Novel synthetic methodology for the assembly of a-carbolines and 7-azaindoles
Date
2018
Authors
Henning, Hendrik
Journal Title
Journal ISSN
Volume Title
Publisher
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
Keywords
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>