Tetrahedron Letters
Copper-mediated Chan-Evans-Lam N-arylation of 5-methylene-4-aryl-
1,5-dihydro-2H-pyrrol-2-one derivatives
a,b
a
a
c
a
Basmah Almohaywi , George Iskander , Tsz Tin Yu , Mohan Bhadbhade , David StC. Black ,
Naresh Kumar
a
a,
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School of Chemistry, The University of New South Wales, Sydney, NSW 2052, Australia
School of Pharmacy, King Khalid University, Abha, Saudi Arabia
Solid State & Elemental Analysis Unit, Mark Wainwright Analytical Centre, Division of Research, UNSW Australia, NSW 2052, Australia
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient procedure for the synthesis of N-aryl 5-methylene-4-aryl-1,5-dihydro-2H-pyrrol-
Received 28 November 2017
Revised 8 January 2018
Accepted 16 January 2018
Available online xxxx
2
-one derivatives has been developed through copper-mediated CAN bond formation. The synthetic pro-
tocol allows for versatile and robust CAN arylation with a range of readily available boronic acids under
mild conditions.
Ó 2018 Elsevier Ltd. All rights reserved.
Keywords:
Chan-Evans-Lam coupling reaction
Pyrrole-2-one
Quorum sensing
Introduction
In line with our continuing interest in developing DHPs as
antimicrobial agents, we sought to further functionalise these
Bacteria utilize intercellular chemical signaling mechanisms to
coordinate group behaviour, including the regulation of virulence
factor production and biofilm formation, in a process known as
DHPs at the basic nitrogen atom, as this modification has not been
previously studied. To install the N-aryl motif, we employed the
Chan-Evans-Lam reaction, which is a CAN forming bond method
that proceeds via the oxidative coupling of an arylboronic acid
and an amine group catalysed by cupric acetate under mild condi-
1
,2
quorum sensing (QS).
Therefore, significant interest has been
devoted to the development of compounds that interfere with bac-
terial signaling as a potential antibacterial strategy. A number of
halogenated furanones, also known as fimbrolides, exhibit antimi-
crobial activities against several bacteria through the disruption of
QS-mediated phenotypes.3 However, the use of fimbrolides has
been limited by their cytotoxicity to mammalian cells and high
7
tions. The Chan-Evans-Lam reaction has been widely used for the
synthesis of biologically active compounds, including N-aryl sub-
8
stituted heterocyclic systems such as N-aryl isatin, N-aryl pyri-
9
10
din-2(1H)-one , N-aryl purine, and N-aryl pyridone, as part of
the process leading to the marketed anti-epileptic drug, peram-
4
11
efflux rate. To circumvent these issues, our group has previously
panel (Fycompa). We report herein a synthetic protocol for the
synthesised 1,5-dihydropyrrol-2-ones (DHPs) bearing
c
-methylene
versatile and robust CAN arylation of DHPs with a range of readily
available boronic acids under mild conditions.
substituents as isosteric analogues of furanones.5 These DHPs
demonstrated good antimicrobial properties against several bacte-
5
rial strains with low cytotoxicity toward mammalian cells. Addi-
Results and discussion
tionally, the DHPs were not bactericidal and therefore have low
propensity to induce resistance.5 Other
c-methylene-c-lactams,
Our initial attempts to prepare N-aryl DHPs utilized a synthetic
targeting the ecdysone receptor with potential as insecticides, have
sequence employing the lactone-lactam conversion method previ-
6
also been reported in the literature. However, N-aryl analogues of
5,12
ously developed within our group (Scheme 1).
Briefly, the syn-
DHPs, based on the 5-methylene-4-aryl-1,5-dihydro-2H-pyrrol-2-
one scaffold 1 (Fig. 1), have been relatively unexplored.
thesis starts with the acid-catalysed condensation of
phenylacetones 2 with glyoxylic acid 3, producing 5-hydroxyfura-
nones 4. The 5-hydroxyfuranones 4 were treated with thionyl chlo-
ride to form the 5-chlorofuranones 5. In the key lactone-lactam
conversion step, furanones 5 were treated with amines to provide
the intermediate 5-hydroxy-lactams 6, which can be subsequently
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040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
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