One-pot Cyclization Research Articles

Ruthenium(II)-Catalyzed C–H Annulation of Mandelic Acids with Internal Alkynes to Construct Isocoumarins

AbstractA series of isocoumarins were synthesized by a one-pot cyclization reaction with mandelic acids and internal alkynes as raw materials, [RuCl2(p-cymene)]2 as a catalyst, and Cu(OAc)2·H2O as an oxidant under reflux conditions in air. By using the established efficient and reliable reaction conditions, a range of substrates were explored, and it was found that both aromatic aldehydes and aromatic acids also reacted smoothly in this system to give moderate yields of the target products. Furthermore, the mandelic acids were shown to be converted into the corresponding benzoic acids as intermediates in the reaction.

K2CO3-nanoparticles catalyzed the synthesis of 3-arylidine imidazo[1,2-c]pyrimidine candidates: Cytotoxic activity and docking study

The present work describes an green and eco-friendly synthetic protocol, and vitro anti-proliferative activity of a new series of 3-arylidine imidazo[1,2-c]pyrimidines. The target molecules 4a–p were synthesized via one-pot cyclization of 6-amino-4-(4-chlorophenyl)-2-thioxo-1,2-dihydropyrimidine-5-carbonitrile(1) with chloroacetyl chloride followed by condensation with a series of aromatic and heteroaromatic aldehydes in the presence of K2CO3-NPs at room temperature. The high yield (80–96%), mild reaction conditions (short reaction time and no heat needed), simple purification, and soft, cheap, high efficiency readily available and stability of K2CO3-NPs are evident features of the present approach. Pyrimidines 4c, 4 g and 4i demonstrated significant anti-proliferative activity against MCF-7 especially compound 4i was found to be the most effective among the tested compounds with IC50 values 3.83 µg/ml in MCF-7 cell line compared to the standard drug doxorubicin. In addition, compounds 4b, 4c, 4d, 4i, and 4n demonstrated high cytotoxic activity against HCT116, particularly compound (4b) was the most potent among the tested compounds with IC50 values 9.3 µg/ml in HCT116 cell line compared to doxorubicin.

One-Pot Cyclization to Large Peptidomimetic Macrocycles by In Situ-Generated β-Turn-Enforced Folding.

Macrocycles have been targets of extensive synthetic efforts for decades because of their potent molecular recognition and self-assembly capabilities. Yet, efficient syntheses of macrocyclic molecules via irreversible covalent bonds remain challenging. Here, we report an efficient approach to large peptidomimetic macrocycles by using the in situ-generated β-turn structural motifs afforded in the amidothiourea moieties from the early steps of the reaction of 2 molecules of bilateral amino acid-based acylhydrazine with 2 molecules of diisothiocyanate. Four chiral and achiral peptidomimetic large macrocycles were successfully synthesized in high yields of 45-63% in a feasible one-pot reaction under sub-molar concentration conditions and were purified by simple filtration. X-ray crystallographic characterization of three macrocycles reveals an important feature that their four β-turn structures, each maintained by four 10-membered intramolecular hydrogen bonds, alternatively network the four aromatic arms. This affords an interesting conformation switching mode upon anion binding. Binding of SO42- to 1L or 1D that contains 4 alanine residues (with the lowest steric hinderance among the macrocycles) leads to an inside-out structural change of the host macrocycle, as confirmed by the X-ray crystal structure of 1L-SO42- and 1D-SO42- complexes, accompanied by an inversion of the CD signals. On the basis of the strong sulfate affinity of the macrocycles, we succeeded in the removal of sulfate anions from water via a macrocycle-mediated liquid-liquid extraction method. Our synthetic protocol can be easily extended to other macrocycles of varying arms and/or chiral amino acid residues; thus, a variety of structurally and functionally diverse macrocycles are expected to be readily made.

Syntheses of Oxazolidinone-2,3-Fused Indoline and Azaindoline Derivatives

AbstractWe herein describe a practical synthetic method to access oxazolidinone-2,3-fused indoline and azaindoline derivatives via one-pot cyclization. These derivatives, which contain sp3-hybridized carbons, may be useful as new scaffolds in medicinal chemistry.

Acyl Amidines by Pd-Catalyzed Aminocarbonylation: One-Pot Cyclizations and 11C Labeling.

