Nitration of pyridazines

When nitration of pyridazine iV-oxides is carried out with acyl nitrates (prepared in situ from acyl chlorides and silver nitrate) the reaction takes place at the /3-position relative to the iV-oxide group. Under these circumstances only mononitro derivatives are formed. For example, nitration of pyridazine 1-oxide with acetyl nitrate yields 3-nitropyridazine 1-oxide (17%) and 5-nitropyridazine 1-oxide (0.8%), whereas with benzoyl nitrate a better yield of 5-nitropyridazine 1-oxide is obtained. 

Nitration of pyridazine A-oxides with acyl nitrates prepared from acyl chlorides and silver nitrate also occurs at the (3-position relative to the /V-oxide group. Thus, pyridazine 1-oxide yields 3-nitropyridazine 1-oxide. 

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. ... 

However, if nitration of pyridazine A-oxides is carried out with silver nitrate in the presence of an acid chloride the reaction takes... 

The 3-, 4-, 5- and 6-positions in the pyridazine nucleus are electron deficient due to the negative mesomeric effect of the nitrogen atoms. Therefore, electrophilic substitution in pyridazines is difficult even in the presence of one or two electron-donating groups. The first reported example is nitration of 4-amino-3,6-dimethoxypyridazine to yield the corresponding 5-nitro derivative. Nitration of 3-methoxy-5-methylpyridazine gives the 6-nitro-,... 

Only a few reports have dealt with the behavior of tetra-azaindenes toward electrophiles, and the reactions reported involved the pyrazole ring. Thus, alkylation of 336 with alkyl halides affords a mixture of the A-alkylated derivatives 337 and 338. Compound 336 is produced by alkylation of 339. Bromination of 339 (R = H) affords the 7-bromo derivative 340 (82JHC817) (Scheme 34). Nitration of 2-methylpyrazolo[3,4-c] pyridazine occured at pyrazole C-3 (73JAP76893). Bromination of 341 with bromine in acetic acid gives 342 (83AP697). 

Nitration of 4-amino-6-methylpyridazin-3(2-ff)-one at C-5 was performed in two steps. Treatment with concentrated nitric acid affords 6-methyl-4-(nitroamino)pyridazin-3(2f/)-one whose rearrangement in concentrated sulfuric acid led to the formation of 4-amino-6-methyl-5-nitropyridazin-3(2/0-one <2001RJ01026>. 

Only a few electrophilic substitution reactions have been reported. The nitration of both (110a) and (110b) occurs in position 2 (68MI31700, 72CPB936). The nitration of 4,7-dichlorofuro[2,3-mixed acid resulted in the recovery of starting material. However, when (112) was allowed to react with acetyl nitrate, (113) was formed (73CPB885). 

The chemistry of thienopyridazines has not been investigated in great detail. Nitration of thieno[2,3-d]pyridazine (311) occurs in the thiophene moiety at C-3 with 61.5% yield. 

Nitration of l,4-diaminopyridazino[4,5-d]pyridazine (68) resulted in the isolation of the nitramine (69). This nitro group could not be rearranged on to the other heterocyclic ring (68JHC53). 

There are few reports of the nitration of the pyridazines and pyrazines. The nitration of phenylpyridazines has been stated to occur exclusively in the phenyl ring (73MI1). The use of fuming nitric acid at 0°C forms only the 4-nitrophenyl derivative (95%), as does 4-chloro-2-phenyl-3-pyridazone (100%), and 4-amino-2-phenyl-3-pyridazone (60%) (47JCS549). 

Several 4-amino-3,6-disubstituted pyridazines were nitrated with fumic nitric add to give the 5-nitro derivatives in good yield. Pyridazine N-oxides are relatively easily nitrated with mixed add to give the 4-nitro derivatives. If this position is blocked, as with 3,6-dimethyl-4-hydroxy-pyridazine 1-oxide, the 5-nitro derivative is formed. Nitration of... 

Nitration of tetrazolo[l,5-a]quinoxaline (10) and its 4-oxo derivative (29) was investigated and was found to lead to two different selective substitutions the fully aromatic compound (10) gave 7-nitro derivative (28) (Equation (5)), whereas the lactam (29) afforded 8-nitro product (30) (Equation (6)) <92JMC3319>. Reactivity of phenyltetrazolo[l,5-Z>]pyridazines was also described <75MIP59122> and nitration of the substituent phenyl ring was reported. 

TL5981>. The proposed mechanism involves the oxidation of the amine to an imine, tautomerization to an enamine, and a sequence of nucleophilic attacks on the pyridazine rings followed by oxidation steps. The oxidant of choice is (bispyridine)silver permanganate <1982TL1847>, which is easily prepared, mild in action, and is soluble in organic media. If R1 = H in the product 77, electrophilic substitution (e.g., bromination, nitration, Mannich, and Vilsmeier-Haack-Arnold reactions) occurs at this position. 

Nitro derivatives of several halogenated pyridazin-3(2//)-ones have been prepared by treating the pyridazinones with a mixture of a nitrate salt and acetic anhydride or trifluoroacetic anhydride <2003JOC9113>. These compounds have been used for the synthesis of nitramines (see Section 8.01.8.3). 

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. 

The reaction of the diamino compound (107) under several different nitration conditions led to the formation of 5-nitroamino-8-aminopyrazino[2,3-d]pyridazine exclusively (68JHC53). 5,8-Dimorpholino substituted pyrazino[2,3-d]pyridazines are known to react with Grignard reagents to give 3-substituted 3,4-dihydro derivatives (75CPB1488). The dimorpholino heterocycles are also known to react photochemically with alcohols and cyclic ethers in the presence of photosensitizers to give 3-substituted 3,4-dihydro derivatives (Scheme 3) (75CPB1500). 

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