Nickel-catalyzed electrochemical synthesis of dihydro-berazo[b]thiophene derivatives

Article abstract of DOI:10.1081/SCC-200030579

The intramolecular electrochemical reductive cyclization of orthohaloaryl allyl thioethers catalyzed by Ni(II) complexes associated to cyclam ligands affords dihydro-benzo[b]thiophene derivatives in moderate to good yields.

Full text of DOI:10.1081/SCC-200030579

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 18, pp. 3343–3348, 2004
Nickel-Catalyzed Electrochemical Synthesis
of Dihydro-Benzo[b]thiophene Derivatives#
1
´ ´
Jeremie Pelletier, Sandra Olivero, and Elisabet Dun˜ach
1
1,2,
*
1
2
Laboratoire Aromes, Syntheses et Interactions and Laboratoire de
ˆ
`
´
Chimie Bioorganique, UMR 6001, CNRS, Universite de Nice-Sophia
Antipolis, Nice, France
ABSTRACT
The intramolecular electrochemical reductive cyclization of ortho-
haloaryl allyl thioethers catalyzed by Ni(II) complexes associated to
cyclam ligands affords dihydro-benzo[b]thiophene derivatives in moder-
ate to good yields.
Key Words: Benzothiophene; Nickel; Electrochemical; Cyclization;
Allyl aryl sulfide.
#Dedicated to Pr. E. Dinjus for its 60th anniversary.
*
Correspondence: Elisabet Dun˜ach, Laboratoire de Chimie Bioorganique, UMR 6001,
´
CNRS, Universite de Nice-Sophia Antipolis, Parc Valrose, 06108 Nice, cedex 2,
France; E-mail: dunach@unice.fr.
3343
DOI: 10.1081/SCC-200030579
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Pelletier, Olivero, and Dun˜ach
Benzo[b]thiophene structures are interesting molecules, in particular
because of their pharmacological properties; some of the derivatives are
known to present antifungic, antimycotic, and analgesic activities.[1] The
chemical preparation of benzo[b]thiophene derivatives has been reported
via a radical-type cyclization in the presence of stoichiometric amounts of tri-
butyltin hydride and AIBN from halogenated aryl thioallyl compounds, in
particular with aryl-iodide derivatives.[2,3] Pd(0)-catalyzed intramolecular
cyclization of allyl o-iodophenyl sulfides in an Heck-type reaction may also
afford related benzo[b]thiophene derivatives in good yields.[4]
Electrochemistry, associated with organometallic catalysis, may consti-
tute an alternative catalytic approach to these cyclization reactions. Thus,
the selective cyclization of halides on unsaturated C–C bond has been
reported in an electrochemical Ni(II)-catalyzed reaction.[5] The process was
highly dependent on the nature of the ligand associated to metal center.[6]
Ni(II) complexes associated with tetraaza macrocyclic ligands such as
cyclam (1,4,8,11-tetraazacyclotetradecane) were able to efficiently catalyze
the intramolecular cyclization.
In the present study, we report on the use of the electrochemical method
for the Ni(II)-catalyzed preparation of dihydrobenzo[b]thiophene derivatives
of type 2 starting from ortho-haloaryl allyl thioethers 1 (Sch. 1).
Scheme 1.

