Heterogeneous Organocatalysts for Light-Driven Reactions in Continuous Flow.

Within the realm of organic synthesis, photocatalysis has blossomed since the beginning of the last decade. A plethora of classical reactivities, such as selective oxidation of alcohol and amines, redox radical formation of reactive species in situ, and indirect activation of an organic substrate for cycloaddition by EnT, have been revised in a milder and more sustainable fashion via photocatalysis. However, even though the spark of creativity leads scientists to explore new reactions and reactivities, the urgency of replacing the toxic and critical metals that are involved as catalysts has encouraged chemists to find alternatives in the branch of science called organocatalysis. Unfortunately, replacing metal catalysts with organic analogues can be too expensive sometimes; however, this drawback can be solved by the reutilization of the catalyst if it is heterogeneous. The aim of this review is to present the recent works in the field of heterogeneous photocatalysis, applied to organic synthesis, enabled by continuous flow. In detail, among the heterogeneous catalysts, g-CN, polymeric photoactive materials, and supported molecular catalysts have been discussed within their specific sections, rather than focusing on the types of reactions.

Oxidative N-Heterocyclic Carbene Catalysis.

N-Heterocyclic carbene (NHC) catalysis is a by now consolidated organocatalytic platform for a number of synthetic (asymmetric) transformations via diverse reaction modes/intermediates. In addition to the typical umpolung processes involving acyl anion/homoenolate equivalent species, implementation of protocols under oxidative conditions greatly expands the possibilities of this methodology. Oxidative NHC-catalysis allows for oxidative and oxygenative transformations through specific manipulations of Breslow-type species depending upon the oxidant used (external oxidant or O2 /air), the derived NHC-bound intermediates paving the way to non-umpolung processes through activation of carbon atoms and heteroatoms. This review is intended to update the state of the art in oxidative NHC-catalyzed reactions that appeared in the literature from 2014 to present, with a strong focus to crucial intermediates and their mechanistic implications.

Oxidative NHC Catalysis: An Unconventional Tool for Macrocyclic Oligoesters Synthesis.

The application of N-heterocyclic carbene (NHC) catalysis under highly diluted oxidative condition to the polycondensation of dialdehydes and diols is herein presented as an alternative, atom-economical synthetic route to macrocyclic oligoesters (MCOs). The disclosed protocol paves the way to the straightforward access to MCOs, starting from commercial dialdehydes, avoiding the use of toxic diacyl chlorides, commonly employed in traditional MCOs synthetic processes. The method is totally metal-free, takes place in the green Me-THF solvent and requires the use of a fully recyclable quinone oxidant. The protocol versatility is confirmed by the employment of fossil-based and bio-based monomers such as 2,5-diformylfuran (DFF), 2,5-bis(hydroxymethyl)furan (BHMF), and isomannide, synthesizing a series of novel and known synthetically relevant macrocyclic oligoesters, fully characterized by NMR and MALDI-TOF MS analysis, with product yields (51-86 %) comparable to those obtained by traditional synthetic routes. Finally, to emphasize the synthetic relevance of the target macrocycles, an entropically-driven ring opening polymerization (ED-ROP) key study has been performed, optimizing the organocatalyzed synthesis of poly(2,5-furan-dimethylene 2,5 furandicarboxylate) (PBHMF) with number-average molecular weight up to 8200 g mol-1 and 66 % isolated yield.

Efficiency in Carbon Dioxide Fixation into Cyclic Carbonates: Operating Bifunctional Polyhydroxylated Pyridinium Organocatalysts in Segmented Flow Conditions.

Novel polyhydroxylated ammonium, imidazolium, and pyridinium salt organocatalysts were prepared through N-alkylation sequences using glycidol as the key precursor. The most active pyridinium iodide catalyst effectively promoted the carbonation of a set of terminal epoxides (80 to >95% yields) at a low catalyst loading (5 mol%), ambient pressure of CO2, and moderate temperature (75 °C) in batch operations, also demonstrating high recyclability and simple downstream separation from the reaction mixture. Moving from batch to segmented flow conditions with the operation of thermostated (75 °C) and pressurized (8.5 atm) home-made reactors significantly reduced the process time (from hours to seconds), increasing the process productivity up to 20.1 mmol(product) h-1 mmol(cat)-1, a value ~17 times higher than that in batch mode.

Photoredox Cross-Dehydrogenative Coupling of N-Aryl Glycines Mediated by Mesoporous Graphitic Carbon Nitride: An Environmentally Friendly Approach to the Synthesis of Non-Proteinogenic α-Amino Acids (NPAAs) Decorated with Indoles.

