Polymer-supported Reagents Research Articles

Microwave-assisted oxidative coupling of thiols using polystyrene supported bromoderivatives of 2-oxazolidone

Polymer-supported reagents have become popular in synthetic organic chemistry over the past decades. But the kinetics of polymer-supported reactions is slow compared to solution phase synthesis because of the poor diffusion of the reactants through the macromolecular polymer matrix. This difficulty can be reduced to a great extent by performing polymer-supported reactions under microwave (MW) conditions. The present work is focussed on the design and development of an innovative, powerful, MW stable and recyclable polymeric reagent prepared by attaching bromoderivative of 2-oxazolidone into the macromolecular matrix of polystyrene. 3% cross-linked polystyrene was prepared by free radical aqueous suspension polymerization technique using tetra ethylene glycol diacrylate as the cross-linking agent and the resulting beads were functionalized by chloromethylation followed by reaction with 2-oxazolidone. Bromine functionality is introduced into the polymer by treating with bromine in carbon tetrachloride. The synthetic utility of the prepared polymeric reagent was demonstrated by the oxidative coupling of thiols to disulfides under MW irradiation. No over oxidation was observed in this protocol and the utilization of polystyrene support simplifies work up and product isolation. The synthesised polymeric reagent displayed good cyclic stability up to five cycles without any substantial decrease in bromine content and satisfactory storage stability under normal laboratory condition. Moreover this may be the first report that uses MW energy for the oxidation of thiols to disulfides using polymer-supported reagents. [Formula: see text]

A new procedure for thioester deprotection using thioglycolic acid in both homogeneous and heterogeneous phase

Classic acetyl thioester protection/deprotection methodologies are widely used in organic synthesis, but deprotection step usually requires harsh conditions not suitable for labile substrates. In this work, a new method for thioester deprotection using a thiotransesterification approach is described. Firstly, thioglycolic acid (TGA) was identified as a good deprotecting reagent in solution. In order to develop a thiol polymer-supported reagent, TGA was anchored to a PEG-based resin through an amide bond (TG-NCO-SH). Both homogeneous and heterogeneous approaches were conveniently carried out at room temperature, in aqueous buffer at pH 8. The mild conditions were suitable for alkyl and phenyl thioesters. Moreover labile thioesters containing thiazolidine and oxazolidine scaffolds, bearing amine, ester and acetal functionalities were also deprotected. The polymer-supported TGA gave better deprotection yields compared to TGA in solution, yields ranging from 61 to 90%. The feasibility of the recovery and reuse of TG-NCO-SH reagent was explored, showing it can be reused at least five times without lossing the activity.

Polymer-Supported Phosphoric, Phosphonic and Phosphinic Acids-From Synthesis to Properties and Applications in Separation Processes.

Efficient separation technologies are crucial to the environment and world economy. The challenge posed to scientists is how to engineer selectivity towards a targeted substrate, especially from multicomponent solutions. Polymer-supported reagents have gained a lot of attention in this context, as they eliminate a lot of inconveniences concerning widely used solvent extraction techniques. Nevertheless, the choice of an appropriate ligand for immobilization may be derived from the behavior of soluble compounds under solvent extraction conditions. Organophosphorus compounds play a significant role in separation science and technology. The features they possess, such as variable oxidation states, multivalence, asymmetry and metal-binding properties, highlight their status as a unique and versatile class of compounds, capable of selective separations proceeding through different mechanisms. This review provides a detailed survey of polymers containing phosphoric, phosphonic and phosphinic acid functionalities in the side chain and covers main advances in the preparation and application of these materials in separation science, including the most relevant synthesis routes (Arbuzov, Perkow, Mannich, Kabachnik-Fields reactions, etc.), as well as the main stages in the development of organophosphorus resins and the most important achievements in the field.

