Abstract
Herein we describe NMR experiments and structural modifications of 4-methyl-2-phenylpyrimidine-N-acylhydrazone compounds (aryl-NAH) in order to discover if duplication of some signals in their 1H- and 13C-NMR spectra was related to a mixture of imine double bond stereoisomers (E/Z) or CO-NH bond conformers (syn and anti-periplanar). NMR data from NOEdiff, 2D-NOESY and 1H-NMR spectra at different temperatures, and also the synthesis of isopropylidene hydrazone revealed the nature of duplicated signals of a 4-methyl-2-phenylpyrimidine-N-acylhydrazone derivative as a mixture of two conformers in solution. Further we investigated the stereoelectronic influence of substituents at the ortho position on the pyrimidine ring with respect to the carbonyl group, as well as the electronic effects of pyrimidine by changing it to phenyl. The conformer equilibrium was attributed to the decoplanarization of the aromatic ring and carbonyl group (generated by an ortho-alkyl group) and/or the electron withdrawing character of the pyrimidine ring. Both effects increased the rotational barrier of the C-N amide bond, as verified by the ΔG≠ values calculated from dynamic NMR. As far as we know, it is the first description of aryl-NAH compounds presenting two CO-NH bond- related conformations.
Highlights
The bioactive N-acylhydrazone (NAH) moiety has been identified in a great number of lead compounds that act on different types of molecular targets [1,2,3,4]
Esters 4a and 4b were chemoselectively obtained in 80% and 73% yield, respectively, through the condensation of benzamidine with (Z/E)-ethyl 2-((dimethylamino)methylene)-3-oxobutanoate (5) and (Z/E)-methyl 2-((dimethylamino)methylene)-3-oxopentanoate (6), respectively, in ethanol and methanol at room temperature (Scheme 2) [11,12]
The synthesis of the pyrimidine nucleus was confirmed by the presence of singlets at 9.17 and 9.12 ppm in the 1H-NMR spectra, which refer to the H-6 attached to the pyrimidine ring in esters 4a and 4b, respectively
Summary
The bioactive N-acylhydrazone (NAH) moiety has been identified in a great number of lead compounds that act on different types of molecular targets [1,2,3,4]. Because of the assemblage of amide and imine functions, NAH compounds may exist as C=N double bond stereoisomers (E/Z). (Scheme 1) and as syn/antiperiplanar conformers about the amide CO-NH bond (Scheme 1) [5]. A research program to develop a series of 2-phenyl-4-methylpyrimidine-N-acylhydrazone compounds with antinociceptive and anti-inflammatory activities led to the discovery of LASSBio-1083. The 1H-NMR spectra revealed the duplication of some signals, indicating the presence of a mixture of stereoisomers or conformers
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