2,2,5,5-Tetramethyloxolane (TMO): A Green Solvent for Buchwald-Hartwig Aminations and Lithiation-Trapping Reactions of N- and O-Heterocycles

This thesis describes the application of 2,2,5,5-tetramethyloxolane (TMO), a solvent with a similar property profile to toluene, in Buchwald-Hartwig aminations and lithiation-trapping reactions of N- and O-heterocycles.
Chapter 2 involves a comparative reaction performance study between TMO and toluene in the synthesis of N-arylamines via Buchwald-Hartwig cross-coupling. The cross-coupling of aryl bromides with primary and secondary amines with NaOt-Bu and Cs2CO3 as the base in TMO is demonstrated and the synthesis of a medicinally-relevant molecule is included.
Chapter 3 describes the use of TMO as solvent for lithiation-trapping reactions of N-Boc heterocycles. The stability of TMO is the presence of s-BuLi is determined and compared against established ether solvent 2-MeTHF. The effect of TMO in enantioselective lithiation-trapping reactions with two chiral ligands is of particular note. Additionally an exploration into the use of chiral auxiliaries for the diastereoselective lithiation-trapping of N-Boc piperazines is carried out.
The use of TMO in the lithiation-transmetallation-arylation of O-heterocycles is presented in chapter 4. New lithiation-trapping and Negishi cross-coupling conditions are developed culminating in the one-pot synthesis of a-aryl O-heterocycles.
The work contained within this thesis demonstrates the significant promise that TMO offers to replace problematic solvents such as toluene and peroxide forming ether solvents in synthetic organic chemistry.