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We herein report a multi-step flow protocol for the synthesis of 1,4-disubstituted 1,2,3-triazoles starting from α,β-unsaturated carbonyls.

We herein report a waste minimization protocol for the β-azidation of α,β-unsaturated carbonyl compounds using TMSN3. The selection of the appropriate catalyst (POLITAG-M-F), in combination with the reaction medium, resulted in enhanced catalytic efficiency and a low environmental footprint. The thermal and mechanical stability of the polymeric support allowed us to recover the POLITAG-M-F catalyst for up to 10 consecutive runs. The CH3CN:H2O azeotrope has a 2-fold positive effect on the process, increasing the efficiency of the protocol and minimizing waste generation. Indeed, the azeotropic mixture, used as a reaction medium and for the workup procedure, was recovered by distillation, leading to an easy and environmentally friendly procedure for product isolation in high yield and with a low E-factor. A comprehensive evaluation of the environmental profile was performed by the calculation of different green metrics (AE, RME, MRP, 1/SF) and a comparison with other literature available protocols. A flow protocol was defined to scale-up the process, and up to 65 mmol of substrates were efficiently converted with a productivity of 0.3 mmol/min. ispartof: ACS SUSTAINABLE CHEMISTRY & ENGINEERING vol:11 issue:7 pages:3074-3084 ispartof: location:United States status: published

Since the identification of human choline kinase as a protein target against cancer progression, many compounds have been designed to inhibit its function and reduce the biosynthesis of phosphatidylcholine. Herein, we propose a series of bioisosteric inhibitors that are based on the introduction of sulphur and feature improved activity and lipophilic/hydrophilic balance. The evaluation of the inhibitory and of the antiproliferative properties of the PL (dithioethane) and FP (disulphide) libraries led to the identification of PL 48, PL 55 and PL 69 as the most active compounds of the series. Docking analysis using FLAP suggests that for hits to leads, binding mostly involves an interaction with the Mg

Flow chemistry is one of the most prominent enabling technologies that has greatly shaped the way chemists’ approach organic synthesis. Specifically, in drug discovery, the advantages of flow techniques over batch procedures allow the rapid and efficient assembly of compound libraries to be tested for biological properties. The aim of the present review is to comment on some representative examples from the last five years of literature that highlight how flow procedures are becoming of increasing importance for the synthesis of biologically-relevant molecules.

Three different basic zirconium potassium phosphate methyl and/or phenyl phosphonates of general formula Zr(PO3OK)2-(x+y)(PO3Me)x(PO3Ph)y namely ZrKP-Me, ZrKP-Ph and ZrKP-MePh have been prepared as amorphous solids. The catalytic activity of the solids was tested in the Knoevenagel condensation between several aldehydes with malononitrile and ethyl cyanoacetate in solvent free condition at room temperature and 50 °C, respectively. The hydrophobic groups on the solid catalysts surface favour reagent diffusion toward the basic sites increasing the catalytic activity of the prepared solids compared to the complete inorganic layered zirconium potassium phosphate, Zr(KPO4)2.

Herein we report an efficient procedure for the C–H functionalization of 1,2,3-triazoles in a continuous flow regime applied to a variety of functionalities and to the inter- or intramolecular versions of the process. The continuous-flow protocol is based on the use of a heterogeneous catalyst (Pd/C), a soluble organic base and GVL as the reaction medium. Flow conditions allow an optimal recovery/reuse and durability of the catalyst, which combined with the simple purification of the products and the recovery of the reaction medium make the proposed protocol operationally simple and very efficient in terms of waste minimization as proven by low metal leaching and a low associated E-factor

Herein we report the first example of a generally useful organic reaction, namely the copper-catalysed azide–alkyne cycloaddition, performed in a Polarclean/water mixture as a reaction medium. The process is very efficient, affording in 24 out of the 26 tested cases the desired triazole in quantitative yields. Product isolation is also very convenient, since the triazoles either precipitate or form a separate liquid phase, without the need to perform chromatographic separations. Moreover, since the metal catalyst is retained in the Polarclean/water phase, the catalyst/reaction medium can be easily reused for consecutive reaction runs, without an apparent loss in efficiency. This methodology is associated with very limited waste production, as evidenced by calculated E-factors in the range 2.6–3.7.

