Unsymmetrical ureas

When the side chain involves an unsymmetrical urea moiety, muscle relaxant activity is often seen. One such agent, 1 id-amidi ne ( ) exerts its activity as an anti peristaltic agent. Its synthesis involves the straightforward reaction of 2,6-di-... 

Recently, Raju et al.6 reported an attractive method for the preparation of unsymmetrical ureas on solid-phase resins, employing nitrophenylcarbamates as the key intermediates. They used this method to synthesize ureas derived from simple amines. Here, we report that unsymmetrical ureas can be formed in high yield and purity using MicroTubes as the solid supports. 

The criteria for an efficient work-up are understandably different for discovery processes and cost-effective large-scale processes. The procedure in Scheme 2.8 provides an efficient, practical route to unsymmetrical ureas (e.g., 30). Volatilizing the acetone byproduct drives the reaction to completion and minimizes the formation of the S5mmetri-cal urea b)q)roducts (Gallou et al., 2005). Simply evaporating the free V-methyl p5rroli-dine and solvent afforded the products, with purities acceptable for assembling libraries of compounds. 

Other unsymmetrical ureas are obtained by starting with a dialkylamine and a primary aromatic amine to give 1,1-dialkyl-3-arylureas (Eqs. 42-46) as shown in Table VII. 

General Procedure for Preparation of Symmetrical and Unsymmetrical Ureas by the Oxidative Carbamoylation Method [79]... 

A similar procedure using 4-phenylsemicarbazide hydrochloride with 2 moles of iodine and 6 moles of the amine (or 1 mole of the amine and 5 moles of triethylamine) gave 90 % yields of unsymmetrical ureas [78] (Eq. 56). 

How an unsymmetrical urea can be prepared from a primary amine with a (diethyl-amino )propyl substituent (A) and ethyl isocyanate is illustrated using the example of compound C. This urea is the starting material for preparing a carbodiimide (see Figure 8.9), which activates carboxylic acids towards heteroatom nucleophiles. 

Paio A, Crespo RF, Seneci P, Ciraco M, Solid-supported benzotriazoles. 2. Synthetic auxiliaries and traceless linkers for the combinatorial synthesis of unsymmetrical ureas, J. Comb. Chem., 3 354-359, 2001. 

The bis(ureido)silanes, Va-Vh, are white, solid or tacky compounds. These monomers are very reactive toward nucleophilic agents, which readily attack the Si-N bond hence, these compounds are very reactive to traces of water to form the corresponding unsymmetrical urea, as shown in equation 4. 

Therefore, 1-chloroalkyl carbonates have been proposed as new acylating agents and thus are valuable precursors to carbamates, thiocarbamates and unsymmetrical ureas as outlined in section 3-3, this volume. 

Recently, this linker has been used for the preparation of arrays of 2 -ami-do-2 -deoxyadenosine derivatives [184] and unsymmetrical ureas [185]. The method has also been applied to the improvement of an anti-trypanosomal lead compound based on a 2 -amido-2 -deoxyadenosine core ]186]. 

It is interesting that in this and in the following selenazoline preparations, starting with unsymmetrical ureas, only one of the two possible isomeric products is produced. Thus, Bulka describes the reaction of monosubstituted or unsymmetrically 1,3-disubstituted selenoureas with a-haloesters to provide only the 2-arylimino derivatives of 4-oxoselenazolidine (72) and 2-benzoylimino-3-aryl-4-oxoselenazolidine (73), respectively, (Scheme 7). 

This relatively simple compound 231 requires the 4-C1 picolinic acid chloride 227 easily made in high yield by the S0C12 reaction described earlier. This has the advantage of simultaneously turning the acid into the acid chloride. Formation of the amide 228 and then the diaryl ether is followed by coupling with an isocyanate 230 to make the unsymmetrical urea 231. This large scale synthesis is planned for manufacture.33... 

For instance, methyl isocyanate can be prepared629 by treating diphenylamine with phosgene, which gives diphenylcarbamoyl chloride this can be converted by methylamine into the unsymmetrical urea derivative this 3-methyl-l,l-diphenylurea (226 g), when heated at 240-290°, affords methyl isocyanate (57 g, 100%), b.p. 38-40°, and the distillation residue consists of diphenylamine. 

