ZnCl2-catalyzed three-component domino reactions for the synthesis of pyrano[3,2-c]quinolin-5(6H)-ones

Article abstract of DOI:10.1016/j.tetlet.2013.04.022

The ZnCl₂-catalyzed three-component synthesis of pyrano[3,2-c]quinolin-5(6H)-ones from the domino reactions of 4-hydroxy-1-methylquinolin-2(1H)-one, nitroketene N,S-methylacetal, and aromatic aldehydes in ethanol in good yields is described. This domino transformation leads to the formation of one ring by creation of two C-C bonds and one C-O bond in a single synthetic operation.

Full text of DOI:10.1016/j.tetlet.2013.04.022

Tetrahedron Letters 54 (2013) 3248–3252
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Tetrahedron Letters
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ZnCl2-catalyzed three-component domino reactions for the synthesis of
pyrano[3,2-c]quinolin-5(6H)-ones
Pethaiah Gunasekaran a, Pitchaimani Prasanna a, Subbu Perumal a, , Abdulrahman I. Almansour b
⇑
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, Tamil Nadu, India
b Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 February 2013
Revised 4 April 2013
Accepted 6 April 2013
Available online 22 April 2013
The ZnCl2-catalyzed three-component synthesis of pyrano[3,2-c]quinolin-5(6H)-ones from the domino
reactions of 4-hydroxy-1-methylquinolin-2(1H)-one, nitroketene N,S-methylacetal, and aromatic alde-
hydes in ethanol in good yields is described. This domino transformation leads to the formation of one
ring by creation of two C–C bonds and one C–O bond in a single synthetic operation.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Three-component reactions
4-Hydroxy-1-methylquinolin-2(1H)-one
N-Methyl-1-(methylthio)-2-nitroprop-1-
en-1-amine
Pyrano[3,2-c]quinolin-5(6H)-ones
Zinc chloride
The pyranoquinolinone scaffold is a privileged sub-structure
prevalent in numerous natural products.1 A variety of bioactive
natural products, especially alkaloids such as flindersine, simulen-
oline, melicobisquinolones (A and B), and huajiaosimuline (Fig. 1)
comprise a pyranoquinolinone hybrid moiety as the basic building
block.2 Structures embedded with pyranoquinolinone units display
potential medicinal properties such as anti-inflammatory,3
anti-allergic,4 antibacterial,5 antimicrobial,6 estrogenic, and
psychotropic.7 In particular, simulenoline, huajiaosimuline, and
zanthodioline are potent inhibitors of platelet aggregation,8 while
N-methylflindersine, isolated from Orixa japonica, acts as an insec-
ticide for livestock.9 Further, pyranoquinolinones often serve as po-
tential synthons for the assembly of natural products such as
dimeric quinolone alkaloids10 and polycyclic heterocycles.11
Reported approaches to synthesize/functionalize pyranoquin-
olinones include: (i) reactions of 4-hydroxy-1-methylquinolin-
2(1H)-one with 1-aryloxy-4-chloro-but-2-yne in the presence of
K2CO3 in butanol or intramolecular annulation of propynyl/butynyl
ethers of 4-hydroxy-1-alkylquinoline-2H-one in chlorobenzene,12
domino Knoevenagel condensation/hetero Diels–Alder reactions
of 4-hydroxy-1,2-dihydro-2-quinolinones and o-prenylated aro-
matic/aliphatic aldehyde,15 (v) VCl3-catalyzed three-component
reactions via aza-Diels–Alder reaction of aldimines with dihydro-
pyran,16 (vi) microwave-mediated three-component reactions of
4-hydroxyquinolin-2(1H)-ones, aromatic aldehydes, and ethyl cya-
noacetate,17 (vii) dehydrocyclization of prenyl and vinylquinolones
effected by DDQ,18 and (viii) tandem Knoevenagel condensation of
4-hydroxyquinolin-2(1H)-ones with aliphatic aldehyde and
O
OH
O
N
O
N
O
N
O
O
O
Simulenoline
Haujiaosimuline
Flindersine
(ii) reaction of 4-hydroxy-2-quinolin-(1H)-one with
a,b-unsatu-
O
rated aldehydes in the presence of Yb(III)triflate/indium(III) chlo-
ride in acetonitrile or iodine in dichloromethane,13 (iii)
intramolecular electrophilic annulation of 2-alkynylquinoline-3-
carboxaldehydes in the presence of N-iodosuccinimide,14 (iv)
O
N
O
N
O
N
N
O
O
O
Melicobisquinolone B
Melicobisquinolone A
Figure 1. Pyranoquinolinone based natural products.
