Published on Web 07/30/2010
A General and Efficient Catalyst for Palladium-Catalyzed C-O
Coupling Reactions of Aryl Halides with Primary Alcohols
Saravanan Gowrisankar, Alexey G. Sergeev, Pazhamalai Anbarasan,
Anke Spannenberg, Helfried Neumann, and Matthias Beller*
Leibniz-Institut fu¨r Katalyse e.V. an der UniVersita¨t Rostock, Albert-Einstein-Strasse 29a,
18059 Rostock, Germany
Received April 17, 2010; E-mail: matthias.beller@catalysis.de
Abstract: An efficient procedure for palladium-catalyzed coupling reactions of (hetero)aryl bromides and
chlorides with primary aliphatic alcohols has been developed. Key to the success is the synthesis and
exploitation of the novel bulky di-1-adamantyl-substituted bipyrazolylphosphine ligand L6. Reaction of aryl
halides including activated, nonactivated, and (hetero)aryl bromides as well as aryl chlorides with primary
alcohols gave the corresponding alkyl aryl ethers in high yield. Noteworthy, functionalizations of primary
alcohols in the presence of secondary and tertiary alcohols proceed with excellent regioselectivity.
during the past decade, was an important step forward.4 Clearly,
each of these protocols has its own virtues; however, limitations
Introduction
The synthesis of (hetero)aryl amines, anilines, (hetero)aryl
ethers, and phenols via palladium- and copper-catalyzed cross-
coupling methodologies has become an efficient and funda-
mental tool for advanced organic synthesis in both academic
and industrial laboratories.1 In addition to well established
Buchwald-Hartwig amination reactions, in particular C-O
bond forming reactions are interesting in organic synthesis due
to the presence of these bonds in numerous natural products,
biological compounds, pharmaceuticals, fragrances, cosmetics,
and polymers.2
still exist with respect to substrate scope as well as an excess
of alkoxides, undesirable solvents, etc. Thus, palladium-
catalyzed intra- and intermolecular cross-coupling reactions of
aryl halides with alcohols offer an interesting complementary
method for the synthesis of aryl ethers under comparably mild
conditions.5 It is important to note that, in contrast to well-
established palladium-catalyzed coupling reactions of tertiary
alcohols and phenols,6 only a few studies on the formation of
alkyl aryl ethers with primary and secondary alcohols have been
performed. On the other hand, aromatic ethers of aliphatic
primary alcohols represent a structural motif in many naturally
occurring and medicinal compounds (Scheme 1).
Traditionally, aryl ethers have been prepared by copper-
mediated Ullmann coupling reactions of aryl bromides/iodides
and phenols with the drawback of harsh reaction conditions and
the need of a stoichiometric amount of metal.3 Thus, the
development of improved procedures, which allowed for the
catalytic use of copper reagents and ligands initiated by
Buchwald and co-workers and followed by many other groups
The general problem in the formation of these aromatic ethers
is the competition of the desired reductive elimination to form
(4) For selected Cu-catalyzed C-O bond formations, see: (a) Marcoux,
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11592 J. AM. CHEM. SOC. 2010, 132, 11592–11598
10.1021/ja103248d 2010 American Chemical Society