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Palladium(ii)-catalyzed regioselective syn-chloropalladation and anti-acetoxypalladation-initiated cascade processes were developed for the synthesis of functionalized tetrahydroquinolines. A series of N-propargyl arylamines tethered with an α,β-unsaturated carbonyl scaffold underwent atom economical cascade reactions to deliver chloro- and acetoxy-substituted tetrahydroquinolines bearing an exocyclic double bond in high yields. A mechanism is proposed for these cascade processes involving a sequential syn-chloropalladation or anti-acetoxypalladation of alkynes followed by intramolecular olefin insertion (6-exo-trig) and protonolysis steps. The reaction was completely regioselective and the terminal aryl/alkyl group of the propargyl moiety dictated the regiochemistry of the initial nucleopalladation. The role of the bidentate nitrogen ligand is crucial to trigger the acetoxypalladation-initiated cascade sequence in contrast to the chloropalladation-initiated process.

Globally, wound infections are considered as one of the major healthcare problems owing to the delayed healing process in diabetic patients and microbial contamination. Thus, the development of advanced materials for wound skin repair is of great research interest. Even though several biomaterials were identified as wound healing agents, gel-based scaffolds derived from either polymer or small molecules have displayed promising wound closure mechanism. Herein, for the first time, we report an injectable and self-healing self-assembled anesthetic oleogel derived from glycolipid, which exhibits antibiofilm and wound closure performance in diabetic rat. Glycolipid derived by the reaction of hydrophobic vinyl ester with α-chloralose in the presence of novozyme 435 undergoes spontaneous self-assembly in paraffin oil furnished an oleogel displaying self-healing behavior. In addition, we have prepared composite gel by encapsulating curcumin in the 3D fibrous network of oleogel. More interestingly, glycolipid in its native form demoed potential in disassembling methicillin-resistant Staphylococcus aureus, methicillin-susceptible Staphylococcus aureus, and Pseudomonas aeruginosa biofilms. Both oleogel and composite gel enhanced the wound skin repair in diabetic induced Wistar rats by promoting collagen synthesis, controlling free radical generation and further regulating tissue remodeling phases. Altogether, the reported supramolecular self-assembled anesthetic glycolipid could be potentially used for diabetic skin wound repair and to treat bacterial biofilm related infections.

One interesting aspect of antioxidant organic molecules is their use as probes for the detection and quantitation of biologically relevant reactive oxidant species (ROS). In this context, a small library of dihydroterphenyl derivatives has been synthesised and studied as fluorescent chemodosimeters for detecting reactive oxygen species and hypochlorite. The fluorescence quantum yields of these molecules are negligible, while the corresponding aromatized compounds formed upon oxidation show moderate to high native fluorescence, depending on their structures. The fluorescence signal is quickly developed in the presence of trace amounts of the probe and the analytes in acetonitrile media at room temperature, with good analytical figures. ROS detection in aqueous media required incubation at 37 °C in the presence of horseradish peroxidase, and was applied to glucose quantitation by coupling glucose oxidation by O 2 to fluorescence detection of H 2 O 2 . The mild reaction conditions and sensitive fluorescent response lead us to propose dihydroterphenyls with an embedded anthranilate moiety as chemosensors/chemodosimeters for ROS detection.

A sequential three-component cascade process was developed for the synthesis of bridged tetrahydroquinolines and chromanes bearing 2,6-methanobenzo[ d ][1,3]diazocine and 2,6-methanobenzo[ g ][1,3]oxazocine scaffolds, respectively, in good yields from readily available materials. The InCl 3 -catalyzed reaction progressed via enamine formation, Michael addition, intramolecular cyclization, and intramolecular iminium ion cyclization steps. Notably, this high atom economic approach (-2H 2 O) allowed the generation of four new bonds (1 C-C and 3 C-N or 1 C-C, 1 C-O and 2 C-N) and two heterocyclic rings in a single operation.

A tandem amidation/epoxidation sequence between various substituted chalcones and N,N -dimethylformamide (DMF) for the synthesis of trisubstituted epoxides employing N-heterocyclic carbene catalysis was developed. This reaction was performed under metal-free conditions in the presence of tert -butyl hydroperoxide (TBHP) as the oxidant. Trisubstituted epoxides bearing a ketone and an amide functionality ( N , N -dimethyl formyl group) were synthesized starting from a wide range of chalcones in moderate to good yields with excellent diastereoselectivity.

