Indium(III) chloride catalyzed convergent, regioselective synthesis of annulated quinoline and pyridine derivatives

Article abstract of DOI:10.1055/s-0031-1290100

A direct convergent two-component regioselective synthesis of annulated pyridine motif from 1-aminopenta-1,4-diene fragment and aromatic aldehyde by indium(III) chloride catalyzed reaction has been developed through a concerted pathway. A series of potent

Full text of DOI:10.1055/s-0031-1290100

LETTER
113
Indium(III) Chloride Catalyzed Convergent, Regioselective Synthesis of
Annulated Quinoline and Pyridine Derivatives
Synthesis of
A
nnu
.
lated Quinoli
C
ne and Pyridine
.
D
erivative
s
Majumdar,*a,b Raj Kumar Nandi,a Sudipta Ponraa
a
Department of Chemistry, University of Kalyani, Kalyani-741235, West Bengal, India
Department of Chemical Sciences, Tezpur University, Napaam, Tezpur 784028, Assam, India
E-mail: kcm_ku@yahoo.co.in
b
Received 1 September 2011
phenanthroline derivatives have made the synthesis of
these molecules more demanding.
Abstract: A direct convergent two-component regioselective syn-
thesis of annulated pyridine motif from 1-aminopenta-1,4-diene
fragment and aromatic aldehyde by indium(III) chloride catalyzed
reaction has been developed through a concerted pathway. A series
of potentially bioactive pyranoquinoline, phenanthroline, and pyri-
dopyrimidine derivatives has been synthesized in high yields by this
protocol.
As a part of our program aiming at developing selective
and environmentally friendly methods for the synthesis of
biodynamic heterocycles15 we explored novel synthetic
strategies for the synthesis of annulated pyridine and quin-
oline, that is, pyridopyrimidine, pyranoquinoline, and
phenanthroline derivatives. Besides traditional approaches,16
the last two decades have seen the development of a num-
ber of useful methods for the synthesis of quinoline and
pyridine derivatives, which include metal-catalyzed reac-
tion, radical-mediated cyclization, iodine-mediated reac-
tion, or Lewis acid catalyzed reaction.17 These are
certainly improvements over traditional approaches, but
also have some limitations. Some are time consuming, not
environmentally benign, required harsh reaction condi-
tions or multistep reaction. In recent years, enormous
progress has been made in expanding the scope of the di-
rect addition of carbon–carbon double bonds to carbon–
nitrogen double bonds either from prepared imines or
from aldehydes and amines in a one-pot procedure by sev-
eral transition-metal catalyst or Lewis acids.18 During the
last decade indium(III) chloride has emerged as a power-
ful Lewis acid catalyst imparting high regio- and
chemoselectivity in various chemical reactions and also
has attracted a great deal of interest due to its relatively
low toxicity, stability in air and water, operational sim-
plicity, strong tolerance to oxygen- and nitrogen-contain-
ing substrates and functional groups, and also
recyclability.19 Its potential as a Lewis acid catalyst for
fundamental reactions, such as the Diels–Alder,20
Friedel–Crafts,21 Mukaiyama aldol,22 and Sakurai–
Hosomi allylation reactions,23 has been extensively inves-
tigated.24 Literature search reveals that addition of car-
bon–carbon double bond to imine bond by indium(III)
catalyst25 is quite rare.
