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 Cs2CO3 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 K2CO3 at room temperature in CH2Cl2, 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.

Catalysis and Synthesis Enabled by P-Chiral Dihydrobenzooxaphosphole Ligands

“…The protocol showed a broad substate scope, providing axially chiral N1-allenyl indoles bearing a stereocenter nonadjacent (β) to the nitrogen in good yields with high N1 selectivity and enantioselectivity (Scheme 38). 82 The palladium source and base also showed significant impact on the reactivity, as no product was obtained with Pd 2 (dba) 3 but a high yield was obtained with [Pd(allyl)Cl] 2 . Meanwhile, the steric hindrance of the ligand dramatically impacted the regioselectivity.…”

Regioselective C3Alkylation of Indoles for the Synthesis of Bis(indolyl)methanes and 3-Styryl Indoles

“…Further-more, the Shao group demonstrated a regiodivergent N 1 and C 3 allenylic alkylation of indoles in the presence of Cs 2 CO 3 and K 2 CO 3 , respectively (Scheme 1B). 21 Recently, we reported a nitrobenzene-involved oxidative reaction for the synthesis of N-heterocycles. 22 In continuation of our interest in constructing complex N-heterocycles from easily accessible substrates, 23 we attempted a reaction of indoles with alcohols that were oxidized by nitrobenzene under strong basic conditions.…”

“…The NH proton of indoles must be taken to generate the nucleophile, which usually require a strong base such as NaH, NaOH/KOH, t BuO-K/ t BuONa/ t BuOLi, and Cs 2 CO 3 (Scheme A). Furthermore, the Shao group demonstrated a regiodivergent N 1 and C 3 allenylic alkylation of indoles in the presence of Cs 2 CO 3 and K 2 CO 3 , respectively (Scheme B) …”

Pd-Catalyzed Enantioselective Creation of All-Carbon Quaternary Center with 2,3-Allenylic Carbonates

“…Recently, much effort has been devoted to the asymmetric synthesis of allenes with a unique axial chirality . One of the most straightforward methods would be the metal-catalyzed enantioselective allenylation of a nucleophile with racemic 2,3-allenol derivatives constructing an axial chirality and/or center chirality within the allene starting material (Scheme a, eq 1). − However, extensive studies on differently substituted 2,3-allenol derivatives have been focused on the construction of a chiral center and/or central chirality of the starting allenes, which are close to those of chiral ligands. Recently, there have been a few reports on enantioselective 2,3-butadienylation of chiral N -Cu-metalated azomethine ylides generating optically active 2,3-butadienyl α-amino acid derivatives using the synergistic Pd/Cu catalysis with either two different or the same chiral ligands (Scheme a, eq 2) .…”