Inverse electron-demand Diels-Alder reactions alkenes, 1,2,4,5-tetrazine

Figure 2.14 The inverse electron-demand Diels-Alder reaction between tetrazines and strained alkenes. The kinetics of the cycloaddition is greatly influenced by the solvent in which the reaction is performed (Blackman et al, 2008). (Reprinted with permission from M.L. Blackman, M. Royzen and J.M. Fox, Tetrazine ligation Fast bioconjugation based on inverse-electron-demand Diels-Alderneactivity, Journal of the American Chemical Society, 130, 41, 13518-13519, 2008. 2008 American Chemical Society.)...

The inverse-electron-demand Diels-Alder reaction of 3,6-dichloro[l,2,4,5]tetrazine with alkenes and alkynes provides the synthesis of highly functionalized pyridazines. ° Also, the 4 + 2-cycloaddition reactions of the parent [l,2,4,5]tetrazine with donor-substituted alkynes, alkenes, donor-substituted and unsubstituted cycloalkenes, ketene acetals, and aminals have been investigated. ... 

Inverse electron demand Diels-Alder reactions of 3,6-bismethylthio-l,2,4,5-tetrazine with a wide range of dienophiles have been shown to give substituted 3,6-bismethylthiopyridazines (148), generally in yields of 60% to 90% (Scheme 111). The reactivity of electron-rich alkynes and alkenes shows the expected order of ynamines > enamines > ketene acetals > enamides > trimethylsilyl or alkyl enol ethers > enol acetates reaction with ynamines is complete at room temperature in one... 

Inverse electron demand cycloaddition of 1,2,4,5-tetrazine with alkenes and alkynes. Inverse electron demand Diels-Alder addition has also been employed for the synthesis of pyridazines and condensed pyridazines. The reaction of olefinic and acetylenic compounds with 3,6-disubstituted 1,2,4,5-tetrazines 142 to yield substituted pyridazines 144 by the intermediacy of 143 was first reported by Carboni and Lindsey (1959JA4342). Analogous reaction of 142 with a variety of aldehydes and ketones 145 in base at room temperature proceeded smoothly to yield the corresponding pyridazines 144. Compounds 146-148 are proposed nonisolable intermediates (1979JOC629 Scheme 26). 

The inverse electron demand Diels-Alder cycloaddition (iEDDA) reaction between strained alkenes and tetrazine derivatives has gained more and more attention for orthogonal labeling of biomolecules in the last years (Fig. IE) [63]. This catalyst-free reaction can be extremely rapid in the case of tranr-cyclooctenes as reactants with second order rate constants of up to 380,000 s in aqueous solutions... 

In comparison, the inverse-electron-demand Diels-Alder (lEDA) reaction between a tetrazine and a strained alkene or allg ne followed by retro-Diels-Alder elimination of nitrogen offers a highly selective alternative, yielding stable dihydropyridazine or pyridazine products. Studies on, e.g., ra s-cyclooctene have revealed rate constants up to 2x10 s , which are much higher than... 

The reversibility of the conventional Diels-Alder reaction makes it a prime candidate for the synthesis of smart materials that exhibit a temperature-dependent transition between two physical properties (such as viscosity or color). However, many applications (such as biological labeling) require irreversible conjugation chemistry that also is very fast under mild and dilute reaction conditions. Eor such purposes, the inverse electron-demand Diels-Alder (IVED-DA) reaction between electron-deficient tetrazine derivatives and various alkenes is incredibly efficient. 

The most intensively studied reactions of 1,2,4,5-tetrazines are cycloaddition reactions with alkenes and alkynes, not only due to theoretical interest but also due to its importance in synthesis. The 1,2,4,5-tetrazines are diene components in this [4 + 2]-cycloaddition reaction while the alkynes and alkenes are the dienophiles. Kinetic studies have shown that these reactions should be classified as Diels Alder reactions with inverse electron demand. Therefore, 1,2,4,5-tetrazines with electron-withdrawing substituents (C02Me, CF3) and dienophiles with electron donating substituents are the most reactive compounds. However, dimethyl... 

The reactions can be described as Diels-Alder reactions with inverse electron demand, according to early kinetic measurements by Sauer (Scheme 5) <62AG353, 66TL4979>. (4-1-2) Cycloaddition reactions of electron-poor tetrazines (9) with electron-rich alkenes (37) or alkynes (36) form unisol-able bicyclic adducts (38) or (35) in the rate-determining step, which extremely rapidly lose nitrogen to yield 4,5-dihydropyridazines (40) or pyridazines (39) <65CB1435> (40) can readily be oxidized to... 

Finally, 1,2,4,5-tetrazines (169) react with electron-rich alkenes in what has been referred to as the Diels—Alder reaction with inverse electron demand to yield, after elimination of N2 and HY, the same pyridazine (170)... 

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