Synthesis of Diazines

Routes for the ring synthesis of the isomeric diazines are, as one would expect, quite different one from the other, and must therefore be dealt with separately. 

1 Ring synthesis of pyridazines I I.I4.I.I From a 1,4-dicarbonyl compound and a hydrazine 

By far the most common method for the synthesis of pyridazines involves a 1,4-dicarbonyl compound reacting with hydrazine unless the four-carbon component is unsaturated, a final oxidative step is needed to give an aromatic pyridazine. 

Maleic anhydride and hydrazine give the hydroxypyridazinone directly, the additional unsaturation in the 1,4-dicarbonyl component meaning that an oxidative step is not required conversion of 3-hydroxypyridazin-6-one into 3,6-dichloropyr-idazine makes this useful intermediate very easily available. 

Saturated 1,4-diketones can suffer in this approach from the disadvantage that they can react with hydrazine in two ways, giving mixtures of the desired dihydropyridazine and an A -aminopyrrole this complication does not arise when unsaturated 1,4-diketones are employed.Synthons for unsaturated 1,4-diketones are available as cyclic acetals from the oxidation of furans (section 15.1.4), and react with hydrazines to give the fully aromatic pyridazines directly.  

The most useful procedure utilises a 1,4-keto-ester giving a dihydro-pyridazinone, which can be easily dehydrogenated to the fully aromatic heterocycle, often by C-bromination then dehydrobromination alternatively, simple air oxidation can often suffice. 6-Aryl-pyridazin-3-ones have been produced by this route in a number of ways using an a-amino nitrile as a masked ketone in the four-carbon component, or by reaction of an acetophenone with glyoxylic acid and then hydrazine. Friedel-Crafts acylation using succinic anhydride is an alternative route to 1,4-keto-acids, reaction with hydrazine giving 6-aryl-pyridazinones. Alkylation of an enamine with a phenacyl bromide prodnces 1-aryl-l,4-diketones, allowing synthesis of 3-aryl-pyridazines.  

Saturated 1,4-diketones suffer, in this approach, from the disadvantage that they can react with hydrazine in two ways, giving mixtures of the desired dihy- 

Cycloaddition of a 1,2,4,5-tetrazine with an alkyne (or its equivalent), with elimination of nitrogen gives pyridazines. 

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The cleavage of fused pyrazines represents an important method of synthesis of substituted pyrazines, particularly pyrazinecarboxylic acids. Pyrazine-2,3-dicarboxylic acid is usually prepared by the permanganate oxidation of either quinoxalines or phenazines. The pyrazine ring resembles the pyridine ring in its stability rather than the other diazines, pyridazine and pyrimidine. Fused systems such as pteridines may easily be converted under either acidic or basic conditions into pyrazine derivatives (Scheme 75). 

Synthesis of tritium-labeled biologically important diazines 99UK254. 

Ortho-dxKCXed lithiation followed by reaction with TSN3 and reduction has led to an improved, general synthesis of aminodiazines 3a-c <96S838>. In some cases, tetrazolo-fused diazines could be isolated as intermediates. 

Phenazine leucos until now are usually substituted at their 3 and 6 positions by amino groups due to the normal method of synthesis of the parent phenazine dyes. These types of leuco dyes are reactive. An alternative method of dye synthesis allows access to phenazine dyes with just one substituent at the 3-position.20 The resulting leuco dyes are called half diazine leucos. The loss of one exocyclic amino group leads to higher redox potential and results in less reactive leuco dyes, more useful in applications such as thermographic and photothermographic imaging, particularly Color Dry Silver. 

The Boger pyrrole synthesis based on a heterocyclic azadiene Diels-Alder strategy (1,2,4,5-tetrazine to 2,2-diazine to pyrrole) was employed by the author for the total synthesis of ningalin B . Thus a Diels-Alder reaction of the electron-rich acetylene 52 with the electron deficient 1,2,4,5-tetrazine 53 proceeded to give the desired diazine 54 which underwent subsequent ring contraction to afford the core pyrrole structure 55. 

Boger and his research group [10] have also developed a very efficient and flexible synthesis of lukianol A as depicted in Scheme 3. The key transformation for the formation of the tetrasubstituted pyrrole precursor (15) involves formation of a symmetrically substituted diazine (14) by a Diels-... 

