The presence of nitrogen in amino functional groups found in many useful natural and synthetic products makes their preparation valuable to chemicals and materials production, biology and medicinal chemistry. Their importance has inspired chemists to design a variety of methodologies for C-H bond activation essential for building amino functional groups. Transition metal-mediated nitrenoid transfer reactions are important chemical processes in which hydrocarbons are transformed to nitrogen containing compounds via direct C-N bond formation. A variety of transition metal catalysts have been developed for the oxidative functionalization of carbon-hydrogen bonds. Although general methods for intramolecular C-H bond amination are relatively new, they have already found application in the preparation of a variety of natural product targets. The objectives of our project are to discover efficient nitrenoid sources for catalytic C-H amination with inexpensive copper complexes as catalysts, and to evaluate the scope and selectivity and mechanism in amination reactions.

Several classes of ligands, including α-amino acids, diamines, diphosphines, bis-oxazolines, and diimines, support efficient copper-catalyzed intermolecular amination of benzylic hydrocarbons by anhydrous chloramine-T. The initial synthetic study of the reactions revealed ligand-accelerated catalysis with significant sensitivity to the electronic character of the substrates and ligands. Intermolecular reaction with various benzylic hydrocarbons gives tosyl-protected amines that can be isolated with moderate to excellent yields and that cleave easily to produce the corresponding free amine. Catalysts derived from homochiral ligands, particularly chiral diimines, and effect amino-sulfonation of benzylic hydrocarbon with low to moderate enantioselectivity. The low enantioselectivity led us to study the mechanism of the amination reaction.

The mechanism of hydrocarbon amination by chloramine-T derivatives catalyzed by (diimine) copper complexes has been investigated. Isotopic effects, stereochemical studies and the electronic nature of the transition state are used to probe the mechanism of the reaction. A kinetic isotope effect of 4.6 was found in the amination of D(H)-cumenes catalyzed by [(diimine)Cu(solv)]Z. Amination of the isomeric substrates cis- and trans-4-t-butyl-1-phenylcyclohexanes with 4-Me-C6H4SO2NNaCl (chloramine-T) or 4-NO2-C6H4SO2NNaCl (chloramine-N) catalyzed by [(diimine)Cu(CH3CN)]PF6 produced in all cases an approximately 1:1 mixture of the corresponding cis- and trans-4-t-butyl-1-phenyl-1-sulfonaminocyclohexanes. Amination of the radical-clock substrate 1-phenyl-2-benzylcyclopropane with chloramine-T/(diimine)Cu(CH3CN)]PF6 gave a mixture of ring-opened and cyclopropylmethylamino derivatives. Together these results are most consistent with a stepwise insertion of an N-Ts unit into the C-H bond, via carbon radicals, and a secondary contribution from a concerted insertion pathway. B3LYP and CASSCF computations (in collaboration with P. Liu and Prof. K. Houk) suggest that the C-H insertion step involves the reaction of the hydrocarbon with a Cu-imido (nitrene) complex, [(diimine)Cu=NSO2R]+. The ground state triplet of the Cu-imido complex is calculated to be more stable than singlet complex. The reaction of each complex with hydrocarbon showed that the C-H insertion transition state for the triplet is lower in energy than the singlet. The triplet reacts by a stepwise H-atom abstraction, while the singlet would react by a concerted C-H insertion. These results and kinetic isotope effect calculations for the singlet (2.9) and triplet (4.8) pathways, respectively, agree with the experimental observations (4.6) and point to a major role for the triplet complex in the stepwise, non-stereoselective insertion pathway.

The discovery of the ligand assisted copper catalyzed intramolecular reaction was another aspect of our amination project. Metal nitrenes for use in C-H insertion reactions were obtained from carbamates in the presence of iodosyl benzene and a Cu(I) ligand complex. The intramolecular C-H amination reaction proceeds smoothly catalyzed by Cu(I)-diimine complexes in moderate to excellent yield. This new methodology allows the amination of benzylic, and aliphatic tertiary, and secondary C-H bonds. The intramolecular reaction provides an interesting route to various substituted oxazolidinones and oxathiazinanes via formation of five-membered and six-membered rings respectively. Employing homochiral diimine ligands affords oxazolidinones and oxathiazinanes with modest enantioselectivity. The development, scope, and limitations of the reactions are discussed herein.