Efficient and Practical Oxidative Bromination and Iodination of Arenes and Heteroarenes with DMSO and Hydrogen Halide: A Mild Protocol for Late-Stage Functionalization

Article abstract of DOI:10.1021/acs.orglett.5b00932

An efficient and practical system for inexpensive bromination and iodination of arenes as well as heteroarenes by using readily available dimethyl sulfoxide (DMSO) and HX (X = Br, I) reagents is reported. This mild oxidative system demonstrates a versatile protocol for the synthesis of aryl halides. HX (X = Br, I) are employed as halogenating reagents when combined with DMSO which participates in the present chemistry as a mild and inexpensive oxidant. This oxidative system is amenable to late-stage bromination of natural products. The kilogram-scale experiment (>95% yield) shows great potential for industrial application.

Full text of DOI:10.1021/acs.orglett.5b00932

Letter
pubs.acs.org/OrgLett
Efficient and Practical Oxidative Bromination and Iodination of
Arenes and Heteroarenes with DMSO and Hydrogen Halide: A Mild
Protocol for Late-Stage Functionalization
Song Song,† Xiang Sun,† Xinwei Li,† Yizhi Yuan,† and Ning Jiao*,†,‡
†State Key Laboratory of Natural and Biomimetic Drugs, Peking University, School of Pharmaceutical Sciences, Peking University,
Xue Yuan Road 38, Beijing 100191, China
‡State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: An efficient and practical system for inex-
pensive bromination and iodination of arenes as well as
heteroarenes by using readily available dimethyl sulfoxide
(DMSO) and HX (X = Br, I) reagents is reported. This mild
oxidative system demonstrates a versatile protocol for the
synthesis of aryl halides. HX (X = Br, I) are employed as halogenating reagents when combined with DMSO which participates
in the present chemistry as a mild and inexpensive oxidant. This oxidative system is amenable to late-stage bromination of natural
products. The kilogram-scale experiment (>95% yield) shows great potential for industrial application.
ryl halides are among the most common and important
chemicals1 and are present in many natural products.2 The
current dominant industrial approach to aryl bromides and
iodides is the halogenation of arenes with X2 (X = Br, I) which
suffers from obvious limitations (Scheme 1a): (1) X2 are
are not good choices for large scale halogenations because of
the expensive price and the generation of organic wastes.
Hydrogen halides (HX), the byproduct of X2-based
halogenations, are readily available, inexpensive, and easy to
store and transport. Inspired by the enzyme-catalyzed oxidative
halogenation in nature,5 various oxidative halogenations
consisting of generating the halogenating reagent in situ from
halide are reported in the literature,6 where residual HX is
oxidized by the oxidants such as selectfluor, persulfates,
hypervalent iodine, molecular oxygen, hydrogen peroxide, etc.
However, limited substrate scope, low atom economy, poor
regioselectivity, or the potential explosivity of oxidants
substantially restricts the utility of these oxidative halogen-
ations. Importantly, the reported oxidative systems show
limitations in halogenation of heteroarenes.6
A
Scheme 1. Bromination and Iodination of Arenes
Dimethyl sulfoxide (DMSO), which is industrially produced
by oxidation of dimethyl sulfide with nitrogen dioxide or
oxygen,7 is utilized as the oxygen,8 carbon,9 or sulfur10 source in
many reactions. The combination of DMSO and HBr has been
used in the bromination of arenes (Scheme 1b, eq 2).11
However, the reported reactions suffered from several draw-
backs (Scheme 1b): (1) The bromination of heteroarenes with
DMSO/HBr has not been reported except for pyrrole
derivatives; (2) the iodination of arenes cannot be achieved
by their strategies; (3) the dibromination was uncontrollable
due to the use of >9 equiv of HBr (thus, the bromination of
electron-rich arenes such as m-dimethoxybenzene mainly
afforded the dibrominated product); (4) a less than 40%
yield was obtained when 2 equiv of HBr were employed. The
hazardous, toxic, and corrosive reagents; (2) Halide-atom
economy is below 50% with HX as the byproduct; (3)
Sometimes, the undesirable byproducts are uncontrollable. To
avoid the use of X2, some modified reagents such as N-
halosuccinimides (NBS or NIS) and their analogues which are
operationally safe in comparison with that of X2 and do not
produce HX, have been developed.3,4 However, these reagents
Received: March 31, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00932
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Letter
a
above-mentioned limitations are why this reaction rarely has
been used in organic synthesis.
Scheme 3. DMSO/HBr for Bromination of Arenes
According to Yoshida’s report, the halide cation would form
X+(DMSO)n in the presence of DMSO (Scheme 1c, eq 3).12
We hypothesized that the excess DMSO strongly reduced the
reactivity of X+ generated from DMSO/HX in Majetich’s
report.11a Therefore, we speculated that the efficient halogen-
ation of arenes with stoichiometric HX would be possible if
stoichiometric DMSO was used as the oxidant instead of as the
solvent. Herein, we describe the simple and practical
bromination and iodination of arenes as well as various
heteroarenes with stoichiometric aqueous HX (X = Br, I) and
DMSO performed in EtOAc (Scheme 1d, eq 4). The high
halide-atom economy, broad substrate scope, easy accessibility,
and low cost of aqueous HX and DMSO make this strategy
extremely attractive in the development of efficient approaches
to aryl bromides and iodides. The mild and simple conditions
are amenable to late-stage functionalization of natural products.
