Pyrazolones, Pyrazolidones, and Derivatives (The Chemistry of Heterocyclic Compounds, Volume 20)

PYRAZOLONES, PYRAZOLIDONES, AND DERIVATIVES Richard H. Wiley Uw'ver5i~of Louimille, Louisville, Kentidzy

Paul Wiley Upjobn Laboratories, Kalamqoo, Micbigan

1964

INTERSCIENCE PUBLISHERS a division of

J O H N WILEY & SONS

N E W YORK

LONDON

SYDNEY

PYRAZOLONES, PYRAZOLIDONES, A N D DERIVATIVES

This is the tiwn?ietll volume in the series

T H E C H E M I S T R Y OF H E T E R O C Y C L I C C O M P O U N D S

T H E C H E M I S T R Y OF H E T E R O C Y C L I C C O M P O U N D S A S E R I E S OF M O N O G R A P H S

A R N 0 LD W EI S S B E R GE R, Consdting Editor

PYRAZOLONES, PYRAZOLIDONES, AND DERIVATIVES Richard H. Wiley Uw'ver5i~of Louimille, Louisville, Kentidzy

Paul Wiley Upjobn Laboratories, Kalamqoo, Micbigan

1964

INTERSCIENCE PUBLISHERS a division of

J O H N WILEY & SONS

N E W YORK

LONDON

SYDNEY

First published by John Wiley t Sons, 1964

All Itight,s Reserved Library of Congress Cat,alog Card Number 63-20237

The Chemistry of Heterocyclic Compounds The Chemistry of heterocyclic compounda is one of the most complex branches of organic chemistry. It is equally interesting for its theoretical implications, for the diversity of its synthetic procedures, and for the physiological and industrial significance of heterocyclic compounds. A field of such importance and intrinsic difficulty should be made as readily accessible as possible, and the lack of a modern detailed and comprehensivepresentation of heterocyclic chemistry is therefore keenly felt. It is the intention of the present aeries to fill this gap by expert presentations of the various branches of heterocyclic chemistry. The subdivisions have been designed to cover the field in its entirety by monographs which reflect the importance and the interrelations of the various compounds and accommodate the specific interests of the authors.

ARNOLD WEISSBERGER Research Laboratories Eastman Rodak Company Rochester, New York

V

Preface Perhaps one of the most unusual facets of pyrazole chemistry is the extensive literatim on the pyrazolin-5-ones. Although this will probably come as no surprise to those who have had any interest in this class of compounds, the basic chemical reasons underlying this extensive literature, and the man-hours of chemical research which have gone into producing it,, deserve careful consideration. There are very real practical and theoretical bases for the situation. Historically, dyes and pharmaceuticals derived from pyrazolin-5-ones were among the first successful commercial synthetic organic chemicals in which interest has continued actively until thc present. Ludwig Knorr’s discovery in 1883 of antipyrine (%,3-dimetliyl-l-phenyl-3-pyrazolin-5-one) and Ziegler’s discovery in 1884 of the yellow dyestuff tsrtrazine: 4-(4sulfophenylazo)-l-(4-sulfophenyl)-5-oxo-2-p~ra~olin-3-car~ox~lic acid gave useful compounds before their structures were known. The value of these materials was immediately recognized and both are still in use. Much of the voluminous literature has resulted from studies directed toward modification of t.hese structures t o enhance thcir useful Characteristics. A group of widely used pharmaceuticals including aminopyrine (4-dimethylamino-2,3-dimcthyll-phenyl-3-pyrazolin-5-onc); dipyrone (2,3-dimethyl-l-pheny1-5-0~0-2-pyrozolin-4-methylaminomethanesdfonic acid sodium salt); and sulfamipyrine (a dipyrone analog) were developed. This research has recently culminated in the discovery of the useful anti-inflammatory properties of I n spite of the phenylbutazone (4-butyl-l,2-diphenyl-3,5-pyrazolidinedione). problems encountered in the undesirable side-reactions, principally agranulocytosiu, produced by these drugs, interest in them has never abated and one feels confident in predicting the discovery of additional useful and improved drugs in this structural classification. The development of new and improved dyes based on pyrazolinone structures has likewise led t o modern developments of no inconsidcrable magnitude. The use of tartrazine as an approved color for foodstuffs is of significance. The development of pyrazolinone dyes for use as magenta couplers and sensitizers in color photography and in metal chelate dye structures has established a renewed, modern interest in these dyes. The chclating characteristics, which will be of continuing toheoreticalstructurc interest in coordination chemistry, have been used in developing picrolonates (salts of 3-methyl-4-nitro-l-~-nitrophengl-~-pyrazolin-5-one) of possible utility in analytical procedures. vii

viii

Preface

The overwhelming deluge of chemical research arising from these utilitarian values has probably obscured the possibilities for fundamental research with these compounds. For the most part the structural problems that have been encountered are not complex. This is probably due in part to the fact that modern organic reaction techniques, such as radiationinduced transformations, modern structural concepts, such as molecular orbital theory and conformational analysis, and modern physical instrumentation, such as n.m.r., have not as yet been applied to the possibilities inherent in the chemistry of these compounds. It is also perhaps unusual that no pyrazolinone has been found to occur in nature. With the discovery in 1959 of /?-(l-pyrazolyl)alaninein the seeds of Gitrullus vulgaris, it would now appear probable that a pyrazolinone may likewise be found in some living tissue. This would certainly provide a new type of fundamental interest in the bio-organic chemistry of these materials. It might lead ultimately t o a clue as t o the mode of action of the pharmaceuticals-a problem about which there appears t o be little or no current available information. With the hope that the availability of the information on pyrazolinones presented in this volume might be of value in the furtherance of both fundamental and applied studies, the publishers and authors have considered i t best to present this material as promptly as possible in the present volume rather than as part of the pyrazole volume for which it was originally intended. The authors are appreciative of this cooperation on the part of the publishers and i t is hoped that users of this book will be aware that the immensity and sheer bulk of the literature has posed an unusual, but altogether interesting, challenge to all concerned in the preparation of this volume. The authors also wish especially to thank Miss Ollidene Weaver who did much of the typing of the manuscript in her spare time.

RICHARD H. WILEY

PAULWILEY

Contents

.

Part 1 Chemistry

.

Chapter I General 1 Introduction ............................................... 2 . Historical .................................................. 3. Structure ................................................. 4 . Synthesis ................................................. 5 Physical Properties ......................................... 6. Chemical Properties .........................................

. .

. . . . .

.

5 9 10 11

.

Chapter II Pyrazolin-5-ones 1 Introduction ............................................... 2 Unsubstituted Alkyl, Alicyclic, Aralkyl, Aryl and Heterocyclic Substituted Derivatives ..................................... A. 2-Pyrazolin-5-ones ....................................... (1) Syntheses .......................................... (2) Physical Properties ................................. (3) Chemical Properties ................................. (4) Hydroxyalkyl Types ................................. (5) AminoalkylTypes ................................... (6) Bis(2-pyrazolin-5-ones)............................... B 2-Pyrazolin.5.thiones ..................................... C 6-Imino-2-pyrazolines .................................... D 3-Pyrazolin-5-ones ....................................... (1) Syntheses .......................................... (2) Properties ......................................... (3) Bis(3-pyrazolin-5-ones)............................... E 3-Pyrazolin-5-thiones and -5-selenones . ..................... F 5-Imino-3-pyrazolines .................................... 3. Hydroxy and Mercapto Derivatives ........................... A . 2-Pyrazolin-5-ones ....................................... B 3-Pyrazolin-5-ones ....................................... 4 Amino, Imino, Hydrazino, Azo and Related Derivatives . . . . . . . . . A 2-Pyrazolin-5-ones ....................................... B 3-Pyrazolin-5-ones ....................................... 5. Halogen Substituted Derivatives ............................. A. 2-Pyrazolin-5-ones ....................................... B . 3-Pyrazolin-5-ones ....................................... 6 . Nitroso Substituted Derivatives .............................. A 2 -Pyrazolin-5-ones ....................................... B 3-Pyrazolin-5-ones ....................................... 1* ix

. .

3 4

. . .

. .

13

13 13 13 18

19 29 30

31 40 41 46 46

49 56

58 59 61 61 63 65 65

76 81 81 83 85 85

87

Contents

9

.

7 Nitro Substituted Derivatives ................................ A 2-Pyrazolin-5-ones ....................................... B 3-Pyrazolin-5-ones ....................................... 8 Aldehydes and Ketones ..................................... A . 2-Pyrazolin-5-ones ....................................... B 3-Pyrazolin-5-ones ....................................... 9 Carboxylic Acids and Derivatives ............................. A 2-Pyrazolin-5-ones ....................................... B 3-Pyrazolin-5-ones ....................................... 10 Sulfonic Acids and Derivatives ............................... A 2 -Pyrazolin-5-ones ....................................... B. 3-Pyrazolin-5-ones ....................................... 11 Functional Group Substituents on Nitrogen ................... A. 2-Pyrazolin-5-ones ....................................... B 3-Pyrazolin-5-ones ....................................... 12 Mercury Substituted Derivatives . . . . . . . . . . . . . . . . A 2-Pyrazolin-5-ones ....................................... B 3-Pyrazolin.5 -ones ....................................... 13 Metallic and Non-metallic Complexes .......................... A 2-Pyrazolin-5-ones ....................................... B 3-Pyrazolin-5-ones ....................................... 14. Miscellaneous Derivatives ....................................

.

. .

. . . . . . . . . . . . .

.

.

88 88

89 89 89 92 95 95 100

101 101 102 102 102 104

104 104 105 105 106 107 108

Chapter 111 2-Pyrazolin-4-ones ......................................

111

. Chapter V . 3-Pyrazolidinones ....................................... Chapter VZ. 3,4-Pyrazolidinediones ................................... Chapter MI. 3,5-Pyrazolidinediones 1. Introduction ............................................... 2 . Alkyl, Aralkyl, Heterocyclicalkyl and Aryl Substituted Derivatives 3. Hydroxy and Alkoxy Substituted Derivatives ................. 4. Amino and Azo Substituted Derivatives ....................... 5 . Halogen Substituted Derivatives ............................. 6 . Nitroso Substituted Derivatives .............................. 7 . C-Acyl Substituted Derivatives ............................... 8. N-Acyl Substituted Derivatives ............................... Chapter VIII. 5-Imino-3-pyrazolidinones 1. Introduction ............................................... 2 . Alkyl, Alicyclic, Aralkyl, Heterocyclicalkyl, Heterocyclic and Aryl

114

Chapter IV 2-Pyrazolin-4, 5-diones ...................................

Substituted Derivatives ..................................... 3. Functional Group Derivatives ................................

.

Chapter IX Miscellaneous 3,5-Pyrazolidinediones and Analogs

...........

115 120 123 124

128 128 129 129 129 130 131

132 137 139

Part 2 . Applications

. Chapter II. Color Photography......................................

Chapter I Medical .................................................

143 148

xi

Contents

.

................................. Chapter IV. Analytical Reagents ..................................... ChapterV.Miscellaneous ........................................... Chapter I11 Textile and Fabric Dyes

.

Appendix Systematic Tables of Pyrazolones and their Derivatives

.......

....................................................... ............................................................

152

155 157 161

References

483

Index

525

Systematic Tables of Pyrazolones and their Derivatives Physical Properties of Antipyrine Investigated . . . . . . . . . . 2-Pyrazolin.5-ones ................................... Section A Alkyl and Alicyclic Substituents ...................... Section B Monoaryl, Alkyl. and Alicyclic Substituents ............ Section C Aralkyl. Heterocyclicalkyl. Aryl. and Alkyl Substituents Section D Polyaryl Substituents ................................ Section E Heterocyclic. Alkyl. and Aryl Substituents ............. Section F a-Hydroxy- and a.Alkoxyalky1. Alkyl. Aralkyl. Aromatic. and Heterocyclic Substituents ........................ Section G. a-Amino- and a.Iminoalky1. Alkyl. and Aryl Substituents . TABLE 111 4.4'.Bis(2.pyrazolin. 5.ones) Linked by a Single Bond ..... TABLE I V 4.4'.Bis(2.pyrazolin. &ones) Linked by a Double Bond .... TABLE V 4.4'.Bis(2.pyrazolin. &ones) Linked by a Carbon Chain Section A. l.l'.Phenyl.3.3 '.methyl Substituents................... Section B Alkyl and Aryl Substituents. ......................... TABLE VI Miscellaneous 4.4 '.Bis( 2.pyrazolin.5.ones) ............... TABLE VII 4.4'.Bis(Z.pyrazolin. 5.ones) Linked by Chains Containing N a n d S ........................................... TABLE MII 3.3'.Bis(2.pyrazolin. 5.ones) ........................... TABLE IX l.l'.Bis(2.pyrazolin. &ones) ........................... TABLE 3 Furlones ........................................... TABLE XI 2 -Pyrszolin-5-thiones ................................ TABLE XII 5-Imino-2-pyrazolines ............................... TABLE XI11 N . N '.Big( 5-imino-2-pyrazolines)....................... TABLE XIV 3-Pyrazolin-5-ones................................... Section A. Alkyl and Alicyclic Substituents ...................... Section B Alkyl and Aryl Substituents .......................... Section C Alkyl. Aralkyl. Heterocyclicalkyl and Aryl Subatituents Section D . Alkyl. Aryl and Heterocyclic Substituents ............. Section E a.Hydroxy.. wdcyloxy.. and a.Alkylthioalky1. Alkyl and Aryl Substituents ................................... Section F a.Amino.. a.Imino.. a.Oximio.. a-Amido- and a-Hydrazinoalkyl. Alkyl and Aryl Substituents................. 4.4'.Bis(3.pyrazolin. 5.ones) Linked by a Single Bond . . . . . TABLE xv 4.4 '.Bis( 3-pyrazolin-5-ones)Linked by Carbon or HeteroTABLE XVI atoms ............................................. Miscellaneous Bis(3-pyrazolin-5-ones) and B i s ( 5 - i h o - 8 TABLE XVII pyrazolines) ........................................ xiii TABLE I

TABLE I1

. . . . . .

.

...

.

.

. . .

..

11 161 161 165 178 185 189

200 202 207 210 211 211 214 217 218 222 224 231 233 234 245 246 246 247 255 263 268 273 278 278 281

xiv

List of Tables 3-Pyrazolin-5-thiones and -5-selenones ................. 5-Imino-3-pyrazolines ............................... 2.Pyrazolin.5.ones . Hydroxy and Mercapto Derivatives . 3.Pyrazolin.B.ones . Alkoxy, Aryloxy, Acyloxy, and Alkylthio Substituents .................................... 2.Pyrazolin.5.ones . Amino, Imino, Hydrazino, Azo. and Related Derivatives ................................. 4-Arylazo-2-pyrazolin-5-ones .........................

TABLE XVIII TABLE XlX

.

TABLE XX TABLE XXI TABLE XXII TABLE XXIII

283 284 288 291 293 303

. . .

303 Section A Alkyl and Aralkyl Substituents ....................... Section B Alkyl, Aryl, and Heterocyclic Substituents ............. 307 Section C Arylazo Substituted with Functional Groups ........... 330 TABLE

xxw

I.Pyrazolin.5.ones . Imino, Amino. Amido. Azo. Aminoazo. 334 and Hydrszido Substituents ..........................

2.Pyrazok.5.ones . Halogen Substituted ................ TABLE XXVI 3.Pyrazolin.5.ones . Halogen and Halogen Combined with Carboxylic Acid and Derivatives ...................... Z.Pyrazolin.5.ones 4-Nitroso Derivatives ............... TABLE XXVII TABLE xxvm 3.Pyrazolin.5.ones Nitroso and Nitro Substituted Dcrivafives ............................................... TABLE XXIX 8.Pyrazolin.B.ones . 4-Nitro Derivatives ................. 2.Pyrazolin.5.ones . Aldehydes and Ketones ............. TABLE xxx TABLE XXXI 3.Pyrazolin.5.ones Acyl Substituents on Carbon . . . . . . . . TABLE XXXII 2-Pyrazolin-5-one-(3 or 4)-carboxylic Acids ............. TABLE xxxm 2.Pyrazolin.5.ones Carboxyl Derivatives Combined with Other Functional Substituents ........................ TABLE XXXIV 3.Pyrazolin.5.ones . Carboxylic Acids and Thiocarboxylic Acids and Derivatives ................................ TABLE w x v 2.Pyrazolin.B.ones . Sulfonic Acids ..................... TABLE x x x v ~ 3.Pyrazolin.6.ones Sdf'onic Acids ..................... TABLE X X X ~ I 2.Pyrazolin.B.ones Acyl and Carboxyl Derivatives and Sulfonyl Substituents on N-1 ......................... TABLE XXXVIII t.Pyrazolin.5.ones Acyl Substituents on Nitrogen ....... TABLE xxx~x Mercurated 3-Pyrazolin-&ones ........................ TABLE XL 2-Pyrazolin-4-ones and 4-Imino-2-pyrazohes ........... TABLE XLI 2.Pyrazolin.4,5.diones ................................ TABLE XLII 3-Pyrazolidinones ................................... Section A All Substituents Except Mercury ..................... Section B Mercury Substitucnts ................................ TABLE xsm 3.Iminopyrazolidines ................................. TDLE XLIV 4-Imino-3-pyrazolidinones ............................ TABLE x L V 4,47Bis(4.imino. 3.pyrazolidinones) ..................... TABLE XLVI Miscellaneous Bis(3,5.pyrazolidinediones), Bis(5-imino-3pyrazolidinones), and Bis(4-imino-3-pyrazolidinones) ..... TABLE

xxv

. . .

344 345 347 3g1

353 354 356 359

.

. .

.

. .

366 366 373 373 374 380 381 382 387 388 388 391 393 394 405 406

List of Tables

xv

3. 5.Pyrazolidinediones ............................... Section A Alkyl and Aralkyl Substituents ....................... Section B Alkyl. Aralkyl. Heterocyclicalkyl. Aryl and Acyl on Carbon Substituents ....................................... TABLE xLvm 3.5.Pyrazolidinediones . Acyl on Nitrogen and Oxygen. Nitrogen. and Halogen Substituents ................... TABLE XLIX 5-1mino.3.pyrazolidinones ............................ Section A . Blkyl. Alicyclic. Aralkyl. Heterocyclicalkyl. Heterocyclic. and Aryl Substituents ............................... Section B Acyl. Carboxyl. and Carboxyl Derivatives .............. Section C . Halogen. Nitroso. Amino. Imino. Azo. and Amido Substituents ........................................... 4.4 '.Bis( 5-imino-3-pyrazolidinones)..................... TABLE L 3-Methyl-1-phenyl-2-pyrazolin-5.ones Dyes . . . . . . . . . . . . TABLE LI 2.Pyrazolin.5.ones . Dyes ............................. TABLE LII 3.PyrazoUn.5.ones Dyes ............................. TABLE LIII 4.Arylazo.3.pyrazolin.5.ones . Dyes .................... TABLE LIV TABLE XLWI

. .

.

.

.

408 408 409 422 424 424 441 443 445 448 461 475 482

PART

I

CHEMISTRY

CHAPTER I

1. Introduction

Pyrazolinones and pyrazolidinones are 0x0 derivatives of pyrazolines and pyrazolidines, respectively, and are so named in Chemical Abstracts at present. However, the usual method of naming in the earlier literature is the pyrazolone-pyrazolidone system. Although a large number of tautomeric structures are possible for pyrazolinones, the usual assignment of ring structures is as shown in (I),(11)and (111). The ChemicaE Abstracts names for these are: (I)%pyrazolin-5-one, (11) HC

-

N2 113

~

N ‘’

46

HC-CH 3

=Or

HC-C=O 4

H./Jz

6/k=O

N ‘’

Na 113

I

J

H2

‘N’

H

H

H

(1)

(11)

(111)

3-pyrazolin-&one and (111) 2-pyrazolin-4-one. The names most frequently used in the literature for (I) and (11) are 5-pyrazolone and 3pyrazolone, respectively. In many cases there has been no certain identification of a compound as a 2-pyrazolin-5-oneor a 3-pyrazolin-5one. Because of this it will be assumed that all pyrazolin-5-ones having no substituent at N-2 are 2-pyrazolin-5-ones unless thfs has been definitely shown to be incorrect. The basic ring structures for pyrazolidinones are (IV) and (V) but no compounds of type (V) have been

4

Part 1. Chapter I

reported. Compounds of type (IV) are usually called pyrazolidones in the literature. The nomenclature used in this discussion will generally be in accordance with Chemical Abstracts, although some trivial names will be used since these are very common among pyrazolinones and are frequently well known. Examples of such names are antipyrine, pyrazole blue and aminopyrine. The numbering is as shown in formulas

WV). As an aid t o classification all compounds in which the tautomerism 1

>CH--C=X

>&XI3

I

can theoretically exist will be considered as > CH-C=X compounds (X=O, S, Se, Te, NH, N l t or NCOK). It is recognized that this will frequently be in disagreement with the actual structure which, if known, will be indicated in the discussion. This review will cover all pyrazolinoncs and pyrazolidinones reported up to and including the 1956 Chemical Abstracts and will cover the morc important publications which have appeared since. However, a number of publications dealing with applications, biological activities and analysis were omitted as they were regarded as being of insufficient significance for coverage. A rather extensive list of the compounds of these types which have been reported is included, although here again there are many omissions. A number of dyes were not included as their structure was uncertain. Some very complex dyes which would require considerable space for inclusion are omitted and a reference t o them is given. I n general, the large number of salts reported were not included and in particular all picrolonates were omitted. However, many of the complexes which pyrazolin-5-ones form so readily are discussed, although in some cases these may be of a salt-like nature. Compounds in which the 0x0 substituents are replaced by such groups as imino, thiono and seleno are considered in this review. The early literature, which is available from standard sources (Beilstein, Meyer-Jacobson) has not been exhaustively compiled. 2. Historical

The well-known German chemist, Ludwig Knorr, reported the preparation of the first pyrazolinone in 1883.*05This compound was 3-methyl-l-phenyl-2-pyrazolin-5-one prepared by the reaction of ethyl acetoacetate with phenylhydrazine. I n the first publication no structure was proposed, but in a, later publication806structure (VI)was suggested.

General

5

I n this same article synthesis of the widely used analgesic and antipyretic, antipyrine, was reported. This was one of the first synthetic

(W organic drugs. It was marketed and used before the correct structure for pyrazolinones was suggested by Knorreo9in 1887 and the name by Ruhemann .Iz3 O 3. Structure

A short time after the discovery of pyrazolin-&ones K n ~ r r ~ ~ ~ proposed the 2-pyrazolin-5-one and the 3-pyrazolin-&one structures on the basis of analyses, methods of preparation and reactions. These structures in the main approximate the correct ones and in some cases are correct. However, a large number of structures are theoretically possible for most pyrazolin-5-ones and in many cases no one structure can be said to fit completely. The tautomeric isomers (VI1)-(XIII) are possible for unsubstituted pyrazolin-5-ones: HC

-

g..

I1

N

H& -

HC =CH

l

c=o

I T " "

l

c=o

HN

N

'N/

H

H

(VW

(VIII)

HC -- CH

1

\N/ H

(XI

I

S O H

HC -

g..

il

N

S O H

\ / N

(XI)

C=O

\N/ (IX)

lii'"

H&-

N \N/

(XIS)

C-OH

HC-CH

I

I

HN

C-OH

\" (XIII)

I n addition a number of ionic tautomeric isomers can be envisaged which could make very important contributions to the over-all structure. These are (X1V)-(XVIII). Substitutions at N-1, N-2 and disubstitntion at G 4 substantially alter the possibilities for various tautomeric

6

Part 1. Chapter I

and resonance forms. Of the possible tautomeric forms shown, only (VII), (VIII) and (X) appear to exist to any extent although Valyashko

H

(XVXI)

(XVIII)

and B l i z n y k ~ v report ~ ~ l ~ diazo structures as present on the basis of rather complex ultraviolet absorption spectra. There is extensive evidence, both chemical and physical for these three structures. The presence of enolic forms is shown by the fact that one of the most common tests for 2-pyrazolin-5-ones is the use of ferric chloride to form a colored complex809~1551 and by the ready formation of 5-alkoxypyrazoles from p y r a z ~ l i n o n e s . ~ ~Dmowska ~~ and St. Weil 376 have claimed the isolation of the keto and enol forms of 4,4'-(3-nitrobenzyliand keto and enol forms dene)bis(3-methyl-l-phenyl-2-pyrazolin-5-one) of similar compounds have been i s 0 1 a t e d . l ~1135 ~ ~ . Existence of the form (VIII) is shown by alkylation of 3-phenyl-2-pyrazolin-5-one to give 2-methy1-3-phenyl-3-pyrazolin-5-0ne.~~ The structures of pyrazolin-5-ones have been very extensively studied using ultraviolet and infrared absorption spectra and such techniques have established unequivocally that (VII), (VIII) and (X) are the chief tautomeric contributors. Most of the workers in this field have emphasized the complexity of ultraviolet spectra due to the existence of tautomeric mixtures. GomezSa4has stated that no deduction can be drawn from the ultraviolet spectra of l-methyl-3-phenyl-2and its 4pyrazolin-ti-one, 2,3-dimethyl-l-phenyl-3-pyrazolin-5-one dimethylamino analog because of the tautomeric equilibria present. The existence of an equilibrium between 2-pyrazolin-5-one and 3pyrazolin-5-one structures has been proposed by Biquard and Grammaticakis 95 for 3-alkyl- 1-aryl- and 1-aryl-3,4-dialkyl-2-pyrazolin-5-ones on the basis of ultraviolet absorptions. Gagnon and

General

7

have been most active in this field and have drawn several conclusions from ultraviolet studies, some of which were in disagreement with infrared absorption spectra interpretations. These workers have found that pyrazolin-5-onesabsorb ultraviolet light either in the neighborhood of 240-260 mp with a log E value of 4.0-4.4 or at 295-325 mp with a, log E value of 3.3-4.0, or in both regions. The shorter wave length absorption is believed to be due to > &C< absorption while the longer is due to > C=N-. Thus type (VII) would show the longer wave length absorption, type (VIII) the shorter, and type (X) both, or a mixture of any two would show absorption at both wave lengths. 4-Alkyl-3-aryl-2pyrazolin-5-ones absorb at the lower wave length only, indicating that they possess only structure (VIII). However, this conclusion was in disagreement with the finding that these compounds exhibited absorption in the infrared at 1600 cm.-l due to >C=Nand at 3300 cm.-l 605 and showed no absorption attributable to carbonyl. Thus they must actually be of type (X). From the ultraviolet spectra 4-alkyl1,3-diaryl-Z-pyrazolin-5-0nes were concluded to be a mixture of types, but the infrared spectra very clearly showed them to be type (VII) as there was only carbonyl and > G=N- absorption. It would appear that the 1-arylpyrazolin-5-oneswith no N-2 substituent are usually of type (VII), since Glauert and Mann578found no imino or hydroxyl absorption in the infrared spectra of 1,4-diaryl-2-pyrazolin-5-ones. Recently 366a the infrared spectra of 3-methyl-, 3-trifluoromethyl-, 1,3-dimethyl-, I-methyl-3-trifluoromethyl- and 1-phenyl-3-trifluoromethyl-2-pyrazolin-5-one have been studied. The presence of absorption bands at 2400-2700 cm. believed due to zwitterionic forms indicated that these compounds exist largely as form (XIV). The effect of substitution on the structure of pyrazolinones is a very important one, because certain of the tautomeric forms then become impossible. For example, substitution at N-1 allows only structures (VII), (VIII) and (X). Substitution at N-2 would make (VIII) and (XIII) the only possible tautomers. A combination of N-1 and N-2 substitution leaves (VIII) as the only possibility. If there is substitution at N-1 and disubstitution at C-4, then only isomer (VII) is possible. There has been little investigation of the possibilities for tautomeric structures of N-2 substituted pyrazolinones. However, K i t a m ~ r a has ?~~ suggested that such compounds exist as a mixture of forms (VIII)and (XIII). There has been considerable discussion of the situation in regard to the ionic structures. About fifty years ago Michaelis 978* 983. Q84.1002~1003 proposed (XIX) as the structure for 1,2-disubstituted pyrazolinones. I n modern terminology this could correspond to structure (XIV).

8

Part 1. Chapter I

Koma.da844-846 recently has used this structure to explain the structure of the tetrabromides of this type of pyrazolinones. l i i t a m ~ r a ~ ~ ~

I

R’ (XIW

has used rather inconclusive chemical evidence in support of the exis tence of 3-pyrazolin-5-ones in form (XVII). Somewhat better evidence for the structural contributions of these resonance forms has been given in the form of dipole moments, ultraviolet data and bond lengths. Jensen and Friedinger715 and Brown et aZ.246have found abnormally high dipole moments for 2,3-dimethyl-l-phenyl-3-pyrazolin-6-one and its thiono analog. This waa considered to be due to contributions by forms (XIV) and (XVII) to the extent of about 35 per cent. A structure analogous to (XVII) has been proposed for 2-pyrazolin-5-thionesalso on the bwis of dipole moments.934Valyashko and Bliznykov1509have found that 4-amino-2,3-dimethyl-I-phenyl-3-pyrazolin-5-ones have ultraviolet spectra very similar to that of 5-chloro-3-methyl-1-phenylpyrazole methochloride, indicating a considerable contribution by form (XIV). Krohs860has demonstrated a considerablc contribution from the carbonyl form, as shown by infiared absorption in the carbonyl region. This has been confirmed by other infrared studies, and it has been proposed on the basis of iliis that form (VIII)is the predominating one in some cases.366aItomain120Ehas studied the bond lengths in 4-bromo-2,3-dimethyl- 1-phenyl-3-pyrazolin-5-one. These bond lengths indicate a resonance hybrid structure composed of forms (VIII) and (XIV) with some contribution from (XVII). Chattaway and co-workers287 -290* 294 have synthesized a number of 1-aryl-2-pyrazolin-4-ones which, as a rule, have been considered to have the 4-hydroxypyrazole structures. However, some of these must have the 2-pyrazolin-4-one structure due to digubstitution at (2-5. Emerson and Beegle 425 have synthesized some 2-pyrazolin-4-ones unsubstituted at N-1 permitting more possibilities for isomerism. These will be discussed later. The pyrazolidinones (IV) present a number of possibilities for structural isomerism, but very little study of their structure has been made. It is generally assumed that they have the classical form (IV).

General

9

Certainly they would not be expected to have the tendency of 2pyrazolin-&ones to enolize, since they could not achieve an aromaticlike structure. 4. Synthesis

Only a few of the principal synthetic methods for pyrazolinones and pyrazolidinones will be discussed at this point. Other methods will be mcntioned in connection with various classes of compounds. The procedures mentioned here will be discussed in greater detail at the appropriate places. By far the most widely used synthesis for 2-pyrazolin-5-onesis the condensation of a B-ketoester with a hydrazine (eq. 1).6,11.64,269.303*805

---I, /_ 1

Ra

IV-

RZ

I I

+

I ~ ~ C O C - - C O O R ~R ~ X H R ’ H ~

R3

---it3

N

\,=o

(1)

N

I

R5

The R groups in this reaction can be almost anything, H, alkyl, aralkyl, aryl, heterocyclic and many others. Nodifications of this procedure have employed /3-thionoesters,1006* loo8 /I-oximinoesters1555 and /3ketoamide~.~Q. Perhaps the most common procedure for preparing 3-pyrazolin-5ones is alkylation of a 2-pyrazolin-&one at N-3 a.s shown for the synthesis of antipyrine (ey. 2).806 Other alkylating agents such as dimethyl

LaH,

JeH,

sulfate781 can be used, and almost any 2-pyrazolin-5-one can be alkylated, although frequently 0-alkylation occurs and also alkylation at N-1 if it has no substituent. Another useful synthesis of 3-pyrazolin5-Ones is the condensation of a /3-ketoester with acetylphenylhydrazine (eq. 3). The acetyl group is lost and the phenyl group appears a t R1COCH2COORa

+ CaH,NHNHCOCH3

---+

\N r H

(3)

Part 1. Chapter I

10

N-2.9s4*g8s*993 A modification of this consists of using a symmetrically

substituted hydrazine to give 1 ,2-disubstituted-3-pyrazolin-5-ones.54 The synthesis of pyrazolidinones is readily achieved by condensaester1209.1569 or amide758with a tion of an cqB-unsaturated hydrazine. In eq. 4 is shown the reaction for an amide. Ra R'R2C=CCOXHR'

I R3

+ RWHNHS

___+

(4)

H

The reaction of a malonic ester or chloride with hydrazines gives 3,5-pyrazolidinediones(eq. 5).1*8.222* 24*. 252.1234

cox I

RWH

I

+ RaNHNHR3 +

O=l-IR'

cox

5. Physical Properties

Most pyrazolinones and pyrazolidinones are solids, although many, some very complex, can be distilled as high-boiling liquids. 2-Pyrazolinlowers 5-one is a liquid boiling at 163". Reduction of the >&Nthis to 132'. Substitution on N-1 and N-2 gives a low-melting solid. However, substitution at C-3 or C-4 has a more pronounced effect, as which melts at 215". Alkyl for example in 3-methyl-2-pyrazolin-5-one, substitution in pyrazolidinones does not have such a marked effect but does raise boiling and melting points. Almost all aryl substituted pyrazolinones and pyrazolidinones are solids, but many can be distilled. The solubility of pyrazolinones and pyrazolidinones is so varied M to make generalizations of little value. The simpler ones, of lower molecular weight, are soluble in hot water and a few are even soluble in cold water. Almost all are soluble in polar organic solvents and many are soluble in ether and benzene. However, most are insoluble in petroleum ether. Ultraviolet and infrared spectra have been considered in some detail in the section dealing with structure. Concerning the ultraviolet spectra it can be stated that, while there is considerable absorption by pryazolinones and some pyrazolidinones, these absorptions are so complex, owing to tautomerism, that little can be deduced from them.

