Pyrazol-3-ones part 1: Synthesis and applications

ADVANCES IN HEIEROCYCLIC CHEMISTRY,VOL. 80

Pyrazol-3-ones Part 1: Synthesis and Applications GEORGE VARVOUNIS, YIANNIS FIAMEGOS, AND GEORGE PILIDIS Depmment

of Chemistry,

University

of Ioanninu,

loannina,

I. Introduction ......................................................... A. Nomenclature and Structure. .......................................... B. Background ....................................................... 11.synthesis ........................................................... A. Synthesis from Aliphatic Compounds. ................................... l.FromB-KetoEsters ............................................... 2.From/%CyanoEsters ............................................. 3.FromB-IminoEsters .............................................. 4.From~-EnaminoEs~rs ............................................ S.Froma.b-U~~ratedEsters ........................................ 6. From Conjugated Amalkenyl Esters .................................. 7,FromAcetylenes ................................................. 8.From~.B-AcetylenicEsters ......................................... 9. FromDialkylmalonates ............................................ 10. FromSuccinates ................................................. II. From y-NitroEsters .............................................. 12. From fi-Keto Amides. ............................................. 13. From p-Hydrazino Esters .......................................... 14. From Hydrazono- or Hydrazinoacetamides ............................. 15. From 2-Oxo-3-hydrazonopropanoic Acids .............................. 16. From Hydrazides. ................................................ 17. From a$-Unsaturated Hydrazides. ................................... 18.FromIminopro~~iones .......................................... B. Synthesis from Three-Membered Rings .................................. 1, From Cyclopropenones ............................................ 2. From Diaziridinones .............................................. C. Synthesis from Five-Membered Rings ................................... 1. From Pyrrolidinones .............................................. 2. FromFuranones ................................................. 3.FrompyraZoles .................................................. 4. From Isoxazolones ............................................... S.FromOxazolones ................................................ 6. From 1.2,4-Oxadiazoles. ........................................... 7. From 1,3,4-Oxadiamles. ........................................... S.FmmSydnones .................................................. Y. From Thiazolidinones ............................................. 10. FromDiazaphospholes ............................................

73

4.~1 IO Greece

74 74 7s 76 76 76 Y2 94 94 95 9s IO0 102 103 104 104 IO.5 107 IO7 108 108 112 112 113 113 113 114 114 115 118 121 122 124 124 124 126 126

Copyright Q 2001 by Academic Press. All tights of reproduction in any form reserved.

0065-272S/Ql$35.00

74

GEORGE VARVOUNIS et al.

D. Synthesis from Six-Membered Rings .................................... 1. From pyrimidinones .............................................. 2. From Pyrimidinediones ............................................ 3.FromTetrazines .................................................. 4.FromPyranones ................................................. 5.FmmOxazinones ................................................ E. Synthesis from Bicyclic 5.5~Membered Fused Rings. ........................ 1. From Pyrazolopyrazoies ........................................... F. Synthesis from Bicyclic 5.6-Membered Fused Rings. ........................ 1. From Pyrazolopyridazinones ........................................ 2.FromImidazotriazines ............................................. 3. FmmBenzo~~~es ............................................. 4.FromPyranopyrazoles ............................................. G. Synthesis from Bicyclic 6.6~Membered Fused Rings. ........................ 1. From Chromenones. .............................................. H. Synthesis from Tricyclic 5.6.~Membered Fused Rings. ...................... 1. Fmm Fumquiuoxalines ............................................ I. Synthesis from Tricyclic 6,6,6-Membered Fused Rings. ...................... 1. From Pyrazolobenzoxazinones. ...................................... III. Physicochemical Properties. ............................................. IV. Applications ......................................................... A. AnalyticalUses.................................................... B. AgrochemicslUses................................................. C.DyechemistryUses ................................................. D.PharmaceuticalUses................................................ E.PhotographicUses .................................................. E MiscellaueousUses ................................................. References ..........................................................

[See. LA 127 127 127 129 130 131 131 131 133 133 134 134 134 136 136 138 138 138 138 139 141 141 141 141 142 142 142 144

I. Introduction A. NOMENCLATURE AND STRUCTURE The nomenclature of pyrazolones has long been confusing because these molecules can adopt several tautomeric forms in solution [64T299; 66BSF755; 67BSF3772; 67BSF3780; 68BSF5019; 69CPB1485; 69T4605; 71BSB17; 73BSB215; 73BSB233; 76AHC(S1)313; 9OJCS(P2)195; 93JA2352; 94JCS(P2) 165 11.For a compound existing in an enol-keto tautomeric equilibrium, the name used in this review is that of the tautomer found in the crystalline state. There are four possible pyrazol-3-one structums I-IV. The nomenclature most frequently used in the literature has been taken from Chemical Abstracts, where for example, structure I is named 2,3-dihydropyrazol-3(lI+n1e and structure II is named 4,5-diiydropyrazol-5(W)-one. Compounds I and II have also been named as pyrazolinones. Compounds with structure IV have been referred to as 2,3-diaza2,4-cyclopentadienones. To avoid this needless confusion, the nomenclature used throughout this review is in accord with the recommendations set forth by IUPAC.

Sec.LB]

PYRAZOLS-ONES

75

Of the four possible pyrazol-3-one structu~s shown. the first two are discussed in the present review.

1 ,Z-dihydrcb3MpymmWone 0 SP

N”N

M

(119

3KpyrazoC3-one

B. BACKGROUND The fust pyrazolone synthesis was reported in 1883 by Knorr (1883CB2597; 1884CB546), who suggested the wrong structure, V. The correct structure, VI, was proposed three years later by the same author (1887LA137). In 1892 Ruhemann and Morel1 provided further confirmation of the structure VI (1892JCS791). A compound with the structure VI was one of the first analgesic and antipyretic drugs to be marketed.

+

01)

Of9

The only major comprehensive work on pyrazolones that includes pyrazolidinones was published by Wiley and Wiley in the Chemistry of Heterocyclic Compounds series of monographs (64MIl) and is now obsolete. Since then, pyrazolones have been mentioned only briefly in other major works such as Comprehensive

76

GEORGE

VARVOUNIS

et al.

[Sec. ILA

Heterocyclic Chemistry and mainly by Elguero (84MIl; 96MIl). 3H-Pyrazol-3ones IV, however, have been reviewed by Costero [93AHC(58)171]. The present review covers primary literature from January 1964 up to July 1999. The intention is to provide a more comprehensive coverage on the synthesis of pyrazolones, together with their physicochemical properties and applications. Since the number of patents referring to applications of pyrazolones is overwhelmingly large, a limited number of patents have been included. The reactions of pyrazol-3-ones will be reviewed in Part 2 of this work.

II. Synthesis A. SYNTHESIS FROM

ALIPHATI~COMPO~NDS

1. From B-Keto Esters a. By Reaction with Hydrazine Hydrate or Monosubstituted Alkyl or Aryl Hydrazines. The mostwidely used method for the synthesis of the pyrazol-3-one ring is cyclocondensation of a &keto ester, which provides the C-C-C fragment, with hydrazine hydrate or a mono- or disubstituted hydrazine, which provides the N-N fragment. The reaction between a /Lketo ester and a hydrazine usually takes place in refluxing ethanol, but acetic acid has also been used. The substituents on the ester and the hydrazine have been greatly varied. All types of alkyl, alicyclic, aralkyl, and heterocyclic substituted esters have been used. Hydra&e hydrate and a large variety of monosubstituted alkyl, aryl, and hetetocyclic hydrazines have been successfully employed. The literature offers few examples of 1,2dihydro-3H-pyrazol-3-ones 3, nearly all of which am synthesized by this method (Scheme 1) (Table I). Reactions that produce side products will be described in more detail separately. The reaction between hydrazine hydrate and ethyl 3oxobutanethiolate 4 has been studied by NMR spectroscopy. It was found to occur via initial formation of addition product 5, cyclization to 6, dehydration to pyrazol-3-one 7, and finally tautomerization to pyrazol-3-one 8 (81CJC629) (Scheme 2).

+

Sec.ILA]

77

PYRAZOL-3-ONES TABLE

I

~~-D~YDRO-3~-PyRAzOL-3-oNES

Characteristic

d,

R=R’=H.d=l R.Ph,R’=R’=H

R’=H,R2=Me,R-

substitution

(3) References

WOW24

69CPB 1467

70BSF247

8OCPB3688

8OJHCS19

R*Ph.ti=Miz,R’=’

82JHC1457

R=

a,

R’=$=H,R3=h&

88BCJ1440

Katritzky and co-workers studied the mechanism of this reaction in detail. His work involved a 13CNMR study of 16reactions of methyl-, phenyl-, 1,2dimethyl-. and I-methyl-2-phenylhydrazine with #?-keto esters. In many cases starting materials, intermediates, and products were detected simultaneously. Most reactions proceed by nucleophilic addition of the less hinde=d hydrazine nitrogen atom to the keto carbon of the keto ester. For example, the pathway given in Scheme 3 for the reaction of methyl 3-oxobutanoate 9 with methyl- or phenylhydrazine 2 (R = Me or Ph) was found to be dominant. The initially formed addition product 10 dehydrates to hydrazone 11, which then isomerizes to hydrazone 12. Intermediate 12 then cyclizes to pyrazol-3-one 13, which tautomerizes to the kinetically more stable pyrazol-3-one 14 [87JCS(P2)969].

78

GEORGE

VARVOUNIS

46)

et nl.

[Sec. ILA

(7)

SCHEME 2

Hydrazine hydrate can often reduce vuhierable substituents on the pyrazolone ring. One such example is the alkene group of the cyclopentenyl ring of pyrazol-3one 16. It was found that heating 4-(1-methoxycarbonyl-2-oxopropyl)-2-cyclopenten-lo1 15 with hydrazine hydrate in ethanol afforded a mixture of pyrazol-3one derivatives 16 and 17 in a 5 : 2 ratio (97JHC233) (Scheme 4). Copper complexes l&t-f of methyl or ethyl 3-oxobutanoate la, 2-bromo3-oxobutanoate lb, 2-(anilinocarbonyl)-3-oxobutanoate lc, 3-oxo-3-phenylpropanoate Id, 2-bromo-3-oxo-3-phenylpropanoate le, or 3-anilino-2-benzoyl-3oxopropanoate If were reacted with phenylhydrazine hydrochloride and sodium

Sec. ILA]

PYRAZOL-3-ONES OH

OH

Me

WI SCHEME 4

PhNHNH#Cl

R2

R’

CU

0

0 RO

WI

(t)R=MeorEt

(191

I

H2S I CuS

(a)R’-H,~=Me,(b)R’=Br,~~MB,(c)R’=PhN~O.~~~. (d)R’rH,$=Ptj,(@R’=Br, =Ph,(f)

Ri=PhNHCOPh,R2=Ph

SCHEME 5

R

R3 0

0

+

H2NNHR

(2)

-

80

GEORGE

VARVOUNIS TABLE

al.

[Sec. I1.A

II

2,3-DIHyDRO-3~-PYRAZOL-3-ONjXS Characteristic

et

(22)

subtituticf~

R=H,R1=H,R2=Br,MeorNO~,R3=H.Meorf% R=H, R1=R2=H, R1=H.R2=MeorRL=R2=Me, R3 = .Bz. Ph. 4-MeOC& or l-naphthyl R=H,R1=R2=Me,R3=CHzBr R=H,Rt=H,R2=R3=Me R = H, R’ = H or Et, R2 = Et, Me, Me#ZI& or MqPh, R’ = R2 = (CH&, R3 = 4-(4-tetmhydrobenz~~imidawlyl)CsH4,4[4-(Pyridyl)]C& or SMe R=4-HzN@Q,R’=H,R2=HorMe,R3=MeorPh R = Me, R’ = SEt, R2 = H. 2 = Me or R = H, Me, (CH2)2CN or I%, RL=SMe,R2=H,R3=Me

References 68BSF5019 69BSF4159 69JOC1717 8OJA4983 87JOC1724 95MIl 7OJCS(C)445 94CCY957

R=Ph,

q H.R3=Me

R’=

80JHC1339

94ccc957 R=HorPh.

R’=

94IJC(B)326

Rwl.R9=Ma

R = Ph or 4-I&C&4, Rt =R2 = H, R3 = pyridin-2-yl, -3-y& -Q-y1 or 2-methylpyridin-5-yl, or R = 4&leOC+H5, R’ = R2 = H. R-’ = pyridin-2-yl or 2-methylpyridin-5-yl R = 3,4-(Cl&H3 or 3$-(c&C&, R’ = R2 = H, R3 = ~-CI~H~~ R = H, Me, HO(CH2)2, Ph, 4-MeC& or 3ClCrjH4. R’ = R2 = H, R3 = 4-(morpholin-4-yl), 4-(piperidin-I-yl) or 4-(-methyl-piperazin-1 -yl)Cf&

68NKZ1093

69BRP1173214 74JAP(K)35278

8OZC258

82JHC437

R = Me or Ph, R’ =R2 R = F%, 3-MeC&, R = Ph or 3-MeC&,

= H, R3 = i-C3H7

or t-QHg

4-ClC& or 4-MeOC&, R’ = R2 = H, R3 = 2-BzOCsH4, R’ =R2 = H, R3 = 2-HOC4Hg

83AP726 88JOC810 89JPS239 87TL5165

(continued)

Sec. ILA]

81

PYRAZOL-?-ONES TABLE Ckmcbristic

R=Ph,R’=R2=H,R3=

H-&N

II (conn’nued) References

substitution

93ZYZ309

x,X=CH2orO

R = H, R” = Me, R’ = R2 = H, 4-MeOC&

93BSB735

or 1 -adamantyl

R’ = H or alkyi, R2 = H, d = alkyl, Bq Ph, Ar or benzimidazolyl, d, d. @= H, aRyl. Ph. Ar, hab. CF3, CO$l or m

R = PH, R2 = H, R’ = Me, R’ = N = 3-Me,4-Bt-C& or 2-Br.4-MeGH3 R= R” = PH. R2 = H, R’ = N = NAr 2-Br,4-MeC& R = COCHzCONHAr, Ar = 2-,3- or 4-EtOCb& or 2- or 4-COzHCbH4, Ar = 4-Me, 4-NO2 or 4-CO&&

NAr where Ar = 2-Me, where

Ar = 2-Me,

4-BrChH3,

4-BrC6H3

or

4-C,&. 2-, 3- or 4-ClC&, 2-, 3- or R2 = H, R” = Me, R’ = N = NAT where

R = Aryl, R2 = H, R3 = Me, R’ = N = NAT where AI = 4-Me, 2-Cl, 3-Cl,4-Br, 4-COzH,2-N02 or 4-NO&&, 2-Cl, 4-NO~C6H~,2-(SO#HPh)c6H4, 2-(SO2NHguanyl. pyrimidyl or pyrazolyI)c6~ or 1 -naphthyl R;q

or

q+-

66CCc4069

8OJIC539

82JIC7 11 94MIl 82PJClSS3

R2=H,R3=n-CgH7. 0

R = R’ = R2 = H, R” = 4-(imidazoly)cgHd

92AF I 350

or CH(Me)CH(OEth

87JOC1724

acetate hihydrate to give the corresponding chelates 19a-f. Subsequent demetallation of chelates 19a-f by treatment with hydrogen sulfide afforded the respective pyrazol-3-ones 2Oa-f in yields of 75-90% (93POL1265) (Scheme 5). Many more 2,3-dihydro-3H-pyrazol-3-one derivatives 22 are reported in the literature. Most of these compounds have been synthesized by the /I-keto esterhydrazine method (Scheme 6) (Table II). Ethyl 3-oxo-2-(2arylhydrazono)butanoates 25a,b, derived from coupling of ethyl 3-oxobutanoate 23 (RI = Me) with diazonium salts 24a,b, were heated with hydmzine hydrate, phenyl hydrazine, or arylhydrazines in ethanol to give pyrazol3-ones 26a,b [78PHA575; 91IJC(B)878] (Scheme 7). Similarly, reaction of ethyl 3-oxo3-phenyl-2-(2-phenylhydrazono)propanoate 25c, derived from coupling of ethyl 3-oxo-3-phenyl-propanoate 23 (R’ = Ph) with benzenediazonium chloride 24 (Ar = Ph), and hydmzine hydrate or phenylsulfonylhydrazide gave pyrazol-3one 26c (85JIC54). 2-(Benzyl or n-propyl)-5-methyl-3H-pyrazole-3,4-dione 4-oximes 31a,b were prepared by two routes. Thus, ethyl 3-oxobutanoate 27 was either heated with

82

GEORGE

VARVOLJMS

et al.

