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Molecules 2011, 16(6), 5020-5034; https://doi.org/10.3390/molecules16065020

Article
Ru/Me-BIPAM-Catalyzed Asymmetric Addition of Arylboronic Acids to Aliphatic Aldehydes and α-Ketoesters
Division of Chemical Process Engineering, Graduate School of Engineering, Hokkaido University, kita 13, Nishi 8, Kita-ku, Sapporo 060-8628, Japan
*
Author to whom correspondence should be addressed.
Received: 31 May 2011; in revised form: 13 June 2011 / Accepted: 15 June 2011 / Published: 17 June 2011

Abstract

:
A ruthenium-catalyzed asymmetric arylation of aliphatic aldehydes and α-ketoesters with arylboronic acids has been developed, giving chiral alkyl(aryl)methanols and α-hydroxy esters in good yields. The use of a chiral bidentate phosphoramidite ligand (Me-BIPAM) achieved excellent enantioselectivities.
Keywords:
asymmetric catalyst; bidentate phosphoramidite ligand; ruthenium catalyzed arylation

1. Introduction

Transmetalation between organoboronic reagents and transition metals is a fundamental process involved in many metal-catalyzed C-C bond-forming reactions [1,2]. In this field, we reported a new catalytic cycle starting from transmetalation to give an organorhodium(I), -palladium(II) or -ruthenium(II) intermediate for 1,4-addition of organoboronic acids to electron-deficient alkenes and arylation of the carbon-heteroatom double bond of aldehydes and N-sulfonylimines [3,4,5]. We have developed new bidentate chiral phosphoramidites [Me-BIPAM (6), N-Me-BIPAM (7)] based on linked-BINOL for enantioselective 1,4-addition of arylboronic acids to enones [6,7], arylation of aldimines [8] and hydrogenation of α-dehydroamino esters [9] with rhodium catalysts. These ligands were also found to be highly efficient for ruthenium-catalyzed enantioselective arylation of aromatic aldehydes [10]. Herein, we report arylation of aliphatic aldehydes 1 and α-ketoesters 2 with arylboronic acids 3 catalyzed by a chiral ruthenium complex, generated in situ from [RuCl2(p-cymene)]2 and (R,R)-Me-BIPAM (6) (Scheme 1).
Scheme 1. Arylation of aliphatic aldehydes and α-ketoesters.
Scheme 1. Arylation of aliphatic aldehydes and α-ketoesters.
Molecules 16 05020 g001

2. Results and Discussion

The arylation of carbonyl compounds with organolithium [11,12], organomagnesium [13,14,15] and organozinc [16,17,18,19,20,21] reagents are the traditional ways to access alkyl(aryl)methanol and α-hydroxy-esters, but there has been recent interest in the transition-metal-catalyzed arylation using tin [22] and boron [23,24,25,26,27] compounds. Since the corresponding rhodium complexes were inefficient, we previously developed a highly enantioselective arylation of aldehydes with boronic acids by using ruthenium catalyst [10]. In our continuing program to expand the utility of the ruthenium/Me-bipam catalyst, we planned to develop an enantioselective addition of arylboronic acids to aliphatic aldehydes. [RuCl2(p-cymene)]/Me-bipam (2 mol%) catalyzed the addition of arylboronic acids to representative aliphatic aldehydes in high yields in the presence of one equivalent of K2CO3 at 60 °C in toluene/H2O (10:1). A variety of aliphatic aldehydes underwent the arylation reaction (Table 1). Not only linear aliphatic aldehydes but also branched ones participated in the arylation reaction. Most reactions took place smoothly in toluene/H2O (10/1), but toluene/H2O (5/1) was a better solvent for the slow addition (Table 1, entries 1, 6, 10, 11, 17-19).
Next, we employed Ru/Me-BIPAM as the catalyst for the addition reaction of arylboronic acids to α-ketoesters, could yield useful α-hydroxy-esters with α-quaternary carbon centers. The rhodium(I)/(S)-Ship complex developed by Zhou and co-workers was the most promising catalyst, achieving 80-93% ee for 2-oxo-2-arylacetate and 2-oxo-4-phenyl-3-butenoate [29]. Several bases were screened for the reactions involving a [RuCl2(p-cymene)]2/2Me-bipam catalyst (Table 2).
Table 1. Arylation of aliphatic aldehydes a. Molecules 16 05020 i001
Table 1. Arylation of aliphatic aldehydes a. Molecules 16 05020 i001
EntryR1 =Ar =Yield (%)ee (%) (abs)
1 bn-C2H5 (1a)Ph (3a)63 (4aa)91 (R)
2n-C4H9 (1b)Ph (3a)93 (4ba)94 (R)
3n-C4H9 (1b)2-naphthyl (3b)98 (4bb)93 (R)
4n-C4H9 (1b)4-MeC6H4 (3c)85 (4bc)92 (R)
5n-C4H9 (1b)4-MeOC6H4 (3d)93 (4bd)92 (R)
6 b,cn-C4H9 (1b)4-ClC6H4 (3e)90 (4be)87 (R)
7n-C4H9 (1b)4-FC6H4 (3f)69 (4bf)91 (R)
8n-C4H9 (1b)3-MeOC6H4 (3h)62 (4bh)90 (R)
9n-C4H9 (1b)3-ClC6H4 (3i)63 (4bi)90 (+)
10 b,dn-C4H9 (1b)3-F-4-MeOC6H3 (3k)65 (4bk)87 (+)
11 b,cn-C4H9 (1b)3,4-(CH2O2)C6H3 (3l)58 (4bl)99 (R)
12n-C5H11 (1c)Ph (3a)91 (4ca)94 (R)
13n-C6H13 (1d)Ph (3a)93 (4da)93 (R)
14 cn-C8H17 (1e)Ph (3a)87 (4ea)92 (R)
15PhCH2CH2 (1f)Ph (3a)99 (4fa)92 (R)
16cyclo-C6H11 (1g)Ph (3a)78 (4ga)94 (R)
17 bi-Pr (1h)Ph (3a)67 (4ha)96 (R)
18 b,c(C2H5)2CH (1j)Ph (3a)54 (4ja)91 (R)
19 b,c,et-Bu (1k)Ph (3a)40 (4ka)99 (R)
a Reaction conditions: A mixture of aldehyde (0.5 mmol), ArB(OH)2 (0.75 mmol), K2CO3 (0.5 mmol), [RuCl2(p-cymen)]2 (1 mol%) and (R,R)-Me-BIPAM (2.2 mol%) in toluene (3 mL) and H2O (0.3 mL) was stirred at 60 °C for 16 h. b toluene/H2O (5/1) was used. c at 80 °C. d KOH was used. e K3PO4 was used.
Table 2. Reaction conditions a. Molecules 16 05020 i002
Table 2. Reaction conditions a. Molecules 16 05020 i002
EntryBaseR3 =Yield (%)ee (%) (abs)
1 bK2CO3Et4093
2 bK3PO4EttraceND
3 bCsFEt4093
4 bKFEt7195
5KFEt7894
6KFi-Pr (2a)8593 (S)
7KFt-Bu8790
8 cKFt-Bu7270
a Reaction conditions: A mixture of alkyl pyruvate (0.5 mmol), PhB(OH)2 (1.0 mmol), base (1.0 mmol), [RuCl2(p-cymen)]2 (1 mol%) and (R,R)-Me-BIPAM (2.2 mol%) in toluene (3 mL) and H2O (0.3 mL) was stirred at 80 °C for 16 h. b at 50 °C. c (R,R)-N-Me-BIPAM was used.
K2CO3, K3PO4 or CsF resulted in lower yields (Table 2, entries 1-3). The highest efficiency with regard to the reaction was observed when KF was used for the arylation of isopropyl pyruvate with phenylboronic acid at 80 °C (Table 2, entry 6). The yield of the product was dependent on the bulkiness of the ester moiety of the substrate (Table 2, entries 5-7), and the best results were obtained with isopropyl ester as the substrate. Among chiral ligands screened, N-Me-bipam (7) achieved a 70% ee (entry 8). Substrate generality was then investigated under the optimized reaction conditions (Table 3). High ee values were obtained with methyl, ethyl, and phenyl-substituted ketoesters. Representative meta- and para-substituted arylboronic acids with electron-donating or electron-withdrawing substituents afforded good yields of tertiary α-hydroxy-esters with high enantioselectivities. (R,R)-Me-bipam has given the products 4 and 5 by the same enantioselection. To elucidate the enantioselection in the mechanism, the characterization of the catalyst and the intermediate are in progress.
Table 3. Arylation of α-ketoesters a. Molecules 16 05020 i003
Table 3. Arylation of α-ketoesters a. Molecules 16 05020 i003
EntryR2 =Ar =Yield (%)ee (%) (abs)
1Me (2a)Ph (3a)85 (5aa)93 (S)
2Me (2a)4-MeC6H4 (3c)84 (5ac)89
3Me (2a)4-MeOC6H4 (3d)84 (5ad)91
4Me (2a)4-FC6H4 (3f)85 (5af)93
5Me (2a)4-CF3C6H4 (3g)64 (5ag)92
6Me (2a)3-MeOC6H4 (3h)73 (5ah)92
7Me (2a)3-FC6H4 (3j)71 (5aj)90
8Me (2a)3-F-4-MeOC6H3 (3k)81 (5ak)87
9Et (2b)Ph (3a)88 (5ba)95
10Et (2b)4-MeC6H4 (3c)90 (5bc)91
11Et (2b)4-FC6H4 (3f)90 (5bf)93
12Et (2b)3-MeOC6H4 (3h)88 (5bh)91
13i-Pr (2c)Ph (3a)41 (5ca)94
14i-Pr (2c)4-MeOC6H4 (3d)42 (5cd)90
15Ph (2d)4-MeC6H4 (3c)82 (5dc)92
16Ph (2d)4-MeOC6H4 (3d)95 (5dd)86
17Ph (2d)4-ClC6H4 (3e)90 (5de)91
18Ph (2d)4-FC6H4 (3f)90 (5df)94
19Ph (2d)3-MeOC6H4 (3h)79 (5dh)92
204-FC6H4 (2e)3-ClC6H4 (3i)67 (5ei)90
a Reaction conditions: A mixture of α-ketoester (0.5 mmol), ArB(OH)2 (1.0 mmol), KF (1.0 mmol), [RuCl2(p-cymen)]2 (1 mol%) and (R,R)-Me-BIPAM (2.2 mol%) in toluene (3 mL) and H2O (0.3 mL) was stirred at 80 °C for 16 h.

