Indian Journal of Chemistry Vol. 41 B, February 2002, pp. 360-367

Chemical transformations on 6-ary 1-3 -cyano:-4-meth y lthio-pyran-2( H)-ones: Synthetic and structural studies on novel N-phenylpyrazoles and N­

phenylpyrazolylcoumarins

Ajay Kumar", Sanjay Malhotra", Archana Vatsa, Himanshu", Sanjay K Singha

, Sunil K Sharmaa, Ashok K

Prasad"*, William Erringtonb, Carl E Olsenc

, Subhash C Jain' & Virinder S Parmar"*

'Department of Chemistry, University of Delhi , Delhi l lO 007, India; bDepartment of Chemistry, University of Warwick, Coventry CV4 7AL, England; cChemistry Department, Royal Veterinary & Agricultural University, 40 Thorvaldsensvey,

Frederiksberg C, DK 1871 Copenhagen, Denmark

Received 8 May 2001 , accepted (revised) 17 October 2001

Seven 6-aryl-3-cyano-4-methylthiopyran-2(H)-ones 1-7 have been prepared and used for the efficient synthesis of twelve 1,3-diaryl-5-cyanomethylpyrazoles 8-19, one 3-cyanomethyl-5-(3,4-methylenedioxyphenyl)pyrazole 22 and one 5-cyanomethyl-3-phenylisoxazole 23. Further, two 1,3-diaryl-5-cyanomethylpyrazoles 10 and 11 have been used for the preparation of three novel N-phenylpyrazolylcoumarins 24-26. Structures of 3-cyano-6-(3,4-methylenedioxyphenyl)-4-methylthiopyran-2(H)-one 7. 3-cyanomethyl-5-(3,4-methylenedioxyphenyl)pyrazole 22 and 5-cyanomethyl-3-phenylisoxazole 23 have been confirmed by their X-ray crystallographic studies.

Nitrogen containing heterocyclic compounds, e.g. alkaloids, amides, nucleosides/nucleotides, etc. are widely distributed in nature and playa vital role in the metabolism of all living cells. However, very few pyrazoles particularly 1,2-pyrazoles and their deriva­tives are naturally occurring; this may be due to the difficulty of living organisms to construct the N-N bond. Like other nitrogen heterocycles, pyrazoles also exhibit a range of biological activities, viz. antioxi­dant, I antiinvasive,2 antiviral,3 antipyretic,4.5 antiln­flammatory,6 antidepressant,7 blood pressure lower­ing,S etc. Pyrazoles are also used as agrochemicals,9.10 d ff II· . I 12 O· h yestu s, m sunscreen matena s, etc. wmg to t e widespread application of pyrazoles and their deriva­tives, we have synthesised a series of pyranones l3, pyrazoles l.13, isoxazoles l3 and pyrazolyl acryloll1 i­triles l, and evaluated their antioxidant I and antiinva­sive2 activities. In continuation, we wish to report herein the synthesis of a few pyranones and their effi­cient conversion into pyrazoles, isoxazoles, N-phenyl­pyrazoles and N-phenylpyrazolylcoumarins which is a combination of two bioactive heterocyclic moieties, i.e. pyrazole and coumarin.

Results and Discussion 6-Aryl-3-cyano-4-methylthiopyran-2(H)-ones 1-7

are synthesized in three steps starting with the condensation of ethyl cyanoacetate with carbon disulfide in sodium ethoxide/ethanol, methylation of

s~ ~s e + H2 e

NC/ 'cae H II 2 5

o

C~I, MeOH .. oOC, stirring

R1

Na, EtOH

oOC, stirring

Scheme I

DMF, KOH, 30°C, stirring

R ~1

1 H Ii

2 CH3 Ii

3 OCH3 Ii 4 F It!

5 CI H

6 Br hi

7 -OCH2~

the disodio salt, followed by the condensation of resulting ethyl 2-cyano-3,3-bismethylthioacrylate with corresponding acetophenones 14.15 in overall

KUMAR et al. CHEMICAL TRANSFORMATIONS ON 6-ARYL-3-CY ANOA-METHYL THIOPYRAN-2(H)-ONES 361

jJ~~N"'N'OCN <.~ ~ I ~ I o

19

CN

yields of 40 to 55% (Scheme J). All the twelve 5-cyanomethyl-l,3-diarylpyrazoles 8-19 have been synthesized by the condensation of arylhydrazine hydrochloride with the appropriate pyranones 1-7 in pyridine in 45 to 54% yields (see Experimental)14. Condensation of 4-methoxyphenylhydrazine hydro­chloride with 6-( 4-chlorophenyl)-3-cyano-4-methyl­thiopyran-2(H)-one 5, and 4-chlorophenyl-hydrazine hydrochloride with 6-( 4-bromophenyl)-3-cyano-4-methylthiopyran-2(H)-one 6 lead to the formation of side products, identified as 3-amino6- (4-chloro­phenyl)-2-(4-methoxyphenyl)-4-oxo-4H-pyrano-[4,3-c]pyrazole 20 and 3-amino-6-(4-bromo-phenyl)-2-(4-

