Advances in Heterocyclic Chemistry Vol 28

Advancesin Heterocyclic Chemistry Volume 28 Editorial Advisory Board R. A. Abramovitch A. Albert A. T.Balaban S.Gro...

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Advancesin

Heterocyclic Chemistry Volume 28

Editorial Advisory Board R. A. Abramovitch A. Albert A. T.Balaban

S.Gronowitz T. Kametani C. W. Rees Yu. N. Sheinker H. A. S t a b M. TiSler

Advancesin

HETEROCYCLIC CHEMISTRY Edited by A. R. KATRITZKY Department of Chemistry University of Florida Gainesville. Florida

A. J. BOULTON Schoolof ChemicalSciences ofEastAnglia University Norwich, England

ACADEMIC

PRESS

Volume28

A Subsidiary of HucourtBrme Jovrnovioh, PubUmhen

N e w York London TorontoSydney Sen Francisco

COPYRIGHT @ 1981,BY ACADEMICPRESS, INC. ALL RIGHTS RESERVED. NO PART OF THIS PUBLICATION MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM OR BY ANY MEANS, ELECTRONIC O R MECHANICAL, INCLUDING PHOTOCOPY, RECORDING, OR ANY INFORMATION STORAGE AND RETRIEVAL SYSTEM, WITHOUT PERMISSION IN WRITING F R O M THE PUBLISHER.

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United KingdomEdition published by ACADEMIC PRESS,INC. ( L O N D O N ) LTD. 24/28Oval Road,LondonN W I 7DX

LIBRARY OF CONGRESS CATALOG CAIWNUMBER: 62-13037 ISBN 0-12-020628-5 PRINTED IN THE UNITED STATES OF AMERICA

81828384

981654321

Contents CONTRIBUTORS .

PREFACE.

. . . . . . . . . . . . . . . . . . . vii . . . . .

. . . . . . . . . . . . . . . . . . . . . ix. . . . .

Polyfluoroheteroaromatic Compounds R .D .CHAMBERS AND C .R .SARGENT I. Introduction . . . . . . . . . . . . . . . . . . .1 . . . . I1.Synthesis. . . . . . . . . . . . . . . . . . . .2 . . . . Ill . Properties andReactions . . . . . . . . . . . . . . .47. . . . 1.2.and2.1.Benzothiazines andRelated Compounds J .G .LOMBARDINOANDD .E .KUHLA

I.Introduction . . . . . . . . . . . . . . . . . . .73. . . . I1.1 2.Benzothiazines . . . . . . . . . . . . . . . . . 74 . . . . 111.NaphthoandDibenzo.1. 2.thiazines . . . . . . . . . . . .103. . . IV.Heterocyclic Ring-Fused 1.2.Thiazines . . . . . . . . . . . 106 . . . V .Ring-Fused 1 2.Benzothiazine Derivatives . . . . . . . . . . .110. . VI.2.I-Benzothiazines . . . . . . . . . . . . . . . . . 116 . . . . VII.Conclusion . . . . . . . . . . . . . . . . . . . 125 . . . . . . . . . NoteAddedinProof . . . . . . . . . . . . . . . . 125

.

.

Isatoic Anhydrides andTheirUsesinHeterocyclic Synthesis T .KAPPEAND W .STADLBAUER

I.Introduction . . . . . . . . . . . . . . . . . . 127 . . . . . I1.Formation ofAnthranilic AcidAmidesand Hydrazides and . . . . . . . . . . . . .141. . . Further Reaction toHeterocycles III.Reaction ofIsatoic Anhydride withCarboxylic Acid . . . . . . . . . . . . . . . . . . . 156 . . . . . Derivatives . IV .Reactions ofIsatoic Anhydride withC=N DoubleBonds . . . . . .166 V .Reactions ofIsatoic Anhydride withCarbanions . . . . . . . . .168. . VI . Miscellaneous Reactions . . . . . . . . . . . . . . .174. . . . VII.Appendix AddedinProof . . . . . . . . . . . . . . .178 . . . . V

vi

CONTENTS

Reactions ofBenzynewithHeterocyclic Compounds MARTINR .BRYCEAND JOHN M .VERNON I.Introduction . . . . . . . . . . . ...... .. .. I1.MethodsofBenzyneGeneration . . . . . . .. .. .. . . 111.Patterns ofBenzyneReaction. . . . . . . .. .. .. . . IV.Reactions withThreeandFour-Membered RingSystems. . . . .

.183 . . 185 . .187 . .192 .

V .Reactions withFive-Membered RingSystems Containing . One Heteroatom . . . . . . . . . . . .. .. .. .. . . 194 VI.Five-Membered RingSystems withTwo orMore 206. Heteroatoms . . . . . . . . . . . .. ........ . . .. .. . . .214 . VII.Six-Membered RingSystems . . . . . . . . . VIII .Seven-Membered andLarger RingSystems. . . . .. . . . . . 224 . IX.Heterocyclic N-Oxides . . . . . . . . . . ....... . .224

Carbenes andNitrenes inHeterocyclic Chemistry: Intramolecular Reactions CURTWENTRUP

I.Introduction . . . . . . . . . . . . .. .. .. .. .. 232 . I1.Vinylnitrenes. 2H.Azirines. andIminocarbenes . . . . .. . . . . 233 . 111.Imidoylcarbenes and 1H-Azirines . . . . . . . .. .. .. . . 252 . IV.Oxocarbenes andOxirenes. . . . . . . . . .. .. .. . . 257 . . V .Thioxocarbenes. Thiirenes. andSelenium Analogs . . . .. . . . . 262 VI.Acylnitrenes andThioAnalogs . . . . . . . . . . . . . 265 . VII.Imidoylnitrenes andNitrilimines (Azocarbenes) . . . . .. . . . . 270 . . VIII.Arylcarbenes andArylnitrenes . . . . . . . . .. .. .. . .279 . . . . . 339 . IX.Five-Membered Heteroarylcarbenes andHeteroarylnitrenes X .Cyclic Aminonitrenes (1.1.Diazenes) . . . . . . . .. ... . . 343 . . XI.Heterocycloalkylidenes . . . . . . . . . .. .. .. .. . 348 XI1.Heterocycloalkylcarbenes andHeterocycloalkylnitrenes . . . . . . . 353 . . XI11.Arylsulfonylcarbenes andArylsulfonylnitrenes . . . . .. . . . . 357 . XIV .Conclusion . . . . . . . . . . . . . . . . . . 361

CUMULATIVE INDEXOF TITLES . . . . . . . . . . . . . . . . 363 . . . .

Contributors Numbersinparentheses indicate thepageson whichtheauthors’ contributions begin.

MARTINR. BRYCE,Department ofChemistry, University of York, Heslington, YorkYO1 5DD, England(183) R. D. CHAMBERS, Department ofChemistry, University ofDurham,Durham City, England(1) T. KAPPE,Institute of OrganicChemistry, University of Graz,A-8010 Graz, Austria (127) D. E . KUHLA,Pfizer Central Research, Groton, Connecticut 06340(73) J.G .LOMBARDINO, PJizer Central Research, Groton, Connecticut 06340 (73) C .R.SARGENT,* Department ofChemistry, University ofDurham,Durham City, England(1) W . STADLBAUER,, Institute ofOrganic Chemistry, University ofGraz, A8010Graz, Austria (127) JOHN M . VERNON,Department of Chemistry, University of York, Heslington, YorkYO1 SDD, England(183) CURTWENTRUP,Department ofchemistry, University ofMarburg, 0-3550 Marburg,WestGermany(231)

’Present address: I.S.C. Chemicals, Ltd., Avonrnouth, Bristol, England. vii

This Page Intentionally Left Blank

Preface Volume28 consists offive contributions that cover a diverse range of A complete organic chemistry basedon fluorocarbon rather than topics. hydrocarbon skeletons canbeconceived: Several general accounts offluorocarbon chemistry havepreviously appeared; now,Chambersand areview toheterocySargent have, forthefirst time, specifically devoted Comclic aspects of this chemistry inthe Polyfluoroheteroaromatic pounds.The 1,2-and 2,l-benzothiazines werevirtually unknown25 yearsago.Todaytheposition isverydifferent, and Lombardino and Kuhlahavegiven usatimely compilation oftheir chemistry. Isatoic anhyindustrial chemical fromwhicha verylarge number dride isan important ofdifferent heterocyclic compoundscaneasily be derived. The usesof isatoic anhydrides inheterocyclic synthesis arenow reviewed by Kappe ofbenzyne chemistry andStadlbauer. Numerousprevious descriptions Forthis reason, Bryce havegivenscant regard toheterocyclic aspects. andVernonhavediscussed thereactions ofbenzynes withheterocyclic compounds. Therole ofcarbenes andnitrenes inheterocyclic chemistry isa verylarge one.Inthis volumeWentruppresents thefirst partofa comprehensive account whichisconcerned withintramolecular reactions. A. R. KATRITZKY A. J.BOULTON

ix


ADVANCES

I N HETEROCYCLIC

CHEMISTRY .VOL 28

Polyfluoroheteroaromatic Compounds R .D .CHAMBERS

AND C .R .SARGENT

Department of Chemistry. Uiiioersity of Durham.Durham City. England

. .. I.Introduction . . . . . . . . . . . . . . . . . . I1.Synthesis . . . . . . . . . . . . . . . . .. . . . . . . A . Introduction ofFluorine into Heterocyclic Systems . . . . .. . . . 1. Electrophilic HalogenExchange . . . . . . . . .. .. . . 2.Nucleophilic HalogenExchange. . . . . . . . .. .. . .

3.Substitution ofHydrogenby Fluorine. . . . . . .. .. . . 4.Substitution ofOtherGroups . . . . . . . . . .. .. . . 5.Saturation-Rearomatization . . . . . . . . . .. . . . . B . Cyclizations UsingFluorinated Precursors . . . . . . .. .. . . 1.Involving Fluorinated Benzene Derivatives . . . . . .... . . 2.Involving Fluorinated Alkenes andAlkynes . . . . . . . . . . 3.Condensation Reactions ofNitrogen-Containing Compounds . . . . ofPerfluoroalkyl Groups . . . . . . . . . . . . . C . Introduction Ill . Properties andReactions . . . . . . . . . . . . .. .. .. . A . Physical Properties . . . . . . . . . . . . .. .. .. . . .. . B . Industrial Applications . . . . . . . . . . . . . C . Nucleophilic Substitution . . . . . . . . . . .. . . . . . 1. Pyridines andRelated Systems . . . . . . . . .. .. .. . 2.FiveandCondensed Five-Membered RingSystems . . .. . . . 3.Fluoride Ion-Induced Reactions . . . . . . . . .. .. . . 4. Reactions Involving SideChains. . . . . . . . .. .. . . D . Reactions withElectrophilic Reagents. . . . . . . . . . . E . Addition Reactions andRadical Processes . . . . . . .. .. . . F. Reactive Intermediates . . . . . . . . . . . .. .. .. . 1.Organometallics . . . . . . . . . . . . . . . . . .. 2.Arynes . . . . . . . . . . . . . . . . . . . . . . G . Fragmentation andRearrangement Processes . . . . . . . .. . . Valence Isomers . . . . . . . . . . . . . .. .. .. ..

.i

.2

.2 .3

.6

.10 .I I

. 12 .14

. 14 .24 .36 .44 .47 .47 .48 .48 .48 .54

.55

. 58 .59 .60 .65 .65 .66 .66 .68

.

I Introduction Inprinciple. a totally synthetic organic chemistry ispossiblelP3 basedon fluorocarbon rather thanhydrocarbon skeletons. together withassociated .Withinthischemistry isthepotentially vastfield of functional groups

* Present address: I.S.C. Chemicals. Ltd., Avonmouth. Bristol BSI1 9HP.England .

See.e.g.. ChambersandH ~ d l i c kand y . many ~ publications referred tothere . R .D .Chambers.Fluorine inOrganic Chemistry. Wiley(Interscience). New York.1973. M . Hudlicky.Chemistry ofOrganic Fluorine Compounds.Ellis-Horwood. Chichester. 1976. 1

Copyright @ 1981by AcademicPress .Inc. Allrights ofreproduction inanyformreserved . ISBN O-IZ-O?~~ZR-S

2

R. D. CHAMBERS

AND C. R. SARGENT

[Sec. 1I.A

heterocyclic compounds, andinthis chapter we willbe concerned specifically withheteroaromatic derivatives, whichhavealso beenincluded indiss remarkable fluorine-containing compounds, including thefollowing: (a) new eflects-new compounds andmaterials arise withoften quite novel properties andeffects-and (b)new chemistry-since functional groups areplaced in ascompared with entirely different electronic environments in fluorocarbon thecorresponding hydrocarbon derivatives, we havea chemistry thatis mechanistically novel, including reactions that areoften complementary to those withwhichwe aremostfamiliar. orpolybromo deThesecommentscould also bemade aboutpolychloro rivatives, whicharerelatively neglected areas; butthere isa unique relationship between fluorocarbon andcorresponding hydrocarbon systems. Thisis dueinpart tosimilar volatilities ofthesystems, andcontrasts withpolychloro orpolybromo derivatives, buttherelationship ismade evenmorestriking by theavailability ofI9F-NMR spectroscopy asa powerful structural probe.

11.Synthesis Thispart ofthediscussion canbedivided into twosections, depending on orwhether the whether fluorine isintroduced into thepreformed heterocycle heterocyclic system isformed by cyclization involving analready fluorinated compound.

A. INTRODUCTIONOF FLUORINE INTO HETEROCYCLIC SYSTEMS Fluorspar istheprimary source offluorine, butsofarno useful process hasbeendeveloped tousethis directly forthepurpose offorming carbonfluorine bonds. Instead, thefluorspar may beconverted toanhydrous hydrooffluorides orspecial reagents genfluoride, elemental fluorine, anda range n so

CaF, A

electrolysis

H F (anhydrous)

F2 + Transition metalfluorides

1

Metalfluorides G. G. Yakobson,T. D. Petrova, and L. S.Kobrina,Fluorine Chem.Rev.7,115 (1974). GmelinHandbuch der Anorganischen Chemie,Perfluorohalogen-organoverbindungen derHauptgruppenelemente, Parts1-6.Springer-Verlag, Berlin andNew York,1973-1978. R. E. Banksand M . G .Barlow,eds.,Fluorocarbon and Related Chemistry,Vols. 1-3. ChemicalSociety, London,1971,1974,1976. M. M. Boudakian, in Pyridine and ItsDerivatives (R.A. Abramovich, ed.), Vol.14 Suppl., Pt.2,p.407.Wiley,New York,1974.

Sec.11. A]

POLYFLUOROHETEROAROMATIC

3

COMPOUNDS

forthepurpose offluorination. Clearly froman economic viewpoint, anhy(AHF)isthereagent ofchoice, butother reagents droushydrogen fluoride arefrequently easier tohandle on a laboratory scale.

1. Electrophilic HalogenExchange

-

-

Thewell-established processBa ofusing hydrogen fluoride, usually withantimonypentafluoride as catalyst, forconverting a trichloromethyl group Ar-CC1,

+

+ HF (SbFS)

ArCCI,-----CI-H

HF

ArCFCI, + HCI

1

ArCF,

attached toan aromatic ringtotrifluoromethyl may be applied tohetero(Eqs.1-3).8b10 Thisprocess probably involves acidaromatic systems induced ionization ofthecarbon-chlorine bond,theaddition ofantimony pentafluoride effectively providing a superacid. Consequently, itisunderstandable that trichloromethyl attached to,forexample, a pyridine system willbe less reactive inthis typeofexchange thanwhen attached tophenyl. CCI, I

cc1, N A N

CF, I

HFiSbF,

CI,CANACC13 H

(45%)

Rangeofpartly fluorinated triazines

(2)

H

(53%)

Various metal fluorides havebeenusedtoformtrifluoromethyl groups in processes ofuncertain mechanism probably involving assistance toionization 8b

A. K. Barbour, L. J.Belf, and M. W. Buxton, Adu. Fluorine Chem. 3,181 (1963). E.T.McBee,H. B.Hass,and E. M. Hodnett, Ind.Eng. Chem.39,389 (1947). E.T. McBee,0. R. Pierce, and R. 0. Bott, Ind.Eng.Chem.39,391 (1947). F. Mutterer and C. D. Weis,H e h . Chim.Actu59,229(1976).

4

R. D. CHAMBERS

[Sec. 1I.A

AND C. R. SARGENT

[e.g., seeScheme1" and Eq.(4)"]; someofthese procedures arerather drastic andtherefore do notconstitute realistic preparative procedures. F,C

P &AF

C12FC

SCHEME

ClF2C

CF,CI

a

1

cw

)--J AgF

F3C

CF,

CI,C

(4)

cc1,

Incertain cases, hydrogen fluoride may be usedtoexchange chlorine for fluorine attached directly toring positions adjacent toring nitrogen (Eqs. 513 and614*i5). Here, itistempting toattribute thereactivity toinitial protonation ofnitrogen (Scheme2). c1

I

I

H

H

I H

SCHEME2 H.Schroeder, R.Ratz, W. Schnabel, H.Ulnch, E.Kober, andC.Grundmann, J. Org.Chem. 27,2589(1962). l 2H. Ulrich, E.Kober,R. Ratz, H. Schroeder, andC.Grundmann, J .Org.Chem.27,2593 (1962). l 3 S . C. Carson andR.D. Howard,British Patent 1,272,475 (1972) [ C A 77,126439(1972)l. l4 E.Kysela, E. Klauke, and H. Schwarz, GermanPatent 2,729,762 (1979) [CA 90,168649 (1979)]. G.Seifert andS.Staeubli, GermanPatent 2,814,450 (1978) [CA 90,23123 (1979)l.

I’

Sec.11.A]


0 \

N

I

\

F

F

5

CI

\

+

N

F

fl

F

CI

HF, 180 C

COMPOUNDS

\

+

F

N

C1

(5)

F

N

(92%)

Vapor-phase fluorination usinghydrogen fluoride and,forexample, a chromiumoraluminum oxide/fluoride catalyst (i.e., theprocedures usedfor (Eq.7). manufacture offluorochloroalkanes16) hasalso beenapplied F

F

CI

(61 KF >> NaF (i.e., withincreasing lattice energy), and because thereactivity offluoride asa nucleophile decreases sharply onsolvation, dipolar aprotic solvents areoften used. Thevery trichloro-l,3,5-triazine(1)isconverted tothetrifluoro derivative (2) reactive withsodiumfluoride" and thetrichloro-l,2,4-triazine(3)apparently requires onlyshort contact inthevaporphaseforsuccessful fluorination.22

cN)KF.450 C

\

N’

"/N

Reaction of pentachloropyridine (4)withpotassium fluoride insulfolane reaction conditions may leads mainly to2,4,6-trifluoropyridine (5)2;milder be employed using potassium fluoride and 18-crown-6 polyether inacetothat evensonitrile butfluorination proceeds onlyto5.24,25 Itisclaimed26

C. W. Tullock and D. D . Coffman,J .Org.Chem.25,2016(1960). M . G. Barlow,R. N. Haszeldine, and D.J. Simpkin, J .C.S.Chem.Commun.,658(1979). 2 3 R. D. Chambers, J. Hutchmson,and W . K. R. Musgrave,Proc.Chem.Soc., London,83 J. Chem.Soc.,3573(1964). (1964); 2 4 N. E.Akhmetova, V. M. Vlasov, and G.G . Yakobson, Bull. Acad.Sci. USSR,Diu.Chem. Sci.27,823(1978). 2 5 R. D. Chambersand D. Pearce, unpublished observations. 2 6 A. Nicholson and R. B. Paton,British Patent1,340,421 (1973) [ C A 80,95756(1974)l.

22

Sec.11.A]


COMPOUNDS

7

diumfluoride may beusedeffectively fortheconversion of4 to5.Thefeature thatlimits theextent offluorination underthese conditions is, essentially, ofthesolvents used. Thisproblemhasbeencircumthethermal stability vented by twoapproaches :(a) using a meltofpotassium fluoride-potassium chloride attemperatures intheregion of750 C2’and,more successfully, (b)employing autoclaves athightemperatures forreactions intheabsence ofa solvent23328 (Eq.9).

A general process hasnow evolved forthesynthesis ofhighly fluorinated oftheperchloro compound, azabenzenoid compounds involving (a) synthesis ofpartly chlorinated compoundswithphosphorus by further chlorination oftheperchloro compoundwith pentachloride and(b) subsequent reaction I.29p44 potassium orevensodiumfluoride. Someexamples areshowninTable H. C.Fielding, L.P.Gallimore, H. L.Roberts, andB.Tittle, J .Chem.Soc.C ,2142(1966). R.E.Banks, R.N. Haszeldine, J.V. Latham, andI.M. Young,Chem.Ind., (London), 835 (1964); J .Chem.Soc., 594(1965). 2 9 R. D. Bowden,M. B. Green, and A. Nicolson, British Patent 1,306,596 (1973) [CA 78, 136089(1973)l. 30 R.E.Banks, R.N.Haszeldine, K . H.Legge, andF.E.Rickett, J.C.S. ferkin I ,2367(1974). 3 1 R.D.Chambers, J.A. H. MacBride, andW. K. R.Musgrave, J.Chem.Soc.C, 2116(1968). 3 2 R.D.Chambers, J .A. H. MacBride, andW. K . R. Musgrave, Chem.Ind., (London), 1721 (1966). 3 3 R. E.Banks, D. S.Field, and R. N. Haszeldine, J .Chem.SOC.C, 1822(1967). 34 Farbenfabriken BayerA. G.,FrenchPatent 1,546,305 (1968) [ C A 72,90492(1970)]. 35 R. E. Banks, D. S.Field, and R. N. Haszeldine. J .Chem.SOC.C, 1280(1970). "C. G. Allison, R. D. Chambers, J .A. H. MacBride, andW. K . R. Musgrave, 1.Chem. Soc.C, 1023(1970). 3 7 D. W. Grisley, E.W. Gluesenkamp, and S.A. Heininger, J .Org.Chem.23,1802(1958). 38 J.K . Chakrabarti, A. F.Cockerill, G . L.0. Davies, T.M. Hotten, D. M. Rackham,and D. E.Tupper, J.C.S. ferkin IZ, 861(1974). R.D.Chambers, M. Hole, B. Iddon, W. K. R.Musgrave, andR.A. Storey, J .Chem.Soc. C, 2328(1966). 40 D. M. W. Van denHam, J .Fluorine Chem.5,537(1975). 41 R. D. Chambers, J.A. H. MacBride, W. K. R. Musgrave, and I.S . Reilly, Tetrahedron Lett., 57 (1970). 4 2 R.D.Chambers, J.A. H. MacBride, andW. K .R.Musgrave, Chem.Commun.,739(1970). 4 3 C.G.Allison, R.D. Chambers, J.A. H. MacBride, andW. K. R. Musgrave, Tetrahedron Lett., 1979(1970). 44 C.G . Allison, R. D. Chambers, J.A. H. MacBride, andW. K. R. Musgrave, J .Fluorine Chem.1,59 (1971-1972).

27

28

’’

8

R. D. CHAMBERS

AND C. R. SARGENT

[Sec. 1I.A

TABLE I DISPLACEMENT OF CHLORINE BY FLUORINE USINGPOTASSIUM OR SODIUMFLUORIDE ~~~

Compound

@ N

/

Conditions (temp., C)

Products (% yields)

References

OH Sulfolane, KF, KOAcethylene (210) glycol

c’&c1(24) F N’ F

29

KF (380)

30

KF(305-310)

31

K F (325-345)

KF (480)

NaF (300)

35

KF (250)

+ partlyfluorinated compounds

X = NO,; CN

@

KF (310-320)

36

KS02F (120-150)

37

Sec.11.A]

POLY FLUO ROH ETE RO A ROM ATIC COMPOUNDS

9

TABLE 1 (Continued) Compound

Conditions (temp.. ’C)

Products ("/"yields)

References

F

I

KF, boiling isobutyl methyl ketone

38

K F (470)

39

K F (420)

39

KF, sulfolane (200)

40

+ partly fluorinated compounds KF,C s F (200)

K F (290)

K F (290)

K F (350)

K F (380)

40

10

R. D. CHAMBERS

AND C. R. SARGENT

[Sec. 1I.A

3. Substitution ofHydrogenby Fluorine Inprinciple, this wouldbethepreferred route, butinpractice no generally successful procedure isavailable forthesynthesis ofhighly fluorinated compoundsdirectly by this approach. Ithasbeenreported thatpentafluoro15% yield by fluorinating pyridine may be obtained in approximately (Eq. But itappears that pyridine overcesiumtetrafluorocobaltate

0 @ 0 N’

+ CsCoF,

+

(ca. 15%)

(ca. 8%)

F

yields diminish withincreasing scale. Silver difluoride hasbeenusedinthe (7)fromtrifluofinal stage ofan earlier synthesis oftetrafluoropyrimidine ropyrimidine (6),’* whichisnow superseded by halogen exchange (see preceding section). Various partly fluorinated compounds may beobtained by direct synthesis using selective fluorinating agents suchastrifluoromethyl

F

45

F

A.J.Edwards,R. G .Plevey, andJ.C.Tatlow, British Patent1,392,571 (1975); R.G .Plevey, private communication.

Sec.11. A]


COMPOUNDS

11

h y p o f l ~ o r ior t eeven ~ ~ ,f~l ~ o r i nas eshown , ~ ~ (Eqs. , ~ ~11and 12),46,48 and (8) areoftremendous clinical importance as compoundslike 5-fluorouracil anticancer drugs. However, theextent offluorination by these procedures is limited. Indeed, theobjective influorinating biologically significant molecules istoachieve verylimited fluorination.

4. Substitution of OtherGroups Various partly fluorinated pyridines canbe synthesized by diazotization oftheaminoderivatives inaqueous hydrofluoric acid,50 orby using anhyofthediazodroushydrogen fluoride followed by thermal decomposition oftheapplication ofthe niumf l ~ o r i d eThere . ~ .are ~ alsomany examples classical Balz-Schiemann reaction toheteroaromatic systems, 334 and the of diazonium tetrafluoroborates hasgivenfluorointeresting photolysis imidazole derivative^^^*^^ and fl~orazoles.~ ofa nitro groupby fluorine insometriazoles hasbeen The replacement achieved usinganhydrous hydrogen fluoride (Eq.13)58and,in2-and 4nitropyridines and 2-nitrothiazole, by usingpotassium fluoride inaprotic (Eq.14).59 solvents

H. Gershon, M. W. McNeil, R. Parmegiani, and P. K. Godfrey, J .Med. Chem.15,987 (1972). 4 D. H . R.Barton. R.H. Hesse, H . T .Toh,andM. M. Pechet, J .Org.Chem.37,329 (1972). 4 8 S.Misaki andY. Furutaka, JapanKokai76/149,287 (1976) [CA 87,135378(1977)l. 49 T. Kanai, M. Ictuno, and T. Nakamura, JapanKokai74/76,882 (1974) [CA 82,16863 (1975)l. 5 0 T.Talik andZ . Talik, Rocz.Chem.47,441(1973) [CA 79,18534(197311. 5 1 M. M. Boudakian, U.S.Patent 3,703,521 (1972) [CA 78,29,635 (1973)l. 5 2 M. M. Boudakian andS.J.Chiras, U S . Patent 3,798,228 (1974) [CA 80,146,026 (1974)l. 5 3 J.L. Lyleand R. W. Taft, J.Hererocycl. Chem.9,745(1972). 5 4 R . K. Smalley, in TheChemistry ofHeterocyclic Compounds (G.Jones, ed.), Vol.32, Chapter 3.Wiley(Interscience), New York.1977. 5 5 K. L. Kirkand L. A. Cohen, J .Am. Cheni.SOC.95,4619(1973). 5 6 K. L.Kirk, W. Nagai, and L. A. Cohen,J .Am. Chem.SOC.95,8389(1973). F.Fabra, J.Vilarrasa, andJ.Coll, J .Helerocycl. Chem.15,1447 (1978). 5 8 S.R. Naik, J.T.Witkowskii, and R. K. Robins. J .Org.Chem.38,4353(1973). 5 9 G. Bartoli, A. Latrofa, F.Naso,andP.E.Todesco, J.C.S. PerkinI ,2671(1972).

46

12

R. D. CHAMBERS

AND C. R. SARGENT

[Sec. 1I.A

A numberoffluorothiophenes havebeenprepared by theaction ofperchloryl fluoride on thienyllithium derivatives, whichwereobtained from thecorresponding bromothiophenes by metal-bromine exchange with ethyllithium.60

5.Saturation -Rearomatization Procedures involving theformation ofsaturated fluorocarbons followed by defluorination (e.g., overiron) havebeenverysuccessful inthesynthesis ofbenzenoid compounds.’ However, defluorination ofperfluoropiperidine (9) isnota practical synthesis ofpentafluoropyridine.61 An indirect process hasbeendescribed recently forthepreparation ofpentafluoropyridine from

perfluoro-N-methylpyrrolidine (10)by passing itoverhotiron.45 10andpentafluoropyridine aretheprincipal products inthe smallSince scale fluorination ofpyridine overcesium tetrafluorocobaltate (Eq.lo), this constitutes an overall direct synthesis of pentafluoropyridine viaa very interesting rearrangement.

6o 61

S.Gronowitz and U. Rosen,Chem.Scr.1,33 (1971) [ C A 75,20080(1971)l. R. E. Banks,A. E. Ginsberg, and R. N. Haszeldine, J .Chem.Sac.,1740(1961).

Sec.11.A]


COMPOUNDS

13

Saturation-rearomatization procedures haveprovided useful routes to A rangeofpolyfluorofurans fluorinated furanand thiophene derivatives. and polyfluorothiophenes isobtained by reaction of products obtained fromtheparent compounds withcobalt trifl~oride,"*~~ ortheless reactive

KC OF,,^^,^^ withpotassium h y d r o ~ i d(Scheme e ~ ~ ,3). ~~ Tetrafluorothiobeenprepared by a route involving a final dechlorinaphene(11)hasalso (Eq.15)67; and2,5-difluorothiophene (13) by theunusual tion step using zinc defluorination of2,2,5,5-tetrafluoro-3-thiolene (12)oversodiumfluoride.68 Perfluorobenzofuran (15)canbe prepared by reaction ofbenzofuran (14) withCsCoF,,followed by defluorination withnickel.69 J.Burdon,G .E.Chivers, E. F.Mooney,and J. C. Tatlow, J .Chem.SOC.C ,1739(1969). J. Burdon,I.W. Parsons, and J. C.Tatlow, J .Chem.SOC.C, 346 (1971). J. Burdon,G. E. Chivers, and J. C .Tatlow, J .Chem.SOC.C, 2585(1969). 6s J. Burdon,G .E. Chivers, and J . C. Tatlow, J .Chem.SOC.C ,2146(1970). 66 J.Burdon,J. G .Campbell, I.W. Parsons, and J . C. Tatlow, J .Chem.SOC.C, 352(1971). 67 E. M. Ilgenfritz and R. P. Ruh, U.S.Patent2,932,651 (1960) [CA 54,18549(1960)l. J. Burdon and I.W. Parsons, J .HuorineChem. 13,159(1979). 69 J . Bailey, R . G . Plevey, and J. C. Tatlow,Tetrahedron L e f t869 . , (1975).

62

63

14

R. D. CHAMBERS

CFCl=CFCF=CFCl

’ "I

3 IS O T F G , F l IS O T

cF&,Fl 1

!eLl

AND C. R. SARGENT

[Sec. 1I.B

-!$ -!$

(15)

B. CYCLIZATIONS USINGFLUORINATEDPRECURSORS 1 . Involving Fluorinated BenzeneDerivatives There isnow asignificant literature onthesubject ofcyclizations involving fluorinated benzene derivatives, and reference should be made to earlier reviewer^’-^*^’ formoregeneral aspects, since here we will onlybeconcerned toaromatic heterocycles asopposed toheterocycles withprocesses that lead that arethemselves notaromatic butareattached toaromatic rings.

a,Intramolecular Nucleophilic Aromatic Displacement of Fluoride.

One ofthemostdirect approaches tothesynthesis ofheteroaromatic compoundsinvolves nucleophiles that arepotentially difunctional. Thegeneral(16)hasa site acidified by thenearby heteroatom, buton subizedsystem stitution theheteroatom may becomea further nucleophilic site andavailableforringclosure. Sometimes these processes canbothbe carried out in one-step procedures, or theintermediate (17)may be isolated before 4).Various benzofuran derivatives havebeenobtained cyclization (Scheme using this procedure71p75 (Eqs. 1671and17,72Scheme573), andtheuseof S.C. Cohen and A. G. Massey,Ado.Fluorine Chem.6,83 (1970). G. G. Yakobson,T. D. Petrova, L. I.Kann,T. I.Savchenko, A. K . Petrov, and N. N . Vorozhtsov, Dokl.Akad.Nauk SSSR 158,926(1964) [CA 62,2755(1965)]. l 2 Y. Inukai, T.Sonoda,and H. Kobayash,Bull. Chem.Soc.Jpn.52,2657(1979). 7 3 G. M. Brooke, Tetrahedron Lett., 2029,4049(1968). ’4 G. M. Brooke, W. K. R. Musgrave,and T. R. Thomas,J .Chem.SOC.C,3596(1971). 7 5 T.D.Petrova, L.1.Kann,V.A.Barkhash, andG.G.Yakobson, Khim.Geterotsikl. Soedin.. 778(1969)[CA72, 111190(1970)].

’O

l1

0

+

MeCOCHC0,Et

THF. NaH [

~

Na+

~ ON

H

c

o

z

E

~(16)

’Me

Me (30’g)

RCH=CR’

I

OSiMe,

& [ R C H ~% ~]

(17)

I

R = Ph,H, H R’ = Ph,Me, H

I

H,S E1OH.OC

SH (56";)

[@’"""]

(85";)

SCHEME5

16

R. D. CHAMBERS

[Sec. 1I.B

AND C. R. SARGENT

thetrimethylsilyl group(Eq.17)isaninteresting variation forthecyclization (19)hasbeengenerated by addition step. Also, theprecursor forcyclization ofwatertotheacetylene (18)ina reaction catalyzed by cesiumfl~oride.’~

(18)

190%)

(19)

Corresponding reactions involving cyclization through s u l f ~(Scheme r ~ ~ , ~ ~

573)havealso beendescribed. Indole derivatives havebeen~ b t a i n e dbY~ ~ - ’ ~ cyclization through nitrogen, butinthese cases theprecursors areoften made (Eq.18),79 wherecarbonyl hasserved fromappropriate carbonyl compounds offacilitating carbanion formation forthefirst displacement of thepurpose function isalso effective forthis purposea0,’’ fluoride inScheme4.Thenitrile (Eq.19). C6F,CH,CPh 0

ZnCI,

I

11

Ph

Ph

Ph (76%)

H

H

(19)

M. R. Wilesand A. G. Massey, J. Organometal. Chem.47,423(1973). 77 M. D. Castle, R. G. Plevey, andJ.C. Tatlow, J. Chem.SOC.C , 1225(1968). ’I3 V. P.Petrov and V. A. Barkhash, J. Gen.Chem. USSR (Engl. Transl.) 39,1583(1969). 79 G. M. Brooke, W. K. R. Musgrave, R.J.D. Rutherford, andT.W. Smith,Tetrahedron 27,5653(1971). R. Filler, S.M. Woods,andA. F.Freudenthal, J. Org.Chem.38,811 (1973). T.D.Petrova, T.I.Savchenko, 0. S.Kukovinets, andG.G.Yakobson, Izu.Sib. Otd.Akad. [CA 81,25488(1974)]. Nauk SSSR,Ser.Khim.Nauk,117 (1974) " V . P.Petrov, V. A. Barkhash, G. S.Shchegoleva, T. D. Petrova, T. I.Savchenko, and G. G. Yakobson, Dokl.Akad.Nauk SSSR 178,864 (1968) [ C A 69,35851(1968)]. 13’ V. P. Petrov and V. A. Barkhash, Khim.Geterotsikl. Soedin., 622 (1970) [ C A 73,98720 (1970)]. 84 T.D.Petrova, T.I.Savchenko, T.F.Ardyukova, andG.G.Yakobson, Izv. Sib.Oid.Akad. [CA 74,53393 (1971)l. Nauk SSSR,Ser.Khim,Nauk,119(1970) V.P.Petrov andV. A. Barkhash, Khim.Geterotsikl. Soedin., 381,385 (1970) [CA 73,25229, 98721(1970)l. 76

Sec.11. B]

POLY FLUOROHETE

RO A ROM ATIC COMPOUNDS

17

The aminofunction may be usedinconjunction withother heteroatoms (Eq.20)toeffect cyclization ina manneranalogous tothat outlined forcarway heterocycles containing two nitrogen banions inScheme4. In this

atomss6 ornitrogen together witho ~ y g e nor ~ s~~,l ~ f u~ r have *~ ~~been ~ ,~ obtained. Intramolecular nucleophilic substitution offluoride by heteroatoms can also leadtotricyclic systems suchasdibenzofuran andacridinonede(Eqs.21 and22). rivatives

a3--a:)

Ringclosure could also be effected viadisplacement offluoride ionby a (20) already having formeda link withtheappropriate heterocarbanion

X

/

(20)

atom.So far, species like 20 havebeengenerated insitu by theinteresting addition ofsulfur (Eq.23) ornitrogen (Eq.24)93 nucleophiles toacetylenedicarboxylic ester. Quite reasonably, thesuccess ofthese reactions hasbeen Y. Inukai, Y .Oono,T. Sonoda,and H. Kobayashi, Bull. Chem.SOC.Jpn.52,516(1979). G. S.Shchegoleva and V. A. Barkhash, Izv. Sib. Otd.Akad.Nauk SSSR,Ser. Khim.Nauk, 123(1971) [ C A 77,48316(1972)l. G.S.Shchegoleva, M. I.Kollegova, and V. A. Barkhash, Izv. Sib. Otd.Akad.Nauk SSSR, [CA 77,101494(1972)]. Ser.Khim.Nauk,126(1971) 89 F. C. Herkes, J .Fluorine Chem.12,1 (1978). 90 P.J. N. Brown,R. Stephens, and J. C. Tatlow,Tetrahedron 23,4041 (1967). 9 1 D. M. Owen, A. E. Pedler, and J .C.Tatlow, J.C.S. PerkinI ,1380(1975). 9z G. M . Brookeand M. A. Quasem,J . Chem.Soc.C ,865 (1967). 9 3 G. M. Brookeand R. J. D. Rutherford. J .Chem.SOC.C , 1189(1967).

86

87

18

R. D. CHAMBERS

[Sec. 1I.B

AND C. R. SARGENT

attributed tosyn-addition toacetylenedicarboxylic ester, therefore allowing oftheintermediate carbanion corresponding to20.Coneasyring closure sequently,lower the yields obtained inthecorresponding reactions using hexafluoro-2-butyne (Eq.25)94may beascribed toacompeting anti-addition, since syn-addition inthis caserequires placing bulky trifluoromethyl groups incloser proximity.

0

SLi

Cz(CozEt)2+

[as-; o ~

,CCO,Et

~

~

c

o

I

C0,Et

(23) z E

1 H,SO, 2.Cu quinoline

I

H

C,F,SLi++ CF,C-CCF,

(11%)

+

F,C

c=c F,C

C=c

CF,+ polymer /

H

involves addition totetrafluorobenzyne, genAn extension ofthe in situ frompentafluorophenyllithium (Eq.26). erated

94 95

G. M. Brookeand M. A.Quasem,J.C.S. PerkinI ,429 (1973). R. D. Chambersand D.J. Spring, Tetrahedron Lett., 2481 (1969).

t

Sec.11.B]

X

=

POLYFLUOROHETEROA

ROM ATIC COMPOUNDS

19

F.OMe

b.From ortho-Dfunctional Compounds.A hydrogenatom is the simplest functional groupina polyfluoroaromatic ringbecause oftheacidifying influence ofadjacent fluorine atoms(e.g., metal-hydrogen exchange occurs withbutyllithium). Metal-bromine exchange occurs more readily, however, anddilithio compoundsgenerated fromappropriate sources have (Eq.27)98 heteroledtosulfur,96 seleni~m, tellurium,97 ~ andphosphorus Octafluorodibenzothiophene (22)may be synthesized by reaction of cycles. dichloride orfromthethioether 23.96 thedilithio compound21 withsulfur

aLi fSC1,

Br

ether.hexane

-78 C

(23)

Replacement ofiodine, inthediiodo derivative 24 by sulfur, selenium, or (25),97 while someheterotellurium also gives thecorresponding heterocycles (Scheme 697). cycles may beobtained directly fromdiiodotetrafluorobenzene Thesereactions arealsoof interest because further interconversion of 25 (X = Te orSe)to25 (X = S)] by heating the heterocycles occurs [e.g., selenium or tellurium compoundswithsulfur.99 Octafluorodibenzothiotooctafluorodibenzofuran (27)by aninteresting phene(22)may beconverted R. D. Chambers,J.A. Cunningham,and D. J.Spring, Tetrahedron 24,3997(1968). S.C . Cohen,M. L. N . Reddy,and A. G. Massey,J .Oryammet.Chem. 11,563(1968); Chem.Commun.,451 (1967). 9 8 R. D. Chambersand D. J.Spring, J .Fluorine Chern.1, 309 (1971/1972). 99 S.C . Cohen and A. G. Massey, unpublished results, quotedin Ref.70. 96

97

20

R. D. CHAMBERS

AND C. R. SARGENT

[Sec.1I.B

(86%) 320 C

SCHEME6

pyrolytic elimination ofSO fromthedioxide (26).’0Related tothese interconversions butnotstrictly involving difunctional derivatives, istheconversionofthemercurial 28 tovarious heterocycles (Eq.28)."’

M

= S,Se,Te

R. D. Chambers,J . A. Cunningham,and D . J. Spring, J .Chem.SOC. C , 1560(1968). C. M. Woodward,G . Hughes,and A. G . Massey,J .Organornet. Chem.112, 9 (1976).

loo 101

SeC.11.B]


COMPOUNDS

21

Itisuncommonforsubstitution ina pentafluorobenzene derivative C6F5X tooccurpredominantly ata position ortho tothefunctional groupX, but when nitro orN-oxide groups arepresent, attack by ammoniaorhydrazine seemsto be governed by hydrogen bondingbetweengroupX and the of incoming nucleophile. The formation ofcyclic compoundsinreactions nitropentafluorobenzene and29 withhydrazine hydrate may beunderstood asformation ofan intermediate hydrazino compoundwhichreacts further 7 andEq.29).’02 A directing influence ofcarbonyl inpentafluoro(Scheme acetophenone to theorthoposition, forattack by amines, may alsobe

NHNH,

SCHEME7

(29)

attributed totheeffects ofhydrogen bonding, andthese substitution products Thistype formcyclized compoundsby reaction withacid(Scheme8’03). of cyclization, viaintramolecular electrophilic aromatic substitution, has similarly beenutilized in thepreparation of a~ridine’~’’~’ and phenanthridine’" derivatives. J . M. Birchall, R. N . Haszeldine, and J. E. G . Kemp, J. Chem.SOC. C, 1519 (1970). T.N. Gerasimova, L. L. Gelumbovskaya, I.I.Baturina, and E. P.Fokin,Izu.Sib. Otd. Akad.Nauk SSSR,Ser.Khim.Nauk,88 (1973)[CA 79,53161 (1973)l. N. A. Orlova, L. L. Dmitneva, T.N.Gerasimova, and E.P.Fokin,Izo.Sib.Otd.Akad. Nauk SSSR,Ser.Khim.Nauk,109 (1976)[CA 85,77984 (1976)]. ’ 0 5T.N. Gerasimova, N. V. Semikolenova, and E.P.Fokin, Izu.Sib.Otd.Akad.Nauk SSSR, Srr. Khim.Nauk,142(1977)[CA87,134160(1977)]. Io6 S.Hayashiand N . Ishikawa, NipponKagaku Kaishi1319 (1973)[CA 79,78576 (1973)l. ’O’S.Hayashiand N . Ishikawa, Chem.Lett., 99 (1972)[ C A 76,113041(1972)]. T.V. Fomenko,T.N . Gerasimova, and E. P. Fokin,Im. Sib. Otd.Akad.Nauk SSSR, Ser.Khim.Nauk,99 (1977)[CA 87,5778 (1977)l.

lo’

0

II

+RC,H,NH, (30)

R in 30= 4-Me,4-Me0,4-Br,

R in30 = 2-Me,2-Me0

4-Me,N,H

SCHEME 8

I

R

NaNO, H2S0,

=

Ph orMe

/

SCHEME 9 0

I/

a-

I

OCHzC02Et

1. NaOH/EtOH 2 H,O’

E 2. P,O, Q J O

SCHEME

A 10

0

Sec.II.B]


COMPOUNDS

23

Other cyclizations ofortho-difunctional compounds areshowninSchemes 91 9and andinEq.(30)."’ c. Miscellaneous. Cyclizations havebeenobserved intheoxidation of fluorinated aromatic aminesto phenazine derivatives by electrochemical 11’1 2 * 1 1 3 )andby reaction withleadtetraacetate.’ l 4 The processes (Scheme classical Fischer indole process canbe applied toappropriate polyfluoroaromatic compoundsas,forexample, in thepreparation of tetrafluorocarbazole (31) (Eq.31)."’

( A 0 = anodic oxidation)

H

Me0

Me0 SCHEME I 1

J . M . Birchall, R. N . Haszeldine, J . Nikokavouras, and E.S.Wilks, 1.Chem.Soc.C ,562 (1971). ’ l oG. M. Brookeand B. S.Furniss, 1 Chrm.Soc.C ,869 (1967). C. M. Jenkins, A. E. Pedler, and J . C. Tatlow,Tetrahedron 27,2557 (1971). A. G. Hudson,A. E.Pedler, and J . C. Tatlow, Tefrahedron 26,3791 (1970). A. G. Hudson,M. L.Jenkins, A. E.Pedler, and J .C.Tatlow, Tetrahedron 26,5781 (1970). J. M. Birchall, R. N. Haszeldine, and J . E. G . Kemp, J . Chem.SOC.C, 449 (1970).

’09

115

T.D. Petrova, V. P. Mamaev, and G. G. Yakobson,Bull. Acad.Sci. USSR,Div.Chem. Sci.,609 (1969).

24

R. D. CHAMBERS

AND C. R. SARGENT

[Sec. 1I.B

2.Involving Fluorinated Alkenes andAlkynes Forconvenience, this section hasbeenformally divided into those reactions involving nucleophilic attack andthose involving cycloaddition. However, insomecases this division isarbitrary (e.g., reactions of1,3-dipoles), andthe ofreactions ofthis typeinto either section should notbe taken placement asa firmopinion ofmechanism, i.e., concerted orstepwise. Inmostcases, themechanistic evidence doesnotallow a clear distinction tobe made.

a. ViaNucleophilic Attack.Itwouldseemobvious that reactions of difunctional nucleophiles withvarious unsaturated fluorocarbons could givecyclized products. Thistypeofreaction hasalready beendescribed in Section II,B,l,a. inrelation toreactions offluorinated benzenes, butinteresting cyclic products may also be obtained from, forexample, fluorinated alkenes. Product 33 fromhexafluoropropene withortho-phenylenediamine may berepresented asarising frominitial addition, accompanied by loss of hydrogen fluoride giving 32,followed by cyclization.’ Similar cyclizations l 7andalso involving different occur withother difunctional nucleophiles’ fluorinated alkenes (Eq.32).’ l8 1 6 y 1

.Oz’

(32)

(33)

CF,,,,,,:,

.-I

’CF--CH(CF,),

R.T

X = H, CH,,orC1,Y X = H orC1,Y = N H

=

0

(32)

X-)-CHKFJZ \ Y lI6

N.Ishikawa and T.Muramatzu,NipponKagukuKuishi563(1973) [CA 78,147873(1973)l. T.Nakai,N . M. Hassan,and N. Ishikawa, Buff. Chem.SOC.Jpn.50,3014(1977). H. Harada,S.Mizutaki, S.Hayashi, and N . Ishikawa, J .Fluorine Chem.12,211 (1978).

Sec.ILB]


25

COMPOUNDS

Ketenimines, formedasintermediates inthereactions ofaromatic amines (34), cyclize in an interesting process witha dimerof hexafluoropropene of variousheterocyclic systems thatyieldsperfluoroalkyl derivatives (Eq.33).’ l9 NPh

YHPh

(33)

(34)

J 1I)

/

-COF,

I oFo’r; flF (X = CI,120/) (X = Br,lo",,)

(X = CI,29"/) (X = Br,32"/,)

(X = CI,18"/,)

(X = Br,14"(cFXH)3

(60)

N d N

Amidines (83) areeasily prepared by theaddition ofammoniatofluoriisthenobtained by heating, nated nitriles, andcondensation oftheamidines

(83) \CN

,NHZ RFC.\ //NH N-C \ RF

/

(84 K. E. Peterman andJ.M. Shreeve, J .FluorineChem.6,83 (1975). E. 1. duPontde Nemours& Co.,British Patent 988,199 (1965) [ C A 63,700(1965)]. W. L. Reilly and H. C. Brown,J .O r y . Chem.22,698(1957). 1 9 2 W. E. Emerson andE.Dorfman, U.S.Patent 3,728,344 (1973) [CA 79,19743(1973)l. 193 N . P.Aktaev, V. A. Pashinin, G.A. Sokol’skii, F.N. Chelobov, andI.L.Knunyants, Bull. Acad. Sci. USSR,Diu.Chem.Sci., 2181(1974). 194 L.1.Ragulin, A. I.Martynov, G.A.Sokol’skii andL.L.Knunyants, Bull.Acad. Sci. USSR, Dit>. Chem.Sci., 2074(1969). 1 9 5 J.L.Zollinger, U S . Patent 3,470,17~: ,969) [ C A 71.124513 (1969)]. 196 E. Dorfmanand W. E.Emerson, FrenchPatent 1,560,303 (1969) [ C A 71,125482(1969)]. 19’ W. E.EmersonandE.Dorfman, FrenchPatent 1.554.658 (1969) [ C A 71,49988(1969)J. 19’ D. Paleta andZ . Prochazkova, Collecr. C;ecll. Chem.Commun. 35,3452(1970) [ C A 74, 13106(1971)]. 199 G .W. figby. U.S.Patent 2,484,528 (1949) [CA 44,5925(1950)].

Ia9

I9O

42

R. D. CHAMBERS

[Sec. 1I.B

AND C. R. SARGENT

liberating theammoniaagain ina stepwise f a s h i ~ n .The ’ ~intermediate ’*~~~ (84)may beisolated andconverted toa t r i a ~ i n e .Ma * "ny - of ~ ~the ~ reactions betweenammoniaandmultiple bondsarereversible because a degree of scrambling occurs when different perfluoroalkyl derivatives areused(Eq. 61),’05 although this canbe minimized inreactions using an anhydride or

R,COOEt

5RFCONHz

RFCN

a

e.g., R, = C,F,, R; = CF, (80%) RF = CF,CICFCICF,. R; = C3F7 (93%)

acidchloride asthecondensing agent (Eq.62).’98,203-208 Trimerization of certain imines may also beachieved (Eq.63).209 ’

N(SCF,),

G. A. Grindahl, W. X. Bajzer, and 0.R. Pierce, J .Org.Chem.32,603(1767).

"’H. C. Brown,J.Polym.Sci.44,9 (1960).

