Ru/Me-BIPAM-catalyzed asymmetric addition of arylboronic acids to aliphatic aldehydes and α-ketoesters

Article abstract of DOI:10.3390/molecules16065020

A ruthenium-catalyzed asymmetric arylation of aliphatic aldehydes and a-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-

Full text of DOI:10.3390/molecules16065020

Molecules 2011, 16, 5020-5034; doi:10.3390/molecules16065020
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Ru/Me-BIPAM-Catalyzed Asymmetric Addition of Arylboronic
Acids to Aliphatic Aldehydes and α-Ketoesters
Yasunori Yamamoto *, Tomohiko Shirai, Momoko Watanabe, Kazunori Kurihara and
Norio Miyaura
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; E-Mail: yasuyama@eng.hokudai.ac.jp;
Tel.: +81-11-706-6560; Fax: +81-11-706-6560.
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 [3-5]. 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

Molecules 2011, 16
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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.
[RuCl2(p-cymene)]2 (1 mol%)
OH
HO
R2
O
O
(R,R)-Me-BIPAM (2.2 mol%)
K2CO3 or KF
OR3
OR3
or
+ ArB(OH)2
(1. 5 - 2 eq)
R1 Ar
*
or
R2
R1
H
*
Ar
O
O
toluene/H2O, 60-80 ºC, 16 h
1
2
3
4
5
X
O
P
O
P
O
O
NMe2 Me2N
6: (R,R)-Me-BIPAM (X = O)
7: (R,R)-N-Me-BIPAM (X = NMe)
2. Results and Discussion
The arylation of carbonyl compounds with organolithium [11,12], organomagnesium [13-15]
and organozinc [16-21] 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 [23-27] 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).

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Table 1. Arylation of aliphatic aldehydes a.
[RuCl2(p-cymene)]2 (1 mol%)
O
OH
R1
Me-BIPAM (2.2 mol%)
ArB(OH)2
+
R1
H
Ar
K2CO3 (1 eq.)
H
toluene/H2O (10/1, 3.3 mL)
3 (1.5 eq.)
60 °C, 16 h
1
4
Entry
1 b
2
3
4
R1 =
Ar =
Ph (3a)
Ph (3a)
Yield (%)
63 (4aa)
93 (4ba)
98 (4bb)
85 (4bc)
93 (4bd)
90 (4be)
69 (4bf)
62 (4bh)
63 (4bi)
65 (4bk)
58 (4bl)
91 (4ca)
93 (4da)
87 (4ea)
99 (4fa)
78 (4ga)
67 (4ha)
54 (4ja)
40 (4ka)
ee (%) (abs)
91 (R)
94 (R)
93 (R)
92 (R)
92 (R)
87 (R)
91 (R)
90 (R)
90 (+)
87 (+)
99 (R)
94 (R)
93 (R)
92 (R)
92 (R)
94 (R)
96 (R)
91 (R)
99 (R)
n-C2H5 (1a)
n-C4H9 (1b)
n-C4H9 (1b)
n-C4H9 (1b)
n-C4H9 (1b)
n-C4H9 (1b)
n-C4H9 (1b)
n-C4H9 (1b)
n-C4H9 (1b)
n-C4H9 (1b)
n-C4H9 (1b)
n-C5H11 (1c)
n-C6H13 (1d)
n-C8H17 (1e)
PhCH2CH2 (1f)
cyclo-C6H11 (1g)
i-Pr (1h)
2-naphthyl (3b)
4-MeC6H4 (3c)
4-MeOC6H4 (3d)
4-ClC6H4 (3e)
4-FC6H4 (3f)
3-MeOC6H4 (3h)
3-ClC6H4 (3i)
3-F-4-MeOC6H3 (3k)
3,4-(CH2O2)C6H3 (3l)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
5
6 b,c
7
8
9
10 b,d
11 b,c
12
13
14 c
15
16
17 b
18 b,c
19 b,c,e
(C2H5)2CH (1j)
t-Bu (1k)
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
b
c
d
H2O (0.3 mL) was stirred at 60 °C for 16 h. toluene/H2O (5/1) was used. at 80 °C. KOH was
used. e K3PO4 was used.
Table 2. Reaction conditions a.
[RuCl2(p-cymene)]2 (1 mol%)
OH
O
Me-BIPAM (2.2 mol%)
OR3
OR3
+
PhB(OH)2
Ph
base (2 eq.)
O
O
toluene/H2O (10/1, 3.3 mL),
80°C, 16 h
(S)-5
2
3a
Entry
1 b
2 b
3 b
4 b
5
Base
R3 =
Et
Et
Et
Et
Et
Yield (%)
ee (%) (abs)
K2CO3
K3PO4
CsF
KF
40
trace
40
71
78
93
ND
93
95
94
KF
6
KF
KF
KF
i-Pr (2a)
t-Bu
t-Bu
85
87
72
93 (S)
90
70
7
8 c
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.

