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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8 Both enantiomers of TMS-diphenylprolinol ether 4 are readily available from d- or l-proline in multigram quantities in a four-step synthesis. For a review regarding the use of this catalyst, see: Palomo C. Mielgo A. Angew. Chem. Int. Ed.  2006,  45:  7876 ; Angew. Chem. 2006, 118, 8042

9

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.

10 Flack HD. Acta Crystallogr., Sect. A.  1983,  39:  876 

11

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.

12

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.