A one-pot synthesis of 1,2,4,5-tetraarylimidazoles using molecular iodine as an efficient catalyst

Article abstract of DOI:10.1016/j.tetlet.2006.05.097

Molecular iodine is a cheap, nontoxic catalyst, which acts as an efficient catalyst for the synthesis of 1,2,4,5-tetraarylimidazoles using benzoin, an aromatic aldehyde and an amine in the presence of ammonium acetate. The advantage of this method is the

Full text of DOI:10.1016/j.tetlet.2006.05.097

Tetrahedron Letters 47 (2006) 5029–5031
A one-pot synthesis of 1,2,4,5-tetraarylimidazoles using
molecular iodine as an efficient catalyst
Mazaahir Kidwai* and Poonam Mothsra
Green Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi 110007, India
Received 22 March 2006; revised 11 May 2006; accepted 17 May 2006
Available online 6 June 2006
Abstract—Molecular iodine is a cheap, nontoxic catalyst, which acts as an efficient catalyst for the synthesis of 1,2,4,5-tetraarylim-
idazoles using benzoin, an aromatic aldehyde and an amine in the presence of ammonium acetate. The advantage of this method is
the direct use of benzoin, which is transformed into benzil in situ and condenses further to generate the imidazole in a one-pot
sequence.
Ó 2006 Elsevier Ltd. All rights reserved.
The prevalence of imidazole in natural products and
pharmacologically active compounds has resulted in a
number of synthetic approaches to these heterocycles.
However, despite intensive efforts, only a handful of gen-
eral methods exist for the construction of highly substi-
tuted imidazoles. Highly substituted imidazoles could
potentially have novel therapeutic activities1 and thus ef-
forts towards obtaining tetrasubstituted imidazoles have
increased. There are several methods reported in the lit-
erature for the synthesis of highly substituted imidazoles
which include a four component condensation using
Wang’s resin in refluxing acetic acid,2 condensation of
diones, aldehydes, primary amines and ammonium ace-
tate in phosphoric acid,3 and in acetic acid,4 using an
result in poor yields. Synthetic alternatives are many
and varied, and have resorted to harsh conditions, for
example, the formamide synthesis, which requires excess
reagents, H2SO4 as a condensing agent and high temper-
ature (150–200 °C) affording 40–90% yields of product
in 4–6 h. Additionally, reagents for these procedures
are not readily or commercially available which is a
key deficiency when developing conditions for library
synthesis. Therefore, the development of simple, effi-
cient, inexpensive, nontoxic and readily available re-
agents providing convenient procedures with improved
yields, are necessary. Owing to its unique catalytic prop-
erties, iodine has been extensively used for a plethora of
organic reactions.13–15
6
organocatalyst in acetic acid,5 as well as in H2SO4 and
DMSO,7 N-alkylation of trisubstituted imidazoles,8 con-
densation of benzoin or benzoin acetate with an alde-
hyde, a primary amine and ammonia in the presence of
copper acetate,9 cyclisations of sulfonamides with meso-
ionic 1,3-oxazolium-5-olates,10 condensation of b-car-
bonyl-N-acyl-N-alkylamines with ammonium acetate
in refluxing acetic acid11 and conversion of N-2-oxoa-
mides with ammonium trifluoroacetate12 under neutral
conditions.
In a broad programme of developing efficient, selective
and eco-friendly synthetic methods for pharmacologi-
cally important moieties,16–18 we explored the catalytic
activity of iodine. Herein, we report a simple, rapid
and one-pot procedure for the synthesis of 1,2,4,5-tetra-
arylimidazoles using iodine as the catalyst (Scheme 1).
Initially, a catalytic evaluation of iodine using benzalde-
hyde 4a was carried out (Table 1).
However, most of these procedures are lengthy and
require expensive and hazardous acid catalysts and
The reaction was carried out by adding benzoin 1,
aniline 2 and ammonium acetate 3 to a solution of benz-
aldehyde 4a and iodine in ethanol at room temperature.
The reaction was complete in 50 min when 10 mol % of
iodine was used. Rate enhancement was observed when
higher mol ratios were used but no significant improve-
ment in the yield was observed.
Keywords: Molecular iodine; Benzoin; Benzil; 1,2,4,5-Tetraaryl-
imidazoles.
