Efficient elemental iodine catalyzed one-pot synthesis of 2,4,5-triarylimidazoles

Article abstract of DOI:10.1007/s00706-006-0518-9

Elemental iodine is used as an efficient catalyst for the synthesis of 2,4,5-triarylimidazoles in excellent yields via condensation of benzoin, ammonium acetate, and aromatic aldehydes. This is a simple, one-pot, high yielding technique using cheap, non-toxic iodine in catalytic amounts.

Full text of DOI:10.1007/s00706-006-0518-9

Monatshefte f€ur Chemie 137, 1189–1194 (2006)
DOI 10.1007/s00706-006-0518-9
Efficient Elemental Iodine Catalyzed
One-Pot Synthesis of 2,4,5-Triarylimidazoles
ꢀ
Mazaahir Kidwai , Poonam Mothsra, Vikas Bansal, and Ritu Goyal
Green Chemistry Research Laboratory, Department of Chemistry, University of Delhi,
New Delhi, India
Received February 2, 2006; accepted (revised) March 7, 2006
Published online August 24, 2006 # Springer-Verlag 2006
Summary. Elemental iodine is used as an efficient catalyst for the synthesis of 2,4,5-triarylimidazoles
in excellent yields via condensation of benzoin, ammonium acetate, and aromatic aldehydes. This is a
simple, one-pot, high yielding technique using cheap, non-toxic iodine in catalytic amounts.
Keywords. Elemental iodine; 2,4,5-Triarylimidazoles; Benzoin; Ammonium acetate; Aromatic
aldehyde.
Introduction
Compounds with an imidazole ring system are biologically important due to its
role in biochemical processes. Substituted imidazoles are well known as inhibitors
of P38MAP kinase [1], fungicides and herbicides [2], plant growth regulators [3],
and therapeutic agents [4]. Imidazole chemistry, because of its use in ionic liquids
[5] and in N-heterocyclic carbenes (NHCs) [6], gave a new dimension in the area
of organometallics and ‘‘Green Chemistry’’. There are several methods reported
for the synthesis of substituted imidazoles [7]. Many of the synthesis protocols for
imidazoles reported so far suffer from one or more disadvantages, such as harsh
reaction conditions, poor yields, longer reaction time periods, and the use of hazard-
ous and often expensive acid catalysts. In addition, a new method based on a
reaction strategy using microwave heating in the solid state has been presented [8],
but this requires special instrumentation. Moreover, the syntheses of these hetero-
cycles have been carried out in DMF, DMSO, and acetic acid leading to complex
isolation and recovery procedures.
Thus, the development of a simple, efficient, and versatile method for the pre-
paration of 2,4,5-triarylimidazoles 4 is an active area of research with a scope for
further improvements towards milder reaction conditions and higher product
yields. In recent times, the use of elemental iodine has received considerable
ꢀ
Corresponding author. E-mail: kidwai.chemistry@gmail.com

1190
M. Kidwai et al.
attention as an inexpensive, non-toxic, and readily available catalyst for various
organic transformations [9]. The mild Lewis acidity associated with iodine en-
hanced its usage in organic synthesis to realize several organic transformations
using stoichiometric levels to catalytic amounts. During the course of our studies
towards the development of new routes to the synthesis of biologically active
heterocycles [10], we wish to report a simple and efficient method for the synthesis
of 2,4,5-triarylimidazoles 4.
Results and Discussions
In the present communication we report the condensation of benzoin (1), ammo-
nium acetate (2), and aromatic aldehydes 3 catalyzed by iodine (Scheme 1). Initi-
ally, a systematic study was carried out for catalytic evaluation of iodine for
benzaldehyde (Table 1).
The reaction went to completion in 2 h at room temperature with 10 mol% I2.
Accordingly, 10 mol% was sufficient to catalyze the reaction. A rate enhancement
with high yield was observed when higher molar ratios of I2 were used. However,
no product formation was observed in absence of I2. Toluene, acetonitrile, dichlor-
omethane, and ethanol were suitable solvents, but we proceeded with ethanol,
Scheme 1
Table 1. Catalytic evalulation of iodine for the synthesis of 4a
Entry
c(I2)=mol%
Time=h
Yield=%b
1
2
3
4
5
0
5
4
0
78
97
99
99
2
10
15
30
2
1.5
1
a
b
Product 4a from benzoin:NH4OAc:benzaldehyde (3a) ¼ 1:2.5:1 at room temperature; isolated
and unoptimized yields
Table 2. Effect of temperature on the yields of 4a
Entry
Temperature=ꢁC
Time=min
Yield=%b
1
2
3
4
room temperature
120
40
97
97
97
98
45
60
75
25
15
a
b
Product 4a from benzoin:NH4OAc:benzaldehyde (3a) ¼ 1:2.5:1 with 10 mol% I2; isolated and
unoptimized yields

