Effective approach to ureas through organocatalyzed one-pot process

Article abstract of DOI:10.1016/j.tetlet.2017.11.030

An efficient approach to N, N′-unsymmetrically substituted ureas 9 has been developed through the ammonolysis process of N-Boc protected anilines 7 with amines prompted by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD). Moreover, a convenient protocol for the

Full text of DOI:10.1016/j.tetlet.2017.11.030

Accepted Manuscript
Effective approach to ureas through organocatalyzed one-pot process
Mingliang Wang, Jilai Han, Xiaojia Si, Yimin Hu, Jidong Zhu, Xun Sun
PII:
S0040-4039(17)31433-8
https://doi.org/10.1016/j.tetlet.2017.11.030
TETL 49473
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 September 2017
10 November 2017
14 November 2017
Please cite this article as: Wang, M., Han, J., Si, X., Hu, Y., Zhu, J., Sun, X., Effective approach to ureas through
organocatalyzed one-pot process, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.11.030
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Mingliang Wanga, Jilai Hana, Xiaojia Sib, Yimin Huc, Jidong Zhub*, Xun Suna,d
*
O
O
R1
TBD(cat.)
R2
RNHBoc
DABCO (cat.)
R
R1
R1
R1
HN
N
H
N
N
H
N
H
(Boc)2O
R2 = H
R2

1
Tetrahedron Letters
journal homepage: www.els evier.com
Effective approach to ureas through organocatalyzed one-pot process
Mingliang Wanga, Jilai Hana, Xiaojia Sib, Yimin Huc, Jidong Zhub*, Xun Suna,d ∗
aSchool of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China;
bInterdisciplinary Research Center on Biology and Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
c Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Shanghai 201203, China.
d The Institutes of Integrative Medicine of Fudan University, 12 Middle Urumqi Road, Shanghai 200040, PR China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient approach to N, N’-unsymmetrically substituted ureas 9 has been developed through
the ammonolysis process of N-Boc protected anilines 7 with amines prompted by 1,5,7-
triazabicyclo[4.4.0]dec-5-ene (TBD). Moreover, a convenient protocol for the synthesis of the
symmetric N, N'-substituted ureas 12 by one-pot diammonolysis process of Boc2O with amines
catalyzed by DABCO has also been achieved. With broad substrate scope and mild conditions,
these two methods demonstrate practical preparation of both unsymmetrical and symmetrical
ureas.
Available online
Keywords:
Ureas
Ammonolysis
Organocatalyzed
DABCO
2009 Elsevier Ltd. All rights reserved.
TBD
Introduction
NC
The discovery of convenient methods for the formation of
carbon-nitrogen bond has always been a focused area in synthetic
organic chemistry, due to wide application in both natural
product synthesis and industrial research and production.1 As a
prime instance, efficient methods toward preparation of urea and
its analogous are very important in synthetic and medicinal
chemistry, because these chemical subunits serve as substructures
for numerous pharmaceuticals2, agrochemicals3, as well as
materials science4. For example, the urea units are present in
F
O
N
N
O
NH
N
N
N
H
N
H2N
H
N
ABT-869 (2)
BEZ235 (1)
O
O
N
CF3
PI3K inhibitors (BEZ235,
PKI-587)5, VEGFR inhibitors
N
H
N
H
N
N
(Sorafenib, ABT-869, Lenvatinib, PD173074)6, TRPV
antagonists (SB705498)7, and p38-MAP kinase inhibitors
(BIBR796)8 (Figure 1). Moreover, urea-containing scaffolds are
frequently used in the design of bifunctional organocatalysts9.
Accordingly, tremendous efforts have been devoted to
Br
N
N
O
SB-705498 (3)
N
N
O
N
O
N
H
N
H
N
PKI-587 (4)
developing methods for the construction of urea motifs, and a
O
N
O
18
number of powerful approaches have been reported10-16,
.
