Asymmetric additive-free aryl addition to aldehydes using perhydrobenzoxazines as ligands and boroxins as aryl source

Article abstract of DOI:10.1039/c1ob05717k

A highly efficient enantioselective aryl addition to aldehydes using boroxins as aryl source and conformationally restricted perhydro-1,3- benzoxazines as ligands is reported. Both enantiomeric forms of chiral arylphenylmethanols and 1,1′-disubstituted diarylmethanols are afforded with excellent yields and enantioselectivities using the same ligand by means of an appropriate combination of boroxin and aromatic aldehyde. The enantiocontrol is not significantly influenced by electronic effects or steric hindrance, even with substituted boroxins. Very homogeneous ee's are reached when substituted arylboroxins are employed, without the use of any class of additive or pre-treatment.

Full text of DOI:10.1039/c1ob05717k

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PAPER
Asymmetric additive-free aryl addition to aldehydes using
perhydrobenzoxazines as ligands and boroxins as aryl source†‡
Rebeca Infante, Javier Nieto* and Celia Andre´s*
Received 6th May 2011, Accepted 21st June 2011
DOI: 10.1039/c1ob05717k
A highly efficient enantioselective aryl addition to aldehydes using boroxins as aryl source and
conformationally restricted perhydro-1,3-benzoxazines as ligands is reported. Both enantiomeric forms
of chiral arylphenylmethanols and 1,1¢-disubstituted diarylmethanols are afforded with excellent yields
and enantioselectivities using the same ligand by means of an appropriate combination of boroxin and
aromatic aldehyde. The enantiocontrol is not significantly influenced by electronic effects or steric
hindrance, even with substituted boroxins. Very homogeneous ee’s are reached when substituted
arylboroxins are employed, without the use of any class of additive or pre-treatment.
transmetallation step is a fast process, in contrast to the long
reaction times described in previous reports.5d
Introduction
The enantioselective synthesis of diarylmethanols has been the
focus of many catalytic studies, due to the value of these
compounds as useful precursors of numerous molecules with
important pharmacological properties, such as antihistaminic,
antiarrhythmic, diuretic, laxative, antidepressive, local-anesthetic
and anticholinergic.1 So far, one of the most efficient and
simple approaches to their preparation is the asymmetric arylzinc
addition to aromatic aldehydes in the presence of a chiral ligand
to form the C–C bond and the stereocenter. In this context, the
in situ generation of arylzinc reagents through a boron-to-zinc
transmetallation process constitutes an important advance.2
In 2002, Bolm et al. reported a general protocol for the
in situ synthesis of arylzinc species from arylboronic acids and
diethylzinc.3 One important advantage of this methodology is that
many aryl boronic acids are commercially available at a convenient
price or can be easily prepared.4 However, a significant drawback
of this method is the large amount of diethylzinc necessary for
the transmetallation step due to the acidity of boronic acids.
More recently, the introduction of triarylboroxins, which can be
easily prepared by heating of the corresponding aryl boronic
acid, has permitted a significant reduction of the amount of
zinc reagent.5 In addition, boroxins represent the most atom-
economical source of aryl groups, and they could also been applied
in an industrial process.6 Theoretical and experimental studies
performed by Perica`s have demonstrated that the boron-to-zinc
The most important feature of this methodology is that the
synthesis of either enantiomer of a diarylmethanol is feasible with
the same chiral ligand by means of an appropriate combination
of arylboronic acid or triarylboroxin and aromatic aldehyde.
Nevertheless, the efficiency and enantioselectivity of these com-
plementary processes usually differ significantly, especially when
neither additives nor pre-treatments are employed.7 Subsequently,
we thought that it was necessary to explore new ligands in
order to overcome this weakness. Considering the excellent and
homogeneous results obtained with conformationally restricted
perhydro-1,3-benzoxazines as ligands for the enantioselective
ethylation of aldehydes,8 we decided that these compounds could
also catalyze the asymmetric addition of arylboroxins to aryl
aldehydes and keep high levels of efficiency and selectivity for
both enantiomeric diarylmethanols.
Results and discussion
The asymmetric arylation of 2-naphthaldehyde by means of
diethylzinc and phenylboroxin as the aryl source in the presence
of catalytic amounts of perhydrobenzoxazines 1a–f derived from
(-)-8-aminomenthol was chosen as a reaction model to examine
both the reaction conditions and the efficiency of these ligands,
previously synthesized in our laboratory (Fig. 1).8–10
This reaction is known to occur in two steps, which involve a
boron-to-zinc transmetallation and the addition of the in situ gen-
erated zinc reagent to the carbonyl component. For the formation
of the zinc reagent we initially employed Perica`s’ protocol, which
requires the heating of a 1 : 4 mixture of triphenylboroxin and
diethylzinc in toluene at 60 ◦C for 30 min,5d although the influence
of the aryl source and the diethylzinc solvent was also studied.
Concerning the addition step, several reaction parameters, such
Instituto CINQUIMA and Departamento de Qu´ımica Orga´nica, Facultad
de Ciencias, Universidad de Valladolid, Dr Mergelinas/n, 47011 Valladolid,
Spain. E-mail: javiernr@qo.uva.es
† Dedicated to the memory of Prof. Rafael Suau.
‡ Electronic supplementary information (ESI) available: Copies of NMR
spectra and copies of the chiral-phase HPLC chromatograms See DOI:
10.1039/c1ob05717k
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with an excellent enantiocontrol (entry 4). Temperature variations
indicated a maximal enantioselectivity in the reactions performed
at 0 ◦C. In this context, when the reaction was run at room
temperature, the chemical yield remained in the same level, but
lower enantiomeric excess was observed (entry 5). Conversely, a
lower temperature, such as -20 ◦C, resulted in a decrease of both
enantioselectivity and yield (entry 6).
No detrimental effect on enantioselectivity was perceived when
the amount of ligand was reduced to 5 mol% (entry 7). Even
at lower catalyst loading, diarylmethanol 2a was obtained with
good yield and substantial enantioselection (83% ee, entry 8).
It is remarkable that only the most efficient ligands keep the
enantioselectivity at 5 mol%, but very few of them are able to
reach good levels of selectivity at 1 mol%, especially without any
class of additive.11 Additionally, that reduction is usually more
noteworthy in the cases where the aryl source is a boroxin.5a,c,e
Next, the effect of the substituent on the stereogenic center
which supports the hydroxyl group in the ligand structure
was studied (entries 3, 12 and 13). The use of the secondary
alcohol 1d led to the product with a moderate selectivity (entry
12). Interestingly, the replacement of the phenyl group in 1e
by an isopropyl substituent (1f) had a dramatic effect on the
enantiocontrol of the process (entries 3, 13). On the other hand,
the unsaturated analogs bearing an isopropenyl group (1a–1c),
instead of an isopropyl group, were also explored as ligands
(entries 9–11). In these cases, the chemical yields were also good,
but the enantioselectivity was not improved with respect to 1e.
In summary, these results demonstrate that a tertiary alcohol
is necessary on the perhydrobenzoxazine structure in order to
obtain good enantioselectivities and they also showed that the
stereocenter substitution is critical, so the optimal ligand was 1e.
Once we had established the optimal reaction conditions, our
attention was turned to exploit the possibility to vary the structure
of the aldehyde and study the asymmetric phenyl addition to a
series of substrates with different steric and electronic properties.
These results are summarized in Table 2.
To our delight, steric effects did not play an important role in the
enantioselection. For instance, ortho-substituted benzaldehydes
underwent the phenyl addition with excellent ee values as well
as their para analogs (entries 2, 3 vs. 7 and 8). Besides, very
interesting was the uniformly high enantiocontrol achieved with
p-tolualdehyde, o-tolualdehyde and p-chlorobenzaldehyde (93–
97% ee; entries 2, 7 and 9), because the corresponding addition
products are high-value building blocks for the medically useful
antihistaminics neobenodine, phenadrine and clemastine. The
highest ee was obtained by using o-tolualdehyde, which furnished
the desired (R)-(phenyl)(o-tolyl)methanol 2b with 97% ee in 88%
yield (entry 2). Phenylation of electron-deficient aldehydes, such as
p-chloro and the highly reactive p-trifluoromethylbenzaldehydes,
provided the corresponding alcohols 2i and 2j in high yields with
very high levels of enantioselection, 93% and 91% ee respectively
(entries 9 and 10). Further investigations into heteroaromatic
aldehydes, such as 2-furfural and 2-thienal, and a,b-unsaturated
aldehydes were carried out, and the corresponding products were
delivered with good to high ee’s (81–91% ee, entries 11–15) and
excellent yields in all cases.
Fig. 1 Perhydrobenzoxazines 1a–f.
