Chiral 1,1′-binaphthylazepine-derived amino alcohol catalyzed asymmetric aryl transfer reactions with boroxine as aryl source

Article abstract of DOI:10.1002/chir.20721

Using chiral 1,1′-binaphthylazepine-derived amino alcohol as catalyst, the direct addition of in situ prepared arylzinc (with triphenylboroxine as aryl source) to various aryl aldehydes can afford optically active diarylmethanols in high yields and enantioselectivities (up to 96%).

Full text of DOI:10.1002/chir.20721

CHIRALITY 22:159–164 (2010)
Chiral 1,10-Binaphthylazepine-Derived Amino Alcohol Catalyzed
Asymmetric Aryl Transfer Reactions with Boroxine as Aryl Source
CAN LIU,1 ZONG-LIANG GUO,1 JIANG WENG,1 GUI LU,1* AND ALBERT S. C. CHAN1,2
*
1Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People’s Republic of China
2Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis and Department of Applied
Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, People’s Republic of China
ABSTRACT
Using chiral 1,10-binaphthylazepine-derived amino alcohol as catalyst,
the direct addition of in situ prepared arylzinc (with triphenylboroxine as aryl source) to
various aryl aldehydes can afford optically active diarylmethanols in high yields and
C
VV
enantioselectivities (up to 96%). Chirality 22:159–164, 2010.
2009 Wiley-Liss, Inc.
KEY WORDS: aryl transfer reaction; boroxine; amino alcohol; diarylmethanol;
aldehydes
INTRODUCTION
alkynylzinc addition reaction.32 Later (1Ra,2S,3R)-1 also
showed excellent enantioselectivities on the aryl transfer
reaction to aldehyde when using aryl boronic acid as aryl
source.33 To reduce the necessary amount of Et2Zn and to
make this catalytic asymmetric process synthetically use-
ful, we attempted to explore the generality of the chiral
ligand (1Ra,2S,3R)-1 in the catalyzed process with aryl
boroxine as aryl source.
From our previous experience, the relatively rigid struc-
ture of chiral amino alcohol presumably provided a better
enantio-locking of the substrate in the aryl transfer reac-
tion.33 The computational study of Goldfuss and Houk on
the chiral inducing mechanism pointed out the crucial role
of the substituent at C(O).34 Taking into account these
studies, we imagined that a further improvement in enan-
tioselectivity could be obtained by inserting an additional
phenyl group on the C(O) of the amino alcohol skeleton
((1Ra,2S)-2 in Fig. 2), which giving rise to steric interac-
tion with both the chiral binaphthyl moiety and the sub-
stituents on the C(O), could ensure a better enantioselec-
tive control.
Chiral diarylmethanols are important precursors for
many biologically active compounds.1–6 Two general
approaches for their enantioselective syntheses have been
developed, either by the reduction of prochiral diaryl
ketones or the stereoselective aryl transfer reactions to ar-
omatic aldehydes. The latter seems easier to realize
because of the significant difference between the hydro-
gen atom and the aryl group of the aldehydes. Major
breakthroughs in this field were obtained by Fu,7 and later
by Bolm and others,8 but high enantioselectivities were
mostly limited to the addition of diphenylzinc to alde-
hydes. In 2002, Bolm and coworkers described arylzinc
species formed in situ from arylboronic acids and diethyl-
zinc, and obtained excellent enantioselectivity in the ary
transfer reaction using planar-chiral ferrocene-based oxa-
zoline ligand.9 However, the arylboronic acid protocol
demands a huge excess of diethylzinc (6–7 equiv) for the
boron–zinc transmetalation due to the acidity of boronic
acid. So, further improvements on this approach were
focused on the amelioration of the aryl sources10–25 and ef-
fectual ligands.8 Triphenylboranes,17–19 triarylborane am-
monia complexes,20 and phenylboroxines21–23 were all
found to be viable aryl sources (see Fig. 1), and triarylbor-
oxine has recently even been applied in industry.26
EXPERIMENTAL SECTION
General
1,10-Binaphthylazepine-based ligands have been known
All experiments were carried out under nitrogen. All sol-
since the early 1980s, and have been tested in several vents were distilled from standard drying agents. Commer-
asymmetric processes. Since 2001 the group of Rosini and cial aldehydes reagents were freshly redistilled before
Superchi has carried out a systematic study aimed at defin-
*Correspondence to: Prof. Dr. Gui Lu, Institute of Medicinal Chemistry,
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou,
P. R. China 510006 and Prof. Dr. Albert S. C. Chan, Department of Applied
ing the structural features of the binaphthylazepine skele-
ton which are responsible for their efficiency as chiral
inducers, and obtained good yields and enantioselectivities
in a series of asymmetric organozinc (including dialkyl-
zinc, diphenylzinc, and alkynylzinc) additions to aromatic
aldehydes.27–31
Biology and Chemical Technology, The Hong Kong Polytechnic University,
Hong Kong. E-mail: lugui@mail.sysu.edu.cn and bcachan@polyu.edu.hk
Contract grant sponsors: National Natural Science Foundation of China
(NSFC), The Scientific Research Foundation for the Returned Overseas
Chinese Scholars ; Contract grant number: 20772161
Received for publication 21 July 2008; Accepted 6 February 2009
DOI: 10.1002/chir.20721
Also, in 2001 our group has demonstrated that the 1,10-
binaphthylazepine-derived amino alcohol (1Ra,2S,3R)-1
(see Fig. 2) was an effective catalyst for the asymmetric
C
Published online 5 May 2009 in Wiley InterScience
(www.interscience.wiley.com).