Indole-decorated glycine derivatives are prepared through an environmentally benign cross-dehydrogenative coupling between N-aryl glycine analogues and indoles (yield of ≤81%). Merging heterogeneous organocatalysis and photocatalysis, C-H functionalization has been achieved by selective C-2 oxidation of N-aryl glycines to afford the electrophilic imine followed by Friedel-Crafts alkylation with indole. The sustainability of the process has been taken into account in the reaction design through the implementation of a metal-free recyclable heterogeneous photocatalyst and a green reaction medium. Scale-up of the benchmark reaction (gram scale, yield of 69%) and recycling experiments (over seven runs without a loss of efficiency) have been performed to prove the robustness of the protocol. Finally, mechanistic studies were conducted employing electron paramagnetic resonance spectroscopy to unveil the roles of the photocatalyst and oxygen in the formation of odd-electron species.

Exploring Oxidative NHC-Catalysis as Organocatalytic Polymerization Strategy towards Polyamide Oligomers.

The polycondensation of diamines and dialdehydes promoted by an N-heterocyclic carbene (NHC) catalyst in the presence of a quinone oxidant and hexafluoro-2-propanol (HFIP) is herein presented for the synthesis of oligomeric polyamides (PAs), which are obtained with a number-average molecular weight (Mn ) in the range of 1.7-3.6 kg mol-1 as determined by NMR analysis. In particular, the utilization of furanic dialdehyde monomers (2,5-diformylfuran, DFF; 5,5'-[oxybis(methylene)]bis[2-furaldehyde], OBFA) to access known and previously unreported biobased PAs is illustrated. The synthesis of higher molecular weight PAs (poly(decamethylene terephthalamide, PA10T, Mn = 62.8 kg mol-1 ; poly(decamethylene 2,5-furandicarboxylamide, PA10F, Mn = 6.5 kg mol-1 ) by a two-step polycondensation approach is also described. The thermal properties (TGA and DSC analyses) of the synthesized PAs are reported.

Phenyl-substituted aminomethylene-bisphosphonates inhibit human P5C reductase and show antiproliferative activity against proline-hyperproducing tumour cells.

In certain cancers, such as breast, prostate and some lung and skin cancers, the gene for the enzyme catalysing the second and last step in proline synthesis, δ1-pyrroline-5-carboxylate (P5C) reductase, has been found upregulated. This leads to a higher proline content that exacerbates the effects of the so-called proline-P5C cycle, with tumour cells effectively using this method to increase cell survival. If a method of reducing or inhibiting P5C reductase could be discovered, it would provide new means of treating cancer. To address this point, the effect of some phenyl-substituted derivatives of aminomethylene-bisphosphonic acid, previously found to interfere with the catalytic activity of plant and bacterial P5C reductases, was evaluated in vitro on the human isoform 1 (PYCR1), expressed in E. coli and affinity purified. The 3.5-dibromophenyl- and 3.5-dichlorophenyl-derivatives showed a remarkable effectiveness, with IC50 values lower than 1 µM and a mechanism of competitive type against both P5C and NADPH. The actual occurrence in vivo of enzyme inhibition was assessed on myelogenous erythroleukemic K562 and epithelial breast cancer MDA-MB-231 cell lines, whose growth was progressively impaired by concentrations of the dibromo derivative ranging from 10-6 to 10-4 M. Interestingly, growth inhibition was not relieved by the exogenous supply of proline, suggesting that the effect relies on the interference with the proline-P5C cycle, and not on proline starvation.

A Visible-Light-Powered Polymerization Method for the Immobilization of Enantioselective Organocatalysts into Microreactors.

A versatile one-step photopolymerization approach for the immobilization of enantioselective organocatalysts is presented. Chiral organocatalyst-containing monoliths based on polystyrene divinylbenzene copolymer were generated inside channels of microfluidic chips. Exemplary performance tests were performed for the monolithic Hayashi-Jørgensen catalyst in continuous flow, which showed good results for the Michael addition of aldehydes to nitroalkenes in terms of stereoselectivity and catalyst stability with minimal consumption of reagents and solvents.

Oxidative NHC-Catalysis as Organocatalytic Platform for the Synthesis of Polyester Oligomers by Step-Growth Polymerization.

The application of N-heterocyclic carbene (NHC) catalysis to the polycondensation of diols and dialdehydes under oxidative conditions is herein presented for the synthesis of polyesters using fossil-based (ethylene glycol, phthalaldehydes) and bio-based (furan derivatives, glycerol, isosorbide) monomers. The catalytic dimethyl triazolium/1,8-diazabicyclo[5.4.0]undec-7-ene couple and stoichiometric quinone oxidant afforded polyester oligomers with a number-average molecular weight (Mn ) in the range of 1.5-7.8 kg mol-1 as determined by NMR analysis. The synthesis of a higher molecular weight polyester (polyethylene terephthalate, PET) by an NHC-promoted two-step procedure via oligoester intermediates is also illustrated together with the catalyst-controlled preparation of cross-linked or linear polyesters derived from the trifunctional glycerol. The thermal properties (TGA and DSC analyses) of the synthesized oligoesters are also reported.

