Regioselective dehydrative intramolecular heteroannulation of β-allyl-β-hydroxy dithioesters: Facile and straightforward entry to 2H-thiopyrans

Article abstract of DOI:10.1016/j.tet.2013.12.020

β-Allyl-β-hydroxy dithioesters have been employed in the synthesis of hitherto unreported and synthetically demanding 2H-thiopyrans via regioselective intramolecular annulation strategy. Lewis acid BF ₃·Et₂O efficiently mediates the

Full text of DOI:10.1016/j.tet.2013.12.020

Tetrahedron 70 (2014) 914e918
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regioselective dehydrative intramolecular heteroannulation of
b-allyl-b-hydroxy dithioesters: facile and straightforward entry
to 2H-thiopyrans
Sushobhan Chowdhury a, Tanmoy Chanda a, Suvajit Koley a, B. Janaki Ramulu a,
,
Keshav Raghuvanshi b, Maya Shankar Singh a
*
a Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi 221005, India
b
€
€
Institut fuer Organische und Biomolekulare Chemie, Georg-August-Universitat Gottingen, Tammannstr. 2, 37077 Goettingen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
b
-Allyl-b-hydroxy dithioesters have been employed in the synthesis of hitherto unreported and syn-
Received 11 November 2013
Received in revised form 2 December 2013
Accepted 8 December 2013
Available online 12 December 2013
thetically demanding 2H-thiopyrans via regioselective intramolecular annulation strategy. Lewis acid
BF3$Et2O efficiently mediates the regioselective dehydration followed by intramolecular thioannulation
at room temperature. The attractive features of this protocol include mild conditions, high atom-
economy and excellent yields with the elimination of water as the only by-product.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
b-Allyl-b-hydroxy dithioesters
BF3$Et2O
Regioselective dehydration
Intramolecular thioannulation
Thiopyrans
1. Introduction
DielseAlder cycloaddition of different functionalized dienes with
activated dienophiles,14 the coupling reaction of benzoyl(acetyl)
Thiopyrans and their derivatives are important privileged
structural motifs present not only in several natural products and
biologically active molecules,1,2 but also frequently utilized as
synthetic blocks in organic synthesis.3 They have been utilized in
the construction of analogues of natural products, such as tetra-
hydrodicranenone B,4 serricornin,5 thromboxanes,6 and cyclo-
pentanoids.7 More specifically, compounds containing the
thiopyran substructure find application in a wide variety of ther-
apeutical areas, which includes antibacterial,8 antihyperplasic,9
antipsychiatric,10 and anticancer activities.11,12 Thiopyran de-
rivatives have also been shown to be powerful inhibitors of deox-
yribonucleic acid protein kinase.13 For these reasons, the
development of new methodologies for the regioselective synthesis
of functionalized thiopyrans continues to be an active area of re-
search in fine chemistry.
thioacetamides with a,b
-unsaturated aldehydes,15 (3,5)-thionium-
ene cyclization reaction of aldehydes and substituted 5-methylhex-
4-ene-1-thiol,16 and metathesis of sulfur containing alkenes.17
Although some multicomponent approaches for the synthesis of
thiopyrans have been developed,18,19 regioselective control of the
functionalization of thiopyran is still the main concern. Fused thi-
opyran skeletons have been achieved via intramolecular hydro-
arylation with arene-yne substrates20 and [4þ2]-cycloaddition of
active methylene compounds with N,N-dimethylformamide di-
methyl acetals.21 Albeit the reported protocols are useful tools for
the construction of thiopyran frameworks, most of them suffer
from significant limitations, such as harsh reaction conditions, poor
yields, limited functional group tolerability and production of
hazardous wastes. Therefore, a robust, practical, efficient, viable
and regioselective method for the synthesis of thiopyrans with
broad scope is highly desirable, and would be of great relevance to
both synthetic and medicinal chemists.
