An unexpected reaction to methodology: An unprecedented approach to transamidation

Article abstract of DOI:10.1039/c6ra23374k

This report describes an unprecedented protocol for the synthesis of N,N′-substituted ureas using a cross-coupling method. Mono substituted ureas were modified by an economically viable and simple method using commercially available isocyanates and sodium hydride as the reagents. In addition, the method involves no expensive metal complexes or catalysts and all reactions are carried out at room temperature. Furthermore, both symmetrical and asymmetrical ureas were successfully obtained in single step reactions with reasonable yields.

Full text of DOI:10.1039/c6ra23374k

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An unexpected reaction to methodology: an
unprecedented approach to transamidation†
Cite this: RSC Adv., 2016, 6, 108315
a
b
b
b
a
*
*
K. P. Rakesh, A. B. Ramesha, C. S. Shantharam, K. Mantelingu and N. Mallesha
Received 20th September 2016
Accepted 3rd November 2016
DOI: 10.1039/c6ra23374k
www.rsc.org/advances
This report describes an unprecedented protocol for the synthesis long reaction time and usage of expensive metal complexes and
of N,N0-substituted ureas using a cross-coupling method. Mono recovery of the same from the reaction mixture, which oen
substituted ureas were modified by an economically viable and simple results in metal contamination of in the product.
method using commercially available isocyanates and sodium hydride
as the reagents. In addition, the method involves no expensive organic synthesis,21 we have developed a simple, unprecedented
In our research on the development of methodologies in
metal complexes or catalysts and all reactions are carried out at room and unusual protocol for N-substituted ureas.
temperature. Furthermore, both symmetrical and asymmetrical
We were trying to prepare one of the impurities (E) of
ureas were successfully obtained in single step reactions with iprodione, which can be prepared theoretically by reacting 3,5-
reasonable yields.
dichlorophenylurea (1a) with isopropyl isocyanate under basic
conditions (Scheme 2). However, when we conducted the
reaction, the starting material was consumed as expected but
analysis showed that the expected product was not obtained;
instead we formed 1-(3,5-dichlorophenyl)-3-isopropylurea (3a)
as an unexpected product. When the same methodology was
reapplied, we conrmed the generality and viability of the
Urea, N-substituted symmetric and asymmetric ureas are
a most important class of compounds which have found
extensive applications in agriculture,1 are medicinally impor-
tant and are found in natural products.2 Many substituted ureas
are also known as potent HIV-1 protease inhibitors.3 Many
classical procedures and catalytic transformations have been
reported in the literature for urea synthesis. Isocyanate4 and
phosgene5 are the most predominant reactants used in the
traditional methods although phosgene surrogates have been
developed to replace the gaseous phosgene.6 Ureas are also
produced using activated carbamates,7 carbonates,8 carbon-
yldiimidazole,9 carbon monoxide10 and carbon dioxide11 at
higher temperatures.
Although a signicant number of cross-coupling methodol-
ogies have been developed for N-arylation,12 few have been
applied to the N-arylation of urea and substituted ureas13–19
(Scheme 1). Very recently ruthenium catalyzed urea synthesis
also reported by Kim et al.20 Nevertheless, none of these
procedures provide a general and practical synthetic method for
the preparation of N-aryl or N-heteroaryl ureas. Problem lies
with above prescribed cross-coupled methods are less in yield,
aR&D Centre, SRI RAM CHEM, Spl-52, Industrial Estate, Hebbal, Mysuru-16, India.
E-mail: research@sriramchem.com
bDOS in Chemistry, University of Mysore, Manasagangothri, Mysuru-06, India. E-mail:
kmantelingu@yahoo.com
Scheme
methods.
1
Previous work on urea synthesis by cross-coupling
† Electronic supplementary information (ESI) available: 1H, 13C-NMR and mass
spectra of products are available. See DOI: 10.1039/c6ra23374k
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Table
1
Optimization of base, solvent and temperature for the
synthesis of 3aa
Entry Solvent
Base (eq.)
Temp. (ꢀC) Time (h) Yieldb (%)
1
2
3
4
5
6
7
8
MTBE
THF
Dioxane NaH (1.0)
NaH (1.0)
NaH (1.0)
RT
RT
RT
RT
RT
2
2
2
2
2
2
2
2
2
2
2
1
1
1
4
12
24
2
2
2
20
83
25
66
—
—
—
30
43
80
70
48
30
22
80
75
70
48
86
85
DMF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
NaH (1.0)
TEA (1.0)
Pyridine (1.0) RT
Scheme 2 Unexpected result from the reaction of 3,5-dichlorourea
(1a) with isopropyl isocyanate.
K2CO3 (1.0)
NaH (1.0)
NaH (1.0)
NaH (1.0)
NaH (1.0)
NaH (1.0)
