One-pot three-component synthesis of 2H-thiopyrano[2,3-b]quinoline-2,3-dicarboxylates from 2-mercaptoquinoline-3-carbaldehydes, dialkyl acetylenedicarboxylates and Ph3P

Article abstract of DOI:10.1080/17415993.2018.1449845

An extremely concise one-pot procedure toward the synthesis of 2H-Thiopyrano [2,3-b]quinoline-2,3-dicarboxylates whose applications as medicines is predictable has been established. This approach produces three fused rings evolving from the formation of four new carbon–carbon bonds and a stereogenic center in a one-pot protocol.

Full text of DOI:10.1080/17415993.2018.1449845

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: http://www.tandfonline.com/loi/gsrp20
One-pot three-component synthesis of 2H-
thiopyrano[2,3-b]quinoline-2,3-dicarboxylates
from 2-mercaptoquinoline-3-carbaldehydes,
dialkyl acetylenedicarboxylates and Ph3P
Abdolali Alizadeh, Atefeh Roosta & Kaveh Amir Ashjaee Asalemi
To cite this article: Abdolali Alizadeh, Atefeh Roosta & Kaveh Amir Ashjaee Asalemi (2018):
One-pot three-component synthesis of 2H-thiopyrano[2,3-b]quinoline-2,3-dicarboxylates from 2-
mercaptoquinoline-3-carbaldehydes, dialkyl acetylenedicarboxylates and Ph3P, Journal of Sulfur
Chemistry, DOI: 10.1080/17415993.2018.1449845
To link to this article: https://doi.org/10.1080/17415993.2018.1449845
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JOURNAL OF SULFUR CHEMISTRY, 2018
https://doi.org/10.1080/17415993.2018.1449845
One-pot three-component synthesis of
2H-thiopyrano[2,3-b]quinoline-2,3-dicarboxylates from
2-mercaptoquinoline-3-carbaldehydes, dialkyl
acetylenedicarboxylates and Ph3P
Abdolali Alizadeh, Atefeh Roosta and Kaveh Amir Ashjaee Asalemi
Department of Chemistry, Tarbiat Modares University, Tehran, Iran
ABSTRACT
ARTICLE HISTORY
Received 31 December 2017
Accepted 4 March 2018
An extremely concise one-pot procedure toward the synthesis of 2H-
Thiopyrano [2,3-b]quinoline-2,3-dicarboxylates whose applications
as medicines is predictable has been established. This approach
produces three fused rings evolving from the formation of four
new carbon–carbon bonds and a stereogenic center in a one-pot
protocol.
KEYWORDS
2-mercaptoquinoline-3-
carbaldehyde; intramolecular
wittig reaction;
thiopyrano[2,3-b]quinolines;
tricyclic framework;
three-component reactions
1. Introduction
The presence of heterocyclic scaffolds in many natural and synthetic products endowed
with biological properties is responsible for extensive research in recent years on the syn-
thesis of useful polycyclic structures that include one or more heteroatoms. The quinolines
and quinoline-fused heterocycles are privileged structural units presented in numerous
natural products and pharmacologically active compounds [1,2].
Over recent decades, these structures have received considerable attention due to their
significant biological and medicinal properties, which include antibacterial [3], antivi-
ral [4], antimalarial [5,6], anti-inflammatory [7,8], antihistamine [9], anti-asthmatic [10],
antitumor agents [11–13], activities and their potential as HIV-integrase inhibitors [14,15].
Amongst the quinoline derivatives, 2H-thiopyrano[2,3-b]quinolines are tricyclic struc-
tures which contain both a quinoline ring and a thiopyran moiety, which have been found
CONTACT Abdolali Alizadeh
aalizadeh@modares.ac.ir
Department of Chemistry, Tarbiat Modares University,
PO Box 14115-175, Tehran, Iran
Supplemental data for this article can be accessed here. https://doi.org/10.1080/17415993.2018.1449845
© 2018 Informa UK Limited, trading as Taylor & Francis Group

2
A. ALIZADEH ET AL.
Scheme 1. Synthesis of 2-chloro-3-formylquinolines and 3-formyl-2-mercaptoquinolines.
to exhibit several fascinating bioactivities. Consequently, it would seem clear that the
fusion of a quinoline unit to thiopyran would generate a molecular architecture possessing
interesting bioprofiles.