The new motif - α,α-difluoromethyl thioamide - has been assembled starting from isothiocyanate (as thioamide precursor) and a formal difluoromethyl-carbanion generated from commercially available TMSCHF2. Upon proper activation of this reagent with potassium tert-amylate, the high-yielding transfer of the difluorinated nucleophile takes place under high chemocontrol. Various sensitive functionalities (e.g. ester, nitrile, nitro, azido groups) can be accommodated across the isothiocyanate core, thus allowing a wide scope. The methodology is highly flexible and adaptable to prepare analogous α,α-difluoromethyl oxoamides by conveniently using isocyanates as the electrophilic building-blocks.

An oxidant-free three-component synthesis of biologically significant 7-amino-6 H -benzo[ c ]chromen-6-ones was established involving a Sc(OTf) 3 catalyzed three-component reaction between primary amines, β-ketoesters and 2-hydroxychalcones under green conditions. In this strategy, both the B and C rings of 6 H -benzo[ c ]chromen-6-ones were constructed simultaneously starting from acyclic precursors by generating four new bonds including two C-C, one C-N and one C-O in a single synthetic operation. The mechanism of this sequential cascade process involves the initial formation of a β-enaminone intermediate followed by Michael addition with 2-hydroxychalcone, intramolecular cyclization, dehydration, lactonization and aromatization steps. Unlike the related literature approaches, this reaction delivered the products without the addition of any external oxidants to achieve the key aromatization step., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The implementation of a novel approach in the development of stimuli responsive supramolecular gels is an important objective that challenges material chemists and biologists in order to access an exclusively new category of smart materials. In this report, non-toxic, bio-based amphiphilic glycosylfurans were designed and synthesized using a biocatalyst, Novozyme 435, an immobilized lipase B from Candida antarctica. The self-assembly of these compounds generated oleogels and hydrogels. To our delight, these bio-based amphiphilic glycosylfurans furnished an in situ stimuli responsive hydrogel with simultaneous encapsulation of various biologically relevant molecules and ions. For the first time we are reporting hydrogelation via in situ molecular tuning followed by a self-sorting mechanism. The sol-to-gel transition in the reported smart hydrogel was observed by the addition of acidic buffer of pH 4.0, which could be potentially used for the stimuli responsive delivery of a signalling molecule, H2S and other biomolecules that regulate many physiological and pathological processes.

An efficient Pd(II)-catalyzed cascade approach was established for the synthesis of 9-chloro-1 H -benzo[ b ]furo[3,4- e ]azepin-1-ones starting from N -propargyl arylamines having a pendant α,β-unsaturated ester scaffold. The mechanism of this sequential process involved intramolecular syn -oxypalladation followed by olefin insertion and ortho sp 2 -C-Cl bond formation reactions. This high atom- and step-economical cascade sequence generated two heterocycle rings and three new bonds in a single synthetic operation.

An efficient green protocol for the synthesis of complex hybrid heterocycles containing [1,6]-naphthyridine and coumarin/pyrazole moieties was established, involving an intramolecular [4 + 2] hetero Diels-Alder reaction as the key step. The biologically significant 12,13-dihydro-6H-benzo[h]chromeno[3,4-b][1,6]naphthyridin-6-ones and 6,10-dihydro-5H-benzo[h]pyrazolo[3,4-b][1,6]naphthyridines were synthesized starting from 2-(N-propargylamino)-arylaldehydes and 3-aminocoumarins or 3-methyl-1-aryl-1H-pyrazol-5-amines in the presence of an Amberlyst-15 catalyst in PEG-200 in good yields. The easy access to diverse complex molecules in a single operation from readily available starting materials, a commercially available, transition metal-free and recyclable catalyst, the use of a green solvent, a very high atom economy and the release of water as the only side product are the highlights of this protocol.

A palladium catalyzed cascade process involving syn-chloropalladation, intramolecular olefin insertion, and oxidative C-Cl bond formation reactions was demonstrated for the synthesis of dichlorinated tetrahydroquinolines in high yields (up to 93%). The N-propargyl arylamines having a tethered α,β-unsaturated carbonyl moiety underwent a regioselective syn-chloropalladation followed by a Heck-type reaction to deliver the tetrahydroquinoline scaffold. The rare insertion of the second chlorine atom was rationalized comprising a Pd II/IV catalytic cycle and oxidative cleavage of the C-Pd II bond.

Tetrahydroquinoline is one of the most important simple nitrogen heterocycles, being widespread in nature and present in a broad variety of pharmacologically active compounds. This Review summarizes the progress achieved in the chemistry of tetrahydroquinolines, with emphasis on their synthesis, during the period from mid-2010 to early 2018.

