The mechanism of oxidative addition of Pd(0) to Si–H bonds: electronic effects,reaction mechanism,and hydrosilylation

The oxidative addition of Pd to Si–H bonds is a crucial step in a variety of catalytic applications, and many aspects of this reaction are poorly understood. One important yet underexplored aspect is the electronic effect of silane substituents on reactivity. Herein we describe a systematic investigation of the formation of silyl palladium hydride complexes as a function of silane identity, focusing on electronic influence of the silanes. Using [(μ-dcpe)Pd]₂ (dcpe = dicyclohexyl(phosphino)ethane) and tertiary silanes, data show that equilibrium strongly favours products formed from electron-deficient silanes, and is fully dynamic with respect to both temperature and product distribution. A notable kinetic isotope effect (KIE) of 1.21 is observed with H/DSiPhMe₂ at 233 K, and the reaction is shown to be 0.5^th order in [(μ-dcpe)Pd]₂ and 1^st order in silane. Formed complexes exhibit temperature-dependent intramolecular H/Si ligand exchange on the NMR timescale, allowing determination of the energetic barrier to reversible oxidative addition. Taken together, these results give unique insight into the individual steps of oxidative addition and suggest the initial formation of a σ-complex intermediate to be rate-limiting. The insight gained from these mechanistic studies was applied to hydrosilylation of alkynes, which shows parallel trends in the effect of the silanes'' substituents. Importantly, this work highlights the relevance of in-depth mechanistic studies of fundamental steps to catalysis.

Mechanistic studies reveal the rate law, an H/D KIE, and that the silane’s electronics impact the thermodynamic and kinetic energetics of the oxidative addition reaction. These electronic effects are relevant in the hydrosilylation of alkynes.     

Preparation of 1,1-disubstituted silacyclopentadienes

Several new 1,1-disubstituted siloles containing substituents on the ring carbon atoms have been synthesized. The new siloles: 1,1-dihydrido-2,5-bis(trimethylsilyl)-3,4-diphenylsilole (5), 1,1-dihydrido-2,5-dimethyl-3,4-diphenylsilole (6), 1,1-dimethoxy-2,5-bis(trimethylsilyl)-3,4-diphenylsilole (7), 1,1-bis(4-methoxyphenyl)-2,5-bis(trimethylsilyl)-3,4-diphenylsilole (8), 1,1-dipropoxy-2,5-bis(trimethylsilyl)-3,4-diphenylsilole (9), and 1,1-dibromo-2,5-bis(trimethylsilyl)-3,4-diphenylsilole (13) were prepared from reactions originating from the previously reported, 1,1-bis(diethylamino)-2,5-bis(trimethylsilyl)-3,4-diphenylsilole (1) or 1,1-bis(diethylamino)-2,5-dimethyl-3,4-diphenylsilole (2). In addition, three other new organosilane byproducts were observed and isolated during the current study, bis(4-methoxyphenyl)bis(phenylethynyl)silane (11), bis(4-methoxyphenyl)di(propoxy)silane (12) and 1-bromo-4-bromodi(methoxy)silyl-1,4-bis(trimethylsilyl)-3,4-diphenyl-1,3-butadiene (14). Compounds 13 and 14 were characterized by X-ray crystallography and 14 is the first 1,1-dibromosilole whose solid state structure has been determined.     

Borane-catalyzed cascade Friedel–Crafts alkylation/[1,5]-hydride transfer/Mannich cyclization to afford tetrahydroquinolines

An unprecedented redox-neutral annulation reaction of tertiary anilines with electron-deficient alkynes was developed that proceeds through a cascade Friedel–Crafts alkylation/[1,5]-hydride transfer/Mannich cyclization sequence. Under B(C₆F₅)₃ catalysis, a range of functionalized 1,2,3,4-tetrahydroquinolines were facilely constructed in moderate to good yields with exclusive 3,4-anti-stereochemistry. The commercial availability of the catalyst and the high atom and step economy of the procedure, together with metal-free and external oxidant-free conditions, make this an attractive method in organic synthesis.

