Phenol ethers, nitration

The ease with which the phenols are nitrated has already been discussed. The process is not satisfactory, however, even when dilute nitric acid is used, because resinous by-products are formed as a result of oxidation and condensation. Nitration with nitrogen peroxide in non-aqueous solvents such as benzene and petrol ether gives better results (Ber., 1921, 54, 1776). 

Phenol ethers, like the parent phenols, are reactive substrates. Phenol ethers like anisole and phenetole are readily nitrated to their picryl ethers, 2,4,6-trinitroanisole and 2,4,6-trinitrophenetole respectively, on treatment with mixed acid composed of concentrated nitric and sulfuric acids at 0 °C. Such reactions are vigorous, prone to oxidative side-reactions, and pose a considerable safety risk. The direct nitration of 2,4-dinitrophenol ethers, obtained from the reaction of 2,4-dinitrochlorobenzene with alkoxides, provides a more practical route to picryl ethers on an industrial scale. ... 

When halogenated phenols or phenolic ethers are nitrated with nitric acid a halogen o- or p- to hydroxyl or alkoxyl group can also be replaced. The ease of replacement appears to be in the order Cl< Br[Pg.128]

High-molecular-weight A-substituted maleimides have been prepared and used as polymeric food antioxidants which can achieve the desired gastrointestinal nonabsorption. A-(3,5-Di-t-Bu -hydroxyphenyl)maleimide was prepared in two steps (a) formation of 2,6-di-t-Bu-4-aminophenol either from 2,6-di-(-Bu-phenol by nitration followed by reduction, or from 4-aminophenol by alkylation, (b) amida-tion of maleic anhydride with the 2,6-di-t-Bu-4-aminophenol followed by dehydration. The nonabsorbable poly(A-(3,5-di-t-Bu-4-hydroxyphenyl)maleimide)s were prepared from the monomeric maleimides by free radical homo- and copolymerization with comonomers of alkyl vinyl ethers (Scheme 5.5) [43]. 

Benzene, alkylbenzenes and phenolic ethers react with CAN in acetonitrile to give nitration of the aromatic ring and, if of-hydrogen atoms are present, also products of side-chain substitution (Din tiirk and Ridd, 1982a, 1982b). With many substrates, for instance with toluene. 

The mixed aliphatic - aromatic ethers are somewhat more reactive in addition to cleavage by strong hydriodio acid and also by constant b.p. hydrobromio acid in acetic acid solution into phenols and alkyl halides, they may be bromi-nated, nitrated and converted into sulphonamides (Section IV,106,2). 

Nitrous acid or nitrite salts may be used to catalyze the nitration of easily nitratable aromatic hydrocarbons, eg, phenol or phenoHc ethers. It has been suggested that a nitrosonium ion (NO + ) attacks the aromatic, resulting initially in the formation of a nitro so aromatic compound (13). Oxidation of the nitro so aromatic then occurs ... 

The methyl ether was introduced after the Wittig reaction which used a protected carboxylic acid (ethyl ester). p-Nitrophenol is available and is one of the products of the nitration of phenol. 

Phenols are easily mononitrated by sodium nitrate in a two-phase system (water-ether) in the presence of HC1 and a catalytic amount of La(N03)3.13 Various lanthanide nitrates have been used in the nitration of 3-substituted phenols to give regioselectively the 3-substituted 5-nitrophenols.14... 

Essentially the same route is followed for the synthesis of the triphenylethylene nitromifene (8-5). The sequence starts with Friedel-Crafts acylation of the alkylation product (8-1) from phenol and 1,2-dibromoethane with the acid chloride from anisic acid (8-2). The displacement of bromine in the product (8-3) with pyrrolidine leads to the formation of the basic ether and thus (8-4). Condensation of that product with benzylmagnesium bromide gives the tertiary alcohol (8-5). This product is then treated with a mixture of nitric and acetic acids. The dehydration products from the first step almost certainly consist of a mixture of the E and Z isomers for the same reasons advanced above. The olefin undergoes nitration under reaction conditions to lead to nitromifene (8-6) as a mixture of isomers [8] the separated compounds are reported to show surprisingly equivalent agonist/antagonist activities. 

Nitration of hydroxypropiophenone (7-1) followed by conversion of the phenol to its methyl ether by means of methyl iodide provides the intermediate (7-2) the nitro group is then reduced to the corresponding amine (7-3) by catalytic reduction. The newly introduced amine is then replaced by a nitrile group by successive conversion to the diazonium salt by means of nitrous acid followed by treatment with cuprous cyanide (7-4). Reaction with aluminum chloride removes the methyl ether to afford the ortho acylphenol (7-5). This is converted to the chromone (7-6) as above by reaction with benzoyl chloride and sodium benzoate. The nitrile is next hydrolyzed to the carboxylic acid (7-7) by means of sulfuric acid. The acid is then converted to its acid chloride by means of thionyl chloride and that treated with 2-(A -piperidyl)ethanol (7-8). There is thus obtained flavoxate (7-9) [8], a muscle relaxant whose name reflects its flavone nucleus. 

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