Direct asymmetric N-propargylation of indoles and carbazoles catalyzed by lithium SPINOL phosphate

Abstract

Catalytic asymmetric functionalization of the N-H groups of indoles and carbazoles constitutes an important but less developed class of reactions. Herein, we describe a propargylation protocol involving the use of a lithium SPINOL phosphate as the chiral catalyst and our recently developed C-alkynyl N,O-acetals as propargylating reagents. The direct asymmetric N-propargylation of indoles and carbazoles provides hitherto inaccessible Nfunctionalized products. Notably, the efficiency of the system allows reactions to be run at a very low catalyst loading (as low as 0.1 mol%). Mechanistic information about the titled reaction is also disclosed. This study represents an advance in the direct asymmetric functionalization of the N-H bonds of indoles and carbazoles, and additionally expands on the application of chiral alkali metal salts of chiral phosphoric acids in asymmetric catalysis.

Enantioselective Catalytic Synthesis of N-alkylated Indoles

“…Propargylic compounds are important building blocks in synthetic chemistry because they can be transformed into a wide range of organic derivatives, including heterocycles [62,63]. Shao and coworkers investigated the enantioselective N-propargylation of indoles and carbazoles (Scheme 33) [64]. The method was based on the in situ generation of alkynyl N-Cbz or N-Boc imines 163a from N,O-acetals 163 followed by the nucleophilic N-addition of indole derivatives 164.…”

Photoinduced, Copper-Catalyzed Enantioconvergent Alkylations of Anilines by Racemic Tertiary Electrophiles: Synthesis and Mechanism

“…To address these shortcomings with respect to reactivity and enantioselectivity, a number of laboratories have pursued the use of transition metals to catalyze substitution reactions of secondary and tertiary alkyl electrophiles by nitrogen nucleophiles. − To date, catalytic enantioconvergent substitutions have only been described for a few families of (mostly secondary) alkyl electrophiles: e.g., allylic electrophiles, α-halocarbonyl compounds, − α-cyano-α-halocarbonyl compounds, , propargylic electrophiles, , benzylic electrophiles, and unactivated alkyl halides that bear a directing group . Relative to secondary electrophiles, catalytic enantioconvergent substitutions of tertiary electrophiles can be more challenging due to increased steric hindrance and to the need for the chiral catalyst to differentiate among three carbon substituents, rather than a hydrogen and two carbon substituents.…”

Construction of Axially Chiral Indoles by Cycloaddition–Isomerization via Atroposelective Phosphoric Acid and Silver Sequential Catalysis

“…In 2015, we introduced C-alkynyl N,O-acetals 1 with the N-Boc protecting group, which are easily prepared and stable, as a new class of versatile reaction partners for the synthesis of chiral nitrogen-containing compounds . A series of asymmetric catalytic transformations with different nucleophiles have been developed by us and other groups . It is noted that these transformations are limited to the assembly of central chirality so far.…”