P.C. R. Inc., FrenchPatent2,166,498 (1973) [ C A 80,70845(1974)l. G.B.Fedorovaand I.M. Dolgopol’skii, J .Gen.Chem.USSR (Engl. Trans/.) 39,2649 (1969). ’04 T. S.Croft and C. E. Snyder, J .Heterocyd. Chem.10,943 (1973). ’ 0 5 H . C. Brown,P.D.Schumann,and J . Turnbull, J .Org.Chem.32,231 (1967). ’06 M. Tsunodaand K. Omata,JapanKokai 77/25,785 (1977) [CA 87,85055(1977)J. J. A. Young and R. L. Dressier, J .Org.Chem.32,2237(1967). ’ 0 8 G. A. Grindahl, 0.R. Pierce, and J. R. Greenwald, US.Patent3,566,835 (1971) [CA 74, 143092(1971)]. ’09 A. Haas and V. Plass, Chem.Ber.105.2047(1972). ’O’

’03

Sec.11.B]

POLYFLUOROHETEROAROM

ATIC COMPOUNDS

43

ii. Ofhersystems. Pyrimidines containing a singleperfluoroalkyl groupareproducedin conventional cyclization procedures210-21 (e.g., Eq.642’O). Perfluoroalkyl derivatives ofisoquinolineZ1 andrelated heterocyclic compoundsZ1 havealsobeenobtained by cyclization procedures.

c. Oligomers and Polymers.A numberof theprocedures described forforming rings (e.g., oxadiazoles ortriazines) havebeenapplied tothe ofpolymers, using appropriate difunctional compounds. Some of synthesis theresulting systems haveveryfavorable thermal and chemical stability characteristics, buttheapplication ofsuchmaterials isinevitably limited by cost. Compoundscontaining twooxadiazole rings may beobtained fromappropriate difunctional compounds’ 7 s . 17 6 * 17 8 , 1 9 0 , 2 1 (e.g., Eq. 65)and a polymermay alsobeobtained (Eq.66).190 A significant research effort hasbeendirected towardfluorinated triazine of theformation of theseinteresting po~ymers,208.218-221 and examples elastomers ofveryhighthermal stability aregiven(Eqs. 67’18and 6821 ’).

A. Kreutzberger and U. H . Tesch, Arc,h. Plzarm. (Weinheim, Ger.) 310,56 (1977) [ C A 86, 189838(1977)J. ’I1 A. Kreutzberger and S . Leyke-Roehling. Arch.Pharm.(Weinheim, Ger.) 311,884 (1978) [ C A 90.38870(1979)l. ’I’ A. Kreutzberger and S . Leyke-Roehiing, J .Heterocycl. Chem.15, 1097(1978). ’ I 3 R. Pastor and A. Cambon,J .Fluorine Chetn.13,279 (1979). P.M. Hergenrother and M. Hudlicky. J .Fluorine Chem.12,439(1978). 2 1 5 I .L.Knunyants, M. P.Krasuskaya, andD.P.Del’tsova, Bull. Acad.Sci. USSR,Dit.. Chem. Sci., 552(1966). ’ l hZ. I.Mazalova, V. A. Lopyrev, and S.V. Sokolov, Zh.Org.Khim.8,531(1972) [CA 77, 34424(1972)l. M. P.Krasuskaya, D.P.Del’tsova, andI.L.Knunyants, Bull. Acad.Sci. USSR,Div.Chem. Sci.. 2002(1965). 2 1 * SeeRef. 156fora detailed discussion. J . R. Greenwald. and 0.R. Pierce, German Patent 1,953,857 (1970) ’19G.A. Grindahl, [ C A 73,56975(1970)]. Y .K. Kim and 0. R. Pierce, German Patent1,928,050 (1969) [ C A 72,67083(1970)]; U.S.Patent 3.847.916 (1974) [ C A 82,112436(1975)l. Y. K. Kim and0. R.Pierce, J .Ory.Chem.34,602(1969). ’lo

*’’

44

R. D. CHAMBERS

AND C. R. SARGENT

[Sec. 1I.C

Related systems arealsopotentially useful as highthermal stability oils,

,tC.222-22 5

C. INTRODUCTION OF PERFLUOROALKYL GROUPS Conversion of carboxyl groupsto trifluoromethyl, usingsulfur tetramay beapplied toheterocyclic systems (e.g., Eqs.69227 and f l ~ o r i6-2 d e29 ,~ 70229) butyields arevariable.

(20%) P.D. SchumanandE.C.Stump,U.S.Patent 3,888,854 (1975) [CA 83,193398(1975)l. T.S.Croft andJ.L.Zollinger, U.S.Patent 3,816,416 (1974) [CA 81,105583(1974)l. 2 2 4 G. B. Fedorova, 1. M. Dolgopol skii, and L.G. Parshina, Zh.Org.Khim.9,1080(1973) [CA 79,53270(1973)l. 2 2 5 T. S.Croft, J.L.Zollinger, and C. E. Snyder, Ind.Eng.Chem.,Prod.Res.Dec.13,144 (1974) [CA 81, 13468(197411. 2 2 6 W. C. Smith, A n p w . Chem.,Int.Ed.Engl.1.467(1962). W. R. Hasek, W. C. Smith, and V. A. Engelhardt, J .Am. Chem.Sor.82,543(1960). Y. Kobayashi, 1. Kumadaki,andY. Hanzawa,Chem. Pharm.Bull. 25,3009(1977). zz9 B. V. Lyalin, A. V. Grigorash, L.A. Alekseeva, andL. M. Yagupol skii, Zh.Org.Khim. 11,460 (1975) [ C A 83,9849(1975)]. 222

2z3

.c]POLY FLUOROHETEROA

SeC. 11

ROMATlC COMPOUNDS

45

Thermalreactions of iodo-or bromopertluoroalkanes withhetero3 0 ~ 2 3 (Eq. 2 71)231 cycles haveledtoperfluoroalkyl derivatives ofpyridine andp y r r ~ l ewhile , ~more ~ recently ithasbeendemonstrated that photo(Eq.72).234 chemical initiation isespecially effective

Polyfluoroalkylcopper compoundsmay be formedinaprotic mediaand havebeenusedsuccessfully fortheintroduction ofperfluoroalkyl into various and pyrimidine aromatic ~ y ~ t e r n ~(Eqs. ~73236 ~ ~ ~ 74228), ~ ~ including ~ derivatives ofbiological interest.237p239 L.M. Yagupol skii, A.G.Galushko, andM. A. Rzhavinskaya, J .Gen.Chem.USSR (Engl. Trans/.) 38,644(1968). 1 3 1 L. M. Yagupol skii, A. G. Galushko. and V. 1. Troitskaya, J.Gen. Chem. U S S R ( E n g / . Trunsl. ) 38.1692(1968). 2 3 2 J . H. Tobin. U.S.Patent 4,101.554 (1978) IC.490.22831(1979)l. 1. Cantacuzene. C .Wakselman. and R.Dorme.J .C.S.Prrkir7 I . 1365(19771. Y. Kobayashi, I . Kumadaki,A. Ohsawa,S.Murakami, and T.Nakano,Chem. Pharm. Bull. 26.1247(1978). 2 3 5 R. Nishiyama. T.Haga.and N. Sakashita. Japan Kokai. Tokyo Koho 79/22371 [CA 11. 56826(197911. 2 3 6 V. C. R. McLoughlin andJ.Thrower, Tetrahedron25.5921(1969). 13 Y. Kobayashi, 1. Kumadaki, andK. Yamamoto.J .C.S. Chem.Commun.. 536(1977). D.Cech,R. Wohlfeil, and G. Etzold. Nurleir AridsRes., Spec. Pub/.1,S5-S8 (1975) [CA 85,46984(1976)]. 239 U. R. Polishchuk, G. Ya. Bekker, E.A. Avetisyan, and L. S.German,Zh.Vses. Khim. 0-zn 21. 222 (1976) [CA 85.63021(1976)l.

230

46

R. D. CHAMBERS

A N D C. R. SARGENT

[Sec. 1I.C

(53%)

Copperderivatives ofpolyhalogenopyridines arereadily formedz4’ and (Eq.75), havebeenusedtomakethecorresponding trifluorovinyl derivatives butreactions ofthecopper compoundswithiodoperfluoroalkanes do not appear tobesuccessful.

h;lm

fi0 cu

CF=CF,

CF,=CFI,

N

(75)

N

A rangeofperfluoroalkyl derivatives ofhighly fluorinated heterocyclic compounds may be obtained influoride-induced reactions withfluorinated 76), willbedescribed inmoredetail later. Copya l k e n e(Eq. ~~~ ’ butthese rolysis ofthiophenethiol withtetrafluoroethylene gives a fused ring system (Eq.77).242

E.J . Soloski, W. E.Ward, and C.Tamborski, J .Fluorine Chem.2,361 (1972/73). R. D. Chambers,J . A. Jackson, W. K. R. Musgrave,and R. A. Storey, J .Chem. Soc.C, 2221(1968). 242 V. E.Platanov, A. M. Maksimov,andG.G.Yakobson, Izv. Akad.Nauk SSSR,Ser. Khim., 2387 (1977)[CA 88,74250(1978)l. 240

241

Sec.111. A]

POLYFLUOROHETE ROAROM

ATIC COMPOUNDS

47

111.Properties and Reactions

A. PHYSICAL PROPERTIES Hexafluorobenzene andbenzene haveverysimilar boiling points andthe generally close relationship between theboiling points ofhydrocarbons and thecorresponding fluorocarbons isreasonably attributed toa significant reduction inintramolecular forces inthefluorocarbon whichoffsets increased molecular weight. Incomparing a series ofazaaromatic compoundswith their perfluorocarbon counterparts (Table 11),243 we seethat boiling points forthefluorocarbons areactually lowerthanthose of thenonfluorinated This, inturn, may be attributed tothefact that thebasestrength analogs. inthefluorine derivatives isveryconsiderably reduced. Indeed, super acids arerequired in orderto obtain salts frompentafl~oropyridine, while ~~ of 3,5-dichlorotrifluoropyridine requires methylfluorosulmethylation f ~ n a t eUsing . ~~ competition methods,244 a comparison of theorders of ofsomesystems hasbeenobtained (Scheme 22); and relative basestrengths itwas concluded, froma comparison withtheorders oftheparent compounds, that themostimportant factor affecting basestrength ofnitrogen in thefluorinated systems isthenumberoffluorine atomsthat flank the nitrogen atom. TABLE I1 BOILING POINTS OF PERFLUOROAZAAROMATIC COMPOUNDSIN COMPARISON WI TH PARENT COMPOUNDS Compound

Boiling point ( C)

Pyridine 115.5 Quinoline 238.0 Isoquinoline 243.3 Pyridazine 208.0 Pyrimidine 123.5-124.0 Pyrazine 115.5-1 15.8 a

of Boiling point perfluorinated derivative (T)h

83.5-84.0 205 212 117 82-83 53-54

SeeRef 243. SeeYakobsonete14.

R.C.Weast, ed. HandbookofChemistry andPhysics, 56thed.Chem.RubberPubl. Co.. Ohio,1975. Cleveland, 244 S.L.Bell, R.D. Chambers, W. K. R.Musgrave, andJ.G.Thorpe, J. Fluorine Chern.I ,51 (1971/1972). 2 4 5 E.Agerand H. Suschitzky, J .Fluorine Clwni. 3,230(1973).

243

48

R. D. CHAMBERS

AND C. R. SARGENT

[Sec. 1II.C

-

Decreasing basestrength SCHEME22

B. INDUSTRIAL APPLICATIONS At thetimeofwriting, many heterocyclic compounds containing fluorine orfluorocarbon groups areeither inuseorunderactive investigation inthe fields of chemotherapy and agrochemicals. The list islongand rapidly changing, and detailed discussions areavailable elsewhere.246 Therehas beenintense activity inbringing into use4-chlorotrifluoropyrimidine asthe basis of various fiber-reactive dyes,247 and thepatent literature abounds withclaims fortheuseofvarious fluorinated systems inthis field andfor other dyeswithhighstability.

C. NUCLEOPHILIC SUBSTITUTION 1.Pyridines and Related Systems Withhighly fluorinated pyridines andrelated compounds, evidence indicates thefamiliar two-step mechanism fornucleophilic aromatic substitution, (k,)being rate-limiting (Eq.78). As withother haloaromatic withthefirst step someof thestrongest evidence thatthis isthecasestems fromthefact thatthemobility order ofthehalogens isF >> C1,Br,I,i.e., showing that there canbe little carbon-halogen bondbreaking intheratedetermining step. Inprinciple, this mobility order neednotalways apply; isevidence that sym-trichlorotriazine ismorereactive than and, indeed, there sym-trifluorotriazine ina reaction withaniline.249 Enormous reactivity increases along theseries ofperfluorinated derivatives ofbenzene, pyridine, pyrimidine, andsym-triazine, illustrating thedominatR. Filler. in Organofluorine Chemicals andtheir Industrial Applications (R.E. Banks, G.T.Newbold.ibid.,Chapter 8. ed.), Chapter 6.Ellis Horwood,Chichester, 1979; 24 W. Harms, in Organofluorine Chemicals andtheir Industrial Applications (R.E.Banks, 10. ed.), Chapter 9.Ellis Horwood,Chichester, 1979;G .Wolfrum,ibid.,Chapter 2 4 8 See, e.g., R.D.Chambers andS.R.Jamesin Comprehensive Organic Chemistry(D.H.R. eds.). Vol.I , p 493,andref. contained therein. Pergamon, Oxford, Barton andW. D.Ollis. 1979. 2 4 9 TranMinh Chinh, J.Kavalek, and M. Vecera, Collect. Czech. Chem.Commun. 37,3328 (1972) [CA 79,136155 (1973)l.

246

(p+ 1 b+

Sec.III.C] POLYFLUOROHETEROAROMATIC

COMPOUNDS

49

Nu

Nu-

+

A

F

N

N’

F-

(78)

N’

inginfluence ofringnitrogens. Itisonlywithhighly halogenated systems thatproblems of orientation arise in nucleophilic aromatic substitution. Theseare, ofcourse, analogous totheclassical problems of electrophilic A comparison ofthepositions aromatic substitution inhydrocarbon systems. reveals thatthering of attack incompounds85 and 86 (Scheme23250) fluorine atomshavean important influence on theorientation ofattack. In 85,thedisposition offluorine atomsforattack at2-,6-,or4-positions is soa preference forattack atthe4-position may be attributed symmetrical, of nitrogen. Therefore, thefact thatattack occurs totheorienting effect froman additional orienting exclusively atthe4-position in86 mustarise ~distinguish ’~-~~~ influence ofthefluorine atomsin86.Ithasbeenp o ~ s i b l eto F

I

(85)(4-: 78’!:,)

(2,6-: 22",,)

(86) (4-: 100%)

SCHEME 23.Positions ofsubstitution by aqueous ammonia.

theseparate activating influences offluorine atomsortho, meta,andparato thecenter under attack, bycomparison ofvarious rate constants forattack on polyfluorobenzenes or -pyridines by aqueous ammoniaormethoxide ion (Scheme 24). Therefore, ithasbeenconcluded that a fluorine atomparato NU-\F

Activating influence ofF atoms

’-.

ortho b m e t a para

meta-> ortho>> para-(benzenes) orrho> meta->> para-(pyridines)

SCHEME24

thesite ofattack isslightly deactivating, whereas fluorine atomsortho and metaarestrongly activating, and therelative magnitude oftheortho and A rationale ofthese effects hasbeenpremetaeffects depends on the system. sented but, whatever thedetailed explanation, theexperimentally determined 250

R. D. Chambers. J. S.Waterhouse. and D. L. H. Williams, J .C. S.Perkiti 11. 585 (19771.

"’R. D. Chambers,D. Close,W. K. R. Musgrave. J.S.Waterhouse. andD. L.H. Williams, J . C .S.PerkinII,1774(1977). R. D.Chambers, D.Close, and D. L. H. Williams. J .C.S .Perkin11.778(1980).

50

R. D. CHAMBERS

(86) X =F (5)x = C1

AND C. R. SARGENT

(87)X = F (85) X =H

(88)

[Sec. 1II.C

(7)

I

(90)

(89)

SCHEME25

activating effects provide an understanding oftheorientation ofattack ina i.e., attack occurs soastomaximize thenumberof numberofsituations, activating fluorine atoms. Positions ofmonosubstitution areindicated by an arrowin thesystems shown in Scheme25.31*250*253,254 In pentafluoropyridine (M), attack atthe4-position isactivated byfour fluorine atoms(two ofattack), whereas attack atthe2-position ortho andtwometatothesite wouldbe activated by onlythree fluorine atoms(oneortho andtwometa). Similar arguments account for theposition ofattack in5,88, and7.However, forthesystems 85 and87 there arethesamenumberoffluorine atomsactivating attack bothatthe4-and6-positions, andmonosubstitution atboth sites occurs; a similar situation applies to89.Of course, this rationale only applies when thenitrogen atomitself isnotdirecting orientation ina highly specific way,asoccurs withperfluoroisoquinoline (90).254 Here, attack occurs exclusively atthe1-position, asdictated bythenitrogen, whereas attack atthe 3-position wouldprovide themaximum numberofactivating fluorine atoms. Reactions involving nucleophilic attack on polyfluoropyridines andrelated systems arereferred toinTable11131,33,35-37,41.43,44,145.146,249,250,25 2-295 R. D. Chambers, J.Hutchinson, and W. K. R. Musgrave, J.Chem.SOC.,5634(1964). R.D.Chambers, M. Hole,W. K. R. Musgrave, R.A. Storey, andB.Iddon, J. Chem.SOC. C , 2331(1966). 2 5 5 R. D. Chambers, J.Hutchinson, and W. K. R. Musgrave, J .Chem.SOC., 3736(1964). 2 5 6 R.E.Banks, J.E.Burgess, W. M. Cheng, andR.N . Haszeldine, J .Chem.SOC.,575(1965). V. M. Vlasov, V. V.Aksenov, N. E.Akhmetova, G.2.Mustakimova, andG.G.Yakobson, Izv. Sib. Ord.Akad.Nauk SSSR,Ser.Khim.Nauk,130(1978) [ C A 90,168411(1979)l. 2 5 8 D. W. R. Headford, J . W. Slater, R. L.Sunley, R.D. Bowden,andM. B.Green, German 2,425,239 (1974) [ C A 83,9802(1975)l. Patent 2 s 9 R. D. Bowden,M. B. Green, andG.T.Brown,GermanPatent 2,127,901 (1972) [CA 76, 153615(1972)]. 260 I. N . RozhkovandN. D.Kuleshova, Bull. Acad.Sci. USSR,Dio.Chem.Sci.25,1919(1976). 26 1 C.B. Barlow, C. D. S.Tomlin, G. M. Farrell, P.F.Freeman, J.W. Slater, andJ.Clayton, 2,139,042 (1972) [CA 76,126795(1972)]. GermanPatent 253 254

*

Sec.III.C]POLYFLUOROHETEROAROM

ATIC COMPOUNDS

51

footnotes (Continued ) R. E. Banksand S.M. Hitchen, J .Fliiorine Chern.12,159(1978). D. Moran.M. Patel, N. A. Tahir. andB.J. Wakefield, J.C.S. PerkinI ,2310(1974). 2b4 I. Collins. S.M. Roberts, and H. Suschitzky, J .Chem.SOC.C , 167(1971). 2 6 5 R. D. Chambers, W. K. R. Musgrave. andP.G . Urben,Chem.Ind.(London), 89 (1975). R. E. Banks,R. N. Haszeldine, D. R. Karsa, F.E. Rickett. and I.M. Young,J .Chem. Soc.C,1660(1969). 2 b 7 G .G. Furin, L.N. Shchegoleva, andG .G. Yakobson, Zh.Org.Khim.11,1290(1975) [CA 83,78777(1975)l. G. G . Furin, Yu. G .Shermolovich, and G . G .Yakobson, Bull. Acad. L. N. Markovskii, Sci. USSR, Dir.Chem.Sci. 26.2628(1977). * K. E.Chippendale, B.Iddon, andH. Suschtzky, J.C.S. PerkinI, 2023(1972). R.N. Haszeldine, E.Phillips, and1. M. Young,J .Chem.SOC.C,2091(1967). R. E.Banks, G .A. WheatonandD. J . Burton, J .Ory.Chem.43,2643(1978). 2 7 2 J . Cooke, M. Green, and F.G .A. Stone. J .Cl7em.SOC.A , 173(1968). 2 7 3 M. I .Bruce. B. L. Goodall. D. N. Sharrocks, and F.G. A. Stone, J .Organornet. Chem. 39,139(1972). 2 7 4 B. L.Booth, R.N. Haszeldine, and I. Perkins. J .Chem.SOC.A , 927(1971); J.C.S. Dalron, 1843(1975). 2 7 5 M. Green, A. Taunton-kgby, and F.G . A. Stone, J .Chem.Sac.A , 2762(1968). 2 7 6 J.Wielgat andZ . Domagala, Roc;.Chem.49, 1039(1975) [CA 83,163948(1975)]. 17 A. F. Hawkins, D. k l e y R. , L. Sunley, andC. D. S .Tomlin, GermanPatent 2,428,305 [CA 82,156090(1975)]. (1975) 2 7 8 R. D. Bowden,M. G .Green, andG .T.Brown.GermanPatent, 2,130,409 (1972) [ C A 76, 140539(1972)]. 79 J . Bratt andH. Suschitzky, J.C.S. Perkin I ,1689(1973). and E. Phillips, J .F h r i n eChern. 9,243(1977). R. E. Banks.R. N. Haszeldine, 2 8 1 R. D. Bowden and R. Slater, British Patent 1.367.383 (1974); [ C A 82,31266(1975)l. R. D. Chambers, D. Lomas,and W. K. R. Musgrave, J .Chem.Soc. C, 625(1968). 2 8 3 R. D. Chambers, D. Lomas,and W. K. R. Musgrave, Tetrahedron 24,5633(1968). 284 R. D. Chambers, J. A. H. MacBride. and W. K. R. Musgrave, British Patent 1,351,032 [CA 81,63653(1974)]. (1974) * D.W. Johnson, V. Austel, R. S.Feld, andD. M. Lemal, J .A m . Chem.Soc.92,7505(1970). Z8b R. E. Banks, D. S.Field, and R. N. Haszeldine, J .Chem.SOC.C, 1866(1969). 2 8 7 R. E. Banks, R. N. Haszeldine, and J . C. Massey, J .Fluorine Chem. 12,331(1978). R. E. Banks.M. G .Barlow, R. N. Haszeldine, andJ.C. Massey, J .Fluorine Chem.12,53 (1978). 0. P.Studentsov, B. A. Ivan, E.G .Sochilin. V . D. Yakovleva, T.A. Petrova, and L. L. [CA 86,190,000 (1977)l. Malyugina, U.S.S.R. Patent 547,447 (1977) z90 0. P.Shkurko, S.G .Baram,and V . P.Mamaev,Izv.Sib.Otd.Akad.Nauk SSSR,Ser. Khim.Nauk,104(1973) [ C A 80,14409(1974)l. 2 9 1 0. P.Shkurko, S.G .Baram,and V. P.Mamaev,Izu.Sib.Otd.Akad.Nauk SSSR,Ser. [CA 80,59913(1974)l. Khim.Nauk,81 (1973) 2 9 2 E.P.Studentsov, B.A.Ivan, N. V. Korableva. andE.G. Sochilin, U.S.S.R. Patent 537,074 [CA 86.189994(1977)]. (1976) 293 D.Baerwolff, D.Cech, G .Etzold, P.Langan, andH.Meinert, German(East) Patent 86,828 [CA 78,72185(1973)l. (1972) 294 A. H. Gulbenk, D.J.Horne, andH. Johnston, U.S. Patent 3,808,208 (1974) [CA 81,105574 (1974)J 2 9 5 G .A. Olah, M. Nojima, andI.Kerekes. Svnrhesis. 487(1973). 262

Zh3

*

TABLE I11 EXAMPLESOF NUCLEOPHILIC ATTACKON PENTMLUOLOPYRIDINE AND SOMERELATEDSYSTEMS ~~

Reagent

Compound

x Q f y X=Y=F

References

Oxygennucleophiles (e.g., NaOMe, aq.KOH ort-BuOH,C6F,0H/KF)

252,253,255-260

Nitrogen nucleophiles (e.g., NH,, pyridine, N,H, * H,O, aminopyridines.

145.146,250.255, 256,261-265

NaN,, c N ’ - N H . diamines)

Sulfur nucleophiles (eg., KSH, Na,SO,, PhSO,Na,PhSH,C6F,SH)

266.267

(EtO),P

268

PhLi,

Li

255,269

NaI/DMF,LiCI/CF,CICO,Me

270,271

Metalcarbonyl anions

272-274

Me,SnLi

275

Difunctional nucleophiles

216

aq.KOH ort-BuOH,RCH,OH, CH,C02K

253,277,278

PhSH

279

NaI

280

NaI,CaCI,

280,281

Perfluoro-3,3’bipyridyl

Alkoxide ions, NH3,N,H, MeLi

282

Perfluoro-2,Z’bipyridyl

NaOMe

Perfluoroquinoline and-isoquinoline

NaOMe. NH,,NZH4

254

NaOCH, NH,,amines, K phthalimide NaSPh LiCl/DMF Metalcarbonyl anions

31 31.284 31 285 272

X=Y=CI

X

=

F,Y

= CI

p \

N

Perfluorophthalazine MeOH, NH,

XIF

x / F

X=F

F

H 2 0 ,MeOH PhNHz,MeNH,, Me,NH NaI/DMF,Lil/DMF C,F,MgBr

41 33 33

Sec.111.C ]

53

POLY FLUOROHETE ROAROM ATIC COMPOUNDS TAHIL 111 (C orr/irrurd)

Compound

Reagent

References

X=H

MeOH; NH,, Me,NH, MeCH=CHLi

35,289-291

X

=

Me

aq.KOH, NaOCH,Ph

292,293

X

=

CI.CF,,NO2,C N

MeOH, NH,, MeCH-CHLi

35

NaOMe, NH,

43

NaOMe, (CH,OH),

36

Perfluoroquinazohne

36.294

Perfluoroquinoxaline

BuLi,MeLi

36

KOH/t-BuOH.NaOMe, N,H,.H20

44

H 2 0 ,MeOH NH,, Et,NH,anilines Carboxylic acids anions Metalcarbonyl

37

37.249 295 272

andsomeuseful interconversion reactions offunctional derivatives arecontained inScheme26.296 Verysuccessful fiber-reactive dyesareavailable by attaching thedyesto fluorinated heterocyclic compounds, whichthenhavesites available forattachment to cellulose (Eq.79). A detailed reviewofthis subject isnow a~ailable. ~

F

0-Cellulose cellulose

Dye-NH

296 297

Seereferences in Table111 and Ref.250 and 297. R. D. Chambers, J. Hutchinson, and W. K . R. Musgrave, J .Chem.Soc., 5040(1965).

54

R. D. CHAMBERS A N D C. R. SARGENT

[Sec. 1II.C

MgBr I

6 6 S0,ONa

c1

NHNH,

N/

N/

l 2..cuso, N1H4+&

N

N

H

SCHEME 26.Nucleophilic attack on pentafluoropyridine and some useful interconversion reactions.

2. Fiveand Condensed FiueMemberedRing Systems Perfluorofuran isdifficult tohandle, tending top ~ l y m e r i but ze, substi~~ tution in 70 occurs readily.298 Perfluorothiophene (11) undergoes attack ; ortho tosulfur.66 Condensed systems havebeeninvestigated inmoredetail

(701

(e.g.,Nu= MeO-,Ph-)

OMe (11)

nucleophilic attack on tetrafluorobenzo[b]thiophene (91) occurs specifically isobtained fromthe atthe6 - p 0 s i t i o nwhile , ~ ~a~ mixture # ~ ofproducts zy8

299

R. D. Chambers, A. A. Lindley, and H . C . Fielding, J. FIuorine Chem.12,337 (1978). G. M. BrookeandM. A. Quasem,Terrahedron Lett., 2507 (1967).

Sec.I1 I.C]

55

POLYFLUOROHETERO AROM ATIC COMPOUNDS

furan derivative (92),300 arising fromattack atthe4-, 6-, and7-positions. Indolederivatives (93) undergo attack atthe4-,and6 - p o ~ i t i o n s . ~ ~ ~ (91) ( 9 2X)=X S =O

J & 5

6\

I

(95) [X = P(0)Ph)

7

(93) X = NH orNR

(94)

I

(96) [X = S,SO,,0. PPh]

Substitution indibenzo derivatives (94)cannow bemostly explained simofwhether 95 or96 ispreferred. When X isP(O)Ph, that is, plyon thebasis a groupwhose0 - value suggests thatitismorecarbanion stabilizing than Otherwise, 96 is referr red.^**^’^ pentafluorophenyl, then95 ispreferred.

3 . Fluoride Ion-Induced Reactions Carbanions, generated by reaction offluoride ionwithunsaturated fluorocarbons, may betrapped byreaction withactivated polyfluoroaromatic comofpolyfluoroalkyl g r o ~ p s . ~These ’~-~’~ pounds, resulting intheintroduction are, ofcourse, reminiscent offamiliar cationic processes andmay bethought ofas"nucleophilic Friedel--Crafts reactions" (Eqs. 80and81).307 G. M . Brooke, B. S.Furniss, and W. K . R. Musgrave, J . Chem.SOC.C ,580 (1968). T. D. Petrova, T. I.Savchenko, 0. C. Kukovinets, and G. G. Yakobson, Izu.Sib.Ord. Akad. Nauk SSSR,Ser.Khim.Nauk,104 (1973)[CA 79,42275 (1973)l. ’ 0 2 R. D.Chambers andD. J.Spring, Terrahedron 27,669 (1971). 3"3 See, e.g., Chambers,’ p.296 forearlier refs. anddetailed examples. 3 " 4 R. D. Chambers, J.Hutchinson, and P.D. Philpot. J .FluorineChem. 9, 15 (1977),and earlier parts ofa series. 3"s C. J.Drayton. W. T.Flowers, and R. N. Haszeldine. J.C.S.PerkinI, 1029 (1975),and references contained. ’06 N. 1. Delyagina, E.Ya.Pervova, B. L.Dyatkin, and I.L. Knunyants, Zh.Ory.Khim.8, 851 (1972)[CA 77, 19266 (1972)]. R. D. Chambers, R. A. Storey, and W. K . R. Musgrave, Chem.Commun.,384 (1966).

’(’"

301

56

R. D. CHAMBERS

A N D C. R. SARGENT

[Sec. 1II.C

I + F(81) I Intrinsically, thesituation isquite complicated because observed reactivityisthe product ofanequilibrium constant K forgeneration ofa carbanion k (Eq.81)whichdepends on thereactivity ofthecarbanda rate constant ofreactivity isthat showninScheme27,andthe anion involved. Theorder fact that perfluoro-tert-butyl isthemostefficient anioninpolyfluoroalkylation processes indicates that theequilibrium concentration ofanionisthe F - +CF,=C
(CF,),C-F> CF,C’

.. F

\*.

F

(- increasing anionstability) SCHEME

27

dominating factor governing efficiency ofreaction. Thestability oftheanions increases aselectron-pair repulsions arereduced. Examples ofmono-and disubstitutions areshowninEqs.(S2)241 and(83).30s

Polysubstitution involves various factors because (a) after twopolyfluoroalkyl groups arepresent these may control thesite offurther attack, (b) some ofthereactions arereversible, and(c) substitution atthesite mostactivated toattack sometimes results incrowding. Thiscanleadtoa competition betweenkinetic andthermodynamic control ofreaction products309 (Scheme 28). Forexample, further attack on thedisubstituted compound(97)occurs ’09

H. C.Fielding, British Patent1,133,492 (1968). S.L. Bell, R. D. Chambers,M. Y. Gribble, andJ . R. Maslakiewicz. J .C.S . Pcvkiii I , 1716 (1973), and references therein.

Sec.III.C] POLYFLUOROHETEROAROMATIC

COMPOUNDS

(98) RF R,

(97)

57

= CF(CF3)2

I

= CF2CF3

RFm +R,

RF

N’

R,

N’

(99) RF = CF(CF3L RF = C(CF313

(100)RF

RF

= CF(CF3)z

SCHEME28

preferentially atthe5-position withtheleast crowdedanions, butwithperfluoroisopropyl theproduct obtained dependson conditions because, at higher temperatures inthepresence offluoride ion, rearrangement of98 to 99(RF= perfluoroisopropyl) occurs. A 2,5-disubstituted product (100) isalso observed. ~ ~complete ’ - ~ ~ ’substitution obtained Only in thecaseof t r i a ~ i n e s IS (Eqs. 84,310and 85j1’),although a pentasubstitution product has readily tetrafl~oroethylene.~~’~~~ In beenobserved frompentafluoropyridine, using ’

some cases, thetriazine systemitself competes veryeffectively forfluoride (101) havebeen~haracterized.~ l4 ionsince stable anions R. L. Dressler and J. A. Young,J.Ury.Chm7. 32,2004 (1967). W. R. Deem, British Patent1,148,676(1969)[CA 71,49994 (1969)]. 3 1 2 R. D. Chambers, W. K . R. Musgrave, and D. E. Wood, J .C. S.Perkiri I . 1978 (1979). 3 1 3M. G. Barlow, R. N. Haszeldine, and J . G. Dingwall. J.C.S.Perkiri I , 1542(1973). R. D.Chambers.P.D. Philpot, and P.L. Russell. J.C. S.PrrkinI , 1605(1977).

310

311

58

R. D. CHAMBERS

AND C. R. SARGENT

L

RF

[Sec. 1II.C

ZNJRF-A4ARFCS+ +

CsF

RF

(RF = F o r C,F,)

(101)

Fluorinated anions havealso beengenerated fromappropriate hydrogencontaining compounds, using fluoride ionasa base(Eq.86).31s

Hexafluoro-2-butyne addsto activated perfluoroaromatic compounds giving corresponding unsaturated side chains, orwiththepyridazine system an interesting cyclization occurs (Eqs.87 and88).316

@

+CF,C-CCF3

CsF. 110 C

suliolanc

F3C

/ \C=CFCF, (C5F4N)

4. Reactions Involving SideChains An interesting mechanism fordisplacement offluorine fromsidechains by 3-trifluoromethylquinoline (Eq. hasbeenidentified3I7 andisillustrated 89). Perfluoroalkyl groups havealso beenfoundtobehave asleaving groups I5

,

V. M . Vlasovand G. G. Yakobson, Zh.Org.Khim. 10,888(1974) [ C A 81,13357(1974)l. R. D.Chambers,S.Partington, and D.B. Speight, J .C.S. Prrkiti I .2673(1974). Y. Kobayashiand 1. Kumadaki,Arc.Cheni.Res.11,197 (1978). and references therein.

Sec.111. D]

POLY FLUOROHETEROA

59

ROM ATIC COMPOUNDS

inreactions of some heteroaromatic derivatives withsodiumamide3"or amrn~nia.~"

(89)

D. REACTIONSWITH ELECTROPHILIC REAGENTS Perfluoroaromatic nitrogen heterocyclic compounds areveryweakbases, by protonic or Lewis butvarious substitution reactions can be induced acids3 19-321 and interesting contrasts inorientation achieved since attack isoften preferred underthese conditions (Eqs. 903" and ortho tonitrogen 91320). OMe

Me0 Br I

(88%

(91"0

Oxidation ofperfluoropyridine andrelated compoundstotheir N-oxides isevidence fortheir intermediacy in hasnotbeendescribed, although there M. I.Bognitskii, G.B. Fedorova, and 1.M. Dolgopol’skii, Zh. Vses. Khim.0-va.24,101 [CA 90,168553(1979)l. (1979) 3 1 9 R. D.Chambers, M. Hole,W. K . R. Musgrave, and J .G.Thorpe, J .Chem.Soc..61 (1971). 320 W. K. R. Musgrave, Chem. Ind.. (London) 943(1969). 321 R. D.Chambers, J .A.H. MacBride, and W. K. R. Musgrave, J .Chem.SOC.C,2989(1968).

318

60

R. D. CHAMBERS

AND C. R. SARGENT

[Sec. 1II.E

theformation ofhydrolysis products.322 However, oxidative displacement orring opening ofperfluoroquinoline (Eq. 92)323 and-isoquinoline offluorine 93)324 occurs withnitric acid. Acidhydrolysis oftrifluoromethyl occurs (Eq. ofother groups hasbeeni n ~ e s t i g a t e d . ~ ~ ~ . ~ in102325andoxidation 0

E. ADDITION REACTIONS AND RADICALPROCESSES Further fluorination ofperfluoroaromatic compounds32s~329 occurs quite 94). smoothly inmanycases, using cobalt trifluoride andrelated reagents (Eq. These reactions areofcourse much easier tocontrol thanfluorinations ofthe corresponding parent compoundscontaining hydrogen; and thedimeric obtained fromperfluoropyrimidine, presents someofthe compound(103), bestevidence fora radical cation process forthis typeofreaction (Scheme 29).Even direct fluorination ofpentafluoropyridine, withfluorine of low G. E. Chivers and H. Suschitzky, J. Chem.SOC.C ,2867(1971). P.Sartori, K. Ahlers, and H. J.Frohn, J. Fluorine Chem.7 ,363(1976). 3 2 4 P.Sartori, K. Ahlers. and H. J.Frohn, J. Fluorine Chem.8,457 (1976). 3 2 5 R. E. Banks, J.E.Burgess, andR. N . Haszeldine, J. Chem.Sac., 2720(1965). 3z6 S.M. Roberts and H. Suschitzky, J. Chem.SOC.C , 1485(1969). 3 2 7 P.B. Domenico, U.S.Patent 3,651,066 (1972) [ C A 77,48271(1972)l. 3 2 8 R. D. Chambers, D. T.Clark, T.F.Holmes,W. K. R. Musgrave, and I.Ritchie, J.C .S. PerkinI ,I14(1974). 3 z 9 R. D. Chambers, R. D. Hercliffe. and W. K. R. Musgrave. J.C . S.Chem. Commun., 304 (1978).

322

323

Sec.III.E] POLYFLUOROHETEROAROMATIC

61

COMPOUNDS

(103) SCHEME29

oxygencontent, be can controlled, giving a mixture ofproducts including a ofchlorine glassy solid thought tobe a mixture of01igomers.~~’ Addition andbis(trifluoromethy1)nitroxide topentafl~oropyridine~~’ occurs andsome dimeric products areobtained incorresponding reactions ofchlorine with ,obtained by theaddition ofClF perfluor~diazines.~~’ An adduct (CF’NCI), totrifluoro-sym-triazine, isreported tobea useful fluorinating agent.333 Bromineandchlorine add2,5-totetraflu~rofuran.~’ An interesting migration ofchlorine fromtheside chain of104 tothering iscatalyzed by iodine.334

& N’

[egX ,

=

&

2 I

r-BuOCI

NH2

N’

NCI,

:& +

F

\

N

NCI

F

\

N

NCI

H,CI,CF(CF,),]

I.J.Hotchkiss, R. Stephens, andJ.C. Tatlow, J .Fluorine Chem.10,541 (1977). R. E.Banks,W. M. Cheng,R.N . Haszeldine, andG. Shaw,J .Chem.SOC.C,55 (1970). 3 3 2 R. D. Chambers, W . K R.Musgrave, andP.G .Urben, J .Fluorine Chem.5,275 (1975). 3 3 3 R. L. Kirchmeier, G. H. Sprenger, and J . M. Shreeve, Inorg.Nucl.Chem. Left. 11,699 330 331

(1975).

334

R. E.Banks,M. G. Barlow, J.C.Hornby, andM. Mamaghani, J .Fluorine Chem.14,183

(1979).

62

R. D . CHAMBERS

[Sec. 1II.E

AND C. R. SARGENT

Photochemical additions ofalkenes toaromatic compounds arenow well (86)occur,335 established and similar additions to pentafluoropyridine whereas a novel insertion the into carbon-chlorine bondoccurs with105,in a process that doesnotappear toinvolve tetrafluoropyridyl radicals.336 It hasalso beendemonstrated recently that Diels-Alder additions occur with

@+CH2=CH2

hv

F

S

F

N

F

+ F

N

SF

F

(107)

the1,2,4-triazine 106,giving bis-adducts (107) withc y ~ l o a l k e nPhotoes.~~~ ofsomealcohols338 orc y ~ l o h e x alead n eto ~~~ chemically induced reactions radical attack specifically atthe4-position inpentafluoropyridine (86) togive, forexample, 108.Reductive additions tofluorinated sym-triazines also occur on irradiation inhydrocarbon solvents.340 M . G. Barlow, D.E. Brown.and R . N . Haszeldine, J .C.S .Perkin I ,363 (1978). M . G. Barlow.R. N. Haszeldine. and J. R. Langridge, J . C. S.Ckem. Commun., 608 (1979). 337 M. G. Barlow, R. N. Haszeldine. and D. J. Simpkin. J. C.S.Chrm.Commurt..658 (1979). B.Sketand M. Zupan,J .Heterocycl. Cheni. 15,527 (1978). 339 B. Sketand M. Zupan,Synthesis, 760 (1978). 340 Y . Kobayashi, A. Ohsawa,and M. Honda,Chem.Pharm.Bull. 21,1575 (1973).

335

336

6

Sec.IILE] POLYFLUOROHETEROAROMATIC

@

COMPOUNDS

63

CH,OH

+MeOH

Ph,CO.lfl;

+ HOCPh2CPhZOH

(108)

(86)

Various pyrolytic processes leadtoproducts that arise fromsubstitution inthering,341*342 andmany canbe simply formulated asradical displacementsof fluorine (Eq.95),341although reaction of chlorofluoropyridines withbromine athightemperatures leads todisplacement ofchlorine.343

47.7

:

22.1

:

30.3

Copyrolysis oftetrafluoroethylene andthepyridine derivatives 109 under flowconditions gavebicyclic products 110 and111.344 Ina sealed system,

(109) X = OMe orNO2

(110)

(111)

reaction occurs athightemperature between pentafluoropyridine andpolytetrafluoroethylene, andtheprocess hasbeenrationalized asinvolving iniofd i f l ~ o r o c a r bAecorresponding ne.~~~.~ reaction ~ ~ withpotastial addition ofpolytetrafl~oroethylene~~ ismoredifficult siumfluoride intheabsence P. H. Oldham,G . H. Williams, and B. A. Wilson, J .Chem.SOC.B, 1346(1970). T.A. Nadervel, V. Sass,L.G. Parshma,G. B. Fedorova, I. M. Dolgapol ski, and S.V. Sokolov, Zh.Org.Khim.15,1095(1979) [CA 91,73912(1979)l. 343 R. D . Bowden and T. Seaton, German Patent2,241,562 (1973) [CA 78,159438(1973)l. 344 G .G . Yakobson, V. E. Platanov, G. G. Furin, N. G. Malyuta, and N.V. Ermolenko, Bull. Acad.Sci.USSR,Diti. Chem.Sci. 20,2491(1971). 3 4 5 R . D. Chambers. R . P.Corbally. T. F.Holmes,and W. K. R . Musgrave, J.C.S.PerkinI . 109(1974). 346 V. E. Platanov, N.V. Ermolenko, and G. G. Yakobson,Izv. Sib.Otd.Akud.Nauk SSSR, Ser.Khim.Nauk,117(1978) [ C A 90.6196(1979)]. 3 4 7 V. E.Platanov, N.V.Ermolenko, and G .G.Yakobson, Bull. Acad.Sci. USSR,Diu.Chem. Sci., 2685(1970). 341

342

64

R. D. CHAMBERS

AND C. R. SARGENT

[Sec. 1II.E

tounderstand (Scheme30)asistheformation oftrifluoromethyl derivatives inthepyrolysis oftetraflu~ropyrimidine.~

KF

I

(6%)

550-560C

+ a- andy-isomers

QCF3 (85-90%)

(5-7 /,)

conversion) (25-300/,

SCHEME30

Radical-anions aregenerated by electrochemical reduction offluorinated pyridines (Scheme31348) and other heterocycle^.^^’ Radical-anions have alsobeen producedfrom polyfluoropyridines by X-ray irradiation and techniques. It was concluded that studied by ESR usingmatrixisolation occurs.35o crossover ofu* and n*-orbitals

x

x

( X = F,C1)

1

b+FfiF hydrcquinone

H

H

\

N

F

X

N/

I

.N

/ /

M/

F

SCHEME31

R. D. Chambers,D. T.Clark, C .R. Sargent, and F.G. Drakesmith, Tetrahedron Lett., 1917(1979).

D. M. W . Van den Ham, G. F.S.Harrison, A. Spaans, and D . Van derMeer,R e d .Truc. Chim.Pays-Bus 94,168 (1975). 3 5 0 M. B. Yim, S.DiGregorio, and D. E. Wood, J .Am. Chem.Suc.99,4260 (1977).

349

Sec.III.F]POLYFLUOROHETEROA

65

ROM ATIC COMPOUNDS

F. REACTIVE INTERMEDIATES 1.Organornetallics Fluorocarbon organometallic compoundshave been discussed more 52generally elsewhere.351 Lithiumderivatives and Grignardreagents3 may be obtained asindicated inScheme32.Thesecomofmetal fluoride, butcanbeused poundsareunstable relative toelimination oftransformations. Attempts togenerate atlowertemperatures fora variety corresponding lithium ormagnesiumderivatives ofperfluorinated diazines resulted intars.286*355 354,240*2709280297

+HBuLi

a N

-

f l L i

2 CO f l C 0 2 H

N

Br I

N

MgBr

C02H

I

I

%R)--JLi5R SCHEME

32

Furanderivatives (112)arealsometallated withb ~ t y I l i t h i u m . ~ ~ * ~ ~ ~

R (112)R = F,CF,

2. HCI

COZH

R . D. Chambers,Fluorine inOrganic Chemistry, Chapter 10.Wiley(Interscience). New York,1973. 3 5 2 R. D. Chambers, F.G. Drakesmith, J.Hutchinson, and W. K. R. Musgrave. Tetrahedron Lett., 1705(1967). 3 5 3 R. D. Chambers, F.G. Drakesmith, and W. K . R. Musgrave, J .Chern.Soc., 5045(1965). 3 5 4 G. G. Furin and G. G. Yakobson, 1 ~ Sib, . Otd.Akad.Nauk SSSR,Ser.Khim.Nauk, 128 (1972) [ C A 78,72263(1973)l. J s R. D. Chambers. W. K . R. Musgrave. and P.J.Urben,unpublished results. 356 R .V .G rigorash, V. V. Lyalin, L.A. Alekseeva. andL.M. Yagupol ski, Zh.Org.Khin?.14. 2623(1978) [CA 90, 137590(1979)l.

35

66

R. D. CHAMBERS

[Sec. 1II.G

AND C. R. SARGENT

2.Arynes

Aryneformation by elimination of lithium fluoride limits thestability of 113;a polymerisformed, butattempts to trapthearyne(114) were unsuccessful.352 Decarboxylation of metalsalts of tetrafluoroisonicotinic acidO C C U ~5 7Sgiving , ~ thecorresponding metal derivative, butpyrolysis of thedisilver salt (115) appears toproduce thearyne (114), since small amounts ofdiazabiphenylenes may beisolated fromthereaction produ~t.~~~*~’~

4’

210-22oc

114

-

G. FRAGMENTATION AND REARRANGEMENT PROCESSES Attempts toeliminate nitrogen fromfluorinated pyridazines andrelated compoundsweremade originally witha viewtothegeneration ofcyclobutadienes oreventetrahedranes as intermediates. Elimination doesoccur

xc-cx

’r

.x.m --+ .: +

x .

etc.

YC-CY

X

Y

e.g., 725 C. X = Y = C,F,(90%) 680 C. X = CF(CF,),; Y = C,F, (84%)

SCHEME 33

"’ P.Sartori and H. Adelt, J. Fluorine C’hem.3,275(1973). 358

359

E.G .Bartsch, A. Golloch, and P.Sartori, Chem.Eer.105,3463 (1972). G . Haegele, P.Sartori, and A. Golloch, Z.Nuturforsch., Ted E 28,758(1973)

Sec.III.G]POLYFLUOROHETEROAROMATIC

-

--

4ooC

_-

COMPOUNDS

RFC--CRF+ RFC-N

67 (96)

R F = CF(CF,), y

3

N A N

II N, I

Y CF3

hv

(97)

T G a CF,CN

insomecases (Scheme 33,360 Eqs.96312 and97125), butthere isnoindication ofcyclic intermediates fromthefluorinated compounds. (116)lead More frequently, thermal reactions offluorinated pyridazines (117)together with, insomecases, small amounts ofpyrazine topyrimidines F

R T

RF+ RF

F

360

R.D.Chambers, M. Clark, J.A. H. MacBride, W. K . R. Musgrave, andK. C.Srivastava, J .C. S.PerkinI, 125 (1974).

68

R. D. CHAMBERS

[Sec. 1II.G

AND C. R. SARGENT

derivatives (118or119). 361-364These reactions proceed insurprisingly high yields butelucidation ofthemechanism hasposedmany problems, notleast ofwhichistherecent discovery364 that thepresence ofonecompoundmay is promote rearrangement oftheother. Itisnow believed365 that this effect a highly efficient process promotedby radicals, possibly asindicated in Scheme34.

