Reaction with methylhydrazine

Disubstituted 1,2,3-triazoles are usually minor components in the product mixtures obtained from reactions of triazole with electrophiles (see Section 5.01.5). The few regioselective syntheses of such compounds include a reaction of aminoacetophenones 1235 with hydrazines. The reaction with methylhydrazine proceeds well without any catalysis, but that with phenylhydrazine requires cupric chloride as a catalyst. It is assumed that hydrazone 1236 that forms in the first step is in a tautomeric equilibrium with its azo form 1237. However, it is not clear how bond formation between the nitrogen atoms and oxidation to the triazole system occurs. 4-Aryltriazoles 1238 are obtained in 50-66% yield (Scheme 205) <2003SC3513>. 

In the reaction with methylhydrazine (36c) and (36d) are obtained in the ratio 1 15. The two isomers are separated by means of aqueous sodium carbonate in which (36c) is soluble. By methyl-ation of (36d) with methyliodide, (36b) is formed exclusively (94% yield). 

The methylamino grouping in Librium is easily displaced by nucleophiles by initial nltrosation to give the N-nltroso derivative, followed by reaction with methylhydrazine (loss of diazomethane) this procedure avoids the usual hydrolysis/chlorlnation seq nce which would have affected the N-oxlde functionality in the substrate. 

A similar cyclization leading to pyrazol-3-one 266 was described by Brugel et al. (06TL3195) (Scheme 59). Beginning with 4-fluorophenyla-cetyl chloride 261, reaction with methylhydrazine at — 78 °C led to the selective formation of 2-(4-fluorophenyl)-N-methylacetohydrazide 262 in 61% yield. Reductive amination with piperidone 263 afforded 264 in excellent yield. A second acylation with 2-methylsulfanylpyrimidine-4-carbonyl chloride 265 in pyridine gave the bis-acylated precycliza-tion intermediate 266 that was cyclized with sodium hydride... 

As previously mentioned, ninopyrazole 5 is one of the regulatory starting materials for sildenafil citrate, so not surprisingly the compound has attracted the attention of fine chemical companies and within Pfizer. The optimization of the condensation reaction to make intermediate 1 has been previously reported. In the medicinal chemistry synthesis, conversion of 1 to compound 3 was accomplished via reaction with hydrazine followed by a methylation reaction. Clearly a more efficient way of making this transformation is to use a regioselective condensation reaction with methylhydrazine. " - ... 

Other methods for determining carbonyl compounds involve derivatization followed by column chromatography or by HPLC or by GC. Total carbonyls in lipid extracts are converted to their 2,4-DNPHs by using a column of diatomaceous earth impregnated with 2,4-DNPH, followed by extraction and spectrophotometric measurement at 340 nm. By reaction with methylhydrazine. 

Hoj o and co-workers prepared 3- and 5-trifluoromethy 1-4-trifluoroacetylpyrazoles 63 and 64 by reaction of p,p-bis(trifluoroacetyl)vinyl ethers 62a, sulfides 62b, and amines 62c with hydrazines in acetonitrile [37]. While the condensation reactions with methylhydrazine led to the 3-trifluoromethylpyrazoles 63 as only isomers in high yields, identical reaction conditions with phenylhydrazine resulted in mixtures of regioisomers 63 and 64, in a 1 5 to 1 19 ratio. In contrast, condensations between either 62b or 62c with t-bntylhydrazine hydrochloride or 62a with p-nitrophe-nylhydrazine yielded the 5-trifluoromelhyl regioisomers 64 as a single product in high yields (Scheme 19). All pyrazoles were then hydrolyzed to the corresponding pyrazole-4-carboxylic acids 65 and 66 in excellent yields. 

An interesting illustration of a bielectrophile contributing two heteroatoms to the resultant five-membered ring is the 2-alkyl-2-chloro- (or fluoro-) sulfonylcarbamoyl chlorides (212). With methylhydrazine initial attack by the more basic nitrogen occurred on the carbamoyl chloride, and this was followed by base-induced cyclization to 1,2,3,5-thiatriazolidine derivative (213) (77JCR(S)238, 77JCR(M)2813). Other reactions of this type are discussed in Chapter 4.28. 

