Reactions of enaminones 2 with diazotized 5-amino-3-phenylpyrazole provide a convenient route to 3-[(4,5-disubstituted-pyrazol-3-yl)carbonyl]-pyrazolo[5,1-c][1,2,4]triazines. Condensation of the latter with hydrazine hydrate yielded the title compounds. The structures of the compounds prepared were elucidated on the basis of their spectral and elemental analyses.
Journal of Advanced Research (2012) 3, 185–188 Cairo University Journal of Advanced Research SHORT COMMUNICATION A new convenient synthesis of 3-hetaryl-pyrazolo[5,1-c][1,2,4]triazines Ahmad S Shawali Department of Chemistry, Faculty of Science, University of Cairo, Giza, Egypt Received June 2011; revised 29 June 2011; accepted 18 July 2011 Available online 27 August 2011 KEYWORDS Hydrazonoyl halides; Heterocycles; Enaminones; Pyrazoles Abstract Reactions of enaminones with diazotized 5-amino-3-phenylpyrazole provide a convenient route to 3-[(4,5-disubstituted-pyrazol-3-yl)carbonyl]-pyrazolo[5,1-c][1,2,4]triazines Condensation of the latter with hydrazine hydrate yielded the title compounds The structures of the compounds prepared were elucidated on the basis of their spectral and elemental analyses ª 2011 Cairo University Production and hosting by Elsevier B.V All rights reserved Introduction A literature survey reveals that there are three synthetic routes for pyrazolo[5,1-c][1,2,4]triazine derivatives I (Chart 1) These synthetic strategies include (i) coupling of diazotized 5-aminopyrazole with b-keto esters and b-diketones, (ii) reaction of 5hydrazinopyrazole with 1,2-diones [1,2] and (iii) cyclization of N-pyrazol-5-yl hydrazonoyl halides [3] In conjunction with our recent work [4–6] on heteroaryl enaminones II (Chart 1), it was thought attractive to explore the utility of such enaminones as precursors for the synthesis of new pyrazolo[5,1c][1,2,4]-triazines that have not been reported hitherto Here E-mail addresses: as_shawali@yahoo.com, as_shawali@mail.com 2090-1232 ª 2011 Cairo University Production and hosting by Elsevier B.V All rights reserved Peer review under responsibility of Cairo University doi:10.1016/j.jare.2011.07.004 Production and hosting by Elsevier we present a new synthetic strategy for the synthesis of the latter heterocyclic ring system via coupling of such enaminones with diazotized 5-amino-3-phenylpyrazole Also, it was thought interesting to examine the reaction of the resulting coupling products with hydrazine hydrate in an attempt to provide a convenient method for synthesis of the title compounds Experimental All melting points were determined on an electrothermal Gallenkamp apparatus Solvents were generally distilled and dried by standard literature procedures prior to use The IR spectra were measured on a Pye-Unicam SP300 instrument in potassium bromide discs The 1H NMR spectra were recorded on a Varian Mercury VXR-300 MHz spectrometer and the chemical shifts d down field from tetramethylsilane (TMS) as an internal standard The mass spectra were recorded on a GCMS-Q1000-EX Shimadzu and GCMS 5988-A HP spectrometers, the ionizing voltage was 70 eV Elemental analyses were carried out at the Microanalytical Center of Cairo University, Giza, Egypt, using automatic CHNS analyzer, Vario EL III – Elemental fabric_Nr 11042023 