Microwave Mediated Synthesis of -Enamino Thioic Acid ...

More documents

Recommendations

Info

nitromethane or acetonitrile at 20 °C or heating up to 80 °C under microwave irradiation in the presence of sodium hydroxide gave no reaction. Synthesis of β-enaminothiones Thioacyl-6-nitrobenzotriazoles 7a-c reacted with ketimine 2a in THF in the presence of ZnBr2 at 20 °C for 3 d to give β-enamino thiones 8a-c in moderate to good yield (Scheme 2). Unfortunately, similar reactions of thioacylbenzotriazoles 7a with ketimine 2i produced under the same reaction conditions thioamide 9 in low 35% yield instead of the expected β-enamino thione 8 (Scheme 2), while the reactions with imines 2e and 2h resulted in complex mixtures of products. It is possible that the formation of complex mixtures is due to the concurrent addition of ionized thioacylbenzotriazole 7 to the imine bond, followed by hydrolysis to thioamides, such as 9. Ph N H S Scheme 2 4-ClC 6H 4 9,35% Ph N ZnBr 2 THF, 20 o C 2i O 2N S N N N 7a-c R 4 Bu N Ph Me 2a ZnBr 2 THF, 20 o C Bu Ph NH S 8a-c R 4 a: R 4 = 4-ClC 6H 4, 91% b: R 4 = 2-thienyl, 76% c: R 4 = 2-furyl, 45% Structures 8a–c were supported by their 1 H and 13 C NMR spectra, and by elemental analyses (see Experimental Section). The order of addition significantly influences the chemical yield. Thus, the best results were obtained when the appropriate thioacylbenzotriazole 7 in THF was first treated with ZnBr2, followed by slow addition of the corresponding imine 2, in contrast to low yields upon the initial addition of the Lewis acid to a solution of ketimine 2a in THF. After screening a series of nucleophiles, including Grignard, organozinc, organolithium reagents, enolates, silyl enol ethers, allyl trimethyl silane, and active methylenes, enamines and aldimines, ketimines were the only nucleophiles found to be effectively thioacylated by 1thioacylbenzotriazoles 7. Conclusions In conclusion, a novel and general approach to β-enamino thioic acid derivatives has been developed. The procedure described appears to be general and represents an efficient, simple and alternative route to β-enamino thioic acid derivatives 4–6. 145
Experimental Section General Procedures. Melting points were determined on a hot-stage apparatus equipped with a digital thermometer and are uncorrected. NMR spectra were recorded on a Varian Gemini 300 spectrometer in CDCl3 with tetramethylsilane as the internal standard for 1 H (300 MHz) or solvent as the internal standard for 13 C (75 MHz) unless otherwise stated. The elemental analyses were performed on a Carlo Erba EA–1108 instrument. Anhydrous THF was used freshly distilled from sodium/benzophenone. Column chromatography was conducted on silica gel 200-245 meshes. Imines 2a–i were prepared according to the published procedures: butyl(1phenylethylidene)amine (2a), colorless oil (91%); 22 butyl[1-(pyridin-4-yl)ethylidene]amine (2b), colorless oil (78%); 23 butyl(1-phenylpropylidene)amine (2c), colorless oil (88%); 24 butyl(cyclohexylidene)amine (2d), colorless oil (83%); 25 benzyl(cyclohexylidene)amine (2e), colorless oil (85%); 26 butyl(butan-2-ylidene)amine (2f), colorless oil (88%); 22 N-(3butenylidene)aniline (2g), colorless oil (73%); benzyl(butylidene)amine (2h), colorless oil (78%); 27 N-(cyclohexylidene)aniline (2i), colorless oil (61%). 28 1-Thioacyl-6-nitrobenzotriazoles 7a-c were prepared according to published procedures: 29 (6-nitrobenzotriazol-1-yl)(2-thienyl)methanethione (7b), gray microcrystals (40%), mp 132−134 °C (lit. 29 mp 133−134 °C); (6-nitrobenzotriazol-1-yl)(2-furyl)methanethione (7c), orange microcrystals (80%), mp 162−163 °C (lit. 29 mp 161−162 °C). (6-Nitrobenzotriazol-1-yl)-4-chlorophenylmethanethione (7a). Recrystallized from hexanes to give pink microcrystals (93%), mp 161−163 °C; 1 H NMR δ 9.49 (d, J = 1.9 Hz, 1H), 8.48 (dd, J = 8.9 , 2.1 Hz, 1H), 8.34 (d, J = 8.9 Hz, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H); 13 C NMR δ 199.4, 149.1, 140.2, 132.9, 132.1, 128.7, 121.9, 121.4, 112.2. Anal. Calcd for C13H7ClN4O2S: C, 48.99; H, 2.21; N, 17.58. Found: C, 49.11; H, 2.19; N, 16.22. Procedure for the preparation of dibenzotriazolylmethanethione (1). Thiophosgene (11.5 g, 10 mmol) was added dropwise to a solution of benzotriazole (4.77 g, 40 mmol) in dichloromethane (50 mL) at 0 ºC. The reaction mixture was stirred at the same temperature for 3h. The mixture was filtered, and the solid residue was washed with dichloromethane (3×30 mL). The filtrate was washed with 5% aqueous Na2CO3 (3×50 mL). The solvent was removed under vacuum to dryness, and the residue was recrystallized from dichloromethane to give di- (1H-benzotriazol-1-yl)methanethione in 87% yield as yellow microcrystals, mp 171 °C (lit. 21 mp 170−172 °C ). General procedure for the preparation of benzotriazolyl β-enaminothiones 3a–h To a solution of dibenzotriazolylmethanethione 1 (280 mg, 1 mmol) in THF (50 mL), appropriate imine 2 (1 mmol) was added at room temperature. The reaction mixture was stirred at the same temperature for 6 h, and then concentrated under vacuum. The residue was dissolved in ethyl acetate (50 mL), and was washed with 5% aqueous Na2CO3 (3×30 mL), followed by 146
Page 1 and 2: Microwave mediated syntheses of β-
Page 3: Treatment of compounds 3a,b under m
Page 7 and 8: (s, 1H), 3.57−3.51 (m, 2H), 2.55
Page 9 and 10: General procedure for the preparati

Microwave Mediated Synthesis of -Enamino Thioic Acid ...

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?