There are two methods for the introduction of a hydroxyalkyl group at position 5 of the pyrazol-3-one ring. Schmidt and Zimmer converted furanediones 258a-k into arylmethylenepyrazol-3-reaction with hydrazine hydrate or methylhydrazine (83Jmechanism proposed for the reaction involves nucleophilic attack of the hydrazine on the ketone carbonyl, followed by attack on the ester carbonyl and ring opening of the... 

To shed light on the reaction pathway, a cyclization with methylhydrazine was carried out (70ZOR439 73ZOR832), since pyrazoles with nonequivalent positions 3 and 5 are obtained in this case. From l-methoxybut-l-en-3-yne and methylhydrazine sulfate a 4 5 mixture of 1,3- (110) and 1,5-dimethylpyrazoles (111) was formed (GLC) (70ZOR439). In the reaction of methoxybutenyne homologs (R = Ft, -Pr) with methylhydrazine (72°C, H", H2O, 2 h), lengthening of the alkyl radical leads to an increase in the content of 1,5-isomer (111), with yields of 50-60%. Thus, when R = Ft, the ratio is 2 3 (73ZOR832). 

Compound 24a was also obtained in 17% yield by heating of 4-hydroxy-3-nitrocoumarin 27 [12] with hydrazine hydrate in ethanol. A similar reaction of 27 with methylhydraine in boiling ethanol did not afford 24b because of the decomposition of the starting coumarin. However, when 27 was treated with methylhydrazine at room temperature for 24 h without solvent, the ring-opened methylhydrazine adduct 28 (36% yield) and 1,2-dihydro-5-(2-hydroxyphenyl)-l-methyl-4-nitro-3H-pyrazol-3-one 26 (ll%yield) were... 

Methylhydrazine can combust spontaneousiy in the presence of air when in the form of a film at the surface of a porous substance. All oxidants give rise to dangerous reactions with this compound. 

Two other results will now be pointed out which presumably also require reinterpretation in the light of the reaction behavior of iminooxophosphoranes. Thus the gas phase pyrolysis of diphenylphosphoryl azide is reported to give monomeric 92 50) and the dehydrohalogenation of phenylphosphoric adamantylamidic chloride with methylhydrazine the heterocumulene 93 51), which is even considered resistant to water. Since partly correct analytical values are available, 92 and 93 may well be oligomers. 

It appears that treatment of phenacyl bromides 1239 with methylhydrazine in refluxing acetic acid leads also to 1,4-disubstituted triazoles 1244. Fivefold excess of methylhydrazine is used in these reactions. According to the proposed mechanism, structures 1240-1243, methylhydrazine has a double role, as a condensing agent and an oxidant. In the final account, three molecules of methylhydrazine have to be used to produce one molecule of triazole 1244, two molecules of methylamine and one molecule of ammonia. The basic triazole 1244 (X = Y = H) is separated in 59% yield. The reactions go well with electron-donating substituents (for X = OH, the yield is 81%), but electron-withdrawing substituents can lower the yield dramatically (11% for X = N02) (Scheme 206) <2003JCM96>. 

Palladium-catalyzed cyclization reactions with aryl halides have been used to synthesize pyrazole derivatives. V-Aryl-lV-(c>-bromobenzyl)hydrazines 26 participated in a palladium-catalyzed intramolecular amination reaction to give 2-aryl-2W-indazoles 27 . Palladium-catalyzed cascade intermolecular queuing-cyclocondensation reaction of o-iodophenol (28) with dimethylallene and aryl hydrazines provided pyrazolyl chromanones 29 <00TL7129>. A novel one-pot synthesis of 3,5-disubstituted-2-pyrazolines 32 has been achieved with an unexpected coupling-isomerization sequence of haloarene 30, propargyl alcohol 31, and methylhydrazine <00ACIE1253>. 

Regioselectivity was observed when the reaction was extended to the use of substituted hydrazines, where the reaction of 3,4-pyridinedicarboximide derivatives 305 or 306 with methylhydrazine in boiling ethanol gave the corresponding 3-methyl-l,4-dioxo-l,2,3,4-tetrahydropyrido[3,4-r pyridazine 307 and 2-methyl-l,4,5-trioxo-1,2,3,4,5,6-hexahydro analogue 308, respectively, via opening of the imide ring and evolution of ammonia gas... 

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