3. Experimental Section

3.1. General

1H–NMR spectra were recorded on a JEOL ECX-400 (400 MHz) in CDCl3 with tetramethylsilane as an internal standard. Chemical shifts are reported in part per million (ppm), and signal are expressed as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br). 13C-NMR spectra were recorded on a JEOL ECX-400 (100 MHz) in CDCl3C = 77.0) with tetramethylsilane as an internal standard. Chemical shifts are reported in part per million (ppm). HPLC analysis was directly performed with chiral stationary phase column, Chiralpak AD-H, IB or Chiralcel OD-H, OB-H purchased from DAICEL Co., Ltd. High resolution mass spectra (HRMS) were recorded on a JEOL JMS 700TZ mass spectrometer at the Center for Instrumental Analysis, Hokkaido University. Optical rotations were measured on a HORIBA SEPA-300 digital polarimeter. Kanto Chemical silica gel 60N (particle size 0.063-0.210 mm) was used for flash column chromatography. RuCl3·xH2O were purchesed from Strem Chemical, Inc. [RuCl2(p-cymene)]2 [28], BIPAM ligands (Me-BIPAM, N-Me-BIPAM) were prepared according to our previous procedure [7,8]. Me-BIPAM was commercially available from Wako Pure Chemical Industries, Ltd.

