2-(2-Furyl)-1(3)H-imidazo[4,5-f]quinoline. Synthesis and electrophilic substitution reactions

Article abstract of DOI:10.1134/S1070428011010155

2-(2-Furyl)-1(3)H-imidazo[4,5-f]quinoline was synthesized by the Weidenhagen reaction of quinoline-5,6-diamine with furfural. Its alkylation with methyl iodide in the system KOH-DMSO gave two isomeric N-methyl derivatives, 2-(2-furyl)-1-methyl-1H- and 2-(

Full text of DOI:10.1134/S1070428011010155

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 1, pp. 120–123. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © A.A. Aleksandrov, A.S. Dedeneva, E.V. Vlasova, M.M. El’chaninov, 2011, published in Zhurnal Organicheskoi Khimii, 2011,
Vol. 47, No. 1, pp. 121–124.
2-(2-Furyl)-1(3)H-imidazo[4,5-f]quinoline. Synthesis
and Electrophilic Substitution Reactions
A. A. Aleksandrov, A. S. Dedeneva, E. V. Vlasova, and M. M. El’chaninov
South Russian State Technical University (Novocherkassk Polytechnical Institute),
ul. Prosveshcheniya 132, Novocherkassk, 346428 Russia
e-mail: aaanet1@yandex.ru
Received March 9, 2010
Abstract—2-(2-Furyl)-1(3)H-imidazo[4,5-f]quinoline was synthesized by the Weidenhagen reaction of quino-
line-5,6-diamine with furfural. Its alkylation with methyl iodide in the system KOH–DMSO gave two isomeric
N-methyl derivatives, 2-(2-furyl)-1-methyl-1H- and 2-(2-furyl)-3-methyl-3H-imidazo[4,5-f]quinolines, the
latter prevailing. 2-(2-Furyl)-3-methyl-3H-imidazo[4,5-f]quinoline was brought into electrophilic substitution
reactions: bromination, nitration, formylation, acylation, sulfonation. Depending on the reaction conditions,
electrophilic attack could be directed at both furan ring and quinoline fragment.
DOI: 10.1134/S1070428011010155
It is known that biheterocycles, i.e., compounds
consisting of two heteroaromatic rings linked by
a single bond, play an important role in modern theo-
retical and applied chemistry. They are used for the
synthesis of effective metal-complex catalysts, analyti-
cal reagents, and pharmaceuticals. This fully applies to
fused 2-hetarylimidazole derivatives. The present work
was aimed at studying methods of synthesis of
2-(2-furyl)-1(3)H-imidazo[4,5-f]quinoline (I) and its
transformations involving the imidazoquinoline and
furan fragments by the action of electrophilic and radi-
cal reagents.
amount of methyl iodide was successful in the system
KOH–DMSO (the yield was nearly quantitative). In-
sofar as molecule I is asymmetric, the alkylation gave
a mixture of two N-methyl derivatives: 2-(2-furyl)-1-
methyl-1H-imidazo[4,5-f]quinoline (II) and 2-(2-fur-
yl)-3-methyl-3H-imidazo[4,5-f]quinoline (III)
1
(Scheme 1). In keeping with the H NMR data,
3-methyl isomer III was the major product; its fraction
in the reaction mixture was about ~90%, whereas the
fraction of 1-methyl isomer II did not exceed 7–9%.
Protons in the methyl group in compound III gave
1
a signal at δ 4.10 ppm in the H NMR spectrum,
whereas the corresponding signal of 1-methyl isomer
II was located at δ 4.42 ppm. Obviously, the downfield
position of the latter signal is determined by stronger
effect of diamagnetic component of the ring current in
the quinoline fragment.
Compound I was synthesized previously in 40%
yield by condensation of 5,6-diaminoquinoline with
furan-2-carboximidic acid ester hydrochloride in alco-
hol [1]. However, we succeeded in obtaining better
result by reacting 5,6-diaminoquinoline with furfural
according to Weidenhagen [2]. In this case, the yield of
2-(2-furyl)-1(3)H-imidazo[4,5-f]quinoline (I) was
72%. Alkylation of compound I with an equivalent
We examined reactions of 2-(2-furyl)-3-methyl-3H-
imidazo[4,5-f]quinoline (III) with some electrophilic
reagents, in particular with bromine in 1,2-dichloro-
Scheme 1.
