E=MCR2! The introduction of orthogonal functional groups in multicomponent reactions (MCRs) with unique solvent and functional‐group compatibility enables their combination with other multicomponent reactions in one pot. The resulting novel 5‐ and 6CRs and an unprecedented 8CR afford very complex products in up to 80 % yields (see picture), with up to nine new bond formations and eleven diversity points in a single reaction.

A multicomponent reaction between alpha-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 alpha-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.

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 Brønsted 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.

Diversity‐oriented synthesis: The multicomponent reaction of α‐isocyano amides, aldehydes or ketones, and amines affords N‐(cyanomethyl)amides, presenting the fourth class of products from this combination of reagents (see scheme). The scope of the reaction is very broad and various functional groups are tolerated. The outcome of the reaction can also be directed to the formation of 2H‐2‐imidazolines by AgI catalysis.

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In situ-generated metal carbonyl-complexed cyclopropenylphosphinidenes undergo a sequence of structural changes leading to phosphorus analogues of Pettit's seminal (η 4 -cyclobutadiene)iron tricarbonyl complex via multiple valence isomers along the reaction pathway and the elimination of one molecule of carbon monoxide.C yclobutadiene (CBD, C) has intrigued chemists for decades, 1 with landmarks such as the isolation of the parent C 4 H 4 inside a hemicarcerand cage, 2 the photoisomerization of a derivative to the highly strained tetrahedrane D, 3 and the formation of the seminal (η 4 -cyclobutadiene)iron tricarbonyl complex (E). 4 One effective route to CBD is ring expansion of the in situ-generated cyclopropenylcarbene B by N 2 elimination from cyclopropenyldiazomethane A. 5 This elegant rearrangement (B f C) has also been applied for sila 6 and aza analogues, 7,8 but detailed mechanistic insight is still lacking. In view of the diagonal CÀP relationship, it is surprising that the phosphacyclobutadiene ring structure (P 1 -CBD) 9 is known only as a rare transition-metal ligand (F) constructed from phosphaalkynes (R 1 CtP) and alkynes 10 and that no phosphatetrahedranes (P 1 -D) have ever been synthesized. 11 Here we report on the application of the phosphorus analogue of the cyclopropenylcarbeneÀ cyclobutadiene rearrangement for the selective formation of the P 1 analogues of Pettit's complex E. A detailed computational study has shown that the facile isomerization of the in situ-generated metal carbonyl-complexed cyclopropenylphosphinidenes P 1 -B 12,13 comes with surprises and has highlighted for the first time the connection of P 1 -B with the corresponding tetrahedranes P 1 -D.In this study, we focused on the rearrangement of the sterically shielded 1,2,3-tris(tert-butyl)cyclopropenyl-substituted phosphinidenes 14 4 bearing the metal carbonyl (ML n ) fragments Fe(CO) 4 (a), W(CO) 5 (b), and Mo(CO) 5 (c) (Scheme 1). These transient intermediates can be generated by thermal fragmentation of the corresponding 3H-3-benzo[d]phosphepines 3. 15 The starting material for 3, bis(trimethylsilyl)-1,2,3-tris(tert-butyl)cyclopropenylphosphane (1) ( 31 P NMR: δ = À134.6 ppm, 1 J PSi = 47.6 Hz) was prepared according to literature procedures 16 and converted quantitatively into its primary phosphane ( 31 P NMR: δ = À119.1 ppm, 1 J PH = 189.3 Hz) using 2.4 equiv of MeOH. Subsequent complexation with the appropriate metal carbonyl source afforded the air-and moisture-stable complexes 2aÀc after purification by column chromatography (54À64%; Scheme 1). Subsequently, the base-catalyzed double hydrophosphination of 1,2-diethynylbenzene with the primary phosphane complexes 2 afforded phosphepines 3, albeit in modest yields [12À41%; 31 P NMR: δ = 36.2 (3a), À16.9 (3b), 1.5 ppm (3c)], which we ascribed to the bulky nature of the P substituent (see the Supporting Information).Thermal fragmentation of 3aÀc at 100°C in toluene selectively generated the η 4 -phosphacyclobutadiene complexes 5 (Scheme 1), which were isol...

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-dihydro-quinazolin-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.

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...