3.6- Disubstituted 1,2,4,5-tetrazines, reaction

Regarding the series of hetero aromatic pentacyclic compounds with three heteroatoms, an accelerated synthesis of 3,5-disubstituted 4-amino-1,2,4-triazoles 66 under microwave irradiation has been reported by thermic rearrangement of dihydro-1,2,4,5 tetrazine 65 (Scheme 22). This product was obtained by reaction of aromatic nitriles with hydrazine under microwave irradiation [53]. The main limitation of the method is that exclusively symmetrically 3,5-disubstituted (aromatic) triazoles can be obtained. 

Refluxing a mixture of hydrazonoyl halides 13 and heterocyclic thiones 14 in ethanol in the presence of triethylamine resulted in the formation of 3-arylazo-l,4-dihydro-l,7-disubstituted-pyrimido[l,2,-3]-l,2,4,5-tetrazin-6-ones 8. The reaction starts with the initial formation of the hydrazidine derivatives 15, which in turn undergo cyclization with the elimination of thiolate to give the desired product 8 (Scheme 1)<2004JCM399>. 

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. 

Synthetic approaches to representatives of this ring system have been discussed in CHEC-II(1996) <1996CHEC-II(8)496>. Research activity in this area has been considerably extended during the past years. Thus, the basic starting material is a 6,6-disubstituted tetrahydro[l,2,4,5]tetrazin-3-thione 52, which has been converted in three different ways reaction with phenacyl bromides led to 3,3-disubstituted 3,4-dihydro-6-phenyl-2//-thiazolo[3,2-4]-[l,2,4,5]tetrazines 53, reaction of 52 with 1,2-dibromoethane gave 3,4,6,7-tetrahydro-2//-thiazolo[3,2-7][l,2,4,5]tetra-zines 54, whereas transformation of 52 with chloroacetic acid in the presence of sodium acetate yields substituted 3,4-di hydro-1-2//-thiazolo[3,2- 1 [ 1,2,4,5]tctrazin-6(7//)-oncs 55 <2001IJB584> (Scheme 17). Details are shown in Table 2. 

Reaction of aldehydes with hydrazine, or mono- or 1,2-disubstituted hydrazines is the method used almost exclusively for the preparation of hexahydro-l,2,4,5-tetrazines (377). All types of hydrazines have been used hydrazine itself, monoalkyl-, monoaryl-, dialkyl-, diaryl-, alkylaryl-, alkylacyl- or arylacyl-hydrazines. The aldehydes used were mainly aliphatic aldehydes. An excellent review by Wiley of the literature on this reaction up to 1974 is available (78HC(33)1075, p. 1190). 

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... 

Another example of inverse-electron demand reactions of 3,6-disubstituted 1,2,4,5-tetrazines is with alkynyl boronic esters which provides a direct and regioselective method for the synthesis of pyridazine boronic esters <05AG(E)3889>. 

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... 

Tetrazinesreact also with the C -N double bond of hydrazones and aldimines. Reaction of AA(trimethylsilyl)benzaldimine with 3,6-disubstituted 1,2,4,5-tetrazines affords 2,5-dihydro-... 

The second (3 + 3) fragment method concerns reactions which can be explained as dimerization of nitrile imines 8. Since in most cases R2 is a substituent and not a proton, these reactions give 1,4-disubstituted 1,4-dihydro-l,2,4,5-tetrazines 9 which cannot be transformed into aromatic 1,2,4,5-tetrazines 10. These reactions will not be discussed in detail. 

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 prediction that electron-withdrawing substituents in tetrazines accelerate, and electron donors decrease the reaction rate was demonstrated by p values of + 1.24 and -1-2.51 for the combination of 3,6-disubstituted 1,2,4,5-tetrazines with styrene and a-methylstyrene respectively <80Mi 62i-oi> and was also confirmed using cyclooctyne as dienophile <83TL1481> for a number of nitrogen... 

Figure 7 Rate constants (10 Aj 1 mol s , 20°C, acetonitrile) for the reaction of l-iV,iV-dimethyl-aminopropyne with heteroaryl 3,6-disubstituted 1,2,4,5-tetrazines.

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). 

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