Tetrazines reactions with nucleophiles

General methods for the preparation of 1,2,4,5-tetraoxanes Key structures for the development of peroxidic antimalarial agents 12KGS60. Reactions oftetrazines with dienophiles 12KGS1237. 1,2,4,5-Tetrazines and azolo[l,2,4,5]tetrazines Synthesis and reactions with nucleophiles 13KGS75. 

There are three groups of substrates for which SNH reactions are especially characteristic (i) neutral azines and azoles (ii) azinium and azolium salts and (iii) nitro-arenes. Their electron-deficiency and, thus, their ability to react with nucleophiles strongly differ from each other. Azinium salts are the more electrophilic and are able to add even neutral nucleophiles very easily. Triazines,. v-tetrazines and polynitro-arenes also possess high electrophilicity. At the same time substrates such as pyridine (82JHC1285, 72JA682) and cinnoline (03CHE87), at a low temperature (e.g. in liquid ammonia as a solvent), do not react even with sodium amide. It should also be... 

Exchange of leaving groups bound to the 1,2,4,5-tetrazine ring by nucleophiles is a well-known and often used reaction in 1,2,4,5-tetrazine chemistry. All types of reactions known from other azabenzene systems have also been observed with 1,2,4,5-tetrazines. Most reported exchange reactions and modifications of substituents are illustrated and compiled with references. In case where R1 is also a leaving group, one or both substituents can be replaced by a nucleophile. 

Another example of the effectiveness of the reaction O -coronaP] arene[3]tetrazines 54, a new class of macrocyclic compounds, were synthesized efficiently in a one-pot reaction via nucleophilic aromatic substitution of 3,6-dichlorotetrazine 53 with 1,4-dihydroxybenzene derivatives 55 in warm acetonitrile (14AGE13548). 

A simple route to unsymmetrically substituted 1,2,4,5-tetrazines is the reaction of triethyl orthoformate (or acetate), or DMFDMA, with S-methylisothiocarbonohydrazide salt (9) in the presence of triethylamine and air. The use of iminium chlorides (10) gives similar products. The methylthio group can be readily displaced by nucleophiles to give other substituted tetrazines [94JOC8284],... 

The analogous reaction between benzocyclopropene and dimethyl l,2,4,5-tetrazine-3,6-di-carboxylate proceeded at room temperature under argon with loss of nitrogen to give dimethyl 4a,8a-methanophthalazine-l,4-dicarboxylate (6) in 97% yield. In contrast to the adducts of triazines, which have a heteroannulene structure, those of tetrazines occur as norcara-dienes. The methanophthalazine 6 underwent nucleophilic addition to the C-N double bond with a variety of mild nucleophiles. 

The examples shown are illustrative of the many easy nucleophilic additions to the polyaza-azines both 3-phenyl-l,2,4,5-tetrazine and 1,3,5-triazine itself add ammonia and simple amines (contrast the requirement for hot sodamide (Chichibabin reaction) for pyridine (8.3.1.2)) and thus amino and alkyamino derivatives can be obtained via oxidative trapping with permanganate. 

Conditions for the reductive desulfurization of 3,6-bis(methylthio)pyridazine (108), (Scheme 70) with Raney nickel have been developed as part of a synthetic approach to 4- or 4,5-disubstituted pyridazines based on Diels-Alder reactions of 3,6-bismethylthio-l,2,4,5-tetrazine. Selective oxidation of (108) can give the monosulfoxide, bis(sulfoxide), and bis(sulfone) depending on the conditions used, and the bis(sulfone) was susceptible to nucleophilic displacement of one sulfonyl group. These studies were limited to the symmetrical substrate (108) <88JOCi4i5>. 

The easy addition at C-5 of 1,2,4-triazines is shown by the VNS (section 2.3.3) reaction of the 3-methylthio-derivatives in the absence of activating groups a closely related addition of nitroalkanes represents a very useful nucleophilic acylation. The ready displacement of methylthio from the same compound is also indicative. " Nucleophilic displacement of methylthio in 1,2,4-triazines and 1,2,4,5-tetrazines by alkoxide and amines is very easy. Mono-displacement can be carried out on 3,6-bis(methylthio)-1,2,4,5-tetrazine but the reaction using methoxide requires careful control of reaction conditions to avoid formation of the dimethoxy derivative. However, reaction of the bis(methylthio) compound with methyllithium resulted in nucleophilic attack at nitrogen ... 

Work by Kotschy and co-workers showed that reactions of different symmetrical 1,2,4,5-tetrazines with a variety of organometallic reagents furnished, depending upon the combination of reactants, azaphilic addition, reduction or complexation products and not the nucleophilic aromatic substitution products <2004T1991>. On the other hand, Benson et al. reported a smooth displacement of one chlorine substituent in chlorotetrazine 136 using cyanide anion as a soft C-nucleophile (Scheme 36) <2000T1165>. 

In the series of azaaromatics pyridine appears to possess the least electron deficiency and cannot be aminated under these conditirms. In contrast, diazines, triazines, tetrazines, quinolines, quinoxalines, quinazolines, naphthiridines, polyazaaromatic compounds, and their nitro derivatives are able to undergo oxidative amination. Moreover, amination of highly Jt-deficient triazines, tetrazines, 3-nitropyridine, 3-nitroquinoline, etc. is possible to perform without KNH2, since ammonia itself serves as nucleophile in such cases (Scheme 6). However, the more electron deficiency of an azine substrate, the less regioselectivity of the reaction. Oxidative amination of 3-nitrop3ridine in Uquid ammonia with potassium permanganate affords a mixture of 2-amino-3-nitro- (33%), 4-amino-3-nitro- (24%), and... 

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