Martin Oestreich

Cooperative Catalytic Activation of Si―H Bonds by a Polar Ru―S Bond: Regioselective Low-Temperature C—H Silylation of Indoles under Neutral Conditions by a Friedel—Crafts Mechanism

Merging cooperative Si-H bond activation and electrophilic aromatic substitution paves the way for C-3-selective indole C-H functionalization under electronic and not conventional steric control. The Si-H bond is heterolytically split by the Ru-S bond of a coordinatively unsaturated cationic ruthenium(II) complex, forming a sulfur-stabilized silicon electrophile. The Wheland intermediate of the subsequent Friedel-Crafts-type process is assumed to be deprotonated by the sulfur atom, no added base required. The overall catalysis proceeds without solvent at low temperature, only liberating dihydrogen.

Enantioselective formal hydration of α,β-unsaturated acceptors: asymmetric conjugate addition of silicon and boron nucleophiles

The direct enantioselective 1,4-addition of water to α,β-unsaturated acceptors is an open challenge in asymmetric catalysis. Enantioselective conjugate addition of either silicon or boron nucleophiles and subsequent enantiospecific oxidative degradation of the carbon-element bond represents, however, an attractive detour. A single extra step thereby enables an indirect enantiocontrolled construction of (in a broader sense) aldols from α,β-unsaturated carbonyl and carboxyl compounds. While that strategy had been obvious for a long time, it was recent stunning progress in transition metal-catalysed activation of interelement linkages that brought about the solution to that long-standing problem. A concise introduction of existing protocols for stereoselective 1,4-addition of oxygen nucleophiles is followed by a comprehensive summary of the recent rapid advances in transition metal-catalysed (and metal-free) asymmetric conjugate transfer of nucleophilic silicon and boron onto α,β-unsaturated acceptors.

Experimental Analysis of the Catalytic Cycle of the Borane-Promoted Imine Reduction with Hydrosilanes: Spectroscopic Detection of Unexpected Intermediates and a Refined Mechanism

The discovery of intermediates that had not been seen before in imine reduction involving borane-mediated Si-H bond activation provided new insight into the mechanism, eventually leading to a refined catalytic cycle that also bears relevance to asymmetric variants. The catalysis proceeds through an ion pair composed of a silyliminium ion and a borohydride that subsequently reacts to yield an N-silylated amine and the borane catalyst. The latter step is enantioselectivity-determining when using a chiral borane. It was now found that there are additional intermediates that profoundly influence the outcome of such enantioselective transformations. Significant amounts of the corresponding free amine and N-silylated enamine are present in equimolar ratio during the catalysis. The free amine emerges from a borohydride reduction of an iminium ion (protonated imine) that is, in turn, generated in the enamine formation step. The unexpected alternative pathway adds another enantioselectivity-determining hydride transfer to reactions employing chiral boranes. The experiments were done with an axially chiral borane that was introduced by us a few years ago, and the refined mechanistic picture helps to understand previously observed inconsistencies in the level of enantioinduction in reductions catalyzed by this borane. Our findings are general because the archetypical electron-deficient borane B(C6F5)3 shows the same reaction pattern. This must have been overlooked in the past because B(C6F5)3 is substantially more reactive than our chiral borane with just one C6F5 group. Reactions with B(C6F5)3 must be performed at low catalyst loading to allow for detection of these fundamental intermediates by NMR spectroscopy.

Catalytic Generation of Borenium Ions by Cooperative B–H Bond Activation: The Elusive Direct Electrophilic Borylation of Nitrogen Heterocycles with Pinacolborane

The B-H bond of typical boranes is heterolytically split by the polar Ru-S bond of a tethered ruthenium(II) thiolate complex, affording a ruthenium(II) hydride and borenium ions with a dative interaction with the sulfur atom. These stable adducts were spectroscopically characterized, and in one case, the B-H bond activation step was crystallographically verified, a snapshot of the σ-bond metathesis. The borenium ions derived from 9-borabicyclo[3.3.1]nonane dimer [(9-BBN)2], pinacolborane (pinBH), and catecholborane (catBH) allowed for electrophilic aromatic substitution of indoles. The unprecedented electrophilic borylation with the pinB cation was further elaborated for various nitrogen heterocycles.

C(sp3)-F bond activation of CF3-substituted anilines with catalytically generated silicon cations: spectroscopic evidence for a hydride-bridged Ru-S dimer in the catalytic cycle.

Heterolytic splitting of the Si-H bond mediated by a Ru-S bond forms a sulfur-stabilized silicon cation that is sufficiently electrophilic to abstract fluoride from CF(3) groups attached to selected anilines. The ability of the Ru-H complex, generated in the cooperative activation step, to intramolecularly transfer its hydride to the intermediate carbenium ion (stabilized in the form of a cationic thioether complex) is markedly dependent on the electronic nature of its phosphine ligand. An electron-deficient phosphine thwarts the reduction step but, based on the Ru-S catalyst, half of an equivalent of an added alkoxide not only facilitates but also accelerates the catalysis. The intriguing effect is rationalized by the formation of a hydride-bridged Ru-S dimer that was detected by (1)H NMR spectroscopy. A refined catalytic cycle is proposed.

