Metal-Free α-Amination of Secondary Amines: Computational and Experimental Evidence for Azaquinone Methide and Azomethine Ylide Intermediates

Abstract

We have performed a combined computational and experimental study to elucidate the mechanism of a metal-free α-amination of secondary amines. Calculations predicted azaquinone methides and azomethine ylides as the reactive intermediates and showed that iminium ions are unlikely to participate in these transformations. These results were confirmed by experimental deuterium labeling studies and the successful trapping of the postulated azomethine ylide and azaquinone methide intermediates. In addition, computed barrier heights for the rate-limiting step correlate qualitatively with experimental findings.

Stronger Brønsted Acids: Recent Progress

“…148 According to the DFT calculation of the uncatalyzed reaction, the reaction is proposed to proceed by way of hemiaminal 132 and then zwitterionic intermediate 133 followed by proton transfer to generate azomethine ylide intermediate 134. 149 It is proposed that acetic acid acts as a proton shuttle within the transition states TS1−3, thereby lowering the activation energy for each step.…”

Selective copper(II) acetate and potassium iodide catalyzed oxidation of aminals to dihydroquinazoline and quinazolinone alkaloids

“…Access to the sometimes more biologically active dihydroquinazolines, such as deoxyvasicine ( 2 ), from quinazolinones requires a subsequent reduction of the amide. In 2008, our group reported the syntheses of deoxyvasicinone ( 4 ) and rutaecarpine ( 6 ) by the potassium permanganate promoted oxidation of aminals, which in turn were obtained from the condensation of ortho -aminobenzaldehydes and simple secondary amines [31–32]. A number of these aminal precursors were prepared in generally good to excellent yields with the scope encompassing various cyclic amines and substituents on the aminobenzaldehyde aryl ring.…”

Tricyclic Quinazoline Alkaloids: Isolation, Synthesis, Chemical Modification, and Biological Activity

“…Reactions of this type, i.e., functionalization of a C-H bond, are often used to synthesize various heterocyclic compounds [110][111][112][113]. The mechanism of formation of tricyclic quinazolines was studied using deuterium exchange [114]. The solvent was deuterated EtOD or deuterated pyrrolidine (ac) and tetrahydroisoquinoline (dc).…”

“…The solvent was deuterated EtOD or deuterated pyrrolidine (ac) and tetrahydroisoquinoline (dc). The reaction proceeded with prolonged refluxing (10-24 h) to give the corresponding deuterated products (113)(114)(115)(116) in 77-96% yields (Scheme 13). Monobromo-and dibromo-substituted (in the benzene ring) tricyclic quinazolones 120 and 121 were obtained as usual from 5-bromo-(117) or 3,5-dibromoanthranilic acids (118) via cyclization with various lactams (87) in the presence of POCl 3 or SOCl 2 [42,115].…”