Iron(III)-Promoted Aza-Prins-Cyclization:  Direct Synthesis of Six-Membered Azacycles

Abstract

[reaction: see text] A new iron(III) halide-promoted aza-Prins cyclization between gamma,delta-unsaturated tosylamines and aldehydes provides six-membered azacycles in good to excellent yields. The process is based on the consecutive generation of gamma-unsaturated-iminium ion and further nucleophilic attack by the unsaturated carbon-carbon bond. Homoallyl tosylamine leads to trans-2-alkyl-4-halo-1-tosylpiperidine as the major isomer. In addition, the alkyne aza-Prins cyclization between homopropargyl tosylamine and aldehydes gives 2-alkyl-4-halo-1-tosyl-1,2,5,6-tetrahydropyridines as the only cyclic products.

Broadening the Synthetic Scope of the Iron(III)‐Catalyzed Aza‐Prins Cyclization

“…We used our previously described conditions based on stoichiometric amounts of FeCl 3 and the catalytic systems FeX 3 /TMSX or Fe(acac) 3 /TMSX. [5,6] We found complete conversion to the desired product when an excess of aldehyde was used (Table 1, entries 4, 7, and 10). In the stoichiometric reaction an excess of FeX 3 was necessary to obtain better yields (Table 1, entries 3 vs. 4).…”

“…However, 2-phenylacetaldehyde and benzaldehyde gave lower yields. [5,6] With these results in hand, we extended our studies to homoallyl(nosyl)amine as the unsaturated amine. Table 2 summarizes the results obtained in this study.…”

“…The process is based on the consecutive generation of a γ-unsaturated iminium ion and subsequent nucleophilic attack by the unsaturated C-C bond. [5] Homoallyl(tosyl)amine (1) gave trans-2-alkyl-4-halo-1-tosylpiperidine 3 as the major isomer. In addition, the alkyne aza-Prins cyclization reaction between homopropargyl(tosyl)amine (4) and aldehydes gave 2-alkyl-4-halo-1-tosyl-1,2,5,6-tetrahydropyridines 5 as the only cyclic products.…”

Sulfamic Acid Catalyzed Five Component Reaction for Efficient and One-Pot Synthesis of Densely Functionalized Tetrahydropyridine Scaffold

“…10 Compounds including tetrahydropyridine motif reveal antimalarial, 11 antibacterial 12 , antihypertensive, 13 anticonvulsant and anti-inflammatory activities. 14 There are various synthetic strategies have been developed for the synthesis of tetrahydropyridine scaffolds, some of the them includes, imino-Diels-Alder reactions, 15 aza-Prins-cyclizations, 16 intramolecular Michael reactions 17 and intra-molecular Mannich reaction onto iminium ions 18 . An alternative current strategy for the synthesis of functionalized tetrahydropyridine is using onepot MCRs.…”

Unexpected halogen exchange with halogenated solvents in the iron(III) promoted oxa-alkyne and aza-alkyne Prins cyclizations

“…The coupling between homopropargyl tosyl amines with aldehydes provides 2-alkyl-4-halo-1-tosyl-1,2,5,6-tetrahydropyridines 6 in good yields (Scheme 1). 10 A critical issue in these reactions is the choice of suitable solvent. We found, in the above two procedures, an unexpected halide exchange with halogenated solvents presumably caused by the vinyl cation intermediates 2 and 5.…”