Facile synthesis of chiral 1,2-chlorohydrins via the ring-opening of meso-epoxides catalyzed by chiral phosphine oxides

Article abstract of DOI:10.1016/j.tet.2013.01.066

The facile synthesis of chiral 1,2-chlorohydrins via the enantioselective ring-opening of meso-epoxides with silicon tetrachloride in the presence of a chiral phosphine oxide was accomplished. The chiral 1,2-chlorohydrins were also obtained from the corresponding cis-alkenes in one-pot without significant loss in the selectivity, thereby permitting easy access to the 1,2-chlorohydrins from cis-alkenes with good yields and enantioselectivities.

Full text of DOI:10.1016/j.tet.2013.01.066

Tetrahedron 69 (2013) 3075e3081
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Facile synthesis of chiral 1,2-chlorohydrins via the ring-opening
of meso-epoxides catalyzed by chiral phosphine oxides
,
b
b
b,
*
Shunsuke Kotani a , Haruka Furusho , Masaharu Sugiura , Makoto Nakajima
*
a Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto, Japan
b Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The facile synthesis of chiral 1,2-chlorohydrins via the enantioselective ring-opening of meso-epoxides
with silicon tetrachloride in the presence of a chiral phosphine oxide was accomplished. The chiral 1,2-
chlorohydrins were also obtained from the corresponding cis-alkenes in one-pot without significant loss
in the selectivity, thereby permitting easy access to the 1,2-chlorohydrins from cis-alkenes with good
yields and enantioselectivities.
Received 14 December 2012
Received in revised form 17 January 2013
Accepted 21 January 2013
Available online 31 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Chlorohydrin
meso-Epoxide
Enantioselective
Halogenation
Lewis base
1. Introduction
synthetic method for producing chiral 1,2-chlorohydrins from cis-
alkenes in one-pot.
The asymmetric desymmetrization of meso-compounds is an
effective strategy for directly accessing optically active chiral
products.1 This reaction is exemplified by the asymmetric desym-
metrization of meso-cyclic compounds via selective ring-opening at
one of the enantiotopic carbons. The meso-epoxides comprise
a versatile class of substrates because they react with a variety of
nucleophiles to afford several types of chiral alcohols with contig-
uous chiral centers. Such products provide useful intermediates
and chiral building blocks.2 For example, the desymmetrization
of meso-epoxides using halide anions produces the chiral
1,2-halohydrins.3 In 1988, Yamamoto developed the chiral
organoaluminium-mediated asymmetric ring-opening of cyclo-
hexene oxide to give the corresponding 1,2-halohydrin.4 Brown
reported the enantioselective synthesis of 1,2-halohydrins using
chiral borane reagents.5,6 In 1998, a striking achievement has been
developed by Denmark, who applied chiral phosphoramides as
a Lewis base catalyst to the ring-opening of meso-epoxides with
silicon tetrachloride, producing chiral 1,2-chlorohydrins enantio-
selectively.3,7,8 Thereafter, exciting advances have been achieved in
this field.9e16 Here, we report a full description of the enantiose-
lective ring-opening of meso-epoxides catalyzed by a chiral phos-
phine oxide.11 We have additionally developed a more convenient
2. Result and discussion
2.1. Enantioselective ring-opening of meso-epoxides cata-
lyzed by phosphine oxide
We initially performed the ring-openingof cis-stilbene oxide (1a)
using 1.5 equiv of silicon tetrachloride in the presence of 10 mol %
(S)-BINAP dioxide (BINAPO) and 1.5 equiv of diisopropylethylamine
(Table 1). The choice of solvent was crucial for the reaction.
Dichloromethane gave the corresponding 1,2-chlorohydrin (2a) in
94% yield and 90% ee (entry 1). In toluene, the solubility of the
phosphine oxide catalyst was quite low, thereby promoting a non-
catalytic process and reducing the enantioselectivity (entry 2).
Propionitrile slightly decreased both the isolated yield and the
enantioselectivity (entry 3). THF gave the same level of the enan-
tioselectivity as dichloromethane (90% ee), but the yield of chloro-
hydrin 2a decreased due to the formation of the by-product 3, which
may have been produced by the reaction with THF (entry 4, Fig. 1).
We next performed the ring-opening of cis-stilbene oxide (1a) using
chloromethylsilanes in place of silicon tetrachloride. The use of
chlorotrimethylsilane dramatically reduced both the yield and
selectivity (entry 5). The use of trichloromethylsilane favored the
product, but the selectivity was lower than the selectivity achieved
using silicon tetrachloride (entry 6).
* Corresponding authors. Tel.: þ81 963714394; e-mail address: skotani@gpo.-
kumamoto-u.ac.jp (S. Kotani).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.066

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S. Kotani et al. / Tetrahedron 69 (2013) 3075e3081
Table 1
We next screened the chiral phosphine oxides in an effort to
increase the selectivity under the optimized conditions (Fig. 2).
Both tol-BINAPO and xyl-BINAPO significantly reduced the enan-
tioselectivities relative to BINAPO. Substituents on the phenyl ring
had a large effect on the enantioselectivities of 1a. H8-BINAPO and
SEGPHOSO, bearing different types of biaryl skeletons, afforded
enantioselectivities similar to that of BINAPO. DIOPO was in-
effective in the enantioinduction of the ring-opening reactions of
meso-epoxides.18 These results indicated that both the biaryl skel-
eton and the phenyl groups were important for obtaining a high
selectivity.
