Diversity oriented catalyst-free and solvent-free one-pot MCR at room temperature: Rapid and regioselective convergent approach to highly functionalized dihydro-4H-thiopyrans

Article abstract of DOI:10.1016/j.tet.2013.07.001

Highly convergent and regioselective approach to hitherto unreported and synthetically demanding 6-cycloamino-2-(methyl/benzyl)sulfanyl-3-(aroyl/ hetaroyl/alkanoyl)-4-aryl-5,6-dihydro-4H-thiopyrans has been developed via one-pot three-component domino coupling of β-oxodithioesters, α,β-unsaturated aldehydes, and cyclic aliphatic secondary amines at room temperature under catalyst-free and solvent-free conditions. The attractive features of this strategy include mild conditions, short reaction time, high atom-economy, excellent yields, and efficacy of forming three new bonds (C-C, C-N and C-S) and one ring in a single stroke.

Full text of DOI:10.1016/j.tet.2013.07.001

Accepted Manuscript
Diversity oriented catalyst-free and solvent-free one-pot MCR at room temperature:
rapid and regioselective convergent approach to highly functionalized dihydro-4H-
thiopyrans
Suvajit Koley, Sushobhan Chowdhury, Tanmoy Chanda, B. Janaki Ramulu, Maya
Shankar Singh
PII:
S0040-4020(13)01067-3
10.1016/j.tet.2013.07.001
TET 24582
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 January 2013
Revised Date: 23 May 2013
Accepted Date: 1 July 2013
Please cite this article as: Koley S, Chowdhury S, Chanda T, Ramulu BJ, Singh MS, Diversity
oriented catalyst-free and solvent-free one-pot MCR at room temperature: rapid and regioselective
convergent approach to highly functionalized dihydro-4H-thiopyrans, Tetrahedron (2013), doi: 10.1016/
j.tet.2013.07.001.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Diversity oriented catalyst-free and solvent-
free one-pot MCR at room temperature:
rapid and regioselective convergent
Leave this area blank for abstract info.
approach to highly functionalized dihydro-
4
H-thiopyrans
Suvajit Koley, Sushobhan Chowdhury, Tanmoy Chanda, B. Janaki Ramulu, Maya Shankar Singh*
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi-221005, India

ACCEPTED MANUSCRIPT
1
Tetrahedron
journal homepage: www.elsevier.com
Diversity oriented catalyst-free and solvent-free one-pot MCR at room temperature:
rapid and regioselective convergent approach to highly functionalized dihydro-4H-
thiopyrans
Suvajit Koley, Sushobhan Chowdhury, Tanmoy Chanda, B. Janaki Ramulu, Maya Shankar Singh∗
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi 221005, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Highly convergent and regioselective approach to hitherto unreported and synthetically
demanding 6-cycloamino-2-(methyl/benzyl)sulfanyl-3-(aroyl/hetaroyl/alkanoyl)-4-aryl-5,6-
Received in revised form
Accepted
Available online
dihydro-4H-thiopyrans has been developed via one-pot three-component domino coupling of β-
oxodithioesters, α,β-unsaturated aldehydes, and cyclic aliphatic secondary amines at room
temperature under catalyst-free and solvent-free conditions. The attractive features of this
strategy include mild conditions, short reaction time, high atom-economy, excellent yields, and
efficacy of forming three new bonds (C─C, C─N and C─S) and one ring in a single stroke.
Keywords:
β-Oxodithioesters
One-pot three-component reaction
2
009 Elsevier Ltd. All rights reserved.
5
,6-Dihydro-4H-thiopyrans
Regioselective
Heteroannulation
Solvent-free condition
7
8
9
10
1. Introduction
B, serricornin, thromoboxanes, and cyclopentanoids
with
promising biological activities. Given their high importance,
many classical methods such as Diels−Alder reaction,
Design and development of practical cascades that provide
11a,b
maximum structural miscellany and intricacy with a minimum
number of straightforward synthetic steps for the rapid generation
of function-oriented molecules is a key goal in modern organic
synthesis. A pressing challenge for synthetic chemists is to
advance new protocols that are not only efficient, selective, and
high yielding but also rapid and eco-compatible. One approach to
address this challenge involves the development of eco-friendly
Michael addition, Pummerer-type thioglycosylation reaction, and
rearrangement of sulfonium ylides have been developed.
12
1
3
Masson and co-workers have revealed the synthesis of
phosphono-substituted dihydrothiopyrans using α-phosphono-
α,β-unsaturated dithioesters. However, one-pot multicomponent
approach to construct this privileged scaffold is still surprisingly
1
4
1
,2
multicomponent procedures. Multicomponent reactions
MCRs) have experienced exponential growth over the past two
rare.
(
Albeit the reported approaches are useful tools for the
synthesis of thiopyrans, most of them suffer from significant
limitations such as harsh reaction conditions, long reaction time,
poor yields, production of wastes, and difficult workup
procedure. Therefore, more general, efficient, rapid, and viable
routes are in high demand, and would be of great relevance to
both synthetic and medicinal chemists. Prompted by the awe-
inspiring chemistry of β-oxodithioesters, on the basis of
retrosynthetic analysis, we envisioned that the scaffold of
dihydro-4H-thiopyran could be constructed via three-component
decades and have become important tools for the rapid generation
of molecular complexity and diversity with predefined
3
,4
functionality in chemical biology and drug discovery. In the
pursuit of a more efficient and greener process, performing the
5
reactions without any solvent has appeared promising.
Thiopyran is a well-known privileged structural motif, as
many of its derivatives possess useful pharmacological
6
activities. They have been frequently utilized in the construction
of analogues of natural products such as tetrahydrodicranenone
—
——
∗
Corresponding author. Fax: +91 542 2368127; e-mail address: mssinghbhu@yahoo.co.in

ACCEPTED MANUSCRIPT
2
Tetrahedron
domino coupling of β-oxodithioesters 1,
α
,
β
-unsaturated
3
4
EtOH
EtOH
DMSO
25
80
25
25
100
25
30 min
30 min
60 min
24 h
24 h
5 min
80
32
65
aldehydes 2, and amines 3 (Scheme 1).
5
6
7
8
c
H O
nr
nr
2
c
H
2
O
none
none
None
92
45
76
9
1
40
15
15 min
60 min
0
Scheme 1. A proposed three-component approach to 5,6-dihydro-
a
Reaction conditions: 1.0 mmol of each 1a, 2a and 3a; and 2 ml of each
4
H-thiopyrans 4.
b
c
solvent was used. Isolated yield. nr = no reaction.
2. Results and discussion
β-Oxodithioesters have received much attention as versatile
Motivated by the above results, we investigated the model
reaction under solvent-free conditions. To our pleasure, a
breakthrough result was achieved that is the desired thiopyran 4a
was obtained in 92% yield at 25 °C in 5 min (Table 1, entry 8).
Next the effect of reaction temperature was also examined, and
the results showed that increasing or decreasing the temperature
did not bring any improvement (Table 1, entries 9 and 10). It was
observed that at elevated temperature (> 40 °C), the lower yield
of the desired product is due to a competitive formation of
15
building blocks in organic synthesis. Our recent efforts in the
development of n6ovel synthetic strategy to construct
a
1
heterocyclic scaffolds utilizing β-oxodithioesters as a key
substrate prompted us to investigate the present coupling reaction
with the aim to devise more general synthetic route for bioactive
heterocycles. Thus, as a part of our recent research program to
1
7
develop solvent-free new MCRs, herein, we report an easy
access to 5,6-dihydro-4H-thiopyrans via one-pot three-
component domino coupling of β-oxodithioesters, α,β-
unsaturated aldehydes, and cyclic aliphatic secondary amines at
room temperature under solvent-free conditions (Scheme 2).
1
6a
thioamide.
Hence, the optimal conditions were equimolar
amounts of 1a, 2a, and 3a at 25 °C under solvent-free conditions
(Table 1, entry 8).With optimal conditions established, we then
investigated the scope and limitations of the reaction using
various β-oxodithioesters 1a-m, α,β-unsaturated aldehydes 2a-b,
and secondary cyclic amines 3a-e. The results are presented in
Table 2.
