Evaluation of reaction conditions for the copper-catalyzed hydrosilylation of allylbenzene. Using allylbenzene (1a) as the model substrate, the Cu-catalyzed hydrosilylation of alkenes was first investigated by assessing the steric effects of different dihydrosilanes, including PhMeSiH2 (2a), mesityl(methyl)silane (2b), and Ph(tBu)SiH2 (2c). Various copper precursors and ligands were also examined for the model reaction. The results of selected experiments are summarized in Table 1. The reactions between allylbenzene and the dihydrosilanes R1R2SiH2 were conducted using 4 mol% Cu(OAc)2 and 8 mol% (R,R)-Ph-BPE (L1) at 40°C (entries 1 − 3). Notably, it was observed that the reaction of allylbenzene with mesityl(methyl)silane (2b) produced the anti-Markovnikov product at 40°C with moderate conversion and a 94:6 enantiomeric ratio (entry 2). Despite PhMeSiH2 (2a) exhibiting a higher conversion rate compared to mesit-yl(methyl)silane (2b) and Ph(tBu)SiH2 (2c), the latter demonstrated better enantioselectivities. A slight enhancement in enantioselectivity was noted upon transitioning from Cu(OAc)2 to CuOAc as the copper precursor (entry 4). Conversely, the use of CuCl as the catalyst did not yield any reaction (entry 5). By increasing the catalyst loading to 8 mol%, the yield of 3ab could be elevated to 58% (entry 6). Encouragingly, incorporating a secondary ligand proved advantageous for this reaction (entries 7 − 10),14 with CyJohnPhos delivering the optimal outcome (95:5 enanti-omeric ratio; entry 10). Ultimately, the best result was obtained when conducting the reaction of 1a with 2b (3.0 equiv) in the presence of CuOAc (10 mol%), (R,R)-Ph-BPE (L1, 11 mol%), and CyJohnPhos (11 mol%) at 40°C for 2 days, resulting in a 75% yield and a 95:5 enantiomeric ratio (entry 11).
Scope of linear-selective hydrosilylation of alkenes. Following the identification of an active catalyst and optimized conditions for the anti-Markovnikov hydrosilylation of allylbenzene (entry 11 in Table 1), we proceeded to explore the substrate scope. Key findings from this investigation are outlined in Scheme 2. Initially, we examined the hydrosilylation of various alkenes using 2b or 2c. Allylbenzene derivatives containing both electron-donating and electron-withdrawing groups could efficiently undergo reactions with mesityl(methyl)silane (2b) to yield the desired chiral linear products, typically achieving moderate to excellent yields with good enantioselectivities (3ab–3fb).
In general, electron-withdrawing allylbenzene proved to be a superior substrate (3db) that yielded the hydrosilylation product with higher efficiency. The efficiency and enantioselectivity of the desired products were slightly influenced as the carbon chain prolonged, as observed in 3hb and 3ib. Additionally, heteroaryl-substituted alkenes served as suitable substrates, producing chiral silanes with high efficiency and enantioselectivity (3jb–3lb). Various functional groups such as amino (3mb), phenoxy (3nb), thioether (3ob), silyloxy (3pb), halogens (3qb) were all compatible. These reactions proceeded smoothly, yielding the corresponding tertiary silane products with good yields (57–91%) and high enantioselectivities (91:9 to 96:4 er). In cases where the substrate contained both terminal and internal olefin units, the reaction selectively occurred at the less sterically hindered terminal olefin, leaving the internal olefin moiety intact (3rb). When tert-butyl group-substituted silane was utilized, the desired products were obtained with improved efficiency and enantioselectivity (3cc–3uc). The absolute configuration of 3tc was determined through X-ray diffraction analysis (CCDC: 2358701). Furthermore, 1,4-diallylbenzene was selectively hydrosilylated, resulting in the bis-silane product 3vc with a yield of 71%, an enantiomeric ratio of 98:2 er, and a diastereomeric ratio of 88:12 dr. Prochiral silanes were examined under identical conditions (Scheme 2). The efficiency and enantioselectivity of the product were significantly influenced by the steric hindrance of the silane. Reactions involving silanes bearing various bulky aryl or alkyl groups exhibited high enantioselectivity, albeit with a slight decrease in efficiency (3ac–3af). A variety of readily available alkylphenylsilanes proved to be suitable substrates (3ah–3aj). Although the desired products were obtained when the arylmethylsilane contained electron-donating or electron-withdrawing groups (3ag, 3ak), their efficiency and enantioselectivity were negatively affected.
