Abstract
The combination of catalytic amounts of optically active dipyridylphosphine and CuF2 along with hydride donor PhSiH3 generated in situ a remarkably reactive catalyst system (substrate-to-ligand molar ratio up to 100,000) for the highly enantioselective hydrosilylation of a broad spectrum of aryl alkyl ketones (up to 97% enantiomeric excess) in normal atmosphere and at mild conditions (ambient temperature to -20°C, compatible with traces of moisture) in the absence of base additives. Furthermore, a highly effective catalytic asymmetric hydrosilylation of unsymmetrical diarylketones using this catalyst system was also realized (up to 98% enantiomeric excess). The introduction of the dipyridylphosphine ligands in the air-accelerated and inexpensive metal-mediated asymmetric hydrosilylation of ketones makes the present system highly attractive and thus provides an excellent opportunity for practical applications.
Keywords: asymmetric catalysis
Considerable efforts have been devoted to the development of efficient methods for the preparation of enantiomerically pure secondary alcohols because of the significance of these intermediates for the manufacture of pharmaceuticals and advanced materials. The catalytic asymmetric reduction of prochiral ketones as a direct route to enantiomeric alcohols is among the most attractive, and various strategies have been developed accordingly (1–5). Although intensive studies have been focused on the asymmetric hydrogenation that shows excellent enantioselectivities for a wide range of simple ketones (refs. 6 and 7 and references therein and refs. 8–18), asymmetric hydrosilylation as a desirable alternative has also attracted much attention, owing to the mild reaction conditions used and technical simplicity (1d). Since the early reports three decades ago (19–23), the asymmetric hydrosilylations of prochiral simple ketones mediated by catalysts of rhodium(I) (4, 24–28) and ruthenium(II) (29, 30) as well as some less expensive metals such as titanium (31–34), zinc (35), tin (36), and copper(I) (37) have been extensively explored. However, most of these reactions were routinely conducted at a low substrate-to-ligand (S/L) ratio (50 to 500). The high cost of catalyst and the low substrate-to-catalyst ratio rendered the previous hydrosilylation work unattractive commercially. More recently, a significant breakthrough in this area was achieved by Lipshutz and coworkers (38–40), who developed a very effective catalyst system formed in situ from CuCl and nonracemic bidentate phosphines [e.g., (6,6′-dimethoxy-biphenyl-2,2′-diyl)bis[di(3,5-dimethylphenyl)phosphine] (41, 42) or (4,4′-bi-1,3-benzodioxol)-5,5′-diylbis(di(3,5-di-tert-4-methoxyphenyl)phosphane) (43)] along with t-BuONa. This system allowed for highly active and enantioselective hydrosilylations of both aryl alkyl and heteroaromatic ketones in the presence of an inexpensive stoichiometric reductant polymethylhydrosiloxane (44) even at a S/L molar ratio up to 100,000, which approached the levels achieved in related ruthenium-based asymmetric hydrogenations (ref. 6 and references therein and refs. 9, 17, and 18). Nevertheless, there are some limitations for Lipshutz and coworkers' system from a practical point of view. For example, the reactions must be performed by using standard Schlenk techniques and at low temperatures (-50 to -78°C) for maximum enantiomeric excess (ee), which could be difficult and costly for large-scale reactions. Additionally, the presence of a base such as t-BuONa was important for the generation of an active catalyst. Sirol et al. (45) recently reported a base-free and air-accelerated CuF2/2,2′-bis(diphenyllphosphino)-1,1′-binaphthyl/PhSiH3 system for this transformation, which furnished secondary alcohols in moderate to good enantioselectivities under ambient conditions at lower S/L ratios of 100–200. Sirol et al.'s system has some advantages over Lipshutz and coworkers' catalyst system, such as air stability and mild reaction temperatures, whereas the activities, enantioselectivities, and the substrate scope are not comparable to those described by Lipshutz and coworkers (38–40, 45). Therefore, the development of a catalyst system for this process that embraces high reactivities and enantioselectivities and can be handled under mild conditions is of high interest to both the academic world and industrial scientists.