R1 R2

8 H H

9 H 9CH 3 10 CH3 H

11 CI H

12 Sr H

13 CH3 OCH3 14 CH3 CI

15 OCH3 Sr

16 CI OCH 3

17 CI CI

18 Sr pi

~R2 1 2 ~ N-N 6' . I ~ 3

R1 R2 I 4 NH2

0 2Q CI OCH 3

21 Sr CI

R1 R2 1Il3

24 CHa OCH H 25 CH3 3CI CI 26 CI CI CI

chlorophenyl)-4-oxo-4H-pyrano-[ 4,3-c ]pyrazole 21 along with N-phenylpyrazoles 16 and 18, res­pectively. The formation of N-phenylpyrazoles 16 and 18 and side products 20 and 21 can be explained by the nucleophilic attack of arylhydrazine at the C-6 and C-4 positions, respectively of the corresponding pyranones (Scheme II). The condensation of pyra­nones of the type 1-7 with hydrazine and its derivatives, and hydroxylamine is a general reaction; thus reaction of hydrazine and hydroxylamine with 3-cyano-6-(3,4-methylenedioxy-phenyl)-4-methylthio­one 7 and 3-cyano-4-methyl-thio-6-phenylpyran-2(H)-one 1 lead to the formation of 3-cyano-

362 INDIAN 1. CHEM .• SEC B. FEBRUARY 2002

~ " ~ C=N

/ ~ (). RI + 0 0

a

,- I NH2-NHR2

-CIilSH tP

rJYC:N ~

H-N--~H

~r y,-OH £X~N HI\I, 0 N-~ RI 0 0

H. ~

~ ~ ~C=N ttN--N

R ~N""P ~-o-H iJ:b~H I ~ I

~ 0 RI 0 0

t ~ ,~

~N""N..~ ~~H ~N RI ~I ft NH

2 0 -CIilSH~ -Co..

RI 0 0

AlCN RI ~N""N..~

Scheme II

methyl-5-(3,4-methylenedioxyphenyl)pyrazole 22 and 5-cyanomethyl-3-phenylisoxazole 23 in 56 and 40% yields, respectively. The pyranone 7, N­pheny/pyrazoles 8, 9, 13-19, side products 20 and 21, and pyrazole 22 have been prepared for the first time and their structures have unambiguously been established on the basis of their spectral data (lR, UV, IH NMR, IJC NMR and EI mass). The known compounds, i.e. pyranones 1_6,13 N-phenylpyrazoles 10,16 11 ,1 5 and 1215 and isoxazole 231 were identified on the basi s of their spectral data which were found identical with the data reported in literature.

Three N-phenylpyrazolylcoumarins 24-26 have been synthesized by the condensation of 5-cyano­methyl-3-(4-methylphenyl)-I-phenylpyrazole 10 with 2-hydroxy-3-methoxybenzaldehyde and 3,5-dichloro-2-hydroxybenzaldehyde, respectively and by the con­densation of 3-( 4-chlorophenyl)-5-cyano-methyl-l­phenylpyrazole 11 with 3,5-dichloro-2-hydroxy­benzaldehyde in alkaline ethanolic solution in 84, 80 and 90% yields. The structures of pyrazolylcoumarins 24-26 have been unambiguously established on the basis of their spectral data (lR, UV, IH NMR, IJC NMR and EI mass).

Sill

0111

Figure 1 - 3-Cyano-6-(3,4-methylenedioxy phenyl)-4-methylthiopyran-2(H)-one 7

Figure 2 - 5-Cyanomethyl-3-(3,4-methylcnedioxyphenyl)pyrazole 22

Figure 3 - 5-Cyanomethyl-3-phenyli soxazole 23

X-ray crystallography The structures of three compounds, 7, 22 and 23

established on the basis of spectral analysis have been confirmed by single crystal X-ray diffraction studies (cf Experimental). The schematic representation of the molecular structures of these compounds are shown in Figures 1-3, respectively.

Experimental Section General. Melting points were determined either on

a Mettler FP62 instrument or in a sulphuric acid bath and are uncorrected. The IR spectra were recorded either on a Perkin-Elmer model 2000 FT-IR or RXI FT-IR spectrophotometer, UV spectra either on a Cary 100 Bio or on a Beckmann DU-64 spectropho­tometer, and IH NMR and IJC NMR spectra on a Bruker AC-300 spectrometer at 300 and at 75 MHz, respectively using TMS as internal standard. The chemical shift values are on 0 scale and the coupling

KUMAR et al. CHEMICAL TRANSFORMATIONS ON 6-ARYL-3-CY ANO-4-METHYL THIOPYRAN-2(H)-ONES 363

constants (1) are in Hz. The ElMS and LCMS were recorded on a Jeol AX 505 Wand Esquire-LC 00141 instruments, respectively at 70 eV.

General procedure for the preparation of 6-aryl-3-cyano-4-methylthiopyran-2(H)-ones 1_7'3. Ethyl 3,3-bis(methylthio)- 2-cyanopropenoate'4 (6.51 g, 0.03 mole) was dissolved in DMF (60 mL) and KOH (3.42 g, 0.06 mole) added to it. The reaction mixture was stirred for 10 min under nitrogen, fol­lowed by the addition of corresponding acetophenone (0.03 mole). The contents of the reaction were further stirred at 28-30°C for 6 hr. The reddish-brown col­oured supernatant liquid was poured on to crushed ice (200 g) and the contents were stirred for 4 hr when a yellow solid precipitated out. It was filtered, dried and purified by column chromatography over silica gel using petroleum ether-ethyl acetate to afford yellow shiny needles of pyranones 1-7 in 40-55% yields. The known compounds 1-6 were identified on the basis of spectral data and by their comparison with those re­ported in the literature 13.

