Reaction of 5-(2-furyl)-1-methyl-1H- and 1-methyl-5-(2-thienyl)-1H- imidazoles with electrophilic reagents

Article abstract of DOI:10.1007/s10593-011-0819-8

5-(2-Furyl)-1-methyl-1H- and 1-methyl-5-(2-thienyl)-1H-imidazoles were synthesized. The electronwithdrawing effect of the 5- and 2-imidazole substituents on the furan ring was studied by ¹H NMR spectroscopy and quantum-chemical calculations. So

Full text of DOI:10.1007/s10593-011-0819-8

Chemistry of Heterocyclic Compounds, Vol. 47, No. 6, September 2011 (Russian original Vol. 47, No. 6, June, 2011)
REACTION OF 5-(2-FURYL)-1-METHYL-1H-
AND 1-METHYL-5-(2-THIENYL)-1H-IMIDAZOLES
WITH ELECTROPHILIC REAGENTS
E. V. Vlasova1*, A. A. Aleksandrov1, M. M. Elchaninov1,
A. A. Milov2, and B. S. Lukyanov3
5-(2-Furyl)-1-methyl-1H- and 1-methyl-5-(2-thienyl)-1H-imidazoles were synthesized. The electron-
1
withdrawing effect of the 5- and 2-imidazole substituents on the furan ring was studied by H NMR
spectroscopy and quantum-chemical calculations. Some electrophilic substitution reactions were inves-
tigated (nitration, bromination, sulfonation, hydroxymethylation, formylation, and acylation). In some
cases, depending on the reaction conditions, both the furan and thiophene ring and the imidazole frag-
ment undergo electrophilic attack.
Keywords: 1-methyl-5-(2-thienyl)-1H-imidazole, 5-(2-furyl)-1-methyl-1H-imidazole, quantum-chemi-
cal calculations, directing effect of substituents, electrophilic substitution.
The mutual effect of heterocyclic radicals in bihetaryls is an interesting and nevertheless inadequately
studied field from the standpoint both of structure and reactivity. In the light of the foregoing our attention was
attracted to derivatives of 5-(2-furyl)- (1) and 5-(2-thienyl)imidazole (2). On account of the presence of the two
pharmacophoric heterocyclic fragments these compounds can be expected to exhibit various types of biological
activity. In addition, the mutual effect of the heterocycles on each other should be reflected in their reactivity. It
is known that the imidazole ring, which is inert to electrophiles in an acidic medium, enters fairly readily into
N
N
N
N
O
N
S
N
O
Me
Me
Me
1
3
2
_______________
*To whom correspondence should be addressed; e-mail: kipyatilnik@inbox.ru.
1South-Russian State Technical University, 132 Prosveshcheniya St., Novocherkassk 346428, Russia.
2Southern Scientific Center, Russian Academy of Sciences, 41 Chehova St., Rostov-on-Don 344006, Russia;
e-mail: fkoh@novoch.ru.
3Institute of Physical and Organic Chemistry, Southern Federal University, 194/2 Stachki Ave., Rostov-on-Don
344090, Russia; e-mail: bluk@ipoc.rsu.ru.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 829–836, June, 2011. Original
article submitted December 8, 2010.
0009-3122/11/4706-0684©2011 Springer Science+Business Media, Inc.
684
ꢀ

electrophilic substitution under neutral conditions [1]. For this reason, whereas it is not difficult to predict the
direction of electrophilic attack on the furan or thiophene ring in an acidic medium, the situation is more
complicated for neutral conditions.
Methods of synthesis and the products of the methylation of 4(5)-(2-furyl)imidazole were studied earlier
[2]. Here it was possible to isolate the corresponding 5-(2-furyl)-1-methylimidazole (1) and, later, 1-methyl-
5-(2-thienyl)imidazole (2) in chromatographically pure form.
