An efficient and mild protocol for the α-arylation of ketones mediated by an (imidazol-2-ylidene)palladium(acetate) system

Article abstract of DOI:10.1016/j.jorganchem.2005.07.083

The activity of well-defined N-heterocyclic carbene (NHC)-palladium acetate complexes has been studied in the α-arylation of ketones. The enolate was generated in situ via use of slight excess of sodium tert-butoxide as base. The results showed a high act

Full text of DOI:10.1016/j.jorganchem.2005.07.083

Journal of Organometallic Chemistry 690 (2005) 5832–5840
www.elsevier.com/locate/jorganchem
An efficient and mild protocol for the a-arylation of ketones
mediated by an (imidazol-2-ylidene)palladium(acetate) system
*
Rohit Singh, Steven P. Nolan
Department of Chemistry, University of New Orleans, New Orleans, LA 70148-2820, USA
Received 30 May 2005; accepted 15 July 2005
Available online 31 August 2005
Abstract
The activity of well-defined N-heterocyclic carbene (NHC)-palladium acetate complexes has been studied in the a-arylation of
ketones. The enolate was generated in situ via use of slight excess of sodium tert-butoxide as base. The results showed a high activity,
allowing for the coupling of non-activated chlorides. The use of hindered substrates provided an avenue for convenient synthesis of
various ketone derivatives. The first examples of a-arylation of ketones at room temperature mediated by an NHC-ligated catalyst
are also presented.
Ó 2005 Elsevier B.V. All rights reserved.
Keywords: Arylation; Ketones; Arylchlorides; N-heterocyclic carbenes; Palladium
1. Introduction
at the carbon a to the carbonyl group has proven to be a
transformation of great utility in pharmaceutical, agro-
chemical and organic synthesis [5]. It has also found an
increasing interest in the synthesis of fine chemicals [6].
The increased acidity ofa proton on a carbon a toa car-
bonyl group helps in its abstraction and generation of an
enolate. The simplicity in methodology offered by in situ
generation of an enolate via deprotonation is an added
advantage of this approach. Initially, the metal mediated
coupling of enolates was achieved by use of stoichiometric
amounts of metal complexes [7]. Moreover some of the
procedures involved use of less readily available carbonyl
alternatives [8]. However, in concurrent work, Buchwald
[9], Hartwig [10] and Miura [11] reported the first exam-
ples of direct, catalytic, a-arylations of ketones in 1997.
Since then, a myriad of reports from these and other
groups have helped establish the catalytic a-arylation of
ketones as an indispensable synthetic tool [12–15].
Transition metal catalyzed cross-coupling reactions
are a popular means of adding a variety of carbon nucle-
ophiles to aryl halides [1]. Development of efficient and
selective catalytic reactions for C–C bond formation has
been a subject of paramount interest in organic and orga-
nometallic chemistry. Catalytic conversion of C–H bond
to a C–C bond is an important subgrouping of such trans-
formations. During the past years, numerous reactions
involving C–H bond transformations have been devel-
oped [2]. Among these, palladium-catalyzed conversion
of C–H bonds to form C–C bonds via coupling of aryl ha-
lides or pseudo aryl halides with carbon nucleophiles is
one of the most widely employed transition metal cata-
lyzed reaction [3]. Finding an efficient and reliable cata-
lytic method to form a bond between an arene and
carbon a to a carbonyl group is a challenging problem
[4]. The use of aryl halides for direct arylation of ketones
Since the discovery of stable N-heterocyclic carbenes
(NHCs), a number of groups have utilized these in catal-
ysis [16]. In the past several years, a number of NHC-
metal complexes serving as efficient catalysts for a
*
Corresponding author. Tel. +1 504 286 6311; fax: +1 504 280 6860.
E-mail address: snolan@uno.edu (S.P. Nolan).
0022-328X/$ - see front matter Ó 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2005.07.083

R. Singh, S.P. Nolan / Journal of Organometallic Chemistry 690 (2005) 5832–5840
5833
O
OAc
O
Pd
O
R2
N
N
R1
R3
O
X
R2
R3
R1
+
Dioxane, NaOtBu, 60 oC
H
Scheme 1. (NHC)Pd(OAc)2 catalyzed a-arylation of ketones.
Table 1
number of reactions have been reported [17]. Such
examples include the palladium-catalyzed a-arylation
of ketones [18]. More recently, we and others [19] have
reported on the synthesis and characterization of (imi-
dazol-2-ylidene)palladium acetate complexes. The com-
plexes were tested for activity in the hydroarylation of
alkynes [20] and in the Suzuki–Miyaura cross-coupling
reaction [17a]. Encouraged by the very attractive reactiv-
ity profile in these transformations mediated by
(NHC)Pd(OAc)2 complexes, results of catalytic study
dealing with a-arylation of ketones with various chlorides
as coupling partners are reported here (see Scheme 1).
The model reaction involving propiophenone with 4-
chlorotoluene revealed the complex (IPr)Pd(OAc)2
[IPr = N,N0-(2,6-diisopropyl phenyl) imidazol-2-ylidene]
to be an active mediator, furnishing quantitative yield of
product in 3 h at 60 °C. This catalytic transformation is
very appealing, especially since the catalyst is very easily
synthesized [21]. With an aim to prove this protocol
practical and amenable to wider laboratory and indus-
trial applications we wish to provide a detailed report
of our studies regarding the optimization, scope and
applicability of a-arylation of ketones.
