Visible light photocatalytic synthesis of benzothiophenes

Article abstract of DOI:10.1021/ol302517n

The photocatalytic reaction of o-methylthio-arenediazonium salts with alkynes yields substituted benzothiophenes regioselectively through a radical annulation process. Green light irradiation of eosin Y initiates the photoredox catalysis. The scope of the reaction was investigated by using various substituted diazonium salts and different alkynes.

Full text of DOI:10.1021/ol302517n

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Visible Light Photocatalytic Synthesis
of Benzothiophenes
€
Durga Prasad Hari, Thea Hering, and Burkhard Konig*
€
€
Institut fu€r Organische Chemie, Universitat Regensburg, Universitatsstrasse 31,
D-93053 Regensburg, Germany
Burkhard.Koenig@chemie.uni-regensburg.de
Received September 12, 2012
ABSTRACT
The photocatalytic reaction of o-methylthio-arenediazonium salts with alkynes yields substituted benzothiophenes regioselectively through
a radical annulation process. Green light irradiation of eosin Y initiates the photoredox catalysis. The scope of the reaction was investigated by
using various substituted diazonium salts and different alkynes.
The synthesis of benzothiophene derivatives has at-
tracted much attention in recent years due to their wide
application in biology,1 pharmacy,2 catalysis,3 and materi-
al science.4 Several active drugs on the market contain
the benzothiophene core: Zileuton is a potent and selective
inhibitor of 5-lipoxygenase,5 while raloxifene6 and arzoxi-
fene7 are selective estrogen receptor modulators and anti-
tubulin agents (Figure 1).
Many elegant methods have been reported for the
synthesis of substituted benzothiophenes.8 Most of these
methodologies rely on two approaches: (a) direct arylation
of the benzothiophene moiety; (b) electrophilic cycliza-
tion and coupling cyclization reactions to construct the
benzothiophene ring.8a,9 Cyclization reactions are of more
interest since they yield only the desired regioisomer.
Typically, cyclization reactions are catalyzed by transition
metals, such as palladium-catalyzed iodocyclizations,10
copper-mediated halocyclizations,11 and gold-promoted
annulation reactions.12 Recently, we have reported a
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r
10.1021/ol302517n
XXXX American Chemical Society

All of these annulation reactions typically require
stoichiometric amounts of transition metals and rather
harsh reaction conditions. Visible light photocatalysis
is emerging as a powerful tool for mild and selective
organic transformations.17 We report here the visible light
mediated synthesis of privileged benzothiophenes through
a radical annulation process catalyzed by eosin Y at
ambient conditions.
Figure 1. Benzothiophene moiety containing drug molecules.
Table 1. Optimizing Reaction Conditions
methodology for the arylation of heteroarenes using aryl
diazonium salts in visible light photocatalysis.13 We used
the reaction for the synthesis of 2-substituted benzothio-
phenes, but unfortunately mixtures of regioisomers were
obtained in rather low yields (Scheme 1a).
entry
conditions
yielda
1
2
3
4
5
6
7
3 (1 mol %), 2a (2 equiv), DMSO
3 (1 mol %), 2a (5 equiv), DMSO
3 (1 mol %), 2a (5 equiv), DMF
3 (5 mol %), 2a (2 equiv), DMSO
3 (5 mol %), 2a (5 equiv), DMSO
3 (5 mol %), 2a (10 equiv), DMSO
rose bengal (5 mol %), 2a (5 equiv),
DMSO
58
64
56
68
75
75
59
Scheme 1. Photocatalytic Approaches to Benzothiophenes
8
9
3 (5 mol %), 2a (5 equiv), DMSO,
no light
15b
12b
no catalyst, 2a (5 equiv), DMSO
a Isolated yields after purification by flash column chromatography
using silica gel. b 36 h irradiation time.
Our initial studies focused on the reaction of the
o-methylthio-benzenediazonium salt 1a with phenyl
acetylene using eosin Y (3) as a photoredox catalyst by
irradiating at 530 nm. We examined the amount of catalyst
loading (Table 1, entries 2 and 5) and different equivalents
of alkyne (Table 1, entries 4, 5, and 6) on this photoreac-
tion. To our delight, when 5 mol % of eosin Y and 5 equiv
of alkyne were used in DMSO, the desired product was
obtainedingoodyield(Table1, entry5). Wealsoexamined
rose bengal as a photocatalyst,22 giving the expected
product in 59% yield (Table 1, entry 7). To prove the
essential role of photocatalysis for the annulation reaction,
experiments without green light irradiation or without dye
To overcome such disadvantages in the direct arylation
of benzothiophene, we decided to explore an annulation
method to construct the benzothiophene ring. Giuseppe
Zanardi et al. first reported the synthesis of benzothio-
phenes from the reaction of o-methylthio-arenediazonium
salts with alkynes using transition metals as catalysts.14 In
2000, Larry G. Huffman, Jr. et al. reported the synthesis of
benzothiophenes from diazonium salts with stoichiometric
amounts of FeSO4 and TiCl3.15 Recently Carl H. Schiesser
et al. prepared a potent AT1 receptor antagonist through a
cyclization process involving the addition of aryl radicals
to alkynes, followed by intramolecular homolytic substitu-
tion at a sulfur or selenium heteroatom.16
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B
Org. Lett., Vol. XX, No. XX, XXXX

under irradiation were performed. As expected, we ob-
served only a 15% and 12% product yield, respectively,
after 36 h at 20 °C (Table 1, entries 8 and 9).
Table 3. Photocatalyzed Annulation of o-Methylthio-
benzenediazonium Salt with Terminal Alkynesa
Table 2. Photocatalyzed Annulation of o-Methylthio-
arenediazonium Salts with Phenyl Acetylenea
entry
substrate
alkyne
R
product
yieldb
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
2a
2b
2c
2d
2e
2f
Ph
4a
4i
75
81
72
62
64
60
45
65
62
30
4-NO2-C6H4
4-OMe-C6H4
3-CF3-C6H4
4-F-C6H4
CO2Me
entry
substrate
R1
alkyne
product
yieldb
3
4j
4
4k
4l
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
H
2a
2a
2a
2a
2a
2a
2a
2a
4a
4b
4c
4d
4e
4f
75
70
72
65
63
72
76
62
5
4-Cl
6
4m
4n
4o
4p
4q
4-Me
5-Cl
7
2g
2h
2i
TMS
8
CO2Et
4-OMe
4-Br
4-OEt
4-F
9
3-C4H3S
n-butyl
10
2j
1g
1h
4g
4h
a The reaction was performed with 1a (0.25 mmol), terminal alkyne
(5 equiv), and eosin Y (0.05 equiv) in 1.0 mL of DMSO. b Isolated yields
after purification by flash column chromatography using silica gel.
a The reaction was performed with 1 (0.25 mmol), phenyl acetylene
(5 equiv), and eosin Y (0.05 equiv) in 1.0 mL of DMSO. b Isolated yields
after purification by flash column chromatography using silica gel.
chemistry.19 We synthesized thionapthene 2,3-dialkyl
esters by simply reacting dialkyl but-2-ynedioate with
o-methylthio-arenediazonium salts using eosin Y in visible
light. The results are summarized in Table 4. Different
diazonium salts were converted with dialkyl but-2-ynedio-
ate affording thionapthene-2,3-dialkyl esters in good to
moderate yield.
Having optimized reaction conditions in hand, we in-
vestigated the reaction scope for o-methylthio-arenediazo-
nium salts with phenyl acetylene for the photoannula-
tion reaction. All diazonium salts were prepared according
to literature described procedures.15 O-Methylthio-arene-
diazonium salts bearing electron-donating substituents
(Table 2, entries 3, 5, and 7) reacted well in the photoreac-
tion to afford the corresponding benzothiophenes in
good yields. Diazonium salts bearing halogen substituents
(Table 2, entries 2, 4, 6, and 8) gave the corresponding
benzothiophenes with an intact carbonÀhalogen bond.
Such molecules are difficult to synthesize using conven-
tional methods and very useful for further synthetic
elaborations.
Table 4. Photocatalyzed Annulation of o-Methylthio-
arenediazonium Salts with Dialkyl But-2-ynedioatesa
Next we investigated the reaction scope of terminal
alkynes in this photoreaction and the results are summar-
ized in Table 3. Aromatic alkynes react smoothly and
afford good yields (Table 3, entries 1À5). 3-Ethynylthio-
phene also reacted with 1a to give the corresponding
product in 62% yield (Table 3, entry 9). Molecules of this
type find applications in the synthesis of optoelectronic
materials. With ester, TMS, and n-butyl substituents on
the alkynes, good to moderate yields (Table 3, entries 6, 7,
8, and 10) were obtained.
entry substrate
R1
alkyne
R2
product yieldb
1
2
3
4
5
6
7
8
9
1a
1a
1h
1h
1g
1f
H
H
5a
5b
5a
5b
5a
5a
5b
5a
5b
CO2Me
CO2Et
CO2Me
CO2Et
CO2Me
CO2Me
CO2Et
CO2Me
CO2Et
6a
6b
6c
6d
6e
6f
61
50
55
42
53
55
40
40
51
4-F
4-F
4-OEt
4-Br
4-Br
5-Cl
5-Cl
1f
6g
6h
6i
1d
1d
Thionaphthene-2,3-dialkyl esters are precursors for the
synthesis of the corresponding cyclohydrazides of thio-
napthene, which are useful as indicators.18 The synthesis