We report a redox-neutral annulation reaction of tertiary amines with electron-deficient alkynes under metal-free and oxidant-free conditions.     

Catalytic Selective Dihydrosilylation of Internal Alkynes Enabled by Rare-Earth Ate Complex

Hydrosilylation of alkynes generally yield vinylsilanes, which are inert to the further hydrosilylation because of the steric effects. Reported here is the first successful dihydrosilylation of aryl- and silyl-substituted internal alkynes enabled by a rare-earth ate complex to yield geminal bis- and tris(silanes), respectively. The lanthanum bis(amido) ate complex supported by an ene-diamido ligand proved to be the ideal catalyst for this unprecedented transformation, while the same series of yttrium and samarium alkyl and samarium bis(amido) ate complexes exhibited poor activity and selectivity, indicating significant effects of the ionic size and ate structure of the rare-earth catalysts.     

Catalytic Selective Dihydrosilylation of Internal Alkynes Enabled by Rare‐Earth Ate Complex

Hydrosilylation of alkynes generally yield vinylsilanes, which are inert to the further hydrosilylation because of the steric effects. Reported here is the first successful dihydrosilylation of aryl‐ and silyl‐substituted internal alkynes enabled by a rare‐earth ate complex to yield geminal bis‐ and tris(silanes), respectively. The lanthanum bis(amido) ate complex supported by an ene‐diamido ligand proved to be the ideal catalyst for this unprecedented transformation, while the same series of yttrium and samarium alkyl and samarium bis(amido) ate complexes exhibited poor activity and selectivity, indicating significant effects of the ionic size and ate structure of the rare‐earth catalysts.     

Stereoretentive and regioselective selenium-catalyzed intermolecular propargylic C–H amination of alkynes

Herein we report an intermolecular propargylic C–H amination of alkynes. This reaction is operationally convenient and requires no transition metal catalysts or additives. Terminal, silyl, and internal alkynes bearing a wide range of functional groups can be aminated in high yields. The regioselectivity of amination for unsymmetrical internal alkynes is strongly influenced by substitution pattern (tertiary > secondary > primary) and by relatively remote heteroatomic substituents. We demonstrate that amination of alkynes bearing α-stereocenters occurs with retention of configuration at the newly-formed C–N bond. Competition experiments between alkynes, kinetic isotope effects, and DFT calculations are performed to confirm the mechanistic hypothesis that initial ene reaction of a selenium bis(imide) species is the rate- and product-determining step. This ene reaction has a transition state that results in substantial partial positive charge development at the carbon atom closer to the amination position. Inductive and/or hyperconjugative stabilization or destabilization of this positive charge explains the observed regioselectivities.

Selenium catalysis enables a general intermolecular propargylic C–H amination of alkynes. The concerted mechanism gives rise to high regioselectivity for the more electron-rich end of the alkyne and retention of the C–H propargylic stereocenter.     

Cobalt-Catalyzed Regiodivergent Double Hydrosilylation of Arylacetylenes

Double hydrosilylation of alkynes represents a straightforward method to synthesize bis(silane)s, yet it is challenging if α-substituted vinylsilanes act as the intermediates. Here, a cobalt-catalyzed regiodivergent double hydrosilylation of arylacetylenes is reported for the first time involving this challenge, accessing both vicinal and geminal bis(silane)s with exclusive regioselectivity. Various novel bis(silane)s containing Si−H bonds can be easily obtained. The gram-scale reactions could be performed smoothly. Preliminarily mechanistic studies demonstrated that the reactions were initiated by cobalt-catalyzed α-hydrosilylation of alkynes, followed by cobalt-catalyzed β-hydrosilylation of the α-vinylsilanes to deliver vicinal bis(silane)s, or hydride-catalyzed α-hydrosilylation to give geminal ones. Notably, these bis(silane)s can be used for the synthesis of high-refractive-index polymers (n_d up to 1.83), demonstrating great potential utility in optical materials.     

Photo-Brook rearrangement of acyl silanes as a strategy for photoaffinity probe design

Photoaffinity labeling (PAL) is a powerful tool for the identification of non-covalent small molecule–protein interactions that are critical to drug discovery and medicinal chemistry, but this approach is limited to only a small subset of robust photocrosslinkers. The identification of new photoreactive motifs capable of covalent target capture is therefore highly desirable. Herein, we report the design, synthesis, and evaluation of a new class of PAL warheads based on the UV-triggered 1,2-photo-Brook rearrangement of acyl silanes, which hitherto have not been explored for PAL workflows. Irradiation of a series of probes in cell lysate revealed an iPr-substituted acyl silane with superior photolabeling and minimal thermal background labeling compared to other substituted acyl silanes. Further, small molecule (+)-JQ1- and rapamycin-derived iPr acyl silanes were shown to selectively label recombinant BRD4-BD1 and FKBP12, respectively, with minimal background. Together, these data highlight the untapped potential of acyl silanes as a novel, tunable scaffold for photoaffinity labeling.

Irradiation initiated 1,2-photo Brook rearrangement of acyl silanes generated α-siloxycarbene intermediates that were used for photoaffinity labeling. Optimization of the acyl silane group produced a probe capable of capturing small molecule–protein interactions.     

Palladium-catalyzed 1,1-alkynylbromination of alkenes with alkynyl bromides

The palladium-catalyzed 1,1-alkynylbromination of terminal alkenes with a silyl-protected alkynyl bromide is reported. The method tolerates a diverse range of alkenes including vinylarenes, acrylates, and even electronically unbiased alkene derivatives to afford propargylic bromides regioselectively. Mechanistic studies and DFT calculations indicate that the 1,1-alkynylbromination reaction proceeds via the migration of the Pd center followed by the formation of a π-allenyl Pd intermediate, leading to the stereoselective reductive elimination of the C(sp³)–Br bond at the propargylic positon.

The first Pd-catalyzed 1,1-alkynylbromination of terminal alkenes using alkynyl bromides, which provides direct access to a variety of functionalized propargylic bromides without the need for an external brominating reagent, is reported.     

Radical-mediated vicinal addition of alkoxysulfonyl/fluorosulfonyl and trifluoromethyl groups to aryl alkyl alkynes

The addition of sulfonyl radicals to alkenes and alkynes is a valuable method for constructing useful highly functionalized sulfonyl compounds. The underexplored alkoxy- and fluorosulfonyl radicals are easily accessed by CF₃ radical addition to readily available allylsulfonic acid derivatives and then β-fragmentation. These substituted sulfonyl radicals add to aryl alkyl alkynes to give vinyl radicals that are trapped by trifluoromethyl transfer to provide tetra-substituted alkenes bearing the privileged alkoxy- or fluorosulfonyl group on one carbon and a trifluoromethyl group on the other. This process exhibits broad functional group compatibility and allows for the late-stage functionalization of drug molecules, demonstrating its potential in drug discovery and chemical biology.

An unprecedented method for vicinal addition of alkoxysulfonyl/fluorosulfonyl and trifluoromethyl groups to aryl alkyl alkynes has been developed to afford useful alkenylsulfonate esters and alkenylsulfonyl fluorides.     

