Diisobutylaluminum Hydride Promoted Selectivity-Switchable Synthesis of Benzothiophene Oxides and Benzothiophenes via an Al-Li-Dimetalated Intermediate

Article abstract of DOI:10.1021/acs.orglett.0c00884

We developed an efficient and direct method for synthesis of benzothiophene oxides from 1-bromo-2-[2-(trimethylsilyl)ethynyl]benzenes and thionyl chloride as an easily accessible source of the sulfinyl group. Benzothiophenes were also synthesized selectiv

Full text of DOI:10.1021/acs.orglett.0c00884

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Letter
Diisobutylaluminum Hydride Promoted Selectivity-Switchable
Synthesis of Benzothiophene Oxides and Benzothiophenes via an
Al−Li-Dimetalated Intermediate
Seiya Uchida, Hidenori Kinoshita,* and Katsukiyo Miura*
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ABSTRACT: We developed an efficient and direct method for
synthesis of benzothiophene oxides from 1-bromo-2-[2-
(trimethylsilyl)ethynyl]benzenes and thionyl chloride as an easily
accessible source of the sulfinyl group. Benzothiophenes were also
synthesized selectively by simply increasing the amount of thionyl
chloride. These methods achieved efficient syntheses of various
benzothiophene oxides and benzothiophenes. The further modification of the benzothiophene oxides obtained was also
demonstrated.
enzothiophene oxides are usually prepared from the
Bcorresponding benzothiophenes through oxidation. Care
is required in some cases for this transformation to avoid over
oxidation, that is, the formation of benzothiophene 1,1-
dioxides, although a few selective mono-oxidations of
benzothiophenes have been reported.1 Methodologies for the
synthesis of benzothiophenes have been intensively developed
to date,2 while straightforward synthesis of benzothiophene
oxides through the formation of rings containing sulfinyl group
is unexplored. Recently, benzothiophene oxides have gained
considerable attention since these oxides serve as high
potential scaffolds for the syntheses of the C2- and C3-
substituted benzothiophenes (Scheme 1a).3 This class of
substituted benzothiophene is among the most important
chemical structures in research fields that range from medicinal
chemistry to materials chemistry; such compounds are found
in various pharmaceutical structures4 and functional materials,
such as semiconductors.5 Therefore, a direct synthesis of
benzothiophene oxides is desirable not only for redox
economy6 but also for providing rapid access to substituted
benzothiophenes. To this end, based on our study on
diisobutylaluminum hydride (DIBAL-H)-promoted silole syn-
thesis,7 we hypothesized that the route shown in Scheme 1c
would afford benzothiophene oxide 2a effectively. The route
consists of the following reactions: regioselective hydro-
alumination of 1a with DIBAL-H,8 isomerization of the
resultant vinylaluminum intermediate B to form C through the
spontaneous in situ isomerization,8,9 lithiation of C to generate
the Al−Li dimetal intermediate D, and double-nucleophilic
substitution of D onto SOCl2 to provide the desired thiophene
oxide 2a. The silyl group at the sp-carbon plays two important
roles for the present cyclization. One role is promoting the site
selective hydroalumination step by α-effect of the silyl group,
which lowers π* level of the C−C triple bond and stabilizes the
newly formed C−Al bond α to silicon by hyperconjugation
with σ* orbital of the C−Si bond. The other role is facilitating
the subsequent geometrical isomerization of the vinyl-
aluminum intermediate B to C. The α-effect of the silyl
group and cooperative interaction with unoccupied p orbital of
the Al metal can polarize the C−C double bond of (Z)-
vinylaluminum intermediate B to lower its rotation barrier.7b,8
In this context, Tsuchiya and co-workers reported to a similar
approach to benzoheteroles, which is a two-pot synthesis
starting from 1a or [2-(2-trimethylsilyl)ethynyl]benzene via
double nucleophilic substitution of the dilithium intermediate
A corresponding to D (Scheme 1b).2a We expected that the
C−Al bond of D is reactive enough for the S−C bond
formation and evaluated the possibility of the one-pot direct
synthesis of benzothiophene oxides via the Al−Li dimetal
intermediate D (Scheme 1c). Our results show that 1a
successfully reacts with SOCl2 to give the desired benzothio-
phene oxide 2a in excellent yield. During this study, we also
found that the corresponding benzothiophene could be
obtained selectively by simply increasing the amount of
SOCl2 used. The synthesis of benzothiophene oxides in a
one-pot procedure involving the direct use of organoaluminum
intermediate has, to the best of our knowledge, not been
achieved. Herein, we report the direct and selective syntheses
of benzothiophene oxides and benzothiophenes using SOCl2
as a sulfur source.
