Regioselective synthesis of polysubstituted 4H-thiopyrans from β-oxodithioesters

Article abstract of DOI:10.1016/j.tetlet.2014.06.013

A simple and efficient method for the synthesis of polyfunctionalized 4H-thiopyrans by highly regioselective cyclocondensation of β- oxodithioesters with 1,1,3-trialkyl or aryl substituted prop-2-yn-1-ols using BF₃·Et₂O as the catalyst is described.

Full text of DOI:10.1016/j.tetlet.2014.06.013

Tetrahedron Letters 55 (2014) 4382–4385
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective synthesis of polysubstituted 4H-thiopyrans
from b-oxodithioesters
a
a
a
Sridhar Madabhushi a, , Srinivas Kurva , Venkata Sairam Vangipuram , Vinodkumar Sriramoju ,
⇑
Kishore Kumar Reddy Mallu a, Jagadeesh Babu Nanubolu b
a Fluoroorganics Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
b Centre for X-Ray Crystallography, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A
simple and efficient method for the synthesis of polyfunctionalized 4H-thiopyrans by highly
Received 12 May 2014
Revised 4 June 2014
Accepted 4 June 2014
Available online 11 June 2014
regioselective cyclocondensation of b-oxodithioesters with 1,1,3-trialkyl or aryl substituted prop-
2-yn-1-ols using BF3ꢀEt2O as the catalyst is described.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
4H-Thiopyrans
b-Oxodithioester
1,1,3-Trisubstituted prop-2-yn-1-ol
Cyclocondensation
BF3ꢀEt2O
Acid catalysis
Among the sulfur containing heterocycles, thiopyran structure
has high significance as a versatile scaffold for the synthesis of cer-
tain natural and unnatural products.1 In the literature, however,
only a few methods exist for the construction of 4H-thiopyrans
and the classical approach is the Diels–Alder reaction of thiabut-
adiene with an activated dienophile.2 Some of the recent methods
reported in the literature for the preparation of thiopyrans include
Grubb’s metathesis approach,3 microwave assisted multicompo-
variety of sulfur heterocycles such as thiophenes,6 dihydro-4H-
thiopyrans,7 2H-chromene-2-thiones,8 tetrahydrothiochromen-
5-ones,9 and benzo[a]quinolizine-4-thiones10 and in addition, they
were also employed as reactive intermediates in the preparation of
other heterocycles such as pyrazoles,11 pyrroles,12 indoles,13
4H-benzo[f]chromenes,14 imidazo[1,2-a]pyridines,15 dihydropyri-
midinones16 etc.
In our laboratory, we recently found that 1,1,3-trisubstituted
prop-2-yn-1-ol readily undergoes dehydrative cyclocondensation
reaction with phenols under Lewis acid catalysis producing
polyfunctionalized chromenes in high yields.17 In view of this,
we studied the scope of similar cyclocondensation reaction of
1,1,3-trisubstituted prop-2-yn-1-ols with b-oxodithioesters and
herein we report for the first time a new and efficient method
for the preparation of polyfunctionalized 4H-thiopyrans in high
yields (72–95%) by the regioselective cyclocondensation of
b-oxodithioesters with a 1,1,3-trisubstituted prop-2-yn-1-ol in
the presence of BF3ꢀEt2O as the catalyst as shown in Scheme 1.
In our initial experiments, we studied the reaction of methyl
3-oxo-3-phenylpropanedithioate 1a with 1,1,3-triphenylprop-2-
yn-1-ol 2a in dichloromethane using a variety of Lewis acid
catalysts such as BF3ꢀEt2O, Zn(OTf)2, Bi(OTf)3, Sc(OTf)3, InBr3, ZnCl2,
AlCl3, and FeCl3 and also with Bronsted acids such as p-toluene
sulfonic acid, and acetic acid. The results are shown in Table 1. In
nent reaction of a,b-unsaturated ketones with Lawesson’s reagent
and alkynes,4 and condensation of b-oxodithioesters with an
aldehyde and a nitrile under base catalysis.
In recent years, studies were extensively focused on the
development of novel catalytic methods for carbonAsulfur bond
formation reactions, particularly through addition of sulfur to
alkenes and alkynes owing to the growing industrial importance
of organosulfur compounds as reactive intermediates, pharmaceu-
ticals, and agrochemicals.5 In recent years, b-oxodithioesters have
emerged as versatile building blocks for the construction of a
⇑
Corresponding author. Tel.: +91 40 27191772; fax: +91 40 27160387.
E-mail addresses: smiict@gmail.com, sridharm@iict.res.in (S. Madabhushi).
http://dx.doi.org/10.1016/j.tetlet.2014.06.013
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