Evaluation of reaction conditions for the copper-catalyzed hydrosilylation of styrene. Based on the aforementioned investigation, we aimed to expand the substrate scope by incorporating aryl alkenes (Table 2). Despite compound (R,R)-5ak demonstrating excellent efficiency and a favorable enantiomeric ratio, the diastereomeric ratio achieved under the optimized conditions (entry 11, Table 1) was only moderately satisfactory (entry 1). It is worth noting that introducing a second ligand in this reaction didn’t have a positive effect (entry 2). When switching from CuOAc to Cu(OAc)2 as the copper precursor (entry 3), a slight increase in diastereoselectivity was observed. Although different chiral ligands were tested, the desired outcomes were not achieved (entries 4–6). En-couragingly, increasing the amounts of the chiral ligand yielded positive results (entries 7–8). Reducing the reaction time to 36 hours did not significantly alter the results, resulting in the target product (R,R)-5ak being obtained in a 91% isolated yield, with a 98:2 er and up to a 95:5 dr ratio (entry 9).
Table 2. Optimization of reaction conditions for the copper-catalyzed hydrosilylation of allylbenzene. a, b, c, d
a Conditions: 4a (0.2 mmol), 2k (0.6 mmol), copper catalyst (4 mol%) and ligand were stirred at 40°C for 2 d under N2 atmosphere. b Yields were determined by 1H NMR using 1,1,2,2-tetrachloroethane as an internal standard. c The dr values were determined by GC analysis of the crude reaction mixture. d The er values were determined by chiral HPLC analysis. e 10 mol% CuOAc. f 36 h. g 24 h. h Isolated yield.
Scope of branched-selective hydrosilylation of alkenes. Under the optimized conditions, we explored the substrate scope as illustrated in Scheme 3. Enantioenriched branched silanes were successfully synthesized, incorporating halo-genated (5bk), electron-rich (5ck), electron-deficient (5fk) aryl groups, or a fused aromatic ring (5gk). Yields varied between 70% and 94%, with diastereomeric ratios ranging from 86:14 to 95:5, and enantiomeric ratios reaching up to 98:2. Notably, the reaction did not accommodate aryl bromide and iodide substrates. A styrene derivative carrying a methylthio group (5ek) was obtained in moderate yield but displayed poor diastereo- and enantioselectivity. Of significance was the selective transformation of aryl alkenes bearing trisubstituted olefin moieties with the silane reagent resulting in high efficiency and stereoselectivity (5dk). Furthermore, a wide array of heteroaryl-substituted alkenes proved to be suitable substrates for the production of chiral silanes exhibiting both C- and Si-stereogenic cen-ters efficiently, enantioselectively, and with moderate diastereoselectivity (5ik–5lp). The absolute configuration of the chiral branched alkylsilane product was conclusively determined through X-ray crystallographic analysis of compound 5lp (CCDC: 2358711).
Next, the investigation focused on the scope of prochiral silanes. Reactions with readily available arylmethylsilanes exhibited remarkable efficiency, diastereoselectivity, and enantioselectivity (5ca, 5cl–5cp). Another alkylarylsilane (5ci) was converted to the target products with a yield of 92%, a diastereomeric ratio (dr) of 94:6, and an enantiomeric ratio (er) of 97:3. However, diarylsilanes and sterically hindered silanes such as mesityl(methyl)silane (2b) and Ph(tBu)SiH2 (2c) were found to be unsuitable substrates for these reactions.
