Development of a general palladium-catalyzed carbonylative heck reaction of aryl halides

Article abstract of DOI:10.1021/ja1059922

The first general palladium-catalyzed carbonylative vinylation of aryl halides with olefins in the presence of CO has been developed. Applying a catalyst system consisting of [(cinnamyl)PdCl]₂ and bulky imidazolyl-phosphine ligand L1 allows for the efficient and selective synthesis of α,β-unsaturated ketones under mild reaction conditions. Starting from easily available aryl halides and olefins, versatile building blocks can be prepared in a straightforward manner. The generality and functional group tolerance of this novel protocol is demonstrated.

Full text of DOI:10.1021/ja1059922

Published on Web 09/24/2010
Development of a General Palladium-Catalyzed Carbonylative
Heck Reaction of Aryl Halides
Xiao-Feng Wu, Helfried Neumann, Anke Spannenberg, Thomas Schulz, Haijun Jiao,
and Matthias Beller*
Leibniz-Institut fu¨r Katalyse e.V. an der UniVersita¨t Rostock, Albert-Einstein-Strasse 29a,
18059 Rostock, Germany
Received July 7, 2010; E-mail: matthias.beller@catalysis.de
Abstract: The first general palladium-catalyzed carbonylative vinylation of aryl halides with olefins in the presence
of CO has been developed. Applying a catalyst system consisting of [(cinnamyl)PdCl]2 and bulky imidazolyl-
phosphine ligand L1 allows for the efficient and selective synthesis of R,ꢀ-unsaturated ketones under mild reaction
conditions. Starting from easily available aryl halides and olefins, versatile building blocks can be prepared in
a straightforward manner. The generality and functional group tolerance of this novel protocol is demonstrated.
Scheme 1. Palladium-Catalyzed Carbonylation Reactions of Aryl Halides
Introduction
Palladium-catalyzed coupling reactions of aryl halides and
related compounds have become a powerful toolbox for
synthetic organic chemistry. Within the last two decades these
methods gained increasing importance both in large scale
industrial processes as well as for the development of new
materials and biologically active compounds owing to their
broad functional group tolerance and wide substrate scope.1
Among the different palladium-catalyzed C-C and C-X (X
) N, O, S) coupling reactions, carbonylation reactions allow
for the straightforward access to (hetero)aromatic carboxylic acid
derivatives.2 Starting from easily available aryl halides the
synthesis of esters, amides, acids, ketones, and aldehydes has
been well established (Scheme 1).3
On the other hand, the seemingly simple carbonylative
coupling of an aryl halide with CO and olefins is merely
described in the literature. Larock and co-workers4 reported the
first intramolecular carbonylative cyclization of aryl iodides to
indanones. Later on, the group of Larhed extended this protocol
(1) Selected books and reviews: (a) Negishi, E.-I. Handbook of Organo-
palladium Chemistry for Organic Synthesis; Wiley: New York, 2002.
(b) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed., Wiley-VCH: Weinheim, 2004. (c) Wolfe, J. P.;
Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998,
31, 805. (d) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046. (e)
Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004, 2337.
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2004, 2283. (g) Chen, G.; Chan, A. S. C.; Kwong, F. Y. Tetrahedron
Lett. 2007, 48, 473.
to aryl bromides and chlorides applying microwave conditions.5
Miura and co-workers presented the cross-carbonylation of aryl
iodides with five-membered cyclic olefins using the PdCl2/PPh3.
However, only two single examples of this type of reaction were
disclosed.6 On the basis of our interest in palladium-catalyzed
carbonylations, we recently reported a novel methodology for
the synthesis of chalcones7 via coupling of aryl/vinyl triflates
with styrenes in the presence of carbon monoxide. Unfortu-
nately, applying more easily available aryl halides as substrates
failed under these conditions. Therefore, the need to develop a
general procedure for carbonylative vinylations of aryl halides
still exists. Herein, we report a novel catalytic process for the
carbonylation of aryl halides that allows carbonylation of aryl
halides with various important classes of olefins such styrenes,
acrylates, and enol ethers for the first time. This process proceeds
under mild conditions and leads to interesting building blocks
for heterocycles and biologically active compounds.
