Ureas, acylation preparation

The iV-acyl ureas 157, prepared by amidine rearrangement (Section II.B.3), undergo thermal elimination of phenyl isocyanate with formation of the amides 158 (Eq. (24)) (01JCS(P1)680). This approach provides access to amides of unstable 2-aminofurans that cannot be prepared by acylation of the primary amine. 

Reaction of 2-aminothiazoles with alkyl isocyanates yields 2-thiazolylureas (256) (Scheme 153) (479-483). This reaction is general and works with acyl isocyanates (484. 485). These heterocyclic ureas are also prepared by the reaction of H2O on 2-thia2olylcyanamide (486) or by action of HjOj on the corresponding thiourea (303, 481). 

Diethyl malonate has uses other than m the synthesis of carboxylic acids One particu larly valuable application lies m the preparation of barbituric acid by nucleophilic acyl substitution with urea... 

Organic Acids and Their Derivatives (Anhydrides, Nitriles, Ureas). Alkyleneamines react with acids, esters, acid anhydrides or acyl hahdes to form amidoamines and polyamides. Various diamides of EDA are prepared from the appropriate methyl ester or acid at moderate temperatures (25,26). 

Hydroquinazolines have been prepared by fusing o-acyl (and formyl) anilines with urea, and the parent substance has also been prepared by fusing potassium isatinate with urea or urethane followed by decarboxylation. ... 

Carbenes from Diazo Compounds. Decomposition of diazo compounds to form carbenes is a quite general reaction that is applicable to diazomethane and other diazoalkanes, diazoalkenes, and diazo compounds with aryl and acyl substituents. The main restrictions on this method are the limitations on synthesis and limited stability of the diazo compounds. The smaller diazoalkanes are toxic and potentially explosive, and they are usually prepared immediately before use. The most general synthetic routes involve base-catalyzed decomposition of V-nitroso derivatives of amides, ureas, or sulfonamides, as illustrated by several reactions used for the preparation of diazomethane. 

The symmetrical anhydride is prepared using dicyclohexylcarbodiimide in dichloromethane, the urea and solvent are removed, and the anhydride is dissolved in dimethylformamide and added to the peptide-resin (see Section 2.5). The anhydride is a more selective acylating agent than the 0-acylisourea and, thus, gives cleaner reactions than do carbodiimides, but twice as much amino-acid derivative is required, so the method is wasteful. It avoids the acid-catalyzed cyclization of terminal glutaminyl to the pyroglutamate (see Section 6.16) and is particularly effective for acylating secondary amines (see Section 8.15). 

The instability of primary nitramines in acidic solution means that the nitration of the parent amine with nitric acid or its mixtures is not a feasible route to these compounds. The hydrolysis of secondary nitramides is probably the single most important route to primary nitramines. Accordingly, primary nitramines are often prepared by an indirect four step route (1) acylation of a primary amine to an amide, (2) A-nitration to a secondary nitramide, (3) hydrolysis or ammonolysis with aqueous base and (4) subsequent acidification to release the free nitramine (Equation 5.17). Substrates used in these reactions include sulfonamides, carbamates (urethanes), ureas and carboxylic acid amides like acetamides and formamides etc. The nitration of amides and related compounds has been discussed in Section 5.5. 

Several different types of linker have been developed that yield amides upon cleavage. These linkers can often also be used to prepare sulfonamides, carbamates, or ureas. There are essentially three different strategies for the release of amides from insoluble supports (a) cleavage of the benzylic C-N bond of resin-bound N-alkyl-N-benzylamides (backbone amide linkers, BAL linkers), (b) nucleophilic cleavage of resin-bound acylating agents with amines, and (c) acylation/debenzylation of resin-bound /V-benzyl-/V,A -dialkylamines. 

A related series of 5-substituted-2-amino-oxadiazole compounds have also been prepared in a one-pot procedure using a microwave-assisted cyclisation procedure (Scheme 6.26)164. Rapid preparation of the pre-requisite ureas from the mono acyl hydrazines and various isocyanates (or the isothiocyanate) was easily achieved by simple mixing. The resulting products were then cyclo dehydrated by one of the two procedures either by the addition of polymer-supported DMAP and tosyl chloride or alternatively with an immobilised carbodiimide and catalytic sulphonic acid. Purity in most cases was excellent after only filtration through a small plug of silica but an SCX-2 cartridge (sulphonic acid functionalised - catch and release) could be used in the cases where reactions required additional purification. 

