Phosphites as ligands for efficient catalysis of Heck reactions

Article abstract of DOI:10.1055/s-1998-1760

The palladium-catalyzed Heck reaction of aryl halides in the presence of phosphite ligands is described for the first time. Aryl bromides and even electron deficient aryl chlorides can be coupled efficiently (turnover numbers up to 31,000) with different

Full text of DOI:10.1055/s-1998-1760

792
LETTERS
SYNLETT
1
Phosphites as Ligands for Efficient Catalysis of Heck Reactions
Matthias Beller , Alexander Zapf
*
Institut für Anorganische Chemie, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany
Fax +89/2891-3473; mbeller@arthur.anorg.chemie.tu-muenchen.de
Received 27 March 1998
Abstract: The palladium-catalyzed Heck reaction of aryl halides in the
presence of phosphite ligands is described for the first time. Aryl
bromides and even electron deficient aryl chlorides can be coupled
efficiently (turnover numbers up to 31,000) with different olefins using
palladium/trialkyl- or triaryl phosphite mixtures as catalysts.
The palladium-catalyzed olefination of aryl and vinyl halides (Heck
2
reaction) is a well established method for C-C coupling reactions and
Scheme 1
has become ”one of the true power tools of contemporary organic
3
synthesis”. A number of the resulting arylalkenes, e.g. cinnamic acid
esters, are important fine chemicals which are produced on multi-ton
scale. However, due to the high costs of aryl-X derivatives which are
easily activated by palladium catalysts such as aryl iodides or aryl
triflates the industrial production of arylalkenes is performed mainly by
4
different means. In order to use electron-rich aryl bromides as well as
chloroarenes which are starting materials of choice for a number of
Heck reactions due to their price and availability large amounts of
5
6
catalyst (> 1 mol%) are required. Recent efforts by us and others to
increase catalyst efficiency for Heck and related reactions led to the
development of improved palladium catalysts with basic phosphines as
6e-g
5
ligands,
highly active ”palladacycles”, and other palladium
6a-c
catalysts.
Nevertheless, further catalyst improvements are still
required for industrial application.
7
As a concept to develop new catalysts for the activation of C-Cl bonds
we studied whether ligands other than phosphines might stabilize Pd(0)
under typical Heck reaction conditions of aryl chlorides. Surprisingly, it
was discovered that phosphites as ligands if provided in a sufficient
amount stabilize Pd(0), thus preventing the formation of inactive
palladium black even after 24 h at 160 °C! Considering the ease of
8
dynamic ligand exchange of ”electron poor” phosphites we assumed
that palladium-phosphite catalysts might be effective in Heck reactions,
too. In this paper we report that contrary to the general belief it is not
necessary to use electron rich phosphines for generating a sufficiently
nucleophilic Pd(0) species that is able to insert into C-Cl bonds. To the
best of our knowledge, the use of phosphite ligands in Heck and related
reactions has never been described.
butylphenyl) phosphite = 1:10, no tetra-n-butylammonium bromide)
were applied to various substrates (Scheme 2, Table 2). A comparison
9
7
of procedure A and B revealed in most runs similar yields for both
systems. However, for certain substrates the reaction outcome was
10
totally different. For example, 4-trifluoromethyl-chlorobenzene reacts
As a model reaction the coupling of 4-trifluoromethyl-chlorobenzene
with styrene in the presence of palladium(II) acetate and various
phosphites was studied (Scheme 1). Addition of tetra-n-butylammonium
bromide as a co-catalyst is a key element to obtain catalytic activity. As
shown in Table 1 the yield and catalyst productivity (TON) is
significantly influenced by the ratio of ligand to palladium. In the
presence of an excess of phosphite with respect to palladium yields up
to 84 % and excellent catalyst productivities up to 840 were obtained.
Interestingly, in the case of trialkyl phosphites a ratio of about 100:1 (P/
Pd) leads to the best results. On the other hand using triaryl phosphites
the optimal P/Pd-ratio lies somewhat lower at about 10:1 (P/Pd). This
effect is explained by the higher hydrolytic stability of sterically
hindered triaryl phosphites. For most test reactions we observed that the
use of sodium carbonate as a base is preferred to sodium acetate.
almost quantitatively with N,N-dimethylacrylamide in the presence of
tris(2,4-di-t-butylphenyl) phosphite, whereas in the presence of triethyl
phosphite only 13 % of the desired product was obtained. In contrast,
the coupling of the sterically more demanding 2-chloro-5-nitrotoluene
with n-butyl acrylate is not catalyzed by the palladium triaryl phosphite
catalysts, but the use of a trialkyl phosphite ligand yields 69 % of the
corresponding cinnamic acid derivative. Interestingly, there is no
appreciable difference in the yields between 3- and 4-trifluoromethyl-
chlorobenzene. Electron-rich bromoarenes as substrates, such as 4-
bromoanisole and 2-bromo-6-methoxynaphthalene, do not need the
addition of activating bromide ions for efficient conversion (procedure
C).
Next the optimized palladium-phosphite catalyst systems (procedure A:
Pd / triethyl phosphite / tetra-n-butylammonium bromide = 1:100:200;
procedure B: Pd
/ tris(2,4-di-t-butylphenyl) phosphite / tetra-n-
butylammonium bromide = 1:10:200; procedure C: Pd / tris(2,4-di-t-
Scheme 2