Table 2
Synthesis of dihydrothiopyrans 4
Entry
Product 4
time in min, yield )
Entry Product 4
a
a
(
(time in min, yield )
1
10
11
Scheme 2. Synthesis of 5,6-dihydro-4H-thiopyrans 4.
2
3
4
β-Oxodithioesters are not commercially sourced, and were
1
5
synthesized by literature methods.
Initially, the three-
component model reaction of methyl 3-oxo-3-phenyl-
propanedithioate (1a), cinnamaldehyde (2a), and piperidine (3a)
was investigated without any catalyst under varying conditions to
optimize the reaction conditions, and the results are listed in
Table 1. Interestingly, DCM and EtOH provided the desired
product at 25 °C (Table 1, entries 1 and 3). Increasing the
temperature decreased the yields drastically (Table 1, entries 2
and 4). The reaction became sluggish in DMSO and yield of the
product decreased considerably (Table 1, entry 5). No reaction
12
13
occurred in H O at 25 °C as well as at 100 °C even after 24 h
2
(
Table 1, entries 6 and 7). This might be due to insolubility of β-
oxodithioesters in water.
5
14
Table 1
a
Optimization of reaction conditions
6
7
15
16
o
b
Entry
Solvent
Temp ( C)
Time
Yield (%)
1
2
DCM
DCM
25
40
30 min
30 min
82
40

ACCEPTED MANUSCRIPT
3
iminium ion intermediate A. Subsequently, Michael-type attack
of enolic form of β-oxodithioester 1 to iminium ion A generated
open-chain intermediate B , which could probably cyclize via its
two possible rotamers B and B through pathways I and II to
furnish dihydrothiopyran 4 and dihydropyran 5, respectively. The
intermediate B undergoes regioselective cyclization by attack
through sulfur via route I to give the desired dihydrothiopyran 4
1
8
17
18
1
2
1
1
7b
9
exclusively in accordance with our previous results.
The
alternative O-cyclization of B via route II could lead to pyran 5,
2
a
which was not observed even in trace during our investigations.
Isolated pure yields.
In general, all reactions were completed within 5 minutes
providing a range of valuable 5,6-dihydro-4H-thiopyrans 4a-r in
3-96% yields. Both electron-rich and electron-poor aryl groups
8
1
at the R position were well tolerated and showed very good
chemical yields of thiopyrans 4. The reaction with extended
aromatic group 1c also proceeded smoothly providing the desired
thiopyran 4c in 85% yield (Table 2, entry 3). In addition, good
1
results were also obtained by using R as hetaryl substituents such
as 2-thienyl, 3-pyridyl, 2-furyl, and 3-(N-methylpyrrole) (Table
2
, entries 4, 6, 9 and 11). Furthermore, aliphatic dithioester 1k
1
containing R as isopropyl group was also successful affording
the product 4l in 93% yield (Table 2, entry 12). Importantly,
ferrocenoyl dithioester 1m was also a viable substrate for this
approach affording the desired thiopyran 4p in 96% yield (Table
2
4
, entry 16). A limited variation has also been made at the 2- and
-position of thiopyran ring providing the desired thiopyran
derivatives in excellent yields (Table 2, entries 8, 10, 15, and 18).
The results showed the good scope and generality of the various
starting substrates.
Scheme 3. Plausible mechanism for the formation of 4.
Furthermore, to expand the scope of this reaction and to gain a
greater insight into the reaction, various primary amines, tertiary
amines, and acyclic secondary amines were also investigated but
unfortunately, primary and tertiary amines could not trigger the
reaction in the desired direction even after 24 h, while acyclic
secondary amines showed a complex TLC pattern of several very
close spots, which could not be isolated. This result limits the
scope of the reaction to some extent. The structural
3. Conclusion
In summary, a rapid and highly efficient regioselective
approach to densely functionalized 5,6-dihydro-4H-thiopyrans
has been developed for the first time via one-pot three-
component domino coupling of β-oxodithioesters,
α,β-
1
unsaturated aldehydes, and cyclic aliphatic secondary amines at
room temperature under catalyst-free and solvent-free conditions
in excellent yields. Importantly, for the first time cyclic aliphatic
secondary amine has been incorporated in the core nucleus of
thiopyran at position 6. The simplicity of execution, mild
conditions, short reaction time (5 min) flexible substitution
patterns, and easy purification make the protocol eye-catching for
academic research and realistic applications.
characterization of 4a-r was achieved by spectroscopic data ( H
1
3
and C NMR, IR, and HRMS) and unequivocally established by
18
the X-ray single crystal diffraction analysis of one of the
representative compound 3-benzoyl-2-methylsulfanyl-4-phenyl-
6-piperidino-5,6-dihydro-4H-thiopyran 4a (Figure 1).
4
. Experimental section
4.1. General
The starting materials were commercially available and used
as received without any further purification. All reagents were
weighed and handled in air at room temperature. β-
Oxodithioesters
1
were prepared following the known
1
5
procedures. Thin-layer chromatography (TLC) was performed
using silica gel 60 F254 precoated plates. Infrared (IR) spectra
-
1
are measured in KBr, and wavelengths (ν) are reported in cm .
1
13
H and C NMR spectra were recorded on NMR spectrometer
operating at 500/300 and 125/75 MHz, respectively. Chemical
shifts (δ) are given in parts per million (ppm) using the residue
solvent peaks as reference relative to tetramethylsilane (TMS).
Coupling constant (J) values are given in hertz (Hz). Mass
spectra were recorded using electrospray ionization (ESI) mass
spectrometry. The melting points are uncorrected.
Fig. 1. ORTEP diagram of 4a.
On the basis of results obtained, a plausible mechanism is
outlined in Scheme 3. We conceived that initially a reaction
between aldehyde 2 and secondary amine 3 would occur to give

ACCEPTED MANUSCRIPT
4
Tetrahedron
+
4
.2. General procedure for the synthesis of dihydro-4H-
70.54, 49.74, 44.38, 35.10, 25.90, 24.27, 18.14; HRMS [M+Na]
calcd for C H NOS Na 438.0990, found 438.0996.
thiopyran (4a-r)
2
2
25
3
To a mixture of β-ketodithioesters 1 (1.0 mmol) and
cinnamaldehydes 2 (1.0 mmol), secondary cyclic amines 3 (1.0
mmol) was added and the reaction mixture was stirred for the
stipulated period of time at room temperature. After completion
of the reaction (monitored by TLC), water (20 mL) was added to
the reaction mixture followed by extraction with ethyl acetate (2
4.2.5. 3-Benzoyl-2-methylsulfanyl-6-morpholino-4-phenyl-5,6-
dihydro-4H-thiopyran (4e).
−1
Pale yellow solid, mp 117-118 °C; FT IR (KBr, cm ): 2956,
1
2
7
4
3
(
1
843 1648, 1594 1247, 1171; H NMR (300 MHz, CDCl
3
): δ
.70 (d, J = 7.51 Hz, 2H), 7.49-7.44 (m, 2H), 7.39-7.23 (m, 6H),
.48 (dd, J = 2.4 Hz, J = 11.1 Hz, 1H), 4.31 (t, J = 3.4 Hz, 1H),
.67 (br, 4H), 2.84-2.67 (m, 4H), 2.45-2.25 (m, 5H); C NMR
): δ 195.47,141.16, 138.16, 133.67, 132.16,
1
2
×
10 mL). The combined organic layer was dried over anhydrous
13
Na SO and then evaporated under vacuo. The crude residue thus
2
4
75 MHz, CDCl
3
obtained was purified by column chromatography over silica gel
using ethyl acetate/hexane mixture as eluent to afford pure
dihydrothiopyran.
28.73, 128.58, 128.27, 128.24, 128.05, 126.97, 69.20, 66.73,
+
4
8.73, 44.00, 34.55, 17.78; HRMS [M+H] calcd for
23 2 2
C H26NO S 412.1399, found 412.1403.
4
.2.6. 2-Methylsulfanyl-6-morpholino-4-phenyl-3-(3-pyridoyl)-
4
.2.1. 3-Benzoyl-2-methylsulfanyl-4-phenyl-6-piperidino-5,6-
5,6-dihydro-4H-thiopyran (4f).
dihydro-4H-thiopyran (4a).
