Phenacylpyridines

The first amination of a halogenopyridine involving a rearrangement was carried out by Levine and Leake in 1955 in an attempt to prepare 3-phenacylpyridine. When 3-bromopyridine (27, X = Br) was allowed to react with sodium amide in liquid ammonia in the presence of sodio-acetophenone, the reaction mixture obtained consisted chiefly of amorphous nitrogenous material from which only 10% of 4-aminopyridine (34, Y = NH2) and 13.5% of 4-phenacylpyridine were isolated. 

Irradiation of 3-benzoyl-2-methoxy-3//-azepine (32) in methanol gives rise to a mixture of the 3-azabicyclo[4.1.0]hepta-2,4-diene 33 (detected by HNMR spectroscopy, but not isolated), 2-methoxy-3-phenacylpyridine(34), and a trace of 2-phenylfuro[2,3-A]pyridine (35), this last product being an artefact derived from the phenacylpyridine 34.246... 

Thermolysis of the 3-acyl-3/f-azepine 32 in Decalin at 250°C also gives the phenacylpyridine but in much reduced yield (6%). In a similar manner, 4-chloro-yV,/V-diethyl-3-phenacylpyridin-2-amine (53 % bp 160 C/0.18 Torr) is produced by the photolysis or thermolysis of 3-benzoyl-5-chloro-Ar,Ar-diethyl-3/f-azepin-2-amine.246 However, if the 3ff-azepine bears a secondary amine residue at the 2-position, e.g. 36, then photolysis or thermolysis yields a pyrrolo[2,3-/>]pyridine by intramolecular cyclization of the 3-phenacylpyridin-2-amine intermediate. 

The hypervalent iodine oxidation of (pyridylalkyl)trimethylsilanes to the corresponding alcohols and esters has been reported <96H(43)1151>. Oxidation of 2-(phenylethynyl)p5nidine with HjOj/AcOH followed by ROH/NajCOj provides 6-alkoxy-2-phenacylpyridines 42 via an intermediate iV-oxide <96H(43)1179>. 

Anomalous isomerizations have been noted during the photolytic and thermal rearrangements of 3-acyl-2-methoxy-3//-azepines (2 R -acyl, R2 = OMe) and 3-acyl-3H- azepin-2-ones (69T5217). Irradiation in methanol solution produces mixtures of 3-azabicyclo[4.1.0]hepta-2,4-dienes (28 R1==acyl and H, R2 = OMe, R3 = H) (or -4-ene-2-ones) and 3-phenacylpyridines (or pyridones), albeit in poor yields. Detailed, but tentative, arguments involving azanorcaradiene and/or diradical intermediates are presented to explain the formation of these unusual products. 

Stefanidis, D. Bunting, J. W. Rate-equilibrium relationships for the deprotonation of 4-phenacylpyridines and 4-phenacylpyridi-nium cations./. Am. Chem. Soc. 1990, 112, 3163-3168. 

Phenacylpyridine and 4-aminopyridine are formed in the reaction of 3-bromopyridine with sodioacetophenone and sodamide in liquid ammonia.272 The 3,4-pyridyne intermediate (156) formed by elimination adds the nucleophiles present in solution. In view of the observations363-365 that when 3-halopyridines are treated with potassium... 

Benzylpyridine forms 2-phenacylpyridine on heating with potassium permanganate (equation 178) [877]. 

Pyridylacetic esters have been obtained previously only by the method of Oparina, through alcoholysis of 2-pyridyl-acetanilide which was obtained by Beckmann rearrangement of the oxime of 2-phenacylpyridine. 

Phenacyl chloride, 97, 1132 Phenacylhydrazine, 443 3 (and 4 )-Phenacylpyridine, 1064 Phenacyltriphenylphosphonium bromide, 1245... 

A soln. of 3 gm. a-phenacylpyridine oxime in abs. ether shaken while gradually treated with no more than 3 gm. of PCI, shaking continued for 3 hrs., then made faintly alkaline with K2C0s — crude a-pyridylacetic acid anilide (Y 90%) dissolved in abs. alcohol, HCl-gas passed in, and boiled 3 hrs. —ethyl a-pyridyl-acetate (startg. m. f. 356) (Y 80-85%). (F. Galinovsky and G. Kainz, M. 77, 137 (1947).)... 

Howton and Golding (115) reduced methyl 2-phenacylpyridinium bromide in methanol with platinum oxide and obtained an 88% yield of l-methyl-2-phenacylpiperidine hydrobromide. In another reduction they allowed uptake to proceed further and claimed that 20% of 1-methyl-2-(hexahydrophenacyl)piperidine was formed. In the hydrogenation of the methobromide and metho-p-toluene sulfonate of 2-phenacylpyridine l-methyl-2-phenacylpiperidine was obtained (116). When the methiodide compound was reduced about 8% of l-methyl-2-(2-hydroxy-2-phenethyl)piperidine was also obtained. 

An examination of the hydrogenation of 2-phenacylpyridines with the ring nitrogen in a shielded or ionic form may indicate how reaction takes place. 

Phenacylpyridine hydrohalide in solution can (or may) exist in equilibrium between the two species seen below ... 

The examples show that form (F) leads to preferential ring reduction. The reduction of (E) should follow the same pathway as (F) because each is in a completely ionic form and the poisoning effect of the nitrogen atom will be neutralized (30). If the proposal that incomplete protonation is due to the insufficiency of acid, further or even complete protonation might be achieved by the addition of excess acid. By this means, unless the catalyst would be adversely affected, 2-phenacyl-piperidine could be obtained directly from 2-phenacylpyridine. It is possible that this selectivity could be extended in the presence of other functional groups. 

CHaCOCeHs 2 equivalents of 3-picoline in an equal volume of benzene added at 5° to 2 equivalents of a suspension of Na-diisopropyl-amide in benzene, stirred 30 min. at 5°, 1 equivalent of ethyl benzoate in an equal volume of benzene added, and stirred an additional hr. at 5° 3-phenacylpyridine. Y 78%.—Similarly, alkyl 3-picolyl ketones have been prepared, for the first time. F. e., also with other pyridine derivatives... 

As mentioned already (p. 204), the formation of 4-phenacylpyridine and 4-aminopyridine from S-bromopyridine, acetophenone and sodamide in liquid ammonia led Levine and Leake to postulate the occurrence of 3,4-pyridyne as an intermediate in the reaction. The results of other reactions in which a 3,4-pyridyne plays a part are collected in Table 5,23. 3-Fluoro-... 

To k] Ionization constants have been reported for a number of amino-, diamino- and hydroxy-pyridines, and nitro- and halogeno-derivatives of these 233 Ionization constant measurements show that, in aqueous solution, phenyl 2-, 3- and 4-picolyl sulphones exist predominantly as such Kt = 107 6 109 6 in their favour). 3- and 4-Phenacylpyridine are chiefly ketonic, but 2-phenacylpyridine contains appreciable amounts of the chelated enol in non-polar media and in the solid state 234a ... 

Picolyl alkyl and aryl ketones have attracted attention because of their chelating and bactericidal properties . In the solid state they exist in the enolic forms (6) and in solution as equilibrium mixtures . Some C-aroyl-2-phenacylpyridines exist in two hydrogen-bond-stabilized enolic forms , (7) and (8). Both C- and O-alkylation and -acylation of these... 

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