Cyclic Urea Research Articles

Light-driven deracemization enabled by excited-state electron transfer.

Deracemization is an attractive strategy for asymmetric synthesis, but intrinsic energetic challenges have limited its development. Here, we report a deracemization method in which amine derivatives undergo spontaneous optical enrichment upon exposure to visible light in the presence of three distinct molecular catalysts. Initiated by an excited-state iridium chromophore, this reaction proceeds through a sequence of favorable electron, proton, and hydrogen-atom transfer steps that serve to break and reform a stereogenic C-H bond. The enantioselectivity in these reactions is jointly determined by two independent stereoselective steps that occur in sequence within the catalytic cycle, giving rise to a composite selectivity that is higher than that of either step individually. These reactions represent a distinct approach to creating out-of-equilibrium product distributions between substrate enantiomers using excited-state redox events.

Photocatalytic deracemization fixes the mix.

Photocatalysis converts racemic mixtures of N -aryl cyclic ureas into single enantiomers

Predicting the Enthalpies of Sublimation of Cyclic Urea Derivatives Using a Model of the Molecular Electrostatic Potential

An equation for estimating the enthalpies of sublimation of cyclic urea derivatives is proposed that considers the correlation between the enthalpy of sublimation, calculated values of the crystal density and molecular surface, and four parameters characterizing the distribution of the electrostatic potential on the surface of a molecule.

Discovery of Ligand-Efficient Scaffolds for the Design of Novel Trichomonas vaginalis Uridine Nucleoside Ribohydrolase Inhibitors Using Fragment Screening.

Trichomoniasis is caused by the parasitic protozoan Trichomonas vaginalis. The increasing prevalence of strains resistant to the current 5-nitroimidazole treatments creates the need for novel therapies. T. vaginalis cannot synthesize purine and pyrimidine rings and requires salvage pathway enzymes to obtain them from host nucleosides. The uridine nucleoside ribohydrolase was screened using an 19F NMR-based activity assay against a 2000-compound fragment diversity library. Several series of inhibitors were identified including scaffolds based on acetamides, cyclic ureas or ureas, pyridines, and pyrrolidines. A number of potent singleton compounds were identified, as well. Eighteen compounds with IC50 values of 20 μM or lower were identified, including some with ligand efficiency values of 0.5 or greater. Detergent and jump-dilution counter screens validated all scaffold classes as target-specific, reversible inhibitors. Identified scaffolds differ substantially from 5-nitroimidazoles. Medicinal chemistry using the structure–activity relationship emerging from the fragment hits is being pursued to discover nanomolar inhibitors.

Nanoscale Restructuring of Polymer Materials to Produce Single Polymer Composites and Miscible Blends.

I summarize work conducted in our laboratories over the past 30 years using small host molecules to restructure polymer materials at the nanometer level. Certain small molecules, such as the cyclic starches cyclodextrins (CDs) and urea (U) can form non-covalent crystalline inclusion compounds (ICs) with a range of guest molecules, including many polymers. In polymer-CD- and -U-ICs, guest polymer chains reside in narrow channels created by the host molecule crystals, where they are separated and highly extended. When the host crystalline lattice is carefully removed, the guest polymer chains coalesce into a bulk sample with an organization that is distinct from that normally produced from its melt or from solution. Amorphous regions of such coalesced polymer samples have a greater density, likely with less chain entanglement and more chain alignment. As a consequence, after cooling from their melts, coalesced amorphous polymers show glass-transition temperatures (Tgs) that are elevated above those of samples prepared from their solutions or melts. Upon cooling from their melts, coalesced samples of crystallizable polymers show dramatically-increased abilities to crystallize more rapidly and much closer to their melting temperatures (Tms). These unique behaviors of polymers coalesced from their CD- and U-ICs are unexpectedly resistant to extended annealing above their Tgs and Tms. Taking advantage of this behavior permits us to create polymer materials with unique and improved properties. Among these are amorphous polymers with elevated Tgs and semi-crystalline polymers with finer more uniform morphologies. Improved mechanical properties can be achieved through self-nucleation with small amounts of the same polymer made rapidly crystallizable through coalescence from its CD- or U-IC. This can lead to single polymer composites with as-received polymer matrices and self-nucleated reinforcements. Through simultaneous formation and subsequent coalescence from their common CD–ICs, stable well-mixed blends can be achieved between any two or more polymers, despite their inherent immiscibilities. Such coalesced and well-mixed blends are also resistant to phase segregation when heated for extensive periods well above their Tgs and Tms.

