Highly regio- and diastereoselective halohydroxylation of olefins: A facile synthesis of vicinal halohydrins

Article abstract of DOI:10.1016/j.tet.2011.06.077

An efficient method for the synthesis of vicinal chlorohydrin or bromohydrin derivatives has been developed on the basis of direct halohydroxylation of various olefins with electrondonating or withdrawing substituent. The reactions were carried out under mild conditions in the presence of N-tosyl-l-threonine (NTsLT) as an acidic additive using chloramine T trihydrate, 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) or N-bromoacetamide (AcNHBr) as the halogen source, respectively, affording the corresponding vicinal halohydrins in good to high yields with excellent regio- and stereoselectivities.

Full text of DOI:10.1016/j.tet.2011.06.077

Tetrahedron 67 (2011) 6859e6867
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Highly regio- and diastereoselective halohydroxylation of olefins: a facile
synthesis of vicinal halohydrins
,
a,b,
*
Jinglei Zhang a, Jie Wang a, Zhuibai Qiu a , Yang Wang
*
a Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China
b State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 April 2011
Received in revised form 17 June 2011
Accepted 24 June 2011
Available online 30 June 2011
An efficient method for the synthesis of vicinal chlorohydrin or bromohydrin derivatives has been de-
veloped on the basis of direct halohydroxylation of various olefins with electrondonating or withdrawing
substituent. The reactions were carried out under mild conditions in the presence of N-tosyl-
L-threonine
(NTsLT) as an acidic additive using chloramine trihydrate, 1,3-dichloro-5,5-dimethylhydantoin
T
(DCDMH) or N-bromoacetamide (AcNHBr) as the halogen source, respectively, affording the corre-
sponding vicinal halohydrins in good to high yields with excellent regio- and stereoselectivities.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Chlorohydroxylation
Chlorohydrin
Bromohydroxylation
Bromohydrin
Olefin
1. Introduction
and low yields caused by formation of regio-isomers or byproducts.
In view of high importance of vic-halohydrins and shortcomings of
Vicinal halohydrins are extremely versatile building blocks in
organic, medicinal, and industrial chemistry and widely used for
transformation into epoxides,1 ketones,2 halogenated marine nat-
ural products,3 unnatural aminoacids or various chiral auxiliaries.4
They have been also utilized as the key intermediates for the
the methodologies mentioned above, the development of new
protocol for the practical synthesis of vic-halohydrins is highly
desirable.
In the course of our recent study on the synthesis of novel cou-
marin derivatives with anti-HIV activities,12 we disclosed an efficient
method for halohydroxylation of olefin derivatives using chloramine
preparation of homochiral b
-adrenergic blockers.5 The most com-
mon method for the preparation of halohydrins involves ring
opening of epoxides by hydrogen halides or metal halides.6 These
procedures are generally associated with the formation of
byproducts, such as vicinal dihalides and diols6c,d and required
prior synthesis of epoxides from olefins. Halohydrins can also be
directly synthesized by functionalization of alkenes to vic-halohy-
drins with a variety of reagents, such as molecular halogen in
combination with water,7 hypoiodous acid generated in situ from
H5IO6 in the presence of NaHSO3,8 N-halosuccinimide with water in
T trihydrate, 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) or
N-bromoacetamide (AcNHBr) as the halogen source under mild
conditions. The remarkable features of the present protocol include
high yields, excellent regio- and stereoselectivities, as well as high
adaptability of the reaction substrates including the olefins with
electrondonating or electron-withdrawing substituent. In the pres-
ent paper, we would like to report the discovery of this new reaction
system and the results on this synthetically and practically useful
transformation.
the presence of b
-cyclodextrin, ionic liquid, NH4OAc or thiourea,9
metal halide along with an oxidizing agent10 or N,N-dibromo-p-
toluenesulfonamide.11 However, the existing methodologies usu-
ally have the disadvantages of danger of manipulation and toxicity,
limited applicability to olefinic substrates, longer reaction time,
2. Results and discussion
2.1. Chlorohydroxylation of olefins
using expensive reagents including b-cyclodextrin or ionic liquid,
As part of program aimed toward the development of novel
anti-HIV agents, Sharpless aminohydroxylation of 4-methyl-9,10-
dihydrobenzo[h]coumarin (1) was carried out by using chlora-
mine T trihydrate (2) as the oxidant (1 equiv) according to the
literature procedure (Scheme 1).13 As expected, the normal
* Corresponding authors. Fax: þ86 21 5198 0115; e-mail addresses: zbqiu@
shmu.edu.cn, ywang.spfdu@gmail.com, wangyang@shmu.edu.cn.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.077

6860
J. Zhang et al. / Tetrahedron 67 (2011) 6859e6867
HO
COOH
NHTs
(NTsLT, 6)
(0.05 eq.)
O
+
S N Cl
O
Na 3H2O
O
O
K2OsO2(OH)4 (0.01 eq.)
Na2CO3 (0.1 eq.)
t-BuOH / H2O (1:1)
1
2
+
+
HO
TsHN
HO
HO
O
O
O
O
O
O
TsHN
Cl
3
4
5a
Scheme 1. The aminohydroxylation of 4-methyl-9,10-dihydrobenzo[h]coumarin (1).
aminohydroxylation products 3 and 4 were obtained in 55% total
yield after stirring for 2 days at room temperature. It is interesting
to note that a chlorohydroxylation product 8-chloro-7-hydroxy-4-
methyl-7,8,9,10-tetrahydrobenzo[h]coumarin (5a) was simulta-
neously isolated in 6% yield, which implied that chloramine T must
be involved in the course of reaction as the Clþ source. A substantial
improvement resulted in selectivity inversion was realized when
acetyl chloride, the chlorohydroxylated product 7a was isolated
in only 49% yield (entry 10). L-Threonine, which is the NH2-
deprotected NTsLT and mildly alkaline, was also tried as the ad-
ditive, but no reaction occur at all (entry 11). These results showed
that eCOOH site of NTsLT and its acidity is crucial to promoting the
chlorohydroxylation. The reaction did not occur without any
acidic additives, which further confirmed the importance of NTsLT
(entry 12). After extensive additive and solvent examination, the
reaction carried out in t-BuOH/H2O (v/v 1:1) mixed solvent and in
the presence of NTsLT additive turned out to be optimal, affording
product 7a in 92% yield (entry 6).
