Synthesis and Some Transformations of 2-(2-Thienyl)-1(3)H-imidazo[4,5-f] quinoline

Article abstract of DOI:10.1134/S1070363212070134

2-(2-Thienyl)-1(3)H-imidazo[4,5-f]quinoline was synthesized by the Weidenhagen reaction of quinoline-5,6-diamine with thiophene-2-carbaldehyde. Its methylation in the system KOH-DMSO gave isomeric 1-methyl-2-(2-thienyl)-1H- and 3-methyl-2-(2-thienyl)-3H-i

Full text of DOI:10.1134/S1070363212070134

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 7, pp. 1263–1266. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © A.A. Aleksandrov, M.M. El’chaninov, A.S. Dedeneva, 2012, published in Zhurnal Obshchei Khimii, 2012, Vol. 82, No. 7, pp. 1163–
1167.
Synthesis and Some Transformations
of 2-(2-Thienyl)-1(3)H-imidazo[4,5-f]quinoline
A. A. Aleksandrov, M. M. El’chaninov, and A. S. Dedeneva
South Russian State Technical University (Novocherkassk Polytechnic Institute),
ul. Prosveshcheniya 132, Novocherkassk, 346428 Russia
e-mail: aaanet1@yandex.ru
Received May 12, 2011
Abstract—2-(2-Thienyl)-1(3)H-imidazo[4,5-f]quinoline was synthesized by the Weidenhagen reaction of
quinoline-5,6-diamine with thiophene-2-carbaldehyde. Its methylation in the system KOH–DMSO gave
isomeric 1-methyl-2-(2-thienyl)-1H- and 3-methyl-2-(2-thienyl)-3H-imidazo[4,5-f]quinolines, the latter being
the major product. The 3-methyl derivative was subjected to electrophilic substitution reactions (bromination,
nitration, formylation, acylation, sulfonation). Depending on the conditions, electrophilic attack was directed at
the thiophene or quinoline fragment or both these.
DOI: 10.1134/S1070363212070134
The chemistry of bihetaryls, i.e., compounds whose
molecule consist of two heteroaromatic fragments linked
through a single bond, attracts increased attention.
Bihetaryls containing a thiophene ring are used as
pharmaceuticals. For example, 4-(2-thienyl)pyridine
derivatives were patented as antiinflammatory agents
[1]. Among 2-hetarylimidazoles, 2-(2-thienyl)benzimida-
zole is known to exhibit antimicro-bial and fungicidal
properties [2, 3]. In view of the above stated, we
focused on 2-(2-thienyl)-1(3)H-imidazo[4,5-f]quinoline
(I) which was not studied previously. Taking into account
exceptional pharmacophoric properties of imidazole
and thiophene, we anticipated diverse biological
activity of compound I and its derivatives. Moreover,
mutual influence of the imidazoquinoline and thio-
phene fragments should interestingly affect the
reactivity of such compounds.
reactivity in comparison with naphtho[1,2-d]imida-
zole analog II.
We initially synthesized 2-(2-thienyl)-1(3)H-imidazo-
[4,5-f]quinoline (I) by analogy with compound II, i.e.,
by condensation of quinoline-5,6-diamine with thio-
phene-2-carbaldehyde in nitrobenzene [4]; however,
the yield of the target product was ~52%. We then
succeeded in obtaining compound I in a higher yield
(72%) according to Weidenhagen [5]. Methylation of I
(as well as of II [6]) was successful with the use of an
equimolar amount of methyl iodide in the system
KOH–DMSO; the yield was nearly quantitative. Due
to their intrinsic asymmetry, both compounds I and II
gave rise to mixtures of 1- and 3-methyl derivatives. 1-
Methyl isomer Ib was formed as minor product,
whereas the major product was 3-methyl derivative Ia,
the ratio Ia:Ib being 95:5. Signals from methyl
protons (δ 4.08 and 4.40 ppm) were assigned to
particular isomers on the basis of their chemical shifts.
