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.

Figure 1

Low Temperature Activation of Lactam 8 and Observation of Diiminium Ion (±)-11 by ¹H NMR.

Scheme 1

A. Electrophilic Tertiary Amide Activation with Tf₂O. B. N-Sulfonylation of Pyridines.

Scheme 2

Electrophilic Activation of Lactams. A. Conversion of lactams 1 to sulfonyl iminium ions 3 and diiminium ethers 6. Conditions: (a) Tf₂O (1.0 equiv), CH₂Cl₂, −78 °C. (b) Tf₂O (0.5 equiv), CH₂Cl₂, −78 °C (6a) or −78→23 °C (6b). B. Representative conversion of lactam 1a to sulfonyl iminium ion 3a monitored by in situ IR. C. Representative conversion of lactam 1a to diiminium ether 6a monitored by in situ IR. Key IR absorption bands are reported in wavenumber and shown in red.

Scheme 3

Formation and Equilibration of Diiminium Ethers. Conditions: (a) Tf₂O (1.0 equiv), CH₂Cl₂, −78→23 °C. (b) 1b (1.0 equiv); −78→23 °C. (c) 1a (1.0 equiv); −78→23 °C. (d) 30 min, 23 °C. Key IR absorption bands are reported in wavenumber and shown in red.

Scheme 4

Deactivation in the Presence of Pyridine. A. Conditions: (a) pyridine (2 equiv), CH₂Cl₂, −78 °C → 23 °C. B. Activation of lactam 1b in the form of sulfonyl iminium ion 3b, followed by its deactivation upon treatment with pyridine. Key IR absorption bands are reported in wavenumber and shown in red.

Scheme 5

Direct Observation and Study of Spirocyclic Diiminium Ion (±)-11. A. Conditions: (a) Tf₂O (1.2 equiv), CH₂Cl₂ or CD₂Cl₂, −78→23 °C. (b) Et₃SiH, 23 °C; LiAlH₄, THF, 0→23 °C. (c) Et₃SiH, 23 °C; pyridine. B. Conversion of lactam 8 to tetracyclic bisiminium ion (±)-11 monitored by in situ IR. Key ¹³C NMR resonances (blue) and IR absorption bands (red) are noted.