Facile construction of densely functionalized thiopyrano[2,3-b]quinolines via three-component reactions catalyzed by l-proline

Article abstract of DOI:10.1039/c4ra05042h

l-Proline catalyzed, three-component reactions of 2-mercaptoquinoline-3- carbaldehyde, malononitrile and thiol-based nucleophiles were developed for the first time, for the synthesis of various 4H-substituted thiopyrano[2,3-b] quinolines derivatives via a Knoevenagel condensation followed by inter-intramolecular double Michael addition reaction. This transformation leads to the generation of a 4-substituted thiopyran ring, together with one C-C and two C-S bonds in a single operation.

Full text of DOI:10.1039/c4ra05042h

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Facile construction of densely functionalized
thiopyrano[2,3-b]quinolines via three-component
reactions catalyzed by L-proline†
Cite this: RSC Adv., 2014, 4, 28798
Received 22nd April 2014
Accepted 16th June 2014
*
Mehul B. Kanani and Manish P. Patel
DOI: 10.1039/c4ra05042h
www.rsc.org/advances
L-Proline catalyzed, three-component reactions of 2-mercaptoqui- the synthesis of novel 4H-thiopyrano[2,3-b]quinolines
noline-3-carbaldehyde, malononitrile and thiol-based nucleophiles (Scheme 1) employing the green organocatalyst, L-proline.
were developed for the first time, for the synthesis of various
L-Proline is an efficient bifunctional abundant organo-
4H-substituted thiopyrano[2,3-b]quinolines derivatives via a Knoeve- catalyst which is inexpensive and facilitates chemical trans-
nagel condensation followed by inter-intramolecular double Michael formations by acting as an acid or base. Further, L-proline have
addition reaction. This transformation leads to the generation of a shown considerable catalytic efficiency in diverse organic
4-substituted thiopyran ring, together with one C–C and two C–S transformations, such as aldol, Mannich, Michael, Hantzsch,
bonds in a single operation.
Diels–Alder/Knoevenagel and other domino process.5 L-Proline,
has also been used as a catalyst in different multicomponent
reactions (MCRs), and the studies have shown that this catalyst
efficiently promoted these protocols.6
MCRs assemble three or more substrates in one pot opera-
tions with high synthetic efficiency7 and hence are important
from a green chemistry perspective.8 As a one-pot, MCRs permit
rapid access to combinatorial libraries of densely functional-
ized complex molecules in a single synthetic operation espe-
cially in drug discovery.9
The importance of quinoline annulated thiopyran derivatives is
well recognized by synthetic and medicinal chemists.
Compounds possessing this ring system have attracted much
attention in recent years because this key moiety emerged in a
large number of bioactive natural products and pharmaceutical
agents.1 Recently a wide range of biological activities associated
with the sulphur-heterocycles scaffolds have been identied.2
Likewise thiopyran and fused-thiopyran derivatives show anti-
inammatory,3a anti-bacterial,3b anti-hyperplasia,3c anti-
psychotic,3d analgesic, and anti-cancer4 activities. Thiopyrano-
quinoline annulated heterocycles are also distinguished by
their biological properties. In addition to the biological
importance, their structural similitude to (i) MT477 is reported
as a potential anticancer drug with a high activity against
protein kinase C (PKC) isoforms 2, (ii) metabotropic glutamate
receptor antagonistic activity that is, mGlu1 receptor activity of
thiopyranoquinoline4 is an added attraction for the interest in
the synthesis of thiopyrano-quinoline.
