Catalyzed asymmetric aryl transfer reactions to aldehydes with boroxines as aryl source

Article abstract of DOI:10.1016/j.tetasy.2005.06.010

Asymmetric aryl transfer of triphenylboroxin to a set of aryl aldehydes has been carried out in the presence of chiral amino alcohols derived from (S)-proline with high enantioselectivity. Substituted phenyl boroxins were also used as aryl source in asymmetric arylation of benzaldehyde.

Full text of DOI:10.1016/j.tetasy.2005.06.010

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2299–2305
Catalyzed asymmetric aryl transfer reactions to aldehydes with
boroxines as aryl source
Xiaoyu Wu, Xinyuan Liu and Gang Zhao*
Laboratory of Modern Synthetic Organic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 FengLin Lu, Shanghai 200032, China
Received 11 May 2005; accepted 9 June 2005
Abstract—Asymmetric aryl transfer of triphenylboroxin to a set of aryl aldehydes has been carried out in the presence of chiral
amino alcoholsderived from ( S)-proline with high enantioselectivity. Substituted phenyl boroxins were also used as aryl source
in asymmetric arylation of benzaldehyde.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
et al. found later that the undesired background reac-
tion could be effectively suppressed by the concomitant
use of Et2Zn with Ph2Zn, using ferrocyl oxazoline and
Chiral diaryl methanolsare important intermediatesfor
the synthesis of biologically active compounds.1 This
kind of alcohol can be obtained by the catalytic asym-
metric addition of aryl zinc species to aromatic alde-
hydes.2 However, when compared to the tremendous
progress achieved in the asymmetric addition of dialkyl
zinc to aldehydes,3 the asymmetric arylation of alde-
hydesusing organozinc reagentsisrelatively unexplored
because of the competitive background reaction of aryl
zinc species with aromatic aldehydes directly without
going through the catalytic process.4–16
7
rhenium-tricarbonyloxazoline asligand. s
In 2002,
Ha et al. reported that binaphthyl based axially chiral
amino alcohols showed high levels of selectivity in the
addition of Ph2Zn to aldehydeswithout adding Et Zn
2
8
asan additive. However, Pericaset al. found that the
use of Et2Zn/Ph2Zn gave better results than only using
Ph2Zn in the presence of a chiral amino alcohol.9 Very
recently, Kim and Bolm reported the use of proline
derived amino alcohol containing perfluoro groupsfor
recycling purposes in the phenylation of aromatic
aldehydes.10
In 1991, Soai et al. initially reported the enantioselective
phenylation of prochiral aldehydesemploying a zinc
reagent prepared in situ from ZnCl2 and phenyl magne-
sium bromide and stoichiometric amounts of N,N-
dibutylnorephedrine.4 Fu et al. reported, in 1997, the
addition of salt-free Ph2Zn to p-chlorobenzaldehyde
using a planar-chiral azoferrocene ligand with moderate
enantioselectivity.5 Since then, many effortshave been
dedicated to develop an efficient system for this aryl
group transfer reaction. Pu et al. reported that perform-
ing the addition reaction at a low concentration of sub-
strate improved the enantioselectivity dramatically,
In 2002, Bolm et al. broadened the scope of the aryl zinc
species using aryl boronic acids as the aryl source by
mixing the boronic acidswith Et 2Zn or Me2Zn at
60 °C for 10 h.11 Recently, Braga et al. and Chan et al.
also reported efficient chiral ligands for phenylation
of aromatic aldehydesuisng phenyl boronic acid as
the aryl source.12,13 Besides aryl boronic acid, Ph3B
and alkenylborane, etc., were also used in this
reaction.14
A threefold excess of Et2Zn isunavoidable in the pro-
cedure of boron–zinc exchanging, since the aryl boronic
acid has two additional hydroxyl groups. We assumed
that Et2Zn could tolerate the B–O bond in boroxin.15 If
so, the amount of Et2Zn used can be reduced sub-
stantially by replacing the boronic acid by boroxin.
Herein, we report an aryl transfer reaction to aromatic
6
using chiral 3,30-diaryl binaphthol asa ligand. Bolm
*
Corresponding author. Fax: +86 21 641 66128; e-mail: zhaog@
mail.sioc.ac.cn
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.06.010

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X. Wu et al. / Tetrahedron: Asymmetry 16 (2005) 2299–2305
N
N
N
N
N
N
N
OH
OH
OH
OH
OH
F
OH
1c
1d
1b
1f
1a
1e
F
N
H
OH
OH
1g
1h
Figure 1. Amino alcoholsderived from ( S)-proline.
aldehydes, using aryl boroxin as the aryl source in the
presence of (S)-proline derived amino alcohol (Fig.
1).16
À15 °C, the selectivity increased slightly, 90% ee (Table
1, entry 5). The enantioselectivity dropped dramatically
when the amount of 1a wasdecreaesd to 0.02 and
0.01 equiv with 25% ee and 21% ee, respectively, due
to the competitive background reaction. Although an
excess of Et2Zn waspreesnt in the reaction mixture,
no ethylated product could be detected under the pres-
ent reaction conditions.
2. Results and discussion
Systematic studies of a model reaction comprising
p-chlorobenzaldehyde 2a, phenyl boroxin 3a, Et2Zn,
and ligand 1a, are summarized in Table 1. Asshown in
Table 1, (S)-p-chlorobenzhydrol 4a wasformed with
good enantioselectivity and high yield in the presence of
1a. The (S)-configuration of the product indicatesthat
the phenyl addition occursat the si-face of the aldehyde,
the same as the Et2Zn addition catalyzed by 1a.17 This
result suggests that the catalytic phenyl transfer reaction
should be mechanistically similar to the Et2Zn addition.