Solvent screeninga
O
Cl
O
(IPr)Pd(OAc)2 (1 mol%)
NaOtBu, 60 oC
+
Entry
Solvent
Time (h)
Yield (%)b
1
2
3
4
5
6
7
a
Toluene
DME
Dioxane
THF
Isopropanol
MTBE
DMAc
1
2
1
1
–
1
–
77
85
87
84
NR
82
NR
Reaction conditions: 1 mol% of(IPr)Pd(OAc)2, 1.2 mmol of pro-
piophenone, 1 mmol of 4-chlorotoluene, 1.5 equiv. of NaOtBu, 1.5 mL
of solvent, 60 °C.
b
GC yields, average of two runs.
2.1. Solvent screening
As a generic reaction, 4-chlorotoluene was reacted
with propiophenone in the presence of 1 mol% of
(IPr)Pd(OAc)2 and 1.5 equiv. of base (sodium tert-
butoxide) at 60 °C. Among various solvents tested for
activity, isopropyl alcohol and N,N-dimethylacetamide
failed to furnish appreciable quantities of product. How-
ever, excellent yields were obtained with other solvents
and 1,4-dioxane was found to provide quantitative con-
version in minimum time, making it the solvent of
choice for our protocol [23].
2. Results and discussion
For the initial optimization studies we chose to fo-
cus on reactions of propiophenone, since it provides
only one site for a possible deprotonation by the base
and avoids potential complications arising from multi-
arylations. For halide coupling partner, we primarily
made use of chlorides. This decision was motivated in
part by our realization that so far very few reports
have been published which employ chlorides
[15c,12c,13e]. Although aryl chlorides have lower costs
and are available in broader diversity as compared to
bromides and iodides, as a general trend they tend to
be less active towards oxidative addition in metal med-
iated couplings [22]. We therefore initiated an investi-
gation of the utility of chlorides in a-arylation of
ketones [18]. For optimization studies, 4-chlorotoluene
was chosen as the halide coupling partner. Initially, an
analysis of various solvents as reaction media was car-
ried out (Table 1).
2.2. Base screening
With the dual influence of base in mind (generation of
active catalytic Pd species and deprotonation of ketone
to generate the enolate), various commercially available
standard alkali metal bases were investigated in the
model reaction (Table 2). Among the productive bases,
NaOtBu was found to be the most affordable.
2.3. Reactions of various halides with propiophenone
With optimum conditions in hand, a survey of reac-
tions between propiophenone and various aryl halides

5834
R. Singh, S.P. Nolan / Journal of Organometallic Chemistry 690 (2005) 5832–5840
Table 2
Table 3
Base screeninga
a-Arylation of various halides with propiophenonea
O
O
O
X
Cl
(IPr)Pd(OAc)2 (1 mol%)
O
(IPr)Pd(OAc)2 (1 mol%)
1,4-Dioxane, 60 oC
+
NaOtBu, p-Dioxane, 60 oC
R
+
R
Entry
1
Aryl halide
Cl
Time (h)
6
Yield (%)b
80 (71)
Entry
Base
Time (h)
Yield (%)b
1
2
3
4
5
6
7
a
NaOtBu
KOtBu
NaH
3
4
2
12
3
5
96
85
85
78
10
60
27
Cl
96 (92)
2
3
KH
Cs2CO3
KOMe
K3PO4
F
Br
I
–
3
4
NR
3
Reaction conditions: 1 mol% of (IPr)Pd(OAc)2, 1.2 mmol of pro-
piophenone, 1 mmol of 4-chlorotoluene, 1.5 equiv. of base, 1.5 mL of
1,4-dioxane, 60 °C.
1
92 (88)
b
GC yields, average of two runs.
5
6
1
2
–
96 (83)
96 (90)
under catalytic conditions was performed. The details
are provided in Table 3. Reactions of para-bromo- and
para-iodotoluene proceeded to furnish quantitative
yields within 1 h (Table 3, entries 4 and 5). More difficult
substrates, chlorobenzene and para-chlorotoluene also
performed well giving good yields (Table 3, entries 1
and 2). A stronger C–F bond in aryl-fluorides prevents
its oxidative addition to the palladium center. Therefore,
the reaction of para-fluorotoluene with propiophenone
under the standard conditions failed to furnish the prod-
uct in appreciable quantity (Table 3, entry 3). Reaction
of ortho-chlorotoluene proceeded to give complete con-
version in less time than para-chlorotoluene (Table 3,
entry 6), indicating a favorable effect of the presence
of steric bulk around the reaction center. This increase
in steric bulk (Scheme 2) expedites the reductive elimina-
tion [24]. Increase in steric bulk around the metal center
increases the energy of the stable, higher co-ordinate
species prompting it to undergo reductive elimination
[25,13a]. Moreover, the presence of sterically hindering
moiety in the final product can act as a deterrent for
multi-arylations.
Cl
Cl
NR
NR
7
NC
Cl
8
–
OHC
a
Reaction conditions: 1 mol% of (IPr)Pd(OAc)2, 1.2 mmol of pro-
piophenone, 1 mmol of aryl halide, 1.5 equiv. of NaOtBu, 1.5 mL of
1,4-dioxane, 60 °C.
b
GC yields (isolated yields in parentheses), average of two runs.
times (Table 4, entries 1–3). However, reactions involv-
ing the electron-withdrawing trifluoromethyl substi-
tuted chlorophenyls displayed poorer performance.
