Electrophilic Activation of S-Si Reagents by Silylium Ions for Their Regio- and Diastereoselective Addition Across C-C Multiple Bonds.

A regioselective silylium-ion-promoted thiosilylation of internal C-C triple bonds with control over the double bond geometry is described. Both a C(sp2)-S and a C(sp2)-Si bond are formed with a trans relationship in this two-component reaction of an alkyne and a thiosilane. The resulting orthogonally functionalized C-C double bond can be chemoselectively defunctionalized or further processed by cross-coupling reactions with the alkene configuration retained. The procedure is also applicable to the regio- and diastereoselective thiosilylation of terminal allenes to arrive at allylic thioethers containing a vinylsilane unit. These reactions involve the electrophilic activation of the S-Si reagent, both a silylated thiophenol and even alkylthiol derivative, by an in situ-generated carbocation intermediate. The catalytic cycle is maintained by a bissilylated aryl- or alkylsulfonium ion as a shuttle for the cationic silicon electrophile. Its independent preparation and structural characterization by X-ray diffraction are also reported.

Chiral Carborane Acids Decorated with Binol-Based Phosphonates: Synthesis, Characterization, and Application.

The syntheses of hexabrominated closo-carborates decorated with different chiral Binol-derived phosphonates and their conjugate acids are described. X-ray diffraction analysis reveals a polymeric structure for the sodium salt with the anionic units connected by [B-Br-Na-O═P]+ linkages. For the acid, coordination of the proton to the phosphonate's P═O oxygen atom is assumed. The pKa value was estimated by combining experiments and computations. Application of these Brønsted acids as chiral catalysts in an imino-ene and a Mukaiyama-Mannich reaction was moderately successful.

Arenium-ion-catalysed halodealkylation of fully alkylated silanes.

'Organic silicon' is not found in nature but modern chemistry is hard to imagine without silicon bound to carbon. Although silicon-containing commodity chemicals such as those emerging from the 'direct process'1-4 look simple, it is not trivial to selectively prepare aryl-substituted and alkyl-substituted (functionalized) silicon compounds, known as silanes. Chlorosilanes such as Me4-nSiCln (n = 1-3) as well as SiCl4 (n = 4) are common starting points for the synthesis of silicon-containing molecules. Yet these methods often suffer from challenging separation problems5. Conversely, silanes with four alkyl groups are considered synthetic dead ends. Here we introduce an arenium-ion-catalysed halodealkylation that effectively converts Me4Si and related quaternary silanes into a diverse range of functionalized derivatives. The reaction uses an alkyl halide and an arene (co)solvent: the alkyl halide is the halide source that eventually engages in a Friedel-Crafts alkylation with the arene to regenerate the catalyst6, whereas the arenium ion acts as a strong Brønsted acid for the protodealkylation step7. The advantage of the top-down halodealkylation methodology over reported bottom-up procedures is demonstrated, for example, in the synthesis of a silicon drug precursor. Moreover, chemoselective chlorodemethylation of the rather inert Me3Si group attached to an alkyl chain followed by oxidative degradation is shown to be an entry into Tamao-Fleming-type alcohol formation8,9.

Intramolecular 7-endo-dig-Selective Carbosilylation of Internal Alkynes Involving Silylium-Ion Regeneration.

A catalytic silylium-ion-promoted intramolecular alkyne carbosilylation reaction is reported. The ring closure is initiated by electrophilic activation of the C-C triple bond by a silylium ion, and the catalytic cycle is then maintained by the protodesilylation of a stoichiometrically added allylsilane reagent. Exclusive 7-endo-dig selectivity is seen, leading to a series of silylated benzocycloheptene derivatives with a fully substituted vinylsilane. Control experiments showed that the catalytically active silylium ion can also be regenerated by protodesilylation of the vinylsilane product.

Catalytically Generated Meerwein's Salt-Type Oxonium Ions for Friedel-Crafts C(sp2)-H Methylation with Methanol.

A catalytic protocol for a Friedel-Crafts-type direct C(sp2)-H methylation of various arenes with methanol is disclosed. The reaction is initiated by counteranion-stabilized silylium or arenium ions, which form Meerwein's salt-like oxonium ions with methanol as the active methylating agents. The silylated methyloxonium ions are stronger electrophiles than their protonated congeners, allowing the Friedel-Crafts alkylation to proceed more efficiently and at a lower reaction temperature. The regeneration of these superelectrophiles within the catalytic cycle is accomplished by the addition of a tetraorganosilane additive, i.e., trimethyl(phenyl)silane or tetraethylsilane, that releases a silylium ion through protodesilylation by the Brønsted acidic Wheland intermediate, thereby acting as a productive "proton-into-silylium ion" generator. By this method, even the C-H methylation of electronically deactivated aryl halides with methanol is achieved. The protocol is also applicable to nonactivated primary as well as π-activated benzylic alcohols. Dialkyl ethers are also competent alkylating agents in the presence of the quaternary phenylsilane additive.