Initially, we chose m-dimethoxybenzene 1a as the substrate,
from which the bromination afforded mono- and dibrominated
products in Majetich’s report (Scheme 1b, eq 2).11a The
bromination of 1a with 1.1 equiv of HBr in DMSO as solvent at
35 °C afforded 2a in only 34% (for 1 h) and 49% yield (for 24
h), respectively (Scheme 2, eq 5), which were in accordance
a
The solution of 1 (0.5 mmol), DMSO (0.55 mmol), and HBr (48%)
in EtOAc (2 mL) was stirred under air at 60 °C. For 1a−k, 1.1 equiv
of HBr was used. For 1m−u, 2.2 equiv of HBr were used. Isolated
Scheme 2. Bromination of m-Dimethoxybenzene
b
c
yields. With 4 equiv of DMSO and HBr. With 8 equiv of DMSO and
HBr in AcOH (2 mL). With 1.05 equiv of DMSO and HBr.
d
Furthermore, the 1.0 kg scale bromination of 1g with a 96%
yield shows great potential for industrial applications of this
low-cost protocol (Scheme 3).
Heteroaromatic halogenations are very important because
they are ubiquitous in modern medicinal chemistry.15 There-
fore, the development of new approaches to heteroaromatic
halides has always drawn chemists’ attention.16 Very recently,
Glorius and co-workers reported the Rh-catalyzed regioselec-
tive halogenation of heterocycles.16a The chlorination of
heteroarenes was realized by using Palau’chlor developed by
Baran.16b We then investigated the heteroaromatic bromina-
tions with the present DMSO/HBr system (Scheme 4). Indole
compounds 3a−k were brominated in excellent yields within an
hour. It is noteworthy that the oxidative bromination of indole
compounds without the protecting group on the nitrogen atom
with Majetich’s report11a (Scheme 1b) and proved that the
reactivity of Br+ in DMSO was very low. To our delight, with
1.1 equiv of DMSO and aqueous HBr (48%) in EtOAc at 35
°C for 1 h, 2a was obtained as the sole product in 90% yield
(Scheme 2, eq 6).
The bromination of 1a proceeded rapidly (15 min) to afford
2a in 94% yield at 60 °C (Scheme 3). Under these conditions,
arenes 1b−k bearing methoxy or hydroxy substituents were
monobrominated in high to excellent yields with selectivity that
at first approximation parallels Friedel−Crafts reactivity
(Scheme 3). The bromination of some electron-rich substrates
1c, 1h, 1j, and 1k performed very rapidly (10−15 min) in high
yields. Vanilli 1i was brominated in 96% yield and the aldehyde
group, which is easily oxidized under oxidative conditions, was
retained.13 Notably, 2,2′-Binol 1l was dibrominated smoothly in
89% yield.
This efficient system could cover the aniline derivatives
(1m−u, Scheme 3). A series of primary 1m−p, secondary 1q−
r, and tertiary amines 1s−u were monobrominated in high
yields with 1.1 equiv of DMSO and 2.2 equiv of HBr. Notably,
the bromination of substrates 1q, 1s, and 1u with unsubstituted
ortho and para positions gave para-brominated products.
Furthermore, the bromination at the benzyl position, which
usually happened in other oxidative processes,14 was not
detected in the present system. The electron-poor arenes such
as benzoic acid, nitrobenzene, or benzonitrile did not work in
the present DMSO/HBr system.
6c
could not be achieved using other oxidants such as O2 or
selectfluor.6i Other heteroarenes including 7-azaindole 3l,
indazole 3m, pyrazoles 3n−o, pyrimidazole 3p, 1,7-diazaindo-
lizine 3q, thiophene 3r, benzothiophene 3s, and benzofuran 3t
could all be regioselectively brominated in good yields.
The bromide substituent can greatly change the drugs’ or
natural products’ properties.17 We tried to expand our simple
and mild method to the direct bromination of natural or
bioactive compounds (Scheme 5). The selective bromination of
δ-tocopherol 5a with Br2 was a challenge and showed poor
regioselectivity even at very low temperature.18 Gratifyingly, the
bromination of 5a with the DMSO/HBr system afforded
monobrominated product 6a as the sole product in 94% yield.
