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1 H and 13 C 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)
Author(s) -
Glaser Robert
Publication year - 1989
Publication title -
magnetic resonance in chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.483
H-Index - 72
eISSN - 1097-458X
pISSN - 0749-1581
DOI - 10.1002/mrc.1260271207
Subject(s) - chemistry , diastereomer , alkane stereochemistry , chemical shift , stereochemistry , nmr spectra database , moiety , ring (chemistry) , vicinal , dihedral angle , cyclohexane conformation , proton nmr , carbon 13 nmr , crystallography , crystal structure , spectral line , molecule , hydrogen bond , organic chemistry , physics , astronomy
The 1 H NMR spectrum (CD 2 Cl 2 ) 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 + HCH 3 moiety. A similar diastereomeric ratio was also noted in 13 C{ 1 H} NMR spectra recorded in either CD 2 Cl 2 or in acidic D 2 O (pD ≈ 1). For the major species in CD 2 Cl 2 solution, four antiperiplanar vicinal 1 H 1 H 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 OC H (Ph)C H (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 OC6C5N dihedral angle of 56.0(7)° for the major equatorial N ‐methyl species in CD 2 Cl 2 solution. CP‐MAS 13 C 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 OC H 2 C H 2 N + H(equatorial CH 3 )— and OCH 2 C H 2 N + H vicinal coupling constants in the two rings suggests dynamic weighted averaging for those in the octagonal ring of the nefopam equatorial N CH 3 diastereomer.