Synthesis of 2-substituted benzo[: B] thiophenes via gold(i)-NHC-catalyzed cyclization of 2-alkynyl thioanisoles

Article abstract of DOI:10.1039/c8ob02196a

Benzo[b]thiophene heterocycles are important components of many important small molecule pharmaceuticals and drug candidates as well as organic semiconducting materials. Many methods have been developed for the construction of a benzo[b]thiophene core via cyclization reaction of alkynes. Although few catalytic reactions were disclosed, most methods rely on stoichiometric activation of alkynes. Here we report an efficient method for the synthesis of 2-substituted benzo[b]thiophenes from 2-alkynyl thioanisoles catalyzed by a gold(i)-IPr hydroxide that is applicable to a wide range of substrates with diverse electronic and steric properties. Additionally, we demonstrate experimentally that the acid additive and its conjugate base are essential to catalyst turnover.

Full text of DOI:10.1039/c8ob02196a

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Synthesis of 2-substituted benzo[b]thiophenes via
gold(I)–NHC-catalyzed cyclization of 2-alkynyl
thioanisoles†‡
Cite this: Org. Biomol. Chem., 2018,
16, 9279
Christopher C. Dillon,
and Hubert Muchalski
Bagieng Keophimphone, Melissa Sanchez, Parveen Kaur
*
Benzo[b]thiophene heterocycles are important components of many important small molecule pharma-
ceuticals and drug candidates as well as organic semiconducting materials. Many methods have been
developed for the construction of a benzo[b]thiophene core via cyclization reaction of alkynes. Although
few catalytic reactions were disclosed, most methods rely on stoichiometric activation of alkynes. Here
we report an efficient method for the synthesis of 2-substituted benzo[b]thiophenes from 2-alkynyl thio-
anisoles catalyzed by a gold(I)–IPr hydroxide that is applicable to a wide range of substrates with diverse
electronic and steric properties. Additionally, we demonstrate experimentally that the acid additive and its
conjugate base are essential to catalyst turnover.
Received 6th September 2018,
Accepted 16th November 2018
DOI: 10.1039/c8ob02196a
rsc.li/obc
carbon is activated with a strong electrophile (route I) is a well-
documented pathway to 2,3-disubstituted benzo[b]thio-
Introduction
Benzo[b]thiophene is an established heterocyclic scaffold for phenes.5 The benzo[b]thiophene heterocycle can also be
preparing organic small molecules that display an array of formed in a reaction of lithiated o-alkynylbenzenes with sulfur
important properties (Fig. 1). For example, materials based on and subsequent cyclization of the generated thiolate anion
BTBT, [1]benzothieno-[3,2-b]benzo-thiophene (1), are superior (route II).6 Palladium complexes were shown to catalyze cross-
organic semiconductors used in air-stable high-performance coupling reactions with subsequent formation of a thiophene
organic field-effect transistors (OFETs).1 Zileuton (2) and serta- ring (route III).7 Although a broad range of substituted benzo
conazole (3) are benzo[b]thiophene-containing pharmaceuti- [b]thiophenes can be accessed rapidly, the reactions require
cals currently on the market for the treatment of asthma and high catalyst loading (typically 5–10%) and harsh reaction con-
fungal infections, respectively.2 Also, new drug candidates ditions. 2-Alkynyl aryl sulfides readily cyclize in the presence
such as 4 3 and others4 are being actively developed and, for of palladium or gold catalysts (route IV)7c,8 but these methods
some compounds, the presence of sulfur can be the determin-
ing factor of biological activity. For example, the binding
affinity of analogs of benzo[b]thiophen-2-ylboronic acid that
lack the electron-rich sulfur heterocycle can be up to three
orders of magnitude lower.4d Therefore, efficient and selective
methods for the construction of substituted benzo[b]thio-
phenes have been a focus of considerable research efforts.
Multiple approaches have been developed for the synthesis
of benzo[b]thiophenes (Scheme 1). For example, the cyclization
of 2-alkynyl aryl thiols and sulfides where the unsaturated
California State University Fresno, 2555 E San Ramon Ave M/S SB70, Fresno,
CA 93740, USA. E-mail: hmuchalski@csufresno.edu
†This article is dedicated to the memory of Prof. Jacek Młochowski (1937–2018).
‡Electronic supplementary information (ESI) available: Synthetic procedures,
results of reaction optimization studies, spectroscopic data of synthesized com-
pounds, and digital images of NMR spectra. See DOI: 10.1039/c8ob02196a
Fig. 1 Examples of materials and pharmaceuticals containing benzo[b]
thiophene heterocycles.
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2-alkynyl thioanisoles. For our model substrate, the reaction
proceeds efficiently in the presence of only 0.5 mol% of
Au(IPr)Cl or Au(IPr)OH. Notably, the reaction only occurs in
the presence of a Brønsted acid of sufficient strength.
Results and discussion
Our studies initiated with the reaction of 2-(phenylethynyl)
thioanisole (5a) in the presence of 5 mol% of common gold(I)
complexes in toluene at 80 °C (Table 1, entries 1–4), but these
preliminary experiments returned the unreacted starting
material. Upon inspection of 1H NMR of the crude reaction
mixture in which Au(IPr)OH was used as a catalyst (entry 4),
we noticed the formation of a new species that was not present
in reactions catalyzed by AuCl or gold(I)–phosphine complexes
(entries 1–3). The relative amount of the new product
increased when 20 mol% of Au(IPr)OH was used (entry 5), but
the resonances for the new compound did not match the
chemical shifts for the expected product, 2-phenylbenzo[b]
thiophene (6a). We did not observe shifts of the SCH3 group in
Scheme 1 Overview of selected methods for synthesis of the benzo[b]
thiophene core.
are limited to substrates containing specific substituents on
sulfur and relatively high catalyst loading is typically required.
Several radical-mediated syntheses of benzothiophenes,
including light-mediated reactions,9 as well as direct
functionalization of benzo[b]thiophenes10 have also been
published.
Over the last two decades, homogeneous gold(I) catalysis
has emerged as a vibrant area of research.11 Catalysts based on
gold(I) are tolerant towards moisture and air (high oxidation
potential), offer high catalyst turnovers,12 and are less toxic
compared to other pi-acidic transition metals. Cationic gold(I)
complexes are now standard catalytic systems for the activation
of alkynes towards nucleophilic additions of a range of hetero-
atom-containing nucleophiles.13 The recent contributions of
Nolan and co-workers prompted increased interest in the use
of N-heterocyclic carbenes (NHCs) as ligands for cationic
gold(I) complexes.14,15 The main feature of NHCs is the strong
p-donating ability combined with highly tuneable sterics,
which is preferable whenever a highly active but stable
metal center is desired. N,N′-(2,6-Diisopropylphenyl)dihydro-
imidazolium (IPr), shown in Fig. 2, has been established as a
nearly universal ligand for gold(I) complexes used in alkyne
addition reactions.16 Nakamura and co-workers demonstrated
that o-alkynylphenyl sulfides containing very electron rich sub-
stituents on sulfur such as O,S-acetals, trialkylsilyl, and
p-anisyl will undergo AuCl-catalyzed cyclization with con-
current migration of the substituent from sulfur to C-3.8
However, to the best of our knowledge, there is no successful
example of gold(I)-catalyzed cyclization of more widely avail-
able thioanisoles. Here we report an efficient method for
gold(I)–NHC-catalyzed synthesis of benzo[b]thiophenes from
1
the H NMR spectrum suggesting that binding of sulfur to the
gold(I) center is not pronounced. However, chemical shifts of
the resonances corresponding to isopropyl groups of the IPr
ligand were shifted compared to the NMR of the pure gold(I)
hydroxide complex.17 We hypothesized that the new species
may be the vinyl gold intermediate 7 (see the discussion of the
mechanism below), but attempts at isolating 7 were unsuccess-
ful. It is worth noting that Nakamura and co-workers observed
productive gold(I)-catalyzed cyclization only when sulfur was
substituted with highly electron-rich groups that can stabilize
the positive charge that develops on carbon during migration.