The synthesis of spirooxindoles bearing tetrahydro-4 H-cyclopenta[ b]furan framework was established starting from isatin-derived aldehydes and 2 equiv of 1,3-dicarbonyl compounds involving a piperidine-catalyzed ABB' three-component domino process. This reaction was highly diastereoselective affording a single diastereomer of spirooxindoles with five consecutive asymmetric carbons including spiro and tetrasubstituted carbon centers. In addition, this waste-free (-2H 2 O) reaction showed high atom economy and step economy by creating four new bonds, including three C-C bonds and one C-O bond, and two rings (one carbo- and one heterocyclic) in a single operation. The mechanism of this three-component domino process involved sequential Knoevenagel condensation-Michael addition-intramolecular oxa-Michael addition-intramolecular aldol reactions.

Flavonoids and their derivatives have been extensively studied for their pharmaceutical applications due to their antioxidant and anti-inflammatory properties. The coordination complexes of several flavonoids have demonstrated DNA binding ability that can confer anticancer properties. The structure of the flavonoid has a pronounced influence on its pharmacological properties. Herein we report the synthesis and characterization of alkylated quercetin and its complex with gadolinium. The structure of the complex was confirmed using spectroscopic techniques. The ability of the gadolinium-alkylated quercetin complex to serve as a magnetic contrast agent was compared with gadolinium-quercetin complex. The quercetin-gadolinium complex was found to exhibit better contrast property with a relaxivity of 0.2952 μg mL -1 s -1 when compared to the gadolinium complex of alkylated quercetin. This difference primarily arises due to the greater hydrophobicity of the alkylated quercetin complex that restricts access of water. However, the alkylated quercetin was found to exhibit better enzyme mimic activity as the metal ion served as a redox center that enabled quantification of hydrogen peroxide in the concentration range 50-450 μM within 5 s with a sensitivity of 64 nA/μM and limit of detection of 7.3 μM. The better sensing performance of the alkylated quercetin-gadolinium complex, reported here for the first time, when compared to quercetin-gadolinium complex can be attributed to the enhanced electroactive area on the working electrode.

In developing countries, wounds are a major health concern and pose a significant problem. Hence, the development of new materials that can act as scaffolds for in situ tissue regeneration and regrowth is necessary. In this report, we present a new class of injectable oleogel and composite gel derived from glycolipids that provide reversible interlinked 3D fiberous network architecture for effective wound closure by tissue regrowth and regeneration. Glycolipids were derived from α-chloralose and various vinyl esters using Novozyme 435, an immobilized lipase B from Candida antarctica as a catalyst, in good yield. These glycolipids undergo spontaneous self-assembly in paraffin oil to form an oleogel, in which curcumin was successfully incorporated to generate a composite gel. Morphological analysis of the oleogel and composite gel clearly revealed the formation of a 3D fiberous network. Rheological investigation revealed the thermal and mechanical processability of the oleogel and composite gel under various experimental conditions. Interestingly, the developed injectable oleogel and composite gel are able to accelerate the wound healing process by regulating the overlapping phases of inflammation, cell proliferation and extracellular matrix remodelling. Since chloralose displays anesthetic properties, this study will establish a new strategy to develop anesthetic wound healing oleogels in the future., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

We investigate the synthesis of bio-based hydrophilic and hydrophobic oligoesters, which in turn are derived from easily accessible monomers from natural resources. In addition to the selection of renewable monomers, Novozyme 435, an immobilized lipase B from Candida antarctica was used for the oligomerization of monomers. The reaction conditions for oligomerization using Novozyme 435 were established to obtain a moderate-to-good yield. The average number of repeating units and the molecular weight distribution of hydrophilic and hydrophobic oligoester were identified by using NMR spectroscopy, gel-permeation chromatography, and MS. The oligoester derived from a hydrophilic monomer self-assembled to form a viscous solution, which upon further heating resulted in the formation of a polymer by the intermolecular Diels-Alder reaction. The viscosity of the solution and the assembly of oligoester to form a fibrous structure were investigated by using rheological studies, XRD, and SEM. The molecular weight of the cross-linked polymer was identified by using matrix-assisted laser desorption/ionization-MS. The thermal properties of the bio-based polymers were investigated by using thermogravimetric analysis and differential scanning calorimetry. For the first time, the self-assembly-assisted polymerization of an oligoester is reported using the intermolecular Diels-Alder reaction, which opens a new avenue in the field of polymer science., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The potential applications of self-assembled supramolecular gels based on natural molecules encouraged the researchers to develop a versatile synthetic method for their structural analogues. Herein, we report a facile synthesis of glycolipid from renewable resources, cashew nut shell liquid,d and d-glucose in good yield. Gelation behavior of these glycolipids were studied in a wide range of solvents and oils. To our delight, compound 5b formed a hydrogel with Critical gelator concentration (CGC) of 0.29% w / v . Morphological analysis of the hydrogel depicts the formation of twisted fibers with an entangled network. Formation of a twisted fibrous structure was further identified by CD spectral studies with respect to temperature. The molecular self-assembly assisted by hydrogen bonding, hydrophobic, and π⁻π stacking interactions were identified by X-ray diffraction (XRD) and FTIR studies. Rheological analysis depicted the mechanical strength and stability of the hydrogel, which is crucial in predicting the practical applications of supramolecular soft materials., Competing Interests: The authors declare no conflict of interest.