[Sec. 1I.A

Hr

H,N-M I

.N

R’

+

x&Ar

-

R’

W”““‘R

N-benzyl or N-propyl-N-nitrosohydrazines 2Sa,b at 50°C for 6 days or nitrosated to ethyl 2-(hydroxyimino)-3-oxobutanoate 29 which was then heated with benzylhydrazine 30a or n-propylhydrazine 30b in ethanol (87JOUl773) (Scheme 8). Krohn and Stenns reacted ethyl 3oxobutanoate with l -(4-methoxyphenyl)hydrazine 32 and managed to obtain pyrazol-3-one 33 and pyrazole 34 in 65 and 20% yield, respectively (89AP351) (Scheme 9). Ciernfk and Mistr (66CCC4669) demonstrated that heating diethyl3,8-dioxodecanedioate 35 and phenylhydrazine under reflux in aqueous ethanol yielded the expected bispyrazol-3-one 36 in 55% yield (Scheme 10). b. By Reaction with Monosubstituted Heterocyclic Hydrazines. The reaction conditions for the condensation of heterocyclic hydrazines with /J-keto esters am very much the same as those used for reactions with simple hydmzines. The substitution in position 4 of the formed pyrazol-3-one ring is limited to H, Me, Et, or (CH&Me and the yields are generally high. Pyrazol-3-ones with the following

Sec. ILA]

83

PYRAZOL-3-ONES Me

Me

EtOHIA E

2 1 ‘N d

3 0

L%XE?ME 9

substitution at position 2 have been reported: pyrimidine, pyridazine, morpholine, naphtho[2,3-hlquinazoline-7,1Zdione, piperidin-l-yl-6,7-dimethoxyquinazoline, quinazoline, 1,2-benzisothiazol-3-yl or cyclohepta[b]pyrrole. c. Solid-Phase Synthesis: By Reacting Polymer-Bound &Yet0 Esters with Hydruzine Hydrate. Tietze and co-workers described (85GEP3416203) a solid-

phase synthesis methodology to synthesize polystyrene resin-bound B-keto esters 37a-d. These were converted into hydrazones 38a-d by reaction with phenylhydmzine in a mixture of THF and trimethylorthoformate (TMOF), then cyclized into pyrazolones 39a-d in acetonitrile containing TFA (Scheme 11). More recently, Tietze and Steinmetz (96X667) used the patented polystyreneresin methodology for for the solid-phase synthesis of a large number of diverse b-keto esters 4Oa-h. These were reacted with phenylhydrazine in THF at room temperature to give hydrazones 41a-h that were then cyclized into 2-phenyl 5-substituted pyrazol-3-ones 42a-h by heating in toluene at 100°C (Scheme 12). One year later, Tietze and co-workers (97BMC1303) presented a general and straightforward method for the synthesis of diverse polymer-bound fi-keto esters starting from acid chlorides and Meldrum’s acid. One such resin-bound /?-keto ester, 43, was treated with hydrazine hydrate in THF to afford resin-free N-2unsubstituted pyrazolone 44 in 84% yield (Scheme 13). In the same paper, the synthesis of a large number of 4,5-disubstituted 2-phenyl-2,4-dihydro-3Wpyrazol3-ones was reported. Ph I “\ MN

0

0 YNNHPh

El

El 0

-/

EtOH/l-plA

0 13s)

N

Lh W)

ScHEm

10

!N

0

84

GEORGE

VARVOUNIS TABLE

substitution

[Sec.

1I.A

III

~-HJTEIwcYcxx-~,~-DIH~DRO-~I~-P~RAZOL-~-ONES characteristic

et al.

(22) Refwfmces

%JSD176

68M2365

94IJC(B)1098 r. R’=+=H.ti=Me,R’=

97JHC1699

91CPBS6 R= -0

921JC(B)421

Kobayashi et al. (98SL1019,99TL1341) developed a solid-phase synthesis of diverse pyrazol-3-one derivatives using polymer-supported acylhydrazones asstarting materials (Scheme 14). Based on the 5(4’-chloromethylphenyl)pentylpolystymne (CMPP) resin, polymer-supported acylhydrazones 46a-I were reacted with ketene silyl acetals 45a-1 in the presence of a catalytic amount of scandium triflate. The resulting p-hydrazino ester resins 4’7a-I were cyclized and cleaved from the support simultaneously by heating under teflux in methanolic sodium methoxide. The cotrespondmg pyrazol-3-ones 48~1-1or 49141 (when R2 = I-I) were obtained in yields ranging from 56% to 88%. Applying the same methodology but using polystyrene resin (1% divinylbenzene) instead of CMPP resin, pyrazol-3-ones 48c,ej,j were synthesized in 88,80,38, and 44% yields, respectively.

Sec. ILA]

85

PYRAZQL-3-ONES

2 R2 0

PhNHN& THF I TMOF

0

MeCN

I TFA

I R.T. Ph (33)

(37)

(39)

(a) R’ = H, R2 = Bz, (CH&p3$6e, Wi&$2I or cyciohewI (b) ti = ?a, R’ = Me. Et, CH$2HCH2, cH2CHCMe2. &Y-l&Me

or CHGW

(c) R’ = Me, Rz = Bz (d) R’ = (Cl-&Me,

ti

= (CH&CCJ$@ %XIEME

11

d. By the Cyclization of Hydrazones. The reaction of @-keto esters with hydrazines in ethanol at room temperature is a gocd method to synthesize hydrazones 50 (Scheme 15). Quite often it is relatively difficult to cyclize the hydrazones, but in some cases simple heating under reflux in ethanol is sufficient. 2,4-Dihydropyrazol-3-ones 22 synthesized in this manner arc listed in Table IV. Hydrazones that arc formed by heating the /?-keto ester and the hydrazine in an alcohol usually require more vigorous conditions in order to cyclize to pyrazol‘s-ones. Thus, hydrazone 52, obtained by heating oxobutanoate 51 and phenylhydrazine in ethanol, required heating under reflux in benzene containing phosphorus pentoxide in order to cyclize into 1,2-dihydropyrazol-3-one 53 (66JOU1103) (Scheme 16). On the other hand, hydrazone 54 cyclized by heating in an ethanolic solution of aqueous sodium hydroxide to give 1,2-dihydropyrazol-3-one 55 in 92% yield (88JHC543) (Scheme 17). In other cases, attempts to cyclize the hydrazone proved more difficult and resulted in mixtures of compounds. The products obtained along with pyrazol3-ones were ring-opened compounds or other pyrazole derivatives. Filgram, who obtained hydrazones 56a,b by standard methodology, reported one such example.

R2 0

0 (44)

-

PhNHNFJHL THF I R.T.

R2 0

N Hd Ph (41)

Toluene / 100 ‘C

1 Rz .&c-J!N Y Ph

(42)

(a) R’ = R2 E Me, (b) R’ = H, R2 = CHMe2, (c) R’ = H. ti = CH$HCM%, (d) R’ = H, R2 = CX-bW4e (a) R’ = H, F$ t or, (t) R’ q H, R2 = CH&H&‘Q, (9) R’ = H, !$ = (CH&$QEt, (h) R’ = Et. R2 = CbCHCMe2 SCHEME

12

GEORGE

VARVOUNIS

(43) scm

13

at al.

[Sec. 1I.A

87

PYRAZOL-3-ONES

Sec. ILA]

TABLE

IV

2,3-DIHyDRO-3~1-PY-~-~~S substitution

References

HorNOz,R’=R2=H,R3=Me

66CB2937 88IJC(B)573

Characteristic

“=ywR4

R4=

(22)

Ryy-=pR

R4 = Ph, 4-Me, 4-Cl or 4-BrCeH4,

R’ = R* = H, R3= Me

69CPB1467

R=

872X637 R3=k=HorNQor$=H,d=N02

EtOH

F-24 v

h

HzNNHPh I b

Me

Et

benzene I A

i’h (63)

Ah

(52) SCHEMEZ 16

Me

Me

Et

EtOH * Hz0 I NaOH I A A S ‘N

A S ‘N

/ \ n -

W4)

(55)

SCHEME? 17

GEORGE

(56) (a) R’ = Me (b) R’ = CFs

etal.

VARVOUNIS

(St) (a) R’ = Me (15%) (b) R’ = CF3 (40%) ScHEMe

[Sec. ILA

(66) (a) R’ = Me (26%) (59) (a) R’ = Me (46%) (b) R’ = CF3 (20%) (b) R’ = CF3 (I I%)

18

Hydrazone 56a was heated for 6 h under reflux in ethanol containing a catalytic amount of hydrochloric acid to afford a mixture of pyrazol-3-one 57a (15%), pyrazole 5% (29%), and hydrazone 59a (49%). The cyclization of hydrazone 56b was much more sluggish. Under similar reaction conditions 5 days was required to give a mixture of pyrazol-3-one 57h (40%), pyrazole 58b (11%), and hydrazone 59b (20%) (8OJHC1413) (Scheme 18). The reaction of ethyl 3-oxobutanoate with 4-aryltetrahydropyridazine-3,6dione 3-hydrazones 60a-d afforded the corresponding hydrazonobutanoates 61a-d. When heated with ethanolic sodium ethoxide, compounds 618-d cyclized to the sodium derivatives 62a-d which, upon acidification, gave the respective pyrazol3-0~5 derivatives 63a-d (97JHC389) (Scheme 19).

-

MeOHIA

I4 (27)

(60) EtONa

Me

Ar $

‘N

(a)

Ar (b) Ar (c) Ar (d) Ar

= = = =

Ph 4-MeCBH4 44X2& 4-M&C&b

m

a

‘H

Sec. KA]

A

PYRAZOL-3-ONES

Me

n-BuLi t THF

+

HzNNHPh

-

I

Ai

Et

Ar

OEt

-?-If I

0

““i”

Ph

(70)

(71) (a) Ar = Ph, (b) Ar = 4-MeOGH4,

-

0

167)

(66)

+

,N “Y Ph

OEt

I=

Ph

(69) (c) Ar = CFC6Hd.

(d) Ar = WeC&,

(e) Ar = CiCeH4, (f) Ar = 2-PhGH4

SCHEME 20

In an altogether different type of approach, the hydrazone is formed in situ as a lithium salt. Wilson et al. (SOJHC389) described this approach in the one-pot synthesis of 5-aryl-2-phenylpyrazol-3-ones 72a-f from the corresponding hydrazones 65a-f (Scheme 20). The latter were obtained by condensing ketones 64a-f with phenylhydrazine. Treatment of hydrazones 65a-f with n-butyllithium in dry THF, followed by the addition of half a molar equivalent of diethyl carbonate 67 and then quenching the reaction mixture with hydrochloric acid, produced pyrazol-3ones 72a-f, along with products 71. The yields of the products 72 are in the range 22-97%. Four intermediates--&a-f, 68a-f, 69a-f, and 7Oa-f-were proposed for this reaction. e. By Reaction with Hydrazides. In the reaction of B-keto esters with hydrazides to give pyrazol-3-ones, the most frequently used ester is ethyl 3-oxobutanoate. Other esters that have been used are ethyl 3-oxohexanoate and ethyl 3-oxo-3-phenylpropanoate. Among the hydrazides used are alkylhydrazides, arylhydrazides, heteroarylhydrazides, aryloxymethylhydrazides, 1-styrylhydrazide, and 1arylsulfonylbydmzides. The reaction conditions vary from heating under reflux in an alcohol with or without an acid or base, to boiling in 1,Zdichlorobenzene, to fusion at 120 or 140°C. A widely used approach is the condensation of (amino, methylamino, or ethylamino)benzohydrazides 73a with ethyl 3-oxobutanoate in boiling ethanol

90

GEORGE

VARVOUNIS

et

al.

[Sec. I1.A

/ Me “PM”

+

H$lHNCOR

-

0 +c

0

(27)

N

!N R

(731

(4Rl-t-d ‘Rl

R’=H,MeorEt

@) R = 2-CIC&ig, 2A-MezCgHS or4-Me&C& (e) R = CH2G2,4-Me&J-i3. CH+3-fde,4-CICel-&

WR=

-J-Q,

(e)R=

bR2

or f&O-3.5Me&H,

R’ = 3-Me, Rz = Ccl, R’= ti = 2,4-Mez, or R’ = H, R2 = CMe&

4

.R=-cmR’

R’=Ph,R2=Me,CIorBr or R’ = H. R2 = MeO, Cl or Br

Rt=HorNq ScEiEME 21

containing p-toluenesulfonic acid. The corresponding pyrazol-3-01~s 74a were obtained in good to excellent yields [88IJC(B)342] (Scheme 21). The reaction conditions differed slightly from the ones used for the analogous reaction of arylhydrazides 73b and aryloxymethylhydrazides 73~ and 73d. Each of these compounds reacted with ethyl 3-oxobutanoate in refluxing methanol to give the wspective pyrazol-3-0~~ 74b-d (85JIC625; 92IJP165). lH-Indol-2-ylhydrazides 73e reacted similarly with ethyl 3-oxobutanoate to afford pyrazol-3ones 74e [88IJC(B)758], whereas the reaction of 2-(1,3-benzoxazol-2-yloxy)methylhydmzide 73f with ethyl 3-oxobutanoate required heating in ethanol to give pyrazol-3one 74f (87IJPS40). In the other extreme, ethyl 3-oxohexanoate 75 required fusion with 3-pyridylhydrazide 73a or 3-hydrazinocarbonyl-pyridine-1 -oxide 73b at 120°C in order to give the corresponding pyrazol-3-ones 76a,b (92AP1350) (Scheme 22). Depending on the reaction conditions, the reaction of ethyl 3-oxo-3-phenylpropanoate 77 and cyanomethylhydrazide 78 gave different products. Thus, fusion at 140°C gave pyrazol-3-one 79 and N,.N’-bis(cyanoacetyl)hydmzine 80, while heating in ethanol

91

PYRAZQL-3-ONES

Sec. ILA]

Me

EtolriP”

0

+

0

&NHNCOR

-

120°c

I731

!N

K

(a) R = 3-pyddyl (b) R = Spyrtdyl-l-oxide

OLR

(75)

(73)

Etw ij

t

+ ,+#-,N~O~,,2~N Oqph +

ti

(76)

W (79)

(77) (106)

(NCCli2CON~2

1EtOH I piperidine IA

SCHEME 22

containing piperidine gave a mixture containing pyrazol-3-one 81, pyrazolo[3,4-b] pyridin-3-one 82, and pyridine 83 (79PJC2225; 92AF1350). 5-Aminopyrazol-3ones have also been synthesized from /I-cyan0 esters (Section II,A,2) and from j!-imino esters (Section II,A,3). The reaction conditions in these condensations are very important in order to achieve optimum results. This can be seen from the following reactions. The preparation of pymzol-3-ones 85a was undertaken by refluxing the appropriate 1-arylsulfonylhydrazide 84a with ethyl 3-oxobutanoate in ethanol containing glacial acetic acid (69JMC726) (Scheme 23). On the other hand, S-hydroxyquinoline5sulfonylhydrazide 84b required first fusion with ethyl 3-oxobutanoate at 21OT and then refluxing in ethanol to give pyrazol-3-one 85b (91PS381). In the reaction of arylhydrazides 73a, benzylhydrazide 73b, aryloxymethylhydrazides 73c, or 1-styrylhydrazide 73d with ethyl 3-oxobutanoate in boiling dioxane, the corresponding hydrazones 86a-d were obtained in good yields. The latter

92

GEORGE VARVOUNIS et al.