3.2. General Procedure for Arylation of Aliphatic Aldehydes (Table 1)

A flask was charged with [RuCl2(p-cymene)]2 (0.005 mmol, 1 mol%) and (R,R)-Me-bipam (0.011 mmol, 2.2 mol%) under a nitrogen atmosphere. Toluene (3.0 mL) was added to the flask and the mixture was then stirred at room temperature for 30 min to prepare the catalyst. Pentanal (1b, 0.5 mmol), phenylboronic acid (3a, 0.75 mmol), K2CO3 (0.5 mmol), and H2O (0.3 mL) were then added to this catalyst solution. The reaction mixture was stirred at 60 °C for 16 h, at which time the crude reaction mixture extracted using ethyl acetate, washed with saturated NH4Cl and brine, and dried over MgSO4. Chromatography of the crude reaction mixture on silica gel gave (R)-1-phenyl-1-pentanol (4ba) [29] in 93% yield; [α]D23 = 33.8 (c 0.80, C6H6), 94% ee [HPLC conditions: Chiralcel OD, hexane/2-propanol = 99/1, flow = 0.85 mL min−1, wavelength = 254 nm, tmajor = 22.7 and tminor = 26.6 min]; 1H-NMR (400 MHz, CDCl3): δ = 7.34-7.25 (m, 5H), 4.65 (t, J = 6.8 Hz, 1H), 1.86-1.70 (m, 3H), 1.39-1.25 (m, 4H), 0.88 (t, J = 7.0 Hz, 3H); HRMS m/z; calcd. For C11H16O: 164.1201; found 164.1203.
(R)-1-Phenyl-1-propanol (4aa) [29,30]: [α]D21 = 43.4 (c 0.87, CHCl3) 91% ee [HPLC conditions: Chiralpak OD, hexane/2-propanol = 99/1, flow = 0.8 mL min−1, wavelength = 254 nm, tmajor = 26.0 and tminor = 33.0 min]; 1H-NMR (400 MHz, CDCl3): δ = 7.34-7.25 (m, 5H), 4.60 (t, J = 6.6 Hz, 1H), 1.88-1.71 (m, 3H), 0.91 (t, J = 7.5 Hz, 3H); HRMS m/z; calcd. for C9H12O: 136.08881; found 136.08881.
(R)-1-(-2-Naphthyl)-1-pentanol (4bb) [31]: [α]D19 = 33.8 (c 1.52, CHCl3), 93% ee [HPLC conditions: Chiralcel OD, hexane/2-propanol = 50/1, flow = 1.0 mL min−1, wavelength = 254 nm, tminor = 27.0 and tmajor = 29.6 min]; 1H-NMR (400 MHz, CDCl3): δ = 7.87-7.77 (m, 4H), 7.51-7.45 (m, 3H), 4.85 (t, J = 6.6 Hz, 1H), 1.94-1.79 (m, 3H), 1.46-1.26 (m, 4H), 0.89 (t, J = 7.0 Hz, 3H).
(R)-1-(4-Tolyl)-1-pentanol (4bc) [29,32]: [α]D22 = 29.4 (c 0.80, C6H6), 92% ee [HPLC conditions: Chiralcel OJ, hexane/2-propanol = 200/1, flow = 1.0 mL min−1, wavelength = 254 nm, tmajor = 20.4 and tminor = 22.6 min]; 1H-NMR (400 MHz, CDCl3): δ = 7.26-7.15 (m, 4H), 4.63 (t, J = 6.2 Hz, 1H), 2.34 (s, 3H), 1.85-1.64 (m, 3H), 1.42-1.20 (m, 4H), 0.88 (t, J = 7.0 Hz, 3H).
(R)-1-(4-Methoxyphenyl)-1-pentanol (4bd) [33]: [α]D19 = 26.9 (c 0.37, CHCl3), 92% ee [HPLC conditions: Chiralcel OD, hexane/2-propanol = 99/1, flow = 0.8 mL min−1, wavelength = 254 nm, tmajor = 37.4 and tminor = 41.0 min]; 1H-NMR (400 MHz, CDCl3): δ = 7.27 (d, J = 8.0 Hz,2H ), 6.89 (d, J = 8.8 Hz,2H), 4.61 (t, J = 6.8 Hz, 1H), 3.81 (s, 3H), 1.85-1.64 (m, 2H), 1.41-1.20 (m, 4H), 0.88 (t, J = 7.4 Hz, 3H); HRMS m/z; calcd. for C12H18O2: 194.13068; found 194.13084.
(R)-1-(4-Chlorophenyl)-1-pentanol (4be) [29]: [α]D22 = 18.3 (c 0.60, C6H6), 87% ee [HPLC conditions: Chiralcel OD, hexane/2-propanol = 99/1, flow = 0.8 mL min−1, wavelength = 230 nm, tminor = 24.5 and tmajor = 27.0 min]; 1H-NMR (400 MHz, CDCl3): δ = 7.34-7.29 (m, 4H), 4.66 (t, J = 7.2 Hz, 1H), 1.82-1.56 (m, 3H), 1.40-1.26 (m, 4H), 0.88 (t, J = 6.2 Hz, 3H); HRMS m/z; calcd. for C11H15C1O: 198.08114; found 198.08132.
(R)-1-(4-Fluorophenyl)-1-pentanol (4bf) [34]: [α]D21 = 40.5 (c 0.50, CHCl3), 91% ee [HPLC conditions: Chiralpak AD-H, hexane/2-propanol = 99/1, flow = 0.8 mL min−1, wavelength = 230 nm, tminor= 27.3 and tmajor = 31.5 min]; 1H-NMR (400 MHz, CDCl3): δ = 7.34-7.26 (m, 3H), 7.06-7.00 (t, J = 8.5 Hz, 2H), 4.66 (t, J = 6.2 Hz, 1H), 1.78-1.61 (m, 3H), 1.35-1.26 (m, 4H), 0.87 (t, J = 6.2 Hz, 3H); 13C-NMR (100 MHz, CDCl3): δ = 162.2 (d, J = 245 Hz), 140.7 (d, J = 2.86 Hz), 127.6 (d, J = 7.63 Hz), 115.3 (d, J = 20.98 Hz), 74.1, 39.0, 28.0, 22.7, 14.1; HRMS m/z; calcd. for C11H15FO: 182.11069; found 182.11040.
(R)-1-(3-Methoxyphenyl)-1-pentanol (4bh) [35]: [α]D20 = 30.2 (c 0.90, THF), 90% ee [HPLC conditions: Chiralcel OD, hexane/2-propanol = 99/1, flow = 0.7 mL min−1, wavelength = 254 nm, tmajor = 58.3 and tminor = 67.9 min]; 1H-NMR (400 MHz, CDCl3): δ= 7.26 (s, 1H), 7.14-7.02 (m, 2H), 6.92 (t, J = 8.4 Hz, 1H), 4.64 (t, J = 6.6 Hz, 1H), 3.81 (s, 3H), 1.83-1.63 (m, 3H), 1.39-1.19 (m, 4H), 0.88 (t, J = 7.0 Hz, 3H); HRMS m/z; calcd. for C12H18O2: 194.13068; found 194.13040.
