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1. The bromination of a complex of acetophenone with aluminum chloride with the formation of m-bromoacetophenone, contrary to the literature data, can be carried out successfully in a suitable solvent (dichloroethane, chloroform), and the excess of aluminum oxide sufficient for the reaction can be reduced to 0.5 mole, instead of 1.5 moles in work without a solvent. 2. The dissociation of the complex observed when the dilution is increased or the solvent is replaced, leads to the formation of phenacyl bromide, the product of bromination of the side chain.

The reaction of 2-benzoylamino-2-methylpropionamidine (III) with 1,3-bifunctional compounds was investigated in connection with studies on 2-benzoylaminoacetamidine(I). In case of the reaction of III an appreciable amount of 5,5-dimethyl-2-phenylimidazolin-4-imide (VIII) was formed, the yield of 2-(1-benzoylamino-1-methylethyl)-4,6-dimethylpyrimidine (VI) being low. On the other hand, III reacted with ethyl acetoacetate to give 2-(1-benzoylamino-1-methylethyl)-4-hydroxy-6-methylpyrimidine (IX) in about 50% yield besides VIII. Both III and I were made to react with ethoxymethyleneacetylacetone to yield 5-acetyl-2-(1-benzoylamino-1-methylethyl)-4-methylpyrimidine (X) and 5-acetyl-2-(N-benzoylaminomethyl)-4-methylpyrimidine (XI), respectively. Reaction of I with ethoxymethylenemalononitrile gave 4-amino-2-(N-benzoylaminomethyl)-5-cyanopyrimidine (XII), but did not proceed with benzoin, malondialdehyde, tetraethoxypropane or phenacyl bromide.

Condensation of an aromatic aldehyde or ketone S-methyl-, allyl-, or benzylisothiosemicarbazone with acetonyl or a phenacyl bromide yielded 1-arylideneamino-2-methylthio-, allylthio-, or benzylthio-4-aryl- or methyl-imidazoles in moderate yields. Treatment of these imidazoles with zinc/acetic acid in the presence of acetic anhydride afforded 1-acetyl-4-substituted imidazoles. Hydrolysis of the arylideneamino linkage succeeded only with the α-methyl-p-methoxybenzylideneamino compound.

Imidazo [2, 1-b] benzoxazoles which have a new ring system were synthesized. Condensation reaction of 2-aminobenzoxazole (I) and bromoacetone afforded 2-imino-3-(2-oxopropyl)-2, 3-dihydrobenzoxazole (IIa). When phenacyl bromide was used instead of bromoacetone, 2-imino-3-phenacyl-2, 3-dihydrobenzoxazole (IVa) was obtained. Cyclization of these imino-derivatives afforded imidazo [2, 1-b] benzoxazoles. On the other hand, imidazo [2, 1-b] benzoxazole (XIII) was prepared from 1-(o-chlorophenyl)-2-hydroxyimidazole (XI) via benzyne intermediate.

2-Amino-5-[p- (bromoacetamidomethyl)benzenesulfonamidopropyl]-6-methyl-4-pyrimidinol (XV) was synthesized by acylation of 2-amino-5-aminopropyl-6-methyl-4-pyrimidinol (III) with p-cyanobenzenesulfonyl chloride followed by catalytic reduction and reaction of the resultant aminomethyl group with p-nitrophenyl bromoacetate. A second irreversible inhibitor of thymidylate synthetase, namely 2-amino-5-[p-(bromoacetyl)benzene-sulfonamidopropyl]-6-methyl-4-pyrimidinol (XVI), was synthesized by acylation of in with p-acetylbenzenesulfonyl chloride followed by bromination. Both XV and XVI were good reversible inhibitors of thymidylate synthetase and inactivated the enzyme when the candidate compound was incubated with the enzyme. Iodoacetamide, which does not form a complex with enzyme, could inactivate thymidylate synthetase almost as well as XV; therefore it appears that XV inactivated the enzyme by a random bimolecular mechanism rather than by the desired active-site-directed mechanism via an enzyme-inhibitor complex. Similar conclusions were reached with XVI since phenacyl bromide could inactivate the enzyme somewhat more rapidly than XVI.

The rates of the bimolecular nucleophilic substitution (SN2 reactions) of phenacyl bromide with sodium para-substituted phenoxides, sodium para-substituted benzoates, and sodium aliphatic carboxylates have been measured in 50% aqueous acetone at 10–70°C. Linear free-energy relationships between the nucleophilic reactivities and basicites (expressed in terms of the pKa’s of the conjugate acids) have been observed in the reactions of para-substituted aromatic nucleophiles, whereas no linear relationships have been seen in the reactions of aliphatic carboxylates except in the cases of sodium acetate, sodium formate, and sodium monochloracetate. An equation, logk2=αpKa+const., has been applied to these reaction series and to the 30 literally-known series of SN2 reactions. The correlation coefficients have then been calculated as a measure of the precision of these linear relationships. Hammett’s ρ values for the reactions of para-substituted aromatic nucleophiles have also been calculated, and the several fac...

