Regioselective bromination of aryl ureas with Phenyliodine(III) diacetate and potassium bromide

Article abstract of DOI:10.1016/j.tet.2019.130621

An efficient regioselective and operationally simple urea bromination method utilizing PIDA and potassium bromide is reported. This protocol proved to be effective on a broad range of substituted ureas in acetone at room temperature, forming the p-brominated compounds in 44–86% yields.

Full text of DOI:10.1016/j.tet.2019.130621

Journal Pre-proof
Regioselective bromination of aryl ureas with Phenyliodine(III) diacetate and
potassium bromide
Chun-Meng Wang, Jian-Yao Du, Jin-Yang Zhang, Kai-Xiang Tang, Tian-Hong Gao,
Yun-Gen Xu, Li-Ping Sun
PII:
S0040-4020(19)30964-0
https://doi.org/10.1016/j.tet.2019.130621
TET 130621
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 June 2019
Revised Date: 16 September 2019
Accepted Date: 18 September 2019
Please cite this article as: Wang C-M, Du J-Y, Zhang J-Y, Tang K-X, Gao T-H, Xu Y-G, Sun L-P,
Regioselective bromination of aryl ureas with Phenyliodine(III) diacetate and potassium bromide,
Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.130621.
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Graphical Abstract
Regioselective Bromination of Aryl Ureas with Phenyliodine(III) Diacetate and Potassium
Bromide
Chun-Meng Wang, Jian-Yao Du, Jin-Yang Zhang , Kai-Xiang Tang , Tian-Hong Gao, Yun-Gen Xu*,
Li-Ping Sun*
Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China
Pharmaceutical University, Nanjing 210009, P. R. China.

1
Tetrahedron
journal homepage: www.elsevier.com
Regioselective Bromination of Aryl Ureas with Phenyliodine(III) Diacetate and Potassium Bromide
Chun-Meng Wanga,b, Jian-Yao Dua,b, Jin-Yang Zhanga , Kai-Xiang Tanga , Tian-Hong Gaoa, Yun-Gen
Xua,*, Li-Ping Suna,*
a Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, P. R. China
bThese authors contributed equally to this work and should be considered co-first authors
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient regioselective and operationally simple urea bromination method utilizing PIDA
and potassium bromide is reported. This protocol proved to be effective on a broad range of
substituted ureas in acetone at room temperature, forming the p-brominated compounds in 44–
86% yields.
Available online
Keywords:
Bromination
Regioselective
PIDA
Metal-free
Potassium Bromide
1. Introduction
We commenced our investigation by selecting 1,1-
dimethyl-3-phenylurea (1a) as a model compound for the
optimization of the reaction conditions (Table 1). At the outset
Urea derivatives are an important compounds which are
widely used in many roles such as biologically active
compounds, pharmaceuticals and agricultural pesticides1.
Therefore, urea derivatives attract scientists’ attention in organic
synthesis. Some methods have been established that use ureas as
directing groups to introduce aryl groups2, alkenyl groups3 and
other functional groups4 to the aryl ring of ureas. However, the
direct bromination of ureas is still limited5.
Table 1. Optimization of reaction conditions
Yieldb
Aryl bromides are versatile structural motifs since they
have been widely utilized as important precursors for the
synthesis of pharmaceuticals and biologically active compounds.
Furthermore, brominated arenes and heteroarenes can be found
in a variety of drugs, pesticides and explosives. The classic
method for the direct bromination of aromatic rings employs
Br2, which is a volatile, toxic, corrosive and polluting agent6. To
overcome these problems, in recent years, a series of transition-
metal-catalyzed C-H halogenation are reported with some
halogen source such as NBS7 and bromate8. However, for the
transition-metal-catalyzed reactions, they suffered from the use
of expensive metal catalysis which hamper the application in a
way. In contrast, the metal-free catalyzed methods was able to
avoid these problems. Though some protocols using oxidants
Entry
Oxidant
Additive
Solvent
2a
2a’
1
2
3
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
TFA
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
DCM
DCE
toluene
THF
DMF
H2O
64
56
44
34
25
58
--
48
--
--
11
8
9
9
9
12
--
10
--
--
--
9
AcOH
PivOH
p-TSA
4
.