Alder/retrograde Diels-Alder reaction sequence of a diaryl alkyne with a 3,6-dicarbomethoxy tetrazine. The resulting diazine (14) is then reduced, cleaved and cyclized with Zn/acetic acid to the 2,3,4,5-tetrasubstituted pyrrole (15), which is then N-alkylated with a-bromo-4-methoxyacetophenone to give a pentasubstituted pyrrole (16). The synthesis of lukianol A is completed by ester hydrolysis, decarboxylation, ring closure and deprotection. 

It is not surprising to see that most of the bio-active compounds discussed in this review are 1,2-diazine derivatives bearing heteroatom substituents either at C-3 or at C-3 and C-6, since pyridazinones and pyridazinediones, utilized as intermediates in the synthesis of such derivatives, have been known for a long period and are generally conveniently accessible. On the other hand, there are so far only a few examples of pyridazine-derived pharmacological agents in which the parent system is linked to a functionalized carbon side-chain only. This may be attributed to the fact that many of the required synthetic building blocks had remained unexplored until very recently [15,173,438-441]). 

Scheme 68 presents simple and convenient approaches to the synthesis of photochromic diazines 234 (02M11), oxazoles 235 (011ZV113),... 

Boger et al. reported the first total synthesis of ningaline D (282) starting from the diphenylacetylene 1092 and dimethyl l,2,3,4-tetrazine-3,6-dicarboxylate (1093) (687). In this synthesis, the key step is the formation of the fully substituted pyrrole core using an inverse electron demand heterocyclic azadiene Diels-Alder reaction followed by a reductive ring contraction of the resultant 1,2-diazine. 

Electron-deficient heteroaromatic systems such as 1,2,4-triazines and 1,2,4,5-tetrazines easily undergo inverse electron demand Diels-Alder (lEDDA) reactions. 1,2-Diazines are less reactive, but pyridazines and phthalazines with strong electron-withdrawing substituents are sufficiently reactive to react as electron-deficient diazadienes with electron-rich dienophiles. Several examples have been discussed in CHEC-II(1996) <1996CHEC-II(6)1>. This lEDDA reaction followed by a retro-Diels-Alder loss of N2 remains a very powerful tool for the synthesis of (poly)cyclic compounds. 

The synthesis of fused 1,2,3-triazoles is nearly always achieved by treating 1,2-diamines attached to diazines with nitrous acid (e.g., [l,2,3]triazolo[4,5-f]pyridazine (Section 10.13.9.2.1(iii)) and [l,2,3]triazolo[4,5-rf pyrimidine (Section 10.13.9.2.1(iv)), <1996CHEC-II(7)489>). When a heterocyclic system containing a diazole fused onto 1,2,4-triazine is required, annulation of the five-membered heterocycle is nearly always the most facile route (e.g., imidazo[4,5-r ][l,2,4]triazine (Section 10.13.9.2.l(i)) and pyrazolo[4,3-r ][l,2,4]triazine (Section 10.13.9.2.1(ii))). In support of the latter, the synthesis of the fused six-membered ring of pyrazolo[3,4-r ][l,2,4]triazine from the pyrazo-ledione was reported as low yielding <1996CHEC-II(7)489>. 

The synthesis of pyridodiazine ring systems can be classified according to the relative location of nitrogen atoms in the diazine nucleus of the fused ring system as shown in formulas 246-248 for pyrido[v,y-2]pyridazines, pyrido[ ,y- ]pyr-imidines, and pyrido[x,y- ]pyrazines, respectively (Figure 2). Such fused ring systems have been subdivided according to the site of fusion z, that is, whether it is b-d. 

Pollet, P. Turck, A. Pie, N. Queguiner, G. Synthesis of chiral diazine and pyridine sulfoxides. Asymmetric induction by chiral sulfox-... 

Pie, N. Turck, A. Heynderickx, A. Queguiner, G. Metalation of diazines. XI. Directed ortho-lithiation of fluoropyrimidines and application to synthesis of an azacarboline./. Heterocyclic Chem. 1994, 31, 1311-1315. 

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