Synthesis of quinoline derivatives by multicomponent reaction using niobium pentachloride as lewis acid

Article abstract of DOI:10.1002/jhet.1980

The aim of this work was to investigate the use of NbCl5 as a Lewis acid in multicomponent reactions between benzaldehyde, aniline derivatives and phenylacetylene in the synthesis of quinoline derivatives. The effects of the temperature and substituents in the aromatic ring of the aniline were also evaluated. The reactions were carried out at low concentration of niobium and in relatively short reaction times, resulting in yields ranging from 67 to 96%.

Full text of DOI:10.1002/jhet.1980

Month 2014
Synthesis of Quinoline Derivatives by Multicomponent Reaction Using
Niobium Pentachloride as Lewis Acid
*
Aloisio de Andrade, Giovanny Carvalho dos Santos, and Luiz Carlos da Silva-Filho
Department of Chemistry, Faculty of Sciences, Laboratory of Organic Synthesis and Catalysis (LOSC),
São Paulo State University (UNESP), 17033-360, Bauru, São Paulo, Brazil
*
E-mail: lcsilva@fc.unesp.br
Received November 6, 2012
DOI 10.1002/jhet.1980
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
The aim of this work was to investigate the use of NbCl5 as a Lewis acid in multicomponent reactions
between benzaldehyde, aniline derivatives and phenylacetylene in the synthesis of quinoline derivatives.
The effects of the temperature and substituents in the aromatic ring of the aniline were also evaluated.
The reactions were carried out at low concentration of niobium and in relatively short reaction times,
resulting in yields ranging from 67 to 96%.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
reaction, the quinoline is obtained by heating aniline and
glycerol, using sulfuric acid as catalyst and dehydrating
agent, in the presence of an oxidizing agent (nitrobenzene).
One variation of the Skraup reaction is the Doebner–von
Miller method [33], in which the glycerol is substituted
by a,b-unsaturated carbonyl compounds. This method,
besides providing the formation of substituted quinoline
derivatives, has several advantages in terms of reaction
conditions, because the reaction can be caused by milder
Brønsted–Lowry acids or yet, by Lewis acids. In general,
these classic methods involve cyclization processes, in
which the substituted aromatic rings are the starting mate-
rials, and the heterocyclic nucleus is synthesized.
In contrast with these classic methods, another method
involving a multicomponent reaction (MCR) between
aromatic aldehydes, aniline derivatives, and phenylacetylene
in the presence of a Lewis acid as catalyst was described by
Zhang et al. [34] (Scheme 1).
Because of the applicability of several Lewis acids in this
type of reaction [35–42], in this work we have reported our
studies on the use of niobium pentachloride (NbCl5) as a cat-
alyst in these multicomponent reactions. The NbCl5 forms
chloro-bridged dimers in its solid state, in which each metal
is surrounded by a distorted octahedron of chlorine atoms.
This dimer can be seen as two octahedrons sharing an edge.
It is highly electrophilic and, therefore, can act as a Lewis
acid, catalyzing several organic reactions [43–50].
The synthesis of quinoline and its derivatives has been of
great interest for organic chemistry and medicinal chemistry
because a large number of natural products and drugs have
this heterocyclic nucleus in their structures [1–5]. Poly-
substituted quinolines, in particular, are very important
compounds, because of their several biological activities,
such as antimicrobial [6–8], antituberculosis [9,10], anti-
inflammatory [11,12], antileishmanial [13,14], antimalarial
[15,16], anticancer [17,18], anticonvulsant and antihyperten-
sive [19], cytotoxic [20,21], and also as HIV-1integrase
inhibitors [22], and so forth. In addition, quinoline deriva-
tives have also been used in polymer chemistry, electronics,
and optoelectronics organic because of their excellent
mechanical, electrical, and optical properties [23–27].
