Acetophenones nitroacetophenones

A variety of aliphatic and aromatic ketones have been investigated (cyclohexanone, cyclopentanone, acetophenone, p-nitroacetophenone) and they all usually lead to 2-R -3-R"-5-nitropyridine in moderate to good yields. Better yields were recorded when enamines of the respective ketones were used. With aldehydes the yields are in general lower than with ketones. 

R = H), and 4-p-nitrophenylpyrimidine (123, R = NO2) by reaction with cyclopentanone, acetophenone, and / -nitroacetophenone, respectively. The yields are, however, quite low (15-30%) and the reaction is found to be applicable to restricted substrates. In some of these reactions A -methyl-a-nitroacetamide could be isolated as the other reaction product. 

The use of dinitrogen pentoxide in the Ponzio reaction for the oxidation-iutration of oximes to em-dinitro groups has been reported by Russian chemists. Millar and co-workers extensively investigated these reactions and reported the synthesis of 2,4,5,7,9,9-hexanitrofluorene (2), a thermally stable explosive with an oxygen balance better than TNT. Other energetic materials containing gem-dinitro functionality were synthesized from the oximes of acetophenone, 4-nitroacetophenone, a-nitroacetophenone and 2-hydroxyacetophenone. 

The CCH of p-nitroacetophenone (5) (Scheme 2) was inefficient and unselective giving p-aminoacetophenone (6) in about 20% yield together with some 10-12% of unindentified compounds (30% mass balance). Attempts to recover more material were unsuccessful. The ECH at a RCu cathode in an alkaline (0.28 M KOH, pH 13.5) MeOH-HzO (1.5% of H2O) solution was reported to give exclusively p-amino-acetophenone (6) (79% yield of isolated product) (3,8). 

An attempt to prepare 2-(2-nitrophenyl)-4,6-diphenylpyrylium from l,3-diphenylprop-2-en-1 -one and 2-nitroacetophenone gave only 2,4,6-triphenylpyrylium (58BSF1458). Similarly, substantial formation of this symmetrical pyrylium salt was observed during syntheses of unsymmetrically substituted salts. Thus, pinacolone and chalcone afforded both 2-f-butyl-4,6-diphenylpyrylium and the 2,4,6-triphenyl derivative. The latter product is considered to arise from a retro-aldol reaction of the enone into a mixture of benzaldehyde and acetophenone the latter reacts with unchanged chalcone to give the unrequired salt (80T679). 

No reference was given to a detailed paper by R. Camps, Arch. d. Pharm. 240, 1 (1902). This author adds the acetophenone to ten times its weight of fuming nitric acid at temperatures of —10 to +20°. At the lower temperature a 96 per cent yield of nitroacetophenones was obtained, consisting of 45 per cent of the ortho derivative and 55 per cent of the meta. 

Experiments on the bromination of equilibrated ketone-acetal systems in methanol were also recently performed for substituted acetophenones (El-Alaoui, 1979 Toullec and El-Alaoui, 1979). Lyonium catalytic constants fit (57), but for most of the substituents the (fcA)m term is negligible and cannot be obtained with accuracy. However, the relative partial rates for the bromination of equilibrated ketone-acetal systems can be estimated. For a given water concentration, it was observed that the enol path is more important for 3-nitroacetophenone than for 4-methoxyacetophenone. In fact, the smaller the proportion of free ketone at equilibrium, the more the enol path is followed. From these results, it can be seen that the enol-ether path is predominant even if the acetal form is of minor importance. The proportions of the two competing routes must only depend on (i) the relative stabilities of the hydroxy-and alkyoxycarbenium ions, (ii) the relative reactivities of these two ions yielding enol and enol ether, respectively, and (iii) the ratio of alcohol and water concentrations which determines the relative concentrations of the ions at equilibrium. Since acetal formation is a dead-end in the mechanism, the amount of acetal has no bearing on the relative rates. Bromination, isotope exchange or another reaction can occur via the enol ether even in secondary and tertiary alcohols, i.e. when the acetal is not stable at all because of steric hindrance. 

