Novel one-pot synthesis of symmetrically substituted ureas

Article abstract of DOI:10.1080/00397911.2016.1205627

We demonstrated a novel, facile, high-yield, and efficient one-pot approach for the synthesis of symmetrically disubstituted ureas from isocyanates in the presence of trimethylsilanol. This novel protocol boasts the use of inexpensive reagents, operational simplicity, excellent yields of products, environmentally friendly conditions, and easy workup. To the best of our knowledge, this is the first example of the synthesis of symmetrically disubstituted ureas from isocyanates in the presence of trimethylsilanol in one pot.

Full text of DOI:10.1080/00397911.2016.1205627

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
A Novel One-Pot Synthesis of Symmetrically
Substituted Ureas
Xingxing Wu, Qingfen Niu & Tianduo Li
To cite this article: Xingxing Wu, Qingfen Niu & Tianduo Li (2016): A Novel One-
Pot Synthesis of Symmetrically Substituted Ureas, Synthetic Communications, DOI:
10.1080/00397911.2016.1205627
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Date: 13 July 2016, At: 19:01

A Novel One-Pot Synthesis of Symmetrically Substituted Ureas
1
1
1
Xingxing Wu , Qingfen Niu , Tianduo Li
1
Shandong Provincial Key Laboratory of Fine Chemicals, Qilu University of Technology,
Jinan, People’s Republic of China
Correspondence Authors E-mails:
Qingfen Niu: qf_niu1216@qlu.edu.cn
Tianduo Li: litianduo@163.com
Abstract
We demonstrated a novel, facile, high-yield and efficient one-pot approach for the
synthesis of symmetrically disubstituted ureas from isocyanates in the presence of
trimethylsilanol. This novel protocol boasts use of inexpensive reagents, operational
simplicity, excellent yields of products, environment-friendly conditions and easy workup.
To the best of our knowledge, this is the first example of synthesis of symmetrically
disubstituted ureas from isocyanates in the presence of trimethylsilanol in one pot.
Graphical Abstract
1

KEYWORDS: One-pot synthesis; High-yield; Urea; Isocyanate; Trimethylsilanol
INTRODUCTION
By the virtue of their numerous important applications, the synthesis and uses of
substituted ureas have attracted special attention in the recent years. Disubstituted ureas
[
1,2]
played an important role in industrial field
as dyes for cellulose fibers, antioxidants in
gasoline, resin precursors and in organic synthesis as starting materials (especially for the
[
3–5]
production of carbamates, isocyanates, polymers and surfactants) and intermediates
especially for the production of cosmetics, pharmaceuticals and agrochemicals),
(
particularly in the medical field as tranquilizing, anticonvulsant, antidiabetic agents as
well as inhibitors of HIV-1 protease. Owing to their increasing application of these
compounds, a great variety of procedures have been used to investigate their
[
6,7]
synthesis
.
A large number of experimental investigations have been made to search for an
efficient and practical method to synthesize various urea-based compounds. The
traditional procedures are available in the literature for the synthesis of substituted ureas
(
Scheme 1). They can be collected and classified into three groups: (i) The reaction of
[
8]
primary amines mainly with phosgene or triphosgene (BTC) ; (ii) Reaction of primary
and secondary amines with isocyanates, prepared mainly from phosgene during organic
2

[
9–10]
synthesis
. However, the phosgene has corrosive nature and its preparation usually
generates excessive toxicological and environmental wastes; (iii) The reaction of primary
amines with carbonyl derivatives (including dicyclohexylcarbodiimide,
carbonyldiimidazole, carbonates and trichloroacetyl chlorides), carbon dioxide, carbon
[
11–14]
monoxide as well as oxygen
. The carboxylation of amines to ureas usually requires
harsh conditions such as high pressure, high temperatures and even microwave irradiation
[
15]
conditions or metal catalysts
.
However, the effectiveness of existing synthetic methods above suffer from some
[
15]
disadvantages such as the use of metal-mediated catalysis, hazardous and expensive
reagents, higher pressure or temperatures conditions, longer reaction times, low yields,
incompatibility with functionalized substrates, multi-step synthesis as well as difficult
workup, which not only reduce process efficiency but also pose serious environment
problems.
As a consequence, the introduction of new methods and/or further work on technical
improvements to overcome these limitations is still an important experimental challenge.
Therefore, from the point of the growing importance of symmetrically substituted ureas,
the development of a simple, efficient and environmentally benign method for their
synthesis is highly desirable. To the best of our knowledge, there are no literature reports
available for the synthesis of symmetrically disubstituted ureas by using trimethylsilanol.
3