*
Corresponding author. Tel./fax: +91 11 27666235; e-mail: Kidwai.
chemistry@gmail.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.097

5030
M. Kidwai, P. Mothsra / Tetrahedron Letters 47 (2006) 5029–5031
Ph
Ph
OH
Ph
Ph
N
N
I2 (10 mol%)
+
+
PhNH
2 + 2 NH4OAc
Ar
Ar CHO
O
Ph
1
2
3
4a-h
5a-h
Scheme 1. Iodine catalysed four component synthesis of 1,2,4,5-tetraarylimidazoles.
Table 1. Catalytic activity evaluation for imidazolea synthesis
Table 3. Iodine promoted synthesis of 1,2,4,5-tetraarylimidazolesa
Entry Aldehyde
Product Time Yieldb Refer-
Entry
Iodine (mol %)
Time
Yieldb (%)
(min) (%)
ence
1
2
3
4
5
0
5
10
15
30
6 h
3 h
50 min
40 min
30 min
0
76
96
97
97
1
2
5a
5b
20
20
96
94
8
CHO
20
20
MeO
CHO
a 1 equiv of benzoin–1 equiv of 4a–1 equiv of NH4OAc–1 equiv of
aniline at room temperature.
b Isolated and unoptimised yields.
OH
3
5c
30
97
CHO
4
5
5d
5e
25
30
98
98
21
25
Cl
CHO
Table 2. Effect of temperature on iodine catalysed imidazolea synthesis
O2N
Entry Aldehyde Product Temperature Time
Yieldb
(°C)
(min) (%)
CHO
1
4a
5a
Room
50
96
temperature
6
7
8
5f
20
25
25
97
95
95
22
25
25
HO
CHO
2
3
4
4a
4a
4a
5a
5a
5a
45
60
75
40
30
20
98
97
98
5g
5h
a Product 5a from 1 equiv benzoin–1 equiv of 4a–1 equiv of NH4OAc–
1 equiv of aniline using 10 mol % of I2.
S
CHO
O
b Isolated and unoptimised yield.
O
CHO
a 1 equiv of benzoin–1 equiv of 4a–h–1 equiv of NH4OAc–1 equiv of
aniline with 10 mol % of I2.
To determine the most appropriate solvent, the reaction
was examined using ethanol, dichloromethane, aceto-
nitrile, toluene and xylene. Ethanol and dichloromethane
were the best solvents in terms of yields. Ethanol being a
‘cleaner’ reaction medium was favoured as water could
be used for the work-up. Faster reactions occurred on
increasing the temperature (Table 2).
b Isolated and unoptimised yield.
which is oxidised by iodine to the imidazole. Such oxida-
tion requires a stoichiometric amount of iodine whereas
we observed an excellent yield with only 10 mol % of
iodine. Hence, this possibility was ruled out and the alter-
native possibility of benzoin undergoing aerial oxidation
to benzil under these conditions was investigated. Thus
two sets of control reactions were carried out (Fig. 1).
Various aldehydes 4a–h (electron withdrawing, electron
donating) exemplify the versatility of this simple proto-
col (Table 3).
In the case of refluxing with 10 mol % of iodine, benzoin
was oxidised to benzil surprisingly after 1 h whereas
only a trace amount was detected after 24 h without
iodine. Another set of control reactions under a nitrogen
Although there are several papers reporting the synthe-
sis of 1,2,4,5-tetraarylimidazoles using 1,2-diketones,
there are very few reports in the literature using a-
hydroxyl ketones as the starting material. It is worth
noting here that 1,2-diketones such as benzil are usually
prepared from benzoin 1 catalysed by various toxic oxi-
dants.19–22 We found that our methodology works very
well for a-hydroxyl ketones such as benzoin 1. Conse-
quently, the direct use of benzoin in our methodology
constitutes a significant improvement in the synthesis
of 1,2,4,5-tetrasubstituted imidazoles 5a–h in terms of
green chemistry.
EtOH, reflux
Benzoin
Benzoin
Benzoin
Benzoin
Benzil
10 mol% I2
EtOH, reflux
Trace Benzil
EtOH, reflux
No product formation
Inert atm., 10 mol% I2
EtOH, reflux
Inert atm.