Oxidative Palladium(II)‐Catalyzed Dehydrogenative CH/CH Cross‐Coupling of 2,3‐Substituted Indolines with Arenes at the C7 Position

Direct cross-coupling of arenes by C H bond activation of both coupling partners is one of the toughest challenges of current transition-metal catalysis. Regioselectivity issues are often overcome by installing a directing group at one of the arenes, the chemoselectivity is usually steered towards the cross-coupling by using the less reactive component in excess. Heeding to these basic considerations, significant progress is currently being made in the arena of palladium(II)and rhodium ACHTUNGTRENNUNG(III)-catalyzed[4,5] dehydrogenative cross-coupling reactions. Methods for the selective C H arylation of indolines at the C7 position are synthetically attractive but rare. The conventional approach involves the established Boc-directed metalation (Boc= tert-butyloxycarbonyl) followed by transmetalation and subsequent Ullmann or Negishi coupling. Direct oxidative C C bond formation at C7 employing an iodine ACHTUNGTRENNUNG(III) reagent was reported by Sanford et al. a few years ago (1 a!2 aa, Scheme 1; top). Shi et al. and Lipshutz et al. later disclosed C H arylations using aryl boronic acids as prefunctionalized coupling partners, the latter proceeding at exceptionally low temperature (1 a!2 aa and 1 b!2 ba, Scheme 1; middle). The C7-selective dehydrogenative cross-coupling of indolines is still elusive (1 a or 1 b! 2 aa or 2 ba, Scheme 1; bottom), and we describe here our efforts to realize this goal. Initial experiments were performed with acetylated indoline 1 a, but we quickly learned that, with stronger terminal oxidants, the unsubstituted indoline is oxidized to the corresponding indole. We, therefore, turned to the annulated indoline 3 a, which would not be prone to oxidation (Table 1). We note here that such structurally interesting indolines are easily accessible by an “intercepted” Fischer indole synthesis followed by the reduction of the intermediate indolenine (for experimental details, see the Supporting Information). Catalyst identification commenced with screening of various Pd ACHTUNGTRENNUNG(OAc)2/oxidant combinations employing commonly used o-xylene as the solvent and, at the same time, as the other coupling partner (3 a!4 ac, Table 1). With CuACHTUNGTRENNUNG(OTf)2

Copper-Catalyzed SiB Bond Activation in Branched-Selective Allylic Substitution of Linear Allylic Chlorides†

The transmetalation of interelement linkages with Cu Oalkyl complexes provides a facile entry into nucleophilic main group element/copper(I) compounds. An intriguing sbond metathesis is believed to be the activating step, thus building a conceptual bridge between the emerging areas of Cu H, Cu B, and Cu Si chemistry (I–III ; Figure 1). Both conjugate addition and allylic or propargylic substitutions with these reagents are currently attracting tremendous attention.

Catalytic dehydrogenative Si–N coupling of pyrroles, indoles, carbazoles as well as anilines with hydrosilanes without added base

A base-free, catalytic protocol for the dehydrogenative Si-N coupling of weakly nucleophilic N-H groups of heteroarenes or aryl-substituted amines with equimolar amounts of hydrosilanes is reported. Cooperative Si-H bond activation at a Ru-S bond generates a silicon electrophile that forms a Si-N bond prior to the N-H deprotonation by an intermediate Ru-H complex, only releasing H(2).

Silylium Ion-Catalyzed Challenging Diels–Alder Reactions: The Danger of Hidden Proton Catalysis with Strong Lewis Acids

The pronounced Lewis acidity of tricoordinate silicon cations brings about unusual reactivity in Lewis acid catalysis. The downside of catalysis with strong Lewis acids is, though, that these do have the potential to mediate the formation of protons by various mechanisms, and the thus released Brønsted acid might even outcompete the Lewis acid as the true catalyst. That is an often ignored point. One way of eliminating a hidden proton-catalyzed pathway is to add a proton scavenger. The low-temperature Diels-Alder reactions catalyzed by our ferrocene-stabilized silicon cation are such a case where the possibility of proton catalysis must be meticulously examined. Addition of the common hindered base 2,6-di-tert-butylpyridine resulted, however, in slow decomposition along with formation of the corresponding pyridinium ion. Quantitative deprotonation of the silicon cation was observed with more basic (Mes)(3)P to yield the phosphonium ion. A deuterium-labeling experiment verified that the proton is abstracted from the ferrocene backbone. A reasonable mechanism of the proton formation is proposed on the basis of quantum-chemical calculations. This is, admittedly, a particular case but suggests that the use of proton scavengers must be carefully scrutinized, as proton formation might be provoked rather than prevented. Proton-catalyzed Diels-Alder reactions are not well-documented in the literature, and a representative survey employing TfOH is included here. The outcome of these catalyses is compared with our silylium ion-catalyzed Diels-Alder reactions, thereby clearly corroborating that hidden Brønsted acid catalysis is not operating with our Lewis acid. Several simple-looking but challenging Diels-Alder reactions with exceptionally rare dienophile/enophile combinations are reported. Another indication is obtained from the chemoselectivity of the catalyses. The silylium ion-catalyzed Diels-Alder reaction is general with regard to the oxidation level of the α,β-unsaturated dienophile (carbonyl and carboxyl), whereas proton catalysis is limited to carbonyl compounds.

Illuminating the Mechanism of the Borane‐Catalyzed Hydrosilylation of Imines with Both an Axially Chiral Borane and Silane

The reduction of C=O groups with silanes catalyzed by electron-deficient boranes follows a counterintuitive mechanism in which the Si-H bond is activated by the boron Lewis acid prior to nucleophilic attack of the carbonyl oxygen atom at the silicon atom. The borohydride thus formed is the actual reductant. These steps were elucidated by using a silicon-stereogenic silane, but applying the same technique to the related reduction of C=N groups was inconclusive due to racemization of the silicon atom. The present investigation now proves by the deliberate combination of our axially chiral borane catalyst and axially chiral silane reagents (in both enantiomeric forms) that the mechanisms of these hydrosilylations are essentially identical. Unmistakable stereochemical outcomes for the borane/silane pairs show that both participate in the enantioselectivity-determining hydride-transfer step. These experiments became possible after the discovery that our axially chiral C(6)F(5)-substituted borane induces appreciable levels of enantioinduction in the imine hydrosilylation.