A Three-Component Synthesis of Spiropyrrolines.

A rapid synthesis of medicinally important spiropyrrolines has been achieved by the reaction of 1,3-indanediones, benzaldehyde, and (1-azidovinyl)benzene under catalyst- and reagent-free conditions. This is the first report to synthesize diverse spiropyrroline compounds from readily available feedstock materials under metal-free conditions.

Cu(II)/PTABS-Promoted, Chemoselective Amination of HaloPyrimidines.

Chemoselective amination is a highly desired synthetic methodology, given its importance as a possible strategy to synthesize various drug molecules and agrochemicals. We, herein, disclose a highly chemoselective Cu(II)-PTABS-promoted amination of pyrimidine structural feature containing different halogen atoms.

Metal-free oxidative coupling of aryl acetylene with elemental sulphur and amines: facile access to α-ketothioamides.

A simple and efficient oxidative coupling of aromatic alkynes with elemental sulphur and secondary amines has been reported. The iodine/DMSO system easily promoted the transformations, affording thioglyoxamides via C-S, C-O, and C-N bond formations. In this context, acetylenic C-H bond oxidation has occurred through iodination, leading to the desired products. Moreover, this metal-free, one-pot protocol is accomplished by using readily available starting materials, without external oxidants, and under aerobic conditions, providing a variety of α-ketothioamide compounds in moderate to good yields.

Visible-light promoted oxidative annulation of 2-naphthols with phenylglyoxal monohydrates toward hydroxy-naphthofuranone and its derivatives.

A highly efficient and innovative method involving base-mediated oxidative annulation between 2-naphthols and phenylglyoxal monohydrate under visible light irradiation has been successfully developed. This method leads to the formation of oxygen-containing heterocyclic compounds, particularly hydroxy-naphthofuranone derivatives, encompassing a unique quaternary carbon center. An X-ray diffraction study has unambiguously confirmed the structure of one such derivative. In particular, water molecules in this reaction serve various functions as a solvent, reagent, and additive, with the conversion of the process found to be influenced by the volume of water present. This atom-economical approach demonstrates tolerance for different substituents in both phenylglyoxal monohydrate and 2-naphthol, enabling the synthesis of a variety of naphthofuranones in satisfactory to good yields. The formation of a naphthofuranium cationic intermediate under acidic circumstances enables the formation of C-C or C-O bonds with a wide range of aromatic or alcoholic nucleophilic partners. Furthermore, the identification and generation of pinacol-type starting precursors from these naphthofuranone derivatives enable the synthesis of highly regioselective naphthofuran derivatives.

Metal-free efficient synthesis of aryl sulfonamides from N-hydroxy sulfonamide and amines.

A simple and novel approach has been developed for the synthesis of sulfonamides from N-hydroxy sulfonamide. Notably, the iodine-tert-butyl hydroperoxide (TBHP) system efficiently promoted the sulfonylation reactions of N-hydroxy sulfonamides and amines via the oxidative cleavage of an S-N bond. A variety of aryl sulfonamides were prepared in moderate to good yields using readily available starting materials and the biomass-derived 2-MeTHF solvent. The present method has the advantages of using metal-free reagents, an eco-friendly medium, cost-effective reagents, wide substrate scope, and mild conditions.

Multi-component forms of the 2nd generation H1 receptor antagonist drug, Bilastine and its enhanced physicochemical characteristics.

Bilastine (BIL) is a novel 2nd generation antihistamine medication is used to treat symptoms of chronic urticaria and allergic rhinitis. However, its poor solubility limits its therapeutic efficacy. In order to enhance the physicochemical characteristics of BIL, various molecular adducts of BIL (Salt, hydrate and co-crystal) were discovered in this study using two distinct salt-formers: Terephthalic acid (TA), 2,4-Dihydroxybenzoic acid (2,4-DHBA), and three nutraceuticals (Vanillic Acid (VA), Hydroquinone (HQN) and Hippuric acid (HA)). Various analytical methods were used to examine the synthesised adducts, including Powder X-Ray Diffraction (PXRD), Single Crystal X-ray Diffraction (SCXRD), and thermal analysis (Thermogravimetric analysis (TGA) and Differential Scanning Calorimetry (DSC)). Single-crystal X-ray diffraction (SCXRD) studies avowed that the architectures of the molecular adducts are maintained in the solid state by an array of strong (N+H⋯O-, NH⋯O, OH⋯O) and weak (CH⋯O) hydrogen bonds. Additionally, a solubility test was performed to establish the in vitro release characteristics of newly synthesised BIL adducts and it observed that most of the molecular adducts exhibit higher rates of dissolution in comparison to pure BIL; in particular, BIL.TA.HYD showed the highest solubility and the fastest rate of dissolution. Moreover, experiments on flux permeability and diffusion demonstrated that the BIL.TA.HYD and BIL.VA salts had strong permeability and a high diffusion rate. In addition, the synthesized adduct's stability was assessed at 25 °C and 90 % ± 5 % relative humidity, and it was found that all the molecular salts were stable and did not undergo any phase changes or dissociation. The foregoing result leads us to believe that the newly synthesized molecular adducts' increased permeability and solubility will be advantageous for the creation of novel BIL formulations.

Four component Ugi reaction based small-molecule probes for integrated phenotypic screening.

Quorum-sensing (QS) is a cell density-dependent signaling pathway regulated by gene expression for intra- and interspecies communication. We have targeted QS activity in Pseudomonas aeruginosa, an opportunistic human pathogen that causes disease in immunocompromised patients, with a set of probes containing a variety of functional groups, including photoreactive (diazirine) and affinity (alkyne) moieties, that were synthesized using a four-component Ugi reaction (Ugi-4CR).

Immunoediting role for major vault protein in apoptotic signaling induced by bacterial N-acyl homoserine lactones.

The major vault protein (MVP) mediates diverse cellular responses, including cancer cell resistance to chemotherapy and protection against inflammatory responses to Pseudomonas aeruginosa Here, we report the use of photoactive probes to identify MVP as a target of the N-(3-oxo-dodecanoyl) homoserine lactone (C12), a quorum sensing signal of certain proteobacteria including P. aeruginosa. A treatment of normal and cancer cells with C12 or other N-acyl homoserine lactones (AHLs) results in rapid translocation of MVP into lipid raft (LR) membrane fractions. Like AHLs, inflammatory stimuli also induce LR-localization of MVP, but the C12 stimulation reprograms (functionalizes) bioactivity of the plasma membrane by recruiting death receptors, their apoptotic adaptors, and caspase-8 into LR. These functionalized membranes control AHL-induced signaling processes, in that MVP adjusts the protein kinase p38 pathway to attenuate programmed cell death. Since MVP is the structural core of large particles termed vaults, our findings suggest a mechanism in which MVP vaults act as sentinels that fine-tune inflammation-activated processes such as apoptotic signaling mediated by immunosurveillance cytokines including tumor necrosis factor-related apoptosis inducing ligand (TRAIL).

Synthetic Strategies of N-Heterocyclic Olefin (NHOs) and Their Recent Application of Organocatalytic Reactions and Beyond.

N-heterocyclic olefin (NHO) derivatives have an electron-rich as well as highly polarized carabon-carbon (C=C) double bond because of the electron-donating nature of nitrogen and sulphur atoms. While NHOs have been developing as novel organocatalysts and ligands for transition-metal complexes in various organic compound syntheses, different research groups are currently interested in preparing imidazole and triazolium-based chiral NHO catalysts. Some of them have been used for enantioselective organic transformations, but were still elusive. N-heterocyclic olefins, the alkylidene derivatives of N-heterocyclic carbenes (NHC), have shown promising results as effective promoters for numerous organic syntheses such as asymmetric catalysis, hydroborylation, hydrosilylation, reduction, CO2 sequestration, alkylation, cycloaddition, polymerization and the ring-opening reaction of aziridine and epoxides, esterification, C-F bond functionalization, amine coupling, trifluoromethyl thiolation, amination etc. NHOs catalysts with suitable structures can serve as a novel class of Lewis/Bronsted bases with strong basicity and high nucleophilicity properties.These facts strongly suggest their enormous chemical potential as sustainable catalysts for a wide variety of reactions in synthetic chemistry. The synthesis of NHOs and their properties are briefly reviewed in this article, along with a summary of the imidazole and triazole core of NHOs' most recent catalytic uses.

