A-Acylanilines

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). 

Remarkably, the tran -sialidases from T. cruzi and T. brucei are not inhibited by Neu2en5Ac [550,809,813]. As this is in contrast to most other sialidases described in the groups 1-3 of the previous section, Neu2en5Ac is probably not an intermediate of the tra 5-sialidase reaction. Furthermore, A-(4-nitrophenyl)oxamic acid and related A-acylanilines do not inhibit T. cruzi or T. brucei trans-sialidases, which is also in contrast to the influence of this substance on the activity of sialidases from V. cholerae and other bacteria [813]. 

For the retrosynthesis of indole (see Fig. 5.8), two routes (I/II) are proposed, as for pyrrole (see p 94). Route I suggests o-aminobenzyl ketone 1 or 6>-alkyl-A -acylaniline 2 as starting material on the basis of operations a - c. Their retroanalysis (d,e) in turn leads to 2-alkylaniline 5 and carboxylic acid derivative 6. Construction of the indole system should thus occur by N- or C-acylation of 5 (utilizing the o-nitrotoluene derivative 4) followed by cyclodehydration of 1/2. The alternative route n, based on retrosynthetic analysis g-i, leads to aniline via the a-(A -phenylamino)ketones 3 and to a-halo ketones 7 as possible precursors for the indole synthesis. 

Despite the stoichiometric requirements of expensive palladium salts, this reaction can be useful in the synthesis of ortho-foxmy -, A,A-dialkylaminomethyl-, and amino-substituted biaryls since variuos nitrogen containing substrates at benzylic position readily form palladacycles, e.g. A,A-dimethylbenzylamine, A-benzylidene-A ,A -dimethylhydrazone, O-methylbenzaldoximes, and A-acylanilines [17,18]. 

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>. 

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). 

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). 

M. Engstler, R. Schauer, M. A. Ferrero-Garcia, A. J. Parodi, T. Storz-Eckerlin, A. Vasella, C. Witzig, and X. Zhu, N-(4-Nitrophenyl)oxamic Acid and Related N-Acylanilines Are Non-competitive Inhibitors of vibrio cholerae sialidase but do not inhibit trypanosoma cruzi or trypanosoma brucei trans-sialidases, Helv. Chim. Acta., 77 (1994) 1166-1174. 

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 iV-(o-vinyl)imino ester is probably an intermediate in the two-step thermal cyclization of 2-vinyl-,/V-acylanilines. A photochemical method also gives high yields except when R = COOMe the thermal method gives none of this product. 

Heterocycle formation. When o-iodination of acylanilines in which the acyl group contains a double bond at a proper distance is followed by several steps, benzomor-pholines result. Unsaturated carbamates and amides form oxazolidinones and lactams under such reaction conditions. 

N-Acylanilines. When electron-rich arenes are treated with a carboxylic acid, hydroxylamine hydrochloride in PPA, several reactions occur in sequence. These are the Friedel-Crafts acylation, oxime formation, and Beckmann rearrangement. Anilides are obtained in 45-95% overall yields (11 examples). 

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. 

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