(2) For reviews on palladium-catalyzed carbonylations see: (a) Brenn-
fu¨hrer, A.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2009,
48, 4114. (b) Brennfu¨hrer, A.; Neumann, H.; Beller, M. ChemCatChem
2009, 1, 28. (c) Barnard, C. F. J. Organometallics 2008, 27, 5402. (d)
Beller, M. Carbonylation of Benzyl- and Aryl-X Compounds. In
Applied Homogeneous Catalysis with Organometallic Compounds, 2nd
ed.; Cornils, B., Herrmann, W. A., Eds.; Wiley-VCH: Weinheim, 2002;
pp 145-156. (e) Skoda-Fo¨ldes, R.; Kolla´r, L. Curr. Org. Chem. 2002,
6, 1097. (f) Tsuji, J. Palladium Reagents and Catalysts: InnoVations
in Organic Synthesis; Wiley: Chichester, 1995. (g) Beller, M.; Cornils,
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9
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Pd-Catalyzed Carbonylative Reaction of Aryl Halides
A R T I C L E S
Scheme 2. Selected Examples of Bioactive Chalcones
Due to the importance of chalcones (1,3-diarylpropen-1-ones)
as part of the flavonoid family, we studied the reaction of
iodobenzene with styrene in the presence of carbon monoxide
as a model system in more detail. Notably, various naturally
occurring chalcones display interesting biological activities,
including anticancer, anti-inflammatory, antioxidant, cytotoxic,
antimicrobial, analgesic, antipyretic, antianginal, antihepatotoxic,
antimalarial, and antiallergic properties (Scheme 2).8 Moreover,
they have been used as key intermediates in the preparation of
novel bioactive compounds.9 In the past chalcones have been
mainly synthesized by aldol condensations between aromatic
aldehydes and ketones (Claisen-Schmidt condensation).10
Unfortunately, in this procedure relatively strong bases are
usually required. Obviously, a general palladium-catalyzed
carbonylative vinylation would represent a valuable complement
for their synthesis.11
Results and Discussion
The initial approach to the carbonylation of iodobenzene with
styrene was based on our previous work applying phenyl triflate.
However, applying the previously optimized catalyst system
with 1,3-bisdiphenylphosphinopropane (dppp) as ligand led to
less than 5% yield of the desired product. On the other hand
the combination of [(cinnamyl)PdCl]2 and L112 in the presence
of NEt3 in dioxane at 5 bar of CO resulted in 15% of chalcone
(Table 1, entry 1). Applying structurally similar ligands or other
commercially available mono- and bidentate ligands showed
disappointingly low reactivity (Table 1, entries 2-10). 1,2-
Bis[{di(adamantan-1-yl)phosphino}methyl]benzene,13 which
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1974, 39, 3318. (b) Schoenberg, A.; Heck, R. F. J. Org. Chem. 1974,
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Wu et al.
Table 1. Optimization of the Model Systema
a Iodobenzene (1 mmol), styrene (2 mmol), [(cinnamyl)PdCl]2 (1 mol %), ligand (6 mol %), NEt3 (2 mmol), dioxane (2 mL), CO (5 bar), 100
°C, 20 h. b Determined by GC; hexadecane as internal standard. c 4 equiv of styrene. d Dioxane (0.5 mL), 4 equiv of styrene. e Dioxane (0.5 mL),
6 equiv of styrene. f Dioxane (0.5 mL), 8 equiv of styrene, PCy3 (tricyclohexylphosphine), DPPE (1,2-bis(diphenylphosphino)ethane), DPPF
(1,1′-bis(diphenylphosphino)ferrocene).
showed high reactivity in the reductive carbonylation of vinyl
triflates, led to complete conversion but gave only 2% of the
target product (Table 1, entry 11). Instead, significant amounts
of benzoic anhydride and N,N-diethylbenzamide are formed.
