Et3N mediated synthesis of polysubstituted thiophenes from α-oxo ketene dithioacetals

Article abstract of DOI:10.1016/j.tetlet.2015.09.089

In this Letter, an efficient synthetic route to prepare polysubstituted thiophene derivatives was achieved via the Et₃N-mediated (Claisen) rearrangement reaction from α-oxo S-methyl-S-propargyl ketenes, which were obtained through alkylation of

Full text of DOI:10.1016/j.tetlet.2015.09.089

Tetrahedron Letters 56 (2015) 6198–6201
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Et3N mediated synthesis of polysubstituted thiophenes from
ketene dithioacetals
a-oxo
a
a
a
a
Xiaoli Kan a, Xiaobing Yang a, Fangzhong Hu a, , Yang Wang , Ying Liu , Xiaomao Zou , Hengyu Li ,
⇑
Hao Li a, Qichun Zhang b,c,
⇑
a State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
b School of Materials Science Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 637371, Singapore
c Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter, an efficient synthetic route to prepare polysubstituted thiophene derivatives was achieved
Received 10 August 2015
Revised 16 September 2015
Accepted 19 September 2015
Available online 28 September 2015
via the Et3N-mediated (Claisen) rearrangement reaction from a-oxo S-methyl-S-propargyl ketenes, which
were obtained through alkylation of b-oxodithioesters with propargylic bromides, followed by
regioselective intramolecular cyclization.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Et3N mediation
Polysubstituted thiophenes
a-Oxo S-methyl-S-propargyl ketenes
Cyclization
Developing an efficient method to prepare heterocycles is very
polarized ketene dithioacetals have been widely utilized as precur-
sors.11,2f Additionally,
-oxo ketene-S,S-acetals are a class of prac-
important in organic synthesis, since heterocyclic compounds play
a key role in current functional materials.1 For example, thiophene,
pyridine, and pyrazine represent important classes of heterocycles
due to their applications in pharmaceuticals,2 organic conductors,3
organic semi-conductors,4 organic light-emitting diodes (OLEDs),5
organic field-effect transistors (OFETs),6 etc. More specifically,
highly substituted thiophenes such as PD 81,723,2a olanzapine,2c
and T-622e (Fig. 1) display significant biological activities.
In fact, numerous efficient and versatile synthetic methods have
been developed for the synthesis of thiophene derivatives.7 In gen-
eral, the construction of the thiophene ring from the annulation of
appropriately substituted open-chain precursors7,8 has attracted
more chemists’ attention than the direct functionalization of the
simple thiophene ring9 since the former strategy provides more
flexible substitution patterns. A representative example of the for-
mer route is the Gewald reaction,10,2d which employs the sulfur
element as the heteroatom source for the formation of thiophene
rings and offers a highly efficient route for the preparation of poly-
substituted thiophenes from simple starting materials under mild
conditions. Of the useful alternative approaches for the synthesis
of substituted thiophenes and thienothiophenes, functionalized
a
tical and available compounds, which have emerged as powerful
synthons in the construction of heterocycles because of their mul-
tiple active centers. More importantly, thiophene derivatives can
also be easily synthesized from
a
-oxoketene-S,S-acetals.11,2f For
example, in 2007, Liu and co-workers reported a one-pot synthesis
of polyfunctionalized thiophenes via an amine mediated ring open-
ing of EWG (electron withdrawing group)-activated 2-methylene-
1,3-dithioles.2f The regioselective synthesis of polysubstituted
thiophenes from gem-dialkylthio vinylallenes and gem-dialkylthio
enynes through intramolecular transannulation has also been
carried out by them.11d,e Recently, Singh et al. found that the
organoindium-mediated coupling of b-oxodithioesters and
propargylic bromides can produce highly functionalized
thiophene derivatives.12 However, the usage of indium13 is imprac-
tical because indium is expensive, poisonous, and environmentally
unfriendly. Therefore, from the point of view of environmental pro-
tection, the development of a metal-free and efficient protocol is
highly desirable. Herein, we report a novel and efficient methodol-
ogy for the synthesis of polysubstituted thiophene derivatives via
the Et3N-mediated rearrangement reaction of
a-oxo S-methyl-S-
propargyl ketenes, which are obtained through the alkylation of
b-oxodithioesters with propargylic bromides in good yield.
Initially, we prepared the starting compounds,
S-methyl-S-propargyl ketenes 3a–u via the reaction between
⇑
Corresponding authors. Tel.: +86 22 23506567; fax: +86 22 23503627 (F.H.);
tel.: +65 67904705; fax: +65 67909081 (Q.Z.).
a-oxo
E-mail addresses: fzhu@nankai.edu.cn (F. Hu), qczhang@ntu.edu.sg (Q. Zhang).
http://dx.doi.org/10.1016/j.tetlet.2015.09.089
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

X. Kan et al. / Tetrahedron Letters 56 (2015) 6198–6201
6199
N
O
O
N
N
F3C
S
S
Cl
H2N
N
H
H2N
S
PD 81,723
T-62
Olanzapine
Figure 1. Biologically active polysubstituted thiophene derivatives.
S
R
O
O
S
OH
S
Br
S
S
Ar
Ar
S
Ar
S
K2CO3, acetone
NaH, DMF/hexane
R
3a-u
1a-o
2a-o
3a: Ar = C6H5, R = H, 75%; 3b: Ar = 4-MeC6H4, R = H, 81%; 3c: Ar = 4-MeOC6H4, R = H, 80%;
3d: Ar = 4-PhOC6H4, R = H, 71%; 3e: Ar = 4-ClC6H4, R = H, 82%; 3f: Ar = 4-IC6H4, R = H, 75%;
3g: Ar = 2-MeC6H4, R = H, 70%; 3h: Ar = 2-FC6H4, R = H, 72%; 3i: Ar = 3-MeC6H4, R = H, 70%;
3j: Ar = 3-CF3C6H4, R = H, 71%; 3k: Ar = 2,4-Me2C6H3, R = H, 68%; 3l: Ar = 2,4-Cl2C6H3, R =
H, 65%; 3m: Ar = 1-Naphthyl, R = H, 70%; 3n: Ar = 2-Furyl, R = H, 66%; 3o: Ar = 2-Thienyl, R
= H, 76%; 3p: Ar = C6H5, R = CH3, 87%; 3q: Ar = 4-MeC6H4, R = CH3, 84%; 3r: Ar =
4-MeOC6H4, R = CH3, 79%; 3s: Ar = 4-ClC6H4, R = CH3, 80%; 3t: Ar = 2,4-Me2C6H3, R = CH3,
74%; 3u: Ar = 2,4-Cl2C6H3, R = CH3, 55%.
Scheme 1. Synthesis of
a
-oxo S-methyl-S-propargyl ketene 3a–u.
Table 1
b-oxodithioesters 2a–o and propargylic bromide in acetone in the
presence of K2CO3 at room temperature according to the similar
reported procedure.7e The desired b-oxodithioesters 2a–o were
obtained in good yields by reacting acetophenone derivatives
(aryl or heteroaryl ethyl ketones) 1a–o with dimethyl
trithiocarbonate in the presence of sodium hydride according to
the previous procedure (see Scheme 1).14
Optimization of the model reactiona
O
O
S
base, solvent
S
S
t, time
S
3a
4a
Next, phenyl-substituted a-oxo S-methyl-S-propargyl ketene 3a
was chosen as a model substrate for the initially-attempted new
cascade processes. The conditions were optimized by screening
various bases and using different solvents (Table 1, entries 1–18).
The best condition to approach polysubstituted thiophene 4a
(yield 66%) was obtained: DMF as the solvent, triethylamine as a
weaker organic base, and reaction temperature of 100 °C (Table 1,
entry 6).
With this optimized reaction condition in hand, we examined
the substrate scope for the synthesis of 2,3,5-trisubstituted and
2,3,4,5-tetrasubstituted thiophene derivatives using a variety of
Entry
Base
Solvent
Temp(°C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
NaHCO3
Na2CO3
K2CO3
Cs2CO3
NaOH
Et3N
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
100
100
100
100
100
100
100
100
100
100
100
100
66
2.5
1.5
4
2
1
2
5
3
3.5
4
45
55
20
NRc
NRc
66
NRc
56
23
20
22
10
53
50
60
57
52
48
DBU
(i-Pr)2NH
Piperidine
n-PrNH2
n-BuNH2
CH3ONa
Et3N
Et3N
Et3N
Et3N
Et3N
9
10
11
12
13
14
15
16
17
18
a-oxo S-methyl-S-propargyl ketene, and the obtained results are
4
6
shown in Table 2.15 In all the cases, the desired thiophenes with
good to excellent yields were observed. The electronic effects of
para-substituents on the aryl ring are investigated by attaching
different electron-withdrawing/donating substituents (such as
chloro, iodo, hydrogen, methyl, methoxy, and phenoxy) on the
aromatic ring with groups. These results suggest that electron-
withdrawing groups normally gave relatively lower yields
compared with electron-donating groups (4a–4f). Interestingly,
ortho-substituted, meta-substituted, and polysubstituted groups
gave similar results (4g–4h, 4i–4j, and 4k–4l), which suggest that
electron-withdrawing groups on the benzene ring were slightly
unfavorable for the reaction. Naphthyl-substituted substrate 3m
gave the worse yield compared with that with a phenyl moiety
3a, which might attribute to the low reactivity of naphthalene
rings in comparison with phenyl rings. Heteroaryl groups, such
as 2-furyl (3n) and 2-thienyl (3o), furnished 4n and 4o in 65%
and 66% yields, respectively. The rule of electronic effects of 2,3,
THF
24
24
5
1.5
3
Acetone
CH3CN
DMSO
Dioxane
Toluene
57
82
100
100
100
Et3N
2.5
a
Reaction conditions: substrate 3a (1.0 mmol, 1.0 equiv), base (3.0 mmol,
3.0 equiv), solvent (10 mL).
b
Isolated yields after silica gel column chromatography.
No reaction.
c
4,5-tetrasubstituted thiophenes are same to that of 2,3,5-trisubsti-
tuted thiophenes (4p–4u).
The possible mechanism for the formation of the thiophene 4
from the
a-oxo S-methyl-S-propargyl ketene 3 is shown in
Scheme 2. The first step involves the Claisen rearrangement of 3