5
BF3 OEt2
6c
7d
8e
9
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
10
11
12
13
14
--
53
53
50
9
with bromate have been established such as H2O2 , Oxone10,
8
8
K2S2O811 and others12, PIDA-mediated the C-Br bond formation
of ureas with KBr has not been reported. Herein, we report the
regioselective para-bromination of ureas, which proceeds under
convenient conditions in the presence of PIDA with KBr utilized
as the halogen source.
aReaction conditions: 1,1-dimethyl-3-phenylurea (1a) (0.18
mmol, 1 equiv), KBr (0.27 mmol, 1.5 equiv), PIDA (0.27 mmol,
1.5 equiv), additive (0.18 mmol, 1 equiv), solvent (3 mL), r.t.
bIsolated yield. TFA (0.54 mmol, 3 equiv). TFA (0.045 mmol,
c
d
0.25 equiv). ethe temperature of reaction was 56 oC.
2. Results and Discussion
of the study, KBr was chosen as the halogen source and TFA
was added as the additive. In the set of oxidants screening, only

2
Tetrahedron
82
64
86
PIDA gave the brominated product in comparison to DDQ,
CAN, Oxone and K2S2O8. Sequentially, additives such as
AcOH, PivOH, p-TSA and BF3 OEt2 were used and no better
.
yield was obtained (Table 1, entries 1–5). Then the loading of
TFA was changed and obviously improved yield was not found
(Table 1, entries 6 and 7). Next the solvent screening showed
that acetone could get the best result among DCM, DCE,
toluene, THF, DMF and H2O tested (Table 1, entries 9–14).
Finally, the standard reaction conditions for the synthesis was
identified as follows: 1.5 equiv. KBr as the halogen source, 1.5
equiv. PIDA as the oxidant, 1 equiv. TFA as the additive and
acetone as the solvent under an air atmosphere at room
temperature.
Table 2. Substrate Scope of the Bromination.
58
65
67
54
58
72
Substrate
Product
Yield
67
82
82
72
85
69
44
52
70
With the optimized reaction conditions established, we set
out to investigate the scope and functional groups compatibility
of this protocol (Table 2). To our satisfaction, substrates
containing all kinds of functional groups including electron-
withdrawing and electron-donating groups work well to provide
products (2b-2l) in moderate to good yields (44-85%).
Disubstituted substrates bearing methyl groups at diverse
positions also provided the products (2m and 2n) in good yields
(86% and 58%). Besides, a disubstituted substrate bearing fluoro
and chloro groups at the 4- and 3-positions also provided the
product (2o) in 65% yield
.
Next, we investigated the application of ureas equipped
with different alkyl substituents on the nitrogen atom. Changing
the dimethylamino moiety to secondary cyclic diamines had no
influence on the reaction, and piperidine and morpholine urea
derivatives reacted excellently to provide 2r and 2s in 58% and
72% yields. At the same time, ureas which were constituted by
primary amines were also studied. We found that N-ethyl and N-
cyclopentyl ureas could be transformed smoothly to 2p and 2q
under the bromination conditions.

3
To fully demonstrate the synthetic potential of the present
method, we tried the bromination of 1a at the gram-scale
(Scheme 1). To our delight, brominated product 2a and 2a’ were
obtained in 59% and 9% yields, respectively. Besides, the sort of
halogen source was taken into consideration (Scheme 2).
Unfortunately, when the KBr was replaced by KCl, para-
chlorination product 3 was not obtained. To our delight, we got
para-iodination product 4 in a moderate yield by using KI as the
halogen source.
moderate to excellent yields. This method represents an
important extension of the chemistry of urea compounds and
these products can offer a platform for further functionalization.
a)
PIDA (1.5 equiv)
TFA(1 equiv)
H
H
N
N
N
N
TEMPO (1.5 equiv)
+
KBr
O
O
acetone, r.t.
Br
1.5 equiv
1a
2a, 47%
b)
O
N
PIDA (1.5 equiv)
TFA(1 equiv)
O
N
+
KBr
O
O
acetone, r.t.
Br
5
1.5 equiv
6a, not obtained
c)
H
N
H
PIDA (1.5 equiv)
TFA(1 equiv)
N
Scheme 1. Gram scale reaction
+
KBr
O
O
acetone, r.t.