Under the optimized reaction conditions, a panel of olefins was
then subjected to chlorohydroxylation. As shown in Table 3, all
cyclic olefins examined resulted in the formation of corresponding
chlorohydroxylation products in >78% isolated yields with exclu-
the reaction was performed by increasing the amount of N-tosyl-L-
threonine (NTsLT, 6) employed. It was found that the yield of
chlorohydroxylation product (5a) was dramatically enhanced to
81% and no products 3/4 were isolated when the amount of NTsLT
was raised to 2 equiv (Table 1, entry 4). These results clearly
demonstrated that NTsLT no longer served as a chiral ligand in the
present chlorohydroxylation reaction system and might play the
role of an acidic additive. Moreover, when the reaction was carried
out in the absence of K2OsO2(OH)4 and alkaline Na2CO3, chlor-
ohydroxylation product (5a) was isolated in 83% yield (entry 5),
indicating the dispensability of catalytic amount of K2OsO2(OH)4
(0.01 equiv) and alkaline Na2CO3 (0.1 equiv) for the efficient
chlorohydroxylation.
sive a-hydroxy-b-chloro regioselectivity. It is worth noting that the
Table 2
Chlorohydroxylation of styrene under various conditionsa
On the basis of the finding for the chlorohydroxylation of 4-
methyl-9,10-dihydrobenzo[h]coumarin (1) mentioned above, we
subsequently take styrene as the standard substrate to investigate
the impacts of acidic additive and solvent on the chlorohydrox-
ylation. As shown in Table 2 (entries 1e6), the reaction of styrene
occurred to afford 2-chloro-1-phenylethanol (7) exclusively in
only moderate yields when NTsLT was replaced by other acidic
additives. It was found that solvent employed in the process also
had significant influence on the yields of chlorohydroxylation
products (entries 6e8). The role of the functional groups
(eCOOH, eOH and eNHTs) of NTsLT were also investigated. If the
COOH group of NTsLT was blocked by esterification with CH3OH,
the chlorohydroxylation reaction did not take place at all with this
additive (entry 9). If the OH group of NTsLT was esterified with
OH
O
S
O
Cl+ source (1 eq.)
3H2O
Cl CH3
N
Cl
Na
Acidic additive (2 eq.)
Cl+ source
Solvent, 48 h
7a
Chloramine T trihydrate (2)
Entry
Acidic additive
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9% HCl
HOAc
PTS
dl-Malic acid
H3PO4
NTsLT
NTsLT
NTsLT
t-BuOH/H2O (1:1)
t-BuOH/H2O (1:1)
t-BuOH/H2O (1:1)
t-BuOH/H2O (1:1)
t-BuOH/H2O (1:1)
t-BuOH/H2O (1:1)
CH3CN/H2O (1:1)
i-PrOH/H2O (1:1)
55
40
37
29
35
92
11
19
HO
AcO
HO
d
COOMe
NHTs
COOH
NHTs
COOH
NH2
9
t-BuOH/H2O (1:1)
d
Table 1
Product distribution of 3/4 and 5a in the reaction of 1 with 2 in the presence of
different amount of NTsLT (6) employeda
10
11
t-BuOH/H2O (1:1)
49c
Entry
Amount of 6 (equiv)
Yield of 5ab (%)
Total yield of 3þ4b (%)
1
2
3
0.05
0.5
1
2
2
6
60
66
81
83
55
23
7
t-BuOH/H2O (1:1)
t-BuOH/H2O (1:1)
d
d
4
d
5c
d
12
a
a
The reaction was carried out under the conditions shown in entry 5 of Table 1 in
the presence of various additives and solvents.
All reactions were carried out under the conditions shown in Scheme 1 with
various amount of 6 in 48 h.
b
b
The yield determined by HPLC analysis.
Yield of isolated product.
c
c
The yield of isolated product.
The reaction was carried out in the absence of K2OsO2(OH)4 and Na2CO3.

J. Zhang et al. / Tetrahedron 67 (2011) 6859e6867
6861
Table 3
occurred at all under the same conditions when the substrates have
electron-withdrawing group situated at either double-bond or
phenyl ring (entries 7 and 8).
Chlorohydroxylation of various olefins with chloramine T trihydrate as the Clþ
source
OH
A probable mechanistic pathway to explain chemo-, regio-, and
stereoselectivity for the reaction of substituted styrenes is
depicted in Scheme 2. A three-membered cyclic chloronium ion
intermediate is expected to be involved in the reaction on the
basis of exclusive trans stereoselectivity in the products of cyclic
styrene derivatives (entries 1e3, vide infra Fig. 1). In the case of
para-alkyl substituted styrene, cyclic chloronium ion intermediate
can be formed at the initial stage of the reaction due to electro-
philic addition of the Clþ ion onto the olefin and will be stabilized
by the presence of electrondonating para-alkyl substituents. The
intermediate undergoes ring opening regioselectively by the nu-
cleophiles, including HOꢀ or TsNHꢀ, via two competitive SN2
pathways, affording chlorohydrin and chloroamine, respectively.
The chloroamination mechanism proposed here is consistent with
that reported by Feng.14 The formation of (2-chlorovinyl)benzene
products were obviously caused by the elimination of Hþ from the
chloronium ion intermediate.
Chloramine T trihydrate (1 eq.)
Ar
Ar
NTsLT (2 eq.), r. t., 48 h
t-BuOH / H2O (1:1)
Cl
Entry
Substrate
Product
Yielda
R
R
80
81
79
1
O
O
O
O
R = R' = Me, 8a
R = Me, R' = H, 8b
R = R' = H, 8c
R'
R'
OH
R'
R'
Cl
R
R
O
83
84
2
HO
Cl
O
O
O
R = Me, 5a
R = H, 5b
OH
OH
Cl
p-RC6H4
3
4
78
90
Cl
Cl
NHTs
Cl
TsNCl Na
TsNH
- H
9a
OH
OH
p-RC6H4
p-RC6H4
R
R
R = Me, t-Bu
Cl
Ph
Cl
7a
Ph
Scheme 2. Probable mechanism of the reaction of para-alkyl substituted styrenes with
chloramine T trihydrate.
OH
36
20
40
In order to elucidate the stereochemistry of two newly-formed
chiral centers in the product, the chlorohydrin 5a was selected to
grow a single crystal and its structure was determined by X-ray
single crystal analysis. As shown in Fig. 1, OH and Cl obviously take
an anti-configuration. We deduce that anti-addition has occurred in
all the rest of the internal olefinic substrates because the reactions
Cl
p-MeC6H4
10a
NHTs
5
p-MeC6H4
Cl
p-MeC6H4
p-MeC6H4
10b
10c
Cl
proceed via the same mechanistic pathway. Chiral HPLC and [a]
D
measurement of product 5a disclosed that no asymmetric in-
duction was attained in reaction.
OH
36 (33)
16 (25)
Cl
t
p-Bu C6H4
11a
11b
11c
NHTs
Cl
t
t
6
7
p-Bu C6H4
p-Bu C6H4
Cl
t
12 (18)
p-Bu C6H4
COOMe
d
d
d
d
Ph
8
m-O2NC6H4
a
The yield of isolated product after chromatographic purification. The yield
shown in parenthesis is obtained by using 2 equiv of chloramine T trihydrate.
reaction of para-alkyl substituted styrenes attained
a-tosylamino-
b
-chloro products (10b, 11b) and (2-chlorovinyl)benzene de-
rivatives (10c, 11c) besides the desired chlorohydrins (10a, 11a) in
a declined yield of 36% (entries 5 and 6). When chloramine T tri-
hydrate employed was further increased to 2 equiv, the yields of
11b and 11c were enhanced to 25% and 18%, respectively, while the
yield of chlorohydrins 11a dropped a little bit (33%). No reaction
Fig. 1. The X-ray single crystal analysis of 8-chloro-7-hydroxy-4-methyl-7,8,9,
10-tetrahydrobenzo[h]coumarin (5a).

