Pd-catalyzed carbonylative α-arylation of aryl bromides: Scope and mechanistic studies

Article abstract of DOI:10.1002/chem.201303384

Reaction conditions for the three-component synthesis of aryl 1,3-diketones are reported applying the palladium-catalyzed carbonylative α-arylation of ketones with aryl bromides. The optimal conditions were found by using a catalytic system derived from [Pd(dba)₂] (dba=dibenzylideneacetone) as the palladium source and 1,3-bis(diphenylphosphino)propane (DPPP) as the bidentate ligand. These transformations were run in the two-chamber reactor, COware, applying only 1.5 equivalents of carbon monoxide generated from the CO-releasing compound, 9-methylfluorene-9-carbonyl chloride (COgen). The methodology proved adaptable to a wide variety of aryl and heteroaryl bromides leading to a diverse range of aryl 1,3-diketones. A mechanistic investigation of this transformation relying on ³¹P and ¹³C NMR spectroscopy was undertaken to determine the possible catalytic pathway. Our results revealed that the combination of [Pd(dba)₂] and DPPP was only reactive towards 4-bromoanisole in the presence of the sodium enolate of propiophenone suggesting that a [Pd(dppp)(enolate)] anion was initially generated before the oxidative-addition step. Subsequent CO insertion into an [Pd(Ar)(dppp)(enolate)] species provided the 1,3-diketone. These results indicate that a catalytic cycle, different from the classical carbonylation mechanism proposed by Heck, is operating. To investigate the effect of the dba ligand, the Pd⁰ precursor, [Pd(η³-1-PhC ₃H₄)(η⁵-C₅H₅)], was examined. In the presence of DPPP, and in contrast to [Pd(dba)₂], its oxidative addition with 4-bromoanisole occurred smoothly providing the [PdBr(Ar)(dppp)] complex. After treatment with CO, the acyl complex [Pd(CO)Br(Ar)(dppp)] was generated, however, its treatment with the sodium enolate led exclusively to the acylated enol in high yield. Nevertheless, the carbonylative α-arylation of 4-bromoanisole with either catalytic or stoichiometric [Pd(η³-1-PhC₃H₄) (η⁵-C₅H₅)] over a short reaction time, led to the 1,3-diketone product. Because none of the acylated enol was detected, this implied that a similar mechanistic pathway is operating as that observed for the same transformation with [Pd(dba)₂] as the Pd source. CO-operation is the key! The first palladium-catalyzed carbonylative α-arylation of aryl bromides is described. A wide array of different aryl 1,3-diketones can be isolated in good-to-excellent yields using only stoichiometric amounts of CO (see scheme). A mechanistic study is presented that suggests the need for enolate coordination prior to oxidative addition when [Pd(dba)₂] is employed as the precatalyst. Copyright

Full text of DOI:10.1002/chem.201303384

DOI: 10.1002/chem.201303384
Pd-Catalyzed Carbonylative a-Arylation of Aryl Bromides: Scope and
Mechanistic Studies
Dennis U. Nielsen,[a] Camille Lescot,[a] Thomas M. Gøgsig,*[a]
Anders T. Lindhardt,*[b] and Troels Skrydstrup*[a]
Abstract: Reaction conditions for the
three-component synthesis of aryl 1,3-
diketones are reported applying the
palladium-catalyzed carbonylative a-ar-
ylation of ketones with aryl bromides.
The optimal conditions were found by
using a catalytic system derived from
13C NMR spectroscopy was undertaken
to determine the possible catalytic
pathway. Our results revealed that the
[Pd(h3-1-PhC3H4)
ined. In the presence of DPPP, and in
contrast to [Pd(dba)2], its oxidative ad-
dition with 4-bromoanisole occurred
smoothly providing the [PdBr(Ar)-
(h5-C5H5)], was exam-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
combination of [Pd
N
was only reactive towards 4-bromoani-
sole in the presence of the sodium eno-
late of propiophenone suggesting that
AHCTUNGTRENNUNG
[Pd
(dba)2]
(dba=dibenzylideneace-
a [Pd
(dppp)(enolate)] anion was ini-
ACHTUNGTRENNUNG
tone) as the palladium source and 1,3-
bis(diphenylphosphino)propane (DPPP)
as the bidentate ligand. These transfor-
mations were run in the two-chamber
tially generated before the oxidative-
addition step. Subsequent CO insertion
into an [Pd(Ar)ACTHNUTRGENNUG(dppp)ACHTUNGTREN(NGUN enolate)] spe-
cies provided the 1,3-diketone. These
results indicate that a catalytic cycle,
different from the classical carbonyla-
tion mechanism proposed by Heck, is
operating. To investigate the effect of
the dba ligand, the Pd0 precursor,
treatment with the sodium enolate led
exclusively to the acylated enol in high
yield. Nevertheless, the carbonylative
a-arylation of 4-bromoanisole with
either catalytic or stoichiometric
reactor,
COware,
applying
only
1.5 equivalents of carbon monoxide
generated from the CO-releasing com-
[Pd(h3-1-PhC3H4)
A
a
short reaction time, led to the 1,3-dike-
tone product. Because none of the acy-
lated enol was detected, this implied
that a similar mechanistic pathway is
operating as that observed for the
pound,
9-methylfluorene-9-carbonyl
chloride (COgen). The methodology
proved adaptable to a wide variety of
aryl and heteroaryl bromides leading
to a diverse range of aryl 1,3-diketones.
Keywords: 1,3-diketones · carbony-
lation · palladium · reaction mecha-
nisms · synthetic methods
same transformation with [Pd
the Pd source.
ACHTUNGRTEN(NUNG dba)2] as
A
mechanistic investigation of this
transformation relying on 31P and
Introduction
tional groups.[1] Nevertheless, there is still a constant strive
dedicated to the development of new carbonylative transfor-
mations, as well as to the improvement of existing Pd-cata-
lyzed carbonylations, including the identification of milder
reaction conditions, alternative substrates, and the use of
lower carbon monoxide pressures.[2] A number of research
groups have been highly active in this field and have demon-
strated great success including those of Beller,[3] Buchwald,[4]
and Larhed.[5] Nevertheless, a particular but important draw-
back when working with this gaseous reagent is its inherent
toxicity resulting in asphyxiation upon its inhalation due to
the high competitive binding between CO and oxygen to he-
moglobin. Hence, there have been some efforts undertaken
toward the development of safer alternatives for the han-
dling of this “synthetically” useful diatomic gas, and in this
respect a variety of CO-releasing molecules (CORMs) have
proven useful.[6]
The palladium-catalyzed carbonylative coupling between an
aryl halide (or a derivatized phenol), with a carbon- or het-
eroatom-based nucleophile represents a powerful method
for the generation of a diverse array of benzoic acid and
aryl ketone derivatives. The method has shown high interest
because of its high compatibility to a wide variety of func-
[a] D. U. Nielsen, Dr. C. Lescot, Dr. T. M. Gøgsig, Dr. T. Skrydstrup
Center for Insoluble Protein Structures (inSPIN)
Interdisciplinary Nanoscience Center (iNANO)
Department of Chemistry Aarhus University
Gustav Wieds Vej 14, 8000 Aarhus C (Denmark)
E-mail: ts@chem.au.dk
[b] Dr. A. T. Lindhardt
Interdisciplinary Nanoscience Center (iNANO)
Biological and Chemical Engineering
Department of Engineering, Aarhus University
Finlandsgade 22, 8200 Aarhus N (Denmark)
E-mail: lindhardt@chem.au.dk
In 2011, we reported a methodology for the controlled lib-
eration of carbon monoxide by the activation of two crystal-
line and readily available CORMs, namely 9-methylfluor-
ene-9-carbonyl chloride (COgen) and diphenylmethylsilacar-
boxylic acid.[7] This controlled CO generation could be
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201303384.
17926
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 17926 – 17938