NH2
However, most of the traditional methods for the preparation of
urea or its derivatives involve the use of phosgene10, metal-
catalysts11, isocyanate12, azide13, carbonyl imidazole derivatives14
and microwave-accelerated conditions15, which are highly toxic,
unstable, or challenging for large scale application. To pursue
green processes, several methods through transition metal-
catalyzed oxidative carbonylation of amines with CO16 or direct
carbonylation of amine by CO217 are developed in recent years.
However, the use of high pressure of CO/CO2 gas still limits lab-
scale application in medicinal chemistry.
N
O
O
O
O
N
N
H
N
N
NH
N
H
N
H
Cl
O
N
H
PD173074 (5)
Lenvatinib (6)
Figure 1. Examples of bioactive molecules containing urea units.
With continuous focus in exploring practical synthetic
methods for the synthesis of natural products and compounds
with medicinal interests18, we decided to develop a convenient
∗
Corresponding author. E-mail: sunxunf@shmu.edu.cn.

2
9
TBD (0.1)
MeCN
100
84b
method for the construction of urea scaffolds. The most
a The reactions were performed with 7a (1.0 mmol), benzylamine (2.0 mmol),
base in solvent (5 mL) under nitrogen atmosphere and the solution was
refluxed for 16h. b Isolated yield. c Checked by LC-MS.
straightforward urea synthesis uses activated carbamates as the
starting materials or key intermediates. For example, very
recently, Me3SiCl, SiI2H2 or Tf2O/Base were reported to activate
the Boc-protected amines19 (Figure 2. eq.1). Starting from
unprotected amines, urea formation can also be achieved with the
promotion of 4-dimethylaminopyridine (DMAP) in the presence
of Boc anhydride20 (Figure 2. eq.2). Herein, we present efficient
approach to obtain ureas with catalytic amount of 1,5,7-
triazabicyclo[4.4.0]dec-5-ene (TBD) (Figure 2. eq. 3) or 1,4-
Diazabicyclo[2.2.2]octane;triethylenediamine (DABCO) (Figure
2. eq. 4).
Next, we turned our attention to investigate the substrates
scope of this direct approach to urea from Boc-protected
amine
7 with different amines 8. As shown in Table 2, when
substituted benzylamines 8a-e were examined under the
above optimal conditions, the desired products were
generated in excellent yields (Table 2, entries 2-5). Reaction
also proceeded smoothly with simple alklyl amines 8f-h to
give urea 9f-h with high yields (Table 2, entries 6-7). It is
noteworthy to mention that even amines with sterically
bulky substituents such as adamantane 8i also afforded
desired products in reasonable yield (51% for 9i) (Table 2,
19, 20
Previous work
Me3SiCl/NEt3
(1)
(2)
R
N C O
Urea
Urea
RNHBoc
or SiI2H2/DIPEA
or Tf2O/Base
entry 9). Various substituted Boc-protected anilines
7 were
also examined and the results were summarized in Table 2
entries 10-13. Electronically different substituions on the
armatics rings (7j-l) can be tolerated. No reaction can be
observed when the NH on the Boc-protected amine is
masked (Table 2, entry 13).
DMAP
+ (Boc)2O
R
NH2
R N C O
This work
O
O
R1
HN
R2
TBD(cat.)
R
R1
(3)
(4)
RNHBoc
+
Table 2. TBD-catalysed synthesis of ureas.
N
H
N
R2
O
Ar
R1
TBD
Ar
H
N
+
R2
H2N
N
N
DABCO (cat)
R
NH2
(Boc)2O
Boc
+
R
R
MeCN
R1 R2
N
H
N
H
7
8
9
Figure 2. Our strategy to urea derivatives.
