Aniline acyl derivatives

Most derivatives of aniline are not obtained from aniline itself, but ate prepared by hydrogenation of their nitroaromatic precursors. The exceptions, for example, /V-a1ky1ani1ines, /V-ary1ani1ines, sulfonated anilines, or the A/-acyl derivatives, can be prepared from aniline and have been discussed. Nitroanilines are usually prepared by ammonolysis of the corresponding chloronitroben2ene. Special isolation methods may be requited for some derivatives if the boiling points are close and separation by distillation is not feasible. Table 6 Hsts some of the derivatives of aniline that are produced commercially. 

Both 2- and 3-nitrothiophenes are reduced by tin and hydrochloric acid to the corresponding aminothiophenes. In contrast to anilines, the free bases are very unstable their salts and acyl derivatives, however, are stable. 2-Aminothiophene can be diazotized and the resulting diazonium salt coupled with /3- naphthol. The chemical instability of aminothiophenes compared with aniline is illustrated by the ring opening of 2-amino-3-ethoxycar-bonylthiophenes (157) with ethanolic sodium ethoxide to give cyanothiolenones (158) <75JPR861). 

Illustrative examples of the acylation of support-bound amines with carbodiimides as coupling agents are listed in Table 13.3. Difficulties are usually encountered in the acylation of a-alkylamino acid derivatives (which are significantly less nucleophilic than simple secondary amines Entries 3 and 4) and Al-alkyl (Entries 5 and 6) or iV-aryl anilines. Acylations with haloacetic or related acids containing a leaving group prone to nucleophilic displacement should not be performed with the aid of HOBt and bases because O-alkylation of HOBt by the product occurs readily. 

Dihydrothieno[2,3-6][l,5]benzothiazepines (42) were synthesized from 2-(2-thienylthio)aniline (40). Compound 40 was acylated by treatment with acetic anhydride or benzoyl chloride to give N-acyl derivatives (41), which afforded compounds 42 by cyclization with phosphorus oxychloride and subsequent reduction with sodium borohydride or Zn/HCl. N-Dimethylaminopropyl derivatives 43 were prepared by reaction with di-methylaminopropyl chloride in the presence of sodium amide (Scheme 13) (67CZP124935 68CCC1846). 

Both phenacetin and the newer replacement acetaminophen are derivatives of p-aminophenol. Although these latter two are analgesics and antipyretics, the aniline-phenol derivatives show little if any antiinflammatory activity. p-Aminophenol itself is toxic, but acylation of the amino group makes it a convenient drug. 

Bowman and Beroza [472] hydrolysed carbamates by heating with 10% NaOH solution and condensed the phenol produced with chlorothiophosphate in the presence of pyridine (Scheme 5.37). The resulting derivative is highly specific for the compound under analysis and, with the use of a flame photometric detector, it permits its sensitive analysis (at the level of hundredths of 1 ppm in foodstuffs). A column packed with 10% of DC-200 was used for the analysis at 190°C. Holden et al. [473] also obtained a high sensitivity in the analysis of N-methyl- and dimethylcarbamates if they condensed amines released by alkaline hydrolysis with l-fluoro-2,4-dinitrobenzene and applied an ECD for detection (2% of XE-60, 190°C). Different substituted anilines were similarly analysed as products from the decomposition of different pesticides [474] in the form of different perfluorinated acyl derivatives. 

The lactim/lactam tautomerism of hydroxamic acids and their O-alkyl and O-acyl derivatives has also been studied [146], Hydroxamic acids exist in the solid state and in polar solvents as the lactam tautomer only, whereas in nonpolar solvents the hydroximic tautomer is also present. Further analogous solvent-dependent lactim/lactam equilibria have been observed for certain Schiff bases (prepared from anilines and 2(4)-hydroxybenzaldehyde [256] or 2-hydroxynaphthaldehyde [257]), for 3-hydroxypyrazole [258], and for 3-methyl-l-phenylpyrazolin-5-one [259]. 

Amines derived from p-alkoxybenzyl-type linkers, despite not being acid cleav-able, still have synthetic utility. Anilines anchored to Wang resin, once converted into carboxamides or sulfonamides by reaction with the appropriate electrophile, can be cleaved with TFA (Figure 14.6) [34]. Sulfonamides of aliphatic amines may also be cleaved with TFA [36]. Stronger acids are generally required for acyl derivatives of amines but this can cause cleavage of the linker benzylic ether bond, leading to formation of p-hydroxybenzylated by-products. 

The only report on the reactions of GAC-sorbed nitrogen compounds (Hwang et al., 1990) similarly indicated that sorbed anilines were converted by HOCl to oxidative coupling products such as azobenzenes (89), unlike solution reactions with HOCl that led to ring substitution. Additional compounds such as formanilides and acetanilides were also identified in some cases the mechanisms of formation of these N-substituted derivatives are unknown, although similar N-acyl derivatives have been reported to occur during the metabolism of anilines (Freitag et al., 1984). 

Anilides n. Acyl derivatives from aniline. Possibly the commonest anilide in the paint trade is acetanilide, C6H5NHCOCH3. 

CgHs-N C CHs+CHaC OH In the above equations, it should be noted that acetyl chloride does not convert aniline completely into the acetyl derivative since the by-product, aniline hydrochloride, is formed and this does not act readily with the reagent. On the other hand, with acetic anhydride the amine is converted quantitatively into the acyl derivative and therefore this latter reagent is of more importance in connection with the preparation of derivatives. It is also of value in quantitative estimations of the amine group, the excess of acetic acid which remains after the reaction being determined volumetrically. Benzoyl chloride, benzenesulfonyl chloride, and other acyl halides that may be used in aqueous solution may also convert the amine completely into an acyl derivative for the reason that they are usually used in the presence of alkali which will combine with the hydrochloric acid generated in the reaction. When benzoyl chloride is used, a small amount of benzoic acid may be formed, due to the following side-reaction ... 

Important analogs of aniline include the toluidines, xyUdines, anisidines, phenetidines, and its chloro-, nitro-. A/-acetyl. A/-alkyl. A/-aryl. A/-acyl, and sulfonic acid derivatives. 

Aminofurans substituted with electron-withdrawing groups e.g. NO2) are known and 3-amino-2-methylfuran is a relatively stable amine which can be acylated and diazotized. 2-Amino-3-acetylfurans are converted into 3-cyano-2-methylpyrroles on treatment with aqueous ammonia. This transformation is a further illustration of the relative instability of the amino derivatives of five-membered ring heterocycles compared with anilines (Scheme 67) (781003821). 

A simple aniline derivative acts as a prostatic antiandro-t (>n. Its synthesis involves simple acylation of disubstituted iiriiline 13 with isobutyryl chloride to give flutamide (14). 

A compound closely related to classical adrenergic agonists in which the para hydroxy function is however replaced by an amino group has been investigated for its activity as a growth promoter in domestic animals. Acylation of the aniline derivative 26 with chloracetyl chloride will afford acetophenone 27 the amino-ketone 28 is obtained on reaction with isopropylamine. Removal of the protecting group (29) followed by reduction of the ketone affords cimaterol (30) 5J. 

In 1978, Sugasawa et al., at Shionogi Pharmaceutical Co. reported ortho-selective Friedel-Craft acylation with free anilines with nitrile derivatives [4]. Sugasawa reported that the reaction requires two different Lewis acids (BC13 and A1C13) and does not proceed when N,N-dialkyl anilines are used. He proposed that boron bridging between nitriles and anilines led to exclusive ortho-acylation but a conclusive mechanism was not elucidated. The report did not offer any reason why two different Lewis acids were required and why the reaction did not progress with N,N-dialkyl anilines. Therefore, we initiated mechanistic studies. 

Nitroanilides, l-acyl-7-nitroindolines, and A -acyl-1,2,3,4-tetrahydro-8-nitroquinolines are readily photolyzed to yield the free carboxylic acids (80-100%) and photoproducts. These nitro derivatives (see Fig. 2) possess higher stability to acid hydrolysis and a lower stability to basic hydrolysis than non-nitrated anilines. Nevertheless, they are unlikely to prove of service to the carbohydrate chemist, unless they can be synthesized from carboxylic acids under milder conditions than those devised to date. 

---