[Sec. ILA

e EwMe

t 0

i+NHNSaAr

-

!N

As 7

0 (27)

(a) Ar = CMeOC,#&, 4-EtOC& (b) Ar = &hydroxy+quinolinyI

oy

WI

or Bz

Ar

W SCHEME23

proved difficult to cyclize and required heating under reflux in 1,Zdichlorobenzene to be converted into the corresponding pyrazol-3-ones 87a-d (89JIC135) (Scheme 24). Surprisingly, arylhydrazones 8Sa-d, upon treatment with l-benzenesulfonylhydrazide 89 in refluxing ethanol, afforded very good yields of pyrazol-3-ones 90a-d (85JIC54) (Scheme 25). 5-Aminopyrazol-3-o have also been synthesizedfrom/J-cyanoesters (Section II,A,2)andfrom /I-iminoestem (Section II,A,3). 2. From /3-Cyano Esters a. From Ethyl 2-Cyanoacetate, Ethyl 2-Cyano-3-(2-thienyl)-3-oxopropanoate, or Ethyl 2-Cyano-2-(9H-thioxanthen-9-yl)acetate. The introduction of an amino

group at position 5 of the pyrazol-3-01~ ring is best achieved by fusion of #Lcyano esters with hydrazines. Treatment of ethyl 2-cyanoacetate 91a with hydrazides 73a-e afforded amidrazones 92a-e which cyclized in the presence of a base to give pyrazol-3-ones 93a-e in 60-75% yields. An NMR study of ketones 93a-e revealed that in DMSO-4 these compounds exist primarily as enols 94a-e (Scheme 26). Reaction of ethyl 2-cyanoacetate 91a with 8-hydroxy-fiquinolinesulfonylhydrazide 2a at 210°C in the presence of sodium ethoxide, followed by heating under reflux in ethanol, yielded 5-aminopyrazol-3-one 95a (91PS381). Shafei and co-workers obtained4-(2-thienoyl)pyrazolone 95b by heating under reflux ethyl 2-cyano-3-(2-thienyl)-3-oxopropanoate 91b and hydrazine hydmte in ethanol containing a catalytic amount of piperidme (92PS121). ElSakka and co-workers found that a higher-boiling solvent, n-butanol, was requited

Me

Et

+

l+NHNCOR

dilxene -

IA

“y-J”

CIA

J *

NHN

=-f-T0

127)

IW

CA

R

CA

SW (a) R = 2-CI.Cm (c) R = C&OCI&

or 4-MeOC&, or 3,5-W&&&, or 2-Cl4-U or 2-NO$&H,OC~. S-24

(37) lb) R = CWh WI R = Cd+&-

R

93

PYFazoL-3-oNEs

Sec. KA]

+

ti@NHS02Ph

-

EtOiiIA

(89)

(90) f%XEME 25

to condense 2-cyano-2-(9H-thioxanthen-9-yl)acetate 91c with hydrazine hydrate in order to obtain 4-(9H-thioxanthen-9-yl)pymzolone 95~ (94AP133). Shafei and co-workers used reaction conditions similar to those used for the condensation of ethyl 2cyano-3-(2-thienyl)-3-oxopropanoate 91b with phenylhydrazine and isolated pyrazol-3-one 96in 77% yield (91PS381). S-Aminopyrazol-3-ones have also been synthesized from #?-keto esters (Section II,A,l,e).

tdl

R = PhCH, ie j R = 4-CIC&iH,

(R’ = H) HzNHNCOR (75) R’

E

-I+

N

0

+

4NHNR

-

(2)

lW

WI

(b) R = H, R’ = 0

(9-d

+

EtCtl I piperidine H2NNHPh

*

SCHEME 26

94

GEORGE

+

ArNHz

VARVOUNIS

et al.

[Sec. 1I.A Toluene

MeOH / tolueoe

I AiWHNHP *

16hlR.T.

16hlA

(97) R = Me or Et

NHAAr -f--jfNMr

MeONa / MeOH,

oQN

I h/A

HN’

kt

k

(a) Ar = 2-NO&&, At = 2,4,6-(Cl)&& (b) Ar = P-CMNO&H3. AI’ = 2,4,6-(C1)&Hz

10% aq. NaOH (S7)R=MeorEt

+

HCI-YNH

MeOHIA

Cl (101)

SCHEME 27

3. From B-Imino Esters a. FromEthylor Methyl3-Ethoxy-3-iminopropanoates. Both .5-amino-2-aryland 2-aryl-5-arylamino-pyrazol-3-ones can be conveniently synthesized by this method. Ethyl 3-oxopentanimidoate hydrochloride 97 (R = Et), derived from 3-oxopentanenitrile and ethanolic hydrogen chloride (Pinner synthesis), was treated with 3-nitroaniline or 2-chloro-5nitroaniline to afford imidoates 98a,b, respectively. The latter were heated with l -(2,4,~trichlorophenyl)hydrazine to give hydrazones 99a,b. Heating hydrazones 9!h,b under basic conditions afforded pymzol-3-ones lOOa,b (7OGEP1935272; 79IHC1279) (Scheme 27). Direct reaction of imidoate hydrochloride 97 (R = Me or Et) with I -(2,4,6-trichlorophenyl) hydra&e hydrochloride in refluxing methanol containing 10% aqueous sodium hydroxide gave 5-aminopyrazol-3-one lOl(88CHS153) (Scheme 27). For other syntheses of 5-aminopyrazol-3-ones, see Sections II,A,l,e and II,A,2.

4. From fi-Enamino Esters a From Ethyl 3-Amino-3-(4-substitutedphenyl)prop-Zenoates. Braibante and co-workers studied the cyclization reaction of fi-enamino esters with methyl hydrazine both in heterogeneous media, using montmorillonite K 10 as solid support under ultrasound conditions, and in homogeneous media such as refluxing in

Sec. &A]

95

PYRAZOL-3-ONES

E~cyqcYR “zNNHCH3, 8 andlor oqtfR 0

NH2

K-l 0 I ultrasound or CH2C12 I A

(103)

(102) (a) R = H, (b) R = Me.

(c)

R = Of@

ww (d) R =

NO2

SCHEME28

dichloromethane. The products were pyrazol-3-ones, and the regiochemistry of the cyclization reactions showed dependence upon the reaction conditions employed as well as upon the substituent in the aromatic ring. Therefore, cyclization of 102a under KlO/ultmsound conditions gave only pyrazol-3-one 103a, whereas in homogeneous media a mixture of pyrazol-3-ones 103a and 104a was isolated. The cyclization of 102b gave a mixture of 103b and 104b independently of the media employed. On the other hand, cyclization of 102~ under K 1O/ultrasound gave a mixture of 103~ and 104c, but in homogeneous media gave only 10%. Interestingly, the cyclization of 102d did not take place in any of the media, and it was suggested that this may be due to the influence of the aromatic ring bonded directly on the qknsaturated system (97JHC1453; 98JHC189) (Scheme 28). 5. From a,@-Unsuturated

Esters

a. From Methyl Crotonate and in Situ-Generated 4-Chlorophenyl Radical. Citterio and colleagues described the free-radical decomposition of 4-chlorobenzenediazonium tetrafluoroborate 105 by titanium chloride, which releases the 4chlorophenyl radical 106, where upon the addition of the latter to methyl crotonate 107 leads to pyrazol-3-one 110. It is proposed that radical 106 adds to both /? and o positions of 107, giving radical adducts 108 and 109, respectively. The a-adduct 108 further leads to pyrazol-3-one 110 whereas the #?-adduct 109 leads to the saturated ester 111. The yield of pyrazol-3-0~~ 110 was reported to be 60% (81 JHC736; 82JOCSl) (Scheme 29). 6. From Conjugated

Azoalkenyl Esters

a. From Ethyl or Methyl 3-[(2-(Amino- or anilinocarbonyl)diazenyl]but-2enoate, or Methyl or tertButy1 2-[(3-Ethoxy(or methoxy)-I-methyl-3-oxopropI-enylldiazene-I-carboxylate. Attanasi and colleagues have reported the synthesis of a large number of pyrazol-3-ones 115a-b by the reaction of conjugated azoalkenyl esters 112a or 112b with heteroarylthiols 113a or alcohols, phenols,

96

M

GEORGEVARVOUNISedal.

+ WW-fd (,os)

-

IMe

[Sec.1I.A

+

-&yy

I

Cl

“Y-Y”

WW-4

0

cBH4Cc4

(Ill)

(1W s-ME

29

or ethyl 2-mercaptoacetate 113b, respectively. The reactions proceed m one step or via the hydrazones 114s,b, depending on the reaction conditions (95JOC149; 971’5617) (Scheme 30). b. From Ethyl or Methyl 3-[(2-(Amino- or anilinocarbonyI)diazenyl]but-2enoate or Ethyl, Methyl, or tert-Butyl 2-[(3-Ethoxy(or methoxy)-I-methyl-3oxoprop-1-enylldiazene-I-carboxylate. Further investigations by Attanasi and co-workers revealed that reaction of thiocarboxylic acids 117a,b with conjugated azoalkenes 116a-g in ethyl acetate at room temperature gave hydrazone 1,4-adducts 118a-g. The reaction most likely takes place via conjugated Michaeltype addition of the sulfur atom of a thicearboxylic acid to the azoene system of the conjugated azoalkene. The ‘HNMR spectra of these intermediates in deuterochloroform solution showed that the hydrazone derivatives 11&k-c exist in nearly equimolar ratio as hydrazono/enamino tautomem, whereas compounds 118d-g exist only in the hydrazono form. The hydrazones 118a-g undergo intramolecular acyl substitution in the presence of sodium hydride to give 4,5dihydro-Wpyrazoles 119a-g as intermediates from which an alcohol molecule is eliminated to afford pyrazol-3-01~ 120a-g in moderate yields (96T1579) (Scheme 3 1). c. From Ethyl or Methyl 2-Bromo-3-[2-(4-nitrophenyl)diazenyl]but-2-enoate. Alkyl but-2enoates 12&b react with morpholine to give intermediates 122a,b

Sec. II.A]

PYRAZOL3-ONES

R’ = Me or Et

MaOH I NaOMe

(115) ,

R’=

a)-

R = CONH2 or CONHPh

or

f&

R=CONH2

(b) R = CO$de. CO@‘, CONH2 or CONHPh R’ = t&O, EtO, PhO, 4-NO&&O or Et02CCH2S SCHEME 30

that undergo ring closure followed by displacement of bromine by alkoxide to form pyrazol-3-one 123a,b (88JPR5 17) (Scheme 32). d. From Alkyl 3-[2-(Substituted carbonyl)diazenyl]but-2-enoate. introduction of a triphenyl-h5-phosphanyhdene group at position 4 of a pyrazol-3-one can be carried out by the reaction of diazenyl esters 124 with triphenyl phosphine. The reaction gives first the stable 15zwitterionic adducts 125 which tautomerize into the hydrazonic forms 126 that cyclize into the betain intermediates 127. The latter lose an alcohol molecule and give pyrazol-3-ones 128 (92T1707) (Scheme 33). Further work from Attanasi and colleagues involved reaction of diazenyl esters 129a-f with either N-methylglycine 130a or glycine 130b ethyl eaters in the presence of methyl acetate trihydrate to give a-aminohydrazones 131a-f. The latter underwent base-promoted heterocyclization to produce pyrazol-3-ones 132a-f (97122329) (Scheme 34). More recent work from Attanasi et al. describes the preparation of pyrrolepyrazol-3-one derivatives 136f-h by the sequential utilization of conjugated azoalkene species that ended by heteroring closure. In summary, diazenyl esters

98

GEORGE

R’

VARVOUNIS

SH I(

Ii

0

VW

NaH I THF

(a) R’ = Me (b) ti = Ph

(120) (a) (c) (a) (g)

R’ R’ R’ R’

= = = =

[SW.

et 01.

Ph. Ph, Me, Me,

R R R R

= = = =

CO$le; (b) R’ = Ph, R = CQEt; C@Bii; (d) R’ = Ph, R = CONb; CONHI; (f) R’ = Ph, R = CONHPh; CONHPh

R

w421 SCHEME 32

1I.A

Sec. ILA]

PYRAZOL-S-ONES

a (125)

(124)

R’ = Me or Et, R = C02Et, CONHz or CONHPh

CO$X4e3,

(127)

R30PfMe Et

0

N+

N

LONHR

(129)

+

Or

MeCO,Ne3H,O THF I MeOH

,R’ 0

x

.HC’

(1Ml

(131)

(a) R = Me, R = H, R’ = Me

OEt

(b) R = Et, R = H, R’ = Me (c)R=Me,R=Ph,R’=Me (d) R = Et, R = Ph. R’ = Me (e)R=Me,R=Ph,R’=H (f) R = Et, R = Ph, R’ = H

(132) SCHEME 34

GEORGE

VARVOUNIS

et al.

[Sec. I1.A

C&Et

NaH / THF t&OH I R.T.

(a) R = C(Mneh, R3 = Et (b)R=85.R3=Me (c)R=Me,d=Et (dJ R’ = NHPh (e) R’ = Me (t) R = C(Meh, R’ = NHPh (g)R=Eu,R’=NHPh (h)R=R’=Me

(136) SW

35

133~c were reacted with l-amidopyrroles 134d,e to give the respective hydmzonk 1,4-adducts 135f-h. In the presence of sodium methoxide, adducts 135f-h were cyclized to the pyrazol-3-ones 136f-h (99SL1367) (Scheme 35). 7. From Acetylenes a. From Dimethyl But-2-ynedioate. 2-Hydrazinophenols 138a-e react with dimethyl but-Zynedioate 137 at room temperatum to give hydrazones 139a-e, which cyclize upon heating to afford pyrazol-3-one esters 140a-e (69LA159) (Scheme 36). When the reaction was repeated with 2-hydrazinocyclohepta[b] pyrrole, the yield of pyrazol-3-01~ 141 was only 2%, the ester 142 being the major product (91BCJ1704). Pyrazol-3-one acid 140f was prepared in two steps from 137 and phenyihydrazine. These two compounds condense when heated together and give hydrazone 139f, which is then cyclized in basic conditions and acidified to give the free acid 14M (73BSF2482).

b. From 1 ,I ,2-Trimethyl-2-(2-phenylethynyl)hy&azine. Croutte and coworkers reacted ynehydrazine 143 with phosgene and obtained, after dechloromethylation, 5-chloropyrazol-3-one 144 in 71% yield (9OBSF745) (Scheme 37). c. From Ethyl 2-Hydroxy-2-methylbut-3-ynoate or Ethyl 2-Hydroxy-2-methyl4-phenylbut-3-ynoate. For the synthesis of 4-hydroxypyrazol-3-one 146, ethyl

2-hydroxy-2-methylbut-3-ynoate 145 was heated with methylhydrazine without solvent. Similarly, ethyl 2-hydroxy-2-methyl+phenylbut-3-ynoate 147 reacted

PYRAZQLS-ONES

Sec. II.A]

R4

R3

+

HNMN

R’ (133)

(139) NHNH2 I ,C””

(140) (141)

~42)

(a)R4=OH,d=Me. RI-R3=H,(b)R4=OH,R5=Me,R1=CI,R2=~=H, (c)~=OH,R3=H,R1=R2=Cl.(d)R4=OH~R5=Me,R1=RZ=R3=CI, (e)R4=OH,R5=Me,R’=R3=H,RZ=C02Et,(fjR1-R5=H SCHEME

36

ph\C \

/N--Me

20% COC12 I toluene * 5’C to 110°C/0.5

Me-N,

h

H

(143)

w4 SCHEME

37

GEORGE

bNNHMe

-

VARVOUNIS

[Sec. KA

et al.

