Methylhydrazine, reaction with methyl

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 availability of o-benzoylbenzenesulfonyl chlorides, prepared by diazotization of o-aminobenzophenones followed by reaction with sulfur dioxide in the presence of cuprous ions, can be exploited in the reaction with hydrazine or methylhydrazine to give 1,2,3-benzothiadiazine 14. Product 14 (R1 = Me) can also be obtained by methylationof 14(R = H) with methyl iodide and sodium hydroxide. The reduced form 15 results from catalytic hydrogenation of 14 (R = H, R2 = H)(68JHC453). Hydra-zobenzene reacts with 2-chlorosulfonylbenzoyl chloride in the presence of triethylamine to give diphenyl derivative 16 (79MI1). 3,1,2-Benzothia-... 

Chloro derivative 291 was obtained from dioxo derivative 70 by treatment of phosphoryl chloride in dimethylformamide at 100°C for 2 hours (80CPB3537). The treatment of chloro derivative 291 with methylhydra-zine in a mixture of ethanol and chloroform under reflux gave 2H-pyrido[ 1,2-a]pyrimidin-2-one 295 and rearranged pyridazino[3,4-6]-quinoxaline 296 in 4.8% and 78% yields, respectively (Scheme 21) (80CPB3537). 3,4-Dihydroquinoxalinone 70 could not be rearranged into pyridazino[3,4-6]quinoxaline 296 by treatment with methylhydrazine. When hydrazine hydrate was employed instead of methylhydrazine, tricyclic ethyl ester 297 (R1 = Et) was obtained. The latter reaction gave methyl ester 297 (R1 = Me) when carried out in a mixture of methanol and chloroform (80CPB3537). 

The 5,6,7,8-tetrahydro-2/7-l,2-oxazocine-3(4/7)-one was detected by gas chromatography-mass spectrometry (GC/ MS) in traces after a reaction sequence starting from e-caprolactone, which was sequentially transformed with HBr in AcOH and MeOH into the corresponding tu-bromo methyl ester, subsequent reaction with A -hydroxyphthalimide, removal of the protecting group with methylhydrazine, and final cyclization with AlMe3 <2003CJC937>. 

Methyl 2-trimethylsilyloxycyclopropanecarboxylates behave as 4-oxoalkanoate equivalents and react with hydrazine to give 4,5-dihydro-3(2/f)-pyridazinones in excellent yield, though pyridazines are not formed with phenylhydrazine <84S786>. A mixture of regioisomers is obtained when cis-aconitic anhydride is allowed to react with methylhydrazine free base in dimethoxyethane, but reaction with the sulfate in water gives the 4-carboxymethyl compound as the sole product <83H(20)2347>. 

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. " - ... 

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... 

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... 

Dihydro-4-methyl-2//,6//-l, 3,4-thiadiazino[2,3-fc]quinazolines (655) were synthesized from isatoic anhydrides and 1-(2-hydroxymethyl)-1-methylhydrazine(79JHC1339). l,3,4-Thiadiazino[2,3- ]quinazolines(657) were also prepared by the reaction of 3-amino-2-mercaptoquinazolinones (656 with a-haloketones [81IJC(B)14 82M1145]. 

Molinate (27) (65USP3198786) is simply made from perhydroazepine and 5-ethyl chlorothioformate, while the recently introduced pyrazolate (28) (75GEP2513750) is synthesized from l,3-dimethylpyrazol-5-one, itself easily made from methylhydrazine and ethyl acetoacetate. Reaction of the pyrazolone with 2,4-dichlorobenzoyl chloride takes place on carbon at the 4-position, and then treatment with toluene-p-sulfonyl chloride gives pyrazolate. Difenzoquat (29) (75USP3922161) is readily available from 3,5-diphenylpyrazole by methylation. Ethofumesate (30) (69GEP1926139) is synthesized from p-benzoquinone (Scheme 8). 

Artemov and Shvaika treated a number of 2-aryl-l,3,4-oxadiazole-5(4//)-thiones (293) with methylhydrazine (R = Me) and obtained a mixture of 1-methyl-1,4-dihydro-1,2,4,5-tetrazine-6(5/f)-thiones (294) and 4-methylamino-l,2,4-triazole-3-thiones (295 R = Me) (71KGS905). A similar reaction was reported by Konig and his coworkers, who treated 5-(4-pyridyl)-l,3,4-oxadiazole-2-thione (293 Ar = py) with hydrazine (R = H) and obtained a compound which was either the l,2,4,5-tetrazine-6-thione (294 R = H) or the 4-amino-l,2,4-triazole-3-thione (295 R = H) (54CB825,56GEP953801). 

The reaction of 208 with methylhydrazine gave the iV -methyhl. SJtriazepine diones 26, 209, and 210. The A2-methyl[l,2,5]triazepine-2,6-diones 211 and 212 were synthesized from the reaction of chloroacetyl (2A)-proline with A2-/i rt-butoxycarbonyl-T1-methylhydrazine. The 1,2,5-triazepine dione 213 was also synthesized similarly. 

The reaction of 2-thiovioluric acid (69) with hydrazine hydrate in boiling ethanol afforded triazolopyrimidine derivative 70, but in boiling acetic acid yielded N-acetyltriazolo[4,5-d]pyrimidine derivative 71. In the same manner, the N-phenyl and A-methyl-l, 2,3-triazolo derivatives 72 and 73 were obtained through the condensation of 69 with phenylhydrazine and with methylhydrazine, respectively (91MI1) (Scheme 13). 

The presence of ferrous salts or ferrous salts with hydroxide ion was also claimed to improve the yields of hydrazines. The shortest reaction time and largest conversion to W/V-di methyl hydrazine was obtained in the presence of 0.5 mmol of ferrous sulfate in the hydrogenation of 15 ml of A-nilrosodi methyl amine over 1 g 5% Pd-C in 135 ml of water at 45°C and 0.28-0.34 MPa H2.212 Under similar conditions, 5% Pd-C containing 5 mmol of sodium hydroxide and 1 mmol of ferrous sulfate per gram of catalyst gave 50% reaction in 57 min, 98.9% N,N-di-methylhydrazine, and a ratio of 41 moles of the hydrazine per mole of amine.213... 

Among examples studied are the nitrosation of hydroxylamine and its methyl derivatives (M. N. Hughes et al., 1968), hydrazine (Perrott et al., 1976) and the methylhydrazines (Perrott et al., 1977). In all cases reaction occurred via the conjugate acid of the substrate, and although thiocyanate ion catalysis is more pronounced than that of bromide ion, the second order rate constants for reaction (25) were found to be approximately 100 times less than for nitrosyl bromide. More recent work with both morpholine and aniline showed the... 

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