The [3]Dendralene Motif as an Entry into Nazarov Cyclizations by Silylium-Ion Initiation.

Geminal alkenes bearing an aryl and an allenyl group contain the motif of [3]dendralenes. The central alkene double bond in these cross-conjugated polyenes can be reacted with a silylium ion, thereby initiating a Nazarov cyclization. The cationic intermediate emerging from the electrocyclic ring closure is captured by hydride in the presence of excess hydrosilane. The resulting benzannulated methylenecyclopentene derivatives bearing a silylalkyl group then engage in silylium-ion regeneration followed by an unusual endo-selective intramolecular hydrosilylation. This cascade eventually leads to the formation of a silicon-containing bicyclo[3.2.1]octane skeleton.

Intermolecular Carbosilylation of α-Olefins with C(sp3 )-C(sp) Bond Formation Involving Silylium-Ion Regeneration.

A regioselective addition of alkynylsilanes across unactivated, terminal alkenes is reported. The reaction is initiated by the capture of a sterically unhindered silylium ion by a silylated phenylacetylene derivative to form a bis(silylated) ketene-like carbocation. This in situ-generated key intermediate is the actual catalyst that maintains the catalytic cycle by a series of electrophilic addition reactions of silylium ions and ß-silicon-stabilized carbocations. The computed reaction mechanism is fully consistent with the experimental findings. This unprecedented two-component carbosilylation establishes a C(sp3 )-C(sp) bond and a C(sp3 )-Si bond in atom-economic fashion.

Perdeuteration of Deactivated Aryl Halides by H/D Exchange under Superelectrophile Catalysis.

Superelectrophilic silylium/arenium ions are shown to be highly effective H/D exchange promoters for the exhaustive deuteration of electron-deficient aryl halides. Several of the resulting perdeuterated aryl halides have been previously inaccessible with existing deuterium-labeling procedures. Using inexpensive C6D6 as the deuterium source, excellent degrees of deuterium incorporation were achieved under ambient reaction conditions. Importantly, the perdeuteration remains unaffected on multigram scale, even at a reduced catalyst loading of 0.1 mol %. By this method, otherwise expensive or noncommercially available NMR solvents such as 1,2-dichloro- and 1,2-difluorobenzene can be prepared.

Silylium-Ion-Promoted Hydrosilylation of Aryl-Substituted Allenes: Interception by Cyclization of the Allyl-Cation Intermediate.

A trityl-cation-initiated, silylium-ion-promoted hydrosilylation of aryl-substituted allenes is reported. Depending on the hydrosilane-to-initiator ratio, the hydrosilylation can be intercepted by an intramolecular electrophilic aromatic substitution or a Nazarov electrocyclization of an allyl-cation intermediate in the form of its endo isomer. By this, the selective formation of either the conventional 1,2-hydrosilylation product (vinylsilane) or a cyclized product (silylated indane) can be controlled.

Competition for Hydride Between Silicon and Boron: Synthesis and Characterization of a Hydroborane-Stabilized Silylium Ion.

Potent main-group Lewis acids are capable of activating element-hydrogen bonds. To probe the rivalry for hydride between silylium- and borenium-ion centers, a neutral precursor with the hydrosilane and hydroborane units in close proximity on a naphthalene-1,8-diyl platform was designed. Abstraction of one hydride leads to a hydroborane-stabilized silylium ion rather than a hydrosilane-coordinated borenium ion paired with [B(C6 F5 )4 ]- or [HCB11 Cl11 ]- as counteranions. Characterization by multinuclear NMR spectroscopy and X-ray diffraction supported by DFT calculations reveals a cationic, unsymmetrical open three-center, two-electron (3c2e) Si-H-B linkage.

The Power of the Proton: From Superacidic Media to Superelectrophile Catalysis.