b
Entry
1
Ar
R1
H
H
H
H
H
H
H
H
H
H
H
H
R2
9a-n
9a
Y%
Results and discussion
3- BrC6H4
3-BrC6H4
3-BrC6H4
3-BrC6H4
3-BrC6H4
3-BrC6H4
3-BrC6H4
3-BrC6H4
3-BrC6H4
4-MeC6H4
4-CF3C6H4
4-MeOC6H4
4-MeC6H4
C6H5CH2-
86
82
83
76
83
91
93
84
51
73
82
71
NR
2
4-MeC6H4CH2
4-ClC6H4CH2
9b
As shown in Table 1, the reaction of Boc-protected 3-
bromoaniline (7a) with benzylamine was used as the template for
our investigation. Firstly, at room temperature, in DCM or
acetonitrile as the solvent, only trace amount (≤5%) of urea
product 9a was observed with 10% TBD, while no reaction can
be detected with catalytic amount of DMAP or DABCO (Table 1,
entries 1-4). When the reaction mixture was heated at 60 oC, the
desired 9a was obtained in 65% yield (Table 1, entry 5). The
reaction was not satisfactory in NaH/THF condition (Table 1,
entry 6). To further investigate this reaction, different
temperatures and amounts of TBD were screened, and the results
3
9c
4
4-MeOC6H4CH2 9d
5
4-CF3C6H4CH2
-Bu
-Bu
9e
9f
6
t
7
n
9g
9h
9i
8
Cyclohexyl
adamantane
C6H5CH2-
C6H5CH2-
C6H5CH2-
9
10
11
12
13
9j
o
indicated that the optimal reaction temperature is 83 C, and the
9k
9l
amount of TBD slightly affected the yield of 9a (Table 1 entries
7-9).
Me C6H5CH2-
9m
Table 1. Optimization of the reaction conditions.
a The reactions were performed with 7 (1.0 mmol), 8 (2.0 mmol), TBD (0.1
mmol) in MeCN (5 mL) under nitrogen atmosphere and the solution was
refluxed for 6-18 h. b Isolated yield.
O
Base
+
H2N
Br
N
H
N
H
Solvent
Br
NHBoc
To test if this method can apply to secondary amine for urea
formation, we investigated the reaction of Boc-protected amine
7a with pyrrolidine. The result showed that the desired urea 10
was smoothly produced in high yield (97%).
7a
9a
Entry Base (equiv)
Solvent Temp (°C)
Y
%
(
9a
)
1
2
3
4
5
6
7
8
DMAP (0.1)
DCM
rt
rt
0c
0c
<5c
5c
65b
< 5c
86b
78b
DABCO (0.1) DCM
Br
Br
TBD (0.1)
TBD (0.1)
TBD (0.1)
NaH (0.1)
TBD (0.1)
TBD (0.05)
DCM
MeCN
MeCN
THF
rt
TBD
O
+
HN
rt
MeCN
H
N
N
H
N
60
60
83
83
Boc
7a
10
MeCN
MeCN
Scheme 1. The preparation of 10.

3
Encouraged by above results (Table 2), we decided to
investigate symmetric urea formation through one-pot process
using amine 11a (Table 3). Recent years, Knölker and co-
workers observed that isocyannates reacted with primary amines
under (Boc)2O/DMAP conditions could smoothly produce ureas.6
With this goal in mind, 3-bromoaniline was firstly treated by di-
tert-butyl pyrocarbonate and only little N-Boc-protected 3-
bromoaniline 7a was obtained (Table 3, entry 1). To our surprise,
when triethylamine (TEA) was added, the urea 12a was obtained
in 90% yield (Table 1 entry 2). When the amount of Boc2O was
reduced, the yield of 12a was declined (Table 3, entries 3). To
obtain the optimal condition, a variety of bases were screened.
The results indicated that the triethylenediamine (DABCO) was
the best choice for the one-pot formation of urea (Table 3, entries
4-10). Almost quantitively yield of 12a can be obtained with
0.01-0.1 equivalent of DABCO and 0.5 equivalent of Boc2O
(Table 3, entries 10-12). It is noteworthy to mention that even in
the solvent of water urea also was obtained as major product
(Table 3, entry 13). Corresponding isocyanate was obtained by
addition of H2SO4 at -30 oC (Table 3, entry 14).
yield of 12q was generated in 86% yield (Table 4, entry 17).
