Cu-mediated selective bromination of aniline derivatives and preliminary mechanism study

Article abstract of DOI:10.1080/00397911.2019.1598558

A simple and efficient bromination of aniline, aniline derivatives, and analogs have been developed. Forty three examples were given and the highest yield reached was 98%. Different substrates including substituted aniline, pyridin-amine, N-substituted aniline, N,N-disubstituted aniline, N-phenyl-amide, N-phenyl-sulfonamide, and nitrogen-containing heterocycles were all reactive and selectively generated desired bromo-products. The method can be applied to synthesize drug intermediate and quinoxaline derivatives.

Full text of DOI:10.1080/00397911.2019.1598558

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Cu-mediated selective bromination of aniline
derivatives and preliminary mechanism study
Hong-Yi Zhao, Xue-Yan Yang, Hao Lei, Minhang Xin & San-Qi Zhang
To cite this article: Hong-Yi Zhao, Xue-Yan Yang, Hao Lei, Minhang Xin & San-Qi Zhang (2019):
Cu-mediated selective bromination of aniline derivatives and preliminary mechanism study,
Synthetic Communications, DOI: 10.1080/00397911.2019.1598558
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https://doi.org/10.1080/00397911.2019.1598558
Cu-mediated selective bromination of aniline derivatives
and preliminary mechanism study
Hong-Yi Zhao, Xue-Yan Yang, Hao Lei, Minhang Xin, and San-Qi Zhang
Department of Medicinal Chemistry, School of Pharmacy, Xi0an Jiaotong University, Xi0an, Shaanxi,
P. R. China
ABSTRACT
ARTICLE HISTORY
Received 12 September 2018
A simple and efficient bromination of aniline, aniline derivatives, and
analogs have been developed. Forty three examples were given and
the highest yield reached was 98%. Different substrates including
substituted aniline, pyridin-amine, N-substituted aniline, N,N-disubsti-
tuted aniline, N-phenyl-amide, N-phenyl-sulfonamide, and nitrogen-
containing heterocycles were all reactive and selectively generated
desired bromo-products. The method can be applied to synthesize
drug intermediate and quinoxaline derivatives.
KEYWORDS
Bromination; copper;
aniline; ambroxol;
quinoxaline
GRAPHICAL ABSTRACT
R2 R1
N
R2 R1
N
mild cinditions;
EtOH solvent;
43 exzamples;
up to 98% yield.
, Bu
4NBr
CuBr2
R3
R3
EtOH
Br
Introduction
As industrially important building blocks, brominated aryl amines are widely used for
the synthesis of bioactive compounds[1] and functional materials.[2] The utility of bro-
minated aryl amines in transformation involves direct carbon ꢀ halogen activation by
transition metals,[3] metal ꢀ halogen exchange using organometallic reagents,[4] or
SNAr-type halogen displacements.[5] Therefore, much attention has been paid to the
synthesis of brominated aryl amines. Traditionally, the hazardous liquid bromine has
widely been used for the bromination process in the industry as well as in academia.
Several other special bromine-carrying agents have also been applied for bromination
such as pyridiniumbromide–perbromide,[6] TBCA (tribromoisocyanuric acid),[7] N-bro-
mosuccinimide
(NBS),[8]
1,2-dipyridiniumdibromide-ethane[9]
and
BR-S
(NaBr–NaBrO3).[10] Despite their widespread success, these protocols still suffer from
toxicity, low functional group tolerance, poor levels of regioselectivity, and over halo-
genation of substrates. In this regard, the concurrent development of methods
CONTACT San-Qi Zhang
sqzhang@xjtu.edu.cn
Department of Medicinal Chemistry, School of Pharmacy, Xi0an
Jiaotong University, Xi0an 710061,Shaanxi, P. R. China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
H.-Y. ZHAO ET AL.
employing transition metals as catalysts to prepare aryl halides has eradicated many of
the problems observed.[11] The copper-mediated bromination of aniline and other acti-
vated arenes was reported in 2007.[12] Aniline was also brominated using superstoichio-
metric amounts of copper(II) bromide with moderate yield (61%). In 2008, Gusevskaya
reported copper-catalyzed bromination and chlorination of aniline derivatives using
acetic acid as a solvent. However, N-substituted aniline is not reactive under the
reported reaction conditions.[13] Subsequently, copper-catalyzed halogenation of arenes
was studied, in which alkoxy, heterocyclic, and amino arenes were all halogenated. In
this report, acetic acid was also used as a solvent with oxygen oxidant. Then, bromina-
tion of aniline derivatives was reported employing oxone as an oxidant and copper(II)
bromide as the brominating reagent.[14] In 2006, palladium acetate catalyzed C–H halo-
genation of acetanilide employing superstoichiometric amounts of copper salts under
the nitrogen atmosphere was demonstrated.[15] Then, the bromination of aniline and
other activated arenes using a special recyclable palladium complex as a catalyst was
reported in 2013.[16] Several other groups also studied palladium as a catalyst for the
halogenation of C(sp2)–H or C(sp3)–H bond.[11b,11c,17] Recently, the copper-catalyzed
mono-bromination and di-bromination of quinoline were described, in which
PhI(AcO)2 (4 Eq.) was used as an oxidant.[18] Employing H2O2 as an oxidant, ortho-
bromination of aniline catalyzed by copper was demonstrated in 2017.[19] However, fur-
ther applications of these transformations are limited due to the use of environmentally
harmful solvent and expensive catalyst, and complex reaction conditions. Therefore, it is
necessary but, challenging to develop a simple and safe method to synthesize bromi-
nated aniline derivatives and analogs.
In this study, we report the bromination of a variety of aniline derivatives and ana-
logs employing cheap and abundant copper(II) bromide as a promoter in EtOH without
additional oxidant. A wide range of substrates can be selectively and efficiently bromi-
nated under benign conditions.
Results and discussion
Optimization of reaction conditions
We initiated our research with the reaction of aniline and copper(II) bromide (CuBr2)
at 100 ꢁC. When 1,2-dimethoxyethane (DME), 1,2-dichloroethane (DCE), CH3CN, tolu-
ene, DMSO, and DMF were used as solvents, only a trace amount of 4-bromoaniline
(1b) was detected (Table 1, Entry 1–6). Further, screen of the solvent showed that
dioxane could give a little bit more product 1b (8%) (Table 1, Entry 7). To our delight,
the yield was increased to 50% upon the addition of 100 mol% of tetrabutylammonium
bromide (Bu4NBr) (Table 1, Entry 8). The increase in the amount of CuBr2 resulted in
a decrease in the yield to 24% (Table 1, Entry 9). Thereafter, we noticed that the reac-
tion can go well at room temperature in dioxane (Table 1, Entry10). Changing the solv-
ent to THF with shorter reaction time improved the yield to 68% (Table 1, Entry
11–12). The increase in the amount of CuBr2 from 100 mol% to 150 mol% slightly
improved the yield to 75% (Table 1, Entry 13). To our satisfaction, it had no effect on
the yield, to use eco-friendly EtOH as solvent (Table 1, Entry 14). Performing the
reaction under the argon atmosphere did not reduce the yield significantly

