Homolytic aromatic substitution: A radical approach towards the synthesis of 5-azaoxindoles

Article abstract of DOI:10.1016/j.tetlet.2005.11.004

A range of 5-azaoxindoles have been synthesised employing homolytic aromatic substitution onto pyridine as the pivotal step.

Full text of DOI:10.1016/j.tetlet.2005.11.004

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 381–383
Homolytic aromatic substitution: a radical approach towards
the synthesis of 5-azaoxindoles
John M. D. Storey* and Mitesh M. Ladwa
Department of Chemistry, University of Aberdeen, Meston Building, Meston Walk, Old Aberdeen, AB24 3UE, UK
Received 25 August 2005; revised 25 October 2005; accepted 2 November 2005
Available online 17 November 2005
Abstract—A range of 5-azaoxindoles have been synthesised employing homolytic aromatic substitution onto pyridine as the pivotal
step.
Ó 2005 Elsevier Ltd. All rights reserved.
Inter and intramolecular homolytic aromatic substitu-
tion reactions have been used for over a hundred years
for the formation of new carbon bonds. Whilst the inter-
molecular process in general shows a lack of selectivity,
there are a few isolated cases where it has been used to
good effect.1 The intramolecular variant however has
been far more widely utilised and has seen something
of a revival over the past 15 years, with many examples
of cyclisation onto arenes as well as onto heteroarenes
being reported.2
isosteres of simple spirocyclic alkaloids such as horsfiline
for biological evaluation.
To our surprise it appears that there are only two
methods documented towards the synthesis of 5-azaox-
indole systems. One approach was based upon the di-
lithiation of pivaloylamino pyridine, followed by carbon
monoxide insertion.9 The other approach involved the
bromination of 5-azaindole, followed by reduction to
give the 5-azaoxindole.10 Both of these methods suffer
from relatively harsh reaction conditions and limited
applicability. Herein, we wish to disclose our investiga-
tions directed towards the synthesis of a range of 5-aza-
oxindoles using the cyclisation of an alkyl radical onto a
pyridine ring as the key synthetic step.
For some time, we have had an interest in the synthetic3
and mechanistic4 aspects of homolytic aromatic substi-
tution but have as yet not investigated this approach
as a method to synthesise fused pyridine-based systems.
It appears that there has been little interest in the syn-
thesis of fused pyridine systems using this method and
as far as we are aware there have been only two reports
of an alkyl radical undergoing an intramolecular radical
cyclisation onto pyridine ring systems. The first of these
was described by Murphy5 and the second more recently
by Zard.6 We viewed azaoxindoles as worthy synthetic
targets to test this approach, as they have many poten-
tial biological applications, one of which is the suppres-
sion of TrK tyrosine kinases,7 which have been
implicated in the development of various cancers includ-
ing breast and prostate cancers.8 Moreover, we wished
to be able to generate a spirocyclic centre at the 3-posi-
tion of these systems which would lead ultimately to bio-
It was envisaged that preparation of the cyclisation
precursors 2a–c (Scheme 1) could be achieved simply
by treatment of amino pyridine with the appropriate
haloacid halide. Along these lines, 4-aminopyridine in
the presence of triethylamine or HunigÕs base was trea-
¨
ted with 2-bromopropionyl bromide. Unfortunately,
O
Me
Me
N
Br
R1
NH2
N
NH
Br
iii
O
i
R2
N
R2
R1
ii
N
Br
2a. R1 = R2 = H
2b. R1 = Me, R2 = H 75%
2c. R1 = R2 = Me
86%
1
61%
Keywords: Homolytic aromatic substitution; 5-Azaoxindoles; Radical
cyclisation; Pyridine.
*
Scheme 1. Reagents and conditions: (i) ClCO Et, HunigÕs base, DCM;
Corresponding author. Tel.: +44 01224 272926; fax: +44 01224
¨
2
(ii) LiAlH4, THF; (iii) Hu¨nigÕs base, DCM.
272921; e-mail: j.storey@abdn.ac.uk
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.004

