A chiral ruthenium-monophosphine catalyst for asymmetric addition of arylboronic acids to aryl aldehydes

Article abstract of DOI:10.1021/jo400850m

A novel ruthenium catalyst on the basis of a chiral monophosphorus ligand is efficient for the asymmetric addition of arylboronic acids to aryl aldehydes, providing a series of chiral diarylmethanols in excellent yields and enantioselectivities (up to 92% ee). Preliminary study has shown that this process is catalyzed by a Ru complex with a single monophosphorus ligand.

Full text of DOI:10.1021/jo400850m

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Note
A Chiral Ruthenium-Monophosphine Catalyst for
Asymmetric Addition of Arylboronic Acids to Aryl Aldehydes
Ke Li, Naifu Hu, Renshi Luo, Weicheng Yuan, and Wenjun Tang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400850m • Publication Date (Web): 27 May 2013
Downloaded from http://pubs.acs.org on June 4, 2013
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A Chiral Ruthenium-Monophosphine Catalyst for
Asymmetric Addition of Arylboronic Acids to Aryl
Aldehydes
Ke Li,a Naifu Hu,b Renshi Luo,b Weicheng Yuan,a,* and Wenjun Tangb,*
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aChengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
bState Key Laboratory of Bi-organic and Natural Products Chemistry, Shanghai Institute of Organic chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
Email: tangwenjun@sioc.ac.cn
Email: yuanwc@cioc.ac.cn
ABSTRACT: A novel ruthenium catalyst on the basis of a chiral monophosphorus ligand is efficient for the asymmetric
addition of arylboronic acids to aryl aldehydes, providing a series of chiral diarylmethanols in excellent yields and
enantioselectivities (up to 92% ee). Preliminary study has shown this process is catalyzed by a Ru complex with a single
monophosphorus ligand.
Chiral diarylmethanols are important building blocks for many antihistamine compounds or therapeutic agents[1] such
as (R)-orphenadrine, (S)-neobenodine,[2] (S)-carbinoxamine,[3] and bepotastine.[3] They also serve as pivotal structural units
for chiral ligands in asymmetric catalysis.[4] Development of asymmetric catalytic methods for the syntheses of chiral
diarylmethanols has thus gained significant interest.[5] Two recent advances include asymmetric hydrogenation of
diarylketones[6] and asymmetric addition of aryl nucleophile to aryl aldehydes.[7] The asymmetric addition of arylboronic
acids to aryl aldehydes to form chiral diarylmethanols remains one of most attractive methods owing to its mild reaction
conditions, and the stable and nontoxic nature of arylboronic acids.[8-12]
Figure1. Antihistimine compounds containing chiral diarylmethanol moiety
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Although most progresses on asymmetric addition of arylboronic acids to aryl aldehydes have been achieved on
chiral rhodium catalysts,9 the development of novel and efficient catalysts with less expensive transition metals, broader
substrate scope, and low catalyst loadings continue to be of great interest. The ruthenium–catalyzed asymmetric addition
of arylboronic acids to aryl aldehydes offers great promise to provide a more economical and practical solution than the
rhodium version. However, it remains an underdeveloped area. Only recently, Miyaura and coworkers have reported a
chiral ruthenium catalyst with a bisphosphoramidite ligand can be highly efficient.[13] Nevertheless, the structure of its
active ruthenium species remains to be elucidated. In addition, no efficient ruthenium catalyst in combination with a
monophosphorus ligand has ever been reported. We herein describe a new and efficient ruthenium catalyst on the basis of
a P-chiral monophosphorus ligand L4 which has provided excellent yields and enantioselectivities for the syntheses of a
wide array of chiral diarylmethanols.
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Figure 2. Chiral monophosphorus ligands
We have developed a series of chiral biaryl monophosphorus ligands for palladium-catalyzed asymmetric Suzuki-
Miyaura coupling reactions (Figure 2).[14] The high tunability of these monophosphorus ligands and the facile syntheses
from chiral triflate 1 (Scheme 1) allowed us to investigate their ruthenium complex as the catalyst for the addition of
arylboronic acids to aryl aldehydes. The asymmetric addition of phenylboronic acid (5a) to 1-naphthaldehyde (4a) to form
enantiomerically enriched naphthalen-1-yl(phenyl)methanol (6a) was studied. The reaction was performed under nitrogen
in dioxane at 60 oC for 16 h with 1 mol % [RuCl2(cymene)]2 and 2 mol % ligand as the catalytic system. Initial screening
of the chiral ligands (Table 1, entries 1-5) demonstrated that the ligand structure plays a significant role on both reactivity
and selectivity. While BI-DIME (L1) provided a high yield and a good ee (82% ee, entry 1), the ligands with substituents
at R’ position provided diminished yields and enantioselectivities (entries 2-3). The substituents on the lower aryl ring of
the ligands also provided profound influence on both reactivity and selectivity.
Scheme 1. Syntheses of Ligand L4 and L5
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Ligand L4 with two phenoxy groups on the low aryl ring further enhanced the enantioselectivity to 86% ee (entry 4).
