, Chem. and Pharm. Bull. (Japan), 1971, 19, 595. J. I. G. Cadogan and S . Kulik, J. Chem. SOC.( C ) , 1971,2621. J. I. G. Cadogan and S . Kulik, Chem. Comm., 1970,233, 792. P. Catsoulacos, J. Heterocyclic Chem., 1970, 7 , 409. A. Hamon, B. Lacoume, and J. Olivie, Bull. SOC.chim. France, 1971, 1472.

794


T Me

HOHN

x

NHOH

(57) =s (58) X = SO

I

0

(59)

x=s

(60) X = SO

(61) X = S (62) X = SO

0 II

q:*D

(63) X = S (64) X = SO


795

4 Thiadiazepines 2,2’-Thiobispropiophenonecondenses with hydrazine to give a mixture of isomeric dihydro-l,4,5-thiadiazepines(56a) and (56b).12 Cyclization of the sulphide (57) or its sulphoxide ( 5 8 ) with polyphosphoric acid gives the oxide (59) or the dioxide (60), respectively, which are reduced (ZnMeC0,H) to the dihydro-derivatives (61) and (62).13 Oxidation with ferric chloride affords dibenzo[b,f][l,4,5]thiadiazepine (63)or its sulphoxide (64), the former undergoing subsequent oxidation with perbenzoic acid to give a mixture of the sulphoxide (65), the dioxide (60), and, with accompanying sulphur extrusion, the benzocinnoline oxide (66). There is evidence that dethionylation leading to compound (66) occurs via the sulphoxide (65) and not via the dioxide (60). In further studiesl4 of the dibenzo[b,f][l,4,5]thiadiazepine system the same authors found that nitration (HN03-H2SOI) of the sulphone (67) affords a mixture of the

c?

0

R NH (72) la l8

l4

I. Sataty, J. Heterocyclic Chem., 1970, 7 , 431. H. H. Szmant and Y. L. Chow,J. Org. Chem., 1971,36,2887. H. H. Szmant and Y. L. Chow, J . Org. Chem., 1971,36,2889.

NH

(73)

796


mononitro- (68) and the dinitro-derivatives (69). Cyclization of the thiol (70) by brief treatment with sodium ethoxide in ethanol gives the thiadiazepine (7 1) which, under prolonged treatment, suffers rearrangement to the benzothiazine (72) or (73).15 l6

T. George and R.Tahilramani, J. Org. Chern., 1971, 36, 2190.

ERRATA Vol. 1, 1970

Page 315. Formula (33) should have appeared as:

Page 469. Formula (85) should have appeared as :

Author Index Abad, A,, 83 Abbasi, M., 594 Abbott, D. J., 50 Abd-El-Halim, M., 242 Abdel-Wahhab, S. M. 406 Abdulvaleeva, F. A., 37 Abe, M., 427 Abe, Y., 90, 93,99 Abegaz B., 100,215 Aberli; M. E., 86 Abou-State, A., 705 Abrahamson, S., 127, 141 Abramenko, P. I., 433,473, 475,478,480,487,493

Abramovitch, R. A., 2, 89, 133

Abrazhevich, A. I., 375, 376

Acheson, R. M., 417, 452, 542

Achmatovicz, S., 258 Ackermann, K., 298 Acton, E. M., 19 Adam, W., 34,171,243 Adams, A., 564 Adams, J., 289 Adams, J. Q., 19 Adams, T.B., 190 Adamson, J., 695 Addor, R. W., 130,266 Adhikary, P., 406 Adickes, H. W., 385 Adman, E., 760, 764 Advani, B. G., 230, 240, 354

Adylov, A,, 677 Afans'eva, Yu. A., 361 Agarwal, N. S.,632 Agarwala, U., 238 Agawa, T., 329, 752 Agenas, L.-B., 181 Ager, E., 69 Ahmed, M., 202, 415, 514, 532, 543

Ahmed, R., 205 Ahn, M.-K., 209 Ahrens, K. H., 234 Aida, T., 16, 92, 159, 326, 327

Ainsworth, C., 746 Aitken, G. B., 281 Ajayi, S. O., 245 Akabori, S., 179 Akaboshi. S.. 236, 619 Akahori, Y.,.754 . Akaiwa, H., 427 Akano, M., 185, 250, 511, 530. 762

Akazawa,T., 130,252, 306

Akerblom, E., 632 Akerfeldt, S., 680 Akerkar, A. S., 584, 602 Akermark B., 199 Akerstrod, S., 267 Akhmedzade, D. A., 405 Akiba, K., 179 Aksanova, L. A., 544 Alaimo, R. J., 425, 659 A1 Aref, A. T., 486, 721 Albert, A., 17 Albert, R., 143 Albitskaya, V. M., 10 Albrecht, W. A., 5 Albriktsen, P., 188 Aiderweireldt, F., 598 Alekseev, N. N., 491 Alekseeva, L. A., 20 Alekseeva, L. Y., 427 Alexander, J. J., 77 Ali, M. I., 236, 705 Ali, M. Y., 252 Aljeva,.S. A., 659, 660 Alimann, D. P., 678 Allam, M. A., 486, 721 Allegra, G., 143 Allen, D. W., 179, 404, 405

Allen, G. R.,75 Allenmark, S., 9, 40 Allingham, Y., 186 Almog, J., 316 Almqvist, S.-O., 172 Alper, A. E., 705 Alper, H:, 212, 705 A1 perovich, M. A., 487 Al-Radhi, A. K., 83 Alterdinger, M., 239 Ames, D. E., 784 Amiel, Y., 58 Amin, S. G., 484 Amirthalingam, V.,279 Ainma, E. L., 279 Ammon, H. L., 105 Amosova, S. V., 31 Anantanarayanan, K. G., 736.

Anastassiou, A. G., 102, 104, 547

Andersen, K. K., 1,41,46, 135

Anderson, E., 31 Anderson, J. E., 175, 178, 365

Ando, K., 94 Ando, W., 21,23,293, 322 Andolsek, A., 633 Andose, J. D., 417 Andree, H., 234

799

Andreev, L. P., 201 Andreeva, G. V., 678 Andrews, G. C., 36 Andrews, S. L., 764 Andrieu, C., 281, 364, 374, 507

Andrieu, C. G., 442 Andrisano, R., 15 Angeloni, A. S., 61 Angier, B., 739 Anisimova, V. Z., 369 Anonimova. I. V.. 188 Anteunis, M., 113, 1GO, 173, 186

Anthoni, U., 264, 272, 733 Antoine, B., 364 Antoine, .M., 244, 275 Antonakis. K.. 53 Antonova.' A,.' 659 Ao, M. S.; 132 Aoki,, O., 752 Aoyama, H., 177,220, 527 Aoyama, T., 780 Appel, R., 328, 330, 334, 335

Appriou, P., 253, 357, 401, 512

ApSimon, J. W., 173 Arabori, H., 90 Arai, K.,177 Araki, Y.,255, 268 Arbuzov, B. A., 188 Archer, R. A., 37 Ardakani, A. A., 93 Arens, J. F., 1 Arhart R. J., 23 Arison: B. H., 270, 645 Armanino, V., 384 Armbruster, R., 266, 724 Armitage, D. A., 67, 68, 91

Armstrong, C., 43 Armstrong, K. J., 443 Arnaud, R., 595 Amaudova, I., 599 Arndt, F., 729 Arnosova, S. V., 26 Arora, S. K., 279 Aroyan, A. A., 594 Artemov, V. N., 236, 271, 643, 648

Arutyunyan, E. A., 231 Arya, V. P., 356, 483 Aryutkma, N. L., 632 Asaba, H., 762 Asai, Y., 237 Asano, T.,430 Asato G 742 AsbriAk, L., 363

800

Author Index

Ash, D. K., 91,93,95,99,

Balz, G., 601 Bambas, L. L., 576 Bambury, R. E., 425 Ban, Y., 149,169,254 Banci, F., 633 Bandoli, G., 552 Banerjee, S., 271,650,748 Banks, C. V., 427 Bannykh, I. V., 237 Banu, E., 594,743 Baranov, S. M.,271 Baranov, S. N.,236,436,

161

Ashbrook, C. W., 427 Ashby, J., 177, 206, 415,

440.442.445.543. 576 Asinger, F:, 103,234,587, 637,638,770 Asker, W.. 538. 706 Aso, C., 422 . Aspila, K. I., 267,268 Asquith, R. S., 252 Asunskis, J. P. 311 Atamenko. M.V.. 678 Atavin. A: S.. 26: 31. 32, 269 . Atkin, C. W., 746 Atkins, G. M.,336 Atkins, P. R., 59 Atkinson. J. R.. 535.537 Atkinson; R. E:, 385,412 Atsushi, T., 285 Attland, H. W., 190 Au, K., 31 Au, A. T., 271 Auerbach, R. A., 37 Augstein, W., 710 Aures, D., 613 Aurivillius, B., 490 Austin, W. C., 423,424 Autrup, H., 354 Avramenko, L. F., 674 Avramenko, N.G., 579 Ayad, M., 440 Ayrey, G., 9 Azogu, C. I., 89 _

,

_

Baarschers, W. H., 168 Babadjamian, A., 269,593,

619. 630

S., 6 654, 680, Babichev, F. S.. 54. 6 80.

681,713,7 16 716.

.

