Isoureas ureas

This compound is called isourea. Urea has a carbon-oxygen double bond and is more stable. 

DCC is a waxy solid that is often difficult to remove from a bottle. Its vapors are extremely hazardous to inhalation and to the eyes. It should always be handled in a fume hood. The isourea by-product of a DCC-initiated reaction, dicyclohexyl urea (DCU) (Figure 3.5), is also water-insoluble and must be removed by organic solvent washing. For synthesis of peptides or affinity supports on insoluble matrices this is not a problem, because washing of the support material can be done without disturbing the conjugate coupled to the support. For solution phase chemistry, however, reaction products must be removed by solvent washings, precipitations, or recrystallizations. 

Ester formation by dimethylsulfate or diazomethane is not satisfactory because the microgels become insoluble when the reaction proceeds to higher conversions. With diazomethane part of the unsaturated groups is involved in a side reaction of a 1,3-dipolar cycloaddition [132]. A more efficient method for ester formation of microgels is the reaction with 0-alkyl-N,N -bisisopropyl isoureas of the alcohols. The alkyl ureas are easily separated from solutions in methanol [294-296]. The esterified microgels were isolated by precipitation and freeze-drying. Depending on the alcohol used for ester formation, the yields of... 

In an extension beyond hetaryl onium salt promoted hemiacetal activation, Ishido and coworkers have reported the carbodiimide activation of hemiacetals [141]. In the method (Scheme 3.13), the hemiacetal donor 1 is treated with a carbodiimide electrophile 83 and copper(I) chloride to provide glycosyl isourea intermediate 85. Highly susceptible to hydrolysis, the isourea 85 was not isolated but could be detected by 13C NMR and IR spectroscopy [142,143], Accordingly, the reaction between intermediate 85 and the glycosyl acceptor (NuH) provides glycoside product 3, along with urea by-product 84. 

In the final step, isourea is released from the guanidinium group of the arginine by hydrolysis (not shown), and is immediately rearranged into urea. In addition, ornithine is regenerated and returns via the ornithine transporter into the mitochondria, where it becomes available for the cycle once again. 

Isourea (less stable) Urea (more stable)... 

Poor nucleophiles react with acyl isoureas B so slowly that the latter start to decompose. In some sense they acylate themselves. The N atom designated with the positional number 3 intramolecularly substitutes the O-bound leaving group that is attached to the carboxyl carbon Cl. A four-membered cyclic tetrahedral intermediate is formed. When the Cl -Ol bond in this intermediate opens up, the N-acyl urea E is produced. Because compound E is an amide derivative it is no longer an acylating agent (cf. Section 6.2). 

In its original form the DCC procedure for peptide synthesis has one basic disadvantage, which you have already learned about as side reaction B —> E in Figure 6.15 When acyl isoureas are exposed to a poor nucleophile, they rearrange to form unreactive A-acyl ureas. These mismatched reactivities characterize the situation encountered in the peptide syntheses in Figures 6.31 and 6.32. The example given in Figure 6.31 uses 0,0-di-fert-butylserine as a... 

SYNS CARBAiMIDE CARBAMIDE RESIN CARBAAfiMIDIC ACID CARBONYL DIAMIDE CARBONYLDIAMINE ISOUREA NCI-C02119 PRESPERSION, 75 UREA PSEUDOUREA SUPERCEL 3000 UREAPHIL UREOPHIL UREVERT VARIOFORM II... 

The reaction is more versatile than selenocyanamidation. /i-Bromocyanamide derivatives were converted in situ to the isourea salts, by treatment with elhanolie hydrochloric acid. The iso urea salt, in the presence of a mild base such as triethylamine, gave the corresponding 2-ethoxy-4,5-dihydro-1//-imidazole. Alternatively the use of more basic conditions (sodium ethoxide) leads to ethyl carboximidate formation69,70. 

The low solubility of 2 in alkanes or ethers and its crystallinity allowed us to carry out a crystal structure analysis. Previous H NMR studies [7] of 2 1 adducts between R-NCO molecules and l,4-bis(trialkylsilyl)-l,4-dihydropyrazines have indicated the formation of both urea and isourea ftinctionalities (Scheme 3). 