6862
J. Zhang et al. / Tetrahedron 67 (2011) 6859e6867
Table 5
A continuous endeavor was made to overcome the shortcom-
Chlorohydroxylation of various olefins using DCDMH (12) as the Clþ source
ings of long reaction time and relatively low yields in some cases as
shown in Table 3. A more reactive Clþ source 1,3-dichloro-5,
5-dimethylhydantoin (12, DCDMH), which has been used for
chlorolactonization reaction,15 was employed and afforded a faster
reaction of about 1 h (Table 4). The chlorohydroxylation of chal-
lenging substrate p-tert-butylstyrene revealed that both the acidic
additive and solvent again affected the yields and distributions of
products greatly. Employing 1 equiv of benzoic acid as the additive
and t-BuOH/H2O (1:1) as the solvent, 1,2-dichloro product (11d)
was afforded in 51% yield as the major and the chlorohydrin (11a) in
18% yield as the minor (Table 4, entries 2). When NTsLTadditive was
OH
DCDMH (1 eq.)
NTsLT (0.5 eq.), r.t.
Acetone / H2O (1:2)
Cl
Entry
1
Substrate
Time (h)
Product
Yielda (%)
93
OH
Cl
1
Ph
7a
Ph
OH
used, a-hydroxy-b-chloro product (11a) was attained as the main
2
3
1
85
79
p-MeC6H4
p-ClC6H4
Cl
p-MeC6H4
p-ClC6H4
10a
product. After an exhaustive screening of the amount of acidic
additive, mixed solvent and its volume ratio, the best result was
obtained in acetone/H2O (1:2) by employing 1 equiv of DCDMH in
the presence of 0.5 equiv of NTsLT additive (Table 4, entry 10),
affording chlorohydrin (11a) in 65% yield and dichlorinated
byproduct (11d) in 13% yield. When the volume ratio of acetone/
H2O was changed to 2:1, the yield of chlorohydrin (11a) was de-
creased to 54% yield (entry 11). The reaction did not occur at all in
the absence of NTsLT (entry 12), which implies that acidic additive
is critically important for the generation of Clþ species.
OH
1
Cl
13a
OH
62
23
Cl
p-MeOC6H4
14a
Cl
4
1
p-MeOC6H4
N
With this new and more efficient chlorohydroxylation system
in hand, the scope of the olefin substrates was then examined
under the optimized reaction conditions. As shown in Table 5,
O
O
N
Cl
p-MeOC6H4
14b
15a
excellent a-hydroxy-b-chloro regioselectivity and exclusive anti-
stereoselectivity were observed regardless of cyclic/acyclic olefins
and the nature of substituents at the phenyl ring. For the reaction
of styrene derivative having electrondonating substituent at
phenyl ring, the chloroamination product (14b) was also attained
besides the normal chlorohydroxylation product (14a) (entry 4),
probably due to the stabilization of the chloronium ion in-
termediate by electrondonating MeO group. Compared with
chloramine T trihydrate as the Clþ source, the more reactive 1,3-
dichloro-5,5-dimethylhydantoin (DCDMH, 12) afforded a faster
and more efficient chlorohydroxylation reaction. In particular, the
yields and selectivity in the chlorohydroxylation of styrene de-
rivatives were enhanced to a significant extent and less byproduct
was detected (Table 5, entries 1e4). The substrates having
electron-withdrawing group situated at either double-bond or
OH
5
6
7
1
2
84
80
96
m-O2NC6H4
Cl
m-O2NC6H4
OH
Ph
Ph
Ph
16a
Ph
Cl
OH
COOMe
COOMe
36
Ph
Ph
17a
Cl
8
1
3
79
99
Cl
9a
OH
Table 4
Chlorohydroxylation of p-tert-butylstyrene using DCDMH (12) as the Clþ source
9b
O
O
O
O
OH
8b
Cl
OH
Entry Additive (equiv) DCDMH (equiv) Solvent
Yielda (%)
10
0.5
68
18a
Cl
11a
11d
1
2
3
4
5
6
7
8
BA (1)b
0.8
1
1
1.1
1
1
1
1
1
1
t-BuOH/H2O (1:1)
t-BuOH/H2O (1:1)
t-BuOH/H2O (5:1)
t-BuOH/H2O (1:1)
t-BuOH/H2O (1:5)
t-BuOH/H2O (1:1)
t-BuOH/H2O (1:2)
t-BuOH/H2O (1:2)
Acetone/H2O (1:2) 56
Acetone/H2O (1:2) 65
Acetone/H2O (2:1) 54
Acetone/H2O (1:2)
36
18
18
50
d
21
51
48
23
d
a
The yield of isolated product after chromatographic purification.
Acetone/H2O (2:1) mixed solvent was employed for the reaction due to the poor
BA (1)b
b
BA (1)b
solubility of the substrate.
NTsLT (2)
NTsLT (2)
NTsLT (1)
NTsLT (1)
NTsLT (0.5)
NTsLT (1)
NTsLT (0.5)
NTsLT (0.5)
d
51
55
50
24
21
14
12
13
15
d
phenyl ring could also be converted to the corresponding chlo-
rohydrin product in good yields (entries 5 and 7 in Table 5), in-
dicating the superior performance of DCDMH (12) as the Clþ
source to chloramine T (entries 7 and 8 in Table 3). In the reaction
of benzo[h]chromen-2-one derivative, up to 99% yield of
chlorohydroxylation 8b was obtained in a shorter reaction time
9
10
11
12
1
1
d
a
The yield of isolated product.
BA: benzoic acid.
b

J. Zhang et al. / Tetrahedron 67 (2011) 6859e6867
6863
Table 7
(Table 5, entry 9). Therefore, DCDMH is obviously a more efficient
Synthesis of bromohydrins from various olefins
chlorohydroxylating reagent than chloramine T trihydrate. The
olefins with two aromatic or saturated substituents, such as 1,2-
diphenylethene and cyclohexene, could also be converted to the
corresponding chlorohydrins in 80% and 68%, respectively (entries
6 and 10).
OH
AcNHBr (1.2 eq.)
NTsLT (1 eq.), r.t.
t-BuOH / H2O (1:1)
Br
Entry
1
Substrate
Time (h)
0.5
Product
Yielda (%)
2.2. Bromohydroxylation of olefins
OH
OH
OH
OH
OH
77
84
77
87
75
p-MeC6H4
Encouraged by the discovery that this new protocol of chlor-
Br
Br
p-MeC6H4
p-ClC6H4
10d
ohydroxylation using DCDMH as Clþ source provided high efficacy
for a wide range of olefin substrates with excellent a-hydroxy-b-
chloro regioselectivity and exclusive anti-stereoselectivity, we
subsequently study bromohydroxylation reactions of olefins, an
analogous transformation to the chlorohydroxylation. As shown in
Table 6, the model bromohydroxylation of styrene proceeded
smoothly by using readily available N-bromoacetamide (AcNHBr,
19) as the Brþ source under various conditions, affording 2-bromo-
1-phenylethanol (7b) in good to high yields. The bromohydrox-
ylation of styrene using 1.2 equiv of AcNHBr in the presence of
1 equiv of NTsLT as additive turned out to optimal, accomplishing
the conversion of substrate in 10 min and affording 7b in 87% iso-
lated yield (entry 4), which is somewhat superior to that of reaction
performed by using NBS as the Brþ source in 30 min (81%, entry 5).
