The first mechanistic investigation
of electrophilic amide activation
of α,α-disubstituted tertiary lactams and the direct observation
of key intermediates by in situ FTIR, <sup>1</sup>H, <sup>13</sup>C, and <sup>19</sup>F NMR in our interrupted Bischler–Napieralski-based
synthetic strategy to the aspidosperma alkaloids, including a complex
tetracyclic diiminium ion, is discussed. The reactivity of a wide
range of pyridines with trifluoromethanesulfonic anhydride was systematically
examined, and characteristic IR absorption bands for the corresponding <i>N</i>-trifluoromethanesulfonylated pyridinium trifluoromethanesulfonates
were assigned. The reversible formation of diiminium ether intermediates
was studied, providing insight into divergent mechanistic pathways
as a function of the steric environment of the amide substrate and
stoichiometry of reagents. Importantly, when considering base additives
during electrophilic amide activation, more hindered α-quaternary
tertiary lactams require the use of non-nucleophilic pyridine additives
in order to avoid deactivation via a competing desulfonylation reaction.
The isolation and full characterization of a tetracyclic iminium trifluoromethanesulfonate
provided additional correlation between in situ characterization of
sensitive intermediates and isolable compounds involved in this synthetic
transformation