However, the phenethylamine only gave product 12r in 56%
yield (Table 4, entry 18). Notably, when sterically hindered
amines were employed, the desired ureas were also produced in
excellent yields (Table 4, entries 19-20). In addition, heterocyclic
substrates, such as 8-aminoquinoline (Table 4, entry 21), were
tolerated as well, demonstrating wide functional group
compatibility of our robust protocols for urea formation.
Table 4. DABCO synthesis of ureas from amines and (Boc)2O a,b
Entry
1
R
12a-t
12a
12b
12c
12d
12e
12f
Y %b
97
89
91
93
83
82
82
91
78
78
86
95
96
94
68
83
86
56
88
82
87
3-BrC6H5-
C6H5-
2
3
4-FC6H4-
4
4-ClC6H4-
4-IC6H4-
Table 3. Optimization of the reaction conditions
5
H
N
H
N
6
4-MeC6H4-
4-MeOC6H4-
4-CNC6H4-
4-CF3C6H4-
4-CO2MeC6H4-
4-CF3OC6H4-
2-MeC6H4-
2-ClC6H4-
2-Cl,4-MeC6H4-
C6H5CH2-
Br
Br
(Boc)2O
Br
7
12g
12h
12i
+
+
O
Base
8
N
NHBoc
Br
Br
NH2
9
C
O
10
11
12c
13
14
15
16
17
18
19
20
21
12j
7a
11a
12a
13
12k
12l
Entrya
R
(Boc)2O (equiv)
Base (equiv)
Yield b
7a 12a 13
12m
12n
12o
12p
12q
12r
12s
12t
1
2
3-BrC6H4-
3-BrC6H4-
3-BrC6H4-
3-BrC6H4-
3-BrC6H4-
3-BrC6H4-
3-BrC6H4-
3-BrC6H4-
3-BrC6H4-
3-BrC6H4-
3-BrC6H4-
3-BrC6H4-
3-BrC6H4-
3-BrC6H4-
1.0
1.0
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
No catalyst
Et3N (1.0)
<5
<5
<5
<5
--
90
76
35
<5
78
85
40
32
97
96
91
83
<5
3
Et3N (0.5)
4-ClC6H5CH2-
Tert-Bu-
4
DIPEA (0.1)
5
imidazole (0.1) <5
C6H5CH2CH2-
Cyclohexyl-
C6H5CH(Me)-
8-quinoline-
6
Py (0.1)
<5
<5
10
<5
7
DMAP (0.1)
TBD (0.1)
8
12u
9
DBU (0.1)
a The reactions were performed with 11/8 (2.0 mmol), (Boc)2O (1.0 mmol),
10
11
12
13c
14d
DABCO (0.1)
DABCO (0.05)
DABCO (0.01)
DABCO (0.05)
DABCO (0.1)
b
DABCO (0.2 mmol) in DCM (5 mL) at room temperature for 30 min to 3h.
Isolated yield. c Scale up batch run at 20 mmol.
Diamine 14 was examined as well. As shown in scheme 1,
when the reaction was treatment with 0.5 equiv. Boc2O in the
presence of DABCO, the cyclized product 15 was generated in
92% yield.
12
65
a The reactions were performed with 11a (2.0 mmol), (Boc)2O, base in DCM
(5 mL) at room temperature for 2 h. b Isolated yield. c water as solvent, 23 °C,
d
DABCO (0.1 equiv)
6 h. -30 °C, 30 min, workup by addition of H2SO4, (7.0 equiv) and
NH
NH2
NH2
subsequent extraction with DCM. eAbbreviations: DMAP
=
4-
(Boc)2O
+
DCM, 23 oC, 2h
92%
N
H
O
dimethylaminopyridine. Py = pyridine. TBD = 1, 5, 7-triazabicyclo [4.4.0]
dec-5-ene. DABCO = triethylenediamine. DBU = 1, 8-diazabicyclo [5.4.0]
undec-7-ene.