Br
1.5 equiv
7
8, 62%
To gain more insight into the reaction mechanism, a series of
control experiments were carried out. 2,2,6,6-tetra-
methylpiperidine N-oxide (TEMPO) was added in the reaction
as the radical quencher to investigate whether these reactions
proceeded via radical pathways (Scheme 3, a). With 1.5 equiv.
of TEMPO, the yield of the desired products was not decreased
obviously. This result suggests that the reactions may not follow
a radical pathway. Next, when phenyl dimethylcarbamate 5 was
used as a substrate, the bromination products were not obtained
(Scheme 3, b), indicating that the NH group of ureas is
indispensable for the regioselective bromination. Besides, the
para-bromination of acetanilide could also be obtained in
moderate yield (Scheme 3, c). Since Br- could also be oxidized
to Br+, in order to verify whether the reaction was performed via
electrophilic substitution, bromine was used as the halogen
source and the result showed that no bromination occurred at
room temperature (Scheme 3, d). Based on this result, another
common bromination reagent NBS was used, and the para-
bromination product can only be obtained in 27% yield (Scheme
3, e).
d)
H
H
N
N
N
N
TFA(1 equiv )
acetone, r.t.
+
Br2
O
O
Br
1a
1.5 equiv
2a, not obtained
e)
H
H
N
N
N
N
+
NBS
O
O
CH3CN, r.t.
Br
1a
1.5 equiv
2a, 27%
Scheme 3. Control experiments
Scheme 4. Proposed mechanism
4. Experimental
4.1. General
Unless otherwise noted, all chemical reagents were
commercially purchased and used without further purification.
Analytical TLC was carried out by using pre-254 coated plates
and visualized with UV light. Melting points (uncorrected) were
Scheme 2. The changes of the halogen sources
1
determined on a RY-1 MP apparatus. H and 13C NMR spectra
Although details about the mechanism remained to be
ascertained, on the basis of these observations and earlier
precedents13, a plausible mechanism for this reaction was
depicted in Scheme 4. As shown in the scheme, firstly, a
nucleophilic attack of urea 1 forms the iodonium intermediate 9.
Then cleavage of the N–I bond furnishes iodobenzene and a
nitrenium ion 10, which is stabilized by the charge
delocalization on the phenyl ring. Finally, the extensively charge
delocalized intermediate 11 reacted with Br- to give the para-
brominated products 2.
were recorded on a Bruker AV-300 spectrometer at 300 MHz
and 75 MHz, respectively. Chemical shifts are reported in δ
(ppm), relative to the internal standard of TMS. The signals
observed are described as: s (singlet), d (doublet), t (triplet), q
(quartet), m (multiple). Coupling constants are reported as J
values in units of Hz. Mass spectrometry was obtained by using
a Q-TOF high-resolution mass spectrometer. Flash column
chromatography was performed over silica gel 200-300 m.
4.2. General Procedure for the Bromination
To a mixture of ureas 1(0.2 mmol, 1 equiv), KBr (0.3 mmol,
1.5 equiv) and PIDA (0.3 mmol, 1.5 equiv) in acetone (2 mL)
was added TFA (0.2 mmol, 1 equiv), then, the resultant mixture
was stirred at room temperature for 0.5 to 6 hours. Then the
mixture was treated with saturated NaHCO3 (10 mL) solution
and extracted with DCM (3 × 10 mL). The combined organic
phase was dried over Na2SO4 and then evaporated of the solvent
under reduced pressure. Next, purification of the crude residue
3. Conclusion
In summary, a novel and efficient protocol of metal-free
aryl C–H bond bromination of ureas has been developed, in
which simple and readily available bromide salt is employed as
the bromine source. This convenient condition makes this
protocol become easy to handle and practical. Besides, the
present method tolerates a variety of functional groups and
allows the synthesis of diverse 4-brominated urea derivatives in

4
Tetrahedron
by flash column chromatography on silica gel afforded the desired
products 2.
121.7, 115.6, 114.2, 102.4, 36.5. HRMS (ESI-QTOF): m/z (M +
H)+ calcd for C10H11BrN3O: 268.0085; found: 268.0078.
