Diverse ortho-C(sp²)–H Functionalization of Benzaldehydes Using Transient Directing Groups

Abstract

Pd-catalyzed C-H functionalizations promoted by transient directing groups remain largely limited to C-H arylation only. Herein, we report a diverse set of ortho-C(sp)-H functionalizations of benzaldehyde substrates using the transient directing group strategy. Without installing any auxiliary directing group, Pd(II)-catalyzed C-H arylation, chlorination, bromination, and Ir(III)-catalyzed amidation, could be achieved on benzaldehyde substrates. The transient directing groups formed in situ via imine linkage can override other coordinating functional groups capable of directing C-H activation or catalyst poisoning, significantly expanding the scope for metal-catalyzed C-H functionalization of benzaldehydes. The utility of this approach is demonstrated through multiple applications, including late-stage diversification of a drug analogue.

Transient Ligand‐Enabled Transition Metal‐Catalyzed C−H Functionalization

“…In 2017, transient ligand ( L6 , L8 , or L9 )enabled Pd‐catalyzed C−H arylation, chlorination, and bromination of benzaldehyde substrates were reported by the groups of Yu and Zhang. They found that the concentration of acid additives and transient ligands played a vital role in the ortho ‐C(sp 2 )−H functionalization of the benzaldehydes (Scheme a–c) . Furthermore, Sorensen and co‐workers reported that the o ‐hydroxylation of benzaldehydes could be achieved using p ‐TsOH as the hydroxy source and 2‐amino‐4‐chlorobenzoic acid ( L10 ) as the transient ligand (Scheme d) .…”

Rhodium‐catalyzed ortho‐C‐H olefination of aromatic aldehydes employing transient directing strategy

“…Initially, benzaldehyde 1a and methyl acrylate 2a were selected as the substrates to screen the reaction conditions in the presence of catalytic amount of glycine that was widely used as an efficient TDG in previous reports . Results are summarized in Table .…”

Methylene C(sp3)–H Arylation of Aliphatic Ketones Using a Transient Directing Group

“…As shown in Table 2, a wide range of aryl iodides with substituents were employed as the coupling partners. Compared with our previous study, 10a the scope of aryl iodide for C(sp 3 )–H arylation of ketones was significantly expanded. Electron-deficient aryl iodides bearing ester, trifluoromethyl and nitro groups at the meta - or para -positions were well tolerated under the standard conditions, providing consistently good yields ( 2a – 2d , 2f ), although the yield slightly dropped to 66% with para -nitro substitution ( 2e ).…”

“…Our investigations regarding the utility of bidentate monoprotected amino acid (MPAA) ligands in transition metal catalyzed C–H functionalizations 8,9 has led us to develop the Pd-catalyzed C(sp 3 )–H functionalization of ketones using a catalytic amino acid as a transient directing group (Scheme 1A). 10,11 Subsequently, the Ge group reported that β-amino acids could serve as transient directing groups that promote palladium-catalyzed β-C–H arylation of aliphatic aldehydes . 12 Despite these advances, the activation of β-methylene C–H bonds of acyclic ketones or aldehydes using either pre-installed or transient directing groups has remained an unsolved challenge.…”

“…10–12 For example, palladium catalyzed C–H arylation of the β-methylene C–H bonds on an acyclic aldehyde has been reported to provide only 25% yield when employing a transient directing group strategy. 12 This is unsurprising as methylene C–H bonds are significantly more resistant to palladium insertion than primary C–H bonds due to the steric hindrance.…”