Racemic 4a was isolated in 86% yield in the absence of
ligand 1a. This result showed a strong background reac-
tion (Table 1, entry 9). Decreasing the amount of phenyl
boroxin from 0.8 to 0.4 equiv had a slightly positive ef-
fect on selectivity (90% ee), but a negative effect on the
isolated yield (Table 1, entries1 and 2). When the reac-
tion wasconducted at 10 °C, the selectivity slightly
decreased from 89% ee (Table 1, entry 3) to 85% ee
(Table 1, entry 4). By lowering the temperature to
Next, we examined the substituent effect of the alcohol
moiety in 1a–h on the level of the asymmetric induction
in the addition of the phenyl zinc species to p-chloro-
benzaldehyde 2a (Table 2). Compound 1a afforded the
best result for this reaction. The enantiomer 1b afforded
the alcohol in 89% ee with an (R)-configuration. Replac-
ing the phenyl groupsin 1a by a five-member ring
caused the selectivity to decrease from 89% ee to 33%
ee (Table 2, entries 1–3). The same results were reported
for ethyl addition to aldehydeswith the methyl group on
N atom in the pyrrole ring of 1a being vital for reactivity
and selectivity.18 Compound 1h, a secondary amine only
afforded 4a in 84% yield and 35% ee (Table 2, entry 8).
The variation of the phenyl group in 1a can also affect
the selectivity of the reaction. Compounds 1d, 1e, and
1f with a methyl group on the para-, meta-, and ortho-
position of phenyl group, respectively, catalyzed the
Table 1. Enantioselective phenyl transfer from phenyl boroxin to p-chlorobenzaldehyde 2aa
1a
OH
Ph
Et2Zn, Hexane
60oC, 10h
aldehyde 2a
(PhBO)3
(p-Cl)Ph
10h
3a
4a
Entry
Ligand 1a (equiv)
(PhBO)3 (equiv)/Et2Zn (equiv)
Temperature (°C)
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9d
0.1
0.1
0.8/7.2
0.4/3.6
0
0
95
88
91
90
99
87
85
74
86
89
90
89
85
90
80
25
21
—
0.1
0.1
0.66/4.0
0.66/4.0
0.67/4.0
0.43/2.6
0.43/2.6
0.43/2.6
0.66/4.0
0
10
À15
0
0.1
0.05
0.02
0.01
—
0
0
0
a The concentration of 2a wasapproximately 0.1 M.
b Isolated yield.
c Determined by chiral HPLC Chiralcel AD column.
d Without the addition of 1a.

X. Wu et al. / Tetrahedron: Asymmetry 16 (2005) 2299–2305
2301
Table 2. Screening of amino alcohols 1a–ha
3–6). According to the results reported by Bolm et al.
and Chan et al., the use of DiMPEG as an additive
increased the enantiomeric excess of the products.11–13
However, in our case, the yield decreased dramatically
(Table 3, entries2 and 12). In contrast to the ethylation
of E-cinnamaldehyde 2j in the presence of 1a, which affor-
ded the product in 100% ee,16a phenylation of 2j resulted
in only moderate selectivity, 59% ee (Table 3, entry 11).
1a-h
OH
Ph
Et2Zn, Hexane
60oC, 10h
aldehyde 2a
(PhBO)3
3a
(p-Cl)Ph
0oC, 10h
4a
Entry
Amino alcohol
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
91
94
91
89
76
79
85
84
89
89d
33
84
85
81
86
35
Further, to optimize these reaction conditions, we found
that pretreating 1a with Et2Zn could improve the enantio-
selectivity of this reaction. For substrate 2a, the enantio-
selectivity increased from 89% ee (Table 3, entry 1) to
95% ee (Table 4, entry 1). Pu et al. also reported the
same effect of pretreating the ligand with Et2Zn using
a chiral binol ligand.6
1g
1h
a 2a/(PhBO)3/Et2Zn/1a–h = 1:0.66:4:0.1.
b Isolated yield.
c Determined by HPLC chiral-AD column.
d (R)-Configuration.
Pretreatment of 1a with Et2Zn could improve the
enantioselectivity except for substrate 2g (Table 3, entry
8 vs Table 4, entry 10). The best result was obtained at
0 °C for substrate 2a, although the selectivity was
slightly lower when the reaction was carried out at 15
and À15 °C, 91% ee and 93% ee, respectively (Table 4,
entries2 and 3). When the amountsof boroxin and
Et2Zn were decreased to 0.38 and 1.3 equiv, the concen-
tration of 2a was increased to 0.2 M with the desired
alcohol 4a being produced in 91% ee in a lower isolated
yield, 62% (Table 4, entry 4). Using 0.05 equiv of 1a
afforded the diaryl methanol in 91% ee (Table 4, entry
5), which iscomparable to that of uisng 0.1 equiv 1a.
For substrate 2j, E-cinnamaldehyde, under these
reaction in a slightly lower enantioselectivity than that
of 1a (Table 2, entries4–6). Compound 1f, containing
an electron withdrawing fluoro on the para-position of
the phenyl group gave the product alcohol in 86% ee.
These results indicate that the substituent on the phenyl
group of amino alcoholshaslittle effect on the
enantioselectivity.