−
1
Pale yellow solid, mp 122-123 °C; FT IR (KBr, cm ): 3028,
-
1
Pale yellow solid, mp 111-113 °C; FT IR (KBr, cm ): 3053,
1
2937, 1639, 1574, 1253, 1183; H NMR (300 MHz, CDCl
8.84 (s, 1H), 8.63 (d, J = 4.5 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H),
7.25-7.18 (m, 5H), 7.09-7.01 (m, 1H), 4.51 (dd, J = 2.7 Hz, J
11.7 Hz, 1H), 4.39 (t, J = 3.4 Hz, 1H), 3.68 (br, 4H), 2.80-2.70
3
): δ
1
2
7
929, 1654, 1575, 1254, 1179; H NMR (300 MHz, CDCl
.69 (d, J = 6.9 Hz, 2H), 7.45-7.25 (m, 8H), 4.53 (dd, J = 1.5
= 12.0 Hz, 1H), 4.32 (t, J = 3.6 Hz, 1H), 2.78 (t, J = 5.2
Hz, 2H), 2.61 (t, J = 5.1 Hz, 2H), 2.36-2.23 (m, 5H), 1.55-1.45
3
): δ
1
1
2
=
Hz, J
2
13
(
3
m, 4H), 2.43-2.27 (m, 5H); C NMR (75 MHz, CDCl ): δ
1
3
(
1
7
m, 6H); C NMR (75 MHz, CDCl
3
): δ 195.58, 141.16, 138.24,
32.08, 130.05, 129.07, 128.74, 128.52, 128.32, 128.22, 126.90+,
0.38, 49.77, 44.14, 34.72, 25.68, 24.13, 17.81; HRMS [M+H]
410.1607, found 410.1616.
1
1
3
89.32, 167.88, 153.87, 151.70, 147.02, 136.12, 135.66, 133.99,
28.73, 128.06, 127.10, 123.30, 69.92, 66.35, 48.67, 43.82,
4.49, 17.28; HRMS [M+H] calcd for C22
+
H
25
N
2
O
2
S
2
413.1352,
calcd for C24H28NOS
2
found 413.1360.
4
.2.2. 3-(2-Bromobenzoyl)-2-methylsulfanyl-4-phenyl-6-
4
.2.7. 3-(2-Methoxybenzoyl)-2-methylsulfanyl-6-morpholino-4-
piperidino-5,6-dihydro-4H-thiopyran (4b).
phenyl-5,6-dihydro-4H-thiopyran(4g).
−
1
Pale yellow solid, mp 142-144 °C; FT IR (KBr, cm ): 3037,
−1
Pale yellow solid, mp 128-129 °C; FT IR (KBr, cm ): 3045,
1
2
7
1
946, 1610, 1491, 1251, 1176; H NMR (500 MHz, CDCl
.47 (d, J = 8.0 Hz, 1H), 7.21-7.16 (m, 3H), 7.10 (t, J = 8.25 Hz,
H), 6.98 (t, J = 7.5 Hz, 1H), 6.91-6.90 (m, 2H), 6.58 (d, J = 7.0
Hz, 1H), 4.38 (dd, J = 8.0 Hz, J = 12.0 Hz, 1H), 4.05 (br, 1H),
.83-2.79 (m, 2H), 2.66-2.65 (m, 2H), 2.54 (s, 3H), 2.46-2.40
m, 2H), 1.58-1.56 (m, 4H), 1.47-1.44 (m, 2H); C NMR (125
MHz, CDCl ): δ 191.62, 142.30, 141.89, 132.05, 129.68, 128.39,
28.01, 127.86, 126.75, 126.67, 124.23, 118.79, 72.16, 49.54,
3.64, 34.32, 25.79, 24.21, 16.35; HRMS [M+H] calcd for
27BrNOS 488.0712, found 488.0717.
3
): δ
1
2
7
1
2
1
1
4
4
952, 1624, 1587, 1286, 1176; H NMR (300 MHz, CDCl
.29-7.20 (m, 7H), 7.08-6.99 (m, 2H), 4.47 (dd, J = 2.7 Hz, J =
1.7 Hz, 1H), 4.29 (t, J = 3.6 Hz, 1H), 3.74-3.67 (m, 7H), 2.80-
.69 (m, 4H), 2.43-2.24 (m, 5H); C NMR (75 MHz, CDCl ): δ
95.22, 159.53, 141.15, 139.60, 133.44, 129.20, 128.61, 128.34,
28.30, 127.00, 121.42, 118.78, 112.64, 69.31, 66.73, 55.25,
3
): δ
1
2
13
1
2
3
2
(
13
+
3
8.72, 43.99, 34.49, 17.79; HRMS [M] calcd for C24
41.1432, found 441.1431.
3 2
H27NO S
1
4
C
+
24
H
2
4
.2.8. 3-Benzoyl-2-benzylsulfanyl-4-(4-methoxyphenyl)-6-
morpholino-5,6-dihydro-4H-thiopyran (4h).
4.2.3. 2-Methylsulfanyl-3-(1-naphthoyl)-4-phenyl-6-piperidino-
5
,6-dihydro-4H-thiopyran (4c).
−1
Pale yellow solid, mp 69-70 °C; FT IR (KBr, cm ): 3039,
1
−
1
2
7
2
4
2
1
1
6
946, 1624, 1566, 1282, 1179; H NMR (300 MHz, CDCl
.60 (d, J = 7.2 Hz, 2H), 7.47-7.20 (m, 8H), 7.05 (d, J = 8.4 Hz,
H), 6.89-6.76 (m, 2H), 4.43 (dd, J = 3.0 Hz, J = 12.0 Hz, 1H),
.18-4.09 (m, 2H), 3.99-3.90 (m, 1H), 3.73-3.65 (m, 7H), 2.77-
.68 (m, 4H), 2.34-2.13 (m, 2H); C NMR (75 MHz, CDCl ): δ
3
95.47, 158.43, 137.72, 137.07, 136.65, 135.44, 132.64, 132.26,
29.23, 128.84, 128.27, 128.24, 127.17, 113.87, 113.65, 69.01,
3
): δ
Pale yellow solid, mp 161-162 °C; FT IR (KBr, cm ): 3016,
1
2
7
7
939, 1645, 1562, 1256, 1183; H NMR (500 MHz, CDCl
.90 (d, J = 8.0 Hz, 1H), 7.79 (dd, J = 8.0 Hz, J = 11.0 Hz, 2H),
.47-7.41 (m, 2H), 7.23-7.14 (m, 4H), 7.03-6.96 (m, 3H), 4.43
= 3.0 Hz, J = 12.0 Hz, 1H), 4.15 (t, J = 3.5 Hz, 1H), 2.83-
.82 (m, 2H), 2.70-2.68 (m, 2H), 2.47 (s, 3H), 2.43-2.25 (m, 2H),
3
): δ
1
2
1
2
1
3
(
dd, J
1
2
2
1
1
1
3
4
1
3
3
.60 (br, 4H), 1.48-1.42 (m, 2H); C NMR (125 MHz, CDCl ): δ
95.05, 133.38, 130.16, 129.80, 128.51, 128.21, 128.03, 126.87,
26.79, 126.08, 125.22, 125.07, 124.50, 71.11, 49.81, 43.40,
3.81, 25.38, 23.93, 16.82; HRMS [M+H] calcd for C28
60.1763, found 460.1767.
+
6.69, 55.10, 48.72, 43.23, 38.99, 34.49. HRMS [M+H] calcd
3 2
for C30H32NO S 518.1818, found 518.1822.
+
H30NOS
2
4
.2.9. 3-(2-Furoyl)-2-methylsulfanyl-4-phenyl-6-(4-
phenylpiperazino)-5,6-dihydro-4H-thiopyran (4i).
4.2.4. 2-Methylsulfanyl-4-phenyl-6-piperidino-3-(2-thienoyl)-5,6-
−
1
dihydro-4H-thiopyran (4d).