More than 80% of chronic infections of bacteria are caused by biofilms. It is also a long-term survival strategy of the pathogens in a nonhost environment. Several amphiphilic molecules have been used in the past to potentially disrupt biofilms; however, the involvement of multistep synthesis, complicated purification and poor yield still remains a major problem. Herein, we report a facile synthesis of glycolipid based surfactant from renewable feedstocks in good yield. The nature of carbohydrate unit present in glycolipid influence the ring chain tautomerism, which resulted in the existence of either cyclic structure or both cyclic and acyclic structures. Interestingly, these glycolipids self-assemble into gel in highly hydrophobic solvents and vegetable oils, and displayed foam formation in water. The potential application of these self-assembled glycolipids to disrupt preformed biofilm was examined against various pathogens. It was observed that glycolipid 6a disrupts Staphylococcus aureus and Listeria monocytogenes biofilm, while the compound 6c was effective in disassembling uropathogenic E. coli and Salmonella enterica Typhimurium biofilms. Altogether, the supramolecular self-assembled materials, either as gel or as surfactant solution could be potentially used for surface cleansing in hospital environments or the food processing industries to effectively reduce pathogenic biofilms.

An efficient and selective procedure for the synthesis of epiminodibenzo[b,f][1,5]diazocines involving a AB 2 three-component reaction is developed. Two equivalents of suitably substituted 2-aminoarylaldehydes reacted with arylamines in the presence of Yb(OTf) 3 to afford the desired products in high yields. The reaction is highly atom-economic and waste-free, in addition to allowing the generation of two heterocyclic rings and four C-N bonds in a single operation. Significantly, this approach is complementary to the existing literature procedures, affording arylamine-derived products that could not be accessed previously. A plausible mechanism is proposed involving an imine formation-intermolecular annulation-intramolecular iminium ion cyclization sequence.

The cerium(IV) ammonium nitrate (CAN)-catalyzed, three-component reaction between primary amines, β-dicarbonyl compounds, and α,β-unsaturated aldehydes in ethanol heated to reflux, constitutes a general, one-pot synthesis of 1,4-dihydropyridines. Their reduction with sodium triacetoxyborohydride furnished piperidine derivatives bearing up to five substituents with full diastereoselectivity in a hitherto inaccessible stereochemical arrangement. The reaction proceeded with no significant loss of enantiomeric purity under mild reduction conditions that are compatible with several functional groups that are normally sensitive to reduction. Octahydroquinolin-5-one derivatives, which were prepared by a modified version of the initial multicomponent reaction, were not suitable substrates for the sodium triacetoxyborohydride mediated reduction, but they were transformed into the corresponding decahydroquinolines, including a precursor of the amphibian alkaloid pumiliotoxin C, by catalytic hydrogenation under a variety of conditions., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The cerium(IV) ammonium nitrate (CAN)-catalyzed sequential multicomponent reaction between tryptamine, α,β-unsaturated aldehydes, and β-dicarbonyl compounds affords highly substituted indolo[2,3-a]quinolizines in a single synthetic operation. Two rings are generated through the creation of two C-C and two C-N bonds by a domino process comprising initial β-enaminone formation, followed by individual Michael addition, 6-exo-trig cyclization, iminium formation, and Pictet-Spengler steps. Furthermore, the reaction is diastereoselective and affords exclusively compounds with a trans relationship between the H-2 and H-12b protons. The use of amines bearing a less nucleophilic side chain aromatic ring (5-bromotryptamine, 3,4-dimethoxyphenylethylamine) prevents the Pictet-Spengler final step and leads to N-indolylethyl or N-phenylethyl-1,4-dihydropyridines, which are cyclized to the corresponding indolo[2,3-a]quinolizines or benzo[a]quinolizines in the presence of HCl in methanol/water. Treatment of the fused quinolizine derivatives with sodium triacetoxyborohydride led to the corresponding indolo[2,3-a]quinolizidines or benzo[a]quinolizidines, possessing four stereogenic centers, as mixtures of two diastereomers., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The CAN-catalyzed reaction between 3,5-disubstituted anilines, vinyl ethers and aromatic aldehydes leads to trans-2-aryl-4-arylaminotetrahydroquinolines, in an AA'BC sequential multicomponent transformation related to the Povarov reaction that was also extended to the use of a second aniline as the C-4 substituent. The unusual trans stereochemistry was explained by stabilization of the corresponding intermediate by intramolecular hydrogen bonding. The presence of the 4-anilino substituent allowed adapting the method to the synthesis of 4-unsubstituted 2-arylquinolines, by treatment of the crude product from the MCR with FeCl(3) in methanol.