Herein, we present our results on the development of a continuous flow protocol enabling the waste minimised synthesis of relevant pharmaceuticals and natural compounds. Heterogeneous manganese catalytic systems have been used in combination with molecular oxygen to promote the C–H oxidative coupling of 2-aminophenols, benzenetriols and o-phenylenediamines to access a variety of 2-aminophenoxazin-3-ones (2a–i) and related diaminophenazines (2j–k) and purpurogallin (2l) with minimal metal contamination. Making use of safe and green cyclopentyl methyl ether (CPME), this methodology allowed a fast synthesis of fully decorated molecular entities, preserving the stability of the heterogeneous catalyst which showed minimal metal leaching, with minimal waste production (low E-factor).

The adoption of flow conditions has been the object of growing attention from both academia and industry. The shift from batch to continuous-flow technology is very stimulating from a cultural and technological point of view. Flow technologies represent a rare opportunity for creating new proprietary access routes to complex target compounds and at the same time, they offer an incredible opportunity for increasing the efficiency of known processes that lead to modern, more sustainable future chemical production. While the general utility of flow conditions is truly convincing, its applicability assumes even greater relevance in the synthesis of Active Pharmaceutical Ingredients (APIs) due to the complexity of the targets and their high commercial value and also the highly selective chemistry involved. This review highlights the key features of flow chemistry in the synthesis of APIs by describing all the relevant literature in the field over the last 5 years, up to mid-2020. Key chemical aspects of the processes, the equipment used, and the features of the flow procedure are presented.

In continuation of our efforts to identify promising antileishmanial agents based on the chroman scaffold, we synthesized several substituted 2H-thiochroman derivatives, including thiochromenes, thichromanones and hydrazones substituted in C-2 or C-3 with carbonyl or carboxyl groups. Thirty-two compounds were thus obtained, characterized, and evaluated against intracellular amastigotes of Leishmania (V) panamensis. Twelve compounds were active, with EC50 values lower than 40 µM, but only four compounds displayed the highest antileishmanial activity, with EC50 values below 10 µM, these all compounds possess a good Selectivity Index &gt, 2.6. Although two active compounds were thiochromenes, a clear structure-activity relationship was not detected since each active compound has a different substitution pattern.

An efficient and selective procedure was developed for the direct C2-H arylation of indoles using a Pd-loaded metal-organic framework (MOF) as a heterogeneous catalyst and the nontoxic biomass-derived solvent γ-valerolactone (GVL) as a reaction medium. The developed method allows for excellent yields and C-2 selectivity to be achieved and tolerates various substituents on the indole scaffold. The established conditions ensure the stability of the catalyst as well as recoverability, reusability, and low metal leaching into the solution. ispartof: CHEMSUSCHEM vol:13 issue:10 pages:2786-2791 ispartof: location:Germany status: published

In this study, we explored a wide range of green solvents to process the semiconductor layer TIPS-PEN (6,13-bis(triisopropylsilylethynyl)pentacene), as well as to demonstrate potential generality, using several p- and n-type organic semiconductors, for the fabrication of organic thin-film transistors (OTFTs). Our data demonstrate that several different solvents enable good semiconductor film-forming morphologies and optimized TIPS-PEN TFT mobilities of ∼0.5–2 cm2 V−1 s−1, thus surpassing those of toxic chlorinated options. Furthermore, we utilized a green cellulose cinnamate-gate dielectric to fabricate TIPS-PEN OTFTs, where both the semiconductor and the dielectric were processed using green solvents demonstrating the feasibility of a more sustainable OTFT technology.

A heterogeneous fluoride catalyst was found to enable the straightforward formation of alkenyl nitriles from the reaction of aldehydes and simple or substituted acetonitriles, in the presence of commercially available silazanes and in solvent-free conditions. The protocol afforded the products in good to excellent yields with selectivity values dependent on the nature of the substrates. It represents an alternative to classic approaches using stoichiometric strong bases, and the catalyst can be easily recovered and reused for consecutive cycles.

Herein, we present our results on the development of a waste minimized protocol for the synthesis of 2-arylbenzoxazoles in continuous flow. Manganese-based heterogeneous catalysts were used in combination with cyclopentylmethyl ether as an environmentally friendly and safe reaction medium. The use of oxygen promotes the oxidative process ensuring at the same time a complete regeneration of the catalyst adopting a flow configuration which does not include the use of an additional mechanical pump. These features allowed for a faster synthesis compared to batch procedures with minimal metal leaching.

