N-Acylureas

A potential undesirable effect of DCC coupling reactions is the spontaneous rearrangement of the o-acylisourea to an inactive N-acylurea (Stewart and Young, 1984) (Figure 3.6). The rate of this rearrangement is dramatically increased in aprotic organic solvents, such as DMF. 

HYDROXYBENZOTRIAZOLE AS AN ADDITIVE THAT SUPPRESSES N-ACYLUREA FORMATION BY PROTONATION OF THE O-ACYLISOUREA... 

FIGURE 2.12 1-Hydroxybenzotriazole as an additive that suppresses N-acylurea formation by protonation of the O-acylisourea (see review by Rich and Singh4). 

Alkyl hypochlorites and N-halo amides add to isocyanides to give, after hydrolysis, carbamates and N-acylureas (ureides), respectively.806... 

Diisopropyl carbodiimide (DIC) is another water-insoluble amide bond-forming agent that has advantages over DCC (Chapter 3, Section 1.4). It is a liquid at room temperature and is therefore much easier to dispense than DCC. Its by-products, diisopropylurea and diisopropyl-N-acylurea, are more soluble in organic solvents than... 

The N-benzylation of N-phenylureas in liquid ammonia does not proceed smoothly and requires the formation of a dianion (Scheme 6.27). Only N,N -diphe-nylurea can be benzylated under these conditions N-phcnylurca or N-acylureas, on the other hand, remain unchanged [114], Attempts to alkylate ureas with alkyl halides in DM SO at room temperature using solid KOH as base yielded only small amounts of N-alkylated ureas [115]. 

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. 

Utilization of this polymer in peptide synthesis afforded only 60 % peptide, the remainder being the N-acylurea. However, the polymer is useful in the Moffat oxidation (see Section 2.4.3). ... 

With some hydroxycarboxylic acids lactone formation is observed in the reaction with carbodiimides.Sometimes N-acylureas are formed as byproducts. For example, in the reaction of -hydroxycarboxylic acids 468 with DCC, y-butyrolactones 469 are produced." ... 

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." ... 

It was shown by radiochemical methods that O- and N-acylureas can form simultaneously. Spectroscopic and kinetic evidence for the formation of O-acylureas in the reaction of N-ethyl-N -(3 -trimethylammonio)propylcarbodiimide perchlorate with acetate buffers was obtained. ... 

The rate of reaction of DCC with aliphatic acids in THF depends on the acid strength, i.e., chloroacetic acid reacts considerably faster than acetic acid." It was also found that the higher the acid strength, the higher the yields of anhydride and urea. The reaction exhibits first order kinetics both in acid and in carbodiimide, and the rate determining step is the formation of the O-acylurea." Solvent effects are also observed in the reaction of DCC with acetic acid. The reaction rates are highest in THF, and the proportion of N-acylurea is also the greatest in THF." ... 

The reaction of allenic acid 500 with carbodiimides affords tricycloundecatrienones 502. The reaction proceeds through (he initially formed linear N-acylurea derivative 501." ... 

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 ... 

The reagent (1) reacts with secondary amides (16) in refluxing chloroform to give chlorotbrmamidinium salts (17) in high yield (85-95%). These salts can be hydrolyzed first to N-(l-chloroalkenyl)ureas (18) and then to N-acylureas (19). Dehydrochlorination of (18) with potassium t-butoxidc gives the hitherto unknown ethynylureas (20). 

Best results are obtained when the reaction is run in CH2CI2 or CHCI3 THF and DMF may be used, but are reported to reduce reaction rates, to enhance formation of the N-acylurea byproduct and to increase the rate of epimerization. In CH2CI2 the resulting N,N -dicyclohexylurea (DCU) is almost insoluble and can be removed by filtration, although minor amounts may still remain in solution and have to be separated by crystallization or chromatography. Reactions should preferably be carried out at lower temperatures and if possible, in the absence of tertiary bases. In most cases the exclusion of water is not necessary as hydrolysis of the intermediate O-acyhsourea is very slow. 

Peptide synthesis. The addition of this triazole (1-2 equivalents) in the DCC-method of peptide synthesis decreases racemization, prohibits the formation of N-acylurea, and improves the yields of high-purity peptides.2 Several substituted 1-hydroxybenzotriazoles are also effective. 

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-... 

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