6200
X. Kan et al. / Tetrahedron Letters 56 (2015) 6198–6201
Table 2
Synthesis of polysubstituted thiophene derivatives 4a–ua,b
O
R
S
O
S
Ar
Et3N (3.0 equiv)
Ar
S
DMF, 100°C, 2-4 h
S
R
4a-u
3a-u
O
O
O
O
S
S
S
S
S
O
S
4c
O
S
4d
S
4a
4b
74% (3.5h)
66% (2h)
69% (2.5h)
67% (2h)
O
O
F
O
O
S
S
S
S
4h
64%(2h)
S
I
Cl
S
S
S
4e
4f
4g
60%(3.5h)
55% (3h)
76% (2h)
O
Cl
O
O
O
F3C
S
S
S
S
S
Cl
S
S
S
S
4k
4l
4i
4j
75% (3.5h)
54% (4h)
67%(2h)
54%(3h)
O
O
O
O
O
S
S
S
S
S
S
S
S
4p
4n
4o
66% (3h)
4m
58% (3.5h)
65% (3h)
67% (2.5h)
Cl
O
O
O
O
O
S
S
S
S
S
Cl
S
S
O
Cl
S
S
S
4u
4t
64% (3.5h)
4q
4r
72% (2h)
4s
68% (2h)
52% (2h)
52% (3.5h)
a
Reaction conditions: substrate 3a–u (1.0 mmol, 1.0 equiv), Et3N (3.0 mmol, 3.0 equiv), DMF (10 mL), 2–4 h at 100 °C.
Isolated yield after silica gel column chromatography.
b
O
R
O
S
R
S
R
S
O
S
R
S
O
S
H
S-cyclization
path I
H
3,3
Ar
Ar
Et3N
Ar
Ar
S
S
B
4
A
3
S
S
R
S
R
H
O-cyclization
X
S
R
Et3N
S
S
path II
Ar
Ar
O
Ar
O
O
4'
A'
B'
Scheme 2. A plausible mechanism for the formation of thiophenes 4.