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SYNTHETIC COMMUNICATIONSV
3
Table 1. Optimization of the reaction conditions for bromination of anilinea.
NH2
NH2
CuBr2
Bu4NBr
solvent
Br
1a
1b
Entry
CuBr2 (mol %)
Bu4NBr (mol %)
Solvents
T (ꢁC)
Time (h)
Yield(%)b
1
2
3
4
5
6
7
8
100
100
100
100
100
100
100
100
150
100
100
100
150
150
150
150
0
0
0
0
0
0
0
100
100
100
100
100
100
100
100
100
DME
DCE
CH3CN
PhMe
DMSO
DMF
Dioxane
Dioxane
Dioxane
Dioxane
THF
THF
THF
EtOH
EtOH
MTBE
c
100
100
100
100
100
100
100
100
100
r.t.
r.t.
r.t.
r.t.
r.t.
12
12
12
12
12
12
12
12
12
10
10
2.5
2.5
4
<5
<5
<5
<5
<5
<5
8
50
24
45
53
68
75
77
70c
35
9
10
11
12
13
14
15
16
r.t.
r.t.
4
4
aReaction conditions: 1a (1 mmol), solvent (4 mL); bIsolated yield; Under argon.
Significance of bold values is the optimal reaction condition.
(Table 1, Entry 15). However, the yield remarkably dropped when methyl tert-butyl
ether (MTBE) was used as the solvent (Table 1, Entry 16). This might be explained by
the poor solubility of copper salt in MTBE. Thus, optimized conditions containing
150 mol% of CuBr2, 100 mol% of Bu4NBr in EtOH at room temperature were achieved.
Scope of substrates
With optimized conditions in hand, we tested the reaction scope of substrates. Substituted
anilines (2a–18a), pyridine-amine (19a–20a), N-substituted anilines (22a–33a), N-phenyl-
amides (34a–39a), N-phenyl-sulfonamide (40a), and nitrogen-containing heterocycles
(41a–42a) were all reactive and selectively brominated under the optimized conditions to
provide mono-brominated products in moderate to excellent yields (Table 2, 2b–42b,
35%-98%). Electron-donating (2b–6b), and electron-withdrawing substituents (7b–18b,
28b–29b, 41b) were all compatible with the reaction conditions.
The bromination of aniline derivatives selectively took place at the para-position of
the amino group (2b–6b, 8b–9b, 11b–14ba, 19b–27b, 30b–40b, 42b), except for those
with a substituent at the para-position of the amino which were brominated at ortho-
position of amino (15b–18b, 28b–29b). It should be noted that the aniline with a nitro
group (7ba–7bb) or trifluoromethyl group (10ba–10bb) at the meta-position gave a
mixture of ortho-brominated and para-brominated products. Moreover, we observed
that the yield of the bromoanilines with an electron-withdrawing substituent (8b–9b,
11b–18b) is higher than those with an electron-donating substituent (2b–6b), despite

