Acta Chim. Slov. 2003, 50, 223-238. 223 SYNTHESIS OF NOVEL SUBSTITUTED [l,2,4]TRIAZOLO[l,5-a]PYRIDINES AND THEIR RELATED PYRANO[2,3-rf]IMIDAZOLE DERIVATIVS Wahid M. Basyouni Pesticide Chemistry Dept, National Research Center, Dokki, Cairo, Egypt Received 26-09-2002 Abstract Synthesis of the diaminopyridine derivatives 3 and 4 from 2-cyanoacetohydrazide 1 was described. The [l,2,4]triazolo[l,5-a]pyridine derivatives 10, 11 and 13-15 were obtained by reaction of 3 with ethyl chloroformate/DMF reagent mixture, acetic anhydride, triethyl orthoformate, -orthoacetate or aromatic aldehydes. Deamination of 3 to the aminopyridine derivatives 17 was carried out. The triazolopvridine derivatives 11 were obtained also in one step svnthesis from 2 and N'-acetyl-2-cyanoacetohydrazide 19. Condensation of the thiohydantion 20 with 2 gave pyrano[2,3-^imidazoles 24. Introduction Pyridines have been reported as biologically interesting molecules1"4 and precursors for the synthesis of triazolo[l,5-a]pyridines. Several methods have previously described the synthesis of triazolo[l,5-a]pyridines from l,6-diaminopyridines.5"" Moreover, triazolo[l,5-a]pyridine systems are reported to be useful compounds as pharmaceuticals,12 fluorescentbrighteners,13 complexing agents,14 herbicides,15 cyan dye mixture for thermal color prooflng, and as jet-printing ink 7' agents. Recently, derivatives of this ring system are prepared from N'-arylmethylidene-2-cyanohydrazide.19 Triazolo[l,5-a]pyridines have also been prepared by ring 90 71 transformation of triazolo[4,3-a]pyridine and from 2-thioxopyrones. In the present investigation the synthesis of some novel substituted triazolo[l,5-a]-pyridines and their related pyrano[2,3-c/jimidazole derivatives was attempted for their expected useful biological properties. Results and Discussion 77 Reaction of 2-cyanoacetohydrazide 1 with (2-furylmethylene)malononitrile 2a in ethanol afforded 1,6-diamino-4-(2-furyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile W. M. Basyouni: Synthesis of Novel Substituted [1,2,4]triazolo[l,5-a]pyridines and their Related... 224 Acta Chim. Slov. 2003, 50, 223-238. 3a (previously reported without data). The l,2,3,4-tetrahydropyridine-3,5-dicarbonitrile derivative 4 was also isolated (Scheme 1). Dehydrogenation of product 4 to 3a was carried out using o-chloranile at room temperature. Structure of 4 was confirmed by careful analysis of its spectral data. Its 'H-NMR spectrum revealed characteristic signals at 3 4.23 ppm (d, J 6A Hz) and 5.09 ppm (d, J 6A Hz) for C4-H and C3-H of the pyridine ring, respectively. Moreover, its EI-MS spectrum showed molecular ion peak (M+) at m/z 243 (100%). Upon carrying out the reaction of 1 with ethyl (L)-2-cyano-3-(2-furyl)acrylate 2b without catalyst no products could be isolated. Whereas, reaction of 1 with 2b in the presence of triethylamine afforded smoothly l,2-diamino-6-oxo-l,6-dihydro-pyridine-3-carboxylate 3b rather than 6-hydroxypyridine-3,5-dicarbonitrile derivative 8 (Scheme 1). Cyclization of products 3a and 3b with ethyl chloroformate/N,N-dimethyl-formamide reagent mixture (which has been previously reported for cyclization of o-amino heterocyclic carboxamides to their condensed pyrimidinone derivatives) yielded 7-(2-furyl)-5-oxo-3,5-dihydro[l,2,4]triazolo[l,5-a]pyridine-6,8-dicarbonitrile (lOa) and ethyl 