While ortho- and para-chloro(trifluoromethyl)phenyls
furnished moderate yields in longer time periods (Table
4, entries 4 and 6), the meta-substituted, 3-chloro(triflu-
oromethyl)phenyl failed to undergo coupling (Table 4,
entry 5). These results represent an interesting trend,
since it is known that usually electron-rich aryl halides
are difficult to activate towards oxidative addition with
palladium [25]. Conceivably, the oxidative addition
does not affect the overall rate of the reaction and is
not the rate determining step. Although in most
cross-coupling reactions of haloarenes, the reaction
rates are usually believed to be controlled by the rate
of oxidative addition [22b] and usually the transmetala-
tion and reductive elimination are more rapid [26],
non-involvement of oxidative addition in dictating the
rate of a reaction is not unprecedented [27]. Since the
presence of electron withdrawing groups around the
metal center should activate it towards transmetalation
with an enolate, it is possible that the presence of elec-
2.4. Study of ortho-, meta-or para-substitution on aryl
chlorides with both electron-donating and electron-
withdrawing groups
To obtain some insight into the substrate scope of
this reaction, we investigated the effect of electron-
donating and electron-withdrawing groups at various
positions on the aryl chlorides. Hence, reactions of
ortho-, meta- and para-substituted chloroanisoles and
chloro(trifluoromethyl)phenyls were performed under
the standard reaction conditions. The substrates with
electron donating methoxy substituent performed
exceedingly well, furnishing excellent yields in short

R. Singh, S.P. Nolan / Journal of Organometallic Chemistry 690 (2005) 5832–5840
5835
2.5. Study of effect of introduction of steric bulk on
position a to carbonyl group in substituted cyclohexyl
ketones
Ar-X
O
R1
[NHC-Pd]
Ar
R2
Given the fact that sterics play an important role in
the a-arylation of ketones, an investigation of effect of
bulk around the ketone, on the generation of enolate
was carried out. To this effect, a limited study with
various substituted cyclohexyl ketones was performed
(Table 5). Unsubstituted, cyclohexyl ketone performed
well under the standard conditions, furnishing good
yield in 2 h. However, poor conversion due to the
presence of methyl groups around the carbonyl car-
bons in 2,6-dimethylcyclohexanone and 2,2,6-trimeth-
ylcyclohexanone was observed. This is indicative of
the sensitivity in generating an enolate in the reaction
in the presence of sterically hindering groups around
the carbonyl group. Furthermore, 2-tert-butylcyclohexa-
none yielded a poor conversion while aryl fused cyclo-
hexanone derivative (a-tetralone) fared better giving
good conversion in 6 h. It is worth mentioning that both
these substrates have an unsubstituted carbon a-to the
Ar
Pd
R2
O
R1
X
NHC
NHC Pd
Ar
O
R1
O
R1
O
R1
+
base
R2
R2
R2
Scheme 2. Proposed catalytic cycle for a-arylation of ketones in
(NHC)Pd(OAc)2 system.
Table 4
Substituent effect on aryl chlorides in a-arylation with propiophenonea
O
Table 5
O
Cl
(IPr)Pd(OAc)2 (1 mol%)
Effect of steric bulk in generation of enolates in cyclohexyl ketone
derivativesa
+
t
NaO Bu, p-Dioxane, 60 oC
R
R
O
O
Cl
(IPr)Pd(OAc)2 (1 mol%)
+
Entry
1
Aryl halide
Time (h)
1
Yield (%)b
98 (94)
NaOtBu, p-Dioxane, 60 oC
R
R
OMe
Cl
Entry
1
Aryl halide
Time (h)
2
Yield (%)b
73 (67)
O
O
O
O
O
O
Cl
Cl
MeO
MeO
2
3
1
3
91 (81)
96 (90)
–
–
2
3
4
5
NR
NR
20
CF3
Cl
Cl
Cl
4
5
12
75 (71)
NR
F3C
F3C
–
12
6
12
71 (69)
a
OMe
–
NR
Reaction conditions: 1 mol% of (IPr)Pd(OAc)2, 1.2 mmol of pro-
piophenone, 1 mmol of aryl halide, 1.5 equiv. of NaOtBu, 1.5 mL of
1,4-dioxane, 60 °C.
b
GC yields (isolated yields in parentheses), average of two runs.
6
6
90 (83)
a
Reaction conditions: 1 mol% of (IPr)Pd(OAc)2, 1.2 mmol of
ketone, 1 mmol of 4-chlorotoluene, 1.5 equiv. of NaOtBu, 1.5 mL of
1,4-dioxane, 60 °C.
tron withdrawing group (especially at the meta-
position) deactivates the substrates towards reductive
elimination.
b
GC yields (isolated yields in parentheses), average of two runs.

5836
R. Singh, S.P. Nolan / Journal of Organometallic Chemistry 690 (2005) 5832–5840
carbonyl group. However, electronic effects come into
play when 2-methoxycyclohexanone is used. In spite
of an unsubstituted carbon a to the carbonyl group,
the electron donating nature of the methoxy group
attenuates acidity of the ketone, deactivating it towards
deprotonation.
It is worthy of note that reactions involving cyclo-
hexyl ketone derivatives demonstrated excellent regiose-
lectivity. In spite of the availability of additional sites for
arylation, only trace amounts of diarylations were ob-
served in these reactions.
2.7. a-Arylation of sterically hindered substrates and
optimum reaction temperature
At this stage we were pleased that our objective of
effecting couplings of non-activated chlorides in a syn-
thetically oriented protocol could be accomplished.
