Bromination of phenyl ether and other aromatics with bromoisobutyrate and dimethyl sulfoxide

Article abstract of DOI:10.1016/j.tetlet.2021.153375

Bromoisobutyrate has been used for the first time as a general brominating source for the direct bromination of a diverse of simple phenyl ethers. Aromatic ethers bearing various substituents could be compatible in this reaction system delivering brominated arenes in moderate to good yields. The reaction system can also be expanded to bromination of phenols and unactivated arene. This process can be regarded as an alternative for the well-established bromination systems for bromoarene synthesis.

Full text of DOI:10.1016/j.tetlet.2021.153375

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Bromination of phenyl ether and other aromatics with bromoisobutyrate
and dimethyl sulfoxide
Jia-Qin Li a, Xiao-Hui Chen a,b, Xian-Xun Wang b, Hai-Lei Cui a,
⇑
a Laboratory of Asymmetric Synthesis, Chongqing University of Arts and Sciences, Yongchuan, Chongqing 402160, PR China
b Tonichem Pharmaceutical Technology Co., Ltd, Huizhou 516008, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Bromoisobutyrate has been used for the first time as a general brominating source for the direct
bromination of a diverse of simple phenyl ethers. Aromatic ethers bearing various substituents could
be compatible in this reaction system delivering brominated arenes in moderate to good yields. The reac-
tion system can also be expanded to bromination of phenols and unactivated arene. This process can be
regarded as an alternative for the well-established bromination systems for bromoarene synthesis.
Ó 2021 Elsevier Ltd. All rights reserved.
Received 13 July 2021
Revised 23 August 2021
Accepted 25 August 2021
Available online xxxx
Keywords:
Bromination
Phenyl ether
Bromoisobutyrate
DMSO
Bromoarene
Bromoarenes are common units appearing in a large number of
natural products, pharmaceuticals and agrochemicals of great
interest as core structures [1]. Brominated aromatics are also
important synthetically useful building blocks and starting materi-
als in the construction of structurally complex molecules and phar-
maceutically important compounds [2]. Therefore, a great number
of brominating reagents and reaction systems have been devel-
oped efficiently in this regard [3].
From the view of green and sustainable chemistry, the develop-
ment of safe, environmentally friendly methodologies for bromina-
tion is an urgent task. To avoid the use of hazard, toxic and harmful
reagent such as Br2, a series of efficient brominating reagents and
convenient reaction systems have been established. Bromoamide
derivatives such as NBS are widely used brominating reagents for
the synthesis of aromatic bromides [4]. Besides, NBS can also be
utilized together with a series of activators such as Lewis acids,
Bronsted acids, Lewis bases and oxidants to realize bromination
of different arenes [5]. Other Br-containing chemicals such as
HBr [6], CBr4 [7] and bromine salts [8] etc [9] have also been
employed frequently as brominating reagents accompanying with
activators, or under special reaction conditions.
operation [10]. DMSO can be used not only as activator of bromine
source, but also as solvent, oxidant and carbon source for a diverse
of reaction systems [11].
For example, as a pioneering work in this research field, Fletcher
and Pan have realized a N-monoalkylation and aryl bromination of
aromatic amines using the combination of ethyl bromide and
DMSO in 1956 [11a]; Megyeri et al have achieved the C-5 bromina-
tion of indole alkaloids utilizing HBr/DMSO as brominating reagent
[11b]; Majetich and co-workers have developed an electrophilic
aromatic bromination with the in situ generated bromodimethyl-
sulfonium bromide from HBr and DMSO [11c]; The Dai group have
brominated aromatic amines and pyrroles with HBr/DMSO [11d];
Jiao et al have reached the bromination of a series of important are-
nes and heteroarenes such as phenols, phenyl ethers, indoles, pyra-
zoles etc. using only 1.1 or 2.2 equivalents of HBr/DMSO in EtOAc
[11e]. These reaction systems can be regarded as attractive alterna-
tives for the well-developed brominating systems.
Very recently, we have developed an efficient formylation and
bromination of pyrroloisoquinolines utilizing ethyl bromoisobu-
tyrate and dimethyl sulfoxide as formylating reagent as well as
brominating reagent (Eq. (6), Scheme 1). During the study, it was
found that when pyrroloisoquinolines without methoxy groups
were treated under the reaction system, bromination occurred
instead of formylation at C-2 position of the pyrrole ring [12a].
What’s more, a formylation/aromatization/bromination cascade
product was obtained unexpectedly in the case of a substrate bear-
ing dimethoxyphenyl group. Bromination occurred at the
The combination of bromide and dimethyl sulfoxide as formy-
lating reagents and brominating reagents has attracted increasing
attention owing to its efficiency, safety, less pollution and easy
⇑
Corresponding author.
E-mail address: cuihailei616@163.com (H.-L. Cui).
https://doi.org/10.1016/j.tetlet.2021.153375
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: Jia-Qin Li, Xiao-Hui Chen, Xian-Xun Wang et al., Bromination of phenyl ether and other aromatics with bromoisobutyrate and
dimethyl sulfoxide, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2021.153375

