Asymmetric Transfer Hydrogenation of Ketimines with Trichlorosilane: Structural Studies

Abstract

A s y m m e t r i c T r a n s f e r H y d r o g e n a t i o n o f K e t i m i n e s w i t h T r i c h l o r o s i l a n e Abstract: We report structural and mechanistic studies on the organocatalytic asymmetric transfer hydrogenation of ketimines with trichlorosilane. Amines were obtained in good yields and moderate enantioselectivities. Both experiment and computation were utilized to provide an improved understanding of the mechanism.The importance of chiral amines lies in their propensity to be fundamentally important building blocks of natural products, drugs, as well as agrochemicals. 1 The asymmetric reduction of imines with a chiral catalyst represents a direct and most appealing approach to enantiomerically enriched amines and the development of asymmetric catalysts for such processes has been the focus of recent research efforts. 2 However, in contrast to the well-developed, effective, and industrially relevant asymmetric reductions of olefins and ketones, the corresponding imine reductions are less advanced. 3 Among various catalytic methods, hydrogenation or transfer hydrogenation of ketimines with a chiral transition metal catalyst system is currently one of the most accessible protocols. 4 Parallel to the quest for more efficient metal catalysts, the discovery of 'green' catalysts has become another focal point. 5 As a consequence, impressive progress has been made recently in the development of organic catalysts for the enantioselective transfer hydrogenation of ketimines using Hantzsch dihydropyridine or trichlorosilane as the hydride donor in conjunction with a chiral organocatalyst that activates the substrate or the reductant (Scheme 1). 6-16 Scheme 1 Organocatalytic asymetric transfer hydrogenation of iminesOur studies revealed that electron-poor thiourea derivatives can activate imines by hydrogen bonding and thus promote the hydrogen transfer from Hantzsch esters to generate amines, but the substrate scope was limited to aliphatic and aromatic aldimines. 17 Unfortunately, chiral thiourea derivatives fail to promote the hydride transfer from Hantzsch esters to ketimines. As part of our efforts in the development of organocatalytic methods for the reduction of ketimines, we turned our attention to trichlorosilane as an alternative organic reducing agent. 18 Inspired by the reduction of aldehydes, ketones, as well as imines with the combination of trichlorosilane and N,Ndimethylformamide, the Matsumura group were the first to develop chiral N,N-dimethylformamide analogues, namely N-formylproline derivatives, as effective activators for asymmetric reductions of ketimines using trichlorosilane as the reducing agent, giving the corresponding amines in moderate enantiomeric excess. 9 Later, significant improvement of the enantiomeric excess was achieved by Malkov et al. by using a new N-methyl-L-valine derived Lewis basic organocatalyst. 12 Since then, considerable efforts have been devoted to the development of this transformation and a rapid evolution of catalyst structures has been made by Matsum...

Evaluation of 3,3′-Triazolyl Biisoquinoline N,N′-Dioxide Catalysts for Asymmetric Hydrosilylation of Hydrazones with Trichlorosilane

“…The structure of the active reducing species generated from a chiral catalyst and HSiCl 3 is considered to play a central role for the enantioselectivity of a reaction. Even with notable advances made in this area (selected references; [35][36][37][38][39][40][41][42][43][44][45]), it remains largely elusive and significantly challenging to control the relative populations and reactivities of diastereomeric reducing species that are reversibly produced from a chiral Lewis-base and trichlorosilane. C 2symmetric 2a and HSiCl 3 can give rise to two diastereomeric complexes that are expected to have different enantioselectivities (as long as 2a acts as a bidentate Lewis-base).…”

“…Trichlorosilane reversibly forms a hypervalent silicon complex with Lewis-bases that is believed to be the active reducing species. Since Matsumura's seminal work, that employed N-formylproline-derived catalysts [33,34], and the milestone achieved by Malkov and Kočovský with their N-methyl-L -valine-based catalysts [35][36][37], numerous chiral Lewis-base catalysts have been reported for the asymmetric hydrosilylation of ketimines with trichlorosilane (selected reviews; [30][31][32], selected references; [38][39][40][41][42][43][44][45]). While the majority of these catalysts are amide-based Lewis-bases, other kinds of Lewis-bases are also reported, which includes pyridine N-oxides (selected references; [46][47][48][49][50][51]), phosphine oxides (selected references; [52][53][54]), and sulfinamides (selected references; [55,56]).…”

Rational Design of Simple Organocatalysts for the HSiCl3 Enantioselective Reduction of (E)-N-(1-Phenylethylidene)aniline

“…Chang-ing the solvent from CH 2 Cl 2 to CHCl 3 in this kind of reaction often provides lower ee values and slower reaction rates [54,[56][57][58], but slower kinetics can enable more accurate NMR kinetic analyses and reduce the contribution of the uncatalyzed reaction. The rate constants were calculated considering a simultaneous contribution of the uncatalyzed and catalyzed reactions with first-order rate equations in both substrate and reagent, in agreement with most mechanistic studies (Scheme 2 and Equation ( 1)) [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42]. Although for axially chiral biscarboline-based alcohols, the participation of two molecules of HSiCl 3 has been included in the reaction mechanism, to consider the quantitative reaction of this reagent with alcohols to produce hydrogen, this could be discarded in our case, as this process was not observed [43].…”

“…To carry out a more rational catalyst design, better insight on the mechanisms for this process is needed to understand the effects of structural modifications. However, only a few computational or experimental systematic mechanistic studies are available, and, in most instances, tentative models are elaborated in order to understand the observed enantioselectivity at the molecular level [40][41][42][43]. In the seminal work of Schreiner and co-workers, a detailed evaluation of the possible mechanism of this reaction using density function theory calculations (B3PW91/cc-pVDZ) was reported [40].…”

“…However, only a few computational or experimental systematic mechanistic studies are available, and, in most instances, tentative models are elaborated in order to understand the observed enantioselectivity at the molecular level [40][41][42][43]. In the seminal work of Schreiner and co-workers, a detailed evaluation of the possible mechanism of this reaction using density function theory calculations (B3PW91/cc-pVDZ) was reported [40]. These studies were performed using simplified models for both ketimine and catalyst.…”