On the other hand, we were not satisfied with the scope
of the process and aspired to further expand it. Given
our past experience [17a,17f], we wished to pursue steri-
cally hindered substrates as prospective coupling part-
ners in this reaction. The use of bromomesitylene in
arylating the ketone in excellent yield was achieved with-
in a very short time (Table 7, entry 1). Unactivated,
ortho-substituted chlorides performed well under our
reaction protocol (Table 7, entries 2–4). In particular,
bulky naphthylchloride gave quantitative yield within
1 h at 60 °C. Furthermore, on testing the performance
of catalyst at optimum temperature in this reaction,
we were pleased to observe formation of arylated prod-
uct. Only few examples of a-arylation of ketones, per-
formed at room temperature have been reported so
far. However, elegant reports by Hartwig [13e] and
Buchwald [12a] have only utilized more reactive bro-
mides. To the best of our knowledge, no reports of room
temperature a-arylation of ketones with chlorides have
been reported to date [29]. To further explore this aspect
of our reaction protocol, we carried out reactions of
2.6. a-Arylation of various substrates including
heterocyclic ketones and chlorides
With an aim to expand the scope of the reaction and
broadening the base of usable substrates, we explored
various chlorides in the a-arylation of ketones. Since
synthesis of heterocyclic compounds is of significant
importance to synthetic and medicinal chemists, we
wished to explore the compatibility of heterocyclic sub-
strates with the present protocol. Moderate success was
achieved in this venture on coupling 2-and 3-chlorothi-
ophene with propiophenone and 2-acetyl-1-methyl-
pyrrole with 2-chlorotoluene (Table 6, entries 3–5).
2-Acetylthiophene did not furnish a good yield in the
reaction with 2-chlorotoluene.
Table 7
a-Arylation of sterically hindered substratesa
O
O
(IPr)Pd(OAc)2 (1 mol%)
X
R
+
R
NaOtBu, p-Dioxane, 60 oC
Table 6
Entry
1
Aryl halide
Br
Product
Temp(˚C) Time (h) Yield (%)b
a-Arylation of various substrates including heterocyclic ketones and
chloridesa
O
O
R1
(IPr)Pd(OAc)2 (1 mol%)
92 (83)
0.5
1
O
60
60
R1
Cl R3
R3
+
NaOtBu, p-Dioxane, 60 o
C
R2
R2
O
Cl
Cl
100 (93)
2
3
Entry
1
Ketone
Aryl halide
Product
O
Time (h) Yield (%)b
O
O
24
80 (75)
Cl
Cl
O
80 (75)
25
12
MeO
MeO
O
O
O
2
3
4
5
12
12
17
42
OMe
Cl
O
78 (71)
73 (67)
41
12
18
4
5
25
25
OMe
OMe
O
S
S
Cl
O
Cl
OMe
O
O
S
O
O
O
Cl
24
6
36
46
Cl
S
6
7
25
25
25
24
12
12
O
Br
I
Cl
Cl
42
N
S
N
S
O
O
75 (70)
8
6
12
13
a
a
Reaction conditions: 1 mol% of(IPr)Pd(OAc)2, 1.2 mmol of
ketone, 1 mmol of aryl halide, 1.5 equiv. of NaOtBu, 1.5 mL of 1,4-
dioxane, 60 °C.
Reaction conditions: 1 mol% of(IPr)Pd(OAc)2, 1.2 mmol of pro-
piophenone, 1 mmol of aryl halide, 1.5 equiv. of NaOtBu, 1.5 mL of
1,4-dioxane.
b
b
GC yields (isolated yields in parentheses), average of two runs.
GC yields (isolated yields in parentheses), average of two runs.

R. Singh, S.P. Nolan / Journal of Organometallic Chemistry 690 (2005) 5832–5840
5837
various halides at room temperature. Herein, we wish to
4.2. Representative procedure for a-arylation of ketones
report the first examples of a-arylation of ketones with
chlorides at room temperature. Reactions of propiophe-
none progress well with 1-chloronaphthalene, 2-chloro-
anisole and 4-chloroanisole (Table 7, entries 3–5).
Reaction of 4-iodotoluene proceeds cleanly to provide
the product in good yield (Table 7, entry 8). However,
when 4-chlorotoluene and 4-bromotoluene are used,
the product is obtained in moderate yields (Table 7, en-
tries 6 and 7). Nevertheless, the activity of (IPr)P-
In a drybox, 1.5 mmol of base was added to a screw-
cap vial charged with 1 mol% of (IPr)Pd(OAc)2 complex.
1.5 mL of solvent was added and the vial sealed with a
rubber septum. Outside the drybox, 1.2 mmol of ketone
was injected in the vial with a syringe. 1 mmol of aryl ha-
lide was injected last. The reaction mixture was allowed
to shake on a Lab-Line Orbit Shaker (set at 60 °C –
J-Kem Scientific, Kem-Lab Controller) or stirred over
a magnetic plate in an oil bath set at 60 °C for the indi-
cated time. The reactions were monitored by gas chro-
matography. After reaching maximum conversion, the
reaction mixture was allowed to cool to room tempera-
ture and it was then quenched with water. The organic
layer was extracted with methyl tert-butyl ether or
diethyl ether and dried over magnesium sulfate. The sol-
vent was then evaporated in vacuo. When necessary the
product was purified by flash chromatography on silica
gel.
d(OAc)2 at room temperature provides
a
new
dimension to the use of this protocol towards more uni-
versal laboratory and industrial applications.
3. Conclusions
In summary, we have described a convenient protocol
for the a-arylation of ketones utilizing an easy to synthe-
size (imidazol-2-ylidene)palladium acetate complex as
catalyst. The best reaction conditions obtained via opti-
mization studies revealed compatibility with a commer-
cially available, inexpensive and convenient base, as
well as solvent making the reaction protocol amenable
to large-scale synthesis. A wide array of functionalized
halides has been investigated in an effort to better under-
stand the bearings of electronics and sterics on the reac-
tion. Coupling of heterocyclic substrates has also been
achieved. In view of the paucity of examples of reactions
at lower temperatures using unactivated aryl chlorides
(particularly ortho-substituted chlorides), we believe these
observations are noteworthy. Efforts aimed at developing
effective catalyst systems for a broad range of substrates
under mild conditions, as well as initiating investigations
of mechanistic aspects at play are ongoing [28].
