Annulation of indole via indole radicals: Addition of the 2-indolyl radical to aromatic rings

Article abstract of DOI:10.1016/S0040-4039(00)00567-0

The reactions of the radicals derived from indoles 4 are described leading to a short synthesis of fused [1,2-a]indoles via radical addition to the benzene ring followed by rearomatisation whilst one example undergoes an unusual radical translocation/addition reaction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00567-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 4209–4211
Annulation of indole via indole radicals: addition of the 2-indolyl
radical to aromatic rings
Andrea Fiumana and Keith Jones ∗
School of Applied Chemistry, Kingston University, Penrhyn Road, Kingston-upon-Thames, Surrey, KT1 2EE, UK
Received 2 March 2000; accepted 4 April 2000
Abstract
The reactions of the radicals derived from indoles 4 are described leading to a short synthesis of fused [1,2-
a]indoles via radical addition to the benzene ring followed by rearomatisation whilst one example undergoes an
unusual radical translocation/addition reaction. © 2000 Elsevier Science Ltd. All rights reserved.
We have recently described the cyclisation of the indolyl-2-radical onto alkenes and alkynes to give
fused [1,2-a]indoles.1 Subsequently, we have investigated the intermolecular addition of the same radical
to electron-deficient alkenes.2 During this latter work we found that in aromatic solvents, addition of the
indole radical to the solvent was significant, a result that caused us to change to the catalytic method of
Stork using t-butanol as solvent.3 The addition of carbon-centred radicals to aromatic rings followed by
rearomatisation of the aromatic ring under apparently reductive conditions is well known. This has been
reported in the case of radical additions to benzene rings4 and has been utilised by Murphy,5 Bowman6
and Moody7 in the addition of alkyl radicals to heterocycles. The apparent ease with which the indole
radical added to aromatic solvents in our studies of its intermolecular reactions caused us to investigate
this process in an intramolecular sense for the annulation of indoles. There has been considerable interest
in tetracycles of this type as they possess a range of biological activities.8
The radical precursors 4a–d were prepared as shown in Scheme 1. The reaction of oxindole 2 with
PBr3/DMF has been reported to give 3 in 28% yield.9 In our hands, we were able to isolate 3 in 47%
yield using a different work-up. However, the most convenient method involved the preparation of 2-
bromoindole from indole 11 followed by formylation with PBr3/DMF. Use of POCl3 in this latter reaction
led to the 2-chloroindole instead. N-Alkylation was achieved by two methods. Reaction of 3 under
Mitsunobu conditions10 with the appropriate alcohol led to 4a and 4b in good yields whilst reaction of 3
with base and the appropriate alkyl bromide gave 4c and 4d in excellent yields. The radical reactions of
indoles 4 revealed some rather unexpected aspects of this system. In order to avoid competitive addition
to the solvent, we initially used cyclohexane as the solvent and syringe pump conditions. Treatment of
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00567-0
tetl 16846

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4a with tributyltin hydride (TBTH) and AIBN under these conditions gave only 5a, the product of direct
reduction, in 78% yield. Using acetonitrile as solvent, a 25% yield of the tetracyclic product 6a was
isolated along with 55% of reduction product 5a. Similar reaction of 4c gave the cyclised indolo[2,1-
a]isoquinoline 6c in 65% yield along with some 20% of reduction product 5c. Presumably the flexibility
imparted by the longer chain favours cyclisation over bimolecular reduction in this case. In the case of 4d,
we fully expected hydrogen atom abstraction from the benzylic position to dominate leading to reduced
product. Much to our surprise, we isolated 37% of the seven-membered ring cyclisation product 6d along
with 32% of reduction product 5d (Scheme 2).
Scheme 1. Reagents and conditions: (i) n-BuLi, THF, −78°C; CO2, t-BuLi, CCl2BrCCl2Br (96%); (ii) PBr3, DMF (70%); (iii)
Ph3P, DEAD, THF, Ph(CH2)nOH (n=1, 75%; n=4, 80%); (iv) K2CO3, acetone, Ph(CH2)nBr (n=2, 91%; n=3, 94%)
Scheme 2.
The most unexpected result arose from the reaction of 4b. The major product, isolated in 48% yield,
proved to be the tricyclic compound 7 which must arise from a [1,5]-hydrogen atom abstraction by the
initial indole radical followed by cyclisation of the resulting alkyl radical onto the indole with subsequent
rearomatisation. The cyclisation of alkyl radicals onto indoles with rearomatisation has been reported7
although the translocation step is unknown and is under further investigation.11 This reaction also gave
27% of reduced product 5b.
In summary, the indolyl-2-radical shows some interesting features in its intramolecular reactions
with aromatic rings. The geometric constraints imposed by the indole skeleton led to considerable
reduction although the seven-membered ring product 6d is formed in moderate yield.12 An unusual
translocation–cyclisation reaction has been uncovered which shows considerable promise for the rapid
synthesis of pyrrolo[1,2-a]indoles.

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Acknowledgements
We thank Kingston University for funding.
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