Pyridazine basicity

Table V shows some of the work we did with variation in the basic pyridazine structure, and also with related nitrogen heterocycles. Moving...

The cleavage of fused pyrazines represents an important method of synthesis of substituted pyrazines, particularly pyrazinecarboxylic acids. Pyrazine-2,3-dicarboxylic acid is usually prepared by the permanganate oxidation of either quinoxalines or phenazines. The pyrazine ring resembles the pyridine ring in its stability rather than the other diazines, pyridazine and pyrimidine. Fused systems such as pteridines may easily be converted under either acidic or basic conditions into pyrazine derivatives (Scheme 75). 

Trimethylpyrazole (336) adds dichlorocarbene generated under basic conditions (CHCla-EtONa) to give 10% of 4-dichloromethyl-3,4,5-trimethylisopyrazole (337 Scheme 28) (bromine also transforms (336) into an isopyrazole (312) Section 4.04.2.1.4(v)). Treatment with sodium ethoxide results in ring expansion of (337) into an ethoxymethyl-pyridazine (338) (B-76MI40402). 

N-Heteroaromatic compounds like pyridine, pyridazine, pyrazine, isoquinoline, and their derivatives42,250 react with diphenyl cyclopropenone in a formal (3+2) cycloaddition mode to the C=N bond of the heterocycle. As expected from the results discussed earlier (p. 67), the reaction is initiated by attack of nitrogen at the cyclopropenone C3 position and followed by stabilization of the intermediate betaine 390 through nucleophilic interaction of the Cl/C3 bond with the activated a-site of the heterocycle, giving rise to derivatives of 2-hydroxy pyrrocoline 391—394). In some cases, e.g. diphenyl cyclopropenone and pyridine42, further interaction with a second cyclopropenone molecule is possible under the basic conditions leading to esters of type 392. 

The pH-independence of Tdhpz at Pt indicates that the driving force for coordination of the nitrogen heteroatom to the Pt surface is much larger than that for protonation even in molar acid. This behavior is in contrast to that of pyridine, where protonation of the nitrogen heteroatom in molar acid hinders N-coordination to the surface (H). Such a difference in chemisorption characteristics may be related to the fact that the basicity of the nitrogen heteroatom in pyridine (pKb =8.8) is much greater than that of the nitrogens in pyridazine (pKb = 11.8) (23.). ... 

The electroreductive hydrogenation of pyridazine-3-ones performed at the first wave, in acidic or basic medium, takes place at the 4,5-double bond. A further reduction of 4,5- dihydropyridazin-3-ones in basic media, affords the corresponding tetrahydro derivatives (Scheme 139) [252]. 

Addition of nucleophiles to the cyano group of cyanothiadiazole under basic conditions takes place with unusual ease <88AG(E)434,94ACS372). Hydrolysis to the amide, for example, can be effected at 0°C in the presence of a catalytic amount of sodium hydroxide or basic ion-exchange resin. At reflux temperature, hydrazine and monosubstituted hydrazines convert 3,4-dicyano-l,2,5-thia-diazole into the l,2,5-thiadiazole[3,4-. The base-catalyzed addition of acetone to cyanothiadiazole forms an enamino ketone, used as a key intermediate for the synthesis of a number of heterocyclic ring systems, e.g. isothiazole, isoxazole, pyrazole, pyrimidine, and thiazole <77H(6)1985>. 

The basicity of the diazines is sharply reduced from that of pyridine (pAfa 5.2) the pKa of pyrazine is 0.4, pyrimidine is 1.1 and pyridazine is 2.1. The significantly higher basicity of pyridazine as compared to pyrazine, unexpected for mesomeric and inductive effects, is attributed to the lone pair-lone pair repulsion which is removed in the cation. 

Pyrimido[4,5-d]pyridazine derivatives are readily cleaved under both acidic and basic conditions. Reaction of 2-phenyl-5,8-dimorpholinopyrimido[4,5-hydrochloric acid gives a mixture of four isolated products 2-phenyl-8-morpholinopyrimido[4,5-d]pyridazin-5(6//)-one (96), 4-hydroxy-6-morpholinopyridazin-3(2jy>one (97), 4-amino-5-formyl-3,6-dimorpholinopyridazine (98) and benzoic acid (99). 

Chloro substituted pyrazino[2,3 -d]pyridazines react readily with amine and alkoxide nucleophiles to give the corresponding amino and alkoxy substituted products (66JHC512). 5,8-Dichloropyrazino[2,3-d]pyridazine (102) can be hydrolyzed in 2% aqueous sodium hydroxide to yield 5-chloropyrazino[2,3-d]pyridazin-8-one (103). Displacement of only one halogen substituent is also observed in the basic hydrolysis of the 5,8-dibromo analog (68JHC53). 

The majority of pyrimido[4,5-c]pyridazines have been prepared from pyrimidine precursors. The chloropyrimidines (176) give the desired heterocyclic ring (177) on reaction with hydrazine (72BSF1483). Hydrazine also reacts with ethyl a-diazo-/3-oxo-5-(4-chloro-2-methylthiopyrimidine)propionate (178) to give the pyrimido[4,5-c]pyridazine-3-carboxamide (78). A mechanism for this interesting reaction has been proposed as shown, on the basis of the detection of hydrogen azide in the reaction mixture. There is no precedent for the reaction of the a-carbon of a-diazo-/3-oxopropionates with nucleophiles under basic conditions (76CPB2637). 

Pyridazine (1,2-diazine) (1) and its benzo analogs cinnoline (1,2-diazanaphthalene) or benzo[c]pyridazine (2) and phthalazine (benzo[rf]pyridazine) (3) have been known since the nineteenth century. Although the basic synthetic principles and reactivity were investigated in the early years, interest in these compounds was not very intense, compared with pyrimidines and their bicyclic analogs, as they were not found in nature. However, during the last three decades intensive research has been stimulated because many derivatives have found application as a result of their biological activity. 

When a second nitrogen atom is introduced into the pyridine ring the basicity is reduced (pjRTa 5.23 for pyridine and 2.33 for pyridazine). The effect of the additional substituents on pKK depends on the position of the substituents (Table 3). An extensive set of pK values of pyridazine derivatives has been submitted to correlation analysis using the Hammett and the two Taft equations, which shows that the pKa values are most sensitive to the effect of a 2-substituent followed by the effects of 3- and 4-substituents. The interactions between nitrogen atom and 2-substituents represent over 70% of the inductive character. The composition of the effects of +M 4-substituents is significantly enriched in the resonance interactions, whereas -M 4-substituents interact with the nitrogen atom mainly by induction (77MI21201). 

---