Key words: indium(III) chloride, imine, Lewis acid, concerted
reaction, electrocyclization, pyranoquinoline, phenanthroline, pyri-
dopyrimidine
The pyridine and quinoline derivatives play a central role
as versatile building blocks of many natural products.1
Many methods are available for the synthesis of quinoline
and pyridine scaffolds containing derivatives due to their
broad spectrum of biological activities with antiasthmatic,
antibacterial, antimicrobial, anti-inflammatory, antipyret-
ic, antidiabetic, cytotoxic, and also having tyrosine kinase
inhibition properties.2 Recently, it has been found that
substituted pyridines efficiently inhibit HMG-CoA reduc-
tase and cholesterol transport proteins.3 It was also shown
that quinoline derivatives can be used as a functional ma-
terial for the preparation of nano and meso structures with
enhanced photonic and electronic properties.4 On the oth-
er hand natural products possessing coumarin, quinolone,
and uracil subunits show a wide range of bioactivity.5
Among them pyranoquinoline and phenanthroline are
main scaffolds of many bioactive alkaloids6 viz. amphi-
medine, dutadrupin, helietidine, and geibalansine.7 Again
pyranoquinoline derivatives are used as potential pharma-
ceuticals for their psychotropic, antiallergic, and estro-
genic activity.8 Recently, the pyridopyrimidine
derivatives has gained enhanced importance because of
their biological and medicinal applications such as anti-
bacterial,9 antiallergic,10 and CNS stimulants,11 and inhib-
itors of enzyme adenosine kinase (AK)12 or
dihydrofolatereductase (DHFR).13 Moreover, due to bio-
activities these low-molecular-weight heterocycles have
received considerable attention in pharmaceutical and
agrochemical sectors.14 These biodynamic properties as-
sociated with pyridopyrimidine, pyranoquinoline, and
We indeed recently demonstrated the synthesis of pyri-
dine derivatives from 1-aminopenta-1,4-diene fragment
and aromatic aldehyde by BF3·OEt2-mediated reaction,26
where the yield of product varied with catalyst loading,
and better results were achieved only by using as high as
40 mol% BF3·OEt2. along with pyrrole derivatives as side
product (Scheme 1).
These results prompted us to search for an improved and
efficient protocol to access the potentially bioactive pyri-
dine-annulated scaffolds exclusively. Indium-catalyzed,
SYNLETT 2012, 23, 113–119
Advanced online publication: 09.12.2011
DOI: 10.1055/s-0031-1290100; Art ID: B17011ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
1

114
K. C. Majumdar et al.
LETTER
BF3•OEt2
(40 mol%)
H
Table 1 Optimization Reaction Conditions for the Formation of
Pyranoquinoline Derivatives
N
Ar
N
+
toluene,
Entry Catalyst
Solvent and conditions Time (h) Yield (%)c
reflux, 12 h
III
IV
(previous work)
NH2
a
1
2
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
toluene, reflux
toluene, reflux
H2O, reflux
10
6.5
64
93
32
39
53
74
68
–
+ ArCHO
b
b
b
b
b
b
b
I
II
InCl3
(10 mol%)
N
Ar
3
6.5
6.5
6.5
6.5
6.5
6.5
6.5
6.5
6.5
6.5
6.5
6.5
6.5
6.5
6.5
6.5
6.5
6.5
6.5
6.5
4
EtOH, reflux
benzene, reflux
MeCN, reflux
xylene, reflux
toluene, r.t.
toluene,
reflux, 6.5 h
III
5
(present work)
Scheme 1 Comparison between present and previous work
6
7
two-component convergent reaction of aldehydes and 1-
aminopenta-1,4-diene fragment has not been explored so
far for the synthesis of the aforesaid heterocyclic scaf-
folds. Herein we report the results of our investigation.
8
b
9
AgSbF6
toluene, reflux
toluene, reflux
toluene, reflux
toluene, reflux
toluene, reflux
toluene, reflux
toluene, reflux
toluene, reflux
toluene, reflux
toluene, reflux
toluene, reflux
toluene, reflux
toluene, reflux
toluene, reflux
62
35
43
26
13
23
17
46
82
57
79
74
–
b
10
11
12
13
14
15
16
17
18
19
20
21
22
BF3·OEt2
The required precursor 1a–c were prepared according to
our earlier published procedure.15c When the substrate 1a
was refluxed with aromatic aldehyde 2a in the presence of
indium(III) chloride (0.1 equiv with respect to substrate
1a) in toluene for 6.5 hours, exclusively a new product 3a
was obtained (mp 240 °C, Scheme 2).The product 3a has
been characterized as 9-methyl-8-phenyl-3H-pyrano[3,2-
f]quinolin-3-one from its spectral and analytical data.27
b
AuCl3
b
AlCl3
b
Yb(OTf)3
b
ZnCl2
b
FeCl3
CuIb
b
InI3
NH2
b
InBr3
O
O
b
N
In(OAc)3
InCl3 (10 mol%)
1a
+
b
In(OTf)3
TfOHb
–
toluene, reflux
6.5 h
CHO
O
O
3a
–
2a
a Conditions: 5 mol%.
b Conditions: 10 mol% of catalyst used.
