Selective monochlorination of unsymmetrical vicinal diols with chlorinated iminium chlorides

Article abstract of DOI:10.1016/j.tet.2020.131114

Chlorinated iminium chlorides have been identified to promote the highly efficient and selective mono-chlorination of unsymmetrical vicinal diols. Vilsmeier reagent, namely, (chloromethylene)dimethyliminium chloride, enables highly reactive and regioselective chlorination of 1,2- and 1,3-diols featured one secondary benzylic hydroxy group and one primary aliphatic hydroxy group to give the corresponding 1,2- and 1,3-chlorohydrins. Viehe's salts (α,α-dichloro iminium salts) exhibit excellent reactivity and good selectivity for vicinal diols to give the corresponding chlorohydrin carbamates via a cyclic intermediate in situ. The chlorination protocols tolerate diverse functional groups, including halogens, naphthalene rings, nitro, and cyano. Moreover, the optical purity of chiral diols could be retained during this chlorination reaction.

Full text of DOI:10.1016/j.tet.2020.131114

Journal Pre-proof
Selective monochlorination of unsymmetrical vicinal diols with chlorinated iminium
chlorides
Liqun Yang, Xiaotong Li, Yu Wang, Chengyang Li, Xiaoyu Wu, Zhaoguo Zhang,
Xiaomin Xie
PII:
S0040-4020(20)30235-0
https://doi.org/10.1016/j.tet.2020.131114
TET 131114
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 January 2020
Revised Date: 24 February 2020
Accepted Date: 9 March 2020
Please cite this article as: Yang L, Li X, Wang Y, Li C, Wu X, Zhang Z, Xie X, Selective monochlorination
of unsymmetrical vicinal diols with chlorinated iminium chlorides, Tetrahedron (2020), doi: https://
doi.org/10.1016/j.tet.2020.131114.
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Selective monochlorination of unsymmetrical
vicinal diols with chlorinated iminium
chlorides
Liqun Yang a, Xiaotong Li a, Yu Wang a, Chengyang Li a, Xiaoyu Wu a, Zhaoguo Zhang a,b, and Xiaomin Xiea,*
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road,
Shanghai 200240, China

1
Tetrahedron
journal homepage: www.elsevier.com
Selective monochlorination of unsymmetrical vicinal diols with chlorinated iminium
chlorides
Liqun Yang a, Xiaotong Li a, Yu Wang a, Chengyang Li a, Xiaoyu Wu a, Zhaoguo Zhang a,b, and Xiaomin
Xiea,
a School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Fenglin Road, Shanghai
200032, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Chlorinated iminium chlorides have been identified to promote the highly efficient and selective
mono-chlorination of unsymmetrical vicinal diols. Vilsmeier reagent, namely,
(chloromethylene)dimethyliminium chloride, enables highly reactive and regioselective
chlorination of 1,2- and 1,3-diols featured one secondary benzylic hydroxy group and one
primary aliphatic hydroxy group to give the corresponding 1,2- and 1,3-chlorohydrins. Viehe’s
salts (α,α-dichloro iminium salts) exhibit excellent reactivity and good selectivity for vicinal
diols to give the corresponding chlorohydrin carbamates via a cyclic intermediate in situ. The
chlorination protocols tolerate diverse functional groups, including halogens, naphthalene rings,
nitro, and cyano. Moreover, the optical purity of chiral diols could be retained during this
chlorination reaction.
Available online
Keywords:
Selective chlorination
Vicinal diols
Chlorinated iminium chlorides
Vilsmeier reagent
Viehe’s salts
2009 Elsevier Ltd. All rights reserved
.
Corresponding author. Tel.: +86-021-5474-8925; fax: +86-021-5474-8925; e-mail: xiaominxie@sjtu.edu.cn

2
1. Introduction
altering the substituent at a position may take advantage to
discriminate the different hydroxyl groups. Herein, we presented
the details of a study about the direct and selective chlorination of
unsymmetrical vicinal diols with chlorinated iminium salts.
Chlorohydrins are an class of versatile synthons for natural
products, pharmaceuticals, pesticides and organic functional
materials.1 Among the multiple accesses to chlorohydrins,
selective chlorination of polyhydroxy compounds might be one
of the most efficient owing to the richness and ready availability
of polyhydroxy compounds.2 Numerous chlorination reagents or
recipes have been developed to the conversion of mono alcohols
to corresponding chlorides, such as hydrogen chloride3, thionyl
chloride4, phosphorus halides5, PPh3/various chlorinated reagents
6, chloro iminium salts2a,7, aromatic chloro carbocations8, and
chlorohydrosilanes9. More recently, catalytic Appel reactions and
formamides catalyzed chlorination have been reported.10
However, the selective chlorination of unsymmetrical
polyhydroxy molecules remains challenging, especially for
vicinal diols wherein the existence of two adjacent -OH groups
usually induces more side reactions like etherification and
rearrangement, let alone the regioselectivity.11 To realize
selective chlorination of the designated hydroxyl group in the
presence of other hydroxyl groups, the use of protecting groups
was generally required.12 Vicinal diols were often firstly
converted to form cyclic intermediates to achieve selective
chlorination such as ketal acids13, sulfates and sulfites14, and
orthoesters15. Nevertheless, these cyclic intermediates must be
preformed and isolated before subjection to chlorination, which
debate themselves for practical applications by rather laborious
and uneconomic steps.
2. Results and Discussion
1-Phenylethane-1,2-diol (1a) was chosen as the model
substrate to explore the direct and selective chlorination of
unsymmetrical vicinal diols (Table 1). We firstly tested the
chlorination of the vicinal diol 1a with Viehe's salts
((dichloromethylene)di-methylammonium chloride) which may
form cyclic intermediates M with diols. To our delight, in the
reaction of 1a with 1.2 molar equivalent of Viehe's salts in
dichloromethane (DCM) at room temperature, the chlorination of
benzyl alcohol, the more acidic alcohol, was dominated to give
mono-chlorinated carbamates in 85% yield and the selectivity of
97:3 (5a:6a) (entry 1). Comparing with classical chlorinating
reagents, the reaction of 1a with SOCl2 or POCl3 only resulted in
trace amount of chlorinated products either at room temperature
or the refluxing temperature, and mixtures of ethers were
observed as the main products (Table 1, entries 2-5). In case of
PPh3/CCl4 as the chlorinating reagent, the reaction proceeded
with poor selectivity to give the monochlorination product 2a in
37% yield and dichlorination product 4a in 4% yield (entry 6).
The results were consistent with the reports.11b,11c Definitely, the
chlorinated iminium salt performed good selectivity and
reactivity for the monochlorination of 1a.
In order to improve the selectivity of the monochlorination of
1a, Vilsmeier reagent ((chloromethylene)dimethyl-ammonium
chloride) was then explored which may display less
electrophilicity than Viehe's salts caused by one chloro
substituent at α position of iminium salt. The reaction of the diol
1a with 1.2 molar equivalent of Vilsmeier reagent at room
temperature showed excellent regioselectivity for the
monochlorination to produce monochlorinated alcohol 2a in 79%
yield, together with 5% yield of monochlorinated ester (7a,
2-chloro-2-phenylethyl formate) and the mixed ethers as main
byproducts. Remarkably, no chlorinated isomer 3a or
dichlorination product 4a was observed (entry 7). Then,
tetramethyl-a-chloro-enamine with less electrophilicity and more
hindrance than Vilsmeier reagent was tested. A lower reactivity
In terms of the direct and selective chlorination of
unsymmetrical polyhydroxy molecules, effective chlorination
reagents or reaction systems were still much sought after until
recently. NCS/Me2S duet selectively chlorinated allylic or
benzylic alcohols over other primary alkyl alcohols at low
temperature.16 Bulky chloroenamines or triphosgene/Et3N
combination allowed the selective chlorination of the primary
over tertiary hydroxy within diols.17 Yasuda et al. reported the
use of HSiMe2Cl/Benzil/InCl3 for the selective chlorination of
tertiary alcohols in the presence of a primary alcohols.9b These
chlorination systems, however, were impotent for the
discrimination between primary and secondary hydroxyls in
diols.9b,17 Only sporadic reports researched the selective
chlorination of unsymmetric vicinal diols. Taneja's group
was
observed.
A
monochlorinated
ester
(7a',
achieved
a
regioselective monochlorination of various
2-chloro-2-phenylethyl isobutyrate) was observed in 36% yield,
and 52% of 1a was converted to 2-hydroxy-2-phenylethyl
isobutyrate (entry 8). In some cases, Vilsmeier reagent could be
replaced with TCT (2,4,6-trichloro[1,3,5]triazine)/DMF or
pivaloyl chloride/DMF which may form the α-chloro iminium
chloride in situ.7d,7e Using pivaloyl chloride/DMF as the
chlorination reagent gave selectively the monochlorinated
product 2a in 45% yield (entry 9). In the case of TCT/DMF, the
reaction gave monochlorination product 2a in only 8% yield with
trace amount of dichlorination product 4a, and the
monochlorinated ester 7a was observed as the main product in
49% yield (entry 10). Formamide-catalyzed chlorination with
unsymmetrical vicinal diol scaffolds via Mitsunobu reaction with
TMSCl as the chlorination reagent.18 Primary hydroxyl in
carbohydrates and other sterically hindered non-saccharide
polyols were preferentially chlorinated, while the chlorination
predominantly occurred at the secondary alcohols with selectivity
ranging from 3:1 to 4:1 for other 1,2- and 1,3-diols.18 Canela and
coworkers used carboxylic acids in the selective chlorination of
1,3-butanediols by TMSCl.19 The in situ formed deoxygenated
ring undergoes nucleophilic ring opening during the chlorination
process. The regioselectivity of the chlorination, which could be
optimized up to 3/1, depends on the pKa value of the carboxylic
acids.19b Accordingly, the development of a highly efficient and
regioselective monochlorination of unsymmetrical vicinal diols is
very attractive and challenging. From the precedents, chlorinated
iminium salts may provide a solution for monochlorination of
TCT as an efficient chlorination system was also be examined10d
.
The monochlorinated alcohol 2a was selectively obtained in 54%
yield and the mixed ethers was observed as byproducts (entry
11). These results demonstrated that Vilsmeier reagent (isolated
α-chloro iminium salts) showed better selectivity for the
chlorination of the diol 1a than the in situ formed α-chloro
iminium salts.
unsymmetrical
vicinal
diols.
Viehe's
salt
((dichloromethylene)dimethylammonium chloride) was reported
to show high selectivity for chlorination in carbohydrates and
symmetric diols by formation in situ of cyclic intermediates.20
We speculated that chlorinated iminium salts may be reacted with
vicinal diols to generate a cyclic intermediate (M) which may
avoid side reactions such as etherification and rearrangement and
the adjustable reactivity of the chlorinated iminium salts by

