Three-Component Thieno[2,3-b]indole Synthesis from Indoles, Alkenes or Alkynes and Sulfur Powder under Metal-Free Conditions

Article abstract of DOI:10.1002/adsc.201701106

A Bronsted acid promoted three-component synthesis of substituted thieno[2,3-b]indole has been developed starting from indoles, alkenes or alkynes, and sulfur powder. N,N-Dimethylformamide plays an important role to convert the starting materials into the fused products. Various functional groups attached to substrates were well tolerated to afford the corresponding products in moderate to good yields under very simple reaction conditions. (Figure presented.).

Full text of DOI:10.1002/adsc.201701106

Title: Three-Component Thieno[2,3-b]indole Synthesis from Indoles,
Alkenes or Alkynes and Sulfur Powder under Metal-Free
Conditions
Authors: Bin Li, Penghui Ni, Huawen Huang, Fuhong Xiao, and Guojun
Deng
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701106
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10.1002/adsc.201701106
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Three-Component Thieno[2,3-b]indole Synthesis from Indoles, Alkenes
or Alkynes and Sulfur Powder under Metal-Free Conditions
Bin Li,a† Penghui Ni,a† Huawen, Huang,a Fuhong Xiao,a* Guo-Jun Deng a,b*
a Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of Education, Hunan Province Key
Laboratory of Green Organic Synthesis and Application，College of Chemistry, Xiangtan University, Xiangtan 411105,
China. E-mail: fhxiao@xtu.edu.cn; gjdeng@xtu.edu.cn
b Beijing National Laboratory for Molecular Sciences and CAS Key Laboratory of Molecular Recognition and Function
Institute of Chemistry, Chinese Academy of Sciences (CAS) Beijing 100190 (P.R. China)
† B.Li and P. Ni contributed equally to this work.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract: A Bronsted acid promoted three-component catalyzed
synthesis of substituted thieno[2,3-b]indole has been
recyclization
of
2-(2-
nitrocyabatophenyl)furanes,[12] and among others.[13]
However, all the aforementioned synthetic methods
use functionalized indoles, furans, isatins and
thiophenes, which require several steps to be
prepared. In view of the concerns about the
influences of trace metals on human consumption
drugs and the efficiency of organic electronic
devices, the development of metal-free catalytic
processes for the direct functionalization of indoles
is of great interest and importance.[14] Efficient
methods for the construction of substituted
thieno[2,3-b]indoles from simple indoles and other
readily available starting materials under metal-free
conditions are highly desirable.
developed starting from indoles, alkenes or alkynes, and
sulfur powder. N,N-Dimethylformamide plays an
important role to convert the starting materials into the
fused products. Various functional groups attached to
substrates were well tolerated to afford the corresponding
products in moderate to good yields under very simple
reaction conditions.