It is obvious that the use of excessive amount of AcNHBr (such as 1.5
or 2 equiv) could result in the formation of byproducts including
(1,2-dibromoethyl)benzene (20), 2-bromo-1-phenylethanone (21)
or both, and the formation of bromohydrin (7b) was generally
quelled (entries 1e3).
2
3
4
5
0.5
0.3
0.3
1
p-ClC6H4
13b
p-MeOC6H4
Br
p-MeOC6H4
14c
t
p-Bu C6H4
Br
t
p-Bu C6H4
11e
m-O2NC6H4
Br
m-O2NC6H4
15b
OH
6
7
1
1
88
70
Br
22
Ph
Ph
Ph
OH
Ph
Ph
Ph
16b
Br
Table 6
OH
Bromohydroxylation of styrene with N-bromoacetamide (AcNHBr, 19) as the Brþ
COOMe
COOMe
8
6
48
0.4
86
81
78
source
Ph
Ph
Ph
17b
Br
OH
COOCH2Ph
COOCH2Ph
9
Ph
23
Br
Entry
NTsLT (equiv)
Brþ source (equiv)
Time (h)
Yielda (%)
7b
20
21
10
Br
1
2
3
4
5
2
2
2
1
1
AcNHBr (2)
AcNHBr (2)
AcNHBr (1.5)
AcNHBr (1.2)
NBS (1.2)
42
1
0.5
0.2
0.5
64
73
80
87
81
9
8
4
d
24
d
d
d
d
9b
OH
11b
0.5
0.2
94
62
d
O
O
a
O
O
The yield of isolated product after chromatographic purification.
OH
OH
8d
Br
12
Under the optimized conditions mentioned above, the bromo-
hydroxylation of a variety of substrates were then examined. As
shown in Table 7, the reaction of all substrates afforded bromohy-
18b
Br
a
The yield of isolated product after chromatographic purification.
Acetone/H2O (2:1) mixed solvent was employed for the reaction due to the poor
b
droxylation products in good yields with excellent a-hydroxy-b-
solubility of the substrate.
bromo regioselectivity and exclusive anti-selectivity (Table 7). Most
of the substituted styrene showed high reactivity to afford bro-
mohydrins with good to excellent yields within 0.5e1 h (entries
1e7). In particular, the reaction of olefins having electron-
withdrawing substituents provided the corresponding bromohy-
drins in good yields (entries 8 and 9) simply by prolonging the
reaction time. The cyclic olefins could also be converted to the
corresponding bromohydrins in good yields within 30 min (entries
10e12). The anti-configuration was determined by analysis of the
coupling constant data of protons attached to the carbons bearing
eOH and eBr groups of the bromohydrins11 and further confirmed
by structural analysis of X-ray crystallography data of compound
24, which was esterified from bromohydrin 8d (Fig. 2).
3. Conclusion
In summary, an efficient method for chlorohydroxylation and
bromohydroxylation of olefins has been established by using
chloramine T trihydrate, DCDMH, or AcNHBr as the halogen source
in combination with NTsLT as the acidic additive. The significant
advantages offered by this method include simple manipulation,
fast reaction, and mild conditions, as well as wide adaptability of
substrates with high yield and excellent regio- and stereoselectivity
(anti) of product, and thus providing a better and practical

6864
J. Zhang et al. / Tetrahedron 67 (2011) 6859e6867
Fig. 2. The structure and X-ray single crystal analysis of (9R,10R)-9-bromo-10-hydroxy-10-O-(ꢀ)-camphanoyl-4-methyl-7,8,9,10-tetrahydrobenzo[h]chromen-2-one (24).
alternative to the existing procedures for the synthesis of vicinal
halohydrins.
selected and mounted on a Bruker Smart CCD diffractometer with
graphite monochromatized Mo K radiation (
¼0.071073 nm).
Diffraction data were collected using scans at room temper-
ꢀ2
a
l
u
q
ature (293 K). A perspective view of the structure is depicted in
Fig. 1. Empirical formula: C14H13ClO3. Formula weight: 264.69.
Crystal system: orthorhombic. Space group: P212121. Unit cell di-
4. Experimental section
4.1. General procedure for the synthesis of chlorohydrins
with chloramine T trihydrate
ꢀ
ꢀ
ꢀ
mensions: a¼5.1157 (10) A, b¼8.0771 (15) A, c¼29.431 (6) A.
3
ꢀ
V¼1216.1 (4) A . Theta range for data collection is from 1.38 to
26.49ꢂ. Z¼4. Dc¼1.446 g/cm3. F (000)¼552. Refinement method:
full-matrix least-squares on F2. Goodness-of-fit on F2: 1.040. Final R
N-Tosyl-
prepared from
L
-threonine (NTsLT, 6) (546 mg, 2 mmol), which was
L
-threonine by following literature procedure,16 was
indices [I>2s(I)]: 0.0626, 0.1493. R indices (all data): 0.0662, 0.1523.
dissolved in t-BuOH/H2O (1:1 volume ratio, 4 mL), then chloramine
T trihydrate (2) (282 mg, 1 mmol) and olefin (1 mmol) were added
to the solution. The mixture was stirred at room temperature until
the reaction was complete (as monitored by TLC). The mixture was
extracted with ethyl acetate (3ꢁ10 mL) and the combined organic
phases were washed with brine (10 mL) and dried over Na2SO4. The
solvent was removed under reduced pressure and the crude resi-
due was further purified by column chromatography to obtain the
corresponding chlorohydrin products.
3
ꢀ
Largest diff. peak and hole: 0.562 and ꢀ0.316 e/A .
4.2.3. 2-Chloro-1-phenylethanol (7a). Colorless oil, 1H NMR
(300 MHz, CDCl3)
d 3.04 (br, 1H, eOH), 3.54e3.68 (m, 2H, 2-H),
4.78e4.82 (m, 1H, 1-H), 7.28e7.33 (m, 5H, PheH).
