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DOI: 10.1055/s-2006-944224
Mono Alkylation of α-Isocyano Acetamide to its Higher Homologues
Publication History
Publication Date:
04 July 2006 (online)
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Abstract
Alkylation of α-isocyano acetamide (2) with alkyl halide in MeCN at 0 °C in the presence of cesium hydroxide afforded the mono-alkylated product 1 in good to excellent yield.
Key words
cesium hydroxide - isonitrile - isocyano acetamide - monoalkylation
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References and Notes
Synthesis of Compound 2a.
To a solution of methyl α-isocyanoacetate (4.4 mmol) in dry MeOH (3.0 mL) was added morpholine (10.3 mmol, 2.3 equiv) and the reaction mixture was stirred at r.t. for 18 h. The volatile was removed under reduced pressure and the crude material was purified by flash chromatography (SiO2, EtOAc-heptane = 2:1) to afford 2a in 85% yield, mp 77-78 °C. IR (CHCl3): 2163, 1658, 1462, 1422, 1274, 1236, 1111, 992 cm-1. 1H NMR (300 MHz, CDCl3): δ = 4.31 (s, 2 H), 3.63 (m, 4 H), 3.54 (m, 2 H), 3.30 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ = 161.3, 160.7, 66.5, 66.1, 45.6, 44.3, 42.6. MS (ES, positive mode): m/z = 177.1 [M + Na]+.
Synthesis of Compound 2d.
To a suspension of potassium salt of α-isocyano acetic acid (4.4 mmol) in dry CH2Cl2 (22 mL) were added Et3N (5.7 mmol), EDCI (5.3 mmol) and hydrochloride salt of MeNH(OMe) (4.8 mmol). After being stirred at r.t. for 20 h, the reaction mixture was quenched with H2O (2 mL) and extracted with CH2Cl2. The combined organic layers were washed with brine, dried and evaporated under reduced pressure. The crude material was purified by flash chromatography (Al2O3, EtOAc-heptane = 2:1) to afford 2d as a brown solid (69%), mp 72-73 °C. IR (CHCl3): 2162, 1681, 1410, 1317, 1179, 963 cm-1. 1H NMR (300 MHz, CDCl3): δ = 4.39 (s, 2 H), 3.69 (s, 3 H), 3.19 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 163.9, 160.7 (141.9), (62.3) 61.7, (52.3) 43.8, (40.7) 32.7. MS (ES, positive mode): m/z = 151.1 [M + Na]+.
Monoalkylation of α-Isocyanoacetamide - A General Procedure.
To a dry test tube containing CsOH·H2O (0.34 mmol, 1.7 equiv) were added, under argon atmosphere, a solution of isocyano acetamide (0.20 mmol) in MeCN (1.0 mL) and alkylating agent (0.21 mmol) at 0 °C. The resulting reaction mixture was stirred at 0 °C. When the reaction was deemed complete by TLC analysis (typically 24 h), the volatile was removed under reduced pressure. Purification of the crude product by either preparative TLC (silica gel) or flash chromatography (silica gel) afforded the desired product.
Compound 1a: yield 94%. IR (CHCl3): 2928, 2863, 2142, 1668, 1496, 1456, 1116 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.26-7.36 (m, 5 H), 4.54 (dd, J = 7.7, 7.0 Hz, 1 H), 3.20-3.69 (m, 10 H). 13C NMR (62.5 MHz, CDCl3): δ = 163.5, 159.8, 135.0, 129.4 (2 C), 128.8 (2 C), 127.7, 66.4, 65.9, 55.0, 46.2, 42.9, 39.1. MS (EI): m/z = 244 [M]+. Anal. Calcd for C14H16N2O2 (%): C, 68.83; H, 6.60; N, 11.47. Found: C, 68.71; H, 6.60; N, 11.47.