Synthesis of 2-Phenylquinoline and its Derivatives by Multicomponent Reaction of Aniline, Benzylamine, Alcohols, and CCl4 Catalyzed by FeCl3·6H2O

Article abstract of DOI:10.1002/jhet.2394

(Chemical Equation Presented) 2-Phenylquinolines, 2-phenyl-3-methyl-quinolines, and 2-phenyl-3-ethylquinolines were synthesized in high yields (78-90%) by the reaction of aniline, benzylamine, aliphatic alcohols (ethanol, n-propanol, n-butanol), and CCl₄ catalyzed by FeCl₃·6H₂O in tetrachloromethane.

Full text of DOI:10.1002/jhet.2394

Month 2015
Synthesis of 2-Phenylquinoline and its Derivatives by Multicomponent
Reaction of Aniline, Benzylamine, Alcohols, and CCl4
Catalyzed by FeCl3·6H2O
*
Ravil Khusnutdinov, Alfiya Bayguzina, Rishat Aminov, and Usein Dzhemilev
Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, 141 Prospekt Oktyabrya, Ufa, 450075, Russia
*
E-mail: khusnutdinovri47@gmail.com
Additional Supporting Information may be found in the online version of this article.
Received October 7, 2014
DOI 10.1002/jhet.2394
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
2-Phenylquinolines, 2-phenyl-3-methyl-quinolines, and 2-phenyl-3-ethylquinolines were synthesized in
high yields (78–90%) by the reaction of aniline, benzylamine, aliphatic alcohols (ethanol, n-propanol, n-
butanol), and CCl4 catalyzed by FeCl3·6H2O in tetrachloromethane.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
benzylidenebenzylamine (3) in a quantitative yield [10]. The
reaction also involves CCl4 (Scheme 2).
2-Phenyl-substituted quinolines are very important quin-
oline derivatives. They serve as synthons for the prepara-
tion of highly efficient antimalarial and antitumor agents [1].
Several methods for the preparation of 2-phenyl-substituted
quinolines are known. For instance, 2-phenylquinoline is pre-
pared by arylation of quinoline or 2-chloroquinoline by
ZnPh2, MgPh2, or PhB(OH)2 in the presence of metal com-
plex catalysts [2]. 2-Phenylquinoline can be prepared accord-
ing to Friedländer by acid-catalyzed cyclocondensation of о-
nitrobenzaldehyde with acetophenone [3], by the reaction of
о-aminobenzyl alcohol with acetophenone (or 1-phenylethanol)
in the presence of ruthenium catalysts [4] or by aniline conden-
sation with benzaldehyde and acrylic acid in the presence of a
palladium catalyst [5].
It should be noted that the synthesis of quinolines can
be implemented through the multicomponent reaction of
anilines with aldehydes and alkenes [6], between anilines
and styrene oxides [7], as well as 2-amino-aryl alcohols
and β-ketoesters [8] under the action of anhydrous FeCl3
as the catalyst.
Relying on these data, we attempted to synthesize 2-
phenyl-substituted quinolines by multicomponent condensation
of aniline, benzylamine, alcohol, and CCl4 using FeCl3·6H2O
as the catalyst with in situ generation of N-benzylideneaniline
4 and aldehyde 2 needed to assemble the quinoline molecule.
In the next stage, compound 4 reacts with RCH2CHO to give
intermediate 5 [11], which undergoes heterocyclization, de-
hydrogenation, and dehydration yielding quinoline. The
chart of the possible transformation is presented in the
succeeding texts (Scheme 3).
This idea was implemented in experiments. The reaction
of aniline with benzylamine and alcohols RCH2CH2OH
(R = H, CH3, C2H5) in the presence of FeCl3·6H2O in tetra-
chloromethane was found to give 2-phenylquinolines 6–8
in 78–90% yield. The reaction proceeds at 140°С over a
8 h period at the following molar ratios of the reactants
and the catalyst: [benzylamine]:[aniline]:[alcohol]:[CCl4]:
[catalyst]= [100]:[30]:[200]:[100]:[1] (Scheme 4).
According to iodometric and mercurimetric titration and
GLC analysis, apart from the starting compounds and 2-
phenylquinolines 6–8, the reaction mixture contained
This communication reports the synthesis of 2-
phenylquinolines by multicomponent condensation of ani-
line, benzylamine, ethyl, n-propyl, or n-butyl alcohol, and
CCl4 catalyzed by FeCl3·6H2O.
+
“active chlorine”, HCl, NH4 , and chloroform. The con-
centration of water determined by the Fischer titration
was 5.2%, being consistent with the theoretical value of
4.6%. The set of these data supports the mechanism of for-
mation of quinolines 6–8 presented in Scheme 3.
RESULTS AND DISCUSSION
To verify this reaction chart, test experiments with synthe-
sized authentic N-benzylideneaniline 4 with ethyl alcohol
and acetaldehyde were carried out. Under typical conditions
(140°C, 8h), compound 4 successfully reacted with ethanol
to give 2-phenylquinoline 6 in a 79% yield. As regards acet-
aldehyde, it smoothly reacts with N-benzylideneaniline 4
without requiring drastic conditions (Scheme 5).
Previously, we have shown that aldehydes can be prepared
by oxidation of primary alcohols with CCl4 in the presence of
metal complex catalysts, in particular, FeCl3·6H2O [9]. An in-
termediate of this reaction is alkyl hypochlorite (1), which de-
composes to afford HCl and aldehyde (2) (Scheme 1).
Meanwhile, FeCl3·6H2O also catalyzes an interesting trans-
formation of benzylamine, resulting in the formation of N-
© 2015 HeteroCorporation

