Synthesis of polysubstituted analogues of the 4-methyl-2-phenylquinoline

Article abstract of DOI:10.14233/ajchem.2013.14253

A simple and convenient synthetic method for the direct synthesis of a series of polysubstituted analogues of the putative antifungal agent 4-methyl-2-phenylquinoline, a mimic of the natural bioactive 4-methoxy-2-phenylquinoline is reported.

Full text of DOI:10.14233/ajchem.2013.14253

Asian Journal of Chemistry; Vol. 25, No. 11 (2013), 6055-6058
http://dx.doi.org/10.14233/ajchem.2013.14253
Synthesis of Polysubstituted Analogues of the 4-Methyl-2-phenylquinoline
*
A.A. AL-QAHTANI, T.M. AL-TURKI, M. KHAN, A.A. MOUSA and H.Z. ALKHATHLAN
Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh-11451, Saudi Arabia
*Corresponding author: Fax: +966 4675992; Tel: +966 4675910; E-mail: khathlan@ksu.edu.sa
(Received: 30 June 2012;
Accepted: 26 April 2013)
AJC-13400
A simple and convenient synthetic method for the direct synthesis of a series of polysubstituted analogues of the putative antifungal agent
4-methyl-2-phenylquinoline, a mimic of the natural bioactive 4-methoxy-2-phenylquinoline is reported.
Key Words: Quinolines, 2-Aminoacetophenone, 2-Hydroxyacetophenones, 2-(4-Methyl-2-quinolinyl)aniline.
fungal activities21b,21d. In particular, 4-methyl-2-phenylquinoline
(1) and 6-bromo-4-methyl-2-(β-pyridyl)quinoline (2) (Fig. 1)
showed highly potent antifungal activities against dermato-
INTRODUCTION
Quinolines are known to play an important and key role
phytes21b,21d. However, perusal of literature reveals that only a
in pharmacologically active substances, clinical drugs and
naturally occurring products1. Quinolines either obtained from
limited number of methods are available for the synthesis of
nature or synthesized have been reported to possess broad
these compounds, which suffer several drawbacks such as
spectrum of biological activities including antimicrobial2,3,
multiple steps20e,22 and use of toxic reagents23. In our continued
anticancer4,5, antimalarial6,7, antiinflammatory8, antileishma-
interest on the synthesis of heterocyclic compounds24 and consi-
nial9,10, antiasthmatic11, antiviral12, antiamoebic13 and tyrosine
dering the promising biological activities of 4-methyl-2-phenyl
kinase inhibitor14 activities. In addition to wide applications
quinolines21b,21d, in this paper, we describe the synthesis of
in pharmaceuticals, quinolines are also used in electronics,
4-methyl-2-phenyl quinoline derivatives 4, 4a and 7a-g.
photonic properties15 and bioorganometallic processes16.
Owing to such a wide range of applications in various fields,
considerable progress in synthetic methodology applicable to
Me
Me
Br
quinoline alkaloids have been made during the past decade17.
Among various synthetic methods available in quinolines
synthesis, Friedlander condensation is still one of the most
N
N
convenient and most frequently used methods for the direct
synthesis of quinolines18. Based on Friedlander annulation
synthesis, several procedures have been reported to be effective
for the synthesis of quinolines19.
1
2
N
Fig. 1. Structure of 2-arylquinolines reported as antifungal agent
EXPERIMENTAL
2-Arylquinoline alkaloids are widely distributed in the
plant family Rutaceae embodying about 160 genera with 1600
species. Varieties of quinoline alkaloids have been isolated
from the plant species belonging to family Rutaceae20. 2,4-
Disubstituted quinolines specifically the 4-alkoxy-2-
arylquinolines which are abundantly present in Lunasia
amara20d,20e,20j and Galipea longiflora20a (family Rutaceae) have
attracted considerable interest due to their important biological
activities20a,20d,20j. Recently some mimic derivatives based on
4-alkoxy-2-aryl quinolines were synthesized21 and reported
to possess potent antiplatelet21a, antiangiogenesis21e and anti-
Melting points were determined on a Gallen Kamp melting
point apparatus and are uncorrected. 1H and 13C NMR spectra
were recorded with a JEOL ECP-400 spectrophotometer. The
NMR samples were prepared in CDCl3 with tetramethylsilane
(TMS) as an internal standard. The chemical shifts and coupling
constants (J) were expressed in δ and Hz, respectively. MS
spectra were recorded on Shimadzu QP5050A GC/MS system.
The thin layer chromatography (TLC) was carried out on
pre-coated Silica gel 60 F254 (0.2 mm, Merck) plates and
compounds were detected by UV light.