One-Pot Synthesis of 2,4,5-Triarylimidazoles
1191
Table 3. Synthesis of 2,4,5-triarylimidazoles 4a
Entry
3
Ar
Time=min
Product
Yield=%b
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
C6H5
15
30
20
28
25
20
20
20
4a
4b
4c
4d
4e
4f
98
96
94
98
97
93
94
97
p-MeOC6H4
o-HOC6H4
p-ClC6H4
m-NO2C6H4
p-HOC6H4
2-thienyl
3g
3h
4g
4h
3,4-piperonyl
a
Product 4a from benzoin:NH4OAc:benzaldehyde (3a) ¼ 1:2.5:1 with 10 mol% I2 at 75ꢁC; b isolated
and unoptimized yields
which is considered as a relatively benign organic solvent. It is important to note
that in case of ethanol, imidazoles 4 precipitated on dilution of the reaction mixture
with an aqueous solution of Na2S2O3 and were isolated by simple filtration whereas
in other solvents hazardous solvents for the extraction of the products were required.
At room temperature, we observed product 4a after 2 h, however, with increase in
temperature, 4a was obtained within a few minutes (Table 2).
Encouraged by these results, we have extended the methodology to a variety of
aldehydes, which are summarized in Table 3. This method is effective for the pre-
paration of 4 from both electron efficient as well as electron deficient aromatic alde-
hydes 3. The aryl groups substituted with different groups and also the same groups
located at different positions of the aromatic ring did not show any effect on the for-
mation of 4. However, there are several reports on the synthesis of 4 using 1,2-dike-
tones but ꢀ-hydroxyketone usage as a starting material viz. benzoin 1, which we have
used, is not very often reported in literature. 1,2-Diketones, such as benzil are usually
prepared from benzoin 1 catalyzed by various toxic oxidants [11]. It is worth noting
here that the direct use of 1 in our methodology constitutes a significant improvement
in the synthesis of 4. A nearly stoichiometric amount of ammonium acetate was used
in the course of the reaction, whereas previously a many-fold of ammonium acetate
was required. This is an additional advantage of the novel methodology.
Initially, it was thought that the possible pathway is via an imidazoline. The subsequent conden-
sation and intramolecular cyclization of ꢀ-aminoketone and aldimine leads to the imidazoline, which
dehydrogenates to 4. It seems probable that the fully conjugated nature of the product results in
rapid oxidation aided by I2, which is a mild oxidizing agent. However, the possibility of dehydrogena-
tion of an imidazoline was ruled out because such kind of oxidation requires stoichiometric amounts
of the oxidizing agent and in the present case we obtained the product in excellent yield with only
10mol% I2. Alternatively, the probability that 1 itself undergoes aerial oxidation to benzil under these
conditions was explored. Thus, two sets of control reactions were carried out to confirm the aerial
oxidation. To our surprise, 1 was converted to benzil when refluxed with 10mol% I2 for 1 h whereas in
absence of I2, only trace amounts of benzil were detected after 24h. The same set of reactions was
performed under N2. Under these conditions no trace of benzil was observed (TLC). This shows that
aerial oxidation takes place and I2 only facilitates=catalyzes the transformation. The benzil so formed
is a well-known substrate for the synthesis of 4 and can react as shown in Scheme 2.
Molecular I2 is capable of binding with the carbonyl oxygen increasing the reactivity of the parent
carbonyl compound. Iodine facilitates the formation of the diimine intermediate, which under mild

