Synthesis of 2-Acylbenzo[b]thiophenes via Cu-Catalyzed α-C-H Functionalization of 2-Halochalcones Using Xanthate

Article abstract of DOI:10.1021/acs.orglett.7b00462

An efficient protocol is described for the synthesis of 2-acylbenzo[b]thiophenes from easily accessible 2-iodochalcones through α-C-H functionalization using Cu(OAc)₂ catalyst and xanthate as sulfur source. Less reactive 2-bromochalcones also yielded the corresponding 2-acylbenzothiophenes in good yield. The reaction proceeds via in situ incorporation of sulfur followed by copper-catalyzed cyclization to generate 2-acylbenzothiophenes without external acyl source. The synthetic importance is showcased by synthesis of 1-(5-hydroxybenzothiophene-2-yl)ethanone, which is a known pre-mRNA splicing modulator.

Full text of DOI:10.1021/acs.orglett.7b00462

Letter
pubs.acs.org/OrgLett
Synthesis of 2‑Acylbenzo[b]thiophenes via Cu-Catalyzed α‑C−H
Functionalization of 2‑Halochalcones Using Xanthate
Subramani Sangeetha and Govindasamy Sekar*
Department of chemistry, Indian Institute of Technology Madras, Chennai 600036, Tamil Nadu, India
S
* Supporting Information
ABSTRACT: An efficient protocol is described for the synthesis of 2-
acylbenzo[b]thiophenes from easily accessible 2-iodochalcones through α-C−H
functionalization using Cu(OAc)2 catalyst and xanthate as sulfur source. Less
reactive 2-bromochalcones also yielded the corresponding 2-acylbenzothio-
phenes in good yield. The reaction proceeds via in situ incorporation of sulfur
followed by copper-catalyzed cyclization to generate 2-acylbenzothiophenes
without external acyl source. The synthetic importance is showcased by
synthesis of 1-(5-hydroxybenzothiophene-2-yl)ethanone, which is a known pre-
mRNA splicing modulator.
Scheme 1. Synthetic Methods of 2-Acylbenzo[b]thiophenes
rganic molecules containing benzo[b]thiophene moiety
Oare quite significant due to their promising properties in
pharmacology, catalysis, and application in material science.1 In
particular, 2-acylbenzothiophenes are privileged scaffolds in
medicinal compounds; for instance, they are used as potent
antimitotic agents, inhibitors of tubulin polymerization,2 potent
inhibitors of 17β-HSD1,3 and antitrypanosomal4 and antiproli-
ferative agents5 (Figure 1). Apart from this, 2-acylbenzothio-
phenes are essential building blocks for numerous biologically
active compounds.6
Figure 1. Selected 2-acylbenzo[b]thiophene derivatives with biological
activities.
along with Pd catalyst.11 Notably, all of the aryl boronates utilized
for palladium cross-coupling reactions have been generated from
the 2-halo/carboxaldehyde of benzothiophene with pyrophoric
n-BuLi at −78 °C. In addition, complexities of these methods
include the use of moisture-sensitive and corrosive acylating
agents, expensive metal catalysts, odor sulfur sources, limited
substrate scope, multistep starting materials, and the requirement
of external ligands.
