Pyridine, reaction with phenacyl bromide

The classic Krohnke aldehyde synthesis results from the displacement of pyridinium salts aromatic nitroso compounds to give nitrones which are hydrolyzed to aldehydes.Phenacyl bromide reacts with pyridine and then nitrosobenzene to give phenylglyoxal in 76% yield after acid hy lysis. The pyridinium salts in these reactions must be activated in some way toward displacement to effect efficient conversions. 

Electronic effects. Nucleophilic attack is favoured by electron-withdrawing groups on the amide and the acyloxyl side chains. Interpolated bimolecular rate constants at 308 K for the series of para-substituted /V-acetoxy-/V-butoxybenzamides 25c, 26b-g and 26i (Table 5) gave a weak but positive Hammett correlation with a constants ip = 0.13, r = 0.86).42,43 These Sn2 reactions are analogous to those of aniline and substituted pyridines with phenacyl bromides, which have similar Arrhenius activation energies and entropies of activation in methanol (EA= 14-16 kcal mol-1, AS = — 27 to —31 calK-1 mol-1) and 4-substituted phenacyl halides afforded a similar Hammett correlation with pyridine in methanol (cr, p — 0.25).175... 

Thiophenes can be synthesized from a sequence involving the reaction of activated methylene compounds with carbon disulfide in base. The resulting disulfide salts, without isolation, are reacted with phenacyl bromide to afford highly substituted thiophenes, 78. Compound 78 reacts with ethyl cyanoacetate, malononitrile, or acrylonitrile to afford thieno[3,2-/ ]pyridine derivatives <1995CCC1578>. 

In a slight variation of the above synthetic approach, 2-phenylimidazo[l,2-a]pyridine (290) was prepared by the reaction of l-phenacyl-2-chloropyridinium bromide (288) with ammonia (289) (55CBIII7). The use of primary amines (291) resulted in l-alkylimidazo[l,2-a]pyridinium halides (292) (69JOC2129), whereas hydroxylamine (293) gave imidazo[l,2-a]pyridine 1-oxides (294) (78JOC658). 

The oxidants dimethyl sulfoxide and nitroso compounds react easily with oL-bromo ketones and convert them into a-dicarbonyl compounds. The reaction with nitroso compounds is usually carried out in the presence of pyridine and proceeds through a nitrone stage. Phenacyl bromide (a-bromoacetophenone) is thus transformed first into phenacylpyridinium bromide and further, with nitrosobenzene, into a-ketoaldonitrone, which is subsequently treated with hydroxylamine to give phenylglyoxal monoxime or with phenylhydrazine to give phenylglyoxal osazone [985] (equation 411). 

The 2-phenacylisothiazolium bromides 79b-d, synthesized by reaction of the corresponding isothiazole with phenacyl bromide (see Scheme 24), were treated with pyridine and afforded 2-benzoyl-2i/-l,3-thiazines 394b-d via deprotonation of the exocyclic methylene group to 393 followed by intramolecular nucleophilic attack on sulfur atom (85BSB149, Scheme 132). 

Arylthiazole 33 with a cyanoacetate moiety at C-4 is prepared via a novel cyclization from iminothiazine hydroperchlorate 31, readily available from the reaction of ethyl 2-cyano-3,3-bis(methylthio)acrylate and phenylthioamide <04H(63)2319>. Treatment of 31 with phenacyl bromide and triethylamine in methanol generates 33, which is converted to the thiazolo[5,4-c]pyridine 34 under acidic conditions. 

Synthesis of Thiophens by Ring-closure Reactions.—The reaction of dipotassium nitroethylenedithiolate and a-chlorocarbonyl derivatives, followed by oxidation with iodine, gave (1). Treatment of pentane-2,4-dione with carbon disulphide in the presence of potassium hydroxide, followed by treatment with ethyl bromoacetate, methyl iodide, and alkali, gave (2). Compounds of type (3) were formed in the reaction of 1-cyanomethylpyridinium chloride with carbon disulphide and alkylating agents such as chloroacetonitrile, ethyl bromoacetate, phenacyl bromide, or chloroacetamide in the presence of alkali, and intramolecularly cyclized to (4). After 5-methylation, the pyridine ring could be cleaved by reaction with phenylsulphonylacetonitrile and alkali in DMSO... 

A four-component tandem reaction is proposed by Zhenjun et al., by treating pyridine (or quinoline) with phenacyl bromides (or bromoacetophenones), ethyl glyoxalate, and Na2C03 in refluxing acetonitrile. The resulting polysubstituted indoUzines are obtained after 16 h of reaction time in moderate-to-good yields [22]. 

A synthesis of 2-alkyl- or 2-aryl-substituted benzo[Z>]thiophens consists of the cyclization of an aryl thioether with an acetonyl or phenacyl group in the or/Ao-position (315) with 48% hydrobromic acid. In order to obtain (315 R = Ph), 2-methylthiobenzyl cyanide is treated with phenyl-magnesium bromide. The reaction of or//to-methylthiostyrene derivatives, especially cinnamic acids (316), with sulphuryl chloride followed by pyridine, probably gives the benzo[6]thiophens (318) via the sulphenyl chloride (317). ... 

Yan et al. (2007) reported that polysubstituted annulated pyridines can be synthesized in high yields by four-component, one-pot cyclocondensation reactions of N-phenacyl pyridinium bromide, aromatic aldehydes, acetophenones or cyclic ketones in the presence of ammonium acetate and acetic acid, assisted by microwave irradiation. Cyclic ketones with two a-CH groups yield annulated pyridines with additional a-benzylidene groups, which are derived in situ from double aldol condensation of cyclic ketones with two moles of aromatic aldehydes. 

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