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

Abstract

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 degrees 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.

A New Synthetic Route to 3-Oxo-4-amino-1,2,3-oxadiazole from the Diazeniumdiolation of Benzyl Cyanide: Stable Sydnone Iminium N-Oxides

“…The reactions of nitric oxide with organic substrates are often strongly dependent upon the base, pressure, temperature, and salts formed. These factors influence the equilibrium between the NO monomer and the NO dimer, both of which are competent electrophiles for these carbanions . Although the products from this reaction, eq and Table , are usually dominated by the bisdiazeniumdiolate imidate salt 7 , conditions for the isolation of 6 in 70% yield and for the 3-oxo-1,2,3-oxadiazole 5 in 22% yield are described.…”

“…The reaction of NO with alkynes returns 3 , eq , while with dimethylmalonate in base the product 4 forms in 31% yield, eq . Unlike the N -aryl/alkyl sydnones 1 , the N -oxides 2A , 3 , and 4 are remarkably stable toward acids and bases and have an emerging unique chemistry that includes the facile electrophilic decarboxylation of 4 and the kinetic or thermodynamically controlled O - or N -methylation . In the course of extending our studies of the diazeniumdiolation of carbanions with nitric oxide we reexamined the reaction of nitric oxide with benzyl cyanide described by Arnold et al and have found that in addition to the nonheterocyclic products described by these authors a new 1,2,3-oxadiazole, 5 , can be isolated from these reaction mixtures .…”

Establishment of Benzodioxazine Core Structure for Sarcodonin Class of Natural Products by X-ray Analysis

“…These data suggested that the iminium N -oxide system bears C( 3b )N( 1a ) + –O – and C( 3b ) − –N( 1a ) + O resonance forms. It appears that the latter form contributes the above-mentioned upfield shift of C-3b (δ 105.1) of 6 …”

Temperature‐Controlled Base‐Promoted Cyclization for the Synthesis of 2‐Amino‐4H‐benzo[d][1,3]thiazin‐4‐ones and 2‐Thioxo‐4(3H)‐quinazolinones

“…Chemodivergent syntheses are of great value for obtaining skeletal divergence in organic and medicinal chemistry . Over the past few decades, chemoselective control achieved utilizing metal catalysts and solvents has received increasing attention, while relatively few papers have described temperature‐dependent reactions . However, since being first discovered by Woodward and Baer in 1944, kinetic and thermodynamic control of reactions have remained as important topics in organic synthesis for enhancing reaction efficiency and for increasing molecular diversity.…”