Parallel synthesis of tri- and tetrasubstituted ureas from carbamoyl imidazolium salts

A method for producing tri- and tetrasubstituted ureas from carbamoyl imidazolium salts is presented. Carbamoyl imidazolium salts are prepared from the reaction of N,N carbonyldiimidazole (CDI) with secondary amines, followed by alkylation with iodomethane. These stable salts can be stored for extended periods and are effective electrophilic carbamoylation reagents. Primary and secondary amines add to carbamoyl imidazolium salts at room temperature to give tri- and tetrasubstituted ureas in excellent yields. This reaction was used to synthesize ureas using both liquid-liquid extraction and solid-phase extraction (cation exchange) purification techniques. Liquid-liquid extraction affords the product ureas more cleanly than cationic exchange. A series of urea compounds were synthesized using parallel synthesis techniques in high yields and with suitable purity for routine in vitro biological tests. These studies validate the utility of carbamoyl imidazolium salts as useful building blocks for combinatorial library synthesis.     

The direct conversion of carbamates to ureas using aluminum amides

The conversion of carbamates into ureas using aluminum amide complexes is reported. This reaction is a convenient method to prepare bi-, tri- and tetra-substituted ureas from carbamate-protected primary or secondary amines by reaction with primary or secondary amines in the presence of stoichometric quantities of trimethylaluminum. A reactivity trend of the various carbamates was observed and methyl and benzyl carbamates were reacted selectively in the presence of t-butyl carbamates.     

Smart cleavage reactions: the synthesis of an array of ureas from polymer-bound carbamates

The solid-phase synthesis of a library of di-, tri-, and tetrasubstituted ureas is described. In this approach, an array of polymer-bound carbamates was synthesized. These polymer-bound primary and secondary amine carbamates were then treated under "smart" diversity-building cleavage conditions using a series of aluminum amide complexes to form the corresponding urea cleavage products. The crude cleavage products from this study were isolated in excellent yield and purity. To show the applicability of this strategy, a series of biaryl ureas were synthesized using sequential solid-phase Suzuki coupling and urea formation reactions.     

Unsymmetrical tetrasubstituted ureas from tertiary carbamoylimidazole: activation by AlMe3

An efficient and general method for the synthesis of unsymmetrical tetrasubstituted ureas from carbamoylimidazole is described. The conversion is achieved by the concurrent quarternization of the imidazole nitrogen and activation of amines with AlMe(3).     

CO2 deactivation of supported amines: does the nature of amine matter?

Adsorption of CO(2) was investigated on a series of primary, secondary, and tertiary monoamine-grafted pore-expanded mesoporous MCM-41 silicas, referred to as pMONO, sMONO, and tMONO, respectively. The pMONO adsorbent showed the highest CO(2) adsorption capacity, followed by sMONO, whereas tMONO exhibited hardly any CO(2) uptake. As for the stability in the presence of dry CO(2), we showed in a previous contribution [J. Am. Chem. Soc.2010, 132, 6312-6314] that amine-supported materials deactivate in the presence of dry CO(2) via the formation of urea linkages. Here, we showed that only primary amines suffered extensive loss in CO(2) uptake, whereas secondary and tertiary amines were stable even at temperature as high as 200 °C. The difference in the stability of primary vs secondary and tertiary amines was associated with the occurrence of isocyanate as intermediate species toward the formation of urea groups, since only primary amines can be precursors to isocyanate in the presence of CO(2). However, using a grafted propyldiethylenetriamine containing both primary and secondary amines, we demonstrated that while primary amines gave rise to isocyanate, the latter can react with either primary or secondary amines to generate di- and trisubstituted ureas, leading to deactivation of secondary amines as well.     

