Unprecedented Access to β-Arylated Selenophenes through Palladium-Catalysed Direct Arylation

Article abstract of DOI:10.1002/chem.201700202

Several reported methods allow access to α-arylated selenophenes, whereas the synthesis of β-arylated selenophenes remains very challenging. Here, the Pd-catalysed coupling of benzenesulfonyl chlorides with selenophenes affording regiospecific β-arylated selenophenes is reported. The reaction proceeds with easily accessible catalyst, base and substrates, and tolerates a variety of substituents both on the benzene and selenophene moieties. This transformation allows the programmed synthesis of polyarylated selenophenes with potential applications in pharmaceutical and materials chemistry, as the installation of aryl groups at the desired positions can be achieved.

Full text of DOI:10.1002/chem.201700202

A Journal of
Accepted Article
Title: Unprecedented access to ꢀ-arylated selenophenes via
palladium-catalysed direct arylation
Authors: Aymen Skhiri, ridha Ben Salem, Jean-Francois Soulé, and
Henri Doucet
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To be cited as: Chem. Eur. J. 10.1002/chem.201700202
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10.1002/chem.201700202
Chemistry - A European Journal
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
-regioselectivity
Unprecedented access to -arylated selenophenes via palladium-catalysed
direct arylation
Aymen Skhiri,[a,b] Ridha Ben Salem,*[b] Jean-François Soulé,*[a] Henri Doucet*[a]
Abstract: Several methods allow the access to -arylated
selenophenes; whereas the synthesis of -arylated selenophenes
remains very challenging. We demonstrated that the Pd-catalysed
coupling of benzenesulfonyl chlorides with selenophenes affords
regiospecifically the -arylated selenophenes. The reaction proceeds
with easily accessible catalyst, base and substrates, and tolerates a
variety of substituents both on the benzene and selenophene
moieties. This transformation allows the programmed synthesis of
Since one decade, the metal-catalysed functionalization of C-H
bonds has emerged as a very powerful method for the simpler access
to molecules useful to materials or biological applications. If
specific C–H bonds of (hetero)arenes can be coupled with arenes, it
provides one of the simplest way for access to bi(hetero)aryls.[5,6]
From thiophene derivatives, by tuning the reaction conditions, both
the - and -arylated thiophenes can be easily obtained using Pd-
catalysed direct arylation.[7,8] In contrast, relatively little effort has
been expended toward developing such metal-catalysed direct
arylations for the synthesis of arylated selenophenes. In 2008, Mori,
Koumura et al. reported the first Pd-catalysed direct arylation of a
selenophene derivative (Scheme 2, top). Using aryl iodides as aryl
source and PdCl2(PPh3)2 catalyst, they obtained regioselectively the
C5-arylated 2-formylselenophenes.[9a] Then, in 2014, Schneider et al.
reported condition allowing the access to -arylselenophenes from
selenophene and aryl halides (Scheme 2, middle). To our knowledge,
the metal-catalysed direct arylation at -position of selenophenes
has not been reported so far (Scheme 2, bottom).[9b] Therefore, it
was of particular interest to us to achieve an arylation at the 3- or 4-
positions of selenophenes.
polyarylated
selenophenes
with
potential
applications
in
pharmaceutical and material chemistry, as the installation of aryl
groups at the desired positions can be achieved.
(Hetero)arylated selenophenes are important structures with several
applications such as in the fields of pharmaceutical chemistry and
organo-electronics.[1] If the biological or physical properties of
several 2-(hetero)arylselenophenes have been studied in detail, on
the other hand, 3-arylselenophenes have attracted less attention. This
is certainly due to the lack of convenient synthetic methods for the
preparation of such structures.[2] Currently, -arylated selenophenes
can be prepared via Suzuki coupling using 3-bromoselenophene
derivatives[3] (Scheme 1) or via Negishi coupling.[4]
Scheme 1. Reported pathways for the synthesis of -arylated
selenophenes from selenophenes.
[a]
[b]
A. Skhiri, Dr. J.-F. Soulé, Dr. H. Doucet
Institut des Sciences Chimiques de Rennes, UMR 6226
CNRS-Université de Rennes 1
"Organométalliques: Matériaux et Catalyse", Campus de
Beaulieu, 35042 Rennes, France.
E-mail: jean-francois.soule@univ-rennes1.fr;
henri.doucet@univ-rennes1.fr
A. Skhiri, Pr. R. Ben Salem
Scheme 2. Pd-catalysed direct arylation of selenophenes.