4
H.-Y. ZHAO ET AL.
Table 2. Reaction scope of brominationa,b
.
R2 R1
N
R2 R1
N
CuBr2, Bu4NBr
EtOH
R3
R3
Br
2a 42a
-
2b-42b
NH2
NH2
NH2
Br
NH2
NH2
Br
NH2
Br
NH2
O
Br
NO2
NO2
O
O
OH Br
Br
1.35
7bb
77%g
:
1
7ba
Br
2b
, 53%
3b
, 55%
5b
, 71%
6b
, 67%
4b
, 58%
NH2
O
NH2
NH2
Br
NH2
NH2
NH2
NH2
Cl
Cl
Br
:
F
Br
CF3
CF3
Br
Br
Br
8b
Br
9b
Br
1.19
1
10bb
10ba
11b
12b
, 88%
, 80%
13b
, 93%
, 78%
, 35%
61%i
NH2
NH2
NH2
NH2
N
NH2
NH2
NH2
Br
Br
Br
Br
CO2Me
N
Br
Br
NO2
Br
CO2Me
F
Br
h
c,i
h
c,i
i
20b
, 66%
g
14ba
19b
, 65%
, 98%
17b
, 78%
15b
, 97%
18b
, 80%
16b
, 95%
Br
(CH2)11CH3
NH
HN
HN
Br
HN
HN
HN
NH2
N
Br
22ba
Br
Br
26b
Br
Br
c
27b
, 89%
, 81%
21b
, 56%
25b
, 88%
, 72%
23b
24b
, 85%
, 90%
O
O
N
N
N
N
N
HN
NO2
Br
O2N
Br
Br
Br
Br
Br
NO2
, 98%
d,g
31b
30b
, 91%
33b
, 84%
, 98%
29b
32b
, 90%
, 44%
28b
O
O
O
O
Br
HN
HN
HN
HN
O
N
H
N
Br
37b
Br
38b
Br
35b
Br
c
34b
, 83%
O
e,g,j
f,g,j
e,g,j
e,g,j
, 93%
, 82%
36b
, 91%
, 96%
O
S
O
Br
Br
HN
HN
O2N
N
H
N
H
Br
Br
40b
e,g,j
e,g,j
i
39b
, 76%
42b
, 76%
, 86%
41b
, 98%
aReaction conditions: substrate (2 mmol), CuBr2 (3 mmol), Bu4NBr(2 mmol) in EtOH (8 mL) at room
c
f
temperature, 2–72 h; bIsolated yields; CuBr2 (3.6 mmol); dCuBr2 (4 mmol);eCuBr2 (6 mmol); CuBr2
g
h
i
j
(7 mmol); At 65 ꢁC; At 55 ꢁC; At 45 ꢁC; Use THF as solvent.