1-(3-Chlorophenyl)-1-pentanol (4bi) [32]: [α]D20 = 24.0 (c 0.39, CHCl3), 90% ee [HPLC conditions: Chiralcel OD, hexane/2-propanol = 99/1, flow = 0.8 mL min−1, wavelength = 230 nm, tminor = 23.1 and tmajor = 25.4 min]; 1H-NMR (400 MHz, CDCl3): δ = 7.40-7.18 (m, 4H), 4.64 (t, J = 6.6 Hz, 1H), 1.83-1.61 (m, 2H), 1.41-1.20 (m, 4H), 0.88 (t, J = 7.0 Hz, 3H); HRMS m/z; calcd. for C11H15ClO: 198.08114; found 198.08097.
1-(3-Fluoro-4-methoxyphenyl)-1-pentanol (4bk): [α]D20 = 23.6 (c 0.33, CHCl3), 87% ee [HPLC conditions: Chiralcel OD, hexane/2-propanol = 99/1, flow = 0.75 mL min−1, wavelength = 230 nm, tmajor = 37.0 and tminor = 40.7 min]; 1H-NMR (400 MHz, CDCl3): δ = 6.94-6.89 (m, 2H), 6.84-6.79 (m, 1H), 4.65 (t, J = 6.6 Hz, 1H), 3.82 (s, 3H), 1.84-1.64 (m, 3H), 1.42-1.22 (m, 4H), 0.89 (t,J = 7.4 Hz, 3H); 13C-NMR (100 MHz, CDCl3): δ = 152.4 (d, J = 246 Hz), 146.9 (d, J = 10.49 Hz), 138.2 (d, J = 4.77 Hz), 121.7 (d, J = 3.81 Hz), 113.8 (d, J = 18.12 Hz), 113.2, 73.9, 56.4, 38.8, 28.0, 22.7, 14.1; HRMS m/z; calcd. for C12H17FO2: 212.12126; found 212.12104.
(R)-1-(5-Benzo[d][1,3]dioxolyl)-1-pentanol (4bl) [36]: [α]D20 = 62.4 (c 0.48, CHCl3), 99% ee [HPLC conditions: Chiralcel OD, hexane/2-propanol = 99/1, flow = 0.8 mL min−1, wavelength = 254 nm, tminor= 39.9 (S) and tmajor = 44.8 min]; 1H-NMR (400 MHz, CDCl3): δ = 6.87 (s, 1H), 6.78 (s, 2H), 5.95 (s, 2H), 4.58 (t, J = 7.2 Hz, 1H), 1.83-1.59 (m, 3H), 1,40-1.18 (m, 4H), 0.88 (t, J = 7.0 Hz, 3H).
(R)-1-Phenyl-1-hexanol (4ca) [37]: [α]D23 = 37.5 (c 0.82, CHCl3), 94% ee [HPLC conditions: Chiralcel OD, hexane/2-propanol = 99/1, flow = 0.9 mL min−1, wavelength = 254 nm, tmajor = 19.2 and tminor = 22.4 (S) min]; 1H-NMR (400 MHz, CDCl3): δ = 7.34-7.25 (m, 5H), 4.66 (t, J = 6.8 Hz, 1H), 1.87-1.61 (m, 3H), 1.42-1.22 (m, 6H), 0.88 (t, J = 7.0 Hz, 3H); HRMS m/z; calcd. for C12H18O: 178.1358; found 178.1353.
(R)-1-Phenyl-1-heptanol (4da) [38,39]: [α]D23 = 31.2 (c 0.85, CHCl3 ), 93% ee [HPLC conditions: Chiralcel OD, hexane/2-propanol = 99/1, flow = 0.9 mL min−1, wavelength = 254 nm, tmajor = 19.9 and tminor = 22.9 min]; 1H-NMR (400 MHz, CDCl3): δ = 7.34-7.25 (m, 6H), 4.66 (t, J = 6.6 Hz, 1H), 1.84-1.56 (m, 2H), 1.40-1.25 (m, 8H), 1.42-1.23 (m, 12H), 0.86 (t, J = 6.6 Hz, 3H); HRMS m/z; calcd. for C13H20O: 192.1514; found 192.1511.
(R)-1-Phenyl-1-nonanol (4ea) [40,41]: [α]D19 = 27.3 (c 1.42, CHCl3 ), 92% ee [HPLC conditions: Chiralcel OD, hexane/2-propanol = 99/1, flow = 0.7 mL min−1, wavelength = 254 nm, tmajor = 25.0 and tminor = 31.8 min]; 1H-NMR (400 MHz, CDCl3): δ = 7.34-7.25 (m, 5H), 4.66 (t, J = 6.1 Hz, 1H), 1.93-1.65 (m, 3H), 1.42-1.19 (m, 12H), 0.87 (t, J = 6.6 Hz, 3H); HRMS m/z; calcd. for C15H24O: 220.1827; found 220.1822.
(R)-1,3-Diphenyl-1-propanol (4fa) [42]: [α]D20 = 15.6 (c 0.85, CH2Cl2), 92% ee [HPLC conditions: Chiralcel OD, hexane/2-propanol = 95/5, flow = 0.7 mL min−1, wavelength = 254 nm, tminor = 28.2 and tmajor = 33.7 min]; 1H-NMR (400 MHz, CDCl3): δ = 7.38-7.14 (m, 10H), 4.68 (t, J = 6.6 Hz, 1H), 2.77-2.65 (m, 2H), 2.15-2.02 (m, 2H), 1.92 (s, 1H); HRMS m/z; calcd. for C15H16O: 212.1201; found 212.1197.
(R)-Cyclohexyl(phenyl)methanol (4ga) [33]: [α]D20 = 39.5 (c 0.23, CHCl3), 94% ee [HPLC conditions: Chiralcel OD, hexane/2-propanol = 99/1, flow = 0.4 mL min−1, wavelength = 254 nm, tminor = 45.2 and tmajor = 48.8 min]; 1H-NMR (400 MHz, CDCl3): δ = 7.35-7.24 (m, 5H), 4.35 (d, J = 7.3 Hz, 1H), 2.03-1.60 (m, 6H), 1.38-0.90 (m, 6H); HRMS m/z; calcd. for C13H18O: 190.1358; found 190.1358.
(R)-2-Methyl-1-phenyl-1-propanol (4ha) [33]: [α]D19 = 11.3 (c 0.42, CHCl3), 96% ee [HPLC conditions: Chiralpak AD-H, hexane/2-propanol = 99/1, flow = 1.0 mL min−1, wavelength = 254 nm, tmajor = 17.6 and tminor = 18.8 min]; 1H-NMR (400 MHz, CDCl3): δ = 7.35-7.28 (m, 5H), 4.35 (d, J = 6.8 Hz, 1H), 2.00-1.89 (m, 1H), 1.82 (broad s, 1H), 1.00 (d, J = 6.8 Hz, 3H), 0.79 (d,J = 6.8 Hz, 3H); HRMS m/z; calcd. for C10H14O: 150.1045; found 150.1043.
(R)-2-Ethyl-1-phenyl-1-butanol (4ja) [43]: [α]D20 = −10.6 (c 0.35, CHCl3), 91% ee [HPLC conditions: Chiralcel OD, hexane/2-propanol = 99/1, flow = 0.5 mL min−1, wavelength = 254 nm, tmajor = 29.2 and tminor = 44.5 min]; 1H-NMR (400 MHz, CDCl3): δ = 7.36-7.24 (m, 5H), 4.63 (d, J = 6.3 Hz, 1H), 1.77 (broad s, 1H), 1.60-1.40 (m, 2H), 0.90-0.82 (m, 6H); HRMS m/z; calcd. for C12H18O: 178.1358; found 178.1354.
(R)-2,2-Dimethyl-1-phenyl-1-propanol (4ka) [33]: [α]D20 = 19.2 (c 0.48, CHCl3), 99% ee [HPLC conditions: Chiralpak OD, hexane/2-propanol = 98/2, flow = 0.9 mL min−1, wavelength = 254 nm, tminor = 7.9 and tmajor = 11.7 min]; 1H-NMR (400 MHz, CDCl3): δ = 7.32-7.26 (m, 5H), 4.40 (s, 1H), 0.93 (s, 9H).

