Efficient synthesis of 2,4-disubstituted quinolines: Calix[n]arene- catalyzed Povarov-hydrogen-transfer reaction cascade

Article abstract of DOI:10.1039/c4ra02036g

A cascade process involving the Povarov reaction and hydrogen transfer catalyzed with p-sulfonic acid calix[4]arene was disclosed and afforded the synthesis of 2,4-disubstituted quinolines in good yields under appropriate conditions in a single pot proces

Full text of DOI:10.1039/c4ra02036g

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Efficient synthesis of 2,4-disubstituted quinolines:
calix[n]arene-catalyzed Povarov-hydrogen-
transfer reaction cascade†
Cite this: RSC Adv., 2014, 4, 18612
Juliana Baptista Simoes,ab Aˆngelo de Fatima,c Adao Aparecido Sabino,c
Received 8th March 2014
Accepted 8th April 2014
˜
´
˜
c
a
*
Luiz Claudio Almeida Barbosa and Sergio Antonio Fernandes
DOI: 10.1039/c4ra02036g
www.rsc.org/advances
A cascade process involving the Povarov reaction and hydrogen quinolines remains poorly explored,11 especially regarding
transfer catalyzed with p-sulfonic acid calix[4]arene was disclosed and synthetic methods involving MCRs.12
afforded the synthesis of 2,4-disubstituted quinolines in good yields
A typical multicomponent Povarov reaction can be used to
prepare tetrahydroquinolines through the reaction of aryli-
mines, which are generated in situ by the condensation of an
amine and an aldehyde, with an electron-rich alkene. The tet-
rahydroquinolines that are formed may be transformed into
quinolines by oxidation.13 One example of this Povarov reaction
utilizes an arylimine as the oxidant in the cascade process.14
The efficiency of the Povarov reaction is primarily associated
with the nature of the alkene. The most commonly used alkenes
are vinyl ethers because they are very nucleophilic.15 The use of
less nucleophilic alkenes, such as styrene and its derivatives, in
the Povarov reaction has been rarely reported in the literature
due to the lower reactivities of these alkenes compared with
vinyl ethers.13a,16
Another important factor in the Povarov reaction is the
catalyst employed. In recent years, our group and others have
initiated the use of calix[n]arenes as catalysts in certain selective
reactions,17 including a Povarov reaction designed for the
synthesis of julolidines.18 Taking advantage of calix[n]arenes as
catalysts, we report an unprecedented tandem multicomponent
synthesis of 2,4-disubstituted quinoline derivatives via a
Povarov reaction in this study. As shown in Scheme 1, the
process involves initial production of the tetrahydroquinoline
derivative catalyzed by p-sulfonic acid calix[4]arene (CX4SO3H).
This intermediate is then dehydrogenated in situ by the imine
generated by condensation of aniline and aldehyde and/or the
acetonitrile, used as the solvent, to afford the desired quinoline
derivatives in a one pot process.
under appropriate conditions in a single pot process.
Introduction
The quinoline nucleus is a common heterocyclic system found
in natural and synthetic compounds, many of which have
interesting biological properties.1 Quinolines have generally
been synthesized using classical reactions, including the
4
Skraup,2 Doebner-von Miller,3 Friedlander, Ptzinger5 and
¨
Combes syntheses.6 Although many of these classical syntheses
were developed many decades ago, they are still frequently used
for the preparation of pharmaceutical agents and other new
quinoline derivatives. Despite the many methods available,
there are still limitations, especially with respect to obtaining an
adequate variety of substituents on both rings.7 Recent devel-
opments in the chemistry of quinoline derivatives have
demonstrated that an acid catalyzed cycloaddition of the
appropriate precursors could compete with the classical
syntheses in terms of efficacy and speed.8 The development of
multicomponent reactions (MCRs) in this eld has shown
interesting advantages typical of an ideal reaction, such as atom
and step economy, convergence, and exploratory power.9
Some 2,4-disubstituted quinolines have been reported as
anthelmintics10 and have been effective in the treatment of
leishmaniasis, a widespread protozoan disease in tropical areas
of South America.11g The synthesis of 2,4-disubstituted
a
´
Departamento de Quımica, CCE, Universidade Federal de Viçosa, Viçosa, MG,
36570-900, Brazil. E-mail: santonio@ufv.br; sefernandes@gmail.com
b
ˆ
˜
ˆ
Departamento de Ensino de Ciencias, Instituito Federal de Educaçao Ciencia e
Tecnologia Fluminense, Itaperuna, RJ, 28300-000, Brazil
cDepartamento de Quımica, ICEx, Universidade Federal de Minas Gerais, Belo
´
Horizonte, MG, 31270-901, Brazil
† Electronic supplementary information (ESI) available: Including experimental
data and characterization data (melting point, IR, 1H NMR, 13C NMR and
ESI-MS) for all compounds. See DOI: 10.1039/c4ra02036g
Scheme 1 Tandem multicomponent synthesis of 2,4-disubstuted
quinoline derivatives via a Povarov reaction.