Among some natural products containing the quinoline
nucleus in their structures, we can name 1-(3,4-dime-
thoxybenzyl)-6,7-dimethoxyisoquinoline (1), known as
papaverine, obtained from poppy extracts (Papaver
somniferum L.). It is a relaxant that acts directly on smooth
muscles, thus being used in the treatment of erectile dysfunc-
tion and as cerebral vasodilator [28]. Compounds 2 and 3 are
examples of indoloquinoline alkaloids, present in a great
number of natural products, particularly the alkaloids
cryptolepine (indolo[2,3-b]quinoline) and camptothecin
(indolo[2,3-c]quinoline), respectively [29,30] (Figure 1).
There are several methods used to form the quinoline
nucleus [31], and the Skraup reaction [32] was one of the
first syntheses developed to obtain quinolines. In this
As part of our research work on synthetic methodolo-
gies using NbCl5 in a variety of reactions [51–60], in this
work, we described our studies in the multicomponent
© 2014 HeteroCorporation

A. de Andrade, G. C. dos Santos, and L. C. da Silva-Filho
Vol 000
Figure 1. Natural products that present the quinoline nucleus in their constitution: papaverine (1), cryptolepine (2) e camptothecin (3).
Scheme 1. Lewis acid-catalyzed multicomponent reaction between aldehydes, primary amines, and terminal alkynes.
Table 1
reactions between benzaldehyde, aniline derivatives, and
Results obtained from MCRs catalyzed by NbCl5.
phenylacetylene, for the synthesis of quinoline deriva-
tives, in the presence of NbCl5.
Temperature
(ꢀC)
Yield (%)
Aniline
R
Time (h)
(Product)a
RESULTS AND DISCUSSION
5a
5a
5b
5b
5c
5c
5d
5d
5e
5e
5f
25
110
25
110
25
110
25
110
25
110
25
110
25
110
25
110
H
H
Cl
Cl
I
96
24
96
24
96
24
96
24
96
24
96
24
96
24
96
24
36 (7a)
74 (7a)
43 (7b)
78 (7b)
48 (7c)
74 (7c)
46 (7d)
68 (7d)
34 (7e)
67 (7e)
49 (7f)
84 (7f)
41 (7g)
81 (7g)
90 (7h)
96 (7h)
The multicomponent reactions between benzaldehyde
(4) (1.0 eq.), aniline derivatives (5a–h) (1.0 eq.), and
phenylacetylene (6) (1.0 eq.) were conducted under air
atmosphere, at room temperature or reflux, under constant
stirring and using anhydrous acetonitrile (CH3CN) as
solvent. Niobium pentachloride was used as a catalyst in
the proportion of 50% for each mole of aniline derivative
used (Scheme 2).
I
Me
Me
Et
Et
OMe
OMe
t-But
t-But
NO2
NO2
5f
The products 7(a–h) were isolated in a chromatographic
column using silica gel and then were characterized by
5g
5g
5h
5h
1
spectroscopic (RMN H, RMN 13C, and FTIR) and spec-
trometric (HRMS) methods. Table 1 shows the results
obtained for these multicomponent reactions that were
catalyzed by NbCl5.
MCRs, multicomponent reaction.
aisolated yield.
Scheme 2. NbCl5-catalyzed multicomponent reaction between benzaldehyde (4), aniline derivatives (5a–h), and phenylacetylene (6).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Quinoline Derivatives by Multicomponent Reaction Using Niobium
Pentachloride as Lewis Acid
Results presented in Table 1 have shown that the
reaction, when carried out under reflux, presents good
yields in a good reaction time. On the other hand, most
reactions—when carried out at room temperature—
presented low yields even when a longer reaction time was
used. However, the reaction in which the aniline derivative
5h was used presented a good yield even at room tempera-
ture. One possible explanation is that the delocalization of
the electrons, promoted by the nitro group, causes the forma-
tion of an aromatic compound, the product of this reaction.
One possible mechanism for the multicomponent reac-
tion between aldehydes, amines, and alkynes catalyzed
by NbCl5 is presented in Scheme 3. We believe the mech-
anism for the reaction to be the same as the one proposed
by Zhang et al. [34], using FeCl3 as a Lewis acid. Initially,
because of the stability of the niobium as a complex, there
is the formation of a complex between the alkyne and the
NbCl5. Following that the complex formed undergoes a
nucleophilic addition of the imine generated in situ from
the aldehyde and the primary amine, producing the
Scheme 3. Proposed reaction mechanism for the multicomponent reaction to the synthesis of quinoline derivatives catalyzed by NbCl5.