Nickel-Catalyzed Electrochemical Synthesis
3345
The electrochemical method was based on the use of a one-compartment
cell fitted with a sacrificial metal anode (generally magnesium) and a con-
centric carbon fibre cathode.[7] The reactions were conducted in acetonitrile
at constant current density of 0.1 A/dm2 (constant current of 60 mA), at
room temperature, with 10 mol% catalyst with respect to the starting ortho-
haloaryl allyl thioethers 1. Allyl thioethers 1 were prepared from ortho-
chloro or bromo thiophenols and the corresponding allyl chlorides or bromides
in DMF, in the presence of K2CO3 at 508C, with yields in the range of 64%
to 95%.
When the bromo derivative 1a was electrolyzed in acetonitrile without
any catalyst in the presence of a Mg anode and a carbon fibre cathode, a
non-selective mixture of compounds 2a–4a was formed in 86% conversion
after 3.3 F/mol. The desired cyclized product, 3-methyl-2,3-dihydroben-
zo[b]thiophene 2a, was obtained in only 3% yield. 2-Bromothiophenol
3a, issued from the cleavage of the S-C(allyl) bond, was formed in 35%
yield, and 4a issued from the double-bond isomerization and the cleavage
of the aryl-bromide bond was obtained in 50% yield (Sch. 2).
The same reaction in the presence of a catalytic amount of Ni(cyclam)Br2
as the catalyst (10 mol%) allowed the chemoselectivity toward the cyclized
compound 2a to improve to 39%. Under these conditions, 3a and 4a were
formed in 39% and 18% yields, respectively.
The nature of the solvent was also examined. Thus, when the
Ni(cyclam)Br2-catalyzed reaction of 1a was run in DMF instead of aceto-
nitrile, the cyclic compound 2a was formed in 25% yield. Acetonitrile was
therefore the solvent of choice for further electrolyses.
Scheme 2.

3346
Pelletier, Olivero, and Dun˜ach

Nickel-Catalyzed Electrochemical Synthesis
3347
A further improvement in the selectivity toward 2a could be achieved by
using Ni(cyclam)(BF4)2 as the catalyst. The electrolysis of 1a with 10 mol% of
Ni(cyclam)(BF4)2 in acetonitrile with Mg/C as the couple of electrodes led to
cyclic 2a in 73% yield.
The influence of the anodic and cathodic materials was examined in reac-
tions of 1a [with Ni(cyclam)(BF4]2 as the catalyst in acetonitrile). The use of
either aluminum or zinc rods as the anodes, combined with a carbon fiber
cathode, led to yields of 2a of 40% and 51%, respectively, and did not allow
the yield of cyclized compound obtained with a magnesium anode to further
improve. By using stainless steel instead of carbon fiber as the cathode (with
a magnesium anode), the cyclization process of 1a was completely inhibited
and the isomerization reaction leading to 4a became the predominant process.
The best electrolytic conditions (see Table 1) were extended to the cycli-
zation of a series of ortho-haloaryl allyl thioethers 1a–1e. Table 1 summarizes
these results.
Whereas the intramolecular cyclization of ortho-bromoaryl allyl thioether
1a afforded 73% yield of 3-methyl-2,3-dihydrobenzo[b]thiophene 2a with
95% conversion after 3.3 F/mol (entry 1), the corresponding chloride deriva-
tive 1b (entry 2) led only to 40% of 3-methyl-2,3-dihydrobenzo[b]thiophene.
Although moderate, this result is interesting because the activation of the aryl-
chlorine bond is more difficult than that of the Ar-Br bond, and the possibility
to get cyclization to 2a from the chloride derivative has not yet been reported
with the more classical stoichiometric chemical procedures, which generally
need the more activated iodo (or sometimes bromo) derivatives.[2,3] In the
electrochemical cyclization of 1b, the main by-product was the cleavage com-
pound 3b (Sch. 2), obtained with 46% yield.
Entries 3–5 involved the cyclization of alkyl-substituted allyl thioethers
1c–1e. With substrate consumptions of 75% to 78%, the yields of the
expected cyclic products 2c–2e were in the range of 59% to 64%.
In conclusion, a series of dihydrobenzo[b]thiophene derivatives could be
prepared from ortho-haloaryl allyl thioethers by using an electrochemical
method, which allows a catalytic intramolecular reductive cyclization of
these derivatives assisted by nickel complexes. The electrochemical process is
of very simple set-up and makes it possible to obtain moderate to good yields
of cyclized compounds, even starting from aryl chloride derivatives.
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Received in the UK April 21, 2004