Valence Isomers A process fortherearrangement offluorinated pyridazines, promoted by ultraviolet radiation, hasnow beenelucidated3669377 andmay besummarized asinScheme35.Eachintermediate stage, i.e., thevalence isomers 120and121, inthis fascinating process hasbeenisolated andcharacterized before further conversion. Conversion ofperfluoro-3,6-dimethylpyridazinetoa pyrazine hasbeendescribedlZ5 andsome 1,2-shifts arealso observed on ultraviolet 6~ ~ . opening of2-trifluoromethylquinoline tothecori r r a d i a t i2~~ 3n6.Ring ~’ responding 3,l-benzoxazepine occurs on i r r a d i a t i ~ n . ~ ~ ’

.+

, +)’X x

Y

N

q

F

’X

I

I

F

F ’X

c

3

Y (121)e.g., X = ’X = Y = F;

X = ’X= C,F,,Y = F; ’X = F,X = Y = C,F,

SCHEME35 R.D.Chambers, J.A.H. MacBride, andW. K. R. Musgrave,J. Chem.SOC. C ,3384(1971). M. Clark, J.R. Maslakiewicz, W. K. R. Musgrave, and P.G. Urben, R. D. Chambers, J.C.S.PerkinI .1513(1974). 3’3 R. D.Chambers, C. R. Sargent, andM. Clark. J .C .S.Chem.Commun.,445(1979). 3’4 R. D. Chambers andC. R.Sargent, J .C.S.Chem.Commun., 446(1979). R. D. ChambersandC. R. Sargent, unpublished results. "’ R.D.Chambers, J.A.H.MacBride. J.R.Maslakiewicz, andK.C.Srivastava, J .C .S.Perkin I. 396(1975). 3 h 7 R. D. Chambers, J.R. Maslakiewicz, andK. C.Srivastava, J . C.S .PerkinI ,1130(1975). 3’8 C. Kaneko, S.Hayashi, andY .Kobayashi, Chem.Phurm.Bull. 22,2147(1974). 361

"’

Sec.III.G]POLYFLUOROHETEROAROMATIC

69

COMPOUNDS

Isomers 120and 121appear tobe theonlyvalence isomers ofaromatic diazines described, andtheyaresurprisingly stable. Evenmorespectacular, however, arethestabilities ofvalence isomers offluorinated pyridines corresponding tostructures 122-124. Sofarhowever, anazabenzvalene derivative (e.g., 125)has not beendescribed. Pyridine itself formsa valence isomer that

a m B 4 (122)

(123)

(124)

(125)

hasstructure 122,369 andthis iswhatmightbeexpected onthebasis ofsimple A moresophisticated approach leads tothesame bondenergy summation. conclusion.37o Insystems withfive perfluoroalkyl groups, onlytheisomer corresponding to 123isobtained, together withazaprismanes (Eq.98,31 Scheme36371), and theformation ofazaprismane 126hasbeenattributed toa 1,3-shift process similar tothat discussed earlier forpyridazines. Compound 127,containing onlytwo perfluoroalkyl groups, alsogives a to123.372,373 Presumably, buttressing ofgroups is product corresponding

bfib ’Ab’hb ’Ab +

L 2.54~

N"

c

" c + c

a = CF,CF, b = CF, c = CF(CF3)2

a

c

C

$. SCHEME 36

K. E. Wilzbach and D. J. Rausch, J .Am. Chen?.Sac.92,2178(1970). M. J . S.Dewar.G .P.Ford, J .P.Ritchie. and H. S. Rzepa, J .Chem. Res.( S ) 26 , (1978). 3 7 1 R.D. Chambers andR. Middleton. J .C. S.Prrkiii I , 1500(1977). 3 7 2 Y . Kobayashi, A. Ohsawa,M. Baba,T.Sato, and I. Kumadaki, Chem. Phurm. Bull. 24, 2219(1976) [CA 86,89545(1977)]. 3’3 Y. Kobayashi andA. Ohsawa.Chem. Phurni.Bull. 24,2225 (1976) [CA 86,105577(1977)l. 369

0 ’ 3

70

R. D. CHAMBERS

[Sec. 1II.G

AND C. R. SARGENT

Me

Me

Me

Me

still highinthissystem, but pyridine derivatives containing threeor four perfluoroalkyl groupsgavethefirst verystable valence isomers corresponding 122(Eqs. 99, tostructure

F3cfiF3 ’hF ’.hRF ’AF F

qF3

F&RF

254nm

RF

F3C

RF

R,

(99)

RF

= CF(CF3),

254nm

F

RF

+

RF

R, = CF(CF3)*

3’4

RF

RF

(99%)

R. D.Chambersand R. Middleton. J .C. S .Chem.Comrnun., 154 (1977).

RF

(100)

Sec.111.G]

POLYFLUOROHETEROAROM

71

ATK COMPOUNDS

A valence isomer isobtained inthephotolysis ofthethiophene derivative

44,whichwas subsequently showntohavethestructure 128.375-378 The

isomer 128hasbeenconverted toa valence isomer (129) ofthecorresponding pyrrole by a novelsequence starting withtheappropriate azide(Eq. 101).379,380

of fluorinated furans didnotgivethevalence isomers but, Irradiation ( instead, themore familiar ringopening tocyclopropenylketones Inthepresence ofalkynes, however, a novel series of(271+ 2n)-cycloadditions ofbenzvalene hasbeenobtained fromthe occurs (Eq.102).381 An analog (46).29 diphosphabenzene

(130)X = CF,,F Me CO hI,

2 Me

Me

+ Me

H. A. Wiebe,S.Bradlavsky, and J.Heicklen, Cun.J.Cliem. 50,2721(1972). Y . Kobayashi, I .Kumadaki, A. Ohsawa,and Y. Sekine, Tetrahedron Left., 2841(1974). 37’ Y. Kobayashi. I.Kumadaki, A.Ohsawa,Y. Sekine, andH. Mochizuki, Chem.Pharm.Bull. 23. 2773(1975) [ C A 84,135384(1976)l. 3 7 * Y. Kobayashi, I.Kumadaki, and A. Ohsawa.Heferocycles 6 ,1587(1977) [CA 88,136394 (1978)l. 3 7 9 Y. Kobayashi, 1.Kumadaki, A. Ohsawa,andA. Ando,J .A m . Chem.SOC.99.7350 (1977). 3 8 u Y. Kobayashi. A. Ando,and I.Kumadaki. J .C .S.Chem.Commun..509(1978). 3 L l ’ Y. Kobayashi and Y. Hanzawa,Tetrahedron Lef!. 44,4301(1978).

375 376


ADVANCES IN HETEROCYCLIC CHEMISTRY. VOL ?X

1.2. and2.1.Benzothiazines andRelated Compounds J .G . LOMBARDINO

AND D .E . KUHLA

Pfizer Central Research. Grotoil. Connecticui

1.Introduction . . . . . . . . . . . . . . . . . . . .. . 13 . 11. 1.2.Benzothiazines . . . . . . . . . . . . . . . . .. .. . 14. A . Syntheses . . . . . . . . . . . . . . . . . . .. .. .14 . 1. 1,2.Benzothiazin.4.ones . . . . . . . . . . . . . . .. . 14. 2. 1.2.Benzothiazin.3.ones . . . . . . . . . . . . . .. . . 83 . . .. .86 3.OtherI ,2.Benzothiazines . . . . . . . . . . . . . B . Reactions. . . . . . . . . . . . . . . . . .. . . .89. 1. 1,2.Benzothiazin.4.ones . . . . . . . . . . . . . .. . . 89 . 2. 1,2.Benzothiazin.3.ones . . . . . . . . . . . . . .. .. 95 . 3. Other1.2-Benzothiazines . . . . . . . . . . . . . .. 96 . C . Spectral Data . . . . . . . . . . . . . . . . . . .. . 91. D . Utility . . . . . . . . . . . . . . . . . . . .. .. loo . . Ill . NaphthoandDibenzo-l.2-thiazines . . . . . . . . . . . . . . .. 103 IV. Heterocyclic Ring-Fused 1, 2.Thiazines . . . . . . . . . . . ... .106 V . Rmg-Fused1,2.Benzothiazine Derivatives . . . . . . . . . . . .. .110 VI .2,1.Benzothiazines . . . . . . . . . . . . . . . . .. . 116 . . A . Syntheses . . . . . . . . . . . . . . . . . . . .. 116 . . B . Reactions. . . . . . . . . . . . . . . . . .. . . 121 1. Reactions of3.4-Dihydro.lH.2. 1.benzothiazine 2.2.Dioxide (223) . . . . 121 2. Reactions of1H.2.1.Benzothiazine 2.2.Dioxide (239) . . . . . .. . 122 3.Reactions of3,CDihydr 0.1 H.2.1-benzothiazin-4-one 2.2-Dioxide (237). . 124 VII. Conclusion. . . . . . . . . . . . . . . . . . .. .. 125 . . NoteAdded inProof. . . . . . . . . . . . . . . ... .125 . . t

.

I Introduction In recent yearstherehasbeena dramatic increase in thenumberof literature references to 1. 2.benzothiazines (1)and 2.1.benzothiazines (2) . Prior to1956. theonlyreference wasthat published in1923by vonBraun. Inthelast 15years. however. many publications havepresented interesting chemistry and important applications .Much oftheliterature deals with 1.2.benzothiazines ( oxicamssuch ) aspiroxicam .The anti-inflammatory J .von Braun.Ber.Dtsch.Chern. Ges.56,2332(1923) . 13

Copyright @ 1981 by Academic Press .Inc. Allrights ofrepro.4 uctioninany lormreserved . ISBN 0-12-0?06?8-5

74

J . G. LOMBARDINO

A N D D. E. KUHLA

[Sec. 1I.A

onlyprior review ofthese compounds, by Protafortheperiod from1972 toearly 1974, reported sixreferences to1,Zbenzothiazines. 5

4

5

4

Thepresent review comprehensively surveys theliterature uptoJuly1979, utilizing ChemicalAbstracts ChemicalSubstance Indexes, through volume90 (January-June, 1979), aswell asthecomputer-based C A CondensateslCASIA andtheDerwentWorldPatents Indexdataretrieval services. The focus of 1 and2 andtheir oxidized this survey isprimarily on thetworing systems derivatives. A few related ringsystems, suchasdibenzoand hetero ringfused1,Zthiazines areincluded whereitappeared appropriate todo so because ofsimilar chemistry oranalogous utility tothebenzothiazine compounds. Thischapter will bring together alloftheliterature references to thetitle compounds, discuss theroutes employed fortheir synthesis, and describe their reported chemical transformations. Spectral dataandutility arealso discussed. Because ofthecommercial importance ofsomeofthese compounds, a significant numberofreferences appear inthepatent literature. Wherever possible, foreign patents havebeentraced toa United States basic patent. Where this was notpossible, theforeign patent and ChemicalAbstracts citations aregiven. Patents found tobeequivalent tooneanother aregrouped under a single reference number.

11. 1,2-Benzothiazines

A. SYNTHESES 1. I ,2-Benzothiazin-l-ones Thisgrouprepresents by farthelargest class of1,2-benzothiazines. Since many of thesecompoundsarecapable of keto-enol tautomerism, the 4-hydroxy-1,2-benzothiazines(3) aswellasthe1,2-benzothiazin-4-ones (4) will begrouped in this section. Wheretheenol formhasbeendemonstrated by spectral evidence, these compoundswill be namedas4-hydroxy deriva-

G. Prota, in Organic CompoundsofSulphur, Selenium and Tellurium(D.H. Reid, ed.), Vol.3,p.708.The ChemicalSociety. London (1975).

Sec.II.A]

75

1,2-AND 2.1-BENZOTHIAZINES

tives rather than1,2-benzothiazin-4-ones. Thisisinkeeping withthepractice ofthemostrecent volumes ofChemicalAbstracts Chemical Substances Index.

(3)

(4)

The earliest report of a 1,2-benzothiazin-4-one isthatofvon Braun. according toelemental Cyclodehydration of carboxylic acid5 produced, analysis, a material assigned thestructure ofa 1,2-benzothiazine-3,4-dione (6) (Eq.1). Sinceno additional proof forthestructure of6 was provided, be excluded. theisomeric benzisothiazole dicarboxylic acid(7)cannot CO,H

&: C02H 0

&COCOJ+

+

\ S02NH,

orj&\

s

\

0 2

(1) 0 2

(7)

(6)

(5)

C02H

Co2H

A versatile synthetic approach to4-hydroxy-1,2-benzothiazineswas dis:2-phenacyl1,2-benzisothiazolin-3-ones covered by Abe and co-workers (8;R = Ar)withstrong baseproduce 3-benzoyl-4-hydroxy-2H-1,2-benzothiazine 1,l-dioxides (9; R = Ar)(Eq.2).Yields up to93% could be obtained using sodiumethoxide inethanol.

&N-CH2COR 0 2

(8)

,

B

~@foR

s

(2)

0 2

(9)

Methylation of compound 9 occurson the sulfonamide nitr~gen.~ Although compound9 was named as a 1,2-benzothiazin-4-one, infrared by theseworker^,^ aswellaslater work by others, spectral dataobtained strongly support a 4-hydroxy tautomeric form. ofAbe et~ 1 were . ~later extended by Zinnes andco-workers4 Thefindings in a series of publications dealing with1,2-benzothiazines. Forexample, K . Abe,S.Yamamoto,and K. Matsui,J .Pharrn.Sac.Jpn.76, 1058 (1956)[ C A 51, 3499 (1957)l. H.Zinnes, R.A. Comes,F.R. Zuleski. A. N. Caro, andJ. Shavel, J .Org.Chern. 30,2241 (I 965).

76

J. G.LOMBARDINO

AND D. E. KUHLA

[Sec. 1I.A

2-acetonyl-l,2-benzisothiazolin-3-one(8;R = Me) was converted by two equivalents ofsodiumethoxide to3-acetyl-4-hydroxy-2H-1,2-benzothiazine 1,l-dioxide (9;R = Me).Evidence was presented to support an initial ofsodiumethoxide, ethanolysis ofcompound8 (R = Me)by oneequivalent oftheintermediate ester. This ring-expansion reaction followed bycyclization hasbeenre~iewed.~ Spectral evidence clearly supports theenolformfor compound9 (R = Me). Unexpectedly, the3-acetyl compoundwas deacylated when heated in benzene withethylene glycol inthepresence ofanacid? The4-ketal produced was thenreadily cleaved by dilute hydrochloric acidtogive3,4-dihydro2H-1,2-benzothiazin-4-one 1,l-dioxide (10). As expected, N-methylation of compound 10 produced2-methyl-3,4-dihydro-2H-l,2-benzothiazin-Cone 1,l-dioxide (11). OH

(10)R = H (11)R = Me

The benzisothiazoline ester 8 (R = OR’)isisomerized to a 1,2-benzo(12)by sodiumethoxide in ethanol"* or by thiazine-3-carboxylic ester to sodiummethoxide indimethyl sulfoxide.’ Thisrearrangement appears bemoresensitive toreaction conditions andsolvent thanthe rearrangement suchas8 (R = Ar)(Eq.2),and of2-phenacyl-1,2-benzisothiazolin-3-ones twol a b o r a t ~ rreport i e s ~unsatisfactory *~ attempts torearrange compound 8 (R = OMe) to12 (R’= Me)withsodiummethoxide inmethanol. Another synthetic route to1,2-benzothiazin-4-one 1,l -dioxides produced (13; 13-19% of compound 11 when o-diazoacetylbenzenesulfonamide (R = Me) was cyclized by formic acidinacetonitrile" (Eq.3).A carbene was suggested as an intermediate inthis transformation." Much better yields (43 -70%)ofthecorresponding N-phenyl compound(14)wereobtained when thecorresponding N-phenylsulfonamide (13;R = Ph)wascyclized.’ " H. Hettler, Ad[>.Heterocycl. Chem. 15,259(1973). R. A. Comes,andJ. Shawl,J .Org.Chem.31,162(1966). H. Zinnes, ’ C. R. Rasmussen, U.S.Patent 3,501,466 (1970) [ C A 72,121562(1970)]. * C. R. Rasmussen, J . Org. Chern. 39, 1554(1974). J. G. Lombardino, E. H. Wiseman,and W. McLamore,J .Med. Chrm.14,1171(1971). l o G . Heyes, G . Holt, and A. Lewis,J .C . S.,PerkinI ,2351(1972).

Sec.II.A]

77

1.2-AND 2,l-BENZOTHIAZINES

(11)R = Me (14)R = Ph

Ringexpansion of 3-bromomethyl-l,2-benzisothiazole1,l-dioxide (15) by sodiumethoxide produced 3,4-dihydro-2H-l,2-benzothiazin-4-one (10) in66% yield.The favored mechanism involves a three-membered cyclic intermediate (16)openedby ethoxide attack on theether portion of 16 (Eq.4). Thissynthetic route wouldappear tobe preferred forpreparing 10. theketone CH,Br

Two additional routes gavelow yieldsof 1,2-benzothiazine-3-carboxamide20 (sudoxicam). Thus,N-carbobenzyloxysarcosine was converted to ofsulfonamide 19using thesulfonyl chlothesarcosine amide18.Formation ride 17 followed by cyclization produced the3-carboxamide 20 (Scheme1). Inanother approach, protection of21 viaformation oftheenolether 22 allowed oxidation oftheacetyl derivative 22 tocarboxylic acid23.Amide 24 yielded compound formation followed by hydrolysis of theenolether 20(Scheme l).

* R.A.Abramovitch, K . M. More,I.Shinkai, and P.C.Srinivasan, J .C .S.,Chem.Commun., 771(1976). J . G. Lombardinoand H. A. Watson,J .Hererocycl. Chem. 13,333 (1976).

l2

78

J.G. LOMBARDINO

[Sec. 1I.A

AND D. E. KUHLA

CONH HN

SO,NMeCH,

I

CHzCO NHMe

(17)

I

(18)

(19)

(21)R = H (22)R = CHMe,

(20)

I

I

A numberof sulfamoyl-substituted 3-acyl-4-hydroxy-l,2-benzothiazine 1,l -dioxides werepreparedby base-catalyzed isomerization ofsulfamoyl derivatives of benzisothiazolin-3-ones by essentially themethodof Abe

(Eq-2). Interest inthe4-hydroxy-2H-1,2-benzothiazine 1,l-dioxides was significantly increased by thediscovery by Lombardino andc ~ - w o r k e r sof ~* ~.~ l 3

l4 l5

A. Kraaijeveld andA. M. Akkerman, U S . Patent 3,284,450 (1966) [CA 66,28789(1967)l; Appl.283,525 [C,462,16262(1965)l. Netherlands Patent J.G. Lombardino, U.S.Patent 3,591,584 (1971) [CA 73,120647(1970) forequivalent GermanPatent 1,943,265)]. J.G. Lombardino, in Antiinflammatory Agents: Chemistry and Pharmacology (R.A. SchemerandM. W. Whitehouse, eds.). Vol.I , p. 129.AcademicPress, New York,1974.

Sec.ILA]

79

1.2-A N D 2,l-BENZOTHIAZINES

potent anti-inflammatory activity in3-carboxamides of4-hydroxy-2H-1,2(25). Synthesis ofcarboxamides suchas25 has benzothiazine 1,l-dioxides unstable beenapproached by several routes. Thus, compound11,although undersomebasic conditions,6 combines withisocyanates inthepresence of sodiumhydride indimethylformamide toproduce thedesired carboxamides 25 (Eq.5).9

0 2

(25)

(11)

Of themany reported analogs of compound 25, thecarboxanilide st~die Its d unusual .~ acidity (pK,’ 7.3) (Ar= Ph)hasbeenmostthoroughly was explained by a stabilized, hydrogen-bonded formoftheenolate (26). TheN-methyl-N-phenylcarboxamide(27), whichlacks anamideproton for stabilizing theenolate, exhibits’ pK,’9.8.Otherexamples of compounds made by theisocyanate methodshowninEq.(5) havebeen Me

(26)

(27)

Anotheruseful synthetic routeto amides25 utilized themethylester (12;R’ = Me) prepared by ringexpansion of thecorresponding benziso8 (R = OMe).9Methylation of12 produced ester 28.Comthiazoline ester 28,orthecorresponding ethyl ester, bination ofvarious amineswithester ofcompound25.7,8,17,18 The useofheterocyclic aminesin gives analogs this reaction hasproduced theN-heterocyclic amides sudoxicam (20)’and (29),20*21 potent anti-inflammatory agents that arediscussed more piroxicam fully inSection I1,D. H. Zinnes, N. A. Lindo, andJ.Shavel, U.S.Patent 3,646,021 (1972) [ C A 77,5499(1972)]. H. Zinnes. N . A. Lindo, J.C.Sircar, M. L.Schwartz, andJ.Shavel, J .Med. Chem.16,44 (1973). J.G. Lombardino, Ory.Prep.Proced. hit.12, 269 (1980). "J. G. Lombardino and E. H. Wiseman,J .Med. Chem. 15,848(1972). ’’ E. H . Wiseman,Y.-H.Chang,and J. G . Lombardino, Arzneitn.-Forsch. 26,1300(1976). J . G. Lombardino, E. H. Wiseman,and J. Chiaini. J . Med. Chem. 16,493 (1973). l6

80

J.G. LOMBARDINO

(28)

AND D. E. KUHLA

[Sec. 1I.A

(29)

An eneamine derivative (30)prepared fromcompound11 canbeacylated withphosgene and theresulting acidchloride 31 thenconverted tothe desired amides25 (Eq.6).’7*22*23 This sequence of reactions alsoproved useful forpreparing 3-aminoalkyl esters and 3-aminoalkylamides related to25.24

dCo 2 25

S’

(6)

\Me

0 2

Many patents coversynthetic routes toanti-inflammatory compounds showninScheme1 areincluded suchas20,25,or29.Thetransformations in processpatent^.^’-^^ Transamidation of certain 3-carboxanilides (32) produces novelN-substituted carboxamides of 4-hydroxy-2H-1,2-benzo(25)(Eq.7).30 thiazine 1,l-dioxides

*’J.C.Sircar, H.Zinnes, andJ.Shavel, U.S Patent 3,821,211 (1974) [see CA 79,146531 (1973)

forequivalent GermanPatent 2,308,305; CA 82,73007 (1975) forGermanPatent 2,365,4361. J.C.Sircar, H. Zinnes, andJ.Shavel, U S . Patent 3,808,205 (1974) [CA 81, 13538(1974)l. 2 4 H. Zinnes, J.Sircar, andJ.Shavel, U S . Patent 3,856,784 (1974) [CA 82,140158(1975)]. "J. G. Lombardino, U.S.Patent 3,853,862 (1974) [CA 82,112092(1975)]. 2 6 J.0 . Lombardino, U.S.Patent 3,927,002 (1975) [CA 84,135693(1976)l. " J.G. Lombardino. U.S.Patent 3.954.786 (1976) [CA 85,46723 (1976)l. 2 8 J.G . Lombardino, U.S.Patent 3,971. 802(1976) [CA 86,5478(1977)l. 23

29

30

J. G. Lombardino, U.S.Patent 3,892,740 (1975) [ C A 83,164213(1975)].

J.G. Lombardino, U.S.Patent 3,891,637 (1975) [CA 83,179077(1975)l.

Sec.II.A]

81

1,2-AND 2,l-BENZOTHIAZINES

rnNHA /

s

(7)

Me

When amides suchas33,unsubstituted onthesulfonamide nitrogen atom, aretreated withbaseandan alkylating agent, alkylation takes place preferentially on thesulfonamide nitrogen toyield 34.31

(33) R (34) R

=

H

= alkyl

(35)

Oxidation of 3-acyl-4-hydroxy-2H-l,2-benzothiazine 1,l-dioxide (9)in methanol bysilver carbonate ortert-butyl hypochlorite produced 3-methoxy4H-1,2-benzothiazin-4-one 1,l-dioxide (35k3apparently by a free radical ofsolvent. mechanism withparticipation The multistep preparation of 3-phenyl-4-hydroxy-2H-1,2-benzothiazine 1,l -dioxide (39) ledfrom3-benzylidene-2-methyl-2H-l,2-benzothiazin-4-one 1,l-dioxide (36) toan epoxide (37) isomerized by borontrifluoride into the deformylation of 38 yielded 39 3-formyl compound38.Acid-catalyzed (Eq. 3 3 3 4Thisreaction provided access to3-aryl-1,2-benzothiazinesfrom readily available 3-benzylidene1,2-benzothiazines (see Section 11,BJ). J . G. Lombardino, Netherlands Patent 7,614,135 (1977) [CA 88,121216(1978)l. H. ZinnesJ.Shavel. and M. S. Sternberg, U S . Patent 3,479,436 (1969) [ C A 72,55476 U S . Patent 3,492,296 (1970) [ C A 72,90487(1970)l. (1970)]; H. Zinnes andJ.Shavel, U.S.Patent 3,692,780 (1972) [ C A 77,152202(1972)l. 3 4 H. Zinnes andJ.Shavel, J .Hrtrrocvcl. Chrm.10,95 (1973).

31

32

82

J.G. LOMBARDINO

[Sec. 1I.A

AND D. E. KUHLA

(38)R = CHO (39) R =H

(37)

An interesting rearrangement was during thepreparation of4-hydroxy-N-(5-methyl-3-isoxazolyl)-2-methyl-2~-1,2-benzoth carboxamide 1,l-dioxide (43)(Eq.9). Sodiummethoxide cleaved thebenzisothiazoline derivative 40 to theexpected benzoate ester 41, butthis was cyclized by basetoa 4-hydroxy-2H-l,2-benzothiazine (42)withsimultaneous oftheisoxazole moietytoan oxadiazole. Compound42 was conversion N-methylated by methyliodide and theproduct converted tothedesired amide43 by treatment withtriethylamine inxylene, a process whichsimultaneously reconverts theoxadiazole side chain toanisoxazole.

OH

N-0 &CONH -..e

c 2. 1.NEi, Me1 -- m

S/

Me (43)

(9)

L C H 2 C O M e

\ 0 2

0-N

S/NH 0 2

(42)

Direct rearrangement of benzisothiazoline amides, suchas compound 8 (R = NHPh),tothe1,2-benzothiazine-3-carboxamide44 hasbeenaccomplished3 indimethyl sulfoxide using sodiummethoxide. A.C.Fabian, J.D.Genzer, C.F.Kasulanis, J.Shavel, andH.Ziniies, U.S.Patent 3,987,038 [CA 86,72679(1977)l; U.S.Patent 4,076,722 (1978) [CA 86,72679(1977)l. (1976) 36 A. C.Fabian. J.D.Genzer, C.F.Kasulanis, J.Shavel, andH.Zinnes, U S . Patent 3,957,772 [CA 85,46725(1976)l; U.S.Patent 4,041,042 (1977) [CA 87, 168068(1977)l; U.S. (1976) Patent 4,022,796 (1977) [CA 87,39523(1977)l; U.S.Patent 4,018,762 (1977) [CA 87,53345 U.S.Patent 3,978,073 (1976) [CA 86,16690(1977)l. (1977)l; 37 H.Zinnes, N. A. Lindo, andJ.Shavel. U.S.Patent 4,074,048 (1978) [ C A 88,190868 (1978)l; U.S.Patent 4,116,964 (1978). 35

Sec.II.A]

aHco 83

1.2-AND 2.1-BENZOTHIAZINES

NaOMe,

R

= NHPh

2. I ,2-Benzothiazin-3-ones Several synthetic approaches to the1,2-benzothiazin-3-ones havebeen described. Usually, an ortho-substituted sulfonamide was cyclized toform For example, Lombardinoand W i ~ e m a n ~treated .~ thethiazine ring. N-methyl-o-toluenesulfonamide (45)withbutyllithium: thedianion with C 0 2produced o-sulfamoylphenylacetic acid46 whichwas cyclodehydrated to3,4-dihydro-2-alkyl-1,2-benzothiazin-3(2H)-one 1,l-dioxide (47)ingood yield (Eq.10). Thissamereaction sequence was applied toanalogs of47 suchasthe7-methyl, the7-chloro, andthe2-benzylderivative^.^’

Or

a

S0,NHR

C

CO2 M

2

S0,NR

(45)

QJ

~

S02NHR

m o S

(10)

R

0 2

(46)

(47)

Sianesi and c o - w o r k e rutilized ~ ~ ~ ,o-aminophenylacetonitrile ~~ (48) as starting material fora four-step synthesis of compoundsrelated to 47. Thus,diazotization ofaniline 48 andtreatment ofthediazonium salt with SO2/CuZCl2 yielded thesulfonyl chloride 49 (Eq.11). Treatment of49 with primary aminesproduced thecorresponding sulfonamides 50 whichwere aqueous cyclized by sulfuric acidtothe3-imino compounds51. Finally, oftheimine51 produced thedesired 1,2-benzothiazin-3(2H)-one hydrolysis 1,l-dioxides (47)(R = H, Et,andPh)(Eq.11). J . G . Lombardinoand E. H . Wiseman,J . Med. Cbem. 14,973 (1971). E.Sianesi, R. Redaelli, M. Bertani, and P. Da Re,Cbem.Ber.103,1992(1970). 40 E.Sianesi, P. Da Re,1. Setnikar, and E. Massarani, U.S.Patent 3,712,889 (1973) [seeCA 78,159641(1973) forequivalent German Patent2065333; CA 74,141829(1971) forGerman 20226941. Patent 39

84

J.G . LOMBARDINO

(4)

(49) R’ (50)R’

= =

AND D. E. KUHLA

[Sec. 1I.A

CI NHR

Another synthetic approach to47 utilized 2-cyanomethylbenzenesulfonyl chloride (49)forthepreparation intwosteps of2-sulfonamidophenylacetic acids (52)whichwerecyclodehydrated by acetic anhydride/sodium acetate 12).41Examples oftheR substituent in47 prepared bythis method to47 (Eq. include n-propyl, isopropyl, n-butyl, allyl, propargyl, chlorophenyl, and yl?’ morpholinoeth

%)-o CHZCOZH

(12)

-47

SO2NHR

(52)

Photolysis of theo-diazoacetylbenzenesulfonamide 13 (R = Me) over of47 (R = Me),’Opresumably viathe sevendaysgives a reasonable yield of thediazoketone to a ketene intermediate (53). Wolffrearrangement Heating 13 (R = Ph) in refluxing chlorobenzene gaveonly30% of 47 (R = Ph)." COCHN, C X S o 2 N H R (131

--+

CH=C=O [ C I S o 2 N H R (531

]47

Zinnes andco-workers4’ report an interesting SemmlerWolfftransforacidoracetic acid/BF, mationoftheoxime54 (Eq.13) by trifluoroacetic tothecorresponding 1,2-benzothiazin-3(2H)-one 1,l-dioxides (55) (Eq.13). Catsoulacos has synthesized 2-substituted 3,4-dihydro-6,7-dimethoxy1,2-benzothiazin-3(2H)-one 1, I-dioxides (58) : chlorosulfonation of 3,441

42

E.Sianesi, R. Redaelli. M. J.Magistretti. and E.Massarani, J .Med.Chem.16,1133(1973). H. Zinnes, R. A. Comes,and J . Shave], J .Heferocycl. Chern.14, 1063(1977).

Sec.II.A]

85

1,2-AND 2,l-BENZOTHIAZINES THCOR

NOH

(13) 0 2

0 2

(54)

(55)

dimethoxyphenylacetic ester gavethesulfonyl chloride (56), whichwas converted into thesulfonamide (57)andcyclodehydrated using phosphorus pentachloride or heatto 58 (R’= H, methyl, isopropyl, phenyl, and p - t ~ l y lThe ) .same ~ ~ ,reactions ~~ gave58 (R = 5-chlor0-2-pyridyl)~~ or58 (R = rnethyl-2-py1-idyl).~~ M e O a C H 2 C 0 2 E i Me0

SO,R

Me0 0 2

(56)R = CI (57) R = NHR’

Williams and Cram4’prepared thecyclic sulfoximide 62,witha chiral sulfur atom,inthree steps from 2-methylthio-5-methylacetophenone(59). The latter compoundwas converted intoa 2-methylthiophenylacetic acid derivative (a), whichwas thenoxidized tothe2-methylsulfinyl compound 61.Compound 61 was cyclized to62 in60% yield usingsodiumazidein sulfuric acid(Eq.14).48 MeaC0CH3

-

SMe (59)

-

Memo MeacH2 MeaCH,CO2H

1 NalO,

SMe

(60)

’

(14)

2. NaN,/H,SO,

SOMe

OH

(61)

(62)

P.Catsoulacos, J .Heterocycl. Chetn.8,947 (1971). P. Catsoulacos and C. Camoutsis, J . Chetn.Eny. Data 22,353 (1977). 4 5 P. Catsoulacos, Chim.Ther.7,243(1972). 46 P. Catsoulacos, Chrm.Chron.3,129(1974) [ C A 84,43960(1976)l. 47 T. R. Williams and D. J . Cram, J .Am. Chnn.Soc.,93,7333(1971). 4R T. R. Williams and D. J . Cram, J .Org.Chetn. 38,20 (1973). 43

44

’Me

86

J . G. LOMBARDINO

[Sec. 1I.A

AND D. E. KUHLA

Stoss andS a t ~ i n g e utilized r ~ ~ ~similar methodology (sodium azide in polyphosphoric acid/P,O,) to prepare examples of 64 from thecorre2-alkylsulfinylphenylacetic esters 63.The4-carboethoxy derivative sponding 65 was prepared by ethanolysis oftheo-chlorocarboxanilide 66.38

(641R = Me, Et.Ph

(65)R = OEt

(66)R

=

NHC,H,Cl(o)

3.Other1,2-Benzothiazines A few reports haveappeared ofsyntheses of 1,2-benzothiazines lacking a ketonegroupin thethiazine ring. Bicking and Spragues2 treated l-(2-chloroethyl)benzene-2,4-disulfonylchloride derivatives (68) with a variety ofprimary amines toafford 7-sulfamoyl-3,4-dihydro-2H-1,2-benzothiazine 1,l-dioxides (69)inpoortofair overall yield. Therequisite starting (68)werereadily prepared by exhaustive chlorosulfonation of materials phenethyl halides (67) (Eq. 15),butthescope waslimited bytheconcomitant substituent intothebenzeneringof the introduction of a sulfamoyl (69). 1,2-benzothiazine 1,l-dioxide RNH,

CISO,

RNHSO,

P.Stossand G . Satzinger, Cliem. Ber.105,2575(1972). P.Stoss and G. Satzinger, German Patent 2,207,235 (1973) [ C A 79, 146571(1973)]. P.Stoss and G. Satzinger, U.S.Patent3,803,131 (1973) [CA 81,3979(1974)l. 5 2 J . B. Bicking and J . M. Sprague, U.S.Patent 3.113,075 (1963) [CA 60,P5514 (1964)l.

49

50

Sec.II.A]

87


In another example, Weinstock and Dunoff 5 3 selectively monochloro5-( 3-chlorobenzyl)-5-methylhydantoin(70) followed bytreatment sulfonated in situwithammonia, whichgave8-chloro-l0a-methyl-1O,lOa-dihydro-l Himidazo[3,4-b] [1,2]benzothiazine-l,3(2H)-dione 5,5-dioxide (71)in high yield. Basic hydrolysis ofthehydantoin ring in71 followed by loss ofcyanate anionafforded 6-chloro-3-methyl-3,4-dihydro-2H-1,2-benzothiazine-3-carboxylic acid1,l-dioxide (72)(Eq.16).

(72)

The exclusive orthoselectivity observed intheabovechlorosulfonation followed earlier observationss4 that theparadirective influence ofa halogen on sulfonation exceeds that ofan alkyl group. Zenno and Mizutani’extended thissynthesis by treating N-(p-nitro(73) withfumingsulfuric acidtogive3,4-dihydro-7phenethy1)acetamide nitro-2H-1,2-benzothiazine1,l-dioxide (74)ingood overall yield (Eq.17). After reduction anddiazotization, thenitro groupin74 couldbe replaced ofother functional groups (oide infra). witha variety a C H 2 C H 2 N H C O M e

H,SO,

SO,

O2N

OZN

a

N

H

(17)

0 2

(73)

(74)

Sianesi and c o - ~ o r k ewere r s ~able ~ to utilize the readily available 2-(2-~hloroethyl)aniline (75)or o-aminophenylacetonitrile (48)as starting s3

J.Weinstock and R. Y.Dunoff, J .O r g . Cheni33,3342(1968).

C. M. Suter. "The Organic Chemistry ofSulfur," p.217. Wiley.New York, 1944. H. ZennoandT. Mizutani, Japanese Patent 44132,404 (1969) [CA 72,79122(1970)l. s 6E. Sianesi, P.Da Re,J.Setnikar, and E.Massarani. U.S.Patent 3,770,733 (1973) [ C A 76, 72535(1972) forthequivalent GermanPatent 2,124,9531. s4

5s

88

J.G. LOMBARDINO

AND D. E. KUHLA

[Sec. 1I.A

materials forthepreparation of 3,4-dihydro-1,2-benzothiazine1,l-dioxide (77). Diazotization oftheaminogroupineither ofthese derivatives (75or 48)followed by treatment withSO,/Cu,Cl, afforded theisomerically pure 76and49(Scheme 2). Treatment of76withexcess ammonia sulfonyl chlorides gave77 directly inhighyield. Reaction of49 withexcess ammoniagave o-cyanomethylbenzenesulfonamide (78) which, after catalytic hydrogenation (palladium on carbon) inanacidic medium,directly cyclized to77.

0,

a a

(77)

(75)

1. N a N O , / H + ,

2 SO,ICu,CI,

CH,CN

SOZCl

T

CH,CN SOZNHZ

(491

SCHEME 2

A slightly different synthetic approach was developed by Hauserand co-workerss whilestudying ring-chain tautomerization insix-membered withbenzonitrile heterocycles. Thedilithiosulfonamides from45 condensed toform, after hydrolysis oftheintermediate iminesulfonamides, o-phenacyl(79)whichwere in equilibrium withthecarbinol benzenesulfonamides sulfonamides 80(ring tautomer) (Scheme 3).Although infrared spectroscopy indicated that this ring-chain tautomeric mixture wasalmost exclusively in dehydration of themixture of79 and80 under theopen-chain form(79), I BuLi

S0,NHR

0, (80)

(79)

0, (81)

SCHEME3 5’

H. Watanable, C.-L.Mao, I.T.Barnish, andC. R. Hauser, J .Ory.Chem. 34,920(1969).

Sec.II.B]


89

either acidic or thermal conditions gave2,3-disubstituted 2H-1,2-benzo(81)inhighyield. thiazine 1,l-dioxides Helferich and Klebert obtained the5,6,7,8-tetrahydro-Zfl-l,2-benzothiazine 1,l-dioxide 84 by treating thebicyclic sultone derivative 83 with aniline (Eq.18).The sultone 83 was readily prepared by reacting thea,/?unsaturated ketone 82 with sulfuric acid/acetic anhydride.

B. REACTIONS 1. 1,2-Benzothiazin-4-ones Acylation and alkylation reactions of theenolic 4-hydroxy-1,2-benzoet~ 10-alkylated . ~ compound21 with thiazines havebeenstudied. Zinnes and isopropyl iodide (potassium carbonate in acetone) (seeSchemel), formedthe4-acetoxy compound85 from2-methyl-2H-1,2-benzothiazin-4one 1,l-dioxide (11)withacetyl chloride and sodiumhydride (Eq.19).6 OCOMe

0

Similarly, bothZinnes et and Rasmussen 6 1 prepared enolcarbonates 86 fromthecorresponding 4-hydroxy-1,2-benzothiazine-3-carboxamides 25 andethyl chloroformate. Excess ofethyl chloroformate inpyridine 87.62 gavehighyields ofthe0,N-bis-acylated derivative ~

5R 59

1

.

~

~

9

~

~

B. Helferich and W. Klebert, Justus Lic+igsAnn. Chem.657,79 (1962). H. Zinnes, M . L.Shwartz, and J.Shavel, U.S.Patent 3,704,298 (1972) [ C A 78.58442 (1973)l.

6 o H . Zinnes, N. A. Lindo,and J . Shavel, U.S.Patent3,646,020 (1972) [CA

77,5500(1972)]. C. R. Rasmussen,U.S.Patent3,925,371 (1975) [CA 84,90162(1976)l. 6 2 C. R. Rasmussen, U.S.Patent3.900,470 (1975) [ C A 83,193356(1975)l.

61

90

[Sec.1I.B

A N D D. E. KUHLA

J. G . LOMBARDINO

&c0NRc02Et

S / \Me 0 2

(87)

dN&

Compound11 forms3-alkylidene derivatives (88) (Eq.20)4*6 withbenzalpyridine-2-carboxaldehyde. dehydeandother aldehydes, including __* PhCHO

\

S

\Me

\

S/

0 2

0 2

(11)

fW

HPh

(20)

Me

Interesting reactions of 3-benzoyl-4-hydroxy-2H-1,2-benzothiazine 1,ldioxide (89) havebeenstudied by Abed.63 Thus,treatment ofcompound 89 withphenylmagnesium bromideproducedgood yields of a product 90(Eq.21). assigned thebenzhydrol structure OH

OH

0 2

0 2

(89)

(90)

The enolic /?-diketone 89 withhydrazine andaminesproduced excellent of thepyrazolo derivative 91 and theenamines 92,respectively yields (Eq.22).63764 Similarly, the3-acetyl compound93yielded thecorresponding pyrazole when combinedwithh y d r a ~ i nand e ,with ~ ~ aminesitgavethe 94. ~~ enaminoketones N . M . Abed,IndianJ.Chem.,Sect. B 14,428(1976). J . Shave1and H. Zinnes,U.S.Patent3,346,572 (1967) [CA 68,95839(1968)j. 6 5 C. R. Rasmussen, U.S.Patent3,476,749 (1969) [CA 72,21727(1970)l. 63 64

Sec.II.B]

91


(92)R’ = Ph (94)R’ = Me

OH

0

Me

Withdibromomethane compound93 alsoundergoes cycloalkylation at boththeoxygen andnitrogen atonis toformanoxazine (95).’ Other reactions cyclized derivatives utilizing thebifunctionality ofcompound93toproduce suchas95 arediscussed ingreater detail inSection IV. Theknown capacity ofthesulfonamide nitrogen in1,Zbenzothiazines to undergoalkylation4 has been extended: 96 withmethylbromoacetate produced ester 97 whichwas further cyclized tothepiperazine derivative 98by sulfuric acid(Eq.23).8

&c0NH2

dCON ’ d

fNH 0, (961

’S

0,

\CH,CO,Me

197)

(98)

Surprisingly, treatment of amide96 withethyl chloroformate didnot produceisolable yields of theexpected 2-ethoxycarbonyl compound99. Instead, a pooryield ofthe3-(N-ethoxycarbonylamide) 100 was obtained.’ 101wasobtained when Thecorresponding 1,"-diethoxycarbonyl derivative excess ethyl chloroformate wascombined with96under alkaline conditions.8

92

J.G. LOMBARDINO

&coNH2

s/

\CO,Et

drNH 0 2

0 2

(99)

[Sec. 1I.B

AND D. E. KUHLA

& S/

(100)

CONHC0,Et

\C02Et

0 2

(101)

Conversion of 1,2-benzothiazin-4-one 102 tothecorresponding oxime 103followed by high-pressure catalytic hydrogenation produced thecyclized amide104(Eq.24).66 Hydrolysis ofcompound104inaqueous acidyielded theamino acid105.By an analogous procedure, 4-amino-3,4-dihydro-2-

dNqfjj s/

CH,CO,M~

0 2

d

0 2

(102) x =0

(103) X = NOH

(104)

AH, CII

66

H.Zinnes, R. A. Comes,and J . Shavel, J .Hererocycl. Chem. 5, 875 (1968).

Sec.II.B]

93

1,2-A N D 2.1-BENZOTHIAZINES

methyl-2H-l,2-benzothiazine1,l-dioxide (106)was made intwo steps via 11 (Eq.25).6 theoximeprepared fromtheketone Sodiumborohydride reduction ofeither 3-acetylor3-benzoyl-4-hydroxy2H-1,2-benzothiazine 1,l-dioxides (e.g., 21,89,93)producedthecorresponding 3-alkylidene compounds Evidently theintermediate alcohols aredehydrated undertheconditions ofthereaction. The authentic benzylidene derivative 108 (R = Ph,R 2 = Me),prepared4 by another route (Eq.20), wasidentical totheproduct isolated fromtheborohydride reduction ofcompound107.

0 2

(21)R 1 = R2 = Me (89) R 1 = Ph,R 2 = H (93) R = Me, R 2 = H (107) R = Ph.R 2 = Me

S 02

(108)

R2

(109)

In two Japanese patents, Hasegawaand c o - ~ o r k e r sdescribed ~ * ~ * the preparation of 1,2-benzothiazines with2-aminoalkyl substituents. Thus, 3-benzoyl-4-hydroxy-2H-1,2-benzothiazine1,l-dioxide was alkylated by piperidinoethyl chloride togivea goodyield of1,2-benzothiazine 109.67 Several compoundsclosely related to109 weresimilarly prepared witha variety ofaminoalkyl s u b ~ t i t u eAlkylation n t s . ~ ~ of3-thenoyl-4-hydroxy-2H1,2-benzothiazine 1,l-dioxide with2-niorpholinoethyl chloride produced6 a compoundcorresponding to109.Thesesameworkers havealsoprepared spirohydantoins (110) from 3,4-dihydro-2H-1,2-benzothiazin-4-one 1,Idioxide (10)using potassium cyanide andammonium carbonate (Eq.26).69 25 (Ar= Ph)usingsodiumhydride Methylation of the3-carboxanilide and dimethyl sulfate gave2-N-dimethyl-4-hydroxy-2H-1,2-benzothiazine3-carboxanilide 1,l-dioxide (27).70 G. Hasegawa. T.Munakata, and T. Yoshida, Japanese Patent 71/00.029 (1971) [CA 74, 141828(1971)l. 6 8 G. Hasegawa, T.Munakata, T. Furutd, and T,Tsuda,Japanese Patent 71122.027 (1971) [CA 75,76815(1971)l. 69 G. Hasegawa, T.Munakata, andT.Furuta, Japanese Patent 70141586 (1970) [ C A 75.20423 (1971)]. 7 0 H. Zinnes. N.A . Lindo, andJ.Shavel. U.S.Patent 3,714,155(1973) [CA 78,136317(1973)]. 67

94

J.G. LOMBARDINO

A N D D. E. KUHLA

[Sec. 1I.B

The ethyl ester 111 and theanionof dimethyl sulfoxide producethe 112 (Eq.27).71 P-sulfinyl ketone

Acylation of 6-aminopenicillanic acidby theactivated ester113 in dichloromethane andtriethylamine gave114.72

(28)R = Me (115)R = H

(47)

von Strandtmann, J.Shavel. S.Klutchko. and M. C0hen.U.S. Patent 3,801,644 (1974) [CA 81,3595(1974)l; U.S.Patent 3,892,739 (1975) [CA 84,43632(1976)]. 1 2 J.C.Sircar. H. Zinnes, andJ.Shavel, U S . Patent 3.878.198 (1975) [CA 83.97274(1975)l: U.S.Patent 3,912,720 (1975) [C,484.44029(1976)l; U S . Patent 3.966.765 (1976) [ C A 86, 5447( I977)]. "M.

Sec.II.B]

95


Specific conditions73 hydrolyze themethylester 28 to thecrystalline -2-methyl -2H-1,2benzot hiazine-3-carboxylic acid I,1-dioxide 4-hydroxy (113,converted by standard methodstoanti-inflammatory amide~.’~ Heterocyclic derivatives of3-acyl1,2-benzothiazin-4-0ne, prepared utilizIV. ingtheir /?-diketonic nature, arediscussed inSection 2. 1,2-Benzothiazin-3-ones The activated 4-methylene function of 3,4-dihydro-2-alkyl1,2-benzothiazin-3(2H)-one 1,l-dioxide (47)permits theformation ofananion. Treatment oftheanionin DMS0’4,38 or DMF74 withisocyanates yields the (116)(Eq.28). corresponding 4-carboxamides Acrylonitrile and theanionof 58 (formed by KOH-MeOH) givethe bis-cyanoethyl adduct117.74 The cyclic amidebondincompound58 was by amines :morpholine atelevated temperatures affords the slowly cleaved 118.46 Pyrrolidine reacts ~imilarly.~’ sulfonamide-carboxamide M

e

o

w S/ ’R’

Me0

M

e

Me0

o

nCH2COR SOZNHR’

0 2

(58)R=H

(118)R = NC4H,0 (119) R = OH

(117)R = CH2CHzCN

Hydroxide cleaved compound58 totheo-sulfamoylphenylacetic acid (119) ina reversal ofthecyclodehydration usedtoprepare 58. Compound 120 can be alkylated atoxygenor nitrogen, depending on thereaction conditions (Eq.29).4’ Usually, N-alkylation to47 wasobserved inthepresence ofbaseinD M F withalkyl halides when 120 was treated 120 suchas propargyl chloride or ally1 b r ~ m i d e . ~However, ’ . ~ ’ treating inDMF withN a H C 0 3 andn-propyl bromide produced a small amountof the0-alkyl compound121 (R = n-propyl) aswellastheN-alkyl derivative (47;R = n - p r ~ p y l ) . ~ ’

mo- -aO S’

’R

0 2

(47)R = alkyl 73

74

W

H S/ 0 2

(120)

(29)

O

0,

(121)

P.D. Hammen,U.S.Patent 4,100.347 (1978) [ C A 88,105385(1978) forequivalent German Patent 27261751. P.Catsoulacos, Chim.Ther.7,351 (1972).

96

J. G . LOMBARDINO

A N D D. E. KUHLA

[Sec. 1I.B

Sianesi and c o - ~ o r k ehave r s ~nitrated ~ the3-amino-1,2-benzothiazine* 122 tothe7-nitro derivative 123 ingoodyield. Reduction and hydrolysis of123gave7-amino-3,4-dihydro-3(2H)-one 1,l-dioxide (124).

(122) X =H (123) X = NO,

The7-amino compound124 wascarbethoxylated by ethyl chloroformate of124. togivea 7-ethoxycarbonylamino derivative Zinnesand c o - ~ o r k ehave r s ~observed ~ oxidative ringcontraction of (126)by KMnO, and 10% sulfuric compound125 toN-methylsaccharin acidatreflux. NHCOCF3

0

(77)R = H (127) R = CH,CO,Et

3. Other1,2-Benzothiazines Sianesi and co-workersS6 havealkylated 3,4-dihydro-2H-l,2-benzothiazine1,l-dioxide (77) withethyl bromoacetate togiveethyl (3,4-dihydro-l,1dioxo-2H-1,2-benzothiazin-2-yl)acetate(127). Theester functionality in127 wasconverted into amides andhydrazides. ZennoandMizutani7 havealso of reported on theN-alkylation of compoundsrelated to 77.Alkylation 7-chloro-3,4-dihydro-2H-1,2-benzothiazine1,l-dioxide (129)witharalkyl halides gavetheN-aralkyl derivatives 130 (e.g., R = CH,Ph)inexcellent overall yield (Eq.30). The starting material 129 was prepared fromthe (74)(see Eq. 17), by a tinfiydrochloric acidr e d ~ c t i o to n ~ 7-nitro analog 128 followed by diazotization and treatment withcuprous chloride to give129.77 Compounds suchas122are represented as3-imino structures intheoriginal papers. H . Zenno and T. Mizutani, JapanesePatent4516262(1970) [ C A 72,PI32759(1970)]. 7 6 H . Zenno and T. Mizutani, Japanese Patent 44132405 (1969) [ C A 72,P79121(1970)l. 7 7 H. Zenno and T. Mizutani, Japanese Patent 4516261(1970) [CA 72,P121561(1970)].

75

Sec.II.C]

74

97


Xa

H

c

l

a

0,

(128) X = NH2 (129) X = CI

N

,

R

(30)

0 2

(130)

Theonlyother reactions reported forthese 1,2-benzothiazines ledtoring cleavage. Hauser andco-workers5’ observed anintramolecular p-elimination sodiumamideorpotassium amideinliquid upontreatment of81 witheither ammonia, andisolated theacetylenic sulfonamide 131inhighyield (Eq.31).

1H

B:

(131)

(81)

Pyrolysis of thetetrahydro-l,2-benzothiazine84 withcopperbronze eliminated sulfur dioxide andformeda fused pyrrole (Eq.32).58

C. SPECTRAL DATA Numerousspectra recorded for1,2-benzothiazines include the’ 3CNMR ofpiroxicam (29),"theelectron spin resonance spectrum oftheparamagnetic semidione obtained frombase/oxygen oxidation of3,4-dihydro-1,2-benzo1,l-dioxide and themass spectral fragmentations thiazin-4(2H)-one of4-hydroxy1,2-benzothiazines described indetail by Rasmussen’ andby ultraviolet, and nuclear magnetic resonance Heyesetal." The infrared, spectra ofvarious l,2-benzothiazines arer e p ~ r t e d . ~ , ~ * ~Repre-~~" arepresented inTableI. sentative spectral dataof1,2-benzothiazines 7*21,34966

’*E. B. Whipple,Org.Magn. Reson.10,23 (1977).

79

G . A. Russell, R. L. Blankespoor, K . D. Trahanovsky, C. S. C. Chung, P. R. Whittle, J. Mattox,C. L. Myers,R. Penny,T.Ku, Y. Kosugi, and R. S.Givens, J .Am. Clzern. SOC. 97, 1906 (1975).