Dong et al. reported in 2009 an example of Pd-catalysed direct
arylation, via a desulfitative coupling, of a quinoline using p-
TolSO2Cl as aryl source.[10,11] Following this seminal result, the use
of ArSO2Cl as aryl source for the Pd-catalysed direct arylations has
been extended to a variety of heteroarenes by several groups.[12,13] In
2014, we described a novel access to -arylated thiophenes from
thiophenes and ArSO2Cl, using desulfitative Pd-catalysed direct
arylation.[14] However, to our knowledge, the desulfitative direct
arylation of selenophenes with ArSO2Cl has not been reported.
Laboratoire de Chimie Organique Physique (UR 11ES74)
Université de Sfax, Faculté des Sciences de Sfax, Route de
la Soukra km 4, 3038 Sfax, Tunisia.
[] We thank the CNRS, Rennes Metropole and Scientific
Ministry of Higher Education and Research of Tunisia for
providing financial support.
Herein, we describe an environmentally benign general protocol
allowing the completely regioselective access to -arylated
selenophenes, using Pd-catalysed desulfitative direct arylation, from
selenophenes and ArSO2Cl (Scheme 2, bottom). The influence of
Supporting information for this article is available on the
WWW under http://www.angewandte.org or from the
author.
1
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10.1002/chem.201700202
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the ArSO2Cl and selenophenes substituents is reported. The high
yielding programmed synthesis of a tetraarylselenophene is also
described.
Based on our previous results as a starting point,[14] we first
examined the influence of several reaction conditions on the product
formation for the reaction of 1.5 equiv. of 4-nitrobenzenesulfonyl
chloride with selenophene at 140 °C during 4 h (Scheme 3 and
Table 1 in SI). Using 10 mol% Pd(OAc)2 catalyst and 3 equiv. of
Li2CO3 as the base in 1,4-dioxane, the C3-arylated selenophene 1a
was regiospecifically obtained in 56% yield. No formation of the
C2-arylated selenophene derivative 1b was observed by GC/MS and
1H NMR analysis of the crude mixture. The use of
PdCl(C3H5)(dppb), PdCl2, PdCl2(MeCN)2 or Pd(PPh3)4 catalysts
also led regiospecifically to product 1a, but in lower yields. On the
other hand, in the presence of a larger excess (6 equiv.) of Li2CO3
base, product 1a was obtained 79% yield. Then, we examined the
influence of other bases such as Na2CO3, K2CO3, Cs2CO3, K3PO4 or
KOAc; however, lower yields in 1a were obtained.
Scheme 3. Influence of the reaction conditions.
Scheme 4. Influence of the substituents on ArSO2Cl.
Then, the influence of the para-substituents on ArSO2Cl for
reaction with selenophene was examined using 10 mol% Pd(OAc)2
catalyst and 6 equiv. of Li2CO3 in dioxane (Scheme 4). First we
employed electron-deficient ArSO2Cl. Cyano- and trifluoromethyl-
substituents on ArSO2Cl gave regiospecifically the C3-arylated
selenophenes 2 and 3 in 88% and 83% yields, respectively.
Relatively good yields were also obtained for the coupling of 4-
chloro and 4-fluoro-benzenesulfonyl chlorides with selenophene, as
the desired products 4 and 5 were isolated in 57% and 72% yields,
respectively. It should be noted that no cleavage of the C-Cl bond
was observed allowing further transformations. Good yields of 71%
and 73% in 6 and 7 were also obtained from PhSO2Cl and p-
TolSO2Cl; whereas, lower yields of 54% and 31% in 8 and 9 were
produced from the electron-rich 4-tert-butyl- and 4-methoxy-
benzenesulfonyl chlorides. The influence of meta-substituents on the
ArSO2Cl partner was also evaluated. ArSO2Cl bearing CF3, Cl or F
meta-substituents were successfully coupled with selenophene,
affording regiospecifically the desired C3-arylated selenophenes 10-
12 in 74-82% yields. ArSO2Cl containing two CF3, Cl or F
substituents also gave the expected products 13-15 in good to high
yields; whereas, the electron-rich 3,4-dimethoxybenzenesulfonyl
chloride afforded 16 in only 24% yield. ArSO2Cl containing cyano
or chloro ortho-substituents were also tolerated affording 18 and 19
in 88% and 76% yields, respectively; whereas a nitro ortho-
substituent gave 17 in only 31% yield. Polyfluorinated molecules
are ubiquitous in medicinal chemistry, owing to fluorine atom
properties which induce a dramatic change in the molecules
behaviour. The use of ArSO2Cl containing fluorine atoms should
offer a straightforward route to (poly)fluorinated 3-arylselenophenes.
Indeed, from ArSO2Cl containing one to three fluoro substituents,
the 3-arylselenophenes 21-23 were produced in 86-90% yields.
