3.6- Disubstituted 1,2,4,5-tetrazines cycloaddition reactions

A common method to synthesize pyridazines remains the inverse electron-demand Diels-Alder cycloaddition of 1,2,4,5-tetrazines with electron rich dienophiles. [4 + 2]-Cycloadditions of disubstituted 1,2,4,5-tetrazine 152 with butyl vinyl ether, acrylamide, phenylacetylene, and some enamines were performed to obtain fully substituted pyridazines 153 . This reaction was accelerated by electron withdrawing groups, and is slowed by electron donating groups, R1 and R2on the tetrazine. 

Tetradehydrodianthracene undergoes 4 + 2-cycloaddition with electron-deficient dienes such as 1,2,4,5-tetrazines.263 The Diels-Alder reactions of [3.3 ortho-anthracenophanes witli A-(p-nitro, chloro, or methoxy-substituted phenyl)malehnides yield approximately equal quantities of inside and outside adducts.264 The photooxidation of bulky water-soluble 1,4-disubstituted naphthalenes with singlet oxygen yields both the expected 1,4- and the unexpected 5,8-endoperoxides.265... 

According to the mechanism proposed, the 1,4-cycloaddition (Diels-Alder reaction) of the diene part of the tetrazine to the dienophile (olefin) gives an unstable bicyclic intermediate, which spontaneously eliminates a molecule of nitrogen, forming a 4,5-dihydropyridazine, which in the absence of appropriate stabilization by gem disubstitution in positions 4 and 5, easily isomer-izes to the thermodynamically more stable 1,4-dihydropyridazine (38). The structure of the latter intermediates were unambiguously proved using NMR.91,92... 

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... 

Sauer et al. reported a one-pot synthesis of a series of semibullvalenes 164 starting from 3,6-disubstituted-l,2,4,5-tetrazines 1 and 1,1 -dimethyl-1,1 -bi(cycloprop-2-ene) 161. A plausible mechanistic explanation for the overall reaction consists of [4-1-2] cycloaddition to give the -isomer of diazanorcaradiene 162. Upon ir /7-ry -isomeriza-tion, another [4-1-2] cycloaddition leads to the final product 164. In the case of aryl substituents, which weaken the tendency for a-ry -isomerization, the corresponding 2,5-diaryldiazanorcaradienes 163 were isolated as the early intermediates in this reaction sequence (Scheme 43) <2002EJ0791>. 

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). 

Warrener reported that when 3,6-disubstituted-s-tetrazine 147 was employed as a heterodiene in Diels-Alder cycloadditions with alkenes such as 146, tandem [4 + 2]/[4 + 2] reaction takes place under high pressure (8-14 kbar, 16h) (Scheme 36) [55]. Due to its high reactivity, initial [4 + 2] cycloaddition of tetrazine 147 and nor-bornene 146 is carried out at atmospheric pressure. Spontaneous elimination of nitrogen from primary formed Diels-Alder adduct liberates the second diene, 1,2-dihydropyridazine. By addition of another equivalent of alkene 148 and application of high pressure, the second [4 + 2] cycloaddition generates the central diazabicy-clo[2.2.2]octene skeleton in high yield. A number of functionalized polynorbornane systems were prepared by this synthetic protocol [56]. 

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