Direct Catalytic Asymmetric and Regiodivergent N1- and C3-Allenylic Alkylation of Indoles

Abstract

Herein we report a Pd-catalyzed asymmetric allenylic alkylation strategy for the direct functionalization of 1H-indoles by employing P-chiral BIBOP-type ligands. The regioselectivity (N1/C3) of this process can be switched efficiently. Using Cs₂ CO₃ at elevated temperatures in MeCN, N1-alkylated indoles bearing axial chirality with a stereocenter non-adjacent (β) to the nitrogen are produced in good yields with high enantioselectivity and complete N1-regioselectivity regardless of the electronic properties and substitution patterns of diverse indoles. Using K₂ CO₃ at room temperature in CH₂ Cl₂ , chiral C3-alkylated indoles can also be obtained. Notably, we introduce a new class of tri-substituted allenylic electrophiles that proceeded through different pathways from di-substituted allenylic electrophiles.

Keywords: Allenylic Alkylation; Asymmetric Synthesis; Indoles; Kinetic Resolution; Regiodivergence.