LongLarf

Strategic functionalization: The direct functionalization of C−H bonds is among the most important transformations in organic synthesis, but its efficiency depends on its selectivity, which can be controlled by the innate reactivity of the substrate or a directing group. While this last strategy has turned out to be efficient, the directing groups need to be installed before and cleaved after the transformation. These two undesired synthetic operations can be avoided by using the transient directing group strategy that is comprehensively overviewed in this review article.

Abstract

The direct functionalization of C−H bonds is among the most fundamental chemical transformations in organic synthesis. However, when the innate reactivity of the substrate cannot be utilized for the functionalization of a given single C−H bond, this selective C−H bond functionalization mostly relies on the use of directing groups that allow bringing the catalyst in close proximity to the C−H bond to be activated and these directing groups need to be installed before and cleaved after the transformation, which involves two additional undesired synthetic operations. These additional steps dramatically reduce the overall impact and the attractiveness of C−H bond functionalization techniques since classical approaches based on substrate pre-functionalization are sometimes still more straightforward and appealing. During the past decade, a different approach involving both the in situ installation and removal of the directing group, which can then often be used in a catalytic manner, has emerged: the transient directing group strategy. In addition to its innovative character, this strategy has brought C−H bond functionalization to an unprecedented level of usefulness and has enabled the development of remarkably efficient processes for the direct and selective introduction of functional groups onto both aromatic and aliphatic substrates. The processes unlocked by the development of these transient directing groups will be comprehensively overviewed in this review article.

Synlett
DOI: 10.1055/s-0040-1720349

The increasing use of acridinium photocatalysts as sustainable alternative to precious metal-based counterparts encourages the design and efficient synthesis of distinct catalyst structures. Herein, we report our exploration of the scope of the aryne–imine–aryne coupling reaction combined with a subsequent acridane oxidation for a short two-step approach towards various acridinium salts. The photophysical properties of the novel photocatalysts were investigated and the practical value was demonstrated by a cation-radical accelerated nucleophilic aromatic substitution reaction.
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

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The development and subsequent application of an in  situ and solid-phase triphenylphosphine (PS-PPh₃) assisted continuous flow protocol to facilitate the coupling of reciprocal primary and secondary halides with aldehyde and ketone-based substrates is described.

Abstract

Described herein is the development of a continuous flow, solid-phase triphenylphosphine (PS-PPh₃) assisted protocol to facilitate the in situ coupling of reciprocal pairs of halogen and carbonyl functionalised molecular pairs by a Wittig olefination within 15 mins. The protocol entails injecting a single solution (1 : 1 CHCl₃ : EtOH) containing the halogenated and carbonyl-based substrates into a continuously flowing stream of CHCl₃ : EtOH (1 : 1), passed through a fixed bed of K₂CO₃ and PS-PPh3. With advancement to the previous PS-PPh₃ coupling procedures, the method employs a traditional polystyrene-based immobilisation matrix, the substrate scope of the protocol extended to substituted ketones, secondary alkyl chlorides, and an unprotected maleimide scaffold.

Nickel-catalyzed cascade reactions are useful tools for the synthesis of carbo- and heterocycles and multiple C−C, C−N bonds formation, which opens up new routes for constructing complex organic molecules of different ring size in a highly regio- and stereo-selective manner from readily available precursors.

Abstract

The formation of molecules with complexity in a simple, straight forward pathway attracts great interest in organic synthesis. Recently, nickel-catalyzed cascade reactions have grown up as a useful tool and contributed significantly to the area of synthetic methodology. In order to furnish high yielding carbo- and heterocycles as building blocks of pharmaceutical compounds and bioactive molecules with high selectivity, nickel-catalyzed reactions render comprehensive coverage of different strategies through compilation of various methodological prospective, such as photoredox decarboxylative vinylation, asymmetric reductive arylalkynation, hydroacylation/ Suzuki cross-coupling reactions, intramolecular annulation cascade reactions, hemiacetalization cascade reactions, and so on. In addition, nickel-catalyzed cascade reactions are also useful for the synthesis of multiple C−C/C−N bonds in acyclic compounds. This Review provides in depth mechanistic insights into on crucial reactions as well as a detailed discussion and critical comments.

Nature Chemistry, Published online: 19 July 2021; doi:10.1038/s41557-021-00746-7

Using synergistic bimetallic catalysis, a general ring expansion strategy has been developed for cross-dimerization between three-membered aza heterocycles and three- and four-membered-ring ketones. This method provides a straightforward and broadly applicable route for the assembly of 3-benzazepinones, dihydropyridinones and uracils, which are versatile units in numerous drugs and biologically active compounds.

Nature, Published online: 19 July 2021; doi:10.1038/s41586-021-03801-y

Cleaving arene rings for acyclic alkenylnitrile synthesis

Catalytic conversion of methane to methanol remains an economically tantalizing but fundamentally challenging goal. Current technologies based on zeolites deactivate too rapidly for practical application. We found that similar active sites hosted in different zeolite lattices can exhibit markedly different reactivity with methane, depending on the size of the zeolite pore apertures. Whereas zeolite with large pore apertures deactivates completely after a single turnover, 40% of active sites in zeolite with small pore apertures are regenerated, enabling a catalytic cycle. Detailed spectroscopic characterization of reaction intermediates and density functional theory calculations show that hindered diffusion through small pore apertures disfavors premature release of CH₃ radicals from the active site after C-H activation, thereby promoting radical recombination to form methanol rather than deactivated Fe-OCH₃ centers elsewhere in the lattice.

The reduction of a cyclic alkyl(amino)carbene (CAAC)-stabilized organoberyllium chloride yields the first neutral beryllium radical, which was characterized by EPR, IR, UV/Vis spectroscopy and X-ray crystallography. DFT calculations show significant spin density at beryllium and confirm donor–acceptor bonding between an alkylberyllium radical fragment and a neutral CAAC ligand.

Abstract

The reduction of a cyclic alkyl(amino)carbene (CAAC)-stabilized organoberyllium chloride yields the first neutral beryllium radical, which was characterized by EPR, IR, and UV/Vis spectroscopy, X-ray crystallography, and DFT calculations.

Nature, Published online: 15 July 2021; doi:10.1038/s41586-021-03819-2

Highly accurate protein structure prediction with AlphaFold

Synthesis
DOI: 10.1055/a-1528-1711

Bicyclic alkenes, including oxa- and azabicyclic alkenes, readily undergo activation with facial selectivity in the presence of transition-metal complexes. This is due to the intrinsic angle strain on the carbon–carbon double bonds in such unsymmetrical bicyclic systems. During the past decades considerable progress has been made in the area of ring opening of bicyclic strained rings by employing the concept of C–H activation. This short review comprehensively compiles the various C–H bond activation assisted reactions of oxa- and azabicyclic alkenes, viz., ring-opening reactions, hydroarylation, and annulation reactions.1 Introduction2 Reactions of Heterobicyclic Ring Systems2.1 Ring-Opening Reactions of Oxa- and Azabenzonorbornadienes2.1.1 Reactions Using 7-Oxabenzonorbornadienes2.1.2 Reactions Using 7-Azabenzonorbornadienes2.2 Hydroarylation Reactions2.3 Annulation Reactions2.4 Other Reactions3 Conclusion
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

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The development of mutually exclusive ‘orthogonal bioorthogonal’ reaction pairs has received increasing attention over the past decade. This minireview discusses strategies that have been employed to achieve successful dual and triple ligation systems that display both good kinetics and minimal cross-reactivities. These tools have potential applications for the observation of simultaneous biological processes both in vitro and in vivo.

Abstract

Over the past decade, several different metal-free bioorthogonal reactions have been developed to enable simultaneous double-click labeling with minimal-to-no competing cross-reactivities; such transformations are termed ‘mutually orthogonal’. More recently, several examples of successful triple ligation strategies have also been described. In this minireview, we discuss selected aspects of the development of orthogonal bioorthogonal reactions over the past decade, including general strategies to drive future innovations to achieve simultaneous, mutually orthogonal click reactions in one pot.

In this study, the complete mechanistic elucidation of rhodium-catalyzed propargylic C−H activation is presented. Particular attention is paid to the deactivation pathway of the catalytic reaction. The associated deactivated species has been studied in detail by NMR and Raman spectroscopy as well as X-ray crystallography. Furthermore, the present work includes a kinetic study carried out by in situ operando NMR spectroscopy.

Abstract

Detailed mechanistic investigations on our previously reported synthesis of branched allylic esters by the rhodium complex-catalyzed propargylic C−H activation have been carried out. Based on initial mechanistic studies, we present herein more detailed investigations of the reaction mechanism. For this, various analytical (NMR, X-ray crystal structure analysis, Raman) and kinetic methods were used to characterize the formation of intermediates under the reaction conditions. The knowledge obtained by this was used to further optimize the previous conditions and generate a more active catalytic system.

Synthesis
DOI: 10.1055/a-1526-7657

(R)-3-[(tert-Butoxycarbonyl)amino]piperidine and (R)-3-[(tert-butoxycarbonyl)amino]azepane were prepared in two steps starting from d-ornithine and d-lysine, respectively. In the key step, N-Boc-protected 3-aminolactams were converted into imido esters by O-alkyl­ation and then hydrogenated to amines, under mild conditions (5 bar H2, room temperature) and without isolation, over a standard hydrogenation catalyst (5% Pt/C).
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

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Nature Reviews Chemistry, Published online: 13 July 2021; doi:10.1038/s41570-021-00300-6

Late-stage C–H functionalization of complex molecules has emerged as a powerful tool in drug discovery. This Review classifies significant examples by reaction manifold and assesses the benefits and challenges of each approach. Avenues for future improvements of this fast-expanding field are proposed.