We have previously reported the synthesis of a atropisomeric dipyridylphosphine ligand 2,2′,6,6′-tetramethoxy-4,4′-bis-(diphenylphosphino)-3,3′-bipyridine (P-Phos) (1a, Fig. 1 and ref. 46) and its analogues (47, 48) and have established their effectiveness for many catalytic asymmetric hydrogenation reactions (46–49), especially the utility of 2,2′,6,6′-tetramethoxy-4,4′-bis[di(3,5-dimethylphenyl)phosphino]-3,3′-bipyridine (Xyl-P-Phos) (1b, Fig. 1 and ref. 48) for Ru-catalyzed hydrogenation of a broad scope of simple ketones (17, 18). Particularly noteworthy was the observation that the Ru-(P-Phos) catalyst system was highly air-stable even in solution (18, 47, 48). Capitalizing on this fact, we conjectured that the air stability of P-Phos-type ligands might be especially favorable for the air-accelerated, copper(II)-catalyzed asymmetric hydrosilylations of unfunctional ketones (45). In this study, we found that the combination of (R)- or (S)-1/CuF2/PhSiH3, particularly in the use of Xyl-P-Phos 1b, served as a highly effective system for the hydrosilylation of a wide array of aryl alkyl ketones without the need for an addition of an organic or inorganic base with competitive levels of enantioselectivities (up to 97% ee) and remarkably high activities (S/L ratio up to 50,000 and 100,000) under air atmosphere and at mild temperatures (room temperature to -20°C). In addition, despite the wide utility of chiral benzhydrol and its derivatives in the synthesis of pharmaceuticals (50, 51), the asymmetric hydrosilylation of unsymmetrical diaryl ketones to benzhydrol has received scant attention and therefore remained a challenge. Brunner and Kürzinger (52) reported the related reaction in 1988 based on the use of rhodium complexes with an ee up to 20%. Hence, another goal of our study was the utilization of the present catalyst system in the hydrosilylation of substituted benzophenones. Good to excellent ee values (ee up to 98%) have been attained for some ortho-substituted benzophenones.
Fig. 1.
Chiral dipyridylphosphine ligands.
Materials and Methods
General Information. 1H NMR, 13C NMR, and 31P NMR spectra were recorded in CDCl3 on a Varian AS 500 NMR spectrometer (500, 202, and 125 MHz, respectively) at room temperature. The conversions and ees of the asymmetric hydrosilylation products were determined by NMR, chiral GC, and HPLC. GC analyses were conducted on a Hewlett–Packard 4890A gas chromatograph with a flame ionization detector. HPLC analyses were performed by using a Waters model 600 analytical liquid chromatography system with a Waters 486 UV detector. Optical rotations were measured on a PerkinElmer model 341 polarimeter in a 10-cm cell. Optically pure P-Phos (1a) and Xyl-P-Phos (1b) were synthesized according to our previously reported procedures (46, 48). Copper fluoride, phenylsilane, polymethylhydrosiloxane, and ketone substrates were purchased from Aldrich or Acros (Hong Kong) and used as received without further purification unless otherwise stated.
A Typical Procedure of Asymmetric Hydrosilylation in Air. CuF2 (5.4 mg, 0.054 mmol) and (S)-Xyl-P-Phos (1b, 2.1 mg, 2.72 × 10-3 mmol) were weighed under air and placed in a 25-ml round-bottomed flask equipped with a magnetic stirrer. Toluene (5.4 ml) was added, and the mixture was stirred at room temperature for 10 min. Phenylsilane (800 μl, 6.43 mmol) and acetophenone (2a, 640 μl, 5.43 mmol) were sequentially added under vigorous stirring, and the flask was fitted with a stopper. The reaction was monitored by TLC. Upon completion, the reaction mixture was treated with 10% HCl (3 ml), and organic product was extracted with ether (3 × 20 ml). The combined extract was washed with water, dried with anhydrous sodium sulfate, filtered through a plug of silica, and concentrated in vacuo to give the crude product. The conversion and the ee of the product (S)-1-phenylethanol [(S)-3a] were determined by NMR and chiral GC analysis to be >99% and 77%, respectively [column, Chirasil-DEX CB 25 m × 0.25 mm, Chrompack (Varian), carrier gas, N2]. The pure product was isolated by column chromatography (ethyl acetate/hexane = 1:4).