Among several elegant approaches reported in the literature to
synthesize thiopyrans, the major routes typically involve the
Present era of organic synthesis is mainly themed on the design
and development of practical cascades that provide maximum
structural intricacy with economies of step, atom, cost and waste
generation. It is pertinent to mention that the rich and fascinating
* Corresponding author. Tel.: þ91 542 6702502; fax: þ91 542 2368127; e-mail
addresses: mssinghbhu@yahoo.co.in, mayashankarbhu@gmail.com (M.S. Singh).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.12.020

S. Chowdhury et al. / Tetrahedron 70 (2014) 914e918
915
chemistry that stems from one-pot annulation strategy, where
several bonds are formed and/or cleaved provides a robust ap-
proach for the construction of diverse molecules. In this context,
intramolecular annulations are coming up with great success. Im-
portantly, the selection of synthons to design such transformations
is highly crucial that governs the success of a protocol. In our recent
hydroxy dithioester containing five reactive sites may undergo
intramolecular heteroannulation to give thiopyran. So far, to the
best of our knowledge, there is no report on the synthesis of thio-
pyrans from
dehydrative heteroannulation strategy. Therefore, we set out to
explore the feasibility of -allyl- -hydroxy dithioesters 1 as reactive
b-allyl-b-hydroxy dithioester through intramolecular
b
b
report,22 we have utilized
b-allyl-
b
-hydroxy dithioesters to gener-
synthon to access thiopyrans 2 (Scheme 2).
ate some valuable synthetic residues, which can be further
employed in different synthetic transformations. In this context, we
report herein a new method for the regioselective synthesis of 2H-
thiopyrans from b-allyl-b-hydroxy dithioesters through a cascade
dehydrative intramolecular annulation sequence.
2. Results and discussion
Scheme 2. Synthesis of thiopyrans 2.
Chemical species containing both electrophilic and nucleophilic
sites have great potential in developing new reaction pathways and
diverse molecular entities. One such simple polyfunctional chem-
We began our studies by using methyl 3-hydroxy-3-(p-tolyl)
hex-5-enedithioate 1c as test substrate. The solution of 1c
(1.0 mmol in 5 mL of dry chloroform) was treated with 1.0 equiv of
BF3$Et2O followed by stirring at room temperature for 15 h till the
completion of the reaction (monitored by TLC). To our delight, work
up of the reaction afforded the desired compound 2c in 85% yield,
characterized as 2-methyl-6-methylsulfanyl-4-p-tolyl-2H-thio-
pyran (Table 1, entry 1). Encouraged by the above result and further
motivated by the importance of thiopyrans in natural products and
medicinal chemistry, we set out to investigate this reaction in de-
tail. To channel the reaction towards the formation of 2c, we carried
out a systematic survey of the reaction conditions by varying the
catalysts, the solvent and the temperature. The results of various
attempts are summarized in Table 1.
ical species is
structure 1 (Fig. 1).
b-allyl-b-hydroxy dithioester with the general
Table 1
Optimization of reaction conditionsa
Fig. 1. Reactive sites of b-allyl-b-hydroxy dithioester 1.
Due to the presence of several reactive sites, such as hydroxyl,
allyl, active methylene and dithioester groups, -allyl- -hydroxy
b
b
dithioesters 1 can be exploited in a regioselective manner to con-
struct five-/six-member and fused heterocycles depending on the
Entry Catalyst
Loading Solvent
(equiv)
Temp (ꢀC) Time (h) Yieldb (%)
reaction conditions. The
commercially sourced, and were synthesized from the corre-
sponding -oxodithioesters in good yields by the regioselective
Grignard addition22,23 (Scheme 1).
The synthetic utility of -oxodithioesters has already been ex-
tensively explored by our group.24 Consequently, as part of our
continuing efforts to explore the chemical features of -allylated
derivatives of -oxodithioesters, we hypothesized that -allyl-
b-allyl-b-hydroxy dithioesters 1 are not
1
2
3
4
5
6
7
8
BF3$Et2O
BF3$Et2O
BF3$Et2O
BF3$Et2O
BF3$Et2O
BF3$Et2O
BF3$Et2O
InCl3
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.2
0.2
0.2
0.2
0.2
0.5
1.5
d
CHCl3
CHCl3
CHCl3
DCE
DCM
CH3CN
THF
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
rt
40
60
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
15
14
12
15
15
48
48
48
48
48
48
48
15
15
48
85
82
75
80
92
dc
dc
dc
dc
dc
dc
dc
71
84
dc
b
b
b
b
b
b-
9
Y(OTf)3
DMAP
DBU
Piperidine
BF3$Et2O
BF3$Et2O
d
10
11
12
13
14
15
The bold entry highlights the optimized condition.
a
Reaction of adduct 1c (1.0 mmol) under various conditions.