Table 1 Some representative results from screening of reaction conditions
for the asymmetric phenyl addition to 2-naphthaldehyde catalyzed by 1a–
1f
Entrya Ligand (mol%) T/◦C Time (min) Yield (%)b ee (%)c,d
1e
2f
3
4
5
6
7
8
9
10
11
12
13
1e (10)
1e (10)
1e (10)
1e (10)
1e (10)
1e (10)
1e (5)
0
0
0
0
25
-20
0
0
0
0
0
0
0
60
60
60
30
60
60
60
60
60
60
60
60
60
90
91
98
97
97
89
88
70
82
81
89
95
87
92
91
94
94
87
91
92
83
42
68
70
60
11
1e (1)
1a (10)
1b (10)
1c (10)
1d (10)
1f (10)
a (PhBO)3/ZnEt2/aldehyde = 0.6 : 2.4 : 1. b Yield of product after purifi-
cation by flash chromatography. c Determined by HPLC analysis using
a chiral Chiralpak AS-H column. d Configuration of the predominant
enantiomer of the product was determined by comparison with the litera-
ture data. e Phenylboronic acid was employed instead of triphenylboroxin.
PhB(OH)2/ZnEt2/aldehyde = 1.2 : 3.8 : 1. f A mixture toluene/hexane 1 : 1
was used as solvent.
as temperature, reaction time, catalyst loading and catalyst, were
examined. The results are collected in Table 1.
When phenylboronic acid was used as the aryl source and
the addition step was carried out at 0 ◦C, employing 10 mol%
of ligand 1e, the product 2a was obtained in good yield and
enantioselectivity (entry 1). Although good enantioselectivities
had been previously found for the addition of arylboroxins to
aldehydes, those values were usually slightly lower and less uniform
than those obtained with the corresponding arylboronic acids.5e,7a
Nevertheless, the opposite behavior was shown by our ligand, and
triphenylboroxin led under the same conditions to the product in
higher yield and improved enantioselection (entry 3). Besides, a
substantial reduction of the amount of diethylzinc (2.4 equiv for
the boroxin vs. 3.8 equiv for the boronic acid) was possible as
previously reported,5a so triarylboroxins were chosen as optimal
aryl sources. With regard to the solvent, toluene was found to be
superior to hexane in terms of yield and selectivity (entries 2, 3).
It can also be observed that the results were not affected by
the reduction of the reaction time for the addition step, and
the product could be isolated almost quantitatively after 30 min
As we commended in the introduction, both enantiomers
became accessible with a single catalyst, although it is known
that the efficiency of these complementary approaches can differ
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Table 2 Catalytic asymmetric phenyl transfer to several aldehydes in the
presence of 1e
Table 4 Catalytic asymmetric aryl transfer to several substituted aldehy-
des in the presence of 1e
Entrya
R
Product Yield (%)b ee (%)c,d
Entrya R1
R2
Product Yield (%)b ee (%)c,d
1
2
3
4
5
6
7
8
2-naphthyl
o-CH3C6H4
o-OCH3C6H4
o-ClC6H4
2a
2b
2c
2d
2e
2f
2g
2h
2i
98
88
97
92
83
96
86
93
98
93
82
85
94
83
92
94
97
93
88
90
91
95
96
93
91
85
91
82
81
87
1
2
3
4
5
6
7
8
p-ClC6H4
o-CH3C6H4
p-ClC6H4
p-CH3C6H4
p-CH3C6H4
2-naphthyl
p-OCH3C6H4 2-naphthyl
2-naphthyl
p-ClC6H4
2-naphthyl
p-CF3C6H4
p-CF3C6H4
p-CF3C6H4
p-CH3C6H4
p-CF3C6H4
o-CH3C6H4
p-ClC6H4
p-CH3C6H4
p-ClC6H4
2-naphthyl
p-CH3C6H4
2p
ent-2p
2q
ent-2q
2r
ent-2r
2s
81
99
98
99
99
90
84
90
99
94
88
95
91
34
96
89
94
97
84
98
95
92
94
93
88
90
89
89
95
96
o-BrC6H4
m-ClC6H4
p-CH3C6H4
p-OCH3C6H4
p-ClC6H4
p-OCH3C6H4 ent-2s
2-naphthyl
p-ClC6H4
2-naphthyl
o-CH3C6H4
p-CH3C6H4
p-CF3C6H4
p-ClC6H4
9
9
2t
ent-2t
2u
2v
2w
ent-2w
2x
10
11
12
13
14
15
p-CF3C6H4
2-furyl
2-thienyl
(E)-C6H5CH CH
(E)-p-OCH3C6H4CH CH 2n
(E)-2-(2-furyl)vinyl
2j
2k
2l
10
11
12
13
14e
15
2m
2o
a 1e/(PhBO)3/ZnEt2/aldehyde = 0.1 : 0.6 : 2.4 : 1. b Yield of product after
purification by flash chromatography. c Determined by chiral HPLC anal-
ysis, see experimental for full details. d Configuration of the predominant
enantiomer of the product was determined by comparison with the
literature data.
a 1e/(ArBO)3/ZnEt2/aldehyde = 0.1 : 0.6 : 2.4 : 1. b Yield of product iso-
lated after purification by flash chromatography. c Determined by chiral
HPLC analysis, see experimental for full details. d Configuration of the
predominant enantiomer of the product was determined by comparison
with the literature data. e 10 mol% of DiMPEG (MW 2000) was used as
additive. The product was isolated as a racemic mixture without any class
of additive.
Table 3 Catalytic asymmetric aryl transfer to benzaldehyde in the
presence of 1e
In this way, (S)-(phenyl)(o-tolyl)methanol ent-2b was readily
obtained in 97% yield with 94% ee (entry 2). Even the bulky
tri(2-naphthyl)lboroxin allowed the desired alcohol ent-2a to be
obtained with good yield and very high enantioselection (95% ee,
entry 1). An excellent result was reached for the reaction between
tri(p-tolyl)boroxin and benzaldehyde, obtaining 97% ee (entry 3).
With this gratifying ligand in our hands and the excellent
results achieved, we were wondering about the flexibility of this
methodology with the goal to investigate the preparation of more
functionalized molecules, like 1,1¢-disubstituted diarylmethanols.
To this aim, a series of reverse combinations of both substituted
boroxins and aldehydes was explored, and the results are summa-
rized in Table 4.
In general, both enantiomers of a given product could be
easily obtained in good yields and high enantioselectivities by
means of the same ligand 1e, independently of the substitution
on the triarylboroxin or the aldehyde employed (entries 1–10).
For example, the reaction between p-tolualdehyde and tri(2-
naphthyl)lboroxin yielded the corresponding product 2r quanti-
tatively with 98% ee (entry 5). Complementarily, when the reverse
combination of substrates was employed (i.e., 2-naphthaldehyde
and tri(p-tolyl)lboroxin, entry 6), the enantiomeric product ent-2r
was also afforded in good yield with no significant reduction in
the enantioselectivity. In a similar way, the enantiomeric partners
2p - ent-2p, 2q - ent-2q, 2s - ent-2s and 2t - ent-2t were isolated with
good or excellent yields and selectivities, observing only minor
differences in terms of ee between the couples (entries 1–2, 7–
10), with the only exception of p-chlorophenyl-p-tolyl-methanol
(entries 3–4).
Entrya
R
Product
Yield (%)b
ee (%)c,d
1
2
3
4
5
2-naphthyl
o-CH3C6H4
p-CH3C6H4
p-OCH3C6H4
p-ClC6H4
ent-2a
ent-2b
ent-2g
ent-2h
ent-2i
89
97
93
95
94
95
94
97
94
88
a 1e/(ArBO)3/ZnEt2/aldehyde = 0.1 : 0.6 : 2.4 : 1. b Yield of product iso-
lated after purification by flash chromatography. c Determined by chiral
HPLC analysis, see experimental for full details. d Configuration of the
predominant enantiomer of the product was determined by comparison
with the literature data.
considerably.4a,4d,7 In order to examine whether different aryl
groups could be transferred to aldehydes with the same stereoselec-
tivity, the asymmetric aryl transfer reactions of some substituted
triarylboroxins to benzaldehyde were examined (Table 3).
Surprisingly, we could observe that the efficiency of the catalytic
system was maintained very high in all cases, independent of the
electronic and steric effects. For example, benzaldehyde underwent
smooth p-methoxyphenyl addition with 94% ee (entry 4), and
the aryl transfer from tri(p-chloropheny)lboroxin to benzaldehyde
afforded the product with 94% yield and 88% ee (entry 5). In
contrast to previously published results,12 an ortho-substituted
arylboroxin was perfectly tolerated and the corresponding alcohol
was isolated with as high enantioselectivity as other substrates.