14
15
Scheme 2. The preparation of 15.
Next, we turned our attention to investigate the substrate scope
for this one-pot urea formation. As shown in Table 4, a variety of
amines were examined under the above optimal conditions
(Table 3, entry 10). When substituted aromatic amines were used,
the corresponding ureas were obtained in excellent yields (Table
4, entries 1-14). The condition can be applied to substituted
benzylamines, with desired ureas produced in moderate yields
(Table 4, entries 15-16). When tert-butylamine was used, the
Two hypotheses are proposed to underlie the mechanism of
this one-pot diammonolysis based on the above results and
previous studies21 (Scheme 3). At the first stage, an equilibrium
between the DABCO/(Boc)2O and 1-(tert-butoxycarbonyl)-1,4-
diazabicyclo[2.2.2]octan-1-ium tert-butyl carbonate 16 is formed.
Nucleophilic addition of the amine on the C=O bond of 16
generates the tetrahedral intermediate 17, which is further
converted to 18 through transprotonation. In path A, the

4
3. (a) Gallou, I. Org. Prep. Proced. Int., 2007, 39, 355-383; (b) Guan,
A. Y.; Liu, C. L.; Yang, X. P.; Dekeyser, M. Chem. Rev., 2014,
114, 7079-7107.
4. (a) Choi, S. J.; Lee, J. H.; Lee, Y. H.; Hwang, D. Y.; Kim, H. D. J.
Appl. Polym. Sci., 2011, 121, 3516-3524; (b) Pereira, E. I.;
Minussi, F. B.; da Cruz, C. C.; Bernardi, A. C.; Ribeiro, C. J.
Agric. Food Chem., 2012, 60, 5267-5272.
5. Wu, P.; Hu, Y. Med. Chem. Commun., 2012, 3, 1337-1355.
6. Musumeci, F.; Radi, M.; Brullo, C.; Schenone, S. J. Med. Chem.,
2012, 55, 10797-10822.
7. Rami, H. K.; Thompson, M.; Stemp, G.; Fell, S.; Jerman, J. C.;
Stevens, A. J.; Smart, D.; Sargent, B.; Sanderson, D.; Randall, A.
D.; Gunthorpe, M. J.; Davis, J. B. Bioorg. Med. Chem. Lett., 2006,
16, 3287-3291.
intermediate 18 is converted to 19, with tert-butoxy group as
the leaving group, leading to the formation of isocyanate 13.
Finally, the other equivalent of amine reacts with isocyanate 13
to form urea 12. In path B, the intermediate 18 decomposes into
tert-butanol, carbon dioxide, DABCO and 7, which then converts
to tert-butanol and isocyanate 13, followed by addition of the
other amine to from 12.
N
N
O
N+
O
N+
-O
+
DABCO
(Boc)2O
O
-O
O
-O
O
O
O
+
R
NH2
8. Regan, J.; Breitfelder, S.; Cirillo, P.; Gilmore, T.; Graham, A. G.;
Hickey, E.; Klaus, B.; Madwed, J.; Moriak, M.; Moss, N.;
Pargellis, C.; Pav, S.; Proto, A. J. Med. Chem., 2002, 45, 2994-
3008.
17
16
9. For recent articles on urea catalysis, see: (a) Hardman, A. M.; So,
S. S.; Mattson, A. E. Org. Biomol. Chem., 2013, 11, 5793-5797; (b)
So, S. S.; Auvil, T. J.; Garza, V. J.; Mattson, A. E. Org. Lett.,
2012, 14, 444-447; (c) Xu, H.; Zuend, S. J.; Woll, M. G.; Tao, Y.;
Jacobsen, E. N. Science, 2010, 327, 986-990; (d) Connon, S. J.
Synlett, 2009, 354-376; (e) Ganesh, M.; Seidel, D. J. Am. Chem.
