Metal- and base-free synthesis of aryl bromides from arylhydrazines

Article abstract of DOI:10.1016/j.tetlet.2020.151959

An efficient method was developed to synthesize brominated aromatic compounds from arylhydrazine hydrochlorides by using BBr₃ in DMSO/CPME (cyclopentyl methyl ether) under air at 80 °C for 1 h without the use of bases or metal catalysts. In particular, this method could be carried out satisfactorily using electron-withdrawing groups to afford aryl bromides in a moderate to excellent yields.

Full text of DOI:10.1016/j.tetlet.2020.151959

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Metal- and Base-free Synthesis of Aryl Bromides from Arylhydrazines
Dat Phuc Tran, Akihiro Nomoto, Soichiro Mita, Chun-ping Dong, Shintaro
Kodama, Takumi Mizuno, Akiya Ogawa
PII:
S0040-4039(20)30402-0
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.151959
TETL 151959
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
5 March 2020
15 April 2020
17 April 2020
Please cite this article as: Phuc Tran, D., Nomoto, A., Mita, S., Dong, C-p., Kodama, S., Mizuno, T., Ogawa, A.,
Metal- and Base-free Synthesis of Aryl Bromides from Arylhydrazines, Tetrahedron Letters (2020), doi: https://
doi.org/10.1016/j.tetlet.2020.151959
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Metal- and Base-free Synthesis of Aryl
Bromides from Arylhydrazines
Leave this area blank for abstract info.
Dat Phuc Tran, Akihiro Nomoto*, Soichiro Mita, Chun-ping Dong, Shintaro Kodama, Takumi Mizuno and
Akiya Ogawa*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Metal- and Base-free Synthesis of Aryl Bromides from Arylhydrazines
a
a,
a
a
a
b
Dat Phuc Tran , Akihiro Nomoto , Soichiro Mita , Chun-ping Dong , Shintaro Kodama , Takumi Mizuno
a,
and Akiya Ogawa 
a
Department of Applied Chemistry, Graduate school of Engineering, Osaka Prefecture University, 1-2, Gakuen-cho, Sakai, Osaka 599-8570, Japan
Morinomiya Center, Osaka Research Institute of Industrial Science and Technology, 1-6-50 Morinomiya, Joto-ku, Osaka 536-8553, Japan
b
—
——
ARTICLE INFO
ABSTRACT


Corresponding author. e-mail: ogawa@chem.osakafu-u.ac.jp
Corresponding author. e-mail: nomoto@chem.osakafu-u.ac.jp
Article history:
Received
An efficient method was developed to synthesize brominated aromatic compounds from
arylhydrazine hydrochlorides by using BBr in DMSO/CPME (cyclopentyl methyl ether) under
3
Received in revised form
Accepted
Available online
air at 80 °C for 1 h without the use of bases or metal catalysts. In particular, this method could
be carried out satisfactorily using electron-withdrawing groups to afford aryl bromides in a
moderate to excellent yields.
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Aryl Bromide
Arylhydrazine
Metal-free
Base-free
Introduction
Aryl bromides are one of the most essential and useful
chemicals as they serve as fundamental substrates in building
1
blocks for organic synthesis reactions such as Heck reaction and
2
cross coupling reactions . Brominated aromatic compounds are
found in many natural organisms, and some of them have
3
biomedical value .
A common bromination method from anilines is the
Sandmeyer reaction. Although various bromination reactions
using anilines have been developed, they require metal-based
catalysts, a strong basic medium, or a long time for the workup
4
process . To overcome these disadvantages, the development of
metal- and base-free synthesis of aryl bromides is strongly
desired. Recently, we effectively synthesized aryl iodides from
5
arylhydrazine without using
a
metal catalyst or base.
, were converted to
6
Arylhydrazines , upon oxidation with I
2
arenediazonium salts, which undergo SET (single-electron
transfer) to form aryl radicals in situ. Based on the aryl radicals
formation from arylhydrazines, we recently developed a series of
arylation reactions of heteroarenes and organochalocogenides .
We expected that the use of a suitable brominating reagent
Herein, we study a method to synthesize brominated aromatics
7
8
from arylhydrazine hydrochlorides by using BBr /DMSO without
3
the use of bases or metal catalysts (Scheme 1).
instead of I
2
will lead to successful formation of the
Results and discussion
corresponding aryl bromides from arylhydrazines. Dimethyl
sulfoxide (DMSO) was used as a solvent, which can dissolve
arylhydrazine hydrochloride salts and will oxidize hydrogen
Initially, the reaction of 4-benzonitrile hydrazine
hydrochloride (1a, 0.5 mmol) with tetrabutylammomium
bromide (TBAB) (0.6 mmol) and boron tribromide (BBr
9
bromide, similar to HI .
3
) (1.0
mmol, 1 M in CH Cl ) in 0.5 mL of normal grade DMSO (not
2
2
dehydrated, 99.0% purity) as a solvent at 80 °C in the air is the
model reaction to achieve the optimal conditions (Table 1).