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In order to study the effect of the triarylboroxin in the arylation
of the challenging electron-poor p-trifluoromethylbenzaldehyde,
a set of experiments was carried out (entries 11–13, 15). To our
surprise, the results in terms of chemical yield and enantioselec-
tivity were excellent as well, even with boroxins bearing electron-
withdrawing groups, such as a chlorine atom (entry 15) or an
ortho substituent (entry 12). Even more challenging was the use
of the electronically deficient tri(p-trifluoromethylphenyl)boroxin
as the aryl source, as in the only previous report5d the product
was obtained in a racemic way. In fact, the alcohol ent-2w was
isolated as a racemate when ligand 1e was employed under the
standard conditions (entry 14). Nevertheless, although a modest
yield of product ent-2w was also obtained, an unprecedented
extraordinary enantioselectivity was achieved when 10 mol% of
DiMPEG [dimethoxypoly-(ethylene glycol), MW 2000] was used
(95% ee, entry 14).13
Unless otherwise indicated, all compounds were purchased from
commercial sources and used as received. All boronic acids used
are commercially available or can be easily prepared.14 Racemic
samples were prepared by addition of Grignard reagents to the
corresponding aldehydes. Triarylboroxins were freshly prepared
by heating the corresponding arylboronic acid for 8 h at 110 ◦C in
a conventional oven and used without further purification.
Ligands 1a–1f were prepared according reported procedures.8–10
Typical procedure for enantioselective addition of aryls to
aldehydes
To a suspension of triarylboroxin (0.3 mmol) in anhydrous toluene
(0.5 mL) under argon atmosphere was added dropwise a 1.1 M
solution of Et2Zn in toluene (1.1 mL, 1.2 mmol). The resulting
mixture was heated at 60 ◦C in a pre-heated bath for 30 min
to give a clear solution. Once this solution was cooled to room
temperature, a solution of ligand 1e (18 mg, 0.05 mmol) in toluene
(0.5 mL) was added. The resulting mixture was then cooled to
0 ◦C in an ice bath and after 15 min of stirring at that temperature,
the aldehyde (0.5 mmol) was added. After 30–60 min, the reaction
mixture was quenched with aqueous saturated NH4Cl, extracted
with CH2Cl2 (3 ¥ 15 mL), dried over MgSO4, filtered off, and
the solvents were evaporated. Purification by silica gel column
chromatography with different mixtures of ethyl acetate/hexane
gave the pure alcohols. Enantiomeric excess was determined by
chiral HPLC.
Conclusions
In summary, we have developed a new catalytic system for
the enantioselective arylation of aromatic aldehydes using chiral
perhydro-1,3-benzoxazines as ligands. The reactions occur in
very good yields and with excellent enantiocontrol without
any pretreatment or additive for a wide variety of aromatic,
heteroaromatic and a,b-unsaturated aldehydes. Furthermore, the
high efficiency is virtually independent of the electronic and
steric characteristics when different substituted triarylboroxins
are transferred to the same aldehyde, allowing the use of ortho-
substituted triarylboroxins and bulky triarylboroxins.
(S)-2-Naphthyl(phenyl)methanol (2a). This compound was
obtained from benzaldehyde (51 ml, 0.5 mmol) and tri(2-
naphthyl)boroxin (138.6 mg, 0.3 mmol) and purified by flash
In addition, the appropriate choice of the two reaction partners,
boroxin and aldehyde, gives access to both enantiomers of the
1,1¢-diarylmethanols with the same catalyst and similarly high
enantioselectivity.
1
chromatography (ethyl acetate/hexane = 1 : 20). White solid H-
NMR (300 MHz, CDCl3) d 2.50 (br s, 1H, OH), 6.00 (s, 1H),
7.27–7.54 (m, 8H), 7.80–7.88 (m, 3H), 7.91 (s, 1H). 13C-NMR
(75 MHz, CDCl3) d 76.3 (CH), 124.7 (CH), 125.0 (CH), 125.9
(CH), 126.2 (CH), 126.7 (2CH), 127.6 (2CH), 128.0 (CH), 128.3
(CH), 128.5 (2CH), 132.8 (C), 133.2 (C), 141.0 (C), 143.6 (C). IR
(KCl) n 3398, 3058, 1602, 1508, 1493, 1452, 1023, 1266, 814, 738,
701 cm-1. HPLC (Chiralpak AS-H, hexane : isopropanol = 90 : 10,
Experimental
All reactions were carried out in anhydrous solvents under
argon atmosphere in flame-dried glassware by means of Schlenk
techniques. 1H-NMR (300 MHz) and 13C-NMR (75 MHz) spectra
were recorded in CDCl3. Chemical shifts for protons are reported
in ppm from tetramethylsilane with the residual CHCl3 resonance
as internal reference. Chemical shifts for carbons are reported
in ppm from tetramethylsilane and are referenced to the carbon
resonance of the solvent. Data are reported as follows: chemical
shift, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; sp,
septet; m, multiplet; br, broad), coupling constants in Hertz, and
integration. Specific rotations were measured using a 5 mL cell
with a 1 dm path length, and a sodium lamp, and concentration
is given in g per 100 mL. Flash chromatography was carried
out using silica gel (230–240 mesh). Chemical yields refer to
pure isolated substances. TLC analysis was performed on glass-
backed plates coated with silica gel 60 and an F254 indicator,
and visualized by either UV irradiation or by staining with I2 or
ethanolic phosphomolybdic acid solution. Chiral HPLC analysis
was performed using a Daicel Chiralcel OD Column, Chiralpak
AD-H or Chiralpak AS-H. UV detection was monitored at
220 nm or at 254 nm. High resolution mass spectrometry analyses
(HRMS) were performed by a quadrupole spectrometer with TOF
analyzer.
1 mL min-1, l = 254 nm) tR = 8.2 min for enantiomer R, tR
=
9.3 min for enantiomer S. Configuration was assigned by compar-
ing HPLC elution order with that of the literature data.5a
(R)-2-Naphthyl(phenyl)methanol (ent-2a). This compound is
the enantiomer of 2a and was obtained from 2-naphthaldehyde
(78.2 mg, 0.5 mmol) and triphenylboroxin (93.6 mg, 0.3 mmol).
(R)-Phenyl(o-tolyl)methanol (2b). This compound was ob-
tained from o-tolualdehyde (60 ml, 0.5 mmol) and triphenylboroxin
(93.6 mg, 0.3 mmol). Both were purified by flash chromatography
1
(ethylacetate/hexane = 1 : 20). White solid. H-NMR (300 MHz,
CDCl3) d 2.28 (s, 3H), 2.73 (br s, 1H, OH), 6.00 (s, 1H), 7.19–7.41
(m, 8H), 7.55 –7.57 (m, 1H). 13C-NMR (75 MHz, CDCl3) d 19.3
(CH3), 73.2 (CH), 126.0 (CH), 126.2 (CH), 127.0 (2CH), 127.4
(CH), 127.5 (CH), 128.4 (2CH), 130.4 (CH), 135.3 (C), 141.3 (C),
142.7 (C). IR (Nujol) n 3196, 2022, 1899, 1809, 1602, 1302, 1014,
765, 698 cm-1. HPLC (Chiralpak AD-H, hexane : isopropanol =
99 : 1, 1 mL min-1, l = 220 nm) tR = 28.0 min for enantiomer R,
tR = 31.0 min for enantiomer S. Configuration was assigned by
comparing HPLC elution order with that of the literature data.4f
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1 mL min-1, l = 220 nm) tR = 41.5 min for enantiomer S, tR
(S)-Phenyl(o-tolyl)methanol (ent-2b). This compound is ena-
ntiomer of 2b and was obtained from benzaldehyde (51 ml,
0.5 mmol) and tri(o-tolyl)boroxin (106.3 mg, 0.3 mmol).