3-(4-bromophenyl)-1,1-dimethylurea
(2a):
Eluent:
3-(4-bromo-2-nitrophenyl)-1,1-dimethylurea (2h): Eluent:
dichloromethane: petroleum ether (15:1). Yellow solid, 25 mg,
yield: 44%, mp: 103-105 oC. 1H NMR (300 MHz, CDCl3): δ
dichloromethane: ethyl acetate (120:1). White solid, 28 mg,
yield: 64%. mp: 170-172 oC. 1H NMR (300 MHz, CDCl3): δ
7.38 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 8.7 Hz, 2H), 6.38 (s, 1H),
3.03 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 155.5, 138.4, 131.7,
121.5, 115.3, 36.4. HRMS (ESI-QTOF): m/z (M + H)+ calcd for
C9H12BrN2O: 243.0133; found: 243.0130.
10.17 (s, 1H), 8.68 (d, J = 9.2 Hz, 1H), 8.37 (d, J = 1.5
Hz, 1H), 7.70 (dd, J = 2.2, 9.2 Hz, 1H), 3.13 (s, 6H). 13C NMR
(75 MHz, CDCl3): δ 154.3, 138.8, 136.6, 135.7, 128.0, 122.8,
113.1, 36.5. HRMS (ESI-QTOF): m/z (M + H)+ calcd for
C9H10BrN3O3: 287.9984; found:287.9977.
3-(2-bromophenyl)-1,1-dimethylurea (2a’): White solid, 5
o
1
mg, yield: 11%. mp: 89-90 C. H NMR (300 MHz, CDCl3): δ
8.23 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.29 (d, J =
7.5 Hz, 1H), 7.01 (s, 1H), 6.85-6.91 (m, 1H), 3.03 (s, 6H). 13C
NMR (75 MHz, CDCl3): δ 155.0, 137.1, 131.9, 128.3, 123.4,
120.9, 113.0, 36.4. HRMS (ESI-QTOF): m/z (M + H)+ calcd for
C9H12BrN2O: 243.0133; found: 243.0140.
3-(4-bromo-3-methoxyphenyl)-1,1-dimethylurea
(2i):
Eluent: dichloromethane: petroleum ether (10:1). White solid,
28 mg, yield: 52%. mp: 140-142 oC. 1H NMR (300 MHz,
CDCl3): δ 7.43 (s, 1H), 7.36 (d, J = 8.5 Hz, 1H), 6.64 (dd, J =
1.8, 8.4 Hz, 1H), 6.51 (s, 1H), 3.87 (s, 1H), 3.03 (s, 6H). 13C
NMR (75 MHz, CDCl3): δ 156.0, 155.4, 140.0, 112.4, 112.3,
104.1, 56.2, 36.5. HRMS (ESI-QTOF): m/z (M + H)+ calcd for
C10H14BrN2O2: 273.0239; found: 273.0237.
3-(4-bromo-2-methoxyphenyl)-1,1-dimethylurea
(2b):
Eluent: dichloromethane: petroleum ether (4:1). Purple oil, 36
mg, yield: 67%. 1H NMR (300 MHz, CDCl3): δ 8.10 (d, J = 8.7
Hz, 1H), 7.07 (d, J = 8.7 Hz, 1H), 7.0 (s, 1H), 6.97 (s, 1H), 3.87
(s, 3H), 3.05 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 155.2,
148.2, 128.3, 123.8, 119.8, 113.8, 113.1, 56.0, 36.3. HRMS
(ESI-QTOF): m/z (M + H)+ calcd for C10H14BrN2O2: 273.0239;
found: 273.0233.
3-(4-bromo-3-methylphenyl)-1,1-dimethylurea
(2j):
Eluent: dichloromethane: petroleum ether (2:1). White solid, 36
mg, yield: 70%. mp: 149-151 oC. 1H NMR (300 MHz, CDCl3): δ
7.27 (d, J = 8.6 Hz, 1H), 7.22 (s, 1H), 6.95 (d, J = 8.4 Hz, 1H),
6.13 (s, 1H), 2.90 (s, 6H), 2.23 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 155.5, 138.4, 138.2, 132.3, 122.1, 118.8, 117.9, 36.5,
23.0. HRMS (ESI-QTOF): m/z (M + H)+ calcd for C10H14BrN2O:
257.0290; found: 257.0286.