General

11

The infrared spectra are as would be expected. In some cases there are clear bands due to carbonyl and > C=N- and in others the carbonyl band is missing but hydroxyl bands are present. Raman spectra of 116' antipyrine and aminopyrine have been investigated.273* DipoIe moments have already been discussed in the section dealing with structure. They have been found to be quite high for the few 3-pyrazolin-5-ones studied. The only value reported for a 2-pyrazolin5 - 0 is~ considerably ~ lower, being 2.54 for 3-methyl-2-pyrazolin-5-one. A number of miscellaneous physical properties of antipyrine and a few of its derivatives have been studied. These are listed with references in Table I. TABLEI . Physical Properties of Antipyrine Investigated

___

Physical Property

Crystal Form Dielectric Constant Dielectric Coefficient Heat Capacity Latent Heat Phase Diagram Surface Activity

Refercncc

___ - _-

- -__ 844 367 367 1466 668 669 561

6. Chemical Properties

Only a few of the more important chemical properties of pyrazolinones and pyrazolidinones will be discussed in this section, since these will be covered more thoroughly in connection with the different classes. The pyrazolinones are in general weak acids805 and many can be titrated with strong bases. The 2-pyrazolin-5-ones are stronger acids than the 3-pyrazolin-5-oneslSz3which are very weak. Most pyrazolinones are readily soluble in bases. The pyrazolidinones are not acidic, unless some special feature makes them so. The most extensive data on basicity have been provided by Veibel and ~ o - w o r k e r slSz2* ~ ~ 1525 ~ ~ who * have titrated a number of pyrazolinones with perchloric acid in acetic acid. The pK, values range from 10.3 to 12.3, except for 4,4-disubstituted and 4-halogen substituted 2-pyrazolin-&ones. The 4,4-disubstituted 2-pyrazolin-5-ones are so weak that they are essentially neutral, while the halogenated compounds have pK, values of about 13.2. Both 2-pyrazolin-5-ones and 3-pyrazolin-5-ones undergo substitution at G 4 in an aromatic faahion. Halogenation, nitration and coupling with diazonium salts occur readily. In 2-pyrazolin-&onessuch reactions

12

Part 1. Chapter I

as condensation with aldehydes and ketones and alkylations occur readily at (2-4. The pyrazolinone and pyrazolidinone rings do not have aromatic stability, although in many cases they can assume an aromaticlike structure. The ring is readily destroyed by acid or base hydrolysis and by oxidation. Pyrazolidinones react very much aa do aliphatic hydrazides .

C H A P T E R I1

Pyrazolin-5-ones 1. Introduction

The pyrazolin-5-ones are classified and discussed according t o their functional groups. Compounds having more than one pyrazolinone ring will be classified similarly to the monocyclic ones and discussed in thc same section. All compounds which can theoretically assume the 2-pyrazolin-5-one structure, except those classified as 3,5-pyrazolidinedione derivatives will be considered to be such. Only those for which this is impossible, i.c. 2-substituted pyrazolin-5-ones, will be considered 3-pyrazolin-&ones. A number of compounds having no functional group on the pyrazolinone ring, which have been synthesized for study as coloring agents are listed in connection with the discussion of pyrazolinones used in photography. A number of very complex compounds of similar type are not included in this review, but references to them are given in the dye section. All compounds having no functional group attached t o the pyrazolinone ring will be considered in the section dealing with alkyl, alicyclic, aralkyl, aryl and heterocyclic substituted pyrazolin-5-ones. All oximes are classified as nitroso compounds unless i t is manifestly impossible to do so as in a case having the substituent =NOR. This would be listed in the section concerning amino-2-pyrazolin-5-ones. The 5-iminopyrazolines and the aminopyrazoles which in this discussion are classified as 5-iminopyrazolines are considered with the 2-pyrazolin-5-ones appropriate to their substitution, as are the 2-pyrazolin-5-thiones. 2. Unsubstituted Alkyl, Alicyclic, Aralkyl, Aryl and Heterocyclic

Substituted Derivatives A. 2-PyrazoLin-5-ones

(1) Syntheses

Syntheses of the 4-pyrazolin-5-one ring will be discussed in this section. Those syntheses of this cla.ss which depend upon introduction 13

Part1. ChapterII

14

of a substituent into the already formed ring will be discussed under reactions. Compounds of this type are listed in Table I1 (see Appendix). Methods for synthesis of 2-pyrazolin-5-onesare extremely numerous but the one most frequently used is that shown in eq. 1, the condensation of a /?-aldehydo-or /?-kcto-esterwith a hydrazine. The substituents on the ester and the hydrazine have been greatly varied. All types of alkyl, alicyclic, aralkyl, aryl and heterocyclic substituted esters have been used. In general the yields are the better the smaller the substituents R2,R3 and R4.I n the case in which R2 and R3 are benzyl, . ~ ~ if ~ pyrazolinone formation does not occur when R4 is p h e n ~ l Also, lt2and R3 are aryl, pyrazolinone formation fails. When R3 is larger than methyl, formation of pyrazolinones is more difficult, although many more complex esters having one a-substituent or none have been Ethyl a,a-diethylacetoacetate does not form a pyrazolinone with hydrazine hydrate, but the corresponding methyl ester does.61 R1 may be hydrogen, in which case the ester would be a #I-aldehydoester,303.813. 1636 or it may be alky1,42,53,61,97,135.572.805.1582 a r ~ 1 469.505 , ~ ~ . heterocyclic,lO.307*682 a l i c ~ c l i c , ~or~ *of other types.12* It has been reported that cyclization of benzoylacetic esters to pyrazolinones is easier than is that of acetoacetic esters.777Almost any monosubstituted hydrazine can be used to prepare a pyrazolinone. The simpler the substituent the better the yield usually is,505 though alky1,250.788a1icyclic,lo1 a r a l k ~ 1 , ~ ~arylZ5. O 136*229* 1251 and heterocyclic 7 4 - 91 833 hydrazines have been successfully employed. The conditions used in condensing /?-ketoesters and hydrazines to form pyrazolinones are quite varied. The most widely used method is simply heating the ester and the hydrazine together without added catalysts. The temperatures used are most frequently 100-200°.250.505*805 Quite frequently the hydrazine is condensed with the ketoester to form a hydrazone under milder conditions than are used in the final cyclization step.505A modification of this is to use an already prepared hydra1490 Acidic 2 5 * 1372 and basic conditions are frequently used, particularly in the cyclization step. Under favorable circumstances the yields are very good. Gagnon and c o - w o r k e r ~have ~ ~ ~prepared a series in yields of 83-96 per cent, of 4-alkyl-3-phenyl-2-pyrazolin-5-ones although yields of corresponding 1-phenyl compounds were much lower, varying from 50 to 81 per cent. I n summarizing this method of synthesis it can be said that it is so extremely general that almost any non-substituted or monosubstituted /3-ketoester will react with almost any monosubstituted hydrazine to form a 2-pyrazolin-5-one. A number of niodifications of the /I-ketoester-hydrazine synthesis 413u

Pyrazolin-5-ones

15

of pyrazolinones has been used. One of these modifications is the use of acid hydrazides (eq. 6).6. 360 Under mild conditions the pyrazolinone 960

CH3COCH&OOC~H,+ RCONHNH,

5 c H 3 ~ . - 0

" H

(6)

obtained has the acyl substituent on N-1, but at temperatures of 25' to 100" this substituent is lost. I n addition to 8-ketoesters, the corresponding amides and anilides have been employed in a number of caaes lg7* 378. 872,1030.1276 under very similar conditions. The amides may or may not be substituted on the nitrogen atom. Mitra1006.1007 has reported the use of /3-thionoacetoacetatesinstead of acetoacetic esters to form pyrazolinones. The use of p-ketoesters in which R1or R2of eq. 1 is CH,CO or C2H500C165.358 gives pyrazolinones with elimination of the acyl substituent. A further modification of this synthesis is shown in eq. 7.

NNHCOCH,

H

A number of syntheses of 2-pyrazolin-5-onesdepend on the reaction of compounds, other than /3-ketoesters, substituted in the p-position or of a,P-unsaturated acids, esters and amides. The most frequently used unsaturated compounds are those having a triple bond in the a,/?position~1023,1024.1075.1548.1680R2 can be H0,1652 RO 1023.1024.1686 or H2N (eq. S).1023-1024 A similar reaction is the condensation of ethyl

H

a-chlorocinnamnte with hydrazine t o give 3-phenyl-2-pyrazolin-Sone.610 This probably goes through an acetylenic intermediate. The condensation of methyl crotonate, isocrotonic esters and methyl methacrylate with hydrazines gives as a side-product small yields of 2-pyrazolin-5-ones, the main products being p y r a z o l i d i n o n e ~ . ~ ~ ~ . ~ ~ ~ ~ The pyrazolidinones are probably dehydrogenated to a slight extent to give the pyrazolinones. The reaction of p-alkoxy-a,/3-unsaturated esters 1023.1024 and /I-alkylthio-and/?-acylthio-a,8-unsaturated esters loo7 with hydrazines to give pyrazolinones (eq. 9) proceeds quite readily. The

Part 1. Chapter I1

16

reaction of ketene with arylhydrazines forms 2-pyrazolin-5-ones.723* 885 R*C=CHCOOCzH,

+ HzNNHz

---+

R1- 11

XRa I

'

?.N,J=o H

X =0 or S;Ra=alkyl or acyl

(9)

The first product formed is the hydrazone of the corresponding acetoacethydrazide (XX). This then cyolizes to the desired product at eleCH,-CCH&ONHNHAr

II

NNHAr (XX)

vated temperatures. The reaction of phenylhydrazine with j?-halogenated acids to give pyrazolinones as shown in eqs. 10 and 11 has been 858 These reactions probably occur by removal of water reported.446*

ClCH,CHCOOH

I

+ C,H5NHNH,

-+

I!

3

\x,

OH

'70

(11)

t'& or hydrogen bromide to give an unsaturated intermediate. It has been shown that such an intermediate, methyl j?-chloroisocrotonate, reacts with hydrazine hydrate to give 3-methyl-2-pyrazolin-5-0ne.~~~ A number of heterocyclic systems react with hydrazine to give pyrazolinones. These are shown in eqs. 12-17 and are of little synthetic utility.

ij K=CH, or C,H,

Pyrazolin-5-ones HOOC--/

O\=O

I1vI

17

-

(14)1553

,N/J=o H CHa-

4,NJ=o

(15)laZ2

H

I

CH3

Ho-,iN'i"" -

R

N v - R

(16)457

H

R = H or CH3

Various pyrazole systems having appropriate substituents in the 6-position can be converted into pyrazolinones. The most frequently used synthesis of this type is hydrolysis of 5-alkoxypyrazoles which is shown with others in eqs. 18-21.

v

N

\

N/-OCZHS

-7 ,i=o HCl

N

\

(18) 1360

(19)460

2 + C.H.C. 20

18

Part 1. Chapter I1

The oxidation of 2-arylpyrazolidinones (eq. 2 2 ) to pyrazolinones occurs readily and yields as high as 95 per cent have been reported.68 or calcium The reagents used were ferric chloride,68.1351 bromine 816 hypoch10rite.l~~~

The decarboxylation of 5-0x0-2-pyrazolin-3-and 4-carboxylicacids has been used frequently to prepare 2-pyrazolin-5-ones. I n the case of the 4-carboxylic acids decarboxylation usually occurs in boiling 532*1228* 1230 The 3-carboxylic acids decarboxylate by pyrowater.308* lysis, at somewhat higher temperatures, or by heating with sodium carbonate or calcium carbonate.506* 1544- 1546 A rather unusual synthesis of pyrazolinoiles from a cyclobutane

derivative has been reported (eq. 23).1277This probably involves cleavage of the 1,3-dione to a p-ketohydrazide which cyclizes. (2) Physical Properties

The 2-pyrazolin-5-ones are almost all solids, but a few are liquids. Their melting points vary a great deal and many melt with deconiposition although some are sufficiently thermally stable to be distilled at temperatures above 200". For many, more than one melting point has been reported and it is usualIy impossible to decide from the published data which is the correct one. The solubilities of these compounds vary greatly, but in general they are insoluble in nonpolar solvents and soluble in polar ones and frequently can be crystallized from hot water. Both acidic and basic properties are possessed by 2-pyrazolin-5They dissolve readily in ammonia and sodium carbonate solutions. The pK, values reported505 are 6.2-1 1.0, compounds unsubstituted at N-1 being somewhat stronger acids than are those

Pyrszolin-5-ones

19

substituted at N-1. Veibel and c o - w ~ r k e r s l1524 ~ ~ ~have . reported that 2-pyrazolin-5-ones have pK, values of 10-13, indicating very weak basicity. Only those compounds which can assume the betaine form shown in (XIV) (p. 6) can be titrated with acid. No basic properties are shown by those compounds in which &substitution at (2-4 precludes the existence of this form. A number of studies of ultraviolet and infrared absorption spectra of 2-pyrazolin-5-ones have been made.95.505-506*578 The ultraviolet spectra show maxima in the neighborhood of 250 mp with log E values of 4.10-4.40 and at about 310 mp with log 6 values of 3.90, or in both of these regions of the spectrum. The shorter wave length absorption is attributed t o the presence of >C==N-- and the longer wave length absorption t o > C==C 6 N - absorption and either at 3300 cm.-l for compounds existing in the enol form, or at 1700-1710 cm.-l for compounds having the carbonyl form. From the spectral data it has been concluded that 2-pyrazolin-5-ones having aryl substitution a t N-1 generally exist in the 0x0 forms (VII) and (VIII) (p. 5 ) unless substitution prevents format.ion of the (VIII) type. If N-1 is unsubstituted, the form (X) predominates. However, recently de Stevens and coworkers 366a have reported somewhat different findings for infrared spectra of 2-pyrazolin-5-ones having H, alkyl and aryl a t N-1 and alkyl groups at G-3. Their results led them t o suggest the form (XIV) as the principal one for these compounds. A study of the absorption of 2-pyrazolin-5-ones by silver bromide has been made by Stolyarova and C h e 1 ’ t ~ o v . lThese ~ ~ ~ workers found that there was absorption of a unimolecular layer of pyrazolinones with the heterocyclic rings parallel to the absorbent surface.

(3) Chemical Properties

The most outstanding chemical property of 2-pyrazolin-5-ones is the activity of the hydrogen atoms at G 4 . This position is very reactive, undergoing the characteristic condensations and substitutions of the active methylene group. Aldehydes and ketones react readily at this position, giving in the simpler cases a mixture of products as shown in eq~~44.22.34.110.296.311,333,633.702.809.980.1123.1241.1250.1263.1288.1351~~s

type of reaction is generally true of aldehydes, but in the case of ketones where one R is aryl only the monopyrazolinone product is obtained.1128 ~ ~ chlora1107*895 Some more active aldehydes such as f ~ r m a l d e h y d eand do not eliminate water but form, as one of the products, a hydroxyalkyl

Part 1.

20

Chapter I1

compound, as shown for formaldehyde in eq. 25. This type of reaction listed is used for synthesis of the 4-(a-hydroxyalkyl)-2-pyrazolin-5-ones RZ-

J- . N J=O

-

+ R3COR4

I

Rl

R3

I

R3

1

R'

I

Rl

Rl

in Table 11, Section F. The formation of the bispyrazolinone can be suppressed by use of acetic acid as the condensing agent.1036.1123 Other condensing agents, such as potassium hydroxide,22 piperidine311 and

I

C6H5

hydrochloric acid 22 have been used, although these are not necessary. This type of reaction has been used extensively to form 4-alkyl- and 4-benzyl-2-pyrazolin-5-ones. The unsaturated product first formed is reduced catalytically to the desired product (eq. 26). Condensation of

I

R'

an aldehyde or ketone with pyrazolinones is the most common method of synthesis for bispyrazolinones of the type shown as a product in eq. 24. A modification of this synthesis which gives d-benzylpyrazolinones is condensation of a pyrazolinone with formaldehyde in the In the presence of an activated aromatic compound such as guaia~ol.~* undergoes presence of piperidine, 3-methyl-l-phenyl-2-pyrazolin-5-one an intermolecular aldol condensation (eq. 27). The carbonyl compounds

..

Pyrazolin-5-onas

el

which have been most frequently condensed with 2-pyrazol?~w5-one8 have been aromatic ones and a very large number of these hav6 Gsen used. Ridi and Checchi l l a 81189 * have studied the condensation-of formamides with 2-pyrazolin-5-ones. This condensation occurs at a' temperature of 160-200" and appears to be an aldol condensation followed by dehydration (eq. 28). R l may be hydrogen, alkyl or aryl, while R2

has been only alkyl and aryl. It3 has been either hydrogen or aryl. Acetamide and other amides also react in this way with 2-pyrazolin5 - 0 n e s . ~ ~1192. * ~ l.l g 3 The compounds synthesized in this manner are shown in Table 11, Section G. It is not completely certain that the 4-substituent is as shown in eq. 28. It may bo the isomeric form, R3N=CH. One of the products frequently obtained in this reaction is a 4,4'-metliylidynebispyrazolinone,formed by the reaction of the first product with the starting material with elimination of ammonia or an amine. A reaction analogous to the condensation of amides with 2pyrazolin-5-ones is the reaction of amidines first reported by Dains This has been extended by Ogata, Tauno and Nishida'O'O (eq. 29).348*349 to vinylogs of amidines of the type CBH,NH(CH=CH),CH=NC,H5.

If a,/3-unsrtturated ketones are condensed with 2-pyrazolin-5-ones the reaction is a Michael addition (eq. 30)686*721resulting in alkylation.

Part 1. Chapter I1

22

The alkylation of 2-pyrazolin-&ones a t (2-4 occurs retl.dily (eq. 31) ‘I3* 1321 with compounds having reactive halogen atoms. An example R

I

I

I C,H,

I

COH,

C,H5

of this is the alkylation of 3-methyl-1-phenyl-?-pyrazolin-5-one with methyl iodide and sodium methoxide to give the corresponding 4,4dimethyl compound.809However, this reaction may give alkylation a t N-2 or 0-alkylation and as a rule it is easier to alkylate at these positions than it is at C-4 when aliphatic halides are used. Indeed, in the N-2 alkylation the case of 3-methyl-1-phenyl-2-pyrazolin-5-one occurs to a much greater extent than does exclusive alkylation at C-4, the products being 2,3-dimethyl-l-phenyl-3-pyrazolin-5-one and 1phenyl-2,3,4-trimethyl-3-pyrazolin-5-one. Various triaryl carbinols and ethers of such carbinols alkylate 2-pyrazolin-5-ones in the presence of acids t o give 4-triarylrnethyl-2-pyra~olin-5-ones.~~~~~~~ A somewhat similar reaction is that of orthoesters (eq. 32).764 2-Xethyl-4-chloroquinoline also alkylates 2-pyrazolin-5-ones at C-4.971 R2--

iI \N

I

/Lo

4 R3C(OR4)3 +

RZ

/

,

=

, ! A

\E;

y

4

(32)

I

R’

R’

A very important reaction in the synthesis of merocyanine dyes is the alkylation of 2-pyrazolin-5-ones with various heterocyclic rings as illustrated in eqs. 33-35.166.238,239 2-Pyrazoljn-5-ones other than the C

H

.. 3

~

E,=o

i

+

c:\’s+lIs

-:,,

N, I

----,

X-

one shown here can be used, and a large variety of heterocyclic compounds such as quinolines, benzoxazoles and numerous others have been employed. The anion may be halogen or p-tosyl.

Pyrazolin-5-ones

23

The hydrazones of 5-formylbarbituric acid react with 2-pyrazolin5-ones in a fashion rather similar to that of aldehydes and ket$ones

+ I

(35)

CBH5

I

CsH5

C6HS

(eqs. 36 and 37).11**Apparently it cannot be predicted which of these two types of reaction will occur.

Part 1. Chapter I1

24

2-Pyrazolin-5-ones can be readily acylated at C-4 with acid chlorides,l1° esters1641 and anhydrides.1279Very few reactions with acid chlorides and esters have been reported but the product is the ketone (XXI), as expected. Phthalic anhydride reacts with two moles

I

It' (XXI)

of 2-pyrazolin-5-one according to eq. 38. Perhaps the first step in this 0

i

I

C,H,

C.3,

reaction is acylation, followed by reaction of a second molecule of pyrazolinone with the ketone first formed. Another reagent which alkylates 2-pyrazolin-5-ones is ethyl isoformanilide, the products being 4-anilinomethylidyne-2-pyrazolin-5ones (eq. 39).823*824 Similar products have been obtained by Losco and Passerini 1089 by reaction of isonitriles with 2-pyrazolin-5-ones.

I JBH6

w

5

As would be expected, 2-pyrazolin-5-ones undergo the lllannich reaction readily (eq. 4O).log8

Pyrazolin-6-ones

25

A variety of functional groups can be introduced directly into the 4-position of 2-pyrazolin-&ones. Perhaps the most important of these is the arylazo group which is introduced by reaction with diazonium This reaction has been used t o prepare a vast salts (eq. 41).333*8090813 R2-__II h\'N J = O

+

ArNaCl

-

I

R2-

(41)

Ig:=Nh

I

R'

R'

number of azo dyes, many of which have been of considerable commercial importance. It will be discussed in more detail in connection with pyrazolinone dyes and preparation of azo derivatives. Another reaction of commercial importance is that of 2-pyrazolin-5-ones with aromatic amines in the presence of oxidizing agents t o form color couplers which (eq. 172).244* 1538 The same kind of are 4-arylimino-2-pyrazolin-5-ones product is obtained by the reaction of 4-arylidene-2-pyrazolin-5-ones with aromatic amines. The net result is replacement of the arylidene group with the arylimino Halogenation at the 4-position also occurs readily with phosphorus p e n t a ~ h l o r i d e , phosphorus ~ ~ ~ . ~ ~ ~ tribromide 333 or bromine.333*809*816 The phosphorus halides form 4,4-dihalogenated derivatives. Direct bromination with a n equivalent but excess of bromine of bromine gives 4-bromo-2-pyrazolin-5-ones, gives the 4,4-dibromo and even some tribromo compound. 2-Pyrazolin5-ones react with nitrous acid to give nitroso derivatives which exist Nitration with usually as the corresponding oximes (XXII).333*809.816

kl

(XXII)

dilute nitric acid forms 4-nitr0-2-pyrazolin-5-ones.~~ 333*806 A 4-formyl group can be introduced by using the Reimer-Tiemann reaction. Sulwith 20 per cent oleuni fonation of 3-methyl-l-phenyl-2-pyrazolin-5-one at 10-15" results in formation of the corresponding 4-sulfonic Higher temperatures cause not only sulfonation of the heterocyclic ring, but sulfonation of the phenyl group. A cyano group can be introduced into the 4-position of 2-pyrazolin-5-ones by reaction with cyanogen bromide in the presence of aluminum chloride.24 These substitutions are much more difficult if an alkyl substituent is present in the 4position, although in some cases such a group is eliminated. 4-Triarylmethyl-2-pyrazolin-6-ones react with diazonium salts with replacement 2*

Part 1. Chapter I1

26

of the triarylmethyl substituent by the arylazo Of course, 4,4-dialkyl-2-pyrazolin-5-ones do not react with these substituting reagents. These reactions are discussed further in sections devoted to preparation of the various types of compounds arising from such reactions. As already mentioned, it is possible for 2-pyrazolin-5-ones to react with alkylating agents at N-2 and at the oxygen atom in addition to (3-4. If there is no substituent at N-1, this position can also be alkylated. Moat alkylations give a mixture of the possible products. However, by alkylation at temperatures of 100-130", with or without basic catalysts, in 2-pyrazolin-5-ones can be converted to 2-alkyl-3-pyrazolin-5-ones excellent yields (eq. 42). This reaction has been extensively studied

I

R1

I

RI

because, in the case of 3-methyl-l-phenyl-2-pyrazolin-5-0ne and methyl iodide, the product is the commercially important analgesic and antipyretic, antipyrine. The most widely used procedure for carrying out this reaction is the use of methyl iodide and methanol at 100".806 Methylation has also been accomplished by use of methyl sulfate and sodium hydroxide,l1° methyl p-toluenesulfonate and sodium meth985 methyl iodide at 130°,1475diazooxide,54 dimethyl methane,94 and methyl iodide and sodium m e t 1 i o ~ i d e . lAlkylation ~~~ under similar conditions with alkylating agents having longer carbon chains, such as ethyl iodide,1205propyl bromide,1321benzyl chloride and 2-dialkylaminoethyl chlorides249 has been successful. Nef 1056 has reported that alkylation of 3-methyl-l-phenyl-2-pyrazolin-5-one with methyl iodide and sodium methoxide occurs at C-4 with no N-2 alkylation, at N-2 with no C-4 alkylation, and at both positions. In 2-pyrazolin-5-ones lacking a 1-substituent alkylation occurs to give 1205 usually with little or no 1-substituted 2-pyra~olin-ti-ones,~~0-alkylation, and alkylation with alkylchloroformates leads to subSomewhat more drastic conditions form stitution only at N-1 5-alko~ypyrazolea.~~ 1331 Acylation of 2-pyrazolin-5-ones having no substituent at N-1 1598 acetic occurs readily with such agents as acetyl chloride,1499* anhydride,1499-1598 benzoyl chloride 1056.1598 and aryl sulfonyl chlorbut acylation ides.1199The usual product is a l-acyl-2-pyrazolin-5-one, may also occur on oxygen, or both on oxygen and at N-2.1598

-

Pyrazolin-5-ones

27

The reaction of 2-pyrazolin-5-oneswith phosphorus oxychloride to ~ . ~ ~loo3. ~ . lZo5 give5-chloropyrazoles(eq.43) is a ~ e r y g e n e r a l o n e . ~985*992.

- RzT-J:;

R2-lr

Y J - R3

POCla

I

(43)

I

R1

R'

The reaction requires temperatures of 100-150" and all pyrazolinones of this type undergo it. The oxygen of 2-pyrazolin-5-ones can also be replaced by sulfur if phosphorus pentasulfide a t about 130-150" is used This reaction is widely used for preparation of 2(eq. 44).759*1343 pyrazolin-5-thiones. R3

R3

I

I

R'

R'

The hydrogen atoms on C-4 of 2-pyrazolin-5-ones are readily attacked by mild oxidizing agent.s. The products of this reaction are bispyrazolinones (eq. 45) when such oxidizing agents as phenyl

I R'

I

R'

I

Rl

(45)

hydrazine333~636.809,818-991 or nitrous acid are used.809 The use of ferric chloride in limited amounts gives the bispyrazolinones in which the two rings are connected by a single bond,1582but larger amounts of ferric chloride give further oxidation and in the product the two pyrazolinone rings are attached to each other by double bondssog as shown in eq. 45. Oxidation of 2-pyrazolin-5-oneshaving a 1-aryl substituent with t-butylhydroperoxidelSz6or oxygen in neutral solution1528 leads to bispyrazolinoncs, as shown in the first step of eq. 45. I n contrast to this, the use of t-butylhydroperoxide in the presence of sodium a l k o x i d e ~ or ' ~ of ~ ~oxygen in acid media1528converts the 2-pyrazolin5-One to the corresponding hydroxy compound. These are excellent

Part 1. Chapt.er I1

28

preparative methods for 4-hydroxy-2-pyrazolin-5-ones. Shirai and Yashiro 1299 have found that some 2-pyrazolin-5-ones can be converted t o bispyrazolinones merely by recrystallization from hot water. 4,4Disubstituted-2-pyrazolin-5-onesdo not undergo the oxidative dimerization, except in the cases of those substituted with a 4-arylidene group which are oxidized by p h e n y l h y d r a ~ i n e .These ~ ~ ~ ~compounds apparently react by replacement of the ArCH= by hydrogen from the phenylhydrazine and the unsubstituted pyrazolinone thus arising is oxidized. Strong oxidizing agents, such as potassium permanganate, completely destroy the 2-pyrazolin-5-one ring, forming pyruvic acid, water, nitrogen and carbon dioxide.154g The heterocyclic ring of 2-pyrazolin-5-ones is quite stable t o catalytic reduction. Aromatic substituents present can be reduced t o cyclohexyl groups by means of various hydrogenation cata,lysts without reduction of the heterocyclic ring.161*859*l m 0The carbonyl function of 2-pyrazolin-5-ones is subject to reduction by various chemical reagents. with zinc results in Treatment of 3-methyl-l-phenyl-2-pyrazolin-5-ones reduction to the corresponding p y r a z ~ l ebut , ~ ~somewhat ~ more drastic conditions cause complete decomposition of the heterocyclic ring, giving aniline and a c e t ~ n i t r i l e .Reduction ~~~ of the same compound with sodium and alcohol forms the corresponding pyrazoline (eq. 46).809The

use of sodium and amyl alcohol on 2-pyrazolin-5-ones forms 5-hydroxyp y r a ~ o l i n e sas , ~ does ~ reduction with 1it.hium aluminum hydride.1505 Although 2-pyrazolin-5-ones are relatively stable t o acid hydrolysis, those having 1-(dinitrophenyl) or 1 -( trinitrophenyl) substituents are decomposed, forming arylhydrazones (eq. 47).777

I

R'

Hydrolysis of 2-pyrazolin-5-ones with 33 per cent sodium hydroxide solution also destroys the ring.1286The hydrolysis products were not identified with certainty, but it was thought that acetic and propionic acids were among them. 2-Pyrazolin-5-ones form a variety of complexes with various metals

Pyrazolin-5-ones

29

and metal salts.393~394~482 3-Methyl-1-phenyl-2-pyrazolin-5-one has been reported to form complexes with iron, cobalt, silver, cupric oxide, cupric iodide, silver iodide, ferric iodide, cobalt iodide and beryllium chloride. These complexes actually are salts of the enolic form of the py-razolinone in many cases, although in others the only bonds may be those formed by donation of the electrons by the C===N-N< group.394 I n some cases both types of linkages are present. The compounds formed usually have the number of molecules of 2-pyrazolin-5-one corresponding to the valence of the metal atom present. (4) Hydroxyalkyl Types

Most of the syntheses of a-hydroxyalkyl and a-alkoxyalkyl-2pyrazolin-5-ones have been discussed in connection with the reactions of 2-pyrazolin-5-ones. However, there is one synthesis by which compounds of this type are obtained directly. This is by reaction of the appropriate alkoxy- or phenoxymethylacetoacetic esters with hydra1562 The reactions of these compounds zines (eq. 48).532*1314.1315,1316.