1192
M. Kidwai et al.
Scheme 2
acid catalysis of I2 condenses further with the carbonyl carbon of the 1,2-diketone followed by
dehydration to afford the iso-imidazole, which rearranges via a [1, 5] sigmatropic shift to the required
2,4,5-triarylimidazole 4.
In conclusion, we have shown that I2 is an excellent catalyst for the one-pot
three-component synthesis of 2,4,5-triarylimidazoles 4. This simple methodology
represents an alternative to existing procedures. This is the first report of an iodine
catalyzed synthesis of 2,4,5-triarylimidazoles from benzoin and thus, this new
methodology opens an important alternative by the use of elemental iodine.
Experimental
Melting points were determined using a Thomas Hoover melting point apparatus. IR spectra were
obtained on a Perkin-Elmer FTIR-1710 spectrophotometer using Nujol film. 1H and 13C NMR spectra
were recorded on a Bruker Avance Spectrospin 300 (300 and 75 MHz) using TMS as internal standard.
Elemental analyses were performed on a Hereaus CHN Rapid analyser and the results were found to be
in good agreement with the calculated values. Mass spectra were recorded on a JEOL JMS-DX 303.
The temperature of the reaction mixture was measured by means of a non-contact infrared thermo-
meter (AZ, Mini Gun type, model 8868). The purity of compounds was checked by TLC on aluminum
plates coated with silica gel (Merck).
General Procedure for the Synthesis of 2,4,5-Triarylimidazoles 4
A mixture of 10mmol 1, 10mmol 2, 10 mmol aromatic aldehyde 3, and I2 (10 mol%) in 2 cm3 ethanol
was stirred at 75ꢁC for the time specified in Table 3. The completion of the reaction was monitored by

One-Pot Synthesis of 2,4,5-Triarylimidazoles
1193
TLC. After completion of reaction, the reaction mixture was diluted with H2O (containing 15%
Na2S2O3). The solid products, which separated, were filtered off, washed with H2O, and dried. The
crude products thus obtained were pure and subjected to further purification by column chromatogra-
phy on silica gel (60–120 mesh size) using 25% ethylacetate in petroleum ether as eluent to yield 4.
2,4,5-Triphenyl-1H-imidazole (4a)
Mp 272–274ꢁC (Ref. [7a] 276–277ꢁC); IR, 1H NMR, 13C NMR, and mass spectra are in accordance
with published data [7h, 8f].
2-(4-Methoxyphenyl)-4,5-diphenyl-1H-imidazole (4b)
Mp 222–224ꢁC (Ref. [7b] 222ꢁC); IR, 1H NMR, 13C NMR, and mass spectra are in accordance with
published data [7h, 8f].
2-(4,5-Diphenyl-1H-imidazol-2-yl)phenol (4c)
Mp 202–204ꢁC (Ref. [7d] 202ꢁC); IR, 1H NMR, 13C NMR, and mass spectra are in accordance with
published data [7h, 8f].
2-(4-Chlorophenyl)-4,5-diphenyl-1H-imidazole (4d)
Mp 262–264ꢁC (Ref. [7c] 261–262ꢁC); IR, 1H NMR, 13C NMR, and mass spectra are in accordance
with published data [8f].
2-(3-Nitrophenyl)-4,5-diphenyl-1H-imidazole (4e)
Mp 300–305ꢁC (Ref. [8f] >300ꢁC); 13C NMR (CDCl3=DMSO-d6): ꢁ ¼ 122.7, 124.2, 127.9, 128.5,
1
129.4, 132.8, 133.1, 146.3, 157.8ppm; IR, H NMR, and mass spectra are in accordance with pub-
lished data [8f].
4,5-Diphenyl-2-thien-2-yl-1H-imidazole (4f)
Mp 255–256ꢁC (Ref. [8b] 254–255ꢁC); 13C NMR (CDCl3=DMSO-d6): ꢁ ¼ 122.2, 125.3, 126.2, 126.5,
1
127.40, 128.13, 129.4, 136.7, 141.35 ppm; IR, H NMR, and mass spectra are in accordance with
published data [8b].
4-(4,5-Diphenyl-1H-imidazol-2-yl)phenol (4g)
Mp 260–261ꢁC (Ref. [7d] 256–257ꢁC); IR, 1H NMR, 13C NMR, and mass spectra are in accordance
with published data [7h 8f].
2-Benzo[1,3]dioxol-5-yl-4,5-diphenyl-1H-imidazole (4h)
Mp 248–250ꢁC (Ref. [8f] 300ꢁC); 13C NMR (CDCl3=DMSO-d6): ꢁ ¼ 92.8, 113.6, 117.2, 121.3, 122.7,
1
126.3, 127.3, 129.1, 136.8, 147.8, 149.7ppm; IR, H NMR, and mass spectra are in accordance with
published data [8f].
Acknowledgements
P. M. thanks the Council of Scientific and Industrial Research, New Delhi, for the award of a Junior
Research Fellowship.
References
[1] Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, McNulty D, Blumenthal N,
Heys JR, Landvatter SW, Strickler JE, McLaughlin MM, Siemens IR, Fisher SM, Livi JP, White
JR, Adams JL, Young PR (1994) Nature 372: 739
[2] Maier T, Schmierer R, Bauer K, Bieringer H, Buerstell H, Sachse B, US Patent (1989) 4820335;
(1989) Chem Abstr 111: 19494