Keywords: Thieno[2,3-b]indole; Sulfur powder; Three-
component reaction; Metal-free; C-H functionalization
Indole and its derivatives widely exist in a variety
of naturally occurring products and are extremely
important in medicinal chemistry for their biological
activities.[1] In particular, the thieno[2,3-b]indoles
are valued for their great potential as antifungal
agent.[2] Thienodolin is a natural product isolated
from Streptomyces albogriseolus and exhibits plant-
growth regulatory properties.[3] The substituted
thieno[2,3-b]indoles are useful for the treatment of
epilepsy, neurological diseases such as Parkinson's
disease and pain.[4] Additionally, thieno[2,3-
b]indole derivatives show great potential
applications in organic electroluminescent devices
and polymer conductors.[5]
There are few methods for the synthesis of
thieno[2,3-b]indoles in the literature, including
deoxygenative
cyclization
in
of
2-(2-
triethyl
nitrophenyl)thiophene
refluxing
phosphate,[6] oxidative cyclization of indolin-2-
thiones,[7] radical or palladium-catalyzed cyclization
of
3-(2-bromoindol-3yl)acrylonitriles,[8]
Scheme 1. Synthesis of indole-fused heterocycles from
condensation of 3-unsubstituted indolin-2-thione,[9]
indoles
intramolecular
NH/CH-coupling
condensation
in
1-
benzo[b]thiophenes,[10]
of
The direct C-H functionalization of hetero C-H bond
is one of the most popular research topics in organic
alkylisatins and acetylated (hetero)arenes,[11] AlCl3-
1
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10.1002/adsc.201701106
Advanced Synthesis & Catalysis
Yield (%)[b]
chemistry since this method can provide a more direct
Entry
Acid
synthetic
route
by
avoiding
substrate
1
2
3
4
5
6
7
8
formic acid
HOAc
TFA
TsOH
MsOH
TfOH
PivOH
benzoic acid
HCl (6 mol/L) (0.1 mL)
HNO3 (6 mol/L) (0.1 mL)
H2SO4 (3 mol/L) (0.1 mL)
H3PO4 (2 mol/L) (0.1 mL)
HCl (3 mol/L) (0.1 mL)
HCl (1 mol/L) (0.1 mL)
HCl (6 mol/L) (0.1 mL)
HCl (6 mol/L) (0.1 mL)
34
70
30
58
16
43
58
58
86
43
59
80
64
46
59
0
prefunctionalization.[15] Among them, indole C-H bond
functionalization has attracted considerable interest
since the indole motif is a privileged functional group
for pharmaceutical drugs and agrochemicals as well as
electronic materials.[16] Recently, we and others have
developed various approaches for the synthesis of
fused heterocycles via indole C-H bond
functionalization. For example, in 2015, we reported a
9
10
11
12
13
14
15[c]
16[d]
palladium-catalyzed
benzothieno[2,3-b]indole
formation using sulfur powder as the sulfur source via
dehydrative-dehydrogenative double C-H sulfuration
under an oxygen atmosphere (Scheme 1, a).[17] In 2016,
we developed a concise synthesis of pyrazolo[1,5-
a]indole derivatives by copper-catalyzed aerobic
oxygenation and cyclization of indoles with oxime
acetates (Scheme 1, b).[18] Very recently, we described
an efficient one-pot two-step indole-to-carbazole
strategy from cheap and readily available indoles,
ketones, and alkenes with oxygen as the sole oxidant
(Scheme 1, c).[19] As our continuing efforts on the
construction of fused heterocycles via indole C-H bond
functionalization, herein, we developed an one-pot
three-component synthesis of substituted thieno[2,3-
b]indoles from readily available indoles, alkenes or
alkynes, and sulfur powder under metal-free conditions
(Scheme 1, d).
[a]
Conditions: 1a (0.2 mmol), 2a (0.4 mmol), S8 (0.125
mmol), acid (5 equiv.), DMF (0.3 mL), 150 C,16 h, under
o
air atmosphere.
[b] GC yield based on 1a.
[c] 130 oC.
[d] Without DMF.
Under the optimized conditions, various indoles and
alkynes were explored as the substrates, and the results
are summarized in Table 2. A series of para-substituted
phenylacetylene smoothly reacted with 1a and sulfur
powder to give thieno[2,3-b]indoles in moderate to
good yields (3aa-3aj). The structure of 3aa was further
confirmed by X-ray crystallography (Fig. S1 in ESI). It
should be noted that cleavage of the C–halogen bond
was not observed as determined by GC-MS analysis.
The reaction yield decreased dramatically when 1-
chloro-2-ethynylbenzene was used as the substrate
(3ak), probably because of the highly steric hindrance.
The reaction yield decreased obviously when using
aliphatic alkynes as the substrate, such as 1-octyne (2m)
and 3,3-dimethylbut-1-yne (2n), which were coupled
with 1a to give the desired products in 31% and 47%
yields, respectively. Upon using diphenyl acetylene
(2o), 3ao was obtained in 34% yields. Furthermore,
indoles bearing various substituents could smoothly
couple with phenylacetylene and sulfur powder. Firstly,
the influence of various substituents at the C-5 position
was evaluated (3ba-3ga). In general, the reactions
proceeded smoothly to give the corresponding
products in moderate to good yields. Functional groups
such as fluoro, chloro, bromo and even iodo were all
compatible under the optimized reaction conditions.
