Benzenoid Intermediates

Anilines have been hydroxylated with hydrogen peroxide in superacid, HF/SbFj, the substituting species being (ref.80). Thus, aniline afforded the hydroxyanilines, 2-hydroxy (29%), 3-hydroxy (51%) and 4-hydroxy (20%). 

A novel neighbouring group has been introduced in which N-methyl-N -phenoxyurea in dichtoromethane after treatment at OX with trifluoroacetic acid was reacted to give N-(2-hydroxyphenyl)-N-methylurea in 85% yield, from which 2-N-methylaminophenol was obtain (ref.81). 

3-Propylaminocydohex-2-enone gave 3-propylaminophenol in 78% yield by refluxing for 10 hours in acetonitrile containing mercuric acetate (ref.82). 

A related compound 3-dimethylaminocyclohex-2-enone in aqueous solution has been dehydrogenated by dropwise addition, vaporisation and passage with nitrogen and hydrogen (3 1) over a palladium-potassium-charcoal catalyst at 300°C to produce 3-dimethylaminophenol in 98% yield (ref.83). 

Cyclohexane-1,3-diones generally, for example the parent compound, dihydroresorcinol, available from rhe hydrogenation of resorcinol, have been aromatised by various techniques including the use of mercuric acetate in the presence of secondary amines to afford yields of 3-substituted aminophenols in the range 32-79% (ref.84). 

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Chemistry of Aromatic lleterocycles. In contrast to the benzenoid intermediates, ii is unusual lo find a heterocyclic intermediate that... 

The vast majority of syntheses of isoquinoline are based on benzenoid intermediates. It is therefore noteworthy that a key step in a recent synthesis of ellipticine involves the construction of a benzene ring onto a pyridine by an intramolecular Diels-Alder addition (Scheme 43). ... 

A number of typical alkylations of various phenols are shown in Table 6.1 (refs. 1-7). A novel feature of four of these procedures is the o-substitution which resulted. This feature, particularly where metallic systems are involved, reflects the tautomeric nature of phenols. While benzenoid intermediates represent the most obvious choice of starting material, the facile dehydrogenation of an alkylated cyclohexanone has also been used. Thus cyclohexanone and propanal (2 equivs.) heated at 150 C in the presence of bis-cyclopentadienyl zirconium dichloride afforded 2,6-di-n-propylphenol in 69% yield (ref.8). 

In early work substituted benzenoid intermediates were employed and subsequently, open-chain precursors in Diels-Alder reactions, Michael additions and organometallic procedures. 

Addition of nitric acid to mixtures of -hydroxyphenyl ketones and glacial acetic acid afforded 3,8-dinitrocoumarins by cyclo-. condensation of nitrated benzenoid intermediates. 

U.S. dye manufacturers have relied to a great extent on European sources for intermediates. The dependence became even greater as major U.S. manufacturers—du Pont, Allied, and GAF—ceased production of dyes between 1974 and 1983. India and Pacific Rim countries are becoming important sources of intermediates. During 1983, the latest year for which government data are available, benzenoid intermediates imported into the United States were valued in excess of 840 million. ... 

Both phenanthrene and anthracene have a tendency to undergo addition reactions under the eonditions involved in eertain eleetrophilic substitutions. For example, in the nitration of anthracene in the presence of hydrochloric acid, an intermediate addition product can be isolated. This is a result of the relatively close balance in resonance stabilization to be regained by elimination (giving an anthracene ring) or addition (resulting in two benzenoid rings). 

The Birch reduction of a benzenoid compound involves the addition of two electrons and two protons to the ring. The order in which these additions occur has been the subject of both speculation and study. Several reviews of the subject are available and should be consulted for details. The present discussion is concerned with summarizing data that is relevant to understanding the reaction from the preparative point of view. For convenience, reaction intermediates are shown without indicating their solvation by liquid ammonia. This omission should not obscure the fact that such solvation is largely responsible for the occurrence of the Birch reduction. 

In their acidity, basicity, and the directive influence exerted on electrophilic substitution reactions in benzenoid nuclei, acylamino groups show properties which are intermediate between those of free amino and hydroxyl groups, and, therefore, it is at first surprising to find that the tautomeric behavior of acylaminopyridines closely resembles that of the aminopyridines instead of being intermediate between that of the amino- and hydroxy-pyridines. The basicities of the acylaminopyridines are, indeed, closer to those of the methoxy-pyridines than to those of the aminopyridines, the position of the tautomeric equilibrium being determined by the fact that the acyl-iminopyridones are strong bases like the iminopyridones and unlike the pyridones themselves. Thus, relative to the conversion of an... 

It is apparent from simple valence bond considerations as well as from calculations of rr-electron density, " that isoindoles should be most susceptible to electrophilic attack at carbon 1. This preference is most clearly evident when the intermediate cations (85-87) from electrophilic attack (by A+) at positions 1, 4, and 5 are considered. The benzenoid resonance of 85 is the decisive factor in favoring this intermediate over its competitors. 

Compounds of special interest whose preparation is described include 1,2,3-benzothiadiazole 1,1-dioxide (a benzyne precursor under exceptionally mild conditions), bis(l,3-diphenylimida-zolidinylidene-2) (whose chemistry is quite remarkable), 6- di-melhylamino)julvene (a useful intermediate for fused-ring non-benzenoid aromatic compounds), dipkenylcyclopropenone (the synthesis of which is a milestone in theoretical organic chemistry), ketene di(2-melhoxyethyl) acetal (the easiest ketene acetal to prepare), 2-methylcyclopenlane-l,3-dione (a useful intermediate in steroid synthesis), and 2-phenyl-5-oxazolone (an important intermediate in amino acid chemistry). 