Table 2
Comparison of this work with literature results for synthesis of 2,4-diphenylquinoline (7a) catalyzed by various Lewis acid.
Entry
Lewis acid
NbCl5
NbCl5
FeCl3
FeCl3
FeCl3
Yb(Pfb)3
Yb(Pfb)3
Yb(Pfb)3
AgNTf2/HOTf
InCl3
In/HCl
I2
AuCl3/CuBr
AlCl3
Solvent
CH3CN
CH3CN
1,2-Dichlorothane
Toluene
None
Temperature
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
Reflux
rt
24
96
12
24
48
12
24
48
24
24
18
12
288
48
48
74
36
93
70
Trace
88
82
10
90
90
72
61
55
Trace
Trace
Reflux
Reflux
110ꢀC
80ꢀC
Reflux
35ꢀC
80ꢀC
Reflux
Reflux
Reflux
rt
None
Toluene
CH2Cl2
Toluene
Toluene
H2O
MeNO2
MeOH
None
9
10
11
12
13
14
15
110ꢀC
110ꢀC
ZnCl2
None
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. de Andrade, G. C. dos Santos, and L. C. da Silva-Filho
Vol 000
8.21 (d, J = 7.3 Hz, 2H), 7.93 (d, J = 8.3 Hz, 1H), 7.84
(s, 1H), 7.73–7.78 (m, 1H), 7.46–7.60 (m, 9H); 13C NMR
(125 MHz, CDCl3): d 157.0, 149.2, 148.9, 139.7, 138.4, 130.2,
129.6, 129.4, 129.3, 128.9, 128.7, 128.5, 127.7, 126.4, 125.8,
125.7, 119.5; FTIR (KBr): 3059, 2924, 2852, 1732, 1589, 1547,
1489, 1358, 1028, 768, 690, 590 cmÀ1; ESI-HRMS: m/z calcd for
propargylamine. The triple bond of the propargylamine can be
activated by the NbCl5, promoting an intramolecular nucleo-
philic attack by the N-substituted aromatic ring. The resulting
complex decomposes generating the dihydroquinoline and
regenerating the catalyst. In the presence of oxygen, the
dihydroquinoline can yet be oxidized, forming a quinoline
derivative.
In Table 2, the results obtained in this work are com-
pared with other studies described in the literature. [34–41]
In Table 2 can be noted, that independent of the Lewis
acid used [34–41], the presence of solvent and high
temperatures are necessary to obtain good yields on synthe-
sis of quinoline derivatives. The NbCl5 when compared with
other Lewis acids is efficient and present similar results, with
good reaction times and competitive yields.
C21H16N [M+ H]+: 282.12827; found 282.1276.
6-Chloro-2,4-diphenylquinoline (7b) [37,40,41]. White solid;
mp 123–125ꢀC; 1H NMR (400 MHz, CDCl3): d 8.15–8.21 (m, 3H),
7.87 (d, J = 2.3Hz, 1H), 7.84 (s, 1H), 7.67 (dd, J = 8.9, 2.3Hz, 1H),
7.45–7.61 (m, 8H); 13C NMR (100 MHz, CDCl3): d 157.1, 148.5,
147.2, 139.2, 137.7, 132.2, 131.7, 130.5, 129.6, 129.5, 128.9,
128.8, 128.7, 127.5, 126.5, 124.5, 120.1; FTIR (KBr): 3057,
2924, 1770, 1587, 1481, 1356, 1151, 883, 823, 777, 754, 696,
544 cmÀ1; ESI-HRMS: m/z calcd for C21H15ClN [M+H]+:
316.08930; found 316.0879.