S. Madabhushi et al. / Tetrahedron Letters 55 (2014) 4382–4385
4383
R2
R3
O
Ph
Ph
Ph
R1
O
Ph
HO
O
Ph Ph
HO
R2
R3
O
S
O
S
BF3.Et2O(20mol%)
CH2Cl2, rt, 1-3h
R1
cyclocondensation
-H2O
Ph
Ph
or
Ph
Ph
Ph
+
+
MeS
S
R4
MeS
S
MeS
S
R4
MeS
R1=aryl,
MeS
Ph
2a
72-95%
3a
1a
3'a
?
R2,R3&R4 =aryl or alkyl
Scheme 2. Structural isomers 3a and 30a.
Scheme 1. Synthesis of polyfunctionalized 4H-thiopyrans.
this study, we obtained the best results with BF3ꢀEt2O, which
promoted the reaction of 1a with 2a in a very short reaction time
(1 h) producing 2-(methylthio)-4,4,6-triphenyl-4H-thiopyran-3-yl)
(phenyl)methanone 3a in high yield (95%) when compared to other
catalysts. In our study, the solvent was found to have profound
influence on the reaction. For example, solvents such as toluene,
methanol, tetrahydrofuran, and acetonitrile, promoted the reaction
relatively slowly when compared to dichloromethane and they
produced 3a in 55%, 50%, 45%, and 20% yields, respectively, in 12 h.
In our study, the present cyclocondensation reaction of 1a with
2a was found to give exclusively one product. However, based on
the NMR, IR, and Mass spectral data (refer Supplementary informa-
tion file) obtained for the product we initially arrived at two
possible structures 3a and 30a as shown in Scheme 2. To rule out
one of the structures, we obtained a crystal of the product suitable
for X-ray crystallography and confirmed the structure of the
product to be 3a, that is, (2-(methylthio)-4,4,6-triphenyl-4
thiopyran-3-yl)(phenyl)methanone 3a (R = R1 = R2 = R3 = Ph). The
ORTEP view of the single crystal X-ray analysis of 3a with atomic
numbering is shown in Figure 1.18
In this study, we prepared a variety of b-oxodithioesters 1a–d
by a base mediated reaction of corresponding acetophenone with
dimethyltrithiocarbonate19 and obtained 1,1,3-trisubstituted
prop-2-yn-1-ols 2a–f by reacting the corresponding lithium aceta-
lide with a ketone.20 Next, we studied reactions of 1a–d with 2a–f
using BF3ꢀEt2O as the catalyst in dichloromethane to obtain the
corresponding polyfunctionalized 4H-thiopyrans 3a–t in 72–95%
yields as shown in Table 2.21
The plausible reaction pathway for the formation of 3 from the
Lewis acid (LA) catalyzed reaction of 1 and 2 is shown in Scheme 3.
In this mechanism, we believe that initially 3-oxodithiocarbonate 1
and propargyl alcohol 2 undergo Lewis acid assisted dehydration
reaction followed by intramolecular cyclization of the resulting
allenyl vinyl thioether and 3,5-H transfer to give a 4H-thiopyran 3.
In summary, we showed a new and efficient method for the
preparation of polyfunctionalized 4H-thiopyrans by highly
regioselective two-component cyclocondensation of b-oxodithio-
esters and 1,1,3-trisubstituted prop-2-yn-1-ols using BF3ꢀEt2O as
the catalyst.
Figure 1. ORTEP diagram of 3a. Displacement ellipsoids are drawn at the 25%
probability level and H atoms are shown as small spheres of arbitrary radius. (CCDC
986964).
Acknowledgments
Authors are thankful to CSIR, New Delhi for the financial sup-
port under the project CSC-0123 (Indus Magic); S.K. and V.S. are
thankful to UGC, New Delhi for the award of Junior Research Fel-
lowship. K.K.R.M. is thankful to CSIR, New Delhi for the award of
Senior Research Fellowship. V.S.V. is thankful to the Director, IICT
for the financial support.
Supplementary data
Supplementary data (experimental procedures, characteriza-
tion data, and 1H and 13C NMR spectra of the compounds 3a–t)
Table 1
Screening of acid catalysts for the preparation of 3a
Ph
Ph
Ph
HO
O
Ph
Ph
O
S
catalyst (20 mol%)
CH2Cl2, rt
Ph
MeS
+
S
3a
Ph
MeS
Ph
2a
1a
Entry
Catalyst
Time (h)
%Yielda
Entry
Catalyst
Time (h)
%Yielda
1
2
3
4
5
BF3ꢀOEt2
Zn(OTf)2
Bi(OTf)3
Sc(OTf)3
InBr3
1
12
12
12
12
95
60
47
64
26
6
7
8
9
10
ZnCl2
AlCl3
FeCl3
PTSA
12
12
12
12
12
37
44
40
55
CH3COOH
N.R.
a
Isolated yields.

4384
S. Madabhushi et al. / Tetrahedron Letters 55 (2014) 4382–4385
Table 2
Synthesis of polyfunctionalized 4H-thiopyrans
R2
R3
R1
HO
R2
R3
O
O
S
R1
BF3-Et2O (20mol%)
CH2Cl2, rt, 1-3h
+
R4
R4
MeS
S
MeS
1a-d
3a-t
2a-f
Entry
R1
R2
R3
R4
%Yielda of 3
Reaction time (h)
Mp (°C)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
Ph
Ph
Ph
Ph
Ph
Ph
4-ClPh
4-MeOPh
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
95
83
79
78
90
81
77
72
90
88
85
82
87
80
72
77
73
75
72
76
1.0
2.0
1.5
3.0
1.0
2.0
1.5
2.5
1.5
2.5
3.0
2.0
1.5
2.5
3.0
2.5
1.0
1.0
1.0
1.0
162–164
135–137
122–124
Liquid
216–218
113–115
Liquid
138–140
189–191
120–122
Liquid
Me
Me
Me
Ph
Me
Me
Me
Ph
Me
Me
Me
Ph
Me
Me
Me
Me
Me
Me
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
2-Thiophenyl
2-Thiophenyl
2-Thiophenyl
2-Thiophenyl
Ph
Ph
4-ClPh
4-MeOPh
Ph
Ph
4-ClPh
4-MeOPh
Ph
Liquid
142–143
102–104
Liquid
Liquid
Liquid
Liquid
Liquid
Liquid
Ph
4-ClPh
4-MeOPh
Ph
Ph
Me
Cyclopropyl
n-Hexyl
Ph
Ph
Ph
Ph
s
t
–CH2–(CH2)3–CH2–
Ph
All the products gave satisfactory 1H and 13C NMR, IR, and Mass spectral data.
a
Isolated yields.
4. Barthakur, M. G.; Chetia, A.; Boruah, C. R. Tetrahedron Lett. 2006, 47, 4925–
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69, 8013–8018.
R1
R2
HO
R3
2
LA
LA
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67, 584–589; (b) Devi, N. S.; Singh, S. J.; Devi, L. R.; Singh, O. M. Tetrahedron Lett.
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Chem. 2012, 5, 967–974; (c) Khan, A. T.; Ghosh, A.; Basha, S. R.; Mir, M. H. Asian
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R1
S
R1
S
R2
R3
R2
R3
R1
R2
R
R1
S
R
R
R
R2
O
H
H
H
H
S
O
O
O
O
-LA
-H2O
MeS
MeS
R3
MeS
MeS
1
R3
LA= Lewis acid
R
R1 R2
O
MeS
S
3
R3
Scheme 3. Plausible mechanism for the formation of 4H-thiopyrans.
17. Madabhushi, S.; Jillella, R.; Godala, K. R.; Mallu, K. K. R.; Beeram, C. R.;
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associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.06.013.
18. X-ray
data
for
3a:
C31H24OS2,
M = 476.62,
colorless
block,
0.26 ꢁ 0.21 ꢁ 0.14 mm3, orthorhombic, space group Pna21 (No. 33),
a = 12.0959(10), b = 21.3527(18), c = 9.6135(8) Å, V = 2483.0(4) Å3, Z = 4,
Dc = 1.275 g/cm3, F000 = 1000, CCD area detector, MoK
a
radiation,
References and notes
k = 0.71073 Å, T = 293(2)K, 2hmax = 50.0°, 23,090 reflections collected, 4368
unique (Rint = 0.0227), Final GooF = 1.078, R1 = 0.0318, wR2 = 0.0807, R indices
r
(I) (refinement on F2), 308 parameters,
1. (a) Lane, S.; Quick, S. J.; Taylor, R. K. J. Chem. Soc., Perkin Trans. 1 1984, 2549–
2552; (b) Ward, D. E. Chem. Commun. 2011, 11375–11393; (c) Ward, D. E.; Gai,
Y.; Lai, Y. Synlett 1996, 261–262; (c) Poleschner, H.; Seppelt, K. Eur. J. Org. Chem.
2001, 2477–2480; (d) Lucassen, A. C. B.; Zwanenburg, B. Eur. J. Org. Chem. 2004,
74–83; (e) Rosiak, A.; Frey, W.; Christoffers, J. Eur. J. Org. Chem. 2006, 4044–
4054.
2. (a) Tominaga, Y.; Okuda, H.; Kohra, S.; Mazume, H. J. Heterocycl. Chem. 1991, 28,
1245–1255; (b) Bell, A. S.; Fishwick, C. W. G.; Reed, J. E. Tetrahedron 1998, 54,
3219–3234; (c) Saito, T.; Takekawa, K.; Takahashi, T. Chem. Commun. 1999,
1001–1002.
based on 4263 reflections with I > 2
= 0.236 mmꢂ1. X-ray diffraction measurement was made on a Bruker Smart
Apex CCD diffractometer with graphite monochromated MoK radiation
(k = 0.71073 Å) with the -scan method. Preliminary lattice parameters and
l
a
x
orientation matrices were obtained from four sets of frames. Unit cell
dimensions were determined using 5482 reflections for AU49 data.
Integration and scaling of intensity data were accomplished using SAINT
program. The structure was solved by Direct Methods using SHELXS972 and
refinement was carried out by full-matrix least-squares technique using
SHELXL97.2 Anisotropic displacement parameters were included for all non-
hydrogen atoms. All H atoms were positioned geometrically and treated as
riding on their parent C atoms, with C–H distances of 0.93–0.97 Å, and with
3. Yoshimura, Y.; Yamazaki, Y.; Kawabata, M.; Yamaguchi, K.; Takahataa, H.
Tetrahedron Lett. 2007, 48, 4519–4522.