6-cyano-7-(2-furyl)-5-oxo-3,5-dihydro[l,2,4]triazolo[l,5-a]pyridine-8-carboxylate (lOb), respectively (Scheme 2). When compound 3a was allowed to react with acetic anhydride two products were formed. Based on their elemental analyses and spectral data (IR, ]H NMR and MS) these were identified as 7-(2-furyl)-2-methyl-5-oxo-3,5-dihydro[l,2,4]triazolo[l,5-a]pyridine-6,8-dicarbonitrile (Ha) and N-acetyl-N-[6-(acetylamino)-3,5-dicyano-4-(2-furyl)-2-oxopyridin-l(2/f)-yl]acetamide (12). Under the same reaction conditions the reaction of 3b with acetic anhydride afforded ethyl 2-methyl-3,5-dihydro[l,2,4]triazolo[l,5-a]-pyridine-8-carboxylate (Hb) as the šole product (Scheme 2). Unexpectedly, upon reacting the pyridine derivatives 3 with either triethyl orthoformate or triethyl orthoacetate in acetonitrile, 3-ethyl-7-(2-furyl)-5-oxo-3,5-dihydro[l,2,4]triazolo[l,5-a]pyridine-6,8-dicarbonitriles 13a and 13b and ethyl 6-cyano-3-ethyl-7-(2-furyl)-5-oxo-3,5-dihydro[l,2,4]triazolo[l,5-a]pyridine-8-carboxylates 13c and 13d were smoothly obtained, rather than the expected products of types 10 and 11 (Scheme 2). 'H NMR spectra of 13 revealed the characteristic N-ethyl proton signals at 5 1.43-1.54 (triplet) and 4.42^1.87 (quartet) ppm for CH3 and CH2, respectively. W. M. Basyouni: Synthesis of Novel Substituted [1,2,4]triazolo[l,5-a]pyridines and their Related... Acta Chim. Slov. 2003, 50, 223-238. 225 Scheme 1 CONHNH2 r R H2C CN 1 + RCH=C(CN)X EtOH YV + Et3N EtOH 2b( X = C02Et) Et02C CONHNH2 2a(X = CN) O-^N' ^NH2 ° N NH2 im NH2 3aNH2 4 v^ C02Et CK N ^NH2 C02Et CK N ^NH2 O^N^OH NH2 7 R = The structure of compounds 13 was also chemically elucidated. Thus, by reaction of products 10 and 11 with either triethyl orthoformate or triethyl orthoacetate the corresponding 3-ethyl-triazolo[l,5-a]pyridine derivatives 13a-d were obtained. Therefore, in the present investigation triethyl orthoformate and triethyl orthoacetate are applied as cyclizing and alkylating agents in the same tirne. Reaction of products 3a and 3b with /?-fluorobenzaldehyde or salicylaldehyde in dioxane containing piperidine as the catalyst afforded unexpected products piperidinium 2-aryl-7-(2-furyl)-5-oxo-3,5-dihydro[l,2,4]triazolo[l,5-a]pyridine-6,8-dicarbonitriles 14a and 14b and piperidinium ethyl 2-aryl-6-cyano-7-(2-furyl)-5-oxo-3,5-dihydro [l,2,4]-triazolo[l,5-a]pyridine-8-carboxylates 14c and 14d, respectively in good yield (Scheme 3). The structure of 14 was elucidated from the analytical and !H NMR spectral data. The latter show signals at S 1.61 ppm and 3.02 ppm that have been assigned to the piperidinium cation. The piperidinium salts 14a-d were formed by formation of a piperidinium cation and a triazole anion26 as shown in Scheme 3. W. M. Basyouni: Synthesis of Novel Substituted [1,2,4]triazolo[l,5-a]pyridines andtheir Related... 226 Acta Chim. Slov. 2003, 50, 223-238. Scheme 2 NC. cr ^N NH2 NH2 3 a) X = CN b) X = CQ2Et R'C(OE1) NC CIC02Et/DMF Ac20 (X = C02Et) H3C^/ N "N N- R' 13 a)R'=H ;X = CN b)R' = CH3 ;X = CN c) R' = H ; X = C02Et d) R' = CH3 ; X = C02Et K ncyVx O^N^NH2 HC* N(CH3)2 9 (CH3)2NH N N HN-^ O^^N^n 10a)X=CN b) X = C02Et R K O^N^\ HN 11a R NC. CH3 C02Et N XN HN- CH, 11b R'C(OEt)3 R = Cr^N^NjHCOCHg H3COC^NvCOCH3 12 10, 11 The dequarternized triazolo[l,5-a]pyridine derivatives 15 were obtained by treating products 14 with