Versatile synthesis of benzothiophenes and benzoselenophenes by rapid assembly of arylzinc reagents, alkynes, and elemental chalcogens

Article abstract of DOI:10.1002/anie.201304546

Rapidly aSSembled: The combination of cobalt-catalyzed migratory arylzincation and copper-mediated/catalyzed chalcogenative cyclization allows the construction of benzothiophenes and benzoselenophenes from arylzinc reagents, alkynes, and elemental chalcog

Full text of DOI:10.1002/anie.201304546

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Angewandte
Communications
DOI: 10.1002/anie.201304546
Synthetic Methods
Versatile Synthesis of Benzothiophenes and Benzoselenophenes by
Rapid Assembly of Arylzinc Reagents, Alkynes, and Elemental
Chalcogens**
Bin Wu and Naohiko Yoshikai*
Benzothiophene is frequently found as a core structure of
biologically active compounds such as raloxifene, sertacona-
zole, and SB-271046,[1] as well as materials for organic
electronics applications.[2] The selenium analogue, benzose-
lenophene, has also attracted increasing attention in the fields
of medicinal chemistry[3] and materials science.[4] Approaches
to their synthesis often involve cyclization of an alkynylarene
bearing an ortho-chalcogen functional group (A, Scheme 1a).
For example, Larockꢀs electrophile (I2, N-bromosuccinimide
(NBS), RSCl) mediated cyclization[5,6] and Nakamuraꢀs
alkynophilic metal (Au or Pt) catalyzed cyclization reac-
tions[7,8] represent efficient and complementary routes to
benzothiophenes and benzoselenophenes. A sequence com-
prising lithiation of an ortho-alkynylaryl bromide, electro-
philic trapping with elemental sulfur or selenium (or tellu-
rium), and cyclization of the resulting chalocogenide anion
also allows preparation of the corresponding benzochalcoge-
nophene.[9–12] Regardless of their efficiency and reliability,
these and other intramolecular cyclization approaches usually
have difficulty in diversifying the benzene ring moiety of
benzothiophene and benzoselenophene, because preparation
of the starting material such as A becomes increasingly
tedious with additional substituents on the benzene ring. We
report here an alternative synthetic approach based on the
assembly of arylzinc reagents, alkynes, and elemental sulfur or
selenium with the aid of cobalt and copper catalysts
(Scheme 1b,c). The modular nature of this approach allows
facile access to diversely functionalized benzothiophenes and
benzoselenophenes that are laborious to synthesize by the
existing synthetic methods.
Given the propensity of chalcogenide anions and chal-
À
cogen H bonds to be oxidized and form chalcogenide
radicals, we conceived that ortho-alkenylaryl metal B1 and
halide B2 would serve as viable precursors to benzochalco-
genophenes (Scheme 1b). Thus, electrophilic or nucleophilic
chalcogenation of B1 or B2, respectively, would be followed
by the formation of a radical species C, which would readily
undergo cyclization onto the alkenyl moiety to afford the
desired product upon oxidation. The apparent simplicity
notwithstanding, this approach cannot be an attractive option
without a convenient method to access starting materials B1
or B2 with diverse substitution patterns and has not been
explored practically.[13] However, we recently developed
a cobalt-catalyzed migratory arylzincation reaction of an
internal alkyne to afford ortho-alkenylarylzinc species B1’ (or
its iodinated product B2’).[14] Thus, we envisioned that
a combination of this reaction and the proposed chalcogena-
tive cyclization would allow divergent synthesis of benzo-
chalcogenophenes containing flexibility with respect to the
functional group on the benzene ring as well as the chalcogen
element (Scheme 1c).
Scheme 1. Synthetic approaches to benzothiophenes and benzoseleno-
phenes. FG=functional group.
[*] B. Wu, Prof. N. Yoshikai
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
Singapore 637371 (Singapore)
E-mail: nyoshikai@ntu.edu.sg
Homepage: http://www3.ntu.edu.sg/home/nyoshikai/
yoshikai_group/Home.html
Along with the above idea, our initial study was focused
on the construction of benzothiophene from ortho-alkenylar-
ylzinc species generated by [CoCl2(Xantphos)]-catalyzed
addition of 4-methoxyphenylzinc reagent 1a to 5-decyne 2a
(Scheme 2). After extensive screening of reaction conditions,
[**] We thank the Singapore National Research Foundation (NRF-
RF2009-05), Nanyang Technological University, and JST, CREST for
financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304546.
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Scheme 2. One-pot and stepwise constructions of benzothiophene 3aa
from 4-methoxyphenylzinc reagent, 5-decyne, and elemental sulfur.
