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Paints and coatings are widely used in modern society and their current production is mainly dependent on the petrochemical industry. The establishment of processes using sustainable alternative monomers based on biorenewable resources, using exclusively biobased reagents and green synthetic transformations are highly warranted for a more sustainable future. Herein, we report on a sustainable polymer and coating system based on the monomer methoxybutenolide, a biobased acrylate alternative. Methoxybutenolide and the comonomer dodecyl vinyl ether are synthesized from biobased platform chemicals using the environmentally benign synthetic transformations photooxygenation and vinylation. For the photooxygenation, a biobased photosensitizer was developed showing high quantum yields. The monomers were copolymerized using biomass derived (photo)initiators to yield fully biobased polymers and coatings with properties comparable to acrylate based coatings.

Multicomponent reactions (MCRs)[1] have emerged as useful tools in diversity-oriented synthesis (DOS).[2] Although a number of substituents can be varied over a broad range, MCRs often access products of one specific scaffold, limiting the overall chemical diversity. To overcome this, MCRs have been combined with other types of reactions such as Diels–Alder reactions,[3] click chemistry,[4] and cyclization strategies[5] to generate structural diversity and a high degree of complexity in a minimal number of reaction steps. Our group contributed in this field by trapping 1-azadienes,[ 6] generated by the three-component reaction (3-CR) between phosphonates, nitriles and aldehydes,[7] with various reactants resulting in novel 4-CRs for a variety of heterocyclic scaffolds.[8]

CXC chemokine receptor-3 (CXCR3) is a G-protein coupled receptor (GPCR) predominantly expressed on activated T lymphocytes that promote Th1 responses. Previously, we described the 3H-quinazolin-4-one containing VUF 5834 (decanoic acid {1-[3-(4-cyano-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-ethyl}-(2- dimethylamino-ethyl)-amide) as a small-molecule CXCR3 antagonist with submicromolar affinity and as a lead structure for the development of CXCR3 antagonists. More recently, the related 3H-pyrido[2,3-d]pyrimidin-4-one compounds AMG 487 and NBI-74330 have been reported as nanomolar CXCR3 antagonists and these ligands are currently under clinical investigation. The aim of this study is to link the structure-activity relationship (SAR) of the previously published class of 3H-quinazolin-4-one containing CXCR3 ligands with these novel clinical candidates. From the modification of the lead structure VUF 5834 emerged the importance of the (4-fluoro-3-(trifluoromethyl)phenyl)acetyl and the 3-methylen-pyridine as substituents to improve the affinity at the human CXCR3 receptor, whereas other features are less important. The described molecules serve as tool to investigate the role of the CXCR3 receptor in various inflammatory conditions. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA.

The feasibility of enantiomeric excess (ee) prediction is demonstrated for asymmetric oxazaborolidine mediated ketone reduction. A quantitative structure-selectivity (QSSR) model of chiral oxazaborolidines was created by using multivariate data analysis. High-throughput methods and regression techniques were used to correlate the model with the ee’s of reactions with a training set and to predict the ee’s for an additional set of oxazaborolidines. The predicted ee’s corresponded well with the actual values, indicating that the model is very useful for the initial selection of catalysts for screening experiments.

The exceptional reactivity connected to isocyanides, as discussed here, is unrivaled by other functional groups and has led to many synthetically useful novel reactions. This chapter deals with multicomponent reactions (MCRs) involving isocyanides as one of the inputs for the synthesis of heterocycles. We focus on the α-acidic isocyanides, which are an appealing class of versatile building blocks. Their use has led to a range of versatile isocyanide-based MCRs (IMCRs), as will become clear from this chapter. From a set of only three different types of α-acidic isocyanides, sometimes inspired by the early work of Schollkopf and van Leusen, a wide range of novel reaction paths were discovered in the last decade. In this way a plethora of mainly heterocyclic scaffolds can be synthesized in a straightforward fashion. The IMCRs discussed are usually robust reactions that can be easily combined in very short sequences with other complexity-generating processes, like cycloadditions or even additional MCRs, leading to yet other classes of heterocyclic motifs. This offers exciting opportunities for library design of highly functionalized heterocyclic scaffolds employing diversity-oriented synthesis approaches.

The exceptional reactivity connected to isocyanides, as discussed here, is unrivaled by other functional groups and has led to many synthetically useful novel reactions. This chapter deals with multicomponent reactions (MCRs) involving isocyanides as one of the inputs for the synthesis of heterocycles. We focus on the α-acidic isocyanides, which are an appealing class of versatile building blocks. Their use has led to a range of versatile isocyanide-based MCRs (IMCRs), as will become clear from this chapter. From a set of only three different types of α-acidic isocyanides, sometimes inspired by the early work of Schollkopf and van Leusen, a wide range of novel reaction paths were discovered in the last decade. In this way a plethora of mainly heterocyclic scaffolds can be synthesized in a straightforward fashion. The IMCRs discussed are usually robust reactions that can be easily combined in very short sequences with other complexity-generating processes, like cycloadditions or even additional MCRs, leading to yet other classes of heterocyclic motifs. This offers exciting opportunities for library design of highly functionalized heterocyclic scaffolds employing diversity-oriented synthesis approaches.