As the use of ArSO2Cl as coupling partners in Pd-catalysed
direct arylations tolerates bromo and iodo substituents,[14b] the
behaviour of several (poly)halobenzenesulfonyl chlorides for
coupling with selenophene was investigated (Scheme 5).
Satisfactory yields in 24 and 25 were obtained in the presence of
ArSO2Cl containing 2- or 4-bromo-substituents. An additional
ortho-ethyl-substituent exhibits a minor influence, as with 2-ethyl-4-
bromobenzenesulfonyl chloride, a high yield of 74% in the target
product 26 was obtained. 2-Bromobenzenesulfonyl chlorides
bearing CF3 or F substituents also led to the expected 3-arylated
selenophenes 27-29 in 75-83% yield. The reactivity of two
dibromobenzenesulfonyl chlorides, which can be easily obtained by
reaction of dibromobenzenes with chlorosulfonic acid, is also
described in the scheme 5. In both cases, the target products 30 and
31 were obtained in good yields, without cleavage of both C-Br
bonds. Then, although C-I bonds on benzene rings are known to be
very reactive in the presence of palladium catalysts, we examined
the reactivity of 4-iodobenzenesulfonyl chloride in the presence of
selenophene. The reaction affords 32 in only 33% yield, but without
cleavage of the C-I bond.
2
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10.1002/chem.201700202
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Scheme 5. Influence of bromo- or iodo-substituents on ArSO2Cl.
The regioselectivity of the arylation of 2- or 3-substituted
selenophenes was also determined (Scheme 6). We first examined
the reactivity of 2-arylselenophenes, which could be easily obtained
via direct arylation of selenophene by aryl bromides using reported
conditions.[9b] High yields in 33-36 were obtained from four 2-
arylselenophenes using CF3- or MeO-substituted ArSO2Cl as aryl
source. In all cases, a complete regioselectivity in favour of the
arylation at C4-position of the 2-arylselenophene was observed. A
bromo-substituent at C2-position on selenophene was also tolerated,
affording the 4-aryl-2-bromoselenophenes 37-39 in 61-70% yields,
without cleavage of the selenophenyl C-Br bond. Moreover, in the
presence of 3,4-dibromobenzenesulfonyl chloride and 4-
iodobenzenesulfonyl chloride, the 4-arylated 2-bromoselenophene
derivatives 40 and 41 were obtained in moderate yields, but without
cleavage of the C-halo bonds on both coupling partners. The
reaction of 3-(4-methoxyphenyl)selenophene
9
with 4-
Scheme 6. Influence of substituents on selenophene.
nitrobenzenesulfonyl chloride regioselectively affords the 3,4-
diarylselenophene 42, which contains two different aryl groups, in
62% yield (Scheme 6, bottom). It was also possible to directly
prepare the 3,4-diarylselenophene 43, bearing two identical aryl
groups, by reaction of selenophene with 3 equiv. of benzenesulfonyl
chloride derivative.
Then, from the previously obtained 2,4-diarylselenophene 34 and 4-
bromochlorobenzene in the presence of 2 mol% Pd(OAc)2 catalyst,
the 2,3,5-triarylselenophene 44 containing three different aryl
groups was obtained in 82% yield (Scheme 7, top). Finally, the
tetraarylated selenophene 45 could be obtained by reaction of the
3,4-diarylselenophene 42 with 3 equiv. of 4-bromobenzonitrile in
the presence of Pd(OAc)2 catalyst (Scheme 7, bottom).
3
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Keywords: Palladium · catalysis · C-H functionalization ·
selenophenes · benzenesulfonyl chlorides
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In summary, we report here the first procedure promoting the
hard-to-achieve arylation at -position of selenophene derivatives.
The reaction proceeds with easily accessible phosphine-free
Pd(OAc)2 catalyst and Li2CO3 as base and tolerates a wide variety
of substituents both on the ArSO2Cl and selenophene coupling
partners. Moreover, this procedure allows the programmed synthesis
of polyarylated selenophenes as the installation of aryl groups at the
desired positions can be achieved. Due to the wide availability of
diversely functionalised ArSO2Cl, this strategy (no expensive base
and ligand) should be very attractive to synthetic or material
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4
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Chemistry - A European Journal
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5
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Entry for the Table of Contents
-regioselectivity
Aymen Skhiri, Ridha Ben Salem,* Jean-
François Soulé,* Henri Doucet * Page –
Page
Unprecedented access to -arylated
selenophenes via palladium-catalysed
direct arylation
The palladium-catalysed coupling of benzenesulfonyl chlorides with selenophene
derivatives allows the access to -arylated selenophenes with complete
regioselectivity. The reaction proceeds with easily accessible catalyst, base and
substrates, without oxidant and tolerates a variety of substituents both on the
benzene and selenophene moieties.
6
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