Pyridazines as Substrates

Earlier work on the photolytic or thermal rearrangement of polyhalogenated pyridazines to corresponding pyrazines has been continued,14,161,774,1690 but the fascinating results offer little of preparative value. It has been reported that 300-nm irradiation of 3,4,5,6-tetra-tert-butylpyridazine (66) gave a quantitative yield of the Dewar isomer (3,4,5,6-tetra-tert-butyl-l,2-diazabicyclo [2.2.0]hexa-2,5-diene 67] that subsequently afforded 2,3,5,6-tetra-tert-butylpyrazine (68) in 18% yield on 254-nm irradiation.1464 

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Primary Syntheses of Phthalazines 8.6.10. Thieno[3,4-[Pg.158]

Recently, in our laboratory, a novel kind of cascade SNH heterocyclization has been discovered (02MC157, 03T7669, 05JHC375, 06T652). All are based on using the 6,8-dimethylpyrimido[4,5-< ]pyridazine-5,7(6//,8//)-dione 227 derivatives as substrates subjected to the action of alkylamine/AgPy2Mn04. 

Besides halopyridazines, pseudohalopyridazines have been used as substrates for Stille reactions [29]. 6-Methylpyridazin-3-yl trifluoromethanesulfonate (96) reacted with arylstannanes using a procedure based on Stille s original conditions for aryl triflates. Although 3-methyl-6-(2-thienyl)pyridazine was obtained in a good yield (77%) under these conditions, trialkyl(phenyl)stannanes reacted only very slowly in comparison with tributyl(2-thienyl)stannane. Trimethyl(phenyl)stannane and tributyl (phenyl) stannane gave 3-methyl-6-phenylpyridazine in only 22 and 6% yield, respectively. 

From Pyridazine Derivatives as Substrates Using One Synthon to Supply C6 + C7 of the Phthalazine... 

Another combination of reagents, in which 3-cyclohexylaminopyrimido-pyridazine 47g is used as substrate and propylamine or butylamine as nucleophile, affords imidazolines 56a,b, isomeric to compounds 49c,d. Apparently, the process starts with oxidation of 3-alkylamino group of the starting aromatic substrate and proceeds as shown in Scheme 33. 

A metal-iodine exchange has been carried out on all three diazine systems under very mild conditions using lithium tri- -butyl magnesate, although only one substrate from each system was used 3-iodo-6-phenylpyridazine, 4-iodo-2-methylthiopyrimidine and 2-iodopyrazine. The pyridazine example was most problematic, possibly due to solubility problems. Aldehydes, benzophenone and diphenyl disulfide were used as the electrophiles <06SL1586>. 

Ejection of dinitrogen from the triazoline adducts to form the related aziridines was promoted by ultraviolet irradiation (300 nm, benzene) and usually proceeded in excellent yield. An exception was found in the irradiation of the triazoline substrate 59, where cleavage of the cyclobutane ring occurred as the dominant reaction pathway to form the pyridazino norbomadiene 61 (and secondary photoproducts derived therefrom), together with the triazole-4,5-diester 62. A role for the pyridazine ring and the 2-pyridyl substituents in stabilising the diradical intermediate 60 has been proposed for this abnormal outcome (Scheme 8). 

Stanovnik and co-workers (100,101) systematically investigated the cycloaddition reactions of diazoalkanes with unsaturated nitrogen heterocycles, such as azolo-[l,5-fl]pyridines, pyridazin-3(2/7)-ones, and [fo]-fused azolo- and azinopyridazines. The Stanovnik group have studied the further transformations of the products and reviews of this chemistry are available. In a typical example, the reaction of 6-chlorotetrazolo[l,5-/7]pyridazine (37) with 2-diazopropane yields the NH,NH-dihy-dro-pyrazolo[4,3-(i]tetrazolo[l,5-/7]pyridazine 38 (102) (Scheme 8.11). The latter substrate reacts with acetone to produce an azomethine imine 39 that thermally rearranges to give the fused dihydro-1,2-diazepine 40. The azomethine imine obtained with glucose can be trapped with methyl acrylate to furnish the C-nucleoside 41 (103). 

The stronger stabilizing effect of a y-aza relative to an a-aza atom is confirmed by the behavior of pyridazine and pyrimidine, which preferably form adducts 29 and 30, respectively. Phenyl substituents discourage ipso attack by NH2", as shown by the observation that in the reactions with 4,6-diphenyIpyrimidine, 2-phenyl-l,3,5-triazine, or 2,4-diphenyl-l,3,5-triazine only CH adducts are detected. However, indirect evidence for adducts resulting from attack at CPh positions is provided by a study of the reaction products from diphenyltriazine and related substrates, unequivocally showing that such adducts are transiently formed along an SN (ANRORC) pathway. 

Finally, a Diels-Alder reaction with inverse electron demand, in which the thiophene acts as the 27r-component, has been reported (78AP728). Tetrazinedicarboxylic ester adds to thiophenes to give the adduct (290) loss of nitrogen from this is followed by oxidation, yielding the thieno[2,3-rf]pyridazines (291) in 10-15% yield. With 2,5-dimethyl-thiophene as the substrate, aromatization is blocked, and the product (292) is obtained in 57% yield. 

Instead, evidence now favors the intermediacy of the highly organized mono-osmium complex 15. Various factors could contribute to its excellent enantioselectivity, the most important one being the formation of a binding site consisting of the two methoxy quinolines and the pyridazine linker. As confirmed by X-ray analysis and NMR studies [35,36], this pocket adopts a U-shaped conformation and is capable of perfectly binding aromatic substrates such as styrene through attractive interactions with the methoxyquinolines. In contrast, bulky... 

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