Nickel/NHC‐Catalyzed Asymmetric C−H Alkylation of Fluoroarenes with Alkenes: Synthesis of Enantioenriched Fluorotetralins

Abstract

Chiral polyfluoroarene derivatives are an important scaffold in chemistry.Anunprecedented enantioselective C À H alkylation of polyfluoroarenes with alkenes is described. The reaction employs bulky chiral N-heterocyclic carbene (NHC) ligands for nickel catalysts to enable exclusive activation of CÀ Hb onds over C À Fb onds and complete endo-selective C À H annulation and excellent enantioselectivity.Awide variety of chiral fluorotetralins,compounds otherwise difficultly accessed but serve as important bioisosteric analogs of both tetralin and heterocycle units for drug design, are expediently synthesized from easily available substrates.T oo ur knowledge,t his is the first example of catalytic enantioselective CÀHf unctionalization of polyfluoroarenes.Pharmaceuticals containing fluoroarenes display unique properties owing to the presence of fluorine atoms,w hich is the most electronegative element and can adjust molecular polarity,pKa-value,lipophilicity,and metabolic stability. [1] In materials science,control of the relative orientation of several C À Fbonds on the polyfluoroarenes unit leads to the design of highly polar compounds,s uch as dielectric materials used in liquid crystals ( Figure 1). [2] Thus,t he construction and modification of fluoroarene derivatives have emerged as af undamental organic transformation of significant importance,and much effort has been devoted to this area. [3] Among them, the C À Hfunctionalization of readily available fluoroarenes is the most atom-and step-economical method. [4,5] Despite recent progress in racemic reactions, [5] the direct catalytic asymmetric CÀHf unctionalization [6] of polyfluoroarenes remains unknown. Importantly,a ne nantioselective CÀHa ctivating cyclization of polyfluoroarenes to access optically active fluorotetralin skeletons has not been reported, though these fluorotetralins serve as important bioisosteres of both tetralin and heterocycle scaffolds for drug design, [7] and are commonly found in pharmaceuticals and materials (Figure 1). [8] Ty pically,t etralin systems are synthesized through Friedel-Crafts type cyclization of aryl derivatives [9] or hydrogenation of naphthalene derivatives. [10] However,t hese two methods are not applicable to chiral fluorotetralin synthesis due to the challenges associated with chemo-, regio-, and stereocontrol and the facile hydrodefluorination side reaction [11] (Scheme 1A,B). To our knowledge,t here are no general catalytic methods for the asymmetric synthesis of unfunctionalized fluorotetralins.Inthis context, we surmised that aN i-catalyzed asymmetric C À Ha lkylation of easily available alkene tethered fluoroarenes by an intramolecular hydroarylation might provide an efficient construction of chiral fluorotetralin derivatives (Scheme 1C). [12,13] However, we noted that several daunting challenges exist in this strategy.F irst, the competitive alkene isomerization through af acile Ni-promoted chain-walking process needs to be suppressed. [14] Second, selective activation of CÀHbonds over multiple CÀFb onds...

Asymmetric Hydroarylation Reactions Catalyzed by Transition Metals: Last 10 Years in a Mini Review

“…The tested commercially available and usually employed chiral diphosphines di lead to active nickel catalysts, while bis-oxazolines gave an incomplete conversion o substrate and low enantioselectivity. Excellent yields and ee were achieved with ster The NHC ligands were also employed in the first example of catalytic enantioselective C-H functionalization of polyfluoroarenes ( 39) by Shi's group in 2019 (Figure 22) [45]. In the same year Shi's work was published, Zhou's group reported the stereoselective synthesis of indanones (43) through the Ni-catalyzed asymmetric intramolecular hydroarylation of enones (42) using a semicorrin ligand [46].…”

“…Figure 21. Chiral and sterically hindered N-heterocyclic carbenes as ligands in the synthesis of 2-and 4-tetrahydroquinolizinones (37 and 38).The NHC ligands were also employed in the first example of catalytic enantioselective C-H functionalization of polyfluoroarenes (39) by Shi's group in 2019 (Figure22)[45]. A careful reaction optimization and screening of the ligands reveled that exclusive endocyclization occurs in excellent yields and enantioselectivity when ANIPE (L*5 and L*7, chiral version of IPr) or SIPE (L*1, chiral version SIPr) ligands are employed.…”