The procedure may be adapted for the preparation of other acyl isocyanates (i.e., dichloroacetyl, trichloroacetyl, phenyl-acetyl, diphenylacetyl, benzoyl, etc) and is generally more convenient than the reaction of acid chlorides with silver cyan-ate3 4 Acyl isocyanates react with amines, alcohols, and mer-captans to yield acyl ureas, carbamates, and thiocarbamates. 

Aresta and Quaranta studied the reactivity of alkylammonium N-alkylcarbamates (RNH3)02CNHR towards a different acylating substrate, such as dimethyl carbonate (DMC) [62a, b]. Carbamate salts (RNH3)02CNHR (R = benzyl, allyl, cyclohexyl), prepared in situ from aliphatic primary amines and C02, reacted with DMC to afford N-alkyl methylcarbamates (Equation 6.6). The reaction requires mild conditions (343-363 K 0.1 MPa C02 pressure) and can be carried out in DMC used as solvent and reagent. At 363 K, carbamate esters were obtained in satisfactory yield (45-92%) with high selectivity, as side products such as ureas, N,N-dialkylcarbamate esters, and alkylated amines were formed in very small amounts. 

A preparatively useful approach to the enantiomerically pure antihypertensive agent (R)-SQ 32,926 was disclosed by Atwal et al. (Scheme 4.13) [169]. In the first step, the 1,4-dihydropyrimidine intermediate 38 is acylated at N3 with 4-nitrophenyl chloroformate followed by hydrolysis with HC1 in THF to give DHPM 39. Treatment with (R)-a-methylbenzylamine provided a mixture of diastereomeric ureas from which the (R,R) isomer 40 was separated by crystallization. Cleavage with TFA provided (R)-SQ 32,926 in high enantiomeric purity. Similar strategies have been used to obtain a number of pharmacologically important DHPM derivatives in enantiomerically pure form [169, 186, 187]. 

The rational synthesis of 12c is shown in Scheme 5.17. The starting monoloop di-urea 15 is prepared in the conventional way analogous to Scheme 5.9 by macro-cyclization of the di-Boc derivative with an activated bisurethane under dilution conditions, followed by deprotection and acylation [50]. Although 15 belongs to the... 

Urea A is the starting material for preparing the carbodiimide C, which activates carboxylic acids according to the same mechanism and for the same reason as DCC, with which you are already familiar (Figures 6.15 and 6.26). If the carbodiimide C from Figure 7.5 were not so much more expensive than DCC, everybody would use the former instead of the latter for carboxylic acid activation. There is a practical reason for this. When a heteroatom nucleophile is acylated with the DCC adduct of a carboxylic acid, besides the desired carboxylic acid derivative one obtains dicyclohexyl urea (formula B in Figure 7.5). This (stoichiometric) by-product must be separated from the acylation product, which is relatively laborious when realized by chromatography or by crystallization. When a carboxylic add has been activated with the carbodiimide C and the subsequent acylation of a heteroatom nucleophile has been effected, one also obtains a urea as a stoichiometric by-product. It has the structure D and is therefore... 

The availability of amino-substituted furazans, both by direct synthesis from aminogly-oximes and via Hofmann degradation of the corresponding carboxamides, allows urea, thiourea, imino and acylamido derivatives, for example, to be prepared by reaction with isocyanates, isothiocyanates, aldehydes and acyl halides, respectively (73JPR791, 77JCS(P1)1616). Alkoxy and acyloxy derivatives are likewise formed from hydroxyfurazans (79JHC689). 

Acyl urea derivatives, (I) and (II), prepared by Laborde (3,4), respectively, were effective as MCP-1 antagonists and used in the treatment of chronic or acute inflammatory or autoimmune diseases associated with aberrant lymphocyte or monocyte accumulation such as arthritis, asthma, and atherosclerosis. 

The compound Ar2Bi(0)0Me, which was prepared via the reaction of ArsBi and 4-MeC6H4S02NClNa, has been reported to acylate amides, thioamides, ureas, and thioureas. The first step of the process is believed to be reaction of the Ar2Bi(0)0Me compound with acetic acid to replace the methoxide with acetate. ... 

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