A slightly lower yield and ee were observed with L5 containing two 1-naphthyloxy substituents (entry 5). The ruthenium
precursors significantly affected the performance of the catalyst. While comparable results were observed with
[RuCl2(C6Me6)]2 as the precursor (entry 6), use of [RuCl2(benzene)]2 as the precursor provided <5% conversion under
similar reaction conditions. This could be largely attributed to the slow complex formation between [RuCl2(benzene)]2 and
L4 at 60 oC (entry 7). The reaction temperature also influenced both the reactivity and selectivity with [RuCl2(cymene)]2 as
the catalyst precursor. Low reactivity and enantioselectivity was observed at 50 oC (entry 8), while a slightly diminished ee
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was also observed at 70 C (entry 9). There were little differences on selectivity when various bases were employed
(entries 10-14). Among them, potassium phosphate offered an excellent yield (96%) and good selectivity (87% ee) (entry
11).
Table 1. Asymmetric addition of phenylboronic acid to 1-naphthaldehyde
entrya L*
Base
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KF
Ru Precursor
[RuCl2(cymene)]2
[RuCl2(cymene)]2
[RuCl2(cymene)]2
[RuCl2(cymene)]2
[RuCl2(cymene)]2
[RuCl2(C6Me6)]2
[RuCl2(benzene)]2
[RuCl2(cymene)]2
[RuCl2(cymene)]2
[RuCl2(cymene)]2
[RuCl2(cymene)]2
[RuCl2(cymene)]2
[RuCl2(cymene)]2
[RuCl2(cymene)]2
Yield (%) ee (%)b
1
2
L1
L2
L3
L4
L5
L4
L4
L4
L4
L4
L4
L4
L4
87
40
45
85
68
85
<5
13
86
40
96
31
45
38
69
6
3
8
4
86
78
84
n.d
64
70
86
87
84
84
84
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7
8c
9d
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12
13
14
K3PO4
CsF
KOH
L4 NaOtBu
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aThe reactions were performed in dioxane at 60 C under nitrogen for 16 h in the presence of 1 mol % Ru precursor and 2 mol % ligand, the
absolute configuration was determined by comparing its optical rotation with reported data;[13a,b] b The ee was determined on a Chiralcel OD-H
column; c T = 50 oC; d T = 70 oC.
We next investigated the substrate scope of this ruthenium catalyzed addition of arylboronic acids to aldehydes. It was
found that excellent yields and enantioselectivities were achieved regardless of the electronic properties and substitution
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pattern of both aldehydes and arylboronic acids (Table 2). Both electronic-donating substituents such as methoxy group
and electronic-withdrawing substituents such as fluoro and bromo groups provided comparably high yields and
selectivities (entries 1-4, 8-10). Slightly lower ee’s were observed when aryl aldehydes containing ortho-substituents were
employed (entries 5-6). The Ru-L4 system also provided excellent yields and enantioselectivies on substrates containing
heteroaryls such as thiophene and furan (entries 13-15). By simply switching the substituents on arylboronic acids and
arylaldehyde in Table 1, the same ruthenium catalyst can produce both enantiomers of the chiral biarylcarbinol in a
comparably high ee and yield (entries 8 and 16), demonstrating the generality and efficiency of this methodology.
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Table 2. Substrate scope of ruthenium-catalyzed addition of arylboronic acids to aryl aldehydes
entrya
Aldhehyde
4-MeO-Ph (4b)
4-F-Ph (4c)
Boronic acid
Ph (5a)
Yield (%)
92 (6b)
95 (6c)
85 (6d)
95 (6e)
90 (6f)
ee(%)b
89
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Ph (5a)
90
4-Br-Ph (4d)
3-MeO-Ph (4e)
2-Cl-Ph (4f)
Ph (5a)
90
Ph (5a)
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Ph (5a)
81
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2-MeO-Ph (4g)
4-NO2-Ph (4h)
2-naphthyl (4i)
2-naphthyl (4i)
2-naphthyl (4i)
2-naphthyl (4i)
Ph (5a)
4-Cl-Ph(5b)
Ph (5a)
90 (6g)
97 (6h)
93 (6i)
91 (6j)
93 (6k)
95 (6l)
84
82
92
86
89
89
8
9
4-Ph-Ph(5c)
4-MeO-Ph(5d)
4-Cl-Ph(5e)
10
11
trans-PhCH=CH
(4j)
12
Ph (5a)
80(6m)
76
13
14
15
16
2-thienyl (4k)
3-thienyl (4l)
2-furyl (4m)
Ph (4n)
Ph (5a)
Ph (5a)
95 (6n)
93 (6o)
89 (6p)
93 (6q)
90
90
87
85
Ph (5a)
2-naphthyl (5f)
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aThe reactions were performed in dioxane at 60 C under nitrogen for 16 h in the presence of 1 mol % Ru precursor and 2 mol % ligand; the
absolute configuration was determined by comparing its optical rotation with reported data; b The ee’s were determined on a Chiralcel OD-H
column.
To better understand the structure of the active ruthenium catalyst for this transformation, we attempted to prepare a
ruthenium complex of ligand L4. Thus, by stirring [RuCl2(cymene)]2 and L4 at Ru:L4 ratio of 1:1 in 1,2-dichloroethane as
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the solvent at 70 C for 18 h, a new aryl-coordinated ruthenium complex 7 without a cymene moiety was isolated in 70%
yield by column chromatography.[15] Interestingly, one phenoxy group of the ligand served as a coordinating aryl group
within the complex, whose structure was confirmed by X-ray crystallography (Scheme 2).[16] Complex 7 could also be
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applied as a catalyst for the nucleophilic addition of 5a to 4a and the addition product 6a was isolated in 84% ee and 80%
yield. The high selectivity and reactivity observed with complex 7 highly suggests that the active ruthenium catalyst for
this transformation is a ruthenium species coordinated with a single monophosphorus ligand. This is in contrast to
Miyaura’s ruthenium system where a bisphosphorus ligand was employed.[13a] Additional experiments with a scalemic
catalyst composition of L1 have shown a linear relationship of ees between the ligand and the product, further
demonstrating the process catalyzed by a ruthenium catalyst coordinated with a single monophosphorus ligand (Figure 3).