FULL PAPER
adapted to carbonylation reactions by using a two-chamber
reactor (COware), in which CO is generated in the first
chamber from one of the two CORMs, and then consumed
in the second chamber in an ensuing Pd-catalyzed carbony-
lation. In particular, we found that the ex situ generation of
only stoichiometric amounts of CO was sufficient to provide
high coupling yields in a variety of these metal-catalyzed
carbonylation reactions, including alkoxy-, amino- and thio-
carbonylations, carbonylative Heck, Sonogashira and
Suzuki, reductive formylations, and others.[7–9] Furthermore,
the method was well-adapted to isotope-labeling studies for
the incorporation of 13C- and 14C-carbon isotopes.[9]
Furthermore, a number of 1,3-diketones display a variety
of biological activities, including antitumor, antioxidant, an-
timicrobial, antiviral, and antifungal activity.[13a] Of particu-
lar interest is the fact that our method is highly adaptable
for the 13C-labeling of these biologically important struc-
tures. Prior to our work, Tanaka and Kobayashi had suc-
cessfully identified conditions for the intermolecular carb-
onylative a-arylation of malonates with aryl iodides
(Scheme 3a).[15] However, besides the use of high carbon
By utilizing this strategy, we recently reported on the Pd-
catalyzed carbonylative coupling between an aryl ketone
and an aryl iodide for the preparation of a number of func-
tionalized aryl 1,3-diketones (Scheme 1).[8f]
Scheme 1. The Pd-catalyzed carbonylative a-arylation of ketones with
aryl iodides.
Scheme 3. a) Summary of Tanaka and Kobayashiꢁs previous carbonylative
a-arylation studies; b) Bellerꢁs synthesis of vinyl benzoates.
This transformation represents a carbonylative analogue
to the well-established catalytic a-arylation of ketones,
esters, amides and other enolizable reagents, pioneered by
the groups of Hartwig and Buchwald.[10,11] The general inter-
est in these compounds is underlined by their various trans-
formations alone in 2012 utilizing a 1,3-keto carbonyl deriv-
ative for the preparation of heterocyclic systems, such as iso-
xazoles, pyrazoles, pyrimidines, and isocoumarins, represen-
tative examples of which are illustrated in Scheme 2.[12–14]
monoxide pressures (20 atm), when simple ketones were
employed, only the acylated enol was obtained. Beller and
co-workers have recently published a general method for
the synthesis of such structures from the corresponding aryl
iodides and bromides (Scheme 3b).[3t]
In this paper, we report on the successful identification of
reaction conditions, which include aryl bromides as viable
electrophiles for the Pd-catalyzed synthesis of aryl 1,3-dike-
tones. This work significantly extends the value of this reac-
tion due to the high number of commercially available aryl
bromides. Moreover, we have carried out a mechanistic in-
vestigation of this Pd-catalyzed transformation by using 31P
and 13C NMR spectroscopy to identify the plausible inter-
mediates of the catalytic cycle and hence the pathway that is
followed for the generation of these dicarbonyl compounds.
Our results suggest that an alternative catalytic cycle to that
of the traditional Heck-type mechanism is operating when
employing sodium enolates in this palladium-catalyzed car-
bonylative reaction. Our data imply that a pre-coordination
of an enolate to the Pd0 species takes place prior to the oxi-
dative addition generating an [Pd(Ar)
ACHUTGTNRENN(GU ligand)HCATUNGTREN(NGUN enolate)]
Scheme 2. Recent synthetic applications of 1,3-diketones.
complex prior to CO insertion and reductive elimination.
Chem. Eur. J. 2013, 19, 17926 – 17938
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
17927

T. Gøgsig, A. T. Lindhardt, T. M. Skrydstrup, et al.
Table 1. Optimization of the carbonylative a-arylation with 4-bromoani-
Results and Discussion
sole.[a]
Carbonylative coupling with aryl bromides: In our initial
report on the Pd-catalyzed carbonylative a-arylation of aryl
iodides applying [PdACHTNUTRGNE(NUG dba)2] as the palladium(0) source, 1,1’-
bis(diisopropylphosphino)ferrocene (DiPrPF) as a bidentate
diphosphine ligand, CO (1.5 equiv) and a sodium amide
base (2 equiv) in THF, we found that 4-bromoanisole could
also be coupled to ethylphenylketone under the same condi-
tions providing the 1-(4-methoxyphenyl)-2-methyl-3-phenyl-
propane-1,3-dione (1). The reaction proved nonetheless to
be sluggish and led only to a 65% conversion after a reaction
time of 42 h (Scheme 4). Optimization of the reaction pa-
Entry Pd source
Ligand
[(mol%)]
Conv. Ratio
Yield
[%][c]
G
[%][b]
ACHTUNGTNER[NUNG 1:2]
1
2
3
[Pd
[PdCl
[PdCl
G
DiPrPF (3.6)
DiPrPF (3.6)
100
100
100
100
100
100
100
100
100
50
93:7 73
87:13 –
91:9 67
90:10 50
86:14
91:9
E
G
E
A
4
5
6
7
8
9
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
N
DiPrPF (3.6)
DPPF (3.6)
–
–
–
–
–
–
tBuPPF (3.6)
DtBuPF (3.6)
BINAP (3.6)
Xantphos (3.6)
DPPE (3.6)
DPPP (3.6)
5:95
81:19
89:11
>95:5
10
11
12
13
14[e,f]
90
91:9 68
HBF4P
N
100
<5:95
36:64
–
–
Scheme 4. Preliminary result on the carbonylative a-arylation of an aryl
bromide.
CataCXium A (7.2) 100
DPPP (3.6) 100
>95:5 79
[a] General conditions: Chamber A: COgen[16] (182 mg, 0.75 mmol), [Pd-
(dba)2] (4.3 mg, 1 mol%), HBF4P(tBu)3 (2.2 mg, 1 mol%), DIPEA
A
ACHTUNGTRENNUNG
(195 mL, 1.5 equiv), and dioxane (3 mL). Chamber B: 4-bromoanisole
(93.5 mg, 0.5 mmol), Pd0 or PdII, ligand, NaHMDS (183 mg, 2.0 equiv),
propiophenone (148 mg, 2.2 equiv), and dioxane (3 mL). Reaction time:
17 h. [b] Determined by 1H NMR spectroscopic analysis. [c] Yield of the
isolated product. [d] cod=1,5-cyclooctadiene. [e] NaHMDS (202 mg,
2.2 equiv). [f] Reaction temperature increased to 908C.
rameters was therefore carried out (Table 1). It should be
noted that all reactions were run in a two-chamber reactor
(COware) as previously described,[7a] and the stoichiometric
carbon monoxide used was generated ex situ applying the
Pd0-catalyzed decarbonylation of 9-methylfluorene-9-car-
bonyl chloride (COgen).[16]
Two products were observed during the optimization; the
desired 1,3-diketone 1 and the direct coupling product 2.
Applying the same reaction conditions as for the aryl io-
dides, albeit increasing the reaction temperature to 808C
and exchanging the solvent from THF (b.p.=668C) to
a higher boiling solvent such as dioxane (b.p.=1018C), re-
sulted in full conversion and a good 93:7 selectivity for car-
bonylation over direct coupling. This led to the isolation of
diketone 1 in a 73% yield (Table 1, entry 1). Variation of
the palladium source did not improve the selectivity
(Table 1, entries 2–4). Applying different phosphinoferro-
cene-based ligands gave similar product selectivities
(Table 1, entries 5 and 6), whereas with DtBuPF instead of
DiPrPF, this resulted in almost complete inversion of the
product selectivity with a preference for compound 2
(entry 7). Hartwig and co-workers have previously reported
the use of this more sterically encumbered ligand in a-aryla-
tions.[10f] Other diphosphine ligands such as BINAP and
Xantphos proved inferior to DiPrPF also with respect to the
product preference (Table 1, entries 8 and 9). On the other
hand, with 1,2-bis(diphenylphosphino)ethane (DPPE) as the
ligand, the reaction proved to be much cleaner than for the
corresponding reaction with DiPrPF (Table 1, entry 10).
Only the desired product 1 was formed, although the con-
version was low. Exchanging DPPE for 1,3-bis(diphenyl-
phosphino)propane (DPPP), which has a slightly larger bite-
angle,[17] led to a modest drop in the selectivity for carbony-
lative a-arylation, but greatly improved the conversion, and
a 68% yield of the diketone 1 could be isolated after
column chromatography (Table 1, entry 11). This selectivity
and the conversion could be improved by slightly increasing
the number of equivalents of sodium bis(trimethylsilyl)a-
mide (NaHMDS) to match that of propiophenone and ele-
vating the reaction temperature to 908C. In this way, com-
pound 1 could be isolated in 79% yield (Table 1, entry 14).
Exploring the possibility of using bulky monodentate phos-
phine ligands such as cataCXium A and PACTHNUTRGENUG(N tBu)3 favored the
undesired product 2 (Table 1, entries 12 and 13).[10f]
With the appropriate conditions in hand for the carbony-
lative a-arylations of 4-bromoanisole, we next turned to ex-
amine the feasibility of these reaction conditions in the car-
bonylative coupling of propiophenone with other aryl bro-
mides (Table 2). Bromobenzene worked well providing the
symmetrical diketone 3 in a 78% yield (Table 2, entry 1).
The ortho-substituents were well tolerated and good cou-
pling yields were obtained as illustrated with compounds 4,
6, and 8. Aryl bromides carrying electron-donating groups
coupled smoothly, and the corresponding 1,3-diketones
could in general be isolated in high yields (4–10), but with
a (S)-trifluoromethylsulfide group in the para position, as
with 11, only a modest yield could be secured. Applying aryl
bromides bearing electron-withdrawing groups proved suc-
cessful (12–16), and the presence of a chloride was even
17928
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 17926 – 17938

