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

Sauer, Jürgen; Bäuerlein, Peter; Ebenbeck, Wolfgang; Gousetis, C.; Sichert, Heinz; Troll, T.; Utz, Ferdinand; Wallfahrer, Uwe

doi:10.1002/1099-0690(200107)2001:14<2629::aid-ejoc2629>3.3.co;2-u

Cited by 10 publications

(13 citation statements)

References 8 publications

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“…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.…”

Section: Resultssupporting

confidence: 88%

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

Yang

Liang

Šečkutė

et al. 2014

Chemistry A European J

117

115

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Substituted cyclopropenes have recently attracted attention as stable “mini-tags” that are highly reactive dienophiles with the bioorthogonal tetrazine functional group. Despite this interest, the synthesis of stable cyclopropenes is not trivial and their reactivity patterns are poorly understood. Here, the synthesis and comparison of the reactivity of a series of 1-methyl-3-substituted cyclopropenes with different functional handles is described. The rates at which the various substituted cyclopropenes undergo Diels–Alder cycloadditions with 1,2,4,5-tetrazines were measured. Depending on the substituents, the rates of cycloadditions vary by over two orders of magnitude. The substituents also have a dramatic effect on aqueous stability. An outcome of these studies is the discovery of a novel 3-amidomethyl substituted methylcyclopropene tag that reacts twice as fast as the fastest previously disclosed 1-methyl-3-substituted cyclopropene while retaining excellent aqueous stability. Furthermore, this new cyclopropene is better suited for bioconjugation applications and this is demonstrated through using DNA templated tetrazine ligations. The effect of tetrazine structure on cyclopropene reaction rate was also studied. Surprisingly, 3-amidomethyl substituted methylcyclopropene reacts faster than trans-cyclooctenol with a sterically hindered and extremely stable tert-butyl substituted tetrazine. Density functional theory calculations and the distortion/interaction analysis of activation energies provide insights into the origins of these reactivity differences and a guide to the development of future tetrazine coupling partners. The newly disclosed cyclopropenes have kinetic and stability advantages compared to previously reported dienophiles and will be highly useful for applications in organic synthesis, bioorthogonal reactions, and materials science.

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Section: Resultssupporting

confidence: 88%

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

Yang

Liang

Šečkutė

et al. 2014

Chemistry A European J

117

115

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“…1A and left column of Fig. 1B) (38)(39)(40). The reaction axis of the Diels-Alder reaction (a→b) is orthogonal to the direction of OEEFs, while the subsequent aromatization process (b→c) presents a nonorthogonal configuration between the reaction axis and OEEFs (Fig.…”

Section: Introductionmentioning

confidence: 99%

Electric field–induced selective catalysis of single-molecule reaction

et al. 2019

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Oriented external electric fields (OEEFs) offer a unique chance to tune catalytic selectivity by orienting the alignment of the electric field along the axis of the activated bond for a specific chemical reaction; however, they remain a key experimental challenge. Here, we experimentally and theoretically investigated the OEEF-induced selective catalysis in a two-step cascade reaction of the Diels-Alder addition followed by an aromatization process. Characterized by the mechanically controllable break junction (MCBJ) technique in the nanogap and confirmed by nuclear magnetic resonance (NMR) in bottles, OEEFs are found to selectively catalyze the aromatization reaction by one order of magnitude owing to the alignment of the electric field on the reaction axis. Meanwhile, the Diels-Alder reaction remained unchanged since its reaction axis is orthogonal to the electric fields. This orientation-selective catalytic effect of OEEFs reveals that chemical reactions can be selectively manipulated through the elegant alignment between the electric fields and the reaction axis.

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“…1 H NMR (400 MHz, CDCl 3 ): δ 8.63 (dt, J = 4.7, 1.4 Hz, 1H), 8.00 (dt, J = 7.9, 1.0 Hz, 1H), 7.78 (td, J = 7.7, 1.7 Hz, 1H), 7.42 (ddd, J = 7. 6,4.7,1.2 Hz,1H),5.74 (dd,J = 7.3,5.5 Hz,1H),3.80 (m,2H),3.50 (s,3H),2.84 (m,1H),2.77 (m,1H),2.63 (dd,J = 14.4,7.3 Hz,1H),2.35 (s,3H),2.29 (dd,J = 14.4,5.5 Hz,1H), 2.09 (m, 2 J ∼ 14 Hz, 2H), 1.41 (s, 9H), 1.40 (m, 2H).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…The inverse electronic demand Diels−Alder (IEDDA) reaction between s-tetrazines and simple alkenes or less reactive alkynes with nitrogen loss leading to pyridazines was first reported by Carboni and Lindsey 1−3 in 1959. Being strained, cyclopropenes are highly reactive alkenes; in terms of the IEDDA reaction, they found application in series of works dedicated to bio-orthogonal ligation 4 due to the advantages of this type of conjugation: it proceeds fast, quantitatively, tolerates aqueous media, and produces only nitrogen as a byproduct. Another example is sequential IEDDA, involving tetrazine and two molecules of cyclopropene applied in construction of semibullvalenes 5 and homotropilidenes, 6 as was reported by Sauer et al Gem-dimethylcyclopropene normally forms diazanorkardienes upon reaction with dimethyl s-tetrazine-3,6-dicarboxylate at a room temperature. 7 Reaction of cyclopropenes with 1,2,4-triazines leading to azepines is much more rarely represented.…”

Section: ■ Introductionmentioning

confidence: 98%

Three-Component Reaction of 3,3-Difluorocyclopropenes, s-Tetrazines, and (benzo) Pyridines

Nechaev¹,

Cherkaev

Boev³

et al. 2020

J. Org. Chem.

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A new three-component reaction leading to 1-α-(pyridyl-2-[1,2,4]triazolyl)-2-alkyl-ethanones has been discovered while studying the reactivity of monosubstituted 3,3-difluorocyclopropenes in an inverse electronic demand Diels−Alder (IEDDA) cycloaddition−cycloreversion sequence with s-tetrazines. The reaction involving the above-mentioned reactants and (benzo)pyridine as a third component results in a complex transformation proceeding in mild conditions in a stoichiometric ratio of reactants and has high functional group tolerance (phenols, amides, ethers, carboxylic acids, ketones, and acrylic esters). As a result, simple pyridines are selectively functionalized at the α-position in good isolated yields. The reaction mechanism includes a rare azaphilic [4 + 2]cycloaddition step between s-tetrazine and intermediate 1-hydroxyindolizine, suggested after byproduct identification and tracked with a deuterium label. To date, it is only the third known example of skewed azaphilic cycloaddition of tetrazine. The reaction is truly three-component and cannot be effectively performed stepwise.

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

Cited by 10 publications

References 8 publications

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

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

Electric field–induced selective catalysis of single-molecule reaction

Three-Component Reaction of 3,3-Difluorocyclopropenes, s-Tetrazines, and (benzo) Pyridines

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