Acylation of aniline

The Sugasawa reaction (ortho-acylation of aniline) was optimized for this route using a combination of BCl3/GaCl3. 

Fig. 6.38. Mechanism of the preparation of an isocyanate by acylation of anilines with tert-butyl dicarbonate in the presence of 4-(dimethylamino)pyri-dine. In the absence of this additive a tert-butyl carbamate would be produced instead of an isocyanate (cf. Figure 6.37.)...

Compounds formed by the acylation of ammonia are familiar to you as amides and those formed by the acylation of anilines are sometimes called anilides. If they are acetyl derivatives they are called acetanilides. We shall not use these names but you may see them in some books. 

The borane 1 can also be used for ortho-acylation of anilines by reaction wdth nitriles. The yields in this reaction are considerably improved by addition of aluminum chloride, but other Lewis acids are ineffective. This reaction is also successful for primary anilines. No other metal halides are effective in these two substitution reactions. 

Lee, studying the acylation of anilines and chloroanilines, found that reaction with TFAA was complete for most of them in 5 minutes at room temperature, and in 15 minutes for all of them with PFPA the reaction was complete for most in 15 minutes at room temperature, and after two hours for all and with HFBA anhydride for most in 18 hours at room temperature and for 30 minutes at 60 °C [54]. 

Synthesis, reactivity and mechanistic studies of the fi-substituted cluster l,7-C2BioHn-9-XAr+ have been reviewed. The kinetics of the acylation of l,7-6js(4-aminophenyl)amido- and l,7-Zj/5(4-aminophenyl)carboxy-l,7-carborane in a variety of organic solvents have been investigated.97 Another kinetics study concentrates on the acylation of aniline by 1,7-carboranecarbonyl chloride. ... 

Ortho acylation of anilines by nitriles in the presence of BCI3 and an auxiliary Lewis acid ... 

Anilide A compound that contains a CsHsNHCO group. An amide formed by acylation of aniline (aminobenzene). 

The section highlights synthesis of compounds demonstrated physiological activities using fluoro- or trifluoromethyl-substituted furans as starting compounds. Acylation of aniline 287 with 5-fluorofuran-2-carbonyl chloride gave amide 288 which inhibited c-jun A-terminal kinase at submicromolar level [162],... 

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). ... 

Although a comparison of the reactivities of the gallium-complexed metal species and the original metal species has not yet been studied in a systematic manner, an example reported by Houpis may be worth noting. BCI3-promoted o-acylation of anilines with nitriles was shown to be considerably promoted in the presence of GaCl3 (Scheme 7.9) [27]. 

The stronger directing effects present in the indoline ring can sometimes be used to advantage to prepare C-substituted indoles. The aniline type of nitrogen present in indoline favours 5,7-substitution. After the substituent is introduced the indoline ring can be aromatized by dehydrogenation (see Section 15.2 for further discussion). A procedure for 7-acylation of indoline... 

Direct nitration of aniline and other arylamines fails because oxidation leads to the formation of dark colored tars As a solution to this problem it is standaid practice to first protect the ammo group by acylation with either acetyl chloride or acetic anhydride... 

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. 

Elimination of the hydroxyaminomethyl moiety from nitro oxime 15 by treatment with a diazonium salt gave hydrazone 43 (75LA1029) (Scheme 15). The same product was obtained by coupling the diazonium salt with the compound 16. On heating in aniline, oxime 15 was transformed into Schiff base 42. Acylation of the oxime 15 with benzoyl chloride in pyridine led to a mixture of furazan 44 and dinitrile 45. 

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. 

Nucleophilic aromatic substitution of the anion from ary lace ton itrile 113 on the dichloroni-trobenzene 114 results in replacement of the para halogen and formation of 115. Reduction of the nitro group gives the corresponding aniline (116). Acylation of the amine with 3,5-diiodoacetylsa-licylic acid 117 by means of the mixed anhydride formed by use of ethyl chloroformate, gives, after alkaline hydroly.sis, the anthelmintic agent closantel (118) [28]. 

The large scale preparation of the drug candidate 2 was accomplished via the Sugasawa reaction (an ortho-selective Friedel-Craft acylation on anilines) and the asymmetric addition to ketimines. Understanding the reaction mechanism and reaction parameters is the only way to gain confidence that the reactions will perform as required upon scale up. Below we discuss both subjects in detail. 

Treated with trifluoroacetic anhydride, sulfoxides 218 undergo conversion to triazapentalenes 219 with high yields. The process must involve acylation of the sulfoxide oxygen atom and generation of a carbocation that attacks the N-2 atom of benzotriazole. Hydrogenation over Raney nickel cleaves the C-S and one of the N-N bonds to generate >rtfe -substituted anilines 220 (Scheme 27) <2002EJ0493>. 

Aniline is very easily sulphonated, for example, by heating its sulphate ( baking process). This change recalls that of aniline acetate into acetanilide. Actually, it is very probable that an analogous product acylated at the amino-group, a sulphaminic acid, is first formed, since examples of this type of change are known, e.g. the conversion of phenylhydroxylamine to p-aminophenol and of phenylnitramine to... 

A kinetic smdy of the acylation of ethylenediamine with benzoyl chloride (110) in water-dioxane mixtures at pH 5-7 showed that the reaction involves mainly benzoylation of the monoprotonated form of ethylenediamine. Stopped-flow FT-IR spectroscopy has been used to study the amine-catalysed reactions of benzoyl chloride (110) with either butanol or phenol in dichloromethane at 0 °C. A large isotope effect was observed for butanol versus butanol-O-d, which is consistent with a general-base-catalysed mechanism. An overall reaction order of three and a negligible isotope effect for phenol versus phenol- /6 were observed and are consistent with either a base- or nucleophilic-catalysed mechanism. Mechanistic studies of the aminolysis of substituted phenylacetyl chlorides (111) in acetonitrile at —15 °C have revealed that reactions with anilines point to an associative iSN2 pathway. ... 

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