Efficient Direct Halogenation of Unsymmetrical N -Benzyl- and N -Phenylureas with Trihaloisocyanuric Acids

Article abstract of DOI:10.1055/s-0036-1589149

A simple and efficient methodology for the direct halogenation of N -phenylureas was developed using trihaloisocyanuric acids in acetonitrile at room temperature. This protocol proved to be effective for the construction of N -phenylureas with different patterns of substitution. Additionally, less reactive N -benzylureas were halogenated in the presence of a mixture of trifluoroacetic acid and acetonitrile at room temperature.

Full text of DOI:10.1055/s-0036-1589149

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 49, A–I
paper
A
en
C. M. Sanabria et al.
Paper
Synthesis
Efficient Direct Halogenation of Unsymmetrical N-Benzyl- and
N-Phenylureas with Trihaloisocyanuric Acids
Carlos M. Sanabria
Bruno B. S. Costa
Gil M. Viana
Lúcia C. S. de Aguiar*
Marcio C. S. de Mattos*
Departamento de Química Orgânica, Instituto de Química,
Universidade Federal do Rio de Janeiro, CP 68545, 21945-970,
Rio de Janeiro, Brazil
luciasequeira@yahoo.com.br
mmattos@iq.ufrj.br
Received: 02.10.2017
Accepted after revision: 14.11.2017
Published online: 13.12.2017
DOI: 10.1055/s-0036-1589149; Art ID: ss-2017-m0635-op
H
H
F3C
Cl
N
N
N
H
O
N
O
O
Abstract A simple and efficient methodology for the direct halogena-
tion of N-phenylureas was developed using trihaloisocyanuric acids in
acetonitrile at room temperature. This protocol proved to be effective
for the construction of N-phenylureas with different patterns of substi-
tution. Additionally, less reactive N-benzylureas were halogenated in
the presence of a mixture of trifluoroacetic acid and acetonitrile at
room temperature.
Sorafenib
CH3
N
H
H
H
N
N
N
Cl
Cl
Cl
CH3
O
N
O
Diuron
Forchlorfenuron
H
N
H
CH3
N
Key words ureas, trihaloisocyanuric acids, halogenation, electrophilic
aromatic substitution, arenes, chemoselectivity, regioselectivity
N
H
N
Cl
OCH3
O
I
O
Br
Metobromuron
ICEU
Substituted ureas have attracted great interest over the
last years due to their diverse properties in several fields of
chemistry. Their structural properties are exploited in supra-
molecular chemistry,1 for preparation of nanosheets,2 as chi-
ral resolving agents,3 and as organocatalysts,4 to name a few.
N-(Halophenyl)ureas are useful building blocks in the
synthesis of more complex molecules.5 Besides, diverse ha-
logenated N-phenylureas exhibit biological activity (Figure
1). In medicinal chemistry, they play an important role as
anticancer agents due to the wide range of activities against
various leukemias and solid tumors.6 For example,
Sorafenib7 (Nexavar®) is a chlorinated biarylurea used as ki-
nase inhibitor drug for the treatment of renal and hepato-
cellular carcinoma, while ICEU8 has antitumor activity in
murine colon carcinoma, and both were shown to block tu-
mor proliferation and angiogenesis. As agrochemicals, halo-
genated derivatives of N-phenylurea are recognized by their
herbicidal activity (Diuron9 and Metobromuron10) and as a
plant growth regulator (Forchlorfenuron11).
Figure 1 Halogenated N-phenylurea derivatives with biological activity
There are only a few methodologies for the direct halo-
genation of N-arylureas.12–14 More commonly, they have
been prepared by the reaction of expensive haloaryl-isocy-
anates with amines5c,15 or isocyanates with halogenated
anilines.1a,8a,16
Being interested in the synthesis of iodinated substitut-
ed N-phenylureas, we have already established that upon
treatment of thioureas with acidic aqueous potassium di-
chloroiodate (KICl2),13 they undergo sequential oxidation
and iodination reactions giving iodoaryl ureas (mono- and
disubstituted). More recently, our group reported another
efficient protocol for direct iodination of N-phenylurea de-
rivatives using iodine and trichloroisocyanuric acid14 under
mild and neutral conditions. This method proved to be effi-
cient for a broad range of substituted N-phenylureas, even
with trisubstituted derivatives, forming the p-iodinated
compound regioselectively in high yields.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 49, A–I

B
C. M. Sanabria et al.
Paper
Synthesis
Trihaloisocyanuric acids (TXCA, Figure 2) are analogue
reagents to the traditional N-halosuccinimides. Among the
trihaloisocyanuric acids, the most widely used is the inex-
pensive and commercially available trichloroisocyanuric
acid (TCCA).17 Although not readily commercially available,
tribromoisocyanuric acid (TBCA)18 can be prepared by a
green methodology using cyanuric acid, KBr and Oxone®,19
while triiodoisocyanuric acid (TICA)20 can be prepared by
reaction of iodine with TCCA. These trihaloisocyanuric ac-
ids are efficient halogenating reagents of activated aromatic
compounds, due to their high capacity to provide halenium
ions (‘X+’).17–22
Based on the above results, we extended our methodol-
ogy to diverse N-phenylureas 1 with different patterns of
substitution (Scheme 2) performing the reactions in a 0.25
mmol scale. It was observed that mono-halogenation reac-
tions take place in good to excellent yields (83–98%), inde-
pendently of the N-phenylurea 1 and trihaloisocyanuric
acid employed. Moreover, increasing the reaction scale to
5.0 mmol, the N-(halophenyl)ureas 2f and 3a were ob-
tained in 96% (crude) and 93% (pure) yield, respectively.
R1
N
O
R1
N
H
N
H
X
X
2 (X = Cl)
3 (X = Br)
4 (X = I)
MeCN
N
R2
N
N
R2
+
r.t.
1–2 h
O
O
O
N
X
O
X
O
1
Cl (TCCA)
X
X
N
N
H
N
H
H
X =
H
N
H
N
Br (TBCA)
I (TICA)
NH2
N
N
O
N
X
O
O
O
O
X
X
X
2a: 90%a (p/o = 67:33)
3a: 91%
2b: 83%a (p/o = 66:34)
3b: 84%
2c: 92%a (p/o = 66:34)
3c: 91%
Figure 2 Trihaloisocyanuric acids (TXCA)
4a: 91%
Continuing our interest on the preparation of haloge-
nated ureas, we decided to investigate the reaction of aryl-
ureas with trihaloisocyanuric acids.
H
N
H
H
H
N
N
N
O
O
X
X
N-Butyl-N′-phenylurea (1a) was chosen as a model sub-
strate for the halogenation reaction (Scheme 1). After test-
ing different urea/TCCA ratios, it was established that with
a 1:0.34 (urea/TCCA) ratio in a 0.25 mmol scale, chlorina-
tion of 1a proceeded smoothly at room temperature (25 °C)
giving the regioisomeric mixture of p- and o-N-(chlorophe-
nyl)ureas 2a and 2a′ in excellent combined yield (90%) with
2:1 selectivity in favor of the para-isomer 2a, after separa-
tion by thin-layer chromatography. On the other hand,
when the same substrate 1a reacted with tribromoiso-
cyanuric acid (TBCA) and triiodoisocyanuric acid (TICA), the
reactions did not reach completion and it was necessary to
increase the amount of the halogenation reagent. Therefore,
using 1:0.5 (urea/TXCA) ratio, both bromination and iodin-
ation of 1a were highly regioselective in the para-position,
forming N-butyl-N′-(4-halophenyl)ureas 3a and 4a as the
major isolated products (91%).
