Pyridazine nucleophilic alkylation

The quaternization of (benzo)pyridazines by alkyl halides (these systems are not readily susceptible to arylation) was reviewed in CHEC-I <84CHEC-l(3B)l>. Monoquaternization of pyridazines occurs more readily than other diazines but less readily than pyridine, reflecting the intermediate basicity/nucleophilicity of pyridazine. Diquaternization of pyridazine can only be achieved with oxonium salts, particularly Me30 BF4 . As with protonation and A-oxidation, mixtures of products are often obtained on quaternization of unsymmetrical pyridazines and have been the subject of theoretical studies. A number of 2-(ribofuranosyl)-3(2//)-pyridazinones have been prepared by stannic chloride catalyzed alkylation of 3-(trimethylsilyloxy)pyridazines with protected 1-0-ace-tylribofuranose <83JHC369>. The quaternization behavior of phthalazines is similar to that of pyridazines, but with cinnolines alkylation usually occurs at N-2, unless there is a particularly bulky substituent at C-3. 

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). 

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. 

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... 

As shown in Scheme 199, the 5-aminopyrimidine stmcture may be also incorporated into a more complex bicyclic system. Thus, diazotization of 3-amino-4-oxo-4//-pyrimido[ 1,23 lpyndazincs 1198 followed by treatment with 50% aqueous tetrafluoroboric acid results in precipitation of salts 1199. When heated with alcohols, nucleophilic attack on the carbonyl group opens the pyrimidine ring. The obtained species 1200 assume conformation 1201 that is more suitable for bond formation between the opposite charged nitrogen atoms. Alkyl l-(pyridazin-3-yl)-l//-l,2,3-triazole-4-carboxylates 1202 are obtained in 31-66% yield <2002ARK(viii)143>. 

In a synthesis of nucleoside analogs, the sodium salts of phthalazine-l,4-dione, phthalazin-l(2//)-one, and two pyridazin-3(2//)-ones, prepared with sodium hydride in DMF, were alkylated with ( )-2,3-0-isopropylidene-l-0-(4-toluenesulfonyl)glycerol by a nucleophilic substitution of the tosyloxy group <1999AP327>. 

Diazinium, oxazinium, and thiazinium cations possess a pyridine-like nitrogen atom, but it is of very weak basicity and nucleophilicity. However, pyridazines do form diquaternary salts with very strong alkylating agents such as oxonium compounds. Electrophilic attack at ring carbon in these compounds is practically unknown. These trends are emphasized in cationic rings with an increased number of nitrogen atoms. 

As already known, a halogen atom at position 4 in the pyridazine ring is more reactive towards nucleophiles then one at position 3. This has been confirmed also with 3,4-dichloro-5,6-diphenylpyridazine and various nucleophiles (81MI2). The high reactivity of 6-halo-1,3-dimethylpyridaz-inium halides or phosphorodichloridates has been used to prepare alkyl halides from alcohols (80S746). 

Pyridazine is the most reactive in alkylation reactions and this again has its origin in the lone-pair/lone-pair interaction between the nitrogen atoms. This phenomenon is known as the a effect and is also responsible, for example, for the relatively higher reactivity of hydrogen peroxide as a nucleophile, compared with water. 

The introduction of a 2- [(ethoxycarbonyl)ethyl]amino group by nucleophilic substitution of the halogen in 3-chloropyridazine-4-carbonitriles (see Vol. E9a, p 631) gives ethyl 3-[(4-cyano-pyridazin-3-yl)amino]propanoates, which can be used for Dieckmann-Ziegler type cycliza-tions to construct the pyridine moiety of ethyl 8-alkyl-5-amino-7,8-dihydropyridazine-6-car-boxylates 9.20... 

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