Organocatalysis in Ionic Liquids: Highly Efficient l-Proline-Catalyzed Direct Asymmetric Mannich Reactions Involving Ketone and Aldehyde Nucleophiles

Abstract

Proline-catalyzed direct asymmetric Mannich reactions of N-PMP protected α-imino ethyl glyoxylate with various aldehydes and ketones in ionic liquids afforded both α- and β-amino acid derivatives with excellent yields and enantioselectivities, providing facile product isolation, catalyst recycling, and significantly improved reaction rates, ca 4- to 50-fold. Three component Mannich reactions involving other imines also worked well in ionic liquids. Significant advantages and limitations of ionic liquid solvents in this reaction have been revealed.

proline - enamine - Mannich reaction - ionic liquids - green chemistry

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<A NAME="RY00403ST-8">8</A>

General experimental procedure: To a glass vial charged with l-proline (3 mg, 0.025 mmol) was added [bmim]BF₄ (1 mL) followed by α-imino ethyl glyoxylate (104 mg, 0.5 mmol), aldehyde (1.5 equiv) or ketone (1 mL) and the reaction was stirred at r.t. for 30 min. After completion of the reaction (as monitored by TLC), the product was isolated by extraction with Et₂O (4 × 5 mL). The combined Et₂O extracts were concentrated to obtain the Mannich product. The ionic liquid containing l-proline was dried under vacuum prior to reuse.

<A NAME="RY00403ST-9">9</A>

General experimental procedure for three component Mannich reaction (Table 3): To a glass vial charged with l-proline (3 mg, 0.025 mmol) were added [bmim]BF₄ (1 mL), p-anisidine (68mg, 0.55 mmol), aldehyde (0.5 mmol) and ketone (1 mL) and the reaction was stirred at r.t. After completion of the reaction (as monitored by TLC), the product was isolated by extraction with Et₂O (4 × 5 mL). The combined ether extracts were concentrated and chromatographed to obtain the Mannich product.

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