of thionapthene-2,3-dialkyl esters is largely unexplored
compared to other benzothiophene derivatives and only
a few literature reports exist including a recent paper by
P. G. Jones et al. describing an approach using palladium
a The reaction was performed with 1 (0.25 mmol), internal alkyne
(5 equiv), and eosin Y (0.05 equiv) in 1.0 mL of DMSO. b Isolated yields
after purification by flash column chromatography using silica gel.
Finally, we employed our methodology to prepare the
key intermediate 7 of the raloxifene synthesis providing
a metal-free route.15 We prepared 1e from the correspond-
ing amine and reacted it with 2c using standard photo-
catalysis conditions to furnish 7 in 70% isolated yield
(Scheme 2).
(18) Huntress, E. H.; Hearon, W. M. J. Am. Chem. Soc. 1941, 63,
2762.
ꢀ
(19) Vicente, J.; Abad, J. A.; Lopez-Nicolas, R.-M. a.; Jones, P. G.
ꢀ
Organometallics 2011, 30, 4983.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Proposed Reaction Mechanism
Scheme 2. Photocatalytic Synthesis of the Key Intermediate 7 of
Raloxifene
To investigate the mechanism of the photoreaction, we
performed radical trapping experiments. TEMPO adducts
13 and 14 (see the Supporting Information for full details)
were identified by mass spectrometry supporting the radi-
cal pathway. In accordance to literature reports13,14,20 and
the radical trapping experiments we propose a tentative
mechanism inScheme3. Initiallyarylradical 8isformedby
SET from the excited state of the photocatalyst to diazo-
nium salt 1a. Addition of 8 to the alkyne yields the cor-
responding vinyl radical 9, which then further cyclizes, to
givesulphuranylradical10. Radical10isoxidizedtocation
11 that transfers a methyl group to nucleophiles present in
the reaction mixture by an SN2 process giving product 12.
Radical 10 is oxidized by either the cation radical of the
photocatalyst to complete the electron transfer cycle or the
diazonium salt in a chain transfer mechanism. Investiga-
tions to elucidate the reaction mechanism in more detail
are ongoing.
In conclusion, the first photocatalytic synthesis of ben-
zothiophenes from diazonium salts has been accom-
plished. The method provides mild and efficient access to
different types of benzothiophenes avoiding metal cata-
lysts and high temperatures. Instead, only green light and
a catalytic amount of organic dye as the catalyst are
required. The substrate scope is large, and many products
have the potential for further synthetic transformations
as demonstrated by the synthesis of the key intermediate
of the drug raloxifene. Experiments to investigate the
mechanism of the reaction, to expand the scope of the
reaction, and to apply it to the synthesis of other biologi-
cally active molecules are ongoing in our laboratory.
Acknowledgment. This work was supported by the
GRK 1626 (Chemical Photocatalysis) of the German
Science Foundation (DFG).
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Nakamura, Y.; Usui, Y. Photochem. Photobiol. 2000, 71, 675. (b) Padon,
K. S.; Scraton, A. B. J. Polym. Sci., Part A: Polym. Chem. 2001, 39, 715.
Supporting Information Available. Experimental pro-
cedures and spectral characterization of all compounds
are available. This material is available free of charge via
the Internet at http://pubs.acs.org.
ꢀ
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rose bengal.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX