Unsymmetrical Ureas Research Articles

Synchronous recognition of amines in oxidative carbonylation toward unsymmetrical ureas.

Unsymmetrical ureas are commonly found in pharmaceuticals and bioactive compounds. However, devising strategies to introduce two distinct amines selectively in the construction of unsymmetrical ureas remains a challenge. In this work, we use a synchronous recognition strategy that takes advantage of radical and nucleophilic activation to discriminate between secondary and primary amines. Specifically, a copper catalyst preferentially oxidizes secondary amines to radical species, whereas a cobalt catalyst carbonylates primary amines to produce cobalt amides. Coupling these fragments by cooperative catalysis produces unsymmetrical ureas with high selectivity, as showcased by the modification of 41 biologically active compounds and six drugs.

Solvent-free catalytic synthesis of ureas from amines and carbon dioxide under atmospheric pressure using oxovanadium(V) catalyst with silylating reagent

Abstract Efficient utilization of carbon dioxide for the synthesis of valuable compounds is considered to be essential for the future sustainable society. Herein, N,O-bis(trimethylsilyl)acetamide (BSA), which acts not only as a silylating reagent but also as a reaction solvent, was demonstrated to facilitate the solvent-free catalytic synthesis of ureas in one-step from amines and carbon dioxide under atmospheric pressure using a commercially available air-stable NH4VO3 catalyst. This catalytic system was applicable to a wide range of substrate and a gram-scale reaction. One-step preferential synthesis of unsymmetrical ureas was also realized.

Deprotective Lossen rearrangement: a direct and general transformation of Nms-amides to unsymmetrical ureas.

Ureas stand out as potent pharmacophores in drug development, rendering them a prime focus for synthesis. Herein, we present an appealing entry point for urea synthesis from protected amines (Nms-amides) and relying on a Lossen-type rearrangement process as an elegant example of deprotective functionalisation. The method developed exhibits an exceptionally broad tolerance towards various protected amines, encompassing numerous drug derivatives, and delivers high reaction yields.

Methyl Pyruvate Oxime as a Carbonyl Synthon: Synthesis of Ureas, Carbamates, Thiocarbamates, and Anilides.

A new strategy for the synthesis of unsymmetrical ureas, carbamates, thiocarbamates, and anilides was developed with methyl pyruvate oxime as the carbonyl synthon. The intrinsic reactivity of the reagent enabled consecutive disubstitution involving direct amidation and one-pot deoximative substitution with various nucleophiles. The utility of the method was demonstrated with the synthesis of bioactive molecules.

Microwave assisted synthesis, spectroscopy, crystal structure, characterization and Hirshfeld surface analysis of ureidopeptides and intermediates derived from α,α-dipeptides C-terminal glycine

This article describes synthetically useful catabolic pathway activation of the primordial peptide cycle through the effect of microwave irradiation, giving a new variety of peptide derivatives: the α,α-ureidopeptides, as 1,3-disubstituted unsymmetrical ureas via hydantoin, starting from NCbz protected α,α-dipeptide methyl esters containing glycine as the C-terminal residue. The new ureidopeptide series were synthesized and structurally characterized by FT-IR, MS, 1H NMR, 13C NMR spectroscopy, and single-crystal X-ray diffraction analysis. Molecular structure and crystal packing of Phe-Gly-ureidopeptide 3h noted C12H14N2O5, in a monoclinic system and C2/c space group with parameters a = 32.42 Å, b = 9.62 Å, c = 8.40 Å, β=103.25°, and Z = 8, Z’=1, confirm assignations evaluated for the new compounds. The procedure has been extended to the isolation of the α,α-ureidopeptide intermediate, the hydantoin Leu-Gly 4e, C9H14N2O4, demonstrating the synthetic mechanism and crystallized in an orthorhombic system, Pbca space group, with parameters a = 5.19 Å, b = 11.49 Å, c = 35.99 Å, α=β=γ=90°, and Z = 8, Z’=2. Hirshfeld surface analysis on crystal structures of both ureic-derivatives revealed crystal packing relevance and stabilization by the competition of predominant supramolecular interactions easily discernible as nonconventional intermolecular CH•••π, and classical NH•••O or C = OOH•••O = COH, forming complex hydrogen bonding patterns.

Metallaphotoredox‐Catalyzed Three‐Component Couplings for Practical Synthesis of Ureas and Carbamates†

Comprehensive SummaryUreas are widely used in drugs, materials and catalysts because of their diamide structure, which can form strong hydrogen bonds. Therefore, it is of great scientific significance to develop efficient and green methods for the synthesis of urea compounds, especially unsymmetrical ureas. Here, we have disclosed novel and highly efficient three‐component coupling reactions of organic halides, sodium cyanate and amines enabled by nickel/photoredox dual catalysis for the preparation of unsymmetrical ureas. The reaction features simple and safe operations, broad substrate scopes, and product diversities. It allows the facile synthesis of N‐aryl/vinyl ureas from readily available, user‐friendly feedstocks under mild conditions (27 examples, 36%—98% yields). In addition, this method is further derived to alcohols as nucleophiles to synthesize a series of carbamates (15 examples, 40%—95% yields). The mechanism experiment shows that the isocyanate produced by the coupling of halide and sodium cyanate may be the key intermediate in this reaction.