Pale yellow solid, mp 101-103 °C; FT IR (KBr, cm ): 3042,
1
2
3
944, 1654, 1589, 1248, 1181; H NMR (300 MHz, CDCl ): δ
7.48-7.36 (m, 2H), 7.20-7.05 (m, 5H), 6.94-6.75 (m,5H), 6.47-
6.28 (m, 1H), 4.45-4.43 (m, 2H), 3.11-3.05 (m, 4H), 2.87-2.74
(m, 4H), 2.39-2.24 (m, 5H); C NMR (75 MHz, CDCl ): δ
182.96, 153.22, 151.02, 145.87, 142.18, 141.29, 132.76, 129.07,
−
1
Pale yellow solid, mp 111-112 °C; FT IR (KBr, cm ): 3028,
1
2
7
932, 1661, 1567, 1251, 1172; H NMR (300 MHz, CDCl
.54 (br, 2H), 7.25-7.13 (m, 5H), 7.02 (br, 1H), 4.52 (dd, J = 1.5
= 11.1 Hz, 1H), 4.36 (t, J = 3.1 Hz, 1H), 2.75 (t, J = 2.5
Hz, 2H), 2.62 (t, J = 7.9 Hz, 2H), 2.47-2.23 (m, 5H), 1.54-1.45
3
): δ
13
1
3
Hz, J
2
128.51, 128.28, 126.88, 120.01, 117.79, 116.28, 112.24, 69.01,
49.20, 48.38, 43.47, 35.22, 18.05; HRMS [M+H] calcd for
1
3
+
(
m, 6H); C NMR (75 MHz, CDCl
3
): δ 188.03, 144.88, 141.13,
139.68, 137.03, 134.37, 133.40, 132.74, 128.44, 127.72, 126.96,
C H N O S 477.1665, found 477.1671.
2
7
29
2
2 2

ACCEPTED MANUSCRIPT
5
128.80, 128.73, 128.51, 128.18, 127.22, 127.11, 125.23,
4
.2.10.4-(4-Methoxyphenyl)-2-methylsulfanyl-6-(4-
125.20, 69.71, 61.52, 48.33, 48.04, 43.93, 43.51, 34.74, 17.46,
+
phenylpiperazino)-3-(3-pyridoyl)-5,6-dihydro-4H-thiopyran (4j).
14.66; HRMS [M+H] calcd for C H F N O S 551.1644, found
2
7
30
3
2
3 2
5
51.1652.
−
1
Pale yellow solid, mp 93-95 °C; FT IR (KBr, cm ): 3051,
1
2
8
7
926, 1641, 1579, 1278, 1152; H NMR (300 MHz, CDCl ): δ
.84 (s, 1H), 8.64 (d, J = 3.3 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H),
.25 (br, 2H), 7.13-7.10 (m, 2H), 6.94-6.81 (m, 6H), 4.59 (dd, J1
= 11.4 Hz, 1H), 4.34 (t, J = 3.9 Hz, 1H), 3.76 (s,
H), 3.16 (br, 4H), 3.00-2.85 (m, 4H), 2.71-2.63 (m, 4H), 2.45-
): δ 193.44, 158.58,
51.86, 151.03, 149.64, 145.99, 135.58, 134.57, 133.14, 131.73,
29.15, 129.09, 123.27, 120.07, 116.31, 114.12, 69.82, 55.16,
3
4
.2.15.3-Benzoyl-2-benzylsulfanyl-6-(1-carboethoxyl)piperazino-
4-phenyl-5,6-dihydro-4H-thiopyran (4o).
−
1
=
2.4 Hz, J
2
Pale yellow solid, mp 67-68 °C; FT IR (KBr, cm ): 3036,
1
3
2
1
1
4
2951, 1662, 1583, 1271, 1161; H NMR (300 MHz, CDCl ): δ
7.59 (d, J = 7.2 Hz, 2H), 7.43-6.97 (m, 13H),4.56 (dd, J = 3.3
Hz, J = 14.1 Hz, 1H), 4.19-3.85 (m, 5H), 3.43 (br, 4H), 2.71-
2.63 (m, 4H), 2.30-2.21 (m, 2H), 1.25 (t, J = 6.4 Hz, 3H);
3
1
3
.31 (m, 5H); C NMR (75 MHz, CDCl
3
1
2
13
C
+
9.22, 48.44, 43.16, 34.96, 17.28; HRMS [M+H] calcd for
NMR (75 MHz, CDCl ): δ 195.31, 155.15, 140.55, 137.67,
3
C
29
H
32
N
3
O
2
S
2
518.1930, found 518.1938.
136.62, 136.51, 135.97, 132.24, 129.16, 128.78, 128.46, 128.22,
1
27.94,127.16, 127.00, 126.91, 68.70, 61.34, 48.43, 48.17, 43.94,
+
4
.2.11. 3-(N-Methyl-2-pyrroloyl)-2-methylsulfanyl-4-phenyl-6-(4-
43.38, 38.92, 34.47, 14.56; HRMS [M+H] calcd for
C H N O S 559.2084, found 559.2087.
phenylpiperazino)-5,6-dihydro-4H-thiopyran (4k).
3
2
35
3
3 2
−
1
Pale yellow solid, mp 154-155 °C; FT IR (KBr, cm ): 3048,
1
4.2.16.6-(1-Carboethoxyl)piperazino-3-ferrocenoyl-2-methyl-
sulfanyl-4-phenyl-5,6-dihydro-4H-thiopyran (4p).
2
7
(
(
916, 1638, 1584, 1228, 1172; H NMR (500 MHz, CDCl
.29-7.26 (m, 6H), 7.21-7.09 (m, 2H), 6.97-6.94 (m, 2H), 6.90
= 2.5 Hz, J = 11.5 Hz, 1H), 4.36
t, J = 4.0 Hz, 1H), 3.62 (s, 3H), 3.24-3.17 (m, 4H), 3.03-3.01 (m,
3
): δ
−
1
t, J = 7.2 Hz, 1H), 4.54 (dd, J
1
2
Pale yellow solid, mp 147-149 °C; FT IR (KBr, cm ): 3041,
1
2
7
4
2
3
922, 1632, 1561, 1245, 1168; H NMR (300 MHz, CDCl ): δ
1
3
2
H), 2.93-2.89 (m, 2H), 2.41 (s, 3H), 2.33-2.31 (m, 2H);
): δ 190.40, 141.27, 136.94, 133.79,
29.20, 128.50, 128.48, 128.23, 128.06, 126.90, 125.74, 123.18,
20.52, 116.56, 110.28, 68.23, 49.48, 48.37, 44.18, 36.62, 34.84,
C
.45-7.25 (m, 5H), 4.87 (br, 1H), 4.59 (br, 1H), 4.49 (br, 3H),
.37 (br, 1H), 3.71 (br, 5H), 3.43 (br, 4H), 2.74-2.64 (m, 4H),
.38-2.22 (m, 5H), 1.25 (t, J = 7.0 Hz, 3H); C NMR (125 MHz,
): δ 199.91, 155.33, 141.48, 137.64, 136.33, 128.95,
28.44, 127.35, 81.10, 71.86, 71.21, 70.60, 70.27, 69.82, 69.02,
NMR (125 MHz, CDCl
3
1
3
1
1
1
4
CDCl
1
6
3
+
8.43; HRMS [M+H] calcd for C28
90.1983.
32 3 2
H N OS 490.1981, found
+
1.46, 48.20, 43.90, 34.73, 18.15, 14.65; HRMS [M] calcd for
C H FeN O S 590.1360, found 590.1360.
3
0
34
2
3 2
4.2.12. 3-Isopropanoyl-2-methylsulfanyl-4-phenyl-6-(4-
phenylpiperazino)-5,6-dihydro-4H-thiopyran (4l).
4
.2.17. 3-Benzoyl-2-methylsulfanyl-4-phenyl-6-pyrrolidino-5,6-
−
1
Pale yellow solid, mp 94-95 °C; FT IR (KBr, cm ): 3017,
dihydro-4H-thiopyran (4q).