Enantioselective ring-opening of cis-stilbene oxide (1a) under various reaction
conditionsa
Entry
Chlorosilane
Solvent
Yield, %b
Ee, %c
1
2
3
4
5
6
SiCl4
SiCl4
SiCl4
SiCl4
Me3SiCl
MeSiCl3
CH2Cl2
Toluene
EtCN
THF
CH2Cl2
CH2Cl2
94
70
83
90
25
74
90
1
56 (29)d
13
O
P
O
P
O
P
Ph
Ph
Ph
Ph
(4-tol)
(4-tol)
(4-tol)
(4-tol)
(3,5-xyl)
(3,5-xyl)
(3,5-xyl)
(3,5-xyl)
84
0
a
The reaction was performed by adding a chlorosilane (1.5 equiv) to a solution
containing 1a (1.0 equiv), diisopropylethylamine (1.5 equiv), and (S)-BINAPO
(10 mol %) at ꢀ78 ꢁC under an argon atmosphere.
P
O
P
O
P
O
b
Isolated yield.
Determined by HPLC analysis.
The yield of by-product 3 is given in parenthesis.
c
(S)-BINAPO:
4 h, 94% yield
90% ee
(S)-tol-BINAPO:
4 h, 92% yield
59% ee
(S)-xyl-BINAPO:
2 h, 95% yield
34% ee
d
O
O
O
P
O
P
Ph
Ph
Ph
Ph
Ph
Ph
P
O
O
O
O
Ph
Ph
Ph
Ph
Ph
Ph
P
O
P
P
O
O
O
(S)-H8-BINAPO:
2 h, 92% yield
86% ee
(S)-SEGPHOSO:
2 h, 93% yield
88% ee
(R,R)-DIOPO:
2 h, 92% yield
17% ee
Fig. 2. Screening of the chiral phosphine oxides.
Fig. 1. Ring-opening of THF.
The ring-opening of various meso-epoxides 1 was achieved us-
ing BINAPO as the catalyst (Table 3). Variations in the substituents
on the aromatic ring did not influence the reaction efficiency, and
high enantioselectivities were obtained in all cases (entries 2e4).
Conversion of the meso-epoxide 1e derived from a linear olefin to
the corresponding chlorohydrin 2e was good, although the selec-
tivity was low, presumably due to the conformational flexibility of
1e (entry 5). Cyclohexene oxide (1f) gave a good selectivity (entry
Additives were screened in dichloromethane (Table 2). Without
additives, the chlorohydrin 2a was obtained quantitatively; how-
ever, the observed selectivity was lower than the selectivity ach-
ieved using diisopropylethylamine (entry 2). The low selectivity
results from the presence of a small amount of hydrogen chloride,
which was adventitiously generated from silicon tetrachloride and
promoted the non-selective reaction course.17 Triethylamine gave
the product with a lower enantioselectivity than was achieved
using diisopropylethylamine (entry 3), whereas pyridine dramati-
cally reduced the selectivity (entry 4). Pyridine may coordinate to
silicon tetrachloride in the reaction media to form an achiral
hypervalent silicon species, yielding the racemic product 2a. In-
terestingly, the addition of 2-methyl-2-butene also improved the
enantioselectivity (entry 5). These results support the notion that
acid scavenging is essential for achieving a high enantioselectivity.
Excess or low equivalents of diisopropylethylamine to silicon
tetrachloride gave almost the same results, but the selectivities
decreased slightly in both cases (entries 6 and 7).
Table 3
Substrate scope of the ring-opening for various meso-epoxides 1a
Entry
Substrate
Time, h Product
2 or 4 Yield, %b Ee, %c (config)
1
1
4
2a
2b
94
90 (1S,2S)
Table 2
Effect of additives on the ring-opening of 1aa
Entry
Additive (equiv)
iPr2NEt (1.5)
None (1.5)
Et3N (1.5)
Pyridine (1.5)
2-Methyl-2-butene (1.5)
iPr2NEt (0.75)
iPr2NEt (3.0)
Yield, %b
Ee, %c
1
2
3
4
5
6
7
94
99
98
83
93
97
90
90
59
82
11
85
86
88
2
3
2
93
84 (1S,2S)
a
The reaction was performed by adding silicon tetrachloride (1.5 equiv) to a so-
lution containing 1a (1.0 equiv), an additive, and (S)-BINAPO (10 mol %) in
dichloromethane at ꢀ78 ꢁC under an argon atmosphere.
0.25
2c
96
86 (1S,2S)
b
Isolated yield.
Determined by HPLC analysis.
c

S. Kotani et al. / Tetrahedron 69 (2013) 3075e3081
3077
Table 3 (continued )
Entry Substrate
Time, h Product
2 or 4 Yield, %b
1
Ee, %c (config)
86 (1S,2S)
4
0.5
2d
97
5
6
12
2e
92
81
35 (1S,2S)
71 (1S,2S)
1
2fd
Fig. 3. X-ray structure of 4j-NB.
7
72
2gd
81
95
50 (1S,2S)
8
9
1
2h
34
1
2id
73
60
39
66
4jd
10
48
Fig. 4. Plausible reaction mechanism for the preparation of 1,4-chlorohydrine 4j.
needed to obtain a desired product.20 One-pot synthetic ap-
proaches are ideally highly efficient and permit ready access to an
optically active product. The meso-epoxides used in the ring-
opening were generally synthesized from the corresponding cis-
alkenes using an oxidant. We therefore sought to combine these
processes in one-pot and to establish a chlorohydrin syntheses
from the cis-alkenes.21
a
The reaction was performed by adding silicon tetrachloride (1.5 equiv) to the
solution containing the meso-epoxide
1 (1.0 equiv), diisopropylethylamine
(1.5 equiv), and (S)-BINAPO (10 mol %) in dichloromethane at ꢀ78 ꢁC under an argon
atmosphere.
b
Isolated yield.
