Regioselective bromination of arenes mediated by triphosgene-oxidized bromide

Article abstract of DOI:10.1016/j.tet.2019.130539

This article first time describes triphosgene (BTC) as an oxidant while the non-toxic and easy-to-handle potassium bromide (KBr) as the source of bromine to the bromination reaction of aromatic substrates. The novel brominating protocol gives excellent para-regioselectivity of the alkoxyl/hydroxyl arenes and high yield, offering good potential of commercial scale applications. The mechanism of “Triphosgene oxidize bromide” was proposed.

Full text of DOI:10.1016/j.tet.2019.130539

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Regioselective bromination of arenes mediated by triphosgene-oxidized bromide
Yingzhou Xu, Dufen Hu, Hui Zheng, David Mei, Zhaobo Gao
PII:
S0040-4020(19)30872-5
https://doi.org/10.1016/j.tet.2019.130539
TET 130539
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 14 June 2019
Revised Date: 17 August 2019
Accepted Date: 20 August 2019
Please cite this article as: Xu Y, Hu D, Zheng H, Mei D, Gao Z, Regioselective bromination of
arenes mediated by triphosgene-oxidized bromide, Tetrahedron (2019), doi: https://doi.org/10.1016/
j.tet.2019.130539.
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Graphical Abstract
Regioselective bromination of arenes mediated by
triphosgene-oxidized bromide
This article first time describes triphosgene (BTC) as an oxidant
while the non-toxic and easy-to-handle potassium bromide
(KBr) as the source of bromine to the bromination reaction of
aromatic substrates. The novel brominating protocol gives
excellent para-regioselectivity of the alkoxyl / hydroxyl arenes
and high yield, offering good potential of commercial scale
applications. The mechanism of “Triphosgene oxidize bromide”
was proposed.
a
a
a
a
a*
Yingzhou Xu , Dufen Hu , Hui Zheng , David Mei , Zhaobo Gao
a
Zhejiang Jiuzhou Pharmaceutical Co. Ltd, Waisha Road 99, Taizhou City, 318000,
China