S. Madabhushi et al. / Tetrahedron Letters 55 (2014) 4382–4385
4385
Uiso(H) = 1.2 Ueq (C) or 1.5 Ueq for methyl atoms. The crystallographic
information file has been deposited with the Cambridge Crystallographic
Data Centre, CCDC 986964
solvent was removed and the crude product was purified by normal column
chromatography (silica gel 60–120 mesh, ethyl acetate/hexane = 1:20) to obtain
2-(methylthio)-4,4,6-triphenyl-4H-thiopyran-3-yl)(phenyl)methanone 3a, as a
white solid (1.10 g, 95%, mp 162–164 °C) which was characterized by the
following spectral data: 1H NMR (300 MHz, CDCl3): d = 7.65–7.61 (m, 4H), 7.41–
19. Nandi, G. C.; Samai, S.; Singh, M. S. J. Org. Chem. 2010, 75, 7785–7795.
20. Hashmi, A. S. K.; Wang, T.; Shi, S.; Rudolph, M. J. Org. Chem. 2012, 77, 7761–
7767.
7.36 (m, 4H), 7.29–7.25 (m, 6H), 7.17–7.08 (m, 6H), 6.73 (s, 1H), 2.28 (s, 3H); 13
C
21. Typical procedure for the synthesis of 4H-thiopyrans 3a–t: Methyl 3-oxo-3-
phenylpropanedithioate 1a (500 mg, 2.38 mmol), 1,1,3-triphenylprop-2-yn-1-ol
2a, (812 mg, 2.85 mmol) and 5 ml dichloromethane were taken in a 50 ml round
bottom flask and to this mixture, BF3ꢀOEt2 (0.053 ml, 0.4 mmol) was added and
stirred at room temperature for 1 h. After completion of the reaction (TLC),
NMR (75 MHz, CDCl3): d = 194.8, 144.2, 137.3, 136.9, 136.8, 134.7, 132.9, 132.5,
129.3, 128.9, 128.8, 128.6, 128.2, 127.8, 127.6, 126.7, 126.6, 57.8, 18.1 ; IR (KBr):
m
3053, 2920, 1648, 1594, 1545, 1490, 1260, 750, 693 cmꢂ1; MS (ESI) 477 (M+H).
ESI-HRMS obtained for C31H25OS2 (M+H) = 477.1332 (calculated: 477.1341).