Tetrazines, reactivity substitution reactions

Indoles have been prepared from reactions of o-aminophenylketones with reactive , or stable " arsonium ylides. Oxo-stabilized ylides reacted with 2-chloro-oximes to give trans-5-acyl-A -isoxazolines, and isoxazoles have been obtained from reactive arsonium ylides and a-isonitrosoketones, and from triphenylarsonium methylide and nitrile oxides The latter ylide reacts similarly with nitrile imines to give pyrazoles. With triphenylarsonium benzylides and benzoylylides,benzene diazonium salts give 1,3,4,6-substituted 1,4-dihydro-1,2,4,5-tetrazines in a reaction in which initial coupling of the reagents is followed by a dimerisation. ... 

Since the initial demonstrations of the participation of substituted l,2,4,S-tetrazines ° and oxa-zoles ° ° in [4 + 2] cycloaddition reactions with alkene and alkyne dienophiles, the investigation and application of the Diels-Alder reactions of heteroaromatic systems possessing reactive azadienes have been pursued extensively. A number of general reviewshave treated the spectrum of heteroaromatic azadienes that participate in [4 + 2] cycloaddition reactions and many of the individual heteroaromatic systems have been reviewed separatcly. ° ° An extensive account was published recently and should be consulted for descriptions of the [4 + 2] cycloaddition reactions of the common heteroaromatic azadienes that have been observed to date. 

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... 

As long as acceptors are used for and R in tetrazines (9) and donors for R or A and B in dienophiles (36) and (37) the cycloadditions in Scheme 5 are quite fast and can in fact approach diffusion-controlled reactions, as kinetic data prove. The great variability of substituents in both reaction partners, 1,2,4,5-tetrazines and dienophiles, is responsible for the increasing importance of the reactions outlined in Scheme 5. A systematic treatment of the dienophile (simple alkenes and alkynes, more complicated alkenes, donor-substituted alkenes and alkynes, hetero 27c-systems, aromatic systems, heteroaromatic dienophiles stereospecificity, regiospecificity, and reactivity data) demonstrates this. The variation of the 1,2,4,5-tetrazine partner is included in this discussion. 

Donor substituents such as NRj, OR, SR, and OSiR, increase the electron density of dienophiles and also their reactivity in cycloadditions with 1,2,4,5-tetrazines. Schemes 21 and 22 <89TH 621-01 > show typical (4 -t- 2) cycloaddition reactions for the parent compound (7) with donor substituted alkenes and alkynes, which make available a large number of simple donor substituted pyridazines (127H136). 

In addition to the [4 + 2] cycloadditions of oxazoles (Section 1) and substituted 1,2,4,5-tetrazines (Section 14), the Diels-Alder cycloadditions of substituted 1,2,4-triazines constitute one of the most thoroughly investigated heteroaromatic azadiene systems capable of 4tt diene participation.3,89 In contrast to the oxazole or sym-tetrazine series, two potential and observed modes of cycloaddition are open to 1,2,4-triazines cycloaddition across C-3/C-6 or C-5/N-2 of the 1,2,4-triazine nucleus, and the former is subject to 1,2,4-triazine substituent control of the observed regioselectivity.90 The complementary addition of electron-withdrawing substituents to the 1,2,4-triazine nucleus generally increases its rate of participation in inverse electron demand Diels-Alder reactions, influences the mode of [4 + 2] cycloaddition (C-3/C-6 versus C-5/N-2 cycloaddition), and controls the observed regioselectivity. In addition, the reactivity of the electron-rich dienophile as well as the reaction conditions, polar versus nonpolar solvent, have a pronounced effect on the observed course of the [4 -I- 2] cycloadditions.89... 

The reactivity of pyridazines in Pd-catalyzed reactions was of interest. For example, the Heck alkenylation at C5 of 6-phenyl-3(2//)-pyridazinones was investigated, with the aim of suppressing production of 4-phenyl-6-substituted-2-phthalazinone byproducts <04TL3459>. In another study, the reactivity of 5-iodopyridazin-3(2f/)-ones in Pd-catalyzed reactions was investigated to develop an efficient route to 2,5-disubstituted pyridazin-3(2/f)-ones <04T12177>. Other pyridazine syntheses relied on condensation approaches. Benzo[g]pyridazino[l,2-i>]-phthalazine-6,13-diones 16 and 17 related to certain anthracyclinones were obtained by cycloaddition of 1,3-dienes to benzo[g]phthalazine-l,4-dione <04H(63)1299>, and pyridazine C-nucleosides synthesized by 14-i-2 cyclocondensation of alkynyl C-nucleosides with substituted tetrazines afforded, upon extrusion of a nitrogen atom, pyrrole C-nucleosides in good yields... 

After Huisgen s explanatory review, there was still silence on this reaction in the scientific community for some years until it was realized by Carboni and Lindsey (1962) that substituted 1,2,4,5-tetrazines are very reactive towards simple alkenes. Sauer et al. (1965), working in the same department as Huisgen at the University of Munich, evaluated such reactions in more detail, including alkynes in addition to alkenes. In the 1970 s, dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate (9.38) became much in demand as a synthon. It is obtained easily by esterification of 9.36, followed by treatment with nitrous gases (9-22 Organic Syntheses, Boger et al., 1992). 

In the past decade, the chemistry of j0-lactam carbenes has proved successful for the construction of complex spiro- or fused heterocyclic scaffolds of medicinal relevance. To that purpose, their synthetic potential has been further explored with a study on their reactivity towards 3,6-di(2-pyrimidinyl)tetrazine (28). Diversely substituted / -lactam carbenes have been found to smoothly react with (28) to furnish the two novel heterocyclic scaffolds (29) or (30) depending solely on the reaction temperature (i.e., 100 and 140 °C, respectively) (Scheme 4). 

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