Determined by HPLC analysis.
Isolated as 4-nitrobenzoate.
c
d
1,2-chlorohydrin 2a was synthesized from cis-stillbene (5a)
(Fig. 5). The reaction was performed via oxidation to the epoxide 1a
in the presence of 1.2 equiv of m-chloroperbenzoic acid (m-CPBA)22
and 10 mol % of BINAPO, followed by ring-opening under the above
reaction condition. Oxidation was completed within 5 h at room
temperature. The resulting solution was cooled to ꢀ78 ꢁC, and
diisopropylethylamine and silicon tetrachloride were added
successively. Fortunately, the desired 1,2-chlorohydrin 2a was ob-
tained in good yield, but the observed enantioselectivity was lower
than was achieved in the ring-opening of isolated meso-epoxide 1a.
6), whereas in the reaction of cyclooctene oxide (1g), the selectivity
of chlorohydrin 2g was modest (entry 7). The heterocyclic epoxides
1h and 1i were smoothly converted into the corresponding prod-
ucts 2h and 2i with modest selectivities (entries 8 and 9). The re-
action of norbornene oxide (1j) yielded the major product in
moderate yield and selectivity (entry 10); however, the product
could not be definitively assigned as 1,2- or 1,4-chlorohydrin by
NMR analysis because the spectra for these chrolohydrins are quite
similar.15,16,19 X-ray crystal structure analysis of the crystalline 4-
nitrobenzoate of the major product revealed that the obtained
product was 1,4-chlorohydrin 4j (Fig. 3). The 1,4-chlorhydrin 4j may
be obtained through the reaction mechanism shown in Fig. 4.16
Norbornene oxide (1j) may be activated by chiral silicon species,
leading to an enantiotopic WagnereMeerwein rearrangement. The
intramolecular addition of a chloride anion from hypervalent sili-
cate to the cationic species, produced the 1,4-chlorohydrin 4j.
2.2. One-pot synthesis of 1,2-chlorohydrins from the cis-
alkenes
Fig. 5. One-pot 1,2-chlorohydrin synthesis from cis-stilbene (5a).
The stepwise and one-pot synthetic approaches differed in the
use of m-CPBA as the oxidant and the production of m-chlorobenzoic
acid. These reagents may interfere with the stereoselective ring-
opening of meso-epoxide 1a, thereby reducing the selectivity.
The combination of stepwise transformations in a one-pot re-
action offers a powerful organic synthesis method by reducing the
number of synthetic process and the amounts of chemical reagents

3078
S. Kotani et al. / Tetrahedron 69 (2013) 3075e3081
Table 5 (continued)
Thus, we reexamined the reaction conditions in an effort to mitigate
the effects of these reagentson the selectivity (Table 4). Lowering the
equivalents of diisopropylethylamine dramatically decreased the
enantioselectivity (entry 2). By contrast, a small excess of the amine
improved the selectivity (entries 3 and 4); 1.6 equiv of diisopropy-
lethylamine gave a level of selectivity similar to the selectivity
achieved for the ring-openingof the isolated meso-epoxide 1a (entry
3); however, excess amounts of amine tended to reduce the selec-
tivity of 2a (entries 4 and 5). Increasing or decreasing both the silicon
tetrachloride and the diisopropylethylamine reduced the selectivity
(entries 6 and 7).
Entry
Substrate
Time A, h Time B, h Product
2, 4 Yield, %b Ee, %c (config)
5
4
5
0.5
3
0.5
1
2e 62
2fd 88
40 (1S,2S)
64 (1S,2S)
6
18
24
2gd 94
47 (1S,2S)
Table 4
Optimization study of the reaction conditions for the one-pot chlorohydrin
synthesisa
7e
8e
72
6
2h 81
2id 61
35
12
5
6
37
67
4jd
9
48
60
Entry
X
Y
Time, h
Yield, %b
Ee, %c
1
2
3
4
5
6
7
1.5
1.5
1.5
1.5
1.5
1.2
2.0
1.5
1.0
1.6
2.0
2.5
1.3
2.1
4
4
2
3
18
1
86
84
83
82
87
87
81
61
29
88
80
43
72
84
a
The reaction was performed by adding m-CPBA (1.2 equiv) to a solution con-
taining the cis-alkene 5 (0.5 mmol) and (S)-BINAPO (10 mol %) in dichloromethane
at room temperature under an argon atmosphere, followed by addition of diiso-
propylethylamine (1.6 equiv) and silicon tetrachloride (1.5 equiv) at ꢀ78 ꢁC.
b
Isolated yield.
c
Determined by HPLC analysis.
Isolated as 4-nitrobenzoate.
5.0 equiv of silicon tetrachloride were used.