However, whether ligand L1 or L4 coordinates with the ruthenium metal through monodentate, bidentate, and/or aryl
coordination during the catalyst cycle remain to be further elucidated.
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Scheme 2. Syntheses of chiral ruthenium complexes 7 and 8 and the X-ray crystal structure of 8 (H atoms and
chloroform are omitted for clarity)
On the basis of these observations, we proposed a mechanistic cycle with a Ru(II)-monophosphine catalyst as
depicted in Figure 4. Transmetallation of a L4-Ru(II) complex with ArB(OH)2 in the presence of a base provided an aryl
Ru(II) complex I. Coordination of an aryl aldehyde to complex I to form intermediate II followed by carbonyl insertion
and transmetallation with ArB(OH)2 provides chiral biarylmethanol IV and regenerate complex I. Further mechanistic
study is ongoing to understand the stereoselection of this reaction and the detailed structure of each catalytic species.
70
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0
0
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ee of L1 (%)
Figure 3. Linear relationship of ees between ligand L1 and product 6a
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Figure 4. A postulated mechanistic cycle
Scheme 3. Synthetic utility of this methodology
To further demonstrate the synthetic utility of this methodology, the Ru-L4 system was employed as a catalyst to
synthesize chiral alcohol 9 (Scheme 3). Thus, Mitsunobu reaction between aldehyde 10 and cyclopentanol 11 provided 8
in 70% yield. The reaction of aldehyde 8 and phenylboronic acid (5a) was catalyzed by 1 mol % [RuCl2(cymene)]2 and 2
mol % L4 to provide 9 in 95% yield and 89 % ee. Compound 9 can be further transformed according to a reported
procedure[1a] to CDP-840,[17] a potent selective phosphodiesterase IV inhibitor.
In summary, we have developed a novel and efficient ruthenium catalyst based on a chiral monophosphorus ligand L4
for asymmetric addition of arylboronic acids to aryl aldehydes, providing a series of chiral diarylcarbinols in excellent
yields and ees. Studies have shown that this transformation is catalyzed by a Ru species coordinated with a single
monophosphorus ligand.
EXPERIMENTAL SECTION
General information. All reactions were carried out under a nitrogen atomosphere unless otherwise specified. Dioxane
(<0.02% water content), Et2O, dioxane, MTBE, DCM, DCE, Xylene and toluene were used directly without further
purifications. Commercialized reagents were used without further purifications. H, 31P and 13C NMR data were recorded
1
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on 400 or 500 MHz at ambient temperature with CDCl3 as the solvent. H shifts were referenced to CDCl3 at 7.26 ppm.
31P shifts were referenced to 85% H3PO4 in D2O at 0.0 ppm as external standard and obtained with H decoupling. 13C
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shifts were referenced to CDCl3 at 77 ppm and obtained with 1H decoupling. The mass analyzer type was Q-TOF used for
the HRMS measurements. Chiral HPLC analyses were performed on a Chiralcel OD-H, Chiralpak AD-H or Lux
Amylose-2 PA column. Racemic addition products were prepared by using [RuCl2(p-cymene)]2 and S-phos as the catalytic
system.
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(S)-3-(tert-Butyl)-4-(2,6-diphenoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxaphosphole 3-oxide (3a). To a mixture of
triflate 1[18] (2.0 g, 5.6 mmol) and arylboronic acid 2a (2.57 g, 8.4 mmol, 1.5 equiv), Pd2dba3 (76.7 mg, 0.084 mmol, 0.03
equiv), S-Phos (0.23 g, 0.56 mmol, 0.2 equiv) and KF (1.3 g, 22.3 mmol, 4 equiv) was charged degassed dioxane (10 mL).
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The mixture was stirred at 100 C under nitrogen for 24 h, concentrated, partitioned with water (30 mL) and DCM (30
mL). The DCM layer was dried over Na2SO4, concentrated, and purified by column chromatography (eluent: hexane to
EtOAc) to provide 3a (1.9 g, 4.2 mmol, 75%) as white solid. 3a: mp 97 -99 °C; 1H NMR (400 MHz, CDCl3) δ 7.31～7.39
(m, 7H), 7.10 (t, J = 7.1 Hz, 3H), 6.92～6.99 (m, 3H), 6.88 (dd, J = 8.2, 3.0 Hz, 1H), 6.51 (d, J = 8.2 Hz, 1H), 6.45 (d, J =
8.3 Hz, 1H), 4.54 (d, J = 14.3 Hz, 1H), 4.41 (dd, J = 13.6, 10.6 Hz, 1H), 1.09 (d, J = 16.0 Hz, 9H); 31P NMR (162 MHz,
CDCl3) δ 62.17; 13C NMR (100 MHz, CDCl3) δ 165.5 (d, J = 19.3 Hz), 158.5, 155.3, 137.0 (d, J = 5.6 Hz), 134.2, 13.5,
124.4 (dd, J = 75.7, 39.0 Hz), 122.0, 121.1, 119.4, 113.9 (dd, J = 166.3, 48.2 Hz), 110.1 (d, J = 73.0 Hz), 65.5 (d, J = 61.0
Hz), 33.8 (d, J = 71.6 Hz), 24.1 (d, J = 8.3 Hz); HRMS (ESI) calcd for C29H28O4P [M + H+] 471.1725, found 471.1729.
