Synthesis of Dihydrothiophenes and Thiophenes by the Strategic Use of 2-Vinylidene-1,3-dithiolane as a Masked Thiolate Anion

Article abstract of DOI:10.1002/ejoc.201301624

Differently substituted 4-(1,3-dithiolan-2-ylidene)but-1-ynes were conveniently converted into the corresponding thiophenes and dihydrothiophenes in good to high yields under mild conditions. 1,3-Dithiolan-2-ylidene acted as a masked thiolate anion and un

Full text of DOI:10.1002/ejoc.201301624

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301624
Synthesis of Dihydrothiophenes and Thiophenes by the Strategic Use of
2-Vinylidene-1,3-dithiolane as a Masked Thiolate Anion
Zhongxue Fang,[a] Peiqiu Liao,[a] Zonglian Yang,[a] Yeming Wang,[b] Biying Zhou,[a]
Yang Yang,[a] and Xihe Bi*[a,c]
Keywords: Sulfur heterocycles / Annulation / Ketenes / Dithioacetals / Fragmentation
Differently substituted 4-(1,3-dithiolan-2-ylidene)but-1-ynes
were conveniently converted into the corresponding thio-
phenes and dihydrothiophenes in good to high yields under
mild conditions. 1,3-Dithiolan-2-ylidene acted as a masked
thiolate anion and underwent tandem fragmentation and 5-
exo-dig annulation with an alkyne moiety to form the five-
membered sulfur heterocycles.
cyclic ketene dithioacetals as a masked thiolate anion[6] in
their novel cyclization for the synthesis of 2,3-dihydrothio-
pyran-4-ones (Figure 1a). Following this seminal work, Liu
and co-workers applied this strategy for the synthesis of a
variety of thiophen-3(2H)-ones, but the reaction proceeded
through unprecedented intramolecular thio-anti-Michael
addition to enones.[7] This strategy is extremely attractive,
because the 1,3-dithiolan-2-ylidene group can be easily pre-
pared and attached to a molecule containing a carbon–car-
bon unsaturated moiety by several processes including cou-
pling and condensation reactions.[8] However, whereas all
these reports are limited to the thioaddition to a C=C bond,
the addition to a CϵC bond by this strategy is yet to be
reported. With our continued interest in the development
of novel carbo- and heterocyclization reactions,[9] we herein
wish to report a novel transannulation reaction of readily
available 4-(1,3-dithiolan-2-ylidene)but-1-yne to afford a
variety of thiophenes and dihydrothiophenes in good to
high yields (Figure 1b). The key ring-closing step involves
the regioselective 5-exo-dig annulation of the in situ gener-
ated thiolate anion with the alkyne group.
In our initial survey of the optimal conditions, the trans-
annulation of 4-cyano-4-(1,3-dithiolan-2-ylidene)-3-methyl-
1,3-diphenylbut-1-yne (1a) was evaluated under various re-
action parameters including base, solvent, and reaction
temperature (Table 1). Delightfully, the desired product 2a
was obtained in 90% yield in the presence of NaOH
(1.0 equiv.) in DMSO at 80 °C (Table 1, Entry 1). Further,
the yield was improved to 95% at a reduced time of 10 min
with NaH as the base (Table 1, Entry 2). On the contrary,
the use of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in
DMSO only afforded a trace amount of product 2a
(Table 1, Entry 3). The amount of NaH also had a signifi-
cant influence on the reaction outcome, because an increase
in the amount of this base to 2.0 equiv. or a decrease to
0.5 equiv. both resulted in reduced product yields (Table 1,
Introduction
Natural and man-made cyclic organosulfur compounds
play a dominant role in both biological and medicinal
chemistry.[1] Among the various sulfur heterocyclic scaf-
folds, thiophenes[2] and dihydrothiophenes[3] are of particu-
lar interest, as they are often found as ring system motifs
in natural and artificial products with a broad spectrum of
biological activities. Also, these compounds have proven to
be versatile intermediates for synthetic applications.[4]
Therefore, the development of novel and efficient synthetic
methods for these two kinds of heterocycles is highly desir-
able. The cyclization of disubstituted alkynes possessing a
sulfur nucleophile in proximity to the triple bond induced
by either a transition-metal catalyst or an electronic reagent
has been shown to be extremely effective for the synthesis