3-Cyano-6-(3,4-methylenedioxyphenyl)-4-methyl­thiopyran-2(H)-one 7. Crystallised from ethyl ace­tate as yellow shiny needles (4.10 g, 52%), m.p. 195-96°C. UV (MeOH): 227, 270 and 308 nm; IR (KBr): 221O(C=N), 1713(C=O), 1663, 1580, 1479, 1449, 1347, 1266, 1114, 1037, 929, 886 and 813 cm· l

; 'H NMR (CDCb): 0 2.70(3H, s, SCH3) , 6.10(2H, s, OCH20), 6.58(lH, s, C-5H), 6.87(1H, d, J = 9.50 Hz, C-5'H), 7.46(1H, d, J = 2.50 Hz, C-2'H) and 7.55(lH, dd, J = 9.50 and 2.50 Hz, C-6'H); LCMS(% reI. int.) : mlz 31O([M+Nat, 80), 288([M+Ht, 100), 215(30), 137(15) and 79(75). The structure of compound 7 was finally confirmed on the basis of its X-ray crystallo­graphic measurements (Figure 1).

General method of preparation of 5-cyanomethyl-1,3-diarylpyrazoles 8-19. To a solu­tion of 6-aryl-3-cyano-4-methylthiopyran-2(H)-one (1-7, 6.0 mmoles) in methanol/pyridine (30 mL) was added arylhydrazine hydrochloride (9.0 mmoles) and the reaction mixture was refluxed for 5-6 hr. The pro­gress of the reaction was monitored on TLC. On completion, the reaction mjxture was concentrated under reduced pressure, poured over crushed ice (200 g) and stirred vigorously until a brownish yellow col­oured solid precipitated out. It was filtered, washed with water, dried and column-chromatographed over silica gel using petroleum ether-ethyl acetate as eluent to afford phenylpyrazoles 8-19 as white/light brown solids in 45 to 54% yields. Compounds 20 and 21 were obtained as mjnor products from the reactions of

pyranones 5 and 6 with 4-methoxyphenylhydrazine hydrochloride and 4-chlorophenylhydrazine hydro­chloride, respectively. The known compounds 10-12 were identified on the basis of spectral data and by their comparison with those reported in the litera­ture'S.'6. New compounds 8,9 and 13-21 were identi­fied on the basis of their spectral data.

5-Cyanomethyl-1,3-diphenylpyrazole 8. Crystal­lised from acetone as light brown needles (0.82 g, 53%), m.p. 72-73°C. UV (MeOH): 229 and 252 nm; IR (KBr): 2720, 2200(C=N), 1625, 1540, 1300, 1220,930 and 720 cm"; 'H NMR (DMSO-d6): 0 4.33(2H, s, CH2CN), 7.04(lH, s, C-4H) and 7.40-7.92(lOH, m, aromatic protons); 13C NMR (DMSO-d6): 0 15.66 (GIzCN), 105.05(C-4), 116.96(CH2CN), 124.63 and 125.33(C-3', C-3" , C-5' and C-5"), 128.13 and 128.33(C-4' and C-4"), 128.74 and 129.45(C-2', C-2" , C-6' and C-6"), 132.31(C-l I), 134.40(C-5), 138.63(C-3) and 150.84(C-l"); ElMS (% reI. int.): mlz 260([M+lt, 21), 259(M+, 1(0), 258(51), 231(20), 219(4), 218(3), 180(2), 155(6), 149(4), 138(5), 130(5), 129(4), 116(8), 103(3), 102(3),89(4) and 77(12).

5-Cyanomethyl-1-( 4-methoxyphenyl)-3-phenyl­pyrazole 9. Crystallised from acetone as white nee­dles (0.85 g, 49%), m.p. 90-91 °C. UV (MeOH): 257 and 293 nm; IR (KBr): 2920, 2260(C=N), 1620, 1525, 1425, 1325, 1245, 1110, 1030, 840 and 760 cm-' ; 'H NMR (CDCb): 0 3.85(2H, s, CH2CN), 3.98(3H, s, OCH3), 6.79(1H, s, C-4H), 6.98(2H, d, J = 7.20 Hz, C-3"H and C-5"H), 7.35(5H, m, Ar'-H) and 7.78(2H, d, J = 7.20 Hz, C-2ltH and C-6 lt H); ElMS (% reI. int.): mlz 290([M+lt, 21), 289(M+, 100), 144(16), 105(15), 91(22) and 77(45).

