Catalytic Asymmetric Aza‐Diels‐Alder Reaction: Pivotal Milestones and Recent Applications to Synthesis of Nitrogen‐Containing Heterocycles

Abstract

In this review, the pivotal achievements and recent advances in catalytic asymmetric aza‐DAR reported up to 2020 are retrospectively considered and their potency for enantioselective synthesis of useful chiral piperidine, quinoline, pyridazine, oxazine and oxadiazine derivatives and fused compounds of higher molecular complexity bearing these pharmacology‐relevant heterocyclic scaffolds is demonstrated. The reported data are systematized according both to key electron transfer modes (normal or invers electron demand reactions) and to main types of attainable heterocyclic products. Of significant attention are an analysis of activation strategies (complexation, enamine or enolate formation, H‐bonding, etc.) applicable to reactions with particular types of dienes and dienophiles and identification of plausible reaction pathways (either concerted or stepwise) over stereoselective cyclization processes. The review contains 310 references and 122 synthetic schemes.

In Situ Anodically Oxidized BMIm-BF4: A Safe and Recyclable BF3 Source

“…In all the cases in this work, the yields obtained are higher when compared with analogous literature data (entry 10). 14 Moreover, the cis isomer was synthesized preferentially, in accordance with other methodologies which employ Lewis acids in classical organic solvents 15 and with opposite diastereoselectivity observed by using I 2 as catalyst ( Table 2 , entry 11). 16 Also in this case, it was possible to reuse the same ionic liquid (entries 1–5, Table 2 ) in subsequent runs without reactivity loss.…”

Recent Developments in Enantioselective Organocatalytic Cascade Reactions for the Construction of Halogenated Ring Systems

“…The reaction may be concerted or stepwise, and piperidines can be obtained by the later strategy through a Mannich/Michael cascade process. [117,118] In 2016 Wang and coworkers reported a formal aza-Diels-Alder reaction between trifluoromethyl hemiaminals (saccharin derivatives, 134) and enones 87 in the presence of a primary amine catalyst (C36), which afforded trifluoromethyl-substituted piperidines 135 via chiral gem-diamine intermediates (Figure 45). [119] Gemdiamine (methylenediamine) has been recognized as an important intermediate in the Mannich reaction, which led to the choice of catalyst for this process.…”

Electrocyclizations of Conjugated Azapolyenes Produced in Reactions of Azaheterocycles with Metal Carbenes

“…The rhodium-catalyzed reactions of azirines 120 with ortho-fused triazoles, [1][2][3]triazolo[1,5-a]pyridines 118, have been studied in [54] (Scheme 23). The final products of the reaction were previously unknown 4H-pyrido[1,2-a]pyrazine derivatives 122, which resulted from 1,6-electrocyclization of 1-(pyridin-2-yl)-2-azabuta-1,3-dienes 121 (1,4-diazahexa-1,3,5trienes with the terminal C=N bond as part of the pyridine system).…”

“…Conjugated azapolyenes such as azabuta-1,3-dienes and aza-/diaza-/oxaza-/oxadiazahexa-1,3,5-trienes (Figure 1) are valuable building blocks in the synthesis of a variety of acyclic and heterocyclic nitrogen-containing compounds [1][2][3][4][5]. These highly unsaturated compounds are generally classified into three types: electron-rich, neutral, and electrondeficient azapolyenes.…”