Highly Efficient Asymmetric Michael Addition Reaction of Malonates to α,β-Unsaturated Ketones Promoted by a Chiral Thiourea/PPY Dual-Catalyst System

Abstract

The enantioselective Michael addition reaction of malonates to α,β-unsaturated ketones is efficiently promoted by a combined dual-catalyst system composed of chiral thiourea and 4-pyrrolidinopyridine (PPY) in toluene. The expected Michael adducts with cyclic and acyclic enones are obtained in excellent yields and with excellent enantioselectivities.

Key words

asymmetric Michael addition - malonates - α,β-unsaturated ketones - chiral thiourea - 4-pyrrolidinopyridine (PPY)

• References and Notes

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Based on our previous observations of thiourea-based organocatalysis, we chose toluene as the best solvent. See:
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• 9 General Procedure To a solution of PPY (14.8 mg, 0.1 mmol), α,β-unsaturated ketone (1, 1.0 mmol), and dialkyl malonate (2, 1.5 mmol) in toluene (1.0 mL) thiourea catalyst C (38.5 mg, 0.1 mmol) was added and the mixture was stirred until the reaction was complete. After concentration, the mixture was purified by silica gel column chromatography (elution with hexane–EtOAc = 4:1) to afford pure product 3.
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• 16a The absolute configuration of the products was determined by comparison with data in the literature. (R)-3b: [α]_D ²⁴ +5.32 (c 1.00, CHCl₃; 98% ee); lit.^16b [α]_D ²⁰ +3.7 (c 1.00, CHCl₃; 86% ee). (S)-3f: [α]_D ²⁴ +13.0 (c 1.00, CHCl₃; 96% ee); lit.⁵ [α]_D ²⁸ +11.8 (c 1.03, CHCl₃; 91% ee). (R)-3g: [α]_D ²⁵ +63.9 (c 1.00, CHCl₃; 76% ee); lit.⁵ [α]_D ^27.5 +50.8 (c 1.07, CHCl₃; 63% ee). (R)-3h: [α]_D ²⁴ +40.5 (c 1.00, CHCl₃; 99% ee); lit.⁵ [α]_D ²⁷ +41.7 (c 1.02, CHCl₃; 93% ee). (S)-3i: [α]_D ²⁵ +16.4 (c 1.00, CHCl₃; 91% ee); lit.⁵ [α]_D ²⁸ +17.8 (c 1.02, CHCl₃; 96% ee). (S)-3j: [α]_D ²⁵ +17.2 (c 1.00, CHCl₃; 88% ee); lit.⁵ [α]_D ²⁹ +18.5 (c 1.02, CHCl₃; 93% ee).
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• 17 The absolute configuration of the products 3c–e was assigned by analogy. Compound 3c: [α]_D ²⁵ +17.9 (c 1.00, CHCl₃; 99% ee). Compound 3d: [α]_D ²⁴ +9.27 (c 1.00, CHCl₃; 99% ee). Compound 3e: [α]_D ²⁵ –3.04 (c 1.00, CHCl₃; 98% ee).
• 18a For a review on the Rauhut–Currier reaction, see: Aroyan CE, Dermenci A, Miller SJ. Tetrahedron 2009; 65: 4069
• 18b The absolute configuration of 4 was determined by comparison with data in the literature. (S)-4: [α]_D ²⁵ +3.52 (c 0.09, CHCl₃, 38% ee); lit.^18c (R)-4: [α]_D ^r.t. –3 (c 1.00, CH₂Cl₂; 47% ee)
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• 18d The ee was determined by chiral HPLC analysis [Chiralpak AD column, 0.46 × 25 cm, hexane–2-PrOH (95:5), 1.0 cm³/min): t _R (R) = 25.1 min; t _R (S) = 35.7 min.
• 19 Although we did not examine the role of PPY in detail, it can be supposed that PPY could suppress the formation of byproduct 4 by promoting the nucleophilic attack of 2 via deprotonation (Scheme 1).
• 20 During the final preparation of a revised version of this paper, Kwiatkowski and co-workers reported a closely related work using catalyst C with benzoic acid in warmed toluene. See: Dudzinski K, Pakulska AM, Kwiatkowski P. Org. Lett. 2012; 14: 4222