Isolated pure yields.
No formation of desired product.
b
c
The above model reaction was investigated at higher tempera-
tures, and the results showed no improvement (Table 1, entries 2
and 3). To determine the ideal solvent for the transformation, we
investigated the above reaction in various other solvents, such as
dichloroethane (DCE), dichloromethane (DCM), CH3CN and THF
Scheme 1. Regioselective synthesis of 1.

916
S. Chowdhury et al. / Tetrahedron 70 (2014) 914e918
(Table 1, entries 4e7). DCM turned out to be an appropriate solvent
affording the best isolated yield (92%) at room temperature. Next,
other Lewis acids, such as InCl3 and Y(OTf)3, and bases like DMAP,
DBU and piperidine were employed as the catalyst, but none of
them could trigger the reaction to the desired direction (Table 1,
entries 8e12). Next, we optimized the catalyst’s loading, and it was
found that either decreasing or increasing the catalyst’s loading did
not improve the result (Table 1, entries 13 and 14). Further, the
blank reaction did not give the desired product in trace even after
48 h (Table 1, entry 15). Ultimately, optimal conditions were iden-
tified as 1.0 equiv of BF3$Et2O in DCM at room temperature (Table 1,
entry 5).
2j and 2k in 90% and 88% yields, respectively. Further, to broaden
the scope of the reaction, -allyl- -hydroxy dithioesters derived
from the dithioesters of cyclohexanone and -tetralones were also
employed in this protocol. To our pleasure, fused thiopyrans 2len
were obtained in 80e84% yields. These results further illustrate the
generality and practical applicability of this novel strategy.
b
b
a
To rationalize the reaction outcomes, we proposed a tentative
mechanism as shown in Scheme 3. The initial step includes the
BF3$Et2O mediated regioselective dehydration to give the conju-
gated diene intermediate I by the removal of a
0-proton of 1.25 In-
termediate I may undergo cyclization by the attack of thiocarbonyl
sulfur to the terminal and non-terminal double bonds activated by
BF3$Et2O via two possible modes a and b to produce thiopyran 2
and dihydrothiophene 3, respectively. Consequently, intermediate I
undergoes regioselective attack of thiocarbonyl sulfur to its ter-
minal double bond through mode a to give the desired thiopyran 2.
During our investigation we did not observe even a trace of 3, and 2
was obtained exclusively. In the total course of the reaction
BF3$Et2O plays a dual role by abstracting the OH for the removal of
water (which probably cause the destruction of the catalyst to some
extent) as well as activating the double bond and hence accounts
for its use in equimolar ratio.
Using the optimized reaction conditions, we evaluated the
substrate scope of the reaction and the results are summarized in
Table 2. As can be seen, a wide range of
b-allyl-b-hydroxy
dithioesters regardless of their electronic and steric nature were
well-tolerated, and in all cases the reactions proceeded smoothly to
afford the corresponding thiopyrans in good to excellent yields.
Notably,
b-allyl-b-hydroxy dithioesters 1 with either mono-
substituted electron-donating or electron-withdrawing groups at
various positions on the aryl ring of substituent R1 showed almost
similar reactivities and reacted efficiently to provide the desired
thiopyrans 2aei in 85e92% yields. Even substrate 1 with R1 as
heteroaromatic substituents like 2-thienyl and 2-furyl took part in
the reaction smoothly and afforded the corresponding thiopyrans
Table 2
Substrate scope for the synthesis of 2
2, time(h), yield(%)
Scheme 3. Possible reaction mechanism.
To gain insight into the reaction mechanism, we treated our
previously isolated diene product 1j022 with BF3$Et2O in DCM at
room temperature. To our delight, the diene has been quantitatively
converted into our desired product 2j within 12 h (observed by
checking TLC pattern of the corresponding compounds) suggesting
the intermediacy of I (Scheme 4).
Scheme 4. Experimental proof of the dehydration.
