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A Simplified Cadogan's Approach to Synthesis of New Isoxazolyl Indazoles

A Simplified Cadogan's Approach to Synthesis of New Isoxazolyl Indazoles

Indian Journal of Chemistry Vol. 47B, October 2008, pp. 1591-1596

Note

A simplified Cadogan’s approach to synthesis activity 13,14 was produced. The chemistry of these of new isoxazolyl linked bi-heterocycles has been the fascinating field of investigation in medicinal chemistry, as they have 15 E Rajanarendar*, A Siva Rami Reddy & Firoz been found to exhibit enhanced biological profile . Pasha Shaik Keeping in view the high potential of indiazoles Department of Chemistry, Kakatiya University, and isoxazoles as drug candidates, the synthesis of Warangal 506 009, India some novel analogs of isoxazolyl indazoles was E-mail: [email protected] undertaken, which are expected to be studied later for their medicinal properties. Received 21 May 2008; accepted (revised) 29 July 2008 The synthesis of a variety of containing Isoxazolyl Schiff bases have been prepared from the heteocycles including indazoles, by de-oxygenative corresponding amines by reaction with 2-nitrobenzalde- cyclization of aromatic nitro compounds was reported hydes.These nitro compounds undergo de-oxygenative cyclization by Cadogan et al. 16,17 . The reaction requires heating to give indazoles via nitrenes on heating with triethyl phosphite in with excess of triethyl phosphite for several hours acetonitrile. Isoxazolyl indazoles have also been synthesized in a under N atmosphere. The reaction mechanism one-pot reaction. 2 involves the generation of a nitrene that is inserted to Keywords: Isoxazolyl indazoles, one-pot synthesis, form a new nitrogen containing ring. Another simplified Cadogan’s synthesis, de-oxygenative cyclization common route to the synthesis of ring system is diazotisation of o-toluidines in acidic or The chemistry of heterocycles lies at the heart of drug neutral aqueous solution 18 . Recently, the synthesis of discovery 1. Many known active compounds contain pyrazolo [3,4-a] isoxazoles from 4-isoxazolyl heterocyclic cores, which are indispensable elements diazonium tetrafluoroborates has been reported under for bioactivity 2. Among aromatic heterocyles, the phase transfer conditions 19 . By adopting Cadogan isoxazole unit constitutes an easily accessible nucleus technique, de-oxygenative cyclization of 3-methyl-4- that is present in a number of natural and nitro-5-styrylisoxazole could not succeed in the pharmacological compounds 3. Additionally, construction of the ring formation, as the isoxazoles display a wide range of organic reactivities reaction resulted in the cleavage of the most liable and could be used as an effective means of preparing nitroisoxazole on heating at high temperature 20 . In new molecular scaffolds 4. Isoxazoles have been view of this, the reaction has been planned in such a repeatedly shown as useful synthons in organic way, that the nitro group does not exist on the synthesis 5. isoxazole ring, so that, the de-oxygenative cyclization Substituted indazoles are a group of heterocycles of isoxazole Schiff bases derived from 2- gaining much importance in the recent research nitrobenzaldehyde could be conducted. The problem leading to discovery of potential drug candidates. of isoxazole ring undergoing cleavage on heating in Compounds derived from indazoles as basic moiety the presence of triethylphosphite 21 could be have been shown to possess a number of medicinal overcome, as the de-oxygenative cyclization was properties, which include, broad spectrum carried out under controlled heating conditions. As a antimicrobial 6,7 , DNA gyrase inhibitors 8, anti parasitic sequel to the interest in the synthesis of isoxazolyl activity 9, activation of soluble guanylate cyclase nitrogen heterocycles 22-25 , herein is reported the ( receptor) 10 , neuronal nitric synthesis of isoxazolyl indazoles for the first time via oxide synthase inhibitor 11 , selective Rho Kinase nitrenes. inhibitors 12 and anti cancer agents (kinase inhibitors) 12 . Results and Discussion

Survey of literature revealed that when one The reaction of 4-amino-3,5-dimethylisoxazole 1 biodynamic heterocyclic system was coupled with with 2-nitrobenzaldehyde was carried out in methanol another, a molecule with enhanced biological in 2 hr. The product obtained was identified as 1592 INDIAN J. CHEM., SEC B, OCTOBER 2008