Tri-tert-butylphosphine and other di-tert-butyl-substituted phos-
phines also gave only low yields (10-13%) of the carbonylative
product (Table 1, entries 12-16). However, to our delight, the
yield of the target product was improved to 42% by decreasing
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Pd-Catalyzed Carbonylative Reaction of Aryl Halides
A R T I C L E S
Table 2. Variation of Aryl Halidesa
the amount of ligand L1 (Table 1, entries 1, 17 and 18). Even
better yields (70%) were obtained by optimizing the concentra-
tion of solvent and styrene (Table 1, entry 21).
With suitable conditions in our hand (Table 1, entry 14), the
scope of the carbonylation process with regard to the aryl halides
and olefins was next examined (Tables 2 and 3). The generality
of the protocol is proven by the reaction of 32 different
substrates, which all gave the desired products in moderate to
excellent yields. Electron-rich and electron-deficient aryl iodides
and bromides gave good yields (57-89%) of the corresponding
R,ꢀ-unsaturated ketones (Table 2, entries 7-14).
Most substrates shown gave clean conversion with no
competing formation of Heck products.14 Heteroaryl substrates,
e.g., 3-iodothiophene (Table 2, entry 15), were also efficiently
transformed, and the reaction showed good functional group
tolerance. In general, both meta- and para-substituted benzenes
were successfully transformed into the corresponding products
with good yields and excellent chemoselectivity (75-90%;
Table 2, entries 2-5). However, ortho-substituted iodobenzene
gave a lower yield of the corresponding ketone together with a
certain amount of 1-methyl-2-styrylbenzene (Table 2, entry 6).
Notably, applying 2-(di-tert-butylphosphino)-1-(naphthalen-1-
yl)-1H-pyrrole together with [(cinnamyl)PdCl]2 and aryl bro-
mides can be transformed into the corresponding chalcones. Best
results are obtained at a slightly increased reaction temperature
(120 °C) and a CO pressure (10 bar) (Table 2, entries 16-22).
Both electron-rich (methoxy- and dimethylamino-substituted
bromobenzenes) as well as electron-poor (ester- and fluoride-
substituted bromobenzenes) aryl bromides gave good isolated
yields of the corresponding products (Table 2, entries 21, 22;
60-72%).
Next, we turned our attention to carbonylative vinylations
with other olefins. Notably, not only styrene but substituted
styrenes and acrylates as well as enol ethers worked well in
our protocol (Table 3)! For example, p-tert-butyl-, p-methoxy-,
m-methyl-, p-fluoro-, and p-chloro-substituted styrenes gave
51-88% of the corresponding chalcone products (Table 3,
entries 1-5). In the case of expensive styrenes, the excess of
olefin can easily be separated from the reaction mixture either
by column chromatography or by distillation. However, even
(12) For some other application of this ligand see: (a) Schulz, T.; Torborg,
C.; Scha¨ffner, B.; Huang, J.; Zapf, A.; Kadyrov, R.; Bo¨rner, A.; Beller,
M. Angew. Chem., Int. Ed. 2009, 48, 918. (b) Sergeev, A. G.; Schulz,
T.; Torborg, C.; Spannenberg, A.; Neumann, H.; Beller, M. Angew.
Chem., Int. Ed. 2009, 48, 7595. (c) Hu, T.; Schulz, T.; Torborg, C.;
Chen, X.; Wang, J.; Beller, M.; Huang, J. Chem. Commun. 2009, 7330.
(d) Schulz, T.; Torborg, C.; Enthaler, S.; Schaffner, B.; Dumrath, A.;
Spannenberg, A.; Neumann, H.; Bo¨rner, A.; Beller, M. Chem.sEur.
J. 2009, 15, 4528.
(13) Neumann, H.; Sergeev, A.; Beller, M. Angew. Chem., Int. Ed. 2008,
47, 4887.
