Acylation aniline derivatives

Tertiary alkyl azides can be prepared by stirring tertiary alkyl chlorides with NaNa and ZnCl2 in 82 ° or by treating tertiary alcohols with NaNa and CFaCOOH or with HNa and TiCLt " or BEa. " Aryl azides can be prepared from aniline and aniline derivatives. Acyl azides, which can be used in the Curtius reaction (18-14),... 

Anilines were also effectively amidated by this procedure. Since aniline-derived acyl-imidazole intermediates are slow reacting considering addition, the removal of the solvent has an accelerating effect (Scheme 3.33, Table 3.17). The difference is most pronounced in the case of a less-reactive substrate (entry 4). 

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. 

Quantitative stoichiometric gas-solid or solid-solid (these at 0 °C) acylations of amines with acid chlorides are varied (Scheme 32). However, for a clean reaction the liberated hydrochloric acid has to be neutralized by an additional gaseous or solid base that may also be a second mole of the amine. The reactions are performed in an evacuated flask or in a ball-mill, respectively. There are only minimal losses of the amides or sulfonamides upon removal of the stoichiometric coproduct with water [91]. The solid-solid reactions can be turned into sustainable 100% yield processes with optimal atom efficiency by milling stoichiometric 1 1 1 mixtures of acid chloride, aniline derivative, and K2CO3... 

Experimental studies of the reactivity of other aniline derivatives in substitution reactions are far more limited, de la Mare and Hassan (1958) and Bradfield and Jones (1928) examined the influence of acyl substituents on the amino function on the rate of halogenation at the para position. These interesting data are too limited to be useful for the evaluation of a linear free-energy relationship and are not included in Table 4. 

Pyrazolo[3,4-Z)]pyridines, the 7-chloro-6-fluoro-2,4-dimethylquinoline and its mercapto-thiadiazolyl or oxadiazolyl quinolines 21 were prepared via Diels-Alder reaction conversion of methyl 2-(3-oxo-3-phenylpropenylamino)benzoate into 3-benzoyl-l.S -quinolin-4-one 22 . A mixture of aniline derivatives and malonic ester gave a variety of 3-aryl-4-hydroxyquinolin-2(l//)-ones 23. Condensation of isatins with ketones afforded quinoline-4-carboxylic acids. 2-Aryl-l,2,3,4-tetrahydro-4-quinolinones 22 and carbazolylquinolone were also prepared. The substitution of 2-chloroquinoline gave the 2-substituted quinolines. Basic alumina has catalyzed the C-C bond formation between 2-hydroxy-1,4-naphthoquinone and 2-chloroquinoline derivative to give 21. Reaction of organic halides with 8-hydroxyquinolines gave the respective ethers. The azodye derivatives of 21 were prepared in the absence of solvent. Silica gel catalyzed the formation of 2-ketomethylquinolines from reaction of 2-methylquinolines with acyl chlorides. 

The yields in the former reactions were generally higher. Intramolecular cyclization of o-unsubstituted aniline derivatives to give quinazolin-2(lH)-ones had never been reported. Recently, however, V-phenyl-V -acyl ureas (21) lacking in ortho-substituents in the benzene ring were cyclized to 4-substituted quinazolin-2(l//)-ones in polyphosphoric acid at 90°-130°C. 4-Aminoquinazolin-2(l//)-ones were prepared by a Chichibabin reaction (NaNHj) from quinazolin-2(l//)-ones. ... 

The intramolecular cyclization of o-allylaniline derivatives (42) and (43) have been studied. The irradiations were carried out in hexane or acetonitrile and irradiation has supplied evidence for the involvement of intramolecular CT complexes. Irradiation of (42) affords the products (44) in the yields shown. The reactivity of (43) was also studied and its cyclization gave the analogous products (45). The influence of substituents on the photochemical reactions of some aniline derivatives (46) has been studied. The unsubstituted derivatives (46) predominantly undergo cyclization. The yield of product is dependent upon the mode of irradiation. Two conditions are described as (a) benzene/air and (b) ben-zene/argon. Under the aerated conditions oxidation of the cyclized product (47) occurs to yield (48). Cyclization is suppressed when the nitrogen is acylated these compounds (46, R = COMe) predominantly undergo a photo-Fries process to yield a mixture of the ortho and para products (49). Detailed studies showed that cyclization occurs from a CT state. 

Reacting 4-substituted aniline derivatives 170 with chlorosulfonyl isocyanate gives the N-acylated products 171 (R = Me, Et, Pr", Ph R = H, Cl), which then cyclize to the 4-alkylated 2//-benzo-l-thia-2,4-diazine-3(4//)-one 1,1-dioxides 172 in the presence of AICI3 (Scheme 13) <2006BMC650>. This reaction constitutes the use of [3-1-3] fragments and is... 

To introduce additional diversity, the 3-nitrophenyl and 4-nitrophenyl derivatives in the R position were further functionalized. For example, the nitro group and enol ether of 3-nitrophenyl 39 were reduced, and the resulting aniline was acylated to give 41 (Scheme 7.9). Alternatively, selective reduction of the nitro group worked most effectively in the presence of ammonium formate to give compounds 42. 

With aromatic amines, it is not only the introduction of the amino group that relies on Pd-catalysis but this process is also mandatory for regioselective substitution of aniline derivatives, as illustrated for their ortho-acylation with the help of aldehydes (see 546) [195]. 

Since acylated heteroaromatics are active intermediates for the synthesis of various pharmaceuticals, catalytic acylation of heteroaromatics using safe and reusable catalysts is important in pharmaceutical industry. It is found that gallium triflate can act as an efficient catalyst for Friedel-Crafts acylation of furan, pyrrole, and indole derivatives (eq 3-5). Friedel-Crafts acylation of acyl anilides using AICI3 requires a stoichiometric amount of the catalyst and the yields are low. Studies showed that catalytic acylation of aniline derivatives can be achieved in high yields using Ga(OTf)3 (10 mol%) in the presence of LiClOa (eq 6). ... 

Nagano and Li reported an intramolecular C-C bond-forming CDC reaction for the synthesis of indole derivatives (Scheme 8.28). Cyclization of aniline derivatives (72) effectively proceeds in the presence of a catalytic amount of tetrabutylammonium iodide and 2.5 equiv. of TBHP to afford a variety of 3-acyl-2-aryl indoles (73). The catalytic formation of iodine (I2) by TBHP seems to be essential for the reaction to occur. 

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. 

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). 

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). 

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