Palladium-Catalyzed Late-Stage ortho-C–H Bond Aroylation of Anilines Using 4-Methoxy-2-pyridinyl as a Removable Directing Group

Abstract

A synthetic methodology for the late-stage ortho-C–H bond aroylation of anilines with aryl aldehydes led to a variety of ortho-aroylated anilines by the use of palladium­(II) acetate, tert-butyl hydroperoxide, and 1,4-dioxane as the catalyst, oxidant, and solvent, respectively, is presented. An N-phenylpyridin-2-amine palladacycle was isolated and characterized by X-ray crystallography. Controlled experiments, radical trapping experiments, and the experiments of the kinetic isotope effect were undertaken to support the proposed reaction mechanism. Syntheses of 2-aminobenzophenone and 9­(10H)-acridanone based on the developed methodology were successfully demonstrated.

Aldehydes: magnificent acyl equivalents for direct acylation

“…In 2019 Chu et al reported Pd(II)-catalyzed late stage ortho C-H bond acylation of anilines with aromatic aldehydes using 3methoxy-2-pyridinyl as removable directing group. 59 A wide substrate scope of differently substituted aryl aldehydes and N-protected anilines was explored to synthesize 26 monoacylated derivatives of aniline using Pd(OAc) 2 as catalyst and TBHP as oxidant (Scheme 25A). However, in few cases along with monoacylated aniline formation diacylated product was observed.…”

Pd(II)-Catalyzed C-H Acylation of (Hetero)arenes—Recent Advances

“…If the pyridine-directing group is linked to the aromatic ring through a heteroatom [ 7 ], it can be easily removed, so further transformations can be performed on the acylated compounds, significantly increasing the synthetic applicability of these transformations. Along these lines, the effect of the substitution on the pyridine ring was studied in the acylation of N -aryl-2-pyridinylamines 10 ( Scheme 3 ) [ 14 ].…”

“…The reaction was extended to a series of aldehydes obtaining 11 in moderate to good yields, although in most cases significant amounts of the diacylated products were also obtained. Both protecting groups could be efficiently removed to obtain amine 12 , which could also be transformed into an acridanone [ 14 ]. Besides the use of simple 2-pyridinyl, other related directing groups based on nitrogen coordination have been developed.…”

One‐Pot Synthesis of 2‐Aminobenzophenones from 2‐Alkynyl Arylazides Catalyzed by Pd and Cu Precursors

“…In 2019, Zhu's group disclosed a photoredox deoxygenative arylation of 2‐(phenylsulfonamido)benzoic acids generated in situ from anthranilic acids and arylsulfonyl chlorides (Scheme 1b) [10b] . In the same year, Wu's group described the formation of 2‐aminobenzophenones by the ortho ‐C−H bond aroylation of anilines containing a 4‐methoxy‐2‐pyridinyl directing group, which could be removed after two simple steps (Scheme 1c) [10c] . Although much progress has been achieved, the development of efficient methods for the synthesis of 2‐aminobenzophenones from novel starting materials is still highly desired.…”