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Methylation of Sydnone N-Oxides:  Kinetic and Thermodynamic Control in the Alkylation Site of an Electron-Rich Heterocycle

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journal contribution
posted on 11.05.2007, 00:00 by D. Scott Bohle, Lindsey E. McQuade, Inna Perepichka, Lijuan Zhang
Methylation of the anionic 4-methylcarboxy 1,2,3-oxadiazolate 3-oxide occurs at either the disubstituted ring nitrogen or the oxygen of the N-oxide depending upon the conditions and reagents employed. Alkylation with methyl iodide leads to N-alkylation, while dimethyl sulfate gives O-alkylation and trifluoromethanemethylsulfonate gives a mixture of the two products. The regioselectivity of these methylations has been confirmed by X-ray diffraction of the two products, and these are in turn correlated with their theoretically predicted (B3LYP//6-311++G**) relative energies and vibrational spectra. Theoretically, N-alkylation is expected to give an isomer that is over 10 kcal mol-1 more stable than the O-alkylated product. As a neat melt the kinetic O-alkylation product cleanly isomerizes in 2 h when heated to 140 °C to give the thermodynamic N-methylated isomer. Taken together the results illustrate the remarkable new sydnone N-oxide derivatives which are readily accessed in this chemistry, with the N-alkylation of the sydnone N-oxide, corresponding to the first case of such an N-alkylation for a diazenium diolate.