382
J. M. D. Storey, M. M. Ladwa / Tetrahedron Letters 47 (2006) 381–383
Table 1. Yield of cyclised product and directly reduced product
complex mixtures of products were formed and poor
yields of the desired amides resulted. The alternative
strategy that we chose to adopt involved mono-methyl-
ation of the 4-aminopyridine to give 1 followed by acyl-
ation with a bromoacid bromide. Two methods for the
formation of 1 were investigated. The first, developed
by Reese11 involved the reaction of 4-aminopyridine
with formaldehyde and p-thiocresol in acetic acid fol-
lowed by reduction with sodium borohydride which
gave 1 in 50% yield. The second approach involved acyl-
ation of 4-aminopyridine with ethyl chloroformate fol-
lowed by reduction with a 1 M solution of LiAlH4 in
THF. This method gave the desired amine 1 in 75% yield
on a multigram scale. The requisite radical precursors
were then generated by treatment with the appropriate
Entry
Cyclisation
precursor
Isolated yield (%)
Cyclised
product
Directly
reduced
product
1a
2a
3b
4b
5c
2b
2c
2c
2b
2b
2c
2a
5a
5b
5c
5d
3b
3c
3c
3b
3b
3c
3a
6a
6b
6c
6d
0
0
41
3
7
68
0
55
73
76
71
4b
0
0
4c
4c
4b
4b
4c
4a
7a
7b
7c
7d
40
25
24
17
0
21
11
12
10
6c
7c
8c
9c
10c
11c
bromoacid bromides, and HunigÕs base in dichlorometh-
¨
a TBTH (1.5 equiv), AIBN (0.1 equiv), substrate (1.0 equiv) as a 0.1 M
solution in toluene.
ane (Scheme 1). Hence, reaction of 1 with 2-bromopro-
pionyl bromide and 2-bromoisobutyryl bromide gave
the corresponding cyclisation precursors 2b and 2c in
75% and 86% yields, respectively. Similarly, treatment
of 1 with 2-bromoacetyl bromide gave 2a as judged by
NMR analysis of the crude reaction mixture. However,
2a was never isolated in a pure form due to its rapid
decomposition. Indeed all three of the a-bromo amide
cyclisation precursors proved to be relatively unstable
and required storage in the dark at low temperature.
b TBTH (1.5 equiv), AIBN (2.0 equiv), substrate (1.0 equiv) as a 0.1 M
solution in toluene.
c Syringe pump addition over 5 h of TBTH (1.5 equiv) and AIBN
(2 equiv) to substrate (1.0 equiv) as a 0.1 M solution in toluene
making a 0.05 M solution upon complete addition.
cyclisation of 2b (entry 5) but was effective in signifi-
cantly increasing the yield of 3c from 2c (entry 6). No
identifiable cyclisation product, reduced product or
starting material could be isolated from the reaction
involving 2a. The combined yield of cyclised and
reduced products from cyclisation of the secondary
bromide precursor 2b was considerably less than that
from the tertiary bromide precursor 2c. The stability
of the secondary bromide 2b to silica during chromato-
graphy was also less than 2c, and 2b appeared to decom-
pose under the cyclisation conditions to some extent.
The primary bromide 2a appeared to be the least stable,
indeed, upon heating 2a alone in deoxygenated toluene
for 30 min resulted in complete degradation. The stabil-
ity of the starting bromide under the reaction condi-
tions, prior to radical formation therefore appears to
be largely responsible for the differences in yields
observed.
Compounds 2b and 2c were subjected to standard tri-
butyltin hydride (TBTH) mediated radical cyclisation
conditions (1.5 equiv of TBTH, 0.1 equiv of AIBN,
1.0 equiv of substrate at a concentration of approxi-
mately 0.1 M in toluene at reflux) (Scheme 2). No cycli-
sation product was detected and surprisingly there was
no evidence of the product resulting from direct reduc-
tion with TBTH in either of these reactions; indeed,
the major product in each case was unreacted starting
material along with some decomposition products
(entries 1 and 2 in Table 1). When these reactions were
repeated using 2 equiv of AIBN, all of the starting mate-
rial was consumed giving the desired cyclised product
and directly reduced product (entries 3 and 4). These
results are in accord with the mechanistic proposals that
we previously outlined4 where at least one full equiva-
lent of AIBN was required for successful homolytic
aromatic substitution involving both benzene and imid-
azole ring systems.
We next directed our attention to the synthesis of spiro-
cyclic 5-azaoxindoles for which we are unaware of any
previously reported synthetic methods. The synthesis
of the cyclisation precursors was achieved by the reac-
tion of 1 with the appropriate bromoacid bromide.
The bromoacid bromides required to synthesise 5b–d
were prepared from commercially available acids using
Hell–Volhard–Zelinsky bromination conditions employ-
ing 2.5 equiv of bromine and a catalytic amount of red
Given the less than ideal yields of cyclisation products
from these reactions, effort was directed at improving
the synthesis by the slow addition of TBTH and AIBN
via syringe pump over a 5 h period. This strategy had
little effect on the yield of cyclised product from the
Me
N
Me
Me
N
O
N
O
R
i
O
N
N
N
1
2
2
1
R
R
2
R
R
1
Br
H
2
R
1
2
1
2
1
2a. R = R = H
3a. R = R = H
4a. R = R = H
1
2
1
2
1
2
2b. R = Me, R = H
3b. R = Me, R = H
4b. R = Me, R = H
1
2
1
2
1
2
2c. R = R = Me
3c. R = R = Me
4c. R = R = Me
Scheme 2. Reagents and conditions: (i) Bu3SnH, AIBN, toluene, 110 °C.

