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Pyrimidine‐Derived Prolinamides as Recoverable Bifunctional Organocatalysts for Enantioselective Inter‐ and Intramolecular Aldol Reactions under Solvent‐Free Conditions
Author(s) -
VizcaínoMilla Pascuala,
Sansano José M.,
Nájera Carmen,
Fiser Béla,
GómezBengoa Enrique
Publication year - 2015
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201500007
Subject(s) - chemistry , aldehyde , aldol reaction , bifunctional , intramolecular force , organocatalysis , ketone , enantioselective synthesis , catalysis , aldol condensation , intermolecular force , enamine , organic chemistry , medicinal chemistry , molecule
Chiral L ‐prolinamides 2 containing the ( R , R )‐ and ( S , S )‐ trans ‐cyclohexane‐1,2‐diamine scaffold and a 2‐pyrimidinyl unit are synthesized and used as general organocatalysts for intermolecular and intramolecular aldol reactions with 1,6‐hexanedioic acid as a co‐catalyst under solvent‐free conditions. The intermolecular reaction between ketone–aldehyde and aldehyde–aldehyde must be performed under wet conditions with catalyst ( S , S )‐ 2b at 10 °C, which affords anti ‐aldols with high regio‐, diastereo‐, and enantioselectivities. For the Hajos–Parrish–Eder–Sauer–Wiechert reaction, both diastereomers of catalyst 2 give similar results at room temperature in the absence of water to give the corresponding Wieland–Miescher ketone and derivatives. Both types of reactions were scaled up to 1 g, and the organocatalysts were recovered by extractive workup and reused without any appreciable loss in activity. DFT calculations support the stereochemical results of the intermolecular process and the bifunctional role played by the organocatalyst by providing a computational comparison of the H‐bonding networks occurring with catalysts 2a and 2b .