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Verma, Vani

University of British Columbia

The research presented in this thesis focuses on the development of methods that utilize reactive intermediates such as N-silylamines, N-silylenamines and imines for the synthesis of pharmaceutically relevant N-heterocycles in a one-pot fashion. The ease of the Si–N bond breakage and the altered electronic properties of N-silylamines allow for complementary reactivity to the non-silylated variants. However, the same facile hydrolytic cleavage poses a limitation for method development if a traditional approach is adopted for the isolation of these ammonia surrogates. As such the synthetic utility of these reactive intermediates in one-pot reactions is presented herein. Pyridine derivatives and 7-10 membered saturated N-heterocycles are important scaffolds which can be found in a plethora of commercially available drugs and biologically active natural compounds, respectively. A one-pot general method for the selective synthesis of less explored/challenging multi-substituted pyridines such as 2,4,5-, 2,3,4- and 3,4,5-trisubstituted pyridines is described. Hydroamination of alkynes with an ammonia surrogate N-triphenylsilylamine generates N-silylenamines. These in-situ obtained N-silylenamines upon reaction with α,β-unsaturated carbonyl compounds and subsequent oxidation generate 30 examples of selectively substituted tri-, tetra- and penta-substituted pyridines in up to 78% yield. This one-pot method serves as a crucial step towards the synthesis of a key pyridine precursor for phenanthroizidine alkaloids such as julandine and cryptopleurine. The N-silylenamine and α,β-unsaturated ketone required for the key reaction were synthesized using a titanium catalyzed hydroamination and the Wittig reaction, respectively. The in-situ generated N-silylenamine upon reaction with the α,β-unsaturated ketone produces the key pyridine precursor in <10% yield. While the synthesis suffers from poor yield for the pyridine precursor, the one-pot method demonstrates improved step economy and features four steps in the longest linear sequence. Lastly, the synthetic methods for the preparation of 7-10 membered saturated N-heterocycles are limited. A titanium catalyzed intramolecular hydroamination for the synthesis of azepane and 1,4-diazocane/hexahydro-1H-pyrrolo[1,2-α]imidazole derivatives is described. An eight-atom carbon backbone aminoalkyne underwent cyclization providing the Markovnikov product, and afforded azepane derivatives upon reduction. Whereas, addition of a N-heteroatom in the same eight-atom tether alters the regioselectivity to anti-Markovnikov product, generating 1,4-diazocane/hexahydro-1H-pyrrolo[1,2-α]imidazole derivative.

Text

2025-06-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/85172

Chemistry

University of British Columbia

UBCV

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