A series of substituted benzaldehydes together with cin-
namaldehyde and 1-naphthyl aldehyde were subjected
to phenylation using 1a asa ligand ( Table 3). The in situ
catalyst formed from 1a and the organozinc species pro-
moted the reaction in high yield and good enantiomeric
excess for all aromatic aldehydes. para-Substituted ben-
Table 4. Phenylation of aldehydeswith further optimized catalyiss
systema
zaldehydesafford better reusltsthan that of the meta-
and ortho-substituted aldehydes (Table 3, entries1 and
O
OH
Ph
(PhBO)3/Et2Zn
R
H
R
toluene/hexane
Table 3. Phenylation reaction of aromatic aldehydesa
1a, 0oC, 10h
2
4
O
OH
Ph
Entry Aldehyde
R
Temperature Yield ee
(%)b (%)c
(PhBO) / Et Zn
3
2
(°C)
toluene/hexane
R
H
R
o
1a, 0 C, 10h
1
2a
2a
2a
2a
2a
2b
2c
2e
2f
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
p-Cl-phenyl
m-Cl-phenyl
o-Cl-phenyl
m-Br-phenyl
p-CF3-phenyl
p-MeO-phenyl
2, 4-Cl, Cl-phenyl
E-Cinnamyl
p-Me-phenyl
1-Naphthyl
2-Naphthyl
o-Br-phenyl
0
15
À15
0
93
84
87
62
93
93
89
93
81
82
73
88
93
87
88
91
95
91
93
91
91
95
95
87
88
90
93
83
88
95
94
92
2a-l
4a-l
2
Entry
Aldehyde
R
Yield (%)b
ee (%)c
3
4d
5e
6
1
2a
2a
2b
2c
2d
2e
2f
p-Cl-phenyl
p-Cl-phenyl
m-Cl-phenyl
o-Cl-phenyl
p-Br-phenyl
m-Br-phenyl
p-CF3-phenyl
p-MeO-phenyl
p-F-phenyl
91
37
87
90
95
90
86
96
96
97
93
47
95
91
89
96
88
83
94
73
79
91
94
83
59
72
87
93
2d
3
0
0
7
0
4
8
0
5
9
0
6
10
11
12
13
14
15
16
2g
2i
0
7
0
8
2g
2h
2i
2j
0
9
2k
2l
0
10
11
12d
13
14
2, 4-Cl, Cl-phenyl
E-Cinnamyl
E-Cinnamyl
p-Me-phenyl
1-Naphthyl
0
2j
2m
2n
0
2j
0
2k
2l
a Concentration of aldehyde isapproximately 0.1 M.
b Isolated yield.
a 2/(PhBO)3/Et2Zn/1a = 1:0.66:4:0.1, aldehyde concentration approxi-
mately 0.1 M.
c Ee valuesdetermined by chiral HPLC, the configuration of 4 deter-
mined by comparison with literature data.
d 2/3a(PhBO)3/Et2Zn/1a = 1:0.38:1.30:0.1, the concentration of 2a
approximately 0.2M.
b Isolated yields.
c Determined by chiral HPLC, the configuration of 4 wasdetermined
by comparing with literature data.
d Using 0.1 equiv DiMPEG (MW 2000) as an additive.
e Using 0.05 equiv ligand 1a.

2302
X. Wu et al. / Tetrahedron: Asymmetry 16 (2005) 2299–2305
100
80
60
40
20
0
0
20
40
60
80
100
ee% of 1a
Figure 2. Nonlinear effect of amino alcohol 1a.
reaction conditionsthe selectivity improved from 59% ee
(Table 3, entry 11) to 83% ee (Table 4, entry 12). Benz-
aldehyde with an ortho and meta substituent gave com-
parable ee valuesto that of the para one (Table 3, entries
1, 3, and 4 and Table 4, entries1, 6–8, and 16). 1-Naph-
thaldehyde and 2-naphthaldehyde afforded excellent
results, 95% ee and 94% ee, respectively (Table 4, entries
14 and 15).
Next, we investigated the possibility of varying the
structure of the aryl source and studied the asymmetric
aryl transfer from various substituted phenyl boroxin to
benzaldehyde, 2o. Asshown in Table 5, pretreatment of
the ligand with Et2Zn improvesthe ee value greatly for
boroxin 3b (81% ee vs27% ee) and 3c (94% ee vs58% ee)
ascompared to that of without pretreatment of Et Zn
2
(Table 5, entries1–4). para- and meta-Bromo substituted
phenyl boroxin afforded the productsin excellent
selectivity, 93% ee and 94% ee, respectively (Table 5,
entries5 and 6). Using p-methoxylphenyl boroxin 3f as
the aryl source, alcohol 4g wasobtained in 92% ee
(Table 5, entry 7), which waslisghtly higher than
that of the phenyl addition of aldehyde 2g (Table 4,
entry 10).
Asshown in Figure 2, 1a shows a weak positive nonlin-
ear effect in the reaction between 2a and the phenyl zinc
species generated from phenylboroxin and Et2Zn. When
p-chlorobenzaldehyde and the zinc species are reacted in
the presence of 20 mol % of 1a in 70% ee, which ispre-
treated with Et2Zn, alcohol 4a isproduced in 91% ee.
This result is comparable to that of using enantiomeri-
cally pure 1a.
3. Conclusion
In conclusion, different protocols for the enantioselec-
tive addition of aryl zinc species to aromatic aldehydes
in the presence of amino alcohols derived from L-proline
have been studied. Generally, the enantioselectivity can
be improved by pretreating the amino alcohol with
Et2Zn. The phenyl groupsin phenyl boroxin are trans-
ferred effectively to a variety of aromatic aldehydesin
high yield and good enantioselectivity. Substituted phe-
nyl boroxins are also used as aryl source, and trans-
ferred effectively in high ee. Although using DiMPEG
asan additive can improve the ee, the yield, however,
dropped greatly.
Table 5. Arylation of benzaldehyde using substituted phenylboroxina
O
OH
Ar
(ArBO)3 / Et2Zn
Ph
H
Ph
toluene/hexane
2o
4
1a, 0 oC, 10h
Entry Boroxin Ar
Product Yield (%)b ee (%)c
1d
2
3b
3b
3c
3c
3d
3e
3f
p-Cl-phenyl
p-Cl-phenyl
p-Me-phenyl
p-Me-phenyl
p-Br-phenyl
m-Br-phenyl
p-MeO-phenyl
4a
4a
4k
4k
4d
4e
4g
89
88
82
97
91
84
87
58
94
27
81
93
94
92
3d
4
5
6
7
4. Experimental
a Asthe procedure dcersibed in
Table 4, 2/3(ArBO)3/Et2Zn/
1a = 1:0.67:4:0.1. The concentration of aldehyde isapproximately
0.1 M.
General: NMR spectra were recorded at 300 MHz for
1H, and 75 MHz for 13C. Chemical shifts are reported
in d ppm referenced to an internal TMS standard for
1H NMR and chloroform-d (d 77.05) for 13C NMR.