Both 3-acetylpyrazoles and enaminones were prepared as previously described from our laboratory [5,7] 186 A.S Shawali R R' N N N I 3-[(4-Benzoyl-1,5-phenyl-pyrazol-3-yl)carbonyl]-7-phenylpyrazolo[5,1-c][1,2,4]-triazine (4a) O N R" Het R'" NMe2 II Chart Structures of pyrazolo[5,1-c][1,2,4]triazine derivatives and heteroaryl enaminones Synthesis of 3-[1,4,5-trisubstituted-pyrazol-3-yl)carbonyl]pyrazolo[5,1-c][1,2,4]triazines (4a,b) General method : A mixture of the appropriate enaminone (1.76 g, mmol) in pyridine (20 mL) was cooled in an ice bath at 0–5 °C while being stirred To the resulting cold solution was added portion wise a cold solution of the diazonium salt of 3-phenyl-5-aminopyrazole, prepared as usual by diazotizing the amine (5 mmol) in hydrochloric acid (6 M, mL) with sodium nitrite (0.35 g, mmol) in water (5 mL) After all the diazonium salt solution was added, the mixture was stirred for further 30 while cooling in an ice-bath The reaction mixture was then left in a refrigerator for three days The solid that precipitated was filtered off, washed with water, dried and finally crystallized from ethanol to give the respective products The compounds 4a,b prepared are listed below together with their physical constants O O R Ph N N DMF-DMA N N HN N HOH R - Me2NH Ph O N O N X R Ph N O Ph H N Ph Ph 2a,b H N N NMe2 N N - Me2NH H OH N H N N N O Ph Ph Ph N Ph N Ph A O N HN N2Cl N N N N R - H2O N H Me2N Ph B O O R Ph 1a,b O Ph Yellow solid, yield 1.80 g, (70%), mp 210–212 °C, IR (KBr) mmax/cmÀ1 1716, 1670 (C‚O), 1028 (C–O–C) 1H NMR (DMSO-d6) d 1.04 (t, J = Hz, 3H, CH3), 4.07 (q, J = Hz, 2H, CH2), 7.36–7.87 (m, 15H, ArH), 8.20 (s, 1H, H-8), 9.96 (s, 1H, H-4); 13C NMR: (DMSO-d6) d 14.0, 61.1, 101.5, 114.5, 120.0, 127.3, 128.1, 128.4, 129.4, 129.5, 131.9, 134.6, 139.5, 141.4, 149.1, 151.8, 153.3, 154.5, 160.5, 182.4; MS m/z (%) 517 (M+2, 1.3), 516 (M++1, 3.3), 515 (M+, 23), 442 (71), 299 (14), 223 (24), 217 (13), 180 (46), 142 (31), 128 (22), 101 (10), 77 (100) Anal Calcd for C30H20N6O3 (514.53) C, 70.03; H, 4.31; N, 16.33 Found: C, 70.13; H, 4.38; N, 16.47 O CH3 Ph O 3-[(4-Ethoxycarbonyl-1,5-diphenylpyrazol-3-yl)carbonyl]pyrazolo-[5,1-c][1,2,4]triazine (4b) O R Ph Yellow solid, yield 2.18 g, (80%), mp 200 °C, IR (KBr) mmax/ cmÀ1 1656 (C‚O) 1H NMR (DMSO-d6) d 7.13–7.35 (m, 20H, ArH), 8.16 (s, 1H, H-8), 9.97 (s, 1H, H-4); 13C NMR (DMSO-d6) d 101.5, 118.0, 119.5, 127.5, 128.1, 128.4, 128.8, 129.0, 129.5, 129.7, 132.1, 134.6, 134.9, 139.5, 140.1, 142.1, 145.5, 151.3, 153.3, 154.5, 181.1, 196.5; MS m/z (%) 547 (M+, 5), 105(26), 92 (10), 76 (100), 65 (12) Anal Calcd for C34H22N6O2 (546.58) C, 74.71; H, 4.06; N, 15.38 Found: C, 74.43; H, 4.15; N, 15.45 N Ph N N 4a,b R : a, Ph; b, EtO Scheme Synthesis of enaminones and their azo coupling reaction A new convenient synthesis of 3-hetaryl-pyrazolo[5,1-c][1,2,4]triazines NH2NH2.H2O 187 N R = Ph O O N R Ph N Ph Scheme N Ph N N N Ph N R = EtO Ph N Ph N N Ph 5a N N O NH2NH2.H2O N N N Ph H N N N Ph N Ph N N 5b Synthesis of pyrazolo[3,4-d]pyridazin-7-yl]-pyrazolo[5,1-c][1,2,4]triazines Synthesis of 3-(pyrazolo[3,4-d]pyridazin-7-yl)-pyrazolo-[5,1c] [1,2,4]pyridazines General method: A mixture of compound 4a (1.09 g, mmol) or 4b (1.02 g, mmol) and hydrazine hydrate (10 ml) in absolute