Tetrahedron
journal homepage: www.elsevier.com
Regioselective bromination of arenes mediated by triphosgene-oxidized bromide
a
a
a
a
a*
Yingzhou Xu , Dufen Hu , Hui Zheng , David Mei , Zhaobo Gao
a
Zhejiang Jiuzhou Pharmaceutical Co. Ltd, Waisha Road 99, Taizhou City, 318000, China
Cell: 15858666966 Office: +86-576-8827632
E-mail: zhaobo.gao@jiuzhoupharma.com
ARTICLE INFO
ABSTRACT
This article first time describes triphosgene (BTC) as an oxidant while the non-toxic and easy-to-
handle potassium bromide (KBr) as the source of bromine to the bromination reaction of aromatic
substrates. The novel brominating protocol gives excellent para-regioselectivity of the alkoxyl /
hydroxyl arenes and high yield, offering good potential of commercial scale applications. The
mechanism of “Triphosgene oxidize bromide” was proposed.
Keywords:
Triphosgene
Oxidizing agent
Potassium bromide
Regioselectivity
1
. Introduction
Aryl bromides are high-valued fundamental building blocks in
Bis(trichloromethyl) carbonate (triphosgene, also known as
BTC) was first developed by Eckert as “green phosgene”.
Attributed to its stable crystalline solid physical properties, BTC
is safer and more convenient to handle, transport and store for
commercial production purpose, which has been proved to be a
useful substitute for phosgene in a variety of synthetic
applications (e.g. chloroformylation, chlorination, carboxylation
and dehydration reactions). Yet to date, among the numerous
reported research on BTC, employing BTC as an oxidizing agent
with good performance and excellent properties remains a huge
agrochemical, pharmaceutical and material synthesis. With the
advancement of transition metal catalysis, the synthetic value of
aryl bromides as versatile coupling partners has been well-
recognized. Nevertheless, compared to the extensive research on
the coupling transformations of aryl bromides, the practical
synthesis of this feedstock chemical remains several unexplored.
Electrophilic bromination of arenes is one of the fundamental
transformations in these constructions of the C–Br bond.
Unfortunately, traditional procedures of bromination usually
involve the use of elemental bromine under harsh reaction
conditions. Owing to its toxic nature, the use of elemental
bromine is not only troublesome and environmentally hazardous,
but also needs cautious control of the addition rate or temperature
to avoid undesirable side reactions. The industry applications of
transition metal catalyzed coupling reactions have raised an
urgent need for more economical and ecological synthesises of
aryl bromides.
10-15
challenge.
O
1-3
O
BTC / ethyl acetate
TBAB / KBr
r. t 19 h
Br
Yield:99%
Scheme 1. Efficient synthesis routes for 1-bromo-4-
methoxybenzene.
To bridge this gap of knowledge, we report herein a new
protocol using BTC as an oxidizing agent. BTC is added to the
mixture of potassium bromide (KBr) and aromatic substrate in
the presence of catalyzed amount of tetrabutylammonium
bromide (TBAB) then stir until the end of the reaction (Scheme
Therefore, a series of elemental bromine-free protocols have
been developed. One alternative method utilizes solid organic
ammonium tribromides such as 2,4-diamino-1,3-thiazole
4a
4b
hydrotribromide, Me NBr , 1,8-diazabicyclo[5.4.0]undec-7-
4
3
4
c
4d, 4e
ene hydrobromide perbromide (DBUHBr3), Bu NBr ,
phenyltrimethylammonium
dipyridiniumditribromide-ethane (DPTBE) and PyHBr ,
4
3
4e
tribromide,
1,2-
4
f
4e, 4g, 4h
.
3
1
). The reaction of anisole as the exemplified compound gives
Another method involves in situ generation of bromine via
5
-9
almost quantitative yield. With the experimental conditions
established, we proceeded to evaluate more aromatic substrates
with different functional groups to expand the scope of this
method. Furthermore, most of these aromatic substrates are a
fragment of some common drugs. Meanwhile, the plausible
reaction mechanism of the “Triphosgene oxidize bromide” is
proposed. It is noteworthy that the method performed in a
regioselective manner, affording mono- and para- brominating
products.
bromic salt oxidation.
In this regard, it requires these
5a-5c
combinations of oxidants and bromides such as H O -HBr,
t-
2
2
5b, 5c
5d
BuOOH-HBr,
H O -V O -Et NBr,
oxone (potassium
2
2
2
5
4
6
a
6b
peroxymonosulfate, KHSO5)
/
NaBr,
oxone
/
HBr,
2
KHSO •KHSO •K SO , cerium (IV) ammonium nitrate (CAN) /
5
4
2
4
7
8
9
KBr, CAN / LiBr, NaBrO -NaBr and Selectfluor / KBr .
3
However, the industrial applications were hindered by the
inherent explosive nature of the reported oxidants.

