Enantioselective Friedel-Crafts Alkylations of Pyrroles and Indoles via α′-Hydroxyenones

Key words

copper(II) - bis(oxazoline) - Friedel-Crafts - indoles - pyrroles

Significance

The Friedel-Crafts reaction is of great value in organic synthesis. In terms of metal-catalyzed Friedel-Crafts alkylations, there are few examples demonstrating high enantioselectivity. In many of the reported cases, strongly coordinating bidentate Michael acceptors are required for good enantiocontrol. Presented herein, non-enolizable α′-hydroxyenones represent the above characteristics and, in the presence of easily accessible tert-butyl-bis(oxazoline) Cu(II) complexes and electron-rich heteroaromatics, provide highly enantioenriched Friedel-Crafts alkylation products. This method is efficient with both pyrrole and indole as nucleophile, and with alkyl or aryl β-substituents.

Comment

The Cu(II)-t-BOX-enone complex makes the enone Si face accessible for nucleophilic attack. Although numerous alkyl and aryl β-substituents were tested, it is noted that aryl β-substituents resulted in a marked reduction in ee. Electron-donating substituents on the benzenoid ring of indole had no adverse effects, although electron-withdrawing substituents were not evaluated. Finally, the products of these reactions were elaborated into various examples of pyrrole- and indole-substituted aldehydes, ketones, and carboxylic acids.