5-Cyanomethyl-1-( 4-methoxyphenyl)-3-( 4-methyl­phenyl)pyrazole 13. Crystallised from acetone as white needles (0.95 g, 52%), mp 98-99°C. UV (MeOH): 272 and 280 nm; IR (KBr): 3000, 2920, 2260(C=N), 1610, 1520, 1440, 1300, 1260, 1180, 1105, 1030, 965, 840 and 790 cm-'; 'H NMR (DMSO-d6): 0 2.33(3H, s, CH3) , 3.84(3H, s, OCH3) ,

4.22(2H, s, CH2CN), 6.92(lH, s, C-4H), 7.11(2H, d, J = 8.84 Hz, C-3"H and C-5"H), 7.24(2H, d, J = 8.81 Hz, C-3'H and C-5'H), 7.51(2H, d, J = 8.84 Hz, C-2"H and C-6 ltH) and 7.76(2H, d, J = 8.81 Hz, C-2'H and C-6'H); 13C NMR (DMSO-d6): 0 15.44(GIzCN), 20.80(CH3), 55.47(OCH3), 104.21(C-4), 1 14.47(C-3' and C-5') , 117.02(CH2CN), 125.18(C-3 1t and C-5 "), 126.34(C-2' and C-6'), 129.29(C-2" and C-6"), 129.68(C-l I), 131.60(C-4'), 134.26(C-5), 137.32(C-3), 156.43(C-l It) and 159.03(C-4"); ElMS (% reI. int.):

364 INDIAN J. CHEM., SEC B, FEBRUARY 2002

mlz 303(M+, 100), 263(3), ISI(3), 146(3), 130(2) and 91 (3).

1-( 4-Chlorophenyl)-S-cyanomethyl-3-( 4-methyl­phenyl)pyrazole 14. Crystallised from acetone as a white fluffy solid (0.83 g, 4S%), m.p. 114-lS°C. UV (MeOH): 2S6 and 296 nm; IR (KEr): 2330(C=N), 1600, IS00, 1390, 1310, 1180, 1070, 960, 830 and 720 cm-'; 'H NMR (DMSO-d6): 8 2.30(3 H, s, CH3), 4.32(2H, s, CH2CN), 6.97(1H, s, C-4H), 7.2S(2H, d, J = 7.97 Hz, C-3'H and C-S'H), 7.64(4H, m, C-2'H, C-2"H, C-6'H and C-6"H) and 7.76(2H, d, J = 7.8S Hz, C-3"H and C-S"H); '3C NMR (DMSO-d6): 8 IS.S3 (CH2CN), 20.76(CH3), lOS. 12(C-4), 116.83(CH2CN), 12S.27 and 126.2 1(C-2', C-3', C-S' and C-6'), 126.S8(C-l'), 129.28 and 129.38(C-2", C-3", C-S" and C-6"), 132.64(C-4'), 134.S0(C-4"), 137.48(C-S), 137.S7(C-3) and IS1.13(C-l"); ElMS (% reI. int.): mlz 309([M+2t, 32), 307(M+, 100),272(12),267(16), 176(20), ISS(lS), 139(13), 128(1 2), 111(7S), 91(4S) , 7S(6S) and 39(38).

1-(4-Bromophenyl)-S-cyanomethyl-3-( 4-methoxy­phenyl)pyrazole 15. Crystallised from acetone as a white fluffy solid (1.S2 g, S2%), m.p. 122-24°C. UV (MeOH): 2S4 and 298 nm; IR (KBr): 2980, 2920, 22S0(C=N), 1620, IS2S, ISlO, 1490, 1370, 12S0, 1180, 1080, lOIS, 840 and 79S cm-'; 'H NMR (DMSO-d6): 8 3.80(3H, s, OCH3), 4.34(2H, s, CH2CN), 6.9S(lH, s, C-4H), 7.00(2H, d, J = 8.73 Hz, C-3'H and C-S'H), 7.S8(2H, d, J = 8.73 Hz, C-2'H and C-6'H) and 7.8 1(4H, m, Ar"-H); I3C NMR (DMSO­d6): 81S.S8(CH2CN), SS .10(OCH3) , 104.9S(C-4), 114. 13(C-3' and C-S'), 116.93(CH2CN), 120.98(C-l'), 124.68(C-4" ), 126.41 and 126.73(C-2', C-3", C-S" and C-6'), 132.34(C-2" and C-6"), 134.44(C-S), 137.95(C-3), IS 1.04(C-l ") and IS9.36(C-4'); ElMS (% reI. int.): mlz 369([M+2t, 100), 367(M+, 99), 184(9), 327(S), 329(4), 146(3), 194(2), 196(2) and ISS(9), IS7(8) .

3-( 4-CWorophenyl)-S-cyanomethyl-l-( 4-meth(]lxy­phenyl)pyrazole 16. Crystallised from acetone as a white fluffy solid (LOS g, S4%), m.p. 91-9S°C. UV (MeOH): 2S0 and 29S nm; IR (KEr): 2980, 28S0, 22S0(C=N), 1630, IS2S , 144S, 130S, 1260, 1030,800 and 700 cm-'; 'H NMR (DMSO-d6): 8 3.84(3H, s, OCH3), 4.24(2H, s, CH2CN), 7.01(1H, s, C-4H), 7.11(2H, d, J = 8.93 Hz, C-3"H and C-S"H), 7.47-7.S4(4H, m, C-2'H, C-2"H, C-6'H and C-6"H) and 7.89(2H, d, J = 8.93 Hz, C-3'H and C-S'H); I3C NMR (DMSO-d6): 8 IS.42(CH2CN), SS.46(OCH3), 104.S4 (C-4), 1 14.48(C-3" and C-S"), 116.92(CH2CN), 126.38 and 128.96(C-2", C-3', C-S' and C-6"),

1 28.73(C-2' and C-6'), 131.31 and 131.S0(C-l' and C-4'), 132.S0(C-3), 134.66(C-S), 149.26(C-l") and IS9.13(C-4" ); ElMS (% reI. int.): mlz 32S([M+2t, 34), 323(M+, 100), 282(S) , 261(3), 150(4), 146(1S) and 111(9).