trifluoroacetic acid at room temperature. !H NMR spectra of 15 revealed the absence of the piperidine proton signals. Also, their mass spectra showed the absence of piperidine fragment peak at m/z 84. N-Deamination of the diaminopyridine derivatives 3a and 3b was also carried out under mild conditions. Thus, upon treating products 3a and 3b with sodium nitrite in aqueous acetic acid, the unexpected 6-amino-2-oxo-l,2-dihydropyridine-3,5- W. M. Basyouni: Synthesis of Novel Substituted [1,2,4]triazolo[l,5-a]pyridines and their Related... Acta Chim. Slov. 2003, 50, 223-238. 227 Scheme 3 K HNO, O^N^NH, i * NH2 a)X=CN b) X = C02Et K n°yStx I N, 16 ArCHO piperidine t R NH, CF3COOH HN-N 18 17,18 a)X=CN b)X=C02Et K jcyVx 14 15 14,15 a)Ar=C6H4.F-p ,X = CN b)Ar=C6H4.OH-o ,X = CN c)Ar=C6H4.F-p ,X = C02Et d)Ar = C6H4.OH-o ,X = C02Et R = O dicarbonitrile 17a and ethyl 2-amino-5-cyano-6-oxo-l,6-dihydropyridine-3-carboxylate 17b were obtained respectively, rather than the expected tetrazolopyridine derivatives 18 (Scheme 3). It worth mentioning that the product 17a has been previously synthesized, although in a relatively low yield, from 4-(2-furyl)-3,5-dicyano-2(l/f)pyridine- 97 selenones. Elemental analysis and spectral data confirmed the proposed structure of 17b. Its IR spectrum (KBr) showed stretching vibration bands for NH and C=0 around 3441- W. M. Basyouni: Synthesis of Novel Substituted [1,2,4]triazolo[l,5-a]pyridines andtheir Related... 228 Acta Chim. Slov. 2003, 50, 223-238. 3291 and at 1694 (COOC2H5) and 1650 cm"1, respectively, (characteristic for pyridone system). On the other hand IR spectrum of 17b in DMSO showed no carbonyl stretching vibrations around 1650 cm"1. ]H NMR spectrum of 17b exhibits proton signal at d 11.66 ppm (down-field shifted), which could be assigned to iminolic form6b 17B. Mass spectrum with M+ at m/z 273 (100%) is also in a good agreement with the proposed structure of 17b. One step synthesis of the triazolo[l,5-a]pyridine derivatives lla and llb was also attempted in the present work. Thus when N'-acetyl-2-cyanoacetohydrazide 19 was heated under reflux in ethanol, containing triethylamine as a catalyst, and unsaturated nitriles 2, the corresponding triazolopyridine derivatives lla and llb were obtained in somewhat low yield (30% for lla, 40% for llb) with respect to a previously reported 98 mechanism (Scheme 4). Scheme 4 CN CONHNHCOCH3 R - CH =< + H2C x CN 2 19 The present work was extended to investigate condensation of 2 with the 90 thiohydantion derivative 20. This reaction produced the fused ring system of pyrano[2,3-c/jimidazole derivatives 24 when carried out in the presence of triethyl amine (Scheme 5). This condensation reaction may initially start with addition of the active methylene group of 20 to the olefmic double bond of 2 giving rise to Michael adduct 21, followed by rearrangement and cyclization to 23. The latter intermediate gave the more stable 5-amino-7-(2-furyl)-2-thioxo-l,2-dihydropyrano[2,3-c/jimidazole-6-carbonitrile W. M. Basyouni: Synthesis of Novel Substituted [1,2,4]triazolo[l,5-a]pyridines andtheir Related... a, X = CN b, X = C02Et Acta Chim. Slov. 2003, 50, 223-238. 229 24a and ethyl 5-amino-7-(2-furyl)-2-thioxo-l,2-dihydropyrano[2,3-^|imidazole-6-carboxylate 24b upon loosing /?