Cyclic Urea Research Articles

Iron‐Catalyzed Intramolecular C—H Amidation of N‐Benzoyloxyureas

Main observation and conclusionA redox‐neutral Fe‐catalyzed intramolecular C—H amidation of N‐benzoyloxyureas is described. This methodology employs a simple iron complex in situ generated from Fe(OTf)2 and bipyridine as the catalyst and N‐benzoyloxyureas as the nitrene precursors without using exogenous oxidants. An array of cyclic ureas were synthesized via aliphatic C(sp3)—H amidation in excellent yields. In addition, this catalytic system is also amenable to aryl C(sp2)—H nitrene insertion to provide benzimidazolones in moderate yields.

Synthesis of amino alcohols, cyclic urea, urethanes, and cyclic carbonates and tandem one-pot conversion of an epoxide to urethanes using a Zn–Zr bimetallic oxide catalyst

The one-pot tandem synthesis of urethanes directly from an epoxide, with urea in solvent-free condition using Zn2ZrOx is demonstrated. The catalyst exhibits excellent activity in cyclic urea, urethane, and cyclic carbonate production in neat conditions.

Cholesteryl ester transfer protein (CETP) inhibitors based on cyclic urea, bicyclic urea and bicyclic sulfamide cores

Cholesteryl ester transfer protein (CETP) inhibitors reduce the transfer of cholesteryl esters from the high-density lipoprotein (HDL-C) to apolipoprotein such as VLDL/LDL, with exchange of triglycerides. Thus, this inhibition increases the HDL-C levels, which is believed to lower the risk for heart disease and stroke. We report here a series of CETP inhibitors based on the cyclic, bicyclic urea and sulfamide cores. These CETP inhibitors exemplified by 15, 31, and 45 demonstrated in vitro potency in inhibiting the CETP transfer activity, and 15, 31 showing in vivo efficacy to increase HDL-C levels in cynomolgus-CETP transgenic mice. The synthesis and biological evaluations of these CETP inhibitors are described.

Advances in the synthesis of heterocycles bearing an endocyclic urea moiety

The review systematizes and summarizes data on the synthesis of structurally diverse cyclic ureas published over the last 10 years. Saturated and unsaturated monocyclic ureas, as well as fused heterocycles containing one urea moiety, are considered. Data on the biological activity of selected compounds of this type are provided. The synthetic approaches to cyclic carbamides are classified in terms of the reaction type and the source of a carbonyl group.The bibliography includes 235 references.

Design and synthesis of novel tetrahydrofuran cyclic urea derivatives as androgen receptor antagonists

In order to improve the antiproliferative activity of androgen receptor (AR) antagonists, which used clinically for the treatment of prostate cancer that is a major cause of male death in worldwide, we report the design and synthesis of a series of tetrahydrofuran cyclic urea-based non-steroidal small molecule AR antagonists and exhibit potent AR antagonistic activity. These molecules with higher stereochemical aspects have been achieved by changing the hydantoin analogue antiandrogens to 4-(2-oxohexahydro-1H-furo[3,4-d] imidazol-1-yl)-2-(trifluoromethyl)benzonitrile analogues. Here, the thio-hydantoin pharmacophore of the recently reported antagonists is replaced by tetrahydrofuran cyclic urea. The antiproliferative properties of these molecules have been evaluated against androgen-dependent (LNCaP) cell line. Among the reported molecules, 4-(2-oxohexahydro-1H-furo[3,4-d]imidazol-1-yl)-2-(trifluoromethyl)benzonitrile (AR04) showed significantly improved in vitro activity, IC50 = 3.926 µM. Molecular structure-activity relationship studies confirm that the oxetane analogue AR04 is distinct from other synthesized AR antagonists. These results have suggested that AR04 exhibiting their potential as a lead compound for the alternative treatment of prostate cancer. To improve the antiproliferative activity of androgen receptor (AR) antagonists, various compounds with tetrahydrofuran cyclic urea ring system were designed and synthesized. Among the synthesized compounds, AR04 showed significantly improved in vitro activity, IC50 = 3.926 µmol, which is almost equal to the commercially available drug, enzalutamide.

