InCl3-driven regioselective synthesis of functionalized/ annulated quinolines: Scope and limitations

Article abstract of DOI:10.1002/asia.201100872

The efficient, regioselective synthesis of functionalized/annulated quinolines was achieved by the coupling of 2-aminoaryl ketones with alkynes/active methylenes/α-oxoketene dithioacetals promoted by InCl ₃ in refluxing acetonitrile as well as under solvent-free conditions in excellent yields. This transformation presumably proceeded through the hydroamination-hydroarylation of alkynes, and the Friedlaender annulation of active methylene compounds and α-oxoketene dithioacetals with 2-aminoarylketones. In addition, simple reductive and oxidative cyclization of 2-nitrobenzaldehyde and 2-aminobenzylalcohol, respectively, afforded substituted quinolines. Systematic optimization of the reaction parameters allowed us to identify two-component coupling (2CC) conditions that were tolerant of a wide range of functional groups, thereby providing densely functionalized/annulated quinolines. This approach tolerates the synthesis of various bioactive quinoline frameworks from the same 2-aminoarylketones under mild conditions, thus making this strategy highly useful in diversity-oriented synthesis (DOS). The scope and limitations of the alkyne-, activated methylene-, and α-oxoketene dithioacetal components on the reaction were also investigated.

Full text of DOI:10.1002/asia.201100872

FULL PAPERS
DOI: 10.1002/asia.201100872
InCl3-Driven Regioselective Synthesis of Functionalized/Annulated
Quinolines: Scope and Limitations
Tanmoy Chanda, Rajiv Kumar Verma, and Maya Shankar Singh*[a]
Abstract: The efficient, regioselective
synthesis of functionalized/annulated
quinolines was achieved by the cou-
pling of 2-aminoaryl ketones with al-
kynes/active methylenes/a-oxoketene
dithioacetals promoted by InCl3 in re-
fluxing acetonitrile as well as under sol-
vent-free conditions in excellent yields.
This transformation presumably pro-
ceeded through the hydroamination–
hydroarylation of alkynes, and the
Friedlꢀnder annulation of active meth-
ylene compounds and a-oxoketene di-
thioacetals with 2-aminoarylketones. In
addition, simple reductive and oxida-
tive cyclization of 2-nitrobenzaldehyde
and 2-aminobenzylalcohol, respectively,
afforded substituted quinolines. Sys-
tematic optimization of the reaction
parameters allowed us to identify two-
component coupling (2CC) conditions
that were tolerant of a wide range of
functional groups, thereby providing
densely functionalized/annulated qui-
nolines. This approach tolerates the
synthesis of various bioactive quinoline
frameworks from the same 2-aminoar-
ylketones under mild conditions, thus
making this strategy highly useful in di-
versity-oriented synthesis (DOS). The
scope and limitations of the alkyne-,
activated methylene-, and a-oxoketene
dithioacetal components on the reac-
tion were also investigated.
Keywords: annulation · cyclization ·
indium · quinolines · solvent-free
synthesis
Introduction
Quinolines are an important class of heterocyclic alkaloids
that are important synthetic targets for the pharmaceutical
industry as well as in academic laboratories because of their
rich chemistry and numerous applications. They are widely
present as key structural motifs in many natural products
and in a large number of bioactive drugs, such as quinine[1]
(I), chloroquine[2] (II), luotonine A[3] (III), and camptothe-
cin[4] (IV; Scheme 1). Numerous quinoline derivatives have
been developed that have useful biological activity, such as
anti-malarial,[5] anti-bacterial,[6] anti-inflammatory,[7] anti-
cancer,[8] anti-diabetic,[9] anti-asthmatic,[10] anti-hyperten-
sive,[11] anti-alzheimer,[12] and anti-platelet activity,[13] HIV-1
replication inhibitor,[14] CysLT (LTD4) receptor antago-
nist,[15] and tyrosine kinase inhibitor.[16] In addition, sulfur-
containing fused-thienoquinolines exhibit a number of phar-
macological activities.[17] Furthermore, many quinoline deriv-
atives have been utilized as chemo- and fluorescent-sensors
for fluoride ions[18] and other metal ions in aqueous solu-
tion.[19] In particular, some quinolines are valuable synthons
for the preparation of nano- and meso-structures with en-
hanced electronic as well as photonic functions,[20] and are
well-known ligands for the preparation of phosphorescent
Scheme 1. Examples of biologically active quinoline frameworks.
complexes for organic light emitting diodes (OLEDs).[21] At
the dawn of the nineteenth century, some quinoline dyes,
such as ethyl red (V) and pinacyanol (VI; Scheme 1), were
used in the first photographic plate.[22] Because of their im-
portance as substructures in a broad range of natural and
synthetic products, significant efforts have been made to
construct new quinoline-based frameworks.
