Graphical Abstract

Zn mediated simple and convenient method for urea bond formation an

easy access for amino group protection
Eppa Gyanchander,
Rajesh S. Bhosale and J. S. Yadav*
Department of Chemistry, Indrashil University, Rajpur, Kadi, Mehsana,
Gujarat-382715, India.

O O
Zn, THF
R NH2 + R
Cl N N N
H
R= alkyl, aryl
Abstract: The present work provides a fast and mild method towards the synthesis of urea
derivatives and application in the amino group protection. This new methodology is
inexpensive, simple, and environmentally safe process for synthesis of urea derivative, and it
well suited for aliphatic amine and aromatic amine. Reaction condition in aliphatic amine the
Zn mediated urea bond formation taking place at normal room temperature and whereas in
the aromatic amine the Zn mediated urea bond formation taking place prolonged time at room
temperature and whereas at 60° C taking 3 h.

Keywords : Methodology, Urea formation, Zinc, N-acylation,

Introduction:

Urea derivatives are very vital role in medical chemistry, drug development due to their urea
functionality to form a hydrogen bonding with receptor and protein such bonding are
responsible for various biological activity.1 Specially urea functionality include drug
properties in the development of antidiabetic agent, anticonvusive, anti HIV, anticancer,
antibacterial and more biological activity.2,3 Urea containing some of the most commonly
FDA approved drug are Cariprazine (21)4, Sorafenib (22)5, Boceprevir (23)6, Ritonavir (24)7,
Lisuride (25)8. Among these FDA approved drugs here we report the synthesis of cariprazine
using our methodologies.

In 1828 German chemist Fredrich Wöhler marked a starting point of organic

chemistry to synthesizing urea.9,10 After all quick growing in synthesis of medical chemistry,
drug discovery, organic chemistry in the latter half of the 20th century.11 During the past few
years, various technique have been disclose for the synthesis of urea derivatives from amine,
aryl halide12, carbamates13, carboxylic azides14, amide15. Synthetic method involves various
bases16,17and one method is cupper catalysed urea formation 18 here we report the instead of
bases Zn mediated urea formation.
 O NH2
O
O H H
N O H
H F N O
N F
O N N H H
H H N N O
F O
HN N 22 O 23
N
S
S
N
N H
N N N
O O
OH HN O NH
N O O
HN N
H
Cl
NH

Cl 25
21 24

Result and discussion:

Presently, we demonstrated the new methodology towards the synthesis urea derivative
through Zn mediated urea bond formation. We wish to report a simple, convenient and
general method for synthesis of urea derivative using dimethylcarbamic chloride and
activated Zn. In aliphatic amine the Zn mediated urea bond formation taking place at normal
room temperature and whereas the aromatic amine the Zn mediated urea bond formation
taking prolonged time at room temperature and at 60° C aromatic amine the Zn mediated urea
bond formation taking 3 h which is shown in table: 1.

O O
Zn, THF
R NH2 + R
Cl N N N
H

Scheme: 1 General method for preparation of urea derivatives

Table: 1 Synthesis of Urea Derivatives

Sr. No. Reactant Product Temperature Time Yield

(°C)

1 H 25-30°C 1h 93 %
N N
NH2
1 O
11
2 O 25-30°C 1h 91 %

NH2 N N
H
2
12
3 O 25-30°C 1h 90 %
NH2 N N
H
13 3

4 NH2 H 25-30°C 3h 83 %
N N

14
4
5 NH2 O 25-30°C 1.5 h 88 %

F F N N
H
15
F F
5
4 NH2 H 25-30°C 89 %
N N

O
16
6
7 O NH2 H 25-30°C 1h 92 %
O N N
O
17 O
O
7
8 NH2 H 60° C 3h 79 %
N N

O
18 8
9 NH2 H 60° C 3h 85 %
N N
Cl O
Cl
19 9
10 NH2 H 60° C 3h 81 %
N N
Br O
20 Br
10

Conclusion:

A new methodology developed for the urea bond formation and Advantage of this this
method such as mild reaction condition, short reaction time, simple workup and high yield.

Acknowledgments: I would like to express special thanks to the Shodh scholarship scheme
Gujarat government. We also thanks to Indrashil University for providing its infrastructural
facility.

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