Reduction of aromatic compounds to dihydro derivatives by dissolved metals in liquid ammonia (Birch reduction) is one of the fundamental reactions in organic chemistry308. When benzene derivatives are subjected to this reduction, cyclohexa-1,4-dienes are formed. The 1,4-dienes obtained from the reduction isomerize to more useful 1,3-dienes under protic conditions. A number of syntheses of natural products have been devised where the Birch reduction of a benzenoid compound to a cyclohex-1,3-diene and converting this intermediate in Diels-Alder fasion to polycyclic products is involved (equation 186)308f h. 

In addition to benzenoid diazo components, diazotised heterocyclic amines in which the amino group is attached to a nitrogen- or sulphur-containing ring figure prominently in the preparation of disperse dyes [87,88], since these can produce marked bathochromic shifts. The most commonly used of these are the 6-substituted 2-aminobenzothiazoles, prepared by the reaction of a suitable arylamine with bromine and potassium thiocyanate (Scheme 4.31). Intermediates of this type, such as the 6-nitro derivative (4.79), are the source of red dyes, as in Cl Disperse Red 145 (4.80). It has been found that dichloroacetic acid is an effective solvent for the diazotisation of 2-amino-6-nitrobenzothiazole [89]. Subsequent coupling reactions can be carried out in the same solvent system. Monoazo disperse dyes have also been synthesised from other isomeric nitro derivatives of 2-aminobenzothiazole [90]. Various dichloronitro derivatives of this amine can be used to generate reddish blue dyes for polyester [91]. 

For reasons already frequently mentioned—cf., for example, pp. 106,178,196—the partially hydrogenated aromatic nucleus is not stable hence the bracketed intermediate product tends to change into the benzenoid form, while hydrogen wanders from the nitrogen to the oxygen atom. 

Validation of the role of femloyl-CoA in the synthesis of the vanillin precursor will be detection of the appropriate intermediates and/or enzyme activities in placental extracts that could account for the production of the predicted levels of capsaicinoids. The presence of low levels of monolignol intermediates could be explained by lignin biosynthesis. An alternate route from phenylalanine to vanillin has been considered by some investigators Orlova et al. [68] demonstrated the role of the benzenoid pathway in petunia flowers for the biosynthesis of phenylpropanoid/benzenoid volatiles. 

UV irradiation of the naphthalen-l,4-imines 104 and 105 promotes their isomerization to 3-benzazepine derivatives 139 and 140. Although no direct evidence was obtained to confirm the formation of azaquad-ricyclanes (138) as intermediates (see Section II,F), the extra strain associated with structure 138 and the extra benzenoid stabilization of the products 139 and 140 make it understandable that the thermal rearrangement of 138 should occur faster than that of 76 or 78. Analogous photochemical transformations are those of compound 106 to trimethyl 3-benzazepin-l,3,5-tricarboxylate, and of 1,4-epoxynaphthalenes to benzoxepin derivatives. ... 

Reduction of benzenoid hydrocarbons with solvated electrons generated by the solution of an alkali metal in liquid ammonia, the Birch reaction [34], involves homogeneous electron addition to the lowest unoccupied 7t-molecular orbital. Protonation of the radical-anion leads to a radical intermediate, which accepts a further electron. Protonation of the delocalised carbanion then occurs at the point of highest charge density and a non-conjugated cyclohexadiene 6 is formed by reduction of the benzene ring. An alcohol is usually added to the reaction mixture and acts as a proton source. The non-conjugated cyclohexadiene is stable in the presence of... 

The mechanism for these electrophilic substitution reactions involves formation of a dication intermediate (13) which, as in the case of benzenoid substitution reactions, loses a proton and reverts to the original stable system. 

These compounds are less common than indole (benzo[ ]pyrrole). In the case of benzo[i>]furan the aromaticity of the heterocycle is weaker than in indole, and this ring is easily cleaved by reduction or oxidation. Electrophilic reagents tend to react with benzo[Z ]furan at C-2 in preference to C-3 (Scheme 7.21), reflecting the reduced ability of the heteroatom to stabilize the intermediate for 3-substitution. Attack in the heterocycle is often accompanied by substitution in the benzenoid ring. Nitration with nitric acid in acetic acid gives mainly 2-nitrobenzo[Z ]furan, plus the 4-, 6- and 7-isomers. When the reagent is in benzene maintained at 10 °C, both 3- and 2-nitro[ ]furans are formed in the ratio 4 1. Under Vilsmeier reaction conditions (see Section 6.1.2), benzo[Z ]furan gives 2-formylbenzo[6]furan in ca. 40% yield. 

Fortunately, there is now a comprehensive body of knowledge on the metabolic reactions that produce reactive (toxic) intermediates, so the drug designer can be aware of what might occur, and take steps to circumvent the possibility. Nelson (1982) has reviewed the classes and structures of drugs whose toxicities have been linked to metabolic activation. Problem classes include aromatic and some heteroaromatic nitro compounds (which may be reduced to a reactive toxin), and aromatic amines and their N-acylated derivatives (which may be oxidized, before or after hydrolysis, to a toxic hydroxylamine or iminoquinone). These are the most common classes, but others are hydrazines and acyl-hydrazines, haloalkanes, thiols and thioureas, quinones, many alkenes and alkynes, benzenoid aromatics, fused polycyclic aromatic compounds, and electron-rich heteroaromatics such as furans, thiophenes and pyrroles. 

Wheland intermediates, a complexes, or arenium ions In the case of benzenoid systems they are cyclohexadienyl cations. It is easily seen that the great stability associated with an aromatic sextet is no longer present in 1, though the ion is stabilized by resonance of its own. The arenium ion is generally a highly reactive intermediate and must stabilize itself by a further reaction, although it has been isolated (see p. 504). 

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