Considering the importance of the above-mentioned applications and activities,
methods for the synthesis of quinoline-fused thiopyran structures are of great inter-
est. Previously, Hekmatshoar et al. [16] developed a method to a synthesis of dialkyl
2H-1-benzothiopyran-2,3-dicarboxylates using triphenylphosphine, dialkyl acetylenedi-
carboxylate and 2-mercptobenzaldehyde. The reported approach is associated with
certain disadvantages, including numerous difficult steps for the synthesis of the 2-
mercaptobenzaldehyde reagent and unacceptably long reaction times. In addition, the
product yields are moderate. Therefore, exploring more effective and flexible strategies and
improvement in the existing synthetic procedures are highly desirable and are important
strategic issues. Therefore, in this study, our goal was to develop an improved proce-
dure, including enhancing the reaction yield of the biologically important thiopyran-fused
quinoline moiety.
In continuation of our program directed toward the synthesis of heterocycles [17,18],
the development of a simple, rapid and cost-effective method for the construction of
quinoline-based sulfur compounds is of value. So we used the above strategy to the syn-
thesis of a new class of thiopyran-based quinolines. The reaction occurred rapidly at room
temperature and the final products were obtained in excellent yield. 3-Formyl-2-chloro-
quinolines 2a,b were prepared from corresponding acetanilides 1a,b via Vilsmeier–Haack
reactions according to the literature [19]. The required 3-formyl-2-mercaptoquinolines
3a,b were obtained by stirring respective 2-chloroquinoline-3-carbaldehydes with sodium
sulfide in DMF at room temperature (Scheme 1) [20].
2. Results and discussion
Following our research interest on the synthesis of quinoline-fused heterocyclic com-
pounds [17,18], we herein used the same strategy reported in the literature for the
synthesis of 2H-thiopyrano[2,3-b]quinoline-2,3-dicarboxylates using a one-pot three
component coupling of 3-formyl-2-mercaptoquinolines, triphenylphosphine and dialkyl
acetylenedicarboxylate (Scheme 2). The reaction was performed at room temperature
within 15–30 min using dichloromethane (DCM) as solvent and afforded the products with
excellent yields (80–90%).
Different solvents were examined to set up standard reaction conditions (Table 1).
Notably, the desired reaction occurred efficiently in dichloromethane at room temperature
in 15–30 min. The reaction did not proceed well in DMF and Et2O at room temperature
(entries 1 and 2).

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3
Scheme 2. Synthesis of 2H-thiopyrano[2,3-b]quinoline- 2,3-dicarboxylates.
Table 1. Optimization of reaction conditions for the formation of 5a.a
Entry
Solvent
Time (min)
Yield (%)b
1
2
3
4
5
6
7
DMF
Et2O
THF
CH2Cl2
EtOAc
Toluene
CH3CN
20
30
20
15
25
30
25
35
35
85
90
80
80
60
aReaction conditions: (i) 4a (1 mmol), 3a (1 mmol), Triphenylphosphine (1 mmol), solvent (5 mL), rt., 15–30 min.
bIsolated yield.
To further validate the synthetic flexibility of this methodology, we envisioned applying
it to various dialkyl acetylenedicarboxylates and also 3-formyl-2-mercaptoquinolines and
the main results of these studies are collected in Table 2.
The structure of all the products was confirmed upon careful analysis of the data
obtained from IR, mass, 1H NMR and 13C NMR spectra. The mass spectrum of 5a dis-
played the molecular ion peak at the appropriate m/z value. In the IR spectrum of 5a, two
absorption bands at 1743 and 1703 cm−1, and three absorption bands at 1650, 1613 and
1565 cm−1, which are related to C O and Ar stretching frequencies, clearly indicated the
=
most significant functional groups of the product. The 1H NMR spectrum of 5a exhibited
two signals at 3.63 and 3.80 ppm, readily recognized as two OMe of two carboxylates. A
signal at 5.13 ppm belonged to the aliphatic CH of thiopyran ring; five other signals in the
range of 7.55–7.94 ppm belong to the five aromatic hydrogens, which gave rise to char-
acteristic signals in the aromatic region of the spectrum. A signal at 8.46 ppm belonged
to the olefinic hydrogen of the thiopyran ring. Observation of 16 distinct signals in the
1H-decoupled 13C NMR spectrum of 5a is in agreement with the proposed structure. The
reaction is assumed to proceed via the formation of a reactive zwitterionic intermediate
6, which is formed from the reaction of triphenylphosphine with dialkyl acetylenedicar-
boxylates. The latter is subsequently protonated by the SH proton of the substrate 3. The
resulting anion 7 then attacks the carbon–carbon double bond of intermediate 8 and fur-
nishes the yield 9 that undergoes an intramolecular Wittig reaction with the carbonyl group
of the aldehyde moiety to form the desired product 5 (Scheme 3).