3-(4-bromo-2-methylphenyl)-1,1-dimethylurea
(2c):
Eluent: dichloromethane: petroleum ether (15:1). White solid,
42 mg, yield: 82%. mp: 90-92 oC. 1H NMR (300 MHz, CDCl3):
δ 7.60 (d, J = 9.2 Hz, 1H), 7.28 (s, 2H), 6.14 (s, 1H), 3.02 (s,
6H), 2.02 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 155.6, 136.4,
132.8, 130.5, 129.5, 124.0, 116.3, 36.4, 17.6. HRMS (ESI-
QTOF): m/z (M + H)+ calcd for C10H14BrN2O: 257.0290; found:
257.0283.
3-(4-bromo-3-chlorophenyl)-1,1-dimethylurea
(2k):
Eluent: dichloromethane: petroleum ether (15:1). White solid,
45 mg, yield: 82%. mp: 165-167 oC. 1H NMR (300 MHz,
DMSO-d6): δ 8.56 (s, 1H), 7.86 (s, 1H), 7.58 (d, J = 8.8 Hz, 1H),
7.42 (d, J = 8.8 Hz, 1H), 2.92 (s, 6H). 13C NMR (75 MHz,
DMSO-d6): δ 155.6, 142.1, 133.7, 133.0, 120.8, 120.0, 112.7,
3-(4-bromo-2-chlorophenyl)-1,1-dimethylurea
(2d):
36.6. HRMS (ESI-QTOF): m/z (M
C9H11BrClN2O: 276.9743; found: 276.9735.
+
H)+ calcd for
Eluent: dichloromethane: petroleum ether (100:1). White solid,
45 mg, yield: 82%. mp: 74-76 oC. 1H NMR (300 MHz, CDCl3):
δ 8.17 (d, J = 8.9 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.35 (dd, J =
2.0, 8.8 Hz, 1H), 6.95 (s, 1H), 3.07 (s, 6H). 13C NMR (75 MHz,
CDCl3): δ 154.6, 135.3, 131.0, 130.7, 122.6, 121.7, 114.2, 36.4.
HRMS (ESI-QTOF): m/z (M + H)+ calcd for C9H11BrClN2O:
276.9743; found: 276.9738.
3-(3,4-dibromophenyl)-1,1-dimethylurea (2l): Eluent:
dichloromethane: petroleum ether (1:2). White solid, 41 mg,
yield: 64%. mp: 175-177 oC. 1H NMR (300 MHz, CDCl3): δ
7.74 (s, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.23 (t, J = 9.2, 7.3 Hz,
1H), 6.44 (s, 1H), 3.00 (s, 6H). 13C NMR (75 MHz, DMSO-d6):
δ 155.6, 142.0, 133.6, 124.0, 123.6, 120.4, 115.1, 36.6. HRMS
(ESI-QTOF): m/z (M + H)+ calcd for C9H11Br2N2O: 322.9218;
found: 322.9217.
3-(2,4-dibromophenyl)-1,1-dimethylurea (2e): Eluent:
dichloromethane: petroleum ether (8:1).White solid, 47 mg,
o
1
yield: 72%. mp: 80-81 C. H NMR (300 MHz, CDCl3): δ 8.16
(d, J = 8.9 Hz, 1H), 7.62 (d, J = 1.3 Hz, 1H), 7.37 (dd, J = 1.5,
8.9 Hz, 1H), 6.96 (s, 1H), 3.06 (s, 6H). 13C NMR (75 MHz,
CDCl3): δ 154.7, 136.4, 133.9, 131.3, 121.8, 114.7, 113.2, 36.4.
HRMS (ESI-QTOF): m/z (M + H)+ calcd for C9H11Br2N2O:
322.9218; found: 322.9212.
3-(4-bromo-2,3-dimethylphenyl)-1,1-dimethylurea (2m):
Eluent: dichloromethane: ethyl acetate (120:1). White solid, 47
mg, yield: 86%. mp: 182-184 oC. 1H NMR (300 MHz, CDCl3): δ
7.23 (d, J = 8.6 Hz, 1H), 7.08 (d, J = 8.6 Hz, 1H), 6.00 (s, 1H),
2.89 (s, 6H), 2.26 (s, 3H), 2.06 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 156.2, 136.4, 136.2, 131.5, 129.9, 123.4, 121.2, 36.5,
20.4, 15.3. HRMS (ESI-QTOF): m/z (M + H)+ calcd for
C11H16BrN2O: 271.0466; found: 271.0438.
