Mild and Regioselective Bromination of Phenols with TMSBr

Article abstract of DOI:10.1002/ejoc.201900794

In this work, an unexpected promoting effect of by-product thioether was observed, leading to a mild and regioselective bromination of phenols with TMSBr. This method can tolerate a series of functional groups such as the reactive methoxyl, amide, fluoro, chloro, bromo, aldehyde, ketone and ester groups, and has the potential to recycle the by-product thioether and isolate the desired product under column chromatography-free conditions. Mechanism studies revealed that O–H···S hydrogen bond may be formed between phenol and by-product thioether. Possibly owing to the steric hindrance effect from by-product thioether, the electrophilic bromination at para-position of phenols is much favorable.

Full text of DOI:10.1002/ejoc.201900794

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Accepted Article
Title: Mild and Regioselective Bromination of Phenols with TMSBr
Authors: Xiantao Ma, Jing Yu, Mengyuan Jiang, Mengyu Wang, Lin
Tang, Mengmeng Wei, and Qiuju Zhou
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900794
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900794
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10.1002/ejoc.201900794
European Journal of Organic Chemistry
COMMUNICATION
Mild and Regioselective Bromination of Phenols with TMSBr
Xiantao Ma,*[a] Jing Yu,[a] Mengyuan Jiang,[a] Mengyu Wang,[a] Lin Tang,*[a] Mengmeng Wei,[a] and
Qiuju Zhou*[a]
Abstract: In this work, an unexpected promoting effect of byproduct
thioether was observed, leading to a mild and regioselective
bromination of phenols with TMSBr. This method can tolerate a
series of functional groups such as the reactive methoxyl, amide,
fluoro, chloro, bromo, aldehyde, ketone and ester groups, and has
the potential to recycle the byproduct thioether and isolate the
desired product under column chromatography-free conditions.
Mechanism studies revealed that O-H…S hydrogen bond may be
formed between phenol and byproduct thioether. Possibly owing to
the steric hindrance effect from byproduct thioether, the electrophilic
bromination at para-position of phenols is much favorable.
YBr/DMSO was generally disposed as toxic and smelly waste.
With our continuous interest in regioselective halogenation[8] and
hydrogen chemistry,[9] herein, we wish to report a mild and
regioselective bromination of phenols with TMSBr (Scheme 1C).
The desired para-brominated phenols could be obtained in high
selectivity (up to 99/1) by using sulfoxides bearing sterically
hindered substituents. Mechanism studies suggested that the
high regioselectivity of the reaction may be ascribed to the weak
interaction between byproduct thioether and phenol via O-H…S
hydrogen bond. Notably, this new method has the potential to
recycle the byproduct thioether and isolate the desired product
under column chromatography-free conditions.
Introduction
Owing to the unique bioactivity of phenol motifs, the
functionalization of phenols has received much attention in the
past.[1] Halogenated phenols, which are frequently used to the
late-stage functionalization of natural products or other complex
molecules,[1] are traditionally obtained by electrophilic aromatic
substitution (EAS) of phenols with hazardous, toxic, and
corrosive X2 (X = Cl, Br, I).[2] However, drawbacks of low
regioselectivity, poor functional group tolerance and
overhalogenations are frequently suffered (Scheme 1A). Then
NXS, YX/oxidant (X = Cl, Br, I; Y = H, TMS, Na etc.) and the
analogues were developed as more preferable electrophilic
halogenating reagents.[3-4] Among them, the use of readily
available YBr/DMSO (Y = H, TMS) for the selective bromination
of phenols seems much attractive, since only a molecule of
dimethyl sulfide is liberated as byproduct (Scheme 1B). Recently,
the reactant ratios, the reaction solvents and the bromo
surrogates were carefully investigated to improve the reaction
yield and selectivity. For example, by careful investigation on the
dosage of DMSO, Jiao and coworkers reported a selective
bromination of phenols with HBr/DMSO at 60 oC;[5] Togni and
coworkers developed a much milder bromination of phenols with
TMSBr/DMSO at room temperature (as to phenol, p/o = 88/12).[6]
However, obtaining high selectivity at para-position of phenols
remains challenging, due to the negligibly electronic differences
between para- position and ortho-position of phenols. Therefore,
further development of a mild and regioselective bromination of
phenols is still highly desired.
Scheme 1. Regioselective bromination of phenols.