4
A. ALIZADEH ET AL.
Table 2. Synthesis 2H-thiopyrano[2,3-b]quinoline-2,3-dicarboxylates.a
Entry
R1
R2
Product
Yield (%)b
1
2
3
4
5
6
7
H
H
H
Me
Et
5a
5b
5c
5d
5e
5f
90
85
80
87
87
83
83
iPr
tBu
Me
Et
H
Me
Me
Me
tBu
5g
aReaction conditions: (i) 4 (1 mmol), 3 (1 mmol), Triphenylphosphine (1 mmol), DCM (5 mL), rt., 15–30 min.
bIsolated yield.
Scheme 3. Plausible mechanism for the formation of 2H-thiopyrano[2,3-b]quinoline-2,3-
dicarboxylates.
3. Conclusion
In conclusion, we have used an efficient and one-pot protocol for the synthesis of N,S-
tricyclic compounds, all of which incorporate thiopyrano[2,3-b]quinoline unit. The out-
come of the work highlights substantial improvements in the reaction rates and yields
without any catalyst and base. Additionally, this protocol offers advantages over the pub-
lished procedure [16], such as efficiency, simplicity, generality, high yields, short reaction
time and ease of product isolation.
4. Experimental
4.1. Materials
All reagents and solvents were of commercial quality and used without further purification.
Dichloromethane solvent was completely dried. Analytical thin-layer chromatography

JOURNAL OF SULFUR CHEMISTRY
5
(TLC) was performed on plates precoated with silica-gel layers. Elemental analyses for C,
H and N were performed using a Heraeus CHN–O–Rapid analyzer. Mass spectra were
recorded on an Aglient Technologies 5975C VL MSD mass spectrometer operating at an
ionization potential of 70 eV. Nuclear magnetic resonance spectra (1H, 13C) were recorded
on 500 or 300 MHz NMR spectrometers. IR spectra were recorded as KBr pellets on a
NICOLET FT-IR 100 spectrometer; absorbencies are reported in cm−1
.
4.2. General procedure for the preparation of compounds 5a–g
2-Mercaptoquinoline-3-carbaldehyde (1 mmol) and triphenylphosphine (1 mmol) were
taken in dichloromethane (2 mL), and dialkyl acetylenedicarboxylate (1 mmol) was added
dropwise to the reaction mixture and stirred for 15–30 min. After conclusion of the reac-
tion (monitored by TLC), the reaction mixture was evaporated and washed with diethyl
ether for 5a and the precipitate thus obtained was filtered. For other compounds 5b–g, we
used column chromatography for the purification.
4.2.1. (RS)-dimethyl 2H-thiopyrano[2,3-b]quinoline-2,3-dicarboxylate (5a)
Yellow powder; mp 185–187°C; yield 0.28 g (90%); IR (KBr) ν¯ cm−1: 1743, 1703, 1650,
1613, 1565; 1H NMR (DMSO) δ (ppm) 3.63 (s, 3 H), 3.80 (s, 3 H), 5.13 (s, 1 H), 7.55 (t,
J = 7.4 Hz, 1 H), 7.76 (t, J = 8.0 Hz, 1 H), 7.83 (d, J = 8.2 Hz, 1 H), 7.89 (d, J = 7.9 Hz, 1
H), 7.94 (s, 1 H), 8.46 (s, 1 H); 13C NMR (DMSO) δ (ppm) 40.52 (CHS), 52.6 (C3–CO2Me),
53.1 (C2-CO2Me), 123.2 (C5a), 123.6 (C4a), 126.2 (CH7), 126.8 (CH6), 127.5 (CH8), 128.8
(CH9), 131.8 (CH5), 137.1 (CH4), 138.1 (C3), 147.7 (C9a), 154.7 (C10a), 164.9 (CO2Me),
170.0 (CO2Me); EI-MS: m/z (%) 315 (14, M+), 283 (2), 258 (15), 257 (41), 256 (100), 226
(2), 213 (3), 212 (3), 199 (3), 198 (17), 197 (14), 196 (25), 185 (3), 153 (4). Anal. Calcd for
C16H13NO4S (315.34): C, 60.94; H, 4.16; N, 4.44%. Found: C, 60.99; H, 4.10; N, 4.41%.
