Ureas acylureas

The activity of acylureas as hypnotic and anticonvulsant agents is dealt with in some detail later. This is again one of the cases in which the functionality rather than structure determines pharmacologic activity. Thus, acylation of urea with phenylacetyl chloride gives the anticonvulsant agent, phenacemide... 

ZrCU RC(0)NHC(0)NH2 ] (R = Me or Ph).132 IR studies indicate that urea coordinates to zirconium through the carbonyl oxygen atom.131 The acylureas coordinate through both oxygen atoms, giving a chelate structure.132... 

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]. 

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." ... 

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." ... 

Both straight-chain and branched acyl halides successfully acylate urea to the mono- and di-acyl derivatives. Yields of 75 85% of either derivative may be obtained. A review of four additional methods for the preparation of acylureas has been made. ... 

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). 

O-acylisourea species 22 are generated easily by reacting car-bodiimides with a mixture of the desired carboxyUc acid and amine. Then, they undergo aminolysis readily to form the amide and the urea by-product (48). Often, formation of unreactive IV-acylurea 23 by acetyl transfer and racemization are observed (see Fig. 7). This side reaction can be minimized substantially by reacting the acid with the carbodiimides at 0°C before adding the amine or by using DMAP or HOBt 24 as adjuvants (49). 

The difficult separation of the A-acylurea byproduct from the desired coupling product can be partly overcome by utilizing water-soluble carbodiimides such as 2, as not only the resulting urea, but also the A-acylurea are water soluble and thus easy to extract. 

Reactions are carried out at room temperature in dichloromethane which is an excellent swelling agent for polystyrene supports. Dimethylformamide can be added to increase the solubility of some amino acid derivatives e.g. Boc-Arg(N02), Boc-Arg(Tos), Boc-His(Tos), Boc-Trp, and Boc-Asn(Xan), but it increases the rate of undesirable rearrangement of O-acylisourea to A-acylurea which is not reactive.P The principal limitations in using car-bodiimides are racemization, rearrangement of O-acylisourea to A-acylurea 5, and dehydration of Asn and Gin side-chain carboxamide groups. Fortunately this dehydration problem is completely avoided by the use of additives such as A-hydroxysuccinimide (HOSu) and 1,2,3-benzotriazol-l-ol (HOBt). Additives also reduce racemization and A-acyl-urea formation. Other carbodiimides have also been used in SPPS such as or N-tert-... 

Ureas and thioureas react with IA (1 and 24) to form quinazolinediones (172)97,211 In this way the alkaloid glycosmicin (172 R1 = H, R = Me)190,211 was synthesized. Cyanamides and IA yield the 2-aminoquinazolinones 173212 with acylureas the quinazolinones 174 were produced213 216 (Scheme... 

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. 

Owing to their different steric configuration, the absorption of acylureas by plants is different from that of the other urea herbicides, which may partly explain their different selectivity. Presumably, these compounds exert their action after hydrolysis of the acid group. 

A -Acylureas or thioureas such as 167a react with elimination of the urea and formation of malonaldehyde derivatives, isolated as perchlorates (Eq. 138a). A-Acetylurea does not react. 

The diverse emissive characteristics of the triplet states of amide-containing molecules (amides, ureas, oxamides, parabanic acids, acylureas etc.) have been rationalized in terms of the amount of 3mr and 9mr character in the lowest... 

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 ... 

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... 

In the absence of a catalyst such as DMAP only low yields (-20%) of esters were obtained, but.a wide variety of reaction products, mainly substituted ureas, appeared. In the presence of DMAP, esterification was the major reaction (typically -80% in 18h at ambient temperatures) with only one important side reaction of DCC forming the N-acylurea. 

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