Ureas. Carbamates are converted to isocyanates by H Sil,. On exposing the isocyanates to amines, unsymmetrical ureas result. 

Ureas. Nitroarenes undergo reductive carbonylation and the in situ trapping with unhindered secondary amines leads to unsymmetrical ureas. 

Ureas. The carbamates RNHCOOCH2CF3 are obtained by an electrochemieal reaction of primary amides (RCONH2) in CF3CH2OH. They undergo aminolysis to afford unsymmetrical ureas. 

Isocyanates and ureas. In the presence of DMAP as a catalyst, amines form isocyanates at room temperamre. On prolonged reaction, ureas are obtained. Unsymmetrical ureas can be synthesized by adding a second amine to the reaction mixture after 10-20 minutes at room temperature." ... 

Ureas. Aminolysis in methanol provides either symmetrical or unsymmetrical ureas in 55-92% yields (9 examples) and 40-65% yields (4 examples), respectively. 

The crude product obtained was purified by column chromatography over silica gel with 1 1 ethyl acetate-hexane as the eluant to secure the final compound (229) in 55% yield. Careful isolahon and characterization showed that one of the major by-products of this reaction to be the bisurea derivative (259) in yields of up to 20%. We explored phe-nylchloroformate as a substitute to triphosgene in the preparation of unsymmetrical urea derivatives. Phenylchloroformate (260) in the presence of an appropriate base on reaction with an amine (241) gave the corresponding carbamate, which on further reaction with A-methyl hydroxylamine gave a urea derivative (229). However, the formation of bisurea... 

A persistent theme in MDPU, DNPU and PNPU crystal structures is the absence of the urea tape network but recurrence of the intramolecular C-H- - -Ourea synthon (Figure 5.18). A slight activation of the proximal C-H donor by an electron-withdrawing group is necessary. The C-H- - -O interaction occurs on the pyridyl side but not the phenyl side in unsymmetrical urea [23]. Similarly, the N02-Ph moiety is co-planar with the urea group but the X-Ph side adopts different conformations in PNPU structures [27]. The recurrence of the intramolecular C-H- - -Ourea interaction was also noted by Steed and co-workers [28] in closely related pyridyl urea systems (Figure 5.19). 

The arylation of urea and its derivatives is a challenging task, as the coordination of the substrate or the product can deactivate the catalyst. Nevertheless, a general method for the synthesis of unsymmetrical urea derivatives via Pd-catalyzed C-N single-bond formation was developed by Kotecki et al. [127]. A bipyrazole-derived electron-rich monodentate phosphine 61 was employed in the arylation of N-phenyl- and N-cyclohexyl-substituted urea with aryl bromides and chlorides (Scheme 13.81). 

The reaction proceeded under mild conditions employing K3PO4 as the base in DME at 85 °C. The unsymmetrical urea derivatives were isolated in excellent yields. However, mostly para-substituted aryl halides were successfully coupled. 

Buchwald et al. expanded this methodology to access unsymmettically substituted urea derivatives with a broad substrate scope. The approach rehes on the sequential amidation of benzyl-protected urea. Functionalized unsymmetrical urea derivatives were obtained exercising an arylation/deprotection/arylation strategy. The potential of this strategy was confirmed by the short synthesis of two complex pharmaceutical target molecules (Scheme 13.82) [128]. 

The HR of A -protected glutamic acid esters 206 proceeds smoothly under electrochemical conditions to afford carbamates 207. The use of the cosolvent trifluoroethanol prevents formation of the cyclized glutarimide, which is a major byproduct (or only product) with conventional (basic) conditions using bromine and sodium methoxide or by running the electrochemistry in methanol. The several trifluoroethyl carbamates (e.g., 203) that were prepared in these electrochemical HR studies react with primary and secondary amines in the presence of sodium hydride to form unsymmetrical ureas. ... 

Bis(4-nitrophenyl) carbonate 717, a very stable reagent, can be converted into carbamates 718 by reaction with equimolecular amounts of primary aliphatic or aromatic amines within 2 h in dichloromethane [503]. Intermediates 718 react further with different primary amines to give the unsymmetrical ureas 719 in good yields. 

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