3
chlorination reagent, the chlorination of 1a in refluxing DCM
Table 1. The optimization of reaction conditions for the
selective chlorination of the vicinal diol (1a)a
gave the monochlorination products (5a and 6a) in a slightly
decreased yield (entry 20). Therefore, the optimized reaction
conditions for the selective chlorination of the unsymmetrical
vicinal diol was 1.2 molar equivalent of Vilsmeier reagent in
refluxing DCM, or 1.2 molar equivalent of Viehe's salts in DCM
at room temperature.
Table 2. The selective chlorination of the unsymmetrical
vicinal diols with vilsmeier reagent a
Entry
Chlorination
reagent
Viehe‘s salts
Solvent Temp. Conv.
%
Yield %
OH
Cl
2a
3a
4a
-
H
Cl
Cl
DCM
reflux
OH
OH
1
2
3
4
5
6
7
DCM
DCM
DCM
DCM
DCM
DCM
DCM
rt
93 85 (5a) 3(6a)
+
N
n
n
R
R
SOCl2
SOCl2
POCl3
POCl3
rt
76
99
98
99
88
99
trace
6
-
-
-
-
-
1
1.2 eq
2
n=1, 2
Cl
40
rt
trace
Cl
Cl
trace
trace
37
-
trace
4
OH
OH
OH
40
rt
R
b
R=H : 2a, 82% (84%b)
Me: 2b, 77%
PPh3/CCl4
-
2d, 72%
Cl
2e, 65%
Cl
OH
Vilsmeier
reagent
rt
79 +
-
-
tBu: 2c, 70%
OH
Cl
O
OH
5 (7a)
&
8
9
a-chloroenamine
DCM
rt
rt
rt
88 36 (7a')
-
-
-
-
-
F3C
F3C
Cl
2g, 75%
2h
3h
OH
Pivaloyl chloride/DMF DCM
92
99
45
63%(91:9)
Cl
Cl
OH
OH
10
TCT/DMF
TCT/DMFc
DCM
8 +
49 (7a)
54
trace
2f, 56%
Br
Cl
11
12
DCM
DCM
40
rt
99
76
-
-
-
-
2j, 71%
Cl
2i, 80%
Cl
Vilsmeierd
reagent
Vilsmeier
reagent
Vilsmeier
reagent
Vilsmeier
reagent
Vilsmeier
reagent
Vilsmeier
reagent
Vilsmeier
reagent
Vilsmeier
reagent
57 +
6 (7a)
93
Cl
OH
OH
OH
Cl
OH
&
13
14
15
16
17
18
19
20
DCM
40
99
99
99
99
99
99
99
-
-
-
-
-
-
Cl
NC
NC
3l
2k, 84%
2m, 76%
2l
Toluene 40
80 +
trace (7a)
60
81%(75:25)
Cl
Cl
OH
DCE
Et2O
40
40
40
40
40
40
trace
5
OH
OH
OH
&
Cl
Cl
53
48
NO2
2o
3o
2q, 85%
THF
trace trace
2n, 52%
83%(80:20)
OH Cl
Cl
OH
MeCN
DMF
DCM
35 +
trace(7a)
46
-
trace
BzO
Cl
OH
3r, 61%
&
trace
-
-
2p
3p
Viehe‘s salts
93 78 (5a) trace
84%(83:17)
a
a
Reaction conditions: 1a (1.0 mmol), chlorination reagent (1.2
mmol), DCM (4.0 mL), 12 h; conversions and yields are
determined by GC (internal standard:
1,2,4,5-tetramethylbenzene).
Reaction conditions: vicinal diol (1.0 mmol), Vilsmeier reagent
o
(153.6 mg, 1.2 mmol), DCM (4.0 mL), 40 C, 12 h; isolated
yields; the ratio of isomers was detected by H NMR of the
regioisomers mixture.
1
b PPh3 (1.2 mmol), CCl4 (1.0 mL).
c TCT (0.4 mmol), DMF (0.4 mmol).
d Vilsmeier reagent (1.0 mmol).
b 1a (1.4 g, 10 mmol ) was reacted.
The scope of the selective chlorination of vicinal diols with
Vilsmeier reagent was then examined under the optimized
reaction conditions. As shown in Table 2, Vilsmeier reagent
exhibited good activity and selectivity in the chlorination of
1,2-diols that feature one benzylic secondary alcohol together
with an aliphatic primary alcohol. For all the diols, the benzylic
second alcohols, the more acidic alcohols, were selectively
chlorinated in good to moderate isolated yields. The chlorination
of alkyl substituted 1-arylethane-1,2-diol (1a-1f) selectively gave
the corresponding chlorination products (2a-2f) in the yields
ranging from 56% to 82%, and no other chlorinated products
Then we explored the effect on the chlorination of the vicinal
diol from the stoichiometry of chlorination reagent, reaction
temperature and solvents. Reducing Vilsmeier reagent to 1.0
equivalent resulted in lower conversion of 1a (entry 12). Raising
the reaction temperature to the reflux temperature of DCM, the
yield of the monochlorination product 2a was increased to 93%
(Table 1, entry 13). In the nonpolar solvents such as toluene,
Vilsmeier reagent retained good selectivity (entry 14). The
chlorination in DCE generated desired product 2a in 60% yield
(entry 15). Using the ether solvents or polar solvents led to a
decreased selectivity (entries 16-19). In DMF, the reaction
generated 2a in 46% yield, and the mixed ethers were observed
as the main byproducts (entry 19). The observation was in accord
with that of pivaloyl chloride/DMF or TCT/DMF as the
chlorination reagent wherein the excess DMF may decrease the
selectivity of the reagent. In case of Viehe's salts as the
were
observed.
The
sterically
hindered
1-(2,6-dimethylphenyl)ethane-1,2-diol (1d) was also reacted
smoothly to give the chlorination product 2d in 72% yield. This
protocol showed good tolerance for functional groups.
2-Chloro-2-phenylethan-1-ol with m-methoxy group (2g) or
p-bromo (2j) was selective obtained in 75% and 71% yield,
respectively.
Even
the
chlorination
could give
of
the
1-o-chlorophenylethane-1,2-diol
(1k)