The synthetic protocols reported earlier for thiopyran fused-
quinoline includes, multi-component reactions involving aromatic
aldehydes, naphthalen-2-amine and tetrahydrothiopyran-4-one
have been reported by Wang et al.10 Similarly, Mahadevan and
co-workers have reported the microwave-assisted synthesis from
3-formyl-quinoline-2-thiones with active methylene esters.11
Recently, Singh et al.12 have reported the synthesis of fused thio-
pyrans via domino Michael addition followed by cyclization
Despite the fact that the chemistry of biological signicance
thiopyrano-quinoline has been much less explored than that of
their pyrano-quinoline analogous. Thus the development of
facile synthetic strategies to access such heterocycles provided
the impetus to investigate the three-component reactions for
Sardar Patel University, Chemistry Department, Nr. University circle, Vallabh
vidyanagar, Gujarat, India. E-mail: patelmanish1069@yahoo.com
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra05042h
Scheme 1
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Table 1 Three component reaction of (1a), malononitrile (2) and thi-
ophenol (3a) under different conditionsa
reactions on 2-thione analogs of 3-formylquinolines using acrylo-
nitrile thus demonstrating for the rst time the potential of
3-formyl-quinoline-2-thiones to undergo nucleophilic additions.
All these methods have some limitations such as high temperature,
longer reaction time, tedious work-up and poor yield.
In our previous studies, we reported a series of new
3,5-dicyanopyridines starting from various aldehydes, malono-
nitrile and thiols.13 Also we have reported the synthesis of
bioactive fused heterocycles via one-pot reaction.14 We now
report rst time a facile route for the synthesis of densely
functionalized thiopyrano[2,3-b]quinolines from the Knoeve-
nagel condensation followed by intra/inter molecular double
Michael addition reaction of 3-formyl-quinoline-2-thiones with
malononitrile and thiophenols in ethanol in the presence of
L-proline in a very short duration of time in good yields
(Scheme 1).
Our initial attempts to convert 2-chloro-3-formylquinoline to
4H-thiopyrano[2,3-b]quinolines using 1.5 equivalent of Na2S,
malononitrile, thiophenol and base mixed together at same
time and also by sequential addition of the reagents with and
without base at room temperature/heating the reactions pro-
ceeded to access 2-((2-chloroquinolin-3-yl)methylene)malono-
nitrile but failed to afford the desired cyclized product 2-amino-
4-(phenylthio)-4H-thiopyrano[2,3-b]quinoline-3-carbonitrile 4a.
Next, we turn our attention to the Knoevenagel condensation
followed by Michael addition/cyclization reactions to the
synthesis of 4a, using 3-formyl-quinoline-2-thione derivatives 1a
as substrates, synthesized from 2-chloro-3-formylquinoline as
literature procedure.
Entry Base
Temp (ꢀC) Solvent
Yields of 4a (%)
1
—
80
80
80
80
80
80
Rt
60
80
80
110
120
80
40
100
60
80
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CH3CN
Toluene
DMF
1,4-Dioxane 30
CH2Cl2
H2O
MeOH
EtOH
00
25
20
35
00
30
—
50
94
37
30
36
2
K2CO3
3
Cs2CO3
4
5
Piperidine
NaOH
6
Et3N
7b
8c
9d
10
11
12
13
14
15
16
17e
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
Pyrrolidine :
acetic acid (1 : 1)
10
10
57
73
a
1a: 0.5 mmol, 2a: 0.5 mmol, 3a: 0.5 mmol, solvent: 1.5 ml, catalyst:
b
c
0.05 mmol, 1.5–2.0 h. Reaction time for 2.0 h. Reaction time for
d
e
1.0 h. Reaction time for 0.5 mmol, 10 min. Reaction time for 45–50
min.
In Table 1, the reaction was performed under catalyst-free
conditions, using ethanol at 80 ꢀC although 1a was almost
consumed in 1.0 h, to form Knoevenagel adduct (A), no Michael
addition of thiophenol 3a took place.
Table 2 Synthesis of 4H-thiopyrano[2,3-b]quinoline-3-carbonitriles
derivatives 4(a–o)
To optimize the reaction conditions for the formation of the
target compounds, we started this study by treating 3-formyl-
quinoline-2-thione 1a with malononitrile 2 and thiophenol 4a.