2
d
a
e
The reaction was performed by adding m-CPBA (1.2 equiv) to a solution con-
taining 5a (1.0 equiv) and (S)-BINAPO (10 mol %) in dichloromethane at room
temperature under an argon atmosphere, followed by the addition of diisopropy-
lethylamine and silicon tetrachloride at ꢀ78 ꢁC.
to the epoxide 1f, which then reacted with silicon tetrachloride to
give the chlorohydrin 2f in good yield with good selectivity (entry
5). By contrast, cyclooctene (5g) was less reactive with respect to
both epoxidation and the ring-opening, giving a modest selectivity
(entry 6). The five-membered cyclic alkenes 5h and 5i bearing
heteroatoms required 5 equiv of silicon tetrachloride to promote
the ring-opening presumably due to the chelating effects of
heteroatoms toward silicon tetrachloride. These reactions afforded
the corresponding chlorohydrins 2h and 2i23 (entries 7 and 8). The
reaction of norbornene (5j) produced 1,4-chlorohydrin 4j in good
yield with good selectivity (entry 9).
b
Isolated yield.
Determined by HPLC analysis.
c
With the optimal conditions in hand, we performed the reaction
using various cis-alkenes 5 (Table 5). The cis-stilbene derivatives 5b
and 5c gave high enantioselectivities similar to those achieved for
ring-opening of the isolated meso-epoxides (entries 2 and 3). 1,4-
Bis(benzyloxy)-2-butene (5e) also afforded the corresponding
chlorohydrin 2e (entry 4). Cyclohexene (5f) was smoothly oxidized
Table 5
3. Conclusion
One-pot chlorohydrin synthesis of various cis-alkenesa
We developed a facile method to synthesize 1,2-chlorohydrins
from meso-epoxides using a chiral phosphine oxide catalyst and sili-
con tetrachloride. We extended the utility of this transformation to
a convenient one-pot approach from the corresponding cis-alkenes,
thereby allowing ready access to the chiral 1,2-chlorohydrins in good
yields without the isolation of the meso-epoxide intermediates.
Entry
1
Substrate
Time A, h Time B, h Product
2, 4 Yield, %b Ee, %c (config)
4. Experimental section
4.1. General
5
6
2
2a 83
88 1S,2S)
1H and 13C NMR spectra were measured in CDCl3 with JEOL JNM-
ECX400 (1H, 400 MHz; 13C, 100 MHz) spectrometer. Tetramethylsi-
lane (TMS) (
d
¼0 ppm) and CDCl3 ( ¼77.0 ppm) were served as in-
d
2
3
7
1
2b 81
85 (1S,2S)
ternal standards for 1H and 13C NMR, respectively. Infrared spectra
were recorded on JEOL JIR 6500-W. Mass spectra were measured
with JEOL JMS-DX303HF mass spectrometer. Optical rotations were
recorded on JASCO P- 1010 polarimeter. High-pressure liquid chro-
matography (HPLC) was performed on JASCO P-980 and UV-1575.
Thin-layer chromatography (TLC) analysis was carried out using
Merck silica gel plates. Visualization was accomplished with UV
8
1
2c 83
85 (1S,2S)

S. Kotani et al. / Tetrahedron 69 (2013) 3075e3081
3079
light, phosphomolybdic acid, and/or anisaldehyde. Column chro-
matography was performed by using Kanto Chemical Silica Gel 60N
(spherical, neutral, 63e210 mm). Dry dichloromethane (dehy-
drated) was purchased from Kanto Chemical. Propionitrile was
(CleCH, s, 1H), 7.24 (AreH, d, J¼8.2 Hz, 2H), 7.31 (AreH, d, J¼8.2 Hz,
2H), 7.49 (AreH, d, J¼8.2 Hz, 2H), 7.52 (AreH, d, J¼8.2 Hz, 2H); The
enantiomeric excess was determined to be 86% ee by HPLC analysis
with Daicel Chiralpak AD-H column [eluent; hex/IPA¼9:1; flow
rate: 0.5 mL/min; detection: 254 nm; tR: 11.8 min (1R,2R), 15.2 min
(1S,2S)].
ꢀ
purchased from Wako Pure Chemical Industries, and stored over 4 A
MS prior to use. All other solvents were purified based on standard
procedures. Silicon tetrachloride was purchased from Tokyo Kasei
Kogyo (TCI) and used without further purification. Chiral phosphine
oxides were prepared byoxidation of the corresponding phosphines
with hydrogen peroxide in acetone.22 m-Chloroperoxybenzoic acid
(m-CPBA, ca.70%) was purified by washing with satd NaHCO3 and
brine, and drying over MgSO4. All other chemicals were purified
based on standard procedures.
4.2.5. (2S,3S)-1,4-Bis(benzyloxy)-3-chlorobutan-2-ol (2e).8 A color-
25
25
less oil; [
a
]
D
þ1.0 (c 1.0, CHCl3) for 35% ee [lit. 8; [
a
]
þ2.8 (c 1.0,
D
EtOH) for (2S,3S)-isomer of 71% ee]; 1H NMR (400 MHz, CDCl3):
d
2.52 (eOH, d, J¼6.0 Hz, 1H), 3.50e3.62 (BnOeCH2, m, 2H),
3.72e3.77 (BnOeCH2, m, 1H), 3.79e3.85 (BnOeCH2, m, 1H),
4.15e4.17 (CHeOH, m, 1H), 4.23e4.26 (CHeCl, m, 1H), 4.54e4.61
(CH2ePh, m, 4H), 7.29e7.37 (AreH, m, 10H); The enantiomeric
excess was determined to be 35% ee by HPLC analysis with
Daicel Chiralcel OD-H column [eluent; hex/EtOH¼24:1; flow rate:
1.0 mL/min; detection: 254 nm; tR: 15.2 min (2S,3S), 19.0 min
(2R,3R)].