3. Conclusions
In summary, we have developed an operationally simple and
straightforward protocol for the synthesis of 2H-thiopyrans
through regioselective intramolecular annulation of
b-allyl-b-hy-
droxy dithioesters mediated by BF3$Et2O at room temperature.

S. Chowdhury et al. / Tetrahedron 70 (2014) 914e918
917
Reasonable mechanistic detail for the proposed intermediate in-
volved in the annulation strategy is provided with experimental
and literature evidences. We hope that the newly synthesized
thiopyrans may act as precursors for further synthetic renovations
to meet the need for diverse useful purposes. Overall, this clean and
efficient protocol may be of value for both synthetic and medicinal
chemists for academic research and practical applications.
d ppm): 137.4, 137.3, 137.2, 134.3, 129.0, 126.1, 119.8, 117.3, 36.7, 21.0,
19.6, 17.9; IR (KBr, nmax, cmꢁ1): 2920,1513,1446, 1019, 816, 796, 528.
4.2.4. 4-(4-Chlorophenyl)-2-methyl-6-methylsulfanyl-2H-thiopyran
(2d). Beige oil. 1H NMR (300 MHz, CDCl3,
d ppm): 7.28 (br, 4H, Ar),
6.47 (s, 1H), 5.66 (d, J¼6.0 Hz, 1H), 3.71e3.67 (m, 1H), 2.49 (s, 3H,
SCH3), 1.41 (d, J¼6.9 Hz, 3H, Me); 13C NMR (75.5 MHz, CDCl3,
d
ppm): 138.6,136.6,135.3,133.3, 128.5,127.6,119.0,118.1, 36.6,19.4,
17.9; IR (KBr, nmax, cmꢁ1): 2923, 2853, 1491, 1092, 1013, 831, 799.
4. Experimental section
4.1. General method
4.2.5. 4-(3-Chlorophenyl)-6-ethylsulfanyl-2-methyl-2H-thiopyran
(2e). Beige oil. 1H NMR (300 MHz, CDCl3,
d ppm): 7.32 (s, 1H, Ar),
7.23 (d, J¼2.7 Hz, 3H, Ar), 6.63 (s, 1H), 5.71 (d, J¼5.7 Hz, 1H),
3.71e3.62 (m, 1H), 3.03e2.83 (m, 2H, CH2 of SEt), 1.40 (d, J¼6.9 Hz,
3H, Me), 1.31 (t, J¼7.3 Hz, 3H, CH3 of SEt); 13C NMR (75.5 MHz,
The commercially available allyl magnesium bromide and bor-
ontrifluoride diethyletherate (BF3$Et2O) were used as received
without any further purification. b-Oxodithioesters were prepared
CDCl3,
d ppm): 141.8, 136.6, 134.2, 133.4, 129.5, 127.4, 126.4, 124.4,
following the literature procedure.26 Thin-layer chromatography
(TLC) was performed using silica gel 60 F254 precoated plates.
Column chromatography was performed with 100e200 mesh silica
122.0, 119.0, 36.5, 29.2, 19.5, 14.7; IR (KBr, nmax, cmꢁ1): 2969, 2925,
2867, 1475, 1447, 781, 694; MS: HRMS: m/z¼282.0304 (Mþ). Found:
283.0317 (Mþþ1).
gel. Infrared (IR) spectra are measured in KBr, and wavelengths (
are reported in cmꢁ1 1H and 13C NMR spectra were recorded on
NMR spectrometers operating at 300 and 75.5 MHz, respectively.
Chemical shifts ( ) are given in parts per million (ppm) using the
n)
.
4.2.6. 4-(2-Chlorophenyl)-2-methyl-6-methylsulfanyl-2H-thiopyran
(2f). Beige oil. 1H NMR (300 MHz, CDCl3,
d ppm): 7.38e7.21 (m, 4H,
d
Ar), 6.29 (s,1H), 5.51 (d, J¼5.7 Hz,1H), 3.73e3.66 (m,1H), 2.44 (s, 3H,
residue solvent peaks as reference relative to TMS. Coupling con-
stant (J) values are given in Hertz. Mass spectra were recorded using
electrospray ionization (ESI) mass spectrometry. The melting points
are uncorrected.
SCH3),1.43 (d, J¼6.9 Hz, 3H, Me); 13C NMR (75.5 MHz, CDCl3,
d ppm):
139.7, 136.6, 132.7, 130.5, 129.7, 128.6, 126.6, 120.8, 120.1, 36.3, 19.6,
17.7; IR (KBr, nmax, cmꢁ1): 2968, 2921, 2854, 1470, 1432, 1036, 757.
4.2.7. 4-(3-Bromophenyl)-2-methyl-6-(methylthio)-2H-thiopyran
4.2. General procedure for the synthesis of 2-methyl-2H-thi-
opyrans (2aen)
(2g). Beige oil. 1H NMR (300 MHz, CDCl3,
d
ppm): 7.48 (d, J¼12.0 Hz,
1H, Ar), 7.40 (d, J¼7.8 Hz, 1H, Ar), 7.29e7.17 (m, 2H, Ar), 6.47 (s, 1H),
5.68 (d, J¼5.7 Hz, 1H), 3.74e3.65 (m, 1H), 2.50 (s, 3H, SCH3), 1.41 (d,
A solution of
b
-allyl-b-hydroxy dithioesters 1 (1.0 mmol) in dry
J¼7.2 Hz, 3H, CH3); 13C NMR (75.5 MHz, CDCl3,
d ppm): 142.5, 138.2,
dichloromethane (10 mL) was degassed for 15 min by continuous
purging of ultrapure argon. Then BF3$Et2O (1.0 equiv) was added
and the mixture was stirred at room temperature for the stipulated
period of time. After completion of the reaction (monitored by TLC),
20 mL of water was added to the reaction mixture followed by
extraction with chloroform (2ꢂ10 mL). The combined organic ex-
tract was dried over anhydrous Na2SO4 and then evaporated in
vacuo. The crude residue thus obtained was purified by column
chromatography over silica gel using increasing amounts of ethyl
acetate in n-hexane as eluent to afford the pure 2-methyl-2H-thi-
opyrans 2.
130.5, 129.9,129.5, 129.3, 125.0, 119.5, 119.2, 118.9, 36.7, 19.5, 18.0; IR
(KBr, nmax, cmꢁ1): 2961, 2922, 2854, 1473, 1072, 780, 693; MS:
HRMS: m/z¼311.9642 (Mþ). Found: 312.9649 (Mþþ1).
4.2.8. 4-(4-Bromophenyl)-6-butylsulfanyl-2-methyl-2H-thiopyran
(2h). Beige oil. 1H NMR (300 MHz, CDCl3,
d
ppm): 7.42 (d, J¼8.4 Hz,
2H, Ar), 7.20 (d, J¼8.4 Hz, 2H, Ar), 6.62 (s, 1H), 5.69 (d, J¼6.0 Hz, 1H),
3.70e3.61 (m,1H), 2.99e2.81 (m, 2H, CH2 of Bu),1.66 (t, J¼7.2 Hz, 2H,
CH2 of Bu),1.41e1.39 (m, 5H, CH3 and CH2 of Bu), 0.89 (t, J¼6.9 Hz, 3H,
CH3 of Bu); 13C NMR (75.5 MHz, CDCl3,
d ppm): 139.0, 136.8, 133.8,
131.4,127.9,121.9,121.5,118.4, 36.6, 35.0, 30.6, 22.2,19.5,13.9; IR (KBr,
nmax, cmꢁ1): 2962, 2923, 1445, 1371, 1128, 1016, 813, 748, 477; MS:
HRMS: m/z¼354.0212 (Mþ). Found: 355.0229 (Mþþ1).
4.2.1. 2-Methyl-6-methylsulfanyl-4-phenyl-2H-thiopyran
(2a). Beige oil. 1H NMR (300 MHz, CDCl3,
d ppm): 7.37e7.27 (m, 5H,
Ar), 6.55 (s, 1H), 5.69 (d, J¼6.0 Hz, 1H), 3.75e3.66 (m, 1H), 2.49 (s,
4.2.9. 6-Isobutylsulfanyl-2-methyl-4-(4-trifluoromethyl-phenyl)-2H-
3H, SCH3), 1.42 (d, J¼6.9 Hz, 3H, Me); 13C NMR (75.5 MHz, CDCl3,
thiopyran (2i). Beige oil. 1H NMR (300 MHz, CDCl3,
d ppm): 7.58 (d,
d
ppm): 140.2, 137.7, 134.5, 128.4, 127.5, 126.3, 119.7, 118.0, 36.7, 19.5,
J¼8.4 Hz, 2H, Ar), 7.45 (d, J¼8.1 Hz, 2H, Ar), 6.65 (s, 1H), 5.76 (d,
18.0; IR (KBr, nmax, cmꢁ1): 2965, 2922, 2857, 1494, 1445, 757, 698;
J¼5.7 Hz, 1H), 3.72e3.67 (m, 1H), 2.91e2.75 (m, 2H, CH2 of Bu),
i
MS: HRMS: m/z¼234.0637 (Mþ). Found: 234.0620 (Mþ).
1.93e1.87 (m, 1H, CH of Bu), 1.42 (d, J¼6.9 Hz, 3H, Me), 1.03 (d,
i
i
J¼6.6 Hz, 6H, 2CH3 of Bu); 13C NMR (75.5 MHz, CDCl3,
d ppm):
4.2.2. 6-Benzylsulfanyl-2-methyl-4-phenyl-2H-thiopyran
143.7, 136.9, 134.8, 129.7, 126.6, 125.4, 125.3, 121.4, 118.7, 43.9, 36.6,
28.9, 21.8, 21.7, 19.5; IR (KBr, nmax, cmꢁ1): 2961, 2928, 1325, 1167,
1127, 1069; MS: HRMS: m/z¼344.0880 (Mþ). Found: 345.0899
(Mþþ1).
(2b). Beige oil. 1H NMR (300 MHz, CDCl3,
d ppm): 7.36e7.22 (m,
10H, Ar), 6.62 (s, 1H), 5.69 (d, J¼6.0 Hz, 1H), 4.13 (s, 2H, CH2Ph),
3.66e3.62 (m, 1H), 1.36 (d, J¼6.9 Hz, 3H, Me); 13C NMR (75.5 MHz,
CDCl3,
d ppm): 139.7, 137.6, 137.3, 132.0, 128.7, 128.3, 128.2, 127.4,
127.0, 126.1, 123.8, 118.6, 39.8, 36.7, 19.6; IR (KBr, nmax, cmꢁ1): 2956,
2926, 2856, 1488, 1073, 1009, 800; MS: HRMS: m/z¼310.0850 (Mþ).
Found: 311.0876 (Mþþ1).
4.2.10. 2-Methyl-6-methylsulfanyl-4-thiophen-2-yl-2H-thiopyran
(2j). Beige oil. 1H NMR (300 MHz, CDCl3,
d
ppm): 7.16 (d, J¼4.8 Hz,
1H, Ar), 7.05 (s,1H, Ar), 6.97 (t, J¼4.2 Hz,1H, Ar), 6.58 (s,1H), 5.81 (d,
J¼6.0 Hz, 1H), 3.73e3.64 (m, 1H), 2.50 (s, 3H, SCH3), 1.41 (d,
4.2.3. 2-Methyl-6-methylsulfanyl-4-p-tolyl-2H-thiopyran
J¼7.8 Hz, 3H, Me); 13C NMR (75.5 MHz, CDCl3,
d ppm): 135.5, 129.3,
(2c). Beige oil. 1H NMR (300 MHz, CDCl3,
d
ppm): 7.25 (d, J¼7.8 Hz,
127.4, 125.6, 124.1, 123.0, 118.4, 116.4, 36.6, 19.4, 17.9.