1
2
7
3
6
944, 1636, 1572, 1284, 1163; H NMR (300 MHz, CDCl ): δ
3
−1
Pale yellow solid, mp 103-105 °C; FT IR (KBr, cm ): 3015,
.35-7.16 (m, 7H), 6.91-6.86 (m, 3H), 4.38-4.32 (m, 2H), 3.15-
.11 (m, 4H), 2.95-2.80 (m, 5H), 2.47-2.37 (m, 5H), 0.99 (d, J =
.6 Hz, 3H), 0.82 (d, J = 6.6 Hz, 3H); C NMR (75 MHz,
1
2
921, 1641, 1587, 1259, 1185; H NMR (300 MHz, CDCl
7.67 (d, J = 6.6 Hz, 2H), 7.66-7.25 (m, 8H), 4.83 (t, J = 5.8 Hz,
H), 4.27 (br, 1H), 2.87 (t, J = 6.1 Hz, 4H), 2.36 (br, 5H), 1.78
3
): δ
13
1
CDCl ): δ 203.10, 153.38, 151.06, 141.67, 129.10, 128.78,
3
13
(
br, 4H); C NMR (75 MHz, CDCl
3
): δ 195.52, 140.93, 138.29,
127.94, 126.99, 126.69, 120.11, 116.35, 69.17, 49.25, 48.15,
+
133.69, 132.05, 129.00, 128.67, 128.50, 128.19, 127.38, 126.85,
42.61, 35.88, 34.31, 19.86, 18.87, 16.75; HRMS [M+H] calcd
+
67.49, 48.32, 44.18, 36.53, 24.18, 17.74; HRMS [M+H] calcd
33 2 2
for C26H N OS 453.2029, found 453.2028.
for C23H26NOS
2
396.1450, found 396.1454.
4
.2.13. 6-(1-Carboethoxyl)piperazino-3-(4-methoxybenzoyl)-2-
4
.2.18. 4-(4-Methoxyphenyl)-3-(4-methylbenzoyl)-2-methyl-
methylsulfanyl-4-phenyl-5,6-dihydro-4H-thiopyran (4m).
sulfanyl-6-pyrrolidino-5,6-dihydro-4H-thiopyran (4r).
−
1
Pale yellow solid, mp 140-141°C; FT IR (KBr, cm ): 3015,
−
1
1
Pale yellow solid, mp 88-90 °C; FT IR (KBr, cm ): 3047,
2
7
2
1
2
925, 1642, 1572, 1282, 1167; H NMR (500 MHz, CDCl
.77 (d, J = 8.5 Hz, 2H), 7.30-7.09 (m, 5H), 6.88 (d, J = 8.5 Hz,
H), 4.52 (dd, J = 2.0 Hz, J = 12.0 Hz, 1H), 4.28 (t, J = 3.7 Hz,
H), 4.13 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 3.48-3.41 (m, 4H),
.77 (br, 2H), 2.65 (t, J = 4.7 Hz, 2H), 2.35 (s, 3H), 2.29-2.25
3
): δ
1
2
7
2
3
942, 1649, 1585, 1273, 1165; H NMR (300 MHz, CDCl ): δ
.64 (d, J = 6.6 Hz, 2H), 7.25-7.15 (m, 4H), 6.80 (d, J = 6.9 Hz,
H), 4.83 (br, 1H), 4.19 (br, 1H), 3.75 (s, 3H), 2.87 (br, 4H), 2.36
1
2
1
3
(
br, 5H), 1.78 (br, 7H); C NMR (75 MHz, CDCl3): δ 195.55,
1
3
158.35, 142.99, 135.39, 133.13, 129.42, 129.25, 129.16, 129.04,
(
m, 4H), 1.25 (t, J = 7.0 Hz, 3H); C NMR (125 MHz, CDCl
3
): δ
1
28.96, 113.83, 64.44, 55.13, 48.18, 43.66, 37.02, 24.55, 24.20,
+
1
1
4
94.55, 163.28, 155.35, 141.18, 136.27, 131.49, 130.46, 128.60,
28.39, 127.03, 113.65, 113.40, 68.62, 61.47, 55.43, 48.52,
8.34, 44.33, 34.97, 18.04, 14.67; HRMS [M+H] calcd for
2 2
21.60, 17.85; HRMS [M+H] calcd for C25H30NO S 440.1712,
+
found 440.1711.
27 33 2 4 2
C H N O S 513.1876, found 513.1901.
Acknowledgments
4.2.14.6-(1-Carboethoxyl)piperazino-2-methylsulfanyl-4-phenyl-
3
-(4-trifluoromethylbenzoyl)-5,6-dihydro-4H-thiopyran (4n).
We gratefully acknowledge the generous financial supports
from the Council of Scientific and Industrial Research (CSIR)
and the Department of Science and Technology (DST), New
Delhi. SK, SC, TC are thankful to UGC and BJR is thankful to
CSIR, New Delhi for research fellowship.
−
1
Pale yellow solid, mp 130-131 °C; FT IR (KBr, cm ): 3034,
1
2
7
5
1
4
3
943, 1629, 1578, 1251, 1162; H NMR (500 MHz, CDCl ): δ
.67 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.38-7.17 (m,
H), 4.52 (dd, J = 2.5 Hz, J = 11.5 Hz, 1H), 4.33 (t, J = 3.7 Hz,
1
2
H), 4.13 (q, J = 7.1 Hz, 2H), 3.49-3.41 (m, 4H), 2.77-2.65 (m,
H), 2.37 (s, 3H), 2.32-2.27 (m, 2H), 1.25 (t, J = 7.2 Hz, 3H);
1
3
C
NMR (125 MHz, CDCl
3
): δ 193.95, 155.33, 141.21, 131.43,

ACCEPTED MANUSCRIPT
6
Tetrahedron
Asokan, C. V.; Suma, S.; Chandran, A.; Retnamma, S.; Anabha,
Supplementary Material
E. R. Tetrahedron Lett. 2007, 48, 8376. (d) Peruncheralathan, S.;
Khan, T. A.; Ila, H.; Junjappa, H. J. Org. Chem. 2005, 70, 10030.
6. (a) Nandi, G. C.; Samai, S.; Singh, M. S. Eur. J. Org. Chem.
2012, 967. (b) Samai, S.; Nandi, G. C.; Singh, M. S. Tetrahedron
Supplementary data associated with this article can be found in
the online version at http://
1
2
012, 68, 1247. (c) Nandi, G. C.; Samai, S.; Singh, M. S. J. Org.
Chem. 2011, 76, 8009. (d) Nandi, G. C.; Samai, S.; Singh, M. S. J.
Org. Chem. 2010, 75, 7785.
References and notes
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8. The crystallographic coordinates have been deposited with the
Cambridge Crystallographic Data Centre; deposition no. CCDC
1
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Wiley-VCH, Weinheim, Germany, 2005, p 1499. (b) Dömling, A.;
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85756 (4a). These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre, 12 Union Rd.,
Cambridge CB2 1EZ, UK or via
www.ccdc.cam.ac.uk/conts/retrieving.html.
(
e) Banfi, L.; Basso, A.; Giardini, L.; Riva, R.; Rocca V.; Guanti,
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ACCEPTED MANUSCRIPT
Diversity oriented catalyst-free and solvent-freeone-pot
MCR at room temperature: rapid and regioselective
convergent approach to highlyfunctionalized dihydro-
4
H-thiopyrans
Suvajit Koley, Sushobhan Chowdhury, Tanmoy Chanda, B. Janaki Ramulu,
and Maya Shankar Singh*
Department of Chemistry, Faculty of Science, Banaras Hindu University,
Varanasi-221005, India
mssinghbhu@yahoo.co.in
Supporting information
45 pages including the cover pages)
(
1
2
3
. Experimental section
S2
. Characterization data of the compounds
S3-S9
1
13
. Copies of the H and C NMR spectra of all
the new compounds
S10-S45
S1

ACCEPTED MANUSCRIPT
1
. Experimental section
General methods
The starting materials were commercially available and used as received without further
purification. β-Oxodithioesters 1 were prepared following the known procedure. Thin-layer
chromatography (TLC) was performed using silica gel 60 F254 precoated plates. Infrared (IR)
-1
1
13
spectra are measured in KBr, and wavelengths (ν) are reported in cm . H and C NMR spectra
were recorded on NMR spectrometer operating at 500, 300, and 125 or 75 MHz, respectively.
Chemical shifts (δ) are given in parts per million (ppm) using the residue solvent peaks as
reference relative to TMS. J values are given in Hertz (Hz). Mass spectra were recorded using
electrospray ionization (ESI) mass spectrometry. The melting points are uncorrected.
General procedure for the synthesis of the dihydro-4H-thiopyran (4a-r)
To a mixture of β-ketodithioester (1.0 mmol) and cinnamaldehyde (1.0 mmol), secondary cyclic
amine (1.0 mmol) was added and the reaction mixture was stirred for the stipulated period of
time at room temperature (Table-1 of main manuscript). After completion of the reaction
(monitored by TLC), water (20 mL) was added to the reaction mixture followed by extraction
with ethyl acetate (2 × 10 mL). The combined organic layer was dried over anhydrous Na SO
2
4
and then evaporated under vacuo. The crude residue was purified by column chromatography
over silica gel (100-200 mesh) using ethyl acetate/hexane mixture as eluent to afford pure
dihydrothiopyran.
S2

ACCEPTED MANUSCRIPT
2
. Characterization data of the compounds
3
-Benzoyl-2-methylsulfanyl-4-phenyl-6-piperidino-5,6-dihydro-4H-thiopyran(4a):
Pale
-1
yellow solid, mp111-113 °C; FT IR (KBr, cm ): 3053, 2929, 1654,
1
1
575, 1254, 1179; HNMR (300 MHz, CDCl ): δ 7.69 (d, J = 6.9
3
O
Hz, 2H), 7.45-7.25 (m, 8H), 4.53 (dd, J = 1.5 Hz, J = 12.0 Hz,
1
2
1
H), 4.32 (t, J = 3.6 Hz, 1H), 2.78(t, J = 5.2 Hz, 2H), 2.61 (t, J = 5.1
N
S
SMe
1
3
Hz, 2H), 2.36-2.23 (m, 5H), 1.55-1.45 (m, 6H); C NMR (75 MHz,
4
a
CDCl ): δ 195.58, 141.16, 138.24, 132.08, 130.05, 129.07, 128.74,
3
+
1
28.52, 128.32, 128.22, 126.90, 70.38, 49.77, 44.14, 34.72, 25.68, 24.13, 17.81; HRMS [M+H]
calcd. For C H NOS 410.1607, found 410.1616.
2
4
28
2
3
-(2-Bromobenzoyl)-2-methylsulfanyl-4-phenyl-6-piperidino-5,6-dihydro-4H-thiopyran
−
1
(
4b): Pale yellow solid, mp 142-144 °C; FT IR (KBr, cm ):
1
3
037, 2946, 1610, 1491, 1251, 1176; H NMR (500 MHz,
O
Br
CDCl ): δ 7.47 (d, J = 8.0 Hz, 1H), 7.21-7.16 (m, 3H), 7.10 (t, J =
3
8
.25 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.91-6.90 (m, 2H), 6.58 (d,
N
S
SMe
4
b
J = 7.0 Hz, 1H), 4.38 (dd, J = 8.0 Hz, J = 12.0 Hz, 1H), 4.05
1
2
(br, 1H), 2.83-2.79 (m, 2H), 2.66-2.65 (m, 2H), 2.54 (s, 3H),
1
3
2
1
7
4
.46-2.40 (m, 2H), 1.58-1.56 (m, 4H), 1.47-1.44 (m, 2H); C NMR (125 MHz, CDCl ): δ
3
91.62, 142.30, 141.89, 132.05, 129.68, 128.39, 128.01, 127.86, 126.75, 126.67, 124.23, 118.79,
+
2.16, 49.54, 43.64, 34.32, 25.79, 24.21, 16.35; HRMS [M+H] calcd. For C H BrNOS
2
4
27
2
88.0712, found 488.0717.
2
-Methylsulfanyl-3-(1-naphthoyl)-4-phenyl-6-piperidino-5,6-dihydro-4H-thiopyran
(4c):
−
1
Pale yellow solid, mp 161-162 °C; FT IR (KBr, cm ): 3016,
1
O
2939, 1645, 1562, 1256, 1183; H NMR (500 MHz, CDCl ): δ
3
7
.90 (d, J = 8.0 Hz, 1H), 7.79 (dd, J = 8.0 Hz, J = 11.0 Hz, 2H),
1 2
7
.47-7.41 (m, 2H), 7.23-7.14 (m, 4H), 7.03-6.96 (m, 3H), 4.43
N
S
SMe
(
dd, J = 3.0 Hz, J = 12.0 Hz, 1H), 4.15 (t, J = 3.5 Hz, 1H), 2.83-
4c
1 2
2
.82 (m, 2H), 2.70-2.68 (m, 2H), 2.47 (s, 3H), 2.43-2.25 (m, 2H),
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1
3
1
1
4
4
.60 (br, 4H), 1.48-1.42 (m, 2H); C NMR (125 MHz, CDCl ): δ 195.05, 133.38, 130.16,
3
29.80, 128.51, 128.21, 128.03, 126.87, 126.79, 126.08, 125.22, 125.07, 124.50, 71.11, 49.81,
+
3.40, 33.81, 25.38, 23.93, 16.82; HRMS [M+H] calcd. For C H NOS 460.1763, found
2
8
30
2
60.1767.
2
-Methylsulfanyl-4-phenyl-6-piperidino-3-(2-thienoyl)-5,6-dihydro-4H-thiopyran (4d): Pale
−
1
yellow solid, mp 111-112 °C; FT IR (KBr, cm ): 3028, 2932, 1661,
1
1
567, 1251, 1172; H NMR (300 MHz, CDCl ): δ 7.54 (br, 2H),
3
O
7
.25-7.13 (m, 5H), 7.02 (br, 1H), 4.52 (dd, J = 1.5 Hz, J = 11.1
1
2
S
Hz, 1H), 4.36 (t, J = 3.1 Hz, 1H), 2.75 (t, J = 2.5 Hz, 2H), 2.62 (t, J
1
3
N
S
SMe
=
7.9 Hz, 2H), 2.47-2.23 (m, 5H), 1.54-1.45 (m, 6H); C NMR (75
4
d
MHz, CDCl ): δ 1 88.03, 144.88, 141.13, 139.68, 137.03, 134.37,
3
1
33.40, 132.74, 128.44, 127.72, 126.96, 70.54, 49.74, 44.38, 35.10, 25.90, 24.27, 18.14; HRMS
+
[
M+Na] calcd. For C H NOS Na 438.0990, found 438.0996.
2
2
25
3
3
-Benzoyl-2-methylsulfanyl-6-morpholino-4-phenyl-5,6-dihydro-4H-thiopyran (4e): Pale
−
1
yellow solid, mp 117-118 °C; FT IR (KBr, cm ): 2956, 2843 1648,
1
1
594, 1247, 1171; H NMR (300 MHz, CDCl ): δ 7.70 (d, J = 7.51
3
O
Hz, 2H), 7.49-7.44 (m, 2H), 7.39-7.23 (m, 6H), 4.48 (dd, J = 2.4 Hz,
1
J2 = 11.1 Hz, 1H), 4.31 (t, J = 3.4 Hz, 1H), 3.67 (br, 4H), 2.84-2.67
1
3
N
S
SMe
(
m, 4H), 2.45-2.25 (m, 5H); C NMR (75 MHz, CDCl ): δ 195.47,
3
O
4e
1
41.16, 138.16, 133.67, 132.16, 128.73, 128.58, 128.27, 128.24,
+
1
28.05, 126.97, 69.20, 66.73, 48.73, 44.00, 34.55, 17.78; HRMS [M+H] calcd. For
C H NO S 412.1399, found 412.1403.
23
26
2 2
2
-Methylsulfanyl-6-morpholino-4-phenyl-3-(3-pyridoyl)-5,6-dihydro-4H-thiopyran
(4f):
−
1
Pale yellow solid, mp 122-123 °C; FT IR (KBr, cm ): 3028, 2937,
1
1
639, 1574, 1253, 1183; H NMR (300 MHz, CDCl ): δ 8.84 (s, 1H),
3
O
8
.63 (d, J = 4.5 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.25-7.18 (m, 5H),
7
.09-7.01 (m, 1H), 4.51 (dd, J = 2.7 Hz, J = 11.7 Hz, 1H), 4.39 (t, J
1 2
N
S
SMe N
=
3.4 Hz, 1H), 3.68 (br, 4H), 2.80-2.70 (m, 4H), 2.43-2.27 (m, 5H);
O
4f
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3
C NMR (75 MHz, CDCl ): δ 189.32, 167.88, 153.87, 151.70, 147.02, 136.12, 135.66, 133.99,
3
+
1
28.73, 128.06, 127.10, 123.30, 69.92, 66.35, 48.67, 43.82, 34.49, 17.28; HRMS [M+H] calcd.