Pd-Catalyzed Carbonylative a-Arylation
FULL PAPER
Table 2. The carbonylative a-arylation of aryl bromides with propiophenone.[a]
Entry
1
Product
Yield[b] [%]
78
Entry
8
Product
Yield[b] [%]
72
2
3
77
86
9
46
77
10
4
5
6
7
64
75
89
75
11
12
13
14
76
35
68
60
[a] General conditions: Chamber A: COgen[16] (182 mg, 0.75 mmol), [Pd
1.5 equiv), and dioxane (3 mL). Chamber B: Aryl bromide (0.5 mmol), [Pd
2.2 equiv), propiophenone (145 mg, 2.2 equiv), and dioxane (3 mL). Reaction time: 17 h. [b] Yield of the isolated product.
A
ACHTUNGRTEN(NUNG tBu)3 (2.2 mg, 1 mol%), DIPEA (195 mL,
AHCTUNGTRENNUNG
inert to these carbonylative coupling conditions as shown
for product 13. However, considerable byproducts were ob-
served in the coupling of 4-cyanophenyl bromide (Table 2,
entry 12), which explains the low carbonylative coupling
yield obtained for the diketone 14.
As shown in Table 3, different heterocyclic aryl bromides
could also be applied to give the corresponding 1-heteroar-
yl-2-phenyl-1,3-diketones. Oxygen-based heterocycles, such
the carbonylative coupling with an aryl bromide (Scheme 5).
As with propiophenone, its homologues, butyrophenone and
butyrothiophenone, also provided good coupling yields of
the corresponding 1,3-diketones 24 and 25, respectively.
Even aliphatic ketones such as 2-methyl-3-heptanone, 3-pen-
tanone, and methyl adamantyl ketone proved feasible for
the carbonylative a-arylations (26–28). On the other hand,
increasing the sterical bulk on the b-carbon of the ketone
such as with 3-methyl-1-phenylbutan-1-one and 1,2-di-
as 6-bromo-2,3-dihydrobenzo[b]ACTHUNTGRNEUNG[1,4]dioxine and 5-bromo-
2,3-dihydrobenzofuran, coupled well providing 17 and 18,
respectively, in good yields. Sulfur-containing ring systems,
represented by a 5-bromobenzo[b]thiophene and 2-bromo-
thiophene, were also adaptable to the coupling conditions,
leading to 19 and 20, respectively, although 20 was isolated
in a low yield due to competition with the direct coupling
pathway. Finally, applying the pyridine, quinolone, and iso-
quinoline skeleton, the corresponding 1,3-diketones (21–23,
respectively) could be isolated in reasonable yields.
phenylACTHNGUTEReNNUG thanone proved detrimental for 1,3-diketone forma-
tion (results not shown). Employing acetophenone led to 29
being isolated in a low yield of only 15%.[3y] This could be
explained by the simultaneous formation of different by-
products related to the higher reactivity of the correspond-
ing less sterically encumbered sodium enolate.
Mechanistic investigations: Having identified reaction condi-
tions that include aryl bromides in the repertoire for the Pd-
catalyzed carbonylative a-arylation of ketones, a mechanistic
study was undertaken in an attempt to understand the
A few ketones were then tested to investigate the struc-
tural influence of this coupling partner on the efficiency of
Chem. Eur. J. 2013, 19, 17926 – 17938
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
17929

T. Gøgsig, A. T. Lindhardt, T. M. Skrydstrup, et al.
Table 3. The carbonylative a-arylation of heterocyclic bromides with pro-
nation and insertion generates an acylpalladium(II) com-
plex. Depending on the reactivity of the nucleophile, this re-
agent can either participate directly by nucleophilic acyl
substitution with the acyl-PdII complex to generate the prod-
uct and Pd0, or by exchange with the leaving group on the
metal center and a subsequent reductive elimination step.
Recently, Lei and co-workers reported kinetic evidence
for an alternative mechanism when studying the palladium-
catalyzed alkoxycarbonylation of aryl iodides with sodium
alkoxides instead of the corresponding alcohols in the pres-
ence of a secondary or tertiary amine base.[19] The catalytic
cycle for these carbonylations proceeds through an initial
oxidative addition with the aryl iodide and then halide–alk-
oxide exchange on the resulting arylpalladium(II) complex
to generate an [Pd(Ar)(OR)] species. This is followed by
piophenone.[a]
Entry
1
Product
Yield[b] [%]
72
2
3
4
5
6
80
70
36
44
63
À
CO insertion into the Pd O bond, and finally reductive
elimination of the intermediate [Pd(Ar)
A
ate ArCOOR. Considering the use of preformed sodium
enolates in our Pd-catalyzed carbonylative a-arylation pro-
tocol, we speculated whether the Lei mechanism could be
operating as well for this catalytic transformation.
The two hypothetical pathways for the carbonylative a-ar-
ylation of ketones are illustrated in Scheme 6. Path 1 repre-
sents the classical Heck mechanism involving initial oxida-
tive addition of the aryl bromide followed by CO insertion
7
70
[a] For general conditions, see Table 2. [b] Isolated Yields.
Scheme 6. Two different pathways considered for the carbonylative a-ar-
ylation of ketones.
to form the benzoylpalladium(II) complex B. Ligation of the
enolate to the PdII-center followed by reductive elimination
or direct nucleophilic acyl substitution would then lead to
1,3-diketone formation. The other possibility (Path 2), in-
spired by the work of Lei and co-workers, involves the liga-
tion of the enolate first to complex A, leading to intermedi-
ate C as either the C- or O-bound-PdII complex. Subsequent
CO insertion and reductive elimination provides the desired
product.
Scheme 5. The carbonylative a-arylation of 4-bromoanisole with ketones.
nature of the intermediates in the catalytic cycle of this
transformation. The generally accepted mechanism for Pd-
catalyzed carbonylation reactions involving an aryl halide
and a nucleophile consists of three principle steps.[18] First,
oxidative addition of the aryl halide followed by CO coordi-
17930
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 17926 – 17938