The dehalogenation of phenacyl bromide by means of lower-oxidation-state metallic ions complexed by DMSO gives 1,2-dibenzoylethane. The by-products are 2,4-diphenylfuran and phenacyl chloride in the presence of Cu(I) chloride, whereas acetophenone and ω-acetoxyacetophenone are produced in the reaction with Cr(II) acetate. Treatment with K3Co(CN)5/DMSO gives 1,2-dibenzoylethane and acetophenone. The second title reaction consists of the photolysis of methyl phenacyl sulfoxides, the isolated by-products being acetophenones and methyl methanethiolsulfonate. The product distribution is strongly affected by the pH of the reaction mixture and also by the benzene-ring substituents.

Since 2-amino-5-benzamidopropyl-6-methyl-4-pyrimidinol (VII) was a reasonably good reversible inhibitor of dihydrofolic reductase, the benzamido group was substituted with p-bromomethyl (XVIIa), m-bromomethyl (XVIIIa), and p-bromoacetyl (XIXa) groups; these compounds, and the corresponding 6-phenylpyrimidines, were synthesized from the proper 2-amino-5-aminopropyl-4-pyrimidinol (V) by devising methods that were compatible with the high reactivity of the halogen. Compounds XVII-XIX showed in-activation of dihydrofolic reductase; the fact that p-nitrobenzyl bromide inactivated the enzyme as rapidly as XVII and XVIII and phenacyl bromide inactivated the enzyme as rapidly as XIX indicated that these inactivations proceeded by a random bimolecular mechanism and not the desired active-site-directed mechanism.

The rate constants and the kinetic parameters of the reaction of phenacyl bromide with mono and disubstituted anilines in ethanol have been determined. The substituent effects on the free energy of activation have been found to be additive. HAMMETT equation for multiple substitution was applied to correlate reactivity with structural parameters. The substituent effect is separated into inductive and resonance effects.

Methylphenylsulphonium phenacylide (II) was isolated as a stable solid upon treatment of methylphenacylphenylsulphonium bromide (I) with bases. No evidence supporting the proposed intermediacy of benzoylcarbene, which was postulated to be formed by thermal decomposition of II and then transformed into 1,2,3-tribenzoylcyclopropane (IV), was obtained, but the reaction of II with I or phenacyl bromide give IV. The ylide II reacted with certain α,β-unsaturated or α-halogenated carbonyl compounds and yielded cyclopropane derivatives (IV, XI–XIII). Treatment of the ylide II with phenyl isocyanate or acid anhydrides resulted in C-acylation affording novel stabilized ylides (XIV–XVI, Table 1), while reaction with acyl halides yielded O-acylated products (XVII, XVIII). Attempted resolution of II and p -iodo derivative (VIII) failed.

The reactions of chloroacetaldehyde with adenosine 3′,5′-cyclic phosphate, and with several analogs modified at C8 of the purine ring or C5, of the sugar, lead to the corresponding 1,N6-etheno derivativesd. Similar reactions using other 2-bromoaldehydes or phenacyl bromide give 1,N6-ethenonucleotides substituted at the α- or β-positions of the etheno bridge respectively. The ability of these compounds to activate the protein kinases from rabbit muscle and calf brain has been evaluated over a wide range of concentrations. While no derivative proved to be more active than adenosine 3′,5′-cyclic phosphate itself using the enzyme from rabbit muscle, a wide spectrum of activities was found using that from calf brain.

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1. 1.|The preparation of derivatives of α-chymotrypsin with p -nitrophenacyl bromide, phenacyl bromide and p -methoxyphenacyl bromide is described. 2. 2.|For the p -nitrophenacyl derivative, the new 350-nm absorption is pH independent from pH 2.88 to 11.25, mitigating against a major change in environment at the new chromophore over this range. 3. 3.|The enzyme derivatives (likely at Met-192) show different decreased but definite catalytic activities towards substrates of α-chymotrypsin. In each case, this activity is due to the modified enzyme itself. 4. 4.|Phenacyl- and p -methoxyphenacylchymotrypsin show generally increased dissociation constants and decreased catalytic constants. Below pH 8.5, p -nitrophenacylchymotrypsin towards ethyl -N- acetyl - l - tryptophanate has only decreased k cat values compared to native enzyme, K m being unaltered. The pH dependencies of k cat below pH 8.5 and K m over the entire range are identical for parent and nitrophenacyl enzyms. Above pH 8.5, k cat for the enzyme derivative increases and is still rising at pH 10, having reached over twice its value at pH 8.5. The effect is reversible. 5. 5.|These results are taken to indicate that the conformational change occurring in α-chymotrypsin at pK 9 occurs for the nitrophenacyl enzyme as well, but, in the latter case, it reverses the original inhibition of k cat by the nitrophenacyl group.