ethanol (40 ml) was refluxed for 10 h and the reaction mixture was cooled The solid that precipitated was filtered off and crystallized from ethanol to give compound 5a and 5b, respectively The compounds 5a and 5b together with their physical constants are given below 3-([2,3,4-Triphenyl-pyrazolo[3,4-d]pyrazin-7-yl)-7-phenylpyrazolo[5,1-c][1,2,4]triazine (5a) Pale green solid, yield 0.71 g (66%), mp 174–176 °C, IR (KBr) mmax/cmÀ1 1623, 1555 (C‚N) 1H NMR (DMSO-d6) d 7.00– 7.46 (m, 20H, ArH), 8.16 (s, 1H, H-8), 9.85 (s, 1H, H-4); 13C NMR (DMSO-d6) d 101.5, 118.2, 125.5, 126.2, 126.8, 127.0, 128.2, 128.4, 129.5, 129.6, 131.2, 131.3, 131.7, 132.2, 135.4, 137.7, 142.3, 146.3, 149.9, 153.3, 156.9, 161.0; MS m/z (%) 544 (M++2, 0.87), 542 (M, 1), 539 (22), 524 (11), 514 (16), 451 (32), 388 (28), 247 (13), 338 (28), 247 (13), 180 (36), 159 (40), 144 (13), 138 (14), 130 (20), 115 (12), 111 (14), 104 (22), 76 (100), 63 (18) Anal Calcd for C34H22N8 (542.59) C, 75.26; H, 4.09; N, 20.65 Found: C, 75.31; H, 4.15; N, 20.86 3-[2,3-Diphenyl-4-oxo-5-H-pyrazolo[3,4-d]pyridazin-7-yl]-7phenyl-pyrazolo[5,1-c][1,2,4]triazine (5b) Pale green solid, yield 0.72 g (78%), mp 240 °C, IR (KBr) mmax/ cmÀ1 3234 (NH), 1671 (C‚O) 1H NMR (DMSO-d6) d 7.37– 7.79 (m, 15H, ArH), 8.04 (s, 1H, H-8), 9.83 (s, 1H, H-4), 12.40 (s, 1H, NH); 13C NMR (DMSO-d6) d 101.5, 111.4, 117.7, 122.5, 127.1, 128.1, 128.4, 129.2, 129.5, 130.3, 131.0, 135.4, 137.8, 145.4, 148.4, 153.3, 158.7, 161.0; MS m/z (%) 482 (M+, 7), 189 (15), 167 (11), 158 (10), 151 (15), 134 (40), 128 (18), 114 (53), 106 (42), 91 (43), 76 (81), 70 (30), 60 (45), 45 (100) Anal Calcd for C28H18N8O (482.49) C, 69.70; H, 3.76; N, 23.22 Found: C, 69.82; H, 3.55; N, 23.30 Results and discussion The starting enaminones 2a,b were prepared by condensation of the respective 3-acetylpyrazole derivatives 1a-b each with dimethylformamide dimethyl acetal (DMF–DMA) as previously described from our laboratory (Scheme 1) [5,7] Coupling of 2a with diazotized 3-phenyl-5-aminopyrazole in pyridine at 0–5 °C gave the coupling product that was identified as 3-[(4benzoyl-1,5-diphenylpyrazol-3-yl)carbonyl]-7-phenyl-pyrazolo[5,1-c][1,2,4]triazine 4a (Scheme 2) Similar reaction of 2b with the same diazonium salt yielded 3-[(4-ethoxycarbonyl-1,5-diphenylpyrazol-3-yl) carbonyl]-7-phenyl-pyrazolo[5,1-c][1,2,4]triazine 4b (Scheme 2) The structures of the products 4a,b were elucidated on the basis of their spectra (IR, 1H NMR and MS) and elemental analyses For example, the IR spectrum of 4b showed two characteristic C‚O bands at v 1716 and 1670 cmÀ1 In addition, 1H NMR spectra of both compounds 4a and 4b revealed, in each case, two characteristic singlet signals near d 8.20 and 9.96 assignable to the H-8 and H-4 of the pyrazolo[5,1-c][1,2,4]-triazine ring residue, respectively To account for the formation of such products, it is suggested as depicted in Scheme 1, that the initially formed coupling product undergoes in situ cyclization via either route A or B (Scheme 1) In the former route A, intramolecular elimination of dimethylamine gives directly as end product In route B, the intermediate is hydrolyzed first to give the respective arylhydrazone derivative X, by analogy to azo coupling of enaminones with aromatic diazonium