Dirhodium-catalyzed C-H arene amination using hydroxylamines

Abstract

Primary and N-alkyl arylamine motifs are key functional groups in pharmaceuticals, agrochemicals, and functional materials, as well as in bioactive natural products. However, there is a dearth of generally applicable methods for the direct replacement of aryl hydrogens with NH2/NH(alkyl) moieties. Here, we present a mild dirhodium-catalyzed C-H amination for conversion of structurally diverse monocyclic and fused aromatics to the corresponding primary and N-alkyl arylamines using NH2/NH(alkyl)-O-(sulfonyl)hydroxylamines as aminating agents; the relatively weak RSO2O-N bond functions as an internal oxidant. The methodology is operationally simple, scalable, and fast at or below ambient temperature, furnishing arylamines in moderate-to-good yields and with good regioselectivity. It can be readily extended to the synthesis of fused N-heterocycles.

Fig. 1. A dramatic shift in chemoselectivity arises with different aminating agents

o-Allylanisole (1) undergoes chemoselective olefin aziridination in the presence of catalytic Rh₂(esp)₂ (6) and aminating agent DPH (2) in 2,2,2-trifluoroethanol (TFE = CF₃CH₂OH) to give 3. Changing the aminating agent to TsONHMe (4a) furnishes the corresponding N-Me aniline (5).

Fig. 2. Direct intermolecular amination of arenes

Reactions were conducted on a 0.1–0.5 mmole scale at 0.1 M using 2,2,2-trifluoroethanol (TFE = CF₃CH₂OH) as solvent or using mixtures of TFE and other solvents as indicated.

Fig. 3. Direct intramolecular cyclization (aza-annulation) of arenes

Cyclizations were conducted at 0.1 M using 2,2,2-trifluoroethanol (TFE = CF₃CH₂OH) as the solvent on a 0.1–0.3 mmol scale unless otherwise indicated.

Fig. 4

Proposed intermediates leading to amination versus aziridination and control study of arene amination vs benzylic C-H insertion.