Various reaction conditions were investigated, including
bases, solvents, and temperatures. Initially, we employed
various bases such as Et3N, K2CO3, NaOH, piperidine and
Cs2CO3 separately, to determine one which can give the best
results. These results showed that the properties of the
employed catalyst have remarkable effect in controlling
the reaction selectivity in terms of addition of thiol group of the
Knoevenagel adduct (A) towards the carbon atom of the nitrile
group (B). This gave us force to further explore the feasibility of
synthesizing 4a from 1a, 2 and 3a by mean of changing the
catalyst. We envisaged that L-proline might be good catalyst for
our model three-component reaction because the reaction of 1a
with nucleophiles, 2 and 3a, needed a denite compounding in
order to obtain 4a. By using L-proline as catalyst yield of 4a
signicantly improved. The unique catalytic activity of L-proline
from its amphoteric nature and the amino group might result in
the formation of imine and the carboxylic group could stabilize
the charge generated on the nitrogen atom (C).15
Substrate R1
R2
Product Time (min) Yield of 4a (%)
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1c
1d
1d
H
H
H
H
H
H
Phenyl
4-CH3–C6H5 4b
4-F–C6H5
Benzayl
Cyclopentane 4e
Cyclohexane 4f
4a
10
10
10
10
20
20
10
10
10
10
20
20
10
20
10
94
97
91
83
75
80
93
89
86
81
85
88
90
92
87
4c
4d
CH3 Phenyl
CH3 4-CH3–C6H5 4h
CH3 4-F–C6H5
CH3 Benzayl
CH3 Cyclopentane 4k
CH3 Cyclohexane 4l
OCH3 4-CH3–C6H5 4m
Cl
Cl
4g
4i
4j
Benzayl
4-F–C6H5
4n
4o
The results show that L-proline was the best organocatalyst
for the three component reaction of 3-formyl-quinoline-2-thi-
one, malononitrile and sulde. We than repeated the same
a
Yield of isolated product.
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Scheme 2 Proposed mechanism for the synthesis of 2-amino-4-((substituted)thio)-4H-thiopyrano[2,3-b]quinoline-3-carbonitrile derivatives.
reaction in a different solvents such as acetonitrile, toluene, and thiophenol 3a in the presence of L-proline (0.5 mmol) was
DMF, 1,4-dioxanedichloromethane, H2O, MeOH are rather poor reuxed in ethanol for 10–20 min and cooled to room temper-
(Table 1, entry 10 to 16). Therefore, the optimal condition ꢀfor ature. The solid formed in the reaction mixture was ltered and
L-proline (0.5 mmol) catalyst system is ethanol solvent, 80 C, dried under vacuum. The crude solid product was puried by
10–20 min (Table 1, entry 9).
recrystallization in ethanol to obtain the pure product 4a in
Mechanistically, formation of 4a from 1a, 2 and 3a in the good yield (94%).
L-proline/ethanol system, a plausible mechanism was then
2-Amino-4-(phenylthio)-4H-thiopyrano[2,3-b]quinoline-3-car-
proposed, as shown in Scheme 2. The reaction commenced with bonitrile (4a). Colorless solid; yield: 94%; m.p. 143 ꢀC; 1H NMR
the formation of an 2-((2-mercaptoquinolin-3-yl)methylene) (400 MHz, DMSO d6): d ¼ 4.85 (s, 1H), 7.32 (s, 2H), 7.50–7.52 (m,
malononitrile (A) from 1a and 2. We realized that Knoevenagel J ¼ 7.6 Hz, 6H), 7.94–7.96 (d, J ¼ 7.2 Hz, 2H), 8.12 (s, 1H), 8.62 (s,
adduct (A) undergo to intra-molecular thiol addition reaction to 1H); 13C NMR (100 MHz, DMSO d6): d ¼ 57.0, 106.5, 117.7,
give 2-imino-2H-thiopyrano[2,3-b]quinoline-3-carbonitrile (C) 123.7, 126.9, 128.2, 128.3, 129.2, 131.8, 136.6, 140.9, 148.4,
stabilized by carboxylic group of L-proline, which is upon 155.7; IR (KBr): 1579, 2204 cmꢁ1. MS calcd for C19H13N3S2 [M+]
intermolecular Michael addition of thiophenol 3a would be 347.06; found 348.50.
accessible to 2-amino-4-(phenylthio)-4H-thiopyrano[2,3-b]quin-
oline-3-carbonitrile 4a (Scheme 2).
