Tetrahedron Letters
Pd-NHC-catalyzed synthesis of diaryl ketones
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Feng Gao, Huangdi Feng, Zhihua Sun
College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai 201620, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 July 2014
Revised 27 September 2014
Accepted 29 September 2014
Available online 5 October 2014
With N-hetereocyclic carbene and palladium catalysis, diaryl ketones with a variety of functional groups
that span from electron withdrawing to electron donating substitutions can be conveniently synthesized
using the corresponding aryl boronic acid and N-acyloxyphthalimide.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Diaryl ketones
N-Heterocyclic carbene
Palladium catalysis
Boronic acid
N-Hydroxy phthalimide
Aryl ketones are important synthetic intermediates for organic
and medicinal chemistry.1 A classical method to synthesize aryl
ketones is the Friedel–Crafts acylation using aryl acid chloride.2
One may also use nucleophilic aryl metal compounds to react with
aryl acid derivatives to form the desired ketone with better regio-
nal control than traditional Friedel–Crafts reactions.3 However,
these synthetic approaches still suffer drawbacks such as limited
compatibility of substitution groups and sometimes harsh or strin-
gent reaction conditions. Recently, palladium catalyzed coupling
between an aryl boronic acid and an aryl acid derivative such as
an acid anhydride or acid chloride opened up new synthetic path-
ways to aromatic ketones with greater control, regioselectivity,
and milder conditions.4
inorganic and organic ligands. The reactions were conducted in tol-
uene with catalyst loading at 5% mole equivalent of the NHP ester.
In these tests, palladium (II) with chloride as counter ions did not
produce isolatable product (entries 1 and 2, Table 1). Other palla-
dium (0) or (II) species could lead to moderate yields of the ketone
(entries 3–6, Table 1). The best result was obtained in a one-pot
reaction with palladium (II) acetate and in situ formed NHC using
a triazole-based NHC precursor (reaction scheme in Table 1) and
Cs2CO3 (entry 7, Table 1), the final yield of the reaction reached
75%.
After this initial investigation, much wider scope of starting
materials was explored using the NHC-Pd catalytic conditions.
Results are summarized in Table 2.
Here, we report our findings in aryl ketone synthesis using
boronic acid and an activated ester in the presence of palladium
catalyst and an N-heterocyclic carbene (NHC) ligand. Our goal
was to develop an efficient procedure using more stable and easier
to handle starting materials rather than aryl acid chlorides or acid
anhydrides. For this purpose, we chose to investigate N-hydroxy
phthalimide (NHP) esters as the carbonyl donor5 and envisioned
that a proper NHC will enhance the catalytic properties of
transition metals so that the desired ketone formation can be
achieved.
The reactions between NHP ester 1a or 1b and different phenyl
boronic acids bearing electron-donating or electron-withdrawing
groups were investigated (entries 1–7, Table 2). Yields of these
transformations were similar, with some preference of electron
withdrawing groups on phenyl boronic acid indicating the good
tolerance of boronic acids in general. When using the NHP ester
1c from 2-nitrobenzoic acid, the strong electron withdrawing nitro
group lowered overall yields of the reaction to moderate but still
acceptable levels (50–65%, entries 8–14, Table 2). For boronic acids,
similar trends existed as shown in the next four examples where
electron withdrawing groups such as fluoro- or trifluoromethyl-
substitution enhanced the reaction yields (entries 10 and 11,
Table 2), while electron donating ones such as methoxy or alkyl
slightly reduced yields (entries 9, 12, and 13, Table 2). Finally,
substrates with expanded conjugated system were also explored
(entries 15–18, Table 2). These examples with NHP esters of either
Initial investigation started from using the NHP ester 1b of
4-methoxybenzoic acid and phenyl boronic acid. Results are listed
in Table 1. Several palladium catalysts were screened with
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0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.