Construction of highly functionalized thiophene and benzo[b]thiophene derivatives via a sequence of propargyl–allenyl isomerization/cyclization/demethylation

Article abstract of DOI:10.1016/j.tetlet.2016.10.025

An efficient one-pot protocol for the synthesis of functionalized thiophene and benzo[b]thiophene derivatives was developed via a sequence of propargyl–allenyl isomerization/cyclization/demethylation. As a result of the readily accessible starting materials, simple operation, and mild conditions, this reaction should have potential utility in organic synthesis.

Full text of DOI:10.1016/j.tetlet.2016.10.025

Accepted Manuscript
Construction of Highly Functionalized Thiophene and Benzo[b]thiophene De-
rivatives via a Sequence of Propargyl–Allenyl Isomerization/Cyclization/De-
methylation
Dianpeng Chen, Gangdong Xing, Xueyuan Chen, Jinzhong Yao, Hongwei Zhou
PII:
S0040-4039(16)31328-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.10.025
TETL 48195
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 July 2016
29 September 2016
8 October 2016
Please cite this article as: Chen, D., Xing, G., Chen, X., Yao, J., Zhou, H., Construction of Highly Functionalized
Thiophene and Benzo[b]thiophene Derivatives via a Sequence of Propargyl–Allenyl Isomerization/Cyclization/
Demethylation, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.10.025
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Construction
of
Highly
Functionalized
Thiophene
and
Benzo[b]thiophene Derivatives via a Sequence of Propargyl–Allenyl
Isomerization/Cyclization/Demethylation
Dianpeng Chen, a,b Gangdong Xing, b Xueyuan Chen, a Jinzhong Yao, a, *
and Hongwei Zhou a,b,*
a
College of Biological, Chemical Sciences and Engineering, Jiaxing University,
Jiaxing 314001, People’s Rupublic of China
b
Department of Chemistry, Zhejiang University (Campus Xixi), Hangzhou 310028,
People’s Republic of China
Fax: (+86) 573-83643264; E-mail: zhouhw@zju.edu.cn
Abstract
An efficient one-pot protocol for the synthesis of functionalized thiophene and
benzo[b]thiophene derivatives was developed via a sequence of propargyl–allenyl
isomerization/cyclization/demethylation. As a result of the readily accessible starting
materials, simple operation, and mild conditions, this reaction should have potential
utility in organic synthesis.
Keywords:
Substituted thiophenes are arguably the most important aromatic heterocyclic
compounds due to their extensive applications in pharmacology,1 material science,2
and organic synthesis.3 Thus, the preparation of polyfunctionalized thiophenes
(benzothiophenes) has been of interest for the organic community over the past
decades. The classical protocols to thiophene derivatives are mainly based on
cyclization reactions or on direct functionalization to thiophene ring.4 For the

construction of polysubstituted thiophenes via cyclization strategies, using mercapto
group as the nucleophile might encounter difficulty because of its acidity, instability
to oxidant and too-strong-nucleophilicity, which makes the design of substrates
challenging (Scheme 1a). Replacement of the mercapto group by a relatively stable
methylthio group might be a feasible solution.5 Based on this idea and our
6
undertanding of organosulfur chemistry
and propargyl-allenyl isomerization,7
herein we wish to report the realization of an efficient access to thiophene and
benzo[b]thiophene derivatives via an intramolecular nucleophilic attack of sulfur to
the in situ generated electron-deficient allene moiety (Scheme 1b).
Scheme 1. Proposal of addition of methyl sulfide to in situ generated allene
As a first attempt, we chose 1-(2-(methylthio)cyclohex-1-enyl)-3-phenylprop-2-yn-
1-ol (1a) as the substrate, which could be readily obtained by treatment of 2-
(methylthio)cyclohex-1-enecarbaldehyde with (phenylethynyl)lithium at -78 oC.
Initial studies focused on the propargyl–allenyl isomerization and cyclization of 1a in
the presence of chlorodiphenyl phosphine and triethylamine in THF at room
temperature.
Fortunately,
the
desired
product
diphenyl(phenyl(4,5,6,7-