4.3. Screening of solvents in a-arylation of ketones
In a drybox, NaOtBu (1.5 mmol, 144 mg) was loaded
in a screw-cap vial charged with (IPr)Pd(OAc)2 complex
(0.01 mmol, 6.1 mg). 1.5 mL of solvent was added and
the vial sealed with a rubber septum. Outside the dry-
box, propiophenone (1.2 mmol, 160 ll) was injected in
the vial with a syringe. Lastly, 4-chlorotoluene (1 mmol,
118 ll) was injected into the vial. The reaction mixture
was allowed to shake on a Lab-Line Orbit Shaker (set
at 60 °C–J-Kem Scientific, Kem-Lab Controller) or stir-
red over a magnetic plate in an oil bath set at 60 °C for
the indicated time. The reactions were monitored by gas
chromatography.
4.4. Screening of bases in a-arylation of ketones
4. Experimental
In a drybox, 1.5 mmol of base was loaded in a screw-
cap vial charged with (IPr)Pd(OAc)2 complex
(0.01 mmol, 6.1 mg). 1.5 mL of dioxane was added and
the vial sealed with a rubber septum. Outside the dry-
box, propiophenone (1.2 mmol, 160 ll) was injected in
the vial with a syringe. Lastly, 4-chlorotoluene (1 mmol,
118 ll) was injected to the vial. The reaction mixture was
allowed to shake on a Lab-Line Orbit Shaker (set at
60 °C – J-Kem Scientific, Kem-Lab Controller) or stir-
red over a magnetic plate in an oil bath set at 60 °C
for the indicated time. The reactions were monitored
by gas chromatography.
4.1. General considerations
All aryl halides and ketones were used as received
(Aldrich, Acros). Bases were stored under argon in an
MBraun glovebox. All solvents were distilled from
appropriate drying agents or were passed through an
alumina column in an MBraun solvent purification sys-
tem. The catalyst was prepared according to the re-
ported procedures [17a,20,30]. All reactions were
carried out under an atmosphere of argon in screw-cap
1
vials. H and 13C NMR spectra were recorded using a
Varian-400 or Varian-300 MHz spectrometer at ambient
temperature in CDCl3 (Cambridge Isotope Laborato-
ries, Inc.). The solvent for NMR spectroscopy was
stored over molecular sieves. Flash chromatography
was performed on silica gel (230–400 mesh) (Natland
International Corporation).
4.5. a-Arylation of various ketones with aryl halides
In a drybox, NaOtBu (1.5 mmol, 144 mg) was
loaded in a screw-cap vial charged with (IPr)Pd(OAc)2

5838
R. Singh, S.P. Nolan / Journal of Organometallic Chemistry 690 (2005) 5832–5840
complex (0.01 mmol, 6.1 mg). 1.5 mL of dioxane was
added and the vial sealed with a rubber septum. Out-
side the drybox, 1.2 mmol of ketone was injected in
the vial with a syringe. 1 mmol of aryl halide was in-
jected last. The reaction mixture was allowed to shake
on a Lab-Line Orbit Shaker (set at 60 °C – J-Kem
Scientific, Kem-Lab Controller) or stirred over a mag-
netic plate (at room temperature or in an oil bath set
at 60 °C) for the indicated time. The reactions were
monitored by gas chromatography. After the maxi-
mum conversion had been reached, the reaction mix-
ture was allowed to cool to room temperature and
quenched with water. The organic layer was extracted
with methyl tert-butyl ether or diethyl ether and dried
over magnesium sulfate. The solvent was then evapo-
rated in vacuo. When necessary, the product was puri-
fied by flash chromatography on silica gel. Identity of
products was confirmed by comparison with literature
spectroscopic data.
1,2-Di-o-tolyl-ethanone [36] (Table 6, entry 1): The
procedure afforded 168 mg (75%) of the compound.
1-Phenyl-2-(2,4,6-trimethyl-phenyl)-propan-1-one [37]
(Table 7, entry 1): The procedure afforded 209 mg
(83%) of the compound.
2-Naphthalen-1-yl-1-phenyl-propan-1-one [38] (Ta-
ble 7, entry 2): The procedure afforded 242 mg
(93%) of the compound.
2-Naphthalen-1-yl-1-phenyl-propan-1-one [38] (Ta-
ble 7, entry 3): The procedure afforded 195 mg
(75%) of the compound.
2-(2-Methoxy-phenyl)-1-phenyl-propan-1-one
[32]
(Table 7, entry 4): The procedure afforded 170 mg
(71%) of the compound.
2-(4-Methoxy-phenyl)-1-phenyl-propan-1-one [10] (Ta-
ble 7, entry 5): The procedure afforded 161 mg
(67%) of the compound.
1-Phenyl-2-p-tolyl-propan-1-one [31] (Table 7, entry
8): The procedure afforded 156 mg (70%) of the
compound.
Isolated products:
1,2-Diphenyl-propan-1-one [13e] (Table 3, entry 1):
The procedure afforded 149 mg (71%) of the
compound.
Acknowledgements
1-Phenyl-2-p-tolyl-propan-1-one [31] (Table 3, entry
2): The procedure afforded 206 mg (92%) of the
compound.
1-Phenyl-2-p-tolyl-propan-1-one [31] (Table 3, entry
4): The procedure afforded 197 mg (88%) of the
compound.
