An Improved Synthesis of Urea Derivatives from N -Acylbenzotriazole via Curtius Rearrangement

Article abstract of DOI:10.1055/s-0039-1689937

The good leaving tendency of the benzotriazole moiety has been exploited for the synthesis of symmetric, unsymmetric, N -acyl, and cyclic ureas in good yields from N -acylbenzotriazoles by treating the latter with various amines in the presence of TMSN ₃ /Et ₃ N in a sealed tube. The salient features of the devised protocol includes the high-yield, mild, metal-free, one-pot reaction conditions, and short reaction time. Furthermore, in many cases, no column chromatography is required for the purification.

Full text of DOI:10.1055/s-0039-1689937

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–H
paper
A
en
A. S. Singh et al.
Paper
Synthesis
An Improved Synthesis of Urea Derivatives from N-Acylbenzotri-
azole via Curtius Rearrangement
Anoop S. Singh
Anand K. Agrahari
Sumit K. Singh
O
Advantage:
One-pot
Short reaction time
Metal-free
for synthesis of symmetric/
unsymmetric/cyclic/N-acyl urea
Easy workup
N
N
Applicable
N
Mangal S. Yadav
Vinod K. Tiwari*
TMSN3
Et3N, r.t.
0
0
0
0-
0
0
0
1-9
2
4
4-8
8
8
9
O
toluene
N3 110 °C
O
Department of Chemistry, Institute of Science,
Banaras Hindu University, Varanasi, 22100, India
tiwari_chem@yahoo.co.in
N
N
NCO
H
H
aryl,
alkyl
+
=
30 examples
yields up to 99%
NH2
Vinod.Tiwari@bhu.ac.in
This manuscript is dedicated to (Late) Prof. Alan R
Katritzky for his contribution to benzotriazole
chemistry.
Received: 09.04.2019
Accepted after revision: 14.05.2019
Published online: 12.06.2019
el.10 For example, carbon monoxide (CO) as the source of
the carbonyl moiety was well explored to afford respective
ureas,11 but these carbonylation reactions generally re-
quired high temperatures and high-pressure conditions.
Furthermore, CO2 as renewable carbon resource12 or CH3OH
as the C-1 source in the presence of ruthenium pincer com-
plexes have also been used for this purpose.13 The stoichio-
metric use of expensive dehydrating reagents such as di-
tert-butyl azodicarboxylate is required to obtain the respec-
tive isocyanates, which again limits the synthetic utility of
procedure.12 Furthermore, Hofmann and related rearrange-
ments including Curtius, Lossen, and Schmidt rearrange-
ment could be considered as well-known protocols to ob-
tain related urea derivatives.14 Thus, the search for a versa-
tile protocol for the synthesis of urea derivatives under mild
reaction conditions remains a major challenge for synthetic
chemists.
A number of important characteristics of benzotriazoles
should be noted: (a) they can be easily synthesized under
standard conditions; (b) they are relatively stable during re-
actions; (c) once introduced then can be activated for a
number of transformations, and (d) they can be easily re-
moved at the end of the reaction sequence. Therefore, a
number of benzotriazole-based substrates, reagents, inter-
mediates, and ligands have long been utilized for the syn-
thesis of a wide variety of molecules for various applica-
tions.15 Furthermore, benzotriazoles are inexpensive, in
many cases solid, moisture-insensitive, highly stable on
storage, generally non-toxic, and easily available, thus mak-
ing the moiety even more attractive for synthesis.15 Recent-
ly, N-acylbenzotriazoles have been established as an alter-
native to acid chloride in N-, C-, O-, and S-acylations for the
synthesis of amides, esters, acid azides, peptides, oxazo-
lines, diketones, and thiazolines.9c,16 Our group has synthe-
sized carbamates, thiocarbamates, and symmetric ureas
from N-acylbenzotriazoles via Curtius rearrangement
DOI: 10.1055/s-0039-1689937; Art ID: ss-2019-z0215-op
Abstract The good leaving tendency of the benzotriazole moiety has
been exploited for the synthesis of symmetric, unsymmetric, N-acyl,
and cyclic ureas in good yields from N-acylbenzotriazoles by treating
the latter with various amines in the presence of TMSN3/Et3N in a sealed
tube. The salient features of the devised protocol includes the high-
yield, mild, metal-free, one-pot reaction conditions, and short reaction
time. Furthermore, in many cases, no column chromatography is re-
quired for the purification.
Key words ureas, benzotriazole, Curtius rearrangement, N-acylbenzo-
triazole, introduction
Substituted ureas are important scaffold in various field
of science,1 and numerous molecules containing a urea
functionality play vital roles in agriculture, pharmaceuti-
cals, analytical and polymer science, and organic synthesis.2
Moreover, the urea core is found in a number of interesting
molecules of pharmaceutical and biological importance,
such as carmustine3 and sorafenib4 (antineoplastic agents),
acetohexamide (antidiabetic activity),5 acecarbromal (hyp-
notic and sedative agent),6 aldioxa (antiulcer activity),7 di-
flubenzuron (insecticidal activity)8 and many more. Thus,
there is increased demand for functionalized ureas that will
allow detailed chemical, biochemical, and pharmacological
investigations. A large number of synthetic methods that al-
low easy access of diverse ureas are well documented.9–14
Traditional methods to access urea derivatives involves the
reaction of amines with phosgene or isocyanates or phos-
gene derivatives (for example, CDI, CDB and DMDTC),9
which is accompanied by considerable toxicological consid-
erations. Alternatively, this scaffold can be obtained
through the reductive and oxidative carbonylation of
amines in the presence of suitable transition-metal cata-
lysts such as palladium, tungsten, cobalt, copper, and nick-
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
A. S. Singh et al.
Paper
Synthesis
(Scheme 1).17 Although this synthetic route is good for sym-
metrical ureas, yet the approach has some limitations with
respect to the formation of unsymmetrical ureas.
benzotriazoles, we followed a procedure in which N,N-di-
cyclohexylcarbodiimide (DCC) and benzotriazole react with
the corresponding acids in dichloromethane.20
Although the reaction of N-acylbenzotriazoles with
NaN3 afforded the respective carbamates, thiocarbamates,
and symmetric ureas in average to good yields via Curtius
rearrangement, a few limitations were still apparent for
this synthetic route; namely, it gives up to 81% yields only
and the method is not equally applicable to produce sym-
metrical as well as unsymmetrical ureas. Therefore, a
straightforward synthesis of both symmetric and unsym-
metrical urea derivatives in excellent yields from N-acyl-
benzotriazoles is a clear objective. We attempted a number
of reactions with a diverse range of reagents and concluded
that N-acylbenzotriazole 2b (1.0 equiv), on treatment with
aniline (1.0 equiv), TMSN3 (1.0 equiv), and triethylamine
(1.0 equiv) in anhydrous toluene at 110 °C, afforded the re-
quired unsymmetric urea derivative 3a in the best yield of 83%.