3.3. General Procedure for Arylation of α-Ketoesters (Table 3)

A flask was charged with [RuCl2(p-cymene)]2 (0.005 mmol, 1 mol%) and (R,R)-Me-bipam (0.011 mmol, 2.2 mol%) under a nitrogen atmosphere. Toluene (3.0 mL) was added to the flask and the mixture was then stirred at room temperature for 30 min to prepare the catalyst. Isopropyl pyruvate (2a, 0.5 mmol), phenylboronic acid (3a, 0.75 mmol), KF (1.0 mmol), and H2O (0.3 mL) were then added to this catalyst solution. The reaction mixture was stirred at 80 °C for 16 h, at which time the crude reaction mixture extracted using ethyl acetate, washed with saturated NH4Cl and brine, and dried over MgSO4. Chromatography of the crude reaction mixture on silica gel gave (S)-isopropyl 2-hydroxy-2-phenylpropanoate (5aa) in 85% yield [44,45,46]. [α]D22 = +40.00 (c 4.2, CHCl3), 93% ee [HPLC conditions: Chiralcel OJ-H column, hexane/2-propanol = 98/2, flow = 1.0 mL/min, wavelength = 230 nm, tmajor = 8.0 min and tminor = 16.4 min]; 1H-NMR (400 MHz, CDCl3) δ = 7.54-7.57 (m, 2H), 7.23-7.36 (m, 4H), 5.05 (sep, J = 6.4 Hz, 1H), 3.85 (s, 1H), 1.75 (s, 3H), 1.28 (d, J = 6.4 Hz, 3H), 1.17 (d, J = 6.0 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ = 175.3, 143.1, 128.3, 127.7, 125.2, 75.7, 70.4, 26.7, 21.8, 21.5; HRMS m/z; calcd. for C12H16O3Na: 231.09917; found 231.09919.
Isopropyl 2-hydroxy-2-(4-tolyl)propanoate (5ac): [α]D22 = +34.40 (c 4.8, CHCl3), 89% ee [HPLC conditions: Chiralcel OJ-H column, hexane/2-propanol = 98/2, flow = 1.0 mL/min, wavelength = 230 nm, tmajor = 7.7 min and tmainor = 14.8 min]; 1H-NMR (400 MHz, CDCl3) δ = 7.43 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 8.2 Hz, 2H), 5.04 (sep, J = 6.4 Hz, 1H), 3.78 (s, 1H), 2.33 (s, 3H), 1.73 (s, 3H), 1.27 (d, 3H, J = 6.5 Hz), 1.18 (d, J = 6.4 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ = 175.4, 140.2, 137.4, 129.0, 125.1, 75.5, 70.3, 26.7, 21.8, 21.5, 21.1; HRMS m/z; calcd. for C13H18O3Na: 245.11482; found 245.11494.
Isopropyl 2-hydroxy-2-(4-methoxyphenyl)propanoate (5ad): [α]D22 = +37.85 (c 5.1, CHCl3), 91% ee [HPLC conditions: Chiralcel OJ-H column, hexane/2-propanol = 98/2, flow = 1.0 mL/min, wavelength = 230 nm, tmajor = 14.1 min and tminor = 31.9 min]; 1H-NMR (400 MHz, CDCl3) δ = 7.45 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 5.03 (sep, J = 6.4 Hz, 1H), 3.79 (s, 4H), 1.72 (s, 3H), 1.27 (d, J = 6.4 Hz, 3H), 1.16 (d, J = 6.0 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ = 175.5, 159.1, 135.2, 126.5, 113.6, 75.3, 70.3, 55.3, 26.7, 21.8, 21.5; HRMS m/z; calcd. for C13H18O4Na: 261.10973; found 261.10988.
Isopropyl 2-hydroxy-2-(4-fluorophenyl)propanoate (5af): [α]D22 = +39.19 (c 5.0, CHCl3), 93% ee [HPLC conditions: Chiralcel OJ-H column, hexane/2-propanol = 98/2, flow = 1.0 mL/min, wavelength = 230 nm, tmajor = 7.2 min and tminor = 10.0 min]; 1H-NMR (400 MHz, CDCl3) δ = 7.50-7.55 (m, 2H), 6.98-7.03 (m, 2H), 5.04 (sep, J = 6.4 Hz, 1H), 3.87 (d, J = 0.9 Hz, 1H), 1.73 (s, 3H), 1.27 (d, J = 6.4 Hz, 3H), 1.16 (d, J = 6.0 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ = 175.1, 162.4 (d, J = 246 Hz), 138.8 (d, J = 2.86 Hz), 127.2 (d, J = 8.58 Hz), 115.1 (d, J = 21.93 Hz), 75.2, 70.5, 26.9, 21.7, 21.5; HRMS m/z; calcd. for C12H15O3FNa: 249.08974; found 249.08998.
Isopropyl 2-hydroxy-2-(4-trifluoromethylphenyl)propanoate (5ag): [α]D22 = +30.04 (c 4.2, CHCl3), 92% ee [HPLC conditions: Chiralcel OJ-H column, hexane/2-propanol = 98/2, flow = 1.0 mL/min, wavelength = 230 nm, tmajor = 8.6 min and tminor = 11.6 min]; 1H-NMR (400 MHz, CDCl3) δ = 7.70 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 8.2 Hz, 2H), 5.05 (sep, J = 6.4 Hz, 1H), 3.91 (s, 1H), 1.76 (s, 3H), 1.29 (d, J = 6.4 Hz, 3H), 1.18 (d, J = 6.4 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ = 174.6, 146.9, 130.0 (q, J = 32.4 Hz), 125.8, 125.5, 125.2 (q, J = 3.81 Hz), 122.8, 75.5, 70.9, 27.0, 21.7, 21.5; HRMS m/z; calcd. for C13H15O3F3Na: 299.08655; found 299.08701.
Isopropyl 2-hydroxy-2-(3-methoxyphenyl)propanoate (5ah): [α]D22 = +26.54 (c 5.1, CHCl3), 92% ee [HPLC conditions: Chiralcel OJ-H column, hexane/2-propanol = 98/2, flow = 1.0 mL/min, wavelength = 230 nm, tmajor = 10.4 min and tmainor = 20.5 min]; 1H-NMR(400 MHz, CDCl3) δ = 7.23-7.27 (m, 1H), 7.11-7.13 (m, 2H), 6.80-6.83 (m, 1H), 5.05 (sep, J = 6.4 Hz, 1H), 3.80 (s, 4H), 1.73 (s, 3H), 1.28 (d, J = 6.4 Hz, 3H), 1.19 (d, J = 6.4 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ = 175.1, 159.6, 144.8, 129.3, 117.6, 113.2, 111.0, 75.7, 70.4, 55.3, 26.8, 21.7, 21.5; HRMS m/z; calcd. for C13H18O4Na: 261.10973; found 261.10993.
Isopropyl 2-hydroxy-2-(3-fluorophenyl)propanoate (5aj): [α]D22 = +34.50 (c 4.0, CHCl3), 90% ee [HPLC conditions: Chiralcel OJ-H column, hexane/2-propanol = 98/2, flow = 1.0 mL/min, wavelength = 230 nm, tmajor = 5.9 min and tminor = 7.7 min]; 1H-NMR (400 MHz, CDCl3) δ = 7.25-7.34 (m, 3H), 6.94-6.99 (m, 1H), 5.05 (sep, J = 6.4 Hz, 1H), 3.86 (s, 1H), 1.73 (s, 3H), 1.29 (d, J = 6.4 Hz, 3H), 1.18 (d, J = 6.4 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ = 174.8, 162.8 (d, J = 245 Hz), 145.7 (d, J = 7.63 Hz), 129.8 (d, J = 8.58 Hz), 121.0, 114.6 (d, J = 20.98 Hz), 112.7 (d, J = 23.84 Hz), 75.3, 70.7, 26.8, 21.7, 21.5; HRMS m/z; calcd. for C12H15O3FNa: 249.08974; found 249.08997.
Isopropyl 2-hydroxy-2-(3-fluoro-4-methoxyphenyl)propanoate (5ak): [α]D22 = +33.22 (c 5.2, CHCl3), 87% ee [HPLC conditions: Chiralcel OJ-H column, hexane/2-propanol = 98/2, flow = 1.0 mL/min, wavelength = 230 nm, tmajor = 13.1 min and tminor = 21.2 min]; 1H-NMR (400 MHz, CDCl3) δ = 7.23-7.30 (m, 2H), 6.90 (t, J = 8.7 Hz, 1H), 5.03 (sep, J = 6.4 Hz, 1H), 3.86 (s, 4H), 1.69 (s, 3H), 1.27 (d, J = 6.4 Hz, 3H), 1.17 (d, J = 6.4 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ = 175.0, 152.0 (d, J = 245 Hz), 147.1 (d, J = 11.44 Hz), 136.1 (d, J = 5.72 Hz), 121.1 (d, J = 2.86 Hz), 113.6 (d, J = 20 Hz), 112.9, 74.9, 70.6, 56.3, 26.8, 21.7, 21.5; HRMS m/z; calcd. for C13H17O4FNa: 279.10031; found 279.10049.
Isopropyl 2-hydroxy-2-phenylbutanoate (5ba): [α]D24 = +38.66 (c 5.2, CHCl3), 95% ee [HPLC conditions: Chiralcel OJ-H column, hexane/2-propanol = 98/2, flow = 1.0 mL/min, wavelength = 230 nm, tmajor = 5.6 min and tminor = 11.0 min]; 1H-MR (400 MHz, CDCl3) δ = 7.58-7.61 (m, 2H), 7.24-7.36 (m, 3H), 5.06 (sep, J = 6.4 Hz, 1H), 3.81 (d, J = 0.92 Hz, 1H), 2.16-2.26 (m, 1H), 1.94-2.03 (m, 1H), 1.30 (d, J = 6.4 Hz, 3H), 1.19 (d, J = 6.4 Hz, 3H), 0.92 (t, J =7.3 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ = 175.0, 142.2, 128.2, 127.6, 125.6, 78.6, 70.4, 32.8, 21.8, 21.6, 8.1; HRMS m/z; calcd. for C13H18O3Na: 245.11482; found 245.11495.