It seemed interesting to investigate the behavior of the undescribed bihetaryls 1 and 2 in certain electro-
philic substitution reactions and to compare them with the chemical characteristics of 2-(2-furyl)-1-methyl-
imidazole 3 [3]. It was shown that the effect of the 2-imidazolyl substituent on five-membered heterocycles with
one heteroatom leads to a general decrease of electron density [4]. At the same time, there is a sharp decrease in
the acidophobic characteristics of these heterocycles, which makes it possible to realize the reaction over a wider
range of conditions, including media with high acidity, elevated temperature, etc. Consequently, in the present
case it would be logical to compare the effect of the 5-imidazolyl radical on the five-membered heterocycles. In
so far as the effect of the 2-imidazolyl group is connected with the conjugation of the hetaryl ring with the C=N
bond of the azole, which is not so in the case of the 5-imidazolyl substituent, it would be reasonable to assume
that mentioned influence is weakened as a result of the conjugation chain elongation.
The calculated data on the charges at the carbon atoms of the furan substituent in the 2-(2-furyl)- and
5-(2-furyl)imidazoles agree with the relative values of the chemical shifts of the corresponding protons in the 1H
NMR spectra (Table 1).
On the basis of the data shown in the table it can be concluded that the deshielding effect of the 5-imid-
azolyl substituent is somewhat lower than in the 2-isomer, and higher reactivity must therefore be expected in
compound 1. In order to confirm this conclusion, 5-(2-furyl)-1-methyl-1H- (1) and 1-methyl-5-(2-thienyl)-1H-
imidazole (2) were investigated in reactions with electrophilic reagents: acetyl nitrate, bromine in dichloro-
ethane, sulfuric acid, urotropine and acetic or benzoic acids in PPA, formalin in an acidic medium, and the
Vilsmeier reagent.
Nitration of the hetarylimidazoles 1 and 2 with nitric acid (d = 1.51 g/cm3) in acetic anhydride or in
PPA, in contrast to compound 3, gives a complex mixture of difficultly separable substances. It was, however,
possible to realize a selective reaction as in the case of thiophenes nitration by the action of a complex of copper
nitrate and acetic anhydride under mild conditions [5]. The optimum ratio of substrate to nitrating agent is 1:1.2
for mononitration and 1:3 for dinitration. It was established that the direction of nitration of the hetarylimida-
zoles 1 and 2 by the copper nitrate–acetic anhydride system differs substantially. In the first case the product of
furan ring mononitration 1a is formed. In the case of compound 2, however, a mixture of compound 2a with
mononitro-substituted thiophene ring and the dinitro derivative 2b substituted both in the thiophene and in the
azole ring is formed. Unfortunately, because of the identical chromatographic mobility, the nitration products 2a
1
and 2b could not be separated. However, it is not difficult to identify them in the H NMR spectrum thanks to
characteristic signals intrinsic for each of the nitro derivatives presence.
TABLE 1. Chemical Shifts of the Protons in the 1H NMR Spectra and the
Charges at the Carbon Atoms of the Furyl Groups in Compounds 1 and 3
Chemical shifts, ꢀ, ppm*
Charges, q*2
ꢂ-4
Compound
ꢁ-3
ꢁ-4
ꢁ-5
ꢂ-3
ꢂ-5
1
3
6.60
6.81
6.43
6.48
7.36
7.46
–0.14
–0.13
–0.15
–0.15
0.14
0.15
_______
*Recorded in CDCl3.
*2Calculated by the B3LYP/6-311G method.
685
ꢀ

Only the furan ring of furylimidazole 3 is brominated in the presence of acids [3]. Under these condi-
tions compound 1 forms a tar, and the hetarylimidazoles 1 and 2 were therefore brominated under neutral
conditions. The first of them is brominated in dichloroethane even at low temperature (from –10 to –15°C) with
the formation of the monobromo derivative 1b. The bromination of compound 2 at 0°C leads to the 4-bromo-
5-(5-bromo-2-thienyl)-1-methylimidazole hydrobromide (2c) with the 70% yield.
As known, thanks to its characteristic acidophobic character, furan is sulfonated best of all with the such
mild reagent as the adduct of sulfur trioxide with pyridine [6]. Taking this into account we first tried to extend
the method to the hetarylimidazoles 1 and 2. It was found that, as also in the case of compound 3, sulfonation
with pyridine–sulfur trioxide does not give a positive result. All compounds were therefore sulfonated with
sulfuric acid (d = 1.84 g/cm3) in PPA at 70–80°C.
R 1
O
O
N
N
N
R
H
R
N
X
N
N
X
X
Me
Me
Me
1ꢀ, 2ꢁ
1d,e, 2f,g
1f, 2h
CH2O,
HCl
DMF,
POCl3
RCOOH,
PPA
or
(CH2)6N4,
PPA
R1
H
3'
2'
4
4'
5'
+
N
N
H2SO4,
PPA
N
Cu(NO3)2, Ac2O
–
SO3
2
5
or
N
S
R
N
X
N
X
Br2, DCE
Me
Me
Me
1a,b, 2a–c
1,2
2d
1 X = O, 1 a R = NO2, R1 = H, b R = Br, R1 = H, d R = Me, e R = Ph, f R = CH2OH, R1 = H; 2 X = S,
2 a R = NO2, R1 = H, b R = NO2, R1 = NO2, c R = Br, R1 = Br, f R = Me, g R = Ph, h R = H, R1 = CH2OH
It was not possible to isolate and identify the sulfonic acid based on the 5-(2-furyl)imidazole 1 since its
very high solubility in water. At the same time the 5'-sulfonic acid (2d), obtained with a yield of 49%, probably
1
exists in the form of an inner salt, since the H NMR spectrum recorded in DMSO-d6 does not contain a signal
for the OH group, which does appear in CF3COOH at 12.28 ppm.
During the Vilsmeier formylation of compound 3 at 95°C, the 5'-formyl derivative is formed with 32%
yield. About 50% of the starting compound is recovered [3]. Compound 1 reacts considerably more readily with
DMF–POCl3. The thiophene analog 2 was inert to the Vilsmeier reagent. However, by using urotropine as
formylating reagent in PPA at 70–80°C we obtained the aldehyde (2e) with 80% yield.
Like compound 3, the hetarylimidazoles 1 and 2 are acylated by carboxylic acids in PPA, but under
significantly milder conditions at 70–80°C. The ketones 1d,e and 2f,g are formed in 40–63% yields.
The hydroxymethylation of compound 3 at position 5 of the furan ring was described in [3]. It takes
place very slowly, and the yield of the hydroxymethyl derivative after boiling (16 h) in formalin solution is only
11%. Under analogous conditions, compounds 1 and 2 react more readily and with high yields. Thus, the
furylimidazole 1 gives the 5-hydroxymethyl derivative 1f in a 53% yield after 4 h, while the thienylimidazole 2
forms the 4-hydroxymethyl derivative 2h in a 85% yield after 5 h. The last result can be explained by the fact
that the reactivity of the imidazole system and of the thiophene ring under neutral conditions is comparable.
Summarizing the data on the electrophilic substitution reactions in the series of 5-(2-hetaryl)imidazoles,
it can be stated that they actually take place more readily than for the previously studied 2-(2-hetaryl)imidazoles.
In acidic media the hetaryl substituent mostly undergoes electrophilic attack. Under neutral conditions, the
reactivity of the imidazole and hetaryl ring becomes comparable, and both the hetaryl and the imidazole rings
undergo substitution.
