Pyridazines from 1,2,3,4-tetrazines

The formation of pyrimidines via aza-Diels-Alder reactions is similar to the preparation of pyridazines from tetrazines (cf. 14.13.1.2). 

The formation of pyridazines from 1,2-diaza-1,3-butadienes and electron-rich dienophiles has been reported [308] on the other hand, tetrazine and triazole derivatives have been prepared from these heterodienes and azo esters [309]. Aza Diels-Alder reactions of 1,4-diaza-1,3-butadienes have been employed for the synthesis of unsymmetrical pyrazine derivatives by Heathcock et al. [310]. 

Extensive studies of preparation of 4-mono- and 4,5-disubstituted pyridazines from 1,2,4,5-tetrazines using donor-substituted alkenes, alkynes, ketene aminals, or styrenes were reported by Sauer. Pyridazine itself can be prepared from 1,2,4,5-tetrazine and acetylene (27% yield), ethyl vinyl ether (78% yield), methyl vinyl sulfide (76% yield), or N,jV-dimethylvinyl-... 

A large number of pyridazines are synthetically available from [44-2] cycloaddition reactions. In one general method, azo or diazo compounds are used as dienophiles, and a second approach is based on the reaction between 1,2,4,5-tetrazines and various unsaturated compounds. The most useful azo dienophile is a dialkyl azodicarboxylate which reacts with appropriate dienes to give reduced pyridazines and cinnolines (Scheme 89). With highly substituted dienes the normal cycloaddition reaction is prevented, and, if the ethylenic group in styrenes is substituted with aryl groups, indoles are formed preferentially. The cycloadduct with 2,3-pentadienal acetal is a tetrahydropyridazine derivative which has been used for the preparation of 2,5-diamino-2,5-dideoxyribose (80LA1307). 

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

The only recorded synthesis of this type from a pyridazine involves the [4 + 2] cycloaddition of the lactim ether (374) with l,2,4,5-tetrazine-3,6-dicarboxylic ester, which proceeds with loss of nitrogen and methanol from the intermediate adduct to give the pyrido[2,3-t/]pyridazine (375) (77AP936). 

Relatively low RE values, compared to that of benzene, of pyridazine, s-triazine, and s-tetrazine (see Table VII) are explained, primarily, by changes in the cr-system that occur in passing from the conjugated system to the reference system, i.e., by the factors, such as the compression energy, that were noted in the discussion of the so-called empirical resonance energies. 

Elimination of nitrogen from Diels-Alder adducts of certain heteroaromatic rings has been useful in the synthesis of substituted aromatic compounds.224 Pyridazines, triazines, and tetrazines react with electron-rich dienophiles in inverse-electron-demand cycloadditions. The adducts then rearomatize with loss of nitrogen and the dienophile substituent.225... 

Apart from a very unconventional synthesis of 274 via fragmentation of the tetrazine 273 in the presence of furan (Equation 97) <2003AJC811>, interest in the furo[3,4-r/ pyridazines has waned since the coverage in CHEC-II(1996) <1996CHEC-II(7)229>. 

The inverse electron demand Diels-Alder [4- -2]-cycloaddition of imidazoles to electron-poor dienes to yield imidazo[4,5-i pyridazines, reported in CHEC-II(1996), has been further developed. It was reported that the reaction of267 with tetrazines 268 was fruitless. However, 267 reacted with excess of 268 to yield aromatic 271 along with 1,4-dihydrotetrazine 270. Most likely, 271 arose from dehydrogenation of first-formed 269 by an extra equivalent of 268 <2001T5497> (Scheme 18). 

Arene oxide-oxepin systems have also been reported to undergo [2 + 4] or [4 + 6] pericyclic cycloaddition reactions with heterocyclic dienes like the tetrazine 279 and the triazine 280. 65 Thus 86 96 reacts with 279 and 280 to yield the dihydrooxepino [4,5-d] pyridazine 281 and the oxepino [4,5-c] pyridine 282, respectively, via a [2 + 4] cycloaddition as well as the phthalazine 283 and isoquinoline 284, respectively, probably via a [6 + 4] cycloaddition reaction. However, 157 gives only 285 and 286 arising from a [2 + 4] cycloaddition reaction. 

Makhluf J. Haddadin was born in Main, Jordan. He holds B.S. and M.S. degrees (Professor C. H. Issidorides) from the American University of Beirut and a Ph.D. degree from the University of Colorado, USA (Professor A. Hassner). He was a research fellow at Harvard University (Professor L. F. Fieser). The art of heterocyclic chemistry has been his main hobby as he worked on heterocyclic steroids, isobenzofurans, isoindoles, quinoxaline 1,4-dioxides (the Beirut reaction), pyridazines, tetrazines, 277-indazoles, and other heterocycles. He rejoined his alma mater in 1964 and currently serves as professor of chemistry. He was vice-president for academic affairs (1987-99). 

In a different pattern, by using silylated acetylenes, substituted pyridazines are obtainable217 from the tetrazine derivative 401 in a diene-type reaction, first introduced by Carboni and Lindsey218. Via this reaction 4-TMS- (402) and 4,5-bis(TMS)-3,6-bis(methoxycarbonyl)pyridazine (403) can be achieved in very high yield, being inert against acid catalyzed desilylation (Scheme 59). 

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