Isopropyl 2-hydroxy-2-(4-tolyl)butanoate (5bc): [α]D25 = +32.62 (c 4.8, CHCl3), 91% ee [HPLC conditions: Chiralcel OJ-H column, hexane/2-propanol = 98/2, flow = 1.0 mL/min, wavelength = 230 nm, tmajor = 6.0 min and tminor = 10.2 min]; 1H-NMR (400 MHz, CDCl3) δ = 7.47 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 8.2 Hz, 3H), 5.04 (sep, J = 6.4 Hz, 1H), 3.76 (s, 1H), 2.32 (s, 3H), 2.15-2.24 (m, 1H), 1.91-2.00 (m, 1H), 1.29 (d, J = 6.4 Hz, 3H), 1.19 (d, J = 6.4 Hz, 3H), 0.91 (t, J =7.3 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ = 175.1, 139.3, 137.2, 128.9, 125.5, 78.5, 70.34, 32.8, 21.8, 21.6, 21.1, 8.1; HRMS m/z; calcd. for C14H20O3Na: 259.13047; found 259.13047.
Isopropyl 2-hydroxy-2-(4-fluorophenyl)butanoate (5bf): [α]D24 = +39.18 (c 5.3, CHCl3), 93% ee [HPLC conditions: Chiralcel OJ-H column, hexane/2-propanol = 98/2, flow = 1.0 mL/min, wavelength = 230 nm, tmajor = 5.5 min and tminor = 7.4 min]; 1H-NMR (400 MHz, CDCl3) δ = 7.55-7.58 (m, 2H), 7.00 (t, J = 8.6 Hz, 2H), 5.05 (sep, J = 6.4 Hz, 1H), 3.84 (s, 1H), 2.13-2.22 (m, 1H), 1.90-1.99 (m, 1H), 1.30 (d, J = 6.4 Hz, 3H), 1.17 (d, J = 6.4 Hz, 3H), 0.90 (t, J = 7.3 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ = 174.80, 162.32 (d, J = 245 Hz), 137.8 (d, J = 2.86 Hz), 127.5 (d, J = 8.58 Hz), 114.9 (d, J = 20.98 Hz), 78.2, 70.6, 32.9, 21.8, 21.6, 8.0; HRMS m/z; calcd. for C13H17O3FNa: 263.10539; found 263.10540.
Isopropyl 2-hydroxy-2-(3-methoxyphenyl)butanoate (5bh): [α]D25 = +26.66 (c 3.1, CHCl3), 91% ee [HPLC conditions: Chiralcel OJ-H column, hexane/2-propanol = 98/2, flow = 1.0 mL/min, wavelength = 230 nm, tmajor = 8.0 min and tminor = 12.7 min]; 1H-NMR (400 MHz, CDCl3) δ = 7.16-7.26 (m, 3H), 6.79-6.82 (m, 1H), 5.05 (sep, J = 6.4 Hz, 1H), 3.79 (s, 4H), 2.14-2.23 (m, 1H), 1.92-2.01 (m, 1H), 1.30 (d, J = 6.4 Hz, 3H), 1.20 (d, J = 6.4 Hz, 3H), 0.91 (t, J = 7.3 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ = 174.8, 159.5, 143.9, 129.1, 118.0, 113.1, 111.3, 78.6, 70.5, 55.3, 32.9, 21.8, 21.61, 8.1; HRMS m/z; calcd. for C12H20O4Na: 275.12593; found 275.12485.
Isopropyl 2-hydroxy-3-methyl-2-phenylbutanoate (5ca): [α]D22 = +5.95 (c 3.4, CHCl3), 94% ee [HPLC conditions: Chiralcel OJ-H column, hexane/2-propanol = 98/2, flow = 1.0 mL/min, wavelength = 230 nm, tmajor = 4.1 min and tminor = 5.2 min]; 1H-NMR (400 MHz, CDCl3) δ = 7.62-7.65 (m, 2H), 7.23-7.34 (m, 3H), 5.03 (sep, J = 6.6 Hz, 1H), 3.71 (s, 1H), 2.59 (sep, J = 6.9 Hz, 1H), 1.32 (d, J = 6.0 Hz, 3H), 1.17 (d, J = 6.0 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H), 0.68 (d, J = 6.9 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ = 175.3, 141.5, 128.0, 127.4, 126.0, 80.7, 70.5, 35.8, 21.8, 21.6, 17.1, 15.9; HRMS m/z; calcd. for C14H20O3Na: 259.13047; found 259.13042.
Isopropyl 2-hydroxy-3-methyl-2-(4-methoxyphenyl)butanoate (5cd): [α]D22 = +36.53 (c 3.5, CHCl3), 90% ee [HPLC conditions: Chiralcel OJ-H column, hexane/2-propanol = 98/2, flow = 1.0 mL/min, wavelength = 230nm, tmajor = 5.9 min and tminor = 7.1 min]; 1H-NMR (400 MHz, CDCl3) δ = 7.54 (d, J = 9.1 Hz, 2H), 6.85 (d, J = 9.1 Hz, 2H), 5.02 (sep, J = 6.4 Hz, 1H), 3.79 (s, 3H), 3.68 (s, 1H), 2.54 (sep,J = 6.9 Hz, 1H), 1.31 (d, J = 6.4 Hz, 3H), 1.17 (d, J = 6.4 Hz, 3H), 0.96 (d, J = 6.4 Hz, 3H), 0.68 (d, J = 7.3 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ = 175.5, 158.9, 133.6, 127.2, 113.3, 80.4, 70.4, 55.3, 35.7, 21.8, 21.6, 17.0, 15.9; HRMS m/z; calcd. for C15H22O4Na: 289.14103; found 289.14093.
Isopropyl 2-hydroxy-2-phenyl-2-(4-tolyl)acetate (5dc): [α]D24 = −4.14 (c 5.2, CHCl3), 92% ee [HPLC conditions: Chiralcel OJ-H column, hexane/2-propanol = 98/2, flow = 1.0 mL/min, wavelength = 230 nm, tmajor = 18.4 min and tminor = 20.8 min]; 1H-NMR (400 MHz, CDCl3) δ = 7.42-7.44 (m, 2H), 7.29-7.34 (m, 5H), 7.13 (d, J = 8.2 Hz, 2H), 5.14 (sep, J = 6.4 Hz, 1H), 4.26 (s, 1H), 2.34 (s, 3H), 1.24 (t, J = 6.4 Hz, 6H); 13C-NMR (100 MHz, CDCl3) δ = 174.2, 142.3, 139.3, 137.7, 128.8, 128.0, 127.9, 127.5, 127.4, 80.7, 71.2, 21.6, 21.2; HRMS m/z; calcd. for C18H20O3Na: 307.13047; found 307.13070.
Isopropyl 2--2-hydroxy-2-(4-methoxyphenyl)-2-phenylacetate (5dd): [α]D25 = +2.10 (c 4.0, CHCl3), 86% ee [HPLC conditions: Chiralcel AS-H column, hexane/2-propanol = 9/1, flow = 1.0 mL/min, wavelength = 230 nm, tmajor = 20.2 min and tminor = 22.8 min]; 1H-NMR (400 MHz, CDCl3) δ = 7.43-7.45 (m, 2H), 7.30-7.36 (m, 5H), 6.87-6.85 (d, J = 8.7 Hz, 2H), 5.15 (sep, J = 6.4 Hz, 1H), 4.28 (d, J = 2.3 Hz, 1H), 3.80 (s, 3H), 1.24 (dd, J = 6.4, 6.4Hz, 6H); 13C-NMR (100 MHz, CDCl3) δ = 174.2, 159.3, 142.4, 134.4, 128.8, 128.1, 128.0, 127.5, 113.4, 80.5, 71.2, 55.4, 21.6, 21.6; HRMS m/z; calcd. for C18H20O4Na: 323.12593; found 323.12614.
Isopropyl 2-(4-chlorophenyl)-2-hydroxy-2-phenylacetate (5de) [47]: [α]D20 = +17.87 (c 4.9, CHCl3), 91% ee [HPLC conditions: Chiralcel AD-H column, hexane/2-propanol = 9/1, flow = 1.0 mL/min, wavelength = 230 nm, tminor = 18.9 min and tmajor = 20.0 min]; 1H-NMR (400 MHz, CDCl3) δ = 7.28-7.40 (m, 9H), 5.15 (sep, J = 6.4 Hz, 1H), 4.30 (s, 1H), 1.24 (dd, J = 6.4, 6.0 Hz, 6H); 13C-NMR (100 MHz, CDCl3) δ = 173.6, 142.0, 140.6, 134.0, 129.0, 128.3, 128.2, 128.2, 127.3, 80.4, 71.5, 21.6; HRMS m/z; calcd. for C17H17O3ClNa: 327.07584; found 327.07589.
Isopropyl 2-(4-fluorophenyl)-2-hydroxy-2-phenylacetate (5df): [α]D24 = +15.96 (c 4.9, CHCl3), 94% ee [HPLC conditions: Chiralcel OJ-H column, hexane/2-propanol = 98/2, flow = 1.0 mL/min, wavelength = 230 nm, tmajor = 10.3 min and tminor = 11.4 min]; 1H-NMR (400 MHz, CDCl3) δ = 7.30-7.44 (m, 7H), 7.00 (t, J = 8.7 Hz, 2H), 5.15 (sep, J = 6.4 Hz, 1H), 4.31 (s, 1H), 1.24 (dd, J = 6.4, 6.4 Hz, 6H); 13C-NMR (100 MHz, CDCl3) δ = 173.9, 162.5 (d, J = 247.0 Hz), 142.1, 137.9 (d, J = 2.86 Hz), 129.40 (d, J = 8.58 Hz), 128.23, 128.17, 127.3, 114.9 (d, J = 20.98 Hz), 80.4, 71.4, 21.6; HRMS m/z; calcd. for C17H17O3FNa: 311.10539; found 311.10545.
Isopropyl 2-hydroxy-2-(3-methoxyphenyl)-2-phenylacetate (5dh): [α]D25 = −3.95 (c 2.7, CHCl3), 92% ee [HPLC conditions: Chiralcel AD-H column, hexane/2-propanol = 9/1, flow = 0.85 mL/min, wavelength = 230 nm, tmajor = 14.5 min and tminor = 15.3 min]; 1H-NMR (400 MHz, CDCl3) δ = 7.41-7.44 (m, 2H), 7.22-7.35 (m, 4H), 7.01-7.03 (m, 2H), 6.84-7.03 (m, 1H), 5.15 (sep, J = 6.4 Hz, 1H), 4.32 (s, 1H), 3.76 (s, 3H), 1.25 (t, J = 6.5 Hz, 6H); 13C-NMR (100 MHz, CDCl3) δ = 173.9, 159.4, 143.6, 142.0, 129.1, 128.1, 128.0, 127.5, 120.0, 113.6, 113.2, 80.8, 71.3, 55.3, 21.6, 21.6; HRMS m/z; calcd. for C18H20O4Na: 323.12593; found 323.12638.
Isopropyl 2-(3-chlorophenyl)-2-(4-fluorophenyl)-2-hydroxyacetate (5ei): [α]D22 = +1.23 (c 5.3, CHCl3), 90% ee [HPLC conditions: Chiralcel OJ-H column, hexane/2-propanol = 98/2, flow = 1.0 mL/min, wavelength = 230 nm, tmajor = 10.9 min and tminor = 12.2 min]; 1H-NMR (400 MHz, CDCl3) δ = 7.25-7.45 (m, 6H), 7.02 (m, 2H), 5.16 (sep, J = 6.4 Hz, 1H), 1.25 (d, J = 6.4 Hz, 6H); 13C-NMR (100 MHz, CDCl3) δ = 173.3, 162.6 (d,J = 247 Hz), 143.9, 137.4 (d, J = 2.86 Hz), 134.2, 129.4, 129.2 (d, J = 8.58 Hz), 128.4, 127.6, 125.7, 115.1 (d, J = 20.98 Hz), 79.9, 71.8, 21.6; HRMS m/z; calcd. for C17H16O3ClFNa: 345.06642; found 345.06639.

