Synthesis of mono-and N , N -disubstituted ureas

Benzotriazole-1-carboxamide is a new efficient reagent for the preparation of mono-and N , N - disubstituted ureas. The title ureas 3 were obtained from benzotriazole-1-carboxamide with primary and secondary aliphatic amines and p -anisidine under mild conditions with simple purification in isolated yields of 61–96%. The procedure developed is suitable for solid-phase work.


Introduction
The urea functionality is a key structural element of many biologically active compounds such as enzyme inhibitors 1 and peptidomimetics. 2 Some compounds containing the urea functionality possess neuroprotective activity, 3 are tachykinin NK 3 selective antagonists, 4,5 show significant activity as neuropeptide Y1-selective receptor antagonist, 6 and have many other applications.
Recently, there have been extensive investigations into synthetic approaches to solidsupported ureas for the preparation of libraries of compounds with potential biological activities. 7However, no reports of solid-phase work have described the preparation of mono-or N,N-disubstituted ureas.
Preparative routes to urea derivatives have been summarized. 8Mono-or N,N-disubstituted ureas have been prepared, (i), by the reaction of unsubstituted urea with alkylamines or their hydrochloride salts, with the loss of ammonia or ammonium halide, to yield the expected substituted ureas, which in some cases may be contaminated with N,N'-disubstituted derivatives; 8,9 (ii), by aminolysis of isonitriles 10 or cyanamides; 11 (iii), by conversion of nitrourea into substituted ureas by the action of amines; 12 (iv), from the reaction of alkali metal cyanates with amines to form ureas; 13 and, (v), by reductive alkylation by which substituents may be introduced into ureas. 8,14The above-mentioned methods usually provide moderate to good yields of the desired products; however, the toxic reagents and relatively harsh conditions required renders them unsuitable, in particular, for solid-phase work.Therefore, practical methods of obtaining urea-containing compounds are of great interest in the lead-optimization process of drug discovery.We now report on benzotriazole-1-carboxamide as a new convenient reagent for the preparation of mono-and N,N-disubstituted ureas.

Results and Discussion
The key compound, benzotriazole-1-carboxylic acid amide 2 was prepared by hydrolysis of 1cyano-benzotriazole 1 with hydrogen peroxide.The 1-cyanobenzotriazole 1 was prepared by a previously published procedure. 15Attempts to hydrolyze 1-cyanobenzotriazole 1 using, (i), hydrogen peroxide in DMSO in the presence of a catalytic amount of potassium carbonate, 16 or (ii), hydrogen peroxide in CH 2 Cl 2 in the presence of a solution of 20% sodium hydroxide with tetrabutylammonium sulfate as a phase-transfer catalyst, 17 failed.The conditions that were found appropriate for the conversion of cyanobenzotriazole 1 into the desired compound 2 are as follows: hydrogen peroxide, CH 2 Cl 2 , room temperature, and tetrabutylammonium hydrogen sulfate as a catalyst (Scheme 1).
Reaction of compound 2 with an appropriate amine gave the desired mono-or N,Ndisubstituted ureas 3 (Scheme 1, Table 1).Alkyl-and dialkyl amines gave the desired ureas 3b-g in 88-96% yield.The reactions were performed at room temperature for 12-16h.Purification of the final ureas is simple: the reaction mixture was merely treated with dry potassium carbonate in order to remove benzotriazole.The pure ureas were obtained after filtration, evaporation of solvent, and recrystallization.Reactions of 2 succeeded with the hindered diisopropylamine, and the desired N,N-di-isopropylurea 3g was obtained in 91% yield under the same mild conditions.
Attempts to prepare arylureas failed, except for 4-methoxyaniline which gave the desired 4methoxyphenylurea 3a in 61% yield.Its participation in the reaction is possibly due to the presence of a strong electron-donating group, which increases the nucleophilicity of 4-anisidine; the preparation of 3a required two moles of compound 2. In this case, equimolar amounts of anisidine and benzotriazole-1-carboxylic acid amide 2 were mixed together in dry THF and allowed to react under reflux overnight; but only after a second equivalent of 2 had been added did the anisidine completely react (TLC control).Addition of a base decomposes the excess of 2 and removes benzotriazole from the reaction mixture.Pure compound 3a was obtained after evaporation of solvent and recrystallization.We have extended the use of benzotriazole-1-carboxylic acid amide 2 to the solid-phase preparation of substituted ureas.Wang's resin-linked secondary amine 4, prepared according to a published procedure, 18 was reacted with benzotriazole-1-carboxylic acid amide 2 for 12h.Analysis of the residue obtained after the cleavage showed the formation of the urea 5 (Scheme 2, Figures 1, 2, see Supplemental Materials).Compound 5 was obtained in 63% yield after the purification by column chromatography on silica.Longer reaction time (24 h) decreased the yield of desired compound 5 to 30%.

Conclusions
Mono-and N,N-disubstituted ureas 3a-g were obtained in 61-96% yields from benzotriazole-1carboxylic acid amide 2 in the reaction with primary and secondary aliphatic amines and panisidine.The desired ureas 3a-g were obtained under mild conditions with simple purification.The procedure developed is suitable for solid-phase work.

Experimental Section
General Procedures.Melting points were determined using a Fluka 51 capillary melting point apparatus equipped with a digital thermometer. 1 H-and 13 C-NMR spectra were recorded on a Gemini 300 MHz NMR spectrometer (300-and 75 MHz, respectively).Tetrahydrofuran (THF) was distilled from sodium/benzophenone under nitrogen immediately before use.Column chromatography was conducted with silica gel, grade 230-400 mesh (for compound 5).All other reagents were of reagent grade and were used without purification.