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Factors that Influence Stereoselectivity in Proline‐Catalyzed Mannich Reactions
Author(s) -
Parasuk Waraporn,
Parasuk Vudhichai
Publication year - 2013
Publication title -
asian journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.846
H-Index - 44
eISSN - 2193-5815
pISSN - 2193-5807
DOI - 10.1002/ajoc.201200116
Subject(s) - chemistry , stereoselectivity , iminium , ring (chemistry) , catalysis , enamine , medicinal chemistry , cyclohexanone , stereochemistry , organic chemistry
The stereoselectivity of the Mannich reaction of cyclohexanone, formaldehyde, and aniline catalyzed by ( S )‐thiazolidine‐4‐carboxylic acid and ( S )‐5,5‐dimethylthiazolidine‐4‐carboxylic acid (referred to hereafter as “thioproline” and “5,5‐dimethylthioproline” for short) were investigated theoretically by using B3LYP/6‐31++G(d,p) calculations. The stereocontrol in the thioproline‐catalyzed reaction originates from the reaction between the enamine and the imine to produce S ‐ or R ‐configured iminium‐ion intermediates. Apart from anti/syn conformations, the pucker of the five‐membered ring is also a critical factor for the stereoselectivity. For thioproline, the reaction barriers of the S pathway with d and u ring puckers are 3.3 and 4.7 kcal mol −1 lower than the corresponding R pathway. With a de ring pucker, smaller S / R barrier differences were calculated. For dimethylthioproline, the S / R barrier difference is larger with d and u ring puckers. Dimethylsulfoxide as a solvent reduces the free energy barriers of the R pathway for the thioproline‐ and dimethylthioproline‐catalyzed reactions. The ring pucker and the solvent dictate the stereoselectivity of thioproline‐catalyzed Mannich reactions.