Synthesis of Benzothienobenzofurans via Annulation of Electrophilic Benzothiophenes with Phenols

Article abstract of DOI:10.1021/acs.orglett.1c00219

We have developed a metal-free, mild, and green synthetic route toward benzothieno[3,2-b]benzofurans by the annulation of 3-nitrobenzothiophene with phenols. The reaction was found to be general with a range of substituted phenols. In addition, we could extend the methodology for the synthesis of pentacenes and could demonstrate the synthesis in gram-scale. Moreover, we extended the strategy for the synthesis of benzothieno[2,3-b]benzofurans by starting from 2-nitrobenzothiophenes.

Full text of DOI:10.1021/acs.orglett.1c00219

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Letter
Synthesis of Benzothienobenzofurans via Annulation of
Electrophilic Benzothiophenes with Phenols
Akhil Krishnan R., Sheba Ann Babu, Nitha P. R., Jagadeesh Krishnan, and Jubi John*
Cite This: Org. Lett. 2021, 23, 1814−1819
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ABSTRACT: We have developed a metal-free, mild, and green synthetic route toward benzothieno[3,2-b]benzofurans by the
annulation of 3-nitrobenzothiophene with phenols. The reaction was found to be general with a range of substituted phenols. In
addition, we could extend the methodology for the synthesis of pentacenes and could demonstrate the synthesis in gram-scale.
Moreover, we extended the strategy for the synthesis of benzothieno[2,3-b]benzofurans by starting from 2-nitrobenzothiophenes.
ubstantial advancements in the research on polycyclic
Saromatic hydrocarbons have been made in the past
decades, which have resulted in the development of materials
for light-emitting diodes, organic semiconductors, photo-
voltaics, and field-effect transistors.1 Recent explorations have
unravelled several heteroacenes incorporating S- or N-atoms
with interesting features that could be applied as functional
materials,2 which in turn has triggered the search for
straightforward synthetic approaches toward π-conjugated
heteroacenes.3 In the present communication, we report a
practical one-pot metal-free methodology toward benzothio-
phene-fused heteroacenes.
Benzothieno[3,2-b]benzothiophenes have been utilized
successfully in organic photovoltaics and organic field-effect
transistors (OFETs).4 Likewise, benzothieno[3,2-b]benzofuran
motifs are also believed to be promising candidates for material
applications as furan has a similar structure and energy profile
as those of thiophene.5 Unfortunately, the applications of
benzothieno[3,2-b]benzofuran are limited due to the lack of
facile synthetic routes toward these heteroacenes. One of the
first reports for the synthesis of benzothieno[3,2-b]benzofuran
was by the flash vacuum pyrolysis of appropriately substituted
phosphorus ylides.6 A Pd-catalyzed intramolecular dual C−H
activation of 3-aryloxybenzo[b]thiophenes was reported by
Satoh and Miura in 2015.7 Later, a Cu-catalyzed Ullmann-type
intramolecular C−O bond formation reaction toward
benzothieno[3,2-b]benzofurans was introduced.8 Very recently
Mitsudo et al. reported an electrochemical synthesis of this
tetracene from 2-(benzo[b]furan-2-yl)benzenethiol via a
dehydrogenative C−S bond formation pathway.9 All the
methods mentioned above required advanced starting
materials, metal catalysts or harsh conditions, and multistep
transformations for the synthesis of benzothieno[3,2-b]-
benzofurans with limited scope (Scheme 1).