6-Iodo-2,4-diphenylquinoline (7c). Light yellow liquid; 1H
NMR (400 MHz, CDCl3): d 8.25 (sl, 1H), 8.16–8.21 (m, 2H),
7.93–7.99 (m, 2H), 7.82 (s, 1H), 7.51–7.61 (m, 8H); 13C NMR
(100 MHz, CDCl3): d 157.4, 148.1, 147.7, 139.2, 138.3, 137.7,
134.4, 131.8, 129.7, 129.5, 128.9, 128.8, 128.7, 127.6, 127.2,
120.0, 92.1; FTIR (KBr): 3059, 2924, 2852, 1701, 1662, 1591,
1491, 1448, 769, 746, 688, 590 cmÀ1; ESI-HRMS: m/z calcd
In conclusion, it has been shown that the NbCl5 is a good
catalyst for multicomponent reactions between benzaldehyde,
aniline derivatives, and phenylacetylene to obtain quinoline
derivatives. The results obtained showed that the reaction,
when carried out under reflux, occurred in a good reaction
time and presented good yields that ranged from 67 to 96%.
for C21H15IN [M + H]+: 408.02492; found 408.0243.
6-Methyl-2,4-diphenylquinoline (7d) [36–40]. Yellow solid;
mp 129–131ꢀC;1H NMR (400 MHz, CDCl3):
d 8.13–8.19
(m, 3H), 7.78 (s, 1H), 7.65 (sl, 1H), 7.49–7.59 (m, 8H), 7.42–7.48
(m, 1H), 2.48 (s, 3H); 13C NMR (100MHz, CDCl3): d 156.1,
148.5, 147.4, 139.8, 138.7, 136.3, 131.8, 129.8, 129.6, 129.2,
128.8, 128.6, 128.3, 127.5, 125.7, 124.4, 119.5, 21.9; FTIR
(KBr): 3051, 2914, 2851, 1616, 1543, 1448, 1356, 877, 825, 785,
EXPERIMENTAL
All reactions were performed under an air atmosphere, unless
otherwise specified. Acetonitrile was distilled from calcium
hydride. All of the chemicals were purchased from Sigma-Aldrich
Chemical Co. (St. Louis, MO, USA) and used without further puri-
fication. Thin-layer chromatography was performed on 0.2 mm
Merck 60 F254 silica gel aluminum sheets, which were visualized
with a vanillin/methanol/water/sulfuric acid mixture. ACROS 80-
230 silica gel 60 was employed for column chromatography. A
Perkin-Elmer RX-FTIR System was used to record IR spectra (neat
or film). Bruker DRX 400 and DRX 500 spectrometers were
employed for the NMR spectra (CDCl3 solutions) using
tetramethylsilane as internal reference for 1H and CDCl3 as an inter-
nal reference for 13C. A Bruker FTIR model VERTEX 70 was used
to record IR spectra (neat or film). HRMS analyses were recorded in a
micrOTOF (Bruker), with ESI-TOF detector oper on positive mode.
General procedure for the multicomponent reaction of
benzaldehyde, aniline derivatives, and phenylacetylene with
754, 696, 548 cmÀ1
; ESI-HRMS: m/z calcd for C22H18N
[M+ H]+: 296.14392; found 296.1443.
6-Ethyl-2,4-diphenylquinoline (7e) [42].
Yellow solid; mp
87–89ꢀC; 1H NMR (400MHz, CDCl3): d 8.14–8.21 (m, 3H), 7.78
(s, 1H), 7.67 (sl, 1H), 7.61 (dd, J= 8.6, 2.0 Hz, 1H), 7.43–7.59
(m, 8H), 2.73–2.81 (m, 2H), 1.25–1.29 (m, 3H); 13C NMR
(100 MHz, CDCl3): d 156.1, 148.6, 147.6, 139.8, 138.6,
133.4, 130.6, 130.0, 129.6, 129.2, 128.8, 128.6, 128.3,
127.5, 125.7, 123.2, 119.5, 29.2, 16.0; FTIR (KBr): 3028, 2962,
2928, 1701, 1518, 1450, 1360, 1028, 887, 820, 760, 692,
;
590 cmÀ1 ESI-HRMS: m/z calcd for C23H20N [M+ H]+:
310.15957; found 310.1594.