4.2. Typical procedure for ring-opening reaction of meso-
epoxides
Under an argon atmosphere, silicon tetrachloride (0.044 mL,
0.38 mmol, 1.5 equiv) was added to a solution of cis-stilbene oxide
1a (50 mg, 0.25 mmol, 1.0 equiv), diisopropylethylamine (0.65 mL,
0.38 mmol, 1.5 equiv), and (S)-BINAPO (16.6 mg, 0.025 mmol,
10 mol %) in CH2Cl2 (1 mL) at ꢀ78 ꢁC. After being stirred for 4 h, the
reaction was quenched with satd NaHCO3 (1 mL) and satd KF/
KH2PO4 (2 mL), and then the slurry was stirred for 0.5 h. The two-
layers mixture was filtered through a cotton pad and the aqueous
layer was extracted with EtOAc (3ꢂ30 mL). The combined organic
layers were washed with brine (30 mL) and dried over Na2SO4.
After filtration and concentration, the obtained crude product was
purified by column chromatography (hex/EtOAc¼10:1, SiO2: 10 g)
to give the corresponding chlorohydrin 2a (55.4 mg, 94% yield).
4.2.6. 4-Chloro-1-tosyl-3-pyrrolidinol (2h).11 Colorless needles;
26
mp: 115.5e116.0 ꢁC; [
a]
þ1.2 (c 1.0, CHCl3) for 34% ee; 1H NMR
D
(400 MHz, CDCl3): d 1.71 (eOH, br s,1H), 2.43 (CH3, s, 3H), 3.39 (CH2,
d, J¼11.4 Hz, 1H), 3.53 (CH2, dd, J¼2.3, 11.4 Hz, 1H), 3.63 (CH2, dd,
J¼4.6,11.4 Hz,1H), 3.86 (CH2, dd, J¼4.6,11.4 Hz,1H), 4.06 (OHeCH, t,
J¼2.3 Hz, 1H), 4.28 (CleCH, br s, 1H), 7.32 (AreH, d, J¼8.3 Hz, 2H),
7.73 (AreH, d, J¼8.3 Hz, 2H); 13C NMR (400 MHz, CDCl3):
d 21.6,
53.0, 53.4, 54.1, 60.0, 127.5, 129.7, 133.5, 143.9; IR (KBr): 1324, 1596,
3467 cm-1; LR-FABMS: m/z 276 [MþH]þ; HR-FABMS: Calcd for
C11H14ClNO3S 276.0461, found 276.0435; The enantiomeric excess
was determined to be 34% ee by HPLC analysis with Daicel Chir-
alpak AD-H column [eluent; hex/IPA¼9:1; flow rate: 1.0 mL/min;
detection: 254 nm; tR: 25.4 min (minor), 27.0 min (major)].
4.2.1. (1S,2S)-2-Chloro-1,2-diphenylethanol (2a).15 A colorless oil;
[
a]
25 þ19.7 (c 1.0, EtOH) for 90% ee [lit. 15; [
a
]
D þ21.2 (c 1.0, EtOH) for
D
(1S,2S)-isomer of 94% ee]; 1H NMR (400 MHz, CDCl3):
d
3.04 (eOH,
4.3. Typical procedure for ring-opening reaction of meso-ep-
d, J¼2.3 Hz,1H), 4.95 (OHeCH, dd, J¼2.3, 8.2 Hz,1H), 4.99 (CleCH, d,
J¼8.2 Hz, 1H), 7.08e7.24 (AreH, m, 10H); The enantiomeric excess
was determined to be 90% ee by HPLC analysis with Daicel Chir-
alpak AD-H column [eluent: hex/IPA¼29:1; flow rate: 1.0 mL/min;
detection: 254 nm; tR: 23.3 min (1R,2R), 25.5 min (1S,2S)].
oxides and 4-nitrobenzoylation
Under an argon atmosphere, silicon tetrachloride (0.087 mL,
0.76 mmol, 1.5 equiv) was added to a solution of cyclohexene oxide
(1f) (0.51 mmol, 1.0 equiv), diisopropylethylamine (0.130 mL,
0.76 mmol, 1.5 equiv), and (S)-BINAPO (33.3 mg, 0.050 mmol,
10 mol %) in CH2Cl2 (2 mL) at ꢀ78 ꢁC. After being stirred for 1 h, the
reaction was quenched with satd NaHCO3 (1 mL) and satd KF/
KH2PO4 (2 mL), and then the slurry was stirred for 0.5 h. The two-
layers mixture was filtered through a cotton pad and the aqueous
layer was extracted with EtOAc (3ꢂ30 mL). The combined organic
layers were washed with brine (30 mL) and dried over Na2SO4.
After filtration and concentration, the obtained crude product was
dissolved in CH2Cl2 (10 mL), and then p-nitrobenzoyl chloride
(470 mg, 2.5 mmol, 5.0 equiv) and triethylamine (0.70 mL,
5.0 mmol, 10 equiv) were added to the resulting solution at room
temperature. After being stirred for 12 h, the reaction was
quenched with H2O (5 mL) and the aqueous layer was extracted
with EtOAc (3ꢂ30 mL). The combined organic layers were washed
with 10% HCl (10 mL), satd NaHCO3 (10 mL), and brine (10 mL), and
dried over Na2SO4. After filtration and concentration, the obtained
crude product was purified by column chromatography (hex/
EtOAc¼12:1, SiO2: 10 g) to give the corresponding product 2f-NB
(116 mg, 81% yield).