Pd-Catalyzed Carbonylative a-Arylation
FULL PAPER
The earlier screening studies revealed that among the dif-
phosphine ligands in the oxidative-addition process. They
ferent metal sources examined, [Pd
deneacetone) was found to be the most effective for the cat-
alytic reaction; hence, stoichiometric experiments with [Pd-
(dba)2] (dba=dibenzyli-
described that the palladium(0) complexes [Pd
(D) and [Pd(dppp)2] (E) were obtained from the addition of
1 equivalent of the diphosphine ligand to [Pd
(dba)2],[22] and
ACHUTGTNREN(NUG dba)ACHTUNGTRENNUNG(dppp)]
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
furthermore determined that D is the active complex for ox-
idative addition to phenyl iodide, whereas complex E is in-
active. When [PdACTHNUTRGNE(UNG dba)2], DPPP, and 4-bromoanisole were
propiophenone with 4-bromoanisole, with the objective of
identifying the intermediate complexes involved. Initially,
[Pd
(dba)2] was subjected to 1 equivalent of DPPP, 1.6 equiv-
stirred at 908C for 1 h in dioxane ([Eq. (2)], Scheme 7), and
the reaction mixture was analyzed by 31P NMR spectrosco-
py, the product of oxidative addition, complex A, could not
be observed by NMR spectroscopy, even after increasing
the aryl bromide addition to 100 equivalents.[23] Instead, two
broad signals at d=13.4 and 8.6 ppm of equal integration
were observed along with a singlet at d=4.1 ppm (Figure 1,
top spectrum). These signals correspond well to those of the
31P NMR spectrum of the nonsymmetrical Pd0 species D and
the symmetrical complex E, respectively, reported earlier by
Amatore and Jutand in THF.[22,24]
alents of 4-bromoanisole and 2.2 equivalents of the sodium
enolate of propiophenone in the two-chamber system with
4.0 equivalents of CO ([Eq. (1)], Scheme 7). This reaction
was performed to ascertain if the diketone could be generat-
ed from the stoichiometric reaction. Indeed, after 30 min at
908C followed by a work up, the diketone 1 could be isolat-
ed in a 47% yield.[20,21]
Efforts were then concentrated on isolating the oxidative-
addition complex A, which is the common denominator for
the two different pathways. Earlier, Amatore and Jutand
studied the rates and mechanism of the palladium species
Although no oxidative addition was observed for 4-bro-
moanisole, this process nevertheless occurs under catalytic,
as well as the stoichiometric
generated in situ from mixtures of [PdACTHNUTRGENUN(G dba)2] and bidentate
conditions, in the presence of
all reagents. Hence, the influ-
ence of the presence of the
sodium enolate for the oxida-
tive addition was investigated.
As shown in Equation (3) in
Scheme 7, the sodium enolate
of propiophenone was intro-
duced together with [PdACHTUNGTRENNUNG(dba)2]
and DPPP in dioxane, and the
solution was analyzed by
31P NMR spectroscopy after
15 min at 258C (Figure 1,
bottom spectrum). Whereas the
[PdACTHNUTRGENN(UG dba)CAHUTNGTREN(NUGN dppp)] signals had
disappeared, two new signals
were observed at d=11.5 and
8.9 ppm corresponding to a new
nonsymmetrical palladium com-
plex F. On the other hand, the
singlet for [PdACHTNUGTRENUNG(dppp)2] re-
mained at d=4.1 ppm. The aryl
bromide and subsequently CO
were introduced to this new
species F, and the reaction mix-
ture was heated to 908C for
30 min. Diketone 1 and ketone
2 were produced in a 7:3 ratio
with a 90% conversion accord-
ing to the 1H NMR spectral
analysis of the crude product
mixture.
This experiment suggests that
the enolate is required to gener-
ate an active Pd0 species capa-
ble of undergoing fast oxidative
Scheme 7. Stoichiometric studies applying [PdACTHNUGTRNEUNG(dba)2] for the carbonylative a-arylation of propiophenone.
Chem. Eur. J. 2013, 19, 17926 – 17938
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
17931

T. Gøgsig, A. T. Lindhardt, T. M. Skrydstrup, et al.
4-bromoanisole to F, the reaction mixture was heated to
908C for 5 min. Although we observed the disappearance of
F in the 31P NMR spectrum, we were not able to character-
ize other species in the spectrum implying that the product
of oxidative addition is not stable. Temperature variation ex-
periments were also conducted to follow the transformation
of F into the oxidative-addition complex by using NMR
spectroscopy. The 31P NMR spectra were recorded with 58C
intervals in range of 25 to 908C. Again, no clear signals
were observed at the intervals between 25–608C and the
peaks corresponding to complex F were still detectable. In-
creasing the temperature beyond this point resulted in
a poorly defined spectrum with only the [PdACTHNURGTNEUNG(dppp)2] com-
plex remaining at 808C according to the 31P NMR spectrum.
Nevertheless, the oxidative addition had occurred because
1
the crude H NMR spectrum of the sample showed the for-
mation of the direct coupling product 2 (results not shown).
We then attempted to employ the sodium enolate derived
from acetophenone because of its potentially higher reactivi-
ty compared with propiophenone and therefore its ability to
form the oxidative-addition complex at lower reaction tem-
peratures. A similar temperature variation experiment was
conducted from 25 to 608C (Figure 3). Gratifyingly,
a smooth transition was observed for the complex [Pd-
ACHUTNGREN(NUG dppp)CAHTUNGTRNE(NUGN enolate)] (F’) present at 258C into a new species G’,
which was completed at 608C. Complex G’ appeared to be
stable and after recooling to 258C another 31P NMR spec-
Figure 1. 31P NMR spectra of the palladium(0) species D, E, and F.
addition with 4-bromoanisole. We propose that F is an
anionic Pd0 complex of the corresponding enolate in equilib-
rium between the O bond- and the C bond-forms of the
complex (Figure 2).
Figure 2. Proposed structure for intermediate F.
That complex F is more active towards oxidative addition
with 4-bromoanisole than the corresponding neutral com-
plex Dis coherent with earlier results reported by Amatore
and Jutand in their work on deciphering the role and posi-
tive effects of halide ion or acetate addition on the rates of
oxidative addition of low ligated Pd0 complexes with phenyl
iodide.[25] In this work, anionic Pd0 complexes, formed from
halide or acetate coordination to Pd0, were identified and
found to be more reactive towards oxidative addition with
aryl halides than their equivalent neutral species.
The same experiment was repeated without the addition
of carbon monoxide, to characterize the oxidative-addition
product generated from the reaction of 4-bromoanisole with
the intermediate F ([Eq. (4)], Scheme 7). After addition of
Figure 3. 31P NMR temperature experiment using an acetophenone-de-
rived enolate.
17932
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 17926 – 17938

Pd-Catalyzed Carbonylative a-Arylation
FULL PAPER
Although our studies on car-
bonylative a-arylation with [Pd-
AHCTUNRTGEG(NUNN dba)2] did not reveal the
nature of the Pd-acyl complex
in the catalytic cycle, these stoi-
chiometric experiments did
point to the importance of
a
possible Pd0 anion with
a bound enolate, necessary for
promoting the oxidative addi-
tion to 4-bromoanisole. A cata-
lytic cycle taking this observa-
tion into consideration is illus-
trated in Scheme 9.
Figure 4. 31P NMR of complex G’ at 258C.
trum was recorded (Figure 4). As well as the singlet corre-
sponding to the non-reactive complex E, two doublets were
observed at d=8.0 and 3.4 ppm with an identical P,P cou-
pling constant of 40.7 Hz. The structure of this complex was
attributed to the arylpalladium enolate species G’ ligated
with DPPP (Figure 4). This structure with a C-bound eno-
late is in accord to that previously published by the group of
Hartwig in their study on the reductive elimination of simi-
lar arylpalladium enolate complexes with the bidentate
phosphine ligand 1,2-bis(diphenylphosphino)benzene.[10n] In
this work, the C-bound complex is preferred over the O-
bound complex for the enolate derived from acetophenone.
Heating complex G’ for 1 h at 908C resulted in the forma-
tion of the direct coupling product 30, although the conver-
sion yield was not exceptional (Scheme 8). Adding 13CO to
Scheme 9. Catalytic cycle proposed with [PdACTHNUGTRENUNG(dba)2].
To examine whether this mechanistic pathway was con-
fined only to carbonylative a-arylations using [Pd(dba)2] as
AHCTUNGTRENNUNG
the palladium source, we repeated the aforementioned ex-
periments with a DBA-free palladium(0) precursor. In this
ACTHNUTRGNEUNG
respect, we chose [Pd(h3-1-PhC3H4)(h5-C5H5)] (31) recently
introduced by Baird.[26] This air-stable complex was shown,
upon addition of a wide variety of mono- and bidentate ter-
tiary phosphines, to rapidly and conveniently generate near
quantitative yields of the corresponding bis(phosphine) Pd0
complexes. First, the ability of this complex as an appropri-
ate Pd source for the catalytic transformation was examined.
Hence, treatment of the aryl bromide with 2.2 equivalents of
the preformed sodium enolate of propiophenone in the
presence of 1.5 equivalents of carbon monoxide, complex 31
and DPPP provided an acceptable yield (65%) of the dike-
tone 1 (Scheme 10).
Scheme 8. Reductive elimination studies with complex G’.
complex G’ led to a variety of different 13CO-containing
products observed in the 13C NMR spectrum of the crude re-
action. Nevertheless, it was pleasing to see that a signal at
d=186.3 ppm resulting from the 13C-isotopically labeled 1,3-
diketone 29 could be detected. Whether the acylpalladium
complex is too reactive and results in decomposition or un-
dergoes attack with the excess of enolate, is not clear. Nev-
ertheless, it is interesting to note that for the catalytic car-
bonylative a-arylation of 4-bromoanisole with acetophe-
none, our best yield of the diketone 29 for this reaction was
only 15% (Scheme 5).
As in the studies with [PdACTHNUTRGNE(UGN dba)2], a stoichiometric experi-
ment was performed with propiophenone and 4-bromoani-
sole as shown in [Eq. (1)], Scheme 11. This furnished dike-
tone 1, isolated in 25% yield, as well as 15% of the direct
coupling product 2. In an attempt to identify the oxidative-
addition complex A, complex 31 was mixed with one equiv-
alent of DPPP and 1.6 equivalents of 4-bromoanisole in di-
oxane at 908C for 5 min ([Eq. (2)], Scheme 11). In contrast
Chem. Eur. J. 2013, 19, 17926 – 17938
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
17933