2
Tetrahedron Letter
3
Table 1. Optimization of bromination with BBr .
a
Entry
TBAB (mmol)
BBr
3
(mmol)
Time (h)
Yield (%)
1
0.6
0.6
0.6
0.6
0
1.0
1.0
1.0
1.0
1.0
0.8
1.2
1.5
1.2
1.2
5
14
5
3
3
3
3
3
5
1
72
61
73
71
83
77
89
89
79
81
2
3b
4c
5
6
0
7
0
8
0
9
0
1
0
0
a
1
Yield was determined by H NMR (CDCl
3
, 1,3,5-trioxane as an internal
standard).
bReaction temperature is 90 °C.
cReaction temperature is 100 °C.
Table 2. Effect of brominating reagents and conditions on
bromination.
Entry
Bromine Conditions
source
Yielda
(%)
Scheme 2. Scope of aryl bromides.
1
2
PBr
BrCCl
3
DMSO (0.5 mL), 80 °C
DMSO (0.25 mL), CH Cl
0 °C
DMSO (1.5 mL), 80 °C
CH Cl (0.4 mL), 60 °C
DMSO (0.2 mL), CH Cl
0 °C
CPME (0.2 mL), DMSO (0.2 mL), 80 °C 99
24
3
2
2
(0.25 mL),
46
Bromination using BrCCl
afforded 2a in moderate yield with
3
8
11
2
the formation of dimethyl sulfide (entry 2). When Br , a
3
4
5
Br
2
47
commonly used bromine reagent, was used, a similar moderate
yield of 2a was obtained (entry 3). Using CH Cl as solvent, no
a was formed (entry 4). The use of a mixed solvent of DMSO
and CH Cl led to the formation of 2a (49%) (entry 5).
BBr
BBr
3
2
2
N.D.
49
2
2
3
2
2
(0.2 mL),
2
8
2
2
6
7
8
BBr
BBr
BBr
3
3
3
Considering the effects of air and moisture, the reaction was
conducted under argon with deoxidized DMSO, but 2a was
formed in 33% yield (Scheme 3, reaction (a)). Interestingly, a use
of cyclopentyl methyl ether (CPME) as a solvent extremely
improved the yield of 2a (99%) (entry 6). To examine the effect
Et
2
O (0.2 mL), DMSO (0.2 mL), 80 °C
48
99
THF (0.2 mL), DMSO (0.2 mL), 80 °C
Reactions were carried out on 0.5 mmol scale.
a
1
Yield was determined by H NMR (CDCl
standard).
3
, 1,3,5-trioxane as an internal
2
of other ethereal solvents, diethyl ether (Et O) and
tetrahydrofuran (THF) were also used. The use of THF resulted
in the formation of 2a with an excellent yield (99%), whereas the
yield of 2a decreased to 48% in the case of Et O. Therefore,
2
ethereal solvents such as CPME and THF are suitable as co-
solvents for the bromination. Hence, CPME is chosen for the
bromination because it is usually used in chemical industries. In
3
comparison with the mixture of DMSO and BBr which reacted
strongly with formation of dimethyl sulfide, the presence of
CPME will make it more gently. Thus, the optimal reaction
After 5 h of reaction, the desired product, 4-bromobenzonitrile
2a), was formed in 72% yield (entry 1). Prolonging the reaction
time resulted in a lower yield (61%, entry 2). When the reaction
was conducted at a higher temperature, the yield of 2a did not
increase (entries 3 and 4). Intriguingly, the use of 1.0 mmol of
(
BBr
3
in the absence of TBAB increased the yield of 2a (83%)
entry 5). Next, we changed the ratio of 1a and BBr (entries 5-
0) and found that 2a was obtained in a good yield (81%) in the
(1.2 mmol) for 1 h (entry 10).
(
1
3
presence of 2.4 equiv. of BBr
3
3
conditions include BBr (2.4 equiv.), DMSO/CPME (0.2 mL/0.2
mL), under air, for 1 h.
Other brominating reagents under different reaction conditions
were also attempted for the bromination (Table 2). Because PBr
3
The scope of bromination was investigated using the
conditions of entry 6 (Table 2) and a range of aryl bromides
could be synthesized in moderate to excellent yields (Scheme 2).
The reaction was carried out satisfactorily with electron-
withdrawing groups (EWG) such as cyano (2a), nitro (2b, 2c, 2d,
has high oxophilicity and bromine content, it serves as a useful
brominating reagent to convert alcohols to the corresponding
1
0
alkyl bromides . The use of PBr
at 80 °C led to only 24% yield of 2a (Table 2, entry 1). BrCCl
a useful brominating reagent for converting arylamines to aryl
3
(2.4 equiv.) in 0.5 mL DMSO
3
is
2
s), trifluoromethyl (2e), and halo groups (2f, 2j, 2k).
4
b
bromides through the SRN1 mechanism under basic conditions .
The bromination of arylhydrazines bearing the substituent
groups at the para position afforded excellent yields of 4-

