Anilines acylation

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. 

It can be seen from the results referred to and also from the earlier data of Holleman and his co-workers [53] that aniline acylation has a decisive influence on the orientation of the nitro group. 

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. 

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). 

These Br nsted-type plots often seem to be scatter diagrams until the points are collated into groups related by specific structural features. Thus, p-nitrophenyl acetate gives four separate, but parallel, lines for reactions with pyridines, anilines, imidazoles, and oxygen nucleophiles.Figure 7-4 shows such a plot for the reaction of trans-cmmm c anhydride with primary and secondary aliphatic amines to give substituted cinnamamides.All of the primary amines without substituents on the a carbon (R-CHi-NHi) fall on a line of slope 0.62 cyclopentylamine also lies on this line. If this line is characteristic of normal behavior, most of the deviations become qualitatively explicable. The line drawn through the secondary amines (slope 1.98) connects amines with the structure R-CHi-NH-CHi-R. The different steric requirements in the acylation reaction and in the model process... 

HOBt, aniline, DMF. These conditions give the amine as the HOBt salt, which may be acylated without the addition of a tertiary amine. 

Hydroquinazolines have been prepared by fusing o-acyl (and formyl) anilines with urea, and the parent substance has also been prepared by fusing potassium isatinate with urea or urethane followed by decarboxylation. ... 

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. 

Arenediazonium ions are relatively weak electrophiles, and therefore react only with electron-rich aromatic substrates like aryl amines and phenols. Aromatic compounds like anisole, mesitylene, acylated anilines or phenolic esters are ordinarily not reactive enough to be suitable substrates however they may be coupled... 

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

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. 

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. 

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