SPECTRAL PROPERTIES ~

Structure

~

TABLE 1 1.2-BENZOTHIAZINE 1 DIOXIDES

OF SOME ~

Ultraviolet spectra" [Lax innm (41

~

Nuclearmagnetic resonance spectra’

Infrared spectra" (!J)

[CDC131 -2.04(enol OH),6.05(OMe), 1.8-2.4 (C,H,), 7.06(NMe)

[CDCI,] -3.44(enol OH), 1.67(NH), 1.82-3.0 (C6H4), 7.13(NMe)

@lMe \

S/NMe

[95% EtOH] 245-248(6100) 320(11,OOO) [NaOH/EtOH] 242( 11,400) 354( 11,200)

Reference

9

W r I 2.95, 6.08, 6.21, 6.46

9

[Nujol] 6.18, 6.28, 6.47

4

W

2"

M

99

00

m

100

J.G. LOMBARDINO

A N D D. E. KUHLA

[Sec. 1I.D

D. UTILITY Biological activities havebeenfoundfor1,2-benzothiazines. The ethyl 111 causes ventricular arrhythmia indogsa0 and and was ester suggested asa biological tool fortesting forantiarrhythmic agents. Diuretic 1,2-benzoactivity was detected ina family of5-chloro-6-sulfamoyl-3-acylthiazines.’ 1,2-Benzothiazines withbasic side chains, for example compound 109,areclaimed68 to be diuretic, anti-inflammatory, and antibacterial agents. Spirohydantoins such as compound110 arediuretic, hypoglycemic, analgesic, andfungicidal agents.70 Antithrombotica3 andlipid-regulatinga4 properties areobserved for4-hydroxy-l,2-benzothiazine-3-carboxamides. Antibacterial activity wasfoundforseveral penicillin derivatives containing 7z a 1,2-benzot hiazinyl fragment. By far thegreatest numberofreports havereferred totheanti-inflammatory activity foundfora variety of 1,2-benzothiazines.’ An initial report by Lombardino et a!.’indicated thatpotent anti-inflammatory activity was present in a series of 4-hydroxy-2H-l,2-benzothiazine-3-carboxanilide 1,l-dioxides. Antiedema activity ina ratmodelindicated that carboxanilide 132 (CP-14, 304)was twiceas potent as thestandard anti-inflammatory agent phenylbutazone. Thisobservation on compound132 was later conStudies ofthemetabolism ofcompound firmed andextended by other^.’^,^^ 132inanimals indicated that a majormetabolite resulted fromhydroxylation ofthecarboxanilide moiety.86 The plasmahalf-life ofcompound132 was foundtobe21 hours inman.86 and As extensions of thefindings withcompound132, Lombardino Wiseman" prepared N-heterocyclic carboxamides of 4-hydroxy-2H-l,2benzothiazine 1,l -dioxide including thepotent anti-inflammatory sudoxicam (20).19921 Sudoxicam issignificantly more acidic (pK,’ 5.3) and a more 132.An internally potent87 anti-inflammatory agent thanthecarboxanilide was suggested as a possible explanation of hydrogen-bonded enolate enhanced acidity.21 The plasmahalf-life ofsudoxicam isextendedz1 and I (1969) [CA 70,86130(1969)l. A.Ferrari, G.Razzaboni, and W. Vergoni, Ria.Farmacol. Ter. 1,161(1970) [CA 75,150161 (1971)]. 8 2 A. Ferrari, C .Razzaboni, and W. Vergoni, Riu.Farmacol. Ter. 1.303 (1970) [CA 75,117040 (1971 )]. 8 3 J.G. Lombardinoand E. H. Wiseman,U.S. Patent3,862,319(1975) [CA 83,72175 (1975)l. 8 4 J.G.Lombardinoand G.F.Holland, U.S.Patent 3,674,876 (1972) [CA 77,109576(1972)l. *’G. DiPasquale, C . L. Rassaert, R. S.Richter, and L. V. Tripp, Arch.Int.fharmacodyn. Ther.203,92 (1973). 8 6 J.Chiaini, E. H. Wiseman,and J.G. Lombardino,J .Med. Chem. 14, 1175(1971). E. H. Wiseman and J . Chiaini, Biochem.Pharmacol. 21,2323(1972). 8 o T. P. Pruss, Toxicol. Appl.Pharmacol. 14, 81

Sec.II.D]

1,2-AND 2,l-BENZOTHIAZINES

101

theproducts ofmetabolism, resulting fromthiazole ringscission, havebeen of sudoxicam include inhibition of platelet identified.88 Otheractivities ofrabbit monoartica g g r e g a t i ~ antithrombotic n , ~ ~ , ~ ’ activity," inhibition ulararthritis,g2 inhibition ofleukocyte anddelayofcastor oildiarrhea inrats.9’ Sudoxicam exhibited morepotent anti-inflammatory acidic anti-inflammatory agents.96 Other activity inanimals than14 other of 1,2-benzothiazines arealsoclaimed N-thiazolylcarboxamide derivatives agent^.^^*^* tobepotent anti-inflammatory AnotherN-heterocyclic 1,2-benzothiazine-3-carboxamiderelated to sudoxicam istheN-(5-methyl-3-isoxazolyl) derivative isoxicam (43),99-’ O’ withmoderate anti-inflammatory a c t i ~ i t yand ~~~ low ’ ’ulcerogenic ’ potentia1.99"02 Compound 43 isprepared by several routes including combinawiththe ester111 in ~ y l e n e ,O4’ ~ ~ . ’ tionof 3-amino-5-methylisoxazole preparation of an eneamine and acylation withphosgene (Eq.6),’ 7,22323 and rearrangement of a benzisothiazoline acetamide (40)(Eq.9).36 The of isoxicam involves cleavage of theisoxazole ring."’Only metabolism modest effects of isoxicamon prostaglandin biosynthesis have been

" D. C. HobbsandT. M.

Tworney, Drug Merab.Di.spos. 5,75 (1977). W. Constantine and I. Purcell. J .Pharmacol. Exp.Ther.187,653(1973). 90 R. Kadatz. in "Platelet Aggregation inthePathogenesis ofCerebrovascular Disorders" eds.), p.216. Springer-Verlag. Berlin andNew York.1977[ C A 88, (A.Agnoli andC.Fazio 58319(1978)l. 9 1 J. G. Lornbardino andE. H. Wisernan, FrenchDernande 2,052,924 (1971) [ C A 76,103755 (I972)l. 92 A. Blackham and H. Radziwonik, AgentsAcrions7,473 (1977). 93 A. Blackhamand R. T.Owen,J .Pharm.Pharmacol. 27,201 (1975). 94 I; Rivkin. G. V. Foschi. and C. H. Rosen,Proc.Soc.Exp.Biol.M e d . 153,236 (1976). 9 5 F.Awouters, C.J.E.Niemegeers, F.M. Lenaerts, andP.A. J. Jansen, J .Pharni. Phartnacol. 30. 41 (1978). 9h J.G. Lornbardino, I.G. Otterness, andE. H. Wiseman,Arznebn.-Forsch. 25,1629(1975). 9 7 K . Thomae GmbH., Netherlands PatentApplication 75/12,271 (1976) [ C A 86,72677 (1977)l; alsoBelgian Patent 835,392 (1976) andGerman Patent 2452996(1976). 9 8 K . Thomae GmbH.,GermanPatent 2756113(1979); EuropeanPatent 2-482(1979). 99 G.DiPasquale, C.Rassaert, R.Richter, P.Welaj. J.Gingold, andR.Singer, AyentsActions 5,256(1975). l o o G .DiPasquale, C.Rassert. P.Welaj. andL.Tripp, AyenrsActions 6,748(1976). 101 G. DiPasquale, C. Rassaert, P.Welaj, J. Gingold, and E.Schwartz, Res.Commun. Chrm. Parhol. Pharmacol. 19,529(1978). l o *K . D. Rainsford. AgentsActions 7,573(1977). lo’H.Zinnes, M. L.Schwartz,and J.Shavel, U.S.Patent 3,787,324(1974); U.S.Patent 3,816.628 [CA 77,164722(1972) forequivalent GermanPatent 2,208,351). (1974) J . D. Genzler andF.C.Fontsere, U.S.Patent 4,024,136 (1977) [ C A 87,68398 (1977)l: U.S. Patent 3,960,856 (1976) [CA 85,46728(1976)l. I o 5 J.P.Viau. J .E. Epps, andF.J.DiCarlo. Fed.Proc., Fed.A m . Soc.E.xp.B i d .34,734(1975).

*’J.

102

J.G . LOMBARDINO

AND D. E. KUHLA

[Sec. 1I.D

observed.’06 An isomeric analog of isoxicam [4-hydroxy-2-methyl-N-(3methyl-5-isoxazolyl)-2H-l,2-benzothiazine-3-carboxamide 1,l-dioxide] also O7 exhibited anti-inflammatory activity.’

(20)R = 2-thiazolyl (29)R = 2-pyridyl

(133)

(43) R = 5-methylisoxazol-3-yI

(132)R = Ph

Much literature exists on thepotent anti-inflammatory agentpiroxicam (29). Lombardino, Wiseman, and co-workers havedescribed thesynthesis ofpiroxicam inanimals.’ 9-21 The biotransandpotent antiedema activity formation products of piroxicam in animals"* and man’" havebeen reported. Piroxicam isan inhibitor ofplatelet aggregation"’ anda potent ofeither MC5-5 cells or inhibitor ofprostaglandin biosynthesis incultures synovial cells."’ In man,piroxicam hasa longhalf-life (45h)l12 and is effective inthetreatment ofrheumatoid l4 osteoarthritis,’ ’ andother painful musculoskeletal conditions’ 6-119 when administered as

G . DiPasquale and D. Mellace. AgentsActions 7 ,481 (1977). H.Zinnes, M. L.Schwartz, N. A. Lindo. andJ.Shavel, US.Patent 3,868,367 (1975) [ C A82, 170994(19791. D. C. HobbsandT. M. Twomey, Pharmacologist 18,152(1976). lo’T.M. Twomey and D. C .Hobbs, Fed.Proc. Fed.Am. Soc.Exp.Biol.,37,271(1978). ’ l o B. J.Gaynor andJ.W. Constantine, Experientia 35. 797(1979). T.J. Carty, J.Eskra, J.G .Lombardino. andW. W. Hoffman, Prostaglandins 19,51 (1980). D. C. Hobbs and T. M. Twomey,J . C’lin. fharmacol. 19,270(1979). C.D.Angevine, andE.C .Atwater, J .Rheumatol. 4,393 (1977). M. Weintraub, R.F.Jacox, Piroxicam, RoyalSociety ofMedicine InternaW. M. OBrienand E.H. Wiseman,eds., New York,1978. tional Congress and SymposiumSeries, No. l.AcademicPress, Eur.J .Rheumatol. Infiamniation 1, 352(1978). H. Telhag, ’I6 P.Widmark,Eur.J .Rheumatol. Inflammation 1,346(1978). ’ I 7 A. K. Jain, F.G. McMahon,J.R. Ryan.H. Raphan, andW. Richard, Eur.J .Rheumatol. Infiammarion 1,356(1978). I.Radi,L.Matoso, A. Posmantir, and P.Papalexiou, Eur.J .Rheumatol. Inflammation 1, 349(1978). E. H. Wiseman,Eur.J .Rheumatol. Ir$ammution1,338(1978).

lob

lo’

Sec.III]

1,2-AND 2,ILBENZOTHIAZINES

103

a single daily doseof20 mg.The history ofthediscovery ofpiroxicam has beenreviewed"’; itispresently marketed inEurope. The 4-carboxamides of 1,2-benzothiazin-3(2H)-one 1,l-dioxide also including the exhibit anti-inflammatory a ~ t i v i t ySeveral . ’ ~ . analogs, ~~ toindomethacin in 4-bromocarboxanilide compound133,wereequivalent anti-inflammatory potency inanimak3* Both hypnotic and anticonvulsant activity wereobserved when fairly l,1-dioxide highdosesof 2-alkyl-3,4-dihydro-l,2-benzothiazin-3(2H)-one (47)wereadministered tom i ~ e . ~ ’ . ~ ’ Stoss hasreporteds antisecretory activity forsulfoximides (64)derived from1,2-benzothiazin-3-0nes. Sianesi and~ o - w o r k eclaimed r s ~ ~ hypnotic and anticonvulsant activity 127. foramidesand hydrazides prepared fromthe1,Zbenzothiazine ester

’

111.NaphthoandDibenzo-1,2-thiazines Compoundsinthis section arediscussed inorderofthepoint offusion of an aromatic ringto the1,2-benzothiazine nucleus. Klivenyi and colZ inattempting toprepare derivatives ofpapaverine-6-sulfonic workers, reacted 134 withchlorosulfonic acidandisolated ingoodyield acid(134), [2,1-b][l, 2lbenzothiazine 2,3, 10,ll-tetraalkoxy-7,8-dihydroisoquinolino (135), a naphtho-1,2-benzothiazineanalog (Eq.33). 8,g-dioxide

’

RO &OR\

HN

OR

/

-’’ R RO O&OR

sNN

(33)

0 2

(134)

(135)

Abramovitch and co-workers, l z 2 investigating thechemistry of aryl(136)which nitrenes andsulfonylnitrenes, thermolyzed biarylsulfonyl azides [ 1,2] thiazine 5,5-dioxide (138)(80%) at 120 Cproduced 6H-dibenzo[c,e] viatheproposed intermediate 137 (Eq.34).N-Alkylation of 138 with

’’I 12’

E.H. WisemanandJ.G. Lornbardino, in"Chronicles ofDrugDiscovery" (J. S.Bindra and D. Lednicer, eds.). Wiley, New York,1981. F.Klivenyi, E. Vinkler, and G. Dombi,fhurmuzie 33,379 (1978). R. A. Abramovitch, T.Chellathurai, J . T.McMaster, T.Takaya, C. 1.Azogu,and D. P. Vanderpool. J .Org.Chem.42,2914 (1977).

104

J. G . LOMBARDINO

AND D. E. KUHLA

[Sec. 111

8-dimethylaminoethyl chloride gaveN-(2-dimethylaminoethyl)-6H-dibenzo[c,e] [1,2] thiazine 5,Sdioxide (139). Ring-substituted derivatives of138have also beenprepared.

(137)

(138)R = H (139) R = (CH,),NMe,

Burmistrov etal.’ 23 prepared 9-methoxy(or 9-phenylsulfamido-) dibenzo[c,e] [1,2] thiazine 5,5-dioxide (142).Diazotization of 140 gave2-(4-substituted-phenyl)benzo-1,2,3,4-thiatriazine 1,l-dioxide (141)whichwastreated withsodiumhydroxide and copperpowderto afford 142. 9-Hydroxydibenzo [c,e] [1,2] thiazine 5,5-dioxide (142c)wasprepared bydemethylation of142a.Thesameworkers showedthat nitration of138afforded the9-nitro 1426.Reduction of1426 totheaminoderivative (14%) followed derivative by treatment withbenzenesulfonyl chloride gave142b.

(142)

a :R = OMe b:R = NHS0,Ph c:R=OH d:R = NO, e:R = NH, K. S.Burmistrov, S.I.Burmistrov, and M. S.Malinovskii, Khim.GeferotsikL Soedin., 1503 (1977)[ C A 88,89599 (1978)l.

Sec.1111

105


Oxidation of142cwithlead tetraacetate gave9H-9-oxodibenzo[c,e] [1,2](143). The redoxpotentials of some 9-substituted thiazine 5,5-dioxide dibenzo[c,e] [1,2] thiazine 5,5-dioxides (142)havebeendetermined. 23 Kaufmann and Zobel24 first prepared2,3-dihydro-3-oxonaphtho[1,8-d,e] [1,2] thiazine 1,l-dioxide (146). More recently, this was prepared by Lombardino by an abbreviated process involving lithiation of 144 andtreatment withcarbondioxide (Eq.35). Cyclization of 145 withpolyphosphoric acidsimultaneously removedthetert-butyl grouptoproduce compound146 directly. H

SOZNHCMe,

(146)

(145)

(144)

BothTrummlitz etal.26 and Steiner appear independently tohave prepared naphtho [2,1-e]-1,2-thiazine analogs ofthepotentoxicamantiinflammatory agents by thereaction sequence ofScheme4.3-Oxonaphth[2,1-d]isothiazoline-2-acetic ester 1,l-dioxides (147)(R = Me or Et)were

-CH,CO,R /

0 2

(147)

@ \

/

S/N\R, R

-

0 2

(148)R = H

(149) R = Me

SCHEME4 lZ5

12

H. Kaufmann and H. Zobel,Chem. Ber.B 55. 1499(1922). J . G. Lombardino, J .Ory.Chem.36,1843(1971). G . Trummlitz, E. Seeger, W. Engel,H. Teufel, G. Englehardt, and W. Haarrnann, U.S. Patent 3,992,535 (1976) [ C A86,72677 (1977) and87,53339 (1977) fortheequivalent German patents 2,452,996 and 2,539,112. respectively]. G . Steiner, Justus Liebigs Ann. Chem.,635(1978).

106

J.G. LOMBARDINO

AND D. E. KUHLA

[Sec. IV

converted in a standard manner to 4-hydroxy-2H-naphtho [2,1-e]-1,2(148) by heating withsodiummethoxide thiazine-3-carboxylate 1,l-dioxides of(148)withmethyl iodide gave149,which intert-butyl alcohol. Alkylation when heated witharomatic orheteroaromatic amines inxylene yielded the desired amides 150. Trummlitz andco-workers 26 also prepared derivatives of150 by treat[2,1 -c][ 1,2]thiazin4-(3H)-one 1,l-dioxide ment of2-methyl-2H-naphtho (151)withsodiumhydride and an arylisocyanate. The starting material (151)forthis sequence was synthesized analogously totherelated benzo11. thiazine 0

IV. Heterocyclic Ring-Fused 1,t-Thiazines The outstanding anti-inflammatory activity exhibited by sudoxicam (20), andpiroxicam (29) (see Section II,D) hasprompted exploration ofstructureactivity relationships (SAR) of oxicam anti-inflammatory agents. This

+

MeNHCH,CO,Et

I I

(SyCO SOZNpCHzC02Et zMe

Sec.IV]

107


effort hasincluded thereplacement ofthebenzoportion ofthe1,2-benzothiazine molecule withheteroaromatic rings. The preparation of two of the threepossible isomeric thieno-1,25 and 6)’ 2 8 involved reactions reported" forthe thiazin-4-ones (Schemes corresponding benzothiazines (seeScheme 1 ).Thus,methyl3-chlorosulfonylthophene-2-carboxylate (152) withsarcosine ethyl ester gavethophene sulfonamide (153)which,with methanolic sodiummethoxide, yielded 3-methoxycarbonyl-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-thiazine 1,ldioxide (154). Heating154 with2-aminothiazole gave155,a thieno-1,2thiazine analog ofsudoxicam (20) (Scheme5). Analogously, methyl4-chlorosulfonylthiophene-3-carboxylate(156)was [3,4-e]-1,2converted to4-hydroxy-3-methoxycarbonyl-2-methyl-2H-thieno (159), whichwith2-aminothiazole gave160. thiazine 1,l-dioxide C0,Me

BH

SO,R 0 2

(156) R = CI (157) R = NHMe (158)R = NMe-CH,CO,Me

(159)R = OMe

N

I \

(160)R = NH--()

S

Pfister and co-workers’ 29 recently prepared derivatives of thethird thieno-1,2-thiazin-4-one. Methyl2-chlorosulfonylthiophene-3-carpossible boxylate (161) withglycine methyl ester gaveintermediate 162,whichafforded thieno [ 3,2-e] -1,2thiazine 1,1 -dioxide 4-hydroxy-3-methoxycarbonyl-2H(163) uponheating withbase. Alkylation of163withmethyliodide/sodium a thieno-l,Zthiazine analog(165)of hydride gave 164 whichafforded (29)when heated with2-aminopyridine (Scheme6). piroxicam A numberof halogenated derivatives of 155,160,and 165 havebeen 29 For example, thethieno-1,2-thiazine analog166 has been prepared.’ 167 whichhasbeenacylated (phosgene/ converted toeneamine derivative triethylamine) toafford acidchloride 168.Treatment of168 with2-aminopyridine gave169 (Eq.36).Thisprocess iscompletely analogous to the 1,2-benzothiazine synthesis depicted inEq.(6). 0. Hromatka, D. Binder, R. Pfister. and P.Zeller, U.S.Patent 4,076,709 (1978) [ C A 85, 63077(1976) fortheequivalent Belgian Patent 832,7071. Related subject matter isdisclosed (1978). inBritish Patents 1.519,811 and 1,519.812 R. Pfister, P.Zeller, D.Binder, and0. Hromatka, British Patent 2,003,877 (1979) [ C A 91. 5233(1979) forequivalent GermanPatent 2,838,8511.

108

J. G. LOMBARDINO

A N D D. E. KUHLA

[Sec.IV

C0,Me

G S O z R (161) R = CI (162) R = NHCH,CO,Me

0 2

(163) R (164)R

= =

H

Me

SCHEME6

(167) R =H (168) R =

(169)

Ester and co-workers’ 30 have alsopreparedthe threeisomeric 171 of 3-(2-Nthieno1,2-thiazin-3-one ringsystems. The acidchloride methylsulfamoy1)thiopheneacetic acid(170) withsodiumbicarbonate gave 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,2-e]-1 ,Zthiazine 1 ,I-dioxide (172) (Eq.37). I3O

R. Pfister, P.Zeller, D . Binder, and 0. Hromatka,British Patent 2,002,771 (1979) [CA 90, 203568(1979) forequivalent German Patent 2,835,7601; U S .Patent4,090.020 (1978) [CA 87,201563(1977) forequivalent Belgian Patent851,6861.

Sec.IV]

109

1,2-A N D 2.1-BENZOTHIAZINES

(37) 0 2

(171)

(170)

(172)

Treatment of 172 witharomatic or heteroaromatic isocyanates yielded 173claimed tohaveanti-inflammatory theexpected 4-carbamoyl derivatives 30 4-Carbamoyl-3,4-dihydro-3-hydroxy-2-methy~-2~-thieno [3,4-elactivity. and[2,3-e]-I,Zthiazine 1,l-dioxides (174and175)wereprepared analogously (cf. Section II,A,2).13

Ci-;

CONHAr

S

0 2

(173)

Me

CONHAr

s&oH I HO&-.-( S/ \Me

0 2

(1741

CONHAr

S/

Me

0 2

(175)

Indole derivatives 3 1 ofsudoxicam (20)havebeenprepared (Scheme7): (176)gavewithsodium methyll-methyl-3-sulfamoylindole-2-carboxylate

131

G.Trummlitz, W. Engel, E.Seeger, W. Haarmann,and G.Engelhardt,U.S. Patent4,137,313 [CA 89,163592(1978) forequivalent GermanPatent 2,704,4851. (1979)

110

J. G . LOMBARDINO

A N D D. E. K U H L A

[Sec. V

methoxide inmethanol theintermediate 4-methyl-2H-isothiazolo[4,5-b]indole-3-(4H)-one 1,l-dioxide sodiumsalt which, when treated withmethyl chloroacetate, gave methyl3,4-dihydro-4-methyl-3-oxo-2H-isothiazolo[4,5-b]indole-2-acetate 1,l-dioxide (177)(>90%).Ringexpansion of 177 (sodium methoxide/toluene) gavemethyl2,5-dihydro-4-hydroxy-5-methyl1,2-thiazino[5,6-b]indole-3-carboxylate1,l-dioxide (178). Alkylation of178 (sodiumhydroxide/methyl iodide) followed by aminolysis afforded the yield (Scheme7).Othersynthetic sudoxicam analog179 ingoodoverall routes (see Section II,A,l) forsimilarly substituted 1,Zbenzothiazines have 31 also beenusedforthese thiazino [5,6-b]indoles.’

V. Ring-Fused 1,2-Benzothiazine Derivatives The two preceding sections havediscussed replacement ofthebenzene withother aromatic orheteroaromatic systems. ring ofa 1,2-benzothiazine Thissection details reactions of1,2-benzothiazines leading tomorecomplex triandtetracyclic 1,2-benzothiazine ring systems. 32 obtained tricyclic, 12-benzothiazines (181)fromethyl Rasmussen’.’ 4-hydroxy-2H-l,2-benzothiazine-3-carboxylate 1,l-dioxide (180)and a,odihalides (e.g., 1,3-dibromopropane) (Eq.38). OH

0 2

(180)

0 2

(181)

Zinnes andco-workers’33*1 34 prepared pyrido [1,2-b] [1,2] benzothiazines 182 withisopropyl iodide and potassium (Scheme8):1,Zbenzothiazine carbonate resulted in spontaneous aldol cyclization of theintermediate enolether183 to 7,8-dihydro-8-hydroxy-ll-isopropyloxy8-substituted 1,2]benzothiazin-l0(9H)-one 5 3 dioxide (184). In sulfuric pyrido[1,2-b][ of184 gavethecorresponding unacid, dehydration and ether cleavage 185.Hydrogenation gavethesaturated analogs 186. saturated fl-diketone An attempt to prepare 186 directly by base-catalyzed cyclization of 187 afforded a highyield of2,3-dihydro-6H-oxepino [3,2-c] [ 1,2]benzothiazin(188) (Eq.39). 5(4H)-one 7,7-dioxide 132

C. R. Rasmussen, U.S.Patent 3,492,299 (1970) [CA 72,79075(1970)l. H. Zinnes, R. A. Comes,and J. Shavel, J .Med. Chem. 10,223(1967). J.Shavel, and H. Zinnes, U.S.Patent 3,408,347 (1968) [ C A 70,68387(1969)l.

133

Sec.V]

111

dCoMe 1.2- A N D 2.1-BENZOTHIAZINES

Me,CHO

CH,COR

S

m

0 2

0

S/ ,

H

0 2

(182)R = H (183) R = CHMe,

I

mR-&f 0

0

0

ci!c 0 2

0 2

(185)

(186)

@ \

0

(CH213Br

~

0 2

\

,NH

(39)

0 2

(188)

(187)

SCHEME8

Kubo andco-workers 35 reacted 2-cyanomethylbenzenesulfonyl chloride (49)with ethylenediamines to afford1-substituted-2,3-dihydroimidazo[3,2-b] [1,2]benzothiazine 5,5-dioxides (189) (Eq.40).Thisis the only sequence inthis section thatdoesnotusea preformed 1,2-benzothiazine asa starting material. The products areclaimed topossess analgesic, antiinflammatory, andantipyretic activities. 35

35

K. Kubo,N. Ito, I.Soto,Y. Isomura. and H. Honma, Japanese Patent 79/22,399 (1979) [ C A 91.5235(1979)l.

112

J.G. LOMBARDINO

A N D D. E. KUHLA

[Sec. V

The versatile ester 180 withN-substituted aziridines (190) affords’36.’ 37 many 1,2,3,4,-tetrahydro11-hydroxypyrazino [ 1,241 [1,2] benzothiazin(191) (Eq.41).1,2,3,4-Tetrahydro-ll-hydroxy-2-(2l(2H)-one 6,6-dioxides hydroxyethyl)pyrazino[ 1,241 [1,2] benzothiazin-l(2H)-one 6,6-dioxide (191; R = CH,CH,OH), after conversion intothemethanesulfonate 192,was Compound treated withbasetogivethetetracyclic system193(Eq.42). 193canbe isolated inthereaction of192withvarious nucleophiles. Thus, reaction of 192 or 193withsecondary aminesand mercaptides produces 191(R = CH2CH2NR’R2)and 191(R = CH,CH,SR),respectively. Reacof192or193withprimary amines gave194(Eq.42).’369’37 tion

0 2

(190)

(191)R = H (192) R = CH2CHzOS02Me

(193)

(194)

Similar ringsystems were prepared from 3-acetyl-4-hydroxy-2H-1,2benzothiazine 1,l-dioxide (93) andethylenimine (190; R = H)’37*’38 (Eq.43) orethylene dibromide (forming 95).8*’ 39 Theethylenimine reaction gaveonly

0 2

(93)

13’

-’ s’

(43)

0 2

(195)

C.R.Rasmussen, U.S.Patent 3,787,398 (1974) [CA 80,95985 (1974)l; U.S.Patent 3,787,401 [CA 80,83060(1974)]; U.S.Patent 3,787,402 (1974) [CA 80,95988(1974)l; U.S. (1974) Patent 3.787.403 (1974) [CA 80.95984 (1974)l; U.S.Patent 3,787,404 (1974) [CA 80,95999 (1974)]. C. R. RasmussenandD. L. Shaw,J.Org.Chem.39, 1560 (1974). C. R. Rasrnussen, U.S.Patent 3,787,399 (1974) [ C A 80,83059(1974)l. C. R. Rasmussen, U.S.Patent 3,821,212 (1974) [CA 81,91546(1974)l.

Sec.V]

113

l,Z-A N D 2.1-BENZOTHIAZINES

a low yieldof 3,4-dihydro1-methylpyrazino[ 1,2-b] [ 1,2]benzothiazin1l(2H)-one 6,6-dioxide (195). The preparation of therelated tricycle (98) waspreviously discussed (Eq.23).8,’40 The reaction of3-benzoyl(or3-acetyl) -4-hydroxy-2H-1 ,2-benzothiazine 1,l-dioxide (89) withhydrazine toproduce pyrazolo[4,3-c] [1,2] benzothiazine5,5-dioxide derivatives was discussed inSection II,B,l (SeeEq. 22). 3-acetyl-l,2-benzothiazines(196)withalkylSteiner141 recently reacted substituted hydrazines; thehydrazones (197) wereusually notisolated but cyclized directly tol-substituted-l,4-dihydro-3-methylpyrazolo[4,3-c] [1,2](198) (Eq.44). benzothiazine 5,5-dioxides

dcoMe OH

\

W\

s/N-R

N

M S/N-R

,NHR’ e

d

0 2

0 2

(196)

(197)

0 2

(198)

Similarly, SteinerI4’ prepared 1,2,3,4-tetrahydro-3-oxopyrazolo[4,3-c][1,2]benzothiazine 5,Sdioxide (200) fromtheester 199andhydrazine (Eq. 45).

fl HN-NH

OZE’

\ 0 2

(199)

s/

(45)

’R

0 2

(200)

R a s m ~ s s e n prepared ’ ~ ~ ~ ’the ~ ~ 2H,SH-1,3-oxazino [5,6-~][1,2]benzo(202)by heating1,2-benzothiazine thiazine-2,4(3H)-dione 5,s-dioxide 201(Eq.46). Anti-inflammatory andantiarthritic activities were derivative claimed for202(R’= a r ~ l ) . ’ ~ ~ C. R. Rasmussen,U.S.Patent3,787,400 (1974) [CA 80,95987(1974)l. G. Steiner, Justus Liebigs Ann. Chem.,643(1978). C. R. Rasmussen,U.S.Patent3,492,298 (1970) [CA 72,66964(1970)l. 143 C. R. Rasmussen, U S . Patent3,923,801 (1975) [ C A 84,59521(1976)]. 141

114

J .G . LOMBARDINO

d

C

0

R

- NI

~

e: [Sec. V

AND D. E. K U H L A

CO,Et

~

s/ \R

(46)

S \

R

0 2

0 2

(202)

(201)

Novel antisecretory and antiallergic pyrano [3,2-c] [ 1,2] benzothiazine (205and207)havebeenprepared by twoprocesses (Scheme 9). 6,6-dioxides In thefirst,2-alkyl-3,4-dihydro-2H-1,2-benzothiazin-4-one 44 1,l-dioxide (203), borontrifluoride etherate, andanacidanhydride afforded theisolable of 204 withtheVilsmeier reagent (P0Cl3/ boroncomplex204.Reaction DMF) gave,after hydrolysis, 3J-disubstituted pyrano [3,2-c] [1,2] benzothiazin-4-(5H)-one 6,6-dioxides (205). The second route45 gives a different 206,when substitution pattern inthepyronering. Thus,B-sulfinyl ketone reacted withaldehydes underbasecatalysis, gave2,5-disubstituted pyrano(207)(Scheme 9). [3,2-c] [1,2] benzothiazin-4(5H)-one 6,6-dioxides F,

0 2

n

u 2

(203)

2

(205)

(204

R

&CH2SOMes/ R

+R

CHO

0 2

&o

s/ R 0 2

(207)

(206)

SCHEME 9 D.Kaminsky, S.Klutchko, andM. vonStrandtmann, U.S.Patent 3,855,216 (1974) [ C A 82, 112087(1975)l; U.S. Patent 3,937,828 (1976) [CA 84,164807 (1976)l; seealso D.Kaminsky, U.S.Patent 3,898,218 (1975) [ C A 84,17388(1976)l; U.S.Patent 3,966,716 (1976) [CA 85, 177502(1976)]. M. von Strandtmann, S.Klutchko, M. P.Cohen,andJ. ShaveI, J. Heteracyrl. them.9, 171(1972); U.S.Patent 3,816,466 (1974).

Sec.V]

115

1.2-A N D 2.1-BENZOTHIAZINES

In studies of heterocyclic steroid analogs, Fravolini and co-workers’ 46 prepared triandtetracyclic 1,2-benzothiazines (Scheme10). 2-Methyl-2H1,2-benzothiazin-4(3H)-one 1,l-dioxide (11)withthioglycolic acidgives intermediate 208,cyclized by polyphosphoric acid to5-methyl-4-oxo-2,3,4,5tetrahydrothiopyrano[3,2-c] [ 1,2] benzothiazine 6,6-dioxide (209). Condenof 209 withdimethyl oxalate gave210 inhighyield. Heating 210 sation ledto decarbonylation, affording the/I-keto ester 213.Reaction of 210 or 213 withhydrazine gave4,ll -dihydro-4-methyl-l-carbomethoxy-3Hpyrazolo[3’,4’-4,5] thiopyrano[3,2-c] [1,2]benzothiazine 5,5-dioxide (212)or l-dihydro-4-methyl-1-hydroxy-3H-pyrazolo[3’,4’-4,5] thiopyrano [3,2-c]4,l [1,2] benzothiazine 5,5-dioxide (214),respectively. Reaction of 210 with Hhydroxylamine in acetic acidyielded 4-methyl-1 -carbomethoxy-4H,ll isoxazolo [5’,4-43 Jthiopyrano [3,2-c] [1,2] benzothiazine 5,5-dioxide (211).

k/

OH

N H

C02Me

OH

u

(211) x=0 (212) X = NH SCHEME 10

SteinerI4l hasalso prepared heterocyclic derivatives inwhicha sevenor of the1,2-benzothiazine eight-membered ringisfusedtothe3,4-position ofester 199withl,Zethanedithiol, 1,3-propanemolecule. Thus,reaction or217,respectively. Similarly reaction dithiol, orethanolamine gave215,216, of199 with2-mercaptophenol, 1,2-benzenedithiol, oro-aminophenol gave 146

A. Fravolini, F. Schiaffella, and G . Strappaghetti, J. Heterocycl. Chem. 16,29 (1979).

116

J.G . LOMBARDINO

A N D D. E. KUHLA

[Sec. VI.A

218,219 or220. 41Thioamide andamidine derivatives of220 havealso beenre~0rted.I~

(218)X = 0,Y = S (219)X = Y = S (220)X = S, Y = NH

(215)n = 2 (216)n = 3

VI. 2,l-Ben20 thiazines A. SYNTHESES LoevandKormendyI4first synthesized a 2,l -benzothiazine 2,2-dioxide 2-(o-nitrophenyl)ethanesulfonylchloride tothesulfonate salt by converting 221whichwascatalytically reduced totheamine222.Treatment of222 with phosphorus pentachloride/acetyl chloride afforded 3,4-dihydro-lH-2,1(223). Theyalsoprepared 4-phenyl-3,4-dihydrobenzothiazine 2,2-dioxide (225)by treating styrene sulfonanilide 1H-2,l-benzothiazine 2,2-dioxide (224;R = Ph)withpolyphosphoric acid. However, theywereunableto cyclize theethylene sulfonamide (224;R = H) to223 using this route.14

(221)R = N O , (222)R = NHZ

14

B. LoevandM. F.Kormendy, J.Org.Chem.30,3163(1965); seealso B.Loev,U.S.Patent 3,303,190 (1967) [ C A 66,P65486(1967)].

Sec.VI.A]

117

1.2-AND 2.I-BENZOTH IAZI NES

The preparation of 223 by pyrolysis of2-(o-aminophenyl)ethanesulfonamide(226) hasalsobeenreported. 14’ Abramovitch andH ~ l c o m balso ’~~ 223together withuncyclized sulfonamides PhCHzCHzSOzNHR prepared of P-phenethylsulfonyl azide227.The bestyields of 223 by thermolysis (ca30%)wereobtained by using a solvent suchasFreon-113 at135 Cfor 49 36 hours.’

Three groups independently synthesized early examples oftheunsaturated

1H-2,l-benzothiazine 2,2-dioxides. RossiandPaganiI5’ reacted o-acylani-

228withvarious sulfonyl chlorides toobtain o-acylsulfonamides 229. lines Treatment of 229 withsodiumethoxide gavenumerous1H-2,l-benzo(230) containing substituents inthe1,3,4 and/or 6 thiazine 2,2-dioxides 47)ingoodtoexcellent yield; butthecyclization failed when positions (Eq. Rossi andPagani150 synthesized these latter bothR’ andR3 werehydrogen. ofester 231,whichafforded thecarboxylic derivatives of230by hydrolysis 232. Heating 232withquinoline/copper powdergave230(R’= R3 = H). acid

"acoR "acoR NHR3

R’CH,SO,CI, E1,N

__*

NSO~CH,R~ I

R

R3

(230)

Sianesi and Redaelli15’ alsousedthesynthetic methodof Eq.(47)to prepare substituted LH-2,l-benzothiazine 2,2-dioxide derivatives. By starting E. Sianesi, G .Bonola, R. Pozzi, and R. Da Re, Chrm.Ber.104,1880(1971). R. A. Abramovitchand W. D. Holcomb.J .Am. Chem. SOC.97,676 (1975). I5O S .RossiandG .Pagani, Ann.Chim.(Rome)56,728(1966) [ C A 65, 10582(1966)]. I s ’ E.Sianesi and R. Redaelli, Ann.Chini. (Rome)57,1426(1967) [ C A 69,2923(1968)l.

’41 ’41

118

J.G. LOMBARDINO

A N D D. E. KUHLA

[Sec. V1.A

witho-aminoacetophenones (233)withsubstituents either orthoand/or (234)with parato theaminogroup,theymade 1H-2,l-benzothiazines , 8 position. substituents inthe3 , 6 and/or R & OzR1

R,? \

R*(:COMe

N/so, H

(231) R (232) R

2I . R NaOEt CH,SO,CI

R3 = =

NH,

Et H

Loev and co-workers 5 2 prepared theunsubstituted 1H-2,l-benzothia(239)by theroute ofScheme11.Methylchlorosulfonylzine2,2-dioxide acetate was converted into thesulfonanilide (235)by reaction withaniline. oftheester groupin235 gave236 which, withpolyphosphoric Hydrolysis (237).Spectral dataindicated acid, cyclized to lH-2,1-benzothiazin-4-one 237existed intheketo form. Ketone 237 wasconverted tothetosylhydrathat zone238 which, bya Bamford-Stevens reaction, afforded 239 ingoodoverall yield. TheN-methyl analog of239 wasalso prepared by theabovereaction sequence using N-methylaniline.

PPA

..

H

aso

,

IR = HI

0 II

..

H

(235) R = Me (236) R =H

I

NNHTS II

(239) SCHEME I I 152

B. Loev.M. F.Kormendy,and K. M. Snader. J.Org.Chem.31.3531 (1966)

Sec.VI.A]

119

I .2-AND 1.1-BENZOTHIAZINES

Rossiand Paganis3 independently prepared ketone237 by thesame Theythenreduced 237 withsodiumborohydride toan route (Scheme11). 1Hunstable alcohol whichspontaneously dehydrated totheunsaturated 2,l -benzothiazine 2,2-dioxide (239). The sameworkersis3 extended a well-known carbostyril synthesis based on cyclization of/?-acylacetanilides tothecorresponding /?-acylsulfanilides. 240 gave4-phenylThus, whenheated inphosphorus oxychloride, sulfanilide (241)(Eq.48). However,the 7-methyl-1 H-2,l -benzothiazine 2,2-dioxide success ofthis reaction appears tobe highly dependent on thesubstituents intheaniline starting material.ls3 Ph I

(241

(240)

An improvedsynthesis of 3,4-dihydro-1 H-2,1-benzothiazin4-one 2,2(237)was reported by Lombardino andTreadway.ls4 N-Methyldioxide (242)withbenzyl bromide andsodium sulfonylanthranilic acid methyl ester (243) which directly cyclizes to hydride givestheN-benzyl derivative 1-benzyl-4-oxo-3,4-dihydro-l H-2,1 -benzothiazine 2,2-dioxide (244). CataLombardino prepared lytic hydrogenation of244 thengave237 (Eq.49).

a:::cH3 a Z 1 I2 C H 3

w

CH,Ph

(242)

(243)

S.Rossi andG. Pagani, Ann. Chim.(Rome) 56,741(1966) [CA 65,10584 (1966)l. J.G. Lombardino andN. Treadway, Org.Prep.Proced. hi.3,33 (1971). 1 5 5 J.G. Lombardino, J .Heterocycl. Chem.9,315 (1972). 153

54

120

J . G. LOMBARDINO

[Sec. VI.A

AND D. E. K U H L A

theN-methyl analog of244 (95%)by cyclization oftheN-methyl analog of243. Nakanishi and Kobayashi 56 similarly prepared 3-ethoxycarbonyl-4hydroxy-lH-2,l-benzothiazine2,2-dioxide (247):ethyl anthranilate (245) gavethesulfonamide 246 whichcyclized withbasetoafford 247 (Eq.50).

I

H (247)

Diphenyl sulfurdiimide, PhN=S=NPh, anddimethyl ketene, Me,C= as2-phenylC=O, gavea numberofproducts,15 onetentatively identified imino-3,3-dimethyl-1H-2,l-benzothiazin-4-one (248). Theisomeric 249could notbecompletely excluded bytheavailable spectral data. Chemical evidence

&Me

ls6

NNS\ N P h H H NPh

H

\NPh NPh

M. Nakanishi and R. Kobayashi, Japanese Patent71/22,152 (1971) [ C A 75,76820(1971)l; Japanese Patent71/22,150 (1971) [CA 75,76818(1971)]. T.Minami,K.Yamataka,Y .Ohshiro, T.Agawa,N.Yasuoka, and N.Kasai, 1.Org.Chem. 37,3810(1972).

Sec.VI.B]

121


initially favored 249 since reductive desulfurization withRaneynickel gave (251)inhighyield. However, since itwas well-known 3,3-dimethyloxindole that2,2-disubstituted indoxyls rearrange to 3,3-disubstituted oxindoles, theoriginal investigators’ concluded that theprobable initial reduction 250 underwent Wagner-Meerwein rearrangements to gve 251. product Therefore, theystill favored structure 248 astheproduct oftheinitial cycloaddition reaction. (253)have been 5,6,7,8-Tetrahydro-1 H-2,l-benzothiazine 2,2-dioxides (252)witheither aromatic or prepared’by heating pulegone-1,Csultone (Eq.51). aliphatic amines Me

Me

B. REACTIONS 1. Reactions of3,4-Dihydro-IH-2,1-benzothiazine 2,2-Dioxide (223) Alkylation andarylation reactions of223 havebeenstudied by Loevand K ~ r m e n d yand ’ ~by ~ Sianesi andc o - w o r k e rAs ~ .expected, ’~~ a variety of (Eq.52). N-alkyl orN-aryl derivatives wereobtained inhighyield

Ph (254)

R (223)

(255)

The samegroups havealso examined electrophilic aromatic substitution Bromination of223 gave reactions, usingboth223 and255 assubstrates. (256;X = Br)orthe6,8-dibromo derivative (257; the6-bromoderivative X = Y = Br)depending on the condition^.’^^ Underall bromination condiafforded onlya 6-monotionsexamined, compound 255 (R = alkyl) 258 (X = Br,Y = H). brominated product

"*

B. Helferich, R. Dhein,K. Geist, H.Jiinger, and D. Wiehle, J u s m Liebigs Ann. Chem. 646,32 (1961).

122

J.G . LOMBARDINO

AND D. E. KUHLA

[Sec. V1.B

(257) R =H (258) R = alkyl

(256)

Nitration of223(65% nitric acidat20 C)gavethe6,8-dinitro derivative 257(X = Y = NO2),whereas nitration atlowertemperatures gavemixtures of mono-nitration products 256 (X = NO2) and 257 (X = H, Y = NO2). of255(R = alkyl) gave258(X = Y = N02).’48 Nitration Abramovitch andH o l ~ o m bflash ’~~ vacuumpyrolyzed 223at650 Cto (75%)and indole (7.7%). Only traces of these compoundswere indoline formedat400 C. LoevandK ~ r m e n d ypreviously ’~~ reported that 223was thermally stable at250 C.

2.Reactions ofIH-2,l-Benzothiazine 2,2-Dioxide (239) In general, reactions similar to thosereported for3,4-dihydro-1 H-2,lbenzothiazine 2,2-dioxide (223) havealso beenexamined withtheunsaturated 5 2 * 1 5 9orarylation,’59 1H-2,l-benzothiazine 2,2-dioxide(239). Alkylati~n’~’*’ orN-aryl derivatives inhighyield. LoevI6’ forexample, afforded N-alkyl H-2,l-benzothiazine hasalsoreported thatl-(y-aminopropy1)-3,4-dihydro-l 2,2-dioxide (260) canbe prepared fromacrylonitrile and239by theMichael addition/reduction sequence pictured inEq.(53).

H (239)

I

CHZCHZCN (259)

B. Loev and K. M. Snader, J.Heterocycl. Chem.4,407(1967). B. L o w , U.S.Patent 3,303,189 (1967) [ C A 66,P65490(1967)l.

Sec.VI.B]

123

1.2-A N D 2.1-BENZOTHIAZINES

Bromination of239, evenwithlimited amounts ofthebrominating reagent, afforded complexmixtures containing a tribromo derivative tentatively 4),6,8-tribromo-lH-2,1-benzothiazine 2,2-dioxide. Howidentified as 3(or ever, bromination oftheN-methyl analog 261 usingN-bromosuccinimide (262) cleanly gave 6-bromo-1-methyl-1 H-2,I-benzothiazine 2,2-dioxide (Eq.54).

Me

Me

(261)

(262)

Catalytic hydrogenation’ 5 9 (Pd/C) of 1H-2,l-benzothiazine 2,2-dioxide (239) gavetheexpected 3,4-dihydro derivative (223). Raneynickel reduc5 8 of5,6,7,8-tetrahydro-l H-2,1 -benzothiazine 2,2-dioxide (253) afforded tion’ 263 of undesignated stereothecompletely saturated 2,l-benzothiazine chemistry (Eq.55).

Me d

s

o

I

R

M

2

(253)

e

d

S

o

I

Z

(55)

R (263)

Two interesting sulfur extrusion reactions havebeenreported forderivatives of239.RossiandPagani,’ 5 0 uponheating 1,4-dimethyl-2,1-benzothiazine2,2-dioxide (264) withcopper powderatapproximately 30O0C,isolated 265ando-isopropenyl-N-methylaniline266(Eq.56). theindole

\

N/soz+ I

Me (264)

Q q M\ e + @

I

NHMe

(56)

Me (263

(266)

Durstand Kingi6’ obtained thepyrrole (268) by photolysis of 5,6,7,8tetrahydro-4,7-dimethyl-l-phenyl-l H-2,l-benzothiazine 2,2-dioxide (267) (Eq.57).

’"T.Durstand J. F.King,Can.J .Chrm.44,1869(1966).

124

J.G. LOMBARDINO

[Sec. V1.B

AND D. E. KUHLA

Ph

3. Reactions of 3,4-Dihydro-l H-2,I-benzothiazin-4-one 2,2-Dioxide (231) Although spectral datashowedno evidence ofenolic character for237, thetautomeric nature ofthe carbonyl groupwasindicated by alkylation or acylation totheexpected N-alkyl (269)and N-acyl(271)products which werealwayscontaminated by 0-alkylation (270)or 0-acylation (272)16 (Scheme12). Lombardino 5 s prepared 4-hydroxy-l-methyl-lH-2,1-benzothiazine-3carboxanilides (273)by thebase-catalyzed reaction of269 witharyl isocya-

// &so2

&502

N/ 1

Me,SO,

(237) H

I

Me

(269)

lMeCO),O

+d:; ..d (270)

/ 0 2

N/

COMe

COMe

1

(271)

SCHEME 12 162

Me

B. LoevandK. M. Snader, J. Heterocvcl. Chem. 4,403 (1967).

I

(272)

Sec.VII]

125

I ,2-AND 2.1-BENZOTHIAZINES

nates. Inthis work269wasprepared by anunambiguous synthesis (cf. Eq.49) inorder toavoidtheproblems associated withalkylation of237.

Ph

Q&CONHAr N/S02

I

Me (273)

@

N/soz H

(274)

PPA

N/SOZ H

(275)

Compound237failed toformtypical carbonyl derivatives, suchasoximes, semicarbazones and eneamines, understandard conditions. 6 2 However, Loev162*163 was abletoprepare a phenylhydrazone (274) from237which 275. withpolyphosphoric acidgavethenoveltetracyclic indole Treatment ofketone 237withnitrous acidgaveonlytheisatin p-oxime (277) by an unusualsulfur extrusion.The 62 expected oxime276 was (Eq. 58). postulated asan intermediate

237

VII.Conclusion Literature reports on heterocyclic compoundscontaining a 1,2or 2,lbenzothiazine ring haveappeared inincreasing numbersinrecent years. This of4trend islikely tocontinue asa result oftheanti-inflammatory activity h ydroxy-2H1,2-benzot hiazine-3 -carboxamide 1,l -dioxides (the oxicams ).

NoteAdded inProof Morerecent patents continue toreport anti-inflammatory oxicams. Thus, etal.64 havefoundsomeN-(benzopyranyl)-4-hydroxy-2-alkyl-2HFerrini 1,2-benzothiazine-3-carboxamide1,l -dioxides to be anti-inflammatory in animals. 163 164

B. Loev,U S . Patent 3,427,311 (1969) [ C A 70,68391(1969)l. G. Ferrini, G. Haas,K. A. Jaeggi, and A. Rossi, European Patent 3-360(1979).

126

J . G. LOMBARDINO

AND D. E. KUHLA

[Sec. VII

After completion ofthis article, a 21-page review on all possible benzothia1,2and2,l-, aswellas 1,3-, 2,3-, 1,4-, and2,4zinone dioxides, including By restricting their subject to 3-oneand benzothiazinones, appeared.165 +one derivatives, these authors found71 literature references tothe1,2and2,l-benzothiazinone dioxides. Thepresent chapter discusses these referencesand a significantly larger numberof patents and scientific articles dealing withall 2,land 1,2-benzothiazines. ACKNOWLEDGMENT The authors thankDr.BerylDominyand Mr.JohnHareofthePfizer Technical Information Department fortheir helpincomputer-assisted searches ofthescientific and patent literature Mrs. TheresaDAmico,and Mrs.Linda Neilanfortyping this and Mrs.Lynn Londregan, manuscript.

165

P.Catsoulacos and C. Camoutsis, J .Heterocycl. Chem. 16, 1503 (1979).

ADVANCES

I N HETEROCYCLIC CHEMISTRY

.VOL

28

Isatoic Anhydrides andTheir Usesin Heterocyclic Synthesis T .KAPPE AND W .STADLBAUER

.

Institute of OrganicChemistry University of Graz. Graz. Austria

I.Introduction . . . . . . . . . . . . . . . . . . . . 127 . . . . A . Historical Aspects andScopeoftheReview . . . . . . . . . . 127 . . B . SynthesesofIsatoic Anhydrideand Related Compounds. . . . . . .129. C . General Mechanistic andTheoretical Aspects . . . . . . . . . . 137 . . I1. Formation ofAnthranilic AcidAmidesandHydrazides and Further Reaction toHeterocycles . . . . . . . . . . . . . .141 . . . A . Reaction ofAmideswithCarbonyl Compounds. . . . . . . . . 141 . . 1. Carboxylic AcidDerivatives . . . . . . . . . . . . . 141 . . . 2. Carbonic AcidDerivatives . . . . . . . . . . . . . . 145 . . . 3.Aldehydes, Ketones, andHeteroanalogs . . . . . . . . . .147 . . Reactions withAnthranilamides . . . . . . . . 148 . . 4. Miscellaneous B . Reactions ofHydrazides andHydroxylamides . . . . . . . . . 150 . . C . Reaction ofIsatoic Anhydride withDiamines . . . . . . . . . 155 . . D . Reaction ofIsatoic Anhydride withEnamines . . . . . . . . . 155 . . . . . . . 156 . . Reaction ofIsatoic Anhydride withCarboxylic AcidDerivatives I11 A . Amides . . . . . . . . . . . . . . . . . . . . 156 . . . . B . Thioamides . . . . . . . . . . . . . . . . . . . 157 . . . . C . Hydrazides . . . . . . . . . . . . . . . . . . . 157 . . . . D .Amidines . . . . . . . . . . . . . . . . . . . . 159 . . . . E . Ureas, Thioureas. andCyanamides. . . . . . . . . . . . 160 . . . F . Isothioureas . . . . . . . . . . . . . . . . . . .161. . . G . a-AminoAcidsanda-Aminoketones . . . . . . . . . . . . 163 . . . H .OtherCarboxylic AcidDerivatives . . . . . . . . . . . . 165 . . . 166. IV. Reactions ofIsatoic Anhydride withC=N DoubleBonds. . . . . . . . A . Azomethines. . . . . . . . . . . . . . . . . . .166. . . B . Heterocumulenes . . . . . . . . . . . . . . . . . .167. . . V . Reactions ofIsatoic Anhydride withCarbanions . . . . . . . . . .168 . . VI. Miscellaneous Reactions . . . . . . . . . . . . . . . . . 174 . . . VII.Appendix AddedinProof . . . . . . . . . . . . . . . . 178 . . .