3
bromobenzonitrile (2a), 1-bromo-4-triflouromethylbenzene (2e),
-bromo-4-fluorobenzene (2k). The brominaiton of
TEMPO to afford 3, which strongly supported a radical
pathway.
4
b
1
arylhydrazines consisting meta substituents also provided very
good yields of 1-bromo-3-nitrobenzene (2c, 90%), and 1-bromo-
3
-chlorobenzene (2h, 90%). In contrast, the ortho substituents
resulted in moderate yields of 1-bromo-2-nitrobenzene (2d, 45%)
and 2-bromotoluene (2o, 30%) due to their steric hindrance. In
particular, in the case of the chloro substituent, the effectivity of
electron-withdrawing ability at the meta position is higher than
that at the para position; thus, the yield of 2h is higher than that
of 2f. The disubstituents of phenyllhydrazine hydrochlorides also
tolerated the optimal conditions to generate the corresponding
aryl bromides. While 1-bromo-2,4-dinitrobenzene (2s) was
obtained in moderate yield (60%), 1-bromo-3,4-dichlorobenzene
(
2i), 1-bromo-2,4-dichlorobenzene (2r), and 1-bromo-3,5-
dichlorobenzene (2t) were synthesized in good yields (83%,
5%, and 97%, respectively). Moreover, the bromination of
7
substrates bearing a methyl group could afford the corresponding
products (2m, 2n, and 2o). Unfortunately, the bromination of p-
or m-methoxyphenyl hydrazine hydrochloride barely occurred
(
2p, 2q), presumably because of the complexation of the
1
2
3 3
methoxy group and BBr . When BrCCl was used instead of
BBr
When the 2-hydrazinopyridine hydrochloride was used as a
substrate, the complexation between pyridine and BBr inhibited
3
, p-methoxyphenyl bromide (2p) was obtained in 42% yield.
Scheme 4. Possible pathways.
3
the desired bromination (2u). Moreover, tert-butyl bromide as an
alkyl bromide was formed in only 14% yield (2v).
Proposed pathways, which include both ionic and radical
mechanisms, are shown in Scheme 4. First, the starting material,
arylhydrazine hydrochloride (1) generates arylhydrazine in
equilibrium. Dimethyl sulfoxide (DMSO) serves as a Lewis base
NHNH2 HCl
BBr3 (2.4 equiv.)
Br
(
a)
Deoxygenated DMSO, Ar, 80 °C, 1 h
NC
and reacts with a Lewis acid, BBr , to form A as a key species,
NC
NC
3
1
a
a
2a, 33%
which can be generated both under argon and under air. In the
case of argon atmosphere, A interacts with the hydrogen atoms of
hydrazine (see B) to form diazene C, where DMSO acts as an
oxidizing agent. Under air, A might play a similar role as the case
under argon, and moreover, air-oxidation of arylhydrazine to C
might be accelerated by the formation of B, although air can
directly oxidize arylhydrazine to C. In an ionic pathway, C
NHNH2 HCl
+
Br
O
TEMPO (3 equiv.)
N
BBr3
+
(b)
DMSO/CPME, air
(1 M in CH Cl )
2
2
NC
NC
8
0 °C, 1 h
1
2.4 equiv.
2a, >99%
3, N.D
Scheme 3. Control experiments.
To understand the bromination mechanism, some control