4
corresponding product 2k in 84% yield. However, an
carbamate 5m in high yields and excellent selectivity. The
electron-withdrawing group on the aromatic group decreased the
chlorination of 1,3-diol 1n with m-nitro group offered the
corresponding mono-chlorinated carbamates (5n and 6n) in 76%
yield and the ratio of 83 : 17. While, in cases of 1,2-diols featured
regioselectivity
for
chlorination.
The
reaction
afforded
of
1-(4-cyanophenyl)ethane-1,2-diol
(1l)
the
monochlorinated products (2l and 3l) in 81% yield with a ratio of
75 : 25, and no hydrolysis of the cyano group was observed.
Moreover, Vilsmeier reagent is also amenable to the selective
a
benzylic and one aliphatic secondary alcohol, the
regioselectivity was also reduced. The reaction of
1-phenylpropane-1,2-diol (1o) gave the monochlorinated mixture
with ratio of 75 : 25. Moreover, in the chlorination of the
unsymmetrical diols (1r-1u) with two similar acidic hydroxyl
groups, the primary alcohol, less sterically hindered alcohol, was
selectively chlorinated. The chlorination of the mono-protected
glycerol (1r) with Viehe's salts gave the monochlorinated
carbamate 6r in 71% yield and >99% selectivity. Even, in the
chlorination of the unsymmetrical diols (1s, 1t and 1u) that
features aliphatic primary and secondary alcohols, successful
discrimination between the aliphatic primary and secondary
alcohols was achieved. The chlorination occurred selectively at
the primary alcohol to give the products in the yields ranging
from 70 to 85%. 5-Phenylpentane-1,3-diol (1u) is chlorinated to
obtain the mono-chlorinated carbamates 6u in 80% yield with the
selectivity of 99:1. The reaction conditions also scale effectively;
selective chlorination of 1-phenylethane-1,2-diol (1a) with
chlorination
of
1,3-diols.
The
chlorination
of
1-phenylpropane-1,3-diol (1m) proceeded efficiently to the
corresponding mono-chlorinated product 2m in 76% yield.
Similarly, the chlorination of 1,3-diol 1n with m-nitro group gave
the monochlorinated product 2n in 52% yield and dichlorinated
product 4n in 21% yield. Changing the aliphatic primary alcohol
of 1,2- and 1,3-diols to aliphatic secondary alcohol, benzyl
alcohols were also chlorinated preferentially, but the
regioselectivity
1-phenylpropane-1,2-diol
was
lower.
(1o)
The
gave a
reaction
mixture
of
of
1-chloro-1-phenylpropan-2-ol
(2o)
and
2-chloro-1-phenylpropan-1-ol (3o) in
a ratio of 80: 20.
1-Phenylbutane-1,3-diol (1p) could also be chlorinated to give
the monochlorination products of 2p and 3p in a 83:17 ratio. In
the case of the diol 1q that featured a primary benzylic and an
aliphatic primary alcohol, the benzylic alcohol also could be
selectively chlorinated to give the corresponding product 2q in
85% yield. Regretfully, the reaction of 1-phenylbutane-1,4-diol
generated the corresponding cyclic ether as the main product.
p-Methoxy substituted 1-phenylethane-1,2-diol was not suitable
for the chlorination, and the rearranged product,
2-(4-methoxyphenyl)acetaldehyde, was observed as the main
product.11f
Viehe's salts afforded
monochlorinated carbamate 5a with the 94:6 selectivity when
performed on a 10 mmol scale.
a
92% isolated yield of the
Table 3. The selective chlorination of the unsymmetrical
vicinal diols with Viehe‘s Salt a
Gratifyingly, the standard conditions were also suitable for the
monochlorination of 1-o-benzylglycerol (1r), the mono-protected
glycerol, Nevertheless, in the case of the diol with the similar
acidic hydroxyl groups, the less sterically hindered primary
alcohol was selectively chlorinated to afford the corresponding
product 3r in 61% yield without the formation of any other
chlorinated products. To evaluate the scalability of this facile
procedure, 10 mmol of 1a was subjected to the optimized
conditions and monochlorinated product 2a was isolated in 84%
yield.
Viehe's salts also exhibited good selectivity for the
monochlorination of the model unsymmetrical diol 1a, and the
mono-chlorinated carbamate 5a was generated as the main
product which is appropriate for further manipulations of the
chloride. Therefore, the scope of the selective chlorination of the
unsymmetrical vicinal diols with Viehe's salts was also examined
under the optimized reaction conditions. As shown in Table 3,
Viehe's salts performed excellent reactivity and good selectivity
in the chlorination of 1-arylethane-1,2-diols (1a-1l). Although the
regioselectivity was slightly lower than Vilsmeier reagent, the
yield of the monochlorination products improved significantly.
The secondary benzylic alcohols with more acidity were also
selectively chlorinated to give 2-chloro-2-arylethyl carbamates
with the diverse substituents (5a-5l) in the yields ranging from
79% to 96% and the selectivity was up to 97:3. The selective
chlorination
(2,6-dimethylphenyl)ethane-1,2-diol
of
sterically
hindered
generated the
(1d)
a Reaction conditions: vicinal diol (1.0 mmol), Viehe's salt (197.0
mg, 1.2 mmol), DCM (4.0 mL), 25 , 12 h; isolated yields; the
ratio of isomers was detected by 1H NMR of the crude products.
b 1a (1.4 g, 10 mmol ) was reacted.
monochlorinated carbamates in 83% yield with the 93 : 7
regioselectivity. Similarly, the presence of an
electron-withdrawing group at the aromatic group decreased the
regioselectivity for chlorination. The chlorination of (4-
trifluoromethylphenyl)ethane-1,2-diol (1h) with Viehe's salts
gave the mono chlorination products in 96% yield and 85 : 15
regioselectivity. 1-Phenylpropane-1,3-diols (1m) also underwent
regioselective chlorination to give the monochlorinated
To probe into the pathway of selective monochlorination of
unsymmetrical vicinal diols with chloro-iminium salts, we

5
carried out several control experiments (Schemes 1 & 2). We
firstly treated (R)-1-phenylethane-1,2-diol (1a', >99% ee) with
Vilsmeier
reagent
under
standard
conditions,
the
monochlorinated product 2a' was obtained in 84% isolated yield
and in 95% ee with the inverted configuration (Scheme 1a). The
observations indicated that the chlorination of vicinal diols with
Vilsmeier reagent may occur mainly through SN2 process rather
than SN1 by using TMSCl under SFRC9d. Therefore, in the
chlorination of (R)-1-phenylpropane-1,3-diol (1m', 94% ee), the
product 2m' with the inverted configuration should be
dominated, although the reduced enantiopure was observed
(Scheme 1b). Furthermore, the cyclic intermediate M preformed
by the reaction of N,N-dimethylformamide dimethyl acetal and
the diol was reacted with Vilsmeier reagent. Only 81%
conversion was observed and the mono- and dichlorination
produc（t 2a and 4a）were obtained a ratio of 1:1.69 (Schemes 1c).
Therefore, the monochlorination of vicinal diols with Vilsmeier
reagent may not involve the cyclic intermediate M. The good
regioselectivity may arise from the discrimination of Vilsmeier
reagent between the alcohols with the different acidity or steric
hindrance under the optimized conditions.
Scheme 2. The selective chlorination of (R)-vicinal diols with
Viehe's Salt
3. Conclusion
In summary, we developed a mild and useful chlorination
method for the selective chlorination of unsymmetrical vicinal
diols by using iminium salts (Vilsmeier reagent and Viehe's salt)
as the reagents. The unsymmetrical vicinal diols with different
acidic hydroxyl groups were selectively chlorinated at the more
acidic alcohol to give the corresponding mono-chlorohydrins or
chlorohydrin carbamates in moderate to good yields. For the
diols with similar electronic nature of alcohols, less sterically
hindered alcohol was selectively chlorination. The chlorination
protocol showed a good tolerance of halogens, naphthalene rings,
nitro, and cyano groups. The optical purity of chiral diols may
also be maintained during this chlorination.
4. Experimental Section
Unless otherwise noted, all reactions were carried out under
an atmosphere of nitrogen using standard Schlenk techniques.
Materials were purchased from commercial suppliers and used
without further purification. The preparation of Vilsmeier reagent
and Viehe's salt was based on the reports7c,21. Anhydrous DCM,
DCE, Toluene, Et2O, THF, DMF and CH3CN were freshly
Scheme 1. The selective chlorination of (R)-vicinal diols and
probably intermediate M with Vilsmeier reagent
1
distilled from calcium hydride or sodium. H NMR, 13C NMR
and 19F NMR spectra were recorded on 400 MHz or 500 MHz
spectrometers, and tetramethylsilane (TMS) was used as a
reference. Chemical shifts were reported in parts per million
(ppm), and the residual solvent peak was used as an internal
reference: proton (chloroform δ 7.26), carbon (chloroform δ
77.16). HRMS were obtained on ESI-TOF mass spectrometer.
Flash column chromatography was performed on silica gel
(300-400 mesh).
In the cases of chlorination with Viehe's salt, the
mono-chlorinated carbamates (5 or 6) were obtained as the main
products in excellent to moderate yields, and the generation of
the mixed ethers as byproducts was depressed greatly. When
(R)-1-phenylethane-1,2-diol
(1a')
and
(R)-1-phenylpropane-1,3-diol (1m') were subjected to the
reaction conditions, the enantiopure of the products (5a' and 5m')
maintained entirely. These observations demonstrated that there
was no nucleophilic attack of free hydroxy groups to the
activated alcohols or the formation of carbocation. Thus, the
chlorination of diols with Viehe‘s salts underwent the cyclic
intermediate M' and the substitution of chlorination occurred by
SN2 pathway. The configuration of 5a' and 5m' should be
inverted to S-type. The two chlorides at α-position of iminium
salt may account for the high activity of Viehe's salts to form the
cyclic intermediate M' with vicinal diols and the high selective
chlorination of aliphatic diols.
4.1. A typical procedure for the selective chlorination of
unsymmetrical vicinal diols with Vilsmeier reagent
A 25 mL oven-dried reaction Schlenk tube was added with the
vicinal diol 1 (1.0 mmol,1.0 equiv) and DCM (4.0 mL).
Vilsmeier reagent (153.6 mg, 1.2 mmol,1.2 equiv) was added to
the solution under nitrogen. The resulting solution was stirred at
o
40 C for 12 h. After cooling to room temperature, the reaction
mixture was added to aqueous NaHCO3 (5%, 10 mL), aqueous
phase was extracted with DCM (5 mL× 3). The combined
organic phase was washed with brine, and then dried over
anhydrous Na2SO4. After the solvent was removed under vacuum
and the residue was purified by column chromatography to give
the corresponding products.
2-Chloro-2-phenylethan-1-ol (2a):22 Yellow liquid, 128.5 mg,
82 % yield. 1H NMR (500 MHz, Chloroform-d) δ 7.47 – 7.31 (m,

