Esters acyl chlorides conversion into

Carboxylic acids with strongly electron-withdrawing groups, for example trifluoro-acetic or 2,4,6-trinitrobenzoic acid [22], are readily converted into esters or amides. The products can, however, be unusually sensitive toward attack by nucleophiles and can readily undergo hydrolysis, transesterification, or transamidation. 2,4,6-Tris(trifluoromethyl)benzoic acid has been reported to undergo conversion into the acyl chloride or esters only with difficulty [23]. 

The formation of the acyl chloride with SOCl2 and the conversion of the a-bromoacyl chloride into the bromoester with MeOH are simple nucleophilic substitutions at the carbonyl group, just like the synthesis of esters from acyl chlorides in Chapter 12. The intermediate stage, the bromination of the very easily enolized acyl chloride, is a typical enol bromination. 

In addition to those described, there are many other methods for purifying organic compounds. Examples which might be irientioned are sublimation, chromatography, and conversion into more crystal-lizable derivatives, such as amines into their acetyl, benzoyl, or other acyl derivatives, or acids into their chlorides, amides, esters, etc. These are the methods which are generally used in research laboratories. Although they are used also in industrial laboratories, and the technical chemist should be familiar with them, it is beyond the scope of this book to treat them in detail. 

Cyanuric chloride has been used for the preparation of acyl chlorides, amides, and peptides. Conversion of cyanuric chloride into 2-chloro-4,6-dimethoxy-l,3,5-triazine (CDMT, 6) leads to a reagent that upon reaction with carboxylic acids produces the highly reactive 2-acyloxy-4,6-dimethoxy-l,3,5-triazines.P l The resulting active ester is a powerful acylating agent for alcohols and amines. The activation is performed in presence of a base, preferentially NMM, which leads to intermediate formation of 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM, 7)P l (Scheme 5). This addition product is readily prepared from the commercially available CDMT (6) and NMM in THF and can be stored as solid compound in the cold.P P l It offers the advantage that it can be used in a one-... 

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. 

In the conversion of an acyl chloride into an ester, the nucleophilic alcohol attacks the carbonyl carbon of the acyl chloride. Because the protonated ether group is a strong acid (Section 1.17), the tetrahedral intermediate loses a proton. Chloride ion is expelled from the deprotonated tetrahedral intermediate because chloride ion is a weaker base than the alkoxide ion. 

All the reactions follow the general mechanism described in Section 17.7. For example, compare the following mechanism for conversion of an acid anhydride into an ester with the mechanism for conversion of an acyl chloride into an ester presented on p. 687. 

Later, Venkataraman and Wagle <1979TL3037> reported the use of TCT as a useful reagent for the conversion of carboxylic acids into chlorides, esters, amides, and peptides the authors proposed the formation of the acyl chloride as shown in Scheme 44. 

In contrast to the reaction of pristinamycin 11 with acid anhydrides, where acylation was only observed with acetic anhydride, the reaction of pristinamycin IIa with acid chlorides (Scheme 10) was demonstrated to be of greater synthetic utility. However, the course of acylation depended strongly on the reactivity of the acid chloride. For example, the reaction of pristinamycin 11 with ethyl malonyl chloride in the presence of triethylamine or pyridine resulted in a quantitative conversion by tic into the ester (50, R = CH2C02Et, 60% isolated yield) whereas the use of more reactive acyl chlorides, for example ethyl chloroformate resulted in acylation of the 37-ketone function as its enol ether (see Sect. 5.4.2). If the acylation reagents were used in excess, a diacylated derivative pf the enol form of pristinamycin 11 (51) was obtained. 

The reaction of carboxylic acid esters with a mixture of chlorosulfonic acid and phthaloyl chloride affords a useful one-step procedure for the conversion of esters directly into the acyl chlorides. For instance, heating an equimolar mixture of chlorofluoroacetate 99, phthaloyl chloride 100 and chlorosulfonic acid afforded chlorofluoroacetyl chloride 101 (88% yield) (Equation 41). ... 

Give reagents and reaction conditions that would allow efficient conversion of 2-methylbutanoic acid into (a) the corresponding acyl chloride (b) the corresponding methyl ester (c) the corresponding ester with 2-butanol (d) the anhydride (e) the Af-methylamide ... 

A key intermediate of the esterification in Figure 9.16 is the iminium ion F. It is identical to the iminium ion B in Figure 6.11, which represents the activated carboxylic acid in the DMF-catalyzed conversion of carboxylic acids into acid chlorides. Thus, the iminium ion F in Figure 9.16 is a potent acylating agent. As such, it reacts with the methoxide ion, a stoichiometric by-product of its formation reaction, via the tetrahedral intermediate C to furnish the corresponding carboxylic acid methyl ester and DMF. 

The Leukart reaction has also been used in the conversion of dehydroepiandro-sterone into 17/3-formylamino-3/3-formyloxyandrost-5-ene, which on reduction with lithium aluminium hydride afforded 3/3-hydroxy-17/3-me thylaminoandrost-5-ene. Acylation with isocaproyl chloride then furnished the N-methyl-N-isocaproyl steroid (197), after selective ester hydrolysis of the initially formed ON-diacyl derivative. The amide (197) was further converted into its 3,5-cyclo-6-ketone via the 3,5-cyclo-6/3-alcohol and thence by reaction with hydrogen bromide into the corresponding 3/3-bromo-5a-6-ketone which upon dehydrobromination furnished a A2-5a-6-ketone and ultimately the 2-monoacetate of the 2/3,3/3-diol (198) after reaction with silver acetate and iodine. Hydrolysis to the 2/3,3/3-diol (198) gave a separable mixture of the 2/3,3/8-dihydroxy-5a- and -5/3-ketones.88... 

At oxidation level 3, acid chlorides occupy a key position, since they may serve as a nearly universal substrate for an isohypsic transformation into any kind of carboxylic acid derivative. Acid halides are electrophiles that are synthetically equivalent to acyl cations (RCO ). In this capacity they are used for the synthesis of such important compounds as esters, amides (and hence, nitriles), thioesters, etc. (see Scheme 2.57), and for the formation of C-C bonds in the Friedel-Crafts reaction (see above). Acid chlorides may readily lose HCl upon treatment with triethylamine. This isohypsic conversion leads to ketenes, important reagents widely employed in [2 + 2] cycloadditions, as we will see later. 

A characteristic reaction of carboxylic acid derivatives is nucleophilic acyl substitution. In this reaction a negative or neutral nucleophile replaces a leaving group to form a substitution product. The leaving groups and nucleophiles are the groups that define the various acid derivatives as a result, the reaction usually involves the conversion of one acid derivative into another. The order of reactivity of acid derivatives is acid chloride > anhydride > acid or ester > amide. In general, reaction of any of these derivatives with water produces acids with alcohols, esters result and with amines, amides are formed. 

The formation of the A-oxide was avoided when trifluoroperacetic acid was reacted with the trifluoroacetate of acetyltropenol (67a, b). Recently it has been shown that hydrogen peroxide in formic acid gave a still better yield of epoxides without detectable A-oxides (67b). Acetylscopine (LXV) has been isolated as the picrate, (m.p. 212°) (67a), identical with the sample obtained from scopine (XLa) (75) hydrochloride by acetyl chloride (67a). The conversion of acetylscopine into ( ) scopolamine (LXV->XLb) has been realized (67b). Hydrolysis with A NaOH in acetone led to scopine (XLa), the hydrochloride of which was acylated, in turn, with acetyltropoyl chloride in nitrobenzene to acetylscopolamine besides a number of by-products. Separation was achieved using cellulose powder chromatography in butanol-A HCl. Acid hydrolysis of this ester with 2A HCl led to ( ) scopolamine hydrochloride (XLb) (67b) identical with the natural... 

Several procedures required for the preparation of porphyrins with labile side chains have already been referred to above or in the earlier article, for example, the conversion of acetoxyethyl or aminoethyl groups (introduced at the pyrrole stage) into vinyl groups. The preparation of porphyrin 3-keto esters has now been improved by the use of imidazolides (rather than acid chlorides) in condensations with magnesium methyl hydrogen malonate. The porphyrin acyl imidazolides have also been converted into acrylic esters by the sequence porCo-imidazole - -CH2OH — CHO - CH = CHC02Me. Alternatively the porphyrin ketoesters may be reduced with borohydride to hydroxyesters and dehydrated to acrylic esters. ... 

Activation of Carboxylic Acids Synthesis of Acyl Imidazoles. iV,AA-Carbonyldiimidazole (1) converts carboxylic acids into the corresponding acylimidazoles (2) (eq 1). The method can be applied to a wide range of aliphatic, aromatic, and heterocyclic carboxylic acids, including some examples (such as formic acid and vitamin A acid) where acid chloride formation is difficult. The reactivity of (2) is similar to that of acid chlorides, but the former have the advantage that they are generally crystalline and easily handled. Isolation of (2) is sirr5>le, but often unnecessary further reaction with nucleophiles is usually performed in the same reaction vessel. Conversion of (2) into acid chlorides (via reaction with HCl), hydrazides, hydroxamic acids, and peroxy esters have all been described. Preparation of the more irr5)ortant carboxylic acid derivatives is described below. 

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