Rapid, clean and efficient one-pot synthesis of thiopyrano[2,3-b]quinolines via domino Michael addition/cyclization reactions

Article abstract of DOI:10.1016/j.tetlet.2012.04.032

Rapid and efficient one-pot synthesis of thiopyrano[2,3-b]quinolines is described from the reaction of 3-formyl-quinoline-2-thiones with acrylonitrile using economical organic base Et₃N at room temperature. The reaction proceeded smoothly via d

Full text of DOI:10.1016/j.tetlet.2012.04.032

Tetrahedron Letters 53 (2012) 3242–3244
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Rapid, clean and efficient one-pot synthesis of thiopyrano[2,3-b]quinolines
via domino Michael addition/cyclization reactions
⇑
Bhawana Singh, Atish Chandra, Mrityunjaya Asthana, Radhey M. Singh
Department of Chemistry, Banaras Hindu University, Varanasi 221005, UP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Rapid and efficient one-pot synthesis of thiopyrano[2,3-b]quinolines is described from the reaction of 3-
formyl-quinoline-2-thiones with acrylonitrile using economical organic base Et3N at room temperature.
The reaction proceeded smoothly via domino Michael addition/cyclization reactions and did not require
dry solvent, inert atmosphere and column chromatography purifications.
Received 18 January 2012
Revised 5 April 2012
Accepted 6 April 2012
Available online 14 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Domino reaction
Michael addition/cyclization
3-Formyl-quinoline-2-thiones
Thiopyrano[2,3-b]quinolines
Et3N
The importance of quinoline and its annelated derivatives is well
recognized by synthetic and biological chemists. Compounds
possessing this ring system have wide applications as drugs, phar-
maceuticals and agrochemicals.1 Similarly, the chemistry of thiopy-
rans has been much less explored than that of the analogous pyrans.
Recently, interest in the sulfur-heterocycles has significantly in-
creased since a wide range of biological activities associated with
the scaffold have been identified. Amongst the thiopyran fused het-
erocycles, thiopyranoquinoline containing both quinoline ring and
thiopyran moieties, have afforded unique biological activities, for
example, thiopyrano[2,3-c]quinoline, MT477 is reported as a poten-
tial anticancer drug with a high activity against protein kinase C
(PKC) isoforms2 and inspite of these thiopyran moieties also exhib-
ited anti-inflammatory, anti-bacterial, anti-microbial, anti-hyper-
plasia, antipsychiatric, analgesic and anti-cancer activities.3,6 Thus,
the development of facile synthetic strategies to access such hetero-
cycles is always of considerable interest.
Consequently, several syntheses have been developed for thio-
pyrans.4 Multicomponent and microwave assisted reactions are
amongst the most useful routes for the synthesis of these
compounds. Recently, multicomponent reactions involving aro-
matic aldehydes, naphthalen-2-amine and tetrahydrothiopyran-
4-one to the synthesis of thiopyran fused-quinolines have been
reported by Wang et al.5 Similarly, Mahadevan and co-workers
have reported the microwave-assisted synthesis from 3-formyl-
quinoline-2-thiones with active methylene esters.6 All these
methods have some limitations such as high temperature, longer
reaction time and poor yields and to the best of our knowledge less
explored on their 2-thione analogs.7
Our group is actively engaged in developing the easily accessi-
ble precursors of quinoline derivatives8 for exploring their
reactivity and synthetic applications. We have reported the
synthesis of cyclopenta, pyrano- and pyrido-annulated quinolines
using 2-chloro-3-formylquinoline precursor via intra and intermo-
lecular cyclization of alkenes/alkynes by choice of suitable
reagents, catalysts and other reactive partners.9
Further, we have also reported the rapid base-free one-pot syn-
thesis of 1,2-dihydrobenzo[b][1,8]naphthyridines from Baylis Hill-
man acetates of 2-chloro-3-formylquinolines with different
amines (approx. 5 min) with excellent yields.10 This observation
inspired us to explore the similar reactions for sulfur analogs using
Na2S to the synthesis of thiopyranoquinolines from Baylis Hillman
reaction. The reaction with Na2S proceeded to give a mixture of
unidentified products. Subsequently, we turned our attention to
multicomponent reaction using 2-chloro-3-formylquinolines,
Na2S, acrylonitrile, with different bases which again afforded the
mixture of undesired products. We then focused on Michael addi-
tion followed by cyclization reactions on 2-thione analogs of 3-
formylquinolines using acrylonitrile and bases. To our surprise,
the reaction was domino and afforded the single desired product
3 in a very short time. Thus, we now report rapid and efficient
one-pot synthesis of thiopyrano[2,3-b]quinolines from 3-formyl-
quinoline-2-thiones with acrylonitrile and Et3N base.
⇑
Corresponding author. Tel.: +91 542 6702482; fax: +91 542 2368127.
E-mail address: rmohan@bhu.ac.in (R.M. Singh).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.032