In contrast to compound 2 with symmetrical insertion, the 2 2 linear adduct 3 exhibits two different unsymmetrical dihydropyrazine rings, including one with both urea and isourea functionalities (Scheme 4). This arrangement is supported by H and NMR data (Table 1) and is in agreement with the results for 2 and previous observations [7], Apparently, the second insertion step at 1 requires greater activation and then proceeds to a different product, i.e., an isourea instead of a silyl-urea arrangement. 

RCO2H, R OH, DCC/DMAP, EtjO, 25°C, l-24h, 70-95% yield. This method is suitable for a large variety of hindered and unhindered acids and alcohols. The use of Sc(OTf)3 as a cocatalyst improves the esterification of 3° alcohols. Carboxylic acids that can form ketenes with DCC react preferentially with aliphatic alcohols in the presence of phenols whereas those that do not show the opposite selectivity. In some sterically congested situations the 0-acyl urea will migrate to an unreactive A-acyl urea in competition with esterification. Carbodi-imide I was developed to make the urea by-product water soluble and thus easily washed out. Isoureas are prepared from a carbodiimide and an alcohol which upon reaction with a carboxylic acid give esters in excellent yield. A polymer supported version of this process has been developed. This process has been reviewed. Note that DCC is a potent skin irritant in some individuals. 

Carbodiimides are traditionally one of the most frequently employed dehydrating reagents for the creation of the ester or amide bond, despite known problems related to difficulties in removing the corresponding generated urea or unreactive acylurea by-products [2]. Therefore, the use of polymer-supported carbodiimides is quite appropriate for the easy elimination of these by-products from the reaction medium by simple filtration, as they will remain anchored to the solid phase. In addition, if an ester or amide formation is intended an excess of acid can be used, as the remainder will also stay anchored as the corresponding isourea. 

Carbodiimide method, a procedure for peptide bond formation using carbodi-imides, R-N=C=N-R, such as dicyclohexyl carbodiimide (DCC), diisopropyl carbodiimide (DIC) and water-soluble carbodi-imides. The carbodiimide reacts in a one-pot procedure with the carboxylate anion of the carboxy component to form a highly reactive O-acylisourea intermediate. The former reacts immediately with the amino function of the amino component to yield the desired peptide derivative and the urea byproduct. Indeed, a more complex mechanism must be taken into consideration. Unwanted side reactions are racemization via the oxazolone mechanism and formation of the unreactive N-acylurea by base-catalyzed acyl migration from the isourea oxygen to nitrogen. The side reactions can be diminished by preparing the O-acylisourea at 0 °C... 

Isourea 70, that shows a great structural resemblance to trehazolin 53, was obtained [87] in an 89% yield by treatment of thiourea 68 with yellow HgO in aqueous dioxane (Scheme 17). The same isourea was previously prepared [84] from protected thiourea 67 by desulfurization using Mukaiyama s reagent [93] in anhydrous acetonitrile to give after debenzylation of 69 a non-resolved mixture of the expected isourea 70 (17%), together with the M,N -bis(j8-D-glucopyranosyl)urea (32%). 

CARBONYLDIAMINE ISOUREA PRESPERSION, 75 UREA PSEUDOUREA SUPERCEL3000 UREAPHIL UREOPHIL UREVERT VARlOFORMll... 

Isotridecyl 3,5,5-trimethylhexanoate Isotridecyl 3,5,5-trimethylhexanoic acid. See Isotridecyl isononanoate Isourea. See Urea... 

As a further consequence of the high reactivity of the excessive 0-acyl isourea in the heterogeneous peptide synthesis mixture, a base-catalyzed intramolecular 0-N-acyl migration takes place, forming the inactive N-acyl dicyclohexylurea. At the same time, this by-product is formed by acylation of already formed still dissolved amounts of dicyclohexylurea, which can be attacked by the symmetric anhydride or the 0-acyl isourea of the carboxylic component as well. Both the N,0-acyl shift and the latter side reaction decrease the total concentration of the activated masked amino acid even N,N -diacyl derivatives of the urea also can be formed as further by-product. Fortunately, all of these acyl urea derivatives are not fixed to the polymer phase and are well soluble in dichloromethane, so that they can be washed out easily from the gel phase after the... 

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