I

R3

.(4W

HOCH2-------Rz HCI

+

4--. 1 N/ I

R3

are the general ones for 2-pyrazolin-5-onesand for hydroxy and alkoxy functions except for the condensation of 4-hydroxymethyl-2-pyrazolin5-ones with another pyrazolinone to give bis(2-pyrazolin-5-ones) (eq. 49).24

Part 1. Chapter I1

30

The a-hydroxyalkyl and a-alkoxyalkyl-2-pyazolin-5-ones are listed in Table 11, Section F. ( 5 ) Aminoalkyl Types

A number of syntheses of compounds having nitrogen on a carbon attached to 2-pyrazolin-5-one rings have already been mentioned, but several others are known. The most important of these is the reaction with hydroxylamine, hydraof 4-formyl- or 4-acyl-2-pyrazolin-5-ones 1641 These compounds zines, semicarbazide and similar chemicals.559can also be obtained by direct synthesis from an appropriate ,9-ketoester or derivative and a hydrazine (eq. 50).138.51a*1100 An interesting syn-

+

R1-NCHZCOCH,COOC2HS

I

R'-N-CH,-

R3NHNH,

Ra I

RZ

?'I, = O

I

(50)

I H3

thesis of this type of compound is that shown in eq. 51.1179Presumably condensation of one molecule of semicarbazide with the ketone carbonyl NHNHCONH2 CE3COONB

C6H,COCH=CHCOOC,H,

l- H,NHNCONH, -----+

I

C'H

CHCOOCaH5 (51)

I

H

is followed by cyclization to the C-3 of the ester with elimination of ammonia after addition of a second molecule of semicarbazide. Two other syntheses of these compounds are shown in eqs. 52 and 53.9a5-l a o 6 CH,

NH20B~ECI

CHS-JTCH=NOH

\N

'N

=O

(62)

I

C*H,

(XXII-B)

+ H,NNH,.H,O 'N

+ cH3-'N

1

68%

(53)

I GH,

The reactions of these derivatives are typical of the functional groups present.

Pyrazolin-5-ones

31

Compounds having nitrogen on a carbon atom which is attached to a 2-pyrazolin-5-onering are listed in Table 11, Section G . ( 6 ) Bis(2-~yrazoZin-5-0~#)

A large number of 2-pyrazolin-5-ones exist in which two or more such rings are combined. These are almost all combined symmetrically, that is Dhe same positions in the two rings are linked, and the vast majority are combined in the 4,4‘-positions, although many are connected at the 3,3’-positions and some by way of the 1,l‘-positions. Those 4,4’-bispyrazolinones in which the two rings are directly connected are listed in Tables I11 and IV. Those having atoms between the rings are listed in Tables V-VII. The 3,3’-bispyrazolinones are listed in Table VIII and the 1,l’-bispyrazolinones in Table IX. The most widely used synthesis of 4,4’-bis(2-pyrazolin-&ones) is mild oxidation of monocyclic 2-pyrazolin-5-ones, which has already been discussed in the section devoted to reactions of 2-pyrazolin-5-ones (eq. 45). These. compounds can also be synthesized by reaction of a,a’-diacylsuccinic esters with hydrazines (eq. 54).357. *15 A number

I

I

R2

R”

of miscellaneous dimerizations of 2-pyrazolin-5-ones and 3-pyrazolin5-ones have been reported to give 4,4’-bis(2-pyrazolin-5-ones).3-Methyl1 -phenyl-2-pyrazolin-5-one reacts with various acylanilidesI1O2 and with sodium ethoxide1s45to give dimers. Ethyl groups are introduced at the 4,4‘-positions by the use of sodium ethoxide. Heating a, 4oximino-2-pyrazolin-5-one has been reported to give a dimer in which the 4-substituent has been eliminated (eq. 55).925 According t o van C H 3 r - Y O H ‘N $0 I

&

CH,-

”--) P---~CH~ -

=o

,N

0-

I

I

I

C6H6

(XXII-C)

N/ I

(55)

&EHS

Alphen 1513it is also obtained by the reductive cyclization of a crotonic ester (eq. 56). The replacement of a 4-imino function in a 2-pyrazolin&one by a 2-pyrazolin-5-one lacking a 4-substituent also leads to a

Part 1. Chapter I1

32

dimer.1538Hydrazines react with various heterocyclic compounds to give 4,4’-bis(2-pyrazolin-&ones). These reactions are shown in eqs. 57-59.129p725*729 Ridi and co-workersllS4have treated various pyrazoloCBH5C=CHCOSS + C6HSNHNH2 --+

u

‘OH5

ik

CBHS (57)

I

I

CsH5

CeHS

R

I

,

I

’I

kJ=o

GHS

R

I

CBH5

2-pyrones and phenylmethyltartonylurea and imide with phenylhydraA variety of zine to give 4,4’-bis(3-methyl-1-phenyl-2-pyrazolin-5-one). other 4,4’-bis(2-pyrazolin-5-ones) can be converted into the type being

I

&fiH5

GH5

I (kH5

(XXII-D)

discussed here. 4-Benzylidene-4,4‘-bis(3-methyl-l-phenyl-2-pyrazolin5-one) reacts with azobenzene or phenylhydrazine to give 4,4’-bis(3methyl-l-phenyl-2-pyrazolin-5-one).10go~1091 Of particular interest is

33

Pyrazolin-5-ones

the addition of various compounds having active methylene to the 4,4‘-bis(2-pyrazolin-5-ones) connected by a double bond since this leads This reaction is shown in in some cases t o trimers.1607.160g.1613.1614 eq. 60. Only a very few 4,4’-bis(2-pyrazolin-5-ones) linked by a double bond have been prepared. The parent compound of this series, 443methyl - 1-phenyl-5-oxo-2 - pyrazolin-4-ylidene)-3-methyl-l-phenyl-2pyrazolin-5-one (XXII-D), is known as pyrazole b l ~ e . ~ ~ ~ . ~ ~ ~ * 1090*1091It was so named by Knorr because of its great resemblance t o indigo blue. All these compounds are strongly colored. The usual synthesis is by ferric chloride oxidation of monomeric 2-pyrazolin-5-ones or by oxidation of the corresponding bis compounds (eq. 61)296*809

C H 3 ~ i \

N/”O

I

FeCI3

(xXI1-D)

(61)

CBH,

linked by a single bond with ferric chloride, nitrous acid, nitric acid or various nitriles.296.333.1090 The product in eq. 61 is pyrazole blue. Other methods of synthesis are treatment of 4-(3-methyl-l-phenyl-Zpyrazolin-5-ylidene)-3-methyl1-phenyl-2-pyrazolin-5-one with bromine in alkali,323 heating of 4-bromo-3-methyl-l-phenyl-2-pyrazolin-5-one CH, I

L-I. with alcohol80Band degradation of trimers.1s07*1e08The trimer degradation procedure gives unsymmetrical compounds of the pyrazole blue type (eq. 62). The double bond connecting the rings in these

34

Part 1. Chapter I1

compounds reacts m do normal olefins and in addition undergoes additions with compounds having active hydrogenlso7.1608 or with such compounds as hydrogen cyanide.lsla 4,4'-bis(Z-pyrazolin-5-0nes)linked by carbon chains have been prepared in a multitude of ways, several of which have been mentioned in the discussion concerning reactions of 2-pyrazolin-&ones. The only method of any importance is the condensation of 2-pyrazolin-&ones with aldehydes and ketones (eq. 24, p. 20) and this has already been discussed. An interesting modification of this is the use of an anil as a substitute for the aldehyde.log4The a d functions similarly to the aldehyde. A second modification in which the aldehyde is generated in the course of the reaction has also been used (eq. 63).1351Another C,H,NHNH,

+

HOHC=CHCOOC,H,

-

C,H,NHXHCH=CHCOOC,H,

I

I

C6H6

C6H5

method used to some extent for the synthesis of 4,4'-bis(Z-pyrazolin&ones) is the reaction of bis-/3-ketoesters with hydrazines (eq. 64).451* 513*514*1154The reaction of 2-pyrazolin-&oneswith amidines to CHaCOCHhOOCzH6

R'-CHCOCHB

I

+

RWHNH,

COOC,H,

I

I

R"

Ra

give substitution at the 4-position has already been mentioned. I n addition to such products this reaction often gives 4,4'-methylidynebis(2-pyrazolin-5-ones) (eq 65).1070~11aa A reaction which appears

I

R'

I

R'

to be very similar to this and gives the same type of product is the condensation of 2-pyrazolin-5-ones with l-phenyl-l,2-dihydro-4,6diamin0-1,3,5-triazines.3~~ The synthesis of 4,4'-methylidynebis(2pyrazolin-&ones) has usually been achieved by condensation of

Pyrazolin-6-ones

36

2-pyrazolin-&ones with ethyl orthoformate 611*1188*1669(eq. 66) or by the condensation of 5-oxo-2-pyrazolin-4-carboxaldehydeswith RZ-

+

R2---CH--gI HC(@&H6)3

_ _ f

{ N K

I

dN)

k'

R' I

R'

(6e)

2-pyrazolin-5-ones (eq. 67).92s,1093,1185The latter condensation can be modified by boiling the aldehyde alone in water which causes partial R2

'N

N

'N

I

R'

I

I

R'

R'

41

hydrolysis of the formyl group. The reactants shown in eq. 67 are then present and can react to form the bis compound. A variety of miscellaneous methods of preparing such compounds is given in eqs. 68-81. CH3

CH3

'N4 I0

0 &aH,

CBH5

(68)"O

CH,C-------CHCOOC2HB

II

NNHCeHs

I

__I,

CH,

\-.....-

d" AI

! *

C,HS

+

(69)117

0€I3CO~H

CHZSCH,

(XXII-A)

C2H60Na

CICHaSCH,

(XXII-A)

(70)"'

36

Part 1. Chapter I1 N C0H,N’

-

1

CCH,

\C - C d H

(7 1) 187

Pyrazolin-5 -ones

37

(78)s77

I

(79) low

OC2H,

OHCHNPI'HCHO

+

CH,COOH

'1

-CH-------

___f

CH3-7---

'h'

\

1

H

0

/LN,?

II

~

O

I

H

CH3 (80)1185

38

Part 1.

Chapter I1

(XXII-B) (81) lla7

4,4’-Arylidenebis(2-pyrazolin-5-ones) can be decomposed by heat or acid to give 4,4’-methylidynebis(2-pyrazolin-5-ones).g3~ lo3* In one was recwe 4,4’-methenylbis(3-methyl-l-phenyl-2-pyrazolin-5-one) ported as the product.22 The melting point given was 177”. This was undoubtedly the 4,4’-methylidyne compound which melts at 185”. The 4,4’-methenylbis compound, which melts at 220”, has been repeatedly reported as melting at 180-185O owing to its easy loss of hydrogen to give the 4,4‘-methylidynebis compound. In some cases this heat degradation of 4,4’-arylidenebispyrazolinonesconverts them back into the mono-2-pyrazolin-5-ones.1036 The degradation of bis(2-pyrazolin-5ones) to mono compounds is also brought about by heating with 4,4’-Methylidynebis-(2-pyrazolin-5-ones) are readily f~rmamide.ll~ ~ converted by treatment with hydroxylamine into the corresponding B-oxo-2-pyrazolin-4-carboxaldehyde oxime 925 or by hydrolysis with base to the 4-carboxaldehyde (eq. S2).926 The bromination of 4,4‘(XXII-B)

H20 __j

NaOH

I

CBH5

methylidynebis(3-methyl-1-phenyl-2-pyrazolin-5-one) has been reported by Ziegler and Sauermilch.les2Bromination replaced the only remaining G 4 hydrogen by bromine. Hydrogen bromide could not be eliminated, but heating with alcohol replaced the halogen by hydrogen. The condensation of a series of 2-pyrazolin-&ones with aryl aldehydes in 70 per cent acetic acid at elevated temperatures has been described as giving the enol form of 4,4’-arylidenebis(2-pyrazolin-5-0nes).~~~~ The corresponding keto forms can be converted into the enols by heating in alcohol. A few 4,4‘-bis(2-pyrazolin-5-ones)are known in which t>helinking chain contains nitrogen atoms. These are Schiff bases and amides. ~-0xo-2-pyrazolin-4-carboxaldehydes react with diamines having two The amides primary amino groups to form 4,4’-bispyrazolinone~.~~~~ are synthesized by reaction of bisisocyanates with 2-pyrazolin-5-ones

Pyrezolin-6-ones

39

(eq. t33).l1l1 This reaction is of particular interest because it illustrates the great activity of the hydrogen atoms at C-4. CH3-

+

LJ\

(CH&H&HzNCO)a

I

CsHs

--..-.+

m-,/ P

CONH(CH&HNOC J

\ ' "

(83) ~

I

CeHs ! O

0

The 3,3'-bis(2-pyrazolin-5-ones)in which the rings are connected by carbon chains (Table VIII) are usually prepared by condensation of a hydrazine with an appropriate j?,/3'-dioxodiester (eq. 84).41s* 462* 1222-1225 Such bispyrazolinones linked by a carbonyl group have been prepared by pyrolysis of the calcium salt of 8-0~0-2-pyrazolin-S-one.~~~~ RIOOCCHaCORCOCHICOOR*

The 1,l'-bis(2-pyrazolin-5-ones) (Table IX)have been prepared by three methods. Two of these are variants on the familiar j?-ketoester condensation with hydrazines but in these cases compounds having two hydrazine moieties are used.lls*zlz-255-4 5 9 - 1037 These two methods are illustrated in eq. 85. The R in the hydrazines used in the direct conR1COCHCOOR3

I

It2

+

K2NHNRNHKH2

u

I

densation is usually aryl. The commonly used hydrazine when going through the bishydrazone has been ~ a r b a z i d e or l~a ~ ~similar com-

Part 1.

40

Chapter I1

The reaction of phosgene with 1-(X-amino-phenyl)-% pyrazolin-&ones also forms l,l'-bis(2-pyrazolin-5-ones) (eq. 86).152* 511 R

tN

+

COCl,

--+

R

J=o

The 1, 1'-bispyrazolines undergo the usual reactions of 2-pyrazolin-6ones. West06 has reported the synthesis of complex bispyrazolinones which he has called furlones.1608.1610*1611These have two 2-pyrazolin5-one rings connected through a dihydrofuran ring which in turn is fused with a pyrazole ring. These were prepared by condensation of 4-ha1ogentted22-pyrazolin-5-ones, together, with l-aryl-2-pyrazolin-5ones, or with pyrazole blue (XXII-D) in the presence of a base and copper sulfate (eq. 87). These compounds are listed in Table X.

B. 2-Pyrazolin-5-thiones

The reaction of 2-pyrazolin-5-ones with phosphorus pentasulfide forms 2-pyrazolin-5-thiones (eq. 44).759* 1343 The reactants are usually heated at the temperature of boiling xylene. A second method used in the preparation of such compounds is the reaction of 5-chloro990.loo3 pyrazoles with potassium hydrogen sulfide (eq. 88).977* 990e

CsHs

CoH,

The properties of these compounds are very similar to those of the 50x0 analogs. They are usually colorless but are yellow if substituted

Pyrazolin-5-ones

41

in the 4-position. Acidic and basic properties are both present. Kendall exist as and Ruffin 759 claim that 3,4,4-trialkyl-2-pyrazolin-5-thiones mercapto pyrazoles having the structure (XXIII). R2

(XXIII)

Reactions of 2-pyrazolin-5-thiones at the 4-position are quite similar to those of the 5-0x0 analogs. Condensation of one mole of the pyrazolinthione with one mole of ketone or aldehyde to form 4-alkylidene- or arylidene-2-pyrazolin-5-thionesoccurs.99o Coupling with diazonium salts forms 4-azo compounds 990 and nitrosation occurs.ggoAlkylation or acylation ordinarily attacks the sulfur atom 990 Oxidation with mild oxidizing to give 5-rnercaptopyra~oles.~~~~ , ~ ~the ~ use of agents such as iodine or nitrous acid forms a d i s ~ l f i d ebut hydrogen peroxide gives a sulfonic acid, according to illichaelis,990or replacement of the sulfur by oxygen, according to K i t a m ~ r a . ~ ~ ~ Mercaptides are formed with mercuric oxide or mercuric salts.990The 4,4'-bis(2-pyrazolin-ti-thiones) cyclize very readily to form a tricyclic compound with elimination of hydrogen sulfide (eq. S9).990 The 2pyrazolin-5-thiones are listed in Table XI.

C. 5-Imino-2-pyramlines

It is probable that most of the 5-imino-2-pyrazolinesexist as the corresponding aminopyrazoles (XXIV). Gagnon, Boivin and Trem-

(XXW

bley50s have studied the ultraviolet absorption spectra of these compounds and concluded that the usual structure is the aminopyrazole

Part 1. Chapter I1

42

one, although frequently more than one isomer is present. The chemical literature usually refers to what are here called 5-imino-2-pyrazolines as 5-aminopyrazoles. The principal methods of preparation of these compounds are very similar to those used for the 5-0x0-compounds, except that nitriles, and in some cases amides, are used instead of esters, acids or acid derivatives. /I-Ketonit_rile~,~~~* 344. 1562 B-aldehydonit,rile~,~27Bi m i n o n i t r i l e ~ ,324*g96* ~ ~ * 1010.1285*1542 +unsaturated trithiones12g and +acetylenic nitrilesloZ5are condensed with hydrazines. I n many caaes the intermediate hydrazones have been isolated and cyclized.86-132*310996*1011*1285-1287 These reactions are shown in eqs. 90 and 91. Worrall and co-workers 1655* 1656 have reported the condensation of aromatic acetylenic amides with hydrazines to give 5-imino-2-pyrazolines (eq. 92). Presumably the amides react like the iminothioacids, hydrogen R'

R'CXCHaCN

+

R'NHNH,

-+

X=O or N H

\II N / J a: '

i

(90)

\H

R'

AT'

sulfide being eliminated. Bottcher and BauerIz9 have condensed a,/?unsaturated trithiones with hydrazines to form ti-imino-2-pyrazolines (eq. 93). CeH5CdHCSSS

+ COHBNHNH,

u

----+

CGHS--I1 N \N'\

I

I

(93) NH

C6H5

Several methods for the synthesis of 5-imino-2-pyrazolines depend upon the amination of a pyrazole ring. 5-Chloropyrazoles react with aniline to give the corresponding 5-amino compound.826-loo2 The chloropyrazoles can be prepared and amination accomplished in one

Pyrazol-in5-onw

43

step by treatment of 2-pyrazolin-5-one with phosphorus oxychloride and aryl amines a t the same time.827*828 Also reduction of a 5-nitrohas pyrazole has been used.1086Ethyl 3-phenylpyrazole-5-carboxylate been converted into a hydrazide, then t o an azide, and finally, by a Curtius rearrangement, to the amino compound (eq. 94).loE6Also amides can be rearranged to give iminopyrazolines.104s

+

CH

4

I/

' N-"\

'K'\

H

HJNH,

COOC2H,

H 1. N s N 0 2 - W C I

CONHNH, (94)

Cusmano 340*3 4 1 * 3 4 5 has converted 5-alkyl- and 5-arylisoxazole-3carboxylic acids into 5-imino-2-pyrazolines by treatment with phenyl hydrazine. Musante has also used this procedure.1043-1045 This reaction goes by way of 8-ketonitrile intermediates and gives very poor yields.86 The decarboxylation of 1,3-diphenyl-5-imino-2-pyrazolin-3carboxylic acid gives 1,3-diphenyl-5-irnin0-2-pyrazoline.~~~ Druey and Schmidt 391 have taken advantage of the selective replacement of an 0x0 group by chlorine over that of an imino group to prepare 5-imino2-pyrazolines (eq. 95).

The reactions of 5-imino-2-pyrazolines are very similar t o those of the 5-0x0 analogs, except for reactions specifically involving the 5-imino group as its amino tautomer. For example, condensations with aromatic aldehydes occur t o form 4,4'-arylidenebis(5-imino-S-pyrazolincs). Michaelis996 has prepared compounds of this type from in which the arylidene groups 3-methyl-1-phenyl-5-imino-2-pyrazoline and melting points are respectively: C6H5CH, 66"; 2-NO2C6H,CH, 89"; X-HOC6H4CH, 120"; 4-CH3C6H,CH, 219'. However, reaction with aldehydes or ketones can also occur at the amino group to give Schiff bases or alkylation.lOll Ketones such as acetoacetic ester used in vigorous conditions give pyra~olopyrimidines.~~~ Halogenation, Qgs.1666

Part 1. Chapter I1

44

nitration,165s n i t r o ~ a t i o n ,loo2* ~~~ l o.l o and coupling with diazonium saltsgg6occur at (2-4 as expected. The nitrosation products are usually oximes. The condensation of phenyl isocyanate with the 5-imino-2pyrazolines occurs to give the 4-carboxyanilides (eq. 96).82s These comCHa-

+

NIi

C,H5SC() --

I

CH3-l

CoKHCSHS

k

i

‘ K ’ \

WHS

CBH5

I I

hC6H5

C6H5

pounds then readily cyclize to quinoline derivatives. Phenyl isothiocyanate, N,N’-diphenylurea and N,N’-diphenylthiourea also react in this way. pNitrophenylsulfeny1 chloride reacts with 3-methyl-1-phenyl 5-imino-2-pyrazoline to give 3-methyl-4-(4-nitropheny1mercapto)-1 phenyl-5-imin0-2-pyrazoline.~~~ Druey and Schmidt391 have reported that alkylation of N-1 unwith dimethyl sulfate substituted 4,4-dialkyl-5-imino-2-pyrazolines occurs at the N-1 position. As illustrated in eq. 97, the acylation of 5-imino-2-pyrazolines

R’

NH

occurs on the 5-imino group rather than at C-4 as in the &ox0 analogs. However, the use of diethylmalonyl chloride gives acylation at both positions.322Aliphatic acid chlorides,391aliphatic anhydrides,325 aromatic acid chlorides340and sulfonyl chlorides325have been used as acylating agents. Carbon disulfide reacts with the imino group to give a bispyrazolylthi~urea.~~~ Nitrous acid diazotizes the 5-imino another argument for its existence in the tautomeric amino form. If insufficient nitrous acid to diazotize all of the 5-imino-2-pyrazolines is used, the resulting diazonium salt couples with undiazotized material, giving an iminoazo compound (XXV). The diazonium salt also couples with phenols. Moureu and Lazennec loZ5were unable to hydrolyze 3-alkyl-5~ ~ ~ to imino-2-pyrazolines to the 5 - O X 0 analogs, but C u ~ r n a n oclaims

Pyrazolin-5-ones

45

have hydrolyzed the imino group of 4-nitroso-l,3-diphenyl-5-imino-2pyrazoline to an 0x0 group using acid conditions.

I

RZ

(XXV)

Michaelis 996 has reported that oxidation of various 5-imino-2 pyrazolines with hydrogen peroxide or nitrous acid gives what were called azipyrazoles of type (XXVI). It seems highly unlikely that these

I

It' (XXVI)

products actually had the structure proposed. It may be that the conipounds formed were 5,5'-bis(5-imino-2-pyrazolines), as indicated in eq. 98, although the evidence is not completely consistent wit.h this interpretation. 5-Imino-2-pyrazolinesare listed in Table XII.

A few bis(2-pyrazolin-5-ones)having one or both 5-0x0 groups replaced by imino groups have been preparcd. The preparation of those having one imino group is shown in eqs. 99 and 100. Those linked

46

Part 1. Chapter I1

through the nitrogen atoms of the 5-imino group are listed in Table XIII. The usual preparation is reaction of a 5-imino-2-pyrazolinehaving no substituent on the 5-imino nitrogen with oxalic or phosgene.301 D. 3-Pyrazolin-5-ones

( 1) Syntheses

As has been mentioned previously (eq. 42, p. 26) the method most frequently used to synthesize 3-pyrazolin-5-ones is alkylation of 2pyrazolin-5-ones at N-2. I n general this can be used only for synthesis The earliest of 2-alkyl-, 2-aralkyl- and 2-heteroalkyl-3-pyrazolin-5-ones. workers used methyl iodide in methanol at temperatures of 1001 30°.806.818* 99a Other methylating agents used have been dimethyl 1173 dimethyl sulfate sulfate at temperatures of 100-130°,113*362~781~ with base,l1° d i a ~ o m e t h a n e methyl ,~~ iodide,141*1475 methyl iodide in the presence of sodium methoxide,1205methanol and dry hydrogen chloride at 140' 1508 and methyl p-toluenesulfonate in the presence of b ; t ~ e . ~A number ~ ~ * of~ other ~ ~short-chain ~ * ~ ~alkyl ~ halides, ~ such as ethyl iodide, ally1 chloride and isopropyl chloride with and without added base have been ~ s e d . ~Benzyl ~ ~ c . h l~ ~ ~ r i d~ e and ~ ~ *' ~ ~~ ~~ ~ ~ xanthhydrol 457 give 2-aralkyl-3-pyrazolin-5-ones. A variety of heteroalkyl chlorides have been condensed with 2-pyrazolin-5-ones using sodamide as the condensing agent.249The yields in these alkylations vary considerably, but in general the more complex the alkyl or aralkyl halide used the lower the yields. Methylation has been reported in yields of 85 per cent,781b u t benzylation occurs only to the extent of 15 per cent.250The usual yields appear to be 40-65 per cent. The chief side reaction occurring is 0-alkylation to give 5-alkoxypyrazoles. Of course, if there is only hydrogen at N-1, alkylation frequently occurs there ais0.54

As shown in eq. 3 (p. 9) the reaction of acyl arylhydrazines with *40*984* l o o l The /3-ketoesters forms 2-ary1-3-pyrazolin-5-0nes.~~~~ acyl group is lost in the cyclization and these products have no N-1 substituent. Formyl-, acetyl- and benzoylhydrazines may be used. This is a very frequently employed method for preparation of 2-aryl-3pyrazolin-5-ones. The condensing agents generally used have been phosphorus trichloride, phosphorus oxychloride and phosphorus pentachloride. A modification of this, also mentioned earlier, has been the condensation of a symmetrically substituted hydrazine with a 8ketoester to give 1,2-disubstituted-3-pyrazolin-5-0nes.~~~ 370 The sub9889

Pyrazolin-5-ones

47

stituents on N-1 and N-2 may be both alkyl or both aryl, although very few 1,2-diaryl-3-pyrazolin-5-ones are known. A large number of other syntheses of 3-pyrazolin-5-oneshave been reported, although most are not of importance as practical methods of preparation. These are illustrated in eqs. 101-113.

R’

R1C€I=CHCOOR2 + CeHSNHNH2 +

(102)EOS.

1568

R2=H or CH3

CH3 CeHsNHNHCOCH,

+

CHaOK

CH,CCH,CONHNHAr

II

R”HA4r

mso

+ 300.

(J6H)-i

(103)a47

‘H”\

CH, ,lL‘l

ArN

(106)sSs

Lecher, Parker and C ~ n n * report *~ that the cyclization of the hydrazone hydrazide, as in eq. 106, is the preferred synthesis for 2-aryl-3-rnethyl-3-pyrazolin-5-ones. A number of 4-heterocyclic-3-pyrazolin-5-ones have been prepared using the appropriate 4-substituted pyrazolinone in the usual reactions

48

Part 1.

Chapter I1

to form the particular heterocyclic ring. For example, 4-amino-2,3dimethyl-l-phenyl-3-pyrazolin-5-one has been condensed with 1,4diketones to form pyrazolinones substituted by p y r r o l e ~ Isatin . ~ ~ ~ has Ar

)--'-7

ArCH=CHCONHKHAr

h \N/\ N

H CeHsNCHaCH2CN

1. KOE. E,O

O

-I

c 6 H 5 N 7

7

(107)1333

H

(106)11aa

O

R

1. 140'

COOH

R= H or CH3

R3

CHO

)=(

R=-X

+

"A I R'

0

'3

CH=CCOR6

it3

R4CH2COR5 +

I

R2-N

I N I

R.1

\

(113)316. BBO

R'

0

been used in the Pfitzinger reaction with 4-acetyl-2,3-dimethyl-lphenyl-3-pyrazolin-5-one to give pyrazolinones substituted by quinolines.903

Pyrazolin-5-ones

49

(2) Properties

Like the 2-pyrazolin-5-ones, most of the 3-pyrazolin-5-ones are solids with a wide range of melting points. Among the 3-pyrazolin-5ones having only alkyl, heterocyclicalkyl and aryl substituents a number having four substituents are very high boiling liquids. Those having fewer substituents are all solids, as are those substituted by aralkyl and heterocyclic groups. Solubility varies greatly and no generalizations can be made. I n contrast to the 2-pyrazolin-5-ones, the 3-pyrazolin-5-ones are It does basic, but usually are not acidiceo7or only very weakly appear that 3-pyrazolin-5-oneshaving no M-1 substituent are more acid than those substituted at N-l,885presumably because they can tautomerize to the lactim structure (XIII). The basic nature of 3-pyrazolin&ones is demonstrated by their ability to form stable hydrochlorides, picrates, methiodides and other salts.B01* 818*984 The infrared and ultraviolet absorption of 3-pyrazolin-5-ones has been discussed previously in connection with the structures of these compounds. The vast majority of reactions undergone by 3-pyrazolin-5-ones occur at the 4-position. These pyrazolinones react by direct substitution, very much aa do activated benzene rings. Such reactions as halogenation, nitrosation, sulfonation, acylation, the Mannich reaction and many others give 4-substituted-3-pyrazolin-5-ones. 3-Pyrazolin-5-ones react with formaldehyde to give 4-hydroxymethyl-3-pyrazolin-5-ones(eq. 114).17 I n the presence of phenols

(eq. further condensation occurs, forming 4-benzyl-3-pyrazolin-5-ones 1 15).20.21 The phenol condenses in the para position. A similar reaction occurs with dia1k~lanilines.l~~~ The Mannich reaction is also a reaction

+

“’I\

CBH,

C,H,OH

+

CH,O

-

&OH

cH3---cHz-

CHJ-1

“’AO

\=z/

(115)

I

C,H,

with formaldehyde, but in the presence of amines and is readily undergone by 3-pyrazolin-5-ones. With aliphatic amines the products are 4-dialkylaminomethyl-3-pyrazolin-5-ones,110~ 637. 945 but aniline gives a 3 + c.a.c. 20

Part 1. Chapter I1

60

4-arylaminomethyl derivative.1483 When methylaniline is used a bispyrazolinone is also obtained by reaction at the amino group and at the 4-position of the aromatic ring.1483Hydroxylamines react analogously to dialkylamines with 3-pyrazolin-5-ones and f0rrna1dehyde.l~~~ Reactions of 3-pyrazolin-5-ones with chloral902*1190 are entirely analogous to their reactions with formaldehyde. This is illustrated in eq. 116. The reaction of aromatic aldehydes with 3-pyrazolin-5-onesis OH

analogous to the reaction of such aldehydes with 2-pyrazolin-5-ones, 988. 99a as except that the products are always bispyrazolinones,21*809. shown in eq. 117. Ar

+ 1

R'

ArCHO +

0 dl

O

0

1

It'

Nitrosation of 3-pyrazolin-5-ones is quite easy, commonly occurring in the 4-position (eq. 118). The usual reagent is nitrous a ~ i d1174 prepared , in~ situ by ~the use ~of sodium ~

I

Rl

~

~

-

nitrite and acid. However, nitrogen trioxide has also been used successfully.1oo1If a substituent is present in the 4-position and the 3-position is vacant, nitrosation occurs to give a 3-nitros0-3-pyrazolin-5-one.~~~ Halogenation of 3-pyrazolin-&ones with elemental chlorine, bromine, and iodine occurs readily t o form the corresponding halogenated ~ ~ m p ~ ~In thencase of d bromine, s .addition ~ ~ frequently occurs to give the 3,4-dibromo derivatives (eq. 119) which lose hydrogen bromide very readily and the usual product is the 4 - b r 0 m o - 3 - p y r a z o l i n - 5 - o n e . ~ O 9Various ~ ~ ~ ~ .other ~~~~~ agents ~ ~ ~ ~ also react with 3-pyrazolin-Ei-onesto introduce halogen at G 4 . Chlorination occurs with sodium h y p o ~ h l o r i t eand ~ ~phosphorus ~ pentachloride.'Ool

~

~

-

Pyrazolin &ones

51

N-Bromosuccinimide brominates 3-pyrazolin-5-onesbut an excess brominates alkyl groups in the 3 - p o ~ i t i o n . Iodination ~ ~ ~ . ~ ~ ~occurs by treatment of 3-pyrazolin-5-ones with mercuric chloride followed by iodine.lool R3--

R

R2A-i

3

q

7

R*N N/\ 1

R’

Y’b R1

0

__f R;yA-i-Br

“’\I

(119)

El

3-Pyrazolin-5-ones react with concentrated nitric acid809*860.888* or an excess of nitrous acidg84-992.1001 to form 4-nitro-3pyrazolin-6-ones. Presumably the excess of nitrous acid first nitrosates and this product is oxidized to the nitro compound. A variety of miscellaneous reactions which occur by substitution at C-4 are illustrated in the following equations. None of these reactions 992.1001

CH31=~

+

CI

has been used, or investigated, extensively. Benzyl chloride has also been used in reaction (121) and only one benzyl moiety is introduced. Reaction (125) may also give 3-substitution if the 4-position is blocked.972

Part 1 .