(14) For reviews and recent selected examples of Heck coupling see: (a)
Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320. (b) Heck,
R. F. Org. React. 1982, 27, 345. (c) Jeffery, T. AdV. Met. Org. Chem.
1996, 5, 153. (d) Stark, G.; Riermeier, T. H.; Beller, M. In Transition
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A.; Lemaitre, F. Chem.sEur. J. 2007, 13, 2002. (l) Knowles, J. P.;
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a Aryl iodide (1 mmol), styrene (6 mmol), [(cinnamyl)PdCl]2 (1 mol %),
L1 (4 mol %), NEt3 (2 mmol), dioxane (0.5 mL), CO (5 bar), 100 °C, 20 h.
b Isolated yield. c 30-40% of the “normal” Heck product was formed. d 80
°C, CO (10 bar), 40 h. e [(Cinnamyl)PdCl]2 (2 mol %), 2-(di-tert-butylphos-
phino)-1-(naphthalene-1-yl)-1H-pyrrole (8 mol %), 120 °C, CO (10 bar).
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Wu et al.
Table 3. Variation of Alkenesa
a Aryl iodide (1 mmol), styrene (6 mmol), [(cinnamyl)PdCl]2 (1 mol %), L1 (4 mol %), NEt3 (2 mmol), dioxane (0.5 mL), CO (5 bar), 100 °C, 20 h.
b Isolated yield. c Trans product was isolated with >99% selectivity. d 3 equiv of alkene.
with a lower amount of alkene (3 equiv), the corresponding
carbonylative products are isolated in 47-55% yield (Table 3,
entries 6, 10). Reactions of inexpensive butyl acrylate and butyl
vinyl ether with aryl iodides in the presence of carbon monoxide
led to interesting functionalized building blocks in 69-78%
yields (Table 3, entries 6-10).15 Notably, all products are
isolated with >99% trans selectivity. To the best of our
knowledge none of these reactions have been described before
and it is clear that they represent valuable extensions of currently
known carbonylation reactions.
The proposed mechanism of the palladium-catalyzed carbo-
nylative vinylation is shown in Scheme 3. In agreement with
previous studies on catalytic carbonylations of aryl halides,16
we suppose that oxidative addition of the aryl halide to Pd(0),
which is easily generated by reduction of Pd(II) with CO, forms
complex 1.17 This complex could be isolated as a stable
intermediate, and the structure was confirmed by NMR and
X-ray studies (Figure 1). Subsequent coordination and insertion
of carbon monoxide leads to the respective acylpalladium
(15) Nilsson, P.; Olofsson, K.; Larhed, M. Focus on Regioselectivity and
Product Outcome in Organic Synthesis. In The Heck Reaction;
Oestreich, M., Ed.; John Wiley and Sons: New York, 2009; p 133.
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Pd-Catalyzed Carbonylative Reaction of Aryl Halides
A R T I C L E S
Scheme 3. Proposed Mechanism
Figure 1. Molecular structure of complex 1. Thermal ellipsoids correspond
to 30% probability. Hydrogen atoms are omitted for clarity. Selected bond
lengths (Å) and angles (deg): Pd1-I1, 2.6140(3); Pd1-P1, 2.2977(8);
Pd1-N1, 2.151(2); Pd1-C36, 2.000(3); C36-Pd1-P1, 103.68(8); N1-
Pd1-P1, 69.12(7); C36-Pd1-I1, 90.26(8); N1-Pd1-I1, 96.94(6).17
intermediate 2. Indeed, reaction of complex 1 under 5 bar of
CO gave 2 as a brown solid within one hour at room temperature
(Figure 2).18 Coordination and insertion of the alkene followed
by ꢀ-hydride elimination produces the desired chalcone.19
Finally, the active palladium species is regenerated by reaction
with NEt3 to complete the catalytic cycle. Most likely, formation
of benzoic acid amide and acid anhydride proceeds via
20
decomposition reactions of NEt3 and reactions with trace
amounts of water. The formation of stilbene (Table 2, entries 6
and 7) can be explained either by direct insertion of the olefin
into complex 1 or by reversible decarbonylation of 2 and
subsequent olefin insertion. However, reaction of complex 2
Figure 2. Molecular structure of complex 2. Thermal ellipsoids correspond
to 30% probability. Selected bond lengths (Å) and angles (deg): C1-Pd1,
1.952(4); N1-Pd1, 2.201(2); P1-Pd1, 2.3198(6); Pd1-I1, 2.6300(2);
C1-Pd1-P1, 103.63(11); N1-Pd1-P1, 68.10(5); C1-Pd1-I1, 88.74(11);
N1-Pd1-I1, 99.72(5).18
(16) For selected examples of mechanistic studies of palladium-catalyzed
carbonylations see: (a) Sergeev, A. G.; Spannenberg, A.; Matthias,
M. J. Am. Chem. Soc. 2008, 130, 15549. (b) Trzeciak, A. M.;
Ziolkowski, J. J. Coord. Chem. ReV. 2005, 249, 2308.