-toluenesulfonic acid and a molecule of hydrogen (Scheme 5). Scheme 5 CN r-CH=^ + X H M----¦ N- I Ts 20 NyO NH2 N^Y^X Ts R 23 N^U .CN S=< Jf HC^ CH XX Ts 21 OH .Or. KnA^hc-x Ts 22 -TsOH -H2 NH2 X N^^O NH2 HSA^XX R B 24 a)X = CN b)X = C02Et R = W. M. Basyouni: Synthesis of Novel Substituted [1,2,4]triazolo[l,5-a]pyridines andtheir Related... 230 Acta Chim. Slov. 2003, 50, 223-238. IR spectra of products 24 (KBr) revealed NH and C=S vibrations in the region of 3435-3200 and 1241-1220 cm"1, respectively. On the other hand, the IR spectra in DMSO lack the C=S stretching vibrations. ]H NMR spectra of products 24 lack the presence of CH2 and tolyl groups, but revealed the other expected characteristic signals. Also, it was noticed that the HN-C=S proton signals were down-field shifted and appeared in S 12.83-12.95 ppm region. This shift can be attributed to the thiol form 24B in solution. Mass spectra of 24a and 24b showed a molecular ion peak (M+) at m/z 258 (in a relative intensitv of 56.39%) and m/z 305 (in a relative intensitv of 87.50%), respectivelv. Table 1. Characterization of the synthesized compounds. Mp (°C) Yield (%) Mol. Formula Analysis Calcd/Found (%) (Solvent) r. tirne (Mol. Wt.) C H N 310-12 60 C„H7N502 54.77 2.93 29.04 (n-butanol) (241.21) 54.78 3.03 29.28 198-200 60 C13H12N404 54.16 4.20 19.44 (EtOH) (288.26) 54.27 4.28 19.59 195-6 13 C„H9N502 54.32 3.73 28.80 (EtOH) (243.22) 54.42 3.87 28.70 274-6 86 C12H5N502 57.37 2.01 27.88 (EtOH/DMF) (251.20) 57.43 2.00 28.00 288-90 77 C14H10N4O4 56.38 3.38 18.79 (Acetonitrile) (298.25) 56.10 3.38 19.00 306-8 33 C13H7N502 58.87 2.66 26.41 (Acetonitrile) (265.23) 58.68 2.92 26.49 291-3 57 C15H12N404 57.69 3.87 17.94 (n-butanol) (312.28) 58.03 4.00 17.99 275-7 15 C17H13N505 55.59 3.57 19.07 (MeOH) (367.31) 55.70 3.50 19.30 266-8 65 C14H9N502 60.21 3.25 25.08 (EtOH/DMF) 10h (279.25) 60.03 3.40 24.81 271-3 60 Ci5H„N502 61.43 3.78 23.88 (Acetonitrile) 5h (293.28) 61.48 4.00 24.13 269-71 70 C16H14N4O4 58.89 4.32 17.17 (EtOH) 10h (326.26) 59.00 4.40 17.00 240-2 64 C17H16N404 59.99 4.74 16.46 (EtOH) 5h (340.33) 60.10 4.70 16.50 344-6 74 C23H19FN602 64.18 4.45 19.53 (Acetonitrile/DMF) (430.43) 64.26 4.52 19.78 Table 1. Continued on the next page. W. M. Basyouni: Synthesis of Novel Substituted [1,2,4]triazolo[l,5-a]pyridines andtheir Related... 3a 3b 4 lOa lOb lla llb 12 13a 13b 13c 13d 14a Acta Chim. Slov. 2003, 50, 223-238. 231 Table 1. Continuedfrom the previous page. 14b 14c 14d 15a 15b 15c 15d 17b 24a 24b 302-4 69 C23H20N6O3 64.47 4.71 19.62 (Acetonitrile) (428.44) 64.41 4.94 19.45 221-2 54 C25H24FN504 62.88 5.07 14.67 (MeOH) (477.48) 63.00 4.90 14.80 225-6 52 C25H25N505 63.15 5.30 14.73 (MeOH) (475.49) 63.00 5.40 14.80 348-50 81 C18H8FN502 62.61 2.34 20.28 (Acetonitrile/DMF) (345.28) 62.80 2.50 20.00 342-4 81 Ci8H9N503 62.97 2.64 20.40 (Acetonitrile) (343.29) 63.10 2.50 20.60 303-5 74 C20H13FN4O4 61.22 3.34 14.28 (MeOH) (392.33) 61.40 3.50 14.20 286-8 79 C2oH14N405 61.54 3.61 14.35 (MeOH) (390.34) 61.70 3.50 14.50 303-5 78 C13H11N3O4 57.14 4.06 15.38 (EtOH) (273.24) 57.21 4.25 15.51 313-5 52 CnH6N402S 51.16 2.34 21.70 (Acetonitrile/DMF) 5h (258.25) 51.26 2.39 21.99 241-3 48 C13H11N3O4S 51.14 3.63 13.76 (EtOH) 10 h (305.30) 51.21 3.90 13.49 Table 2. Spectral determinations for the synthesized products. Cmpd uNH IR (KBr) cm-1 uCN uCO uCS 1HNMR(DMSO-rf6)* 5ppm MS m/z 3a 3b 00 en 2210 1650 13 15 2210 1683 11 1660 3408 3292 3280 2183 1710 5.65 (br s, 2H, N-NH2), 6.82 (dd, 1H, J3.6, 1.42 Hz, C4.