Showing papers in "ACS Combinatorial Science in 2008"
TL;DR: Although no longer in the spotlight and heralded as the savior of the drug industry, “combinatorial chemistry” is alive and well; in fact, combinatorial chemistry science is more prevalent and wide-spread than ever before.
Abstract: The science that established combinatorial chemistry as important new discipline in the 1980s and 1990s has re-emerged and infiltrated every sub-discipline within modern drug discovery and has profound impact. The application of combinatorial chemistry science has revolutioned high-throughput screening paradigms, chemical lead optimization, library purification, and post-purification sample handling, as well as in vitro and in vivo drug metabolism and pharmacokinetic assays. Although no longer in the spotlight and heralded as the savior of the drug industry, “combinatorial chemistry” is alive and well; in fact, combinatorial chemistry science is more prevalent and wide-spread than ever before.
200 citations
116 citations
TL;DR: The power of synthetic mixture-based combinatorial libraries lies in their ability to accelerate the acquisition of information regarding specific functionalities at each variable position in the library that determines the activity of a specific chemical scaffold or pharmacophore.
Abstract: Since its inception more than 20 years ago with highthroughput parallel synthesis for oligonucleotides and peptides, synthetic combinatorial methods have fundamentally advanced the ability to synthesize and screen large numbers of compounds because of improvements made in technology, instrumentation, and library design strategies. This discipline was readily accepted initially and is now an embedded component of the drug discovery process worldwide. While there are a range of combinatorial approaches, the use of mixture-based libraries made up of tens of thousands to billions of compounds is the approach that enables the most rapid and economical acquisition of chemical and biological information. Mixture-based libraries represent powerful tools that can be used for the identification of active individual compounds for a wide range of important targets, as reviewed. In the past decade, such approaches have been expanded to include the synthesis of low molecular weight acyclic and heterocyclic compounds. As with most innovations, synthetic combinatorial methods developed for the synthesis and screening of mixture-based libraries were slow to gain acceptance because of the conceptual distance between these approaches and the traditional methods previously used in the pharmaceutical industry. This was, and is, especially true for mixture-based libraries composed of tens of thousands to billions of different compounds, but such methods are now being used by an increasing number of groups for the identification of highly active, novel compounds in research and drug discovery programs. Mixture-based libraries are systematically arranged mixtures of synthetic compounds having both defined and mixture positions of diversity. This permits information to be gathered regarding both the activity and importance of every functionality at each position of the library. Post synthetic chemical modification of such existing mixturebased libraries using the “libraries from libraries” approach now enables the ever-increasing generation of low molecular weight compounds. Thus, for the last 16 years, we have successfully used this approach for the design and the generation of a range of peptidomimetic and small molecule libraries from resin-bound polyamides. We have also used this approach combining solidand solution-phase synthesis methods for the synthesis of a nitrosamine library and a platinum tetraamine coordination complex library. The power of synthetic mixture-based combinatorial libraries lies in their ability to accelerate the acquisition of information regarding specific functionalities at each variable position in the library that determines the activity of a specific chemical scaffold or pharmacophore. Another advantage of mixture-based libraries resides in the very high densities of compounds that can be synthesized in narrow areas of chemical space. When compared to existing high-throughput screening (HTS) programs, in which tens of thousands of individual compounds are screened against therapeutically important targets, millions of compounds formatted as mixtures can be examined using substantially less material and at much lower time/labor economics than if these same mixture-based diversities were made and screened as individual compounds. This unique combinatorial library approach can be applied to virtually any existing bioassay for the identification of novel ligands. For example, a novel, highly active tetrapeptide agonist for the κ-opioid receptor was identified from a positional scanning library of 6.25 * To whom correspondence should be addressed. Phone: 858-455-3805. Fax: 858-455-3804. E-mail: rhoughten@tpims.org. † Torrey Pines Institute for Molecular Studies. ‡ University of Arizona. § PsychoGenics, Inc. | Carnegie Mellon University. ⊥ Current address: College of Pharmaceutical Science, Zijin Campus, Zhejiang University, Hangzhou 310058, P. R. China. J. Comb. Chem. 2008, 10, 3–19 3
116 citations
TL;DR: A sequential one-pot two-step protocol for microwave-assisted synthesis of Hantzsch-type hexa-substituted 1,4-dihydropyridines has been developed and is complementary to the classical HantzSch synthesis.
