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Since the pioneer reports of the groups of Akiyama and Terada on Brønsted acid organocatalysis, this field never stopped growing with the development of ingenious strategies for the activation of challenging poorly reactive substrates. The development of superacidic organocatalysts is an important way to selectively functionalize reluctant electrophiles and other approaches have also emerged such as the combination of Lewis and Brønsted acids as well as the consecutive organocatalysis and superacid activation. This Concept aims to highlight these different strategies and demonstrate their complementarity. [ABSTRACT FROM AUTHOR]

Understanding the influence of emerging fluorinated motifs is of a crucial importance in the context of the exponentially growing exploitation of fluorine in many fields. Herein, we report on the dramatic effect of a local partial charge inversion by replacing a CHCH3 group by a CFCF3. This strategy allows the diastereoselective reduction of 5-membered ring oxocarbenium ions to access highly substituted tetrahydrofurans. [ABSTRACT FROM AUTHOR]

Enantioenriched complex fused‐tricyclic azepanes or bridged‐polycyclic azocanes were constructed via a two‐step sequence involving an enantioselective organocascade followed by superacid activation of the domino adduct. The activated oxa‐bridged azepane acts as a key hidden heptacyclic chiral N‐acyl iminium ion triggering a chemo‐ and diastereoselective intramolecular mono‐ or di‐arylation. [ABSTRACT FROM AUTHOR]

The insertion of fluorine atoms and/or fluoroalkyl groups can lead to many beneficial effects in biologically active molecules, such as enhanced metabolic stability, bioavailability, lipophilicity, and membrane permeability, as well as a strengthening of protein–ligand binding interactions. However, this "magic effect" of fluorine atom(s) insertion can often be meaningless. Taking advantage of the wide range of data coming from the quest for carbonic anhydrase (CA) fluorinated inhibitors, this Minireview attempts to give "general guidelines" on how to wisely insert fluorine atom(s) within an inhibitor moiety to precisely enhance or disrupt ligand–protein interactions, depending on the target location of the fluorine substitution in the ligand. Multiple approaches such as ITC, kinetic and inhibition studies, X‐ray crystallography, and NMR spectroscopy are useful in dissecting single binding contributions to the overall observed effect. The exploitation of innovative directions made in the field of protein and ligand‐based fluorine NMR screening is also discussed to avoid misconduct and finely tune the exploitation of selective fluorine atom insertion in the future. [ABSTRACT FROM AUTHOR]

The insertion of fluorine atoms and/or fluoroalkyl groups can lead to many beneficial effects in biologically active molecules, such as enhanced metabolic stability, bioavailability, lipophilicity, and membrane permeability, as well as a strengthening of protein–ligand binding interactions. However, this "magic effect" of fluorine atom(s) insertion can often be meaningless. Taking advantage of the wide range of data coming from the quest for carbonic anhydrase (CA) fluorinated inhibitors, this Minireview attempts to give "general guidelines" on how to wisely insert fluorine atom(s) within an inhibitor moiety to precisely enhance or disrupt ligand–protein interactions, depending on the target location of the fluorine substitution in the ligand. Multiple approaches such as ITC, kinetic and inhibition studies, X‐ray crystallography, and NMR spectroscopy are useful in dissecting single binding contributions to the overall observed effect. The exploitation of innovative directions made in the field of protein and ligand‐based fluorine NMR screening is also discussed to avoid misconduct and finely tune the exploitation of selective fluorine atom insertion in the future. [ABSTRACT FROM AUTHOR]

Achieving in a straightforward way the synthesis of enantioenriched elaborated three‐dimensional molecules related to bioactive natural products remains a long‐standing quest in organic synthesis. Enantioselective organocatalysis potentially offers a unique opportunity to solve this problem, especially when combined with complementary modes of activation. Here, we report the sequential association of organocatalytic and superacid activations of simple linear achiral readily available precursors to promote the formation of unique highly elaborated chiral methylene‐bridged benzazocanes exhibiting three to five fully‐controlled stereocenters. This peculiar backbone, difficult to assemble by standard synthetic approaches, is closely related to bioactive natural and synthetic morphinans and benzomorphans. The formation of a highly reactive chiral 7‐membered ring N‐acyl iminium superelectrophilic ion, evidenced by low‐temperature in situ NMR experiments, triggers a challenging stereoselective Friedel–Crafts‐type cyclization. [ABSTRACT FROM AUTHOR]