undergoes coordination with BBr
nucleophilic substitution (S Ar) to afford 2. In a radical pathway,
air-oxidation of C leads to aryl radical E, which abstracts
bromine atom from BBr or A to afford 2 (atom-transfer
reaction) . If E abstracts Br from A, the concomitantly formed
Br BO• might contribute to the formation of arylhydrazine to C.
3
or A (see D) and then aromatic
N
experiments were investigated (Scheme 3). Although, under
argon, 2a was formed in 33% yield (reaction (a)), atmospheric
exposure led to 2a in almost quantitative yield (entry 6 in Table
3
17
2
2
). Therefore, air plays as an important role in bromination.13 To
clarify whether the bromination involves a radical pathway,
,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) was added to the
bromination of 1a (reaction (b)). The almost quantitative
formation of 2a even in the presence of TEMPO without the
Conclusion
A metal- and base-free synthetic method of aryl bromides
from arylhydrazine hydrochlorides is developed. Various aryl
bromides can be successfully prepared without using any metal
catalysts or bases.
2
formation
of
4-((2,2,6,6-tetramethylpiperidin-1-yl)oxy)-
benzonitrile 3 strongly suggests the present bromination reaction
might not involve a radical process at least in the key steps.
Acknowledgments
To get more information about the mechanism, we
investigated a Hammett linear free energy relationship study of
the bromination using four kinds of arylhydrazines 2b, 2e, 2l, and
D.P.T. is grateful for the support of the Ministry of Education,
Culture, Sports, Science and Technology (MEXT) Scholarship
Program. This research was supported by JSPS KAKENHI ( Ｂ,
19H02791) and (Ｂ, 19H02756), from the Ministry of Education,
Culture, Sports, Science and Technology, Japan, and by Kyoto-
Advanced Nanotechnology Network.
2
m (for the detailed experiments, see Supporting Information).
The determined ρ value, ρ = +0.63, is inconclusive to determine
the mechanism; namely, a radical pathway such as an atom-
transfer reaction14,15 and an ionic pathway such as an aromatic
1
6
N
nucleophilic substitution (S Ar) are both possible .
References and notes
In our previous study of the iodination of arylhydrazines with
2
, however, a TEMPO trapping experiment indicated the
formation of 3, suggesting a radical pathway. In addition, Stack’s
report concerning the bromination of anilines to give aryl
bromides also described a successful trapping of aryl radical by
5
I
1
. (a) I. P. Beletskaya, A. V. Cheprakov, Chem. Rev. 100 (2000) 3009-3066.
b) W. Cabro, I. Candiani, Acc. Chem. Rev. 95 (1995) 2457-2483.
(
2. (a) N. Miyaura, A. Suzuki, Chem. Rev. 95 (1995) 2457-2483.
(b) R. Chinchilla, C. Nájera, Chem. Soc. Rev. 40 (2011) 5084-5121.
3
. (a) G.W. Gribble, J. Chem. Educ. 81 (2004) 1441-1449.