The National Science Foundation is gratefully
acknowledged for financial support of this work and
Umicore AG is gratefully acknowledged for the generous
gift of Pd(OAc)2. We are also grateful to Boehringer-
Ingelheim Pharmaceuticals Inc. for an unrestricted grant.
1-Phenyl-2-p-tolyl-propan-1-one [31] (Table 3, entry
5): The procedure afforded 185 mg (83%) of the
compound.
References
1-Phenyl-2-o-tolyl-propan-1-one [31] (Table 3, entry
6): The procedure afforded 202 mg (90%) of the
compound.
2-(2-Methoxy-phenyl)-1-phenyl-propan-1-one [32] (Ta-
ble 4, entry 1): The procedure afforded 225 mg
(94%) of the compound.
2-(3-Methoxy-phenyl)-1-phenyl-propan-1-one [13e]
(Table 4, entry 2): The procedure afforded 194 mg
(81%) of the compound.
[1] For reactions of aryl halides with carbon nucleophiles such as
Grignard reagents, boronic acids and tin reagents see F. Diede-
rich, P.J. Stang, Metal-Catalyzed Cross-Coupling Reactions,
Wiley–VCH, Weinheim, 1998, p. 517.
[2] (a) F. Kakiuchi, N. Chatani, Adv. Synth. Catal. 345 (2003) 1077;
(b) J.A. Labinger, J.E. Bercaw, Nature 417 (2002) 507;
(c) M. Miura, M. Nomura, Cross-Coupling Reactions, Springer,
Berlin, Germany, 2002, p. 211;
(d) F. Kakiuchi, S. Murai, Acc. Chem. Res. 35 (2002) 826;
(e) V. Ritleng, C. Sirlin, M. Pfeffer, Chem. Rev. 102 (2002) 1731;
(f) R.H. Crabtree, Dalton Trans. (2001) 2437;
(g) Y. Guari, S. Sabo-Etienne, B. Chaudret, Eur. J. Inorg. Chem.
(1999) 1047;
2-(4-Methoxy-phenyl)-1-phenyl-propan-1-one
[10]
(Table 4, entry 3): The procedure afforded 216 mg
(90%) of the compound.
(h) R.H. Crabtree, Chem. Rev. 85 (1985) 245.
[3] (a) J. Hassan, M. Sevignon, C. Gozzi, E. Schulz, M. Lemaire,
Chem. Rev. 102 (2002) 1359;
1-Phenyl-2-(2-trifluoromethyl-phenyl)-propan-1-one
[33] (Table 4, entry 4): The procedure afforded
197 mg (71%) of the compound.
1-Phenyl-2-(4-trifluoromethyl-phenyl)-propan-1-one
[33] (Table 4, entry 6): The procedure afforded
192 mg (69%) of the compound.
2-p-Tolyl-cyclohexanone [34] (Table 5, entry 1): The
procedure afforded 126 mg (67%) of the compound.
2-p-Tolyl-3,4-dihydro-2H-naphthalen-1-one [35] (Ta-
ble 5, entry 6): The procedure afforded 196 mg (83%)
of the compound.
(b) N. Miyaura, A. Suzuki, Chem. Rev. 95 (1995) 2457;
(c) J.K. Stille, Angew Chem., Int. Ed. Engl. 25 (1986) 508;
(d) E. Negishi, Acc. Chem. Res. 15 (1982) 340.
[4] (a) Catalytic reactions for synthesis of a-aryl ketones M.
Durandetti, J.-Y. Nedelec, J. Perichon, J. Org. Chem. 61 (1996)
1748;
(b) M. Kosugi, I. Hagiwara, T. Sumiya, T. Migita, Bull. Chem.
Soc. Jpn. 57 (1984) 242;
(c) I. Kuwajima, H. Urabe, J. Am. Chem. Soc. 104 (1982) 6831;
(d) K. Tamao, M. Zembayashi, M. Kumada, Chem. Lett. (1976)
1239.

R. Singh, S.P. Nolan / Journal of Organometallic Chemistry 690 (2005) 5832–5840
5839
[5] (a) D.R. Bhowmik, R.V. Venkateswaran, Tetrahedron Lett. 40
(1999) 7431;
(d) G. Pandey, M. Karthikeyan, A. Murugan, J. Org. Chem. 63
(1998) 2867;
(b) A. Srikrishna, T.J. Reddy, Tetrahedron 54 (1998) 8133;
(c) J. Morgan, J.T. Pinhey, B.A. Rowe, J. Chem. Soc. Perkin
Trans. I (1997) 1005;
(d) S. Takano, K. Inomata, T. Sato, M. Takahashi, K. Ogasa-
wara, J. Chem. Soc., Chem. Commun. (1990) 290;
(e) V. Nair, G.A. Turner, S.D. Chamberlain, J. Am. Chem. Soc.
109 (1987) 7223.
(e) J.H. Ryan, P.J. Stang, Tetrahedron Lett. 38 (1997) 5061.
[16] (a) H.-W. Wanzlick, E. Schikora, Angew. Chem. 72 (1960) 494;
(b) H.-W. Wanzlick, H.-J. Kleiner, Angew. Chem. 73 (1961) 493;
(c) H.-W. Wanzlick, Angew. Chem. 74 (1962) 129;
(d) A. Igau, H. Gruetzmacher, A. Baceiredo, G. Bertrand, J. Am.
Chem. Soc. 110 (1988) 6463;
(e) A. Igau, A. Baceiredo, G. Trinquier, G. Bertrand, Angew.
Chem., Int. Ed. Engl. 28 (1989) 621;
(f) A.J. Arduengo III, R.L. Harlow, M. Kline, J. Am. Chem. Soc.