=
45.9 min for enantiomer R. Configuration was assigned by
comparing HPLC elution order with that of the literature data.5a
(R)-(o-Methoxyphenyl)(phenyl)methanol (2c). This compound
was obtained from o-methoxybenzaldehyde (62 ml, 0.5 mmol)
and triphenylboroxin (93.6 mg, 0.3 mmol) and purified by flash
(R)-Phenyl(p-tolyl)methanol (2g). This compound was ob-
tained from p-tolualdehyde (56 ml, 0.5 mmol) and triphenylboroxin
(93.6 mg, 0.3 mmol) and purified by flash chromatography
1
chromatography (ethylacetate/hexane = 1 : 10). White solid. H-
1
(ethylacetate/hexane = 1 : 20). White solid. H-NMR (300 MHz,
NMR (300 MHz, CDCl3) d 3.67 (br s, 1H, OH), 3.87 (s, 3H), 6.25
(s, 1H), 7.02 (d, J = 8.2 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.41–7.54
(m, 5H), 7.58–7.62 (m, 2H). 13C-NMR (75 MHz, CDCl3) d 55.0
(CH3), 71.4 (CH), 110.4 (CH), 120.5 (CH), 126.3 (2CH), 126.8
(CH), 127.4 (CH), 127.8 (2CH), 128.3 (CH), 131.8 (C), 143.2 (C),
156.3 (C). IR (Nujol) n 3422, 3062, 3030, 2028, 1948, 1902, 1601,
1490, 1243, 1113, 1184, 1027, 856, 755, 699, 652 cm-1. HPLC
(Chiralcel OD, hexane : isopropanol = 98 : 2, 1 mL min-1, l =
220 nm) tR = 42.3 min for enantiomer S, tR = 53.5 min for
enantiomer R. Configuration was assigned by comparing HPLC
elution order with that of the literature data.7b
CDCl3) d 2.56 (s, 3H), 3.65 (br s, 1H, OH), 5.84 (s, 1H), 7.34 (ps d,
J = 7.9 Hz, 2H), 7.43 (ps d, J = 8.1 Hz, 2H), 7.46–7.55 (m, 5H). 13C-
NMR (75 MHz, CDCl3) d 20.9 (CH3), 75.5 (CH), 126.3 (2CH),
126.4 (2CH), 127.0 (CH), 128.1 (2CH), 128.8 (2CH), 136.7 (C),
140.8 (C), 143.8 (C). IR (Nujol) n 3270, 3081, 2022, 1941, 1897,
1489, 1309, 1171, 1037, 1019, 795, 775, 692 cm-1. HPLC (Chiralcel
OD, hexane : isopropanol = 90 : 10, 0.8 mL min-1, l = 254 nm)
tR = 13.3 min for enantiomer S, tR = 14.9 min for enantiomer R.
(Chiralpak AS-H, hexane : isopropanol = 95 : 5, 1 mL min-1, l =
254 nm) tR = 8.8 min for enantiomer R, tR = 9.7 min for enantiomer
S. Configuration was assigned by comparing HPLC elution order
with that of the literature data.5a
(R)-(o-Chlorophenyl)(phenyl)methanol (2d). This compound
was obtained from o-chlorobenzaldehyde (56 ml, 0.5 mmol) and
triphenylboroxin (93.6 mg, 0.3 mmol) and purified by flash
(S)-Phenyl(p-tolyl)methanol (ent-2g). This compound is the
enantiomer of 2g and was obtained from benzaldehyde (51 ml,
0.5 mmol) and tri(p-tolyl)boroxin (106.3 mg, 0.3 mmol).
1
chromatography (ethylacetate/hexane = 1 : 15). White solid. H-
NMR (300 MHz, CDCl3) d 3.29 (br s, 1H, OH), 6.19 (s, 1H), 7.22–
7.44 (m, 8H), 7.64 (dd, J1 = 7.7 Hz, J2 = 1.8 Hz, 1H). 13C-NMR (75
MHz, CDCl3) d 72.3 (CH), 126.8 (2CH), 126.9 (CH), 127.6 (CH),
127.8 (CH), 128.3 (2CH), 128.5 (CH), 129.3 (CH), 132.2 (C), 140.8
(C), 142.1 (C).). IR (Nujol) n 3338, 2019, 1491, 1308, 1183, 1055,
1020, 752, 698 cm-1. HPLC (Chiralcel OD, hexane : isopropanol =
98 : 2, 1 mL min-1, l = 220 nm) tR = 26.5 min for enantiomer R,
tR = 34.9 min for enantiomer S. Configuration was assigned by
comparing HPLC elution order with that of the literature data.15
(R)-(p-Methoxyphenyl)(phenyl)methanol (2h). This com-
pound was obtained from p-methoxybenzaldehyde (61 ml,
0.5 mmol) and triphenylboroxin (93.6 mg, 0.3 mmol) and purified
by flash chromatography (ethylacetate/hexane = 1 : 15–1 : 10).
White solid. 1H-NMR (300 MHz, CDCl3) d 2.40 (br s, 1H, OH),
3.80 (s, 3H), 5.80 (s, 1H), 6.88 (ps d, J = 9.0 Hz, 2H), 7.27–7.41 (m,
7H). 13C-NMR (75 MHz, CDCl3) d 55.0 (CH3), 75.4 (CH), 113.6
(2CH), 126.3 (2CH), 127.1 (CH), 127.8 (2CH), 128.2 (2CH), 136.1
(C), 143.9 (C), 158.7 (C). IR (KBr) n 3406, 3065, 2952, 2837, 1896,
1612, 1511, 1494, 1449, 1304, 1266, 1173, 1111, 1035, 810, 780,
729, 699 cm-1. HPLC (Chiralpak AD-H, hexane : isopropanol =
90 : 10, 1 mL min-1, l = 220 nm) tR = 14.2 min for enantiomer
R, tR = 15.3 min for enantiomer S. Configuration was assigned
by comparing HPLC elution order with that of the literature
data.4h
(R)-(o-Bromophenyl)(phenyl)methanol (2e). This compound
was obtained from o-bromobenzaldehyde (92.2 mg, 0.5 mmol)
and triphenylboroxin (93.6 mg, 0.3 mmol) and purified by flash
chromatography (ethylacetate/hexane = 1 : 20). Colorless oil. 1H-
NMR (300 MHz, CDCl3) d 2.61 (d, J = 3.7 Hz, 1H, OH), 6.19 (d,
J = 3.5 Hz, 1H), 7.17 (td, J1 = 7.7 Hz, J2 = 1.8 Hz, 1H), 7.27–7.44
(m, 6H), 7.56 (dd, J1 = 7.9 Hz, J2 = 1.3 Hz, 1H), 7.60 (dd, J1 = 7.7
Hz, J2 = 1.8 Hz, 1H). 13C-NMR (75 MHz, CDCl3) d 74.7 (CH),
122.7 (C), 127.0 (2CH), 127.7 (2CH), 128.4 (3CH), 129.0 (CH),
132.8 (CH), 142.1 (C), 142.4 (C). IR (Film) n 3347, 3064, 3031,
1654, 1569, 1494, 1466, 1452, 1438, 1184, 1016, 751, 720, 699 cm-1.
HPLC (Chiralcel OD, hexane : isopropanol = 98 : 2, 1 mL min-1,
l = 220 nm) tR = 29.0 min for enantiomer R, tR = 42.2 min for
enantiomer S. Configuration was assigned by comparing HPLC
elution order with that of the literature data.5a
(S)-(p-Methoxyphenyl)(phenyl)methanol (ent-2h). This com-
pound is the enantiomer of 2h and was obtained from ben-
zaldehyde (51 ml, 0.5 mmol) and tri(p-methoxyphenyl)boroxin
(120.6 mg, 0.3 mmol).
(R)-(p-Chlorophenyl)(phenyl)methanol (2i). This compound
was obtained from p-chlorobenzaldehyde (72.8 mg, 0.5 mmol)
and triphenylboroxin (93.6 mg, 0.3 mmol) and purified by flash
1
(R)-(m-Chlorophenyl)(phenyl)methanol (2f). This compound
was obtained from m-chlorobenzaldehyde (58 ml, 0.5 mmol)
and triphenylboroxin (93.6 mg, 0.3 mmol) and purified by flash
chromatography (ethylacetate/hexane = 1 : 15). White solid. H-
NMR (300 MHz, CDCl3) d 4.00 (ps d, J = 3.3 Hz, 1H, OH), 5.64
(ps d, J = 3.1 Hz, 1H), 7.26 (ps d, J = 8.3 Hz, 2H), 7.33–7.45
(m, 7H). 13C-NMR (75 MHz, CDCl3) d 75.1 (CH), 126.3 (2CH),
127.5 (CH), 127.7 (2CH), 128.3 (4CH), 132.8 (C), 141.9 (C), 143.1
(C).). IR (Nujol) n 3337, 3086, 3064, 1958, 1911, 1491, 1271, 1181,
1092, 1034, 1013, 791, 760, 742, 720, 702 cm-1. HPLC (Chiralpak
AD-H, hexane : isopropanol = 90 : 10, 1 mL min-1, l = 220 nm)
tR = 8.6 min for enantiomer R, tR = 9.3 min for enantiomer S.
