A simple method for the preparation of di-, tri- and tetrasubstituted non-symmetrical ureas

Article abstract of DOI:10.1055/s-2005-923584

The synthesis of a series of di-, tri- and tetrasubstituted non-symmetrical ureas is described. Di- and trisubstituted ureas are prepared in excellent yield by treatment of a phenyl carbamate in a self-tunable single-mode microwave synthesizer with a primary or secondary amine. The synthetically more challenging tetrasubstituted urea can be prepared using the 4-nitrophenyl carbamate and a secondary amine. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-923584

LETTER
243
A Simple Method for the Preparation of Di-, Tri- and Tetrasubstituted
Non-Symmetrical Ureas
Urea Synthesis ve Bridgeman, Nicholas C. O. Tomkinson*
School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff, CF10 3AT, UK
Fax +44(29)20874030; E-mail: tomkinsonnc@cardiff.ac.uk.
Received 30 September 2005
Carbamates are traditionally used as effective protecting
groups for the amine functionality and have a well estab-
lished and reliable reactivity profile, the low electrophilic-
ity of the carbonyl rendering them particularly unreactive
Abstract: The synthesis of a series of di-, tri- and tetrasubstituted
non-symmetrical ureas is described. Di- and trisubstituted ureas are
prepared in excellent yield by treatment of a phenyl carbamate in a
self-tunable single-mode microwave synthesizer with a primary or
secondary amine. The synthetically more challenging tetrasubstitut- to nucleophiles.10 However, we have found that both phe-
ed urea can be prepared using the 4-nitrophenyl carbamate and a
secondary amine.
nyl- and 4-nitrophenyl carbamates are effective precur-
sors to the urea motif when treated with either primary or
Key words: urea, microwave-assisted synthesis, carbamate
secondary amines under microwave irradiation.
As a starting point we prepared the phenyl carbamate 1 by
reaction of 3,4-dimethoxyaniline with phenyl chlorofor-
mate in dioxane (97%). Treatment of 1 with one equiva-
lent of pyrrolidine with an initial power of 50 W at 100 °C
for 15 minutes in a self-tunable single-mode microwave
synthesizer gave the desired non-symmetrical urea 2 in
97% isolated yield without the need for aqueous work up
(Scheme 1; see experimental section for full details of
reaction conditions).
The urea functionality remains an important and common
structural motif within many biologically active com-
pounds due to its hydrolytic stability, molecular rigidity
and the considerable amount of molecular diversity that
can readily be introduced from cheap, commercially
available amine starting materials.1,2 Entrenched methods
for their preparation include the use of toxic and highly re-
active phosgene3 and isocyanates.4 More recently, alterna-
tive more controlled protocols have been introduced
through the use of 1,1¢-carbonylbisbenzotriazole5 or
carbonyldiimidazoles6 amongst others.7,8
O
N
H
H
N
N
Ph
Ph
N
O
MW, 100 °C
15 min, MeOH
Although these newer methods are effective, practical
issues and general applicability of the procedures still
reveal limitations for the preparation of this crucial and
valuable functional group. Of particular note is the need
for protection of nucleophilic functional groups such as
alcohols in the activated intermediate, which leads to the
need for protecting group strategies to be employed which
can prove particularly cumbersome, especially when con-
sidering the focus on high throughput synthesis within the
pharmaceutical industry.9 Herein, we report a simple and
practical, microwave-assisted method for the controlled
and reliable preparation of di-, tri- and tetrasubstituted
ureas, that proceeds in excellent yields and is tolerant of
unprotected alcohols in both amine components, greatly
adding to the synthetic utility of the procedure.
H
O
1
97%
2
Scheme 1
H
H
N
H
MeO
MeO
N
OPh
OPh
OPh
Ph
N
OPh
O
O
O
O
HO
3 (97%)
4 (92%)
5 (98%)
H
N
MeO
HO
OPh
N
N
O
OPh
O
HO
6 (98%)
7 (82%)
8 (93%)
Figure 1 Phenyl carbamates prepared (yields in parentheses)
HO
OH HO
O
O
NH2
O
MeHN
H2N
OH
HN
OH
OH
OH
H2N
HN
17
N
N
H
10
N
H
HN
H
9
11
12
13
14
15
16
18
Figure 2 Amines used in the preparation of ureas
SYNLETT 2006, No. 2, pp 0243–0246
0
1.