After the first formal synthesis of quinoline by Skraup,[23]
several synthetic variations on the original Skraup synthesis,
such as the Combes,[24] Conrad–Lympach,[25] Doebner von
Miller,[26] Pfitzinger,[27] and Niementowski modifications,[28]
and the Friedlꢀnder synthesis[29] have been developed. Re-
cently, a modified-Friedlꢀnder reaction of 2-aminobenzylal-
cohol with an array of activated methylenes was repor-
[a] T. Chanda, R. K. Verma, Dr. M. S. Singh
Department of Chemistry
Faculty of Science, Banaras Hindu University
Varanasi-221005 (India)
Fax : (+91)542-2368127
E-mail: mssinghbhu@yahoo.co.in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100872.
778
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Chem. Asian J. 2012, 7, 778 – 787

ted.[29j,k] Amongst these reported methodologies, the Fried-
lꢀnder annulation is a very simple, straightforward, and
powerful tool, and is one of the “evergreen” methods of
choice for researchers. Recently, quinolines have been syn-
thesized by the treatment of 2-aminoarylcarbonyl com-
pounds with alkynes through hydroamination of the alkyne
followed by cyclodehydration.[30] In addition, different
Lewis[31] and Brønsted[32] acids/bases, heterogeneous and
solid-supported reagents,[33] ionic liquids,[34] and microwave
irradiation[35] have also been utilized for the synthesis of
quinoline derivatives. However, most of these methods suf-
fered from limitations, such as low yield, poor selectivity, te-
dious work-up, the use of hazardous organic solvents, harsh
reaction conditions,[36] multistep reactions,[37] large amounts
of base,[38] expensive and/or harmful catalysts,[39] and the
need for oxidants for the aromatization step[40] or other pro-
moters/additives.[41] Therefore, more general, efficient, and
viable routes with operational simplicity for the synthesis of
quinoline derivatives are highly desirable, and would be of
great relevance to both synthetic and medicinal chemists.
Because of the growing concern regarding the harmful ef-
fects of organic solvents on the environment and on the
human body, solvent-free reactions[42] have aroused the at-
tention of organic chemists owing to their more-efficient
and less-labor-intensive methods. Because of their cost-ef-
fectiveness and waste-minimization, solvent-free methods
have been used to modernize classical procedures by
making them cleaner, safer, and easier to perform. There-
fore, one pressing challenge facing organic chemists is to ad-
vance new processes that are not only efficient, selective,
and high yielding but are also environmentally friendly. In
recent years, indium chloride[43] has emerged as a highly effi-
cient and effective Lewis acid catalyst that can promote a
variety of chemical transformations chemo-, regio-, and ste-
reoselectively, owing to its air- and water stability, opera-
tional simplicity, and remarkable ability to suppress side re-
actions in acid-sensitive substrates. We have been committed
to the development of efficient synthetic procedures that
mainly use solvent-free conditions.[44] In particular, we re-
cently reported the InCl3-catalyzed synthesis of important
heterocycles, such as xanthenes,[44a–c] naphthopyranopyrimi-
Results and Discussion
A survey of the literature revealed that there were no re-
ports of the use of InCl3 as a catalyst in the synthesis of
quinoline derivatives by the coupling of 2-aminoaryl/alkyl
ketones with alkynes/active methylenes/a-oxoketene di-
thioacetals, either in acetonitrile or under solvent-free con-
ditions. To explore suitable reaction conditions, we began
with the reaction of 2-aminobenzophenone (1a, 1.0 mmol)
with phenylacetylene (2a, 1.2 mmol) in the presence of P2O5
(20 mol%) under solvent-free conditions at 1008C for
2 hours (monitored by TLC). Work-up of the reaction mix-
ture afforded the unexpected 6,12-diphenyldibenzo
ACHTUNGTRENNUNG[b,f]-
AHCTUNGTRENNUNG
ubstituted quinoline (4a) was obtained in only 18% yield
(Scheme 2). The formation of compound 3 as the major
Scheme 2. Reaction of 2-aminobenzophenone (1a) with phenylacetylene
(2a).