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5
Traditional method:
OH
NH2
NH2
NH2
Br
Br
Br
CO2Me
CO2Me
Br2
CO2Me
CO2Me
N
H
AcOH
Br
Br
14a
Our method:
Ambroxol
14bb
NH2
NH2
400 mol% CuBr2
EtOH
40°C reflux
6 h
Br
14a
10 g
14bb
95%
Scheme 1. Synthesis of 14bb employing our method.
the higher reaction temperature compared to the electron-rich anilines. The bromina-
tion of pyridine-amine also occurred with moderate yields (19b–20b, 65–66%).
Interestingly, 8-aminoquinoline, which was reported as a directing group for C–H acti-
vation by Dauglis, was able to be brominated in a moderate yield (21b, 56%).[20] The
secondary anilines were also efficient under the optimized conditions giving moderate
to excellent yield (22b–28b, 72–98%). In accordance with the discovery above, substrate
27a was brominated at the para-position of the amino group to give 27b, while the
para-substituted substrate 28a provided the ortho-brominated product 28b at high reac-
tion temperature compared to 27a. Furthermore, cyclic tertiary aniline and branched
tertiary aniline were brominated to produce bromine-substituted products under the
reaction conditions (29b–33b, 44–98%). Notably, the bromination of N-phenyl-amides
and N-phenyl-sulfonamide also occurred to selectively provide para-brominated prod-
ucts with good to excellent yields (34b–40b, 76–96%) in spite of the use of superstoi-
chiometric amounts of CuBr2 and somewhat high reaction temperature in THF. We
observed the lower conversion of the N-phenylamide in EtOH than in THF probably
due to the oxidation of ethanol by CuBr2 at high temperature.[21] A variety of amides
including aroyl aniline, alkyl acyl aniline, and cycloalkyl acyl aniline were all efficient
under our reaction conditions. Additionally, nitrogen-containing heterocycles tested
were also able to exclusively give mono-brominated products 41b and 42b, respectively.
5-Nitroindole was selectively brominated to provide 2-bromo-5-nitroindole (41b), while
carbazole was brominated at the para-position of the nitrogen atom to give 3-bromo-
9H-carbazole (42b).
To validate the application of our method in drug synthesis, we developed a new syn-
thetic approach to produce methyl 2-amino-3,5-dibromobenzoate (14bb), an important
intermediate of expectorant drug ambroxol (Scheme 1),[22] with the optimized reaction
conditions. The dibromo-product 14bb was prepared using more CuBr2 (400 mol%)
compared to 14ba in EtOH without Bu4NBr circumventing the hazardous Br2 and acid
solvent (AcOH), and was isolated with an excellent yield (95%). Moreover, the simple
workup process made this new approach potentially applicable in the industry (see sup-
porting information). However, the recycle of CuBr waste (see proposed mechanism)
remained a challenge. Also, brominated products can be used to synthesize bioactive
quinoxaline derivatives.[23] As shown in Scheme 2, 1c was produced through bromina-
tion, Buchwald coupling[24]/dehydrogenation in sequence.

6
H.-Y. ZHAO ET AL.
1) Pd(OAc)2, Pd2(dba)3, BINAP,
Cs2CO3, PhMe, dioxane,
95°C, 6 h
O
H
O
H
N
N
N
170 mol% CuBr2,
100 mol% Bu4NBr
40°C, 10 h,
N
N
H
N
H
O
2) 50 °C, air balloon, 18 h
75%
Br
71%
1c
43a
43b
Scheme 2. Synthesis of 1c using brominated product 43b.
NH
NH
NH
standard conditions
Br
+
with or without Bu4NBr
Br
22bb
Br
22ba
22a
total yield: 77%
total yield: 68%
1
1
14.4
4.2
with Bu4NBr:
without Bu4NBr:
:
:
Scheme 3. Control experiment for the study of Bu4NBr.
Br
(a)
150 mol% CuBr2
100 mol% Bu4NBr
Br
EtOH, r.t.
24 h
44a
44a
44b
, 45%
Br
(b)
150 mol% CuBr2
without Bu4NBr
Br
EtOH, r.t.
24 h
44b
, 68%
Scheme 4. The reaction using styrene as substrate.
Mechanism study
To get an insight into the reaction mechanism of the bromination, we determined the
role Bu4NBr played in the reaction by conducting control experiment using N-methyla-
niline (22a) as the substrate (Scheme 3). More dibrominated product (22bb) was iso-
lated from the reaction mixture in the absence of Bu4NBr compared to that in the
presence of Bu4NBr as evidenced by the yield ratio of 22ba and 22bb (14.4:1 and 4.2:1,
respectively). We speculated that Bu4NBr lowered the reactivity of CuBr2 and improved
the selectivity of reaction by the formation of low reactive bromo-cuprate complexes to
reduce the number of by-products.[25] In the absence of Bu4NBr, more byproducts
except for 22bb might form. As a result, the total yield of 22ba and 22bb was lower
than that with Bu4NBr.
In our experiment, we noticed that the white solid precipitated upon the addition of
water to the reaction mixture. Furthermore, we observed the acidic pH of the final reac-
tion mixture. Therefore, we performed the reaction using styrene (44a) as a substrate
under the standard conditions to explore whether the reaction proceeded through