⇑
Corresponding author. Tel./fax: +91 452 2459845.
E-mail address: subbu.perum@gmail.com (S. Perumal).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.022

P. Gunasekaran et al. / Tetrahedron Letters 54 (2013) 3248–3252
3249
Table 1
Screening of catalysts, solvents, and reaction conditions for the synthesis of 4a
Me
H
Me
O
HN
HN
Me
NO2
NO2
Ar
S
O
O
Ar
O
3
Me
Me
OH
N
N
EtOH
ZnCl2
EtOH-reflux
reflux
2
N
Me
OHHO
N
Me
O
catalyst-free
1
5a
4a
Ar = p-ClC6H4
Entry
Catalysta
Solvent
Time (h)
Yield (%)
5ab
4ab
c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
14
15
16
17
18
19
20
—
—
—
—
Solvent-free
Water
Ethanol
Acetonitrile
Ethanol
Acetonitrile
Ethanol
Acetonitrile
Ethanol
Ethanol
Acetonitrile
Water
Ethanol
Ethanol
Ethanol
Ethanol
Acetonitrile
THF
Dioxane
Acetonitrile
Ethanol
10
13
7
9
8
6
7
7
6
7
5
8
3
4
7
10
7
9
—
—
—
—
—
—
—
—
—
—
—
—
63
—
c
c
c
35
20
73
67
68
50
67
65
40
c
c
Et3N
c
Pyrrolidine
Pyrrolidine
NH4OAc
NH4OAc
Yb(OTf)3
Yb(OTf)3
ZnCl2
ZnCl2 (100)
ZnCl2 (30)
ZnCl2 (20)
ZnCl2 (10)
ZnCl2
ZnCl2
ZnCl2
CuBr2
CuBr2
CuCl2
CuCl2
c
c
c
c
c
c
c
—
—
—
—
c
92
92
78
60
73
56
35
40
70
55
45
c
c
c
—
4
29
11
4
10
5
14
9
6
9
8
Ethanol
Acetonitrile
7
a
b
c
100 mol % of catalysts employed unless stated in parenthesis.
Yield of isolated product.
Product not obtained.
Michael-type 1,4-addition of enamine, derived from aldehyde and
diethylamine, to quinone methide.19 These methods, however, suf-
fer from one or more disadvantages such as low/inconsistent
yields, tedious work up, the need for column chromatographic
purification, etc.
Under this context, we now report an expedient, three-
component protocol for the synthesis in good yields of novel
pyrano[3,2-c]quinolin-5(6H)-ones from the reaction of 4-hydro-
xy-1-methylquinolin-2(1H)-one 1, aromatic aldehydes 2, and
nitroketene N,S-methylacetal 3 in the presence of anhydrous ZnCl2
in ethanol (Tables 1 and 2).