0
2.
2
0
0
6
Advanced online publication: 23.12.2005
DOI: 10.1055/s-2005-923584; Art ID: D29805ST
© Georg Thieme Verlag Stuttgart · New York

244
E. Bridgeman, N. C. O. Tomkinson
LETTER
Table 1 Preparation of Non-Symmetrical Di- and Trisubstituted
Ureas from Phenyl Carbamates 3–6a
Encouraged by this initial result we went on to investigate
whether this was a general method for the preparation
of a variety of ureas and prepared the phenyl carbamates
3–8 (Figure 1).
Entry Reaction Urea
Yield (%)
The carbamates 3–8 were reacted with a series of primary
and secondary amines (Figure 2) under our standard reac-
tion conditions to provide, in most cases, the correspond-
ing ureas (Table 1).11 The reaction worked well for the
preparation of disubstituted ureas with the introduction of
a variety of amines proceeding smoothly (entries 3, 8, 11
and 12). This was also the case for trisubstituted ureas for
aliphatic amines (entry 1) as well as the introduction of
amines containing unprotected hydroxyl functionalities
(entry 2). Crucially, we were also able to form the desired
ureas in the presence of a free hydroxyl on the carbamate
moiety, greatly adding to the synthetic utility of this pro-
cedure (entries 4–12). We were unable to bring about any
reactivity in the reaction of the disubstituted carbamates 7
and 8, even under more forceful reaction conditions (up to
150 W initial power) with both secondary (pyrrolidine)
and primary (benzylamine) amines no observable reaction
took place, only starting material being isolated from the
reaction mixture. It is probable that with the phenyl car-
bamates 3–6, the reaction proceeds via an intermediate
isocyanate, formed in situ by deprotonation of the car-
bamate, followed by nucleophilic attack of the amine.
This is not possible with the substrates 7 and 8, whose re-
action would have to proceed via a different mechanism.
O
O
1
3 + 9
96
H
N
MeO
MeO
N
O
OH
H
N
2
3
4
3 + 11
3 + 13
4 + 11
90
92
93
MeO
N
O
O
MeO
MeO
H
N
H
N
OH
MeO
OH
H
N
N
O
HO
HO
OH
H
N
5
4 + 12
95
N
O
O
Comparison of the microwave-assisted and thermal pro-
cesses revealed the reactions to be more efficient, cleaner
and considerably quicker using the microwave-assisted
reaction conditions. For example, reaction of carbamate 6
with enthanolamine 15 at room temperature for three days
gave the corresponding urea in 64% isolated yield. Heat-
ing the reaction at reflux did improve the rate, with the
reaction going to completion in 24 hours, however, no real
improvement in yield was observed (68%) (cf. Table 1,
entry 11: 90% yield, 15 min).
H
N
N
O
6
7
4 + 14
5 + 18
94
95
OH
HO
Ph
H
N
N
O
O
H
N
H
N
Ph
Ph
8
9
5 + 15
5 + 17
96
96
OH
In a search for more reactive substrates to prepare the elu-
sive tetrasubstituted non-symmetrical ureas by a similar
method we reasoned that increasing the leaving group
ability of the carbamate substituent could lead to an in-
creased electrophilicity of the carbamate carbonyl group,
despite the fact that formation of an intermediate isocyan-
ate was not possible from these substrates. We therefore
prepared the 4-nitrophenylchloroformate derivatives 19–
21 (Figure 3) by treatment of the secondary amine with 4-
nitrophenylchloroformate, providing the required starting
materials for this part of the investigation in excellent
yield.12
H
N
N
O
OH
H
N
10
11
12
6 + 11
6 + 15
6 + 10
92
90
93
MeO
N
O
HO
H
N
H
MeO
N
OH
OH
With the more reactive substrates 19–21 we found that
this proved to be a particularly effective method for the
formation of the synthetically challenging non-symmetri-
cal tetrasubstituted urea motif. The results obtained are
outlined in Table 2. The method was efficient for the
introduction of both acyclic (entries 1, 5 and 6) and cyclic
(entries 2–4 and 7, 8) amines, with both alkyl (entries 1,
2) and aryl (entries 4–8) 4-nitrophenyl carbamates.