The downfield signal was assigned to 1-methyl-2-(2-
thienyl)-1H-imidazo[4,5-f]quinoline (Ib), for the
methyl protons in its molecule are additionally
deshielded by the quinoline fragment.
The present study was aimed at developing a con-
venient procedure for the synthesis of 2-(2-thienyl)-
1(3)H-imidazo[4,5-f]quinoline (I) and examine its
N
N
N
N
N
N-Methyl derivative Ia was subjected to reactions
with several electrophiles, namely bromine in di-
chloroethane, paraformaldehyde in concentrated hyd-
rochloric acid, hexamethylenetetramine in poly-
phosphoric acid (PPA), acetic anhydride, and benzoic
S
S
H
H
I
II
1263

1264
ALEKSANDROV et al.
Me
N
MeI
KOH−DMSO
N
N
N
N
N
N
+
S
S
S
N
N
Me
Iа, 95%
H
I
Ib, 5%
and sulfuric acids in PPA; in addition, compound Ia
was nitrated with dilute nitric acid (d 1.42 g/cm3).
The bromination of Ia in dichloroethane afforded
monobromo derivative Id having a bromine atom in
position 5 of the thiophene ring. Further bromination at
position 4 of the quinoline fragment occurred under
prolonged heating of compound Ia with 3 equiv of
bromine. The yield of dibromide Ie was only 28%. For
comparison, 3-methyl-2-(2-thienyl)-3H-naphtho[1,2-d]
imidazole (IIa) under analogous conditions was
directly converted into the corresponding dibromide in
82% yield [6].
Electrophilic substitution in 2-thienylimidazoles Ia
and IIa generally requires severe conditions, which
indicates considerable deactivation of the thienyl
fragment. Obviously, this is the result of electron-
withdrawing effect of the imidazol-2-yl substituent
fused to quinoline or naphthalene; the effect becomes
stronger upon protonation [7]. It is seen that molecule
Ia is capable of taking up two protons; in this case,
electron density on the thiophene ring could be
reduced to a greater extent as compared to IIa. This
assumption was confirmed by the results of B3LYP/6-
31G(d,p) quantum-chemical calculations of the total
(σ+π) electron charges on atoms in the thiophene rings
of protonated compounds Ia and IIa. The charge of the
thiophene ring in doubly protonated thienylimida-
zoquinoline Ia is –0.388 against –0.485 for singly pro-
tonated compound IIa. Insofar as all transformations
of Ia occurred in strongly acidic medium, reduced
relative reactivity of thiophene ring in Ia might be
expected. In fact, our results confirmed this assumption.
Like naphthoimidazole IIa studied previously, 3-
methyl-2-(2-thienyl)-3H-imidazo[4,5-f]quinoline (Ia)
failed to undergo Vilsmeier formylation with DMF–
POCl3 even at elevated temperature (80–90°C). On the
other hand, heating of Ia with hexamethylenetetramine
in polyphosphoric acid at 90–100°C produced 31% of
2-(5-formylthiophen-2-yl) derivative If; analogous
derivative of IIa was synthesized in 60% yield [6].
We succeeded in acetylating compound Ia in a poor
yield (~18%) only by the action of acetic anhydride in
PPA at 110–120°C, though its analog IIa gave rise to
the corresponding acetyl derivative more smoothly
(yield 36%). Unlike acetylation, benzoylation of Ia
was more selective due to the absence of activated
methyl group in the acylation product, and the yield of
phenyl ketone Ih was 49%. Analogous 5-benzoyl
derivative of IIa was obtained in 55% yield [6].
The nitration of Ia with the copper nitrate–acetic
anhydride complex, i.e., under the conditions
corresponding to the nitration of IIa, was characterized
by a very poor yield. Therefore, we tried to perform
radical nitration of Ia with dilute nitric acid (d = 1.42
g/cm3). In this case, we obtained 53% of 5-nitro
derivative Ic. The latter was also synthesized
independently by ipso-substitution of the bromine
In contrast to naphthoimidazole analog IIa, we
failed to isolate sulfonation product of compound Ia in
the reaction with a mixture of sulfuric and
polyphosphoric acids. Presumably, the reason is double
atom
in
3-methyl-2-(5-bromothiophen-2-yl)-3H-
imidazo[4,5-f]quinoline (Id) by nitro group.