1,3-Bis( 4-chlo ro phen y I)-S-cyan omethy I pyrazole 17. Crystallised from acetone as whi te needles (1.00 g, SI %), m.p. 115-16°C. UV (MeOH): 26S and 300 nm; IR (KBr): 3040, 2960, 2280(C=N), 1600, IS00, 1440, 1360, 1280, 109S, 960, 830 and 790 em" ; 'H NMR (DMSO-d6): 8 4.36(2H, s, CH2CN), 7.07(l H, s, C-4H), 7.S0(2H, d, J = 8.32 Hz, C-2"H and C-6"H), 7.66(4H, m, C-2'H, C-3"H, C-S"H and C-6'H) and 7.92(2H, d, J = 8.33 Hz, C-3'H and C-S'H); I3C NMR (DMSO-d6): 8 IS .S9(CH2CN), lOS.44(C-4), 116.82 (CH2CN), 126.32 and 127.10(C-2', C-3', C-S' and C-6'), 128.79(C-3" and C-5"), 129.45(C-2" and C-6"), 130.99(C-l'), 132.78(C-4"), 132.89(C-4') , 134.9S(C­S), 137.3S(C-3) and 149.98(C-l"); ElMS (% reI. int. ): mlz 331([M+4t, 11), 329([M+2t, 64), 327(M+, 100), 289(S), 287(6), 16S(2), 164(2), 163(2), IS2(4), IS0(11), 113(1 1) and 111(30).

3-(4-Bromophenyl)-I-( 4-chlorophenyl)-S-cyano­methylpyrazole 18. Crystalli sed from acetone as white needles (1.16 g, 52%), m.p. 122-24°C. UV (MeOH): 2S2 and 314 nm; IR (KBr): 29S0, 2860, 23S0(C=N), 1660, 1460, 1380, 1220, 1020, 980 and 780 em-i; 'H NMR (CDCI3): 8 3.76(2H, s, CH2CN), 6.82(1H, s, C-4H), 7.41(2H, d, J = 8.86 Hz, C-2"H and C-6"H), 7.S 1(2H, d, J = 8. 14 Hz, C-2'H and C-6'H), 7.S4(2H, d, J = 8.86 Hz, C-3"H and C-S "H) and 7.70(2H, d, J = 8.14 Hz, C-3'H and C-S'H); I3C NMR (CDCI3): 8 16.l6(CH2CN), 10S.60(C-4), 11S .2S (CH2CN), 122.48(C-4'), 126.40(C-2" and C-6"), 127.26(C-3' and C-S') , 129.91(C-3" and C-S"), 131.08 and 131.87(C-l', C-2' and C-6'), 133.01 (C-4"), 13S.02(C-S), 136.88(C-3) and IS 1.42(C-l "); ElMS (% reI. int.): mlz 37S([M+2t, 98), 374([M+lt, 24), 373(M+, 100), 347(4), 34S(12), 343(9), 19S(2), 187(4), 18S(3), ISS(3), IS0(4), 149(3), IIS(4), 111 (6) and 7S (S).

S-Cyanomethyl-3-(3,4-methylenedioxyphenyl)-I­phenylpyrazole 19. Crystallised fro m acetone as a buff coloured solid (0.87 g, 48%), m.p. lOS-06°C. UV (MeOH): 229, 274 and 299 nm; IR (KEr): 27S0, 23S0(C=N), 1600, 1510, 1340, 1220, 1040, 940 and 720 cm-' ; 'H NMR (DMSO-d6): 84.30(2H, s, CH2CN), 6.06(2H, s, OCH20 ), 6.96(l H, s, C-4H) and 7.40-7.60(8H, br m, aromatic protons); '3C NMR (DMSO-d6): 8 15.6S(CH2CN), 101.11(OCH20 ),

KUMAR et at. CHEMICAL TRANSFORMATIONS ON 6-AR YL-3-CY ANO-4-METHYL THIOPYRAN-2(H)-ONES 36S

104.81 (C-4), lOS.66(C-2'), 108.S3(C-5'), 116.98 (CH2CN), 119.20(C-6') , 124.S7(C-3" and C-S") , 126.S6(C-4") , 128.23 and 129.43(C-l', C-2" and C-6"), 134.26(C-S), 138.63(C-3), 147.26 and 147.73 (C-3' and C-4') and IS0.66(C-l "); ElMS (% reI. int.): mlz 304([M+ 1 t, 29), 303(M+, 100), 302(19), 263(3), 244(4), 218(2), 20S(3), 167(4), IS2(7), 149(15), 138(5), 109(2),89(2) and 77(5).

