Direct electroreductive preparation of indolines and indoles from diazonium salts

Article abstract of DOI:10.1021/ol0262643

Indolines and indoles are prepared for the first time by direct electrochemical reduction of arenediazonium salts.

Full text of DOI:10.1021/ol0262643

ORGANIC
LETTERS
2002
Vol. 4, No. 16
2735-2738
Direct Electroreductive Preparation of
Indolines and Indoles from Diazonium
Salts
,†
Franck LeStrat,† John A. Murphy,* and Mark Hughes‡
aDepartment of Pure and Applied Chemistry, UniVersity of Strathclyde,
b
295 Cathedral Street, Glasgow G1 1XL, Scotland, and Glaxo SmithKline
Pharmaceuticals, New Frontiers Science Park, Third AVenue, Harlow,
Essex CM19 5AW, U.K.
john.murphy@strath.ac.uk
Received May 30, 2002
ABSTRACT
Indolines and indoles are prepared for the first time by direct electrochemical reduction of arenediazonium salts.
The pressing need to develop clean methodology (“green
chemistry”) for synthetic reactions is widely recognized1. One
aspiration of green chemistry is to replace current methods
of forming C-C bonds that use toxic reagents with “rea-
gentless” reactions that are induced simply by energy:
electrical, thermal, photochemical, or other. This paper deals
with electrochemistry; although it is a valuable tool in
synthesis2, there are many areas of organic chemistry where
it has not yet been applied. Here we describe a new
application of controlled potential electrochemistry to the
synthesis of indolines and indoles, both of which are
important pharmacophores.
then depends on the energy separation between the two
electron-transfer steps.
Scheme 1
Cathodic reduction of an aryl halide 1 could occur by an
initial one-electron reduction to form the radical anion 2,
which could dissociate into an aryl radical and a halide anion.
This radical could then cyclize onto appropriate unsaturated
side-chains to form the five-membered heterocyclic ring in
4. However a second reductive step, converting the aryl
radical 3 to an anion equivalent, 4′, could also occur.
Selectivity for formation of the radical 4 versus the anion 4′
It has been reported3 that direct electrochemical reduction
of aryl halides such as 1 does not lead to radical cyclization
but instead to products resulting from the formation of
anionic intermediates. However, this may depend on the
† University of Strathclyde.
‡ Glaxo SmithKline Pharmaceuticals.
(1) See special issue: Pure Appl. Chem. 2000, 72, 1207-1403.
(2) For a review, see: Eberson, L.; Scha¨fer, H. Fortschr. Chem. Forsch.
1971, 21, 5.
(3) Olivero, S.; Clinet, J. C.; Dunach, E. Tetrahedron Lett. 1995, 36,
4429.
10.1021/ol0262643 CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/12/2002

aryl halides, controlled potential reduction of arenediazonium
salts should allow extremely mild and selective formation
of aryl radicals for cyclization reactions. Surprisingly, the
only report of electrochemical activation of a diazonium salt
for cyclization relates to a Pschorr reaction11. Notably,
electrolysis was conducted at a very mild 0 V vs SCE.
We began with a study of simple arenediazonium salts
5a and 5b.12 Using a platinum cathode, the cyclic voltam-
mogram showed the first reductive half-wave potential at
-0.2V vs SCE. In the preparative experiments, maintaining
the potential at -0.4V vs SCE and using a divided cell
afforded a complex mixture as seen by NMR spectroscopy.
From the 1H NMR spectrum, it was clear that the diazonium
group was no longer present. Some aryl radical cyclization
had taken place, but alkene peaks remained in the crude
product. The presence of alkene protons, despite the complete
absence of diazonium salts, was curious. If the diazonium
salt had converted to an aryl radical, a very rapid cyclization
would have followed, thereby removing both groups. The
data suggested that a side-reaction had consumed some of
the diazonium groups. A clue came from the report by
Minisci et al.13 that carbon radicals can add efficiently to
arenediazonium salts in normal (i.e., nonelectrochemical)
solution; in our case, this would be a very likely reaction at
the cathode because of the expected high local concentration
of diazonium cations. Thus, cyclized radical 6 attacks
diazonium salt 5 to afford coupled azo radical-cation 7. Facile
electrochemical reduction of 7 would yield neutral azo
compound 8; in turn, this could undergo tautomerism to
afford the hydrazone 9. (The alternate sequence of attack
by cyclized radical 6 on an aryldiazo radical, may also be
valid.14)
Scheme 2
conditions used and on the properties of the individual
substrates, since a number of electrochemical cyclizations
of aryl halides onto arenes have been reported by Grimshaw
et al.4 and by Gottlieb and Neumeyer.5 Very recently,
Munusamy et al.6 also reported elegant work on the cathodic
cyclization of iodophenyl alkylcinnamides.
In cases where difficulties occur in selectively generating
the aryl radicals by electrochemical means, successful radical
generation and cyclization can often be achieved in an
indirect electrochemical way by using nickel or cobalt
complexes to mediate the reactions.3,7 In these cases, an
added nickel or cobalt complex is reduced electrochemically
in situ, and the reduced complex then carries out the desired
radical-forming reaction.
Regardless of the substrate dependencies of these reactions,
electrochemical reduction of aryl halides (or of the metal
mediators described above) generally occurs at a highly
reductive -1.5 to -2.5 V relative to SCE. These are brutal
conditions to use on sensitive substrates. By contrast,
arenediazonium salts are excellent single-electron acceptors,
and polarographic studies by Elofson et al.8 Atkinson et al.,9
and Kochi10 have confirmed this. Therefore, in contrast to
Although it was not possible to isolate any pure compound
from these experiments, the working hypothesis just dis-
cussed proved very useful in focusing on the need to
terminate the cyclized radical 6 before intermolecular reaction
could occur. Hence substrates 10 and 11 were synthesized
bearing a sulfide and sulfoxide group, respectively (Scheme
3).
These were converted into diazonium tetrafluoroborates
that were used in situ and afforded an excellent 90% of
Scheme 3a
a Reagents and conditions: (a) DEAD, PPh3, THF, 0° to rt, 96%. (b) TBAF, THF, 95%. (c) PBr3, THF, 0 °C to rt, 80%. (d) PhSH, NaH,
THF, 98%. (e) NaIO4, MeOH, H2O, 91%. (f) Cu(acac)2, NaBH4, EtOH, 85% for sulfide, 65% for sulfoxide. (g) NOBF4. (h) Pt cathode,
-1.1 V vs SCE, 0.06-0.08 M [ArN2]BF4 in 0.1 M NaClO4/DMF, reaction scale ) 0.7 mmol to 1 mmol of [ArN2]BF4, 90% for sulfide,
70% for sulfoxide.
2736
Org. Lett., Vol. 4, No. 16, 2002

