Influence of A(1,3)-strain on the conformational preferences and stereodynamics of N-formyl-cis-2,6-diarylpiperidines

Ten N-formyl-cis-2,6-diarylpiperidines have been prepared and their preferr ed conformations are determined using NMR spectral studies and semiempirica l calculations (AM1 and PM3 of MOPAC 6). The severe A(1,3)-strain due to th e interaction between the N-C=O group (coplanar to the C2-N1-C6 plane) and the adjacent aryl group forces the N-formyl-cis-2,6-diarylpiperidines 19-28 to prefer flattened boat conformations with nitrogen at one of the base po sitions (VIA and VIE; Figure 1). Employing variable temperature NMR studies , the barriers for N-C rotation in the N-formylpiperidin-4-one 19 and the N -formylpiperidine 28 are found to be 72.5 and 65.8 kJ mol(-1), respectively , which are in general, lower than those of the corresponding N-nitrosopipe ridines. The lower energy barrier (Delta G(#)) of the N-formylpiperidine 28 compared to the N-formylpiperidin-4-one 19 (by 6.7 kJ mol(-1)) is attribut ed to the larger ground state destabilization of N-formylpiperidine 28 than 19. Semiempirical calculations show a hydrogen bond type of attraction bet ween the electron-rich oxygen atom of N-C=O group and the electron deficien t hydrogen at alpha-position (H2).