Superacidic media became famous in connection with carbocations. Yet not all reactive intermediates can be generated, characterized, and eventually isolated from these Brønsted acid/Lewis acid cocktails. The counteranion, that is the conjugate base, in these systems is often too nucleophilic and/or engages in redox chemistry with the newly formed cation. The Brønsted acidity, especially superacidity, is in fact often not even crucial unless protonation of extremely weak bases needs to be achieved. Instead, it is the chemical robustness of the aforementioned counteranion that determines the success of the protolysis. The advent of molecular Brønsted superacids derived from weakly coordinating, redox-inactive counteranions that do withstand the enormous reactivity of superelectrophiles such as silicon cations completely changed the whole field. This Perspective summarizes general aspects of medium and molecular Brønsted acidity and shows how applications of molecular Brønsted superacids have advanced from stoichiometric reactions to catalytic processes involving protons and in situ generated superelectrophiles.

Silylium Ions: From Elusive Reactive Intermediates to Potent Catalysts.

The history of silyl cations has all the makings of a drama but with a happy ending. Being considered reactive intermediates impossible to isolate in the condensed phase for decades, their actual characterization in solution and later in solid state did only fuel the discussion about their existence and initially created a lot of controversy. This perception has completely changed today, and silyl cations and their donor-stabilized congeners are now widely accepted compounds with promising use in synthetic chemistry. This review provides a comprehensive summary of the fundamental facts and principles of the chemistry of silyl cations, including reliable ways of their preparation as well as their physical and chemical properties. The striking features of silyl cations are their enormous electrophilicity and as such reactivity as super Lewis acids as well as fluorophilicity. Known applications rely on silyl cations as reactants, stoichiometric reagents, and promoters where the reaction success is based on their steady regeneration over the course of the reaction. Silyl cations can even be discrete catalysts, thereby opening the next chapter of their way into the toolbox of synthetic methodology.

Silylium-Ion-Promoted (5+1) Cycloaddition of Aryl-Substituted Vinylcyclopropanes and Hydrosilanes Involving Aryl Migration.

A transition-metal-free (5+1) cycloaddition of aryl-substituted vinylcyclopropanes (VCPs) and hydrosilanes to afford silacyclohexanes is reported. Catalytic amounts of the trityl cation initiate the reaction by hydride abstraction from the hydrosilane, and further progress of the reaction is maintained by self-regeneration of the silylium ions. The new reaction involves a [1,2] migration of an aryl group, eventually furnishing 4- rather than 3-aryl-substituted silacyclohexane derivatives as major products. Various control experiments and quantum-chemical calculations support a mechanistic picture where a silylium ion intramolecularly stabilized by a cyclopropane ring can either undergo a kinetically favored concerted [1,2] aryl migration/ring expansion or engage in a cyclopropane-to-cyclopropane rearrangement.

Synthesis of a Counteranion-Stabilized Bis(silylium) Ion.

The preparation of a molecule with two alkyl-tethered silylium-ion sites from the corresponding bis(hydrosilanes) by two-fold hydride abstraction is reported. The length of the conformationally flexible alkyl bridge is crucial as otherwise the hydride abstraction stops at the stage of a cyclic bissilylated hydronium ion. With an ethylene tether, the open form of the hydronium-ion intermediate is energetically accessible and engages in another hydride abstraction. The resulting bis(silylium) ion has been NMR spectroscopically and structurally characterized. Related systems based on rigid naphthalen-n,m-diyl platforms can only be converted into the dications when the positively charged silylium-ion units are remote from each other (1,8 versus 1,5 and 2,6).

Efficient Biocatalytic Synthesis of Dihalogenated Purine Nucleoside Analogues Applying Thermodynamic Calculations.

The enzymatic synthesis of nucleoside analogues has been shown to be a sustainable and efficient alternative to chemical synthesis routes. In this study, dihalogenated nucleoside analogues were produced by thermostable nucleoside phosphorylases in transglycosylation reactions using uridine or thymidine as sugar donors. Prior to the enzymatic process, ideal maximum product yields were calculated after the determination of equilibrium constants through monitoring the equilibrium conversion in analytical-scale reactions. Equilibrium constants for dihalogenated nucleosides were comparable to known purine nucleosides, ranging between 0.071 and 0.081. To achieve 90% product yield in the enzymatic process, an approximately five-fold excess of sugar donor was needed. Nucleoside analogues were purified by semi-preparative HPLC, and yields of purified product were approximately 50% for all target compounds. To evaluate the impact of halogen atoms in positions 2 and 6 on the antiproliferative activity in leukemic cell lines, the cytotoxic potential of dihalogenated nucleoside analogues was studied in the leukemic cell line HL-60. Interestingly, the inhibition of HL-60 cells with dihalogenated nucleoside analogues was substantially lower than with monohalogenated cladribine, which is known to show high antiproliferative activity. Taken together, we demonstrate that thermodynamic calculations and small-scale experiments can be used to produce nucleoside analogues with high yields and purity on larger scales. The procedure can be used for the generation of new libraries of nucleoside analogues for screening experiments or to replace the chemical synthesis routes of marketed nucleoside drugs by enzymatic processes.