1194
M. Kidwai et al.: One-Pot Synthesis of 2,4,5-Triarylimidazoles
[3] Schmierer R, Mildenberger H, Buerstell H, German Patent (1987) 361464; (1988) Chem Abstr
108: 37838
[4] Heeres J, Backx LJJ, Mostmans JH, Vancustem J (1979) J Med Chem 22: 1003
[5] Wasserscheid P, Keim W (2000) Angew Chem Int Ed Eng 39: 3772
[6] Bourissou D, Guerret O, Gabbai FP, Bertrand G (2000) Chem Rev 100: 39
[7] a) Davidson D, Weiss M, Jelling M (1937) J Org Chem 2: 319; b) Cook AH, Jones DC (1941) J
Chem Soc 278; c) White DM, Sonnenberg J (1964) J Org Chem 23: 1926; d) Japp FR, Robinson
MM (1882) Chem Ber 15: 1269; e) Clark NG, Lawkill E (1975) Tetrahedron Lett 2717; f) Zhng C,
Moran EJ, Woiwode TF, Shart KM, Mjalli AMM (1996) Tetrahedron Lett 37: 751; g) Frantz DE,
Morency L, Sohili A, Murry JA, Grabowski EJJ, Tillyer R (2004) Org Lett 6: 843; h) Siddiqui
SA, Narkhede VC, Palimkar SS, Daniel T, Lahoti RJ, Srinivasan KV (2005) Tetrahedron 61:
3539
[8] a) Balalaie S, Arabanian A (2000) Green Chem 2: 274; b) Usyatinsky AY, Khmelnitsky YL
(2000) Tetrahedron Lett 41: 5031; c) Cobb JM, Grimster N, Khan N, Lai JYQ, Payne MJ, Payne
LJ, Raynham T, Taylor J (2000) Tetrahedron Lett 43: 7557; d) Xu L, Wan Li-F, Salchi H, Deng
W, Guo Q-X (2004) Heterocycles 63: 1613; e) Wolkenberg SE, Wisnoski DD, Leister WM,
Wang Y, Zhao Z, Lindsley CW (2004) Org Lett 6: 1453; f) Zhou JF, Song Y-Z, Yang Y-L, Zhu
Y-L, Tu S-J (2005) Synth Commun 35: 1369
[9] Wang Shun-Yi (2004) Syn Lett 14: 2642, and references therein
[10] a) Kidwai M, Mishra P, Dave B, Bhushan KR, Saxena RK, Singh M (2000) Monatsh Chem 131:
1207; b) Kidwai M, Saxena S, Mohan R, Venkatramanan R (2002) J Chem Soc, Perkin Trans 1
1845; c) Kidwai M, Mothsra P, Mohan R, Biswas S (2005) Bioorg Med Chem Lett 15: 915
[11] a) Weiss M, Abbel M (1948) J Am Chem Soc 70: 3666; b) McKillop A, Swann B, Ford ME,
Taylor EC (1973) J Am Chem Soc 95: 3641; c) Zhang GS, Shi QZ, Chen MF, Cai K (1997) Syn
Commun 27: 953