Solvent-free synthesis of substituted thiopyrans via multicomponent reactions of α-haloketones

Article abstract of DOI:10.1016/j.cclet.2013.10.016

A straightforward and efficient method for the synthesis of thiopyran derivatives via three-component reaction of alkyl propiolate, benzoylisothiocyanate or its derivatives and α-haloketones in the presence of triphenylphosphine under solvent-free conditions at 70 C without using any catalyst is reported. The method offers several advantages including high yields of products and an easy work-up procedure.

Full text of DOI:10.1016/j.cclet.2013.10.016

Chinese Chemical Letters 25 (2014) 152–154
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Solvent-free synthesis of substituted thiopyrans via multicomponent
reactions of -haloketones
a
b
c
Fatemeh Sheikholeslami-Farahani a, , Zinatossadat Hossaini , Faramarz Rostami-Charati
*
a Department of Chemistry, Firoozkooh Branch, Islamic Azad University, Firoozkooh, Iran
b Department of Chemistry, Qaemshahr Branch, Islamic Azad University, Qaemshahr, Iran
c Department of Chemistry, Facualty of Science, Gonbad Kavous University, Gonbad, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
A straightforward and efficient method for the synthesis of thiopyran derivatives via three-component
reaction of alkyl propiolate, benzoylisothiocyanate or its derivatives and -haloketones in the presence of
Received 6 September 2013
Received in revised form 26 September 2013
Accepted 8 October 2013
a
triphenylphosphine under solvent-free conditions at 70 8C without using any catalyst is reported. The
method offers several advantages including high yields of products and an easy work-up procedure.
ß 2013 Fatemeh Sheikholeslami-Farahani. Published by Elsevier B.V. on behalf of Chinese Chemical
Society. All rights reserved.
Available online 12 November 2013
Keywords:
Thiopyran
Triphenylphosphine
a
-Haloketones
Solvent-free conditions
Benzoyl isothiocyanate
1. Introduction
2. Experimental
At present, heterocycles with sulfur atoms, like thiopyrans,
have attracted increased attention. These compounds have
different biological activities [1] that have been recognized [2].
Thiopyrans are used in medicinal chemistry, but receive relatively
less attention [3]. Also, thiopyrans are often in the structure of
natural products with different pharmaceutical activities such as
anti-bacterial [4], anti-hyperplasia [5], anti-psychiatric [6], and
anticancer activities [7]. Investigation of anticancer activity of
thiopyran derivatives showed that they have antiproliferative
activity against tumor cell lines [8]. It has also been described that
substituted thiopyrans are powerful inhibitors of deoxyribonucleic
acid-protein kinases [9]. However, the methods for synthesis of
these important compounds often feature tedious synthetic routes,
long reaction time, harsh reaction conditions, and narrow
application scope of substrates. In addition, to the best of our
knowledge, there have been few reports about the synthesis of
thiopyran derivatives [10–12]. Hence, we describe herein the
All chemicals used in this work were purchased from Fluka
(Buchs, Switzerland) and were used without further purification.
Melting points were measured on an Electrothermal 9100
apparatus. Elemental analyses for C, H, and N were performed
using
a Heraeus CHN-O-Rapid analyzer. Mass spectra were
recorded on a FINNIGAN-MAT 8430 spectrometer operating at
an ionization potential of 70 eV. IR spectra were measured on a
Shimadzu IR-460 spectrometer. 1H NMR and 13C NMR spectra were
measured with a BRUKER DRX-500 AVANCE spectrometer at
500.1MHz and 125.8 MHz, respectively. 1H NMR and 13C NMR
spectra were obtained for solutions in CDCl3 using TMS as the
internal standard or 85% H3PO4 as the external standard.
General procedure for preparation of compounds 5a–e.
a-
Haloketones (2-mmol) and triphenylphosphine (2 mmol) were
stirred at 70 8C for 45 min. After 45 min, triethylamine (2 mmol)
and alkyl propiolate (2 mmol) were added to the mixture. Then,
arylisothiocyanate (2 mmol) was added after 15 min. The reaction
mixture was stirred for 8 h at 70 8C. After completion of reaction
(monitored by TLC), 15 mL H2O was poured into the reaction
mixture, and the solid residue was filtered and washed by cold
diethylether (Et2O) to afford 5.
reaction of alkyl propiolate 1, benzoylisothiocyanate 2 and
a-
haloketones 3 in the presence of triphenylphosphine 4 under
solvent-free conditions to produce substituted thiopyran deriva-
tives 5 in good yield (Scheme 1).
