Regioselective Cyclization of 2-Isothiocyanatobenzonitrile with Carbon 1,1-Dinucleophiles

Abstract

The one-pot cyclization of 2-isothiocyanatobenzonitrile with 1,1-dinucleophiles regioselectively afforded 2-alkylidene-4-imino-1,4-dihydrobenzo[d][1,3]thiazines.

cyclizations - N-heterocycles - isothiocyanates - nitriles - regioselectivity

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13

General procedure A: To a THF suspension of 2-isothiocyanatobenzonitrile (1a) and sodium hydride was added phenylacetonitrile (2a) at 0 °C. The mixture was heated at reflux for 72 h, cooled to room temperature and subsequently an aqueous solution of NH₄Cl (20 mL, 1 M) was added. The organic and the aqueous layers were separated and the latter was extracted three times with ether (30 mL). The combined organic layers were dried (Na₂SO₄), filtered and the solvent of the filtrate was removed in vacuo. The residue was recrystallized from ethanol. Starting with 2a (0.351 g, 3.0 mmol), 1a (0.320 g, 2.0 mmol), sodium hydride (0.096 g, 3.0 mmol) and 15 mL of THF, 3a was obtained as a pale yellow solid (0.345 g, 62%, E/Z = 8:1).
General procedure B: To a THF solution of phenylacetonitrile was added n-BuLi (1.6 M solution in hexane) at 0 °C. After stirring for 1 h at 0 °C, the solution was cooled to -78 °C and a THF solution of 2-isothiocyanatobenzonitrile was added. After stirring for 30 min at -78 °C an aqueous solution of NH₄Cl (20 mL, 1 M) was added. After warming to room temperature the organic and the aqueous layers were separated and the latter was extracted three times with ether (30 mL). The combined organic layers were dried (Na₂SO₄), filtered and the solvent of the filtrate was removed in vacuo. The residue was recrystallized from ethanol. Starting with 2a (0.28 g, 2.3 mmol), n-BuLi (3.3 mL, 1.6 M), 1a (0.32 g, 2.0 mmol) and 15 mL of THF, 3a was obtained as a pale yellow solid (0.24 g, 43%).
¹H NMR (DMSO-d ₆, 300 MHz): δ 7.24-7.41 (m, 3 H, CH), 7.43-7.65 (m, 5 H, CH), 8.68 (dd, ⁴ J = 1 Hz, ³ J = 8 Hz, 1 H, CH), 9.30 (s, 1 H, NH), 12.34 (s, 1 H, NH). ¹³C NMR (DMSO-d ₆, 75 MHz, major isomer): δ_c 82.29 (C), 114.67 (CN), 116.30 (CH), 121.20 (C), 124.44, 124.95, 128.92, 129.21, 129.96 (CH), 132.64 (C), 133.69 (CH), 136.80, 141.75, 170.63 (C). MS (70 eV): m/z (%): 277 (100, M⁺), 244(9), 217(18), 190(12), 165(4). IR (KBr, cm^-1): 3370 (s), 3207 (w), 3174 (m), 3143 (w), 3309 (m), 3068 (w), 2194 (s), 1608 (s), 1589 (s), 1551 (m), 1496 (s), 1449 (m), 1417 (m). Anal.: Calcd. for C₁₆H₁₁N₃S: C 69.29, H 4.00; found C 69.64, H 3.97.

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