Xantphos=4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.
we managed to establish two independent protocols (see the
Supporting Information for the optimization study). In one
protocol, the generation of the key arylzinc intermediate from
1a (prepared from ZnCl2·TMEDA and 4-methoxyphenyl-
magnesium bromide) was followed by treatment with CuI and
elemental sulfur at 908C for 4 h, thereby affording the desired
benzothiophene 3aa in 63% yield in a one-pot manner
(protocol A). Although 3aa was obtained even in the absence
of CuI, the Zn-to-Cu transmetalation significantly improved
the yield. Alternatively, the ortho-alkenylarylzinc intermedi-
ate (prepared in a one-pot manner from 4-iodoanisole,
Zn·LiCl, and 5-decyne with the Co-Xantphos catalyst)[15]
was first quenched with iodine, and the resulting ortho-
alkenylaryl iodide 4aa was subjected to copper-catalyzed
thiolation using CuI, S, and K2CO3 in DMF to afford the
product 3aa cleanly in 90% yield (protocol B).[16] Note that
neither protocol required any particular external oxidant,
thus suggesting that CuI, elemental sulfur, or residual
molecular oxygen served as oxidants for the ring-closure/
aromatization process. Alternatively, oxidation may take
place during the workup.
The scope of the benzothiophene synthesis was explored
first using different arylzinc reagents and 5-decyne
(Scheme 3). Benzothiophenes 3aa–3ia bearing various func-
tional groups at the C6-position could be prepared in
moderate to good yields with either protocol A or B. The
one-pot protocol A was applicable to arylzinc reagents
bearing electron-donating substituents (3aa and 3ca). On
the other hand, protocol A worked poorly with an electron-
withdrawing substituent on the zinc reagent and produced
a significant amount of the corresponding protonation
product, while the stepwise protocol B cleanly furnished the
desired benzothiophene (3ea–3ia). Note that the synthesis of
3ha could be performed on a 2 mmol scale in 85% yield.
Regioselective migratory addition of meta-substituted aryl-
zinc reagents, controlled either by steric hindrance or by
coordination,[14] was applied to the regioselective synthesis of
6-methyl-, 6,7-methylenedioxy-, and 7-methoxybenzothio-
phenes 3ja–3la. The low yield of 3ja was not due to
formation of its regioisomer, but because of the sluggish
reaction of the m-tolylzinc reagent. Thieno[2,3-b]quinoline
3ma was also synthesized with exclusive regioselectivity. 6-
Hydroxybenzothiophene 3na was obtained from a Boc-
protected precursor iodide, where removal of the Boc group
Scheme 3. Benzo[b]thiophenes synthesized from different arylzinc
reagents and 5-decyne (0.5 mmol and 0.2 mmol scales for protocols A
and B, respectively). The yields for protocols A and B are based on 5-
decyne and the ortho-alkenylaryl iodide (4), respectively. The two-step
yields for protocol B (based on 5-decyne) are shown in parentheses.
[a] The starting material was protected with a Boc group, which was
removed during the reaction. [b] Yield is based on 5-decyne (2a).
Boc=tert-butoxycarbonyl.
À
coincided with C S coupling/cyclization. 6-Aminobenzothio-
phene 3oa was obtained from p-bromoaniline protected in
the form of the acetophenone imine in a respectable yield of
42% (based on 5-decyne) through a sequence comprising
cobalt-catalyzed zinc insertion,[15] migratory arylzincation to
À
5-decyne, iodination, copper-catalyzed C S coupling/cycliza-
tion, and acidic hydrolysis.
Benzothiophenes bearing different substituents on the
C2- and C3-positions were also synthesized from a series of
internal alkynes (Scheme 4). The one-pot protocol A was
applicable to the condensation of the 3,4-methylenedioxy-
phenylzinc reagent, dialkyl- or alkylarylalkyne, and elemental
sulfur to afford the corresponding benzothiophenes 3kb–3kf
in reasonable yield. With alkylarylalkynes bearing sterically
hindered aryl groups, protocol B allowed synthesis of benzo-
thiophenes 3ah and 3ai in excellent yields. The reaction of 1-
trimethylsilyl-1-propyne by using protocol A resulted in
partial loss of the trimethylsilyl group, which was completely
removed by further treatment of the crude product with KOH
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Scheme 4. Benzo[b]thiophenes synthesized from different alkynes
(0.5 mmol and 0.2 mmol scales for protocols A and B, respectively).
The yields for protocols A and B are based on the alkyne and the ortho-
alkenylaryl iodide (4), respectively. The two-step yields for protocol B
(based on the alkyne) are shown in parentheses. [a] The reaction was
performed using 1-trimethylsilyl-1-propyne, and the SiMe3 group was
removed by treatment with KOH/MeOH.