product was attributed to the self-coupling–cyclodehydra-
tion of compound 1a in the presence of P2O5. To confirm
the P2O5-catalyzed formation of compound 3, 2-aminoben-
zophenone (1a) was heated in the presence of P2O5
(20 mol%) under solvent-free conditions at 1008C for
2 hours, thereby resulting in the formation of compound 3a
as the sole product in 96% yield. 2,8-Dichloro-6,12-
diphenyldibenzoACTHNUGTRENNUG[b,f]ACHTUNTGREN[NUGN 1,5]diazocine (3b) exhibited hormone-
like activity[45a] and was confirmed to be structurally identi-
cal to the reported compound[45] by single-crystal X-ray dif-
fraction (Figure 1; also see the Supporting Information).[46]
dines,[44d] chromene-2-thiones,[44e] chromeno
ACTHNUTRGNE[NUG 2,3-d]pyrimidi-
nones,[44f] and diazabenzo[b]fluorenones[44f] under solvent-
free conditions. Consequently, in light of other work in the
literature, and as part of our ongoing efforts towards the de-
velopment of new synthetic methods[44] for the synthesis of
heterocycles, herein, we report the InCl3-catalyzed one-pot
coupling of 2-aminoarylketones with alkynes/active methyl-
enes/a-oxoketene dithioacetals in acetonitrile as well as
under solvent-free conditions to provide densely functional-
ized/annulated quinolines in high yields. InCl3 not only
makes the synthetic process clean, safe, and inexpensive, but
also can provide various bioactive quinoline frameworks
from the same 2-aminoaryl/alkylketones.
Figure 1. ORTEP of compound 3b.
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779

M. S. Singh et al.
FULL PAPERS
These results encouraged us to optimize the quinoline
yield by changing the reaction conditions. Thus, the proto-
type reaction between compounds 1a and 2a was performed
in the presence of different Lewis acids, such as CuBr2,
NiCl2, SnCl4, AlCl3, and InCl3 (20 mol% each) under sol-
vent-free conditions. CuBr2, NiCl2, and AlCl3 failed to pro-
duce the desired quinoline, even after 4 hours, whereas
SnCl4 triggered the reaction, but gave only trace amounts of
the desired product (Table 1). To our delight, InCl3 was an
tion was demonstrated by synthesizing a series of substituted
quinolines by varying both the carbonyl and alkyne compo-
nents (Schemes 3–5). 2-Aminoarylketones (1) and alkynes
Table 1. Optimization of the catalyst.[a]
Entry
Catalyst [mol%]
Solvent
T [8C]
t [h]
Yield[b] [%]
18
1
2
3
4
5
6
7
8
P2O5 (20)
CuBr2 (20)
NiCl2 (20)
SnCl4 (20)
AlCl3 (20)
InCl3 (20)
InCl3 (20)
InCl3 (20)
InCl3 (20)
InCl3 (20)
InCl3 (10)
InCl3 (30)
P2O5 (20)
CuBr2 (20)
NiCl2 (20)
SnCl4 (20)
AlCl3 (20)
none
none
none
none
none
100
100
100
100
100
100
82
80
66
110
82
82
2
4
4
4
4
2.5
3
5
5
5
4
3
3
6
6
6
6
[c]
–
–
[c]
trace
[c]
–
none
68
93
–
Scheme 3. Synthesis of quinolines 4.
CH3CN
EtOH
THF
[c]
[c]
9
–
(2) were well-tolerated under the optimized reaction condi-
tions, thereby providing the corresponding quinolines (4a–
4d) in 92–94% yield (Scheme 3, Table 2). The reactions
10
11
12
13
14
15
16
17
toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
81
85
90
45
–
–
82
82
82
82
[c]
Table 2. Synthesis of quinolines 4a–4 f.
[c]
Entry
X
R1
R2
t [h]
Yield [%][a]
trace
[c]
4a
4b
4c
4d
4e
4 f
H
H
Cl
Cl
H
H
C6H5
C6H5
C6H5
C6H5
Me
C6H5
p-MeC6H4
C6H5
p-MeC6H4
p-MeC6H4
C6H5
3
3
3
3
3
3
93[b]
92[b]
94[b]
93[b]
93[c]
92[c]
82
–
[a] Reaction of 2-aminobenzophenone 1a (1.0 mmol) with phenylacety-
lene 2a (1.2 mmol). [b] Yield of isolated product. [c] No quinoline was
formed.