2H, Ar), 7.13 (d, J¼7.8 Hz, 2H, Ar), 6.54 (s, 1H), 5.66 (d, J¼5.7 Hz, 1H),
3.74e3.65 (m, 1H), 2.49 (s, 3H, SCH3), 2.34 (s, 3H, CH3 attached
to aryl ring), 1.41 (d, J¼7.2 Hz, 3H, Me); 13C NMR (75.5 MHz, CDCl3,
4.2.11. 2-Methyl-6-methylsulfanyl-4-furan-2-yl-2H-thiopyran
(2k). Beige oil. 1H NMR (300 MHz, CDCl3,
d ppm): 7.35 (br, 1H, Ar),

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S. Chowdhury et al. / Tetrahedron 70 (2014) 914e918
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3.72e3.68 (m, 1H), 2.49 (s, 3H, SMe),1.41 (d, J¼3.9 Hz, 3H); 13C NMR
(75.5 MHz, CDCl3,
d ppm): 141.8, 140.4, 134.4, 120.0, 116.4, 114.9,
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2001, 5, 80.
111.1, 105.3, 36.1, 19.6, 17.9.
4.2.12. 3-Methyl-1-(methylthio)-5,6,7,8-tetrahydro-3H-isothio chro-
mene (2l). Beige coloured viscous liquid. (Diastereomeric mixture)
1H NMR (300 MHz, CDCl3,
d
ppm): 5.96 (d, J¼6.0 Hz, 1H), 3.72e3.68
(m, 1H), 2.49 (s, 3H, SMe), 2.17 (br, 8H), 1.41 (d, J¼3.9 Hz, 3H); 13C
NMR (75.5 MHz, CDCl3,
d ppm): 137.2, (131.6, 131.1), (126.8, 126.7),
122.3, 41.2, 37.0, 28.5, 25.9, (23.2, 22.6), (20.0, 19.9), (17.3, 17.2).
4. (a) Casy, G.; Taylor, R. J. K. Tetrahedron 1989, 45, 455; (b) Casy, G.; Taylor, R. J. K. J.
Chem. Soc., Chem. Commun. 1988, 454.
4.2.13. 2-Methyl-4-(methylthio)-5,6-dihydro-2H-benzo[f]isothio
5. Ward, D. E.; Jheengut, V.; Beye, G. E. J. Org. Chem. 2006, 71, 8989.
6. (a) McDonald, B. P.; Steele, R. W.; Sutherland, J. K.; Leslie, B. W.; Brewster, A. J.
Chem. Soc., Perkin Trans. 1 1988, 675; (b) Casy, G.; Lane, S.; Taylor, R. J. K. J. Chem.
Soc., Perkin Trans. 1 1986, 1397.
7. McAllister, G. D.; Taylor, R. J. K. Tetrahedron Lett. 2001, 42, 1197.
8. Brown, M. J.; Carter, P. S.; Fenwick, A. S.; Fosberry, A. P.; Hamprecht, D. W.;
Hibbs, M. J.; Jarvest, R. L.; Mensah, L.; Milner, P. H.; O’Hanlon, P. J.; Pope, A. J.;
Richardson, C. M.; West, A.; Witty, D. R. Bioorg. Med. Chem. Lett. 2002, 12, 3171.
9. Quaglia, W.; Pigini, M.; Piergentili, A.; Giannella, M.; Gentili, F.; Marucci, G.;
Carrieri, A.; Carotti, A.; Poggesi, E.; Leonardi, A.; Melchiorre, C. J. J. Med. Chem.
2002, 45, 1633.
10. Van Vliet, L. A.; Rodenhuis, N.; Dijkstra, D.; Wikstrom, H.; Pugsley, T. A.; Serpa,
K. A.; Meltzer, L. T.; Heffner, T. G.; Wise, L. D.; Lajiness, M. E.; Huff, R. M.;
Svensson, K.; Sundell, S.; Lundmark, M. J. Med. Chem. 2000, 43, 2871.
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cancer Res. 2001, 21, 2629.
chromene (2m). Beige coloured viscous liquid. (Diastereomeric
mixture) 1H NMR (300 MHz, CDCl3,
d
ppm): 7.52 (t, J¼2.7 Hz, 1H,
Ar), 7.24e7.12 (m, 3H, Ar), 6.99 (d, J¼5.7 Hz, 1H), 3.62e3.57 (m, 1H),
2.87e2.68 (m, 4H), 2.45 (s, 3H, SMe), 1.39 (dd, J¼3.0, 1.5 Hz, 3H); 13
C
NMR (75.5 MHz, CDCl3,
d ppm): 137.4, 134.8, 134.7, 132.1, (127.7,
127.5), (127.1, 127.0), (126.6, 126.4), 124.2, (123.6, 123.5), (118.4,
118.1), (35.1, 34.9), 29.6, 27.2, (19.7, 19.6), (19.0, 18.8); HRMS: m/
z¼260.0693 (Mþ). Found: 260.0641 (Mþ).
