Tetrahedron Letters
Palladium catalysed hydrolysis-free arylation of aliphatic nitriles for the
synthesis of 4-arylquinolin-2-one/pyrazolone derivatives
Singarajanahalli Mundarinti Krishna Reddy, Subramaniyan Prasanna Kumari,
⇑
Subramaniapillai Selva Ganesan
Department of Chemistry, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur 613401, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Palladium catalysed addition of arylboronic acid to the readily available 2-cyano-(N-aryl)-acetamide or
ethyl-2-cyanoacetate followed by subsequent reaction transform them into the biologically significant
4-arylquinolin-2-one or pyrazolone derivatives. The reaction conditions are robust enough to prevent
the hydrolysis of ester/amide moiety during arylation. In addition, the unactivated nitrile moiety in
the acetonitrile also converted to the corresponding acetophenone derivative.
Received 27 April 2021
Revised 14 July 2021
Accepted 18 July 2021
Available online 22 July 2021
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Palladium catalysis
Arylation
Nitrogen heterocycle
Pyrazolone
Quinolinone
Introduction
The previously reported method started with benzyl nitrile [6]
or isatoic anhydride [10] as substrates for synthesizing 4-
Transformation of a readily available substrate into a biologi-
cally significant molecule in minimal number of steps is always
attractive since it not only minimizes the cost of production of
the target molecule but also substantially reduces the quantum of
solvent waste [1]. Among the biologically significant molecules,
pyrazolones and 4-arylquinolin-2-ones are representative exam-
ples of nitrogen heterocycles bestowed with numerous biological
activities. Pyrazolone derivatives display good antipyretic [2],
anti-inflammatory [3] and SARS-CoV 3CL protease inhibitory prop-
erties [4]. The pyrazolone derivatives were generally synthesized
by the reaction between b-ketoester and substituted hydrazines [5].
4-Arylquinolin-2-one derivatives display good activity against
Chagas disease, one of the most neglected diseases of the world
[6]. Tipifarnib is yet another example of a 4-arylquinolin-2-one
derivative used to treat breast cancer as well as leukemia [7].
The 4-arylquinolin-2-one derivatives display good anticancer
activity [8] and also function as a potassium channel opener [9].
Activation of potassium (BK) channel provides therapeutic avenues
to treat urinary incontinence, injury in the brain, stroke, etc.
Despite the significance associated with 4-arylquinolin-2-one core,
this moiety is accessed by multi-step synthesis (Chart 1).
arylquinolin-2-one core. Apart from the overall lower yield
obtained in these methods; they also utilize harmful (or) pyropho-
ric reagents such as n-butyllithium, t-BuOK, etc. In our method, the
4-arylquinolin-2-one core can be readily obtained in an one-pot
operation from the 2-cyano-(N-aryl)-acetamide substrate
(Chart 1).
The major challenge associated with the proposed methodology
is the transformation of less reactive alkyl nitriles to a ketone
through palladium catalysed arylation reaction. Unlike aryl nitriles
[11,12], the alkyl nitriles display higher stability towards the
organopalladium species [13] and hence several palladium cataly-
ses were performed successfully in acetonitrile solvent without the
interference of the nitrile functionality in the solvent. The use of
harsher acidic reaction conditions for the transformation of the
unactivated aliphatic nitrile functionality could affect the struc-
tural integrity of the substrate by hydrolyzing the relatively vul-
nerable ester/amide functional groups on the substrates [14].
Apart from the undesired hydrolysis,
a-arylation of the aliphatic
nitriles are yet another side reaction in palladium catalysis [15a,
b]. To suppress the formation of the aforementioned by-products,
aliphatic nitrile functionalization was performed with activated
nitrile substrates such as cyanoformates [16], (arylsulfonyl)ace-
tonitriles [17], etc. Further,
were elegantly employed to prevent the undesired
reactions [18]. In the absence of an activated nitrile group or
a
-substituted aliphatic nitriles
a-arylation
⇑
Corresponding author.
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.