Babson, R. D., 266,671 Babuyeva, T. M.,593 Bach, E., 238 Bachmann. W. E.. 742 Back, T.G., 67,91 Bacon, C. C., 36,79, 119,

149,152,329

Badcock, C. C., 133 Bagal, L. I., 742 Bananz. H.. 561 Baaey, 'A. S., 89 Bailey, D. S., 150,159,325 Baker, J. A., 694 Baker, J. T.,17 Baker. R..395 Balashova, T. A., 491 Balasubramanian, K. K.,

408

Baldwin, J. E., 16,29,58,

65, 96, 251, 294, 295, 709,710

Baldwin, J. F., 105 Baldwin, M. A., 285 Balkau, F., 442 Ball, D. H., 141 Ballentine, J. A., 414 Balquist, J. M.,116,119 Balucani, D., 429,543 Balyan, K. V., 27

491,642,643,644,648

,

Baranova, N.A., 242 Barbarella, G., 116, 144,

291

Barbaro, A. M., 427 Barber, W., 264 Barbieri, R.,678 Barkalaya, E.V., 754 Barkemeyer, H., 270,645 Barker, J. M., 407 Barkhash, V. A., 248 Barlin, G. B., 275 Barmina, V. V., 271,649 Barnes, A. N.M., 746 Barnes, C. S., 737 Barnett, G. H., 212 Barney, G. S., 304 Barni, E., 711 Barnikow, G., 252 Barnish, I. T., 474 Barnum, H. W., 90 Baron, H., 557 Barrett, G. C., 233, 604,

624,625

Barringer, W. C., 736 Barroeta, N., 75 Barron, R., 508 Bartalits, L., 625,761 Bartho, B., 515 Bartle, K. D., 442,470 Barton, D. H. R., 8, 17, 65,66,83,100, 165,168,

191,192, 193,210,258, 764

Barton, T. J., 26,104,111,

155,463 Bartsch, R. A., 665 Baskakov, Y. A., 632 Bastian. J. M..469.470 Battaglla, A., 216,217,320 Battaglia, J. R., 594 Battjsti, A., 142,528 Battistoni, C., 267 Batz, H. G., 648 Bau. Y..87 Baudet,-P., 663 Bauer, L., 22 Bauer, S. H., 363 Bauer, V. J., 426 Baues. M.. 526 Bauman, R. A., 283 Baumann, M., 746 Baumann, M.F., 143 Bauscher, L. P., 610,611 Bayer, E., 207 Bayer, M.,243 Bazavova, I. M., 246,657,

729

Beak, P., 15 102 214 Beard, R.DI, 61,'313 Beatson, R. P., 78, 118,

227,317

Beauregard, Y., 12 Bebesel, E., 744 Bechgaard, K., 517 Beck, A. K., 34,253 Beck, B. R., 14 Beck, C. W.. 626 Beck, J., 336 Becke-Goehring, M., 247 Becker, C. H., 745 Becker. G.. 60.317 Becker; R.'F.,'233,283 Bednyagina, N.P., 659 Beer, R. J. S., 232, 502,

509,510

Begtrup, M., 8 Behera, G. B., 608 Behforouz, M., 93 Behringer, H., 291, 499,

503

Beierbeck, H., 173 Beilan, H. S., 323 Beilin, V. G., 242,269 Beiner, J.-M., 251 Beishekeev, Z., 780 Belen'kii, L. I., 372, 374,

375,376,383,384

Beletskaya, V. I., 428 Belinskaya, R. V., 579 Bell, A. P., 77 Belletire, J. L.,168 Bellinger, N., 537 BtSlovskY, O., 407 Beltrame, P., 337 Belyaev, V. F., 375,376 Benati, L., 382,383,447 Benedetti, E., 143,752 Benschop, H. P., 576 Bentley, K. W., 63 Bentley, M.D., 68,98 Bentley, R.K., 81 Bentley, T. W., 285 Bentz, F., 337,603,743 Berchtold, G. A., 143,293 Berdinski, I. S., 426 Bergeou, M.-T., 518 Berger, A., 42 Bergman, J., 141 Bergmann, E. D., 64 Bergmann, F., 231,283 Beriel, H., 593 Berkelhammer, G., 736,

742

Bernal, I., 179 Bernardi, G. C., 133 Bernat, J., 266 Bernet, C.-R., 190 Berrany, B., 33 Berry, R. O., 563 Berse, C., 10 Bertani, M., 759 Bertin, D. M., 364 Bertini, D., 206 Bertini, F., 670 Bertini, V., 752 Berzina,I. M., 238 Beskina, I. G., 677

Author Index Bessarabova, 1. M., 286 Bessin, P., 602 Bettelli, M., 429 Beutler, R., 236 Beveridge, S., 17 Beverly, G . M., 71 Bexell, G., 593 Beyer, H., 588, 594 Beyer, L., 204, 279 Bhaduri, A. P., 236 Bhagwat, V. S., 609 Bhargava, P. N., 633 Bhattacharjee, M. K., 455 Bhereur, M., 12 Biagi, G. L., 427 Bialecka, E., 25 Bialy, G., 453 Biba, A. D., 69 Bichan, D., 164 Bickel, H., 198, 199 Bickelhaupt, F., 18 Biddles, I., 19 Bidman, T. A., 428 Biedermann, H. G., 678 Bielich, F., 729 Biellmann, J. F., 28, 527 Bieniek, D., 149 Bierbusse, H., 239 Biezais-Zirnis, A., 542 Biffar, B., 230 Biffin, M. E. C., 57 Bignebat, J., 502 Billiau, F., 246 Billman, F. L., 136 Binder, U., 743 Binenfeld, Z., 93 Birch, A., 470 Birch A. J., 50 Bisseh, F. H., 178 Bitter, I., 483 Bittner, S., 149 Black. D. St. C.,. 111,. 179, 228. Black, L. L., 558 Black, W. B., 743 Blackbourn, G. P., 190 Blackburn. E. V.. 460 Blackman; A. J., -80 Bladen, P., 756 Blaga, A., 240, 594 Blagoveshchenskii, V. S., 141, 187, 526 Blanc-Guenee, J., 313 Blankenstein, G., 603, 743 Blankespoor, R. L., 53 Blanton, C. D., 536 Bleisch, S., 286 BIezard, M., 43 Blickens, D. A., 426 Blinova, L. S., 237 Blinova, V. G., 279 Bloch A., 141 Block: E., 2, 97, 98, 288 Block, H. D., 4, 9 Blume, W. J., 668 Bobek, M., 141 Boberg, F., 241, 514 Bocher S., 84 Bohme’ H 61, 230, 234, 240, ?40,”588, 639, 766

27

801 Boekelheide, V., 179, 294, 787

Boeiens, H., 96, 358 Boler, J., 411 Boshagen, H., 579, 580, 765 Bogacheva, L. V., 495 Bogatskii, A. V., 111 Bogdanov, V. S., 26, 275, 369, 399, 428 Bogdanowicz, M. J., 115, 289 Bogeso, K. P., 780 Boggs, L. E., 769 Boggs, L. M., 769 Bognar, R.,.588, 635, 656 Bogoslowskii, N. W., 428 Bohen, J. M., 180 Bohlmann, F., 423 Boicelli, C. A,, 369 Boiko, S. A., 88 Boissicr, J. R., 612 Bokadia, M. M., 240 Boldyrev, B. G., 99 Bolman, P. S. H., 104, 142 Bolourtschi, A., 541 Bolshakova, N. S., 594 Bolte, J., 82 Bonamico, M., 279 Bonati F., 678 Bond, M., 286 Bondar, E. N., 376, 428 Bonhomme, M., 232, 480, 48 1. Bonnier, J. M., 595 Bonola, G., 759 Booms, R. E., 47 Borch, G., 282 Bordas, B., 251 Bordwell, F. G., 60, 107 Borisevich, A. N., 229 Borisov, S. I., 405, 428 Borisova, L. N., 544 Borisova, M. A., 650 Borka, L., 699 Bormann, G., 688 Bornstein, J,, 87 Borsdorf, R., 551, 553 Bortnikov, G.N., 369 Borum, 0. H., 556 Bory, S., 156, 314 Bos, H. J. T., 7, 113, 219, 355, 410, 539 Bos, J., 386 BOSCO,R., 678 Bose, A. K., 199, 588 Bose, R. J., 249 Bosscher, J. K., 15, 98 Bossert, F., 537 Bosshard, H., 23, 143 Bosworth, N., 5 5 Boucasse, L., 565 Boucherle, A,, 593 Boudet, R., 765 Bouguerra, M. L., 284 Bouin, D., 595, 599 Bould, L., 83 Bourdais J 544 Bourdon: J.: 243 Bourgoin-Legay, D., 765

A.

Bourguignon, J., 394 Bouquet, F. P., 282 Boussard, G., 94 Boustany, K., 10, 91 Boustany, K. S., 67 Bovey, F. A., 186, 283 Bower, J. D., 434, 665 Bowhuis, E., 412 BOWIC,5. H., 173, 371 Boyd, D. B., 288 Boyd, G. V., 233, 734 Bozic, J., 427 Brabander, H. J., 435 Bradamante, S., 86, 117, 315, 360, 529, 530 Bradshaw, J. S., 14,51, 133 Brady, W. T., 642 Brain, E. G., 22, 54 Brand, W. W., 64 Brandsma, L., 1, 27, 96, 200, 201, 355, 358, 410, 543 Brasen, W. R., 326 Brasington, R. D., 9 Braslavsky, S., 142 Braun, M., 33 Braun, R., 240, 588,751 Braunschweig, H., 204 Braunton, P. N., 179 Braverman, S., 1 Bravo, P., 52, 262, 296, 298, 313, 437 Braye, E. H., 403 Bredereck, H.,234 Bree, A., 442 Brelivet, J., 253, 357, 401, 512 Bremner, J. B., 764 Breslow, R., 610, 611 Bressel, U., 537 Brewster, K., 160 Bridgart, G. J., 74, 266 Briggs, P. R., 661 Brimacombc, J. S.,83 Brink, M., 18, 183 Brinkhoff, H. C., 267, 278 Broadhurst, M. J., 75, 415, 416 Brodbeck, U., 53 Brody, G., 659 Broens, J. B., 225 Brois, S. J., 90 Bromley, D., 373 Brook, A. J. W., 83 Broom, A. D., 205 Brophy, G. C., 443 Brown, B. R., 89 Brown, C., 1 Brown, D., 267 Brown, D. J., 80 Brown, E. I. G., 205, 501 516, 534 Brown, E. V., 454 Brown, I., 443 Brown, G. R., 231, 688 Brown, H. C., 17, 71 Brown, J. E., 58 Brown, M. D., 138, 156 Brown, M. S., 42 Brown, N. M. D., 443,756

Author Index Brown, P. M., 35 Bruning, K., 619 Bruggink, A., 61 Brunetti, H., 243 Brunfeldt, K., 35 Brunn, E., 413 Brush, C. K., 79 Brutane, D., 236 Brutovska, A., 263 Bryukhova, E. V.,69 Bryzzheva, T. L., 248 Brzozowski, Z., 245 Buben, N. Ya, 384 Bubenko, R. G., 246 Bubnovskaya, V. N., 716 Buchanan, D. N., 160 Buchanan, G. W., 188 Buchi, G., 147 Buchshriber, J. M., 202, 514, 532 Buddhasukh, D., 419 Budylin, V. A., 449 Budzikiewicz. H.. 579. 745 Buchler, R., 222 ' ' Bugg, C. E., 279 Bugge, A., 403, 430, 432, 495 Buggle, K., 537 Buhler, R., 166 Buisson, J.-P., 478 Bulavin, L. G., 103 Bulka, E., 271 Bullock, C., 83 Bulman, M. J., 368 Bundegaerd, H., 197 Buniatyan, Yu. A., 242 Bunton, C. A., 86 Burakevich, J. V., 177, 229 Buratti, W., 670 Burckhalter, J. H., 209 Burdon, J., 7, 141, 175, 187, 368, 383, 388, 390 Burgess, E. M., 132, 336 Burighel, A., 84, 111 Burkhardt, J., 237 Burmistrov, S. I., 597, 671 Burov, A. I., 369 Burpitt, R. D., 131, 187 Bursey, M. M., 285, 370 Bursics, L., 236 Burton, H. R., 536 Busch, D. H., 179 Busch, M., 745 Busetti, V., 328 Busev, A. I., 609, 610 Bushweller, C. H., 135, 178, 179 Busse, K. D., 213 Busse, W.-D., 519 Butalina, R. Kh., 427 Buter, J., 102, 222, 363 Butler, A. R., 371, 372, 395, 396 Butler, R. N., 665 Buttimore, D., 573 Buttkus, H., 249 Buu-Hoi, N. P., 418, 441, 443, 478, 492, 496, 544, 713,784 Buyanov, V. N., 634

Buys, H. R., 173 Buza, D., 522 Buzas, A., 655 Bycroft, B. W., 17, 212 Byers, G. W., 94 Byron, D. J., 407 Cabiddu, S., 23 Cadogan, J. I. G., 780,793 Cagniant, D., 375, 376, 378, 379, 381, 446, 447, 494, 537, 543 Cagniant, P., 364, 375, 376, 378, 379, 381, 446, 447, 459, 493, 494, 495, 537, 543 Caillaud, G., 232, 507, 516 Cain, E. N., 760 Callaghan, P. D., 232 Calligaris, M., 243 Calvert, J. G., 133 Camaggi, C. M., 382,447 Cameron, A. F., 324, 617, 760 Campaigne, E., 358, 439, 442, 445, 453, 471, 511, 536 Campbell, D. S., 677 Campbell, E. C., 695 Campbell, J. B., 535 Campbell, J. D., 99 Campbell, J. G., 141, 368, 390 Campbell, M. J. M., 678 Campbell, M. M., 177,217 Canalini, G., 540 Canfield, N. D., 34, 164, 262, 524 Cannon, J. R., 419 Canonne, P., 662 Cantrell, T. S., 394 Capell, L. T., 653 Capozzi, G., 84, 85, 111 Cappozzi, G., 437 Capuano, L., 238, 483, 541, 685 Carboni, S., 206 Card, D. W., 678 Carey, F. A., 168 Carey, M. A., 427 Carlson, K. D., 103 Carney, J. F., 743 Carney, R. W. J., 230 Caronna, T., 671 Carpanelli, C., 41 Carpenter, J., 14 Carpenter, J. M., 64 Carpino, L. A,, 108 Carr, A., 756 Carr, J. B., 790 Carraz, G., 593 Carrington, D. E. L., 73, 582,583 Carroll, F. I., 242, 247 Carroll, J. T., 240, 618 Carson, C. G., 209 Carson, J. F., 769 Cartwright, D., 232, 502 Casadevall, A., 81 Casagrande, C., 780

Casalone, G., 177 Casanova, J., 296 Casaux, L., 188, 189 Caserio, M. C., 26, 94, 210, 291 Casini, G., 577 Cassidy, F., 54 Castenet, J., 10 Castle, R. N., 209, 756 Cato, V., 35 Caton, M. P. L., 254, 569, 571 Catsoulacos, P., 542, 659, 760, 793 Catteau, J. P., 111, 567 Caullet, C., 407, 455 Cauquis, G., 203 Cava, M. P., 433, 439 Cavadia, E., 234 Cavalieri d'Oro, P., 369 Cavazza, M., 75 Cavins, J. F., 13 Ceccarelli, G., 9 Cederlund, B., 397 Cefalu, R., 678 Cerfontain, H., 1, 81 Cermakova, L 41 Cervinka, O., 207 Chadha, V. K., 704 Chadwick, D. J., 364 Chakrabarti, C. L., 267 268 Chakrabarti, P. M., 358, 445 Chakraborty, A., 650, 748 Chakraborty, A. C., 271 Chalapathi, V. V., 201 Chalvet, O., 442 Chamberlain, K. B., 50 Chamberlain, P., 54 Chambers, J., 364 Chambers, J. Q., 34, 164, 262, 524 Chambers, R. D., 441 Chan, A. S. K., 212 Chan, A. W. K., 128, 566, 572, 575, 586 Chan, T.-H., 92 Chande, M. S., 243, 265 Chandra, D., 780 Chang, C. T., 780 Chang, F.-H., 231 Chang Kakati, D. K., 427 Chanon, M., 266,269,271, 593, 619, 630 Chao, B. Y.-H., 102, 104, 'id7

Ciapius, J., 298 Chapman, N. B., 431,445, 453, 478, 486 Chanman. N. P.. 358 Chapman; 0.L.; 122,233, 748 Chapmann, N. B., 216 Chapmans, N. B., 429 Chappaz, R., 12 Chasar, D. W., 41, 542 Chatfield, P. V., 694 Chattopadhyay, S. S., 270 Chaturvedi, M., 237 Chaudhary, H.S., 704

Author Index Chaudhury, D. N., 238, 709 Chaurasia, M. R., 633 Chauvette, R. R., 194 Chen, C.-T., 51 Chen, F., 112, 158 Chen, H.-W., 108 Chen, J.-Y., 508 Chen, T. H., 182 Cheney, L. C., 270, 453 Chepurnenkova, T. P., 532 Cherkasov, L. N., 27 Cherkesova, L. V., 428 Chernov, V. A., 778 Chernyshev, E. A., 369 Chetverikov, B. N., 237 Chew-g, K. K., 378 Cheutin. A.. 478 Chia-Chen, 'C., 656 Chiellini, E., 9 Childress, S. J., 694 Chippendale, K. E., 473 Chizhevskava. I. I.. 644 Chizhov, 0:S., 365, 371 Chkeidze, I. I., 383, 384 Choi, S. C., 65, 105 Cholerton, T. J., 460 Choubey, V. N., 243, 633 Chou-Chin, 753 Chouteau, J., 565, 660 Chow, Y. L., 795 Christensen, A. T., 289 Christensen, B. G., 164, 251, 427 Christensen, B. W., 46 C%!;lsctensen, L. W., 83, 87, J1J

Christiaens, L., 386, 435, 492, 493, 541 Christiansen, H., 368 Christophersen, C., 249, 259. 266 Christy, M. F., 116 Chu, C., 357,438 Chu, S.-H., 148, 255, 286 Chuang, C. R., 668 Chuiguk, V. A., 655, 688 Chun, M. C., 231, 617 Chupp, J. P., 230,231,240, 358 Churkin, Yu. D., 405, 428 Churn. M. C., 89 Chursina, V. M., 404 Chzi-Chzhun, C., 654 Ciminale. F.. 35 Cimino, G., '772 Cinquini, M., 38, 42 Ciuffarin, E., 67, 70, 86,97 Claes, P., 196 Clardy, J., 25, 144, 463 Clark, A. D., 271,625,683 Clark, D. T., 362,499 Clark, G. L., 656 Clark, J., 239, 285 Clark, M. J., 67, 68, 91 Clark. W. G.. 613 Clarke, G. M.,565 Clarke, K., 73, 358, 445, 453, 458, 459, 477, 478, 486, 582, 583

803 Clarke, P. L., 92 Clarkson, R., 732 Claus, P., 15, 51, 323, 325, 327 Clayton, J. P., 16, 195, 197 Cleary, J, C., 343 Clementi, D. A., 552 Clementi, S., 20, 372, 373, 442 Clesse, F., 207, 217, 407, 518 Cleveland, J. P., 97 Clezy, P. S., 72, 416 Clive, D. L. J., 83, 168, 256 Closier, M. D., 632, 736 Closson, W. D., 83 Coakley, M. P., 427 Coburn, R. A., 596 Cocanour, P. M., 71 Coe, P. L., 7 Coen, S., 518 Coffen, D. L., 2, 34, 164, 168, 172, 251, 262, 524 Cohen, A. I., 612 Cohen, S. G., 20 Coleman, R. A., 275 Collin, P. J., 449 Collins, N. C., 337 Colonna. M.. 777 Colonna; S.,. 38, 42, 46, 50, 329 Colter, A. K., 59 Comanita, E., 244 Combrisson, S., 365 Combs. G.. 238 Comer: F..' 191 Commeyras, A., 81 Condon, F. E., 633 Condorelli, P., 776, 777 Confer, A. H.,67 Congiu, L., 75 Connor, D., 52, 230, 313 Connor, J. A,, 413 Conover, L. H., 424 Constantine, M. F., 54 Conte, M., 266 Cook, A. H., 628 Cook. M. J.. 138. 156 Cook: R. E.: 159: 324 Cooper, C. M.,17,65, 191, 192, 193 Cooper, J., 443, 444,445 Cooper, M. K., 212 Cooper, R. D. G., 37, 65, 192, 193, 194, 195, 764 Cooper, W. F., 523 Coppens, P., 523 C O : ~ ,E. J., 21, 29, 169, L11

Corfield, P. W. R., 60. 107 Cormons, A., 595Corner, F., 65 Cornwell, R. L., 423 Corrao, A., 384 Correa. A.. 284 Corsi, N., '144 Corson, F. P., 87 Cossais, F., 655 Costa, G., 662

Costakis, E.,662 Costin, R., 426 Cottam, J., 535 Cotterill, W. D., 535, 537 Cottrell, P. T., 77 Coulibaly, O., 507 Coulombe, R., 10, 187 Coulson, C. J., 88 Couquelet, J., 407, 668 Coutts, I. G.C., 419 Coutts, R. S. P., 260, 267 Coutts, R. T., 777, 778 Couture, A,, 393 Coufurier, R., 216, 511 Coviallo, D. A., 173 Cox, M., 201 Coxon, 5. M., 190 Crabb. T. A.. 186 Cragg,' R. H.;17, 31 Craig, W. G., 173 Cram, D. J., 47, 48, 132, 331. 347 Cram& F., 39 Crampton, M. R., 7 Crank, G., 633 Creasey, S. E., 86 Creasy, W. S., 190 Creese, M. W., 5 Crenshaw, R. R., 453,455, 563 Crescente, O., 394 Crescenzi, S., 772 Critchley, J. P., 392 Croisy, A,, 443, 543, 544, 713 Crombje, D. A., 470 Crombie. L.. 31 1 Crosby, J., 611, 612 Cross, B., 263 Crossland, R. K., 82 Crow, W. D., 128, 566, 572. 574. 575. 586 Crowther, 'A. F., 454 Crozet, M.-P., 138, 174 Csavassy, G., 594 Csizmadia, I. G., 88, 110, 175 Csizmadia, 1. Z., 2 Csonka-Horvai, J., 279 Csuros, Z., 483 Cugnon de Skvricourt, M., 232, 483, 484 Cunningham, L. W., 69 Curcumelli-Rodostamo, M., 631 Currie, B. L., 205 Curtis, R. F., 141, 378, 385 Curtis, V. A., 277 Cyvin, B. N., 363, 736 Cyvin, S. J., 363, 736 Czombos, J., 95 Daams, J., 755 Dabard, R., 463 Dabrowska, J., 205 Dabrowska, U., 205 Dlhler, G., 639 Dahl, B. M., 264, 276,282 Dahl, O., 239, 265 Dahlen, B., 141

Author Index Dahlgren, T., 489 Dahlqvist, K.-I., 490 Daicoviciu, C., 743 Dakin, H. D., 556 Dale, A. J., 291 Damanski, A., 93 Damon, E. K., 133 Dando, S. R., 734 Danehy, J. P., 1, 13, 141, 162 Daneke, J., 782 D’Angeli, F., 238 Dangyan, M. T., 242 Daniels, C. J., 194, 764 Daniels, C. M., 194 Danilewicz, J. C., 90 Danilina, N. E., 425 Danison, W. C., 328 Danks, L. J., 86, 227, 320 Danyushevskii, Ya. L., 425 Da Re, P., 759 Darken, J., 201 DaSettimo, A., 206 Dash, B. C., 238, 240, 266, 593,594, 631 Dashkevich, L. B., 242, 269. Daunis, J., 245, 246, 248, 275 Dautzenberg, J. M. A., 267 Daves, G. D., 652 Diivid, A., 279 Davidenko, T. I., 111 Davidovics, G., 565, 660 Davjdson, R. S., 7 Davidson, S., 505 Davies, A. G., 9 Davjes, D. I., 2, 24, 57 Davies, J. S., 311 Davies. R.. 18 Davies: R.‘A.. 123. 180 Davin-ePretelli; E., -681 Davis, D. R., 175 Davis, F. A., 67, 68, 69 Davis, G. W., 92 Davis, J. E., 160 Davis. M.. 62. 576. 577 Davis; R. ’E., ‘668 ’ Daxenbichler, M. E., 103 Day, J., 47, 331 Dayagi, S., 429 De, S. K., 280 Deaken, D. M., 226 Dean, F. M., 176, 250 Dean, L., 612 de Boer, Th. J., 151, 183, 362, 367 Deckers, F. H., 110 Deckers, F. H. M., 539 Decoret, C., 362 Decroix, B., 481 Defay, N., 598 De Filippo, D., 78, 645 Degani, I., 540 Degani, Y., 73, 74 de Gaudemaris, G., 658 Degen, P., 147 Deich, V. D., 236 Deinhammer, W., 464 de Jong, F., 370, 387

de Jongh, C., 744 Dekarz, B., 594 Delahunty, J. J., 537 De Leenheer, A., 209 Delepine, M., 740 Deliwala, C. V., 593, 736 Della Casa, C., 15 Dell’Erba, C., 7, 384, 385, 411,491 Del Re, G., 362 De Luca, G., 395 Demant, E. B., 18 De Marco, P. V., 37, 173 De Maria, P., 61, 63 De Mayo, P., 86, 113, 116, 181, 218, 219, 225, 226, 318 Dembech, P., 8 Dembecki, M., 238 Demchuk, 0. G., 236 Demerseman, P., 442, 478 Demetresco, C., 244 Demian, H., 739 De Milo, A. B., 240 Demin, P., 245 de Munno, A., 752 de Nardo, M., 243 Denes, A. S., 110 Denes, V. I., 670 Denis-Garez, C., 232 Denisova, T. V., 492 Denivelle, L., 266 Denkewalter, R. G., 270, 645 Denny, G. H., 266, 671 de Pessemier, F., 186 Depoorter, H., 668 Dereppe, J.-M., 365 Derissen, J. L., 363 Derkach, G. I., 69, 258 Derkach, N. Y.,88 de Roos, K. B., 755 Derrick, P. J., 363 Deryagina, E. N., 428 Deryckere, A., 232, 412, 476,477 Desai, R. B., 740, 748 Dessy, G., 279 de Stefano, S., 679, 772 de Stevens, G., 230 Desvoye, M.-L., 478 Deutsch, J., 231 Deutscher. R. L.. 427 Devi, N. G., 43 ’ Devon, T. J., 69 de Vries-Miedema, A. T., 189 de Waard, E. R., 110, 539 Dewan, C. K., 702 Dewar, M. J. S., 361, 544 Dewar, P. S., 35 Dewey, R. S., 270, 645 de Wit, J., 458 Dey, K., 245 Dhawale, S. W., 609 Diakiv, V., 416 Diamond, L., 238 DjBelIo, C., 238 Dice, J. R., 594 Dichmann, K., 164

Dickinson, R. P., 448 Diebel, K., 245 Diebert. C. E..~. 100. 166. 21 5 Diehl, P., 365 Dietschmann, H., 4, 207 D i p a l l , J. G., 217 Dijkirk, J., 311, 536 Dik. J. K.. 392 di Modica: G.. 659. 711 Dines, M..B., 136 . Dingwall, J. G., 4, 500, 531 Dinner, A., 439, 445, 453 Di Salvo, A. L., 87 Dittmer. D. C.. 106. 116. 119, 128, 134; 208Divald, S., 67 Divisia, B., 203 Divorne, C., 684, 688 Dmytraczenko, A., 83 Doane, W. M., 280 Doddi, G., 384 Dodson, R. M., 111, 114, 123, 160, 180, 210, 631 Doherty, D. G., 620 Dokoshi, N., 676 Doleschall, G., 749 Dolfini, J. E., 427 Dondoni, A., 216, 217, 320, 552 Donk, L., 7 Donnelly, D. J., 406 Donnelly, J. A., 406 Doomes, E., 60, 107 Doorenbos, N. J., 588 Dopper, J. H., 449, 450, I

_

‘

Ah2

Dorange, G., 250 Dore, G., 232, 480, 481 Dormidontov, Y. P., 428 Dorofeenko. G. N.. 428. 436, 488 Doroshenko, V. V., 258 Dorsey, E. D., 642 Dost, F., 307 Dou, H. J. M., 384, 564, 587, 597, 671 Doucet. J.. 5 1 Doughty, R. M., 761 Douglass, I. B., 1, 2, 68, ,

*

71. . - , 98 _ -

Douma, G. J., 433, 543 Dovlatyan, V. V., 269 Downer, R. N., 641 Downie, J. L., 328 Doyle, F. P., 665 Doyle, T. W., 183 Drabowicz, J., 39 Drager, M., 250, 258, 285 Draghici, C., 594, 743 Dragnet, C., 538 Draminski, M., 242 Dransch, G., 561 Drenth, W., 7 Dressler, M. L.. 476 Dressner, S. A.,. 190 Drewry, D. T., T.,-374 374 Driscoll, P. R., 438, 454 Dronkina. Dronkina, M. I.. I., 673 Dronov, V: V. I., -45 4511

Author Index Drozd, V. N., 64 Dryanska, V., 599 Dubcnko, R. G., 657, 721, 729 DUbosc, J.-P., 243 Dubs, P., 104, 234 Ducep, J. B., 28, 527 Duchamp, D. J., 47, 331 Duclos, J. M., 603 Dudykina, N. V., 535 Dueber, T. E., 84 Durbeck, H. W., 401 Duesberg, G., 243 Duffin, B., 324 Dufour, M., 478 Dufour, R., 493 Dugas, R., 249 Duguay, G., 207, 250, 413, 502,515 Duhamel, L., 174 Duhamel, P., 174 Dujmovits, H., 243 Duke, C. C., 17 Dulenko, L. V., 436, 488 Dulenko, V. I., 436, 488, 49 1 Du Manoir, J., 626 Duncan, J. A., 251, 709, 710 Duncan, J. L., 281 Dunina, V. V., 238 Dunwell, D. W., 688 Dupuy, C., 138, 174 Durand-Henchoz, S., 231 Durgaprasad, G., 281 Duro, F., 777, 784 Durst, T., 38, 42, 43, 48, 49, 133, 153, 155, 180, 181, 288, 314, 626 Duthey, S. D., 105 Dutra, G. A., 448 Duty, R. C., 541 DUUS,F., 149, 216 Dyachenko, S. A., 755 Dyadyusha, G. C., 675 Dykman, E., 98 Dyott, T. M., 190 Dyson, W. R., 231, 688 Dzerovicz, A., 437, 439, 463 Dzhemilev, U. M., 35 Dzhundubaev, D., 780 Eaborn, C., 395, 396, 449 Eachus, A. H., 270 Eakin. M. A.. 9

Ebel, M.,254, 255, 538, 767

Ebnother, A., 469, 470 Eck, D. L., 358, 535 Eck. H.. 32. 172 Eck; J., ‘279’ Eckau, H., 745 Eckelmann, U., 207 Eckroth, D. R., 233, 748

805 Edgerley, P. G., 746 Edman, P., 74 Edmonds, A. C. F., 39, 48 Edmonds, C. G., 170 Edmonds, J. W., 523 Edqvist, O., 363 Eeckhaut, Z., 287 Effenberger, F.,82 Efimovsky, O., 634 Efros, L. S., 756 Egan, R. S., 173 Egawa, Y.,231 Egger, H., 490 Eg ers, H. J., 652 Egfngton, A. J., 22 Egorochkin, A. N., 236, 369, 746 Egorova, V. S., 405 Ehlers, A., 535, 785, 788 Ehlers, D., 271 Ehrenstein, W., 526 Eibisch, H., 752 Eichenhofer, K. W., 335 Eidam, A., 618, 624 Eiden, F., 242, 631 Eiho, J., 309 Eisenberg, R.,279 Eisner, U., 148, 533, 545 Eitelman, S. J., 68 El-All. F. A.., 239.. 245., 628,‘ 629 El-Deen, M. M. N., 242 Elguero, J., 624 Ella, V. J., 13, 141, 162 Eliel, E. L., 166, 167, 170, 183 Ellestad, 0. H., 175 Ellis, J., 256 Elmaleh, D., 26, 495 Elmes, B. C., 53, 312 Elmore, N. F., 617, 760 Elnagdi, M. H., 239, 245, 538, 628, 629 Eloy, F., 232,412,476,477 El-Rayyes, N. R., 406 El-Saycd. A. A., 236 Elslager, E. F., 426,479,7 12 El’tsov, A. V., 234, 467, 468, 519 Elwood, T. A., 370 EmanuBl, N. M., 452 Emerson, D. W.; 169, 184 Emi, T., 133 Emmcrt, D. E., 266, 766 Endo, T., 72, 270 Engberts. J. B. F. N.. 61.’ 77, 78,’ 87, 183, 278 Engelhardt, G., 700 Engelhardt, P. R,,268 Engels-Henriksen, L., 265 Engler, R., 250 Enikeev. R. S.. 140 Eon, C.; 428 . Erickson, B. W., 21, 169 Erickson, W. F., 16, 295 Erickson. W. K.. 294 Ermakova, Z. I.; 780 Ermili, A., 360, 736 Ernstbrunner, E. E., 290, 339

Eschenmoser, A., 104, 234 Estcp, R. E., 43 Esterbauer, H., 11 Etlis, V. S., 264, 634 Evans, B. W., 190 Evans, D., 688 Evans, D. A., 36 Evans, E. L., 739 Evans, T. E., 87 Evans, Z., 91 Evers, R., 676 Evgenios, D. M., 177, 217 Ewing, D. F., 365, 445 Exner, O., 181, 286 Exner, S., 239 Faber, J. S., 386 Fabian, J., 362, 488, 517, 551

Fabian, K., 515, 517, 521 Fabrjchnyi, B. P., 381, 418 Fabrissin, S., 243 Fackler, I. P., 279, 285 Fderber, P., 231, 236 Fahmy, S. M., 538 Faitel’son, F. D., 440 Falch, E., 688 Falkcnberg, J., 503 Fal’ko, V. S., 451 Faller, P., 442 Falletti. L.. 659 123, 160, 761 Farkas, I., 588, 656 Farkas, M., 593 Farnum, D. G., 271 Farrington, A., 34 Fattorusso, E., 679, 772 FauchB, J., 550 Faust, J., 515 Fava, A., 70, 75, 97, 116, 144, 152, 291 Favre, H., 59 Fay, D. P., 427 Fayat, C., 642 Fechlig, B., 198, 230 Fedorov, B. P., 31, 388 Fedoseeva, V. N., 92 Fehlhaber, H., 554 Fehor, F., 93 Feichtinger, H., 578 Feijen, J., 402, 431 Feinstein, A., 449 Feldshtein, M. S., 677 Felton, D. G. I., 509 Feng, R. H. C., 18 Fenn, D. J., 190 Fenner, H., 778 Fenselau, A. H., 56 Fenwick, R. G., 414 Ferguson, G., 378 Ferranti, F., 78 Ferrier, R. J., 75 Ferrini, R., 780 Fessler, D. C., 9 Festal, D., 507

Author Index Fetchin, J. A., 285 Fetter, J., 236 Feutrill, G. I., 8 Feuz, J., 427 Fiandanese, V., 59 Fickentscher, K., 554 Field, L., 67, 69, 90, 91,

94, 98, 132, 135, 162, 265, 268, 288

Fields. E. K., 251,. 370,. 383-

Fieldsteel, A. H., 659 Fife, T. H., 31 Fikentscher, K., 440 Filira. F.. 238 FilleukBlanchard. M.-L., 518

Findlay, J. A., 603 Fini, A., 61, 63 Finley, J. H., 568 Firestone. R. A.. 427 Fjr1,- J., 286 . Firouzabadi, H., 93 Fischer, J. W., 764 Fischer, N. H., 107, 201, 288

Fischler. H. M.. 259 Fish, R.‘ H., 291 Fish, V. B., 617 Fisher, J. W., 193, 194 Fiszer, B., 242 Fitjer, L., 135 Fitton, A. O., 264, 710 Fitzgerald, P. H., 71, 110 Fleckenstein, E.,6 Fleming, I., 8 4 . Flesch, P., 772 Flippen, J. L., 148, 255 Flockhart, B. D., 77 Flohe. L.. 12 Flores, S.’ E., 394 Flowers, W. T., 72, 733 Fochi, R., 540 Fohlisch, B., 751 Foglia, T. A., 264, 636 Folkers, K., 652 Follweiler, J., 341, 533 Fong, C. W., 2, 77 Fong, W. C., 141 Fontana, A., 647 Fookes, C. J. R., 72 Foote, C. S., 35, 175 Forrester, A. R., 35 Forsgren, U., 411, 489 Fortea-Laguna, J., 483 Foster, A. W., 66 Foster, B. J., 194, 764 Foster, H. M., 438, 454 Foster, N. G., 370 Foster, W. H., 275 Foucaud, A., 642 Foulkes, D. M., 613 Fournari, P.,365,468,487 Fourneau, J. P., 634 Fournik-Zaluski, M. C.,

France, C. J., 535, 537 Frank, A., 243 Frankel, M., 149 Frankham, D. B., 176,250 Fransen, J., 186 Franz, J. E., 558 Franzen, V., 294 Fraser, R. R., 38, 94, 314 Freche, A., 141 Frederiksen, P. A. A., 272 Fredga, A., 91, 542 Freeman, B. H., 339 Freeman, J. P., 59, 111, 117, 122, 319

Freidlin. L. Kh.. 404 Freidlina, R. K.;630 Frejd, T., 387 Frensdorff, H. K., 135,179 Frese, E., 208, 516 Freund, M., 731 Fridinger, T. L., 164 Fridman, S. G., 714 Friedman, M., 13 Friedmann, A., 595, 599, 600

Friedrich, J., 451 Friedrich, K., 306 Frier, R. D., 256 Fries, D. C., 279 Friess, R., 251 Fringuelli, F., 396, 495 Fritzsche, B., 79 Frohlich, J., 607 Frolov, A. N., 742 Fronza, G., 296 Froyen, P., 291 Frucht, M., 283 Frydman, N., 84 Fuchs, E., 243 Fuchs, P. L., 169 Fuchsgruber, A., 243 Fueno, T., 383 Fujieda, K., 368 Fujikawa, F., 238 Fujimori, S., 525 Fujimoto, T., 19 Fujino, Y., 91, 99, 163,

744

Gaiani, G., 41 Gaiffe, A., 10, 384 Gaignault, J. C., 634 Gait. R. J.. 232. 502 Gakhar H. K.,‘ 688, 7 50 Galkin;, T. M., 480 Gallagher, R. A., 427 Galli, A,, 780 Galli, R., 670, 671 Gallo. R.. 271 Galstukhova, N. B., 238 Galushko, A. G., 597 Gamba, M. F., 427 Gandelsman, L. Z., 20 Ganko, T., 275 Ganson, J. R., 83 Ganter, C., 39, 137, 151 Ganther, H. E., 20 Garbarino, G., 411, 491 Garbesi, A., 116, 144, 152, 29 1.

Gardini, G. P., 670 Garg, H. G., 594 Garnovskii, A. D., 659, 660, 677

Garrard, T. F., 54 Garratt, P. G., 179 Garratt, P. J., 401 Garreau, M., 490 Garrett, P. E., 34, 164,262, 524

Garwood, D. C., 47, 48, 33 1

Gassman, P. G., 15 Gastaldi, L., 279 Gattow, G., 203, 250, 258, 262?269, 285

Gaudiano, G., 52, 262, 296, 298, 313, 431

Fujisawa, T., 21, 90, 93 Fujita, S., 55, 360, 676 Fukada, N., 250, 511, 530 Fukunaga, M., 177 Fukuyama, M., 103, 200 Fukuyama, T., 128, 148 Fulder, H. U.,671 Fuller, M. W., 442 Funakoshi, W., 22 Funke, B., 234 Funke, E., 215, 413, 614 Furlani, C., 254 Furst, A., 652 Furuhashi, A., 213 Furukawa. M.. 91.99.163.

