Synthesis of thieno[2,3-d]pyridazines and thieno[3,4-d]pyridazines from thiophene derivatives

Abstract

The title compds. were prepd. by cyclization of N2H4 and dicarbonyl derivs. of thiophene (I), which were formed in turn from dihalo derivs. of I. Thus, a soln. of 32.6 g. 3-bromothiophene in 60 ml. Et2O was added during 30 min. to a soln. prepd. from 8.10 g. Li, 80 g. BuBr, and 350 ml. Et2O, and cooled to -60 Deg. The mixt. was stirred 50 min., treated during 2 hrs. with a soln. of 45.8 g. HCONMe2 (II) in 220 ml. Et2O, kept 15 hrs. at -50 Deg, and warmed to -30 Deg during 3 hrs. to give 11.2 g. 2,3-diformylthiophene (III), b0.2 90-5 Deg, m. 78 Deg; bis(semicarbazone) m. 290 Deg (H2O-EtOH). The IV prepd. are listed in the table. In the prepn. of V, the mixt. was refluxed 1 hr. after the addn. of II; III and (IV, R1 = CHO, R2 = Br, R3 = R4 = H) (VI) were obtained as by-products. [TABLE OMITTED] A soln. of 10 g. ethylene acetal (VII) of VI in 25 ml. Et2O was added at -55 Deg to a soln. prepd. from 0.87 g. Li, 8.7 g. BuBr, and 50 ml. Et2O. The mixt. was stirred 1 hr., treated with a soln. of 2.61 g. EtCN in 25 ml. Et2O, stirred 1 hr. at -10 Deg to give 40% (IV, R1 = CHO, R2 = EtCO, R3 = R4 = H) (VIII), m. 92 Deg. A mixt. of 41.7 g. 3-acetylthiophene, 24 ml. (CH2OH)2, a few crystals of p-MeC6H4SO3H, and 215 ml. C6H6 was refluxed 5 hrs. with azeotropic removal of H2O to give 80% 2-methyl-2-beta -thienyl-1,3-dioxolane (IX), b18 103-5 Deg. Treatment of IX with BuLi and II as described previously gave 70% 2-(2-formyl-3-thienyl)-2-methyl-1,3-dioxolane (X), b1 120-4 Deg, m. 40 Deg. A mixt. of 5 g. X, and 50 ml. 5% aq. HCl was stirred 2 hrs. at room temp. and extd. with Et2O, which ext. was evapd. to give 90% (IV, R1 = CHO, R2 = Ac, R3 = R4 = H) (XI), m. 61 Deg. A soln. of 30 g. ethylene acetal (XII) of 3-formylthiophene in 70 ml. Et2O was added at -10 Deg to a soln. of BuLi (from 3.45 g. Li and 34.2 g. BuBr) in 80 ml. Et2O. The mixt. was refluxed 15 min., cooled to -10 Deg, treated with a soln. of 20 g. AcNMe2 in 50 ml. Et2O, and stirred 1.5 hrs. at 20 Deg to obtain 40% 2-(2-acetyl-3-thienyl)-1,3-dioxolane, b2 134-6 Deg, m. 60 Deg, hydrolysis of which with aq. HCl gave 90% IV (R1 = Ac, R2 = CHO, R3 = R4 = H), m.48 Deg. A soln. of 23.2 g. IX in 50 ml. Et2O was added at -10 Deg to a soln. of BuLi (from 2.54 g. Li and 25.4 g. BuBr) in Et2O. The mixt. was refluxed 15 min., poured on a suspension of dry ice in Et2O, kept 30 min., and treated with H2O to give 70% IV (R1 = CO2H, R2 = Ac, R3 = R4 = H) (XIII), m. 151 Deg. The reaction mixt., of 10 g. XII (in 50 ml. Et2O) and BuLi (a mixt. of 1.33g. and 13.2 g. BuBr in 50 ml. Et2O) (prepd. at -10 Deg), was refluxed 15 min., cooled to -10 Deg, and treated with a soln. of 11 g. EtO2CCONEt2 (XIV) in 40 ml. Et2O. The mixt. was stirred 45 min. at 0 Deg, 30 min. at 20 Deg to give 60% 3-(2-m-dioxolanyl)thiophene-2-glyoxylic acid N,N-diethylamide (XV), b0.6 218-22 Deg, m. 78 Deg. Hydrolysis of 9.2 g. XV with 80 ml. 50% aq. AcOH gave 90% 3-formyl-2-thiopheneglyoxylic acid N,N-diethylamide, b0.6 140-5 Deg, m. 60 Deg. Similarly, VII was converted in 55% yield to 2-(2-m-dioxolanyl)thiophene-3-glyoxylic acid N,N-diethylamide, b0.3 175-80 Deg, which was hydrolyzed by 5% aq. HCl at room temp. to give 