6
5H), 5.00 (dd, J = 7.5, 5.0 Hz, 1H), 3.99 – 3.86 (m, 2H), 2.17
(brs, 1H). 13C NMR (126 MHz, CDCl3) δ 137.9, 129.0, 128.9,
127.6, 68.0, 65.0. (S)-2-Chloro-2-phenylethan-1-ol (2a'):23
Yellow liquid, 131.6 mg, 84 % yield. HPLC: Chiralcel AD-H
column, hexane/i-PrOH=99/1, 0.8 ml/min, 230 nm, t1=26.1 min,
t2=29.6 min. [α] 2D5 = + 111.0 (c =0.10 in CHCl3) for
2-(4-Bromophenyl)-2-chloroethan-1-ol (2j):24 Yellow liquid,
1
167.2 mg, 71 % liquid. H NMR (400 MHz, Chloroform-d) δ
7.56 – 7.47 (m, 2H), 7.33 – 7.27 (m, 2H), 4.94 (t, J = 6.4 Hz,
1H), 3.97 – 3.85 (m, 2H), 2.11 (t, J = 7.2 Hz, 1H). 13C NMR (101
MHz, CDCl3) δ 137.1, 132.1, 129.3, 123.0, 67.9, 64.0.
2-Chloro-2-(2-chlorophenyl)ethan-1-ol (2k): Yellow liquid,
161.0 mg, 84 % yield. 1H NMR (400 MHz, Chloroform-d) δ 7.70
– 7.54 (m, 1H), 7.45 – 7.22 (m, 3H), 5.56 (dd, J = 7.6, 4.0 Hz,
1H), 4.07 – 3.83 (m, 2H), 2.32 (s, 1H). 13C NMR (101 MHz,
CDCl3) δ 135.3, 133.0, 129.9, 129.8, 129.2, 127.5, 66.9, 61.1.
HRMS-ESI (m/z): Calculated for C8H835Cl2ONa (M + Na)+:
212.9844, Found: 212.9848.
23
(S)-enantiomer with 95.2% ee. (Lit. [α]2D0 = +52.7 (c =1.0 in
CHCl3) for (S)-enantiomer with 44% ee).
2-Chloro-2-(p-tolyl)ethan-1-ol (2b):24 Light yellow liquid,
131.1 mg, 77 % yield. 1H NMR (400 MHz, Chloroform-d) δ 7.32
– 7.26 (m, 2H), 7.21 – 7.14 (m, 2H), 4.95 (t, J = 5.6 Hz, 1H),
3.99 – 3.79 (m, 2H), 2.35 (s, 3H), 2.23 (s, 1H). 13C NMR (101
MHz, CDCl3) δ 139.0, 135.0, 129.6, 127.5, 67.9, 64.9, 21.3.
4-(1-Chloro-2-hydroxyethyl)benzonitrile (2l): Yellow liquid,
111.0 mg, 61 % yield. 1H NMR (400 MHz, Chloroform-d) δ 7.72
– 7.65 (m, 2H), 7.59 – 7.50 (m, 2H), 5.00 (t, J = 6.0 Hz, 1H),
3.94 (t, J = 6.4 Hz, 2H), 2.21 (t, J = 6.8 Hz, 1H). 13C NMR (126
MHz, CDCl3) δ 143.2, 132.7, 128.5, 118.4, 112.8, 67.6, 63.3.
HRMS-ESI (m/z): Calculated for C9H835ClNO (M) +:181.0294,
Found: 181.0293.
2-(4-(tert-Butyl)phenyl)-2-chloroethan-1-ol (2c): White solid,
1
149.0 mg, 70 % yield. M.P.:67.1-68.5 . H NMR (400 MHz,
Chloroform-d) δ 7.44 – 7.37 (m, 2H), 7.37 – 7.29 (m, 2H), 4.99
(dd, J = 7.6, 5.6 Hz, 1H), 4.01 – 3.86 (m, 2H), 2.15 – 2.02 (m,
1H), 1.32 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 152.2, 134.9,
127.3, 125.9, 68.0, 65.0, 34.8, 31.4. HRMS-EI (m/z): Calculated
for C12H1735ClO (M)+: 212.0968, Found: 212.0970.
4-(2-Chloro-1-hydroxyethyl)benzonitrile (3l): Yellow liquid,
21.8 mg, 12 % yield. H NMR (400 MHz, Chloroform-d) δ 7.68
1
2-Chloro-2-(2,6-dimethylphenyl)ethan-1-ol (2d): Colorless
liquid, 133.1 mg, 72 % yield. 1H NMR (400 MHz, Chloroform-d)
δ 7.08 – 6.94 (m, 3H), 4.92 (dd, J = 8.0, 5.6 Hz, 1H), 3.98 – 3.85
(m, 2H), 2.33 (s, 6H), 2.13 (brs, 1H). 13C NMR (126 MHz,
CDCl3) δ 138.6, 137.7, 130.7, 125.3, 67.9, 65.1, 21.4. HRMS-EI
(m/z): Calculated for C10H1335ClO (M)+: 184.0655, Found:
184.0660.
(d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 5.02 – 4.94 (m, 1H),
3.76 (dd, J = 11.2, 3.6 Hz, 1H), 3.62 (dd, J = 11.6, 8.4 Hz, 1H),
2.81 (d, J = 3.2 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 145.1,
132.6, 127.0, 118.6, 112.4, 73.3, 50.5. HRMS-ESI (m/z):
Calculated for C9H835ClNO (M) +:181.0294, Found: 181.0294.
3-Chloro-3-phenylpropan-1-ol (2m):18 Yellow liquid, 129.4
mg, 76 % yield. H NMR (400 MHz, Chloroform-d) δ 7.48 –
7.28 (m, 5H), 5.21 – 5.07 (m, 1H), 3.94 – 3.82 (m, 1H), 3.79 –
3.68 (m, 1H), 2.42 – 2.19 (m, 2H), 1.79 (brs, 1H). 13C NMR (101
MHz, CDCl3) δ 141.6, 128.8, 128.5, 127.1, 60.4, 59.9, 42.3.
(S)-3-Chloro-3-phenylpropan-1-ol (2m'):25 HPLC (Chiralcel
AD-H column, hexane/i-PrOH = 99/1, 1.0 mL/min, 250 nm): t1 =
24.2 min, t2 = 29.2 min. [α]2D5 = – 72.0 (c = 0.10 in CHCl3) for
(S)-enantiomer with 69.4% ee.
2-Chloro-2-(naphthalen-2-yl)ethan-1-ol (2e):24 White solid,
1
1
134.0 mg, 65 % yield. M.P.:59.8-61.6 . H NMR (400 MHz,
Chloroform-d) δ 7.97 – 7.80 (m, 4H), 7.61 – 7.42 (m, 3H), 5.17
(dd, J = 7.2, 5.2 Hz, 1H), 4.13 – 3.96 (m, 2H), 2.11 (brs, 1H). 13C
NMR (101 MHz, CDCl3) δ 135.2, 133.5, 133.1, 129.0, 128.2,
127.9, 127.1, 126.8, 126.8, 124.8, 67.9, 65.1.
2-Chloro-2-(naphthalen-1-yl)ethan-1-ol (2f):24 Light yellow
liquid, 115.0 mg, 56 % yield. 1H NMR (400 MHz, Chloroform-d)
δ 8.13 (d, J = 8.4 Hz, 1H), 7.93 – 7.84 (m, 2H), 7.73 (d, J = 7.2
Hz, 1H), 7.62 – 7.47 (m, 3H), 5.86 (t, J = 6.4 Hz, 1H), 4.22 –
4.12 (m, 2H), 2.43 (brs, 1H). 13C NMR (101 MHz, CDCl3) δ
133.9, 133.3, 130.7, 129.6, 129.2, 126.9, 126.1, 125.4, 125.4,
122.7, 67.3, 61.4. HRMS-EI (m/z): Calculated for C12H1135ClO
(M)+: 206.0498, Found: 206.0497.
3-Chloro-3-(3-nitrophenyl)propan-1-ol (2n)： Yellow liquid,
112.0 mg, 52 % yield. 1H NMR (400 MHz, Chloroform-d) δ 8.32
– 8.24 (m, 1H), 8.19 – 8.11 (m, 1H), 7.76 – 7.68 (m, 1H), 7.60 –
7.51 (m, 1H), 5.11 (dd, J = 8.8, 4.0 Hz, 1H), 3.86 – 3.75 (m, 1H),
3.65 – 3.56 (m, 1H), 2.32 – 2.06 (m, 3H). 13C NMR (101 MHz,
CDCl3) δ 148.7, 146.2, 132.0, 129.8, 122.9, 120.9, 70.4, 41.6,
41.4. HRMS-ESI (m/z): Calculated for C9H1035ClNO3 (M)
+:215.0349, Found: 215.0350.
1-Chloro-1-phenylpropan-2-ol (2o):26 Yellow liquid, 143.3 mg,
84% yield (2o:3o=80:20). H NMR (400 MHz, Chloroform-d) δ
7.42 – 7.35 (m, 5H), 4.75 (d, J = 7.6 Hz, 1H), 4.22 – 4.09 (m,
1H), 2.63 (d, J = 3.6 Hz, 1H), 1.12 (d, J = 6.4 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ 138.6, 128.8, 128.8, 127.8, 72.1, 71.2, 19.5.
2-Chloro-2-(3-methoxyphenyl)ethan-1-ol (2g): Light yellow
liquid, 140.0 mg, 75 % yield. 1H NMR (400 MHz, Chloroform-d)
δ 7.33 – 7.27 (m, 1H), 7.01 – 6.94 (m, 2H), 6.91 – 6.86 (m, 1H),
4.96 (dd, J = 6.8, 6.0 Hz, 1H), 3.96 – 3.90 (m, 2H), 3.82 (s, 3H),
2.09 (dd, J =8.0, 6.4 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ
159.8, 139.4, 129.9, 119.8, 114.3, 113.3, 67.9, 64.6, 55.4.
HRMS-EI (m/z): Calculated for C9H1135ClO2 (M)+: 186.0448,
Found: 186.0446.
1
4-Chloro-4-phenylbutan-2-ol (2p): Yellow liquid, 152.8 mg,
83% yield(2p:3p=83:17). H NMR (400 MHz, Chloroform-d) δ
1
2-Chloro-2-(4-(trifluoromethyl)phenyl)ethan-1-ol
(2h):
Yellow liquid, 141.5 mg, 63% yield (2h:3h=91:9). 1H NMR (400
MHz, Chloroform-d) δ 7.71 – 7.64 (m, 2H), 7.61 – 7.54 (m, 2H),
5.05 (t, J = 6.0 Hz, 1H), 4.12 – 3.89 (m, 2H), 2.22 (brs, 1H). 13C
NMR (101 MHz, CDCl3) δ 141.9, 131.2(q, J = 32.8 Hz), 128.1,
125.9(q, J = 3.7 Hz), 123.9(q, J =273.3 Hz), 67.8, 63.7. 19F NMR
(376 MHz, CDCl3) δ -62.76. HRMS-EI (m/z): Calculated for
C9H835ClF3O (M)+: 224.0216, Found: 224.0219.
7.48 – 7.28 (m, 5H), 5.08 (t, J = 7.2 Hz, 1H), 3.75 – 3.62 (m,
1H), 2.41 – 2.30 (m, 1H), 2.23 – 2.11 (m, 1H), 1.64 (s, 1H), 1.21
(d, J = 6.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 141.2, 128.8,
128.6, 127.3, 65.9, 60.8, 49.0, 23.9. HRMS-ESI (m/z):
Calculated for C10H1335ClO (M – H2O) :166.0549, Found:
+
166.0551.
2-(4-(Chloromethyl)phenyl)ethan-1-ol (2q): White solid, 145.0
2-Chloro-2-(4-chlorophenyl)ethan-1-ol (2i):24 Light yellow
liquid, 152.9 mg, 80 % yield. 1H NMR (400 MHz, Chloroform-d)
δ 7.43 – 7.29 (m, 4H), 5.03 – 4.88 (m, 1H), 3.96 – 3.82 (m, 2H),
2.38 (brs, 1H). 13C NMR (101 MHz, CDCl3) δ 136.5, 134.8,
129.1, 129.0, 67.8, 63.9.
mg, 85% yield. M.P.:61.8-64.9
.
1H NMR (500 MHz,
Chloroform-d) δ 7.39 – 7.31 (m, 2H), 7.25 – 7.19 (m, 2H), 4.57
(s, 2H), 3.83 (t, J = 6.5 Hz, 2H), 2.85 (t, J = 6.5 Hz, 2H), 1.78 (s,
1H). 13C NMR (126 MHz, CDCl3) δ 139.1, 135.7, 129.5, 128.9,