6056 Al-Qahtani et al.
Asian J. Chem.
General procedure for the preparation of the quinoline
derivatives 4, 4a and 7a-g
Hz), 7.91 (d, 1H, J = 8.06 Hz). 13C NMR (100 MHz, CDCl3):
MS: m/z (%) 253 (M+), 220, 207, 181, 102, 90, 63.
2-(5'-Chloro-2'-hydroxyphenyl)-4-methylquinoline
(7c): Orange crystal; m.p. 150 ºC; 1H NMR (400 MHz, CDCl3)
δ s, 3H), 6.98 (d, 1H, J = 8.80 Hz), 7.21 (dd, 1H, J = 8.80 and
2.20 Hz), 7.54 (m, 1H), 7.68 (s, 1H), 7.70 (m, 1H), 7.78 (d,
1H, J = 2.20 Hz), 7.91 (m, 1H), 7.97 (m, 1H). 13C NMR (100
MHz, CDCl3): MS: m/z (%) 269 (M+), 254, 204, 102, 63.
2-(5'-Bromo-2'-hydroxyphenyl)-4-methylquinoline
(7d): Brown crystal; m.p. 154 ºC; 1H NMR (400 MHz, CDCl3)
δ s, 3H), 6.98 (d, 1H, J = 8.80 Hz), 7.35 (dd, 1H, J = 8.80 and
2.20 Hz), 7.59 (m, 1H), 7.75 (m, 1H), 7.77 (s, 1H), 7.97 (d,
1H, J = 2.20 Hz), 7.99 (m, 1H), 8.07 (m, 1H). 13C NMR (100
MHz, CDCl3): MS: m/z (%) 314 (M+), 313, 298, 204, 191,
117, 102, 63.
Compounds 4 and 4a: In a 100 mL conical flask, 2-
aminoacetophenone (1 g, 7.4 mmol), one drop of diluted
hydrochloric acid and 0.8 g of silica gel were shaken well and
then subjected to microwave irradiation at 440 watt for 0.5 h.
The reaction flask was taken out of the microwave oven and
allowed to cool down at room temperature. The cooled reaction
mixture was dissolved in chloroform, silica gel was filtered
off and the filtrate was evaporated under vacuum. The resulting
oily material was digested with ethanol and cooled down to
give compound 4. The latter compound was refluxed with a
mixture of 5 mL acetic acid and 0.2 mL acetic anhydride for
2 h. Crushed ice was added to the reaction mixture and the
resulting solid was filtered and washed with cold water to
obtain 4a.
2-(2'-Hydroxy-5'-methoxyphenyl)-4-methylquinoline
(7e): Brown crystal; m.p. 98 ºC; 1H NMR (400 MHz, CDCl3)
δ s, 3H), 3.82 (s, 3H), 6.93 (dd, 1H, J = 8.80 and 2.93 Hz),
6.99 (d, 1H, J = 8.80 Hz), 7.35 (d, 1H, J = 2.93 Hz), 7.50 (m,
1H), 7.66 (m, 1H), 7.69 (s, 1H), 7.88 (m, 1H), 7.94 (m, 1H).
13C NMR (100 MHz, CDCl3): MS: m/z (%) 265 (M+), 250,
194, 168, 115, 102, 63.
Compounds 7a-g: To a mixture of 2-aminoacetophenone
(1 g, 7.4 mmol) and the appropriate 2-hydroxyacetophenone
derivative (8.148 mmol) in 100 mL conical flask, one drop of
diluted hydrochloric acid and 0.8 g of silica gel were added
and the reaction flask was shaken well and subjected to
microwave irradiation at 600 watt for 1 h. The reaction flask
was taken out of the microwave oven and allowed to cool down
at room temperature. The cooled reaction mixture was dissolved
in chloroform and filtered with chloroform washing to isolate
organic material from silica gel. The chloroform soluble
material was concentrated and the resulting solid was recrys-
tallized from ethanol to give the quinoline derivatives 7a-g.
2-(3',5'-Dichloro-2'-hydroxyphenyl)-4-methylquinoline
(7f): Brown crystal, m.p. 205 ºC; 1H NMR (400 MHz, CDCl3)
δ s, 3H), 7.41 (d, 1H, J = 2.93 Hz), 7.63 (m, 1H), 7.75 (d, 1H,
J = 2.93 Hz), 7.76 (s, 1H), 7.79 (m, 1H), 8.00 (m, 1H), 8.10
(m, 1H). 13C NMR (100 MHz, CDCl3): MS: m/z (%) 304 (M+),
303, 288, 204, 115, 102, 63.
2-(2'-Hydroxy-6'-methoxyphenyl)-4-methylquinoline
(7g): Dark brown powder; m.p. 115 ºC; 1H NMR (400 MHz,
CDCl3) δ s, 3H), 3.91 (s, 3H), 6.50 (d, 1H, J = 8.06 Hz), 6.74
(d, 1H, J = 8.06 Hz), 7.22 (t, 1H, J = 8.06 Hz), 7.51 (m, 1H),
7.64 (m, 1H), 7.90 (m, 1H), 7.98 (m, 1H), 8.28 (s, 1H). 13C
NMR (100 MHz, CDCl3): MS: m/z (%) 265 (M+), 250, 234,
144, 115, 102, 63.
Spectral data for compounds
2-(2'-Aminophenyl)-4-methylquinoline25,26 (4):Pale yellow
powder; m.p. 58-59 ºC; 1H NMR (400 MHz, CDCl3): δ 2.74