of a variety of sulfur heterocycles.[5] Generally, the sulfur
sources that are used in these reactions include thio-
ethers[5a–5n] and thiols.[5o–5r] Whereas the former are com-
monly limited to specific molecular structures such as ortho-
alkynylaryl thioether systems, the latter are difficult to han-
dle owing to their sensitivity to oxidation conditions. As a
result, a readily available and flexible sulfur functional
group that is capable of taking part in thio-heterocycli-
zation reactions of alkynes is of high interest.
Results and Discussion
In 2000, Asokan and co-workers reported a strategy in-
volving the use of the 1,3-dithiolan-2-ylidene group of
[a] Department of Chemistry, Northeast Normal University,
Changchun 130024, China
E-mail: bixh507@nenu.edu.cn
[b] Department of Chemistry, Jilin Normal University,
Siping 136000, China
[c] State Key Laboratory of Elemento-Organic Chemistry,
Tianjin 300071, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301624.
924
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Synthesis of Dihydrothiophenes and Thiophenes
dramatically influence the results. Notably, the formation of
the 5-methylene group of dihydrothiophenes 2 was stereose-
lective, as confirmed by X-ray diffraction analysis of 2g
(Figure 2). Delightfully, upon applying the protocol to cy-
clic substrates, corresponding spirothiophenes 2l–n were ob-
tained in good yields. The formation of the cis isomer only
of
2 may be ascribed to steric hindrance and to
van der Waals repulsion between the R3 and R1/R2 groups.
Therefore, we have demonstrated herein a novel and ef-
ficient approach to a variety of highly functionalized 2,3-
dihydrothiophenes with reactive substituents, including
cyano, vinylthio, and methylene groups, as well as a spiro
structure. These structural features render 2,3-dihydrothio-
phenes 2 an attractive class of synthetic intermediates for
further synthetic modifications.
Figure 1. Strategic use of 2-vinylidene-1,3-dithiolane as a masked
thiolate anion to construct sulfur heterocycles.
Entries 4 and 5). Notably, the reaction temperature only af-
fected the time of the reaction but not the product yield.
Thus, if the temperature was reduced to 25 °C, 2a was ob-
tained in 93% yield, although a longer reaction time of
150 min was required (Table 1, Entry 6). Furthermore, poor
product yields were realized if the solvent was changed from
DMSO to solvents such as toluene and CH3CN (Table 1,
Entries 6 and 7). Consequently, the reaction conditions
listed in Entry 2 were optimal and were selected for further
investigations on the reaction scope.
Table 1. Optimization of the reaction conditions.[a]
Entry
Base
(1.0 equiv.)
Solvent
Temp.
[°C]
Time
[min]
Yield[b]
[%]
Scheme 1. Synthesis of dihydrothiophenes 2.
1
2
3
4
5
6
7
NaOH (1.0)
NaH (1.0)
DBU (1.0)
NaH (2.0)
NaH (0.5)
NaH (1.0)
NaH (1.0)
DMSO
DMSO
DMSO
DMSO
DMSO
toluene
CH3CN
80
80
80
80
25
80
80
30
10
10
60
150
60
90
95
trace
73
46
0
60
66
[a] All reactions were performed with 1a (0.2 mmol) in the presence
of base (1.0 equiv.) in solvent (1 mL). [b] Yield of isolated product.
With the optimal conditions in hand, the reaction scope
for the synthesis of 2,3-dihydrothiophenes 2 was investi-
gated. 4-(1,3-Dithiolan-2-ylidene)but-1-ynes 1 containing a
quaternary carbon center between the ketene dithioacetal
Figure 2. X-ray crystal structure of 2g.
Next, with the aim to prepare thiophene derivatives, the
and alkyne groups were examined in this transannulation base-mediated transannulation of 4-(1,3-dithiolan-2-ylid-
reaction. As summarized in Scheme 1, we found that the ene)but-1-ynes 3 having a tertiary carbon atom between the
reactions of 1a–k all proceeded smoothly and efficiently to alkyne and ketene dithioacetal groups (i.e., R1 = H) was
afford 2,3-dihydrothiophenes 2a–k in good to excellent performed under the optimal conditions. As summarized in
yields (82–96%). Systematic variation of the R1, R2, and Table 2, the reactions all proceeded smoothly to afford fully
R3 substituents from (hetero)aryl to alkyl groups did not substituted thiophenes 4 in moderate to high yields. Various
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925

