Expanding the Utility of Inexpensive Pyridine‐N‐oxide Directing Group for the Site‐selective sp²/sp³γ‐C−H and sp²δ‐C−H Functionalization of Carboxamides

Abstract

We have shown our efforts toward expanding the utility of the relatively inexpensive pyridine-N-oxide directing group in the Pd(II)-catalyzed site-selective γ-C(sp 2 )À H, γ-C(sp 3 )À H and δ-C(sp 2 )À H functionalization. The functionalization βÀ CÀ H bonds using bidentate directing group (DG) pyridine-N-oxide which operates through the N,O-coordination mode has been well documented in the literature. However, there exist rare reports dealing with the functionalization of remote sp 2 /sp 3 γand δ-CÀ H bonds of carboxamides assisted by the bidentate directing groups operating via the N,O-coordination. In this paper, the scope of pyridine-N-oxide DG was examined for accomplishing the siteselective (mono) γ-C(sp 2 )À H arylation in substrates containing competitive C(sp 3 )À H and C(sp 2 )À H bonds. The investigation has enabled to assemble a library of pyridine-N-oxide-based biarylacetamides, heteroaryl-based biaryl carboxamides, tricyclic quinolones, arylheteroarylmethanes, biaryl-based aliphatic carboxamides and mono (ortho) arylated phenylglycine derivatives. In general, biaryl derivatives and in particular, arylacetamide, arylacetic acid derivatives and pyridine-N-oxide (2-aminopyridyl) motifs are medicinally relevant classes of compounds. This work enabled the assembling of a library of the above-mentioned types of compounds through the pyridine-N-oxide directing groupaided site-selective sp 2 /sp 3 γ-CÀ H and sp 2 δ-CÀ H functionalization of carboxamides.

Assembling of Polyaryls (Terphenyls, Tetraphenyls, Pentaphenyls, and Hexaphenyls) through Pd(II)‐catalyzed C−H Arylation of Biaryl Carboxamides with Iodobiaryls

“…The mono C−H arylated products from the C−H arylation of aromatic substrates containing two equivalent ortho β ‐C−H or γ ‐C−H bonds are seldom obtained [8–10] . For example, under suitably optimized conditions or using a moderately efficient directing group the mono C−H arylation product can be obtained [10i] . In the current investigation, the C−H arylation of aromatic substrates containing two equivalent ortho β ‐C−H or γ ‐C−H bonds afforded the bis C−H arylated products as the major products.…”

Pd‐Catalyzed Arylation and Benzylation of Tyrosine at the δ−C(sp2)−H and C(2) Positions: Expanding the Library of Unnatural Tyrosines

“…Due to a steric hindrance by the OTBS substituent at the meta‐ position in 4 b ‐(DL), the C(2)−H arylation yielded only the mono arylated products 8 a – f ‐(DL). This is a commonly observed trend in aromatic compounds possessing a substituent at the meta‐ position [2,11b,18a,21c] …”

Construction of β‐Phenylalanine Derivatives through Pd‐Catalyzed, C(sp2)−H (ortho) Functionalization

“…The ortho C−H arylation in the meta and para dimethoxy substituted substrate 4 f ‐(RS) has occurred only at the less hindered C(sp 2 )−H ( ortho ) bond. In general, this is an observed trend that aromatic carboxamides possessing a substituent at the meta position were found to yield the mono arylated products [3,7b,9b] …”