90% 2-formyl-3-thiopheneglyoxylic acid N,N-diethylamide, m. 68 Deg. A soln. of 2.2 g. III, 1.33 g. N2H4.N2O, and 15 ml. abs. EtOH was refluxed 30 min. and concd. in vacuo to give 80% thieno[2,3-d]pyridazine (XVI, R = H) (XVIa), m. 167 Deg (C6H6); methiodide m. 225 Deg (MeOH); hydrochloride m. 198 Deg (Me2CO-MeOH). A mixt. of 1 g. XVIa, 10 ml. 30% H2O2, and 20 ml. AcOH was kept 70 hrs. at room temp. and concd. to give 55% thieno[2,3-d]pyridazine N-oxide, m. 183 Deg (Me2CO). The following XVI were similarly prepd. (R, % yield, m.p., and m.p. of hydrochloride and methiodide are given): 5-Br, 70, 154 Deg (MeOH), -, 251 Deg (EtOH); 1-Me, 70, 67 Deg, 225 Deg, 235 Deg (MeOH); 4-Me, 60, 131 Deg, 225 Deg (MeOH), 192 Deg; 4-Et, 75, 58 Deg, -, -; 1-CONEt2 (XVII), 60, 63-4 Deg, -, -; and thieno[3,4-d]pyridazine, 80, 135-6 Deg, 175 Deg (Me2CO-MeOH), 182 Deg (EtOH); and 80% XVIII (R = H) XVIIIa), m. 220-1 Deg (H2O). Also prepd. were (R, % yield, and m.p. given): XVIII: 4-Me, 85, 290 Deg; 2-Ph, 75, 154 Deg (Et2O-CHCl3); 2-(CH2CH2OH), 50, 131 Deg (Me2CO) (acetate m. 45 Deg); XIX: H, 80, 239-40 Deg (H2O); 3-Ph, 70, 88-9 Deg; 3-(p-O2NC6H4), 75, 276 Deg; XX: H, 80, 252-3 Deg; 2-Ph, 70, 102 Deg (EtOH-CHCl3). A mixt. of 1 g. XVII and 50 ml. 20% aq. HCl was refluxed 1 hr. to give 80% XVI (R = CO2H), m. 265 Deg; XVI (R = CO2Me), m. 205 Deg (CHCl3-Et2O); XVI (R = CONH2), m. 230 Deg (H2O); XVI (R = CONHNH2), m. 213 Deg (MeOH); XVI (R = CN) (XXI), m. 157 Deg. A soln. of 0.5 g. XXI, 5 ml. C5H5N, and 0.5 ml. Et3N was satd. with H2S, kept 10 hrs. at room temp., and evapd. to give XVI (R = CSNH2), m. 195 Deg (MeOH). A mixt. of 1.66 g. 2-formylthiophene, 2 g. BzNHNH2, and 15 ml. EtOH was refluxed 2 hrs. to give 95% 2-formylthiophene benzoylhydrazone, m. 205 Deg (MeOH). The following derivs. of 2-formyl-3-carboxythiophene were similarly prepd. (deriv., % yield, and m.p. are given): phenylhydrazone, 90, 223 Deg; p-nitrophenylhydrazone, 90, 319 Deg (Me2CO); N-benzoylhydrazone, 75, 256 Deg (MeOH); N-tosylhydrazone, 80, 242 Deg (MeOH). A mixt. of 1 g. XVIIIa and a soln. prepd. from 0.17 g. Na and 50 ml. abs. EtOH was refluxed 1 hr., treated with 0.42 g. Me2SO4, and refluxed 8 hrs. to give 40% XVIII (R = 2-Me), m. 114 Deg (MeOH). The following were prepd. similarly (R, % yield, and m.p. are given): XVIII: 2-PhCH2, 60, 106 Deg (Et2O); 2-(2-piperidinoethyl), 60, 98 Deg (EtOH); 2-(2-pyrrolidinoethyl), -, 221 Deg (MeOH); 2, [Me2N(CH2)3], -, 267 Deg (EtOH); XIX: 3-Me, 65, 135 Deg (CHCl3Et2O); 3-PhCH2, 65, 153 Deg; 3-Me2NCH2CH2, 65, 334 Deg (MeCN). To a soln. of 1 g. XVIIIa in 50 ml. CH2:CHCN was added 0.2 ml. 40% soln. of PhCH2NMe3 OH in MeOH. The mixt. was refluxed 3 hrs. and evapd. to dryness to give 80% XVIII [R = (2-CH2CH2CN)], m. 120 Deg (Me2CO); XIX [R = (3-CH2CH2CN)], m. 137 Deg (Me2CO), was prepd. similarly. A mixt. of 1 g. XVIII, 50 ml. EtOH, and 13 ml. 30% aq. CH2O was refluxed 1 hr., treated with 13 ml. CH2O soln., and refluxed 2 hrs. to give 80% XVIII [R = (2-CH2OH)] (XXII), m. 140 Deg (Me2CO); XIX (R = 3-CH2OH), m. 162 Deg (Me2CO), was prepd. similarly in 75% yield. XXII (0.5 g.) was mixed with 10 ml. PBr3 and refluxed 15 min. to give 70% XVIII [R = (2-CH2Br)], m. 140 Deg (CHCl3). N.M.R. and ir spectra are given. 40 references. [on SciFinder (R)]