Configuration was assigned by comparing HPLC elution order
with that of the literature data.4h
1
chromatography (ethylacetate/hexane = 1 : 15). White solid. H-
NMR (300 MHz, CDCl3) d 3.11 (ps d, J = 3.3 Hz, 1H, OH),
5.70 (ps d, J = 2.8 Hz, 1H), 7.20–7.38 (m, 8H), 7.40 (s, 1H). 13C-
NMR (75 MHz, CDCl3) d 75.4 (CH), 124.5 (CH), 126.5 (3CH),
127.5 (CH), 127.8 (CH), 128.5 (2CH), 129.6 (CH) 134.2 (C), 143.0
(C), 145.6 (C). IR (Nujol) n 3356, 3063, 3029, 2019, 1950, 1890,
1596, 1575, 1493, 1472, 1432, 1185, 1079, 1036, 1022, 888, 781,
765, 701 cm-1. HPLC (Chiralcel OD, hexane : isopropanol = 98 : 2,
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(S)-(p-Chlorophenyl)(phenyl)methanol (ent-2i). This com-
pound is the enantiomer of 2i and was obtained from benzaldehyde
(51 ml, 0.5 mmol) and tri(p-chlorophenyl)boroxin (124.2 mg,
0.3 mmol).
d 74.7 (CH), 126.2 (2CH), 126.5 (2CH), 127.5 (CH), 127.6 (CH),
128.4 (4CH), 130.2 (CH), 131.4 (CH), 136.4 (C), 142.6 (C). IR
(Nujol) n 3351, 3084, 3058, 3027, 2019, 1954, 1883, 1654, 1599,
1492, 1472, 1013, 966, 744, 694 cm-1. HPLC (Chiralcel OD,
hexane : isopropanol = 90 : 10, 1 mL min-1, l = 254 nm) tR = 17.3
min for enantiomer S, tR = 22.9 min for enantiomer R. (Chiralpak
AS-H, hexane : isopropanol = 95 : 5, 1 mL min-1, l = 254 nm)
tR = 10.9 min for enantiomer S, tR = 12.5 min for enantiomer R.
Configuration was assigned by comparing HPLC elution order
with that of the literature data.5b
(R)-Phenyl(p-(trifluoromethyl)phenyl)methanol (2j). This com-
pound was obtained from p-(trifluromethyl)benzaldehyde (69 ml,
0.5 mmol) and triphenylboroxin (93.6 mg, 0.3 mmol) and purified
by flash chromatography (ethylacetate/hexane = 1 : 10). White
1
solid. H-NMR (300 MHz, CDCl3) d 3.53 (br s, 1H, OH), 5.74
(br s, 1H), 7.31–7.42 (m, 5H), 7.46 (ps d, J = 8.1 Hz, 2H), 7.61 (ps
d, J = 8.1 Hz, 2H). 13C-NMR (75 MHz, CDCl3) d 75.5 (CH),
124.1 (q, JC-F = 272 Hz, 1C), 125.2 (CH), 125.3 (CH), 126.6
(4CH), 128.0 (CH), 128.6 (2CH), 129.5 (q, JC-CF = 32 Hz, 1C),
143.0 (C), 147.4 (C). 19F-NMR (282 MHz, CDCl3) d -62.76 (s,
3F). IR (KBr) n 3371, 3068, 3029, 2637, 1932, 1618, 1493, 1450,
1419, 1329, 1163, 1125, 1112, 1068, 1016, 731, 698 cm-1. HPLC
(Chiralcel OD, hexane : isopropanol = 90 : 10, 1 mL min-1, l = 220
nm) tR = 11.1 min for enantiomer R, tR = 12.3 min for enantiomer
S. Configuration was assigned by comparing HPLC elution order
with that of the literature data.16
(S,E)-3-(p-Methoxyphenyl)-1-phenylprop-2-en-1-ol (2n)18. This
compound was obtained from (E)-p-methoxycinnamaldehyde
(82.6 mg, 0.5 mmol) and triphenylboroxin (93.6 mg, 0.3 mmol) and
purified by flash chromatography (ethylacetate/hexane = 1 : 10).
Yellow oil. [a]D -28.7 (c 1.7, CHCl3). 1H-NMR (300 MHz, CDCl3)
d 2.56 (br s, 1H, OH), 3.82 (s, 3H), 5.35 (d, J = 6.6 Hz, 1H), 6.27
(dd, J1 = 15.8 Hz, J2 = 6.8 Hz, 1H), 6.63 (d, J = 15.8 Hz, 1H),
6.87 (ps d, J = 8.8 Hz, 2H), 7.34 (ps d, J = 8.8 Hz, 2H), 7.36–
7.48 (m, 5H). 13C-NMR (75 MHz, CDCl3) d 55.2 (CH3), 75.1
(CH), 113.9 (2CH), 126.2 (2CH), 127.6 (CH), 127.7 (2CH), 128.5
(2CH), 129.2 (C), 129.3 (CH), 130.0 (CH), 142.9 (C), 159.2 (C).
IR (film) n 3349, 3031, 2837, 1891, 1654, 1608, 1511, 1451, 1301,
1251, 1175, 1093, 1034, 968, 832, 761, 701 cm-1. HPLC (Chiralcel
OD, hexane : isopropanol = 90 : 10, 1 mL min-1, l = 254 nm) tR
= 18.2 min for enantiomer R, tR = 20.5 min for enantiomer S.
Configuration was assigned by assuming an analogous mechanism
for the aryl transfer.
(R)-2-Furyl(phenyl)methanol (2k). This compound was ob-
tained from 2-furfural (42 ml, 0.5 mmol) and triphenylboroxin
(93.6 mg, 0.3 mmol) and purified by flash chromatography
1
(ethylacetate/hexane = 1 : 10). White solid. H-NMR (300 MHz,
CDCl3) d 3.41 (br s, 1H, OH), 5.78 (br s, 1H), 6.14 (ps d, J =
3.3 Hz, 1H), 6.35 (dd, J1 = 3.3 Hz, J2 = 2.0 Hz, 1H), 7.33–7.48
(m, 6H). 13C-NMR (75 MHz, CDCl3) d 69.7 (CH), 107.2 (CH),
110.0 (CH), 126.5 (2CH), 127.7 (CH), 128.2 (2CH), 140.7 (C),
142.2 (CH), 155.8 (C). IR (KBr) n 3368, 3102, 3064, 3032, 2881,
1603, 1492, 1452, 1198, 1142, 1011, 940, 9276, 815, 737, 700 cm-1.
HPLC (Chiralcel OD, hexane : isopropanol = 98 : 2, 1 mL min-1,
l = 220 nm) tR = 34.5 min for enantiomer S, tR = 43.5 min for
enantiomer R. Configuration was assigned by comparing HPLC
elution order with that of the literature data.7a
(S,E)-3-(2-Furyl)-1-phenylprop-2-en-1-ol (2o)19. This com-
pound was obtained from (E)-3-(2-furyl)acrylaldehyde (63.0 mg,
0.5 mmol) and triphenylboroxin (93.6 mg, 0.3 mmol) and purified
by flash chromatography (ethylacetate/hexane = 1 : 10–1 : 8). Red
oil. [a]D -44.1 (c 1.6, CHCl3). 1H-NMR (300 MHz, CDCl3) d 2.70
(br s, 1H, OH), 5.33 (d, J = 5.9 Hz, 1H), 6.28 (d, J = 3.3 Hz, 1H),
6.63–6.41 (m, 2H), 6.53 (d, J = 15.8 Hz, 1H), 7.30–7.44 (m, 6H).
13C-NMR (75 MHz, CDCl3) d 74.4 (CH), 108.3 (CH), 111.2 (CH),
118.5 (CH), 126.3 (2CH), 127.6 (CH), 128.5 (2CH), 130.0 (CH),
141.9 (CH), 142.5 (C), 152.1 (C). IR (Film) n 3368, 3030, 2871,
1654, 1602, 1560, 1492, 1453, 1256, 1152, 1068, 1013, 962, 884, 862,
737, 700 cm-1. HPLC (Chiralpak AS-H, hexane : isopropanol =
95 : 5, 1 mL min-1, l = 254 nm) tR = 12.8 min for enantiomer S,
tR = 16.2 min for enantiomer R. Configuration was assigned by
assuming an analogous mechanism for the aryl transfer.
