Új átrendezodések a tercier propargil-amin-N-oxidok körében

Translated title of the contribution: Novel rearrangements of tertiary propargylamine-N-oxides

I. Hermecz, Anna Szabó, Gézáné Galambos, Géza Timári, Kálmán Simon, Lelle Vasváriné Debreczy, Zoltán Mucsi

Research output: Contribution to journalArticle

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Abstract

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.

Original languageHungarian
Pages (from-to)43-45
Number of pages3
JournalMagyar Kemiai Folyoirat, Kemiai Kozlemenyek
Volume109-110
Issue number1
Publication statusPublished - Mar 2004

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Aldehydes
Oxides
Acrylamide
Amines
Protonation
Free energy
Nitrogen
Chemical activation
Derivatives
Atoms
Monoamine Oxidase Inhibitors
Discrete Fourier transforms
Reaction kinetics
Isotopes
Labeling
Anions
Hydrogen
Hydrogen bonds
Alcohols
propargylamine

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Hermecz, I., Szabó, A., Galambos, G., Timári, G., Simon, K., Vasváriné Debreczy, L., & Mucsi, Z. (2004). Új átrendezodések a tercier propargil-amin-N-oxidok körében. Magyar Kemiai Folyoirat, Kemiai Kozlemenyek, 109-110(1), 43-45.

Új átrendezodések a tercier propargil-amin-N-oxidok körében. / Hermecz, I.; Szabó, Anna; Galambos, Gézáné; Timári, Géza; Simon, Kálmán; Vasváriné Debreczy, Lelle; Mucsi, Zoltán.

In: Magyar Kemiai Folyoirat, Kemiai Kozlemenyek, Vol. 109-110, No. 1, 03.2004, p. 43-45.

Research output: Contribution to journalArticle

Hermecz, I, Szabó, A, Galambos, G, Timári, G, Simon, K, Vasváriné Debreczy, L & Mucsi, Z 2004, 'Új átrendezodések a tercier propargil-amin-N-oxidok körében', Magyar Kemiai Folyoirat, Kemiai Kozlemenyek, vol. 109-110, no. 1, pp. 43-45.
Hermecz I, Szabó A, Galambos G, Timári G, Simon K, Vasváriné Debreczy L et al. Új átrendezodések a tercier propargil-amin-N-oxidok körében. Magyar Kemiai Folyoirat, Kemiai Kozlemenyek. 2004 Mar;109-110(1):43-45.
Hermecz, I. ; Szabó, Anna ; Galambos, Gézáné ; Timári, Géza ; Simon, Kálmán ; Vasváriné Debreczy, Lelle ; Mucsi, Zoltán. / Új átrendezodések a tercier propargil-amin-N-oxidok körében. In: Magyar Kemiai Folyoirat, Kemiai Kozlemenyek. 2004 ; Vol. 109-110, No. 1. pp. 43-45.
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title = "{\'U}j {\'a}trendezod{\'e}sek a tercier propargil-amin-N-oxidok k{\"o}r{\'e}ben",
abstract = "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.",
author = "I. Hermecz and Anna Szab{\'o} and G{\'e}z{\'a}n{\'e} Galambos and G{\'e}za Tim{\'a}ri and K{\'a}lm{\'a}n Simon and {Vasv{\'a}rin{\'e} Debreczy}, Lelle and Zolt{\'a}n Mucsi",
year = "2004",
month = "3",
language = "Hungarian",
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pages = "43--45",
journal = "Magyar Kemiai Folyoirat, Kemiai Kozlemenyek",
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TY - JOUR

T1 - Új átrendezodések a tercier propargil-amin-N-oxidok körében

AU - Hermecz, I.

AU - Szabó, Anna

AU - Galambos, Gézáné

AU - Timári, Géza

AU - Simon, Kálmán

AU - Vasváriné Debreczy, Lelle

AU - Mucsi, Zoltán

PY - 2004/3

Y1 - 2004/3

N2 - 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.

AB - 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.

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