(R)-3-(tert-Butyl)-4-(2,6-diphenoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxaphosphole (L4). To a solution of 3a (1.2 g,
2.5 mmol) in THF (12 mL) at rt was added PMHS (2.4 g) and Ti(OiPr)4 (1.4 g, 5.0 mmol, 1.2 equiv). The mixture was
stirred at reflux under nitrogen for 12 h, and then concentrated under vacuum to remove most THF. To the residue was
treated carefully with 30% NaOH solution (15 mL). Gas was generated during addition. The resulting mixture was further
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stirred at 60 C for 0.5 h. To the mixture at rt was added Et2O (20 mL). The Et2O layer was separated and the aqueous
layer was washed with Et2O under nitrogen. The Et2O solution was dried, concentrated, and purified by passing through a
neutral alumina plug (eluent: hexanes to hexanes/ether 5/1) to give the desired product L4 as a white crystalline solid (1.0
g, 2.25 mmol, 90 %). L4: mp 76 -78 °C; 1H NMR (400 MHz, CDCl3) δ 7.27 (dd, J = 11.2, 4.4 Hz, 2H), 7.16 (dd, J = 11.0,
4.6 Hz, 2H), 7.02～7.10 (m, 3H), 6.95 (dd, J = 7.3, 4.2 Hz, 5H), 6.73～6.80 (m, 2H), 6.56 (d, J = 8.2 Hz, 1H), 6.49 (d, J =
8.2 Hz, 1H), 4.85 (t, J = 45.5 Hz, 1H), 4.46 (dd, J = 25.1, 12.6 Hz, 1H), 0.81 (d, J = 12.1 Hz, 9H); 31P NMR (162 MHz,
CDCl3) δ -8.61; 13C NMR (100 MHz, CDCl3) δ 162.5, 155.3 (dd, J = 46.0, 34.4 Hz), 135.7, 128.6 (dd, J = 106.1, 65.8 Hz),
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122.7 (t, J = 46.7 Hz), 118.8 (d, J = 6.6 Hz), 110.5, 69.4 (d, J = 27.5 Hz), 30.0 (d, J = 18.7 Hz), 25.9 (d, J = 14.7 Hz);
HRMS (ESI) calcd for C29H28O3P [M + H+] 455.1776, found 455.1772.
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(S)-4-(2,6-Bis(naphthalen-1-yloxy)phenyl)-3-(tert-butyl)-2,3-dihydrobenzo[d][1,3]oxaphosphole 3-oxide (3b). To
a mixture of the chiral triflate (1, 307 mg, 0.86 mmol), 2,6-bis(naphthalen-1-yloxy)phenylboronic acid (2b, 420 mg, 1.03
mmol, 1.2 equiv), Pd2dba3 (23.5 mg, 0.0257 mmol, 0.03 equiv), BI-DIME[14c] (17.8 mg, 0.054 mmol, 0.061 equiv), and
potassium fluoride (150 mg, 2.6 mmol, 3.0 equiv) was charged degassed dioxane (5 mL). The mixture was stirred at
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100 C under nitrogen for 24 h and then concentrated to remove most of dioxane. To the residue was added with
dichloromethane (10 × 2 mL) and water (10 mL) and the mixture was filtered over a celite pad. The organic
layer was separated, washed with brine, concentrated, and purified by silica gel column chromatography (eluent:
hexane to EtOAc) to give 3b as white crystalline solid (293 mg, 0.515 mmol, 60%). 3b: mp 199 -200 °C; 1H NMR
(500 MHz, CDCl3) δ 8.25 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.79 (s, 1H), 7.64 (d, J = 7.9 Hz, 1H),
7.58 (d, J = 7.8 Hz, 1H), 7.29～7.52 (m, 8H), 7.11 (t, J = 8.2 Hz, 3H), 6.79 (d, J = 8.0 Hz, 1H), 6.57 (dd, J = 20.4, 8.3 Hz,
2H), 4.60 (d, J = 13.6 Hz, 1H), 4.43～4.49 (m, 1H), 1.23 (d, J = 15.8 Hz, 9H); 31P NMR (162 MHz, CDCl3) δ 62.83; 13
C
NMR (125 MHz, CDCl3) δ 156.0, 152.7 (d, J = 87.8 Hz), 135.3, 129.9, 127.8, 127.3 (d, J = 18.9 Hz), 126.6 (d, J = 9.0
Hz), 126.2, 125.96 (d, J = 15.3 Hz), 125.7 (d, J = 7.8 Hz), 124.5, 123.6 (d, J = 19.2 Hz), 122.7, 122.0, 121.7, 115.9, 113.2
(d, J = 20.8 Hz), 111.8 (d, J = 5.5 Hz), 65.3 (d, J = 60.0 Hz), 29.3 (d, J = 71.3 Hz), 24.1 (d, J = 1.3 Hz); HRMS (ESI)
calcd for C37H32O4P [M + H+] 571.2038, found 571.2030.