The enantiomeric excess of 4a–n wasdetermined by
b Isolated yields.
c Ee valuesdetermined by chiral HPLC, the configuration of 4 deter-
mined by comparison with literature data.
d The ligand wasnot pretreated with Et 2Zn.

X. Wu et al. / Tetrahedron: Asymmetry 16 (2005) 2299–2305
2303
Chiral HPLC. THF was freshly distilled over sodium/
benzophenone before use. Toluene was freshly distilled
from CaH2.
4.1.4. Preparation of 1d. The compound wasprepared
analogously to 1a: purified by silica gel chromatography
with ethyl acetate and methanol (10:1 to 3:1), then
recrystallized from hexane to give a white crystalline
20
1
4.1. Preparation of amino alcohol 1a–h
solid. Mp 94–96 °C; ½aŠ ¼ þ19.7 ðc 2.00; CHCl3Þ; H
D
NMR (CDCl3) d 7.51–7.47 (d, 2H, J = 8.1 Hz), 7.41–
7.38 (d, 2H, J = 8.1 Hz), 4.70 (s, 1H), 3.60–3.54 (dd,
1H, J = 9.3, 3.9 Hz), 3.12–3.05 (m, 1H), 2.50–2.35 (m,
1H), 2.25 (s, 6H), 1.95–1.85 (m, 1H), 1.82 (s, 3H),
1.75–1.59 (m, 3H); 13C NMR (CDCl3) d 145.5, 144.0,
135.4, 135.3, 128.6, 125.3, 125.1, 77.1, 71.8, 59.1, 43.0,
29.8, 23.9, 20.9, 20.7; IR (KBr) 3355, 3093, 3057, 2967,
2948, 2872, 2789, 1798, 1507, 1459, 1371, 1175, 1042,
799, 778, 735 cmÀ1; HRMS for C20H26NO (M+H)+
296.2009, found 296.2009.
4.1.1. Preparation of amino alcohol 1a. A solution of
methyl L-1-ethoxycarbonylprolinate (8.6 g, 42 mmol) in
THF (20 mL) wasplaced in the addition funnel and
added slowly to a solution of phenyl magnesium bro-
mide (90 mmol) at 0 °C in 20 min. After the addition,
the mixture wastsirred at room temperature for 0.5 h
and then heated at reflux for 4 h. The mixture was
cooled to room temperature, and then an ice-cold solu-
tion of saturated NH4Cl wasadded. The aqueouslayer
wasextracted with ether. The combined organic layer
wasdried over anhydrousNa 2SO4. Removal of the sol-
vent gave the crude product asa yellow solid, which was
recrystallized from ethyl acetate to afford a white crys-
talline solid (9.3 g, 78%), which was used directly in
the next step.
4.1.5. Preparation of 1e. The compound wasprepared
analogously to 1a, then recrystallized from hexane to
give
a
white crystalline solid. Mp 63–64 °C;
20
D
½aŠ ¼ þ30.2 ðc 0.829; CHCl3Þ; 1H NMR (CDCl3) d
7.46 (s, 1H), 7.41–7.38 (d, 1H, J = 7.5 Hz), 7.36 (s,
1H), 7.31–7.28 (d, 1H, J = 7.5 Hz), 7.20–7.10 (t, 1H,
J = 7.5 Hz), 6.98–6.90 (m, 2H), 4.73 (s, 1H), 3.65–3.55
(dd, 1H, J = 9.0, 5.2 Hz), 3.12–3.05 (m, 1H), 2.50–
2.35 (m, 1H), 2.31 (s, 3H), 2.30 (s, 3H), 1.95–1.85 (m,
1H), 1.80 (s, 3H), 1.75–1.59 (m, 3H); 13C NMR
(CDCl3) d 148.1, 146.6, 137.4, 127.6, 126.7, 126.1,
122.6, 122.3, 77.3, 71.9, 59.1, 42.9, 29.8, 23.9, 21.6;
IR (KBr) 3315, 3093, 3057, 2987, 2943, 2856, 2792,
1601, 1486, 1459, 1387, 1157, 1041, 782, 770,
709 cmÀ1; HRMS for C20H26NO (M+H)+ 296.2009,
found 296.2010.
To a flame dried 250 mL three-necked flask was added
anhydrousTHF (50 mL) under an inert atmosphere of
argon. LAH (2.7 g, 71 mmol) wasadded in three por-
tions. A solution of the product in first step (25 mmol)
in THF (30 mL) wasadded dropweis through a
100 mL addition funnel at 0 °C. Then the mixture was
heated at reflux for 4 h. The reaction wasquenched by
water after being cooled to 0 °C. The mixture wasacidi-
fied to pH 3 with 1 M HCl, washed with Et2O, and made
alkaline with concentrated aqueousNaOH. The precipi-
tate wasfiltered off and washed with ethyl acetate. The
organic layer wasesparated, and the filtrate extracted
with CH2Cl2. The combined extract wasdried over anhy-
4.1.6. Preparation of 1f. The compound wasprepared
analogously to 1a, and purified by silica gel column
chromatography to give a colorless oil (84%), which
drousNa SO4 and evaporated under reduced pressure.
2
Compound 1a was obtained as a white crystalline solid
(6.69 g, 96%) after being recrystallized from hexane.
solidified after being stored in an icebox for several days.