18612 | RSC Adv., 2014, 4, 18612–18615
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increase in the reaction time led to an increase in the yield even
with smaller amounts of catalyst (entries 17–18).
Results and discussion
We further investigated the effect of the acid catalyst on the
product distributions (Table 2). The use of a macrocycle con-
sisting of six phenolic units, p-sulfonic acid calix[6]arene,
(CX6SO3H) afforded the desired quinoline in 63% yield, which
was similar to the result obtained with CX4SO3H (65%).
However, the use of the monomer 4-hydroxysulfonic acid (PHA)
as the catalyst resulted in only a 12% yield of the desired
quinoline (Table 2, entries 1–3). These results indicate that the
sulfonic and phenolic groups on the calix[n]arene structures are
not solely responsible for its catalytic effect. Among the other
Brønsted acids tested (Table 2, entries 4–6), only triuoroacetic
acid resulted in a yield comparable to those obtained with calix-
[n]arenes. However, the calix[n]arenes have the advantage of
been easily recovered and reused.17–19 Among the organic acids
tested, lactic, oxalic and citric acids afforded the desired quin-
oline in 9%, 33% and 24% yields, respectively (entries 7–11).
To investigate the scope of this auto-tandem catalysis in a
Povarov-hydrogen-transfer reaction cascade, several anilines
were subjected to the optimized conditions (acetonitrile as the
solvent, 1 mol% of CX4SO3H, 80 ꢀC, 12 h). The results are
provided in Fig. 1.
For the initial investigation of the use of CX4SO3H as a catalyst
in this process, 4-bromoaniline (1a), benzaldehyde (2) and
styrene (3) were employed as the substrates. The results for
optimization of the solvent, reaction time and catalyst concen-
tration are presented in Table 1. The use of acetonitrile provided
the desired 2,4-disubstuted quinoline 4a in 54% yield (entry 1).
Biodegradable green solvents, such as diethyl carbonate and
ethyl lactate, and common solvents, such as tetrahydrofuran,
dimethylsulfoxide and chloroform, did not provide good yields
of the desired product (entries 2–6). With the exception of ethyl
lactate, other solvents resulted in the formation of the imine 7a
in moderate to good yields (41–80%).
When the reaction was carried out in toluene, water, ethanol
or without solvent, mixtures of products 4a–7a were obtained,
including the desired quinoline in low yields (8–25%) (entries
7–10). As shown in entries 8 and 9, the use of polar protic
solvents (ethanol and water) favored the formation of the
intermediate tetrahydroquinoline in 46–49% yield.
The catalyst concentration was reduced to 1 mol% with only
a slight decrease in the yield (entries 11–16); however, an
The use of anilines with weak electron-withdrawing groups
(4a–c) or electron-donating substituents (4d–g) resulted in
better yields than the use of anilines with strong electron-
withdrawing substituents (4h–i). Quinolines that were di- and
tri-substituted on the aniline component were also obtained
Table 1 Optimization of the reaction conditionsa
Table 2 Effect of different Brønsted acid catalysts on the Povarov
reactiona
Yieldb (%)
CX4SO3H
Entry Solvents
(mol%)
4a 5a
6a 7a Totalc
1
2
3
4
5
6
7
8
CH3CN
Diethyl carbonate 25
25
54
—
—
—
—
—
5
—
—
—
8
42
—
—
—
—
74 79
—
60 60
80 80
41 49
50 75
25 88
30 92
96
Ethyl lactate
THF
DMSO
CHCl3
Toluene
H2O
25
25
25
25
25
25
25
25
20
10
—
Yieldc (%)
25 Trace
8
9
—
6
7
Entry
Catalystb (mol%)
4a
5a
6a
7a
Totald
49e
9
EtOH
—
46f
1
2
3
4
5
6
7
9
CX4SO3H (1.0)
CX6SO3H (0.7)
PHA (4.0)
CF3CO2H (4.0)
CH3CO2H (4.0)
H2SO4 (2.0)
Lactic acid (4.0)
Succinic acid (2.0)
Oxalic acid (2.0)
Citric acid (1.3)
65
63
12
64
—
7
29
—
33
24
—
8
—
—
—
—
Trace
—
—
34
18
—
33
—
—
58
8
—
7
99
96
65
97
73
77
87
38
73
74
10
11
12
13
14
15
16
17
18
17 10
15 40 82
40
33
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CNd
CH3CNd
58
59
43
40
46
5
—
—
—
—
98
92
43
81
53
—
73
70
—
30
40
Trace
5.0
2.0
1.0
0.5
10
1.0
36
5
22 20 88
—
—
—
—
32
34
78 83
—
—
62
65
94
99
10
11
Trace
50
Trace
a
The reaction of an aniline 1a (1 mmol), benzaldehyde 2 (1.2 mmol),
a
b
and styrene 3 (1.5 mmol) was performed at 80 ꢀC. Isolated yield.
