Pyridazines amination

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). ... 

Methyl- and 6-methoxy-3-methylpyridazine are aminated at N-2, while 3-methoxy-pyridazine reacts at N-1. 

Pyrimidin-4-one, 2,5,6-triamino- N NMR, 3, 64 (78HCA2108) Pyrimido[4,5-d]pyridazin-5-amine, JV-benzyl-8-chloro-2-phenyl-pXa, UV, 3, 337 <76BSF(2)1549) Pyrimido[4,5-d]pyridazin-5-amine, JV-butyl-8-chloro-2-phenyl-... 

Pyrido[2,3-(i]pyridazines, 3, 232-233 alkylation, 3, 238 amination, 3, 239 azolo fused... 

Some substituents such as the acylamino group are readily decomposed by many nucleophiles to give a poorer leaving group (e.g., amino). Others, such as nitroamino and sulfonylamino, are less reactive when they are anionized by the nucleophile. 3-Nitroamino-pyridazine (117) and its 6-methyl derivative are readily aminated with benzylamine (130°, short time ). 4,6-Dimethyl- and 6-methyl-2-nitroaminopyrimidine undergo 2-substitution on warming a few minutes with hydroxylamine, hydrazine, primary or secondary alkylamines, or anilines. 

These pyridazines are subject to direct deactivation of the leaving group. It would appear from the conditions used in its reactions with ammonia (115°) and methylamine (50°) that 4-chloro-2-ethylthiopyrimidine (225) is somewhat deactivated (indirect). In various aminations of pyrimidines, the effect of an alkylthio group seems to be very mildly deactivating, like that of methyl groups. However, these surmises from the conditions used are not as reliable as the direct qualitative comparison described above and the kinetic data. 

The catalytic effect of protons, of bifunctional catalysts, and of base is demonstrated in the amination of chloro derivatives of pyridazine, pyrimidine, and s-triazine (Tables V and VI). Anilino-s-triazines containing NH groups act as catalysts in their own formation. The catalytic action of protons on anhino-dechlorination of 2-chloro-4,6-diamino-s-triazine and of 2-amino-4-chloropyrimidine was reported in the classic paper by Banks. ... 

Whereas silylation-amination of 2-amino-5,8-dihydroxypyrimido[4,5-d]pyridazine 269 with 3-amino-l-propanol, HMDS 2, and TsOH affords, after 24 h at 120-140 °C, the mono-8-hydroxypropylamino derivative 270 in 50% yield [79], reaction of 269 with a shght excess of ethanolamine and HMDS 2 provides, after 30 h at 120-150°C, only 20% of the bis(amino) product 271 [79]. (Scheme 4.31) A larger excess of ethanolamine and longer reaction times wiU certainly increase the yield of 271. 

The silylation-amination of l-benzyl-4,7-dihydroxy-l,2,3-triazolo[4,5-d]pyridazine 272 with N-methylpiperazine, HMDS 2, and (NH4)2S04 gives, after 24 h at... 

Likewise, l-[4-methylbenzyl]-4,7-dihydroxy-l,2,3-triazolo[4,5-d]pyridazine 275 reacts with phenylhydrazine, HMDS 2, and (NH4)2S04 to give the monoamino product 276 in 60% yield [83]. Reaction of l-benzyl-3-n.-butyl-4-hydroxy-l,2,3-triazo-lo[4,5-d]-pyrimidine 277 for 8 h at 120°C with cyclopentylamine, HMDS 2, and (NH4)2S04 affords the aminated product 278 in 49% yield [84] (Scheme 4.33). 

TL5981>. The proposed mechanism involves the oxidation of the amine to an imine, tautomerization to an enamine, and a sequence of nucleophilic attacks on the pyridazine rings followed by oxidation steps. The oxidant of choice is (bispyridine)silver permanganate <1982TL1847>, which is easily prepared, mild in action, and is soluble in organic media. If R1 = H in the product 77, electrophilic substitution (e.g., bromination, nitration, Mannich, and Vilsmeier-Haack-Arnold reactions) occurs at this position. 

Intermolecular cross aldolization of metallo-aldehyde enolates typically suffers from polyaldolization, product dehydration and competitive Tishchenko-type processes [32]. While such cross-aldolizations have been achieved through amine catalysis and the use of aldehyde-derived enol silanes [33], the use of aldehyde enolates in this capacity is otherwise undeveloped. Under hydrogenation conditions, acrolein and crotonaldehyde serve as metallo-aldehyde enolate precursors, participating in selective cross-aldolization with a-ketoaldehydes [24c]. The resulting/ -hydroxy-y-ketoaldehydes are highly unstable, but may be trapped in situ through the addition of methanolic hydrazine to afford 3,5-disubstituted pyridazines (Table 22.4). 

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. ... 

Similar conclusions are also reached for the magnetic shielding of atoms, as revealed by a detailed study of a series of amines, nitriles, ammonia, pyridine, pyra-zine, pyrimidine, and pyridazine [119]. Their local diamagnetic shielding is virtually... 

In 2006 Maes and co-workers described the intramolecular Pd-catalyzed amination of A-(2-chloropyridin-3-yl)pyr-idazin-3-amine and A-(3-bromopyridin-2-yl)pyridazin-3-amine which involves intramolecular coordination of Pd(ll) to the N-2 nitrogen of the A-arylpyridazin-3-amine entity (Equation 8). A-(2-Chloropyridin-3-yl)pyridazin-3-amine and A-(3-bromopyridin-2-yl)pyridazin-3-amine are intermediates in the auto tandem amination of 2-chloro-3-iodo-pyridine and 2,3-dibromopyridine with pyridazin-3-amine, respectively <2004CC2466, 2006JOC260>. In the former case the ring closure proceeds partly via an SNAr process. 

In the reaction of pyridazine 26 with perfIuoro-(2-butyl-3-propyloxaziridine) 38 both pyridazin-1-oxide 39 and T-(perf1uorobutanoyl)pyridazinium-l-aminide 40 were formed (Equation 9) <1996J(P1)2517>. In CHEC(1984) <1984CHEC(2)1> and CHEC-II(1996) <1996CHEC-11(6)1>, the N-amination with hydroxylamine-O-sulfonic acid and derivatives was covered. 

This section is new and only one article appeared in this area. The reaction of iV-/-butyl-iV -pyridazin-3-ylcarbodi-imide with amines, thiols, and alcohols was studied by Rakowitz and co-workers and yielded respectively novel guanidines, isothioureas, and isoureas <2002JHC695>. 

Aryloxy groups have also been used as leaving groups. Reaction of 1-chloro- and l-methanesulfonyl[l,4]benzo-dioxino[2,3-r/]pyridazine 164 and 4-chloro[l,4]benzodioxino[2,3-Hpyridazine with NaOMe afforded ring-opened and cyclized pyridazines (Scheme 40). Their reaction with amines afforded 1-substituted [l,4]benzodioxino[2,3-rf]pyr-idazines 165, 4-substituted [l,4]benzodioxino[2,3-f]pyridazines 166, and/or 2-hydroxyphenoxypyridazines 167 (Scheme 41) <2004H(63)591>. 

There are also other examples where a halogen atom in the 4- or 5-position of the nucleus is involved in a Suzuki reaction <2002SL223, 2003SL1482>. The ort o-brominated pyridazinamines 4-bromo-6-phenylpyridazin-3-amine 177 and A -benzyl-4-bromo-6-phenylpyridazin-3-amine 178 are especially interesting since, as observed for 6-halo-pyridazin-3-amines, no protection of the primary or secondary amino group is required (Equation 33) <2003SL1482>. 

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