Conditions of the Analysis of Chiral Secondary Alcohols. 1-Phenylethanol (3a). Capillary GC, Chirasil-DEX CB column; 120°C; isothermal; tR (2a) = 5.25 min; tR (R) = 10.36 min; tR (S) = 11.09 min.
1-Phenylpropanol (3b). Capillary GC, Chirasil-DEX CB column; 122°C; isothermal; tR (2b) = 7.35 min; tR (R) = 15.62 min; tR (S) = 16.12 min.
1-(2′-Naphthyl)ethanol (3c). Capillary GC, Chirasil-DEX CB column; 160°C; isothermal; tR (2c) = 13.40 min; tR (R) = 20.71 min; tR (S) = 21.65 min.
1-(2-Methylphenyl)ethanol (3d). Capillary GC, Chirasil-DEX CB column; 140°C; isothermal; tR (2d) = 3.79 min; tR (R) = 7.78 min; tR (S) = 8.90 min.
1-(2-Chlorophenyl)ethanol (3e). Capillary GC, Chirasil-DEX CB column; 145°C; isothermal; tR (2e) = 4.91 min; tR (R) = 9.40 min; tR (S) = 11.02 min.
1-(2-Bromophenyl)ethanol (3f). Capillary GC, Chirasil-DEX CB column; 150°C; isothermal; tR (2f) = 5.21 min; tR (R) = 11.79 min; tR (S) = 14.48 min.
1-(3-Methylphenyl)ethanol (3g). Capillary GC, Chirasil-DEX CB column; 122°C; isothermal; tR (2g) = 6.90 min; tR (R) = 14.02 min; tR (S) = 15.05 min.
1-(3-Methoxyphenyl)ethanol (3h). Capillary GC, Chirasil-DEX CB column; 135°C; isothermal; tR (2h) = 8.11 min; tR (R) = 16.50 min; tR (S) = 17.63 min.
1-(3-Bromophenyl)ethanol (3i). Capillary GC, Chirasil-DEX CB column; 145°C; isothermal; tR (2i) = 6.65 min; tR (R) = 15.19 min; tR (S) = 16.32 min.
1-(3-Trifluromethylphenyl)ethanol (3j). Capillary GC, Chirasil-DEX CB column; 125°C; isothermal; tR (2i) = 3.82 min; tR (R) = 9.90 min; tR (S) = 11.06 min.
1-(4-Methylphenyl)ethanol (3k). Capillary GC, Chirasil-DEX CB column; 125°C; isothermal; tR (2k) = 6.93 min; tR (R) = 10.78 min; tR (S) = 12.01 min.
1-(4-Chlorophenyl)ethanol (3l). Capillary GC, Chirasil-DEX CB column; 144°C; isothermal; tR (2l) = 5.75 min; tR (R) = 10.89 min; tR (S) = 11.97 min.
1-(4-Bromophenyl)ethanol (3m). Capillary GC, Chirasil-DEX CB column; 150°C; isothermal; tR (2m) = 6.87 min; tR (R) = 13.02 min; tR (S) = 14.15 min.
1-(4-Trifluromethylphenyl)ethanol (3n). Capillary GC, Chirasil-DEX CB column; 125°C; isothermal; tR (2n) = 4.72 min; tR (R) = 12.38 min; tR (S) = 14.53 min.
