Chiral Ammonium Salt Catalyzed Asymmetric Alkylation of Unactivated Amides

Abstract

A chiral spirocyclic quaternary ammonium salt catalyzed asymmetric alkylation of unactivated amides under homogeneous conditions has been developed, giving the target products with up to 60% ee. This novel methodology provides a general and concise protocol for asymmetric α-functionalization of unactivated amides.

Key words

unactivated amides - asymmetric alkylation - homogeneous catalysis - kinetics control - ammonium salt catalyst

Publication History

Received: 01 February 2022

Accepted after revision: 11 March 2022

Accepted Manuscript online:
11 March 2022

Article published online:
31 March 2022

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• 17 Representative Procedure for Asymmetric Alkylation A Schlenk tube was charged with 1 (0.2 mmol) and 3k (0.02 mmol, 18.4 mg) under a nitrogen atmosphere, then NaHMDS (0.2 mmol, 0.4 mL, 0.5 M in toluene) and 2 (0.4 mmol) in toluene (1.0 mL) were added separately. The reaction mixture was stirred at –80 °C and monitored by TLC. When completed, the reaction mixture was diluted with water (5.0 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layer was washed with brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography column on silica gel (ethyl acetate/petroleum ether = 1:30 to 1:10) to afford product (S)-4. (S)-2-Methyl-N,N,3-triphenylpropanamide (4a) Colorless oil; 60% yield; 43% ee; [α]_D ²⁵ –79.6 (c 1.0, CHCl₃). HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₂H₂₂NO⁺: 316.1695; found: 316.1695. ¹H NMR (500 MHz, CDCl₃): δ = 7.50–6.67 (m, 15 H), 3.06 (dd, J = 15.0, 10.0 Hz, 1H), 2.92–2.72 (m, 1 H), 2.59 (dd, J = 15.0, 5.0 Hz, 1 H), 1.20 (d, J = 5.0 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 176.2, 142.9, 140.1, 129.7, 129.5, 128.9, 128.4, 126.6, 126.5, 41.1, 40.2, 18.4. HPLC (Chiralpak Daicel AS-H, hexane/isopropanol = 95:5, 0.5 mL/min, 254 nm), t _R(min) = 13.9 min, t _R(maj) = 22.9 min.