Gautheron, D., 13 Gautier, J. A., 313 Gautschi, F., 147 Gavatzhan. A. D.. 659 Gavar, M.’ P., 428 Gay R 578 Gaydon: E., 102, 216 Geens, A., 113, 160, 186 Gehlen, H., 245 Geiger, W., 579, 580, 765 Gelan, J., 173, 186 Gelas, J., 187 Genov. L.. 427 Georg&M. V., 258 George, T., 796 George T. J., 535 Geraci,’G., 13 Germain, G., 378 Gerrard, J., 427 Gerson, F., 499 Gerster, J. F., 229 Gesler, R. M., 641 Gestblom, B., 430, 43 8 Gewald, K., 231, 355, 520,

Fusco ,’R .,’360

Ghabgharan, F., 425

166, 258

365, 366

Fowden, L., 18 Fowler, J. S., 373 Fowler, P. J., 780 Foye, W. O., 201

Gabriel, S., 636 Gafurov, T. G., 677 Gagarina, A. B., 452 Gagiu, F., 594, 613, 743,

590

Author Index Ghate, S. P., 356, 483 Ghersetti, S., 321 Ghosh, A. K., 280 Gjacobbe, T. J., 9 Gianelh. M.. 577 Gianni, ‘M. H., 10 Gibbs, D. E., 13 Gibs, G. J., 486, 736 Gibson, H. W., 58, 174 Gibson, M. S., 232 Giere. H. H.. 322 Gierk, P. L.; 389 Gilardi, R. D., 508 Gilbert, E. E., 58 Gilbert, J. R., 128 Gilchrist, T. L., 36 Giles, H. G., 94 Giles. P. M.. 98 Gilles, L., 43 Gillis, H. A., 7 Gilman, B. F., 787 Gilman, H., 390 Gilmore, J. R., 20 Ginak. A. I.. 231. 271, 649,‘ 650 Ginanneschi, M., 737 Giner-Sorolla, A., 272 Ginesina, A. A., 467, 468 Ginsberg, A., 723 Giordano, C., 234 Giordano, F., 775 Giorgianni, P., 217, 320 Giuliani, A. M., 277 Giumanini, A. G., 388, 410 Giurdaru, G., 670 Gjw, N., 377, 387, 388 Gladkaya, V. A., 673 Gladysheva, F. N., 264, 634 Glass, W. K., 337 Glasser, A. C., 238, 761 Glassman, R., 119 Glazer, A. N., 2 Gleason, J. G., 17, 91, 95, 99, 111, 136, 160, 161, 162, 181 Gleiter, R., 499 Glick, L. A., 438, 454 Glick. M. D.. 68. 159. 324 Glily-Terry, S., 53 . Globokar, M., 425 Glover, E. E., 695 Glue, S., 183 Glushkov, R. G., 784 Gmelin. R.. 238 Gnad, G., 717 Gnichtel, H., 239 Goddard, D. R., 245 Godfrey, J. C., 764 Goerdeler, J., 1, 231, 238, 242, 568, 616, 619, 717, 721, 723, 724 Gotschi, E., 234 Goetz, H., 290, 325 Goggin, C. B., 81 Go te, V. N., 454 Go%, L. P., 752 Goldberg, I., 429, 430 Goldberg, S. Z., 288 I

,

,

Gol’dfarb, Ya. L., 22, 72, 275, 365, 369, 371, 372, 374, 375, 376, 377, 381, 398, 399, 400, 418, 420, 425, 428, 430, 432, 452, 495 Goldman, I. M., 695 Goldsack, R. J., 737 Goldschmid, H. R., 419 Goldsmith, B. B., 731 Goldstein, D., 679 Goldstein, M., 678 Golgolab, H., 249 Golini J. 179 GollniLk,’K., 15, 43 Golloch, A., 67 Golub, D. K., 714 Gomez, H., 631 Gompf, T. E., 241, 658 Gompper, R., 35, 89, 230, 354 Gonishkina, G. I., 72 Gonzalez, E., 624 Goodman, L., 19 Goodman, M., 647 Goodson, T., 427 Goralski, C. T., 58 Gorbaty, M. L., 60 Gorbenko, E. F., 721 Gordadze, G.N., 147 Gordon, J. A., 62 Gordon, M., 369 Gordon, M. P., 764 Gordon, R. D., 660 Gore, B. A., 453 Gore P. H., 449 Goreiik, M. V., 677 Gorushkina, G. I., 374 Gosney, I., 128, 566, 574, 575 Gosselck, J,, 60, 172, 289, 307. 317 Goto,‘T., 613 Gotschi, E., 104 Gott, P. G., 131, 187 Gotthardt, H., 26, 111, 113, 219, 413 Gottstein. W. J.. 270 Goudie, R, S., 18 Grabenko, A. D., 229, 234, 632. Grabowski, Z. R., 451 Graf, R., 559 Grandberg, 1. I., 659, 660 Grandin. A.. 515 Granik, V. G., 784 Grashey, R., 734, 746 Grasse, S., 410 Gratz, R. F., 136 Gravel, D., 59 Gray, E. A., 71 Grayshan, R., 167 Gra son, B. R., 1 Gregennikov, A. V., 593 Green, C. H., 188 Green, D. M., 453 Green, J. H. S., 363 Green, N. M., 147 Greene, F. D., 82, 597 Greene, J. L., 38

Gregorowicz, Z., 267, 743 Gregory, L. M., 264, 636 Greibrokk, T., 696, 697 Greidanus, J. W., 4, 131, 177, 205, 217 Greig, D. G. T., 65, 191, 192, 193 Gribble, G. W., 282 Griesbaum, K., 2 Griffin, C. E., 369 Griffith, E. A. H., 279 Griffith, M. G., 7 Grifiths, N. D., 784 Grigg, R., 415, 416, 565 Grigorian, G. L., 677 Grill, H., 132, 329, 336 Grimmer, R., 80 Grinev, A. N., 217, 356, 378,428,483 Grinsteins, V., 238, 281 Grinvalde, A., 28 1 Griselli, F., 67 Grishuk, A. P., 240 Gritsenko, A. N., 780 Grivas, J. C., 14 Grobovsky, L. V. 626, 627 Groen, M. B., 393, 404, 460,462 Grol, C. J., 386 Grom, 0. L., 649 Gromova, G. P., 375 Gronowitz, S., 368, 376, 377, 381, 386, 387, 388, 389, 397, 404, 411, 419, 438, 448, 464, 465, 466, 468, 476, 477, 483, 489 Groschopp, H., 724 Gross, M., 70 Grotens, A. M., 278 Grubb, S. D., 170 Gruber, R., 112, 138 Gruen, H., 94 Griinert, C., 600, 601, 667 Grunert, K., 241 Gruenwedel, D. W., 23 Gruetzmacher, G., 15 Grundon, M. F., 62 Grundtvig, F., 519 Grunwell, 1. R., 263, 328, 520 Gryff-Keller, A., 522 Grzeskowiak, R., 678 Gualtiere, F., 659 Gualtieri, F., 577 Guanti, G., 7, 384, 411, 49 1 Guaraldi, G., 70 Gubnitzkaya, E. S., 631 Giinther. D.. 559 Guerchais, J E., 250 Guerra, M. C., 427 Guglielmetti, R., 660, 681 Guilard, R., 364, 468 Guillemonat. A.. 102. 216 Guiochon. G.. 428 ’ Gunar, V.. I., 231 Gund, P. H., 736 Gunning, H., 102 GuDta. C. M.. 236 Gubta; S. K.,’54, 306

Author Index Gupta, T. K., 246 Gupte, S. S., 357 Gurina, S. K., 427 Guryanova, E. N., 93, 677 Gusarov, A. V., 26, 269 Gusarova, N. K., 26, 31 Guseinova, M. M., 405 Gusinskaya, S. L., 599 Guthrie, R. D., 75, 86 Gutowski, G. E., 194, 196, 764

Guttenplan, J., 20 Guy, R. G., 73 Gverdtsiteli, D. D., 441 Gyorfi, Z., 613 Gyorgydeak, Z., 635, 656 Gyulai, P., 243 laake, M., 307, 334, 336 -Iaake, P., 603, 610, 611 labermalz, U., 607 -Iackler, R. E., 294 lafeliger, O., 441 lafelinger, G., 279, 553 lartel, M., 422 lagburg, C. E., 40 lagen, G., 175 lagenmaier, H., 285 lagio, K., 297 lagio, S., 117 lahn, V., 231 lahnkamm, V., 269 daiduc, I., 390 daidukewych, D., 108 laines, A. H., 280 lair, N. J., 324, 617, 760 HAkansson,. R.,. 366,. 367,. 390 391

Halas:, A. F., 271, 659 Hales, R. H., 51, 133 Haley, N. F., 479 Halford. M. H.. 141 3al1, S.’S., 31 lallas. M. D., 4 lallberg, A., 411 lallew, A., 233 !€allstein,R. E., 541 3alstroem. J.. 35 FIamamura, E. H., 56 Kamana, M., 580 Hamashima, Y., 605 Hamblin, P. C., 190 Hambly, A. N., 86 Hambright, P., 609 Kamel, C. R., 488,489 Hamid, I. S., 745 Hamilton, R. D., 511 Hamlet, Z., 59 Hammen, P. D., 123, 180 Hammerich, O., 555 Hamminga, D., 426 Hamon, A., 793 Hamor, T. A., 187 Hampel, W., 249,451, 632 Hamplova, J., 41 Hamprecht, G., 43 Hamprecht, R., 746 Hamura, I., 736, 744 Hamuro, Y., 238 Han, C.-H., 95

Hanack, M., 84 Hanaki, A., 620 Hanessian, S., 53 Hanley, W. S., 90, 91 Hannout, I. B., 486, 721 Hans, W., 662 Hansen, D. W., 185 Hansen, E., 508 Hansen, L. K., 497, 498 Hanson, C., 427 Hanson, J. C., 54 Hantschmann, A., 470 Hanus, V., 22 Haq, M. Z., 148 Harada, K., 327 Haran, G., 96, 141 Hardegger, E., 5 Harding, C. E., 84 Harding, D. R. K., 61, 226,318,633

Hardy, F. E., 88, 412 Hardy, P. M., 92 Hargrove, R. J., 84 Harhash, A. H., 239, 245,

Haszeldine, R. N., 16, 96 Hatam, N., 176, 250 Hatch, M. J., 153 Hatfield, L. D., 193, 194, 764

Hatfield, W. E., 285 Hatton, B. T., 710 Hatton, C. J., 425 Hatton, J. R., 509 Haugwitz, R. D., 707 Hauptmann, S., 357, 470 Hauser, C. R., 61, 326, 557, 578

Hausman, M., 238, 560, 571, 575

Hawkins, R. T., 389 Hawley, D. M., 378 Hawson, A., 226, 227 Hay, G. W., 138, 257, 527 Hayami, J., 15 Hayano, F., 620 Havashi. S.. 91. 99. 163.