Soc., 2008, 130, 16464-16465; (f) Robak, M. T; Trincado, M.;
Ellman, J. A. J. Am. Chem. Soc., 2007, 129, 15110-15111; (g)
Doyle, A. G.; Jacobsen, E. N. Chem. Rev., 2007, 107, 5713-5743.
10. (a) Bigi, F.; Maggi, R.; Sartori, G. Green Chem., 2000, 2, 140-148;
(b) Majer, P.; Randad, R. S. J. Org. Chem., 1994, 59, 1937-1938.
11. (a) Díaz, D. J.; Darko, A. K.; McElwee-White, L. Eur. J. Org.
Chem., 2007, 2007, 4453-4465; (b) Kumar, G. S.; Kumar, R. A.;
Kumar, P. S.; Reddy, N. V.; Kumar, K. V.; Kantam, M. L.;
Prabhakar, S.; Reddy, K. R. Chem. Commun., 2013, 49, 6686-
6688; (c) Kim, S. H.; Hong, S. H. Org. Lett., 2016, 18, 212–215.
12. (a) Wei, Y.; Liu, J.; Lin, S.; Ding, H.; Liang, F.; Zhao, B. Org.
Lett., 2010, 12, 4220-4223; (b) Huang, X.; Xu, S.; Tan, Q.; Gao,
M.; Li, M.; Xu, B. Chem. Commun., 2014, 50, 1465-1468.
13. Zhao, J.; Li, Z.; Yan, S.; Xu, S.; Wang, M.-A.; Fu, B.; Zhang, Z.
Org. Lett., 2016, 18, 1736-1739.
N
DABCO
+
N
N+
O
N+
O
+t-BuOH
-t-BuOH
HO
Path A
-O
O
-O
O
O
CO2 t-BuOH
+
+
R-NH=C=O
O
R
NH
NH
R
13
19
18
Path B
2RNH
CO2
DABCO
+
+
O
R
H
N
RNH2
+
-H+
tBuO
R
R
O
-
N
O
N
H
N
H
tBuOH
+
R-N=C=O
R
+
+H+
O
O
12
7
13
Scheme 3. The proposed mechanism to urea.
Conclusions
14. (a) Duspara, P. A.; Islam, M. S.; Lough, A. J.; Batey, R. A. J. Org.
Chem., 2012, 77, 10362–10368; (b) Katritzky, A. R.; Pleynet, D. P.
M.; Yang, B. J. Org. Chem., 1997, 62, 4155–4158.
15. Kulkarni, A. R.; Garai, S.; Thakur, G. A. J. Org. Chem. 2017, 82,
992-999.
16. (a) Gabriele, B.; Salerno, G.; Mancuso, R.; Costa, M. J. Org.
Chem., 2004, 69, 4741-4750; (b) Gabriele, B.; Mancuso, R.;
Salerno, G.; Costa, M. Chem. Commun., 2003, 486-487; (c) Zhang,
L.; Darko, A. K.; Johns, J. I.; McElwee-White, L. Eur. J. Org.
Chem., 2011, 2011, 6261-6268.
17. (a) Ion, A.; Parvulescu, V.; Jacobs, P.; Vos, D. D. Green Chem.,
2007, 9, 158-161; (b) Jiang, T.; Ma, X.; Zhou, Y.; Liang, S.;
Zhang, J.; Han, B. Green Chem., 2008, 10, 465-469; (c) Fuchter,
M. J.; Smith, C. J.; Tsang, M. W. S.; Boyer, A.; Saubern, S.; Ryan,
J. H.; Holmes, A. B. Chem. Commun., 2008, 2152-2154.
18. (a) Tang, M.-L.; Peng, P.; Liu, Z.-Y.; Zhang, J.; Yu, J.-M.; Sun, X.