Silylium-Ion-Promoted Ring-Opening Hydrosilylation and Disilylation of Unactivated Cyclopropanes.

A silylium-ion-promoted ring-opening hydrosilylation of unactivated cyclopropanes is reported. The reaction is facilitated by the γ-silicon effect, and the regioselectivity is influenced by various stabilizing effects on the carbenium-ion intermediates, including the ß-silicon effect. The experimental observations are in accord with the computed reaction mechanism. The work also showcases the ability of silylium ions to isomerize cyclopropyl to allyl groups, and the resulting α-olefins engage in a silylium-ion-mediated disilylation with hexamethyldisilane.

Intramolecular Friedel-Crafts alkylation with a silylium-ion-activated cyclopropyl group: formation of tricyclic ring systems from benzyl-substituted vinylcyclopropanes and hydrosilanes.

A trityl-cation-initiated annulation of benzyl-substituted vinylcyclopropanes (VCPs) with hydrosilanes is reported. Two Si-C(sp3) bonds and one C(sp2)-C(sp3) bond are formed in this process where an intramolecular 6-endo-tet Friedel-Crafts alkylation of a silylium-ion-activated cyclopropane ring is the rate-determining key step. The reaction mechanism is proposed based on computations and is in agreement with experimental observations. The new reaction leads to an unprecedented silicon-containing 6/6/5-fused ring system. A phenethyl-substituted VCP derivative yields another unknown tricycle having 6/6/6 ring fusion by reacting in a related but different way involving a 6-exo-tet ring closure.

Si-H Bond Activation with Bullock's Cationic Tungsten(II) Catalyst: CO as Cooperating Ligand.

An in-depth investigation of the reaction of tertiary hydrosilanes with [CpW(CO)2(IMes)]+[B(C6F5)4]- reveals a fundamentally new Si-H bond activation mode. Unlike the originally proposed oxidative addition of the Si-H bond to the tungsten(II) center, there is strong experimental and NMR spectroscopic evidence for the involvement of one of the CO ligands of the cationic complex in the Si-H bond breaking event. The Si-H bond is heterolytically cleaved to form a tungsten(II) hydride and a silylium ion, which is stabilized by one of the CO ligands. This reactive hydrosilane adduct was eventually isolated and characterized by X-ray diffraction analysis. Quantum-chemical calculations support a cooperative mechanism, but a stepwise process consisting of oxidative addition and subsequent tungsten-to-oxygen silyl migration in the tungsten(IV) silyl hydride is also energetically feasible. However, our combined spectroscopic and computational analysis favors the cooperative pathway. The newly identified hydrosilane adduct is the key intermediate of Bullock's ionic carbonyl hydrosilylation.

Catalytic Difunctionalization of Unactivated Alkenes with Unreactive Hexamethyldisilane through Regeneration of Silylium Ions.

A metal-free, intermolecular syn-addition of hexamethyldisilane across simple alkenes is reported. The catalytic cycle is initiated and propagated by the transfer of a methyl group from the disilane to a silylium-ion-like intermediate, corresponding to the (re)generation of the silylium-ion catalyst. The key feature of the reaction sequence is the cleavage of the Si-Si bond in a 1,3-silyl shift from silicon to carbon. A central intermediate of the catalysis was structurally characterized by X-ray diffraction, and the computed reaction mechanism is fully consistent with the experimental findings.

Characterization of hydrogen-substituted silylium ions in the condensed phase.

Hydrogen-substituted silylium ions are long-sought reactive species. We report a protolysis strategy that chemoselectively cleaves either an Si-C(sp2) or an Si-H bond using a carborane acid to access the full series of [CHB11H5Br6]--stabilized R2SiH+, RSiH2 +, and SiH3 + cations, where bulky tert-butyl groups at the silicon atom (R = tBu) were crucial to avoid substituent redistribution. The crystallographically characterized molecular structures of [CHB11H5Br6]--stabilized tBu2HSi+ and tBuH2Si+ feature pyramidalization at the silicon atom, in accordance with that of tBu3Si+[CHB11H5Br6]- Conversely, the silicon atom in the H3Si+ cation adopts a trigonal-planar structure and is stabilized by two counteranions. This solid-state structure resembles that of the corresponding Brønsted acid.