B. Singh et al. / Tetrahedron Letters 53 (2012) 3242–3244
3243
Initially, we attempted multicomponent reactions using sub-
CHO
CN
CN
Et3N
strate 2-chloro-3-formylquinoline (1a), Na2S, acrylonitrile and
base all together and also by sequential addition of the reagents
with and without base at room temperature/heating, the reactions
proceeded but failed to afford the desired cyclized product 2H-
thiopyrano[2,3-b]quinoline-3-carbonitrile (3a).
Next, we turn our attention to the Michael addition/cyclization
reactions to the synthesis of 3, using 3-formyl-quinoline-2-thione
derivatives 2 as substrates, prepared from the compounds 1 using
1.5 equiv sodium sulfide in DMF at room temperature (85–95%,
Scheme 1), for finding the optimization reaction conditions. Thus,
3-formyl-quinoline-2-thione (2a) was treated with 1.5 equiv acry-
lonitrile, 1.5 equiv Et3N in 4.0 mL DMF at room temperature, the
reaction was completed in 5 min and afforded only a single prod-
uct with 93% yield, which was characterized from its spectral
and analytical data as 2H-thiopyrano[2,3-b]quinoline-3-carboni-
trile (3a) (Scheme 2, Table 1, entry 1).
+
N
S
DMF, r.t., 5 min.
N
S
H
3a
2a
OH
-H2O
CN
H
N
S
NEt3
Scheme 2. Synthesis of thiopyrano[2,3-b]quinoline (3a) from 3-formyl-quinoline-
2-thione (2a).
Table 1
Optimization of reaction condition using different bases and solvents
We further examined various parameters such as solvents and
bases to optimize the reaction conditions for cyclization. The re-
sults are reported in Table 1 (entries 1–14). Among the bases,
Et3N afforded the pure cyclized product without further purifica-
tion in excellent yield (entry 1). DBU base was found equally effec-
tive and afforded similar yield of the cyclized product (entry 2).
However, using DABCO base, the cyclized product was found in
lower yield (entry 3). It is noteworthy that, the reaction was also
completed in 5 min using inorganic bases such as K2CO3,ÁCs2CO3,
t-BuOK and K3PO4 but afforded the mixture of unidentified prod-
ucts (Table 1, entries 4–7). Thus, it is found that organic bases
are more efficient than the inorganic bases for the addition/cycliza-
tion reactions. We further examined the effect of various solvents
such as DMF, CHCl3, THF, CH3CN, DCM, Toluene, MeOH and H2O.
The results are reported in Table 1 (entries 8–14). It was found that
DMF solvent gave the best yield (93%, Table 1, entry 1) whereas
CHCl3 and THF were equally effective as DMF with slightly lower
yields, respectively (88%, 80%, Table 1, entries 8 and 9). With
CH3CN and DCM the same product was obtained in 5 min with
moderate yields (Table 1, entries 10 and 11). It is noteworthy that
with nonpolar solvent like toluene and protic polar solvents such
as MeOH and H2O reaction did not proceed (entries 12–14).
With optimal conditions in hand, various substituted quinolines
2b–i were allowed to react with acrylonitrile for the cyclizations.
All reactions proceeded smoothly and provided the corresponding
thiopyrano[2,3-b]quinolines 3b–i in good to excellent yields. The
results are summarized in Table 2 (entries 2–9). The similar reac-
tion rates were observed with electron-donating and electron-
withdrawing substituents on the quinoline moiety. However, the
yields with electron donating substituents at positions 6 and 7 in
3b–c and 3e–f are slightly higher (entries 2, 3, 5 and 6) as com-
pared to electronwithdrawing substituents at 6 and 7 positions
in 3d and 3g, respectively (entries 4 and 7).
Entry
Substrate
Base
Solvent
Product
Yield of 3a (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
Et3N
DBU
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CHCl3
THF
CH3CN
DCM
Toluene
MeOH
H2O
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
93
90
76
00
00
00
00
88
80
42
50
00
00
00
DABCO
K2CO3
Cs2CO3
t-BuOK
K3PO4
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Table 2
Synthesis of thiopyrano[2,3-b]quinolines 3 from 3-formyl-quinoline-2-thiones 2
Entry
Substrate
R
Product
Time (min)
Yield of 3 (%)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
5
5
5
5
5
5
5
5
5
93
93
89
85
90
89
81
86
85
88
71
6-Me
6-OMe
6-Br
7-Me
7-OMe
7-Cl
8-Me
8-Et
H
10a
11b
2a
2a
3j
3k
15
15
H
a
Methyl acrylate.
Crotonaldehyde used.
b
We further examined the reactions with other activated alkenes
under similar reaction conditions such as ester (methylacrylate)
and aldehyde (crotonaldehyde) to understand the effect of the sub-
stituents of the activated alkene on the reaction rate and yields. In
both cases, reaction proceeded smoothly affording the desired cy-
clized product in 15 min with 88% and 71% yield, respectively (Ta-
ble 2, entries 10 and 11), presuming the reaction rate was
dependent on the substituents of the alkenes.
In conclusion, we have developed the conditions for domino
reaction to the rapid and efficient synthesis of thiopyrano[2,3-
b]quinolines using cheap base Et3N. Experimental procedures11
are simple and eliminate the need of anhydrous solvent, inert
atmosphere and further purifications. The final compounds could
be used as a valuable synthon in various organic transformations.
Further, investigations of the compound with the various binucle-
ophiles to the synthesis of annulated heterocycles are on
underway.
CHO
Cl
CHO
S
Na2S
Acknowledgments
DMF, r.t., 5 min
N
N
H
R
R
We thank the CSIR (New Delhi) and the UGC (New Delhi) for
funding. B.S. is thankful to the CSIR, New Delhi, for the award of
Senior Research Fellowship, A.C. to the UGC, New Delhi for DSK-
Postdoctoral fellowship and M.A. to the BHU fellowship.
2
1
85-95%
R = H, Me, Et, OMe
Scheme 1. Synthesis of precursor 3-formyl-quinoline-2-thiones.