After achieving this result, we further optimized the re-
action conditions in terms of reagent and base equivalents,
solvent medium, reaction time and temperature, and estab-
lished the optimum yield of compound 3a (isolated in 97%
after column chromatography), when N-acylbenzotriazole
2b (1.0 equiv) was heated at 110 °C with 1.0 equiv of ani-
line, 1.1 equiv of TMSN3 and 2.0 equiv of triethylamine in
anhydrous toluene for 60 minutes (Table 1, entry 13). We
Previous work:
O
O
R1
NaN3
R1
N
H
N
H
R1
N
N
water/THF, 90 °C
N
symmetric urea
Present work:
O
O
R1
R2
TMSN3, Et3N, toluene
N
H
N
H
N
R1
R2
, 110 °C
NH2
N
symmetric &
unsymmetric urea
N
Scheme 1 Previous and present approaches from our group
Herein, we report a practical, one-pot method to syn-
thesize urea derivatives with an aid of N-acylbenzotriazoles
as a synthetic auxiliary via generation of N-acylazides. Un-
doubtedly, the acyl-azide on heating is first converted into
the corresponding isocyanate intermediate via Curtius rear-
rangement, which further reacts with amines under mild
conditions to allow easy access to libraries of symmetric,
unsymmetric, N-acyl and cyclic urea derivatives.
Our synthetic strategy begins with the N-acylbenzotri-
azoles 2 (Figure 1), obtained from the corresponding car-
boxylic acids by utilizing well-known methods; namely, re-
action of carboxylic acids with thionyl chloride or NBS/PPh3
or PySSPy/PPh3 and 1H-benzotriazole in dichlorometh-
ane.18,19 Whereas, for the formation of N-o-aminobenzoyl
Table 1 Reaction Optimization Study for the Synthesis of Urea from N-
Acylbenzotriazole via Curtius Rearrangement
O
O
O
H
N
H
N
O
TMSN3, Et3N, aniline
solvent
N
N
N
N
N
N
Bt
O
N
N
N
N
2b
3a
2a (95%)
2b (87%)
2c (83%)
O
O
O
Entrya TMSN3 (equiv) Et3N (mol%) Solventb
Time (min) Yield (%)
N
N
N
N
N
N
N
N
1
2
1.0
1.0
1.0
1.0
1.1
1.2
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
2.0
1.0
–
toluene
toluene
toluene
–
120
120
120
120
120
120
120
120
120
120
120
120
60
93
83
23
36
97
96
94
81
85
85
88
69
97
96
68
Cl
Cl
2e (81%)
2d (88%)
2f (72%)
O
OMe
O
3
O
MeO
N
N
N
N
N
N
4
4.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
N
N
N
Br
5
toluene
toluene
benzene
CH2Cl2
DMSO
CHCl3
2i (77%)
2h (89%)
2g (83%)
6
O
O
O
Cl
F
7
N
N
N
N
N
N
N
N
N
8
2j (72%)
Cl
F
2k (69%)
2l (61%)
9
O
O
N
O
N
N
10
11
12
13
14
15
N
N
N
THF
N
N
N
NH2
NH
O
DMF
2m (62%)
2o (63%)
2n (67%)
toluene
toluene
toluene
N
N
N
30
O
15
2p (71%)
a Reaction carried out in a sealed tube at 110 °C.
b Anhydrous solvents are used.
Figure 1 N-Acylbenzotriazoles 2a–p used in our investigation
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

C
A. S. Singh et al.
Paper
Synthesis
also carried out the reaction under neat conditions (ab-
sence of any solvent) but only 36% yield was obtained (en-
try 4), whereas performing a similar reaction in absence of
base resulted in the formation of the respective product 3a
in only 23% yield.
was independent of the nature of the amines (Scheme 2).
When a similar reaction was carried out with compound 2a
and propargyl amine under the optimized conditions, N-
(prop-2-yn-1-yl)benzamide was isolated as the sole prod-
uct instead of the desired urea. The structure of all the de-
veloped compounds 3a–s were confirmed by extensive
spectral analyses, including NMR (1H and 13C), IR and MS
data.
To improve the usefulness of this methodology, we also
investigated this protocol for the synthesis of symmetric
urea 4 and N-acylurea derivatives 5. For the synthesis of
symmetric urea 4a–f, we took selective aromatic N-acyl-
benzotriazoles and anilines with the same aromatic rings
present on aromatic N-acylbenzotriazoles and then per-
formed the reaction under the above optimized reaction
conditions (Scheme 3).
To establish the range and practical efficiency of this
methodology, a library comprised of diverse urea deriva-
tives 3a–s was developed by simply varying N-acylben-
zotriazoles 2a–p and a series of amines under the opti-
mized reaction conditions (Scheme 2). Furthermore, we
tried to find out the effect on the reaction yields of varying
the nature and position of the substituents on the benzene
ring of N-acylbenzotriazoles, and also the type of aliphatic
and aromatic amine used in our reaction. The experimental
results demonstrated that the reaction yield is not signifi-
cantly dependent to the nature or position of the substitu-
ent present on the benzene ring of N-acylbenzotriazoles.
Moreover, the reaction also gave average to good yields
when compound 2b was heated with a variety of amines.
This trend further indicates that the yield of this reaction
O
O
TMSN3, Et3N, 110 °C
anhydrous toluene
R1
R1
R1
+
Bt
R1
N
H
N
H
H2N
2
4a–f
O
O
O
O
O
R1
TMSN3, Et3N, anhydrous toluene, 110 °C
amine
Bt
R1
N
H
N
H
N
N
N
H
N
H
N
H
N
H
H
H
O
O
3a–s
2a–g
4a (99%)
4b (96%)
4c (72%)
H
N
H
H
H
N
H
N
H
N
Br
N
N
Cl
Br
Br
O
O
O
O
O
O
3c (93%)
N
H
N
H
3b 91%)
N
H
N
H
3a (97%)
N
H
N
H
4e (92%)
4d (95%)
4f (84%)
H
N
H
N
H
N
H
N
H
N
H
N
Scheme 3 Molar ratios: N-Acylbenzotriazoles (1.0 equiv), TMSN3 (1.1
equiv), Et3N (2.0 equiv), aniline (1.0 equiv)
O
O
O
O
Cl
3e (73%)
3d (93%)
3f (71%)
F
F
H
N
H
N
1-(1H-Benzo[d][1,2,3]triazol-1-yl)-2-phenylethane-1,2-
dione (2o), on reaction with 1.0 equiv of various aniline un-
der the optimum reaction conditions, resulted in the re-
spective N-acyl urea derivatives 5a–c in average to good
yield (Scheme 4).