Solid-phase synthesis of trisubsituted guanidines

The solid-phase library synthesis of trisubstituted guanidines was accomplished. Amines were loaded onto the 4-formyl-3,5-dimethoxyphenoxymethyl linker via reductive amination. Subsequent acylation with Fmoc-4-aminomethylbenzoic acid followed by Fmoc deprotection gave solid-supported primary amines. Alternatively, sulfonylation of resin-bound secondary amines with 4-cyanobenzenesulfonyl chloride followed by borane reduction also gave solid-supported primary amines. Both resins were acylated with isocyanates to furnish solid-supported ureas. Dehydration of ureas with p-toluenesulfonyl chloride in pyridine gave solid-supported carbodiimides. Nucleophilic addition of amines to the carbodiimide bond followed by cleavage off the solid support gave trisubstituted guanidines.     

Facile direct synthesis of unsymmetrical ureas from N-Alloc-, N-Cbz-, and N-Boc-protected amines using DABAL-Me3

A practical synthetic method for the direct synthesis of unsymmetrically substituted ureas from N-Alloc-, N-Cbz-, and N-Boc-protected amines is described. In this study, efficient direct conversion of the Alloc-, Cbz-, and Boc-carbamate compounds to ureas was achieved in the presence of DABAL-Me₃, an air stable and easily handled reagent. Using this reaction method, both protected aromatic and aliphatic amines were successfully transformed into various trisubstituted and tetrasubstituted ureas with high yields without side product. Our findings offer promising guidelines for direct preparation of useful ureas from N-Alloc-, N-Cbz-, and N-Boc-carbamates.     

Non-nanogold catalysis of carbon monoxide oxidative amination

Bulk metallic gold particles ( approximately 1000 nm) catalyze the reaction of CO, O2, and primary amines (R-NH2) to give ureas (RNH)2C=O. Isocyanates (R-N=C=O) are identified as intermediates in the reactions and are shown to react with primary and secondary amines to give ureas under the conditions of the gold-catalyzed reactions. Although many recent studies indicate that nanosized particles of gold are required for the catalytic oxidation of CO, the results presented in this paper show that bulk gold is capable of catalyzing the oxidative amination of CO under mild conditions (45 degrees C, 1 atm CO and O2).     

Efficient synthesis of ureas by direct palladium-catalyzed oxidative carbonylation of amines

A general synthesis of symmetrically disubstituted ureas and trisubstituted ureas by direct Pd-catalyzed oxidative carbonylation of primary amines or of a mixture of a primary and a secondary amine, respectively, with unprecedented catalytic efficiencies for this kind of process, is reported. Reactions are carried out at 90-100 degrees C in DME as the solvent in the presence of PdI(2) in conjunction with an excess of KI as the catalytic system and under 20 atm of a 4:1 mixture of CO and air. In some cases, working in the presence of an excess of CO(2) (40 atm) in addition to CO and air (60 atm total) had a beneficial effect on substrate reactivity and product yield. Cyclic five-membered and six-membered ureas were easily formed from primary diamines. The methodology has been successfully applied to the synthesis of pharmacologically active ureas, such as those deriving from alpha-amino esters or urea NPY5RA-972, a potent antagonist of the neuropeptide Y5 receptor.     

A new practical method for the synthesis of unsymmetrical ureas via high-pressure-promoted condensation of 2,2,2-trichloroethyl carbamates (Troc-carbamates) with amines

A new practical method for the synthesis of unsymmetrical ureas was achieved by condensation between 2,2,2-trichloroethyl carbamates (Troc-carbamates) and primary or secondary amines under high-pressure conditions.     