52

Chapter I1

Those 3-pyrazolin-5-ones which have no X-1 substituent can be alkylated at this position by use of methyl iodide in ~ i i e t h a n o l ~ ~ ~ ~ ~ ~ ~ or dimethyl sulfate (eq. 126).10010-Methylation occurs as a side-

CH3T=-I CH,N

"'\

+ (&H,NHCONHC&

I

+ CH31__1rCONHC6H, CH3N

-..Pi I 0

I 0 CBHJ

(124)828

CsH,

CH,

reaction. Krohs 860 has reported that halogenated pyridines, pyrimidines and thiazoles in the presence of sodamide react with the oxygen rather than the nitrogen (eq. 127). An analogous reaction occurs between such

3-pyrazolin-5-ones and benzenesulfonyl chloride and acyl chlorides to give O-acylpyrazoles.988~1001 The reaction of phosphorus oxychloride with 3-pyrazolin-&ones is rather similar t o the reaction with 2-pyrazolin-5-ones in that oxygen is replaced by halogen. I n those cases in which there is no substitution at N-1 and aryl substitution occurs at N-2, chloropyrazoles are formed,

+

RT===l Ar-N \

N'\ H

POCI,

-*r-L'--(, ,'. N F

O

(128)

C1

as shown in eq. 128.984-988*1001 This reaction takes a different course In these cases t.he when the N-2 substituent is alkyl or aralky1.700-795 N-2 substituent is eliminated (eq. 129). I n cases in which both nitrogen

Pyrazolin-5-ones

53

atoms are substituted, the 3-pyrazolin-5-oneis converted to a quaternary salt of a 5-chloropyrazole (eq. 130).789 The 3-pyrazolin-&one ring is stable to mild catalytic reductions, such as reduction with low pressure hydrogen in the presence of platinum or palladium catalyst.532.860 However, under extremely drastic conditions, hydrogen at-a pressure of 1000 atmospheres and a tem-

(130)

perature of 180" and nickel catalyst, ring cleavage occurs859 with elimination of one nitrogen atom and formation ofanilides (eq. 131). R3CH,CHC0NHR1

I

(131)

R4

Hot acid destroys the ring system of 3-pyrazolin-5-0nes.~~~~~~~ Various products have been reported from this reaction, depending upon substituents in the pyrazolinone ring and conditions. Destruction of the 3-pyrazolin-5-onering system with base 700 leads to a j?-ketoanilide. The reaction of zinc with 2,3-dimethyl-l-phenyl-3-pyrazolin-5-one has been reported by Knorr807to give benzene, aniline and unidentified products. Heymons and R ~ h l a n dtreated ~ ~ ~ 1,2-diphenyl-3-methy1-3pyrazolin-5-one with metallic sodium, obtaining addition of sodium a t the 1,4-position of the conjugated system present (eq. 132). CH,-

-I

lk

~

C'eHsN \

hT-

1%

CBH5

*

5

Na

cH3J--

'

CeHsN

"'\

I'

1

(132)

(IN&

C,H,

The compounds discussed in the previous sections are listed in Sections A, B, C , and D of Table XTV. 3-Pyrazolin-&ones having 3- and 4-a-hydroxyalkyl substituents are prepared in a number of ways. Two of these, alkylation of the corresponding 2-pyrazolin-5-one at N-2 and reaction of 3-pyrazolin-5ones with aliphatic aldehydes, have already been mentioned. The

Part 1. Chapter I1

54

reduction of 4-acyl substituents will be discussed in the section dealing with such 3-pyrazolin-&ones. A fourth method used has been the at elevated temperhydrolysis of 3-bromomethyl-3-pyrazolin-5-ones atures (eq. 133).532*s97 The reactions of these compounds are those of ZcHOCH,7=rC2H,

BrCHZ---C,H5 CH,NJ

HZO

"'\ I

'"\I

CH3N

4-N02C&,

0

I

(133)

0

4-NOPC,H4

alcohols and esters and of 3-pyrazolin-5-ones,except for a few special in mild acid solution form ones. 4-Hydroxymethyl-3-pyrazolin-5-ones 4,4'-bis( 3-pyrazolin-5-ones) (eq. 134).970The alcohols obtained by con-

-

---CH,OH %-N-I

"'\

I

CBH,

CH,-------CHT j,-l

" 4

0

CHz

PH3

P"

NCH3 (134)

0

I 0 Ct3H6

JBH6

densing chloral with 3-pyrazolin-5-ones decompose in the presence of potassium carbonate to give the corresponding 4-carboxaldehydes (eq. 135).107*196~889 This is the principal method used for preparation

of such aldehydes. These compounds are listed in Table XIV, Section E. Bodendorf and Ziegler 113 have reported the conversion of a 4-(1-hydroxy-2-methylaminopropyl)-3-pyrazolin-5-one into a 4-( 2oxopropyl)-3-pyrazolin-5-onein the presence of acid (eq. 13G).

CH,-----CH,I$-/

-:rcHcH,

HCI

CH3----CHZCOCHB

AHCHiHC1~~~4-1

';;"'.\ CBH,

(136)

"'\

I 0 CeHs

Only a few ol-alkylthiomethyl-3-pyrazolin-5-ones are known.1127 These have been prepared by reaction of mercaptans with 4-dimethylaminomethyl-2,3-dimethyl-l-phenyl-3-pyrazolin-5-one (eq. 137). These compounds are listed in Table XlV, Section E.

Pyrazolin-5-ones

55

The most frequently used method of preparation of compounds having nitrogen attached to a carbon atom which is substituted on the 3-pyrazolin-5-one ring is reaction of hydroxylamine, amines, hydrazines, hydrazides, etc., with 5-oxo-3-pyrazolin-4-carboxaldehydes.

This will be discussed in more detail in the section devoted to the reactions of the 4-carboxaldehydes. A frequently used method for preparing 4-dialkylaminomethyl-3-pyrazolin-5-onesis the Hoffmann A rather interesting method for preparing amines (eq. 138).697.1318.1319

synthesis of 4-benzsmidomethyl-3-pyrazolin-5-ones has been published by Monti.1°14N-Methylolbenzamide was condensed with 2,3-dimethyll-phenyl-3-pyrazolin-5-one (eq. 139).

The reactions of these compounds are for the most part normal for such functional groups. The only unusual one reported is the rearrangement shown in eq. 140.110*1483Hellmann and Schumachers3* have

reported that 4-dimethylaminomethy1-3-pyrazolin-5-ones can react ;t8 alkylating agents. Nitro- and formamidomalonic esters react with these

Part 1.

58

Chapter I1

pyrazolinones by elimination of dimethylamine and introduction of the 5-oxo-3-pyrazolin-4-methyl system into the ma,lonic ester (eq. 141).

I

AH3

CHq=---CH,K CH,N " \ '

- CH,I

+

OHCNHCH(COOCH,),

hH3

I 0 C,Hs

C830Ns

,CH,--CH&(COOCH3)a

cH3'EL AHCHO

(141)

ha& 0 This reaction is quite analogous to such alkylations with gramine. These compounds are listed in Table XIV, Section F. (3) Bis(3-pyrazolin-5-onea) Only a very few 4,4'-bis(3-pyrazolin-&ones) are known in which the rings are linked directly. These are prepared by methylation of 4,4'-bis(2-pyrazolin-5-ones) 807.809 or by treatment of the methiodides of 4-(5-chloropyrazol-4-y1)-3-pyrazolin-5-ones with alkali .99 These compounds are listed in Table XV. Bis(3-pyrazolin-5-ones)in which the linking chain is not attached to the pyrazolinone nucleus by functional groups are listed in Tables XVI and XVII. Most of these compounds have as the linking chain an arylidene group and are prepared by the reaction of 3-pyrazolin-5-ones as shown in eq. 117 (p. 50). with aryl aldehydes,66g~668~669~80'~1001~1133 Some aliphatic aldehydes have also been used in this reaction.409 3-Pyrazolin-5-ones react with formaldehyde or formamide to form the llS2 Under basic conditions corresponding bis compounds (eq. 142).910.

4-hydroxymethyl-3-pyrazolin-5-ones condense to form bispyrazolinones apparently by partial elimination of the 4-hydroxy(eq. 134),107*481 methyl group and the condensation of this product with unchanged starting material. Bis(2-pyrazolin-5-ones) can be converted into the as is done so corresponding 3-pyrazolin-5-onesby alkylation at N--2,ll6 frequently in the mononuclear series. 4,4'-Methylenebis(3-pyrazolin-5ones) have been prepared by reduction of the corresponding ketone with pEg6

Pyrazolin-5-ones

57

zinc and acid.740A variety of 3-pyrazolin-5-oneshaving a 4-acyl substituent react with various reagents to form bis(3-pyrazolin-5ones).31a~79g~90a These preparations are illustrated in eqs. 143-145. The

R'

R '

R'

Mannich reaction using primary amincs, when applied to 3-pyrazolin-5ones, forms bispyrazolinone~.~~~ Two more preparations of such compounds are shown in eqs. 146 and 147.

+

C6H&kCCOOCzH,

CH&H~CHXNNHC,H~ CzHs __f

CeHS--COHS-N

1\x/\ H

I

//'X/

O

O

PJ-C,H,

H

(146)

C6H5

C6H5

I

I

n

3*

rArCeH

CA-

(147)Ioe4 CH3K

Part 1. Chapter I1

58

Very little investigation of the reactions of bis(3-pyrazolin-&ones) has been done, but presumably the typical reactions occurring at C-4 in the mononuclear compounds would not occur. Ginzburg and cow o r k e r ~5 6~8 *~6sg~ have * published a number of papers concerned with oxidation of 4,4'-arylidenebis(3-pyrazolin-5-ones).A mixture of nitrous and nitric acids was used as the oxidant and the tertiary carbon atom connecting the pyrazolinone rings was oxidized to a carbinol (eq. 148). Pyrolysis of 4,4'- (4-dimethylaminobenzylidene)bis(2,3 -dimethyl-1phenyl-3-pyrazolin-5-one) in the presence of carbon dioxide at 175-1 80" has been reported1133to cause loss of hydrogen. AT

AT

E. 3-Pyrazolin-5-thiones and -5-selenones

A large number of 3-pyrazolin-5-thiones and a few 5-seleno analogs (Table XVIII) have been prepared. Almost all of these have been synthesized by reaction of the methochloride or methiodide of a 3- or 5halogenated pyrazole with potassium hydrogen 984. 988. gga potassium sulfide, sodium sulfide 981 or potassium hydrogen ~ e l e n i d e . ~ ~ ~ This method of synthesis is illustrated in eq. 149 for a 5-halopyrazole.

I n one case the substituents on the nitrogen atoms were both p h e n ~ 1 . ' ~ ~ Two other methods of synthesis of the 3-pyrazolin-5-thioneshave been reported. Michaelis 99a has claimed the conversion of 1,2-dimethyl-3phenyl-3-pyrazolin-5-one to the thione analog by reaction with potassium hydrogen sulfide. Worrall 1663 has reported the synthesis shown in eq. 150. Although comparatively little has been published concerning the properties and reactions of 3-pyrazolin-5-thionesand -5-selenones,it is apparent that in general they are very similar to the comparable 0x0

Pyrazolin-5-ones

59

compounds. These compounds are basic, forming stable salts with mineral acids.978.984* 986 They undergo nitration at C-4 and presumably would react similarly in other electrophilic substitutions. Reaction with CEH6-C.H,WCSNHR

+

H,NNH,

+

c6H57i-

(rN

HN

(150)

H N/\ S

'NY

halogens gives a perhalide having four atoms of halogen per molecule of p y r a z o l i n ~ n eThese . ~ ~ ~then ~ ~lose ~ ~ halogen readily to leave a dihalo derivative, which is probably the corresponding 4,5-dihalo-3-pyrazolidinethione or -3-pyrazolidineselenone.Alkylation of the sulfur or selenium or other atom occurs by heating the methiodide (eq. 151)984*988*992 .CHJ

"')

b

R2-_-

R I T I "P\

(151)

SCH,

AH3

alkyl iodides. The 3-pyrazolin-5-thionesare capable of oxidation at the sulfur atom and several such oxidation products have been reported. K i t a m ~ r a ' ~has ~* found ~ ~ ~that oxidation of 2,3-dimethyl-l-phenyl-3pyrazolin-5-thione with hydrogen peroxide gives 2,3-dimethyl-lphenyl-3-pyrazolin-5-one. K ~ r n a d a has ~ * oxidized ~ the same compound with chlorine, hydrogen peroxide, sodium hypochloride and perbenzoic acid to give what was called a dioxide, the structure of which was not reported. The oxidation of various 3-pyrazolin-5-thiones with gives what was called a p e r o ~ i d e ' ~or~with . ~ ~chloririe978~985~988~1001 ~ trioxide. It is possible that this is a zwitterion a9 shown in eq. 152. A

few 5-oxo-5'-thiono-,5,5'-thiono- and 5,5'-selenobis(3-pyrazolines)have been prepared by methods used for the mono compounds and they are listed in Table XV.785*986.gg1 F. 5-Imino-3-pyrazoliies

A number of 5-imino-3-pyrazolines are known and are listed in Table XIX. Those which have no subst,ituent at N-1 can exist as

Part 1.

60

Chapter IT

aminopyrazoles and probably are in this tautomeric form. Most preparative methods for these compounds depend upon conversion of chloropyrazoles or 3-pyrazolin-5-ones t o 5-imino-3-pyrazolines, although they can be formed directly from noncyclic compounds. This is shown in eq. 153.1025Michaelis has prepared 5-imino-3-pyrazolines by R'CEXCK

+

R'NHNHZ +

(153)

H

NH

reaction of the methochlorides of chloropyrazoles with ammonia or amines (eq. 154).985*996*1352 From an analogous reaction with aryl-

amines RiIichaelis1002suggested that the products were of the type (XXVII). It seems much more likely that these were 5-arylimino-3

-4r (XXBII)

pyrazolines. 5-Imino-3-pyrazolines can also be prepared by treatment of 5-imino-2-pyrazolino methiodides with sodium hydroxide.996 3-Pyrazolin-5-one hydrochlorides react with hydrazines a t about 100" to form 5-imino compounds (eq. 155).983 A similar reaction has

R'l=l.HCl + RZN

'x'g

ArNHKHz

R3-___f

R k1-'

I

R'

0

"'\I ?rNHAr

(155)

R'

been reported for 3-pyrazolin-5-thion~s.'~~~ Other syntheses are shown in equations 156826and 157.*02Very little has been published concerning reactions and properties of these compounds.

Pyrazolin -5-0110s

61

A few Fi-imino- and 5,5'-iminobis(3-pyrazolines) are listed in Table XV. These are prepared by reaction of the appropriate chloropyrazole inethiodide with

3. Hydroxy and Mercapfo Derivatives A. 2-Pyrazolin-5-ones

Both 3-hydroxy- and 4-hydroxy-2-pyrazolin-5-ones can exist theoretically and quite a number of 4-hydroxy compounds are known. are tautomeric with 3,5-pyrazoliThe 3-hydroxy-2-pyrazolin-5-ones dinediones which probably exist principally as the 3-hydroxy isomers. However, for the purposes of this discussion these compounds will be considered as diones. The most widely used and certainly most general procedure for is that developed by preparation of 4-hydroxy-2-pyrazolin-5-ones Veibel, Linholt and W e s t o ~ . ~ ~ Usually ~ ~ oxidations of 2-pyrazolin5-ones lead to formation of bispyrazolinones. These workers found that in alkaline solutions gave oxidation of 1-substituted-2-pyra.zolin-5-ones very good yields of the 4-hydroxy analogs (eq. 158). Oxidizing agents R3

used were hydroperoxides and oxygen. Acid media were also found to suppress the formation of bis(2-pyrazolin-&ones). Various other methods have been used for preparation of 4-hydroxy-2-pyrazolin-5ones but none extensively. Thoms and SchmuppI49' have used catalytic reduction of 2-pyrazolin-4,5-diones. The &OX0 group is reduced to hydroxyl in preference to other unsaturated centers. Bulow and Haas,262 with zinc and in reducing 4-phenylazo- and 4-nitro-2-pyrazolin-5-ones acetic acid, obtained as side-products 4-hydroxy-2-pyrazolin-5-ones. The oxidation of 4,4'-bis[3-methyl-1-(4-nitropheny1)-2-pyrazolin-5-one] with ferric chloride forms the corresponding mononuclear 4,4'-dihydroxy compound.690The condensation of a-acyloxy-/3-ketoesterswith

62

Part 1.

Chapter I1

an equivalent of phenylhydrazine gives rise to a 4-acyloxypyrazolinone, but excess phenylhydrazine forms the 4-hydroxy analog (eq. 159).372 CH3COCHCOOC,Hs f CeHsNHNH,

__f

cH3-

4

AO’

“\

bR R =H or acyl

I

(159)

c8H6

3-Alkoxy-2-pyrazolin-5-ones have been prepared by two methods. I n one of these a hydrazine is condensed with a /3-substituted ester (eq. 160).698.1143 The second is 0-alkylation of a 4,4-disubstituted-l-

substituted-3,5-pyrazolidinedione(eq. 161). The reagents used have R’

R’ (161)

CeH,

been diazomethane 41 and methyl iodide and potassium hydroxide.g94 With diazomethane N-alkylation also occurs. The only example with an alkoxy group in the 4-position found in the literature is 4-hydroxy-4methoxy-3-methyl-l-(4-nitrophenyl)-2-pyr~zo~n-5-one, obtained by repeated crystallization of the corresponding 4,4-dihydroxy compound from methanol.6s0 One method of preparing acyloxy-2-pyrazolin-5-oneshaa already been mentioned (eq. 159). The second method is acylation of 3,5pyrazolidinediones having no N-2 substituent (eq. 162). The acylations R2

OHN = ’ I -

R’

R3Co”_

R3COO--

\N

\

(162)

bl

have been achieved by use of acetic anhydride,1234benzoyl chloridegg8 and by trans-esterification.Zo0

Pyrazolin-5-ones

63

A number of 4-arylmercapto-2-pyrazolin-5-ones have been prepared by reaction of a 2-pyrazolin-5-one with aryl mercaptans (eq. It wa8 concluded that the first reaction was oxidation of the 163).27*28 CH3

4 I

+

ArSH

___+

cH3p

4

”’\

ySAr (163)

I

Ce.&

CBH5

mercaptan to a disulfide which then reacted with the pyrazolin-5-one. I n support of this theory it was found that disulfides give the same reaction. The same types of compounds were also prepared by reaction of 4-bromo-3-methyl-l-phenyl-2-pyrazolin-5-one with the sodium salts of various rnercaptan~.~’* 28 Takahashi and Yoshii 14?* have treated 6-ethoxy-5-methyl-6-carbethoxypyrido-[2,3 :2’,3’J-p-thiazine with hydrazine and obtained a 4-arylmercapto-2-pyazolin-5-one.This is scarcely a practical synthetic method. a-Arylmercapto- and a-acylmercaptoacetoacetic esters react with hydrazines to give sulfurcontaining substituents at G4.27 This group of compounds is listed in Table XX. A few bis(2-pyrazolin-5-ones) having alkoxy substituents are known and are listed in Table 111. These are prepared by addition of alcohols to the double bond connecting the pyrazolinone rings in pyrazole blue. A few 4,4’-bis(2-pyrazolin-5-ones) in which the rings are linked by sulfur atoms are known. The linking group is almost always disulfide and is prepared by oxidation of 2-pyrazolin-5-onessubstituted in the 4-position with mercaptoaryl groups.578These compounds are listed in Table VII. The few 3-acyloxy-5-imino-2-pyrazolines known are prepared by acylation of 5-imin0-3-pyrazolidinones.~~~. 5 9 4 * 1599 Crippa and Gaumeri 32 have treated 3-methyl-l-phenyl-5-imino-2-pyrazoline with p nitrophenylsulfenyl chloride to obtain a 4-arylmercapto compound. These compounds are listed in Table XII. B. 3-Pyrazolin-5-ones

The two possible hydroxy-3-pyrazolin-5-ones (3-hydroxy and 4hydroxy) are isomeric with pyrazolidinediones, the former with 3,S-pyrazolidinediones and the latter with 3,4-pyrazolidinediones. In conformity with the usage of this discussion the hydroxy-3-pyrazolin5-ones will be considered as the isomeric diones. However, the derivatives of the hydroxyl groups will be considered in this section. Konek

Part 1. Chapt.er I1

64

and Szasz 7 0 3 have methylated 4-acyloxy-3-methyl-1-phenyl-Z-pyrazolin-5-ones a t N-2 with methyl iodide t o give the 4-acyloxy-3-pyrazolin-5-ones. Treatment of 3,5-pyrazolidinediones having no substihent at the 4-position with diazomethane has been used by Arndt and cow o r k e r ~t o~give ~ 3-methoxy-3-pyrazolin-5-ones. It is necessary t o have a 2-substituent. 3-Acyloxy-3-pyrazolin-5-ones have been prepared in a similar fashion by acylation of 3,5-pyrazolidinediones.200~1048 A number have been synthesized by the reaction of 4-acyloxy-3-pyrazolin-5-ones of 2,3-dimethyl- 1-phenyl-3,4-pyrazolidinedione with various chlorinated aromatic compounds (eq. 164). The halogen in the aromatic halide waa C & - n i = O CH,N

+

Iir~l

C,H,

CHzl----CH,N- T O A r

(164)

X ‘ \’

‘Xi\

I

-

0

I

0

C,H5

usually quite active, for example picryl chloride. The preparation of sulfur analogs of these compounds according to eq. 165 has been CH,SC,H,

OH

reported by Poppelsdorf and Holt. 1127 These compounds are listed in Table XXI. The only bis(3-pyrazolin-5-one) having alkoxy or aryloxy substituents has been prepared as shown in eq. 164, except that a disubstituted aromatic compound was This compound is included in Table XVI. Bis(3-pyrazolin-5-ones) having the 4,4‘-positions connected by a disulfide bridge have been prepared by the action of sulfur dichloride (eq. 166).8.848The same on 2,3-dimethyl-l-phenyl-3-pyrazolin-5-one

type of compound is formed as a by-product in the reaction of 4-bromo2,3-dimethyl-l-phenyl-3-pyrazolin-5-one with potassium thiocyanate to form the 4-thiocyano compound742 and also by treatment of the 4thiocyano compound with acid, base or heat.742The disulfides shown as

Pyrazolin-5-onee

65

products in eq. 166 have been reported by K ~ n e to k ~react ~ ~with mercury to give products of the type (XXVIII). A few bis(3-pyrazolinNR

CHC--S-H~*--J~~==~CAI

‘7

”

/

0 ‘ C*H,

0

&HE

(XXVIII)

5-ones) in which the pyrazolinone rings are linked by selenium in the 4,4’-positions are known. Preparation of these is by the reaction of mono-3-pyrazolin-5-ones with selenium,545selenium selet e t r a ~ h l o r i d eIn . ~the ~ ~ first two cases the nium d i ~ h l o r i d or e ~selenium ~~ bridge is one selenium atom; in the third there is a mixture of selenide

-Se-

4 . In the last case the bridge Se is a dichloroselenide function. These last two types of bridge systems and a two-atom bridge of the type

CH3--

rCH,

p

C € 1‘N3 k - I ’ T C H 3 N/ I 0 C8HS X =C1, or Se

~

CH3-CH3&-CseATZ N ‘\’

d*H,

/

I , O CBHl

0

N’

(167)

1 CsH,

can be converted into monoselenides by base, acid or heat treatment (eq. 167). These bispyrazolinones are listed in Table XVI. 4. Amino, Imino, Hydrazino, Azo and Related Derivatives A. 2-Pyrazolii-5-ones

All functional groups having nitrogen attached to the pyrazolinone nucleus are considered in this section except nitroso, nitro and some oximes. Only those oximes which cannot be considered as tautomeric with the nitroso group are discussed here. Hydrazones are in this section. These compounds are listed in Tables XXII and XXIII. All of these derivatives of 2-pyrazolin-5-oneshave a nitrogen atom substituted at the 4-position as the 3-nitrogen-substituted-2-pyrazolin5-ones are tautomeric with the 5-imino-3-pyrazolidinonesand are considered as such in this discussion. The 4-nitrogen-substituted-2pyrazolin-5-ones are not usually prepared by cyclization directly to the desired pyrazolinone ring but rather by modification of already formed pyrazolinones. The methods used are usually those employed in

Part 1. Chapter I1

66

preparing such derivatives in aliphatic or aromatic compounds. For example, 4-amino-2-pyrazolin-5-ones in which the amine is primary are prepared by reduction of 4-oximino-, 4-nitro- or 4-azo-2-pyrazolin5-ones. For the reduction of 0 x i m e ~ Og2 ~ 8 and n i t r o - g r o ~ p s * ~ * ~ ~ ~ ~ stannous chloride has been commonly used. Azo compounds have been reduced catalytically with hydrogen"O and with a zinc and acid mixture.307Michaelis and co-workers~gshave reported the oxidation of 4-phenylazo-3-methyl-I-phenyl-5-imino-2-pyrazoline to a fused pyrazolinone-azirane system aa shown in eq. 168 and subsequent CHS-1-

4 I

N=NCd%

NaNOa __j

"ANH

cH331N:.,,, "

c H 3 ~ ~ + , H 54 N'

'I

CeH5

&BH5

\

I 0 CsH5

reduction of this to the 4-amino-2-pyrazolin-5-one which was isolated only aa its oxidation product, rubazonic acid. The structure proposed for the intermediate seems most unlikely. Four methods have been reported for the direct preparation (i.e., with no amino intermediate) of secondary and tertiary 4-amino-2-pyrazolin-5-ones. Only one product has been synthesized by each of these routes. M a e d ~ Ohas ~ ~heated 2,3-dimethyl-4-dimethylamino-l-phenyl-3-pyrazolin-5-one (aminopyrine) in the presence of salicylic acid or barbital causing rearrangement of the 2-methyl substituent to the 4-position (eq. 169). I n the

oxidation of 3-methyl-l-phenyl-2-pyrazolin-5-one with nitrobenzene P e r r o n ~ i t o has l ~ ~found ~ that the principal product is the expected is bispyrazolinone, but 4-snilino-3-methyl-l-phenyl-2-pyrazolin-5-one also formed. This may occur through reaction of nitrobenzene reduction products formed by oxidation of some of the 3-pyrazolin-5-one. The cyclization of a tertiary amino /?-aldehydoester to a pyrazolinone has Itanosg5has used a method for preparation been reported (eq. 170).1537 OHCCHCOOC,H5 CH3AcHCOOC,H,

1

CHO

+

C,H,NHNH,

+

EIICH=NNHCoH5

' "'1I &OOC,H,

JsH5

(170)

Pyrazolin-5-ones

67

of such compounds that may be fundamentally the same as that of Perroncito, the reaction of an amine with a 2-pyrazolin-&one in the presence of an oxidant (eq. 171).

4-Imino-2-pyrazolin-5-ones of the type (XXIX) have become very important in the field of color photography and will be discussed in

ANR3

R 2 7 -

"\ dl

(XXIX)

more detail in respect to this use. They have been particularly investigated at Eastman Kodak by Weissberger and Vittum who oxidized an alkaline solution of a 2-pyrazolin-&one and 2-amino-5-diethylaminotoluene with silver nitrate or silver chloride (eq. 172) to obtain the

CH3

(172)

desired 4-iminopyrazolinones. Gerbeaux519 has used the same procedure and in addition has used potassium ferricyanide and sodium hypochlorite as oxidizing agents. Mann rand HaworthgP3and Gerbeaux519 have taken advantage of the active hydrogen atoms in the 4-position of 2-pyrazolin-5-ones for the preparation of the imino derivatives. Various aromatic nitroso compounds were condensed with X-pyrazolin5-ones (eq. 173). Brooker and White240have prepared this same type R

+

J 2

'K

\

dl

O

R~~ K O --+

"=T " \o

I

R'

(173)

Part 1.

68

Chapter I1

of compound by reaction of 4-nitroso (or oximino)-2-pyrazolin-5-ones with quaternary salts of heterocyclic compounds having active hydrogen on a methyl substituent (eq. 174).Similar products are obtained by

+

q '7 a

R'--NO

n

R3

C-CHa \ NP,

---+

R4 I X-

' 'N

R1

n '

R2-------- NCH=C

R3

N'

I

dl

R4

\

(174)

O

the reaction of 4-benzylidene-2-pyrazolin-5-oneswith aromatic a r n i n e ~ . 'The ~ ~ ~benzylidene group is replaced by an arylimino group (eq. 175). CH,

4 1A \=/

OCH3 i- (C2H&XQ-NH2

-CH

\N

I

CH'S

(173)

CBIh

Synthesis of 4-amino-2-pyrazolin-5-ones is usually achieved by treatment of an a-amido-/3-aldehydo- or /3-ketoester with hydrazines according to the classical method for preparation of %-pyrazolin-5-ones. Variants on this procedure consist of using an a-amidoester which has /+substituents whose reaction is equivalent to that of a ,!I-carbonyl substituent. Such compounds are D-benzylpenicilloic acid a-methyl ester,lo2' ethyl ~ h e n y l p e n a l d a t eand ~ ~ ~the acetal of an a-amido-pformyl ester.59*243 Cornforth has isomerized 2-phenyl-4-hydrazinoThe same methylidyneoxazolidone to d-benzamido-2-pyrazolin-5-one. compound was obtained by treatment of 1-ethoxyvinyl-2-phenyloxazolidone with p h e n y l h y d r a ~ i n e . ~ ~ ~ The synthesis of 4-azo-3-methyl-l-phenyl-2-pyrazolin-5-one is shown in eq. 176.114* The +hydrazones of 2-pyrazolin-4,5-diones have .OH

+

__j

I so,

CH3-

+

.

Pyrazolin-5-ones

69

been prepared by Auwers and c o - ~ o r k e r who s ~ ~ used the reaction of a hydrazine with the 4,Fi-diOne (eq. 177). This same compound was CH,

F\"\r o

+

C,H,N?JH2

N

+

4

CH3r=N (177) \Iv

AH3

AeH,

\

AH3

h a 6

synthesized by methylation of 3-methyl-4-phenylazo-l-phenyl-2pyrazolin-5-one and by cyclization of the bis(phenylmethy1hydrazone) of ethyl a,P-diketobutyrate. These compounds are listed in Table XXI. The 4-amino-2-pyrazolin-5-ones react as do other arnines. They can be alkylated with alkyl halidesgg2and react with aldehydes to form Schiff base^."^.^^^ Oxidation of these amino compounds with ferric chloride leads to the rubazonic acids (eq. 178) in which two 2-pyrazolin-

R2i--r..H, "b' I

R'

R2/,N--,j?R2 N

"-% 1

R'

0

A N / 0 A 1

(178)

5-one rings are connected at the 4,4'-position by nitrogen having no hydrogen. Rubazonic acid itself is 4-(3-methyl-1-phenyl-5-0x0-2-pyrazolin-4ylideneamino)-3-methyl-l-phenyl-2-pyrazolin-5-one. 4-Arylimino-2pyrazolin-&ones are readily reduced to the corresponding 4-arylamino2-pyrazolin-5-0nes.~~~~ 2-Pyrazolin-5-ones react with 4-arylimino-2pyrazolin-5-ones to give bispyrazolinones (eq. 179).1538

4-Arylazo-2-pyrazolin-5-ones are strongly colored and have good dyeing properties. These compounds have been prepared in vast numbers for use in dyeing all types of fabrics and are of great importance in the dye industry. They will be discussed fully from this viewpoint in the section dealing with pyrazolinone dyes. The 4-arylazo-2-pyrazolin5-ones are listed in Table XXIII. Of the many methods which have been used for preparing 4arylazo-2-pyrazolin-5-onesby far the most important is the direct coupling of a diazonium salt with a 2-pyrazolin-&one (eq. 41).77.809.813.818.980~1251 This reaction goes extremely readily with

Chapter I1

Pert 1.