Results and Discussion
The reaction of phenol (1a) and bromotrimethylsilane (2a) at
room temperature was firstly screened with various sulfoxide
surrogates 3 (Table 1, runs 1-7). When dimethyl sulfoxide was
employed as the surrogate, the target 4a and byproduct 5a were
obtained in a ratio of 88/12 (run 1). Then other alkyl sulfoxides
such as dipropyl-, dibutyl-, dibenzyl- sulfoxide were screened to
improve the reaction selectivity (runs 2-4). As shown in table 1,
as the carbon chain of sulfoxide grows, the selectivity of 4a/5a
becomes much higher, revealing the steric hindrance effect of
carbon chain on sulfoxide may account for the high
regioselectivity of the reaction (vide infra). However, some
unidentified byproducts were also detected, and the desired 4a
could be obtained only in moderate yields. Then diphenyl-, di-4-
chlorophenyl- and di-4-tolyl- sulfoxide were further screened
(runs 5-7),[10] to our delight, the reaction with di-4-chlorophenyl
sulfoxide gives the target 4a in highest 90% yield with the
highest selectivity of 97/3 (run 6). Bromo surrogates were then
screened. The reaction with HBr is rather slugglish and the
selectivity of 4a/5a is 92/8 (run 8). The combination of HBr with
sulfoxide was generally supposed as the equivalent to Br2.[5,11]
Despite the wide applications of byproducts as a catalyst,
additive, or reagent in tandem reactions,[7] byproduct dimethyl
sulfide generated from the oxidative bromination reaction of
[a]
Dr, X. Ma, Miss J. Yu, M. Jiang, M. Wang, Dr. L. Tang, Miss M. Wei
and Dr. Miss Q. Zhou
College of Chemistry and Chemical Engineering, ,
Xinyang Normal University
Xinyang, Henan 464000, China.
E-mail: xiantaoma@126.com; http://cce.xynu.edu.cn/jsdw/2542.htm;
lintang@xynu.edu.cn; http://cce.xynu.edu.cn/jsdw/849.htm
zhouqiuju@iccas.ac.cn; http://cce.xynu.edu.cn/jsdw/2525.htm
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201900794
European Journal of Organic Chemistry
COMMUNICATION
Likewise, the reaction with liquid bromine under standard
conditions also gave a complex mixture with low selectivity (run
9). These experimental results may suggest that TMSBr is an
indispensable bromo surrogate for this mild and highly
regioselective bromination method and that a new reaction
mechanism may be involved (vide infra). Finally, the reaction
solvents and temperatures were then screened to get better
reaction selectivity, but no better yields and selectivities could be
obtained (runs 10-13).
reaction of anisole using DMSO as the sulfoxide surrogate
instead of 3f, the target 4s was obtained in comparable yields
with the same selectivity (run 20). Likewise, when the present
method was extended to bromination of toluene, only a mixture
of para- and ortho-bromotoluene was obtained (run 21). These
experimental results revealed that the method is much suitable
for phenols and the reaction mechanism of anisole or toluene
may be different from that of phenols (vide infra).
Table 1. Optimization of the reaction conditions[a]
Table 2. Mild and regioselective bromination of phenols with
TMSBr[a,b]
run
1
2
3
4
5
6
7
8
2
3: R
solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
4a%[b] 4a/5a[c]
2a: TMSBr
2a: TMSBr
2a: TMSBr
2a: TMSBr
2a: TMSBr
2a: TMSBr
2a: TMSBr
2b: HBr
3a: Me
65
78
75
70
90
90
90
35
72
65
88/12
92/8
94/6
97/3
96/4
97/3
96/4
92/8
87/13[d]
89/11
90/10
92/8
3b: n-Pr
3c: n-Bu
3d: Bn
3e: Ph
3f: 4-ClC6H4
3g: 4-MeC6H4 MeCN
3f: 4-ClC6H4
3f: 4-ClC6H4
3f: 4-ClC6H4
3f: 4-ClC6H4
3f: 4-ClC6H4
3f: 4-ClC6H4
MeCN
MeCN
THF
Toluene 75
CHCl3
MeCN
9
2c: Br2
10
11
12
2a: TMSBr
2a: TMSBr
2a: TMSBr
78
80
13[e] 2a: TMSBr
[a]
97/3
Unless otherwise noted, the mixture of 1a (0.50 mmol), 2 (0.55 mmol),
sulfoxide (0.55 mmol), in a solvent (1.0 mL) was sealed under N2 in a Schlenk
tube, stirred at 25 oC for 6 h, and monitored by TLC and/or GC-MS. [b] isolated
yield based on 1a. [c] determined by GC-MS. [d] overbromination was observed.
[e] 0 oC.
