We report the first efficient enantioselective Friedel-Crafts hydroxyalkylation of pyrroles having one electron-withdrawing group at the α, β or N-positions with alkyl glyoxylates catalyzed by readily available chiral BINOL-Ti(IV) complexes (1-5 mol %). The reaction regioselectively led to the desired pyrrole-hydroxyacetic acid derivatives with good yields (70-96%) and enantiomeric excesses up to 96%, and is applicable in multigram scale with low loading of the catalyst (1 mol %).
An efficient Friedel-Crafts reaction of a series of 2-substituted thiophenes with alkyl glyoxylates has been developed using a catalytic amount of an easy accessible 6,6'-dibromo-BINOL/Ti(IV) complex. A variety of hydroxy(thiophene-2-yl)acetates can be synthesized in high enantioselectivites (92-98% ee) and good yields. This is the first report on the efficient asymmetric F-C reaction of thiophenes with alkyl glyoxylates. Starting from simple thiophene and n-butyl glyoxylate, we demonstrated the formal synthesis of duloxetine.
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