Ester synthesis heating with alcohol

The second step, nucleophilic attack of an alcohol or phenol on the activated carboxylic acid RCOIm (carboxylic acid imidazolide), is usually slow (several hours), but it can be accelerated by heating[7] or by adding a base[8] [9] such as NaH, NaNH2, imidazole sodium (ImNa), NaOR, triethylamine, diazabicyclononene (DBN), diazabicycloimdecene (DBU), or /7-dimethylaminopyridine to the reaction mixture (see Tables 3—1 and 3—2). This causes the alcohol to become more nucleophilic. Sodium alcoholate applied in catalytic amounts accelerates the ester synthesis to such an extent that even at room temperature esterification is complete after a short time, usually within a few minutes.[7H9] This catalysis is a result of the fact that alcoholate reacts with the imidazolide very rapidly, forming the ester and imidazole sodium. 

Imidazolides of aromatic sulfonic acids react much more slowly in alcoholysis reactions than the carboxylic acid imidazolides. Although the reaction with phenols is quantitative when a melt is heated to 100 °C for several hours, with alcohols under these conditions only very slight alcoholysis is observed. In the presence of 0.05 equivalents (catalytic amount) of sodium ethoxide, imidazole sodium, of NaNH2, however, imidazolides of sulfonic acids react with alcohols almost quantitatively and exothermically at room temperature in a very short time to form sulfonic acid esters (sulfonates). (If the ratio of sulfonic acid imidazolide to alcoholate is 1 2, ethers are formed see Chapter 17). The mechanism of catalysis by base corresponds to that operative in the synthesis of carboxylic esters by the imidazolide method. Because of the more pronounced nucleophilic character of alkoxide ions, sulfonates can also be prepared in good yield by alcoholysis of their imidazolides in the presence of hydroxide ions i.e., with alcoholic sodium hydroxide. 45 Examples of syntheses of sulfonates are presented below. 

Although the ability of microwaves (MW) to heat water and other polar materials has been known for half a century or more, it was not until 1986 that two groups of researchers independently reported the application of MW heating to organic synthesis. Gedye et al. [1] found that several organic reactions in polar solvents could be performed rapidly and conveniently in closed Teflon vessels in a domestic MW oven. These reactions included the hydrolysis of amides and esters to carboxylic acids, esterification of carboxylic acids with alcohols, oxidation of alkyl benzenes to aromatic carboxylic acids and the conversion of alkyl halides to ethers. 

An ester is formed when a nitrile is heated with an alcohol in the presence of concentrated sulphuric acid, thus providing a two-step synthesis of an ester from an alkyl halide. Examples are to be found in Expt 5.152. The reaction proceeds by way of an intermediate imino-ester (7) which is not usually isolated, but may be if so required.163... 

To complete the total synthesis of the optically active form of veatchine, the successful resolution of the synthetic racemic ketone 244 was accomplished. Compound 244 was reduced stereoselectively with sodium boro-hydride to give the alcohol 248. The latter was heated with succinic anhydride and pyridine in xylene to yield the racemic half-ester 249. Treatment of 249 with brucine afforded the diastereoisomeric brucine salts, which were separated by fractional crystallization. The separated salts were decomposed... 

Esters can also be made in satisfactory yields by heating an alcohol with the ammonium salt of an acid under conditions permitting removal of both ammonia and water from the reaction mixture. The method is general and is especially recommended where acid conditions are deleterious to the reactants. An example is the synthesis of 2-ethylhexyl glycolate (20) (Reaction XIII). 

The above directions are based upon the methods of Hoogewerff and Van Doip, as modified by Holm and by Hale and Honan. -Alanine has also been prepared by the action of h3q)obromite upon succinimide and hydrolysis of the resulting /3-ureidopropionic acid by the action of ammonia upon /3-iodo-propionic acid by the hydrolysis of methyl carbomethoxy-/8-aminopropionate, obtained by the action of sodiiun methoxide on succinbromimide by the reduction of 3-nitrosopropionic acid by heating ethyl acrylate with alcoholic ammonia from succinyl-glycine ester by the azide synthesis and by the action of liquid ammonia upon methyl acrylate. ... 

Johnson, Faulkner, et al.B have developed another approach to synthesis of polyisoprenoids which also utilizes the Claisen rearrangement to establish trans-trisubstituted double bonds. In a model experiment, the allylic alcohol (5) was heated with 7 equivalents of triethyl orthoacetate and 0.06 equivalent of propionic acid at 138° for 1 hour with provision for distillative removal of ethanol the diene ester (6) was obtained in 92% yield. Analysis by vpc indicated that (6) is the trans isomer to the extent of > 98% with less than 2% of the cis isomer. If the classical... 

On the other hand, the esters of the polypeptides are of the greatest importance and they are prepared by the action of alcoholic hydrochloric acid. Hydrolysis of the polypeptide does not occur if prolonged heating be avoided, nor does hydrolysis occur when the esters are saponified by dilute cold caustic alkali. The esters have served in particular for the further synthesis of polypeptides and for the isolation of dipeptides from mixtures on treatment with alcoholic ammonia, the dipeptide esters are converted into their diketopiperazines. They are not soluble in petroleum ether and they are soluble with difficulty in ether, and they thus differ from amino acid esters. Chloroform dissolves them, and in this solvent their combination with acid chlorides has been generally effected. 

The synthesis began with the formation of allylic alcohols 28 and 29 from the chiral starting material (+)-pulegone in 58and 42% yields, respectively. These intermediate alcohols were then treated with 5-isovaleryl-Meldrum s acid to give the desired fS-keto esters 30 and 31 (Scheme 8.16). After heating at 220 °C for 2h,... 

W. S. Johnson and coworkers developed this protocol in the course of endeavours towards the synthesis of all /ra 5 -squalene. Upon heating with ethyl orthoacetate, the bis-allylic alcohol 342 yielded di-ester 343 to accomplish a double homologation strategy. Johnson recognized the potential of this [3,3]-sigmatropic rearrangement since the operation simultaneously produced two -trisubstituted alkenes as a single diastereomer. Further elaboration of intermediate 343 resulted all ( )-squalene. 

The Weinstock variant of the Curtius rearrangement has also foimd application in amino acid synthesis. For example, a route toward y amino acids employed a chiral auxiliary to prepare alkylated succinic acid monoester 64 in enantiomerically enriched form. Under the Weinstock conditions, smooth rearrangement to the isocyanate occurred, and, without isolation, this was heated with tert-butyl alcohol, providing the Boc-protected y5-amino ester 65. ... 

---