4.2.2. (RS)-diethyl 2H-thiopyrano[2,3-b]quinoline-2,3-dicarboxylate (5b)
Light yellow powder; mp 137–139°C; yield 0.29 g (85%); IR (KBr): ν¯ cm−1 1738, 1703,
1
1653, 1613; H NMR (CDCl3): δ (ppm) 1.20 (t, J = 7.1 Hz, 3 H), 1.34 (t, J = 7.1 Hz, 3
H), 4.12 (q, J = 7.1 Hz, 2 H), 4.29 (q, J = 7.1 Hz, 2 H), 4.87 (s, 1 H), 7.41 (t, J = 7.1 Hz, 1
H); 7.64 (t, J = 7.6 Hz, 1 H), 7.68 (d, J = 8.2 Hz, 1 H), 7.83 (s, 1 H), 7.87 (d, J = 8.6 Hz, 1
H), 7.91 (s, 1 H); 13C NMR (CDCl3): δ (ppm) 14.1 (OCH2CH3), 14.3 (OCH2CH3), 41.4
(CHS), 61.8 (OCH2CH3), 62.3 (OCH2CH3), 123.9 (C5a), 124.1 (C4a), 126.6 (CH7), 126.7
(CH6), 128.2 (CH8), 128.4 (CH9), 131.5 (CH5), 137.4 (CH4), 137.5 (C3), 148.6 (C9a), 155.5
(C10a), 165.0 (CO2Et), 169.8 (CO2Et); EI-MS: m/z (%) 343 (10, M+), 273 (2), 272 (12), 271
(31), 270 (100), 256 (4), 244 (4), 243 (11), 242 (61), 198 (7), 197 (8), 196 (17), 186 (3), 154
(2). Anal. Calcd for C18H17NO4S (343.40): C, 62.96; H, 4.99; N, 4.08%. Found: C, 62.99;
H, 4.01; N, 4.02%.
4.2.3. (RS)-diisopropyl 2H-thiopyrano[2,3-b]quinoline-2,3-dicarboxylate (5c)
Yellow powder; mp 115–117°C; yield: 0.29 g (80%); IR (KBr): ν¯ cm−1 1729, 1643; 1H NMR
(CDCl3): δ (ppm) 1.17 (d, J = 6.5 Hz, 3 H), 1.19 (d, J = 6.5 Hz, 3 H), 1.29 (d, J = 6.5 Hz,
3 H), 1.32 (d, J = 6.5 Hz, 3 H), 4.81 (s, 1 H), 4.92 (sept, J = 6.5 Hz, 1 H), 5.14 (sept,
J = 6.5 Hz, 1 H), 7.41 (t, J = 7.0 Hz, 1 H), 7.63 (t, J = 7.0 Hz, 1 H), 7.69 (d, J = 7.5 Hz,
1 H), 7.80 (s, 1 H), 7.87 (d, J = 8.5 Hz, 1 H), 7.91 (s, 1 H); 13C NMR (CDCl3): δ (ppm)