A protocol for the carbonylative synthesis of acyl amidines from aryl halides, amidines, and carbon monoxide catalyzed by Pd(0) is reported herein. Notably, carbon monoxide is generated ex situ from a solid CO source, and several productive palladium ligands were identified with complementary benefits and substrate scope. Furthermore, sequential one-pot, two-step protocols for the synthesis of 1,2,4-triazoles and 1,2,4-oxadiazoles via acyl amidine intermediates are reported. In addition, this approach was extended to isotopic labeling using [11C]carbon monoxide to allow, for the first time, synthesis of 11C-labeled acyl amidines as well as a 11C-labeled 1,2,4-oxadiazole.

Palladium-Mediated Synthesis of [Carbonyl-11C]acyl Amidines from Aryl Iodides and Aryl Bromides and Their One-Pot Cyclization to 11C-Labeled Oxadiazoles.

Positron emission tomography (PET) is a highly valuable imaging technique with many clinical applications. The possibility to study physiological and biochemical processes in vivo also makes PET an important tool in drug discovery. Of importance is the possibility of labelling the compound of interest with a positron-emitting radionuclide, such as carbon-11. Carbonylation reactions with [11C]carbon monoxide ([11C]CO) has been used to label a number of molecules containing a carbonyl derivative, such as amides and esters, with carbon-11. Presented herein is the palladium-mediated carbonylative synthesis of [carbonyl-11C]acyl amidines and their subsequent cyclization to 11C-labeled 1,2,4-oxadiazoles. Starting from amidines, [11C]CO, and either aryl iodides or aryl bromides, [carbonyl-11C]acyl amidines were synthesized and isolated in good to very good radiochemical yields (RCY). The 11C-labeled 1,2,4-oxadiazoles were synthesized without the isolation of the intermediate [carbonyl-11C]acyl amidines and isolated in useful RCYs, including the NF-E2-related factor 2 activator DDO-7263. 3-Phenyl-5-(4-tolyl)-1,2,4-(5-11C)oxadiazole was synthesized and isolated with a clinically relevant molar activity. The broadened substrate scope, together with the good RCY and high Am, demonstrates the utility of this method for the incorporation of carbon-11 into acyl amidines and 1,2,4-oxadiazoles, structural motifs of pharmacological interest.

Imidazo[1,5-a]pyridine-Based Fluorescent Probes: A Photophysical Investigation in Liposome Models.

Imidazo[1,5-a]pyridine is a stable scaffold, widely used for the development of emissive compounds in many application fields (e.g., optoelectronics, coordination chemistry, sensors, chemical biology). Their compact shape along with remarkable photophysical properties make them suitable candidates as cell membrane probes. The study of the membrane dynamics, hydration, and fluidity is of importance to monitor the cellular health and to explore crucial biochemical pathways. In this context, five imidazo[1,5-a]pyridine-based fluorophores were synthesized according to a one-pot cyclization between an aromatic ketone and benzaldehyde in the presence of ammonium acetate and acetic acid. The photophysical features of prepared compounds were investigated in several organic solvents and probes 2–4 exhibited the greatest solvatochromic behavior, resulting in a higher suitability as membrane probes. Their interaction with liposomes as artificial membrane model was tested showing a successful intercalation of the probes in the lipid bilayer. Kinetic experiments were carried out and the lipidic phase influence on the photophysical features was evaluated through temperature-dependent experiments. The results herein reported encourage further investigations on the use of imidazo[1,5-a]pyridine scaffold as fluorescent membrane probes.

DBU- and DABCO-Promoted Selective Access to 2,5-Diarylnitrobenzoates and Cyclohexenones via One-Pot Reactions

AbstractRemarkable organobase-controlled selective synthesis of a wide breadth of valuable 2,5-diaryl-4-nitrobenzoates and 1-hydroxy-4-oxocyclohexencarboxylates bearing a tetrasubstituted stereogenic carbon is reported. This one-pot cyclization reaction operates between a bunch of 3-nitroallylarenes and β,γ-unsaturated α-ketocarbonyls by carefully choosing DBU or DABCO as an organobase under aerobic conditions. Notably, as a nucleophilic base, DABCO favors the Nef reaction over the dehydration–aerial oxidation process, aiming for unexpected cyclohexanone architectures. Moreover, this operationally simple technique holds a few positive qualities: good yields with diastereoselectivities (dr ≤ 91:9), broad substrate scope, no added oxidant, excellent functional group compatibility, 100% carbon-economical, etc. Furthermore, the obtained 4-nitrobenzoate framework has been utilized for the synthesis of a range of valuable compounds such as 2-phenylcarbazole-3-carboxylate, 3-bromoaniline derivative, and 2,5-diphenylbenzoic acid, among others.