Synthesis of Solid-phase Supported Chiral Amines and Investigation of Stereoselectivity of Aldol Reactions of Amine-free Tropinone Enolate

Seven selected chiral mono-, di-, and tridentate amines supported on insoluble polymer were effectively prepared from corresponding primary amines or secondary amino alcohols and Merrifield resin. The reaction of the polymer-supported amines with excess n-butyllithium gave the corresponding lithium amide bases, which were tested in the aldol reactions of tropinone with benzaldehyde. The deprotonation reactions were carried out with or without separation of the lithium enolate from polymer-supported reagents. Using the procedure with separation of lithium enolate from supported chiral reagent different results were obtained with or without the addition of LiCl despite the fact that aggregate formation of Merrifield resin supported Li-amides is hindered. Without the additive, the aldol products were obtained in low diastereoselectivity and enantioselectivity, whereas the addition of LiCl resulted in a significant increase of de and ee even when LiCl was added after the deprotonation step and separation of the chiral amine.

Effects of Solvent Polarity on the Reaction of Aldehydes and Ketones with a Hydrazide-Bound Scavenger Resin.

Polymer-supported reagents have been extensively studied and used in various applications, such as condensation reactions and multiple component reactions. This paper examines the reactions between a solid-functionalized resin, named Amb15-Iso, and aldehydes and ketones that have been solubilized in different solvents. The reactions between these molecules and a hydrazide (isoniazid) in both neutral and acidic media were also studied. The results showed that the solvent polarity influenced the kinetics of the reaction and the yields of carbonyl compounds that were captured by the resin, particularly, for less-reactive molecules. The reactions using the resin were faster than those using free isoniazid in solution, likely because the acidic sites remaining in the resin can catalyze the reaction, increasing the rate of capture. A high dependence on the presence of acidic compounds and the rate of the reaction was observed, in which trifluoroacetic acid was used to catalyze the reaction between the tested molecules and isoniazid in solution. The differential reactivities of the examined ketones and aldehydes in these condensation reactions demonstrate that the resin can provide selective criteria, preferentially scavenging aldehydes from solution. While benzaldehyde reacted quite quickly with the resin, acetophenone barely had any reaction and remained in solution.

Synthesis of coumarin derivative using polymer supported reagents

Recently, there has been a surge in use of polymer-supported reagents and catalysts become common tools for organic synthesis in what is known as polymer-assisted synthesis since they can simplify product isolation and purification. In this context, coumarin derivative 3 was prepared in good yield and high purity, starting from 3-methoxy salicylaldehyde, using reagents supported on a macroporous ion exchange resin. For this purpose, iminocoumarin and unsaturated nitrile were used as starting materials. The synthesized compounds were characterized by IR, NMR and mass spectrometry.

An approach to shortening the timeframe between the emergence of new compounds on the drugs market and the availability of reference standards: The microscale syntheses of nitrazolam and clonazolam for use as reference materials, utilizing polymer-supported reagents.

Nitrazolam and clonazolam are 2 designer benzodiazepines available from Internet retailers. There is growing evidence suggesting that such compounds have the potential to cause severe adverse events. Information about tolerability in humans is scarce but typically, low doses can be difficult to administer for users when handling bulk material. Variability of the active ingredient in tablet formulations can also be of a concern. Customs, toxicology and forensic laboratories are increasingly encountering designer benzodiazepines, both in tablet and powdered form. The unavailability of reference standards can impact on the ability to identify these compounds. Therefore, the need arises for exploring in-house approaches to the preparation of new psychoactive substances (NPS) that can be carried out in a timely manner. The present study was triggered when samples of clonazolam were received in powdered and tablet form at a time when reference material for this drug was commercially unavailable. Therefore, microscale syntheses of clonazolam and its deschloro analog nitrazolam were developed utilizing polymer-supported reagents starting from 2-amino-2'-chloro-5-nitrobenzophenone (clonazolam) and 2-amino-5-nitrobenzophenone (nitrazolam). The final reaction step forming the 1,2,4-triazole ring moiety was performed within a gas chromatography-mass spectrometry (GC-MS) injector. A comparison with a preparative scale synthesis of both benzodiazepine derivatives showed that microscale synthesis might be an attractive option for a forensic laboratory in terms of time and cost savings when compared with traditional methods of synthesis and when qualitative identifications are needed to direct forensic casework. The reaction by-product profiles for both the micro and the preparative scale syntheses are also presented.