6
A. ALIZADEH ET AL.
21.4 (OCHMe2), 21.5 (OCHMe2), 21.76 (OCHMe2), 21.84 (OCHMe2), 41.7 (CH–S), 69.3
(OCHMe2), 69.8 (OCHMe2), 124.0 (C5a), 124.3 (C4a), 126.5 (CH7), 126.5 (CH6), 128.0
(CH8), 128.2 (CH9), 131.2 (CH5), 137.0 (CH4), 137.1 (C3), 148.4 (C9a), 155.5 (C10a), 164.3
i
i
(CO2 Pr), 169.2 (CO2 Pr); EI-MS: m/z (%) 372 (M+ + 1, 28), 371 (M+, 38), 370 (5), 329
(2), 312 (2), 300 (2), 287 (5), 286 (24), 285 (54), 284 (95), 283 (26), 270 (10), 269 (19), 258
(3), 256 (5), 244 (24), 243 (52), 242 (100), 241 (24), 214 (7), 199 (5), 198 (22), 197 (38), 196
(53), 186 (9), 185 (4), 170 (3), 154 (7), 153 (12), 152 (9), 140 (4), 128 (6), 127 (5), 126 (4),
115 (3), 101 (2), 85 (2), 69 (5). Anal. Calcd for C20H21NO4S (371.45): C, 64.67; H, 5.70; N,
3.77%. Found: C, 64.61; H, 5.79; N, 3.71%.
4.2.4. (RS)-di-tert-butyl 2H-thiopyrano[2,3-b]quinoline-2,3-dicarboxylate (5d)
Cream powder; mp 157–159°C; yield 0.35 g (87%); IR (KBr) ν¯ cm−1: 1718, 1644, 1613,
1556; 1H NMR (CDCl3) δ (ppm) 1.37 (s, 9 H), 1.54 (s, 9 H), 4.73 (s, 1 H), 7.40 (t, J = 7.3 Hz,
1 H), 7.62 (dt, J = 8.1 Hz, J = 1.0 Hz, 1 H), 7.68 (d, J = 8.2 Hz, 1 H), 7.72 (s, 1 H), 7.87 (d,
J = 8.0 Hz, 1 H), 7.87 (s, 1 H); 13C NMR (CDCl3) δ (ppm) 27.9 (OCMe3), 28.2 (OCMe3),
42.9 (CHS), 82.2 (OCMe3), 82.5 (OCMe3), 124.3 (C5a), 125.8 (C4a), 126.5 (CH7), 126.7
(CH6), 128.2 (CH8), 128.3 (CH9), 131.2 (CH5), 136.4 (CH4), 136.9 (C3), 148.5 (C9a), 155.9
(C10a), 164.0 (CO2 Bu), 168.9 (CO2 Bu); EI-MS: m/z (%) 300 (4), 299 (12), 298 (49), 271
(2), 270 (9), 245 (2), 244 (13), 243 (35), 242 (100), 198 (6), 197 (6), 196 (11), 186 (2), 58 (5),
57 (88), 41 (7). Anal. Calcd for C22H25NO4S (399.50): C, 66.14; H, 6.31; N, 3.51%. Found:
C, 66.10; H, 6.35; N, 3.56%.
t
t
4.2.5. (RS)-dimethyl 9-methyl-2H-thiopyrano[2,3-b]quinoline-2,3-dicarboxylate (5e)
Yellow powder; mp 164–166°C; yield 0.29 g (87%); IR (KBr) ν¯ cm−1: 1741, 1705, 1646,
1610, 1573; 1H NMR (CDCl3) δ (ppm) 2.70 (s, 3 H), 3.71 (CO2Me), 3.87 (CO2Me), 4.91 (s,
1 H), 7.33 (t, J = 7.6 Hz, 1 H), 7.51 (d, J = 7.0 Hz, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.85 (s,
1 H), 7.89 (s, 1 H); 13C NMR (CDCl3) δ (ppm) 17.9 (Me), 41.3 (CHS), 52.8 (CO2Me), 53.3
(CO2Me), 123.1 (C5a), 123.6 (C4a), 126.4 (CH8), 126.5 (CH7), 126.6 (CH6), 131.7 (CH5),
136.5 (C9), 137.96 (CH4), 138.01 (C3), 147.8 (C9a), 154.0 (C10a), 165.6 (CO2Me), 170.4
(CO2Me); EI-MS: m/z (%) 330 (3, M+ + 1), 329 (17, M+), 297 (2), 273 (2), 272 (15), 271
(39), 270 (100), 227 (3), 213 (2), 212 (13), 211 (10), 210 (21), 199 (2), 179 (3), 178 (2), 166
(3). Anal. Calcd for C17H15NO4S (329.37): C, 61.99; H, 4.59; N, 4.25%. Found: C, 61.90;
H, 4.55; N, 4.29%.