A

w65)

HflNHz-l+O

I A

I--

WV blfjH~~~ HflNHMe

-

Ml;

IA h

fhe

(149a)

(149b)

SCHEME 38

with hydrazine hydrate or methylhydrazine to give the 4hydroxypyrazol-3-ones 148 and 149a, respectively. A probable reason for obtaining tautomer 149a instead of 149b is that the former is less acidic (84BSF129) (Scheme 38). 8. From a&Acetylenic

Esters

a. From Ethyl 3-Phenylprop-Z-ynoate. The reaction of ethyl 3phenylprop 2-ynoate 150 with hydrazine hydrate 2 (R= H) at low temperature or phenylhydrazine 2 (R=Ph) at ambient temperature gave the corresponding hydrazides lSla,b. When the latter were heated above their melting points, pyrazolS-ones 152a,b were isolated, respectively. When, however, the reaction was repeated in refluxing ethanol, pyrazol-3-ones 154a,b were isolated, being formed via the intermediates 153a,b (7OTL875) (Scheme 39). Derivatives 154~ were obtained similarly from ethyl 3-phenylprop-2-ynoate 150 and 4-methoxy- or 4-nitrophenylhydmzine (94T895). Methyl 3-alkylprop-2-ynoates and alkyl hydra&es have given 2,5-dialkylpyrazol-3-ones (71 JOC2542). b. From Ethyl 3-Phenylprop-2-ynoate ynoate. 2-Phthalazin-I-ylpyrazol-3-ones 1-hydrazino-phthalazine

or Ethyl 3-(4-Acetylphenyl)prop-2156a,b were obtained by heating

155 (R = H) with ethyl 3-phenylprop-2-ynoate

150

Sec. ILA]

103

PYRAZOL-3-ONES Ar

Ar

E R=H/O’C

(lfw +

uw

(~52)

HzNHNR

‘2)

1 EtOH/At

[ jj]

)

0 (a)R=H,Ar=Ph (b) R = Ph, Ar = Ph (C)R = 4-WC&, or 4-NO&H,,

qA’

t VW

VW

Ar = Ph

SCHEME 3’1

(Ar = Ph) or ethyl 3-(4-acetylphenyl)prop-2-ynoate 150 (Ar = 4-MeCOC&) in ethanol (SlPHA472) (Scheme 40). The synthesis of derivatives 156c,d from ethyl 3-phenylprop-2-ynoate 150 (R = Ph) and I-hydrazino-4-phenylphthalazine 155 (R = Bz) or 1-hydrazino4benzyl phthalazine 155 (R = Bz) worked equally well in methanol at room temperature for 72 h or in refluxing methanol for 1 h (91PHA105). 9. From Dialkylmalot~utes a. From Dimethyl (Methoxymethylene)malonate or Diethyl2-Acetylmulonate. Heating dimethyl (methoxymethylene)malonate 157 and methylhydrazine under

(150)

(155)

(a) R = H, Ar = Ph, (b) R = H, Ar = 4-MeCOC+14, SCHEME 40

(1W (c) R = Ph. Ar = Ph, (d) R = Bz, Ar = Ph

104

GEORGE

Yl=cz+

H$+HNMe

4

VARVOUNIS

et al.

[Sec.

1I.A

M&HlA -

R

E

0

OEt

+

YNNMe2

0

(a) R = Me (b) R=Ph (c) R E C&(CO)#CcCy

reflex in methanol for 4 h afforded methyl 5-oxopyrazole-4-carboxylate 158 (SSJOCSlO) (Scheme 41). The reaction took a different route, producing pyrazolone aminimides NOa-c when diethyl2acetyhnalonate 159a, diethyl2benzoylmalonate 159b, or diethyl2-[2-(phthalimidyl)acetyl]malonate 159c were heated with 1,l -dimethylhydrazine in glacial acetic acid at 80°C (SOTL5059). 10. From Succinates a. From Diethyl2-Oxosuccinate, Dimethyl 2-Oxosuccinate, Diethyl2-Methyl3-oxosuccinate, or Diethyl 2-Acetylsuccinate. Diethyl 2-oxosuccinate 162, formed in situ by the action of sulfuric acid on sodium 1,4-diethoxy-1 A-dioxobut2-en-2-elate 161, was heated under reflux in ethanol containing hydrazine hydrate to afford pyrazol-3-one 163 (82JOC214) (Scheme 42). A similar reaction of diethyl 2-methyl-3-oxosuccinate 164 and hydra&e hydrate gave pyrazol-3-one 165. Hydrazone 166, derived from dimethyl 2-oxosuccinate and 3-chloro-Ghydrazinopyridazine, was converted into pyrazol-3-one 167 in 90% yield by heating in ethanol with a base (83H765). A neat method to introduce an ethoxycarbonylmethyl group at position 4 of a pyrazol-3-one ring is the condensation of diethyl 2acetylsuccinate 168 with hydrazines. Sawhney and colleagues used 2-hydrazino4-aryl-1,3&iazoles 169a and 2-hydrazino-1,3henzothiazoles 169b in this reaction and obtained the corresponding pyrazol-3-ones 170a,b [82JJC(B)869]. 11. From y-Nitru Esters a. From Ethyl 34Vitropropionate. Reaction of ester 171 with aryldiazonium chlorides in ethanolic sodium ethoxide yielded hydrazones 172a-e. The latter were converted into pyrazol-3-ones 174a-e by catalytic hydrogenation. The reaction

PYRAZOLS-ONES

Sec. ILA]

0 E Et ‘4661’

Me

+

H$JHNAr

AcOHlEtOH

W9)

a (170)

wAr= y* R=H,CI,OMeorNq R = H. CL. or Er

SCHEME42

proceeds probably via cyclization of intermediate amidrazones 173a-e in situ (83JHC773) (Scheme 43).

formed

12. From /I-Keto Amides a. From 3-Oxo-N’,N5-diarylpentanediamides, N-Hydroxy-3-oxo-N-phenylbutanamide, or 3-Oxobutanamide. When acetonedicarboxylic acid dianilides 175a-d are refluxed in glacial acetic acid with phenylhydrazine or 2,4-dinitrophenylhydrazine, pyrazol-3-01~ 177a-d are obtained via arylhydrazones 176a-d. The synthesis of 2-unsubstituted pyrazol-Zones 177e required that dianilides 175a,c,d be treated with hydrazine hydrate in refluxing ethanol (79JPR1047) (Scheme 44). The reaction of N-hydroxy-3-oxo-N-phenylbutanamide 175

GEORGE

VARVOUNIS

et al.

[Sec. 1I.A

(a) Ar = Ph

(a) Ar = 4-CIcfi

(R’ = OH, R” = Ph, R’ = Me) with hydrazine hydrate or phenylhydrazine requires mild conditions, stirring in chloroform at room temperature, to give pyrazol-3ones 177f,g (81CPB244). A brief 20-min heating of 3-oxobutanamide 175 (R’ = R” = H, R’ = Me) and N’-phenyl4hyd-1 -benzenesulfonamide at 70-75°C in water gave pyrazol-3-01~ 177h (94JOU780). On the other hand, hydrazone 176i

-

(176) (a) R’=H,R”=Fh,R=Ph,R’=CH$CWPh (b) R’=H,R=Ph,R=2&(NC&C& R’ = C~HPh Q R=H,R”=CMeOC&.R=2,4+O&C&, R’ - CH~coM~OMe(4-) (d) R’ - H, R” = 4-C&H4. R = Ph, R’ = CycONHC&Cl(4-) @)R=H.R1=~.4-WX+H~w4-CQH4 0 R-oH,R~-P~,R=YR’=M~ (tllR’=OH,R’=Ptl.R=Ph.R’=Me (~)R’=R”=H,RP~-~~N~,R’IMB (I) i3; = R” = N(CH#&O, R = H, = I

$e”BIA I R’

(178)

PYRAZOL-S-ONES

Sec. KA]

(a)R=Ph (b) R = f’W%k (c) R = (M+C+iCH,

(1432)

Me CH&H(Mek

“I/u O”N’

NH

N&Me MeoH17ooc

&ml

proved to be very stable: refluxing in xylene was required for its cyclization into pyrazol-3-one 178i (91JMC1440).

13. From ,i%Hydrazino Esters a. From Methyl 3-(2-Benzoylhydrazino)-2,2-dimethylpropanoates. Hydrazino esters Ma-c, derived from the cormsponding benzoyl hydrazones 179a-c and silyl enolate 180, were converted into the respective 2,4-dihydropyrazol-3-ones 182a-c in high yields by heating in methanolic sodium methoxide. Likewise, hydrazinoester 183 gave 1,2-dihydro-3f-Z-pyrazol-3-one 184 in 81% yield (98SL249) (Scheme 45).

14. From Hydrazono-

or Hydrazinoacetamides

a. From3-Hydrazinopropanamide. Heating 3-hydrazinopropanamide 185 and cyclohexanone gave hydrazone 186 which was hydrogenated with Adam’s catalyst at 120°C and 200 atm to afford, via intermediate 187,2-cyclohexylpyrazolidin-3one 188. Treatment of 188 with tosyl chloride in pyridine and detosylation of the resulting 1-tosyl derivative in the presence of sodium hydride afforded pyrazol-3one 189 (66AG676) (Scheme 46). b. From 2-Cyano-2-(Z-arylhydrazorw)acetamides. Heating hydrazonoacetamides 19Oa-c with hydrazine hydrate at 100°C gave pyrazol-3-ones 191~c in excellent yields [87IJC(B)832] (Scheme 47).

108

GEORGE

VARVOUNIS

et al.

[Sec. 11-A

(1W

(188) YIfWi

J20% \ t3P

dN

I200

atm.

(i)TSCI/ppi!lilW TH

- (ii) NaH

-

[ “.+&)

(18’11

b

(1881

VW

s-46

15. From 2-Oxo-3-hydrazonopropanoic

Acids

a. From 2-0xo-3-[2-phenyldiazenyE]-3-[2-phenylhydrazono]propanoic

Acid.

Reparation of a stable 4-gem-diol-pyrazol-3-one has been reported by Neugebauer and Fischer. Thus, cyclization of hydrazonopropanoic acid 192 with zinc chloride as a catalyst gave 4,4-diiydroxypyrazol-3-one 193 (79CB1477) (Scheme 48). 16. From Hydrazides

a. From 3-Ethoxy-N’-phenylprop-2-enohydrazides. Hydrazides 195a-q derived from #kthoxyacryloyl chlorides 194a-c and hydmzines 2, were cyclized in concentrated hydrochloric acid into pyrazol-3-ones 196a-c (69CB3260) (Scheme 49).

NH#l&Of

100°C

Sec. ILA]

PYRAZOL-3-ONES

109

0 H

bN,P” 3%

0

HN’

t

(i) ZnCc,

I AqO

(ioH

t’h

Ah

(193)

VW SCHEME 48

b. From 3-Chloroprop-2-enohydrazides. The use of symmetrically disubstituted hydrazines 19&1-c in the reaction with 1,3-dichloroprop-2en- 1-ones 197a-c gave pyrazol-3-ones 2OOa-c via hydrazides 199a-c. The use of monosubstituted hydrazines 2d-f, instead of hydrazines 198a-c, afforded two isomeric pyrazol-3ones, 201d-f and 202d-f (6933453) (Scheme 50). c. From N’-Phenylbenzothiohydrazide or 3-Oxo-N,N’-diarylbutanohydrazides.

The pyrazol-3-01~ ring can be constructed from N,N’-disubstituted hydrazines or N-substituted thiohydrazides and acetic anhydride in the presence of a heterocyclic base. Using this method, thiohydrazide 203 was converted into pyrazol-3-one 204 [76JCS(P1)38], whereas N,N’-diarylhydrazines 205a-e gave a mixture of pyrazol3-ones 208a-e and 209a-e. Intermediate hydrazide 206 either cyclocondenses directly to product 209 or is N-acetylated to intermediate 207 which cyclizes to 208 via an internal aldol condensation and subsequent dehydration (91M537) (Scheme 51). d. From Cyanoacetohydrazides. The introduction of an amino group at position 5 of a pyrazol-3-one may be achieved by base-induced cyclization of cyanoacetylhydrazines. Latif et al. reported the cyclization of cyanofluorenylacetylhydrazines 210a-e into 5-amino-4-fluorenylpyrazol-3-ones 211a-e in good yields (77AJC2255) (Scheme 52).

(I=)

VW (a)R=Ph.R’=H (b)R=Ph.R’=Me (c) R = (Cl-&R,

SCHEME 4’1

R’ = H

R’NHNHd:

-

(d)R’=Me,@=Et,d=ti=Me (e)R’=Ms,ti=Et, R3=ti=Et (f)R’=Ph,ti=Et, R’=R’+Ei

(202)

SCHEME so

(e)R=:Bt

Sec. ILA]

111

PYRAZOL-3-ONES

lalR=H NaOMe

I MeOH (e) R = CH2Ph

lh (2fO)

e. From NJ’-Diacyl-N,N’-dimethylhydrazidees. Magedov and Smushkevick reported a new method for the synthesis of pyrazol-3-ones from N,N’-diacyl-N,N’dimethylhydrazines which involves an intramolecular aldol condensation. In the first step the monoenolates 213a-i are formed by the reaction of hydrazides 212a-i with either phenyllithium or lithium bis(trimethylsilyl)amide. Intramolecular aldol condensation of compounds 213a-i gives alkoxides 214a-i that react further with the base to provide the dianions 215a-i from which lithium oxide is eliminated to afford pyrazol-3-0~~s 216ai (91CHE741; 913845) (Scheme 53).

f. From Ethyl 3-(1,2-DimethyE-2-propionylhydrazino)but-2-enoate. Endo and Shudo cyclized hydrazide 217 with LDA in a step that involves intramolecular addition of an enolate carbon atom to the iminium group of the intermediate 219. The intermediate pyrazolidinone 220 formed loses a molecule of ethyl acetate to give pyrazol-3-one 221(92H91) (Scheme 54).

PhLi or LiN(BiMe~2 Et20 I HMPA or TMEDA I THF I-78%

(214 (a) R’ = Ph. ti = Me, Et, i-Pr or Bz (b) R’ = I-naphthyl. ti = H or Me (c)R’=+=Me (d)R’=Ph,R2=H (a) R’ = H, ti = Ph (I) R’ = Me, ti = CH$H$‘h (a) R’ = Bz, ti = Et (h) R’ = 3-lndolyt. ti = Me (i) R’=Ph,R’=Bz

1

25

R2

T.-Ml3

@IV SCHEME 53

z?E-

W(5)

GEORGE

-

VARVOUNIS

et al.

[Sec. 1I.A

-

g. From 3-Chioro-N’-(diphenylmethylene)propanohydrazide. Greenwald and Taylor described the intramolecular dehydrogenation of ptopanohydrazides 222a-c that gave the inner salts 223~c. The diphenyl derivative 223a was converted into pyrazol-3-one 224 by treatment with potassium t-butoxide in refluxing benzene (68JA5273; 81 JA7743) (Scheme 55). 17. From a,fi-Unsaturated

Hydrazides

a. From Acrylohydrazides. Pyrazol-3-ones 226 have been prepared by palladium-promoted cyclization of hydrazides 225; however, yields are moderate and no attempt has been made to effect a catalytic conversion (76CIL1032) (Scheme 56). 18. From Iminopropanediones a. From 1,3-Dichloro-3-(cyclohexyexylimino)propane-I ,2-dione. Treatment of dione 227 with 1,2diphenylbydrazine 22Sa or 1,2-bis(3-chlorophenyI)hydrazine

Rz-

N8H

KOButlO,&lA

(a) R’ I f$ = ph, @) R’ = t8u,

R2 = Ph, (c) R’ = H. ti

SCHEME 5.5

= Ph

Sec. KB]

113

PYRAZOL-3-ONES

(229 R’=P?=H,alkylorPh SCHEME 56

228b at a low temperature afforded pyrazol-3-ones 230a,b,respectively (88LA132) (Scheme 57). B.

SYNTHESIS

THREE-MEMBERED RINGS

FROM

I. From Cyclopropenones a. From 2,3-Diphenylcycloprop-2-en-l -one. The reaction of cyclopropenone 231 with hydrazines leads to pyrazol-3-ones 232a-g. The reaction is postulated to occur by initial addition of 2 mol of a hydrazine, ring opening with loss of an amine, reversible ring closure of the resulting cmnamohydrazide to the corresponding pyrazolidinone, and loss of ammonia to afford the appropriate pyrazol-3-one (87H79) (Scheme 58). 2. From Diaziridinones a. From 1,2-Diftert-butylj-l,2-diaziridin-3-one. Komatsu and co-workers studied the ring opening of diaziridinone 233 with in situ generated m-lithiopropionitrile 234a which afforded the 1: 1 adduct 5aminopyrazol-3-one235 in 93% yield

Q 23 H

+

RNHNHR

-

N-H

7-R

ww

(a)R=Ph,(b)R=34C& SCHEME 57

GEORGEVARVOUNISetal.