113 (1991) 361;
(g) A.J. Arduengo, H.V.R. Dias, R.L. Harlow, M. Kline, J. Am.
Chem. Soc. 114 (1992) 5530;
(h) , For comprehensive reviews on NHC see:M. Regitz, Angew.
Chem., Int. Ed. Engl. 35 (1996) 725;
[6] M. Beller, A. Zapf, W. Magerlein, Chem. Eng. Technol. 24 (2001)
575.
[7] (a) Intermolecular arylation of an ester enolate: A.A. Millard,
M.W. Rathke, J. Am. Chem. Soc. 99 (1977) 4833;
(b) , Intramolecular arylation of an ester enolate:M.F. Semmel-
hack, R.D. Stauffer, T.D. Rogerson, Tetrahedron Lett. (1973)
4519.
[8] (a) T. Mino, T. Matsuda, K. Murahashi, M. Yamashita,
Organometallics 16 (1997) 3241;
(i) A.J. Arduengo, R. Krafczyk, Chem. Z. 32 (1998) 6;
(j) D. Bourissou, O. Guerret, F.P. Gabbai, G. Bertrand, Chem.
Rev. 100 (2000) 39;
(k) W.A. Herrmann, Angew. Chem., Int. Ed. Engl. 41 (2002)
1290;
(l) B. Yong, S.P. Nolan, Chemtracts 16 (2002) 205;
(m) A.C. Hillier, S.P. Nolan, Platinum Met. Rev. 46 (2002) 50;
(n) L. Jafarpour, S.P. Nolan, Adv. Organomet. Chem. 46 (2002)
181.
(b) M.W. Rathke, D. Vogiazoglou, J. Org. Chem. 52 (1987) 3697;
(c) J.P. Marino, J.C. Jaen, J. Am. Chem. Soc. 104 (1982) 3165;
(d) H. Sakurai, A. Shirahata, Y. Araki, A. Hosomi, Tetrahedron
Lett. 21 (1980) 2325;
(e) L.F. Kelly, A.S. Narula, A. Birch, Tetrahedron Lett. 21 (1980)
2455;
(f) I. Al Adel, B. Adeoti Salami, J. Levisalles, H. Rudler, Bull.
Soc. Chim. Fr. (1976) 930;
(g) C.E. Sacks, P.L. Fuchs, J. Am. Chem. Soc. 97 (1975) 7372;
(h) L.S. Hegedus, R.K. Stiverson, J. Am. Chem. Soc. 96 (1974)
3250;
[17] (a) R. Singh, M.S. Viciu, N. Kramareva, O. Navarro, S.P. Nolan,
Org. Lett. 7 (2005) 1829;
(b) O. Navarro, Y. Oonishi, R.A. Kelly, E.D. Stevens, O. Briel,
S.P. Nolan, J. Organomet. Chem. 689 (2004) 3722;
(c) H. Kaur, F.K. Zinn, E.D. Stevens, S.P. Nolan, Organomet-
allics 23 (2004) 1157;
(i) H.C. Brown, H. Nambu, M.M. Rogic, J. Am. Chem. Soc. 91
(1969) 6855;
(j) H.C. Brown, H. Nambu, M.M. Rogic, J. Am. Chem. Soc. 91
(1969) 6852;
(d) O. Navarro, H. Kaur, P. Mahjoor, S.P. Nolan, J. Org. Chem.
69 (2004) 3173;
(k) P.R. Jones, J.R. Young, J. Org. Chem. 33 (1968) 1675;
(l) M.S. Newman, M. Farbman, J. Am. Chem. Soc. 66 (1944)
1550.
(e) G.A. Grasa, R. Singh, E.D. Stevens, S.P. Nolan, J. Organo-
met. Chem. 687 (2003) 269;
(f) O. Navarro, R.A. Kelly, S.P. Nolan, J. Am. Chem. Soc. 125
(2003) 16194;
(g) M.S. Viciu, R.M. Kissling, E.D. Stevens, S.P. Nolan, Org.
Lett. 4 (2002) 2229.
[9] M. Palucki, S.L. Buchwald, J. Am. Chem. Soc. 119 (1997) 11108.
[10] B.C. Hamann, J.F. Hartwig, J. Am. Chem. Soc. 119 (1997) 12382.
[11] T. Satoh, Y. Kawamura, M. Miura, M. Nomura, Angew. Chem.
Int. Ed. 36 (1997) 1740.
[12] (a) T. Hamada, A. Chieffi, J. Ahman, S.L. Buchwald, J. Am.
Chem. Soc. 124 (2002) 1261;
[18] (a) a-Arylation of ketones with aryl chlorides: M.S. Viciu, R.A.
Kelly, E.D. Stevens, F. Naud, M. Studer, S.P. Nolan, Org. Lett.
5 (2003) 1479;
(b) , Vinylation of enolates:A. Chieffi, K. Kamikawa, J. Ahman,
J.M. Fox, S.L. Buchwald, Org. Lett. 3 (2001) 1897;
(c) J.M. Fox, X. Huang, A. Chieffi, S.L. Buchwald, J. Am. Chem.
Soc. 122 (2000) 1360;
(d) . Asymmetric arylation of ketone enolates:J. Ahman, J.P.
Wolfe, M.V. Troutman, M. Palucki, S.L. Buchwald, J. Am.
Chem. Soc. 120 (1998) 1918.
(b) M.S. Viciu, R.F. Germaneau, S.P. Nolan, Org. Lett. 4 (2002)
4053.
[19] (a) For examples of (NHC)palladium acetate systems see: M.J.
Schultz, S.S. Hamilton, D.R. Jensen, M.S. Sigman, J. Org. Chem.