4.2.14. 7-Methoxy-2-methyl-4-(methylthio)-5,6-dihydro-2H-benzo
[f]isothiochromene (2n). Beige coloured viscous liquid. (Di-
astereomeric mixture) 1H NMR (300 MHz, CDCl3,
d ppm): 7.24e7.11
(m, 2H, Ar), 6.74 (d, J¼6.0 Hz, 1H, Ar), 6.00 (d, J¼6.0 Hz, 1H), 3.82 (s,
13. Hollick, J. J.; Golding, B. T.; Hardcastle, I. R.; Martin, N.; Richardson, C.; Rigoreau,
L. J.; Smith, G. C.; Griffin, R. J. Bioorg. Med. Chem. Lett. 2003, 13, 3083.
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Fishwick, C.W. G.;Reed, J. E.Tetrahedron 1998, 54, 3219;(d)Dentel, H.;Chataigner, I.;
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2007, 4948.
3H, OMe), 3.61e3.54 (m, 1H), 2.88e2.66 (m, 4H), 2.44 (s, 3H, SMe),
1.39 (d, J¼3.9 Hz, 3H); 13C NMR (75.5 MHz, CDCl3,
d ppm): 156.1,
135.9, 134.7, 132.4, 126.6, 126.2, 123.9, (118.6, 118.5), 116.1, 108.8,
(55.5, 55.4), 35.1, 26.7, 21.5, 19.6, 19.0.
15. Jagodzinski, T. S.; Sosnicki, J. G.; Wesolowska, A. Tetrahedron 2003, 59, 4183.
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(b) Rostami-Charati, F. Synlett 2013, 2137.
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M. S. Tetrahedron 2013, 69, 8013.
Acknowledgements
We gratefully acknowledge the generous financial support
from SERB, the Department of Science and Technology (Grant No.
SR/S1/OC-66/2009), the Council of Scientific and Industrial Re-
search (Grant No. 02(0072)/12/EMR-II), and the UGC-UKIERI
Partnership-2013 (Grant No. 184-16/2013(IC), New Delhi). We are
thankful to Prof. Ganesh Pandey, CBMR, SGPGI, Lucknow and Prof.
Manas Ghorai, IIT Kanpur for their help in recording of HRMS
spectra.
20. Kenny, R. S.; Mashelkar, U. C.; Rane, D. M.; Bezawada, D. K. Tetrahedron 2006,
62, 9280.
21. Gabbutt, C. D.; Hepworth, J. D.; Heron, B. M. J. Chem. Soc., Perkin Trans. 1 1992,
2603.
22. Chowdhury, S.; Chanda, T.; Nandi, G. C.; Koley, S.; Ramulu, B. J.; Pandey, S. K.;
Singh, M. S. Tetrahedron 2013, 69, 8899.
Supplementary data
23. Masson, S.; Thuillier, A. Tetrahedron Lett. 1982, 23, 4087.
24. Recent papers on dithioesters: (a) Nandi, G. C.; Samai, S.; Singh, M. S. J. Org.
Chem. 2010, 75, 7785; (b) Nandi, G. C.; Samai, S.; Singh, M. S. J. Org. Chem. 2011,
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13, 3762; (d) Nandi, G. C.; Singh, M. S.; Ila, H.; Junjappa, H. Eur. J. Org. Chem.
2012, 967; (e) Verma, R. K.; Verma, G. K.; Raghuvanshi, K.; Singh, M. S. Tetra-
hedron 2011, 67, 584; (f) Verma, G. K.; Verma, R. K.; Singh, M. S. RSC Adv. 2013, 3,
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vastava, A.; Raghuvanshi, K. Green Chem. 2013, 15, 954; (h) Ramulu, B. J.;
Chanda, T.; Chowdhury, S.; Nandi, G. C.; Singh, M. S. RSC Adv. 2013, 3, 5345; (i)
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Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.12.020.
References and notes
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