Xanthotoxin 5b was brominated in high yield without affecting
the furan or lactone group. The bromination of two alkaloid
natural products19 esermethole 5c and desoxyeseroline 5d
proceeded smoothly to afford monobrominated alkaloids 6c−d
in high yields. Sinomenine 5e was brominated in 75% yield
tolerating ketone, amino, and alkene groups. Furthermore,
B
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Letter
a
equiv of DMSO in EtOAc at 60 °C (see Supporting
Information). Under the optimized conditions, a series of
arenes were iodinated successfully (Scheme 7). The iodination
Scheme 4. DMSO/HBr for Bromination of Heteroarenes
a
Scheme 7. DMSO/NH4I for Iodination of Arenes
a
The solution of 3 (0.5 mmol), DMSO (0.6 mmol), and HBr (48%,
0.6 mmol) in EtOAc (2 mL) was stirred under air at 60 °C. Isolated
b
c
yield. With 1.5 equiv of DMSO and HBr. With 1.5 equiv of DMSO
and 2.5 equiv of HBr. With 4 equiv of DMSO and HBr.
d
Scheme 5. DMSO/HBr for Bromination of Natural
Products
a
a
The solution of arene, DMSO, NH4I (y equiv), and H2SO4 in EtOAc
b
c
d
e
was stirred under air at 60 °C. 80 °C. y = 3, 80 °C. y = 2, 80 °C. y
= 2, 80 °C, 3.5 equiv of H2SO4.
of anisole derivatives performed well to afford 7b−e in high
yields. Phenol derivatives bearing methyl 7f, 7i−l, benzyl 7g,
phenyl 7h, or iodo 7l substituents were iodinated in good to
high yields. Heteroaromatic iodides including thiophene 7m,
benzothiophene 7n, indole 7o, 7-azaindole 7p, and pyrazole 7q
were also synthesized by the present DMSO/HI system. The
gram-scale synthesis of 1-iodo-2-naphthol 7a (16.1 g) was also
achieved in 86% yield.
Notably, the mono- and dihalogenation could be efficiently
controlled by only adjusting the dosage of HX (X = Br, I) and
DMSO (Scheme 8). For example, diiodinated or dibrominated
a
The solution of 5, DMSO (1.1 equiv), and aquesous HBr in EtOAc
b
c
was stirred under air at 60 °C. With 1.1 equiv of HBr. With 3 equiv
of DMSO and HBr. With 3 equiv of HBr. With 2.2 equiv of HBr in
CHCl3/EtOAc (1:3). With 8 equiv of DMSO and HBr.
d
e
Scheme 8. DMSO/HX for Dihalogenation of Arenes
f
exposure of calix[4]arene 5f to 8 equiv of DMSO and HBr in
EtOAc afforded the desired tetrabrominated product 6f in 82%
yield. These brominations indicate that the DMSO/HBr system
is amenable to late-stage functionalization of natural products
and show high potential applications in biological evaluation.
Majetich and co-workers investigated the iodination of
arenes with HI in DMSO; however, no aryl iodides were
obtained.11a Inspired by the above bromination reaction, we
expected that if stoichiometric DMSO was used as the oxidant,
the iodination of arenes would be possible. As expected, with
1.5 equiv of HI and DMSO in EtOAc at 60 °C, the iodination
of 2-naphthol afforded 7a in 67% yield (Scheme 6).
arenes 8 were obtained in high yields with 2 equiv of HX.
Compared to the previous reports on the adjustment of mono-
and dihalogenation by the reaction time or reaction temper-
ature,6c,11 the present strategy shows higher selectivity.
According to previous research,20 [Br+DMS]Br− would be
generated in situ from DMSO and HBr.21 Based on previous
reports and our experimental results, we proposed the
mechanism of halogenations with DMSO/HX (Scheme 9).
We thought that the HX was oxidized by DMSO to X2 or
DMS·X2. The reaction of X2 or DMS·X2 with arene afforded
the aryl halides with the formation of HX which was oxidized
by DMSO for the next oxidative cycle. Thus, stoichiometric
DMSO and HX is sufficient for full conversion of the arenes.
The slow generation of X2 in situ is crucial for highly
regioselective halogenation of arenes in our strategy.
After extensively screening parameters of the reaction
conditions, we were delighted to find that the best yield was
obtained with 1.2 equiv of NH4I, 1.8 equiv of H2SO4, and 3.6
Scheme 6. Iodination of 2-Naphthol
C
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practical oxidative DMSO/HX system for the halogenation of
arenes and heteroarenes. This mild oxidative system is effective
as a versatile protocol for the synthesis of aryl halides and a
mild method for late-stage modification of natural products.
Efforts to expand this DMSO/HX system to other reactions are
continuing.
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ASSOCIATED CONTENT
* Supporting Information
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Experimental procedures, full characterization of products, and
copies of NMR spectra. The Supporting Information is
available free of charge on the ACS Publications website at
DOI: 10.1021/acs.orglett.5b00932.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jiaoning@pku.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Basic Research Program of
China (973 Program) (grant No. 2015CB856600), National
Natural Science Foundation of China (Nos. 21325206,
21172006), and National Young Top-notch Talent Support
Program are greatly appreciated. We also thank Guangxin Liang
at NKU and Yanxing Jia at PKU for natural products donation.
We thank Xiaoqiang Huang in this group for reproducing the
results of 4l, 4n, and 6a.
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(12) Ashikari, Y.; Shimizu, A.; Nokami, T.; Yoshida, J. J. Am. Chem.
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