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Table 1
Povarov reaction–aerobic dehydrogenation, which provides the
synthesis of polysubstituted quinolines relevant to pharmaceuti-
cals, especially antimalarials (Scheme 1).
Screening of catalysts and reaction conditionsa
We envisaged that the selection of a catalyst could be the key in
chemoselective-activation of reactants toward three-component
Povarov reaction and the aerobic dehydrogenation in domino
mode and to minimize the possible competing reactions. The supe-
rior activation of reactants and chemoselectivity in reactions med-
iated by heterogenized-catalysts are well known.13,14 Initially, we
decided to study the solid supported Povarov reaction under open
air, using SiO2/montmorillonite containing 15 mmol % (mol per
weight) of Lewis acids/Brönsted acids.14 p-Chlorobenzaldehyde,
aniline, and phenylacetylene were chosen as model substrates
(Table 1).
Entry
Catalyst/solid support
Solvent (T °C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
HClO4–SiO2
HClO4–SiO2
ZrCl4–SiO2
CeCl3–SiO2
25
70
70
70
25
25
70
70
70
70
70
70
9
17
45
25
28
7
HClO4–Mont.
HBF4–Mont.
HClO4–Mont.
Natural K-10 Mont.
HBF4–Mont.
HCl–Mont.
CeCl3–K-10 Mont.
ZrCl4–K-10 Mont.
HClO4–Mont.
HClO4
65
41
30
33
30
50
69c
15
10
NR
NR
NR
NR
16
The screening of catalysts in this multicomponent hetero Diels–
Alder reaction-aerobic oxidation revealed that Brönsted acid-mod-
ified montmorillonite showed better activity than Brönsted acid
non-covalent heterogenized on silica gel, while Lewis acids ad-
sorbed on montmorillonite or SiO2 exhibited similar activities. In
general, montmorillonite modified with Brönsted acids are more
active than those modified with Lewis acids. In the activation of
montmorillonite with different acids, (HClO4, HBF4, and HCl),
HClO4–montmorillonite (HClO4–Mont.) showed the highest activ-
ity. The natural K-10 Mont. activated at 100 °C for 72 h under vac-
uum without modification by treating with Lewis/Brönsted acid
was found to lower the reaction rate and yield (41%, entry 8, Table
1), and the reaction using o-nitroaniline (in place of aniline) re-
sulted 2-(4-chlorophenyl)-8-nitro-4-phenylquinoline in poorer
yield (21% vs 56%). These indicate that the acid modification by
perchloric acid of montmorillonite enhances its activity for pro-
moting the reaction. To examine the plausible higher activity of
HClO4–Mont., we also performed the solution phase reactions. It
is well recognized that water as a solvent accelerates multicompo-
nent and cycloaddition reactions and the presence of dissolved
oxygen in water can favor the aerobic dehydrogenation. But in
our investigations, the reaction catalyzed by HClO4, phosphomo-
lybdic acid, CeCl3 and ZrCl4 in water at same temperature (70 °C)
were found to be very slow and unsuccessful (Table 1, entries
14–17). Prolonging the reaction in the case of HClO4 caused the
formation of a complex mixture of products. Use of EtOH as the
solvent in the reaction catalyzed by ZrCl4 did not also improve
the yield. Sc(OTf)3 and InCl3, which were demonstrated1a as effi-
cient catalysts in Povarov reactions, have also been found ineffec-
tive (Table 1, entries 19 and 20). All together, these imply that
montmorillonite modified with perchloric acid possess the supe-
rior catalytic activity toward the three-component Povarov reac-
tion and aerobic dehydrogenation in domino fashion. When the
reaction was done under oxygen atmosphere in place of open air,
it increased the yield slightly from 65% to 69% (Table 1, entry 7
vs entry 13). The reaction performed under nitrogen resulted in a
complex mixture of products containing desired quinoline in 39%
yield as revealed by HPLC. Aniline (1 equiv), aldehyde (1 equiv), al-
kyne (1.5 equiv), and 15 mmol % (mol/w) of HClO4–Mont. were
found to be optimum to provide the best results. The reaction pro-
cedure was simple and straightforward.15
70
H2O, 70
H2O, 70
H2O, 70
H2O, 70
EtOH, 70
EtOH, 70
MeCN, 70
Phosphomolybdic acid
CeCl3Á7H2O
ZrCl4
ZrCl4
Sc(OTf)3 (20 mol %)
InCl3 (10 mol %)
a
Aldehyde (1 mmol), amine (1 mmol), alkyne (1.5 mmol), and catalyst
(0.3 mmol) for solid-supported and solution phase reactions and 2 g of solids for
solid-supported reactions were used, Each experiment was done with 30 mmo-
l % equiv. Lewis/Brönsted acids, NR: no reaction after 14 h. For incomplete reactions,
yields are noted for reactions continued for 14 h.
b
Isolated yields.
Reaction was done under oxygen.
c
good yields (Table 2). The diverse elements could be introduced
into quinoline ring at 2- and 4-positions and the substitutions in
aromatic amines used. 8-Nitroquinolines are known to be impor-
tant precursors for synthesis of primaquine drug-like molecules,
and primaquines with 2- and 4-ring relevant substitutions were re-
ported to possess higher radical curative antimalarial activity com-
pared to that of primaquine.16 Recent studies have exploited that
the introduction of 2-tert-butyl into quinoline ring of primaquine
offers the tremendous improvement in its blood-schizontocidal
antimalarial activity.8a,16a The reported syntheses of these 8-nitro-
quinolines involve the drawbacks of use of harsh conditions,
expensive reagents, and multiple reaction steps.16,17 In contrast,
this new milder convenient method offers in one-step the prepara-
tion of targeted 8-nitroquinolines in good yields (Table 2, entries
9–14). Moreover, the multicomponent nature of the process and
the easy accessibility of starting materials (versatile aldehydes
and amines are commercially available and alkynes can be pre-
pared from aldehydes in one-step) bestow the opportunity of syn-
thesis of focused library of relevant substituted 8-nitroquinolines.
The well known advantages of using heterogenized catalysts in or-
ganic synthesis are their remarkable thermal, mechanical, and
chemical stabilities especially under oxidizing conditions, easy
handling and low toxicity, facile separation from reaction mixture
through filtration, and recyclability. In the present protocol,
HClO4–Mont. showed its recyclable efficiency up to three times
(65%, 61%, 55% yields, entry 1, Table 2). These attributes of the pro-
cess make it synthetically useful.
Interestingly, the versatile polysubstituted and medicinally rel-
evant quinolines were prepared by this process in moderate to
Since the process involves the Povarov reaction (an inverse
electron demand hetero Diels–Alder reaction), the higher yield-
formation of quinolines from anilines or aldehydes with electron-
withdrawing groups is reasonable. The aliphatic alkynes (hexyne
and octyne), which are not sufficiently electron-rich dienophiles,
did not undergo the [4+2]-cycloaddition with N-arylimines. In
Scheme 1. Domino process of Povarov reaction–aerobic dehydrogenation.
Guchhait, Sankar K.