Similarly, elegant methods have been developed for the
synthesis of the benzo[b]thiophene core by either electrophilic
cyclization or coupling cyclization reactions using different sulfur
sources in the presence of metal or under metal-free
conditions.1b Simultaneously, aryl halides activated with Cu
In general, Brønsted or Lewis acid catalyzed direct Friedel−
Crafts acylation of benzothiophene results in 3-acylbenzothio-
phene rather than 2-acylbenzothiophene (Scheme 1a, eq 1).7
However, 2-acylbenzothiophene can be selectively prepared
through 2-lithiobenzothiophene using n-BuLi followed by
reaction with an aldehyde and then oxidation of the
corresponding alcohol (Scheme 1a, eq 2).8 Conversely, synthesis
of 2-acylbenzothiophenes by cyclization of specific starting
materials is also reported in which sulfur is either part of the
molecule or added from an external source.9 Recently, palladium-
catalyzed cross-coupling reactions have been explored using a
variety of benzo[b]thiophene-2-ylboronic acids10a with ligands
like imidazolinium carbene10b or phosphine salts10c (Scheme
1b). Subsequently, iridium was used as a transmetalation agent
Received: February 15, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00462
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Organic Letters
Letter
catalyst for Heck-type coupling reactions have been established
by activated olefins with different coupling partners.12 However,
to the best of our knowledge, examples of sulfur and its analogues
contributing to Cu-catalyzed cyclization to generate the
benzothiophene core for the synthesis of 2-acylbenzothiophene
are unknown. As part of our ongoing research toward Cu-
catalyzed in situ C−S bond formation using potassium ethyl
xanthate as a sulfur surrogate,13 herein we report Cu-catalyzed
synthesis of 2-acylbenzo[b]thiophene from α-C−H functional-
ization of 2-halochalcones (Scheme 1c).14
Initially, 2-iodochalcone 1a was examined as a model substrate
for the synthesis of 2-benzoylbenzothiophene 2a with 10 mol %
of Cu(OAc)2 and potassium ethyl xanthate (2 equiv) as sulfur
precursor in dimethyl sulfoxide at 80 °C. To our delight, the
reaction yielded 58% of 2a in 5 h (Table 1, entry 1).15
improve the yield of 2a, the reaction was screened with various
bases and ligands, but the yield was not fruitful. When xanthate
was added in two equal portions in 1 h time interval, it afforded
82% of 2a in DMF (entry 13). In DMSO solvent, the yield of 2a
was increased to 87% in 4 h (entry 14). When the reaction was
carried out under inert (N2) atmosphere, the yield was reduced
to 23%. Increasing or decreasing the xanthate quantity under N2
atmosphere did not improve the yield (entries 15−17).
Importantly, use of 5 mol % of Cu(OAc)2 reduced the product
yield (entry 18). Finally, when the reaction was carried out with
no catalyst, it yielded only 6% of 2a (entry 19).16
The optimized reaction conditions of the reaction (entry 14)
were explored with various substrates, and the results are
summarized in Scheme 2. Initially, 2-iodochalcones prepared
a
Scheme 2. Synthesis of 2-Acylbenzo[b]thiophenes
a
Table 1. Optimization of Reaction Conditions
b
xanthate
(equiv)
temp
time
(h)
yield
(%)
entry
Cu salt
solvent
DMSO
(°C)
c
1
2
3
4
5
6
7
8
Cu(OAc)2
Cu(OTf)2
CuBr2
2
2
2
2
2
2
2
2
80
80
80
80
80
80
80
80
5
6
7
8
5
6
4
7
58
c
DMSO
DMSO
DMSO
DMF
56
c
57
CuCl
48
65
62
41
58
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
DMA
NMP
DMF +
toluene
9
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
2
2
DMF
100
110
100
100
100
100
100
100
100
100
100
4
3
72
73
10
11
12
13
14
15
16
17
18
19
DMF
d
1
DMF
12
4
38
3
DMF
68
e
1 + 1
1 + 1
1 + 1
0.7 + 0.7
1.5 + 1.5
1 + 1
1 + 1
DMF
4
82
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
4
87
f
4
23
f
4
16
a
Reaction conditions: 1 (0.5 mmol), xanthate (0.5 + 0.5 mmol), Cu
f
4
27
catalyst (10 mol %) in DMSO (2 mL) at 100 °C. All yields are isolated
yields.
g
10
4
52
6
a
Standard reaction conditions: 1a (0.5 mmol), xanthate, Cu catalyst
b
c
from acetophenones substituted with electron-donating groups
reacted smoothly and gave products 2b, 2c, and 2d in good
yields. Further, this methodology was employed for various 2-
iodochalcones substituted with halogen groups to afford
moderate yields of 2e, 2f, and 2g, which are useful initial
scaffolds for conventional coupling reactions. Subsequently,
ortho-substituted 2-iodochalcones were well tolerated, and 61%
of 2h, 84% of 2i, and 90% of 2j were obtained. Interestingly,
dimethoxy- and methylenedioxy-substituted chalcones were
more appropriate for the cyclization and provided 2k and 2l in
appreciable yield.
