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Group 5 alkyltantalum and ureate catalyst systems : hydroaminoalkylation reactivity and applications in selective syntheses of structurally diverse amines

University of British Columbia

Alkyltantalum precatalysts for intermolecular hydroaminoalkylation reactions between alkene and amine substrates are explored to gain insight into catalyst structure/activity relationships and to develop new methods for the regioselective and diastereoselective synthesis of amines and N-heterocycles. This thesis addressed significant challenges with widespread adoption of hydroaminoalkylation towards synthesizing products that display concrete applications in agricultural or pharmaceutical industries. First, we synthesized alkyltantalum starting materials and combined them with new ureate ligand salts for in situ catalyst mixtures that display promising reaction rates. Substrate scope in this section emphasized reactivity using switchable ureate salts for either terminal or internal alkenes while maintaining chemoselectivity with diene substrates. We then probed reaction scope changes that resulted from varying ligand steric and electronic factors. We extended this to study chiral cyclic ureate ligands to attempt enantioselective catalysis, these ligands resulted in poor ee’s, but presented unprecedented reactivity with challenging aliphatic amine substrates. Comparative hydroaminoalkylation reactivity with different Ta halides revealed that a brominated Ta started material is slightly more reactive than its chlorinated counterpart, while a fluorinated complex was not active at all. Catalysis with a new chiral ureate salt accomplished highly chemo- and regioselective C- C bond formation between substituted N-methylanilines and either limonene or pinene. We confirmed that hydroaminoalkylation does not racemize allylic stereocentres and can be selective for terminal alkenes. Further, pinene-containing products were consistently generated with high diastereoselectivity. All products were isolated using a simple filtration protocol. iii The catalyst system highlighted towards the end of this thesis was the first generally reactive hydroaminoalkylation system. Reactivity was excellent with aromatic or aliphatic amines, terminal or internal alkenes, and most importantly saturated N-heterocycles. Exploring substrate scope with these N-heterocycles resulted in consistently good yields, with good regio- and diastereoselectivity when unactivated alkene partners are used. However, additional data highlighted the linear dependence of regioisomer product ratios as a function of alkene electronic factors when combining piperidine with styrene partners. This discovery of substrate-controlled product selectivity allowed for only linear product to be obtained in select cases. Final results applied N-heterocycle reactivity to a two-step, one-pot catalytic, regiodivergent synthesis of indolizine and quinolizine alkaloids.

Text

2022-09-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/75551

Chemistry

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/