With the optimized conditions (Table 1, run 6) in hand, we next
explored the scope of this mild and regioselective bromination
method. As shown in Table 2, this method can tolerate a series
of functional groups such as the reactive methoxyl, amide, fluoro,
chloro, bromo, aldehyde, ketone, carboxyl and ester groups
(Table 2, runs 5-13). Similar to the model reaction (run 1), ortho
or meta-substituted of phenols bearing electron-donating or
electron-withdrawing substituent on the phenyl ring gave
moderate to high yields of the para-brominated products with
high selectivities (runs 1-3, 5-13). As to para-substituted phenols,
the ortho-brominated products were obtained in good yields with
high selectivities (runs 4, 14-15). The method can also be
applied to 1-naphthol or 2-naphthol, affording the desired
products with exclusive selectivity (runs 16-17). However,
possibly owing to the inefficient generation of reaction
intermediates with TMSX (X = Cl, I), the present method is not
suitable for the synthesis of chlorinated or iodinated phenols
even at high reaction temperatures (runs 18-19). [12] The reaction
with anisole is sluggish under standard conditions, but by
increasing the reaction temperature to 60 oC, the target 4s could
be obtained in 63% yield (run 20). Possibly owing to the high
reactivity of hydroxyl group over that of methoxy group, the
reaction of 1e or 1n could afford the desired product under mild
conditions with high selectivity (runs 5, 14). However, the
[a]
[b]
Unless otherwise noted, see run 6 of table 1 for details.
isolated yield
[c]
based on 1, and the ratio of 4/5 in parenthesis was determined by GC-MS.
For runs 4, 14, 15 and 17, ortho-brominated products were obtained, the
regioselectivities were listed in parenthesis.. [d] 35 oC, 12 h. [e] 0 oC. [f] TMSX (for
run 18, X = Cl; run 19, X = I ) was used instead of TMSBr. [g] 60 oC, 12 h. [h]
DMSO 3a (1.1 equiv.) was used instead of 3f.
Taking advantage of the less dissolubility of byproduct di-4-
chlorophenyl thioether (6f) in acetonitrile and the acidic
character of phenol, the potential to recycle byproduct thioether
6f and isolate the desired product 4a under column
chromatography-free conditions is anticipated. A 5 mmol scale
reaction of 1a and 2a could afford the target product 4a in 85%
yield (0.735 g, >95% purity) only by simple filtration and
extraction.[13] Meanwhile, the byproduct 6f could be easily
recycled in >95% yield, followed by readily oxidized to sulfoxide
3f,[14] thus entering into the next reaction cycle (eq. 1).[13]
Control experiments were then carried out to understand the
reaction mechanism. As shown in eq. 2, an additive (Mg or
styrene) that could quench the possible Br2 generated from the
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10.1002/ejoc.201900794
European Journal of Organic Chemistry
COMMUNICATION
reaction of TMSBr and sulfoxide was then added to the model
reaction of 1a and 2a under standard conditions, instantly, only
trace to low yield of target 4a was obtained, suggesting the
possible generation of Br2. However, the reactions with HBr or
Br2 only give poor selectivities (Table 1, runs 8-9). These results
revealed that this new reaction may not just follow a typical EAS
mechanism.
(Table 2, runs 20-21).[13] Therefore, the high regioselectivity of
this new method may be ascribed to the temporary steric
hindrance effect from byproduct.
Based on these experimental results and the literature
reports,[5,11,15] the possible reaction pathway for this mild and
regioselective bromination of phenols is depicted in scheme 2.[19]
Sulfoxide
3 is initially activated by TMSBr 2a, affording
bromosulfonium bromide 8, which might be coexisted with 9 in
an equilibrium.[11,15] Then the reaction might follow two pathways,
i.e., the direct EAS of phenol with bromosulfonium bromide 8
leads to the target product 4 (Scheme 2, path a) or a temporary
steric hindrance effect from byproduct leading to regioselective
bromination of phenols, affords the target 4. Owing to that the
selectivity of 4a/5a in model reaction is 97/3, but not high to
>99/1, both two pathways might be involved in the reaction
(paths a and b), however, a selective bromination of phenols
through intermediate 10 by temporary steric hindrance effect
from byproduct thioether via O-H…S hydrogen bond may be the
major path (path b). Besides, as to anisole or toluene, since no
hydrogen bonds could be formed with thioether, the reaction
may mainly follow path a, therefore, an inferior selectivity is
obtained (Table 2, runs 20-21).