3244
B. Singh et al. / Tetrahedron Letters 53 (2012) 3242–3244
5. Wang, X.-S.; Li, Q.; Wu, J.-R.; Tu, S.-J. J. Comb. Chem. 2009, 11, 433.
Supplementary data
6. Nandeshwarappa, B. P.; Kumar, D. B. A.; Kumaraswamy, M. N.; Ravi Kumar, Y.
S.; Bhojya Naik, H. S.; Mahadevan, K. M. Phosphorus, Sulfur Silicon 2006, 181,
1545.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.04.
032. These data include MOL files and InChiKeys of the most
important compounds described in this article.
7. Majumdar, K. C.; Ponra, S.; Ghosh, T. RSC Adv. 2012, 2, 1144.
8. Upadhyay, S.; Chandra, A.; Singh, R. M. Indian J. Chem. 2009, 48B, 152.
9. (a) Singh, B.; Chandra, A.; Singh, S.; Singh, R. M. Tetrahedron 2011, 67, 505; (b)
Chandra, A.; Singh, B.; Singh, R. M. J. Org. Chem. 2009, 74, 5664; (c) Singh, R. M.;
Chandra, A.; Singh, B.; Upadhyay, S. Tetrahedron 2008, 64, 11680; (d) Singh, R.
M.; Singh, B.; Chandra, A.; Upadhyay, S. Tetrahedron Lett. 2008, 49, 6423; (e)
Singh, R. M.; Singh, M. K.; Chandra, A.; Singh, B. Tetrahedron Lett. 2007, 48,
5987; (f) Singh, R. M.; Chandra, A.; Singh, M. K. Synth. Commun. 2007, 37, 1689;
(g) Singh, R. M.; Srivastava, A.; Chandra, A. Indian J. Chem. 2007, 46B, 303; (h)
Singh, R. M.; Srivastava, A.; Singh, M. K. Indian J. Chem. 2006, 45B, 292; (i) Singh,
R. M.; Srivastava, A.; Chandra, A. Indian J. Chem. 2005, 44B, 2077.
10. Singh, B.; Chandra, A.; Singh, R. M. Tetrahedron 2011, 67, 2441.
11. To a stirred solution of 2 (0.25 mmol) in DMF (4 mL) was added acrylonitrile
(0.37 mmol) and Et3 N (0.37 mmol) at room temperature for 5–15 min. After
completion of the reaction (as monitored by TLC), the reaction mixture was
allowed to pour into chilled water and precipitate was filtered out. The crude
product 3 was pure enough for analysis; 2H-thiopyrano[2,3-b]quinoline-3-
carbonitrile (3a): light yellow solid; yield: 93%; mp 153 °C; 1H NMR (300 MHz,
CDCl3): d = 3.93 (s, 2H), 7.49 (t, J = 7.2 Hz, 1H), 7.69–7.75 (m, 3H), 7.82 (s, 1H),
7.91 (d, J = 8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3): d = 27.7, 106.5, 117.7, 123.7,
126.9, 128.2, 128.3, 129.2, 131.8, 136.6, 140.9, 148.4, 155.7; IR (KBr): 1579,
2204 cmÀ1. HRMS calcd for C13H9N2S [M+H]+ 225.0486; found 225.0483.
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