RESUMO
The stereochemical properties of N-acyl-5H-dibenzo[b,d]azepin-7(6H)-ones (2a-c), which inhibit potassium channels in T cells, were examined by freezing their conformational change due to 4-methyl substitution. N-Acyl-5H-dibenzo[b,d]azepin-7(6H)-ones exist as pairs of enantiomers [(a1R, a2R), (a1S, a2S)], and each atropisomer is separable at room temperature. An alternate procedure for preparing 5H-dibenzo[b,d]azepin-7(6H)-ones involves the intramolecular Friedel-Crafts cyclization of N-benzyloxycarbonylated biaryl amino acids. Consequently, the N-benzyloxy group was removed during the cyclization reaction to produce 5H-dibenzo[b,d]azepin-7(6H)-ones suitable for the subsequent N-acylation reaction.
RESUMO
In this study, the conformational properties of tertiary trifluoroacetamides in dibenzoazepine (1a and 1b) and benzodiazepine (2a and 2b) derivatives, which exist as equilibrated E- and Z-amide conformers in solution, were investigated by 1H and 19F NMR spectroscopy. In all cases, one of the methylene protons neighboring the nitrogen atom of the minor conformer showed a finely split pattern due to coupling with the trifluoromethyl fluorine atoms, as confirmed by 19F-decoupling experiments. One-dimensional (1D) and two-dimensional (2D) 1H-19F heteronuclear Overhauser spectroscopy (HOESY) experiments were performed to confirm whether these couplings are attributable to through-bond spin-spin couplings (TBCs) or through-space spin-spin couplings (TSCs). HOESY cross-peaks between CF3 (19F) and one of the CH2-N protons of the minor conformers indicate that the two nuclei are spatially close to each other, thus establishing the stereochemistry of the major (E-) and minor (Z-) conformers. The E-amide preferences of the trifluoroacetamides are consistent with the results of density functional theory calculations and X-ray crystallographic analyses. Furthermore, the otherwise incomprehensible 1H NMR spectra were accurately assigned using the HOESY-determined TSCs. The 1H NMR assignments of the E- and Z-methyl signals of N,N-dimethyl trifluoroacetamide, the simplest tertiary trifluoroacetamide, were revised for the first time in half a century.
RESUMO
The stereochemistry of N-acyl/N-sulfonyl 5H-dibenzo[b,d]azepin-7(6H)-ones (I, II) was examined in detail by freezing the conformation with a methyl group at the C-4 of dibenzoazepine. Because the two axes (axis 1, axis 2) move together concertedly, I and II exist only as a pair of enantiomers [(a1R, a2R) and (a1S, a2S)], which was confirmed by X-ray analysis of IIBc. It was elucidated that the amide derivatives I exist in equilibrium with the E/Z-amide (100:2-100:34), which means that the exocyclic bond (axis 3) is not in concert with the endocyclic axes (axis 1, axis 2). For the preparation of 5H-dibenzo[b,d]azepin-7(6H)-one, the intramolecular Friedel-Crafts acylation of N-(1,1')-biphenyl-2-yl-glycine derivatives was revisited. It was revealed that the electron-withdrawing property of the amino-protective group was a key to the success of seven-membered cyclization.