tetrahydrobenzo[b]thiophen-2-yl)methyl)phosphine oxide (2a) was obtained in 12%
yield (Table 1, entry 1). Then we began to optimize the reaction with different
conditions. Replacing triethylamine by N,N-diisopropylethylamine (DIPEA) gave
similar yields and the stronger organic bases such as DBU and DBN gave an
unidentified mixture (Table 1, entries 2–4). Subsequent screening of other common
solvents, such as, dichloroethane, 1,4-dioxane, acetonitrile and DMF did not improve
the yield except toluene (Table 1, entries 5–9). Besides that, the temperature was
found to influence the reactivity (Table 1, entries 9-11). Raising the temperature to
o
100 C improved the yield significantly. For further optimization, we examined
several triethylamine-compatible Lewis acids to promote the reactions (Table 1,
entries 12-14), and Ga(OTf)3 was demonstrated to be effective, affording the desired
product 2a in 85% yield (entry 12).8 Based on these optimization studies, we
confirmed that 1a (0.5 mmol), Ph2PCl (0.6 mmol), Ga(OTf)3 (0.025mmol) and TEA
(1.5mmol) in 5 mL toluene stirring at 100 oC offered the best conditions for this
reaction (Table 1, entry 12).
Table 1. Optimization of the Reaction Conditions a
Entry Additive
Base
TEA
Solvent
THF
T(oC) Yield(%)
1
2
3
4
5
-
-
-
-
-
r.t.
r.t.
r.t.
r.t.
r.t.
12
10
DIPEA
DBU
DBN
TEA
THF
THF
trace
trace
6
THF
DCE

6
7
-
-
-
-
-
-
TEA 1,4-dioxane r.t.
8
TEA
TEA
TEA
TEA
TEA
MeCN
DMF
r.t.
r.t.
NR
NR
18
16
32
85
77
81
8
9
toluene
toluene
toluene
toluene
toluene
toluene
r.t.
10
11
12
13
14
60
100
100
100
100
Ga(OTf)3 TEA
Zn(OTf)2
TEA
AgOTf
TEA
a Conditions: 1a (0.5 mmol), Ph2PCl (0.6 mmol), Ga(OTf)3 (0.025mmol) and TEA (1.5mmol)
in 5 mL toluene were stirred at 100 oC under nitrogen.
With the optimized reaction conditions in hand, the scope of this reaction was
examined (Table 2). This protocol is successful for the one-pot construction of both
thiophene (2a-2i) and benzo[b]thiophene (2j-2m) derivatives. R1 can be alkyl (2i, 2m),
alkenyl (2h, 2l) or phenyl group optionally substituted with either an electron-
donating group (2b, 2c, 2f, 2g) or an electron-withdrawing group (2d); R2 can be
alkyl (2a-2f) or phenyl group (2g-2i).
Table 2. Synthesis of thiophene and benzo[b]thiophene derivatives. a

a
Conditions: 1 (0.5 mmol), Ph2PCl (0.6 mmol), Ga(OTf)3 (0.025 mmol) and TEA
(1.5mmol) in 5 mL toluene were stirred at 100 oC under nitrogen.

Aside the rearrangement of propargyl phosphite to allenyl phosphonate,
base−assisted H−shift propargyl–allenyl isomerization is also a facile method for in
situ generating allenes. We examined the Sonogashira coupling/propargyl–allenyl
isomerization of propargyl ether with electron-deficient alkenyl iodides and obtained
benzo[b]thiophenes 4a and 4b, illustrating that this benzo[b]thiophene formation
strategy might tolerate diverse functionalization (Scheme 2).
Scheme 2. Benzo[b]thiophene formation via Sonogashira pathway.
We proposed a plausible pathway as shown in Scheme 3. First, intermediate A is
formed via the propargyl phosphite/allenyl phosphonate rearrangement; then assisted
with Ga(OTf)3, intermediate A undergoes an intramolecular nucleophilic attack of
methylthio group to the electron-deficient allene moiety, affording the sulfonium
intermediate B, which experiences demethylation to give product 2a (Scheme 3).
Scheme 3. Plausible mechanism.

In conclusion, we have developed an efficient protocol for the synthesis of
functionalized thiophene and benzo[b]thiophene derivatives via a sequence of
propargyl–allenyl isomerization/cyclization/demethylation in one pot. The products
can be serviceable building blocks and applied widely in Wittig-type olefination.10
This reaction demonstrates good functional group compatibility, and further studies
on the synthetic application are currently ongoing.
Acknowledgements
Financial support from Natural Science Foundation of China (Nos. 21606080 and
21401078), Zhejiang Provincial Natural Science Foundation of China (No.
LY14B020008) and Summit Program of Jiaxing University for Leading Talents is
greatly appreciated.
Supplementary data
Supplementary data associated with this article can be found, in the online version.
Notes and reference

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Graphical abstract
Abstract
An efficient one-pot protocol for the synthesis of functionalized thiophene and
benzo[b]thiophene derivatives was developed via a sequence of propargyl–allenyl
isomerization/cyclization/demethylation. As a result of the readily accessible starting
materials, simple operation, and mild conditions, this reaction should have potential
utility in organic synthesis.
Key words: thiophene; benzo[b]thiophene; propargyl–allenyl isomerization;
cyclization; demethylation

Graphical abstract

Highlights
 Good functional group compatibility.
 Stable and available starting materials.
 The products can be serviceable building blocks.