1-(4-Nitrophenyl)ethanol (3o). Capillary GC, Chirasil-DEX CB column; 172°C; isothermal; tR (2o) = 5.86 min; tR (R) = 14.01 min; tR (S) = 15.30 min.
o-Chlorobenzhydrol (5a). The conversion was determined by capillary GC with a 30 m × 0.25 mm J & W Scientific (Folsom, CA) INNOWax column; 232°C; isothermal; tR (4a) = 8.60 min; tR (5a) = 14.88 min. The ee value was determined by chiral HPLC analysis with a 25 cm × 4.6 mm Daicel (Fort Lee, NJ) Chiralcel OD column (eluent, 10:90 2-propanal/hexane; flow rate, 1.0 ml/min; detection, 254 nm light); tR (R) = 8.33 min; tR (S) = 10.33 min.
o-Fluorobenzhydrol (5b). The conversion was determined by capillary GC with a 30 m × 0.25 mm J & W Scientific INNOWax column; 230°C; isothermal; tR (4b) = 6.23 min; tR (5b) = 9.95 min. The ee value was determined by chiral HPLC analysis with a 25 cm × 4.6 mm Daicel Chiralcel OD column (eluent, 4:96 2-propanal/hexane; flow rate, 0.4 ml/min; detection, 254 nm light); tR (R) = 29.96 min; tR (S) = 34.35 min.
o-Methylbenzhydrol (5c). The conversion was determined by capillary GC with a 30 m × 0.25 mm J & W Scientific INNOWax column; 230°C; isothermal; tR (4c) = 6.18 min; tR (5c) = 11.76 min. The ee value was determined by chiral HPLC analysis with a 25 cm × 4.6 mm Daicel Chiralcel OB-H column (eluent, 10:90 2-propanal/hexane; flow rate, 0.5 ml/min; detection, 254 nm light); tR (R) = 19.96 min; tR (S) = 21.74 min.
o-Trifluromethylbenzhydrol (5d). The conversion was determined by capillary GC with a 30 m × 0.25 mmJ&W Scientific INNOWax column; 230°C; isothermal; tR (4d) = 5.06 min; tR (5d) = 6.96 min. The ee value was determined by chiral HPLC analysis with a 25 cm × 4.6 mm Daicel Chiralcel OD column (eluent, 10:90 2-propanal/hexane; flow rate, 0.9 ml/min; detection, 254 nm light); tR (R) = 6.39 min; tR (S) = 7.64 min.
m-Methylbenzhydrol (5e). The conversion was determined by capillary GC with a 30 m × 0.25 mm J & W Scientific INNOWax column; 232°C; isothermal; tR (4e) = 6.90 min; tR (5e) = 10.73 min. The ee value was determined by chiral HPLC analysis with a 25 cm × 4.6 mm Daicel Chiralcel OB-H column (eluent, 10:90 2-propanal/hexane; flow rate, 0.9 ml/min; detection, 254 nm light); tR = 14.96 min (minor) and 27.55 min (major).
p-Chlorobenzhydrol (5f). The conversion was determined by capillary GC with a 30 m × 0.25 mm J & W Scientific INNOWax column; 232°C; isothermal; tR (4f) = 9.20 min; tR (5f) = 19.93 min. The ee value was determined by chiral HPLC analysis with a 25 cm × 4.6 mm Daicel Chiralcel OB-H column (eluent, 10:90 2-propanal/hexane; flow rate, 0.8 ml/min; detection, 254 nm light); tR (R) = 19.98 min; tR (S) = 29.03 min.
p-Methylbenzhydrol (5g). The conversion was determined by capillary GC with a 30 m × 0.25 mm J & W Scientific INNOWax column; 230°C; isothermal; tR (4g) = 8.13 min; tR (5g) = 12.28 min. The ee value was determined by chiral HPLC analysis with a 25 cm × 4.6 mm Daicel Chiralcel OB-H column (eluent, 10:90 2-propanal/hexane; flow rate, 0.4 ml/min; detection, 254 nm light). tR (R) = 28.90 min; tR (S) = 33.38 min.