Jia-Qin Li, Xiao-Hui Chen, Xian-Xun Wang et al.
Tetrahedron Letters xxx (xxxx) xxx
Scheme 1. Bromination of aromatics based on transformation of DMSO and
bromide and our previous work.
Scheme 2. Bromination of phenyl ethers. a Reaction conditions: 1 (0.4 mmol), 2 (5
equiv), and DABCO (1 equiv) in DMSO (2.0) mL at 130 oC. b Isolated yields. c The
yields were determined by 1H NMR using CH2Br2 as internal standard. d Based on
the recovery of starting material. e Not detected.
electron-rich dimethoxyphenyl ring. A reasonable explanation for
this phenomenon is that the dimethoxy groups act as activating
group for electrophilic bromination. At the same time, we have
reached a mild NBS-mediated construction of 9-bromo-6,11-dihy-
dro-5H-indolizino[8,7–b]indole derivatives through a cyclization/
bromination cascade (Eq. (7)) [12b]. Encouraged by these results,
we envisioned that electron-rich phenyl ethers can be brominated
by the treatment of bromoisobutyrate and dimethyl sulfoxide
affording synthetically useful aromatic bromide [13]. Herein, we
report our development of a convenient bromination of phenyl
ethers and other aromatics using bromoisobutyrate and dimethyl
sulfoxide as brominating reagents.
As shown in Scheme 2, trimethoxybenzenes can be easily
brominated giving compounds 3a-3d (65%–80% yields) [14]. Good
yields were observed in these cases. Alkyl groups such as methyl
and ethyl groups could be introduced into methoxyarenes success-
fully yielding compounds 3e-3g (46%–69% yields). Unfortunately,
the presence of amide at the phenyl ring resulted in the decompo-
sition of starting material (3h). Incorporation of Cl under the cur-
rent system was achieved leading to the formation of compound
3i in 73% yield. Cyano group has a negative effect for this reaction
as no product can be obtained in this case (3j). Compounds 3k and
3l possessing carbonyl group can be produced readily under the
reaction system in 60% and 33% yield respectively. Disappointingly,
3,5-dimethoxybenzoic acid was not suitable substrate for this reac-
tion (3m). Pleasingly, a chiral acid can be brominated successfully
leading to the formation of compound 3n. A scaled-up reaction
(1.8 mmol) was also successful giving chiral acid 3n in 80% yield.
The use of 1-methoxynaphthalene and 2-methoxynaphthalene
resulted in production of corresponding bromoarenes 3o and 3p
in 99% and 52% yield respectively. Dibrominated products can be
detected by HRMS in some cases with relatively lower monobromi-
nation yields such as 3c and 3e, but no pure products could be
isolated.
We wondered whether this brominating system can be used for
the bromination of other aromatics such as phenol and unactivated
arene. As shown in Scheme 3, attempts of other aromatics have
2

Jia-Qin Li, Xiao-Hui Chen, Xian-Xun Wang et al.
Tetrahedron Letters xxx (xxxx) xxx
tion. Ethyl 2-hydroxy-2-methylpropanoate can be observed by
crude 1H NMR, providing evidence for our proposal on reaction
mechanism. The role of DABCO might be to facilitate the proton
transfer in this process and to neutralize the reaction system
preventing further side reactions of product 3 [15].
In conclusion, we have developed an efficient bromination of
phenyl ethers with bromoisobutyrate and dimethyl sulfoxide as
brominating reagent. To the best of our knowledge, it is the first
time that bromoisobutyrate has been used as a general brominat-
ing source for the bromination of a diverse of simple electron-rich
aromatic ethers. The current reaction system could also be
expanded to bromination of other aromatics such as phenol and
unactivated arene. In this process, DMSO acts as the solvent as well
as activator of bromoisobutyrate and an oxidant. This process can
be regarded as an alternative way for the well-developed bromina-
tion systems of arenes.
Scheme 3. Expansion of the substrate scope to other aromatics.
been conducted. No product 5a was detected in the case using
trimethoxyphenol due to decomposition. Bromination of 2-naph-
thol can be achieved giving compound 5b in 65% yield. 9-bromoan-
thracene 5c can be obtained under the current reaction system in
80% yield.
Brominated arenes are useful synthetic intermediates for com-
plex molecules construction and starting material for
organometallic reagent synthesis. To show the potent application
of the obtained bromides, transformation of 3n has been carried
out (Scheme 4). Treatment of compound 3n with BnNH2 and EDCI
gave chiral amide 6 in 59% yield.
On the basis of our results and previous studies [11,12], a
plausible mechanism has been proposed as shown in Scheme 5.
Nucleophilic attack of DMSO to ethyl bromoisobutyrate 2 would
lead to the formation of intermediate A, which would then react
with bromine ion to give intermediate B. Molecular bromine can
be generated by attack of bromine ion to intermediate B. Bromi-
nation of 1a can be finally realized by electrophilic addition of
molecular bromine with trimethoxybenzene 3a and rearomatiza-
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
We are grateful for the support provided for this study by the
National Natural Science Foundation of China (21871035,
21502013) and Chongqing Research Program of Basic science and
Frontier Technology (cstc2019jcyj-msxm2653).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153375.
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descreased yield (45%, 2 h).
2 (2.5 equiv) gave
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54% yield.
4