4.2.2. (1S,2S)-2-Chloro-1,2-di(4-tolyl) ethanol (2b).15 A colorless oil;
[
a]
29 e41.7 (c 0.98, CHCl3) for 84% ee [lit. 15; [
a
]
D ꢀ37.0 (c 0.8, CHCl3)
D
for (1S,2S)-isomer of 89% ee]; 1H NMR (400 MHz, CDCl3):
d
2.27
(CH3eAr, s, 3H), 2.29 (CH3eAr, s, 3H), 2.97 (eOH, d, J¼2.8 Hz, 1H),
4.93 (HOeCH, dd, J¼2.8, 8.2 Hz, 1H), 4.98 (CleCH, d, J¼8.2 Hz, 1H),
7.00e7.02 (AreH, m, 4H), 7.02 (AreH, d, J¼8.2 Hz, 2H), 7.08 (AreH,
d, J¼8.2 Hz, 2H); The enantiomeric excess was determined to be
84% ee by HPLC analysis with Daicel Chiralpak AD-H column [elu-
ent: hex/IPA¼9:1; flow rate: 0.5 mL/min; detection: 254 nm; tR:
19.6 min (1R,2R), 21.9 min (1S,2S)].
4.2.3. (1S,2S)-2-Chloro-1,2-bis(4-fluorophenyl) ethanol (2c).15
colorless oil; [
28 e3.1 (c 0.91, CHCl3) for 86% ee [lit. 15; [
D ꢀ4.0 (c
0.85, CHCl3) for (1S,2S)-isomer of 93% ee]; 1H NMR (400 MHz,
CDCl3):
A
a
]
a]
D
d
3.05 (eOH, d, J¼2.3 Hz, 1H), 4.89 (HOeCH, dd, J¼2.3,
8.7 Hz, 1H), 4.92 (CleCH, d, J¼8.7 Hz, 1H), 6.86e6.95 (AreH, m, 4H),
7.02e7.07 (AreH, m, 2H), 7.09e7.14 (AreH, m, 2H). The enantio-
meric excess was determined to be 86% ee by HPLC analysis with
Daicel Chiralpak AD-H column [eluent: hex/IPA¼97:3; flow rate:
0.5 mL/min; detection: 254 nm; tR: 23.0 min (1R,2R), 25.0 min
(1S,2S)].
4.3.1. (1S,2S)-2-Chlorocyclohexyl 4-nitrobenzoate (2f-NB). Yellow
needles; mp: 58.0e59.0 ꢁC; [
a
]
25 þ67.3 (c 1.0, CHCl3) for 71% ee; 1H
D
NMR (400 MHz, CDCl3):
d 1.38e1.57 (CH2, m, 3H), 1.73e1.84 (CH2,
4.2.4. (1S,2S)-2-Chloro-1,2-bis(4-trifluoromethylphenyl)ethanol
m, 3H), 2.25e2.35 (CH2, m, 2H), 4.01e4.06 (OeCH, m, 1H),
5.05e5.11 (CleCH, m, 1H), 8.23 (AreH, d, J¼9.2 Hz, 2H), 8.33 (AreH,
(2d).15 A colorless oil; [ 30 e11.6 (c 0.82, CHCl3) for 86% ee [lit. 15
a] ;
D
[
a
]
ꢀ11.9 (c 0.65, CHCl3) for (1S,2S)-isomer of 87% ee]; 1H NMR
d, J¼9.2 Hz, 2H); 13C NMR (400 MHz, CDCl3):
d 23.3, 24.6, 30.8, 34.9,
D
(400 MHz, CDCl3):
d
3.05 (eOH, br s, 1H), 5.02 (HOeCH, s, 1H), 5.04
60.5, 76.6, 123.5, 130.8, 135.6, 150.6, 163.8; IR (KBr): 1278, 1529,

3080
S. Kotani et al. / Tetrahedron 69 (2013) 3075e3081
1726 cm-1; LR-FABMS: m/z 166, 283 [M]þ; HR-FABMS: Calcd for
C13H14ClNO4 283.0611, found 283.0627; The enantiomeric excess
was determined to be 71% ee by HPLC analysis with Daicel Chir-
alpak AD-H column [eluent: hex/IPA¼99:1; flow rate: 0.5 mL/min;
detection: 254 nm; tR: 53.0 min (major), 56.4 min (minor)]. The
absolute configuration was determined to be 1S,2S after the con-
reaction was quenched with satd NaHCO3 (3 mL), and 10% Na2S2O3
(1 mL), and then the slurry was stirred for 0.5 h. The two-layer
mixture was filtered through a cotton pad and the aqueous layer
was extracted with EtOAc (3ꢂ10 mL). The combined organic layers
were washed with 10% HCl (10 mL), satd NaHCO3 (10 mL) and brine
(10 mL), and dried over Na2SO4. After filtration and concentration,
the obtained crude product was purified by column chromatogra-
phy (hex/EtOAc¼12:1, SiO2: 10 g) to give the product 2a (95.8 mg,
83% yield).
version to 2f by the comparison of the sign of the optical rotation
20
([
a]
þ29.9 (c 1.0, CHCl3) for 71% ee) [lit. 24; [
a
]
D
þ32.9 (c 2.18,
D
EtOH) for (1S,2S)-isomer of 79% ee].