R

OHC R H C NH N CH R N 3 2 H3C H3C N O2N (EtO) P 3 N O ethanol N O N N O 2 CH3CN O CH3 CH3 CH3 1 2 3

2a, R= H 3a, R=H 2b, 3b, R=Cl R= Cl Scheme I

R

OHC R N CH NH2 R N ON (EtO) P N N 2 3 H C O ethanol N ON CH CN N 3 H C O 2 3 O 3 H3C 4 5 6

5a, R= H 6a, R= H 5b, R= Cl 6b, R= Cl Scheme II isoxazole Schiff base 2 after purification by array of substituents on the benzene ring. To the best recrystallization from ethanol. of the knowledge, this report is the first of its kind to The nitro compounds 2 on heating while stirring in construct an indazole ring on isoxazole employing a the presence of triethyl phosphite in acetonitrile for 4 simplified hr underwent deoxygenative cyclization to give Cadogan reaction, as the reaction was carried out in isoxazolyl indazoles 3 in moderate to good yields, a one-pot method and without using N 2 atmosphere without using N 2 atmosphere, which is generally (Scheme II , Scheme III) . required in Cadogan’s approach. The reaction In conclusion, a new protocol has been successfully mechanism involves the generation of nitrenes that demonstrated for the synthesis of isoxazolyl indazoles underwent insertion to form indazoles through N-N by simplified Cadogan reaction in a one-pot method. bond formation (Scheme I) . In view of potential activity of isoxazoles and Synthesis of the isoxazolyl indazoles in a one-pot indazoles, it is predicted that the newly synthesized reaction could also be successfully completed. The isoxazolyl indazoles may be drug candidates and the two step Cadogan’s reaction for the synthesis of activity data will be published later. indoazoles was simplified to a one-pot reaction. For example, a mixture of 2-nitrobenzaldehyde, Experimental Section aminoisoxazole in equimolar ratio with excess of All the melting points were determined on a Cintex triethyl phosphite on heating while stirring in melting point apparatus and are uncorrected. acetonitrile resulted in the formation of indazole 3. Analytical TLC was performed on Merck precoated Finally, the results indicate that the current method 60 F 254 silica gel plates. Visualization was done by is compatible with various functional groups and the exposing to iodine vapour. IR spectra (KBr pellet) approach proved to be of general applicability as the were recorded on a Perkin-Elmer BX series FT-IR reaction was carried out on different isoxazoles. This spectrophotometer. 1H NMR spectra were recorded on synthetic strategy permits the introduction of a diverse a Varian Gemini 300 MHz spectrometer. Chemical

NOTES 1593

R

OHC R H C NH 3 2 H C N CH H C N ON 3 R 3 N 2 (EtO) P N 3 O N N Ar ethanol O ON CH3CN O CH CH St 2 St 7 8 9

