Pyridazine alkylation

In general, pyridazine can be compared with pyridine. It is completely miscible with water and alcohols, as the lone electron pairs on nitrogen atoms are involved in formation of hydrogen bonds with hydroxylic solvents, benzene and ether. Pyridazine is insoluble in ligroin and cyclohexane. The solubility of pyridazine derivatives containing OH, SH and NH2 groups decreases, while alkyl groups increase the solubility. Table 1 lists some physical properties of pyridazine. 

On the other hand, perfluoro(tetraphenylpyridazines) and some perfluoro(alkyl-pyridazines) undergo nitrogen elimination, or both nitrogen elimination and rearrangement, to give perfluoroalkynes and perfluoropyrimidines (Scheme 7) (74JCS(P1)1513). 

Photolysis of pyridazine IV-oxide and alkylated pyridazine IV-oxides results in deoxygenation. When this is carried out in the presence of aromatic or methylated aromatic solvents or cyclohexane, the corresponding phenols, hydroxymethyl derivatives or cyclohexanol are formed in addition to pyridazines. In the presence of cyclohexene, cyclohexene oxide and cyclohexanone are generated. 

Reaction of various pyridazine derivatives with nitromethane or nitroethane in DMSO affords the corresponding 5-methyl and 5-ethyl derivatives. The reaction proceeds as a nucleophilic attack of the nitroalkane at the position 5. In this way, 3,6-dichloro-4-cyano-pyridazine, 4-carboxy- and 4-ethoxycarbonyl-pyridazin-3(2//)-ones and 4-carboxy- and 4-ethoxycarbonyl-pyridazin-6(lH)-ones can be alkylated at position 5 (77CPB1856). 

Alkylthio- and arylthio-pyridazines can be prepared from the corresponding halo-substituted pyridazines by using appropriate alkyl and aryl thiolates. 

Alkyl- and aryl-pyridazines can be prepared by cross-coupling reactions between chloropyridazines and Grignard reagents in the presence of nickel-phosphine complexes as catalysts. Dichloro[l,2-bis(diphenylphosphino)propane]nickel is used for alkylation and dichloro[l,2-bis(diphenylphosphino)ethane]nickel for arylation (78CPB2550). 3-Alkynyl-pyridazines and their A-oxides are prepared from 3-chloropyridazines and their A-oxides and alkynes using a Pd(PPh3)Cl2-Cu complex and triethylamine (78H(9)1397). 

Reaction of pyridazine 1-oxide with phenylmagnesium bromide gives 1,4-diphenyl-butadiene as the main product and l-phenylbut-l-en-3-yne and 3,6-diphenylpyridazine as by-products, while alkyl Grignard reagents lead to the corresponding 1,3-dienes exclusively (79JCS(P1)2136>. 

Since the pyridazine ring is generally more stable to oxidation than a benzene ring, oxidation of alkyl and aryl substituted cinnolines and phthalazines can be used for the preparation of pyridazinedicarboxylic acids. For example, oxidation of 4-phenylcinnoline with potassium permanganate yields 5-phenylpyridazine-3,4-dicarboxylic acid, while alkyl substituted phthalazines give pyridazine-4,5-dicarboxylic acids under essentially the same reaction conditions. 

Side-chain lithiation with lithium diisopropylamide and subsequent alkylation or acylation is a practical method for the preparation of various alkyl-, alkenyl- and acyl-methyl-pyridazines 78CPB2428, 78CPB3633, 79CPB916) (Scheme 47). 

There are some recent examples of this type of synthesis of pyridazines, but this approach is more valuable for cinnolines. Alkyl and aryl ketazines can be transformed with lithium diisopropylamide into their dianions, which rearrange to tetrahydropyridazines, pyrroles or pyrazoles, depending on the nature of the ketazlne. It is postulated that the reaction course is mainly dependent on the electron density on the carbon termini bearing anionic charges (Scheme 65) (78JOC3370). 

The most useful syntheses of pyridazines and their alkyl and other derivatives begins with the reaction between maleic anhydride and hydrazine to give maleic hydrazide. This is further transformed into 3,6-dichloropyridazine which is amenable to nucleophilic substitution of one or both halogen atoms alternatively, the halogen(s) can be replaced by hydrogen as shown in Scheme 110. In this manner a great number of pyridazine derivatives are prepared. 

Protonation of pyrido[2,3-d]pyridazine (pK 2.01) is believed to occur at position 1 as predicted by MO calculations (68AJC1291), although alkylation results (see below) cast doubt on this. Covalent hydration has not been observed in this series, nor in the slightly weaker [3,4-d] base (pX a 1.76), which probably protonates at N-6, though this is not certain. 

Pyrazino[2,3-d]pyridazin-8-one, 5-chloro-synthesis, 3, 347 Pyrazino[l, 2-a]pyrimidine reactions, 3, 350 structure, 3, 339-340 synthesis, 3, 256, 365 Pyrazino[ 1,2-a]pyrimidine, 2-hydroxy-alkylation, 3, 351... 

Pyridazino[4,5 -c]isoquinoIine, 6-aryI-synthesis, 3, 244 Pyridazino[3,4-c]isoquinoIines alkylation, 3, 238 JV-oxide, 3, 327 synthesis, 3, 247-248 Pyridazino[4,3-c]isoquinolines synthesis, 3, 247 Pyridazino[4,5-c]isoquinolines alkylation, 3, 238 Pyridazin-3(2H)-one, 6-acryIoxy-polymers, 1, 288... 

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

The mesomeric effect of the C=S linkage is very pronounced and is responsible for the facile quaternization of heterocyclic N-alkylated thiones (159) this effect is operative even when such a shift does not increase the aromaticity of the ring. Thione derivatives of pyridazine, benzothiazole, quinazoline, 1,3-thiazine, triazole,and isoindole are examples of compounds which readily form quaternary salts. 

In work on 6-methoxypyrimidines (130), the 4-methylsulfonyl group was found to be displaced by the sulfanilamide anion more readily than were 4-chloro or trimethylammonio groups. This reactivity may be partly due to the nature of the nucleophile (106, Section II, D, 1). However, high reactivity of alkyl- and aryl-sulfonyl heterocycles with other nucleophiles has been observed. A 2-methylsulfonyl group on pyridine was displaced by methoxide ion with alkaline but not acidic methanol. 3,6-Bis(p-tolylsulfonyl)-pyridazine reacts (100°, 5 hr) with sulfanilamide anion and even the... 

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