4.3.2. 2-Chlorocyclooctyl 4-nitrobenzoate (2g-NB).25 Yellow nee-
4.5. Typical procedure for one-pot chlorohydrin synthesis
from cis-alkenes and 4-nitrobenzoylation
26
dles; mp: 86.0e87.0 ꢁC; [
a]
þ42.9 (c 1.0, CHCl3) for 50% ee; 1H
D
NMR (400 MHz, CDCl3):
d 1.45e1.63 (CH2, m, 3H), 1.77e1.80 (CH2,
m, 4H), 1.88e1.94 (CH2, m, 3H), 2.05e2.12 (CH2, m, 1H), 2.27e2.34
(CH2, m, 1H), 4.35e4.40 (OeCH, m, 1H), 5.35e5.41 (CleCH, m, 1H),
8.22 (AreH, d, J¼7.5 Hz, 2H), 8.29 (AreH, d, J¼7.5 Hz, 2H); The
enantiomeric excess was determined to be 50% ee by HPLC analysis
with Daicel Chiralcel OJ column [eluent: hex/IPA¼49:1; flow rate:
0.5 mL/min; detection: 254 nm; tR: 29.3 min (1S,2S), 37.4 min
(1R,2R)]. The absolute configuration was determined to be 1S,2S
Under an argon atmosphere, a solution of purified m-chlor-
operoxybenzoic acid(103.6 mg, 0.6 mmol,1.2 equiv)in CH2Cl2 (1 mL)
was added to a solution of cyclohexene (5f) (0.05 mL, 0.5 mmol,
1.0 equiv) and (S)-BINAPO (32.7 mg, 0.05 mmol, 10 mol %) in CH2Cl2
(1 mL) at room temperature, and the reaction mixturewas stirredfor
3 h. Diisopropylethylamine (0.14 mL, 0.8 mmol,1.6 equiv) and silicon
tetrachloride (0.086 mL, 0.75 mmol, 1.5 equiv) were added to the
mixture at ꢀ78 ꢁC successively. After being stirred for 1 h, the re-
action was quenched with satd NaHCO3 (3 mL) and 10% Na2S2O3
(1 mL), and then the slurry was stirred for 0.5 h. The two-layers
mixture was filtered through a cotton pad and the aqueous layer
was extracted with EtOAc (3ꢂ10 mL). The combined organic layers
were washed with 10% HCl (10 mL), satd NaHCO3 (10 mL), and brine
(10 mL), and dried over Na2SO4. After filtration and concentration,
the crude product was dissolved in CH2Cl2 (5 mL) and then
p-nitrobenzoyl chloride (188.0 mg, 1.0 mmol, 2.0 equiv), triethyl-
amine (0.21 mL, 1.5 mmol, 3.0 equiv), and DMAP (2 mol %) were
added to the solution at room temperature. After being stirred for
16 h, the reaction was quenched with H2O (5 mL). The two-layers
mixture was separated and the aqueous layer was extracted with
EtOAc (3ꢂ10 mL). The combined organic layers were washed with
10% HCl (10 mL), satd NaHCO3 (10 mL), and brine (10 mL), and dried
over Na2SO4. After filtration and concentration, the obtained crude
product was purified by column chromatography (hex/EtOAc¼12:1,
SiO2. 10 g) to give the product 2f-NB (123.8 mg, 88% yield).
after the conversion to 2g by the comparison of the sign of the
20
optical rotation ([
a
]
þ18.6 (c 1.15, CHCl3) for 50% ee) [lit. 16; [
a]
D
D
ꢀ26.4 (c 1.0, CHCl3) for (1R,2R)-isomer of 90% ee].
4.3.3. 3-Chloro-2-tetrahydrofuranyl 4-nitrobenzoate (2i-NB). A col-
orless oil; [
CDCl3):
a
]
28 þ43.3 (c 1.34, CHCl3) for 39% ee; 1H NMR (400 MHz,
D
d
4.03e4.08 (CH2, m, 2H), 4.33e4.41 (CH2, m, 2H), 4.47e4.47
(OeCH, t, J¼2.3 Hz, 1H), 5.55 (CleCH, d, J¼4.1 Hz, 1H), 8.21 (AreH, d,
J¼9.2 Hz, 2H), 8.31 (AreH, d, J¼9.2 Hz, 2H); 13C NMR (400 MHz,
CDCl3):
d 58.9, 71.3, 74.4, 81.5, 123.6, 130.9, 134.4, 150.9, 163.6; IR
(neat): 1268,1527,1727 cm-1; LR-FABMS: m/z 271 [M]þ; HR-FABMS;
Calcd for C11H10ClNO5 271.0248, found 271.0274; The enantiomeric
excess was determined to be 39% ee by HPLC analysis with
Daicel Chiralpak AD-H column [eluent hex/IPA¼19:1; flow rate:
0.5 mL/min; detection: 254 nm; tR: 49.2 min (major), 55.1 min
(minor)].
