The N-alkylation of substituted 4-tetrazolo[1,5-a]pyridines

Easy access to a new series of electrophiles

Guillaume Berionni, Mathieu Branca, Bruce Pégot, Jérome Marrot, Elyane Kizilian, Régis Goumont

Research output: Contribution to journalArticle

Abstract

The alkylation of 4-substituted tetrazolo-pyridines bearing electron-withdrawing groups 7a-f to give the expected tetrazolo-pyridinium salts 7a-f,Me or 7a-f,Et as a mixture of two N3/N2 isomers in good to quantitative yields in toluene, has been investigated. The nature of the alkyl group did not significantly affect the chemical shifts of the salts or the N3/N2 ratio, which was approximately 9:1, except for 7d,Me for which a 1:1 ratio was obtained. The alkylated tetrazolo-pyridines were shown to react with cyclopentadiene and, in some cases, with 2,3-dimethylbutadiene and isoprene, whereas the neutral tetrazolo-pyridines remained unreactive towards dienes, indicating experimentally an increase in the electrophilicity of the heterocycles upon alkylation. TheDiels-Alder adducts were fully characterized through an extensive NMR and crystallographic study. It was found that the tetrazolo-pyridinium salts either do not react or react very slowly with cyclohexadiene, showing the limitations of the scope of this activation. The theoretical scale of electrophilicity introduced by Domingo et al. on the basis of the global electrophilicity index, Ï, defined by Parr, is also a very useful tool to discuss the relative reactivities of the various salts. The Ï and ÎN indexes are shown to highlight the electrophilic activation of tetrazolo-pyridines, 7a,Me and 7b,Me, which have indexes close to those of 4,6-dinitrotetrazolo-pyridine, which is one of the most electrophilic neutral heterocycles known to date. Using the known N and s parameters, which characterize the nucleophilicity of nucleophiles, the rate constants were found to fit the three-parameter equation logk2 = s(N + E) introduced by Mayr to describe the feasibility of nucleophilic-electrophilic combinations. Based on this, the electrophilicity parameter E of 7a-b,Me was determined. With E values around -7, this corresponds to a positioning of the reactivity of the carbocyclic ring of the tetrazolo-pyridinium salts in a domain of high electrophilicity previously defined for nitrobenzofuroxans. The alkylation of a series of tetrazolo-pyridines results in the formation of tetrazolo-pyridinium salts that are sufficiently electrophilic to react with dienes such as cyclopentadiene. The electrophilicity of these salts were determined theoretically and experimentally in two cases. With E values around -7, these salts have high electrophilicity, as previously defined for nitrobenzofuroxans.

Original languageEnglish
Pages (from-to)5104-5113
Number of pages10
JournalEuropean Journal of Organic Chemistry
Issue number26
DOIs
Publication statusPublished - Sep 2011
Externally publishedYes

Fingerprint

Pyridines
alkylation
Alkylation
pyridines
Salts
salts
Cyclopentanes
dienes
Bearings (structural)
reactivity
Chemical activation
activation
Nucleophiles
nucleophiles
Toluene
Chemical shift
Isomers
adducts
positioning
chemical equilibrium

Keywords

  • Cyclization
  • Cycloaddition
  • Dienes
  • Electronic structure
  • Electrophilic addition