114

EtOH P

[sec. 1I.C

I NaOH

Ph

(232) (a) R = Ph, (b) R = H, (c) R = Me. (d) R = (f) R = 4-NWeH4. (01 R = ZYNWzW3

4-MeCBH4,8)

R=

MIc6H4,

SCHEME 58

(9OTL5327) (Scheme 59). Under similar conditions, reaction of 233 with in situ generated a-sodium benzylcyanide 234b gave iminopyrazol-3-one 236 and aminopyrazol-3-one 237 in 80 and 16% yield, respectively (9OTL5327). If the nucleophiles in the reaction with 233 are sodium malononitrile 238a or sodium a-cyanoacetamide 2388, the products ate the expected 5-aminopyrazol-3-ones 239a or 239b, which are obtained in 92 and 19% yield, respectively, analogously to the previously described reaction. When, however, sodium methyl 2-cyanoacetate 240 and 233 were reacted, they gave, along with the predicted 5-aminopyrazol-3one 241, the spiro compound 242 and the acyclic adduct 243 (92JOC7359).

C. SYNTEXE~I~FROMFIVE-MEMBEREDRINGS

1. From Pyrrolidinones An interesting ring transfora. From 5-fBenzyloxycarbonyl)pyrrolidin-2-one. mation of pyrrolidmone 244 into pyrazol-3-one 248 was reported by Bowler et al. [91JCS(CC)314] (Scheme 60). Pyrrolidinone 244 was converted into the cortesponding enamine 245 using tert-butoxybis(dimethylamino)methane. Hydrolysis of enamine 245 to the aldehyde 246 required very carefully controlled acidic conditions. When 246 was treated in situ with 4nitrophenylhydrazine at pH 5, pyrazol-3-one 248 was obtained via intramolecular rearrangement of intermediate 247.

sec.ILC]

PYRAZOL-3-ONES

+ 1%’ c--g + bsicN -EL Y0d ww (233) Na+ PhCHCN

I P

I THF

WW NH

25

+

J%“’ r?

ww

(237)

Na+

B”’

0=-g + YBu’

(i) RikN

i THF (238) (8) R = CN (b) R = CONH2

(i) H+

(239)

Nzi+

(ij h4eO&HCN (i0 H’

(240)

P”’

+ (241)

(242) SCHEME 59

2. From Furanones A freqnently used transformation of a five-membered ring with one heteroatom to a pyrazol-3-one is that from furanone derivatives. Venturello and D’Aloisio reported the a. From 2,-T-Dimethylfuran-3(2H)-one. azo coupling of furanone 249 with arenediazonium salts 250a to give Z-arylazo

116

GEORGE VARVOUN’IS et a~.

[sec. 1I.C

(247)

SCHEME60

derivatives 251a. Upon acidification, compounds 251a afforded pyrazol-3-ones 252a. Yields are moderate, but good yields am obtained for substrates withelectronwithdrawing substituents on the phenyl ring (798283) (Scheme 61). Using similar methodology, Ahnerico and Boulton [85JCS(CC)204] reported the synthesis of pyrazol-3-01~ 252b. b. From 3-Acetyldihydrojiwan-2(3H)-one. Several approaches can be used to introduce a hydmxyaJky1 group in the pyrazol-3-one ring. An approach that introduces a hydroxyethyl group at position 4 of the pymzolone ring requires reacting 3acetylfuranone 253 with either aryl hydrazines in the presence of sodium ethoxide or with aminoguanidine bicarbonate. The reaction of 253 with ethoxide is postulated to give first the intermediate keto ester 254 which reacts with hydrazines 255a-d to give pyrazol-3-ones 256a-d. Yields are in the range 5776% (84CZ285) (Scheme 62). The cyclocondensation of 253 with aminoguanidine bicarbonate gives pyrazoL3-one 257 in 76% yield (88EJM349). There are two methods for the introduction of a hydroxyaJky1 group at position 5 of the pyrazol-3-one ring. Schmidt and Zimmer converted furanediones 25Sa-k into arylmethylenepyrazol-3-ones 259a-k regiospecificahy by reaction with hydrazine hydrate or methylhydmzine (83JOC4367) (Scheme 63). The mechanism proposed for the reaction involves nucleophilic attack of the hydrazine on the ketone carbonyl, followed by attack on the ester carbonyl and ring opening of the

117

PYRAZOL-S-ONES

(250)

(249)

wnc.

HCI

- -Ii+ OH

Me

(a) R = H, 2-Ma, 3-M+, 4-Ms. 3,5-(Mf~)~, 2-MeO, z-cc%+, 2-CQ#e. 4-a. 2.5-m2, 2,4.5-m, 3-N@, 4-Ne.4-OH of

4-W&

(b) R = NQ

(252) SCHEME 6 I

P’

(a)R’=H.ti=CI (b)R’=R*=CI (c) R’ = H, ti (d)R’=H,R’=Me

M”

l$NHN/c‘Nl-!+CO,

SCHEME 62

= Ne,

“S

118

GEORGE VARVOUNIS eral.

[sec. I1.C

R’HNH

(a) R’ = H. $ = 3Am%hylenWoxy, (b) R’ q H. $ = 3,4.3-trime#~my. (c) R’ - H. $ = Cdrbro (d) R’ = H. + - Z-chbm. (t) R’ = Me, ti = m, (0) R’ = Me, @ = 3,4-metJ’1ylenedi0~y (h) R’ = Me, ti = 3,4dhWhoay, (i) R’ = Me, d: = 3,4,Bb’bneUmxy, 0) R’ = Ma, ti = 4-chbm (k)R’=Me,#=H SCHEME 63

resulting oxadiazobicycloheptane to give, after dehydration, the corresponding pyrazol-3-one. c. From Furan-2,3,4(5H)-trione 3,4-Bis(N-arylhydrazones). Furanonehydrazones 26Oa-h can be transformed into pyrazol-3-ones 261a-h upon treatment with 2 N sodium hydroxide. The reaction proceeds by lactone ring opening followed by ring closure involving the appropriate hydrazone residue (81PHA509; 88PHA77) (Scheme 64).

3. From Pyrazoles a. From Ary1(4,4-dimethyl-5-methylenepyrazol-l-yl)methunones, 3-Benzyl-4phenyl-5-hydroxy-IH-pyrazole, Ethyl 5-Hydroxy-I-phenyl-IH-pyrazole-4-carboxylate, or 2-[(I-Benzyl-IH-pyrazol-4-yl)oxy]acetic Acids. Pyrazol-3-ones 263~ were obtained in good yields by oxidation of the corresponding S-methylenepymzoles 262~ with 3-chloroperbenzoic acid (91JHC49) (Scheme 65). The use of tert-butyl hydroperoxide effected the oxidation of pyrazole 264 into pyrml3-one 265. Pyrazole 264 was synthesized by condensation of ethyl 3-0x0-2,4diphenylbutanoate with hydrazine hydrate [81JCS(P1)1371]. When pyrazole 266

Sec. KC]

PYRAZOL-3-ONES

2N NaOH 70 - 80°C -

(a) R’ (b) R’ (c) R’ (d) R’ (e) R’ (f) R’ (g) R’ (h) R’

= $ = S&NH-2-pydmidinyl, R3 = C&i&H(OH) = R* = SO$VH-2-(Cmethoxypyrimidinyl), R3 = C&l&H(OH) = R2 = WNHZ, R3 = 4-CIC&l&H(OH) = ti = S@NH-2-(4-methoxypyiimidinyl), R3 = 4-CIC&CH(OH) = R2 = S&NH-2-(4-methoxypyrimidinyl), R3 = 4-MeOC&l&H(OH) = ti = SQNHg R3 = 3-N02C6H4CH(Oti) = R2 = SO$JH-2-(4-methoxypydmiiiyi), ti = %FlO&H,CH(OH) = Ph. ti = 2-M&& ti = CH(OH)CH(Oti)CH~H SCEIEME64

(261)

was reacted with dimethyl sulfate in aqueous sodium hydroxide, pyrazole 267 together with pyrazol-3-one 268 were isolated in 16 and 33% yield, respectively (95JHC1341). The reaction of pyrazole acetic acids 269a-c with two equivalents of bromine in water gave the corresponding monobromopyrazol-3-ones 27Oa-c. When acids 269d,e were reacted with three equivalents of bromine, the respective dibromopyrazol-3-ones 271d,e were isolated (98JPR437) (Scheme 66). b. From 3-Methyl-lH-pyrazole-4,Sdione or 3-Aroyl-I-aryl-IH-pyrazole-4,5dione. Pyrazole-4Jdiones are converted into pyrazol-3-ones by nucleophilic addition reactions at the keto group. Thus pyrazole-4,Sdione 272 was reacted with either malononitrile or ethyl acetoacetate and a base to afford 4-methylenepyrazol3-ones 273a-b. Compound 272 was also reacted with primary abphatic amiues or with amino acids to afford bis(pyrazo13-one) 277, in most cases in excellent yield. The proposed mechanism predicts a transamination reaction of 272 with the amino component that proceeds via the imine intermediates 274 and 275. Addition of water to 275 and loss of the appropriate ketone gives 276 that transforms into 277 by air oxidation (848927) (Scheme 67). When pyrazoIe-4,5-diones 279a,b,d,e were heated with methanol, the 4-hydroxy-4-methoxypyrazol-3-ones 278a,b,d,e were obtained in good yields. In an

120

GEORGE

-

VARVOUNIS

[sec.KC

et al.

MCPBA

CH$&,

25’C

COAr

(a)R=Me.Ar=Ph,(b)R=Me,Ar=~MeCeH4,(c)R=Nle,Ar=s4-CICsH4 (d) R = H, Ar = 4-MeCgH4, (e) R = Ph, Ar = dMeQH4

h

(270)

(2W

(~)R’~~~,~Ic~,(~)R’~~=Me,(e)R’=CI,~=Me.(d)R’=~=~.(~)R’=~.~=~~ SCHEME 66

(271)

121

PYRAZOL-3-ONES

(a)R’=$=CN (b) R’ = COW

Rz = CO@

(273)

(272) H2NCHR’f+ H$IEtOH/A

(274

WW

(2751

(277)

(a)R’=~=H.(b)R1=H,dL=Me,(c)Ri=H.R2=Et,(d)R’=R2=Me,(e)R’=H.~=~2Me, (~R’=H.~=CH(Me)2.(g)R’=~=(~(h)R’=H.~=C~H,(t)R1=CH(MB)2.~=C~H, ()) R’ = CH$X-t)~, ti = CO& (k) R’ = Bz. ti = CQH, (1) R’ = CH2C&OH-4,

CW

(279)

(a) R’ =4-W&H,,. ti = Ph. (b) R’ = 4-Ma0, d = Ph. (c) R’ = 4-&C&~ R2=Ph,(e)R’=bN02~~R2~Ph,(1)R’=d:E6C)CdHq,(g)R’=6MBC$L~,R2=CMBOCBH4, (h) R’ = 4MeC& ti = &C&HI

ti = CO$4

ww R* = Ph, (d) R’ = 4-ClC&

SCHEME 67

analogous manner, heating pyrazole-4,Sdiones 279a-h in water afforded the 4,4-dihydroxypyrazol-3-ones 28Oa-h (92JOU302). 4. From koxazolones a. From 4-Acylisoxazol-5(4H)-ones or 5-Hydrazinoisoxazoles. The reaction of isoxazol-5ones 281a-g with hydrazine sulfate or phenylhydrazine yielded a tautomeric mixture consisting of pyrazol-3-01~s 284a-g and 3-hydroxypyrazoles 285a-g. The initial step of this reaction probably involves condensation of the hydrazine with the exocyclic carbonyl group to give 282. Intramolecular attack

GEORGE

(a) (b) (c) (d) (8) [f) (g)

VARVOUNIS

et

al.

R’ = H, $ = Ph. d - H R’=Ph,+=Me,d=H R’ = Ph, R2 = Me, R3 = Ph R’=Me,ti=Ph,#=H R’ = Me, R2 = Ph. R3 - Ph R’=Ph,$=Ph,R3=H R1=Ph,$=Ph,R3=Ph

@W

w4)

SCHEME68

of the hydrazone nitrogen of 282 onto the carbonyl group with the following ring opening/ring closure yields the unstable pyrazolone 283 that loses hydroxylamine to give the tautomeric mixture 284 and 285 (71S216) (Scheme 68). Adembri and co-workets found that thermal isomerization of 5hydrazinoisoxazoles 286a-d afforded a mixture containing mainly 1-aminopyrazolJ-ones 288~d, 4-aminopyrazol-5-ones 289a-d+ and 1,2,4-triazin-6-ones 290a-d. The ratios of these products am dependent on the nature of the substituents and the solvents used. A detailed mechanistic study is reported using substituted hydrazines. The rearrangement of hydrazines 286a-d is rationalized in terms of a transient diradical cyclizing into a W-azirine 287, which subsequently rearranges to the products f72JHC1219; 77JCS(P1)971] (Scheme 69). Further work by Adembri et al. describes the irradiation of 5hydrazinoisoxazoles 291a-b under nitrogen, which gives a mixture of products analogous to that obtained by thermal isomerization: 5-methylaminopyrazol-3-ones 292sb, 4-aminopyrazol-3-ones 293a-b, and 1,2,4-triazin-6-ones 294a-b (78TL4439).

5. From Oxazolones a. From 2-(4-Methoxyphenyl)-4-phenyl-l,3-oxuzol-5(4H)-one. A different synthetic approach to pyrazolones was used with 1,3-oxazol-5(4I+ones as the starting materials. Oxazolone 2% was reacted with hydrazonoyl chlorides 296a-b under phase-transfer conditions to give good yields of pyrazol-3-ones 298a-b, possibly via the imine intermediates 297 (88H141 I) (Scheme 70).

123

PYRAZOL-3-ONES

NHNHz

HzNH

-

$kR1 + :e’ + *r [ ‘$mp~f+~ A PW A rfiH, WV

(288)

(290)

(a)R=Ph,R’=H,

(b)R=Ph,R’=Me,(c)R=R’=Ph,(d)R=t&,R’=Ph,

(a) R = R’ = H. (b) R = Me, R’ = H SCHEME. 69

l-l \ 2 Q

,NHAr

Ph

Af lN+ +

0

(2W

\T

OMe

\

,c-cl

-

ROZC

W7)

(ZW

(a) R = Me, Ar = 3,4-(U)&H3, 3-C~4i,, 34tte~&, 3W&SsH3, =Ieoc$14,3-Me4grcBH, ‘-J’GM,, 3.-3W-h or 4cW4 (b) R = Et, Ar = Ph, 4-CNGJi4 or 3-NO&H4

M

1298) SCrnME

70

124

GEORGE

VARVOUNIS

et al.

[sec.

ILC

NH20H N-

(299)

(JW

WI) 0

R

I

--f

4

(a)Ar=Ph.R=Me (b) Ar = 2,4,6-(C&$,9&, (cl Ar = 2,4,6-(CI)&,HZ, ((0 Ar = 2,4&(Ct),C&,

KOHIEtOH/A

R = Me R = CH(C,H&QHg2.4-(rtrrt-pentyl)2 R = CH(Et)eH,-3-r+&,

SCHEME 71

6. From I ,2,4-Oxadiazoles a. From 2-(5-Alkyl-I,2,4-oxadiazol-3-yl)-N-arylacetamides. Kim and coworkers described the preparation of pymzol-3-01~ 303 by intramolecular rearrangement of 1,2,4-oxadiazoles 302. The overall synthesis requires four steps from 2-cyanoacetanilides 299a-d. Addition of hydroxylamine to the latter gives amidoximes 300a-d which are treated with an appropriate anhydride to afford oxadiazoles 302a-d via 0-acylamidoximes 301. Upon heating in a base, compounds 302a-d are converted into products 303a-d (84JOC5247) (Scheme 71).