Abstract: A sequential one-pot two-step protocol for microwave-assisted synthesis of Hantzsch-type hexa-substituted 1,4-dihydropyridines has been developed. The three-component reactions of β-aroylthioamides with aldehydes and acetonitrile derivatives produce the intermediates in situ followed by a S-alkylation to afford hexa-substituted 1,4-dihydropyridines. The reaction presumably proceeds via a Knoevenagel condensation−Michael addition−cyclocondensation−rearrangement−SN2 reaction sequence. Target compounds were obtained in high yields and simply purified by recrystallization. The novel method is complementary to the classical Hantzsch synthesis in that it is well-suited to the preparation of hexa-substituted 1,4-dihydropyridines.
105 citations
TL;DR: A methodology has been developed to rank binding affinities for ligands based on NMR screens that use 1D (1)H NMR line-broadening experiments, and the results were found to give good agreement with previous affinITIES that have been reported for these same ligands with HSA.
Abstract: Many of today’s drug discovery programs utilize high-throughput screening methods that rely on quick evaluations of protein activity to rank potential chemical leads. By monitoring biologically relevant protein-ligand interactions, NMR can provide a means to validate these discovery leads and to optimize the drug discovery process. NMR-based screens typically use a change in chemical shift or linewidth to detect a protein-ligand interaction. However, the relatively low throughput of current NMR screens and their high demand on sample requirements generally makes it impractical to collect complete binding curves to measure the affinity for each compound in a large and diverse chemical library. As a result, NMR ligand screens are typically limited to identifying candidates that bind to a protein and do not give any estimate of the binding affinity. To address this issue, a methodology has been developed to rank binding affinities for ligands based on NMR-based screens that use 1D 1 H NMR line-broadening experiments. This method was demonstrated by using it to estimate the dissociation equilibrium constants for twelve ligands with the protein human serum albumin (HSA). The results were found to give good agreement with previous affinities that have been reported for these same ligands with HSA.
89 citations
82 citations
TL;DR: Synthesis of a novel class of highly substituted 3,4-dihydroquinoxalin-2-amine derivatives including spirocyclic compounds from three-component condensation reaction of o-phenylenediamines, diverse carbonyl compounds, and isocyanides in the presence of a catalytic amount of p-toluenesulfonic acid in good to excellent yields at room temperature is described.
Abstract: Synthesis of a novel class of highly substituted 3,4-dihydroquinoxalin-2-amine derivatives including spirocyclic compounds from three-component condensation reaction of o-phenylenediamines, diverse carbonyl compounds, and isocyanides in the presence of a catalytic amount of p-toluenesulfonic acid in good to excellent yields at room temperature is described.
72 citations
TL;DR: Tandem addition-cyclization reactions of 2-alkynylbenzenamines with isothiocyanates catalyzed by silver triflate are described; they provide an efficient and practical route for the synthesis of 2,4-dihydro-1 H-benzo[ d][1,3]thiazines.
Abstract: Tandem addition-cyclization reactions of 2-alkynylbenzenamines with isothiocyanates catalyzed by silver triflate are described; they provide an efficient and practical route for the synthesis of 2,4-dihydro-1H-benzo[d][1,3]thiazines.
69 citations
TL;DR: Combinatorial and high-throughput optimization of improved ternary Pt alloy electrocatalysts for the oxidation of methanol for use in direct methnol fuel cell (DMFC) anodes and "consensus maps" are pointed to a new optimized ternaries alloy Electrocatalytic activity for meethanol electrooxidation with an overall composition of Pt18Co62Ru20.
Abstract: We report the combinatorial and high-throughput optimization of improved ternary Pt alloy electrocatalysts for the oxidation of methanol for use in direct methanol fuel cell (DMFC) anodes. Following up on the discovery of a ternary Pt20Co60Ru20 catalyst(1) with significantly improved electrocatalytic activity for methanol oxidation over standard Pt−Ru catalysts, we optimize the electrocatalytic activity of this composition using a closely sampled Pt−Co−Ru “optimization library”. We also screen for compositional and structural stability using high-throughput methods. Composition−activity maps confirmed improved activity in compositional neighborhood of the Pt20Co60Ru20 catalyst. Activity trends of Pt−Ru binary alloys were in excellent agreement with fundamental surface electrochemical studies. Structural and compositional catalyst stability was probed using X-ray diffraction (XRD) and energy dispersive X-ray analysis (EDX). Combination of the stability−composition and activity−composition maps resulted in ...