T. Gøgsig, A. T. Lindhardt, T. M. Skrydstrup, et al.
observation confirms that the structure of complex G’ is not
the [PdBr(Ar)ACHTUNTRGNEUNG(dppp)] complex (A) arising from the dis-
placement of the Pd-bound enolate with bromide after oxi-
dative addition. Pleasingly, when the same complex A was
subjected to 13CO and allowed to react for 30 min at 908C,
the resulting benzoylpalladium(II) complex B was formed.
This complex was assigned by 31P and 13C NMR spectrosco-
py (Figure 6). The 31P NMR spectrum revealed two sets of
double doublets at d=9.6 and À10.3 ppm, with a P,P cou-
pling constant of 72 Hz, a cis-P,C coupling constant of
17 Hz, and a trans-P,C coupling constant of 129 Hz. For the
13C NMR spectrum, only a double doublet at d=232.0 ppm
was observed corresponding to the carbonyl shift, with a cis-
and trans-C,P coupling constant of 17 and 129 Hz, respec-
tively.
Scheme 10. Application of complex 31 as a Pd0 precursor in the catalytic
carbonylative a-arylation of propiophenone.
to the non-reactivity of the [PdACHTUNRGTNEUNG(dba)2]/DPPP combination
with 4-bromoanisole, in this case a fast transformation to
a new species was observed after 5 min at 908C. The
31P NMR spectrum displayed two doublets at d=11.6 and
À13.1 ppm with a coupling constant of 51 Hz (Figure 5).
This data matches those reported by Jutand and co-workers
for similar complexes,[22] and hence the structure of this new
Pd species was assigned to complex A. The chemical shifts
of the two doublets in the 31P NMR spectrum of complex A
are quite different from the oxidative-addition product bear-
ing the enolate as observed for complex G’ (Figure 4). This
To study the possible negative influence of the presence
of the DBA ligand on the oxidative-addition step, an experi-
ment was performed in which complex 31, DPPP (1 equiv),
and 4-bromoanisole (1.6 equiv) were mixed together with
two equivalents of DBA at 908C in dioxane for 10 min
([Eq. (3)], Scheme 11). According to the 31P NMR spectrum
of the reaction mixture, this resulted in the formation of the
Pd0 complexes D and E as earlier observed with [Pd
ACHTUNGTRENNUNG(dba)2].
Again, no oxidative-addition
product A was observed, imply-
ing that the complexes D and E
are rapidly formed preventing
the oxidative-addition step.
With the ability to generate
the acyl-PdII complex B, we
subjected this organometallic
species to 2.2 equivalents of the
sodium enolate of propiophe-
none ([Eq. (4)], Scheme 11).
Strikingly, after heating at 908C
for 30 min and after work up,
the 1,3-diketone 1 was not ob-
served, but rather the vinyl ben-
zoate 32 in a good (70%) yield.
No trace of compound 1 could
be detected in the crude prod-
uct mixture upon 1H NMR
analysis. The vinyl benzoate
was undoubtedly formed by an
alkoxycarbonylation mechanism
with the sodium enolate, either
by direct attack of the oxygen
nucleophile to the acyl carbonyl
of complex B or through reduc-
tive elimination of an inter-
mediate acyl-Pd complex with
an O-bound enolate. This result
is interesting in light of the out-
come from the Pd-catalyzed
carbonylative a-arylation of
propiophenone and 4-bromo-
Scheme 11. Stoichiometric studies applying complex 31 for the carbonylative a-arylation of propiophenone.
ACHTUNGTNERaNUNG nisole promoted by the metal
17934
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 17926 – 17938

Pd-Catalyzed Carbonylative a-Arylation
FULL PAPER
product can be converted to the
desired diketone with excess
enolate, it is not apparent that
this is the mechanism operating
under our catalytic conditions
in which the enolate is present
from the start. Furthermore,
when 4-bromoanisole, DPPP
and 2.2 equivalents of enolate
are added at the same time to-
gether with the complex 31, and
the mixture is submitted to CO
for only 10 min at 908C, a trace
amount of the diketone 1 was
Figure 5. 31P NMR spectrum of complex A[a]
.
1
observed in the crude H NMR
spectrum as indicated by the
signals at d=5.20 ppm (quartet)
from the single a-carbon
proton, and at d=1.59 ppm
(doublet) from the methyl
group. No trace of vinyl ben-
zoate 32 displaying among
other signals at d=6.01 or
1.76 ppm could be detected.
With this in consideration in-
cluding the results from the
above experiment, which led to
the vinyl benzoate 32 in good
yield from the treatment of 2.2
equivalents of enolate with the
acyl-PdII complex (13C–B in
[Eq. (4)], Scheme 11), these ob-
servations tend to lean towards
the absence of a mechanism in-
volving the formation of com-
plex B, and instead a mechanism
in which the 1,3-diketone is
formed directly from a catalytic
cycle as proposed in the case of
Figure 6. a) 31P NMR spectrum of B with H3PO4 in CDCl3 using H3PO4 as external standard. b) 13C NMR spec-
trum of complex B in CDCl3, 13CO signal.
[PdACHTNUTGREN(UNG dba)2]. Further studies
must be performed to provide
convincing evidence of this pro-
posal, but the above results do
complex 31, generating exclusively the diketone 1 in a 65%
yield. We hypothesized therefore that the formation of
1 could result from the reaction of vinyl benzoate 32 with
excess enolate as would be the situation in the catalytic re-
action. Repeating the same experiment with 4.2 equivalents
of enolate, as shown in Scheme 11 [Eq. (5)], led to full con-
version after 30 min at 908C and only provided diketone
1 in a 34% yield. Furthermore, subjecting the vinyl ben-
zoate to 1.0 equivalent of the sodium enolate of propiophe-
none overnight at 908C in dioxane led to full conversion to
reveal the potential pitfalls of the premature assignment of
an intermediate in the catalytic cycle and thereby a possible
description of an incorrect catalytic cycle.
Conclusion
We have identified reaction conditions for the three-compo-
nent synthesis of aryl 1,3-diketones from the palladium-cata-
lyzed carbonylative a-arylation of ketones with aryl bro-
1
the 1,3-diketone according to the H NMR spectrum of the
mides applying a catalytic system generated from [PdACHTUNGTRENNUNG(dba)2]
crude product mixture (result not shown).
Although we prepare the vinyl benzoate in the stoichio-
metric reactions of the preformed acyl complex 31, and this
and the bidentate ligand DPPP. Notably, with this approach
is the ability to run these reactions in the presence of only
stoichiometric amounts of carbon monoxide generated from
Chem. Eur. J. 2013, 19, 17926 – 17938
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
17935