An Improved Synthesis of Urea Derivatives from N-Acylbenzotriazole via Curtius Rearrangement

The good leaving tendency of the benzotriazole moiety has been exploited for the synthesis of symmetric, unsymmetric, N-acyl, and cyclic ureas in good yields from N-acylbenzotriazoles by treating the latter with various amines in the presence of TMSN3/Et3N in a sealed tube. The salient features of the devised protocol includes the high-yield, mild, metal-free, one-pot reaction conditions, and short reaction time. Furthermore, in many cases, no column chromatography is required for the purification.

Recent Advances in the Chemical Fixation of Carbon Dioxide: A Green Route to Carbonylated Heterocycle Synthesis

Carbon dioxide produced by human activities is one of the main contributions responsible for the greenhouse effect, which is modifying the Earth’s climate. Therefore, post-combustion CO2 capture and its conversion into high value-added chemicals are integral parts of today’s green industry. On the other hand, carbon dioxide is a ubiquitous, cheap, abundant, non-toxic, non-flammable and renewable C1 source. Among CO2 usages, this review aims to summarize and discuss the advances in the reaction of CO2, in the synthesis of cyclic carbonates, carbamates, and ureas appeared in the literature since 2017.

Catalytic Diastereo- and Enantioselective Synthesis of 2-Imidazolinones.

Chiral cyclic ureas (2-imidazolinones) were prepared by the reaction of nitrones and isocyanoacetate esters using a multicatalytic system that combines a bifunctional Brønsted base-squaramide organocatalyst and Ag+ as a Lewis acid. The reaction could be achieved with a range of nitrones derived from aryl- and cycloalkylaldehydes with moderate diastereo- and good enantioselectivity. A plausible mechanism involving an initial formal [3 + 3] cycloaddition of the nitrone and isocyanoacetate ester, followed by rearrangement to an aminoisocyanate and cyclization to the imidazolinone, is proposed.

Total Synthesis of Pactalactam, an Imidazolidinone-Type Pactamycin Analogue.

The first total synthesis of pactalactam was accomplished using substrate-controlled stereoselective aziridination and regioselective aziridine ring-opening to construct three continuous amino groups on an octasubstituted cyclopentane core. The cyclopentane framework was obtained by ring-closing metathesis and aldol coupling using a l-threonine-derived oxazoline compound. Cyclic urea formation, m-acetylphenyl group introduction by Chan-Lam coupling, and primary alcohol-selective acylation yielded the reported pactalactam structure. The presence of pactalactam in the fermentation broth of pactamycin-producing bacteria was also confirmed.

Synthesis of Imidazolidinone, Imidazolone, and Benzimidazolone Derivatives through Oxidation Using Copper and Air.

A new synthetic method of urea derivatives using copper and air was developed. These mild conditions provided moderate to very good yields for 15 examples (53-93%), while low yields were obtained with sterically hindered substrates (3 examples). The reaction was found to go through an in situ generated copper- N-heterocyclic carbene, which was then oxidized into cyclic urea derivatives possessing alkyl, benzyl, aryl, hydroxy, Boc-protected, and tertiary amine groups.

Stereocontrolled synthesis of bicyclic ureas and sulfamides via Pd-catalyzed alkene carboamination reactions

The synthesis of bicyclic ureas and sulfamides via palladium-catalyzed alkene carboamination reactions between aryl/alkenyl halides/triflates and alkenes bearing pendant cyclic sulfamides and ureas is described. The substrates for these reactions are generated in 3–5 steps from commercially available materials, and products are obtained in good yield with up to >20:1 diastereoselectivity. The stereochemical outcome of the sulfamide alkene addition is consistent with a mechanism involving anti-aminopalladation of the alkene, whereas the stereochemical outcome of the urea alkene addition is consistent with a syn-aminopalladation mechanism.

