New organic activators for the enantioselective reduction of aromatic imines with trichlorosilane

Abstract

Abstract-N-Picolinoyl-(2S)-(diphenylhydroxymethyl)pyrrolidine was found to work as an organic activator in the reduction of aromatic imines to the corresponding amines by Cl 3 SiH. The highest selectivity was 80%ee. This is the first data showing that N-formyl group is not always essential as N-protecting group of pyrrolidine derivatives for the reduction of imines by Cl 3 SiH.Enantioselective reduction of ketones 1 and imines 2 has been one of recent topics in asymmetric synthesis. 3 A variety of reducing reagents have been used in the reductions but it is still worthwhile to exploit new methods which can be carried out using inexpensive reducing reagents under mild conditions. One of such reagents may be trichlorosilane (Cl 3 SiH), a liquid material easily available from silicon industry, 4 though some activator is necessary for Cl 3 SiH to efficiently reduce ketones and imines. 5 We already reported chiral N-formylpyrrolidine derivatives 1 as organic activators in the enantioselective reduction of ketones 6 and imines 7 with Cl 3 SiH. The reduction proceeds smoothly at room temperature with good yields and enantioselectivity of up to 43%eefor the reduction of ketones and 66%ee for the reduction of imines. Recently, a new activator 2 for Cl 3 SiH in reducing imines with high enantioselectivity (up to 92%ee) was reported. 8 The noticeable point in those reductions was that the presence of N-formyl substituent was essential for those reductions. In our continuing effort to exploit new chiral organic compounds in place of 1 to activate Cl 3 SiH, 9 we found N-picolinoylpyrrolidine derivatives 3a-f to also work as organic activators in the reduction of aromatic imine 4 to amine 5 (Eq 1). This is the first data showing that N-formyl group is not always essential in the structure of organic activators for Cl 3 SiH.10,11

Mechanistic investigations of the asymmetric hydrosilylation of ketimines with trichlorosilane reveals a dual activation model and an organocatalyst with enhanced efficiency

“…Matsumura's work had previously shown that the deoxy-picoline derivative 24 catalyzed the asymmetric hydrosilylation of N-phenyl ketimine 25 but led to poor selectivity compared to the parent catalyst 23, inferring the need for a hydrogen bond to effectively coordinate with the ketimine substrate, leading to the commonly accepted model shown. 12 In order to compare this effect in the imidazole series, removal of the hydrogen bond acceptor was achieved by methylation of catalyst 17 with sodium hydride and methyl iodide giving the O-Me catalyst 26 in 56% yield (Scheme 3). For comparison purposes, Matsumura's picolinic acid derived catalyst 23 was prepared from commercially available 2-picolinic acid by treating with oxalyl chloride, then reaction with α,α-diphenylprolinol 13.…”

“…Since the first chiral Lewis-base derived catalyst was reported in 2001, 1 there have been many variants of catalyst prepared and evaluated; 2,3 selected examples include formamides, [4][5][6][7] sulfinimides, 8,9 pyridines, [10][11][12] and organophosphorus compounds. [13][14][15] The main focus of research from this group has been using an imidazole derived catalyst that has been shown to function as efficiently as the reported analogous picolinoyl series, 16 in addition to being amenable to reductive amination protocols.…”

Cinchona‐Derived Picolinamides: Effective Organocatalysts for Stereoselective Imine Hydrosilylation

“…[8] Among the most successful Lewis bases used to activate HSiCl 3 are the picolinamides, simply synthesized by connecting picolinic acid to a chiral carbon skeleton. [9] We now wish to report our preliminary results on the application of novel picolinamide-cinchona organocatalysts for the successful highly enantioselective trichlorosilanemediated reduction of ketomines to chiral amines; more-remarkably high turnover frequencies for the hydrosilylation of imines were observed; the catalyst of choice proved to be active even at a loading of only 1 mol-%. The loading was further reduced to 0.5 mol-%, and for very short reaction times (15 min) very impressive asymmetric catalyst efficiency speed values were reached.…”

Direct Asymmetric Hydrosilylation of Indoles: Combined Lewis Base and Brønsted Acid Activation

“…Subsequently, a variety of chiral Lewis base organocatalysts, which have been effectively utilized in several asymmetric hydrosilylation reactions with HSiCl 3 over the past years, [14] were extensively screened to induce chirality in the product. [15] Pleasingly, both chiral picolinoylpyrrolidine [16] (1 b) and N-formyl l-pipecolinamide [17] (1 d) exhibited high catalytic activity, and more importantly, promising enantioselectivity ( (Table 1, entry 6). It seems that the acid additive just supplies a proton, and might not be involved in the key asymmetric reduction step.…”