Me
[a] Yield of isolated product. [b] Reaction performed in MeCN. [c] Reac-
tion performed under solvent-free conditions.
effective catalyst for this reaction, thereby providing quino-
line 4a in 68% yield within 2.5 hours (Table 1, entry 6), to-
gether with the undesired product (3a) in 26% yield. En-
couraged by this result, the effects of different solvents, such
as acetonitrile, ethanol, tetrahydrofuran, and toluene, were
also investigated in the presence of InCl3 (20 mol%) with a
view to increase the yield of quinoline. In ethanol and tetra-
hydrofuran, the reaction did not occur and the starting ma-
terials remained unreacted. In acetonitrile, the desired quin-
oline (4a) was obtained exclusively in 93% yield (Table 1,
entry 7). Next, the InCl3 loading was examined (Table 1, en-
tries 11 and 12), and we found that 20 mol% of InCl3 in ace-
tonitrile provided the maximum yield in the minimum time.
Furthermore, the catalysts P2O5, CuBr2, NiCl2, SnCl4, and
AlCl3 were also investigated in acetonitrile. P2O5 catalyzed
the reaction to furnish the quinoline, albeit in low yield,
CuBr2 and NiCl2 were completely ineffective, and SnCl4 pro-
vided only trace amounts of the desired quinoline (Table 1,
entries 13–17). Thus, InCl3 was clearly the catalyst of choice.
The highest yield, cleanest reaction, and most-facile work-
up was achieved with 20 mol% InCl3 in acetonitrile. The
catalytic role of InCl3 was evident from the fact that control
experiments in the absence of InCl3 did not afford the de-
sired product.
were generally clean and no side-products, such as dihydro-
quinoline, were detected in the NMR spectra of the crude
products. Surprisingly, when 2-aminobenzophenone (1a)
was replaced with 2-aminoacetophenone (1b), the reaction
did not proceed at all in acetonitrile and compound 1b was
recovered unconsumed. However, under solvent-free condi-
tions, quinolines 4e and 4 f were obtained in 93% and 92%
yield, respectively (Table 2). This inconsistency may be due
to the formation of the enol form of 2-aminoacetopheone
(1b) in acetonitrile, which inhibited the progress of the reac-
tion. Furthermore, when a terminal aliphatic alkyne (1-
octyne) and an internal alkyne (1-phenyl-1-butyne) were
used under the optimized conditions, the desired quinoline
was not obtained, even in trace amounts. This result limits
the scope of the reaction to some extent.
To further study the scope of this quinoline synthesis, the
reactions of compound 1 with various internal alkynes (5)
were examined under the optimized conditions, with a view
to synthesize 2,3,4-trisubstituted quinolines. The expected
quinolines (7) were obtained in good yield within 3 hours.
The reaction between compounds 1 and 5 was also per-
formed under solvent-free conditions in the presence of
InCl3 (20 mol%) at 808C. Satisfyingly, quinolines 7a–7 f
Subsequently, with optimal conditions in hand, the scope
and generality of this one-pot two-component coupling reac-
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Chem. Asian J. 2012, 7, 778 – 787

InCl3-Catalyzed Regioselective Synthesis of Quinolines
were obtained exclusively in 92–97% yield within 50 mi-
nutes, except for compound 7g, which was obtained in mod-
erate yield (46%) after a longer reaction time (Scheme 4,
Table 3). Coupling 2-aminoaryl/alkyl ketone 1 with com-
gioselectively attacked the carbon atom of the alkyne that
contained the phenyl group because intermediate 6 was sta-
bilized by an electron-withdrawing CO2Et group.
Furthermore, to expand the scope of this synthesis and to
gain a greater insight into the reaction, we also performed
the reaction of 2-nitrobenzaldehyde (8) with symmetrical
alkyne 5 in the presence of SnCl2·2H2O and InCl3 in etha-
nol. The reduction of compound 8 with SnCl2·2H2O[48a,b] to
2-aminobenzaldehyde (8A) followed by reaction with com-
pound 5 afforded quinoline (9) in good yield (Scheme 5).
Scheme 4. Synthesis of quinolines 7.
Table 3. Synthesis of quinolines 7a–7g.
Scheme 5. Synthesis of quinolines 9.
Entry
X
R1
R2
R3
t [min]
Yield[a] [%]
7a
7b
7c
7d
7e
7 f
7g
H
H
Cl
Cl
Cl
H
C6H5
C6H5
C6H5
C6H5
2-ClC6H4
Me
CO2Et
CO2Me
CO2Et
CO2Me
CO2Et
CO2Et
C6H5
CO2Et
CO2Me
CO2Et
CO2Me
CO2Et
CO2Et
CO2Et
50
50
50
50
50
94
94
97
96
92
93
46
The regiochemistry of the reaction depended on the experi-
mental conditions. The reaction proceeded faster and afford-
ed higher yields in the presence of InCl3, whilst in the ab-
sence of InCl3, the desired quinoline (9) was obtained in
poor yield along with the self-condensed product of com-
pound 8A.[49] Thus, InCl3 clearly inhibited the formation of
the self-condensed product of compound 8A, which was
highly prone to self-condensation, and promoted the forma-
tion of the desired quinoline (9). This was the first direct
quinoline synthesis from the reaction of 2-nitrobenzalde-
hyde (8) with dialkyl acetylenedicarboxylates (5). Surpris-
ingly, when compound 8 was treated with an unsymmetrical
alkyne (p-tolyl acetylene) in the presence of SnCl2·2H2O
and InCl3, the desired quinoline was obtained in only 12%
yield, thus limiting the scope of the reaction to some extent.
