New Pd-catalyzed cross coupling reactions with Boronic Acids
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mülheim an der Ruhr, Germany
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New palladium(0)-catalyzed cross coupling reactions between arylboronic acids or esters and alkyl bromides, which do not
contain β-hydrogen atoms, are presented. Thus, various arylacetic esters and amides were synthesized in the presence of
K PO and a catalyst generated in situ
from palladium acetate and commercially available tri(1-naphthyl)phosphine.1
Palladium-catalyzed Suzuki-coupling reactions between arylboronic acids and aryl
Methylenecarboxyl groups are important functionalities in biologically active
or vinyl halides have found broad application in organic synthesis.2
compounds such as the antiinflammatory and analgesic drugs Indomethacin or
examples of coupling reactions between boronic acids and alkyl
Aclofenac. Mild and efficient procedures for the introduction of the
been reported.3 Main reason for this is the strong tendency of alkyl halides to
methylenecarboxyl group into functionalized molecules are thus of great interest,
undergo β-hydride elimination after their oxidative addition to a palladium catalyst.
especially since traditional syntheses involve multistep procedures that are
Our goal was to investigate if alkyl halides which lack β-hydrogens are suitable as
usually incompatible with sensitive functionalities. We thus chose α-
substrates for Pd-catalyzed coupling reactions.
halocarboxylic acids as the first substrate class for our new coupling reaction.
Development of the catalyst system
We developed the catalyst system on the reaction of benzeneboronic acid with
The high selectivity is also demonstrated by the arylation of 4-bromobutylbromo-
ethyl bromoacetate. Under standard Suzuki
conditions with tetrakis(triphenylphos-
acetate which takes place exclusively in α position to to the carbonyl group.
phine)palladium and K CO in DMF, only trace amounts of the coupling product
Table 2. Preparation of functionalized arylacetic acid derivatives
were detected. Instead, large amounts of biphenyl and benzene were formed.
Scheme 1. Product spectrum of the coupling reaction
The selectivity of the reaction could however, completely be inverted when bulky,
palladium. Tri-1-naphthylphosphine proved to be the best ligand for this
transformation. The choice of the base was also important. For these substrates,
potassium phosphate gave best results. THF proved to be the most effective
solvent. The presence of small amounts of water is beneficial both for the speed
Table 1. Effects of the reaction conditions on the product distribution.
aConditions: A) 1.2 equiv. arylboronic acid, 3 mol% Pd(OAc)2, 9 mol% P(Nap)3,
5 equiv. K3PO4, 2 equiv. H2O, 20 °C, THF; B) 1.2 equiv. pinacol boronate, 3mol% Pd(OAc)2, 9 mol% P(Nap)3, 5 equiv. K3PO4, 2 equiv. H2O, 20 °C, THF;
bIsolated yields (GC-determined yields in parentheses); cKF instead of K3PO4.
Many functionalized pinacol boronates are conveniently accessible from aryl
halides and pinacol borane4 so that an extension of our reaction to this substrate
class (Scheme 2) appeared desirable. We were pleased to find that the best
conditions for the conversion of the boronic acids turned out also to be the
optimum conditions for pinacol boronates (Table 2, “method B”).
Conditions: 3 mol% Pd(OAc)2, 9 mol% ligand, 5 equiv. base, 2 equiv. H2O, 20 °C;a) Selectivities determined by GC b) (dba)3Pd2 instead of Pd(OAc)2
Scheme 2. Conversion of pinacol boronates
Scope of the new transformation
The generality and selectivity of the reaction were investigated using a number of
 L. J. Gooßen, Chem. Commun
, 679 - 670 and literature cited.
arylboronic acids in combination with several alkyl halides (Main Scheme). As can
 N. Miyaura, A Suzuki, Chem. Rev
, 2457 - 2483.
be seen in table 2, electron-poor and electron-rich compounds are equally
 M. Sato, N. Miyaura, A. Suzuki, Chem. Lett. 1989
suitable for the transformation (Method A). Even sterically hindered substrates or
 M. Murata, T. Oyama, S. Watanabe, Y. Masuda, J .Org. Chem, 2000, 65
substrates containing enolizable groups are smoothly converted.
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