A simple and efficient synthesis of N-benzoyl ureas

Article abstract of DOI:10.1016/j.tetlet.2012.05.158

A novel, operationally simple, method for the preparation of acyl ureas is described. The procedure is high yielding and tolerant of a wide range of functional groups.

Full text of DOI:10.1016/j.tetlet.2012.05.158

Tetrahedron Letters 53 (2012) 4802–4804
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A simple and efficient synthesis of N-benzoyl ureas
⇑
Stephen Stokes, Nathaniel G. Martin
AstraZeneca, Mereside, Alderley Park, Macclesfield, SK10 4TG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel, operationally simple, method for the preparation of acyl ureas is described. The procedure is high
yielding and tolerant of a wide range of functional groups.
Received 2 March 2012
Revised 11 May 2012
Accepted 31 May 2012
Available online 19 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Acyl urea
Microwave-assisted synthesis
Facile preparation
Acyl carbamates
Functional group tolerant
The N-benzoyl urea moiety is an important functional group in
the fields of both medicinal chemistry1 and agrochemicals.2 More-
over, a number of N-benzoyl ureas show promising anti-tumour
properties3 and some have found commercial use in agriculture
as insecticides.4 As part of an ongoing research programme, we
sought a mild and efficient route to this class of acyl ureas.
N-Acyl ureas are classically prepared by reaction of N-acylisocy-
anates with amines5 or amides with isocyanates.6 The N-acylisocy-
anates are typically prepared from the corresponding amides by
reaction with oxalyl chloride.7 These highly acidic conditions pre-
clude the use of many substrates which are unstable or reactive
under these conditions. Several alternative methods have been
published to overcome these limitations, including the acylation
of alkenyl esters,8 palladium-catalysed carbonylation of ureas9
and boronic acid catalysed condensation of acids with ureas.10
We found these methods unsuitable to prepare reliably a subset
of compounds that we required as part of an ongoing project. Dur-
ing this work we found two interesting reports11 which we be-
lieved would allow us to prepare a wide range of acyl ureas
under neutral thermal conditions by reaction of acyl carbamates
with amines (Scheme 1).
Initially, we investigated the reaction of phenyl benzoylcarba-
mate with aniline in various solvents. The reaction was tolerant
of a wide variety of both polar and non polar solvents (Table 1).
We found that using toluene was the most convenient procedure
due to the propensity of the products to precipitate from the reac-
tion mixture after the reaction was complete.14 The reactions re-
ported herein were carried out by microwave heating, however
as expected, they proceeded equally well when subjected to con-
ventional heating techniques.
With our preferred conditions in hand we next investigated a
range of different amines as the nucleophilic partner. As can be
seen in Table 2, the reaction was highly tolerant of the amine struc-
ture. Aromatic or aliphatic primary amines were tolerated; even
weakly nucleophilic amines (entries 6–10) reacted in good yield.
Secondary aliphatic amines, both cyclic and acyclic, were tolerated
as was the sterically hindered t-butyl amine (entry 12). The only
exception was the highly hindered 2,2,6,6-tetramethylpiperidine
(entry 13) which failed to react. Furthermore, these extremely mild
conditions allowed for the use of acid sensitive groups (entry 5)
which would not withstand many of the existing methods for
N-acyl urea synthesis.
N-Benzoyl carbamates are easily prepared by the reaction of
benzamides with the requisite carbonate and sodium hydride.12,13
Herein, we report the reaction of N-benzoyl carbamates derived
from diphenyl carbonate, and show that the phenoxy carbamate
products are easily accessible and stable precursors of N-benzoyl
ureas when heated in the presence of amines.
Finally, we looked at varying the structure of the carbamate and
found that both electron- donating and electron-withdrawing sub-
stituents on the benzoyl group were well tolerated in the reaction
O
O
O
O
R1
R2
R1
Δ
R
N
H
N
HN
R2
N
H
O
R3
R3
⇑
Corresponding author.
E-mail address: nmartin@acalenergy.co.uk (N.G. Martin).
Scheme 1. General reaction scheme.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.158