Herein, we have presented our new strategy, a novel, facile, high-yield and efficient
one-pot synthesis of symmetrically disubstituted ureas from corresponding isocyanates in
the presence of trimethylsilanol under mild conditions.
RESULTS AND DISCUSSION
The desired products disubstituted ureas 3 were obtained with isocyanates 1 (1.0 equiv)
3 3
in CH CN at room temperature for 3-6 hours in the presence of Me SiOH (1.0 equiv) as
shown in Scheme 2. The experimental results were summarized in Table 1. From the
results in Table 1, it is concluded that all of the expected substituted ureas (3a-g) were
obtained in excellent yields (90–98%). To our delight, unsubstituted aryl isocyanates
were well reacted with trimethylsilanol under the optimized conditions (entries 2 and 5).
To our satisfaction, the reaction can tolerate aryl substituents of different electronic
effects at the meta or para positions, affording excellent yields (entries 3, 4, 6). However,
2
certain functional group such as NO group with strong electron-withdrawing nature was
not tolerated in the protocol (entry 8). In order to further extend the substrate scope of the
protocol, aliphatic substrates such as isocyanatocyclohexane and
1
-isocyanato-2-methylbenzene with steric hindrance were tested. It is noteworthy that
this reaction protocol can be successfully carried out by using aliphatic substrates to
afford the corresponding products in excellent yields (up to 92%) after 6 h (entries 1 and
7
). Therefore, this metal-free synthetic method could potentially be a mild and convenient
4

method of accessing such aryl, alkyl, and cyclohexyl structures. Products 3a-f are known
[
16–18]
compounds
and were confirmed by the comparison of their spectral data with
literature. Among these products, the product 3g is as a new compound and fully
1
13
characterized by IR, H NMR, C NMR and HRMS measurements.
In order to study the mechanism of these reactions, the proposed reaction mechanism
of disubstituted ureas 3 is suggested in Scheme 3. The first step is nucleophilic attack of
oxygen atom of Me
3
SiOH upon the carbon atom of the carbonyl group of 1 to give rise to
SiOH oxygen atom on the carbon
intermediate A. Next, nucleophilic attack of the Me
3
atom of the carbonyl group of A leads to the formation of intermediate B. Then the
reductive elimination of intermediate B delivers compound C to furnish intermediate D.
Finally, the end-product of disubstituted urea 3 is produced from 1 via nucleophilic attack
of nitrogen atom of R-NH
2
upon the carbon atom of the carbonyl group of 1.
CONCLUSIONS
In summary, we have successfully developed a one-pot, facile, high-yield and efficient
approach for the synthesis of symmetrically disubstituted ureas from corresponding
isocyanates including aryl, alkyl, and cyclohexyl substrates in the presence of
trimethylsilanol. This novel method offers several advantages such as use of inexpensive
5

reagents, excellent yields of products, environment-friendly conditions, and simple
experimental and work-up procedures. We expect that the metal-free synthetic approach
would be highly practical and safe for the synthesis of symmetrically disubstituted ureas
in the field of organic and medicinal chemistry.
EXPERIMENTAL
General
Unless otherwise stated, all solvents and reagents were of analytical grade from
commercial suppliers, and were used without further purification. Infrared measurements
–
1
with the KBr pellet technique were performed within the 4000–400 cm region on a
1
13
Bruker ALPHA FT-IR spectrometer. H NMR and C NMR spectra were recorded on a
1
Bruker Avance Ⅱ400 using TMS as an internal standard operating at 400 MHz for H
1
3
6
NMR and 100 MHz for C NMR in DMSO-d , respectively. High resolution mass
spectra (HRMS) were obtained from Agilent 6510 Accurate-Mass Q-TOF LC/MS
system.
General Procedure For The Synthesis Of Symmetrically Substituted Urea 3
To a well-stirred, isocyanate (1, 1.0 mmol) was added in MeCN (10 mL, anhydrous), then
trimethylsilanol (2, 1.0 mmol) was added in the reaction system. The reaction mixture
6

was stirred for 3–6 h at room temperature. After that, the solvent was removed to afford
the corresponding symmetrically substituted urea product 3.
1
,3-Bis(2-(Tert-Butyldimethylsilyloxy)Ethyl)Urea (3g)
-1
Yield 90%; Light yellow liquid; IR (KBr, cm ): ν = 3425 (NH), 2979, 2808, 2472, 2633
1
(
C=O(NH)), 1459,1392, 1154, 1040, 803; H NMR (400 MHz, DMSO-d
6
): δ = 5.93 (s,
13
2
H), 3.5 (t, J = 6.0 Hz, 4H), 3.05 (t, J = 6.0 Hz, 4H), 0.85 (s, 18H), 0.01 (s, 12H); C
6
NMR (100 MHz, DMSO-d ): δ = 157.914, 62.424, 41.749, 25.788, 17.845, -5.67; HRMS:
+
+
m/z calculated 376.2673 [M+H] , found 377.3441 [M+H] .
[
16-18]
The products 3a-f are known compounds
and were characterized by comparing the
1
13
IR, H NMR, C NMR and HRMS spectroscopic data with authentic samples reported in
the literature. See supplementary data for the characterization of products 3a-f.
ACKNOWLEDGEMENTS
We gratefully acknowledge the support by NSF China No. 21376125 and Program for
Scientific Research Innovation Team in Colleges and Universities of Shandong Province.
7

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10

a
3
Table 1. Synthesis of disubstituted ureas 3 using isocyanates and Me SiOH.
d
Entry
Substrate
Product
Yield (%)
c
1
92
95
91
98
94
b
2
c
3
b
4
b
5
c
6
96
90
c
7
e
8
NR
a
Reaction conditions: isocyanates (1, 1.0 equiv.) and trimethylsilanol (2, 1.0 equiv.) were
b
c
d
e
reacted at room temperature; 3 h; 6 h; isolated yields; No reaction.
11

Scheme 1. The conventional procedures for synthesis of substituted ureas in literature.
12

Scheme 2. One-pot synthesis of substituted ureas 3 from isocyanates in the presence of
trimethylsilanol.
13

Scheme 3 The proposed reaction mechanism of disubstituted ureas 3.
14