The chemistry of electrophilic benzannulated heterocycles
was studied extensively by several groups.10 In particular,
electrophilic indole moieties (with electron-withdrawing
groups on the N-atom and C-2 or C-3 carbon atoms) were
utilized in different annulation reactions for the generation of
fused indoline/indole scaffolds.11,12 In a similar way, 2- or 3-
nitrobenzothiophenes were also investigated for reactivity in
annulation reactions toward fused heterocycles.13 We were
enthused by the report from Hajra and co-workers on the
synthesis of substituted furans by the reaction of nitrostyrenes
with 1,3-dicarbonyl compounds or phenols.14 Due to our
continued interest in utilizing electrophilic benzannulated
Received: January 20, 2021
Published: February 16, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00219
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1814−1819
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Letter
proved to be the best medium for the reaction (Table 1, entries
6−10). In all the reactions mentioned above, we observed that
a small proportion of 3-nitrobenzothiophene 1a remained
unreacted after the duration of the reaction. Hence, we
increased the amount of 4-methoxyphenol 2a and found that
1.3 equiv was required to furnish the product 3a in 94% yield
(Table 1, entries 11 and 12). Finally, the reaction failed to
proceed in the absence of base (Table 1, entry 13).
Scheme 1. Synthetic Routes toward Benzothieno[3,2-
b]benzofuran
Next, we devoted our efforts on checking the generality of
the annulation under the optimized conditions [1 (1.0 equiv),
2 (1.3 equiv), K2CO3 (0.5 equiv), EtOH, 80 °C, 24 h]
(Scheme 2). The reaction of 1.0 g of 1a with 4-methoxyphenol
Scheme 2. Generality of Benzothieno[3,2-b]benzofuran
a
Synthesis
heterocycles for the generation of functionalized hetero-
acenes,15 we were motivated to check the reactivity of
electrophilic benzothiophenes/indoles with phenols.
Our investigations commenced with 3-nitrobenzothiophene
1a and 4-methoxyphenol 2a as substrates. The first reaction
was set up with 1a and 2a in the presence of KOH as the base
in EtOH at 80 °C. As expected, we could isolate 8-
methoxybenzothieno[3,2-b]benzofuran 3a in 31% yield
(Table 1, entry 1). The product was characterized by
spectroscopic techniques, X-ray crystallographic studies, and
also comparison with literature reports.
We then moved on with optimizing the reaction conditions
with 1a and 2a as substrates. From the bases tested (NaOH,
KOH, Na2CO3, Cs2CO3, DBU and K2CO3), the highest yield
was obtained from the reaction with K2CO3(Table 1, entries
1−6). We focused on using green solvents for the present
annulation reaction. Among the solvents screened, EtOH
a
Table 1. Optimisation Studies for the Synthesis of 3a
a
Reaction conditions: 1a (1.0 equiv, 100 mg), 2 (1.3 equiv), K2CO3
b
(0.5 equiv), EtOH (0.28 M), 80 °C, 24 h; From 1 g of 1a.
entry
base
solvent
T (°C)
yield of 3a (%)
1
2
3
4
5
6
7
8
9
10
NaOH
KOH
Na2CO3
Cs2CO3
DBU
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
iPrOH
EtOAc
MeOH
H2O
80
80
80
80
80
80
80
80
60
100
80
80
80
31
38
66
35
21
82
59
38
75
47
92
94
NR
2a afforded the product 3a in 80% yield. Unsubstituted phenol
afforded benzothieno[3,2-b]benzofuran 3b in 67% yield. The
presence of electron-donating substituents were found to have
a positive influence on the outcome of the reaction. In this line,
the reactions of p-cresol, p-tert-butylphenol, and [1,1′-
biphenyl]-4-ol with 1a furnished the corresponding products
3c, 3d, and 3e in 73−81% yields. However, the reaction of p-
nitrophenol failed to furnish the expected annulated product 3f
which might be due to the lack of nucleophilicity.
Halogenated phenols such as p-bromophenol and p-
chlorophenol reacted well with 3-nitrobenzothiophene 1a
yielding products 3g and 3h in 72% and 74% yields,
respectively (Scheme 2). Next we checked the reactivity of
3-methoxyphenol with 1a from which 3i was isolated in 60%
yield, and 3i′ was found to occur in trace amounts. We then
b
11
12
13
EtOH
EtOH
EtOH
c
a
Reaction conditions: 1a (1.0 equiv., 0.28 mmol), 2a (1.0 equiv), base
(0.5 equiv), solvent (1.0 mL), 24 h. 2a (1.2 equiv). 2a (1.3 equiv).
b
c
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focused on the reactivity of ortho-substituted phenols with 3-
nitrobenzothiophene 1a. 2-Methoxyphenol and [1,1′-biphen-
yl]-2-ol underwent annulation efficiently with 1a, affording
products 3j and 3k in good yields. The reaction of o-
aminophenol with 1a failed to afford any isolable compound.