VV
2009 Wiley-Liss, Inc.

160
LIU ET AL.
Fig. 1. Various aryl sources.
use. Crude products were purified by flash chromatogra-
Compound (1Ra,2S)-2 was prepared analogously to
phy using Qing Dao Sea Chemical Reagent silica gel (1Ra,2S,3R)-1. White solid, 86 mg, 76%. [a]2D0 5 233.3 (c
1
(200–300 mesh). NMR spectra were recorded on a Mer- 0.6, CH2Cl2). H NMR (300 MHz, CDCl3) d 7.89-7.86 (d, J
cury Plus 300 spectrometer (Varian). Chemical shifts were 5 8.1 Hz, 2H, ArH), 7.76-7.71 (m, 4H, ArH), 7.45-7.32 (m,
reported in d ppm referenced to an internal TMS standard 10H, ArH), 7.15-7.25 (m, 6H, ArH), 7.03-6.97 (m, 2H, ArH),
1
for H NMR. HPLC analyses were conducted on a Promi- 6.92-6.87 (t, J 5 7.2 Hz, 1H, ArH), 6.56-6.53 (d, J 5 8.4 Hz,
nence LC-10A instrument (Shimadzu) using Daicel col- 2H, ArH), 4.84 (s, 1H, NCH), 3.65-3.60 (d, J 5 12.3 Hz,
umns (0.46 cm diameter 325 cm length). The absolute 2H, CH2N), 3.36-3.31 (d, J 5 12.3 Hz, 2H, CH2N). 13C
configurations of the products were determined based on NMR (75 MHz, CDCl3) d 149.5, 145.5, 139.2, 135.0, 133.8,
the comparison of HPLC traces and/or the direction of op- 132.9, 131.6, 131.1, 128.2, 128.1, 128.0, 127.6, 127.5, 127.3,
tical rotation with known compounds.
126.3, 125.5, 125.4, 125.3, 79.7, 76.1, 54.4. ESI-MS (m/z)
for C42H33NO [M1H]1: 568.3, found 568.1.
Preparation of Chiral Amino Alcohol
(1Ra,2S,3R)-1 and (1Ra,2S)-2
General Procedure for the Preparation
of Arylboroxines
A solution of (1R,2S)-(1)-2-amino-1,2-diphenylethanol
(0.25 mmol, 52.6 mg) in 22 mL CH3CN was added drop-
wise to a flask containing 0.25 mmol (R)-2,20-dibromo-
methyl-1,10- binaphthyl (109.7 mg), 0.5 mmol Et3N, and 2.0
mL toluene.32 The mixture was stirred under reflux for 24
h and the solvent was removed. The residue obtained was
dissolved in CH2Cl2 and the undissolved solid was
removed by filtration. The filtrate was evaporated and the
crude product obtained was purified via column chroma-
tography (silica gel, petroleum ether/ethyl acetate 5
120:1) to afford a white solid of (1Ra,2S,2R)-1, (R)-N-
[(1S,2R)-1,2-diphenyl-2-hydroxyethyl]-3,5-dihydro-4H-di-
naphtho[2,1-c:10,20-e]-azepine (98.7 mg, 80%). [a]D205 280.0
Phenyl boronic acid was heated at 1108C for 6 h in an
oven and was converted to phenyl boroxine quantitatively
by this procedure.21 1H NMR (CDCl3) d 8.20-8.30 (m, 6H),
7.40-7.60 (m, 9H). Other arylboroxines were prepared
similarly.
General Procedure for the Aryl Transfer Reaction
Phenylboroxine (0.198 mmol, 61.7 mg) was mixed with
diethylzinc (1 M in hexane, 1.2 mmol, 1.2 mL) in a sealed
vessel and stirred for 10 h at 608C. Another tube was
charged with chiral (1Ra,2S,3R)-1 (0.03 mmol, 14.7 mg),
freshly distilled toluene (0.5 mL) and diethylzinc solution
(1 M in hexane, 0.06 mmol, 0.06 mL) and stirred for 0.5 h
at room temperature for the pretreatment of the ligand.
