Radical cyclisation reactions with indoles

Article abstract of DOI:10.1016/S0040-4039(03)00094-7

Several radical cyclisation reactions involving indoles are described. Most notably, we have shown that radical additions to C3 of an indole are frequently facile. A dichotomy in the course of radical cyclisation reactions to C2 of the indole has also been exposed wherein 6-endo-trig cyclisations are propagated by the loss of a hydrogen atom from C2 while 5-exo-trig cyclisations are propagated by hydrogen atom abstraction at C3 from tributyltin hydride. Cyclisations involving the addition of indolyl radical intermediates to arenes have also been demonstrated.

Full text of DOI:10.1016/S0040-4039(03)00094-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1795–1798
Radical cyclisation reactions with indoles
Stuart R. Flanagan, David C. Harrowven* and Mark Bradley
Department of Chemistry, The University of Southampton, Southampton, SO17 1BJ, UK
Received 12 December 2002; accepted 10 January 2003
Abstract—Several radical cyclisation reactions involving indoles are described. Most notably, we have shown that radical
additions to C3 of an indole are frequently facile. A dichotomy in the course of radical cyclisation reactions to C2 of the indole
has also been exposed wherein 6-endo-trig cyclisations are propagated by the loss of a hydrogen atom from C2 while 5-exo-trig
cyclisations are propagated by hydrogen atom abstraction at C3 from tributyltin hydride. Cyclisations involving the addition of
indolyl radical intermediates to arenes have also been demonstrated. © 2003 Elsevier Science Ltd. All rights reserved.
Intramolecular additions of carbon centred radical
intermediates to arenes and aromatic heterocycles have
gained considerable prominence in recent years as they
provide mild and often high yielding routes to con-
densed aromatic ring systems.1,2 One unusual feature of
such processes is that products derived from a non-
reducing pathway are frequently observed even when
tributyltin hydride is employed as a mediator.1 In this
letter we describe a series of radical cyclisation reac-
tions in which an indole is employed as a radical
acceptor.3 Notably, cyclisations to C2 and C3 have
each been accomplished providing access to various
benzocarbazoles and indoline derivatives.
Notably, no products derived from rearrangement or
fragmentation of the radical intermediate 10 were
observed (Scheme 3).5
A fragmentation reaction was however observed when
ether 14 was treated with tributyltin hydride. The pri-
mary product of the reaction was the expected spirocy-
cle 18 derived from a 6-exo-trig spirocyclisation to C2
Our first objective was to see if radical cyclisations to
C3 of an indole could be effected.3j–k To that end
indoles 1 and 3 were prepared and treated with tri-
butyltin hydride under standard radical forming condi-
tions using 20 mol% AIBN as an initiator. For 2-
styrylindole 1, cyclisation occurred to C3 of the indole
by a 6-endo-trig pathway giving benzo[c]carbazole 2 in
58% yield, together with 26% recovered 1. By contrast,
3 gave spirocycle 4 as the major product in 55% yield
(Scheme 1). Spirocyclisation was more pronounced
when an ether was used to conjoin the radical precursor
to the indole;4 5 giving spirocycle 6 in 72% yield
(Scheme 2).
Scheme 1.
A similar reactivity profile was noted with indoles 7 and
9. While 3-styrylindole 7 underwent cyclisation to ben-
zo[a]carbazole 8 in 90% yield, the analogous alkane 9
gave mainly spirocycle 12, with benzocarbazole 13
accounting for the remainder of the mass balance.
* Corresponding author.
Scheme 2.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(03)00094-7