2-Amino-4-(p-tolylthio)-4H-thiopyrano[2,3-b]quinoline-3-car-
bonitrile (4b). Colorless solid; yield: 82%; m.p. 156 ꢀC; 1H NMR
With the optimized reaction condition in hand, we probe the (400 MHz, DMSO d6): d ¼ 2.25 (s, 3H, CH3), 5.55 (s, 1H), 7.00–
scope of the reaction (Table 2). Thiophenols with different 7.07 (m, 4H), 7.16–7.18 (d, J ¼ 8.0 Hz, 2H), 7.39 (s, 1H), 7.71–7.77
substituents, such as methyl, uoro and mercaptans, like (m, 3H), 7.88–7.93 (t, 1H); IR (KBr): 818, 1643, 2191, 3317 cmꢁ1
.
benzyl, cyclopenate and cyclohexane all smoothly reacted, MS calcd for C14H11N2S [M+] 361.07; found 361.05.
producing the corresponding 4H-thiopyrano[2,3-b]quinolines
2-Amino-7-methoxy-4-(phenylthio)-4H-thiopyrano[2,3-b]-
in good to excellent yields. Thiophenols were proved to be more quinoline-3-carbonitrile (4m). Colorless solid; yield: 93%; mp
1
ꢀ
capable than mercaptane.
143 C; H NMR (400 MHz, DMSO d6): d ¼ 2.26 (s, 3H, CH3),
3.84 (s, 3H, OCH3), 6.65 (s, 1H), 6.93 (s, 2H, NH2), 7.12–7.14 (t, J
¼ 7.6 Hz, 2H), 7.34 (m, 2H), 7.97–7.99 (d, J ¼ 8.0 Hz, 2H), 8.52 (s,
1H); 13C NMR (100 MHz, DMSO d6): 19.7 (CH3), 55.9 (OCH3),
56.0 (CH), 99.4, 106.7, 119.9, 121.5, 122.0, 124.7, 127.1, 127.36,
128.3, 129.9, 138.4, 154.3, 156.8, 158.2, 159.4, 159.6, 162.0; IR
Experimental section
Typical experimental procedure for 4a: a mixture of 3-formyl-
quinoline-2-thione, 1a (1.0 mmol), malononitrile 2 (1.0 mmol)
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(KBr): 785, 1039, 2223, 2942 cmꢁ1. MS calcd for C20H14FN3S2
[M+] 391.06; found 391.0.
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Conclusions
In conclusion, we have developed a general, practical, and
environmentally benign method to construct densely func-
tionalized 4H-thiopyrano[2,3-b]quinolines via the three
component reaction of 3-formyl-quinoline-2-thiones, malono-
nitrile, and thiols (nucleophile) in ethanol in the presence of
green catalyst, L-proline. This one-pot transformation involves
the formation of one C–C bonds and two C–S bond to attained
4-substituted thiopyran ring in a single synthetic operation.
Further, investigations of the compound with the various
nucleophiles to the synthesis of the present methodology are
underway. Also, such type of compounds can serve as a good
starting point for drug discovery.
6 (a) A. Kumar, M. K. Gupta and M. Kumar, Green Chem., 2012,
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Acknowledgements
´
One of the authors (M.B. Kanani) is grateful to UGC, New Delhi
for Research Fellowship in Sciences for Meritorious Students.
The authors are thankful to Head, Department of Chemistry,
Sardar Patel University for providing research facilities. We are
also thankful to DST, New Delhi for the central facility for mass
spectrometry sponsored under PURSE program. We are also
thankful to The assistance in form of concessional analysis by
SICART, Vallabh Vidyanagar.
S. Perumal and J. C. Menendez, Green Chem., 2011, 13,
3248; (d) C. Mukhopadhyay, P. K. Tapaswi and
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