70

practically all 2-pyrazolin-4-ones having no 4-substituent. Coupling occurs with any aromatic amine capable of forming a diazonium salt and under a wide variety of conditions. Even 4-substituted-2-pyrazolin5-ones have been reported to react with diazonium salts by replacement of the 4-substituent to form a 4-arylazo-2-pyrazolin-5-one. Substituents replaced have been t r i a r ~ l m e t h y l , ~a~ ~ ' y l and ~ ~ halogen.1514 l 4,4'Arylidenebis(2-pyrazolin-5-ones)react with diazonium salts to form 4-arylazo compounds (eq. 180).1255.1351 A variation of this procedure is Ar'

I

+

&N,X

-

R'

R'

reaction of a 5-acyloxypyrazole with a diazonium salt.5g1This reaction hydrolyzes the ester linkage and, if an acyl substituent is present at the 4-position, replaces it to form 4-arylazo-2-pyrazolin-5-ones (eq. 181).

R*rxR3 +

\N

I

R'

OCOR'

ArNaX

__f

N=NAr

RaJr-J\ "

I

(181)

R'

R3= H or R'CO

A method frequently used and capable of a large number of variations is the cyclization of a-substituted-p-ketoesters,amides or hydrazides with hydrazinea to 4-arylazo-2-pyrazolin-5-ones. One variant of this is the treatment of an a,p-diketoester with hydrazine (eq. 182).627* l w 3 -1574.1 5 ' ~ Instead of the ester, hydrazides of a$-diketoacids

Ar

have been used.99A very similar synthesis is the use of an a-oximinop-ketoester and a h y d r a ~ i n eAlso . ~ ~ quite similar is the cyclization of an or or$-diketoa-hydrazone of an a,/?-diketoestera55.259'262.314.732 amideZ6lwith a hydrazine. The bishydrazones of a,/?-diketoestersalso 257 It is react with hydrazines to form 4-arylaz0-2-pyrazolin-5-ones.~~~~ not necessary that the a-substituent be unsaturated. a-Amino-p-ketoesters,1535a-chloro-p-ketoesters1513.1514 and a-acyloxyesters372 have

71

Pyrazolin-5-ones

also been used (eq. 183). Apparently an oxidation of a hydrazino to an azo function occurs in the course of the reaction. RCOCHCOOC2HS

I X

+ 2ArNHNH2

4

(183)

"\

X=CI, Br, NH, or CH,COO

h

Cyclization of a variety of bishydrazones of a,B-diketoacid~,~~* 285 a,/3-diketoester~~~*~~~* 397-732. 782 and a , / M i k e t o a r n i d e ~ ,using ~ ~ ~ either acid, base or heat, to 4-arylazo-2-pyrazolin-5-ones has been reported (eq. 184). I n this reaction the aryl groups have usually been the same

Ra=OH, WDH6or NH,

1r1 b

although Kleene 782 has used different aryl groups. Another modification of this reaction is due to Chargaff and M a g a ~ a n i k , ~ who * ~ report that oxidation of the 1,2-bisphenylhydrazoneof mesoxaldehyde gave rise to 4-phen ylazo - 1-pheny1-2-pyrazolin-5-one. F i ~ h t e has r ~ reported ~~ an arylazopyrazolinone as one of the products from the reaction of a,a'-dibromo-a-methylsuccinicacid with p-bromophenylhydrazine (eq. 185). Br

4-BksH4

Huebner and Links70 have prepared 4-arylazo-2-pyrazolin-5-ones by the reaction of hydrazines with 4-hydroxycoumarin, 3,3'-methylenebis(4-hydroxycoumarin) and with 2,3,4-triketochroman derivatives. In the case of the 4-hydroxycoumarins oxidation by phenylhydrazine occurs to give the bisphenylhydrazone of an a,@-ketoester.The reaction then proceeds rm previously discussed for such compounds. Bulow and Hecking 263 have treated 4-arylazoisoxazolidoneswith hydrazines to form 4-arylazo-2-pyrazolin-5-ones (eq. 186) and other heterocycles undergo similar transformations.l18

i)

R

b

Part 1.

72

Chapter I1

A number of 2-pyrazolin-5-ones having substituents at C-4 react with arylhydrezines by replacement of the substituent to give 4-arylazo derivatives. These syntheses are illustrated in eqs. 187 and 188. xa---.-O

L

" \o

I

iArNHNH2

1%'

+

CH3-,--C1

CBH$"HNHs

4% deH,

__f

]tZ-----

"J\

N-=Nh (187) 12s.680

I

R' cH3--p

J J " I

N=NCBH,

\

( 188)151*

CBH,

Ridi llE5has reported that the reaction of 2,3-dimethyl-l-phenyl4-nitroso-3-pyrazolin-5-one with phenylhydrazine gives 4-phenylazo-3methyl-l-phenyl-2-pyrazolin-5-one. This may occur by replacement of the methylphenylhydrazine moiety in the 3-pyrazolin-5-oneby phenylhydrazine. The 4-oximino-2-pyrazolin-4-one could then react with phenylhydrazine t o give the reported product. Although in this discussion the 4-arylazo-2-pyrazolin-5-ones have been written as &OX0 compounds, it is likely that they exist largely in the tautomeric en01 form.262 The methylation of 4-arylazo-2-pyrazolin-5-ones has already been mentioned.52 Nitration occurs with replacement of the 4-arylazo group.262Reduction occurs readily but two different paths are followed. As mentioned earlier, 4-amino-2-pyrazolin-5-ones can be obtained by catalytic reduction 670 and with zinc and hydrochloric acid.397However, reduction with zinc and acetic acid leads to rubazonic acids (eq. 189).

The conditions which determine the course of this reduction are not known. The most important reactions of 4-arylazo-2-pyrazolin-5-ones are those with various salts to form metal complexes. These products are of great importance in the dye industry and will be discussed more completely in the section devoted to dyes. Chromium complexes are prepared by reaction of a 4-arylazo-2-pyrazolin-5-one with inorganic compounds213- 1457 including chromium sulfate 475 and chromium trifluoride,l*l6 with organic chromium compounds, such as chromium

73

Pyrazolin-5-ones

f ~ r m a t and e~~ chromium ~ complexes with salicylic acid.207Copper,213 lead,213 zinc 1616 and cobalt l 6 O 0 have also been used. The aromatic moiety of the arylazo group usually has a hydroxyl or carboxyl group ortho to the azo linkage. The complexes thus obtained with chromium contain either one or two molecules of the dye per atom of

-

I-

Na+

SOeNH,

(XXXI)

metal. The metal atoms react with the (2-5 oxygen of the pyrazolinone ring in its enol form and with the hydroxyl group of the aromatic ring to form more or less covalent bonds. There is also electron donation by other oxygen atoms and by the azo nitrogen atoms to the metal atom. The structure (XXX) has been proposed for 1 : 1 ~ o m p l e x e sand ' ~ ~ ~ ~ ~ ~ ~ ~ (XXXI) for 2 : 1 c0mplexes.~~59

Part 1. Chapter I1

74

Amino-substituted bis(2-pyrazolin-5-ones)have been prepared in which the rings are linked by carbon chains or by nitrogen atoms. The former are listed in Tables VIII and I X and the latter in Tables V I I and VIII. In most of those cases in which carbon chains link the two rings the amino substituents are introduced as they are in monop y r a z ~ l i n o n e s . ~ Eisner, ~ ~ * * ~Elvidge ~ and Linstead419 have prepared some amino bis(2-pyrazolin-5-ones) by direct cyclization (eq. 190). (CaH~OOC)~CHCOCH~HCOCH(COOC2Hs)l + C,H,NHNHz

Some 1,1'-bis(4-arylideneamino-2-pyrazolin-5-ones) have been prepared by Furuya and Ueno 494 by treating bis(2-pyrazolin-5-ones) with oxidizing agents in the presence of arylamines. The best known series of amino bis(2-pyrazolin-5-ones) is the rubazonic acid series. I n this case the two rings are linked by a single nitrogen atom. The preparation of rubazonic acid itself by oxidation with ferric chloride of 4-amino-3-methyl-l-phenyl-2-pyrazolin-5-one has already been mentioned (eq. 178).809 This is a general method for the preparation of rubazonic 397*611 although other oxidizing agents are sometimes used.480Votocek and Wichterle 15~' have reported the isolation of a rubazonic acid analog as a side-product in the reduction of 4-oximino-3-phenyl-l-(2-phenethyl)-2-pyrazolin-5-one to the corresponding amine using zinc and acetic acid. The reduction of 4-phenylazo-2-pyrazolin-5-one haa also been found to give a rubazonic acid.1552Wohl and Doll1676have prepared rubazonic acid analogs by the reaction of an a,P-diketoester with hydrazine (eq. 191) and a someR'COCOCOORa

+ H2NNH2

- RIJ-,,-/B"l 'z'

/

0

"

(191)

H

what analogous method has been reported by Wislicenus and Moureu, Choivin and Petitloz2 have obtained a very low yield of a rubazonic acid by the reaction of ethyl cr-bromocinnamate with phenylhydrazine. 4,4'-Bis(2-pyrazolin-5-ones) linked by a single azo group and by --N=N-R-N=Nhave been reported, although these compounds are very few. Diazotization of 4-amino-2-pyrazolin-5-ones

Pyrazolin-5-ones

76

followed by coupling with an appropriate acetoacetic ester derivative and cyclization gives 4,4'-azobis(2-pyrazolin-5-0nes).~~~~ von Walther and R o t h a ~ k e have r ~ ~ claimed ~~ that the reaction of 4,4-dichloro-3methyl-l-phenyl-2-pyrazolin-5-one and 3-methyl-1-phenyl-2-pyrazolin5-one in the presence of hydrazine gives the same type of product. The compounds having two azo groups in the chain are prepared by coupling of tetrazotized diamines with acetoacetic esters followed by cyclization to 2-pyrazolin-5-0nes,~~~ coupling of tetrazotized diamines with pyraz~linones,~~'. 1245*1359 or a combination of these.259 Priewe and Poljak114' reduced 5-oxo-2-pyrazolin-4-oximeswith hydrogen or sodium hyposulfite and obtained 4,4'-bis(5-0~0-2-pyrazolin-4-yl)hydrazines. Oxidation of these compounds gave 4,4'-aZO derivatives. 3,3'Tmino bis(2-pyrazolin-&ones) have been prepared by condensation of 3-amino-1-aryl-2-pyrazolin-5-ones ( 1-aryl-5-imino-2-pyrazolidinones) with ammonia or amines (eq. 192).595*59e R

The most interesting of the aminobispyrazolinones are the rubazonic acids having the =N- linkage. These compounds are quite strong acids, although no quantitative data on this are available. As would be expected, reduction of the extranuclear C=Noccurs readily with stannous chloride to give the corresponding tertiary amine. Rubazonic acid is decomposed completely by sodium hydroxide and reverts to a monomer (eq. 193) upon treatment with phenylhydrazine.809.992The NaOR

- I

CH,CCOCOOH II

~HC,H, (193)

3,3'-iminobia(2-pyrazolin-5-ones)react with formaldehyde and ethyl orthoformate at the reactive 4,4'-positions to give tricyclic comp o u n d ~ If . ~there ~ ~ is no substituent on the linking nitrogen atom, reaction with dimethyl sulfate causes methylation at this nitrogen.705

76

Part 1.

Chapter TI

Treatment with chlorosulfonic acid gives sulfonation in the benzene ring, when present.705 Michaelis and co-workersggOhave prepared 3-methyl- l-phenyl-4phenylazo-2-pyrazolin-5-thioneby coupling of the corresponding pyrazolinthione with phenyldiazonium chloride. 5-Imino-2-pyrazolines having nitrogen substituents a t the 4position have been reported by Michaelis and c o - w o r k e r ~ 996. ~ ~Ioo2 ~* The 4-amino compounds have been prepared by reduction of 4-oximino analogs1002and by reduction of arylazopyrazoles 995 (eq. 194) with

mild reducing agents, such as sodium hydrosulfite. These amino compounds react with ketones and isocyanates as do other amines. 4Arylazo-5-imino-2-pyrazolines have been prepared ;19 are the 5-Ox0 analogs.ggsThese compounds are listed in Table XII. B. 3-Pyrazolin-5-ones

3-Pyrazolin-5-ones having nitrogen substituents in the 3- or 4-positions, except primary amino, secondary amino, amido having hydrogen on the nitrogen, nitroso and nitro are discussed in this section. Although primary and secondary amino- and amido-3-pyrazolin-5-ones undoubtedly exist as the 3-pyrazolin-5-one tautomer, they are discussed under the heading of the 4-imino-3-pyrazolidinone and 5 imino-3-pyrazolidinone tautomers because of the convention adopted in this discussion regarding compounds having such tautomeric possibilities. These compounds are listed in Table XXIV. The most important amino-3-pyrazolin-5-one is aminopyrine, which is 4-dimethylamino-2,3-dimethyl-l-phenyl-3-pyrazolin-5-one. This compound has been widely used as an antipyretic and analgesic, particularly in Europe, and as a consequence its preparation and chemistry have been studied extensively. Most of the methods used have been those for synthesizing 4-dialkylamino-2-pyrazolin-5-ones used for the 4-dimethylamino compounds. Most syntheses of tertiary amino-3-pyrazolin-5-ones are based on an alkylation by one means or another of the primary or secondary amino analogs. I n some cases simultaneous reduction of a nitroso or nitro compound or of a Schiff base and alkylation of the amine so formed is carried out . 4-Dimethy lamino-3-pyrazolin-5-ones (amino-

Pyrazolin-5-ones

77

pyrine and analogs) have been synthesized by application of the Eschweiler-Clarke procedure to 4-amino-3-pyrazolin-5-ones(eq. 195).548,860.941Other alkylating agents used have been alkyl CHZO

___, HCOOH

(195)

halides,130* dimethyl sulfate 984. 992 and methyl-p-toluenesulf ~ n a t e . l 3-Pyrazolin-5-ones l~~ dialkylated a t N-4 have frequently been prepared by alkylation of the primary amine by such means as treatment with an aldehyde111s172and reduction of the Schiff base followed by alkylation. The final alkylation has been achieved by treatment with an alkyl halide,524*1298 by heating with an amine hydrochloride'll and by treatment with an aldehyde followed by reduction.860 A special type of alkylation of secondary amines is that reported by Bochmiihl and Stein.lo5 Secondary amines were treated with formaldehyde and sulfur dioxide or an alkali bisulfite to give an aminomethanesulfonic acid (eq. 196). Several patents have reported the synthesis of amino-

-

R2 C H 3 - q - N HI

CH3N 'X'\

L

RS

C H 3 7 - w ~I NCH2SOJH CH3N

(196)

"/'\ I Rl

O

0

pyrine starting with reduction of 4-nitroso-2,3-dimethyl-3-pyrazolin-5one with sodium bisulfite to give the 4-sulfamino analog (eq. 197). This CH~T---?IO CH3--N 'X/\ I 0 C6H5

1

-

CH3~--rNHS03H

CHa-N

\ ' y

CeH5

-

cH37==/N,LH, CH3

CH3-N

\n

3

(197)

is then methylated by various means. The most common method is use of formaldehyde and formic a ~ i d . ~ ~ 1174 ~ .Alkylation ~ ~ ~ ,with ~ ~ ~ . ~ ~ ~ . dimethyl sulfate 144. 1256 and electrolysis in the presence of formaldehyde and sulfuric acid691have also been used. Reduction of 4-nitroso-2,3-dimethyl-l-phenyl-3-pyrazolin-5-one with zinc or iron and a ~ i d or ~ catalytically551 ~ ~ * ~ in ~ the ~ presence * ~ ~ ~ of formaldehyde also gives aminopyrine. The analogous 4-nitro compound can also be reduced catalytically in the presence of formaldehyde

78

Part 1. Chapter I1

to form arnin~pyrine.~~O* 1356 Sonn and Litten 1320 have replaced the bromine atom in 4-bromo-3-benzyl-2-methyl-l-phenyl-3-pyrazolin-5one with dimethylamine. A variety of 4-amino-5-alkoxy- and acyloxy-1,3-disubstitutedpyrazoles have been treated with alkylating agents such as alkyl halides to give 4-dialkylamin0-3-pyrazolin-5-ones.~~~ There is a simultaneous alkylation of ring nitrogen and extranuclear nitrogen. The reported decomposition of 4-dimethyltriazeno-2,3-dimethyl-lphenyl-3-pyrazolin-5-oneto a r n i n ~ p y r i n e has ~ ~ ~ been shown by Stoltz 1353 to be incorrect. Most 4-amido-3-pyrazolin-5-ones have been prepared either by acylation of secondary amines 537* 1471 (4-alkylimino-3-pyrazolidinones) or by acylation of the primary amine 1471 followed by a l k y l a t i ~ n Shimidzu . ~ ~ ~ 1297 has reported the replacement of a methyl group by a cyan0 group and conversion of this to a thiourea (eq. 198). 618n

CH,

I

CsHs

4-Amino-3-pyrazolin-5-ones (4-imino-3-pyrazolidinones) react with aldehydes and ketones to form 4-alkylidene- and arylideneamino-3pyrazoIin-5-0nes.~~~. 984* 1365*1592 Formaldehyde,172aromatic aldeh y d e ~heterocyclic ,~~~ aldehydes lm4*1186 and aromatic ketones g92 have been used. Eisenstaedt 417 and Emerson and Kelly426have prepared somewhat similar compounds by condensation of 4-amino-3-pyrazolin5-ones with phenols and various amines in the presence of oxidizing agents, such as ferric chloride and potrtssium ferricyanide (eq. 199).

.99)

The same type of condensation occurs with 2-pyrazolin-5-ones having no substituent in the 4 - p o ~ i t i o nHere, . ~ ~ ~of course, it is unnecessary for

Pyrazolin-5-onea

79

the aromatic ring to assume a quinnooid form, as the 3-pyrazolin-$one analogs do, since two active hydrogen atoms are present on the C-4. 4-Amino-2-pyrazolin-5-onesreact with Schiff bases to form the 4arylideneamin0-3-pyrazolin-5-ones.~~~ R u b t s o ~reports ~ ~ ~ the ~ condensation of this amine with sodium 1,2-naphthoquinone-4-sulfonab to give a quinoncimine by replacement of the sulfonate group. The 4-arylideneamino substituent has been introduced by condensation of a 4-nitroso-3-pyrazolin-5-one with f l u o r e n e ~The . ~ ~condensation ~ occurs at the active methylene group of the fluorene. Michaelis and coworkerslOol have prepared a compound which they believe to have a sulfur-nitrogen double bond at least formally similar to the > C-Nsubstituents discussed here. This was prepared by condensation of a 4-amino-3-pyrazolin-5-one with thionyl chloride and supposedly gave a 4-OS-Nsubstituent. However, it appears unlikely that this type of compound W M actually prepared. The only amino 4,4’-bis(3-pyrazolin-5-one) reported is N,N’[bis(2,3-dimethyl-1-phenyl- 5 - 0x0 -3-pyrazolin- 4-yl)l -N,8’dimethylmethylenediamine prepared by acid treatment of the sodium salt of N-sulfomethyl-N-methylaminoantipyrine with 4-Amino-3-pyrazolin-5-ones (4-imino-3-pyrrtzolidinones)react with nitrous acid as do ordinary aromatic amines to form diazonium salts.426.984~ 1353 These then couple readily with aromatic 1323 and aliphatic compounds having amines,1017.1018.lo60 phenolssg2~ active hydrogen atom,426~1017 such aa acetoacetic esters. The products are 4-azo-3-pyrazolin-5-ones (eq. 200). The diazonium salts also couple

CaH,

with 2-pyrazolin-5-onesin the 4 - p o ~ i t i o nSimilar . ~ ~ ~ compounds can be prepared by the coupling of an aromatic diazonium salt with a 3pyrazolin-5-one. Coupling occurs in these cases either at the 3- or the 4-position, whichever is u n s u b ~ t i t u t e d .loo4 ~ ~ ~Huebner * and Linka70 prepared 4-arylazo-3-pyrazolin-5-onesby reaction of 2,3,4-trioxochromane-3,4-bis(phenylhydrazone) and 3-arylhydrazone with phenylhydrazine. The 3-arylhydrazone group becomes the 4-arylazo group in the final product.

Parb I.

80

Chapter I1

The preparation of l-(2,3-dimethyl-l-phenyl-5-oxo-3-pyrazolin-4yl)-3,3-dialkyltriazeneshas been accomplished by reaction of 2,3dimethyl-l-phenyl-5-oxo-3-pyrazolin-4-diazoniumchloride with dialkylamines (eq. 201).1353 The previously reported method of preparation527was found to be in error.

I

CeH3

2,3-Dimethyl-l-phenyl-5-oxo-3-pyrazolin-4-diazonium chloride reacts with hydrazoic acid to form the corresponding 4 - a ~ i d eT.h~ is~ ~ azide decomposed to form 4-(2,3-dimethyl-l-phenyl-5-oxo-3-pyrazolin4-yl)azo-2,3-dimethyl-l-phenyl-3-pyrazolin-5-one. Dihlmann3'l has determined the R, values of 4-amino- and 4amido-3-pyrazolin-5-ones by using butanol-acetic acitf-water as solvent and ferric chloride or p-dimethylaminobenzaldehydeas developer. The rearrangement of 4-dimethylamino-2,3-dimethyl-l-phenyl-3pyrazolin-5-one to a 2-pyrazolin-5-onehas already been mentioned (eq. 169). 4-Benzylideneamino-2,3-dimethyl-l-phenyl-3-pyrazolin-~-one reacts with dimethyl sulfate in aqueous media to give the 4-methylamino analog.940Presumably the Schiff base is hydrolyzed and the resulting amino group is methylated. 4-Dimethylamino-3-pyolin-5ones react with phosphorus oxychloride by conversion to the methochloride of a pyrazole.looO 4-Arylazo-3-pyrazo,oln-5-ones have been used as dyes. They form complexos with chromium which have good dyeing properties.1060 Michaelis, Kotelmann and Drewsga4report the reduction of 4-aryl-azo3-pyrazolin-5-ones having no 1-substituent to pyrazoles by use of phosphoma pentasulfide (eq. 202). Reaction of such azo compounds

pa88_

R31R1-N

(202)

H

with phosphorus oxychloride leads to the corresponding 5-chloropyra~ole.~~~

Pyrazolin-5-ones

81

The only 4-dialkylamino-3-pyrazolin-5-thionereported in the l i t e r a t ~ r e was ~ ~ prepared ~ - ~ ~ ~by ~ the action of sodium sulfide or potassium hydrogen sulfide on the methochloride of the corresponding 5-chloropyrazole. A very few bis(3-pyrazolin-5-ones) in which the two rings are connected by the azo group have been prepared. The preparation of these via the 4-azid0-3-pyrazolin-5-ones~~~ haa already been mentioned. These bispyrazolinones have also been prepared by coupling diazonium salts with 3-pyrazolin-5-ones (eq. 203).gs4.loolScott and c o - w ~ r k e r s ~ ~ ~ *

have reported a bis(3-pyrazolin-5-one)having a very extended bridge system prepared by reaction of a 3-pyrazolin-5-one diazonium chloride with N,N'-dibenzylidenediaminoguanidine. 5. Halogen Substituted Derivatives A. 2-Pyrazolin-5-ones

Halogenated 2-pyrazolin-5-ones having halogen a t N-1, C-3 and C-4 are known, but by far the largest number of such compounds have the halogen atom at C-4. Such compounds are usually prepared by direct halogenation with elemental halogen. Chlorination or bromination of 2-pyrazolin-5-ones having no 4-substituent with one equivalent of halogen gives the 4-monohalogeno product (eq. 204), but an excess 809* 1605 of halogen gives the 4,4-dihalo derivative.355* X

I

R'

I

R'

I

R'

4-Iodo- and 4,4-di-iodo-2-pyrazolin-5-ones can be prepared by treatment of 2-pyrazolin-5-ones with iodine-potassium iodide in an alkaline s01ution.l~~~ Here, again, either the mono or the dihalogeno product is formed, depending upon the amount, of halogen used. 4

+ C.H.C.

20

Part 1.

82

Chapter I1

Extremely good yields have been reported in these ha10genations.l~~~ 4-Alkyl-2-pyrazolin-5-ones react with halogens readily, but even with an excess only monohalogenated products have been obtained.lBo5 Smith and co-workers1309 have found that 1,3-dimethyl-2-pyrazolin-5one reacts with bromine to give both the expected 4-bromo product and also l-bromo-3-methyl-2-pyrazolin-5-one. This same compound ww obtained by bromination of 3-methyl-2-pyrazolin-5-one with N-bromos u c ~ i n i m i d e . ' ~4-Bromo-2-pyrazolin-5-ones ~~ have been prepared 1209 (eq. 205) with by bromination of 2-nitroso-3-pyrazolin-5-ones

I

I

H

H

bromine. Treatment of 3-pyrazolidinones with bromine results in oxidation of the pyrazolidinone to a pyrazolinone followed by bromination.818.1028Unless the temperature is controlled this reaction leads to a mixture of mono-, di- and tribromo-2-pyrazolin-5-ones. However, Muckermann1028WM able to obtain the monobromo derivative at 0" and the dibromo at room temperature. A number of reagents other than elemental halogen have been used for the introduction of halogen into 2-pyrazolin-5-ones.Treatment of 2-pyrazolin-5-ones with phosphorus p e n t a ~ h l o r i d e809= ~ ~ g80 ~ . or with sodium hypochloriteloo4 forms 4,4-dichloro-2-pyrazolin-5-ones. An analogous reaction is the formation of 4,4-dibromo analogs by use of phosphorus t r i b r ~ m i d e The . ~ ~ ~methods already discussed for halogenation of 2-pyrazolin-5-ones lead exclusively to the 4-substituted products, but 3-halogenated-2-pyrazolin-5-ones are known. These have been prepared by Michaelis and co-workersgg4.gg8 by reaction of one molar equivalent of phosphorus oxychloride with l-phenyl-3,5-pyrazolidinediones (eq. 206) or with 3-methoxy-1-phenyl-2-pyrazolin-5-ones. R'

O,-LIP

..i,/L0 dsH,

+

P0Cl3

-

R' LR2

C I I / N'N

Jz0

(206)

I

GHs

Some halogenated 2-pyrazolin-5-ones have been prepared by cyclization of various aliphatic compounds. Darapsky, Berger and a @-hydrazinohydrazide with bromine to N e ~ h a u shave ~ ~ treated ~ achieve cyclization, oxidation and halogenation in one step (eq. 207).

Pyrazolin-5-ones

83

The cyclization of a P-phenylazo-a$-unsaturated ester with hydrochloric acid has been reported by van A l ~ h e n ll5I4 ~ ~to~give . a 4-chloro2-pyrazolin-5-one. Br

R'CHCH&ONHNH,

(207)

I

NHNH, H

These compounds are listed in Table XXV. are reduced with hydriodic The 4,4-dichloro-2-pyrazolin-5-ones acid to the corresponding monochloro compound.1605The 4-monohalogenated-2-pyrazolin-5-ones react readily with another mole of the same compound or with unhalogenated 2-pyrazolin-5-ones to give bis(2-pyrazolin-5-ones).In the former case the two rings are linked by a double bond,1307and in the latter by a single bond.1528 Only two halogenated bis(2-pyrazolin-5-ones)have been reported (Table VI). One of these is prepared by bromination of 4,4'-methylidynebis(3-methyl-l-phenyl-2-pyrazolin-5-one) with bromine to give the 4-bromo analog.lsa2 I n the second case1109 bromine is added to a diolefinic system connecting two 2-pyrazolin-5-onerings. A number of halogenated 5-imino-2-pyrazolineshave beenreported. These are included in Table XII. They are usually prepared by direct halogenation.996* 1655 Another preparative method which has been used is treatment of a 5-imino-3-pyrazolidinonewith phosphorus oxychloride.391Micha,elishas reported the treatment of a compound, which he believed to have the azipyrazole structure (XXVI, p. 45), with 4-Chloro-3halogen acids to give halogenated 5-imin0-2-pyrazolines.~~~ has been prepared dichloromethyl-1-phenyl-5-phenylimino-2-pyrazoline with by treatment of l,l-bisanilino-2,4,4-trichloro-l-buten-3-one phenylhydrazine.lZo1The reactions of halogenated iminopyrazolinones are essentially the same as of those having no halogen. B. 3-Pyrszolin-5-ones

These compounds are listed in Table XXVI. As is the case with 2-pyrazolin-5-ones7direct bromination of 3pyrazolin-5-ones can be used to prepare the 4-bromo derivatives. This bromination is not complicated by substitution of a second bromine at the same carbon atom, but further bromination occurs to give 3pyrazolin-5-ones containing two or three atoms of bromine. I n spite of considerable investigation of these polybrominated 3-pyrazolin-5ones, their structures have not been conclusively established and several

84

Part 1. Chapter I1

very bizarre suggestions as to their nature have been made. Knorrso9 and other early w ~ r k e r found ~ ~ ~ that~ reaction * ~ ~ of ~ one mole of bromine with one mole of a 3-pyrazolin-5-onegave a compound whose molecular formula was that to be expected from addition of the bromine to the ring double bond to give 4,5-dibromo-3-pyrazolidinonesand it was suggested that this was the structure of the products. This view was held for many years1320 until Kitamura and S ~ n a g a w a ~ g ~ . ~ s ~ suggested that these compounds might be the hydrobromides of 4bromo-3-pyrazolin-5-ones in the betaine form. The ready conversion of these dibromo-3-pyrazolin-5-ones t o the corresponding 4-bromo-3pyrazolin-5-ones by treatment with base and the reaction of the monobromo compounds with hydrogen bromide to give the dibromo derivatives make the argument of Kitamura and Sunagawa very compelling. Westoo1605has agreed with this proposal and it seems very likely to be correct. Reaction of excess of bromine with 3-pyrazolin-5ones leads to the compounds called perbromides, generally considered to be tribromo compounds, although K ~ m a d aclaimed ~ ~ ~ to have obtained tetrabromo derivatives also. These claims have been discounted by others.794These perbromides have usually been considered as a molecular complex of the halogen and 4-bromo-3-pyrazolin-5-ones. Kitamura and S ~ n a g a w ahave ~ ~ ~proposed more definite structures involving dimerization, with the dimers bound by resonance. However, their suggested structure seems inherently improbable. Whatever may be the structures of these compounds, two of the bromine atoms must be very loosely held, as they are lost by treatment with ~ a t e r , ~ ~ ~ ~ ~ giving a 4-bromo-3-pyrazolin-5-one. Direct chlorinationgaa and iodination 540* with the elemental halogens to give 4-halogeno-3pyrazolin-5-ones have also been reported. Ledrut and co-workers362* a99 have found that bromination of 3-pyrazolin-&ones having hydroxymethyl, formyl and carboxyl groups at C-4 results in replacement of the 4-substituent by bromine. M i c h a e l i ~earlier ~ ~ ~ had reported this replacement if a 4-nitro group was present. A variety of other halogenating agents have been used to prepare 4-halogeno-3-pyrazolin-5-ones.N-Bromosuccinimide362~a99 replaces hydrogen or other substituents in the 4-position with bromine. Hydrobromic acid in the presence of peroxide g07 and bromocyanogen1491 also bring about bromination. 4-Chloro-2,3-dimethyl-l-phenyl-3-pyrazolin6-one is obtained in excellent yield by chlorination of 2,3-dimethyl-lphenyl-3-pyrazolin-5-onewith sodium h y p o c h l ~ r i t e . gOa ~ ~ ~5,5.~~~Dimethyl-l,3-dichlorohydantoinalso gives 4-chlorination of 3-pyrazolin-5-0nes.~6~4-Iodo-3-pyrazolin-5-oneshave been obtained by replacement of a 4-chloromercuri group with iodine.loO'*1155 3,4-

Pyrazolin &on@

85

Dichloro-2-phenyl-3-pyrazolin-5-one has been prepared by treatment of perchloro-1-penten-$-onewith phenylhydrazine.laol The halogen in these 3-pyrazolin-5-ones is readily replaced with hydrogen by catalytic reduction 697, 698 or by treatment with acetone.793 A few halogenated 3-pyrazolin-5-thionesare known (Table XVIII). These are prepared from the methyl chlorides of 3- or 4,5-dichloropyrazole by reaction with sodium sulfide or potassium hydrogen 981 Michaelis988-992 has reported that 3-pyrazolin-5-selenones sulfide.795* form dichlorides and di- and tetrabromides when treated with chlorine or bromine. No specific structures were suggested. 6. Nitroso Substituted Derivatives A. 2-Pyrazolin-5-ones

Although the compounds obtained by introduction of a nitroso group at G-4 in 2-pyrazolin-5-ones are considered as 4-nitroso-2pyrazolin-5-ones for purposes of classification in this discussion, they actually exist aa the oximino isomers (eq. 208) and are usually so

considered in the literature. These compounds are always strongly colored, being light yellow to deep red. Such compounds are listed in Table XXVII. by treatment Knorr 809 first prepared 4-oximino-2-pyrazolin-5-ones of 2-pyrazolin-&ones with nitrous acid (eq. 208) and this has remained If an excess the standard method of preparation.Z5*413*446*818*1004*1549 of nitrous acid is used, the nitroso substituent introduced is oxidized further to a nitro s u b s t i t ~ e n t Amy1 . ~ ~ ~ nitriteg and nitrogen trioxide355*406 have also been used as nitrosating agents, though not extensively . The standard p-ketoester-hydrazine reaction for preparation of 2-pyrazolin-5-oneshas been used for direct synthesis of the 4-oximino derivatives by starting with an a-oximino-j?-ket~ester.~~~*~~~~* 1534. 1536 I n a modification of this by Biilow and B o ~ e n h a r d at ~hydrazone ~~ of the a-oximino-j?-ketoesterwas used. Ponzio and Ruggeri 1125 have used a-oximino-8-hydrazonohydroxamicacids and hydrazines, and other oximino compounds, as illustrated in eq. 209.

86

Part 1. Chapter I1

It has been claimed that 3-pyrazolidinones can be converted to 4-oxiniino-2-pyrazolin-5-ones by treatment with nitrous acid.816.1550 However, later 1491 report that this reaction gives Ar I --=NOH ArCOCCHzKOz

1

I1

RNHNHZ

?r'

-__f

\N,

RNHNHa

=O

II

I

AOH

A r C O b C C O A r NOCOCH,

(209)

II

NOCOCH,

It

nitrosation at N-1.Since neither Knorr and Duden816nor von Rothenburg1550give sufficient physical data to identify their products, it may well be that they were actually 1-nitroso-3-pyrazolidinones. Curtius and Bleicher 335 have isomerized 1-nitroso-3-pyrazolidinones by boiling with dilute sulfuric acid, thus causing rearrangement of the nitroso group to the 4-position and oxidation to a pyrazolinone (eq. 210). Qvist 1153 has (210) I

I

H

H

rearranged 3-hydrazino-4-nitroso-5-arylisoxazoles to 4-oximino - 2 pyrazolin-5-ones by heating in aqueous sodium hydroxide. Freri 480 has reported a very interesting synthesis of 4-oximino3-methyl-2-pyrazolin-5-one. This consisted in the treatment of citraconic acid hydrazide with nitrous acid (eq. 21 1).The physical data which 4780

CHCONHNH, CH34CONHNHz II

+ HNOz

C'H,--r----NOH I/

YNi=o

('11)

H

were reported for the product were consistent with those reported by other workers for the same compound. The reaction may go by preferential Curtius rearrangement of one hydrazide to form /3-aminocrotonic acid hydrazide which cyclizes and is nitrosated. Treatment with nitrous acid of a 4-substituted-2-pyrazolin-&one having no substituent on N-1 gives the 1-nitroso derivative.262 I n the section dealing with 4-amino-2-pyrazolin-5-ones the reduction of 4-oximino-2-pyrazolin-5-ones and their reaction with active hydrogen atoms of heterocyclic compounds (eq. 174, p. 6s) have been discussed. The oximino group is readily oxidized to the nitro group by ozone478.480 or nitric a ~ i d . *The ~ ~hydrogen * ~ ~ ~of the oximino group can be replaced by silver by use of silver nitrate866.1553 and the silver salt thus formed can be alkylated to form an 0-alkyl oxime. The oximino group can be replaced by a hydrazino group.1549

Pyrazolin-5-ones

87

Only one oximinobis(2-pyrazolin-5-one) is known.459 This is 2,3-bis(4-oximino-3-phenyl-5-oxo-2-pyrazolin-l-yl)naphthalene prepared by nitrosation with nitrous acid. 4-Nitroso-5-imino-2-pyrazolines are capable of existing in several tautomeric forms, (XXXII), (XXXIII) and (XXXIV). Although there -NOH

R Z -

N ‘

I

1

,!=NH

‘N

I

R1

R’

R’

(XXXII)

(XXXIII)

(XXrn)

is little experimental evidence concerning structures, these compounds have usually been considered to exist in the oximino-imino form loo2 (XXXIII).996@ Preparation has usually been by the nitrosation of the 5-imino-2pyrazolines with nitrous acid.340.996*1002*lolo Qvist 1153 has prepared them by thermal rearrangement of nitrosoisoxazoles (eq. 212). The C,HSNHNHqN

~

\o

N -R

O

+

R =,,NO€I

=NH

NN ,

(212)

J6H6

4-oximino-5-imino-2-pyrazolines may be reduced to amines or oxidized with potassium permanganate to nitro compounds, similarly to their &OX0 analogs.lO10However, oxidation with sodium hypochlorite forms furoxazans (eq. 213).1010

B. 8-Pyrszolin-5-ones

3- and 4-Nitroso-3-pyrazolin-5-ones can only exist as the nitroso compounds. They are green, aa would be expected, and somewhat unstable to heat. In many cases they melt with deflagration. They are basic enough to form stabIe hydrochlorides, which are usually red. This probably means that these hydrochlorides are actually alkyl chloride salts of 4-oximino-2-pyrazolin-5-ones. The 4-nitroso-3-pyrazolin-5-ones have been of great commercial interest because 4-nitroso-2,3-dimethyl1-phenyl-3-pyrazolin-5-one is an intermediate in the preparation of the

Part 1. Chapter I1

88

analgesic, aminopyrine. The 4-nitroso33-pyrazolin-5-ones are listed in Table XXVIII. are alwaysprepared by nitrosation The 4-nitroso-3-pyrazolin-5-ones of 3-pyrazolin-5-oneswith nitrous aCid.99.103.145.647.781.807.809.854,888. 972.978. 984 Only one 3-nitroso-3-pyrazolin-5-one has been This was prepared by nitrosation of 3-pyrazolin-5-one having a 4methyl substituent and no substituent at C-3. has already been The reduction of 4-nitroso-3-pyrazolin-5-ones discussed in connection with the synthesis of 4-dialkylamino-3-pyrazolin-5-ones. This reduction occurs readily to give the corresponding amine when catalytic hydrogenation or various chemical combinations461.99a*'174~1175 are used. Oxidation of nitroso to nitro occurs in the presence of excess of nitrous acid or by use of nitric a ~ i d . ~ ~ ~ * ~ ~ ~ 7. Nitro Substituted Derivatives A. 2-Pyrazolin-Ci-ones

Only a few 4-nitro-Z-pyrazolin-5-0nes are known. They are listed in Table XXIX. The best-known of these compounds is picrolonic acid, This which is 4-nitro-3-methyl-l-(4-nitrophenyl)-2-pyrazolin-5-one. compound is widely used to form salts of basic compounds for isolation or identification. The hydrogen atom at C-4 is acidic in the 4-nitro-2pyrazolin-5-ones because of the two adjacent electron-withdrawing groups. This hydrogen is easily replaced by metals when treated with metal a l k o x i d e ~and l ~ ~reacts ~ with dia~omethane.~'~ is by nitration The usual synthesis of the 4-nitro-2-pyrazolin-fi-ones of 2-pyrazolin-5-onesunder mild conditions (eq, 214).61~872~690.1004.1683

I

Rl

I

R'

In the case of picrolonic acid further nitration can be brought about to give the 4,4-dinitro compound.6g0The oxidation of 4-nitroso-2-pyrazolin-5-ones has already been mentioned in the section dealing with the nitroso compounds. Ajellog has been able to nitrate 3-methyl-2pyrazolin-5-one using amyl nitrite in acetone or ether for several days. Hill and Blacks53 have reported the cyclization of N,N'-diacetylnitromalondialdimine with base to give 4-nitro-2-pyrazolin-5-one7 but such a course for this reaction seems unlikely. The reaction of furlones with sodium nitrite and sulfuric acid to give as one of the products 4-nitro-2pyrazolin-5-0nes~ has ~ ~already ~ been illustrated in eq. 62 (p. 33).

89

Pyrazolin-5-ones

The alkylation of 4-nitro-2-pyrazolin-5-ones at C-4 with diazomethane478has already been mentioned. This hydrogen atom is also replaceable with bromine.1642 Reduction of the nitro group with stannous chloride forms the corresponding amine.478* 480 Picrolonic acid condenses with itself to form a bis(2-pyrazolin-5-one) connected by a double bond at the 4,4'-position, with elimination of two moles of nitrous acid.690Condensat,ion also occurs in the presence of phenylhydrazine, but 4,4'-bis[3-methyl-1-(4-nitrophenyl)-2-pyrazolin-5-one] is formed.690 Two 4-nitro-5-imino-2-pyrazolines are listed in Table XII. One of these was prepared by permanganate oxidation of the 4-oximino compound1010and the other by direct nitration.1656These compounds were believed to be aminopyrazoles rather than 5-imino-2-pyrazolines. B. 3-PyrazoIin-5-ones

The 4-nitro-3-pyrazolin-5-ones are listed in Table XXVIII. They have been prepared most frequently by direct nitration of 3-pyrazolin~ i d 1320 . 5-ones, usually with concentrated nitric a The oxidation of 4-nitroso-3-pyrazolin-5-onesto give the 4-nitro compounds has been mentioned in connection with reactions of the 4-nitroso compounds. Nitration of 3-pyrazolin-5-ones with nitrogen tetroxide has been acc~rnplished.'~~~ The nitro group of 4-nitro-3-pyrazolin-5-ones is readily reduced to an amino group by metal-acid combinations.g84* lool 8

8. Aldehydes and Ketones A. 2-Pyrazolin-5-ones

A large number of 2-pyrazolin-5-one aldehydes and ketones are known. These are listed in Table XXX. It is possible to have both 3and 4-formyl and acyl substituents and both are known, although only one 5-oxo-2-pyrazoline-3-carboxaldehyde has been reported. There has been very little study of the effect of 4-acyl substituents on the structure of 2-pyrazolin-5-ones, but it seems probable that such compounds would tend to exist to a large extent as the 5-hydroxypyrazoles since they would be 1,3-dicarbonyl compounds. The preparation of the 5-0x0-2-pyrazolinecarboxaldehydesis usually done by procedures which are not applicable to preparation of the acyl homologues. The most extensively used method for preparing the aIdehydes is hydrolysis of their Schiff bases,824.1089*1092*1186,1188 4*

~

~

Part 1. Chapter I1

90

illustrated in eq. 215. R3 is usually aromatic, although it may be hydrogen.586-lI8* This hydrolysis occurs in the presence either of base or of acids. A second method of preparation is treatment of 4-(2,2,2trichloro-l-hydroxyethyl)-2-pyrazolin-5-ones, obtained by reaction of

I

R'

2-pyrazolin-5-ones with chloral, with potassium ~arb0nate.l~'von R o t h e n b ~ r g has ' ~ ~reported ~ that heating of the calcium salt of 5-0x02-pyrazolin-3-carboxylicacid in the presence of calcium oxide and Howcalcium formate formed 5-oxo-2-pyrazolin-3-carboxaldehyde. ever, his product was not well characterized and the work has not been confirmed. 4-Acyl-2-pyrazolin-5-ones have been synthesized by three general methods. These are cyclization of aliphatic compounds, conversion of other 2-pyrazolin-5-onesand conversion of other heterocycles. As might be expected the reaction of 13-ketoesters with hydrazines has been ~ t i l i z e d . l ~ 1532.1533 * . ~ ~ ~ ~I n* this case the p-ketoester has an a-acyl substituent (eq. 216). Both Borsche and LewinsohnlZ4 and Vila1533 R2COCHCOOR3

+ R4NFKNHa

R1roRa Y&-

+

-0

R'bO

(216)

A4

have used a-hydrocinnamoylacetoacetic ester in this reaction. The former workers claim that the 4-acetyl products are obtained, while Vila 4reported the products were 4-hydrocinnamoyl-2-pyrazolin-5-ones. Acetyl-2-pyrazolin-5-oneshave been obtained by cyclization of hydrazones of 8-ketoesters with acetic anhydride.1oo9Kendall and Fry767 have obtained 3-acyl-2-pyrazolin-5-ones by the reaction sequence shown in eq. 217. The reaction of P,y-diketoesters with hydrazines also forms 3-aoyl-2-pyrazolin-5-0nes.~~~ (CH3CO)2CHCH2COOC2H5 + CeH5NzCl

CH3COCHCHzCOOC2H,

1

N=NCeHS

Pyrazolin- 5 -ones

91

Acylation of 2-pyrazolin-5-ones leads to 4-acyl-2-pyrazolin-5-ones. This has been done by treatment with aromatic acid chloridesl10 and with ethyl oxalate in the presence of potassium. A modification of this procedure is acylation of 2-pyrazolin-5-onesto give 4-acyl-5-acyloxy1056 followed by hydropyrazoles 591.977 or 2,4-diacyl-3-pyrazolin-5-ones lytic removal of the N-acyl or 0-acyl groups. The 4-acyl compounds can also be prepared by hydrolysis of their Schiff bases as shown in eq. 215. The reaction of hydrazine with appropriately substituted isoxazo(eq. lones or isoxazolinones also forms 4-acyl-2-pyrazolin-5-ones 218).947.1295 R2 I

5-Qxo-2-pyrazolin-4-carboxaldehydes are oxidized to the corresponding acid by perrnanganate.lo7 These aldehydes under various and heating conditions form 4,4'-methylidynebis(2-pyrazolin-5-ones), This same type alone brings about this reaction (eq. 219).1089*1093.1188

I

R'

I

R,'

I

R'

of product is obtained by the reaction of the 2-pyrazolin-5-one aldehydes with 2-pyrazolin-5-0nes.~~~~ Reaction of these aldehydes with Such alde%methylindole also gives the bis(2-pyrazolin-5-0nes).~~~~ hydes react normally with amines and hydroxylamines to give Schiff undergo the Manbases and oximes.lla8 The 4-acyl-2-pyrazolin-5-ones nich reaction.log8Treatment of acylpyrazolinones with diazonium salts results in replacement of the acyl group by an arylazo Kendall and Fry7a8.770 have prepared 3-acetyl-4-phenylazo-2pyrazolin-5-one by the reaction of ethyl 8-acetyl-8-oxovalerate with two equivalents of phenyldiazonium chloride. 4-Benzoyl-3-methyl-l-phenyl-2-pyrazolin-5-thione has been prepared by Michaelis and co-workers977~990 by the reaction of sodium and 1-phenylpotassium hydrogen sulfide with 4-benzoyl-5-chloro-3-methylpyrazole. The thiono compound forms a methiodide and gives the characteristic reactions of both ketones and 2-pyrazolin-5-thiones.

Part 1. Chapter I1

92

B. a-Pyrazolin-5-ones

There has been considerable interest in the preparation of 5-0x0-3pyrazolin-4-carboxaldehydes(listed in Table XXXI) because of their close relationship to antipyrine (2,3-dimethyl-l-phenyl-3-pyrazolin-5one). The most frequently used preparation of these compounds has already been mentioned (eq. 135, p. 54). This consists of treating the condensation products of 3-pyrazoIin-5-ones and chloral with b a ~ e The McFadyen-Stevens . ~ aldehyde ~ syn~ thesis has been applied to the preparation of both 5-0x0-3-pyrazolin-3892*1634 This is illuscarboxaldehydes 698 and -4-~arboxaldehydes.~~~* trated in eq. 220. The final step is usually carried out in glycerol at C!HS---CH:,-S

145' > 145' 222a 168' 178' 117' 109O 115" 99O 56". 86" 120° 59O 650

M.P.

1119 962 1118,1119 1118,1119 1119 1119

135 1480 96 564 1317 866 962 866 866 866 866 866 1221 1221 1221 $88,985, 1622 250 250 250 206,250, 1681 250 206 206 1118,1119

Reference

--

B$

* w

El

aa

c

CH3

188O

240"

H H

182' 193' 197" 158' 198" 178' 182O 273" H H H H H H H H

H H H H H H H H

I

232' 211°

H H

H H

H H

229"

H

H

CizHa, HOCH&Hz CH3CH I OH HOOCCHS C,H,OOCCH=C

272'

1288

349

513,514,516

So, 1171

0

5 $

2.

?

P

93

I 1645 81,358,359,660, 729,1012. 1645 730 359, 720, 1522, 1646 250 883, 1522, 1648 1526 917 1012 6. 1606 U

c3 61,358,359,892, 1012, 1631, a

B

m

3

1684

1119 1684 1884 1884

1119

-

-

-

-

liquid

146"

H

H

H H H H

11

H

bH HOaSCH2CHCHS I bH H

H H H H

AH3 ~so-C,H,~OOCCH&H, H03SCH2CH1 HO,SCH&H2 HO3SCHSCHCHS

I

H

NCCHCHS

CH3

H

H

H H

0

CH3 CH3

CH3

H

H

R=

RI

TABLE 11, Section A (contind) _____

_.-___

H

NO&HzC

\ CH3

/

AH3 CH,

NHaNHCOCH

_^_.______

R3

-

-

H

H H H H H H H H H CH3

H

H

3%.

224"

76" 105"

74" 109'. 268"

840 71' 113' 850 84" 83"

94"

133"

-

212"

M.p.

1579

1522 1522 250 260 260 250 250 61,368,359, 769, 1012, 1531,1560 81 61,769,1522

51, 1531 1522

64

1277

Referenee

- + r

c1

* ;-

a

37

.a

GJ

Systematic Tables of Pyrazolones and their Derivatives

x

X

X

I

165

R'

R=

TABLE 11, Section B (eonlind) R3

I1

H H

H

H H

H H H H H

H H H H H

H H H H

110"

100' 99" 165' 110.5" 186' 81" 182" 191' 83' 180" 79'. 107'

-

142' 207' 127", 213'

127'

-

177O 126' 217' 210° 225' 290' (dec.) 233' 205'

H H H H H

H

M.P.

R'

181 835 1577 1675 622 68,95,629, 723, 788, 805,806, 809,811,816, 838 1569 64,992, 1660 64,1531, 1680 564 1686 303 505 1688 505 1588 1294 1640 1686 506 97, 448, 1589, 1590 1582, 1689, 1590

467

798

446

1004

Reference

3

01 01

Y

LLPI

1221

'PLZ

8LL

OZLI

0911

0921

'H@3

H

'H33

0

H

H

-\ H

H

H e'H83 H LlH83 H Q'HLD

~

H H H H H H H H H H H H

'Hb

e

H

H crH83

'H%

909 €PI

909 €FI

909 €*I M)9

bl MM 'PZOI '€201

0691 '6891

0011

-

r,OPZ 0 96 OL9 0001

09L

O B I

09'LOI 09XL

099

H H

H

'HQ3

06SI

1ZH0l3

€I

H H H H

0801 028 0911

H

H

H

8111 9EQ

0%

H

"H93

SH@:,

ZP

e8EI

H

H 0

H

H

'6891 '88!2l

06EI

H

1x3 IZZI

'H@D 'HQ3 EHQ3 9 ~ 'Hg3 'HQ3 H EHQ3 H 'H*3 H 'Hg3

9013

96

9891 '069T '6891 '8207

3

3

~

~

~

R'

__

1

Fe I

hJ

R=

____

TABLE 11, Section B (continued)

H H H

H

H H

H H H H

H H

H

H

H

H

H

R4

H

R=

172'

131'

182", 199'

132'

1494 296.838 296,838, 1002

192, 296, 838,

492 863

470

192

197

838 902 1149

122O

-

68,723,806, a38 1477

806, 838, 1524, 1584 723, 838 1477

628

F W erenee

91.50,1400 104"

104" 103"

143", 183'

186"

M.P.

1

* %

0, 00

Y

bH 4-(4-C6HsCO)C& 2-HOOCC6H4 3-HOOCCeH4 4-HOOCC,H, 4-CaH500CCeH4 4-(3-HOOC-4HOC~H,NHCO)CBH, 2-HO3SCBH4 3-HO3SCeHI 3-HO,SCeH, 4-HOSSCeH4

I

H

H H

H

H H H

CZHl H H

H

H H H H H H

212"

H H H

248'

237O

-

> 3Oo0

306"

-

205O

-

-

278" 145'

-

170' 189"

-

134" 233" 170" 196" 185' 220"

H H H H H H

26

1306 593 1348 191. 356,684, 1163 694 1481 324, 328, 356, 695, 1475, 1476, 1628

1497 1004, 1520 165, 1270 356 1490 1361

1683 1569 303 446 837 777,838,1282, 1372 303 1684 1684

?. %

%


266 241°

H CH,

H

H

H

265"

205"

223'

-

-

H

4-(4-H03SCeR*CH~NH).J-CH&H&H=

2-HO3S-4-(4-NO&H*CONH)C6H5 C6HS CH3 CeH,CH= CeHsCH=

358

662

1498. 1499

1361 3, 1640 1343 351 1004 1371

Appendix

cd m

CD

m

2

d

m

FD rn CI

X

X

x

z

X

X

x

X

X

X

l . 3

x

x

Syst,ematic Tables of Pyrazolories and their Derivatives

191

W

W m

i ~

0

W

2

X

X

iI I

3;

I

x

x

X

rl

192

Appendix

X

2

X

x

X

$1

x

X

X

51

$1

Systematic Tables o f Pyrazolones and their Derivatives

193

%

2 m

s2

i2

8

z

w

w

W

W

w

X

w

w

W n

*

5

z!

Q)

0, a

X

W

W

w

PI

w

E

V

f

mi

cu

3

0,

i Y

t 3

Appendix

X

w

X

X

z

$:

X

X

Systematic Tables of Pyrazolones and t.heir Derivatives

W

(D W

r-

m -8 d

X

8

x

X

V

0e 0 4

u"

x4

G

8

x

d

2

I4

V

m cv m

Appendix

Q)

rg

0 Q,

El *)

*

c-

$1

X

bx

-V

4

V

Systematic Tables of Pyrazolonea and their Derivatives

lw

E:

m v)

v)

2

3

(d

rch

k

c1

X

d

V

197

Appendix

rm m

ac,

1n

x

"

m

m m t-

E

X

I

I

x

X

Systematic Tables of Pyrazolones and their Derivatives

199

l -

2

00 r’ m

CI

0

P

8

0

8

X

X

X

==!\

I-

/

0

X

i

I

a V

H

H

H H H

H H H

Section F. a-Hydroxy- and a-Uoxyalkyl, Alkyl, Aralkyl, Aromatic, and Heterocyclic Substituents

TABLE I1 (condinwd)

0

H

0

TABLE 11, Section E (colatinued)

H CH3 CZH,

H

H

148' 135" 99"

216'

m2o

1315 1314 1314

1147

1147

Es

8

191°

bH CI,CCH

I

OH

C6H8

I

CZH, CZHSOC=

130"

120"

CH:, C2HsOC=

I

129O

CzH50C=

H

184O

OH C1,CCH

I

1316 532 24 895

82O 158' 189O

H H HOCH, CIaCCH

764

764

1190

1194

254O

I

lalo

-

H

i? ;i'

B

-9

0

8

E

2

a c .

8

m

3

_ _ _ ~

CH, CH3

H

H

co

2-HOOCCEH,CONHCH,

CH3

Ra

H

_____-_-___

R'

-

__

-

H

H

NNHC,H,

/I

NH CsH5.C

I/

H

N

H

192"

1tX0

230°

> 300" H

NH C,H,C

II

280'

H

__

CH3C

-

145' 166'

h1.p.

_

-

H H

90"

R4

R"

Section G. a-Amino- and a-Iminoalkyl Alkyl, and Aryl Substituents

T A B L E I1 (continued)

I / \o /-

TABLE 11. Section F (continued)

-

138

138

1193

1193

1193

Reference

1562 1562

764

* x

E

31

CD

N

N 0

II

NH

NH C*H&

II

CH,C

NCH,

c

137" 201 184O

110"

H H H

H

68"

172'

H H

224"

210" 221" 221O

H

H

H

170"

H H H 1550

171O

H

H

283' 863" 240" 172O

H H H H

H H H H

(Table COJr(inWd)

1206 348, 823, 824, 923, 1070, 1088, 1089, 1090 1189

1193

1193

1192, 1193

1W8

925 1189 1189 1008 1098

1179

1188, 1189 1188 1188 1179

53

N

*

CBH5

H'

CH3

It2

TABLE 11, Section G (continued)

I 2-ROOk&H,

310'

301

CeH,

CH3

H

184O

998

cd&

CH,

-

322

CH&O

CeH, CH3

243'

301 973

CEH6

H

0 0

40 0

JjJ0

H C,H,CO

II

-cnone

-

0-

iso-C3H7 iao-C3H, ~o-C~H, iso-C,H, iso-C,H,

H

H

850

66"

b3161"

H

c-

135" 40"

H

H CH3 H

174"

H

It2

H

___--~-___

M.P.

R3

_R4

Section A. Alkyl and Alicyclic Substituents

T A B LE X I V. 3-Pyrazolin-5-ones

"'

250 250 250 250 260

101

101, 103, 859

101

1205 1205 54, 788, 789, 985

54, 788, 860.

Reference

x

32:

> CJ

H

166"

-

CH3

H H

H

H

CH3

H H

CH3

H

CH3

H H

H

280' 270' 169O 196' 217" 227' 245O 239" 233' 266" 180" 231O 240" 130"

165'

H H

CeHs CH3

H

126" 117'

H

H

H

155'

H

H

H

H

M.P.

H

R'

R2

RJ

R'

Section B.Alkyl and Aryl Substituents

TABLE X I V (continued)

_ .-

.$ -

1001

( Tabk ccmtinuld)

679 885 885 370

448

446 1001 885

Ei,

P 4

P

c

!2

460, 858, 993, 5: 9. 1122, l&S, P, 1559 446 e a 108 64, 1205 0 95, 247, 788, 826, 885, 888, 988. 1522, 1624, 1559,1669 972, 1569 1023, 1024 1023. 1024 P, 988, 1524 988 446

Referonce

R'

-_

R=

TABLE XIV, Section B (Con6inued) RJ

______--

H

R'

95, 808, 1023, 1024, 1042, 1071, 1333, 1522,1524 1524 670

256'

1477 115O

9oo 219'

113" lOS0 256" 65" 121" 172"

781, 785, 801, 806, 807, 1173, 1174, 1198,1508 95, 888, 1522 992 95,984 1252 303 95, 984, 1522, 1524 1321 250

113"

207 O 222"

Reference

M.p.

_ _ _ __

t4 P

W

b,.o,201

137' 98'

-

b0.061850

H

H H H H

O

96 ' 169' 161.5' H H CZH,

NO,

I

NHCHO (Hp,C,OOC)2CCH,

-

1430

NHCHO ( H,C,0C)C)2CCH,

I

181'

NO2 (H,COOC),CCHg

I

-

I

NHCOC6H5 H5C200CCHCNz

I

228'

-

86' b2.,178' 115" 186" 147"

NH, HOOCCHCHz

I

H H HOCHzCHz HOOCCHz H,C,OOCCHZ H$IOCCHZ HOOCCHCH,

1477

988 145

806

1477

806 988 1524

638

638

638

638

638

636 1252 1171 638 638 638 638

1

E.

50

E:

T A B L E X I V , Section B (continued)

H

H H H H H

H

H H H H H H

H

H

540 1001 446 978 978 978 1475, 1476 361

150' 126' 188' 98" 132' 248' 239'

296

645 296 296

-

113' 89 126'

-

-

-

167" 119" 199" 221O 261 251O 266'

H H H H H H

H

-

541 978 978 978 978 978 978 674, 1290 674 645

146 1149 978 978 978 978

902

chloroplatiate)

165" 148' 210' 270' (dec.,

56 '

81'

-

H

H H H H H H

E3

CH3 BrCH2

H

CHP

-

129" 175' 130" 150'

H H H

H

147' (racemic)

97.5" 143'

H

H

H H H

95, 362, 809. 814, 1056, 1252

806 899 647,789 818

141

546 679 296

-

td

% f: 0

Systematic Tables of Pyrazolones and their Derivatives

2 3

x"

8--0x" 4

"

II

sR z

0 =o ? i

X

8

3T

0

x"

V

g

G

d

253

264

Appendix

Systematic Tables of Pyrazolones and their Derivatives

*

m fl

I

255

CH3

CH,

C6H5

R'

CEH,

-

R'

__

TABLE XIV, Section C (continued)

H

H

H

R3 .I

-~

_____

i'

L'-CH2

R' ~

-__ ___

149"

110

99" 152" 2209 114"

110

110, 1483 110 110

2.50 1321 21,563 110, 1483

87 128.5' 204" 140"

897

___-

378

-

Reference

118'

2580

N.P. -

7,

K i h

C8H5

C6H5

c8H5

CeHs

CH,

,c=o

\

C6H5

L-NH

o=c/

H

N-C=CH

378 89"

224' (dec.)

263'

696

696

195" (dec., HBr) 799

700

192'

110

110 21 107, 316

152"

1910

2-CH3-4-HO-5-iso-C3H,C,HnCH,

C8H,COCH=CH CeHsCHz

CsHlCHa 199"

165'

20

20

270"

139" 171"

\-coo-

a-' 7CH3CCH3 7:L02H)

21 21 20

155'

218"

2-HzN-5-CH3CeH3CHS 2-CH,CONH-5-CH3C6H&HS

3-CH30-4-

(

2,4-(HO)&,H3CHZ 3,4-(HO)&,H&Hz 3-CH,O.4-HOCsH&Ha 3-CH30-4-CaH&OOC6H&H2 v1

-.c -.3 C P

9'

5

ec

a

1

Q

(LI

s z3

3

cd

%

(LI

B

4 Q

c)

.l:?

Y, %

258

Appendix

m 0, m

2 a2

0

8 hl

0 (0 W

c3

d

w"

U

G

U

Syskmatic Tables of Pyrazolones and their Derivatives

w"

V

@V

8

259

260

Appendix

rl

*

W

::

#T

V

Systematic Tables of Pyrazolones and their Derivatives

3

-f W

261

Appendix

262

m m t-

t-

2

3

X

Systematic Tables of Pyrazolones and their Derivatives

3

u3

5:

w

dr

m

0

5:

X

x"

V

x"

V

a

263

X

R'

94

231"

CH3

NHh'HCOCH3

94

152"

CH,

s

94

130"

CH3

Reference

94

I

COOH

h1.D.

236'

R'

903

R3

- _ - .-__ ___

284"

R'

T A B L E XIV, Section D (continued) Q,

N I&

Systematic Tables of Pyrazolones and their Derivatives

< V

265

CH3

CH3

N

N

f J ) -

H

194O

202O, 280°

220"

799

799, llao

991

991

Systematic Tables of Pyrazolones and their Derivatives

c 4, a 00

El -Y 0

267

It=

(3%

-___._

CH3

R3

C H . ! ,

HOOC-

114

1

N

,!LH3

4OOH

-

R'

R3

HOCH, HOCH, HOCH, CH3 HOCH, HOCH2

R=

CH3 CHs CH3 CH3 CHa CHB

__

17

CH3

CH,

H

-

528 532

158 170 HOCH,

-

698 538 532 H

145 223

Hcference

378

452

Reference

H

__

144"

2560

M.P.

