RESUMEN
A synthesis of N-monodeuteriomethyl-2-substituted piperidines is described. An efficient and readily scalable anodic methoxylation of N-formylpiperidine in an undivided microfluidic electrolysis cell delivers methoxylated piperidine 3, which is a precursor to a N-formyliminium ion and enables C-nucleophiles to be introduced at the 2-position. The isotopically labelled N-deuteriomethyl group is installed using the Eschweiler-Clarke reaction with formic acid-d2 and unlabelled formaldehyde. Monodeuterated N-methyl groups in these molecular systems possess small isotropic proton chemical shift differences important in the investigation of molecules that are able to support long-lived nuclear spin states in solution nuclear magnetic resonance.
Asunto(s)
Piperidinas , Electroquímica , Piperidinas/químicaRESUMEN
We have recently shown that the small proton chemical shift difference in 2-methyl-1-(methyl-d)piperidine supports a long-lived nuclear spin state. To identify additional candidate molecules with CH2D groups exhibiting accessible long-lived states, and to investigate the factors governing the magnitude of the shift differences, we report a computational and experimental investigation of methyl rotational equilibria and proton chemical shifts in a variety of 2-substituted 1-(methyl-d)piperidines. The polarity and size of the 2-substituent affect the 1,2-stereoisomeric relationship, and consequently, the strength of the rotational asymmetry within the CH2D group. Nonpolar and large 2-substituents prefer the equatorial position, and relatively large shift differences (i.e., > 13 ppb) are observed. Polar and small substituents, however, increasingly prefer the axial position, and medium to small shift differences (i.e., 0 to 9 ppb) are observed. In addition, the diastereotopic CH2D proton chemical shift difference for tricarbonyl(1-chloro-2-deuteriomethylbenzene) chromium(0) was computed, showing that reasonable predictions of these small shift differences can be extended to more complex, organometallic species.