Herein, we report the use of γ-valerolactone as a new biomass-derived reaction medium for microwave assisted organic synthesis. The interaction of this solvent with microwaves and its heating profile under microwave irradiation has been fully characterized for the first time, demonstrating its stability and the applicability in microwave assisted Pd/C catalysed reactions avoiding the arcing phenomena frequently observed in these conditions. The use of γ-valerolactone demonstrated to be compatible with aliphatic and aromatic amines in the hydrogen transfer Pd/C mediated synthesis of benzimidazoles. ispartof: SCIENTIFIC REPORTS vol:8 issue:1 ispartof: location:England status: published

In the last decade, transition‐metal catalyzed C−H functionalization reactions have progressed enormously, becoming a useful tool in organic synthesis and a practical alternative to well‐established methodologies. Very recently, research efforts have also been devoted to developing more sustainable C−H functionalization protocols, in order to increase their applicability. One of the most promising approaches in this sense is represented by the substitution of common reaction media with bio‐based solvents. In the present contribution a general perspective on the benefits of this approach is given, followed by key literature examples.

A survey of papers exploring the scope of click chemistry in the area of π-conjugated polymers for organic electronics is given., Given the wide utility of click-chemistry reactions for the preparation of simple moieties within large architecturally complex materials, this minireview article aims at surveying papers exploring their scope in the area of π-conjugated polymers for application in organic electronics to enable advanced functional properties.

A new protocol for the diasteroselective synthesis of pyrrolidin-2-ones 4–14 is presented. Aquivion PFSA effectively catalyzed the diasteroselective nitro-mannich/lactamization cascade reaction between the imine formed from aldehydes 1a–g and amines 2a–b with methyl 3-nitropropanoate 3. The use of flow conditions allow a very efficient waste minimization confirmed by representative green metrics calculations.

A clean and efficient protocol for the synthesis of a wide variety of N-Boc-s-amino ketones 3a-g has been defined using flow approach. The multistep procedure is based on the s-azidation of unsaturated ketones, consecutive reduction of the azido group, and concomitant amino group protection, and furnishes the desired products in good yields and very low E-factors ranging from 3.1 to 5.6. In batch conditions and by water as reaction medium, poorer yields and complicated reaction mixtures are obtained. Adoption of the flow approach, which combines transformations performed in solvent-free conditions and in EtOAc, has been essential in order to avoid side reactions, poisoning of the reduction catalyst, and use of minimal amount of reactants.

Commiphora erythraea (Burseraceae) resin derives from the bark injury of the plant, a small tree native to the Arabian Peninsula. The resin is commonly known as myrrh and it is traditionally used to protect livestock from ticks and to treat diseases related to inflammation. The resin is constituted by a volatile and a non-volatile fraction. The volatile fraction is a source of furanosesquiterpenoids among which furanodienone showed to be the most promising pharmacological active compound. The composition and pharmacological activities of the extracts and the isolated compounds have been reviewed.

The drive toward greener process chemistry has stimulated the development of strong solid acids to replace traditional catalysts for efficient biodiesel production from free fatty acid (FFA) enriched biomass feedstocks. Notably, heterogeneous systems enable simple product isolation procedures and improve the catalyst recyclability. They may also be used in continuous reactors. Increasing interest is directed toward organic polymer-supported solid acid catalysts, holding the promise of easy incorporation of the catalyst into the support with high density and easy tuning of the support microstructure/morphology. In the present review, the focus is set on the most widely employed members of this class, including cation-exchange resins, micro- and mesoporous acidic resins, as well as supported acidic ionic liquids and ionomeric membranes. Moreover, we present the use of alternative organic polymer-based acidic catalysts (hybrid systems). Attention is paid to correlations between parameters such as catalyst morphology, excess of alcohol required, FFA content in oil feedstock, presence of impurities and the performance of resin-supported acid catalysts, as well as to the catalyst recyclability. Finally, a brief survey illustrates the use of resin-supported acid catalysts for the preparation of biofuel additives alkyl levulinates – structurally quite similar to the biodiesel – starting from biomass derived levulinic acid.

Silyl enol ethers are extremely useful nucleophilic intermediates for chemical transformations because they are synthetically versatile substrates for a wide range of C–C bond-forming reactions. Here, we present a new, mild, and solvent-free procedure for the synthesis of silyl enol ethers that employs a catalytic amount of solid-supported base and an equimolar amount of N,O-(bistrimethylsilyl)acetamide as a silylating agent.