H
H
N
H
N
H
N
N
O
O
O
O
3g (83%)
3h (98%)
3i (74%)
Cl
H
N
H
N
H
N
H
N
O
H
N
H
N
O
Cl
O
R
O
TMSN3, Et3N, 110 °C
anhydrous toluene
O
O
3j (77%)
3l (68%)
Bt
O
N
H
N
H
3k (63%)
R = H (63%)
R = Me (72%)
R = Br (69%)
H
N
H
N
H
N
H
N
O
H
N
H
N
Br
2o
5a–c
O
O
3o (90%)
3m (51%)
O
Scheme 4 Synthesis of N-acylureas. Molar ratio: 1-(1H-benzo
[d][1,2,3]triazol-1-yl)-2-phenylethane-1,2-dione (2o) (1.0 equiv),
3n (67%)
TMSN3 (1.1 equiv), Et3N (2.0 equiv), aniline (1.0 equiv)
H
H
N
H
H
N
H
N
H
N
N
N
O
O
Cl
O
Cl
Furthermore, we exploited this reaction for the synthe-
sis of cyclic urea; for this, we carried out the reaction of 2m
and 2n under the optimized conditions described above
and isolated cyclic urea 6a and 6b in very good yields via
intramolecular cyclization via the isocyanate intermediate
(Scheme 5).
3p (62%)
3r (91%)
3q (62%)
H
N
H
N
O
3s (47%)
Scheme 2 Developed unsymmetric urea derivatives 3a–s obtained
from N-acylbenzotriazole 2 via Curtius rearrangement using TMSN3
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

D
A. S. Singh et al.
Paper
Synthesis
O
1-(4-Methylphenyl)-3-phenylurea (3a); Typical Procedure21
H
N
TMSN3, Et3N, 110 °C
anhydrous toluene
In a sealed tube, a suspension of 2b (1.1 equiv), aniline (1.0 equiv),
azidotrimethylsilane (TMSN3) (1.1 equiv), and triethylamine (Et3N)
(2.0 equiv) were taken in anhydrous toluene and the reaction mixture
was stirred under heating at 110 °C for 1 h. After completion of the
reaction (monitored by TLC), the reaction mixture was concentrated
in vacuo. The crude reaction mixture thus obtained was washed with
dichloromethane, then with EtOAc and finally with MeOH (1 mL
each) to afford 3a. Finally, the reaction product was subjected to re-
crystallization using EtOAc (in warm conditions) to afford the desired
urea 3a in pure form.
Bt
O
N
NH
X = H (95%)
X = Me (91%)
X
X
6a,b
2m,n
Scheme 5 Synthesis of cyclic urea derivatives. Molar ratios: Acyl benzo-
triazoles (1.0 equiv), TMSN3 (1.1 equiv), Et3N (2.0 equiv), aniline (1.0
equiv). Yields reported after purification by column chromatography (SiO2).
A plausible mechanistic approach to explain the product
formation and rearrangement is depicted in Scheme 6. In-
termediate acyl azide A is formed by the nucleophilic addi-
tion of azide ion to carbonyl carbon of acyl benzotriazole 2
through replacement of the benzotriazole moiety. This in-
termediate underwent Curtius rearrangement to form the
respective isocyanate intermediate B, with the subsequent
loss of molecular nitrogen (N2). Finally, the resulting isocya-
nate intermediate B is immediately captured by the amine
to afford the respective urea derivative 3–6.
Yield: 0.23 g (97%); white crystalline solid; mp 214–216 °C (lit. mp
218 °C); Rf = 0.5 (25%, EtOAc/n-hexane).
1H NMR (500 MHz, CDCl3, DMSO-d6):  = 8.29 (s, 1 H), 8.22 (s, 1 H),
7.36 (d, J = 8.0 Hz, 2 H), 7.24 (d, J = 8.5 Hz, 2 H), 7.18–7.14 (m, 2 H),
6.98 (d, J = 7.5 Hz, 1 H), 6.87 (t, J = 7.5 Hz, 1 H), 2.19 (s, 3 H).
13C NMR (125 MHz, CDCl3, DMSO-d6):  = 152.6, 139.3, 136.6, 130.8,
128.8, 128.3, 121.5, 118.2, 118.0, 20.2.
1-(4-Chlorophenyl)-3-phenylurea (3b)22
Yield: 0.11 g (91%); white crystalline solid; mp 236–238 °C (lit. mp
239 °C); Rf = 0.5 (25%, EtOAc/n-hexane).
O
O
TMSN3
– Bt-
1H NMR (500 MHz, CDCl3, DMSO-d6):  = 7.96 (s, 1 H), 7.84 (s, 1 H),
6.89–6.87 (dd, J = 3.0, 5.5 Hz, 4 H), 6.71–6.65 (m, 4 H), 6.43–6.40 (m,
1 H).
N
R1
N
R1
Bt
N
2
A
13C NMR (125 MHz, CDCl3, DMSO-d6):  = 152.3, 139.0, 138.0, 128.3,
N2
128.1, 125.7, 121.7, 119.2, 118.0.
O
R1
R2
R2 NH2
R1
N
O
N
N
H
H
1-(4-Bromophenyl)-3-phenylurea (3c)23
3, 4, 5 or 6
B
Yield: 62 mg (93%); white crystalline solid; mp 228–232 °C (lit. mp
235 °C); Rf = 0.6 (25%, EtOAc/n-hexane).
1H NMR (500 MHz, CDCl3, DMSO-d6):  = 8.37 (s, 1 H), 8.24 (s, 1 H),
7.38 (d, J = 8.0 Hz, 2 H), 7.34–7.28 (dd, J = 3.0, 4.5 Hz, 4 H), 7.22–7.19
(m, 2 H), 6.92 (t, J = 7.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3, DMSO-d6):  = 152.4, 138.8, 138.4, 131.0,
128.3, 121.8, 119.6, 118.2, 113.5.
Scheme 6 Plausible reaction mechanism for the synthesis of diverse
urea derivatives 3–6 from N-acylbenzotriazoles 2a–p
In summary, we have developed a convenient, one-pot
method to achieve excellent yield of symmetrical and un-
symmetrical ureas under mild reaction conditions. N-Acyl-
benzotriazoles were explored as a synthetic auxiliary in the
presence TMSN3 to achieve libraries of diverse urea deriva-
tives. In many cases, column chromatography was avoided
by instead conducting simple filtration and washing with
suitable solvent; thus, the method may be considered for
practical application in academia and industry.
1-(3-Methylphenyl)-3-phenylurea (3d)23
Yield: 0.22 g (93%); white crystalline solid (recrystallization in EtO-
Ac); mp 174–176 °C (lit. mp 174–175 °C); Rf = 0.5 (25%, EtOAc/n-hex-
ane).
1H NMR (500 MHz, CDCl3, DMSO-d6):  = 8.34 (s, 1 H), 8.26 (s, 1 H),
7.37 (d, J = 7.5, 2 H), 7.23 (s, 1 H), 7.18–7.11 (m, 3 H), 7.05 (t, J =
7.0 Hz, 1 H), 6.88 (t, J = 8.0 Hz, 1 H), 6.71 (d, J = 8.0 Hz, 1 H), 2.23 (s,
3 H).
All reagents and solvents were of pure analytical grade. Sealed tubes
(Ace Pressure tube) used in our synthesis were purchased from Sig-
ma–Aldrich. Thin-layer chromatography (TLC) was performed on 60
F254 silica gel, pre-coated on aluminum plates and revealed with a
UV lamp ( max = 254 nm). Solvents were evaporated under reduced
pressure at <50 °C. Column chromatography was carried out on silica
gel (230–400 mesh, E Merck). Distilled n-hexane and EtOAc were
13C NMR (125 MHz, CDCl3, DMSO-d6):  = 152.6, 139.3, 139.1, 137.8,
128.3, 128.2, 122.5, 121.6, 118.7, 118.1, 115.2, 21.1.