Molecules 2011, 16
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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.
[RuCl2(p-cymene)]2 (1 mol%)
OH
O
Me-BIPAM (2.2 mol%)
OiPr
OiPr
+
ArB(OH)2
R2
Ar
KF (2 eq.)
R2
O
O
toluene/H2O (10/1, 3.3 mL),
80°C, 16 h
3 (2 eq.)
2
5
Entry
R2 =
Ar =
Yield (%)
85 (5aa)
84 (5ac)
84 (5ad)
85 (5af)
64 (5ag)
73 (5ah)
71 (5aj)
81 (5ak)
88 (5ba)
90 (5bc)
90 (5bf)
88 (5bh)
41 (5ca)
42 (5cd)
82 (5dc)
95 (5dd)
90 (5de)
90 (5df)
79 (5dh)
67 (5ei)
ee (%) (abs)
1
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Et (2b)
Et (2b)
Et (2b)
Et (2b)
Ph (3a)
93 (S)
89
91
93
92
92
90
87
95
91
93
91
94
90
92
86
91
94
92
90
2
4-MeC6H4 (3c)
4-MeOC6H4 (3d)
4-FC6H4 (3f)
3
4
5
4-CF3C6H4 (3g)
3-MeOC6H4 (3h)
3-FC6H4 (3j)
6
7
8
3-F-4-MeOC6H3 (3k)
Ph (3a)
9
10
11
12
13
14
15
16
17
18
19
20
4-MeC6H4 (3c)
4-FC6H4 (3f)
3-MeOC6H4 (3h)
Ph (3a)
i-Pr (2c)
i-Pr (2c)
Ph (2d)
4-MeOC6H4 (3d)
4-MeC6H4 (3c)
4-MeOC6H4 (3d)
4-ClC6H4 (3e)
4-FC6H4 (3f)
Ph (2d)
Ph (2d)
Ph (2d)
Ph (2d)
3-MeOC6H4 (3h)
3-ClC6H4 (3i)
4-FC6H4 (2e)
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.

Molecules 2011, 16
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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 CDCl3 (δC = 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
23
(4ba) [29] in 93% yield; [α]D = 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.
21
(R)-1-Phenyl-1-propanol (4aa) [29,30]: [α]D = 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
1
tminor = 33.0 min]; H-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.
19
(R)-1-(-2-Naphthyl)-1-pentanol (4bb) [31]: [α]D = 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
1
tmajor = 29.6 min]; H-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).

Molecules 2011, 16
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22
(R)-1-(4-Tolyl)-1-pentanol (4bc) [29,32]: [α]D = 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).
19
(R)-1-(4-Methoxyphenyl)-1-pentanol (4bd) [33]: [α]D = 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,
t
major = 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
1
tmajor = 27.0 min]; H-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.
21
(R)-1-(4-Fluorophenyl)-1-pentanol (4bf) [34]: [α]D = 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,
1
tminor = 27.3 and tmajor = 31.5 min]; H-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,
13
3H); C-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.
20
(R)-1-(3-Methoxyphenyl)-1-pentanol (4bh) [35]: [α]D = 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,
1
tmajor = 58.3 and tminor = 67.9 min]; H-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.
20
1-(3-Chlorophenyl)-1-pentanol (4bi) [32]: [α]D = 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
1
tmajor = 25.4 min]; H-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.
20
1-(3-Fluoro-4-methoxyphenyl)-1-pentanol (4bk): [α]D = 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,
t
major = 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,
13
3H); C-NMR (100 MHz, CDCl3): δ = 152.4 (d, J = 246 Hz), 146.9 (d, J = 10.49 Hz), 138.2 (d,

Molecules 2011, 16
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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.
20
(R)-1-(5-Benzo[d][1,3]dioxolyl)-1-pentanol (4bl) [36]: [α]D = 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
1
tminor = 22.4 (S) min]; H-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.
23
(R)-1-Phenyl-1-heptanol (4da) [38,39]: [α]D = 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
1
tminor = 22.9 min]; H-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.
19
(R)-1-Phenyl-1-nonanol (4ea) [40,41]: [α]D = 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
1
tminor = 31.8 min]; H-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.
20
(R)-1,3-Diphenyl-1-propanol (4fa) [42]: [α]D = 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
1
tmajor = 33.7 min]; H-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
1
tmajor = 48.8 min]; H-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.
19
(R)-2-Methyl-1-phenyl-1-propanol (4ha) [33]: [α]D = 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,
1
tmajor = 17.6 and tminor = 18.8 min]; H-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.

Molecules 2011, 16
5027
(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.
20
(R)-2,2-Dimethyl-1-phenyl-1-propanol (4ka) [33]: [α]D = 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,
1
tminor = 7.9 and tmajor = 11.7 min]; H-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
22
2-hydroxy-2-phenylpropanoate (5aa) in 85% yield [44-46]. [α]D = +40.00 (c 4.2, CHCl3), 93% ee
[HPLC conditions: Chiralcel OJ-H column, hexane/2-propanol = 98/2, flow = 1.0 mL/min,
1
wavelength = 230 nm, tmajor = 8.0 min and tminor = 16.4 min]; H-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
13
(d, J = 6.4 Hz, 3H), 1.17 (d, J = 6.0 Hz, 3H); C-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.
22
Isopropyl 2-hydroxy-2-(4-tolyl)propanoate (5ac): [α]D = +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,
13
J = 6.5 Hz), 1.18 (d, J = 6.4 Hz, 3H); C-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,
t
major = 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
13
(d, J = 6.0 Hz, 3H); C-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.