4.2.6. (RS)-diethyl 9-methyl-2H-thiopyrano[2,3-b]quinoline-2,3-dicarboxylate (5f)
Yellow powder; mp 165–167°C; yield 0.29 g (83%); IR (KBr): ν¯ cm−1 1730, 1692, 1578;
1H NMR (CDCl3): δ (ppm) 1.24 (t, J = 6.5 Hz, 3 H), 1.37 (t, J = 7.5 Hz, 3 H), 2.72 (s,
3 H), 4.15 (m, 2 H), 4.32 (m, 2 H), 4.89 (s, 1 H), 7.35 (t, J = 7.5 Hz, 1 H); 7.52 (d,
J = 7.0 Hz, 1 H), 7.58 (d, J = 8.5 Hz, 1 H), 7.87 (s, 1 H), 7.93 (s, 1 H); 13C NMR (CDCl3):
δ (ppm) 13.9 (OCH2CH3), 14.2 (OCH2CH3), 17.7 (Me), 41.5 (CHS), 61.6 (OCH2CH3),
62.1 (OCH2CH3), 123.5 (C5a), 123.6 (C4a), 126.2 (CH8), 126.3 (CH7), 126.5 (CH6), 131.5
(CH5), 136.4 (C9), 137.5 (CH4), 137.6 (C3), 147.7 (C9a), 154.1 (C10a), 165.0 (CO2Et), 169.9
(CO2Et); EI-MS: m/z (%) 357 (8, M+), 356 (2), 312 (6), 286 (7), 285 (20), 284 (100), 270
(2), 258 (4), 257 (10), 256 (57), 255 (2), 228 (3), 212 (6), 211 (8) 210 (17), 209 (4), 200 (2),
179 (2), 178 (4), 167 (3), 166 (4), 140 (3), 139 (3), 69 (6), 57 (17), 55 (3). Anal. Calcd for
C19H19NO4S (357.42): C, 63.85; H, 5.36; N, 3.92%. Found: C, 63.80; H, 5.32; N, 3.99%.

JOURNAL OF SULFUR CHEMISTRY
7
4.2.7. (RS)-di-tert-butyl 9-methyl-2H-thiopyrano[2,3-b]quinoline-2,3-dicarboxylate
(5g)
Yellow powder; mp 158–160°C; yield 0.34 g (83%); IR (KBr) ν¯ cm−1: 1726, 1693, 1575,
1472; 1H NMR (CDCl3) δ (ppm) 1.41 (s, 9 H), 1.57 (s, 9 H), 2.73 (s, 3 H), 4.77 (s, 1 H), 7.34
(t, J = 7.0 Hz, 1 H), 7.51 (d, J = 7.0 Hz, 1 H), 7.56 (d, J = 8.0 Hz, 1 H), 7.75 (s, 1 H), 7.88
(s, 1 H); 13C NMR (CDCl3) δ (ppm) 17.9 (Me), 27.8 (OCMe3), 28.1 (OCMe3), 43.0 (CHS),
82.1 (OCMe3), 82.3 (OCMe3), 123.8 (C5a), 125.4 (C4a), 126.16 (CH8), 126.18 (CH7), 126.5
(CH6), 131.4 (CH5), 136.1 (C9), 136.4 (CH4), 137.3 (C3), 147.3 (C9a), 154.6 (C10a), 164.0
t
t
(CO2 Bu), 169.0 (CO2 Bu); EI-MS: m/z (%) 413 (6, M+), 314 (27), 313 (68), 312 (100),
284 (34), 259 (11), 258 (65), 257 (84), 256 (79), 255 (72), 212 (24), 211 (54), 210 (78), 209
(16), 178 (14), 166 (15), 139 (9), 58 (15), 57 (98). Anal. Calcd for C23H27NO4S (413.53):
C, 66.80; H, 6.58; N, 3.39%. Found: C, 66.85; H, 6.52; N, 3.32%.
Disclosure statement
No potential conflict of interest was reported by the authors.
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