The indium trichloride-catalyzed reaction between aromatic imines and α,β-unsaturated N,N-dimethylhydrazones in acetonitrile afforded 1,2,3,4-tetrahydroquinolines bearing a hydrazone function at C4 through a one-pot diastereoselective domino process that involves the formation of two C-C bonds and the controlled generation of two stereocenters, one of which is quaternary. This reaction constitutes the first example of an α,β-unsaturated dimethylhydrazone that behaves as a dienophile in a hetero Diels-Alder reaction. The related reaction between anilines, aromatic aldehydes, and methacrolein dimethylhydrazone in CHCl(3) with BF(3)⋅Et(2)O as catalyst afforded polysubstituted 1,2,3,3a,4,8b-hexahydropyrrolo[3,2-b]indoles as major products through a fully diastereoselective ABB'C four-component domino process that generates two cycles, three stereocenters, two C-C bonds, and two C-N bonds in a single operation., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

1-Allyl(propargyl)-6-allyl(propargyl)oxy-1,4,5,6-tetrahydropyridines, obtained through a CAN-catalyzed four-component reaction, were transformed into highly functionalized pyrido[2,1-b][1,3]oxazepines by ring-closing metathesis (RCM) and ring-closing enyne metathesis (RCEYM) processes, which constitute the first examples of the preparation of 1,3-oxazepine systems using metathesis reactions.

The use of cerium(IV) ammonium nitrate as a catalyst of the Friedländer reaction allows the synthesis of polysubstituted quinoline derivatives in excellent yields, avoiding the traditional harshly basic or acidic conditions. Unlike most other previously known reagents, CAN allows double condensations and is also an excellent catalyst for the Borsche variation of the Friedländer reaction, which has been applied to the very efficient synthesis of the antitumor alkaloid luotonin A.

Molecular diversity: A cerium(IV) ammonium nitrate (CAN) catalyzed, four-component reaction from very simple acyclic starting materials afforded densely substituted tetrahydropyridines, which were transformed into homoquinolizines by using a gamma-alkylation-ring-closing metathesis (RCM) sequence (see scheme).The cerium(IV) ammonium nitrate (CAN) catalyzed, four-component reaction between primary aliphatic amines, beta-ketoesters or beta-ketothioesters, alpha,beta-unsaturated aldehydes, and alcohols provided a very efficient and atom-economical access to substituted 6-alkoxy-2-methyl-1,4,5,6-tetrahydropyridines. These materials were then transformed into homoquinolizine derivatives in excellent yields by using a two-step sequence comprised of regioselective gamma-deprotonation-allylation and ring-closing metathesis reactions. The possibility of displacing the alkoxy group by allylsilane nucleophiles, presumably through a vinylogous acyliminium intermediate species, was also demonstrated.

The cerium(IV) ammonium nitrate (CAN)-catalyzed sequential, one-pot reaction between alkylamines, beta-ketoesters, and chalcones afforded cis-4,6-disubstituted 2-alkylaminocyclohexene-1-carboxylic esters with complete diastereoselectivity. The carbon-carbon double bond of these compounds was reduced with sodium triacetoxyborohydride, again with complete diastereoselectivity. This novel two-step route allows the transformation of very simple acyclic starting materials into tetrasubstituted cyclohexane derivatives bearing four functional groups, including a cis-beta-aminoester moiety, and generates four stereocenters, three of which are adjacent and one of which is quaternary.

The reaction between aromatic imines and methacrolein dimethylhydrazone in the presence of 10% indium trichloride affords in good to excellent yields biologically and synthetically relevant 1,2,3,4-tetrahydroquinolines bearing a hydrazone function at C-4 in a one-pot process that involves the formation of two C-C bonds and the stereoselective generation of two stereocenters, one of them quaternary, and this constitutes the first example of an alpha,beta-unsaturated dimethylhydrazone behaving as a dienophile in a hetero Diels-Alder reaction and the first vinylogous aza-Povarov reaction.