4.3.4. 1-Chlorobicyclo[2.2.1]heptyl 7-(4-nitrobenzoate) (4j-NB). Yel-
low needles; mp: 94.5e95.5 ꢁC; [ 29 e12.1 (c 1.06, CHCl3) for 67%
a]
D
ee; 1H NMR (400 MHz, CDCl3):
d 1.24e1.36 (CH2, m, 2H), 1.73e1.78
(CH2, m, 1H), 1.82e1.86 (CH2, m, 1H), 2.28 (CH2, dd, J¼7.8, 14.2 Hz,
1H), 2.36 (CH2, dd, J¼4.1, 14.2 Hz, 1H), 2.52 (CH2, d, J¼4.1 Hz, 1H),
2.70 (CH2, d, J¼4.1 Hz, 1H), 4.07 (CleCH, dd, J¼4.1 Hz, 7.8 Hz, 1H),
5.07 (OeCH, s, 1H), 8.27-8.31 (AreH, m, 4H); 13C NMR (400 MHz,
4.6. Procedure for one-pot chlorohydrin synthesis from
2,5-dihydrofuran (5i) and 4-nitrobenzoylation
Under an argon atmosphere, a solution of purified m-chlor-
operoxybenzoic acid (103.6 mg, 0.6 mmol, 1.2 equiv) in CH2Cl2
(1 mL) was added to a solution of 2,5-dihydrofuran (5i) (0.038 mL,
0.5 mmol,1.0 equiv) and (S)-BINAPO (32.7 mg, 0.05 mmol,10 mol %)
in CH2Cl2 (1 mL) at room temperature, and the reaction mixture
was stirred for 12 h. Diisopropylethylamine (0.14 mL, 0.8 mmol,
1.6 equiv) and silicon tetrachloride (0.286 mL, 2.5 mmol, 5.0 equiv)
were added to the mixture at ꢀ78 ꢁC successively. After being
stirred for 6 h, the reaction was quenched with KF/KH2PO4 (5 mL),
and then the slurry was stirred for 0.5 h. The two-layers mixture
was filtered through a cotton pad and the aqueous layer was
extracted with CH2Cl2 (3ꢂ5 mL). The combined organic layers were
washed with brine (10 mL) and dried over MgSO4. After filtration
and concentration, the crude product was dissolved in CH2Cl2
(5 mL) and then p-nitrobenzoyl chloride (188.0 mg, 1.0 mmol,
2.0 equiv), triethylamine (0.21 mL, 1.5 mmol, 3.0 equiv), and DMAP
(2 mol %) were added to the obtained crude product at room
temperature. After being stirred for 16 h, the reaction was
quenched with H2O (5 mL). The two-layers mixture was separated
and the aqueous layer was extracted with EtOAc (3ꢂ10 mL). The
combined organic layers were washed with 10% HCl (10 mL), satd
NaHCO3 (10 mL), and brine (10 mL), and dried over Na2SO4. After
filtration and concentration, the obtained crude product was
CDCl3) :
d 24.2, 24.8, 39.5, 41.7, 46.9, 59.6, 81.5, 123.5, 131.0, 135.6,
150.5, 164.6; IR (KBr): 1278, 1525, 1720 cm-1; LR-FABMS: m/z
295 [M]þ; HR-FABMS: Calcd for C14H14ClNO4 295.0611, found
295.0639; The enantiomeric excess was determined to be 67% ee by
HPLC analysis with Daicel Chiralpak AS-H column [eluent: hex/
IPA¼99:1; flow rate: 1.0 mL/min; detection: 254 nm; tR: 19.4 min
(minor), 24.4 min (major)]. Crystallographic data (excluding
structure factors) for this structure have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publi-
cation numbers CCDC 915590.
4.4. Typical procedure for one-pot chlorohydrin synthesis
from cis-alkenes
Under an argon atmosphere, a solution of purified m-chlor-
operoxybenzoic acid (103.6 mg, 0.6 mmol, 1.2 equiv) in CH2Cl2
(1 mL) was added to a solution of a cis-stilbene (98.0 mg, 0.5 mmol,
1.0 equiv) and (S)-BINAPO (32.7 mg, 0.05 mmol, 10 mol %) in CH2Cl2
(1 mL) at room temperature, and the reaction mixture was stirred
for 6 h. Diisopropylethylamine (0.14 mL, 0.8 mmol, 1.6 equiv) and
silicon tetrachloride (0.086 mL, 0.75 mmol,1.5 equiv) were added to
the mixture at ꢀ78 ꢁC successively. After being stirred for 2 h, the

S. Kotani et al. / Tetrahedron 69 (2013) 3075e3081
3081
7. For reviews of Lewis base catalysis reactions, see: (a) Orito, Y.; Nakajima, M.
purified by column chromatography (hex/EtOAc¼12:1, SiO2: 10 g)
to give the product 2i-NB (82.5 mg, 61% yield).
ꢁ
ꢂ
Synthesis 2006, 1391; (b) Malkov, A. V.; Kocovsky, P. Eur. J. Org. Chem. 2007,
29; (c) Denmark, S. E.; Beutner, G. L. Angew. Chem. 2008, 120, 1584 Angew.
Chem., Int. Ed. 2008, 47, 1560; (d) Benaglia, M.; Guizzetti, S.; Pignataro, L.
Coord. Chem. Rev. 2008, 252, 492; (e) Benaglia, M.; Rossi, S. Org. Biomol.
Chem. 2010, 8, 3824.
Acknowledgements
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11. For the preliminary communication, see: Tokuoka, E.; Kotani, S.; Matsunaga,
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This work was partially supported by JSPS KAKENHI Grant
Number 22790014 and by a Grant-in-Aid for Scientific Research on
Innovative Areas ‘Advanced Molecular Transformations by Orga-
nocatalysts’ from The Ministry of Education, Culture, Sports, Sci-
ence and Technology, Japan.
12. Simonini, V.; Benaglia, M.; Benincori, T. Adv. Synth. Catal. 2008, 350, 561.
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17. SiCl4 promoted ring-opening under the reaction condition even in the absence
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22. mCPBA was purified by washing with satd NaHCO3 and brine, follows by drying
with MgSO4 prior to use.
23. Chlorohydrin 2i was decomposed by quenching with 10% aq Na2S2O3 leading to
a decrease in the yield. The procedure is described in detail in Experimental
Section 4.6.
24. Fukuzawa, T.; Shimoji, Y.; Hashimoto, T. Tetrahedron: Asymmetry 1996, 7, 1649.
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