Multicomponent reactions (MCRs)[1] have emerged as useful tools in diversity-oriented synthesis (DOS).[2] Although a number of substituents can be varied over a broad range, MCRs often access products of one specific scaffold, limiting the overall chemical diversity. To overcome this, MCRs have been combined with other types of reactions such as Diels–Alder reactions,[3] click chemistry,[4] and cyclization strategies[5] to generate structural diversity and a high degree of complexity in a minimal number of reaction steps. Our group contributed in this field by trapping 1-azadienes,[ 6] generated by the three-component reaction (3-CR) between phosphonates, nitriles and aldehydes,[7] with various reactants resulting in novel 4-CRs for a variety of heterocyclic scaffolds.[8]

Optimising synthetic conversions and assessing catalyst performance is a tedious and laborious endeavour. Herein, we present an automated alternative to the commonly applied sequential approaches that are used to increase catalyst discovery process efficiencies by increasing the number of entities that can be tested. This new approach combines conversion of the reactants and determination of product formation into a single comprehensive reaction detection system that can be operated with minimal catalyst and reactant consumption. With this approach, rudimentary reaction conditions can be quickly optimised and the same system can then be used to screen for the optimal homogenous catalyst in a selected solution-phase synthetic conversion. The system, which is composed of standard HPLC components, can be used to screen catalyst libraries at a repetition rate of five minutes and can be run unsupervised. The sensitive mass spectrometric detection that is implemented in the reaction detection methodology can be used for the simultaneous monitoring of reactants, catalysts and product ions. In the experiments, the three-component reaction that gives a substituted 2imidazoline was optimised. Afterwards, the same method was used to assess a library of ferrocene-based Lewis acid catalysts for performance in the aforementioned conversion in six different solvents. We demonstrate the feasibility of using this methodology to directly compare the performance results obtained in different solvents by calibrating the solvent-specific MS responses. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA,.

Selective formation of 2H-2-imidazolines and 2-substituted oxazoles by using a multicomponent reaction of amines, either aldehydes or ketones, and alpha-acidic isocyano amides or esters is described. By selecting the appropriate solvent, Ag(I) or Cu(I) catalyst, or by employing a weak Bronsted acid, the product formation can be fully controlled and directed quantitatively to the desired heterocyclic scaffold. The described experimental procedures not only significantly increase the scope of compatible inputs for this complexity-generating three-component reaction, but also allow for considerable chemical diversity: At least four diversity points in two distinct scaffolds can be exploited in this way.

An integrated online screening system was developed to rapidly screen homogeneous catalysts for activity toward a selected synthesis. The continuous-flow system comprises standard HPLC pumps for the delivery of substrates, an HPLC autosampler for the injection of homogeneous catalysts, a thermostated reactor to mediate synthesis, and a single-stage quadrupole mass spectrometer (MS) equipped with atmospheric pressure chemical ionization for the determination of product formation. MS detection offers sensitivity, specificity, and speed when applied to the analysis of dynamic processes in the condensed phase. By applying the present methodology for the study of substrate conversion mediated by homogeneous catalysts, the concentration of substrates and reaction product could be monitored while information about the catalysts could also be obtained. In an initial screening application, the performance of a selected number of Lewis acids in the multicomponent synthesis of a highly substituted 2-imidazoline was determined. Limit of detection and limit of quantitation were determined by injecting different concentrations of 2-imidazoline standards and proved to be 1.6 and 5.2 nM, respectively. The results obtained with the new screening method were in good agreement with a traditional bench-scale experiment. Moreover, the system was capable of determining catalyst performance with very low catalyst and solvent consumption while the ruggedness of the system was exhibited with a 24-h continuous analysis of 280 successive catalyst injections with a peak area variation within 7% relative standard deviation. © 2008 American Chemical Society.

(Chemical Equation Presented) A multicomponent reaction between α-acidic isonitriles, primary amines, and carbonyl compounds was studied using 14 different solvents. Depending on the isocyanide that was used, optimal yields for the three-component synthesis of 2H-2-imidazolines were observed in different solvents. The solvents could be used as purchased, and in situ preformation of the imine was not required. By selecting the appropriate solvent, it was possible to considerably expand the range of compatible isocyanides toward less α-acidic isocyanides. Further process simplification was achieved by performing the reaction at higher concentrations and avoiding purification by column chromatography, resulting in a fast, easy to perform, and resource-efficient protocol for this three-component reaction. © 2007 American Chemical Society.