Scheme 2 Two-component synthesis of pyranoquinoline from 5-al-
lyl-6-aminocoumarin and benzaldehyde
c Isolated yield of 3a.
Table 1 (entries 3–7). The reaction did not proceeded at
all in the presence of Brønsted acid or in the absence of a
catalyst (Table 1, entries 21 and 22), the reaction also
failed at room temperature (Table 1, entry 8). To our de-
light, the two-component cyclization reaction proceeded
smoothly and generated the desired product pyranoquino-
line 3a in 93% yield, giving the best results when 10
mol% of InCl3 was used as a catalyst in the absence of any
co-catalyst or activator (Table 1, entry 2). Other indi-
um(III) salts InI3, InBr3, In(OAc)3, and In(OTf)3 also gave
the same products (57–74% yields, Table 1, entries 17–
20) but none gave better results than indium(III) chloride.
Decrease in catalyst loading of InCl3 to 5 mol% resulted
in lowering the yield of the product even when the reac-
tion was allowed to continue for a longer reaction time
(Table 1, entry 1). The reaction was also examined by us-
ing 10 mol% BF3·OEt2 as a catalyst which afforded only
35% yield of 3a (Table 1, entry 10).
To optimize the reaction conditions, in order to obtain a
maximum yield of the cyclized product, a set of experi-
ments were carried out with the substrate 1a by changing
different parameters like nature of catalyst, solvent, and
catalyst loading (Table 1). Among the various catalyst
used coinage metal catalyst AgSbF6, AuCl3, and CuI gave
the corresponding cyclized product in moderate yield
(43–62%, Table 1, entries 9, 11, and 16).
Other metal-based Lewis acids like Yb(OTf)3, AlCl3,
ZnCl2, and FeCl3 also showed poor results (13–26%,
Table 1, entries 12–15). When the reaction was performed
in the presence of InCl3 (0.1 equiv) in toluene, an excel-
lent yield of the compound 3a was obtained in 6.5 hours
(Table 1, entry 2). On examining the role of the solvents
for improving the efficiency of this reaction, it was found
that the reaction in toluene gave better results compared to
H2O, EtOH, benzene, MeCN, and xylene as shown in
Synlett 2012, 23, 113–119
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LETTER
Synthesis of Annulated Quinoline and Pyridine Derivatives
115
Table 2 InCl3-Catalyzed Synthesis of Various Pyranoquinoline Derivatives and Phenanthroline Derivative
Ar
NH2
N
ArCHO
+
O
X
O
X
2a–h
3a–i
1a–c
Entry
2-Allyl amine 1
Aldehyde 2
Product 3
Yield (%)a
CHO
1
2
3
4
NH2
NH2
NH2
NH2
93
84
89
94
N
O
O
O
O
O
2a
O
3a27
O
1a
Br
CHO
N
Br
O
O
O
2b
1a
3b
CHO
Cl
N
Cl
O
2c
O
O
1a
3c
OMe
CHO
N
OMe
O
O
O
2d
1a
3d
OMe
OMe
CHO
5
6
NH2
NH2
NH2
90
88
N
MeO
OMe
O
O
O
O
2e
1a
3e
S
N
OHC
S
2f
O
O
O
O
1a
3f
Cl
CHO
7
89
N
O
N
Cl
O
N
Me
Me
2g
1b
3g
© Thieme Stuttgart · New York
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K. C. Majumdar et al.