For C H N O S 413.1352, found 413.1360.
2
2
25
2
2 2
3
-(2-Methoxybenzoyl)-2-methylsulfanyl-6-morpholino-4-phenyl-5,6-dihydro-4H-thiopyran
−
1
(
4g): Pale yellow solid, mp 128-129 °C; FT IR (KBr, cm ): 3045,
1
2
952, 1624, 1587, 1286, 1176; H NMR (300 MHz, CDCl ): δ 7.29-
3
O
7
.20 (m, 7H), 7.08-6.99 (m, 2H), 4.47 (dd, J = 2.7 Hz, J = 11.7
1
2
Hz, 1H), 4.29 (t, J = 3.6 Hz, 1H), 3.74-3.67 (m, 7H), 2.80-2.69 (m,
N
S
SMe
13
4
H), 2.43-2.24 (m, 5H); C NMR (75 MHz, CDCl ): δ 195.22,
3
O
OMe
4
g
1
59.53, 141.15, 139.60, 133.44, 129.20, 128.61, 128.34, 128.30,
+
1
27.00, 121.42, 118.78, 112.64, 69.31, 66.73, 55.25, 48.72, 43.99, 34.49, 17.79; HRMS [M]
calcd. For C H NO S 441.1432, found 441.1431.
2
4
27
3 2
3
-Benzoyl-2-benzylsulfanyl-4-(4-methoxyphenyl)-6-morpholino-5,6-dihydro-4H-thiopyran
−
1
(
4h): Pale yellow solid, mp 69-70 °C; FT IR (KBr, cm ): 3039,
OMe
1
2
7
2
4
2
1
946, 1624, 1566, 1282, 1179; H NMR (300 MHz, CDCl ): δ
3
.60 (d, J = 7.2 Hz, 2H), 7.47-7.20 (m, 8H), 7.05 (d, J = 8.4 Hz,
H), 6.89-6.76 (m, 2H), 4.43 (dd, J = 3.0 Hz, J = 12.0 Hz, 1H),
O
S
1
2
.18-4.09 (m, 2H), 3.99-3.90 (m, 1H), 3.73-3.65 (m, 7H), 2.77-
N
S
1
3
.68 (m, 4H), 2.34-2.13 (m, 2H); C NMR (75 MHz, CDCl ): δ
3
O
4h
95.47, 158.43, 137.72, 137.07, 136.65, 135.44, 132.64, 132.26,
1
3
29.23, 128.84, 128.27, 128.24, 127.17, 113.87, 113.65, 69.01, 66.69, 55.10, 48.72, 43.23, 38.99,
+
4.49; HRMS [M+H] calcd. For C H NO S 518.1818, found 518.1822.
3
0
32
3 2
3
-(2-Furoyl)-2-methylsulfanyl-4-phenyl-6-(4-phenylpiperazino)-5,6-dihydro-4H-thiopyran
−
1
(
4i): Pale yellow solid, mp 101-103 °C; FT IR (KBr, cm ):
1
3
042, 2944, 1654, 1589, 1248, 1181; H NMR (300 MHz,
O
O
CDCl ): δ 7.48-7.36 (m, 2H), 7.20-7.05 (m, 5H), 6.94-6.75
3
(
m, 5H), 6.47-6.28 (m, 1H), 4.45-4.43 (m, 2H), 3.11-3.05
N
S
SMe
13
N
(m, 4H), 2.87-2.74 (m, 4H), 2.39-2.24 (m, 5H); C NMR
4
i
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(
75 MHz, CDCl ): δ 182.96, 153.22, 151.02, 145.87, 142.18, 141.29, 132.76, 129.07, 128.51,
3
1
28.28, 126.88, 120.01, 117.79, 116.28, 112.24, 69.01, 49.20, 48.38, 43.47, 35.22, 18.05; HRMS
+
[
M+H] calcd. For C H N O S 477.1665, found 477.1671.
2
7
29
2
2 2
4
-(4-Methoxyphenyl)-2-methylsulfanyl-6-(4-phenylpiperazino)-3-(3-pyridoyl)-5,6-dihydro-
4H-thiopyran (4j): Pale yellow solid, mp 93-95 °C; FT IR
p-MeO.C H
O
6
4
−
1
1
(
KBr, cm ): 3051, 2926, 1641, 1579, 1278, 1152; H NMR
N
S
N
(300 MHz, CDCl ): δ 8.84 (s, 1H), 8.64 (d, J = 3.3 Hz, 1H),
3
SMe
N
4
j
7.89 (d, J = 7.8 Hz, 1H), 7.25 (br, 2H),7.13-7.10 (m, 2H),
6
.94-6.81 (m, 6H), 4.59 (dd, J = 2.4 Hz, J = 11.4 Hz, 1H),
1 2
4
2
1
4
5
.34 (t, J = 3.9 Hz, 1H), 3.76 (s, 3H), 3.16 (br, 4H), 3.00-2.85 (m, 4H), 2.71-2.63 (m, 4H), 2.45-
1
3
.31 (m, 5H); C NMR (75 MHz, CDCl ): δ 193.44, 158.58, 151.86, 151.03, 149.64, 145.99,
3
35.58, 134.57, 133.14, 131.73, 129.15, 129.09, 123.27, 120.07, 116.31, 114.12, 69.82, 55.16,
+
9.22, 48.44, 43.16, 34.96, 17.28; HRMS [M+H] calcd. For C H N O S 518.1930, found
2
9
32
3
2 2
18.1938.
3
-(N-Methyl-2-pyrroloyl)-2-methylsulfanyl-4-phenyl-6-(4-phenylpiperazino)-5,6-dihydro-
H-thiopyran (4k): Pale yellow solid, mp 154-155 °C; FT
4
−
1
1
IR (KBr, cm ): 3048, 2916, 1638, 1584, 1228, 1172; H
O
NMR (500 MHz, CDCl ): δ 7.29-7.26 (m, 6H), 7.21-7.09
3
(
m, 2H), 6.97-6.94 (m, 2H), 6.90 (t, J = 7.2 Hz, 1H), 4.54
N
CH3
N
S
SMe
(dd, J = 2.5 Hz, J = 11.5 Hz, 1H), 4.36 (t, J = 4.0 Hz,
1
2
N
4
K
1
2
H), 3.62 (s, 3H), 3.24-3.17 (m, 4H), 3.03-3.01 (m, 2H),
1
3
.93-2.89 (m, 2H), 2.41 (s, 3H), 2.33-2.31 (m, 2H);
C
NMR (125 MHz, CDCl ): δ 190.40, 141.27, 136.94, 133.79, 129.20, 128.50, 128.48, 128.23,
3
1
1
28.06, 126.90, 125.74, 123.18, 120.52, 116.56, 110.28, 68.23, 49.48, 48.37, 44.18, 36.62, 34.84,
+
8.43; HRMS [M+H] calcd. For C H N OS 490.1981, found 490.1983.
2
8
32
3
2
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-Isopropanoyl-2-methylsulfanyl-4-phenyl-6-(4-phenylpiperazino)-5,6-dihydro-4H-
thiopyran (4l): Pale yellow solid, mp 94-95 °C; FT IR
−
1
1
(
KBr, cm ): 3017, 2944, 1636, 1572, 1284, 1163; H NMR
O
(
300 MHz, CDCl ): δ 7.35-7.16 (m, 7H), 6.91-6.86 (m, 3H),
3
4
.38-4.32 (m, 2H), 3.15-3.11 (m, 4H), 2.95-2.80 (m, 5H),
N
S
SMe
2
.47-2.37 (m, 5H), 0.99 (d, J = 6.6 Hz, 3H), 0.82 (d, J = 6.6
N
4l
13
Hz, 3H); C NMR (75 MHz, CDCl ): δ 203.10, 153.38,
3
1
51.06, 141.67, 129.10, 128.78, 127.94, 126.99, 126.69,
+
1
20.11, 116.35, 69.17, 49.25, 48.15, 42.61, 35.88, 34.31, 19.86, 18.87, 16.75; HRMS [M+H]
calcd. For C H N OS 453.2029, found 453.2028.
