Alberto Coelho

Pyridazine derivatives. Part 33: Sonogashira approaches in the synthesis of 5-substituted-6-phenyl-3(2H)-pyridazinones ☆

Several 6-phenyl-3(2H)-pyridazinones bearing different alkynyl groups at position 5 have been prepared by a palladium-catalysed Sonogashira cross-coupling reaction. An interesting base-promoted electronically permitted isomerization has been observed during the coupling of 1-phenyl-2-propyn-1-ol. This rearrangement afforded the E-chalcone 6 in excellent yield.

Pyrimidine Derivatives as Potent and Selective A3 Adenosine Receptor Antagonists

Two regioisomeric series of diaryl 2- or 4-amidopyrimidines have been synthesized and their adenosine receptor affinities were determined in radioligand binding assays at the four human adenosine receptors (hARs). Some of the ligands prepared herein exhibit remarkable affinities (K(i) < 10 nm) and, most noticeably, the absence of activity at the A(1), A(2A), and A(2B) receptors. The structural determinants that support the affinity and selectivity profiles of the series were highlighted through an integrated computational approach, combining a 3D-QSAR model built on the second generation of GRid INdependent Descriptors (GRIND2) with a novel homology model of the hA(3) receptor. The robustness of the computational model was subsequently evaluated by the design of new derivatives exploring the alkyl substituent of the exocyclic amide group. The synthesis and evaluation of the novel compounds validated the predictive power of the model, exhibiting excellent agreement between predicted and experimental activities.

Pyridazines. Part 34: Retro-ene-assisted palladium-catalyzed synthesis of 4,5-disubstituted-3(2H)-pyridazinones ☆

The efficient one-pot bis-functionalization of the 4,5-positions of the 3-pyridazinone ring has been performed using Suzuki, Sonogashira and Stille cross-coupling reactions assisted by a retro-ene fragmentation. This route allows access in a shorter synthetic sequence to several pharmacologically useful 3(2H)-pyridazinones.

Discovery of 3,4-Dihydropyrimidin-2(1H)-ones As a Novel Class of Potent and Selective A2B Adenosine Receptor Antagonists.

We describe the discovery and optimization of 3,4-dihydropyrimidin-2(1H)-ones as a novel family of (nonxanthine) A2B receptor antagonists that exhibit an unusually high selectivity profile. The Biginelli-based hit optimization process enabled a thoughtful exploration of the structure-activity and structure-selectivity relationships for this chemotype, enabling the identification of ligands that combine structural simplicity with excellent hA2B AdoR affinity and remarkable selectivity profiles.

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.

Pyridazines. Part 25: Efficient and selective deprotection of pharmacologically useful 2-MOM-pyridazinones using Lewis acids ☆

Abstract An efficient and selective procedure for the cleavage of a methoxymethyl group at the 2-position in acid-sensitive pyridazinones is presented. Deprotection with Lewis acids (boron tribromide or aluminium chloride) affords 3(2 H )-pyridazinones under mild conditions without affecting multiple bonds in substituents.

Supported p-toluenesulfonic acid as a highly robust and eco-friendly isocyanide scavenger.

We document here the use of polymer-supported p-toluenesulfonic acid as a highly effective, robust, economical and eco-friendly isocyanide scavenger. The herein described strategy circumvent the intense and repulsive odor of volatile isocyanides, enabling simplified and odorless workup and purifications. The usefulness of the new scavengers has been validated in a set of diverse isocyanide-based organic transformations and this approach is also amenable to parallel synthesis techniques.

Multicomponent Assembly of Diverse Pyrazin-2(1H)-one Chemotypes

An expedient and concise Ugi-based approach for the rapid assembly of pyrazin-2(1H)-one-based frameworks has been developed. This convergent approach encompasses skeletal, functional and stereochemical diversity, exhibiting an unusually high bond-forming efficiency as well as high structure and step economies. The method involves the use of readily available commercial reagents and is an example of the reconciliation of structural complexity with operational simplicity in a time- and cost-effective manner.

Divergent solution-phase synthesis of diarylpyrimidine libraries as selective A3 adenosine receptor antagonists.

A practical and divergent solution-phase synthetic strategy has been optimized to prepare a highly diverse library of 2,4-diaryl- and 2,6-diarylpyrimidines. Structural elaboration of the starting heterocyclic scaffolds was accomplished by exploiting the potential for diversity offered by the Suzuki-Miyaura cross-coupling reaction. These studies enabled the identification of structurally simple, highly potent, and selective A(3) adenosine receptor antagonists.

Click Chemistry Approach to Assembly Proline Mimetic Libraries Containing 1,4-Substituted 1,2,3-Triazoles

Jose E. Rodriguez-Borges,* Sofia Goncalves, Maria Luisa do Vale, Xerardo Garcia-Mera, Alberto Coelho, and Eddy Sotelo CIQ-Departamento de Quimica, Faculdade de Ciencias, UniVersidade do Porto, Rua do Campo Alegre, 687, 4169-007 Porto, Portugal, and Departamento de Quimica Organica and Instituto de Farmacia Industrial, Facultade de Farmacia, UniVersidade de Santiago de Compostela, Santiago de Compostela, 15782 Spain