2
Tetrahedron
2
. Results and discussion
BTC results in a decrease of product yield (entries 4, 7, 8, 9, 10,
1, 15). To have the optimal yield, the equivalent of BTC
1
To find the best conditions for these reactions, the
between 1.1 and 1.3 would be the best choice. In addition, even
though the reaction time was prolonged, product could not be
detected in the system without BTC or TBAB during the reaction
process (entries 12 and 15). This shows that BTC and TBAB play
critical roles in the reaction. Interestingly, products could be still
detected in the system of TBAB with high yields (entries 13 and
bromination reaction of anisole 1a was studied using different
ratios of BTC, TBAB and KBr in ethyl acetate at room
temperature (Table 1). The best molar ratio of BTC / BTAB /
KBr was 1.3:0.5:1.1 (Table 1, entry 6). All compounds of molar
equivalent ratios are calculated according to the molar equivalent
of anisole. When decreasing KBr from 1.9 to 1.1 (entries 1-6),
the product yield has no obvious change. Reducing the amount of
1
4), suggesting that TBAB may serve as a bromine source.
Table 1. Optimization of reaction conditions.
a
b
Entry
BTC (equivalent)
TBAB (equivalent)
KBr (equivalent)
Yield (%)
1
2
3
4
5
6
7
8
9
1.3
1.3
1.3
1.3
1.3
1.3
1.1
0.90
0.90
0.60
0.30
1.3
1.3
1.3
0
0.10
0.10
0.30
0.50
0.50
0.50
0.50
0.50
0.10
0.10
0.10
0
1.5
1.9
1.5
1.5
1.3
1.1
1.5
1.5
1.1
1.1
1.1
1.5
0
93
94
95
100
100
100
98
92
89
86
67
0
1
1
1
1
1
1
0
1
2
3
4
5
2.0
91
89
0
1.1
0
0.10
1.5
a
Anisole, TBAB and BTC in the system of ethyl acetate and water at room temperature for 19 h.
Yields refer to HPLC analysis.
b
Under the optimized reaction conditions (Table 1), the
substrate scope was further explored (Table 2). It is proved that
these aromatic substrates 1a-1r with different alkoxyl or
hydroxyl groups, including methoxy groups (Table 2, entries 1-2,
85% yields, respectively. 4-Brominated products 2l, 2m were
efficiently synthesized in excellent yields from 1,3-
dimethoxybenzene 1l and 1,2-dimethoxybenzene 1m respectively
(entries 12 and 13). These reactions with 2-methoxy-1,1'-
biphenyl 1p and (benzyloxy)benzene 1q gave para-position
products 2p and 2q exclusively (entries 16 and 17). 4-Bromo-
2,6-diisopropylphenol 2r was observed in excellent yield from
phenol grafting two isopropyl groups at the ortho-position (entry
18).17 It’s worth mentioning that only 4-brominated products 2a,
2b, 2p, 2q and 2r were obtained in these crude reaction mixtures,
and no di- or tri-brominated products were detected. Few tri-
brominated product 4c was detected by LC-MS analysis of the
crude reaction mixtures. In all of the above cases, these ratios of
desired brominated products were more than 95% in the obtained
products. Based on above result, it is suggested that para-
regioselectivity is observed for the bromination of the alkoxyl /
hydroxyl arenes and the chemo-selective property may open up
8
, 12-13, 16), ethoxy group (entry 9), ether (entry 17) and
hydroxyl groups (entries 3-7, 10-11, 14-15, 18), all worked well
to furnish the para-brominated products 2a-2r in excellent
yields.16 In parallel with anisole 1a and phenol 1c, naphthalen-1-
ol 1d and 1-methoxynaphthalene 1b were para-brominated at 4-
position to give products 2a, 2c, 2d and 2b (entries 1-4). While
naphthalen-2-ol 1e was brominated at ortho-position providing 1-
bromonaphthol 2e in >90% yield (entry 5). Phenol 1f, 1g, 1h, 1i,
1
j, 1o bearing a functional group (methyl, chloro, methoxy,
ethoxy, hydroxyl, or phenyl group) at the ortho-position could
also be brominated, providing expected para-brominated products
2
f, 2g, 2h, 2i, 2j, 2o exclusively, as evidenced by the 1H NMR
spectroscopic analysis of these crude reaction mixtures, in >80%
yield (entries 6-10 and 15). Phenol 1k and 3-fluorophenol 1n
with the hydroxyl group or fluoro group at meta-position (entries
16, 18
more opportunities for long steps of total synthesis,
but also
have extensive application opportunities in multiple industry
fields.
1
1 and 14) were also competent substrates in this transformation,
and 4-brominated products 2k and 2n were afforded in 84% and
Table 2. Different substrates evaluated in bromination reactions.
a
b
Entry
1
Substrate
BTC (equivalent)
Product
By-product
Isolated yield (%)
Ratio (%)
1.3
---
99%
2a = 100

2
3
1.3
1.3
---
65%
96%
2b = 100
2
c : 3c : 4c = 99.74 : 0.23 :
0
.03
4
5
6
1.3
1.3
1.3
89%
94%
98%
2d : 3d = 96.23 : 3.77
2e : 3e = 96.3 : 3.7
2f : 3f = 98.5 : 1.5
7
8
9
1.3
1.35
1.3
92%
89%
95%
88%
84%
2g : 3g = 97 : 3
2h : 3h = 99.88 : 0.12
2i : 3i = 99.74 :0.26
2j : 3j = 96.4 :3.6
1
0
1
1.0
1
1.3
2k : 3k = 97.5 : 2.5
1
1
2
3
1.3
1.3
96%
94%
2l : 3l = 99.24 : 0.76
2m : 3m = 98.91 : 1.09
1
1
4
5
1.3
1.3
85%
94%
2n : 3n = 97.16 : 2.84
2o : 3o = 98.3 : 1.7
1
1
6
7
1.3
1.3
---
---
99%
96%
2p = 100
2q = 100

