Abdallah, Magda A

Mosselhi, Mosselhi AN

Riyadh, Sayed M

Shawali, Ahmad S

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Indian Journal of GhemistryVol. 36B, December 1997, pp.1175 - 1177A convenient synthesis of 5-amino-4-(2-benzothiazolyl)pyrazolesMagda A Abdallah, Mosse1hi AN Mosselhi,Sayed M Riyadh & Ahmad S Shawali*gepartment of Chemistry, Faculty of Science,University of Cairo, Giza, EgyptReceived 4 November 1996; accepted (revised) 12 June 1997Reaction of 2-cyanomethylbenzothiazole 1 withhydrazonoyl halides 2A-D in ethanol in the presence ofsodium ethoxide affords 5-amino-4-(2-benzothiazolyl)-pyrazoles 6.Heterocycles bearing a benzothiazole ring residueare reported to show a broad spectrum ofbiological activities 1-3. It is also reported that manypyrazole derivatives have found applications inboth pharmaceutical and agrochemical fields4. Inview of these observations we thought of jnterestto investigate the synthesis of novel 4-(2-benzothiazolyl)pyrazole derivatives which may beof pharmaceutical interest as the related 1-(2-benzothiazolyl)pyrazoles have significant anti-inflammatory activity", The known method6adopted for synthesis of the latter compounds wasnot useful for the preparation of the titlecompounds. Therefore we developed a generalsynthetic route for the preparation of 5-amino-4-(2-benzothiazolyl)pyrazoles with various func-tionalities (Scheme I).Results and DiscussionReaction of 2-cyanomethylbenzothiazole 1 witheach of the hydrazonoyl chlorides 2A-D in ethanolin the presence of sodium ethoxide in a 1:1 molarratio afforded, in each case, a single product asevidenced by TLC and IH NMR spectral analyses.The structures of the isolated products wereestablished as 6A-D by analytical and spectral data1 .(IR, H NMR and MS) (see Experimental).' Theassigned structures were further supported by theirchemical reactions. Thus, each of the products 6Baand 6Db, taken as representative examples of theseries prepared, yielded the corresponding N-acetylderivatives 7Ba and 7Db, respectively uponTreatment with acetic anhydride at reflux (Scheme I).NoteIn addition, diazotization of each 6AB and 6Bafollowed by coupling with 2-naphthol in sodiumhydroxide solution afforded the corresponding azoderivatives 9Ab and 9Ba, respectively (Scheme I).The structures of the latter products wereconsistent with their spectral data (IR and IHNMR) and analytical data (see Experimental).The formation of 6 from the reaction of 1 with 2seems to follow the sequence outlined in Scheme1. It is suggested that direct nucleophilic attack ofthe carbanion of 1 at the hydrazonoyl chloride 2 or1,3-addition of 1 to the nitrile imide 3, generatedin situ from 2, gives 4. The latter undergoesintramolecular cyclization as soon as it is formedto give 5. Aromatization of 5 via imine-enaminetautomerism leads to the end product 6. The twosteps 4=>5=>6 are analogous to those involved inthe conversion of arylhydrazone derivatives of a-cyanoketones into 5-aminopyrazole derivatives 7.Experimental SectionMps. were measured on a Gallenkamp apparatusand are uncorrected. 1H NMR spectra wererecorded in eH]-chloroform on a Varian Gemini200 spectrometer using TMS as internal referenceand mass spectra on a GCMS-QP 100 EXspectrometer. Elemental analyses were carried outat the Microanalytical Laboratory at CairoUniversity, Giza, Egypt. The starting 2-cyanomethylbenzothiazole 18 and the hydrazonoylchlorides 2A_D9-11 were prepared as previouslydescribed.Reaction of 1 with 2: General procedure. Toa stirred ethanolic sodium ethoxide solution,prepared from sodium metal (0.23 g, 10 mg atom)and abs ethanol (20 ml), was added 2-cyanomethylbenzothiazole 1 (1.74 g, 10 mmol).After 10 min, the appropriate hydrazonoyl chloride2 (10 mmol) was added to the resulting solutionand the mixture was stirred at room temperaturefor 12 h, during which the chloride 2 dissolved andthe crude reaction product 6 precipitated. The latter"~s filtered, washed with water, dried and finallycrystallized from the proper solvent. The physicalconstants of the products 6A-D are as follows.6Aa (65%), m.p. 184-86°C (ethanol); IR (KBr):1176 INDIAN J CHEM, SEe. B, DECEMBER 1997OC:~~CN ~ OC:~CHCN.1 IRe(Ct):NNHArt~(~rCOCH,s R ~N •.•N"'Ar7Ra Hb 4-CH3e 4-CId 4-BrA CH3COB C2HS.OCOC C"'30COo C6H5NHCO3410-3240 (NH2), 1676 crn' (CO); IH NMR(CDC)}): 8 2.70 (3H, s), 6.5 (2H, s), 7.0-8.0 (9H,m): MS: m/z 334 (M+) (Found: C, 64.5: H, 4.1; N,16.4; S, 9.4. CI8 H14 N40S requires C, 64.67; u,4.19; N, 16.76; S, 9.58%).6Ab (60%), m.p. 150°C (methanol),IR (KBr):3430-3244 (NH2), 1686 em·1 (CO); 1H NMR(CDCl)) 82.45 (3H, s), 2.7 (3H, s), 6.5 (2H, s), 7.0-8.1 (8H, m); MS: m/z 348 (M+) (Found: C, 65.1;H, 4.3; N, 15.8; S, 9.1. CI9HlbN40S requires C,65.51; H, 4.59; N, 16.09; S, 9.19%).6Ac (60%), m.p. 190°C (ethanol), IR (KBr):3423-3239 (NH2), 1683 em·1 (CO); 1H NMRI-HCI+ -R-C =N -N -Ar + 13ElONai ElOHii (CHj:O~O/CH3COOHIII NaN021 Hel ICH3COOHIv 2-Naphthol I NaOHScheme I(CDCI]) 8 2.6 (3H, s), 6.5 (2H, s), 7.1-8.0 (8H. m):MS: mlz 368 (M+) (Found: C, 58.2; H, 3.3: N,14.9; S, 8.4. Cl8HlJClN40S requires C, 58.61; 1·1.3.52; N, 15.19; S, 8.68(10).6Ba (60%), m.p. 160°C (ethanol); IR (KBr):3431-3260 (NHz), 1708 em·1 (CO); 1H NMR(CDCl): 8 1.47 (3H, t), 4.50 (2H, q), 6.5 (2H, s),7.0-8.0 (9H, m); m/z 364 (M+) (Found: C, 62.3; H.4.4; N, 14.9; S, 8.6. CI9H16N402S requires C,62.63; H, 4.39; N, 15.38; S, 8.79%).6Bb (65%), mp. 178°C (ethanol);IR (KBr):3429-3271 (NH2), 1729 em·l (CO); 1H NMR(CDCl)) 8 1.48 (3H, t), 2.4 (3H,s), 4.5 (2l-L q), 6.4(2H, s), 7.0-8.2 (8H, m); mlz 378 (M+) (Found: C,63.3; H, 4.5; N, 14.6; S, 8.5. C2oHIsN402S requiresC, 63.49; H, 4.76; N, 14.81; S, 8.46%).6Bd (65%), m.p. 150°C (ethanol), IR (KBr):3430-3243 (NH2), 1712 ern" (CO); IH NMR(CDCI3): 0 1.48 (3H, t), 4.5 (2H, q), 6.5 (2H, s),7.0-8.2 (8H, m), mlz 443 (M+) (Found: C, 51.7; H,3.4; N, 12.8; S, 7.1. CI9HI5BrN402S requires C,51.46; H, 3.38; N, 12.64; S, 7.22%).6Ca (65%), m.p.186-87°C (methanol), IR(KBr): 3405-3265 (NH2), 1728 cm·1 (CO); IHNMR (CDCI3): 04.15 (3H, s), 6.47 (2H, s), 7.26-7.95 (9H, m); mlz 350 (M+) (Found: C, 61.9; H,3.9; N, 15.8; S, 9.0; CIsHI4N402S requires C,61.71; H, 4.00; N, 16.00; S, 9.14%).6Da (65%), m.p 186-87°C (methanol); IR(KBr): 3405-3265 (NH2), 1658 cm·1 (CO); IHNMR (CDCI3): 06.5 (2H, s), 7.2-8.1 (9H, m), 8.9(lH, s); MS: mlz 411 (M+) (Found: C, 67.0; H,4.1; N, 16.9; S, 7.9. C23HI7N50S requires C, 67.15;H, 4.13; N, 17.03;S, 7.78%).6Db (70%) mp. 186-88°C (dioxane-ethanol), IR(KBr): 3421-3298 (NH2), 1681 em-I (CO); IHNMR (CDCl3): 0 2.4 (3H? s), 6.5 (2H, s), 7.0-8.2(8H, m), 8.9 (IH, s); MS: mlz 425 (M+) (Found:C, 67.5; H, 4.3; N, 16.5; S, 7.5. C24HI9N50Srequires C, 67.76; H, 4.47; N, 16.47; S, 7.52%).6Dc (70%) mp. 244-46°C (dioxane-ethanol); IR(KBr): 3422-3293 (NH2), 1680 em-I (CO); IHNMR (CDCI3): 0 6.6 (2H, s), 7.1-8.2 (8H, m), 8.9(IH, s); m/z 445 (M+) (Found: C, 61.8; H, 3.7; N,15.8; S, 6.9. C23HI6ClN50S requires C, 61.95; H,3.59; N, 15.71; S, 7.18%).Acetylation of 6. To a solution of theappropriate 6 (0.005 mol) in acetic acid (5 mL)was added acetic anhydride (1 mL). The reactionmixture was refluxed for 3 h and then poured intoice-cold water. The crude solid that precipitatedwas filtered, dried and crystallized from ethanol togive the corresponding acetyl derivative 7.7Ba (60%), m.p. 180-81°C(ethanol), IR (KBr):3260 (NH), 1718, 1704 em-I (CO); IH NMR(CDCI3): 0 1.45 (3H, t), 2.09 (3H, s), 4.54 (2H, q),7.37-8.00 (9H, m), 10.25 (1H, s) (Found :C, 61.9;H, 4.3; N, 13.9; S, 7.7. C21HIsN403S requires C,62.06; H, 4.43; N, 13.79; S, 7.88%).7Db (63%), m.p. 244-45°C (acetic acid-eth~nol), IR (KBr): 3354-3210 (NH), 1703, 1669em (CO) (Found: C, 66.6; H, 4.5; N, 15.0; S, 6.8.C26H21N50zS requires C, 66.80; H, 4.49; N, 14.98;S,6.85%).NOTES 1177Preparation of the azo derivatives 9. To acold solution of 6Ab (or 6Ba) (5 mmol) in glacialacetic acid (3 mL) and cone. (3 mL) was added asolution of sodium nitrite (0.345 g, 5 mmol) inwater (3 mL) gradually with stirring and cooling toO°e. The resulting diazonium salt solution wasadded portionwise to a cold solution of 2-naphthol(0.72 g, 5 mmol) in NaOH (0.2 g, 5 mmol) inwater (10 mL). The reaction mixture was stirredwhile being cooled for 2 h, during which red solidprecipitated. The latter was filtered, washed withwater, dried and crystallized from the propersolvent to give the corresponding azo derivative 9.9Ab (70%), m.p. 250-52°C (acetic acid-methanol); UV (methanol) (log c) 490 nm (3.589);IR (KBr): 3350 (OH), 1685 (CO); IH NMR(CDCI3): 02.5 (3H, s), 2.74 (3H, s), 6.4-8.49 (14H,m), 16.0 (1H, s) (Found: C, 68.9; H, 4.0; N, 13.7;S, 6.5. C29H21N502Srequires C, 69.18; H, 4.17; N,13.91; S, 6.36%).9Ba (75%), m.p. 278-80°C (acetic acid-water); UV(methanol) (log c) 482 nm (3.519); IR (KBr): 3320(OH), 1718 em-I (CO); IH NMR (CDCI3): 1.4 (3H,t), 4.5 (2H, q), 6.5-8.5 (15H, m), 15.9 (JH, s)(Found : C, 67.0; H, 3.9; N, 13.1; S, 5.9.C29H2IN503S requires C, 67.05; iI, 4.04; N, 13.48;S,6.16%).ReferencesI Knierzinger A & Wolfbeis 0 S, J Heterocycl Chem, 17,1980,225.2 Shigeta S, Hosoya M, Mochizuki S & Chiba T, YakugakuZasshi, 108,1988,856; Chem Abstr, 110,1989, 306u.3 Babichev F S, Patratii V K, Volovenko Yu M, ProdanchukN G, SinchenkoV G & Nemazanyi A G, Khim Farm Zh, 22,1988, 1223; Chem Abstr, I I I, 1989, 7285r.4 Elguero J, Comprehensive heterocyclic Chemistry, edited byA R Katritzky, (Pergamon Press, New York), , Vol. 5, 1984,p. 291; Sugiura S, Ohno S, Ohtani 0, Izumi K, KitamikadoT, Asai H, Kato K, Hori M & Fujimura H, J Med Chem, 20,1977,80.5 Singh S P & Vaid R K, Indian J Chem, 25B, 1986,288.6 Mahesh V K, Chauhan V K, Prakash I & Prakash 0, JIndidn Chem Soc, 60, 1983,269.7 (a) Shawali A S, Hassaneen H M, Sami M &. Elfahham HM, Heterocycl Chem 13, 1976, 1137; (b) Takamizawa A &Hamashima Y, Yakugaku Zasshi, 84, 1964, 1113; ChemAbstr, 62, 1965,5276.8 N. M. Fathy, F. M. Abdelmotti and G. E. H. Elgemeie,Arch. Pharm, 321,1988, 509.9 A. S. Shawali and A. Osman, Tetrahedron, 27,1971, 2517.10 A. S. Shawali, N. F. Eweiss, H. M. Hassaneen and M. Sami,Bull. Chern. Soc. Jpn., 48, 1975, 365 and the referencesthere in.II A. S~Shawali, S. T. Ezmirly and H. M. Hassaneen, 1.Chern.Engng. Data, 34, 1989, 259, and the references cited therein.

A convenient synthesis of 5-amino-4-(2-benzothiazolyl)pyrazoles

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A convenient synthesis of 5-amino-4-(2-benzothiazolyl)pyrazoles

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