Pyridine 1-oxide, 4-chloro-, amination

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... 

All these amination reactions show exclusive SNH substitution. There is hardly any indication for the formation of 3-nitropyridines, in which the chloro or methoxy group was replaced by an amino group, even when these leaving groups are present at the reactive a-position of the pyridine ring. It seems to be a characteristic feature of the oxidative amination... 

Polymer-bound reagents have also been used. The synthetically important Weinreb amides [RCON(Me)OMe, see 16-82] can be prepared from the carboxylic acid and MeO(Me)NH HCl in the presence of tributylphosphine and 2-pyridine-A -oxide disulfide. Di(2-pyridyl)carbonate has been used in a related reaction that generates amides directly. The reaction of a carboxylic acid and imidazole under microwave irradiation gives the amide. Microwave irradiation of a secondary amine, formic acid, 2-chloro-4,6-dimethoxy[l,3,5]tria-zine, and a catalytic amount of DMAP (4-dimethylaminopyridine) leads to the formamide. ° Ammonium bicarbonate and formamide converts acids to amides with microwave irradiation. Lactams are readily produced from y- or 8-amino acids, for example. 

There are numerous investigations of the reactivity of di- and polyhalo-pyridazines, particularly polyfluoropyridazines. Aminolysis of l-phenyl-4,5-dichloropyridazin-6-one has been studied in detail. In this and other reactions with nucleophiles, the halogen atom at position 4 is substituted preferentially, although a mixture of 4-amino and 5-amino derivatives is formed in the reaction between 4,5-dihalopyridazin-6-ones and ammonia or amines. It has been now firmly established that displacement reactions on 3,6-dichloropyridazine 1-oxide with sulfur nucleophiles take place at position 6 in contrast to nitrogen or oxygen nucleophiles, where the 3-chlorine atom is replaced preferentially. In connection with the previously observed self-condensation of 3-chloro-6-methylpyridazine to a tricyclic product, the reaction between 3,6-dichloropyridazine and pyridine N-oxides was investigated. 3,6-Dichloropyridazine with 2-methylpyridine N-oxide at 100°-110°C affords three compounds (171, 172, and 173). With 2,6-dimethylpyridine N-oxide, an ether (174) is also formed. The isolation of... 

Chloropyridine-l-oxide when heated with 30% aqueous methylamine at 140° for 18 hours gives 4-methylaminopyridine-l-oxide. Several substituted 4-methylaminopyridines are similarly prepared. 2-Propylaminopyridine and 2-phenethylaminopyiidine are obtained by heating 2-bromopyridine with propylamine and phenethylamine, respectively. 2-Bromopyridine also reacts with 1-aminoindane to give 2-(l-indanylamino)pyridine. 2,6-Di-chloropyridine reacts with butylamine to give 2-butylamino-6-chloropyri-dine. 2-Benzylamino-3-nitropyridine and 2-(chlorobenzylamino)-3-nitro-pyridine are readily prepared from 2-chloro-3-nitropyridine with benzyl amine and p-chlorobenzyl amine, respectively. ... 

Muller and others (1975) described the preparation of 3-fluoromethyl-3-cephem esters and their corresponding acids. The deacetyl-2-cephem benzhydryl ester (218) was treated with 2-chloro-l,l,2-trifluorotriethyl-amine, and after chromatography 3-fluoromethyl-2-cephem ester (219) was isolated in 36% yield as a crystalline substance. Oxidation of 219 with m-chloroperbenzoic acid yielded the sulfoxide (220) which was subsequently reduced to 3-fluoromethyl-3-cephem ester 221. Treatment of 221 with PCls-pyridine at -5 to - 10 C resulted in side-chain cleavage and isolation of the nucleus (221, R = H) in 74% yield. Reacylation of 221 with the mixed anhydride, made from (V-BOC-D-phenylglycine and isobutylchloroformate, provided 222 from which the crystalline acid (223) was prepared by treatment with trifluoroacetic acid in anisole. The acid displayed only low antibacterial activity in vitro and in vivo, because it is unstable in aqueous solution. 

Pyridine JV-oxide, amino-, 133-134 2-bromo-4-ethoxy-, amination of, 137 2-chloro-, animation of, 133 electron densities, experimental, 161-162... 

Tertiary amides (and thioamides) with an a-proton react instead to give chloro enamines. These can undergo nucleophilic substitution (eq 15). CSiloro enamines are also intermediates in synthetically useful dehydrogenation reactions, using Pyridine N-Oxide or DMSO as oxidant (eq 16). Tertiary ureas and thioureas form related adducts which have been utilized in the synthesis of hindered guanidine bases by further reaction with amines (eq 17).33... 

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