63 citations
TL;DR: It is shown that the use of a not very large set of starting compounds can lead to the synthesis of a thousand-member 2-amino-spiro[(3' H)-indol-3',4-(4 H)-pyran] library.
Abstract: A convenient method of synthesis of substituted and annulated 2-amino-spiro[(3′H)-indol-3′,4-(4H)-pyrans] at mild conditions and in good yields is developed. Three component reaction of wide variety of substituted isatins, cyanoacetic acid derivatives, and carbonyl compounds or phenols gives the target compounds. Forty new spiropyrans were obtained, and their structures were proved by elemental analysis and 1H NMR and IR spectral data. It is shown that the use of a not very large set of starting compounds can lead to the synthesis of a thousand-member 2-amino-spiro[(3′H)-indol-3′,4-(4H)-pyran] library.
62 citations
TL;DR: An efficient and convenient method was developed for the preparation of 2,4(1H,3H)-quinazolinediones and 2-thioxoquinazolinones, suitable for library synthesis in drug discovery efforts.
Abstract: An efficient and convenient method was developed for the preparation of 2,4(1H,3H)-quinazolinediones and 2-thioxoquinazolinones. Substituted methyl anthranilate reacted with various iso(thio)cyanates in DMSO/H2O without any catalyst or base by using microwave irradiation to generate diversity on the 2,4(1H,3H)-quinazolinediones or 2-thioxoquinazolinones. A variety of substrates can participate in the process with good yields and high purities, making this methodology suitable for library synthesis in drug discovery efforts.
TL;DR: A diverse 51-member library of 3,4,5-trisubstituted isoxazoles has been generated using palladium-catalyzed processes adapted to parallel synthesis utilizing commercially available boronic acid, acetylene, styrene, and amine sublibraries.
Abstract: The iodocyclization of O-methyloximes of 2-alkyn-1-ones affords 4-iodoisoxazoles, which undergo various palladium-catalyzed reactions to yield 3,4,5-trisubstituted isoxazoles. The palladium-catalyzed processes have been adapted to parallel synthesis utilizing commercially available boronic acid, acetylene, styrene, and amine sublibraries. Accordingly, a diverse 51-member library of 3,4,5-trisubstituted isoxazoles has been generated.
TL;DR: Combinatorial solid-phase synthesis of bis-heterocyclic compounds, characterized by the presence of two heterocyclics cores connected by a spacer of variable length/structure, provided structurally heterogeneous libraries with skeletal diversity.
Abstract: Combinatorial solid-phase synthesis of bis-heterocyclic compounds, characterized by the presence of two heterocyclic cores connected by a spacer of variable length/structure, provided structurally heterogeneous libraries with skeletal diversity. Both heterocyclic rings were assembled on resin in a combinatorial fashion.
TL;DR: Compared with the classical synthetic method, this new method has the advantages of short reaction time, high yields, convenient manipulation, and high regioselectivity.
Abstract: 1,2,3,5-Tetrasubstituted and 1,2,3,4,5-pentasubstituted pyrroles may be synthesized through three-component reaction of 1,3-diketones, aldehydes, and amines induced by low-valent titanium reagent. High regioselectivity was achieved. Compared with the classical synthetic method, this new method has the advantages of short reaction time (15 min), high yields, convenient manipulation, and high regioselectivity.
TL;DR: The solution-phase parallel synthesis of a 121-member library of multi-substituted benzo[ b]furans is described, which yields 3-iodobenzofurans are readily prepared in good to excellent yields.
Abstract: The solution-phase parallel synthesis of a 121-member library of multi-substituted benzo[b]furans is described. 2,3,5-Trisubstituted benzo[b]furans have been prepared by the palladium-catalyzed substitution of 3-iodobenzofurans by Suzuki−Miyaura, carbonylative Suzuki, Sonogashira, Heck, and carboalkoxylation chemistry. The 3-iodobenzofurans are readily prepared in good to excellent yields by the palladium/copper-catalyzed cross-coupling of various o-iodoanisoles and terminal alkynes, followed by electrophilic cyclization with ICl.
TL;DR: The screening of a rosamine dye library against diverse macromolecules led to the discovery of a highly sensitive human serum albumin binder, G13, with approximately 36-fold fluorescence intensity change, which showed a highly selective response to HSA.
Abstract: A fluorescent dye library approach for the development of a bioanalyte sensor was sought. The screening of a rosamine dye library against diverse macromolecules led to the discovery of a highly sensitive human serum albumin binder, G13, with ∼36-fold fluorescence intensity change. G13 showed a highly selective response to HSA over other macromolecules including albumins from other species. The potential use of G13 for the detection of HSA in biofluids is described.
