One-pot synthesis of disubstituted imidazole derivatives from α-azido ketones catalyzed by potassium ethylxanthate

Article abstract of DOI:10.1016/j.tetlet.2013.01.042

An efficient, novel procedure for the synthesis of new imidazole derivatives from α-azido ketones is described. This reaction proceeds via dimerization of aryl glyoxal imino generated from α-azido ketones in the presence of potassium ethylxanthate as a catalyst. A possible mechanism for the entire sequence is proposed.

Full text of DOI:10.1016/j.tetlet.2013.01.042

Tetrahedron Letters 54 (2013) 1572–1575
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One-pot synthesis of disubstituted imidazole derivatives from
ketones catalyzed by potassium ethylxanthate
a-azido
⇑
⇑
Jun Chen, Wenteng Chen, Yongping Yu , Guolin Zhang
Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, novel procedure for the synthesis of new imidazole derivatives from
described. This reaction proceeds via dimerization of aryl glyoxal imino generated from
in the presence of potassium ethylxanthate as a catalyst. A possible mechanism for the entire sequence is
proposed.
a
-azido ketones is
Received 11 October 2012
Revised 4 January 2013
Accepted 11 January 2013
Available online 18 January 2013
a-azido ketones
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Disubstituted imidazole
a-Azido ketones
Potassium ethylxanthate
Catalyst
Dimerization
Imidazole is a privileged heterocyclic scaffold. It has been uti-
lized in the synthesis of N-heterocyclic carbenes1 and other syn-
thetic aspects.2 This privileged structure is also present in some
significant molecules,3 such as biotin, histindine,4 topsentine, and
nortopsentine.5 Moreover, imidazole containing natural products
have been reported with a wide range of biological activities6–8
and some major marketed drugs contain imidazole.9
The range of biological, industrial, and synthetic applications
led to the focus of imidazole derivatives. 2-(p-Hydroxybenzoyl)-
4-(p-hydroxyphenyl) imidazole, which is isolated from the red
ascidian Botryllus leachi, has been the subject of biological
research.10 To the best of our knowledge, the main synthetic
methodology for the synthesis of disubstituted imidazole is the
condensation of arylglyoxals11 and cathodic reduction of 2-azido-
1-phenylethanone.12 However, some of the methods are limited
by either the complex preparation of starting materials, or the
harsh reaction conditions. In light of this, a general and straightfor-
ward methodology to rapidly prepare disubstituted imidazole
derivatives is still in demand.
Table 1
Optimization of the reaction conditiona
H
N
O
O
N
O
base
+
N3
2
N
N
H
solvent, T, 6h
1a
1b
Entry
Additive
Solvent
T (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
No
i-PrOH
DMF
Dioxane
Toluene
70
70
70
70
70
70
70
70
70
70
70
70
70
40
60
80
n.r.c
19
28
14
24
73
79
18
Trace
33
30
79
70
50
74
65
C2H5OCSSK (1.0 equiv)
C2H5OCSSK (1.0 equiv)
C2H5OCSSK (1.0 equiv)
C2H5OCSSK (1.0 equiv)
C2H5OCSSK (1.0 equiv)
C2H5OCSSK (1.0 equiv)
KOH (1.0 equiv)
CH3ONa (1.0 equiv)
Et3N (1.0 equiv)
AcONa (1.0 equiv)
C2H5OCSSK (0.5 equiv)
C2H5OCSSK (0.25 equiv)
C2H5OCSSK (0.5 equiv)
C2H5OCSSK (0.5 equiv)
C2H5OCSSK (0.5 equiv)
Acetonitrile
EtOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
S
H
O
R
N
O
R
N
O
O
SK
+
N3
2
N
H
b
i-PrOH, 700C, 6h
R
N
a
R
R
Figure 1. One-pot synthesis of imidazole from a-azido ketones.
a
Reaction condition: 2-azido-1-phenylethanone (1 mmol) and base in solvent
(8 ml), for 6 h.
b
⇑
Corresponding authors. Tel.: +86 571 88208450.
E-mail addresses: yyu@zju.edu.cn (Y. Yu), guolinzhang@zju.edu.cn (G. Zhang).
Isolated yield for isomer a and isomer b.
No reaction.
c
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.042