686
ꢀ

TABLE 2. Characteristics of Synthesized Compounds
Found, %
Empirical
formula
mp, ºꢂ
IR spectrum,
ꢃ, cm–1
Yield,
%
Calculated, %
H
Compound
(alcohol)*
C
N
1a
C8H7N3O3
C8H7BrN2O
C9H8N2O2
C10H10N2O2
C15H12N2O2
C9H10N2O2
C8H8N2S
50.07
49.75
42.65
42.32
61.12
61.36
62.88
63.15
71.54
71.42
60.92
60.67
58.72
58.51
–
3.37
3.65
2.88
3.11
4.71
4.58
5.53
5.30
5.03
4.79
5.33
5.66
5.07
4.91
–
22.03
21.75
12.55
12.34
16.22
15.90
15.05
14.73
10.78
11.10
16.04
15.72
16.94
17.06
–
129–130
82–83
1360 sym. (NO2)
1545 asym. (NO2)
52
66
67
45
63
53
1b
–
1c
126–127
120–121
128–129
164–165
98–100
–
1670 (C=O)
1680 (C=O)
1670 (C=O)
1130 (OH)
–
1d
1e
1f
2
2a+2b*2
C8H7N3O2S
C8H6N4O4S
1380 sym. (NO2),
1560 asym. (NO2)
78
70
49
80
52
40
85
2c*3
C8H7Br3N2S
C8H8N2O3S2
C9H8N2OS
24.15
23.85
39.56
39.33
55.88
56.23
58.46
58.23
67.28
67.14
55.79
55.65
2.07
1.75
3.47
3.30
3.92
4.19
5.17
4.89
4.42
4.51
4.88
5.19
–
198–199
276–277
157–159
115–116
144–145
178–180
–
2d
11.22
11.47
14.66
14.57
13.66
13.58
10.72
10.44
1260 (SO2)
1650 (C=O)
1650 (C=O)
1660 (C=O)
1140 (OH)
2e
2f
2g
C10H10N2OS
C15H12N2OS
C9H10N2OS
2h
14.67
14.42
_______
*Compound 2d was crystallized from water, 1c from hexane.
1
*2According to the H NMR spectrum, the ratio of the compounds 2a:2b
was 2:1.
*3Found, %: Br 59.78. Calculated, %: Br 59.49.
EXPERIMENTAL
The IR spectra were recorded on a Specord IR-75 spectrometer in chloroform (compounds 1a,c–f,
2a+2b, 2e–h) and vaseline oil (compound 2d). The 1H NMR spectra were recorded on a Bruker-250 instrument
(250 MHz, compounds 1a,c, 2a+b, 2c,e–h) and a Varian Unity-300 instrument (300 MHz, compounds 1b,d–f,
2d) in the Fourier pulse regime. The residual signals of the protons of deuterated solvents CDCl3 and DMSO-d6
(ꢀ 7.26 and 2.50 ppm respectively) were used as internal standard. Elemental analysis was performed on a
Perkin-Elmer 2400 analyzer. The melting points were determined by capillary method on a melting point
apparatus. The reactions and the individuality of the products were monitored by TLC on plates with aluminum
oxide Brockmann II (development with iodine vapor) or on Silufol UV-254 plates in CH2Cl2.
5-(2-Furyl)-1-methyl-1H-imidazole (1) and 1-methyl-5-(2-thienyl)-1H-imidazole (2) were obtained by
the method described in [2].
1-Methyl-5-(5-nitro-2-furyl)-1H-imidazole (1a). Preparation of the nitration mixture: Acetic anhy-
dride (40 ml) was added with strong cooling in small portions to Cu(NO3)2ꢄ3H2O (16.9 g, 70 mmol) while
ensuring that the temperature of the reaction mixture did not rise above 30–40°C. At the end of the exothermic
reaction the mixture was kept at room temperature for 24 h, after which the precipitated copper(II) acetate was
filtered off. The obtained mixture was kept at 5–10°C for not more than 10 days.