LETTER
Table 2 InCl3-Catalyzed Synthesis of Various Pyranoquinoline Derivatives and Phenanthroline Derivative (continued)
Ar
NH2
N
ArCHO
+
O
X
O
X
2a–h
3a–i
1a–c
Entry
2-Allyl amine 1
Aldehyde 2
Product 3
Yield (%)a
Me
CHO
NH2
8
94
N
O
N
Me
O
N
Et
Et
2h
1c
3h
Cl
CHO
NH2
9
83
N
O
N
Cl
O
N
Et
Et
2g
1c
3i
a Isolated yield.
The optimized reaction conditions were then applied to The reaction of aliphatic aldehydes gave inseparable mix-
other substrates to examine the scope of this protocol to tures showing very close spots on TLC.
synthesize a range of pyranoquinoline derivatives
(Table 2). When the substrate 1a was treated with differ-
The formation of the pyridine derivatives 3 and 5 from the
substrates 1 and 4, respectively, can be rationalized by the
ent aromatic aldehydes 2b–e under the optimized reaction
initial formation of imine A from the reaction of 1-amino-
conditions, that is, 10 mol% InCl3, toluene, under reflux
penta-1,4-diene fragment and 2 by a simple condensation
reaction. This intermediate A is not isolable under these
for 6.5 hours, the corresponding cyclized products 3b–e
were obtained in 84–94% yield (Table 2. entries 2–5). In
reaction conditions, so the reaction may occur via a con-
case of heterocyclic aldehyde like thiophene-2-carbalde-
certed pathway involving a sequence of steps viz. isomer-
hyde the desired product 3f was obtained in 88% yield
ization of the olefinic double bond simply catalyzed by
(Table 2, entry 6). The reaction does not seem to be affect-
Lewis acid InCl3 or through tandem [1,5]-H and [1,7]-H
ed by the substituents present in the aromatic ring of the
shifts to generate the intermediate C, followed by a 6p-
electrocyclization and [1,5]-hydrogen shift leading to the
intermediate E, which may then undergo aromatization to
give the desired products. Formation of D from C is some-
aldehydes. We have also examined the application of this
methodology for the synthesis of phenanthroline deriva-
tives with the substrates 1b,c. The reaction of various sub-
stituted benzaldehyde with 1b,c under the optimized
what unfavorable if R = O2NC6H4, due to the strong elec-
reaction conditions gave the corresponding phenanthro-
tron-withdrawing property of the NO2 group which may
line derivatives in 83–94% yield (Table 2, entries 7–9).
decrease the electron density of one of the interacting or-
As a part of our continuing efforts towards the synthesis bital of B for electrocyclization. Perhaps this may explain
of bioactive pyridopyrimidine derivatives28 we have also the failure of the reaction of 1 or 4 with NO2-substituted
tested this protocol with the substrate 6-allyl-5-amino- aromatic aldehydes to give the expected cyclized products
1,3-dimethylpyrimidine-2,4(1H,3H)-dione.15d
Various 3 and 5. Earlier, pyridopyrrole derivatives were isolated as
pyridopyrimidine derivatives 5a–l29 have been similarly a side product from the reaction of 4 and 2 when BF3·OEt2
synthesized in 84–96% yield from the corresponding aro- was used in place of InCl3.26 This pyrrole derivative was
matic and heteroaromatic aldehydes 2a,b,d,f–n obtained exclusively when nitro-group-containing alde-
(Scheme 3). It should be noted that 1-aminopenta-1,4-di- hydes were used. But in our present work pyridopyrimi-
ene fragment, that is, 1a–c and 4 failed to give the corre- dine derivatives are obtained exclusively by the
sponding expected cyclized product (annulated pyridine indium(III) chloride catalyzed reaction. This is probably