7
63.5, 46.2, 38.9. HRMS-ESI (m/z): Calculated for C9H1135ClONa
(M + Na) +: 193.0391, Found: 193.0396.
1-(Benzyloxy)-3-chloropropan-2-ol (3r):18 Yellow liquid, 122.5
mg, 61% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.41 – 7.28
(m, 5H), 4.57 (s, 2H), 4.01 (t, J = 5.6 Hz, 1H), 3.70 – 3.54 (m,
4H), 2.60 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 137.7, 128.6,
128.1, 127.9, 73.7, 70.9, 70.4, 46.2.
δ 155.9, 135.3, 133.4, 133.1, 128.8, 128.2, 127.8, 126.9, 126.7,
126.6, 124.8, 68.8, 60.6, 36.6, 36.0. HRMS-ESI (m/z):
Calculated for C15H1635ClNO2Na (M + Na) : 300.0762, Found:
+
300.0774.
2-Chloro-2-(3-methoxyphenyl)ethyl dimethylcarbamate (5g):
Yellow liquid，222.0 mg, 86% yield (5g:6g = 93:7). H NMR
1
(400 MHz, Chloroform-d) δ 7.33 – 7.24 (m, 1H), 7.02 – 6.94 (m,
2H), 6.91 –6.84 (m, 1H), 5.16 – 4.99 (m, 1H), 4.47 – 4.36 (m,
2H), 3.82 (s, 3H), 2.91 (brs, 3H), 2.87 (brs, 3H). 13C NMR (101
MHz, CDCl3) δ 159.9, 155.9, 139.5, 129.8, 119.8, 114.5, 113.1,
69.0, 60.4, 55.4, 36.6, 36.0. HRMS-ESI (m/z): Calculated for
C12H1635ClNO3Na (M + Na) +: 280.0711, Found: 280.0720.
4.2. A typical procedure for the selective chlorination of
unsymmetrical vicinal diols with Viehe's salt
A 25 mL oven-dried reaction Schlenk tube was added with the
vicinal diol 1 (1.0 mmol,1.0 equiv) and DCM (4.0 mL). Viehe's
salt (197.0 mg, 1.2 mmol,1.2 equiv) was added to the solution
under N2. The resulting solution was stirred at room temperature
for 12 h. The reaction mixture was added to aqueous NaHCO3
(5%, 10 mL), aqueous phase was extracted with DCM (5 mL ×
3). The combined organic phase was washed with brine, and then
dried over anhydrous Na2SO4. After the solvent was removed
under vacuum and the residue was purified by column
chromatography to give the corresponding products.
2-Chloro-2-(4-(trifluoromethyl)phenyl)ethyl
dimethylcarbam-ate (5h): Yellow liquid, 266.0 mg, 96% yield
1
(5h:6h = 85:15). H NMR (400 MHz, Chloroform-d) δ 7.68 –
7.61 (m, 2H), 7.58 – 7.53 (m, 2H), 5.14 (t, J = 6.8 Hz, 1H), 4.43
(d, J = 6.8 Hz, 2H), 2.91 (brs, 3H), 2.85 (brs, 3H). 13C NMR (126
MHz, CDCl3) δ 155.7, 142.0,131.1(q, J = 32.6 Hz), 128.0,
127.0,125.8(q, J = 4.0 Hz), 123.9(q, J = 272.8 Hz),68.6, 59.2,
36.6, 35.9. 19F NMR (471 MHz, CDCl3) δ -62.7. HRMS-ESI
(m/z): Calculated for C12H1335ClF3NO2Na (M + Na) : 318.0479,
+
Found: 318.0446.
2-Chloro-2-phenylethyl dimethylcarbamate (5a): Yellow
liquid, 196.2 mg, 86% yield (5a:6a = 97:3). 1H NMR (400 MHz,
Chloroform-d) δ 7.45 – 7.30 (m, 5H), 5.10 (dd, J = 7.6, 6.0 Hz,
1H), 4.48 – 4.38 (m, 2H), 2.91 (brs, 3H), 2.86 (brs, 3H). 13C
NMR (126 MHz, CDCl3) δ 155.9, 138.0, 128.9, 128.8, 127.6,
69.0, 60.4, 36.6, 36.0. HRMS-ESI (m/z): Calculated for
C11H1435ClNO2 Na (M + Na) +:250.0605, Found: 250.0623.
(R)-2-Chloro-2-phenylethyl dimethylcarbamate (5a'): Yellow
liquid, 200.4 mg, 88% yield (5a:6a = 97:3). HPLC (Chiralcel
IA-3 column, hexane/i-PrOH = 90/10, 0.6 mL/min, 254 nm): t1 =
9.4 min, t2 = 9.8 min. [α]2D5 = +73.8 (c = 0.10 in CHCl3) for
(S)-enantiomer with 99.9% ee.
2-Chloro-2-(4-chlorophenyl)ethyl dimethylcarbamate (5i)：
Yellow liquid, 221.0 mg, 85% yield (5i:6i = 92:8). 1H NMR (400
MHz, Chloroform-d) δ 7.39 – 7.33 (m, 4H), 5.07 (t, J =7.2 Hz,
1H), 4.42 – 4.37 (m, 2H), 2.91 (brs, 3H), 2.85 (brs, 3H). 13C
NMR (101 MHz, CDCl3) δ 155.8, 136.6, 134.8, 129.0, 129.0,
68.7, 59.4, 36.6, 36.0. HRMS-ESI (m/z): Calculated for
C11H1335Cl2NO2Na (M + Na) +: 284.0216, Found: 284.0229.
2-Chloro-2-(2-chlorophenyl)ethyl dimethylcarbamate (5k)：
1
Yellow liquid, 224.6 mg, 86 % yield (5k:6k = 96:4). H NMR
(400 MHz, Chloroform-d) δ 7.66 – 7.60 (m, 1H), 7.41 – 7.24 (m,
4H), 5.64 (dd, J = 7.2, 5.6 Hz, 1H), 4.50 – 4.38 (m, 2H), 2.91
(brs, 3H), 2.87 (brs, 3H). 13C NMR (101 MHz, CDCl3) δ 155.8,
135.6, 133.2, 130.0, 129.7, 129.2, 127.5, 67.9, 56.1, 36.6, 36.0.
2-Chloro-2-(p-tolyl)ethyl dimethylcarbamate (5b): Yellow
liquid, 217.6 mg, 90% yield (5b:6b = 94:6). 1H NMR (400 MHz,
Chloroform-d) δ 7.33 – 7.27 (m, 2H), 7.20 – 7.14 (m, 2H), 5.07
(t, J = 7.2 Hz, 1H), 4.45 – 4.37 (m, 2H), 2.91 (brs, 3H), 2.87 (brs,
3H)., 2.35 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 156.0, 138.8,
135.1, 129.5, 127.4, 68.9, 60.4, 36.6, 36.0, 21.3. HRMS-ESI
+
HRMS-ESI (m/z): Calculated for C11H1335Cl2NO2Na (M + Na) :
284.0216, Found: 284.0222.
2-Chloro-2-(4-cyanophenyl)ethyl dimethylcarbamate (5l):
1
Yellow liquid, 217.3 mg, 86% yield (5l:6l = 85:15). H NMR
+
(m/z): Calculated for C12H1635ClNO2Na (M + Na) : 264.0762,
(400 MHz, Chloroform-d) δ 7.70 – 7.61 (m, 2H), 7.57 – 7.50 (m,
2H), 5.10 (t, J = 6.8 Hz, 1H), 4.39 (d, J = 6.8 Hz, 2H), 2.88 (brs,
3H), 2.81 (brs, 3H). 13C NMR (101 MHz, CDCl3) δ 155.5, 143.1,
128.4, 118.3, 112.7, 68.3, 58.8, 36.6, 35.9. HRMS-ESI (m/z):
Calculated for C12H1435ClN2O2 (M + H) +: 253.0738., Found:
253.0723.
Found: 264.0776.
2-(4-(tert-Butyl)phenyl)-2-chloroethyl dimethylcarbamate
(5c): White solid, 255.0 mg, 90% yield (6c:7c = 92:8). 63.5-65.0
. 1H NMR (400 MHz, Chloroform-d) δ 7.42 – 7.32 (m, 4H),
5.09 (dd, J = 7.6, 5.2 Hz, 1H), 4.48 – 4.36 (m, 2H), 2.91 (brs,
3H), 2.89 (brs, 3H)., 1.32 (s, 9H). 13C NMR (126 MHz, CDCl3) δ
156.0, 152.0, 134.9, 127.2, 125.7, 69.0, 60.5, 36.6, 36.0, 34.8,
31.4. HRMS-ESI (m/z): Calculated for C15H2235ClNO2Na (M +
Na)+: 306.1231, Found: 306.1247.
3-Chloro-3-phenylpropyl dimethylcarbamate (5m): Yellow
liquid, 224.2 mg, 93% yield. 1H NMR (500 MHz, Chloroform-d)
δ 7.42 – 7.28 (m, 5H), 5.00 (dd, J = 8.5, 6.0 Hz, 1H), 4.29 – 4.10
(m, 2H), 2.90 (brs, 3H), 2.87 (brs, 3H), 2.49 – 2.33 (m, 2H). 13C
NMR (126 MHz, CDCl3) δ 156.4, 141.2, 128.9, 128.6, 127.0,
62.5, 60.3, 39.4, 36.6, 36.0. HRMS-ESI (m/z): Calculated for
C12H1635ClNO2Na (M + Na) +: 264.0762, Found: 264.0772.
2-Chloro-2-(2,6-dimethylphenyl)ethyl
dimethylcarbamate
1
(5d): Yellow liquid, 212.4 mg, 83% yield (5d:6d = 93:7). H
NMR (400 MHz, Chloroform-d) δ 7.02 (s, 2H), 6.96 (s, 1H), 5.03
(dd, J = 8.0, 5.6 Hz, 1H), 4.46 – 4.33 (m, 2H), 2.92 (brs, 3H),
2.89 (brs, 3H), 2.32 (s, 6H). 13C NMR (126 MHz, CDCl3) δ
156.0, 138.4, 137.8, 130.6, 125.3, 69.1, 60.8, 36.6, 36.0, 21.4.
(S)-3-Chloro-3-phenylpropyl
dimethylcarbamate
(5m'):
Yellow liquid, 217.0 mg, 90% yield. HPLC (Chiralcel AS-H
column, hexane/i-PrOH = 99/1, 0.8 mL/min, 230 nm): t1 =14.5
min, t2 = 18.7 min. [α]2D3 = 56.0 (c = 0.10 in CHCl3) for
(R)-enantiomer with 95.8% ee.
+
HRMS-ESI (m/z): Calculated for C13H1835ClNO2Na (M + Na) :
278.0918, Found: 278.0930.
3-Chloro-3-(3-nitrophenyl)propyl dimethylcarbamate (5n):
Yellow liquid, 217.3 mg, 76% yield (5n:6n = 83:17). H NMR
(500 MHz, Chloroform-d) δ 8.26 (t, J = 2.0 Hz, 1H), 8.21 – 8.15
(m, 1H), 7.77 – 7.72 (m, 1H), 7.56 (t, J = 8.0 Hz, 1H), 5.07 (dd, J
= 8.5, 6.0 Hz, 1H), 4.32 – 4.13 (m, 2H), 2.90 (brs, 3H), 2.87 (brs,
2-Chloro-2-(naphthalen-2-yl)ethyl dimethylcarbamate (5e):
1
White solid, 180.2 mg, 79% yield (5e:6e = 97:3). M.P.: 88.9-90.1
1
. H NMR (400 MHz, Chloroform-d) δ 7.92 – 7.78 (m, 4H),
7.57 – 7.42 (m, 3H), 5.27 (t, J = 6.8 Hz, 1H), 4.52 (d, J = 6.8 Hz,
2H), 2.89 (brs, 3H), 2.82 (brs, 3H). 13C NMR (101 MHz, CDCl3)

