Synthesis of 4-Azaindolines Using Phase-Transfer Catalysis via an Intramolecular Mannich Reaction

Abstract

A series of bifunctional asymmetric phase-transfer catalysts containing novel fluorine-containing urea groups derived from cinchona alkaloids have been synthesized and successfully applied in the asymmetric intramolecular Mannich reaction. The 4-azaindoline products bearing multiple substrates were obtained in excellent yield (90−99%), with high enantioselectivity (up to 95%) and diastereoselectivity (up to >99:1).

Assisted by Hydrogen-Bond Donors: Cinchona Quaternary Salts as Privileged Chiral Catalysts for Phase-Transfer Reactions

“…Carbanions formed in this way can undergo cyclization through electrocyclization 31 or 5-endo-dig cyclization 32 in an enantioselective manner. In a recently published paper, Lin and Duan 33 M. Majdecki et al…”

Asymmetric Synthesis of 3-Phenyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-3-carbonitriles Catalyzed by Phase-Transfer Catalyst Derived from tert-Leucine

“…In previous work, the cyano group of product 3l have been successfully reduced and subsequently acylated. 15 By direct acylation of 4v, product 5 (Scheme 2) was obtained in high yield with high ee value (93% ee, >99:1 dr). 10 Scheme 2 Derivatization of 4v to the corresponding acetylated product 5.…”

“…Further increase or decrease of temperature did not improve the reaction results (entries 12 and 14). In addition, we also tried to add 3 Å, 4 Å, and 5 Å molecular sieves, but the addition of molecular sieves did not further improve the experimental results (entries [15][16][17]. We also tried to use different solvents, but the reaction got worse (see Scheme 1 in the Supporting Information).…”

“…In previous work, the cyano group of product 3l have been successfully reduced and subsequently acylated. 15 By direct acylation of 4v, product 5 (Scheme 5) was obtained in high yield with high ee value (93% ee, >99:1 dr). 10 In conclusion, we synthesized a series of phase-transfer catalysts with a large hindered quaternary ammonium group using tertiary leucine as a chiral framework and successfully used them to catalyze the asymmetric synthesis of 4-azaindoline derivatives.…”

“…14 Based on this, in 2020, our group has developed a novel ureabased bifunctional asymmetric phase-transfer catalyst derived from quinine and successfully used it in the preparation of nitrile-containing 4-azaindole derivatives (Scheme 1c). 15 The development of inexpensive, readily available, and highly efficient chiral catalysts for the asymmetric synthesis of 4-azaindolines is still urgently needed. In this paper, we would like to report tert-leucine derived phasetransfer-catalyzed asymmetric synthesis of 4-azaindolines, it is worth noting that both enantiomers of corresponding products can be obtained in high yields with high stereoselectivities and diastereoselectivities.…”