70 (2005) 3343;
(b) J.A. Mueller, C.P. Goller, M.S. Sigman, J. Am. Chem. Soc.
126 (2004) 9724;
[13] (a) D.A. Culkin, J.F. Hartwig, Acc. Chem. Res. 36 (2003) 234;
(b) S. Lee, N.A. Beare, J.F. Hartwig, J. Am. Chem. Soc. 123
(2001) 8410;
(c) M.M. Konnick, I.A. Guzei, S.S. Stahl, J. Am. Chem. Soc. 126
(2004) 10212.
[20] M.S. Viciu, E.D. Stevens, J.L. Peterson, S.P. Nolan, Organomet-
allics 23 (2004) 3752.
[21] The precursor for synthesis of catalyst, IPr Æ HCl is com-
mercially available from: Strem Chemicals, Inc. and from
Sigma/Aldrich.
[22] (a) For a discussion, see: V.V. Grushin, H. Alper, in: S. Murai
(Ed.), Activation of Unreactive Bonds and Organic Synthesis,
Springer, Berlin, 1999, p. 193;
(c) S. Lee, J.F. Hartwig, J. Org. Chem. 66 (2001) 3402;
(d) S.R. Stauffer, N.A. Beare, J.P. Stambuli, J.F. Hartwig, J. Am.
Chem. Soc. 123 (2001) 4641;
(e) M. Kawatsura, J.F. Hartwig, J. Am. Chem. Soc. 121 (1999)
1473;
(f) K.H. Shaughnessy, B.C. Hamann, J.F. Hartwig, J. Am. Chem.
Soc. 63 (1998) 6546.
[14] T. Satoh, J. Inoh, Y. Kawamuro, M. Miura, M. Nomura, Bull.
Chem. Soc. Jpn. 71 (1998) 2239.
[15] (a) F. Kakiuchi, Y. Matsuura, S. Kan, N. Chatani, J. Am. Chem.
Soc. 127 (2005) 5936;
(b) V.V. Grushin, H. Alper, Chem. Rev. 94 (1994) 1047.
[23] Although initially THF also performed equally well, on individual
optimization of the reaction, it was found that 1,4-dioxane
performs better.
(b) O. Prieto, D.J. Ramon, M. Yus, Tetrahedron:Asymmetry 14
(2003) 1955;
[24] R.H. Crabtree, The Organometallic Chemistry of the Transition
Metals, third ed., Wiley, New York, 2001.
(c) A. Ehrentraut, A. Zapf, M. Beller, Adv. Synth. Catal. 344
(2002) 209;
[25] A.F. Littke, G.C. Fu, Angew. Chem. Int. Ed. Engl. 41 (2002)
4176.

5840
R. Singh, S.P. Nolan / Journal of Organometallic Chemistry 690 (2005) 5832–5840
[26] L.M. Alcazar-Roman, J.F. Hartwig, J. Am. Chem. Soc. 123
(2001) 12905.
[27] For a recent example in palladium catalyzed arylation of indoles
see: B.S. Lane, M.A. Brown, D. Sames, J. Am. Chem. Soc. 127
(2005) 8050.
[28] Efforts to reduce catalyst loadings and include a wider array of
non-activated chlorides (especially ortho-substituted) are being
undertaken. Analysis of factors governing the mechanism at play
is also being conducted.
[29] G. Bertrand, J. Am. Chem. Soc. 127 (2005).
[30] (a) For synthesis of carbenes see: M.S. Viciu, O. Navarro, R.F.
Germaneau, R.A. Kelly, W. Sommer, N. Marion, E.D. Stevens,
L. Cavallo, S.P. Nolan, Organometallics 23 (2004) 1629;
(b) A.J. Arduengo III, R. Krafczyk, R. Schmutzler, A. Craig, A.
Hugh, J.R. Goerlich, J.M. William, M. Unverzagt, Tetrahedron
55 (1999) 14523;
(e) A.J. Arduengo III, S.F. Gamper, J.C. Calabrese, F.J.
Davidson, J. Am. Chem. Soc. 116 (1994) 4391;
(f) A.J. Arduengo, R.L. Harlow, M. Kline, J. Am. Chem. Soc.
113 (1991) 361.
[31] D.A. Culkin, J.F. Hartwig, J. Am. Chem. Soc. 123 (2001)
5816.
[32] H.C. Bell, J.T. Pinhey, S. Sternhell, Aust. J. Chem. 35 (1982)
2237.
[33] K.C. Nicolaou, T. Montagnon, P.S. Baran, Y.-L. Zhong, J. Am.
Chem. Soc. 124 (2002) 2245.
[34] S. Nakamura, M. Kaneeda, K. Ishihara, H. Yamamoto, J. Am.
Chem. Soc. 122 (2000) 8120.
[35] K. Hino, Y. Nagai, H. Uno, Y. Masuda, M. Oka, T. Karasawa,
J. Med. Chem. 31 (1988) 107.
[36] P. Nilsson, M. Larhed, A. Hallberg, J. Am. Chem. Soc. 23 (2001)
8217.
(c) P.L. Arnold, F.G.N. Cloke, T. Geldbach, P.B. Hitchcock,
Organometallics 18 (1999) 3228;
[37] P.J. Wagner, B. Zhou, J. Am. Chem. Soc. 110 (1988)
611.
(d) A.J. Arduengo III, F. Davidson, R. Krafczyk, W.J. Marshall,
M. Tamm, Organometallics 17 (1998) 3375;
[38] S.S. Hecht, M. Loy, R. Mazzarese, D. Hoffmann, J. Med. Chem.
21 (1978) 38.