Synthesis and Biological Investigation of 1,2,4-Triazolo[4,3-a]azines as Potential HSF1 Inductors

AbstractDerivatives of fused 1,2,4-triazines containing heterocyclic and metallocene fragments were obtained by one-pot oxidative cyclization of heterocyclic hydrazones in the presence of hypervalent iodine(III) reagents. For 1,2,4-triazolo[4,3-a]azines, the ability to activate HSF1 was investigated. The obtained compounds were shown to increase the degree of HSF1 activation. It was shown that the 1,2,4-triazines can be used to induce Hsp70 expression and decrease the extent of mutant HTT aggregate formation.

Chalcogenacalix[4]dithienoselenophene: Synthesis and Properties of Cyclic Thio- and Selenoether of Dithienoselenophene

Abstract Two kinds of thia- and selenacalix[4]dithienoselenophene, a cyclic dithieno[3,2-b:2′,3′-d]selenophene (DTS) oligomers bridged with divalent chalcogen atoms (S or Se), were successfully prepared via a one-pot cyclization protocol. A palladium-catalyzed coupling of dibromo DTS derivative and (Bu3Sn)2Ch (Ch = S or Se) afforded the cyclic compounds in moderate yield. We have also developed a preparation strategy for the starting DTS derivatives in multi-gram quantity. X-ray analysis revealed that these macrocyclic compounds have different conformations depending on the linker atoms. Thiacalix derivatives form an annular geometry consisting of two sets of vertical and horizontal DTS pairs, while selenacalix derivatives forms a highly symmetrical alternate arrangement of DTS units. The latter macrocycle gave a channel framework to form cavity assembled porous material. Cyclic voltammetry and differential pulse voltammetry measurements for these macrocycles indicated lower redox potentials compared to those of dithienothiophene analogues reported before. Both compounds form a 1:2 complex with C60 in the solid state through face-to-face and S⋯π interactions between DTS and C60. Two guest C60 molecules were captured in the identical space formed by a symmetrical 1,3-alternate conformer.

Front Cover: Multicomponent Domino Reactions for the Synthesis of Variable Hydrogenated Imidazo[1,2‐a]pyridines (Asian J. Org. Chem. 2/2022)

The cover art illustrates autocatalyzed one-pot cyclization of polyfluoroalkyl-3-oxo esters and ethylenediamine with aldehydes for the synthesis of new octa-, tetra- and hexahydroimidazo[1,2-a]pyridines. The proposed PASE approach provides “greening” of the synthetic pathway. The obtained variety of products is realized thanks to the skill of a chemist, which can be compared to the art of growing a bonsai tree. Thus, each branch corresponds to different reaction routes for the azaheterocycle formation. More information can be found in the Research Article by Victor Saloutin et al.

Iron-catalyzed one-pot cyclization and amination of 2-alkynylthioanisoles using nitrosobenzenes as the amine source

A direct strategy for the synthesis of 3-phenylaminobenzothiophene via iron-catalyzed cyclization of 2-alkynylthioanisoles and nitrosoarenes is presented in this work.

A Facile Synthesis of Nido-Carborane Polymers via Dynamic Self-Assembly by Poly(carboxybetaine methacrylate).

Carborane are widely applied in boron neutron capture therapy (BNCT) field, but it is difficult to perform biocompatibility with cells due to its own water solubility differences, so how to solve the water solubility problem has always been the focus of research. A simple, inexpensive and effective method was used to study the synthesis of nido-carborane azaspirodecanium poly(carboxybetaine methacrylate) by one-pot cyclization of nido-carborane azaspirodecanium under the synergistic effect of inorganic bases and conventional organic solvents. Its characterization is mainly to use 1H-NMR nuclear magnetic resonance spectrum and infrared spectroscopy to determine the characteristic peak and range of borane. Through transmission electron microscope (TEM), it can be observed that the white nanoparticles, namely carborane, are completely contained by polymer ions, which not only increases the surface area but also the concentration of boron uptake in the cell is 100 times that of borono-phenylalanine (BPA). Based on the successful synthesis of N-CB5-4 and N-CB6-5 without harsh conditions, a feasibility point of view was put forward, namely, super water-soluble carborane polymer.

Functionalized Polyhydroquinolines from Amino Acids Using a Key One-Pot Cyclization Cascade and Application to the Synthesis of (±)-Δ7-Mesembrenone.

Substituted polyhydroquinolines are ubiquitous skeletal cores found in drugs and bioactive natural products. As a new route to access this motif, we successfully developed a one-pot cyclization cascade with high chemocontrol and diastereoselectivity. The sequence generates two cycles, three carbon-carbon bonds, and an all-carbon quaternary center in a highly convergent process. Functionalized polyhydroquinolines and congeners can be accessed from commercially available amino acids. This versatile and robust strategy was applied to the synthesis of (±)-Δ7-mesembrenone.

