Certain propargyl-substituted tertiary amines are irreversible monoamine oxidase (MAO) inhibitors. One major metabolic degradation path of tertiary amines starts with oxidation of the tertiary nitrogen atom which can be followed by enzymatic and chemical transformations. The Meisenheimer [2,3] sigmatropic rearrangement of tertiary propargylamine-N-oxides in aprotic medium to give O-allenylhydroxylamines has been described for cyclic-, aromatic- and benzylamine derivatives. The O-allenylhydroxylamine product is known to undergo further sigmatropic rearrangement. N-oxides having a hydrogen atom in a position β to the nitrogen may undergo the Cope elimination. We investigated the reactivity of Pargilin-N-oxide (1a) in protic media, where two new products, the enamino-aldehyde (4a) major -, and the acrylamide (5a) minor product (Scheme 1) were isolated. Formation of these new products was interpreted by assuming novel rearrangements. Based on experimental results with properly substituted Pargilin derivatives (1b,c), isotope labeling, and relevant literature data, the following mechanisms for these competing rearrangements were suggested: the enamino-aldehyde (4) is formed by an ionic mechanism, through isoxazolinium-ring intermediates (7 and 8) (Scheme 2), whereas the acrylamide (5) arises from the Meisenheimer rearrangement by further transformation of the primarily formed O-allenylhydroxylamine (2) (Scheme 3). Effect of the reaction conditions on the ratio of the competing rearrangements was investigated on cyclic propargylamine-N-oxide model (1d) by reaction kinetic measurements. The free energy of activation concerning to the rate-determining step of the enamino-aldehyde formation and the difference between the free energy of activation of the competing routes (ΔGB#-ΔGA#) were determined. The rate of the enamino-aldehyde (4d) formation and its ratio in the N-oxide transformations was found to increase significantly with decreasing anion solvating ability (acity) of the different alcohols (Table 1.) supporting the proposed mechanism. To understand the energy difference between the competing routes, theoretical method (DFT) was applied. Based on ab-initio studies, the possible structures of the transition states and intermediates were determined and the energy profiles of these transformations were drawn. (Scheme 4.) In protic medium both rearrangements were found to go through an isoxazolinium-type, zwitterionic intermediate (7) stabilized by hydrogen bonds. 7 is formed in the rate determining, slow, ring-closure reaction step, and is the common intermediate of both transformations. Product distribution is determined by subsequent fast reactions: the enamino-aldehyde (4) is formed from 7 following protonation and ring-opening. Without protonation, 7 rearranges into the O-allenylhydroxylamine (2) Meisenheimer product. The acrylamide (5) and secondary amine (6) products arise from 2 by further transformations.
|Translated title of the contribution||Novel rearrangements of tertiary propargylamine-N-oxides|
|Number of pages||3|
|Journal||Magyar Kemiai Folyoirat, Kemiai Kozlemenyek|
|Publication status||Published - márc. 1 2004|
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