methyl 5-bromo-2-(3,3-dimethylureido)benzoate (2f):
Eluent: dichloromethane: petroleum ether (15:1). White solid,
51 mg, yield: 85%. mp: 143-144 oC. 1H NMR (300 MHz,
CDCl3): δ 10.62 (s, 1H), 8.57 (d, J = 9.2 Hz, 1H), 8.13 (d, J =
2.2 Hz, 1H), 7.60 (dd, J = 2.2, 9.2 Hz, 1H), 3.94 (s, 1H), 3.11 (s,
6H). 13C NMR (75 MHz, CDCl3): δ 168.2, 155.2, 142.7, 137.2,
133.0, 121.1, 115.2, 112.6, 52.4, 36.3. HRMS (ESI-QTOF): m/z
(M + H)+ calcd for C11H14BrN2O3: 301.0188; found: 301.0185.
3-(4-bromo-2,5-dimethylphenyl)-1,1-dimethylurea (2n):
Eluent: dichloromethane: petroleum ether (15:1). White solid,
31 mg, yield: 58%. mp: 112-113 oC. 1H NMR (300 MHz,
CDCl3): δ 7.64 (s, 1H), 7.30 (s, 1H), 6.08 (s, 1H), 3.03 (s, 6H),
2.34 (s, 3H), 2.18 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 155.7,
136.3, 135.9, 133.3, 127.6, 124.6, 118.9, 36.4, 22.6, 17.0.
HRMS (ESI-QTOF): m/z (M + H)+ calcd for C11H16BrN2O:
271.0466; found: 271.0441.
3-(4-bromo-2-cyanophenyl)-1,1-dimethylurea
(2g):
Eluent: dichloromethane. White solid, 37 mg, yield: 69%. mp:
118-120 oC. 1H NMR (300 MHz, CDCl3): δ 8.21 (d, J = 9.6 Hz,
1H), 7.61 (d, J = 7.6 Hz, 1H), 7.59 (s, 1H), 6.96 (s, 1H), 3.06 (s,
6H). 13C NMR (75 MHz, CDCl3): δ 154.0, 141.6, 137.2, 133.7,
3-(4-bromo-3-chloro-2-fluorophenyl)-1,1-dimethylurea
(2o): Eluent: dichloromethane: petroleum ether (15:1). White
o
1
solid, 38 mg, yield: 65%. mp: 126-128 C. H NMR (300 MHz,

5
CDCl3): δ 8.04 (t, J = 8.8, 8.2 Hz, 1H), 7.36 (dd, J = 1.6, 8.8 Hz,
1H), 6.55 (s, 1H), 3.06 (s, 6H). 13C NMR (75 MHz, CDCl3): δ
2. a) Nishikata, T.; Abela, A. R.; Huang, S.; Lipshutz, B. H.
J. Am. Chem. Soc. 2010, 132, 4978-4979. b) Nishikata, T.;
Abela, A. R.; Lipshutz, B. H. Angew. Chem. Int. Ed. 2010, 49,
781-784. c) Jiang, Z.; Zhang, L.; Dong, C.; Su, X.; Li, H.;
Tang, W.; Xu, L.; Fan, Q. RSC Advances, 2013, 3, 1025-1028.
154.5, 148.6(d, J = 240 Hz), 128.3, 128.2, 119.8, 115.1, 36.5. 19
F
NMR (282 MHz, CDCl3): δ -127.39—127.43(m). HRMS (ESI-
QTOF): m/z (M + H)+ calcd for C9H10BrClFN2O: 294.9649;
found: 294.9648.
3. a) Willwacher, J.; Rakshit, S.; Glorius, F. Org. Biomol.
Chem. 2011, 9, 4736-4740. b) Manna, M. K.; Hossian, A.;
Jana, R. Org. Lett. 2015, 17, 672-675.
1-(4-bromo-2-methylphenyl)-3-ethylurea (2p): Eluent:
dichloromethane: ethyl acetate (80:1). White solid, 34 mg, yield:
o
1
67%. mp: 184-185 C. H NMR (300 MHz, DMSO-d6): δ 7.78
(d, J = 8.7 Hz, 1H), 7.59 (s, 1H), 7.18 (d, J = 8.9 Hz, 1H), 6.52
(s, 1H), 3.06-3.00 (m, 2H), 2.10 (s, 3H), 0.99 (t, J = 7.1 Hz, 3H).