p-Trifluromethylbenzhydrol (5h). The conversion was determined by capillary GC with a 30 m × 0.25 mmJ&W Scientific INNOWax column; 230°C; isothermal; tR (4h) = 4.67 min; tR (5h) = 9.62 min. The ee value was determined by chiral HPLC analysis with a 25 cm × 4.6 mm Daicel Chiralcel OB-H column (eluent, 10:90 2-propanal/hexane; flow rate, 0.8 ml/min; detection, 254 nm light); tR (R) = 9.17 min; tR (S) = 11.95 min.
Results and Discussion
In a preliminary study, a series of copper(I)- and copper(II)-halides were examined (Scheme 1) in the hydrosilylation of acetophenone (2a) in toluene at ambient temperature and under N2 atmosphere using (S)-1a ligand and PhSiH3 as a hydride donor. Consistent with Sirol et al.'s finding (45), the reaction rate largely relied on the choice of halogen in copper salts, and fluoride in the copper precursor was crucial for the generation of an active catalyst. Thus, CuF2 provided desirable product (S)-3a in quantitative yield with 79% ee after 24 h. In contrast, other copper(I) and copper(II) salts showed disappointing reactivities under otherwise identical conditions (conversions were <23%).
Scheme 1.
The effect of copper halide precursor on asymmetric hydrosilylation of acetophenone.
Next, we investigated the effect of air on the catalyst activity and the results showed that the presence of air in the reaction system markedly enhanced the reaction rates (Table 1, entries 2 and 5 vs. entries 1 and 4). For example, when the hydrosilylation of 2a was carried out with 3 mol% CuF2 and (S)-Xyl-P-Phos (1b) at room temperature under N2, 63% conversion was observed after 3 h (Table 1, entry 4). In contrast, under air atmosphere, complete conversion was observed in only several minutes at S/L of 2,000 with no diminution of enantioselectivity (Table 1, entry 5 vs. entry 4), which was much faster than that with the parent ligand P-Phos (1a, Table 1, entry 5 vs. entry 2). Especially, a side-by-side comparison study showed that the catalytic activities of the systems both with P-Phos (1a) and Xyl-P-Phos (1b) were far superior to that with the use of 2,2′-bis(diphenyllphosphino)-1,1′-binaphthyl (Table 1, entries 2 and 5 vs. entries 6 and 7, ref. 45). Further investigation indicated that lowering of the reaction temperature from room temperature to -20°C significantly enhanced the enantioselectivity (Table 1, entries 8 and 9 vs. entries 3 and 5).
Table 1.
Asymmetric hydrosilylation of acetophenone 2a catalyzed by CuF2 and dipyridylphosphine 1
| Entry | CuF2, mol % | Ligand | S/L | T, °C | Atmosphere | Time | Conversion, % | ee,* % |
|---|---|---|---|---|---|---|---|---|
| 1 | 3 | (S)-1a | 33 | RT | N2 | 3 h | 20 | 78 (S) |
| 2 | 1 | (S)-1a | 2,000 | RT | Air | 25 min | 52 | 77 (S) |
| 3 | 1 | (S)-1a | 2,000 | RT | Air | 3 h | >99 | 78 (S) |
| 4 | 3 | (S)-1b | 33 | RT | N2 | 3 h | 63 | 76 (S) |
| 5 | 1 | (S)-1b | 2,000 | RT | Air | 10 min | >99 | 77 (S) |
| 6 | 1 | (R)-Binap | 2,000 | RT | Air | 25 min | 14 | 73 (R) |
| 7† | 0.5 | (S)-Binap | 200 | RT | Air | 6 h | 94 | 78 (S) |
| 8 | 3 | (S)-1a | 33 | -20 | Air | 24 h | 91 | 89 (S) |
| 9 | 3 | (S)-1b | 100 | -20 | Air | 6 h | >99 | 87 (S) |
Given the remarkable performance of the present catalyst system in the hydrosilylation of acetophenone, its general applicability in the hydrosilylation of a broad range of aryl alkyl ketones 2b–2o was examined under air atmosphere and a given set of conditions, and the representative results are listed in Table 2. Complete hydrosilylations of most substrates by using 1b were realized in a few hours (4–12 h). The positioning of the substituents on the aromatic ring of acetophenone had significant effect on the outcome of reactions. The ortho-substituted acetophenones (2d–2f) were converted to the desired alcohols with moderate enantioselectivities (70-77% ee, Table 2, entries 3–5), whereas meta- and para-substituted acetophenones (2g–2o) gave consistently high enantioselectivities (87–97% ee, Table 2, entries 6–20).