3-Amino-6-( 4-chlorophenyl)-2-( 4-methoxypheny 1)-4-oxo-4H -pyrano[ 4,3-c ]pyrazole 20. Crystallised from acetone as a pale yellow solid (O.IS g, 7%), m.p. 213- 14°C. UV (MeOH): 249 and 302 nm; IR (KBr): 3460, 3360(NH2), 3100, 2950, 1730(0-C=0), 1640, 1520, 1375, 1260, 1100, 1040,920 and 840 cm· l

; IH NMR (DMSO-d6): 8 3.83(3H, s, OCH3), 6.73(2H, brs, NH2), 7.1O(2H, d, J = 8.0 Hz, C-3'H and C-S'H), 7.23(1H, s, C-7H), 7.47-7.S7(4H, m, C-2'H, C-2"H, C-6'H and C-6"H) and 7.91(2H, d, J = 8.0 Hz, C-3"H and C-5"H); 13C NMR (DMSO-d6) : 8 S5.46(OCH3), 89.S0(C-9), 9S.96(C-7), 114.61(C-3' and CoS') , 126.08 and 126.77(C-2", C-3" , C-S" and C-6"), 128.86(C-2' and C-6'), 130.2 1(C-6), 131.18(C-l"), 134.22(C-4"), 148.29(C-l '), 148.44(C-8), 153.91 (C-4'), IS8 .08(C-3) and IS8 .8S(C-4); ElMS (% reI. int.): mlz 369([M+2t, 33), 367(M+, 100), 341(1), 339(3), 324(6), 298(S), 256(10), 149(4), 139(12) and 108(S).

3-Amino-6-( 4-bromophenyl)-2-( 4-chlorophenyl)-4-oxo-4H-pyrano[ 4,3-c ]pyrazole 21. Crystallised from acetone as a pale yellow solid (0.15 g, 6%), m. p. 289-91°C. UV (MeOH): 26S, 287 and 301 nm; IR (KBr): 3343(NH2), 2923, 2853, 1714(0-C=0), 1634, 1487, 1397, 12S2, 1006 and 809 cm· l

; IH NMR (DMSO-d6): 8 7.26(1H, s, C-7H), 7.47(2H, brs, NH2), 7.S8(2H, d, J = 8.7 Hz, C-3"H and C-S"H), 7.62-7.68(4H, m, C-2"H, C-3'H, C-S'H and C-6"H) and 7.78(2H, d, J = 8.7 Hz, C-2'H and C-6'H); l3C NMR (DMSO-d6): 8 91.27(C-9), 93.04(C-7), 1 16.87(C-4'), 126.33(C-2" and C-6"), 127.35(C-3' and CoS'), 129.9S(C-l"), 131.08(C-3" and C-5"), 131.61(C-6), 132.43(C-2' and C-6'), 132.64(C-4"), 137 .62(C-l '), 148.01(C-3), 149.46(C-8) and 159.75(C-4) ; ElMS (% reI. int.): mlz 419([M+4t, 27), 417([M+2t, 100), 415([Mt, 76), 387(12), 389(16), 358(4), 360(6), 185(5), 183(5), 157(3), 154(2), 137(10) and 44(24).

3-Cyanomethyl-5-(3, 4-methylenedioxyphenyl)­pyrazo1e 22.. To a solution of 3-cyano-6-(3,4-methylenedioxyphenyl)-4-methylthiopyran-2(H)-one (7, 1.72 g, 6 mmoles) in methanol (30 mL), hydrazine monohydrate (0.3 g, 9 mmoles) was added and the reaction mixture was refluxed for 6 hr. The progress

of the reaction was monitored on TLC. On comple­tion, the reaction mixture was concentrated under re­duced pressure, poured over crushed ice (200 g) and stirred vigorously until a brownish-yellow solid sepa­rated out. It was filtered, washed with water (2x25 mL), dried and column chromatographed over silica gel using ethyl acetate-petroleum ether as eluent to afford pyrazole 22 which crystallised out from ethyl acetate as white shining needles (0.76 g) in S6% yield, m.p. 170-71 °C. UV (MeOH): 266 and 299 nm; IR (KBr): 3244(NH), 22S3(C=N), IS01, 1475, 1440, 1234, 1035, 1010, 933, 874, 820 and 788 cm-I; IH NMR (CDCI3): 83.78 (2H, s, CH2CN), 6.02 (2H, s, OCH20), 6.4S(1H, s, C-4H), 6.87(lH, d, J = 9.00 Hz, C-S'H), 7.03(1H, d, J = 2.30 Hz, C-2'H), 7.08(1H, dd, J = 9.00 and 2.30 Hz, C-6'H) and 7.38(1H, s, NH); 13C NMR (CDCI3): 818.30 (CH2CN), 101.80 and 10 1.90(C-4 and OCH20), 106.02 and 109.0S(C-S' and C-6'), 116.08 (C=N), 119.S0 (C-2'), 123.02 (C- l '), 143.0S and 14S.08 (C-3 and CoS), and 148.70 and 148.80 (C-3' and C-4'); LCMS (% reI. int.): mlz 2S0 ([M+Nat, 4), 228 ([M+Ht, 100), 170 (6) and 79 (4). The structure of pyrazole 22 was finally confirmed on the basis of its X-ray crystallographic studies (Figure 2) .

