Synthesis and properties of 1-methyl-2-phenyl-5-(2-furyl)- and 1-methyl-2-phenyl-5-(2-thienyl)imidazoles

Article abstract of DOI:10.1134/S1070427210060194

2-Phenyl-5-(2-furyl)- and 2-phenyl-5-(2-thienyl)imidazoles were synthesized by condensation of 2-furoylmethyl and 2-thenoylmethyl acetates with benzaldehyde under the conditions of Weidenhagen reaction. The products were converted to N-methyl derivatives in the KOH-acetone system. The electrophilic substitution reactions of the products (acylation, bromination, nitration, sulfonation, hydroxymethylation) were studied.

Full text of DOI:10.1134/S1070427210060194

ISSN 1070-4272, Russian Journal of Applied Chemistry, 2010, Vol. 83, No. 6, pp. 1027–1031. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © E.V. Vlasova, A.A. Aleksandrov, M.M. El’chaninov, 2010, published in Zhurnal Prikladnoi Khimii, 2010, Vol. 83, No. 6, pp. 974–
977.
ORGANIC SYNTHESIS AND INDUSTRIAL
ORGANIC CHEMISTRY
Synthesis and Properties of 1-Methyl-2-phenyl-5-(2-furyl)-
and 1-Methyl-2-phenyl-5-(2-thienyl)imidazoles
E. V. Vlasova, A. A. Aleksandrov, and M. M. El’chaninov
South-Russian State Technical University (Novocherkassk Polytechnic Institute), Novocherkassk, Rostov oblast, Russia
Received June 23, 2009
Abstract—2-Phenyl-5-(2-furyl)- and 2-phenyl-5-(2-thienyl)imidazoles were synthesized by condensation of 2-
furoylmethyl and 2-thenoylmethyl acetates with benzaldehyde under the conditions of Weidenhagen reaction.
The products were converted to N-methyl derivatives in the KOH–acetone system. The electrophilic
substitution reactions of the products (acylation, bromination, nitration, sulfonation, hydroxymethylation) were
studied.
DOI: 10.1134/S1070427210060194
Polycyclic fluorophores are widely used today in
designing fluorescent dyes. For example, derivatives of
naphthoylbenzimidazole [1], oxazole [2], and oxadi-
azole [3] find growing application. The electronic
structure and spectral properties of fused 2-hetaryl-
imidazoles were studied previously [4].
reactions of these compounds, performed to prepare
potential luminophores.
4(5)-(2'-furyl)imidazole was prepared previously
from furoyl chloride, diazomethane, and potassium
acetate, with the subsequent condensation of the
resulting 2-furoylmethyl acetate with formalin under
the conditions of Weidenhagen reaction [5]. We were
able to synthesize compounds VII and VIII by the
similar reaction but without using dangerously
explosive diazomethane:
This paper deals with the synthesis of 2-phenyl-
4(5)-(2'-furyl)imidazole VII and 2-phenyl-4(5)-(2'-thi-
enyl)imidazole VIII and with electrophilic substitution
AcOK
MeOH
CuBr2
(AcO)2Cu·H2O
N
EtOAc/CHCl3
O
O
(1)
O
NH4OH, 25% PhCHO
X
X
X
X
N
H
Br
OAc
I, II
III, IV
V, VI
VII, VIII
X = O (I, III, V, VII), S (II, IV, VI, VIII).
We were able to methylate 2-phenyl-4(5)-(2'-hetaryl)
imidazoles VII and VIII in almost quantitative yield
with an equivalent amount of methyl iodide in the
KOH–acetone system [6], which, in contrast to the
reaction in alcoholic alkaline solutions, considerably
accelerates the reaction and virtually fully excludes
quaternization. Because of the asymmetric structure of
the imidazole anions, two isomers (4- and 5-) were
obtained in each case IX–XII.