-H (furyl)), 7.35 (d, 1H, J3.6 Hz, C3.-H (furyl)), 8.08 (d, 1H, J 1.42 Hz, C5-H (furyl)), 8.42 (br s, 2H, NH2). 0.94 (t, 3H, J7.16 Hz, CH3), 3.98 (q, 2H, J 7.16 Hz, CH2), 5.70 (br s, 2H, N-NH2), 6.72 (dd, 1H, J2.72, 1.64 Hz, C4-H (furyl)), 6.93 (d, 1H, J2.72 Hz, C3-H (furyl)), 7.90 (d, 1H, J 1.64 Hz, C5.-H (furyl)), 8.30 (br s, 2H, NH2). 4.23 (d, 1H, J 6.4 Hz, C4-H), 5.09 (d, 1H, J 6.4 Hz, C3-H), 5.30 (br s, 2H, N-NH2), 6.32 (dd, 1H, J3.26, 1.8 Hz, C4-H (furyl)), 6.46 (d, 1H, J3.26 Hz, C3-H (furyl)), 6.95 (br s, 2H, NH2), 7.62 (d, 1H, J 1.8 Hz, C5-H (furyl)). 241 (M+) 288 (M+) 243 (M+) Table 2. Continued on the next page. W. M. Basyouni: Synthesis ofNovel Substituted[1,2,4]triazolo[l,5-a]pyridines andtheir Related... 232 Acta Chim. Slov. 2003, 50, 223-238. Table 2. Continuedfrom the previous page._________________________________________ lOa 3120 2204 1650 6.78 (dd, 1H, J3.6, 1.5 Hz, C4-H (furyl)), 251 7.20 (d, 1H, J3.6 Hz, C3-H (furyl)), 8.01 (M+) (d, 1H, J 1.5 Hz, C5'-H (furyl)), 8.20 (br s, 1H, NH), 8.28 (s, 1H, C2-H). lOb 3120 2214 1691 1.07 (t, 3H, J7.10 Hz, CH3), 4.08 (q, 2H, J 298 1650 7.10 Hz, CH2), 6.65 (dd, 1H, J3.52, 1.42 (M+) Hz, C4>-H (furyl)), 6.82 (d, 1H, J3.52 Hz, C3>-H (furyl)), 7.81 (d, 1H, J 1.42 Hz, C5-H (furyl)), 8.22 (s, 1H, C2-H), 8.30 (br s, 1H, NH). lla 3440 2220 1650 2.58 (s, 3H, CH3), 6.77 (dd, 1H, J3.6,1.50 265 Hz, C4>-H (furyl)), 7.17 (d, 1H, J3.60 Hz, (M+) C3-H (furyl)), 7.99 (d, 1H, J 1.50 Hz, C5-H (furyl)), 8.21(brs, 1H, NH). llb 3340 2229 1695 1.04 (t, 3H, J7.18 Hz, CH3-ethyl), 2.53(s, 312 1671 3H, CH3), 4.11 (q, 2H, J7.18 Hz, CH2), (M+) 6.74 (dd, 1H, J3.60,1.50 Hz, C4-H (furyl)), 6.91 (d, 1H, J3.60 Hz, C3-H (furyl)), 7.87 (d, 1H, J 1.50 Hz,C5-H (furyl)), 7.95 (br s, 1H, NH). 12 3461 2225 1738 2.38 (d, 9H, J4.94, 3CH3), 6.76 (dd, 1H, J 367 1707 3.60, 1.70 Hz, C4-H (furyl)), 7.09(d, 1H, J (M+) 1674 3.60 Hz, C3>-H (furyl)), 8.00 (d, 1H, J 1.70 Hz, C5>-H (furyl)), 13.15 (br s, 1H, NH). 13a 2215 1685 1.52 (t, 3H, J7.40 Hz, CH3), 4.51 (q, 2H, J 279 7.40 Hz, CH2), 6.87 (dd, 1H, J3.60,1.50 Hz, (M+) C4-H (furyl)), 7.40 (d, 1H, J 3.60 Hz, C3>-H (furyl)), 8.16 (d, 1H, J 1.50 Hz, C5-H (furyl)), 9.27 (s, 1H, C2-H). 13b 2215 1680 1.43 (t, 3H, J6.90 Hz, CH3-ethyl), 2.70 (s, 293 3H, CH3); 4.87 (q, 2H, J 6.90 Hz, CH2), (M+) 6.85 (dd, 1H, J3.60, 1.60 Hz, C4>-H (furyl)), 7.40 (d, 1H, J3.60 Hz, C3-H (furyl)), 8.13 (d, 1H, J 1.60 Hz, C5-H (furyl)). 13c 2206 1724 1.07 (t, 3H, J7.15 Hz, CH3, OEt), 1.54(t, 1647 3H, J 7.20 Hz, CH3, NEt), 4.10 (q, 2H, J 7.15 Hz, OCH2), 4.47 (q, 2H, J 7.20 Hz, NCH2), 6.72 (dd, 1H, J3.60, 1.80 Hz, C4-H (furyl)), 6.95 (d, 1H, J 3.60 Hz, C3-H (furyl)), 7.90 (d, 1H, J 1.80 Hz, C5-H (furyl)), 10.64 (s, 1H, C2-H). Table 2. Continued on the next page. W. M. Basyouni: Synthesis ofNovel Substituted[1,2,4]triazolo[l,5-a]pyridines andtheir Related... Acta Chim. Slov. 2003, 50, 223-238. 233 Table 2. Continuedfrom the previous page.__________________________________________ 13d 2204 1701 1.07 (t, 3H, J7.15 Hz, CH3, OEt), 1.46 (t, 340 1664 3H,J7.28Hz, CH3, NEt), 3.14 (s, 3H, (M+) CH3), 4.10 (q, 2H, J7.15 Hz, OCH2), 4.42 (q, 2H, J 7.28 Hz, NCH2), 6.71 (dd, 1H, J 3.50,1.50 Hz, C4>-H (furyl)), 6.94(d, 1H, J 3.50 Hz, C3-H (furyl)), 7.88 (d,lH, J 1.50 Hz, C5>-H (furyl)). 