Received: March 9, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00884
© XXXX American Chemical Society
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time after the addition of SOCl2 decreased the yield to 71%
(entry 6). Varying the reaction temperature and time was not
effective in improving the yield. A large-scale reaction with 10
mmol of 1a also proceeded smoothly to give 2a in 88% isolated
yield (8.8 mmol, 1.96 g).
Scheme 1. Synthetic Applications of Benzothiophene
Oxides and Our Strategy for Their Synthesis
With the optimized reaction conditions in hand, we next
investigated the scope of the transformation (Scheme 2).
a
Scheme 2. Synthesis of Benzothiophene Oxides
We initially examined the one-pot three-step synthesis of 2a
from 1a and SOCl2 under the reaction conditions (solvents,
temperatures, and times) shown in Table 1. After evaluating
the amounts of DIBAL-H, BuLi, and SOCl2 (entries 1−5), we
found that the reaction gave the best result with a small excess
(1.2 equiv) of the reagents (entry 5). An elongated reaction
a
All reactions were carried out with 1 (0.50 mmol), DIBAL-H (0.60
mmol), BuLi (0.60 mmol), SOCl2 (0.60 mmol), hexane (0.5 mL),
b
and THF (0.5 mL). Isolated yields are shown. NMR yield (Bn2O
was used as an internal standard).
Table 1. Optimizing the Synthesis of Benzothiophene Oxide
2a
a
Methylated benzothiophene oxides 2b and 2c were obtained in
96% and 54% yields, respectively. The structure of the
unknown compound 2b was clearly confirmed by X-ray
analysis.10 Halo groups such as F and Cl were tolerated under
the reaction conditions, and 2d and 2e were obtained in good
yields. Naphtho[1,2-b]thiophene oxide 2f and naphtho[2,3-
b]thiophene oxide 2g were successfully synthesized under
these conditions. The reaction of 1h bearing an anthracene
core gave anthra[2,3-b]thiophene 3h in 47% yield as the sole
product instead of its oxide 2h. Benzothienothiophene oxide 2i
was also prepared under the same conditions in good yield.
While 2j−m were observed in the crude products, they were
inseparable due to their instabilities on the silica gel column.
The crude oxides 2j and 2l were successfully reduced to the
corresponding thiophenes 3j and 3l by DIBAL-H, which were
purified by reduced pressure distillation and properly
identified.10 The reaction of 2-[methyl(diphenyl)-
silylethynyl]-1-bromobenzene (1n) gave the corresponding
thiophene oxide 2n in moderate yield. We also examined the
reactions of substrates, which are substituted at the position
b
DIBAL-H x
BuLi y
SOCl2 z
yield of 2a
entry
(equiv)
(equiv)
(equiv)
(%)
1
2
3
4
5
1.05
1.05
1.05
1.2
1.2
1.2
1.05
1.05
1.2
1.2
1.2
1.05
1.1
1.05
1.05
1.2
47
32
30
60
c
93
c
d
6
1.2
1.2
71
a
All reactions were carried out with 1a (0.50 mmol), DIBAL-H, BuLi,
SOCl2, hexane (0.5 mL), and THF (0.5 mL). NMR yields are shown
(Bn2O was used as an internal standard). Isolated yields are shown.
b
c
d
The reaction time after addition of SOCl2 was 20 h.