Good yields were observed when the substituents were
located at the C-6 position and C-7 position of 1-
methyl-1H-indole (3ha-3ja). To our delight, free
indole (1k) could also couple with 2a and the yield was
as good as 1-methylindole. Meanwhile, 1-ethyl-1H-
indole (1l) and 1-isopropyl-1H-indole (1m) were also
To obtain optimized reaction conditions for the
direct
cyclization,
1-methylindole
(1a),
phenylacetylene (2a) and sulfur powder were
initially used as the standard substrates under
different conditions (Table 1). When the reaction
was performed using formic acid as the acid at 150
oC in DMF for 16 h, the desired annulation product
3a was obtained in 34% yield (Table 1, entry 1). This
result encouraged us to test a series of organic acids
such as HOAc, TFA, TsOH, MsOH, TfOH, PivOH,
and BzOH (Table 1, entries 2–8). Among them,
HOAc increased the yield of 3a to 70% (Table 1,
entry 2).
Several inorganic acids were also
investigated for this transformation (Table 1, entries
9–12), of which hydrochloric acid (6 M) showed the
best efficiency to give the corresponding product 3a
in 86% yield (Table 1, entry 9). Decreasing the
reaction temperature or the concentration of
hydrochloric acid both slightly decreased the
reaction yield (Table 1, entries 13-15). No desired
product 3a was observed when the reaction was
carried out in the absence of DMF (Table 1, entry 16
and Table S1 in the Supporting Information).
Table 1. Optimization of reaction conditions.[a]
2
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10.1002/adsc.201701106
Advanced Synthesis & Catalysis
participated well in this protocol to provide the
corresponding product 3ka in 74% yield. We further
tested this method with N-ethylindole and 1-isopropyl-
1H-indole, and the reaction proceeded smoothly to
provide the desired products in good yields (3la-3na).
suitable substrates for this kind of reaction to give the
corresponding products (3la-3oa) in good yields.
Table 2. Substrate scope with respect to the indoles and
alkynes.[a]
Table 3. Substrate scope with respect to the indoles and
alkene [a]
[a] Conditions: 1 (0.2 mmol), 4 (0.4 mmol), S8 (0.125 mmol),
HCl (6 M, 0.03 mL), HOAc (0.07 mL) DMF (0.3 mL), 150
oC, 16 h, under air atmosphere. Isolated yield based on 1.
[a] Conditions: 1 (0.2 mmol), 2 (0.4 mmol), S8 (0.125 mmol),
o
HCl (6 M, 0.1 mL), DMF (0.3 mL), 150 C, 16 h, under air
atmosphere. Isolated yield based on 1.
Control experiments were carried out to gain
preliminary insight into the reaction mechanism.
Treatment of 2a or 4a with sulfur powder under
standard conditions without 1-methyl-indole (1a) for
16 h gave N,N-dimethyl-2-phenylethanethioamide (5a)
in 55% and 45% yields, respectively (Scheme 2, a and
b). Trace amount of the desired product was obtained
when 1-methyl-3-styryl-1H-indole (6a) was treated
with sulfur powder (Scheme 2, c). Further treatment of
N,N-dimethyl-2-phenylethanethioamide (5a) with 1-
methyl-indole (1a) afforded the desired product 3aa in
45% yield. No desired product was observed when the
reaction was carried out in the absence of S8, and the
product 3aa could be gained in 77% yield when 3 equiv.
