Development of nickel-catalyzed hydroamidation of arylalkenes with 1,4,2-dioxazol-5-ones

Abstract

The synthesis of amides is of a great importance for manufacturing of many bioactive natural products and pharmaceutical compounds. Amides are commonly prepared by the coupling of activated carboxylic acids with amines. Recently, transition metal-catalyzed hydroamidation of alkenes, whereby the N-H bond of amines is formally added across the carbon-carbon π-bond, is an attractive strategy for the amides synthesis because this transformation provides a direct access to amides from simple precursors. It is anticipated that the σ-alkyl metal species formed by the hydrometallation of alkenes are active for the further functionalization by amidating reagents to offer the amide products. Moreover, an enantioselective synthesis of chiral amides is conceivable if chiral ligands are employed. In this thesis, we describe the development of the Ni-catalyzed hydroamidation of arylalkenes with 1,4,2-dioxazol-5-ones and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Reacting arylalkenes (0.2 mmol) with 1,4,2-dioxazol-5-ones (0.4 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.3 mmol), 6,6'-dimethyl-2,2'-dipyridyl (12 mol%) and Ni(ClO4)2·6H2O (10 mol %) offered the desired amide compounds in up to 91% yields with good functional groups tolerance. Moreover, this reaction shows Markovnikov regioselectivity exclusively. In addition, the preliminary mechanistic study revealed that the carboradical intermediates were unlikely to be involved. As for the study of the enantioselective nickel-catalyzed amidation of arylalkenes, a series of chiral bis(oxazoline) ligands was tested. Treating 4-tert-butylstyrene (0.2 mmol), 3-phenyl-1,4,2-dioxazol-5-one (0.4 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.3 mmol), (+)-2,2′-isopropylidenebis(4R)-4-phenyl-2-oxazoline (12 mol%) and Ni(ClO4)2·6H2O (10 mol%) in DCE at 40°C for 12 h furnished the corresponding amide products in up to 82% yields with 84:16 enantiomeric ratio (er). The linear free energy relationship between the para-substituted alkenes and enantioselectivities was explored to imply that the migration of Ni-H species to alkenes was unlikely to be the enantioselectivity-determining step (EDS).