Asymmetric Sulfa-Michael Addition of α,β-Unsaturated Esters/Amides Using a Chiral N-Heterocyclic Carbene as a Noncovalent Organocatalyst

Abstract

We report an asymmetric sulfa-Michael reaction of α,β-unsaturated amides and esters using a chiral N-heterocyclic carbene as the HOMO-raising organocatalyst. We discovered an interesting correlation between ¹³C NMR shifts of substrates and ee of their products. More electron-deficient Michael acceptors afforded higher enantioselectivity.

Key words

N-heterocyclic carbenes - noncovalent catalysis - sulfa-Michael - organocatalysis - asymmetric synthesis

• References and Notes


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• 8 General Procedure for the NHC-Catalyzed Sulfa-Michael Addition Reaction NHC precursor 4a (4.2 mg, 0.01 mmol) and oven-dried 4 Å MS (100 mg) were mixed in dry toluene (0.6 mL) in a 10 mL test tube. The reaction vessel was degassed and back-filled with argon three times before LiHMDS (1 M in THF–ethylbenzene, 10 μL, 0.01 mmol) was slowly added. The mixture was stirred at r.t. for 30 min and another 30 min at –78 °C. Thiol 1 (0.2 mmol) was slowly added, and the mixture was stirred for 30 min at –78 °C. A solution of substrate 2 (0.1 mmol) in toluene (0.6 mL) was slowly added over 30 min. The reaction was stirred at –78 °C for 48 h. The reaction was quickly filtered through a plug of silica gel and concentrated. The residue was purified by silica gel flash column chromatography (eluent: hexane–EtOAc = 50:1) to give product 3. Compound 3aa: 27 mg; 96% yield; colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.51–7.19 (m, 8 H), 7.10 (d, J = 7.7 Hz, 2 H), 3.97–3.77 (m, 2 H), 3.36–3.18 (m, 1 H), 2.87 (dd, J = 15.4, 6.5 Hz, 1 H), 2.73 (dd, J = 15.4, 7.9 Hz, 1 H), 1.43 (d, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 169.87 (s), 150.58 (s), 138.08 (s), 129.43 (s), 128.87 (s), 128.58 (s), 127.10 (s), 125.90 (s), 121.54 (s), 42.09 (s), 36.05 (s), 35.38 (s), 21.34 (s). Chiral HPLC (AD-H, 5% EtOH in hexanes, 1.0 mL/min, 210 nm): t _R (major) = 7.4 min, t _R (minor) = 6.4 min, 67% ee. HRMS (ESI⁺): m/z calcd for C₁₇H₁₈O₂NaS⁺ [M + Na]⁺: 309.0925; found: 309.0920.