In the last decade, transition-metal catalyzed C-H functionalization reactions have progressed enormously, becoming a useful tool in organic synthesis and a practical alternative to well-established methodologies. Very recently, research efforts have also been devoted to developing more sustainable C-H functionalization protocols, in order to increase their applicability. One of the most promising approaches in this sense is represented by the substitution of common reaction media with bio-based solvents. In the present contribution a general perspective on the benefits of this approach is given, followed by key literature examples.

This review summarizes recent contributions on the use of fluoride catalysts immobilized on polymer supports. Besides the commercially available Amberlyst fluoride, TBAF on silica gel, and TBAF on alumina, that have proved widely useful for several interesting and valuable synthetic C–N, C–O, and C–C bond transformations, novel catalysts based on the DABCO moiety have allowed access to very useful, new transformations. 1 Introduction 2 Polystyryl-DABCOF2 3 Polystyryl-DABCOF 4 Amberlyst Fluoride (Amb-F) 5 TBAF on Alumina or on Silica Gel 6 Conclusion

Given the wide utility of click-chemistry reactions for the preparation of simple moieties within large architecturally complex materials, this minireview article aims at surveying papers exploring their scope in the area of π-conjugated polymers for application in organic electronics to enable advanced functional properties.

A heterogeneous fluoride catalyst was found to enable the straightforward formation of alkenyl nitriles from the reaction of aldehydes and simple or substituted acetonitriles, in the presence of commercially available silazanes and in solvent-free conditions. The protocol afforded the products in good to excellent yields with selectivity values dependent on the nature of the substrates. It represents an alternative to classic approaches using stoichiometric strong bases, and the catalyst can be easily recovered and reused for consecutive cycles.

PS-BEMP was used as a heterogeneous catalyst for the phospha-Michael addition of phosphorus nucleophiles to a variety of electron-poor alkenes. The addition reactions were generally performed with equimolar amounts of reagents under solvent free conditions. The protocol proved to be very efficient for the addition to aromatic, non-aromatic and cyclic ketones, giving good yields (78-85%) in all cases. The protocol was also extended with good results to α,β-unsaturated esters and nitriles. This demonstrates that PS-BEMP is a good catalyst for the phospha-Michael addition to electron-poor alkenes.

The reactions between N -benzylideneanilines and ­Danishefsky’s diene proceed smoothly in acidic aqueous medium in the presence of a catalytic amount of copper(II) triflate–sodium dodecyl sulfate [Cu(OTf) 2 –SDS] to afford the corresponding 1,2-diphenyl-2,3-dihydro-4-pyridones in excellent yields of 84–95%. The aqueous solution containing the catalyst is recovered and reused without any loss in efficiency.

Novel solid fluorides were prepared to optimize the β-azidation of α,β-unsaturated ketones. The higher loading of these catalysts compared to that of commercially available fluorides has allowed the use of a smaller mass of catalyst helping the mixing of the reaction mixture. Porous polymeric supports have proved to be more efficient in the presence of water as reaction medium. Water has played a crucial role showing a beneficial effect on the reactivity by improving dispersion of the reaction mixture and also by avoiding organic fouling caused by the retention of the reaction mixture within the polymeric matrix. This has facilitated the recovery of the products from the catalyst. The protocol reported has allowed a significant reduction in the organic solvent required for the complete recovery of the pure product whilst leaving the catalyst clean and reusable. E-factors are in the range of 5.9–10.5 and therefore ca. 3 times smaller than previous procedures operating under solvent-free conditions. To further improve the efficiency of our approach we have developed a protocol operating in a continuous-flow manner that has allowed us to achieve an E-factor of 1.7–1.9, with a reduction of ca. 80% of the corresponding batch conditions. The continuous-flow protocol has allowed us to minimize the use of trimethylsilyl azide making the recovery and reuse of water and catalyst 5f very efficient and simple. Finally, a novel reduction system using palladium on alumina (5 mol%) and equimolar amount of formic acid has been used in the presence of 1 equivalent of di-tert-butyl pyrocarbonate to set a multistep protocol operating in continuous-flow conditions for the preparation of two representative N-Boc-β-amino ketones starting from the corresponding enones with E-factors of 3.2 and 2.7, respectively.

Although its intriguing features, such as uniform functionalization through the entire beads and a very high-loading capacity are suitable candidates for solid-phase synthesis and reagent-scavenging, the use of Rasta resin as support for organocatalysis has been little explored. In this contribution, Rasta polymer has been used to preparation of high-loading Rasta-TBD. This catalyst has been able to efficiently promote several organic transformations with constantly good and promising results.