Achieving in a straightforward way the synthesis of enantioenriched elaborated three‐dimensional molecules related to bioactive natural products remains a long‐standing quest in organic synthesis. Enantioselective organocatalysis potentially offers a unique opportunity to solve this problem, especially when combined with complementary modes of activation. Here, we report the sequential association of organocatalytic and superacid activations of simple linear achiral readily available precursors to promote the formation of unique highly elaborated chiral methylene‐bridged benzazocanes exhibiting three to five fully‐controlled stereocenters. This peculiar backbone, difficult to assemble by standard synthetic approaches, is closely related to bioactive natural and synthetic morphinans and benzomorphans. The formation of a highly reactive chiral 7‐membered ring N‐acyl iminium superelectrophilic ion, evidenced by low‐temperature in situ NMR experiments, triggers a challenging stereoselective Friedel–Crafts‐type cyclization. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract In superacid, such as HF/SbF 5 , functionalized organic molecules can be (poly)protonated to deliver cationic species which can react with very poor nucleophiles. This superelectrophilic activation can be applied to the development of unprecedented organic reactions. Through the use of ammonium-carbenium dications, activated keteniminium, or other modes of superelectrophilic activation, fluorinated nitrogen-containing building blocks can be efficiently generated. This mode of activation can also be applied for the late-stage insertion of fluorinated moieties on elaborated synthetic or natural bioactive compounds. [ABSTRACT FROM AUTHOR]

A broadly applicable copper catalyst for photoredox transformations of organic halides is reported. Upon visible light irradiation in the presence of catalytic amounts of [(DPEphos)(bcp)Cu]PF6 and an amine, a range of unactivated aryl and alkyl halides were shown to be smoothly activated through a rare Cu(I)/Cu(I)*/Cu(0) catalytic cycle. This complex efficiently catalyzes a series of radical processes, including reductions, cyclizations, and direct arylation of arenes. [ABSTRACT FROM AUTHOR]

Ynamides have recently evolved as remarkably reactive and versatile building blocks for chemical synthesis. The development of efficient and robust methods for their preparation combined with their recent commercialization have facilitated both the design of an ever-growing number of original methods based on their unique reactivity and their use in other areas such as medicinal chemistry. One crucial aspect of the reactivity of these building blocks is based on their anionic chemistry, which has been extensively studied during the last decade and enabled not only the design and development of remarkably efficient and original reactions but also brought general answers to long-standing problems in organic chemistry and contributed to the emergence of new synthetic paradigms. In this short review, the anionic chemistry of ynamides is overviewed. [ABSTRACT FROM AUTHOR]

Two new cationic dinuclear gold(I) complexes, [Au2{μ(P,N)-5}2]X2--in which X=NTf2 (7; Tf=trifluoromethanesulfonate) or SbF6 (8) and 2-(diphenylphosphanyl)benzonitrile (5) is a P,N-bridging donor--have been synthesized and structurally characterized. These air-stable species and their dimeric and polymeric analogues possessing 1'-(diphenylphosphanyl)-1-cyanoferrocene (1) as the bridging ligand, [Au2{μ(P,N)-1}2](NTf2)2 and [Au{μ(P,N)-1}]n[SbF6]n, were used as precatalysts in various Au-mediated C-C and C-O bond-forming reactions. The reactivity of these complexes revealed the hemilabile nature of their P,N ligands. In the series of tested precatalysts, complex 8 exerted particularly high catalytic activity at low Au loading, even in reactions that usually require high amounts of gold catalyst to proceed efficiently under standard reaction conditions. [ABSTRACT FROM AUTHOR]

On the basis of DFT computations and experimental results, we show that the presence of the ester group in the backbone of organic substrates can influence the mechanism of metal-catalyzed carbocyclization reactions. The non-innocent role of the ester functionality in lowering the activation barrier of the key step of the gallium- and indium-catalyzed cycloisomerization of 1,6-enynes is revealed. In the case of the gallium-catalyzed hydroarylation of arenynes, the esters in the tether can deprotonate the Wheland intermediate, thus avoiding more energetically demanding [1,3]- or [1,2]/[1,2]-H shifts. As for the gallium-catalyzed Friedel-Crafts alkylation, an unusual concerted SEAr mechanism involving the esters has been calculated. Lastly, computations evidence that the ester group of methyl propiolates enables a divergent mechanism in the platinum-catalyzed intramolecular hydroarylation. [ABSTRACT FROM AUTHOR]

[IPr·InBr2][SbF6] (2) (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) has been synthesized and characterized in the solid state. This complex proved to be a very active catalyst for hydroarylations, transfer hydrogenations, and cycloisomerizations. [ABSTRACT FROM AUTHOR]

We report a rare case of alkene transfer hydrogenation using a main-group compound instead of a transition-metal complex as catalyst. We disclosed that 1,4-cyclohexadiene can be used as H2 surrogate towards olefin reduction in the presence of [IPrGaCl2][SbF6]. Hydrogenative cyclizations have also been carried out because this cationic gallium complex is also a potent hydroarylation catalyst. [ABSTRACT FROM AUTHOR]

Here we report a method to reorganize the core structure of aliphatic unsaturated nitrogen‐containing substrates exploiting polyprotonation in superacid solutions. The superelectrophilic activation of N‐isopropyl systems allows for the selective formal Csp3−H activation/cyclization or homologation / functionalization of nitrogen‐containing substrates. This study also reveals that this skeletal reorganization can be controlled through protonation interplay. The mechanism of this process involves an original sequence of C−N bond cleavage, isopropyl cation generation and subsequent C−N bond and C−C bond formation. This was demonstrated through in situ NMR analysis and labelling experiments, also confirmed by DFT calculations. [ABSTRACT FROM AUTHOR]