In addition, 2-acetylthiophene- and 3-acetylindole-derived 2-
iodochalcones progressed efficiently, and products 2m and 2n
were isolated in 77% and 92% yield, respectively. Notably, 2-
iodochalcone substituted with an electron-withdrawing group
was found to be a suitable substrate for this reaction, yielding 61%
of 2o. Strikingly, 2-acetonaphthone and trimethoxy-substituted
ketone derived chalcones produced 58% of 2p and 72% of 2q in 3
h. Next, the optimized reaction conditions were tested with
(10 mol %) in 2 mL of solvent. Isolated yield. Average yield of three
repetitions. Starting material remained. 1 equiv of xanthate was
added after 1 h. Under N2 atm. 5 mol % of Cu(OAc)2 was used.
d
e
f
g
Encouraged by these results, we screened various copper salts to
improve the efficiency of the reaction (entries 2−4). Though all
of the copper salts provided 2a in more or less the same yield,
copper acetate was chosen as it gave the highest yield (entry 1 vs
2−4). Then the effect of solvent was studied, and the results
revealed that DMA and NMP produced lower yields of 2a than
DMF (entries 5 vs 6 and 7).
The reaction was also conducted in a mixture of DMF and
toluene (1:1), and it provided a better yield of 58% compared to
other mixtures of solvents (entry 8). When the reaction
temperature was increased to 100 °C, the yield increased to
72%, but identical results were observed at 100 or 110 °C (entries
9 and 10). Next, the xanthate equivalent was evaluated, and using
1 equiv of xanthate gave only 38% yield (entry 11). Use of 3 equiv
of xanthate reduced the yield of 2a to 68% (entry 12). In order to
B
DOI: 10.1021/acs.orglett.7b00462
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Letter
substituents on the iodo-attached benzene ring of 2-iodochal-
cone. Consequently, fluoro-, chloro-, and bromo-substituted 2-
iodochalcones underwent the cyclization reaction nicely, and the
corresponding cyclized products 2r, 2s, 2u, and 2v were obtained
in good yields. The structure of 2u was further confirmed by
single-crystal XRD analysis (CCDC no. 1525720 with 30%
probability ellipsoids). Importantly, nitro-substituted chalcone
with 1 equiv of xanthate provided 42% of 2t. Thus, the reaction
was conducted with an initial addition of 2 equiv of xanthate. As
expected, the reaction yield of 2t was increased to 62% in 1 h.
Remarkably, aliphatic ketone derived chalcones were effectively
converted into the cyclized products 2w and 2x in commendable
yield. It is worth mentioning that compound 2w is synthetically
important and can be used for anti-osteoporosis, which is directly
accessed using this methodology.17 The optimized conditions
were then employed for substitution on both phenyl rings of the
chalcone to produce 56% of 2y.
modulator, namely, 1-(5-hydroxybenzothiophene-2-yl)ethanone
6, by demethylation as shown in Scheme 4.18c
Several experiments were conducted to reason out the increase
in the yield of the product when xanthate was added portionwise
(Scheme 5). The reaction was examined with a moderate polar
Scheme 5. Controlled Reactions
The methodology was examined for less reactive bromo
substrates such as 2-bromochalcone 3. Under the optimized
reaction conditions (100 °C), the 2-bromochalcone failed to
yield the expected product. However, 78% of 2a was obtained
when the reaction temperature was increased to 120 °C (Scheme
3). Then several 2-bromochalcones were successfully converted
Scheme 3. Synthesis of 2-Acylbenzo[b]thiophenes from 2-
a
Bromochalcone
solvent like ethyl acetate with 10 mol % of Cu(OAc)2 and 2 equiv
of xanthate at 80 °C. This reaction produced 23% of 2a in 21 h
along with 7% of 7a, which was not observed in DMSO and DMF
solvents (Scheme 5a). The compound 7a was confirmed by
single-crystal XRD analysis (CCDC no. 1525719). The
mechanism for the formation of 7a was hypothesized to proceed
via coupling of 2-iodochalcone with xanthate sulfur in the
presence of Cu catalyst followed by inter- and intramolecular
Michael addition and ene reaction with loss of acetophenone.19
This observation shows that compound 2a is competing with 7a
where intermolecular Michael addition takes place after xanthate
coupling. When 1o was subjected to the initial reaction
conditions (entry 1, Table 1), this reaction furnished 32% of
2o and 17% of 8o (Scheme 5b). We speculated that compound
7o20 is the intermediate in the formation of 8o through
intramolecular Michael addition after coupling with xanthate.
Compound 8o was confirmed by X-ray diffraction analysis
(CCDC no. 1525721). From these experiments, we found that
xanthate activates the Michael addition when 2 equiv of xanthate
is added at one time. Formation of 7a can be controlled either by
reducing the quantity of xanthate or by the slow addition of
xanthate. This might be the reason for the increase in yield when
xanthate is added portionwise (entry 9 vs 13, Table 1).
