A Mannich-Cyclization Approach for the Asymmetric Synthesis of Saturated N-Heterocycles

Abstract

A concise asymmetric synthesis of disubstituted N-heterocycles is reported. Our approach utilizes an optimized Mannich reaction of functionalized aldehydes, followed by a novel dehydrative cyclization mediated by the Staab reagent (1,1′-carbonyldiimidazole, CDI). The method was applied to the synthesis of azetidines, piperidines and pyrrolidines.

stereoselective synthesis - heterocycles - cyclizations - azetidines - organocatalysis

References

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A solution of the corresponding amino alcohol (0.2 mmol) and 1,1′-carbonyldiimidazole (0.4 mmol) in MeCN (10 mL) was refluxed for 2 h. The solvent was evaporated in vacuo and the intermediate carbamates were heated (150 °C) in a Kugelrohr oven under high vacuum (0.05 mbar) for 2 h. The residue was purified by flash chromatography on silica gel to afford the azetidines. Products of lower molecular weight were collected in the receiving flask. Spectral data for 22d: colorless oil; R _f = 0.29 (Et₂O-pentane 1:10). ¹H NMR (400 MHz, CDCl₃): δ = 6.80 (d, J = 8.9 Hz, 2 H), 6.51 (d, J = 8.9 Hz, 2 H), 3.77 (m, 1 H), 3.75 (s, 3 H), 3.62 (dd, J = 8.0, 6.8 Hz, 1 H), 3.48 (dd, J = 6.8, 3.2 Hz, 1 H), 2.65 (m, 1 H), 1.83 (m, 2 H), 1.30 (d, J = 7.2 Hz, 3 H), 0.92 (t, J = 7.5 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 152.2, 147.4, 114.5 (2 C), 113.5 (2 C), 67.9, 58.1, 55.7, 27.5, 23.8, 14.7, 10.2. IR (capillary): 2961 (s), 2873 (m), 2834 (m), 1511 (s), 1465 (s), 1293 (m), 1240 (s), 1120 (m), 1041 (m), 819 (s) cm^-1. MS (EI): m/z (%) = 205 (100) [M⁺], 176 (58), 163 (52), 135 (45), 134 (54). HRMS (EI): m/z calcd for C₁₃H₁₉NO [M⁺]: 205.1467. Found: 205.1467. [α]_D ²⁵ -146.5 (c 1.04, CHCl₃).

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