of sulfur powder was added to the reaction (Scheme 2,
e). The product 3aa could be gained in 77% yield when
using 2-phenylthiirane (7a) as the substrate with 1-
methyl-indole (1a). Based on these observations, a
plausible mechanism to rationalize this transformation
is illustrated in Scheme 3. Initially, intermediate A is
generated from 2a or 4a with DMF and sulfur powder
Furthermore, we examined the reactions between
indoles and various substituted alkenes (Table 3). We
re-optimized the reaction conditions and were
delighted to find that the reactions could be smoothly
performed in HCl:HOAc (v/v=3:7) as the
combinational acid, which afforded the desired product
3aa in 76% yield. In general, reactions between 1-
methyl-indole and the styrene derivatives bearing
electron-donating groups such as CH3 or OCH3, or
halogens such as F, Cl, or Br on the aromatic ring all
gave the desired products in moderate to good yields
(3ab, 3af-3aj). The positions of the substituents on the
phenyl ring significantly affected the reaction yields,
and 3ak was obtained in only 30% yield when 1-
chloro-2-vinylbenzene was used. Subsequently, a wide
range of substituted indoles were screened to couple
with styrene in moderate to good yields, regardless of
the functional groups at the C-5, C-6, or C-7 position.
A broad range of functional groups on the indole ring
such as methyl, methoxy, fluoro, chloro and bromo
were tolerated well. Notably, unprotected 1H-indole
(Willgerodt–Kindler reaction)[20] or from 5a via
[21]
resonated procedure
Then, 1-methyl-indole (1a)
reacts with intermediate A to afford an intermediate B,
3
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10.1002/adsc.201701106
Advanced Synthesis & Catalysis
Experimental Section
which can be further converted into the desired product
(3aa) under acidic conditions. DMF plays an imprtant
role to convert the starting materials into the final
product.
General procedure
1-Methyl-1H-indole (25.0 μL, 0.2 mmol), phenylacetylene
(44 μL, 0.4 mmol) and sulfur powder (32.0 mg, 1.0 mmol)
were added to a 20 mL reaction vessel. HCl (6 M, 0.1 mL)
and DMF (0.3 mL) were then added by syringe. The sealed
reaction vessel was stirred at 150 oC under air for 16 h. After
cooling to room temperature, the reaction was diluted with
ethyl acetate (5 mL) and washed with saturated salt water.
The organic layer was separated, and the aqueous layer was
extracted with ethyl acetate for three times. The combined
organic layer was dried over sodium sulfate, the volatiles
were removed under reduced pressure. The residue was
purified by column chromatography on silica gel (petroleum
ether/EtOAc = 300:1) to yield the desired product 3aa as
white solid (40.0 mg, 76% yield), mp 136-138 oC. Rf = 0.60
(100:1 petroleum ether/EtOAc).
CCDC-1501644
contains
the
supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge
Crystallographic
Data
Centre
via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21572194, 21372187, 21502160), Hunan
Provincial Natural Science Foundation of China (16JJ3112), the
Scientific Research Fund of Hunan Provincial Education
Department (YB2016B024), and the Hunan Provincial Innovative
Foundation for Postgraduate (CX2016B260).
Scheme 2. Control experiments.
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Scheme 3. Proposed reaction pathway.
In summary, we have developed a simple and
efficient method for the synthesis of thieno[2,3-
b]indole from indoles, alkenes or alkynes, and sulfur
powder under metal-free conditions. DMF plays an
important role to convert the starting materials into
the fused products. Various functional groups were
well tolerated under the optimized reaction
conditions. This method affords an efficient and
general approach for the synthesis of biologically
important substituted thieno[2,3-b]indole from
readily available strarting materials under simple
reaction conditions.
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Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201701106
Advanced Synthesis & Catalysis
COMMUNICATION
Facile Three-Component Thieno[2,3-b]indole
Synthesis from Indoles, Alkenes or Alkynes and
Sulfur Powder under Metal-Free Conditions
Adv. Synth. Catal. Year, Volume, Page – Page
Bin Li, Penghui Ni, Huawen Huang, Fuhong
Xiao,* Guo-Jun Deng *
6
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