O
HO
OH
H
N
MeO
HO
O
a All reactions performed at an initial power of 50 W for 15 min.
Synlett 2006, No. 2, 243–246 © Thieme Stuttgart · New York

LETTER
Urea Synthesis
245
Table 2 Microwave-Assisted Preparation of Non-Symmetrical
Tri- and Tetrasubstituted Ureas from Carbamates 19–21a
Significantly, the reaction was tolerant of nucleophilic hy-
droxyl groups within the starting carbamate (entries 6–8),
which is not the case for alternative methods within the
literature,13 providing a convenient, high yielding and
valuable route to this class of compounds. Reaction times
varied with this conversion depending on the inherent
nucleophilicity of the amine, with cyclic amines typically
going to completion in 45 minutes, whereas with the less
nucleophilic acyclic amines 90 minutes were required.
Increasing the initial power of the microwave irradiation
did lead to shorter reaction times but isolated yields fell by
5–10%, leading us to adopt 50 W as the standard reaction
power.
Entry Reaction
Urea
Yield (%)
H
N
1
2
19 + 16
19 + 18
91
93
N
N
Ph
O
O
O
N
MeO
MeO
N
N
3
4
20 + 17
20 + 10
93
92
O
MeO
MeO
N
O
N
O
OH
O
O
NO2
NO2
OH
OH
19 (98%)
20 (97%)
MeO
N
N
N
N
O
O
O
MeO
MeO
O
HO
NO2
H
N
21 (98%)
5
6
20 + 13
21 + 12
90
97
Figure 3 4-Nitrophenyl carbamates prepared (yields in paren-
theses)
MeO
N
N
OH
An indication of the increased reactivity that can be ob-
tained by the use of the microwave is exemplified by the
fact that no product could be detected in the thermal reac-
tion between the carbamate 20 and pyrrolidine 17, at re-
flux, even after 7 days, providing further evidence of the
useful modification of reactivity profile that can be ob-
tained using these instruments.
O
HO
OH
7
8
21 + 14
21 + 10
94
95
N
N
O
HO
HO
OH
In summary, we have discovered a simple, high yielding
method for the preparation of non-symmetrical di-, tri-
and tetrasubstituted ureas by the preparation of either the
phenyl- or 4-nitrophenyl carbamates, followed by treat-
ment with either primary or secondary amines in a self-
tunable microwave synthesizer. The reactions proceed
without the need for aqueous work-up and can be purified
directly after completion of the reaction.
OH
N
N
O
a Reactions performed at an initial power of 50 W for 45–90 min.
br d, 1 H), 2.14–2.05 (m, 1 H), 2.01–1.98 (m, 1 H). 13C NMR (100
MHz, MeOD): d = 157.9, 150.7, 147.0, 134.9, 115.2, 113.6, 108.4,
71.6, 57.2, 56.7, 55.5, 45.3, 35.0. MS (APcI): m/z (%) = 267 (100)
[MH]+.
Typical Experimental Procedure for the Preparation of Trisub-
stituted Ureas: N-[(3S)-Pyrrolidinol]-N¢-(3,4-Dimethoxy)phen-
yl Urea (Table 1, entry 2)
Typical Experimental Procedure for the Preparation of Tetra-
substituted Ureas: N-Methyl-N-(3,4-dimethoxy)phenyl Pyrroli-
dine Urea (Table 2, entry 3)
N-(3,4-Dimethoxyphenyl)-O-phenyl carbamate (0.25 g, 0.92
mmol) and 3-(S)-pyrrolidinol (0.11 mL, 1.37 mmol) were dissolved
in MeOH (3 mL) in a microwave reaction tube. The reaction mix-
ture was stirred in a single-mode microwave reactor for 15 min at
100 °C (initial power 50 W). The solvent was removed under re-
duced pressure and the crude mixture was purified by column chro-
matography (eluting solvents acetone–hexane, 3:1) to give the title
compound (0.22 g, 92%) as a colourless crystalline solid; mp 131–
132 °C. HRMS: m/z calcd for C13H18N2O4 [MH]+: 267.1339; found:
267.1341. IR (nujol): nmax = 3508 (NH), 3387 (OH), 1666 (C=O)
N-(3,4-Dimethoxyphenyl)-N-methyl-O-(4-nitrophenyl) carbamate
(0.25 g, 0.75 mmol) and pyrrolidine (0.13 mL, 1.5 mmol) were dis-
solved in MeOH (3 mL) in a microwave reaction tube. The reaction
mixture was stirred in a single-mode microwave reactor for 30 min
at 100 °C (initial power 50 W). The solvent was removed under re-
duced pressure and the crude product was purified by column chro-
matography (eluting solvent acetone–hexane, 1:1) to give the title
compound (0.19 g, 93%) as a colourless oil. HRMS: m/z calcd for
1
cm–1. H NMR (400 MHz, MeOD): d = 7.14 (d, J = 2.2 Hz, 1 H),
C14H20N2O3 [MH]+: 265.1547; found: 265.1547. IR (nujol): nmax
=
6.92 (dd, J = 8.6, 2.2 Hz, 1 H), 6.87 (d, J = 8.6 Hz, 1 H), 4.47–4.45
(m, 1 H), 3.83 (s, 3 H), 3.81 (s, 3 H), 3.16–3.55 (m, 3 H), 3.45 (app.