One-Pot Cyclization and Cleavage of Peptides with N-Terminal Cysteine via the N,S-Acyl Shift of the N-2-[Thioethyl]glycine Residue.

We developed a one-pot method for peptide cleavage from a solid support via the N,S-acyl shift of N-2-[thioethyl]glycine and transthioesterification using external thiols to produce cyclic peptides through native chemical self-ligation with the N-terminal cysteine. The feasibility of this methodology is validated by the syntheses of model short peptides, including a tetrapeptide, the bicyclic sunflower trypsin inhibitor SFTI-1, and rhesus Θ-defensin RTD-1. Synthesis of the whole peptide precursor can be fully automated and proceeds without epimerization or dimerization.

Synthesis of 1,2-Amino Alcohols by Photoredox-Mediated Decarboxylative Coupling of α-Amino Acids and DNA-Conjugated Carbonyls.

We report a DNA-compatible photoredox decarboxylative coupling of α-amino acids with carbonyl compounds to access DNA-encoded sp3-rich 1,2-amino alcohols. The reaction proceeds efficiently for a wide range of DNA-conjugated aldehydes and ketones and provides the desired 1,2-amino alcohols with conversions generally >50%. Additional utility of the developed protocol is demonstrated by one-pot cyclization of DNA-conjugated 1,2-amino alcohols into oxazolidiones and morpholinones. Lastly, qPCR and sequencing data analysis indicates no significant DNA damage upon photoredox decarboxylative coupling.

6-Hydroxy-2-methylbenzofuran-4-carboxylic Acid

6-Hydroxy-2-methylbenzofuran-4-carboxylic acid was synthesized in two steps, starting from 3,5-dihydroxybenzoate. The product was obtained through a direct thermal one-pot cyclization with propargyl bromide, followed by a base-catalyzed hydrolysis. Its molecular structure was elucidated by means of mono- and bidimensional NMR techniques, ESI-MS, FT-IR and single-crystal X-ray diffraction.

One-pot synthesis, crystal structure, hirshfeld, DFT and anticancer study of ethyl 2-(3-fluoro-4-methylphenyl)-1-propyl-1H-benzo[d]imidazole-5-carboxylate

Abstract In the present study, a novel ethyl 2-(3-fluoro-4-methylphenyl)-1-propyl-1H-benzo[d]imidazole-5-carboxylate was synthesized by an efficient one-pot nitro reductive cyclization method using sodium dithionite as reductive cyclizing agent in DMSO medium. Title compound was recrystallized in Dimethyl formamide solvent. Single crystal X-ray studies revealed that the title compound crystallized in monoclinic system (P21/c space group with Z = 4) and molecules are linked with C—H…O intermolecular hydrogen bonds. The Hirshfeld surfaces computational method applied to visualize and analyze the intermolecular interactions within the crystal structure. The theoretical structural optimization of the title compound was carried out using B3LYP/6-311++G (d,p) level of theory. Anticancer screening result of compound showed promising activity against human malenoma A375 and mouse malenoma B16F10 cancer cell line with IC50 value of 33.99 μM and 31.14 μM in comparison to the standard drug Cisplatin with IC50 12.99 μM and 20.33 μM respectively.

Selenacalix[4]selenophene: Synthesis, Structure, and Gel Formation of Cyclic Selenoether of Selenophene.

A selenacalix[4]selenophene derivative, a cyclic selenophene oligomer linked with divalent selenium atoms, was successfully synthesized via a one-pot cyclization reaction using 2,5-dibromo-3,4-bis(4-t-butylphenyl)selenophene and (Bu3Sn)2Se. The X-ray analysis revealed an annular geometry consisting of two sets of vertical and horizontal selenophene pairs. The observed geometry was preserved by intermolecular Se···Se and Se···π interactions, leading to a one-dimensional array. This self-assembled network results in a supramolecular gel, despite the absence of any hydrogen bonding sites.

Rapid One-Pot Sequential Cyclization, Palladium Precatalyst Mediated Coupling Reactions of 6-Bromo-2-Chloroquinoline-3-Carboxaldehyde in Aqueous Medium

Xanthene-1,8(2H)-diones, 4 were obtained from 6-bromo-2-chloro quinoline-3-carboxaldehyde, 3 in water reflux and subsequently underwent Suzuki-Miyaura cross/Sonogashira/Stille coupling utilizing second generation XPhos Palladium preformed catalyst 1. Low catalyst loading, ambient temperature and wide scope of boronic acids, enantioselectivity are the advantages.