B
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ortho to the alkynyl group; however, this class of substrates did
not work.10
To our surprise, 2-(trimethylsilyl)benzo[b]thiophene (3a)
was formed with an increased amount of SOCl2. The reaction
with 1.7 equiv of SOCl2 gave 3a in 36% yield along with 2a
(Table 2, entry 1). Benzothiophene 3a was obtained as the sole
respectively. At this stage, the reason for the observed
desilylation is unclear. Ethynylthiophenes 1j−m were not
suitable substrates for this transformation under the optimized
conditions, and unidentifiable complex mixtures were obtained
in all cases.
We investigated the reason that the reaction direction
toward benzothiophene oxides or benzothiophenes depends
on the amount of SOCl2 (Scheme 4). It is known that SOCl2
a
Table 2. Optimizing the Synthesis of Benzothiophene 3a
Scheme 4. Investigating the Selective Formation of 2 and 3
b
yield (%)
entry BuLi (equiv) SOCl2 (equiv) temp (°C) time (h) 2a
3a
1
2
3
4
5
6
7
8
9
1.2
1.2
1.2
1.5
1.5
1.2
1.2
1.2
1.2
1.7
2
5
2
5
5
5
5
5
50
rt
rt
50
rt
rt
rt
50
50
18
18
18
2
18
18
24
18
18
45
0
0
0
0
0
0
0
0
36
73
85
47
64
84
82
88
94
c
c
c
c
d
a
All reactions were carried out with 1a (0.50 mmol), DIBAL-H
(0.525 mmol), BuLi, SOCl2, hexane (0.5 mL), and THF (0.5 mL).
b
NMR yields are shown (Bn2O was used as an internal standard).
c
d
Isolated yield. DIBAL-H (0.60 mmol) was used.
product, when 2.0 equiv of SOCl2 was used (entry 2). The
isolated yield of 3a was improved to 94% (entry 9) after
examining several reaction conditions (entries 3−9). A large-
scale reaction with 4.0 mmol of 1a also proceeded smoothly to
give 3a in 93% isolated yield (3.7 mmol, 0.76 g) without any
loss of reaction efficiency.
We next investigated the scope of the selective synthesis of
benzothiophenes (Scheme 3). Except for a few examples,
thiophene derivatives 3 were successfully prepared in good
yields. The reactions of 1c and 1i provided the desilylated
benzothiophenes 3c′ and 3i′ in 59% and 49% yields,
reacts with water to form H2SO3 (Scheme 4a) and H2SO3 is a
powerful reducing reagent. This fact strongly suggests that the
H2SO3 generated from the excess SOCl2 by the aqueous
workup should reduce 2a to 3a. To provide evidence for this
hypothesis, we treated benzothiophene oxide 2a with SOCl2 (4
equiv) under the same conditions as the workup process.
When the reaction mixture was stirred in aqueous HCl/
hexane/AcOEt for 1 h at ambient temperature,10 as expected,
benzothiophene 3a was isolated in 70% yield (Scheme 4b). We
also conducted the reaction of the oxide 2a with aqueous
H2SO3 in hexane/AcOEt at an ambient temperature for 0.5 h
(Scheme 4c). Consequently 3a was obtained quantitatively.
Next we considered the possibility that SOCl2 itself reduced
the benzothiophene oxides to the corresponding benzothio-
phenes in situ. To investigate the possibility, we conducted the
reaction of 1a under the conditions for the preparation of
benzothiophene 3a but added undecane to prevent exposure of
the product to the harsh conditions (Scheme 4d).11 Without
the workup using diluted hydrochloric acid, the volatile
reagents and solvents, including excess SOCl2, were evapo-
a
Scheme 3. Synthesis of Benzothiophenes
1
rated, and the residue was directly analyzed by H NMR
spectroscopy. The result showed that benzothiophene 3a was
formed in 40% yield. We then mixed 2a with an excess amount
of SOCl2 in hexane/AcOEt at 50 °C for 18 h (Scheme 4e).
The residue was examined after removing all volatiles, which
confirmed that 3a had been formed in 35% yield along with an
identifiable complex mixture. These observations indicate that
2a is partly reduced by SOCl2 itself or H2SO3, which is
generated during these processes from a small amount of
atmospheric water and SOCl2, in the examples shown in
Schemes 4d and 4e. However, the yield of 3a was much lower
than that of the reaction conducted under the optimized
reaction conditions (Table 2, entry 9). Considering all of the
a
All reactions were carried out with 1 (0.50 mmol), DIBAL-H (0.60
mmol), BuLi (0.60 mmol), SOCl2 (2.50 mmol), hexane (0.5 mL),
and THF (0.5 mL). Isolated yields are shown.
