Hydrazine methyl-substituted derivatives

The 1-isopropoxymethyl derivative of pyrrolo-benzothiazepine 376 can be obtained from aldehyde 375 through the tosyl hydrazone followed by reduction with sodium borohydride in 2-propanol. 1-Methyl substituted 378 is available from aldehyde 375 and hydrazine monohydrate followed by potassium tert-butoxide (Scheme 76, Section 5.1.1 (2004JMC143)). 

Cyano-3-methyl-5,6-dihydro-l//-pyrido[l,2-a]quinazoline-l,6-dione and its 5-substituted derivatives were prepared from 2-cyano-3-methylpyrido[l,2-a][3,l]benzoxazin-6-one with ammonium acetate at 200°C for 4 h, with hy-droxylamine hydrochloride and (thio)ureas in a boiling mixture of pyridine and ethanol for 4-7 h, with hydrazine hydrate, phenylhydrazide, primary aliphatic and (hetero)aromatic amines in boiling ethanol for 3-6 h (93CCC1953). 

In 1958, Ikekawa10 synthesized 2,7-naphthyridine and various substituted derivatives. His approach involved the reaction of 4-methylnicotinic acid with formaldehyde to afford the lactone 99 (R = H). The reaction of 99 with ammonia in methanol yields the amide (100) which, on oxidation with chromium trioxide, afforded 2,7-naphthyridin-l-one (101). This substance was converted into 2,7-naphthyridine (102, R = H) by consecutive treatment with phosphorus oxychloride, hydrazine, and copper sulfate. The 3-methyl derivative was similarly prepared starting with acetaldehyde. 

Dihydrofuran was used as an aldehyde equivalent in a reaction with an aryl hydrazine under strongly acidic conditions to give the 3-substituted indole in high yield. The isolation of the 2-methyl indole derivative depicted below as a single regioisomer by this method is noteworthy <04OL79>. 

Some substituents such as the acylamino group are readily decomposed by many nucleophiles to give a poorer leaving group (e.g., amino). Others, such as nitroamino and sulfonylamino, are less reactive when they are anionized by the nucleophile. 3-Nitroamino-pyridazine (117) and its 6-methyl derivative are readily aminated with benzylamine (130°, short time ). 4,6-Dimethyl- and 6-methyl-2-nitroaminopyrimidine undergo 2-substitution on warming a few minutes with hydroxylamine, hydrazine, primary or secondary alkylamines, or anilines. 

Alkylthio, arylthio, and thioxo. The thioxo group in pyrimidine-2,4-dithione can be displaced by amines, ammonia, and amine acetates, and this amination is specific for the 4-position in pyrimidines and quinazolines. 2-Substitution fails even when a 5-substituent (cf. 134) sterically prevents reaction of a secondary amine at the 4-position. Acid hydrolysis of pyrimidine-2,4-dithione is selective at the 4-position. 2-Amination of 2-thiobarbituric acid and its /S-methyl derivative has been reported. Under more basic conditions, anionization of thioxo compounds decreases the reactivity 2-thiouracil is less reactive toward hot alkali than is the iS-methyl analog. Hydrazine has been reported to replace (95°, 6 hr, 65% 3deld) the 2-thioxo group in 5-hexyl-6-methyl-2-thiouracil. Ortho and para mercapto- or thio- azines are actually in the thione form. ... 

Condensation of ethyl acetoacetate with phenyl hydrazine gives the pyrazolone, 58. Methylation by means of methyl iodide affords the prototype of this series, antipyrine (59). Reaction of that compound with nitrous acid gives the product of substitution at the only available position, the nitroso derivative (60) reduction affords another antiinflammatory agent, aminopyrine (61). Reductive alkylation of 61 with acetone in the presence of hydrogen and platinum gives isopyrine (62). Acylation of 61 with the acid chloride from nicotinic acid affords nifenazone (63). Acylation of 61 with 2-chloropropionyl chloride gives the amide, 64 displacement of the halogen with dimethylamine leads to aminopropylon (65). ... 

Nucleophilic Substitution in a-Haloalkylnitrones a-Monobromo-methyl derivatives of nitrones (298a) react with primary amines or hydrazine, giving de-oxygenated products (213a). With a-bromoethyl derivatives (298b)... 

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... 

The chloromethylpyrimido[5,4-( ]-l,2,4-triazine 86 is an extremely versatile starting material (see Section 10.20.7.2, Equation 12) and was synthesized from the commercially available thiol 151 as shown in Scheme 25. Thus, 6 -methylation of compound 151 gave the sulfide 152, which was nitrosated to allow access to the nitroso-thiomethyl derivative 153. Nucleophilic substitution of the thiomethyl group by hydrazine gave the cyclization precursor 154, which underwent cyclization with chloroacetaldehyde diethyl acetal under acidic conditions to give the chloro-methylpyrimido[5,4-( ]-l,2,4-triazine 86 after workup with aqueous ammonia <2003BML2895>. 

All nuclear nucleophilic substitutions on derivatives of compound 4 have involved the replacement of a substituent at position 7 (the equivalent of the y -position in pyridine). In the 7-chloro derivative 244, replacement is possible by methoxide ion,151 by ammonia (with some rearrangement)192 and by amines,151 and by thiourea to give the sulfide (245).151 Substituted 7-chloro derivatives undergo replacement by benzyl oxide ion to give a 7-benzyloxy derivative155,220 and by azide,153 hydrazine,216 hydrosulfide (to give the 7-thione166), and methyl thiolate.220 Some of these compounds carry D-ribofuranosyl benzoate substituents on N-2 or N-3, and methoxide ion... 

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