Pyridazines, sulfur derivatives

The pyridazine dioxide derivative (108) was made by intramolecular nitroso compound dimerization as shown (Scheme 23). 1,2-Oxathiin 2,2-dioxides are obtained by the addition of sulfuric acid to a,(3-unsaturated ketones, e.g. (109) — (110) (66HC(21-2)774). 1,2-Dithiins are synthesized from conjugated diynes using benzyl thiol reductive debenzylation of intermediate (111) by sodium in liquid ammonia at - 70°C gives, after aerial oxidation, the 1,2-dithiin (112) (67AG(E)698). 

Pyridazine and its fused derivatives react readily with diphenylcyclopropenethione to give pyrazolo[l,2-a]pyridazines. The derivatives of diphenylcyclopropenone are sometimes also available (Scheme 108). The proximity of the sulfur or oxygen atom to one of the aromatic protons causes a considerable downfield shift, as shown in Scheme 108 (71CJC3119). 

In forcing conditions with excess of reagents the 5,8-bis derivative was obtained in the above cases, with hydrazine and with sulfur nucleophiles. Other authors have also observed selective reactions in the pyrido[2,3-[Pg.242]

On boiling the methiodide with 70% sulfuric acid an N-methyl-oxo derivative was obtained, and this in turn gave 3-amino-2-phenyl-quinoline, methylamine, and ammonia on fusion with soda lime. The bulk of the evidence therefore favors quaternization at N-2 (cf, 154), in which case the acid-hydrolysis product is 155. Quaternization at N-2 would be expected because of the steric influence of the 10-phenyl group and the influence of the 4-amino group (cf. 4-hydroxy-pyridazine ) in the pyridazine-type ring, although the partial double-bond character of that ring is probably different from that in pyridazine itself. 

The values of perhydropyrido[l,2-f)]pyridazine and its 2-oxo derivative were found to be 2.80 0.04 and 7.32 0.03, respectively (72KGS220), whereas that of anhydro 4-hydroxy-2-methyl-5,6,7,8-tetrahydropyrido(l,2-6]pyridazinium hydroxide (16) was determined by spectrophotometry to be 2.77 (71CPB159). UV spectroscopic measurements in sulfuric acid gave a pKa value of -0.25 for pyrido[l,2-6]cinnoline derivative (17, R = H) (74JHC125). 

In the 1,4-dinucleophile - 1,2-dielectrophile approach the most common situation is where heteroatoms function as nucleophiles and 1,2-dicarbonyl compounds, 1,2-dihalides or sulfonate esters, a-halocarbonyl compounds, etc., as the dielectrophile component. Representative examples are given in equations (76)-(79). Condensation of hydrazine and its derivatives with 1,4-dicarbonyl compounds is the common situation in the 1,2-dinucleophile- 1,4-dielectrophile approach, and the vast majority of pyridazine derivatives are prepared in this way (e.g equations 80 and 81). Sulfur 1,4-dielectrophiles have been used in related processes, but the method is not readily adaptable to the synthesis of oxygen heterocycles. 

Two methods for the preparation of [l,2,3]triazolo[4,5-, pyridazine-4-thione 29 were reported by Bussolari et al. involving nucleophilic substitution of sulfur by displacement of the 4-chloro substituent from 28 and of the oxygen atom of 4-lactam derivative 30 using sodium thiosulfate and phosphorus pentasulfide, respectively (Scheme 18) <1996BMC1725>. 

Pyridazine 1-oxide and many of its substituted derivatives undergo nitration with nitric and sulfuric acids to form the corresponding 4-nitropyridazine 1-oxides. If the 4-position is occupied nitration can occur at the 6-position. 

Reduction of pyridazin-4-ones seems not to have been reported, f. Derivatives of Cinnoline. 3-Hydroxycinnoline (222)44 is reduced in a two-electron wave from pH 0 to 11. In strongly acid solution the main product is 1-aminooxindole (223), which is also obtained on reduction with zinc and sulfuric acid.232 Reduction in an emulsion of an aqueous phosphate buffer (pH 6.5) and n-butanol produced a nearly quantitative yield of 3-keto-l,2,3,4-tetrahydrocinnoline (224) this compound was easily reoxidized to 3-hydroxycinnoline. 

Nitration of pyridazine 1-oxide (113, R = Rx = H) - and many of its 3- or 6-substituted and 3,6-disubstituted analogs (113, R and/or Rj= alkyl, alkoxy, or chloro) with a mixture of fuming nitric and concentrated sulfuric acid afforded the corresponding 4-nitro-pyridazine 1-oxide derivatives (114). Under similar reaction conditions nitration of 3-methylpyridazine 1-oxide could not be accomplished and even after 6 hours at 100° starting material was recovered, whereas 3-methylpyridazine 2-oxide is nitrated to give 3-methyl-5-nitropyridazine 2-oxide in excellent yield. ... 

Ring contraction of a pyridazine with concurrent cyclization to indole derivatives proceeds with l-aryl-6-oxo-l,4,5,6-tetrahydro-pyridazines having at position 3 a carboxyl or methyl group (161). 137,186,707 reaction is usually performed in ethanolic solution containing hydrogen chloride or sulfuric acid, and also potassium hydroxide. Indoles of the general formula 162 (R2 = COOEt, COOH, or Me) are obtained. 

There are numerous investigations of the reactivity of di- and polyhalo-pyridazines, particularly polyfluoropyridazines. Aminolysis of l-phenyl-4,5-dichloropyridazin-6-one has been studied in detail. In this and other reactions with nucleophiles, the halogen atom at position 4 is substituted preferentially, although a mixture of 4-amino and 5-amino derivatives is formed in the reaction between 4,5-dihalopyridazin-6-ones and ammonia or amines. It has been now firmly established that displacement reactions on 3,6-dichloropyridazine 1-oxide with sulfur nucleophiles take place at position 6 in contrast to nitrogen or oxygen nucleophiles, where the 3-chlorine atom is replaced preferentially. In connection with the previously observed self-condensation of 3-chloro-6-methylpyridazine to a tricyclic product, the reaction between 3,6-dichloropyridazine and pyridine N-oxides was investigated. 3,6-Dichloropyridazine with 2-methylpyridine N-oxide at 100°-110°C affords three compounds (171, 172, and 173). With 2,6-dimethylpyridine N-oxide, an ether (174) is also formed. The isolation of... 

Pyrido[2,3-t/]pyridazine resists bromination by bromine/silver(I) sulfate in sulfuric acid or by bromine/65 % oleum, but can be converted into the 3-bromo derivative 6 via the 3,4-dibromide and subsequent dehydrobromination, which is best effected by pyrolysis.83... 

Chlorine atoms undergo nucleophilic substitutions with oxygen, sulfur and nitrogen nucleophiles. Thus, alkoxy derivatives are accessible by reaction with alkoxides in the corresponding alcohol. If more than one chlorine atom is present in the pyridazino[4,5-rf]pyridazine, a mixture of products may be obtained.24... 

A similar approach with pyridazine and 3-methylpyridazine, but using 1-trichloroethoxycarbonyl derivatives, allows the nucleophilic addition of thiazolones and 1,4-thiazinones (Scheme 16). The initial 1,4-dihydro adducts are oxidised and deacylated by treatment with sulfur in boiling DMF <87CPB2243, 90CPB45>. 

---