R. Khusnutdinov, A. Bayguzina, R. Aminov, and U. Dzhemilev
Vol 000
Scheme 1.
Scheme 2. Synthesis of N-benzylidenebenzylamine (3).
Scheme 3. The proposed mechanism of the reaction.
Scheme 4. Synthesis of 2-phenylquinolines 6–8.
Scheme 5. Verification synthesis reaction of 2-phenylquinoline (6).
Thus, the multicomponent condensation of aniline,
benzylamine, alcohol, and CCl4 catalyzed by FeCl3·6H2O
provided the synthesis of 2-phenylquinolines 6, 2-phenyl-
3-methyl-quinolines 7, 2-phenyl-3-ethylquinolines 8 in
90, 84, and 78% yields, respectively.
stirring and controlled heating. The ampoule was charged with
FeCl3·6H2O (0.027 mmol), benzylamine (2.8 mmol), аniline
(0.86 mmol), alcohol (5.6 mmol) and carbon tetrachloride
(0.27 mmol) in an argon flow. The sealed ampoule was placed
in an autoclave. The autoclave was air-tightly closed and heated
at 140°С for 8 h under continuous stirring. After completion of
the reaction, the autoclave was cooled to room temperature, the
ampoule was opened, and the reaction mixture was treated with
diluted (10%) hydrochloric acid. The water layer was separated,
neutralized with 10% solution of sodium hydroxide, and
extracted with dichloromethane. The solvent was removed. The
organic residue was distilled in vacuo. The purity of the end
product was 98% (GLC). Oily liquid; bp 143–144°С/0.2 mm;
yield 90%; 1H NMR (CDCl3, 400.13 MHz, ppm): δ 7.76 (d,
J = 8 Hz, 1H, СH), 7.83 (d, J = 8 Hz, 1H, CH), 7.85 (t, J = 8 Hz,
1H, СH,), 7.40–7.60 (m, 1H, СH), 8.33 (d, J = 8.8 Hz, 1H, СH),
8.50 (d, J = 8.4 Hz, 1H, СH), 8.18 (d, J = 7.6 Hz, 1H, СH,), 8.18
(d, J = 7.6 Hz, 1H, СH), 7.40–7.60 (m, 3H, СH). 13C NMR
EXPERIMENTAL
1Н, 13С NMR spectra were measured on a Bruker Avance-400
spectrometer (400.13 and 100.62 MHz, respectively) in CDCl3;
the chemical shifts are referred to TMS. Mass spectra were run
on a Shimadzu GCMS-QP2010Plus GC/MS spectrometer (an
SPB-5 capillary column, 30 m × 0.25 mm, helium as a carrier
gas, temperature programming from 40 to 300°C at 8 °C/min,
evaporation temperature 280°C, temperature of the ion source
200°C, ionization energy 70 eV).
The synthesis of 2-phenylquinoline (6)[12]. The reactions
were carried out in a glass ampoule (V = 10 mL), placed in a
stainless steel micro autoclaves (V = 17 mL) under constant
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis of 2-Phenylquinolines
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(CDCl3, 100.62 MHz, ppm): δ 119.52, 127.15, 127.21, 127.67,
127.80, 131.83, 139.01, 145.91, 157.89, 128.21, 129.07, 130.40,
137.16. MS: m/z (%) = 205.00[M]+ (100), 102 (10), 176 (5), 76
(4), 51 (2).
3-Methyl-2-phenylquinoline (7)[12].
Following the same
procedure described for the synthesis of (6). Oily liquid; bp
1
137–138°С/0.2 mm; yield 84%; H NMR (CDCl3, 400.13 MHz,
ppm): δ 2.41 (s, 3H, CH3), 7.38–7.48 (m, 5H, СH), 7.55–7.58
(m, 1H, СH), 7.60–7.64 (m, 1H, СH), 7.93 (s, 1H, СH), 8.13
(d, J = 8 Hz, 2H, СH,). 13C NMR (CDCl3, 100.62 MHz, ppm):
δ 20.53, 126.23, 126.50, 127.45, 127.96, 128.11, 129.19,
136.61, 146.40, 160.30, 128.65, 128.79, 129.04, 140.73. MS:
m/z (%) = 218.05[M]+ (100), 209 (5), 75 (4), 63 (4), 40 (3).
3-Ethyl-2-phenylquinoline (8)[12].
Following the same
procedure described for the synthesis of (6). Oily liquid; bp
1
150–152°С/0.2 mm; yield 78%; H NMR (CDCl3, 400.13 MHz,
ppm): δ 1.22 (t, J = 8 Hz, 3H, CH3), 2.66 (q, J = 8 Hz, 2H, CH2),
7.35–7.65 (m, 5H, СH), 7.62–7.68 (m, 1H, СH), 7.75–7.80 (m,
1H, СH), 8.06 (s, 1H, СH), 8.17 (d, J = 7.6 Hz, 2H, СH). 13C
NMR (CDCl3, 100.62 MHz, ppm): δ 14.75, 26.04, 126.20,
127.15, 127.67, 127.80, 129.72, 131.83, 134.96, 146.38,
160.66, 128.32, 128.76, 129.27, 140.94. MS: m/z (%) = 232.00
[M]+ (100), 217 (35), 109 (21), 77 (8), 63 (6), 52 (2).
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Acknowledgements. This work was financially supported by the
Russian Foundation for Basic Research (Grant No. 12-03-00183)
and a Grant of the RF President (Sci. Sch.–2136.2014.3).
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet