ORFEO-CINQA Research Network

1,5-Disubstituted bicyclo[2.1.1]hexanes are bridged scaffolds with well-defined exit vectors that are becoming increasingly popular building blocks in medicinal chemistry because they are saturated bioisosteres of ortho-substituted phenyl rings. Here we have developed a Lewis-acid-catalysed [2 + 2] photocycloaddition to obtain these motifs as enantioenriched scaffolds, providing an efficient approach for their incorporation in a variety of drug analogues. Retention of the biological activity of the bicyclo[2.1.1]hexane-containing analogues in the specific proteins targeted by the original drugs has confirmed the suitability of this moiety to serve as a bioisostere of ortho-substituted phenyl rings. Moreover, we have studied the potential of the different enantiomers of the drug analogues to selectively induce cytotoxicity in a panel of tumour cell lines, observing markedly differential effects for the two enantiomers and a substantial improvement over the corresponding sp2-based drugs. This showcases that the control of the absolute configuration and tridimensionality of the drug analogue has a large impact on its biological properties.

Preformed Ni(0) complexes are rarely used as precatalysts in cross-coupling reactions, although they can incorporate catalytically active nickel directly into the reaction. In this work, we focus on the preparation and the catalytic application of low-coordinate Ni(0) complexes supported by bulky monophosphine ligands in C-S cross-coupling reactions. We have prepared two families of Ni(0) complexes, bis-phosphine aducts of the type [Ni(PR2Ar')2] (Ar' = m-terphenyl group) and monophosphine derivatives of the type [Ni(PR2Ar')(DVDS)] (DVDS = divinyltetramethyldisiloxane). DFT calculations were used to account for the atypical bent structures displayed by the bis-phosphine Ni(0) complexes. Monophosphine-Ni(0) complexes display catalytic activity superior to bis-phosphine Ni(0) adducts, which suggests that the former facilitate the generation of highly reactive monoligated PNi(0) species. Furthermore, the reactivity of monophosphine-Ni(0) precatalysts outperform that observed with Ni(II) precatalysts with the same phosphine ligands, supporting a more facile activation step to the same catalytic species. This enhanced reactivity allows for the use of lower catalyst loadings (1-5 mol%) and for carrying out the challenging coupling between aryl chlorides and alkylthiols.

The growing interest in the catalytic activity of earth-abundant 3d transition-metals has led to the development of new and more sustainable methods for C-H bond functionalization reactions. However, this is an emerging field which involves considerable mechanistic complexity as the mode of action of 3d transition metals differs markedly from the well-studied mechanisms of precious metals. In this review, we present an overview of the research efforts in Ni-, Cu-, Fe- and Co-catalyzed directed C(sp3)-H bond functionalization reactions, covering design principles and mechanistic discussions, along with potential applications and limitations. To conclude, the unresolved challenges and future viewpoints are highlighted. We aspire for this review to serve as a relevant and valuable reference for researchers in this swiftly progressing field, helping to inspire the development of more original and innovative strategies.

[(L1)Au(μ-H)2MCp2][BF4] complexes (M = Mo and W) featuring cavity-shaped tris-2-(4,4'-di-tert-butylbi-phenylyl)phosphine (L1) have been isolated. The tungsten derivative showed a remarkably fast reactivity in photolytic hydride transfer to generate the mononuclear gold hydride (L1)AuH. Both bimetallic adducts trap Ag+ cations, forming unprecedented {Au(μ-H)M(μ-H)Ag} trimetallic assemblies with destabilized Au-M interactions.

Abstract A modular, 3‐steps protocol for the synthesis of N‐sulfonyl squaramides has been developed. The strategic installation of a tetrahedral, electron‐withdrawing sulfonyl group into the squaramido core allowed the prevention of undesired self‐aggregations, therefore upgrading the solubility in common organic solvents, and moreover, enhancing their H‐bond donor abilities for molecular recognition. These unique features have been efficiently exploited in two different ion‐pairing reactions: (i) the challenging C4‐selective dearomatization of 2‐picoline with silyl ketene acetals and (ii) the tritylation of N‐methylindole. Furthermore, their catalytic activities have been directly compared with other common and well‐established (thio)urea analogues and related H‐bond donors, revealing that highly acidic designs are essential to reach optimal catalytic performances.