No product formation
It is possible that the Lewis acidity of iodine may pro-
mote the formation of an a-amino ketone and aryl
aldimine, which then condense to form an imidazoline
Figure 1.

M. Kidwai, P. Mothsra / Tetrahedron Letters 47 (2006) 5029–5031
5031
14. Ko, S.; Sastry, M. N. V.; Lin, C.; Yao, C.-Fa. Tetrahedron
Lett. 2005, 46, 6345.
15. Jianwei, S.; Dong, Y.; Cao, L.; Wang, X.; Wang, S.; Hu,
Y. J. Org. Chem. 2004, 69, 8932.
16. Kidwai, M.; Saxena, S.; Khan, M. R. K.; Thukral, S. S.
Eur. J. Med. Chem. Lett. 2005, 40, 816.
17. Kidwai, M.; Mothsra, P.; Mohan, R.; Biswas, S. Bioorg.
Med. Chem. Lett. 2005, 15, 915.
atmosphere with or without 10 mol % iodine did not
give any product. The reactions in Figure 1 highlight
the role of molecular iodine in promoting the aerial oxi-
dation to benzil. There are earlier examples of iodine
based oxidation of benzoin to benzil under basic condi-
tions,23 therefore this is not a conceptually unprece-
dented process.
18. Kidwai, M.; Mothsra, P. Synth. Commun. 2006, 36, 817.
19. McKillop, A.; Swann, B. P.; Taylor, E. C. J. Am. Chem.
Soc. 1973, 95, 3641.
20. Heinz, J.; Baumgaertel, H.; Zimmermann, H. Chem. Ber.
1968, 101, 3504.
21. Park, S.; Know, Oh-Hoon.; Kim, S.; Park, S.; Choi, M.-G.;
Cha, M.; Park, S. Y.; Jang, Du.-J. J. Am. Chem. Soc. 2005,
127, 10070.
22. Buttke, K.; Baumgaertel, H.; Nicolas, H. J.; Scheider, M.
J. Parkt. Chem. 1997, 339, 721.
23. Corson, B. B.; McAllister, R. W. J. Am. Chem. Soc. 1929,
51, 2822.
24. General procedure for the synthesis of 1,2,4,5-tetraaryl-
imidazoles 5a–h: A 50 ml round bottom flask was charged
with benzoin 1 (10 mmol), aniline 2 (10 mmol), ammo-
The Lewis acidity of iodine makes it capable of binding
with the aldehyde carbonyl oxygen increasing the reac-
tivity of the parent carbonyl compounds. Iodine reacts
initially with aldehyde 4 to produce a diamine inter-
mediate, which condenses with the activated benzil and
subsequent elimination of water affords 1,2,4,5-tetraaryl-
imidazoles 5a–h.
In summary, we have developed a simple, convenient
and efficient synthetic protocol for 1,2,4,5-tetraarylimid-
azoles using cheap, readily available and nontoxic iodine
in a catalytic amount.24
nium acetate
3 (10 mmol), aromatic aldehyde 4a–h
(10 mmol) and iodine (10 mol %) followed by 5 ml of
ethanol. The mixture was then stirred at 75 °C until the
reaction was complete (TLC). The reaction mixture was
treated with aqueous Na2S2O3 solution. The solid imid-
azole product that separated out, filtered, then washed
with water and dried. The crude product, thus obtained
was subjected to purification by column chromatography
on silica gel (60–120 mesh size) using 25% ethyl acetate in
petroleum ether as eluent to yield 1,2,4,5-tetraarylimida-
zoles 5a–h. The structures of all the products were
unambiguously established on the basis of spectral anal-
Acknowledgements
Poonam Mothsra gratefully acknowledges financial
support from the Council of Scientific and Industrial
Research, New Delhi, India.
References and notes
1. Lee, J. C.; Laydon, J. T.; McDonnell, P. C.; Gallagher, T.
T.; Kumar, S.; Green, D.; McKulty, D.; Blumenthal, M.;
Heys, J. R.; Landvatter, S. W.; Strikler, J. E.; McLaugh-
lin, M. M.; Siemen, I. R.; Fisher, S. M.; Livi, G. P.; White,
J. R.; Adams, J. L.; Young, P. R. Nature 1994, 372, 739.
2. Zhang, C.; Moran, E. J.; Woiwade, T. F.; Short, K. M.;
Mjalli, A. M. M. Tetrahedron Lett. 1996, 37, 751.