8
3H), 2.51 – 2.36 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 156.2,
148.5, 143.4, 133.2, 130.0, 123.5, 122.2, 76.9, 62.1, 58.6, 39.3,
36.6, 36.0. HRMS-ESI (m/z): Calculated for C12H1635ClN2O4 (M
+ H) +: 287.0793, Found: 287.0788.
Chem. Pharm. Bull. 1995, 43, 1067-1069; (e) Corey, E. J.;
Helal, C. J. Angew. Chem. Int. Ed. 1998, 37, 1986-2012; (f)
Couladouros, E. A.; Dakanali, M.; Demadis, K. D.; Vidali, V. P.
Org. Lett. 2009, 11, 4430-4433; (g) Daub, M. E.; Prudhomme, J.;
Le Roch, K.; Vanderwal, C. D. J. Am. Chem. Soc. 2015, 137,
4912-4915.
3-Chloro-1-(3-nitrophenyl)propyl dimethylcarbamate (6n):
Yellow liquid, 22.9 mg, 8% yield. 1H NMR (500 MHz,
Chloroform-d) δ 8.21 (t, J = 2.0 Hz, 1H), 8.19 – 8.13 (m, 1H),
7.70 – 7.67 (m, 1H), 7.58 – 7.51 (m, 1H), 5.93 (dd, J = 9.0, 5.0
Hz, 1H), 3.69 – 3.46 (m, 2H), 3.02 (s, 3H), 2.90 (s, 3H), 2.48 –
2.35 (m, 1H), 2.25 – 2.17 (m, 1H). 13C NMR (126 MHz, CDCl3)
δ 155.4, 148.7, 143.0, 132.7, 129.8, 123.2, 121.0, 73.2, 40.5,
39.6, 36.7, 36.1. HRMS-ESI (m/z): Calculated for
C12H1635ClN2O4 (M + H) +: 287.0793, Found: 287.0796.
2. (a) Gomez, L.; Gellibert, F.; Wagner, A.; Mioskowski, C.
Tetrahedron Lett. 2000, 41, 6049-6052; (b) Xu, L.-W.; Li, L.; Xia,
C.-G.; Zhao, P.-Q. Tetrahedron Lett. 2004, 45, 2435-2438.
3. For example references on chlorination of alcohols with HCl: (a)
Brown, H. C.; Rei, M.-H. J. Org. Chem. 1966, 31, 1090-1093; (b)
Tundo, P.; Selva, M. Green Chem. 2005, 7, 464-467; (c)
Borukhova, S.; Noël, T.; Hessel, V. ChemSusChem 2016, 9,
67-74.
4. For example references on chlorination of alcohols with SOCl2:
(a) Lewis, E. S.; Boozer, C. E. J. Am. Chem. Soc. 1952, 74,
308-311; (b) Schreiner, P. R.; Schleyer, P. v. R.; Hill, R. K. J.
Org. Chem. 1993, 58, 2822-2829; (c) Mondal, D.; Li, S. Y.;
Bellucci, L.; Laino, T.; Tafi, A.; Guccione, S.; Lepore, S. D. J.
Org. Chem. 2013, 78, 2118-2127; (d) Pluempanupat, W.;
Chavasiri, W. Tetrahedron Lett. 2006, 47, 6821-6823.
1-Chloro-1-phenylpropan-2-yl dimethylcarbamate (5o) ：
1
Yellow liquid, 200.2 mg, 83% yield. (5o:6o = 75:25). H NMR
(400 MHz, Chloroform-d) δ 7.41 – 7.29 (m, 7H), 5.26 – 5.16 (m,
1H), 4.89 (d, J = 6.8 Hz, 1H), 2.93 (s, 6H). HRMS-ESI (m/z):
5. Tipson, R. S. J. Org. Chem. 1962, 27, 1449-1449.
+
Calculated for C12H1635ClNO2Na (M + Na) : 264.0762, Found:
6. For examples on chlorination of alcohols with PPh3/various
chlorinated reagents: (a) Lee, J. B.; Nolan, T. J. Can. J. Chem.
1966, 44, 1331-1334; (b) Magid, R. M.; Talley, B. G.; Souther, S.
K. J. Org. Chem. 1981, 46, 824-825; (c) Castro, B. R. Org. React.
(N. Y.) 1983, 29, 1-162; (d) Drabowicz, J.; Luczak, J.;
Mikolajczyk, M. J. Org. Chem. 1998, 63, 9565-9568; (e) Jaseer,
E. A.; Naidu, A. B.; Kumar, S. S.; Rao, R. K.; Thakur, K. G.;
Sekar, G. Chem. Commun. 2007, 867-869.
7. For examples on chlorination of alcohols with chlorinated
iminium salts: (a) Hanessian, S.; Plessas, N. R. J. Org. Chem.
1969, 34, 2163-2170; (b)Viehe, H. G.; Janousek, Z. Angew. Chem.
Int. Ed. 1973, 12, 806-818; (c) Yoshihara, M.; Eda, T.; Sakaki, K.;
Maeshima, T. Synthesis 1980, 746-748; (d) De Luca, L.;
Giacomelli, G.; Porcheddu, A. Org. Lett. 2002, 4, 553-555; (e)
Dubey, A.; Upadhyay, A. K.; Kumar, P. Tetrahedron Lett. 2010,
51, 744-746; (f) Dai, C.; Narayanam, J. M.; Stephenson, C. R.
Nat. Chem. 2011, 3, 140-145.
264.0764.
1-(Benzyloxy)-3-chloropropane-2-yl dimethylcarbamate (6r):
Yellow liquid, 192.9 mg, 71% yield. 1H NMR (500 MHz,
Chloroform-d) δ 7.41 – 7.27 (m, 5H), 5.13 – 5.03 (m, 1H), 4.61 –
4.52 (m, 2H), 3.84 – 3.62 (m, 4H), 2.90 (brs, 3H), 2.84 (brs, 3H).
13C NMR (101 MHz, CDCl3) δ 155.6, 138.0, 128.6, 127.9, 127.8,
73.5, 72.5, 68.6, 43.7, 36.6, 36.1. HRMS-ESI (m/z): Calculated
for C13H1835ClNO3Na (M + Na) +:294.0867, Found: 294.0872.
1-Chloro-4-phenylbutan-2-yl dimethylcarbamate (6s): Yellow
1
liquid, 179.0 mg, 70% yield (5s:6s = 6:94). H NMR (500 MHz,
Chloroform-d) δ 7.31 – 7.27 (m, 2H), 7.22 – 7.17 (m, 3H), 5.01 –
4.94 (m, 1H), 3.74 – 3.59 (m, 2H), 2.93 (s, 3H), 2.90 (s, 3H),