1-(3-Chlorophenyl)-3-phenylurea (3e)22
Yield: 91 mg (73%); white crystalline solid; mp 178–180 °C (lit. mp
183–184 °C); Rf = 0.4 (25%, EtOAc/n-hexane).
1H NMR (500 MHz, CDCl3, DMSO-d6):  = 8.48 (s, 1 H), 8.31 (s, 1 H),
7.59–7.58 (m, 1 H), 7.34–7.32 (m, 2 H), 7.17–7.07 (m, 4 H), 6.89–6.82
(m, 2 H).
1
used for column chromatography. H and 13C NMR were recorded at
500 and 125 MHz, respectively. Chemical shifts are given in ppm
downfield from internal TMS; J values in Hz.
13C NMR (125 MHz, CDCl3, DMSO-d6):  = 152.4, 140.7, 138.9, 133.6,
129.4, 128.4, 121.9, 121.3, 118.3, 117.8, 116.1.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

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A. S. Singh et al.
Paper
Synthesis
1-(2-Methoxyphenyl)-3-phenylurea (3f)24
1-(4-Methylphenyl)-3-(4-methoxyphenyl)urea (3l)23
Yield: 0.13 g (71%); white crystalline solid; mp 144–148 °C (lit. mp
Yield: 91 mg (68%); white crystalline solid (recrystallization in EtOAc);
155 °C); Rf = 0.5 (25%, EtOAc/n-hexane).
mp 214–216 °C (lit. mp 236 °C); Rf = 0.4 (25%, EtOAc/n-hexane).
1H NMR (500 MHz, CDCl3, DMSO-d6):  = 8.19 (d, J = 9.5 Hz, 1 H),
7.32–7.30 (m, 1 H), 7.24 (d, J = 5.0 Hz, 1 H), 6.58 (d, J = 9.0 Hz, 2 H),
6.35 (t, J = 7.5 Hz, 2 H), 6.07–5.98 (m, 4 H), 2.98 (s, 3 H).
1H NMR (500 MHz, CDCl3, DMSO-d6):  = 7.68 (d, J = 17.0 Hz, 2 H),
6.84–6.80 (m, 4 H), 6.55 (d, J = 8.0 Hz, 2 H), 6.31 (d, J = 8.5 Hz, 2 H),
3.25 (s, 3 H), 1.77 (s, 3 H).
13C NMR (125 MHz, CDCl3, DMSO-d6):  = 152.5, 147.3, 139.5, 128.5,
13C NMR (125 MHz, CDCl3, DMSO-d6):  = 154.4, 152.9, 136.7, 132.3,
128.3, 121.4, 121.3, 120.3, 118.3, 117.8, 109.8, 55.2.
130.6, 128.7, 120.0, 118.2, 113.5, 54.9, 20.2.
1-(3-Methoxyphenyl)-3-phenylurea (3g)24
1-(4-Methylphenyl)-3-cyclohexylurea (3m)27
Yield: 0.16 g (83%); white crystalline solid; mp 152–154 °C (lit. mp
155 °C); Rf = 0.45 (25%, EtOAc/n-hexane).
Yield: 62 mg (51%); white crystalline solid; (lit. mp 201 °C); Rf = 0.5
(20% EtOAc/n-hexane).
1H NMR (500 MHz, CDCl3, DMSO-d6):  = 8.39 (d, J = 16.5 Hz, 2 H),
7.36 (d, J = 8.0 Hz, 2 H), 7.18–7.15 (m, 3 H), 7.05 (t, J = 8.0 Hz, 1 H),
6.89–6.79 (m, 2 H), 6.44–6.42 (m, 1 H), 3.68 (s, 3 H).
13C NMR (125 MHz, CDCl3, DMSO-d6):  = 159.5, 152.3, 140.6, 139.2,
129.0, 128.3, 121.6, 118.0, 110.2, 106.9, 103.8, 54.6.
1H NMR (500 MHz, CDCl3, DMSO-d6):  = 7.84 (s, 1 H), 7.18 (d, J =
8.5 Hz, 2 H), 6.93 (d, J = 8.5 Hz, 2 H), 5.66 (d, J = 8.0 Hz, 1 H), 3.51–3.50
(m, 1 H), 2.18 (s, 3 H), 1.84–1.81 (m, 2 H), 1.64–1.60 (m, 2 H), 1.52–
1.50 (m, 1 H), 1.31–1.04 (m, 5 H).
13C NMR (125 MHz, CDCl3, DMSO-d6):  = 154.8, 137.3, 129.9, 128.6,
117.7, 47.6, 33.1, 25.1, 24.3, 20.1.
1-(Naphthalen-2-yl)-3-phenylurea (3h)23
1-(4-Bromophenyl)-3-(4-methylphenyl)urea (3n)28
Yield: 0.19 g (98%); white crystalline solid (recrystallization in EtOAc);
Rf = 0.5 (20%, EtOAc/n-hexane).
Yield: 107 mg (67%); white crystalline solid; Rf = 0.6 (25%, EtOAc/n-
hexane).
1H NMR (500 MHz, DMSO-d6):  = 8.86 (s, 1 H), 8.73 (s, 1 H), 8.09 (s,
1 H), 7.81- 7.75 (m, 3 H), 7.49–7.46 (m, 3 H), 7.42–7.39 (m, 1 H), 7.32–
7.25 (m, 3 H), 6.95 (t, J = 6.5 Hz, 1 H).
1H NMR (500 MHz, CDCl3, DMSO-d6):  = 7.75 (s, 1 H), 7.56 (s, 1 H),
6.56–6.45 (m, 6 H), 6.20 (d, J = 7.5 Hz, 2 H), 1.40 (s, 3 H).
13C NMR (125 MHz, DMSO-d6):  = 152.6, 139.6, 137.3, 133.7, 129.1,
13C NMR (125 MHz, CDCl3, DMSO-d6):  = 152.1, 138.9, 138.8, 136.5,
128.8, 128.4, 127.4, 126.9, 126.3, 123.9, 121.9, 119.6, 118.2, 113.4.
136.4, 131.0, 130.6, 128.8, 119.6, 119.5, 118.2, 118.1, 112.9, 20.2.
1-(3,5-Diflurophenyl)-3-phenylurea (3i)
1-(4-Phenylmethyl)-3-(4-methylphenyl)urea (3o)27
Yield: 71 mg (74%); white crystalline solid; mp 184–186 °C; Rf = 0.4
(25%, EtOAc/n-hexane).
Yield: 113 mg (90%); white crystalline solid; Rf = 0.5 (25%, EtOAc/n-
hexane).
