Asymmetric Organocatalytic Domino Reactions of γ-Nitroketones and Enals

Abstract

Chiral substituted cyclohexene carbaldehydes are readily synthesized in excellent enantiomeric excesses from simple nitro­ketone and enal precursors. The domino Michael addition-aldol condensation reaction catalyzed by a chiral secondary amine involves tandem iminium-enamine activation.

Michael additions - aldol reactions - asymmetric synthesis - domino reactions - organocatalysis

References and Notes

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CCDC number 642547 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

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<A NAME="RG13407ST-11">11</A>

All new compounds were fully characterized (mp, optical rotation, NMR, IR, MS, elemental analysis) and the spectroscopic and analytical data are in agreement with the assigned structures.

<A NAME="RG13407ST-12">12</A>

General Procedure
To a solution of nitroketone 2 (3.0 mmol) and TMS-ether (S)-4 (0.60 mmol, 20 mol%) in toluene (3.0 mL) was added enal 3 (3.75 mmol, 1.25 equiv) and benzoic acid (20 mol%). The reaction vessel was then flushed with argon gas, stoppered and stirred at 9 °C for 6-15 d.
Workup A: Direct purification of the reaction mixture by flash chromatography (2:1 pentane-Et₂O) afforded cyclohexenes 1.
Workup B: The crude reaction mixture was diluted with CHCl₃ (8.0 mL) and heated in the presence of PhCO₂H (150 mg) at 65 °C for 2.5 h. Following dilution with Et₂O (75 mL), the organic layer was washed with sat. aq NaHCO₃ (15 mL) and brine (15 mL), dried (MgSO₄), concentrated and purified by flash chromatography (2:1 pentane-Et₂O) to afford cyclohexenes 1.¹¹ (5 R ,6 R )-2-Methyl-5-nitro-6-phenylcyclohex-1-ene Carbaldehyde (1a)
Isolated after 7 d as a pale yellow solid (315 mg, 43%). The ee was determined by HPLC on a chiral stationary phase (Daicel Chiralpak IA, n-heptane-i-PrOH = 95:5, 1.0 mL/min), t _R = 13.7 min(major), 17.0 min(minor). An analytical sample was prepared by recrystallization (CH₂Cl₂-Et₂O-hexane, slow evaporation); mp 89 °C; [α]_D ²⁴ -347 (c 1.02, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 2.02 (dddd, J = 14.7, 10.3, 7.0, 3.5 Hz, 1 H, CHHCH₂), 2.32 (s, 3 H, Me), 2.33-2.60 (m, 3 H, CHHCH ₂), 4.67 (dd, J = 7.3, 3.6 Hz, 1 H, CHNO₂), 4.80 (br s, 1 H, CHPh), 7.13-7.18 (m, 2 H, o-Ph), 7.22-7.26 (m, 1 H, p-Ph), 7.28-7.34 (m, 2 H, m-Ph), 10.11 (s, 1 H, CHO) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 18.4 (Me), 20.8 (C-4), 29.6 (C-3), 41.4 (C-6), 85.7 (C-5), 127.4 (p-Ph), 127.9 (o-Ph), 128.9 (m-Ph), 131.1 (ipso-Ph), 140.1 (C-1), 155.7 (C-2), 189.1 (CHO) ppm. IR (KBr): 3061, 3024, 2973, 2891, 1668, 1639, 1544, 1446, 1371, 1236, 759, 702 cm^-1. MS (CI, CH₄): m/z (%) = 246 (20) [M⁺ + 1]. Anal. Calcd for C₁₄H₁₅NO₃: C, 68.56; H, 6.16; N, 5.71. Found: C, 68.28; H, 6.08; N, 5.53.