Cycloadditions forming pyridazines

With heterocyclic dienophiles, however, tetrazines react quite differently with thiophene and 1-methylimidazole, they form bicyclic products whereas, with 1-methylpyrrole a complex reaction involving a second cycloaddition forms the bispyridazine 30. The cycloaddition of 2,5-dimethylfuran is followed by ring opening to give 31 and with methylenethietane a spiro-pyridazine derivative 32 is formed (Scheme 1). 

The (4+2)-cycloaddition reactions are theoretically and experimentally well founded for electron-rich dienes. However, those reactions with electron-rich dienophiles are less investigated. An early application of the inverse type of (4+2)-cycloaddition to pyridazine synthesis, i.e., from electron-deficient azoalkenes and alkenes, was reported by Sommer in 1977, [Eq. (4)]. A mixture of regioisomeric products 22 and 23 was obtained.107 108 However, in the presence of diphenylketene, products of either (2 + 2)- and/or (4+2)-cycloaddition (i.e., pyridazines) are formed arylazoalkenes thus behave similarly to a,/ -unsaturated carbonyl compounds in cycloadditions.109 2-Phenylazo-l-alkenes dimerize (a (4+2)-cycloaddition) in the absence of solvent to give pyridazines, or they may react with dienophiles.110-115 Some other cycloadditions of this type are reported.116-120... 

Diels-Alder cycloaddition as a way of combining 4+2 atoms to form pyridazines and condensed pyridazines... 

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... 

Hexahydropyrido[l,2-6]pyridazin-8-ones 178 and a 2,3-tetramethylene derivative were formed on the intramolecular cycloaddition of 177, formed in situ by dehalogenation of hydrazones of the hex-5-enoic acid derivatives 176 [87JCS(P1)2511]. Intramolecular cycloaddition of hydrazones 179 in... 

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). 

Dipolar cycloadditions lead to six-membered rings. Rearrangements may be encountered. Thiazole or 2-methylthiazole (129 R = H and Me) with DMAD forms an initial 1,4-dipolar species (130). Reaction of (130) with a second DMAD gives a 1 2 adduct, presumably (131). Ring opening to (132), followed by cyclization in the alternative mode, resulted in (133) (78AHC(23)263) (see also CHEC 4.19). For the similar reactions of pyridine with DMAD and pyridazine with maleic anhydride see Section 3.2.1.3.7. 

The cycloaddition of 3,6-diphenyl-l,2,4,5-tetrazine (51) with 6-dimethylaminofulvene (195) has been studied by Sasaki et al. (75JOC1201) and by Neunhoeffer and Bachmann (79LA675). The Japanese group claim to have isolated 4,7-diphenyl-5,6-diazaazulene (196), produced via a [6 + 4] cycloaddition and dimethylamine elimination, but Neunhoeffer and Bachmann found that the reaction proceeds by a [4 + 2] cycloaddition, then loss of nitrogen and dehydrogenation, to form 5-dimethylaminomethylene-l,4-diphenyl-5//-cyclopenta[ /]pyridazine (197). 

The synthesis of pyrano[3,4-Z>]pyrroles was achieved utilizing a zinc-mediated ring contraction of pyridazines 07EJ03296 07SL403>. The pyridazines were formed by the cycloaddition of alkynes with tetrazines. 

A pyridazine ring can be formed in a cycloaddition reaction of diazo compounds or diazonium salts, with alipahtic or cyclic azo compounds. It can also be formed by cycloaddition of various 1,2,4,5-tetrazines and dienophiles in inverse electron demand Diels-Alder reactions. As shown later, this synthetic approach has been used extensively and with success in the 1980s. 

The cycloaddition reaction of cyclobutadienes with azodicarboxylates gives 3,6-bonded Dewar pyridazines. An example of this type of reaction has already been reported before94. A further example is described by the reaction sequence (147)158,159). The formed cycloadduct a hydrolyzed, decarboxylated, and oxidized to 3,6-bonded Dewar pyridazine which loses nitrogen to form cyclobutadiene (147). 

The preparation of pyridazines by cycloaddition of ynamines to 1,2,4,5-tetrazines, followed by extrusion of nitrogen, has been described. However, when 1-diethylaminopropyne reacted with l,2,4,5-tetrazine-3,6-dicarboxamides (27 = 4, 5) besides the corresponding pyridazines (28), almost equal amounts of the new tetrazines (29) were also obtained. These are formed by addition of the ynamine across the amide carbonyl. 

The dipolar cycloaddition of 2-diazopropane to l-methyI-3-phenyl-pyridazin-6-one proceeds at 0°C via an unstable cycloadduct (143), which is thermally decomposed to 144 as the main product, together with 145 and 146. " A cycloadduct is also formed between ergosteryl acetate and the diazaquinone formed from maleic hydrazide. ... 

In the last decade new reactions have been elaborated in which pyridazines can be transformed into a variety of other heterocycles. Esters of pyridazine-carboxylic acids and 1-diethylaminopropyne undergo cycloaddition reactions with inverse electron demand. The orientation of the two reactants depends on the position of the carboxylate group in the pyridazine ring. For example, from methyl pyridazine-4-carboxylate the pyridine derivative 245 was formed via the adduct 244 and subsequent elimination... 

The primary adducts, cyclohexadiene derivatives, formed by [4+2] cycloaddition of thiophene dioxides with dienophiles, may further undergo [4+2] cycloaddition with the dienophiles. Thus, the adducts 84 of 3,4-di-ferf-butylthiophene dioxide 83 with maleic anhydride and AT-phenylmaleimide further react with these dienophiles to give excellent yields of bis-adducts, which are composed of the endo-endo and endo-exo isomers, 85a and 85b (Scheme 49) [160]. A similar reaction was also observed with 3,4-dichlorothiophene 1,1-dioxide with N-butyl- and A-p-nitrophenylmaleimides (Scheme 50) [133]. The reaction of highly congested thiophene dioxides 87 with 4-phenyl-1,2,4-triazoline-3,5-dione provides a unique pyridazine synthesis since the bis-adducts 88 are converted into the corresponding pyridazines 89 in one pot and in good yields by treatment with KOH in methanol (Scheme 51) [174]. 

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