Synthesis of diaryl ketones via a phosphine-free Fukuyama reaction

Article abstract of DOI:10.1039/c1cc16114h

The synthesis of unsymmetrical diaryl ketones via the Fukuyama coupling of thioesters and organozinc reagents is described. Typically, the synthesis of diaryl ketones using this methodology provides low yields. The simple complex, Pd(dba)₂, was found to convert a variety of aryl thioesters to diaryl ketones in good yields. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1cc16114h

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Synthesis of diaryl ketones via a phosphine-free Fukuyama reactionwz
Kamala Kunchithapatham, Chad C. Eichman and James P. Stambuli*
Received 1st October 2011, Accepted 17th October 2011
DOI: 10.1039/c1cc16114h
The synthesis of unsymmetrical diaryl ketones via the Fukuyama
coupling of thioesters and organozinc reagents is described.
Typically, the synthesis of diaryl ketones using this methodology
provides low yields. The simple complex, Pd(dba)2, was found to
convert a variety of aryl thioesters to diaryl ketones in good
yields.
The diaryl ketone is an important moiety embedded in
medicinal compounds,10 such as ketoprofen and suprofen.
Recently, we desired a mild method to prepare the diaryl
ketone (2a), which contains an ester functionality. Surveying
current literature routes to access diaryl ketones,8–33 the mild
conditions for the Fukuyama reaction would provide straight-
forward access to 2a. Although diaryl ketones were not
commonly published using Fukuyama conditions, expansion
of this method to cover diaryl ketone substrates would be a
useful extension. Through this reaction optimization, conditions
for a phosphine-free Fukuyama reaction was discovered that
produces good to high yields of functionalized, unsymmetrical
diaryl ketones.
Palladium-catalyzed cross-coupling reactions offer synthetic
chemists the ability to construct carbon–carbon and carbon–
heteroatom bonds in a highly efficient and predictable manner.
In general, most methods to construct C–C bonds through
palladium-catalyzed processes involve the coupling of an
organohalide with an organometallic or organometalloid species.1
Fukuyama reported a method to form C–C bonds using
thioesters as a coupling partner in place of aryl halides.2–5
This cross-coupling reaction proceeds through C–S bond
activation of the thioester followed by transmetallation with
an organozinc reagent, and reductive elimination to provide
the desired product. This mild method furnishes high yields of
many ketones at ambient temperatures (Scheme 1).
Compound 1a was prepared from the corresponding acid in
near quantitative yield. Treating 1a under the standard conditions
reported for the Fukuyama coupling reaction resulted in
incomplete reaction conversion and formation of the desired
diarylketone 2a in only a 30% isolated yield (eqn (1)). The
conversion to product was low, likely a result of the self-
consumption of the organozinc reagent, as a significant
amount of biphenyl was formed during the reaction. Employing
DMF as a solvent in the reaction only slightly increased reaction
yield, as 35% of diaryl ketone 2a was isolated.
In addition to the Fukuyama reaction, Liebeskind and Srogl
developed a protocol to prepare diaryl ketones from the
corresponding thiol esters and boronic acids.6,7 This method
requires excess copper reagent in addition to the palladium
catalyst, and did not work for our purposes. Iron has also been
utilized to cross-couple thioesters.8 However, acyl chlorides
were used to form diaryl ketones. The use of nickel to form
diaryl ketones from a thioester has also been described, but the
reported conditions provided ester-containing substrates in
low yields.9 Despite the various reports of Fukuyama cross-
couplings and the broad scope of this reaction, a general
method to prepare diaryl ketones using this methodology is
absent from the literature. In Fukuyama’s original reports,
diaryl ketones were not listed. A single example employing
phenylzinc bromide was coupled with an alkyl thioester to give
only 50% of the desired ketone product using 10 mol%
PdCl2(PPh3)2 as catalyst.4
ð1Þ
We turned our attention to catalyst modification to
improve reaction yield. After an extensive ligand screening,
the palladium dimer containing 10 mol% tri-tert-butyl-
phosphine ([Pd(PtBu3)Br]2) was initially identified as the optimal
ligand for reaction conversion (Table 1, entry 2). Employing
ligands such as triphenylphosphine (PPh3), 1,10-bis(diphenyl-
phosphino)ferrocene (dppf), tri-ortho-tolylphosphine (P(o-tol)3),
and tri-(2-furyl)phosphine (TFP) all gave inferior results
Department of Chemistry, The Ohio State University,
100 West 18th Avenue, Columbus, Ohio 43210, United States.
E-mail: stambuli@chemistry.ohio-state.edu
w This article is part of the ChemComm ‘Advances in catalytic C–C
bond formation via late transition metals’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
procedures, characterization of newly synthesized compounds, and
reaction optimization tables. See DOI: 10.1039/c1cc16114h
Scheme 1 Fukuyama reaction for the synthesis of ketones.
Chem. Commun., 2011, 47, 12679–12681 12679
c
This journal is The Royal Society of Chemistry 2011