Debenzylation of tertiary amines using phosgene or triphosgene: an efficient and rapid procedure for the preparation of carbamoyl chlorides and unsymmetrical ureas. Application in carbon-11 chemistry

Efficient and rapid preparations of carbamoyl chlorides and unsymmetrical ureas from tertiary amines and phosgene or its safe equivalent triphosgene [bis(trichloromethyl)carbonate, BTC] are described. First, the reaction of stoichiometric amounts of phosgene with secondary amines was revisited, and it was shown that the formation of carbamoyl chlorides in high yields required careful adjustments of experimental conditions and the use of pyridine as an HCl scavenger. A phosgene-mediated dealkylation of triethylamine was observed when this base was used instead of pyridine. Taking advantage of this observation, a strategy of synthesis of carbamoyl chlorides from tertiary amines and phosgene has been developed. N-Alkyl-N-benzyl(substituted)tetrahydroisoquinolines, -piperazines, -piperidines, or -anilines were treated with stoichiometric amounts of phosgene (or BTC) in CH(2)Cl(2). Tertiary amines bearing electron-enriched benzyl group(s) afforded carbamoyl chlorides in excellent yields and without any contamination by symmetrical ureas. Subsequent additions of primary or secondary amines to these carbamoyl chlorides produced unsymmetrical ureas in single-pot and high-yielding operations. This methodology was applied in (11)C-chemistry. From [(11)C]phosgene, a common precursor used in the preparation of radiotracers for positron emission tomography, a rapid and efficient synthesis of (11)C-carbamoyl chlorides and (11)C-unsymmetrical ureas derived from tetrahydroisoquinoline and piperazine is described. The first example of (11)C-amide formation from the reaction of a (11)C-carbamoyl chloride and an organometallic (cyanocuprate or a Grignard reagent in the presence of a nickel catalyst) is also presented.     

Titanium(IV) isopropoxide mediated solution phase reductive amination on an automated platform: application in the generation of urea and amide libraries

Amine libraries and their derivatives are important targets for high throughput synthesis because of their versatility as medicinal agents and agrochemicals. As a part of our efforts towards automated chemical library synthesis, a titanium(IV) isopropoxide mediated solution phase reductive amination protocol was successfully translated to automation on the Trident(TM) library synthesizer of Argonaut Technologies. An array of 24 secondary amines was prepared in high yield and purity from 4 primary amines and 6 carbonyl compounds. These secondary amines were further utilized in a split synthesis to generate libraries of ureas, amides and sulfonamides in solution phase on the Trident(TM). The automated runs included 192 reactions to synthesize 96 ureas in duplicate and 96 reactions to synthesize 48 amides and 48 sulfonamides. A number of polymer-assisted solution phase protocols were employed for parallel work-up and purification of the products in each step.     

丁基锂与氯化铜存在条件下仲胺偶联形成N-N键的新方法

报道了以仲胺反应底物经丁基锂夺去活性质子,无水氯化铜氧化偶联形成N—N键的新方法.共完成了11种底物尝试,所得产物肼的产率在17％～76％之间.相关合成方法是一种从仲胺制备对称取代肼的高效合成方法.     

Structure Based Library Approach to Photosynthesis Inhibitors:The Solid Phase Synthesis of Hydro-Uracils and Thiouracils

Combinatorialchemistryhasemergedasanefficienttoolforchedriststosynthesize"comPoundslibraries"fortheraPididentificationandoPtforizationofnewleads-lSolidphaseorganicsynthesisprovidesaraPidmeansforpreparationofcomPoundslibraries,andhasbeenusedfortheconstrUctionofoligomericcomPounds,'andsmallorganicmoleculessuchasbenzodiazepine,'9-lactams,'andquinolones.'ThemajortargetfortheinhibitionofphotosystemII(PSII)istheDlprotein,apolyPePtidewithamolecularweightof32kDa.'Wehavedevelopedmodelsoftheher-b…     

Fragmentation of Optically Active (1-Phenylethyl)- and (1-Naphthylethyl)ureas in Refluxing Alcohols: Easy Preparation of Optically Active Amines of High Optical Purity

(1-Phenylethyl)- and (1-naphthylethyl)ureas, obtained in the reaction of racemic amines with optically pure isocyanates, are separated and then decomposed in refluxing alcohols, to afford optically pure secondary amines and optically pure alkyl carbamates in quantitative yields. The scope of this fragmentation for the resolution of racemic mixtures of amines is illustrated by several examples of biologically important compounds. Carbamates obtained by this fragmentation can readily be recycled.     