5-Cyanomethyl-3-phenylisoxazole13 23. Hydroxyl­amine hydrochloride (7 mmoles) was added to a solu­tion of 3-cyano-4-methylthio-6-phenylpyran-2(H)-one (1, 972 mg, 4 mmoles) in pyridine (10 mL) and the reaction mixture stirred for 4Shr at 70-80°C. Pyridine was distilled off under reduced pressure and the resi­due taken up in ethyl acetate, washed with water, dil. HCI and dried over anhydrous Na2S04. The gummy residue obtained after removal of ethyl acetate was subjected to column chromatography over silica gel using petroleum ether-ethyl acetate to afford the isoxazole 23 which crystallised out from ethyl acetate as white shiny needles (29S mg, m.p. 8S-86°C; lit. 13

m.p. 83-84°C) in 40% yield. The structure of isoxa­zole 23 was confirmed by X-ray crystallographic studies (Figure 3).

General method of preparation of N-phenyl­pyrazolylcoumarins 24-26. To a solution of 1,3-diarylpyrazole (10111, 2 mmoles) in ethanol (20 mL) was added 2-hydroxy-3-methoxybenzaldehyde/3,5-dichloro-2-hydroxybenzaldehyde (2.4 mmoles), fol­lowed by aqueous sodium hydroxide (10%, IS mL). The reaction mixture was stirred for 1 hr at 45-50°C, cooled in an ice bath and acidified with dilute hydro­chloric acid. The solid that separated on acidification

366 INDIAN 1. CHEM ., SEC B, FEBRUARY 2002

was filtered, dried and crystallised from a mixture of petroleum ether-ethyl acetate to afford light yel­low/yellow crystals of N-phenylpyrazolyl-coumarins 24-26 in 80 to 90% yields.

8-Methoxy-3-[3-( 4-methy Iphenyl)-l-phenylpyra­zol-5-yl]coumarin 24. Light yellow needles (685 mg, 84% yield), m.p. 92-93°C. UV (MeOH): 291, 355 and 379 nm; IR (KBr): 3020, 2945, 2890, 1735(C=O), 1680, 1615, 1530, 1365, 1285, 1250, 1095, 1018,930 and 760 cm·l

; IH NMR (CDCb + a drop of TFA): 8 2.25(3H, s, CH3), 3.75(3H, s, OCH3), 6.70(1H, s, C-4'H), 7.18(2H, d, J = 8.0 Hz, C-3 tt H and C-5 tt H), 7.40-7.44(5H, m, Ar'''-H), 7.46(2H, d, J = 8.0 Hz, C-2ttH and C-6tt H) and 7.50-7.60(4H, m, C-4H, C-5H, C-6H and C-7H); ElMS (% rel. int.): mlz 408(M+, 7), 292(29), 291(100), 273(12), 248(37), 247(70), 130(34), 115(6),91(8) and 77(15).

6,8-Dichloro-3-[3-( 4-methylphenyl)-1-phenylpyra­zol-5-yl]coumarin 25. Yellow needles (715 mg, 80% yield), m.p. 190-91°C. UV (MeOH): 257, 285 and 355 nm; IR (KBr): 2940, 2880, 1750(C=O), 1670, 1600, 1505, 1460, 1350, 1240, 1105, 980, 860, 835 and 765 em-I; IH NMR (CDCI3 + a drop of TFA): 8 2.43(3H, s, CH3), 7.26(1H, s, C-4'H), 7.35-7.53(5H, m, Artt'-H), 7.56(2H, d, J = 13.4 Hz, C-3 tt H and C-5tt H), 7.63(1H, s, C-5H), 7.65(1H, s, C-7H), 7.73(2H, d, J = 13.4 Hz, C-2ttH and C-6 tt H) and 7.90(1H, s, C-4H); l3C NMR (CDCb + a drop of TFA): 8 21.30(CH3), 107.68(C-4'), 112.22(C-5 and C-7), 116.75(C-3 tt & C-5 tt ), 120.97(C-4a), 121.28(C-8), 126.48(C-2tt and C-6"), 126.58(C-4"'), 130.46 and 130.60(C-2"', C-3"', C_5'tt and C-6"'), 131.49(C-3), 132.91(C-6), 137. 14(C-4tt), 142.93(C-l tt), 143.82(C-3'), 149.36 and 149.78(C-5' and C-8a), 150.16(C-l 'tt), I 52.22(C-4 ) and 196. 16(C-2); ElMS (% rel. int.): mlz 449([M+2t, 6), 448([M+lt, 20), 447(M+, 10), 446(30),417(34),320(9),299(11),291(69),273(100), 247(54),138(15),130(17),115(6),91(9) and 77(13).