Table 2
Synthesis of 4H-pyrano[3,2-c]quinolin-5(6H)-ones 4
Me
Me
HN
HN
NO2
Ar
Me
NO2
3
OH
O
The nitroketene N,S-methylacetal20 3 is a versatile synthon with
an electron-releasing MeNH and an electron-withdrawing NO2, be-
sides having a nucleofuge (MeS). These functionalities enable this
unique synthon to display nucleophilic and electrophilic character
at the adjacent olefinic carbons (Fig. 2) and to be a good Michael
acceptor, facilitating the incorporation of diverse nucleophiles by
addition–elimination mechanism at the carbon bearing the amino
S
ZnCl2
EtOH-reflux
H
N
Me
O
N
O
Me
1
2
4
Entry
Compd
Ar
Time (h)
Yield of 4 (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4-ClC6H4
4
6
5
8
4
7
7
8
7
6
6
4
6
5
8
92
91
85
90
89
90
93
89
87
88
92
92
89
91
88
4-MeC6H4
4-MeOC6H4
4-PriC6H4
2-MeC6H4
C6H5
4-FC6H4
2-ClC6H4
3-FC6H4
3-BrC6H4
4-O2NC6H4
1-Naphthyl
2,3-Cl2C6H3
2,4-Cl2C6H3
2,5-(MeO)2C6H3
Nucleophilic
carbon
H
S
NO2
Leaving
group
N
H
Electrophilic
carbon
Figure 2. Unique structural features of nitroketene N,S-methylacetal 3.

3250
P. Gunasekaran et al. / Tetrahedron Letters 54 (2013) 3248–3252
and sulfanyl groups, while the alkenic carbon bearing the nitro
group can function as a nucleophilic center. This intramolecular
polarization can be advantageously employed for the assembly of
novel heterocyclic ring systems by reaction with an electrophilic
as well as a nucleophilic reactant together in a one pot multi-
component domino reaction.21
It is pertinent to note that domino reactions have emerged as a
powerful synthetic tool from the perspective of green chemistry
and atom economy,22 as they provide a rapid, convergent, and ele-
gant synthesis of complex organic molecules without isolation
and/or purification of intermediates. In particular, the develop-
ment of domino reactions for the construction of medicinally rele-
vant heterocycles has been a fertile research area in organic
synthesis,23 besides being an important goal in combinatorial
chemistry. The present work stems as a part of our continued
exploratory research on the construction of novel structurally di-
verse heterocycles24 employing tandem/domino/sequential pro-
cesses and green transformations.
We have initiated our study by performing the model reaction
of equimolar amounts of 4-hydroxy-1-methylquinolin-2(1H)-one
1, 4-chlorobenzaldehyde 2, and nitroketene N,S-methylacetal 3
in the absence of any catalyst under solvent-free conditions, in
water, ethanol, and acetonitrile (Table 1). No reaction was found
to occur in water, while the reaction in ethanol, acetonitrile,
and solvent-free conditions led to the formation of 5a arising
from the reaction of two molecules of 4-hydroxy-1-methylquino-
lin-2(1H)-one with one molecule of 4-chlorobenzaldeyde, leaving
nitroketene N,S-methylacetal and 50% of 4-chlorobenzaldehyde
unreacted (Table 1). The above reaction in the presence of trieth-
ylamine, pyrrolidine, ammonium acetate, or Yb(OTf)3 as catalysts
also furnished only 5a (Table 1, entries 5–11), while the reaction in
the presence of CuBr2 and CuCl2 furnished the desired product, 4a
along with 5a (Table 1, entries 17–20). It is gratifying to find that
the reaction in the presence of ZnCl2 led exclusively to the forma-
tion of 4-(4-chlorophenyl)-6-methyl-2-(methylamino)-3-nitro-4H-
pyrano[3,2-c]quinolin-5(6H)-one 4a (Table 1) in 92% yield. The
maximum yield in the shortest reaction time was obtained when
the ZnCl2–ethanol combination was employed (Table 1, entry 13).