2-Chlorophenol, 2-bromophenol, and 2-iodophenol partici-
pated in the current annulation methodology furnishing the
corresponding products 3m, 3n, and 3o in good yields.
Multisubstituted phenol such as 2,5-dimethylphenol yielded
the product 3p in 55% yield, whereas the reaction with 2-
bromo-4,5-difluorophenol afforded 3q in 71% yield. The
reactions of 5-bromo-3-nitrobenzothiophene 1b with unsub-
stituted phenol and p-cresol were found to be better yielding in
comparison with the ones with 1a. In addition, we synthesized
bis-halogenated benzothieno[3,2-b]benzofurans 3t and 3u in
good yields from the reaction of 3-nitrobenzothiophene with 4-
bromophenol and 4-iodophenol, respectively. Finally, we
utilized 3-nitrobenzothiophene-5-carbonitrile 1c for annulation
with 2a and obtained the expected product 3v in 70% yield. By
this methodology, we could introduce halogens at different
positions of benzofuran and benzothiophene moieties which
was not an easy task with existing methods. All these points of
functionalization could be utilized for making scaffolds for
material applications.
the reaction in 65% yield. The characterization of 3z revealed
that annulation had taken place at the third carbon of 2-
naphthol (sterically favorable) rather than the more reactive α-
position. The reaction of 6-bromonaphthalen-2-ol with 1a and
the reaction of 2-naphthol with 1b also afforded the respective
products in good yields.
Based on our observations and on literature reports,14 we
have proposed a mechanism as depicted in Scheme 5. The first
Scheme 5. Mechanism of the Synthesis of Benzothieno[3,2-
b]benzofuran
step will be the addition of phenol (via the carbon ortho to the
hydroxyl moiety) to the C-2 of 3-nitrobenzothiophene to yield
the adduct A. Next, intramolecular cyclization occurs in A from
the oxygen end of phenol to the C-3 of benzothiophene to
furnish B. Finally, elimination of hyponitrous acid and water
from B follows to generate benzothieno[3,2-b]benzofuran.
Intrigued by this facile strategy for the synthesis of
benzothieno[3,2-b]benzofuran from 3-nitrobenzothiophene
and phenol, we were motivated to check the feasibility of
benzothieno[2,3-b]benzofuran synthesis. There are only scant
reports available for the synthesis of this heteroacene which
utilizes multistep synthesis or metal catalysis.16 In our initial
attempt, 2-nitrobenzothiophene 4 was treated with 4-
methoxyphenol 2a under the optimized mentioned above. As
expected, the reaction afforded 2-methoxybenzothieno[2,3-
b]benzofuran 5 in 38% yield (Scheme 6). The detailed
optimization and generality studies on this transformation are
underway in our lab.
Our efforts were then directed on checking the reactivity of
phenolic natural products toward this annulation method
(Scheme 3). We first performed the reaction of thymol 2s with
Scheme 3. Synthesis of Benzothieno[3,2-b]benzofuran with
Phenolic Natural Products
Scheme 6. Synthesis of Benzothieno[2,3-b]benzofuran by
the Annulation of 2-Nitrobenzothiophene
1a from which the substituted benzothieno[3,2-b]benzofuran
3w was obtained in 62% yield. Next, we checked the reactivity
of eugenol which also underwent the annulation, affording the
corresponding product 3x in 64% yield.