4
Tetrahedron
1
8
1.3
---
99%
2r = 100
a
A substrate, TBAB and BTC in the system of ethyl acetate and water at room temperature for 19 h.
Yields refer to HPLC analysis.
b
The above experimental evidence points out the plausible
mechanism outlined in Scheme 2.
O
Cl
Cl
Bu N
4
KBr
O
Cl
Br
Cl
A
K
Bu N
4
Br
O
O
Cl
O
Br-
Cl
O-
Br
Cl
Cl
Cl
O
Cl
Cl
Cl
B
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
O
O
Cl
O
O
C
Cl
Cl
Cl
O
CO
+
Cl
Cl
O
Cl
Br
O
O
Br
1a
Scheme 2. Plausible mechanism of the reaction.
The bromide ion, under the reaction condition, is a strong
nucleophile that attacks the carbonyl carbon of triphosgene
giving diphosgene and phosgene. In turn, diphosgene reacts with
bromide ion to give two molecules of phosgene (Scheme 2).
Owing to the nucleophilicity for bromine ion of TBAB exceeded
that of the phosgene, the bromide ion from potassium bromide by
+
the phase transfer catalyst Bu N attacking phosgene initially
4
19
generates intermediate A. Due to the instability of the
negatively charged body, the intermediate A was added at the
19
carbon of phosgene to provide intermediate B. Meanwhile,
intermediate B is converted into a more stable intermediate C by
extruding a chloride ion. Then compound 1a and intermediate C
obtain desired product 1-bromo-4-methoxybenzene by a Friedel-
Crafts pathway with releasing a CO, a chloride ion and one
equivalent phosgene. The key breakdown pathway of
intermediate C is shown in arrows. Phosgene / BTC actually acts
as an oxidant with the driving force by breakdown of
intermediate C in the process, which has not previously been
reported. Based on above data (Table 1, entries 12 and 15), it is
demonstrated that product could not be detected in the system
without BTC or TBAB. Meanwhile, the existence of CO is
proved by the alarm of CO detector. The amount of the releasing
CO was detected and shown in Figure 1. From Figure 1, it could
be clearly observed that the amount of CO is increasing with the
addition of BTC. In addition, the brilliant mono- and para-
regioselectivity indicate that there is a reaction intermediate with
much more sterict hindrance than elemental bromine. As far as
we know, only intermediate C could match well with all the
profiles of the theoretical reaction intermediate in view of all the
factors.
Figure 1. Experiment of the anisole with adding the amount of
triphosgene and releasing the amount of carbon monoxide.
3
. Experimental section
General methods
Reactions were monitored using Thin Layer Chromatography
(
TLC) using aluminium-backed Silica-Gel 60 F254 plates.
Column chromatography was performed using Silica-Gel 60
Merck). All chromatography was carried out using
(
a
combination of n-hexane and ethyl acetate as an eluent.
Preparative TLC was performed using Silica-Gel 60 HF254+366.
NMR spectra were recorded using a Bruker and Varian 400 MHz
1
13
NMR instrument ( H NMR at 400 MHz, C NMR at 100 MHz)
in CDCl . All chemical shifts are reported in ppm and J values
3
are quoted in Hz.
4
. Conclusion
A novel bromination method by BTC / KBr / TBAB was
reported, which provided
a good potential protocol for

Tetrahedron Lett. 1998, 39, 6349-6350; (c) Barhate, N. B.; Gajare, A. S.;
Wakharkar, R. D. and Bedekar, A. V. Tetrahedron 1999, 55, 11127-
commercial scale applications. BTC acts as an oxidizing agent to
convert KBr into a highly regioselective agent with excellent
yield. The mechanism of “Triphosgene oxidize bromide” was
proposed. We believe that the novel regioselective bromination
method will be a promising method for the bromination of
aromatic compounds in pharmaceutical chemistry field. Further
research of aromatic bromination into alkene substrates is
currently ongoing.
1
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgments
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These investigations were supported by Zhejiang Jiuzhou
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5

Highlight
1
2
3
. The novel brominating protocol gives excellent para-regioselectivity of the
alkoxyl / hydroxyl arenes and high yield.
. The triphosgene shows good oxidation properties in the method. And Potassium
bromide (KBr) provides a good bromine source in bromination reaction.
. The method has good industrial application prospect.