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Water versus Solvent‐Free Conditions for the Enantioselective Inter‐ and Intramolecular Aldol Reaction Employing L ‐Prolinamides and L ‐Prolinethioamides as Organocatalysts
Author(s) -
Almaşi Diana,
Alonso Diego A.,
Balaguer AndreaNekane,
Nájera Carmen
Publication year - 2009
Publication title -
advanced synthesis and catalysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.541
H-Index - 155
eISSN - 1615-4169
pISSN - 1615-4150
DOI - 10.1002/adsc.200800814
Subject(s) - aldol reaction , chemistry , cyclohexanone , enantioselective synthesis , organocatalysis , intramolecular force , solvent , nucleophile , catalysis , organic chemistry , medicinal chemistry
Organocatalysts 1 , derived from L ‐proline and (1 S ,2 R )‐ cis ‐1‐aminoindan‐2‐ol or ( R )‐1‐aminoindane, are evaluated as promoters in the direct asymmetric aldol reaction between ketones and aromatic aldehydes in the presence of water and under solvent‐free reaction conditions. L ‐Prolinethioamides 1c and 1d exhibited higher enantioselectivity than the corresponding prolinamides 1a and 1b in the model aldol reaction between cyclohexanone and 4‐nitrobenzaldehyde in the presence of 4‐nitrobenzoic acid as cocatalyst. In particular, L ‐prolinethioamide 1d (5 mol%), derived from L ‐proline and ( R )‐1‐aminoindane, is shown as the most efficient organocatalyst studied promoting the direct aldol reaction of cycloalkyl, alkyl, and α‐functionalized ketones with aromatic aldehydes in the presence of water and under solvent‐free reaction conditions employing only 2 equivalents of nucleophile. Generally, anti ‐aldol products are obtained in high yields and excellent diastereo‐ and enantioselectivities (up to >98/2 anti / syn , up to 98% ee ). Solvent‐free conditions give slightly higher dr and ee than using water as solvent. In addition, organocatalyst 1d can be easily recovered by extractive work‐up and reused. Prolinethioamide 1d (5 mol%) in combination with 4‐NO 2 C 6 H 4 CO 2 H (5 mol%) is also a very effective organocatalytic system for the asymmetric solvent‐free intramolecular Hajos–Parrish–Eder–Sauer–Wiechert reaction with comparable or higher levels of enantioselectivity (up to 88% ee ) to other reported catalysts in organic solvents.