8 , 9 St=CH CH Ar, R= H 8a, Ar = C H 6 5 9a, Ar = C6H5 8b, Ar = 4- CH C H 3 6 4 9b, Ar = 4- CH3C6H4 8c, Ar = 4- OCH C H 3 6 4 9c, Ar = 4- OCH3C6H4 8d, Ar = 4- ClC H 6 4 9d, Ar = 4- ClC6H4 8e, Ar = 2- ClC H 6 4 9e, Ar = 2- ClC6H4 8f, Ar =2- CH C H 9f, Ar = 2- CH C H 3 6 4 3 6 4 Scheme III shift values are given in ppm ( δ) with tetra- General procedure for the synthesis of N-(5- methylsilane as interal standard. Mass spectral methylisoxazol-3-yl)-N-(( E)-1-(2-nitrophenyl)met- measurements were carried out by EI method on a hylidene)amines , 5a ,b. A mixture of 3-amino-5- Jeol JMC-300 spectrometer at 70 eV. Elemental methyl-isoxazole 4 (0.01 mole) and 2-nitrobenzalde- analyses were performed on a Carlo Erba 106 Perkin- hyde (0.01 mole) were refluxed in ethanol (10 mL) Elmer model 240 analyser. for 2 hr. The resultant solution was cooled, the solid General procedure for the synthesis of N-(3,5- thus separated was filtered and purified by recrystal- dimethylisoxazol-4-yl)-N-(( E)-1-(nitrophenyl)met- lization from pet-ether. N N E hylidene) amines , 2a ,b. A mixture of 4-amino-3,5- -(5-Methylisoxazol-3-yl)- -(( )-1-(2-nitrophe- nyl)methylidene)amine , 5a . Yield: 85%. m.p. 52- dimethyl-isoxazole 1 (0.01 mole) and 2- -1 1 nitrobenzaldehyde (0.01 mole) were refluxed in 55°C; IR (KBr): 1635 (s), 1530 (s), 1360 (s) cm ; H δ ethanol (10 mL) for 2 hr. The resultant solution was NMR (200 MHz, CDCl 3): 2.4 (s, 3H, CH 3), 5.5 (s, 1H, isoxazole-H), 7.6-8.2 (m, 4H, Ar-H),10.4 (s, 1H, - cooled, the solid thus separated was filtered and + purified by recrystallization from pet-ether. N=CH); EI-MS: m/z 232 (M+H) . Anal. C 11 H9N3O3: Found C, 57.16; H, 3.84; N, 18.14. Calcd. C, 57.14; N N E -(3,5-Dimethylisoxazol-4-yl)- -(( )-1-(nitrophe- H, 3.89; N, 18.18%. nyl)methylidene)amine , 2a . Yellow colour comp- N-[( Z)-1-(5-Chloro-2-nitrophenyl)methylidene]- ound; Yield: 85%. m.p. 56-58°C; IR (KBr): 1615 (s), N -1 1 -(5-methyl-3-isoxazolyl)amine , 5b . Yield: 75%. 1515 (s), 1415(s) cm ; H NMR (200 MHz, CDCl 3): m.p. 97-100°C; IR (KBr): 1630 (s), 1540 (s), 1390 (s) δ 2.5 (s, 3H, CH 3), 2.6 (s, 3H, CH 3), 7.6-8.4 (m, 4H, -1 1 δ + cm ; H NMR (200 MHz, CDCl 3): 2.6 (s, 3H, CH 3), Ar-H), 9.0 (s, 1H, -N=CH-); EI-MS: m/z 245 (M ). 5.8 (s, 1H, isoxazole-H), 7.4-8.2 (m, 3H, Ar-H), 10.9 Anal. C 12 H11 N3O3: Found C, 58.74; H, 4.40; N, 17.11. (s, 1H, -N=CH); EI-MS: m/z 266 (M+H) +. Anal. Calcd. C, 58.77; H, 4.48; N, 17.14%. C12 H10 N3O3Cl: Found C, 49.78; H, 3.09; N, 15.88. N-[( Z)-1-(5-Chloro-2-nitrophenyl)methylidene]- Calcd. C, 49.81; H, 3.01; N, 15.84%. N-(3,5-dimethyl-4-isoxazolyl) amine , 2b .Yellow General procedure for the synthesis of N-(3- colour compound; Yield: 75%. m.p. 93-95°C; IR methyl-5-(( E)-2-phenyleth-1- enyl)isoxazol-4-yl)-N- (KBr): 1620 (s), 1530 (s), 1410 (s) cm -1; 1H NMR (200 (( E)-1-(2-nitrophenyl)methylidene)amines , 8a ,f. A MHz, CDCl 3): δ 2.4 (s, 3H, CH 3), 2.6 (s, 3H, CH 3), mixture of 4-amino-3-methyl-5-styrylisoxazole 7 7.7-8.6 (m, 3H, Ar-H), 9.1 (s, 1H, -N=CH-); EI-MS: (0.01 mole) and substituted 2-nitrobenzaldehyde (0.01 + m/z 279 (M ). Anal. C 12 H10 N3O3Cl: Found C, 51.66; H, mole) were refluxed in ethanol (10 mL) for 2 hr. The 3.63; N, 15.01. Calcd. C, 51.61; H, 3.58; N, 15.05%. resultant solution was cooled, the solid thus separated