3. Liu, J.; Chem, J.; Zhao, J.; Zhao, Y.; Li, L.; Zhang, H.
Synthesis 2003, 2661.
1
ysis (IR, H, 13C NMR and mass spectral data).
25. Spectral data for novel compounds:
2-(3-Nitrophenyl)-1,4,5-triphenyl-1H-imidazole (5e). Mp
244–246 °C; IR (cmÀ1, Nujol): 1597 (C@C), 1576 (C@N);
1H NMR (CDCl3/DMSO, 300 MHz): d 7.31–7.68 (m,
15H), 7.81–8.23 (m, 4H); 13C NMR (CDCl3/DMSO,
75 MHz): d 123.1, 125.2, 126.0, 128.0, 128.2, 128.4, 128.6,
128.7, 129.9, 130.7, 133.1, 134.6, 137.1, 137.4, 144.3, 153.4;
C27H19N3O2 (417): calcd C, 77.68; H, 4.59; N, 10.07.
Found C, 77.69; H, 4.55; N, 10.15.
4. Sarshar, S.; Siev, D.; Mjalli, A. M. M. Tetrahedron Lett.
1996, 37, 835.
1,4,5-Triphenyl-2-thiophen-2-yl-1H-imidazole (5g). Mp
5. Frantz, D. E.; Morency, L.; Soheilli, A.; Murry, J. A.;
Grabowski, E. J. J.; Tillyer, R. O. Org. Lett. 2004, 6, 843.
6. Weinmann, H.; Hahhe, M.; Koeing, K.; Mertin, E.;
Tilstam, U. Tetrahedron Lett. 2002, 43, 593.
7. Clark, N. G.; Cawkill, E. Tetrahedron Lett. 1975, 2717.
8. Davidson, D.; Weiss, M.; Jelling, M. J. Org. Chem. 1937,
2, 319.
247–251 °C; IR (cmÀ1
, Nujol): 1596 (C@C), 1577
(C@N); 1H NMR (CDCl3/DMSO, 300 MHz): d 6.73–
6.86 (m, 2H), 7.14–7.23 (m, 15H), 7.58–7.61 (m, 1H); 13C
NMR (CDCl3/DMSO, 75 MHz): d 125.3, 126.3, 126.5,
127.0, 127.4, 128.1, 128.4, 129.1, 129.4, 130.0, 131.0, 132.9,
134.0, 132.9, 134.1, 136.1, 136.8, 141.4; C25H18N2S (378):
calcd C, 79.33; H, 4.79; N, 7.40. Found C, 79.33; H, 4.68;
N, 7.43.
9. Lipshutz, B. H.; Morey, M. C. J. Org. Chem. 1983, 48,
3745.
2-Benzo[1,3]dioxol-5-yl-1,4,5-triphenyl-1H-imidazole (5h).
Mp 194–195 °C; IR (cmÀ1, Nujol): 1596 (C@C), 1572
(C@N); 1H NMR (CDCl3/DMSO, 300 MHz): d 6.01 (s,
2H), 6.96–7.42 (m, 18H); 13C NMR (CDCl3/DMSO,
75 MHz): d 91.6, 113.2, 116.7, 120.9, 125.9, 126.3, 126.6,
127.4, 128.1, 128.3, 129.4, 130.2, 131.0, 132.8, 134.2, 136.6,
137.3, 147.3, 148.1; C28H20N2O2 (416): calcd C, 80.75; H,
4.84; N, 6.73. Found C, 80.78; H, 4.82; N, 6.78.
10. Consonni, R.; Croce, P. D.; Terracioli, R.; Rosa, C. L.
J. Chem. Res. (S). 1991, 188.
11. Evans, D. A.; Lundy, K. M. J. Am. Chem. Soc. 1992, 114,
1495.
12. Caliborne, C. T.; Liverton, K. J.; Kguyen, K. T. Tetra-
hedron Lett. 1998, 39, 8939.
13. Cooke, L. A.; Frauendorf, C.; Gilea, M. A.; Holmes, S.
C.; Vyles, J. S. Tetrahedron Lett. 2006, 47, 719.