TL;DR: It is demonstrated how the rapid generation of minilibraries of substituted alkoxy benzenes can be screened, both against insect antennae and against expressed pheromone-binding proteins from the gypsy moth, Lymantria dispar.
Abstract: We describe methods for the rapid generation of minilibraries of substituted alkoxy benzenes (consisting of 4-5 compounds), for screening as insect olfaction or gustation inhibitors. Synthetic or commercially available monoalkoxy benzene compounds were mixed and reacted with various alkyl halides to afford a first set of minilibraries. A second and third set were generated from allyloxy minilibraries via the Claisen rearrangement and subsequent alkylation of the ortho-allyl phenols. We have chosen to prepare a collection of small libraries (as opposed to one large library) to test the response insects exhibit toward blends of compounds. We demonstrate how our minilibraries can be screened, both against insect antennae and against expressed pheromone-binding proteins from the gypsy moth, Lymantria dispar.
TL;DR: The novel one-pot synthesis of 2,3,4, 5-tetrahydro-1 H-1,5-benzodiazepine-2-carboxamide derivatives using an aromatic diamine, a linear or cyclic ketone, an isocyanide, and water in the presence of a catalytic amount of p-toluenesulfonic acid at ambient temperature in high yields is described.
Abstract: A new approach to the design of multicomponent reactions is introduced. As a result, the novel one-pot synthesis of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-2-carboxamide derivatives using an aromatic diamine, a linear or cyclic ketone, an isocyanide, and water in the presence of a catalytic amount of p-toluenesulfonic acid at ambient temperature in high yields is described.
TL;DR: A novel MW-assisted protocol for the efficient amination of aryl halides with various amines in the presence of Cu(OAc)2 and a much broader substrate scope: both aromatic and aliphatic amines and various substituted aryL halides can be applied.
Abstract: The significance of amination of aryl halides has been manifested by its wide applications in the synthesis of the organically and medicinally interesting building blocks containing the N-aryl moiety throughout pharmaceuticals, agrochemicals, natural products, and materials. The stateof-the-art in the area includes the copper-mediated Ullmann coupling and the Buchwald-Hartwig reaction by utilizing the palladium-catalyzed arylation of amines. Although these methods are highly effective, there is still much room for improvement, for example, these methods usually require long reaction times and high reaction temperatures, and moreover some of them suffer from a relatively narrow scope of substrates. Microwave (MW)-assisted organic reactions have been demonstrated as a powerful means in significantly accelerating organic processes including aromatic nucleophilic substitution reactions. Notably, Tu and Meciarova, respectively, reported the construction of arylamines using this technique. Our group also have achieved success by using arylboronic acids and amines as the substrates. However, the described methods are only limited to electronrich aliphatic amines or imidazole. The electron-deficient nitrogen-containing aromatic heterocycles were found to be less reactive or unreactive. Herein, we wish to report a novel MW-assisted protocol for the efficient amination of aryl halides with various amines in the presence of Cu(OAc)2. Several distinguished features of the process are deserved to be mentioned: (i) proceeding faster and generally giving good to excellent yields, (ii) using Cu(OAc)2 without requiring any other additives, and more significantly, (iii) a much broader substrate scope: both aromatic and aliphatic amines and various substituted aryl halides can be applied. Initially, we studied the MW-assisted amination of aryl halides using iodobenzene and imidazole as the model substrates for optimization of the reaction conditions, and the results are summarized in Table 1. No coupling occurred in the absence of the Cu(OAc)2 (entry 1, Table 1), while the addition of 1.0 equiv of Cu(OAc)2 resulted in the formation of the desired coupling product in 77% yield after 10 min of irradiation at 120 °C in the presence of DBU (entry 2, Table 1). Probing of the solvent effect revealed that DMSO was superior to dioxane or DMF (entries 2-4, Table 1). We next examined the effect of base on the coupling reaction. It was found that the nature of bases had a pronounced impact on the process. DBU turned out to be better than NEt3, while the inorganic base NaOH was ineffective (entries 2, 5 and 6, Table 1). Finally, the increase of the reaction temperature to 130 °C in the presence of 1.0 equiv of Cu(OAc)2 and 2.0 equiv of DBU led to better results (entry 12, Table 1). No gain was observed when the reaction temperature was further increased (entries 13, Table 1). When comparing microwave reactions with conventional preheated oil bath reaction, we observed a sharp decrease in yield (27%) under conventional thermal condition (entries 