Organocatalytic Asymmetric Triple Domino Reactions of Nitromethane with α,β-Unsaturated Aldehydes

Abstract

An organocatalytic asymmetric multicomponent domino reaction employing the bulk chemical nitromethane and α,β-unsaturated aldehydes as substrates is described. The new triple cascade reaction based on two subsequent Michael additions and an intramolecular aldol condensation provides an atom-economic entry to diastereo- and enantiomerically pure 5-nitrocyclohexene carbaldehydes after flash chromatography.

Key words

domino reaction - organocatalysis - Michael addition - nitroalkane - aldol condensation

References and Notes

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CCDC-743470 (3a) contains the supplementary crystallographic data for this paper. More 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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General Procedure
In an ordinary vial equipped with a magnetic stirring bar, the α,β-unsaturated aldehyde 1 (2.2 mmol, 2.2 equiv) was dissolved in CHCl₃ (1 mL). The catalyst (S)-2 (0.2 mmol, 0.2 equiv) and nitromethane (1 mmol, 1 equiv) were added to the solution. The vial was sealed, and the mixture was stirred for 20 h at r.t. The crude reaction mixture was diluted in CH₂Cl₂, washed with H₂O, and dried over MgSO₄. After concentration, the crude product was purified by flash chromatography (silica gel, pentane-EtOAc). All new compounds gave satisfactory spectroscopic and analytical data. As a typical example, the data of the compound 3a are given.
(4 S ,5 R ,6 R )-5-Nitro-4,6-diphenylcyclohex-1-ene carbaldehyde (3a, Figure 2)
Isolated as a yellow solid (202 mg, 65%). The ee (>99%) was determined by HPLC on a chiral stationary phase [Chiralcel OD; n-heptane-i-PrOH (8:2); 1.0 mL/min, t _R = 9.93 min(major), 18.25 min (minor, based on the racemic mixture)]; mp 108 ˚C; [α]_D ^²0 -123 (c 1.1, CHCl₃). IR (ATR): 3060, 2807, 2718, 2323, 2115, 1684, 1653, 1547, 1494, 1450, 1410, 1366, 1247, 1162, 1078, 946 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.89 (ddd, J = 5.2, 5.2, 20.0 Hz, 1 H, H₃); 3.25 (dddd, J = 2.4, 11.2, 11.2, 20.0 Hz, 1 H, H_{3 ′}), 3.35-3.40 (m, 1 H, H₄), 4.32-4.38 (m, 1 H, H₆); 4.96 (dd, J = 1.9, 3.0 Hz, 1 H, H₅), 7.03-7.07 (m, 2 H, H_{Ph- para} ), 7.22-7.38 (m, 9 H, H_Ph and H₂), 9.57 (s, 1 H, H_CHO). ^¹³C NMR (100 MHz, CDCl₃): δ = 28.0 (C₃), 37.3 (C₄), 43.2 (C₆), 91.3 (C₅), 127.3 (CH), 128.0 (CH), 128.9 (CH), 129.2 (CH), 137.9, 138.0, 138.8 (C_Ph, C₁), 150.4 (C₂), 191.65 (CHO). HRMS (EI): m/z calcd for C₁₉H₁₇0₃N₁: 307.1203; found: 307.1208.

Figure 2