The compound was characterized and found to be identical
to the reported one.[48c]
Inspired by these results, and keeping in mind the versatil-
ity of the InCl3, we performed the reaction of 2-aminoben-
zylalcohol (10) with dialkyl acetylenedicarboxylates (5) in
the presence of 20 mol% of InCl3 in acetonitrile. However,
the reaction was less efficient, and only afforded the desired
quinolines (9) in moderate yield (Scheme 6).
The scope of this InCl3-catalyzed procedure was further
evaluated by performing the Friedlꢀnder reaction between
compound 1 and cyclic/acyclic active methylene compounds
(11), with a view to synthesizing annulated quinolines (12;
Scheme 7).
50
210
Cl
C6H5
[a] Yield of isolated product.
pound 5 gave intermediate 6, which underwent an InCl3-
mediated intramolecular cyclodehydration to yield the de-
sired quinoline (7) in excellent yield. One attractive feature
of this reaction was that we were able to isolate and charac-
terize intermediates 7Ia and 7Ib, when the reaction was per-
formed at room temperature in the presence of 20 mol%
InCl3.[47,30f] The mechanism could be further rationalized
from our experimental observations, as an aliphatic terminal
alkyne (1-octyne) did not undergo the reaction, owing to the
poor electrophilicity of the carbon center of the alkyne bear-
ing the alkyl group, which was not sufficient enough for the
nucleophilic attack. The internal alkyne (1-phenyl-1-butyne)
also did not undergo the reaction because the carbanion,
like intermediate 6, became unstable owing to the presence
of the electron-donating ethyl group. Although there have
been a few reports where terminal aliphatic alkynes undergo
this reaction in the presence of transition-metal Lewis acid
catalysts, which played dual roles as a Lewis acid and a p-ac-
tivator by coordinating to the acetylene bond,[30f–i] in our
case, indium did not possess such p-activation capability.
However, the reaction of compound 1 with an unsymmetri-
cal internal alkyne (ethyl-3-phenylpropiolate) furnished the
desired quinoline in low yield. In this case, compound 1 re-
Friedlꢀnder annulations are typically either carried out by
refluxing an aqueous/alcoholic solution of the reactants in
the presence of acid/base or by heating the mixture of reac-
tants at 150–2208C in the absence of a catalyst.[29] Herein,
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781

M. S. Singh et al.
FULL PAPERS
Table 4. Synthesis of annulated/substituted quinolines 12 and 4.
Entry 2-Aminoaryl/al- Active meth- Product
kylketone 1 ylene 11
t
Yield
[h] [%][a]
1
2
3
4
4
93[b]
3.5 94[b]
4
94[b]
Scheme 6. Synthesis of quinolines 9.
3.5 95[b]
5
6
3
3
96[b]
95[b]
Scheme 7. Friedlꢀnder synthesis of quinolines 12 and 4.
we report an efficient Friedlꢀnder annulation[50] promoted
by InCl3 under mild conditions, which overcomes the prob-
lems arising from the use of stoichiometric amounts of
Brønsted and Lewis acidic or basic reagents. Thus, when 2-
aminobenzophenone (1a, 1.0 mmol) was treated with dime-
done (1.0 mmol) in the presence of 20 mol% of InCl3 in ace-
tonitrile, the annulated quinoline (12a) was obtained exclu-
sively in 93% yield. To obtain a broad range of annulated
quinolines (12), the tolerance of precursors 1 and 11 were
investigated under the optimized conditions, and resulted in
the formation of annulated/substituted quinolines (12 and 4)
in excellent yield (Table 4, entries 1–10). Surprisingly, when
2-aminoacetophenone (1b) was used in the place of 2-ami-
nobenzophenone (1a), no quinoline was observed; however,
under solvent-free conditions, the reaction proceeded
smoothly to give the desired quinolines (4e and 4 f) in quan-
titative yield (Table 4, entries 11 and 12).