Methyl 2-(benzoilimino)-6-phenyl-2H-thiopyran-3-carboxylate
(5a): Yellow oil, yield: 0.45 g (65%) IR (KBr, cmÀ1):
n
1738,
1725, 1695, 1587, 1463, 1348, 1259. 1H NMR (500.1 Hz, CDCl3):
3.78 (s, 3 H, MeO), 6.37 (d, 1 H, 3J = 7.8, CH), 7.28 (d, 1 H, 3J = 7.8,
d
*
Corresponding author.
E-mail address: sheikholeslami@iaufb.ac.ir (F. Sheikholeslami-Farahani).
1001-8417/$ – see front matter ß 2013 Fatemeh Sheikholeslami-Farahani. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.10.016

F. Sheikholeslami-Farahani et al. / Chinese Chemical Letters 25 (2014) 152–154
153
Ar'
O
O
H
Solvent-free
S
O
Br
+
PPh3
+
+
Ar
N
C
S
70 oC, 8 h
Ar'
Ar
N
CO2R
CO2R
3
4
2
1
5
Ar'
1, 2, 3, 5
Yield of 5 (%)
R
Ar
Ph
Me
Me
Ph
a
b
65
70
4-MeO-C6H4
4-MeO-C6H4
4-MeO-C6H4
4-Me-C6H4
4-Br-C6H4
4-MeO-C6H4
c
d
e
78
75
60
Me
Me
Et
4-Me-C6H4
4-NO2-C6H4
Scheme 1. Reaction of propiolates, aroyl isothiocyanates and
a-halo carbonyl compounds in the presence of triphenylphosphine.
CH), 7.38 (t, 1 H, 3J = 7.4, CH), 7.56 (m, 3 H, 3 CH), 7.64 (t, 2 H,
3J = 7.8, 2 CH), 7.78 (d, 2 H, 3J = 7.6, 2 CH), 8.14 (d, 2 H, 3J = 7.6, 2 CH).
(500.1 Hz, CDCl3): d
1.27 (t, 3 H, 3JHH = 7.4, Me), 3.86 (s, 3 H, MeO),
4.26 (q, 2 H, 3J = 7.4, CH2O), 6.18 (d, 1 H, 3J = 7.5, CH), 7.14 (d, 2 H,
3J = 7.6, 2 CH), 7.38 (d, 1H, 3J = 7.5, CH), 7.56 (d, 2 H, 3J = 7.6, 2 CH),
7.63 (d, 2 H, 3J = 7.6, 2 CH), 8.34 (2 H, d, 3J = 7.8, 2 CH). 13C NMR
13C NMR (125.7 Hz, CDCl3):
d 52.4 (MeO), 118.6 (C), 128.2 (CH),
129.4 (CH), 130.2 (2 CH), 130.6 (2 CH), 131.4 (2 CH), 131.8 (2 CH),
133.2 (CH), 134.8 (C), 135.4 (C), 141.7 (C), 143.6 (CH), 160.4 (C55O),
162.7 (C55N), 172.4 (C55O). EI-MS: m/z 349 (10, M+), 318 (86), 105
(100), 77 (88), 31 (100). Anal. Calcd. for C20H15NO3S (349.40): C
68.75, H 4.33, N 4.01; found C 68.83, H 4.42, N 4.12%.
(125.7 Hz, CDCl3):
d 14.2 (Me), 55.6 (MeO), 61.4 (CH2O), 114.2 (2
CH), 117.8 (C), 124.8 (2 CH), 127.5 (2 CH), 128.6 (CH), 129.6 (C),
130.2 (2 CH), 138.6 (C), 143.2 (CH), 143.8 (C), 152.4 (C), 161.4
(C55O), 161.8 (C), 162.4 (C55N), 176.8 (C55O). Anal. Calcd. for
Methyl
thiopyran-3-carboxylate (5b): Yellow oil, yield: 0.57 g (70%). IR
(KBr, cmÀ1): 1735, 1728, 1695, 1654, 1588, 1474, 1357. 1H NMR
(500.1 Hz, CDCl3):
2-(4-methoxybenzoilimino)-6-(4-methoxyphenyl)-2H-
C22H18N2O6S (438.45): C 60.27, H 4.14, N, 6.39; found: C 60.34, H
4.22, N 6.45%.