13C NMR (75 MHz, DMSO-d6): δ 155.5, 138.3, 132.7, 129.5,
129.1, 122.1, 113.5, 34.4, 18.0, 15.8. HRMS (ESI-QTOF): m/z
(M + H)+ calcd for C10H14BrN2O: 257.0290; found: 257.0281.
4. a) Rauf, W.; Thompson, A. L.; Brown, J. M. Chem.
Commun. 2009, 26, 3874-3876. b) Kovács, S.; Tóth, B. L.;
Borsik, G.; Bihari, T.; May, N. V.; Stirling, A.; Novák, Z. Adv.
Synth. Catal. 2017, 359, 527-532. c) Wang, C.-M.; Tang, K.-
X.; Gao, T.-H.; Chen, L.; Sun, L.-P. J. Org. Chem. 2018, 83,
8315-8321.
1-(4-bromo-2-methylphenyl)-3-cyclopentylurea
(2q):
5. Sanabria, C. M.; Casal, M. T. d.; Souza, R. B. A. d.; Aguiar,
L. C. S. d.; Mattos, M. C. S. d. Synthesis. 2017, 49, 1648-1654.
Eluent: dichloromethane. White solid, 32 mg, yield: 54%. mp:
o
1
128-130 C. H NMR (300 MHz, DMSO-d6): δ 7.88 (d, J = 8.3
Hz, 1H), 7.54 (s, 1H), 7.30 (s, 1H), 7.22 (d, J = 6.8 Hz, 1H),
6.67 (d, J = 5.3 Hz, 1H), 3.90 (d, J = 5.5 Hz, 1H), 2.49 (s, 1H),
1.81 (s, 2H), 1.54-1.59(m, 4H), 1.35 (s, 2H),. 13C NMR (75
MHz, DMSO-d6): δ 155.1, 138.3, 132.7, 129.1, 128.9, 121.6,
113.2, 51.3, 33.3, 23.6, 18.0. HRMS (ESI-QTOF): m/z (M + H)+
calcd for C13H18BrN2O: 297.0603; found: 297.0595.
6. Saikia, I.; Borah, A. J.; Phukan, P. Chem. Rev. 2016, 116,
6837-7042.
7. a) Schroder, N.; Wencel-Delord, J.; Glorius, F. J. Am.
Chem. Soc. 2012, 134, 8298-8301. b) Du, Z.-J.; Gao, L.-X.;
Lin, Y.-J.; Han, F.-S. ChemCatChem 2013, 6, 123-126. c) Du,
B.; Jiang, X.; Sun, P. J. Org. Chem. 2013, 78, 2786-2791. d)
Wang, L.; Ackermann, L. Chem. Commun. 2014, 50, 1083-
1085. e) Yu, D.-G.; Gensch, T.; Azambuja, F. De.; Vasquez-
Cespedes, S.; Glorius, F. J. Am. Chem. Soc. 2014, 136, 17722-
17725. f) Pawar, A. B.; Lade, D. M. Org. Biomol. Chem.
2016, 14, 3275-3283. g) Kathiravan, S.; Nicholls, I. A. Chem.
– Eur. J. 2017, 23, 7031-7036.
N-(4-bromo-2-methylphenyl)pyrrolidine-1-carboxamide
(2r): Eluent: dichloromethane. White solid, 33 mg, yield: 58%.
mp: 135-137 oC. 1H NMR (300 MHz, CDCl3): δ 7.74 (d, J = 8.4
Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.26(s, 1H), 5.96 (s, 1H), 3.44
(s, 4H), 2.09 (s, 3H), 1.97 (s, 3H). 13C NMR (75 MHz, CDCl3):
δ 153.7, 136.4, 132.7, 129.6, 123.3, 115.8, 45.8, 25.6, 17.5.
HRMS (ESI-QTOF): m/z (M + H)+ calcd for C12H16BrN2O:
283.0446; found: 283.0440.
8. a) Song, B.; Zheng, X.; Mo, J.; Xu, B.; Adv. Synth. Catal.
2010, 352, 329-335. (b) Zhang, P.; Hong, L.; Li, G.; Wang, R.