4.2.4. 9-Chloro-10-hydroxy-4,8,8-trimethyl-7,8,9,10-tetrahydrobenzo
[h]chromen-2-one (8a). White solid, mp 178e181 ꢂC. 1H NMR
(300 MHz, CDCl3)
d 1.00 (s, 3H, 8-CH3), 1.22 (s, 3H, 8-CH3), 2.41 (s,
3H, 4-CH3), 2.82 (s, 2H, 7-H), 4.07e4.12 (m, 2H, 9-H, eOH),
5.25e5.27 (m, 1H, 10-H), 6.24 (s, 1H, 3-H), 7.03 (d, J¼8.4 Hz, 1H, 6-
4.2. General procedure for the synthesis of chlorohydrins
with DCDMH
H), 7.48 (d, J¼7.8 Hz, 1H, 5-H). 13C NMR (CDCl3, 75 MHz)
d 160.38,
153.23, 152.44, 140.25, 124.86, 124.50, 124.29, 118.46, 114.04, 72.45,
70.83, 42.96, 36.31, 21.67, 19.09. MS (EI) m/z (%): 292 (Mþ, 35.03),
239 (26.27), 202 (91.26), 174 (75.76), 171 (59.21), 155 (48.73), 146
(53.46), 91 (100.00). HRMS: calcd mass for C16H17O3Cl 292.0866,
found 292.0864.
NTsLT (6) (137 mg, 0.5 mmol) was dissolved in acetone/H2O (1:2
volume ratio, 4 mL), then DCDMH (12) (197 mg, 1 mmol) and olefin
(1 mmol) were added to the solution. The mixture was stirred at
room temperature until the reactionwas complete (as monitored by
TLC). The mixture was extracted with ethyl acetate (3ꢁ10 mL) and
the combined organic phases were washed with brine (10 mL) and
dried over Na2SO4. The solvent was removed under reduced pres-
sure and the crude residue was further purified by column chro-
matography to obtain the corresponding chlorohydrin products.
4.2.5. 9-Chloro-10-hydroxy-4-methyl-7,8,9,10-tetrahydrobenzo[h]
chromen-2-one (8b). White solid, mp 187 ꢂC (decomposed). 1H
NMR (400 MHz, CDCl3) d 2.12e2.17 (m, 1H, 8-H), 2.43 (s, 3H, 4-CH3),
2.45e2.52 (m, 1H, 8-H), 2.81e2.91 (m, 1H, 7-H), 3.14e3.19 (m, 1H,
7-H), 3.71 (br, 1H, eOH), 4.51e4.53 (m, 1H, 9-H), 5.35 (d, J¼2.4 Hz,
1H, 10-H), 6.26 (s, 1H, 3-H), 7.12 (d, J¼8.0 Hz, 1H, 6-H), 7.50 (d,
4.2.1. 8-Chloro-7-hydroxy-4-methyl-7,8,9,10-tetrahydrobenzo[h]
chromen-2-one (5a). Colorless needle crystal, mp 160e162 ꢂC. 1H
J¼8.4 Hz, 1H, 5-H). 13C NMR (CDCl3, 75 MHz)
d 160.97, 153.37,
NMR (400 MHz, CDCl3) d 2.16e2.25 (m,1H, 9-H), 2.42 (s, 3H, 4-CH3),
152.89, 141.01, 125.06, 123.99, 123.49, 118.18, 114.01, 65.90, 58.57,
29.88, 24.75, 19.01. MS (EI) m/z (%): 264 (Mþ, 5.59), 171 (37.04), 155
(33.81), 108 (13.64), 107 (22.22), 91 (100.00), 89 (10.23), 65 (28.44),
63 (11.98). HRMS: calcd mass for C14H13O3Cl 264.0553, found
264.0559.
2.49e2.56 (m, 1H, 9-H), 2.88 (s, 1H, eOH), 2.96e3.04 (m, 1H, 10-H),
3.16e3.24 (m, 1H, 10-H), 4.21e4.26 (m, 1H, 8-H), 4.82e4.85 (m, 1H,
7-H), 6.27 (s, 1H, 3-H), 7.49e7.53 (m, 2H, 5-H, 6-H). 13C NMR (CDCl3,
75 MHz)
d 160.98, 152.80, 150.87, 139.86, 124.12, 123.88, 122.68,
119.01, 114.99, 73.66, 62.11, 28.25, 21.57, 18.99.
4.2.6. 9-Chloro-10-hydroxy-7,8,9,10-tetrahydrobenzo[h]chromen-2-
one (8c). White solid, mp 191e194 ꢂC. 1H NMR (300 MHz, CDCl3)
4.2.2. X-ray single crystal data of 8-chloro-7-hydroxy-4-methyl-
7,8,9,10-tetrahydrobenzo[h]chromen-2-one (5a). Crystal with di-
mensions of 0.496ꢁ0.411ꢁ0.403 mm for compound 5a was
d
2.16e2.18 (m, 1H, 8-H), 2.45e2.50 (m, 1H, 8-H), 2.86e2.92 (m,
1H, 7-H), 3.14e3.19 (m, 1H, 7-H), 3.38 (br, 1H, eOH), 4.51e4.54 (m,

J. Zhang et al. / Tetrahedron 67 (2011) 6859e6867
6865
1H, 9-H), 5.37 (d, J¼1.5 Hz, 1H, 10-H), 6.39 (d, J¼6.9 Hz, 1H, 3-H),
4.2.15. 1-tert-Butyl-4-(1,2-dichloroethyl)benzene
(11d). Colorless
7.10 (d, J¼6.0 Hz, 1H, 6-H), 7.37 (d, J¼6.0 Hz, 1H, 5-H), 7.70 (d,
oil, 1H NMR (400 MHz, CDCl3)
d 1.33 (s, 9H, eCH3), 3.91e4.02 (m,
J¼7.2 Hz, 1H, 4-H). 13C NMR (CDCl3, 75 MHz)
d
160.74, 151.29,
2H, eCH2Cl), 5.00 (t, J¼7.43, 7.04 Hz, 1H, eCHCle), 7.34 (d,
J¼8.21 Hz, 2H, AreH), 7.42 (d, J¼8.61 Hz, 2H, AreH). 13C NMR
143.50, 139.75, 125.87, 123.82, 123.79, 117.73, 116.51, 73.67, 62.12,
28.27, 21.38. MS (EI) m/z (%): 252 (17.18), 250 (Mþ, 50.50), 197
(82.44), 188 (78.24), 160 (100.00), 132 (49.02), 131 (28.89), 115
(15.07), 91 (26.32). HRMS calcd mass for C13H11ClO3 250.0397,
found 250.0395.
(CDCl3, 75 MHz) d 152.45, 135.18,127.26,125.99, 62.05, 48.64, 34.90,
31.47. MS (EI) m/z (%): 230 (Mþ, 15.70), 217 (64.37), 215 (100.00),
181 (25.10), 145 (19.52), 128 (17.81), 151 (13.98), 115 (17.41). HRMS
calcd mass for C12H16Cl2 230.0629, found 230.0625.
4.2.7. 8-Chloro-7-hydroxy-7,8,9,10-tetrahydrobenzo[h]chromen-2-
4.2.16. 2-Chloro-1-(4-chlorophenyl)ethanol (13a). Colorless oil, 1H
NMR (400 MHz, CDCl3) d 2.75 (br, 1H, eOH), 3.58e3.73 (m, 2H, 2-
one (5b). White solid, mp 169e171 ꢂC. 1H NMR (400 MHz, CDCl3)
d
2.16e2.26 (m, 1H, 9-H), 2.49e2.56 (m, 1H, 9-H), 2.96e3.04 (m, 1H,
H), 4.86e4.89 (m, 1H, 1-H), 7.31e7.36 (m, 4H, AreH).