.

I Introduction

A . HISTORICAL ASPECTSAND SCOPEOF

THE

REVIEW

When Friedlander andWleiigel’ in 1883reacted theso-called anthranil (2. 1.benzisoxazole) (2) withethyl chloroformate. theyobtained a compound (C.H.NOJ) whichtheycalled anthranilic carboxylic acid .A yearlater. P.Friedlander and S.Wleiigel. Ber.Dtsch .Chem .Ges.16.2227(1883) . I27

Copyright @ 1981by A’ddemicPress. Inc Allrights ofreproduction inm y formreserved ISBN 0-1?-0?06?8-5

128

T. KAPPE AND W. STADLBAUER

[Sec. 1.A

Kolbe inhislast papers described a compoundwiththesameformula, (3) withCrO,,andcalled it isatoic acid. formedby oxidation ofisatin Meyer3provedtheidentity ofbothcompounds, andNiementowski and Rozanski4 werethefirst toestablish thecorrect formula (1) whentheyfound chloroformate. a new synthesis fromanthranilic acid(4)andethyl In1899, Erdmann obtained thesamecompoundingoodyield fromanthranilic acid andphosgene andsuggested thename isatoic anhydride. An alternative synthesis of isatoic anhydride [2H-3,1 -benzoxazine-2,4( 1H ) dione, subsequently abbreviated asIA] wasfoundby Curtius andSemper6 (5)viao-carboxyphenyl isocyanate. Similar fromphthalic acidmonoazide rearrangements werediscovered by Bredt andHof [frompotassium phthal(6)] andbyMohr [from phthalimide (7)] leading toIAviaa Hoffmann imide reaction. brought two typesof reaction: Initial investigations of I A * chemistry ring opening toanthranilic acid d e r i v a t i v e ~ -and ~ ~substitution ~ ~ ~ ~ . in O the aromatic nu~leus.~*~J No commonlyavailable reviewof IA hasyetbeenpublished (toour knowledge there areonlychemical companybrochures available 2).Theaim istocover theuseofIA asa starting material forheterocyclic ofthis chapter compounds. Otherfields of application arenotincluded [e.g., reactions leading onlytoopen-chain anthranilic acidderivatives, useinthemanufacture ofagricultural chemicals, dyes, pigments, cross-linking agents and chain stoppers inresins andother usesinpolymer andrubber chemistry, inprotein andcarbohydrate substrates (wool, paper, texuseasa modifier tiles), useasa petroleum additive (fuels andlubricants), useasa blowing agentforpolymer foams, a flameproofing agent, anda corrosion inhibitor, useinmetalfinishing, forfoods andbeverages, soaps anddetergents, perfumes, cosmetics, anduseinmedicines andpharmaceuticals.] Throughout this chapter, IA isusedtodenote theparent isatoic anhydride (1); I A sisused todenote IA and various benzene ringsubstituted analogs. H. Kolbe, J .Prakt. Chem.[2]30,84, 124,467 (1884). E. von Meyer,J .Prakt. Chem.[2]30,484 (1884); G. Schmidt, aid. 36,370(1889). S.Niementowski and B. Rozanski, Ber.Dtsch. Chem.Ges.22,1672(1889). E. Erdmann,Ber.Drsch. Chem.Ges.32,2159 (1899). T. Curtius and A. Semper,Ber.Drsch.Chem.Ges. 46,1162(1913). J. Bredtand H. Hof,Ber.Dtsch. Chem.Ges.33,27 (1900). ti E. Mohr,J .Prakt. Chem.[2]79,281 (1909). W. Panatovic, J .Prakt. Chem.[2]33,57 (1886). l o E. Meyer and T. Bellmann, J .Prakt. Chem.[2]33,18 (1886). I R. Dorsch, J .Prakt. Chem.[2]33,32 (1886). l 2 J .W . Long,ed., Chemistry ofIsatoic Anhydride,3rded.SherwinWilliams Chemicals, 1975.

Sec.I.B]

B. SYNTHESES

ISATOIC ANHYDRIDE

OF ISATOIC

129

ANHYDRIDEAND RELATEDCOMPOUNDS

Therearenow three types ofreaction commonlyusedforpreparing IA. 1.Cyclization ofanthranilic acid withcarbonic acid derivatives (phosgene, 3-26 The reaction mechanism and ethyl chloroformate, seeScheme by PeetandSunder.27 theby-products werestudied l).435*1

l3

l4

l6

Merck & Co..Inc. (byF.C. Novello). U.S.Patent 2,910,488 (1959) [CA 54,2271(1960)]. E. C. Wagnerand M. F. Fegley, Org.Synth. 27,45 (1947); Collect. Vol.III,488 (1356). I.G. Farbenindustrie A. G. (byA. Ossenbeck and A. Tietze), GermanPatent 500,916 [ C A 24,4793(1930)l; British Patent 311,336(1928) [CA 24,972(1930)l. (1928) Farbenfabrik BayerA. G. (byM. Gallus, G . Lorenz, and G. E. Nischk), Ger.Offen. 1,949,014 [ C A 74,76430(1971)l. Parke, Davisand Co.(byR. A. Scherrer), FrenchPatent M 3,007(1965) [CA 62,14684 Belgian Patent 637,515 (1964) [CA 63, 4307 (1966)l; Aktieselskabet Gea (by (1965)]; SouthAfrican Patent 6804 065(1969) [CA 72,12408(1970)l. B. AlhedeandK.Neuhold),

*’

130


[Sec. 1.B

2. Oxidation ofisatin inglacial acetic acidwithCrO, orperoxy carboxylic (see Scheme1). 3. Rearrangement ofphthalic acidderivatives. Treatment ofphthalic anwhich hydride withammonia and NaOH leads to phthalamic acid(8), Thesameresult canbeachieved starting rearranges withNaOCl toIA.33*34 (7)8p23735-38 orN-chlorophthalimide (9).39 Similar reacwithphthalimide tions starting withphthalic acidoranhydride viatheazide (5)alsogive IA6,40*41 (see Scheme1). J.Martens, K.Praefcke, andU.Schulze, Synthesis, 532(1976); R.V.Coombs,J. Org.Chem. 42,1812(1977); J.H. Sellstedt, C. J.Guinosso, A. J.Begany, andM. Rosenthale, J. Med.

(1975). Chem.18,926 G. M. Coppola, J. Heterocycl. Chem.15,645(1978). 2o Hodogaya Chemical Co.,Ltd. (byM. Suzuki, K.Yoshihara, andN. Igari), Japanese Patent 16,891 (1963) [CA 60,2858(1964)]. BASF A. G.,British Patent 783,067 (1957) [CA 52,2930(1958)l. 2 2 F.E.Sheibley, J. Org.Chem.3,414(1938). 23 HookerChem.Corp. (byN. E. Boyer), Tech.Apskats 30, 5 (1961); 31,13(1961) [CA 59, 1524,1526(1963)]. 24G.E. Hardtmann, G . Koletar, and 0.R. Pfister, J. Heferocycl. Chem. 12,565 (1975). 2 5 T.H Althuis. P.F.Moore,and H. J.Hess, J.Med.Chem.22,44 (1979). 2 6 D. L. Goldhamer, M. Onyszkewycz, and A. Wilson,Tetrahedron Lett., 4077(1968); K. Kurita, T.Matsumara, andY. Iwakura, J .Org.Chem.41,2070(1976). 2 7 N. P.Peet and S.Sunder, J.Org.Chem.39,1931(1974). 2 8 Parke, Davisand Co. (by R. A. Scherrer), U.S.Patent 3,238.201 (1966) [ C A 64, 17614 (1966)l. 29 Searle, G. D. & Co.(byJ.W. Cusic), U.S.Patent 3,509,149 (1970) [CA 73,3931(1970)l. 30 H. Rupe and L. Keraten, Helu.Chim.Acfa9, 578(1926). 3 1 S.Inagaki,J. Pharm.SOC.Jpn.58,946,961 (1938); 1.Nabih, andM. Abbasi, J. Pharm.Sci. 601251(1971); K.Geckeler andJ.Metz.Arch.Pharm.13,842(1979); G. Reissenweber and Angew.Chem.92,196(1980). D. Mangold, 3 2 J.Wegmann and H. Dahn,Hela. Chim.Acfa 29,415(1946). 3 3 BASF A. G .(byH. J.Quadbeck-Seeger andP.Tonne), Ger.Offen. 2,346,308 (1975) [CA 83,4335(1975)l; Ger.Offen. 2,258,150 (1974) [CA 81, 105532(1974)l. 34 Farbenfabrik BayerA. G.,Fr.Demande2,008,946 (1968) [CA 73,45177(1970)l. 35 Maumee Chemical Co.(byD. R. Hill andW. A. Shire), U.S.Patent 3,324,119 (1967) [CA 68,2904 (1968)l; French Patent 1,500,957 (1967) [CA 70,11707(1969)l. 36 Imp.Chem.Ind., Ltd.(byA. A. Kommanderand1.Hodginson), British Patent 1,436,810 [CA 85, 192397(1976)l. (1976) 3 7 BASF A. G. (byH. J.Sturm, H. Armbrust, and F.E. Kempter), Ger.Offen. 1,950,281 [CA75,5495(1971)]. (1971) 3 8 BASF A. G. (byH. J,Sturm, F.E. Kempter, and H. Armbrust), U.S.Patent 3,847,974 [CA 83, 79255(1975)l. (1975) 39 Sherwin Williams Co.(byL.C.Vacek), Ger.Offen. 2,230,374 (1973); Ger.Offen. 2,152,722 U.S.Patent 3,734,921 (1973); French Patent 2,153,766 (1973) [ C A78,159629 (1973); (1973); 79,32064, 42525,92192(1973)l. 40 G. Caronna, Gaii. Chim.Iful. 71,189(1941). 4 1 G. Caronna, Gaiz. Chim.Ifal. 71,475(1941). l9

Sec.I.B]

ISATOIC ANHYDRIDE

131

SCHEME2

Othermethodsofobtaining IA include oxidizing phthalamic acid(8)with P ~ ( O A C ) ,thermally , ~ ~ * ~cyclizing ~ thephthalamic acidderivative or treating N-hydroxyphthalimide (11) withbenzenesulfonyl chloride (12)45 (Schemes 1 and2). N-Substituted anthranilic acidderivatives arethestarting materials of other preparations yielding IA.Heating of13,4614,47,48 or15,28 oroxidizing 1628givesvarious yields of I A . A 2-Isocyanatobenzoate (17), whichis obtained either fromphthalic anhydride andtrimethylsilyl orfrom anthranilic acid silyl isinequilibrium withN-trimethylsilyl-substituted IA,49a,49b fromwhichIA canbe isolated by treatment withaqueous 42

J3

A. L.J. Beckwith, Ger.Offen. 1,926,475 (1969) [ C A 74,76430 (1971)l; A. L.J.Beckwith and R.J. Hickman, J .Chem.SOC.C,2756(1968). Sherwin Williams Co.(byA. L.J.Beckwith), U.S.Patent 3,947,416 (1976) [CA 85,33073

(1976)]. C. D. Hurd,C. M. Buess, andL. Bauer, J .Org.Chrm. 17,865(1955). J5 L. Bauerand S.V. Miarka, J .Am. Chem.SOC.79,1983(1957). 46 S . Tohyjama, M. Kurihara, and N. Yoda,BUN. Chem. SOC.Jpn.43, 1246(1970). 4 7 P.Karrer, G. H. Dieckmann, and W. T.Haller, Helu.Chim.Acta7, 1031(1924). 48 E.V. Crabtree, D. N. Crarner, and B. L. Murr, J .Org.Cbem.43,268 (1978). 49a S.S.Washburne, W. R. Peterson, andD.A. Berman, J .Org.Chem.37,1738(1972). 49b G. Greber and H. R. Kricheldorf, Anyew.Cbem.80,1029(1968); H. R. Kricheldorf and G. Greber, Chem. Ber. 104,3131,3168 (1971); V. R. Kozyukov,V. N. Mironova, and V. F.Mironov, Zh.Obsbch. Khim.49,784(1979) [ C A 91,20592(1979)]. 44

132

[Sec. 1.B

T.KAPPE A N D W. STADLBAUER

.

.

0

0

II

C- OCOMe

N=C=O

R

@:

11

a A

(R = SiMe,)

0 C-OSiMe, II

Me31N1,

0 a c - O /I s i M e 3

N=C=O

0

NH2

(17) SCHEME

3

ethanol.43a AnothermethodtoobtainIA derives fromtheisocyanate 1849c (Schemes 2 and 3). N-Substituted IA canbeobtained by treating theunsubstituted IA (1)with orarylhalides (ort o s y l a t e Reaction ~ ) . ~ ~of * ~o-~ NaH or K,C03 and alkyl0

eLo

1. NaH or K,CO, 2. RX

1. K,CO,/Cu.RNH, 2. C0Cl2

-1

4

R

(20) R = Alkyloraryl

(21) R

=

CHMe,

COCI,

NHCHMe,

21

(22)

SCHEME4 49c 50

L.Hoeschand A. S.Dreiding, Helu.Chim.Acra58,980(1975). R. W. Hall, F.C.Bernhardt, and C. F.Beam,J .Heterocycl. Chern.15,495(1978).

Sec.I.B]

133

ISATOIC ANHYDRIDE

chlorobenzoic acid(19)withcopper and primary aminesandcatalytic reduction ofo-nitrobenzoic acid(22)inthepresence ofacetone, followed by ring closure withphosgene,24 areother methods ofobtaining N-substituted IA (20,and21)(Scheme 4). N-Methyl IA(24), prepared fromIA anddiazomethane ordimethyl sulfate, iscommercially available. Thiscompoundwas isolated asa by-product of isocyanate (Eq.l).51 thereaction of23 withphenyl

a -a PhNCO

NHMe

0

C02H

N -CO-NHPh Me

(23)

Me (24)

Usually, N-substituted IA saresynthesized by theaction ofphosgene on thecorresponding N-substituted anthranilic acids, forexample, thetricyclic derivative (26) wasrecently prepared inhighyield fromtetrahydroquinoline8-carboxylic acid(25).19 An earlier preparation of26 required a five-step synthesis ofIA itself viathe synthesis via2752(Eq.2).(Fortheanalogous corresponding chloronitroquinoline derivative seeRef.53).

(25)

0

0

(26)

(27)

Aza analogs of IA39*42*43,54,55 and polycondensed analogss6 (28)canbe prepared by thesameprocedures asshowninScheme5.

M. Kuriharaand N. Yoda.Bull. Chem.Soc.Jpn.39,1942(1966); Tetrahedron Lett., 2597 (1965). 5 2 E. Ziegler and T.Kappe,Monatsh.Chem.95,59 (1964). 5 3 T. Kappe and E. Ziegler, Monatsh.Chem.95,415 (1964). 5 4 Sherwin Williams Co.(byG.F.Schlaudecker), U.S.Patent3,622,573 (1971) [ C A 76,46210 SherwinWilliams Co.(byL. C. Vacek). U.S.Patent3,828,038 (1974) [ C A 81, (1972)l; SherwinWilliams Co. (byA. L.J . Beckwith), U.S.Patent3,887,550 (1975) 136171(1974); [CA 83,147504(1975)l. 5 5 C. D. Hurd and V. G .Bethune, J .Org.Chem.35,1471(1970); H. R. Kricheldorf, Chem. H. R. Kricheldorf, Makromolek. Chem.173,13 (1973). Ber.105,3958 (1972); 56 D. A. Heroldand R. D. Rieke, J .Ory.Chem.44,1359(1979); J.M. Saaand M. P.Cava, J .Org.Chem.43,1096 (1978); BASF A . G.(byF.Ebeland R. Randebrock), British Patent 719,193(1954) [ C A 50,409 (1956)l.

51

134

[Sec. 1.B


C02H

z-&co2H

c0nh2

CON, 0

SCHEME5

Reaction ofanthranilic acidamides(29) withnitrous acidgives 4-benzotriazinones (30) whichinmany reactions behaveinthesameway asIA57-62; n

,IN,/

R2d--

(30)R ’

(29)

H

NflN

R2&/R3

’

=

R2

(31)

(30) R3

= Alkyl

SCHEME6

’’ J.G.Archer, A. J.Baker, and R. K. Smalley, J. Chem.SOC.,1169(1973). S.M. Gadekarand E. Ross,J .Org.Chem.26,613(1961). H . Mehner,J .Prukt. Chem.[2]63,241 (1901). 6o A. Weddigeand H. Finger, J .Prakf. Chem.[ 2 ]35,262(1887). 6 1 G .Heller and A. Siller, J .Prukr. Chem.[2]116,9 (1927). H. Finger, J .Prakr. Chem.[2]37,431 (1888). 58

59

Sec.I.B]

135

ISATOIC ANHYDRIDE

forinstance, thermolysis of30 yields thesamecompound(31) asdoesthe ofIA.57Theformation of31 asa by-product isobserved inthereheating ofIA withless reactive substrates (see also Section 1,C). action Kametanihas recently shown that3,2,l-benzoxathiazin-4( lH)-one-Z (32), theso-called sulfinamide anhydride, whichisisolated fromthe oxide reaction ofanthranilic acid andthionyl asanunstable oil (Eq.3), undergoes reactions similar toI A butundermildercondition^.^"^’ This observation will probably havean important impact on IA chemistry.

(32)

(4)

Thethio analog ofIA (34) andits rearrangement product (35) canbeprepared from2-isocyanatobenzoyl chloride (33)7andthioacetamide orfromanthrae n e4). ~ ~The trithio compound36,which nilic acid(4)andt h i ~ p h o s g (Eq.

(33)

(34)

(35)

hasbeensynthesized fromIA andphosphorus p e n t a ~ u l f(Eq. ide 51, ~reacts ~ R. GrafandW. Langer, J .Prakr. Chem.[2]148,161(1937). T.Kametani, C.vanLOC,T.Higa,M . Koizumi, M. Ihara, andK.Fukumoto, Heterocycles 4, 1487(1976). 6 5 T.Kametani andK. Fukumoto, Heterocycles 7 ,615(1977). 66 T.Kametani, T.Ohsawa,M. Ihara, andK. Fukumoto, Chem.Pharm.Bull. 26,1922 (1978). 67 T.Kametani, C.vanLOC,T.Higa, M . Koizumi, M . Ihara, andK.Fukumoto, J .Am. Chem. Soc.99,2306(1977). h R T.Kametani, T. Higa,C .vanLOC,M. Ihara, and K. Fukumoto, Chem.Pharm.Bull. 25. 2735(1977). 6 9 T.Kametani, T.Higa, C.vanLOC,M. Ihara, M. Koizumi, andK. Fukumoto, J .Am. Chem Sac.98,6186(1976). O T.Kametani, T. Higa,K. Fukumoto, and M. Koizumi, Heterocycles 4, 23 (1976). C.F.Beam,N.D.Heindel, M. Chun,andA.Stefanski, J .Heterocycl. Chem.13,421 (1976). J.R. Marshall, 1.Chem.Soc.,938(1965); H. R. Kricheldorf, Chem.Ber.104,3146,3156 (1971). 7 3 G. Wagnerand L. Rothe, Pharmazie26,271 (1971); W. Walter, T. Fleck, J.Voss,and M. Gerwin, Liebigs Ann.Chem., 275(1975). 63 64

136


0

[Sec. 1.B

S

(5) (1)R = H (24)R = Me

inamannersimilar toIA.74 Theuseof2-Isocyanatobenzoyl chloride (33), an results intheformation important andpowerful intermediate inIA chemistry, ofheterocyclic compounds. Itisprepared fromIA withSOCI,,COCl,,or PC15(Eq.6).26,75-79 Anthranilic acid(4)andcyanogen bromide orphenyl

:;pl+ f J SOCI,

IA

C0Cl

N=C=O (33)

isocyanate react to give37, iminoanalogs to IA,whichundergo facile rearrangements tothequinazolinediones 38 (Eq. 7).51*80-82

S.Leistner, A. P.Giro, andG.Wagner, Pharmazie 33,185(1978); 34,390(1979); G.Wagner andL.Rothe, Z.Chem.7,339(1967); Pharmazie 25,595(1970); S .Leistner andG.Wagner, 2.Chem. 13,428(1973); S. Leistner andG.Wagner,Pharmazie 35,124(1980); S. Leistner, G. Wagner,and T. Strohscheidt, ibid. 35, 293 (1980);S. Leistner, G. Wagner,and K. Hentschel, Z.Chem.20,143 (1980). " Y . Iwakura, K. Uno, andS.Kang,J .Org.Chem.31, 142 (1966). " N. P. Peetand S . Sunder, f. Org.Chem.40, 1909 (1975). H. Ulrich, B. Tucker, andA. A. R. Sayigb, J. Org. Chem.32,4052 (1967). " C.Vigne, M. Buti, C.Montginoul, E.Toreilles, andL.Giral, J. Heterocycl. Chem.13,921 74

’’

(1976).

N. P.Peet, S. Sunder, and W. H. Braun, f. Org.Chem.41,2728 (1976). K. LempertandG. Doleschall, Monatsh. Chem.95,950,1083(1964). G. Doleschall andK. Lempert, ActuChim.Acad.Sci.Hung. 48.77 (1966). **K. LempertandG. Doleschall, Tetruhedron Lett, 781 (1963).

l9

Sec.I.C]

ISATOIC ANHYDRIDE

137

C. GENERALMECHANISTIC AND THEORETICAL ASPECTS Theexceptional versatility ofI A arises fromtheeasewithwhichitenters into condensation andsubstitution reactions. Thehetero ring ishighly susceptible tocleavage [(i)or(ii)] and canbe N-substituted withorwithout (see Scheme4) ringopening. Generally, theanthranilic carbonyl group(C-4) ismorereactive thanthe isatoic carbonyl group (C-2). Steric hindrance andN-substitution sometimes IA inalkali ortreatment withaqueous acids reverse this trend. Refluxing acid (4). 92*8 Releads toquantitative decomposition toC 0 2andanthranilic action withone-half molealkali orBa(OH),formsanthraniloyl anthranilic acid andthepresence ofalcohols andbasecatalysts gives thecorresponding anthranilates (39).7.83p85 Uncatalyzed high-temperature esterioftheunsubstituted 1A yields theisatoate 41,3,4*6,83,85 whichcan fication

(4)

\or

i

tOH -

0

SCHEME 7 8 3 R. P.Staiger andE. B. Miller, J.Org.Chem.24, 1214(1959).

Meckel, andE.Miiller, Angew.Makromol. Chem.26,29 (1972). D. H. Heyman,J. Heterocycl. Chetn.15,1131 (1978).

M 4 J.Blahak. W. 85

138

[Sec. 1.C


be further converted to 39.s5 The mechanism1--t 41 -, 39 involving 2carboxyphenyl isocyanate asa reactive intermediate intheformation of41 hasbeendiscusseds5 (Scheme7). The reaction withammoniaorprimary aminesinaqueous systems has beeninvestigated repeatedly. Generally, twotypes ofproducts areobtained during thereaction. The primary product isthering-opened isatoic amide 42,whichreacts withloss ofC 0 2 ,favored by a lowratio ofamine, tothe while a highratio ofamineorbulky anthranilic acidamide(43),2*6,’09s6-ss amines leads toisatoic diamides (45), whichundergo facile cyclization tothe quinazoline diones 36by heating.86*s9-93 The kinetics ofthereaction ofIA withn-butylamine showthat therate lawforformation of43 iszeroorder n C O N H R

’NHCO,H IA

+ R-NH,

low ratio

oramine, -CO,

fl CONHR

v’1

(42)

NH

*

(43) ofamine

H

(46) SCHEME8 R.P.Staiger andE.C.Wagner,J.Org.Chem.13,347(1948). H. Finger, J. Prakt. Chem.[2]48,92 (1893). BayerA. G .(byK.W. KrebsandC.Metzger), Ger.Offen. 2,719,020 (1978) [CA 90,71928 (1979)]. R. P.Staiger andE. C.Wagner,J. Org.Chem.18,1427(1953). 90 F.R. Sheibley, J. Org.Chem.3,415(1938); 12,743 (1947); 17,221(1952). 9 1 M. Covello, D. Dini, andF.De Simone, Rend.Accad. Sci.Fis.Mar.,Naples36,61 (1969) (CA 75,49011(1971)l. R. H. ClarkandE.C. Wagner,J. Org.Chem.9,55(1944). 93 R. L. McKee,M. K. McKee.and R. W. Bost, J. Am. Chem.Soc.69,940(1947). 86

’’

Sec.I.C]

139

ISATOIC ANHYDRIDE

inamineandfirst order inbutylammonium ion; formation of44 isfirst order inamineandzeroorder inbutylammonium ion.94 Underthesamereaction IA s conditions, tert-butylamine and IA formedonly44.94N-Substituted 44.s3*94 Analogous results wereobtained produce exclusively N-substituted withesterificationss5 (Scheme8). Withhydroxylamine, IA reacts togivethe0-acylated while 0-substituted hydroxylamines yield theanthranilic acidh y d r o ~ y l a m i d e s ~ ~ Eq.(14)]. Reaction ofamides withIA results intheformation ofquinazo[cf. line derivatives (see Section III,A), andthefirst reaction stephasbeenproof theamidefollowed by decarboxylation and ring posedas acylation mechanism9canbe proposed forthereacc l o s ~ r eA. similar ~ ~ * ~reaction tionbetween1A andC=N double bondsystems (Eq.8)(seeSection IV).

However, analternative reaction mechanism98 couldbethecycloaddition oftheiminoketene 47 (X = NH, NR) derived fromIA by loss ofC 0 2tothe doublebond system. The work of Ziegler and co-workers on salicyloyl

(48)X

= O,NH,NR

0

0

(49)

(3)

(30)R

=

H, Ph

J.F.Bunnett and M. B. Naff, J. Ain.Cliem. Soc.88,4001 (1966). A. W. Scott and B. L.Wood, J. Ory.Chem.7,508 (1942). 96 P.Mamalis, M. J.Rix,andA. A. Sdrsfield, J .Chem.Soc., 6278(1965); H. KohlandE.Wolf, Liebigs Ann.Chem.766,106(1972). T.Kappe,W. Steiger, and E.Ziegler. Monursh. Cliem98,214 (1967). 9 8 E.Ziegler. T. Kappe,andW. Steiger. 2.Nuturforsch., TeilB 20,812 (1965).

95

95

140


[Sec.1.C

chloride (49),99s’00 whichwaslater extended tothecyclic carbonate (50),’O1 had suggested the analogintermediate (47;X= 0)in corresponding O2 reactions.’ When heated ina high-boiling inert solvent, IA gavebenzoxazinone 31 in20% yield.57*’03,’04 The samecompoundwasshowntoresult fromphotolysis andthermolysis ofbenzotriazinone (30;R = H);inbothreactions the valence tautomeric fl-lactam (48)werepostulated as ketene imine47 orits intermediates. Trapping reactions,""’dimerization or otherinternal 7,103,104,107.108,f 10-1 2 0 stabilization5 ofIA,30, orrelated compoundscon(47,48). firmtheassumption oftheexistence ofthese intermediates IRspectra ofIA andN-methyl IA(24) during thermal decomposition show bandsof1810-1830cm-’,whichareinaccordance withtheproposed fllactam 48."’Analogous decomposition of30 (R = phenyl) showsbandsat 1830cm-’ 106~108Theconcentration of47 inthis thermolysis reaction was toosmall fordetection inIR,butUV showsabsorption at575nm,indicating thepresence of47.’06Photochemical decomposition ofphthaloyl peroxide 47 and48 (X = 0), showing IR frequencies at1904 cm-’ (48)and yields 2139cm-’(47),’09 whichcould also be observed inthethermal decompoofsalicylic acidchloride (49) with1930 cm-’ and2070cm-l.12’ sition

’’

E.Ziegler andH. D. Hanus,Monatsh. Chem.95,1053(1964); 96,411(1965). E.Ziegler, G. Kollenz, andT.Kappe,Monatsh. Chem.99,804,2024,2167(1968). ’’I G. Kollenz andE.Ziegler, Monatsh. Chem.101,97 (1970). lo’R. Gompper, Angew.Chem.81,361(1969); Angew.Chem.,Int. Ed.Engl.8,312(1969). R. K. Smalley, H. Suschitzky, and E. M. Tanner, Tetrahedron Lett., 3469(1966). H . E. Crabtree, R. K. Srnalley, andH. Suschitzky, J. Chem.Soc.C,2730(1968). H. Herlinger, Angew.Chem.76,437(1964); Angew.Chem.,Int.Ed.Engl.3,378(1964). loci G. Ege,Chem.Ber.101,307Y (1968); G. Ege and F.Pasedach, [bid., 3089. Io7 G. Ege,Angew.Chem.77,723(1965); Angew.Chem.,Int. Ed.Engi.4 ,699(1965); G.Ege andE.Beisiegel, Angew.Chem.80,316 (1968); Angew.Chem., Int. Ed.Engl.7,303 (1968); D. H. Hey,C. W. Rees,andA. R.Todd,Chem.I d .(London), 1332(1962). lo’ A. W. Murrayand K. Vaughan, J. Chem.SOC.C,2070(1970). 0. L. Chapman,C.L.McIntosh, J.Pacansky, G. V. Calder, and G. Om,J .Am. Chem. SOC.95,4061(1973). ’lo A. T.Fannings andT.Roberts, Tetrahedron Lett., 805(1971). A. T.Fannings, G. R. Bickford, andT.D. Roberts, J.Am. Chem.Soc.94,8505(1972). T. McC. Paterson, R. K. Smalley, and H. Suschitzky, Synthesis, 187(1975). ’ 1 3 D. H. Hey,C. W.Rees, andA. R. Todd,J. Chem.SOC.C ,1028(1968). ’I4 P.Ahern, T.Navratil, andK. Vaughan, Tetrahedron Lett., 4547(1973). P.T.Ahern,H. Fong,and K. Vaughan,Can.J. Chem.54,290(1976). ’16 A. J.Barker and R. K. Smalley, Tetrahedron Lett., 4629(1971). E.M. Burgess andG. Milne, Tetrahedron Lett., 93(1966). J.Adamson,D. L. Forster, T.L.Gilchrist, andC.W. Rees, J.Chem.SOC.C,981(1971). ’I9 C.T.ChenandC.J.Hsu,Bull. Inst. Chem.,Acad.Sin. 14,57 (1967) [CA 69,35639(1%8)]. AmericanCyanamidCo. (byG. R. Allenand R. F.R. Church), SouthAfrican Patent 7,100,512 (1971) [CA 76,140237 (1972)l. E.Ziegler andH. Sterk, Monatsh. Chem.99,1958(1968). 99

loo

Sec.ILA]

ISATOIC ANHYDRIDE

141

Inthelight ofthese results, IA could react intwoways:(1) formation of by [4 + 21-cyclotheiminoketene (orp-lactam) by lossofC 0 2 followed addition or(2)acylating thereaction partner inthefirst stepwiththeanofC 0 2 asthesecond thranilic acidcarbonyl groupandcyclizing withloss case islargely dependent onthesubstrate step. Themechanism ina particular usedandthereaction conditions. Azomethines andheterocumulenes seem toundergo cycloaddition reactions inmodest yields,98 while astepwise mechanismoccurs faster andwithbetter yields9 withamides, thioamides, and related compounds. Analogous findings werereported withthe sulfinamide (32),6 70whereacycloaddition ispresumed, buta stepwise mechanhyride anismcouldnotbe ruled out.

11.Formation ofAnthranilic AcidAmidesand Hydrazides and Further Reaction toHeterocycles A. REACTIONOF AMIDESWITH CARBONYLCOMPOUNDS 1. Carboxylic AcidDerivatives Formation ofanthranilic acidamides (43)fromIA isanestablished reacI,C), andClark andWagner92 isolated thequinazoline 51 from tion (Section closure withorthoformate. Analogous reactions werecarried IAvia43byring IAs,2 2 p 12 5 primary a m i n e ~ , and ~ ~formic - ~ acid ~ outwithN-substituted 52 (R3= H).Ringclosure withother carboxylic acid derivatives, yielding 52 (R3= alkyl, a r ~ l ) ~; substitution O - ~ ~ ofbothnitroderivatives produce 53.lS5Reduction ofanthranilamide (43)followed by ring gensof43 gives B. R.Baker, R.E.Schaub, J.P.Joseph, F.J.McEvoy,andH. J.Williams, J. Org.Chem. 17,164 (1952). 1 2 3 Mead Johnson & Co.(byH. S.Scarborough and J.L. Minielli), U.S.Patent 3,119,824 [CA 60,9293(1964)l. (1964) l Z 4M. K. McKee, R. L. McKee,and R. W. Bost, J.Am. Chem.SOC.69,184(1947). M. Vincent, J.C.Poignant, and G. Remond,J.Med. Chem.14,714(1971). CibaLtd.(byS.Janiak), Ger.Offen. 1,908,097 (1969) [ C A 71,12448(1969)l. B. R. Baker, M. V. Querry, A. F.Kadish, andJ.H. Williams, J .Org.Chem.17,35(1952). S.JohneandB. Jung, Pharmazie 33,299(1978). S.Johne, M. Susse, andB. Jung,Pharmazie 33,821(1978). 130T.Hisano, M. Ichikawa, A. Nakagawa, andM. Tsuji, Chem.Pharm.Bull. 23,1910 (1975); K. Muraoka, M. Ichikawa, andT.Hisano, YakugakuZasshi100,375(1980). S. Hayayo,H. J.Haven,W. G. Stryker, and E. Hong,J. Med. Chem.12,936(1969). 13 I. M. Heilbron, F.N.Kitchen, E.B.Parks, andG.D.Sutton, J .Chem.Soc.127,2167(1925). T. Hisano, M. Ichikawa, G. Kito, and T.Nishi, Chem.Pharm.BUN. 20,2575(1972). 134 G.Doleschall andK. Lempert, Tetrahedron 25,2539(1969). L.Bonola, M. J.Magistretti, I.Setnikar, andE. Massarani, Eur.J .Med.Chem.-Chim. 9,639(1974). Ther. I22

142

[Sec. 1I.A

T.KAPPE AND W. STADLBAUER

eNR1 1

c MeS0,H HK O-

\

’

2. 1. LiAIH, HC0,H

R 2 f x c 0 N H R 1

~

NHR

R

(53) R = CHZCOC1

z

R

(54) R = CH,Ph

(43)

SCHEME 9

closure withformicacidleadsto (Scheme9).Usingtryptamine (55) astheprimaryamine,ringclosure takesplacetoform thealkaloids 3,14dihydrorutecarpine (56)withI A ’3 7 orevodiamine (57) withN-methylIA (24) (Eq.9).’ 38 Recently, these reactions wererepeated with"sulfinamide anhydride" (32).6"67*69*70 a 7 ( c H 2 ) 2 - N H 2

or N-Mahyl (24) 1A IA’

m

IN H

H (55)

RHN Iy

O

HC(OEt1,

HCOIH

’

(!%)R=H (57) R = Me

’" W. L.F.Amarego,J .Chem.Soc., 2697(1961). 13’

"*

K. Horvath-Dora and 0. Clauder, Acra Chim.Acad.Sci.Hung. 84,93 (1975); 72,221 (1972): T.Kamikado,S.Murakoshi, andS.Tamura,Agric. Biol. Chem.42,1515 (1978). Y. Asahinaand T.Ohta,Ber.Dtsch. Chem.Ges.61,319(1928).

Sec.II.A]

143

ISATOIC ANHYDRIDE

4-Aminoquinazolines (59)areobtained either conventionally by treating

51 (see Scheme9)withPCl,andamineLZ4 orby reacting IA withammonia orphosgene14’ inDMF togivetheformamidine 58,which andP0C13139

isthencyclized by heating withammoniaorprimary amines toproduce 59l 39 (Eq.10).Reaction ofphthalic anhydride withanthranilamide (43)forms2-

inDMF

(58)

(59)

carbamoylphthalanilic acid(62),whichcanbeconverted tothequinazolone 63 by treatment withsodiumhydroxide141 ;reaction withhypohalite yields (64)141 ;withacetic anhydride thephthalimide 65 was obbenzimidazolone tothecondensed quinazolone 61142 tained.141*’42 Thermolysis of62 leads (Scheme10).

0

C.H.Foster andE.U. Elam,J .Ory.Chem.41,2646(1976); EastmanKodakCo.(byC. H. Foster), U.S.Patent 3,985,749 (1976) [ C A 86,43733(1977)l. 1 4 0 BASF A. G .(byD. Schneider andH. Scheuermann), Ger.Offen. 2,628,055 (1978) [CA 88, 104955(1978)l. 14’ D. A. Heyman,J .Hererocycl. Chem.15,573(1978). 14’ M. Kurihara, J .Org.Chem.34,2123(1969). 139

144

[Sec. 1I.A


y-Ketocarboxylic acids (66)react withanthranilamides (43) andacid cata(67), pyrroloquinazolones lysts togive, viaacylated anthranilamides thequinoline carboxylate 69.25 Withoxalyl chloOxalic ester and43 produce 70 isobtained which, uponthermolysis, ride inthefirst step theoxanilide gives mainly thequinazolinedione 71,withquinazolones 72143b asside prodAddition of43 toacetylenic dicarboxylate (73)formsthe ucts (Scheme11). R’

R’

CONHR2

R3-CO(CH~)~C02H

NHCO(CH2),COR3

R

R

(71) mainproduct

(72) sideproducts

(if R = H)

SCHEME 1 1

primary adduct 74,whichundergoes ring closure ontreatment withalcoholateyielding thequinazolone 75144*’45 ; first observations interpreted interms havebeenc o r r e ~ t e d(Eq. ’ ~11). ~.’~~ ofa seven-membered ring C.S.Rao,A. D.Pandya, P.N. Mody,and M. P.Dave,Indian J .Chem..Sect. B 14,705 (1976). ’43b J .Gilbert, D. Rousselle, C.R .Acad.Sci., Ser.C 279,159(1974). 144 N. D. Heindel and L.A. Schaeffer, J .Org.Chem.35,2445 (1970). 1 4 5 T. F.Lemke,H. W. Snady, and N . D. Heindel, J .Org.Chem.37,2337(1972). ’46N. D. Heindel, V. B. Fish, and T.F.Lemke,J .Org.Chem.33,3997(1968). 143s

Sec.II.A]

145

ISATOIC ANHYDRIDE

2. Carbonic AcidDerivatives Urea,urethane, thiourea, andanthranilamide (43)furnish thecorresponding0x0-or thioquinazolones (76)92*147 ;ethyl chloroformate, thiophosgene, andphosgene react inthesamemanner.39q 48-Reduction oftheanthranilic acid carbonyl groupwithLiAlH,followed by cyclization withphosgene yields thequinazolone 7715 (Scheme12). Aryland alkyI isocyanates and R

R

cI = x R 4 == NH,.OEt.Cl NH,. RI OEt.CI

x=o.s

R

ex: R

SCHEME12 14 S.Toyoshima, K. Shimada, S.Hamano,andT.Ogo,J .Pharm.Soc.Jpn.85,502(1965). Casella Farbwerke MainkurA. G. (byR. Beyerle and A. Stachel), Ger.Offen. 1,934,037 [ C A 74,88029(1971)l. (1971) 1 4 9 Parke, Davisand Co.(byR. F.Parcell), Ger.Offen. 2,342,028 (1974) [CA 80, 146,190

(1974)]. R. L.Jacobs, J .Heterocycl. Chem.7, 1337(1970). S . Hayayo,H. J.Havera, W. G. Stryker, T.J.Leipzig, R.A. Kulp,and H. E. Hartzler, J .Med.t h e m .8,807(1965). G.D.& Co.(byJ.W Cusic andW. E.Coyne), U.S.Patent 3,509,149 (1970[CA 73. Searle. 3931(1970)l.

146


[Sec. 1I.A

isothiocyanates react withanthranilamides (43)togiveuramidobenzamides (78), whichcyclize toquinazolones 79 when treated with (isatoic diamides) of78 produces thequinazolines (Scheme 13). The POC1,.’s3 Heating compounds78 and80 (X = 0) werealsoobtained by reaction ofIA with 46).Anthraniloyl anthranilic aminesonly(see Section I,C, Scheme8,45 -, Rt

x

0 /I

X (78)X

(79)

=

(80) X = 0, S

0. S

SCHEME13

IA

4S

NNH, HH0 , C

D

R

I

(81) "",’OH

’54

W. Dymec and B. Lucka-Sobstel, Diss. Pharm.17,195 (1965)[ C A 63, 16347 (1965)l. A. Singhand B. M. Bhandari, IndianJ. Chem.,Sect. B 14,67 (1976).

Sec.II.A]

ISATOIC ANHYDRIDE

147

acid (81)resulting fromIA andanthranilic acid (4), gives withcarbon disul82,whichreacts withcoldthionyl chloride yielding fide thethioquinazolone thequinazolinobenzothiazinone (83); withhotthionyl chloride orHC1 the thio groupof82 isonlyconverted toa carbonyl groupand84 isobtained’ 55 (Scheme 14).

3. Aldehydes, Ketones, and Heteroanalogs Anthranilamides (43)and aldehydes (ortheiracetals) reactwhen heated’ " or~xidized’~’ togive quinazolones 85.Thealkaloid dihydro(88)was obtained by thesame sequence of reactions as isoevodiamine evodiamine (57)[cf. Eq.(9)], using formaldehyde instead offormic acid.’ 58 Ketones give thecorresponding 2,2-disubstituted quinazolones (86),’ s9 while diketones suchasacetylacetone leadinan acidcatalyzed reaction withanthranilamides (43)orthioanthranilamides toquinazolones oftype 87,which aremethaqualone analogs16’ (Scheme 15).

SCHEME15 155 156

Is’

’

58

15’

Ih0

S.M . Singh, S.Kaur,andA. N. Kaushal, J .hdiunChern.SOC.53,382(1976). Pennwalt Corp.(byB. V. Shetty), U.S.Patent 3,761,480 (1973) [CA 79,137186(1973)l. H. L. Yaleand M. Kalkstein. J .Med. Chem.10,334(1967). B. Danieli andG .Palmisano. Gaiz.Chim.I id. 105,99 ( 1975). H. L. Yale,J . Hecerocycl. Chern.14, 1357(1977); N. Hirose, S. Kuriyama, S . Sohda, K. Sakaguchi, andH. Yamamoto,Cheni. Pharrn. Bull. 21,1005(1973). M. S.Manhas,S.G. Amin,andV. V. Rao.Swthesis, 309(1977).

148

[See. 1I.A


Heteroanalog carbonyl compounds suchasthionyl chloride react with43 togivebenzothiadiazines (89)19,161; theaction ofnitrous acidon 43 yields benzotriazinones (30)57-62*87 (Eq.12).

4. Miscellaneous Reactions withAnthranilamides Reaction of43 withethylene oxide followed by chlorination withthionyl chloride gives thechloroethyl-substituted amide90,whichcyclizes withsodiumhydride tothebenzodiazepine 91,converted by ethyl carbazate (92)to triazolobenzodiazepinones (93).’ 6 2 When N-substituted anthranilamides are reacted withphosphorus trichloride followed by hydration, benzodiazaphos(94)163 areobtained (Scheme16). phorines Aminoalcohols 95 and IA leadtotheanthranilamides 96, whichare cyclized by arylsulfochlorides in refluxing ethanol toformthebenzodi-

tx:::,,)2-c,@-J

*

R’

R’

43

i

1. cn -CH

2. 1 H,O PCI, /O’

-3%

(90)

SCHEME 16 16’ 16’

R

(91)

(93)

A. A. Santilli and T.S.Osdene,J .Org.Chem.29,2717(1964). UpjohnCo.(J.B. Hester), U.S.Patent3,717, 654(1973) [CA 78,136352(1973)l. G.M. Coppola and R. I.Mansukhani, J .Heterocycl. Chem.15,1169 (1978); 16,897 (1979).

Sec.II.A]

149

ISATOIC ANHYDRIDE

S02R2 (98) X =0

(97)

(W)X=S

SCHEME17

azepinones 97.160Reaction inpyridine at0 Cyields oxazolines (98), which thiazolines 99164(Scheme17). AnthranilwithP,S5givethecorresponding amides (43)withareneboronic acids (100) innonprotic solvents yield benzodiazaborins 101 (R = aryl) and 102 (R = OH)’65; theratio of 101 to 102 depends on thesuccess inremoving thewater formed during the reaction. In contrast totheir carbon isosteres, theboronheterocycles dissolve inaqueous alkali toformstable anions. Theadducts of101andphosphorus oxychloride gwe ethoxyandaminobenzodiaza-borins (Eq.13).

(101) R 2 = Aryl (102) R2 = OH

(103) X = OEt orNH2 AmericanHome Products Corp.(byA. A. Santilli and T.S.Osdene), U S .Patent 3,452, G.M. CoppolaandG.E.Hardtmann, Synthesis 63(1980). 032(1969)CCA71,81338 (1969)l; 1 6 5 H. Yale, J .Heteroeycl. Chem. 8,193(1971).

150


[Sec. 1I.B

The section concerning reactions ofanthranilic acidamidesdeals solely withpublished reactions starting fromIA.

B.

REACTIONS OF

HYDRAZIDES AND HYDROXYLAMIDES

Anthranilic acidhydrazides (104), preparedfrom IA and hydrazines,10.87~92*166 areusedasprecursors forquinazolines, benzotriazinones, of 104withformic acidgives3-aminoand benzotriazepines. Cyclization quinazolone (105)’ 6 7 * 168; 3-aminoquinazolinedione (106) isobtained from ureaand theunsubstitutedhydrazide 104(RZ= R3 = H),76 while ring closure isreported toformtriazepine-diones withphosgene orethyl chloroformate (107).76,169-171 N, N’-D’ imethylhydrazide (104)(R2 = R 3 = Me) and aldehydesproducethecorresponding benzotriazepine 108.’ 7 1 Monomethylsubstituted hydrazides 104(R3= H) lead, withorthoesters ofcarboxylic 10!9,’~~*’ 7 2 * 1 7 3whichsuffer ringcontraction in acids, to thetriazepines 110’ ’’ refluxing sodiumethylate toyield theN-methylaminoquinazolones (Scheme18). Anthranilic acidhydrazides (104) withdimethyl acetylenedi111,whichcyclize on heating toquinazolines carboxylate yield the enamines (112) and nott r i a ~ e p i nCyclization e s . ’ ~ ~ of 104 withnitrous acidyields 3-aminobenzotriazinones (113)’6’*’75 (Scheme19). Spiroquinazolines (114) canbe obtained fromhydrazides 104andcyclo(X = CHz)or1-methyl-4-piperidone (X= NMe).’76 y-Ketocarboxhexanone ylic acids as2-acetylpropionic acid(115)formthecondensed quinazolones 116or117, depending onthesubstitution ofthering andhydrazine nitrogens. theanalogous tetracyclic derivative 119is With2-acetylbenzoic acid(118), obtained’76,’77 (Scheme 20). Halfa moleofhydrazine hydrate withonemole l h 6 M. S . Gibson andM. Green,Tetrahedron 21,2191(1965). I6’S.Petersen, H. Herlinger, E.Tietze, andW. Siefken, Angew.Chem.74,855(1962). and A. Scriabine, J.Med. Chem.11,130(1968). H. J.Hess,T.H. Cronin, 169 S.Sunder, N. P.Peet, and D. L.Trepanier, J .Org.Chem.41,2732(1976). 0. Hromatka, F.Krenmiiller, and M. Knollmiiller, Monatsh. Chem.100,934(1969). 1 7 ’ 0. Hromatka, F.Krenmiiller, and M. Knollmiiller, Monufsh. Chew.100,941(1969). 1 7 ’ R. W. Leiby andN. D. Heindel, J. Org.Chem.41,2736 (1976); 42,161(1977). 1 7 3 N. P.Peet and S.Sunder, J. Heterocycl. Chem.13,967(1976). C. F.Beam,C. A. Park,N. D. Heindel, and W. P.Fives, J.Heterocycl. Chem.14,703 (1977). 1 7 5 Sandoz-Wander Inc. (byF.G. Kathawala), U.S.Patent 3,818.001 (1974) [CA 81,105597 (1974)l. 1 7 6 Sterling DrugInc. (byF.K. Kirchner andA. W. Zalay), U.S.Patent 3,843,645 (1974) [CA 82,112089(1975)l. "’ AmericanHoechst Corp.(byE. H. Wolfand B. J.Duffy), U.S.Patent 3,883,524 (1975) [CA 83,131624(1975)].

0

1

(R’. R’ -CHO R’ = Me1

(X = CI.OEl) 4

R1&N(Me \ .JHMe

R

k4

1

NaOEt (R = H )

SCHEME18

R’

CONHNHR~ NHC=CHCO,Me I

-’ A

R 1 d N N F E : M e NkCH,CO,Me H

R

1

~

~

R’

R’ 3RJ&

R 0

Sec.II.B]

153

ISATOIC ANHYDRIDE

ofIA gives thebis-acylhydrazine 120,whichcyclizes normally withcarbox(121)’7 8 , 1 7 9andwithnitrous acid ylic acids oraldehydes tobis-quinolones to bis-triazinones (122).l7*Heating120 withpolyphosphoric acidforms oxadiazoles (123)179(Scheme21). IA andhydrazinoalcohols (124)formtheanthranilic acidhydrazides 125; subsequent reaction withCS2 gives thethioxoquinazolines 126, whichcyoxathiadiazocinoquinazolones (127)or clize withthiophosgene affording oxadiazinoquinazolones (130),depending onthe substituents. Another cycliiseffected withtrifluoroacetic anhydride (128)followed by potassium zation (129)180(Scheme 22). carbonate, yielding thiadiazinoquinazolones

OH

J

CSCI,

IR

=

H)

12 I . TFAA K,CO,(128) \?he) I R =HI

"’ Farbwerke Hoechst A. G. (byH. Kohl.N. J.De Souza,J.Patel, andP.D. Desai). Ger. Offen. 2,232,532 (1974) [ C A 80,121007(1974)]. K . Nagahara and A. Takada, Chmi.Pharm.Bull. 25,2713(1977). "’S. Sunder andN. P.Peet, Pror. Int.Conyr.Hetrroc.vc1. Chem.,7th.1979Abstract, p.206 J .Hrtrrocycl. Chtw7. 16.1319(1979). (1979):

154

[Sec. I1.B

T. KAPPE A N D W. STADLBAUER

IA and 0-substituted hydroxylamines (131) giveanthranilic acidhydrox(132)96 (hydroxylamine itself formsthe0-acyl derivative9’). Carylamides boxylic acids andanhydrides cyclize 132tothequinazolones 13396 (Eq.14).

(134)

(135)

SCHEME23

(136) (ifn

= 0)

Sec. II.D]

155

ISATOIC ANHYDRIDE

C. REACTIONOF ISATOICANHYDRIDEWITH DIAMINES Aromatic andaraliphatic diamines (134) withIA (without isolation ofan 135inpoor intermediate anthranilamide) yield thecondensed quinazolones *’- 8 3 Foro-phenylenediamine themain product istheimidazole yield.’ 136.18’ IA andtheuracil 137furnish a mixture ofthetheophylline 138together withthebenzodiazepine 139besides theexpected quinazolone 140 andthetricycloquinazoline 1411 8 1 * 1 8 4(Scheme23). Treatment oftheaminothiazoline 142 withIA andcyclization oftheexpected amide143 withacetic anhydride formsa condensed quinazoline, 144 or 145.Mechanistic considerations favor144,butthere isno either evidence todistinguish them’85 (Eq.15).

IA

HN

CONH2

HN

(142)R = H (143)R = anthraniloyl

or

D. REACTION

OF ISATOIC ANHYDRIDEW I T H

ENAMINES

Ethyl 0-aminocrotonate (146;R = OEt)oracetylacetone imine(146;R = Me) react withIA,withloss ofethyl acetate oracetone,’86 togivethesame (87), alsoobtained fromanthranilamide andacetylacetone (see quinazolone

Is’

E. C.Taylor and F.Yoneda,Angew.Chem.79,901 (1967); Angew.Chem..In!.Ed.Engl. 6 ,878 (1967). V. P.Arya.K. G. Dave,V. G. Khadse, andS.J. Shenoy, IndianJ .Chem.,Sect. B 14,879

(1976).

A. L. L.Poot, J.F.Willems, andF.C.Hevgebaert, Bull. Soc.Chim.Belg. 72,365 (1963). F.Yonedaand K. Mera,Chem.Pharm.Bull. 20,1815 (1972). l S 5 A. Singh, Res.J. Sci.1,45 (1974). ’’’ C. Mayerand T. Kappe,2.Narurforsrk., Ted B 32,1214 (1977). lE4

156


[Sec. 1II.A

Scheme15).160 Similarly, thehydrazone 147 reacts attheamino(andnot azomethine) moiety, toyield theamide148,whichcyclizes withdimethyl 149l7 4 (Scheme24). acetylenedicarboxylate togivethequinazolone

111. Reaction ofIsatoic Anhydride with Carboxylic AcidDerivatives

A. AMIDES IA withaliphatic andaromatic carboxylic amides(150;X = 0) gives the 151 (Eq.16). Lactams similarly yield C-2-N-3bridged quinazolones quinazolones’ *2,192-196 [e.g., thenatural products courupitine A 152196and J.F.Meyerand E.C. Wagner,J .Org.Chem.8,239(1943). R. Pater, J. Heterocycl. Chem.8,699(1971). AmericanCyanamidCo.(byH. G. Brooks), Ger.Offen. 2,027,791 (1970) [ C A 74,53833 (1971)l. 19’ E.Ziegler, W. Steiger, andT.Kappe,Moiiarsh. Chem. 100,150, 948(1969). 19’Sumitomo Chemical Co.,Ltd(byE. Yamada,K. Sato,M. Sugihara, and K. Ohtake), Japenese Patent 7,404,810 (1974) [CA 81,171355(1974)l. 1 9 2 E. Splth and F.Kuffner, Ber.Drsch.Chem.Ges.71,1657(1938). 1 9 3 E.Spiith andN. Platzer, Ber.Disch. Chem.Ges.68,2221(1935). 194 K. H. Mentzel, R.Putter, andG. Wolfrum, Anyew.Chem.74,839(1962). 195 D. B. Reisner, B.J.Ludwig, E.Simon,T.Dejneka, andR. D. Sofia, Arzneim-Forsch. 27, 766(1977); Carter Wallace Inc. (byD. B.Reisner, B.J.Ludwig, and F.M. Berger), Ger. Offen. 2,149,677 (1972) [CA 77,34562 (1972)l. 19’ J.Bergman, B. Egstad, andJ.0. Lindstrom, Tetrahedron Lert., 2625(1977). lS7

lS8

Sec. III.C]

157

ISATOIC ANHYDRIDE

peg-9-en-8-one (Spathnumbering) s 153l 93]. Similar results wereobtained 32 (Eq.3).64-68 with sulfinamide anhydride

(151)R = alkyl, aryl

R 2 = aryl, CN, CO,Et,H 0

0

0 (152)Courupitine A

(153)Peg-9-en-8-one

B. THIOAMIDES Thioamides (150;X = S) react withI A inbetter yield tothe quinazolones (151;R = CH2Ph,R2 = H)wasobtained 151 90 [the alkaloid glycosminine (cf. Eq.1 )andthioacetamide form inthis way)(Eq.16)].N-Methyl1A (24) (154; R = Me) 90; withphenylacetothioamide thealthealkaloid glomerin kaloid arborin (155;R = CH,Ph)was obtained (Eq.17). Recently, the of thesealkaloids was repeated using sulfinamide anhydride synthesis (32)64,67 instead ofI A .

0

Me (154) Glomerin: R = Me

(155) Arborin: R = CH2Ph

C. HYDRAZIDES I A withacylhydrazines (156)yields 157,whichcondenses withortho esters oraldehydes tothequinazolones 158. 97,Sulfuric 98 acidcyclizes Nacetyl-N-methylhydrazine (156)tothequinazolone 159.197 Polyphosphoric 19

N. P.Peet, S.Sunder, and R. J.Cregge, J .Urg.Chem.41,2733(1976). E.Tietze, F.Hoffmeister, andW. Wirth), British Farbenfabrik BayerA. G.(byS.Petersen, [ C A 60,4162(1964)l. Patent 932,680 (1964)

158

[Sec. I1I.C


-

0 0 R 1a C - N H II - N R 3 - C - R zi1

0 I1

IA’s+ R2-C-NR3NH2 (156)

NHZ (157) (R’

=

R’

=

Me

(W

(159)

(158)

SCHEME 25

acidand 157 were reported to yield tria~epines’~~; however, others have shown thattheproducts areoxadiazoles 160,confirming theformation of theintermediates 157200-202 (Scheme25). Ringclosure of157withCS2 or 0

157

I.cs, or KSCN

2. H f

H0

R’

&xNH-c\R2

(R’ = H )

H

1

POCI,

(163)

SCHEME 26

AmericanHome Prod.Corp.(byA. L.Langis), U.S.Patent 3,542,767 (1970) [CA 74,88089 (1970)l. M. Takahashi, S.Onizawa,and T. Satoh, Bull.Chem. SOC.Jpn.47,2724(1974). BASF A. G. (byP.Dimrothand W. Lotsch). Ger.Offen2,432,838 (1976) [ C A 84,137207 (1976)l. ’ 0 2 BASF A. G. (byP.Dimroth, H. Scheuer, H. Junge, and W. Kurtz), Ger.Offen. 2,417,217 (1975) [CA 84,61177(1976)l. lg9

Sec.111. D]

159

ISATOIC ANHYDRIDE

KSCN formsthequinazolones 161,whichwithPOCl,givethiadiazoloquinazolinones 162.203 Cyclization of157 withHN02 formsbenzotriazin98.204 (Scheme26). ones(163)’

D. AMIDINES IA andamidines (163) givequinazolinones 164187,205-207 (Eq.18). Amidrazones(166) withIA giveseven-membered triazepines (169).200 With ami168isobtained, whichiscyclized by formaldehyde doximestheintermediate

&z: 0

R’-C RNR ’NHR

+

IA

(165) X = OH (166)X= NH2

\

lH*

S.K . Modi,V. Kumar,and K. S.Narang,IndiunJ. Chem. 8,710(1970). HoechstA. G.,British Patent1,429,339 (1976) [CA 85,63095(1976)l. ’O’ Hisamitsu Pharmaceutical Co.,Inc.(byT. Hisano, M. Ichikawa, H. Ide,K. Noda,A. Nakagawa,and T.Motomura), Japanese Kokai73/62, 772(1973) [ C A 79,146542(1973)l. * 0 6 K. Nagahara, K. Takagi, and T.Ueda,Chem. Pharm.Bull. 24,1197(1976). ’O’ M. Takahashi, S.Onizawa, and R. Shioda, NipponKagakuKaishi8,1259 (1972) [ C A 78, 72078(1973)l. ’03

*04

160


[Sec. 1II.E

tothequinazolinone 170.207 Treatment of 168withacidorbasecatalyst (171)208-210 (Scheme 27). gives oxadiazoles

E. UREAS,THIOUREAS, AND CYANAMIDES Ureasandthioureas react withIA (1and24)toformquinazolinediones R’ = H,R = (172).97,21’ Inthis way thealkaloid glycosmicin(172; was synthesized. Cyanamidesand IA yieldthe2-aminoquinazolinones 173212;with acylureas thequinazolinones 174wereproduced2’ 3 - 2 1 6(Scheme

(173)

(174)

SCHEME28 BASF A. G.(byH. Junge, W. Kurtz, P.Dimroth. and H. Scheuer). Ger.Offen. 2,457,687 [ C A 85,95739(1976)l; BASF A. G. (byW. Kurtz, D. Horn,andW. Diller), Ger. (1976) Offen. 2,721,955 (1978) [CA 90,105613(1979)l. ’ 0 9K. Nagahara, K. Takagi, andT.Ueda,Chem.Pharm.Bull. 23,3178(1975). 210 H. L.Yaleand E. R. Spitzmiller, J .Heterocycl. Chern.15,1373(1978). * 1 1 W. Steiger, T. Kappe,and E.Ziegler, Monatsh.Chem. 100,528 (1969). 2 1 2 E. Ziegler, W. Steiger, and T. Kappe,Monatsh.Chem.99,1499(1968). 2 1 3 Sumitomo Chemical Co.,Ltd(byE.Shigaru, K. Satoh, andG .Suzuki), Japanese Patent [ C A 81,65222(1974)l. 7,332,409 (1973) 2 1 4 Sandoz Patent GmbH (byW. Koch), Ger.Offen. 2,447,878 (1975) [CA 83,116962(1975)l. 2 1 5 SandozLtd. (by W. Koch), Ger.Offen. 2,306,843 (1973) [CA 80,49260(1974)l. 216 Sandoz WanderInc. (byW. Koch), U.S.Patent 4,007,188 (1977) [CA 86,173073(1977)l. 2"*

Sec.III.F]

ISATOIC ANHYDRIDE

161

c:

28). Semicarbazide gives 3-aminoquinazolinedione (175).76*207 Reaction of I A withguanidine formsthediquinazolone 177207and withcyclic ureas (Scheme29). quinazolones (178)are suchas176 tetracyclic

F. ISOTHIOUREAS Isothioureas (179)heatedwithI A in aqueousmediagivequinazolinediones (180).212 Heating indrysolvents (e.g. DMF) leads toquinazolinones 18 1,212,218-222182 2 1 1 , 2 2 3or183 2 1 1 9 2 1 2 , 2 2 0(Scheme 30).Cyclic isothioureas (184)yield imidazo ( n = 1)or pyrimido ( n = 2) -quinazolones (185).2 2 7

G.E.Hardtmann, B.S.Huegi, J.H. Gogerty. L.C.Iorio, andW. H.Barnes, J .Med.Chem. 14,878 (1971). I8 SandozWanderInc. (byG. E.Hardtmann), U.S.Patent 4,020,062 (1977) [CA 87,35039 (1977)]. 19 Sandoz WanderInc. (byG. E.Hardtmann), U.S.Patent 3,963,453 (1976) [CA 84,164,832 (1976)]. 2 2 0 G. M. Coppola, G. E. Hardtmann, and0. R.F lister, J .Org.Chem.41,825(1976); G. M. Coppolaand G. E. Hardtmann, J . Heferocycl. Chew.16,1605(1979); SandozInc.(by U.S. Patent 4,117.137(1978) [CA 90,54834 (1979)l. G. E.Hardtmann), G.E.Hardtmann, G .Koletar, 0. R. Pfister, J . H . Gogerty, andL.C.Iorio, J .Med.Chem. 18,447 (1975). 2 2 2 G. M. Coppola, J .Heterocycl. Chem. 15,645 (1978). 2 2 3 SandozWanderInc. (byG. E. Hardtmann), U.S.Patent 3,959,279 (1976) [CA 85,78159 (1976)].

162


R

R

R’dA +

R

NHR~ R3N/c--SR4 I

0

(186)

SCHEME 31

[Sec. 1II.F

Sec.IKG]

ISATOIC ANHYDRIDE

163

Recently, this reaction was usedtoprepare a numberofpharmaceutically active triandtetracyclic quinazolinones ( e g 186221)212~2’7~2’8~220,22 , (Scheme 31).

G. Q-AMINO ACIDSAND

Q-AMINOKETONES

cx-Aminoacids(187)( g l ~ c i n e glycine , ~ ~ ’ ethyl . ~ ~ e~ ~ t e r ,and ~ ~ ~ * ~ N-substituted glycine esters242.245) undergo ringclosures withIA resulting SandozWanderInc. (ByG. E. Hardtmann), U.S.Patent 3,969,506 (1976) [ C A 86,5485 (1977)J 2 2 5 Sandoz WanderInc. (ByG . E.Hardtmann), U.S.Patent 3,978,059 (1976) [CA 86,29867 (1977)]. 2 2 6 Sandoz WanderInc. (byG. E. Hardtmann), U.S.Patent 4,013,646 (1977) [ C A 87,23325 3,975,386 (1976) [ C A 86,5487(1977)l; U.S.Patent 3,868, 372(1975) (1977)l; U.S.Patent [ C A 83,28269(1975)l. 2 2 7 T.Jen, B.Dienel, H. Bowman,J.Petta, A.Heet, andB.Loev,J .Med.Chem.15,727(1972). 22n SandozWanderInc. (byG . E. Hardtmann), U.S.Patent 4,025,511 (1977) [ C A 87,85044 (1977)]. 2 2 9 Sandoz WanderInc. (byG. E.Hardtmann), U.S. Patent 3,963,720 (1976) [ C A 85,160146 (1976)]. 2 3 0 SandozLtd. (byG. E. Hardtmann), Ger.Offen. 2,257,376 (1973[ C A 79,42540(1973)l. 2 3 1 Smith Kline andFrench Lab.(byT.Y. JenandB.Loev), U.S.Patent 3,745,216 (1973) [CA 79,92273 (1973jl; SmithKline Corp.(byD.W. Blackburn, R.F.Devenney, andT.Y.Jen), U.S.Patent 3,790,573 (1974) [ C A 80,83038(1974)]. SandozLtd.(byG. E. Hardtmann), Ger.OtTen. 2,319,851 (1973) [ C A 80,27284(1974)l. 2 3 3 SandozWander Inc. (byG . E. Hardtmann), U.S.Patent 3,772,230 (1973) [ C A 80,59956 (1974)]. 234 SandozLtd. (byG. E.Hardtmann), Ger.Offen. 2,402,454 (1974) [ C A 81,120678(1874)l. 2 3 5 Sandoz WanderInc. (byG. E.Hardtmann), U.S.Patent 3,919,210 (1975) [CA 84,59548 (1976)]. 2 3 6 Sandoz WanderInc. (byG . E.Hardtmann), U.S.Patent 3,912,731 (1975) [CA 84,74299 (1976)]. 2 3 7 SandozLtd. (byG. E.Hardtmann), US. Patent 3,894,022 (1975) [ C A 83,164225(1975)l. 2 3 8 G. E. Hardtmann, U.S.Patents 3,875,160, 3,875,161 (1975) [ C A 83,79274(1975)l. 2 3 9 Sandoz Ltd.(byG. E. Hardtmannj, SouthAfrican Patent 7,302,111 (1974) [ C A 83,97352 (1975)l. 2 4 0 A. Ermili andG . Filacchioni. Ann. Chirn. ( R o ~ I59. K )770(1969). 2 4 ’ American Home Products Corp.(byD. H. Kim),U.S.Patent 3,925,361 (1975) [CA 84, 105665(1976)l. 242 D. H. Kim,J .Heterocycl. Chem.12.1323(1975). 2 4 3 American Home Products Corp.(byD. H. Kim),U.S.Patent 3,904,603 (1975) [CA 83, 193413(1975)l. 244 J.H. Gogerty, R.G .Griot, D. Habeck. L.C lono, andW. J.Houlian, J .Med.Chem.20, 952(1977). 2 4 5 P. M. Carabateas and L. S . Harris, J .Med Chem.9,6 (1966).

224

"’

164

&jRi

[Sec. 1II.G


R &))o

NHR

CHR

R

CO,R*+

R

R

RU l ; N H - C H 2 - - C

0

II -Ph A

inbenzodiazepines (188).Cyclic a-amino acids ( p r ~ l i n ehydroxypro,~~~- ~~ N- andS-ring systems249,254*255) give thecorrespondline,249*253 andrelated [I=; R2-R3 = (CH2)3, CH(OH)CH,CH,, ingtricyclic benzodiazepines (189)and IA react CH2SCH2,and many others]. o-Aminoacetophenone on heating tobenzodiazepine 191256J57 (Scheme toform190,whichcyclizes

32).

246

247

Sterling Drug Inc.(byP. M. Carabateas), U.S.Patent 3,860,600 (1975) [CA 83,58892

(1975)].

AmericanCyanamidCo.(byW. B. Wright), Ger.Offen. 2,513,417 (1975) [CA 84,59602

(1976)].

AmericanCyanamidCo.(ByW. B. Wright), U.S.Patent 3,947,408 (1976) [CA 85,46771 (197611. 249 Sterling Drug Inc.(byP. M. Carabateas), US. Patent 3,732,212 (1973) [CA 79,42570 (1973)]. 2 5 0 American CyanamidCo.(byW. B. Wright), U.S.Patent 3,968,230 (1976) [CA 85,112758 (197611. 2 5 1 American CyanamidCo.(By W. B. Wright), U.S.Patent 3,984,562 (1976) [CA 86,55500 (1977)]. 2 5 2 W. B. Wright, U.S.Patent 3,985,732 (1977) [CA 86,29897(1977)J 253 Fujisawa Pharmaceutical Co.,Ltd.(byK. Karigomeand H. Yazawa), Japanese Patent 74/25,277 (1974) [CA 82,140192(1975)l. 2 5 4 W. B. Wright, H.J.Brabander, E.N. Greenblatt, I.P.Day,andR.A. Hardy, J. Med.Chem. 21,1087(1978). 2 5 5 R. B.Stevens, R. M. Corey, andS. Rossens, J.C.S., Chem.Comm., 742(1975). 2 5 6 F.P.Woerner, H. Reimlinger. and R. Merenyi, Chem.Ber.104,2789(1971). 2 5 7 A. A. Santilli andT. S.Osdene, J. Org.Chem.29,1998(1964). 248

Sec.III.H]

( 1 )R = H (24) R = Me (R = M e )

R’

165

ISATOlC ANHYDRIDE

I

(193)

(192)

4

0

CO -NH NHMe HO,C

R’

H. OTHER CARBOXYLIC ACIDDERIVATIVES Alkyl-and aryl-substituted carboxylic acidderivatives suchasethyl 4methoxybenzoate, diethyl phthalate, O 4 aryland alkylcarboxylic acidhaO T 2 ’ *give benzoxazinones (193). When I Awasbrominated lides oranhydrides’ 193 (R2 = CHBr,)was obtained.2s9 Anthranilic acid inglacial acetic acid, (4)withN-methyl IA (24)leads to194,whichcyclizes insulfuric acidtothe benzoxazinone 19s34 (Scheme33).Reaction of N-formylanthranilic acid (196) (available fromIA and formic acid) withIA againyields thequina19710-260 (Eq.19). zolinone 0

IA-tHCd

’OH

0

CO,H

NH -C\

(196)

IA

4

+

H (197)

SherwinWilliamsCo. (byR. L. Jacobsand R. L. Hively), Ger.Offen.2,556,590 (1976) [CA 85,160115(1976)l. 2 5 9 R. Bertelson and W. Becker, J.Heterocycl. Chem. 3,422(1966). z60 R. Anschiitz and 0.Schmidt, Ber.Drsch.Chem.Ges.35,3470(1902).

258

166


[Sec. 1V.A

IV. Reactions ofIsatoic AnhydridewithC=N DoubleBonds Carbon-nitrogen doublebondsystems suchasazomethines orheterocurnulenes react withIA withloss ofC 0 2 .Formechanistic considerations seeSection 1,C.

A. AZOMETHINES Treatment ofIA withazomethines leads to 1,2-dihydroquinazolinones

(198).261*262 W ithcyclohexanone anil (199), a spiro compound(201)isobtained; however, five-, seven-, and eight-membered anils (200)gaveonly (202)262 (Scheme34).Benzoxazole (203)andIA do not quinazolinediones formtheexpected tetracyclic adduct 204,butyield thequinazolinone 20598 by ring opening (Eq.20). 0

0

*" 262

0

R. P.Staiger, C. L. Moyer,and G. R. Pitcher, J. Chem.Eng. Data8,454 (1963). W. Steiger, T.Kappe, and E.Ziegler, Monatsh.Chem. 100,146(1969).

Sec.IV.B]

ISATOIC ANHYDRIDE

167

B. HETEROCUMULENES Arylisocyanates and isothiocyanates withI A givethequinazolinones 206.261,263 Carbodiimides (207) yield either theaminoquinazolinones 208 (from IA) ortheiminoderivatives 209(from N-substituted IA) (Scheme 35).

(208) R =H

(209)R # H SCIIEME 35

263

K. Srivastava, IndianJ .Appl.Chem.34,113(1971); C.Wang,T.C.Feng, andB.E.Christensen, J .Am. Chem.SOC.72,4887 (1950).

168

[Sec. V


V. Reactions ofIsatoic Anhydride withCarbanions Compoundscontaining active methylene groupsadjacent to carbonyl derivatives. Staiger and MillerE3 obtained react withIA togivequinoline thequinoline 211(R2= Me)byreaction ofIA withsodiumethyl acetoacetate (210). Thisreaction wasextended toother 1,3-dicarbonyl compounds yielding to 211.2209264*26s either thequinolones 212,forR = H can tautomerize Nitroacetate furnishes 215.220*266 o-Fluorobenzoyl acetate (214) wasshown togivea product whichringcloses againtoformthebenzopyranoquino36). Malonic acidesters givecarbostyrils (216)2203 linedione 214267 (Scheme R’

0

lR

mz2Et I::-n:,.

R’

or

R

\

9.

RZ

(212) R #H

CO-CH-COZEt

R

R\ ~

I

:

2

Me

L.A. Mitscher, H. E.Gracey, G.W. Clark, andT.Suzuki,J .Med. Chem.21,485(1978); L. A. Mitscher, D.L.Flynn, H. E.Gracey, andS. D.Drake, $id.22,1354(1979). 2 6 5 M. R. Bell, A. W. Zalay, R. Oesterlin, P.Shane, andG. 0. Potts, J .Med.Chem.13,664 (1970); Sterling DrugInc. (byR. M. Bell), U.S.Publ. Patent Application B 402,162 (1976) [CA 85,46425(1976)l. SandozPatent GmbH (byG.E.Hardtmann), Ger.Offen. 2,631,317 (1977) [CA 86,189742 (1977)l. *" SandozWanderInc.(G.E.HardtmannandG.M. Coppola), US.Patent 4,017,499 (1977) [CA 87,39454(1977)l; G. M. CoppolaandG. E. Hardtmann, J .Heferocycl. Chem. 16, 829(1979). 264

Sec.V]

R’

169

ISATOIC ANHYDRIDE

OH

(217)

R’

BH

(218)

SCHEME37 64*2 8p2 ’ ;malonodinitrile yields the2-aminoquinoline 217.2 O 7 9 2 O2T 2 Ethylisocyanoacetate reacts withIA to giveoxazoloquinolinones (218), whichsuffer ringcleavage withHCl togive3-amino-Chydroxycarbostyrils (219)’9*220,274 (Scheme37). Sulfonylmethylene compoundssuch as methylsulfonylacetate (220; R2 = Me, R3 = OEt)orphenylphenacyl sulfone (220;R2 = R3 = Ph)give withN-substituted IA thecorresponding 4-hydroxy-3-sulfonyl-2-quinolones

D. R. Shridar, C .V. ReddySastry, A. K. Mehrotra, C .Seshagiri Rao,and V. Taneja, Indian J .Chem.,Sect. B 17,488 (1979). 269 Sandoz Ltd.(byG. E.Hardtmann), Fr.Demande2,205,327 (1974) [CA83,147400 (1975)]; Ger.Offen. 2,706,752 (1977) [ C A 88,6753(1978)l; Ger.Offen, 2,354,145 (1974) [CA 81, 37488(1974)l. 2 7 0 CibaGeigyA. G (byP.G. Ferrini, G. Haas,and A. Rossi), SwissPatent 578,536 (1976) [CA 86,29659(1977)l. 2 7 ’ L. A. Mitscher, G. W. Clark, T.Suzuki, and M. S.Bathala, Heterocycles 3,913(1975). 2 7 2 SandozInc. (byG. E. Hardtmann), U.S.Patent 4,119,720 (1979) [ C A 90,54843(1979)]. 2 7 3 S.B. KadinandC. H. Lamphere, Synthesis, 500(1977); P k e rInc. (byS . B. Kadin). Ger. Offen. 2,801,248 (1978) [CA 89,146784(1978)l. 2 7 4 M. Suzuki, K. Matsumoto, M. Miyoshi, N. Yoneda,and R. Ishida, Chem.Pharrn.Bull. 25,2602(1977); TanabeSeiyaku Co., Ltd,(byM. Miyoshi, N. Yoneda,K. Matsumoto, Japanese Kokai77/46,085 (1977) [ C A 87, 135110(1977)]. and M. Suzuki),

170

dlomrzRz T. KAPPE AND W. STADLBAUER

R’

R’

[Sec.V

OH

R’ --SO2 (R’ =Ph. -cH OEt) -COR’*

(220)

R

(221) R2

= Me. Ph

221.’93220Reaction of thecarbanion 222 results in theformation of the 223,whichon treatment withacids ornitrosobenzene is acetophenone ylid 224 or225.275Ringclosure of223 with converted totheindole derivatives orthoesters yields thequinolones 226275*276; withcarbondisulfide 227 is ofIA withdimsyl sodium(228)leads obtained275 (Scheme38).Treatment to229,fromwhichwithaldehydes thequinolinones 231 are~ b t a i n e d . ~ ~ ~ 232,277and withcarboxyReaction withH N 0 2 leadsto thecinnoline A. M. van Leusenand E. C. Taylor, J .Org.Chem.33,66 (1968). R. Albrecht, Chim.Ther.8,45 (1973). 2 7 7 M. von Strandmann, S.Klutchko, M. P. Cohen,and J. Shavel, J .Helerocycl. Chem.9, 173 (1972); Warner LambertCo. (byM. von Strandmann, J. Shavel, S. Klutchko, and U.S.Patent 3,798,219 (1974) [ C A 80,146187(1974)]. M. Cohen), 275 276

Sec.V]

ISATOIC ANHYDRIDE

171

methylene triphenylphosphorane (230)thequinolinone 233 isformed278 (Scheme 39). Two novelroutes forthepreparation ofindigo starting withIA havebeen (Scheme39)dimsylsodiumand developed r e ~ e n t l yAs. just ~ described I A yield 229,whichcanbe converted, via235 ordirectly, toindigo (237)in 39% yield. A moresatisfactory yield (77%)ofthePummererrearrangement acetylated in benzeneto 234. was observed when 229 (R = H) was first Indigo was alsoobtained by a Nef reaction from236,whichisavailable anionfollowed by a ~ e t y l a t i(Scheme o n ~ ~40). fromIA and nitromethane Quinolinonephosphonic esters (239)areisolated fromthereaction of I A withcyanomethyl phosphonate (238).220*280 Withbutyrolactone phosphoIA (1;R = H) thebenzoxazine 241isobtained. nate(240)andunsubstituted 240 and N-substituted I A ina sealed tubewithbenzenesolvent Heating 242,whilea DMF solvent formsthefuroquinoline yields thebenzoxazine 243,alsoavailable from242 by rearrangement inDMFZ8l (Scheme41). The phosphonium ylid244 giveswithIA a quinoline phosphonium ylid (245). *With pyridinium esterbetaines (246),the formation of the M. von Strandman, D. Connor, andJ.Shave], J. Heterocycl. Chem.9,1975(1972). Helu.Chim.Acra60,1980(1977); Ger.Offen. 2,658,306 (1978). 2 8 0 Sandoz Inc. (byG. E.Hardtmann andG. M. Coppola) U S .Patent 4,070,468 (1978) [CA 88,136468(1978)l; U.S.Patent 4, 124,588(1978) [CA 90,87664(1979)l. T.Minami,M. Matsumoto, H. Suganuma, andT.Agawa,J. Org.Chem.43,2149(1978). 2 8 2 D. T.Connorand M. von Strandman, J.Org.Chem.38,1047(1973). 278

2 7 9 J.Gosteli,

172

[Sec. V


IA

MeSOCH

1. C

H~NO~

2.Ac,O

’ I

0

II

C-CHINOz

229(R= H) 234(R = Ac)

ii i

i

v

+

NH-COMe 0

Sec.V]

173

ISATOlC ANHYDRIDE

& H

H

0-

0R (252)R2 = H,CHzOH

R

R

(253)

(254)

SCHEME43

174

[Sec. VI

T. KAPPE A N D W. STADLBAUER

pyridinium ylid 248 isobserved,283 whilewithethyl 2-pyridylacetate (247) theisomer 249 isformed283 (Scheme 42).2-Picoline-N-oxide (250)andI A furnish theacetophenone 251,284whichisprecursor ofheterocycles 252, withformaldehyde, orthoformate, or HNOzZs5 253, and 254, obtained (Scheme 43).

VI. Miscellaneous Reactions IA andhydrogen sulfide react toformtheisatoates 255andtheir decar1,286-288 Oxidation of256 withiodine or boxylated products 256.110* H202286*287 leads tobenzoisothiazolinones (259). Treatment of256 with benzothiadiazinone (258), l 1 which isoamyl nitrite orHNOz produces

IA s + HS-

-

0

0 __.*

(255)

(256)

0

M. Hariri, Ph.D.Thesis, University ofGraz,Austria (1976); T. Kappe,M. Hariri, and E.Pongratz, Monatsh. Chem.(inpress). 284 D. T.Connor, P.A. Young,andM. von Strandman, J. Heterocycl. Chem.14,139 (1977). 2 8 5 D. T.Connor, P.A. Young,andM. vonStrandman, J. Heterocycl. Chem.14,143 (1977). 18 A. H. Albert, R. K. Robins, and D. E.OBrien,J .Heterocycl. Chem.10,413 (1973). A. H. Albert, D. E. OBrien,and R. K. Robins, J .Heterocycl. Chem.15,529 (1978). 288 J.Faust andR. Mayer,J. Prukt. Chem.318,161 (1976).

Sec.VI]

175

ISATOIC ANHYDRIDE

hasbeenshowntodecompose either viaan arynemechanism (trapped as orviaa mixture of aryne(257) andB-thiolactone (260) (orthe trypticene) isomeric ketene 261), forming various dimers, adducts, andrearrangement products’ l o , l l(Scheme l 44).N-Phenyl IA and thiophenates react togive anthranilic acidthioesters (2621, which undergointramolecular photoFriedel-Crafts reaction togiveacridone (263)"(Eq.21).Friedel-Crafts 0

hv

Ph

NHPh SNa (262)

0

(263)

acylation of benzeneby I A yields benzophenones (264),289 whichcan IA be cyclized withacetylenedicarboxylate toyield thequinoline 265.290 andsodiumazide inDMF give viaCurtius rearrangement thefive-membered (Eq.22). benzimidazolone (266)291 CO,R

0

c

Ill

Ph

&co2R

C,H,,AICI,,

CO2R

(264)

(265)

H S.Statham, J. Chem. SOC., 213 (1951); B. K. Misra,Y. R. Rao,and S.N. Mahapotra, IndkrnJ. Chem.,Sect. B 18,19 (1979); Sumitorno Chem.Co.,Ltd.(byM. Akatsu, M. Yamamoto,K. Ishizumi, Y. Kume, M. Koshiba, s.Inaba,and H. Yamamoto),JapaneseKokai 72/34352 (1972) [CA 78,43047 (1972)l. 2 9 0 E. C. Taylor and N. D. Heindel, J.Ory.Chem. 32,1666(1967). S.Marburgand P.A. Grieco, Telrahedron Lett., 1305(1966).

289

176


[Sec. VI

Reaction of N-haloalkyl IA (267)withaminesdoesnotstopatthe anthranilamide step. Witha fourorfive carbon chainthecorresponding 268 areobtained. When N-bromopyrrolidinyl orpiperidinyl benzamides ethyl IA (267;n = 2)was treated withmethylamine, thebenzoxadiazonine (269)wasformed, by trapping thecarboxylate anionofthering ring system openedIA instead ofC 0 2 loss, followed by a rearrangement step. With dimethylamine theelusive intermediate oftheformer reaction, theoxazol270, was synthesized. Surprisingly, treatment withammonia also idine 271andnotthering system of269.Thepossibility ofanalternative afforded mode ofreaction withdimethylamine orammoniaviao-uramidobenzoic acids to yield a seven-membered ringsystem, was excluded by spectral 45). data292 (Scheme

l R( zn = N H21 z

\NH

(270)R = Me (271)R = H

SCHEME 45

2-Isocyanatobenzoyl chloride (33;cf. Eq.6)fromIA andSOCl,,COCl,, usedasa reactive IA intermediate, orPCl,(Section 1,B) was a mixture ofquinazolines (46)andbenzoxazines (272)when reacted giving 33 dimerizes readily toquinwithprimary a m i n e (Eq. ~ ~ 23). ~ .Compound ~ ~ (273)79 and undergoes thesamereactions asIA with azolinobenzoxazine (274)or substituted andunsubstituted hydrazines togivebenzotriazepines 3-aminoquinazolines (17s;cf. Scheme8).76 2-Aminothiophenol treated with 33 furnishes 275,andwitho-phenylenediamine 135 (cf. Scheme23;n = O).71 292

S.Barcza, G .M . Coppola,and M. J. Shapiro, J.Heterocycl. Chem. 16,439(1979).

Sec.VI]

177

ISATOIC ANHYDRIDE

H

(33)

(46)

An analogous compound(276) wasobtained with1,8-diaminonaphthalene 46). (Scheme

\

33

\&

NH2 NH,

.

I35 ( I 1 = 0)

Reaction ofIA withaziridine inthepresence ofhydrogen sulfide leads to theunstable intermediate 277,whichproduced thethiazoloquinazoline 278 24).293 Ringopening ofIA totheanthranilate withethyl chloroformate (Eq. 293

N. Kaur,I.Singh, andH. Singh, IndianJ .Chern.1,308(1963).

178

[Sec. VI


0

279 followed by a Grignard reaction tothealcohol 280 gives thecinnoline 282 by subsequent dehydratation anddiazotization (Eq. 25).294 N-Methyl-IA

IA

-

OH

R

MeOH HCI

R

WN ’ ’ Me I

@="’;

Me I

(25)

N~NO,

NH,

N’

(24)reacts withdiethyl sodiophosphonate (283)togivedimethyl isoindigo

Whileacylations ofIA withcarboxylic, sulfonic, orphosphoric acid 285 yields chlorides werenotsuccessful, reaction withthesulfenyl chloride Indolylmagnesium bromide (287) andIA givethe theN-acylated IA 286.296 288,whichundergoes cyclization withaqueous hydrochloric anthranilamide acidtogivetheindoloquinazolone 289 (Scheme47).297

VII.AppendixAdded inProof Since theoriginal preparation ofthis review, additional reports havebeen published whichgivefurther information on thechemistry ofIA’sandtheir usesinheterocyclic synthesis. Thisappendix extends thereferred literature, R. N. Castle. K. Adachi, andW. D. Guither, J .Heterocycl. Chem.2,459 (1965). T.Minami,M. Matsumoto, andT.Agawa,J.C.S., Chem.Commun.,1053(1976). 296 H. R. Kricheldorf, Angew.Chem.85,86(1973). 29’ E.E.Garcia, A. Arfai, andR. I.Fryer, J .Heterocycl. Chem.7,1161(1970).

294

z95

Sec. VI]

ISATOIC ANHYDRIDE

179

and reports whicharesimilar topreviously described reactions areaddedto theparticular references. In themeantime, a reviewby G. M. Coppolaon hasappeared.298 allaspects ofIA chemistry G .M. Coppola, Synthesis, 505(1980)

180

[Sec. VII


Thephenylhydrazone ofIA (291), whichisnotavailable fromIA directly, oftheisatin 290 inthepresence of was syntherixed viaa ringexpansion CuCl,(Eq.~ 6 ) .Reaction ~" oftheamino-substituted anthranilic hydrazide 104 withdimethyl acetylenedicarboxylate leads tothepyrazoloquinazolone N-NHPh

293 viathehydrazone 292 (Eq.27),300 incontrast totheresults obtained 104 (cf. Scheme19). Dilithioacetophenone oxime withamino-unsubstituted C0,Me

r

(294)was condensed withI A s togivetheenols 295,whichcyclize tothe 296 withsodiummethoxide (Eq.28).301 When reacted with quinolinoles IA afforded anthraniloyl anthranilamide (297),which anthranilamide, undergoes cyclization withHNO, togivethetriazinone 298,whichcanbe

E.Sayed, H. E.Ashry, andY.E.Kilany, Indian J .Chem.,Sect. B 16,1036(1978). C.F.Beam,J.Brown,D.R.Dawkins, W. P.Fives, andN. D.Heindel, J .Heterocycl. Chem. 16,957 (1979). 30’ J.Brown, K. L.Sides, T.D.Fulmer, andC.F.Beam,J.Heterocycl. Chem. 16,1669 (1979).

299 300

Sec.VII] NOLi

OH

I/

R

181

ISATOIC A N H Y D R I D E

C

o c \ C H 2 L i

NaOMe

I1

k:;HL0

R-

N

/

\ (294)

R

(296)

(295)

(28)

usedas o-aminobenzoylating agent. Treatment withbasesyields therearrangement product 299(Eq.29).302 0

0

(298)

NH2

(299)

Lactimethers andthioethers (300) furnish condensed quinazolones 301 when interacted withIA.303 Ringopeningof IA sto thecorresponding anthranilic acidsand reaction of itspotassium salts withchloroacetone 302.304 Potassium cyanide withN-substituted IA s yields 2-indolyl ketones produces iminoindolinones 303,whichwere readily hydrolyzed to the of 303 to thespiroindoloquinazoline corresponding isatins.jo5 Reaction 304 takes place when KCN istreated withexcess IA (Scheme 48).jo6 When F.D. Eddy,K. Vaughan, andM. F.G.Stevens, Can.J. Chem.56,1616(1978); C.Hinman andK.Vaughan, Synthesis 719 (1980). 303 K. Bhandan, V. Virmani, V. A. Murti, P.C.Jain, andN. Anand,Indian J .Chem., Secf. B 17,107 (1979). 304 P.C. Unangst, R. E. Brown,A. Fabian, and F. Fontstre, J .Heferocycl. Chem. 16,661

302

(1979).

305 306

G .M. Coppola, J. Heferocycl. Chem.16,827 (1979). G. M. CoppolaandR. E. Damon,J .Heferocycl. Chem.16,1501(1979).

182

[Sec. VII


\OH-

(301) X = O,S,NR Yz = S,CHz 0,s

2 CI-CH,-COCH,

\ R’

KCN

v

R’

R’

glycine isallowed toreactwithIA’satlow temperature, thehippuric acid 305 isisolated, whichcyclizes at elevated temperatures yielding benzodiazepinediones 306 (Eq.30).307

0 R’

IA’s

NH,-CH,-CO,H+

CO-NH-CH2COzH NHR

R

(305)

’07

@?

M. Gates,J .Org.Chern. 45,1675 (1980).

(306)

(30) O

ADVANCES

IN HETEROCYCLIC

CHEMISTRY

.VOL

ZX

Reactions ofBenzyne withHeterocyclic Compounds MARTIN R . BRYCE AND JOHN M .VERNON Department of Chemistry. Uniuersitv of York. Heslington. York.England

I. Introduction . . . . . . . . . . . . . . . . . . . .. 183 . . I1.MethodsofBenzyneGeneration . . . . . . . . . . . . . .. .185 . A . From Halogenobenzenes . . . . . . . . . . . . . . .. .185 . B . Elimination ofStable Molecules from o-Disubstituted Benzenes. . .. . 185 C . Thermal Cleavage ofCyclic Systems. . . . . . . . . .. . 186 . D .Photochemical Methods . . . . . . . . . . . . .. . 187 . . 111.Patterns ofBenzyne Reaction . . . . . . . . . . . . .. . 187 . . A . Open-Chain Additions . . . . . . . . . . . . . .. .. 188 . . B . 1,2-Cycloadditions . . . . . . . . . . . . . . ... .190 . . C . 1,3-Cycloadditions . . . . . . . . . . . . . . .. . 190 . . D . 1,4-Cycloadditions . . . . . . . . . . . . . . .. .. 191 . . E . 1.5-. 1.6-. and 1,8.Cycloadditions . . . . . . . . . . . .. 192 . IV. Reactions withThreeandFour-Membered RingSystems. . . . . . .. 192 V . Reactions withFive-Membered RingSystems Containing One Heteroatom. . 194 A .Furansand Benzofurans . . . . . . . . . . . . . . . 194 . . . . B . ThophenandBenzothiophens . . . . . . . . . . . . . 197 . . . C . Pyrroles. Indoles. andIsoindoles: Naphthalen.1, 4.imines and . . . . . . . . . . . . . . . 200 . . . . Anthracen-9.10-imines D .Silicon andGermaniumHeterocycles . . . . . . . . . . . 205 . . . . VI.Five-Membered RingSystems withTwo orMore Heteroatoms. . . . . 206 A .Heterocycles Containing a FormalDieneSystem. . . . . . . .206 . . CompoundsandHeterocycles without a FormalDime System. . 210 B . Mesoionic VII. Six-Membered RingSystems. . . . . . . . . 214 . . . . A.Azines. . . . . . . . . . . . . . . . . . . .214 ofAzines. . . . . . . . . . . . .217 . . . B . HydroxyDerivatives . . . C . ReducedAzines. . . . . . . . . . . . . . . . . .220 D . RingsContaining Heteroatoms OtherthanNitrogen . . . . . . . 222 . . VIII.Seven-Membered andLarger RingSystems. . . . . . . . . . .224. . N-Oxides. . . . . . . . . . . . . . . . .224 . . . IX.Heterocyclic

.

I Introduction The termbenzyne denotes ortbbenzyne. alsoknown as 1.Zdehydr o. benzene orinChemical Abstracts as1.3.cyclohexadien.5.yne .Thelast name ismisleading, since benzyne lacks two ortho hydrogen atomsofbenzene ofdouble bonds .It butnotthestabilization associated withdelocalization 1-3.Thereisnow a very iscommonlyrepresented by anyofthestructures I83

Copyright @ I Y R I by Academic Press. Inc. Allrights of reproduction ina n y form reserved . ISBN 0-12-0?(628-5

184

MARTIN R. BRYCE AND JOHN M. VERNON

[SecI .

extensive chemistry ofbenzyne and of someofits substituted derivatives analogs of benzyne (arynes) less s2;usehasbeenmade of heterocyclic isknownofmetaandpara-benzyne isomers. (hetaryne~),~ andevenless

(1)

(2)

(3)

Observations oftheUV absorption4 attributable tobenzyne inthevapor phase, evidence fromtime-resolved massspectr~metry,~ andmorerecently ofbenzyne ina matrix atverylowtemperature leave no oftheIR spectrum6 doubtas totheexistence ofsucha transient intermediate. Itslifetime in issupported ona polymer phase.Results solution isextended whenbenzyne ofcompetitive trapping experiments, when benzyne isgenerated fromdifferent precursors, and theclassical experiments ofRoberts etal.on cinesubstitution intheamination of chlorobenzene confirm theformation of benzyne asan intermediate.’^^ Apart fromHoffman comprehensive s treatment oftheliterature to1966, thenumerous previous accounts ofbenzyne chemistry2 have 0* given but scant attention tothereactions withheterocyclic compounds, whichform thebasis forthepresent chapter. We include selective coverage ofrelevant I

lo

R.W. Hoffmann,Dehydrobenzene andCycloalkynes. AcademicPress, New York,1967, in Chemistry ofAcetylenes (H.G.Viehe, ed.), andreferences therein; R. W. Hoffmann, Chapter 16.Dekker, New York,1969. E.K . Fields, in Organic Reactive Intermediates (S. P.McManus.ed.). Chapter 7.AcademicPress, New York,1973. in Chemistry ofAcetylenes (H.G. Viehe, ed.), H.J.denHertog andH. C.vanderPlas, Angew.Chem., Chapter 17.Dekker, New York,1969; T.Kauffmann and R. Wirthwein, Int.Ed.Engl.10,20 (1971). G. N. Spokes, and M. Stiles, J.Am. Chem.SOC.84,3570(1962). R. S.Berry, J.Clardy, and M. E.Schafer, J. Am. Chem.SOC.86,2738(1964). R. S.Berry, 0. L.Chapman,K. Mattes, C.L.Mclntosh, J .Pacansky, G.V.Calder, andG.Orr, J .Am. Chem.SOC.95,6134 (1973); 0. L.Chapman,C.-C.Chang, J .Kole,N. R.Rosenquist, and H. Tomioka, ibid. 97,6586(1975). P.Jayalekshmy and S.Mazur,J .Am. Chem.SOC.98,6710(1976). R. Huisgenand R. Knorr, Tetrahedron Lett., 1017(1963). J.D. Roberts, H. E. Simmons,L.A. Carlsmith, andC.W. Vaughan. J. Am. Chem.SOC. 75,3290(1953); J.D. Roberts, D.A. Semenov, H. E.Simmons, andL.A. Carlsmith, ibid. 78,601(1956). R. Huisgen, in Organometallic Chemistry(H.Zeiss, ed.), Chapter 2. Van NostrandAngew Chem.72,91 Reinhold, Princeton, New Jersey, 1960;R. Huisgenand J.Sauer, J.Chem.Educ.38,278(1961); H. Heaney, Chem.Rev.62,81 (1962); (1960); J.Bunnett, G. Wittig, Angew.Chem.,Int.Ed.Enyl.4, 731(1965). T. L. Gilchrist and C. W. Rees, Carbenes, Nitrenes, and Arynes,Chapter 8.Nelson, Essays Chem.1,95(1970); N. S.Isaacs, Reactive Intermediates London, 1969; H.Heaney, inOrganic Chemistry, Chapter 7.Wiley, New York,1974.

Sec.II.B]

185

REACTIONS OF BENZYNE

reactions ofsubstituted benzynes aswellassomeintramolecular reactions ofparticular interest involving arynes andheterocycles. A related area, the ofheterocyclic products fromreactions ofbenzyne withacyclic formation compounds, ismentioned onlyinpassing.

11.MethodsofBenzyneGeneration Thissection describes themoreimportant methodsby whichbenzyne is generated forcapture by heterocyclic compounds; itisnota comprehensive 1 and2).The account ofallknown routes tobenzyne (for whichseeRefs. ofa variety ofprecursors andconditions forbenzyne generation importance isto provide compatibility withheterocyclic co-reactants havingwidely differing properties.

A. FROMHALOGENOBENZENES The useof sodiumamideor potassium amideinliquid ammoniawith bromo-orchlorobenzene leads inevitably tothecapture ofbenzyne by its reaction withammonia.However, theutility ofbromo-orchlorobenzene asa benzyne precursor isextended toethereal solvent systems by employing secondary amine(diisopropylamine, 2,2,6,6theconjugate baseofa hindered tetramethylpiperidine) whichcan be formedin situfromtheamineand alkyllithium. Alternatively, butyllithium itself isusedwiththehalogenobenzene, andpentafluorobenzene andbutyllithium aretheusualsource of tetrafluorobenzyne. In allof thesereactions thearyneisgenerated by ofano-halogenoaryl anionattemperatures below0 C. decomposition Theformation ofbenzyne viao-FC,H,MgBr fromo-bromofluorobenzene and magnesiumisclosely related inmechanismtothebase-induced eliminations, butthereaction conditions fortheGrignard method(inrefluxing tetrahydrofuran) areoften moreconvenient. Benzyneisalsoproduced from o-bromofluorobenzene andbutyllithium, andhexachlorobenzene istheusual oftetrachlorobenzyne (Eq.1). precursor forgeneration C,CI, + BuLi

-C,CI,Li

C,CI,

(1)

B. ELIMINATION OF STABLEMOLECULES FROM O-DISUBSTITUTED BENZENES Aprotic diazotization ofanthranilic acid, usually withpentyl nitrite, gives benzyneviathereaction sequence showninScheme1.The intermediate benzenediazonium-2-carboxylate (4)isexplosively unstable, butifitisisoa clean source ofbenzyne lated by performing thefirst step at0 Citprovides

186


[Sec. 1I.C

SCHEME1

forreactions on a small scale.Controlled decomposition of4 orofits orchlohydrochloride isaccomplished above40 C,commonlyin ethers rinated solvents atreflux temperature. A majoradvantage ofthis method istheabsence oforganometallic reagents andhenceofstrongly basic conby theisolation ofproducts ditions. Stepwise decomposition of4 isimplied in some caseswhichincorporate thestructure of theintermediate (5). Substituted anthranilic acidsareavailable as precursors forthecorresponding arynes. Thetriazene 6,also derived fromanthranilic acid, ismorestable than4 and cansafely bestored inquantity. Benzyne, carbon dioxide, anddimethylamine areformedby decomposition of6 inchlorobenzene atreflux temperature, orinbenzene at80 Cinthepresence oftrichloroacetic acid.Benzyne isalso produced on pyrolysis of diphenyliodonium-2-carboxylate(7)in various solvents at160-220 C.14

C. THERMALCLEAVAGEOF CYCLICSYSTEMS Theanalog of4 withasulfinate group replacing thecarboxylate exists inthe in solution at 10 Cto givebenzyne, ring-closed form8;itdecomposes ofl-aminobenzotriazole (9) with nitrogen, andsulfur dioxide. Oxidation leadtetraacetate orother oxidants isanother efficient source ofbenzyne via 10.l6 fragmentation oftheintermediate nitrene L.Friedmanand F.M. Logullo, J .Am. Chem.SOC.85,1549(1963); M. Stiles, R.G .Miller, and U. Burckhardt, aid., 1792;L. Friedmanand F.M. Logullo, J .Org.Chem.34,3089 A. H. Seitz, and L.Friedman, Org.Synth., Collecr. Vol. 5,54(1973). (1969);F.M. Logullo, J.Nakayama,0. Simamura,and M. Yoshida, Chem.Commun.,1222 (1970);Chem.Lett.,

l2

l4

Is l6

451 (1973). E.Le Goff, J .Am. Chem.SOC.84,3786(1962); F.M. Beringer andS.J.Huang,J .Org.Chem. r), 445 (1964). G.Wittig and R.W. Hoffmann,Angew.Chem.73,435(1961); Chem.Ber.95,2718(1962); R. W. Hoffmann,W. Sieber, and G. Guhn, aid. 98,3470 (1965). C. D. Campbelland C. W. Rees,J .Chem.SOC.C,742, 752 (1969).

Sec.1111

187


NH2 (9)

(10)

(11)

Benzyne isproduced inthevaporphaseby thefragmentation ofphthalic (11) at690 C, also of4-phenylanhydride andofo-sulfobenzoic anhydride (12), phthaloyl peroxide (13),19anda variety ofother 1,2,3-benzotriazine cyclic systems atappropriately hightemperatures. From thepoint ofviewof studying thereactions of benzynewithheterocycles, these methodsare necessarily restricted intheir application.