Our success in the annulation of electrophilic benzothio-
phenes with phenol for the synthesis of heteroacenes made us
check the reactivity of naphthols (Scheme 4). Initially, 3-
nitrobenzothiophene 1a was treated with 1-naphthol 2u, and
as expected, we isolated benzothieno[3,2-b]naphthofuran 3y in
65% yield. Next, the reactivity of 2-naphthol 2v was assessed
toward the synthesis of pentacenes, and 3z was obtained from
Finally, we wanted to check the annulation of phenol with
electrophilic indole. We treated N-Ts-3-nitro-indole 6 with 4-
methoxyphenol 2a under the optimized conditions (Scheme
7). The reaction afforded benzofuro[3,2-b]indole 7 in trace
Scheme 7. Synthesis of Benzofuro[3,2-b]indole by the
Annulation of Electrophilic Indole
Scheme 4. Generality of Synthesis of Benzothieno[3,2-
b]naphthofuran
a
amounts. The major transformation that occurred was the N-
Ts deprotection of 6 by phenol to afford 3-nitroindole 8 and 4-
methoxyphenyl 4-methylbenzenesulfonate 9. This interesting
synthetic route toward benzofuro[3,2-b]indole will also be
studied in detail.
a
Reaction conditions: 1a (1.0 equiv, 100 mg), 2 (1.3 equiv), K2CO3
(0.5 equiv), EtOH (0.28 M), 24 h.
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In conclusion, we have developed a facile methodology for
the synthesis of benzothieno[3,2-b]benzofuran, which other-
wise required metal catalysis, multiple step transformations,
and harsh conditions. The reaction occurs by the annulation of
phenols on electrophilic benzothiophenes. The methodology
was found to be general for a range of substituted phenolic
substrates and was scalable to gram scale. It is noteworthy to
mention that by this methodology halogen moieties could be
introduced at will, either on the benzothiophene or benzofuran
units. We could also utilize phenolic natural products in this
annulation for the generation of highly functionalized
benzothieno[3,2-b]benzofurans. Finally, we extended the
annulation strategy for the synthesis of benzothieno[2,3-
b]benzofuran starting from 2-nitrobenzothiophene and also to
benzofuro[3,2-b]indole from N-Ts-3-nitroindole. We are
currently working on utilizing the developed methodology
for synthesizing functionalized heteroacenes for material
applications, the results of which will be reported in due
course.
and Technology (CSIR-NIIST), Thiruvananthapuram
695019, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00219
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.K.L and J.J. thank DST for DST-SERB Project [DST/
SERB/F/481]. S.A.B. and N.P.R. thank CSIR for research
fellowship. J.J. also thanks CSIR (HCP-029) for financial
assistance. The authors thank Director, CSIR-NIIST for the
support. The authors thank Prof. Mahesh Hariharan and Mr.
Alex Andrews of IISER-Thiruvananthapuram for single-crystal
X-ray analysis. The authors also thank Mrs. Saumini Mathew
and Mrs. Viji S. of CSIR-NIIST for recording NMR and mass
spectra respectively.
ASSOCIATED CONTENT
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AUTHOR INFORMATION
Corresponding Author
■
Jubi John − Chemical Sciences and Technology Division,
CSIR-National Institute for Interdisciplinary Science and
Technology (CSIR-NIIST), Thiruvananthapuram 695019,
India; Academy of Scientific and Innovative Research
(AcSIR), Ghaziabad 201002, India; orcid.org/0000-
0003-0483-2026; Email: jubijohn@niist.res.in
Authors
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Akhil Krishnan R. − Chemical Sciences and Technology
Division, CSIR-National Institute for Interdisciplinary Science
and Technology (CSIR-NIIST), Thiruvananthapuram
695019, India
Sheba Ann Babu − Chemical Sciences and Technology
Division, CSIR-National Institute for Interdisciplinary Science
and Technology (CSIR-NIIST), Thiruvananthapuram
695019, India; Academy of Scientific and Innovative
Research (AcSIR), Ghaziabad 201002, India
Nitha P. R. − Chemical Sciences and Technology Division,
CSIR-National Institute for Interdisciplinary Science and
Technology (CSIR-NIIST), Thiruvananthapuram 695019,
India; Academy of Scientific and Innovative Research
(AcSIR), Ghaziabad 201002, India
Jagadeesh Krishnan − Chemical Sciences and Technology
Division, CSIR-National Institute for Interdisciplinary Science
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