2.77 – 2.63 (m, 2H), 2.16 – 1.93 (m, 2H). 13C NMR (101 MHz,
CDCl3) δ 155.9, 141.3, 128.6, 128.4, 126.2, 73.3, 46.4, 36.6,
35.9, 33.5, 31.6. HRMS-ESI (m/z): Calculated for C13H1935ClNO2
(M + H) +: 256.1099, Found: 256.1085.
8. For examples on chlorination of alcohols with aromatic chloro
carbocations: (a) Kelly, B. D.; Lambert, T. H. J. Am. Chem. Soc.
2009, 131, 13930-13931; (b) Nguyen, T. V.; Bekensir, A. Org.
Lett. 2014, 16, 1720-1723; (c) Lee, C.-H.; Lee, S.-M.; Min, B.-H.;
Kim, D.-S.; Jun, C.-H. Org. Lett. 2018, 20, 2468-2471.
9. For examples on chlorination of alcohols with chlorohydrosilanes:
(a) Lee, J. G.; Kang, K. K. J. Org. Chem. 1988, 53, 3634-3637;
(b)Yasuda, M.; Yamasaki, S.; Onishi, Y.; Baba, A. J. Am. Chem.
Soc.2004, 126, 7186-7187; (c)Yasuda, M.; Shimizu, K.;
Yamasaki, S.; Baba, A. Org. Biomol. Chem. 2008, 6, 2790-2795;
(d) Ajvazi, N.; Stavber, S. Tetrahedron Lett. 2016, 57, 2430-2433;
(e) Balme, G.; Fournet, G.; Gore, J. Tetrahedron Lett. 1986, 27,
1907-1908.
10. (a) Denton, R. M.; An, J.; Adeniran, B.; Blake, A. J.; Lewis, W.;
Poulton, A. M. J. Org. Chem. 2011, 76, 6749-6767; (b) Longwitz,
L.; Jopp, S.; Werner, T. J. Org. Chem. 2019, 84, 7863-7870; (c)
Huy, P. H.; Motsch, S.; Kappler, S. M. Angew. Chem. Int. Ed.
2016, 55, 10145-10149; (d) Huy, P. H.; Filbrich, I. Chem. Eur. J.
2018, 24, 7410-7416; (e) Zheng, D.; Mao, L.-L.; Zhu, X.-H.;
Zhou, A.-X. Synth. Commun. 2018, 48, 2793-2800.
11. (a) Barry, C. N.; Evans, S. A., Jr. J. Org. Chem. 1983, 48, 2825-8;
(b) Liu, C.; Coward, J. K. J. Org. Chem. 1991, 56, 2262-2264; (c)
Beuerle, T.; Engelhard, S.; Bicchi, C.; Schwab, W. J. Nat. Prod.
1999, 62, 35-40; (d) Shi, H.; Du, C.; Zhang, X.; Xie, F.; Wang, X.;
Cui, S.; Peng, X.; Cheng, M.; Lin, B.; Liu, Y. J. Org. Chem. 2018,
83, 1312-1319; (e) Giomi, D.; Malavolti, M.; Piccolo, O.; Salvini,
A.; Brandi, A. RSC Adv. 2014, 4, 46319-46326; (f) Tiwari, P. K.;
Sivaraman, B.; Aidhen, I. S. Eur. J. Org. Chem. 2017, 2017,
3594-3605.
1-Chlorodecan-2-yl dimethylcarbamate (6t): Yellow liquid,
223.4 mg, 85% yield (5t:6t = 11:89). H NMR (400 MHz,
Chloroform-d) δ 4.95 – 4.85 (m, 1H), 3.71 – 3.55 (m, 2H), 2.92
(s, 6H), 1.74 – 1.63 (m, 2H), 1.40 – 1.18 (m, 12H), 0.88 (t, J =
6.8, 6.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 156.0, 73.8,
1
46.4, 36.5, 35.9, 31.9, 31.7, 29.5, 29.3, 25.2, 22.8, 14.2.
+
HRMS-ESI (m/z): Calculated for C13H2735ClNO2 (M + H)
264.1725, Found: 264.1728.
:
1-Chloro-5-phenylpentan-3-yl
dimethylcarbamate
(6u):
1
Yellow liquid, 215.7 mg, 76% yield (5u:6u > 1:99). H NMR
(500 MHz, Chloroform-d) δ 7.35 – 7.27 (m, 3H), 7.25 – 7.17 (m,
3H), 5.05 – 4.96 (m, 1H), 3.65 – 3.54 (m, 2H), 2.95 (s, 3H), 2.90
(s, 3H), 2.76 – 2.64 (m, 2H), 2.19 – 2.04 (m, 2H), 2.04 – 1.87 (m,
2H). 13C NMR (126 MHz, CDCl3) δ 156.3, 141.6, 128.5, 128.4,
126.1, 72.5, 41.1, 37.9, 36.6, 36.4, 35.9, 31.8. HRMS-ESI (m/z):
Calculated for C14H2135ClNO2 (M + H) +: 270.1255, Found:
270.1254.
Acknowledgments
We thank the National Natural Science Foundation of China
and the Interdisciplinary Program of Shanghai Jiao Tong
University (YG2017MS26) for financial support.
12. (a) Mouné, S.; Niel, G.; Busquet, M.; Eggleston, I.; Jouin, P. J.
Org. Chem. 1997, 62, 3332-3339; (b) Akio, M.; Masayuki, S.;
Yasukatsu, O.; Tomoji, I.; Takeshi, Y. Chirality 2001, 13,
601-605; (c) Orsini, F.; Selloa, G.; Bestettib, G. Tetrahedron:
Asymmetry 2001, 12, 2961-2969; (d) Patil, M. N.; Gonnade, R. G.;
Joshi, N. N. Tetrahedron 2010, 66, 5036-5041.
References and notes
13. Newman, M. S.; Chen, C. H. J. Am. Chem. Soc. 1972, 94,
2149-2150.
14. (a) Nymann, K.; Svendsen, J. S. Acta Chem. Scand. 1994, 48,
183-6; (b) Miller, J. J. J. Org. Chem. 1962, 27, 2680-2681.
1. (a) Nicolaou, K. C.; Papahatjis, D. P.; Claremon, D. A.; Magolda,
R. L.; Dolle, R. E. J. Org. Chem. 1985, 50, 1440-1456; (b)
Gribble, G. W. J. Nat. Prod. 1992, 55, 1353-1395; (c) Godard, A.;
Lamour, P.; Ribereau, P.; Quéguiner, G. Tetrahedron 1995, 51,
3247-3264; (d) Ohshiba, Y.; Yoshimitsu, T.; Ogasawara, K.