The study of the effect of catalyst loading on the model reaction
leading to 4a with different amounts of ZnCl2 in ethanol (Table 1,
entries 13–16) show that the yield remains almost the same, when
30 or 100 mol % of ZnCl2 was employed, while lower amounts
diminished the yield significantly. Although this ZnCl2-catalyzed
reaction failed to proceed in water as the sole reaction medium
(Table 1, entry 12), the release of 1 M equiv of water into the
ethanol medium during the course of the reaction apparently does
not impede the reaction significantly as evident from the formation
of a high yield of the product. However, the yield of the product 4a
dropped significantly to 78%, when 10% water–90% ethanol (v/v)
mixture was employed, compared to 92% yield of 4a when absolute
ethanol was used. Consequently, for all subsequent reactions,
30 mol % of ZnCl2 was employed in absolute ethanol at reflux tem-
perature. Interestingly, the products precipitated from the reaction
mixtures and could be brought to high purity by a single recrystal-
lization from dichloromethane, thus avoiding the need for extrac-
tion and chromatographic purification stages. These are
important characteristics of our method, since it is well known that
waste generation from synthetic operations is mostly due to the
isolation and purification stages. The fact that ZnCl2 has emerged
as the most suitable catalyst for this transformation, renders the
protocol attractive, as ZnCl2 is an abundant and inexpensive Lewis
acid. For all these reactions absolute ethanol was employed.
Presumably, ZnCl2 can activate both aldehyde 2 and nitroketene
N,S-methylacetal 3 as well as intermediates involved in complexa-
O
Ar
2
Ar
O
O
Ar
O
O
H
H
NO2
Me
Me
Zn2+
Me
N
N
H
O
O H
Zn2+
N
-H2O
..
S
Zn2+
N
O
H
3
H
7
6
1
Zn2+
Ar
H
O
O
Ar
O
Ar
O
H
Me
NO2
Me
NO2
NO2
Me
N
N
N
-MeSH
+
O-
Me
S
NHMe
N
H
O
NHMe
Zn2+
S
4
8
9
Scheme 1. Plausible mechanism for ZnCl2-catalyzed formation of 4H-pyrano[3,2-c]quinolin-5(6H)-ones 4.
H
H
3.39, d, J=5.1 Hz
29.7
Me
HN
HN
2
H
NO2
10.28, s
7.97, dd, J=7.8,
NO2
158.1
7.31, d, J=7.8 Hz
1.2 Hz
H
1
3
O
H
128.9
O
H
H
7.05, d, J=7.8 Hz
148.9
4
10
H
H
H
138.4
128.5
10a
6a
9
8
1a
4a
1'
2'
H
136.7
4'
160.2
N
5
H
H
6
3'
139.1
Me
N
O
O
7
2.24, s 21.1
5.46, s, 37.3
H
H
Me
3.63, s, 28.3
H
H
Figure 3. HMB correlations of compound 4b.

P. Gunasekaran et al. / Tetrahedron Letters 54 (2013) 3248–3252
3251
tion, thereby catalyzing the reaction (Scheme 1). It is pertinent to
Supplementary data
note that ZnCl2 catalyzes diverse organic reactions such as
tandem/domino coupling of enones25 and Mukaiyama aldol lacton-
ization26 and enables the synthesis of pyrimidines,27 pyridines,28
1,2,4-oxadiazoles,29 benzofurans/indoles,30 3-aminopyrazinones,31
etc.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
04.022.
With the above results in hand, the scope of the reaction was
investigated under the optimal conditions established above (Table
2) with a series of substituted aromatic aldehydes. Typically, the
reaction of a mixture 4-hydroxy-1-methylquinolin-2(1H)-one 1
(1 mmol), aromatic aldehydes 2 (1 mmol), and nitroketene N,S-
methylacetal 3 (1 mmol) in ethanol (15 ml) at reflux for 4–8 h
afforded a library of novel 4-aryl-6-methyl-2-(methylamino)-3-
nitro-4H-pyrano[3,2-c]quinolin-5(6H)-ones 4 in 85–93% yields.32
The structure of compounds 4 is in accord with elemental anal-
ysis and NMR spectroscopic (1H, 13C, and 2D NMR) data as illus-
trated for a representative example 4b (Fig. 3).33 In the 1H NMR
spectrum of 4b, the methyl hydrogens of the NCH3 group attached
to the pyran ring give a doublet at 3.39 ppm (J = 5.1 Hz), which
shows HMBCs with C-2 at 158.1 ppm, while the N–CH3 hydrogens
of the quinolinone ring appear at 3.63 ppm and show HMBC with
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Acknowledgment
S.P. and A.I.M. acknowledge the Deanship of Scientific Research
at King Saud University for funding through the research Grant
RGP-VPP-026.