Migration of the silyl or p-anisyl group from sulfur to the vinyl
carbon bound to gold releases the metal and allows for catalyst
turnover.8 Since the methyl group is insufficiently stabilized to
migrate to the vinyl position, we considered adding a Brønsted
acid to facilitate recycling of the catalyst through protodeaura-
tion. Water and methanol (entries 6 and 7, respectively) were
not effective protodeauration additives. To our delight, when 1
equiv. of acetic acid was added, complete conversion of the
starting material was observed and the benzo[b]thiophene
product was isolated in 95% yield (entry 8). Conversely, the
reaction of 5a in the presence of 1 equiv. of triethylamine
returned the unreacted substrate (entry 9). Catalytic activity
appears to be specific to gold(I)–NHC complexes because
gold(I)–phosphine catalysts with non-coordinating counterions
such as Au(PPh3)BF4 did not yield 6a when acetic acid was
added (entry 10). We then investigated the catalyst turnover
limits and found that the reaction is nearly complete
(92% conversion) after 6 h with only 0.5 mol% of Au(IPr)OH
(entry 11). We also found that less expensive, more widely
available Au(IPr)Cl can catalyze the cyclization, but the reac-
tion is slower (entry 12). We used the slower reaction catalyzed
by Au(IPr)Cl to probe the effect of solvent on the reaction. The
reaction is significantly slower in a polar nonprotic solvent
such as acetonitrile (entry 13). Protic solvents such as ethanol
Fig. 2 Gold(I)–NHC complexes evaluated in this study.
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Table 1 Optimization of reaction conditions
Entry
Catalyst [mol%]
Additive
Conditions
Conversiona [%]
Yieldb [%]
1
2
3
4
5
6
7
8
AuCl [5]
—
—
—
—
—
H2O
MeOH
AcOH
Et3N
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
Toluene, 80 °C, 20 h
Toluene, 80 °C, 20 h
Toluene, 80 °C, 20 h
Toluene, 80 °C, 20 h
Toluene, 80 °C, 20 h
Toluene, 80 °C, 20 h
Toluene, 80 °C, 20 h
Toluene, 80 °C, 20 h
Toluene, 80 °C, 20 h
Toluene, 80 °C, 20 h
Toluene, 80 °C, 6 h
Toluene, 80 °C, 6 h
MeCN, 80 °C, 6 h
<5
<5
<5
<5
15
<5
<5
99
—
<5
92
75
22
71
91
99
99
3
Au(PPh3)Cl [5]
Au(PPh3)BF4 [5]
Au(IPr)OH [5]
Au(IPr)OH [20]
Au(IPr)OH [5]
Au(IPr)OH [5]
Au(IPr)OH [5]
Au(IPr)OH [5]
Au(PPh3)BF4 [5]
Au(IPr)OH [0.5]
Au(IPr)Cl [0.5]
Au(IPr)Cl [0.5]
Au(IPr)Cl [0.5]
Au(IPr)Cl [0.5]
Au(IPr)Cl [0.5]
Au(IPr)OH [0.5]
Au(IPr)Cl [1]
—
—
—
—
—
—
95
—
—
—
—
—
—
—
92c
97c
—
—
97c
9
10
11
12
13
14
15
16
17
18
19
20
AcOH, 80 °C, 6 h
No solvent, 80 °C, 6 h
Toluene, 100 °C, 20 h
Toluene, 100 °C, 20 h
Toluene, 100 °C, 1 h
Toluene, 100 °C, 1 h
Toluene, 100 °C, 20 h
Au(IPr)OH [1]
Au(IPr)OH [1]
58
99
a Conversion was determined using 1H NMR analysis (100% method) of post-reaction mixtures. b Isolated yield after chromatography. c Average of
three experiments.