6-Methoxy-2,4-diphenylquinoline (7f) [37–40]. Yellow solid;
mp 118–120ꢀC; 1H NMR (400 MHz, CDCl3): d 8.16–8.33 (m, 3H),
7.80 (s, 1H), 7.41–7.63 (m, 9H), 7.21 (d, J =1.5Hz, 1H), 3.82
(s, 3H); 13C NMR (100 MHz, CDCl3): d 158.0, 154.4, 147.9, 144.6,
139.6, 138.5, 131.5, 129.3, 128.9, 128.8, 128.6, 128.3, 127.5,
126.7, 122.3, 119.9, 103.7, 55.5; FTIR (KBr): 3055, 2928, 1734,
NbCl5.
To a solution of NbCl5 (50 mol%) in 7.0 mL of
anhydrous acetonitrile, maintained at room temperature, under
an air atmosphere, we added a solution of the benzaldehyde
(1.0 mmol), phenylacetylene (1.0 mmol), and respectively
aniline (5a–h) (1.0 mmol) in 3.0 mL of anhydrous acetonitrile.
After completion of the addition, stirring was continued at
room temperature or reflux (Table 1). The reaction mixture
was quenched with water addition (3.0 mL). The mixture was
extracted with ethyl acetate (10.0 mL). The organic layer was
separated and washed with saturated sodium bicarbonate
solution (3 Â 10.0 mL), saturated brine (2 Â 10.0 mL), and then
dried over anhydrous magnesium sulfate. The solvent was
removed under vacuum and the products were purified by
column chromatography through silica gel using mainly a
mixture of hexane and ethyl acetate (9.5:0.5) as eluent.
1618, 1547, 1489, 1360, 1221, 1026, 835, 760, 694, 615cmÀ1
;
ESI-HRMS: m/z calcd for C22H18NO [M + H]+: 312.13884; found
312.1381.
6-(tert-Butyl)-2,4-diphenylquinoline (7g).
Light yellow
1
liquid; H NMR (400 MHz, CDCl3): d 8.14–8.22 (m, 3H), 7.87
(d, J = 2.0 Hz, 1H), 7.84 (dd, J = 8.8, 2.0 Hz, 1H), 7.79 (s, 1H),
7.42–7.61 (m, 8H), 1.35 (s, 9H); 13C NMR (100 MHz, CDCl3):
d 156.4, 149.2, 149.0, 147.3, 139.9, 138.6, 129.6, 129.2, 128.8,
128.6, 128.4, 127.5, 126.1, 125.2, 120.5, 119.5, 35.1, 31.5;
FTIR (KBr): 3053, 2955, 2864, 1618, 1585, 1522, 1356, 1026,
895, 771, 690, 588, 548 cmÀ1; ESI-HRMS: m/z calcd for
C25H24N [M + H]+: 338.19087; found 338.1900.
2,4-Diphenylquinoline (7a) [36–40].
White solid; mp
6-Nitro-2,4-diphenylquinoline (7h) [41,42]. Yellow solid; mp
106–108ꢀC; 1H NMR (500 MHz, CDCl3): d 8.26 (d, J= 8.6 Hz, 1H),
256–258ꢀC; 1H NMR (400 MHz, CDCl3): d 8.87 (d, J=2.4Hz, 1H),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Quinoline Derivatives by Multicomponent Reaction Using Niobium
Pentachloride as Lewis Acid
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8.51 (dd, J= 9.2, 2.4Hz, 1H), 8.35 (d, J= 9.2Hz, 1H), 8.25 (m, 2H),
7.99 (s, 1H), 7.51–7.67 (m, 8H); 13C NMR (100 MHz, CDCl3):
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Acknowledgments. The authors would like to thank Fundação de
Amparo à Pesquisa do Estado de São Paulo (FAPESP), Conselho
Nacional de Desenvolvimento Científico e Tecnológico (CNPq),
Coordenadoria de Aperfeiçoamento de Pessoal do Nível
Superior (CAPES), and Pró-Reitoria de Pesquisa da UNESP
(PROPe-UNESP) for their financial support. We would also like
to thank CBMM – Companhia Brasileira de Mineralogia e
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet