Oxidative β-Halogenation of Alcohols: A Concise and Diastereoselective Approach to Halohydrins

Article abstract of DOI:10.1055/s-0037-1610385

β-Halohydrins bearing transformable halo- and hydroxyl groups, are easily converted into various valuable blocks in organic and pharmaceutical synthesis. A diastereoselective β-halogenation of benzylic alcohols was achieved under simple and low-cost conditions, which provided a direct synthesis of β-halohydrins. The simple reaction conditions, easily available reagents, high diastereoselectivities, and additional oxidant-free make this reaction very attractive and practical.

Full text of DOI:10.1055/s-0037-1610385

SYNLETT
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Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
A
en
L. Ai et al.
Letter
Synlett
Oxidative β-Halogenation of Alcohols: A Concise and Diastereose-
lective Approach to Halohydrins
Lingsheng Aia
Weijin Wanga
Jialiang Weia
Qing Lia
Song Song*a,b
Ning Jiao*a,b
OH
OH
OH
OH
NaX/H2SO4
DMSO
NaX/H2SO4
DMSO
or
X
Ar
Ar
n
n
X
n = 1, 2, 3
X = Br, I
√ Halogenation of alcohol
√ High diastereoselectivity
√ Without additional oxidant
√ High-value product
0
0
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0
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3-0
2
9
0-9
0
3
4
a State Key Laboratory of Natural and Biomimetic Drugs, School of
Pharmaceutical Sciences, Peking University, Xue Yuan Rd. 38,
Beijing 100191, P. R. of China
ssong@bjmu.edu.cn
jiaoning@pku.edu.cn
b State Key Laboratory of Drug Research Shanghai Institute of
Materia Medical Chinese Academy of Sciences, Shanghai
201203, P. R. of China
Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue
Received: 26.08.2018
Accepted after revision: 23.10.2018
Published online: 21.11.2018
halosuccinimides and their analogues which are not good
choices for large-scale halogenations because of expensive
price and low atomic economy. Inspired by the enzyme-cat-
alyzed aerobic oxidative halogenation in nature,8 a sophisti-
cated approach by in situ generating the halogenating re-
agent from oxidant and halide salts is widely applied in ha-
logenations9,10 especially in the oxidative halohydroxylation
of olefins which provided a direct approach to halohy-
drins,10 although solvent, halide source, acid, oxygen
source, and oxidant were required in these approaches.
DOI: 10.1055/s-0037-1610385; Art ID: st-2018-b0556-l
License terms:
Abstract β-Halohydrins bearing transformable halo- and hydroxyl
groups, are easily converted into various valuable blocks in organic and
pharmaceutical synthesis. A diastereoselective β-halogenation of ben-
zylic alcohols was achieved under simple and low-cost conditions,
which provided a direct synthesis of β-halohydrins. The simple reaction
conditions, easily available reagents, high diastereoselectivities, and ad-
ditional oxidant-free make this reaction very attractive and practical.
A) The synthesis of halohydrins
Y
Key words halogenation, alcohols, dimethyl sulfoxide, halohydrins,
oxidation
R
R
OH
Ar
Ar
Ar
or
or
R
X
O
Ar
O
R
X
Organohalides are one of the most widespread and im-
portant chemicals and are present in more than 4500 natu-
ral products,1 as well as a great number of industrially valu-
able products such as pharmaceuticals, fire retardants, ag-
rochemicals, and some new materials.2 In addition, it is no
doubt that organohalides with their general reactivity
make the chemical synthesis more simple, accessible, and
valuable. β-Halohydrins, bearing a hydroxyl and halide
functional group, are privileged building blocks in organic
synthesis and could be conveniently converted into other
significant organic intermediates such as azido alcohols,
amino alcohols, and epoxides, all of which are widely used
in the synthesis of many highly value-added chemicals.3 Up
to date, halohydrins could be prepared by halohydroxyl-
ation of olefins,4 reduction of haloketones,5 ring-opening
reaction of epoxides,6 and nucleophilic substitution of ben-
zyl halides7 (Scheme 1, A). In most cases, the halo atom of
halohydrins was introduced by the halo cation such as N-
Ar
halohydrin
X
B) The halogenation of alcohols with low efficiency
Al(OtBu)3
OH
Br
O
O
OH
OH
PyHBr3
+
+
+
Ar
+
Ar
Ar
Ar
Ar
Ar
Ar
toluene, 60 °C
Br
Br
OH
R
OY
X
OY
R
X
NCS or NBS
+
+
Ar
Ar
HOY
Ar
R
R
X
R
Y = H or Me
C) β-Halogenation of alcohols (this work)
OH
OH
n
OH
OH
NaX/H2SO4
X
NaX/H2SO4
or
Ar
Ar
DMSO
DMSO
R = H
n
X
n = 1, 2, 3
X = Br, I
√ Halogenation of alcohol
√ High diastereoselectivity
√ Without additional oxidant
√ High-value product
Scheme 1 The synthesis of halohydrins
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
L. Ai et al.
Letter
Synlett
The β-halogenation of alcohols11 provides another di-
rect approach to halohydrins. However, the reported β-ha-
logenation of alcohols with halo cations always delivered
mixtures of products (Scheme 1, B).12 As our continuous de-
velopment of DMSO-based reactions,13 we herein reported
our success in β-halogenation of alcohols with in situ gen-
eration of halo cation from sodium halides and DMSO
(Scheme 1, C). The magic multiple role of DMSO14 as sol-
vent, oxidant,15 stabilizer of halo cations,10j and nucleo-
phile16 successfully enabled this novel transformation. Very
importantly and interestingly, the diastereoselectivities of
this transformation were very high (>25:1)
This reaction began with an unexpected bromination.
As reported,12a,17 the combination of aqueous HBr and
DMSO showed high efficiency in the aromatic bromination
of 2-naphthol 1 to deliver aryl bromide 2 in 79% yield
(Scheme 2, eq 1). To our surprise, when changing the sub-
stituent of naphthalene from –OH (1) to –CH(OH)CH3(3a),
the aromatic bromination was totally supressed, and ali-
phatic bromination at the methyl group occurred to afford
bromohydrin 4a in 33% yield (Scheme 2, eq 2).18 Due to the
importance of the halohydrins, this bromination drew our
great interest.
Table 1 Optimization of the Reaction Conditionsa
OH
OH
Br
[Br], additive
Me
DMSO, T °C, 24 h
3a
4a
Entry
[Br]
(equiv)
Additive (equiv) Solvent
T
(°C)
Yield
(%)b
1
2
KBr (2)
–
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DCE
60
60
60
60
60
60
40
80
60
60
60
60
60
0
KBr (2)
H2SO4 (2)
H2SO4 (2)
TsOH (2)
MsOH (2)
TfOH (2)
H2SO4 (2)
H2SO4 (4)
H2SO4 (4)
H2SO4 (8)
H2SO4 (4)
H2SO4 (4)
H2SO4 (4)
38
44
25
27
44
trace
mess
73
45
46
0
3
NaBr (2)
NaBr (2)
NaBr (2)
NaBr (2)
NaBr (2)
NaBr (2)
NaBr (2)
NaBr (2)
NaBr (1.2)
NaBr (2)
NaBr (2)
4
5
6
7
8
9
10
11
12
13
THF
0
Br
a Reaction conditions: The solution of 3a (0.5 mmol), bromide source, and
additive in solvent (1 mL) was stirred under air for 24 h.
b Isolated yields.
OH
OH
48% HBr (2 equiv)
DMSO, 60 °C
(eq 1)
1
2, 79%
We then investigated the substrate scope of this novel
bromination (Scheme 3). Various benzylic alcohols worked
well under the standard conditions. It was noteworthy that
when an electron-donating group such as methoxy, tert-bu-
tyl, or methyl was contained at the aryl ring, the corre-
sponding bromohydrins 4d,e and 4g were highly selectively
obtained in good yields, respectively. The reported bromi-
nation on the electron-rich arenes was not detected in this
protocol. In addition, heteroarenes such as benzothiophe-
nyl- and benzofuranyl-substituted alcohols were well toler-
ated in this transformation and converted into bromohy-
drins 4m,n in moderate yields. Furthermore, the gram-
scale reaction of 3a with 69% yield shows the potential ap-
plication of this low-cost protocol. However, no bromohy-
drin was detected when alcohols without benzylic substit-
uent was exposed under the standard conditions.
It is very challenging to control the diastereoselectivity
of β-functionalization of alcohols. To our delight, the six-
membered cyclic alcohols 3o,p produced trans-bromohy-
drins 4o,p as the sole product in high efficiency (Scheme 4).
Although the five-membered and seven-membered cyclic
alcohols 3q,r afforded the target bromohydrins 4q,r in
moderate yields, the diastereoselectivities of these bromi-
nations were also very high (>25:1).18 The substituents on
the phenyl ring had little influence on the efficiency and di-
astereoselectivity.