687
ꢀ

TABLE 3. 1H NMR Spectra of Synthesized Compounds
Chemical shifts, ꢀ, ppm (J, Hz)*
Compound
N–CH3
(3H, s)
H-4'
(1ꢁ, d)
H-3'
H-4
(1ꢁ, s)
H-2
(1ꢁ, s)
Other signals
(1ꢁ, d)
1ꢂ
1b
1c
1d
1e
3.75
3.66
3.74
3.75
3.76
7.38
6.81
7.54
7.12
7.48
7.40
7.44
7.47
7.40
7.41
7.48
7.49
–
(J3,4 = 3.8)
(J4,3 = 3.8)
6.35
(J3,4 = 3.5)
6.58
(J4,3 = 3.5)
–
7.28
(J3,4 = 3.5)
6.83
(J4,3 = 3.5)
9.55 (1H, s, CHO)
2.48 (3H, s, CH3)
7.25
(J3,4 = 3.5)
6.78
(J4,3 = 3.5)
7.26
(J3,4 = 3.7)
6.86
(J4,3 = 3.7)
7.50–7.52 (3H, m,
ꢁ-3'',4'',5''); 7.94
(2ꢁ, d, J = 7.0,
H-2'',6'')
1f
2
3.72
3.63
3.68
3.98
3.66
3.64
3.77
3.69
3.72
6.40
6.58
7.14
7.02
7.21
–
7.44
7.36
7.45
8.02
8.33
7.45
7.45
7.42
7.52
4.15 (1ꢁ, s, ꢅꢁ);
4.93 (2ꢁ, s, Sꢁ2)
(J3,4 = 3.4)
(J4,3 = 3.4)
6.95–7.00
(m)
7.13
(J4,3 = 5.2)
7.20 (1H, d,
4,5 = 3.6, H-5')
J
2a
2b
2c
2d
2e
2f
7.57
(J3,4 = 4.1)
7.24
(J4,3 = 4.1)
–
7.83
(J3,4 = 4.4)
8.14
(J4,3 = 4.4)
–
–
–
7.27
(J3,4 = 4.1)
7.35
(J4,3 = 4.1)
–
7.57
(J3,4 = 3.6)
6.98
(J4,3 = 3.6)
6.96
7.23
7.17
7.22
7.66
(J3,4 = 4.1)
7.33
(J4,3 = 4.1)
9.83 (1ꢁ, s, Sꢁꢅ)
2.48 (3ꢁ, s, Sꢁ3)
7.58
(J3,4 = 3.8)
7.24
(J4,3 = 3.8)
2g
7.57
(J3,4 = 3.8)
7.30
(J4,3 = 3.8)
7.40–7.50 (3ꢁ, m,
ꢁ-3'',4'',5''); 7.84
(2ꢁ, d, J = 8.2,
ꢁ-2'',6'')
2h
3.66
7.00–7.05
(m)
7.17
(J4,3 = 4.1)
–
7.37
4.30 (1ꢁ, s, ꢅꢁ);
4.82 (2ꢁ, s, Sꢁ2);
7.34 (1ꢁ, d, J = 5.1,
ꢁ-5')
_______
*Solvents: CDCl3 (compounds 1, 1a–f, 2, 2a,b,e–h) and
DMSO-d6 (compounds 2c,d).
The nitration mixture (1.4 ml) was added under vigorous stirring in small portions at room temperature
to a solution of compound 1 (0.74 g, 5 mmol) in freshly prepared acetic anhydride (5 ml). The reaction time was
30–40 min. Cold water (25 ml) was then added to the obtained mixture, and the mixture was neutralized with a
25% ammonia solution. The precipitate was filtered off, washed thoroughly with water, and chromatographed
on a column of aluminum oxide using dichloromethane as eluent. The product was crystallized from alcohol.
Yield 0.5 g.
A mixture of 1-methyl-5-(5-nitro-2-thienyl)-1H-imidazole (2a) and 1-methyl-4-nitro-5-(5-nitro-
2-thienyl)-1H-imidazole (2b) was obtained similarly to compound 1a.
5-(5-Bromo-2-furyl)-1-methyl-1H-imidazole (1b). Bromine (0.8 g, 5 mmol) was added to a solution of
compound 1 (0.74 g, 5 mmol) in dichloroethane (10 ml) at a temperature between –10 and –15°C. The reaction
688
ꢀ

mixture was stirred at –10°C for 30 min and washed with of a 5% ammonia solution (20 ml) and with water
(2×20 ml). The dichloroethane layer was dried with anhydrous Na2SO4 and chromatographed on a column of
aluminum oxide using dichloromethane as eluent. Yield 0.75 g.
4-Bromo-5-(5-bromo-2-thienyl)-1-methyl-1H-imidazole Hydrobromide (2c). Bromine (1.6 g,
10 mmol) was added dropwise at 0°C to a stirred solution of compound 2 (0.82 g, 5 mmol) in dichloroethane
(10 ml). The reaction mixture was stirred at 0°C for 30 min, and the solvent was then evaporated under reduced
pressure at room temperature. The residue was recrystallized from alcohol. Yield 1.41 g.