derivatives) with the reaction of nitro-substituted aromat- due to the greater Lewis acid character and complexation
ic aldehyde viz. 3-O2NC6H4CHO and 4-O2NC6H4CHO. ability of In(III) than BF3·OEt2. To form pyrrole deriva-
tives, In(III) should coordinate with the olefinic p-bond
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LETTER
Synthesis of Annulated Quinoline and Pyridine Derivatives
117
O
O
Me
O
N
Ar
Me
O
NH2
InCl3 (10 mol%)
N
N
ArCHO
+
toluene, reflux, 6.5 h
N
N
2a,b,d,f–n
2m = 2-MeO-3-t-BuC6H3CHO
2n = furfuraldehyde
Me
Me
4
5a–l
Br
OMe
O
N
O
O
Me
O
N
Me
O
N
Me
N
N
N
N
N
O
N
Me
Me
Me
5a,29 91%
5b, 89%
5c, 95%
Cl
O
S
O
O
Me
O
N
Me
O
N
Me
O
N
N
N
N
N
N
N
Me
Me
Me
5e, 91%
5d, 87%
5f, 94%
OMe
O
O
O
Me
N
Me
N
Me
N
N
Cl
N
N
OMe
OMe
O
N
O
N
O
N
Me
Me
Me
5g, 86%
5h, 88%
5i, 87%
Cl
O
O
O
O
Me
O
N
Me
O
N
Me
N
N
N
N
OMe
OMe
N
N
O
N
Me
Me
Me
5j, 84%
5k, 91%
5l, 96%
Scheme 3 Indium(III) chloride catalyzed synthesis of pyridopyrimidine derivatives
followed by a nucleophilic attack of the lone pair of the ni- ed pyridine derivatives from the 1-aminopenta-1,4-diene
trogen. In(III) is very much prone to coordinate with the fragment and an aromatic aldehyde by the indium(III)
nitrogen lone pair rather than the olefinic double bond due chloride catalyzed reaction through a concerted pathway.
to its greater Lewis acidity (Scheme 4).
In conclusion, we have developed an efficient, rapid, and
To our knowledge this is the first report of a direct conver- high-yielding procedure. Notable features of this protocol
gent, two-component regioselective synthesis of annulat- are mild reaction conditions, greater selectivity, improved
In(III)
In(III)
N
In(III)
N
R
R
NH2
N
R
H
InCl3
1,5-H shift
1,7-H shift
+
RCHO
2
– H2O
B
C
H
A
6π-ECR
H
N
R
N
R
N
R
O
1,5-H shift
H
aromatization
E
D
H
NH2
••
NH2
N
InCl3 (10 mol%)
toluene, reflux, 10 h
Scheme 4 The proposed mechanism for the synthesis of pyridine derivative
© Thieme Stuttgart · New York
Synlett 2012, 23, 113–119

118
K. C. Majumdar et al.
LETTER
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midine derivatives of biological relevance from easily
available starting materials.
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Acknowledgment
We thank the CSIR (New Delhi) and DST (New Delhi) for financial
assistance. Two of us (R.K.N, and S.P.) are grateful to the CSIR
(New Delhi) for research fellowships. We also thank the DST (New
Delhi) for providing Bruker NMR Spectrometer (400 MHz),
Perkin-Elmer CHN Analyzer, and Perkin-Elmer FT-IR under its
FIST program.
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Synlett 2012, 23, 113–119
© Thieme Stuttgart · New York

LETTER
Synthesis of Annulated Quinoline and Pyridine Derivatives
119
(20) (a) Teo, Y.-C.; Loh, T.-P. Org. Lett. 2005, 7, 2539.
(b) Babu, G.; Perumal, P. T. Tetrahedron Lett. 1998, 39,
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(21) Miyai, T.; Onishi, Y.; Baba, A. Tetrahedron Lett. 1998, 39,
6291.
product thus obtained was recrystallized from MeCN to give
compound 3a as white powder with an isolated yield of 93%;
mp 240 °C. IR (KBr): 2924, 2853, 1728 cm–1. 1H NMR (400
MHz, CDCl3): d = 2.57 (s, 3 H, CH3), 6.63 (d, 1 H, J = 10.0
Hz, ArH), 7.47–7.54 (m, 3 H, ArH), 7.60–7.66 (m, 3 H,
ArH), 8.28 (d, 1 H, J = 9.2 Hz, ArH), 8.40 (s, 1 H, ArH), 8.46
(d, 1 H, J = 9.6 Hz) ppm. 13C NMR (100 MHz, CDCl3):
d = 21.2, 112.1, 116.2, 119.8, 123.4, 128.5, 128.6, 128.9,
130.8, 131.4, 134.4, 138.4, 140.0, 143.7, 153.6, 160.3, 160.7
ppm. HRMS (ES+): m/z calcd for C19H13NO2 [M + H]:
288.0017; found: 287.9302.
