Tuneable radical cyclisations: A tin-free approach towards tricyclic and spirocyclic heterocycles via a common precursor

Article abstract of DOI:10.1039/c4ra02420f

A novel common precursor approach towards both tricyclic and spirocyclic heterocycles is described. Cyclisations are based on thiyl radical/isocyanide methodology and avoid the use of tin.

Full text of DOI:10.1039/c4ra02420f

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COMMUNICATION
Tuneable radical cyclisations: a tin-free approach
towards tricyclic and spirocyclic heterocycles via a
common precursor†
Cite this: RSC Adv., 2014, 4, 18930
Received 11th March 2014
Accepted 1st April 2014
*
B. Patel, G. Saviolaki, C. Ayats, M. A. E. Garcia, T. Kapadia and S. T. Hilton
DOI: 10.1039/c4ra02420f
www.rsc.org/advances
A novel common precursor approach towards both tricyclic and spi- Takeda et al. have reported an attractive radical route to the core
rocyclic heterocycles is described. Cyclisations are based on thiyl structure of Martinelline,7 whilst Beckwith and Storey have
radical/isocyanide methodology and avoid the use of tin.
developed a route towards oxindoles via hydrogen atom
abstraction using tributyltin hydride.8 Despite the large number
of reports towards both classes of compound, many rely upon
the use of organo-tin hydride reagents as a way of mediating
these processes.7,8 An alternative method for the formation of
nitrogen heterocycles that avoids the use of tin involves the
addition of thiyl radicals to isocyanides, generating a-imidoyl
radicals which can undergo cyclisation onto a pendant alkene/
alkyne.9 However, there is no approach that allows for the
synthesis of both chemical classes commencing from a
common precursor. We now wish to disclose a novel tuneable
approach to both tricyclic and spirocyclic heterocycles that is
able to select for both classes via simple modication of the
reaction conditions. The disconnection sequence towards both
the pyrroloquinoline core 8 and the spirocyclic structure 9 from
reaction of the precursor 11 is shown in detail (Scheme 1).
We envisaged that under suitable reaction conditions the
intermediate a-imidoyl radical derived from addition of a thiyl
radical to the isocyanide 11, would undergo either 6-endo or 5-
exo cyclisation to generate either the tricyclic core 8, or the
spirocyclic structure 9 respectively. Our approach was inspired
Tricyclic heterocycles and their related spirocyclic congeners
are attractive synthetic targets due to their occurrence in natural
products and their frequent use as therapeutics.1 Nearly all
members of these two distinct chemical series possess potent
and widely differing biological activities and have attracted
signicant attention from both synthetic and medicinal chem-
ists.1 In particular, martinelline 1 and martinellic acid 2 – iso-
lated from the roots of Martinella iquitosensis, have featured
frequently in the literature, due to their unique occurrence in
nature and their antibiotic/antagonistic activity towards several
G-protein coupled receptors (GPCR) systems including brady-
kinin and muscarinic receptors.2 Amongst the non-natural
product based compounds, the related tricyclic molecule – NVP-
BEZ235 3, which is a dual inhibitor of PI3K/mTor pathway
serves to highlight the anticancer potential of this class of
compound.3 Related to their tricyclic counterparts, the spi-
rooxindole heterocycles have also attracted signicant atten-
tion, not least due to their structural complexity. This ranges
from simple members such as horsline 4 and coerulescine 5,4
through to more substituted derivatives such as alstonisine 6
and spirotryprostatin A 7.5,6 There have been a signicant
number of synthetic efforts directed towards 7 and related
derivatives due to its potent antinioplastic activity via inhibition
of the cell cycle (Fig. 1).6
There have been several approaches to both these classes of
compound using radical methodology as a result of the mild
exible and predictable conditions that can be used, preventing
the need for protection/deprotection steps.7 In particular
UCL School of Pharmacy, 29-39 Brunswick Square, London, UK. E-mail: s.hilton@ucl.
ac.uk; Fax: +44 (0)2077535964; Tel: +44 (0)2077535804
† Electronic supplementary information (ESI) available: Experimental details and
characterisation of all compounds and copies of all spectra are available. See DOI:
10.1039/c4ra02420f
Fig. 1 Spirocyclic and tricyclic heterocycles.
18930 | RSC Adv., 2014, 4, 18930–18932