Me
MeI, KOH–DMSO
N
N
N
N
O
N
O
N
N
O
+
N
H
N
Me
I
II
III
120

2-(2-FURYL)-1(3)H-IMIDAZO[4,5-f]QUINOLINE.
121
Scheme 2.
8
9
7
Dilute HNO3
Br2–dichloroethane
(CH2O)n–HCl/H2O
O
PhCOOH, (CH2)6N4
Ac2O, PPA
X
N
N
5'
N
N
O
N
O
R
III
2'
2
3
N
5
4'
3'
4
Me
IVa–IVd
Me
IVe–IVg
Y
Y = H, X = O2N (a), Br (b), ClCH2 (d); X = Y = Br (c); R = H (e), Me (f), Ph (g).
ethane, with paraformaldehyde in concentrated hydro-
chloric acid, with urotropine in polyphosphoric acid
(PPA), with acetic anhydride, and with benzoic and
sulfuric acids in PPA. In addition, compound III was
nitrated with dilute nitric acid (d = 1.42 g/cm3).
Taking into account strong deactivating effect of the
imidazoquinoline fragment on the furan ring, com-
pound III underwent acetylation only by the action of
acetic anhydride in PPA at 110–120°C. The reaction
was not selective and was accompanied by formation
of a number of by-products which were not identified.
The contribution of side processes increased as the
temperature rose; therefore, the yield of methyl ketone
IVf did not exceed 33%. The acylation of III with
benzoic acid was carried out under analogous condi-
tions, but at higher temperature (140–150°C). Unlike
acetylation, the benzoylation of III occurred smoothly
and was not accompanied by formation of by-products
(in this case, the product contained no activated methyl
group which is capable of being involved in further
transformations). The yield of ketone IVg was 67%.
On the whole, electrophilic replacement in com-
pound III occurred smoothly, and the yields were
fairly high. Unlike benzimidazole [3], compound III
failed to undergo nitration with acetyl nitrate at 0°C;
therefore, we tried radical nitration of III by heating in
dilute nitric acid (d = 1.42 g/cm3). We thus isolated
47% of 5-nitro derivative IVa. Compound IVa was
also synthesized by replacement of the bromine atom
in 2-(5-bromofuran-2-yl)-3-methyl-3H-imidazo[4,5-f]-
quinoline (IVb) by nitro group. The bromination of III
with molecular bromine in 1,2-dichloroethane gave
compound IVb having a bromine atom in position 5 of
the furan ring. By prolonged heating of compound III
with 3 equiv of bromine in boiling dichloroethane we
obtained 31% of dibromo derivative IVc, the second
bromine atom being introduced into position 4 of the
imidazoquinoline fragment (Scheme 2).
In contrast to benzimidazole analogs, we failed to
isolate sulfonation product in the reaction of com-
pound III with a mixture of sulfuric and polyphos-
phoric acids. Presumably, the reason is double protona-
tion of the imidazoquinoline fragment and consider-
able enhancement of its deactivating effect on the
furan ring.
Chloromethylation of furylimidazoquinoline III
occurred very difficultly, and the complete conversion
was attained only after prolonged heating. The product
isolated as hydrochloride was strongly contaminated,
so that it was identified via transformation into the free
base by treatment with alkali and subsequent purifica-
tion by column chromatography. The yield of 5-chloro-
methyl derivative IVd was as poor as 27% since the
chloromethyl group underwent partial hydrolysis upon
alkalization.
EXPERIMENTAL
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 (300 MHz, CDCl3, TMS). The progress
of reactions was monitored by TLC on aluminum
oxide of Brockmann activity grade II; methylene
chloride and chloroform were used as eluent; spots
were visualized by treatment with iodine vapor. The
elemental compositions were determined on a Perkin–
Elmer 2400 analyzer. The melting points were meas-
ured in capillaries on a PTP melting point apparatus.
Like naphthoimidazole studied previously [4],
2-(2-furyl)-3-methyl-3H-imidazo[4,5-f]quinoline (III)
failed to undergo formylation according to Vilsmeier
even at elevated temperature (80–90°C). On the other
hand, the reaction of III with urotropine in PPA at 90–
100°C gave 47% of the corresponding 5-formyl deriv-
ative IVe as the only product.
2-(2-Furyl)-1(3)H-imidazo[4,5-f]quinoline (I).