(17) Crystal data of complex 1: C46H66IN2OPPd, Mr ) 927.28, monoclinic,
space group P21/n, a ) 13.7393(3) Å, b ) 18.4558(4) Å, c )
with styrene in between room temperature and 100 °C did not
result in the formation of stilbene. Notably, at room temperature
no chalcone is detected even after 24 h; however, at 100 °C the
product is formed after 30 min. Apparently, insertion of styrene
into the benzoylpalladium species constitutes the rate-determin-
ing step under these conditions.
17.0955(4) Å, ꢀ ) 90.225(2)°, V ) 4334.9(2) Å3, Z ) 4, Fcalcd
)
1.421 g ·cm-3, µ ) 1.213 mm-1, T ) 200 K, 60956 reflections
collected, 8511 independent (Rint ) 0.0503) and 5820 observed [I >
2σ(I)] reflections, final R indices [I > 2σ(I)]: R1 ) 0.0301, wR2
0.0542, R indices (all data): R1 ) 0.0556, wR2 ) 0.0577, 476 refined
parameters. Crystal of the compound contained diethylether as solvent,
which is not depicted in Figure 1.
)
(18) Crystal data of complex 2: C46.2H65.3I1.1N2O1.9PPd, Mr ) 956.06,
monoclinic, space group P21/c, a ) 12.7752(2) Å, b ) 14.9793(3) Å,
c ) 23.3956(4) Å, ꢀ ) 102.3919(14)°, V ) 4372.76(13) Å3, Z ) 4,
Fcalcd ) 1.452 g ·cm-3, µ ) 1.276 mm-1, T ) 200 K, 69762 reflections
collected, 10055 independent (Rint ) 0.0463) and 7119 observed [I >
Conclusion
2σ(I)] reflections, final R indices [I > 2σ(I)]: R1 ) 0.0255, wR2
)
In summary, we have developed a general and efficient
protocol for carbonylative Heck reactions of aryl iodides and
bromides. This methodology represents a useful extension of
the established carbonylative Suzuki and carbonylative Sono-
gashira reactions. For the first time, various aromatic and
aliphatic alkenes work well in our system and afford good yields
of the corresponding R,ꢀ-unsaturated ketones (41-90%). Start-
0.0474, R indices (all data): R1 ) 0.0476, wR2 ) 0.0501, 491 refined
parameters. Crystal of the compound contained diethylether as solvent,
which is not depicted in Figure 2. 10% of L1PdI2 besides the desired
complex 2 was obtained in the solid state. The I ligand with a side
occupancy factor of 0.1 is omitted in Figure 2.
(19) For some examples of insertion of olefins into acylpalladium complexes
see: (a) Hamada, A.; Braunstein, P. Organometallics 2009, 28, 1688.
(b) Zuidema, E.; Bo, C.; van Leeuwen, P. W. N. M. J. Am. Chem.
Soc. 2007, 129, 3989. (c) Agostinho, M.; Braunstein, P. Chem.
Commun. 2007, 58. (d) Takeuchi, D.; Yasuda, A.; Osakada, K.
J. Chem. Soc., Dalton Trans. 2003, 2029. (e) Schwarz, J.; Herdtweck,
E.; Herrmann, W. A.; Gardiner, M. G. Organometallics 2000, 19,
3154.
(20) Negishi, E.-I.; Coperet, C.; Ma, S.; Mita, T.; Sugihara, T.; Tour, J. M.
J. Am. Chem. Soc. 1996, 118, 5904.
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A R T I C L E S
Wu et al.
2008, A64, 112) and refined by full-matrix least-squares techniques
on F2 (SHELXL-97: Sheldrick, G. M. Acta Crystallogr. 2008, A64,
112). XP (Bruker AXS) was used for graphical representations.
