Y.-G. Chang et al. / Tetrahedron Letters 42 (2001) 8197–8200
8199
O
Cl
O
R1R2NH
+
+
HCl
S2
S
N
2R1RN
CN
S
1
S8
3
R1R2NH
+
2
HCN
Scheme 3.
Compound 1 was reacted with p-anisidine in the pres-
ence of pyridine (4 equiv.) under the same conditions to
give 3 (R1=p-MeOC6H4, R2=H) in 39% yield along
with unreacted 1 (28%), while p-chloroaniline which is
a deactivated aromatic amine, did not react with 1 with
quantitative recovery of the starting material 1.
2. (a) Petersen, U. Methoden der Organishen Chemie,
Houben-Weyl, E4, G. Thieme Verlag: New York, 1983;
p. 334; (b) Ozaki, S. Chem. Rev. 1972, 72, 457–496.
3. Kotachi, S.; Tsuji, Y.; Kondo, T.; Watanabe, Y. J. Chem.
Soc., Chem. Commun. 1990, 549–550.
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2915.
6. Takeda, K.; Ogura, H. Synth. Commun. 1982, 12, 213–
217.
7. Abrahart, E. N. J. Chem. Soc. 1936, 1273–1274.
8. Adamiak, R. W.; Stawinski, J. Tetrahedron Lett. 1977,
18, 1935–1936.
Despite unsatisfactory yields of 3, unsymmetrical ureas
were prepared from cyanoformamides 3 and primary of
secondary alkylamines. For example, treatment of
cyanoformamide 3n with i-propylamine (6 equiv.) for 5
h in CH2Cl2 at rt afforded unsymmetrical urea 4 (83%)
(Scheme 2). Similarly, unsymmetrical urea 5 (97%) was
prepared from cyanoformamide 3l and diethylamine (5
equiv.) under the same conditions.
9. Leung, M.-k.; Lai, J.-L.; Lau, K.-H.; Yu, H.-h.; Hsiao,
H.-J. J. Org. Chem. 1996, 61, 4175–4179.
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3304–3305; (b) Franz, R. A.; Applegath, F.; Morriss, F.
V.; Baiocchi, F. J. Org. Chem. 1961, 26, 3306–3308; (c)
Franz, R. A.; Applegath, F.; Morriss, F. V.; Baiocchi, F.;
Bolze, C. J. Org. Chem. 1961, 26, 3309–3312.
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Nagano, Y. Tetrahedron Lett. 1986, 27, 1809–1810; (b)
Fournier, J.; Bruneau, C.; Dixneuf, P. H.; Le´colier, S. J.
Org. Chem. 1991, 56, 4456–4458.
The mechanism for the formation of ureas 2 may be
explained by a nucleophilic attack of alkylamine to the
carbonyl carbon of 1, followed by extrusion of S2
concomitant with the liberation of chloride ion, yielding
cyanoformamide 3 (Scheme 3). Displacement of cya-
nide ion by another molecule of alkylamine would give
2.
12. (a) Yamazaki, N.; Higashi, F.; Iguchi, T. Tetrahedron
Lett. 1974, 15, 1191–1194; (b) Yamazaki, N.; Iguchi, T.;
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13. Ogura, H.; Takeda, K.; Tokue, R.; Kobayashi, T. Syn-
thesis 1978, 394–396.
In conclusion, we have developed a convenient method
for the synthesis of symmetrical N,N%-dialkylureas from
4-chloro-5H-1,2,3-dithiazol-5-one and primary and sec-
ondary alkylamines, and amino acid esters. Cyanofor-
mamides may be utilized for the synthesis of
14. Katritzky, A. R.; Pleynet, D. P. M.; Yang, B. J. Org.
unsymmetrical
N,N%-dialkylureas.
The
method
Chem. 1997, 62, 4155–4158.
15. Lamothe, M.; Perez, M.; Colovray-Gotteland, V.;
Halazy, S. Synlett 1996, 507–508.
described herein offers the advantage of producing
desired ureas under the mild conditions without the use
of poisonous and dangerous materials.
16. Kno¨lker, H.-J.; Braxmeier, T.; Schlechtingen, G. Synlett
1996, 502–504.
17. Majer, P.; Randad, R. S. J. Org. Chem. 1994, 59, 1937–
1938.
18. Park, Y. S.; Kim, K. Tetrahedron Lett. 1999, 40, 6439–
6442.
19. Appel, R.; Janssen, H.; Siray, M.; Knoch, F. Chem. Ber.
1985, 118, 1632–1643.
Acknowledgements
This work was supported by a Korea Research Foun-
dation Grant (KRF-2000-DP-0261).
20. Typical procedure: To a suspension of leucine methyl
ester hydrochloride (302 mg, 1.66 mmol) in CH2Cl2 (15
mL) was added 4-chloro-5H-1,2,3-dithiazol-5-one (1)
(121 mg, 0.788 mmol), followed by addition of Et3N (168
mg, 1.66 mmol). The mixture was stirred for 24 h at rt.
After removal of the solvent in vacuo, the residue was
chromatographed on a silica gel (70–230 mesh, 2×10 cm).
Elution with n-hexane gave sulfur (22 mg, 44%). Subse-
quent elution with a mixture of n-hexane and EtOAc
(5:1) gave unreacted 1 (31 mg, 26%). Continuous elution
with same solvent mixture (3:1) gave N-[(2-methoxycar-
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