A practical synthesis of 2,4(5)-diarylimidazoles from simple building blocks

Article abstract of DOI:10.1021/jo070187d

(Chemical Equation Presented) A simple and efficient approach to selectively obtain 2,4(5)-diarylimidazoles suppressing formation of 2-aroyl-4(5)-arylimidazoles is described. The yield of each of the two products strongly depends on the reaction condition

Full text of DOI:10.1021/jo070187d

aldehydes and ammonia, to obtain 2,4,5-triphenylimidazoles.6,7
Subsequently, many other syntheses of this important hetero-
cycle have been published.8 For example, 2,4-diaryl-1H-
imidazoles are often obtained from amidines and R-bromo
arylketones.9 Moreover, Zhang and Chen described an efficient
procedure to obtain unsymmetrical, C5 unsubstituted 2,4-
diarylimidazoles. In this approach acetophenones are oxidized
in situ to R-tosyloxyacetophenones, which then condense with
arylamidines to obtain the desired compounds.10 Another
important procedure to prepare imidazoles was described by
Ueno and Togo. In this approach the heteroaromatic compounds
were prepared reacting a polymer-supported [hydroxy(sulfony-
loxy)iodo]benzene with ketones or alcohols, followed by the
treatment with benzamidine.11 Finally, it is also useful to
mention the synthesis of 2,4-diarylimidazoles through Suzuki
coupling, proposed by Langhammer and Erker.12
A Practical Synthesis of 2,4(5)-Diarylimidazoles
from Simple Building Blocks
Valentina Zuliani,† Giuseppe Cocconcelli,*,‡ Marco Fantini,†
Chiara Ghiron,‡ and Mirko Rivara†
Dipartimento Farmaceutico, UniVersita´ degli Studi di Parma, V.
le G.P. Usberti, 27/A, I-43100 Parma, Italy and Siena Biotech
S.p.A., Via Fiorentina, 1, I-53100 Siena, Italy
gcocconcelli@sienabiotech.it
ReceiVed January 30, 2007
The aim of the present work was to prepare imidazoles
introducing functionality in the C2 and C4 positions while
leaving the C5 position unsubstituted, elaborating a simple and
one-pot solution-phase synthesis methodology to produce a
small library of biologically active compounds (e.g., 2,4(5)-
diarylimidazoles are known to be NPY5 receptor antagonists).13
The first step in designing a scaleable process was to identify
a suitable synthetic route. Desirable characteristics would include
a reduced number of synthetic and purification steps and
commercially available starting materials. Subsequently, reaction
conditions such as temperature, solvent, reaction times, and
addition sequence of reactants were optimized, with the aim to
obtain a versatile and high-yielding route. After evaluation of
various synthetic procedures, we thought to modify Radzisze-
wski’s synthesis,6 in particular using phenylglyoxals 1, benzal-
dehydes 2, and ammonium acetate as ammonia source (Scheme
1). Although this type of reaction is routinely used to build
imidazoles, we found no examples concerning the preparation
of C5 unsubstituted 2,4-diaryl-1H-imidazoles.
We found however that when using acetic acid as the solvent
as reported in the literature, very low yields of the desired
compounds 3 were obtained, and a high percentage of ben-
zoylphenylimidazoles 4 was also formed. Thus, in our quest to
improve the yields and the selectivity toward the initial 2,4(5)-
diarylimidazole targets (3), we conducted the reaction modifying
the temperature and the solvent, while keeping the reaction time
unchanged (overnight). As shown in Table 1, these attempts at
optimization were applied to the synthesis of the unsubstituted
compound 3a. However, after refluxing the reaction mixture in
acetic acid, only decomposition products were detected.
Then, as reported in Table 1, we selected three solvents
according to their characteristics to engage different types of
A simple and efficient approach to selectively obtain 2,4-
(5)-diarylimidazoles suppressing formation of 2-aroyl-4(5)-
arylimidazoles is described. The yield of each of the two
products strongly depends on the reaction conditions em-
ployed. This reaction provides a simple method to prepare
small libraries of biologically active compounds by parallel
synthesis.
The imidazole ring system is one of the most important
substructures found in a large number of natural products and
pharmacologically active compounds. For example, the amino
acid histidine, the hypnotic agent etomidate,1 the antiulcerative
agent cimetidine,2 the proton pump inhibitor omeprazole,3 the
fungicide ketoconazole,4 and the benzodiazepine antagonist
flumazenil5 are imidazole derivatives. Therefore, there is a
continuous need for developing concise and practical synthetic
methods for the preparation of imidazole and related compounds.
Japp and Radziszewski proposed the first synthesis of the
imidazole core in 1882, starting from 1,2-dicarbonyl compounds,
(6) Radziszewski, B. Chem. Ber. 1882, 15, 1493-1496.
(7) Japp, F. R.; Robinson, H. H. Chem. Ber. 1882, 15, 1268-1270.
(8) For example, see: Grimmett, M. R. In ComprehensiVe Heterocycle
Chemistry II; Katritzky, A. R., Rees, C., Scriven E. F. V., Eds.; Pergamon
Press: Elmsford, NY, 1996; Vol. 3, pp 77-220.
(9) Li, B.; Chiu, C. K.-F.; Hank, R. F.; Murry, J.; Roth, J.; Tobiassen,
H. Org. Proc. Res. DeV. 2002, 6, 682-683.
(10) Zhang, P.-F.; Chen, Z.-C. Synthesis 2001, 14, 2075-2077.
(11) Ueno, M.; Togo, H. Synthesis 2004, 16, 2673-2677.
(12) Langhammer, I.; Erker, T. Heterocycles 2005, 65, 1975-1984.
(13) Elliott, R. L.; Oliver, R. M.; LaFlamme, J. A.; Gillaspy, M. L.;
Hammond, M.; Hank, R. F.; Maurer, T. S.; Baker, D. L.; DaSilva-Jardine,
P. A.; Stevenson, R. W.; Maek, C. M.; Cassella, J. V. Bioorg. Med. Chem.
Lett. 2003, 13, 3593-3596.
† Universita´ degli Studi di Parma.
‡ Siena Biotech S.p.A.
(1) Wauquier, A.; Van Den Broeck, W. A. E.; Verheyen, J. L.; Janssen,
P. A. J. Eur. J. Pharmacol. 1978, 47, 367-377.
(2) Brimblecombe, R. W.; Duncan, W. A. M.; Durant, G. J.; Emmett, J.
C.; Ganellin, C. R.; Parons, M. E. J. Int. Med. Res. 1975, 3, 86-92.
(3) Tanigawara, Y.; Aoyama, N.; Kita, T.; Shirakawa, K.; Komada, F.;
Kasuga, M.; Okumura, K. Clin. Pharmacol. Ther. 1999, 66, 528-534.
(4) Heers, J.; Backx, L. J. J.; Mostmans, J. H.; Van Cutsem, J. J. Med.
Chem. 1979, 22, 1003-1005.
(5) Hunkeler, W.; Mo¨hler, H.; Pieri, L.; Polc, P.; Bonetti, E. P.; Cumin,
R.; Schaffner, R.; Haefely, W. Nature 1981, 290, 514-516.
10.1021/jo070187d CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/09/2007
J. Org. Chem. 2007, 72, 4551-4553
4551