7
8
10
3
88[b]
95[b]
9
3
3
94[b]
10
96[b]
With a variety of multifunctional, substituted, and annu-
lated quinolines in hand, we successfully applied our
method to the synthesis of thienoquinolines (15). Thienoqui-
nolines are known to exhibit various biological activities.[17]
The regioselectivity of the reaction could be rationalized by
the mechanism depicted in Scheme 8. Presumably, the trans-
formation was facilitated by the condensation of compound
1 with compound 13 to afford the imine intermediate 14,
which presumably underwent tautomerization through two
different pathways (a and b). Route a furnished enamine
14a, which underwent intramolecular regiospecific cyclode-
hydration through intermediate 14a’ to furnish quinolines
11
12
2.5 95[c]
2.5 96[c]
[a] Yield of isolated product. [b] Reaction performed in MeCN. [c] Reaction performed
under solvent-free conditions.
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InCl3-Catalyzed Regioselective Synthesis of Quinolines
heterocycles.[53] There are only few reports on the synthesis
of quinolines using ketene dithioacetals.[54] a-Oxoketene di-
thioacetals 18a–18m were prepared according to a literature
procedure.[55] Therefore, we envisaged that a tandem reac-
tion between 2-aminoarylketones (1) and a-aroylketene di-
thioacetals (18) would furnish quinolines 19 (Scheme 10).
Scheme 8. Mechanism for the formation of thienoquinolines 15.
Scheme 10. Friedlꢀnder synthesis of quinolines 19.
15a and 15b in 96 and 94% yields, respectively.[51] The ob-
served regioselectivity was ascribed to the stabilization of
enamine 14a by conjugative interaction of the enamine
group with sulfur, which was not possible for the regioiso-
meric 14b. Route b may lead to regioisomeric enamine 14b,
which could provide quinoline 14b’; compound 14b’ was not
observed even in trace amounts during our investigation.
Not only, there are limited examples of double Friedlꢀnd-
er annulations, but also they have been performed under
harsh acidic/basic conditions. Herein, we performed the re-
action of compound 1 (2.0 mmol) with 1,2-cyclohexanedione
(16, 1.0 mmol) in acetonitrile in the presence of 20 mol% of
InCl3 to afford pentacyclic 5,8-diphenyl-6,7-dihydrodibenzo-
We began with a typical reaction of 2-aminobenzophe-
none (1a) and 3,3-bis(methylthio)-1-naphthalen-1-yl-prope-
none (18a) under optimized conditions (20 mol% InCl3,
CH3CN), which provided the desired compound in 75%
yield. When the reaction was carried out in the presence of
20 mol% of InCl3 under solvent-free conditions, the desired
quinoline was formed in 88% yield. Furthermore, when the
InCl3 loading was decreased from 20 mol% to 10 mol%, the
yield of the quinoline increased to 90%. Finally, the reaction
temperature was also examined and 708C was found to be
the optimum temperature, as it afforded the best compro-
mise between reaction profile and reaction rate. Thus, the
highest yield, cleanest reaction, and most-facile work-up was
achieved with 10 mol% of InCl3 at 708C under solvent-free
conditions.
Under these optimized conditions, we studied the sub-
strate scope and generality of this one-pot Friedlꢀnder reac-
tion by synthesizing a small library of highly functionalized
quinolines (19a–19v) in excellent yields (Scheme 10,
Table 5). Notably, a wide range of 2-aminoarylketones (1a–
1e) and a-oxoketene dithioacetals (18a–18m) were well-tol-
erated under the optimized reaction conditions and fur-
nished a broad spectrum of densely functionalized quino-
lines (19). Even extremely electron-rich aromatic a-oxoke-
tene dithioacetals, such as compounds 18i and 18j, reacted
smoothly. In addition to the incorporation of aryl, heteroar-
yl, and aliphatic substituents, the h5-ferrocenyl group was
also tolerated by this procedure (Table 5, entry 20).