salts [8,9] The latter intermediate X undergoes in turn cyclization via dehydration to give as end product However, all attempts to isolate intermediate of type X failed Next, the condensation of the products 4a,b with hydrazine hydrate was examined In our hands, such a reaction yielded products that were identified, on the basis of their spectral and elemental analyses, as the respective 3-[2,3,4-triphenylpyrazolo[3,4-d]pyridazin-7-yl]-7-phenyl-pyrazolo[5,1-c][1,2,4] triazine 5a and 3-(2,3-diphenyl-4-oxo-5H-pyrazolo[3,4-d]-pyridazin-3-yl)-7-phenyl-pyrazolo[5,1-c][1,2,4]triazine 5b, respectively (Scheme 2) For example, the IR spectrum of compound 5a showed the absence of carbonyl absorption bands present in the IR spectrum of its precursor 4a Also, the spectrum of 5b reveals two bands due to cyclic amide moiety at v 3234 (NH) and 1671 (C‚O) cmÀ1 Furthermore, its 1H NMR spectrum showed a characteristic NH signal at d 12.4 In conclusion, the studied azo coupling reaction of the enaminones and the hydrazinolysis of the resulting products provide a convenient route for the title compounds References [1] Partridge MW, Stevens MFG Pyrazolo-as-triazines Part I J Chem Soc C Organ 1966:1127–31 188 [2] Shawali AS, Abdallah MA The chemistry of heterocyclic hydrazonoyl halides Adv Heterocycl Chem 1995;63(C):277–338 [3] Elnagdi MH, Elmoghayer MRH, Kandeel EM, Ibrahim MKA Reactions with heterocyclic diazonium salts: new routes for the synthesis of pyrazolo[1,5-c]1,2,4 triazoles and pyrazolo[1,5-c] as triazines J Heterocycl Chem 1977;14(2):227–30 [4] Shawali AS, Farghaly TA, Aldahshoury AIR An efficient synthesis of functionalized 3-(hetaryl)pyrazoles Arkivoc 2010:19–30 [5] Shawali AS Synthesis, reactions and antitumour screening of new enaminones J Chem Res 2010(11):630–4 [6] Shawali AS, Sherif SM, Darwish MAA, El Merzabani MM Synthesis and antitumor screening of new 1,7-diphenyl-3-(1,3- A.S Shawali disubstituted-1H-pyrazole-4-carbonyl)-[1,2,4]triazolo[4,3a]pyrimidin-5(1H)-ones Arch Pharm Res 2010;33(1):55–60 [7] Shawali AS, Farghaly TA, Al Dahshoury AR Synthesis, reactions and antitumor activity of new b-aminovinyl 3pyrazolyl ketones Arkivoc 2009(14):88–99 [8] Al Shiekh MA, Medrassi HY, Elnagdi MH, Hafez EA Studies with 2-arylhydrazono-3-oxopropanals: routes for the synthesis of pyridazine-3,4-dicarboxylate and 3,5-diaroyl pyrazoles Arkivoc 2008;xvii:36–47 [9] Al Zaydi KM, Borik RM Microwave assisted condensation reactions of 2-aryl hydrazonopropanals with nucleophilic reagents and dimethyl acetylenedicarboxylate Molecules 2007;12(8):2061–79 ... Shawali AS, Farghaly TA, Aldahshoury AIR An efficient synthesis of functionalized 3-(hetaryl)pyrazoles Arkivoc 2010:19–30 [5] Shawali AS Synthesis, reactions and antitumour screening of new enaminones... disubstituted-1H-pyrazole-4-carbonyl)-[1,2,4]triazolo[4, 3a] pyrimidin-5(1H)-ones Arch Pharm Res 2010;33(1):55–60 [7] Shawali AS, Farghaly TA, Al Dahshoury AR Synthesis, reactions and antitumor activity of new b-aminovinyl 3pyrazolyl ketones Arkivoc 2009(14):88–99 [8] Al... [6] Shawali AS, Sherif SM, Darwish MAA, El Merzabani MM Synthesis and antitumor screening of new 1,7-diphenyl-3-(1,3- A. S Shawali disubstituted-1H-pyrazole-4-carbonyl)-[1,2,4]triazolo[4, 3a] pyrimidin-5(1H)-ones