1594 INDIAN J. CHEM., SEC B, OCTOBER 2008

was filtered and purified by recrystallization from pet- dene]amine , 8f . Yield: 75%. m.p. 64-67°C; IR (KBr): ether. 1650 (s), 1535 (s), 1420 (s) cm -1; 1H NMR (200 MHz, N E -(3-Methyl-5-(( )-2-phenyleth-1-enyl)isoxazol- CDCl 3): δ 2.3 (s,3H, CH 3), 2.6 (s, 3H, CH 3), 7.2 (d, 4-yl)-N-(( E)-1-(2-nitrophenyl) methylidene)amine , 1H, CH=CH), 7.3-8.0 (m, 8H, Ar-H and 1H, - 8a . Yield: 85%. m.p. 72-75°C; IR (KBr): 1625 (s), CH=CH), 10.1 (s, 1H, -N=CH-); EI-MS: m/z 348 -1 1 + 1550 (s), 1440 (s) cm ; H NMR (200 MHz, CDCl 3): (M+H) . Anal. C 20 H17 N3O3: Found C, 69.10; H, 4.86; δ 2.3 (s, 3H, CH 3), 7.2 (d, 1H, CH=CH),7.6–8.0 (m, N, 12.65. Calcd. C, 69.16; H, 4.89; N, 12.61%. 9H, Ar-H and 1H, -CH=CH), 10.0 (s, 1H, -N=CH-); General procedure for the synthesis of 4-(2 H- + EI-MS: m/z 334 (M+H) . Anal. C 19 H15 N3O3: Found C, indazol-2-yl)-3,5-dimethyl isoxazoles , 3a -f: Schiff 68.40; H, 4.52; N, 12.66. Calcd. C, 68.46; H, 4.50; N, base 2 (0.01 mole) and excess of triethyl phosphite (3 12.61%. mL ) were taken in acetonitrile (15 mL) and the N-3-Methyl-5-[( E)-2-(4-methylphenyl)-1-ethen- contents were heated with stirring for 4 hr. The excess yl]-4-isoxazolyl-N-[( Z)-1-(2-nitro phenyl)methyli- reagent was distilled off under reduced pressure and dene]amine , 8b . Yield: 70%. m.p. 67-69°C; IR the resultant gummy product was processed with pet. (KBr): 1640 (s), 1565 (s), 1485 (s) cm -1; 1H NMR ether. Purification by recrystallization from methanol

(200 MHz, CDCl 3): δ 2.3 (s,3H,CH 3), 2.5 (s, 3H, gave pure product. H CH 3), 7.0 (d, 1H, CH=CH),7.5–8.6 (m, 8H, Ar-H and 4-(2 -Indazol-2-yl)-3,5-dimethylisoxazole , 3a . 1H, -CH=CH), 10.1 (s, 1H, -N=CH-); EI-MS: m/z 348 Yield: 85%. m.p. 87-90°C; IR (KBr): 1650 (s), 1575 + -1 1 (M+H) . Anal. C 20 H17 N3O3: Found C, 69.13; H, 4.91; (s) cm ; H NMR (300 MHz CDCl 3 ): δ 2.2 (s, 3H, N, 12.15. Calcd. C, 69.16; H, 4.89; N, 12.10%. CH 3 ), 2.4(s, 3H,CH 3), 7.5-7.7 (m, 4H, Ar-H), 8.0 N-5-[( E)-2-(4-Methoxyphenyl)-1-ethenyl]-3-me- (s,1H, indazole-H); EI-MS: m/z 213(M +). Anal. thyl-4-isoxazolyl-N-[( Z)-1-(2-nitro phenyl)meth- C12 H11 N3O: Found C, 67.66; H, 5.12; N, 19.77. Calcd. ylidene]amine , 8c . Yield: 80%. m.p. 90-93°C; IR C, 67.60; H, 5.16; N, 19.71%. (KBr): 1645 (s), 1510 (s), 1480 (s) cm -1; 1H NMR 4-(5-Chloro-2H-2-indazolyl)-3,5-dimethylisoxaz-

(200 MHz, CDCl 3): δ 2.2 (s, 3H, CH 3), 3.8 ole , 3b . Yield: 75%. m.p. 101-02°C; IR (KBr): 1665 -1 1 (s,3H,OCH 3), 6.9 (d, 1H, CH=CH),7.9–8.8 (m, 8H, (s), 1590 (s) cm ; H NMR (300 MHz CDCl 3): δ 2.4 Ar-H and 1H, -CH=CH), 10.0 (s, 1H, -N=CH-); EI- (s, 3H, CH 3 ), 2.7(s, 3H, CH 3), 7.1-7.5 (m, 3H, Ar-H ), + + MS: m/z 364 (M+H) . Anal. C 20 H17 N3O4: Found C, 8.2 (s, 1H, indazole-H); EI-MS: m/z 247 (M ). Anal. 66.14; H, 4.70; N, 11.53. Calcd. C, 66.11; H, 4.68; N, C12 H10 N3O3Cl: Found C, 58.24; H, 4.07; N, 17.06. 11.57%. Calcd. C, 58.29; H, 4.04; N, 17.00%. N-5-[( E)-2-(4-Chlorophenyl)-1-ethenyl]-3-meth- General procedure for the synthesis of 3-(2 H- yl-4-isoxazolyl-N-[( Z)-1-(2-nitro phenyl)methylide- indazol-2-yl)-5-methylisoxazoles , 6a ,b: Schiff base 5 ne]amine , 8d . Yield: 75%. m.p. 110-12°C; IR (KBr): (0.01 mole) and excess of triethyl phosphite (3 mL) 1665 (s), 1590 (s), 1410 (s) cm -1; 1H NMR (200 MHz, were taken in acetonitrile (15 mL) and contents were

CDCl 3): δ 2.6 (s, 3H, CH 3), 6.9 (d, 1H, CH=CH), 7.1– heated with stirring for 4 hr. The excess reagent was 8.0 (m, 8H, Ar-H and 1H, -CH=CH), 9.4 (s, 1H, - distilled off under reduced pressure and the resultant + N=CH-); EI-MS: m/z 368 (M+H) . Anal. C 19 H14 N3O3Cl: gummy product was processed with pet. ether. Found C, 62.15; H, 3.89; N, 11.43. Calcd. C, 62.12; Purification by recrystallization from methanol gave H, 3.81; N, 11.44%. pure product. N-5-[( E)-2-(2-Chlorophenyl)-1-ethenyl]-3-meth- 3-(2 H-Indazol-2-yl)-5-methylisoxazole , 6a . Yield: yl-4-isoxazolyl-N-[( Z)-1-(2-nitro phenyl)methyli- 85%. m.p. 98-102°C; IR (KBr): 1655 (s), 1560 (s) cm - 1 1 dene]amine , 8e . Yield: 70%. m.p. 118-20°C; IR ; H NMR (300 MHz, CDCl 3): δ 2.3 (s, 3H, CH 3), 5.6 (KBr): 1685 (s), 1595 (s), 1435 (s) cm -1; 1H NMR (s, 1H, isoxazol-H), 7.2-7.8 (m, 4H, Ar-H), 8.3 (s, 1H, + (200 MHz, CDCl 3): δ 2.5 (s, 3H, CH 3), 7.3 (d, 1H, indazole-H); EI-MS: m/z 200(M+H) . Anal. CH=CH), 7.6-8.0 (m, 8H, Ar-H and1H, -CH=CH), C11 H9N3O: Found C, 66.30; H, 4.58; N, 21.05. Calcd. 9.3 (s, 1H, -N=CH-); EI-MS: m/z 368 (M+H) +. Anal. C, 66.33; H, 4.52; N, 21.10%. H C19 H14 N3O3Cl: Found C, 62.18; H, 3.83; N, 11.47. 3-(5-Chloro-2 -2-indazolyl)-5-methylisoxazole , Calcd. C, 62.12; H, 3.81; N, 11.44%. 6b . Yield: 75%. m.p. 112-15°C; IR (KBr): 1645 (s), -1 1 N-3-Methyl-5-[( E)-2-(2-methylphenyl)-1-ethen- 1575 (s) cm ; H NMR (300 MHz, CDCl 3): δ 2.1 (s, yl]-4-isoxazolyl-N-[( Z)-1-(2-nitro phenyl) methyli- 3H, CH 3), 5.7 (s, 1H, isoxazole H), 7.4-8.0 (m, 3H,

NOTES 1595

Ar-H), 8.6 (s,1H, indazole-H); EI-MS: m/z 234 (d, 1H, CH=CH), 7.1 (d, 1H, CH=CH), 7.2-7.8 (m, + (M+H) . Anal. C 11 H8N3O3Cl: Found C, 56.60; H, 8H, Ar-H), 8.1 (s, 1H, indazole-H); EI-MS: m/z 336 + 3.47; N, 18.09. Calcd. C, 56.65; H, 3.43; N, 18.02%. (M+H) . Anal. C 19 H14 N3OCl: Found C, 68.01; H, General procedure for the synthesis of 4-(2 H- 4.10; N, 12.55. Calcd. C, 68.05; H, 4.17; N, 12.53%. indazol-2-yl)-3-methyl-5-(( E)-2-phenyleth-1-enyl)- 4-(2 H-2-Indazolyl)-3-methyl-5-[( E)-2-(2-methyl- isoxazoles , 9a-f: Schiff base 7 (0.01 mole) and excess phenyl)-1-ethenyl]isoxazole , 9f . Yield: 75%. m.p. of triethyl phosphite (3 mL) were taken in acetonitrile 106-08°C; IR (KBr): 1675 (s), 1545 (s), 995 (s) cm -1; 1 (15 mL) and contents were heated with stirring for 4 H NMR (300 MHz, CDCl 3): δ 2.3 (s, 3H, CH 3), 2.6 hr. The excess reagent was distilled off under reduced (s, 3H, CH 3), 6.8 (d, 1H, CH=CH), 7.2 (d, 1H, pressure and the resultant gummy product was CH=CH), 7.4-8.0 (m, 8H, Ar-H), 8.0 (s, 1H, indazole- + processed with pet. ether. Purification by recrystal- H); EI-MS: m/z 316 (M+H) . Anal. C 20 H17 N3O: lization from methanol gave pure product. Found C, 76.11; H, 5.37; N, 13.30. Calcd. C, 76.19; 4-(2 H-Indazol-2-yl)-3-methyl-5-(( E)-2-phenyl- H, 5.39; N, 13.33%. eth-1-enyl)isoxazole , 9a . Yield: 80%. m.p. 102-05°C, One-pot synthesis of isoxazolyl indazoles 3/ 6/ 9 . IR (KBr): 1655(s), 1515(s), 980 (s) cm -1; 1H NMR A mixture of amino isoxazole 1/ 4/ 7 (0.01 mol)

