CC BY-ND-NC 4.0 · Synlett 2019; 30(04): 483-487
DOI: 10.1055/s-0037-1610384
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Catalytic Enantioselective Synthesis of 4-Amino-1,2,3,4-tetrahydropyridine Derivatives from Intramolecular Nucleophilic Addition Reaction of Tertiary Enamides

Shuo Tong*
,
MOE Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084, P. R. of China   Email: tongshuo@mail.tsinghua.edu.cn   Email: wangmx@mail.tsinghua.edu.cn
› Author Affiliations
We thank the National Natural Science Foundation of China (No. 21320102002, 91427301) for financial support.
Further Information

Publication History

Received: 30 September 2018

Accepted after revision: 22 October 2018

Publication Date:
15 November 2018 (eFirst)

  

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

Supporting Information

 
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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.