Carboxylic esters, from acyl alcohols

On the pages which follow, general methods are illustrated for the synthesis of a wide variety of classes of organic compounds including acyl isocyanates (from amides and oxalyl chloride p. 16), epoxides (from reductive coupling of aromatic aldehydes by hexamethylphosphorous triamide p. 31), a-fluoro acids (from 1-alkenes p. 37), 0-lactams (from olefins and chlorosulfonyl isocyanate p. 51), 1 y3,5-triketones (from dianions of 1,3-diketones and esters p. 57), sulfinate esters (from disulfides, alcohols, and lead tetraacetate p. 62), carboxylic acids (from carbonylation of alcohols or olefins via carbonium-ion intermediates p. 72), sulfoxides (from sulfides and sodium periodate p. 78), carbazoles... 

The reaction of alcohols with acyl chlorides is analogous to their reaction with p toluenesulfonyl chloride described earlier (Section 8 14 and Table 15 2) In those reactions a p toluene sulfonate ester was formed by displacement of chloride from the sulfonyl group by the oxygen of the alcohol Carboxylic esters arise by displacement of chlonde from a carbonyl group by the alcohol oxygen... 

The chemical diversity of carboxylic acid esters (R-CO-O-R ) originates in both moieties, i.e., the acyl group (R-CO-) and the alkoxy or aryloxy group (-OR7). Thus, the acyl group can be made up of aliphatic or aromatic carboxylic acids, carbamic acids, or carbonic acids, and the -OR7 moiety may be derived from an alcohol, an enol, or a phenol. When a thiol is involved, a thioester R-CO-S-R7 is formed. The model substrates to be discussed in Sect. 7.3 will, thus, be classified according to the chemical nature of the -OR7 (or -SR7) moiety, i.e., the alcohol, phenol, or thiol that is the first product to be released during the hydrolase-catalyzed reaction (see Chapt. 3). Diesters represent substrates of special interest and will be presented separately. 

Esters are produced by acid-catalysed reaction of carboxylic acids with alcohols, known as Fischer esterification. They are also obtained from acid chlorides, acid anhydrides and other esters. The preparation of esters from other esters in the presence of an acid or a base catalyst is called transesterification. All these conversions involve nucleophilic acyl suhstitu-tions (see Section 5.5.5). 

Amides can be obtained from acyl halides, carboxylic anhydrides, or esters with amines or ammonia. The mechanisms of these reactions are very similar to the corresponding reactions of alcohols ... 

Lipase-catalyzed acylation of one isomer of iV-hydroxymethyl /3-lactam 121 by vinyl butyrate in acetone yielded the ester 122, which afforded 123 after acidic hydrolysis and ion-exchange chromatography (Scheme 7). The unesterified alcohol 124 gave the /3-amino acid 125. Similar reactions yielded 2-aminocyclohex-3-en-l-carboxylic acid and 2-aminocyclohex-4-ene-l-carboxylic acid from l-azabicyclo[4.2.0]oct-3-en-8-one and l-azabicyclo[4.2.0]oct-... 

It is rather difficult to convert carboxylic acids to decarboxylative alcohols. However, treatment of O-acyl esters (2) in the presence of Sb(SPh)3 and molecular oxygen, followed by hydrolysis, generates the corresponding decarboxylative alcohols. Eq. 8.11 shows the preparation of a sex pheromone of the citrus mealybug from (+ )-ds-pinonic acid [30-32]. When 1802 instead of 1602, is used in this reaction, 180-alcohols can be obtained. 

The addition of an alcohol to the carbonyl group of a carboxylic acid in the presence of an acid catalyst leads to ester formation (Scheme 2.15a). The acid catalyst increases the electron deficiency of the carbonyl carbon, thus overcoming the electron-donating effect of the hydroxyl group of the acid. This enhancement of the electron deficiency of the carbonyl group of the carboxylic add may be brought about by converting the acid to a derivative such as the anhydride or the acyl chloride. The reaction of these with alcohols leads to esters (Scheme 2.15b). Another method is to carry out the reaction of the alcohol with an acyl chloride or anhydride in the presence of a base such as pyridine, which may facilitate the removal of a proton from the alcohol. 

Esters can also be synthesized by a nucleophilic acyl substitution reaction of a carboxylic acid with an alcohol. Fischer and Speier discovered in 1895 that esters result simply from heating a carboxylic acid in alcohol solution containing a small amount of strong acid catalyst. Yields are good in this Fischer esterification reaction, but the need to use excess alcohol as solvent limits the method to the synthesis of methyl, ethyl, and propyl esters. 

Keto esters and amides are versatile intermediates in organic synthesis and often are prepared from acyl Meldrum s acid adducts. This method involves formation of acyl Meldrum s adducts by reaction of Meldrum s acid with activated carboxylic acids followed by decarboxylation in the presence of nucleophiles such as alcohols or amines (Scheme 21.2). The ability of readily available acyl Meldrum s acids to react with various nucleophiles allows quick access to a variety of functionalized compounds. Apphcation of this methodology in synthetic chemistry has been widely exploited. For example, acyl Meldrum s adducts can react with imines to prepare pyridinones or... 

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