N
N
N
N
N
N
N
O
diluted HNO3
PhCO2H−(CH2)6N4
R
S
AC2O−PPA
Br2−C2H4Cl2
S
S
R
N
N
Me
R'
Me
Me
Iе, Ig, Ih
Ic, Id, Ie
Iа
I, R = NO2, R' = H (c); R = Br, R' = H (d); R = R' = Br (e); R = H (f), Me (g), Ph (h).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 7 2012

SYNTHESIS AND SOME TRANSFORMATIONS
1265
Table 1. Yields, melting points, and elemental analyses of compounds I and Ia–Ih
Found, %
Calculated, %
H
Comp.
no.
Yield,
%
mp,
°С
Formula
С
Н
N
C
N
72
95
5
53
66
28
31
18
49
305–306
154–155
145–146
265–266
175–176
250–251
247–248
120–121
185–186
67.22
68.23
68.17
57.73
52.67
42.77
65.27
66.17
70.88
3.47
3.92
4.33
3.57
3.17
1.88
4.04
4.55
4.07
17.09
16.17
15.99
17.72
11.89
–
14.66
13.88
–
C14H9N3S
66.91
67.90
67.90
58.06
52.34
42.58
65.51
66.43
70.57
3.61
4.18
4.18
3.25
2.93
2.14
3.78
4.26
4.23
16.72
15.84
15.84
18.05
12.21
–
14.32
13.67
–
I
C15H11N3S
Iа
Ib
Ic
Id
Ie
If
C15H11N3S
C15H10N4O2S
C15H10BrN3S
C15H9Br2N3S
C16H11N3OS
C17H13N3OS
C21H15N3OS
Ig
Ih
protonation of the imidazoquinoline fragment, which
considerably deactivates the thiophene ring toward
electrophilic substitution.
potassium. The mixture was stirred for 2 h, poured into
200 ml of water, and extracted with chloroform
(2×50 ml), the extract was evaporated to a volume of
20 ml, dried over sodium sulfate, filtered, and eva-
porated to obtain 4.13 (78%) of isomer mixture Ia/Ib.
The isomers were separated by column chromato-
graphy (70×3.5 cm) on Al2O3 using chloroform as
eluent. The yields, melting points, elemental analyses,
and 1H NMR spectral data of compounds Ia and Ib are
given in Tables 1 and 2.
EXPERIMENTAL
The IR spectra were recorded on a Specord 75 IR
spectrometer from samples dispersed in mineral oil.
The 1H NMR spectra were measured on a Varian Unity
300 instrument (300 MHz) from solutions in CDCl3
using tetramethylsilane as internal reference. The
progress of reactions was monitored by TLC on Al2O3
(Brockmann activity grade II) using methylene
chloride or chloroform as eluent; spots were developed
by treatment with iodine vapor. The elemental
compositions were determined on a Perkin–Elmer
2400 analyzer. The melting points were determined in
capillaries using a PTP melting point apparatus.
3-Methyl-2-(5-nitrothiophen-2-yl)-3H-imidazo-
[4,5-f]quinoline (Ic). a. A solution of 2.65 g (0.01 mol)
of compound Ia in 25 ml of nitric acid (d = 1.42 g/cm3)
was stirred for 1 h at 40°C. The mixture was poured
into 100 ml of cold water, and the precipitate was
filtered off and washed with 2–3 portions of cold water.
b. Sodium nitrite, 0.21 g (0.003 mol), was added in
portions to a solution of 0.34 g (0.001 mol) of
compound Id in 5 ml of acetic acid, and the mixture
was heated for 1 h, cooled, poured into 20 ml of water,
and then treated as described above in a. Samples of Ic
obtained by the two methods were identical in the
melting point (no depression of the melting point was
observed on mixing).
2-(2-Thienyl)-1(3)H-imidazo[4,5-f]quinoline (I).