2d: 93%a (p/o = 71:29)
3d: 82%
2e: 98%a (p/o = 66:34b)
3e: 91%
O
H
N
H
H
N
N
N
N
N
O
O
O
X
X
X
2f: 89%a (p/o = 66:34)
3f: 96%
2h: 95%a (p/o = 65:35)
3h: 95%
2g: 96%a (p/o = 66:34)
3g: 98%
4f: 92%
X
X
H
H
N
N
N
N
O
O
H3C
I
2i: 71%
3i: 78%
2j: 63%
3j: 66%
Scheme 2 Halogenation of N-phenylureas with trihaloisocyanuric ac-
ids (isolated yields of pure products). a Combined yield. b Determined by
NMR spectroscopy.
H
H
N
N
Once more, the reactions with TCCA led to a regio-
isomeric mixture of o- and p-chlorinated products with
nearly 1:2 ratio in favor of the para-isomer, while reactions
with TBCA and TICA led to the halogenated products with a
high para-regioselectivity. The regioisomeric chlorinated
products were separated by using a silica gel thin-layer
chromatography plate with hexanes/ethyl acetate as eluent.
On the other hand, NMR analyses of the crude bromination
and iodination reactions indicated, in some cases, the for-
mation of trace amounts of the o-isomers, which were lost
during the workup process (simple vacuum filtration). In-
terestingly, iodination reactions of 1a and 1f with TICA gave
similar results to those obtained with the more convenient
O
H
H
1a
N
N
MeCN
+
r.t.
2 h
O
O
X
X
X
2a: X = Cl (90%, o and p)
3a: X = Br (91%)
4a: X = I (91%)
N
N
O
N
X
O
Scheme 1 Reaction of N-butyl-N′-phenylurea with trihaloisocyanuric
acids
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 49, A–I

C
C. M. Sanabria et al.
Paper
Synthesis
iodination system I2/TCCA.14 Furthermore, when the para-
position of a N-phenylurea was blocked with a substituent,
as in 1i (-Me) and 1j (-I), the halogenation reactions still oc-
curred, but with a small decrease in the yields (63–78%).
In addition, it was observed that by doubling the
amount of trihaloisocyanuric acids and increasing the reac-
tion time, the dihalogenated N-phenylureas 5a (76%) and 6a
(69%) were produced. However, even with a large excess of
the halogenating reagents, the introduction of a third halo-
gen atom was difficult and the trihalogenated products 5b
(39%) and 6b (26%) were obtained in low yields (Scheme 3).
O
O
O
R1
N
R2
CF3CO2H
MeCN
X
X
R1
N
N
N
N
N
R2
H
+
H
r.t.
6 h
O
N
X
O
X
7
8 (X = Cl)
9 (X = Br)
O
O
N
N
N
H
N
H
H
X
X
8b: 51%a (p/o 47:53)
9b: 76%a (p/o 52:48)
8a: 59%a (p/o 53:47)
9a: 82%a (p/o 46:54)
Scheme 4 Halogenation of N-benzylureas with trihaloisocyanuric acids
(isolated yields of pure products). a Combined yield.
O
H
H
MeCN
X
X
N
N
N
N
+
N
N
r.t.
17–24 h
N-benzylureas are less reactive than their phenyl analogues,
they can also be halogenated in the presence of trifluoro-
acetic acid. Furthermore, by increasing the amount of TXCA,
polyhalogenated N-phenylureas can be obtained.
O
O
O
N
X
O
Xn
5a,b, X = Cl
6a,b, X = Br
1h
(excess)
X
X
H
N
H
N
N
N
O
O
X
X
X
TCCA was purchased from Aldrich and used as received. Commercially
available reagents and solvents were used without further purifica-
tion. TBCA,19 TICA20 and N,N-diethyl-N′-(4-iodophenyl)urea14 1j were
prepared as described. Substituted N-phenylureas 1 were prepared by
reaction of p-toluyl or phenyl isocyanate with the corresponding
amine in CH2Cl2 or hexanes while substituted N-benzylureas 7 were
5a: 76%
6a: 69%
5b: 39%
6b: 26%
Scheme 3 Polyhalogenation of N,N-diethyl-N-phenylurea with triha-
loisocyanuric acids (isolated yields of pure products)
13
prepared via treatment of the corresponding thioureas with KICl2
Interestingly the halogenation reactions of N-benzyl-N′-
phenylureas (1c–e) were highly chemoselective, affording
only halogenated N-phenylureas (2c–e and 3c–e), with no
halogenation on the benzylic ring being detected. Several
attempts to chlorinate or brominate N-benzylureas using
trihaloisocyanuric acids in acetonitrile were unsuccessful
and unreacted substrates were recovered, even using excess
of the halogenating reagents, higher temperatures or long
reaction times.
(see the Supporting Information). The reactions were monitored by
TLC and the crude products were purified by thin-layer chromatogra-
phy (silica gel, 35 mesh) or column chromatography (silica gel, 230–
400 mesh) using hexanes/EtOAc as eluent. 1H and 13C NMR spectra
were recorded with Bruker Avance 300 and 500 MHz spectrometers
using CDCl3 or DMSO-d6 as solvents and TMS as internal standard. IR
spectra were recorded with a Nicolet 6700FT-IR spectrophotometer
as neat films on KBr plates. HRMS were obtained with a Brukermicro-
TOF II mass spectrometer using ESI.
Monohalogenation of N-Arylureas 1; General Procedure for the
Preparation of N-(Haloaryl)ureas 2–4
As the reactivity of trihaloisocyanuric acids with arenes
is highly affected by the acid strength of the reaction me-
dia,23 we investigated the halogenation reaction on the ben-
zene moiety of some N-benzylureas 7 using trifluoroacetic
acid or a mixture of it with acetonitrile (1:1) as the reaction
solvent. Under these acidic media, the reaction took place
giving the corresponding halogenated products 8 and 9 in
moderate to good yields (51–82%), as shown in the Scheme
4. However, with regard to the halogenation of the N-
phenylureas, the regioselectivity was lost and ca. 1:1 mix-
tures of o- and p-halobenzylureas were obtained. Unfortu-
nately, the reactions with TICA under these conditions led
to a mixture of several unidentified products.
In conclusion, it was established that trihaloisocyanuric
acids are efficient reagents for the direct halogenation of a
variety of N-phenylureas, even when the para-position is
blocked. This process takes place in high yields under mild
and neutral reaction conditions. The bromination of N-phenyl-
ureas stands out due to its higher para-selectivity. Although
TCCA (0.083 mmol) was added to a stirred solution of the substituted
N-phenylurea (0.25 mmol) in MeCN (5–10 mL) at r.t. (25 °C) and the
mixture was stirred until completion of the reaction (TLC). The reac-
tion was quenched with 15% NaHSO3 (10 mL). The final mixture was
extracted with EtOAc and washed with brine and water. The organic
layer was separated, dried over anhydrous sodium sulfate followed by
removal of solvent under reduced pressure. The crude products were
separated on silica gel thin-layer chromatography plates using EtO-
Ac/hexanes as eluent.
For the bromination and iodination reactions, the above procedure
was performed using 0.125 mmol of TBCA or TICA. After quenching
the reaction with NaHSO3 solution, the crude products precipitated
and were filtered off. They did not require further purification.
N-Butyl-N′-(4-chlorophenyl)urea (2a)24
Yield: 34.0 mg (60%); white powder; mp 161–162 °C (Lit.24 173–
174 °C); Rf = 0.47 (EtOAc/hexanes, 1:1).
IR (KBr): 3328, 3299, 2959, 2936, 2866, 1630, 1589, 1561, 1519, 1489,
1233, 1091, 832, 687 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 49, A–I

D
C. M. Sanabria et al.
Paper
Synthesis
1H NMR (300 MHz, DMSO-d6): δ = 8.54 (s, 1 H), 7.41 (d, J = 8.8 Hz,
2 H), 7.24 (d, J = 8.8 Hz, 2 H), 6.16 (t, J = 5.5 Hz, 1 H), 3.07 (dd, J = 12.6,
6.5 Hz, 2 H), 1.45–1.20 (m, 4 H), 0.88 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 155.0, 139.6, 128.4, 124.3, 119.0,
38.7, 31.8, 19.5, 13.6.
N-Benzyl-N′-(2-chlorophenyl)urea (2c′)25
Yield: 20.2 mg (31%); white powder; Rf = 0.62 (EtOAc/hexanes, 1:1).
IR (KBr): 3440, 3307, 3024, 1689, 1637, 1589, 1549, 1469, 1440, 1384,
1301, 1233, 743, 700 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 8.21 (s, 1 H), 8.15 (d, J = 8.3 Hz,
1 H), 7.61 (s, 1 H), 7.39 (d, J = 8.0 Hz, 1 H), 7.37–7.30 (m, 4 H), 7.29–
7.20 (m, 2 H), 6.95 (t, J = 7.7 Hz, 1 H), 4.31 (d, J = 5.4 Hz, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C11H16ClN2O: 227.094567; found:
227.094371.
13C NMR (125 MHz, DMSO-d6): δ = 154.9, 139.9, 136.7, 129.1, 128.4,
127.4, 127.3, 126.9, 122.5, 121.3, 120.9, 42.8.
N-Butyl-N′-(2-chlorophenyl)urea (2a′)12
Yield: 17.0 mg (30%); white powder; mp 110–111 °C; Rf = 0.62 (EtO-
Ac/hexanes, 1:1).
N-(4-Chlorophenyl)-N′-[(1R)-phenylethyl]urea (2d)28
IR (KBr): 3346, 3283, 2961, 2934, 2871, 1635, 1587, 1553, 1473, 1440,
Yield: 45.3 mg (66%); white powder; mp 162–163 °C; Rf = 0.65 (EtO-
Ac/hexanes, 1:1).
1298, 1231, 1056, 1031, 746 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 8.16 (dd, J = 8.3, 1.4 Hz, 1 H), 7.97
(s, 1 H), 7.37 (dd, J = 8.0, 1.4 Hz, 1 H), 7.25–7.18 (m, 1 H), 6.99 (t,
J = 5.4 Hz, 1 H), 6.92 (ddd, J = 8.0, 7.4, 1.6 Hz, 1 H), 3.09 (dd, J = 12.3,
6.6 Hz, 2 H), 1.46–1.24 (m, 4 H), 0.89 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 154.7, 136.8, 129.0, 127.4, 122.2,
121.0, 120.6, 38.7, 31.6, 19.5, 13.6.
IR (KBr): 3301, 3090, 3034, 2970, 1632, 1591, 1565, 1490, 1450, 1397,
1235, 1090, 1023, 834, 803, 744, 693 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 8.75 (s, 1 H), 7.38 (d, J = 8.8 Hz,
2 H), 7.32–7.29 (m, 4 H), 7.21 (d, J = 8.8 Hz, 2 H), 7.18–7.15 (m, 1 H),
6.86 (d, J = 7.8 Hz, 1 H), 4.79 (quint, J = 7.0 Hz, 1 H), 1.35 (d, J = 7.0 Hz,
3 H).
13C NMR (126 MHz, DMSO-d6): δ = 154.3, 145.2, 139.5, 128.4, 128.4,
128.3, 126.6, 125.8, 124.4, 119.0, 48.6, 23.0.
HRMS (ESI): m/z [M + H]+ calcd for C11H16ClN2O: 227.094567; found:
227.093817.
HRMS (ESI): m/z [M + H]+ calcd for C15H16ClN2O: 275.094567; found:
275.093955.
N-(4-Chlorophenyl)urea (2b)25
Yield: 23.5 mg (55%); white powder; mp 210 °C (dec.) (Lit.26 212 °C,
dec.); Rf = 0.08 (EtOAc/hexanes, 1:1).
N-(2-Chlorophenyl)-N′-[(1R)-phenylethyl]urea (2d′)28
IR (KBr): 3427, 3314, 3214, 1655, 1612, 1587, 1550, 1491, 1401, 1357,
Yield: 18.5 mg (27%); white powder; Rf = 0.74 (EtOAc/hexanes, 1:1).
1251, 1091, 821 cm–1
.
IR (KBr): 3300, 3031, 2976, 2932, 1633, 1588, 1558, 1493, 1472, 1441,
1H NMR (300 MHz, DMSO-d6): δ = 8.78 (s, 1 H), 7.42 (d, J = 8.7 Hz,
2 H), 7.24 (d, J = 8.7 Hz, 2 H), 5.94 (s, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 156.0, 139.6, 128.4, 124.5, 119.2.
HRMS (ESI): m/z [M + Na]+ calcd for C7H7ClN2NaO: 193.013911;
found: 193.014674.
1248, 1233, 1052, 744, 696 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 8.13–8.10 (m, 1 H), 8.09 (s, 1 H),
7.59 (d, J = 7.6 Hz, 1 H), 7.38–7.34 (m, 1 H), 7.32 (d, J = 4.3 Hz, 4 H),
7.24–7.15 (m, 2 H), 6.92–6.89 (m, 1 H), 4.80 (quint, J = 6.9 Hz, 1 H),
1.37 (d, J = 6.9 Hz, 3 H).
13C NMR (126 MHz, DMSO-d6): δ = 153.9, 145.0, 136.7, 129.0, 128.3,
127.4, 126.7, 125.8, 122.3, 120.9, 120.4, 48.8, 23.1.
N-(2-Chlorophenyl)urea (2b′)25
Yield: 12.0 mg (28%); white powder; mp 177 °C (dec.) (Lit.27 175 °C,
HRMS (ESI): m/z [M + H]+ calcd for C15H16ClN2O: 275.094567; found:
dec.); Rf = 0.19 (EtOAc/hexanes, 1:1).
275.093953.
IR (KBr): 3423, 3294, 3204, 1653, 1603, 1580, 1519, 1480, 1442, 1357,
1062, 771, 757, 734, 691, 604 cm–1
.
N,N-Diethyl-N′-(4-chlorophenyl)urea (2f)29
1H NMR (300 MHz, DMSO-d6): δ = 8.13 (d, J = 8.3 Hz, 1 H), 8.08
(s, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), 7.22 (t, J = 7.8 Hz, 1 H), 6.94
(t, J = 7.6 Hz, 1 H), 6.42 (s, 2 H).
Yield: 33.3 mg (59%); white powder; mp 108–110 °C; Rf = 0.43 (EtO-
Ac/hexanes, 1:1).
IR (KBr): 3328, 3254, 3107, 2983, 2936, 2874, 1634, 1589, 1519, 1494,
1418, 1304, 1086, 1011, 818 cm–1
.
13C NMR (75 MHz, DMSO-d6): δ = 155.6, 136.8, 129.0, 127.3, 122.5,
1H NMR (500 MHz, CDCl3): δ = 7.33 (d, J = 8.9 Hz, 2 H), 7.21 (d,
J = 8.8 Hz, 2 H), 6.34 (s, 1 H), 3.35 (q, J = 7.1 Hz, 4 H), 1.21 (t, J = 7.2 Hz,
6 H).
121.4, 121.2.
N-Benzyl-N′-(4-chlorophenyl)urea (2c)25
13C NMR (126 MHz, CDCl3): δ = 154.5, 138.0, 128.8, 127.8, 121.2, 41.8,
Yield: 39.8 mg (61%); white powder; mp 160 °C (dec.); Rf = 0.47 (EtO-
Ac/hexanes, 1:1).
14.0.
IR (KBr): 3422, 3313, 3062, 1636, 1594, 1566, 1489, 1398, 1237, 1088,
747, 698, 655 cm–1
.
N,N-Diethyl-N′-(2-chlorophenyl)urea (2f′)30
1H NMR (300 MHz, DMSO-d6): δ = 9.10 (s, 1 H), 7.45 (d, J = 8.1 Hz,
2 H), 7.34–7.24 (m, 5 H), 7.25 (d, J = 8.2 Hz, 2 H), 7.02 (s, 1 H), 4.29 (d,
J = 5.0 Hz, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 155.2, 140.3, 139.7, 128.4, 128.3,
127.1, 126.7, 124.4, 119.1, 42.7.
Yield: 16.9 mg (30%); yellow oil; Rf = 0.57 (EtOAc/hexanes, 1:1).
IR (KBr): 3443, 3335, 3070, 2973, 2932, 2874, 1678, 1594, 1518, 1489,
1440, 1301, 1263, 1234, 1159, 1097, 1034, 974, 936, 751 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.25 (dd, J = 8.3, 1.5 Hz, 1 H), 7.32 (dd,
J = 8.0, 1.5 Hz, 1 H), 7.25–7.21 (m, 1 H), 7.00 (s, 1 H), 6.93 (td, J = 7.9,
1.5 Hz, 1 H), 3.41 (q, J = 7.2 Hz, 4 H), 1.26 (t, J = 7.2 Hz, 6 H).
HRMS (ESI): m/z [M + Na]+ calcd for C14H13ClN2NaO: 283.060861;
found: 283.060099.
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C. M. Sanabria et al.
Paper
Synthesis
13C NMR (126 MHz, CDCl3): δ = 154.0, 136.2, 128.8, 127.8, 122.8,
122.1, 120.8, 42.0, 14.0.
IR (KBr): 3446, 3336, 2973, 2931, 2873, 1674, 1612, 1583, 1520, 1486,
1403, 1300, 1264, 1159, 1097, 819 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C11H16ClN2O: 227.094567; found:
227.094860.
1H NMR (500 MHz, CDCl3): δ = 8.09 (d, J = 8.4 Hz, 1 H), 7.13 (s, 1 H),
7.03 (d, J = 8.4 Hz, 1 H), 6.88 (s, 1 H), 3.39 (q, J = 7.2 Hz, 4 H), 2.26 (s,
3 H), 1.24 (t, J = 7.2 Hz, 6 H).
N,N-Diisopropyl-N′-(4-chlorophenyl)urea (2g)30
13C NMR (126 MHz, CDCl3): δ = 154.2, 133.7, 132.7, 129.0, 128.4,
122.0, 120.9, 41.9, 20.5, 14.0.
Yield: 40.1 mg (63%); white powder; mp 137–138 °C; Rf = 0.62 (EtO-
HRMS (ESI): m/z [M + H]+ calcd for C12H18ClN2O: 241.110217; found:
Ac/hexanes, 1:1).
241.109766.
IR (KBr): 3319, 2968, 2933, 2759, 1636, 1591, 1525, 1494, 1431, 1395,
1375, 1334, 1261, 1242, 824, 608 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.30 (d, J = 8.8 Hz, 2 H), 7.21 (d,
J = 8.9 Hz, 2 H), 6.20 (s, 1 H), 3.97 (hept, J = 6.8 Hz, 2 H), 1.32 (d,
J = 6.9 Hz, 12 H).
N,N-Diethyl-N′-(2-chloro-4-iodophenyl)urea (2j)
Yield: 55.6 mg (63%); yellow-redish oil; Rf = 0.54 (EtOAc/hexanes,
1:1).
13C NMR (126 MHz, CDCl3): δ = 154.6, 138.0, 129.0, 128.9, 127.8,
121.2, 45.8, 21.6.
IR (KBr): 3442, 2969, 2927, 2871, 1673, 1574, 1510, 1402, 1377, 1299,
1269, 1259, 1234, 1160, 1082, 833, 818, 749, 725 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C13H20ClN2O: 255.125867; found:
255.124831.
1H NMR (500 MHz, CDCl3): δ = 8.06 (d, J = 8.8 Hz, 1 H), 7.63 (d,
J = 2.0 Hz, 1 H), 7.51 (dd, J = 8.8, 2.0 Hz, 1 H), 6.96 (s, 1 H), 3.39 (q,
J = 7.2 Hz, 4 H), 1.25 (t, J = 7.2 Hz, 6 H).
N,N-Diisopropyl-N′-(2-chlorophenyl)urea (2g′)30
13C NMR (126 MHz, CDCl3): δ = 153.7, 136.7, 136.7, 136.3, 122.8,
122.2, 83.8, 42.0, 13.9.
Yield: 21.0 mg (33%); white powder; mp 63–64 °C; Rf = 0.68 (EtO-
HRMS (ESI): m/z [M + Na]+ calcd for C11H14ClIN2NaO: 374.973159;
Ac/hexanes, 1:1).
found: 374.971995.
IR (KBr): 3455, 3202, 2964, 2928, 1628, 1584, 1525, 1481, 1442, 1338,
1260, 1100, 1056, 1033, 803, 609 cm–1
.
N-Butyl-N′-(4-bromophenyl)urea (3a)12
Yield: 61.5 mg (91%); white powder; mp 184–185 °C (Lit.35 185 °C); Rf
1H NMR (500 MHz, CDCl3): δ = 8.25 (dd, J = 8.4, 1.3 Hz, 1 H), 7.31 (dd,
J = 8.0, 1.4 Hz, 1 H), 7.22 (t, J = 7.9 Hz, 1 H), 6.93 (s, 1 H), 6.93–6.87 (m,
1 H), 4.06 (hept, J = 6.9 Hz, 2 H), 1.35 (d, J = 6.9 Hz, 12 H).
= 0.47 (EtOAc/hexanes, 1:1).
13C NMR (126 MHz, CDCl3): δ = 154.2, 136.5, 128.8, 127.8, 122.6,
121.9, 121.0, 45.7, 21.5.
IR (KBr): 3350, 3277, 2959, 2929, 2857, 1745, 1636, 1582, 1553, 1467,
1296, 1045, 1025, 744, 642 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C13H20ClN2O: 255.125867; found:
255.125135.
1H NMR (300 MHz, DMSO-d6): δ = 8.92 (s, 1 H), 7.36 (s, 4 H), 6.46 (t,
J = 5.4 Hz, 1 H), 3.05 (dd, J = 12.5, 6.4 Hz, 2 H), 1.43–1.21 (m, 4 H), 0.87
(t, J = 7.2 Hz, 3 H).
N-(4-Chlorophenyl)morpholine-4-carboxamide (2h)31
Yield: 39.1 mg (65%); white powder; mp 198–199 °C (Lit.32 199–
13C NMR (75 MHz, DMSO-d6): δ = 155.2, 140.2, 131.2, 119.4, 111.9,
62.8, 38.5, 31.8, 19.5, 13.6.
HRMS (ESI): m/z [M + H]+ calcd for C11H16BrN2O: 271.044052; found:
202 °C); Rf = 0.17 (EtOAc/hexanes, 1:1).
271.043038.
IR (KBr): 3296, 2953, 2889, 2849, 1634, 1591, 1510, 1498, 1422, 1305,
1276, 1248, 1115, 833, 822, 812 cm–1
.
N-(4-Bromophenyl)urea (3b)25
Yield: 45.4 mg (84%); white powder; mp 270 °C (dec.) (Lit.36 265–
1H NMR (500 MHz, DMSO-d6): δ = 8.65 (s, 1 H), 7.49 (dd, J = 8.9,
2.5 Hz, 2 H), 7.27 (dd, J = 8.9, 2.5 Hz, 2 H), 3.60 (s, 4 H), 3.41 (s, 4 H).
268 °C, dec.); Rf = 0.06 (EtOAc/hexanes, 1:1).
13C NMR (125 MHz, DMSO-d6): δ = 155.0, 139.5, 128.2, 125.5, 121.1,
66.0, 44.2.
IR (KBr): 3427, 3310, 3214, 1654, 1610, 1584, 1549, 1487, 1399, 1356,
1249, 1072, 817, 721 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C11H14ClN2O2: 241.073832; found:
241.072879.
1H NMR (300 MHz, DMSO-d6): δ = 8.98 (s, 1 H), 7.55–7.21 (m, 4 H),
6.01 (s, 2 H).
N-(2-Chlorophenyl)morpholine-4-carboxamide (2h′)33
Yield: 18.0 mg (30%); white powder; mp 124–126 °C (Lit.34 125 °C);
13C NMR (75 MHz, DMSO-d6): δ = 156.0, 140.1, 131.2, 119.6, 112.2.
HRMS (ESI): m/z [M + Na]+ calcd for C7H7BrN2NaO: 236.963396;
Rf = 0.32 (EtOAc/hexanes, 1:1).
found: 236.964329.
IR (KBr): 3323, 2964, 2911, 2888, 2853, 1632, 1512, 1453, 1290, 1251,
1119, 1071, 1001, 752 cm–1
.
N-Benzyl-N′-(4-bromophenyl)urea (3c)25
1H NMR (500 MHz, DMSO-d6): δ = 8.23 (s, 1 H), 7.51 (d, J = 8.0 Hz,
1 H), 7.45 (d, J = 8.0 Hz, 1 H), 7.28 (t, J = 7.7 Hz, 1 H), 7.14 (t, J = 7.7 Hz,
1 H), 3.61 (s, 4 H), 3.42 (s, 4 H).
Yield: 69.2 mg (91%); white powder; mp 208–210 °C; Rf = 0.47 (EtO-
Ac/hexanes, 1:1).
IR (KBr): 3315, 3289, 3030, 2932, 2884, 1634, 1590, 1561, 1484, 1474,
13C NMR (126 MHz, DMSO-d6): δ = 155.2, 136.5, 129.2, 128.2, 127.2,
1238, 1009, 745, 701 cm–1
.
127.0, 125.6, 66.0, 44.2.
1H NMR (300 MHz, DMSO-d6): δ = 8.72 (s, 1 H), 7.37 (s, 4 H), 7.34–
7.22 (m, 5 H), 6.67 (t, J = 5.9 Hz, 1 H), 4.30 (d, J = 5.9 Hz, 2 H).
N,N-Diethyl-N′-(2-chloro-4-methylphenyl)urea (2i)
13C NMR (75 MHz, DMSO-d6): δ = 155.0, 140.2, 139.9, 131.3, 128.3,
127.1, 126.7, 119.6, 112.4, 42.7.
Yield: 42.5 mg (71%); yellow oil; Rf = 0.52 (EtOAc/hexanes, 1:1).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 49, A–I

F
C. M. Sanabria et al.
Paper
Synthesis
HRMS (ESI): m/z [M + Na]+ calcd for C14H13BrN2NaO: 327.010346;
found: 327.008886.
IR (KBr): 3295, 3096, 3068, 2970, 2908, 2846, 1639, 1586, 1510, 1419,
1284, 1246, 1113, 1080, 828 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 8.64 (s, 1 H), 7.47–7.42 (m, 2 H),
7.41–7.37 (m, 2 H), 3.62–3.56 (m, 4 H), 3.43–3.39 (m, 4 H).
N-(4-Bromophenyl)-N′-[(1R)-phenylethyl]urea (3d)28
13C NMR (125 MHz, DMSO-d6): δ = 154.9, 139.9, 131.3, 121.4, 113.3,
66.0, 44.1.
Yield: 65.2 mg (82%); white powder; mp 190–191 °C; Rf = 0.52 (EtO-
Ac/hexanes, 1:1).
HRMS (ESI): m/z [M + H]+ calcd for C11H14BrN2O2: 285.023316; found:
285.022839.
IR (KBr): 3301, 3086, 2981, 1627, 1587, 1556, 1486, 1450, 1394, 1234,
1131, 1022, 832, 697 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 8.52 (s, 1 H), 7.35 (d, J = 4.0 Hz,
4 H), 7.33 (d, J = 4.3 Hz, 4 H), 7.23 (dq, J = 8.6, 4.2 Hz, 1 H), 6.66 (d,
J = 7.8 Hz, 1 H), 4.81 (quint, J = 7.0 Hz, 1 H), 1.38 (d, J = 7.0 Hz, 3 H).
13C NMR (126 MHz, DMSO-d6): δ = 154.2, 145.0, 139.8, 131.4, 128.3,
126.7, 125.8, 119.5, 112.3, 48.6, 23.0.
N,N-Diethyl-N′-(2-bromo-4-methylphenyl)urea (3i)
Yield: 55.4 mg (78%); yellow oil; Rf = 0.48 (EtOAc/hexanes, 1:1).
IR (KBr): 3432, 3336, 2973, 2930, 2872, 1674, 1609, 1577, 1519, 1487,
1401, 1298, 1275, 1159, 1802, 820, 749 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C15H16BrN2O: 319.044052; found:
319.043238.
1H NMR (500 MHz, CDCl3): δ = 8.09 (d, J = 8.4 Hz, 1 H), 7.30 (d,
J = 1.8 Hz, 1 H), 7.10–7.03 (m, 1 H), 6.89 (s, 1 H), 3.40 (q, J = 7.2 Hz,
4 H), 2.27 (s, 3 H), 1.26 (t, J = 7.2 Hz, 6 H).
13C NMR (126 MHz, CDCl3): δ = 154.2, 134.8, 133.3, 132.3, 129.1,
121.1, 113.0, 42.0, 20.5, 14.0.
N-(4-Bromophenyl)-N′-[(1S)-phenylethyl]urea (3e)28
Yield: 72.3 mg (91%); white powder; mp 190–191 °C; Rf = 0.52 (EtO-
Ac/hexanes, 1:1).
HRMS (ESI): m/z [M + H]+ calcd for C12H18BrN2O: 285.059702; found:
285.059040.
IR (KBr): 3301, 3086, 2981, 1627, 1587, 1556, 1486, 1450, 1394, 1234,
1131, 1022, 832, 697 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 8.52 (s, 1 H), 7.36 (d, J = 4.0 Hz,
4 H), 7.33 (d, J = 4.3 Hz, 4 H), 7.23 (dt, J = 8.6, 4.4 Hz, 1 H), 6.66 (d,
J = 7.8 Hz, 1 H), 4.81 (quint, J = 7.0 Hz, 1 H), 1.38 (d, J = 7.0 Hz, 3 H).
13C NMR (126 MHz, DMSO-d6): δ = 154.2, 145.0, 139.8, 131.3, 128.3,
126.7, 125.8, 119.5, 112.3, 48.6, 23.0.
N,N-Diethyl-N′-(2-bromo-4-iodophenyl)urea (3j)
Yield: 65.5 mg (66%); yellow-reddish oil; Rf = 0.59 (EtOAc/hexanes,
1:1).
IR (KBr): 3428, 3339, 2972, 2930, 2872, 1674, 1578, 1567, 1509, 1488,
1463, 1400, 1296, 1268, 1232, 1159, 1029, 829, 748 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.06 (d, J = 8.8 Hz, 1 H), 7.79 (d,
J = 2.0 Hz, 1 H), 7.54 (dd, J = 8.8, 2.0 Hz, 1 H), 6.98 (s, 1 H), 3.40 (q,
J = 7.2 Hz, 4 H), 1.26 (t, J = 7.2 Hz, 6 H).
13C NMR (126 MHz, CDCl3): δ = 153.7, 139.6, 137.3, 137.3, 122.4,
113.4, 84.3, 42.0, 14.0.
N,N-Diethyl-N′-(4-bromophenyl)urea (3f)33
Yield: 64.8 mg (96%); white powder; mp 114–116 °C; Rf = 0.43 (EtO-
Ac/hexanes, 1:1).
IR (KBr): 3330, 3259, 2982, 2935, 1635, 1584, 1529, 1518, 1490, 1418,
1303, 1284, 1078, 817 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C11H15BrIN2O: 396.940700; found:
396.938756.
1H NMR (500 MHz, DMSO-d6): δ = 7.36 (d, J = 8.9 Hz, 2 H), 7.27 (d,
J = 8.9 Hz, 2 H), 6.32 (s, 1 H), 3.35 (q, J = 7.2 Hz, 4 H), 1.21 (t, J = 7.2 Hz,
6 H).
13C NMR (125 MHz, DMSO-d6): δ = 154.4, 138.6, 131.8, 121.5, 115.3,
41.8, 14.0.
N-Butyl-N′-(4-iodophenyl)urea (4a)14
Yield: 72.3 mg (91%); white powder; mp 187–188 °C; Rf = 0.51 (EtO-
Ac/hexanes, 1:1).
HRMS (ESI): m/z [M + H]+ calcd for C11H16BrN2O: 271.044052; found:
271.043975.
IR (KBr): 3329, 2954, 2930, 2862, 1633, 1588, 1561, 1483, 1300, 1236,
829, 629, 502 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 8.50 (s, 1 H), 7.51 (d, J = 8.8 Hz,
2 H), 7.23 (d, J = 8.8 Hz, 2 H), 6.14 (t, J = 5.4 Hz, 1 H), 3.06 (dd, J = 12.7,
6.8 Hz, 2 H), 1.43–1.36 (m, 2 H), 1.29 (dq, J = 14.2, 7.1 Hz, 2 H), 0.88 (t,
J = 7.3 Hz, 3 H).
N,N-Diisopropyl-N′-(4-bromophenyl)urea (3g)37
Yield: 73.2 mg (98%); yellow powder; mp 155–157 °C (Lit.37 160–
162 °C); Rf = 0.62 (EtOAc/hexanes, 1:1).
13C NMR (125 MHz, DMSO-d6): δ = 155.0, 140.5, 137.1, 119.9, 83.4,
38.7, 31.8, 19.5, 13.7.
IR (KBr): 3319, 2999, 2969, 2933, 1636, 1588, 1525, 1490, 1430, 1391,
1375, 1334, 1241, 1145, 1054, 822, 607 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.37 (d, J = 8.8 Hz, 2 H), 7.27 (d,
J = 8.8 Hz, 2 H), 6.18 (s, 1 H), 3.96 (hept, J = 6.8 Hz, 2 H), 1.32 (d,
J = 6.9 Hz, 12 H).
HRMS (ESI): m/z [M – H]– calcd for C11H14N2OI: 317.0145; found:
317.0151.
13C NMR (126 MHz, CDCl3): δ = 154.4, 138.6, 131.8, 121.3, 115.1, 45.7,
N,N-Diethyl-N′-(4-iodophenyl)urea (4f)14
21.7.
Yield: 73.1 mg (92%); pale-yellow powder; mp 104–106 °C; Rf = 0.47
(EtOAc/hexanes, 1:1).
HRMS (ESI): m/z [M + H]+ calcd for C13H20BrN2O: 299.075352; found:
299.074008.
IR (KBr): 3333, 3259, 3093, 2977, 1635, 1580, 1487, 1415, 1382, 1304,
1241, 816, 501 cm–1
.
N-(4-Bromophenyl)morpholine-4-carboxamide (3h)33
1H NMR (500 MHz, DMSO-d6): δ = 7.55 (d, J = 8.8 Hz, 2 H), 7.18 (d,
J = 8.8 Hz, 2 H), 6.30 (s, 1 H), 3.35 (q, J = 7.0 Hz, 4 H), 1.21 (t, J = 7.0 Hz,
6 H).
Yield: 67.2 mg (95%); white powder; mp 160 °C (dec.); Rf = 0.17 (EtO-
Ac/hexanes, 1:1).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 49, A–I

G
C. M. Sanabria et al.
Paper
Synthesis
13C NMR (125 MHz, DMSO-d6): δ = 154.3, 139.3, 137.7, 121.8, 85.6,
N,N-Diethyl-N′-(2,4,6-tribromophenyl)urea (6b)
41.8, 14.0.
Reaction using TBCA (1.0 mmol) for 24 h.
HRMS (ESI): m/z [M + H]+ calcd for C11H16N2OI: 319.0302; found:
319.0298.
Yield: 27.7 mg (26%); white powder; mp 152–153 °C; Rf = 0.48 (EtO-
Ac/hexanes, 1:1).
IR (KBr): 3244, 2976, 2927, 1638, 1565, 1541, 1505, 1485, 1454, 1401,
Di- and Trihalogenation of N,N-Diethyl-N′-phenylurea (1f); Gener-
al Procedure for Preparation of N′-(Polyhalophenyl)ureas 5 and 6
1276, 1173, 1096, 856, 754, 739 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.69 (s, 2 H), 6.07 (s, 1 H), 3.40 (d,
J = 7.2 Hz, 4 H), 1.26 (t, J = 7.2 Hz, 6 H).
13C NMR (126 MHz, CDCl3): δ = 153.8, 136.1, 134.6, 123.7, 119.7, 41.9,
TXCA (0.17–1.0 mmol) was added to a stirred solution of N,N-diethyl-
N′-phenylurea (1f; 0.25 mmol) in MeCN (5–10 mL) at r.t. (25 °C) and
the mixture was stirred for 17–24 h. The reaction was quenched with
15% NaHSO3 solution (10 mL). The final mixture was extracted with
EtOAc and washed with brine water. The organic layer was separated,
dried over anhydrous sodium sulfate followed by removal of solvent
under reduced pressure. The crude products were separated by silica
gel column chromatography using EtOAc/hexanes as eluent.
14.1.
HRMS (ESI): m/z [M + Na]+ calcd for C11H13Br3N2NaO: 448.847020;
found: 448.846456.
Halogenation of N-Benzylureas 7; General Procedure for Prepara-
tion of N-(Halobenzyl)ureas 8 and 9
N,N-Diethyl-N′-(2,4-dichlorophenyl)urea (5a)33
TXCA (0.125 mmol) was added to a stirred solution of the appropriate
substituted N-benzylurea 7 (0.25 mmol) in MeCN–CF3CO2H 1:1 (3 mL)
(or CF3CO2H (3 mL) for 8a/a′) at r.t. (25 °C) and the mixture was
stirred until completion of the reaction (TLC). The reaction was
quenched with 15% NaHSO3 solution (10 mL) and carefully neutral-
ized with NaHCO3. The final mixture was extracted with EtOAc and
washed with brine water. The organic layer was separated, dried over
anhydrous sodium sulfate followed by removal of solvent under re-
duced pressure. The crude products were separated by silica gel col-
umn chromatography using EtOAc/hexanes as eluent.
Reaction using TCCA (0.17 mmol) for 17 h.
Yield: 49.4 mg (76%); yellow oil; Rf = 0.68 (EtOAc/hexanes, 1:1).
IR (KBr): 3444, 3336, 3115, 3077, 2974, 2932, 2874, 1674, 1578, 1514,
1402, 1382, 12991261, 1159, 1098, 862, 843, 792, 751 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.23 (d, J = 9.0 Hz, 1 H), 7.33 (d,
J = 2.4 Hz, 1 H), 7.21 (dd, J = 9.0, 2.4 Hz, 1 H), 6.94 (s, 1 H), 3.40 (q,
J = 7.2 Hz, 4 H), 1.26 (t, J = 7.2 Hz, 6 H).
13C NMR (126 MHz, CDCl3): δ = 153.8, 135.1, 128.4, 127.9, 127.2,
122.5, 121.6, 42.0, 13.9.
HRMS (ESI) m/z [M + Na]+ calcd for C11H14Cl2N2NaO: 283.037539;
N-Butyl-N′-(4-chlorobenzyl)urea (8a)38
Yield: 18.8 mg (31%); white powder; mp 83–85 °C; Rf = 0.21 (EtO-
found: 283.037884.
Ac/hexanes, 1:1).
N,N-Diethyl-N′-(2,4,6-trichlorophenyl)urea (5b)
IR (KBr): 3329, 2954, 2928, 2870, 1620, 1588, 1523, 1491, 1467, 1257,
1092, 1033, 1013, 816, 650 cm–1
.
Reaction using TCCA (0.34 mmol) for 24 h.
1H NMR (500 MHz, CDCl3): δ = 7.22 (d, J = 8.4 Hz, 2 H), 7.13 (d,
J = 8.4 Hz, 2 H), 5.37 (s, 1 H), 4.99 (s, 1 H), 4.21 (d, J = 5.9 Hz, 2 H),
3.13–3.01 (m, 2 H), 1.42–1.35 (m, 2 H), 1.31–1.23 (m, 2 H), 0.87 (t,
J = 7.3 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 158.7, 138.2, 133.0, 128.8, 128.7, 43.7,
40.3, 32.4, 20.1, 13.9.
Yield: 28.6 mg (39%); white powder; mp 141–142 °C; Rf = 0.61 (EtO-
Ac/hexanes, 1:1).
IR (KBr): 3247, 2979, 2931, 2872, 1640, 1579, 1555, 1505, 1488, 1278,
1173, 1084, 858, 846, 815, 800, 755, 704 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.34 (s, 2 H), 6.05 (s, 1 H), 3.40 (q,
J = 7.1 Hz, 4 H), 1.25 (t, J = 7.1 Hz, 6 H).
13C NMR (126 MHz, CDCl3): δ = 154.0, 133.5, 133.2, 131.7, 128.3,
HRMS (ESI): m/z [M + Na]+ calcd for C12H17ClN2NaO: 263.092162;
found: 263.091920.
41.9, 14.0.
HRMS (ESI): m/z [M + H]+ calcd for C11H14Cl3N2O: 295.016623; found:
295.016609.
N-Butyl-N′-(2-chlorobenzyl)urea (8a′)
Yield: 16.7 mg (27%); white powder; mp 108–110 °C; Rf = 0.32 (EtO-
Ac/hexanes, 1:1).
N,N-Diethyl-N′-(2,4-dibromophenyl)urea (6a)
IR (KBr): 3335, 2956, 2929, 2871, 1625, 1589, 1468, 1442, 1412, 1290,
Reaction using TBCA (0.5 mmol) for 17 h.
1251, 1047, 1037, 756 cm–1
.
Yield: 60.0 mg (69%); red oil; Rf = 0.55 (EtOAc/hexanes, 1:1).
IR (KBr): 3429, 2973, 2931, 2872, 1676, 1583, 1571, 1513, 1041, 1378,
1H NMR (500 MHz, CDCl3): δ = 7.35–7.32 (m, 1 H), 7.31–7.28 (m, 1 H),
7.20–7.13 (m, 2 H), 5.34 (t, J = 5.8 Hz, 1 H), 4.93 (s, 1 H), 4.37 (d,
J = 6.2 Hz, 2 H), 3.18–2.97 (m, 2 H), 1.46–1.33 (m, 2 H), 1.28 (dq,
J = 14.3, 7.2 Hz, 2 H), 0.87 (t, J = 7.3 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 158.6, 137.0, 133.3, 129.4, 128.6,
127.1, 42.2, 40.4, 32.4, 20.1, 13.9.
1297, 1268, 1257, 1231, 1159, 1079, 1032, 832, 749 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.18 (d, J = 8.9 Hz, 1 H), 7.62 (d,
J = 2.3 Hz, 1 H), 7.38 (dd, J = 8.9, 2.2 Hz, 1 H), 6.97 (s, 1 H), 3.40 (q,
J = 7.2 Hz, 4 H), 1.26 (t, J = 7.2 Hz, 6 H).