4
Tetrahedron Letter
(
b) Y. Xu, J. M. Foulks A. Clifford, B. Brenning, S. Lai, B. Luo, K. M.
11. I. Saikia, A. J. Borah, P. Phuka, Chem. Rev. 116 (2016) 6837−7042.
12. F. L. Benton, T. E. Dillon, J. Am. Chem. Soc. 64 (1942) 1128-1129.
13. The bromination reaction was performed in the air atmosphere (open-air
condition) in which the reaction was exposed to both oxygen and moisture.
Air plays an important role in the bromination, because it can oxidize
arylhydrazines 1 to diazene D. On the other hand, a small amount of
moisture contaminated from the atmosphere does not play significant effect
Parnell, S. Merx, M. V.McCullar, S. B.Kanner, K-K. Ho, Bioorg. Med.
Chem. Lett. 23 (2013) 4072–4075.
4
. (a) I. P. Beletskaya, A. S. Sigeev, A. S. Peregudov, P. V. Petrovskii,
Synthesis 16 (2007) 2534-2538.
b) D. A. Leas, Y. Dong, J. L. Vennerstrom, D. E. Stack, Org. Lett. 19
2017) 2518-2521.
. C-p. Dong, K. Nakamura, T. Taniguchi, S. Mita, S. Kodama, S.
Kawaguchi, A. Nomoto, A. Ogawa, T. Mizuno, ACS Omega 3 (2018) 9814-
(
(
5
3
on the bromination. Since BBr , a Lewis acid, is sensitive to water, the
addition of water to the reaction system is unfavorable.
14. For an iodine-abstruction by aryl radicals, see for example: W. H. Davis,
Jr., J. H. Gleaton, W. A. Pryor, J. Org. Chem. 42, (1977) 7-12.
15. For a review concerning Hammett relationship in radical reactions, see for
example, T. Otsu, T. Yamamoto, Synth. Org, Chem., Jpn. 23 (1965) 643-
659.
9
6
821.
. A. Hosseinian, R. Mohammadi, S. Ahmadi, A. Monfared, Z. Rahmani,
RSC Adv. 8 (2018) 33828-33844
. (a) T. Taniguchi, M. Imoto, M. Takeda, F. Matsumoto, T. Nakai, M.
Mihara, T. Mizuno, A. Nomoto, A. Ogawa, Tetrahedron 72 (2016) 4132-
140.
b) T. Taniguchi, M. Imoto, M. Takeda, T. Nakai, M. Mihara, T. Mizuno, A.
Nomoto, A. Ogawa, Synthesis 49 (2017) 1623-1631.
7
4
(
N
16. For a S 2Ar reaction, see for example: L.A. Montoya, T. F. Pearce, R. J.
Hansen, L. Zakharov, M. D. Pluth, J. Org. Chem. 78 (2013) 6550-6557.
17. J. R. Lawson, E. R. Clark, I. A. Cade, S. A. Solomon, M. J. Ingleson,
Angew. Chem. Int. Ed. 52 (2013) 7518-7522.
8
. (a) T. Taniguchi, T. Naka, M. Imoto, M. Takeda, T. Nakai, M. Mihara, T.
Mizuno, A. Nomoto, A. Ogawa, J. Org. Chem. 82 (2017) 6647−6655.
(
b) T. Taniguchi, A. Murata, M. Takeda, T. Mizuno, A. Nomoto, A.
Ogawa, Eur. J. Org. Chem. (2017) 4928-4934.
c) Y. Yamamoto, F. Sato, S. Kodama, A. Nomoto, A. Ogawa, Heteroatom
Supplementary Material
(
Chem. 29 (2018) 21471
. For arene bromination using HBr/DMSO, see:
Supplementary material can be attached
9
2
(a) S. Song, X. Sun, X. Li, Y. Yuan, N. Jiao, Org. Lett. 17 (2015) 2886-
889
(
b) G. Majetich, R. Hicks, S. Reister, J. Org. Chem. 62 (1997), 4321-4326.
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0. L. G. Jr. Wade, Organic Chemistry (6th ed.), Pearson Prentice Hall, USA,
005, p. 477.
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Metal- and Base-free Synthesis of Aryl
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Bromides from Arylhydrazines
Highlights.
Da t Ph uAc Tm r ea tn a, l A- ak ni hdi r bo a Ns eo -mf roe t eo *m, Se to hi co hd irt oo Ms yi tna t,h Ce sh iuz ne -ping Dong, Shintaro Kodama, Takumi Mizuno and
Akiya Ogawa*
aryl bromides was developed.

The use of CPME or THF as a co-solvent
improved the bromination.

Arylhydrazines with EWG is effectively
converted to aryl bromides.