Enantioselective Desymmetrization of 1,4-Dihydropyridines by Oxidative NHC Catalysis.

The unprecedented desymmetrization of prochiral dialdehydes catalyzed by N-heterocyclic carbenes under oxidative conditions was applied to the highly enantioselective synthesis of 1,4-dihydropyridines (DHPs) starting from 3,5-dicarbaldehyde substrates. Synthetic elaboration of the resulting 5-formyl-1,4-DHP-3-carboxylates allowed for access to the class of pharmaceutically relevant 1,4-DHP-3,5-dicarboxylates (Hantzsch esters). DFT calculations suggested that the enantioselectivity of the process is determined by the transition state involving the oxidation of the Breslow intermediate by the external quinone oxidant.

Enantioselective Dearomatization of Alkylpyridiniums by N-Heterocyclic Carbene-Catalyzed Nucleophilic Acylation.

A chiral NHC-catalyzed dearomatizing reaction of activated N-alkylpyridinium salts with aliphatic aldehydes is described. The resulting acylated 1,4-dihydropyridines have been obtained with complete C4 regioselectivity and enantioselectivities in the range 52-78% ee. The (4R)-absolute configuration of the synthesized compounds has been determined by the TD-DFT simulation of the electronic circular dichroism spectra.

Aerobic oxidation of 5-hydroxymethylfurfural to 5-hydroxymethyl-2-furancarboxylic acid and its derivatives by heterogeneous NHC-catalysis.

The application of the oxidative system composed of a heterogeneous triazolium pre-catalyst, iron(ii) phthalocyanine and air is described for the selective conversion of 5-hydroxymethylfurfural (HMF) into the added-value 5-hydroxymethyl-2-furancarboxylic acid (HMFCA). The disclosed one-pot two-step procedure involved sequential oxidative esterifications of HMF to afford a polyester oligomer having hydroxyl and carboxyl terminal groups (Mw = 389-1258), which in turn was hydrolyzed by a supported base (Ambersep 900 OH) to yield HMFCA in 87% overall yield. The same strategy was adopted for the effective synthesis of ester and amide derivatives of HMFCA by nucleophilic depolymerization of the oligomeric intermediate with methanol and butylamine, respectively. The utilization of the disclosed oxidative system for the direct conversion of HMF and furfural into their corresponding ester, amide, and thioester derivatives is also reported.

Native Quercetin as a Chloride Receptor in an Organic Solvent.

The binding properties of quercetin toward chloride anions were investigated by means of ¹H-NMR, 13C-NMR, and electrospray ionization mass spectrometry (ESI-MS) measurements, as well as computational calculations. The results indicate that quercetin behaves primarily as a ditopic receptor with the binding site of the B ring that exhibits stronger chloride affinity compared to the A ring. However, these sites are stronger receptors than those of catechol and resorcinol because of their conjugation with the carbonyl group located on the C ring. The 1:1 and 1:2 complexation of this flavonoid with Cl- was also supported by ESI mass spectrometry.

Fluorous-tag assisted synthesis of bile acid-bisphosphonate conjugates via orthogonal click reactions: an access to potential anti-resorption bone drugs.

The synthesis of a small collection of novel bile acid-bisphosphonate (BA-BP) conjugates as potential drug candidates is reported. The disclosed methodology relied on the installation of azide and thiol functionalities at the head and tail positions, respectively, of the BA scaffold and its subsequent decoration by orthogonal click reactions (copper-catalyzed azide-alkyne cycloaddition, thiol-ene or thiol-yne coupling) to introduce BP units and a fluorophore. Because of the troublesome isolation of the target conjugates by standard procedures, the methodology culminated with the functionalization of the BA scaffold with a light fluorous tag to rapidly and efficiently purify intermediates and final products by fluorous solid-phase extraction.

Synthesis of functionalized imidazolidine-2-thiones via NHC/base-promoted aza-benzoin/aza-acetalization domino reactions.

A strategy for the synthesis of biologically relevant 5-hydroxy-imidazolidine-2-thione derivatives is presented. A novel class of α-sulfonylamines have been suitably prepared (46-81% yield) as precursors of formal benzylidenethiourea acceptors; these are generated in situ and intercepted by N-heterocyclic carbene (NHC)-activated aldehydes affording open-chain aza-benzoin-type adducts, which in turn undergo an intramolecular aza-acetalization reaction in a one-pot fashion. A thiazolium salt/triethylamine couple proved to be the more effective system to trigger the domino sequence giving the target heterocycles in good yields (45-97%) and diastereoselectivities (up to 99 : 1 dr). The multigram scale synthesis and elaboration of a selected 5-hydroxy-imidazolidine-2-thione compound is also described.