(R)-2-Thienyl(phenyl)methanol (2l). This compound was ob-
tained from 2-thiophenecarboxaldehyde (47 ml, 0.5 mmol) and
triphenylboroxin (93.6 mg, 0.3 mmol) and purified by flash
1
chromatography (ethylacetate/hexane = 1 : 15). White solid. H-
NMR (300 MHz, CDCl3) d 2.87 (ps d, J = 3.7 Hz, 1H, OH), 6.01
(ps d, J = 3.3 Hz, 1H), 6.90 (ps d, J = 3.5 Hz, 1H), 6.97 (dd, J1 =
5.0 Hz, J2 = 3.5 Hz, 1H), 7.28 (ddd, J1 = 5.0 Hz, J2 = 1.3 Hz, J3
= 0.5 Hz, 1H), 7.32–7.48 (m, 5H). 13C-NMR (75 MHz, CDCl3)
d 72.2 (CH), 124.8 (CH), 125.3 (CH), 126.2 (2CH), 126.5 (CH),
127.9 (CH), 128.4 (2CH), 143.0 (C), 148.0 (C). IR (Nujol) n 3256,
3090, 3033, 1961, 1895, 1655, 1560, 1492, 1280, 1264, 1198, 1144,
1031, 1011, 919, 853, 742, 724, 700 cm-1. HPLC (Chiralcel OD,
hexane : isopropanol = 98 : 2, 1 mL min-1, l = 220 nm) tR = 37.0 min
for enantiomer S, tR = 40.9 min for enantiomer R. Configuration
was assigned by comparing HPLC elution order with that of the
literature data.17
(S)-(p-Chlorophenyl)(o-tolyl)methanol (2p). This compound
was obtained from p-chlorobenzaldehyde (72.8 mg, 0.5 mmol)
and tri(o-tolyl)boroxin (106.3 mg, 0.3 mmol) and purified by flash
1
chromatography (ethylacetate/hexane = 1 : 15). White solid. H-
NMR (300 MHz, CDCl3) d 2.23 (s, 3H), 2.85 (br s, 1H, OH), 5.87
(s, 1H), 7.15–7.32 (m, 3H), 7.22 (ps d, J = 8.6 Hz, 2H), 7.30 (ps d,
J = 8.6 Hz, 2H), 7.42–7.45 (m, 1H). 13C-NMR (75 MHz, CDCl3) d
19.2 (CH3), 72.4 (CH), 126.1 (CH), 126.2 (CH), 127.6 (CH), 128.3
(2CH), 128.4 (2CH), 130.5 (CH), 133.1 (C), 135.2 (C), 140.9 (C),
141.2 (C). IR (Nujol) n 3256, 3059, 1969, 1901, 1953, 1488, 1406,
1176, 1088, 1015, 864, 817, 752, 730 cm-1. HPLC (Chiralcel OD,
hexane : isopropanol = 99 : 1, 1 mL min-1, l = 254 nm) tR = 74.3
min for enantiomer R, tR = 81.4 min for enantiomer S. (Chiralpak
AD-H, hexane : isopropanol = 95 : 5, 1 mL min-1, l = 254 nm)
tR = 12.0 min for enantiomer S, tR = 13.0 min for enantiomer R.
(S,E)-1,3-Diphenylprop-2-en-1-ol (2m). This compound was
obtained from (E)-cinnamaldehyde (64 ml, 0.5 mmol) and triph-
enylboroxin (93.6 mg, 0.3 mmol) and purified by flash chromatog-
raphy (ethylacetate/hexane = 1 : 15–1 : 10). White solid. 1H-NMR
(300 MHz, CDCl3) d 2.62 (br s, 1H, OH), 5.39 (d, J = 6.4 Hz,
1H), 6.42 (dd, J1 = 15.8 Hz, J2 = 6.6 Hz, 1H), 6.71 (d, J =
15.8 Hz, 1H), 7.26–7.50 (m, 10H). 13C-NMR (75 MHz, CDCl3)
6696 | Org. Biomol. Chem., 2011, 9, 6691–6699
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Configuration was assigned by comparing HPLC elution order
with that of the literature data.12c
1121, 1033, 865, 818, 780, 762, 738, 703 cm-1. HPLC (Chiralcel
OD, hexane : isopropanol = 90 : 10, 1 mL min-1, l = 254 nm)
tR = 21.0 min for enantiomer S, tR = 25.1 min for enantiomer
R. Configuration was assigned by comparing HPLC elution order
with that of the literature data.21
(R)-(p-Chlorophenyl)(o-tolyl)methanol (ent-2p). This com-
pound is the enantiomer of 2p and was obtained from o-
tolualdehyde (60 ml, 0.5 mmol) and tri(p-chlorophenyl)boroxin
(124.2 mg, 0.3 mmol).
(R)-(p-Methoxyphenyl)(2-naphthyl)methanol
(ent-2s). This
compound is the enantiomer of 2s and was obtained
from 2-naphthaldehyde (78.2 mg, 0.5 mmol) and tri(p-
methoxyphenyl)boroxin (120.6 mg, 0.3 mmol).
(R)-(p-Chlorophenyl)(p-tolyl)methanol (2q). This compound
was obtained from p-chlorobenzaldehyde (72.8 mg, 0.5 mmol)
and tri(p-tolyl)boroxin (106.3 mg, 0.3 mmol) and purified by flash
1
chromatography (ethylacetate/hexane = 1 : 15). White solid. H-
(S)-(p-Chlorophenyl)(2-naphthyl)methanol (2t). This com-
pound was obtained from p-chlorobenzaldehyde (72.8 mg, 0.5
mmol) and tri(2-naphthyl)boroxin (138.6 mg, 0.3 mmol) and
purified by flash chromatography (ethylacetate/hexane = 1 : 15).
NMR (300 MHz, CDCl3) d 2.35 (s, 3H), 2.32–2.41 (br s, 1H, OH),
5.77 (br s, 1H), 7.14–7.18 (m, 2H), 7.22–7.27 (m, 2H), 7.31 (s,
4H). 13C-NMR (75 MHz, CDCl3) d 21.1 (CH3), 75.4 (CH), 126.5
(2CH), 127.7 (2CH), 128.5 (2CH), 129.3 (2CH), 133.1 (C), 137.6
(C), 140.5 (C), 142.3 (C). IR (Nujol) n 3283, 2019, 1900, 1511,
1190, 1179, 1087, 1038, 1012, 799, 766 cm-1. HPLC (Chiralcel OD,
hexane : isopropanol = 95 : 5, 1 mL min-1, l = 220 nm) tR = 14.4 min
for enantiomer R, tR = 15.7 min for enantiomer S. Configuration
was assigned by comparing HPLC elution order with that of the
literature data.12c
1
White solid. H-NMR (300 MHz, CDCl3) d 3.50 (ps d, J = 3.3
Hz, 1H), 5.80 (ps d, J = 2.6 Hz, 1H), 7.26–7.33 (m, 4H), 7.36
(dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1H), 7.54–7.59 (m, 2H), 7.79 (s,
1H), 7.82–7.89 (m, 3H). 13C-NMR (75 MHz, CDCl3) d 75.4 (CH),
124.4 (CH), 125.0 (CH), 126.0 (CH), 126.2 (CH), 127.6 (CH),
127.8 (2CH), 127.9 (CH), 128.3 (CH), 128.4 (2CH), 132.7 (C),
133.0 (C), 133.1 (C), 140.4 (C), 141.7 (C). IR (Nujol) n 3339, 3055,
1952, 1906, 1601, 1508, 1489, 1166, 1122, 1092, 1013, 953, 867, 810,
775, 764, 748 cm-1. HPLC (Chiralcel OD, hexane : isopropanol =
90 : 10, 1 mL min-1, l = 254 nm) tR = 19.7 min for enantiomer S,
tR = 22.4 min for enantiomer R. Configuration was assigned by
comparing HPLC elution order with that of the literature data.21
(S)-(p-Chlorophenyl)(p-tolyl)methanol (ent-2q). This com-
pound is the enantiomer of 2q and was obtained from p-
tolualdehyde (56 ml, 0.5 mmol) and tri(p-chlorophenyl)boroxin
(124.2 mg, 0.3 mmol).
(S)-2-Naphthyl(p-tolyl)methanol (2r)20. This compound was
obtained from p-tolualdehyde (56 ml, 0.5 mmol) and tri(2-
naphthyl)boroxin (138.6 mg, 0.3 mmol) and purified by flash
(R)-(p-Chlorophenyl)(2-naphthyl)methanol (ent-2t). This com-
pound is the enantiomer of 2t and was obtained
from 2-naphthaldehyde (78.2 mg, 0.5 mmol) and tri(p-
chlorophenyl)boroxin (124.2 mg, 0.3 mmol).
1
chromatography (ethylacetate/hexane = 1 : 20). White solid. H-
NMR (300 MHz, CDCl3) d 2.43 (s, 3H), 3.10 (s, 1H, OH), 5.93
(s, 1H), 7.22 (ps d, J = 7.9 Hz, 2H), 7.35 (ps d, J = 7.9 Hz, 2H),
7.47 (ps d, J = 8.3 Hz, 1H), 7.55–7.58 (m, 2H), 7.83–7.93 (m, 4H).