D. PHOTOCHEMICALMETHODS Photochemical generation has provedparticularly important forthe I), butitisnot characterization ofbenzyne byspectroscopic methods (Section much usedtostudy thereactions ofbenzyne on a preparative scale. Benzyne ofeither 13 or14.6Flash isgenerated inanargon matrix at8 K by photolysis photolysis of4 wasemployed by Berry etal. toobtain UV andmassspectral ofbenzyne4. ;andphotolysis of1,2,3-benzothiadiazole 1,I-dioxide evidence (8),o-iodophenylmercury derivatives, andother compounds insolution also serves togenerate benzyne.

111.Patterns ofBenzyneReaction The reactions ofbenzyne arealladditions totheformal triple bond of 1.The variety ofsuchreactions canbe clarified interms ofopenstructure chainadditions andcycloadditions, although theisolated products arein many cases derived fromsecondary decomposition ofsuchprimary adducts. Theisolation orpostulation ofcycloadducts inveryfewcases provides any E.K. Fields andS. Meyerson, Chern. Comrnun., 474 (1965);S.MeyersonandE.K. Fields, ibid., 275( 1966). S.Bradbury, M. Keating, C. W. Rees.and R. C. Storr, Chern.Commun., 827 (1971). G . Wittig and H. F.Ebel, JustusLicbrgs Ann. Chem.650,20 (1961).

188

[Sec. 1II.A

MARTIN R. BRYCE AND JOHN M . VERNON

meaningful evidence abouttheconcertedness ofthecycloaddition step. On thecontrary, a polar two-step mechanism ismorelikely formany ofthese reactions. Thereactions ofbenzyne withheterocyclic compoundsareoften paralleled by reactions ofacetylenedicarboxylic esters.

A. OPEN-CHAINADDITIONS Benzynereacts withcompoundscontaining an X-H bond,wherethe orismade tobe soby deprotonation; this gives an atomX isnucleophilic PhX.A simple example istheformation ofaniline when benzyne is adduct generated inliquid ammonia. Heterocyclic secondary amines (e.g., piperidine) andother heterocyclic compoundscontaining NH groups (e.g., indoles) are converted into thecorresponding N-phenyl derivatives. When benzyne reacts 15 may undergo anintramolecwitha tertiary amine, thefirst-formed betaine ularHofmannelimination (e.g., ifR = Me),oritmay be protonated and suffer displacement ofonealkyl groupfromthequaternary ammoniumion, oraninternal proton redistribution may givetheylid16,whichthendoesa Stevens rearrangement (e.g., ifR = Ph).21 Thesereactions areshownaspaths ofbenzyne withsulfides are a,b,andc,respectively, inScheme2.Reactions similar. R,,

@/CH2

\R (15)

PhNR,

+ alkene

2

Ph

+

N

,CHR

R

R\

Ph/

/ R

N-CH

R

(16)

R \ + / , CH,R N ---+ Ph R

PhNR,or

R\

Ph/

NCH2R

SCHEME 2

Benzynealsoreacts withcompoundscontaining nucleophilic carbon atomssuchasenolates andaryl anions. Intramolecular nucleophilic addition toanaryne bytheortho ring carbon atomofanother benzene ring substituted R. M. Acheson, Ado.Heterocycl. Chem.1,125(1963); R. M. Achesonand N . F.Elmore, ibid. 23,263(1978). 2 1 G. Wittig and W. Merkle,Chem.Ber.76,109(1943); G. Wittig and E. Benz,ibid. 92,1999 (1959); cf.A. R. Lepley, Prepr., Div.Pet.Chem.,Am. Chem.Soc.14,C43 (1969). 2 2 V. Franzen, H. I.Joschek, and C. Mertz,Justus Liebigs Ann. Chem.654,82 (1962); H. Hellmannand D. Eberle, ibid. 662,188(1963).

2o

Sec.III.A]


189

by ananionic groupisthekeystep ina recent synthesis ofphenanthridines, 3).23 Reactions of diazaphenanthrenes, andfused phenanthridines (Scheme this typewithheterocyclic substrates havebeendeveloped forthesynthesis ofsomenatural products (Section VI1,C).

SCHEME 3

Theformation ofbiphenyl by theformal insertion ofbenzyne into a C-H bondofbenzene occurs incompetition withcycloaddition processes, particularly whenbenzyne isgenerated athightemperatures inthevaporphase.17 The enereaction (Eq. 2)provides a nonpolar mechanism foropen-chain ofbenzyne tocompounds containing anallylic hydrogen atom. The addition ofadouble bondisnotalways apparent fromthestructure implied migration oftheadduct. The enereaction frequently occurs incompetition with1,2cycloaddition; someexamples aredescribed inRefs. 1 and2.

Aryneinterconversion, involving thetransfer tobenzyne oftwohydrogen ofanother aromatic compound, isapparently atomsfromadjacent positions V,B).1,4possible athightemperatures (see discussion ofthiophen, Section Abstraction ofhydrogen atomsby benzyne isthemostprobable explanation ofbenzyne andsomestyrene ofthearomatization oftheDiels-Alder adducts derivatives undertherelatively mildconditions usedforbenzyne generationfromo-bromofluorobenzene or benzenediazonium-2-carboxylate (4) (Scheme 4).24 2 3 S.V. Kessar, AN. 24

Cbem.Res.11,283 (1978). and references therein. W. Daviesand J.R. Wilmshurst, J .Chem.SOC., 4079(1961); S.F.Dyke,A. R. Marshall, 22,2515 (1966); E.Wolthuis and W. Cady,Angew.Chem., and J.P.Watson,Tetrahedron In!. Ed.Engl. 6,555 (1967).

190

[Sec. 1II.C


Y

SCHEME4

B. l72-CYCLOADDIT1ONS (17)isan example of The dimerization ofbenzyne toformbiphenylene 1,Zcycloaddition whichoccurs inparticularly highyield when benzyne is (9)16butalso by other methods, ifthe generated from1-aminobenzotriazole concentration orreactivity ofother potential benzyne traps islow. Nucleoof enolates to benzyneisfollowed by closure to a fourphilic addition memberedring whichisfrequently re-opened ina subsequent reaction step.25 Similarly, benzyne andtetrahalogenobenzynes react withenamines togive abenzocyclobutene structure (e.g., 18).26 Analogous benadducts containing fromindoles andpyrroles (Section zyneadducts areisolable ina fewcases V,C),and 1,Zcycloaddition ofbenzyne followed by rearrangement ofthe primary adduct ispostulated toexplain certain other reactions withheterocycles.

x (17)

(18) X = H, F,CI

(19)

c . 173-CYCLOADDITIONS Benzynecanbe trapped in1,3-dipolar cycloaddition reactions provided that the1,3-dipolar species issufficiently stable undertheconditions necessary forbenzyne generation. As anillustration ofthis, benzyne reacts withthe nitrile oxide groupinpreference tothefuran ring ofcompound19,whereby 20 isobtained. Benzyneandthenitrone 21 giveadduct 22?*and adduct P.Caubtre, Acc.Chem.Res.7 .301 (1974), and references therein. M. E.Kuehne,J. Am. Chem.SOC.84,837(1962); J. P.N. Brewer,H. Heaney,S.V. Ley, and T.J . Ward, J .C. S.,PerkinI, 2688(1974); H. Heaneyand S.V. Ley,ibid., 2693. T. Sasakiand T.Yoshioka, Bull.Chem.SOC.Jpn.42,826 (1969). 2 8 R. Huisgen and R. Knorr,Naturwissenschaffen 48,716(1961); H. Seidl, R. Huisgen, and R. Knorr, Chem.Ber.102,904(1969). 26

Sec.III.D]

191


similar reactions withazides orwithdiazoketones produce benzotriazole or indazole derivatives, respectively, inhighyield.29.30 1,3-Dipolar cycloaddition reactions leadtoheterocyclic products, butour concern will be onlywiththose inwhicha hetero-ring isalready present in IX)andmesoreactions involving benzyne. Heterocyclic N-oxides (Section VI,B)provide mostexamples ofthis type, although ionic heterocycles (Section ofbenzyne toheterocycles there aresomecases ofapparent 1,3-cycloaddition isidentifiable. inwhichno formal 1,3-dipole

D. 1,4-CYCLOADDITIONS Benzyne isreactive asa dienophile andprovides many examples ofDielsItisefficiently trapped byanthracene togive triptycene andby Alder addition. of tetracyclone togive1,2,3,44etraphenylnaphthaleneviadecarbonylation adduct 23,reactions whicharecommonlyusedtoquantify theformation of benzyne undergiven conditions. 1,4-Cycloaddition ofbenzyne andoftetrahalogenobenzynes alsooccurs withsimple monocyclic benzenoid compounds, andathigher temperatures ifbenzyne isgenerated fromphthalic anhydride) adducts suchas24 may (e.g., rearomatize by elimination ofacetylene. 1,CCycloadducts ofbenzyne and heterocyclic substrates aresometimes isolable, butfrequently theytooreact V, VI, further by a variety ofpathways togivesecondary products (Sections andVJI). Ph

\

\

/

Ph (23)

(24)

(23

G. A. Reynolds, 2.Org.Chem.29,3733(1964); W. R i d and M. Schon,Chem.Ber.98, 3142(1965); R. Huisgen, R. Knorr,L. Mobius,and G. Szeimies, ibid., 4014. 30 W. Ried and M . Schon,Justus Liebigs Ann. Chem.689,141 (1965); T. Yamazaki and Tetrahedron Lett., 4533(1972); C. Tuchscherer, M . Bruch,and D. Rewicki, H. Shechter, ibid., 865 (1973); T .Yamazaki,G. Baum, and H. Shechter, ibid., 4421(1974). l9

192


(26)

(27)

[Sec. IV

(28)

Nucleophilic addition ofdienolates tosubstituted benzynes isfollowed by closure ofa six-membered ring toformnaphthalene derivative^.^’

E. 1,5-,1,6-,AND

1,8-CYCLOADDITIONS

1,5-Cycloaddition ofbenzyne occurs intwo cases ofhomo-Diels-Alder tonorbornadiene) reported inRef.1. additions (e.g., A 1,6-cycloaddition waswrongly claimed tooccur withbenzyne andcycloheptatriene. Thestructure ofthecycloadduct isreliably established as25,and 26 derived froman "ene"reaction was also~btained.~’ 1,stheisomer (27)togive 28. Cycloaddition ofbenzyne occurs with8-cyanoheptafulvene Itisclearly possible toenvisage similar reactions occurring withheterocyclic compounds, although nonehasyetbeenreported.

IV. Reactions withThreeand Four-Membered RingSystems 2,3-Diphenyl-l-azirine (29) andbenzyne yield the1:1adduct 31 (50%) and 1:2adduct 32 (14%).34 Theformation ofthese indoles canbeexplained by

assuming 1,2-cycloaddition ofbenzyne, reorganization ofthestrained intermediate 30,andsomeN-phenylation of31 by further reaction withbenzyne.

(31) R =H (32) R = Ph

P.G. Sammes andT. W. Wallace, J. C. S., PerkinI ,1377(1975). I.Tabushi, H. Yamada,Z. Yoshida, and H. Kuroda,Tetrahedron Lett., 1093(1974); L. Lombard0and D. Wege,ibuf., 3981. 3 3 M. Oda andY. Kitahara, Bull. Chem.SOL-. Jpn.43, 1920(1970). ’*V. NairandK. H. Kim,J .Org.Chem.40,3784(1975).

31

32

Sec.IV]

193


N-Benzylaniline (14%)wasobtained fromN-benzylaziridine andbenzyne (fromfluorobenzene andb~tyllithium).~ Thestrongly basic conditions may causetheelimination ofacetylene froman intermediate N-vinylaniline (33) asoutlined inScheme5.

Y-7 N

+1-

I

CH,Ph Ph,

,CH=CH L’H /NJ PhCH,

-

PhNHCH,Ph

(33)

5

SCHkME

Styrene oxide andbenzyne arereported togivethe1:1 adducts 35 and36 respectively), bothderived fromthesameintermediate 34.36 (9%and6% yield, However, propene oxide isapparently unreactive tobenzyne, since its useis advocated toreact withthehydrogen chloride whichisreleased when benzyneisgenerated by decomposition ofo-carboxybenzenediazonium chloride II,B).~~,~~~,~ (Section

-

@

phb * +

o o > H p h

\

\

Ph

(35)

(34)

PhOCH=CHPh (36)

Although benzyneisformedby decomposition of4-phenyl-l,2,3-benzo(12)above500"C,’* 2-phenylbenzazete (37) hasbeenisolated on a triazine of12 at420-450"C.38 A by-product coldfinger by flash vacuumpyrolysis (38), whichmay result fromaddition of ofthis reaction is10-phenylacridine A. G. Giumanini. J. Org.Chem.37,513(1972). M. Stiles andA. Haag,personal communication, 1964,reported inRef.1. 3 7 L. Friedman, personal communication, 1965, reported inRefs.1 and 2;cf.experimental procedure described inRefs. 37a,b. 3 7 a G . Kaupp, J.Perreten, R. Leute, and H. Prinzbach, Chem. Ber. 103,2288(1970). 3 7 b N. Dennis, A. R. Katritzky, and M. Ramaiah, J . C. S., PerkinI ,1506(1975). 3 8 B.M. Adger, M. Keating, C.W. Rees, andR.C.Storr, J. C. S.,Chem.Commun., 19(1973). 35

36

194

[Sec. V.A


benzyne across theC=N bondof37,although analternative route involving formation anddecomposition ofa dimerof37 wasshowntogive38 asthe temperature wasraised from195K.

\ (12)

N/

/

(3)

(37)

V. Reactions withFive-Membered RingSystems Containing One Heteroatom A. FURANS AND BENZOFURANS The veryefficient reaction offuran withbenzyne, discovered by Wittig andPohmerwastheearliest example ofbenzyne behaving asa dien~phile.’~ Formation oftheoxygen-bridged adduct 39 andits acid-catalyzed isomerization into1-naphthol areoften useddiagnostically forthedetection of benzyne generated by new pathways. ?H Q+1-

(39)

Thecorresponding Diels-Alder adducts havebeenprepared fromsubstiA previous tuted furans, including methylfurans andtetraphenylf~ranPO-~~ ofthearomatization under review44 summarizes someinteresting features acidic conditions ofderivatives ofstructure 39 containing methyl groups at thebridgehead p o ~ i t i oAddition n s ~ ~of ~hydrogen ~~ totheisolated double G. Wittig and L.Pohmer,Angew.Chem.67,348 (1955);Chem.Ber.89,1334 (1956). E. Wolthuis, J. Org.Chem.26,2215 (1961). L. F.Fieser and M. J.Haddadin, Can.J. Chem.43, 1599 (1965). ’’ E.Wolthuis, B. Bossenbroek, G. DeWall, E.Geels, andA. Leegwater, J.Org.Chem.28, 148 (1963);W. Tochtermann, G. Stubenrauch, and H. Zimmermann,Chem.Ber.108, 39

’O

2510 (1975).

" G. Wittig andE. Knauss, Chem. Ber.91,895

(1958).

L.J . KrickaandJ. M. Vernon, Ado.Heterocycl. Chem. 16,87 (1974). " M. Fetizon and N. T.Anh,Bull. SOC.Chim.Fr., 3208 (1965);cf.R. W. Franckand K. Yanagi, Tetrahedron Left., 1789 (1967); J .Org.Chem.33,811 (1968).

44

Sec. V.A]


195

bondof39andcycloadditions ofdiazomethane, phenyl azide, anddienes have ;pyrolysis ofthe2,3-dihydro derivative orthetetracybeenreported3941 theunsubstituted benzo[c]furan (42).4 46 clone adduct of39 affords

@

(401

(41)

Benzyneaddsto thefuranophane 40 to givesuccessively 1:1 and 2:1 adducts; thelatter (41)probably hastheanti c~nfiguration.~ 1,3-Diphenylbenzo[c]furan (43) isalsoan efficient trap forbenzyne, andtheadduct 44 gives 9,lO-diphenylanthracene indiglyme at162 C, oron reduction withzinc andacetic acid.14s4* Some other instances oftheloss ofthebridging oxygen atomoffuran adducts occur whenthearyne inquestion isgenerated froman by theaction oflithium amalgam, e.g., theisolation of trio-aryl dihalide phenylene (77%)instead of theexpected adduct46 fromcapture of9,lOdehydrophenanthrene by f ~ r a n . ~ ~

(42)R = H (43)R = Ph

(44)x = 0 (45) = s

x

Tetrahalogenobenzynes havebeentrapped withfuranto giveadducts F,CI,Br,orI ;thetetrachloro derivative of44 analogous to39 containing hasalso beenprepared.50,51 Theadducts obtained fromfuran anda number ofother arynes aredocumented inRef.1. U . E. Wiersumand W. J .Mijs, J . C. S . ,Cliem. Commun.,347(1972). L.A. Kapicakand M. A. Battiste. J . C. S.,Chem.Commun.,930 (1973). 48 G. Wittig, E. Knauss, and K. Niethammer. Justus Liebigs Ann. Chem.630,10 (1960). 49 G.Wittig, W. Uhlenbrock, andP.Weinhold, Chem.Brr.95,1692(1962); cf.T.Kauffmann Boettcher, ibid., 949;T.Kauffmann andK. Udluft, Angew.Chem..Int. Ed.Enyl. andF.-P. 2,45 (1963). P. L. Coe,R. Stephens, and J.C. Tatlow, J . G e m . SOC.,3227(1962); cf.B. Hankinson. J .C .S.,PerkinI ,2372(1972). H. Heaney,and R. P.Sharma, H. HeaneyandJ . M. Jablonski, J . Chem.Soc.C, 1895(1968); H . Heaney,K. G. Mason, ibid., 567(1971). andJ.M. Sketchley,

46

47

196

[Sec. V.A


Tetrahydrofuran iswidely employed asa solvent forreactions involving benzyne, yetithasbeenshowntobeattacked by benzyne (from anthranilic aciddiazotized insitu) togiveproducts derived viathebetaine 47.52Inthe 48 and49 areobtained (23%and8%, respectively), whereas presence ofwater of47 underanhydrous conditions themainproduct is50 (17%)by reaction PhO(CH,),OR

(47)

(48)R=H (49) R = Ph

withanthranilic acid andfurther N-phenylation by benzyne. A ring-opened product, 4-(tetrachlorophenoxy) butyl tetrachlorobenzoate, isreported from therelated reaction oftetrahydrofuran withtetrachlorobenzyne (from tetrachloroanthranilic acid).52 Tetrahydrofuran isalso a component ina remark(63%): theinterpretation isthat ablesingle-stage synthesis of anthracene 2,2,&,6-tetramethylpiperidide) benzyne(frombromobenzene and lithium addstothelithium enolate ofacetaldehyde, whichisproduced fromtetrahydrofuran understrongly basiccondition^.^

I

OLi

ii

0

SCHEME6

A recent synthesis ofanthraquinones involves thebase-catalyzed addition of phthalides to arynes (generated fromthecorresponding arylbromide andlithium diisopropylamide), asoutlined inScheme6.54 E. Wolthuis, B. Bouma, J. Modderman,and L. Sytsma,Tetrahedron Lett., 407 (1970); G . I.Frayand R. G. Saxton, Tetrahedron 34,2663(1978). 5 3 I.Flemingand T. Mah, J . C. S., Perkin2,964(1975). 5 4 P. G. Sammes and D. J . Dodsworth, J .C. S.,Chem.Commun., 33 (1979).

52

Sec.V.B]

197


B. THIOPHEN AND BENZOTHIOPHENS Although thiophen fails toreact withbenzyne atordinary temperatures, itisattacked by themore reactive dienophile, tetrafluorobenzyne (from pentafluorophenyllithium at 15 C), to give1,2,3,4-tetrafluoronaphthalene (52)(26%). Transient NMR absorptions attributable tothebridgehead and vinylic hydrogenatomsof theintermediate Diels-Alder adduct51 were ~ b s e r v e Ad .minor ~ product ofthesamereaction, pentafluorothiophenol, isknown tobe formedfrompentafluorophenyllithium andsulfur; thesulfur 7).1,3-Dichlorointhis instance comesfromthearomatization of51(Scheme 2,4-difluoronaphthalene (36%)was obtained similarly fromthemixedhalogenobenzyne andt h i ~ p h eTetrafluorobenzyne n.~~ and tetrachlorothiophen tetrachlorotetrafluoronaphthalene in only low gave the corresponding yield.5s

(51) X =F

(52)X = F

SCHEME7

Benzyne(frompyrolysis ofphthalic anhydride) reacts withthiophen at 690 Ctogivemainlynaphthalene, benzo[b] thiophen (54), 2-and3-phenylthiophens, andb i t h i e n ~ The l .bithienyl ~ (probably the2,2 -isomer) isalso formed fromthiophen alone underthesameconditions. Thephenylthiophens C-H bondsofthiophen. The source of arise by insertion ofbenzyne into naphthalene ismostlikely tobeviaa Diels-Alder reaction (Scheme 7,X = H), andFields andMeyersonassumea mechanisminvolving initially 1,2-cyclotoaccount fortheformation addition ofbenzyne toa C-S bondofthiophen of 54 (Scheme8).2*57,58 However,there isno evidence tosupport sucha thiepin (53) route, whichseemsunconvincing, notleast because benzo[b] D.D.Callander, P.L.Coe,andJ .C.Tatlow, Chem.Commun.,143(1966); D.D.Callander, P. L. Coe,J . C .Tatlow, and A. J. UH; Tetrahedron 25,25 (1969). 5 6 S.Hayashiand N . Ishikawa. Yuki GoseiKuyuku KyokaiShi28,533(1970) [CA 73.45241 (1970)]. 5 7 E. K . Fields and S.Meyerson,Chem. Commun.,708 (1966); Prepr., Dio.Petrol. Chem., Am. Chem.SOC.12,57 (1967); in Organosulfur Chemistry(M.J. Jansen, ed.), p. 143. Wiley,New Y ork,1967;J .Org.Chem.34.2475(1969). 5 8 E. K. Fields and S.Meyerson, Adr. Phys.Org.Chem.6,1 (1968). 55

198

MARTIN R. BRYCE A N D JOHN M. VERNON

[Sec. V.B

SCHEME8

veryreadily loses sulfur rather thana~etylene. We therefore ~ prefer a simpler mechanism involving 1,3-cycloaddition ofbenzyne tothiophen asshownin Scheme9.59a

(91 SCHEME9

Minorproducts frombenzyneandthiophen include thethiophthen 55, thebenzothiophthen 57,andnaphtho [2,3-b] thiophen (56). Theirformation isingeniously explained intermsofthearyneinterconversion togive2,3(Eq.31,followed by reactions ofthelatter asoutlined in dehydrothiophen boththereaction of 2,3-dehydrothiophen with Scheme 10.We consider 1,3-cyclothiophen andthatof55 withbenzyneinScheme10 toinvolve of1,2-cycloadditions additions analogous tothat showninScheme9 instead benzene wasalso detected asoriginally ~ u g g e s t e dAs . required ~ ~ ~ by Eq.(3), amongthepyrolysis products fromphthalic anhydride andthiophen, neither ofwhichoriginally contained anybenzene. 2,3-Dehydrothiophen could also beinvolved inanalternative route leading ; this isunlikely tobe important, since tetrato54 (Scheme1l y 8however, oftetrachlorophthalic anhydride) andthiochlorobenzyne (frompyrolysis V.J.Traynelis, Y.Yoshkama,J.C.Sih,andL.J.Miller, J .Org.Chem.38, 3978(1973); V. J.Traynelis, in Seven-membered Heterocyclic Compoundscontaining Oxygenand cf. Sulfur (A.Rosowsky, ed.), Chapter 11.Wiley. New York,1972;R. M. Acheson, An Introduction totheChemistry of Heterocyclic Compounds, 3rded.,Chapter 10,and references therein. Wiley, New York,1976. 5 9 a Cf.D. DelMazza andM. G. Reinecke, J.C.S.,Chem.Commun., 124(1981). 59

Sec.V.B]

199


(3)

I

I

(55)

naphthalene

hcnzyne

phengivetetrachlorobenzo [b] thiophen aswellastetrachloronaphthalene, tetrachlorophenylthiophen, andtetrachlorobenzothiophthen.

(54) STHEME 1 1

The sameauthors havealsoreported thereactions ofother arynes with Theypresent speculative thiophen andthereactions ofbenzyne with54.57.58 of products, whichin reaction mechanisms toaccount fortheformation many cases areimperfectly identified frommassspectra alone. Forexample, although theyacknowledge an inability todistinguish betweenanthracene and~henanthrene,~’ theyclaim, inthesamearticle, bothofthese asproducts ofdistinct reactions of benzynewith54.Two minorproducts areclaimed tobe 59 and60,respectively, and toprovide evidence fortheintervention of2,3-dehydrobenzo[h] thiophen (58).

a&(9)

(59)

(@)

200


[Sec. V.C

3-Vinylbenzo [b] thiophen and benzyne(fromo-bromofluorobenzene) 62 (13%); dehydrogenation ofthe1:1 adduct 61 ispossibly induced afford by attack ofbenzyne.60 Formation ofthe1:1 adduct 45 (14%), frombenzyne [c] thiophen (143)isaccompanied by somedesulfurand1,3-diphenylbenzo (9%)48 ;45 also loses sulfur at250 C. ization togive 9,lO-diphenylanthracene

C. PYRROLES, INDOLES,AND ISOINDOLES: NAPHTHALEN1,4-IMINESA N D ANTHRACEN-9,lO-IMINES A previous review44 deals withtheaddition ofbenzynetopyrroles and isoindoles togivenitrogen-bridged structures. Although pyrrole itself and benzyne (from o-FC6H4MgBr) giveonly2-phenylpyrrole, pyrrylmagnesium 67 inlow yield.61 iodide and benzyneafford thenaphthalen-lP-imine Simplepyrroles substituted on nitrogen by an electron-withdrawing group (C02R,S0,Ar)react withbenzynetogiveadducts ofthesametype(e.g., 68) ingood yield,37a,62 since theN-substituent inhibits further attack of benzyne atthenitrogen atom.From N-benzyl-, N-methyl-, andN-phenyl63 isisolable, atbest, inlow pyrrole thecorresponding Diels-Alder adduct 64 or itsfurther yield; itmay rearrange toa l-naphthylamine derivative of rearranged 1:2adducts reaction withbenzyneleadsto theformation (65or66)asshowninScheme12.61,63 Except incases wherethesubstituent on nitrogen iselectron-withdrawing (CO,Me),thenitrogen-bridged adducts derived from 1,2,5-trisubstituted pyrroles areparticularly labile, and theyrearrange to 2-naphthylamine derivatives (e.g., 70 4 75)whicharetheisolable products ofreactions with 71 -, 76 isinduced by treatment b e n ~ y n eThe . ~ similar ~ . ~ ~rearrangement withacid, butreduction orhydrolysis oftheNC0,Me group of71 ispossible underbasic conditions togive72 or73,re~pectively.~~ The preferred route to naphthalen-1,4-imines unsubstituted on nitrogen, suchas 73 and 80, T.G. Corbett and Q. N. Porter, A w l .J.Chem.18,1781(1965). G. Wittig and B. Reichl, Chem.Ber.%, 2851 (1963). 6 2 L.A. Carpino and D. E. Barr,J.Org.Chem.31,764 (1966). b 3 G. Wittig and W. Behnisch, Chem.Ber.91,2358(1958). 64 E. Wolthuis, D. V. Jagt, S . Mels.and A. DeBoer,J .Org.Chem.30, 190(1965). b5 J. M. Vernon,M. Ahmed, and J . M. Moran,J .C. S.,Perkin I , 1084(1977).

’O

61

Sec.V.C]

201


fyJd RNH

\

RNPh

/

/

aR,

p J

Me

@"’" I

R’

I

Me

(67) R =H (68)R = C0,-t-Bu (69)R =NO

(70) R = Ph,R ’ = H (71) R =t02Me, R’ = H (72) R = Me. R’ = H (73) R = R’ = H (74) R’ = Me

Me

(75)R (76) R

=

Ph

= C0,Me

involves addition of benzynes to N-trimethylsilylpyrroles, when theprotecting groupisremovedduring an aqueous work-upprocedure.66 Some other transformations ofN-substituents, whichhavebeenaccomplished with oftheacid-sensitive naphthalen-l,gimine ringsystem, include preservation 68 -, 67,67 -, 69,and80 -8162*66; , otherexamples arereported inRef. 44. 1:2 adduct77 From pentamethylpyrrole and benzynetherearranged wasobtained; butfromsomeother pentasubstituted pyrroles thenaphthalen74 couldbe isolated, and two ofthese (R = n-Bu,cyclo-C,H, 1,Cimines 66

P. S.Anderson, M. E.Christy. G. F. Lundell, and G. S.Ponticello, Tetrahedrori Lett., 2553(1975); P. S.Anderson, M. E. Christy, E. L. Engelhardt, G. F.Lundell, and G .S. Ponticello, J. Heteroc.yc1. Chem. 14,213 (1977).

202

[Sec. V.C


werethen converted into benzo [alcarbazole derivatives analogous to77 by a subsequent reaction withb e n ~ y n e . ~ ~

@

0,Me Me

Me

W

C

O

2

Me

Me

(78)

(77)

e

C02Me

C0,Me Me

M

Me (79)

Naphthalene is formedfrom theN-nitrosoimine 69 at 45 C via a cheletropic reaction6 Insomeinstances benzyne induces deamination of naphthalen-1,4-imines, since naphthalene was a by-product ofthereaction 79 isproofbenzyne withN-methylpyrr~le,~~ and thenaphthalene ester ducedby reaction of78 withbenzyne.68 An indication of thefate ofthe extruded nitrogen-containing fragment isprovided by theidentification of N-methylcarbazole asa product ofthereaction of82withbenzyne. 81-84)havebeenprepared fromN-substituted Diels-Alder adducts (e.g., ~ ~ * ~ adducts ~~~~~~~ pyrroles withtetrafluoroandt e t r a c h l o r ~ b e n z y n e .These areless readily isomerized tonaphthylamine derivatives andless proneto react further withbenzyne. A minorproduct ofthereaction oftetrachloro85 (273,forwhich benzyne withN-tert-butylpyrrole isthe1,Zcycloadduct F JJfF F (80)R = H (81)R = M e

y& Cl

uB-*; R

(82) R = Me, R = H (83) R = t-Bu,R = H (84)R = R = Me

c1 (85)

there areprecedents in enaminechemistry.26 Compound 81 undergoes ;83 cleaves to rearrangement andfragmentation reactions on pyrolysis of81 totetrafluoroacetylene andanisoindole above200 C.70Deamination E.Wolthuis andA.DeBoer, J. Ory.Chem.30,3225 (1965); E.Wolthuis. W. Cady.R.Roon, and B. Weidenaar, ibid. 31,2009(1966). b8 L. J.Kricka and J.M. Vernon,J. C. S.,Perkin I, 766(1973). b9 G .W. Gribble, N. R. Easton, and J.T.Eaton,Tetrahedron Lett., 1075(1970). 70 M. Ahmed and J.M. Vernon, J.C. S.,Cbem. Commun., 462 (1976); J.M. Vernon,M. Ahmed,and L. J.Kricka, J.C . S.,PerkinI ,837(1978). 7 1 P.L.Coe andA. J.Uff, Tetrahedron 27,4065(1971); H. Heaneyand S.V. Ley,J. C. S., PerkinI. 2698(1974). b7

Sec.V.C]

203


naphthalene (52)occurs on treatment withrn-chloroperbenzoic acid,72 and 52 andheterocyclic products areobtained by reaction of81 withdimethyl acetylenedicarb~xylate.~~ Anthracen-9,lO-imines (e.g., 86-90)areobtained by addition ofbenzyne synthesis (from various precursors) toi s o i n d ~ l e and s the , ~scope ~ ~ ~of~this .~ ~ benzynes and hasrecently beenextended toinclude theuseofsubstituted affords 89 (43%)without somenew i s ~ i n d o l1,3-Diphenyl-2H-isoindole es.~~

@&J& \

/

/ / Me

\

/\

R

(86) R = R = Me (87) R = Me, R = H (88) R = Ph,R = H (89) R = H, R = Ph (90)R = Me, R = Ph

Me

(91)

-

Me

Me

(93) @rH2Ph

(92)

N-phenylation. The further reaction of 87 and 88 withbenzynetogive 91 (cf. themechanism outlined inScheme12) 9-aminoanthracene derivatives isblocked by thepresence ofsubstituents atthebridgehead positions asin 86.Anthracene (9%)isalso produced fromthereaction of87 withbenzyne?* ofthetetramethyltriptycene 93 frombenzyne and the and theformation 92 isattributed to a similar deamination of an intermediate isoindole of86 and 87 ismore conveniently anthra~en-9,lO-imine.~~ Deamination accomplished by treatment withhydrogen peroxide. Thereaction ofindole withbenzyne hasbeenstudied only under strongly basic conditions inwhichindole isfirst converted into its lithium orsodium derivative. Indol1-yllithium and benzyne (fromo-FC,H,MgBr)gavethe 1:ladduct 98 as themain product (8%)together withsmall tetracyclic G . W. Gribble, R.W. Allen, P.S.Anderson, M. E.Christy, and C. D.Colton, Tetrahedron Lett., 3673(1976). 7 3 J.C. Emmett and W . Lwowski, Tetrahedron 22,1011(1966); R.Harrison, H. Heaney,and

P. Lees,ibd. 24,4589(1968). P.S.Anderson, M. E. Christy, C. D. Colton, W. Halczenko, G . S.Ponticello, and K. L. Shepard, J .Org.Chem.44,1519(1979); Merck and Co.,Inc., German Patent2,521,519 [CA 84,59189(1976)l.

204

[Sec. V.C

MARTIN R . BRYCE AND JOHN M. VERNON

amountsof N-phenylindole (94)and 3-phenylindole (95).75 l-Methyl-3(96) (4%)wasformedfromN-methylindole andbenzyne under phenylindole

(94)R = Ph,R = H (95) R = H, R = Ph (96)R = Me, R = Ph

thesameconditions. Indole andbenzyne (frombromobenzene andsodium (20%)but amideinliquid ammonia)gavemore ofthetwo phenylindoles noneof98,because protonation oftheintermediate anion(97)was faster cyclization to98. thanits 1,3-Cycloaddition ofbenzyneto3-diazooxindole (99) led, viarearrangeindazole derivative 101 ment of thespiro adduct100,to thecondensed (91%),thestructure ofwhichwas confirmed by anindependent ~ynthesis. ~

(pN & N

/

d

o H

+ ....NAo

-

H

(99)

(100)

(101)

Julia etal.haveemployedintramolecular reactions ofarynes generated fromindoline derivatives forclosure ofa six-membered ringlinking the3and4-positions. Thus,103isobtained from102 by treatment withsodium Me0,C

B

r

d

3

c

0

z

M

e

Meo2c&l)

Ac (102)

l6

Ac (103)

M. E. Kuehne and T.Kitagawa, J .Org.Chem.29,1270(1964). T.YamazakiandH . Shechter, Tetrahedron Lerr., 1417(1973).

H

Ac

(104)

Sec.V.D]

205


amidein liquid ammonia,and a similarly conceived synthesis givesthe 104.77 lysergic acidanalog

D. SILICON AND GERMANIUMHETEROCYCLES 1,4-Silicon-bridged adducts (106)wereobtained ingoodyield fromfully (105)and benzyne(fromdiazotization of anthranilic substituted siloles (107), andthe Pyrolysis of106at300 Cgavetetraphenylnaphthalene ofdiphenylcomplementary silylene fragment was captured inthepresence acetylene. Thecorresponding 1:1adduct 110fromthesilole 108andbenzyne (froml-aminobenzotriazole and leadtetraacetate) isstable insolution at 50 C,butitdecomposes belowroom temperature togive1P-diphenyln a ~ h t h a l eThe n e .difference ~~ inthermal stability of 106 and 110 may be steric hindrance involved intheformation of107from106. duetothegreater Ph Ph2 $ e , + 1 -

R,

(105) R = Me, Ph

aph Wph Ph

\

Ph

Ph

(106) R = Me. Ph

4 \

+ [SiR,]

Ph

(107)

If benzynewas generated instead from o-carboxybenzenediazonium chloride inthepresence of 108,theremarkable siloxepine 111 was formed (>70%);its structure was confirmed by X-rayd i f f r a ~ tIt i owas n .shown ~~ 1:1 adduct110 reacts withbenzenediazonium-2-carthat theintermediate (4)ata lowertemperature thanisrequired forthedecomposition boxylate 4+5 1 (Scheme1); this step includes theformation ofthestrong Si-0 lossof nitrogen and cyclization leadto 111.The bond,and subsequent germanium analog of111 wassimilarly obtained from109.

(108) X = SiMe, (109) X = GeMe,

(110) X = SiMe,

(111)

M. Julia. F. Le Goffie, J. Igolen, and M. Baillarge, Bull. Soc. Chim.Fr.,1071(1968); Tetrahedron Left., 1569(1969). H. Gilman,S.G .Cottis, and W. H . Atwell. J .Am. Chem. Soc. 86,1596.5584(1964). 79 T.J. Barton, A . J .Nelson, and J.Clardy, J .Ory.Chem.37,895 (1972).

77

206

MARTIN R. BRYCE A N D JOHN M. VERNON

[Sec. V1.A

VI. Five-Membered RingSystems withTwo orMore Heteroatoms A. HETEROCYCLES CONTAINING A FORMALDIENE SYSTEM Imidazole, benzimidazole, andbenzotriazole giveN-phenyl derivatives in understandably fails to lowyield withbenzyne’ ;1-methylbenzotriazole react.8’ Incontrast, 2-methylbenzotriazole reacts withbenzyne (from oxidation of9 withleadtetraacetate) togive1-phenylbenzotriazole (112)(22%)." The mechanismsuggested to account forincorporation of benzyneand oftheN-methyl groupisoutlined inScheme13;formaldeoxidative removal hydemay befurther oxidized underthese conditions. 2-Benzylbenzotriazole andbenzyne underthesameconditions afforded 112 andbenzoic acid." itreacted with2-methylbenzoWhen benzyne wasgenerated from4 instead, triazole togivephenaziiie (2%)andno 112." ’ y 8 0

112

+ CHzO + Ac,O

SCHEME13

Benzo[c]cinnoline (114)(3%) was separated froma complexmixture of colored products obtained fromtheoxidation of9 withactive manganese of114suggests thestepwise loss ofnitrogen, 10 --+113 -+ 1, dioxide; formation and 1,Cdipolar cycloaddition of benzyneto 113.16 Oxidation of9 with (473,1-phenylbenzotriazole (112) (diacetoxyiodo)benzene gaveazobenzene

(9)R = NH2

(112)R = Ph

A. F.Pozharskii, T. M. Meleshko, and A. M. Simonov, Khim.Geterorsikl. Soedin., 473

[ C A 65,8895(1966)l. (1966) C. D. Campbell andC. W. Rees, J .Chem.SOC.C,748(1969). C.D. Campbell, C. W. Rees,M. R. Bryce, M. D. Cooke,P.Hanson,andJ.M. Vernon, J.C. S., PerkinI, 1006(1978).

Sec.VLA]

207


(373, andtwoother heterocyclic products believed tobe 116 and117 (20% together); azobenzene and 112 werealsoobtained using nickel peroxide theproduction ofbothbenzyne astheoxidant.16 Formation of112 implies conditions, andformation ofazobenandbenzotriazole from9 underthese zenewasexplained intermsofan initial attack ofbenzyne atthe2-position An alternative possibility isthat attack ofbenzyne atthe of9 (Scheme14). exocyclic nitrogen atomcouldleadvia115 toazobenzene.

c$a -

-

N=NPh

PhN=NPh+N,

N=NH

H

SCHEME14

R

H (115)

I

R

(116) R = H, R = Ph (117)R = R = Ph

Thecompounds previously represented by structures 116and117 arenow 116aand117a, knowntobethe2-(o-aminophenyl) benzotriazole derivatives respectivelysza; these revised structures areconfirmed by an independent synthesis of117a.Theirformation isrationalized by a 1,3-cycloaddition of benzyneto 9,followed by rearrangement togive118,and successive Nphenylation, 118+ 116a+ 117a.

R -N,

R

(118)R = R = H (116a) R = H, R = Ph (117a) R = R = Ph

82a

P.G .Houghtonand C .W. Rees,J .Chrm.Rex ( S )303,( M )3888(1980).

208

[Sec. V1.A


Anthranil (119)andbenzyne (from oxidation of9 withleadtetraacetate) afford acridine (5%)";depending on thesequence of bond forming and (120) may breaking, anoxygen-bridged cycloadduct and/or acridine N-oxide 120 isknown to be intermediates inthis reaction (Scheme15), although IX). Theaddition ofbenzyne react withbenzyne ina different sense (Section to oxazoles leads, ultimately, to anthracene derivatives in highoverall yield."

I

mo+l \ lN’

(119)

SCHEME 15

Reactions of a number of heterocycles containing the heterodiene system N=C-C=N havebeenstudied (see also Section VII). Withveryfew exceptions, products arising fromDiels-Alder additions arenotobserved; butsomeother reactions occur, asalready exemplified by 2-methylbenzotriazole. The1,2,5-oxadiazole 121and2,1,3-benzoxadiazole (126) areunreactive toward benzyne, whichgaveonlybiphenylene inhighyield." However, fourproducts obtained frombenzyneand 3,4-dimethyl-l,2,5-thiadiazole (122)provide evidence fortwocompeting cycloadditions tothis ring system : thequinoxaline 123 andsulfur result fromattachment ofbenzyne atboth (45%)andacetonitrile nitrogen atoms, and3-methyl-l,2-benzisothiazole(125) ofbenzyne atring carbon andsulfur atoms.83 (53%)fromattachment Me

(121) X =0 (122) x=s

(125)

G. S.Reddy and M. V. Bhatt, Tetrahedron Lett. 21,3627 (1980). M. R. Bryce, P.Hanson,and J. M. Vernon,unpublished results.

82b 83

(123) R = Me (124) R = C0,Me

Sec. VLA]

209


2,1,3-Benzoselenadiazole(128)behaves asa heterodiene towarddimethyl 124andselenium. acetylenedicarboxylate, withwhichitgives thequinoxaline But 128 reacts differently withbenzyne(generated from4 or from9) to 132 (88%) anda small amountofa givethe1,2-benzisoselenazole derivative cis,trans stereoisomer of 132.82 The analogous adduct131 isobtained in loweryield frombenzyne and2,1,3-benzothiadiazole (127). The structure of these benzyneadducts isstrikingly reminiscent of 135,whichisobtained ofdimethyl acetylenedicarboxylate to 126 froma photochemical addition viaa nitrile oxidei ~ ~ t e r r n e dHowever, iate.~ for ~ reasons givenelsewhere,82 a nitrile selenide isunlikely tobe an intermediate intheformation of132, whichisbetter explained by themechanismoutlined inScheme16.As in isa 1,3-cycloaddition (inoneortwo thecaseofthiophen (Section V,B), this ofbenzyne totheheterocycle, enabled by theuseofd orbitals on the steps) sulfur orselenium atom. R

(126)R = H,X = 0 (127)R = H, X = S (128)R = H,X = Se (129)R = Me, X = Se (130)R = CI,X = Se

(131)R = H,X = S (132)R = H,X = Se (133)R = Me, X = Se (134)R = CI,X = Se

(135)

SCHEME 16

A series of adducts analogous to 132 hasbeenprepared frombenzyne and substituted 2,1,3-benzoselenadiazoles.84aThe adduct133,from 5,6dimethyl-2,1,3-benzoselenadiazole(129),undergoes a further remarkable rearrangement either thermally orphotochemically togive theselenocyanate 136.Thecorresponding compound137isobtained directly fromthereaction ofbenzyne with130,whichimplies that theadduct 134 isevenmorelabile I.Yavari, S.Esfandiari, A.J. Mostashari, and P.W. W. Hunter,J .Org.Chem.40,2880 (1975); W. Heinzelmann and P.Gilgen, Helu.Chim.Acra59,2727 (1976). 84a M. R. Bryce, C.D. Reynolds. P.Hanson.and J .M. Vernon,J .C.S . , PrrkinI,607 (1981). 84

210

[Sec. V1.B


than133. A possible mechanism toaccount forthis rearrangement isshown inScheme17. R

R

(136) R = Me R = CI (137) SCHEME 17

B. MESOIONIC COMPOUNDS AND HETEROCYCLES WITHOUT A FORMAL DIENE SYSTEM Recent developments inthechemistry ofmesoionic compounds85 include cycloaddition-elimination reactions, whichafford novel synthetic routes to a variety ofheterocyclic systems. Thesereactions may be seenasinvolving 1,3-dipolar cycloadditions, following Huisgen,86 oralternatively as1,bcycloadditions toheterodiene systems,87 depending on thechoice ofcanonical structure torepresent themesoionic compound. Benzyne hasbeenemployed insuchreactions less frequently thanmore stable acetylenic or ethylenic dipolarophiles. istheaddition ofbenzyne (generated from4 orby The earliest example ofanthranilic acid in situ) toN-phenyl sydnone (3-phenyl-1,2,3diazotization 138)88 ;spontaneous loss ofcarbon dioxide fromthe oxadiazolium Soxide, 139 gwes2-phenylindazole (140). Later workers have intermediate adduct 140 inhigher yield (73%)andthecorresponding 2,3-disubstituted obtained indazoles fromtwo other sydnones using benzyne generated by oxidation Fora recent review seeW. D.Ollis and C.A. Ramsden,Adu.Hererocycl. Chem.19,1 (1976). R. Huisgen,Chem. Sac.,Spec.Pub/.21,51 (1967); R. Huisgen,H . Gotthardt, and R.Grashey, Chem.Ber.101,536(1968); H.Gotthardt and R.Huisgen,ibid., 552;R.Huisgen ibid., 1059;H. Gotthardt and R. Huisgen, ibid. 103,2611 (1970). and H. Gotthardt, Cf.K. T.Potts, E. Houghton,and U .P.Singh, Chem. Commun., 1129(1969); K. T.Potts and D. McKeough,J .A m . Chem.Sac.95,2750(1973). 88 A. Ya. Lazaris, Zh. Org. Khim. 2, 1322(1966) [CA 66,65426(1967)l; H. Gotthardt, R. Huisgen, and R. Knorr,Chem. Ber.101,1056(1968).

85 86

Sec.VI.B]

211


of9.89 The samemethodofbenzyne generation achieves no reaction with 1,4-diphenyl-l,2,4-triazolium3-oxide (141),butata higher temperature with141 togive140(34%).89 benzyne generated from7 reacts

mo-

do +I

PhN@0

-

N

a N P h + C O l

(140)

(13%

(1%)

The primary cycloadduct 145 fromthemesoionic 1,3-thiazol-5-one (144) andbenzyne (generated from9)wasisolated in78% yield. Thermal decomposition of145 (inboiling xylene) gave1,3-diphenylbenzo[c]thiophen (143) andphenyl isocyanate, butinstriking contrast UV irradiation of145yielded 1,2,4-triphenylisoquinolin-3-one(146)by extrusion ofsulfur.89 The 1:I ad4-oxides and dimethyl ductscorresponding to 145 from 1,3-thiazolium acetylenedicarboxylate or dibenzoylacetylene arenot isolable, but they orthiophen fragment underthereaction conditions toeither pyridin-Zone derivatives, depending on thepattern ofsubstitution inthemesoionic comp o ~ n d The . ~mesoionic ~ , ~ ~ 1,3-dithiol-4-one 142 andbenzyne (from oxidationof9) alsoafforded 143 (36%)by a similar cycloaddition and lossof carbonyl sulfide.89

*doPh (141)

(142)

-

phHoS@NPh @ \ Y Ph +1

(144

Y NPh

Ph (143)

@ h

\ \NPh + S

Ph

Ph

(145)

(146)

2-Phenylazo-l,3-benzothiazole(150)(I1%) andazobenzene (9%)werethe products obtained fromthereaction of2,3-diphenyltetrazolium 5-sulfide 89

S.Nakazawa,T. Kiyosawa, K. Hirakawa,and H. Kato,J .C. S . ,Chem. Commuri., 621 (1974). K. T.Potts, E.Houghton, and U. P.Singh, J .Org.Chem.39,3627(1974); cf.K. T.Potts, J. Baum, E. Houghton, D. N. Roy,and U. P.Singh,ibid., 3619.

212

[Sec. V1.B


(dehydrodithizone, 147)and benzyne (fromanthranilic acid)." Theseazo and/or dimerization ofaryl compounds areconsidered tobeformedby loss acetylenedicarboxylate nitrenes froma rearranged adduct148.Dimethyl theanalogous adduct 149,thestructure ofwhichwasestablished and147give by X-raydiffra~tion.~’ However, decomposition of149 was notobserved. Ph

I 1,2-Dithiole-3-thiones (e.g. 151)arenotmesoionic according totheusual d e f i n i talthough i ~ n , ~ the ~ ring system becomes aromatic ifcharge separation isallowed. Theaddition ofbenzyne to151(Ar= Ph)hasbeenreported by tworesearch groups using various methods forbenzyne ;the highest yield (55%)ofa 1:1 adduct, 2-thiophenacylidene-l,3-benzodithiole (152;Ar = Ph), was obtained using 9 asthebenzyne precursor. Formation of152 may occur ina single step asshown, orviacycloaddition ofbenzyne tothe1,3-dipolar S-C-=S system preceding opening ofthedithiole ring. fromother1,2-dithiole-3Adducts analogous to 152 havebeenobtained (lS4-156)93 although the4-phenyl derivative (157)and benzyne thiones 158 instead oftheexpected thioaldehyde, probably afforded thealdehyde ofoxidation bylead tetraacetate (for generation ofbenzyne from9).92 because A comparison ofthereactions of151witharylacetylenes andwithdimethyl acetylenedicarboxylate isagain i n f ~ r m a t:i1: v1eadducts ~~ corresponding G. V. Boyd,T.Norris, P.F.Lindley, and M. M . Mahmoud, J .C .S., Perkin I ,1612(1977). D. B. J.Eastonand D. Leaver, Chem.Commm.,585(1965). D. B. J. Easton, D. Leaver, and T.J. Rawlings, J .C. S., PerkinI ,41 (1972). 9 3 J.-M. Decrouen. D. Pacquer. and R. Pou.C. R. Acad. Sci.. Ser.C 279.259 (1974); D. Pacquerand R. Pou.Bull. Soc.Chim.Fr.,120(1976). 94 H. Behringer, D . Bender, J.Falkenberg, and R.Wiedenmann,Chem.Ber.101,1428(1968); H. Davy,M. Demuynck,D. Pacquer, A. Rouessac, and J. Vialle, Bull. SOC.Chim.Fr., 2057(1968). 92

Sec.VI.B]

213


to152 areobtained, butwiththeacetylene ester 1:2adducts withtheinteresting spiro structure 159 havealso been~haracterized.~

\

(154) R = R = Me (155) R. R = (CH,), (156) R = Ph,R = Me (157)R = H,R = Ph

(158)

Pacquer et al.alsorecognized a secondseries of intensely colored 1:l 153,frombenzyne and5-aryl-l,2-dithiole-3adducts, thetrithiapentalenes (151).93 Although verylittle of153 (Ar= Ph)was obtained (28OO A) of a variety of isoxazoles (58) leads tocleavage oftheN - 0 bondandformation ofvinylnitrenes (59), whichmay alsobe formulated as mesomeric diradicals. In (60)insynthetically useful many instances, thelatter cyclize to2H-azirines yields (Eq.17).59 Several cases ofisomerization ofisoxazoles (e.g., 61)tooxazoles (e.g., 63) via2H-azirines (e.g., 62)havebeenreported.60*61 Theazirine 62wasisolable, T.Nishiwaki, Synthesis, 20(1975); T.Nishiwaki, K . Azechi, andF.Fujiyama, J .C.S.Perkin I, 1867(1974); G. Adembri,A. Camparini, F.Ponticelli, and P.Tedeschi, ibid.. 971(1977). 6 o D . A. Murature, J. D. Perez, M. M. De Bertorello, and H. Bertorello, An. Asoc.Quim. Argenr. 64,337 (1976) [CA 89,128847(1978)]. 59

Sec.II.E]

249

CARBENES AND NITRENES

\ R’

/

pox N:

(59)

X = OR,SR,NH2. NHR, NHNH,, Ph,Me R’ = aryl, Me R 2 = H, aryl, Me

andunderwent further rearrangement to63 at500-600"C inthegasphase (Eq.18).60 Thesereactions constitute thereverse ofthereactions shownin Scheme11. Me

hvorA

Me\

/Me \n

2 Me

l&

Me

(18)

The kinetics ofa further series ofisoxazole-2H-azirine rearrangements at Theactivation parameters for3-phenyl165-185 Chasbeeninvestigated.62 (AH* = 38 ? 1 kcal/mol; ASf = 3.6& 2 eu)arein 5-methoxyisoxazole N-0 bondbreakage [DHo(PhOgoodaccord withthepostulated initial NR,) = 38-39kcal/m01~~]. Thep h o t o ~ h e m iand cal t~ h~ e r m a conversion P to involve an intermediate of benzisoxazoles to benzoxazoles appears spiroazirine. M. Maeda andM. Kojima, J. C .S.Perkin I, 239(1977); G. J.deVoghel, T.L.Eggerichs, B.Clarnot, andH.G.Viehe, Chimia30,191 (1976); K.Dietliker, P.Gilgen, H.Heimgartner, Helu.Chim.Acra59,2074 (1976); A. Padwa,E.Chen,andA. Ku,J.Am. andH. Schmid, K. Isomura, Y. Hirose, H.Shugama, S.Abe,G.-I. Ayabe, and Chem.SOC.W,6484(1975); H. Taniguchi, Heterocycles 9,1207(1978). 6 2 M. 1.Komendantov, R.R.Bekmukharnetov, andR.R.Kostikov, Khim.Geterotsikl. Soedin. 8,1053(1978) [CA 89,214685(1978)l. K. W. Eggerand A. T.Cocks,Helv.Chim.Acta56,1516(1973). 64 K. H. Grellrnann and E.Tauer, J.Photochem. 6,365(1977). 6 5 K. L. Davies, R. C. Storr, andP.J .Whittle, Chem.Commun.,9 (1978).