9
15. (a) Newman, M. S.; Chen, C. H. J. Am. Chem. Soc. 1973, 95,
278-279; (b) Elsenbaumer, R. L.; Mosher, H. S. J. Org. Chem.
1979, 44, 600-604; (c) Konopelski, J. P.; Boehler, M. A.;
Tarasow, T. M. J. Org. Chem. 1989, 54, 4966-4970; (d) Kolb, H.
C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515-10530; (e)
Alberti, M. N.; Vassilikogiannakis, G.; Orfanopoulos, M. Org.
Lett. 2008, 10, 3997-4000.
16. Corey, E. J.; Kim, C. U.; Takeda, M. Tetrahedron Lett. 1972, 13,
4339-4342.
17. (a) Ayala, C. E.; Villalpando, A.; Nguyen, A. L.; McCandless, G.
T.; Kartika, R. Org. Lett. 2012, 14, 3676-3679; (b) Munyemana,
F.; George, I.; Devos, A.; Colens, A.; Badarau, E.;
Frisque-Hesbain, A.-M.; Loudet, A.; Differding, E.; Damien,
J.-M.; Rémion, J.; Van Uytbergen, J.; Ghosez, L. Tetrahedron
2016, 72, 420-430.
18. Dar, A. R.; Aga, M. A.; Kumar, B.; Yousuf, S. K.; Taneja, S. C.
Org. Biomol. Chem. 2013, 11, 6195-207.
19. (a) Eras, J.; Méndez, J. J.; Balcells, M.; Canela, R. J. Org. Chem.
2002, 67, 8631-8634; (b) Eras, J.; Méndez, J. J.; Balcells, M.;
Canela, R. Synth. Commun. 2007, 36, 1167-1175.
20. (a) Leclef, B.; Mommaerts, J.; Stelander, B.; Viehe, H. G. Angew.
Chem. 1973, 85, 445-446; (b) Benazza, M.; Uzan, R.; Beaupère,
D.; Demailly, G. Tetrahedron Lett. 1992, 33, 3129-3132; (c)
Benazza, M.; Uzan, R.; Beaupère, D.; Demailly, G. Tetrahedron
Lett. 1992, 33, 4901-4904.
21. Fujisawa, T.; Sato, T., Org. Synth. 1988, 66, 121-126.
22. Chatterjee, R.; Samanta, S.; Mukherjee, A.; Santra, S.; Zyryanov,
G. V.; Majee, A. Tetrahedron Lett. 2019, 60, 276-283.
23. de Andrade, V. S. C.; de Mattos, M. C. S., Synthesis 2016, 48,
1381-1388.
24. Jiang, Y.; Chen, W.; Lu, W. Tetrahedron 2013, 69, 3669-3676.
25. Isleyen, A.; Tanyeli, C.; Dogan, O. Tetrahedron: Asymmetry
2006, 17, 1561-1567.
26. (a) Paek, S. H.; Shim, S. C.; Cho, C. S.; Kim, T.-J. Synlett 2003,
849-851; (b) Denmark, S. E.; Barsanti, P. A.; Wong, K.;
Stavenger, R. A. J. Org. Chem. 1998, 63, 2428-2429.
Supplementary Material
Supplementary data (experimental information and
characterisation data for vicinal diols (1) as well as the spectra
copies of the diols and the products) associated with this article
can be found, in the online version, at.

Selective monochlorination of unsymmetrical vicinal diols with
chlorinated iminium chlorides
Liqun Yang a, Xiaotong Li a, Yu Wang a, Chengyang Li a, Xiaoyu Wu a, Zhaoguo
Zhang a,b, and Xiaomin Xiea,
a School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240,
China
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Fenglin Road, Shanghai 200032, China
Highlights
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Easily available chlorination reagents
Mild conditions and medium to excellent yields
High chemo- and regio-selectivity
Chlorohydrins and chlorohydrin carbamates as the products
The monochlorinated products with retained enantiopure
Corresponding author. Tel.: +86-021-5474-8925; fax: +86-021-5474-8925; e-mail: xiaominxie@sjtu.edu.cn

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: