Simon Duttwyler

Proton-Catalyzed, Silane-Fueled Friedel-Crafts Coupling of Fluoroarenes

Putting the F in Friedel-Crafts The Friedel-Crafts class of reactions, among the oldest and most broadly applied in organic chemistry, form carbon-carbon bonds between aromatic rings and a variety of non-aromatic substituents, such as alkyl groups. Generally, a metal complex is used to activate chlorinated or brominated precursors of these substituents, but by using silicon-based reagents to activate a fluorinated precursor, Allemann et al. (p. 574) extend the reaction to coupling of two different aromatic sites, leading to efficient formation of elaborate polycyclic structures. The method relies on the unusual strength of silicon-fluorine bonds as a driving force. Silicon-fluorine bond formation expands the range of compounds that can be used in a reaction that forms carbon-carbon bonds. The venerable Friedel-Crafts reaction appends alkyl or acyl groups to aromatic rings through alkyl or acyl cation equivalents typically generated by Lewis acids. We show that phenyl cation equivalents, generated from otherwise unreactive aryl fluorides, allow extension of the Friedel-Crafts reaction to intramolecular aryl couplings. The enabling feature of this reaction is the exchange of carbon-fluorine for silicon-fluorine bond enthalpies; the reaction is activated by an intermediate silyl cation. Catalytic quantities of protons or silyl cations paired with weakly coordinating carborane counterions initiate the reactions, after which proton transfer in the final aromatization step regenerates the active silyl cation species by protodesilylation of a quaternary silane. The methodology allows the high-yield formation of a range of tailored polycyclic aromatic hydrocarbons and graphene fragments.

Highly Diastereoselective Synthesis of Tetrahydropyridines by a C–H Activation–Cyclization–Reduction Cascade

A versatile reaction cascade leading to highly substituted 1,2,3,6-tetrahydropyridines has been developed. It comprises rhodium(I)-catalyzed C-H activation-alkyne coupling followed by electrocyclization and subsequent acid/borohydride-promoted reduction. This one-pot procedure affords the target compounds in up to 95% yield with >95% diastereomeric purity.

C-F activation of fluorobenzene by silylium carboranes: evidence for incipient phenyl cation reactivity.

Author(s): Duttwyler, Simon; Douvris, Christos; Fackler, Nathanael LP; Tham, Fook S; Reed, Christopher A; Baldridge, Kim K; Siegel, Jay S | Abstract: Si(mply) rips it apart: C-F activation of fluorobenzene has been achieved using the extremely strong silyl Lewis acids [Et3Si(X)]+ (X=PhF or Et3SiH) and [(2,6-dixylyl-C6H 3)SiMe2] + paired with the anion CHB 11Cl11-. They abstract fluoride from unactivated fluorobenzene to give arylated products, consistent with phenyl-cation-like reactivity (see scheme).

Proton donor acidity controls selectivity in nonaromatic nitrogen heterocycle synthesis.

Acid-Derived Diversity Compounds with nitrogen-bearing rings have proven rather promising in pharmaceutical research, spurring the need for improved synthetic methods to access structurally diverse variants of this motif. Duttwyler et al. (p. 678) show that applying acids of different strengths to a dihydropyridine intermediate leads to selective protonation at either of two sites, depending on whether the reaction proceeds under kinetic or thermodynamic (that is, equilibrated) control. The protonations in turn activate the rings for addition of various carbon nucleophiles to the periphery, thereby affording multiple different substitution patterns for use in screening studies. Acids of different strengths propel a common intermediate to a diverse array of compounds sought in pharmaceutical research. Piperidines are prevalent in natural products and pharmaceutical agents and are important synthetic targets for drug discovery and development. We report on a methodology that provides highly substituted piperidine derivatives with regiochemistry selectively tunable by varying the strength of acid used in the reaction. Readily available starting materials are first converted to dihydropyridines via a cascade reaction initiated by rhodium-catalyzed carbon-hydrogen bond activation. Subsequent divergent regio- and diastereoselective protonation of the dihydropyridines under either kinetic or thermodynamic control provides two distinct iminium ion intermediates that then undergo highly diastereoselective nucleophilic additions. X-ray structural characterization of both the kinetically and thermodynamically favored iminium ions along with density functional theory calculations provide a theoretical underpinning for the high selectivities achieved for the reaction sequences.