OH
OH
Br
OH
Br
48% HBr (2 equiv)
DMSO, 60 °C
+
(eq 2)
3a
4a, 33%
5, trace
Scheme 2
We then optimized the bromination conditions (Table 1).
The reaction did not work when changing aqueous HBr to
KBr (Table 1, entry 1). This experiment revealed the acidic
conditions were essential for this reaction. When HBr was
generated by KBr and H2SO4 in situ, 4a could be obtained in
38% yield (Table 1, entry 2). The yield increased to 44% using
NaBr instead of KBr (Table 1, entry 3). Other organic acids
such as TsOH, MsOH, or TfOH showed lower efficiency than
that of H2SO4 (Table 1, entries 3–6). The amount of acidic
additive influenced the yield strongly. Compound 4a was
obtained in 73% yield when 4 equiv of H2SO4were employed
(Table 1, entry 9). When the reaction preformed with 1.2
equiv of NaBr, only 46% yield of 4a was obtained (Table 1,
entry 11). Compound 4a was not detected when the reac-
tion was carried out in other solvents (Table 1, entries 12
and 13). These results indicated that DMSO was indispens-
able in this bromination.
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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L. Ai et al.
Letter
Synlett
OH
OH
OH
Me
OH
Me
NaBr (2 equiv), H2SO4 (4 equiv)
DMSO, 60 °C, 24 h
Br
Br
NaBr (2 equiv), H2SO4 (4 equiv)
DMSO, 60 °C, 24 h
Ar
Ar
(eq 3)
3
4
4c, 45%b
4d, 76%c
4e, 72%
4f, 64%
4g, 77%
4h, 33%b
R = H
HO
OH
OH
3u
R = 4-OMe
R = 4-tBu
R = 4-Ph
R = 4-Me
R = 4-I
4u, 52% (one isomer)
Br
R
cis/trans = 1.4:1
Br
Br
OH
OH
I
NaI, H2SO4
4a, 73%
1.38 g, 69%
(eq 4)
4b, 74%
DMSO/DCE, 60 °C, 24 h
OH
OH
6, 53%
3a
Me
OH
Br
Br
Me
Br
Br
Scheme 5
MeO
4i, 73%
OH
4k, 86%
4j, 47%
The bromohydrin 4a was conveniently converted into
other valuable products (Scheme 6). Azido alcohol 7, the
key intermediate of β-blocker pronethalol19a and other bio-
active molecules,19b was synthesized in 98% yield by stirring
4a with NaN3 at 60 °C in DMSO. Exposure of 4a with aque-
ous NaOH solvent in THF afforded epoxide 8 in 95% yield,
which could easily react with amines to produce amino al-
cohol drugs.19c Amino alcohol 9 also could be synthesized
by treating 4a with ammonium hydroxide in MeOH. The re-
action of 4a and CO2 in the presence of NMe4HCO3 provided
carbonic ester 10 in 97% yield.
OH
Br
OH
Br
O
O
O
S
Br
4n, 62%c
4l, 87%
4m, 56%
Scheme 3 Substrate scope of benzylic alcohols.a aReaction conditions:
The solution of 3a (0.5 mmol), NaBr (1 mmol), and H2SO4(2 mmol) in
DMSO (1 mL) was stirred under air at 60 °C for 24 h. Isolated yields.
bH2SO4(4 mmol) was used. cH2SO4(1.2 mmol) was used.
OH
OH
OH
O
Br
NaBr (2 equiv), H2SO4 (4 equiv)
N3
R
R
b)
a)
DMSO, 60 °C, 24 h
n
X
n
X
OH
3
4
Br
7, 98%
8, 95%
OH
OH
Br
OH
c)
d)
Br
O
O
4a
Br
O
OH
O
NHBoc
trans-4p, 72%
trans-4q, 51%
trans-4o, 87%
HO
OH
OH
Br
9, 72%
10, 97%
Br
MeO
Br
Br
Scheme 6 Transformation of bromohydrin 4a. Reaction conditions:
a) NaN3 (2 equiv), DMSO, 60 °C, 12 h. b) Aqueous NaOH (4 equiv), THF,
0 °C, 1 h. c) NH3·H2O (28%), MeOH, 25 °C, 4 h, then Boc2O (2 equiv), NEt3
(2 equiv), DCM, 25 °C, 4 h. d) NH4HCO3 (2 equiv), CO2 (1 atm), MeCN,
25 °C, 0.5 h.
trans-4s, 53%b
trans-4r, 32%
trans-4t, 88%
Scheme 4 Diastereoselective bromination of alcohols.a a Reaction con-
ditions: The solution of 3 (0.5 mmol), NaBr (1 mmol), and H2SO4
(2 mmol) in DMSO (1 mL) was stirred under air at 60 °C for 24 h. Isolat-
ed yields. b H2SO4(4 mmol) was used.
To investigate the mechanism of this bromination, con-
trol experiments were performed. Ethyl naphthalene 11
could not be brominated under the standard conditions, in-
dicating the hydroxyl was indispensable for present bromi-
nation (Scheme 7, eq 5). Treatment of alcohol 3a under
standard conditions in the absence of NaBr afforded alkene
12 in 39% yield (Scheme 7, eq 6). Subjecting the obtained
alkene 12 back to the standard conditions led to 4a in 76%
yield, which indicated that alkene 12 might be the key in-
termediate of this transformation (Scheme 7, eq 7).
When mixture of cis/trans (1.4:1) alcohol 3u was sub-
jected to the standard conditions, bromohydrin 4u was pro-
duced with only one diastereoselective isomer in 52% yield
(Scheme 5, eq 3). This experiment demonstrates the excel-
lent diastereoselectivity of present bromination reaction.
Compared to C–Br bond, the C–I bonds are more reactive
but hard to construct. To our delight, the β-iodination of al-
cohol 3a also underwent smoothly and produced the de-
sired iodohydrin 6 in 53% yield using NaI and H2SO4 as the
simple reagents (Scheme 5, eq 4).
Previous studies reported that the hydrobromic acids
could be oxidized by DMSO to molecular bromine (Scheme
7, eq 8).17 If Br2 was generated, it would readily react with
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

D
L. Ai et al.
Letter
Synlett
OH
Me
Br
OH
standard conditions
Br
(eq 5)
(eq 6)
DMSO, NaBr, H2SO4
11
3a
ND
OH
4u
Me
3u
H+
HBr
H2SO4 (4 equiv)
NaBr + H2SO4
Me
hydrolysis
+
DMSO, 60 °C, 24 h
DMSO
S(Me)2
O
12, 39%
4a, 76%
H
OH
H2O
DMSO
Br
Br
standard conditions
(eq 7)
(DMSO)nBr+DMS
n = 1–3
Br
A (favored)
Me
12
C
Me
Me
12u
Br2
H2O
OH
DMSO
+
2HBr
+
(eq 8)
(eq 9)
H
Br
Br
Br
Br
H2SO4 (4 equiv)
B (unfavored)
DMSO, 60 °C, 24 h
Scheme 8 Proposed mechanism
trans-13
4p, 27%, trans/cis = 9:1
DMSO
as the solvent
DMSO
Br+
(DMSO)nBr+ (n = 1–3)
HBr
(eq 10)
Funding Information
Scheme 7
Financial support from the National Basic Research Program of China
(973 Program) (grant No. 2015CB856600), the National Natural Sci-
ence Foundation of China (Nos. 21602005, 21632001, 21772002), and
the State Key Laboratory of Drug Research are greatly appreciated.
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the in situ generated alkene 12 to afford a trans-dibromi-
nated product 13.13d However, exposure of trans-13 under
the conditions for 24 h provided the product 4p only in 27%
yield and showed much lower diastereoselectivity (trans/cis
= 9:1, Scheme 7, eq 9). This experiment demonstrated that
the corresponding dibromination was not involved in this
process. We therefore suspected that the HBr was oxidized
to bromo cation (Br+) which was stabilized by DMSO
through coordination (Scheme 7, eq 10).10j
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610385.
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References
On the basis of the above experimental results and pre-
vious reports,18,20 we proposed the mechanism of this halo-
genation of alcohols in Scheme 8. Under acidic conditions,
alkene 12u is generated by the hydroxyl elimination pro-
cess. Meanwhile, Br+ is generated and immediately coordi-
nated by DMSO to give (DMSO)nBr+DMS (n = 1–3).10j The
electrophilic addition of Br+ to alkene 12u preferentially af-
fords bromonium A rather than B because of the steric hin-
drance of the methyl group. Further nucleophilic attack of
DMSO to A delivers the alkoxysulfonium C which quickly
decomposes to produce trans-bromohydrin 4u.10j,16a,i
In conclusion, we have developed a novel β-halogena-
tion of benzylic alcohols for the efficient synthesis of high-
value halohydrins. The simple reaction conditions, easily
available reagents, and high diastereoselectivity control
make this protocol very attractive and practical. Mechanis-
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halogen is involved in the transformation. This reaction
demonstrates a new application of DMSO and HX in organic
synthesis and would promote the application of the alkene
in situ generation strategy.
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Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E