A mixture of 6.36 g (40 mmol) of 5,6-diaminoquino-
line in 75 ml of isopropyl alcohol, 16 g of copper
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 1 2011

ALEKSANDROV et al.
122
acetate in 200 ml of water, and 3.84 (40 mmol) of
furfural 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. The precipitate of copper sulfide
was filtered off, the filtrate was evaporated by half,
and the precipitate was filtered off and recrystallized
from ethanol. Yield 6.77 g (72%), mp 280–281°C.
Found, %: C 71.83; H 4.16; N 18.03. C14H9N3O. Cal-
culated, %: C 71.48; H 3.86; N 17.86.
2-(2-Furyl)-1-methyl-1H-imidazo[4,5-f]quinoline
(II) and 2-(2-furyl)-3-methyl-3H-imidazo[4,5-f]-
quinoline (III). Methyl iodide, 3.12 g (22 mmol), was
added dropwise under vigorous stirring at 15–20°C to
a solution of 4.70 g (20 mmol) of compound I in 20 ml
of DMSO containing 1.24 g (22 mmol) of powdered
potassium hydroxide. The mixture was stirred for 2 h,
poured into 200 ml of water, and extracted with
chloroform (2×50 ml). The extracts were combined,
evaporated to a volume of 20 ml, dried over sodium
sulfate, filtered, and evaporated to obtain 4.08 g (82%)
of isomer mixture II/III. Individual compounds II and
III were isolated by chromatography on a column
(70×3.5 cm) charged with aluminum oxide using
chloroform as eluent.
b. Sodium nitrite, 0.21 g (3 mmol), was added in
small portions to a solution of 0.33 g (1 mmol) of
compound IVb in 5 ml of acetic acid, and the mixture
was heated for 1 h under reflux, cooled, poured into
20 ml of water, and treated as described above in a.
The products obtained according to methods a and b
were identical in melting point (no depression of the
melting point was observed on mixing). Yield 0.19 g
(66%), mp 263–264°C (from ethanol). IR spectrum:
1
ν 1370 cm–1 (NO2). H NMR spectrum, δ, ppm: 4.21 s
(3H, NCH3), 7.43 d (1H, 3′-H, J = 3.9 Hz), 7.52 d (1H,
4′-H, J = 3.9 Hz), 7.55 d.d (1H, 8-H, J = 4.4 Hz),
7.77 d (1H, 4-H, J = 9.3 Hz), 8.06 d (1H, 5-H, J =
9.0 Hz), 8.93 d (1H, 7-H, J = 4.5 Hz), 8.95 d (1H, 9-H,
J = 8.0 Hz). Found, %: C 60.88; H 3.67; N 18.77.
C15H10N4O3. Calculated, %: C 61.22; H 3.43; N 19.04.
2-(5-Bromofuran-2-yl)-3-methyl-3H-imidazo-
[4,5-f]quinoline (IVb). Bromine, 0.53 ml (10 mmol),
was added to a solution of 1.24 g (5 mmol) of com-
pound III in 25 ml of 1,2-dichloroethane, the mixture
was heated for 4 h under reflux and evaporated in air,
and the residue was recrystallized from alcohol. Yield
1
1.26 g (77%), mp 168–169°C. H NMR spectrum, δ,
ppm: 4.13 s (3H, NCH3), 6.55 d (1H, 4′-H, J = 3.6 Hz),
7.15 d (1H, 3′-H, J = 3.6 Hz), 7.52 d.d (1H, 8-H, J =
4.2 Hz), 7.73 d (1H, 4-H, J = 9.0 Hz), 8.00 d (1H, 5-H,
J = 9.3 Hz), 8.90 d (1H, 7-H, J = 4.4 Hz), 8.97 d (1H,
9-H, J = 8.1 Hz). Found, %: C 55.23; H 3.32; N 13.07.
C15H10BrN3O. Calculated, %: C 54.90; H 3.07; N 12.80.
Isomer II. Yield 0.25 g (7%), mp 66–67°C (from
1
ethanol). H NMR spectrum, δ, ppm: 4.42 s (3H,
NCH3), 6.68 d.d (1H, 4′-H, J = 3.5 Hz), 7.12 d (1H,
3′-H, J = 3.5 Hz), 7.42 d (1H, 5′-H, J = 1.8 Hz),
7.45 d.d (1H, 8-H, J = 4.4 Hz), 7.73 d (1H, 4-H, J =
9.1 Hz), 8.07 d (1H, 5-H, J = 9.1 Hz), 8.69 d (1H, 9-H,
J = 7.8 Hz), 8.09 d (1H, 7-H, J = 4.4 Hz). Found, %:
C 72.43; H 4.12; N 17.10. C15N11N3O. Calculated, %:
C 72.28; H 4.45; N 16.86.