SCHEME 1. Synthesis of Compounds of General Formula 3
and 4
TABLE 1. Reaction Conditions Employed and Yields of the
Products Synthesized
FIGURE 1. Probable equilibrium existing between the tautomers of
the phenylglyoxal.
hemiacetal form, which supports formation of the desired 2,4-
(5)-diphenylimidazole product.
solvent
temperature
3aa
4aa
CH3COOH room temp
CH3COOH reflux
DCM
DMF
CH3OH
traces
dec
9%
12%
83%
77%
dec
91%
78%
11%
This condition should favor the incorporation of benzaldehyde
at the C2 position of the imidazole central core. The data
reported in Table 1 suggest that, in other solvents, there is a
competition between aldehyde and glyoxal for the C2 position
of the heterocycle, with the preferred formation of the ben-
zoylphenylimidazoles 4.
room temp
room temp
room temp
a Chromatographic yields.
This efficient synthetic route was then exploited in the
preparation of a small library of compounds through parallel
synthesis. The input selection was made with the aim to modify
the electronic properties of the central core, considering the
synthetic and, initially, the commercial accessibility of the
starting building blocks. A series of substituted-2,4(5)-diphe-
nylimidazoles were thus synthesized (Table 2).
The data reported in Table 2 show that all of the compounds
synthesized were obtained in good yields with a simple workup
and without chromatographic purification.
We also prepared two derivatives characterized by the
presence of a pyridine ring in the 2 position of the imidazole
central core (Figure 3).
The pyridine compounds were readily obtained in 77% yield
(3r) and 71% yield (3s), thus indicating that the proposed
synthetic route could be a viable and efficient way to prepare
2,4(5)-heteroarylimidazoles.
interactions with solutes: apolar aprotic, such as methylene
chloride (DCM); polar aprotic, such as N,N-dimethylformamide
(DMF); and polar protic, such as methanol. The results are
reported in Table 1, together with the reaction condition
employed.
As can be seen from Table 1, methanol at room temperature
afforded the best yield in 2,4(5)-diphenylimidazole 3a (83%),
which we postulate arises from an equilibrium between the
hydrated, hemiacetal, and aldehyde forms of phenylglyoxal
(Figure 1).
In the presence of methanol, we postulate that these equilibria
would be mainly shifted toward the hemiacetal form, and a
formal benzaldehyde excess would effectively be present. This
hypothesis is supported by NMR studies conducted on the
dicarbonyl compound in chloroform-d (CDCl3), in the absence
1
or presence of 2 equiv of methanol (Figure 2). The H NMR
spectrum recorded in CDCl3 without methanol (Figure 2a) shows
a peak corresponding to the phenylglyoxal aldehyde group
(9.70 ppm), thus confirming the presence of the dicarbonyl
form.14 This could be the reactive species in solvents such as
DCM and DMF, supporting the autocondensation reaction and
the formation of the benzoylphenylimidazole as the major
component. The NMR spectrum recorded in CDCl3 in presence
of methanol (Figure 2b) shows instead a new peak near the
methanolic methyl chemical shift (3.51 ppm), and the aldehyde
peak disappears. This would confirm the existence of the
In summary, the described synthetic protocol allows for the
preparation of a variety of 2,4(5)-diarylimidazoles through one-
pot parallel synthesis, without the use of expensive or sensitive
reagents. Moreover, a careful study of the reaction conditions
allowed us to selectively prepare 2,4(5)-diarylimidazoles sup-
pressing formation of unwanted 2-aroyl-4(5)-arylimidazoles. The
products obtained belong to a class of biologically active
compounds.
Experimental Section
Representative Procedure. Preparation of 3a. To a solution
of benzaldehyde (0.70 mmol, 74 mg) and ammonium acetate
(14) De Meester, J. W. G.; van der Plas, H. C. J. Heterocycl. Chem.
1987, 24, 441-451.
4552 J. Org. Chem., Vol. 72, No. 12, 2007