The reaction of 6-amino-1, 3-dimethyluracil (I) with phenacyl bromide in DMF gave 1, 3-dimethyl-6-phenylpyrrolo [2, 3-d] pyrimidine-2, 4 (1H, 3H)-dione (II) in high yield. The reaction of I and phenacyl bromide in acetic acid afforded the isomeric 1, 3-dimethy1-5-phenylpyrrolo [2, 3-d] pyrimidine-2, 4 (1H, 3H)-dione as a byproduct besides II. Nitrosation of II gave 1, 3-dimethy1-5-nitroso-6-phenylpyrrolo [2, 3-d] pyrimidine-2, 4 (1H, 3H)-dione (III) along with the corresponding 5-nitro derivative. Ring expansion of III by the Beckmann rearrangement was carried out to give 1, 3-dimethy 1-5-hydroxy-6-phenylpyrimido [4, 5-d]-pyrimidine-2, 4 (1H, 3H)-dione. Denitrosation of III by the action of sulfuric acid was observed.

Active mono-S-alkyl esters prepared from 1-(dithio-acetic acid)-pyridinium betaine (III) were found to be sufficiently stable for screening as radiation-protective agents, and e-withdrawing substituents in the pyridine ring gave stable betaines. Reaction of the methyl ester of III with phenacyl bromide and alkali resulted in S-alkylation to give a ketene mercaptal betaine (VIII). Both the allyl and p-nitrobenzyl esters of 1-(dithioacetic acid)-pyridinium halides were radiation-protective in mice, and betaines with substituents in the pyridine ring were radiation-protective in a bacterial test.

The reaction of 2-mercapto-3-acetamido-5-(or 6-)chloropyridines with phenacyl bromide and substituted phenacyl bromides yielded 2-(phenacylmercapto)-3-acetamidopyridines, while the reaction of the former with γ-chloroacetoacetic ester yielded 2-(carbethoxyacyl-methylmercapto)-3-acetamidopyridlnes.

The reaction of phenacyl bromide with aniline and in derivatives is a bimolecular nucleophilic sub­stitution reaction. The values a Arrhenius parameters in the equation k=Ae -E/RThave been calculated for the reaction, which are found to be more or Less constant throughout the series. The effect of the sub­stituents in benzene nucleus of aniline has also been calculated and the additivity rule has been found to hold good for the series. The plots of specific rate constants of different reactions against the dipole moments of substituted anilines have been shown to be linear. The Hammetts equation also applies well to the reaction series. The change of solvent from methyl to iso-amyl alcohol does not change the frequency factor; but a slight change is only observed in energy of activation.

2-(2-Thienyl)-5-phenylthiazolo[2,3-b]-1,3,4-thiadiazole was synthesized and evaluated for its diuretic action. The effect of 2-substitution on the ease of cyclization to a bicyclic system was studied. The carboxylic acid hydrazides were converted to dithio-carbazates which, on cyclization, gave 2-substituted 5-thio-1,3,4-thiadiazoles. Thiothiadiazoles were converted to the bicyclic system by the action of phenacyl bromide.

Furocoumarins have been obtained by fusing either a furan ring to the benzene nucleus of coumarinsor an \(\propto\)-pyrone ring to coumarans.

In dialkyl phenacyl sulfonium ions the C—S(+) bond is reduced with uptake of two electrons at relatively positive potentials. Acetophenone formed in this process is reduced in another more negative step. A round maximum was observed on the limiting current of the first step, followed by desorption phenomena. Methyl butyl phenacyl sulfonium hydroxide is a weak base (pK 7·7).

Furocoumarins have been obtained by fusing either a furan ring to the benzene nucleus of coumarins or an .\(\propto\)-pyrone ring to coumarans.

Arrhenius parameters have been determined for the reaction of aniline, ortho-, meta- and paraphenylene diamines (PDA) with phenacyl bromide in nitrobenzene. The amino group at ortho- position of aniline does not alter the rate to a great extent possibly due to a hydrogen bonded structure. The meta- and para-isomers increase the rate to avery great extent with considerable change in the value of energy of activation. The reaction has also been studied in a number of solvents and an attempt has been made to correlate the solvent effect.