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7
2CuBr2
2CuBr + Br2
R1 R2
N
R1 R2
N
+
–
R1 R2
N
H+
δ
δ
Br Br
+
R
R
R
Br–
H
Br
Br
Scheme 5. Proposed mechanism for the bromination.
electrophilic bromination by molecule bromine (Scheme 4). Interestingly, (1,2-dibro-
moethyl)benzene (44b) was isolated from the final reaction mixture either with
(Scheme 4(a)) or without Bu4NBr (Scheme 4(b)), which confirmed the existence of mol-
ecule bromine in the reaction mixture. Furthermore, the distinct yield between (a) and
(b) was consistent with our aforementioned effect of Bu4NBr
Based on our observations and mechanism investigation experiments, we proposed
an electrophilic bromination mechanism. As shown in Scheme 5, CuBr2 decomposed to
generate CuBr and Br2. Subsequently, electrophilic bromination by Br2 led to the forma-
tion of the bromo-product. Consistent with the proposed mechanism, the substrate with
electron-withdrawing substituent required higher reaction temperature and longer reac-
tion time (e.g. 16b, 65 ꢁC, 10 h) than that with electro-donating substituent (e.g. 2b, r.t.,
4 h). Furthermore, the white solid found was CuBr, and production of HBr led to acidic
pH of the reaction mixture according to the proposed mechanism.
Conclusions
In summary, we have developed an attractive approach for bromination of aniline
derivatives and analogs mediated by copper(II) bromide in EtOH without using brom-
ine and acid. Substituted anilines, pyridine-amine, N-substituted anilines, N, N-disubsti-
tuted aniline, N-phenyl-amide, N-phenyl-sulfonamide, and nitrogen-containing
heterocycles were all reactive and selectively brominated in the conditions. Furthermore,
we provided an alternative approach for the synthesis of an important intermediate of
ambroxol and quinoxaline derivatives confirming the practicability of our method.
Experimental study of mechanism suggested that the reaction perhaps proceeded
through electrophilic bromination. These findings provide a safe and effective method
to prepare brominated aniline derivatives and analogs for small-scale production in the
lab. And the protocol also has the potential to be used in industrial production.
Experimental section
1H and 13C NMR spectra were recorded on a Bruker 400 MHz NMR Fourier transform
spectrometer (400 MHz or 100 MHz, respectively) using tetramethylsilane as an internal
reference, and chemical shifts (d) and coupling constants (J) were expressed in ppm and
Hz, respectively. Mass (MS) analysis was obtained using LC-MS1000 (Skyray Instrument)
with ESI. Melting point was determined on X-4 series microscope melting point apparatus.
Flash chromatography was performed using standard grade silica gel (200–300 mesh).

8
H.-Y. ZHAO ET AL.
Analytical TLC was performed with HG/T2354-2010 GF254 precoated silica gel plates
with visualization by UV (254 nm). All the solvents and commercially available reagents
were purchased from commercial sources and used without further purification.
General procedure for the synthesis of 1b–14ba, 15b–44b
A round bottom flask was charged with Bu4NBr (2 mmol, 0.64 g), EtOH (8 mL) and 2-
methylaniline (2 mmol, 0.21 g) followed by CuBr2 (3 mmol, 0.67 g). The resulting mix-
ture was stirred at 25 ꢁC. After the completion of the reaction (monitored by TLC), the
solvent was evaporated under reduced pressure. To the residue, ammonium hydroxide
(5 mL, 25% w/v) and water (5 mL) was added with stirring, and the suspension was
extracted with DCM (10 mL ꢂ 4) The organic phase was washed with saturated brine
and dried over anhydrous Na2SO4. The product 2b was obtained using flash chromatog-
raphy column eluted with PE:EA ratio of 5:1.
4-bromo-2-methylaniline (2b)
NH2
Br
Yellow solid, 53% yield, mp 58.4–60.1 ꢁC, using PE:EA ¼ 5:1 as eluent.
1H NMR (CDCl3) d 7.19 (d, J ¼ 1.8 Hz, 1H), 7.14 (dd, J ¼ 8.4, 2.2 Hz, 1H), 6.57 (d,
J ¼ 8.4 Hz, 1H), 3.62 (s, 2H), 2.16 (s, 3H). 13C NMR (CDCl3) d 143.7, 132.8, 129.6,
124.5, 116.3, 110.1, 17.3. MS (ESI): m/z calcd. for C7H9BrN: 186.0 [M þ H]þ; found:
186.1 (79Br, 100%), 188.1 (81Br, 98%).
The experimental detail and characterization data of other compounds can be found
via the “Supplementary Content” section of this article’s webpage.
Funding
Financial support from The National Natural Science Foundation of China (Grant No. 81673354)
is gratefully acknowledged.
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