Insertion of Imines into Vinylcyclopropanes Catalyzed by Nucleophilic Iron Complexes: A Formal [3+2]-Cycloaddition Strategy for the Synthesis of Substituted Pyrrolidine Derivatives

Abstract

Pyrrols are substructures in various biological active molecules. A straightforward iron-catalyzed synthesis of pyrrols via insertion of an imine into a vinylcyclopropane is presented. The corresponding pyrrols are obtained in moderate to good yields. Scope and limitations will be discussed.

Key words

catalysis - vinylcyclopropane - iron - cycloaddition - pyrrolidine

• References and Notes


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• 13 General Procedure Ligand L5 (0.04 mmol) was placed in a 10 mL Schlenk tube and dissolved in THF (1 mL). NaNH₂ (0.05 mmol) was added, and the reaction mixture was stirred at r.t. for 45 min, after which TBA[Fe] (0.04 mmol) was added. The reaction mixture was stirred for 1 h at 80 °C to allow the ligand to coordinate. Afterwards the vinylcyclopropane (0.4 mmol) and the imine (0.5 mmol) were added subsequently. The reaction mixture was stirred at 80 °C for 18 h. The product was purified by column chromatography on silica gel. 2-(4-Fluorophenyl)-1-tosyl-5-vinylpyrrolidine-3,3-dicarbonitrile (3) The product was obtained following the general procedure using vinylcyclopropane 1 (0.4 mmol, 1 equiv) and the corresponding imine (0.5 mmol, 1.25 equiv.) after column chromatography (PE–EtOAc, 5:1) as a brown solid (0.38 mmol, 95%). Diastereomers (dr = 1.12:1) were separated via semipreparative HPLC (PE–EtOAc, 6:1). Diastereomer 1: ¹H NMR (300 MHz, CDCl₃): δ = 7.61–7.56 (m, 2 H), 7.41–7.33 (m, 2 H), 7.30 (d, J = 8.0 Hz, 2 H), 7.13–7.05 (m, 2 H), 6.12 (m, 1 H), 5.45 (dd, J = 18.3, 13.6 Hz, 2 H), 5.33 (s, 1 H), 4.57 (q, J = 7.2 Hz, 1 H), 2.69 (dd, J = 13.3, 7.0 Hz, 1 H), 2.54 (dd, J = 13.3, 8.0 Hz, 1 H), 2.44 (s, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 165.2, 161.9, 145.0, 135.2, 133.8, 130.3 (d, J = 3.2 Hz), 129.9, 129.5 (d, J = 8.7 Hz), 127.9, 119.9, 116.2, 115.9, 113.4, 111.8, 70.2, 61.5, 40.3, 21.6 ppm. IR (film): ν = 2924 (w), 1605 (w), 1510 (m), 1359 (m), 1227 (m), 1165 (s), 1091 (m) cm^–1. GC–MS (ESI): m/z (%) = 418 (100) [M⁺ + Na]. ESI-HRMS: m/z calcd for C₂₁H₁₈FN₃O₂S + Na⁺: 418.0996; found: 418.0986. Diastereomer 2: ¹H NMR (300 MHz, CDCl₃): δ = 7.61–7.53 (m, 2 H), 7.27 (m, 4 H), 7.10 (m, 2 H), 5.83 (dt, J = 16.8, 9.7 Hz, 1 H), 5.62 (s, 1 H), 5.38 (d, J = 16.8 Hz, 1 H), 5.16 (d, J = 10.0 Hz, 1 H), 4.82 (m, 1 H), 3.02–2.91 (m, 1 H), 2.60 (m, 1 H), 2.42 (s, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 165.1, 161.8, 144.4, 137.2, 135.3, 130.7 (d, J = 3.4 Hz), 129.5, 129.1 (d, J = 8.7 Hz), 127.7, 120.2, 116.3, 116.1, 115.1, 111.8, 71.0, 62.0, 40.8, 21.6 ppm. IR (film): ν = 2924 (w), 1604 (w), 1511 (m), 1351 (m), 1228 (m), 1158 (s), 1106 (m) cm^–1. GC–MS (ESI): m/z (%) = 418 (100) [M⁺ + Na]. ESI-HRMS: m/z calcd for C₂₁H₁₈FN₃O₂S + Na⁺: 418.0996; found: 418.1004.

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