(R)-4-(2,6-Bis(naphthalen-1-yloxy)phenyl)-3-(tert-butyl)-2,3-dihydrobenzo[d][1,3]oxaphosphole (L5). Ligand L5
was prepared according to a similar procedure described for L4. L5: white crystalline solid; 78% yield; mp 180 -
182 °C; 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 8.1 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.77 (d,
J = 7.3 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.41～7.53 (m, 6H), 7.31 (t, J = 7.9 Hz, 1H), 7.11～7.19 (m, 2H), 6.95～7.07
(m, 3H), 6.65～6.76 (m, 3H), 4.88 (dd, J = 12.5, 1.5 Hz, 1H), 4.55 (dd, J = 25.1, 12.6 Hz, 1H), 1.01 (d, J = 12.2 Hz, 9H);
31P NMR (162 MHz, CDCl3) δ -8.38; 13C NMR (125 MHz, CDCl3) δ 163.5, 156.4, 155.4, 153.2 (d, J = 4.3 Hz), 136.9 (d, J
= 18.0 Hz), 135.0, 130.6, 129.1, 127.6 (d, J = 36.6 Hz), 126.9, 126.6, 125.8, 125.4, 124.9 (d, J = 14.8 Hz), 123.6, 122.76,
122.4 (d, J = 5.3 Hz), 122.0, 113.9, 113.4, 112.9, 109.9, 70.4 (d, J = 27.5 Hz), 31.2 (d, J = 18.6 Hz), 27.1 (d, J = 14.6 Hz);
HRMS (ESI) calcd for C37H32O3P [M + H+] 555.2089, found 555.2093.
Ruthenium complex 7. To a Schlenk flask was charged L4 (100 mg, 0.22 mmol) and 1,2-dichloroethane (2 mL)
followed by [RuCl2(p-cymene)]2 (64 mg, 0.11 mmol) and the resulting dark red solution was stirred at reflux under
nitrogen for 18 h. Solvent was removed under vacuum to yield a red solid. The crude product was purified by flash
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chromatography (eluent: ethyl acetate/hexanes 2:1) to yield 7 (79 mg 0.13 mmol, 60%) as a red solid. 7: H NMR (400
MHz, CDCl3) δ 7.40 (dt, J = 18.3, 9.3 Hz, 4H), 7.21 (t, J = 7.1 Hz, 1H), 7.00 (dd, J = 22.2, 9.3 Hz, 5H), 6.81 (d, J = 8.3
Hz, 1H), 6.13 (s, 1H), 5.78 (s, 1H), 5.68 (d, J = 5.4 Hz, 2H), 5.23 (s, 1H), 5.16 (d, J = 12.9 Hz, 1H), 5.04 (dd, J = 12.6, 5.2
Hz, 1H), 1.11 (d, J = 15.3 Hz, 9H); 31P NMR (162 MHz, CDCl3) δ 45.99; 13C NMR (100 MHz, CDCl3) δ 164.2, 157.9,
155.2, 150.4, 134.7, 132.7, 131.2, 129.9 (d, J = 57.6 Hz), 127.6, 125.0 (d, J = 17.1 Hz), 120.3, 116.7, 114.4, 112.7, 95.1 (d,
J = 10.9 Hz), 92.9, 89.7, 74.8, 70.7, 66.6, 38.6 (d, J = 13.8 Hz), 27.44 (d, J = 3.1 Hz); HRMS (MALDI) calcd for
C29H27ClO3PRu C37H32O3P 591.0430 found 591.0435 [M - Cl]+.
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General procedure for asymmetric addition of arylboronic acids to aldehydes. To a mixture of arylaldehyde (0.2
mmol, 1 equiv), arylboronic acid (0.4 mmol, 2 equiv), K2CO3 (43 mg, 0.2 mmol, 1 equiv), ligand L1 or L4 (0.0042 mmol,
2.1 mol %) and [RuCl2(p-cymene)]2 (1.2 mg, 0.002 mmol, 1.0 mol %) in a Schlenk tube was added dioxane (0.5 mL). The
mixture was stirred at 60 o C for 16 h, then concentrated, and purified by silica gel column chromatography (eluents:
hexanes/ethyl acetate 4/1) to afford the addition product. The enantioselectivity was determined by chiral HPLC on a
chiralcel OD-H, chiralcel AD-H, or Lux Amylose-2 column.
(R)-Naphthalen-1-yl(phenyl)methanol (6a).[13] Liquid, 96% yield, 87% ee: [α]D20 = +33.8 (c = 1.1, CHCl3) (lit.6
[α]D = -46.3 (c = 0.3, CHCl3) for 98% ee, (S)); 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 7.4
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Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.59 (d, J = 7.1 Hz, 1H), 7.40～7.47 (m, 3H), 7.36 (t, J = 9.1 Hz, 2H), 7.29 (t, J = 7.3
Hz, 2H), 7.27～7.22 (m, 1H), 6.47 (s, 1H), 2.46 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 143.1, 138.8, 133.9, 130.7, 128.8,
o
128.5, 128.5, 127.7, 127.1, 126.2, 125.6, 125.3, 124.6, 124.0, 73.6. Chiral HPLC conditions: Lux Amylose-2 PA, 25 C,
flow rate: 1.0 mL/min, heptane/isopropanol: 90/10, 254 nm, 8.6 min (S), 11.7 min (R).
(R)-(4-Methoxyphenyl)(phenyl)methanol (6b).[9f] Liquid (92% yield); 89% ee; [α]D20 = 5.18 (c = 0.17, CHCl3); (lit.6
[α]D20 = -14.8 (c = 0.81, CHCl3) for 92% ee, (S)); 1H NMR (400 MHz, CDCl3) δ 7.23～7.29 (m, 4H), 7.20～7.17 (m, 3H),
6.78 (d, J = 8.7 Hz, 2H), 5.71 (s, 1H), 3.70 (s, 3H), 2.18 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 159.1, 144.0, 136.2, 128.4,
127.9, 127.4, 126.4, 113.9, 75.8, 55.9. Chiral HPLC conditions: Lu-Amylose-2 PA, 25 oC, flow rate: 1.0 mL/min,
heptane/isopropanol: 90/10, 254 nm, 10.98 min (R), 12.0 min (S).