12, 14, Table 1). With the optimized conditions in hand, we then examined the generality of the process. As shown in Tables 2 and 3, we were pleased to find that the method was applicable to a broad substrate scope on both aryl halides and amines. First, the new process was applied to a variety of nitrogencontaining compounds, including aliphatic morpholine, isopropylamine, and aromatic amines imidazole, pyrazole, indole, pyrrole, benzimidazole, and substituted 1,2-dihydropyridin-2-one, with iodoor bromobenzene. The desired amination products were obtained in moderate to excellent yields (Table 2). Both the aliphatic amines and nitrogen heterocycles were effective in the formation of C-N bond (entries 1-6, and 9-12, Table 2). This coupling reaction is sensitive to steric hindrance. Moderate yields were observed for 2-methylimidazole and 2-isopropylimidazole (entries 7 and 8, Table 2). The scope of the process with respect to the variation of aryl halides was investigated next (Table 3). The coupling reaction of imidazole, which proved to be a difficult substrate with poor reaction yields, with a vast array of aryl halides containing various electron-donating and -withdrawing substituents were also carried out under the optimal reaction conditions. As shown, the corresponding N-arylation products were obtained in moderate to excellent yields (entries 1-6
TL;DR: The generation of three different heterocycle libraries furnishing thiophenes, oxindoles, and benzimidazoles using the new rotor types using disposable glass vials in multimode microwave reactors is described.
Abstract: New rotor types using disposable glass vials for small-scale parallel synthesis in multimode microwave reactors are introduced. One rotor comprises 16 groups of four vials, whereas the second uses four silicon carbide plates with a 6 × 4 matrix to process the vials. Both rotors achieve utmost temperature homogeneity upon microwave irradiation and can be used for microwave-mediated reactions at temperatures of up to 200 °C and pressures of 20 bar. The generation of three different heterocycle libraries furnishing thiophenes, oxindoles, and benzimidazoles using the new rotor types is described.
TL;DR: A column chromatography-free parallel solution-phase synthesis that exploits the reaction between azides and alpha-keto phosphorus ylids, which is known to regioselectively generate the 1,5-disubstituted triazoles is developed.
Abstract: Combretastatin A-4 is an antitumoral and antitubulin agent that is active only in its cis configuration. In the present manuscript, we have synthesized cis-locked combretastatins containing a triazole ring (combretatriazoles). To achieve this, we have developed a column chromatography-free parallel solution-phase synthesis that exploits the reaction between azides and α-keto phosphorus ylids, which is known to regioselectively generate the 1,5-disubstituted triazoles. The prepared compounds were screened as antitubulinic agents, allowing us to identify three new compounds with high potency, two of which show a new mechanism of action that induces cells to appear multinucleated and display a high number of mitotic spindles.
TL;DR: A scalable method for the preparation of 4,5-disubstituted thiazoles and imidazoles as distinct regioisomeric products using a modular flow microreactor has been devised.
Abstract: A scalable method for the preparation of 4,5-disubstituted thiazoles and imidazoles as distinct regioisomeric products using a modular flow microreactor has been devised. The process makes use of microfluidic reaction chips and packed immobilized-reagent columns to effect bifurcation of the reaction pathway.
TL;DR: A MOOP method based on Derringer's desirability function that allows conducting global QSAR studies, simultaneously considering the potency, bioavailability, and safety of a set of drug candidates, is introduced and a validation method of the ranking process, as well as a quantitative measure of the quality of a ranking, the ranking quality index (Psi), is proposed.
Abstract: Up to now, very few applications of multiobjective optimization (MOOP) techniques to quantitative structure−activity relationship (QSAR) studies have been reported in the literature. However, none of them report the optimization of objectives related directly to the final pharmaceutical profile of a drug. In this paper, a MOOP method based on Derringer’s desirability function that allows conducting global QSAR studies, simultaneously considering the potency, bioavailability, and safety of a set of drug candidates, is introduced. The results of the desirability-based MOOP (the levels of the predictor variables concurrently producing the best possible compromise between the properties determining an optimal drug candidate) are used for the implementation of a ranking method that is also based on the application of desirability functions. This method allows ranking drug candidates with unknown pharmaceutical properties from combinatorial libraries according to the degree of similarity with the previously det...