1H NMR (500 MHz, DMSO-d6):  = 9.03 (s, 1 H), 8.79 (s, 1 H), 7.41 (d,
J = 8.5 Hz, 2 H), 7.25 (t, J = 7.5 Hz, 2 H), 7.15 (d, J = 8.5 Hz, 2 H), 6.95 (t,
J = 7.5 Hz, 1 H), 6.72 (t, J = 9.5 Hz, 1 H).
1H NMR (500 MHz, CDCl3, DMSO-d6):  = 7.80 (s, 1 H), 7.24–7.16 (m,
7 H), 6.96 (d, J = 7.5, 2 H), 6.08 (s, 1 H), 4.32 (d, J = 4.5 Hz, 2 H), 2.19 (s,
3 H).
13C NMR (125 MHz, DMSO-d6):  = 163.6, 163.5, 161.7, 161.6, 153.8,
152.2, 142.6, 142.5, 142.3, 139.1, 128.8, 128.6, 122.3, 120.5, 118.5,
101.0, 100.9, 100.8, 100.7, 96.9, 96.6, 96.4.
13C NMR (125 MHz, CDCl3, DMSO-d6):  = 155.4, 139.3, 136.8, 130.5,
128.6, 127.8, 127.0, 126.4, 118.0, 43.1, 20.1.
1-(3-Chlorophenyl)-3-(diphenylmethyl)urea (3p)29
1-(3,5-Dichlorophenyl)-3-phenylurea (3j)25
Yield: 110 mg (62%); white crystalline solid; mp 212–216 °C; Rf = 0.5
(25%, EtOAc/n-hexane).
Yield: 0.15 g (77%); white crystalline solid (recrystallization in EtOAc);
mp 176–178 °C; Rf = 0.5 (25%, EtOAc/n-hexane).
1H NMR (500 MHz, CDCl3, DMSO-d6):  = 8.26 (s, 1 H), 7.56–7.55 (m,
1 H), 7.28–7.20 (m, 10 H), 7.19–7.15 (m, 2 H), 7.08–7.03 (m, 2 H), 6.00
(s, 1 H).
13C NMR (125 MHz, CDCl3, DMSO-d6):  = 154.2, 142.2, 140.9, 133.6,
129.2, 128.0, 127.9, 127.4, 126.8, 126.6, 120.8, 117.3, 115.4, 56.9.
1H NMR (500 MHz, DMSO-d6):  = 8.97 (s, 1 H), 8.79 (s, 1 H), 7.48 (d,
J = 2.0 Hz, 2 H), 7.41 (d, J = 7.5 Hz, 2 H), 7.23 (d, J = 8.0 Hz, 2 H), 7.07 (t,
J = 2.0 Hz, 1 H), 6.95 (d, J = 8.0 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6):  = 152.2, 142.3, 139.1, 134.0, 128.7,
122.3, 120.8, 118.6, 116.2.
1-(3-Chlorophenyl)-3-(tert-butyl)urea (3q)30
1-(3-Methylphenyl)-3-(4-methylphenyl)-Urea(3k)26
Yield: 47 mg (62%); crystalline solid; Rf = 0.6 (25%, EtOAc/n-hexane);
Yield: 79 mg (63%); white crystalline solid; Rf = 0.5 (25%, EtOAc/n-
mp 150–152 °C.
hexane).
1H NMR (500 MHz, CDCl3):  = 7.36 (br. s, 2 H), 7.09 (br. s, 2 H), 6.92
(br. s, 1 H), 5.42 (s, 1 H), 1.33 (s, 9 H).
13C NMR (125 MHz, CDCl3):  = 155.1, 140.6, 134.6, 129.9, 122.6,
119.5, 117.4, 50.7, 29.3.
1H NMR (500 MHz, CDCl3, DMSO-d6):  = 7.87 (s, 2 H), 7.01 (d, J =
6.5 Hz, 3 H), 6.87 (d, J = 8.0 Hz, 1 H), 6.82 (t, J = 8.0 Hz, 1 H), 6.75 (d, J =
9.0 Hz, 2 H), 6.47 (d, J = 7.5 Hz, 1 H), 1.99 (s, 3 H), 1.97 (s, 3 H).
13C NMR (125 MHz, CDCl3, DMSO-d6):  = 152.8, 139.1, 137.9, 136.5,
1-(2-Methylphenyl)-3-(phenyl)urea (3r)31
130.9, 128.8, 128.1, 122.4, 118.7, 118.3, 115.2, 21.0, 20.2.
Yield: 143 mg (91%); crystalline solid; mp 194–196 °C; Rf = 0.5 (25%,
EtOAc/n-hexane).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

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A. S. Singh et al.
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1H NMR (500 MHz, CDCl3, DMSO-d6):  = 8.59 (s, 1 H), 7.77 (d, J =
8.5 Hz, 1 H), 7.59 (s, 1 H), 7.37 (d, J = 8.5 Hz, 2 H), 7.18–7.14 (m, 2 H),
7.05 (t, J = 7.5 Hz, 2 H), 6.88–6.84 (m, 2 H), 2.19 (s, 3 H).
13C NMR (125 MHz, CDCl3, DMSO-d6):  = 152.9, 139.3, 136.8, 129.7,
128.3, 127.4, 125.9, 122.5, 121.5, 121.3, 118.0, 17.7.
1,3-Di-p-tolylurea (4e)33
Yield: 116 mg (92%); white crystalline solid (recrystallization in EtO-
Ac); Rf = 0.5 (25%, EtOAc/n-hexane).
1H NMR (500 MHz, CDCl3, DMSO-d6):  = 6.78 (s, 2 H), 6.09 (d, J =
8.0 Hz, 4 H), 5.82 (d, J = 8.5 Hz, 4 H), 1.04 (s, 6 H).
13C NMR (125 MHz, CDCl3, DMSO-d6):  = 152.4, 136.8, 136.7, 130.3,
128.7, 118.3, 117.9, 20.1.
1-Phenyl-3-undecylurea (3s)32
In a sealed tube, a suspension of 2p (1.1 equiv), aniline (1.0 equiv),
azidotrimethylsilane (TMSN3) (1.1 equiv), and triethylamine (Et3N)
(2.0 equiv) were taken in anhydrous toluene and the reaction mixture
was stirred under heating at 110 °C for 1 h. After completion of the
reaction (monitored by TLC), the reaction mixture was concentrated
in vacuo. The crude reaction mixture was purified directly using flash
column chromatography (SiO2) to afford 3s in pure form.
1,3-Bis(4-bromophenyl)urea (4f)33
Yield: 82 mg (84%); white crystalline solid (recrystallization in EtO-
Ac); Rf = 0.6 (25%, EtOAc/n-hexane).
1H NMR (500 MHz, DMSO-d6):  = 8.80 (s, 2 H), 7.39 (t, J = 9.5 Hz, 8 H).
13C NMR (125 MHz, DMSO-d6):  = 152.2, 138.9, 131.5, 120.2, 113.4.