(R)-(4-Fluorophenyl)(phenyl)methanol (6c).[12c] Solid (95% yield); 90% ee; [α]D20 = -5.46. (c = 1.02, CHCl3); H
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NMR (400 MHz, CDCl3) δ 7.25～7.15 (m, 7H), 6.92 (t, J = 8.7 Hz, 2H), 5.70 (s, 1H), 2.32 (s, 1H); 19F NMR (376 MHz,
CDCl3) δ -114.46; 13C NMR (100 MHz, CDCl3) δ 163.4, 160.9, 143.6, 139.5, 128.6, 128.43, 126.5, 115.3, 75.6. Chiral
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HPLC conditions: Chiralcel OD-H, 25 C, flow rate: 1.0 mL/min, heptane/isopropanol: 90/10, 230 nm, 9.3 min (R), 9.8
min (S).
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(R)-(4-Bromophenyl)(phenyl)methanol (6d).[13] Liquid (85% yield); 90% ee; [α]D20 = -6.31 (c = 0.63, CHCl3); H
NMR (400 MHz, CDCl3) δ 7.50 (d, 2H), 7.34 (d, J = 4.4 Hz, 4H), 7.24～7.30 (m, 3H), 5.79 (s, 1H), 2.24 (s, 1H); 13C
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NMR (100 MHz, CDCl3) δ 143.3, 142.7, 131.5, 128.6, 128.2, 127.9, 126.5, 121.4, 75.7. Chiral HPLC conditions:
Chiralcel AD-H, 25 oC, flow rate: 1.0 mL/min, heptane/isopropanol: 90/10, 230 nm, 8.4 min (R), 9.4 min(S).
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(R)-(3-Methoxyphenyl)(phenyl)methanol (6e).[13] Liquid (95% yield); 87% ee; [α]D20 = -5.18 (c = 1.80, CHCl3); H
NMR (400 MHz, CDCl3) δ 7.31～7.38 (m, 4H), 7.24～7.27 (m, 2H), 6.94 (d, J = 7.4 Hz, 2H), 6.79～7.81 (m, 1H), 5.80 (d,
J = 3.0 Hz, 1H), 3.78 (s, 3H), 2.28 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 159.8, 145.5, 143.7, 129.6, 128.5, 127.6, 126.6,
118.9, 113.0, 112.1, 76.2, 55.2. Chiral HPLC conditions: Lux Amylose-2 PC, 25 oC, flow rate: 1.0 mL/min,
heptane/isopropanol: 75/25, 254 nm, 6.0 min (R), 6.9 min (S).
(R)-(2-Chlorophenyl)(phenyl)methanol (6f). Liquid (90% yield); 81% ee; [α]D20 = 16.4 (c = 1.1, CHCl3) (lit. [13]
[α]D20 = +16.2 ( c = 1.05, CHCl3) for 82% ee, (R)); 1H NMR (400 MHz, CDCl3) δ 7.58～7.61 (m, 1H), 7.19～7.58 (m, 8H),
6.14 (s, 1H), 1.93 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 142.2, 141.0, 132.5, 129.5, 128.8, 128.5, 128.0, 127.8, 127.1,
126.9, 72.7. Chiral HPLC conditions: Chiralcel OD-H, 25 oC, flow rate: 1.0 mL/min, heptane/isopropanol: 90/10, 230 nm,
8.4 min (R), 9.9 min (S).
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(R)-(2-Methoxyphenyl)(phenyl)methanol (6g).[13] Liquid (90% yield); 84% ee; [α]D20 = +16.3 (c = 0.62, CHCl3); H
NMR (400 MHz, CDCl3) δ 7.29 (d, J = 7.2 Hz, 2H), 7.22 (t, J = 7.4 Hz, 2H), 6.77～6.86 (m, 3H), 6.84 (t, 1H), 6.78 (d, J
= 8.0 Hz, 1H), 5.95 (s, 1H), 3.68 (s, 3H), 3.00 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 156.7, 143.3, 132.0, 128.7, 128.2,
127.8, 127.1, 126.6, 120.8, 110.8, 72.2, 55.4. Chiral HPLC conditions: Lux Amylose-2 PA, 25 oC, flow rate: 1.0 mL/min,
heptane/isopropanol: 75/25, 230 nm, 3.7 min (R), 4.2 min (S).
(S)-(4-Chlorophenyl)(4-nitrophenyl)methanol (6h).[13] Solid (96% yield); 82% ee; [α]D20 = -11.58 (c = 1.57, CHCl3);
1H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 7.3 Hz, 2H), 7.55 (d, 2H), 7.26～7.35 (m, 4H), 5.90 (s, 1H), 2.44 (s, 1H); 13C
NMR (125 MHz, CDCl3) δ 170.7, 135.1, 134.4, 133.4, 133.2, 132.8, 128.6, 128.4, 128.1, 127.1, 126.7, 126.4, 125.8, 123.8,
o
38.8, 34.3. Chiral HPLC conditions: Chiralcel AD-H, 25 C, flow rate: 1.0 mL/min, heptane/isopropanol: 90/10, 210 nm,
13.8 min (S), 16.6 min (R).