Adv. Synth. Catal. 2014, 357, 345-349. (c) Zhan, B.-B.; Liu,
Y.-H.; Hu, F.; Shi, B.-F. Chem. Commun. 2016, 52, 4934-
4937.
N-(4-bromo-2-methylphenyl)morpholine-4-
carboxamide (2s): Eluent: dichloromethane. White solid, 43 mg,
yield: 72%. mp: 160-162 oC. 1H NMR (300 MHz, CDCl3): δ
7.49 (d, J = 8.7 Hz, 1H), 7.31 (s, 1H), 7.29 (d, J = 8.7 Hz, 1H),
6.16(s, 1H), 3.74 (t, J = 4.6, 4.8 Hz, 4H), 3.46 (t, J = 4.6, 4.8 Hz,
4H), 2.21 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 155.1, 135.9,
133.0, 131.3, 129.7, 117.1, 66.5, 44.3, 17.6. HRMS (ESI-QTOF):
m/z (M + H)+ calcd for C12H16BrN2O2: 299.0395; found:
299.0392.
9. a) Roche, D.; Prasad, K.; Repic, O.; Blacklock, T. J.
Tetrahedron Lett. 2000, 41, 2083-2085. (b) Goodman, M. A.;
Detty, M. R. Organometallics. 2004, 23, 3016-3020.
10. a) Kavala, V.; Naik, S.; Patel, B. K. J. Org. Chem. 2005,
70, 4267-4271. (b) Wang, Y.; Wang, Y.; Jiang, K.; Zhang, Q.;
Li, D. Org. Biomol. Chem. 2016, 14, 10180-10184. (c) Olsen,
K. L.; Jensen, M. R.; MacKay, J. A. Tetrahedron Lett. 2017,
58, 4111-4114.
Acknowledgements
We are grateful to the funds supported by Natural Science
Foundation of Jiangsu Province (CN) (NO. BK20181333) and
Excellent Science and Technology Innovation Team of Jiangsu
Province in 2015.
11. Jiao, J.-Y.; Mao, Y.-J.; Feng, A.-W.; Li, X.-F.; Li, M.-T.;
Zhang, X.-H. Tetrahedron 2017, 73, 1482-1488.
12. a) Mattos, M. C. De.; Esteves, P. M.; Almeida, L. S. De.;
Synthesis. 2006, 2, 221-223. (b) Shi, L.; Zhang, D.; Lin, R.;
Zhang, C.; Li, X.; Jiao, N. Tetrahedron Lett. 2014, 55, 2243-
2245. (c) Motati, D. R.; Uredi, D.; Watkins, E. B. Chem. Sci.
2018, 9, 1782-1788.
References and notes
1. a) Teegarden, B. R.; Li, H.; Jayakumar, H.; Strah-Pleynet,
S.; Dosa, P. L.; Selaya, S. D.; Kato, N.; Elwell, K. H.;
Davidson, J.; Cheng, K.; Saldana, H.; Frazer, J. M.; Whelan,
K.; Foster, J.; Espitia, S.; Webb, R. R.; Beeley, N. R.;
Thomsen, W.; Morairty, S. R.; Kilduff, T. S.; Al-Shamma, H.
A.; J. Med. Chem. 2010, 53, 1923-1936. b) Zheng, Q.-Z.;
Cheng, K.; Zhang, X.-M.; Liu, K.; Jiao, Q.-C.; Zhu, H.-L. Eur.
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A. K.; Lee, J. H.; Seo, S. H.; Cho, N. C.; Pae, A. N.; Keum, G.
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Regioselective Bromination of Aryl Ureas with Phenyliodine(III) Diacetate and
Potassium Bromide
Chun-Meng Wang, Jian-Yao Du, Jin-Yang Zhang , Kai-Xiang Tang , Tian-Hong Gao,
Yun-Gen Xu*, Li-Ping Sun*
Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry,
China Pharmaceutical University, Nanjing 210009, P. R. China.
A novel and efficient protocol of metal-free aryl C–H bond bromination of ureas has been
developed, in which simple and readily available bromide salt is employed as the bromine source.
This convenient conditions make this protocol very easy to handle and practical. Besides, the
present method tolerates a variety of functional groups and allows the synthesis of diverse
4-brominated urea derivatives in moderate to excellent yields.