Phenacyl bromide and its derivatives in the presence of zinc undergo coupling reactions to 1,4-diketones; free radicals, detected and identified by e.s.r. in the above reactions, also undergo anti-Markownikov additions with terminal olefins.

The reaction between ethyl 2-quinolylacetate and phenacyl bromide has been re-investigated and is now shown to proceed via C-alkylation to yield 2-(1-benzoyl-2-ethoxycarbonylethyl)quinoline. Treatment of this compound with acetic anhydride yielded 2-benzoyl-3-ethoxycarbonyl-1-methylpyrrolo[1,2-a]quinoline and 3-ethoxycarbonyl-1-phenylpyrrolo[1,2-a]quinoline.

The reaction of phenacyl bromide with benzylamine affords 1,2-dibenzyl-1,2-dihydro-2,5-diphenylpyrazine (59%) and 1,2-dibenzyl-1,2-dihydro-3,6-diphenylpyrazine (21%), contrary to previous reports. In a series of reactions of N-alkylphenacylamines thermally induced self-condensation is followed by a regiospecific 1,3-alkyl shift to a substituted carbon atom, to give in good yield 1,2-dialkyl-1,2-dihydro-2,5-diphenylpyrazines at temperatures ranging from ambient to 140°. The reaction of phenacyl bromide with methylamine gives N-methyldiphenacylamine, then the reactive 1,4-dihydro-1,4-dimethyl-2,6-diphenylpyrazine. The latter readily forms an addition product with methanol and separately forms an odd-electron species characteristic of 1,4-dialkyl-1,4-dihydropyrazines.

Ylids generated by bases from pyridinium salts containing an activated methylene group can be C-alkylated in aprotic solvents. Reductive cleavage of the pyridine residue then affords alkylated ketones or esters. The reaction sequence constitutes an overall synthesis which is formally analogous to syntheses from β-keto esters.��� Alkylation of N-pyridinium phenacylid with phenacyl bromide gave chiefly 1,2,3-tribenzoylpropene, the tautomerism of which was examined.

The synthesis of some 1-aminoimidazoles from N-acetylamidrazones and phenacyl bromide is reported. Quaternisation and subsequent oxidation of the 1-aminoimidazolium salts gave 1,1′-azoimidazolium salts.

3-Nitrophenacyl bromides of 4-bromo-, 4-chloro-, 4-methyl-, and 4-hydroxy-acetophenones are obtained in excellent yield by the nitration of the corresponding phenacyl bromides in fuming nitric acid (d, 1·42) at 5°. Nitration of 4-phenylphenacyl bromide yields 3-nitro-4-(4-nitrophenyl)phenacyl bromide. The identity of these products has been established by inverse substitution with acidified potassium iodide solution.

A number of 2-phenacylisothiouronium bromides have been prepared from phenacyl bromide and substituted thioureas. The tautomeric nature of the products has been studied spectroscopically. The products have been dehydrated to the corresponding thiazoles.

The relative ease of deoxygenation of 1-substituted, 3-substituted, and 1,3-disubstituted pyrido[1,2-a]pyrazinium 2-oxide salts has been investigated; large hydrocarbon substituents in the 1- or 3-position facilitate-deoxygenation. Attempts to prepare 1,3-diphenylpyrido[1,2-a]pyrazinium 2-oxide salts from the quaternary salt formed between 2-benzoylpyridine oxime and phenacyl bromide gave, depending upon the reaction conditions, either the rearrangement product, 4-bromo-1,2-dihydro-1-oxo-2,3-diphenylpyrido[1,2-a]pyrazinium bromide, or 1,3-diphenylpyrido[1,2-a]pyrazinium bromide, the product of cyclisation accompanied by deoxygenation.

Cyclization of l-benzyl-2-ethoxycarbonylmethylene-1,2-dihydropyridine in acetic anhydride is shown to depend on the basicity of the reaction medium. The reaction between activated 2-methylpyridinium salts and ethyl chloroformate in aqueous base has provided a novel synthesis of 2-ethoxycarbonyl-methylene-l,2-dihydropyridines. Nass spectra of four 2-methylene-l,2-dihydropyridines are presented together with N.M.R. evidence for their 2-E configuration. Pyrophthalone (15) reacted with benzyl chloride in boiling nitrobenzene to give 2-benzylpyrophthalone. With phenacyl bromide, pyrophthalone gave 3-phenyl-1,2-phthaloylindolizine (6-phenylbenzo[f]pyrido[1,2-a]isoindole-7,12-dione) rather than the 3-benzoylindolizine (18). Quinophthalone reacted similarly, and the formation of both phthaloylindolizines has been attributed to a novel rearrangement of the 2-phenacylindan-l,3-dione system in the intermediate, alkylated products. Mass spectra of both phthalones and three phthaloylindolizines are presented.