Catalytic Enantioselective Synthesis of 4-Amino-1,2,3,4-tetrahydropyridine Derivatives from Intramolecular Nucleophilic Addition Reaction of Tertiary Enamides

Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue

Abstract

A general and efficient method for the synthesis of highly enantiopure 4-amino-1,2,3,4-tetradydropyridine derivatives based on chiral phosphoric acid catalyzed intramolecular nucleophilic addition of tertiary enamides to imines has been developed. We have also demonstrated a substrate engineering strategy to significantly improve the enantioselectivity of asymmetric catalysis

Key words

tertiary enamides - 1,2,3,4-tetrahydropyridines - asymmetric catalysis - chiral phosphoric acid - substrate engineering

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• 23 General Reaction Procedure A mixture of enamides 1a (0.5 mmol) and amines 2b (0.5 mmol) in dry CCl₄ (25 mL) was stirred at ambient temperature for 5 min. Chiral phosphoric acid catalyst CC8 (75 mg, 0.1 mmol, 0.2 equiv) was added to the reaction system. Upon completion of the reaction, which was monitored by TLC, the reaction mixture was quenched with 10 mL sat. NaHCO₃ solution, then extracted with 3 × 10 mL CH₂Cl₂. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After removal of the solvent, the residue was purified by column chromatography on silica gel to yield pure product 4ab. Oil (98% yield); ee 88.8% (chiral HPLC analysis). IR (KBr): 3422, 1723, 1656, 1601 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.21–7.44 (m, 17 H), 6.99 (br s, 2 H), 5.50 (br s, 1 H), 5.08 (s, 1 H), 4.05 (br s, 1 H), 3.74 (br s, 1 H), 3.41 (br s, 1 H), 2.00 (br s, 2 H), 1.62 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.9, 144.0, 143.8, 140.6, 137.8, 136.2, 131.2, 130.7, 128.7, 128.6, 128.3, 128.1, 127.5, 127.34, 127.27, 127.2, 121.3, 118.6, 64.4, 48.8, 44.1, 31.2. HRMS (ESI): m/z calcd for C₃₁H₂₇BrN₂O [M + Na]⁺, [M + 2 + Na]⁺: 521.1229, 523.1213; found: 521.1226, 523.1216.