T. Gøgsig, A. T. Lindhardt, T. M. Skrydstrup, et al.
COgen in the two-chamber reactor, COware. The methodol-
ogy proved adaptable to a wide variety of aryl bromides ex-
posing either electron-donating or -withdrawing substituents,
including a number of heteroaryl bromides for accessing a di-
verse range of aryl 1,3-diketones. To provide mechanistic in-
formation of the catalytic cycle, 31P and 13C NMR spectro-
scopic analysis of a series of reactions with stoichiometric
palladium complexes was undertaken. Our results indicated
that a catalytic cycle is operating that is different from the
classical carbonylation mechanism proposed by Heck, and
which involves the initial formation of a Pd0 anion with a C-
or O-bound enolate. Subsequent oxidative addition into the
aryl-halide bond to generate an aryl- and enolate-bound PdII
complex, followed by CO insertion and reductive elimina-
tion generates the desired product. Further work is under-
way to understand the mechanistic pathway of alternative
carbonylative enolate reactions that are being developed in
this group.
[1] For some recent reviews on Pd-catalyzed carbonylations, see: a) X.-
F. Wu, H. Neumann, M. Beller, ChemSusChem 2013, 6, 229–241;
b) X.-F. Wu, H. Neumann, M. Beller, Chem. Rev. 2013, 113, 1–35;
c) X.-F. Wu, H. Neumann, M. Beller, Chem. Soc. Rev. 2011, 40,
4986–5009; d) I. Omae, Coord. Chem. Rev. 2011, 255, 139–160;
e) R. Grigg, S. P. Mutton, Tetrahedron 2010, 66, 5515–5548; f) A.
Brennfꢃhrer, H. Neumann, M. Beller, ChemCatChem 2009, 1, 28–
41; g) C. F. J. Barnard, Organometallics 2008, 27, 5402–5422; h) A.
Brennfꢃhrer, H. Neumann, M. Beller, Angew. Chem. 2009, 121,
4176–4196; Angew. Chem. Int. Ed. 2009, 48, 4114–4133; i) R.
Skoda-Foldes, L. Kollar, Curr. Org. Chem. 2002, 6, 1097–1119; j) I.
Ryu, N. Sonoda, Angew. Chem. 1996, 108, 1140–1157; Angew.
Chem. Int. Ed. Engl. 1996, 35, 1050–1066; k) J.-J. Brunet, R. Chau-
vin, Chem. Soc. Rev. 1995, 24, 89–95; l) M. Beller, B. Cornils, C. D.
Frohning, C. W. Kohlpaintner, J. Mol. Catal. A: Chem. 1995, 104,
17–85.
[2] For discussions on the influence of carbon monoxide pressure, see:
a) C. F. Barnard, Org. Process Res. Dev. 2008, 12, 566–574; b) C. M.
Kormos, N. E. Leadbeater, Synlett 2007, 2006–2010; c) R. GaviÇo, S.
Pellegrini, Y. Castanet, A. Mortreux, O. Mentrꢄ, Appl. Catal. A
2001, 217, 91–99.
[3] For recent contributions from the Beller group, see: a) X.-F. Wu, H.
Neumann, A. Spannenberg, T. Schulz, H. Jiao, M. Beller, J. Am.
Chem. Soc. 2010, 132, 14596–14602; b) X.-F. Wu, H. Neumann, M.
Beller, ChemCatChem 2010, 2, 509–513; c) X.-F. Wu, H. Neumann,
M. Beller, Chem. Eur. J. 2010, 16, 9750–9753; d) X.-F. Wu, H. Neu-
mann, M. Beller, Angew. Chem. 2010, 122, 5412–5416; Angew.
Chem. Int. Ed. 2010, 49, 5284–5287; e) X.-F. Wu, H. Neumann, M.
Beller, Tetrahedron Lett. 2010, 51, 6146–6149; f) X.-F. Wu, H. Neu-
mann, M. Beller, Chem. Eur. J. 2010, 16, 12104–12107; g) X.-F. Wu,
B. Sundararaju, H. Neumann, P. H. Dixneuf, M. Beller, Chem. Eur.
J. 2011, 17, 106–110; h) X.-F. Wu, H. Neumann, M. Beller, Chem.
Eur. J. 2012, 18, 419–422; i) X.-F. Wu, H. Neumann, M. Beller,
Chem. Eur. J. 2012, 18, 12595–12598; j) X.-F. Wu, H. Neumann, M.
Beller, Chem. Asian J. 2012, 7, 282–285; k) H. Neumann, R. Kady-
Experimental Section
General procedure for the formation of 1,3-diketones
1-(4-Methoxyphenyl)-2-methyl-3-phenylpropane-1,3-dione (1): Cham-
ber A: NaHMDS (202 mg, 1.10 mmol, 2.2 equiv) was weighed out in
a glass vial (4 mL) and dissolved in dioxane (1 mL). Propiophenone
(148 mg, 1.10 mmol, 2.2 equiv) dissolved in dioxane (1.0 mL) was added
drop-wise to the NaHMDS solution and the reaction was stirred for
1 hour at room temperature. The solution was added to chamber A of
the two-chamber system containing 1-bromo-4-methoxybenzene
(93.5 mg, 0.50 mmol), DPPP (7.4 mg, 0.018 mmol, 3.6 mol%) and [Pd-
ACHTUNGTRENNUNG(dba)2] (8.6 mg, 0.015 mmol, 3 mol%) in dioxane (1.0 mL). The chamber
was fitted with a Teflon-sealed screwcap.
AHCTUNGERTGrNNUN ov, X.-F. Wu, M. Beller, Chem. Asian J. 2012, 7, 2213–2217; l) X.-F.
Wu, J. Schrank, M. Beller, ChemCatChem 2012, 4, 69–71; m) X.-F.
Wu, H. Neumann, M. Beller, Tetrahedron Lett. 2012, 53, 582–586;
n) X.-F. Wu, H. Neumann, M. Beller, Chem. Eur. J. 2012, 18, 8596–
8599; o) X.-F. Wu, H. Neumann, M. Beller, Chem. Eur. J. 2012, 18,
3831–3834; p) J. Schranck, X.-F. Wu, H. Neumann, M. Beller,
Chem. Eur. J. 2012, 18, 4827–4829; q) X.-F. Wu, J. Schrank, M.
Beller, Chem. Asian J. 2012, 7, 40–44; r) X.-F. Wu, H. Neumann, M.
Beller, Chem. Asian J. 2012, 7, 1199–1285; s) X.-F. Wu, H. Neu-
mann, M. Beller, Chem. Eur. J. 2012, 18, 12599–12602; t) J.
Schranck, A. Tlili, H. Neumann, P. G. Alsabeh, M. Stradiotto, M.
Beller, Chem. Eur. J. 2012, 18, 15592–15597; u) X.-F. Wu, H. Jiao,
H. Neumann, M. Beller, Chem. Eur. J. 2012, 18, 16177–16185;
v) P. G. Alsabeh, M. Stradiotto, H. Neumann, M. Beller, Adv. Synth.
Catal. 2012, 354, 3065–3070; w) X. Fang, M. Zhang, R. Jackstell, M.
Beller, Angew. Chem. 2013, 125, 4743–4747; Angew. Chem. Int. Ed.
2013, 52, 4645–4649; x) X.-F. Wu, M. Sharif, K. Shoaib, H. Neu-
mann, A. Pews-Davtyan, P. Langer, M. Beller, Chem. Eur. J. 2013,
19, 6230–6233; y) J. Schranck, A. Tlili, P. G. Alsabeh, H. Neumann,
M. Stradiotto, M. Beller, Chem. Eur. J. 2013, 19, 12624–12628.
[4] For contributions from the Buchwald group, see: a) J. R. Martinelli,
D. M. M. Freckmann, S. L. Buchwald, Org. Lett. 2006, 8, 4843–4846;
b) J. R. Martinelli, T. P. Clark, D. A. Watson, R. H. Munday, S. L.
Buchwald, Angew. Chem. 2007, 119, 8612–8615; Angew. Chem. Int.
Ed. 2007, 46, 8460–8463; c) R. H. Munday, J. R. Martinelli, S. L.
Buchwald, J. Am. Chem. Soc. 2008, 130, 2754–2755; d) J. R. Marti-
nelli, D. A. Watson, D. M. M. Freckmann, T. E. Barder, S. L. Buch-
wald, J. Org. Chem. 2008, 73, 7102–7107; e) D. A. Watson, X. Fan,
S. L. Buchwald, J. Org. Chem. 2008, 73, 7096–7101.
Chamber B: 9-Methylfluorene-9-carbonyl chloride (COgen; 182 mg,
0.750 mmol, 1.0 equiv), [Pd
ACHTUNGRTEN(NUNG dba)2] (4.3 mg, 0.00750 mmol, 1.0 mol%),
and HBF4P(tBu)3 (2.2 mg, 0.00750 mmol, 1.0 mol%) were added to
ACHTUNGTRENNUNG
chamber B of the two-chamber system and then dissolved in dioxane
(3 mL). Diisopropylethylamine (DIPEA, 195 mL, 1.13 mmol, 1.5 equiv)
was added as the final reagent and the chamber was fitted with a Teflon-
sealed screw-cap.
The two-chamber system was heated at 908C for 17 h. The crude mixture
was quenched with 1m HCl (1.3 mL), extracted with CH2Cl2 (3ꢂ20 mL),
dried over Na2SO4, concentrated in vacuo and purified by flash column
chromatography eluting with pentane/CH2Cl2/Et2O (2:1:3%) affording
106.6 mg (79% yield) of
1
as an yellow oil. 1H NMR (400 MHz,
[D1]CHCl3): d=7.95 (d, J=8.40 Hz, 4H), 7.54 (t, J=7.60 Hz, 1H), 7.44
(t, J=8.00 Hz, 2H), 6.93 (d, J=8.80 Hz, 2H), 5.21 (q, J=7.20 Hz, 1H),
3.85 (s, 3H), 1.59 ppm (d, J=7.20 Hz, 3H); 13C NMR (100 MHz,
[D1]CHCl3): d=197.2, 195.8, 163.8, 135.8, 133.3, 130.9, 128.8 (2 C), 128.6
(2 C), 128.5 (2 C), 114.1 (2 C), 55.5, 51.0, 14.5 ppm; HRMS: m/z calcd
for C17H16O3: 291.0997 [M+Na+]; found: 291.0993.
Acknowledgements
We thank the Danish National Research Foundation (DNRF59), the
Villum Foundation, the Danish Council for Independent Research: Tech-
nology and Production Sciences, the Lundbeck Foundation, the Carlsberg
Foundation, and Aarhus University for generous financial support of this
work.
[5] For contributions from the Larhed group, see: a) N.-F. K. Kaiser, A.
Hallberg, M. Larhed, J. Comb. Chem. 2002, 4, 109–111; b) P.-A. En-
quist, P. Nilsson, M. Larhed, Org. Lett. 2003, 5, 4875–4878; c) J.
Wannberg, M. Larhed, J. Org. Chem. 2003, 68, 5750–5753; d) J.
17936
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 17926 – 17938

Pd-Catalyzed Carbonylative a-Arylation
FULL PAPER
Georgsson, A. Hallberg, M. Larhed, J. Comb. Chem. 2003, 5, 350–
352; e) X. Wu, P. Nilsson, M. Larhed, J. Org. Chem. 2005, 70, 346–
349; f) X. Wu, R. Rçnn, T. Gossas, M. Larhed, J. Org. Chem. 2005,
70, 3094–3098; g) X. Wu, M. Larhed, Org. Lett. 2005, 7, 3327–3329;
h) J. Wannberg, D. Dallinger, C. O. Kappe, M. Larhed, J. Comb.
Chem. 2005, 7, 574–583; i) X. Wu, J. K. Ekegren, M. Larhed, Orga-
nometallics 2006, 25, 1434–1439; j) O. Lagerlund, M. Larhed, J.
Comb. Chem. 2006, 8, 4–6; k) R. K. Arvela, S. Pasquini, M. Larhed,
J. Org. Chem. 2007, 72, 6390–6396; l) L. R. Odell, J. Sꢅvmarker, M.
Larhed, Tetrahedron Lett. 2008, 49, 6115–6118; m) A. Wiꢄckowska,
R. Fransson, L. R. Odell, M. Larhed, J. Org. Chem. 2011, 76, 978–
981; n) P. Nordeman, L. R. Odell, M. Larhed, J. Org. Chem. 2012,
77, 11393–11398.
Hartwig, J. Am. Chem. Soc. 2002, 124, 9330–9331; j) N. A. Beare,
J. F. Hartwig, J. Org. Chem. 2002, 67, 541–555; k) M. Jørgensen, S.
Lee, X. Liu, J. P. Wolkowski, J. F. Hartwig, J. Am. Chem. Soc. 2002,
124, 12557–12565; l) T. Hama, X. Liu, D. A. Culkin, J. F. Hartwig, J.
Am. Chem. Soc. 2003, 125, 11176–11177; m) X. Liu, J. F. Hartwig, J.
Am. Chem. Soc. 2004, 126, 5182–5191; n) D. A. Culkin, J. F. Hart-
wig, Organometallics 2004, 23, 3398–3416; o) T. Hama, D. A.
Culkin, J. F. Hartwig, J. Am. Chem. Soc. 2006, 128, 4976–4985;
p) W. Su, S. Raders, J. G. Verkade, X. Liao, J. F. Hartwig, Angew.
Chem. 2006, 118, 5984–5987; Angew. Chem. Int. Ed. 2006, 45, 5852–
5855; q) X. Liao, Z. Weng, J. F. Hartwig, J. Am. Chem. Soc. 2008,
130, 195–200; r) T. Hama, J. F. Hartwig, Org. Lett. 2008, 10, 1545–
1548; s) T. Hama, J. F. Hartwig, Org. Lett. 2008, 10, 1549–1552;
t) G. D. Vo, J. F. Hartwig, Angew. Chem. 2008, 120, 2157–2160;
Angew. Chem. Int. Ed. 2008, 47, 2127–2130; u) S. Ge, J. F. Hartwig,
J. Am. Chem. Soc. 2011, 133, 16330–16333.
[6] For examples of different CORMs, see: alkyl formates: a) T. Schar-
eina, A. Zapf, A. Cottꢄ, M. Gotta, M. Beller, Adv. Synth. Catal.
2010, 352, 1205–1209; molybdenuym hexacarbonyl, see ref. [5] and:
b) J. Wannberg, M. Larhed, in Modern Carbonylation Methods (Ed.:
L. Kolla), Wiley-VCH, Weinheim, 2008, Chap. 4; c) K. Ikeda, T.
Morimoto, K. Kakiuchi, J. Org. Chem. 2010, 75, 6279–6282. Oxalyl
chloride: d) M. L. N. Rao, V. Venkatesh, P. Dasgupta, Tetrahedron
Lett. 2010, 51, 4975–4980. Lithium formate: e) C. S. Elmore, D. C.
Dean, D. G. Melillo, J. Labelled Compd. Radiopharm. 2000, 43,
1135–1144; f) J. P. Simeone, M. P. Braun, L. Liu, S. R. Natarajan, J.
Labelled Compd. Radiopharm. 2010, 53, 511–516; g) C. S. Elmore,
P. N. Dorff, J. R. Heys, J. Labelled Compd. Radiopharm. 2010, 53,
787–792. Aldehydes: h) T. Morimoto, K. Fuji, K. Tsutsumi, K. Ka-
kiuchi, J. Am. Chem. Soc. 2002, 124, 3806–3807; i) K. Fuji, T. Mori-
moto, K. Tsutsumi, K. Kakiuchi, Angew. Chem. 2003, 115, 2511–
2513; Angew. Chem. Int. Ed. 2003, 42, 2409–2411; j) T. Morimoto,
M. Fujioka, K. Fuji, K. Tsutsumi, K. Kakiuchi, Chem. Lett. 2003, 32,
154–155.
[11] For contributions from the Buchwald group, see: a) M. Palucki, S. L.
Buchwald, J. Am. Chem. Soc. 1997, 119, 11108–11109; b) J. Ahman,
J. P. Wolfe, M. V. Troutman, M. Palucki, S. L. Buchwald, J. Am.
Chem. Soc. 1998, 120, 1918–1919; c) J. M. Fox, X. Huang, A. Chief-
fi, S. L. Buchwald, J. Am. Chem. Soc. 2000, 122, 1360–1370;
d) W. A. Moradi, S. L. Buchwald, J. Am. Chem. Soc. 2001, 123,
7996–8002; e) E. J. Hennessy, S. L. Buchwald, Org. Lett. 2002, 4,
269–272; f) D. Spielvogel, S. L. Buchwald, J. Am. Chem. Soc. 2002,
124, 3500–3501; g) O. Gaertzen, S. L. Buchwald, J. Org. Chem.
2002, 67, 465–475; h) J. L. Rutherford, M. P. Rainka, S. L. Buch-
wald, J. Am. Chem. Soc. 2002, 124, 15168–15169; i) T. Hamada, A.
Chieffi, J. ꢆhman, S. L. Buchwald, J. Am. Chem. Soc. 2002, 124,
1261–1268; j) J. Chae, J. Yun, S. L. Buchwald, Org. Lett. 2004, 6,
4809–4812; k) R. Martꢇn, S. L. Buchwald, Angew. Chem. 2007, 119,
7374–7377; Angew. Chem. Int. Ed. 2007, 46, 7236–7239; l) R.
Martꢇn, S. L. Buchwald, Org. Lett. 2008, 10, 4561–4564; m) J.
Garcꢇa-Fortanet, S. L. Buchwald, Angew. Chem. 2008, 120, 8228–
8231; Angew. Chem. Int. Ed. 2008, 47, 8108–8111; n) A. M. Taylor,
R. A. Altman, S. L. Buchwald, J. Am. Chem. Soc. 2009, 131, 9900–
9901; o) M. R. Biscoe, S. L. Buchwald, Org. Lett. 2009, 11, 1773–
1775; p) P. Li, S. L. Buchwald, Angew. Chem. 2011, 123, 6520–6524;
Angew. Chem. Int. Ed. 2011, 50, 6396–6400.
[7] a) P. Hermange, A. T. Lindhardt, R. H. Taaning, K. Bjerglund, D.
Lupp, T. Skrydstrup, J. Am. Chem. Soc. 2011, 133, 6061–6071;
b) S. D. Friis, R. H. Taaning, A. T. Lindhardt, T. Skrydstrup, J. Am.
Chem. Soc. 2011, 133, 18114–18117.
[8] a) P. Hermange, T. M. Gøgsig, A. T. Lindhardt, R. H. Taaning, T.
Skrydstrup, Org. Lett. 2011, 13, 2444–2447; b) D. U. Nielsen, R. H.
Taaning, A. T. Lindhardt, T. M. Gøgsig, T. Skrystrup, Org. Lett.
2011, 13, 4454–4457; c) K. Bjerglund, A. T. Lindhardt, T. Skrydstr-
up, J. Org. Chem. 2012, 77, 3793–3799; d) D. U. Nielsen, K. Neu-
mann, R. H. Taaning, A. T. Lindhardt, A. Modvig, T. Skrydstrup, J.
Org. Chem. 2012, 77, 6155–6165; e) Z. Xin, T. M. Gøgsig, A. T.
Lindhardt, T. Skrydstrup, Org. Lett. 2012, 14, 284–287; f) T. M.
Gøgsig, R. H. Taaning, A. T. Lindhardt, T. Skrydstrup, Angew.
Chem. 2012, 124, 822–825; Angew. Chem. Int. Ed. 2012, 51, 798–
801; g) T. M. Gøgsig, D. U. Nielsen, A. T. Lindhardt, T. Skrydstrup,
Org. Lett. 2012, 14, 2536–2539; h) M. N. Burhardt, R. H. Taaning,
N. C. Nielsen, T. Skrydstrup, J. Org. Chem. 2012, 77, 5357–5363;
i) M. N. Burhardt, R. H. Taaning, T. Skrydstrup, Org. Lett. 2013, 15,
948–951; j) S. Korsager, R. H. Taaning, T. Skrydstrup, J. Am. Chem.
Soc. 2013, 135, 2891–2894; k) S. Korsager, R. H. Taaning, A. T.
Lindhardt, T. Skrydstrup, J. Org. Chem. 2013, 78, 6112–6120; l) S.
Korsager, D. U. Nielsen, R. H. Taaning, T. Skrydstrup, Angew.
Chem. 2013, 125, 9945–9948; Angew. Chem. Int. Ed. 2013, 52, 9763–
9766.
[12] a) H. Cheng, J. Wan, M.-I. Lin, Y. Liu, X. Lu, J. Liu, Y. Xu, J. Chen,
Z. Tu, Y.-S. E. Cheng, K. Ding, J. Med. Chem. 2012, 55, 2144–2153;
b) Y. Ohtsuka, D. Uraguchi, K. Yamamoto, K. Tokuhisa, T. Yamaka-
ˇ
ˇ
wa, Tetrahedron 2012, 68, 2636–2649; c) D. Sterk, Z. Casar, M.
ˇ
Jukic, J. Kosmrlj, Tetrahedron 2012, 68, 2155–2160; d) Z.-Y. Ge, X.-
D. Fei, T. Tang, Y.-M. Zhu, J.-K. Shen, J. Org. Chem. 2012, 77,
5736–5743.
[13] For a review on the synthesis and application of 1,3-diketones, see:
a) A. V. Kelꢁin, Curr. Org. Chem. 2003, 7, 1691–1711; b) A. V.
Kel’in, A. Maioli, Curr. Org. Chem. 2003, 7, 1855–1886.
[14] For some recent examples of synthetic approaches to 1,3-diketones,
see: a) D. Lim, F. Fang, G. Zhou, D. M. Coltart, Org. Lett. 2007, 9,
4139–4142; b) K. Sato, S. Yamazoe, S. Yamamoto, S. Ohata, A.
Tarui, M. Omote, I. Kumadaki, A. Ando, Org. Lett. 2008, 10, 2405–
2408; c) G. Zhou, D. Lim, D. M. Coltart, Org. Lett. 2008, 10, 3809–
3812; d) S. Bogdan, Org. Lett. 2010, 12, 2900–2903.
[15] T. Kobayashi, M. Tanaka, Tetrahedron Lett. 1986, 27, 4745–4748.
[16] COgen is commercially available from Sigma–Aldrich and SyTracks.
[17] The bite-angle for DPPE and DPPP is 85 and 918, respectively.
[18] a) P. E. Garrou, R. F. Heck, J. Am. Chem. Soc. 1976, 98, 4115–4127;
b) A. M. Trzeciak, J. J. Ziꢈłkowski, Coord. Chem. Rev. 2005, 249,
2308–2322; c) H. Neumann, A. Brennfꢃhrer, P. Groß, T. Riermeier,
J. Almena, M. Beller, Adv. Synth. Catal. 2006, 348, 1255–1261; d) W.
Mꢅgerlein, A. F. Indolese, M. Beller, J. Mol. Catal. A: Chem. 2000,
156, 213–221.
[9] For 14C-labeling, see: A. T. Lindhardt, R. Simonssen, R. H. Taaning,
T. M. Gøgsig, G. N. Nilsson, G. Stenhagen, C. S. Elmore, T. Skryd-
ACHTUNGTRENNUNGstrup, J. Label. Compd. Radiopharm. 2012, 55, 411–418.
[10] For contributions from the Hartwig group, see: a) B. C. Hamann,
J. F. Hartwig, J. Am. Chem. Soc. 1997, 119, 12382–12383; b) K. H.
Shaughnessy, B. C. Hamann, J. F. Hartwig, J. Org. Chem. 1998, 63,
6546–6553; c) M. Kawatsura, J. F. Hartwig, J. Am. Chem. Soc. 1999,
121, 1473–1478; d) D. A. Culkin, J. F. Hartwig, J. Am. Chem. Soc.
2001, 123, 5816–5817; e) S. Lee, N. A. Beare, J. F. Hartwig, J. Am.
Chem. Soc. 2001, 123, 8410–8411; f) S. Lee, J. F. Hartwig, J. Org.
Chem. 2001, 66, 3402–3415; g) S. R. Stauffer, N. A. Beare, J. P.
Stambuli, J. F. Hartwig, J. Am. Chem. Soc. 2001, 123, 4641–4642;
h) J. Wolkowski, J. F. Hartwig, Angew. Chem. 2002, 114, 4465–4467;
Angew. Chem. Int. Ed. 2002, 41, 4289–4291; i) D. A. Culkin, J. F.
[19] Y. Hu, J. Liu, Z. Lꢃ, X. Luo, H. Zhang, Y. Lan, A. Lei, J. Am.
Chem. Soc. 2010, 132, 3153–3158.
[20] From the [PdACHTNUTRGNEUNG(dba)2] and DPPP complexation studies (see Figure 1),
complexes D and E are present in a 93:7 ratio as calculated from
the integration of the signals on the 31P NMR spectrum. Hence,
14% of DPPP is bound to Pd0 in the non-reactive complex [Pd-
Chem. Eur. J. 2013, 19, 17926 – 17938
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
17937