and acetic acid (entry 14) are also applicable, but a longer reac- tion conditions.§ In general, substrates containing electron-
tion time is required and catalyst decomposition was often rich and alkyl substituents delivered the corresponding
observed. We observed significant conversion (91%) in the benzo[b]thiophenes in excellent yields. The position of the
reaction carried out without a solvent (entry 15), but solvent- electron-withdrawing substituent on the aromatic substituent
free conditions did not translate universally to other substrates (5g–5i) has little effect on the product yield. The alkyne 5k
and we recommend using a small amount of non-polar solvent readily converts to benzo[b]thiophene 6k as evidenced by
such as toluene. Additionally, the intermolecular addition 1H NMR of the post-reaction mixture. However, the isolated
reaction between the alkyne and ethanol or acetic acid is sig- yield obtained by chromatography was significantly lower
nificantly slower because we did not observe the typical pro- than expected due to reduced solubility of 6k in the mobile
ducts of hydroalkoxylation or hydroacetoxylation.13d The phase. When we carried out the reaction on a larger scale, the
gold(I)–IPr chloride catalyst is also capable of fully converting isolated yield improved because the product could be purified
the alkyne to benzo[b]thiophene. After 20 h, the yields obtained by trituration with cold methylene chloride. Alkynes contain-
from the chloride are comparable to that of the hydroxide cata- ing Lewis-basic functional groups such as dimethylamino
lyst (entries 16 and 17). There appears to be, however, an (5m) and ester (5o) reacted slower in comparison and it was
induction period for the chloride catalyst. After 1 h the reac- necessary to double the amount of catalyst to achieve com-
tion catalyzed by Au(IPr)Cl shows that only 3% of the alkyne plete consumption of the starting material. The reaction of
reacted (entry 18) compared to 58% for Au(IPr)OH (entry 19). bisphenyl-substituted alkyne 5q was unsuccessful, even with
We believe that it is partially due to the insolubility of Au(IPr) 5 mol% of the catalyst, which we attribute to the very low
Cl in the reaction mixture in the first 2 hours of heating. A pre-
liminary survey of other substrates indicated that some deriva-
tives react slower than alkyne 5a. Thus, for the study of the
§Preparation of 2-phenylbenzo[b]thiophene (5a): In a 2-dram vial was added the
substrate scope, we modified the general reaction conditions catalyst (2.50 mmol), alkyne (0.250 mmol), acetic acid (15.0 μL, 0.250 mmol) and
toluene (240 μL). The vial was capped and the mixture was heated at 100 °C for
20 h. The mixture was then cooled to rt and the product was purified by flash
to use 1 mol% of Au(IPr)OH in toluene at 100 °C for 20 h.
With optimized reaction conditions in hand, we began
exploring the substrate scope of substituted 2-ethynyl thioani-
soles for the gold(I)-catalyzed cyclization (Scheme 2). A variety
column chromatography (SiO2, 2% ethyl acetate in hexanes) to give the product
as a white solid (51.0 mg, 97%). 1H NMR (300 MHz, CDCl3) δ 7.87 (ddd, J = 7.2,
1.9, 0.8 Hz, 1H), 7.85–7.79 (m, 1H), 7.79–7.72 (m, 2H), 7.59 (d, J = 0.8 Hz, 1H),
of different substituents were well tolerated under the reac- 7.51–7.43 (m, 2H), 7.43–7.32 (m, 3H).
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Scheme 3 Reaction carried out in the presence of acetic acid-d pro-
duces benzo[b]thiophene with up to 85% isotopic enrichment at the
vinylic position as shown by the reduced intensity of vinylic resonance.
Reaction mechanism
We then performed control experiments to gain more insight
into the mechanism. When the reaction of alkyne 5a was
carried out in the presence of 1 equiv. of acetic acid-d, 1H
NMR showed approximately 85% of deuterium incorporation
at the vinylic position (Scheme 3), which confirms the involve-
ment of acetic acid in protodeauration and catalyst turnover.