(22) Loh, T.-P.; Wei, L.-L. Tetrahedron Lett. 1998, 39, 323.
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159. (b) Harada, S.; Handa, S.; Matsunaga, S.; Shibasaki, M.
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K.; Takemoto, Y. Adv. Synth. Catal. 2005, 347, 1632.
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Synlett 2010, 116. (b) Majumdar, K. C.; Ponra, S.; Ganai, S.
Synlett 2010, 2575. (c) Majumdar, K. C.; Ponra, S.; Ghosh,
D.; Taher, A. Synlett 2011, 104. (d) Majumdar, K. C.;
Ponra, S.; Ghosh, D. Synthesis 2011, 1132.
(29) Procedure for the Preparation of Compound 5a
A mixture of 6-allyl-5-amino-1,3-dimethylpyrimidine-2,4
(1H,3H)-dione 4 (200 mg, 1.02 mmol), benzaldehyde (2a,
108.1 mg, 1.02 mmol) was stirred in toluene at r.t. for 10
min. After addition of indium(III) chloride (22.5 mg, 0.102
mmol), the reaction mixture was refluxed for 6.5 h (the
completion of the reaction was monitored by TLC). The
reaction mixture was cooled and to avoid any further
workup, the mixture was dry packed over a silica gel (230–
400 mesh) column. The pure product was obtained by
eluting the column with a PE–EtOAc mixture (1:1). The
product thus obtained was recrystallized from MeCN to give
compound 5a as white powder. Yield: 91%; mp 218–
220 °C. IR (KBr): 2948, 1714, 1666, cm–1. 1H NMR (400
MHz, CDCl3): d = 2.51 (s, 3 H, CH3), 3.54 (s, 3 H, NCH3),
3.64 (s, 3 H, NCH3), 7.41–7.48 (m, 4 H, ArH), 7.45–7.56 (m,
2 H, ArH), ppm. 13C NMR (100 MHz, CDCl3): d = 21.1
(CH3), 29.0, 30.6, 123.6, 128.2, 128.4, 129.3, 129.8, 136.6,
137.9, 138.8, 150.8, 155.3, 160.7 ppm. ESI-HRMS: m/z
calcd for C16H15N3O2 [M + H]+: 282.1250; found: 282.1237.
(25) (a) Babu, G.; Perumal, P. T. Tetrahedron Lett. 1998, 39,
3225. (b) Yadav, J. S.; Reddy, B. V. S.; Rao, R. S.; Kumar,
S. K.; Kunwar, A. C. Tetrahedron 2002, 58, 7891.
(c) Duvelleroy, D.; Perrio, C.; Parisel, O.; Lasne, M.-C. Org.
Biomol. Chem. 2005, 3, 3794.
(26) Majumdar, K. C.; Ponra, S.; Nandi, R. K. Eur. J. Org. Chem.
2011, 6909.
(27) Procedure for the Preparation of Compound 3a
A mixture of 5-allyl-6-amino-2H-chromen-2-one (1a, 200
mg, 0.995 mmol, 1.0 equiv) and benzaldehyde (2a, 105.5
mg, 0.995 mmol, 1.0 equiv) was stirred in toluene at r.t.
for 10 min. After addition of InCl3 (21.9 mg, 0.0995 mmol,
0.1 equiv), the reaction mixture was refluxed for 6.5 h
(completion of the reaction was monitored by TLC).
The reaction mixture was cooled and to avoid any further
workup, the mixture was directly dry packed over a silica gel
(230–400 mesh) column. The pure product was obtained by
eluting the column with PE–EtOAc mixture (4:1). The pure
© Thieme Stuttgart · New York
Synlett 2012, 23, 113–119

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