T. Gøgsig, A. T. Lindhardt, T. M. Skrydstrup, et al.
A
[24] For studies on the role of the DBA ligand, see: a) Y. Macꢄ, A. R.
Kapdi, I. J. S. Fairlamb, A. Jutand, Organometallics 2006, 25, 1795–
1800; b) C. Amatore, A. Jutand, Coord. Chem. Rev. 1998, 178–180,
511–528; c) I. J. S. Fairlamb, A. R. Kapdi, A. F. Lee, G. P. McGlack-
en, F. Weissburger, A. H. M. de Vries, L. Schmieder-van de Vonder-
voort, Chem. Eur. J. 2006, 12, 8750–8761.
[25] C. Amatore, M. Azzabi, A. Jutand, J. Am. Chem. Soc. 1991, 113,
8375–8384.
[26] a) A. W. Fraser, J. E. Besaw, L. E. Hull, M. C. Baird, Organometal-
lics 2012, 31, 2470–2475; b) D. M. Norton, E. A. Mitchell, N. R.
Botros, P. G. Jessop, M. C. Baird, J. Org. Chem. 2009, 74, 6674–
6680.
47%.
[21] Considerable degradation was observed in this stoichiometric reac-
tion. One concern would be the reaction of the sodium enolate with
the stoichiometric amount of DBA. However, an experiment, in
which the two were dissolved together in dioxane and heated to
808C for 30 min, only revealed the presence of unreacted ethyl
phenyl ketone and DBA according to the 1H NMR spectrum of the
crude product mixture after workup.
[22] C. Amatore, G. Broeker, A. Jutand, F. Khalil, J. Am. Chem. Soc.
1997, 119, 5176–5185.
[23] These results are in accordance with earlier work performed by
Jutand and co-workers: M. Alami, C. Amatore, S. Bensalem, A.
Choukchou-Brahim, A. Jutand, Eur. J. Inorg. Chem. 2001, 2675–
2681.
Received: August 28, 2013
Published online: November 21, 2013
17938
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 17926 – 17938