O-Acylaniline

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>. 

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 intermediate in the Gabriel-Posner synthesis of quinazolin-2(lH)-one (fusion of o-aminobenzaldehyde with excess of urea), was found to be o-ureidobenzylidene urea (19), which then cyclized on heating, or in the presence of acid, with elimination of urea. The intermediate reacted with aniline, iV-methylaniline, and N,V-dimethylaniline to form 4-p-aminophenyl, 4-p-methylaminophenyl, and 4-p-dimethylaminophenyl quinazolin-2(lH)-ones in an unusual manner. Several quinazolin-2(li/)-ones were prepared by converting o-acylanilines into o-ureidophenyl ketones followed by cycli-zation in acetic acid medium for long periods at 55°C. A novel modification of this cyclization involved a Curtius or Hofmann reaction on 2 -benzoyl-oxanilic acid chlorides (20 = Cl) or amides (20 = NH2), respectively. 

An alternative retrosynthesis is represented by path B in Scheme 31. The most common route to the starting materials is by alkylation of o-acylanilines. Usually an EW substituent is required as the R substituent in the 2-position. For example, 2-benzoyl <72JOC3622>, 2-ethoxycarbonyl <92JMC4823>, and 2-cyanoindoles <72JHCi6i> (Equation (19)). 

Subjecting alkyl nitrates to hydrogenolysis conditions gave alcohols (Scheme 28). Transfer hydrogenolysis using ammonium formate has also been used for N—O cleavage at 60 °C to give o-acylaniline 83 from benzisoxazole 82 in 66% yield (Scheme 29). 

Nakaura and Ukita devised a simple indole synthesis from the Rh-catalyzed condensation of a-diazophospho-nates and o-acylanilines (Scheme 6, equation 1) [58]. Moody and colleagues combined diethyl diazomalonate and Af-alkylanilines in a Rh-catalyzed synthesis of indox-ylic acid esters (equation 2) [59], This chemistry represents a simple synthesis of these rare indoxyl-2-carboxylates. 

The Camps reaction is the base-catalyzed intramolecular condensation of an A-acyl o-acylaniline 39 to form either a 4-hydroxyquinoline 40 or a 2-hydroxyquinoline 41 or mixtures of both depending on the nature of the substrate. Due to the possibility of the... 

Aminoquinazoline is best obtained by boiling o-aminobenzalde-hyde with guanidine carbonate in Decalin. o-Acylanilines, also react with cyanoguanidines to give 2-guanidinoquinazolines. An extension of this method makes use of acetone anil as the source of o-amino-acetophenone (see 6b). 

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