Pyridazines 1.2.4.5- tetrazines

Pyrimidine Pyrazine Pyridazine 1,2,4,5-Tetrazine 1,2,3,4-Tetrazine 1,2,3,5-Tetrazine... 

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). 

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). 

While enamines are poor dienophiles for Diels-Alder reactions, their addition to tetrazines has provided a route to pyridazines (595). 

The reaction of oxepin with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate affords a 2 1 mixture of products 9 a and 10, whose formation can be rationalized by a [4+2] and a [4 + 6] cycloaddition, followed by nitrogen extrusion.235 With 2,7-dimethyloxepin, only dimethyl 6,8-dime-thy 1-2.4a-dihydrooxepino[4,5-c/]pyridazine-l,4-dicarboxy late (9b) as product of the [4 + 2] cycloaddition can be isolated.235 236... 

The cycloaddition reactions of the novel 3-methylsulfrnyl-6-methylthio- 37 and 3-(benzyloxycarbonyl)amino-6-methylsulfinyl- 38 -1,2,4,5-tetrazine to afford the corresponding pyridazines 39-40 proceeded with a regioselectivity opposite to expected and complementary to that observed for the corresponding sulfides <06JOC185>. 

The cycloaddition of acetylenes to 3,6-di(pyridin-2-yl)-l,2,4,5-tetrazines to give the corresponding di(pyridin-2-yl) pyridazines was considerably accelerated under microwave assisted conditions <06JOC4903>. 

The [4+2] cycloaddition of dimethyl-1,2,4,5-tetrazine-3,6-dicarboxylate 41 with ketene A, O-acetals or cyanamide yielded tetrafunctionalized pyridazines 42 or 1,2,4-triazine 43 respectively. Treatment of 42-43 with zinc dust in AcOH afforded pyrrole 44 or imidazole 45 derivatives <06S1513>. 

The DA reaction of tetrazines such as 3 was also studied by use of the GS/ MW process [26, 27]. The expected adduct, however, decomposed by nitrogen elimination followed by dehydrogenation, giving a pyridazine or a dihydropyrida-zine [23-25], With 2,3-dimethylbutadiene and cyclopentadiene as dienophiles, SMWI gave dihydropyridazines 8 and 9, as with classical heating [23] (Tab. 7.1, entries 6 and 7). 

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. 

Similarly, [4 + 2]-cycloadditions were used to prepare the pyridazine moiety in fused tetraheterocyclic azepine 155 syntheses. In this reaction, the 1,2,4,5-tetrazines 154 function both as the 47t-components and the oxidizing agents thereby requiring four equivalents of tetrazine for optimal yield. . 

These authors found that the tetrazinylhydrazone derivative 46 when reacted with pyrrolidinoenamine 47 in methanol yields the cyclopenta-fused derivative of the title ring system 48 in 94% yield. A similar transformation was carried out successfully by using morpholine-enamine in somewhat poorer yield. When the transformation was tried in acetonitrile as a solvent, a totally different reaction was observed a regular Diels-Alder reaction between the tetrazine ring and the enamine double bond (of inverse electron demand) took place to yield pyridazines. 

The inverse-electron-demand Diels-Alder reaction of 3,6-dichloro[l,2,4,5]tetrazine with alkenes and alkynes provides the synthesis of highly functionalized pyridazines. ° Also, the 4 + 2-cycloaddition reactions of the parent [l,2,4,5]tetrazine with donor-substituted alkynes, alkenes, donor-substituted and unsubstituted cycloalkenes, ketene acetals, and aminals have been investigated. ... 

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... 

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 pyrrolo[2,3- 7 pyridazines can be achieved by starting either with pyridazine, a tetrazine, or a pyrrole. Pyridazinone 80 reacts with bromomethyl derivatives to give poor yields of 81 <1996H(43)1863> (Equation 34), while 5-acetyl-2-methyl-4-nitro-6-phenyl-3(2//)-pyridazinone, after treatment with sarcosine ethyl ester for a brief time at room temperature, followed by acid hydrolysis afforded a good yield of 82 (70%) <1994S669>. 

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>. 

Cycloaddition of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate with EWG-substituted primary ketene N,0-acetals provides a tetrasubstituted pyridazine, methyl 4-amino-5,7-dioxo-6,7-dihydro-5/7-pyrrolo[3,4-4pyridazine-3-carboxylate <200681513>. 

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). 

Two complementary routes to the synthesis of pyrido[, y-i/ pyridazines have been developed, the first of which begins by constructing the pyridine ring, and the second by constmcting the pyridazine ring. In addition, ring transformations of pyrrolopyridine, pyridooxazine, pyridopyrimidine, and tetrazine derivatives to the pyrido[x,y-t7 pyridazines have also been reported. 

Much effort has been devoted to the study of the electronic spectra of aza analogues of pyridine (pyridazine, pyrimidine, pyrazine, sym. (l,3,5-)triazine, and sym. (l,2,4,5-)tetrazine) as well as of derivatives of all these compounds. Most of these absorption spectra are similar to those of the parent compounds, except for a band corresponding to the n -> it transition which appears in the long-wavelength... 

Position Pyridine Pyridazine Pyrimidine Pyrazine Triazine Triazine Triazine Tetrazine... 

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