Preparation of CO2 adsorbent with N1-(3-(trimethoxysilyl)propyl)-1,3-propanediamine and its performance

N1-(3-(trimethoxysilyl)propyl)-1,3-propanediamine (2NS-P), a diaminosilane having a propyl spacer between the two amino groups was successfully synthesized, and a CO2 adsorbent functionalized with 2NS-P was prepared via impregnation of it into silica. The adsorption performance and stability of 2NS-P/Kona95 were examined and compared to that of N1-(3-(trimethoxysilyl)propyl)ethane-1,2-diamine (2NS)/Kona95 having an ethyl spacer. 2NS-P/Kona95 exhibited better CO2 adsorption capacity and CO2/N efficiency. The adsorbents were subjected to ten cycles of temperature swing adsorption (TSA), demonstrating that stability of 2NS-P/Kona95 was better than that of 2NS/Kona95. The spent 2NS-P/Kona95 showed the absence of cyclic urea formation in FT-IR spectrum, explaining the better stability of 2NS-P/Kona95 than 2NS/Kona95.

N-Heterocyclic Carbenes Reduce and Functionalize Copper Oxide Surfaces in One Pot.

Benzimidazolium hydrogen carbonate salts have been shown to act as N-heterocyclic carbene precursors, which can remove oxide from copper oxide surfaces and functionalize the resulting metallic surfaces in a single pot. Both the surfaces and the etching products were fully characterized by spectroscopic methods. Analysis of surfaces before and after NHC treatment by X-ray photoelectron spectroscopy demonstrates the complete removal of copper(II) oxide. By using 13 C-labelling, we determined that the products of this transformation include a cyclic urea, a ring-opened formamide and a bis-carbene copper(I) complex. These results illustrate the potential of NHCs to functionalize a much broader class of metals, including those prone to oxidation, greatly facilitating the preparation of NHC-based films on metals other than gold.

An AIE‐Active Tetraphenylethylene‐Based Cyclic Urea as a Selective and Efficient Optical and Colorimetric Chemosensor for Fluoride Ions

AbstractAnion sensing is a very challenging and important issue in many diverse fields, including biological, medical and environmental sciences. In this paper, we report the serendipitous synthesis of a tetraphenylethylene (TPE) bearing a cyclic urea (coded as: 1). This easy‐to‐make, simple chemosensor shows high selectivity towards fluoride (F−) ions. Importantly, this work demonstrates two important factors: firstly, the use of cyclic urea for ion sensing and secondly, the use of aggregation induced emission (AIE)‐ TPE signalling units. This selective fluoride sensing can be observed by the naked eye, UV‐vis absorption, fluorescence spectroscopy, and 1H‐NMR spectroscopy. Solutions of sensor 1 are fluorescent in DMSO with fluorescence quantum yield Φ=1.3 and upon addition of fluoride ions the emission is quenched with ΦF=0.07. Notably, other anions, such as CN−, AcO−, NO3−, H2PO4−, HSO4−, I−, OH−, ClO4−, SCN− and Cl−, do not show any quenching effect. The binding constant (K) between sensor 1 and fluoride was found to be 4.90×108 M−2 with a detection limit of 30 μM. We also studied AIE‐activity of 1 in THF/water mixture. As such the fluorescence quantum yield (ΦF) of 1 in pure THF solution shown to be 0.05 % which was enhanced 22‐fold to 1.98 and 6.65 % at fw=90 and 99 %, respectively. This is clear confirmation that compound 1 is AIE active due to decreased solubility and increased molecular self‐assembly as the water fraction is increased.

Catalytic Dealkylative Synthesis of Cyclic Carbamates and Ureas via Hydrogen Atom Transfer and Radical-Polar Crossover.

Guided by the transition-metal hydrogen atom transfer and radical-polar crossover concepts, we developed a functional-group-tolerant and scalable method for the synthesis of cyclic carbamates and ureas, which are found in the structures of bioactive compounds. This method provides not only a common five-membered ring but also six-to-eight-membered ring products. The reaction proceeds through the intramolecular displacement of an alkylcobalt(IV) intermediate and dealkylation by 2,4,6-collidine; the activation energies of these steps were calculated by DFT.

