One-Pot, Three-Component, Highly Diastereoselective Metal-Free Synthesis of 2,3,4,5-Tetrasubstituted Pyrrolidines

Abstract

An extremely efficient, highly diastereoselective, metal-free synthesis of 2,3,4,5-tetrasubstituted pyrrolidines is described. The three-component reaction between aldehydes, aminomalonates, and nitroalkenes proceeds with high diastereoselectivities and high yields.

metal-free - cycloaddition - three component - pyrrolidines - stereoselectivity

References and Notes

1

ICREA Researcher at University of Barcelona.

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12

Chloroform was bought from Aldrich and was used as received.

13

Typical Experimental Procedure for the Three-Component Synthesis of Pyrrolidine Derivatives
To a stirred solution of aldehyde 3 (0.375 mmol, 1.5 equiv) in CHCl₃ (0.5 mL) at r.t., diethyl 2-aminomalonate (2a, 0.375 mmol, 1.5 equiv) was added. The reaction was stirred at r.t. for 30 min and then nitroalkene 1 was added. The reaction was then stirred at r.t. overnight. Next the crude was purified by silica gel column chromatography to afford the pyrrolidine derivative 4.
Compound 4d: colorless oil. ^¹H NMR (400 MHz, CDCl₃): δ = 7.48-7.44 (m, 2 H), 7.33-7.28 (m, 7 H), 5.58 (dd, J = 6.8, 8.0 Hz, 1 H), 5.46 (d, J = 8.4 Hz, 1 H), 5.12 (d, J = 7.2 Hz, 1 H), 4.42-4.21 (m, 2 H), 3.91 (q, J = 7.6 Hz, 1 H), 3.46 (q, J = 7.6 Hz, 1 H), 1.29 (t, J = 7.6 Hz, 3 H), 0.78 (t, J = 7.6 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 171.1, 168.4, 135.7, 134.9, 132.4, 131.6, 130.9, 128.9, 128.7, 128.6, 128.3, 122.9, 93.5, 75.9, 63.8, 62.2, 62.0, 51.9, 14.0, 13.3.