Isomer III. Yield 3.38 g (93%), mp 69–70°C (from
ethanol). 1H NMR spectrum, δ, ppm: 4.10 (3H, NCH3),
6.61 d.d (1H, 4′-H, J = 3.5 Hz), 7.15 d (1H, 3′-H, J =
3.5 Hz), 7.49 d.d (1H, 8-H, J = 4.4 Hz), 7.64 d (1H,
5′-H, J = 1.8 Hz), 7.69 d (1H, 4-H, J = 9.1 Hz), 7.96 d
(1H, 5-H, J = 9.1 Hz), 8.88 d (1H, 7-H, J = 4.4 Hz),
8.98 d (1H, 9-H, J = 7.4 Hz). Found, %: C 72.28;
H 4.57; N 16.77. C15H11N3O. Calculated, %: C 72.28;
H 4.45; N 16.86.
3-Methyl-2-(5-nitrofuran-2-yl)-3H-imidazo-
[4,5-f]quinoline (IVa). a. A solution of 1.24 g
(5 mmol) of compound III 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 precip-
itate was filtered off and washed with 2–3 small
portions of cold water. Yield 0.69 g (47%).
4-Bromo-2-(5-bromofuran-2-yl)-3-methyl-3H-
imidazo[4,5-f]quinoline (IVc). Bromine, 0.80 ml
(15 mmol), was added to a solution of 1.24 g (5 mmol)
of compound III in 25 ml of 1,2-dichloroethane. The
mixture was heated for 8 h under reflux and evaporat-
ed in air, and the residue was dissolved in methylene
chloride and subjected to column chromatography on
aluminum oxide (15×2.5 cm) using methylene chlo-
ride as eluent. Yield 0.63 g (31%), mp 134–135°C.
1H NMR spectrum, δ, ppm: 4.13 s (3H, NCH3), 6.57 d
(1H, 4′-H, J = 3.6 Hz), 7.30 d (1H, 3′-H, J = 3.6 Hz),
7.59 d.d (1H, 8-H, J = 4.5 Hz), 8.14 s (1H, 5-H),
9.04 d (1H, 7-H, J = 4.5 Hz), 9.05 d (1H, 9-H, J =
8.0 Hz). Found, %: C 43.98; H 2.38; N 10.07.
C15H9Br2N3O. Calculated, %: C 44.26; H 2.23; N 10.32.
2-(5-Chloromethylfuran-2-yl)-3-methyl-3H-
imidazo[4,5-f]quinoline (IVd). A mixture of 1.24 g
(5 mmol) of compound III, 1.15 g (13 mmol) of
paraformaldehyde, and 10 ml of hydrochloric acid (d =
1.19 g/cm3) was heated for 8 h at 70–80°C. The mix-
ture was cooled and carefully neutralized with 10% so-
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2-(2-FURYL)-1(3)H-IMIDAZO[4,5-f]QUINOLINE.
123
dium hydroxide to pH 7–8. The product was extracted
into 50 ml of methylene chloride and purified by
chromatography in a column (15×2.5 cm) charged
with aluminum oxide using methylene chloride as
chloride and purified by column chromatography using
methylene chloride as eluent. Yield 0.48 g (33%),
mp 91–92°C (from isopropyl alcohol). IR spectrum:
ν 1660 cm–1 (C=O). 1H NMR spectrum, δ, ppm: 2.57 s
(3H, CH3), 4.27 s (3H, NCH3), 7.36 d (1H, 3′-H, J =
3.5 Hz), 7.37 d (1H, 4′-H, J = 3.5 Hz), 7.55 d.d (1H,
8-H, J = 4.5 Hz), 7.76 d (1H, 4-H, J = 9.0 Hz), 8.04 d
(1H, 5-H, J = 9.0 Hz), 8.93 d (1H, 7-H, J = 4.4 Hz),
8.97 d (1H, 9-H, J = 8.1 Hz). Found, %: C 69.78;
H 4.43; N 14.17. C17H13N3O2. Calculated, %: C 70.09;
H 4.50; N 14.42.