General Procedure for Catalytic Reactions. A 10 mL Schlenk
flask was charged with [(cinnamyl)PdCl]2 (26 mg, 1 mol %), 2-(di-
1-adamantylphosphino)-1-(2,6-diisopropylphenyl)-1H-imidazole
(105.8 mg, 4 mol %), NEt3 (1.4 mL, 2 equiv), and dioxane (2.5
mL). Then, hexadecane (1 mL, internal GC standard) and 0.98 mL
of this clear, brown stock solution were transferred into four vials
(12 mL reaction volume) equipped with a septum, a small cannula,
a stirring bar, 1 mmol of the corresponding aryl iodides and 6 mmol
of styrenes. The vials were placed in an alloy plate, which was
transferred into a 300-mL autoclave of the 4560 series from Parr
Instruments under argon atmosphere. After flushing the autoclave
three times with CO and adjusting the pressure to 5 bar, the reaction
was performed for 20 h at 100 °C. After the reaction, the autoclave
was cooled down to room temperature, and the pressure was
released carefully. The product was washed with water and extracted
with 2 mL of ethyl acetate three times; after being concentrated
under reduced pressure, the product was purified by silica gel
chromatography using n-heptane/AcOEt (40:1) as an eluent.
ing from easily available aryl iodides and bromides, interesting
building blocks are obtained under mild conditions.
Experimental Section
General Comments. All reactions were carried out under argon
atmosphere. Dioxane, triethylamine, THF, diethyl ether, and heptane
were distilled from sodium ketyl or CaH and stored in Aldrich Sure/
Stor flasks under argon. Aryl iodides and styrenes were purchased
from Aldrich or ABCR and used as received. 2-(Di-1-adamantyl-
phosphino)-1-(2,6-diisopropylphenyl)-1H-imidazole,12 Pd(COD)-
(CH2SiMe3)2,21 and [(cinnamyl)PdCl]222 were synthesized according
to reported procedures. Column chromatography was performed
using Merck Silicagel 60 (0.043-0.06 mm). NMR data were
recorded on Bruker ARX 300 and Bruker ARX 400 spectrometers.
1
13C and H NMR spectra were referenced to signals of deutero
solvents and residual protiated solvents, respectively. 31P NMR
chemical shifts are reported relative to 85% H3PO4. Gas chroma-
tography analysis was performed on an Agilent HP-5890 instrument
with a FID detector and HP-5 capillary column (polydimethylsi-
loxane with 5% phenyl groups, 30 m, 0.32 mm i.d., 0.25 µm film
thickness) using argon as carrier gas. Gas chromatography-mass
analysis was carried out on an Agilent HP-5890 instrument with
an Agilent HP-5973 Mass Selective Detector (EI) and HP-5
capillary column (polydimethylsiloxane with 5% phenyl groups,
30 m, 0.25 mm i.d., 0.25 µm film thickness) using helium carrier
gas. ESI and HR-MS measurements were performed on an Agilent
1969A TOF mass spectrometer. Melting points were measured by
GalenTMIII. X-ray crystal structure analysis of complexes: data
were collected on a STOE IPDS II diffractometer using graphite-
monochromated Mo KR radiation. The structures were solved by
direct methods (SHELXS-97: Sheldrick, G. M. Acta Crystallogr.
Acknowledgment. We thank the state of Mecklenburg-
Vorpommern and the Bundesministerium fu¨r Bildung und Forschung
(BMBF) for financial support. We also thank Mrs. S. Leiminger, Mrs.
K. Mevius, Drs. W. Baumann, C. Fischer, and Mrs. S. Buchholz
(LIKAT) for analytical support.
Supporting Information Available: Optimization data, NMR
data for all products, X-ray crystallographic and NMR studies
for complexes 1 and 2. This material is available free of charge
via the Internet at http://pubs.acs.org.
(21) Pan, Y.; Young, G. B. J. Organomet. Chem. 1999, 577, 257.
(22) Auburn, P. R.; Mackenzie, P. B.; Bosnich, B. J. Am. Chem. Soc. 1985,
107, 2003.
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