TL;DR: A diverse collection of pyrroles has been prepared using a one-pot, domino aldehyde/amine condensation, [3,3]-aza-Claisen rearrangement, imine-allene cyclization strategy, which provided very good levels of conversion after reacting for only 30 min.
Abstract: A diverse collection of pyrroles has been prepared using a one-pot, domino aldehyde/amine condensation, [3,3]-aza-Claisen rearrangement, imine-allene cyclization strategy. This protocol was accelerated by microwave irradiation and provided very good levels of conversion after reacting for only 30 min.
TL;DR: A novel one-pot tandem synthesis of 2-styryl-4(3 H)-quinazolinones in an acidic ionic liquid is reported and an aromatic aldehyde is added to the mixture to afford the title compounds in high to excellent yields.
Abstract: A novel one-pot tandem synthesis of 2-styryl-4(3H)-quinazolinones in an acidic ionic liquid is reported. In this procedure isatoic anhydride, a primary aniline or ammonium acetate, and triethylorthoacetate are reacted in the presence of imidazolium trifluoroacetate [Hmim]TFA. Subsequently an aromatic aldehyde is added to the mixture to afford the title compounds in high to excellent yields.
TL;DR: Indole ring formation with a gold(III) catalyst reported by Marinelli et al. is focused on, and novel immoblization methods for metal catalysts, microencapsulation and polymer-incarcerated methods are tried.
Abstract: Immobilized catalysts provide among the most effective tools for chemical library synthesis because the procedures are simple and applications to automated systems are feasible. In recent years, use of gold catalysts in organic synthesis has expanded rapidly, and accordingly, development of immobilized gold catalysts is strongly demanded. In the course of our program to develop new methods for library synthesis, we focused on indole ring formation with a gold(III) catalyst reported by Marinelli et al. (Scheme 1). While we and other groups have reported immobilized gold catalysts, most of them are gold(0), and only one approach for immobilizing gold(III) was reported by Corma and Hashmi et al., in which cerium(IV) oxide was used as inorganic support and a mixture of gold(0), gold(I), and gold(III) was obtained. Since we have already reported novel immoblization methods for metal catalysts, microencapsulation and polymer-incarcerated methods, 6 we decided try these methods for gold(III) immobilization. First we attempted to prepare polymer-incarcerated (PI) Au(III) from copolymer A and sodium tetrachloroaurate(III) via coacervation in THF-hexane and cross-linking by heating according to the standard method (Table 1). Unexpectedly, this potential catalyst had no activity toward the reaction for the conversion of alkynyl aniline 1a to the indole 2a (entry 1). Next cross-linking by acid treatment was tried. Although after treatment with hydrochloric acid the catalyst worked well for the indole synthesis, serious gold leaching into the reaction mixture was observed (entry 2). Cross-linking with other acids under various conditions also failed. We then prepared a microencapsulated gold(III) catalyst (MC Au) without the cross-linking step and applied it to indole synthesis. To our delight, 2a was obtained in 45% yield without significant gold leaching. Moreover, the MC Au was reused at least three times (entries 3–5), and characteristically displayed lower yields with fresh catalyst rather than in reuse. Further investigations revealed that 2a was retained in the catalyst. To prevent this retention, MC Au catalysts on various inorganic supports were prepared and tested (Table 2). Among these inorganic supports, silica gel (SiO2) afforded the best result in term of the yield, gold leaching, and reusability (entry 8). We decided to use MC Au on SiO2 in subsequent experiments. We next investigated the ratio of the three components of the copolymer: styrene, styrene with an epoxide moiety, and styrene with a tetraethylene glycol moiety (Table 3). After careful examination, the best ratio of styrene, styrene with epoxide unit, and styrene with tetraethylene glycol unit was
TL;DR: A straightforward two-step protocol for the synthesis of 2-aryl-substituted 4-thiazolidinone and 4- fourthiazinanone libraries has been developed.
Abstract: A straightforward two-step protocol for the synthesis of 2-aryl-substituted 4-thiazolidinone and 4-thiazinanone libraries has been developed. The one-pot, three-component reactions of fluorous benzaldehydes with amines and mercaptoacetic acid or mecaptopropanoic acid produce the heterocyclic systems. Intermediates purified by fluorous solid-phase extraction are subject to microwave-assisted palladium-catalyzed coupling reactions to simultaneously cleave the fluorous tag and introduce the biaryl and thioaryl functional groups to the 2-position of 4-thiazolidinones and 4-thiazinanones.