The Regio‐ and Stereoselective Synthesis of trans‐2,3‐Dihydropyridine N‐oxides and Piperidines

Abstract

Reactivity N-Own: Pyridine N-oxides can be used for the complete regio- and stereoselective synthesis of trans-substituted piperidines. The sequential addition of Grignard reagents and aldehydes or ketones to pyridine N-oxides yields a complete regio- and stereoselective trans 2,3-addition reaction in high yields, and the substituted 2,3-dihydropyridine N-oxide can be reduced to form 2,3-trans-substituted piperidines (see scheme).

Computational Study of Selected Amine and Lactam N-Oxides Including Comparisons of N-O Bond Dissociation Enthalpies with Those of Pyridine N-Oxides

“…In the context of the present work, it is interesting to compare the corresponding steps in the reduction of pyridine N-oxide to piperidine N-oxide (Equation (9)). In contrast to Equations (7) and (8), there were no corresponding experimental data for Equation (9) [ 50 ]. Indeed, catalytic hydrogenation of pyridine N-oxide produced pyridine [ 51 ].…”

“…Based on comparison of ΔH1 (pyridine N-oxide) and ΔH3 (benzene), the overall calculated resonance energy in pyridine N-oxide was 28.7 kcal/mol (B3LYP/6-31G*) or 34.2 (8) In the context of the present work, it is interesting to compare the corresponding steps in the reduction of pyridine N-oxide to piperidine N-oxide (Equation ( 9)). In contrast to Equations ( 7) and ( 8), there were no corresponding experimental data for Equation ( 9) [50]. Indeed, catalytic hydrogenation of pyridine N-oxide produced pyridine [51].…”

Reactions between Grignard reagents and heterocyclic N-oxides: Stereoselective synthesis of substituted pyridines, piperidines, and piperazines

“…This finding was further confirmed by 2D-NMR, noesy and hmbc experiments, and the elucidation of a crystal structure. 23 Furthermore, H-NMR analysis of the crude reaction mixture confirmed that the 2,3-trans dihydropyridine N-oxide 17a isomer was formed exclusively, with the cis isomer not being detected at all. The diastereomeric mixture formed in the reaction results from the third stereocentre created at the benzylic carbon.…”

“…diastereomeric ratio (dr) of 82/18, is rather impressive, especially considering that three stereocentra are formed in one reaction step (Scheme 9). 23 Further investigation of the scope of the reaction was performed with different pyridine N-oxides 1 and PhMgCl followed by sequential addition of benzaldehyde, butyraldehyde or cyclohexanone. These experiments demonstrated that the reaction is compatible with these electrophiles (Scheme 10).…”

Intramolecular cyclizations of alkyl pyridines & alkylidene dihydropyridines as synthetic intermediates toward synthesis of bis(piperidine) alkaloids

“…Almquist and coworkers have shown that organo-magnesium reagents can add to pyridinium N-oxides selectively at the C-2 position in the presence of suitable electrophiles (e.g., benzaldehyde) to obtain functionalized trans-2,3-dihydropyridines (1.52) in a completely regio-and stereoselective process (Scheme 1.13). 56 Another potentially powerful tool for heterocyclic synthesis is asymmetric addition of nucleophiles to activated pyridine substrates. Even though this has proven to be effective with the use of stoichimetric chiral auxiliaries, there are only a few reports describing catalytic asymmetric additions of nucleophiles to pyridinium salts.…”