A mixture of 6.36 g (0.04 mol) of quinoline-5,6-
diamine in 75 ml of isopropyl alcohol and, 16 g of cop-
per acetate in 200 ml of water, and 4.48 g (0.04 mol) of
thiophene-2-carbaldehyde was heated for 2 h at 80–90°C.
The mixture was cooled, the precipitate of copper salt
was filtered off and dispersed in 100 ml of isopropyl
alcohol, and hydrogen sulfide was passed through the
suspension over a period of 1 h. Copper sulfide was
filtered off, the filtrate was evaporated by half, and the
precipitate was filtered off and recrystallized from
ethanol. The yield, melting point, and elemental
analysis of compound I are given in Table 1.
3-Methyl-2-(5-bromothiophen-2-yl)-3H-imidazo-
[4,5-f]quinoline (Id). Bromine, 1.06 ml (0.02 mol),
was added to a solution of 2.65 g (0.01 mol) of com-
pound Ia in 25 ml of dichloroethane. The mixture was
heated for 4 h under reflux and evaporated in air, and
the residue was recrystallized from alcohol.
3-Methyl-2-(2-thienyl)-3H-imidazo[4,5-f]quinoline
(Ia) and 1-methyl-2-(2-thienyl)-1H-imidazo[4,5-f]-
quinoline (Ib). Methyl iodide, 3.12 g (0.022 mol), was
added dropwise at 15–20°C under vigorous stirring to
a solution of 5.02 g (0.02 mol) of compound I in 20 ml
of DMSO containing 1.24 g (0.022 mol) of powdered
4-Bromo-2-(5-bromothiophen-2-yl)-3-methyl-3H-
imidazo[4,5-f]quinoline (Ie). Bromine, 0.80 ml
(0.015 mol), was added to a solution of 1.33 g
(0.005 mol) of compound Ia in 25 ml of dichloro-
ethane. The mixture was heated for 8 h under reflux
and evaporated in air, and the residue was dissolved in
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 7 2012

1266
ALEKSANDROV et al.
Table 2. IR and 1H NMR spectral parameters of compounds Ia–Ih
Comp.
no.
IR spectrum,
1H NMR spectrum (CDCl3), δ, ppm
ν, cm–1
–
–
4.08 s (3H, NCH3), 7.22 t (1H, HTh, J = 4.0 Hz), 7.48 d (1H, HTh, J = 4.0 Hz), 7.53 d.d (1H, Harom, J = 8.3 Hz),
7.57 d (1H, HTh, J = 4.8 Hz), 7.72 d (1H, Harom, J = 9.0 Hz), 7.97 d (1H, Harom, J = 9.1 Hz), 8.90 d (1H, Harom
J = 4.5 Hz), 8.98 d (1H, Harom, J = 7.4 Hz)
Ia
Ib
Ic
Id
,
4.40 s (3H, NCH3), 7.15 t (1H, HTh, J = 3.9 Hz), 7.46 d (1H, HTh, J = 3.9 Hz), 7.47 d.d (1H, Harom, J = 4.4 Hz),
7.65 d (1H, HTh, J = 4.8 Hz), 7.80 d (1H, Harom, J = 9.0 Hz), 8.05 d (1H, Harom, J = 9.1 Hz), 8.69 d (1H, Harom
J = 7.8 Hz), 8.90 d (1H, Harom, J = 4.4 Hz)
,
1360 (NO2, sym.) 4.14 s (3H, NCH3), 7.50 d (1H, HTh, J = 4.2 Hz), 7.53 d.d (1H, Harom, J = 8.3 Hz), 7.58 d (1H, Harom, J = 4.2 Hz),
1545 (NO2,
asym.)