It is well documented that sulfoxide is initially reacted with 2a,
giving
a bromosulfonium bromide which may be further
transformed to byproduct thioether and Br2 (vide infra),[5,15]
therefore, sulfoxide may not directly involved in the electrophilic
bromination process. These controversial phenomena prompted
us to investigate the possible roles of byproduct thioether. As
shown in eq. 3, the reaction of 1a and Br2 in the blank reaction
afforded a mixture of para-, ortho- and over-brominated phenols
in a ratio of 68.5/4.4/27.1 by means of GC-MS (Table 3, run 1);
In contrast, the reactions with thioether gives the target 4a in
high selectivitities and the reaction with 6f bearing longest
carbon chain gives the target 4a in highest selectivity (Table 3,
runs. 2-3).[13,16] These experimental results suggested that the
steric hindrance effect from byproduct thioether may affect the
selectivity of the electrophilic bromination process.
Scheme 2. Possible reaction pathway
Conclusion
Table 3. Investigation on the roles of byproduct thioether[a]
We developed a mild and regioselective bromination of phenols
with TMSBr. This method is easily scaled up and has the
potential to recycle the byproduct thioether and isolate the
desired product under column chromatography-free conditions.
Control experiments revealed that hydrogen bond may be
formed between phenol and byproduct thioether. Possibly owing
to the steric hindrance effect from byproduct thioether, the
electrophilic bromination at the para-position of phenols is much
favorable. Further application of this novel method for the
regioselective functionalization of phenols is under way.
run
1
2
additive
none
Me2S (6a)
(4-ClC6H4)2S (6f)
4a/5a/7[b]
68.5/4.4/27.1
79.9/3.3/16.8
85.8/3.4/10.8
3
[a]
Unless otherwise noted, the mixture of 1a (0.50 mmol), 2c (0.55 mmol),
additive (0.55 mmol), in MeCN (1.0 mL) was sealed under N2 in a Schlenk
tube, stirred at 25 oC for 6 h. The ratios were determined by means of GC-
[b]
MS
1
Then H NMR titration techniques were employed to investigate
Experimental Section
the possible interaction between phenol and thioether,[9,17]
revealing O-H…S hydrogen bond may be formed between
phenol and thioether,[18] but not between anisole/toluene and
thioether, which is well consisted with the experimental results
A mixture of phenol 1a (0.50 mmol), bromotrimethylsilane 2a (0.55 mmol),
di-4-chlorphenyl-sulfoxide (0.55 mmol) and acetonitrile (1.0 mL) was
stirred under nitrogen at room temperature for 6 h. Then the solvent was
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R. Pedrosa, R. Sanz, Adv. Synth. Catal. 2018, 360, 2216−2220. d) Y. Guo,
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eluting with ethyl acetate/petroleum ether (0/100~1/10), to give
compound 4a.
[8] X.-T. Ma, S.-K. Tian, Adv. Synth. Catal. 2013, 355, 337-340.
[9] (a) X. Ma, J, Yu, C. Han, Q. Zhou, M. Ren, L. Li and L. Tang, Adv. Synth.
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[10] The byproduct sulfide 6 was isolated, see SI for details.
[11] L. H. Choudhury, T. Parvin, A. T. Khan, Tetrahedron 2009, 65, 9513-9526.
[12] Possibly owing to the inefficient activation of sulfoxide by TMSX (X = Cl, I),
the reaction with TMSX (X = Cl, I) is sluggish. Afterall, it is still not very
clear at present.
Acknowledgements
We thank the Foundation of Henan Province Department of
Science and Technology (192102310031, 172102210456), the
Key research programs in universities of Henan Province
(19B150018, 18A150049, 17A150049), the Young Core
Instructor Program of XYNU (2018GGJS—05) and. the Nanhu
Scholars Program for Young Scholars of XYNU.
[13] See SI for details.
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Keywords: Phenol • Byproduct • Regioselective Bromination •
Hydrogen bond • Steric Hindrance Effect
[16] The high regoselectivity of this new method is also ascribled to the slow
release of Br2 from the reaction of TMSBr with sulfoxide, see refs. 5-6 for
details.
[17] P. Thordarson, Chem. Soc. Rev. 2011, 40, 1305-1323.
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European Journal of Organic Chemistry
COMMUNICATION
Table of Contents
COMMUNICATION (Regioselective Bromination)
An unexpected promoting effect of
byproduct thioether was observed,
leading to a mild and regioselective
bromination of phenols with TMSBr.
The desired para-brominated phenols
could be obtained in high selectivity
(up to 99/1) by using sulfoxides
X. Ma,* J. Yu, M. Jiang, M. Wang, L.
Tang,* M. Wei, Q. Zhou*
Page No. – Page No.
Mild and Regioselective Bromination
of Phenols with TMSBr
bearing
sterically
hindered
substituents.
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