14a 3440 2206 1660 1.60 (m, 6H, 3CH2, piper.), 3.02 (m, 4H, 345 2CH2, piper.), 6.79 (dd, 1H, J3.50, 1.80 Hz, (M+ -C4>-H (furyl)), 7.21 (d, 1H, J3.50 Hz, C3-H piper.) (furyl)), 7.37 (m, 2H, 2CH (aryl)), 8.02 (d, 1H, J 1.80 Hz, C5>-H (furyl)), 8.22 (m, 4H, 2CH (aryl), NH2). 14b 3440 2212 1646 1.64 (m, 6H, 3CH2, piper.), 3.02 (m, 4H, 343 2CH2, piper.), 6.83 (dd, 1H, J3.42, 1.80 Hz, (M+ -C4>-H (furyl)), 7.06 (m, 2H, 2CH (aryl)), piper.) 7.28 (d, 1H, J3.42 Hz, C3-H (furyl)), 7.43 (m, 1H, CH (aryl)), 8.11 (m, 2H, C5-H (furyl), CH (aryl)), 8.26 (br s, 2H, NH2), 11.29(brs, 1H, OH). 14c 3446 2210 1710 1.10 (t, 3H, J7.02 Hz, CH3); 1.62 (m, 6H, 392 1650 3CH2, piper.), 3.01 (m, 4H, 2CH2, piper.), (M+ - 4.12 (q, 2H, J 7.02 Hz, CH2), 6.67 (dd, 1H, piper.) J3.60, 1.50 Hz, C4'-H (furyl)), 6.82 (d, 1H, J3.60 Hz, C3>-H (furyl)), 7.35 (m, 2H, 2CH (aryl)), 7.82 (d, 1H, J 1.50 Hz, C5-H (furyl)), 8.18 (m, 2H, 2CH (aryl)), 8.30 (br s, 2H, NH2). 14d 3415 2210 1700 1.15 (t, 3H, J7.12 Hz, CH3), 1.60 (m, 6H, 390 1660 3CH2, piper.), 3.02 (m, 4H, 2CH2, piper.), (M+ - 4.14 (q, 2H, J 7.12 Hz, CH2), 6.67 (dd, 1H, piper.) J3.36, 1.50 Hz, C4'-H (furyl)), 6.84 (d, 1H, J3.36 Hz, C3>-H (furyl)), 7.00 (m, 2H, 2CH (aryl)), 7.37 (m, 1H, CH (aryl)), 7.84 (d, 1H, J 1.50 Hz, C5>-H (furyl)), 8.10 (m, 1H, CH (aryl)), 8.24 (br s, 2H, NH2), 12.10 (br s, 1H, OH). 15a 3448 2216 1650 6.79 (dd, 1H, J3.60, 1.50 Hz, C4>-H (furyl)), 7.21 (d, 1H, J3.60 Hz, C3-H (furyl)), 7.37 (m, 2H, 2CH (aryl)), 8.02(d, 1H, J 1.50 Hz, _________________________________C5-H (furyl)), 8.23 (m, 2H, 2CH (aryl)).___________ Table 2. Continued on the next page. W. M. Basyouni: Synthesis ofNovel Substituted[1,2,4]triazolo[l,5-a]pyridines andtheir Related... 234 Acta Chim. Slov. 2003, 50, 223-238. Table 2. Continuedfrom the previous page.__________________________________________ 15b 3440 2218 1650 6.81 (dd, 1H, J3.36, 1.50 Hz, C4-H(furyl)), 343 7.03 (m, 2H, 2CH (aryl), 7.27 (d, 1H, J3.36 (M+) Hz, C3.-H (furyl)), 7.41 (m, 1H, CH (aryl)), 8.04 (d, 1H, J 1.50 Hz, C5-H (furyl)), 8.10 (m, 1H, CH (aryl)). 15c 3440 2224 1703 1.07 (t, 3H,J7.12 Hz, CH3), 4.13 (q, 2H, J 392 1654 7.12 Hz, CH2), 6.71 (dd, 1H,J3.38, 1.60, (M+) C4-H (furyl)), 6.90 (d, 1H, J 3.38 Hz, C3-H (furyl)), 7.43 (m, 2H, 2CH (aryl)), 7.89 (d, 1H, J 1.60 Hz, C5-H (furyl)), 8.23 (m, 2H, 2CH (aryl)). 15d 3365 2225 1730 1.13 (t, 3H, J7.08 Hz, CH3), 4.14 (q,2H, J 390 1647 7.08 Hz, CH2), 6.71 (dd, 1H, J3.36,1.70 Hz, (M+) C4-H (furyl)), 6.88 (d, 1H, J 3.36 Hz, C3-H (furyl)), 7.06 (m, 2H, 2CH, (aryl)), 7.47 (m, 1H, CH, (aryl)), 7.89 (d, 1H, J 1.70 Hz, C5-H (furyl)), 8.09 (m, 1H, CH, (aryl). 17b 3441 2214 1694 0.93 (t, 3H, J7.10 Hz, CH3), 3.95 (q, 2H, J 273 3291 1650 7.10 Hz, CH2), 6.72 (dd, 1H, J3.60,1.60 Hz, (M+) C4-H (furyl)), 6.92 (d, 1H, J 3.60 Hz, C3-H (furyl)), 7.56 (br s, 2H, NH2), 7.89 (d, 1H, J 1.60 Hz, C5-H (furyl)), 11.66 (br s, 1H, OH). 24a 3357 2204 1220 6.79 (dd, 1H, J3.56, 1.74 Hz, C4-H (furyl)), 258 3280 7.45 (d, 1H, J 3.56 Hz, C3-H (furyl)), 8.02 (M+) (d, 1H, J 1.74 Hz, C5-H (furyl)), 8.28 (br s, 2H, NH2), 12.95 (br s, 1H, SH). 24b 3435 1711 1241 1.29 (t, 3H, J7.10 Hz, CH3), 4.28 (q, 2H, J 305 3280 7.10 Hz, CH2), 6.69 (dd, 1H. J3.56,1.70 Hz, (M+) 3200 C4-H (furyl)), 7.43 (d, 1H, J 3.56 Hz, C3-H (furyl)), 7.90 (d, 1H, J 1.70 Hz, C5-H (furyl)), 8.03 (br s, 2H, NH2), 12.83 (br s, _______________________________1H, SH).