ACHTUNGTRENNUNG[b,j]ACHTUNGTRENNUNG[1,10]phenanthrolines (17) through double Friedlꢀnder
annulation[52] in 84–87% yield (Scheme 9). Compounds 17
are used as receptors, owing to their interesting chelating ca-
pacity,[52c] and are widely used to develop dye-sensitized
nanocrystalline metal–oxide solar cells.[52d,e]
Furthermore, to make this century-old Friedlꢀnder reac-
tion more practical and general, we attempted to develop a
Friedlꢀnder annulation that uses a-oxoketene dithioacetals
as an electrophilic partner instead of enolizable carbonyl
compounds. a-Oxoketene dithioacetals are versatile inter-
mediates in organic synthesis and have been extensively
used in the construction of various five- and six-membered
Structural determination of all of the quinoline derivatives
1
(19a–19v) was performed from their H and 13C NMR, IR,
and MS data. We unequivocally established the regiochemis-
try of two representative compounds (19a and 19c) by
single-crystal X-ray diffraction analysis (Figure 2).[46]
On the basis of these above results, the probable mecha-
nistic pathway for the formation of compound 19 is shown
Scheme 9. Synthesis of dibenzoACTHNUGTRENNUG[b,j]ACHTUTGNREN[NUGN 1,10]phenanthrolines 17.
Chem. Asian J. 2012, 7, 778 – 787
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www.chemasianj.org
783

M. S. Singh et al.
FULL PAPERS
Table 5. Scope of the synthesis of quinolines 19.
termediate 18B. Upon subsequent loss of H2O and MeSH,
intermediate 18B affords the desired quinoline (19).
Entry
X
R1
R2
Product
Yield[a] [%]
1
2
3
4
5
6
7
8
H
H
H
Cl
H
H
Cl
Cl
H
C6H5
CH3
C6H5
C6H5
C6H5
CH3
C6H5
2-ClC6H4
C6H5
CH3
C6H5
2-ClC6H4
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
1-naphthyl
1-naphthyl
4-OMeC6H4
4-OMeC6H4
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
2-ClC6H4
2-ClC6H4
C6H5
19a
19b
19c
19d
19e
19 f
19g
19h
19i
90
92
92
95
91
86
93
81
91
82
92
84
89
88
90
88
90
89
84
83
92
91
Conclusions
Structurally diverse quinolines have been synthesized by the
one-pot two-component regioselective coupling of 2-amino-
arylketones with alkynes/active methylenes/a-oxoketene-di-
thioacetals promoted by InCl3 in acetonitrile as well as
under solvent-free conditions; these reactions proceeded by
the hydroamination–hydroarylation of alkynes, and the
Friedlꢀnder annulation of active methylene compounds and
a-oxoketene dithioacetals. InCl3 was used in all of the reac-
tions and no co-catalyst or activator was needed. This
method not only provides an excellent complement to sub-
stituted/annulated quinoline synthesis, but also avoids the
use of hazardous acids or bases and harsh reaction condi-
tions. The merits of this procedure are its mild reaction con-
ditions, high selectivities, excellent yields, ease of purifica-
tion, economic viability, and ready availability of the catalyst
and starting materials. In addition to its simplicity and selec-
tivity, this reaction can tolerate a variety of functional
groups and is a viable alternative to the currently used pro-
cedures.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
H
19j
19k
19l
Cl
Cl
H
Cl
Cl
H
Cl
Cl
NO2
Cl
Cl
Cl
C6H5
p-biphenyl
p-biphenyl
4-BrC6H4
2-furyl
19m
19n
19o
19p
19q
19r
19s
19t
2-furyl
2-thienyl
2-thienyl
2-ferrocenyl
tBu
19u
19v
OEt
[a] Yield of isolated product.
Experimental Section
General
All starting materials were commercially available and used as received
without further purification. a-Oxoketene dithioacetals (18) were pre-
pared according to a literature procedure.[55] Thin-layer chromatography
(TLC) was performed on silica gel 60 F254 precoated plates. IR spectra
1
were measured in KBr, and wavelengths (n) are reported in cmÀ1. H and
13C NMR spectra were recorded on NMR spectrometers operating at 300
and 75.5 MHz, respectively. Chemical shifts (d) are given in parts per
million (ppm) using the residue solvent peaks as reference relative to
TMS. J values are given in Hz. Mass spectra were recorded using electro-
spray ionization (ESI) mass spectrometry. C, H, and N analysis was per-
formed by the microanalytical laboratory. The melting points are uncor-
rected.
Figure 2. ORTEP of compounds 19a and 19c.
in Scheme 11. It is conceivable that nucleophilic attack of
the amine group of compound 1 on the methylthio-substitut-
ed b-carbon of compound 18 gives intermediate 18A, which
then undergoes an intramolecular aldol reaction to give in-
General Procedure for the Synthesis of 6,12-
DiphenyldibenzoACTHNUTRGENNUG[b,f]ACHTUNGTREN[NUNG 1,5]diazocine (3)
A mixture of 2-aminobenzophenone (1a; 1.0 mmol) and P2O5 (0.2 mmol)
in a 25 mL round-bottomed flask was heated at 1008C for 2 h. After
completion of the reaction (monitored by TLC), water (15 mL) was
added and the reaction mixture was extracted with EtOAc (3ꢂ10 mL).