20
D
Mp 61–62 °C; ½aŠ ¼ þ30.6 ðc 1.4; CHCl3Þ; 1H NMR
20
23
½aŠ ¼ þ59 ðc 0.77; CHCl3Þ {lit.16a ½aŠ ¼ þ57ðc 1.0;
(CDCl3) d 7.50–7.10 (m, 6H), 7.00–6.85 (m, 2H), 4.85–
4.60 (br, 1H), 3.65–3.55 (m, 1H), 3.15–3.05 (m, 1H),
2.50–2.35 (m, 1H), 2.31 (s, 6H), 2.00–1.50 (m, 7H); 13C
NMR (CDCl3) d 148.2, 146.6, 137.5, 127.6, 126.7,
126.1, 122.6, 122.3, 77.3, 71.9, 59.1, 42.9, 29.9, 23.9,
21.6; IR (KBr) 3317, 3093, 3057, 2943, 2914, 2856,
2792, 1602, 1486, 1459, 1387, 1156, 1041, 782, 770,
709 cmÀ1; HRMS for C20H26NO (M+H)+ 296.2009,
found 296.2005.
D
D
CHCl3Þ}; 1H NMR (CDCl3) d 7.70–7.05 (m, 10H),
4.80–4.75 (m, 1H), 3.65–3.55 (dd, 1H, J = 9.6, 3.9 Hz),
3.15–3.00 (m, 1H), 2.50–2.35 (m, 1H), 2.10–1.50 (m, 7H).
4.1.2. Preparation of ligand 1b. The compound was
20
D
prepared analogously to 1a: ½aŠ ¼ À60 ðc 0.69;
23
D
1
CHCl3Þ {lit.16a ½aŠ ¼ À57 ðc 1.00; CHCl3Þ]; H NMR
(CDCl3) d 7.70–7.05 (m, 10H), 4.80–4.75 (m, 1H),
3.65–3.55 (dd, 1H, J = 9.6, 3.9 Hz), 3.15–3.00 (m, 1H),
2.50–2.35 (m, 1H), 2.10–1.50 (m, 7H).
4.1.7. Preparation of 1g. The compound wasprepared
analogously to 1a, then recrystallized from hexane to
20
D
4.1.3. Preparation of 1c. Thiscompound wasprepared
from methyl L-1-ethoxycarbonylprolinate and the Grig-
nard reagent prepared from 1,4-dibromobutane accord-
ing to the procedure described for compound 1a,
purified by silica gel column chromatography with ethyl
acetate and methanol (3:1) asa light yellow oil (81%
give a white crystalline. ½aŠ ¼ þ41 ðc 1.05; CHCl3Þ
20
D
{lit.16b ½aŠ ¼ þ40.5 ðc 1.75; CHCl3Þ}; 1H NMR
(CDCl3) d 7.60–7.40 (m, 4H), 7.00–6.90 (m, 4H), 4.82
(m, 1H), 3.60–3.55 (dd, 1H, J = 11.4, 4.8 Hz), 3.15–
3.08 (m, 1H), 2.50–2.40 (m, 1H), 1.95–1.55 (m, 7H).
20
1
yield). ½aŠ ¼ À49 ðc 1.36; CHCl3Þ; H NMR (CDCl3)
4.1.8. Preparation of 1h. The compound wasprepared
according to the literature procedure.19 ½aŠ
D
20
D
d 7.70–7.05 (10H), 4.80–4.75 (m, 1H), 3.13–3.05 (m,
1H), 2.45 (s, 3H), 2.40–2.30 (m, 2H), 1.90–1.40 (m,
12H); 13C NMR (CDCl3) d 82.4, 73.2, 58.8, 43.5, 40.8,
37.1, 28.7, 24.5, 23.2; IR (KBr) 3446, 2961, 2871, 2848,
¼
20
D
À54.6 ðc 2.34; CHCl3Þ {lit.19 ½aŠ ¼ À53.5 ðc 0.26;
CHCl3Þ}; 1H NMR (CDCl3) d 7.60–7.45 (m, 4H),
7.35–7.15 (m, 6H), 4.70–4.50 (br, 1H), 4.30–4.20
(t, 1H, J = 4.5Hz), 3.06–2.90 (m, 2H), 1.80–1.50 (m,
1H).
2786, 1458, 1382, 1040, 1002 cmÀ1
;
HRMS for
C12H19NO (M+Na)+ 192.1359, found 192.1357.

2304
X. Wu et al. / Tetrahedron: Asymmetry 16 (2005) 2299–2305
4.2. Typical procedure for the preparation of
arylboroxines
22.3 ðc 1.75; CHCl3Þ, for 96% ee (R)-4c}; 1H NMR
(CDCl3) d 7.63–7.59 (d, 1H, J = 7.5 Hz), d 7.41–7.20
(m, 8H), d 6.20–6.23 (d, 1H, J = 3.9 Hz), d 2.42–2.39
(d, 1H, J = 3.9 Hz); HPLC: Daicel Chiralcel OD
column, hexane/i-PrOH = 9:1, 0.75 mL/min, k = 254 nm,
tR(R) = 15.8 min, tR(S) = 19.85 min.
Phenyl boronic acid washeated at 110 °C for 6 h in an
oven; boronic acid wasconverted to phenyl boroxin
quantitatively by thisprocedure. 1H NMR (CDCl3) d
8.20–8.30 (m, 6H), d 7.40–7.60 (m, 9H).
4.3.4. (S)-(4-Bromophenyl)phenyl-methanol 4d.7a The
compound wasobtained asa white oslid; mp 56–
Other arylboroxineswere prepared by the ams e
procedure.
