Chiral Brønsted Acid Catalyzed Enantioselective Friedel–Crafts Reaction of Indoles and α‐Aryl Enamides: Construction of Quaternary Carbon Atoms

Abstract

The asymmetric construction of a stereogenic carbon center with four non-hydrogen substituents, that is, a quaternary carbon atom, represents one of the most challenging and demanding topics in the synthesis of natural products and chiral drugs.[1] The construction of quaternary carbon centers bearing a nitrogen atom, which is a fairly ubiquitous structure in natural alkaloids, [2] has drawn increasing attention and several catalytic asymmetric procedures have been successfully developed.[3] The catalytic asymmetric Friedel-Crafts reaction has attracted much attention over the past decades as a versatile C À C bond-forming process, and great progress has been reported.[4] However, to the best of our knowledge, no efficient method has been reported for the creation of a nitrogen-containing quaternary carbon center by using the asymmetric Friedel-Crafts reaction.[5] Herein, we describe an enantioselective Friedel-Crafts reaction of indoles (2) with aaryl enamides 3 catalyzed by chiral Brønsted acids 1[6] to provide chiral tertiary amines 4 with a quaternary carbon center in excellent yields and high enantioselectivities (Scheme 1). [7] It is noteworthy that while the enamides have generally been used as nucleophiles in acid-catalyzed reactions, [8] the a-aryl enamides 3 have played the role of the electrophile in the reaction with indoles. [9] The initial reaction of indole (2 a) and a-phenyl enamide (3 a) was performed at room temperature in dichloromethane in the presence of 10 mol % of the chiral binol-based phosphoric acid 1 a as the catalyst (binol = 2,2'-dihydroxy-1,1'-binaphthyl). The Friedel-Crafts product, N-(1-(3-indolyl)-1-phenylethyl)acetamide (4 aa) was obtained in 74 % yield but with almost no enantioselectivity (Table 1, entry 1). We then concentrated on the modification of the structure of the chiral phosphoric acid catalyst. A series of chiral phosphoric acids 1 with different substituents at the 3,3'-positions of the binaphthyl ring were prepared and tested in the reaction of indole (2 a) and a-phenyl enamide (3 a). The sterically congested phosphoric acid catalysts were found to be crucial for achieving high enantioselectivity, with the catalyst 1 j bearing bulky 2,4,6-triisopropylphenyl groups at Scheme 1. Asymmetric Friedel-Crafts reaction of indole (2 a) and N-(1-phenylvinyl)acetamide (3 a) catalyzed by a chiral Brønsted acid. ee [%][c]

Asymmetric Organocatalysis

“…The Friedel-Crafts reaction has been found to be general for Zhou accomplished an enantioselective Friedel-Crafts reaction of indoles with a-aryl enamides catalyzed by chiral Brønsted acids (Scheme 40) [107]. In the presence of 10 mol% of chiral phosphoric acid 116e, chiral amides with a quaternary stereogenic center were produced in high enantioselectivity.…”

Chiral Lewis Acids and Brønsted Acids in Asymmetric Synthesis

“…It is interesting that this methodology is an effi cient alternative to the generation of aliphatic imines, which are generally labile and diffi cult to isolate (Scheme 3.32 ). The Zhou group reported a similar reaction between indole and various α -aryl enamides to give the F -C products with quaternary carbon center [59] . N -methylated enamide showed no reactivity, which provides further evidence that the reactive proceeded through the corresponding ketimines by protonation to enamides.…”

Enantioselective Synthesis of Amines by Chiral Brønsted Acid Catalysts

“…The method provides an efficient pathway to balkyl-b-aminocarbonyl derivatives in optically active forms. (2 mol% Shortly thereafter, Zhou and coworkers independently reported the enantioselective F-C reaction of indoles with a-aryl-substituted enamides catalyzed by chiral phosphoric acid catalyst 1q (Scheme 3.22) [52], in which the quaternary stereogenic center bearing the nitrogen atom was constructed in a highly enantioselective manner.…”