M.p.

-

li'

Section E.a-Hydroxy-,a-Acyloxy-,and a-Alkylthioalkyl,Alkyl and Aryl Substituents

TABLE XIV (continued)

C6HB

Rl

T A B L E XIV, Section D ( d i n a e d )

N

g:x

T

ab

%

CBH6

I-CH&&

CH,

CEH6

HOCHS HOCH, HOCHa HOCHa CH3

HOCHS HOCH, HOCH,

190 173 156" 191" 140'

AH C13CCH AH C13CCH

AH C13CCH OH Cl,CCH

OH C13CCH

188"

OH Br3CCH

OH

I

OH NCCH

I

188"

I

OH CI,CCH

I

I

I

244 183 109 197

CH3 CzHs C9H6 CoH, C13CCH

-

186

-

107

889,902

902

889

901

532 532 532 532 107, 196, 889. 895

532 532 532

-.

U

z.

cc 3-

5a

P

0

2s.

u)

x8

R'

-___--

CH3

Ha

T A B L E X I V , Section E (continued)

CH3

CH3

CH3

H3

-___

I

AH

CBH,CH

iso-C,H,NH

bH

CH,CHCH

I

AH CaHeNH

I

CH3CHCH

NHCH3

bH

CH,CHCH( HCl)

1

OH h'H2

I

CH,CHCH( HCI)

R' -

173'

165'

162'

123"

103" (threo) 220" (erythro)

M.p.

977

112

112

112

112, 113

113

Reforence

0

-.I

le

H

i)H

970 970 895

895

154O

141

1194

800

-

-

164'

227'

240'

152'

P

0

3' F

s

U

m

6r

R=

TABLE XIV, Section E (eonfinued) Ra

-~

135"

im-C+H,COOCH

C,H,NHCOOCHa CZHSSCH, CdHVSCHB CIHVSCHP CBH,CH,SCH, CBH~SCH:,

CBr,

1

C6HsCOOCH

Cur3

I

CH,COOCH

&I3

3 HO,SC,H,COOCH

1127

53 O 1000

102"

1127 1127

1127 1127 640

402 97"

895

895

891i

895

a05

Reference

271.5'

170"

13ao

230'

160'

4-NO&H~COOCH

bl3

214'

C6HGCOOCH

Ll,

(333

136'

I

__

M.p.

C,H,COOCH

H'

_....- -_

m

-1

ts

w

M 0

C6H6

C6H0

P HI

i:

RZ

I

I

.._

CH, CH3

CHaCHNHCHB

CH3

RJ -

-

I

CaHs C6H,NHCH

I

C6H6NHCHa 4-CH3C6HSNHCHa CH3NHCH

H H HJCH, CHaNHCHZ(HNO3) CaH5KHCHa

R4

__--

945 1318 68"

(Table conlinued)

945 945

93O 66' 132'

1094

110,111,1483 110 112 185O

17l0,143' 140" 105"

107

88"

1319

697 697 901 107 107

Reference

70' 83" 168'

b1.p.

$ Section F. a-Amino-, a-Imino-, a-Oximino-,a-Amido- and a-Hydrazinoalkyl, Alkyl a.nd Aryl Substituents

0

-w a

ts

k2

Ef.

8.

U

r 2.

ct

Ea

8

I

E

s

cd

: F

i.

u1

5

274

Appendix

4

Y

g g

an

6

n

6

6

CH3

CH3

CH3 CH3

CH,

CH3

CHa

192' 163' 215'

Z-CHJ&H,N=CH 4-C2HSOC6H*N=CH 2-HZNCeH4NdH 4-OHCCSHJVdH

232

152"

148'

CBHsN----CH

K=CH

0

-

-

S03Xa CzHsN=CH CH,N=CH

I

120" (dec.)

C6HsPiHCH

S03Na

I

150' (dec.)

S03Na 4-CZH,OCGH*NHCH

202, 891

1700

107, 202, 891, 897 891 891 1190 891

107,891

107 107

203, 891

202, 891

202, 891, 894

110, 1483

128"

-

I

107

165'

I S0,Na I-H,NO&X,H,NHCH

107

167"

$, d 8

5 ?.

ti

a

3

a

B

3

0

E

21

%

c3

3 H

13

u1

2

R'

____

R=

TABLE XIV, Section F (catinued) R3

211O

215"

hH2CI HaNXS

I

C,H5NHN=CH 4-hTOaCEH4NHN=CH 2,4-(XOz)~C~H,XHNdH CBHbNHN=C

C6H5N€IN=CH

C6H6

I

_

_

_

_

~

Reference

_

977

902, 1186 201, 1183 698 799

202 891 891 1190 1186 202. 891, 902 1183 196, 201, 889, 1092,1181 1190 977

_

225", 236", 255" 196,201, 889. 1181, 1182 230" 1190 2720 201,1181 260' 201 260" 977

210" 239O 227"

C6Hs HON=CH HON=CH H Ha"=€!

I

2210 197"

HON=CH HON=C

I

190" 97O 135' 161" 140a 220"

-

Y.P.

^

4-HaN02SC6HINdH 3-HO-4-HOOCCaH,N=CH l-CloH,h'-l=H 4-C&OC6HdNH=CH 4-'&H60C,H,N=CH CEHsN=CH C&N==CH HON=CH

R*

.

;e

s

t3:

t.3

4 -7

CH3

I

256" 210°, 256' 226", 246" 238' (dec.) 246" 215" 233" 233"

HZXCONHNdH HZNCONHNdH HZNCSNHNdH HaNCSNHN=CH C2H5NHCSNHNSH CBH*NHCSNHTT=CH HZNCSNHNdH H~NCSNHNdH

235"

216' (dec.) 204O, 223", 245'

I

160"

-

260"

900

900

698 201,204, 892, 1181 1186 201,1180 510, 818, 799, 900 1190 900 900

799

1186 1186 799

412

270"

AH3 CH2Cl CeHeNHNdH HZNCONHNSH

I

hHaCl 3-CH30-4-HOCeH&H=NN&

CeHsNHNSH 4-C2HsOCeH*NHN&H C,H,CH=CHCH"---C

696

263"

-1

t3

P

p,

s2.

U

g.

3-

8

EL e

rd

P

e

0

rT.

BP

r/,

3ct

Appendix

278

:-rp:;l =x

y=

N

I

I

R1

R'

T A B L E X V . 4,4'-Bis(3-pyrazolin-5-ones) Linked by a Single Bond H'

S

Y

0

0

25.4"

S

237" 270' 250" 225" 269O 215' 240' 203"

S Se NH 0 0 0 0 0

0

0

It

R3---.-.

Rz-$----l

\

Se HN S HN C6H5,N

/==o

N

I

T A B L E XVI.

=-R3

I

-j

4N

R1

785, 807, 809,991 785,991 986 991 991 991 991 807 1056

N-R2 /

I

It'

4,4'Bis(3-pyrazolin-5-onea)Linked by Carbon or Heteroatoma

R

Xp.

Reference

CH3CH,CH < CH2

180" 192O 155". 178'

902 1042 19, 740, 910, 1192, 1483 107,896 107 107

239" 204O 92"

HOOCCH< H3COOCH< C,H,OOCH< 0

II

CH=CHCCH=CH (CH&CHCH&H< CeH,CH< 4-CH30CeH4CH< CeHSCH < 4-CH30CeH,CH
245"

-

I QAg 2-HOCeH&H= ;"JHB C,H,CH=X 44C~HS)~NCEH,N= 2-CH3-4-(CsH&,NCeHJ= COHONHXSHCHN-

333

-

(CEH,NH)2;?I=

-~

Reference

ALP.

H4

H H H

H

H

H

R3

-

c. 5'

s

b 5

rp

w

N

Systematic Tables of Pyrazolones and their Derivatives

X XX

295

Appendix

296

2 El

% w

0 cd., l

0

c4 d

-

c

ci

a,

a, W

0

U3 2

4 V

4 u

H H H

H

H

4-(CaH&KCeH41C== O-HOCeH*CH=N 4-CHsOC,HdCH=N 4-N02C6H,CH=N

CH3 NH,

Br

CCHCONH

/ I

\

240

52 52 536

225" (dec.)

183"

992 519 992 992 992

> 175' (HCl salt) 96" 230' (dec.) 220" (dec.) 250" (dec.)

-

536

240

186' (.. c.)

-

240

220" (dec.)

G'

4-CH3CeH4

R'

Ra

TABLE S X I I (eatinued)

-.

R=

-

R'

144' 1890 148" 169' iiao

-

246' (dec.)

b1.p.

494 494,519 244 244 244 519

240

Hcference

t3

m

0,

Sysbmatic Tables of Pyrazolones and their Derivatives

3

E)

z

x

299

300

Appendix

% El

3

3

C

0

8A

d

0

*

0 CI

0

t 0) -

E3

i?

N

d

V

A

c o R

0

4

A

Systematic Tables of Pyrazolones and their Derivatives

A

d

a,

d

a,

30 1

Appendix

302

3

rn

4

V

Systematic Tables of Pyrazolones and their Derivatives

0

c1

Ig2

X

X

td*

m

B

303

314

-

> 250"

866

152"

238"

247"

-

865 865 263, 264 283, 264

582 582 582 963

-

27TQ

-

190°

234" 267' (dec.) > 280" 268" > 250' > 250" 223' (dec.) 235"

Reference

263,264 262,263, 264 263,264 262,264 263, 264 314 314 314 260 262 260 1467 263 223'

x.p.

H

Ar

1251

R*

H

H H H H H H H H H H H H H H H H H H H H H H

R'

__.____I

T A B L E X X I I I , Section A (continued)

Z'

E.

B

b Lcr

4 0

W

I

HOOCCH~CH, C2HsOOCCH2CH2 ~EO-C~H~OOCCH&H~ CIHeOOCCH2CH2 CiHBOOCCH2CHz iso-C4HsOOCCHzCH2 iso-C7Hl500CCH2CH2 CH,CHOOCCH&Hz

(Table continued)

1118 1118 1118

206 208 228, 1681 206 253 253 253 253 253 253 253, 1463 283, 1469 253 253,1463 206 206 206 1118 1118 1118 1118 1118 1118 1118 1118 1118 1118

1560

UI

w

C.

f

Ea

Appendix

306

2 ,-I 4

b) l-

31"

38

$

x"

8 0

6'-9. 0

Systematic Tables of Pyrazolones and their Derivatives

gg g ggg

407

__-

_.

-

308" (dec.)

H

-

-

-

-

__

-

-

__

-

-

-

-

-

___ -

_.

-

H H

H H H H H

H

H

H

H

H

H H H

H H H H

H H

H H H H

H

-

-

-

H

_________

M.R.

-

_______

dr

H

H H

R=

_ I _

782 782 782 782 782 782 782 782 782 782 782 782 782 782 782 782 782 782 782 782 782 782 782 782 782 782 782 782 782 782 285

Reference

0

00

R'

__

w --

___

-~

TABLE X X I I I , Section B (confinued)

Systematic Tables of Pymzolones and their Derivatives

c61 t.l

309

T A B L E X X I I I , Section B (continued)

1591

1591

255O

1691 1591 1591 1591 1591

280

-

243"

192" 154'

2470

150"

-

-

240"

280

327 864 1677

-

260"

4-CH3CCgHa 2-(C,H,SO,NHOC)CeH4 4-(4-PSO&H,SO2)CsH, 3-Ka03SC6H4 4-Na03SC6H, 4-CIO,SC6H, 4-H&02SC6H4 4-C€I,NHO2SC,H, 4-(C2H5)2NO,SCeH4 4-C6H,NHO2SC6H4

II

327

278.327 278, 327 278, 327 278, 327 263, 278, 732 327 327

148'

187"

136"

198"

183O

209'

140' 151'

4-CHSCCeH4 NKHCOKH2

/I

NOH NNHU,H,

/I

4-C1C6H4 4-BrC6H, 2-N0,C6H* 3-NOzCgHd 4-KOZC6H4 4-CH3COC6H4 4-CHSCCeH4

W w

(Table wntinued)

649 374 211 228, 1681 278 280 278 180 278 278 263 263 1462 203 625 625 626 180 142

648

864 327 327 280 1462 1461 211, 1446, 1461 211 219 650 225 650

c

R'

--

__

TABLE X X I I I , Section B (continued) Iil

-

__I

._

M.P.

T',]l/k\,

1_ -i

2-HO-4-HO&l-C1,H, 2-C~Ii~C00-4-HO~S-6-NOa-1-C,,H,

2-HO-4-HO3S-6-CH3O-1-Cl0HS

3,4-(CH3)2-2-H03SC6Hz 3-NO2-4-CH3-5-HO3SCBHZ 2-HO-4-HS-5-C1C6Hz 2-HO-4-N02-5-CH3OJXsH, 2-KO-3-H03S-S-ClCeH, 2-H0-3-H2NO$-S-N02CBH2 2,5-(CZH,O)2-4-CeH&ONHCeHz 2-CeH,C00-3-HO&5-NO,C,H, 2-CeH&O0-3-H0&5-ClCeHz 2-CBH,CO0-3-HOOC-4-H03SCsH, 2-(~ - N O & ~ H ~ C O O ) - ~ - H O ~ S - ~ - N O Z C ~ H ~ 2-HO-3-H0&5-[2,2,4-(CH3)3C5BalCBH, 2-HO-3,6-C12-5-H03SCBH 2-HO-3,5-ClZ-4-HSC,H 1*C10H7 2-CioH7 2-h'OZ- 1-C,oH, 4-XOz-l-C1oHe 1-NaO3S-2-C,,-,H, 2-C3H,C00.4-HO,S-l-C,oHs 2-CeHsCO0.4-H038C1oHs

Ir

- .-

327

214 885 442 442 442 442 1386 276 879 263,278, 327 263,278, 327 327 327 280 442 442 189, 1616 441, 1618 442

1444

523 123 879 1445

Referonce

H

32

b W

ha

i

t3

Systematic Tables of Pyrazolones and their Derivatives

ED

0, m

c4 0.1 P-

I

g

11*

313

R' RZ

__-

TABLE X X I I I , Section B ( d i n u e d )

Ar Reference

1493

281

281

281

281

M.p.

-

160"

206'

215'

248'

x

3E

ab

lb

Y

w

1535 1576 403 397 397 397 627 1118 1118 1398 1398 1398 397 1462 1462 1462 987 625 625 02.5 180 1458, 1402 1383 125 403, 576 79 878 878 877, 878 878 878 209 878

R1

_-

342-HO-l-CIoHeCONH)Ce& 4-(2-HO-l-C~oH&ONH)C6H+ 3-!2-HO-l-C1~CON)CeH, 4-(2-HO.l-CloH&ONH)CeH, 3-(2-HO- 1-CioH&ONH)CBH, C-CH,OC& 4-CH3OCeH, 4-CzH,OCeH4 4-CzH60CeH4 2-CICeH, 2-CICeH4 2-CICeH, 2-CICeH4 2-CICeH4 2-ClCEH4 2-CICeHa 2-CICeH4 3-CICeH, 3-CICeH4 3-CICeH4 3-ClCeHd 3-ClC6Ha 3-ClCBH4 3-C1C6H, 3-CICeH4 3-ClCgH4

3-(2-HO-l-CloHeCONH)C6H,

4-NHgCeH4 ~-C~H$~OZNHC~H~ 4-(4-HOOCCeHQSO,NH)CpHI 34~ - H O - I - C ~ O H & O N H ) C ~ H ~

I _ _

__ .

-

2-(5-CH3-2-iso-C3H,CeH3SOzNHSOz)CBH4

2-(4-CICeH&02NHSO~)-5-ClC~H~

180 180

180

397 217

442

1456

1398

877 877 1456 1456 1456 1456 296 1034 1398 1398

877

226 465 160 857 877 877 877

_ _ _ _ ~

Reference .

2-(5,6,7,8-H4-1-CIoH#O&HSO&pH,

ALP.

2-(l-CloH7S02NHSOZ)C~H4 2-(2-CloH,SOzNHSOa)CBH, 2-(~-CH~-~-~BO-C~H,C~H~SOZNHSO~)C~H,

.

180 180 180 180 180

4-HO,SOCH&H&OzCBH, 2-HO-6-HsC2SOzCeH3 2-C,H~C00-4-HO,S-l-C~oC~ 2-CIC6HI 2-Hz,C,oOOCCeH, 2-(3,4-Cl,CeH,S0,NHSOz)Ce~ 2 42,4,5-CI~CeH2SOJiESO2)CBH(

4-Na00CCHzCHzCOOCHzCHzSOzC~H4 4-Na00CH=CHC00CH2CHzSOzCeH,

-

2-HOOC-4-HO3SC6H3 4-HO3S-2-CloHe 2,3,5-C13-6-HOOCC,H 2-CH30-5-CICBH, 2-CH30-4-CICaH3 2-CH3.4-C1C6H, 2-CH3-4-CIC6H3 2-CF3-4-C1CeH3 3-ClCBH4 l-CioH, 2-HO-5-CICeH3 2-HO-4-HzNOzSC6H3 ~-HO-~-H~NOZSC~H~ 2-HO-6-HZNO&!,H3 2-CICeH4 4-HOOCCH~CHzCOOCH&HzSO~CeH~

Ar

% 2.

* z

'Q

2 CQ

.I

$

la

* .-I

2

(pmU?lUaJYW,z)

19PI 'WI I IZ 11z og9 9W.I "IZ 802 962 0%I 08I OBI

5

08I 0%I

-3

9

a

08 I

08I 08I OBI 08 I 08 I

081 08 I 081

rn a,

-8 ! pc

ru 0

m

08I

0

3 08I 081

8 081

0

di

4

.I

A

B

c3

m

08I 081 081 08I 08 I OBI 08 r 08 I 08I

'H3 "H3 'H3 EH3 'H3 "H3 EH3

"H3 "H3 "H3 'H3 CH3 "3

"3 'H3 CH3 CH3 CH3 =H3 "H3 "H3 "H3

EH3 "H3 "3

"HD

CH3

"3 eH3 'H3 "H3 EH3 "H3 "H3

TABLE X X I I I , Section B ( d i n z c e d )

-.-

2,4.(h'On)CeH3 2,4-(KOa)CeH, 2-HO-5-C1CeH, 2-HO-5-H&"ZSC& CeHs 2-ClCSH4 4-NOzCeH, 2,5-CI&eHa 2-HO-5-ClCBHa 2-HO-PH$JO&&H3 2-Cl-5-(3,4-CI~C~H~SO,NHSO~)C,H3 CsHs

2-(5,6,7,8-H+-l-CioH@O~NIISOa)Ce& 2-(8,G,7,8-Hl-2-C1,H,SOaNHSO,IC,H,

2-HO-4-CH3HKOaCeH3 2-HO-5-CH3OaSCeH3 4-BTCeH4 2 4 2-CH3-5-iso-C3H,CeH3SOzNHSOz)C~H4 2-(5-CH,-2-iao.C3H,CeH3S0,h'HS02)CeH4 2-(l-C,oH$3OzNHSOn)CsH, 2-(2-C,oH,SOaNHSO&&HI

2-HO-5-C2H50&&H3 2-HO-5-ClCHgO&&€I3 2-HOOC-5-ClCHz02SCeH3 2-HO-4-NOa-5-CH3SO&pH, 2-HO-3-Pu'Oa-5-ClCHaOoSC,K, 4-ClCeH, 2-HO-5-CH3HNO&Y&H3

2-HO-3-CH3CONH-5-CH3O$CeHa

2-H0*4-(C,H&NOpSCeH3

-____-______ x p .

1004

1466 1456 180

591

125 125 1456 1453, 1456 690, 732 268 732

180

180

180 180 180

180

446

254

225, 1460, 1681 228

296

211 211 219 223 223 1445 223

Reference

x

3E

* 21

z

W

(Tabla continued)

1617 1444

1680 1444 1617

1680

1616 180 195,1617 195 207

189

1460 203 189

864 864 864

1293 1619

661

651 651 651 648 651 651

661

356 1461

980

980

W

R'

-RZ

T A B L E X X I I I , Section B (continued) Ar

___________.____

31.p.

____-

279, 913. 914 279 279 279 279 279 1062 324 324 324 324 324, 356

1062

217, 935 356 173 217 1620 475 1620 716 623 1392 1421 442 1059 1616 1060 1060

.

Refcrence

2 FL z.

b

.a

0

to

w

CeH, Z-HO~S-4,.5-(CH3)&6H3 2-HOOC-4-C,H&ONHC6H3

2-(5,6,7,8-H4-1-CloH~SO~NHSO2)C6H~ 2-(5,6,7,8-H*-2-CloH&lO,NHSO1)CgH,

2-(l-C1oH$3OgNHSOz)CeH4 2-(2-CloH,SOzNHSO,)CeH4

2-CH3-5-(CeH,SO2NHSOs)C,H3

2-HO-3-NO2-5-HO3SC6HZ Z-HO-3-HO3S-5-CH3CeHz 3-(4-CH3CeH4SOzNHSOZ)CsH, 3-[X,Y-(CH3)zCeH3SOaNHSOz]CeHI 3-(4-CH3CeH,SO2NHSO2)-4-CH,CBH3 2-CH3-5-(4-CH3CeH4SO&HSOz)CBH, 2-C1-544-CH3CeH4SOzNHS02)CeH3

2-HOOC-4-(2-HOC2H4NHOzS)CeH3

Z-HOOC-4-H,NO2SCeH3

2-(5-CH3-2-iso-C3H,CeH3S02NHS02)CeH3

Z-HOOCCeH, 2-F,C-4-ClC,H, 2-HO-5-CH3NH02SCeH3 2-HO3S-4-ClCeH3 2-CICeH4 CeHs 2,4-(CH3)zCeH3 2-Cl-B-(C~H,SOZNHSO~)C,H~ 2-HO-5-HO3SCeHg 2-(2-CH3-5-i~o-C3H,CeH3S0,NHSOa)CeH4

180 180 180 180 651 523 176

180 180 180

180

180 180

80

80

180 208 208

80 180

160 651 1460 651 651 296 1438 180

1629

8

3. F

U

Ei'

0

r

c+

6a

m

2

3 0

1

+d

%

g

8 c5. 2

5 !

m v

R=

T A B L E X X I I I , Section B (eontind)

651 913 40 173 173 173 1486 1486 1382 1382 1382 1382 1382 180

2.H03SCeH4 4-H03SCeH, 4-HO3SCsHI 3-C17H35CONHSOJ&H4 3-C15H31CONHSOzCeH4

3-CF3C6H. 3-CF&H* 2-HOOCCOH, 2-HOOC-4(or 5)-H03SCeH3 2(0r 6)-HO-3-H03S-5-NOaC6H2 2-HOOCC,H, %HO-P(or5)-N02C,H3 2-C1-5-(4-ClC6H4SO&HSOa)CeH3

3-C17H36CONHS02-4-CH30C6H3

652 1331

3-CH,=CHSOaCeHI 4-(CaHj)&CeH,

1486 217 176 176 173 1486 1620 173 263 1620 1488

180

1361

Itelerence

a 2.

P3

* a

M

E3

w

Systematic Tables of Pyrazolones and their Derivatives

.t r( c1

I

d

L3

2

I

32 3

-_____

Fl1

0

H'

~-

TABLE X X I I I , Section B (continued) Ar

-_____

2-CH3C6H4 3-CH&H, 4-CH3CeHt Z-CHaOCeH, 4-CH30C,H, 2-C,HsOC,H,

0

.____

__

-

179' 193", 242" 209" 187" 206"

183', 226"

173'

413

237"

278, 1552 278 278, 1552 278 278 278

1673

129, 278, 372, 818, 1003, 1514, 1652,

413

1251

Reference

-

M.P.

x

N It-

w

N

\ /--

ii-7

203

176"

-

238", 196' 175'. 225"

-

206O 244"

-

2M" 220'

-

-

281

280 280 278 278 280 278 278 280 180 278, 1662 278. 1662 280

269

177' 193" 216" 231O 204O 203" 2450 195'

-

278 259 269 278 278 278 278 278 278 278 259

177" 208O

R1

_-

R'

- .

TABLE X X I I I , Section B (continued) Ar

_____ -

281

281

281

1145

212"

271'

265'

141O 189" 205 a 285' 139', 149" 267" 137' 236" 177' 213'

670 670 670, 1581 1581 1581 1581 129, 1581 1581

670

Reference

31.p.

___

a

f3

W

201' 227' 231O 223" 103" 260'

200"

165" 195" 187' 190" 193" 164" 198' 173"

-

I

-

-

-

-

194"

2250

179" 290" 200" 239"

-

-

-

-

77 278, 1499 278 278 278 278 278 278 278 278 278 278 278 278 278 278

77 77

1580 1580 1580 180 1003 1574 1581 1581 1004 1004 279 279 279 279 279 279

32L

Appendix

3

0.1 4,

0

m

3

I

/'\a

(R

0,

x

x,

4-NaO3SC,H, 4-Na03SC6H, 4-Na03SC6H, 4-Na0,SC6H, 4-Na0,SC,H4 4-Na0,SC6H4 2-C,H30 2-C4H30 2-C4H,O 2-C,H,O 2-C4H30 2-C4H30

2-C,H30

693

180"

lMO

C.H&ON=-

4-(CH3),CCBH*OCHCON=

593

-

279 279 279 279 279 279

281

Ce& 2-NO&,H4 4-NO&eH+ 2-CH3-4-CIC6H.g 2-CH3-5-ClC,H3 2,5-C1aC6H3

-

287"

c!

eB

Ca

.;

B

m

%

HOOC

CBH6 2-CH3CaHS 4-CH,C6H4 3-HZ?r'C,H, 3-ClC,H* 3-CIC,H4 3-CICSH4 4-ClCBH4 4-BSeHa 3-?JO,C,H* 2-H03SC6HI 4-H03SC,H,

4-HO3SCeHS

C6H5

H

H

H

C6HS

CH&O HOOC HOOC HOOC HOOC HOOC HOOC HOOC HOOC HOOC HOOC HOOC HOOC HOOC HOOC HOOC HOOC

TABLE XXIII

C&s C6H5 3-CH3C,H4 2-HOOCCG11, CaH6 4 - BrC,H, 2-CH3C6H, 4-CH3CBHd 4-[3-H038-4-(4-H03SC,H,PI'=.-N)CBH,NHCO]C!eH* 2-HO-3-NO2-5-CeHllC6H~ 2-IIO-3-N02-5-t-C,H,,C,Ha 2-HO-3-NOo-5-CBH,C6Ho 4-CICnHa

1'. 1

323' (dec.)

-

-

-

254' (dec.) 260" (dec.)

-

-

229' (dec.) 233' [dec.) . .

-

227 O 230'

-

182" (dec.) > 250"

1629

768, 770 449, 1545 449 1552 292, 1082 292 293 293 215 873 873 873 29 1 291 276 1079 57 1

0

w w

H H H CH3 C8H5 2-CH,CVH,

H H H H H H

4-HzNOaSCsH, 2-CH3-4-H03SCeH3 2,4-ClzCeH, 3,4-ClzCeH3 3,4-CI&eH, 3,6-ClZCeH, 3,6-C1,C,H3 2,4-BraC6H, 2-CH3-4-HO3S-6-ClCsHa 4-Ns03SCeH4 5-HO-7-Na0,S-2-CloH, H H H H H H 4-BrCOH, 2,4-Br1C6H3 H H H

HOOC HOOC HOOC HOOC HOOC HOOC HOOC HOOC HOOC NaOOC NaOOC H3COOC H3COOC HaCOOC H,COOC H,COOC HaCOOC H3COOC H&OOC C2HSOOC CzHsOOC C2H500C C2HsOOC C2HSOOC CzH500C CaH5OOC CpHSOOC C2H,00C C2HsOOC CzHSOOC CzHsOOC CZHSOOC CzH,OOC C,H,OOC 2-CH3C,H,

C6HS

4-H,XOZSC,H* 2-HO3S-4,5-(CHj)&eHz 2,4-C1&H4 2-HO-3-N02-G-CeH,,C6Ha 2-HO-3-NOz-5-L-CsHllC6H~ 2-HO-3-NOp-5-t-CSHllCeHz ~.HO-~-NO~-~-C~H,,CBH~ 2,4-Br2C6H3 3-CF,C6H, 4-Na038CeH4 5-H0-7-Ka0&2-CloH, CeH5 2--UOz-4-CH30C6H3 2-NO2-4-CzHEOC6H3 2-N0,-4-CIC6H3 2-N02-4-CH,COCsH3 2-~0z-.1-C4HgNH02SC,H3 4-Br(!,H4 2,4-Br2C6H3 2-HOOCC,H, CsH, 2-x0&&4 2-N02-4-F3CC6H3 2-NO2-4-CH3OCeH3 2-KO2-4-ClCBH3 2-P102-4-C2HsOOCCeH3 2-N0+4-HOCH&HsNHCOC6H3 2-N02-4-CH30CH&HzNHCOC,H3 2-iYOz-4-CzH6NHSOZC6H3 2-NOZ-4-C,H,NHSO&6H3 2-NO2-4-SCNCeHa 4-CH3OCeH4 209" 243' 244O 225' 254' 230" 213' 233" 255" 241" 256' 186" 246' 228' 205" 154" 226' 251' 230" 125" 152' 145'

-

-

248"

-

continued)

369 369 369 369 369 369 369 1357 594 37,44.1240 293,445

1549 369 369 369 369 369 291 291 1552 1544,1546 369 369

71

1628, 1662 523 291 873 873 873 873 291 1486 768,770,1066

( Tnble

252" (dec.)

-

-

5

c

La

0 m

2.

E

?'

8

U

EG.

c

3

?

6

0

2

'+'d

L?

0

n

c

0

2=. 4

u1

3 g

~-

R'

-

C2HsOOC C,H,OOC CpH600C CzH500C CzHsOOC CpHBOOC CZHSOOC C2H500C C2H500C CZHSOOC CaHsOOC C,H500C CoH5OOC CpHSOOC CZHSOOC CzHsOOC C,H,OOC C,H,OOC C2H500C CzH,OOC CzH500C CzH500C C,HsOOC C2H600C C2Hs00C C2H600C C2H500C C,HSOOC CzH600C C2H500C CzH,OOC

Ra

T A B L E X X I I I , Section C (cmtinued)

-~~

-

170" (dec.)

216' (dec.) 2-C10H7

158' 213" 229'

165'

-

-

190" 160' 260" 246O, 260" 224' (dac.) 132' 228"

-

143' 198" 228' 179'

-

146' 143" 177' 152' 195' 146"

h1.p.

1-C10H7

-

2-HO-3-h'0~-~-t-CsHl1C~Hz

2-HO-3-NOp-5-t-CsH,lC,H1 3,4-( CH3)aCeHa 2-CH,-4-NOzCeH, 2,5-CI,C6H3 2,4-BrzC6H3

2-HO-3-n'0,-5-t-C,H,,CeH2

3.CH&H4 4-CH3CeH4 2-CH40C6H* 2-CzH,OCeH* 2-HzNC6HI 3*H,PU'CeH, 2-CH3-4-ClCeH, 4-HzNCeH, 4-CeHJ=NCpH, 2-CH3-4-ClC6H3 Z-ClCeH, 2-C1-5-(2,4,B-C13CBH,SO*NHSO2)C~H3 4-ClCeHI 3-BrCsH4 I-BJC~H, 4-NO&H, 4-HOOCC6H4 3-C,H,OOCCeH, 4-(2-CioH,OCO)CgH, 4-H03SCeH4 CeH5 2-HO-3-n'Oz-5-t-C5H11C,Ha

Ar _ _ -

-

874 1450 1450 1661 1661 285 291 874 768, 770 768, 770

661

878 444 770 a77 1661 180 291, I661 1661 291 444, 770 768, 770 1661 I661 444

444

445 293,445 1661 1661 444

Referenoe

-

j?'

