Chemical transformations on 6-aryl-3-cyano-4-methylthio-pyran-2(<i>H</i>)-ones: Synthetic and structural studies on novel N-phenylpyrazoles and <i>N-</i>phenylpyrazolylcoumarins

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Indian Journal of Chemistry

Vol. 41B, 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 Vatsâ, Himanshu", Sanjay K Singhâ, Sunil K Sharmaâ, Ashok K Prasad"*, William Errington^b, Carl E Olsen^c, Subhash C Jain' & Virinder S Parmar"*

'Department of Chemistry, University of Delhi, Delhi llO 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. antioxi- dant, I antiinvasive,2 antiviral,3 antipyretic,4.5 antiln- flammatory,6 antidepressant,7 blood pressure lower- ing,S etc. Pyrazoles are also used as agrochemicals,9.10 d yestu s, m sunscreen matena s, ff ^{I I ·} ^. I 12 etc. O· wmg to t e h widespread application of pyrazoles and their derivatives, we have synthesised a series of pyranonesl3, pyrazoles l.13, isoxazoles l3 and pyrazolyl acryloll1i- trilesl, and evaluated their antioxidant ^I and antiinva- sive2 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

+

e

H2 NC/

'cae

_II _{2 5}^H

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

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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 9C^{H 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-methylthio- one 7 and 3-cyano-4-methyl-thio-6-phenylpyran- 2(H)-one 1 lead to the formation of 3-cyano-

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

~

/ ~ ^~(). ^C=N

"

RI

+

⁰ ⁰

,-

a

^I

^NH2-NHR2 ^-CIilSH

t

^P

rJYC:N ~

H-N--~H

~r HI\I, y,-OH 0

£X~N

N-~ RI 0 0

H.

~

^~C=N

^ttN--

^~^N

R I

~N""P ~-o-H

~ I

iJ:b~H

~

⁰ ^RI ⁰ ⁰

~ ~N""N..~ ~~H

^~N

t

^,~

RI ~I ⁰

f t

^NH²

-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, N- pheny/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 10,1611^,15and 12¹⁵and isoxazole 23¹were identified on the basis 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-l- phenylpyrazole 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-methylenedioxyphenyl)-4- methylthiopyran-2(H)-one 7

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

Figure 3 - 5-Cyanomethyl-3-phenylisoxazole 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

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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 literature13

.

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. Crystal- lised 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-d_6):

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, OCH_3),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-6ltH); 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-d_{6 ):}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-6ltH) and 7.76(2H, d, J

=

8.81 Hz, C-2'H and C-6'H); 13C NMR (DMSO-d_6):

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.):

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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-d_6):8 2.30(3H, s, CH3), 4.32(2H, s, CH2CN), 6.97(1H, s, C-4H), 7.2S(2H, d, J

=

^7.97Hz, 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 126.21(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(12), 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-d_6): 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

=

^8.73Hz, C-2'H and C-6'H) and 7.81(4H, m, Ar"-H); I3C NMR (DMSO- d_6): 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(]lxy- phenyl)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-d_6):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(OCH_3), 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(lH, 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);^I3^{C NMR}

(DMSO-d_{6 ):} 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(C- S), 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(11) and 111(30).

3-(4-Bromophenyl)-I-( 4-chlorophenyl)-S-cyano- methylpyrazole 18. Crystallised 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.S1(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)-I- phenylpyrazole 19. Crystallised from 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-d_{6 ):} 84.30(2H, s, CH2CN), 6.06(2H, s, OCH₂0), 6.96(lH, s, C-4H) and 7.40-7.60(8H, br m, aromatic protons); '3C NMR (DMSO-d_{6 ):} 8 15.6S(CH₂CN), 101.11(OCH₂0),

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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-d_{6 ):}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'), 130.21(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-d_6):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-d_6):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 (CDCI 3): 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-phenylisoxazole¹³23. Hydroxyl- amine 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 hydro- chloric acid. The solid that separated on acidification

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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-phenylpyra- zol-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-3tt

H and C-5tt 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-phenylpyra- zol-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-3ttH and C- 5ttH), 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-3tt & C-5tt), 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-8_{a ),}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-phenylpyra- zol-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-3tt 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 compounds 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-PLUSI7

and refined with SHELXL-96Is . 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. C12H9N302, 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 full- matrix least squares on F2; data/restraints/parameters 1797/01158; goodness-of-fit on F2 1.160;

R(f)[I>2cr(l)] = 0.0781; WR2 = 0.2120; 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

= 0.71073

A.

Monoclinic

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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-of- fit 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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