Improved Synthesis of Unsymmetrical Ureas via Carbamates

AbstractAn efficient, cost-effective, easy and green method is reported for the preparation of N,N′-alkyl aryl ureas and N,N′-dialkylureas via carbamates. This improved procedure is devoid of any hazardous reagents such as phosgene and isocyanates, and shows broad substrate scope with good to excellent yields. As compared to previous reports, this procedure offers an operationally simple, potentially scalable, and, significantly, benign way to synthesize these important urea motifs.

Oxovanadium(V)-Catalyzed Synthesis of Unsymmetrical Ureas by Activation of Carbon Dioxide under Ambient Pressure

Oxovanadium(V)-Catalyzed Synthesis of Unsymmetrical Ureas by Activation of Carbon Dioxide under Ambient Pressure

Environmentally benign synthesis of unsymmetrical ureas and their evaluation as potential HIV-1 protease inhibitors via a computational approach.

The present work reports the cost-effective, high yielding and environmentally acceptable preparation of unsymmetrical ureas from thiocarbamate salts using sodium percarbonate as an oxidant. Efficacy of the unsymmetrical ureas as potential human immune deficiency virus (HIV-1) protease inhibitors has been evaluated via in silico approach. The results revealed interactions of the urea compounds at the active site of the enzyme with favorable binding affinities causing possible mutations hindering the functioning of the enzyme. Further computational assessment of IC50 using known references satisfactorily authenticated the inhibitory action of the selected compounds against HIV-1 protease. Added to the easy synthesis of the ureas following an environmentally benign protocol, this work may be a valuable addition to the ongoing search for drugs with better efficacy profiles and reduced toxicity against HIV.

“On-Water” Reaction of (Thio)isocyanate: A Sustainable Process for the Synthesis of Unsymmetrical (Thio)ureas

We describe a facile, sustainable, and chemoselective process for the synthesis of unsymmetrical (thio)ureas through the “on-water” reaction of (thio)isocyanates with amines. Detailed mechanistic studies revealed that the physical nature and solubility of reagents in water are responsible for the observed reaction rate and selectivity. Significant efforts have been made to design a scalable process to achieve the “zero waste” “water-mediated” protocol for the synthesis of (thio)ureas from (thio)isocyanates and amines. The decisive advantages of the process are the simple product isolation through filtration and the recycling of the water effluent. It also avoids the use of sensitive anhydrous reaction conditions and toxic volatile organic solvents. The developed process ensures that chemoselectivity and robustness and are successfully scaled-up to produce 100 g of isoproturon in high yield and purity. Green chemistry parameters such as process mass intensity, reaction mass efficiency, and molar efficiency values (with and without solvent) were calculated and compared.

“Urea to Urea” Approach: Access to Unsymmetrical Ureas Bearing Pyridyl Substituents

AbstractA protocol for the synthesis of unsymmetrical ureas substituted by pyridyl/quinolinyl moiety has been developed. This method concluded in metal‐ and base‐free reamination of N,N‐dimethyl‐N‘‐hetaryl ureas with a wide range of aryl and alkyl amines. The isolated yields vary from 40 to 96% depending on the nucleophilicity of the amines. The scope of this method includes more than 50 examples. The reaction is not hindered by either donor or acceptor groups as well as diverse functionalities. The synthesis can be easily scaled to gram quantities. Theoretical calculations supported by experimental data allowed us to propose a plausible mechanism for the process. This reaction takes place through the intermediate formation of hetaryl isocyanate.magnified image

2,2,2-Trifluroenthanol promoted synthesis of unsymmetrical ureas from dioxazolones and amines via tandem lossen rearrangement/condensation process

A 2,2,2-trifluroenthanol (TFE) promoted synthesis of unsymmetric ureas was described. This approach enabled the construction of a variety of ureas from the readily prepared and easy-to-handle dioxazolones and amines via tandem Lossen rearrangement/condensation process. The reaction featured mild conditions for the urea synthesis under metal-free conditions, which was successively applied in the scale-up synthesis of herbicides Monuro and Isoproturon.

