Enantioselective Bifunctional Ammonium Salt‐Catalyzed Syntheses of 3‐CF₃S‐, 3‐RS‐, and 3‐F‐Substituted Isoindolinones

Abstract

We herein report the ammonium saltcatalyzed synthesis of chiral 3,3-disubstituted isoindolinones bearing a heteroatom functionality in the 3-position. A broad variety of differently substituted CF 3 Sand RS-derivatives were obtained with often high enantioselectivities when using Maruoka's bifunctional chiral ammonium salt catalyst. In addition, a first proof-of-concept for the racemic synthesis of the analogous F-containing products was obtained as well, giving access to one of the rare examples of a fairly stable α-F-α-amino acid derivative.

Recent Advances in the Direct Functionalization of Isoindolinones for the Synthesis of 3,3‐Disubstituted Isoindolinones

“…Up to now, several electrophiles such as α,β-unsaturated aldehydes, α,β-unsaturated ketones, aldehydes and sulfur reagents have been investigated in this transformation for the assembly of 3,3-disubstituted isoindolinones. In the reported examples, the installation of an electron-withdrawing group such as ester, [33][34] and CN [35] is necessary for activating the benzylic carbon at the C3-position, thus facilitating the downstream Michael addition, [33][34] aldol reaction [35][36] sulfenylation reaction [37] and fluorination. [37]…”

“…In the reported examples, the installation of an electron-withdrawing group such as ester, [33][34] and CN [35] is necessary for activating the benzylic carbon at the C3-position, thus facilitating the downstream Michael addition, [33][34] aldol reaction [35][36] sulfenylation reaction [37] and fluorination. [37]…”

“…In 2021, the Waser group utilized the general potential of chiral ammonium salt catalysis for enantioselective α-functionalization reactions and uncovered the first example of ammonium salt catalyzed synthesis of chiral 3,3-disubstituted isoindolinones bearing a heteroatom functionality at the C3position. [37] By employing Maruoka's bifunctional ammonium salt 123 as chiral catalyst, a broad series of differently substituted 3-CF 3 S-and 3-RS-containing 3,3-disubstituted isoindolinones 124 and 126 can be obtained with high enantioselectivities (Scheme 39). It should be noted that the N-substituent has a pronounced impact on the reaction outcome in terms of yield and ee values.…”

“…In Waser's work, [37] they also explored the electrophilic α‐fluorination of isoindolinones in the presence of TEBAC (benzyltriethylammonium chloride) as an achiral ammonium salt phase‐transfer catalyst using NFSI as the fluorination reagent. Moderate yields were obtained for CN and ester functionalized substrates 127 a – 127 b (Scheme 40).…”

“…However, the heterofunctionalization of 3‐substituted isoindolinones, leading to the construction of C−X bond, has been rarely reported until recently. In 2021, the Waser group utilized the general potential of chiral ammonium salt catalysis for enantioselective α‐functionalization reactions and uncovered the first example of ammonium salt catalyzed synthesis of chiral 3,3‐disubstituted isoindolinones bearing a heteroatom functionality at the C3‐position [37] . By employing Maruoka's bifunctional ammonium salt 123 as chiral catalyst, a broad series of differently substituted 3‐CF 3 S‐ and 3‐RS‐containing 3,3‐disubstituted isoindolinones 124 and 126 can be obtained with high enantioselectivities (Scheme 39).…”