N-Acylanilines

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. 

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). 

N-Alkylation of N-acylanilines. These substances can be alkylated in aqueous NaOH-benzene with use of this phase-transfer catalyst. ... 

RearramgemeM of oMUks. N>Acylanilines rearrange when heated with this catalyst at 160-245° for 2-9 minutes (equation I). ... 

A related protocol to directly access indolines from anilines by sp C-H activation was reported by Glorius et al. [146]. N-acylanilines underwent C-H activation in the presence of Pd(OAc)2, AgOAc, and Na2COj and were thus converted into indohnes in good yields (Scheme 13.101). 

An ecofriendly solvent-free Fries rearrangement with acyl/alkyl migration has been observed by Selvakumar et al. (2007). Rearrangement of N-acylaniline in presence of AlClj adsorbed on neutral alumina under microwave irradiation afforded exclusively the p-rearranged product. Reactions were completed within 3-5 min and the yield varies between 86-96%. 

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. 

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. 

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). 

N-alkoxyalkyl derivatives of acylanilines are of current interest due to their biological activity. However, up to this time the most facile method for their synthesis utilizes a PEG—PTC catalyzed reaction where yields in excess of 90% were reported [150]. When this reaction was catalyzed by benzyltriethylammonium chloride, a considerable dimer formation was reported [150]. 

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