7.72 d (1H, Harom, J = 9.1 Hz), 7.98 d (1H, Harom, J = 9.1 Hz), 8.90 d (1H, Harom, J 4.5 Hz), 8.99 d (1H, Harom
,
J = 8.4 Hz)
–
4.05 s (3H, NCH3), 7.14 d (1H, HTh, J = 3.9 Hz), 7.30 d (1H, HTh, J = 3.9 Hz), 7.50 d.d (1H, Harom, J = 4.2 Hz),
7.70 d (1H, Harom, J = 9.3 Hz), 7.98 d (1H, Harom, J = 9.3 Hz), 8.90 d (1H, Harom, J = 4.4 Hz), 8.95 d (1H,
Harom, J = 7.4 Hz)
–
4.03 s (3H, NCH3), 7.15 d. (1H, HTh, J = 3.9 Hz), 7.31 d (1H, HTh, J = 3.9 Hz), 7.56 d.d (1H, Harom, J = 4.2 Hz),
8.09 s (1H, Harom), 8.95 d (1H, Harom, J = 6.6 Hz), 9.03 d (1H, Harom, J = 4.4 Hz)
Ie
If
1630 (C=O)
4.14 s (3H, NCH3), 7.54 d (1H, Harom, J = 4.2 Hz), 7.73 d (1H, Harom, J = 9.0 Hz), 7.74 d (1H, HTh, J = 4.0 Hz),
7.84 d (1H, HTh, J = 4.0 Hz), 8.02 d (1H, Harom, J = 9.0 Hz), 8.93 d (1H, Harom, J = 4.5 Hz), 8.97 d (1H, Harom
,
J = 7.8 Hz), 9.98 s (1H, HO)
1650 (C=O)
1670 (C=O)
2.58 s (1H, H3), 4.16 s (3H, NCH3), 7.56 d.d (1H, Harom, J = 4.2 Hz), 7.71 d (1H, Harom, J = 9.0 Hz), 7.72 d
(1H, HTh, J = 3.9 Hz), 7.86 d (1H, HTh, J = 3.9 Hz), 8.00 d (1H, Harom, J = 8.9 Hz), 8.95 d (1H, Harom, J = 4.5 Hz),
8.98 d (1H, Harom, J = 7.8 Hz)
Ig
Ih
4.16 s (3H, NCH3), 7.54 d.d (1H, Harom, J = 4.4 Hz), 7.50–7.53 m (3H, Harom), 7.73 d (1H, HTh, J = 9.0 Hz),
7.73 d (1H, HTh, J = 4.0 Hz), 7.75 d (1H, HTh, J = 4.0 Hz), 7.91 d (2H, Harom, J = 8.4 Hz), 8.03 d (1H, Harom
,
J = 9.0 Hz), 8.92 d (1H, Harom, J = 4.5 Hz), 9.00 d (1H, Harom, J = 7.8 Hz)
methylene chloride and applied to a column
(15 ×2.5 cm) charged with aluminum oxide; the
column was eluted with methylene chloride.
150–160°C. The product was isolated as described
above for Ig.
The yields, melting points, elemental analyses, and
IR and 1H NMR spectra of compounds Ic–Ih are given
in Tables 1 and 2.
5-(3-Methyl-3H-imidazo[4,5-f]quinolin-2-yl)thio-
phene-2-carbaldehyde (If). A mixture of 1.33 g
(0.005 mol) of compound Ia, 2.8 g (0.02 mol) of
hexamethylenetetramine, and 20 g of polyphosphoric
acid was stirred for 4 h at 90–100°C. The mixture was
then diluted with 100 ml of water and carefully
neutralized with a solution of ammonia. the precipitate
was filtered off and recrystallized from isopropyl
alcohol.
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1-ethanone (Ig). A mixture of 1.33 g (0.005 mol)
of compound Ia, 1.53 g (0.015 mol) of acetic an-
hydride, and 20 g of PPA was stirred for 20 h at 110–
120°C. The mixture was diluted with 50 ml of water,
carefully neutralized with aqueous ammonia, and
extracted with methylene chloride. The product was
isolated by column chromatography using methylene
chloride as eluent and additionally purified by
recrystallization from isopropyl alcohol.
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[5-(3-Methyl-3H-imidazo[4,5-f]quinolin-2-yl)thio-
phen-2-yl]phenylmethanone (Ih). A mixture of 1.33 g
(0.005 mol) of compound Ia, 20 g of PPA, and 1.8 g
(0.015 mol) of benzoic acid was stirred for 10 h at
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