N
N
MeI
X
KOH/Me2CO
Ph
(2)
Ph
X
N
N
H
Me
N
VII, VIII
IX, X
+
Ph
N
X
Me
XI, XII
1
According to the H NMR spectrum, the isomer
X = O (VII, IX, XI), S (VIII, X, XII).
ratio in the mixture is 1 : 2, with isomers XI and XII pre-
1027

1028
VLASOVA et al.
vailing. By fractional crystallization, previously un-
known imidazoles XI and XII were isolated in the spectro-
scopically pure form and were subjected to the action
of electrophilic agents [carboxylic acids in polyphos-
phoric acid (PPA), acetyl nitrate, mixtures of sulfuric
and polyphosphoric acids, hexamethylenediamine and poly-
phosphoric acid, formalin in the presence of catalytic
amounts of HCl, bromine in dichloroethane (DCE)]:
RCOOH
(CH2)6N4
R2
H2SO4 + PPA
N
N
N
(3)
PPA
CH2O/HCl
Br2/DCE
R
Ph
Ph
Ph
N
X
N
R1
X
N
Xu(NO3)2/(MeCO)2O
X
Me
Me
Me
XXI−XXVI
XI, XII
XIII−XX
X = O, R = CH (XIII), COMe (XIV), COPh (XV), CH2OH (XVI); X = S, R = CHO (XVII), COMe (XVIII), COPh (XIX),
CH2OH (XX); X = O, R1 = Br, R2 = H (XXI), R1 = NO2, R2 = H (XXII), X = S, R1 = SO3H, R2 = H (XXIII), R1 = Br, R2 = H
(XXIV), R1 = H, R2 = Br (XXV), R1 = NO2, R2 = H (XXVI).
Compounds XI and XII readily react with car-
boxylic acids and hexamethylenetetramine in poly-
phosphoric acid to form derivatives with 5'-formyl or
5'-acyl substituents in the hetaryl ring (XIII–XV,
XVII–XIX). Alcoholic solutions of these compounds
show strong fluorescence under UV irradiation, which
gives grounds to believe that these compounds exhibit
photoluminescence properties. Hydroxymethylation of
XI and XII in boiling formalin upon addition of a drop
of concentrated hydrochloric acid occurs fairly
smoothly, in contrast to 2-(2-hetaryl)imidazoles inert
in the process [7]. The reaction gives compounds XVI
and XX in 58 and 64% yields, respectively. These
results indicate that the electron-withdrawing effect
exerted on the hetaryl rings by 5-imidazolyl substituent
is weaker, compared to the previously studied 2-
hetarylimidazoles [7, 8].
Bromination of XI in dichloroethane at 80°C yields
monobromide XXIV, whereas for the thiophene
analog XII it is not so selective and yields, according
to 1H NMR spectrum, a mixture of monobromo
derivatives XXIV and XXV. Unfortunately, we failed
to separate these isomers because of their similar
chromatographic mobility. However, their identifica-
1
tion in the H NMR spectra involves no problems,
because each isomer has certain specific features. In
addition, for more accurate signal assignment, we
prepared compounds XXIV and XXV by independent
synthesis following scheme (1) from 5-bromo-2-
acetylfuran or -thiophene.
Nitration of 1-methyl-2-phenyl-5-(2-furyl)imida-
zole XI and 1-methyl-2-phenyl-5-(2-thienyl)imidazole
XII with acetyl nitrate at 0–10°C is accompanied by
the formation of an intractable mixture of nitro
derivatives. With the aim to perform a selective
reaction under mild conditions, we used the procedure
reported previously [9] for nitration of 2-thiophene-
carbaldehyde with a complex of copper nitrate and
acetic anhydride. The most favorable conditions for the
mononitration were found at the molar ratio of XI or
XII and nitrating agent of 1 : 1.2. As a result, we
obtained 5'-nitro derivatives XXII and XXVI.
It is known that furan, because of its acidophobic
properties, is best sulfonated with such a mild agent as
adduct of sulfuric anhydride with pyridine. Taking this
fact into account, we first attempted to apply this
method to hetarylimidazoles XI and XII. We found
that sulfonation with pyridine–sulfur trioxide in
refluxing dichloroethane did not give positive results.
Therefore, these compounds were sulfonated with
sulfuric acid (d = 1.84) in PPA at 80–100°C. We failed
to isolate and identify the sulfonic acid derived from 5-
(2-furyl)imidazole XI because of its very high
solubility in water. Sulfonic acid XXIII was isolated in
86% yield. It apparently exists in the betaine form, as
indicated by the absence of the sulfonic acid proton
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian
Unity-300 spectrometer (300 MHz), with the residual
protons of the deuterated solvent (CDCl3 7.26 ppm and
DMSO-d6 2.45 ppm) and TMS as internal references.
Elemental analysis was performed with a Perkin–
Elmer 2400 analyzer. The melting point was
1
signal in the H NMR spectrum recorded in DMSO-d6
and by the presence of such signal in the spectrum
recorded in trifluoroacetic acid.
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SYNTHESIS AND PROPERTIES OF 1-METHYL-2-PHENYL-5-(2-FURYL)-...
Yield and properties of compounds IX–XXVI
1029
Yield,
%
mp, °C
Formulaa
1H NMR spectrum, δ, ppm (J, Hz)
IX
X
25
28
62
52–60 C14H12N2O
42–43 C14H12N2S
40–41 C14H12N2O
3.77 s (3H, CH3), 6.42-6.44 m (1H, H-4'), 6.49 d (1H, H-3', J 3.3), 7.26 s (1H,
imide), 7.35 d (1H, H-5', J 1.8), 7.41–7.46 m (3H, arom.), 7.62 d (2H, arom., J 7.7)
3.74 s (3H, CH3), 7.01–7.05 m (1H, H-4'), 7.18 s (1H, imide), 7.24 d (1H, H-3',
J 4.0), 7.30 d (1H, H-5', J 5.0), 7.41–7.46 m (3H, arom.), 7.62 d (2H, arom., J 7.7)
XI
3.71 s (3H, CH3), 6.42-6.44 m (1H, H-4'), 6.67 d (1H, H-3', J 3.3), 7.18 s (1H,
imide), 7.37 d (1H, H-5', J 1.8), 7.41–7.46 m (3H, arom.), 7.62 d (2H, arom.,
J 7.7)
XII
56
55–56 C14H12N2S
3.73 s (3H, CH3), 7.01–7.05 m (1H, H-4'), 7.18 s (1H, imide), 7.26 d (1H, H-3',
J 3.9), 7.32 d (1H, H-5', J 4.9), 7.41–7.46 m (3H, arom.), 7.66 d (2H, arom., J 7.8)
XIII
XIV
XV
41 120–121 C15H12N2O2
35 130–132 C16H14N2O2
58 115–117 C21H16N2O2
3.93 s (3H, CH3), 6.72 d (1H, H-3', J 3.6), 7.35 d (1H, H-4', J 4.6), 3.72 s (1H,
imide), 7.50–7.56 m (3H, arom.), 7.68 d (2H, arom., J 7.2), 9.65 s (1H, CHO)
2.52 s (3H, CH3), 3.78 s (3H, NCH3), 6.85 d (1H, H-3', J 3.6), 7.45 d (1H, H-4',
J 3.6), 7.30 s (1H, imide), 7.47 t (3H, arom., J 7.1), 7.64 d (2H, arom., J 7.2)
3.93 s (3H, CH3), 6.71 d (1H, H-3',J 3.7), 7.33 d (1H, H-4', J 3.7), 7.47 s (1H, imide)
7.48–7.54 m (3H, arom.),7.64 d (2H, arom., J 7.2), 7.64–7.67 m (3H, arom.), 7.97 d
(2H, arom., J 7.2)
XVI
44 143–144 C15H14N2O2
2.18c (1H, OH), 3.74c (3H, CH3), 4.73c (2H, CH2), 6.50 d (1H, H-4', J 3.5), 6.70 d
(1H, H-3',J 3.5), 7.22 s (1H, imide), 7.42–7.45 m (3H, arom.), 7.63 d (2H, arom.,
J 7.8)
XVII 57
XVIII 45
79–80 C15H12N2OS 3.78 s (3H, CH3), 7.35 s (1H, imide), 7.44 d (1H, H-3', J 4.0), 7.49 t (3H, arom.,
J 6.70), 7.66 d (2H, arom., J 7.2), 7.70 d (1H, H-4', J 4.0), 9.86 s (1H, CHO)
86–87 C16H14N2OS 2.55 s (3H, CH3), 7.30c (1H, imide), 7.36 d (1H, H-3', J 4.0), 7.47 t (3H, arom.,
J 7.0), 7.64 d (2H, arom., J 7.2), 7.66 d (1H, H-4', J 4.0)
XIX
XX
64 123–124 C21H16N2OS 3.77 s (3H, CH3), 7.34 s (1H, imide), 7.41 d (1H, H-3', J 4.0), 7.49 t (4H, arom.,
J 6.7), 7.50 d (1H, arom., J 7.2), 7.56 d (1H, arom., J 7.2), 7.61 d (1H, H-4', J 4.0)
7.66 d (2H, arom., J 7.7), 7.87 d (2H, arom., J 7.0)
77 157–158 C15H14N2OS 2.20 s (1H,OH), 3.74 s (3H, CH3), 4.90 s (2H, CH2), 7.30 s (1H, imide), 7.32 d (1H,
H-4', J 3.9), 7.34 d (1H, H-3', J 3.9), 7.45 t (3H, arom., J 7.0), 7.63 d (2H, arom.,
J 7.2)
XXI
56 112–113 C14H11BrN2O 3.75 s (3H, CH3), 6.40 d (1H, H-4', J 3.5), 6.65 d (1H, H-3', J 3.5), 7.18 s (1H,
imide), 7.42–7.45 m (3H, arom.), 7.63 d (2H, arom., J 7.7)
XXII 20
91–93 C14H11N3O3
3.80 s (3H, CH3), 6.92 d (1H, H-3', J 3.8), 7.42 d (1H, H-4', J 3.8), 7.48–7.51 m (3H,
arom.), 7.47 s (1H, imide), 7.64 d (2H, arom., J 7.7)
XXIII 75 307–308 C14H12N2O3S2 3.82 s (3H, CH3), 7.15 d (1H, H-3', J 3.7), 7.35 d (1H, H-4', J 3.7), 7.67 t (3H, arom.,
J 7.0), 7.83 d (2H, arom., J 7.8), 8.12 s (1H, imide)
XIV
33
89–90 C14H11BrN2S 3.74 s (3H, CH3), 7.30 s (1H, imide.), 7.15 d (1H, H-4', J 4.0), 7.35 d (1H, H-3',
J 4.0), 7.48 t (3H, arom., J 6.9), 7.63 d (2H, arom., J 7.2)
XV
31
95–97 C14H11BrN2S 3.76 s (3H, CH3), 7.05 d (1H, H-5', J 1.3), 7.28 d (1H, H-3', J 1.3), 7.32 s (1H,
imide), 7.49 t (3H, arom., J 6.9), 7.63 d (2H, arom., J 7.2)
XVI
66 132–133 C14H11BrN3O2S 3.69 s (3H, CH3), 7.31 d (1H, H-3', J 4.2), 7.48–7.51 m (3H, arom.), 7.68 s (1H,
imide), 7.70 (2H, arom., J 7.7), 8.01 d (1H, H-4', J 4.2)
a
The results of elemental analysis for the C, H, and N content agree with the calculated values within ±0.34%. The 1H NMR spectrum of
XXIII was recorded in DMSO-d6.
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VLASOVA et al.
determined by the capillary method with a PTP device.
The yield and properties of the compounds are given in
the table.
XII and 1.4 g (0.01 mol) of hexamethylenetetramine in
15 g of polyphosphoric acid was stirred at 70–80°C for
1–3 h. Then the mixture was diluted with 50 ml of
water. The reaction product was isolated in the same
way as acyl derivatives XIV and XV.
