A tautomeric ligand enables directed C‒H hydroxylation with molecular oxygen

Abstract

Hydroxylation of aryl carbon-hydrogen bonds with transition metal catalysts has proven challenging when oxygen is used as the oxidant. Here, we report a palladium complex bearing a bidentate pyridine/pyridone ligand that efficiently catalyzes this reaction at ring positions adjacent to carboxylic acids. Infrared, x-ray, and computational analysis support a possible role of ligand tautomerization from mono-anionic (L,X) to neutral (L,L) coordination in the catalytic cycle of aerobic carbon-hydrogen hydroxylation reaction. The conventional site selectivity dictated by heterocycles is overturned by this catalyst, thus allowing late-stage modification of compounds of pharmaceutical interest at previously inaccessible sites.

Fig. 1.. C–H hydroxylation with molecular oxygen.

(A) Early observation of directed C–H hydroxylation using molecular oxygen. (B) Inspiration from monooxygenases and organometallic complexes. (C) Ligand-enabled C‒H hydroxylation of heterocyclic carboxylic acids with O₂.

Fig. 2.. Ligand design and computational rationalization.

(A) Catalyst design based on ligand tautomerization. (B) Ligand effect on the C‒H cleavage step. See the supplementary materials for computational details.

Fig. 3.. Bidentate pyridone ligand enabled C–H hydroxylation with molecular oxygen and derivatization of the product.

The reaction was performed with carboxylic acid (0.1 mmol), Pd(OAc)₂ (0.01 mmol), L42 (0.01 mmol), BQ (0.15 mmol), and KOAc (0.2 mmol) in DMF (0.8 ml) under O₂ (1 atm) at 110°C for 24 hours. Isolated yield. *48 hours †Determined by ¹H-NMR using 1,3,5-trimethoxybenzene as the internal standard. ‡See the supplementary materials for experimental details. Fmoc, fluorenylmethyloxycarbonyl; DPPB, 1,4-bis(diphenylphosphino)butane; Tol, p-tolyl.

Fig. 4.. Selective C H hydroxylation and late-stage modification.

Standard conditions entailed carboxylic acid (0.1 mmol), Pd(OAc)₂ (0.01 mmol), L42 (0.01 mmol), BQ (0.15 mmol), and KOAc (0.2 mmol) in DMF (0.8 ml) under O₂ (1 atm) at 110°C for 24 hours. Isolated yields are reported. TBHP, tert-butyl hydroperoxide; DCE, 1,2-dichloroethane.