Then the in situ prepared phenylzinc reagent in the first
vessel was transferred to the second tube via a syringe
and the resulting mixture was stirred for 0.5 h at room
temperature. The tube was cooled to 08C, and a solution of
p-chlorobenzaldehyde (0.3 mmol, 42.2 mg) in toluene (1.5
mL) was then added dropwise and stirred for 10 h. The
reaction was quenched with 1 N HCl, extracted with
EtOAc (3 3 10 mL), the combined organic layer was
washed with saturated brine and dried over Na2SO4. The
crude diarylmethanol was purified by column chromatog-
raphy (silica gel, EtOAc/petroleum ether 5 1:20) to give
the product in 87% yield and 93% ee. Enantiomeric excess
was determined by chiral HPLC analysis with Chiralcel
AD-H column (Daicel Chemical Industry), eluent: hexane/
i-PrOH 5 90:10, 1.0 mL/min, k 5 254 nm, tR(R) 5 7.8
min, tR(S) 5 8.5 min.
1
(c 1.0, CH2Cl2). H NMR (300 MHz, CDCl3) d 7.97-7.92
(t, J 5 8.4 Hz, 3H, ArH), 7.53-7.45 (m, 3H, ArH), 7.40-7.38
(d, J 5 8.1 Hz, 2H, ArH), 7.31-7.28 (d, J 5 7.8 Hz, 3H,
ArH), 7.19-7.16 (m, 5H, ArH), 7.03-7.02 (d, J 5 5.1 Hz, 4H,
ArH), 6.79-6.77 (m, 3H, ArH), 5.29-5.28 (m, 1H, NCH),
4.07-4.03 (d, J 5 12.0 Hz, 2H, CH2N), 3.32-3.28 (d, J 5 12.3
Hz, 2H, CH2N). 13C NMR (75 MHz, CDCl3) d 140.9,
137.2, 135.4, 133.6, 133.3, 131.4, 129.8, 128.5, 128.4, 127.8,
127,7, 127.6, 127.5, 126.8, 126.1, 126.0, 125.7, 74.1, 72.1,
53.3. ESI-MS (m/z) for C36H29NO [M1H]1: 492.6, found
493.0, [M12H]21: 493.6, found 494.0.
(R)-(4-Chlorophenyl)phenylmethanol21
.
1H NMR
Fig. 2. Binaphthyl-derived amino alcohols.
Chirality DOI 10.1002/chir
(300 MHz, CDCl3) d 7.40-7.21 (m, 9H, ArH), 5.79 (s, 1H,

ASYMMETRIC ARYL TRANSFER WITH BOROXINE
161
1H
CH). HPLC: Daicel Chiralcel AD-H, hexane/i-PrOH 5
(R)-(4-Trifluoromethylphenyl)phenyl-methanol21
.
90:10; 1.0 mL/min, k 5 254 nm, tR(R) 5 7.8 min, tR(S) 5 NMR (300 MHz, CDCl3) d 7.60-7.58 (d, J 5 8.1 Hz, 2H,
8.5 min.
ArH), 7.52-7.49 (d, J 5 9.0 Hz, 2H, ArH), 7.36-7.26 (m, 5H,
ArH), 5.88-5.87 (d, J 5 2.7 Hz, 1H, CH), 2.49 (s, 1H, OH).
HPLC: Daicel Chiralcel OJ-H, hexane/i-PrOH 5 95:5,
0.75 mL/min, k 5 254 nm, tR(R) 5 14.7 min, tR(S) 5
16.3 min.
(R)-(3-Chlorophenyl)phenylmethanol21
.
1H NMR
(300 MHz, CDCl3) d 7.32-7.16 (m, 9H, ArH), 5.71-5.70 (d, J
5 2.7 Hz, 1H, CH). HPLC: Daicel Chiralcel OD-H, hex-
ane/i-PrOH 5 95:5, 0.75 mL/min, k 5 254 nm, tR(S) 5
23.8 min, tR(R) 5 26.3 min.
.
(R)-(1-Naphthyl)phenylmethanol33 1H NMR (300
MHz, CDCl3) d 8.05-8.02 (d, J 5 8.7 Hz, 1H, ArH), 7.88-
7.81 (m, 2H, ArH), 7.65-7.63 (d, J 5 6.9 Hz, 1H, ArH), 7.52-
7.26 (m, 8H, ArH), 6.53 (s, 1H, CH). HPLC: Daicel Chiral-
cel OD-H, hexane/i-PrOH 5 90:10, 1.0 mL/min, k 5 254
nm, tR(S) 5 15.2 min, tR(R) 5 31.0 min.
(R)-(2-Chlorophenyl)phenylmethanol33
.
1H NMR
(300 MHz, CDCl3) d 7.63-7.60 (m, 1H, ArH), 7.38-7.23 (m,
8H, ArH), 6.20 (s, 1H, CH). HPLC: Daicel Chiralcel OD-H,
hexane/i-PrOH 5 95:5; 1.0 mL/min, k 5 254 nm, tR(R) 5
11.7 min, tR(S) 5 14.7 min.
.
(R)-(2-Naphthyl)phenylmethanol33 1H NMR (300
(R)-(4-Methoxyphenyl)phenylmethanol21
.
1H NMR
MHz, CDCl3) d 7.88-7.86 (m, 4H, ArH), 7.43-7.38 (m, 8H,
ArH), 6.00 (s, 1H, CH). HPLC: Daicel Chiralcel OD-H,
hexane/i-PrOH 5 95:5, 1.0 mL/min, k 5 254 nm, tR(S) 5
29.3 min, tR(R) 5 35.9 min.
(300 MHz, CDCl3) d 7.39-7.26 (m, 7H, ArH), 6.88-6.85 (d, J
5 8.7 Hz, 2H, ArH), 5.81 (s, 1H, CH), 3.80 (s, 3H, CH3).
HPLC: Daicel Chiralcel AD-H, hexane/i-PrOH 5 90:10,
1.0 mL/min, k 5 254 nm, tR(R) 5 39.4 min, tR(S) 5 43.2
min.
(R)-(2-Furyl)phenylmethanol33
.
1H
NMR
(300
MHz, CDCl3) d 7.45-7.43 (m, 2H, ArH, ꢀꢀCH¼¼O), 7.41-
7.31 (m, 4H, ArH), 6.33-6.31 (m, 1H, 5CH-), 6.12-6.11 (d, J
5 3.3 Hz, 1H, 5CHꢀꢀ), 5.84-5.83 (d, J 5 4.2 Hz, 1H, CH).
HPLC: Daicel Chiralcel OD-H, hexane/i-PrOH 5 97:3, 1.0
mL/min, k 5 254 nm, tR(S) 5 25.3 min, tR(R) 5 31.2 min.
(R)-(3-Methoxyphenyl)phenylmethanol33
.
1H NMR
(300 MHz, CDCl3) d 7.37-7.25 (m, 6H, ArH), 6.96 (m, 2H,
ArH), 6.82-6.79 (d, J 5 7.5 Hz, 1H, ArH), 5.80 (s, 1H, CH),
3.79 (s, 3H, CH3), 2.28 (m, 1H, OH). HPLC: Daicel Chiral-
cel OD-H, hexane/i-PrOH 5 95:5, 0.8 mL/min, k 5 254
nm, tR(S) 5 30.0 min, tR(R) 5 43.2 min.
(S)-(E)-1,3-Diphenyl-2-propenol33
MHz, CDCl3) d 7.46-7.27 (m, 10H, ArH), 6.72-6.67 (d, J 5
.
1H NMR 15.9 Hz, 1H, PhCH5CH), 6.44-6.36 (m, 1H, PhCH 5 CH),
.
1H NMR (300
(R)-(2-Methoxyphenyl)phenylmethanol33
(300 MHz, CDCl3) d 7.42-7.26 (m, 7H, ArH), 6.89-6.99 (m, 5.39-5.37 (d, J 5 6.6 Hz, 1H, CH). HPLC: Daicel Chiralcel
2H, ArH), 6.08 (s, 1H, CH), 3.82 (s, 3H, CH3). HPLC: Dai- OD-H, hexane/i-PrOH 5 80:20, 0.8 mL/min, k 5 254 nm,
tR(S) 5 10.9 min, tR(R) 5 13.4 min.
cel Chiralcel OD-H, hexane/i-PrOH 5 97:3, 0.8 mL/min, k
5 254 nm, tR(S) 5 30.4 min, tR(R) 5 31.7 min.
(S)-1-Phenyl-1-butanol35 1H NMR (300 MHz,
.
.
(R)-(4-Bromophenyl)phenylmethanol21 1H NMR
CDCl3) d 7.27-7.18 (m, 5H, ArH), 4.61-4.58 (t, J 5 6.6 Hz,
1H, OH), 1.83 (s, 1H, CH), 1.76-1.56 (m, 2H, CH2), 1.40-
1.18 (m, 2H, CH2), 0.87-0.84 (t, J 5 7.4 Hz, 3H, CH3).
HPLC: Daicel Chiralcel OB-H, hexane/i-PrOH 5 97:3, 0.5
mL/min, k 5 254 nm, tR(S) 5 14.0 min, tR(R) 5 16.8 min.
(300 MHz, CDCl3) d 7.47-7.44 (d, J 5 8.1 Hz, 2H, ArH),
7.34-7.25 (m, 7H, ArH), 5.80 (s, 1H, CH), 2.28 (s, 1H, OH).
HPLC: Daicel Chiralcel AD-H, hexane/i-PrOH 5 90:10;
0.75 mL/min, k 5 254 nm, tR(R) 5 11.5 min, tR(S) 5 13.0
min.
.
(R)-(3-Bromophenyl)phenylmethanol21 1H NMR
RESULTS AND DISCUSSION
(300 MHz, CDCl3) d 7.56-7.51 (m, 1H, ArH), 7.40-7.28 (m,
7H, ArH), 7.21-7.16 (m, 1H, ArH), 5.79 (s, 1H, CH), 2.39
(s, 1H, OH). HPLC: Daicel Chiralcel OD-H, hexane/i-
PrOH 5 90:10; 0.75 mL/min, k 5 254 nm, tR(S) 5 12.4
min, tR(R) 5 13.7 min.
We first synthesized chiral ligands (1Ra,2S,3R)-1 and
(1Ra,2S)-2, and examined their catalytic performance in
the enantioselective aryl transfer reaction of 4-chloroben-
zaldehyde with phenyl boroxine as aryl source. We
adopted an optimized procedure developed by Wu et al.21
and the results were listed in Table 1. Both catalysts pro-
vided the corresponding diaryl methanols in good yields
and fine ees, but (1Ra,2S,3R)-1 showed higher efficiency,
affording an ee about 6% higher than (1Ra,2S)-2. It seems
that the minor structural modification on the substitute at
C(O) did not provide better control of stereochemistry.
Previous studies on the aryl transfer reaction with bor-
.
(R)-(4-Tolyl)phenylmethanol21 1H NMR (300 MHz,
CDCl3) d 7.39-7.33 (m, 4H, ArH), 7.29-7.25 (m, 3H, ArH),
7.16-7.14 (d, J 5 7.5 Hz, 2H, ArH), 5.82 (s, 1H, CH), 2.35
(s, 3H, CH3), 2.22 (m, 1H, OH). HPLC: Daicel Chiralcel
OD-H, hexane/i-PrOH 5 90:10; 0.75 mL/min, k 5 254
nm, tR(S) 5 12.0 min, tR(R) 5 12.8 min.
.
(R)-(3-Tolyl)phenylmethanol24 1H NMR (300 MHz, onic acid as the aryl source had shown that the presence
CDCl3) d 7.40-7.28 (m, 5H, ArH), 7.23-7.15 (m, 3H, ArH), of polyethers as DiMPEG could lead to a significant
7.10-7.07 (d, J 5 8.1 Hz, 1H, ArH), 5.81 (s, 1H, CH). increase in enantioselectivity.10 We also studied the influ-
HPLC: Daicel Chiralcel OB-H, hexane/i-PrOH 5 90:10; ence of such modifiers in this new protocol, and found
1.0 mL/min, k 5 254 nm, tR(R) 5 16.7 min, tR(S) 5 29.6 that at low catalyst loading (5 mol % catalyst), by the addi-
min.
tion of 10 mol % of DiMPEG to the reaction mixture,
Chirality DOI 10.1002/chir

162
LIU ET AL.
TABLE 1. Optimization of the phenylation reactiona
TABLE 3. Asymmetric aryl transfer to benzaldehydea
Catalyst DiMPEG
(mol %)
Entry
Ar in boroxine
Yield (%)b
ee (%)c
Entry
Ligand
(mol %) Yield (%)b ee (%)c
1
2
3
4
5
6
p-chlorophenyl
p-methylphenyl
1-naphthyl
2-naphthyl
m-methylphenyl
m-chlorophenyl
85
98
90
87
37
84
78(S)
94(S)
88(S)
91(S)
rac
1
2
3
4
5
(1Ra,2S,3R)-1
(1Ra,2S)-2
(1Ra,2S,3R)-1
(1Ra,2S,3R)-1
(1Ra,2S,3R)-1
10
10
5
0
0
0
87
81
47
34
69
93(R)
87(R)
44(R)
94(R)
56(R)
5
5
10
25
71(S)
aReaction conditions: Aldehyde/ligand/phenylboroxine/diethylzinc 5 1/
0.1/0.66/4 (molar ratio), toluene as solvent, 608C, 10 h.
bIsolated yields.
aConditions: Aldehyde/(1Ra,2S,3R)-1/arylboroxine/diethylzinc 5 1/0.1/
0.66/4 (molar ratio), toluene as solvent, 608C, 10h.
bIsolated yields.
cEnantiomeric excess was determined by HPLC analysis. Absolute config-
urations were determined by comparison of the order of peak elution from
HPLC analyses with literature values.
cEnantiomeric excess was determined by HPLC analysis. Absolute config-
urations were determined by comparison of the order of peak elution from
HPLC analyses with literature values.
TABLE 2. Asymmetric phenyl transfer to various
aldehydesa
achiral metal catalysts and prevent their nonenantioselec-
tive contribution on the overall process.10
We then investigated the phenyl transfer reaction for a
variety of aromatic aldehydes under the optimal conditions
(Table 2). The reaction generally proceeded well with up
to 96% ee. The scope of substrate was not limited to para-
substituted aromatic aldehydes, the meta- or ortho- substi-
tuted substrates also afforded the corresponding products
with good yields and excellent ees. Electronic effects were
not significant, both electron-withdrawing substituent and
electron-donating group giving comparable results. A use-
ful intermediate for the antihistamine neobenodine could
be obtained by the phenyl addition to para-tolualdehyde in
considerable high yield (87%) and 93% ee (Entry 4). Aro-
matic aldehydes possessing steric hindrance, such as 1-
naphthaldehdye and 2-naphthaldehyde, also proved to be
suitable substrates for the asymmetric phenylation reac-
tion (Entries 11 and 12). The in situ prepared phenylzinc
reagents also worked well for the phenyl addition to 2-fur-
aldehydes, and a,b-unsaturated trans-cinnamyl aldehydes,
giving products with good ees (Entries 13 and 14). But for
aliphatic aldehyde substrate as n-butylaldehyde, both yield
and stereoselectivity were moderate and some side prod-
uct existed (Entry 15).
Besides phenylzinc, various arylzinc reagents could also
be easily transferred to aldehydes by using different sub-
stituted phenylboroxine as aryl source (Table 3). We
found that the reaction was rather sensitive to the elec-
tronic effect of arylboroxines. The presence of an electron-
donating group in the arylboroxine greatly facilitated the
addition process to give high ee (up to 94% for 4-methyl-
phenylboroxine versus 78% for 4-chlorophenylboroxine).
Steric hindrance around the boron atom retarded the rate
of reaction and lowered both yield and enantioselectivity.
The use of 3-methylphenylboroxine afforded the product
in 37% yield and nearly racemic form (Entry 5), while 3-
chlorophenylboroxine produced the product in 84% yield
Entry
Aldehyde (R5)
p-chlorophenyl
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
87
80
93
87
79
81
75
85
87
84
84
87
86
70
64
93(R)
94(R)
93(R)
93(R)
88(R)
94(R)
95(R)
95(R)
94(R)
94(R)
96(R)
89(R)
81(R)
82(S)
65(S)
p-methoxyphenyl
p-bromophenyl
p-methylphenyl
p-trifluoromethylphenyl
m-bromophenyl
m-chlorophenyl
m-methoxyphenyl
o-chlorophenyl
o-methoxyphenyl
1-naphthyl
2-naphthyl
2-furyl
(E)-cinnamyl
n-propyl
aConditions: Aldehyde/(1Ra,2S,3R)-1/phenylboroxin/diethylzinc
0.1/0.66/4 (molar ratio), toluene as solvent, 608C, 10 h.
bIsolated yields.
5 1/
cEnantiomeric excess was determined by HPLC analysis. Absolute config-
urations were determined by comparison of the order of peak elution from
HPLC analyses with literature values.
although high ee value (up to 94%) was obtained, the yield
was low. A similar phenomenon was also observed with a
proline-derived amino alcohol catalyst.21 We assumed that
the addition of PEG ethers would suppress some
unwanted nonasymmetric pathways by deactivating the
Chirality DOI 10.1002/chir

ASYMMETRIC ARYL TRANSFER WITH BOROXINE
163
7. Dosa PI, Ruble JC, Fu GC. Planar-chiral heterocycles as ligands in
metal-catalyzed processes: enantioselective addition of organozinc
reagents to aldehydes. J Org Chem 1997;62:444–445.
8. Schmidt F, Stemmler RT, Rudolph J, Bolm C. Catalytic asymmetric
approaches towards enantiomerically enriched diarylmethanols and
diarylmethylamines. Chem Soc Rev 2006;35:454–470 and references
cited therein.
9. Bolm C, Rudolph J. Catalyzed asymmetric aryl transfer reactions to
aldehydes with boronic acids as aryl source. J Am Chem Soc 2002;
124:14850–14851.
Fig. 3. The possible transition state of the phenylation.
10. Rudolph J, Hermanns N, Bolm C. The MPEG effect: improving asym-
metric processes by simple additives. J Org Chem 2004;69:3997–4000.
and 71% ee (Entry 6). The presence of a bulky meta
methyl substitute on the aryl ring showed a detrimental
effect on the selectivity albeit 3-methyl was also an elec-
tron-donating group.