Cascade Nucleophilic Addition-Cyclic Michael Addition of Arynes and Indoles Bearing Michael Acceptor: A Strategy to Construct Pyrroloacridines and Study of Their Physicochemical Properties.

A facile synthetic approach to 6H-pyrrolo[3,2,1-de]acridines has been developed by using cascade N-nucleophilic addition-cyclic Michael addition process of arynes and indoles substituted with Michael acceptors under metal-free conditions. Additionally, photophysical studies of a few of the newly synthesized pyrroloacridine compounds indicated good fluorescence emission properties.

Cu(II)/PTABS-Promoted, Regioselective SNAr Amination of Polychlorinated Pyrimidines with Mechanistic Understanding.

Regioselective amination of polyhalogenated heteroarenes (especially pyrimidines) has extensive synthetic and commercial relevance for drug synthesis applications but is plagued by the lack of effective synthetic strategies. Herein, we report the Cu(II)/PTABS-promoted highly regioselective nucleophilic aromatic substitution (SNAr) of polychlorinated pyrimidines assisted by DFT predictions of the bond dissociation energies of different C-Cl bonds. The unique reactivity of Cu(II)-PTABS has been attributed to the coordination/activation mechanism that has been known to operate in these reactions, but further insights into the catalytic species have also been provided.

Pd-catalyzed homo-coupling of benzofurans: one-pot synthesis of diverse 3,3'-bisbenzofurans.

An efficient and one-pot synthesis of 3,3'-bisbenzofuran derivatives has been developed. The protocol involved the use of a Pd catalyst and Cu(OAc)2 along with molecular oxygen as the oxidant to afford bisbenzofurans via a dehydrogenative homo-coupling reaction. The reaction exhibited good functional group/heterocycle tolerance and is amenable for gram scale synthesis.

I2/TBHP-mediated oxidative cascade cyclization of vinyl azide and benzylamine to construct 2,5-disubstituted oxazoles.

A one-pot facile synthesis of disubstituted oxazoles has been achieved from vinyl azide and benzylamine. A coherent mixture of iodine and tert-butyl hydroperoxide (TBHP) efficiently promoted oxidative cascade cyclization to construct 2,5-disubstituted oxazoles under aerobic conditions. Notably, the oxidative cyclization involves feasible C(sp3)-functionalization with the elimination of the azide group as the intermediate step. In consequence, the consecutive C-N and C-O bond formations lead to a variety of disubstituted oxazole derivatives. Moreover, the one-pot methodology features a metal-free strategy, readily available reagents, shorter times, good yields, and mild reaction conditions.

Zinc-catalyzed transamidation and esterification of N-benzoyl cytosine via C-N bond cleavage.

We have utilized N-benzoyl cytosine for efficient transamidation and esterification via catalytic C-N bond cleavage. The one-pot strategy involves the reaction of secondary amide with various aliphatic or aromatic amines and alcohols in the presence of zinc triflate and DTBP, affording diverse amides and esters in excellent yields.

Copper-catalysed chemoselective C-OH bond activation of N-benzoyl cytosine: facile access to 2-(dimethylamino)pyrimidine.

A novel method for the direct amination of N-benzoyl cytosine has been developed, giving access to 2-(dimethylamino)pyrimidine derivatives. A copper(II) catalyst and tert-butyl hydroperoxide easily promote the selective amination process that proceeds via C-OH bond activation. This practical approach can utilize different formamide molecules, N,N-dimethylformamide and N,N-diethylformamide, as efficient amino (-NMe2, -NEt2) sources. Moreover, the facile nature of the procedure, its broad tolerance of aliphatic and aromatic substrates, the high yields and ease of separation of the products, and the fact that it can be conducted under aerobic conditions are all notable advantages of the present protocol.

Copper catalysed oxidative cascade deamination/cyclization of vinyl azide and benzylamine for the synthesis of 2,4,6-triarylpyridines.