4. Conclusions

In summary, we have developed a catalytic asymmetric arylation of aliphatic aldehydes and α-ketoesters with arylboronic acids by RuCl2(p-cymene)/Me-BIPAM catalyst. With this catalyst system, a broad range of enantiopure alkyl(aryl)methanols and α-hydroxy-esters were easily prepared. Studies on further applications of Me-BIPAM to other C-C bond-forming reactions are in progress in our group.

Acknowledgments

This work was supported in part by the Global COE Program (Project No. B01, Catalysis as the Basis for Innovation in Materials Science) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

References and Notes

  1. Miyaura, N.; Yamamoto, Y. Boron in Comprehensive Organometallic Chemistry III; Crabtree, R.H., Mingos, M.P., Knochel, P., Eds.; Elsevier: Oxford, UK, 2007; Volume 9, pp. 146–244. [Google Scholar]
  2. Miyaura, N. Metal-catalyzed reactions of organoboronic acids and esters. Bull. Chem. Soc. Jpn. 2008, 81, 1535–1553. [Google Scholar] [CrossRef]
  3. Yamamoto, Y.; Nishikata, T.; Miyaura, N. Rhodium (I)- or palladium (II)-catalyzed 1,4-additions of organoboron, -silicon and -bismuth compounds to electron-deficient alkenes. J. Synth. Org. Chem. Jpn. 2006, 64, 1112–1121. [Google Scholar] [CrossRef]
  4. Yamamoto, Y.; Nishikata, T.; Miyaura, N. 1,4-Addition of arylboron, -silicon, and -bismuth compounds to α,β-unsaturated carbonyl compounds catalyzed by dicationic palladium(II) complexes. Pure Appl. Chem. 2008, 80, 807–817. [Google Scholar] [CrossRef]
  5. Miyaura, N. On palladium (II)-catalyzed additions of arylboronic acids to electron-deficient alkenes, aldehydes, imines and nitriles. Synlett 2009, 2039–2050. [Google Scholar]
  6. Yamamoto, Y.; Kurihara, K.; Sugishita, N.; Oshita, K.; Piao, D.-G.; Miyaura, N. Chiral bis-phosphoramidities based on linked-BINOL for rhodium-catalyzed 1,4-addition of arylboronic acids to α,β-unsaturated carbonyl compounds. Chem. Lett. 2005, 34, 1224–1225. [Google Scholar] [CrossRef]
  7. Kurihara, K.; Sugishita, N.; Oshita, K.; Piao, D.-G.; Yamamoto, Y.; Miyaura, N. Enantioselective 1,4-addition of arylboronic acids to α,β-unsaturated carbonyl compounds catalyzed by rhodium(I)-chiral phosphoramidite complexes. J. Organomet. Chem. 2007, 692, 428–435. [Google Scholar]
  8. Kurihara, K.; Yamamoto, Y.; Miyaura, N. N-linked bidentate phosphoramidite ligand (N-Me-BIPAM) for rhodium-catalyzed asymmetric addition of arylboronic acids to N-sulfonylarylaldimines. Adv. Synth. Catal. 2009, 351, 260–270. [Google Scholar] [CrossRef]
  9. Kurihara, K.; Yamamoto, Y.; Miyaura, N. A chiral bidentate phosphoramidite (Me-BIPAM) for Rh-catalyzed asymmetric hydrogenation of α-dehydroamino esters, enamides and dimethyl itaconate. Tetrahedron Lett. 2009, 50, 3158–3160. [Google Scholar]
  10. Yamamoto, Y.; Kurihara, K.; Miyaura, N. Me-bipam for enantioselective ruthenium (II)-catalyzed arylation of aldehydes with arylboronic acids. Angew. Chem. Int. Ed. 2009, 48, 4414–4416. [Google Scholar] [CrossRef]
  11. Abenhaïm, D.; Boireau, G.; Deberyl, A. Asymmetric synthesis using chiral lithium alkoxytrialkylaluminates: Obtention of (2S)-2-hydroxy-2-phenyl-4-methylpentanoic acid with 85% optical purity. J. Org. Chem. 1985, 50, 4045–4047. [Google Scholar] [CrossRef]
  12. Mash, E.A.; Fryling, J.A. Enantioselective pure acetals in organic synthesis. 2. Diastereoselective alkylation of enantiomeric lithio alkyl lactyl tetrahydropyranosides and related enolates. J. Org. Chem. 1991, 56, 1094–1098. [Google Scholar] [CrossRef]
  13. Rzeszotarski, W.J.; Gibson, R.E.; Eckelman, W.C.; Simms, D.A.; Jagoda, E.M.; Ferreira, N.L.; Reba, R.C. Analogues of 3-quiuclidinyl benzilate. J. Med. Chem. 1982, 25, 1103–1106. [Google Scholar] [CrossRef]
  14. He, X.-C.; Elitel, E.L. Highly enantioselective synthesis of α-hydroxyacids using N-benzyl-4,4,7α-trimethyl-trans-octahydro-1,3-benzoxazine as a chiral adjuvant. Tetrahedron 1987, 43, 4979–4987. [Google Scholar] [CrossRef]
  15. Muramatsu, Y.; Harada, T. Catalytic asymmetric alkylation of aldehydes with Grignard reagents. Angew. Chem. Int. Ed. 2008, 47, 1088–1090. [Google Scholar] [CrossRef]
  16. DiMauro, E.; Kozlowski, M.C. Development of bifunctional salen catalysts: Rapid, chemoselective alkylations of α-ketoesters. J. Am. Chem.Soc. 2002, 124, 12668–12669. [Google Scholar] [CrossRef]
  17. DiMauro, E.; Kozlowski, M.C. The first catalytic asymmetric addition of dialkylzincs to α-ketoesters. Org. Lett. 2002, 4, 3781–3784. [Google Scholar] [CrossRef]
  18. Funabashi, K.; Jachmann, M.; Kanai, M.; Shibasaki, M. Multicenter strategy for the development of catalytic enantioselective nucleophilic alkylation of ketones: Me2Zn addition to a ketoesters. Angew. Chem. Int. Ed. 2003, 42, 5489–5492. [Google Scholar] [CrossRef]
  19. Fennie, M.W.; DiMauro, E.F.; O’Brien, E.M.; Annamalai, V.; Kozlowski, M.C. Mechanism and scope of salen bifunctional catalysts in asymmetric aldehydes and α-ketoester alkylation. Tetrahedron 2005, 61, 6249–6265. [Google Scholar] [CrossRef]
  20. Blay, G.; Fernández, I.; Marco-Aleixandre, A.; Pedro, J.R. Enantioselective addition of dimethylzinc to α-keto esters. Synthesis 2007, 3754–3757. [Google Scholar]
  21. Wieland, L.C.; Deng, H.; Snapper, M.L.; Hoveyda, A.H. Al-catalyzed enantioselective alkylation of α-ketoesters by dialkylzinc reagents. Enhancement of enantioselectivity and reactivity by an achiral Lewis base additive. J. Am. Chem. Soc. 2005, 127, 15453–15456. [Google Scholar]
  22. Oi, S.; Moro, M.; Fukuhara, H.; Kawanishi, T.; Inoue, Y. Rhodium-catalyzed addition of arylstannanes to carbon-heteroatom double bond. Tetrahedron 2003, 59, 4351–4361. [Google Scholar] [CrossRef]