It was unclear, however, what was the fate of the sulfide
methyl group. We hypothesized that the methyl group is trans-
ferred from the methylsulfonium anion to the acetate anion
generated during protodeauration to give methyl acetate. 1H
NMR analysis of the unpurified post-reaction mixture (with
reaction solvent), contains two additional singlet resonances
of equal integration at 2.06 and 3.67 ppm (see the ESI‡ for
details). The chemical shifts matched the expected values for
methyl acetate and suggested the involvement of the acetate
anion in the catalytic cycle. This hypothesis was tested by car-
rying out the reaction using ethyl sulfide derivative 5t. The
proton spectrum of the post-reaction mixture (Fig. 3, bottom)
displayed complete consumption of 5t (Fig. 3, top) as indi-
cated by the disappearance of the quartet at 3.2 ppm and the
appearance of the resonance at 4.2 ppm (characteristic of the
methylene group in ethyl acetate), thus confirming the transfer
of the alkyl group from sulfide to acetate. The ratio of ethyl
acetate to product was approximately 1 : 1 suggesting that it is
the main alkyl transfer pathway under the reaction conditions.
Our experimental observations are consistent with the
mechanism presented in Scheme 4 and reveal that carboxylic
acid and its conjugate base both play a role in the overall trans-
Scheme 2 The substrate scope of gold(I)-catalyzed synthesis of benzo
[b]thiophenes from 2-alkynyl thioanisoles. a Isolated yield. b Conversion
was determined by 1H NMR analysis of unpurified reaction mixtures.
c 2 mol% of catalyst was used. d 5 mol% of catalyst in toluene–THF (1 : 1,
v/v). e The reaction returned a complex mixture of products and isolation
of the expected benzo[b]thiophene was unsuccessful.
solubility of 5q in toluene. When the reaction was carried out formation. Research by Nolan and co-workers18 suggests that
in toluene–THF (1 : 1 v/v), we observed consumption of the under the reaction conditions the hydroxide anion in
alkyne but the reaction mixture contained multiple products Au(IPr)OH will rapidly exchange with acetic acid and the
and isolation of 6q was unsuccessful. The reaction is also acetate is likely the counterion in the active catalyst (X = OAc
applicable to substrates carrying substituents on the parent in Scheme 4). The metal center coordinates to alkyne pi elec-
thioanisole ring. Trifluoromethyl derivative 5s was efficiently trons and activates the carbon toward nucleophilic attack by
converted to the corresponding benzo[b]thiophene (NMR sulfur of the methyl sulfide to give vinyl gold intermediate 7.
yield >97%). Low solubility of 6s allowed for isolation by Acetic acid facilitates the collapse of the vinyl gold complex
direct filtration from the reaction mixture.
through protodeauration to produce methylsulfonium inter-
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Acknowledgements
We are grateful for financial support from the College
of Science and Mathematics at California State University
Fresno. M. S. thanks the CSU-LSAMP program (NSF grant
#HRD-1302873) and ASI for financial support. B. K. thanks the
CSUPERB for the Presidents’ Commission Scholar Award. We
thank Ms Dana Lichtenstein for assistance during the syn-
thesis of diaryl alkynes. We are also thankful to Dr Krish
Krishnan for assistance in 13C NMR analysis of fluorinated
compounds.
Notes and references
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Fig. 3 Proton NMR spectra (CDCl3) of alkyne 5t (top) and post-reaction
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Scheme 4 Plausible mechanism of gold(I)–NHC-catalyzed cyclization
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Conclusions
We developed an efficient method for the synthesis of 2-substi-
tuted benzo[b]thiophenes. The reaction is catalyzed by a gold
(I)–IPr hydroxide complex and proceeds smoothly with as little
as 0.5 mol% of the catalyst. The reaction tolerates a broad
range of substrates and can be carried out in air using com-
mercial grade reagents and solvents. Additionally, we demon-
strated experimentally that a Brønsted acid and its conjugate
base are necessary for catalyst turnover.
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Conflicts of interest
There are no conflicts to declare.
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suggested by one of the referees that the sulfide group
might bind to the gold(I) center deactivating it and the
role of Brønsted acid is to disrupt binding by reversible
protonation of the sulfide. When a solution of the
alkyne and catalyst was examined by 1H NMR we
observed chemical shift changes for the IPr ligand but
we did not observe changes in the chemical shift of the
alkyl sulfide group. Thus, we believe the role of Brønsted
acid additive is limited to the protodemetallation
process.
9284 | Org. Biomol. Chem., 2018, 16, 9279–9284
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