AbstractsChemistry

The development of new methods of generating alpha-amino acid derivatives via multi-component reactions remains an important challenge. The primary goal of this study is to develop new transition metal-mediated routes to synthesize these alpha-amino acid derivatives using combinations of simple reagents, such as imines, carbon monoxide, acid chlorides and organotin reagents. The proposed approach requires the sequential insertion of imine and carbon monoxide into late transition-metal sigma-bonds, as well as the further reactivity of the products. In chapter 2, the ability of the nickel complex L2Ni(CH 3)N(R)=C(H)R'+X- (L2 = chelating nitrogen ligands, X- = non-coordinating counteranion) to mediate the insertion of imines is examined. Although L2Ni(CH3)N(R)=C(H)R' +X- does not undergo direct imine insertion into the Ni-CH3 bond, the addition of CO leads to the generation of the novel nickel complex (L2)Ni[n2-CH(R')NRCOCH 3]+X- via the insertion of imine into the nickel-acyl bond of L2Ni(COCH3)N(R)=C(H)R' +X-. This demonstrates as proof of concept, that these nickel complexes can mediate the sequential insertion of CO and imine into nickel-methyl bonds, in direct analogy to well known CO/olefin insertions. Further reactivity studies have demonstrated that the amide bound nickel chelates generated via the sequential insertion of CO and imines are generally inert towards subsequent migratory insertion with CO, imine and olefins (Chapter 3). These complexes are also inert towards auxiliary ligand exchange or amide de-chelation, with both mono- and bidenate nitrogen and phosphine ligands. Studies involving the use of imines and alkenes as interchangeable insertion substrates, (Chapter 4) resulted in the first example of a metal mediated cyclocarbonylation incorporating imine as a formal insertion substrate. Based on these studies, one-pot sequential insertion cascade of CO, olefin, a second unit of CO, and imine was developed for the synthesis of 5 and 6 membered lactams. In addition, the competitive insertion propensity of imines and alpha-olefins was examined, and clear steric and electronic effects were identified. The isoelectronic palladium-bound amide complexes, generated via the oxidative addition of N-acyl iminium salts (R(H)C=N(R')COR") to Pd2(dba) 3·CHCl3 can undergo a Stille-tye coupling with organotin reagents to generate alpha-substituted amide derivatives (Chapter 5). This reactivity was extended into a convenient and general one-pot synthesis of alpha-substituted amides and N-protected amines by a palladium-catalyzed three-component coupling of imines, acid chlorides or chloroformates, and organotin reagents. Mechanistically, this process provides an oxidative addition/reductive elimination-based alternative to nucleophilic approaches to C-C bond formation with imines, in which the imines are activated towards addition to palladium by RCOCl.