n
d
3.75 (s, 3 H, MeO), 3.82 (s, 3 H, MeO), 3.87 (s, 3
3. Results and discussion
H, MeO), 6.29 (d, 1 H, 3J = 7.5, CH), 7.12 (d, 2 H, 3J = 7.6, 2 CH), 7.22
(d, 2 H, 3J = 7.6, 2 CH), 7.30 (d, 1 H, 3J = 7.5, CH), 7.62 (d, 2 H, 3J = 7.6,
The reaction of alkyl propiolate 1, benzoyl isothiocyanate 2 and
alkyl bromide 3 in the presence of triphenylphosphine 4 under
solvent-free conditions produced substituted thiopyran deriva-
tives 5 in good yield (Scheme 1).
The starting point for our experiments was to optimize the
reaction conditions such as solvent and reaction time for the
production of 2H-thiopyranes which have anti-bacterial [4], anti-
hyperplasia [5], anti-psychiatric [6], and anticancer activities [7]
(see Table 1).
To achieve suitable conditions for the above transformation, a
series of experiments was carried out. First, we investigated the
reaction of methyl propiolate, benzoyl isothiocyanate, and
phenacyl bromide in the presence of triphenyl phosphine in
various solvents, in water and under solvent-free classical heating
conditions. The reaction proceeds in organic solvents and water
with low yield (Table 1, entries 1–10). In the absence of solvent and
at 70 8C, the reaction was performed with good yield after 8 h.
Structures of compounds 5a–e were determined based on their IR,
2 CH), 8.04 (d, 2 H, 3J = 7.6, 2 CH). 13C NMR (125.7 Hz, CDCl3):
d 51.8
(MeO), 54.5 (MeO), 55.2 (MeO), 115.4 (2 CH), 116.5 (2 CH), 118.3
(C), 128.5 (CH), 129.4 (C), 130.4 (2 CH), 131.2 (2 CH), 142.7 (C),
145.2 (CH), 158.3 (C), 161.4 (C55O), 162.5 (C55N), 164.7 (C), 171.9
(C55O). Anal. Calcd. for C22H19NO5S (409.45): C 64.54, H 4.68, N
3.42; found: C 64.63, H 4.76, N 3.54%.
Methyl 2-(4-methoxybenzoilimino)-6-(4-methylphenyl)-2H-thio-
pyran-3-carboxylate (5c): Yellow oil, yield: 0.61 g (78%). IR (KBr,
cmÀ1):
n
1732, 1712, 1687, 1646, 1547, 1485, 1362, 1295. 1H NMR
(500.1 Hz, CDCl3):
d
2.36 (s, 3 H, Me), 3.78 (s, 3 H, MeO), 3.85 (s, 3 H,
MeO), 6.19 (d, 1 H, 3J = 7.4, CH), 7.23 (d, 2 H, 3J = 7.8, 2 CH), 7.34 (d, 1
H, 3J = 7.5, CH), 7.38 (d, 2 H, 3J = 7.5, 2 CH), 7.58 (d, 2 H, 3J = 7.6, 2
CH), 8.14 (d, 2 H, 3J = 7.6, 2 CH). 13C NMR (125.7 Hz, CDCl3):
d 22.3
(Me), 51.8 (MeO), 55.4 (MeO), 114.8 (2 CH), 117.8 (C), 127.4 (CH),
129.6 (2 CH), 130.2 (C), 131.4 (2 CH), 132.3 (2 CH), 133.7 (C), 137.6
(C), 141.6 (C), 144.8 (CH), 161.7 (C55O), 162.8 (C55N), 163.8 (C),
175.4 (C55O). Anal. Calcd. for C22H19NO4S (482.50): C 67.16, H 4.87,
N 3.56; found: C 67.04, H 4.76, N 3.45%.