X. Kan et al. / Tetrahedron Letters 56 (2015) 6198–6201
6201
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(Et3N–DMF), undergoes a proton abstraction to give the two possi-
ble enolate anion rotamers B and B0, through pathways I and II, to
further yield 4 and 40, respectively. The intermediate B undergoes
regioselective intramolecular S-cyclization via route I to give the
desired product 4 exclusively. The alternative O-cyclization of B0
via route II could lead to the formation of furan 40, which was
not observed even in trace during our investigations, confirming
that the protocol is highly regioselective.
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In conclusion, we have developed a novel, efficient, and highly
regioselective procedure for the synthesis of polysubstituted thio-
phene derivatives in good yields via the Et3N-mediated Claisen
rearrangement reaction of
a-oxo S-methyl-S-propargyl ketenes,
which can be further extended to the preparation of other hetero-
cycles. This method is very efficacious due to its environmental
benignity, metal-free mediation, and high atom economy. Further
synthetic applications of this methodology are currently underway
in our laboratory.
Acknowledgements
F.H. gratefully acknowledges financial support from the
National Twelfth Five-Year Plan for Science & Technology of China
(No. 2011BAE06B03-12). Q.Z. acknowledges financial support from
ACRF Tier 1 (RG133/14) and Tier 2 (ARC 20/12 and ARC 2/13) from
MOE, and the CREATE program (Nanomaterials for Energy and
Water Management) from NRF, Singapore.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.09.
089.
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15. Typical procedure for the synthesis of polysubstituted thiophenes 4a–u: A mixture
of
3-(methylthio)-1-phenyl-3-(prop-2-yn-1-ylthio)prop-2-en-1-one
3a
(0.25 g, 1 mmol) and triethylamine (0.30 g, 3 mmol) in DMF (10 mL) was
heated at 100 °C. The heating was continued till the completion of the reaction
(2 h, monitored by TLC). The reaction mixture was cooled, poured into water,
and extracted using ethyl acetate (3 ꢀ 15 mL). The combined organic extract
was washed with brine (2 ꢀ 20 mL), dried over anhydrous sodium sulfate, and
the solvent was removed under vacuum. The residue was purified by column
chromatography over silica gel using ethyl acetate/petroleum ether (1:80, v/v)
as eluent to give 3-benzoyl-5-methyl-2-methylthio-thiophene 4a: yield
0.164 g (66%); yellow viscous liquid; 1H NMR (CDCl3, 400 MHz): d = 7.75 (dd,
4
3
4
3JH–H = 8.5 Hz, JH–H = 1.4 Hz, 2H, ArH), 7.53 (tt, JH–H = 7.4 Hz, JH–H = 1.2 Hz,
1H, ArH), 7.45 (t, 3JH–H = 7.2 Hz, 2H, ArH), 6.91 (d, 4JH–H = 0.9 Hz, 1H, 4-H), 2.57
(s, 3H, SCH3), 2.43 (d, JH–H = 0.9 Hz, 3H, CH3); 13C NMR (CDCl3, 100 MHz):
4
d = 189.9, 150.9, 139.4, 136.2, 134.5, 131.7, 129.0, 128.2, 19.0, 15.4; HRMS (ESI)
m/z [M+H]+ calculated for C13H13OS2: 249.0408, found: 249.0405.