__________________________________ * NH2, OH and SH groups are D20-exchangeable. Experimental Melting points are uncorrected. Microanalyses were done in the Microanalytical Laboratory, National Research Centre, Cairo, Egypt. IR spectra (KBr disc) were recorded using a Jasco FT/IR-300E spectrophotometer. 'H NMR spectra were recorded in DMSO-c/^ using Varian Mercury 300 MHz and Varian Gemini 200 MHz. The chemical shifts are reported in S relative to Me4Si. Mass spectra were recorded on GC/MS Finnigan SSQ 7000 spectrometer. W. M. Basyouni: Synthesis ofNovel Substituted[1,2,4]triazolo[l,5-a]pyridines andtheir Related... Acta Chim. Slov. 2003, 50, 223-238. 235 l,6-Diamino-4-(2-furyl)-2-oxo-l,2-dihydropyridine-3,5-dicarbonitrile(3a)and l,6-diamino-4-(2-furyl)-2-oxo-l,2,3,4-tetrahydropyridine-3,5-dicarbonitrile (4). A mixture of 1 (1 g, 0.01 mol) and 2a (1.44 g, 0.01 mol) in absolute ethanol (20 mL) was heated under reflux for 3 h. The precipitated product was filtered off and purified by crystallization from «-butanol to give 3a (1.45 g, yield 60%, Tables 1 and 2). When the mother liquor of the reaction was thermally concentrated and left to cool, another crop of a solid product was obtained (which was crystallized from ethanol) and identified as product 4 (0.32 g, 13%). Dehydrogenation of 4 to 3a. To a suspension of 4 (0.24 g, 1 mmol) in dry diethyl ether (30 mL) was added o-chloranile (1 mmol). The reaction mixture was stirred at room temperature (-25 °C) for 2 h. The solid product obtained was filtered off, washed with diethyl ether and crystallized from «-butanol to give 3a (0.2 g, 84% yield). Ethyl 5-cyano-l,2-diamino-4-(2-furyl)-6-oxo-l,6-dihydropyridine-3-carboxyl-ate (3b). A mixture of 1 (Ig, 0.01 mol) and 2b (1.91 g, 0.01 mol) in absolute ethanol (20 mL) containing triethvlamine (0.5 mL) was heated under reflux for 4 h and the reaction mixture was left to cool. The solid product obtained was filtered off and crystallized for purification from ethanol to give 3b (1.73 g, 60%). Reaction of 3a and 3b with ethyl chloroformate/DMF reagent mixture. To a mixture of ethyl chloroformate/N,N-dimethylformamide (30 mL, 1:5) compound 3a or 3b (0.01 mol) was added and the reaction mixture was heated under reflux for 3 h. The reaction mixture was evaporated to drvness under reduced pressure and the residue was triturated with MeOH (5 mL). The solidified material was filtered off, washed several times with MeOH and then crystallized for purification from the proper solvent to give 10. 7-(2-Furyl)-2-methyl-5-oxo-3,5-dihydro[l,2,4]triazolo[l,5-h]-pyridine-6,8-di-carbonitrile (lla) and N-acetyl-N-[6-(acetylamino)-3,5-dicyano-4-(2-furyl)-2-oxo-pyridin-l(2H)-yl]acetamide (12). A mixture of 3a (0.5 g) and acetic anhvdride (15 mL) was heated under reflux for 5 h. The solid product obtained was filtered off and W. M. Basyouni: Synthesis of Novel Substituted [l,2,4]triazolo[l,5-a]pyridines andtheir Related... 