Here we report a method to reorganize the core structure of aliphatic unsaturated nitrogen‐containing substrates exploiting polyprotonation in superacid solutions. The superelectrophilic activation of N‐isopropyl systems allows for the selective formal Csp3−H activation/cyclization or homologation / functionalization of nitrogen‐containing substrates. This study also reveals that this skeletal reorganization can be controlled through protonation interplay. The mechanism of this process involves an original sequence of C−N bond cleavage, isopropyl cation generation and subsequent C−N bond and C−C bond formation. This was demonstrated through in situ NMR analysis and labelling experiments, also confirmed by DFT calculations. [ABSTRACT FROM AUTHOR]

Exploiting trimethylsilyltrifluoromethanesulfonate as Lewis acid, (hetero)aromatics underwent regioselective and direct carbamoylation. The method is based on the in situ generation of a highly electrophilic carbamoyl triflate active species. TMSOTf acts as Lewis acid to activate carbamoyl chlorides and generates highly electrophilic carbamoyl triflates in situ; these are active species for late‐stage aromatic carbamoylation. [ABSTRACT FROM AUTHOR]

Optimized reaction conditions including 1,4-cyclohexadiene as hydrogen source in combination with a gallium carbene complex catalyst allow hydrogenative cyclization, hydroarylation, and reduction of olefins. [ABSTRACT FROM AUTHOR]

A method to extend the scope of the aza-Piancatelli reaction between 2-furylcarbinols and anilines is depicted. We found that 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) is the solvent of choice for this transformation, as it outcompetes the usual solvents in terms of rate and yield. Side reactions and other issues raised by the title reaction are prevented, thereby providing an avenue to complex molecules that were previously inaccessible. Lewis acidity studies and computations were carried out to unveil the role of HFIP. Based on these results, we propose that HFIP is, in fact, acting as a Lewis acid and that its acidity can be enhanced when combined with a calcium(II) salt. [ABSTRACT FROM AUTHOR]

The field of medicinal chemistry is currently witnessing a deuterium rush owing to the remarkable properties of this element as bioisoster of hydrogen atom. Aromatic hydrogen isotope exchange (HIE) is one of the most studied strategies nowadays as it promises to access deuterium‐modified drugs directly from their non‐labeled parents. While most of the recent studies focus on metal‐catalyzed C−H activation strategy, the use of superacidic conditions has been largely overlooked. This study shows that the use of TfOD as reaction medium allows the late‐stage polydeuteration of a broad library of pharmaceuticals bearing a wide array of functional groups, complementing existing procedures. [ABSTRACT FROM AUTHOR]

Direct alkenylation of a variety of alcohols with vinylboronic acids has been accomplished using the airstable calcium(II) complex Ca(NTf2)2 under mild conditions with short reaction times. For reluctant transformations, an ammonium salt was used as an additive to circumvent the reactivity issue. [ABSTRACT FROM AUTHOR]

The transformation of glycals into 2,3‐unsaturated glycosyl derivatives, reported by Ferrier in 1962, is supposed to involve an α,β unsaturated glycosyl cation, an elusive ionic species that has still to be observed experimentally. Herein, while combination of TfOH and flow conditions failed to observe this ionic species, its extended lifetime in superacid solutions allowed its characterization by NMR‐based structural analysis supported by DFT calculations. This allyloxycarbenium ion was further exploited in the Ferrier rearrangement to afford unsaturated nitrogen‐containing C‐aryl glycosides and C‐alkyl glycosides under superacid and flow conditions, respectively. [ABSTRACT FROM AUTHOR]

The transformation of glycals into 2,3‐unsaturated glycosyl derivatives, reported by Ferrier in 1962, is supposed to involve an α,β unsaturated glycosyl cation, an elusive ionic species that has still to be observed experimentally. Herein, while combination of TfOH and flow conditions failed to observe this ionic species, its extended lifetime in superacid solutions allowed its characterization by NMR‐based structural analysis supported by DFT calculations. This allyloxycarbenium ion was further exploited in the Ferrier rearrangement to afford unsaturated nitrogen‐containing C‐aryl glycosides and C‐alkyl glycosides under superacid and flow conditions, respectively. [ABSTRACT FROM AUTHOR]

A general and efficient procedure for the copper-catalyzed photoinduced radical domino cyclization of ynamides and cyanamides providing an efficient access to complex tri-, tetra- and pentacyclic nitrogen heterocycles is reported. Upon visible light irradiation in the presence of catalytic amounts of [(DPEphos)(bcp)Cu]PF6 and an amine, a range of unactivated aryl and alkyl iodides were shown to be smoothly transformed to the corresponding radical species, initiating the radical domino cyclization. This procedure provides a unified entry to rosettacin, luotonin A, and deoxyvasicinone that could be efficiently prepared in a limited number of steps. [ABSTRACT FROM AUTHOR]

Alkenylation of alcohols with vinylboronic acids is readily achieved in generally moderate to good yields using Ca(NTf2)2 as an air stable catalyst. [ABSTRACT FROM AUTHOR]