J. Chen et al. / Tetrahedron Letters 54 (2013) 1572–1575
1573
Table 2
Synthesis of imidazolea
S
H
N
O
SK
O
R
O
R
N
O
(50% mmol)
+
N3
2
N
N
H
a
R
R
R
i-PrOH, 700C, 6h
b
a
Reaction was performed in i-PrOH (8 ml) at 70 °C with 0.5 equiv of potassium ethylxanthate for 6 h. The a/b ratio was determined by 1H NMR.
In this Letter, we present a one-pot, general approach for the
synthesis of disubstituted imidazole via the dimerization of aryl
The reaction of 2-azido-1-phenylethanone was chosen as the
model reaction (Table 1). No reaction was observed when no base
was used (Table 1, entry 1). The transformation occurred in the
presence of a variety of additives to form isomer a and isomer b
glyoxal imino generated from
a-azido ketones in situ in the pres-
ence of potassium ethylxanthate as a catalyst (Fig. 1).

1574
J. Chen et al. / Tetrahedron Letters 54 (2013) 1572–1575
S
S
OEt
II
S
S
OEt
O
S
O
N
N
O
R
N
N
N
S
OEt
R
N
NH
I
R
H
IV
N2
III
HN
N
N
H
O
R
OH
R
R
R
N
O
VI
V
HN
N
H
O
R
Pathway a
R
R
R
R
R
N
a
N
[1, 5]-hydrogen shift
O
VI
N
H
O
N
Pathway b
R
N
R
N
[1, 5]-hydrogen shift
H
O
VI
b
Scheme 1. Proposed mechanism.
OH
S
O
O
H
H
N
N3
N3
O
SK
N
N
HO
i-PrOH, 700C, 6h
N
O
O
HO
1
:
1
OH
H
N
H
N
HO
N
O
N
O
:
2
Scheme 2. Reaction between two asymmetric a
-azido ketones.aReaction condition: 2-azido-1-phenylethanone (1 mmol), 2-azido-1-(4-hydroxy phenyl)ethanone (1 mmol),
and C2H5OCSSK (0.5 mmol) in i-PrOH (8 ml), for 6 h at 70 °C.
as the major products (Table 1). Screening of bases revealed potas-
sium ethylxanthate was the most efficient one (Table 1, entries 7–
11). Optimization of the solvent showed that i-PrOH (Table 1, entry
7) was superior to other aprotic and protic solvents (Table 1, en-
tries 2–7). The reaction was also assessed at different temperatures
and quantity of bases (Table 1, entries 12–16). The yields of entries
7 and 12 verified that potassium ethylxanthane could be used as a
catalyst. A change in temperature or lower quantity of the additive
resulted in a decrease in yield (Table 1, entries 13–16). Based on
this initial study, the optimal reactivity was obtained in i-PrOH
at 70 °C when potassium ethylxanthate (0.5 equiv) was employed
(79%, Table 1, entry 12).
With the optimized reaction conditions in hand, the scope of
the reaction was studied using a set of -azido ketones. As shown
in Table 2, an array of disubstituted imidazoles was prepared from
the corresponding -azido ketones in moderate to good isolated
yields. Based on the data from Table 2, it was found that aryl
groups of -azido ketones that contained either electron with-
drawing substituents (Table 2, entries 2, 8, and 13) or electron
donating substituents (Table 2, entries 3–5, 7, 11, 12, 15, and 16)
could be utilized in this process, except for one strong electron
withdrawing substituent. (Table 2, entry 6).
a
a
a
The isolated yields of entries 8 and 13 showed that the sterics
are not a limiting factor in this approach. In addition, the hydroxyl