Organocatalytic Synthesis of Enantioenriched Five- and Six-Membered Cyclic Ureas

Organocatalytic Synthesis of Enantioenriched Five- and Six-Membered Cyclic Ureas

Synthesis of Imidazolidin-2-ones and Imidazol-2-ones via Base-Catalyzed Intramolecular Hydroamidation of Propargylic Ureas under Ambient Conditions.

The first organo-catalyzed synthesis of imidazolidin-2-ones and imidazol-2-ones via intramolecular hydroamidation of propargylic ureas is reported. The phosphazene base BEMP turned out to be the most active organo-catalyst compared with guanidine and amidine bases. Excellent chemo- and regioselectivities to five-membered cyclic ureas have been achieved under ambient conditions, with a wide substrate scope and exceptionally short reaction times (down to 1 min). A base-mediated isomerization step to an allenamide intermediate is the most feasible reaction pathway to give imidazol-2-ones, as suggested by DFT studies.

Rapid and Efficient Synthesis of 11C‐Labeled Benzimidazolones Using [11C]Carbon Dioxide

Abstract[11C]Carbon dioxide is an attractive synthon for the labeling of positron emission tomography (PET) tracers for subsequent use in biomedical research and drug development. In this study, [11C]CO2 was used for direct 11C‐labeling of a set of cyclic aromatic ureas starting from their corresponding ortho‐phenylenediamines, BEMP (2‐tert‐butylimino‐2‐diethylamino‐1,3‐dimethylperhydro‐1,3,2‐diazaphosphorine) as fixation base, and Mitsunobu reagents (DBAD, nBu3P) for the intramolecular cyclization. The procedure is rapid (6 minutes total synthesis time), mild (proceeds at room temperature) and provided a set of 11C‐benzimidazolones in good to excellent radiochemical yields. As a final testament to the utility of this method, the beta‐adrenoceptor PET ligand [11C]CGP12177, was successfully prepared using the optimized conditions.

Synthesis and Biological Evaluation of 3,9-Dioxatetraasteranes as C2-Symmetric HIV-1 Protease Inhibitors and Docking Study.

A series of tetraethyl 2,4,8,10-tetramethyl-6,12-diaryl-3,9-dioxahexacyclo[6.4.0.02,7.04,11.05,10]dodecane-1,5,7,11-tetracarboxylates (simplified as 3,9-dioxatetraasteranes) with C2-symmetric structural characteristics were synthesized through the [2 + 2] photocycloaddition of the diethyl 2,6-dimethyl-4-aryl-4H-pyran-3,5-dicarboxylates. Besides, their anti-human immunodeficiency virus (HIV)-1 activities were evaluated by enzyme-linked immunosorbent assay (ELISA) assay against HIV-1 (IIIB) replication in MT-4 cell culture. The result showed that the tested compounds exhibited potential activates with IC50 values less than 110 nM. Furthermore, docking study was carried out to study the binding mode of these compounds. The results indicated that the overall orientation of the inhibitors in the active site were similar to that of the cyclic urea AHA001 and a hydrogen bond with the protein residues might play a crucial role in their anti-HIV-1 activities. Such results will provide a theoretical foundation for further investigations on the biological activity of 3,9-dioxatetraasteranes.

Flow Electrochemical Cyclizations via Amidyl Radicals: Easy Access to Cyclic Ureas

Flow chemistry has advantages over batch processes and can achieve the synthesis of substances in high yield under safe working conditions. The combination of electrochemistry and flow microreactor technology has made chemical transformations possible without the use of oxidants or catalysts. Herein, we report flow electrosynthesis of cyclic ureas via oxyamination of N-allylic ureas. We have found that continuous flow is able to outperform its batch counterpart, producing cyclic ureas in excellent yields.