Yield: 0.045 g (47%); white crystalline solid; Rf = 0.4 (10%, EtOAc/n-
hexane); mp 88–90 °C (lit. mp 86–89 °C).
N-(Phenylcarbamoyl)benzamide (5a)34
1H NMR (500 MHz, DMSO-d6):  = 8.32 (s, 1 H), 7.32 (d, J = 7.5 Hz,
2 H), 7.17–7.13 (m, 2 H), 6.84–6.81 (m, 1 H), 6.04 (br. s, 1 H), 3.01 (s,
2 H), 1.36 (s, 2 H), 1.20 (s, 16 H), 0.80 (t, J = 6.5 Hz, 3 H).
13C NMR (125 MHz, DMSO-d6):  = 155.7, 141.1, 129.1, 121.3, 118.0,
40.2, 31.8, 30.2, 29.5, 29.3, 29.2, 26.9, 25.6, 22.6, 14.4.
Yield: 151 mg (63%); crystalline solid; Rf = 0.6 (25%, EtOAc/n-hexane);
mp 210–212 °C.
1H NMR (500 MHz, CDCl3, DMSO-d6):  = 11.00 (s, 1 H), 10.33 (s, 1 H),
8.08 (d, J = 7.5 Hz, 2 H), 7.63–7.58 (m, 3 H), 7.52–7.49 (m, 2 H), 7.39–
7.33 (m, 2 H), 7.15–7.12 (m, Hz, 1 H).
13C NMR (125 MHz, CDCl3, DMSO-d6):  = 168.4, 151.4, 136.8, 132.6,
131.7, 128.4, 128.1, 127.6, 123.6, 119.8.
1,3-Diphenylurea (4a)17
Yield: 94 mg (99%); white crystalline solid (recrystallization in EtO-
Ac); Rf = 0.7 (30%, EtOAc/n-hexane); mp 240–242 °C (lit. mp 238 °C).
N-(p-Tolylcarbamoyl)benzamide (5b)35
1H NMR (500 MHz, CDCl3, DMSO-d6):  = 8.35 (s, 2 H), 7.39 (d, J =
7.5 Hz, 4 H), 7.21–7.18 (m, 4 H), 6.92–6.89 (m, 2 H).
Yield: 79 mg (72%); crystalline solid; mp 228–232 °C; Rf = 0.6 (25%,
EtOAc/n-hexane).
1H NMR (500 MHz, DMSO-d6):  = 10.95 (s, 1 H), 10.72 (s, 1 H), 7.98
13C NMR (125 MHz, CDCl3, DMSO-d6):  = 152.4, 139.2, 128.2, 121.5,
(br. s, 2 H), 7.60–7.43 (m, 5 H), 7.12 (s, 2 H), 2.23 (s, 3 H).
117.9.
13C NMR (125 MHz, DMSO-d6):  = 168.7, 151.2, 135.1, 133.1, 132.9,
132.4, 129.5, 128.7, 128.4, 119.9, 20.5.
1,3-Di-o-tolylurea (4b)17
Yield: 97 mg (96%); white crystalline solid; Rf = 0.6 (25%, EtOAc/n-
hexane); mp 234–236 °C (lit. mp 245–247 °C).
N-[(4-Bromophenyl)carbamoyl]benzamide (5c)35
1H NMR (500 MHz, CDCl3, DMSO-d6):  = 8.14 (s, 1 H), 8.11 (s, 1 H),
7.81 (d, J = 7.5 Hz, 2 H), 7.14–7.09 (dd, J = 7.5, 9.5 Hz, 4 H), 6.94–6.91
(m, 2 H), 2.29 (s, 6 H).
13C NMR (125 MHz, CDCl3, DMSO-d6):  = 152.8, 137.2, 129.7, 127.5,
125.7, 122.3, 121.4, 17.9.
Yield: 97 mg (69%); crystalline solid; Rf = 0.5 (25%, EtOAc/n-hexane).
1H NMR (500 MHz, DMSO-d6):  = 10.93 (s, 1 H), 10.79 (s, 1 H), 8.01
(d, J = 8.0 Hz, 2 H), 7.64 (s, 1 H), 7.57–7.50 (s, 6 H).
13C NMR (125 MHz, DMSO-d6):  = 168.5, 150.9, 136.9, 132.8, 132.1,
131.5, 128.4, 128.1, 121.7, 115.3.
1,3-Bis(2-methoxyphenyl)urea (4c)17
2-Benzimidazolone (6a)36
Yield: 77 mg (72%); white crystalline solid (recrystallization in EtOAc);
Rf = 0.4 (25%, EtOAc/n-hexane); mp 182–184 °C (lit. mp 185–186 °C).
Yield: 151 mg (95%); white crystalline solid; Rf = 0.5 (25%, EtOAc/n-
hexane).
1H NMR (500 MHz, DMSO-d6):  = 8.91 (s, 2 H), 8.15–8.13 (m, 2 H),
7.04–7.02 (m, 2 H), 6.99–6.95 (m, 2 H), 6.92–6.89 (m, 2 H), 3.89 (s,
6 H).
1H NMR (500 MHz, DMSO-d6):  = 10.52 (s, 2 H), 6.87 (s, 4 H).
13C NMR (125 MHz, DMSO-d6):  = 155.2, 129.6, 120.3, 108.4.
13C NMR (125 MHz, DMSO-d6):  = 152.6, 148.1, 128.8, 121.8, 120.4,
119.1, 110.7, 55.6.
N-Methylbenzimidazolone (6b)37
Yield: 161 mg (91%); white crystalline solid; Rf = 0.5 (25%, EtOAc/n-
hexane).
1,3-Di-m-tolylurea (4d)17
1H NMR (500 MHz, DMSO-d6):  = 10.76 (s, 1 H), 7.02–7.01 (m, 1 H),
6.97–6.92 (m, 3 H), 3.22 (s, 3 H).
13C NMR (125 MHz, DMSO-d6):  = 154.4, 130.9, 128.2, 120.7, 120.6,
108.5, 107.5, 26.3.
Yield: 93 mg (95%); white crystalline solid (recrystallization in EtOAc);
Rf = 0.5 (25%, EtOAc/n-hexane); mp 224–228 °C (lit. mp 217 °C).
1H NMR (500 MHz, DMSO-d6):  = 8.51 (s, 2 H), 7.26 (s, 2 H), 7.18 (d,
J = 8.5 Hz, 2 H), 7.10 (t, J = 8.5 Hz, 2 H), 6.74 (d, J = 6.5 Hz, 2 H), 2.23 (s,
6 H).
13C NMR (125 MHz, DMSO-d6):  = 152.4, 139.6, 137.9, 128.5, 122.5,
118.6, 115.3, 21.2.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

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A. S. Singh et al.
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Synthesis
Funding Information
(9) (a) Padiya, K. J.; Gavade, S.; Kardile, B.; Bajare, M. S.; Mane, M.;
Gaware, V.; Varghese, S.; Harel, D.; Kurhade, S. Org. Lett. 2012,
14, 2814. (b) Artuso, E.; Degani, I.; Fochi, R.; Magistris, C. Synthe-
sis 2007, 3497. (c) Katritzky, A. R.; Pleynet, D. P. M.; Yang, B.