J. M. D. Storey, M. M. Ladwa / Tetrahedron Letters 47 (2006) 381–383
383
Me
N
cient route to synthesise 5-azaoxindoles and spirocyclic
5-azaoxindoles. Clearly, the main limitation to this
method is the instability of the a-bromoamide cyclisa-
tion precursors making this method poor when second-
ary a-bromoamides are involved, and inappropriate
when primary a-bromoamides are involved.
Me
N
Me
N
O
i
O
O
n
N
N
Br
N
n
n
5a. n = 1
5b. n = 2
5c. n = 3
5d. n = 4
6a. n = 1
6b. n = 2
6c. n = 3
6d. n = 4
7a. n = 1
7b. n = 2
7c. n = 3
7d. n = 4
Acknowledgements
Scheme 3. Reagents and conditions: (i) Bu3SnH, AIBN, toluene,
110 °C.
We gratefully thank Kingston University and The Uni-
versity of Aberdeen for financial support for M.M.L. In
addition, we would like to thank Dr Steve Hilton for
helpful discussions and the EPSRC National Mass Spec-
troscopy Centre at the University of Wales, Swansea for
providing accurate mass measurements.
phosphorus. Each was purified by fractional distillation
prior to coupling with 1 under the conditions previously
adumbrated to give the cyclisation precursors 5b–d in
86%, 85% and 81% yields, respectively. For the prepara-
tion of 5a, 1-bromocyclopropanecarbonyl chloride was
synthesised by intramolecular cyclisation of 2,4-bromo-
butanoate in the presence of tetrabutylammonium
hydrogen sulfate and potassium carbonate in toluene,
to give the monobromoester. This was then treated with
6 M HCl to furnish the bromoacid, followed by conver-
sion to the acid chloride by treatment with thionyl chlo-
ride giving 1-bromocyclopropanecarbonyl chloride in
56% yield.12 This was then coupled with 1 to give 5a
in 83% yield.
References and notes
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The cyclisation of substrates 5a–d (Scheme 3) afforded a
range of spiro azaoxindoles in reasonable yields (entries
8–11). With the exception of the cyclisation of 5a it
would appear that the size of the spirocyclic ring has lit-
tle effect on the selectivity between cyclisation and direct
reduction with TBTH. Interestingly, the cyclisation of
5a gave significantly less cyclisation product than the
other cases investigated even though the reactivity of a
cyclopropyl radical has been shown to be similar to a
vinyl radical. This is about one order of magnitude less
reactive than a phenyl radical, but considerably more
reactive than an alkyl radical in addition reactions to
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of course electron-rich aromatic systems compared to
pyridine. Of the four tertiary radicals being considered
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identical conditions, the ratio of cyclised to reduced
products for each substrate provides an approximate
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rate-determining step of cyclisation, and kH is the rate
constant for hydrogen atom transfer from the TBTH
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In general, we have demonstrated the feasibility of using
homolytic aromatic substitution onto pyridine as an effi-