Table 2.
Asymmetric hydrosilylation of aromatic ketones 2 catalyzed by Cu(II) and dipyridylphosphine 1 in air
| Entry | Ketone | Ar | R | CuF2, mol% | Ligand | S/L | T,°C | Time | ee,* % |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 2b | C6H5 | CH2CH3 | 3 | (S)-1b | 100 | -20 | 12 h | 93 |
| 2 | 2c | 2′-naphthyl | CH3 | 3 | (s)-1b | 100 | -10 | 24 h | 92 |
| 3 | 2d | 2-CH3C6H4 | CH3 | 3 | (s)-1b | 100 | -20 | 24 h | 72 |
| 4 | 2e | 2-ClC6H4 | CH3 | 3 | (s)-1b | 100 | -20 | 10 h | 77 |
| 5 | 2f | 2-BrC6H4 | CH3 | 3 | (s)-1b | 100 | -20 | 10 h | 70 |
| 6 | 2g | 3-CH3C6H4 | CH3 | 3 | (s)-1b | 100 | -20 | 12 h | 87 |
| 7 | 2h | 3-CH3OC6H4 | CH3 | 3 | (s)-1b | 100 | -20 | 12 h | 92 |
| 8 | 2i | 3-BrC6H4 | CH3 | 3 | (s)-1b | 100 | -20 | 12 h | 89 |
| 9 | 2j | 3-CF3C6H4 | CH3 | 3 | (s)-1b | 100 | -20 | 12 h | 91 |
| 10 | 2k | 4-CH3C6H4 | CH3 | 3 | (s)-1b | 100 | -20 | 24 h | 91 |
| 11 | 2l | 4-ClC6H4 | CH3 | 3 | (s)-1b | 100 | -20 | 6 h | 94 |
| 12 | 2m | 4-BrC6H4 | CH3 | 3 | (s)-1b | 100 | -20 | 6 h | 96 |
| 13 | 2n | 4-CF3C6H4 | CH3 | 3 | (s)-1a | 33 | -20 | 24 h | 96 |
| 14 | 2n | 4-CF3C6H4 | CH3 | 3 | (s)-1b | 100 | -20 | 6 h | 94 |
| 15 | 2o | 4-NO2C6H4 | CH3 | 1 | (s)-1b | 100 | RT | 1 h | 93 |
| 16 | 2o | 4-NO2C6H4 | CH3 | 3 | (s)-1b | 100 | -20 | 4 h | 97 |
| 17 | 2o | 4-NO2C6H4 | CH3 | 1.2 | (s)-1b | 20,000 | RT | 30 min | 91 |
| 18† | 2o | 4-NO2C6H4 | CH3 | 1.2 | (s)-1b | 100,000 | RT | 20 h | 90 |
| 19 | 2o | 4-NO2C6H4 | CH3 | 3 | (s)-1b | 50,000 | -10 | 48 h | 94 |
| 20 | 2m | 4-BrC6H4 | CH3 | 3 | (s)-1b | 50,000 | -10 | 48 h | 93 |
Reaction conditions: 100 mg to 42 g of substrate, substrate concentration = 0.6–1 M in toluene, >99 % conversion was observed in all cases. RT, room temperature.
The absolute configuration was determined by comparison of the sign of optical rotation or the retention times with the data of ref. 8
The yield of the product isolated by column chromatography was 95%
To further evaluate the activity and air stability of the present catalyst, we performed the experiment of reducing 2o in air at room temperature with a S/L ratio of 20,000. No unreacted 2o was detected after only 30 min (Table 2, entry 17). Moreover, this reaction worked well even when the S/L ratio was increased to as high as 100,000. Thus, in the presence of only 2 mg of (S)-1b, hydrosilylation of 42 g of 2o proceeded smoothly at room temperature under normal atmosphere and led to 99% conversion within 20 h to furnish (S)-3o neatly bearing consistently high enantioselectivity (Table 2, entry 18 vs. entries 15 and 17). Furthermore, excellent catalytic efficiency of (S)-1b/CuF2/PhSiH3 was confirmed by carrying out the reactions at -10°C with S/L ratios of 50,000. Net conversions and high enantioselectivities were maintained for the hydrosilylation of both 2m and 2o (Table 2, entries 19 and 20). These results indicated that the activity of this air-accelerated copper (II)-catalyst system using dipyridylphosphine ligand is significantly greater than that using 2,2′-bis(diphenyllphosphino)-1,1′-binaphthyl (45) and is among the most effective systems reported thus far for hydrosilylation of simple ketones with inexpensive metal. It is of great interest that the experiments can be conveniently conducted in air at mild temperature without the addition of base, which makes the present system highly attractive for potential commercial applications.
Unlike the mechanism of asymmetric hydrogenations that has been well elucidated (1–5), the mechanism of asymmetric hydrosilylation is much less understood. The unique efficacy of the dipyridylphosphine ligand for this air-accelerated system is of high interest. It appears that air plays a key role in the formation of the active catalyst precursor during the catalytic cycle and thus the air stability of the diphosphine ligands is becoming very crucial.
It is well known that a usual problem associated with the use of metal phosphine catalysts is that most of them are air-sensitive, especially in solution, and trace amounts of air in the reaction system often destroy the active catalysts and produce irreproducible results. Our previous studies on catalytic asymmetric hydrogenation reactions demonstrated that the dipyridylphosphine ligands possessed better air stability than that of 2,2′-bis(diphenyllphosphino)-1,1′-binaphthyl (47, 48). In the present air-accelerated system, air is one of the key factors for the enhancement of reaction rates, and consequently, dipyridylphosphines with good air stability exhibited extraordinary advantages to other common diphosphines.
Additionally, as part of our ongoing effort to broaden the application scope of the present catalyst system, we were interested in the extension of our system to the hydrosilylation of substituted benzophenones for producing chiral benzhydrol, which are widely used as intermediates for the commercial synthesis of pharmaceuticals. We discovered that this system also worked effectively for a variety of these ketones in air and under very mild conditions (Table 3).
Table 3.