July 1998
SYNLETT
793
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It is noteworthy that the important non-steroidal anti-inflammatory drug
nabumetone is obtained directly via coupling reaction of 2-bromo-6-
methoxynaphthalene with 3-buten-2-ol and subsequent in situ
isomerization. Regarding catalyst efficiency considerable conversion
(31 %) is observed for deactivated aryl bromides even with catalyst
concentrations as low as 0.001 mol% (TON = 31,000).
11
In conclusion, we have demonstrated for the first time that Heck
coupling reactions of deactivated bromo- and activated chloroarenes
proceed smoothly in the presence of a palladium catalyst with
phosphites as ligands. Outstanding turnover numbers which are among
the highest ever reported for Heck reactions of aryl chlorides can be
obtained applying a higher P/Pd ratio compared to conventional
phosphines. From an economic point of view this ligand excess is
compensated by the lower price of phosphites, their ease of handling,
and their availability. We believe that further variation of the phosphite
ligand structure will lead to even more productive catalysts. It is
foreseeable that this new principle will be successful in other palladium-
catalyzed reactions, too.
(7) Grushin, V. V.; Alper, H. Chem. Rev. 1994, 94, 1047.
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(9) Experimental procedure: In an ACE pressure tube (Aldrich) 10
mmol aryl halide, 15 mmol olefin, 12 mmol base, 2.0 mmol tetra-
n-butylammonium bromide (for chloroarenes), an appropriate
amount of phosphite and palladium(II) acetate, and 500 mg
diethyleneglycol di-n-butyl ether (as internal standard) is
dissolved in 10 ml N,N-dimethyl acetamide under an argon
atmosphere. The tube is sealed and put in a 140 or 160 °C hot bath
of silicon oil. After 24 h the mixture is cooled to room temperature
Acknowledgement: This work was supported by the Bayerische
Forschungsverbund Katalyse (FORKAT). A. Z. thanks the
Studienstiftung des deutschen Volkes and the Max-Buchner-
Forschungsstiftung for support. Generous gifts of precious metals and
chemicals from Degussa AG, Heraeus AG, and Hoechst AG are
gratefully acknowledged. Dr. T. H. Riermeier (Hoechst AG) is thanked
for many discussions.
Cl and 10 ml of 2 N HCl were added. The organic
and 10 ml CH
2
2
phase is analyzed by gas chromatography. After washing the
organic phase with water and brine, drying and evaporating the
solvents the products were isolated by crystallization from
methanol/acetone mixtures or by column chromatography (silica
gel, hexane/ethyl acetate mixtures).
(10) It is important to note that every given yield has been reproduced
at least twice. In few cases however, deviations to lower but also to
higher values have been observed.
References and Notes:
(1) Part 5 of the series Palladium-Catalyzed Reactions for Fine
Chemical Synthesis; for part 4 see Beller, M.; Riermeier, T. H.
Europ. J. Inorg. Chem. 1998, 29.
(11) Asslam, M.; Elango, V. US Patent 5,225,603 (1993). b) Dales, J.
R. M. CH Patent 677,622 (1991).