S. Stokes, N. G. Martin / Tetrahedron Letters 53 (2012) 4802–4804
4803
Table 1
Table 3
Investigation of the effect of various solvents
Investigation of the scope of the carbamate
Solvent,
amine
O
O
O
O
PhNH2
100°C
O
O
O
O
R1
60 min
R
N
H
N
H
R
N
H
O
N
H
O
N
H
N
H
100
°
C
toluene, 0.1 M
15 min
0.1 M
Entry
1
R
Amine
Yield (%)
Cl
N
H2N
S
Entry
Solvent
Yield (%)
OMe
OMe
1
2
3
4
5
Toluene
THF
NMP
H2O
87
83
88
39
82
80a
EtO
N
O
DCE
Cl
N
N
H2N
S
2
56
Table 2
O
Investigation of the scope of the amine
Cl
N
H2N
S
OMe
OMe
O
O
O
O
amine
3
4
5
71
89
88
R
100°C
N
N
R'
N
H
O
N
15 min
H
toluene, 0.1 M
Cl
N
N
H2N
S
Entry
1
Amine
Yield (%)
87
NC
Cl
NH2
NH2
N
H2N
2
3
95
91
F
F
NH2
N
O
a
Heated for 15 min.
H
N
4
5
75
96
Br
H
(Table 3). It is worth noting that attempts to synthesise this class of
N-benzoyl ureas via the corresponding N-acylisocyanate5,7 or by
coupling of the benzamide with an isocyanate6 were highly unsat-
isfactory due to low and variable yields and significant by-product
formation.
In conclusion, we have developed a highly practical and conve-
nient synthesis of N-benzoyl ureas by the reaction of N-phenyl
carbamates with various amines. The reaction is tolerant of a wide
variety of amines and carbonates under extremely mild conditions.
These advantages make it now possible to access a wide variety of
N-acyl ureas which hitherto would have been difficult to synthe-
sise in high yield.
H2N
N
O
O
N
N
NH2
6
7
79
83
NH2
NH2
N
O
8
9
61
95
N
O
S
NH2
N
NH2
N
10
81
N
Supplementary data
N
11
12
81a
71b
NH
NH2
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.05.
158.
13
0
NH
References and notes
NH2
NH
1. (a) Decastro, S.; Peromingo, M. T.; Naesens, L.; Andrei, G.; Snoeck, R.; Balzarini,
J.; Velazquez, S.; Camarasa, M. J. Med. Chem. 2008, 51, 5823–5832; (b) Arbuzov,
B. A.; Fedotova, N. R.; Zobovi, N. N.; Nazyrova, A. Z.; Anan’ev, E. V.; Gorbunov, S.
M. Khim. Farm. Zhl. 1989, 23, 682–683; c Laborde, E.; Robinson, L. M.; Meng, F.;
Peterson, B. T.; Villar, H. O.; Anuskiewicz, S. E.; Ma, W.; Matsumoto, Y.; Baba, K.;
Inagaki, H.; Tanaka, K.; Ishiwata, Y.; Yokochi, S.; Okamoto, M.; Nakamura, T.;
Miyachi, A.; Takeuchi, M.; Matsushima, K.; U.S. Patent 20040198719, Chem.
Abstr. 2004, 141, 332185.
14
15
16
72
68b
89a
NH2
O
a
Purified by normal phase chromatography.
Purified by reverse phase chromatography.
2. (a) Wellinga, K.; Mulder, R.; Van Daalen, J. J. J. Agric Food Chem. 1973, 21, 348;
(b) Yu, C. C.; Kuhr, R. J. J. Agric. Food Chem. 1976, 24, 134; (c) Worthing, C. R.;
b

4804
S. Stokes, N. G. Martin / Tetrahedron Letters 53 (2012) 4802–4804
Walker, S. B. The Pesticide Manual, 7th ed.; The British Crop Protection Council:
London, 1983.
12. Verbrugge, P. A. European Patent, EP0387946; Chem. Abstr. 1991, 114, 121769.
13. See Supplementary data for preparation of phenyl benzoylcarbamate.
14. Typical Procedure: N-Benzoyl carbamate (0.5 mmol) and 2-aminopyridine
(0.5 mmol) were suspended in toluene (5 ml) and sealed in a microwave
tube. The reaction was heated to 100 °C for 15 min in a Biotage Initiator
microwave reactor and cooled to rt. On cooling a solid formed which was
filtered and dried to give N-(pyridin-2-ylcarbamoyl)benzamide (95 mg, 79%)
(Table 2, entry 6); white solid; mp 201.5 °C; 1H NMR (DMF-d7, 400 MHz): d
(ppm) 6.97–7.05 (m, 1H), 7.44 (t, J = 7.7 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.67–
7.74 (m, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.98–8.04 (m, 2H), 8.19–8.24 (m, 1H),
11.02 (s, 1H), 11.22 (s, 1H); 13C NMR (176 MHz, DMF-d7) d (ppm) 113.98,
120.27, 129.06, 129.27, 133.38, 133.79, 139.00, 149.03, 151.73, 152.29, 169.81;
IR (Nujol) 1720, 1690 cmÀ1; HRMS (ES): m/z [M+H]+ calcd for C13H12N3O2:
242.0924, found: 242.0924.
3. (a) Wang, H.; Lim, Z.-Y.; Zhou, Y.; Ng, M.; Lu, T.; Lee, K.; Sangthongpitag, K.;
Goh, K. C.; Wang, X.; Wu, X.; Khng, H. H.; Goh, S. K.; Ong, W. C.; Bonday, Z.; Sun,
E. T. Bioorg. Med. Chem. Lett. 2010, 20, 3314–3321; (b) Okada, H.; Kato, M.;
Koyanagi, T.; Mizuno, K. Chem. Pharm. Bull. 1999, 47, 430–433.
4. Matsumura, F. Pestic. Biochem. Physiol. 2010, 97, 133–139.
5. Speziale, A. J.; Smith, L. R. J. Org. Chem. 1805, 1963, 28.
6. Wiley, P. F. J. Am. Chem. Soc. 1949, 71, 1310.
7. Speziale, A. J.; Smith, L. R. J. Org. Chem. 1962, 27, 3742.
8. Seiller, B.; Hins, D.; Bruneau, C.; Dixneuf, P. H. Tetrahedron 1995, 51, 10901.
9. Liprot, D.; Alcaraz, L.; Roberts, B. Adv. Synth. Catal. 2010, 352, 2183.
10. Maki, T.; Ishihara, K.; Yamamoto, H. Synlett 2004, 1355.
11. (a) Basterfield, S.; Greig, M. E. Can. J. Chem. 1933, 8, 450; (b) Wellinga, K.;
Mulder, R. German Patent, DE2123236; Chem. Abstr. 1972, 76, 85578.