Mono Alkylation of α-Isocyano Acetamide to its Higher Homologues

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.

cesium hydroxide - isonitrile - isocyano acetamide - monoalkylation

References and Notes

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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]⁺.

<A NAME="RG12906ST-16">16</A>

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.

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