Acylureas carboxylic acids

FIGURE 7.1 A carbodiimide reacts with a carboxylic acid (A) to give the O-acylisourea, which may rearrange (B) to the A-acylurea. It also reacts with amino groups (C) to produce guanidines if no carboxyl group is available. 

The esterification of support-bound carboxylic acids has not been investigated as thoroughly as the esterification of support-bound alcohols. Resin-bound activated acid derivatives that are well suited to the preparation of esters include O-acylisoureas (formed from acids and carbodiimides), acyl halides [23,226-228], and mixed anhydrides (Table 13.15). A-Acylurea formation does not compete with esterifications as efficiently as it does with the formation of amides from support-bound acids. Esters can also be prepared from carboxylic acids on insoluble supports by acid-catalyzed esterification [152,229]. Alternatively, support-bound carboxylic acids can be esteri-fied by O-alkylation, either with primary or secondary aliphatic alcohols under Mitsu-nobu conditions or with reactive alkyl halides or sulfonates (Table 13.15). 

Carboxylic acids react under Pfitzner-Moffatt conditions, resulting in the formation of methylthiomethyl esters and /V-acylureas.41 Nevertheless, although the authors are not aware of any report involving the selective oxidation of alcohols in the presence of a carboxylic acid, such outcome would be likely with carboxylic acids with little nucleophilicity, as standard Pfitzner-Moffatt oxidations are performed in the presence of trifluoroacetate that is known for not to interfere. 

With increasing steric hindrance, the rate of esterification is decreased and the formation of N-acylureas may become a serious side reaction. This is indicated by the decrease 1n yield 1n the esterification of 2,5-cyclohexadiene-l-carboxylic acid with different alcohols MeOH (95%), EtOH (84%), i-PrOH (75%), e-CgHjjOH (65%), t-BuOH (65%).Diminished acidity because of the influence of electron-donating substituents 1n aromatic carboxylic acids can also lead to low yields. 

Reaction with Carboxylic and Inorganic Acids. The reaction of carbodiimides with carboxylic acids has dual character because acyl ureas 484 or acid anhydrides 485 are formed. Often mixtures of both products are formed. The product formation depends on the nature of the reagents and the reaction conditions. With aromatic carboxyhc acids mainly N-acylureas are formed, and in the presence of tertiary amines the anhydride formation is inhibited." ... 

Dicarboxylic acids with two or three methylene groups give cyclic anhydrides, while di-carboxylic acids with four or more methylene groups 508 (n = > 4) give bis-N-acylureas 509 ... 

Poly(carbodiimides) are sometimes used as adhesive primers. Film forming carbodiimide homo- or copolymers have been used in microencapsulation techniques for pressure sensitive copy paper. Oligomeric acylureas are obtained from polyunsaturated carboxylic acids and carbodiimides as monomers for coatings. ... 

The inconveniences of DCC, A-acylurea formation, dehydration of Asn and Gin residues, and racemization, can be reduced by performing the acylation step in the presence of a suitable nucleophile which reacts very quickly with the G-acylisourea before side reactions can occur. An acylating agent of lower potency but still sufficiently reactive toward aminolysis and more resistant towards side reactions and racemization is formed. The additive is usually applied in equimolar amount with the two components to be coupled. As a result, there are two moles of nucleophiles, the additive and the amino component, present in the reaction mixture for each mole of carboxylic acid component or carbodiimide. Therefore the lifetime of highly reactive intermediates, such as G-acylisoureas and symmetrical anhydrides is considerably reduced. The concentration of the additive that acts as a second nucleophile increases with respect to the carboxylic component during the coupling reaction, because it is continuously regenerated. The most commonly used additives used in combination with DCC are shown in Scheme 2. 

Alcohols from acids. After formation of 0-acylureas by reaction of carboxylic acids with Af.N -dicyclohexylcarbodiimide, reduction leads to the alcohols. 

A number of protic acids have been used to catalyze acylation reactions. It is assumed that the reactions involve the generation of acylium ions. Polymeric reagents such as Nafion-H have been used for example 2-fluorobenzoyl chloride and toluene give the benzophenone derivatives with an ortho.para ratio of 4 81. ° A zeolite-catalyzed acylation (equation 6) has been reported to afford 4-dodecenoyltol-uene in 96% yield but the yields are low with short chain carboxylic acids. Early examples of the use of trifluoroacetic and perchloric acids reported good yields of products. Some more recent examples are shown in equations (7) to (9). Phosphoric and polyphosphoric acids have been used together with carboxylic acids (equation 10),anhydrides and acylureas (equation 11). °... 

It has been known for some time that carbodi-imides react with carboxylic acids (a) giving acid anhydrides and ureas, or (b) iV -acylureas. Khorana and Todd have been successful in converting dibenzyl hydrogen phosphate into the pyrophosphate by the following reaction with dicyciohexylcarbodi-imide ... 

The most frequently used approaches for derivatizing carboxylic acids are esterification with a variety of single-enantiomer alcohols, or formation of amides with single-enantiomer amines [234,252]. The formation of amide derivatives requires activation of the carboxylic acid by formation of the acid chloride with thionyl chloride, mixed anhydrides with chloroformates, N-acylimidazoles with 1,1 -carbonyldiimidazole or N-acylureas with dicyclohexylcarbodiimide. Esterification reactions generally re-... 

When low dielectric constant solvents are used, the carboxylic acid tends to dimerize, thus promoting symmetrical anhydride formation. This intermediate is stable enough to give good yields of the desired product. High dielectric solvents such as DME retard acylation of amino acids, and Al-acylurea can he a major byproduct. Unfortunately, many starting materials require polar solvents for dissolution. 

Carboxylic acid amides and urethans or carboxylic acid esters from acylureas... 

Acylureas from carboxylic acid chlorides COCl CONHCON <... 

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