Tetrahedron Letters
Regioselective intramolecular annulations of ambident b-enamino esters:
A diversity-oriented synthesis of nitrogen-containing privileged molecules
a
Srinivasarao Yaragorla a, , Abhishek Pareek
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a School of Chemistry, University of Hyderabad, Gachibowli 500046, Telangana, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Diversity-oriented, regioselective, intramolecular annulation of b-enamino esters is described under solvent-
free, calcium-catalysis. 2-aminoaryl ketones and alkyl propiolates undergone a [4+2] annulation to yield
substituted quinolines; with an excess of alkyl propiolates, benzodiazepines were formed via a [4+2+1] annu-
lation. We also described a one-pot, 3-component synthesis of quinoline derivatives via a [4+2+2] annulation.
Interestingly, 2-aminoaryl ketones undergone a self-condensation [4+4] and gave the dibenzodiazocines.
Ó 2018 Elsevier Ltd. All rights reserved.
Received 10 December 2017
Accepted 21 January 2018
Available online xxxx
Keywords:
b-enamino esters
Diversity-oriented synthesis
Regioselective
Intramolecular annulation
Calcium catalysis
The small molecules, especially nitrogen-containing heterocyclic
compounds have been serving as viable research tools in the drug
discovery.1,2 The major class of current FDA approved drugs are
small molecules.3 Hence the pharmaceutical industries screen a
large number of small molecules in a traditional high-throughput
screening (HTS) to identify the bioactive molecules and lead com-
pounds for drug discovery.4,5 The results of HTS iterates the need
to have functionally diverse small molecules, and as a consequence,
the diversity-oriented synthesis (DOS) has emerged as a new branch
of organic synthesis, aimed to fill the chemical space with efficient
synthetic strategies.6 On the other hand, privileged molecules are
one of the important concepts in the rationale drug discovery.7 If
one can combine both the concepts together, that is a DOS to make
the libraries of privileged molecules, that could be a much more effi-
cient tool for the drug discovery than the individual strategies.
b-enamino esters are versatile intermediates in organic synthesis;
they are an integral part of many natural and synthetic bioactive
molecules.8 As depicted in Fig. 1, one can presume the b-enamino
esters as ambident substrates due to the reason that they have an
electrophilic carbon and also a nucleophilic carbon. Therefore we
designed our synthetic plan to explore the ambident reactivity of
b-enamino esters for the synthesis of quinolines and benzodi-
azepines. As part of our research aimed for the development of
new synthetic methods towards privileged molecules of medicinal
importance,9 herein we report a diversity-oriented synthesis of
nitrogen-containing privileged molecules, such as quinolines,
benzodiazepines, and dibenzodiazocines (Fig. 2).
Initially, we planned to synthesize the quinolines and hence
chose 2-amniobenzophenone (1a) and ethyl propiolate (2a) as
the model substrates (Table 1).10 A mixture of 1a, 2a, and 10 mol
% of Ca(OTf)2 and Bu4NPF6 (additive) was refluxed in 1,2-DCE for
24 h to isolate the desired quinoline 3a in 52% yield (entry 1,
Table 1). Encouraged by this result, we screened few other solvents
such as acetonitrile (entry 2), ethanol (entry 3) and toluene (entry
4) to see the maximum yield of the reaction. Unfortunately, none of
them gave better results. Nevertheless, we were delighted to note
that under the solvent-free conditions quinoline 3a was isolated in
76% yield in 3 h (entry 5). We also confirmed that the combination
of catalyst and additive is necessary for the quinoline synthesis
(entries 6, 7, and 11 Table 1). Further experiments to minimize
the catalyst loadings were unsuccessful. Finally, we found that
entry-5 (Table 1) as the best condition for the synthesis of quino-
line 3a in 3 h with 76% yield.
Having the optimum condition in hand for a [4+2] annulation of
1a and 2a, we aimed to check the generality of this reaction con-
cerning the two reacting partners, i.e., 2-aminobenzophenone
and alkyne (Table 2). Under the standard conditions (Table 1, entry
5) ethyl propiolate reacted with substituted 2-aminoaryl ketones
and furnished the respective quinoline derivatives 3b-3d in good
yields. An obvious and similar reactivity was also observed with
methyl propiolate and substituted amino ketones while obtaining
the quinoline derivatives 3e-3h (Table 2) in good yields. Encour-
aged by the reactivity of terminal alkynes, we then treated the
2-amino ketones with internal alkynes, activated on both sides
and obtained the fully substituted quinolines 3i-3L. It is worth to
note that the yields of quinoline derivative with the internal-
alkynes activated on both sides were better than terminal alkynes.
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Corresponding author.
0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.