%

3*

ci,

W

W

l-NaO3S-2-CloH~

4-BIC,H4 CH3 CH&O CsH5CO C6HsCO CeHSCO CEHSCO HZNCO HZNCS

CH, CeH5

2-CHaOCeH4 3-CIC6H5 3-HZK02SCEH4 2-CI-5-HzNO2SC6H, 3-H,NOZS-4-ClCEH3 H 3-H,N0,SC6H, 3-HOCHzCHzNHOgSCeH,

C6t1.5

C8H6

C6H3

2,4.BrzC!,H3 H H

a$-( HO3S)z-2-C,oH,

CZH5OOC C H 00C C,H,OOC H,NOC C4H,NHOC HzNOC H,NOC HZNOC HzNOC HZNOC HZNOC HaNOC HZNOC C4H,HNOC CH3NHOC CH3NHOC HOCH&HzNHOC H,NHNOC ONC CN 180

768, 770 770 291 369 226 1218 1218 1218 1218

-

-

1450 874 874 1464 1450 1450 1450 212' 594 253' 594 152' (dec.), 126, 768 189' 203" 126 120' (exp.) 594 199" 1560 209" 264 171" 264 412" 264 224" 264 355 217" 355

-

-

I

-

200" (dec.) 260' 178" 218'

W

w

w

P

5

b 3.e P

5a

It'

I

N

/1=0

,

4-CH&Ha P-CH&,H, 4-CH3CBH4 4-CHJ&H,

4-CH3CeHI 4-BrC,H4

H H H H

H H

-

CeH5 CeH, CeH, 4 CH3C6H+

CeH5CHaN

CHJ

CH3 CH3

CH, CH3 CH3 CH3

CH3 CH3 CH3 CH3

CH3

CH,

/ \

I CHa I CHl I N

CH3

CH3

I

305" 190°

CH, (CeHB),C=N (CH3)zN

I

233" 235' 217" 302O

232' 303"

245O

248'

216"

-

C,H,CH=N 4-CH,0CoH4CH=N C,H,CH=CHCH=N C,H,C=N

coow

CeIT,CH=lc' 4-CH30CsH,CH=N C,H,CH=CHCH=N CH3C=li

H

(CHJAJ

____I

3-Pyrazolin-5-ones. Imino, Amino, Amido, Azo, Aminoazo, and Hydrazido Substituenta __ - -_ -_ - - H* R3 R' b1.p. - .__

H H H H

C6H5

H

--_____I_

R=

_-

TABLE X X I V .

--

Ra--?i

984 1001

984 984 984

984

984 984 984 984

1052

860

Rcfcrcwe -

--

__

+

w w

4-BrC,HI

H

CH3 CH, CH3

4-BrC6H, 4-BrCeHI 4-BrC,H4 4-BrCeH4 4.BrC6H4

H H H H H

CH3

HO,SCHpY

lOl0 105'

102O

Oil

74' 118'

106"

130,743 130

134,172 133,144,160,172, 371, 463, 526, 527, 560, 561, 554, 603, 661, 691, 781, 915, 938, 941. 1198, 1256, 1356 984 992 992 431

860

74"

-

105

1001 1001 1001 1001 1001

153' (dec.)

199O

274"

249" 303" 340"

ti' 0

CT

P

g-

9

'

k

-7

0

2 F rn

C6H5

R'

H3

1184

157O 151' 206"

155"

198" 173" 177' 213' 230'

151'

173"

821,940,1592 992 430,954 992 992 821 430 992 430, 821 992

I

COOC,H, CeH,CH=N CBH,CH=N 2-HOCeH,CH=N 2-HOCeH*CH=N 4-CH,OCgH,CH=N 3-N OpCeHaCH=N 2,3-(OCH,O)C,H,CK=N 4-NOpC6H,CH=N CeH,CH=CHCH=N CeH6CH=CHCH=N

101

94'

a21

101

Reference

84"

M.P.

CH3C=N

n*

Q,

R'

-.

w

W

TABLE X X I V (continued)

ts 0

CEH5

CH, (HOCH,CH,),N (HOCH&H&H,),N (HOCH2CH,CHzCHz)zN (CH,)ZNCHzCH,N I

460 460 460 111, 1298 111

-

213" (HCI) Oil

-

-

993

1217

167"

227' (dec.)

4

Appendix

338

" 2

d -

l-

I

d

T

9

9

3 P

-$

*

I

I

r(

0

Syatematic Tables of Pyrazolones and their Derivatives

r0

cv

0

0

2

0

n

cv La

d

V

B w

339

Appendix

340

d o 0

M

d

oocn

t-

b b 20,

$

V

Syst!ematicTables of Pyrazolones and their Derivatives

3

3

mQ eO 4 C O

gg

gg

gv gv

t-

2

3

34 1

1017 1017

1018

999 1323

181" 199"

142'

174' 266"

426, 1017

1149 1149 1320 1365 984 1001 426, 1353 992 972 885 984 1060 1060 1001 1004 670 670 174"

253' 210" 189" 205"

-

99 O 236" 215' -

-

-

120"

-

111"

82' 139"

Systematic Tables of Pyrazolones and their Derivatives

0" d

I

t6" 0

0 0 1 1 0 0

w vw wv wv wo v

v6'

343

31.p.

68" 83"

-

116' 171" 202O 116'

-

65' 800

-

170' (HBr salt) 132" 59 81O 143' 198" 178' 188' 153" 128'

78'

182'

-~

980 1309 1522,1528, 1605 1605

1004

1028,1029 1309 1309 355,1028,1029 333 333 981,994 1028, 1560 353 335 1513, 1514 809,818, 1056, 1307, 1605 1605 809, 816,1605 809,816, 1605 1605 351 1513

Reference

-

__ __

c1

__ - --

It2-L-I

\/ I

fi3---R4

_ _ ~

C,H&H=

____I__

H Br H Br Br Br H

I CH3 H H 225' 220" 250" 144O 130' (dec.) 146"

160'

70' bza170" 210° 110' 108"

~

~

_.

CH3 H H H

CSHS

H H

~

R'

--

-_----____

4-BrCeHI

Ce&

C6H5

C6H6

CH3 C2H6 CH,

RZ

CH3 CH3 c1 c1 CHa CH3 CH3

R3

~

__-

C1

Br Br H H Ci Br

R'

218" 39" 67 O 117O 261' 241" (deo.) 220"

J1.p.

R' TABLE XXVI . 3-Pyrazolin-5-ones. Halogen and Halogen Combined with Carboxylic Acid and Derivatives

- ___

C6H5

-

CH3 CH3 CH3 cH3 CeHs CeHs

.

Br Br Br Br Br Br NO

CeHs CeHK.

2-CH3CeHd C6HS CH3CO H,NOC H,NSC H,NSC H,NOC H,NSC

c1

c1 Br

C1

* 2-HOOCCeH4

CH3 CHB

CH3

C6H6

E CeH5

-

(Table contenued)

1205 981 981 988 988 1001

1205

Reference

-~-

1605 994,998 1004 351 994 1309 355 355 355 357 357 994

%

W

z. -4 8

T.

5.
316". 218' 173' 198" 167' 232 ' liquid 225O

134' (def.)

213" 113' (def.)

-

235' 179' 144"

ALP.

1595 499 499 498 506 594 1595 498 506 924 24, 924.925 1310 1186 1310 924 498 1190

Refcrencc

w 0, Ip

Systematic Tables of Pyrazoloncs and their Derivatives

365

R3

TABLE XXXIII, 2-Pyrazolin-5-ones. Carboxyl Derivatives Combined with Other Functional Substituents R'

. RZ

-_

-

-

R3

H'

-

H H

C6H5CH=X HOOC

HOOC SO

H H

C6H5 CBH5 4-HOaSC6H4

HOOC HOOC HOOC HOOC H,COOC C,H500C C,H500C CzH500C C2H,OOC CzH,OOC CzH5OOC CzH500C CzH5OOC C,H,OOC C2H,00C H,NOC

SO H2N

H H H H H H H H H H H H

cPH6

H H H H HzNOC H,NOC CeH5 C6H5

C6H5 CfiH5 C,H,CO C,H5

H2N CH,CONH XO

C',H,O C,H,S

YO

HOOCCHzCHL UN C,H&O?rT H C6H5S 4-(C211[5)zNC,H,S= 2-CH3-4-(C2H&SC,H3K= C,H,CH, 2-CH,-4-(~,H,),SC,H,S~-

Xp.

___

H

-

>280° 215O (dec.)

-

22.50

216"

-

Reference 557 1545

1036 292 36 292

1549

213' 213' 1820 170"

G77 675

195"

366

183.5' l5O0 161' 217'

077 519 244 497

210°

-044

1545 1252 292

(tlr.c..)

H CH3

H,NHSOC I3,KHXOC

SO

H

CPH5C0 C6H5C0

H,NHNOC N,OC

C,H,CH2 C6H5CH2

H

H

C,H,CONHNHCO

C,H5C0

H

H,S?;-E

178"

H

112O (exIJ.1 203' 135' (def.) 214'

1549 594 497 497

337

Rl

I

=

O

CH, C,H, CH3 CH3 CH, CH3 CH, CH, CH,

CoHs CeHs CsHs 4-CHSCeH4 CeHs CeH5

C6H5

C6HJ

CH,

CH,

CHJ

HOOC

C6H5

HOOC CH, HOOC HOOC

CH3

CeH,

C6H5

CH,

C6H5

HOOC H HOOC

H

-

R3

CsHo

C6H5

CH, CH,

c6H5

H

C6H5

-

HZ

-

It'

__

HOOC

H HOOC H

-

(dec.) 121" 138' 15p' la70 oil

189O

73Q 110" 186' 107" 187' 189"

178O

72"

-

C'& HOOC iso-C3H, C6H5CH, HOOC COHS HOOC HSOC HSSC

__

216" (dec.) 198O 220" 205O (dec.) 214'

--

___ J1.p.

HOOC

__

R'

T A B L E XXXIV. 3-Pyrazolin-5-oncs. Carboxylic Acids and Thiooarboxylic Acida and Derivatives -____

y

1 1

R3 ___- R4 R2-N

la. 741 993 1228

109

698 370

17, 107, 741, as6 167 741 167 167 107. 196 167 196 107,109 109, 831

108 370

ioa

993

Ncfcrenee

W

3

3 sf

aa

0,

CH, H,SCSHCH,CH,OOC (',H,C'H,OOC C,H500C Z-CH3OC,H,OOC 2-CH,OOCCaH,OOC 2-C,H,OOCC,H,OOC 1-C,,H,OOC 2-C1,H,OOC

Il

0

4-C,H5OC~H,NHCH&H,OOC 4-C,H,OOCIC',H,NHCH,CHaOOC (C6Hs)2XCH,CHz00C 1-C,HsOC6H,NHCHOOC

C'H, ('€1,

I

186"

C6HSSHCH2CHZOOC

CH,

CH, CH,

2420 (dec.)

H,SCH,CH,OOC VH3NHCH2CH,00C (C€13)2XCH2CHz00C

coniinued)

74 1 74 1 74 1 741 741 741 74 1 ( Tabk

74 1 126" 198' 163" 138" 179' 175" 188'

74 1

160'

130"

741 741 741

741 175" 134"

(dec.)

208" 202"

(dcc.) ,260'

741 74 1 741

74 1

144"

230'

99"

152" 960 73" 101" 1110

CH, CH, "H,

1230 370 107, 741 167 1339 167 741 74 1 741

71'

-

ko-C1,H7 ieo-C,H, iso-C,HgOOC iso-CSH,,OOC CICH,CH200C NCCH,CH,OOC

CH,

C2HsOOC H C2HjOOC

H C2H,00C CH3 C,H,OOC C,H500C C2H500C CH, CH3 CH, CH,

4

368

Appendix

u3 W m

V

0

C6H6

C6H5

\/

i B o c

Br

I

Br H,NCONHOC (CH3)&H&HOCNHOCNHOC

I

CH3CONHCONHOC (CZH5)zCOCPU'HOCNHOC

197"

169"

203" 261 26" 174' 304" 172" 210" 230"

194"

741

741

74 1

741 741 74 1 74 1

741 74 1 741 741 541 74 1 741 741 741

74 1

180"

74 1 74 1 74 1

74 1 74 1

741 741

370" (dec.) 260" 246' 230" 228O

250 O 208"

141'

-

250"

182'

249"

$. 4 R 2. 8

U

2.

e 1

5$a.

8

1

e0

R

Go

370

Appendix

CH,

H,NHNOC H,XHNOC

CgH5

CH, CH,

H,NHNOC

HJHXOC HzNHNOC H,NHNOC H,NHNOC HJHR'OC

H,NHPU'OC CH,

H,NHNOC CH,

C6HSSOzMHNHOC

CH3

CsHj

I

H

H H

SH

I

8H 1-C1oHTX=C

I

SH C,HSHNSC C8H,X=C

HN=C 830 829

830

698

183"

167

(CZHSOH)

229' 698 (dec.) . . 171' 167 200", 270' 696, 892, 1634 158' 167 262" 892, 204, 1634 175' 167 113' 167, 1387 145' 167 191O 167 75" 167

247"

233", 147' 167,698, 1387

l52O 206"

197'

q

1, m

0

0,

h

$f m r

SH

ClCH2COOOc CeHSCOOOC CeHjS030C C-CH,CeH$O3OC

ChT CN ClOC NCOC CH,COOOC (C2H5)&HCOOOC

CeHs iso-C3HT CN

ieo.C3H, s.C4H, CeHsCHz

H H

H

(exp.1 97" (dec.) 167 92" (dec.) 167 224' 741, 928, 1181 188" 1183 186O 1180 171" 18,107,741 174' 741 154O 741 74 1 218O (dec.) 122" 23 185" 741 103" 74 1 102O 741

90" lloo(dec.) 167 167

167 (exp.) 95O (dec.) 167, 1387 117O 167 (dec.) 88' (dec.) 167, 1387 110"

b

z.

3 %

cb

w

Systematic Tables of Pyrazoloncs and their nerivat,ives

37 3

I

R' TABLE XXXV.

2-Pyrazolin-5-ones. Sulfonic Acids R'

Referanca

n1.p.

1671 684,685,738,745, 1671, 1672 1674 1671, 1672, 1674 1674 1671 684,685 1671

i

R' TABLE XXXVI.

3-Pyrazolin-&ones. Sulfonic Acids

R'

HO HO CI H2N CH3HN (C2H5)2N C,H5NH 4-C2HsOCeH,NH 4*H,NOZSCpHINH CoH5CONH

M.p.

___ - __

276O (dec.)

-

1Ol0 228" 193" 153O 203" 93 213O 242'

-

-

Reference 738,745,1249 738 745, 1248, 1249 745, 1248, 1219 745, 1248 745, 1248 746 745 1248 745

\/\"

co

q

CH3CO

CH3C0 CH3C0 CH,CO CH3CO CHaCO

R'

TABLE X X X V I I .

A1

/ I 1 \/-

H

H

H

H

H H

H H

R'

2-Pyrazolin-5-ones. Acyl and Carboxyl Derivatives and Sulfonyl Subatituenta on N-1

R3

> 3w0

237'

719

718

6

6

1498, 1499

866 1531 1557, 1560 302 1598

116' 126" 168O 128' 127' 153"

Rcfcrence

3r.p.

jjl.

1

*

v

2

w

Systematic Tables of Pyrazolones and their Derivatives

0

5

I

I

W

X

W

8

V

0

2

m

3

X

w

a

X

W


300"

237"

H

CgHsNHOC

HpNOC

C,H,CH=

192'

H

HZNOC

H 181" 318' 131'

CaH6 CeH, CBHsCHZCHp

H H

H2NOC

E; H,NOC

d

W

-.

9e. 2

p.

1

3 8s

3g

r:

378

Appendix

X

X

X

X

Z

$

e

:

X

X

X

'

X

X

X

I

.

-

-

C2H,00CCH=CNHCS CeH5SHCS C6H,NHCS 4-CH3C,H,NHCS 4-CH3CsH4NHCS C,H,NHNHCS

CH,

H H H H H H H H H H H H

H H H

H H H

H,WS CH,?;HCS C,H,SHCS

HJCS H

H

H H

C,H,OOCCH,C=NSHCO

I

175' 117' 127" 1210 10F" -

179"

161" 84"

230' (dcc.) 180"

355 357 357 357 357 GO2

~- ..

1037, 1632 355, 358, 421 357 357 357

359

180'

CH,

H

H

2-CloH,lTHC

I/

359

249

H

H

4-CH,CsH,NHC ?U'-2-C1,H7

I!

K'-4-CH3CeH,

u

4

w

2.

5

8

i! 83

w Y

a

5

Y P

Bc, 0

Ft

m Y

Appendix

380

R"N

\ /=o h'

I

I 280'

244'

202" 80'

-

705

507

239"

200'

507 500 498

498

594 1597 594 501 501 508 508 507 507 507 507

152"

234'

2220

208' 243' 242' 247" 128" 145' 133" 190' 136' 131'

01

426

Appendix

xxxxxxxxxxxxxxxx

xxzx?i

x

xxxxxxxxxxxxzxxx

z

Systematic Tables of Pyrazolones and their Derivatives

0

I-

cc.4 l

I

I

88 /\

/\

a

xxx

X

X

X

x

X

X

xxx

X

X

X

X

X

X

xxx

W

X

X

X

w

427

CEH5

H H H

H H H H

H

H H H H

H H H H

H

H

H H H H

H H H H

H H

H

H H H H

H H H

H H H

H H

H H H

H H H H

H H H

H

H

H

R4

R3

Ha

CEH5

R'

TABLE XLIX, Section A ( h i n d )

I

188O

215" -

220° 220"

195"

-

170'

-

-

co

3-HzN-4-Ci8H370CeH3CO 3-NO,-4-C1,H,,OCeH,CO 3-{2-[2,4-(t-C5H11),C,H30]-5-H,NCeH3CO)CBH,CO 3-{2-[2,4-(t)C5H11)&H,O]-5-[2,5-(CH,OOC)2C~H3XHCOCONH]C,H3CONH}CeH4CO 3-(3-CIO&K&H4CONH)-4-Cl~H3~OCBH,CO 3-(3-C120~SCeH4CONH)-4-Cl~H~~OC6H~CO

-

152'

205"

-

1380 155'

1246 1246

1246 1246 1087 1087

776 1602 693, 1595 67, 1139, 1247 67, 1247 1139 67 1602

693, 1139, 1595 1594 1602 1255

595,596

290"

218'

Reference

M.P.

3-{[4-(4-t-C5H11C6H4O)C6H4NHCO]C~H4SOaNH)CGH,-

3-OzNC6H5CO 2-HzNOCCeH4CO 3-(3-C102SC~H4NH)C,H4CO

CH3COSCH,C0 CeH6HNCHZCO CEH5C0 3-H2NCBH4CO

C6H5

I

HSCH,CO BICH&O CH,CH.&HCO

CEHS CH&O

R'

~

6

m _.

H H H H H H H H H H H H

H H H H H

H

H H H H H H H

H H

H

H

H H H H H

H

H H H H

CBH5 CeHs C6H6

CfiH5

CeH5

H H

H H H H H 11 H

H H H H

H H H H

H H

H H

H H

H H

1247

1247 1347 1247

1246 591

1246 1246 1246 1246

1246 1246

(?'able continued)

E3

P

c


i , =x \

z

x "% uov

0

I/

x

x

X

xxxx

x

xxxxxxxxxx

x

x

x

xxxx

x

XXXXXXXXmx

x

x

2

xxxx

x

x2xxxxxxxx

413

N

H

0-

R'

H

H

Q-

H

H H

H H

H H H H H H H H H H

H

H H H

H H H

H

H H H H H H H H

H H H

H H H H H

R'

H H H H H H H H H H H H H H H H H H

R3

R=

TABLE X L I X , Seotion A (continued)

-

Xp.

Refereuce

H

H

H CeH&H&O CBH5C0 3-HgNCeH*CO 3-NOzCeH*CO

188"

277O

-

1600

1142, 1601

1254 922 932 1254 12.54 922 ~-[~,~.(S-C~H,)&H~OCH&'ONH]C~E[,CO 13S0, 220" 922, 1603 342.44 t-C~H1l)&eH30CH&ONH]C~H4CO 922 H 922 C,H&H&O 274' 922 CeH,CO 270' 922 3-(4-t'CjH1IC~H,O)CeH4CO 922 ~-[~,~-(s-C,H,)&~H~OCH&ONH]C~H+CO 922 225' ~.[~,~(~-CSH~~)~C~H~OCH~CONH]C~H,CO 1604 2,4-(t-C,H11)zC6H,OCH&H&O CeHSCO 1604 1604 3-[2,4-(t-C5H11)2CeH30CH2CO]CsH&O H 223' 13, 14 13, 14 234" CBH5C0

RU

--

&

.FI w

Systematic Tables of Pyrazolones and their Derivatives

0

435

0

2

r; CJ

N

X

X

X

24

X

x

x

X

X

X

X

24

x

E

X

X

x

X

ez L/ I

x

x

H

H

R'

\

'\/-

B

H

H

H

Qq

H

H3

€1

R'

T A B L E X L I X , Section A (continued) _-_ --. --

H

€1

H H CH,OOC H H H

H CH3 H

H H H

H CSHSOOC

H

H

CBH,CO

H

CH3C0

H'

H

H

H

H

H

R'

1601

1600

Reference

196' 85" 1010 79" 86"

200"

140' 2800 223 ' 249'

499 507 167 391 499 499 499 499

499

499

218" (dec.) 1600

196O

252'

M.P.

0,

w

b b

H H H H H CH,

H

H

H H H

H

H H H

H

H H

H

H H H H H H H H H H

H H H H H H CH3 CH, CH3 H

H CBH5 H

CeH5

H H H H

H

H

H

H CZHSOOC CeHsCO

H

H

iso-C3H,00C H H

CzH,OOC

H H

C6HSC0 CZHSOOC C4HBOOC HOCH,CH,OOC H CZHSOOC

498 498 498

498

(Table continued)

206" 178' 225'

154"

208" 391 192' 391 175'. 236" 391, 507 223 507 200" 507 242 ' 501 230" 167, 697, 1339, 1387 69" 1052 257" 1339 233" 1339 167,1387 222O 194" 167 212" 167 137' 499 242 ' 499 227 ' 501 145', 226' 167, 499, 1398 213" 167,499, 1395 211O 167 213' 501 215" 391 167" 498

W 4

Ip

8

5.

3. F

U

2z.

?L

P

R

3

'd

%

3 eD

5.

'D

2

m

2

H

H

CHSCOSCHZCO

H

H

219"

165"

H

H

H H 238'

C6H50CHaCHz CeHsOCH2CHzCHz H

CeHa

I

100' 397" 102

H CeH5CO CH&H&HCO c6H5

M.P.

RS

H

H

R'

136" lOS0

C,HS C@HJ

H H

____-

R3

H H

Ra

R'

._

TABLE X L I X , Section A (continued)

776

776

501

801

60 1

498, 501 498 1255

Reference

Systematic Tables of Pyrazoiones and their Derivatives

w

'$$$ \ W

Ma5 x

/

I

X

x

439

H H H

CH300C CzH500C iso-C3H700C C3HSOOC CICH,CH,OOC HOCH,CH,OOC HZNOC H CH3OOC H CH300C H H H CH300C CzH500C

H H CH&O C,H5C0 H H H H CH,OOC iso-C,H,OOC H CH300C H H

140" 190" 206j" 178" 141' 188" 135" 186" 155" 1570 157' 144' 141' 204"

391 391 391 391 499 499 499 167 167 167 167 167 391 167, 1395, 1400 126" 167 167 141O 167 139" 167 102') 167 135" 167 136" 167 166' 2049 167 109O 167 137' 167 158' 167 138' 391 105O 391 204", 230' 1395, 1400 126" 1395 141' 1395

Reference

E

3

b

f

H CBHd

H H

H H H H

NNHC~H~

2,4(t-C,H,,)2C8H,OCH&O

H

H

CH3CO HOOC CzH,OOC C2HsOOC C,H,OOC C2H,00C C2HsOOC CHaC I/

CeH.5 H H H R H H

__

R3

R1

Scction B. Acyl, Carboxyl. and Carboxyl Derivatives ~- - _ _ _ -____ -

T A B L E X L I X (continued)

H

R'

H

2,4-(t-C5H11)2CeH~OCH&O

H

CeH5 2-CHaCeH, 4-CH,CeH, HOOC

H

140"

-

Refereucc

-__

187 167 167 167 391 391 391

501

1395 1395 317

591

498,1599 557 1083 194O 1650 215' 1650 200" 1650 187' 557 185' (dec.)557

233' >3Oo0

-

H

~

B1.p.

~

204" 126' 211° 259O 241O 124O 205" 191" 76' b13 173' b0.* 155"

R'

CHaOOC H CpH6QOC H

H

CH,OOC H H H CHaOOC

H

e

@

CEH&O C,H,CO C,H,CO C&,CO C,H,CO CeHSCO H,NOC HaNOC H,KOC

H H H

H

H kl H H H H

H H H H H

H,NOC HpNOC H,NOC H,NOC HzNOC C,HSNHOC

H CH,CO H H H H C,H&O C,H,CO CEHeCO CgHsCO CEH&O C&.CO CeHSCO

CHZCO H CH3C0 CEH~CO CeH,CO C&CO H

H H H H H H

R=

Rl R'

H

Ra

H

TABLE XLIX, Section B (continued)

H H H H H H

273" 261O 270" 266' 259' 117"

300"

498 498 498 498 498 506

497 497 497 497 497 497 498 498 498

236' 235" 238' 236' 237' 238' 304" 278'

H H H H H H H H H

Reference

207' (dec.) 1598 203' 1598 594 195" 198' 1598 171" 594 160' 497 234' 497 232" 497 233' 497 235' 497 234" 497 236' 497 236' 497

M.p.

CEHS CiH, CH3C0 CeHs CEH&O CpH6OOC H H H H H H H

R4

g

3

* ?

rp,

IP

C6H5

CEHL

--____

lt1

- -

H H

C,H, CH3 CH3 H H CH, H H H

__

R'

I

HOE=

CZHB 2-CH3-4-(C2H&NCeH,X= 2-CH3-4-(CZH&NCeHaN=

H2IS HOCH2NH HaN 4-(CsH5)2NCeHdN= 4- (CaH&NCsHIN= 4-(HOCH&H2N)CeH,N=

Br

BK

K3

H H H H H

R'

-

I

C6H5

H

H CHaOOC CeH5CHzOOC H H H H CH,CO H

- - -_

_Re

Section C. Halogen, Nitroso, Amino, Imino, Azo, and Amido Substituents

TABLE X L I S (continued)

CeH,NHOC CeH5NHOC C,H,NHOC CeH,NHOC CeH5NHOC CeHSNHOC CeH6NHOC C,H&HOC CeHSXHOC

__

-

__

-

__

._

.-

Reference

506 506 506 506 506 506 506

____-

-

506 506

148', 169" 244, 519 173' 244

180" 78' 125' 180"

644 1339 519 519 519

644

223" 317 102O 167 212' (dec.) 697

-

M.p.

- ^

167'

loo0

234" 95"

264O 240"

115' 113" 110"

P

E
3m0 644 218' (dee.) 337 174' (dec.) 337 1649 193" (dee.) 1339 21 1 (dec.) 1649 2740 356 920 __ 920 920 172' 594 181" 594 2.100 594 175" .591 2180

207'

168'

Xp.

CsH5 H H CH,CO H 3-{2-[2,4(t-C~Hl1)2C,H,0]*5-(2-H03SCeH,CONH)CBH3CONH}CeH4C0 3-(2-[2,4-(t-C5Hll)~CeH30]-5-[3,5-(CH30OC)z205' CeH,NHCOCONH]CeH,CONH}CeH4C0

I

CH3CHzCHC0

H CeH5 CH&O H CzH,OOC H 2,4-(5-C,H,l)zCoH,OCH&O

H

C6H5

CBH5C0 4-CICsHaCO H CH300C CzH,OOC CeH5 H

CeH5

I

CH,CH,CHCO

R6

x

TE

*

v

lb

lb rp

Systematic Tables of Pyrazolones and their Derivatives

445

4-CH,OSHC,

\

1

-iq

$-

o-'

CeH5

4-CH30CoH4CH

C-CH,OCeH,

Rl

R

TABLE L (continued)

CeHli

K'

- _

CEHS

Reference

1254

198" 170"

1603

1603 1603 1603 203" 192O

1603

I603

1603 1603

1254

215'

150'

120" 1254

145'

*

lb

+P

% x

31

Y?

___-aa

142" 1255

N.p.

~

218O

173'

170"

~-[~-(~-CIH,)C~H,O]C~H~ 4-[4-(C+H,)CeH4OICeHICO

CeHs

I

CH,CH&HCO

R=

___

4-{4-[3-(t-CsH11)CeHdO]C6- CH,CH&HCO H4CONH}C6H4(CHz)4C0 I CeHs

C6H5

I

CH&H&HCO

CeH5

I

CH3CHzCHCO

R2

-_

Systematic Tables of Pyrazolones and their Derivatives

03 u)

447

m

In

2

a a x x A

0

0

2

h

Appendix

448

CH3

I

CII,

257" (dec.)

754

290"

761

449

Systematic Tables of Pyrazolones and their Derivatives TABLE L I ( d i n u e d )

234"

776

256"

776

188"

776

1516

287"

488

238"

235

Appendix

450

T A B L E LI ( m t i n d ) R

M.p.

Reference

210"

236, 1667

218

237

184",212"

747. 237, 772.773

216" (dec.)

620, 772, 1668

205"

620

-

707

257"

747

CH,

(Tubls continued)

Systematic Tables of Pyrazolones and their Derivatives

461

T A B L E LI (continua?) R

M.p.

Reference

248'. 281'

741, 764, 172

254'

147, 764, 765

130" (dec.)

741

183"

747.712

IOO0

141

197"

741

209"

747

180"

747. It34

(Tabla m i n u & )

Appendix

452 T AB L E LI (continued)

222O

747

251

747

loOD

764

238"

764

260"

764

208'

771

226'

771

CHCH=

N I

Systematic Tables of Pyrazolones and their Derivatives

453

T A B L E LI (continued)

233"

771

145' (dec.) i 7 1

I

CH,

'Jon,171"

772, 1668

(dcc.)

171"

772

162"

1069

224'

1110

CHCH=

OCH, I

454

Appendix

TABLE LI (continued)

258"

1213

258"

1214

156"

1328

239"

1328

1616

178" (dec.)

1668

287" (dec.)

1670

Systematic Tables of Pyrazolones and their Derivatives

455

TABLE L I (continued)

I-C,H,OC,H, I N-f

,

II1.p.

Reference

141"

776

248O

776

165'

78

194'

776

0

4-C2H,0C,H4 1488

I

CzH6

I-

I CBHs 30

29,30,31

(Tuble confinued)

456

Appendix

TABLE LI (conlinmd)

204"

748

219O

749

293' (dec.)

241

194'

765

258'

755

Systematic Tables of Pyrszolonea and their Derivatives

457

TABLE LI (contiad) 31.p.

Heference

236'

755

212O

755

260"

755

193"

755

257 O

382

Appendix

458

TABLE LI (continued) R

M.P.

Reference

OH -/-CH=CHCH=CHCH=

-

382

ti""" S

C H 3 - P CH=CHCH=CHCH=

382

N

382

L

139' (dec.)

775

139"

775

242'

775

225"

776

0 CN

(Table cotuinued)

Systematic Tables of Pyrazolones and their Derivatives

459

T A B L E LI ( c o n l i n d ) - __ __ R

__

~

-

~

-

y

I

CH,N

.

____

M.p.

Reference

169"

776

-

776

185"

1519

230' (dec.)

1519

242

1472

240" (dec.)

1519

-

382

216'

763

154'

1129

S

CHCHdHCHdH-

(Table continued)

460

Appendis

T A B L E LI (eonlinued)

178'

1129

171'

1129

-

1129

150'

1129

TTO

1129

210Q

1129

167"

1129

146'

1129

194O

1129

218'

1129

155'

1129

2203

1129

Systematic Tables of Pyrazolones and their Derivatives eu

8 n

$2

m" 0) cu

M

*

w

I

I 4i

L?

n w

I

j

I i

i

21

s;"

u

i

i3

I I

i

I 1

i

I I

..

n

5

461

Appendix

462

4

2

0

I ?

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