Molecules 2011, 16
5028
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,
1
tmajor = 7.2 min and tminor = 10.0 min]; H-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),
13
1.16 (d, J = 6.0 Hz, 3H); C-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.
22
Isopropyl 2-hydroxy-2-(4-trifluoromethylphenyl)propanoate (5ag): [α]D = +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,
13
J = 6.4 Hz, 3H), 1.18 (d, J = 6.4 Hz, 3H); C-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,
13
3H), 1.19 (d, J = 6.4 Hz, 3H); C-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.
22
Isopropyl 2-hydroxy-2-(3-fluoro-4-methoxyphenyl)propanoate (5ak): [α]D = +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,

Molecules 2011, 16
5029
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
13
(d, J = 6.4 Hz, 3H), 1.19 (d, J = 6.4 Hz, 3H), 0.92 (t, J =7.3 Hz, 3H); C-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.
25
Isopropyl 2-hydroxy-2-(4-tolyl)butanoate (5bc): [α]D = +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,
t
major = 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
13
(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); C-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.
24
Isopropyl 2-hydroxy-2-(4-fluorophenyl)butanoate (5bf): [α]D = +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,
1
tmajor = 5.5 min and tminor = 7.4 min]; H-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
13
(d, J = 6.4 Hz, 3H), 1.17 (d, J = 6.4 Hz, 3H), 0.90 (t, J = 7.3 Hz, 3H); C-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,
1
tmajor = 8.0 min and tminor = 12.7 min]; H-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,
13
J = 6.4 Hz, 3H), 1.20 (d, J = 6.4 Hz, 3H), 0.91 (t, J = 7.3 Hz, 3H); C-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.
22
Isopropyl 2-hydroxy-3-methyl-2-phenylbutanoate (5ca): [α]D = +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,
t
major = 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
13
(d, J = 6.0 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H), 0.68 (d, J = 6.9 Hz, 3H); C-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.
22
Isopropyl 2-hydroxy-3-methyl-2-(4-methoxyphenyl)butanoate (5cd): [α]D = +36.53 (c 3.5, CHCl3),
90% ee [HPLC conditions: Chiralcel OJ-H column, hexane/2-propanol = 98/2, flow = 1.0 mL/min,
1
wavelength = 230nm, tmajor = 5.9 min and tminor = 7.1 min]; H-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

Molecules 2011, 16
5030
13
(d, J = 7.3 Hz, 3H); C-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.
24
Isopropyl 2-hydroxy-2-phenyl-2-(4-tolyl)acetate (5dc): [α]D = −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,
t
major = 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,
13
6H); C-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.
25
Isopropyl 2--2-hydroxy-2-(4-methoxyphenyl)-2-phenylacetate (5dd): [α]D = +2.10 (c 4.0, CHCl3),
86% ee [HPLC conditions: Chiralcel AS-H column, hexane/2-propanol = 9/1, flow = 1.0 mL/min,
1
wavelength = 230 nm, tmajor = 20.2 min and tminor = 22.8 min]; H-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),
13
4.28 (d, J = 2.3 Hz, 1H), 3.80 (s, 3H), 1.24 (dd, J = 6.4, 6.4Hz, 6H); C-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.
20
Isopropyl 2-(4-chlorophenyl)-2-hydroxy-2-phenylacetate (5de) [47]: [α]D = +17.87 (c 4.9, CHCl3),
91% ee [HPLC conditions: Chiralcel AD-H column, hexane/2-propanol = 9/1, flow = 1.0 mL/min,
1
wavelength = 230 nm, tminor = 18.9 min and tmajor = 20.0 min]; H-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,
1
wavelength = 230 nm, tmajor = 10.3 min and tminor = 11.4 min]; H-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.
25
Isopropyl 2-hydroxy-2-(3-methoxyphenyl)-2-phenylacetate (5dh): [α]D = −3.95 (c 2.7, CHCl3), 92%
ee [HPLC conditions: Chiralcel AD-H column, hexane/2-propanol = 9/1, flow = 0.85 mL/min,
1
wavelength = 230 nm, tmajor = 14.5 min and tminor = 15.3 min]; H-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.
22
Isopropyl 2-(3-chlorophenyl)-2-(4-fluorophenyl)-2-hydroxyacetate (5ei): [α]D = +1.23 (c 5.3,
CHCl3), 90% ee [HPLC conditions: Chiralcel OJ-H column, hexane/2-propanol = 98/2,

Molecules 2011, 16
5031
1
flow = 1.0 mL/min, wavelength = 230 nm, tmajor = 10.9 min and tminor = 12.2 min]; H-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,
13
J = 6.4 Hz, 6H); C-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.
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Sample Availability: Me-BIPAM and N-Me-BIPAM are available from the authors.
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