(300 MHz, CDCl 3): δ 2.5 (s, 3H, CH 3 ), 6.6 (d, 1H, and 2-nitro benzaldehyde (0.01 mol) was heated in CH=CH ), 7.2 (d, 1H, CH=CH), 7.5-8.0 (m, 9H, Ar- acetonitrile with stirring for 30 min. Later, triethyl H), 8.4 (s, 1H, indazole-H); EI-MS: m/z 301 (M +). phosphate (3 mL) was added to this reaction mixture Anal. C 19 H15 N3O: Found C, 75.71; H, 4.94; N, 13.99. and heating continued with stirring for another 3 hr Calcd. C, 75.74; H, 4.98; N, 13.95%. (monitored with TLC). The removal of solvent and 4-(2 H-2-Indazolyl)-3-methyl-5-[( E)-2-(4-methyl- excess reagent under reduced pressure resulted a phenyl)-1-ethenyl]isoxazole , 9b . Yield: 70%. m.p. gummy product which was processed with pet. ether. 84-87°C; IR (KBr): 1640 (s), 1580 (s), 985 (s) cm -1; Purification by recrystallization from ethanol gave 1 pure products 3/6/9 . The products obtained by this H NMR (300 MHz, CDCl 3): δ 2.4 (s,3H,CH 3), 2.5(s, method are found to be similar to that of a two-step 3H, CH 3), 6.8 (d, 1H, CH=CH), 7.0 (d, 1H, CH=CH), 7.2-7.9 (m, 8H, Ar-H), 8.1 (s, 1H, indazole-H); EI- process. + MS: m/z 315 (M ). Anal. C 20 H17 N3O: Found C, 76.13; H, 5.35; N, 13.38. Calcd. C, 76.19; H, 5.39; N, Acknowledgements 13.33%. The authors are thankful to Prof. S. SriHari, Head, 4-(E)-2-[4-(2 H-2-Indazolyl)-3-methyl-5-isoxazo- Department of Chemistry, Kakatiya University, lyl]-1-ethenylphenyl methyl ether , 9c . Yield: 70%. Warangal for the facilities and to the Director, Indian 1 m.p. 93-95°C; IR (KBr): 1665 (s), 1530 (s), 910 (s) Institute of Chemical Technology, Hyderabad for H -1 1 NMR and mass spectra. cm ; H NMR (300 MHz, CDCl 3): δ 2.4 (s, 3H, CH 3), 3.8 (s, 3H, OCH 3), 6.8 (d, 1H, CH=CH), 7.1 (d, 1H, CH=CH), 7.5-8.4 (m, 8H, Ar-H), 8.3 (s, 1H, indazole- References + 1 (a) Tempest P A, Curr Opin Drug Discov Dev, 8, 2005 , 776; H ); EI-MS: m/z 332 (M+H) . Anal. C 20 H17 N3O2: (b) Sperry J B & Wrigth D L, Curr Opin Drug Discov Dev , 8, Found C, 72.51; H, 5.16; N, 12.72. Calcd. C, 72.50; 2005 , 723; (c) Merino P, Curr Med Chem Anti-infective H, 5.13; N, 12.68%. Agents, 1, 2002 , 389; (d) Domling A, Curr Opin Chem Biol , 5-[( E)-2-(4-Chlorophenyl)-1-ethenyl]-4-(2 H-2- 4, 2000 , 318. indazolyl)-3-methylisoxazole , 9d . Yield: 75%. m.p. 2 Houghten R A, Wilson D B & Pinilla C, Drug Discov Today, -1 5, 2000 , 276. 130-32°C; IR (KBr): 1655 (s), 1510 (s), 950 (s) cm ; 3 (a) Barot V M, Patel M R & Naik H B, Asian J Chem , 13, 1 H NMR (300 MHz, CDCl 3): δ 2.2 (s, 3H, CH 3), 6.9 2001 , 341; (b) Bang-Andersen B, Ahmadiah H, Lenz S M, (d, 1H, CH=CH), 7.1 (d, 1H, CH=CH), 7.2-7.8 (m, Stensbol T B, Madsen V, Bogeso K P & Krogsgaard Larsen 8H, Ar-H), 8.2 (s, 1H, indazole-H); EI-MS: m/z 336 P, J Med Chem, 43, 2000 , 4910; (c) Ikegami F, Yamamoto A, + Sekine T, Ishikawa T, Kusamae-Eguchi K, Kusama T & (M+H) . Anal. C 19 H14 N3OCl: Found C, 68.01; H, Watanabe K, Chem Pharm Bull, 48, 2000 , 278; (d) He H, Li 4.14; N, 12.50. Calcd. C, 68.05; H, 4.17; N, 12.53%. M & Huang G, Nongyao, 39, 2000 , 4; (e) Kusumi T, Chang C 5-[( E)-2-(2-Chlorophenyl)-1-ethenyl]-4-(2 H-2- C, Wheeler M, Kubo I, Naganishi K & Naoki H, Tetrahedron indazolyl)-3-methylisoxazole , 9e . Yield: 80%. m.p. Lett, 22, 1981 , 3451; (f) Murthy A K, Rao K S, R K M & Rao -1 N V S, Indian J App Chem, 35, 1972, 90. 138-40°C; IR (KBr): 1645 (s), 1560 (s), 960 (s) cm ; 4 Wakefield B J & Wright D J, Adv Heterocycl Chem, 25, 1979 , 1 H NMR (300 MHz, CDCl 3): δ 2.3 (s, 3H, CH 3), 6.8 147.

1596 INDIAN J. CHEM., SEC B, OCTOBER 2008

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