7. From 1,3,4-Oxadiazoles a. From 1-(5-Alkyl or arylthio- I ,3,4-oxadiazol-2-yl)acetones. An acidcatalyzed rearrangement of oxadiazoles 304a-c into 1-acylpyrazol-3-ones 306a-c was described by Jonsson and co-workers. The reaction proceeds by cleavage of the oxadiazole ring followed by intramolecular condensation of the intermediate N’-acetoacetylhydde 305 (95SSO5) (Scheme 72). 8. From Sydnones a. From 4-Acetyl-3-arylsydnones. The transformation of mesoionic compounds 307a-g into pyrazol-3-0~s 313a-g occurs easily on reaction with hydrazine

sec.KC]

R~--+j,

PYRAZDL3-ONES

EtOH t2N

_

(304

(305) (a) R = MeS, (b) R = allylthii,

(c) R = CCCbenzytlhio

SCErEME 72

hydrate. The mechanism for the reaction was rationalized as follows. Initial attack of hydrazine at the sydnone acetyl group gives addition compound 308. From 308 two products are produced: stable 309 by deacetylation and intermediate 310 by dehydration. The latter cyclizes to bicycle 311. Loss of Ihe acidic hydrogen atom from 311 and subsequentrupture of the sydnone ring give intermediate pyrazolone 312. Finally, loss of nitrogen oxide ion from 312 affords the stable pyrazol-3-one 313 (99H95) (Scheme 73).

H2NNH2 I EtOH

(307)

VW

(a) Ar = Ph. (b) Ar = 4-MeCC&f4. (c) Ar = 2-MaC&L+, (e) Ar = 4-ClC6H4, (t) Ar = 2-FC$H,+ (g) Ar = 4-FC& SCHEME 73

(d) Ar = 4-MeC6H4,

126

GEORGE

(314)

VARVOUNIS

et al.

[sec.

KC

PW

(a) R

= H, (b) R = Me, (c) R = Ph (U) R’ = Ci$Ph, (e) R’ = Et,(f) R’ = CH&H=Cb

9. From Thiazolidinones a. From3-Alkyl-5-benzylidene-I,3-thiazolidine-2,4-diones. 1,3-Thiazolidine2,4-diones 314d-f were converted into pyrazol-3-0~s 318~ in relatively good yields by reacting with hydrazines 2a-c. The reaction proceeds via an addition compound 315 that rearranges into 316 to give, after elimination of an N-alkylthiocarbamic acid molecule, 317. The isolation of a mixture containing 315 (R = Ph, R’ = CH2Ph) and 317~ formed by treating 314d with excess phenylhydrazine supports this mechanism (81S742) (Scheme 74). 10. From Diazaphospholes a. From Intermediate Diazaphospholes. Baccolini and Sgarabotto introduced a mild route to (E)- and (Z)-2-alkenylpyrazol-3-ones 322a-h involving the onepot reaction of ketone alkylhydrazones 319a-h, phosphorus trichloride and methyl 3-oxobutanoate 9 at room temperature. The reaction is postulated to occur in two stages, first the formation in situ of chlorodihydrodiazaphosphole 320 in equilibrium with a hypothetical ring-opened product 321, then the addition of methyl 3-oxobutanoate 9 to 321 leading to a mixture of(E)- and (Z)-pyrazol-3-ones 322 [91JCS(CC)34; 92JCS(P1)1729] (Scheme 75). With the use of a variety of enolizable ketones for the preparation of hydrazones 319, the reaction always occurs with the predominance of the (E) isomer. X-Ray structure determinations of derivatives (E)-322~. HCl and (Z)-322b permitted the assignment of their structures.

Sec. II.D]

127

PYRAZOL-3-ONES

(319)

(320)

(321) MeC02CH2COMe 1

(9)

e (a) R’ = R* = Ph, (b) R’ = Ph, R* = Me, (c)R’ = Me, R2 = Ph (d) R’ = $ = Me, (e) R’ = Et, R2 = Me, (f) R’ = Me, R2 = Et (g) R’ = mPr, R2 = Et, (h) R’ = Me, R* = allyl

Z-(322)

+

di”

N flN’Me R’

-0

R2

E-(322) SCHEME 75

D. SYNTHESIS PROM SIX-MEMBERED RINGS 1. From Pyrimidinones a. From 5-Amino-6-methyl-3-phenylpyrimidin-4(3H)-one. The transformation of pyrimidin-4-ones into pyrazol-3-ones is not a synthetically useful reaction for the preparation of the latter. For example, Ueda and co-workers treated 5amino6-methyl-3-phenylpyrimidin4(3/f)-one 323 with hydrazine hydrate and obtained pyrimidin-4-one 326 and pyrazol-3-one 327 in 71 and 19% yield, respectively. The reaction proceeds by addition of hydrazine to C4 of 323 to give 324 that ring-opens to hydrazide 325 which then ring-closes to the products 326 and 327 (8OCPB2144) (Scheme 76). 2. From Pyrimidinediones a. From 5-Bromo-I ,3,6-trisubstituted Pyrimidine-2,4(1H,3H)-diones. The work of Hirota et al. refers to the transformation of pyrimidine-2,4-diones 328ax into pyrazol-3-ones 334a and 337b-c [82JCS(P1)277] (Scheme 77). According to a generalized mechanism, hydrazines add to C6 of 328 and the resulting adducts 329a-c ring-open to intermediates 33Oa-c. Intermediate 330a tautomerizes to 331a which then cyclizes to hydantoin 332a. Intramolecular amino group attack on the carbonyl group of 332a gives 333a from which N,fV’-dimethyhrrea is lost to furnish 334a. Intermediates 330b,c undergo an intramolecular &2 reaction and

0 Ph.

NY Me

wo

(323) -PhNH2

I

NY

HzN-.

e +

Me A

s-

77

(333)

PYRAZQLS-ONES

Sec. ILD]

R’ONa

I R’OH

(338)

IA

(339)

R’ (a) R = H, R’ = Et (b) R = Me, R’ = Et (c) R = H, R’ = Me ww

(341) SCHEME 78

ring closure to hydantoins 335b,e that undergo a similar intramolecular cyclization to 336b,c and then tautomerize to give 337b,c [82H2309; 85JCS(Pl)l137]. Kitade and co-workers heated 2,4-dioxopyrimidine-5carbohydrazides 338a,b in methanol or ethanol containing the corresponding alkali alkoxides and obtained pyrazol-3-ones 341a-c. The reaction involves an intramolecular attack of carbazido anion 339 onto C5, subsequent ring opening to pyrazol-3-one 340, and conversion of the latter to the ester 341[93JCR(M)lOl] (Scheme 78). b. From Uracil or Thymine. Reaction of uracil 342 with methylhydrazine at 80°C caused rearrangement of the pyrimiclme ring to give N-(l-methyl-fioxopyrazolidin-3-yl)urea 343 which, upon acidification, afforded 2-methylpyrazol-3-one 344. Similar treatment of thymine 345 with methylhydrazine afforded 2,4-dimethylpyrazol-3-one 346 directly [65LA134; 67JCS(C)1528] (Scheme 79). 3. From Tetrazines

a. From 1,2,4,.5-Tetrazin-3-yl(phenyl)methanol. The conversion of 1,2,4,5tetrazine 347 into pyrazol-3-one 350 is the only example of this type of reaction and requires tefluxing in methanolic potassium hydroxide. Initially, hydroxide ion attack at the ttrazine ring carbon and resultant loss of nitrogen gives intermediate 348 or its tautomer 349. The latter species ring-closes to 350 with loss of hydride ion [81JCS(P1)1371] (Scheme 80).

130

GEORGE

VARVOUNIS

[Sec. 1I.D

et al.

0 H.

r4

CP-/ k

I

+

MeNHNY

-

tie (340

(342)

0 Me +

MeNHNH2

+

-

H3NCONH2

SCHEME 79

4. From Pyranones a. From 2H-Pyran-2-ones. Heating phenylhydrazones of pyran-2-ones 351a-e in acetic acid resulted in their rearrangement into pymzol-3-ones 352a-e in 65-78s yields. The reaction involves nucleophilic attack of the aniline nitrogen at the C2 lactone carbonyl with simultaneous ring opening of the pyranone ring and ring closure to the pyrazolone ring (83JOC4078) (Scheme 81). Ayoub and Mohammad reported two examples of pyranone to pyrazolone interconversion. Pyran-2-ones 353 were reacted with hydrazine hydrate in refluxing methanol to afford pyrazol-3-ones 354 and hydroxypyrazoles 355 as tautomeric mixtures (84JHC1755). b. From Dehydro+ascorbic Acid Aryl Osazone. Khadem and El Ashry used mild oxidizing agents such as cupric chloride, ferric chloride, or iodine to convert osazone 356 (IX = H) into 3,6-anhydro-3-phenylazo-2-oxo-L-gulono-6-lactone PhvOH

-4

-

PYRAZOL-3-ONES

Sec. IKE]

131

0 0

R MeCQH

2

I A *

‘N

% d 6h

(353)

(354) R = Z-thienyl Scmm

(a) R’ = R2 = Me (b) R’ = Me, $ = Et (c) R’ = Me, R* = Ph (d) R’ = Ph. R2 = Me (e)R’=R*=Ph

(356)

or PhCH=CH 81

phenylhydrazone 357. Hydrazone 357 was then cyclized into pyrazol-3-one 358 by heating in 2 N sodium hydroxide solution. Osazones 356a could be directly converted into pyrazol-3-0~s 359a by treating with a base [68JCS(C)2248; 68JCS(C)2251] (Scheme 82).

5. From Oxazinones a. From (1,3-Oxuzin-3-ium-3-yl]henzenolate or Benzenethiolate. 4,4-Diphenylpyrazol-3-one 360 could be prepared from benzenolate 361 or from benzenethiolate 362 by reacting them with hydrazine hydrate in methanol. The former reaction requited heating, whereas the latter worked well at room temperature (73JOC2650) (Scheme 83).

E. SYNTHESIS FROMBICYCLIC~,~-MEMBEREDFUSEDRINGS

1. From Pyrazolopyrazoles a. From Pyrazolo[lZ-a]pyrazole-l,7-diones. Kosower and co-workers studied the reaction of pyrazolopyrazoledione 363 with acetyl hypofluorite at -75°C and isolated pyrazol-3-one 368 and the fluorinated pyrazolopyrazolediones 369 and

132

GEORGE

VARVOUNIS

et al.

[Sec. 1I.E

R

N/)JPh Fe&

I EtOH

I A

R=H

(357) 1) -OH I Hz0 2) H+IHfl

l)‘OHI~O 2) H+/H@ R

t

I

(3W

(a) R = Me, Cl, Br or I

SCHEME 82

4

HHWAO MeOH

I R.T.

(3W

SCHEME 83

Sec.II.F]

PYRAZOL3-ONES Me\

Me

(368)

k a+

(369

Me

/N\

+

h Y”

0

(367)

0 (370)

(371)

(372) SCHEME84

370 in 50,25, and 5% yields, respectively. It is proposed that acetyl hypofluorite acts as a p donor, forming an iminium acetate ion pair 364. The ion pair 364 can lose acetic acid and give 369, release acetyl hypofluorite and give 370, or form an adduct 365. The ring opening of 365 to 366, hydrolysis of 366 to 367, and subsequent decarboxylation of 367 afford product 368 (85JOC4152) (Scheme 84). Kanety and Kosower hydrolyzed pyrazolopyrazolediones 371a-c with aqueous sodium hydroxide and, after acidification, obtained pyrazol-3-ones 372a+ in good to excellent yields (82JOC4222).

F. SYNTHESIS FROM BIWXIC

5.6~MEMBERED FUSED RINGS

1. From Pyrazolopyriduzinones

a. From Pyrazolo[3,4-dlpyridazin-4-one. Ring opening the pyridazin-3-one group of 373 by sodium ethoxide in refluxing ethanol gave pyrazol-3-one 375. The reaction is very likely to occur via the ester 374 (88JHC139) (Scheme 85).

134

GEORGE

(373)

VARVOUMS

(374)

et nl.

[Sec. 1I.F

(375)

SCHEME 85

2. From Imidazotriazines a. From Imidazo[S,I -c][l,2,4] triazines. Stevens and co-workers demonstrated that pyrazol-3-ones 377a,b can be synthesized by reacting ester 376a or ketone 378a with hydrazine hydrate or phenylhydrazine. A study of the mechanism of the reaction showed that the primary amino group of a hydrazine attacks C4 of 376 in one case and the exocyclic carbonyl group in 378 in the other. For example, the transformation of 376e to 377~ proceeds via tautomer 379, followed by ring opening to 380 which undergoes intramolecular acyl substitution followed by tautomerization to afford 377~ [82JCS(P1)181 l] (Scheme 86). 3. From Benzofuranones a. From Benzojkranone Acetates. Benzofuranone acetates 383a-d have been prepared from phthalic anhydride 381 and a?bromo esters 382a-d in the presence of zinc-copper couple. When acetates 383a,b were heated with hydrazine hydrate in ethanol, pyrazol-3-01~ 384413 were isolated as single products. However when compounds 383c,d were treated with hydrazine hydrate, a mixture of pyrazol-3ones 384c,d and phthalazinones 385c,d was isolated (91JOC2587) (Scheme 87). 4. From Pyranopyrazoles a. From Pyrano[2,3-clpyrazoles. A novel synthesis of 4-arylidinepyrazol-3one derivatives 387 by reaction of pyrano[2,3-clpyrazole 386 with benzaldehyde, 4-methylbenzaldehyde, 4-methoxybenzaldehyde, or thiophene-2-carbaJdehyde, was reported by Atta et al. Unexpectedly, the reaction of 386 with formaldehyde afforded pyrazol-3-one 388 (98HEC553) (Scheme 88).

135

PYRAZOL-3-ONES

Sec. ILF]

(373)

II

R’ = NH2

(a) R = H, R’ = Ph (b) R = R’ = Ph (c) R = H, R’ = NH2 CoNH2

1379)

(330) SCHEME X6

0 zniTHF/DMF BC(R’R2)CqR

(384)

(3333 H2NN~.H20 EtOH I A

(cl, (d) (a)R=Et,R’=$=H (b)R=Et,R’=Me,+=H (c) R = Et, R’ = Ph, R2 = H (d)R=Et,R’=+=Me

(384)

+ 0

(386) SCHEMEW

GEORGEVARVOUNISet al.