11. Ji JX, Wu J, Au-Yeung TTL, Yip CW, Haynes RK, Chan ASC. Highly
enantioselective phenyl transfer to aryl aldehydes catalyzed by easily
accessible chiral tertiary aminonaphthol. J Org Chem 2005;70:1093–
1095.
This methodology was quite flexible for the synthesis of
diaryl methanols. With appropriate combinations of aryl-
boroxine and aromatic aldehydes, a diverse array of oppo-
sitely configured chiral diaryl methanols can be obtained
(Entry 4 of Table 2 versus Entry 2 of Table 3).
12. Braga AL, Lu¨dtke DS, Vargas F, Paix˜ao MW. Catalytic enantioselec-
tive arylation of aldehydes: boronic acids as a suitable source of trans-
ferable aryl groups. Chem Commun 2005;19:2512–2514.
13. Jimeno C, Sayalero S, Fjermestad T, Colet G, Maseras F, Perica`s MA.
Practical implications of boron-to-zinc transmetalation for the catalytic
asymmetric arylation of aldehydes. Angew Chem Int Ed 2008;47:
1098–1101.
Possible transition states of the phenyl transfer step
were similar to ethylation and alkynylation.29,31,32 The ste-
reoselective phenylation of aldehydes was promoted by
the chelated phenylzinc alkoxide, which coordinated with
both the carbonyl compound and a second molecule of
phenylzinc reagent (see Fig. 3). The migration of the phe-
nyl moiety to the carbonyl then occurred through a tricy-
clic transition state. With ligand (1Ra,2S,3R)-1, the phenyl
group on zinc(Ph*, with the relevant phenyl ring tilting
up) forced the aryl ring of the coordinated aryl aldehyde
to take a position away from Ph*, consequently the phenyl
transferred on the Re face of the carbonyl to afford pre-
dominant product with (R)-configuration.
14. Braga AL, Lu¨dtke DS, Schneider PH, Vargas F, Schneider A, Wessjo-
hann LA, Paix˜ao MW. Catalytic enantioselective aryl transfer: asym-
metric addition of boronic acids to aldehydes using pyrrolidinylmetha-
nols as ligands. Tetrahedron Lett 2005;46:7827–7830.
15. Braga AL, Milani P, Vargas F, Paix˜ao MW, Sehnem JA. Modular chi-
ral thiazolidine catalysts in asymmetric aryl transfer reactions. Tetra-
hedron Asymmetry 2006;17:2793–2797.
16. Jin M-J, Sarkar SM, Lee D-H, Qiu H. Highly enantioselective aryl
transfer to aldehydes: a remarkable effect of sulfur substitution in
amino thioacetate ligands. Org Lett 2008;10:1235–1237.
17. Rudolph J, Schmidt F, Bolm C. Highly enantioselective synthesis of
secondary alcohols using triphenylborane. Adv Synth Catal 2004;346:
867–872.
18. Rudolph J, Lormann M, Bolm C, Dahmen S. A high-throughput
screening approach for the determination of additive effects in organo-
zinc addition reactions to aldehydes. Adv Synth Catal 2005;347:1361–
1368.
In conclusion, we have demonstrated that 1,10-binaph-
thylazepine-derived amino alcohol (1Ra,2S,3R)-1 is a good
catalyst for the asymmetric aryl transfer reaction with bor-
oxines as the aryl source. Various enantiopure diarylme-
thanols were obtained directly altering the structures of
substrates and nucleophiles. These results compared
favorably with other known amino alcohol ligands in simi-
lar reaction.
19. Ozcubukcu S, Schmidt F, Bolm C. Organosilanols as catalysts in
asymmetric aryl transfer reactions. Org Lett 2005;7:1407–1409.
20. Dahmen S, Lormann M. Triarylborane ammonia complexes as ideal
precursors for arylzinc reagents in asymmetric catalysis. Org Lett
2005;7:4597–4600.
21. Wu XY, Liu XY, Zhao G. Catalyzed asymmetric aryl transfer reactions
to aldehydes with boroxines as aryl source. Tetrahedron Asymmetry
2005;16:2299–2305.
LITERATURE CITED
1. Nilvebrant L, Andersson K-E, Gillberg P-G, Stahl M, Sparf B. Toltero-
dine-a new bladder-selective antimuscarinic agent. Eur J Pharmacol
1997;327:195–207.
22. Chai Z, Liu X, Wu X, Zhao G. Synthesis of modular thiophene-oxazo-
line ligands and their application in the asymmetric phenyl transfer
reaction to aldehydes. Tetrahedron Asymmetry 2006;17:2442–2447.
2. Welch WM, Kraska AR, Sarges R, Koe BK. Nontricyclic antidepres-
sant agents derived from cis- and trans-1-amino-4-aryltetralins. J Med
Chem 1984;27:1508–1515.