Polystyrene-supported chiral 2,2′-methylenebis[(4S)-4-tert-butyl-2-oxazoline] is a promising heterogeneous catalyst for the enantioselective Henry reaction of nitromethane with substituted benzaldehydes. The process is carried out in ethanol as a green solvent, and the corresponding chiral β-nitroalcohols are obtained in 56–95 % yield with 49–88 % ee.

Zirconium phosphates methyl and/or phenyl phosphonates-supported l-proline have been prepared as amorphous solids by precipitation of (4R)-4-(phosphonooxy)-l-proline, methyl and/or phenyl phosphonic acid with ZrOCl2. The supported l-proline catalysts were tested on the direct asymmetric aldol addition of cyclohexanone to p-nitrobenzaldehyde in DMF/H2O (9:1) and in sole water. The hydrophobic groups on solid surface favor reagents’ diffusion toward proline chiral moiety increasing the catalytic activity of supported l-proline. High diastereoselectivity (anti/syn up to 94:6) and high enantiomeric excess up to 97% have been obtained.

The reaction of β-nitroacrylates with pyrroles, under solvent- and catalyst-free conditions, allows the formation of Friedel–Crafts adducts which, after in situ treatment with Amberlyst 15 in isopropyl alcohol under reflux, provide polysubstituted indoles, via a benzannulation reaction, in a one-pot process.

New zirconium hydrogen phosphate alkyl and/or aryl phosphonates of general formula Zr(PO 3 OH) 2−( x + y ) (PO 3 R) x (PO 3 R 1 ) y have been prepared as amorphous solids. The presence of hydrophobic groups such as Me, Ph and Pr and their percentage have an important role in the definition of the corresponding solid structure. All the prepared solids are micro- and mesoporous and show an extraordinary surface area (200–380 m 2 /g). The Bronsted acid catalytic activity of the solids was tested on the direct aza-Diels–Alder reaction of 2-cyclohexen-1-one with N-PMP- p Cl-benzaldimine in aqueous medium. The hydrophobic groups on the solid catalyst surface favor reagents’ diffusion toward the acidic sites, aiding proton transfer to reagents, increasing the catalytic activity of the prepared solids compared with the layered α-zirconium hydrogen phosphate (α-ZrP).

The effect of the addition of ionic liquids (ILs) during the hydrodistillation of Myristica fragrans Houtt. (nutmeg) essential oil was studied. The essential oil of M. fragrans is characterized by the presence of terpenes, terpenoids, and of phenylpropanoids, such as methyl eugenol and safrole, that are regarded as genotoxic and carcinogenic. The aim of the work was to determine the best ionic liquid to improve the yield of the extraction of M. fragrans essential oil and decrease the extraction of toxic phenylpropanoids. Six ILs, namely 1,3-dimethylimidazolium chloride (1), 1,3-dimethylimidazolium dimethylphosphate (2), 1-(2-hydroxyethyl)-3-methylimidazolium chloride (3), 1-(2-hydroxyethyl)-3-methylimidazolium dimethylphosphate (4), 1-butyl-3-methylimidazolium chloride (5), and 1-butyl-3-methylimidazolium dimethylphosphate (6), were prepared by previously reported, innovative methods and then tested. An experimental design was used to optimize the extraction yield and to decrease the phenylpropanoids percentage using the synthesized ILs. The influence of the molarity of ILs was also studied. MODDE 12 software established 0.5 M 1-butyl-3-methylimidazolium chloride as the best co-solvent for the hydrodistillation of M. fragrans essential oil.

2-tert-Butylimino -2-diethylamino-1,3 -dimethylperhydro-1,3,2 -diazaphosphorine supported on polystyrene (PS-BEMP) is an efficient catalyst for the addition of nitroalkanes (1-1.5 equiv.) to α,β-unsaturated carbonyl compounds (1.0 equiv.) in the absence of a reaction medium (solvent-free conditions). The corresponding γ-nitro carbonyl compounds have been isolated in excellent yields but the catalyst can be satisfactorily recovered and used for only 3 times due to the magnetic stirring which caused crunching of the catalyst beads thus hampering its complete recovery. To optimize the catalyst's reuse and improve the environmental efficacy of solvent-free conditions, the first solvent-free cyclic continuous-flow reactor has been set up. This reactor has allowed the product to be isolated in an almost quantitative yield by using a very small amount of organic solvent, making the recovery and reuse of the catalyst efficient and reproducible.