An Efficient Enantioselective Method for Asymmetric Friedel–Crafts Alkylation of Indoles with α,β‐Unsaturated Aldehydes

Abstract

The Lewis base-Lewis base bifunctional catalytic system has been developed and successfully applied to the asymmetric Friedel-Crafts alkylation of indoles with a,b-unsaturated aldehydes. The reactions are promoted by chiral diphenylprolinol trimethylsilyl ether in the presence of triethylamine. By this protocol, optically active 3-substituted indoles can be obtained in an organocatalytic process that is free of Lewis or protic acid in high yields with up to 98% ee. Besides, this reaction could be carried out on a gram scale without any loss in the enantioselectivity.

Diarylprolinol Silyl Ether Catalyzed Asymmetric Friedel–Crafts Alkylation of Indoles with α,β‐Unsaturated Aldehydes: Enhanced Enantioselectivity and Mechanistic Investigations

“…[10] termined that catalyst 5 gives better enantioselectivity than those reported for other organocatalysts in previous methods [7][8][9][10] under the same conditions. With these conditions in hand, the scope of the asymmetric Friedel-Crafts alkylation of indoles was subsequently explored by using 5 as the organocatalyst and acetonitrile as the solvent (Scheme 2).…”

“…When the reaction was performed at -20°C the enantioselectivity was also found to be excellent (98 % ee, 65 % yield; Table 1, Entry 16). On the basis of other reports [9,10] and the present findings, we de- [9] : cinnamaldehyde (0.5 mmol, 1 equiv. ), indole (1.0 mmol, 2 equiv.…”

“…This is in accordance with the previous report that the addition of a tertiary amine is important for the enhancement in the enantioselectivities. [10] Indeed, catalyst 5, which is easily prepared from l-proline and (4-bromophenyl)-N,N-dimethylmethanamine, had a very positive effect on asymmetric induction in comparison to that of catalyst 4 under different conditions. For example, catalyst 4 bearing no additional group gave the product with only moderated enantioselectivities (49-73 % ee) in most of solvents, which are lower than those obtained with catalyst 5 (76-92 % ee) under almost the same conditions (Table 1; Entry 5 vs. 4, entry 7 vs. 6, entry 9 vs. 8, and entry 11 vs. 10).…”

“…[7,8] The diarylprolinol silyl ether catalyzed asymmetric Friedel-Crafts alkylation of indoles with α,β-unsaturated aldehydes has recently been reported by the groups of Bao [9] and Wang [10] independently. Excellent enantiomeric excess of the Friedel-Crafts adducts (up to 98 % ee) was attainable in the reported reactions; however, large amounts of a tertiary amine as additive (Et 3 N, 50-100 mol-%) and an expensive solvent (methyl tert-butyl ether, MTBE) were required for these reactions.…”

Asymmetric Synthesis with Silicon‐Based Bulky Amino Organocatalysts

“…[58] MacMillan was the first to report the asymmetric Michael addition of indoles to a,b-unsaturated aldehydes by use of imidazolidinone via a LUMO-lowering activation (Scheme 30). [59] Very recently, Wang et al [60] reported the diphenylprolinol silyl ether-catalyzed Michael addition of a,b-unsaturated aldehydes with indoles in the presence of Lewis base. In their catalyst screen, the outcomes of silylated diarylprolinol cata- lysts varied dramatically when changing the trimethylsilyl group into either a tert-butyldimethylsilyl group (13l) or a triethylsilyl group (13e).…”