Table 1 Reaction optimizationa,b
for coupling reactions without external ligands is rare. The
reaction scope to produce diaryl ketones was examined using
catalytic Pd(dba)2.
The reaction provided good yields of various diaryl ketone
products with Pd(dba)2 as catalyst (Table 2). The reaction
proceeded smoothly in the presence of methyl esters and
heterocyclic functional motifs to provide diaryl ketones 2a,
2b, 2c, and 2g in good yields. The electronics of the aryl
thioester or the aryl zinc reagent did not have a dramatic effect
on the course of the reaction, as almost all cases gave good
yields of diaryl ketone products. Notably, sterically hindered
diaryl ketones are readily produced in this reaction without
requiring an increase in reaction temperature or catalyst
loading (2h–2j).
Entry
ArZnX
Pd source (mol%)
P : SM
1
2
3
4
5
PhZnl
PnZnl
PhZnl
PhZnCl
PhZnCl
PdCl2(PPh3)2 (10)
[PD(Br)PtBu3]2 (10)
[PD(Br)PtBu3]2 (0.2)
Pd(dba)2 (1)
38 : 62
495 : 5
495 : 5
495 : 5
78 : 22
Pd(dba)2 (0.5)
a
Reaction performed on 1 mmol scale of thioester with 1.2 equiv.
b
arylzinc reagent. P : SM is the ratio of product to starting material as
We were interested in probing the selectivity of the thioester
moieties in the presence of aryl halides under these new
monitored by 1H NMR spectroscopy.
Table 3 Fukuyama and Negishi reactions of thioesters in the
presence of aryl halidesa
(see Supporting Information). We were pleased to find that a
significant reduction in catalyst loading (0.2 mol%) provided
excellent reaction conversion (entry 3). As a control, the use of a
palladium complex (Pd(dba)2) lacking a phosphine ligand was
screened to investigate the necessity of an external phosphine
ligand. Surprisingly, employment of 1 mol% of Pd(dba)2 in
toluene at ambient temperature provided high conversion of
starting material (1a) to product (2a) (entry 4). Decreasing the
amount of the Pd(dba)2 catalyst to 0.5 mol% significantly
decreased reaction conversion (entry 5). To our knowledge, this
is the first report of a Fukuyama reaction catalyzed simply by
Pd(dba)2. There has been a report of the use of Pd/C to promote
this reaction,29 but this catalyst did not work well under our
reaction conditions. Moreover, the reported Pd/C catalyst has
not been shown to be an efficient catalyst to prepare diaryl
ketones.
The solubility of Pd(dba)2 in most organic solvents is
typically poor. Therefore, the use of Pd(dba)2 as a catalyst
Table 2 Reaction scope for Pd(dba)2-catalyzed Fukuyama reactiona
a
a
Yields are an average of two reactions at 1 mmol scale.
Yields are an average of two reactions at 1 mmol scale.
c
12680 Chem. Commun., 2011, 47, 12679–12681
This journal is The Royal Society of Chemistry 2011

catalytic conditions. We suspected that a complex mixture of
products may be produced if an aryl halide were appended to
the aromatic ring containing the thioester. Under the phosphine-
free conditions, a complex mixture of products was indeed
observed. However, upon addition of tri-2-furylphosphine as
ligand, a selective process was uncovered. Employing thioesters
containing appended aryl bromides, the cross-coupling pro-
ceeded to yield diaryl ketones in good yields using 0.5 mol%
Pd(dba)2 and 0.7 mol% tri-2-furylphosphine (2k–m, Table 3).
In contrast, with an aryl iodide present, complete conversion
to a biaryl Negishi product was observed (3n–3q). Finally,
compound 3p, produced from the coupling of the thioester of
3-bromo-5-iodobenzoic acid with o-anisyl zinc reagent, retains
both the reactive thioester functionality and the aryl bromide
that can be employed in additional cross-coupling reactions.
These results suggest that thioesters are more reactive towards
oxidative addition than aryl bromides.
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In summary, we have described significant improvements in
the diaryl ketone synthesis via the Fukuyama reaction. The use
of Pd(dba)2 without an external ligand provided an active
catalyst that promoted the formation of diaryl ketones in good
to high yields at ambient temperature. The chemoselectivity of
this reaction was also investigated by employing thioester
substrates containing aryl halides. In the presence of aryl
iodides, the major product arose from a Negishi cross-coupling
reaction, whereas in the presence of aryl bromides, the major
product arose from a Fukuyama coupling at the thioester.
We gratefully acknowledge The Ohio State University for
support of this research, and Johnson Matthey for generously
providing ([Pd(PtBu3)Br]2).
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 12679–12681 12681