Palladium(II)-Catalyzed Sp3/Sp2 γ- and δ-C-H Functionalization of Aryl Amines using 5-Methylisoxazole-3-Carboxamide as Directing Group

A dual objective-based study comprising exploration of 5-methylisoxazole-3-carboxamide (MICA) as a directing group (DG) for the Pd(II)-catalyzed sp(3)/sp(2) gamma- and delta-C-H activation/functionalization of aryl amines and assembling of various MICA motifs are reported. The Pd(II)-catalyzed MICA-aided gamma-C(sp(3))-H arylation/acetoxylation of ortho-toluidines gave various 2-aminodiphenylmethanes and 2-aminobenzyl acetates, respectively. The Pd(II)-catalyzed MICA-aided gamma-C(sp(2))-H arylation/acetoxylation of benzylamines gave the corresponding arylated/acetoxylated products. Furthermore, the Pd(II)-catalyzed MICA-aided delta-C(sp(2))-H amidation/alkenylation of phenethylamines were also explored. Representative control reactions were done to assess the relative effectiveness of MICA for the gamma-C(sp(3))-H arylation and MICA is a removable DG. Apart from the usage of MICA as a DG for the sp(2)/sp(3) C-H functionalization of aryl amines, indirectly this process has led to the construction of a library of MICA motifs. This is an added advantage to note as the MICA-based motifs are valuable small molecules in medicinal chemistry.