25
D
58 °C; ½aŠ ¼ þ18 ðc 1.08; PhHÞ for 94% ee {lit.20
25
D
½aŠ ¼ 21 ðc 0.8; PhHÞ, for enantiomeric pure (R)-4d};
4.3. Typical procedure for the phenyl transfer reaction
1H NMR (CDCl3) d 7.50–7.20 (m, 9H), d 5.82–5.81 (d,
1H, J = 7.5 Hz), d 2.23–2.19 (d, 1H, J = 3.9 Hz); HPLC:
Daicel Chiralcel AD column, hexane/i-PrOH = 9:1,
0.75 mL/min, k = 254 nm, tR(R) = 14.3 min, tR(S) =
15.8 min.
A flame dried Schlenk tube wascharged with phenyl
boroxine (62 mg, 0.6 mmol) under an inert atmosphere
(Ar). Et2Zn (1.2 mmol, 1 M in hexane) wasadded via
a syringe. The mixture was stirred for 10 h at 60 °C.
Another Schlenk tube wasthen charged with 1a (8 mg,
0.03 mmol) and freshly distilled toluene (0.5 mL) under
an Ar atmosphere, and then stirred for 0.5 h at room
temperature. The clear solution in the first tube was
transferred to the second tube via a syringe. The result-
ing mixture wasstirred for 0.5 h at room temperature.
After the mixture wascooled to 0 °C in an ice bath,
p-chlorobenzaldehyde 2a (42 mg, 0.3 mmol) dissolved
in toluene (1.5 mL) was added dropwise via a syringe.
The whole mixture wastsirred for 10 h at 0 °C. Then
the reaction wasquenched with 1 M HCl and extracted
with ethyl acetate, the combined organic layer was
washed with saturated brine and dried over anhydrous
Na2SO4. Removal of the solvent and purification by sil-
ica gel column chromatography with ethyl acetate and
hexane gave the product alcohol 4a. Enantiomeric
excess was determined by chiral HPLC.
4.3.5. (S)-(3-Bromophenyl)phenyl-methanol 4e.7a The
25
D
compound wasobtained asa colorlessoil;
½aŠ ¼
1
þ25.7 ðc 0.944; CHCl3Þ for 87% ee; H NMR (CDCl3)
d 7.57 (s, 1H), d 7.40–7.15 (m, 8H), d 5.81–5.78 (d, 1H,
J = 3.3 Hz), d 2.29–2.27 (d, 1H, J = 3.3 Hz); HPLC:
Daicel Chiralcel OD column, hexane/i-PrOH = 9:1,
0.75 mL/min, k = 254 nm, tR(S) = 28.3 min, tR(R) =
31.9 min.
4.3.6. (S)-(4-Trifluoromethylphenyl)phenyl-methanol 4f.
The compound wasobtained asa light yellow oil;
25
D
1
½aŠ ¼ À61.5 ðc 0.291; CHCl3Þ for 88% ee; H NMR
(CDCl3) d 7.70–7.25 (m, 9H), d 6.33–6.30 (d, 1H,
J = 3.6 Hz), d 2.33–2.30 (d, 1H, J = 3.6 Hz); HPLC:
Daicel Chiralcel OJ column, hexane/i-PrOH = 9:1,
0.75 mL/min, k = 254 nm, tR(R) = 15.6 min, tR(S) =
20.4 min.
Pretreatment of amino alcohol 1a: To a solution of 1a
(8 mg, 0.03 mmol) in toluene wasadded Et 2Zn
(0.06 mmol, 1 M in hexane) and stirred for 0.5 h at room
temperature.
4.3.7. (S)-(4-Methoxylphenyl)phenyl-methanol 4g.8 The
compound wasobtained asa white solid; mp 62–63 °C;
25
25
D
½aŠ ¼ À14 ðc 0.627; PhHÞ for 91% ee {lit.8 ½aŠ
¼
D
þ17 ðc 2.5; PhHÞ, for 98% ee (R)-4g}; 1H NMR
(CDCl3) d 7.40–7.20 (m, 7H), 6.90–6.80 (m, 2H), 5.81–
5.79 (m, 1H), 3.78 (s, 3H), 2.27–2.18 (m, 1H); HPLC:
Daicel Chiralcel OJ column, hexane/i-PrOH = 4:1,
0.75 mL/min, k = 254 nm, tR (R) = 28.8 min, tR(S) =
31.4 min.
4.3.1. (S)-(4-Chlorophenyl)phenyl-methanol 4a.8 The
compound wasobtained asa white oslid; mp 54–
20
D
55 °C; ½aŠ ¼ þ22 ðc 0.48; CHCl3Þ for 95% ee {lit.8
25
D
1
½aŠ ¼ À18.3 ðc 0.86; CHCl3Þ, for 94% ee (R)-4a}; H
NMR (CDCl3) d 7.40–7.25 (m, 9H), d 5.83–5.81 (d,
1H, J = 3.3 Hz), d 2.25–2.22 (d, 1H, J = 3.3 Hz); HPLC:
Daicel Chiralcel AD column, hexane/i-PrOH = 9:1,
1 mL/min, k = 254 nm, tR(R) = 10.4 min, tR(S) =
11.4 min.
4.3.8. (S)-(4-Fluorophenyl)phenyl-methanol 4h.16b The
compound wasobtained asa colorsloesil;
25
½aŠ ¼ þ5.4 ðc 0.76; CHCl3Þ for 94% ee; 1H NMR
D
(CDCl3) d 7.40–7.28 (m, 7H), 7.06–6.95 (m, 2H), 5.86–
5.83 (d, 1H, J = 3.6 Hz),
d
2.21–2.19 (d, 1H,
4.3.2. (S)-(3-Chlorophenyl)phenyl-methanol 4b.8 The
J = 3.6 Hz); HPLC: Daicel Chiralcel OB-H column,
hexane/i-PrOH = 4:1, 0.75 mL/min, k = 254 nm, tR
(R) = 20.0 min, tR(S) = 23.6 min.
compound wasobtained asa colorsloesil;
25
25
D
½aŠ ¼ þ35.7 ðc 0.27; acetoneÞ for 95% ee {lit.8 ½aŠ
¼
D
À27.6 ðc 1.12; acetoneÞ, for 92% ee (R)-4b};1H NMR
(CDCl3) d 7.45–7.20 (m, 9H), d 5.81–5.79 (d, 1H,
J = 3.9 Hz), d 2.29–2.28 (d, 1H, J = 3.9 Hz); HPLC:
Daicel Chiralcel OD column, hexane/i-PrOH = 19:1,
0.75 mL/min, k = 254 nm, tR(S) = 36.1 min, tR(R) =
39.7 min.
