Method Development for the Palladium-Catalyzed Synthesis of Nitrogen Heterocycles and Mechanistic Analysis of Migratory Alkene Insertion into Pd-N Bonds

Abstract

The present dissertation describes the specific utilization of palladium-catalyzed carboamination reactions to yield fully saturated 1,4-benzodiazepines and 1,4-benzodiazepin-5-ones in good yield and diastereoselectivity. Although these carboamination reactions are restricted to the use of terminal alkene substrates, a wide variety of aryl synthons were successfully incorporated into the heterocyclic products. These reactions are highly sensitive to the nature of the in situ generated palladium-catalyst, with smaller monodentate ligands giving best results. A boat-like transition state is invoked to rationalize the stereochemical prevalence (>20:1 diastereomeric ratio) for the 2,3-cis-disubstituted-1,4-benzodiazepine products. In addition, efforts toward mechanistic study of intramolecular migratory alkene insertion into Pd–N bonds are summarized. Spectroscopic evidence was gained for the rapid formation of Pd-amido complexes from potassium anilide salts and (dppf)Pd(Ar)(Br) complexes near ambient temperature. Moreover, spectroscopic evidence was obtained for Pd-amido complexes undergoing intramolecular syn-aminopalladation of a pendant alkene into the Pd–N bond to afford observable (dppf)Pd(aryl)(pyrrolidin-2-ylmethyl) complexes. These (dppf)Pd(aryl)(pyrrolidin-2-ylmethyl) complexes participate in C–C bond-forming reductive elimination to afford 2-benzylpyrrolidines. Kinetic data were recorded for both syn-aminopalladation and C–C reductive elimination by monitoring the reactions using 19F NMR spectroscopy. The mechanistic data were most consistent with the overall process proceeding through: (1) fast alkene association to form a transient 5-coordinate Pd-species; (2) rate determining dissociation of one phosphorus atom of the dppf P–P chelate from the Pd-complex; (3) fast syn-aminopalladation of the alkene; and (4) measurable C–C reductive elimination from the resulting (dppf)Pd(aryl)(pyrrolidin-2-ylmethyl) complex.