136

CN

[Sec.ILG

ArCHO -

Ar = Ph, 4-hleC&i.+ 4-MeOC& or 2-thimyl SCHEME 88

G. SYNTHESIS FROM BICYCLIC 6,6-MEMBERED FUSED RINGS

1. From Chromenones a. From 4Hydroxy-2H-Chromen-d-ones. The reaction of &omen-Zone 389a with hydrazine hydrate to give pyrazol-3-one 390a was fnst studied by Mustafa et al. (66LA166) (Scheme 89). Eighteen years later, Chantegrel and Gelin reported the synthesis of pyrazol-3-ones 390b-g by the reaction of the corresponding chrome+Zones 389b-g with methylhydrazine (85S548). More recently Takagi and co-workem reported a more detailed study of this transformation. Hydrazide 392 was isolated from the reaction of&omen-2-one 391 with methylhydmzine and provided proof for the mechanism of this transformation, since heating 392 with triethylamine caused dehydration to give pyrazol-3-one 393. Similarly, reaction of 391 with hydrazine hydrate provided pyrazol-3-one 395, as expected. This transformation also worked for 4-methoxy-W-&omen-2one 394. Furthermore, reaction of 394 with methylhydrazine gave pyrazol-3-one 393. Postulated intermediate 396 in the last reaction was not isolated (UBJM239). Recently, Froggett and co-workers reported the synthesis of pyrazol-3-01~ 390&i by heating 389a in toluene with phenylhydrazine or 4-chlorophenylhydrazine, respectively [97JCR(S)30]. b. From Ethyl 3-Amino-2-cyuno-3-(2-oxo-2H-chromen-3-yl)prop-2-enoate. The reaction of ester 397 with hydrazine hydrate or phenylhydrazine yielded methylidenepyrazol-3-ones 39&b in 65 and 60% yields, respectively. The formation of compounds 398a,b from 397 is assumed to proceed via elimination of ethanol (82M985) (Scheme 90). This is in contrast to the reported addition of hydrazines to a double bond in enamino esters and enamino nitriles under similar

sec.IX]

137

PYRAZOL-3-ONES

-R’

OH RNHNHz EtOH of tohme

IA

(a)R=R’=R2=H (b)R=Me,R’=R2=H (c)R=Me,R’=Me,R2=H (d)R=Me,R’=H,R2=Me, (e)R=Me,R’=R’=Me, (f)R=Me,R’=OH,@‘H (g)R=Me,R’=MeO,$=H (h)R=Ph.R’=+=H (i)R=4-ClC&,R1=$~H

OH Et$‘itA

(394)

YNNH2.H20 I

MeNHNH2

RNHNY

(a) R A (397)

= H (b) R = Ph

138

GEORGE

VARVOUNIS

et al.

r :p.-R’ \t ‘R 0 [aI, Nj $1

(~)R=R’=H,(b)R=MB,R’~H,(c)R~Pfl,R’~H.(d)R=R’=Me

SCHEME91

conditions (74T2791). The inactivity of the exocyclic double bond in 397 toward hydrazines is rationalized by the decrease in its reactivity by conjugation with the chromenone ring. H. SWSIS

FROM TRICYCLIC 5,6,6A&MBERED

FUSED RINGS

1. From Furoquinoxulines a. From N,N-Dimethyljko[2,3-b]quinoxaline-3-carboxamide. Knrasawaand T&da synthesized pyrazol-3-onederivatives 402a-c by reacting furo[2,3-blquinoxaline 399 with hydrazine hydrate, methylhydrazine, and phenylhydrazine, respectively. The reaction occurs via the hydrazide derivatives4Ola-c by intmmolecular attack and cleavage of the furan ring, as indicated by the isolation of derivative 401d from the reaction of 399 with l,l-dimethylhydrazine 400d. The yields in these reactions am in the range of 85-96% (80H281; 81CPB2871) (Scheme 91).

I. SYNTHESIS FROM TzzrcycL~c 6,6,6-MEMBERED FUSED RINGS

1. From Pyrazolobenzoxazinones a. From 1,6,9a-Trimethy1-2-pheny1-1,9a-dihydropyrazo1o[3,4-b][1,4]benzoxazin-3(2H)-one. Dave and co-workers found that borohydride reduction of pyrazolo[3,4b][lQ]benzoxazinone 403 gave reduction product 404 which was not stable in air at room temperature. Compound 404 was found to rearrange slowly to pyrazol-3-one 405 by ring opening of the morpholino ring (74CJC2932) (Scheme 92).

Sec. III.]

139

PYRAZDL-3-ONES

Mk\/ ’ OMS l+ dN-Me bh

H

t+JaBH, I THF I MeOH

Ph (404)

SCHEME92

III.

Physicochemical

Properties

The p& values of 49 derivatives of pymzol-3-one were measured by potentiometric titration and their lH NMR spectra were recorded in DMSO-de. The experimental acidity order correlates for structurally similar compounds as do substituent constants and HMO electron densities (76JPR555). For pyrazol-3-ones the following spectral and X-ray data are available. UV data: 65LA134; 66CCC4669; 67JCS(C)1528; 68BSF5019; 68JA5273; 68JCS(C)2251; 68M2365; 70BSF247; 72JHC1219; 74CJC2932; 76JCS(P1)38; 79CB1477; 8OJA4983; 8OJHC519; 818742; 81SA(A)519; 81ZC410; 82JCS(P1)277; 82JCS(P1)1811; 82JOC4222; 83JOC4078; 83JOC4367; 84BSFl64; 88IJC(A)94; 9 1JCS(CC)3 14; 92JOU302; 95DP131; %MI2. JR data: 65LA134; 68BSF5019; 68JA5273; 68JCS(C)2251; 68M2365; 69BSF4159; 69JOC1717; 69LA159; 6933453; 70BSF247; 7OJCS(C)445; 718216; 72JHC1219; 73BSF2482; 73JOC2650; 74CJC2932; 76JCS(P1)38; 76JPR555; 77AJC2255; 77JCS(P1)971; 79CB1477; 79JHC1279; 79JPR1047; 79PJC2225; 798283; 8OCPB2144; 8OCPB3688; 80H281; 8OJA4983; 8OJHC389; 80JHC519; 8OJHC1339; 8OJHC1413; 8OJIC539; 81CPB244; 81CPB2871; 81JA7743; 81JCS(P1)1371; 81JHC763; 81JOC1532; 818742; 82CB2766; 82H2309; 82JCS(P1)1811; 82JHC437; 82JHC1457; 82JIC711; 82JOC81; 82JOC214; 82JOC4222; 82M985; 83H765; 83JHC773; 83JOC4078; 83JOC4367; 84BSF129; 84JHC1755; 84JOC5247; 848548; 848927; 85JCS(Pl)l137; 85JIC625; 85JOC4152; 87EJM239; 87H79; 87IJC(B)832; 87JOC1724; 87JOU1773; 87ZC367; 88BCJ 1440; 88H1411; 88IJC(B)342; 88IJC(B)573; 88IJC(B)758; 88JHC139; 88JHC543; 88JOC810; 88JPR517; 88PHA77; 89JIC135; 89JOC379; 89JPS239; 90BSF745; 90JHC683; 9OSC3213; 9OTL5327; 91BCJ1704; 91CHE741; 91CPB86; 91IJC(B)878; 91JCS(CC)314; 91JHC49; 91M537; 91PHA105; 91PS381; 92AF1350; 92IJC(B)421; 92IJP165; 92JCS(P1)1729; 92JOC7359; 92JOU302; 92PS121; 92JOC7359; 92T1707;

140

GEORGE

VARVOUNIS

et al.

[sec.

III.

93BSB735; 93JCR(M)lOl; 94AP133; 94CCC957; 94IJC(B)326; 94IJC(B)1098; 94JOU780; 94T895; 95JOC149; %MI2; 96T1579; 97JCR(S)30; 97JHC233; 97JHC389; 9735617; 98JPR437; 99H95. ‘H NMR data: 65LA134; 68BSF5019; 68JA5273; 69JOC1717; 69LA159; 69T3453; 7OBSF247; 7OT1571; 718216; 71TL2929; 72JHC1219; 73BSF2482; 73JOC2650; 74CJC2932; 76JCS(P1)38; 77AJC2255; 77JCS(P1)971; 79CB1477; 79JHC1279; 79JPR1047; 79PJC2225; 798283; 8OCPB3688; 8OCPB2144; 80H281; 8OJA4983; 8OJHC389; 80JHC519; 8OJHC1339; 80JHC1413; 81CJC629; 81CPBW 81CPB2871; 81JHC763; 81JA7743; 81JCS(P1)1371; 81JOC1532; 818742; 82CB2766; 82H2309; 82JCS(P1)1811; 82JCS(P1)277; 82JHC437; 82JHC753; 82JHC1457; 82JOC81; 82JOC214; 82JOC4222; 82M985; 83H765; 83JHC773; 83JOC4078; 83JOC4367; 84BSF129; 84CZ285; 84JHC1755; 84JOC5247; 848548; 84S927; 84SA(A)397; 85JCS(Pl)ll37: 85JIC625; 85JOC4152; 87EJM239; 87H79; 87IJC(B)832; 87JOC1724; 87ZC367; 88BCJ144Q 88H1411; 88IJC(B)342; 88IJC(B)573; 88IJC(B)758; 88JHC139; 88JHC543; 88JOC810; 88JPR517; 88PHA77; 89JIC135; 89JOC379; 89JPS239; 90BSF745; 9OJHC683; 9OSC3213; 9OTL5327; 91BCJ1704; 91CHE741; 91CPB86; 91IJC(B)878; 91JCS(CC)34; 91JCS(CC)314; 91JHC49; 91JMC1440; 91M537; 91JOC2587; 91PHA105; 91PS381; 91S845; 92AF1350; 92H799; 92JJC(B)421; 92JOC7359; 93JCR(M)lOl; 92JCS(P1)1729; 92JOC7359; 92JOU3Q 92PS121; 92T1707; 93BSF735; 93122749; 94AP133; 94CCC957; 94IJC(B)326; 94JOU780; 943895; 95JHC1341; 95JOC149; 958805; 9631579; 97JCR(S)30; 97JHC233; 97JHC389; 97JHCl453; 97JHC1699; 9735617; 98JPR437; 98JHC189; 99H95. 13C NMR data: 8OJHC519; 82JHC753; 83JOC4.078; 83JOC4367; 83JOC4367; 84SA(A)397; 87H333; 88H1411; 88JHC543; 89JOC379; 90BSF745; 9OMRC817; 91JCS(CC)34; 91JCS(CC)314; 91JHC641; 9OJHC683; 91M537; 92H799; 92JOC7359; 92JOC7359: 93BSB735; 93122749; 95JHC1341; 95JOC149; 953805; %T1579; 97JHC233; 97JHC1453; 97T5617; 98JHC189. 15N NMR data: 9OJCS(P2)203; 93122749. Mass spectral data: 69OMS697; 69OMS1289; 730MS89; 82JHC55; 85CHE1368; 68JA5273; 73JOC2650; 74CJC2932; 78MI5; 798283; 80H281; 8OJA4983; 8OJHC1339; 8OJHC1413; 81CPB244; 81CPB2871; 81JA7743; 81JHC763; 81JOC1532; 82JHC437; 8WHC753; 82JoC81; 82JOC214; 82JOC4222; 84CZ285; 85PHAl lo; 87JOC1724; 88JHC543; 88JOC810;90TL5327;91JHC49;91S845;92AF1350;92UC(B)421;9UOC7359; 92JOC7359; 93BSF735; 943895; 95JHC1341; 96MI2; 97JHC233; 99H95. X-Ray data: 71AX(B)1227; 73AX(B)714; 73CSC473; 73CSC469; 80AX(B)2794,8OCSC435; 84CPB318; 85AJC401; 87CJC2082; 88AX(C)1587; 9OJCS(P2)203; 91AX(C)1854; 91JCS(CC)34; 92H799; 92JCS(P1)1729; 93BSFV35; 93122749; 95AX(C)1310; 95JOC149; 96AX(C)447; %MI2; 96T1579; 97JHC389.

sec.NC]

141

PYRAZOL-3-ONES

IV. Applications Pyrazol-3-ones are very versatile compounds and are important as products and intermediates in analytical, agricuhural, biological, and pharmaceutical chemistry.

A. ANALYTICALUSES The use of pyrazol-3-ones as analytical reagents has been reported in numerous articles and patents. For example, certain derivatives are useful for the extraction and separation of various metal ions [79MI2; 81JINC1583; 81TAL49; 82IJC(B)176; 82IJC(B)177; 88JIC6611; for the determination of phenol (68CCC42; 7OCCC3 1; 7OCCC1567; 87CJC2082), cyanides, and ammonia (77AC516; 78ZN450); and as photographic sensitizers (7OGEP1800581; 71USP 3615608). Trofimov and colleagues summarized the uses of pyrazol-3-one dyes as analytical reagents (82MIl).

B. AGROCE~EMICALUSES Fungicides: 65CJC1618; 67’11238; 69IJA116; 71IC2407; 73IC644; 74JIC351; 74JIC374; 75JIC533; 75JIC 1196; 76X668; 76JIC830; 77IJC(B) 1062; 77IJC(I3)1146; 77JIC485; 78JIC593; 78JIC829; 78JIC907; 78MI4; 8OJAP157504, 8OJIC212; 8OJICl108; 81JIC337; 81JIC547; 81JIC695; 81MIl; 82JIC7 11; 84IJC(A)429; 86JIC784; 87MIl; 87USP4666933; 89JIC135; 9 1JIC 165; 92IJP165; 99MIl. Herbicides: 84JAP(K)5 197; 85BSF147; 92JIC 162; 96JAP(K)2 17777. Insecticides:

99MI2.

c. DYE

CHEMISTRY

USES

The applications of pyrazol-3-ones as dyes have been mentioned in one of the major works (84MI2). Pyrazol-3-ones proved to be good merocyanin dyes (681412365; 69USP3441563) and quinomerocyani.ne dyes (68KG91), and useful for dyeing polyamide fibers (69GEP 1800581), polyester fibers (78MI3) and acrylic fibers (72MIl).

142

GEORGE VARVOUNIS et al.

[sec. 1v.P

D. FHARML~~XJTICAL USES Pynuol-3-ones exhibit a wide range of biological properties: analgesic [64AC(R)5u); 64MI2; 7OAF1019; 66MI2; 67MIl; 74JAP(K)35278; 88EJM349; 91SUL151; 93MIl], antibacterial (69IJA116; 74JIC351; 75APP433; 75EJPS407; 75JIC228; 75JIC1196; 76JIC830; 78MI4; 78PHA264; 78PHA575; 82JIC711; 87MIl), antitumor (69IJA116; 74JIC351; 76JIC830; 88MIl; 92FA319), antidiuretic (68JGC1647), anti-inflammatory [64MI2; 6QAC(R)520; 69AF1721; 7OAF1019; 74JAP(K)35278; 74MIl; 77IJC(B)125; 80PHA596; 81PHA93; 82IJC(B)869; 82JIC711; 84IJC(B)125; 88EJM349; 88IJC(B)1019; 92IJC(B)421; 93MIl], antipyretic [64AC(K)520; 64MI2; 66MI2; 67MIl; 7OAF1019; 74JAP(K)35278; 8OEJP207; 82KFZ61; 88EJM349; 88GEP254938; 9OAP833; 93MIl], antirheumatic (68CCC425), antiviral (87IJPS40), hypoglycemic (81PHA91), hypotensive (81PHA471). Pyrazol-3-0~s have also been the subject of more general biological studies [65IJC139; 66USP3244593; 66MIl; 72G491; 77MIl; 78IJC(l3)638; 78MI2; 78PHA722; 8OCPB1820; 84FRP2529786; 84MIl; 86BSF861; 88GEP254938; 88USP46669331 and their medical applications’have been recorded in one of the major works (84MI2).

E. ~OTOGRAPHIC USES Certain pyrazol-3-ones have been patented as color formers for purple dyes in silver halide color photography (68BEP712086; 7OGEP1930337) and have proved to be photographically useful magenta couplers (77M12; 82MI2). Photographic material containing puke-releasing pyrazolone DIR coupler in combination with a pyrazolone or pyrazolotriazole coupler has also been patented (99EUP924565). Several other pyrazol-3-ones have also been patented and reported in the primary literature as photographic dye couplers (64GEP1181057; 69GEP180042~ 69BRP1173214; 71GEP3615608; 78JIC712; 78JPC857). They are also useful as photographic sensitizers (69GEP1800581) and as silver-free image recording materials (83GEP159223).

F. MISCELLANEOUS USES The absolute rate constants for the reaction of a variety of electrophilic free radicals with 4-(dimethylamino)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazo1-3one (aminopyrine) and 1,5-dimethyl-2-phenyl- 1,2-dihydro-3H-pyrazol-3one

sec.IV.F]

143

PYRAZQL-3-ONES

(antipyrine) have been measured by pulse radiolysis. Studies of the reaction of the radical cations with reducing agents suggest that aminopyrine in particular may prove to be a useful reference in studies of free-radical one-electron oxidations [88JCS(P2)1.579]. Asano and co-workers have reported the kinetic effects of pressure, solvent, and substituent on geometric isomerization abut the carbon-nitrogen double bond for pyrazol-3-one azomethmes 406 (R = H), 406 (R = NOz) and 407, (Scheme 93). The results demonstrate the versatility of the inversion mechanism. The rotation mechanism has been invalidated. First-order rate constants and activating volumes for thermal E-Z isomerization for 406 (R = H) and 406 (R = NOZ) ate given at 25°C in benzene and methanol (89JOC379).

(e) R =

(a) R = H ,W @)R

=

‘i\ NH

(c)R=

+f Me

(0 R =

(d) R = OMe %XFiME

94

144

GEORGE

H

VARVOUNIS

et al.

Me

3

[Refs.