(s, 3H), 6.10 (brs, 2H), 6.81 (m, 2H), 7.20 (m, 1H), 7.53 (t,
1H, J = 8.06 Hz), 7.66 (s, 1H), 7.69 (t, 1H, J = 8.06 Hz), 7.70
(m, 1H), 7.96 (d, 1H, J = 8.06 Hz), 8.08 (d, 1H, J = 8.06 Hz).
13C NMR (100 MHz, CDCl3): 19.2, 117.5, 117.7, 121.2, 121.8,
123.7, 126.1, 126.6, 129.3, 129.5, 129.9, 130.3, 145.1, 146.6,
147.3, 158.9. MS: m/z (%) 235 (M+), 233, 219, 109.
2-(2'-Acetamidophenyl)-4-methylquinoline (4a): White
fine crystal; m.p. 120 ºC; 1H NMR (400 MHz, CDCl3): δ 2.23
(s, 3H), 2.79 (s, 3H), 7.20 (m, 1H), 7.44 (m, 1H), 7.61 (t, 1H,
J = 8.06 Hz), 7.72 (s, 1H), 7.77 (t, 1H, J = 8.06 Hz), 7.81 (m,
1H), 8.02 (d, 1H, J = 8.06 Hz), 8.04 (d, 1H, J = 8.06 Hz), 8.60
(m, 1H), 12.92 (brs, 1H). 13C NMR (100 MHz, CDCl3): δ 19.3,
25.4, 121.5, 123.4, 124.0, 125.1, 126.8, 126.9, 128.8, 129.3,
130.2, 130.6, 138.5, 143.9, 145.6, 146.9, 157.4, 168.8. MS:
m/z (%) 276 (M+), 261, 233, 217, 115.
RESULTS AND DISCUSSION
In a previous study24d, we prepared a series of imine
derivatives (Schiff bases) from the reaction of 2-hydroxy-
acetophenones with alkyl amines under microwave irradiation.
However, when the same reaction was carried out using 2-
aminoacetophenones with alkyl amines under the same
conditions, the reaction did not proceeded and we obtained
only starting materials even after heating the reaction mixture
for long periods of time. In order to obtain an appropriate
reaction condition for the synthesis of the desired imine
derivatives, we examined the reaction of 2-aminoacetophenones
with amino derivatives in the presence of silica gel and a drop
of diluted hydrochloric acid which upon purification led to
the formation of a light yellow powder, that turned out not to
be the expected schiff base 3 (Scheme-I). Analysis of the
spectral data (MS, 1H and 13C NMR) of the product ruled out
the possible formation of the schiff base 3. The structure
features of the product confirmed the formation of 2-(2'-amino-
phenyl)-4-methylquinoline (4) (Scheme-I). This reaction was
repeated many times with and without amine derivatives and
found that the formation of the quinoline derivative 4 was not
affected by the presence of the amines. Quinoline moiety 4
2-(2'-Hydroxyphenyl)-4-methylquinoline (7a): Brown
yellow powder; m.p. 70 ºC; 1H NMR (400 MHz, CDCl3) δ s,
3H), 6.92 (t, 1H, J = 8.06 Hz), 7.08 (d, 1H, J = 8.06 Hz), 7.31
(t, 1H, J = 8.06 Hz), 7.53 (m, 1H), 7.69 (m, 1H), 7.80 (s, 1H),
7.88 (d, 1H, J = 8.06 Hz), 7.92 (m, 1H), 7.98 (m, 1H). 13C
NMR (100 MHz, CDCl3): MS: m/z (%) 235 (M+), 220, 207,
181, 102, 90, 63.
2-(5'-Fluoro-2'-hydroxyphenyl)-4-methylquinoline
(7b): Grey crystal; m.p. 76 ºC; 1H NMR (400 MHz, CDCl3) δ
s, 3H), 6.98 (d, 1H, J = 8.80 Hz), 7.02 (dd, 1H, J = 8.80 and
2.93 Hz), 7.48 (d, 1H, J = 2.93 Hz), 7.51 (t, 1H, J = 8.06 Hz),
7.60 (s, 1H), 7.67 (t, 1H, J = 8.06 Hz), 7.87 (d, 1H, J = 8.06

Vol. 25, No. 11 (2013)
Synthesis of Polysubstituted Analogues of the 4-Methyl-2-phenylquinoline 6057
2-phenylquinolines are being prepared via dimerization of
2-aminoacetophenones.
N
R
X
NH2
3
O
Silica gel, dil. HCl
R-NH2
+
ACKNOWLEDGEMENTS
M.W.
NH2
Ac2O
This project was supported by King Saud University,
Deanship of Scientific Research, College of Science, Research
Center.
AcOH,
∆
N
N
H2
N
HN
O
4
4a
Scheme-I
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Scheme-II
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We have developed a convenient, safe and efficient one
step procedure for the direct synthesis of biologically important
polysubstituted quinolines. Synthetic methods for the construc-
tion of putative antifungal 4-methyl-2-phenylquinoline,
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