In recent years, mechanochemistry has become an innovative and sustainable alternative to traditional solvent-based synthesis. Mechanochemistry rapidly expanded across a wide range of chemistry fields, including diverse organic compounds and active pharmaceutical ingredients, coordination compounds, organometallic complexes, main group frameworks, and technologically relevant materials. This Review aims to highlight recent advancements and accomplishments in mechanochemistry, underscoring its potential as a viable and eco-friendly alternative to conventional solution-based methods in the field of synthetic chemistry.

Using single-crystal to single-crystal solid/gas reactivity the gold(I) acetylene complex [Au(L1)(η2-HC≡CH)][BArF 4] is cleanly synthesized by addition of acetylene gas to single crystals of [Au(L1)(CO)][BArF 4] [L1=tris-2-(4,4'-di-tert-butylbiphenyl)phosphine, ArF=3,5-(CF3)2C6H3]. This simplest gold-alkyne complex has been characterized by single crystal X-ray diffraction, solution and solid-state NMR spectroscopy and periodic DFT. Bonding of HC≡CH with [Au(L1)]+ comprises both σ-donation and π-backdonation with additional dispersion interactions within the cavity-shaped phosphine.

Abstract Using single‐crystal to single‐crystal solid/gas reactivity the gold(I) acetylene complex [Au(L1)(η2‐HC≡CH)][BArF4] is cleanly synthesized by addition of acetylene gas to single crystals of [Au(L1)(CO)][BArF4] [L1=tris‐2‐(4,4′‐di‐tert‐butylbiphenyl)phosphine, ArF=3,5‐(CF3)2C6H3]. This simplest gold‐alkyne complex has been characterized by single crystal X‐ray diffraction, solution and solid‐state NMR spectroscopy and periodic DFT. Bonding of HC≡CH with [Au(L1)]+ comprises both σ‐donation and π‐backdonation with additional dispersion interactions within the cavity‐shaped phosphine.

The low-electron count, air-stable, platinum complexes [Pt(ItBu')(ItBu)][BArF] (C1) (ItBu=1,3-di-tert-butylimidazol-2-ylidene), [Pt(SiPh)3(ItBuiPr)2][BArF] (C2) (ItBuiPr=1-tert-butyl-3-iso-propylimidazol-2-ylidene), [Pt(SiPh)3(ItBuMe)2][BArF] (C3), [Pt(GePh3)(ItBuiPr)2][BArF] (C4), [Pt(GePh)3(ItBuMe)2][BArF] (C5) and [Pt(GeEt)3(ItBuMe)2][BArF] (C6) (ItBuMe=1-tert-butyl-3-methylimidazol-2-ylidene) are efficient catalysts (particularly the germyl derivatives) in both the silylative dehydrocoupling and hydrosilylation of electron rich alkenes derived from enamines. The steric hindrance exerted by the NHC ligand plays an important role in the selectivity of the reaction. Thus, bulky ligands are selective towards the silylative dehydrocoupling process whereas less sterically hindered promote the selective hydrosilylation reaction. The latter is, in addition, regioselective towards the β-carbon atom of both internal and terminal enamines, leading to β-aminosilanes. Moreover, the syn stereochemistry of the amino and silyl groups implies an anti Si-H bond addition across the double bond. All these facts point to a mechanistic picture that, according to experimental and computational studies, involves a non-classical hydrosilylation process through an outer-sphere mechanism in which a formal nucleophilic addition of the enamine to the silicon atom of a platinum σ-SiH complex is the key step. This is in sharp contrast with the classical Chalk-Harrod mechanism prevalent in platinum chemistry.

Amino alcohols play a crucial role in the realm of biologically active compounds due to their functional diversity. In this study, we introduce a metal-free energy transfer (EnT) photocatalytic method for the preparation of 1,4-aminoalcohols from readily available alcohols feedstocks. The key feature of this transformation is the simultaneous generation of an iminyl and oxygen-centered radicals via EnT. The process embraces a fragmentation/decarboxylation/1,5-HAT (hydrogen atom transfer) processes leading to the formation of a C(sp3)-hybridized radical, which undergo a selective radical-radical cross-coupling or a radical chain event to yield the desired products. In addition, the protocol was also found suitable for N-tosylamines giving rise to 1,4-diamines. Our approach combines experimental mechanistic investigations with detailed computational studies using density functional theory (DFT) that provide insights into the reaction mechanism. This innovative method offers a novel route for the preparation of δ-amino alkyl alcohols and amines.