13C-NMR (75 MHz, CDCl3) d 21.0 (CH3), 75.9 (CH), 124.7 (CH),
124.8 (CH), 125.7 (CH), 126.0 (CH), 126.6 (2CH), 127.5 (CH),
128.0 (CH), 128.1 (CH), 129.0 (2CH), 132.7 (C), 133.1 (C), 137.1
(C), 140.6 (C), 141.2 (C). IR (Nujol) n 3294, 1601, 1508, 1332,
1243, 1166, 1122, 1026, 1016, 868, 822, 778, 763, 745 cm-1. HPLC
(Chiralcel OD, hexane : isopropanol = 95 : 5, 1 mL min-1, l = 254
nm) tR = 27.2 min for enantiomer S, tR = 30.7 min for enantiomer R.
Configuration was assigned by assuming an analogous mechanism
for the aryl transfer.
(S)-2-Naphthyl(p-(trifluoromethyl)phenyl)methanol (2u). This
compound was obtained from p-(trifluoromethyl)benzaldehyde
(69 ml, 0.5 mmol) and tri(2-naphthyl)boroxin (138.6 mg, 0.3 mmol)
and purified by flash chromatography (ethylacetate/hexane =
1 : 15). White solid. [a]D -45.3 (c 2.2, CHCl3). 1H-NMR (300 MHz,
CDCl3) d 2.87 (br s, 1H, OH), 5.95 (s, 1H), 7.38 (dd, J1 = 8.6 Hz,
J2 = 1.8 Hz, 1H), 7.49–7.57 (m, 2H), 7.51 (ps d, J = 7.3 Hz,
2H), 7.60 (ps d, J = 8.3 Hz, 2H), 7.70–7.80 (m, 4H). 13C-NMR
(75 MHz, CDCl3) d 75.7 (CH), 124.1 (q, JC-F = 272 Hz, 1C),
124.4 (CH), 125.4 (3CH), 126.3 (CH), 126.4 (CH), 126.7 (2CH),
127.7 (CH), 128.0 (CH), 128.7 (CH), 129.6 (q, JC-CF = 32 Hz, 1C),
133.0 (C), 133.1 (C), 140.3 (C), 147.2 (C). 19F-NMR (282 MHz,
CDCl3) d -62.81 (s, 3F). IR (Nujol) n 3369, 2019, 1924, 1618,
1499, 1336, 1168, 1157, 1127, 1108, 1069, 1016, 846, 822, 814,
776, 762, 744 cm-1. HRMS calcd for C18H13F3O + Na+, 325,0816;
found, 325,0822. HPLC (Chiralcel OD, hexane : isopropanol =
90 : 10, 1 mL min-1, l = 220 nm) tR = 19.8 min for enan-
tiomer S, tR = 22.5 min for enantiomer R. Configuration was
assigned by assuming an analogous mechanism for the aryl
transfer.
(R)-2-Naphthyl(p-tolyl)methanol (ent-2r). This compound is
enantiomer of 2r and was obtained from 2-naphthaldehyde
(78.2 mg, 0.5 mmol) and tri(p-tolyl)boroxin (106.3 mg, 0.3 mmol).
[a]D -30.5 (c 1.9, CHCl3).
(S)-(p-Methoxyphenyl)(2-naphthyl)methanol (2s). This com-
pound was obtained from p-methoxybenzaldehyde (61 ml, 0.5
mmol) and tri(2-naphthyl)boroxin (138.6 mg, 0.3 mmol) and
purified by flash chromatography (ethylacetate/hexane = 1 : 10–
1 : 8). White solid. 1H-NMR (300 MHz, CDCl3) d 2.73 (br s, 1H,
OH), 3.79 (s, 3H), 5.93 (s, 1H), 6.88 (ps d, J = 8.8 Hz, 2H), 7.32 (ps
d, J = 8.3 Hz, 2H), 7.42 (dd, J1 = 8.6 Hz, J2 = 1.8 Hz, 1H), 7.48–
7.54 (m, 2H), 7.79–7.90 (m, 4H). 13C-NMR (75 MHz, CDCl3)
d 55.2 (CH3), 75.7 (CH), 113.8 (2CH), 124.6 (CH), 124.7 (CH),
125.8 (CH), 126.1 (CH), 127.6 (CH), 128.0 (3CH), 128.1 (CH),
132.7 (C), 133.1 (C), 135.9 (C), 141.3 (C), 158.9 (C). IR (KBr) n
3368, 3056, 2837, 1896, 1610, 1585, 1509, 1463, 1441, 1249, 1175,
(S)-o-Tolyl(p-(trifluoromethyl)phenyl)methanol
(2v). This
compound was obtained from p-(trifluoromethyl)benzaldehyde
(69 ml, 0.5 mmol) and tri(o-tolyl)boroxin (106.3 mg, 0.3 mmol)
and purified by flash chromatography (ethylacetate/hexane =
1 : 15). White solid. [a]D -34.5 (c 2.3, CHCl3). 1H-NMR (300
MHz, CDCl3) d 2.26 (s, 3H), 3.68 (s, 1H, OH), 5.88 (s, 1H),
7.20–7.24 (m, 1H), 7.26–7.31 (m, 2H), 7.35–7.40 (m, 1H), 7.40
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(ps d, J = 8.1 Hz, 2H), 7.61 (ps d, J = 8.1 Hz, 2H). 13C-NMR (75
MHz, CDCl3) d 19.1 (CH3), 72.4 (CH), 124.1 (q, JC-F = 272 Hz,
1C), 125.2 (2CH), 126.2 (CH), 126.5 (CH), 127.1 (2CH), 127.9
(CH), 129.7 (q, JC-CF = 32 Hz, 1C), 130.7 (CH), 135.4 (C), 140.6
(C), 146.6 (C). 19F-NMR (282 MHz, CDCl3) d -62.81 (s, 3F).
IR (Nujol) n 3325, 3069, 3024, 2645, 2019, 1924, 1619, 1490,
1417, 1327, 1166, 1126, 1058, 1017, 863, 840, 816, 787, 752 cm-1.
HRMS calcd for C15H13F3O + Na+, 289.0816; found, 289.0806.
HPLC (Chiralcel OD, hexane : isopropanol = 90 : 10, 1 mL min-1,
l = 220 nm) tR = 10.9 min for enantiomer R, tR = 12.2 min
for enantiomer S. Configuration was assigned by assuming an
analogous mechanism for the aryl transfer.
Junta de Castilla y Leo´n (GR168). R. I. also thanks Junta de
Castilla y Leo´n for a predoctoral fellowship.
Notes and references
1 (a) W. M. Welch, A. R. Kraska, R. Sarges and B. K. Koe, J. Med.
Chem., 1984, 27, 1508–1515; (b) K. Meguro, M. Aizawa, T. Sohda,
Y. Kawamatsu and A. Nagaoka, Chem. Pharm. Bull., 1985, 33, 3787–
3797; (c) V. Barouh, H. Dall, D. Patel and G. Hite, J. Med. Chem.,
1971, 14, 834–836; (d) S. Stanchev, R. Rakovska, N. Berova and G.
Snatzke, Tetrahedron: Asymmetry, 1995, 6, 183–198; (e) P. C. Astles,
T. J. Brown, F. Halley, C. M. Handscombe, N. V. Harris, T. N. Majid,
C. McCarthy, I. M. McLay, A. Morley, B. Porter, A. G. Roach, C.
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P. D. O’Shea, A. Roy and R. D. Tillyer, Org. Lett., 2004, 6, 111–
114.
(R)-p-Tolyl(p-(trifluoromethyl)phenyl)methanol
(2w). This
compound was obtained from p-(trifluoromethyl)benzaldehyde
(69 ml, 0.5 mmol) and tri(p-tolyl)boroxin (106.3 mg, 0.3 mmol)
and purified by flash chromatography (ethylacetate/hexane =
1 : 15). White solid. [a]D -44.3 (c 1.8, C6H6), 1H-NMR (300 MHz,
CDCl3) d 2.28–2.35 (br s, 1H, OH), 2.35 (s, 3H), 5.86 (s, 1H), 7.17
(ps d, J = 7.9 Hz, 2H), 7.25 (ps d, J = 8.1 Hz, 2H), 7.51 (ps d, J = 8.1
Hz, 2H), 7.60 (ps d, J = 8.3 Hz, 2H). 13C-NMR (75 MHz, CDCl3)
d 21.1 (CH3), 75.5 (CH), 124.3 (q, JC-F = 272 Hz, 1C), 125.3 (CH),
125.4 (CH), 126.5 (2CH), 126.6 (2CH), 129.4 (2CH), 129.6 (q,
JC-CF = 32 Hz, 1C), 137.9 (C), 140.3 (C), 147.7 (C). 19F-NMR
(282 MHz, CDCl3) d -62.82 (s, 3F). IR (Nujol) n 3326, 2666,
2019, 1924, 1618, 1509, 1338, 1162, 1128, 1110, 1069, 1017, 873,
833, 800, 762 cm-1. HPLC (Chiralcel OD, hexane : isopropanol =
90 : 10, 1 mL min-1, l = 220 nm) tR = 9.1 min for enantiomer R,
tR = 10.7 min for enantiomer S. Configuration was assigned by
comparing the sign of optical rotation with that of the literature
data.22
2 For reviews on catalyzed asymmetric arylation reactions, see: (a) C.
Bolm, J. P. Hildebrand, K. Mun˜iz and N. Hermanns, Angew. Chem.,
Int. Ed., 2001, 39, 1488; (b) F. Schmidt, R. T. Stemmler, J. Rudolph
and C. Bolm, Chem. Soc. Rev., 2006, 35, 454; (c) V. Dimitrov and K.