Chem.-Eur. J., 2016, 22, 14535-14539; (b) Tang, M.-L.; Zhong,
C.; Liu, Z.-Y.; Peng, P.; Liu, X.-H.; Sun, X. Eur. J. Med. Chem.,
2016, 113, 63-74; (c) Xu, G.; Lv, B.; Roberge, J. Y.; Xu, B.; Du,
J.; Dong, J.; Chen, Y.; Peng, K.; Zhang, L.; Tang, X.; Feng, Y.;
Xu, M.; Fu, W.; Zhang, W.; Zhu, L.; Deng, Z.; Sheng, Z.;
Welihinda, A.; Sun, X. J. Med. Chem., 2014, 57, 1236-1251; (d)
Zhong, C.; Liu, X.-H.; Chang, J.; Yu, J.-M.; Sun, X. Bioorg. Med.
Chem. Lett., 2013, 23, 4413-4418;
In summary, we established an efficient method to prepare N, N’-
unsymmetrically substituted ureas 9 through the ammonolysis of
N-Boc protected anilines 7 with amines prompted by TBD.
Furthermore, one-pot approach, for the preparation of symmetric
N, N'-substituted ureas 12 by the diammonolysis process of
Boc2O with 2 equivalents of amines, was also achieved,
catalyzed by DABCO. The methods for the urea formation
reported in this study are convenient, practicable and efficient. It
can be applied to a broad spectrum of amine substrates under
mild conditions. Further efforts on the synthetic application of
this approach are on-going in our laboratory.
Acknowledgments
We thank the National Natural Science Foundation of China
(No. 81673297), the Shanghai Municipal Committee of Science
and Technology (No.17431902500, 17JC1400200 and
15ZR1449000). We also thank Dr. Chang-Mei Si (School of
Pharmacy, Fudan University) for helpful in preparation of
manuscript.
19. (a) Spyropoulos, C.; Kokotos, C. G. J. Org. Chem., 2014, 79,
4477-4483; (b) Kim, H.-K.; Lee, A. Tetrahedron Lett., 2016, 57,
References and notes
4890-4892; (c) Bana, P.; Lakó, Á.; Kiss, N. Z.; Béni, Z.;
Szigetvári, Á.; Kóti, J.; Túrós, G. I.; Éles, J.; Greiner, I. Org.
Process Res. Dev., 2017, 21, 611-622.
1. (a) Hili,R; Yudin, A.K. Nat. Chem. Biol., 2006, 2, 284-2877; (b)
Shin, K; Kim, H; Chang, S. Acc. Chem. Res., 2015, 48, 1040-
1052.
20. Knölker, H.-J.; Braxmeier, T.; Schlechtingen, G. Angew. Chem.,
Int. Ed., 1995, 34, 2497-2500.
21. Baidya, M.; Kobayashi, S.; Brotzel, F.; Schmidhammer, U.;
Riedle, E.; Mayr, H. Angew. Chem., Int. Ed., 2007, 46, 6176-6179.
2. For selected references see: (a) Kozikowski, A. P.; Zhang, J.; Nan,
F. J.; Petukhov, P. A.; Grajkowska, E.; Wroblewski, J. T.;
Yamamoto, T.; Bzdega, T.; Wroblewska, B.; Neale, J. H. J. Med.
Chem., 2004, 47, 1729-1738; (b) Terefenko, E. A.; Kern, J.;
Fensome, A.; Wrobel, J.; Zhu, Y.; Cohen, J.; Winneker, R.; Zhang,
Z. M.; Zhang, P. W. Bioorg. Med. Chem. Lett., 2005, 15, 3600-
3603; (c) Li, Q.; Li, T. M.; Woods, K. W.; Gu, W. Z.; Cohen, J.;
Stoll, V. S.; Galicia, T.; Hutchins, C.; Frost, D.; Rosenberg, S. H.;
Sham, H. L. Bioorg. Med. Chem. Lett., 2005, 15, 2918-2922.
Supplementary Material
Supplementary data associated with this article can be found
in the online version.

5
Research highlights
Organocatalytic urea formation is described.
Non-toxic reagents are used instead of reported toxic reagents.
Mild reaction conditions and applicable to large scale synthesis.