Origin of Stereoselectivity in FLP-Catalyzed Asymmetric Hydrogenation of Imines

Abstract

Development of metal-free strategies for stereoselective hydrogenation of unsaturated substrates is of particular interest in asymmetric synthesis. The emerging chemistry of frustrated Lewis pairs offers a promising approach along this line as demonstrated by recent achievements. However, the stereocontrol elements in these reactions are not clearly recognized thus far. Herein, we analyze the origin of stereoinduction in direct hydrogenation of imines catalyzed by a set of chiral boranes. We use the tools of computational chemistry to describe the elementary steps of the catalytic cycle, and we pay special attention to the stereoselectivity-determining hydride transfer process. The enantioselectivities predicted by the applied computational approach are in very good agreement with previous experimental observations. We find that the stereoselectivity is governed by a thermodynamically less favored conformer of the borohydride intermediate and not by the experimentally observed form. The most favored hydride transfer transition states are stabilized by specific aryl–aryl and alkyl–aryl noncovalent interactions, which play an important role in stereoinduction. This computational insight is exploited in proposing additional borane variants to improve the enantioselectivity, which could be demonstrated experimentally

Three‐Component Reaction to 1,4,2‐Diazaborole‐Type Heteroarene Systems

“…Compound 17 a is analogous to the recently reported structure of 17 b,that was obtained upon treatment of FpxylBH 2 •SMe 2 [Fpxyl:2 ,5bis(trifluoromethyl)phenyl] with the CN-Xyl reagent 13 b at 80 8 8C. [13] Formation of dihydro-1,4,2-diazaborole derivatives Thei ncipient B/N FLP reactivity [11] of the FmesBH 2 / isonitrile system was used for the preparation of asmall series of dihydro-1,4,2-diazaboroled erivatives.T he reaction between benzyl isocyanide(13 a), the FmesBH 2 dimer (10) 2 and 4-iodobenzonitrile was carried out as as equential threecomponent reaction (r.t.,1d). Workup gave the dihydro-1,4,2-diazaborole derivative 18 a as ay ellow solid in 41 % yield (see Scheme 4).…”

“…Scheme 3s hows ap ossible rationalization of the formation of compound 14.I nitial isonitrile insertion into aB -H unit of the reagent 10 would give the intermediate 11 a,which could react as atypical geminal frustrated B/N Lewis pair [9][10][11] (B/N FLP) with the C-H acidic alkyne [12] to give 15,followed by internal borohydride iminium reduction. Dimerization of 16 by two-fold Lewis pair formation would then give the observed product 14 (see Scheme 3).…”

“…Workup gave the dihydro-1,4,2-diazaborole derivative 18 a as ay ellow solid in 41 % yield (see Scheme 4). In CD 2 Cl 2 solution (299 K), it shows at ypical 11 TheX-ray crystal structure analysis of compound 18 a (see Figure 1) shows the largely delocalized five-membered heteroarene core [independent molecule A: B1AÀC1A 1.448- (8) ,C 1AÀN1A 1.399 (6) ,N 1AÀC2A 1.353 (6) ,C 2AÀ N2A 1.357 (6) ,and N2AÀB1A 1.454 (7) ;the independent mol. Binthe unit cell shows similar values].The boron atom B1 has the bulky Fmes substituent attached [torsion angle q C1A-B1A-C31A-C32A 123.5(7) 8 8].…”

Lewis Acidity of Carbon in Activated Carbonyl Group vs. B(C6F5)3 for Metal‐Free Catalysis of Hydrogenation of Carbonyl Compounds

“…Calorimetric and kinetic studies have shown that entropic effects play an essential role in the formation of the encounter complex. [19][20][21] Hydrogenation of carbonyl compounds is one of the reactions that experimentally shown to be catalyzed in the presence of the B(C 6 F 5 ) 3 as the LA and ethereal solvents as Obearing LBs. [22,23] The major advantages of using ethereal solvents are solvation and stabilizing the proton formed by heterolytic H 2 cleavage and the possibility of proton-delivery to another O-based LB that can be employed in hydrogenation of ketones.…”

“…In FLP chemistry, it is important that the LA and LB molecules have enough noncovalent interactions to form an initial encounter complex. Calorimetric and kinetic studies have shown that entropic effects play an essential role in the formation of the encounter complex [19‐21] …”