.
Angewandte
Communications
DOI: 10.1002/anie.201308785
Heterocycles
Synthesis of Bis(heteroaryl) Ketones by Removal of Benzylic CHR and
CO Groups**
Arun Maji, Sujoy Rana, Akanksha, and Debabrata Maiti*
Abstract: A copper-catalyzed method for synthesis of diaryl
ketones (Ar-CO-Ar’) through removal of benzylic -CH2-,
-CO-, and -CHR- groups from Ar-CO-CXR-Ar’ has been
discovered. A number of symmetrical and unsymmetrical
heterocyclic ketones, which are usually difficult to synthesize,
can be prepared in good to excellent yields. This method was
applied to the synthesis of the nonsteroidal anti-inflammatory
drug suprofen (47% yield over three steps). Based on
preliminary mechanistic and kinetic studies, an active Cu/O2
species is proposed to mediate the rearrangement reaction.
Figure 2. Select examples of diaryl ketones as pharmacueticals.
C
arbon–carbon bonds constitute the basic foundation of
synthetic chemistry. Protocols for the generation and cleavage
of such bonds are indispensable for the synthesis of new
organic scaffolds. Although carbon–carbon bond-formation
techniques have been studied extensively, the cleavage of
carbon–carbon bonds is still a difficult objective. The inert
nature of the carbon–carbon bond makes its cleavage
problematic, and gaining control of it is even more challeng-
ing.[1] Despite reports on carbon–carbon single-,[2] double-,[3]
amide,[7] aldehyde,[8] acyl transfer,[9] ketonic partner
exchange,[10] and rearrangement reactions.[11] However,
diaryl ketone and heterocyclic ketone synthesis starting
from a-arylated ketones by C(CO)-C(a) bond cleavage is
yet to be reported.
Herein, we report an effective method of removing
a benzylic carbon moiety to synthesize symmetrical/unsym-
metrical diaryl ketones and bis(heteroaryl) ketones. This
method connects the benzylic aromatic ring directly to the
ketone by eliminating the benzylic -CH2-, -CHR-, and -CO-
groups without changing the connectivity with the ring
(Scheme 1).
and triple-bond cleavage,[4] the development of a C C bond-
disconnection approach to construct a new C C bond still
remains a formidable task.
Industrially ketones are utilized as pharmaceutical drugs,
polymer precursors, and as biologically and chemically
important building blocks. Development of a new synthetic
approach for their synthesis is therefore of great significance
(Figures 1 and 2). Synthetically C(CO)-C(a) bond cleavage
has been utilized (Figure 1) to generate acid,[5] ester,[6]
À
À
Scheme 1. Diaryl ketone synthesis by C(CO)-C(a) cleavage.
We envisioned removal of the a-carbon centers of 2-
phenylacetophenone through formation of an imine and
subsequent Cu/O2 chemistry/rearrangement reactions. Such
a reaction, in essence, also mimics DNA demethylase activity
wherein an active methyl group is removed from nucleotide in
DNA.[12] Notably, 2-phenylacetophenone derivatives are
accessible by various methods, for example, a-arylation of
acetophenone,[13] Wacker oxidation of internal olefin,[3b,14]
etc.[15]
Figure 1. The cleavage of the C(CO)-C(a) bond of a ketone.
[*] A. Maji, S. Rana, Akanksha, Prof. D. Maiti
Department of Chemistry, Indian Institute of Technology Bombay
Powai, Mumbai-400 076 (India)
We started our investigation by reacting an imine,
generated in situ from aniline and 2-phenylacetophenone,
with a Cu/O2 active species to induce rearrangement reaction
(Table 1). Polar aprotic solvents such as DMF and DMSO
proved to be high yielding. DMSO is likely to stabilize the
copper catalyst and also assist in the aerobic oxidation
process.[16] Subsequently we realized p-toluidine was better
E-mail: dmaiti@chem.iitb.ac.in
[**] This activity was supported by DST, India. Financial support
received from CSIR-India (A.M. and S.R.) is gratefully acknowl-
edged. D.M. thanks Prof. Steve Buchwald (MIT) for insightful
discussions.
Supporting information for this article is available on the WWW
2428
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 2428 –2432