10-H), 3.18e3.25 (m, 1H, 10-H), 4.20e4.26 (m, 1H, 8-H), 4.84 (t,
J¼7.7 Hz, 1H, 7-H), 6.42 (d, J¼9.4 Hz, 1H, 3-H), 7.40 (d, J¼8.2 Hz, 1H,
6-H), 7.51 (d, J¼7.8 Hz, 1H, 5-H), 7.70 (d, J¼9.8 Hz, 1H, 4-H). MS (EI)
m/z (%): 250 (Mþ, 34.50), 215 (17.37), 198 (14.15), 197 (42.57), 188
(100.00),187 (44.58),159 (25.73),131 (15.52). Elemental Anal. Calcd
for C13H11O3Cl: C, 62.29; H, 4.42; Cl, 14.14. Found: C, 62.29; H, 4.43;
Cl, 14.82.
4.2.17. 2-Chloro-1-(4-methoxyphenyl)ethanol (14a). Colorless oil,
1H NMR (400 MHz, CDCl3)
d 2.62 (s, 1H, eOH), 3.61e3.72 (m, 2H, 2-
H), 3.81 (s, 3H, eOCH3), 4.85 (d, J¼8.25 Hz, 1H, 1-H), 6.90 (d,
J¼8.55 Hz, 2H, AreH), 7.31 (d, J¼8.56 Hz, 2H, AreH).
4.2.18. 1-Chloro-3-(2-chloro-1-(4-methoxyphenyl)ethyl)-5,5-
dimethylimidazolidine-2,4-dione (14b). White solid, mp 76e77 C.
4.2.8. 2-Chloro-1,2,3,4-tetrahydro-1-naphthol (9a). White solid, mp
1H NMR (400 MHz, CDCl3)
d 1.46 (s, 6H, CH3), 3.79 (s, 3H, CH3O),
92e93 ꢂC (lit.17 91 ꢂC). 1H NMR (400 MHz, CDCl3)
d
2.12e2.22 (m,
3.87 (dd, J¼5.09, 11.74 Hz, 1H, CH2), 4.71 (t, J¼11.74 Hz, 1H, CH), 5.32
(dd, J¼5.09, 11.74 Hz, 1H, CH2), 6.87 (d, J¼9.00 Hz, 2H, AreH), 7.41
(d, J¼8.61 Hz, 2H, AreH). MS (EI) m/z (%): 330 (Mþ, 6.47), 281
(20.00), 260 (38. 71), 231 (100.00), 175 (28.15), 162 (62.79), 134
(12.93), 91 (11.40).
1H, 3-H), 2.39e2.46 (m, 1H, 3-H), 2.53 (d, J¼4.5 Hz, 1H, 2-H),
2.88e3.03 (m, 2H, 4-H), 4.20e4.25 (m, 1H, 1-H), 4.78e4.81 (m, 1H,
eOH), 7.10e7.12 (m, 1H, 7-H), 7.21e7.27 (m, 2H, 5-H, 8-H),
7.52e7.55 (m, 1H, 6-H).
4.2.9. 2-Chloro-1-p-tolylethanol (10a). Colorless oil, 1H NMR
4.2.19. 2-Chloro-1-(3-nitrophenyl)ethanol (15a). Colorless oil, 1H
(400 MHz, CDCl3)
d
2.36 (s, 3H, eCH3), 2.63 (s, 1H, eOH), 3.62e3.74
NMR (400 MHz, CDCl3) d 2.93 (br,1H, eOH), 3.64e3.69 (m,1H, 2-H),
(m, 2H, 2-H), 4.86e4.88 (m, 1H, 1-H), 7.19 (d, J¼7.82 Hz, 2H, AreH),
3.80 (dd, J¼11.35, 3.52 Hz, 1H, 2-H), 5.04 (dd, J¼8.22, 3.52 Hz, 1H, 1-
H), 7.57 (t, J¼7.83 Hz, 1H, 50-H), 7.75 (d, J¼7.43 Hz, 1H, 60-H),
8.18e8.21 (m, 1H, 40-H), 8.29 (s, 1H, 20-H).
7.28 (d, J¼8.21 Hz, 2H, AreH).
4.2.10. N-(2-Chloro-1-p-tolylethyl)-4-methylbenzenesulfonamide
(10b). White solid, mp 130e131 ꢂC. 1H NMR (400 MHz, CDCl3)
4.2.20. 2-Chloro-1,2-diphenylethanol (16a)9d. syn: Colorless oil,
d
2.30 (s, 3H, eCH3), 2.40 (s, 3H, eCH3), 3.67e3.76 (m, 2H, eCH2Cl),
yield 33%. 1H NMR (400 MHz, CDCl3)
d
3.05 (d, J¼2.74 Hz, 1H, eOH),
4.49e4.53 (m, 1H, AreCH), 5.04 (d, J¼6.26 Hz, 1H, eNH), 7.00 (d,
J¼8.21 Hz, 2H, AreH), 7.06 (d, J¼7.82 Hz, 2H, AreH), 7.21 (d,
J¼8.21 Hz, 2H, AreH), 7.63 (d, J¼8.22 Hz, 2H, AreH).
4.95 (dd, J¼2.35, 8.61 Hz, 1H, 1-H), 5.01 (d, J¼8.61 Hz, 1H, 2-H),
7.09e7.12 (m, 2H, AreH), 7.16e7.24 (m, 8H, AreH). anti: Colorless
oil, yield 47%. 1H NMR (400 MHz, CDCl3)
d 2.38 (br, 1H, eOH), 5.01
(d, J¼6.65 Hz, 1H, 1-H), 5.09 (d, J¼6.26 Hz, 1H, 2-H), 7.27e7.35 (m,
4.2.11. 1-(2-Chlorovinyl)-4-methylbenzene (10c). Colorless oil, 1H
10H, AreH).
NMR (400 MHz, CDCl3)
d
2.34 (s, 3H, eCH3), 6.21 (d, J¼8.22 Hz,
0.25H, (Z)-20-H), 6.57e6.61 (m, 1H,10-H), 6.80 (d, J¼13.69 Hz, 0.75H,
(E)-20-H), 7.13 (d, J¼8.22 Hz, 2H, AreH), 7.19 (d, J¼7.83 Hz, 2H,
AreH).
4.2.21. Methyl 2-chloro-3-hydroxy-3-phenylpropanoate
(17a). Colorless oil, 1H NMR (400 MHz, CDCl3)
d 3.04 (d,
J¼4.30 Hz, 1H, eOH), 3.80 (s, 3H, eOCH3), 4.39 (d, J¼7.82 Hz, 1H, 2-
H), 5.03e5.06 (m, 1H, 3-H), 7.35e7.40 (m, 5H, AreH).