David Colin Sherrington. 5 March 1945—4 October 2014

David Colin Sherrington began life as a Liverpool docker's son and became an internationally recognized authority on reactive polymers and using polymer-supported reagents in novel applications. His research career began at University of Liverpool with his PhD work on the mechanisms of cationic polymerization. From 1972 until retirement in 2010, Strathclyde University was his chief research base. In the very early years he continued with mechanistic and kinetic studies of cationic polymerization, but soon moved to the field of polymer-supported reactions and reagents, to which he devoted the rest of his research career. An important contribution to the direction of his scientific activity was the secondment years he spent at Unilever, where he became involved in polymeric high internal phase emulsions (polyHIPEs). In the following years, he devoted much effort to accurate characterization of these and other porous polymer supports, frequently involving him in learning new techniques (e.g. neutron scattering). An important feature was the use of polymer supports to catalyse oxidation reactions, especially olefin epoxidation. He gained valuable insight into many aspects of his research from the many visiting professorships over his career. He was involved on the editorial board of Reactive Polymers continuously from 1982 until 2010 and he was awarded many honours. His free time was mainly devoted to fishing, particularly for salmon, an activity he shared with his wife and a group of friends for many years. His warmth, intellect and clear interest in the careers of his research students were key components in creating the polymer ‘family’ to which they belonged. His years of retirement were saddened by multiple system atrophy, a devastating illness throughout which he was cared for by Val, his wife.

Parallel Kinetic Resolution of N-Heterocycles by N-Acylations in Flow

Key words flow chemistry - acylation - N-heterocycles - parallel kinetic resolution - polymer-supported reagents

Flow chemistry and polymer-supported pseudoenantiomeric acylating agents enable parallel kinetic resolution of chiral saturated N-heterocycles

Kinetic resolution is a common method to obtain enantioenriched material from a racemic mixture. This process will deliver enantiopure unreacted material when the selectivity factor of the process, s, is greater than 1; however, the scalemic reaction product is often discarded. Parallel kinetic resolution, on the other hand, provides access to two enantioenriched products from a single racemic starting material, but suffers from a variety of practical challenges regarding experimental design that limit its applications. Here, we describe the development of a flow-based system that enables practical parallel kinetic resolution of saturated N-heterocycles. This process provides access to both enantiomers of the starting material in good yield and high enantiopurity; similar results with classical kinetic resolution would require selectivity factors in the range of s = 100. To achieve this, two immobilized quasienantiomeric acylating agents were designed for the asymmetric acylation of racemic saturated N-heterocycles. Using the flow-based system we could efficiently separate, recover and reuse the polymer-supported reagents. The amide products could be readily separated and hydrolysed to the corresponding amines without detectable epimerization. Parallel kinetic resolution (PKR) of N-heterocycles via asymmetric acylation has been achieved using quasienantiomers of polymer supported hydroxamic acid reagents. Flow techniques provide physical separation of the reagents, establishing a practical implementation of PKR. The enantioenriched amide products can be readily deprotected to reveal the desired amine without detectable epimerization.

Pyrrolo[3,4-c]pyridine-1,3(2H)-diones: A Novel Antimycobacterial Class Targeting Mycobacterial Respiration.

High-throughput screening of a library of small polar molecules against Mycobacterium tuberculosis led to the identification of a phthalimide-containing ester hit compound (1), which was optimized for metabolic stability by replacing the ester moiety with a methyl oxadiazole bioisostere. A route utilizing polymer-supported reagents was designed and executed to explore structure-activity relationships with respect to the N-benzyl substituent, leading to compounds with nanomolar activity. The frontrunner compound (5h) from these studies was well tolerated in mice. A M. tuberculosis cytochrome bd oxidase deletion mutant (ΔcydKO) was hyper-susceptible to compounds from this series, and a strain carrying a single point mutation in qcrB, the gene encoding a subunit of the menaquinol cytochrome c oxidoreductase, was resistant to compounds in this series. In combination, these observations indicate that this novel class of antimycobacterial compounds inhibits the cytochrome bc1 complex, a validated drug target in M. tuberculosis.