4.3.9. (S)-(2,4-Dichlorophenyl)phenyl-methanol 4i.21 The
compound wasobtained asa colorsloesil;
25
25
D
½aŠ ¼ À6.1 ðc 3.83; acetoneÞ for 93% ee {lit.21 ½aŠ
¼
D
þ6.7 ðc 5.00; acetoneÞ for 86% ee (R)-4i}; 1H NMR
(CDCl3) d 7.70–7.20 (m, 8H), 6.20–6.10 (d, 1H,
J = 3.6 Hz), 2.40–2.30 (d, 1H, J = 3.6 Hz); HPLC: Dai-
cel Chiralcel OD column, hexane/i-PrOH = 4:1,
0.75 mL/min, k = 254 nm, tR(S) = 10.0 min, tR(R) =
11.3 min.
4.3.3. (S)-(2-Chlorophenyl)phenyl-methanol 4c.8 The
compound wasobtained asa colorsloesil;
25
D
25
D
½aŠ ¼ À26 ðc 0.58; CHCl3Þ for 93% ee {lit.8 ½aŠ
¼

X. Wu et al. / Tetrahedron: Asymmetry 16 (2005) 2299–2305
2305
4.3.10. (R)-(E)-1,3-Diphenyl-2-propenol 4j.9 The com-
Chem. Pharm. Bull. 1985, 33, 3787; (d) Toda, F.; Tanaka,
K.; Koshiro, K. Tetradedron: Asymmetry 1991, 2, 873; (e)
Stanev, S.; Rakovska, R.; Berova, N.; Snatzke, G.
Tetradedron: Asymmetry 1995, 6, 183; (f) Bota, M.;
Summa, V.; Corelli, F.; Pietro, G. D.; Lombardi, P.
Tetradedron: Asymmetry 1996, 7, 1263; (g) Corey, E. J.;
Heldal, C. J. Tetradedron Lett. 1996, 4837.
pound
wasobtained
asa
colosroleisl;
25
D
20
D
½aŠ ¼ þ30.5 ðc 0.33; CHCl3Þ for 83% ee {lit.22 ½aŠ
¼
À32.1 ðc 0.5; CHCl3Þ for enantiomerically pure (R)-
1
4j}; H NMR (CDCl3) d 7.50–7.20 (m, 10H), d 6.70–
6.60 (d, 1H, J = 15.9 Hz), 6.40–6.30 (dd, 1H, J = 15.9,
6.6 Hz), 5.40–5.33 (d, 1H, J = 5.4 Hz), 2.25–2.15 (m,
1H); HPLC: Daicel Chiralcel OD column, hexane/
i-PrOH = 9:1, 0.75 mL/min, k = 254 nm, tR(R) = 31.1
min, tR(S) = 40.8 min.
2. For a recent review on metal-catalyzed asymmetric aryl-
ation reacion, see: Bolm, C.; Hildebrand, J. P.; Muniz, K.;
Hermanns, N. Angew. Chem., Int. Ed. 2001, 40, 3282.
3. (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed.
Engl. 1991, 30, 49; (b) Soai, K.; Niwa, S. Chem. Rev. 1992,
92, 383; (c) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757.
4. Soai, K.; Kawase, Y.; Oshio, A. J. Chem. Soc., Perkin
Trans. 1 1991, 1613.
5. Doso, P. I.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1997, 62,
444.
6. (a) Huang, W.-S.; Hu, Q.-S.; Pu, L. J. Org. Chem. 1999,
64, 7940; (b) Huang, W.-S.; Pu, L. J. Org. Chem. 1999, 64,
4222; (c) Huang, W.-S.; Pu, L. Tetrahedron Lett. 2000, 41,
145.
7. (a) Bolm, C.; Muniz, K. Chem. Commun. 1999, 1295; (b)
Bolm, C.; Kesselgraber, M.; Hermanns, N.; Hildebrand, J.
P.; Raabe, G. Angew. Chem., Int. Ed. 2001, 40, 1488; (c)
Bolm, C.; Hermanns, N.; Hildebrand, J. P.; Muniz, K.
Angew. Chem., Int. Ed. 2000, 39, 3465; (d) Hermanns, N.;
Dahmen, S.; Bolm, C.; Brase, S. Angew. Chem., Int. Ed.
2002, 41, 3692.
8. Ko, D.-H.; Kim, K. H.; Ha, D. C. Org. Lett. 2002, 4,
3759.
9. Fontes, M.; Verdaguer, X.; Sola, L.; Pericas, M. A.; Riera,
A. J. Org. Chem. 2004, 69, 2532.
4.3.11. (S)-(4-Methylphenyl)phenyl-methanol 4k.8 The
compound wasobtained asa white oslid; Mp 59–
25
D
60 °C; ½aŠ ¼ À7.6 ðc 0.33; PhHÞ for 88% ee {lit.8
25
D
½aŠ ¼ þ9.0 ðc 0.5; PhHÞ for 97% ee (R)-4k}; 1H
NMR (CDCl3) d 7.40–7.10 (m, 9H), 5.80–5.83 (d, 1H,
J = 3.0 Hz), 2.33 (s, 3H), 2.20–2.15 (m, 1H); HPLC:
Daicel Chiralcel OD column, hexane/i-PrOH = 9:1,
0.75 mL/min, k = 254 nm, tR(S) = 16.6 min, tR (R) =
18.5 min.