4.2.12. 1-(4-tert-Butylphenyl)-2-chloroethanol (11a). Colorless oil,
1H NMR (400 MHz, CDCl3)
d
1.33 (s, 9H, eCH3), 2.63 (d, J¼2.35 Hz,
4.2.22. 2-Chlorocyclohexanol (18a). Colorless oil, 1H NMR
(400 MHz, CDCl3) d 1.25e1.32 (m, 4H, eCH2e), 1.63e1.75 (m, 2H,
eCH2e), 2.09e2.12 (m, 1H, eCH2e), 2.20e2.24 (m, 1H, eCH2e),
2.44 (br, 1H, eOH), 3.41e3.54 (m, 1H, eCHe), 3.69e3.75 (m, 1H,
eCHe).
1H, eOH), 3.64e3.77 (m, 2H, 2-H), 4.89 (d, J¼9.00 Hz, 1H, 1-H), 7.33
(d, J¼8.61 Hz, 2H, AreH), 7.41 (d, J¼8.21 Hz, 2H, AreH).
4 . 2 .13 . N - ( 1 - ( 4 - t e r t - B u t yl p h e nyl ) - 2 - ch l o ro e t hyl ) - 4 -
methylbenzenesulfonamide (11b). White solid, mp 115e117 C. 1H
NMR (400 MHz, CDCl3) d 1.27 (s, 9H, eCH3), 2.38 (s, 3H, eCH3), 3.73
(d, J¼5.87 Hz, 2H, eCH2Cl), 4.55e4.59 (m, 1H, AreCH), 5.24 (d,
J¼5.26 Hz, 1H, eNH), 7.02 (d, J¼8.21 Hz, 2H, AreH), 7.16 (d,
J¼7.82 Hz, 2H, AreH), 7.20e7.23 (m, 2H, AreH), 7.59 (d, J¼8.61 Hz,
4.3. General procedure for the synthesis of bromohydrins
with AcNHBr
2H, AreH). 13C NMR (CDCl3, 75 MHz)
d
151.44, 143.48, 137.18, 134.17,
NTsLT (6) (273 mg, 1 mmol) was dissolved in t-BuOH/H2O (1:1,
4 mL), then AcNHBr (19) (165 mg, 1.2 mmol) and olefin (1 mmol)
were added to the solution. The mixture was stirred at room
temperature. When the yellow color of the mixture faded, the re-
action was complete (also monitored by TLC). Na2SO3 (50 mg) was
added to the mixture, then extracted with ethyl acetate (3ꢁ10 mL)
and the organic phases were washed with brine (10 mL) and dried
over Na2SO4. The solvent was removed under reduced pressure and
the crude residue was further purified by column chromatography
to obtain the corresponding bromohydrin products.
129.60, 127.40, 126.76, 125.67, 58.38, 48.06, 34.68, 31.44, 21.71. ESI-
þ
MS m/z (%): 383.0 (MþNH4
, 30). HRMS: calcd mass for
C19H24ClNNaO2S 388.11085, found 388.11238.
4.2.14. 1-tert-Butyl-4-(2-chlorovinyl)benzene (11c). Colorless oil, 1H
NMR (400 MHz, CDCl3)
d
1.33 (s, 9H, eCH3), 6.24 (d, J¼8.22 Hz,
0.25H, (Z)-20-H), 6.60e6.64 (m,1H,10-H), 6.83 (d, J¼13.70 Hz, 0.75H,
(E)-20-H), 7.26 (d, J¼8.21 Hz, 2H, AreH), 7.37 (d, J¼7.83 Hz, 2H,
AreH).

6866
J. Zhang et al. / Tetrahedron 67 (2011) 6859e6867
4.3.1. 2-Bromo-1-phenylethanol (7b). Colorless oil, 1H NMR
(400 MHz, CDCl3)
H), 4.97e5.00 (m, 1H, 1-H), 7.38e7.45 (m, 5H, AreH).
(400 MHz, CDCl3) d 2.17e2.20 (m, 1H, 8-H), 2.43 (s, 3H, eCH3),
d
2.72 (d, J¼2.44, 1H, eOH), 3.58e3.72 (m, 2H, 2-
2.49e2.57 (m, 1H, 8-H), 2.88e2.95 (m, 1H, 7-H), 3.15e3.23 (m, 1H,
7-H), 4.61e4.62 (m, 1H, 9-H), 5.50 (d, J¼2.74 Hz, 1H, 10-H), 6.27 (s,
1H, 3-H), 7.13 (d, J¼8.22 Hz, 1H, 6-H), 7.50 (d, J¼8.22 Hz, 1H, 5-H).
4.3.2. (1,2-Dibromoethyl)benzene (20). White solid, mp 74e75 ꢂC
13C NMR (CDCl3, 75 MHz)
d 160.83, 153.30, 152.80, 140.84, 125.06,
(lit.18 72 ꢂC). 1H NMR (400 MHz, CDCl3)
d
4.46 (s, 2H, eCH2Br),
124.06, 123.44, 118.21, 114.07, 66.27, 51.26, 25.85, 25.25, 19.02. MS
(EI) m/z (%): 229 (93.04), 211 (100.00), 212 (79.30), 174 (73.83), 146
(83.17), 128 (37.44), 115 (59.74), 91 (46.17). HRMS: calcd mass for
C14H13O3Br 308.0048, found 308.0045.
5.13e5.17 (m, 1H, eCHBre), 7.35e7.42 (m, 5H, AreH).
4.3.3. 2-Bromo-1-phenylethanone (21). White solid, mp 49e50 ꢂC
(lit.18 48 ꢂC). 1H NMR (400 MHz, CDCl3)
d 4.00e4.10 (m, 2H,
eCH2Br), 7.50 (t, J¼7.31, 8.29 Hz, 2H, 30-H, 50-H), 7.60e7.64 (m, 1H,
4.3.15. 2-Bromocyclohexanol (18b). Colorless oil, 1H NMR
40-H), 7.99 (d, J¼8.29 Hz, 2H, 20-H, 60-H).
(400 MHz, CDCl3)
d 1.23e1.37 (m, 4H, eCH2e), 1.76e1.84 (m, 2H,
eCH2e), 2.10e2.13 (m,1H, eCH2e), 2.30e2.35 (m,1H, eCH2e), 2.66
(br, 1H, eOH), 3.56e3.62 (m, 1H, eCHe), 3.85e3.92 (m, 1H, eCHe).
4.3.4. 2-Bromo-1-p-tolylethanol (10d). Colorless oil, 1H NMR
(400 MHz, CDCl3)
d
2.36 (s, 3H, eCH3), 2.61 (d, J¼2.35 Hz, 1H, eOH),
3.51e3.64 (m, 2H, 2-H), 4.90 (d, J¼9.00 Hz, 1H, 1-H), 7.19 (d,
4.3.16. X-ray single crystal data of (9R,10R)-9-bromo-10-hydroxy-
10-O-(ꢀ)-camphanoyl-4-methyl-7,8,9,10-tetrahydrobenzo[h]chro-
men-2-one (24). Crystal with dimensions of 0.356ꢁ0.193
ꢁ0.147 mm for compound 24 was selected and mounted on
J¼7.83 Hz, 2H, AreH), 7.27 (d, J¼8.22 Hz, 2H, AreH).