The combined organic extracts were washed with brine and dried over
anhydrous Na2SO4. The solvent was evaporated in vacuo to afford the
pure product (3).
General Procedure for the Synthesis of 2,4-Disubstituted quinolines (4)
InCl3 (0.2 mmol) was added to a mixture of compounds 1 (1.0 mmol) and
2 (1.2 mmol) either in CH3CN (Table 2, 4a–4d) or under solvent-free
conditions (Table 2, 4e and 4 f). The reaction mixture was heated to
reflux in CH3CN (or at 1008C under solvent-free conditions) for the
stipulated period of time. After completion of the reaction (monitored by
TLC), the solvent was evaporated (for the reaction in CH3CN). Then,
water (15 mL) was added and the reaction mixture was extracted with
EtOAc (3ꢂ10 mL). The combined organic extract was washed with brine
Scheme 11. Plausible mechanism for the synthesis of quinolines 19.
784
www.chemasianj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2012, 7, 778 – 787

InCl3-Catalyzed Regioselective Synthesis of Quinolines
and dried over anhydrous Na2SO4. The solvent was evaporated under
vacuo and the residue was purified by column chromatography on silica
gel (EtOAc/n-hexane, 1:49) to afford the pure 2,4-disubstituted quinoline
(4).
General Procedure for the Synthesis of Quinolines 19
A mixture of 2-aminoaryl/alkyl ketone 1 (1.0 mmol) and a-oxoketene di-
thioacetal 18 (1.0 mmol) was heated at 708C in the presence of InCl3
(10 mol%, 0.1 mmol, 0.022 g) for the stipulated period of time (0.5–2.0 h)
until the reaction had been completed (monitored by TLC). The mixture
was treated with water (20 mL) and extracted with EtOAc (1ꢂ20 mL).
The combined organic extract was washed with brine (1ꢂ20 mL) and
dried over anhydrous Na2SO4. The solvent was evaporated under vacuum
to give the crude product, which was either purified by crystallization
from EtOH or by column chromatography on silica gel (EtOAc/n-
hexane, 1:49).
General Procedure for the Synthesis of 2,3,4-Trisubstituted Quinolines 7
A mixture of compound 1 (1.0 mmol), dialkyl acetylenedicarboxylate 5
(1.2 mmol), and InCl3 (0.2 mmol) was heated at 808C in a 25 mL round-
bottomed flask for the stipulated period of time (Table 3). After comple-
tion of the reaction (monitored by TLC), water (15 mL) was added and
the reaction mixture was extracted with EtOAc (3ꢂ10 mL). The com-
bined organic extract was washed with brine and dried over anhydrous
Na2SO4. The solvent was evaporated under reduced pressure and the res-
idue was purified by column chromatography on silica gel (EtOAc/n-
hexane, 3:47) to afford the pure 2,3,4-trisubstituted quinoline (7).
Acknowledgements
General Procedure for the Synthesis of Quinoline 9 from o-
Nitrobenzaldehyde
We gratefully acknowledge the generous financial support from the
Council of Scientific and Industrial Research (CSIR) and the Depart-
ment of Science and Technology (DST), New Delhi. T.C. and R.K.V. are
thankful to the UGC and CSIR, New Delhi, respectively, for research fel-
lowships.
A mixture of o-nitrobenzaldehyde (8, 1.0 mmol), dialkyl acetylenedicar-
boxylate 5 (1.2 mmol), SnCl2·2H2O (4.0 mmol), InCl3 (0.2 mmol), and
EtOH (5 mL) was heated to reflux in a 25 mL round-bottomed flask with
continuous stirring for 3.5 h. After completion of the reaction (monitored
by TLC), the solvent was evaporated. Then water (15 mL) was added
and the reaction mixture was extracted with EtOAc (3ꢂ10 mL). The
combined organic extract was washed with brine and dried over anhy-
drous Na2SO4. The solvent was evaporated under vacuo and the residue
was purified by column chromatography on silica gel (EtOAc/n-hexane,
3:17) to give the pure product.
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General Procedure for the Synthesis of Quinoline 9 from o-
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InCl3 (0.2 mmol) was added to a mixture of o-aminobenzylalcohol (10,
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General Procedure for the Synthesis of Quinolines 12 and 15
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General Procedure for the Synthesis of 5,8-Diphenyl-6,7-
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Received: October 22, 2011
Published online: February 6, 2012
Chem. Asian J. 2012, 7, 778 – 787
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
787