23. Tomita D, Kanai M, Shibasaki M. Nucleophilic activation of alkenyl and
aryl boronates by a chiral Cu(I)F complex: catalytic enantioselective alke-
nylation and arylation of aldehydes. Chem Asian J 2006;1:161–166.
3. Astles PC, Brown TJ, Halley F, Handscombe CM, Harris NV, Majid
TN, McCarthy C, McLay IM, Morley A, Porter B, Roach AG, Sargent
C, Smith C, Walsh RJA. Selective ETA antagonists. 5. Discovery and
structure-activity relationships of phenoxyphenylacetic acid deriva-
tives. J Med Chem 2000;43:900–910.
24. Wu KH, Gau HM. Remarkably efficient enantioselective titanium(IV)-
(R)-H8- BINOLate catalyst for arylations to aldehydes by triaryl(tetra-
hydrofuran)aluminum reagents. J Am Chem Soc 2006;128:14808–14809.
25. Kim JG, Walsh PJ. From aryl bromides to enantioenriched benzylic
alcohols in a single flask: catalytic asymmetric arylation of aldehydes.
Angew Chem Int Ed 2006;45:4175–4178.
4. Bolshan Y, Chen C, Chilenski JR, Gosselin F, Mathre DJ, O’Shea PD,
Roy A, Tillyer RD. Nucleophilic displacement at benzhydryl centers:
asymmetric synthesis of 1,1-diarylalkyl derivatives. Org Lett 2004;6:
111–114.
26. Magnus NA, Anzeveno PB, Coffey DS, Hay DA, Laurila ME, Schker-
yantz JM, Shaw BW, Staszak MA. Optimized catalytic enantioselective
aryl transfer process gives access to mGlu2 receptor potentiators. Org
Process Res Dev 2007;11:560–567.
27. Mecca T, Superchi S, Giorgio E, Rosini C. 1,10-Binaphthylazepine-
based ligands for asymmetric catalysis. Part 1: Preparation and charac-
terization of some new aminoalcohols and diamines. Tetrahedron
Asymmetry 2001;12:1225–1233.
5. Barouh V, Dall H, Patel D, Hite G. Stereochemical aspects of antihist-
amine action. 4. Absolute configuration of carbinoxamine antipodes.
J Med Chem 1971;14:834–836.
6. Meguro K, Aizawa M, Sohda T, Kawamatsu Y, Nagaoka A. New 1,4-di-
hydropyridine derivatives with potent and long-lasting hypotensive
effect. Chem Pharm Bull 1985;33:3787–3797.
Chirality DOI 10.1002/chir

164
LIU ET AL.
28. Superchi S, Mecca T, Giorgio E, Rosini C. 1,10-Binaphthylazepine-
based ligands for asymmetric catalysis. Part 2: New aminoalcohols as
chiral ligands in the enantioselective addition of ZnEt2 to aromatic
aldehydes. Tetrahedron Asymmetry 2001;12:1235–1239.
29. Superchi S, Giorgio E, Scafato P, Rosini C. Rational design of chiral 1,10-
binaphthylazepine-based ligands for the enantioselective addition of ZnEt2
to aromatic aldehydes. Tetrahedron Asymmetry 2002;13:1385–1391.
32. Lu G, Li XS, Zhou ZY, Chan WL, Chan ASC. Enantioselective alkyny-
lation of aromatic aldehydes catalyzed by new chiral amino alcohol-
based ligands. Tetrahedron Asymmetry 2001;12:2147–2152.
33. Lu G, Kwong FY, Ruan JW, Li YM, Chan ASC. Highly enantioselective
addition of in situ prepared arylzinc to aldehydes catalyzed by a series
of atropisomeric binaphthyl-derived amino alcohols. Chem Eur J
2006;12:4115–4120.
30. Pisani L, Superchi S. 1,10-Binaphthylazepine-based ligands for the
enantioselective dialkylzinc addition to aromatic aldehydes. Tetrahe-
dron Asymmetry 2008;19:1784–1789.
34. Goldfuss B, Houk KN. Origin of enantioselectivities in chiral b-amino
alcohol catalyzed asymmetric additions of organozinc reagents to
benzaldehyde: PM3 transition state modeling. J Org Chem 1998;63:
8998–9006.
31. Pizzuti MG, Superchi S. Enantioselective alkynylation and phenylation of
aromatic aldehydes promoted by atropisomeric 1,10-binaphthylazepine-
based amino alcohols. Tetrahedron Asymmetry 2005;16:2263–2269.
35. Muramatsu Y, Harada T. Catalytic asymmetric alkylation of aldehydes
with Grignard reagents. Angew Chem Int Ed 2008;47:1088–1090.
Chirality DOI 10.1002/chir