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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 Tel. +49-208-306-2392; Fax +49-208-306-2985; e-mail [email protected] Abstract
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 Introduction
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 halides have 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
Literature
The generality and selectivity of the reaction were investigated using a number of [1] L. J. Gooßen, Chem. Commun. 2001, 7, 679 - 670 and literature cited.
arylboronic acids in combination with several alkyl halides (Main Scheme). As can [2] N. Miyaura, A Suzuki, Chem. Rev. 1995, 95, 2457 - 2483.
be seen in table 2, electron-poor and electron-rich compounds are equally [3] M. Sato, N. Miyaura, A. Suzuki, Chem. Lett. 1989, 1405-1408.
suitable for the transformation (Method A). Even sterically hindered substrates or [4] M. Murata, T. Oyama, S. Watanabe, Y. Masuda, J .Org. Chem, 2000, 65, 164.
substrates containing enolizable groups are smoothly converted.

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