236 Acta Chim. Slov. 2003, 50, 223-238. crystallized from acetonitrile to give lla (0.18 g, 33% yield). When the mother liquor of the reaction was evaporated till dryness under reduced pressure an oily residue was obtained which solidified upon trituration with ethyl acetate. The solid obtained was filtered off and crystallized from methyl alcohol to give 12 (0.11 g, 15% yield). Ethyl 5-cyano-7-(2-furyl)-2-methyl-5-oxo-3,5-dihydro[l,2,4]triazolo-[l,5-h]-pyridine-8-carboxylate (llb). A mixture of 3b (0.5 g) and acetic anhydride (15 mL) was heated under refmx for 5 h. The reaction mixture was then evaporated to dryness under reduced pressure. The obtained residue solidified when triturated with MeOH. The solid product was filtered off, washed with MeOH and then crystallized from «-butanol to give llb (0.31 g, 57% yield). General Procedure for the Svnthesis of 3-ethyl[l,2,4]triazolo[l,5-h]pyridine derivatives 13: MethodA: A mixture of 3a or 3b (0.01 mol) and triethyl orthoformate or triethyl orthoacetate (0.02 mol) in acetonitrile (50 mL) was heated under reflux for 5-10 h. The reaction mixture was then evaporated to dryness under reduced pressure, and the obtained residue was triturated with methyl alcohol. The obtained solid product was filtered off and crystallized from the appropriate solvent to give 13 (Table 1). MethodB: A mixture of 10 or 11 (0.01 mol) and triethyl orthoformate or triethyl orthoacetate (0.03 mol) in acetonitrile (20 mL) was heated under reflux for 5-10 h. The reaction mixture was evaporated to dryness under reduced pressure. The obtained residue was treated with methanol. The solid product was filtered off and crystallized from the appropriate solvent to give 13. Product (yield, reaction tirne): 13a (73%, 10 h), 13b (72%, 5 h), 13c (69%, 10 h), and 13d (70%, 5 h). Reaction of 3a and 3b with aldehydes. A mixture of 3a or 3b (0.01 mol) and the desired aldehyde (0.01 mol) in l,4-dioxane (50 mL) containing piperidine (1 mL, 0.012 mol) was heated under reflux for 3 h and then left to cool. The solid product obtained (for products 14c and 14d the reaction mixture was evaporated to drvness under reduced W. M. Basyouni: Synthesis of Novel Substituted [l,2,4]triazolo[l,5-a]pyridines andtheir Related... Acta Chim. Slov. 2003, 50, 223-238. 237 pressure and then treated with methanol) was filtered off and crystallized for purification from the appropriate solvent to give 14. Treatment of products 14 with trifluoroacetic acid. A suspension of 14 (0.2 g) in trifluoroacetic acid (5 mL) was stirred at room temperature (~25 °C) for 5 min and then poured into cold water. The solid product obtained was filtered off and crystallized from the appropriate solvent to give 15. Reaction of products 3a and 3b with nitrous acid. To a suspension of 3a or 3b (0.01 mol) in aqueous acetic acid (100 mL, 60%), sodium nitrite (0.015 mol in 5 mL water) was added. The resulting mixture was stirred at room temperature (~25 °C) for 2 h and then left over night. The solid product obtained was filtered off, washed with water several times and crvstallized to give 17. 6-Amino-2-oxo-l,2-dihydropyridine-3,5-dicarbonitrile 17a: 85% yield, mp 340-42 °C (lit.27 45% yield, mp 340 °C). 2-Methyl[l,2,4]triazolo[l,5-a]pyridines lla and b. A mixture of 19 (0.01 mol) and 2a or 2b (0.01 mol) in absolute ethanol (30 mL) containing triethylamine (0.5 mL) was heated under reflux for 5-10 h. The reaction mixture was evaporated to drvness under reduced pressure. Trifluoroacetic acid was added to the resulting oil and the solution was poured into cold water. The resulting solid material was filtered off and crvstallized to give lla (0.80 g, 30% yield, 5 h) or llb (1.25 g, 40% yield, 10 h). Synthesis of 5-amino-7-(2-furyl)-2-thioxo-l,2-dihydropyrano[2,3-