Z. Fang, P. Liao, Z. Yang, Y. Wang, B. Zhou, Y. Yang, X. Bi
SHORT COMMUNICATION
aromatic groups including phenyl, methoxyphenyl, and
naphthyl were tolerated in the 4-position of the thiophene
ring, and π-conjugated 3-arylthiophenes were thereby ob-
tained. In addition, substrates bearing the vinylthio (elec-
tron-donating) and cyano (electron-withdrawing) groups
delivered thiophenes 4, which are a new group of donor–
acceptor thiophenes that would be useful in materials
science.[10]
Conclusions
We have developed an efficient and atom-economic ap-
proach to densely functionalized 2,3-dihydrothiophenes and
thiophenes. For the first time, the strategic use of 1,3-di-
thiolan-2-ylidene as a masked thiolate anion was applied in
addition reactions to an alkyne group. The novel reaction
is particularly attractive because of the ready availability of
the substrates, mild reaction conditions, high reaction effi-
ciency, and high product yields. Functional groups on the
dihydrothiophenes and thiophenes such as cyano, vinylthio,
aryl, and methylene groups render these five-membered
sulfur heterocycles useful synthetic intermediates in organic
synthesis.
Table 2. Synthesis of thiophenes 4.
Entry
R2
R3
4
Yield[a]
[%]
Experimental Section
Representative Procedure: NaH (6.8 mg, 0.2 mmol) was added to a
solution of 1a (69.5 mg, 0.2 mmol) in DMSO (1.0 mL). The reac-
tion mixture was heated to 80 °C and stirred for 30 min until 1a
was consumed, as indicated by TLC. The resulting mixture was
cooled to room temperature and poured into ice-cold water
(50 mL) whilst stirring. The precipitated solid was collected by fil-
tration, washed with water (3ϫ 10 mL), and dried in vacuo to af-
ford the crude product, which was purified by flash chromatog-
raphy (silica gel; petroleum ether/ethyl acetate, 100:1 v/v) to give 2a
(66.0 mg, 95%).
1
2
3
4
5
6
7
8
Ph
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
1-naphthyl
Ph
Ph
Ph
Ph
Ph
Ph
4a
4b
4c
4d
4e
4f
68
69
73
74
60
55
63
80
4-FC6H4
4-MeC6H4
nBu
Ph
Ph
4g
4h
[a] Yield of isolated product.
On the basis of these experimental results and other pre-
cedents,[6,7] a plausible reaction mechanism for the synthesis
of 2,3-dihydrothiophenes 2 and thiophenes 4 is proposed
and depicted in Scheme 2. First, the fragmentation of the
1,3-dithiolan-2-ylidene group occurs through extraction of
an acidic methylene hydrogen atom by NaH, which gener-
ates thiolate anion intermediate A. It seems very likely that
deprotonation of the CH2 group occurs at both the C-4 and
C-5 positions. Only the (Z) anion with the correct orienta-
tion of the thiolate center to the CϵC bond undergoes
cyclization. Apparently, the opposite isomer of the anion is
reversibly converted into the starting material. Following
the one-step regioselective addition of the thiolate anion to
the alkyne unit, olefinic carbanion intermediate B is
formed. Finally, 2,3-dihydrothiophenes 2 are produced if
R1/R2 ϶ H, whereas thiophenes 4 are generated if R1 = H.
Supporting Information (see footnote on the first page of this arti-
cle): General experimental procedures and spectroscopic data (1H
NMR, 13C NMR, and HRMS) for the corresponding products.
Acknowledgments
This work was supported by the National Natural Science Founda-
tion of China (NSFC) (21172029, 21202016, 21372038) and the
Ministry of Education of the People’s Republic of China (NCET-
13-0714).
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Synthesis of Dihydrothiophenes and Thiophenes
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