6-Chloropyridazin-3-amine

Substituted 6-iodopyridazines were the first representatives studied <1995JOC748>. Interestingly, a free amino group is well tolerated and a comparison of Stille reactions on 6-iodo- 170 and 6-chloropyridazin-3-amine 171 with aryl(tributyl)stannanes remarkably revealed that the latter react substantially faster (Equation 28 and Table 7) <2000T1777>. 

Chloropyridazines seem to be preferred over 3-iodopyridazincs in this type of crosscoupling reaction [50]. Maes and co-workers compared Stille reactions of 6-chloropyridazin-3-amine and 6-iodopyridazin-3-amine under identical reaction conditions. Remarkably, using the same aryl(tributyl)stannane cross-coupling on the chloropyridazine was substantially faster than the same reaction on the corresponding iodo derivative although oxidative addition on the latter is certainly easier. 

At elevated temperatures, potassium carbonate in dimethylformamide will effect the condensation of the methyl group of the 3-acetamido function with the carbonyl group of the adjacent benzoyl group of Ar-acetyl-4-benzoyl-6-chloropyridazin-3-amine to give 3-chloro-5-phenylpyri-do[2,3-c]pyridazin-7(8//)-one (8) in 74% yield.19... 

A mixture of A-acetyl-4-benzoyl 6-chloropyridazin-3-amine (276 mg, 1 mmol), K2C03 (138 mg, lmmol) and DMF (10 mL) was stirred at 120 LC for 2 h. After removal of the solvent, the residue was partitioned between CH2C12 and H20. The organic layer was dried (Na2S04), evaporated and recrystallized (EtOAc) yield 190 mg (74%) colorless crystals mp 253 °C. 

In a one-step transformation, 4-benzoyl-6-chloropyridazin-3-amine reacts with /V,/V-dimethyl-acetamide dimethyl acetal as condensation reagent to give 3-chloro-7V,iV-dimethyl-5-phenylpyrido[2,3-c]pyridazin-7-amine (13a) in 63% yield with other acetamide acetals, prepared from V Y V-dirnethylaceLamide dimethyl acetal and the corresponding dialkylamine (see Houben-Weyl, Vol. E5, p 138f), the reaction affords 3-chloro-5-phenylpyrido[2,3-c]pyridazines bearing various dialkylamino substituents at C7.19... 

Condensation of 4-benzoyl-6-chloropyridazin-3-amine with 1,1,1-triethoxyethane, followed by base-catalyzed ring closure, gives the corresponding 7-ethoxy compound.19... 

A mixture of A W-dimethylacetamide dimethyl acetal (1.33 g, 10 mmol) and the anhyd cyclic amine (20 mmol) was heated to 190 rC for 5 h, a slow stream of dry N2 being bubbled through the solution. After cooling, 4-benzoyl-6-chloropyridazin-3-amine (234 mg, 1 mmol) was added. The mixture was heated to 120 "C for 30 min, then it was evaporated in vacuo. The products were purified by column chromatography and recrystallized (EtOAc). 

Acetylene is also protected as propargyl alcohol (300)[2H], which is depro-tected by hydrolysis with a base, or oxidation with MnOi and alkaline hydrolysis. Sometimes, propargyl alcohols are isomerized to enals. Propargyl alcohol (300) reacts with 3-chloropyridazine (301) and EtiNH to give 3-diethylami-noindolizine (303) in one step via the enal 302[2I2]. Similarly, propargyl alcohol reacts with 2-halopyridines and secondary amines. 2-Methyl-3-butyn-2-ol (304) is another masked acetylene, and is unmasked by treatment with KOH or NaOH in butanol[205,206,213-2l5] or in situ with a phase-transfer cata-lyst[2l6]. 

Dichloropyridazine 1-Oxide produces both isomers with alkoxides. However, the ratio is dependent on the size of the alkoxy group. In the reaction with sodium methoxide 80% of 6-chloro-3-methoxypyridazine 1-oxide and 7.5% of 3-chloro-6-methoxypyridazine 1-oxide are formed. Similar results are also obtained with sodium ethoxide, while sodium propoxide affords only 6-chloro-3-propoxypyridazine 1-oxide. Amines react similarly, while only chlorine at the 3-position can be substituted with an azido group to give 3-azido-6-chloropyridazine 1-oxide. 