13C NMR (126 MHz, CDCl3): δ = 153.8, 136.7, 134.0, 131.4, 122.0,
114.5, 113.2, 42.0, 14.0.
HRMS (ESI): m/z [M + Na]+ calcd for C12H17ClN2NaO: 263.092162;
found: 263.091923.
HRMS (ESI): m/z [M + Na]+ calcd for C11H14Br2N2NaO: 370.936508;
found: 370.936685.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 49, A–I

H
C. M. Sanabria et al.
Paper
Synthesis
N,N-Diethyl-N′-(4-chlorobenzyl)urea (8b)
IR (KBr): 3336, 2970, 2929, 1626, 1535, 1487, 1401, 1282, 1040, 1011,
789 cm–1
.
Yield: 16.2 mg (27%); pale-yellow oil; Rf = 0.26 (EtOAc/hexanes, 1:1).
1H NMR (500 MHz, CDCl3): δ = 7.42 (d, J = 8.4 Hz, 2 H), 7.16 (d,
J = 8.3 Hz, 2 H), 4.73 (s, 1 H), 4.36 (d, J = 5.7 Hz, 2 H), 3.26 (q, J = 7.1 Hz,
4 H), 1.12 (t, J = 7.1 Hz, 6 H).
13C NMR (126 MHz, CDCl3): δ = 157.2, 139.2, 131.6, 129.4, 120.9, 44.3,
41.3, 14.0.
IR (KBr): 3322, 2970, 2930, 2870, 1623, 1537, 1490, 1451, 1425, 1403,
1310, 1283, 1016, 833, 767, 654, 581 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.27 (d, J = 8.4 Hz, 2 H), 7.22 (d,
J = 8.5 Hz, 2 H), 4.71 (s, 1 H), 4.38 (d, J = 5.7 Hz, 2 H), 3.26 (q, J = 7.1 Hz,
4 H), 1.13 (t, J = 7.1 Hz, 6 H).
13C NMR (126 MHz, CDCl3): δ = 157.2, 138.7, 132.9, 129.0, 128.7, 44.3,
41.4, 14.0.
HRMS (ESI): m/z [M + Na]+calcd for C12H17BrN2NaO: 307.041646;
found: 307.042468.
HRMS (ESI): m/z [M + Na]+calcd for C12H17ClN2NaO: 263.092162;
found: 263.092251.
N,N-Diethyl-N′-(2-bromobenzyl)urea (9b′)
Yield: 25.9 mg (36%); white powder; mp 100–101 °C; Rf = 0.32 (EtO-
Ac/hexanes, 1:1).
N,N-Diethyl-N′-(2-chlorobenzyl)urea (8b′)
IR (KBr): 3350, 3066, 2976, 2930, 1627, 1541, 1494, 1461, 1441, 1410,
Yield: 14.4 mg (24%); white powder; mp 82–83 °C; Rf = 0.34 (EtO-
Ac/hexanes, 1:1).
1377, 1266, 1209, 1027, 739 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.53 (dd, J = 7.9, 0.8 Hz, 1 H), 7.43 (dd,
J = 7.6, 1.4 Hz, 1 H), 7.29–7.25 (m, 1 H), 7.12 (td, J = 7.7, 1.6 Hz, 1 H),
4.93 (s, 1 H), 4.48 (d, J = 6.0 Hz, 2 H), 3.26 (q, J = 7.2 Hz, 4 H), 1.14 (t,
J = 7.2 Hz, 6 H).
13C NMR (126 MHz, CDCl3): δ = 157.1, 138.9, 132.6, 130.7, 129.0,
127.8, 123.8, 45.3, 41.4, 14.0.
IR (KBr): 3355, 3065, 2968, 2929, 1627, 1534, 1443, 1412, 1363, 1290,
1263, 1100, 1047, 1038, 798, 739, 557 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.41 (dd, J = 7.3, 1.9 Hz, 1 H), 7.33 (dd,
J = 7.5, 1.6 Hz, 1 H), 7.24–7.17 (m, 2 H), 4.90 (s, 1 H), 4.49 (d, J = 5.9 Hz,
2 H), 3.25 (q, J = 7.1 Hz, 4 H), 1.13 (t, J = 7.2 Hz, 6 H).
13C NMR (126 MHz, CDCl3): δ = 157.2, 137.3, 133.6, 130.4, 129.5,
128.6, 127.1, 43.0, 41.4, 14.0.
HRMS (ESI): m/z [M + Na]+calcd for C12H17BrN2NaO: 307.041646;
found: 307.043161.
HRMS (ESI): m/z [M + Na]+calcd for C12H17ClN2NaO: 263.092162;
found: 263.092107.
Acknowledgment
N-Butyl-N′-(4-bromobenzyl)urea (9a)
Yield: 27.0 mg (38%); white powder; mp 110–111 °C; Rf = 0.26 (EtO-
Ac/hexanes, 1:1).
The authors would like to thank CNPq and FAPERJ for financial sup-
port. C.M.S. thanks CAPES and M.C.S.M. thanks CNPq for fellowships.
We also thank Professor Rodrigo da Silva Ribeiro for the kind prepara-
tion of TICA.
IR (KBr): 3325, 3133, 2960, 2927, 2860, 1621, 1581, 1487, 1472, 1403,
1261, 1099, 1069, 1028, 1012, 809, 645 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.38 (d, J = 8.4 Hz, 2 H), 7.09 (d,
J = 8.3 Hz, 2 H), 5.27 (s, 1 H), 4.90 (s, 1 H), 4.21 (d, J = 5.9 Hz, 2 H), 3.08
(q, J = 7.0 Hz, 2 H), 1.39 (quint, J = 7.2 Hz, 2 H), 1.28 (dq, J = 14.3,
7.2 Hz, 2 H), 0.88 (t, J = 7.3 Hz, 3 H).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1589149.
13C NMR (126 MHz, CDCl3): δ = 158.6, 138.8, 131.7, 129.1, 121.1, 43.8,
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
40.4, 32.4, 20.1, 13.9.
HRMS (ESI): m/z [M + Na]+calcd for C12H17BrN2NaO: 307.041646;
found: 307.041137.
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Yield: 31.2 mg (44%); white powder; mp 133–134 °C; Rf = 0.35 (EtO-
Ac/hexanes, 1:1).
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.
1H NMR (500 MHz, CDCl3): δ = 7.47 (dd, J = 7.9, 0.9 Hz, 1 H), 7.32 (dd,
J = 7.7, 1.2 Hz, 1 H), 7.20 (td, J = 7.5, 0.9 Hz, 1 H), 7.07 (td, J = 7.8,
1.6 Hz, 1 H), 5.49 (s, 1 H), 5.07 (s, 1 H), 4.33 (d, J = 6.2 Hz, 2 H), 3.08 (q,
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127.7, 123.4, 44.6, 40.4, 32.4, 20.2, 13.9.
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found: 307.041679.
N,N-Diethyl-N′-(4-bromobenzyl)urea (9b)
Yield: 28.1 mg (39%); pale-yellow oil; Rf = 0.24 (EtOAc/hexanes, 1:1).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 49, A–I

I
C. M. Sanabria et al.
Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 49, A–I