Controlling Regioselectivity in the Enantioselective N‐Alkylation of Indole Analogues Catalyzed by Dinuclear Zinc‐ProPhenol

Abstract

The enantioselective N-alkylation of indole and its derivatives with aldimines is efficiently catalyzed by a zinc-ProPhenol dinuclear complex under mild conditions to afford N-alkylated indole derivatives in good yield (up to 86%) and excellent enantiomeric ratio (up to 99.5: 0.5 e.r.). This protocol tolerates a wide array of indoles, as well as pyrrole and carbazole, to afford the corresponding N-alkylation products. The reaction can be run on gram scale with reduced catalyst loading without impacting the efficiency. The chiral aminals were further elaborated into various chiral polyheterocyclic derivatives. The surprising stability of the chiral N-alkylation products will open new windows for asymmetric catalysis and medicinal chemistry.

Dinuclear Metal‐ProPhenol Catalysts: Development and Synthetic Applications

“…A remarkable change in regioselectivity was observed by the Trost group when N ‐Boc and N ‐Cbz imines 124 were applied as the electrophiles. Using Zn‐ L‐1 a as the catalyst, a wide range of N ‐alkylated indoles 160 were obtained in up to 99 % ee (Scheme ) . The change in regioselectivity might be attributed to the two‐point binding of N ‐carbamoyl imines to the catalyst, whereas N ‐PMP or N ‐Ts imines can only undergo a single‐point coordination.…”

Organocatalytic Enantioselective Construction of Acyclic N,N‐Acetals via Aza‐Addition of Arylamines to Ketimines

“…As an important breakthrough, Trost et al. developed a Zinc complex mediated N ‐alkylation of indole and its derivatives with aldimines for the construction of chiral aminals [4] . Quite differently, Zeng and Zhong et al.…”

Recent developments in enantioselective zinc-catalyzed transformations

“…Scheme 120. N-Alkylations of indoles, methyl pyrrole-2-carboxylate and carbazole with N-protected aldimines in the presence of (S,S)-ProPhenol [155].…”