Kinetik und umsetzungen von 1.2.4.5-tetrazinen mit winkelgespannten und elektronenreichen doppelbindungen

Sauer, Jürgen; Heinrichs, G.

doi:10.1016/s0040-4039(00)90312-5

Cited by 78 publications

(38 citation statements)

References 7 publications

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“…Similarly, the epimeric P-alcohol (81) is converted into the 8-trans form (82). Using optically active compounds, Woodward and Kafz [loo] showed that this reaction does not involve dissociation into the fragments cyclopentadiene and cyclopentadienol, but is intramolecular.…”

Section: E On the Mechanism Of Diels-alder Reactionsmentioning

confidence: 99%

Diels‐Alder reactions II: The Reaction Mechanism

Sauer¹

1967

Angew. Chem. Int. Ed. Engl.

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514

130

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Section: E On the Mechanism Of Diels-alder Reactionsmentioning

confidence: 99%

Diels‐Alder reactions II: The Reaction Mechanism

Sauer¹

1967

Angew. Chem. Int. Ed. Engl.

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514

130

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“…In his pioneering studies of tetrazine reactivity with dienophiles, Sauer described and measured the rapid reaction of tetrazine with cyclopropene and 3-methylcyclopropene. [13] However, development of a practical cyclopropene mini-tag required balancing the rate of reaction, which depends heavily on substitution pattern, and the poor stability of unsubstituted cyclopropenes, which tend to react with each other through ene chemistry. [14] Considering these requirements, we introduced two methylcyclopropene mini-tags as fast and stable dienophiles for reaction with tetrazines.…”

Section: Introductionmentioning

confidence: 99%

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

116

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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“…The formation of product 10 was rationalized by the formation of an intermediate cycloadduct 8, which spontaneously loses N 2 and subsequently cyclopentadiene in a cycloreversion process [11]. Phthalazine derivative 6 reacted with 7-oxabenzotrinorbornadiene in an analogous cycloaddition/cycloreversion manner [12] (Scheme 3). By thermal fragmentation of the initially formed adduct 12, isobenzofuran 13 was obtained and trapped in situ with Nmethylmaleimide, yielding exo-and endo-adducts 14 and 15 in a 1 : 2 ratio.…”

mentioning

confidence: 99%

Rigid Alicyclic Molecules from Bicyclo[2.2.1]hept‐2‐enes (=8,9,10‐Trinorbornenes) and 1,4‐Dipyridin‐2‐ylphthalazines as Stereoselective Coupling Agents

Margetić

Murata

Komatsu

et al. 2009

Helvetica Chimica Acta

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For the preparation of rigid polycyclic molecules from 8,9,10-trinorbornenes (¼ bicyclo[2.2.1]hept-2-enes), 1,4-dipyridin-2-ylphthalazines were used. Cycloaddition reactions with trinorbornenes gave coupled products in a stereoselective manner. In these reactions, the phthalazines delivered a new bicyclo[2.2.2] moiety at the junction of two trinorbornene units, which could bear appropriate functional groups (Schemes 4 and 5). The crystal structure of a key cycloadduct, i.e., of 18 was also determined (Fig. 2). Relative reactivities for a series of phthalazines (Fig. 3) were estimated by density-functionaltheory (DFT) calculations at the B3LYP/6-31G* level (Table). The calculations indicated an increase of reactivity when the aromaticity of the phthalazine moiety is decreased. Finally, experimentally observed stereoselectivities of the phthalazine reactions with trinorbornenes were readily predicted by DFT calculations (Fig. 4).

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Kinetik und umsetzungen von 1.2.4.5-tetrazinen mit winkelgespannten und elektronenreichen doppelbindungen

Cited by 78 publications

References 7 publications

Diels‐Alder reactions II: The Reaction Mechanism

Diels‐Alder reactions II: The Reaction Mechanism

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

Rigid Alicyclic Molecules from Bicyclo[2.2.1]hept‐2‐enes (=8,9,10‐Trinorbornenes) and 1,4‐Dipyridin‐2‐ylphthalazines as Stereoselective Coupling Agents

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