Research Progress in the Modification of Quercetin Leading to Anticancer Agents.

The flavonoid quercetin (3,3',4',5,7-pentahydroxyflavone) is widely distributed in plants, foods, and beverages. This polyphenol compound exhibits varied biological actions such as antioxidant, radical-scavenging, anti-inflammatory, antibacterial, antiviral, gastroprotective, immune-modulator, and finds also application in the treatment of obesity, cardiovascular diseases and diabetes. Besides, quercetin can prevent neurological disorders and exerts protection against mitochondrial damages. Various in vitro studies have assessed the anticancer effects of quercetin, although there are no conclusive data regarding its mode of action. However, low bioavailability, poor aqueous solubility as well as rapid body clearance, fast metabolism and enzymatic degradation hamper the use of quercetin as therapeutic agent, so intense research efforts have been focused on the modification of the quercetin scaffold to obtain analogs with potentially improved properties for clinical applications. This review gives an overview of the developments in the synthesis and anticancer-related activities of quercetin derivatives reported from 2012 to 2016.

Cross-benzoin and Stetter-type reactions mediated by KOtBu-DMF via an electron-transfer process.

The condensation of aromatic α-diketones (benzils) with aromatic aldehydes (benzoin-type reaction) and chalcones (Stetter-type reaction) in DMF in the presence of catalytic (25 mol%) KOtBu is reported. Both types of umpolung processes proceed with good efficiency and complete chemoselectivity. On the basis of spectroscopic evidence (MS analysis) of plausible intermediates and literature reports, the occurrence of different ionic pathways have been evaluated to elucidate the mechanism of a model cross-benzoin-like reaction along with a radical route initiated by an electron-transfer process to benzil from the carbamoyl anion derived from DMF. This mechanistic investigation has culminated in a different proposal, supported by calculations and a trapping experiment, based on double electron-transfer to benzil with formation of the corresponding enediolate anion as the key reactive intermediate. A mechanistic comparison between the activation modes of benzils in KOtBu-DMF and KOtBu-DMSO systems is also described.

Electron-transfer-initiated benzoin- and Stetter-like reactions in packed-bed reactors for process intensification.

A convenient heterogeneous continuous-flow procedure for the polarity reversal of aromatic α-diketones is presented. Propaedeutic batch experiments have been initially performed to select the optimal supported base capable to initiate the two electron-transfer process from the carbamoyl anion of the N,N-dimethylformamide (DMF) solvent to the α-diketone and generate the corresponding enediolate active species. After having identified the 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine on polystyrene (PS-BEMP) as the suitable base, packed-bed microreactors (pressure-resistant stainless-steel columns) have been fabricated and operated to accomplish the chemoselective synthesis of aroylated α-hydroxy ketones and 2-benzoyl-1,4-diones (benzoin- and Stetter-like products, respectively) with a good level of efficiency and with a long-term stability of the packing material (up to five days).

Androgen Receptor Targeted Conjugate for Bimodal Photodynamic Therapy of Prostate Cancer in Vitro.

Prostate cancer (PC) represents the most common type of cancer among males and is the second leading cause of cancer death in men in Western society. Current options for PC therapy remain unsatisfactory, since they often produce uncomfortable long-term side effects, such as impotence (70%) and incontinence (5-20%) even in the first stages of the disease. Light-triggered therapies, such as photodynamic therapy, have the potential to provide important advances in the treatment of localized and partially metastasized prostate cancer. We have designed a novel molecular conjugate (DR2) constituted of a photosensitizer (pheophorbide a, Pba), connected to a nonsteroidal anti-androgen molecule through a small pegylated linker. This study aims at investigating whether DR2 represents a valuable approach for PC treatment based on light-induced production of single oxygen and nitric oxide (NO) in vitro. Besides being able to efficiently bind the androgen receptor (AR), the 2-trifluoromethylnitrobenzene ring on the DR2 backbone is able to release cytotoxic NO under the exclusive control of light, thus augmenting the general photodynamic effect. Although DR2 is similarly internalized in cells expressing different levels of androgen receptor, the AR ligand prevents its efflux through the ABCG2-pump. In vitro phototoxicity experiments demonstrated the ability of DR2 to kill cancer cells more efficiently than Pba, while no dark toxicity was observed. Overall, the presented approach is very promising for further development of AR-photosensitizer conjugates in the multimodal photodynamic treatment of prostate cancer.

Nucleophilic and electrophilic double aroylation of chalcones with benzils promoted by the dimsyl anion as a route to all carbon tetrasubstituted olefins.

Dimsyl anion promoted the polarity reversal of benzils in a Stetter-like reaction with chalcones to give 2-benzoyl-1,4-diones (double aroylation products), which, in turn, were converted into the corresponding tetrasubstituted olefins via aerobic oxidative dehydrogenation catalyzed by Cu(OAc)2.