Stereoselective Synthesis of Amido and Phenyl Azabicyclic Derivatives via a Tandem Aza Prins-Ritter/Friedel–Crafts Type Reaction of Endocyclic N-Acyliminium Ions

Abstract

A simple protocol is described for the synthesis of amido and phenyl hexahydroindolizin-3(2H)-one, hexahydro-1H-quinolizin-4(6H)-one, and 1,3,4,10b-tetrahydropyrido[2,1-a]isoindol-6(2H)-one derivatives via endo-trig (aza-Prins type) cyclization followed by an intermolecular Ritter/Friedel-Crafts reaction of cyclic N-acyliminium ions, which are derived from the boron trifluoride etherate treatment of regioselectively reduced N-homoallyl imides. The reactions are highly diastereoselective with excellent yields.

A Stereoselective aza-Prins Reaction: Rapid Access to Enantiopure Piperidines and Pipecolic Acids

“…In the absence of a suitable nucleophile, it is also known that solvents, such as acetonitrile or benzene, can trap the cyclic secondary carbocation, in an aza-Prins-Ritter or aza-Prins-Friedel-Crafts cascade. 21,36 Using pTSA in acetonitrile gave good yields of the 4-NHAc trapped products (Table 3), again as a single enantiomer and diastereomer. In place of TFA or TsOH, the alternative is to use a Lewis acid to promote the aza-Prins cyclisation, with iron and indium trihalides being particularly prevalent in the literature.…”

Synthesis of Azabicycles via Cascade Aza-Prins Reactions: Accessing the Indolizidine and Quinolizidine Cores

“…Reddy 20 , Saikia 21,22 , Overman 23 and Waters 24 have all prepared azabicyclic systems using a Prins or related cyclisation process, but have either started from an intact or commercial mono-cyclic system, 24 or have required the sequential formation and purification of the mono-cyclic precursors, followed by a second cyclisation process. 23 Thus the uniqueness and advantage of this approach in the one-pot double cyclisation, forming both rings in a single transformation.…”

Cascade Intramolecular Prins/Friedel–Crafts Cyclization for the Synthesis of 4-Aryl-tetralin-2-ols and 5-Aryl-tetrahydro-5H-benzo[7]annulen-7-ols

“…Cascade Prins/Friedel-Crafts reaction to form multiple chemical bonds in one operation has emerged as a very important atom-economic strategy for the construction of oxygen-containing heterocycles. [10][11][12] For example, Nagumo and coworkers have developed a Prins/Friedel-Crafts cyclization of homocinnamyl alcohols with aromatic aldehydes under action with BF3Et2O affording 2H-indeno[1,2-b]furan derivatives. 13 Likewise, Hinkle and coworkers reported in 2017 a three-step domino alkynyl-Prins cyclization, Friedel-Crafts alkenylation, and dehydration/aromatization reaction between 1-aryl-3-hexyne-2,6-diol derivatives and aldehydes, and this led to the formation of 1,4-dihydro-2H-benzo[f]isochromenes.…”