Rational design of bifunctional catalyst from KF and ZnO combination on alumina for cyclic urea synthesis from CO2 and diamine

This study is mainly focused on the design of stable, active and selective catalyst for direct synthesis of 2-imidazolidinone (cyclic urea) from ethylenediamine and CO2. Based on the rationale for the catalyst properties needed for this reaction, KF, ZnO and Al2O3 combination was selected to design the catalyst. ZnO/KF/Al2O3 catalyst was prepared by stepwise wet-impregnation followed by the removal of physisorbed KF from the surface. High product yield could be achieved by tuning acid-base sites by varying the composition and calcination temperature. The catalysts were characterized by various techniques like XRD, N2-sorption, NH3-TPD, CO2-TPD, TEM, XPS and FT-IR measurements. It is shown that acidic and basic properties of the solvent can influence the activity and product selectivity for this reaction. Under optimized condition; 180 °C, 10 bar and 10 wt.% catalyst in batch mode, 96.3 % conversion and 89.6 % selectivity towards the 2-imidazolidinone were achieved.

Enantioselective Vinylogous Mannich‐Type Reactions to Construct CF3S‐Containing Stereocenters Catalysed by Chiral Quaternary Phosphonium Salts

AbstractA series of benzyl trifluoromethyl sulphides bearing a nitro group were utilized as CF3S‐containing building blocks to construct chiral CF3S‐containing molecules via enantioselective vinylogous Mannich‐type reactions. In such reactions, high yields and enantioselectivities were obtained using chiral quaternary phosphonium salts derived from amino acids. Moreover, a chiral cyclic urea bearing the CF3S moiety was obtained from further transformation of the product.magnified image

Deracemization Enabled by Visible-Light Photocatalysis.

Deracemization is an ideal but challenging strategy for the conversion of a racemic mixture into a single enantiomer. Recent studies have demonstrated that visible-light photocatalysis could be utilized to promote selective deracemization of axially chiral allenes as well as cyclopropylquinolones and cyclic ureas with central chirality either through energy transfer or through a sequence of electron, proton, and hydrogen-atom transfer.

Remote Directed Isocyanation of Unactivated C(sp3)-H Bonds: Forging Seven-Membered Cyclic Ureas Enabled by Copper Catalysis.

Reported herein is an unprecedented copper-catalyzed site-selective δ-C(sp3)-H bonds activation of aliphatic sulfonamides for constructing the synthetically useful seven-membered N-heterocycles. A key to success is the use of in-situ-formed amide radicals, to activate the inert C(sp3)-H bond, and inexpensive TMSNCO, as a coupling reagent under mild conditions. To the best of our knowledge, this represents the first use of alkylamine derivatives as a five-membered synthon to prepare a seven-membered N-heterocycles.

Copper‐Catalyzed Construction of Trinuclear N‐Fused Hybrid Scaffolds Using Cyclic Ureas as New Building Blocks

2‐(2‐Bromoaryl)‐ and 2‐(2‐bromovinyl)‐benzimidazoles are coupled and cyclized with cyclic ureas as new building blocks in dimethylformamide in the presence of a catalytic amount of a copper catalyst and a base to give the corresponding trinuclear N‐fused hybrid scaffolds in good yields. Trinuclear N‐fused hybrid scaffolds having methoxy group on benzimidazole moiety are readily oxidized to unprecedented benzimidazolequinone‐fused hybrid scaffolds in high yields by treatment of ceric ammonium nitrate in acetonitrile/H2O.

Identification of novel GPR81 agonist lead series for target biology evaluation

GPR81 is a novel drug target that is implicated in the control of glucose and lipid metabolism. The lack of potent GPR81 modulators suitable for in vivo studies has limited the pharmacological characterization of this lactate sensing receptor. We performed a high throughput screen (HTS) and identified a GPR81 agonist chemical series containing a central acyl urea scaffold linker. During SAR exploration two additional new series were evolved, one containing cyclic acyl urea bioisosteres and another a central amide bond. These three series provide different selectivity and physicochemical properties suitable for in-vivo studies.

Ruthenium-catalyzed synthesis of vinylamides at low acetylene pressure.

The reaction of cyclic amides with acetylene under low pressure, using ruthenium-phosphine catalysts, afforded a broad variety of N-vinylated amides including (azabicyclic) lactams, oxazolidinones, benzoisoxazolones, isoindolinones, quinoxalinones, oxazinanones, cyclic urea derivatives (imidazolidinones), nucleobases (thymine), amino acid anhydrides and thiazolidinone.