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Table 1 Optimisation of reaction conditions for obtention of both
tricyclic and spirocyclic heterocycles 8 and 9 respectivelya
Product ratio
Concentration
(M)
AIBN
(equiv.)
PhSH
(equiv.)
6-endo
(8)
5-exo
(9)
Entry
Scheme 1 Disconnection of the tricyclic and spirocyclic cores.
1
2
3
4
5
6
7
8
9
10
0.2
0.1
0.3
0.3
0.3
0.3
0.5
0.1
1.0
1.5
1.5
0.1
5
5
5
5
5
5
5
5
50
50
100
100
56
11
48
100
42
13
0
0
0
44
89
52
0
58
87
100
6
0.05
0.03
0.05
0.05
0.05
0.05
0.05
0.05
by the reports of Saegusa, Fukuyama and Rainier who had
demonstrated precedent for 5-exo cyclisation, but there was
limited evidence for successful obtention of the product of
6-endo cyclisation.9,10 The synthesis of the cyclisation precursor
11 commenced with iodination of methyl-4-aminobenzoate 12
to give the palladium coupling precursor 13 in 80% yield.11 Use
of Suzuki–Miyaura conditions for the formation of amine 15
proved problematic with commercially available N-Boc-pyrrole-
2-boronic acid 14. However, switching to the use of freshly
prepared 14 following the procedure of Martina,12 amine 15 was
obtained in 82% yield. Subsequent formylation with formic
acetic anhydride,13 followed by dehydration with phosphorus
oxychloride and diisopropylamine proceeded smoothly, result-
ing in isocyanide 11 in 79% yield (Scheme 2).14
94
a
Ratios of 8 and 9 were determined from the 1H-NMR spectrum of the
crude reaction mixture. All reactions were carried out at 80 ꢀC in toluene
for 2 hours by direct addition of reagents.
rapidly trapped and that the reaction itself is reversible.
However, when the concentration of AIBN is low, the rate of
cyclisation and subsequent reduction is slow and accordingly,
the more stable thermodynamic 6-endo product predominates.
To conrm the effects of the equivalents of AIBN on the reaction
outcome, a large excess of thiophenol was used whilst varying
the amount of AIBN (Table 1, entries 9 and 10). There was little
difference on the reaction outcome when 50 equivalents of
thiophenol were used, with selectivity easily tuned for either
5-exo or 6-endo addition.
With conrmation that the equivalents of AIBN and reaction
concentration were critical, the reaction was carried out on a
larger scale to fully isolate and characterise both products. As
predicted, the tricyclic heterocycle 8 was obtained in 62% iso-
lated yield when the reaction was carried out with 0.1 equiva-
lents of AIBN. On repeating the reaction, but with conditions
tuned for the synthesis of the spirocyclic product, compound 9
was isolated in 47% yield. A second product – 17 was also
observed following purication, which corresponded to the
double bond isomer, in 18% yield, from the parent compound
9. On contact with silica, the double bond undergoes a
1,3-hydride shi to give 17 and both products in a combined
yield of 64% (Scheme 3).
With the cyclisation precursor 11 in hand, investigation of a
range of conditions were explored in order to select for either
6-endo or 5-exo cyclisation in a thermodynamic or kinetic manner
respectively and the results are outlined below (Table 1).
Evaluation of the effects of reaction concentration (Table 1,
entries 1–3) on the ratio of 8 and 9, showed that only the 6-endo
product 8 was formed at higher concentrations, but under more
dilute conditions (entries 3–4), the ratio of 8 : 9 changed to a
more favorable 11 : 89 ratio of the two products. At this point, it
was evident that the reaction was tunable and either the product
of 5-exo or 6-endo addition could be readily selected. Simple
variation of the amount of AIBN (Table 1, entries 4–8), whilst the
amount of thiophenol and the reaction concentration were kept
constant also insinuated that the radical cyclisation could be
tuned easily. The kinetic 5-exo spirocycle was favoured at higher
concentrations of AIBN, suggesting that the cyclised product is
In summary, we have developed a novel approach towards
the synthesis of pyrroloquinoline and spirocyclic heterocycles
using tin-free radical methodology, starting from a common
precursor. This short exible reaction sequence will provide a
rapid approach to structurally diverse compounds of signicant
interest and the application of this methodology is currently
under active investigation using other heterocyclic motifs.
Examination of their corresponding biological effects and the
results obtained will be reported in due course.
Scheme 2 Synthesis of common cyclisation precursor 11.
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