1
eluent. Yield 0.40 g (27%), mp 68–69°C. H NMR
spectrum, δ, ppm: 4.12 s (3H, NCH3), 4.93 d (2H,
CH2, J = 3.6 Hz), 6.52 d (1H, 4′-H, J = 3.5 Hz), 7.10 d
(1H, 3′-H, J = 3.5 Hz) 7.50 d.d (1H, 8-H, J = 4.5 Hz),
7.67 d (1H, 4-H, J = 9.0 Hz), 7.94 d (1H, 5-H, J =
9.0 Hz), 8.86 d (1H, 7-H, J = 4.5 Hz), 8.98 d (1H, 9-H,
J = 7.4 Hz). Found, %: C 64.77; H 3.88; N 14.27.
C16H12ClN3O2. Calculated, %: C 64.54; H 4.06;
N 14.11.
[5-(3-Methyl-3H-imidazo[4,5-f]quinolin-2-yl)-
furan-2-yl](phenyl)methanone (IVg). A mixture of
1.24 g (5 mmol) of compound III, 20 g of PPA, and
1.8 g (15 mmol) of benzoic acid was stirred for 8 h at
140–150°C. The product was isolated as described
above for acetyl derivative IVf. Yield 1.18 g (67%),
mp 180–181°C (from ethanol). IR spectrum:
ν 1640 cm–1 (C=O). 1H NMR spectrum, δ, ppm: 4.21 s
(3H, NCH3), 7.38 d (1H, 3′-H, J = 3.9 Hz), 7.44 d (1H,
4′-H, J = 3.9 Hz), 7.51–7.56 m (3H, 8-H, m-H), 7.62 t
(1H, p-H, J = 7.2 Hz), 7.76 d (1H, 4-H, J = 9.0 Hz),
7.98 d (2H, o-H, J = 8.4 Hz), 8.04 d (1H, 5-H, J =
9.0 Hz), 8.93 d (1H, 7-H, J = 4.1 Hz), 8.97 d (1H, 9-H,
J = 8.2 Hz). Found, %: C 75.07; H 4.53; N 12.17.
C22H15N3O2. Calculated, %: C 74.78; H 4.28; N 11.89.
5-(3-Methyl-3H-imidazo[4,5-f]quinolin-2-yl)-
furan-2-carbaldehyde (IVe). A mixture of 1.24 g
(5 mmol) of compound III and 2.8 g (20 mmol) of
urotropine in 20 g of polyphosphoric acid was stirred
for 3 h at 90–100°C. The mixture was diluted with
100 ml of water and carefully neutralized with
a solution of ammonia. The precipitate was filtered off
and recrystallized. Yield 0.66 g (47%), mp 219–220°C
(from isopropyl alcohol). IR spectrum: ν 1680 cm–1
(C=O). 1H NMR spectrum, δ, ppm: 4.28 s (3H, NCH3),
7.42 d (1H, 3′-H, J = 3.6 Hz), 7.44 d (1H, 4′-H, J =
3.6 Hz), 7.55 d.d (1H, 8-H, J = 4.2 Hz), 7.76 d (1H,
4-H, J = 9.0 Hz), 8.04 d (1H, 5-H, J = 9.3 Hz), 8.93 d
(1H, 7-H, J = 4.2 Hz), 8.97 d (1H, 9-H, J = 8.1 Hz),
9.75 s (1H, CHO). Found, %: C 69.66; H 4.17;
N 14.87. C15H11N3O2. Calculated, %: C 69.30; H 4.00;
N 15.15.
REFERENCES
1. Oleinikova, L.Ya., Cand Sci. (Chem.) Dissertation,
Rostov-on-Don, 1972.
1-[5-(3-Methyl-3H-imidazo[4,5-f]quinolin-2-yl)-
furan-2-yl]ethanone (IVf). A mixture of 1.24 g
(5 mmol) of compound III and 1.53 g (15 mmol) of
acetic anhydride in 20 g of PPA was stirred for 6 h at
110–120°C. The mixture was then diluted with 50 ml
of water and carefully neutralized with a solution of
ammonia. The product was extracted into methylene
2. Weidenhagen, R., Ber., 1936, p. 2263.
3. El’chaninov, M.M., Oleinikova, L.Ya., and Simo-
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