The much greater ease of disubstitutionof 2,4-dichloropy-rimidines with hydrazine (20°) than with ammonia (180°) is not a valid indication of less deactivation by the hydrazirvo group in the intermediate since hydrazine is a far better nucleophile than ammonia. This difference is illustrated by the failure to aminate 4-chloropyridazine-3,6-dione with ammonia at 160° overnight while it reacted with hydrazine at 20° in a few minutes (with heat evolution). 

The p-thiophenol linker 1.18 (75), prepared from aminomethyl PS resin and 3-(4-thiophenyl)-propionic acid, was used to support a chloropyridazine and to release after SPS decorated aminopyridazines by treatment with primary or secondary amines and anilines for 24-48 h at 90 °C. 

The introduction of a second amino group by halogen replacement requires more drastic conditions. 3-Amino-6-chloropyridazine is converted into 3,6-diaminopyridazine in poor yield the reaction between 3,6-dichloropyridazine and most aliphatic amines stops at monosubstitution, but with aromatic amines 3-mono- and 3,6-disubstituted aminopyridazines have been obtained. Similarly, 3-alkylamino-6-chloropyridazines failed to react with aniline and 3,5-diamino-6-methoxypyridazine could not be produced from 3-amino-5-chloro-6-methoxypyridazine even at elevated temperatures. 

Use of other aminating agents, such as urea, is also successful. The Bucherer reaction gives aminopyridazines in low yield. Amination of 3,6-dichloropyridazine with sodium amide, reported to provide 5-amino-3-chloropyridazine, has been shown to give 6-chloro-3(2iI)-pyridazinone in low yield together with recovered starting material. ... 

It is well known that halomethyleneiminium salts, often prepared in situ (see Section 2.1.2.2) react with ammonium salts, primary amines, secondary amides, urea and IV-substituted ureas to afrbrd amidinium salts, from which the free amidines can be obtained by addition of bases. > 4 Some recent results are given below. Dimethylformamide chloride and other 7V,iV-disubstituted formamide chlorides were reacted with acetanilides, chloroacetanilides, 6-aminopenam derivatives, 2-aminopyrimidine, 4-aminouracil, 2-amino-4-chloropyridazine, 2-aminothiazole, 2-aminobenzothiazole and thiobenzamides to give the amidines via the amidinium salts. In the reaction of MA -disubstituted formamide chlorides with thiobenzamides the solvent seems to be decisive for the course of the reaction. In tertiary formamides the thiobenzamides are desulfurized to nitriles, whereas in CHCI3 or CCI4 amidinium salts (296 Scheme 45) are formed. From trimethylsilyl isocyanate and the fluorinated amine (297) the /V-fluorocarbonylamidine (298) is accessible. ... 

Nitro-6-chloropyridazine 1-oxide reacts with nucleophiles with displacement of the 6-chlorine atom (even with acetyl bromide), except with sodium methoxide. Merer, the 3-nitro group is diplaced. Nucleophilic substitution with amines was investigated for various monoalkoxydihalo-or dialkoxyhalopyridazines. Normally, the chlorine atom is replaced, but in 3-chloro-4,6-dialkoxy- or 4-alkoxy-3,6-dichloropyridazines the alkoxy group may be replaced preferentially or concurrently. The 6-chlorine atom of methyl (3,6-dichloropyridazin-4-yl)-acetate was displaced by hydrazine or on hydrolysis. ... 

Perfluoroazapropene reacts with heteroaromatic amines to give carbo-imides 110. In the case of 3-amino-6-chloropyridazine, this imide dimerizes... 

Some modifications of amino and hydrazino groups were also performed. An amino group can be replaced in the reaction with amines, although in low yield.442 To the few known pyridazinonimines some new compounds have been added. The imines (203) are prepared from the corresponding pyridazinium salts and sodium hydride.443 Hydrazinopyridazines upon nitrosation are transformed into azido- or tetrazolopyridazines. The reaction can be complicated by aza-transfer reactions with a heterocyclic diazo compound. For example, 3-chloro-6-hydrazinopyridazine, when treated with 3-diazoindazole in methanol, is transformed into a mixture of 3-amino-6-chloropyridazine, 6-chloro-, and 6-methoxytetrazolopyridazine, indazole and its 3-amino and 3-azido derivatives.444... 

---