Catalytic Enantioselective Synthesis of 1,4-dihydropyridines the Addition of C(1)-ammonium Enolates to Pyridinium Salts

Overview

Journal Chem Sci

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2021 Oct 20

PMID 34667566

Citations 8

Authors

Calum McLaughlin

Jacqueline Bitai

Lydia J Barber

Alexandra M Z Slawin

Andrew D Smith

Affiliations

Soon will be listed here.

Abstract

The regio- and stereoselective addition of C(1)-ammonium enolates - generated from aryl esters and the isothiourea catalyst ()-BTM - to pyridinium salts bearing an electron withdrawing substituent in the 3-position allows the synthesis of a range of enantioenriched 1,4-dihydropyridines. This represents the first organocatalytic approach to pyridine dearomatisation using pronucleophiles at the carboxylic acid oxidation level. Optimisation studies revealed a significant solvent dependency upon product enantioselectivity, with only toluene providing significant asymmetric induction. Using DABCO as a base also proved beneficial for product enantioselectivity, while investigations into the nature of the counterion showed that co-ordinating bromide or chloride substrates led to higher product er than the corresponding tetrafluoroborate or hexafluorophosphate. The scope and limitations of this process are developed, with enantioselective addition to 3-cyano- or 3-sulfonylpyridinium salts giving the corresponding 1,4-dihydropyridines (15 examples, up to 95 : 5 dr and 98 : 2 er).

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