The role of polarizability in determining metal ion affinities in polymer-supported reagents: monoprotic phosphates and the effect of hydrogen bonding

Communication between an immobilized ligand and an ion relies on their polarizabilities and hydrogen bonding when ion exchange sites are introduced.

Synthesis of a Functionalized Polymer Based on a Calix[4]resorcinarene via Covalently Anchored Cationic Moieties: A Reactive Solid Support for Ring Transformation and Expansion of Thiopyrylium Salts

In this work, for the first time, a cationic polymer containing pendant pyridinium groups was synthesized via post-functionalization of the polymeric backbone based on a calix[4]resorcinarene, and characterized by AFM, TEM, analytical CHN, TGA, and DTG techniques. The functionalized polymer is conveniently loaded with desired anions, thereby providing novel and recyclable polymer-supported reagents for achieving synthetic goals. The thermal stability of this cationic polymer (up to 250 °C by TGA) allows thermally demanding ring transformation and expansion of 2,4,6-triarylthiopyrylium salts on its side chains and polymeric backbone without decomposition and leaching of active species in the reaction media. This green method furnished a straightforward route for the synthesis of valuable 2,4,6-triarylpyridines, along with novel 2,5,7-triaryl-1,3-thiazepine derivatives, which are widely present as motifs in an assortment of biologically active molecules.

The role of polarizability in determining metal ion affinities in polymer-supported reagents: Phosphorylated ethylene glycol

This is the first of a series of reports that probes the polarizabilities of different immobilized ligands in order to build toward a rational design of ion-selective polymer-supported reagents. In this report, the polarizabilities of four ligands on a polystyrene backbone (phosphorylated ethylene glycol (pEG1), ethylene glycol (EG1), sulfonic acid, and dimethylamine (DMA)) are evaluated with Au(III) and Eu(III) as representative of soft and hard ions, respectively. Interactions are followed by the extent of sorption, the effect of acid concentration, band shifts in FTIR spectra, and Langmuir plots. The phosphoryl oxygen, hydroxyl OH, and amine show an affinity of Au(III)>Eu(III) while Eu(III)>Au(III) is evident with the sulfonic acid. The PO stretching frequency shifts from 1263 to 1249cm−1 upon Au(III) binding. The affinities indicate that oxygen can be considered soft and hard, depending on its microenvironment: neutral oxygen is soft while anionic oxygen may be classified as hard. Though Eu(III) prefers ionic binding with a strong acid ligand, it is also capable of weak binding with a neutral oxygen donor at pH 3 and 4. Sorption is affected by solution acidity despite the absence of ion exchange. Three routes to enhancing ion–interactions thus emerge: preparing single-site ligands whose polarizability matches the targeted metal ion, preparing ligands with multiple binding sites each of which bind weakly on their own, and preparing single-site ligands with dual ion exchange/coordination character.

New developments in redox chemical delivery systems by means of 1,4-dihydroquinoline-based targetor: Application to galantamine delivery to the brain

The therapeutic efficiency of palliative treatments of AD, mostly based on acetylcholinesterase (AChE) inhibitors, is marred by serious adverse effects due to peripheral activity of these AChE inhibitors. In the literature, a redox-based chemical delivery system (CDS) has been developed to enhance drugs distribution to the brain while reducing peripheral side effects. Herein, we disclose two new synthetic strategies for the preparation of 1,4-dihydroquinoline/quinolinium salt redox-based systems particularly well designed for brain delivery of drugs sensitive to alkylation reactions. These strategies have been applied in the present case to the AChE inhibitor galantamine with the aim of alleviating adverse effects observed with cholinergic AD treatment. The first strategy is based on an intramolecular alkylation reaction as key step, whilst the second strategy relies on a useful coupling between galantamine and quinolinium salt key intermediate. In the course of this work, polymer-supported reagents and a solid-phase synthesis approach revealed to be highly helpful to develop this redox-based galantamine CDS.