Mechanistic Investigation. Deuterium labeling experiments were conducted as part of the investigation into the reaction mechanism. Initially, the isotopically labeled substrate methyl(phenyl)silane-d2 (2a-d2) was subjected to standard conditions, leading to the formation of deuterated products 3aa-d2 and 5aa-dn, illustrated in Scheme 5a. To enhance our comprehension of the reversibility factors that influence the reaction steps, multiple control experiments were performed. When styrene (4a), 2a-d2, and (4-methoxyphenyl)(methyl)silane (2m) were simultaneously employed under standard conditions, the integration of the Si- H/D peaks of 5aa-dm and 5am-dm gives a ratio of approximately 1:1. The obtained result provides further evidence for the reversibility of migratory insertion and β-hydride elimination.15 Another crossover experiment was performed using 1.0 equiv 2a-d2 and 2m reacting without an alkene under standard conditions. The presence of deuterium crossover was confirmed through 1H NMR analysis. These findings strengthen our conclusion that the generation of copper hydride species, migratory insertion, and β-hydride elimination display reversibility (Scheme 5b). Based on this data, we propose a potential reaction mechanism for the copper-catalyzed intermolecular regiodivergent and stereoselective hydrosilylation of alkenes (Scheme 5c).
Computational studies. To elucidate the origin of the regio- and stereoselectivities observed in the reaction, we resorted to DFT studies on the hydride-insertion and the subsequent metathesis steps (See SI for the details). The potential energy surface leading to the linear products was explored with 1-butene as the model substrate (Scheme 6a). The migratory insertion step from S1 to TS1 has a barrier of 10.9 kcal/mol, generating the linear alkyl Cu(I) P1, with an energy downhill of 23.1 kcal/mol. Subsequent silane association leads to further energy downhill of 3.3 kcal/mol. From S2, the conformation space of the metathesis step was mapped similarly. Our calculation shows that the most energetically favored pathway proceeds through transition structure TS2_conf B_R (in favor of the R-product) with a barrier of only 13.4 kcal/mol, which is much more favored (by 13.0 kcal/mol) than the β-H elimination backward pathway (26.4 kcal/mol), in congruent with the absence of H/D scrambling observed experimentally (Scheme 5a). The second lowest-energy TS is TS2_conf A_S which is 3.8 kcal/mol higher, in good agreement of the sense and degree of enantiocontrol observed experimentally.
For the reaction with styrene as starting material, we systematically sampled the conformational space of the hydrocupration and metathesis transition states in the formation of the branched product. It was found that the relative energy of the conformational of the R configuration was lower than that of the S configuration, where TS1’_conf 2_re was the conformation with the lowest energy (Scheme 5b). The results show that the Cu–H insertion TS forming terminal C–Cu bond (TS1’_r.r.) is 8.8 kcal/mol higher than TS1’_conf 2_re, which is consistent with the exclusive regioselectivity observed experimentally. The most stable conformation TS1’_conf 2_re leads to the lowest energy benzyl-Cu(I) intermediate P1’_conf 2_re, which then associates with the phenyl silane to give the σ-complex S2’ with a 3.8 kcal/mol energy drop. Subsequently, the conformational space of the metathesis with Ph(Me)SiH2 was also mapped. Of these transition structures, TS2’_conf b_R,R and TS2’_conf d_R,R converged to the same structure which was found to be lowest in energy. Notably, there is only a small energy difference of 1.9 kcal/mol between the β-H elimination from the benzylic Cu(I) and the metathesis, suggesting of a partially reversible hydrometallation step before the rate-determining metathesis. This can explain the isotope scrambling observed in the mechanistic experiments (Scheme 5a, 5b). According to distortion interaction analysis (DIAS) of these TSs, it can be concluded that for both substrates, the configuration established at the silicon atom are a result of differences of the distortion of the silane moiety.