192
Y. Deng, D. J. Hlasta / Tetrahedron Letters 43 (2002) 189–192
The diversity of the azoles in Table 2 that afford
2-substituted azole products in good yield is notewor-
thy, and highlights the broad scope of this chemistry.
The products in Table 2 can be readily transformed by
direct solvolysis chemistry into a range of functional-
ized azole derivatives, since the a-carbamyl group is a
good leaving group. We previously described a limited
number of nucleophile examples in the solvolysis reac-
tions of 2-(a-diisopropylcarbamoylbenzyl)-1-benzylimi-
dazole. In Table 3 are shown additional examples of
this chemistry. Solvolysis reactions of both the 2-substi-
tuted-1-methylimidazole and the 2-substituted-thiazole
gave good yields of the desired products.
1–38 and references cited therein; (f) Itoh, T.; Miyazaki,
M.; Nagata, K.; Ohsawa, A. Tetrahedron 2000, 56, 4383–
4395.
3. Hlasta, D. J. Org. Lett. 2001, 3, 157–159.
4. Clement, O.; Roszak, A. W.; Buncel, E. J. Am. Chem.
Soc. 1996, 118, 612–620.
5. The formation of N-acylimidazolium salts by the reaction
of N-methyl imidazole with a carbamoyl chloride was
reported previously: Dadali, V. A.; Lapshin, L. M.;
Litvinenko, L. M.; Simanenko, Yu. S.; Tishchenko, N. A.
J. Org. Chem. USSR (Engl. Transl.) 1978, 14, 2076–2082.
6. Similar observations were made on carbamoyl imida-
zolium salts in CD3OD (personal communication from
Robert A. Batey). For synthetic examples on the use of
carbamoyl imidazolium salts as carbamoylating reagents,
see: Batey, R. A.; Yoshina-Ishii, C.; Taylor, S. D.; San-
thakumar, V. Tetrahedron Lett. 1999, 40, 2699–2672;
Batey, R. A.; Santhakumar, V.; Yoshina-Ishii, C.; Tay-
lor, S. D. Tetrahedron Lett. 1998, 39, 6267–6270.
7. Bourissou, D.; Guerret, O.; Gabbai, F. P.; Bertrand, G.
Chem. Rev. 2000, 100, 39–91.
The breadth and scope of the chemistry described
herein demonstrates the broad application of this chem-
istry in the synthesis of azoles, including imidazoles,
thiazoles, benzimidazoles, and triazoles, with a wide
diversity of substitution patterns. The simplicity and
efficiency of these reactions make this method particu-
larly appealing for application to the solid-phase syn-
thesis of compound libraries for high-throughput
screening against therapeutic targets. In due course, the
extension of this reaction to solid-phase synthesis will
be reported.
8. (a) Bordwell, F. G.; Hughes, D. L. J. Am. Chem. Soc.
1984, 106, 3234–3240; (b) Bordwell, F. G.; Hughes, D. L.
J. Org. Chem. 1984, 48, 2206–2215; (c) Bunting, J. W.;
Mason, J. M.; Heo, C. K. M. J. Chem. Soc., Perkin
Trans. 1 1994, 2291–2300.
9. Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.;
Blackwell Science, 2000; pp. 402–430.
Acknowledgements
10. Typical procedure: To a solution of 1-methyl imidazole
(164 mg, 2.0 mmol) in acetonitrile (5 mL) under nitrogen,
was added subsequently diisopropylcarbamyl chloride
(360 mg, 2.2 mmol), benzaldehyde (0.31 mL, 3.0 mmol)
and diisopropylethylamine (1.0 mL, 6 mmol) at room
temperature. The resulting mixture was stirred at reflux
for about 24 h. The solvent was then removed. The
residue was purified by flash chromatography on a silica
gel with 50% ethyl acetate in hexanes to give entry 1
product in 85% yield.
We thank the Johnson & Johnson Corporate Office of
Science and Technology for postdoctoral fellowship
funding for Y.D. through the Excellence in Science
Award Program. We also thank Diane Gauthier for
assistance in the 2D NMR structure assignments of
these compounds, and Dr. Charles Reynolds for the ab
initio calculations.
11. Jaguar 4.1, Schrodinger, Inc., Portland, OR, 1991–2000.
12. (a) Becke, A. D. Phys. Rev. A 1988, 38, 3098–3100; (b)
Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37,
785–789.
References
1. Grimmett, M. R. In Comprehensive Heterocyclic Chem-
istry; Katritzky, A. R.; Ress, C. W.; Scriven, E. F. V.,
Eds.; Pergamon Press: Oxford, 1996; Vol. 3, pp. 77–220.
2. Selected methods to prepare 2-substituted azoles: (a)
Merino, P. Prog. Heterocyl. Chem. 1999, 11, 21–44 and
references cited therein; (b) Regel, E.; Buchel, K.-H.
Liebigs Ann. Chem. 1977, 145–158, 159–168; (c) Roe, A.
M. J. Chem. Soc. 1963, 2195–2200; Papadopoulos, E. P.
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1681–1706; Dondoni, A. Phosphorus and Sulfur 1985, 24,
13. Typical procedure for solvolysis: To a solution of imida-
zole carbamate (315 mg, 1.0 mmol, Table 3, entry 1) in
THF (5 mL), was added morpholine (0.9 mL, 10 mmol)
and TFA (0.44 mL, 6 mmol) under nitrogen at room
temperature. The resulting mixture was refluxed
overnight. After cooling to room temperature, saturated
NaHCO3 aqueous solution (10 mL) was added into the
reaction mixture, followed by extraction with CH2Cl2.
The organic phases were combined, dried and concen-
trated in vacuo. The residue was purified by flash chro-
matography on a silica gel column with 2% MeOH in
ethyl acetate to yield the desired product in 82% yield.