4.3.12. (S)-(1-Naphthyl)phenyl-methanol 4l.7a The
compound wasobtained asa white oslid; Mp 68–
25
D
70 °C; ½aŠ ¼ À44 ðc 0.48; CHCl3Þ for 95% ee; 1H
NMR (CDCl3) d 8.05–7.20 (m, 12H), 6.50–6.45 (d, 1H,
J = 3.6 Hz), 2.75–2.45 (d, 1H, J = 3.6 Hz); HPLC: Daicel
Chiralcel OD column, hexane/i-PrOH = 4:1, 1 mL/min,
k = 254 nm, tR(S) = 15.8 min, tR(R) = 34.8 min.
4.3.13. (S)-(2-Naphthyl)phenyl-methanol 4m.8 The
compound wasobtained asa white oslid; Mp 86–
10. Park, J. K.; Lee, H. G.; Bolm, C.; Kim, B. M. Chem. Eur.
J. 2005, 11, 945.
25
D
87 °C; ½aŠ ¼ À7.0 ðc 0.39; PhHÞ for 94% ee {lit.8
11. (a) Bolm, C.; Rudolph, J. J. Am. Chem. Soc. 2002, 124,
14850; (b) Rudolph, J.; Hermanns, N.; Bolm, C. J. Org.
Chem. 2004, 69, 3997; (c) Rudolph, J.; Schmidt, F.; Bolm,
C. Synthesis 2005, 5, 840; (d) Ozcubukcu, S.; Schmidt, F.;
Bolm, C. Org. Lett. 2005, 7, 1407.
25
D
½aŠ ¼ þ6.3 ðc 1.00; PhHÞ for 97% ee (R)-4m}; 1H
NMR (CDCl3) d 7.90–7.70 (m, 4H), 7.50–7.20 (m,
8H), 5.90–5.80 (m, 1H), 2.60–2.50 (m, 1H); HPLC: Dai-
cel Chiralcel OD column, hexane/i-PrOH = 9:1, 1 mL/
min, k = 254 nm, tR(S) = 22.1 min, tR(R) = 26.9 min.
12. Braga, A. L.; Ludtke, D. S.; Vargas, F.; Parxio, M. Chem.
Comm. 2005, 2512.
13. Ji, J.-X.; Wu, J.; Yeung, T.-L.; Yip, C.-W.; Haynes, R. K.;
Chan, A. S. C. J. Org. Chem. 2005, 70, 1093.
14. (a) Rudolph, J.; Schmit, F.; Bolm, C. Adv. Synth. Catal.
2004, 346, 867; (b) Bra¨se, S.; Dahmen, S.; Ho¨fener, S.;
Lauterwasser, F.; Kreis, M.; Ziegert, R. E. Synlett 2004,
2647.
4.3.14. (2-Bromophenyl)phenyl-methanol 4n.13 The
compound wasobtained asa colorsloesil;
25
D
25
D
½aŠ ¼ À56.5 ðc 0.45; acetoneÞ for 92% ee {lit.21 ½aŠ
1
¼ 46.6 ðc 1.3; acetoneÞ for 95% ee (R)-4n}; H NMR
(CDCl3) d 7.60–7.10 (m, 9H), 6.20–6.10 (d, 1H,
J = 3.0 Hz), 2.60–2.55 (d, 1H, J = 3.0 Hz); HPLC: Dai-
cel Chiralcel OD column, hexane/i-PrOH = 9:1, 1 mL/
min, k = 254 nm, tR(R) = 13.5 min, tR(R) = 20.6 min.
15. The bond anglesin the B O3 ring are very near the 120°
3
values. B3O3 ring isalmots a planar and the B 3O3 ring
containspartially aromatic character: Brock, C. P.;
Minton, R. P.; Niedenzu, K. Acta Cryst. 1987, C43, 1775.
16. (a) Ligand 1a wasfirts reported by Soai: Soai, K.;
Ookawa, A.; Kaba, T.; Ogawa, K. J. Am. Chem. Soc.
1987, 109, 7115; In 2001 our group reported the phenyl-
ation of arylaldehydesusing PhLi/ZnCl 2 asnucleophille in
the presence of 1a: (b) Zhao, G.; Li, X.-G.; Wang, X.-R.
Tetrahedron: Asymmetry 2001, 12, 399.
Acknowledgments
Financial support by the Major State of Basic Research
Development Program (No. G2000048007), the Na-
tional Natural Science Foundation of China (No.
D20032010), QT Program and Shanghai Natural Sci-
ence Council are gratefully acknowledged.
17. Corey, E. J.; Yuen, D.-W.; Hannon, F. J.; Wierda, D. A.
J. Org. Chem. 1990, 55, 784.
18. Wallbaun, S.; Martens, J. Tetrahedron: Asymmetry 1993,
4, 637.
19. Dominique, D.; Maurice, C. J. Chem. Soc., Perkin Trans.
1 1994, 3041.
References
20. Wu, B.-Q.; Mosher, H. S. J. Org. Chem. 1986, 51,
1904.
1. (a) Sperber, N.; Paga, D.; Schwenk, E.; Sherlock, M.
J. Am. Chem. Soc. 1949, 71, 887; (b) Harms, A. F.; Nauta,
W. T. J. Med. Pharm. Chem. 1960, 2, 57; (c) Meguro, K.;
Aizawa, M.; Sohda, T.; Kawamatsu, Y.; Nagaoka, A.
21. Brown, E.; Leze, A.; Touet, J. Tetrahedron: Asymmetry
1992, 3, 8417.
22. Ross, G. H.; Donovan, A. R. Tetrahedron: Asymmetry
1999, 10, 991.