23 H

-

Me

-

NzMe

NN’Me

7

& (4W

(4101

Ravindranath and co-workers studied the electrochemical behavior of li-amino2-phenyl-4-arylazo-1,2-diiydro-3H-pyrazol-3-one (9OIJC864) and 5-methyl+ arylazo-2-(pyridin-2-ylcarbonyl)-2,4-diiydro-3H-p~l-3-one (9OIJC895). Similar studies were undertaken by Jain and Damodharan of pyrazol-3-ones 408a-f (95CJC176) (Scheme 94). The underlying rationale for this study on the electrochemical reduction of these biologically important pyrazol-3-ones is that it can lead to information on the reaction routes and mechanisms of biological redox reactions. Sircar and co-workers reported that some pyrazol-3-ones possess potent and selective inhibitory phosphodiesterase activity which is primarily responsible for their inotropic action (87JGC1724). Tamaoku and colleagues presented an efficient enzymatic photometric determination of hydrogen peroxide that is essentially a color reaction resulting from the oxidative condensation of N-ethyl-N-(2-hydroxy-3-sulfopropyl)aniline derivatives with LGaminoantipyrine in the presence of hydrogen peroxide and peroxidase (82CPB2492). A similar calorimetric detection of hydrogen peroxide has been patented (83GEP3301470). A thin-layer chromatography assay was developed for the simultaneous determination of the three major hydroxylated metabolites of antipyrine 409,410, and 411 in urine of humans and other animals (82JPP168) (Scheme 95). Some other pyrazol-3-one derivatives studied by biological chemistry are muscimol analogs and bacterial metabolites of antipyrine [77ZN(C)557; 79ACSA (B)294].

REFERENCES 1883CB2597 1884CB546

L. Knorr, L. Knorr,

Chern. Ber, 16,2597 (1883). Chem. Ber. 17,546 (1884).

PYRAZOL-3-ONES

Refs.] 1887LAJ37 1892ICS791 @AC(R)520 64GEP1181057 64MIl 64M12 64T29Y 65CJCl618 65X139 65LAl34 66AG676 66BSE755 66CB2937 664xC466Y 66JOUllO3 66JOU524 66LAl66 66MIl tiMI 66USP3244593 67BSF3772 67BSF3780 67JCS(C)lS28 67MI1 67YZ38 68BEP712086 68BSF5019 68CCC42 68CCC425 68JA5273 68JCS(C)2248 68JCS(C)225 68JOCl647 68KG9 1 68M2365

1

145

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146

GEORGE

68NKZ1093 69AF1721 69BRPll73214 69BSF41.59 69CB3260 69CPB1467 69CPB1485 69GEPl800420 69GEPl80058 69IJA116 69JMC726 69JOC1717 69LA159 69MI1299 69OMS697 690MS1289 69T3453 69T4605 69USP3441563 7oAF1019 7OBSF247 7OCCC31 7OCCCl567 7OGEPl800581 7OGEP1930337 7OGEP1935272 7OJCS(C)445 70-I-1571 7oTL875 71AX(B)1227 71BSB17 7lGEP3615608 71lC2407 71JOC2542 718216

1

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et al.

[Refs.

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PYRAZOL-3-ONES

Refs.] 71TL2929 72649

I

72JHCl219 72Ml I 72USP36156OS 73AX(B)714 73BSB215 73BSB233 73BSF2482 73CSC469 73csc473 73IC644 73JOC2650 73OMSS9 74CJC2932 74JAP(K)35278 74JIC35 I 74JIC374 74MIl 741279 l 75APP433 7SEJP407 7SJIC228 7SJICS33 75JIC1196 76AHC(S1)313 76CIL 1032 76IJC668

147

J. I&champs, H. Sauvaitre, J. Arriau, A. Maquestiau, Y. van Haverbeke, and R. Jacquerye, Tetrahedron Lett. 31,2929 (197 1). G. Desiioni, A. Gamba, I? Righetti, and G. Tacconi, Guzz. C&z. Ital. 102,491 (1972). G. Adembri, F. Ponticelli, and P. Tedeschi, J. Heterocycl. Chem. 9,1219 (1972). A. Arcoria, S. Fisichella, S. Occhipinti, and D. Sciotlo, Chin. Ind. 54, 865 (1972). J. E. Van Lave and Eastman Kodak Co., U.S. Pat. 3,615X88 (1972) [CA 76, 114853 (1972)]. T. P. Singh and M. Vijayan, Acw Crysmllogr. (B) 29,714 (1973). A. Maquestiau, Y. van Haverbeke, and R. Jacquerye, Bull. Sot. Chim. Belg. 82,215 (1973). A. Maquestiau, Y. van Haverbeke, and R. Jacquerye, Bull. Sot. Chim. Belg. 82,233 (1973). P. Bouchet, J. Elguero, and J.-M. Pereillo, Bull. Sot. Chim. Fr., 2482 (1973). F. Bechtel, J. Gaultier, and C. Hauw, Cryst. Struct. Commun. 3, 469 (1973). F. Bechtel. J. Gaultier, and C. Hauw, Cryst. Strut. Common. 3, 473 (1973). C. T. Spencer and L. T. Taylor, Inorg. Chem., 644 (1973). M. J. Haddadin and A. Hassner, J. Org. Chem. 38,265O (1973). E. Larson, J. H. Qureshi, and J. Moller, Org. Mass. Spectrom. 7, 89 (1973). V. Dave, J. B. Stothers, and E. W. Warnhoff, Cnn. J. Gem. 52, 2932 (1974). M. Nakanishi and M. Shiraki, Jpn. Kokai 35,278 (1974) [CA 83,10006S (1974)]. G. S. Saharia and H. R. Sharma, J. In&n Chem. Sot. 51,351 (1974). S. P. Suman and S. C. Babel, J. Indian Chem. Sot. 56,374 (1974). R. A. Scherrer and M. W. Whitehouse, “‘Antiinflammatory Agents,” Vol. 1. Academic Press, New York, 1974. M. H. Elnagdi, Tetrahedron, 30,279 1 (1974). U. Wrzeciono, B. Krzytifik, and E. Danielewicz, Acta Pal. Pharm. 30, 433 (1975) [CA 84,30956 (1976)]. I. M. Roushdi, E. A. Ibrahim, and N. S. Habib, Egypt, J. Pharm. Sci. 16, 407 (1975). P. N. Dhal, T. E. Achary, and A. Nayak, J. Indian Ckm. Sot. 52,228 (1975). B. Nanda, S. Padmanavan, B. Tripathi, aud A. S. Misra, J. Indian Chem. sot. 52,533 (1975). P. N. Dhal, T. E. Achary, and A. Nay&J. Indian. Chem. Sot. 52,1196 (1975). J. Elguero, C. Marzin, A. R. Kairitzky, and P. Linda, Adv. ffeterocycl. Chem. Suppl. 1,313 (1976). A. Kasahara, Chevz. hi. (Lmdon) 1032 (1976). S. B. Bamela, R. S. Pandit, and R. S. Seshardri, Indian J. Chem. 14,668 (1976).

148 76JIC830 76JCS(P1)38 76JPR555 77AC.516 77AJC2255 77LJC(B)125 77IJC(B)1062 77IJC(B)1146 71JCS(P1)971 77JIC485 77MIl 77MI2 77zN(C)557 78IJC(B)638 78JIC593 78JIC712 78X829 78JIC907 78JPC857 78MI2 78MI3 78MI4 78MI5 78PHA264 78PHA575 78PHA722 78TL4439 78ZN450 79ACSA(B)294 79CB 1477 79JHc 1279 79JPRlO47

GEORGE

VARVOUNIS

d nl.

[Refs.

P. S. Fernandes, B. Sandya, G. Philip, and V. V. Nadkamy, J. Indinn Chem. Sac. 53,830 (1976). D. H. R. Barton, J. W. Ducker, W. A. Lord, andP. D. Magnus,J. C/tern. Sot., Perkin Trans. I, 38 (1976). F. D. H6ppner, E. Kleinpeter, C. Weiss, H. J. Hofmann, and W. Schindler, J. Prakt. Chem. 318,555 (1976). I. Gilath,Anal. Chem. 49,516 (1977). N. Latif, N. Mishriky, and M. Hammad, Amt. J. Chem. 30,2255 (1977). S. N. Sawhney, S. P. Sin& and 0. I? Bansal, Indian J. Chem., Sect. B 15,125 (1977). S.RaoandA.S.Mittra,IndianJ.Chem.,Sect. B15,1062(1977). S. K. Mohanty, R. Sridhar, S. Rao, S. Y. Padmanavan, and A. S. Mittra, Indian J. Chem.. Sect. B 15,1146 (1977). G. Adembri, A. Camparini, E Ponticelli, and P. Tedeschi, 1. Chem. Sot., Perkins Trans. I, 971 (1977). A. Nayak, S. Das, C. R. Mishra, and A. S. Mittra, J. Indian Chem. Sot. 54,485 (1977). L. A. Mitscher and D. Lednicer. ‘The Organic Chemistry of Drug Synthesis,” John Wiley and Sons, New York, 1977. L. J. Fleckenstein, ‘The Theory of the photographic Process,” 4th ed. (T. H. James, ed.). Macmillan, New York, 1977. K. Sauber, R. Mueller, E. Iceller. and I. J. Eberspsecher, 2. Naturforsch., C. Biosci. 32,577 (1977). N. B. Das and A. S. Mittra, Indian J. Chem., Sect. B. 638 (1978). A. Nayak and A. S. Mittra, J. Indian Chem. Sot. 55,593 (1978). P. K. Jesthi, M. Boy, and S. K. Mohapatra, J. Indiun Chem. Sot.. 712 (1978). N. B. Das and A. S. Mittra, J. Itian Chem. Sot. 55,829 (1978). N. B. Das and A. S. Mittra, J, Indian Chem. Sot. 55,907 (1978). A. M. Osman, M. S. K. Ycussef, and K. M. Hassan, J. P rakt. Chem. 320, 857 (1978). M. Arisawa, M. Fujiu, Y. Suhara. and H. B. Maruyama, Mu.@. Res. 57, 287 (1978). F. A. Amer. T. Zimaity. and M. A. Metwally. J. Appl Chem. Biotechnof. 28,560 (1978). S. A. ShamsEl-Dine and N. S. Habib.Sci. fhurm. 46,194 (1978). M. Ragab and N. S. Habib, Sci. Pharm. 46,254 (1978). U. Wrzeciono, K. Pietlciewicz, E. Jobke. and W. Michalska, Pharmazie 33,264 (1978). U. Wrzeciono, K. Pietkiewkczk, B. Krzysztofik. W. Michalska, and M. Drozdowski, Pharmazie 33,575 (1978). G. Scheunig and D. ziebarth, Pharmazie 33,722 (1978). G. Adembri, A. Camparini, D. Don&i, and I? Ponticceli, Tetrahedron Len., 4439 (1978). A. M. Qureahi and A. N. Patel, Z. Naturforsch. 33,450 (1978). H. Hans and P. Krogsgaard, Acta Chem. Scan& Ser. B 33,294 (1979). F. A. Neugebauer and H. Fischer, Chem. Ber. 112,1477 (1979). D. J. Tracy, J. Heterocycl. Chem. 16,1279 (1979). M. I. Ali and M. M. S. El-Morsy, J. Pmkt. Chem. 321,1047 (1979).

Refs.] 79MIl 79PJC2225 793283 8OAX(B)2794 80CPB 1820 8OCPB2144 8OCPB3688 8OCSC435 8OEJP207 8OH281 8OJA4983 8OJAP157504 80JHC389 8OJHCS 19 80JHC1339 8OJHC1413 8OJIC212 8OJICS39 SOJICl108 80PHA596 8072.5059 802C258 81CJC629 81 CPB244 81CPB2871 81 JA7743 81JCS(P1)1371 81 JHC763 81JIC337 81 JICS47 81 JIC695 SlJINC1583 81JOCl532 8lMIl

PYRAZOL3-ONES

149

A. I. Eid, M. A. Kira, and H. H. Fahmy, J. Pharr~. Be&. 33,303 (1978) [CA 90,152073 (1979)]. R. Balicki and P Nahtka-Namirski, Pal. J. Chem. 53,222s (1979). C. Venturello and R. D’ Aloisio. Synthesis, 283 (1979). T. Uno and N. Shimizu, Acta Crystallogr., Sect. B 36,2794 (1980). A. Sakai and A. Tanimura, Chem. Pharm. Bull. 28, 1820 (1980). T. Ueda, N. Oda, and I. Ito, Chem. Pharm. Bull. 28,2144 (1980). Y. Muto, H. Ichikaku, and K. Takagi, Chem. Pharm. Bull. 28, 3688 (1980). N. Shimizu and T. Uno, Cryst. Strut. Comnwn. 9,435 (1980). H. Abou Shady, M. M. El-Kerdawy, and M. A. Massoud, Egypt. J. Pharm. Sci. 19,207 (1980). Y. Kurosawa and A. Takada, Heterocycles 14,281 (1980). E. M. Kosower and B. Pazhenchevsky, J. Am. Chem. Sac. 102,4983 (1980). Sankyo Co. Ltd., Jpn. Pat. 157,XM (1980) [CA, 94,1.51890 (1981)]. J. D. Wilson, T. D. Fuhner, L. P. Dasher, and C. F. Beam, 1. Heterocycl. Chem. 17,389 (1980). G. Bobowski and J. Shavel, Jr., 1. Heterocycl. Chem. 17,519 (1980). I. Okabayashi, J. Heterocycl. Chem. 17,1339 (1980). K. Pilgram, J. Heterocycl. Chem. 17, 1413 (1980). S. P. Suman and S. C. Bahel, J. Indian Chem. Sot. 57,2 12 (1980). V. S. Jolly, A. K. Shrivastava, S. P. Singh, and K. S. Tiwari, J. Indian Chem. Sot. 57,539 (1980). R. B. Pathak and S. C. Bahel, J. Indian Chem. Sot. S7,1108 (1980). A. M. Farghaly, A. A. B. Hazzaa, and M. S. Abouzeit-has, Phnrmazie 35,596 (1980). M. Poje and N. Bregant, Tetrahedron L&t. 21, SO59 (1980). G. Bamikow and I. Strickmann, 2. Chem. 20,258 (1980). M. Cohvera, S. Basu, L. Copp, and V. MaIatesta, Gun. J. Chem. 59,629 (1981). K. Tabei, E. Kawashima, and K. Tetsuko, Chem. Pharm. Bull. 29,244 (1981). Y. Kurosawa and A. Takada, Chem. Phurm. Bull. 29,287l (1981). E. C. Taylor, F. H. Neil, and J. C. Robert, J. Am. Chem. Sot. 103,7743 (1981). D. Hunter and D. G. Neilson,.f. Chem. Sac., Perkin Trans. 1, 137 I ( 198 I). A. Citterio, M. Ramp&i, and E. Viimara, J. Heterocycl. C&m. 18,763 (1981). B. B. Mabapatra, N. B. Das, A. Nayak, and A. S. Mitra, J. Indian Chem. Sot. 58,337 (1981). B. B. Mahapatra, N. B. Das, A. Nayak, and A. S. Mitra, J. Indtim Chem. Sot. 58,547 (1981). P. Mitra and A. S. Mittra, J. hdkzn Chem. Sot. 58,695 (1981). N. R. Shah and J. R. Shah, J.Inorg. Nucl. Chem. 43, 1583 (1981). C. D. Poufter, P. L. Wiggins, and T. L. Plummer, J. Org. Chem. 46,1532 (1981). S. Rao and A. S. Mittra, Acts Cienc. In&a (Ser.) Chem. 7, 177 (1981) [CA 97,23684 (1982)].

150 81PHA91 8 lPHA93 81PHA471 81PHA509 818742 SlSA(A)519 81TAL49 81ZC410 82CB2766 82CPB2492 82FA319 82H2309 82IJC(B)176 82IJC(B)l77 82IJC(B)869 82JCS(P1)277 82JCS(P1)1811 82JHC.55 82JHC437 82JHC753 82JHC 1457 82JIC7 11 82JOC81 82JOC214 82JOC4222 82JPP168 82KFZ61

82M985

82PJC1553

GEORGE R. Soliian,

VARVOUNIS

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