Synthesis and structural characterizations of novel atropoisomeric ferrocene-containing six-membered cyclic ureas

The stereochemical phenomenon that arises from hindered rotation around bonds in nonplanar molecules is termed the atropoisomerism. During our previous work we noted the presence of this kind of isomerism in 1-aryl-4-ferrocenyl-3-phenyltetrahydropyrimidin-2(1H)-ones obtained from ortho-substituted 3-(arylamino)-1-ferrocenylpropan-1-ols. Inspired by an interesting biological/medical features of six-membered cyclic ureas and characteristic of “atropoisomers - things that rotate”, herein we present an easy performable synthesis and full characterisation of novel atropoisomeric ferrocene-containing six-membered cyclic ureas. In addition, we successfully determined the crystal structure of two atropoisomers for the same compound. Molecular structural properties and intermolecular interactions of these two structures have been compared and analyzed in detail. Interesting, it has been found that these two isomers although quite similar in conformation and geometrical parameters, form very different crystal packing.

Molecular Modeling of Anti HIV Drugs of Protease Inhibitor Group by CoMFA

An anti-HIV agent may exert its activity by inhibiting a variety of steps in the life cycle of virus. In recent advances medicinal chemists have focused their attention mainly on virial binding to target cells, virus-cell fusion, virus uncoating, reverse transcription of genomic RNA, viral integration, gene expression, cleavage events through protease inhibitors and virion mutarotation. In present study cleavage events through protease inhibitors have been done by CoMFA. There are a number of physical, structural and chemical descriptors which may be helpful in computer aided drug designing. Out of them hydrophobicity in particular can be easily quantified for complete molecule or even for individual substituent. 26 derivatives of cyclic urea and 8 derivatives of Isosteres belonging to non-peptidic and peptidic PR inhibitors were taken as study material and a number of MLR equations using different combinations of descriptors have been developed. On the basis of these regression values, theoretical activity of the various models is predicted which provides an insight into structural and binding features of the proposed models.

Pd-Catalyzed Asymmetric Allylic Cycloaddition of N-Containing Allylic Carbonates with Isocyanates.

An efficient method for the enantioselective synthesis of cyclic ureas has been developed through Pd-catalyzed asymmetric allylic cycloaddition of readily accessible nitrogen-containing allylic carbonates with isocyanates. By using a palladium complex in situ generated from Pd2(dba)3·CHCl3 and phosphoramidite L1 or L3 as a ligand under mild reaction conditions, the process afforded imidazolidinones and tetrahydropyrimidinones with high yields and high levels of enantioselectivities.

Quantitative structure-activity relationship (QSAR) models and their applicability domain analysis on HIV-1 protease inhibitors by machine learning methods

HIV-1 protease inhibitors (PIs) make a vital contribution on highly active antiretroviral therapy (HAART) of human immunodeficiency virus (HIV). In this study, 14 quantitative structure-activity relationship (QSAR) models on 1238 PIs were built by four machine learning methods, including multiple linear regression (MLR), support vector machine (SVM), random forest (RF) and deep neural networks (DNlN). For the best model Model2G constructed by DNN algorithm, the coefficient of determination (R2) of 0.88 and 0.79, the root mean squared error (RMSE) of 0.39 and 0.51 were obtained on training set and test set, respectively. For model Model2G, the applicability domain threshold (ADT) of 1.765 was obtained for training set, a compound that has a similarity distance (d) less than the ADT is considered to be inside the applicability domain, could be predicted accurately, and thus 65.37% compounds in test set performed reliable. In addition, the 1238 PIs were manually divided into eight subsets containing different scaffolds. It was found that hydroxylamine derivatives and seven-member cyclic urea derivatives showed highly inhibitory activity comparing with other subsets. We also built QSAR models with SVM, RF and DNN methods on two subsets of 299 hydroxylamine derivatives inhibitors (Dataset2) and 377 seven-member cyclic urea derivatives inhibitors (Dataset3). For the best model Model3A on Dataset2, R2 of 0.71 and RMSE of 0.53 were obtained for test set. For the best model Model4B on Dataset3, R2 of 0.82 and RMSE of 0.51 were obtained for test set. At last, we analyzed the descriptors which make significant contributions on the bioactivity of inhibitors among these two subsets. It was found that highly active inhibitors of seven-member cyclic urea derivatives usually contained several aromatic nitrogen heterocyclic ring substituents such as the inidazole and the pyrazole. The oxazolidinone group and sulfanilamide mainly appeared in highly active inhibitors of hydroxylamine derivatives. These observations may be utilized further in designing promising HIV-1 protease inhibitors.