A highly efficient one-pot method for the synthesis of 2,4,6-triaryl pyridines has been developed via cascade deamination and annulation. Copper triflate and molecular iodine easily promoted the oxidative cyclization reaction of vinyl azide and benzylamine to access a wide variety of substituted pyridine substrates under an oxygen atmosphere. The presence of benzyl amine enables the cyclization process by providing the aryl functionality and the nitrogen source. Moreover, a broad range of substrates with good functional group tolerance, avoidance of external oxidants, excellent product yields, operational simplicity and mild conditions are the notable advantages of the present protocol.

A Method to Access Highly Functionalized Dibenzobicyclo[3.2.1]octadienones: Application to the Construction of the 6/6/5/6/6 Carbon Skeleton of Rubialatin A.

The dibenzobicyclo[3.2.1]octadienone scaffold, which has been found in naphthocyclinones, engelharquinones, rubialatin A, etc., has been synthesized under mild transition metal-free conditions by aryne insertion reaction with 2-keto-1,3-indandiones. The application of this methodology has been demonstrated for the synthesis of the 6/6/5/6/6 scaffold of rubialatin A. 1H NMR experimental studies confirm that the reaction proceeds through the formation of benzocyclobutane followed by a 7-member carbocycle ring.

Iodine-TBHP mediated efficient synthesis of α-ketoamides from vinyl azides and amines under mild conditions.

A convenient and practical synthetic approach for α-ketoamides has been developed under mild conditions. The facile synthesis of α-ketoamides has been accomplished using aryl vinyl azides and secondary amines at room temperature. The inexpensive and readily available iodine and TBHP easily promoted the oxidative amidation process to afford diketoamide derivatives in high yields. This method involves the synthesis of ketoamide compounds via sequential C-O and C-N bond formation. Moreover, metal-free and aerobic conditions and wide substrate scope are the notable advantages of this protocol.

Room-Temperature Amination of Chloroheteroarenes in Water by a Recyclable Copper(II)-Phosphaadamantanium Sulfonate System.

Buchwald-Hartwig amination of chloroheteroarenes has been a challenging synthetic process, with very few protocols promoting this important transformation at ambient temperature. The current report discusses about an efficient copper-based catalytic system (Cu/PTABS) for the amination of chloroheteroarenes at ambient temperature in water as the sole reaction solvent, a combination that is first to be reported. A wide variety of chloroheteroarenes could be coupled efficiently with primary and secondary amines as well as selected amino acid esters under mild reaction conditions. Catalytic efficiency of the developed protocol also promotes late-stage functionalization of active pharmaceutical ingredients (APIs) such as antibiotics (floxacins) and anticancer drugs. The catalytic system also performs efficiently at a very low concentration of 0.0001 mol % (TON = 980,000) and can be recycled 12 times without any appreciable loss in activity. Theoretical calculations reveal that the π-acceptor ability of the ligand PTABS is the main reason for the appreciably high reactivity of the catalytic system. Preliminary characterization of the catalytic species in the reaction was carried out using UV-VIS and ESR spectroscopy, providing evidence for the Cu(II) oxidation state.

Ultrasound assisted rapid synthesis of mefenamic acid based indole derivatives under ligand free Cu-catalysis: Their pharmacological evaluation.

An improved and rapid synthesis of mefenamic acid based indole derivatives has been achieved via the ligand free Cu-catalyzed coupling-cyclization method under ultrasound irradiation. This simple, straightforward and inexpensive one-pot method involved the reaction of a terminal alkyne derived from mefenamic acid with 2-iodosulfanilides in the presence of CuI and K2CO3 in PEG-400. The reaction proceeded via an initial CC bond formation (the coupling step) followed by CN bond formation (the intramolecular cyclization) to afford the mefenamic acid based indole derivatives in good to acceptable yields. Several of these compounds showed inhibition of PDE4 in vitro and the SAR (Structure Activity Relationship) within the series is discussed. The compound 3d has been identified as a promising and selective inhibitor of PDE4B (IC50 = 1.34 ± 0.46 µM) that showed TNF-α inhibition in vitro (IC50 = 5.81 ± 0.24 µM) and acceptable stability in the rat liver microsomes.