¹H and ¹³C NMR studies on the oxydimethyleneaminomethyl fragment in six‐ and eight‐membered rings. The solution stereochemistry of N‐methyl diastereomers of phendimetrazine (an oxazine anorexic drug) versus nefopam (a benzoxazocine analgesic drug)

The ¹H NMR spectrum (CD₂Cl₂) of the mesylate analogue of phendimetrazine bitartarate, a central nervous system stimulant and an anorexic drug, showed two isomers (ratio ≈ 17:1) differing in the stereochemistry of the N⁺HCH₃ moiety. A similar diastereomeric ratio was also noted in ¹³C{¹H} NMR spectra recorded in either CD₂Cl₂ or in acidic D₂O (pD ≈ 1). For the major species in CD₂Cl₂ solution, four antiperiplanar vicinal ¹H¹H coupling constants indicated a chair‐conformation 2,3‐trans‐1,4‐oxazine ring with equatorially oriented 2‐phenyl, 3‐methyl and N‐methyl substituents. The minor species also has the same chair conformation with equatorially oriented 2‐phenyl and 3‐methyl substituents, since the coupling constant for the minor species vicinal OCH(Ph)CH(Me)N methine protons was also antiperiplanar in magnitude. Axial N‐methyl stereochemistry was assigned to the minor species, since chemical shifts of the ring carbons gauche to N‐methyl (and of the N‐methyl carbon atom itself) were shifted characteristically upfield relative to absorbances for the corresponding carbons in the major [equatorial N‐methyl] species. The R‐factor method was used to estimate an OC6C5N dihedral angle of 56.0(7)° for the major equatorial N‐methyl species in CD₂Cl₂ solution. CP‐MAS ¹³C NMR chemical shifts for solid‐state phendimetrazine bitartarate are the same as those for the solution‐state equatorial N‐methyl diastereomer. The oxydimethyleneaminomethyl fragment in the equatorial N‐methyl phendimetrazine chair conformation was used as a model for the corresponding fragment in the eight‐membered ring of nefopam. Comparison of OCH₂CH₂N⁺H(equatorial CH₃)— and OCH₂CH₂N⁺H vicinal coupling constants in the two rings suggests dynamic weighted averaging for those in the octagonal ring of the nefopam equatorial NCH₃ diastereomer.