Scheme 5. Synthesis of benzo[b]selenophenes through copper-cata-
À
lyzed C Se coupling/cyclization (0.2 mmol scale). The two-step yields
in MeOH to afford 3-methylbenzothiophene 3aj in 50%
yield.
based on the alkyne are shown in parentheses. [a] The starting material
had an OBoc group as the R group, which was removed after the
reaction. [b] The reaction time was 36 h. [c] The starting material had
a SiMe3 group as the R1 group, which was removed during the
reaction. NMP=N-methyl-2-pyrrolidone.
Attempts to expand the above benzothiophene synthesis
to benzoselenophenes met with a challenge. The one-pot
approach through copper-mediated reaction of ortho-alken-
ylarylzinc species with selenium powder resulted in a complex
mixture with no indication of benzoselenophene formation.
Nevertheless, careful examination of the stepwise route
allowed us to establish suitable reaction conditions for the
À
copper-catalyzed C Se coupling/cyclization of ortho-alkenyl-
aryl iodide, where the choice of NMP as the solvent and an
elevated temperature of 1208C were crucial (Scheme 5).[17]
Thus, selenium analogues of many of the benzothiophenes
presented in Schemes 3 and 4 could be synthesized in
moderate to good yields. Selenopheno[2,3-b]thiophene 5pa
is a notable additional example, as preparation of its sulfur
analogue was unsuccessful for unknown reasons.
We encountered difficulty in further extension of the
present approach to benzotellurophene synthesis. As was the
case with benzoselenophene, the one-pot approach was not
Scheme 6. Synthesis of benzo[b]tellurophene through iodine–magne-
sium exchange/trapping with tellurium.
7-one 8 (Scheme 7a). Second, O-acetyloxime 9 derived from
6-acetylbenzothiophene 3ia was subjected to rhodium(III)-
catalyzed redox-neutral annulation with diphenylacetylene[21]
to afford thieno[3,2-g]isoquinoline 10 (Scheme 7b). Finally,
imine 11 derived from 6-aminobenzothiophene 3oa and
acetophenone participated in a palladium-catalyzed dehy-
drogenative cyclization reaction[22] to afford 7H-thieno[3,2-
À
successful. Furthermore, copper-catalyzed C Te coupling/
À
cyclization reactions of ortho-alkenylaryl iodide under vari-
ous conditions produced the desired benzotellurophene,
however, as an inseparable mixture with a substantial
amount of a deiodination product.[18] As a compromise to
these problems, benzotellurophene 6aa was synthesized in
moderate yield from the iodide 4aa through iodine–magne-
sium exchange[19] followed by electrophilic trapping with
tellurium powder (Scheme 6).
f]indole 12. In all of these examples, C H functionalization
took place at the less hindered position.
In summary, we have established versatile and flexible
synthetic methods for benzothiophenes and benzoseleno-
phenes through the combination of cobalt-catalyzed migra-
tory arylzincation and copper-mediated or -catalyzed chalco-
genative cyclization reactions. The present one-pot or two-
step, three-component coupling approach allows expedient
synthesis of a wide variety of functionalized benzothiophenes
and benzoselenophenes, which are not easily accessible by the
existing synthetic methods, with minimum synthetic labor.
Further studies on the use of ortho-alkenylarylzinc com-
pounds and ortho-alkenylaryl iodides as reagents for the
construction of benzo-fused heterocycles are ongoing in our
laboratory, in light of growing interest in nonconventional
The functional groups on the cyclization products offer us
diverse opportunities for the extension of the p-conjugated
À
system through C H bond functionalization (Scheme 7).
First, condensation of benzothiophene-6-carbaldehyde 3ha
with p-anisidine was followed by rhodium(III)-catalyzed,
aldimine-directed oxidative annulation with diphenylacety-
lene[20] to afford, upon hydrolysis, 7H-indeno[5,6-b]thiophen-
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Scheme 7. Transformation of functionalized benzothiophenes through
À
C H bond functionalization. Reaction conditions: a) p-anisidine, 4 ꢀ
MS, toluene, 80%; b) diphenylacetylene, [{Cp*RhCl2}2] (5 mol%),
Cu(OAc)2·H2O, DMF, 808C, then 3N HCl, 55%; c) NH2OH·HCl,
pyridine, EtOH, 608C then Ac2O, DMAP, pyridine, RT, 65%; d) diphe-
nylacetylene, [{Cp*RhCl2}2] (5 mol%), Cu(OAc)2 (10 mol%), DMF,
808C, 48%; e) acetophenone, 4 ꢀ MS, toluene; f) Pd(OAc)2
(10 mol%), Cu(OAc)2, DMSO, 608C, 36% (2 steps). PMP=p-methox-
yphenyl, Cp*=C5Me5, DMAP=4-dimethylaminopyridine, MS=molec-
ular sieves.
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Received: May 27, 2013
Published online: August 19, 2013
Keywords: copper · heterocycles · multicomponent coupling ·
.
selenium · sulfur
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