Catalytic enantioselective synthesis of 1,4-dihydropyridines via the addition of C(1)-ammonium enolates to pyridinium salts
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The regio- and stereoselective addition of C(1)-ammonium enolates – generated in situ from aryl esters and the isothiourea catalyst (R)-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).
McLaughlin , C , Bitai , J , Barber , L , Slawin , A & Smith , A D 2021 , ' Catalytic enantioselective synthesis of 1,4-dihydropyridines via the addition of C(1)-ammonium enolates to pyridinium salts ' , Chemical Science , vol. Advance Article . https://doi.org/10.1039/D1SC03860E
Copyright © 2021 The Author(s). Open Access. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
DescriptionAuthors thank the EPSRC (EP/M508214/1, C.M.) for funding. A.D.S. thanks the Royal Society for a Wolfson Research Merit Award.
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