Acylanilines

Retrosynthetic path b in Scheme 3.1 corresponds to reversal of the electrophilic and nucleophilic components with respect to the Madelung synthesis and identifies o-acyl-iV-alkylanilines as potential indole precursors. The known examples require an aryl or EW group on the iV-alkyl substituent and these substituents are presumably required to facilitate deprotonation in the condensation. The preparation of these starting materials usually involves iV-alkyla-tion of an o-acylaniline. Table 3.3 gives some examples of this synthesis. 

When o-aminobenzophenone is heated with formamide in the presence of formic acid at 150°C for 20 min, a quantitative yield of 4-phenylquinazoline is obtained. In the absence of formic acid longer heating is necessary. Although this reaction does not proceed with o-acylamidobenzophenones, its extension to other o-acylanilines with aliphatic amides may prove fruitful. 

A variety of substituted dibenzo-fused derivatives 126 have been prepared for evaluation of their biological activities. The synthesis of these compounds involves the reaction of o-acylanilines with pyrroloindolones 125, in boiling butan-l-ol with pyridinium />-toluenesulfonate as catalyst (Equation 8). Compounds such as 126 which contain the benzo[5,6]pyrrolizino[l,2-A]quinoline skeleton exhibit cytotoxicity against several cancer cell lines <2004BML2363>. 

The Friedlander reaction is the acid- or base-catalyzed condensation of an ortho-acylaniline with an enolizable aldehyde or ketone. Henichart and coworkers have described microwave-assisted Friedlander reactions for the synthesis of indoli-zino[l,2-b]quinolincs, which constitute the heterocyclic core of camptothecin-type antitumor agents (Scheme 6.238) [421], The process involved the condensation of ortho-aminobenzaldehydcs (or imines) with tetrahydroindolizinediones to form the quinoline structures. Employing 1.25 equivalents of the aldehyde or imine component in acetic acid as solvent provided the desired target compounds in 57-91% yield within 15 min. These transformations were carried out under open-vessel conditions at the reflux temperature of the acetic acid solvent. 

Ring closure y to a heteroatom is also a rather uncommon [5 + 1] procedure although there are some important exceptions. The most widely investigated is the Bernthsen acridine synthesis in which a diarylamine is condensed with a carboxylic acid in the presence of a Lewis acid (equation 73). More recently, it has been shown that acylanilines react with the Vilsmeier-Haack reagent to give quinolines in good yield (e.g. equation 74) and the mechanism of the reaction has been elucidated. A final example of [5 +1] ring closure y to a heteroatom which is of occasional use is the pyrazine synthesis outlined in equation (75). 

Halomethylcarbonyl compounds provide one-carbon components. For example, phenacyl bromide with o-acylanilines leads to indoles (92) (72JOC3622) by intramolecular aldol condensation of intermediate (91). 

The usual precursor is an appropriately orf/to-disubstituted benzene. Thus, quinazolines (290) can be prepared by the reaction of o-acylanilines (289 R = alkyl) with amides RCONH2. Heating anthranilic acid (289 R = OH) with amides or amidines yields 4-quinazolinones (291). The second nitrogen can be introduced into (289) before ring closure, as in (292) + HC(OEt)3 — (293). 

The presence of the /3-hydroxypropionic ester unit in deacetylpicraline is established by oxidation with chromic acid in acetone, which yields an aldehyde base, picralinal, C21H22N2O4 the latter is readily deform yla ted by short treatment with methanolic potassium hydroxide, which affords picrinine in quantitative yield. Reduction of picralinal with sodium borohydride regenerates deacetylpicraline. Vigorous treatment of deacetylpicraline with sodium borohydride gives a noncrystalline indoline base, which exhibits the UV-absorption of an anilinium ion in concentrated perchloric acid hence, the Na-carbinol-amine ether function must have suffered reduction. Since acetylation of the noncrystalline base gives a product which exhibits acylaniline UV-absorption, picraline and its derivatives must contain an NaH group (53, 54). 

Reaction of complex (90) with methyllithium followed by acid and carbon monoxide affords a mixture of acylated complexes (Scheme 149). Reaction of an oxime complex with organocuprates followed by acetic anhydride, carbon monoxide, and potassium carbonate gives meta-acylaniline derivatives (Scheme 150). In both cases, the nucleophile probably initially adds to the metal followed by an acyl transfer. 

Acylanilines 47 were prepared in moderate yields from 3-hydroxy-2-indolinones 46 by air oxidation with a copper(I) chloride-DBU catalyst (84JAP(K)134757). 

An interesting reaction that represents a half-way point between the quinamine and benzidine rearrangements can be also mentioned here129, namely the conversion of A-acetyl-0,A-diphenylhydroxylamine 78 into biphenyls 79 and 80 (equation 32) (see Section IILA.4.C about rearrangements of A-acylanilines and Section m.C.l concerning rearrangements of hydroxylamines). 

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