title: Direct Observation of Intermediates Involved in the Interruption of the Bischler-Napieralski Reaction.
abstract: 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, (1)H, (13)C, and (19)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 N-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.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
authors.forename: Kolby L
authors.initials: KL
authors.lastname: White
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
authors.forename: Marius
authors.initials: M
authors.lastname: Mewald
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Movassaghi
mesh_terms: D000470:Alkaloids / Q000737:chemistry; D000577:Amides / Q000737:chemistry; D030009:Aspidosperma / Q000737:chemistry; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D007769:Lactams / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008698:Mesylates / Q000737:chemistry*; D015394:Molecular Structure; D011726:Pyridinium Compounds / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000470:Alkaloids; D000577:Amides; D005462:Fluorine Radioisotopes; D007769:Lactams; D008698:Mesylates; D011726:Pyridinium Compounds; C012077:trifluoromethanesulfonic acid