Methyl 2-(4-methylbenzoilimino)-6-(4-bromophenyl)-2H-thio-
pyran-3-carboxylate (5d): Yellow oil, yield: 0.66 g (75%). IR (KBr,
Table 1
Optimization of reaction conditions of compound 5a
.
cmÀ1):
n
1732, 1715, 1695, 1648, 1537, 1465, 1374, 1283. 1H NMR
Entry
Solvent (5 mL)
Temp. (8C)
Time (h)
Yield (%)a
(500.1 Hz, CDCl3):
d
2.38 (s, 3 H, Me), 3.82 (s, 3 H, MeO), 6.23 (d, 1 H,
3J = 7.6, CH), 7.35 (d, 1 H, 3J = 7.6, CH), 7.43 (d, 2 H, 3J = 7.6, 2 CH),
7.58 (d, 2 H, 3J = 7.8, 2 CH), 7.63 (d, 2 H, 3J = 7.6, 2 CH), 7.86 (d, 2 H,
1
DMF
90
70
90
70
90
90
120
50
70
90
50
70
12
15
15
14
14
24
24
12
12
12
8
None
32
2
Toluene
Toluene
CH3CN
CH3CN
EtOH
3
40
3J = 7.8, 2 CH). 13C NMR (125.7 Hz, CDCl3):
d 22.5 (Me), 52.3 (MeO),
4
45
118.7 (C), 124.3 (C), 126.2 (CH), 128.6 (2 CH), 129.4 (2 CH), 130.7 (2
CH), 135.2 (2 CH), 135.8 (C), 136.2 (C), 136.8 (C), 143.8 (CH), 144.0
(C), 160.6 (C55O), 162.3 (C55N), 174.6 (C55O). Anal. Calcd. for
5
45
6
25
7
EtOH
25
8
H2O
Trace
Trace
15
C21H16BrNO3S (442.32): C 57.02, H 3.65, N 3.17; found: C 57.15, H
9
H2O
3.74, N 3.26%.
10
11
12
H2O
Solvent-free
Solvent-free
58
Ethyl
2-(4-nitrobenzoilimino)-6-(4-methoxyphenyl)-2H-thio-
8
65
pyran-3-carboxylate (5e): Yellow oil, yield: 0.53 g (60%). IR (KBr,
cmÀ1):
n
1733, 1716, 1696, 1675, 1578, 1465, 1385, 1263. 1H NMR
Isolated yield.
a

154
F. Sheikholeslami-Farahani et al. / Chinese Chemical Letters 25 (2014) 152–154
Ar'
4. Conclusion
+
O
_
Ph3P
+
Et3N, 1
O
2
PPh3 Br
In conclusion, we found that the reaction of alkyl propiolate
with benzoyl isothiocyanate and alkyl bromide in the presence of
triphenylphosphine leads to a facile synthesis of some function-
alized thiopyrans under solvent-free conditions, without using any
catalyst.
3 + 4
Ar'
_
H
CO2R
6
7
_
Ar'
O
Ar'
S
+
+
_
O
References
Ph3P
Ph3P
_
O
S
PPh3O
O
5
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N
Ar
N
H
H
Ar
CO2R
CO2R
9
8
Scheme 2. Proposed mechanism for the synthesis of compound 5.
1H NMR, 13C NMR and 31P NMR spectra. The mass spectra of these
compounds show molecular ion peaks at the appropriate m/z
values. In the 1H NMR spectrum of 5a displayed one singlet at 3.78
for methoxy protons, two doublets at 6.37 (d, 3J = 7.8, CH) and 7.28
(d, 3J = 7.8, CH) for methine protons along with signals for an
aromatic moiety. The carbonyl group’s resonances in the 13C NMR
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appropriate m/z values.
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A proposed mechanism for this reaction is shown in Scheme 2.
On the basis of phosphorus nucleophile chemistry, it is reasonable
to presume that triphenylphosphonium bromide 6 results from
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initial addition of the triphenylphosphin 4 to
a-haloketones 3.
Intermediate 6 is reacted with alkyl propiolate 1 in the presence of
triethylamine as the base for production of zwitterionic species 7.
Then, nucleophilic attack of this intermediate on benzoyl
isothiocyanate 2 produces intermediate 8. Finally, by intramolec-
ular cyclization, compound 9 is afforded by elimination of
triphenylphosphine oxide, which is converted to 5 as the product.