Cite this

Berionni, Guillaume ; Branca, Mathieu ; Pégot, Bruce ; Marrot, Jérome ; Kizilian, Elyane ; Goumont, Régis. / The N-alkylation of substituted 4-tetrazolo[1,5-a]pyridines : Easy access to a new series of electrophiles. In: European Journal of Organic Chemistry. 2011 ; No. 26. pp. 5104-5113.
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abstract = "The alkylation of 4-substituted tetrazolo-pyridines bearing electron-withdrawing groups 7a-f to give the expected tetrazolo-pyridinium salts 7a-f,Me or 7a-f,Et as a mixture of two N3/N2 isomers in good to quantitative yields in toluene, has been investigated. The nature of the alkyl group did not significantly affect the chemical shifts of the salts or the N3/N2 ratio, which was approximately 9:1, except for 7d,Me for which a 1:1 ratio was obtained. The alkylated tetrazolo-pyridines were shown to react with cyclopentadiene and, in some cases, with 2,3-dimethylbutadiene and isoprene, whereas the neutral tetrazolo-pyridines remained unreactive towards dienes, indicating experimentally an increase in the electrophilicity of the heterocycles upon alkylation. TheDiels-Alder adducts were fully characterized through an extensive NMR and crystallographic study. It was found that the tetrazolo-pyridinium salts either do not react or react very slowly with cyclohexadiene, showing the limitations of the scope of this activation. The theoretical scale of electrophilicity introduced by Domingo et al. on the basis of the global electrophilicity index, {\"I}, defined by Parr, is also a very useful tool to discuss the relative reactivities of the various salts. The {\"I} and {\^I}N indexes are shown to highlight the electrophilic activation of tetrazolo-pyridines, 7a,Me and 7b,Me, which have indexes close to those of 4,6-dinitrotetrazolo-pyridine, which is one of the most electrophilic neutral heterocycles known to date. Using the known N and s parameters, which characterize the nucleophilicity of nucleophiles, the rate constants were found to fit the three-parameter equation logk2 = s(N + E) introduced by Mayr to describe the feasibility of nucleophilic-electrophilic combinations. Based on this, the electrophilicity parameter E of 7a-b,Me was determined. With E values around -7, this corresponds to a positioning of the reactivity of the carbocyclic ring of the tetrazolo-pyridinium salts in a domain of high electrophilicity previously defined for nitrobenzofuroxans. The alkylation of a series of tetrazolo-pyridines results in the formation of tetrazolo-pyridinium salts that are sufficiently electrophilic to react with dienes such as cyclopentadiene. The electrophilicity of these salts were determined theoretically and experimentally in two cases. With E values around -7, these salts have high electrophilicity, as previously defined for nitrobenzofuroxans.",
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The N-alkylation of substituted 4-tetrazolo[1,5-a]pyridines : Easy access to a new series of electrophiles. / Berionni, Guillaume; Branca, Mathieu; Pégot, Bruce; Marrot, Jérome; Kizilian, Elyane; Goumont, Régis.

In: European Journal of Organic Chemistry, No. 26, 09.2011, p. 5104-5113.

Research output: Contribution to journalArticle

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T1 - The N-alkylation of substituted 4-tetrazolo[1,5-a]pyridines

T2 - Easy access to a new series of electrophiles

AU - Berionni, Guillaume

AU - Branca, Mathieu

AU - Pégot, Bruce

AU - Marrot, Jérome

AU - Kizilian, Elyane

AU - Goumont, Régis

PY - 2011/9

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N2 - The alkylation of 4-substituted tetrazolo-pyridines bearing electron-withdrawing groups 7a-f to give the expected tetrazolo-pyridinium salts 7a-f,Me or 7a-f,Et as a mixture of two N3/N2 isomers in good to quantitative yields in toluene, has been investigated. The nature of the alkyl group did not significantly affect the chemical shifts of the salts or the N3/N2 ratio, which was approximately 9:1, except for 7d,Me for which a 1:1 ratio was obtained. The alkylated tetrazolo-pyridines were shown to react with cyclopentadiene and, in some cases, with 2,3-dimethylbutadiene and isoprene, whereas the neutral tetrazolo-pyridines remained unreactive towards dienes, indicating experimentally an increase in the electrophilicity of the heterocycles upon alkylation. TheDiels-Alder adducts were fully characterized through an extensive NMR and crystallographic study. It was found that the tetrazolo-pyridinium salts either do not react or react very slowly with cyclohexadiene, showing the limitations of the scope of this activation. The theoretical scale of electrophilicity introduced by Domingo et al. on the basis of the global electrophilicity index, Ï, defined by Parr, is also a very useful tool to discuss the relative reactivities of the various salts. The Ï and ÎN indexes are shown to highlight the electrophilic activation of tetrazolo-pyridines, 7a,Me and 7b,Me, which have indexes close to those of 4,6-dinitrotetrazolo-pyridine, which is one of the most electrophilic neutral heterocycles known to date. Using the known N and s parameters, which characterize the nucleophilicity of nucleophiles, the rate constants were found to fit the three-parameter equation logk2 = s(N + E) introduced by Mayr to describe the feasibility of nucleophilic-electrophilic combinations. Based on this, the electrophilicity parameter E of 7a-b,Me was determined. With E values around -7, this corresponds to a positioning of the reactivity of the carbocyclic ring of the tetrazolo-pyridinium salts in a domain of high electrophilicity previously defined for nitrobenzofuroxans. The alkylation of a series of tetrazolo-pyridines results in the formation of tetrazolo-pyridinium salts that are sufficiently electrophilic to react with dienes such as cyclopentadiene. The electrophilicity of these salts were determined theoretically and experimentally in two cases. With E values around -7, these salts have high electrophilicity, as previously defined for nitrobenzofuroxans.

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KW - Cyclization

KW - Cycloaddition

KW - Dienes

KW - Electronic structure

KW - Electrophilic addition

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