J. Chen et al. / Tetrahedron Letters 54 (2013) 1572–1575
1575
group is well tolerated in this reaction and in fact does not need to
be protected. (Table 2, entries 4, 12, and 15).13 Moreover,
-azido
Supplementary data
a
ketones with alkyl substituents (Table 2, entry 10) and heterocyclic
substituents (Table 2, entries 9 and 17) were obtained in the same
reaction condition in good isolated yields, excluding entry 14.
On the basis of the results presented above, we proposed the
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
01.042.
References and notes
possible mechanism in Scheme 1. Reaction of the starting a-azido
ketones (I) and potassium ethylxanthate (II) affords the imino
intermediate (IV) with a molecule of N2 lost. The reaction is be-
lieved to involve the dimerization of the imino intermediate (IV)
followed by dehydration. Two isomers (a and b) can be generated
via [1,5]-hydrogen shift as shown in Scheme 1.11
1. (a) Yang, C.; Lee, H. M.; Nolan, S. P. Org. Lett. 2011, 3, 1511; (b) Herrmann, W. A.
Angew. Chem., Int. Ed. 2002, 41, 1290; (c) Zhao, Y.; Zhou, Y.; Ma, D.; Liu, J.; Li, L.;
Zhang, T. Y.; Zhang, H. Org. Biomol. Chem. 2003, 1, 1643.
2. Bao, W.; Wang, Z.; Li, Y. J. Org. Chem. 2003, 68, 591.
3. (a) Faulkner, D. J. Nat. Prod. Rep. 2000, 17, 7; (b) Ho, J. Z.; Hohareb, R. M.; Ahn, J.
H.; Sim, T. B.; Rapoport, H. J. Org. Chem. 2003, 68, 109.
Furthermore, we carried out a ‘mix’ experiment between 2-azi-
do-1-phenylethanone and 2-azido-1-(4-hydroxy phenyl)ethanone
(Scheme 2). The experimental reaction resulted in the production
of four products. The ratio was determined by HPLC.
In conclusion, we report an efficient, novel procedure for the
synthesis of new imidazole derivatives. This reaction was realized
4. Grimmett, M. R. In Comprehensive Heterocyclic Chemistry II; Katritsky, A. R.,
Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 3, pp 77-220.
5. Kawasaki, L.; Yamashita, M.; Ohta, S. Chem. Pharm. Bull. 1996, 1831, 44.
6. (a) Maier, T.; Schmierer, R.; Bauer, K.; Bieringer, H.; Buerstell, H.; Sachser, B.
German Patent 317,094, 1983.; (b) Scmierer, R.; Mildenberger, H.; Buerstell, H.
German Patent 3,614,364, 1987.; (c) Schmierer, R.; Mildenberger, H.; Buerstell,
H. Chem. Abstr. 1988, 108, 37838.
7. (a) Lo, Y. S.; Nolan, J. C.; Maren, T. H.; Welstead, W. J., Jr.; Gripshover, D. F.;
Shamblee, D. A. J. Med. Chem. 1992, 35, 4790; (b) Bhat, N. R.; Zhang, P. S.;
Mohanty, S. B. Neurochem. Res. 2007, 32, 293.
8. (a) Heers, J.; Backx, L. J. J.; Mostmans, J. H.; Van Cutsem, J. J. Med. Chem. 1979,
22, 1003; (b) Tanigawara, Y.; Aoyama, N.; Kita, T.; Shirakawa, K.; Komada, F.;
Kasuga, M.; Okumura, K. Clin. Pharmacol. Ther. 1999, 66, 528.
9. (a) Lombardino, J. G.; Wiseman, E. H. J. Med. Chem. 1974, 17, 1182; (b)
Lombardino, J. G. Ger offen 2,155,558, 1972.
through the condensation of readily available
a-azido ketones in
the presence of potassium ethylxanthate as a catalyst in good
yields. Moreover it is economical in atom count as only a molecule
of nitrogen is lost in the entire process.
10. (a) Durán, R.; Zubía, E.; Ortega, M. J.; Naranjo, S.; Salyá, J. Tetrahedron 1999, 55,
13225; (b) Manzanaro, S.; Salvá, J.; De la Feunte, J. A. J. Nat. Prod. 2006, 69,
1485.
Acknowledgments
11. (a) Khalili, B.; Tondro, T.; Hashemi, M. M. Tetrahedron 2009, 65, 6882; (b)
Zuliani, V.; Cocconcelli, G.; Fantini, M.; Ghiron, C.; Rivara, M. J. Org. Chem. 2007,
72, 4551.
12. (a) Batanero, B.; Escudero, J.; Barba, F. Org. Lett. 1999, 1, 1521; (b) Benati, L.;
Leardini, R.; Minozzi, M.; Nanni, D.; Spagnolo, P.; Strazzari, S.; Zanardi, G.;
Calestani, G. Tetrahedron 2002, 58, 3485.
We would like to thank The Project of Science Technology
Department of Zhejiang Province (2012C33065), the Program for
Zhejiang Leading Team of S&T Innovation (2011R50014), and Pro-
ject of Education Department of Zhejiang Province (Y201223193)
for funding this work. The work was supported by Diabetes Na-
tional Reseach Group, Inc.
13. Mahboobi, S.; Sellmer, A.; Burgemeister, T.; Lyssenko, A.; Schollmeyer, D.
Monatsh. Chem. 2004, 135, 333.