The method is especially valuable for the preparation of certain substituted acetophenones, namely, o- and p-nitroacetophenone and o-chloro-acetophenone. Methods involving Grignard, Friedel-Crafts, or nitration reactions are apparently not applicable for the preparation of these nitro compounds, and the Friedel-Crafts reaction is not applicable to the preparation of o-chloroacetophenone. Although the acetoacetic ester synthesis has been used for the preparation of these and other substituted acetophenones, it may be complicated by O-acylation and also by cleavage at either acyl group (cf. method 212). 

The nitration of acetophenone has been extensively studied. It is carried out at a low temperature (5° to -20°) by the action of nitric and sulfuric acids and gives m-nitroacetophenone (55 83%) and smaller amounts of o-nitroacetophenone. Under similar conditions, benzalde-hyde is converted to m-nitrohenzaldehyde (84%). If nitration is performed on benzaldehyde diacetate, C(HsCH(CXZCXZH3)2, with subsequent hydrolysis, p-nitrobenzaldehyde (73%) is obtained furthermore, a slight modification of this procedure causes the formation of mainly the ortho isomer (43%). ... 

For acetophenone, only meta-nitration has preparative value. As for benz-aldehyde, this is favored by a large excess of concentrated or, better, fuming sulfuric acid and by reaction at as low a temperature as possible 209 yields of jw-nitroacetophenone exceeding 90% have been obtained in this way.210,211 Use of nitric acid alone or increase in the reaction temperature increases the amount of ortho-isomer formed,212 but this is nevertheless not a satisfactory method of synthesis. 

Acetophenone possesses the properties characteristic of aromatic compounds. When heated with dilute nitric acid it is oxidized to benzoic acid with concentrated nitric acid nitro derivatives are formed. The chief product of nitration is m-nitro-acetophenone a small proportion of the ortho compound is also formed. p-Nitroacetophenone can be prepared from p-nitro-benzoyl chloride and acetoacetic ester. 

Walther Borsche and Alfred Herbert first reported the spontaneous cyclization of an ort/io-diazonium acetophenone in 1941, as part of a larger study on the synthetic transformations of 2-bromo-5-nitroacetophenone carried out at the University of Frankfurt am Main. The authors did not draw especial attention to this observation, and it was not until four years later that Schofield and Simpson suggested that this reaction might offer a general route to 4-cinnolones. After 70 years, this general reaction yielding 4-cinnolones remains one of the most useful methods for the synthesis of cinnolines. 

A less obvious example in which the success of a synthesis depends on the order of substituent placement on the ring is illustrated by the preparation of m-nitroacetophenone. Although both substituents are meta-directing, the only practical synthesis involves nitration of acetophenone (disconnection a). 

Acetophenone, methyl-/7-tolyl ketone p-chloroacetophenone, /7-bromoaceto-phenone, methyl -anisyl ketone, 2,4-di-methoxyacetophenone,2-methyl-4-metho-xyacetophenone, 5-methyl-2-methoxyace-tophenone, acetocumene, 2,5-trimethyl-acetophenone, 0-, m-, p-hydroxyaceto-phenone, 2,4-dihydroxyacetophenone, 3-methoxy-4-hydroxyacetophenone, o-nitroacetophenone, m-nitroacetopheno-ne, /7-nitroacetophenone, o-, m-, /7-ami-noacetophenone, 2-aceto-l -naphthoxy-acetic acid, 2-aceto-4-bromo-l-naphtho-xyacetic acid... 

We also have to beware of the limitations of each type of substitution process. We recall that Friedel— Crafts acylation does not occur when the ring contains a meta-directing group. For example, we can make w-nitroacetophenone by nitration of acetophenone, but not from Friedel—Crafts acylation of nitrobenzene. 

Acetophenone is readily available (and if it were not, it s simple to make by a Friedel-Crafts acylation reaction), and it is readily nitrated to weta-nitroacetophenone. For the reduction of the ketone to a hydrocarbon. I ve chosen a new reaction, the Wolff-Kishner reduction, which we... 

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