Palladium-catalyzed direct functionalization of 2-aminobutanoic acid derivatives: application of a convenient and versatile auxiliary.

The last decade has witnessed great progress on transitionmetal-catalyzed C H bond functionalization. Although many synthetically useful methods for regioselective functionalization of the C(sp) H bond of arenes and heteroarenes have been discovered, direct functionalization of C(sp) H bonds in common alkyl groups is still challenging. This challenge arises from the inert nature of most C(sp) H bonds and the difficulty in controlling regioselectivity. A promising approach is to use directing groups which can bind to metal centers and selectively deliver the catalyst to a proximal C H bond. For this strategy to be synthetically useful, an ideal directing group should be readily available, easily introduced and removed under mild reaction conditions, and even applicable for further chemical manipulations to afford desired functional groups. To date, a considerable number of auxiliaries derived from carboxylic acids have been demonstrated to have the directing ability to promote metalcatalyzed C(sp) H bond activation, and include amides derived from 8-aminoquinoline, O-methyl hydroxyamine, 2-methylthioaniline, 2,3,4,5,6-pentafluoro-aniline, or 4-trifluoromethyl-2,3,5,6-tetrafluoro-aniline, oxazoline, esters, and even carboxylic acid itself. However, only three structurally similar directing groups derived from amines have been discovered (Figure 1). In 2005, Daugulis and co-workers reported that palladium-catalyzed g arylation of amine derivatives could be achieved by employing a picolinamide auxiliary as the directing group. The difficulty in removing this amide auxiliary prompted Chen, He and co-workers to employ 3-[(tert-butyldimethylsilyloxy)methyl]picolinamide as a modified directing group, which can be removed through intramolecular acyl transfer under acidic conditions, although it is not conveniently available. Recently, Carretero and co-workers described that N-(2pyridyl)sulfamide could serve as the directing group for palladium-catalyzed g arylation of amino acid derivatives. The auxiliary could be easily removed in this case by treatment with zinc/NH4Cl. However, their arylation step needed relatively high reaction temperatures (ca. 150 8C) to ensure satisfactory conversion, and led to the desired arylation product being isolated in a low yield (44%) when a 2-aminobutanoic acid derivative was used as the substrate. Herein, we wish to report 2-methoxyiminoacetyl (MIA) as a powerful auxiliary for promoting palladium-catalyzed functionalization of the C(sp) H bonds of amines. The corresponding amides, derived from substituted aminobutanoic acids, can couple with aryl iodides in the presence of Pd(OAc)2 at 60–100 8C to afford the g-arylation products 2 in good yields. The amides 2 can be hydrolyzed at room temperature and hydrogenated to deliver the substituted homophenylalanines 3 and homophenylalanine-embodied peptides 4, respectively. Noteworthy is that substituted homophenylalanines have been frequently used in developing peptidomimetics which possess important biological activities. This effort has led to the discovery of several marketed drugs such as the antihypertensives enalapril and quinapril, and the antitumor agent carfilzomib (Figure 2). Thus, synthetic methods for quick assembly of substituted homophenylalanines are highly desirable so as to fully explore the structure–activity relationship of homophenylalanine-embodied peptidomimetics. As indicated in Table 1, we started our exploration by conducting the direct arylation of 1a, which was derived from methyl (2S)-aminobutanate and 2-methoxyiminoacetic acid by condensation. To our delight, reaction of 1a with 4iodoanisole in the presence of 10 mol% Pd(OAc)2 and Figure 1. Auxiliary-directed g arylation of C(sp) H bond. Boc= tertbutoxycarbonyl, TBS= tert-butyldimethylsilyl.