Enantioselective Brønsted Acid Catalyzed Conjugate Addition of Aryl Methyl Ketone Derived Enamines to Nitroalkenes

Abstract

A novel Brønsted acid catalyst has been developed for the conjugate addition of aryl methyl ketone derived enamines to ­nitroalkenes in good yield and moderate enantioselectivity.

Key words

Brønsted acid - organocatalysis - nitroalkene - thiourea - enantioselective

References and Notes

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• 9a

  Chiral HPLC analysis was performed on Daicel Chirapak AD or AS columns (25 cm × 0.46 cm diameter). The absolute configurations of 8 and 16ad were determined by optical rotation {8: [α]₅₇₈ ²³ +21.5 (57% ee, c 1.1, CH₂Cl₂); lit. [9b] : S-enantiomer [α]₅₇₈ ²⁰ -19.2 (55% ee, c 1.2, CH₂Cl₂). Compound 16ad: [α]_D ²⁵ +7.44 (54% ee, c 0.44, CHCl₃); lit. [9c] : R-enantiomer [α]_D ²⁵ +20.71 (86% ee, c 1.79, CHCl₃).

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• 9e

  All other adducts 16 have no previously reported optical rotation and the absolute stereochemistry was assumed to be the same as that for 8 and 16ad since the order of the major and minor peaks in the chiral stationary phase HPLC chromatogram and the sign of the optical rotation were the same in all cases.

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• 12 General Method for Conjugate Addition Reactions. A solution of enamine 14 (2.25 mmol, 3 equiv) and 13a (55 mg, 0.075 mmol, 0.1 equiv) in toluene (3 mL) at -50 °C was added to the nitroalkene 15 (0.75 mmol, 1 equiv) at -50 °C and the resulting solution stirred at this temperature for 65 h. The reaction mixture was poured rapidly into dilute HCl (5 mL, 3.0 mol dm^-3), stirred at r.t. for 10 min and extracted with CH₂Cl₂ (2 × 3 mL). The combined organic extracts were dried (MgSO₄), filtered, concentrated under reduced pressure and the residue was purified by flash column chromatography (15:85 EtOAc-hexanes). Spectroscopic data for 8: white powder; mp 73-75 °C; [α]_D ²⁵ +7.34 (57% ee, c 1.24, CHCl₃); [α]₅₇₈ ²³ +21.5 (57% ee, c 1.1, CH₂Cl₂). IR: ν_max = 2988, 2901, 1687, 1541, 1378 cm^-1. 1H NMR (500 MHz, CDCl₃): δ = 7.95 (2 H, d, J = 8.0 Hz), 7.59 (1 H, t, J = 8.0 Hz), 7.47 (2 H, t, J = 8.0 Hz), 7.37-7.27 (5 H, m, Ph), 4.85 (1 H, dd, J = 12.5, 6.5 Hz), 4.70 (1 H, dd, J = 12.5, 7.0 Hz), 4.26 (1 H, qn, J = 6.5 Hz), 3.50 (1 H, dd, J = 17.5, 6.5 Hz), 3.44 (1 H, dd, J = 17.5, 7.0 Hz); all data are consistent with those previously reported. See: Kim DY. Huh SC. Tetrahedron  2001,  57:  8933 
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17

Synthesis of 13a.
A solution of (R,R)-(1,2)-diaminocyclohexane (9.5 g, 83 mmol, 1.5 equiv), tetraphenylphthalic anhydride (25 g, 55.2 mmol, 1.0 equiv) and (±)-camphorsulfonic acid (15.4 g, 66.2 mmol, 1.2 equiv) in xylene (750 mL) was refluxed for 16 h. The reaction mixture was allowed to cool to r.t. and the solvent was removed under reduced pressure. The residue was slurried in aq KOH solution (400 mL, 1 mol dm^-3) and extracted with CH₂Cl₂ (3 × 200 mL). The combined organic extracts were dried (K₂CO₃), filtered and concentrated under reduced pressure. The residue was re-dissolved in THF (500 mL) and 4-nitrophenyl isothiocyanate (29 g, 166 mmol, 3 equiv) was added in three portions at room temperature. The reaction mixture was stirred at r.t. for 18 h, concentrated under reduced pressure and purified by flash column chromatography (20:80 to 100:0 EtOAc-hexane) to give a viscous yellow oil that was re-dissolved in minimal Et₂O. Addition of pentane gave the thiourea 13a (8.0 g, 11.0 mmol, 20%) as a yellow powder; mp 150-151 °C; [α]_D ²⁵ -61.1
(c 3.43, CHCl₃). IR: ν_max = 3329, 2988, 2910, 1766, 1703, 1596, 1522, 1371, 1329 cm^-1. ¹H NMR (500 MHz, d ₆-DMSO, 353 K): δ = 9.77 (1 H, br s), 8.11 (2 H, d, J = 9.0 Hz), 7.81 (1 H, br d, J = 7.5 Hz), 7.68 (2 H, d, J = 9.0 Hz), 7.16-7.02 (10 H, m), 6.85-6.63 (10 H, m), 4.85 (1 H, m), 3.95 (1 H, td, J = 12.0, 3.5 Hz), 2.31 (1 H, br q, J = 9.5 Hz), 2.13-2.05 (1 H, m), 1.79-1.74 (3 H, m), 1.32-1.28 (3 H, m). ¹³C NMR (125 MHz, d ₆-DMSO, 353 K): δ = 180.5, 167.0, 147.8, 142.7, 138.9, 138.4, 136.2, 131.0, 130.3, 128.1, 127.29, 127.27, 127.2, 127.1, 126.5, 124.6, 121.1, 54.4, 54.3, 32.1, 28.8, 25.4, 24.8. ESI-MS [ESI - H⁺]: m/z calcd for C₄₅H₃₇N₄O₄S⁺: 729.2530; found: 729.2531.