LETTER
Microwave-Assisted Synthesis of N-Monosubstituted Urea Derivatives
2441
Table 2 Synthesis of N-Monoalkylureas (continued)
Acknowledgment
Ureaa
Yieldb
88%
This work was financially supported by the Università degli Studi
di Sassari and the MIUR (Rome) within the project PRIN: ‘Struc-
ture and Activity Studies of DNA Quadruplex through the Exploita-
tion of Synthetic Oligonucleotides and Analogues’.
Entry Amine
O
O
NH2
11
N
H
NH2
NH2
1k
References and Notes
2k
2l
(1) (a) Tsopmo, A.; Ngnokam, D.; Ngamga, D.; Ayafor, J. F.;
Sterner, O. J. Nat. Prod. 1999, 62, 1435. (b) Funabashi, Y.;
Tsubotani, S.; Koyama, K.; Katayama, N.; Harada, S.
Tetrahedron 1993, 49, 13.
(2) (a) Sartori, G.; Maggi, R. In Science of Synthesis, Vol. 18;
Knight, J. G., Ed.; Thieme Verlag: Stuttgart, 2005, 665.
(b) Bigi, F.; Maggi, R.; Sartori, G. Green Chem. 2000, 2,
140. (c) Tafesh, A. M.; Weiguny, J. Chem. Rev. 1996, 96,
2035.
(3) (a) Matsuda, K. Med. Res. Rev. 1994, 14, 271. (b) Getman,
D. P.; Decrescenzo, G. A.; Heintz, R. M.; Reed, K. L.;
Talley, J. J.; Bryant, M. L.; Clare, M.; Houseman, K. A.;
Marr, J. J.; Mueller, R. A.; Vazquez, M. L.; Shieh, H. S.;
Stallings, W. C.; Stegeman, R. A. J. Med. Chem. 1993, 36,
288. (c) Vyshnyakova, T. P.; Golubeva, I. A.; Glebova, E. V.
Russ. Chem. Rev. (Engl. Transl.) 1985, 54, 249.
(d) Melnikov, N. N. In Chemistry of Pesticides; Gunther,
J. D., Ed.; Springer-Verlag: Berlin, 1971, 225.
(4) (a) Papesch, V.; Schroeder, E. F. J. Org. Chem. 1951, 16,
1879. (b) Clark, R. L.; Pessolano, A. A. J. Am. Chem. Soc.
1958, 80, 1658. (c) Cassar, L. Chem. Ind. 1990, 72, 18.
(5) (a) Jefferson, E. A.; Swayze, E. E. Tetrahedron Lett. 1999,
40, 7757. (b) Burgess, K.; Ibarzo, J.; Linthicum, S. D.;
Russell, D. H.; Shin, H.; Shitangkoon, A.; Totani, R.; Zhang,
A. J. J. Am. Chem. Soc. 1997, 119, 1556. (c) Knapp, S.;
Hale, J. J.; Bastos, M.; Molina, A.; Cheng, K. Y. J. Org.
Chem. 1992, 57, 6239.
NH2
12
75%
N
H
1l
O
13
86%
83%
HOOC
N
NH2
NH2
HOOC
NH2
NH2
H
1m
2m
O
14
HOOC
N
H
HOOC
1n
2n
O
O
15
78%
90%
HOOC
N
H
NH2
NH2
HOOC
1o
NH2
NH2
2o
16
HOOC
N
H
HOOC
1p
2p
(6) (a) Peng, X.; Li, F.; Xia, C. Synlett 2006, 1161; and
references cited therein. (b) Mizuno, T.; Mihara, M.; Iwai,
T.; Ito, T.; Issino, Y. Synthesis 2006, 2825; and references
cited therein. (c) Orito, K.; Miyazawa, M.; Nakamura, T.;
Horibata, A.; Uscito, H.; Nagasaki, H.; Yuguchi, M.;
Yamashita, S.; Yamazaki, T.; Tokuda, M. J. Org. Chem.
2006, 71, 5951. (d) Zhu, B.; Angelici, R. J. J. Am. Chem.
Soc. 2006, 128, 14460. (e) Nishiyama, Y.; Kawamatsu, H.;
Sonoda, N. J. Org. Chem. 2005, 70, 2551. (f) Enquist,
P.-A.; Nilsson, P.; Edin, J.; Larhed, M. Tetrahedron Lett.
2005, 46, 3335; and references cited therein.
O
17
89%
68%
85%
HOOC
N
NH2
HOOC
NH2
H
1q
2q
O
N
18
19
HOOC
N
H
NH2
COOH
1r
2r
MeS
MeS
(7) Liu, Q.; Luedtke, W.; Tor, Y. Tetrahedron Lett. 2001, 42,
1445.
O
(8) 4-Nitrophenyl-N-benzylcarbamate was prepared by
condensing benzylamine with 4-nitrophenyl-chloroformate.
(9) Artuso, E.; Degani, I.; Fochi, R.; Magistris, C. Synthesis
2007, 3497.
HOOC
N
NH2
HOOC
NH2
H
1s
2s
a All the ureas were characterized by 1H NMR, 13C NMR, and HRMS
or elemental analysis.
(10) Wertheim, E. J. Am. Chem. Soc. 1931, 53, 200.
(11) (a) Williams, A.; Jencks, W. A. J. Chem. Soc., Perkin Trans.
2 1974, 1753. (b) Williams, A.; Jencks, W. A. J. Chem. Soc.,
Perkin Trans. 2 1974, 1760.
b Overall isolated yield.
(12) (a) Libassi, G.; Ventura, P.; Monguzzi, R.; Pifferi, G.
Gazz. Chim. Ital. 1977, 107, 253. (b) Stella, V.; Higuchi, T.
J. Org. Chem. 1973, 38, 1527. (c) Taillades, J.; Boiteau, L.;
Beuzelin, I.; Lagrille, O.; Commeyras, A. J. Chem. Soc.,
Perkin Trans. 2 2001, 1247.
(13) A similar reaction was carried out in a domestic MW oven
with very low yields and not reproducible results: Verardo,
G.; Geatti, P.; Strazzolini, P. Synth. Commun. 2007, 37,
1833.
In conclusion we have developed an easy microwave-as-
sisted procedure for converting a set of various amines
into N-substituted ureas even in large scale. The method-
ology uses mild reaction conditions and cheap and com-
mercially available reagents, is high-yielding and allows
the recovery of the desired product by an easy and conve-
nient workup.
Synlett 2010, No. 16, 2439–2442 © Thieme Stuttgart · New York