FIGURE 2. 1H NMR spectra of the phenylglyoxal in CDCl3 solutions recorded (a) without CH3OH and (b) with 2 equiv of CH3OH.
TABLE 2. 2,4(5)-Diarylimidazoles Synthesized
FIGURE 3. Pyridine compounds synthesized (3r, s).
mixture was obtained using SCX-2 column (2 g, 30-90 µm, loading
0.4 mequiv/g). The column is prewashed with 1:1 DCM/methanol
(10 mL), the non-basic products were eluted with methanol (10
mL), and then the desired 2,4(5)-diphenylimidazole was eluted with
a 5% w/w methanolic ammonia solution (10 mL). The hydrochlo-
ride salt was prepared by treating the free base with a 5% w/w
ethanolic HCl solution. The product was then crystallized from
absolute ethanol/dry diethyl ether. 2,4(5)-Diphenylimidazole (3a).15
entry
R
R1
R2
R3
yield (%)a
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
H
H
H
NO2
H
OCH3
H
Cl
H
CF3
H
H
H
H
H
H
H
H
H
H
H
H
H
NO2
H
OCH3
H
H
H
H
H
H
H
H
H
H
H
NO2
H
OCH3
H
Cl
H
83
68
59
57
62
60
56
74
66
65
52
70
57
76
83
65
81
NO2
H
OCH3
H
Cl
H
CF3
H
1
83% yield, mp 274-275 °C. H NMR (300 MHz, DMSO-d6): δ
7.46 (t, J ) 7.23, 1H), 7.55 (t, J ) 7.68, 2H), 7.66 (t, J ) 3.24,
3H), 8.05 (d, J ) 7.35, 2H), 8.30-8.33 (m, 3H). 13C NMR (100
MHz, DMSO-d6): δ 117.3, 123.9, 126.6, 127.7, 128.1, 129.7, 129.8,
129.9, 132.6, 134.5, 145.0. MS (EI) 221 [M+]. Anal. Calcd for
C15H12N2‚HCl: C, 70.17; H, 5.10; N, 10.91. Found: C, 69.85; H,
5.15; N, 10.59.
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
CF3
H
CF3
Acknowledgment. Financial support from Italian MIUR and
Siena Biotech S.p.A. is gratefully acknowledged. We are grateful
to the Centro Interdipartimentale Misure of the University of
Parma for providing the NMR instrumentation.
a Isolated yields of analytically pure products.
(3.41 mmol, 262 mg) in methanol (3.5 mL) was added, over a
period of 10 min, a solution of the commercially available
phenylglyoxal monohydrate (0.70 mmol, 106 mg) in methanol (3.8
mL). The reaction mixture was stirred overnight at room temper-
ature, then the solvent was evaporated, and the residue was
partitioned between saturated aqueous NaHCO3 solution (20 mL)
and methylene chloride (20 mL). The organic phase was dried over
Na2SO4, and the solvent was removed in vacuo. The selective
isolation of either non-basic (2-benzoyl-4(5)-phenylimidazole) or
basic (2,4(5)-diphenylimidazole) compounds from the crude reaction
Supporting Information Available: 1H and 13C NMR spectra
and characterization data of all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO070187D
(15) Wegner, K.; Schunack, W. Arch. Pharm. (Weinheim, Ger.) 1974,
307, 492-495.
J. Org. Chem, Vol. 72, No. 12, 2007 4553