2-Phenyl-4(5)-(2'-hetaryl)imidazoles VII and VIII.
To a solution of 6.86 g (0.07 mol) of potassium acetate
in 100 ml of methanol, we added 0.05 mol of 2-
bromoacetylfuran (-thiophene) III or IV. The mixture
was refluxed for 2 h under stirring with a magnetic
stirrer. The KBr precipitate was filtered off, and the
filtrate was added to a solution containing 100 g
(0.5 mol) of copper acetate in 1200 ml of 25%
ammonia solution and 5.3 g (0.05 mol) of benzal-
dehyde. The mixture was refluxed for 1.5 h, after
which the copper salt was separated, suspended in
100 ml of water, and decomposed by passing hydrogen
sulfide for 0.5 h. The resulting solution was acidified
with concentrated HCl, and CuS was separated. Then
the filtrate was alkalized with 25% ammonia solution.
The precipitate of VII and VIII was filtered off and
crystallized from alcohol; mp 160–162°C (VII), 173–
175°C (VIII).
1-Methyl-2-phenyl-5-(5'-hydroxymethyl-2'-het-
aryl)imidazoles XVI–XX. To a mixture of 0.005 mol
of XI or XII with 70 ml of formalin, we added a drop
of concentrated HCl and refluxed for 2 h. Then the
mixture was poured into 100 ml of cold water and
neutralized with a 25% NH4OH solution to pH 7–8.
The precipitate was filtered off and thoroughly washed
with cold water. The product was crystallized from
alcohol.
1-Methyl-2-phenyl-5-(5'-sulfo-2'-thienyl)imidazole
XXIII. A mixture of 1.2 g (0.005 mol) of XII, 0.98 g
(0.01 mol) of sulfuric acid (d = 1.84), and 20 g of
polyphosphoric acid was heated at 100–110°C for 2 h.
Then the mixture was cooled and diluted with 50 ml of
water, and the precipitate of sulfonic acid XXIII was
filtered off. The product was crystallized from water.
1-Methyl-2-phenyl-4(5)-(2'-hetaryl)imidazoles
IX–XII. Isomer mixture. To a mixture of 0.01 mol of
VII or VIII, 0.62 g (0.011 mol) of powdered KOH,
and 10 ml of acetone, we added dropwise with
vigorous stirring at 3–5°C 0.68 g (0.011 mol) of
methyl iodide, avoiding warm-up of the reaction
mixture over 8°C. The mixture was stirred at this
temperature for 1 h and poured into 100 ml of water,
and the precipitated product was filtered off. By
fractional crystallization from hexane we isolated and
identified compounds XI and XII. Compounds IX and
X were not isolated pure.
1-Methyl-2-phenyl-5-(5'-bromo-2'-furyl)imidazole
XXI. To a stirred solution of 1.12 g (0.005 mol) of XI
in 10 ml of dichloroethane, we added dropwise at 0°C
1.6 g (0.01 mol) of bromine. The mixture was stirred
for 0.5 h at 0°C and poured into 25 ml of a 25%
ammonia solution. The organic layer was washed with
water (2 × 25 ml), dried for 10 min over anhydrous
sodium sulfate, and chromatographed on a column (h =
20 cm, d = 2.5 cm) packed with 70 ml of aluminum
oxide (eluent chloroform).
1-Methyl-2-phenyl-5-[4'(5')-bromo-2'-thienyl]-
imidazoles XXIV and XXV. Isomer mixture. To a
solution of 1.12 g (0.005 mol) of XII in 20 ml of
dichloroethane, we gradually added at room tempera-
ture a solution of 0.8 g (0.005 mol) of bromine in
10 ml of dichloroethane. After adding the whole
amount of bromine, the mixture was refluxed for
30 min. The precipitate of hydrobromides XXIV and
XXV was separated, converted to the base by
treatment with an ammonia solution, and chromato-
graphed as in the previous experiment.
1-Methyl-2-phenyl-5-(5'-acyl-2'-hetaryl)imida-
zoles XIV, XV, XVIII, and XIX. General procedure.
A mixture of 0.005 mol of XI or XII and 0.01–
0.015 mol of appropriate acylating agent (acetic acid,
benzoic acid) in 10 g of polyphosphoric acid was
stirred for 2–4 h at 90–100°C. Then the mixture was
cooled by dilution with 50 ml of cold water and
carefully neutralized with a 25% NH4OH solution. The
precipitated product was extracted with methylene
chloride (3 × 15 ml), the extract was dried over CaCl2,
the solvent was evaporated, and the residue was passed
through a column packed with alumina, 15 cm long
and 1 cm in diameter. The eluent was methylene
chloride.
1-Methyl-2-phenyl-5-(5'-nitro-2'-hetaryl)imidazoles
XXII–XXVI. To prepare the nitrating mixture, a
100-ml Erlenmeyer flask was charged with 16.5 g
(0.07 mol) of Cu(NO3)2·3H2O, and 40 ml of acetic
anhydride was added in small portions with strong
cooling, avoiding warm-up of the mixture over 30–40°C.
After the exothermic reaction was complete, the
1-Methyl-2-phenyl-5-(5'-formyl-2'-hetaryl)imida-
zoles XIII and XVII. A mixture of 0.005 mol of XI or
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SYNTHESIS AND PROPERTIES OF 1-METHYL-2-PHENYL-5-(2-FURYL)-...
1031
mixture was allowed to stand at room temperature for
24 h, after which the copper(II) acetate precipitate was
filtered off. The resulting mixture was stored for no
more than 10 days at 5–10°C.
(3) Electrophilic substitution in 1-methyl-2-phenyl-
5-(2'-hetaryl)imidazole molecules occurs exclusively
in the hetaryl ring.
REFERENCES
To a solution of 0.005 mol of XI and XII in 5 ml of
freshly distilled acetic anhydride, 1.4 ml of the
nitrating mixture was added in small portions with
vigorous stirring at room temperature. The reaction
time was 30–40 min. Then 25 ml of cold water was
added, and the mixture was neutralized with a 25%
ammonia solution. The precipitate was filtered off,
thoroughly washed with water, and chromatographed
on a column packed with aluminum oxide (eluent
methylene chloride). The product was crystallized
from alcohol.
1. Krasovitskii, B.M., Pereyaslava, D.G., and Yushko, E.T.,
in Monokristally, stsintillyatory
i
organicheskie
lyuminofory (Single Crystals, Scintillators, and Organic
Luminophores), Kharkov: Vses. Nauchno-Issled. Inst.
Monokristallov, Stsintillyatsionnykh Materialov
i
Osobo Chistykh Khimicheskikh Veshchestv, 1968,
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tivnaya khimiya lyuminoforov (Preparative Chemistry of
Luminophores), Kharkov: Folio, 1997, p. 206.
CONCLUSIONS
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1962, vol. 17, pp. 173–179.
6. Kirugava, Y., Synthesis, 1981, no. 2, pp. 124–127.
(1) A procedure was developed for preparing 2-
phenyl-4(5)-(2'-hetaryl)imidazoles by condensation of
2-furoylmethyl and 2-thenoylmethyl acetates with
benzaldehyde under the conditions of Weidenhagen
reaction without using dangerously explosive
diazomethane.
7. Stoyanov, V.M., El’chaninov, M.M., and Pozharskii, A.F.,
Khim. Geterotsikl. Soedin., 1991, no. 10, pp. 1414–1418.
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and Pozharskii, A.F., Khim. Geterotsikl. Soedin., 1989,
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Soedin., 1968, no. 2, pp. 369–370.
(2) The 1-methyl-2-phenyl-5-(2'-furyl)imidazoles
and 1-methyl-2-phenyl-5-(2'-thienyl)imidazoles studied,
in contrast to the related 1-methyl-2-(2'-hetaryl)-
imidazoles, are more reactive toward electrophilic agents.
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 83 No. 6 2010