Scheme 4a
a Reagents and conditions: (a) NBS, Me2S, DCM, 0 °C to rt, 95%. (b) NaH, THF, cis-but-2-en-1,4-diol, 0 °C to rt, 60%. (c)
2-nitrobenzenesulfonamide, DEAD, PPh3, THF, 98%. (d) TBAF, THF, 95%. (e) NBS, Me2S, DCM, 0 °C to rt, then NaH, PhSH, THF,
84%. (f) NaIO4, 2 equiv, H2O, MeOH, rt, 59%. (g) SnCl2, MeOH, ∆, 82% for sulfide. (h) Cu(acac)2, NaBH4, EtOH, 89% for sulfone. (i)
NOBF4, DCM, -5 °C. (j) Pt cathode -1.1 V vs SCE, 0.06 M [ArN2]BF4 in 0.1 M NaClO4/DMF, reaction scale ) 0.1 mmol to 0.7 mmol
of [ArN2]BF4, 76% from sulfide 18, 65% from sulfone 20.
vinylindoline 12 from the reaction of sulfide 10, and 70%
from reaction of sulfoxide 11. (Our preparative experiments
were generally conducted at -1.1V vs SCE for the conven-
ience of achieving a rapid preparative conversion, although
they could be carried out more slowly at less reducing
potentials, as described above for 5a,b. The first reduction
potentials seen in the c.v. data for compounds 5a,b were
assumed to be also representative for the first reduction
potentials of other diazonium salts in our work).
To test whether the electrochemistry could be applied to
more complex substrates, sulfide 19 and sulfone 21 were
prepared as shown in Scheme 4. The diazonium salts were
again used in situ and afforded yields of 76% of 22 from
the sulfide and 65% from the sulfone.
Having successfully synthesized a range of indolines, the
next step was to prepare indoles using substrates 23 (Scheme
5). Cyclization of the electroreductively generated aryl radical
would afford radical 24, which should cause a rapid
elimination of the bromine atom from the adjacent carbon
to afford an exocyclic alkene 25; tautomerism in the presence
of a trace of acid15 would then provide the desired indoles
26. The substrates 23b,c were prepared as described previ-
ously,15 and 23a was prepared analogously. Controlled
potential electrolysis of these substrates led to rapid reaction
of the diazonium salts. (Reaction scale ) 0.2-0.25 mmol
of [ArN2]BF4). Isolation of the products by chromatography
on silica gel in each case afforded the exocyclic alkene 25
rather than the thermodynamically more stable indole 26 as
Scheme 5
Org. Lett., Vol. 4, No. 16, 2002
2737

the principal product. However, and intriguingly, a second
product type, alcohol 29, was also isolated from two of the
substrates. The oxidized products 29a,c are formed in the
reductive cathode compartment of a divided cell. Their
formation may arise by (direct or indirect) 1,2-bromine
shift15,16 from radical 24; oxidation of the resulting benzylic
radical 27 could occur by electron transfer to a diazonium
cation, present in high concentration around the cathode.
Proton loss then forms the bromoalkyl indole 28, which
would undergo easy hydrolysis to the observed alcohol 29.
In summary, arenediazonium salts are easily converted to
aryl radicals under controlled potential electrolysis. The aryl
radicals are useful precursors of indolines, provided that an
appropriate leaving group is present to preempt intermo-
lecular reactions of intermediate radicals 6. Phenylthio is a
very useful leaving group in this context. The aryl radicals
are also useful precursors of indoles. However, an unexpected
reaction is frequently seen in these reactions, which may arise
from initial 1,2-bromine atom shift. Investigation of alterna-
tive leaving groups is currently in progress.
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Acknowledgment. We thank the Royal Society for a
Leverhulme Senior Research Fellowship to J.A.M.; EPSRC
and SB for a CASE award to F.LeS.; EPSRC Mass
Spectrometry Service Swansea for mass spectra; and Dr. L.
E. A. Berlouis for assistance with electrochemistry.
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Supporting Information Available: 1H and 13C NMR
spectra together with combustion analysis and/or high-
resolution mass data on all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(13) Minisci, F.; Coppa, F.; Fontana, F.; Pinese, G.; Zhao, L., J. Org.
Chem. 1992, 57, 3929.
OL0262643
(14) We thank Professor W. R. Bowman for this suggestion.
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A. R.; Lewis, N. J. Chem. Soc., Perkin Trans. 1 2000, 2395 and references
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