Functionalizations pyridazine

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. ... 

Pyridazine boronic esters are substrates in Suzuki cross-coupling reactions. [4-I-2] Cycloaddition reactions of 1,2,4,5-tetrazine derivatives 1 with alkynyl boronic esters 257 provide easy access to functionalized pyridazine boronic esters 258. New unsymmetrical 1,2,4,5-tetrazines 259 and 261 have been prepared and tested in reactions with alkynyl boronic esters 257, providing the corresponding pyridazines 260 and 262 as single regioisomers (Scheme 64) <2005AGE3889>. 

W-Functionalization. Pyridazine can be functionalized at the nitrogen position to form N-0, N-N, and N-C bonds. The resulting products enhance the reactivity at the Cs-position and provide a handle toward the formation of more complex heterocycles. For instance, pyridazine dissolved in an aqueous mixture of hydroxyl amine sulfonic acid (HOS A), potassium iodide, and potassium hydrogen carbonate affords the corresponding aminated pyridazine (eq 2). ... 

N-protonation the absolute magnitude of the Ad values is larger than for Af-methylation <770MR(9)53>. Nuclear relaxation rates of and have been measured as a function of temperature for neat liquid pyridazine, and nuclear Overhauser enhancement has been used to separate the dipolar and spin rotational contributions to relaxation. Dipolar relaxation rates have been combined with quadrupole relaxation rates to determine rotational correlation times for motion about each principal molecular axis (78MI21200). NMR analysis has been used to determine the structure of phenyllithium-pyridazine adducts and of the corresponding dihydropyridazines obtained by hydrolysis of the adducts <78RTC116>. 

The photoelectron spectra of pyridazine have been interpreted on the basis of many-body Green s function calculations both for the outer and the inner valence region. The calculations confirm that ionization of the first n-electron occurs at lower energy than of the first TT-electron (79MI21201). A large number of bands in the photoelectron spectrum of 3,6-diphenylpyridazine in stretched polymer sheets have been assigned to transitions predicted... 

A very useful procedure for introducing a cyano group into a pyridazine ring is the Reissert-type reaction of the A/-oxide with cyanide ion in the presence of an acyl halide or dimethyl sulfate. The cyano group is introduced into the a-position with respect to the A-oxide function of the starting compound. The yields are, however, generally poor. In this way, 6-cyanopyridazines (111) can be obtained from the corresponding pyridazine 1-oxides (Scheme 33). 

Synthesis and chemistry of pyridazines functionalized in positions 3 and 5 with heteroatoms 98JHC1 111. 

Ab initio Hartree-Fock and density functional theory calculations were performed to study the transition state geometry in intramolecular Diels-Alder cycloaddition of azoalkenes 55 to give 2-substituted 3,4,4u,5,6,7-hexahydro-8//-pyrido[l,2-ft]pyridazin-8-ones 56 (01MI7). 

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. . 

Because of the presence of two azide groups in positions adjacent to the ring nitrogen atoms in compound 13a, valence bond isomerization can result in formation of 6-azido-7-methyltetrazolo[l,5-A pyridazine 14a, 6-azido-8-methyltetrazolo[l,5-A pyridazine 15a, and the bis-tetrazole compound 16a. Calculations have been carried out by using hybrid density functional theory (B3LYP/6-311+G(d,p)) and complete basis set treatments (CBS-4M). All calculations revealed that the 8-methyl derivative 15a is the most stable isomer. Similar studies on the triazide derivative 13b, however, indicated that in this case the equilibrium is shifted to the 7-methyl form 14b. All these conclusions proved to be in entire agreement with the experimental findings (see Section 11.18.3.2.). 

For several pyridazine derivatives reported in the patent literature a muscle relaxant activity has been claimed. In this context, oxadiazolylpyridazines (35) [117] and 6-aryl-4,5-dihydropyridazine-3(2/f)-ones bearing various functionalized alkyl side-chains at N-2 [163, 174, 188, 189] are to be mentioned. Denpidazone (56) (CAS 42438-73-3), a l,2-diphenylpyridazine-3,6-dione derivative, is listed as a muscle relaxant [96]. 

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]). 

Nucleophilic substitution with heteroaryl halides is a particularly useful and important reaction. Due to higher reactivity of heteroaryl halides (e.g. 35, equation 24) in nucleophilic substitution these reactions are widely employed for synthesis of Al-heteroaryl hydroxylamines such as 36. Nucleophilic substitution of halogen or sulfonate functions has been performed at positions 2 and 4 of pyridine , quinoline, pyrimidine , pyridazine, pyrazine, purine and 1,3,5-triazine systems. In highly activated positions nucleophilic substitutions of other than halogen functional groups such as amino or methoxy are also common. 

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