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N. Xi et al. / Tetrahedron Letters 46 (2005) 7315–7319
methyl isothiocyanate 11a reacted with 10 to give the
cyclic thiourea 12a in 80% yield, which is in accordance
with the direct formation of the cyclic thiourea in the
Marckwald synthesis. Similarly, coupling of 10 with
KNCS in hot aqueous tert-butanol afforded the cyclic
thiourea 12b in 81% yield (Table 1, entry 2,).10 Coupling
of 11c and 11d with 10, however, led to a 3:2 mixture of
the cyclic and acyclic thioureas (12c and 13c) and the
acyclic thiourea 13d, respectively (for structures of 13c
and 13d, see Scheme 3). In both cases, prolonged heating
did not improve the yields of the cyclized products 12c
and 12d (monitored by LC–MS at 254 and 210 nm).
desulfurization conditions. Further elaboration at the
2-position of the imidazole ring is possible with the tran-
sition metal catalyzed coupling reactions. We are cur-
rently evaluating these reactions and the results will be
reported in due course.
References and notes
1. For recent reviews, see: Menge, W. M. P. B.; Timmerman,
H. Pharmacochem. Lib. 1998, 30, 145 (Histamine H3
Receptor).
2. Grimmett, M. S. In Comprehensive Heterocyclic Chemistry
II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Elsevier Science: Oxford, 1996; Vol. 3, pp 185–211.
3. Grimmett, M. S. In Comprehensive Heterocyclic Chemistry
II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Elsevier Science: Oxford, 1996; Vol. 3, pp 108–116.
4. Sezen, B.; Samers, D. J. Am. Chem. Soc. 2003, 125, 5274–
5275.
5. Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233–1236.
6. Joule, J. A.; Mills, K.; Smith, G. F. Heterocyclic Chem-
istry, 3rd ed.; Chapman & Hall: London, 1995; pp 372–
373.
Clearly, a more effective method was needed for the cyc-
lodehydration of 13c,d to form 12c,d. In a test study, the
acyclic thiourea 13d was dissolved in toluene and heated
to 120 °C for 4 h in the presence of 10% pyridinium p-
toluenesulfonate (PPTS).11 As expected, the cyclic thio-
urea 12d was obtained in 88% isolated yield. To combine
the acyclic thiourea formation and the subsequent cyc-
lodehydration into a one-pot process, the reaction mix-
ture of 11c with 10 was concentrated in vacuo and
directly subjected to the PPTS catalyzed cyclization.
The desired cyclic thiourea 12c was isolated in 75% yield
after refluxing in toluene for 4 h. Generally, the yields of
this one-pot procedure to form cyclic thioureas are good
to excellent, as can be seen in Tables 1 and 2.
7. Marckwald, W. Chem. Ber. 1892, 25, 2354.
8. Hartley, J. A.; Hazrati, A.; Kelland, L. R.; Khanim, R.;
Shipman, M.; Suzenet, F.; Walker, L. F. Angew. Chem.,
Int. Ed. 2000, 39, 3467–3470; Husbands, S.; Suckling, C.
A.; Suckling, C. J. Tetrahedron 1994, 50, 9729–9742;
Dondoni, A.; Perrone, D. Synthesis 1993, 11, 1162–1176;
Lygo, B. Synlett 1992, 10, 793–795.
9. Satoh, K.; Imura, A.; Miyadera, A.; Kanai, K.; Yuki-
moto, Y. Chem. Pharm. Bull. 1998, 46, 587–590.
10. For the formation of acyclic thioureas, see: Winterfeld, G.
A.; Khodair, A. I.; Schmidt, R. R. Eur. J. Org. Chem.
2003, 1009.
11. Ac2O/MeOH condition was also successfully used for the
cyclization, see: Fuentes, J.; Pradera, M. A.; Robina, I.
Tetrahedron 1991, 47, 5797; Fuentes, J.; Moreda, W.;
Ortiz, C.; Robina, I.; Welsh, C. Tetrahedron 1992, 48,
6413.
12. (a) Grivas, S.; Ronne, E. Acta Chem. Scand. 1995, 49, 225;
(b) Karkhanis, D. W.; Field, L. Phosphorus, Sulfur Silicon
Relat. Elem. 1985, 22, 49; (c) Frachey, G.; Crestini, C.;
Bernini, R.; Saladino, R.; Mincione, E. Heterocycles 1994,
38, 2621; (d) Dener, J. M.; Zhang, L.-H.; Rapoport, H. J.
Org. Chem. 1993, 58, 1159.
Conversion of cyclic thioureas to imidazoles can be
achieved under either oxidative12 or reductive13 condi-
tions. We chose two established methods, that is, Raney
Nickel/EtOH and H2O2/AcOH, to remove the sulfur.
As exemplified in Table 2, the two protocols provided
comparable results for the imidazole formation. For
molecules that are susceptible to oxidative conditions,
a reductive desulfurization is preferred, and vice versa.
For example, the tetrahydrofuran analog 15a favors
Raney Nickel reduction, whereas the iodo analog 12d
requires oxidative condition for removal of sulfur atom
due to the phenyl iodide functionality.
The method was applied to a variety of amino acids and
isothiocyanates, providing structurally diversified imi-
dazoles, as illustrated in Table 2. Disubstituted imida-
zoles, 16c, 16e, and 16g, were also prepared for
comparison. Amino acids with both alkyl and aryl side
chains are good substrates, as seen within entries 3
and 5. The substitution on the amino group showed lit-
tle effect on the cyclization and desulfurization steps, as
exemplified by sarcosine, N-methyl phenylalanine, and
proline (entries 7–9). Thus, the elusive bicyclic imidazole
16i was conveniently prepared. Most notably, the two
imidazole regioisomers, 14a and 16h, were readily avail-
able with unambiguous regio-specificity using this
method.14
13. OÕConnell, J. F.; Parquette, J.; Yelle, W. E.; Wang, W.;
Rapoport, H. Synthesis 1988, 767. For reviews, see:
BelenÕkii, L. I. In Chemistry of Organosulfur Compounds:
General Problems; BelenÕkii, L. I., Ed.; Ellis Horwood:
Chichester, 1990; Chapter 9.
14. A typical procedure for synthesizing the N-substituted
imidazoles from a-aminocarbonyl salt 13 is as follows: A
solution of salt 13 (3.0 g, 1 equiv), an isothiocyanate
(1.2 equiv) and triethylamine (1.5 equiv) in 50 mL of
ethanol was heated to 50 °C for 4 h. The reaction mixture
was then concentrated in vacuo to dryness. The residue
was suspended in 50 mL of toluene with PPTS (0.1 equiv).
The mixture was heated to 120 °C for 4 h and then cooled
to room temperature. The resulted solution was diluted
with 50 mL of ethyl acetate, washed with 50 mL of
saturated aqueous NaHCO3 solution and brine, and dried
over Na2SO4. The organic phase was concentrated in
vacuo and the residue was re-crystallized with 50%
EtOAc/hexanes to give the desired cyclic thiourea.
A suspended solution of cyclic thiourea and Raney nickel
(5 equiv) in EtOH (50 mL) was heated to reflux for 8 h.
In summary, we demonstrated that a variety of amino
acids are convenient starting materials for the syntheses
of N-substituted imidazoles in a regio-controlled man-
ner. Many functional groups, such as ester, iodo, nitro,
and iodole moieties, are compatible with the process. In
addition, reducible or oxidizable functional groups in
the cyclic thioureas are tolerated by using different
Xi, Ning
