Tf2O-Promoted Morgan–Walls Reaction: From a Flexible Approach to Functionalized Phenanthridines and Quinazolines to the Short and Divergent Total Syntheses of Alkaloids

Abstract

A new protocol for the direct transformation of secondary amides (N-acyl-o-xenylamines) into phenanthridines under mild conditions is reported. The method features trifluoromethanesulfonic anhydride (Tf2O)/2-fluoropyridine as the efficient amide activation system and MeCN or CH2Cl2 as the solvent. For some substrates, MeCN participated in the reaction, which affords a mild access to polysubstituted quinazolines. By employing the Tf2O/2,4,6-tri-tert-butylpyrimidine (TTBP) combination, the method was extended to an N-formyl-o-xenylamine, which represents a recalcitrant amide substrate type for the dehydracyclization reaction. More importantly, a one-pot method was established for the direct and divergent synthesis of four types of phenanthridinoids from o-xenylamines, which features both tert-N-formyl-o-xenylamines and phenanthridinium salt as key and versatile intermediates. The investigation resulted in one of the shortest and the most efficient total syntheses of three natural products: trisphaeridine, 5,6-dihydrobicolorine, N-methylcrinasiadine, and in the formal total syntheses of other three ones: 3-hydroxytrisphaeridine, bicolorine, and zephycandidine A.

One-pot synthesis of 1,3-oxazin-4-ones through an Ir-catalyzed mild formal condensation reaction of secondary amides with acyl chlorides

“…Benefiting from the significant progress in the selective direct transformations of secondary amides under mild conditions over the past decades, 11 secondary amides have served well as the surrogates of imines and aldehydes, 12 and moreover as starting materials to install biologically important heterocycles. 13 It is noteworthy that stoichiometric amounts of activating reagents, such as Tf 2 O or Cp 2 ZrHCl, were used in these protocols. Delightfully, Brookhart disclosed a reduction of secondary amides to imines at room temperature catalyzed by commercially available [IrCl(COE) 2 ] 2 .…”