D. Roy, K. Ali and G. Panda
Journal of Molecular Structure 1239 (2021) 130493
between p-QM 3 and the anion was attempted (Scheme 2). But
unfortunately, this reaction did not work to afford the desired
product. This is perhaps because of steric hindrance on methine
carbon atom. Heating the reaction mixture and employing various
bases also did not yield any positive results. Our final target was
to introduce –CH2OH in place of hydroxyl group of bedaquiline
through p-QM chemistry which will provide enough chemical
space and optimization and subsequent application for patents.
Unsuccessful approach revoked our thought process to synthesize
different kind of bedaquiline analogs by using another approach
given below.
Fig. 1. Janssen developed bedaquiline from preliminary hit molecule.
Our second approach towards bedaquiline analogs was designed
to simplify the incorporation of amine moiety in place of hy-
droxyl group of bedaquiline to have another hydrophilic function-
ality as well as scope for formation of salts thereafter. Moreover,
introduction of amine containing quaternary center in bedaquiline
molecule is not covered in the literature. In this context, we have
chosen O-Donell Schiff’s base [28] (6) as another coupling part-
ner which will couple with p-QM 3 and thus will give the corre-
sponding adduct by following few steps. To persue this, we have
prepared two types of O-Donell’s Schiff bases following litera-
ture known procedures. Benzophenone imine reacted with glycine
ethyl ester hydrochloride or L-alanine ethyl ester hydrochloride in
DCM for 20h at rt to furnish O-Donell’s Schiff bases (6) in excel-
lent yields (See ESI). A second strategy to access bedaquiline ana-
logues from p-QM 3 was then developed with the key reaction
being the Cs2CO3 mediated 1, 6- addition of p-QM 3 with ethyl
2-((diphenylmethylene) amino) acetate (6a) derived from glycine
ethyl ester hydrochloride as a model reaction (Scheme 3).
appeared based on the synthetic approaches towards bedaquiline
and its derivatives reported by Calvert et al. [25].
Recently, quinone methides (QMs), also known as methylene
quinines and quinine methines, are considered to be one of the
highly reactive intermediates that have been widely exploited [26].
They are classified into two types namely, 1,2-quinone methides or
“o”-quinone methides (o-QMs) and 1,4-quinone methides or “p”-
quinone methides (p-QMs). Aromatization is the driving force for
their unique reactivity towards various nucleophiles, and therefore,
these compounds act as valuable synthons for various biologically
significant molecules.[27] Currently, p-QMs based chemistry is also
well known for making various biologically active frameworks. Our
goal is to construct anti-tubercular drug TMC207 like new skeleton
using novel p-QM as a useful synthon that enabled the incorpora-
tion of three crucial aryl rings in one reaction as well as installa-
tion of various amine and hydroxyl functionality into the pharma-
cophore of Bedaquiline.
Initially, 2-((diphenylmethylene) amino) acetate (6a) was re-
acted with p-QM 3 in the presence of 1.1 equiv of Cs2CO3 to afford
the ethyl 3-(6-bromo-2-chloroquinolin-3-yl)-3-(3, 5-di-tert-butyl-
4-hydroxyphenyl)-2-((diphenylmethylene) amino) propanoate (7)
in 60% yield. Then the imine (7) was readily converted to corre-
sponding amine derivative (8) by acidification with 55% yield. After
getting this positive result, we tried to incorporate a small methyl
group to amine carbon to make it quaternary center in the amine
derivative (8). To get this, we have already prepared the start-
ing material ethyl (R)-2-((diphenylmethylene) amino) propanoate
(6b) by literature known procedure (See supporting information).
Unfortunately, the same reaction did not proceed when we per-
formed the reaction with ethyl (R)-2-((diphenylmethylene) amino)
propanoate. This is perhaps due to the steric hindrance, that’s
why the negative ion on center carbon atom of ethyl (R)-2-
((diphenylmethylene) amino) propanoate perhaps did not gener-
ate for further reactions. In this case also, we had tried various
methods (Cs2CO3, n-BuLi, t-BuLi, LiHMDS etc.) to generate the neg-
ative ion on the particular center but was not successful. With this
observation, we tried to introduce naphthyl group in place of the
methyl group of O-Donell’s Schiff base to get naphthylated analog,
but it was not fruitful either. So, with this model reaction (Scheme
3), we attempted to elaborate it to make amine-containing de-
naphthylated bedaquiline analog in a stepwise manner (Scheme 4).
2. Result and discussion
The aim of this investigation was the invention of alterna-
tive pathways towards the synthesis of library of bedaquiline ana-
logues that might help to explore new drug candidate in future.
To achieve this, quinoline containing p-QM 3 was identified as a
key starting material in the synthetic pathway, providing substrates
that could be further elaborated to get bedaquiline like molecules.
Our first approach towards bedaquiline analogues was designed to
facilitate the incorporation of the diethyl 2-(naphthalen-1-yl) mal-
onate moiety from the corresponding aryl halide. Initially, we car-
ried out synthesis with p-QM 3 and diethylmalonate as a model re-
action by using K2CO3 in toluene at RT for 24h. After completion of
the reaction, we got the diaryl methine (4) as a product with 70%
yield (Scheme 1). With this acceptable reaction conditions in hand,
we then tried to achieve our next target. Primarily, this approach
was conducted in a step-wise fashion. To explore this, a suitable
coupling partner (5) was prepared from 1-bromonaphthalene and
diethylmalonate using Pd(dba)2 as a catalyst. (See supporting in-
formation ESI).
Employing potassium carbonate to generate the 1, 3-diethoxy-
2-(naphthalen-1-yl)-1, 3-dioxopropan-2-ide from diethyl 2-
(naphthalen-1-yl) malonate, a metal-free 1, 6-addition reaction
Scheme 1. Synthesis of diaryl methine from 3.
2