Synthesis of meta-carbonyl phenols and anilines

Abstract

Phenols and anilines are of extreme importance for medicinal chemistry and material science. The development of efficient approaches to prepare both compounds has thus long been a vital research topic. The utility of phenols and anilines directly reflects the identity and pattern of substituents on the benzenoid ring. Electrophilic substitutions remain among the most powerful synthetic methods to substituted phenols and anilines, yet in principle achieving ortho- and para-substituted products. Therefore, the selective preparation of meta-substituted phenols and anilines is the most significant challenge. We herein report an efficient copper-catalyzed dehydrogenation strategy to exclusively synthesize meta-carbonyl phenols and anilines from carbonyl substituted cyclohexanes. Mechanistic studies indicate that this transformation undergoes a copper-catalyzed dehydrogenation/allylic hydroxylation or amination/oxidative dehydrogenation/aromatization cascade process.

Fig. 1. Synthesis of meta-carbonyl phenols and anilines.

a Synthesis of phenols and anilines. b Recent work. c Proposed reaction process.

Fig. 2. Substrate scope for synthesis of meta-carbonyl phenols.

a Substrate scope of aryl ketones. b Substrate scope of conjugated enones. c Substrate scope of aliphatic ketones and aldehydes. Reaction conditions: substrate (0.25 mmol), CuI (10 mol%), AgOAc (9 mol%), and TFA (10.0 equiv) in DMSO (1 mL), H₂O (50 μL) under O₂ at 90 ^oC for 60 h. Isolated yields are reported. ^aReaction conducted with 1a (5.5 mmol). ^bAgOAc (9.5 mol%) was used. ^c48 h. ^d100 ^oC. ^eNo addition of H₂O. ^fPd(OAc)₂ (15 mol%) was used instead of AgOAc.

Fig. 3. Substrate scope for synthesis of meta-carbonyl anilines.

a Substrate scope of anilines. b Substrate scope of aromatic ketones. c Substrate scope of N-acetyl anilines. d Substrate of N-propionyl aniline. e Substrate of N-tert-butoxycarbonyl aniline. Reaction conditions: 1 (0.25 mmol), 11 (0.5 mmol) or 14 (0.5 mmol) or 15 (0.5 mmol), CuI (10 mol%), TBHP (2.2 equiv), and TFA (10.0 equiv) in DMSO (1 mL) at 90 ^oC for 60 h. Isolated yields are reported. ^aTBHP (1.1 equiv). ^bTBHP (2.0 equiv). ^c36 h. ^dAgOAc (9 mol%) instead of TBHP. Boc, tert-butoxycarbonyl.

Fig. 4. Mechanistic investigation.

a ¹⁸O-labeled water experiment. b Deuterium-labeling experiments. c Kinetic isotope effect studies. d Intermediate traping experiments and kinetic profiles. e Kinetic studies.