Novel synthetic methodology for the assembly of a-carbolines and 7-azaindoles
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Date
2018
Authors
Henning, Hendrik
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Abstract
The a-carbolines and 7-azaindoles are part of a larger family of compounds derived from
indoles and other heterocyclic compounds that are prevalent in nature often as biologically
active compounds. The synthesis of a-carbolines and 7-azaindoles described in this
thesis is built on several key reactions developed in our laboratories, namely the light
mediated t-BuOK ring closure method used previously to form carbazoles, naphthalenes
and anthracenes; as well as an acid mediated ring closure of acetylene containing 2-
aminopyridines to form 7-azaindoles; and lastly catalytic palladium chemistry is used in
some critical carbon carbon bond forming reactions, namely through the Sonogashira
reaction.
The bromine atoms on several 3-bromo-2-aminopyridine compounds is substituted with
1-ethynyl-2-methyl-benzene in a Sonogashira coupling reaction, followed by ring closure
forming the respective 2-(2-methylphenyl)-1H -pyrrolo[2,3-b]pyridines (2-(o-tolyl)-1H -7-
azaindoles). After formylation on the 3 position, forming 2-(2-methylphenyl)-1H -pyrrolo
[2,3-b]pyridine-3-carbaldehydes (3-formyl-2-(o-tolyl)-1H -7-azaindoles), and N -benzylation
on the 1 position, furnishing 1-benzyl-5-methyl-2-(2-methylphenyl)-pyrrolo[2,3-b]pyridine
-3-carbaldehydes (3-formyl-2-(o-tolyl)-1-benzyl-7-azaindoles), the compounds were subjected
to the light mediated ring closing methodology described, yielding 11-benzyl-benzo
-a-carbolines (11-benzyl-11H -benzo[g]pyrido[2,3-b]indoles). The final debenzylation on
11-benzyl-benzo-a-carbolines (11-benzyl-11H -benzo[g]pyrido[2,3-b]indoles) synthesised
furnished 11H -a-carbolines (11H -benzo[g]pyrido[2,3-b]indole). The novel synthesis of
a-carbolines and 7-azaindoles through these methods proved successful, even though in
low overall yields. The methodology was further extended to allow further substitution
on a-carbolines. This was achieved by bromination on the initial 2-aminopyridine
starting material in the 5 position, followed by iodination on the 3 position. The iodide
of the 2-aminopyridine could then be selectively substituted using Sonogashira
coupling as discussed, followed by Suzuki coupling on the bromide, in this case with 3,4-
dimethoxy-phenyl boronic acid. The synthesis of 11H -3-(3,4-dimethoxyphenyl)-benzo-a-
carboline was then completed using Suzuki coupling methodology to add the 3,4-dimethoxyphenyl
functionality from (3,4-dimethoxyphenyl)boronic acid.
The heterocycles synthesised in this thesis were tested against African sleeping sickness
parasite Trypanosoma brucei. The compound 5-(3,4-dimethoxyphenyl)-2-(2-methylphenyl)
-1H -pyrrolo[2,3-b]pyridine-3-carbaldehyde was found to have an IC50 value of 10 mM,
with several others showing activity in the range of 12-27 mM. The antimalarial studies
in contrast showed only one significant hit, 11-benzyl-3-(3,4dimethoxyphenyl)-benzo-
a-carboline had an IC50 value of 26 mM.
Overall, the study resulted in the successful synthesis of a-carbolines and 7-azaindoles,
as well as the discovery of biologically active heterocycles effective against malaria and
African sleeping sickness. These heterocycles could be used as lead compounds for
further research.
Description
A thesis submitted to the
Faculty of Science,
University of the Witwatersrand,
Johannesburg,
in fulfilment of the requirements for the degree of
Doctor of Philosophy
Johannesburg, February 2018
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Citation
Henning, Hendrik (2018) Novel synthetic methodology for the assembly of a -carbolines and 7-azaindoles, University of the Witwatersrand, Johannesburg, <http://hdl.handle.net/10539/25742>