[4+2] Cycloadditions of 1,2,4,5-Tetrazines and Cyclopropenes − Synthesis of 3,4-Diazanorcaradienes and Tetracyclic Aliphatic Azo Compounds

Abstract

1,2,4,5‐Tetrazines 1 readily react with cyclopropenes 2 to form 3,4‐diazanorcaradienes 3, 4, 7 and 8 in a cycloaddition − cycloelimination sequence. Compounds 3 and 4 still act as 1,3‐dienes with cyclopropenes 2, producing aliphatic azo compounds 5 and 6, versatile starting compounds in thermolysis and photolysis reactions.

Synthesis and Reactivity Comparisons of 1‐Methyl‐3‐Substituted Cyclopropene Mini‐tags for Tetrazine Bioorthogonal Reactions

“…The reaction resulted in isomers of 3,4-diazanorcaradiene derivatives 39 in 97 % yield based on reacted started material through an electrocyclic ring-opening and closing process. [16, 28] The products appear to be stable to hydrolysis over the 18 h reaction in line with previous reports of diazanorcaradiene stability. [29] We are currently investigating the implementation of this reactive pair in bioconjugation applications.…”

Synthesis and Reactivity Comparisons of 1‐Methyl‐3‐Substituted Cyclopropene Mini‐tags for Tetrazine Bioorthogonal Reactions

“…The reaction resulted in isomers of 3,4-diazanorcaradiene derivatives 39 in 97 % yield based on reacted started material through an electrocyclic ring-opening and closing process. [16, 28] The products appear to be stable to hydrolysis over the 18 h reaction in line with previous reports of diazanorcaradiene stability. [29] We are currently investigating the implementation of this reactive pair in bioconjugation applications.…”

Correlation of the Chemical Reactivity of Some Tetrazine Derivatives with Their Reactivity toward Ortho-positronium Atoms and Their LUMO Energies

“…In the “inverse electron demand” Diels−Alder reactions of tetrazines the same trend is observed. 1 is known to react with electron-rich olefins, and the reaction of 2 was also reported …”

“…1 is known to react with electron-rich olefins, 24 and the reaction of 2 was also reported. 25 The other tetrazines 3-8 on the other hand did not react with the same reagents even under forcing conditions. 17…”

Alkene Distortion Energies and Torsional Effects Control Reactivities, and Stereoselectivities of Azide Cycloadditions to Norbornene and Substituted Norbornenes

“…While reactions of this type are often called strain-promoted, this study and others by our group − indicate that reduction of distortion energy controls rates of cycloaddition. This can be manifested in predistortion as in 3 – 6 discussed here or in reduction of distortion energies caused by angle strain as in cyclopropene. − The reactions are distortion-accelerated, subtly different from strain-promoted. The strain results in a predistortion of the alkene, which resembles the transition structure.…”

Synthesis and Reactivity Comparisons of 1‐Methyl‐3‐Substituted Cyclopropene Mini‐tags for Tetrazine Bioorthogonal Reactions

“…The reaction resulted in isomers of 3,4-diazanorcaradiene derivatives 39 in 97 % yield based on reacted started material through an electrocyclic ring-opening and closing process. [16, 28] The products appear to be stable to hydrolysis over the 18 h reaction in line with previous reports of diazanorcaradiene stability. [29] We are currently investigating the implementation of this reactive pair in bioconjugation applications.…”

Correlation of the Chemical Reactivity of Some Tetrazine Derivatives with Their Reactivity toward Ortho-positronium Atoms and Their LUMO Energies

“…In the “inverse electron demand” Diels−Alder reactions of tetrazines the same trend is observed. 1 is known to react with electron-rich olefins, and the reaction of 2 was also reported …”

“…1 is known to react with electron-rich olefins, 24 and the reaction of 2 was also reported. 25 The other tetrazines 3-8 on the other hand did not react with the same reagents even under forcing conditions. 17…”

Alkene Distortion Energies and Torsional Effects Control Reactivities, and Stereoselectivities of Azide Cycloadditions to Norbornene and Substituted Norbornenes

“…While reactions of this type are often called strain-promoted, this study and others by our group − indicate that reduction of distortion energy controls rates of cycloaddition. This can be manifested in predistortion as in 3 – 6 discussed here or in reduction of distortion energies caused by angle strain as in cyclopropene. − The reactions are distortion-accelerated, subtly different from strain-promoted. The strain results in a predistortion of the alkene, which resembles the transition structure.…”

Synthesis and Reactivity Comparisons of 1‐Methyl‐3‐Substituted Cyclopropene Mini‐tags for Tetrazine Bioorthogonal Reactions

“…The reaction resulted in isomers of 3,4-diazanorcaradiene derivatives 39 in 97 % yield based on reacted started material through an electrocyclic ring-opening and closing process. [16, 28] The products appear to be stable to hydrolysis over the 18 h reaction in line with previous reports of diazanorcaradiene stability. [29] We are currently investigating the implementation of this reactive pair in bioconjugation applications.…”

Correlation of the Chemical Reactivity of Some Tetrazine Derivatives with Their Reactivity toward Ortho-positronium Atoms and Their LUMO Energies

“…In the “inverse electron demand” Diels−Alder reactions of tetrazines the same trend is observed. 1 is known to react with electron-rich olefins, and the reaction of 2 was also reported …”

“…1 is known to react with electron-rich olefins, 24 and the reaction of 2 was also reported. 25 The other tetrazines 3-8 on the other hand did not react with the same reagents even under forcing conditions. 17…”

Alkene Distortion Energies and Torsional Effects Control Reactivities, and Stereoselectivities of Azide Cycloadditions to Norbornene and Substituted Norbornenes

“…While reactions of this type are often called strain-promoted, this study and others by our group − indicate that reduction of distortion energy controls rates of cycloaddition. This can be manifested in predistortion as in 3 – 6 discussed here or in reduction of distortion energies caused by angle strain as in cyclopropene. − The reactions are distortion-accelerated, subtly different from strain-promoted. The strain results in a predistortion of the alkene, which resembles the transition structure.…”