Palladium-Catalyzed Aerobic Oxidative Carbonylation of Amines Enables the Synthesis of Unsymmetrical N,N′-Disubstituted Ureas

AbstractA ligand-free palladium-catalyzed aerobic oxidative carbonylation of amines for the synthesis of ureas, particular unsymmetrically N,N′-disubstituted ureas, which cannot be accessed by any other palladium-catalyzed oxidative carbonylation of amines to date, is presented. An array of symmetrical and unsymmetrical ureas were straightforwardly synthesized by using inexpensive, readily available, stable, and safe amines with good to excellent yields under a pressure of 1 atm. This novel method employs oxygen as the sole oxidant and offers an attractive alternative to transition-metal-based oxidant systems

Synthesis of unsymmetrical urea from aryl- or pyridyl carboxamides and aminopyridines using PhI(OAc)2via in situ formation of aryl- or pyridyl isocyanates

The synthesis of unsymmetrical ureas (N-aryl-N′-pyridylurea and N,N′-bipyridylurea) from aryl- or pyridyl carboxamides and aminopyridines in the presence of PhI(OAc)2 has been reported. The formation of pyridylisocyanates from their corresponding carboxamides via Hofmann rearrangement is confirmed.

Synthesis of potentially biologically active novel phenolic derivatives of unsymmetrical ureas from substituted phenethylamines

Unsymmetrical urea derivatives have been reported to play a significant role in plethora of biological pathways (e.g., neurotransmission, neuromodulation). Notably, urea-based scaffolds are increasingly employed in medicinal chemistry campaigns to engage key protein interactions owing to their tunable physicochemical and structural properties. In this study, we disclose the first examples of unsymmetrical phenethylamine based urea derivatives in aqueous conditions. The reactions involving in-situ generated imidazolide intermediate proceed to completion in the absence of base and under air at room temperature thus allowing access to sensitive functional groups. We also demonstrate a useful product functionalization (i.e., demethylation of 4-methoxyphenethylamine via BBr3) to access the corresponding tyramine analogues. All urea and phenolic derivatives were characterized with 1H NMR, 13C NMR, FT-IR, and elemental analysis.

Photocatalyzed synthesis of unsymmetrical ureas via the oxidative decarboxylation of oxamic acids with PANI-g-C3N4-TiO2 composite under visible light

The synthesis of unsymmetrical ureas via the photocatalyzed oxidative decarboxylation of oxamic acids has been developed. The carbamoyl radicals were generated from oxamic acids in the presence of a hypervalent iodine reagent and the PANI(Polyaniline)-g-C3N4-TiO2 composite under visible light irradiation. The radicals were converted in situ into the corresponding isocyanates, which were then trapped by amines to afford the corresponding products in moderate to good yields. This protocol avoided the direct use of environmentally unfriendly isocyanates and a series of substrates were tolerated. Moreover, the photocatalyst could be readily recovered by simple filtration and be reused for several runs with only a slight decrease in the catalytic activity.

Ir-Catalyzed C-H Amidation Using Carbamoyl Azides for the Syntheses of Unsymmetrical Ureas.

An iridium-catalyzed C-H amidation for the syntheses of unsymmetrical urea was developed using carbamoyl azides (R(R')N-C(O)-N3) as the nitrogen source. A combination of iridium and silver gave an active catalyst for C-N bond formation. A variety of urea derivatives were synthesized using carbamoyl azides with only dinitrogen byproducts. Finally, the use of the transient directing group strategy with carbamoyl azides extended the substrate scope of the catalytic C-H amidation to yield aldehyde-containing unsymmetrical ureas.

Electrochemical Synthesis of Carbodiimides via Metal/Oxidant-Free Oxidative Cross-Coupling of Amines and Isocyanides.

This work discloses an electrochemical oxidative cross-coupling of amines with aryl and aliphatic isocyanides. In an undivided cell, the reaction proceeds without involving any transition-metal catalyst, oxidant, or toxic reagents providing carbodiimides in good yields, thereby circumventing stoichiometric chemical oxidants, with H2 as the only byproduct. Moreover, carbodiimides were in situ converted into unsymmetrical ureas in moderate to good yields using an electricity ON-OFF strategy.

Visible-light-promoted oxidative desulphurisation: a strategy for the preparation of unsymmetrical ureas from isothiocyanates and amines using molecular oxygen

A green and efficient visible-light promoted oxidative desulphurisation protocol has been proposed for the construction of unsymmetrical ureas under mild conditions with broad substrate scope and good functional group tolerance.

Palladium‐Catalyzed Synthesis of Symmetrical and Unsymmetrical Ureas Using Chromium Hexacarbonyl as a Convenient and Safe Alternative Carbonyl Source

Pd‐catalyzed synthesis of urea derivatives from aryl iodides and different aliphatic and aromatic amines using sodium azide and chromium hexacarbonyl is described. In this process, carbonylation of aryl iodides, Curtius rearrangement of aroyl azides, and nucleophilic addition of amines sequentially occur to afford the products in good to excellent yields. This protocol is operationally simple and displays a broad substrates scope.