The reaction of an aniline 1a (1 mmol), benzaldehyde 2 (1.2 mmol),
b
c
e
d
and styrene 3 (1.5 mmol) was performed at 80 ꢀC. The concentration
Sum of the
% yields of 4a–7a. Reaction time of 12 hours.
of H+ was kept constant. c Isolated yield. d Sum of the % yields of 4a–7a.
RSC Adv., 2014, 4, 18612–18615 | 18613
Diastereomeric excess ¼ 60% cis. f Diastereomeric excess ¼ 58% cis.
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Scheme 2 Possible oxidative processes.
Fig. 1 The scope of auto-tandem catalysis in a Povarov hydrogen-
transfer cascade.
acts as an auto-tandem catalyst activating two mechanistically
distinct reactions in the Povarov hydrogen-transfer reaction
cascade. To verify that the acetonitrile reaction solvent also acts
as an oxidant, the reaction was conducted under the same
experimental conditions but with an inert atmosphere; the
conversion of tetrahydroquinoline 5a to quinoline 4a was 19%.
This result indicates the participation of acetonitrile in the
oxidation process, which had not previously been reported.
Aer the tetrahydroquinoline is transformed into 1,2-di-
hydroquinolines in situ, it can be oxidized to the corresponding
quinoline by a weak oxidizing agent. Based on the experimental
results, we suggest that the rst hydrogen-transfer might occur
between the tetrahydroquinoline and acetonitrile or the imine.
Further oxidation might proceed through disproportionation or
hydrogen abstraction from the imine formed by the initial
reduction of acetonitrile.
(4j–l). The reaction of meta-substituted anilines gave single
regioisomers (4m and 4n).
As we have demonstrated so far, under the conditions
described, the Povarov reaction can afford, in one pot, the
corresponding quinoline instead of the commonly obtained
1,2,3,4-tetrahydroquinoline.13 The oxidation of 1,2-di-
hydroquinoline has already been investigated in detail, and it
has been demonstrated that this type of oxidation can be ach-
ieved through the use of oxygen, Fe3+, and organic oxidants,
such as benzaldehyde, imines and enones.20 The dispropor-
tionation of 1,2-dihydroquinoline can also occur in the pres-
ence of HCl.21 The aromatization of some Povarov adducts has
been reported, but in such cases, oxidizing agents such as Br2,
DDQ and NaIO4 were used.13d To the best of our knowledge, only
one report on the successive dehydrogenation of Povarov-
produced tetrahydroquinoline into quinoline has been repor-
ted, but in that case, the process was mediated by excess imine
in the presence of acid.13b In our method, we used 1.0 equivalent
of the aniline and 1.2 equivalent of the aldehyde. Therefore, if
quinoline formation occurred through dehydrogenation medi-
ated by the imine the maximum quinoline yield would be 33%,
which is much lower than the yields observed in most instances.
Thus, we hypothesized that acetonitrile is acting as a hydride
acceptor. We then examined the details of the oxidation of the
isolated tetrahydroquinoline (Scheme 2).
The oxidation of tetrahydroquinoline 5a under an oxygen
atmosphere at 80 ꢀC for 12 h in the absence of the catalyst
results in less than 5% conversion to quinoline 4a; however, in
the presence of the catalyst, the conversion was 11%. On the
other hand, a 25% conversion of tetrahydroquinoline 5a to
quinoline 4a was observed at 80 ꢀC for 12 h in the presence of 1
equivalent of imine 7a and CX4SO3H (1 mol%). However, in the
absence of the catalyst, no hydrogen-transfer occurred. These
1
Fig. 2 (a) H NMR spectrum (300 MHz, CD3CN) of 6a in presence of
1
CX4SO3H. (b) H NMR spectrum of reaction between 5a and 7a with
CX4SO3H. (c) 1H NMR spectrum of reaction of 5a in presence of
CX4SO3H. (d) 1H NMR spectrum of reaction of 5a in absence of
results suggest that the imine acts as an oxidant and CX4SO3H CX4SO3H.
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Checking the participation of acetonitrile, the reaction of
tetrahydroquinoline 5a was carried in deuterated acetonitrile
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presence of CX4SO3H (1 mol%) without the imine 7a presents a
large signal in 2.9 ppm (Fig. 2c). Whereas the 1H NMR spectrum
of tetrahydroquinoline 5a maintained under the same reaction
conditions but in absence of catalyst and imine (Fig. 2d), not
present this signal, we conclude that this signal is due to the
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Conclusions
In conclusion, we have developed a cascade process involving
an efficient three-component reaction followed by oxidative
aromatization for the synthesis of 2,4-disubstuted quinolines
using p-sulfonic acid calix[4]arene (CX4SO3H) as a catalyst. We
have veried that in addition to the participation of the imine
¨
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the tetrahydroquinolines to quinolines. The developed method
affords 2,4-disubstuted quinolines with electron donating or
electron withdrawing groups from the aniline component.
Further applications of this methodology are under investiga-
tion and will be reported in due time.
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We thank the Brazilian agency CNPq for research fellowships
(AF, LCAB, SAF) and the Brazilian agencies FAPEMIG and
CAPES for their nancial support.
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