J. Org. Chem. 1997, 62, 4155. (d) Bigi, F.; Maggi, R.; Sartori, G.
Green Chem. 2000, 2, 140. (e) Babad, H.; Zeiler, A. G. Chem. Rev.
1973, 73, 75.
The authors thank the Science and Engineering Research Board
(SERB), Department of Science & Technology, New Delhi (Grant No.
EMR/2016/001123) for funding. The authors sincerely thank CISC-
Banaras Hindu University (BHU), Varanasi for all the infrastructure
and instrument support. A.K.A. and M.S.Y. acknowledge Council of
Scientific & Industrial Research (CSIR), New Delhi for Senior and Ju-
nior Research Fellowships, and S.K.S. thanks University Grant Com-
(10) (a) Hegarty, A. F.; Drennan, L. J. In Comprehensive Organic Func-
tional Group Transformations, Vol. 6; Gilchrist, T. L., Ed.; Perga-
mon Press: Oxford, 1995, 499. (b) Cavalieri, L. F.; Blair, V. E.;
Brown, G. B. J. Am. Chem. Soc. 1948, 70, 1240. (c) Sawai, H.;
Takizawa, T. Tetrahedron Lett. 1972, 42, 4263. (d) Schreiber, J.;
Witkop, B. J. Am. Chem. Soc. 1964, 86, 2441. (e) Yoneda, F.;
Tanaka, K.; Yamato, H.; Moriyama, K.; Nagamatsu, T. J. Am.
Chem. Soc. 1989, 111, 9199. (f) Kehm, B. B.; Whitehead, C. W.
Org. Synth. Coll. Vol. IV; John Wiley & Sons: London, 1963, 515.
(g) Xu, D.; Ciszewski, L.; Li, T.; Repic, O.; Blacklock, T. J. Tetrahe-
dron Lett. 1998, 39, 1107. (h) McCusker, J. E.; Main, A. D.;
Johnson, K. S.; Grasso, C. A.; McElwee-White, L. J. Org. Chem.
2000, 65, 5216. (i) Gupte, S. P.; Rode, C. V.; Kelkar, A. A.; Mulla, S.
A. R. J. Mol. Catal. A: Chem. 1997, 122, 103. (j) Bassoli, A.;
Rindone, B.; Tollari, S.; Chioccara, F. J. Mol. Catal. 1990, 60, 41.
(11) (a) Orito, K.; Miyazawa, M.; Nakamura, T.; Horibata, A.; Ushito,
H.; Nagasaki, H.; Yuguchi, M.; Yamashita, S.; Yamazaki, T.;
Tokuda, M. J. Org. Chem. 2006, 71, 5951. (b) Guan, Z. H.; Lei, H.;
Chen, M.; Ren, Z. H.; Bai, Y.; Wang, Y. Y. Adv. Synth. Catal. 2012,
354, 489.
(12) (a) Honda, M.; Sonehara, S.; Yasuda, H.; Nakagawa, Y.; Tomisige,
K. Green Chem. 2011, 13, 3406. (b) Kong, D.-L.; He, L.-N.; Wang,
J.-Q. Synlett 2010, 1276. (c) Peterson, S. L.; Stucka, S. M.;
Dinsmore, C. J. Org. Lett. 2010, 12, 1340. (d) Jiang, T.; Ma, X.;
Zhou, Y.; Liang, S.; Zhang, J.; Han, B. Green Chem. 2008, 10, 465.
(13) Kim, S. H.; Hong, S. H. Org. Lett. 2016, 18, 212.
(14) (a) Hemantha, H. P.; Chennakrishnareddy, G.; Vishwanatha, T.
M.; Sureshbabu, V. V. Synlett 2009, 407. (b) Lebel, H.; Leogane,
O. Org. Lett. 2006, 8, 5717. (c) Dube, P.; Nathel, N. F. F.; Vetelino,
M.; Couturier, M.; Abossafy, C. L.; Pichette, S.; Jorgensen, M. L.;
Hardink, M. Org. Lett. 2009, 11, 5622.
mission (UGC), New Delhi for Junior Research Fellowship.
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Acknowledgment
The authors sincerely thank CISC-Banaras Hindu University, Varanasi
for all the infrastructure and instrument support.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1689937.
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References
(1) (a) Geldern, T. W. V.; Hutchins, C.; Kester, J. A.; Wu-Wong, J. R.;
Chiou, W.; Dixon, D. B.; Opgenorth, T. J. J. Med. Chem. 1996, 39,
957. (b) von Geldern, T. W.; Kester, J. A.; Bal, R.; Wu-Wong, J. R.;
Chiou, W.; Dixon, D. B.; Opgenorth, T. J. J. Med. Chem. 1996, 39,
968. (c) Gennäs, G. B.; Mologni, L.; Ahmed, S.; Rajaratnam, M.;
Marin, O.; Lindholm, N.; Viltadi, M.; Gambacorti-Passerini, C.;
Scapozza, L.; Yli-Kauhaluoma, J. ChemMedChem 2011, 6, 1680.
(d) Verheijen, J. C.; Wiig, K. A.; Du, S.; Connors, S. L.; Martin, A.
N.; Ferreira, J. P.; Slepnev, V. I.; Kochendörfer, U. Bioorg. Med.
Chem. Lett. 2009, 19, 3243. (e) McEwan, J. F.; Veitch, H. S.;
Russell-Jones, G. J. Bioconjugate Chem. 1999, 10, 1131.
(2) (a) Irschik, H.; Gerth, K.; Höfle, G.; Kohl, W.; Reichenbach, H. J.
Antibiot. 1983, 36, 1651. (b) Tafesh, A.; Weiguny, M. Chem. Rev.
1996, 96, 2035. (c) Spanu, P.; Ulgheri, F. Curr. Org. Chem. 2008,
12, 1071. (d) Zakrzewski, J.; Krawczyk, M. Heteroat. Chem. 2006,
17, 393. (e) Das, J.; Lin, J.; Moquin, R. V.; Shen, Z.; Spergel, S.;
Wityak, H. J.; Doweyko, A. M.; De Fex, H. F.; Fang, Q.; Pang, S.;
Pitt, S.; Shen, D. R.; Schieven, G. L.; Barrish, J. C. Bioorg. Med.
Chem. Lett. 2003, 13, 2145. (f) Kurihara, M.; Rouf, A. S. S.; Kansui,
H.; Kagechika, H.; Okuda, H.; Miyata, N. Bioorg. Med. Chem. Lett.
2004, 14, 4131. (g) Tewari, N.; Tiwari, V. K.; Mishra, R. C.;
Tripathi, R. P.; Srivastava, A. K.; Ahmad, R.; Srivastava, R.;
Srivastava, B. S. Bioorg. Med. Chem. 2003, 11, 2911.
(3) Ewend, M. G.; Brem, S.; Gilbert, M.; Goodkin, R.; Penar, P. L.;
Varia, M.; Cush, S.; Carey, L. A. Clin. Cancer Res. 2007, 13, 3637.