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S. R. Flanagan et al. / Tetrahedron Letters 44 (2003) 1795–1798
Scheme 4.
Scheme 3.
observation can be attributed to steric factors, with
hydrogen atom abstraction from tributyltin hydride
favouring the course of lowest steric demand.
of the indole. The only other product to have been
identified conclusively was aldehyde 19, which is pre-
sumably formed by hydrogen atom abstraction, viz.
15“17. Ejection of PhCH2, or intermolecular trapping
with molecular oxygen, then facilitates collapse to alde-
Cyclisations wherein the indole serves as a radical
donor and the arene as a radical acceptor have also
been examined.8 For cis-3-iodo-2-styrylindole 32, the
’
hyde 19 (Scheme 4).
Our attention next turned to radical cyclisation reac-
tions of N-(o-halobenzyl)indoles. Pleasingly, when a
toluene solution of 20 was heated at 90°C with tri-
butyltin hydride and 20 mol% AIBN, the product mix-
ture comprised of N-benzylindole 24 and 10b,11-dihy-
dro-6H-isoindolo[2,1-a]indole 25.6 In stark contrast to
the cyclisation 9“13, radical intermediate 23 was
quenched by tributyltin hydride rather than suffer loss
of a hydrogen atom leading to 21 (Scheme 5). It is also
pertinent to note that attempts to effect an analogous
five ring closure to a pyridine had given only products
derived from carbon to halogen bond reduction.5 It
therefore seemed appropriate to study this reaction in
more detail.
We soon established that the efficiency of such 5-exo-
trig radical cyclisations to indoles was strongly influ-
enced by substituents on the arene ring. Thus, while the
unsubstituted arene 20 gave dihydroisoindoloindole 25
in a modest 32% yield, the corresponding trimethoxy
derivative 26 gave 28 in 80% yield (Scheme 6). The
stereochemical course of such reactions was also influ-
enced by arene substitution (Scheme 7, Table 1).7 This
Scheme 5.

S. R. Flanagan et al. / Tetrahedron Letters 44 (2003) 1795–1798
1797
Scheme 8.
The cis-alkene tether was found to be essential for
achieving efficient cyclisation reactions with this system;
3-iodoindoles 37 and 38 giving benzocarbazoles 39 and
41, respectively, in low yield. The products of halide
reduction, 40 and 42, accounted for much of the mass
balance in each case (Scheme 9).
Scheme 6.
In conclusion, several radical cyclisation reactions
involving indoles have been studied. Most notably, we
have shown that radical additions to C3 of an indole
can be achieved in good yield through both 5-exo-trig
spirocyclisation (e.g. 9“12) and 6-endo-trig ortho-cycli-
sation of a suitably functionalised cis-2-styrylindole
derivative (e.g. 1“2). A dichotomy in the course of
radical cyclisation reactions to C2 of the indole has also
been exposed. While 6-endo-trig cyclisation reactions
Scheme 7.
expected benzocarbazole 35 was given in a modest 46%
yield together with trans-2-styrylindole 36 (34%).
Remarkably, under the same reaction conditions the
analogous N-methyl derivative 33 gave benzocarbazole
34 in 95% yield (Scheme 8)! The result suggests that
isomerisation of the alkene, by addition and elimination
’
of Bu3Sn , only competes with carbon to halogen bond
homolysis when the alkene tether is conjugated to the
indole ring system. Substituents on nitrogen render this
conformation less favourable and hence retard the rate
at which the byproduct is formed.
Scheme 9.
Table 1. Summary of reactions illustrated in Scheme 77
Entry
R1
R2
R3
X
30 (%)
31 (%)
a-:b-CH3
a
b
c
d
e
H
H
H
H
H
H
H
H
Br
I
Br
I
11
16
26
30
10
38
35
54
56
66
1:1
1:1
3:2
2:1
1:3
OCH2O
OMe
OMe
OMe
OMe
OMe
I

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S. R. Flanagan et al. / Tetrahedron Letters 44 (2003) 1795–1798
(e.g. 9“11) are propagated by the loss of a hydrogen
atom from C2, 5-exo-trig cyclisations (e.g. 22“23) are
propagated by hydrogen atom abstraction from trib-
utyltin hydride. Finally, cyclisation reactions involving
the addition of indolyl radical intermediates to arenes
have been demonstrated.
Harrowven, D. C.; Nunn, M. I. T.; Blumire, N. J.; Fen-
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Acknowledgements
The authors thank Merck Sharp and Dohme for finan-
cial support.
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