Some interesting ¹H NMR features of ortho substituted N-methoxy-N-methyl benzamides

During synthetic efforts towards positional isomers of FTY720, using building blocks based on Weinreb amide (WA) functionality, interesting 1H NMR pattern for ortho-methyl-N-methoxy-N-methyl benzamide have been encountered. The 1H NMR spectrum has shown broad humps for N-methoxy and N-methyl units in WA functionality, whereas the spectrum for the corresponding meta-and para-isomer, displays two sharp singlets for the same units. This interesting spectral difference has been rationalized. Several ortho-substituted N-methoxy-N-methyl benzamides have been tailor-made and generality has been established. The broadening of the peaks is due to the presence of rotamers and variable temperature NMR study has unraveled that the energy barrier of two rotamers of ortho-substituted benzamides is more at room temperature, unlike para and meta substituted benzamides.