An Adverse Effect of Higher Catalyst Loading and Longer Reaction Time on Enantioselectivity in an Organocatalytic Multicomponent Reaction

• Published in: Chemistry : a European journal Vol. 24; no. 23; pp. 6036 - 6040
• Main Authors: Khopade, Tushar M., Mete, Trimbak B., Arora, Jyotsna S., Bhat, Ramakrishna G.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 20.04.2018; Wiley Subscription Services, Inc
• Subjects: adverse effect; Aldehydes; Amides; Carboxylic acids; Catalysis; Catalysts; Chemistry; Chemistry, Multidisciplinary; Enantiomers; enantioselectivity; Esters; hetero-Diels–Alder cycloaddition; Ketones; multicomponent reaction; organocatalysis; Physical Sciences; Reaction mechanisms; Reaction time; Science & Technology; Side effects; enantioselectivity; CYCLOADDITION REACTIONS; MICHAEL; ONE-POT; hetero-Diels-Alder cycloaddition; ALDEHYDES; organocatalysis; MANNICH REACTION; KETONES; ALDER; adverse effect; CHEMISTRY; multicomponent reaction; 3-COMPONENT
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201800278

An enantioselective organocatalytic multicomponent reaction of aldehydes, ketones, and Meldrum's acid has been developed. A cinchona‐based primary amine (1 mol %) catalyses the multicomponent reaction via the formation of the Knoevenagel product and a chiral enamine to form enantiopure δ‐keto Meldrum's acids in a tandem catalytic pathway. An adverse effect of higher catalyst loading and longer reaction time on enantioselectivity was studied. This mild protocol provides an easy access to enantiopure carboxylic acids, esters and amides and the method is scalable on a gram quantity. DFT calculations were carried out on the proposed reaction mechanism and they were in close agreement with the experimental results. Cause and effect: An adverse effect of higher catalyst loading and longer reaction time on enantioselectivity was studied. An enantioselective organocatalytic multicomponent reaction of aldehydes, ketones and Meldrum's acid was developed (up to 99 % ee). This mild protocol provides an easy access to enantiopure carboxylic acids, esters and amides with high enantioselectivities and the method is scalable.