Synthesis and properties of 2,5-bis(furan-2-yl)-1H-imidazole

Article abstract of DOI:10.1134/S1070363217020141

2,5-Bis(furan-2-yl)-1H-imidazole was synthesized by the Weidenhagen reaction of [2-(furan-2-yl)-2-oxoethyl]acetate with furfural. Alkylation of the title compound with methyl iodide in acetone in the presence of potassium hydroxide gave a mixture of isome

Full text of DOI:10.1134/S1070363217020141

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ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 2, pp. 239–243. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © M.M. El’chaninov, E.V. Vlasova, I.M. El’chaninov, 2017, published in Zhurnal Obshchei Khimii, 2017, Vol. 87, No. 2, pp. 263–267.
Synthesis and Properties of 2,5-Bis(furan-2-yl)-1H-imidazole
M. M. El’chaninov*, E. V. Vlasova, and I. M. El’chaninov
Platov South-Russian State Polytechnic University, pr. Prosveshcheniya 132, Novocherkassk, 346428 Russia
*e-mail: elchaninov-43@mail.ru
Received October 6, 2016
Abstract—2,5-Bis(furan-2-yl)-1H-imidazole was synthesized by the Weidenhagen reaction of [2-(furan-2-yl)-
2-oxoethyl]acetate with furfural. Alkylation of the title compound with methyl iodide in acetone in the presence
of potassium hydroxide gave a mixture of isomeric N-methyl derivatives, 2,5-bis(furan-2-yl)-1-methyl-1H-
imidazole being the major one. Electrophilic substitution reactions of the latter (nitration, bromination,
sulfonation, hydroxymethylation, and acylation) were studied.
Keywords: [2-(furan-2-yl)-2-oxoethyl]acetate, furfural, methyl iodide, alkylation, 2,5-bis(furan-2-yl)-1-methyl-
1H-imidazole
DOI: 10.1134/S1070363217020141
Compounds containing two or more heterocyclic
fragments attract great attention due to specificity of
their structure and mutual effects of these fragments on
the reactivity. Of particular interest are derivatives of
previously unknown 2,5-bis(furan-2-yl)imidazole. The
presence of three pharmacophoric heterocyclic
fragments in its molecule is expected to endow it with
diverse biological activity.
acetone in the presence of potassium hydroxide accord-
ing to the procedure described in [2] quantitatively
afforded a mixture of isomeric 2,5-, and 2,4-bis(furan-
2-yl)-1-methyl-1H-imidazoles 2 and 3 (Scheme 2). As
we showed previously [3], methylation of 4(5)-(furan-
2-yl)-1H-imidazole gives 4-(furan-2-yl)-1-methyl-1H-
imidazole as a minor product, while the major product
is 5-(furan-2-yl)-1-methyl-1H-imidazole; according to
the 1H NMR data, the isomer ratio was 1:2.
In this work we studied methods of synthesis of 2,5-
bis(furan-2-yl)-1H-imidazole (1) and its reactions with
some electrophiles, which could lead to potential
luminophores. Schubert et al. [1] synthesized 2,4(5)-
bis(furan-2-yl)-1H-imidazole (1) by reaction of furoyl
chloride with diazo ketone and potassium acetate,
followed by condensation of the [2-(furan-2-yl)-2-oxo-
ethyl]acetate thus obtained with formaldehyde accord-
ing to Weidenhagen. We succeeded in synthesizing com-
pound 1 in a similar way but without using explosive
diazo ketone (Scheme 1).
1
In our case, the H NMR spectrum of the isolated
product contained only traces of 3. Protons of the furan
ring in position 2 of the imidazole ring displayed a
larger paramagnetic shift than those of the furan ring in
the 5-position. This suggests stronger conjugation of
the 2-furyl substituent with the imidazole C=N bond;
therefore, the furan ring in position 5 of the imidazole
ring in 2 should be expected to be more reactive
toward electrophiles. In fact, the further transforma-
tions of 2 confirmed this assumption. 2,5-Bis(furan-2-
yl)-1-methyl-1H-imidazole (2) was isolated by frac-
tional crystallization and brought into reactions with
such electrophiles as acetyl nitrate, bromine in 1,2-
The alkylation of 2,4(5)-bis(furan-2-yl)-1H-imida-
zole (1) with an equimolar amount of methyl iodide in
Scheme 1.
O
N
N
(AcO)2Cu_H2O
NH4OH, 25%
furfural
O
O
O
OAc
H
1
239

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240
EL’CHANINOV et al.
Scheme 2.
N
N
N
MeI
O
Fu
Fu
+ Fu
KOH_Me2CO
O
N
N
N
O
H
Me
Me
2
3
1
Scheme 3.
N
N
N
HNO3
Ac2O
Cu(NO3)2
Ac2O
N
N
N
O
O
O
O
O
O2N
NO2
Me
Me
Me
4
2
2a
Scheme 4.
3'
3
N
4
5
4'
5'
N
O
O
DMF_POCl3
Br2, 1,2-dichloroethane
CH2O, C5H5N, _SO3
Me
2
N
RCOOH_polyphosphoric
acid
N
Fu
N
R1
O
O
R1
R2
N
O
Me
2b_2d
Me
O
2e_2g
R1 = R2 = Br (b); R1 = H, R2 = SO3H (c); R1 = Н, R2 = CH2OH (d), H (e), Me (f), Ph (g).
dichloroetane, a mixture of sulfuric and polyphos-
phoric acids, formaldehyde, Vilsmeier reagent, and
carboxylic acids in polyphosphoric acid (PPA).
2b in 48% yield. Pyridine–sulfur trioxide is known as
a mild sulfonating agent ensuring best results in the
sulfonation of acidophobic furan ring. The sulfonation
of 2 with pyridine sulfur trioxide in boiling 1,2-
dichloroethane afforded 37% of sulfonic acid 2c. The
sulfonation selectively involved the furan ring in posi-
tion 5 of imidazole (Scheme 4).
The nitration of 2 with a mixture of fuming nitric
aid and acetic anhydride at 0°C unexpectedly afforded 2-
(5-nitrofuran-2-yl)-1-methyl-1H-imidazole 4 (Scheme 3).
Presumably, the reactions involved complete oxidative
decomposition of the furan ring on C5, and that on C2
underwent nitration. We succeeded in performing
selective nitration of 2 according to the procedure
described in [4] for the nitration of thiophenes with the
copper(II) nitrate–acetic anhydride complex at 0°C. In
this case, nitro group entered the furan ring on C5,
while the other furan ring in molecule 2 remained
intact. The yield of 2-(furan-2-yl)-1-methyl-5-(5-nitro-
furan-2-yl)-1H-imidazole (2a) was ~49%.
Formaldehyde is a weak electrophile; however,
Stoyanov [5] described hydroxymethylation of 2-(furan-
2-yl)imidazole at the 5-position of the furan ring. The
reaction was very slow, and the yield was as low as
11% after refluxing for 16 h. Under analogous condi-
tions, compound 2 was converted to hydroxymethyl
derivative 2d at the furan ring in the 5-position of
imidazole (yield 49%; Scheme 4).
Stoyanov et al. [6] reported the reaction of 2-(furan-
2-yl)imidazole with Vilsmeier reagent at 95°C, which
produced the corresponding furancarbaldehyde in a
poor yield, and about 50% of the initial compound was
The bromination of 2 in chloroform at –10 to –15°C
resulted in introduction of bromine into position 5 of
both furan rings with formation of dibromo derivative
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241
SYNTHESIS AND PROPERTIES OF 2,5-BIS(FURAN-2-YL)-1H-IMIDAZOLE
Table 1. Yields, melting points, and elemental analyses of compounds 1–4
Founda, %
Calculated, %
Comp. Yield,
mp, °С
Formula
no.
%
76
68
49
48
37
49
77
52
43
60
С
Н
N
C
H
N
144–146
113–115
188–190
136–138
350–352
207–209
129–131
154–156
169–171
152–154
65.77
67.56
59.54
49.57
49.32
63.66
64.15
65.89
71.40
50.09
3.92
4.88
3.87
2.32
3.22
5.21
4.27
4.55
4.22
3.77
14.33
13.27
17.13
17.55
9.80
С11Н8N2O2
С12Н10N2О2
С12Н9N3О3
С12Н8Br2N2O2
С12Н10N2О5S
С13Н12N2O3
С13Н10N2O3
С14Н12N2O3
С19Н14N2О3
С8Н7N3O3
60.00
67.28
59.26
49.36
48.98
63.93
64.46
65.62
71.69
49.75
4.03
4.71
3.73
2.55
3.43
4.95
4.16
4.72
4.43
3.65
14.00
13.08
17.28
17.71
9.52
1
2
2а
2b
2c
2d
2e
2f
2g
4b
11.55
11.88
11.17
9.13
11.47
11.56
10.93
8.80
22.03
21.75
a
The results were consistent with the calculated values within ±0.34%.
mp 153–154°C [6].
b
recovered from the reaction mixture. Presumably, hyd-
rogen chloride liberated during the process reacts with
the initial imidazole to give imidazolium salt which is
inert toward electrophiles. Compound 2 reacted with
DMF–POCl3 much more readily, and the only product
was aldehyde 2e (yield 77%; Scheme 4). Like 2-(2-
hetaryl)imidazoles, the acylation of 2 according to
Gardner [7] with carboxylic acids or anhydrides in
polyphosphoric acid occurred under considerably
milder conditions (70–80°C). For example, the
acetylation of 2-(2-hetaryl)imidazoles required heating
to 110–120°C, and benzoylation, to 140–160°C. The
acetylation of 2 with acetic acid afforded 52% of 5-(5-
acetylfuran-2-yl) derivative 2f, and 5-(5-benzoylfuran-
2-yl)-2-(furan-2-yl)-1-methyl-1H-imidazole (2g) was
isolated in the reaction of 2 with benzoic acid in PPA
(Scheme 4).
The IR spectra were recorded on a Specord 75IR
spectrometer from samples dispersed in mineral oil.
The 1H NMR spectra were measured on a Varian Unity
300 instrument at 300 MHz using CDCl3 as solvent
and tetramethylsilane as internal standard. The progress
of reactions was monitored by TLC on Al2O3 plates
(Brockmann activity grade II) using methylene
chloride or chloroform as eluent; spots were visualized
by treatment with iodine vapor. The elemental analyses
were obtained with a Perkin Elmer 2400 analyzer. The
melting points were measured in capillaries with a PTP
melting point apparatus.
2,5-Bis(furan-2-yl)imidazole (1). 2-Bromo-1-(furan-
2-yl)ethanone, 8.85 g (0.05 mol), was added to a
solution of 6.86 g (0.07 mol) of potassium acetate in
100 mL of methanol, and the mixture was refluxed for
2 h under vigorous stirring. The precipitate of
potassium bromide was filtered off, and the filtrate was
added to a solution of 100 g (0.5 mol) of copper(II)
acetate in 1200 mL of 25% aqueous ammonia
containing 4.8 g (0.05 mol) of furfural. The mixture
was refluxed for 1.5 h, the copper salt was filtered off
and dispersed in 100 mL of water, and a stream of
hydrogen sulfide was passed through the suspension
over a period of 0.5 h. The resulting solution was
acidified with concentrated aqueous HCl, copper(II)
sulfide was filtered off, and the filtrate was made
alkaline by adding 25% aqueous ammonia. The
precipitate of 1 was filtered off and recrystallized from
alcohol. Yield 7.6 g, off-white crystals.
The structure of all newly synthesized compounds
1
was confirmed by IR and H NMR spectra and ele-
mental analyses (Tables 1, 2).
Thus, 2,5-bis(furan-2-yl)-1-methyl-1H-imidazole (2)
reacts with electrophiles to give mainly derivatives at
the furan ring in position 5 of the imidazole ring,
which is likely to be determined by stronger deactiva-
tion of the furan ring in position 2 due to conjugation
with the C=N bond of imidazole.
EXPERIMENTAL
The spectral studies were performed using the
facilities of the Joint Center at the Platov South-
Russian State Polytechnic University.
2,5-Bis(furan-2-yl)-1-methyl-1H-imidazole (2).
Methyl iodide, 5.68 g (0.04 mol), was added dropwise
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242
EL’CHANINOV et al.
Table 2. IR and 1H NMR spectra of compounds 1–4
Comp. IR spectrum,
no.
1H NMR spectrum,a δ, ppm (J, Hz)
ν, cm–1
1
–
6.43–6.45 m (1H, 4′-H), 6.48–6.50 m (1H, 4″-H), 6.58 d (1H, 3′-H, J = 3.3), 6.80 d (1H, 3″-H,
J = 3.6), 7.12 s (1H, 4-H), 7.34 d (1H, 5′-H, J = 1.2), 7.48 d (1H, 5″-H, J = 1.8)
2
–
3.69 s (3H, NCH3), 6.42–6.44 m (1H, 4′-H), 6.47– 6.49 m (1H, 4″-H), 6.60 d (1H, 3′-H, J = 3.2),
6.81 d (1H, 3″-H, J = 3.6), 7.10 s (1H, 4-H), 7.36 d (1H, 5′-H, J = 0.8), 7.46 d (1H, 5″-H, J = 1.8)
2a 1542 [νas(NO2)], 3.87 s (3H, NCH3), 6.56–6.58 m (1H, 4″-H), 6.75 d (1H, 3′-H, J = 3.4), 6.85 d (1H, 3″-H, J = 3.2),
1386 [νs(NO2)]
7.28 s (1H, 4-H), 7.37 d (1H, 4′-H, J = 3.4), 7.58 d (1H, 5″-H, J = 1.8)
2b
–
3.75 s (3H, NCH3), 6.30 d (1H, 4′-H, J = 3.8), 6.39 d (1H, 4″-H, J = 3.6), 6.65 d (1H, 3′-H, J =
3.8), 6.86 d (1H, 3″-H, J = 3.6), 7.15 s (1H, 4-H)
2cb 1280 (SO2)
3.82 s (3H, NCH3), 6.52–6.54 d (1H, 4″-H), 6.61 d (1H, 4′-H, J = 3.3 Hz), 6.65 d (1H, 3′-H, J =
3.3 Hz), 6.84 d (1H, 3″-H, J = 3.8 Hz), 7.13 s (1H, 4-H), 7.50 d (1H, 5″-H, J = 0.8 Hz), 12.08 s
(1H, SO3H)
2d 1138 (OH)
3.70 s (3H, NCH3), 4.28 s (1H, OH), 5.07 s (2H, CH2), 6.45 d (1H, 4′-H, J = 3.5), 6.52–6.54 m
(1H, 4″-H), 6.55 d (1H, 3′-H, J = 3.5), 6.88 d (1H, 3″-H, J = 3.2), 7.10 s (1H, 4-H), 7.53 d (1H,
5″-H, J = 1.8)
2e 1666 (C=O)
2f 1648 (C=O)
2g 1685 (C=O)
3.84 s (3H, NCH3), 6.51–6.53 m (1H, 4″-H), 6.78 d (1H, 3′-H, J = 3.5), 6.84 d (1H, 3″-H, J =
3.2), 7.10 s (1H, 4-H), 7.18 d (1H, 4′-H, J = 3.5), 7.50 d (1H, 5″-H, J = 0.8), 9.51 s (1H, CHO)
2.55 s (3H, CH3), 3.84 s (3H, NCH3), 6.48–6.51 m (1H, 4″-H), 6.75 d (1H, 3′-H, J = 3.5), 6.82 d
(1H, 3″-H, J = 3.6), 7.12 s (1H, 4-H), 7.22 d (1H, 4′-H, J = 3.5), 7.48 d (1H, 5″-H, J = 1.8)
3.78 s (3H, NCH3), 6.51–6.53 m (1H, 4″-H), 6.72 d (1H, 3′-H, J = 3.2), 6.80 d (1H, 3″-H, J =
3.6), 7.15 s (1H, 4-H), 7.20 d (1H, 4′-H, J = 3.2), 7.50 d (1H, 5″-H, J = 1.8), 7.50–7.52 m (3H,
m-H, p-H), 7.92 d (2H, o-H, J = 7.2)
4
1540 [νas(NO2)], 4.03 s (3H, NCH3), 7.03 s (1H, 4-H), 7.08 d (1H, 3′-H, J = 3.4), 7.03 s (1H, 5-H), 7.43 d (1H,
1380 [νs(NO2)] 4′-H, J = 3.4)
a
Primed locants refer to the furan ring on C5, and double-primed, to the furan ring on C2.
The 1H NMR spectrum was recorded in trifluoroacetic acid.
b
with vigorous stirring to a cold (3–5°C) mixture of 7.6 g
(0.038 mol) of compound 1, 2.24 g (0.04 mol) of
powdered potassium hydroxide, and 40 mL of acetone,
maintaining the temperature no higher than 8°C. The
mixture was kept for 1 h at that temperature and
poured into 300 mL of water. The product was filtered
off, dried, and subjected to fractional crystallization
from hexane. Yield 5.82 g, white crystals.
5 mL of freshly distilled acetic anhydride, and 0.56 mL
of the nitrating mixture was added in portions at room
temperature. The reaction time was 30–40 min. The
mixture was then treated with 15 mL of cold water and
neutralized with 25% aqueous ammonia. The pre-
cipitate was filtered off, thoroughly washed with water,
and purified by column chromatography on aluminum
oxide using methylene chloride as eluent. The product
was additionally recrystallized from ethanol. Yield
0.12 g, yellow crystals.
2-(Furan-2-yl)-1-methyl-5-(5-nitrofuran-2-yl)-1H-
imidazole (2a). 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 efficient cooling so that the temperature
did not exceed 30–40°C. When the exothermic
reaction ceased, the mixture was left to stand for 24 h
at room temperature, and the precipitate of copper(II)
acetate was filtered off. The filtrate (nitrating mixture)
was stored in a refrigerator for no longer than 10 days
[4]. Compound 2, 0.21 g (1 mmol), was dissolved in
1-Methyl-2-(5-nitrofuran-2-yl)-1H-imidazole (4).
A solution of 0.42 g (2 mmol) of compound 2 in 5 mL
of freshly distilled acetic anhydride was cooled to 0°C,
0.76 g (12 mmol) of nitric acid (d = 1.5 g/cm3) was
added, and the mixture was stirred for 1 h at room
temperature. The mixture was then poured into 20 mL
of water, neutralized with 25% aqueous ammonia, and
extracted with 10 mL of chloroform. The extract was
dried over anhydrous sodium sulfate, and the product
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 2 2017