628, 629

Harman, M. W., 669 Harmon, R. E., 54, 306 Harness, J., 33, 141 Harpp, D. N., 14, 17, 67,

73, 91, 92, 93, 95, 99, 111, 136, 160, 161, 162, 181, 182, 266, 450 Harries, H. J., 427 Harris, C. M., 343 Harris, D., 232, 502 Harris, G., 628 Harris, M., 131, 187 Harris, R. L., 311, 343,345 Harris, R. L. N., 17, 240 Harris, T. M., 343 Harrison, D. R., 417 Harrison, W. A., 631 Harshbarger, W. R., 363 Hart, H., 142 Hartford, A. jun., 441 Hartgerink, J. W., 183 Hartke, H., 591 Hartke, K., 207, 255 Hartmann, A. A., 166, 167 Hartmann, H., 359, 385, 488, 515, 517, 521, 534 Hartmann, O., 430 Hartmann, W., 259 Harts, G. H., 755 Hartshorn, M. P., 190 Hartter, P., 12 Hartzler, H. D., 524, 525 Hasan, S. K., 195 Hase, T., 83 Hasegawa, G., 760 Hasegawa, J., 94 Haseman, M., 445 Hashimoto, K., 11 Hashimoto, M., 614 Hashimoto, S., 665 Hashimoto, Y.,723 Hashizume, T., 236 Haslinghuis, W. P., 76 Hassfeld, M., 552 Hassner, A., 169, 659

Hayatsu, H., 80, 81 Hayazaki, T., 780 Hazama, M., 290 Heacock, R. A., 81 Heath, D. R., 653 Heath, G. A., 213, 286 Heatlie, J. W. M., 732 Heaton, B. G., 358 Heaton, P. R., 169 Hebert, M., 407, 455 Heckel, K., 138 Heckley, P. R., 267, 269 Hedayatullah, M., 266 Hedblom. M.-0.. 160 Hedegaard, B., 212, 2 398,410

Heeres, G. J., 362, 466 Heffernan, M. L., 442 Hege, H. G., 245 Heicklen. J.. 114. 142 Heilbron; I.; 628’ Heimer, N. E., 67, 132, 265

Heindel, N. D., 231, 617 Heine, H.-G., 259 Heinisch, L., 247 Heinrickson, R. L., 13 Heinzer, J., 499 Held, P., 70 Helder, R., 417 Heller, D., 236 Hellier, D. G., 188 Helmers, R., 403 Helmy, E. E., 39, 48 Hemke, G. J. K., 61 Henbest, H. B., 24 Henck, C. C., 166 Hendrickson, J. B., 760 Hendry, J. B., 371, 372 Henegarn, O., 613, 744 Henery-Logan, K. R., 164, 626

Henion, R. S., 116

809

Author Index Henriksen, L., 128, 164, 272, 354 Herber, R. H., 678 Herman, M. A., 287 Herr. M. E.. 190 Hertner, C., '450 Hervieu, G., 207, 512 Herz, J. E., 173 Herzschuh, R., 553 Hess, B. A., 783 Hetschko, M., 172, 289 Hettler, H., 579, 584 Hetzel, F. W., 3 Heuck, C. C., 222 Heugebaert, F. C., 738 Heusler, K., 197, 198 Hewett, L., 445 Hewitson. B.. 16 Hewitt, G., '17, 65, 19'1, 192, 193 Hewlins, M. J. E., 279 Hey, D. H., 24 Hicter, M. I., 593 Higa, T., 113 Higginbottom, B., 16 Higgins, J., 426 Higgins, R. W., 370 Highsmith, R. E., 91 Higo, M., 297, 303, 309 Hilfiker. F. R.. 139 Hill, A.' W., 176, 250 Hillers, S., 594 Hine, J., 59 Hino, T., 236, 275, 619 Hinsberg, O., 756 Hinsche, G., 204 Hirabavashi. Y..289 Hirai, K.,18, 25, 114, 238, 521, 591, 592 Hirano, H., 592, 593 Hirao, I., 725 Hirayama, T., 238 Hirota. H.. 119. 152 Hirota; T.,' 725 ' Hirotsu, Y.,622, 624 Hirschmann, R., 270, 645 Hisada, R., 82 Hisano, T., 657 Hiskey, R. G., 92 Hiyama, T., 55 Hlavacek, R. J., 631 Hloch, B., 58, 107, 108 Hocker, J;, 230 . Hofle, G., 65, 96, 105,624 Hohne, E., 279 Horhold. H. H.. 336. 752 Hornfeldt, A.-B:, 387, 397, 438, 490 Hover, W., 230 Hoffman, R. A., 438, 742 Hoffman, V. L., 323 Hoffmann, J. M., 57, 546 Hoffman, L., 289 Hoffmann, R., 288 Hofmann, H., 436, 535, 536, 551 Hofmann, H.-J., 470 Hofmann, I., 355 Hogg, D. R., 1, 2, 66, 71 Hoggett, J. G., 87

Hohberg, H., 290 Hokama, K., 407 Hokonoki, H., 33 Holah. D. G.. 260. 267. 269 ' Holdrege, C. T., 764 Holger, M., 650 Holik, M., 383 Holland, R. J., 291 Holland. W.J.. 427 H[olliman, F. G., 81 H[ollins, R. A., 179, 783 H[olm, A., 259, 262, 266 H[olm, B., 389 H[olmes, A. B., 179, 547 H[olmes, J. L., 594 H[olsboer, D. H., 25 H[olst, J., 279 H[oh, G., 77 H[onda, S., 72 Hlonig, L. M., 426 H[onjo, T., 700 Hlonkanen, E., 259 H[onzl, J., 22 H[oogzand, C., 403, 480 Hlope, D. B., 3 H[ope, H., 495 H[orik, V., 441, 452 H[ordvik, A., 497, 498, 506. 508. 511. 519 Hori, .Me, 343 Horii, T., 6, 93 Horrnuth, P. B., 247 Horner, L., 339 Hornig, P., 376 Horning, D. E., 298 Hornyak, G., 749 Hortmann, A. G., 311, 373, 345 Horton, D., 33 Horvath, G., 156, 279 Hoshi, H., 359, 557 Hoskins. B. F., 279 Hoskins; J. A.,, 80 Hosoi, K., 296 Houbiers, J. P. M., 420 Hough, L., 34, 83 Houghton, E., 615, 719, 748 Houk, K. N., 595 Wouser, R. A., 107, 144 Houser, R. W., 64, 117, 119 Hovius, K., 87 Howard, J. A., 149 Howard, J. C., 560 Howarth, G. B., 30 Howe, R., 454 Howell, H. G., 30 Howes. H. L.. iun.. 424. 425 Hoyer, E., 272, 285 Hradil, F., 541 Hromtka, O., 588.701 Huang, C. L.,780 Huana. M. C.. 186 Hubert, A. J.,'659 Huckerby, T. N., 365, 366, 369 Huddleston, P. R., 407 I

I

,

-

I

_

I

Hudec, J., 18 Hudson, A., 19, 369 Hudson. R. F.. 268 Hunig, S., 6, 246, 522, 584, 608, 665 Huttenrauch, R., 697 Huffman, G. W., 194, 427 Hufnagel, E. J., 522, 523 Hufzhes. A. N.. 269 Hughes; C. G:,-216, 429, 43 1,477,478 Hughes, N. A., 33, 141 Huisgen, R., 215,413, 559, 614, 636, 734 Huisman, H.O., 110, 311, 536, 539 Hulley, R. M., 71 Hulpke, H., 765 Hummel, K., 84 Humphlett, W. H., 557 Humphries, A. J., 453, 477 Hunt, J. D., 373 Hunt, T., 14 Huppatz, J. L., 544 Huppertz, A., 723 Hurd, C. D., 69 Husain, S., 615, 682, 719, 748 H usband, J. P. N., 17, 31 H usbands, G. E. M., 433 Hussein, M. H. M., 242 H uston, B. L., 226, 227 H utchinson, B. J., 156 H utley, B. G., 404, 405 H utzinger, O., 70 H uurdeman, W. E. J., 169 H wol, R. F., 307 H uyser, E. S., 18 H vistendahl, G., 694 Ichikawa, K., 50 Iddon, B., 69, 435, 448, A7 3

Iedema, A. J. W., 61 Ignatov, V., 659 Ignatova, L. A., 238, 243, 763 Jida, S., 80 Jio. A.. 567 Jkari, N., 94 Ikeda, Y.,50 Ikezaki, M., 793 Ikura, K., 119 Illuminati, G., 384 Imai. T.. 534 lmai; Y.; 676 Imamoto, T., 762 Imazawa, M., 6, 232 Imbach, J. L.,624 Imhoff, M. A., 84 Imoto, E., 43, 305, 313 Imoto, M., 90 Inamoto, N., 74, 97, 102, 132, 133, 165, 179, 232, 238, 239 Ingold, C. K., 1 Ingram, A. S., 35 Inokawa, S., 252,259, 260 Inokuma, S., 296 Inomata, K., 9, 266