6’

250

[Sec. 1I.E

CURT WENTRUP

An elegant application oftheisoxazole-azirine rearrangement hasbeen ofthefused azirine 64 which, on further photolysis, usedinthegeneration 65 asshowninEq.(19).66 underwent ring expansion tothecyclic ketenimine

67 -1-I--:: hv

Me,CO

0-0 N-0

N

O

N=C-

:N ..

0

0

The formation ofbenzonitrile, methyl2-methylpropenyl ketone, andthe 67 (ratio 2.3:2.3: 1)inthethermolysis (160-180 7-10 C, torr) ofthe azirine 66 canbe explained by initial N - 0 bondcleavage tobiradical oxazoline (Eq. 20).67 ornitrene intermediates

1

/

Ph

0

66 67

S.Albanesi, A. Marchesini, and B.Gioia, Tetrahedron Lett., 1875(1979). L. G . Zaitseva, 0. S. Chizhov, and I .G. Bolesov, Zh.Org.Khim.11,1347(1975): J.Urg. Trans/.), 1333(1975) [ C A 83,206142(1975)l. Chem.U S S R (English

Sec.II.E]

251


Isoxazol-5(4H)-ones rearrange to azirines and ketenimines on flash vacuumpyrolysis, probably viathe5-hydroxyisoxazoles (Eq.21).68

Ph I. I

N

--+

Ph-N=C=CH,

(21)

4-Methyleneisoxazol-5(4H)-ones (68, 70,73)rearrange topyrroles (69,71, 72,74)at800 C torr).68 Hydroxyisoxazoles and nitrenes arelikely intermediates (Scheme 12). Me

Me

COOH Me

R = Me orPh

(73)

R

=

(74)

Me orPh

SCHEME 12 68

K.-P. NetschandC.Wentrup, unpublished results (1979); H.-J. Wollweber, Ph.D.Thesis, ofMarburg(1980). University

252

CURT WENTRUP

[Sec. 111

111.Imidoylcarbenes and 1H-Azirines Imidoylcarbenes (76and78)areisomeric withvinylnitrenes andcanin R’\ ,C=C=N-R3

R2 (80)

R3

RJ

..

I R3

(81)

principle cyclize totheformally antiaromatic 1H-azirines 77 orundergo a IV)toketenimines (80). Examples of Wolff-type rearrangement (cf. Section of1,2,3-triazoles werereported by Burgess theformation of80by photolysis et~ 1(75, . R’,RZ ~ = ~ H, Ph;R3 = Ph). MIND0/3 andNDDO calculations indicate that the1H-azirines 77 may be stable relative tothecarbenes 76 and78,andhenceaninterconversion ofthecarbenes canbeexpected prior to theWolffrearrangement.70 The gas-phase pyrolysis of unsubstituted 1,2,3-triazole withdirect microwave spectroscopy oftheproducts didnot allowthedetection of 1H-azirine, acetonitrile beingthemajorp r ~ d u c t . ~ ’ Evidence forcarbene interconversion via1H-azirines was,however, reported 81(R3= phthalimido), by Reesandco-workers who isolated the2H-azirine presumably formed by rearrangement of77.72*7 Interconversion ofthecarbenes could also be demonstrated when R 3 = Me;inthis casea rearrangement toisoquinolines tookplace, asexemplified E. M. Burgess, R. Carithers, and L. McCullagh, J .Am. Chem.SOC.90, 1923(1968). M. J.S. Dewar and C.A. Ramsden,Chem.Commun.,688(1973). ’’ M. Winnewisser, J . Vogt,and H. Ahlbrecht, J .Chem.Res.(9, 298 (1978). ’’ T. L. Gilchrist, G. E. Gymer,and C.W. Rees,Chem.Commun.,835(1973). " T.L.Gilchrist, G . E. Gymer,and C. W. Rees,J .C. S.PerkinI ,555(1973).

69 ’O

Sec.1111

253

CARBENES AND NITRENES Me

Me

CH,

Me

p+

Ill

N@

SCHEME 13

inScheme13.74 Similarly, l-vinyl-1,2,3-triazoles gavepyrroles on pyrolysis, probably viaanalogous 1H-azirine intermediate^.^^ A 13C-labeling studyshowedthat an lH-azirine isalsoinvolved inthe formation of3-phenylindole by flash pyrolysis of1,5-diphenyl-1,2,3-triazole; suchanintermediate isnotrequired, however, fortheformation ofthesame (Scheme 14).75 product from1,Cdiphenyl-1,2,3-triazole toa Wolff-type rearrangeThegas-phase pyrolysis ofbenzotriazole leads mentto1-cyanocyclopentadiene innearly quantitative yield; 1% ofaniline isformedasa by-product (Eq.22).76,77 The sameproducts areformedby n . ~methyl-substituted ~ isatins, it thermal extrusion of2CO fromi ~ a t iUsing was shownthattheimidoylcarbene and/or diradical intermediates interof convert totheextent of10-12%viaIH-benzazirine prior toformation 74

76

T.L. Gilchrist, G. E.Gymer,and C.W. Rees,J .C.S.PerkinI ,1 (1975).

T.L.Gilchrist, C. W. Rees,and C. Thomas,J .C. S.PerkinI ,8 (1975).

W. D.Crow and C. Wentrup,Chem.Commun.,1026 (1968). C. Wentrupand W. D. Crow, Tetrahedron 26,3965 (1970);27,880 (1971).

254

[Sec. I11

CURT WENTRUP

Ph N

I

I

I :=-x -+Qr phlNpH Ph

Ph

I

J

H

N

H

mph pr)==C=NPh

Ph

I

Ph

Ph

I

H

NPh

PhCH=C=NPh

H

*=

3C

I OhH,

I O

C

N

(22)

anilines, asexemplified for5- and&methylisatin in Scheme 15.78 Results in agreement withthis schemewerealsoobtained fromtheothermethylis at in^.^’ Furthermore, a 3C-labeling study showed that themainproduct, complete interconversion of the 1-cyanocyclopentadiene, isformedafter iminocarbenes via1H-benzazirine (Scheme16).79 Rapid1,5-sigmatropic ofthecyanogroup7leadtoscrambling oftheringlabel in82 over shifts all ring positions, giving 83. 13

C.Wentrup, Helo.Chim.Acta55,1613(1972). C. Thetazand C. Wentrup,J . Am. Ctiern. SOC.98,1258 (1976).

0

f

\ /

g

P

256

CURT WENTRUP

[Sec. 111

Ringcontractions of this type, by pyrolysis of thecorresponding triazoloarenes, havebeenusedforthepreparation ofcyanoindenes andcyanopyrroles (Eq.23).77

TheGraebe-Ullmann synthesis ofcarbazoles bygas-phase pyr~lysis~ -~~ or p h ~ t o l y sof i l-aryl-1,2,3-benzotriazoles s~~ involves thecyclization of imidoylcarbenes (orthemesomeric 1,3-diradicals) ontoaromatic rings (Eq.24). Thiscyclization isapparently veryrapid, fortheuseofsubstituted

(85)

derivatives showedthat thecarbene 84 doesnotinterconvert withthe1Hbenzazirine 85 prior tocarbazole formation undereither photo~hemical~~ orthermal78 conditions.* Variations ofthecarbazole synthesis include theuseof1-(2-pyridy1)-,85.86 1-(2-pyrimidyl)-,87 1-(2-phenylq~inazolin-4-y1)-,~~ and1-(2-benzimidazolyl)* The triplet groundstates ofiminocyclohexadienylidenes of type84 havebeenobserved as 1.3-diradicals. Triplet 84 decays (to carbazole) with by ESR at77 K andarebestdescribed [H.Murai,M. Torres, and 0. P.Strausz, J . Am. an activation energyofabout5.2kcal/mol Chem.SOC.102.1421(19XO)I. JustusLiebigs Ann. Chem.291,16 (1896). C.Graebeand F.Ullmann, F.Ullmann, JustusLiebigs Ann. Chem.332,82(1904); Chem. Ber.31,1697(1898). W. Borsche and M. Feise, Chem.Ber.40,378(1907). 8 3 W. Freudenberg, Heterocycl. Camp. 3,298(1952). 8 4 M. Ohashi, K. Tsujimoto, andT.Yonezawa, Chem.Commun., 1089(1970). 8 5 A. J.Hubert, J .Chem.SOC.C , 1334(1969). 8 6 P.Nantka-Namirski andJ.Kalinowski, AcraPol. Pharm.31,137(1974) [CA 81,152112 (1974)l. A. J.Hubert and H. Reimlinger, Chem.Ber.103, 381I (1970). A. J.Hubert,J .Hererocycl. Chem.11,737(1974).

Sec.IV]

257


Cr

-+QD+ H

SCHEME 17

1,2,3-ben~otriazoles~~ asshowninthegeneral Scheme17,aswellas the formation of benzoxazoles and phenanthridinones from 1-acylbenzotriaz~les.~~.~~

IV. Oxocarbenes and Oxirenes The Wolffrearrangement andtheinvolvement ofoxirenes (86) hasbeen 18).’0,92*93 reviewed (Scheme Although theoretical calculations giveconflicting answers regarding the ofoxocarbenes and o x i r e n e ~the , ’fact ~ . ~that ~ carbenerelative energies indicarbene interconversion canbeobserved under thermalcondition^^^.^^ higher energy thanthe cates thattheoxirenes cannotbe of significantly carbenes. Prooffortheintermediate formation of oxirenes fromacyclic 0 N*

I1 II

R-C-C-R’

A

0

0

.. R-C-C-R’ II

R

/ \

R-C=C-R

I

k C = O R’

0

.. II R-C-C-R’

(86)

R

R’

I

kc=o

SCHEME 18 J . de Mendoza and J.Elguero, Bull. SOC.Chim.Fr., 2987(1974). R. Huisgenand M. Seidel, Chem.Ber.94,2509(1961). 9 1 H. Meierand I.Menzel, JustusLiebigs Ann. Chem.739,56 (1970). y 2 H. Meierand K.-P. Zeller, Angew.Chem., hi.Ed.Engl.14,32 (1975). 93 W. Riedand H. Mengler, Fortschr. Chem.Forsch. 5,1 (1965). 94 0. P.Strausz, R.K. Gosavi, A.S.Denes,and I.G . Csizmadia, J .Am. Chem.SOC.98,4784 0. P.Strausz, R. K. Gosavi, and H. E.Gunning,Chem.Phys.Lett. 54,510(1978). (1976); 9 5 S.A. M a t h and P.G . Sammes,J .C .S.Perkin I ,2623(1972). y6 U. Timm, K.-P. Zeller, and H. Meier,Chem.Ber.111,1549(1978). 89

yo

258

[Sec. IV

CURT WENTRUP

oxocarbenes hasbeengiven using 1,2-hydrogen shifts intherearranged and unrearranged ~arbenes, or ’by ~ -isotopic ~~ labeling.98-100 However, noevidencecould befoundfortheinvolvement ofoxirenes inthereactions ofthe naphthoquinodiazides," cc-diazocyclohexanone,lo2or cc-diazohomoadaO3 Only inthecaseof 2-diazo-1 2-methylcyclododecan-1-one mantanone.’ (87) wasevidence obtained forpartial reaction viatheannelated oxirene 88 ( 20% thermally and60% photo~hemically).~~

-

(87)

(88)

Theseresults require some explanation. Ithaslongbeenknown that acyclic a-diazoketones and -esters exist predominantly inthes-cis form (89)’ 04-1O8 although theenergy barriers towardinterconversion (89+ 90) arelow. 104.1 0 5 . 107

(89)

(90)

It hasalsobeensuggestedlo4 thatthes-cis forms(89) may undergo a Wolffrearrangement duetothefavorable anti relationship beconcerted tweenthemigrating groupR’ andthedeparting nitrogen molecule. Indeed, CIDNP evidence hasbeenproduced todemonstrate that diazoacetaldehyde R. A. Cornier, K. M. Freeman, andD. M. Schnur, Tefruhedron Lett., 2231(1977); R. A. Cornier, b i d 21, . 2021(1980). 98 J.Fenwick, G.Frater, K. Ogi,and 0. P.Strausz, J .Am. Chem.Soc.95,124(1973). 99 K.-P. Zeller, H. Meier, H. Kolshorn, andE. Miiller, Chem.Ber.105,1875(1972). l o oK.-P. Zeller, Chem.Ber.112,678(1979). K.-P. Zeller, Chem.Ber.108,3566(1975). lo’U. Timm, K.-P. Zeller, andH. Meier, Tetrahedron 33,453(1977). K.-P. Zeller, Z.Nuturforsch., Teil B 31,586(1976); Z.Majerski andC.S.Redvanly, Chem. Commun.,694(1972). F.KaplanandG. K. Meloy,J .Am. Chem.Soc.88,950(1966). C. Wentrupand H. Dahn,Helo.Chim.Acta53,1637(1970). S.Sorriso, G. Piazza, andA. Foffani, J. Chem.Sac.B, 805(1971). l o ’G. Paliani, S.Sorriso, andR.Cataliotti, J .C. S .Perkin II,707(1976). 1.G. Csizmadia, S. A. Houlden, 0. Meresz, andP.Yates, Tetrahedron 25,2121(1969). 97

Sec.IV]


259

undergoes a concerted (i.e., noncarbene) Wolffrearrangement ins~lution.’’~ (91) undergo intramolecular Moreover, ithasbeenshownthat a-diazoamides photochemical C-H insertion togive thelactam 92 together withtheketene in a noncarbene process."’ From theeffects ofsensitizers andquenchers it N,=CH-CO-NEt,

+ Et,N-CH=C=O

hs

Me (92)

’[CH-CO-NEt2]

(25) o o E t (93)

wasconcluded that theWolffrearrangement aswellastheformation of92 involve theexcited singlet state ofthediazo compound(Eq. 25)."’ Incontrast, they-lactam 93 was formedfromthesinglet carbene. Itwas further suggested that suchprocesses areconformationally dependent, i.e., thes-cis aretheonesundergoing direct reaction (substitution andWolff forms(89) give free carbenes.’ lo rearrangement), andthes-trans forms(90) On theother hand,thelabeling experiments cited above(Scheme18) constitute almost irrefutable evidence fortheexistence ofthefree oxocarbenes inall those cases whereoxirene participation hasbeendemonstrated. Notably, this hasbeenthecasemostfrequently inphotochemical andinthermal gas-phase reactions, i.e., under conditions ofrelatively highenergy wherethe 89 @ 90will be rapid andtheequilibrium concentration of interconversion 90relatively high. Some Wolffrearrangement cannow takeplace ina conwhile thes-trans forms(90)will give certed mannerinthes-cis forms(89), free carbenes. The latter alsoundergo theWolffrearrangement, butafter interconversion withoxirenes according toScheme18.Alltherigid cyclic diazoketones cited" O 3 areconformationally constrained totheplanar s-cis forms; henceno oxirene participation was observed. The situation is constraints disfavor thes-cis form. quite different in87:hereconformational Consequently, carbenic Wolffrearrangement isobserved photochemically aswellasthermally. Apartfromthewell-known Arndt-Eistert homologization ofcarboxylic acids andthemanyandvaried intermolecular reactions oftheketenes formed

’-’

l o 9 H.

D.Rothand M. L.Manion,J A m . Chem. SOC.98,3392 (1976); H. D. Roth,Arc.Chem.

Rex 10,85 (1977).

H . Tornioka. H . Kitagawa, and Y . Izawa,J .Org.Chem. 44,3072(1979).

’lo

260

[Sec. IV

CURT WENTRUP

SO,H

SO,H SCHEME19

inWolffrearrangements, these reactions arealso ofvalue forthesynthesis Siis hasshownthat o-quinoneofaromatic andheteroaromatic compounds. diazides photolytically rearrange toketenes, whichwithwater ornucleophiles afford carboxylic acidderivatives ofcyclopentadiene, indene, pyrrole, and other heterocyclic systems (Scheme 19)."1-114 Related rearrangements of naphthoquinonediazides havebeencarried outboththermally"5 and photolytically."6 The formation of indole-30. Siis, Justus Liebigs Ann.Chem.556,56,85 (1944); 557,237 (1947); 579,133 (1953). 0. Siis, M. Glos, K.Moller, andH.-D.Eberhardt, Justus Liebigs Ann.Chem.583, 150(1953). 0. Sus and K. Moller, JusrusLiebigs Ann.Chem.593,91 (1955); 599,233 (1956). 0.Siis, H. Steppan, and R. Dietrich, JusrusLiebigs Ann. Chem.617,20 (1958). ’"P.A. S.Smithand W. L. Berry,J.Org.Chem.26,27 (1961). K . Nakamura,S Udagawa,and K. Honda,Chem.Letf. 763 (1972).

’I’

’I2

Sec.IV]


261

carboxylic acidderivatives hasbeenstudied in detail by Tisler and co94 aretransformed into pyrazolotriazoles (95) workers.’ Thediazoketones by photolysis inthepresence ofalcohols."* Ringcontraction in diazopyl9 rimidinediones anddiazopyridazinediones hasalso beenreported.’ 0

(95)

(94)

R = Me orPh R’ = alkyl

Thefirst stable benzothiete (97, X = S)wasprepared by Wolffrearrange96 (X = s); benzoxetes and benzazetes canbe mentof thediazoketone (Eq.26)’2o prepared analogously

x = NH, NMe, 0,S A fewselected examples ofother usesofoxocarbenes (orcarbenoids) in thesynthesis ofheterocyclic compoundsareshowninScheme20.121-’24 Applications ofintramolecular addition reactions ofz-oxocarbenes inthe synthesis ofnatural products havebeen~urnmarized.’~~ J.T.Carlock, J.S.Bradshaw, B. Stanovnik, and M. Tisler, J.Heterocycl. Chem.14,519 (1977); J .Org.Chem.42,1883 (1977); B.Stanovnik, M. Tisler, andJ.T.Carlock, Synthesis, 754(I976). B. Stdnovnlk, M. Tisler, B. Kirn, and I.Kovac,J.Heterocycl. Chem.16,195 (1979). ’I9 B. Stanovnik, M. Tisler, and E.Voncina, Heterocycles 12,761 (1979);B. Stanovnik, M. Tisler, J.Bradac, B. Budic, B. Koren,and B. Mozetic-Rescic, ibid., 457. "* E.VoigtandH. Meier,Chem.Ber.110,2242 (1977). Y. SakumaandF.Yonedo,Heterocycles 6,1911 (1977). M. Hamaguchi, Chem.Commun.,247 (1978). I.Ernest, Tetrahedron 33,547 (1977), andliterature therein. T. Hudlicky. J .P.Sheth, V. Gee,and D. Barnvos, Tetrahedron Lett., 4889 (1979). l Z 5 S.D.BurkeandP.A. Grieco, Org.React. 26,361 (1979).

’I’

’*’ ’’*

262 0

[Sec. V

CURT WENTRUP

0 Ref.121

SCHEME20

V. Thioxocarbenes, Thiirenes, sndSelenium Analogs Earlywork on these species hasbeensummarized." Inthemeanwhile, thiirene (99)and several substituted derivatives,’ 26-1 29 as wellas selen26 havebeenmatrix-isolated and observed by IR spectroscopy on irene,’ of1,2,3-thiadiazoles orselenadiazoles (Eq.27). Thesamespecies photolysis ofvinylene trithiocarbonates (loo).’ 28* arealso obtained by photolysis * The involvement of2-phenylthiirene inboththermolysis andphotolysis of5-phenylL2.3[U.Timm. U.Merkle, and H. Meier. Chum. thiadiazole hasbeenascertained by "C labeling En..113,2519(1980)l. A. Krantz and J.Laureni, J. Am. Chem.SOC.99,4842(1977); J.Laureni, A. Krantz, and R.A. Hajdu, &id. 98,7872(1976). A. Clement, J.E.Bertie, H. E.Gunning, and0. P.Strausz. J .Org.Chem.43, M. Torres, 2490(1978). A. Clement, J.E.Bertie, H. E.Gunning, and 0. P.Strausz. N o w .J .Chim.3, M. Torres, 149(1979). 1 2 9 A. Krantz and J.Laureni, J. Org.Chem.44,2730(1979); B. A. Hess,L.J.Schaad, and Am. Chem.Soc.102.102,2507 (1980). C. S.Ewig,J.

Sec.V]

CARBENES

263

A N D NITRENES

(9%)

(99)

R)=(R

sYs S (100)R

=

H orCF,

Thephotolysis ofbenzothiadiazole at8 K gavea species whichhasnotyet (101). Further irradibeenfully identified butmay havebeenbenzothiirene ation caused rearrangement tothethioketene 102 (Eq.28).127

(101)

(102)

Previous evidence fortheexistence ofbenzothiirene insolution hadbeen ’ ~ obtained ~ a mixture (about 1:1)ofthireported by Cadoganet~ 1 . who anthrenes 103and 104 by thermolysis ofsodiumo-bromobenzenethiolate (Eq.29).

Me

Me

M e \

S

(103)

Me

’ (104)

Usingsimilar criteria, theinvolvement ofbenzothiirene inthethermolysis of1,2,3-benzothiadiazole was indicated by theisolation of and photolysis mixedthianthrenes orthiophenols,’31 although a report tothecontrary has 13’

J. I.G. Cadogan,J.T.Sharp, and M . J.Trattles, Chem.Comrnun., 900(1974). T.Wooldridge and T.D. Roberts, Tetrahedron Left., 2643(1977); R. C. White,J . Scoby. and T.D . Roberts, ibid.,2785(1979).

264

[Sec. V

CURT WENTRUP

also appeared.’ 3 2 A thiirene wasnotinvolved inthethermolysis orphotolysis of 4,5,6,7-tetrahydrocyclohexa[l,2-~][1,2,3]thiadia~ole.’~~ Thus, while definitive proof isstill lacking, theexistence ofbenzothiirene, 111), isfairly certain. Incontrast, all like that of 1H-ben~azirine~~ (Section attempts to findevidence forbenzoxirene as an intermediate insimilar 30 andflash reactions havefailed (thermolysis ofsodium o-bromophenoxide,’ pyrolysis ofo-q~inonediazide,’~~ salicylic acid’ 34 orits methyl ester,’35 in1-’ 3C]~alicylate’ 36).Calculations indicate, however, that cluding methyl[ theenergy differences between oxirene andformylcarbene on theone hand, 37 andthiirene andthioformylcarbene on theother, arefairly similar.’ Flashthermolysis isa convenient way of producing thioketenes from 3 4 * 1 3 8 3 1 3Thiirenes 9 areformed prior tothioketenes inthe 1,2,3-thiadiazoles.’ gasphase’40 ormatrix’ 27 photolysis of 1,2,3-thiadiazoles. The triplet thiobenzoylphenylcarbene (105)hasbeendetected by ESR spectroscopy inthephotolysis of4,5-diphenyl-1,2,3-thiadiazole.’ 41 Diphenwasformedon warmingtoroomtemperature (Eq.30). ylthioketene Ph Ph

N - i hv ii7

s’

phi. ._

d A

Ph

S

Ph Ph

(30)

(105)

Interestingly, thioketenes arealso formed ingoodyields by flash thermolysis (530-590"C/lOtorr) ofisothiazoles. Thioxocarbenes and/or thiirenes werepostulated as intermediate^.’^^ Flash pyrolysis of1,2,3-selenadiazoles gives selenoketenes whicharestable at-196 Candwereidentified by IR andmicrowave spectro~copy.’~~ On (Eq. 31). warming, dimerization occured L.Benati, D. C. Montevecchi, and G.Zanardi, J .Org.Chem.42,575(1977). U . Timm, H. Biihl, and H. Meier,J .Heterocycl. Chem. 15,697 (1978). 1 3 4 R. Schulz and A. Schweig, Tetrahedron Lett., 59(1979). 1 3 5 H. F.Griitzmacher and J.Hiibner, Justus Liebigs Ann.Chem.748, 154(1971); 793,(1973). 136 C. ThCtaz, Ph.D.Thesis, pp.54-59.University ofLausanne(1977). 37 0. P.Strausz, R.K.Gosavi, F.Bernardi, P.G.Mezey,J .D.Goddard,andI.G.Csizmadia, Chem.Phys.Lett. 53,211 (1978). 1 3 * G. Seybold and C. Heibl, Chem.Ber.110,1225(1977); Angew. Chem., Int. Ed.Eng[.14, 248 (1975); E. Schaumann, J. Ehlers, and H. Mrotzek, JustusLiebigs Ann. Chem.,1734 (t979). 139 H. Bock,B.Solouki, G.Bert, and P.Rosmus,J .Am. Chem.Soc. 99,1663(1977). 140 J. Font, M. Torres, 0. P.Strausz, and H. E.Gunning, J .Org.Chem.43,2487 (1978). 141 H. Murai, M. Torres, and 0. P.Strausz, J.Am. Chem.SOC.101,3976 (1979). 1 4 2 G. E. Castillo and H. E. Bertorello, J .C.S. PerkinI ,325(1978). 1 4 3 A. Holm,C. Berg, C. Bjerre, B.Bak,and J.Svanholt, Chem.Commun.,99 (1979); B. Bak, 0. J. Nielsen, J . Svanholt, and A. Holm.Chem.Phys.Lett. 53,374(1978); 55,36 (1978). 132

133

Sec.VI]


R

N

\\

A

__*

+

R-CH=C=Se

"’=(

265

1: hCHR

(31)

Theinteresting capacity ofannelated selenadiazoles tolose nitrogen and (Eq.32)isalsoof selenium,’44 possibly viaintermediate selenoxocarbenes potential usefortheproduction ofnovel heterocyclic compounds.

A

d

Finally, itshould be notedthat S-methylthiirenium salts (106)arestable isevenstable atroom temperat~re.’~’ below-40 C;106(R = tert-butyl) Thismay beascribed toreduced antiaromaticity ofthethiirene ring. R

w

R

S+

I

SbC16-

CH, (106)

VI. Acylnitrenes and ThioAnalogs Acylnitrenes (oxonitrenes) aretheazaanalogs of oxocarbenes. Much evidence hasbeenproduced toshowthat theCurtius andrelated rearrangementsleading toisocyanates do notinvolve a ~ y l n i t r e n e(see s ’below, ~~.’~~ however). Incontrast, alkoxycarbonylnitrenes areformed boththermally and photolytically fromthecorresponding azides, butsuchnitrenes rarely undergo theCurtius rearrangement.I4* H. MeierandK.-P.Zeller, Angew). Chem.,Int. Ed.Engl.16,835 (1977); H. Biihl, U. Timm, andH. Meier, Chem.Ber.112,3728(1979). 145 G. Capozzi, V. Lucchini, G. Modena,and P.Scrimin, Tetrahedron Left., 911(1977). W. Lwowski, Angew.Chem.,Int.Ed.Engl.6 ,897(1967). 14’S.Linke, G .T.Tisue, andW. Lwowski, J. Am. Chem. Soc.89,6308(1967); G. T.Tisue, S.Linke, andW. Lwowski, ibid.,6303. 14* R. Puttner. W. Kaiser, and K. Hafner, Tefruhedron Lett., 4315(1968). 144

266

CURT WENTRUP

[Sec. VI

Acylnitrenes areformedby photolysis ofacyl azides andreact intramolec49-1 5 4 Evidence was adducedthatitisa singlet ularly toformlactams. ofthesulfilimine nitrene whichcyclizes to thelactam108 on photolysis 107.5 5 Thermolysis gaveonlymesityl isocyanate (109).155 Isocyanates often,156 butnotalways157 accompany photolyses ofacyl azides; butgenerally this isthought tobea nonnitrene process (see below, however).

Me G

N C

O

(33)

Me (109) (96%)

Eibler andSauer demonstrated withtheaidofcompetition experiments that thesameintermediate, inall likelihood thebenzoylnitrene, was formed by photolysis of 110-112 (Eq.34).Phenylisocyanate was formedboth thermally andphotolytically fromallthree precursors, butno evidence for a nitrene wasobtained underthermal conditions. W. Lwowski, in Nitrenes (W.Lwowski, ed.), Chapter 6.Wiley(Interscience), New York, 1970. 0. E. Edwards, in Nitrenes (W. Lwowski,ed.), Chapter 7.Wiley(Interscience), New York,1970. Intermediates (M.Jonesand R. A. Moss,eds.), Chapter 6. W. Lwowslu,in Reactive Wiley, New York,1978. 15* W. LwowskiandS.Linke, Justus LiebigsAnn. Chem., 8 (1977). Can.J .Chem.55,2510(1977). P.F.Alewood,M. Benn,J.Wong, andA. J.Jones, 154 J.J.Wright andJ.B. Morton, Chem.Commun.,668(1976). 15 N. Furukawa, T Nisluo, M. Fukumura, andS.Oae,Chem.Lett., 209(1978); N. Furukawa, M. Fukumura, T.Nishio, andS.Oae,Phosphorus Sulfur 5 ,231(1978). 1 5 5 a N. Furukawa, M. Fukumura, T.Nishio, andS.Oae,J. C.S.PerkinI, 96(1977). 1 5 6 V. P.Semenov, A. N. Studenikov, A. D. Bespalov, and K. A. Ogloblin, Zh.Org.Khim. 13, 2202(1977); V. P.Semenov, A. N. Studenikov, A. P.Prosypkina, andK. A. Ogloblin, ibid., 2207. 15 A. F.M. Fahmy,G. H. Sayed, A. A. Hamed,andA. A. Morsy,Indian J. Chem.,Sect. B 16,869(1978). E. Eibler andJ.Sauer, Tetrahedron Lett., 2565(1974).

14

Sec.VI]

267


. I.

\

N-0 /I \

hu

0

/I

..+ Ph-N=C=O

C-N:

(34)

U

(111)

Ph-C

/N3

\O

(112)

The photolysis ofaminimides produces acylnitrenes, whichhaveusually 5 9 Again, isocyanates often beentrapped inintermolecular reactions.’ Naccompanythereactions. The thermolysis of 2,4,6-triphenylpyridine acylimines at170-250 C affords isocyanates ingoodyields.’ 6o Evenifno nitrenes areproduced asintermediates, theisocyanates formed forthesynthesis ofheterocyclic inCurtius-type rearrangements areofvalue compounds. Forexample, transient isocyanates cyclize untoazine rings, 2l).I6 ’N,N-Diphenylcarbamoyl azide reargiving imidazoazines (Scheme diphenylaranges thermally to1-phenylindazolone (Eq.35)viatheelusive minoisocyanate.’ Further examples havebeensummarized by R e i ~ h e n . ’ ~ ~ ’ 9 ’

PhZN-CON,

- Q: A

[Ph,N-NCO]

\

(35)

0

Inthecaseoftheoxocarbenes (Section IV)proof fortheexistence offree carbenes couldbe obtained whenever theparticipation ofoxirenes inthe A. R.Lepley, in "Chemically Induced Magnetic Polarization" (A.R.Lepley andG.L.Closs, eds.), p.358.Wiley, New York,1973;T.Sasaki, K. Kanematsu, A. Kakehi, I.Ichikawa, J .Org.Chem.35,426 (1970). andK. Hayakawa, J. B.Bapat, R.J. Blade, A. J. Boulton, J.Epsztajn, A. R. Katritzky, J. Lewis, P.MolinaLett., 2691(1976). Buendia, P.-L. Nie,and C. A. Ramsden.Tetrahedron 1 6 ’ M. IwaoandT.Kuraishi, J .Heterocycl. Chem.16,689 (1979); R. L.Williams andM. G . ElFayoumy,ibid. 9,1021(1972). M. KurzandW. Reichen, Tetrahedron Lett., 1433(1978); R. Richter andH. Ulrich, J .Org. Chem.43,3060(1978). 1 6 3 W . Reichen, Chem.Rev.78,569(1978). 159

268

[Sec. VI

CURT WENTRUP

X

= CH

orN

NH

CON,

H SCHEME 21

Wolff rearangement wasdemonstrated. A similar reaction inan acylnitrene (113) wouldleadtothepotentially antiaromatic oxazirine (114)(Eq.36). By

I

R-N=C=O

JI +

R-C-N-0

-

(116)

ring opening, a nitrene-carbene rearrangement to115 should then bepossibuta mesomeric orhigh-energy formofa ble. Compound 115 isnothing hasneverbeenobserved, butthe nitrile oxide (116). Sucha rearrangement reverse, thethermal or photochemical rearrangement ofnitrile oxides to

Sec.VI]


269

isocyanates, isa well-known r e a ~ t i 0The n .fact l ~that ~ nitrile oxides dorear(113)are, after all, range thermally toisocyanates indicates that acylnitrenes possible isocyanate precursors. The onlyalternative wouldbe a concerted Ab initio calculations indicate that rearrangement of 114 to isocyanate. 114(R = H)isnota true energy minimum, andthat 113(R = H)isomsinglet erizes toHNCO withanactivation energy ofonlyabout4 kcal/mo1.’6s-’67 Thissmall barrier explains why thenitrene-carbene rearrangement 113+ 115 hasnotbeenobserved, andwouldseemalsotobe consistent withthe failure totrap (singlet) acylnitrenes inthermal reactions leading toisocyanates. The question remains astothenature ofthe(singlet) species which can be trapped inphotochemical reactions, andwhichdoesnotgiveany isocyanate. Sucha species isalsoformedby photolysis of nitrile oxides (Eq.37).16’ 0I

A reasonable explanation of alltheexperimental datawouldbe that singlet nitrenes areinfact formedinthermal reactions, buttheyrearrange toisocyanates. The intermediates whichgiveC-H inextremely rapidly sertion products inphotochemical reactions mustthenbe excited states of or,when thestarting material isnotan azide, anexcited state of theazides thenitrene itself [e.g., inEqs.(33), (34), and(37)].* Therelative stabilities ofnitrenes andthree-membered heterocyclic rings seemtobe reversed inthesulfur series: Holm and co-workers found3phenylthiazirine (117)asa stable intermediate inthephotolysis ofseveral

* Apparently, benzoylnitrene isformedin thethermolysis ( I20C)of 0.N-bis(trimethy1withcyclohexene togive N-(3-cyclohexenyl)benzamide sily1)benzocarboximidic acid andtrapped ( together withphenyl isocyanate.’68a Benzoylnitrene isapparently alsoformedby sulfilimine photolysis andtrapped withcyclohexene togive N-benzoyl-7-azabicyclo[4.1.O]heptane (15.673’5 5 a 164 J. A. Chapman, J.Crosby, C. A. Cummings,R. A. C. Rennie, and R. M. Paton, Chem. Commun.,240 (1976);C.Grundmannand S.K. Datta, J. Org.Chem.34,2016(1969);C. P.Kochs,andJ.R.Boal, JusrusLiebigs Ann.Chem.761, 162 (1972). Grundmann, 1 6 5 D. Poppinger, L. Radom,and J.A. Pople, J.Am. Chem.SOC.99,7806 (1977). 166 A. Rauk andP.F.Alewood, Can.J .Chem.55, 1498 (1977). 16’ D.Poppinger andL.Radom,J. Am. Chem.Soc.100,3674 (1978). 1 6 8 G. Just andW. Zehetner, Tetrahedron Lett., 3389 (1967). 168a J.Rigaudy, E. Lytwyn, P.Wallach, andN. K. Cuong,Tetrahedron Lett. 21, 3367 (1980).

270

CURT WENTRUP

PhCN

[Sec. VI1.A

+S

SCHEME 22

heterocycles (Scheme22)at 10-15K,’69butno evidence fortheinitial 7 0 117 rearranged tobenzoformation ofthioacylnitrenes was obtainable.’ nitrile sulfide on warmingabove20 K, andathigher temperatures (220K) lost sulfur, gving benzonitrile (Scheme 22).’ 7 1 ~712

VII.Imidoylnitrenes and Nitrilimines (Azocarbenes) A. ACYCLICNITRENFS Imidoylnitrenes areazaanalogs ofbothvinylnitrenes and acylnitrenes. Not unexpectedly, therefore, thetwomajorreactions arecyclization onto aromatic rings, forming benzimidazoles, and a Wolff-type rearrangement (118)forms a mixtureof 2tocarbodiimides. 1,5-Diphenyltetrazole phenylbenzimidazole (119)(23%)anddiphenylcarbodiimide (120) (76%)on 73,1 7 4 However, onlythebenzimidazole was thermolysis above200 C.’ formed by photolysis.’ 75 A. Holm,N. Harrit, andI.Trabjerg, J. C.S.PerkinI ,746(1978). Holm,L.Carlsen, and E. Larsen, J. Org.Chem.43,4816(1978). A. Holm,J.J. Christiansen, andC.Lohse, J .C .S .Perkin I ,960(1976); A. Holm andN.

1 7 0A. 17’

ibid., 1445(1978); cf.R. K. Hove,T.A. Gruner, L.G. Carter, L. L.Black, H. Toubro, J .Org.Chem.43,3736(1978); R. K. Hove andJ. E.Franz, ibid., 3742. andJ. E.Franz, 17’ A. Holm,Adv. Hererocycl. Chem.20,145(1976). 1 7 3 P.A. S .Smithand E.Leon, J .Am. Chem.Soc.80,4647 (1958); J. VaughanandP.A. S. Smith, J. Org.Chem.23,1909(1958). 174 P.A. S.Smith, in"Nitrenes" (W.Lwowski, ed.), Chapter 4.Wiley(Interscience), New York, 1970. R. M. Moriarty andJ. M. Kliegman, J .Am. Chem.SOC.89,5959(1967).

Sec.VII.A]

271


(120)

(119)

(118)

Therelated compounds 121’ 7 6 and122l"gave onlythecarbodiimide 120 on thermolysis, buta 3% yield ofthebenzimidazole 119together with62% of120wasobtained by photolysis of121.’"6,’78

Phky/Ph N,

,s=o

0

phb/ Ph

y0,PPh3 (122)

(121)

Incontrast, theoxadiazolones 123and124gaveonlybenzimidazole (119) on t h e r r n ~ l y s iwhereas s , ’ ~ ~an * additional ’~~ 2% yield ofthecarbodiimide wasformed photoiytically ineach

N \ O A

PhkT’Ph NYo

(123)

(124)

ph)-*/

Ph

0

The differences observed areprobably tosome extent due todifferent A moresystematic study by Reesandco-workers shows reaction conditions. 125),tetrazoles (128), andoxathatvariously substituted sulfilimines (e.g., (131) give bothcarbodiimides (126) andbenzimidazoles (129and diazolones 130)together withtheinteresting cyclopenta[d]pyrimidines 127 on flash by vacuump y r o l y s i ~ Compounds . ’ ~ ~ * ’ ~126 ~ and 127werealsoobtained photolysis of125and 128(Scheme 23).The formation ofalltheproducts theimidoylcanbe rationalized withtheaidofa common intermediate, 132 (Scheme24)whicheither isomerizes to thecarbodiimide or nitrene R.Rajagopolan andB.G.Advani, J .Ory.Chem.30,3369(1965); A. Dondoni, G .Barbaro, andA. Battagha, ibid. 42,3372(1977). 17’ R. HuisgenandJ.WulfT,Tetrahedron Lett., 921 (1967). "I3 J.Sauer andK . K. Mayer,Telrahrdron Lett., 325 (1968). 179 T.Bacchetti andA. Alemagna, A t l iAccad. Naz.Lincei, CI.Sci.Fis., Mat.Nut., Rend.22, 637 (1957) [CA 52, 15511(1958)l. I S 0 J .H. Boyerand P.S . Ellis, J. C.S .PerkinI, 483(1979). "’ J.H. Boyerand P.J.A. Frints, J .Heterocycl. Chem.7 ,59,71 (1970). T. L.Gilchrist, C. J.Moody,and C.W. Rees,J .C.S .PerkinI ,1964(1975). T.L.Gilchrist, C. J.Moody,and C.W. Rees,J .C. S .PerkinZ, 1871(1979).

176

272

[Sec. VI1.A

CURT WENTRUP

uMe

q N = C = N - P h +

I

N=SMe,

Me

Ph

Me

600 C

126

+ 127+

i/ /

(128)

Me

SCHEME 23 126

bNTph Me

125,128, 131

--+

\

Me

Me &&Ph \

(132)

N

Me (133)

h K y

Me 127

t-

A /

Me

&yph --N

Qph

+

Me

Me SCHEME 24

129,130

Sec.VII.A]

CARBENES

A N D NITRENES

273

cyclizes tothetransient 3aH-benzimidazole 133.Several other examples of suchreactions havebeendescribed.’ 83*’84 Further studies showedthat, when an o-nitro groupispresent, thecar134-137 bodiimides formedby liquid-phase thermolysis oftheheterocycles underwent a novelrearrangement to 2-arylbenzotriazoles (138).’ 8 5 The yield of thelatter was almostquantitative starting from134 or 135,but 139wasthemainproduct from136 and137 (Scheme25). thebenzimidazole

2

255 C

(13% SCHEME25

Photolysis of 1-phenyl-5-phenoxytetrazoleresults in nitrogen lossand cyclization to 2-phenoxybenzimidazole; theintermediate imidoylnitrene (Eq.38).’86 couldbetrapped withisopropanol C. W. Rees,PureAppl.Chem.51,1243(1979); T.L. Gilchrist, P.F.Gordon,D. F.Pipe, and C. W. Rees,J .C. S.PerkinI, 2303(1979). P. G. Houghton,D. F.Pipe.and C. W. Rees,Chem. Commun., 771 (1979). F.L. Bach,J . Karliner, and G. E. van Lear,Chem. Commun.,1 1 10 (1969).

274

[Sec. VI1.A

CURT WENTRUP

oyo!%

.. N-N / f

l ! ! L

PhO

&Ph

Ph I

\

N

H

(38)

IFOH

PhOC(NH)NHPh

Flashvacuum pyrolysis of 5-phenoxytetrazole (140)tooka different (90%)indicates theforcourse: one pathleading to2-aminobenzoxazole mationoftheimidoylnitrene 141;theother path, giving benzaldehyde in 10% yield, involves theexpulsion oftwomolesofnitrogen. Thiscould occur (142)andphenoxycarbene (Scheme 26)."’ viaphenoxydiazomethane

(140)

[Ph-O-CH=N2

-N

(141)

..

2 Ph-0-CHI

Ph-CHO

(142)

SCHEME26

Direct evidence fortheformation ofaryldiazomethanes by flash vacuum of5-aryltetrazoles and5-(a-heteroaryl)tetrazoleshasbeensecured pyrolysis observation at -196 Cwhen by isolation,and by IR spectroscopic a-heteroaryldiazomethanes werecondensed directly on a KBr theunstable forthe diskcooled by a liquid nitrogen cryostat.lS9 Possible mechanisms formation ofdiazomethanes aresummarized inScheme27.

"’

I

RN o I

..

:N

(358)

by flash thermolysis, they, too, expel nitrogen toformcyanodienynes (Eq. 1 butwhengenerated insolution by lead tetraacetate oxidation ofthe

amines, ringexpansion to1,2,3-triazines occurs (Scheme 69).408 The latter areuseful starting materials forbenzazetes (359)by flash thermolysis or T.L.Gilchnst, G. E.Gymer,andC.W. Rees, J .C .S.PerkinI ,1747(1975). D. Christophe, R. Promel, and M. Maeck,Tetrahedron Lett., 4435(1978). 404 C.W. ReesandD. E.West, Chem.Commun.,647(1969); J .Chem.SOC.C ,583(1970). 4 0 5 K. Sakai and J.-P. Anselme, Bull. Chem.SOC.Jpn.45,307(1972). 406 R. S.Atkinson andC. W. Rees,J. Chem.SOC.C,772(1969). 407 B. M. Adger, M. Keating, C. W. Rees, and R. C. Storr, J.C. S.PerkinI ,41 (1975). 4n8 B. M. Adger, S.Bradbury, M. Keating, C.W. Rees, andR. C.Storr, J. C .S.PerkinI ,31 (1975).

402

4n3

346

[Sec. X

CURT WENTRUP

otxo R

X = CH or N 16-90%

(359)

I

SCHEME69

photoly~is.~’~ At higher temperatures, complete fragmentation into benzyne and benzonitrile takes place.409 (361) isformedby oxidation ofthel-aminotri1,8-Dehydronaphthalene 360;itundergoes stereospecific [2 21-cycloadditions toolefins (Eq. azine

+

111).410

(360)

(361)

Ringexpansion isobserved on oxidation ofl-aminooxindole406 (Eq.112) and hasalsobeeninvokedtoexplain theproducts formedfrom l-amino3,4,5,6-tetraphenyIpyridin-2-0ne.~’

NHz

C . W. Rees,R. C. Storr, and P. J. Whittle, Chem.Commun.,411 (1976); B. M. Adger, C. W. Rees,and R. C. Storr, J .C.S.PerkinI ,45 (1975). 410 C. W. Reesand R.C.Storr, J.Chem.Soc.C,760,765(1969); R. W. Hoffmann,G. Guhn, M. Preiss, and B.Dittrich, ibid., 769. 4 1 1 C. W. Reesand M. Yelland, Chem.Commun.,377(1969).

409

Sec.XI

CARBENES

347

A N D NITRENES

Thediazenes formed fromderivatives of1,2,3-benzotriazin-4-one havethe interesting property ofextruding oneortwomolecules ofnitrogen, whereby theresulting fragments apparently collapse tobenzocyclopropenone before 70).41 2,41 being trapped by methanol (Scheme Li+

R&,fNTos \

N’

t

SCHEME 70

A remarkable intramolecular addition ofaminonitrenes toa double bond 362.414 across space leads tothecagecompounds

A

(CH d o or i

Nothing appears tobeknownaboutheterocyclic aminocarbenes. M. S.Ao. E. M. Burgess, A. Schauer, and E. A . Taylor, Chem.Commun.,220(1969). J.Adamson,D.L. Forster, T.L. Gilchrist, and C.W. Rees,Chem.Commun.,221 (1969); J. Adamson,D.L.Forster, T.L. Gilchrist, and C.W. Rees,J .Chem.Soc.C ,981 (1971); M. G. Reinecke, L.-J. Chen,and A. Almqvist, Chem.Commun.,585 (1980). 4 1 4 L. Hoesch, N . Egger,and A. S. Dreiding, Helu.Chim.Acta61,795 (1978). 412

413

348

[Sec. XI

CURT WENTRUP

XI. Heterocycloalkylidenes Oxiranylidene (3f4)hasbeengenerated by flash thermolysis ofthenorbornadiene derivative 363(Eq.113).415

I

CH,=C=O

The reaction products werebenzene and ketene, anditwas shownby 364doesnotinterconvert withoxirene prior toproduct isotopic labeling that MO calculation^^^ indicate that the f~rmation.~ Indeed, double-zeta-SCF rearrangement of364 toketene ismorefacile ( E ,31.5kcal/mol) thanthat ( E ,74.6kcal/mol). A direct pathfrom364 tooxirene was toformylcarbene notinvestigated inthis butMIND0/3calculations wouldsuggest a 44 kcal/mol barrier forthatpro~ess.~ On theother hand, theMIND0/2 methodhadpredicted that cyclopropylidene formscyclopropene much faster thanallene,4 butthis isindisagreement withtheexperimental observation that cyclopropylidenes doopen veryefficiently toa l l e n e ~ . ~ l - ~ ~ l (365) andthietanylidene (366)havebeengenTetramethyl-3-oxetanylidene erated by thermolysis oftosylhydrazone lithium salts.422 The former ring opens, butthelatter isomerizes toa methylenethiirane, thereby paralleling 114-1 thebehavior ofc y ~ l o b u t y l i(Eqs. dene ~ ~ ~15).*

*Theunsubstituted oxetene hasbeenprepared andisolated by themethodshowninEq.(114) and foundtorearrange toacrolein withan activation energy ofabout24 kcal/mol [P.C. Martino andP.B.Shevlin, J. Am. Chem.SOC. 102,5429(1980)l. 4 1 5 R. W. Hoffmann and R. Schuttler, Chem.Ber.108,844(1975). 416 0. P.Strausz, R. K. Gosavi, andH. E.Gunning, Chem. Phys.Lett. 54,510(1978). 4 1 7 M. J.S.&war andC. A. Ramsden, Chem.Commun.,688(1973). 4 1 8 N. Bodor, M. J.S.Dewar,andZ.B.Maksic, J. Am. Chem.SOC.95,5245(1973). 4 1 9 P.W. Dillon andG. R. Underwood, J .Am. Chem.SOC.99,2435(1977). 420 P.S.Skell, J.E.Villaume, J.H.Plonka, andF.A.Fagone,J. Am. Chem.SOC.93,2699 (1971). 4 2 1 D. J.Pasto, M. Haley, andD. M. Chipman, J .Am. Chem.SOC.100,5272(1978). 4 2 2 A. G. Hortmann andA. Bhattacharjya, J. Am. Chem.SOC.98,7081(1976). 423 W. W. Schoeller, J. Am. Chem.SOC.101,4811(1979).

Sec.XI]

349

CARBENES A N D NITRENES

(366)

Theunsubstituted 2-methylenethiirane (367)hasbeenproduced inseveral of3-thietanylidene andcycloways, including flash pyrolytic rearrangements (Eq.116).424 The corresponding thietane sulfone extrudes propanethione SO,,however (Eq.117).425

O 0’a N N T o S

Na+

(367)

L

bC

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