Kostova, Lett. Org. Chem., 2006, 3, 176; (d) M. W. Paixao, A. L. Braga
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cited therein.
3 C. Bolm and J. Rudolph, J. Am. Chem. Soc., 2002, 124, 14850–14851.
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3997–4000; (b) S. Ozc¸ubukc¸u, F. Schmidt and C. Bolm, Org. Lett., 2005,
7, 1407–1409; (c) J. Rudolph, F. Schmidt and C. Bolm, Synthesis, 2005,
840–842; (d) J. Rudolph, M. Lormann, C. Bolm and S. Dahmen, Adv.
Synth. Catal., 2005, 347, 1361–1368; (e) F. Schmidt, J. Rudolph and
C. Bolm, Adv. Synth. Catal., 2007, 349, 703–708; (f) A. D. Wouters,
G. H. G. Trossini, H. A. Stefani and D. S. Lu¨dtke, Eur. J. Org. Chem.,
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D. Rodrigues, M. W. Paixao, M. Godoi and A. L. Braga, Eur. J. Org.
Chem., 2010, 3574–3578; (h) A. V. Moro, R. T. Tiekink, J. Zukerman-
Schpector, D. S. Lu¨dtke and C. R. D. Correia, Eur. J. Org. Chem.,
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Tetrahedron, 2008, 64, 2559.
5 (a) X. Wu, X. Liu and G. Zhao, Tetrahedron: Asymmetry, 2005, 16,
2299–2305; (b) X. Y. Liu, X. Y. Wu, Z. Chai, Y. Wu, G. Zhao and S.
Z. Zhu, J. Org. Chem., 2005, 70, 7432–7435; (c) Z. Chai, X. Liu, X.
Wu and G. Zhao, Tetrahedron: Asymmetry, 2006, 17, 2442–2447; (d) C.
Jimeno, S. Sayalero, T. Fjermestad, G. Colet, F. Maseras and M. A.
Perica´s, Angew. Chem., Int. Ed., 2008, 47, 1098–1101; (e) C. Liu, Z.-L.
Guo, J. Weng, L. Gui and A. S. C. Chan, Chirality, 2010, 22, 159–164.
6 (a) N. A. Magnus, P. B. Anzeveno, D. S. Coffey, D. A. Hay, M. E.
Laurila, J. M. Schkeryantz, B. W. Shaw and M. A. Staszak, Org.
Process Res. Dev., 2007, 11, 560–567; (b) T. D. Aicher, G. S. Cortez,
T. M. Groendyke, A. Khilevich, J. A. Knobelsdorf, N. A. Magnus,
F. P. Marmsater, J. M. Schkeryantz, T. P. Tang, PCT Int. Appl. WO
2006/057670A1 20060601, 2006.
7 (a) G. Lu, F. Y. Kwong, J.-W. Ruan, Y.-M. Li and A. S. C. Chan, Chem.–
Eur. J., 2006, 12, 4115–4120; (b) J. Ruan, G. Lu, L. Xu, Y. M. Li and A.
S. C. Chan, Adv. Synth. Catal., 2008, 350, 76–78; (c) M. Godoi, E. E.
Alberto, M. W. Paixa˜o, L. A. Soares, P. H. Schneider and A. L. Braga,
Tetrahedron, 2010, 66, 1341–1345. See also references 3, 4h, 5a, 5d and
5e.
8 C. Andre´s, R. Infante and J. Nieto, Tetrahedron: Asymmetry, 2010, 21,
2230.
9 R. Pedrosa, C. Andre´s, C. D. Roso´n and M. Vicente, J. Org. Chem.,
2003, 68, 1852.
10 C. Andre´s, I. Gonza´lez, J. Nieto and C. D. Roso´n, Tetrahedron, 2009,
65, 9728.
11 J.-X. Ji, J. Wu, T. T-L. Au-Yeung, C-W. Yip, R. K. Haynes and A. S. C.
Chan, J. Org. Chem., 2005, 70, 1093. See also references 4a, 4h, 7a and
7c.
12 In very few previous studies the addition of ortho-substituted aryls
to benzaldehyde has been reported, and in most of them the results
in terms of enantioselectivity were poor or even racemic: (a) M-C.
Wang, Q-J. Zhang, W-X. Zhao, X.-D. Wang, X. Ding, T-T. Jing and
M-P. J. Song, J. Org. Chem., 2008, 73, 168; (b) X-F. Yang, T. Hirose
and G-Y. Zhang, Tetrahedron: Asymmetry, 2009, 20, 415; (c) X-B.
Wang, K. Kodama, T. Hirose, X-F. Yang and G-Y. Zhang, Tetrahedron:
Asymmetry, 2010, 21, 75. See also references 5a and 7a.
(S)-p-Tolyl(p-(trifluoromethyl)phenyl)methanol (ent-2w). This
compound is enantiomer of 2w and was obtained
from p-tolualdehyde (56 ml, 0.5 mmol) and tri(p-
(trifluoromethyl)phenyl)boroxin (154.7 mg, 0.3 mmol). [a]D
=
+40.6 (c 0.4, C6H6).
(S) - (p - Chlorophenyl)(p - ( trifluoromethyl ) phenyl ) methanol
(2x). This compound was obtained from p-(trifluoromethyl)-
benzaldehyde (69 ml, 0.5 mmol) and tri(p-chlorophenyl)boroxin
(124.2 mg, 0.3 mmol) and purified by flash chromatography
(ethylacetate/hexane = 1 : 15). White solid. [a]D -27.1 (c 2.3, C6H6).
1H-NMR (300 MHz, CDCl3) d 2.48 (ps d, J = 3.3 Hz, 1H, OH),
5.85 (br s, 1H), 7.27–7.35 (m, 4H), 7.48 (ps d, J = 8.1 Hz, 2H),
7.61 (ps d, J = 8.1 Hz, 2H). 13C-NMR (75 MHz, CDCl3) d 75.0
(CH), 124.0 (q, JC-F = 272 Hz, 1C), 125.5 (CH), 125.6 (CH),
126.6 (2CH), 127.9 (2CH), 128.9 (2CH), 129.9 (q, JC-CF = 33
Hz, 1C), 133.8 (C), 141.5 (C), 147.0 (C). 19F-NMR (282 MHz,
CDCl3) d -62.93 (s, 3F). IR (Nujol) n 3260, 3055, 1929, 1618,
1491, 1331, 1169, 1156, 1109, 1092, 1070, 1040, 1014, 872, 854,
834, 792, 764 cm-1. HPLC (Chiralcel OD, hexane : isopropanol =
95 : 5, 1 mL min-1, l = 220 nm) tR = 15.2 min for enantiomer S,
tR = 16.7 min for enantiomer R. Configuration was assigned by
comparing the sign of optical rotation with that of the literature
data.23
Acknowledgements
We acknowledge the financial support from the Spanish Ministerio
de Ciencia e Innovacio´n (project CTQ2008-03960/BQU) and
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13 Beneficial effects of the use of polyethers, such as DiMPEG, had
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14 Boronic Acids: Preparation and Applications in Organic Synthe-
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Du and C.-S. Da, Chem.–Eur. J., 2010, 16, 7988.
18 N. Tokunaga and T. Hayashi, Tetrahedron: Asymmetry, 2006, 17, 607.
19 B. C. Ranu and S. Samanta, Tetrahedron, 2003, 59, 29.
20 M. Kuriyama, N. Ishiyama, R. Shimazawa and O. Onomura, Tetrahe-
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21 J. G. Kim and P. J. Walsh, Angew. Chem., Int. Ed., 2006, 45, 4175.
22 J. Capillon and J.-P. Guette´, Tetrahedron, 1979, 35, 1801.
23 S. Stanchev, R. Rakovska, N. Berova and G. Snatzke, Tetrahedron:
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The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6691–6699 | 6699
©