Regio‐ and Stereoselective 1,2‐Dihydropyridine Alkylation/Addition Sequence for the Synthesis of Piperidines with Quaternary Centers

The first example of Cu2005alkylation of 1,2-dihydropyridines with alkyl triflates and Michael acceptors was developed to introduce quaternary carbon centers with high regio- and diastereoselectivity. Hydride or carbon nucleophile addition to the resultant iminium ion also proceeded with high diastereoselectivity. Carbon nucleophile addition results in an unprecedented level of substitution to provide piperidine rings with adjacent tetrasubstituted carbon atoms.

Intramolecular halogen stabilization of silylium ions directs gearing dynamics.

2,6-Bis(2,6-difluorophenyl)phenyldimethylsilanium ion (1a) adopts a ground-state C(2) trigonal-bipyramidal geometry in which fluorines from opposing 2,6-difluorophenyl groups coordinate to the apical positions of the pentavalent silyl cation. Exchange of fluorine at silicon occurs by a disrotatory gearing mechanism wherein one fluorine remains coordinated to silicon throughout the circuit. The cogwheel transition state is C(s)-symmetric, with one ring having a dihedral angle of 0 degrees and the other a dihedral angle of 90 degrees. This correlated dynamic process is a function of the coordinating halogen. The chloro derivative (1b) adopts a similar ground-state geometry, but exchange of chlorine at silicon follows a conrotatory process.

Competition between π-arene and lone-pair halogen coordination of silylium ions?

In 2,6-diarylphenylSiR(2) cations, the 2,6-diarylphenyl (m-terphenyl) scaffold blocks incoming nucleophiles and stabilizes the positive charge at silicon by lateral ring interactions. Direct ortho-halogen and π-electron-rich face coordination to silicon has been seen. For a series of cations bearing 2,6-difluoro-2,6-dimethyl-X(n)-substituted rings, the relative contribution of these two modes of stabilization has been assessed. Direct coordination from an aryl fluoride is found to be comparable to that from the mesityl π-face.

Rhodium(III)-Catalyzed Alkenylation-Annulation of closo-Dodecaborate Anions through Double B-H Activation at Room Temperature.

1,2,3-Trisubstituted closo-dodecaborates with B-O, B-N, and B-C bonds as well as a fused borane oxazole ring have been synthesized by rhodium-catalyzed direct cage B-H alkenylation and annulation of ureido boranes in the first reported example of regioselective B-H bond functionalization of the [B12 H12 ]2- cage by transition-metal catalysis. This reaction proceeded at room temperature under ambient conditions and exhibited excellent selectivity for efficient monoalkenylation with good functional-group tolerance. The urea moiety enabled B-H activation by acting as a directing group, was incorporated in the oxazole ring inu2005situ, and also avoided multiple alkenylation. A possible mechanism is proposed on the basis of the isolation of a rhodium agostic intermediate and control experiments.

Synthesis and Crystal Structure of a Silyl‐Stabilized Allyl Cation Formed by Disruption of an Arene by a Protonation–Hydrosilylation Sequence

Sly silyl caught in the act: Protonation of a mesitylene ring by the strongly acidic arenium carborane [CH(3)C(6)H(6)]- [CHB(11)Me(5)Br(6)] initiates a cascade reaction that results in a stable beta-silyl allyl cation (see picture, H yellow, C blue, silyl allyl group red). Remarkably, the driving force in the reaction suffices to disrupt a stable aromatic ring in favor of a cationic reactive intermediate.

Synthesis and full characterization of an iridium B–H activation intermediate of the monocarba-closo-dodecaborate anion

The preparation and full characterization of an iridium complex of the monocarba-closo-dodecaborate anion is reported. It was prepared by B-H bond activation using a tosyl amide directing group. Analysis by spectroscopic methods and X-ray crystallography revealed the presence a direct B-Ir interaction. The carborane acts as a B,N chelating ligand towards the Ir(Cp*)(solvent) fragment, resulting in a monomeric complex that is inert in solution and the solid state. Treatment with N-chlorosuccinimide resulted in selective monochlorination of the B-Ir position. In addition, its structure, spectroscopic features and reactivity were investigated by DFT calculations.