One-pot protection-glycosylation reactions for synthesis of lipid II analogues.

(2,6-Dichloro-4-methoxyphenyl)(2,4-dichlorophenyl)methyl trichloroacetimidate (3) and its polymer-supported reagent 4 can be successfully applied to a one-pot protection-glycosylation reaction to form the disaccharide derivative 7 d for the synthesis of lipid II analogues. The temporary protecting group or linker at the C-6 position and N-Troc protecting group of 7 d can be cleaved simultaneously through a reductive condition. Overall yields of syntheses of lipid II (1) and neryl-lipid II N(ε)-dansylthiourea are significantly improved by using the described methods.

Molecular iodine in monomer and polymer designing

Not only does the molecular iodine play a leading role in organic synthesis but also in the polymer synthesis. Different kinds of polymerization initiated by molecular iodine are herein screened: cationic polymerization, radical polymerization, living/controlled radical polymerization (LCRP) such as reverse iodine transfer polymerization, polycondensation, and ring-opening polymerization (ROP). Also, the functionalization of polymers using molecular iodine, such as the acetylation of polysaccharides (cellulose, starch), and the use of iodine–polymer complex in organic synthesis are also discussed. Numerous natural and synthetic polymers are prone to make complexes with molecular iodine, and one feature of such complexes is their propensity as polymer-supported reagent and catalysts in many organic syntheses.

An Innovative and Atom-Efficient Synthesis of Bioactive 2-Aroylfuran Derivatives Using Macroporous Polymer-Supported Cyanide

A novel and safe approach was developed for the synthesis of bioactive 2-aroyl-3,5-diarylfurans in excellent yields by using a cyanide-impregnated anion-exchange resin as a versatile reagent. The possibility of reusing the polymer-supported reagent makes the process environmentally friendly and economically advantageous.

A FAST PROCEDURE FOR THE PREPARATION OF BENZIMIDAZOLE DERIVATIVES USING POLYMER-SUPPORTED WITH TRIFLUOROMETHANESULFONIC ACID AS NOVEL AND REUSABLE CATALYST

ABSTRACT A highly selective synthesis of benzimidazoles from the reaction of o-phenylenediamines and aromatic aldehydes in the presence of PVP- trifluoromethanesul-fonic acid is reported, and morphological investigation was reported by FT-IR. The remarkable advantages of this method are the simple experimental procedures, shorter reaction times, high yields of product, and non-toxic catalyst. However, the reactions were performed in solvent-free and the catalyst could be reused for several runs. Keywords: Green chemistry; polymer-supported reagents; Benzimidazoles; reusable catalyst e-mail: Changiz.Karami@gmail.com INTRODUCTION In the last ten years, supported reagents on polymers have become increas-ingly applied in organic synthesis 1 , because the reactions are carried out with simple work-up, easy product isolation, and mild reaction conditions 2 . Benz-imidazole is a kind of substances which have found practical applications in organic synthesis 3 , and the benzimidazole nucleus are found in a variety of pharmaceuticals as cardiotonic agents,

Copper-Catalyzed Huisgen 1,3-Dipolar Cycloaddition under Oxidative Conditions: Polymer-Assisted Assembly of 4-Acyl-1-Substituted-1,2,3-Triazoles

We herein document the first example of a reliable copper-catalyzed Huisgen 1,3-dipolar cycloaddition under oxidative conditions. The combined use of two polymer-supported reagents (polystyrene-1,5,7-triazabicyclo[4,4,0]dec-5-ene/Cu and polystyrene-2-iodoxybenzamide) overcomes the thermodynamic instability of copper(I) species toward oxidation, enabling the reliable Cu-catalyzed Huisgen 1,3-dipolar cycloadditions in the presence of an oxidant agent. This polymer-assisted pathway, not feasible under conventional homogeneous conditions, provides a direct assembly of 4-acyl-1-substituted-1,2,3-triazoles, contributing to expand the reliability and scope of Cu(I)-catalyzed alkyne-azide cycloaddition.