(4) Escudier, B.; Eisen, T.; Stadler, W. M.; Szczylik, C.; Oudard, S.;
Siebels, M.; Negrier, S.; Chevreau, C.; Solska, E.; Desai, A. A.;
Rolland, F.; Demkow, T.; Hutson, T. E.; Gore, M.; Freeman, S.;
Schwartz, B.; Shan, M.; Simantov, R.; Bukowski, R. M. N. Engl. J.
Med. 2007, 356, 125.
(5) Pezeshk, A.; Pezeshk, V. J. Inorg. Biochem. 1990, 38, 185.
(6) Elks, J. The Dictionary of Drugs: Chemical Data: Chemical Data
Structures and Bibliographies; Springer: Switzerland, 2014.
(7) Uchida, M.; Nishimura, N.; Misaki, N.; Ikarashi, Y.; Kobayashi,
M.; Kawano, O. Nihon Yakurigaku Zasshi. 1990, 95, 185.
(8) Liptrot, D.; Alcaraz, L.; Roberts, B. Adv. Synth. Catal. 2010, 352,
2183.
(15) (a) Katritzky, A. R.; Lan, X.; Yang, J. Z.; Denisko, O. V. Chem. Rev.
1998, 98, 409. (b) Katritzky, A. R.; Rachwal, S. Chem. Rev. 2010,
110, 1564. (c) Kale, R. R.; Prasad, V.; Mohapatra, P. P.; Tiwari, V.
K. Monatsh. Chem. 2010, 141, 1159.
(16) (a) Katritzky, A. R.; Rogovoy, B. V.; Kirichenko, N.; Vedensky, V.
V. Bioorg. Med. Chem. Lett. 2002, 12, 1809. (b) Katritzky, A. R.;
Suzuki, K.; Singh, S. K.; He, H.-Y. Org. Chem. 2003, 68, 5720.
(c) Wang, X.; Zhang, Y. Synth. Commun. 2003, 33, 2627.
(d) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Wang, M. J. Org. Chem.
2003, 68, 4932. (e) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Wang,
M. J. Org. Chem. 2003, 68, 1443. (f) Katritzky, A. R.; Shestopalov,
A. A.; Suzuki, K. Synthesis 2004, 1806. (g) Katritzky, A. R.; Cai, C.;
Suzuki, K.; Singh, S. K. J. Org. Chem. 2004, 69, 811. (h) Katritzky,
A. R.; Abdel-Fattah, A. A. A.; Gromova, A. V.; Witek, R.; Steel, P. J.
J. Org. Chem. 2005, 70, 9211. (i) Katritzky, A. R.; Suzuki, K.;
Wang, Z. Synlett 2005, 1656. (j) Katritzky, A. R.; Widyan, K.;
Kirichenko, K. J. Org. Chem. 2007, 72, 5802. (k) Lim, D.; Fang, F.;
Zhou, G.; Coltart, D. M. Org. Lett. 2007, 9, 4139. (l) Wang, X.;
Wang, W.; Wen, Y.; He, L.; Zhu, X. Synthesis 2008, 3223.
(m) Zhou, G.; Lim, D.; Fang, F.; Coltart, D. M. Synthesis 2009,
3350. (n) Li, J.; Sun, Y.; Chen, Z.; Su, W. Synth. Commun. 2010,
40, 3669.
(17) Singh, A. S.; Kumar, D.; Mishra, N.; Tiwari, V. K. RSC Adv. 2016, 6,
84512.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

H
A. S. Singh et al.
Paper
Synthesis
(18) (a) Katritzky, A. R.; Zhang, Y.; Singh, S. K. Synthesis 2003, 2795.
(b) Singh, A. S.; Agrahari, A. K.; Mishra, N.; Singh, M.; Tiwari, V.
K. Synthesis 2019, 51, 470.
(29) Ichihara, O.; Sampson, D.; Whittaker, M.; Bradley, M.; Cho, J. K.
Comb. Chem. High Throughput Screening 2007, 10, 261.
(30) Basavaprabhu, H.; Sureshbabu, V. V. Org. Biomol. Chem. 2012,
10, 2528.
(31) Hosseinzadeh, R.; Tajbakhsh, M.; Aghili, N. Heteroat. Chem.
2015, 26, 175.
(32) Piana, F.; Case, D. H.; Ramalhete, S. M.; Pileio, G.; Facciotti, M.;
Day, G. M.; Khimyak, Y. Z.; Angulo, J.; Brown, R. C. D.; Gale, P. A.
Soft Matter 2016, 12, 4034.
(33) Pfeifer, L.; Engle, K. M.; Pidgeon, G. W.; Sparkes, H. A.;
Thompson, A. L.; Brown, J. M. Gouverneur V. J. Am. Chem. Soc.
2016, 138, 13314.
(34) Bjerglund, K.; Lindhardt, A. T.; Skrydstrup, T. J. Org. Chem. 2012,
77, 3793.
(35) Yang, G.; Chen, Z.; Zhang, H. Green Chem. 2003, 5, 441.
(36) Rekunge, D. S.; Khatri, C. K.; Chaturbhuj, G. U. Tetrahedron Lett.
2017, 58, 4304.
(19) (a) Singh, A. S.; Agrahari, A. K.; Singh, M.; Mishra, N.; Tiwari, V.
K. ARKIVOC 2017, (v), 80. (b) Singh, M.; Singh, A. S.; Mishra, N.;
Agrahari, A. K.; Tiwari, V. K. Synthesis 2019, 51, 2183.
(20) Kanışkan, N.; Kökten, S.; Çelik, İ. ARKIVOC 2012, (viii), 198.
(21) Badekar, P. S.; Kumbhar, A. A. New J. Chem. 2018, 42, 9168.
(22) Kulkarni, A. R.; Gaai, S.; Thakur, G. A. J. Org. Chem. 2017, 82, 992.
(23) Wang, L.; Wang, H.; Li, G.; Min, S.; Xiang, F.; Liu, S.; Zheng, W.
Adv. Synth. Catal. 2018, 360, 4585.
(24) Sribalan, R.; Sangili, A.; Banuppriya, G.; Padmini, V. New J. Chem.
2017, 41, 3414.
(25) Rakesh, K. P.; Ramesha, A. B.; Shantharam, C.; Mantelingu, K. N.
RSC Adv. 2016, 6, 108315.
(26) Ricci, A.; Carra, A.; Rolli, E.; Bertoletti, C.; Morini, G.; Incerti, M.;
Vicini, P. J. Plant Growth Regul. 2005, 23, 261.
(27) Zhu, T.; Xu, X.; Cao, J.; Wei, T.; Wang, S. Adv. Synth. Catal. 2014,
356, 509.
(37) Das, R.; Banerjee, M.; Rai, R. K.; Karri, R.; Roy, G. Org. Biomol.
Chem. 2018, 16, 4243.
(28) Frøyen, P. Phosphorus, Sulfur Silicon Relat. Elem. 1993, 81, 37.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H