Asymmetric hydrosilylation of substituted benzophenones 4 catalyzed by Cu(II) and dipyridylphosphine 1 in air
| Entry | Ketone | CuF2, mol % | Ligand [mol %] | T, °C | Time, h | Conversion, % | ee,* % |
|---|---|---|---|---|---|---|---|
| 1 | 4a | 3 | (s)-1a [3] | RT | 30 | 96 | 81 (R) |
| 2 | 4a | 4 | (s)-1a [4] | -10 | 72 | 99 | 90 (R) |
| 3 | 4a | 4 | (s)-1b [4] | -10 | 48 | 82 | 91 (R) |
| 4 | 4b | 4 | (s)-1a [4] | -10 | 48 | >99 | 63 (R) |
| 5 | 4b | 4 | (s)-1b [4] | -10 | 48 | >99 | 75 (R) |
| 6 | 4c | 4 | (s)-1a [4] | -10 | 72 | 99 | 83 (R) |
| 7 | 4c | 4 | (s)-1b [4] | -10 | 48 | >99 | 75 (R) |
| 8 | 4d | 4 | (s)-1a [4] | -10 | 72 | 85 | 98 (R)† |
| 9 | 4d | 4 | (s)-1b [4] | -10 | 48 | 88 | 95 (R)† |
| 10 | 4e | 4 | (s)-1b [4] | -10 | 48 | >99 | 6 (+) |
| 11 | 4f | 4 | (s)-1a [4] | -10 | 48 | >99 | 36 (S) |
| 12 | 4f | 4 | (s)-1b [4] | -10 | 48 | >99 | 43 (S) |
| 13 | 4g | 4 | (s)-1a [4] | -10 | 48 | >99 | 27 (S) |
| 14 | 4g | 4 | (s)-1b [4] | -10 | 48 | >99 | 39 (S) |
| 15 | 4h | 4 | (s)-1a [4] | -10 | 48 | >99 | 25 (S) |
| 16 | 4h | 4 | (s)-1b [4] | -10 | 48 | >99 | 41 (S) |
Reaction conditions: 100 mg to 150 mg of substrate, substrate concentration = 0.6–1 M in toluene. RT, room temperature.
The absolute configuration was determined by comparison of the sign of optical rotation or the retention times with the data of ref. 9
In a like manner for aryl alkyl ketones, lower reaction temperature gave higher enantioselectivity at the expense of reaction rate (Table 3, entry 2 vs. entry 1). A range of ortho-substituted benzophenones (4a–4d) were reduced to benzhydrols with good to excellent enantioselectivity (Table 3, entries 1–9). In the case of 4d, the highest enantioselectivity of 98% ee (Table 3, entry 8) was attained at -10°C with (S)-1a ligand. In addition, substrates with bulkier ortho-substituent reacted favorably to give products of higher enantiopurities (Table 3, entries 2, 6, and 8 vs. entry 4). It therefore seems that steric effects of the ortho substituents affect the extent of the coplanarity of the benzene rings with C—O function in the transition state, thereby generating an asymmetric bias. As expected, meta- and para-substituted benzophenones (4e–4h) were transformed to the corresponding alcohols with low to moderate enantioselectivities (Table 3, entries 10–16). Notably, (S)-1a or (S)-1b afforded ortho-substituted benzhydrols with (R)-configurations (Table 3, entries 1–9), whereas the absolute configurations were inverted for para-substituted products (Table 3, entries 11–16).
Conclusions
In conclusion, the combination of catalytic amounts of dipyridylphosphine and CuF2 along with hydride donor PhSiH3 generated in situ a remarkably reactive and base-free catalyst system in normal atmosphere, which promoted the highly enantioselective hydrosilylation of a broad spectrum of aryl alkyl ketones. The present catalyst system achieved an important breakthrough in this area and realized the highly effective catalytic asymmetric hydrosilylation of unsymmetrical diarylketones (ee up to 98%), which also broadened the substrate spectrum of asymmetric hydrosilylations. Taking into account the combination of desirable features, such as high air stability, wide substrate scope, fast rate of reaction, excellent enantio-selectivity, high S/L ratio, and exceedingly mild conditions (ambient temperature to -20°C, compatible with traces of moisture), we believe that the present catalyst system is of great potential for practical applications.
Acknowledgments
We thank the University Grants Committee Areas of Excellence Scheme in Hong Kong (Grant AoE P/10-01) and the Hong Kong Polytechnic University Area of Strategic Development Fund for financial support.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: ee, enantiomeric excess; S/L, substrate to ligand; P-Phos, 2,2′,6,6′-tetramethoxy-4,4′-bis-(diphenylphosphino)-3,3′-bipyridine; Xyl-P-Phos, 2,2′,6,6′-tetramethoxy-4,4′-bis[di(3,5-dimethylphenyl)phosphino]-3,3′-bipyridine.
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