The plausible mechanism of the cyclization reaction is
proposed as shown in Scheme 6. According to the previous
report1c,13d it is assumed that 2-iodochalcone 1 with copper
acetate may give oxidative addition intermediate A, which gives
intermediate B in the presence of xanthate. Then intermediate B
may provide intermediate C via reductive elimination. Finally,
the intermediate C in the presence of excess xanthate will yield
product 2. The second equivalent of xanthate is expected to
cleave the S−C bond to give thiolate, which will cyclize via
reaction with olefin activated by Cu.21 However, in-depth
mechanistic studies and further application of the newly
developed reaction are underway.
a
Reaction conditions: 3 (0.5 mmol), xanthate (0.5 + 0.5 mmol), Cu
catalyst (10 mol %) in DMSO (2 mL) at 120 °C.
to the corresponding cyclized products 2j, 2g, 2i, and 2n in
moderate to excellent yield. It is important to mention that only
the 2-bromophenyl ring attached to the alkene part selectively
underwent cyclization by keeping the 4-bromophenyl ring
tethered to the ketone part unaffected. This might be due to
olefin coordination with the metal, which could cause direct
selectivity.
2-Benzoylbenzothiophene 2a was further functionalized into
useful moieties like benzo[b]thiophene-2-yl(phenyl)methanol
(see the SI, compound 4) by reduction with NaBH4 and
subsequent reduction of the resulting secondary alcohol with
sodium borohydride and trifluoroacetic acid to yield 5, which is a
precursor molecule for the treatment of insulin resistance and
hyperglycemia18a and inactivators of protein tyrosine phospha-
tase 1B (PTP 1B)18b (Scheme 4). To showcase the application of
this synthetic method, 2a was converted to a pre-mRNA
Scheme 4. Synthetic Application of 2-Acylbenzothiophenes
In conclusion, the synthesis of 2-acylbenzo[b]thiophene
derivatives from easily accessible 2-iodo or 2-bromo chalcones
has been developed using copper catalyst and odorless xanthate
C
DOI: 10.1021/acs.orglett.7b00462
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Scheme 6. Proposed Mechanism
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Angew. Chem., Int. Ed. 2012, 51, 1958.
as a sulfur surrogate. The methodology proceeds via in situ sulfur
incorporation followed by cyclization to generate 2-acylbenzo-
thiophenes without external acyl source. Compounds with
various substituents including halogen derivatives of 2-
acylbenzothiophene can be synthesized, which shows the
robustness of the method. The synthetic application of this
method was also showcased by synthesizing 1-(5-hydroxybenzo-
thiophene-2-yl)ethanone, which is known as a pre-mRNA
splicing modulator.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00462.
(15) 12% of compound 8a with its trace isomer (Scheme 5b) was
isolated along with 2a.
Detailed experimental procedures, characterization data,
and NMR spectra (PDF)
(16) This product might have formed by an SNAr mechanism. When
the ketone analogue of 1a was used (3-(2-iodophenyl)-1-phenyl-
propane-1-one) under the optimized reaction conditions, it did not give
product 2a, which supports formation of a trace amount of 2a with 1a by
an SNAr mechanism in the absence of Cu catalyst.
(17) Liu, Z.-y.; He, X.-b.; Yang, Z.-y.; Shao, H.-y.; Li, X.; Guo, H.-f.;
Zhang, Y.-q.; Si, S.-y.; Li, Z.-r. Bioorg. Med. Chem. Lett. 2009, 19, 4167.
(18) (a) Wrobel, J. E.; Dietrich, A. J.; Li, Z. US6110962A, 2000.
(b) Shrestha, S.; Hwang, S. Y.; Lee, K.-H.; Cho, H. Bull. Korean Chem.
Soc. 2005, 26, 1138. (c) Schmitt, C.; Miralinaghi, P.; Mariano, M.;
Hartmann, R. W.; Engel, M. ACS Med. Chem. Lett. 2014, 5, 963.
(19) 5% yield for acetophenone was obtained (calculated by 1H
NMR).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gsekar@iitm.ac.in.
ORCID
Govindasamy Sekar: 0000-0003-2294-0485
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(20) The expected structure of 7o is
We thank the DST New Delhi (Project No. SB/S1/OC-72/
2013) for financial support. S.S. thanks IIT Madras for a
fellowship.
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(21) The controlled reactions were carried out using TEMPO (2,2,6,6-
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D
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