Author Index

810 Inoue, H., 793 Inoue, M., 81 Inoue, S.,91, 139, 163, 527 Inouye, K., 516 Inui, T., 92 Ioffe, I. S., 244, 248, 249, 2 74 Ireland, C. J., 102 Irick, G., 714 Iriuchijima, S., 42, 153 Irving, H. M. N. H., 95, 245, 280, 745 Isaev, S. D., 593 Isakson, G., 277 Isbrandt, R., 454 Ishiba, T., 114, 592 Ishibe, N., 134, 140, 218, 531, 532 Ishida, N., 64 Ishihara, H., 289 Ishii, Y.,237, 259, 275 Ishizuka, K., 736 Islip, P. J., 632, 736 Isola, M., 67, 86 Isono, M., 77 Itani, H., 102, 145, 258 Ito, H., 605 Ito. T.. 780 Ito; Y . ;12, 67, 231, 322 Itoh, K., 237, 259 Itoh, O., 50 Itoh, T., 661, 702 Ivanov, C., 599 Ivanov. V. M.. 610 Ivanova, I. A.; 31 Ivanova, M. I., 526 Ivanova, V. N., 405 Ivanova, Zh. M., 230 Ivin, K. J., 77 Iwakura, Y., 243,286,620, 657 Iwamoto, T., 238 Iwamura, H., 23, 177, 294 Iwamura, M., 23, 294 Iwanami, S., 86, 117, 131, 227, 319, 320, 759 Iwanami, Y., 760 Iwata, K., 291 Iwata, R.,6 Izvekov, V. P., 428 Jackson, B. G., 764 Jackson, J. R.,4 Jacob, G., 459 Jacobsen, C., 77, 260 Jacobsen, H. L., 378 Jacobsen, S. E., 77 Jacobson, C. F., 623 Jacqmin, G., 210, 451 Jacquet, J. P., 655 Jacquier, R., 245,246, 248, 275, 624, 634 Jacquignon, P., 418, 441, 443, 478, 544, 713 Jahnke, U., 782 Jahns, H.-J., 244 Jain, A. C., 237 Jain, S. K., 783 Jakkal, V. S., 279 Jakobsen, H. J., 369, 387

Jakopcic, K., 231 James, B. G., 52, 313 James, T. L., 361 Jancis, E. H., 111, 123 Janda, M., 383, 408 Janiga, E. R., 307 Jankowski, K., 187 Janousek, Z., 232 JanouSova, A., 383 Janowski, A., 275 Janssen, M. J., 201, 240, 362, 370, 386, 387, 412 Japelj, M., 425 Jarvje, A. W. P., 17 Jarvis, B. B., 105 Javaid, K. A., 138 Jeffries, A. T., 386, 388, 453, 474 Jeffreys, K. D., 77 Jeffreys, P. D., 77 JehliEka, V., 286 Jeminet, G., 59, 62 Jencks, W. P., 7 Jenkins, C. S. P., 280 Jensen, G. M., 262 Jensen, K. A., 128, 164, 201, 265, 272, 280, 282, 354 Jensen, L. H., 760, 764 Jesperson, A., 397 Jesthi, P. K., 593, 608 Jhina, A. S., 454 Jilek, J. O., 551 Job, P., 743 Jerrgensen, C. K., 280 Johansson, N. G., 199 Johar, G. S., 238 Johns, J. W. C., 202 Johnson, A. W., 415, 416 Johnson, A. Wm., 288 Johnson, B. J., 20 Johnson, C. R., 36, 52, 78, 79, 87, 116, 118, 119, 125, 136, 149, 153, 159, 228, 307, 324, 325, 329, 330, 331, 332, 333 Johnson, D. L., 1 Johnson, D. R., 202 Johnson, J. L.,240, 617 Johnson, J. R., 684 Johnson, L. F., 37 Johnson, P. L., 177, 508 Johnson, R. A., 190 Johnson, S. M., 176 Johnson, W. O., 474 Johnsson, H., 9 Johnston, D. B. R., 427 Johnstone, R. A. W., 285, 502 Jokubaityte, S., 242 Joly, P., 684 Jonas, K., 616 Jonas, V., 277 Jones, A. R., 135 Jones, D. H., 569, 573,782 Jones, D. M., 141, 378, 385 Jones, D. N., 39, 48 Jones, D. W., 20, 442, 470 Jones, E., 377

Jones, E. M., 413 Jones, F. B., 68 Jones. F. N.. 170. 262 Jones; I. W.; 56 . Jones, J. B., 167 Jones, J. K. N., 30, 83 Jones, R. A. Y., 103 Jones. R. M.. 423 Jones; W. C.; 92 Jones, W. M.. 84 Jonsson, E. -U., 79, 87, 118, 228, 329, 331 Jordens, P., 386, 464, 466 Joris, S. J., 267, 268 Joscheck. H. I.. 294 Jose, F. L., 192, 193, 194 Joseph-Nathan, P., 173 Joshua, H., 270, 645 Josse, A., 207, 503 Joullie, M. M., 180, 476 Jourdenais, R. A., 466 Jowitt, R.-N., 267 Jucker, E., 469, 470 Julshamn, K., 498, 506, 508 Juinar, A., 70 Just, G., 761 Kadentsev, V. I., 371 Kagemoto, A., 619 Kahmann, K., 412 Kai, K., 80, 81 Kaiser, C., 780 Kaiser, E. M., 61, 170 Kaiser, G. V., 195, 427 Kaisin, M., 598 Kaji, A., 15, 255, 268 Kaji, K., 209 KakaE, B., 441 Kakkar, G. F., 307 Kakudo, M., 329, 752 Kalabin, G. A., 26, 32 Kalik, M. A., 275, 376, 377, 398, 399, 400, 428 Kalinovskii, 0. A., 381, 428 Kalinowski, H.-O., 278 Kalish, R.,257, 529 Kallen, R. G., 8 Kalman, A,, 181, 324 Kalyavin, V. A., 147 Kalzendorf, I., 637 Kamata, K., 87 Kambe, S., 185 Kamber, B., 92 Kamei, T., 35 Kamel, M., 486, 721 Kamemoto, K., 169 Kamienska-Trela, K., 205 KamiCnski, B., 368 Kamigata, N., 62 Kaminskii, Y. G., 13 Kaminura, A., 232 Kamiya, M., 754 Kammel, G., 307, 309,329 Kammereck, R. F., 104 Kampe, K.-D., 89 Kampmeier, J. A., 11, 94 Kanazawa, T., 736 Kandabarova, S., 88

Author Index

81 1

Kaneko, T., 622, 624 Kanematsu, K., 378 Kang, E., 609 Kano, H., 665, 667 Kano. M. 0.. 322 Kano; N., 275 Kano, S., 723 Kantor, S. W., 326 Kantyukova, R. G., 35 KaDer. L.. 362. 367 Kapovits,'I., 181 Kapp, M., 249, 632 Karaban, E. F., 674 Kargcr, M. H., 82 Karle, 1. L., 508 Karle, J., 255 Karmanova. I. B.. 375.376 Karpinskii, V. S.,.780 Kasa!, K., 556 Kasai, N., 329, 752 Kasai, T., 189 Kascheres. A.. 169 Kashima, 'C., 531 Kashima, N., 140 Kashman, Y., 135 Kasperek, G. J., 99 Kassabov, G., 427 Katadu, M., 580 Kataev, E. G., 492 Kataeva, L. M., 492 Katagiri, T., 28, 174, 212 Katekar, G. F., 52, 332, '

535

Kato, A., 162 Kato, H., 143, 163, 228, 499, 525, 587, 614 Kato, K., 234, 242 Kato, M., 243, 619 Kato, S., 289 Kato, Y., 725 Katritzky, A. R., 103, 138, 156, 537 Katts, I. G., 436, 488 Kauffmann, T., 412 Kaufman, E. D., 135 Kaufman, H. A., 438, 454 Kavun, S. M., 677 Kawabe, K., 736 Kawaguti, T., 360 Kawamoto, H., 427, 701 Kawamoto, K., 104 Kawamura, M., 525 Kawamura, S., 6, 90, 93 Kawamura, T., 19 Kawanishi, S., 213 Kawano, S., 778 Kay, I. T., 59, 183 Kay, J., 68 Kaya, T., 243 Kazan, J., 275, 597 Kazimirchik, I. V., 141, 187, 526 Kee, M.-L., 2, 71 Keiner, H. J., 671 Kellogg, R. M., 100, 102, 222, 363, 392, 393, 411, 460 Kemp, D. R., 218 Kemp, D. S., 596 Kemp, R. H., 369

Kempter, G., 237, 240, 593, 710 Kemula, W., 275 Kendall, R. V., 751 Kenner, G.W., 88 Kenny, D., 91 Kenny, N. C., 523 Kepert, D. L., 427 Kerber, R., 58 Kergomard, A., 82 Kerr, D. A., 56 Kessenikh, A. V., 428 Kessler, H., 277, 278 Ketcham, R., 684 Keung, E. C. H., 705 Keydal, M., 231 Khachatryan, R. M., 238 Khaletskii, A. M., 231, 753, 754 Khan, M. S., 19 Khanna, N. M., 236 Kharchenko, V. G., 532 Khare, A., 248, 425 Khare, B. N., 3 Khare, G. P., 279 Khasanova, M. N., 630 Khetrapal, C. L.,365 Khilya, V. P., 654 Khim, Y. H., 162 Khitar, B. E., 236 Khmelnitskii, L. I., 428 Kho, B. T., 743 Khodot, G. P., 674 Khokkar, A. R., 625 Khorkhoyanu, L. V., 780 Khovratovich, N. N., 644 Khuddus. M. A,. 54 Khullar, K.K., 22 Khym, J. X.,620 Kiang, W. K. T., 476 Kibirev, V. K., 713 Kice, J. L., 2, 78, 97, 99 Kiel. G.. 203. 258 Kier, L.

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