NaH (1.0)
NaH (1.0)
NaH (1.0)
NaH (1.0)
NaH (1.0)
NaH (0.5)
NaH (1.5)
NaH (2.0)
RT
10
20
30
40
50
60
70
RT
RT
RT
RT
RT
RT
9
method for N-substituted ureas and developed a working
protocol.
10
11
12
13
14
15
16
17
18
19
20
In order to obtain the optimal reaction conditions, 3,5-
dichlorourea (1a) was considered as a model substrate, and
several bases and solvents were screened at different tempera-
tures (Scheme 3). The obtained results are tabulated in Table 1.
Several solvents were screened to check their effect on yield.
THF was found to be the best among the solvents employed
(Table 1, entries 1–4), even though DMF did increase the yield
relative to MTBE and dioxane. Knowing the importance of
basicity, organic and inorganic bases were selected for the
reaction and sodium hydride was found to be the best (Table 1,
entries 3, 5–7). Temperature is a critical parameter in the
reaction; at temperatures lower than room temperature (RT),
the reaction did not reach completion, resulting in a very low
yield, while at temperatures higher than RT, no signicant
improvement in the yield was observed, which might be due to
the decomposition of the product formed (Table 1, entries
8–14). An increase in the reaction time did not make any
difference to the yields of the reaction (Table 1, entries 15–17).
However, upon decreasing the amount of the base NaH from
1.0 eq. to 0.5 eq., the yield of the product was decreased (Table
1, entry 18). No signicant improvement in the yield was
observed when NaH was increased from 1.0 eq. to 1.5 eq. or 2.0
eq. (Table 1, entries 19 and 20).
The developed method was utilized to explore its tolerance to
different functional groups. Thus, different ureas and isocya-
nates (Scheme 4) were reacted under optimized conditions, and
the obtained results are tabulated in Table 2.
Initially, isopropyl, tert-butyl and phenyl isocyanates were
treated with dichlorophenylurea, and the corresponding N,N0-
substituted ureas (entries 3a–3c) were formed without affecting
the chloro groups. Phenylureas and 4-methoxy phenylureas
were also obtained in good yields from the corresponding
substituted ureas (entries 3d–3i) without any major additional
products. Aliphatic ureas reacted similarly, and simply con-
verted to N,N0-substituted ureas (entries 3j–3l). In order to check
a
Reactions were performed with 1 mmol of 1a and 1.2 mmol of
b
isocyanate (2a).
puried compounds.
Yields relate to isolated chromatographically
the effect on reactivity of different positions of the methyl group
using dimethylphenylurea substrates, we synthesized 3m–3p.
It was clear that 2,6-dimethylphenylurea yields less compared to
2,4, 3,4 or 3,5-dimethylphenylureas, which might be due to
steric hindrance from the methyl groups.
Both electron-rich and electron-decient substrates gave
similar yields, and various functionalities were tolerated
including halo, ether, methyl and aliphatic groups. These
examples clearly demonstrate the utility of the protocol for
wider applicability. The products were obtained in reasonable
purity by column chromatography followed by a simple
aqueous workup.
Interestingly, to study the mechanism of the reaction, we
tried different supporting reactions (Scheme 5), but we have
failed to conclude the exact mechanism used.
Initially urea was treated with sodium hydride, to nd out
whether urea was converting to aniline (A) in situ, and then
reacting with isocyanate to yield the urea product, but even aer
24 h there was no change in the starting material, which indi-
cates that there was no formation of aniline in the reaction. Next
thiourea was treated with isocyanate (B), and the substituted
thiourea was formed, revealing that the reaction was taking
place at the N0-nitrogen moiety. Finally the urea substrate was
Scheme 3 Reaction of 3,5-dichlorourea (1a) with isopropyl isocyanate Scheme 4 Symmetrical and asymmetrical ureas from sodium hydride
with different bases, solvents and temperatures.
and isocyanate.
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Table
Yields of N,N0-substituted ureas from different urea
RSC Advances
2
are the mild reaction conditions, the ambient reaction
temperature, the use of inexpensive sodium hydride, the
exceptional functional group tolerance and the good-to-
excellent yields. We are convinced that this procedure is, and
will be, of signicant value for the synthesis of a variety of
amides which are signicant in organic and medicinal chem-
istry. A mechanism study using labelled starting materials is in
progress.
substrates
Acknowledgements
All authors are thankful to SRI RAM CHEM management for
their continuous moral and nancial support towards research
in chemistry.
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