Synthesis of Symmetrical and Unsymmetrical Ureas Using Unsymmetrical Diaryl Carbonates

Appropriately substituted unsymmetrical diaryl carbonates react smoothly with primary amines to give the carbamates derived by nucleophilic displacement of the less electron rich aromatic substituent. Subsequent treatment of the carbamates with primary and secondary amines gives either symmetrical or unsymmetrical ureas in excellent yield and the overall process can be carried out as a “one pot” operation. Acetonitrile is the preferred solvent and addition of DBU facilitates the carbamate → urea transformation.     

An efficient and mild protocol for the synthesis of unsymmetrical ureas in the absence of catalyst and additives

<正>A new practical method for the synthesis of unsymmetrical ureas was achieved by reaction of phenylurea with primary and secondary amines under neutral and mild condition in very good yields.The reaction took place in refluxing dioxane and does not require any catalyst or additives.     

Novel steroid mimics directed towards the estradiol skeleton

A series of non-symmetrical tri- and tetra-substituted ureas have been prepared to mimic the rigid tetracyclic core of estradiol. Tetra-substituted ureas were prepared by a five-step protocol, involving activation and displacement of a carbonyldiimidazole adduct in 48-67% overall yield. This method was unsuccessful for tri-substituted ureas, which were prepared in 42-74% yields by an alternative four-step method, which included a one-pot 4-nitrophenyl carbamate formation/displacement sequence.     

Microwave assisted,sequential two-step,one-pot synthesis of novel imidazo[1,2-a]pyrimidine containing tri/tetrasubstituted imidazole derivatives

A series of novel imidazo[1,2- a ]pyrimidine containing tri/tetrasubstituted imidazole derivatives (1-10) has been synthesized via sequential two-step, one-pot, multicomponent reaction using imidazo[1,2- a ]pyrimidine-2-carbaldehyde, benzil, primary amines, and ammonium acetate catalyzed by p -toluenesulfonic acid under microwave-assisted conditions. The results showed that target compounds can be obtained from a wide range of primary amines bearing different functional groups with moderate to good yields (46%-80%) under optimum reaction conditions. This method provides a green protocol for imidazo[1,2- a ]pyrimidine containing tri/tetrasubstituted imidazole derivatives due to ethyl alcohol as a green solvent, microwave irradiation as a greener heating method and one-pot multicomponent reaction as a green technique. The synthesized compounds have been elucidated using various spectroscopic tools such as FT-IR, ¹H NMR, ¹³ C NMR, and MS.     

Pd(OAc)2-catalyzed carbonylation of amines

A phosphine-free catalytic system [Pd(OAc)2-Cu(OAc)2-air] induced a substrate-specific carbonylation of amines in boiling toluene under CO gas (1 atm). Symmetrical N,N'-dialkylureas were obtained by the carbonylation of primary amines. N,N,N'-Trialkylureas were selectively formed by addition of a secondary amine to the above reaction vessel. Secondary amines did not give tetraalkylureas. However, dialkylamines with a phenyl group on their alkyl chains, such as N-monoalkylated benzylic amine or phenethylamine derivatives, underwent a direct aromatic carbonylation to afford five- or six-membered benzolactams. In the carbonylation, the chelation effect or steric repulsion between Pd(II) and the meta-substituent in the ortho-palladation and the ring sizes of cyclopalladation products that were formed prior to carbonylation were found to generate good site selectivity and increase the reaction rate. In contrast, carbonylation of omega-arylalkylamines with a hydroxyl group gave neither ureas nor benzolactams but instead produced 1,3-oxazolidinones smoothly. Hydrochlorides of amines also underwent carbonylation to afford the corresponding amides under the conditions used. This procedure made it possible to prepare ureas of amino acid esters and N-alkylcarbamates in practical yields.