  23. Sakai, M.; Ueda, M.; Miyaura, N. Rhodium-catalyzed addition of organoboronic acids to aldehydes. Angew. Chem. Int. Ed. 1998, 37, 3279–3281. [Google Scholar] [CrossRef]
  24. Ganci, G.R.; Chisholm, J.D. Rhodium-catalyzed addition of aryl boronic acids to 1,2-diketonesters and 1,2-ketoesters. Tetrahedron Lett. 2007, 48, 8266–8269. [Google Scholar] [CrossRef]
  25. Miyamura, S.; Satoh, T.; Miura, M. Rhodium-catalyzed diarylation of oxalates using arylboron compounds. J. Org. Chem. 2007, 72, 2255–2257. [Google Scholar] [CrossRef]
  26. He, P.; Lu, Y.; Hu, Q.-S. Phosphinite- and phosphite-based type I palladacycles as highly active catalysts for addition reactions of arylboronic acids with aldehydes, α,β-unsaturated ketones, α-ketoesters, and aldimines. Tetrahedron Lett. 2007, 48, 5283–5288. [Google Scholar] [CrossRef]
  27. He, P.; Lu, Y.; Dong, C.-G.; Hu, Q.-S. Anionic four-electron donor-based palladacycles as catalysts for addition reactions of arylboronic acids with α,β-unsaturated ketones, aldehydes and α-ketoesters. Org. Lett. 2007, 9, 343–346. [Google Scholar] [CrossRef]
  28. Bennett, M.A.; Huang, T.-N.; Matheson, T.W.; Smith, A.K. (η6-Hexamethylbenzene)ruthenium complexes. Inorg. Synth. 1982, 21, 74–78. [Google Scholar] [CrossRef]
  29. Yong, K.H; Taylor, N.J.; Chong, J.M. Enantioselective alkylation of aldehydes with chiral organomagnesium amides (COMAs). Org. Lett. 2002, 4, 3553–3556. [Google Scholar] [CrossRef]
  30. Li, Y.; Ding, K.; Sandoval, C.A. Hybrid NH2-benzimidazole ligands for efficient Ru-catalyzed asymmetric hydrogenation of aryl ketones. Org. Lett. 2009, 11, 907–910. [Google Scholar] [CrossRef]
  31. Jones, G.; Heaton, S.R. Catalytic asymmetric induction part 2. Chiral tricarbonyl (η6 arene) chromium (0) complexes as enantioselective catalysts. Tetrahedron Asymmetry 1993, 4, 261–272. [Google Scholar] [CrossRef]
  32. Hatano, M.; Miyamto, T.; Ishihara, K. 3,3’-Diphosphoryl-1,1’-bi-2-naphthol-Zn(II) complexes as conjugate acid-base catalysts for enantioselective dialkylzinc addition to aldehydes. J. Org. Chem. 2006, 71, 6474–6484. [Google Scholar] [CrossRef]
  33. Glynn, D.; Shannon, J.; Woodward, S. On the scope of trimethylaluminium-promoted 1,2-additions of ArZnX reagents to aldehydes. Chem. Eur. J. 2010, 16, 1053–1060. [Google Scholar]
  34. Coldham, I.; Patel, J.J.; Raimbault, S.; Whittaker, D.T.E.; Adams, H.; Fang, G.Y.; Aggarwal, V.K. Asymmetric lithiation-substitution of amines involving rearrangement of borates. Org. Lett. 2008, 10, 141–143. [Google Scholar] [CrossRef]
  35. DeBerardinis, A.M.; Turlington, M.; Pu, L. Activation of functional arylzincs prepared from aryl iodides and highly enantioselective addition to aldehydes. Org. Lett. 2008, 10, 2709–2712. [Google Scholar] [CrossRef]
  36. Koul, S.; Koul, J.L.; Singh, B.; Kapoor, M.; Parshad, R.; Manhas, K.S.; Taneja, S.C.; Qazi, G.N. Trichosporon beigelli esterase (TBE): A versatile esterase for the resolution of economically important racemates. Tetrahedron Asymmetry 2005, 16, 2575–2591. [Google Scholar] [CrossRef]
  37. Inagaki, T.; Phong, L.T.; Furuta, A.; Ito, J.-I.; Nishiyama, H. Iron- and cobalt-catalyzed asymmetric hydrosilylation of ketones and enones with bis(oxazolinylphenyl)amine ligands. Chem. Eur. J. 2010, 16, 3090–3096. [Google Scholar] [CrossRef]
  38. Dahmen, S.; Lormann, M. Triarylborane ammonia complexes as ideal precursors for arylzinc reagents in asymmetric catalysis. Org. Lett. 2005, 7, 4597–4600. [Google Scholar] [CrossRef]
  39. Onodera, G.; NIshibayashi, Y.; Uemura, S. Ir- and Ru-catalyzed sequential reactions: Asymmetric α-alkylative reduction of ketones with alcohols. Angew. Chem. Int. Ed. 2006, 45, 3819–3822. [Google Scholar] [CrossRef]
  40. Vettel, S.; Vaupel, A.; Knochel, P. Nickel-catalyzed preparations of functionalized organozincs. J. Org. Chem. 1996, 61, 7473–7481. [Google Scholar] [CrossRef]
  41. Huang, H.; Okuno, T.; Tsuda, K.; Yoshimura, M.; Kitamura, M. Enantioselective hydrogenation of aromatic ketones catalyzed by Ru complexes of Goodwin-Lions-type sp2N/sp3N hybrid ligands R-BINAN-R’-Py. J. Am. Chem. Soc. 2006, 128, 8716–8717. [Google Scholar]
  42. Stymiest, J.L.; Dutheuil, G.; Mahmood, A.; Aggarwal, V.K. Lithiated carbamates: Chiral carbenoids for iterative homologation of boranes and boronic esters. Angew. Chem. Int. Ed. 2007, 46, 7491–7494. [Google Scholar] [CrossRef]
  43. Fontes, M.; Verdaguer, X.; Solà, L.; Pericàs, M.A.; Riera, A. 2-Piperidino-1,1,2-triphenylethanol: A highly effective catalyst for the enantioselective arylation of aldehydes. J. Org. Chem. 2004, 69, 2532–2543. [Google Scholar] [CrossRef]
  44. Blay, G.; Fernández, I.; Marco-Aleixandre, A.; Pedro, J.R. Catalytic asymmetric addition of dimethylzinc to α-ketoesters, using mandelamides as ligands. Org. Lett. 2006, 8, 1287–1290. [Google Scholar] [CrossRef]
  45. Wu, H.-L.; Wu, P.-Y.; Shen, Y.-Y.; Uang, B.-J. Asymmetric addition of dimethylzinc to α-ketoesters catalyzed by (−)-MITH. J. Org. Chem. 2008, 73, 6445–6447. [Google Scholar] [CrossRef]
  46. Zheng, B.; Hou, S.; Li, Z.; Guo, H.; Zhong, J.; Wang, M. Enantioselective synthesis of quaternary stereogenic centers though catalytic asymmetric addition of dimethylzinc to α-ketoesters with chiral cis-cyclopropane-based amide alcohol as ligand. Tetrahedron Asymmetry 2009, 20, 2125–2129. [Google Scholar] [CrossRef]
  47. Duan, H.-F.; Xie, J.-H.; Qiao, X.-C.; Wang, L.-X.; Zhou, Q.-L. Enantioselective rhodium-catalyzed addition of arylboronic acids to α-ketoesters. Angew. Chem. Int. Ed. 2008, 47, 4351–4353. [Google Scholar]
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