1633 (C=O) cm–1. 1H NMR (400 MHz, MeOD): d = 6.83 (d, J = 8.5
Synlett 2006, No. 2, 243–246 © Thieme Stuttgart · New York

246
E. Bridgeman, N. C. O. Tomkinson
LETTER
(4) (a) Vishnyakova, T. P.; Golubeva, I. A.; Glebova, E. V.
Russ. Chem. Rev. 1985, 54, 249. (b) Ozaki, S. Chem. Rev.
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Hz, 1 H), 6.69 (d, J = 2.5 Hz, 1 H), 6.87 (dd, J = 8.5, 2.5 Hz, 1 H),
3.72 (s, 3 H), 3.71 (s, 3 H), 3.05 (s, 3 H), 2.95 (app. t, J = 6.7 Hz, 4
H), 1.62–1.59 (m, 4 H). 13C NMR (100 MHz, MeOD): d = 162.0,
151.2, 148.6, 140.5, 119.2, 113.3, 111.3, 56.6, 56.6, 56.1, 40.62,
29.5. MS (APcI): m/z (%) = 265 (100) [MH]+.
(6) (a) Batey, R. A.; Santhakumar, V.; Yoshina-Ishii, C.; Taylor,
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(7) For a review on the use of phosgene substitutes, see: Biggi,
F.; Maggi, R.; Sartori, G. Green Chem. 2000, 2, 140.
(8) For recent developments in urea synthesis, see: Gallou, I.;
Eriksson, M.; Zeng, X.; Senanayake, C.; Farina, V. J. Org.
Chem. 2005, 70, 6960; and references cited therein.
(9) Merritt, A. T. Comb. Chem. High Throughput Screening
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P. J. Protecting Groups; Thieme: Stuttgart, 1994.
(11) All compounds prepared were characterised by mp, 1H
NMR, 13C NMR, IR, MS and HRMS.
(12) Bis(4-nitrophenyl)carbonates have been used previously in
the synthesis of symmetrical and non-symmetrical
disubstituted ureas, see: Izdebski, J.; Pawlak, D. Synthesis
1989, 423.
Acknowledgment
The authors would like to thank BBSRC (EB) and EPSRC (NCOT)
for financial support and the Mass Spectrometry service, Swansea,
for high-resolution spectra.
References and Notes
(1) Sartori, G.; Maggi, R. Science of Synthesis, Vol. 18; Thieme:
Stuttgart, 2005, 665.
(2) For relevant compounds with biological activity see: Regan,
J.; Breitfelder, S.; Cirilo, P.; Gilmore, T.; Graham, A. G.;
Hickey, E.; Klaus, B.; Madwed, J.; Moriak, M.; Moss, N.;
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cited therein.
(3) Smith, M. B.; March, J. March’s Advanced Organic
Chemistry. Reactions, Mechanisms, and Structure, 5th ed.;
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(13) Bridgeman, E.; Cavill, J. L.; Schofield, D. J.; Wilkins, D. S.;
Tomkinson, N. C. O. Tetrahedron Lett. 2005, 46, 8521.
Synlett 2006, No. 2, 243–246 © Thieme Stuttgart · New York