(R)-Naphthalen-2-yl(phenyl)methanol (6i).[13] Solid (93% yield); 92% ee; [α]D20 = -5.99 (c = 1.5, CHCl3); H NMR
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(400 MHz, CDCl3) δ 7.85 (s, 1H), 7.75～7.82 (m, 3H), 7.47～7.43 (m, 2H), 7.39 (dd, J = 6.4, 4.4 Hz, 3H), 7.32 (dd, J =
10.1, 4.7 Hz, 2H), 7.23～7.27 (m, 1H), 5.94 (s, 1H), 2.44 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 143.6, 141.1, 133.2,
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132.9, 128.6, 128.3, 128.1, 127.7, 126.7, 126.5, 126.0, 125.0, 124.8, 76.3. Chiral HPLC conditions: Chiralcel OD-H, 25 oC,
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flow rate: 1.0 mL/min, heptane/isopropanol: 90/10, 254 nm, 15.68 min (S), 18.66 min (R).
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(R)-Biphenyl-4-yl(naphthalen-2-yl)methanol (6j). Solid (91% yield); 86% ee; [α]D20 = -15.8 (c = 0.62, CHCl3); H
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NMR (500 MHz, CDCl3) δ 7.95 (s, 1H), 7.82～7.88 (m, 3H), 7.58 (d, J = 8.3Hz, 1H), 7.42～7,47 (m, 5H), 7.44 (t, J =
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7.7Hz, 2H), 7.35 (t, J = 7.4Hz, 1H), 6.06 (s, 1H), 2.39 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 170.7, 135.1, 134.4, 133.4,
133.2, 132.8, 128.6, 128.4, 128.1, 127.1, 126.7, 126.4, 125.8, 123.8, 38.8, 34.3. HRMS (ESI) calcd for C23H18O [M + H+]
o
310.1358, found 310.1538. Chiral HPLC conditions: Chiralcel AD-H, 25 C, flow rate: 1.0 mL/min, heptane/isopropanol:
95/5, 254 nm, 14.4 min (S), 15.3 min (R).
(R)-(4-Methoxyphenyl)(naphthalen-2-yl)methanol (6k).[21] solid (93% yield); 89% ee; [α]D20 = -7.92 (c = 1.28,
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CHCl3); H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.77～7.84 (m, 3H), 7.43～7.49 (m, 2H), 7.40 (d, J = 7.7 Hz, 1H),
7.31 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 5.95 (s, 1H), 3.78 (s, 3H), 2.25 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
159.1, 141.3, 136.0, 133.2, 132.8, 128.2, 128.1, 127.6, 126.1, 125.9, 124.7, 113.9, 75.9, 55.37. Chiral HPLC conditions:
Lux Amylose-2 PA, 25 oC, flow rate: 1.0 mL/min, heptane/isopropanol: 90/10, 254 nm, 15.0 min (S), 17.0 min (R).
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(R)-(4-Chlorophenyl)(naphthalen-2-yl)methanol (6l).[21] Liquid (95% yield); 89% ee; [α]D = +5.04 (c = 2.5,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.80～7.89 (m, 4H), 7.47～7.51 (m, 2H), 7.26～7.41 (m, 5H), 5.98 (s, 1H), 2.82 (s,
1H); 13C NMR (125 MHz, CDCl3) δ 170.7, 135.1, 134.4, 133.4, 133.2, 132.8, 128.6, 128.4, 128.1, 127.1, 126.7, 126.4,
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125.8, 123.8, 38.8, 34.3. Chiral HPLC conditions: Chiralcel OD-H, 25 C, flow rate: 1.0 mL/min, heptane/isopropanol:
90/10, 254 nm, 16.6 min (S), 18.4 min (R).
(S)-1,3-diphenylprop-2-en-1-ol (6m).[9f] Liquid (80% yield); 76% ee; [α]D20 = +16.1 (c = 0.68, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.35～7.42 (m, 2H), 7.34 (t, J = 7.8Hz, 4H), 7.22～7.30 (m, 3H), 7.20～7.24 (m, 1H), 6.66 (d, J = 15.9Hz,
1H), 6.36 (dd, J = 6.5Hz, J = 15.9Hz, 1H), 5.35 (d, J = 6.5Hz, 1H), 2.22 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 170.7,
135.1, 134.4, 133.4, 133.2, 132.8, 128.6, 128.4, 128.1, 127.1, 126.7, 126.4, 125.8, 123.8, 38.8, 34.3. Chiral HPLC
conditions: Chiralcel OD-H, 25 oC, flow rate: 1.0 mL/min, heptane/isopropanol: 95/5, 230 nm, 7.8 min (S), 9.3 min (R).
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(R)-Phenyl(thiophen-2-yl)methanol (6n). Liquid (95% yield); 90% ee; [α]D20 = -7.6 (c = 0.59, CHCl3) (lit. [13] [α]D
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+10.0 ( c = 0.32., CHCl3) for 92% ee, (S)); 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 7.1Hz, 2H), 7.35 (t, J = 7.3Hz, 2H),
7.27～7.31 (m, 1H), 7.23 (dd, J = 5.1, 1.1 Hz, 1H), 6.92 (dd, J = 5.0, 3.5 Hz, 1H), 6.85 (d, J = 3.5 Hz, 1H), 6.00 (s, 1H),
2.60 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 148.1, 143.1, 128.5, 128.0, 126.7, 126.3, 125.5, 124.9, 72.4. Chiral HPLC
conditions: Chiralcel OD-H, 25 oC, flow rate: 1.0 mL/min, heptane/isopropanol: 90/10, 230 nm, 6.6 min (S), 7.0 min (R).