4.3.5. 2-Bromo-1-(4-chlorophenyl)ethanol (13b). White solid, mp
61e63 ꢂC (lit.19 61e62 ꢂC). 1H NMR (400 MHz, CDCl3)
d
2.65 (d,
a Bruker Smart CCD diffractometer with graphite mono-
J¼2.93 Hz, 1H, eOH), 3.49e3.64 (m, 2H, 2-H), 4.91e4.93 (m, 1H, 1-
chromatized Mo K
were collected using
a
radiation (
l
¼0.071073 nm). Diffraction data
H), 7.32e7.38 (m, 4H, AreH).
u
ꢀ2 scans at room temperature (293 K). A
q
perspective view of the structure is depicted in Fig. 2. Empirical
formula: C24H25BrO6. Formula weight: 489.35. Crystal system: or-
thorhombic. Space group: P212121. Unit cell dimensions: a¼6.1497
4.3.6. 2-Bromo-1-(4-methoxyphenyl)ethanol (14c). Colorless oil, 1H
NMR (400 MHz, CDCl3)
(m, 2H, 2-H), 3.81 (s, 3H, eOCH3), 4.88 (d, J¼8.79 Hz, 1H, 1-H), 6.90
(dd, J¼6.76, 1.83 Hz, 2H, AreH), 7.30 (dd, J¼6.78, 1.83 Hz, 2H, AreH).
d
2.61 (d, J¼2.56 Hz, 1H, eOH), 3.50e3.62
3
ꢀ
ꢀ
ꢀ
ꢀ
(5) A, b¼11.6780 (10) A, c¼31.186 (3) A. V¼2239.6 (3) A . Theta
range for data collection is from 1.31 to 27.50ꢂ. Z¼4. Dc¼1.461 g/
cm3. F (000)¼1008. Refinement method: full-matrix least-squares
4.3.7. 2-Bromo-1-(4-tert-butylphenyl)ethanol (11e). Colorless oil,
on F2. Goodness-of-fit on F2: 0.898. Final R indices [I>2
s(I)]: 0.0345,
1H NMR (400 MHz, CDCl3)
1H, eOH), 3.53e3.65 (m, 2H, 2-H), 4.89e4.93 (m, 1H, 1-H),
7.31e7.41 (m, 4H, AreH).
d
1.30 (s, 9H, eCH3), 2.59 (d, J¼2.92 Hz,
0.0685. R indices (all data): 0.0529, 0.0780. Largest diff. peak and
hole: 0.504 and ꢀ0.237 e/A .
3
ꢀ
Acknowledgements
4.3.8. 2-Bromo-1-(3-nitrophenyl)ethanol (15b). Colorless oil, 1H
NMR (400 MHz, CDCl3) d 2.85 (br,1H, eOH), 3.53e3.57 (m,1H, 2-H),
Financial support from the National Natural Science Foundation
of China (No. 20972033), National Drug Innovative Program (Grant
No. 2009ZX09301-011), and the State Key Laboratory of Drug Re-
search, Shanghai Institute of Materia Medica, Chinese Academy of
Sciences (SIMM1004KF-08) is gratefully acknowledged.
3.69 (dd, J¼10.56, 3.52 Hz, 1H, 2-H), 5.05 (dd, J¼8.22, 3.52 Hz, 1H, 1-
H), 7.57 (t, J¼8.21 Hz, 1H, 50-H), 7.74 (d, J¼7.43 Hz, 1H, 60-H),
8.19e8.21 (m, 1H, 40-H), 8.29 (s, 1H, 20-H).
4.3.9. 1-Bromo-2-phenyl-2-propanol (22). Colorless oil, 1H NMR
(400 MHz, CDCl3) d 1.68 (s, 3H, eCH3), 2.58 (s, 1H, eOH), 3.69e3.78
(m, 2H, 1-H), 7.28e7.48 (m, 5H, AreH).
References and notes
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New York, NY, 2001; p 478, and references cited therein.
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NY, 1986; Vol. V, p 131.
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York, NY, 1990; Vols. 1e12; (b) Shimizu, M.; Yoshida, A.; Fijisawa, T.
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4.3.10. 2-Bromo-1,2-diphenylethanol (16b). White solid, mp
85e86 ꢂC (lit.20 83e86 ꢂC). 1H NMR (400 MHz, CDCl3)
d 2.39 (d,
J¼3.13 Hz, 1H, eOH), 5.10 (d, J¼6.65 Hz, 1H, 2-H), 5.20e5.21 (m, 1H,
1-H), 7.30e7.40 (m, 10H, AreH).
4.3.11. Methyl 2-bromo-3-hydroxy-3-phenylpropanoate
(17b). Colorless oil, 1H NMR (400 MHz, CDCl3)
d 3.22 (br, 1H,
eOH), 3.80 (s, 3H, eOCH3), 4.38 (d, J¼8.22 Hz, 1H, 2-H), 5.08 (d,
J¼8.22 Hz, 1H, 3-H), 7.34e7.41 (m, 5H, AreH).
4.3.12. Benzyl 2-bromo-3-hydroxy-3-phenylpropanoate
(23). Colorless oil, 1H NMR (400 MHz, CDCl3)
1H, eOH), 4.43 (d, J¼8.21 Hz, 1H, 2-H), 5.08e5.12 (m, 1H, 3-H),
5.19e5.26 (m, 2H, eCH2Ar), 7.31e7.38 (m, 10H, AreH).
d
3.16 (d, J¼5.48 Hz,
7. Rolston, J. H.; Yates, K. J. Am. Chem. Soc. 1969, 91, 1469.
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shavardhan, S. J.; Janardhana Chary, Ch.; Gupta, M. K. Tetrahedron Lett. 2005, 46,
3569; (c) Das, B.; Venkateswarlu, K.; Damodar, K.; Suneel, K. J. Mol. Catal. A:
Chem. 2007, 269, 17; (d) Bentley, P. A.; Mei, Y.; Du, J. Tetrahedron Lett. 2008, 49,
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S. L.; Lee, K. H. Bioorg. Med. Chem. Lett. 2007, 17, 4316.
4.3.13. 2-Bromo-1,2,3,4-tetrahydro-1-naphthol (9b). Colorless oil,
1H NMR (400 MHz, CDCl3)
d 2.25e2.33 (m, 1H, 3-H), 2.49e2.55 (m,
2H, 3-H, eOH), 2.93e2.98 (m, 2H, 4-H), 4.34e4.39 (m, 1H, 2-H),
4.90e4.93 (m, 1H, 1-H), 7.10e7.12 (m, 1H, 7-H), 7.22e7.25 (m, 2H, 5-
H, 8-H), 7.51e7.53 (m, 1H, 6-H).
4.3.14. 9-Bromo-10-hydroxy-4-methyl-7,8,9,10-tetrahydrobenzo[h]
chromen-2-one (8d). White solid, mp 194e196 ꢂC. 1H NMR

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