Diverse ortho C-H Functionalizations of Benzaldehydes Using Transient Directing Groups

Abstract

Benzaldehydes are abundant and synthetically versatile intermediates in organic synthesis; yet their potentials for direct C-H functionalizations at the ortho position have been rarely explored. The development of such methods is hampered by the weak coordinating ability of the aldehyde’s group, its susceptibility towards undesired oxidation as well as competitive metal insertions into the formyl C-H bonds.

We sought to develop new transient directing groups (TDGs) and oxidative conditions for the diverse ortho C-H functionalizations of benzaldehydes through Pd and Ir catalysis. Using anthranilic acid as a TDG precursor, fluorenones were synthesized directly from benzaldehydes and aryl iodides via a Pd-catalyzed dual C-H functionalization process. The selective ortho hydroxylation of benzaldehydes was achieved with the assistance of a similar TDG precursor, but in this case, an electrophilic F+ reagent was used as the bystanding oxidant for Pd and p-TsOH as the oxygen nucleophile.

Two other challenging transformations, ortho C-H methylation and fluorination of benzaldehydes were also developed through Pd catalysis. In these reactions, the use of orthanilic acids as new TDG precursors were the key to promote the otherwise difficult reactivities. By fine tuning of reaction conditions, the F+ reagents could either serve as a bystanding oxidant in the C-H methylation reaction, or an electrophilic fluorinating reagent in the C-H fluorination reaction. A single X-ray crystal structure of the benzaldehyde ortho C-H palladacycle was also obtained by trapping the insertion intermediate with PPh3.

Switching the transition metal catalyst from Pd to Ir led to the development of a new method for benzaldehyde ortho C-H alkylations using aniline as a transient ligand. Both heteroaromatic aldehydes and enals were tolerated in this reaction.