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(R)-Phenyl(thiophen-3-yl)methanol (6o).[21] Solid (93% yield); 90% ee; [α]D20 = -5.09 (c = 1.83, CHCl3); H NMR
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(400 MHz, CDCl3) δ 7.32～7.39 (m, 4H), 7.24～7.30 (m, 2H), 7.16 (dd, J = 1.8, 1.0 Hz, 1H), 6.98 (dd, J = 5.0, 1.0 Hz,
1H), 5.86 (s, 1H), 2.33 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 145.3, 143.4, 128.6, 127.8, 126.5, 126.4, 126.2, 121.7, 72.9.
Chiral HPLC conditions: Chiralcel OD-H, 25 oC, flow rate: 1.0 mL/min, heptane/isopropanol: 90/10, 230 nm, 10.4 min (S),
11.8 min (R).
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(R)-furan-2-yl(phenyl)methanol (6p).[13] Liquid (89% yield); 87% ee; [α]D20 = +5.03 (c = 1.65, CHCl3) (lit.6 [α]D20 = -
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4.71 ( c = 0.64, CHCl3) for 82% ee, (S)); H NMR (400 MHz, CDCl3) δ 7.44～7.39 (m, 2H), 7.29～7.35 (m, 4H), 6.29
(dd, J = 3.2, 1.9 Hz, 1H), 6.09 (d, J = 3.2 Hz, 1H), 5.78 (s, 1H), 2.60 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 156.0, 142.6,
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140.9, 128.5, 128.1, 126.7, 110.3, 107.5, 70.1 Chiral HPLC conditions: Chiralcel OD-H, 25 C, flow rate: 1.0 mL/min,
heptane/isopropanol: 90/10, 230 nm, 9.3 min (S), 11.2 min (R).
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(S)-naphthalen-2-yl(phenyl)methanol (6q).[13] Liquid (93 % yield); ee 85%; [α]D20 = 10.81 (c = 0.57, CHCl3); H
NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 7.4 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.59 (d, J = 7.1 Hz,
1H), 7.40～7.47 (m, 3H), 7.36 (t, J = 9.1 Hz, 2H), 7.29 (t, J = 7.3 Hz, 2H), 7.27～7.22 (m, 1H), 6.47 (s, 1H), 2.46 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 143.1, 138.8, 133.9, 130.7, 128.8, 128.5, 128.5, 127.7, 127.1, 126.2, 125.6, 125.3, 124.6,
124.0, 73.6. Chiral HPLC conditions: Chiralcel OD-H, 25 oC, flow rate: 1.0 mL/min, heptane/isopropanol: 80/20, 254 nm,
15.6 min (S), 18.4 min (R).
3-(Cyclopentyloxy)-4-methoxybenzaldehyde (8).[19] To a mixture of 3-hydroxy-4-methoxybenzaldehyde (10, 1.5 g,
10 mmol, 1 equiv), cyclopentanol (11, 1.7 g, 20 mmol, 2 equiv) and triphenylphosphine (1.7 g, 10 mmol, 1 equiv) in dry
THF (10 mL) at 0 oC under nitrogen was added dropwise diethyl azodicarboxylate (1.7 g, 10 mmol, 1 equiv) over 10 min.
The mixture was allowed to warm to rt and stir overnight and then quenched with 5% HCl (10 mL) and ether (10 mL).
The organic phase was separated and the aqueous layer was further extracted with ether (2 × 10 mL). The combined ether
solution was dried over sodium sulfate, concentrated, and purified by column chromatography (eluent: EA/Hexane 1:4) to
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6.96 (d, J = 8.2 Hz, 1H), 4.85 (dt, J = 9.4, 3.1 Hz, 1H), 3.93 (s, 3H), 1.96～2.04 (m, 2H), 1.81～1.91 (m, 4H), 1.61～1.65
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 191.0, 155.4, 148.3 130.1 126.3, 112.1, 110.8 80.5 56.2 32.7, 24.1.
(R)-(3-(Cyclopentyloxy)-4-methoxyphenyl)(phenyl) methanol (9).[20] Liquid (90% yield); 89% ee; [α]D20 = +4.2 (c =
0.20, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.30～7.38 (m, 4H), 7.23～7.27 (m, 1H), 6.90 (d, J = 1.9 Hz, 1H), 6.85 (dd,
J = 8.3, 1.9 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 5.76 (s, 1H), 4.74 (s, 1H), 3.81 (s, 3H), 2.30 (s, 1H), 1.78～1.90 (m, 6H),
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1.54～1.63 (m, 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 149.5, 147.7, 144.0, 136.5, 128.4, 127.5, 126.4, 118.9, 113.5,
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111.8, 80.4 75.99, 56.11, 32.78, 24.09. Chiral HPLC conditions: Chiralcel AD-H, 25 oC, flow rate: 1.0 mL/min,
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heptane/isopropanol: 95/5, 230 nm, 12.9 min (S), 13.7 min (R).
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ACKNOWLEDGMENT
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We are grateful to NSFC-21272254; the “Thousand Plan” Youth program, the Innovation Fund of State Key Laboratory of
Bioorganic and Natural Products Chemistry, and Boehringer Ingelheim.
ASSOCIATED CONTENT
Supporting Information. NMR spectra of L4 and L5, HPLC traces and NMR spectra of chiral diarylcarbinol
products. This material is available free of charge via the Internet at http://pubs.acs.org.
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