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32. General procedure for the synthesis of 4H-pyrano[3,2-c]quinolin-5(6H)-ones 4: a
33. The spectroscopic data for representative compounds 4a and 4b: 4-(4-
chlorophenyl)-6-methyl-2-(methylamino)-3-nitro-4H-pyrano[3,2-c]quinolin-
5(6H)-one (4a). Yellow solid; yield 92%; mp 325 °C; 1H NMR (300 MHz, CDCl3)
dH: 3.42 (d, 3H, J = 3.0 Hz, NHCH3), 3.65 (s, 3H, NCH3), 5.46 (s, 1H, CH), 7.19–
7.24 (m, 2H, Ar-H), 7.34–7.42 (m, 4H, Ar-H), 7.67 (td, 1H, J = 7.8 Hz, 0.9 Hz, Ar-
H), 7.98 (d, 1H, J = 7.2 Hz, Ar-H), 10.28 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3)
dC: 27.7, 28.9, 36.5, 108.0, 111.9, 113.8, 121.4, 121.9, 127.2, 129.1, 131.1, 131.5,
139.5, 157.0, 159.2. ESI-MS m/z calcd for C20H16ClN3O4 [M+H]+ 398.08, found
398.28. Anal. Calcd for C20H16ClN3O4: C, 60.38; H, 4.05; N, 10.56. Found: C,
60.44; H, 4.12; N, 10.64.
6-Methyl-2-(methylamino)-3-nitro-4-p-tolyl-4H-pyrano[3,2-c]quinolin-5(6H)-
one (4b). Yellow solid; yield 91%; mp 320 °C; 1H NMR (300 MHz, CDCl3) dH:
2.24 (s, 3H), 3.39 (d, 3H, J = 5.1 Hz, NHCH3), 3.65 (s, 3H, NCH3), 5.46 (s, 1H, CH),
7.05 (d, 2H, J = 7.8 Hz, Ar-H), 7.29–7.40 (m, 4H, Ar-H), 7.65 (td, 1H, J = 8.1 Hz,
1.5 Hz, Ar-H), 7.97 (dd, 1H, J = 7.8 Hz, 1.2 Hz, Ar-H), 10.28 (br s, 1H, NH). 13C
NMR (75 MHz, CDCl3) dC: 21.1, 28.3, 29.8, 37.3, 109.0, 112.8, 113.0, 114.5,
122.1, 122.5, 128.5, 128.9, 131.6, 136.7, 138.4, 139.1, 148.9, 158.1, 160.3. ESI-
MS m/z calcd for C21H19N3O4 [M+H]+ 377.18, found 378.20. Anal. Calcd for
mixture of 4-hydroxy-1-methylquinolin-2(1H)-one
1 (1 mmol), aromatic
aldehydes 2 (1 mmol), and nitroketene N,S-methylacetal 3 (1 mmol) in the
presence of ZnCl2 (30 mol %) in ethanol (15 ml) was stirred at reflux for the
time given in Table 3. After completion of the reaction (TLC), the reaction
mixture was cooled to room temperature and the resulting solid was filtered
off and recrystallized from dichloromethane to obtain pure products 4.
C21H19N3O4: C, 66.83; H, 5.07; N, 11.13. Found: C, 66.98; H, 5.19; N, 11.27.