Binary organocatalytic system for ring-opening polymerization of ε-caprolactone and δ-valerolactone: Synergetic effects for enhanced selectivity

Phosphazenes have attracted considerable attention in the field of ring-opening polymerization (ROP) of cyclic esters. However, the application of phosphazenes as catalyst is subject to a trade-off between activity and selectivity (chain propagation versus transesterification/back-biting reaction, e.g., controlled polymerization). Despite extensive research efforts, the development of a new catalytic system having concurrent high activity and selectivity remains a great challenge. In this work, we report that the binary organocatalytic system comprised of cyclic trimeric phosphazene base (CTPB) and ureas shows both of high activity and selectivity for the ROP of ε-caprolactone (ε-CL) and δ-valerolactone (δ-VL) in the presence of alcohol as initiator. It is found that the introduction of ureas would significantly increase the catalytic selectivity during ROP without sacrificing the catalytic activity of CTPB. Moreover, the polymerizations catalyzed by the title catalytic system exhibit immortal characteristics and thus thousands equivalent of monomer could be converted to polymer efficiently with desired MWs and microstructures. Linear diblock copolymer AB and star copolymers (AB)3 with three identical diblock arms could be readily synthesized by sequential copolymerization using different alcohols as initiators.

Efficient Non‐Catalytic Carboxylation of Diamines to Cyclic Ureas Using 2‐Pyrrolidone as a Solvent and a Promoter

AbstractCarboxylation reactions of diamines were found to proceed rapidly and non‐catalytically, producing corresponding cyclic ureas in excellent yields and selectivities when 2‐pyrrolidone (2‐PY) was used as a solvent. A similar promoting effect with 2‐PY was also observed for the carboxylation of monoamines by carbon dioxide (CO2). Most notably, the carboxylation reactions of mono‐ and diamines conducted in 2‐PY afforded 2–4 times higher yields of corresponding dialkyl ureas and cyclic ureas compared with those in N‐methyl‐2‐pyrrolidone (NMP). Such a dramatic promoting effect using 2‐PY is believed to be associated with the multiple hydrogen bonding interactions between 2‐PY and the CO2‐containing species of amines. Due to such favorable interactions, carboxylation reactions seem to be more facilitated in 2‐PY than in NMP.magnified image

Enantioselective Organocatalytic Amine-Isocyanate Capture-Cyclization: Regioselective Alkene Iodoamination for the Synthesis of Chiral Cyclic Ureas.

Ureas of chiral diamines are prominent features of therapeutics, chiral auxiliaries, and intermediates in complex molecule synthesis. Although many methods for diamine synthesis are available, metal-free enantioselective alkene functionalizations to make protected 1,2- and 1,3-diamines from simple achiral starting materials are rare, and a single reagent that accesses a cross-section of each congener with high enantiomeric excess is not available. We describe a method to synthesize enantioenriched cyclic 5- and 6-membered ureas from allylic amines and an isocyanate using a C2-symmetric BisAmidine (BAM) catalyst that delivers N-selectivity from an ambident sulfonyl imide intermediate, overcoming electronic and steric deactivation at nitrogen. The geometry of 1,2-disubstituted alkenes is correlated to 5-exo and 6-endo cyclizations without altering alkene face selectivity, which is unexpectedly opposite that observed with O-nucleophiles. Straightforward product manipulations to diamine and imidazolidinone derivatives are underscored by the synthesis of an NK1 antagonist.

Structure Design of Low-Temperature Regenerative Hyperbranched Polyamine Adsorbent for CO2 Capture.

A novel low-temperature regenerative hydroxy-functionalized hyperbranched polyamine adsorbent (0.16OH-HBPA) for CO2 capture was readily prepared using glutaraldehyde to cross-link amino-terminated hyperbranched polymers (HBP) and functionalized with glycidol, followed by the reduction of the imino groups of 0.16OH-HBPA to alkyl aminos using NaBH4. Here, the HBP has been prepared through the one-pot reaction between pentaethylenehexamine and methyl acrylate. The as-prepared 0.16OH-HBPA adsorbent showed a high adsorption capacity (4.05 mmol/g) for CO2 (concentration, 10%) in the presence of water at 25 °C, and the alkyl amino utilization efficiency reached 73%. More importantly, the CO2-adsorbed 0.16OH-HBPA showed excellent regenerative performance at low temperatures (85 °C, under pure CO2 gas) due to the introduced hydroxyl that can cooperatively adsorb CO2 via the amino groups to form stable carbamic acid. This process suppressed the formation of open-chain urea and cyclic urea and could overcome the disadvantages of high regeneration temperatures (≥90 °C, under pure inert gas) of CO2-adsorbed traditional solid amine adsorbents.