2
6
33
2
2
6
-(1-Carboethoxyl)piperazino-3-(4-methoxybenzoyl)-2-methylsulfanyl-4-phenyl-5,6-
dihydro-4H-thiopyran (4m): Pale yellow solid, mp 140-
−
1
1
1
2
41°C; FT IR (KBr, cm ): 3015, 2925, 1642, 1572, 1282,
O
1
167; H NMR (500 MHz, CDCl ): δ 7.77 (d, J = 8.5 Hz,
3
H), 7.30-7.09 (m, 5H), 6.88 (d, J = 8.5 Hz, 2H), 4.52
N
S
OMe
SMe
(
dd, J = 2.0 Hz, J = 12.0 Hz, 1H), 4.28 (t, J = 3.7 Hz,
1 2
O
N
4m
1
H), 4.13 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 3.48-3.41 (m,
H), 2.77 (br, 2H), 2.65 (t, J = 4.7 Hz, 2H), 2.35 (s, 3H),
O
4
1
3
2
1
5
5
.29-2.25 (m, 4H), 1.25 (t, J = 7.0 Hz, 3H); C NMR (125 MHz, CDCl ): δ 194.55, 163.28,
3
55.35, 141.18, 136.27, 131.49, 130.46, 128.60, 128.39, 127.03, 113.65, 113.40, 68.62, 61.47,
+
5.43, 48.52, 48.34, 44.33, 34.97, 18.04, 14.67; HRMS [M+H] calcd. For C H N O S
2
7
33
2
4
2
13.1876, found 513.1901.
6
-(1-Carboethoxyl)piperazino-2-methylsulfanyl-4-phenyl-3-(4-trifluoromethylbenzoyl)-5,6-
dihydro-4H-thiopyran (4n): Pale yellow solid, mp
−
1
1
30-131 °C; FT IR (KBr, cm ): 3034, 2943, 1629,
O
1
1
578, 1251, 1162; H NMR (500 MHz, CDCl ): δ 7.67
3
(
d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.38-7.17
m, 5H), 4.52 (dd, J = 2.5 Hz, J = 11.5 Hz, 1H), 4.33 (t,
N
S
CF3
SMe
(
1
2
O
N
4n
J = 3.7 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 3.49-3.41 (m,
O
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4
H), 2.77-2.65 (m, 4H), 2.37 (s, 3H), 2.32-2.27 (m, 2H), 1.25 (t, J = 7.2 Hz, 3H); C NMR (125
MHz, CDCl ): δ 193.95, 155.33, 141.21, 131.43, 128.80, 128.73, 128.51, 128.18, 127.22,
3
1
27.11, 125.23, 125.20, 69.71, 61.52, 48.33, 48.04, 43.93, 43.51, 34.74, 17.46, 14.66; HRMS
+
[
M+H] calcd. For C H F N O S 551.1644, found 551.1652.
2
7
30
3
2
3 2
3
-Benzoyl-2-benzylsulfanyl-6-(1-carboethoxyl)piperazino-4-phenyl-5,6-dihydro-4H-
thiopyran (4o): Pale yellow solid, mp 67-68 °C; FT IR
−
1
1
(
KBr, cm ): 3036, 2951, 1662, 1583, 1271, 1161; H
O
NMR (300 MHz, CDCl ): δ 7.59 (d, J = 7.2 Hz, 2H),
3
7
.43-6.97 (m, 13H), 4.56 (dd, J = 3.3 Hz, J = 14.1 Hz,
1 2
N
S
S
O
N
1H), 4.19-3.85 (m, 5H), 3.43 (br, 4H), 2.71-2.63 (m,
4o
1
3
O
4H), 2.30-2.21 (m, 2H), 1.25 (t, J = 6.4 Hz, 3H);
C
NMR (75 MHz, CDCl ): δ 195.31, 155.15, 140.55,
3
1
1
37.67, 136.62, 136.51, 135.97, 132.24, 129.16, 128.78, 128.46, 128.22, 127.94, 127.16, 127.00,
+
26.91, 68.70, 61.34, 48.43, 48.17, 43.94, 43.38, 38.92, 34.47, 14.56; HRMS [M+H] calcd. For
C H N O S 559.2084, found 559.2087.
32
35
3
3 2
6
-(1-Carboethoxyl)piperazino-3-ferrocenoyl-2-methylsulfanyl-4-phenyl-5,6-dihydro-4H-
thiopyran (4p): Pale yellow solid, mp 147-149 °C; FT IR
−
1
1
(
KBr, cm ): 3041, 2922, 1632, 1561, 1245, 1168; H NMR
O
(
300 MHz, CDCl ): δ 7.45-7.25 (m, 5H), 4.87 (br, 1H), 4.59
3
Fe
(br, 1H), 4.49 (br, 3H), 4.37 (br, 1H), 3.71 (br, 5H), 3.43 (br,
N
S
SMe
4
3
1
H), 2.74-2.64 (m, 4H),2.38-2.22 (m, 5H), 1.25 (t, J = 7.0 Hz,
O
N
4
p
1
3
H); C NMR (125 MHz, CDCl ): δ 199.91, 155.33, 141.48,
3
O
37.64, 136.33, 128.95, 128.44, 127.35, 81.10, 71.86, 71.21,
+
7
0.60, 70.27, 69.82, 69.02, 61.46, 48.20, 43.90, 34.73, 18.15, 14.65; HRMS [M] calcd. For
C H FeN O S 590.1360, found 590.1360.
30
34
2
3 2
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-Benzoyl-2-methylsulfanyl-4-phenyl-6-pyroldino-5,6-dihydro-4H-thiopyran (4q): Pale
−
1
yellow solid, mp 103-105°C; FT IR (KBr, cm ): 3015, 2921, 1641,
1
1
587, 1259, 1185; H NMR (300 MHz, CDCl ): δ 7.67 (d, J = 6.6
3
O
Hz, 2H), 7.66-7.25 (m, 8H), 4.83 (t, J = 5.8 Hz, 1H), 4.27 (br, 1H),
1
3
2
.87 (t, J=6.1 Hz, 4H), 2.36 (br, 5H),1.78 (br, 4H); C NMR (75
N
S
SMe
4q
MHz, CDCl ): δ 195.52, 140.93, 138.29, 133.69, 132.05, 129.00,
3
1
28.67, 128.50, 128.19, 127.38, 126.85, 67.49, 48.32, 44.18, 36.53, 24.18, 17.74; HRMS
+
[
M+H] calcd. For C H NOS 396.1450, found 396.1454.
2
3
26
2
4
-(4-Methoxyphenyl)-3-(4-methylbenzoyl)-2-methylsulfanyl-6-pyroldino-5,6-dihydro-4H-
thiopyran(4r): Pale yellow solid, mp 88-90 °C; FT IR (KBr,
OMe
−
1
1
cm ): 3047, 2942, 1649, 1585, 1273, 1165; H NMR (300 MHz,
CDCl ): δ 7.64 (d, J = 6.6 Hz, 2H), 7.25-7.15 (m, 4H), 6.80 (d, J
3
O
=
6.9 Hz, 2H), 4.83 (br, 1H), 4.19 (br, 1H), 3.75 (s, 3H), 2.87 (br,
1
3
4
1
1
H), 2.36 (br, 5H), 1.78 (br, 7H); C NMR (75 MHz, CDCl ): δ
3
N
S
SMe
95.55, 158.35, 142.99, 135.39, 133.13, 129.42, 129.25, 129.16,
4r
29.04, 128.96, 113.83, 64.44, 55.13, 48.18, 43.66, 37.02, 24.55,
+
2
4.20, 21.60, 17.85; HRMS [M+H] calcd. For C H NO S 440.1712, found 440.1711.
2
5
30
2 2
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3
. Copies of the H and C NMR spectra of all the new compounds
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