Sulfonyl Ynamides as Useful Tools for N-Heterocyclic Chemistry

Sulfonyl ynamides are highly versatile and synthetically useful reagents. This thesis details the modular synthesis and use of sulfonyl ynamides in order to access N-heterocyclic scaffolds, such as quinolines and pyrazoles.

The synthesis of a wide array of sulfonyl ynamides can be realized via copper-catalyzed amidative cross-couplings or by elimination of dichloroenamide precursors. Additionally the use of Sonogashira chemistry to further diversify terminal ynamides and the synthesis of solid-supported ynamides was investigated.

Electrophilically-activated amides can be reacted with sulfonyl ynamides in order to access highly functionalized 4-aminoquinolines. The straightforward amide activation procedure with triflic anhydride and 2-chloropyridine was found to tolerate a wide range of substrates, which allowed for the development of a library of 4-aminoquinolines with ease. Moreover, 4-aminopyrazoles can be prepared by reacting terminal sulfonyl ynamides with sydnones under copper catalysis. However, as the copper catalysts were also found to promote the degradation of the ynamides, a copper-free strain-promoted alternative was developed. An in situ prepared 3-azacyclohexyne was found to tolerate a wide array of C-4 substituted sydnones, producing a mixture of both the 3,4- and 4,3-fused pyrazoles in good yields.

Additional investigations into heterocyclic methodology led to the development of highly sophisticated, non-symmetrical and axially-chiral dibenzo-1,3-diazepines, -oxazepines and -thiazepines from simple, commercially available anilines. The anilines were coupled to their corresponding reaction partners via a chloromethyl intermediate and the 7-membered ring was subsequently formed using direct arylation.