1-Methyl-5-(5-sulfo-2-thienyl)-1H-imidazole (2d). A mixture of compound 2 (0.82 g, 5 mmol), sulfuric
acid (d = 1.84 g/cm3) (0.98 g, 10 mmol), and PPA (20 g) was heated at 70–80°C for 1 h. The reaction mixture was
cooled and diluted with water (50 ml), and the precipitated sulfonic acid was separated. Yield 0.77 g.
5-(5-Formyl-2-furyl)-1-methyl-1H-imidazole (1c). POCl3 (4.6 g, 30 mmol) was added at 0–5°C drop-
wise under stirring to compound 1 (0.74 g, 5 mmol) in DMF (4.75 g, 65 mmol) . The mixture was stirred at the
same temperature for 10 min and at 60°C for 30 min. After cooling, the reaction mixture was neutralized to pH 7
with a concentrated ammonia solution and extracted with chloroform (25 ml). The extract was dried with
anhydrous Na2SO4 and chromatographed on a column of aluminum oxide using chloroform as eluent. The
product was crystallized from hexane. Yield 0.59 g.
5-(5-Formyl-2-thienyl)-1-methyl-1H-imidazole (2e). A mixture of compound 2 (0.82 g, 5 mmol) and
urotropine (1.4 g, 10 mmol) was stirred in PPA (15 g) at 70–80°C for 2 h. The reaction mixture was then diluted
with water (50 ml) and carefully neutralized with a 25% ammonia solution under cooling. The precipitate was
extracted with dichloromethane (3×15 ml), and the extract was dried over CaCl2. The solvent was evaporated,
and the residue was chromatographed on a column using dichloromethane as eluent. Yield 0.77 g.
5-(5-Acetyl-2-furyl)-1-methyl-1H-imidazole (1d) and 5-(5-Benzoyl-2-furyl)-1-methyl-1H-imidazole
(1e). A mixture of compound 1 (0.74 g, 5 mmol) and acetic or benzoic acid (10 mmol) was stirred in PPA (10 g)
for 2–4 h until the starting compound had disappeared according to TLC. The products (1d,e) were isolated
similarly to compound 2e with yields of 0.43 and 0.79 g respectively.
5-(5-Acetyl-2-thienyl)-1-methyl-1H-imidazole (2f) and 5-(5-Benzoyl-2-thienyl)-1-methyl-1H-imid-
azole (1g). These compounds were obtained similarly to compounds 1d,e from compound 2 with yields of 0.54
and 0.54 g respectively.
5-(5-Hydroxymethyl-2-furyl)-1-methyl-1H-imidazole (1f). A drop of hydrochloric acid was added to
a solution of compound 1 (0.74 g, 5 mmol) in formalin (35 ml) . The mixture was boiled for 4 h. It was then
poured into cold water (100 ml) and neutralized to pH 7–8 with a 25% ammonia solution. The precipitate was
filtered off and washed thoroughly with cold water. Yield 0.47 g.
4-Hydroxymethyl-5-(2-thienyl)-1-methyl-1H-imidazole (2h). The compound was obtained similarly
to compound 1f from compound (2) (5 mmol). Yield 0.82 g.
REFERENCES
1.
2.
3.
K. Schofield, M. Grimmett, and B. Keene, Heteroaromatic Nitrogen Compound. The Azoles, Cambridge
Univ. Press (1976), 437 pꢆ.
E. V. Vlasova, V. M. Stoyanov, M. M. Elchaninov, and B. S. Lukyanov, Khim. Geterotsikl. Soedin., 849
(2010). [Chem. Heterocycl. Comp., 46, 681 (2010)].
V. M. Stoyanov, M. M. Elchaninov, A. M. Simonov, and A. F. Pozharskii, Khim. Geterotsikl. Soedin.,
1396 (1989). [Chem. Heterocycl. Comp., 25, 1168 (1989)].
4.
5.
M. M. Elchaninov, Thesis Dr. Chem. Sci. [in Russian], Rostov-on-Don (2006).
Yu. D. Churkin and V. I. Savin, Khim. Geterotsikl. Soedin., 369 (1968) [Chem. Heterocycl. Comp., 4,
273 (1968)].
6.
A. P. Terent’ev and L. A. Kazitsina, Zh. Org. Khim., 723 (1948).
689
ꢀ