Ir-Catalyzed Asymmetric Hydroarylation of Alkynes for the Synthesis of Axially Chiral Heterobiaryls

Abstract

The catalytic hydroarylation of alkynes has emerged as an excellent methodology for the synthesis of functionalized alkenes with excellent levels of regio- and stereocontrol (syn). However, in spite of the great progress in this field, the number of asymmetric methodologies is still scarce. Herein, we report an atroposelective Ir-catalyzed C–H hydroarylation of alkynes, which enables the asymmetric synthesis of axially chiral heterobiaryl trisubstituted olefins in good to high yields and enantioselectivities up to 98% ee.

Atroposelective desymmetrization of 2-arylresorcinols via Tsuji-Trost allylation

“…Strategies to control a stereogenic axis are generally classified into several categories [16][17][18][19][20][21][22][23] , such as direct cross-coupling, dynamic kinetic resolution, ring formation, and desymmetrization (Fig. 1a) [24][25][26][27][28][29][30][31] . As each strategy inherently possesses its own strengths and weaknesses, they are necessarily complementary to each other depending on a target molecule.…”

Enantioselective Synthesis of Axially Chiral 1-Arylisoquinolines by Iridium(I)-Catalyzed Hydroarylation of Alkynes

“…Notably, by lowering the amount of alkyne to one equivalent, the yield of 3aa improved to 93% (entry 14; 93% NMR yield, 96% ee), whereas five equivalents of alkyne were used in a recent related work. 12 In addition, a 97% isolated yield and 96% ee were obtained when the reaction was performed in 0.2 mmol scale at a higher concentration (0.2 N; 1 mL THF) (entry 15). Overall, the optimized reaction conditions were identified as the following: 1a (1.0 equiv), 2a (1.0 equiv), [Ir(cod)Cl] 2 (5 mol%), L4 (10 mol%), and NaBAr F (20 mol%) in THF (0.2 N) at 80 °C under Ar.…”

“…The absolute configurations of products 3ja and 3na were assigned as S a by comparing the signs of their optical rotations with those of the known compounds. 12 The absolute configurations of other products were assigned by analogy.…”

“…11 However, the related C–H functionalization by alkynes toward axially chiral molecules has been less-well investigated. 12 Considering the importance of axially chiral 1-arylisoquinolines and our continuing interest in the synthesis of biaryl atropisomers, 6 7 13 we envisioned that isoquinoline-directed hydroarylation of alkynes by C–H functionalization might be feasible as a means of providing axially chiral alkenylated 1-arylisoquinolines with high atom economy (Scheme 1b ). Here, we report the details of this study.…”

Stereodynamic Strategies to Induce and Enrich Chirality of Atropisomers at a Late Stage

“…In 2023, Fernández, Lassaletta, Ros, and co-workers reported the synthesis of axially chiral styrenes by the N -directed Ir-catalyzed hydroarylation of internal alkynes with heterobiaryls (Figure ). A reaction between naphthylisoquinolone ( 28.1 ) and diphenylacetylene ( 28.2 ) afforded the heterobiaryl product ( 28.3 ) in 95% yield and 95% ee when conducted in the presence of 1.25 mol % of [IrCl­(cod)] 2 , 3 mol % of ( S , S )-QUINOX-P ( 28.4 ), 10 mol % of NaBAr F in MTBE at 50 °C. In addition to its impact on the enantioenrichment of the product, the chiral ligand also allowed for the reaction to be run at decreased temperature (from 80 °C) and Ir-catalyst loading.…”