6,8-Dichloro-3-[3-( 4-chlorophenyl)-1-phenylpyra­zol-5-yl]coumarin 26. Yellow needles (841 mg, 90% yield), m.p. 227-28°C. UV (MeOH): 257, 293 and 336 nm; IR (KBr): 3090, 2920, 1750(C=O), 1670, 1600, 1508, 1460, 1365, 1238, 1110, 980, 950, 860, 822, 785 and 695 em-I; IH NMR (CDCb+ a drop of TFA): 8 7.26(1H, s, C-4'H), 7.31(1H, s, C-7H), 7.48-7.55(5H, m, Ar"'-H) and 7.72-7.78(6H, m, C-2ttH, C-3"H, C-5 tt H, C-6"H, C-4H and C-5H); l3C NMR (CDCb+ a drop of TFA): 8 112. 16(C-4'), 116.69(C-8), 119.49(C-5), 121.22(C-4a), 123.30(C-7), 126.20(C-2tt and C_6 tt ), 126.74(C-4"'), 128.22(C-2"',

C-3''', C-5'" and C-6"'), 130.04 and L30.49(C-3 tt and C-5"), 131.37(C-6), 132.02(C-3), 134.35(C-4" ), 138.15(C-ltt), 140. 16(C-3'), 145.23(C-5'), 148.06(C-8a), 149.32(C-4), 158.26(C-l "') and I 95.00(C-2); ElMS (% rel. int.): mlz 470([M+4t, 35), 468([M+2t, 100), 466(M+, 99), 451 (10), 449( 10), 439(15), 437(14),234(9),233(8), 184(3), 138(4) and 77(8) .

X-ray crystallography The crystallographic measurements on comp­

ounds 3-cyanomethyl-6-(3,4-methylenedioxyphenyl)-4-methylthiopyran-2(H)-one 7, 3-cyanomethyl-5-(3,4-methylenedioxyphenyl)pyrazole 22 and 5-cyanomethyl-3-phenylisoxazole 23 were made using a Siemens SMART area-detector diffractometer. Graphite monochromated Mo-Ka radiation was used in all the cases. The structures were solved using SHELXTL-PLUS I7 and refined with SHELXL-96 Is. The crystal data of compounds 7,22 and 23 are given below.

3-Cyanomethyl-6-(3, 4-methylenedioxyphenyl)-4-thiomethyl-pyran-2(H)-one 7. C I4H9N04S, M = 287.28, T = 220(2) K, A = 0.71073 A. Monoclinic a = 11.206(9), b = 7.260(8), C = 15.268(12) A, ~ = 99.25(7)°, V = 1239(2) A3, space group P2(1)/C, Z = 4, Dx = 1.540 Mg/m3, I-l = 0.274 mm· l

, F (000) = 592. Crystal size 0.38xO.13xO.03 mm; 8 range for data collection 2.68 to 24.05°, limiting indices 0 ~ h ~12 , -1 ~ k ~ 8, -17 ~l~ 17; reflections collected 2406; in­dependent reflections 1941 [R(int) = 0.0733]; reflec­tions method full-matrix least squares on F2; data/restraints/parameters 1936/0/182; goodness-of-fit on F2 0.964; R(f)[1>2cr(I)] = 0.0712; WR2 = 0.1726, largest diff. peak and hole 0.629 and -0.491 eA.-3

3-Cyanomethyl-5-(3, 4-methylenedioxyphenyl)­pyrazole 22. C 12H9N302, M = 227.22, T = 293(2) K, A = 0.71073 A. Triclinic a = 6.7967(8), b = 7.5179(9) A, c = 11.1202(13) A, ~ = 72.9460(10)°, V = 521.39 (11) A3, space group PI, Z = 2, Dx = 1.447 Mg/m3, 1-l=0.103 mm· l

, F (000) = 236. Crystal size 0.44xO.20xO.18 mm; 8 range for data collection 1.93 to 24.99°, limiting indices -8 ~ h ~ 8, -9 ~ k ~ 9, -14 ~ I ~ 14; reflections collected 2720; independent reflec­tions 1797 [ROnt) = 0.0486]; refinement method full­matrix least squares on F2; data/restraints/para­meters 1797/01158; goodness-of-fit on F2 1.160; R(f)[I>2cr(l)] = 0.0781; WR2 = 0.2 120; largest diff. peak and hole 0.446 and -0.281 eA3.

5-Cyanomethyl-3-phenylisoxazole 23. C II HsN20 , M = 184.19, T = 293(2) K, A = 0.7 1073 A. Monoclinic

KUMAR et al. CHEMICAL TRANSFORMATIONS ON 6-ARYL-3-CYANO-4-METHYLTHIOPYRAN-2(H)-ONES 367

a = 2l.7371(9), b = 5.7571(3), c = 7.1457(4) A, ~ = 90.823(2t, V = 894.14(8) A3, space group P21/C, Z = 4, Dx = 1.368 Mg/m3, J.! = 0.091 mm-I , F(OOO) = 384. Crystal size 0.40 x 0.20xO.24 mm; e range for data collection 1.87 to 25.00°; limiting indices -22 ~ h ~ 28, -7 ~ k ~ 6, -9 ~ I ~ 9; reflections collected 4500; inde­pendent reflections 1556 [R(int) = 0.0860]; refinement method full-matrix least squares on F2; data/restraints/parameters 1556 / 0 / 128; goodness-of­fit on F2 0.961; R(f)[I>2cr(I)] = 0.0709; WR2 = 0.1544; largest diff. peak and hole 0.341 and -0.375 eA?

Acknowledgements We thank Danish International Development

Agency (DANIDA, Denmark) and CSIR, New Delhi, for financial assistance.

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