C
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data together, we conclude that most of 2a is reduced
efficiently by H2SO3 to give 3a during the aqueous workup
process.
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Since aqueous H2SO3 generated from SOCl2 and aqueous
HCl successfully reduces benzothiophene oxide 2a to
benzothiophene 3a (Scheme 4b), we attempted to reduce
oxides 2c and 2i under the conditions shown in Scheme 4b to
produce the 2-silylated benzothiophenes 3c and 3i, which
could not be obtained directly from 1c and 1i. As shown in
Scheme 5, the reduction proceeded smoothly to form the 2-
silylated benzothiophenes in good yield without the loss of the
silyl group.
AUTHOR INFORMATION
Corresponding Authors
■
Hidenori Kinoshita − Department of Applied Chemistry,
Graduate School of Science and Engineering, Saitama
University, Saitama 338-8570, Japan; orcid.org/0000-
0002-9761-9015; Email: hkino@mail.saitama-u.ac.jp
Katsukiyo Miura − Department of Applied Chemistry, Graduate
School of Science and Engineering, Saitama University, Saitama
338-8570, Japan; orcid.org/0000-0002-4535-8677;
Email: kmiura@apc.saitama-u.ac.jp
Scheme 5. Reducing Silylated Benzothiophene Oxides to
the Corresponding Benzothiophenes
Author
Seiya Uchida − Department of Applied Chemistry, Graduate
School of Science and Engineering, Saitama University, Saitama
338-8570, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00884
We further examined the derivatization of 2 according to the
method reported by Procter and co-workers (Scheme 6).3
Notes
The authors declare no competing financial interest.
Scheme 6. Derivatization and Applications
REFERENCES
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Surprisingly, the expected products 5 were not obtained, but
the unexpected desilylated product or benzothienobenzofuran
6 was isolated even in low yield. Several synthetic method-
ologies for 6 have been reported;12 however, its synthesis from
silylated benzothiophene oxides is unknown.
In conclusion, we developed an efficient method for
switchable synthesis of benzothiophene oxides and benzothio-
phenes by simply changing the amount of SOCl2 used as the
sulfur source. This transformation represents a straightforward
method for the preparation of benzothiophene oxides directly
from acyclic starting materials. Al−Li dimetal intermediates
like C (Scheme 1c) enable the present reaction. The
benzothiophene oxides obtained in this manner can be
converted into benzothienobenzofuran. This novel reaction is
under further investigation in this laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
sı
́
(3) (a) Shrives, H. J.; Fernandez-Salas, J. A.; Hedtke, C.; Pulis, A. P.;
Procter, D. J. Nat. Commun. 2017, 8, 14801−14807. (b) He, Z.;
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00884.
́
́
Shrives, H. J.; Fernandez-Salas, J. A.; Abengozar, A.; Neufeld, J.; Yang,
K.; Pulis, A. P.; Procter, D. J. Angew. Chem., Int. Ed. 2018, 57, 5759−
5764. (c) Yang, K.; Pulis, A. P.; Perry, G. J. P.; Procter, D. J. Org. Lett.
2018, 20, 7498−7503.
Experimental procedures and characterization data; Xray
crystallographic data for 2b (PDF)
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involving benzothiophene structure, see: (a) Rackham, M. D.;
Brannigan, J. A.; Rangachari, K.; Meister, S.; Wilkinson, A. J.;
Holder, A. A.; Leatherbarrow, R. J.; Tate, E. W. J. Med. Chem. 2014,
Accession Codes
CCDC 1987428 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
D
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(9) We observed that the isomerization reaction of A to B in Scheme
1b proceeded smoothly at 50 °C for 2 h, although Hoveyda and co-
workers conducted the reaction at 55 °C in ref 8.
(10) See the Supporting Information.
(11) After evaporation of all volatile solvents and reagents, the
reaction residue was able to be exposed harsh conditions and the
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E
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