Phenanthroline-imine ligands for iron-catalyzed alkene hydrosilylation

Iron-catalyzed organic reactions have been attracting increasing research interest but still have serious limitations on activity, selectivity, functional group tolerance, and stability relative to those of precious metal catalysts. Progress in this area will require two key developments: new ligands that can impart new reactivity to iron catalysts and elucidation of the mechanisms of iron catalysis. Herein, we report the development of novel 2-imino-9-aryl-1,10-phenanthrolinyl iron complexes that catalyze both anti-Markovnikov hydrosilylation of terminal alkenes and 1,2-anti-Markovnikov hydrosilylation of various conjugated dienes. Specifically, we achieved the first examples of highly 1,2-anti-Markovnikov hydrosilylation reactions of aryl-substituted 1,3-dienes and 1,1-dialkyl 1,3-dienes with these newly developed iron catalysts. Mechanistic studies suggest that the reactions may involve an Fe(0)–Fe(ii) catalytic cycle and that the extremely crowded environment around the iron center hinders chelating coordination between the diene and the iron atom, thus driving migration of the hydride from the silane to the less-hindered, terminal end of the conjugated diene and ultimately leading to the observed 1,2-anti-Markovnikov selectivity. Our findings, which have expanded the types of iron catalysts available for hydrosilylation reactions and deepened our understanding of the mechanism of iron catalysis, may inspire the development of new iron catalysts and iron-catalyzed reactions.

Newly developed iron complexes bearing 2-imino-9-aryl-1,10-phenanthroline ligands were successfully used to catalyze hydrosilylation of terminal alkenes and conjugated dienes in high yields with excellent anti-Markovnikov selectivity.     

Cover Picture: Highly Regioselective Sequential 1,1‐Dihydrosilylation of Terminal Aliphatic Alkynes with Primary Silanes (Chin. J. Chem. 5/2019)

The cover picture shows that sequential 1,1‐dihydrosilylation of terminal aliphatic alkynes with primary silanes enabled by one earth‐abundant cobalt catalyst has been developed. This protocol is operationally simple using readily available aliphatic alkynes, including simple acetylene and complex drug derivative, for efficient access to valuable gem‐bis(dihydrosilyl)alkanes in highly regioselective and atom‐economic manners. Corresponding asymmetric transformations are achieved with excellent enantioselectivities. More details are discussed in the article by Lu et al. on page 457–461.

     

Late-stage modification of peptides and proteins at cysteine with diaryliodonium salts

The modification of peptides and proteins has emerged as a powerful means to efficiently prepare high value bioconjugates for a range of applications in chemical biology and for the development of next-generation therapeutics. Herein, we report a novel method for the chemoselective late-stage modification of peptides and proteins at cysteine in aqueous buffer with suitably functionalised diaryliodonium salts, furnishing stable thioether-linked synthetic conjugates. The power of this new platform is showcased through the late-stage modification of the affibody zEGFR and the histone protein H2A.

New operationally simple platform for the chemoselective arylation of cysteine in peptides and proteins to access a variety of high value bioconjugates.     

Nickel-catalyzed enantioselective 1,2-vinylboration of styrenes

A novel nickel-catalyzed asymmetric 1,2-vinylboration reaction has been developed to afford benzylic alkenylboration products with high yields and excellent enantioselectivities by using a chiral bisoxazoline ligand. Under optimized conditions, a wide variety of chiral 2-boryl-1,1-arylvinylalkanes are efficiently prepared from readily available olefins and vinyl halides in the presence of bis(pinacolato)diboron as the boron source in a mild and easy-to-operate manner. This three-component cascade protocol furnishes exceptional chemo- and stereoselectivity, and its usefulness is illustrated by its application in asymmetric modifications of several structurally complex natural products and pharmaceuticals.

A novel nickel-catalyzed asymmetric 1,2-vinylboration reaction has been developed to afford benzylic alkenylboration products with high yields and excellent enantioselectivities by using a chiral bisoxazoline ligand.     

Chlorination of geminal bis(alkoxy-NNO-azoxy) compounds with sodium hypochlorite

Chlorination of geminal bis(alkoxy-NNO-azoxy) compounds with sodium hypochlorite involves the central carbon atom and gives 1,1-bis(alkoxy-NNO-azoxy)-1-chloroalkanes with high yield. Dichlorobis-(methoxy-NNO-azoxy)methane oxidizes sodium iodide to elemental iodine. The signal from the central carbon atom in the ¹³C NMR spectra of bis(alkoxy-NNO-azoxy)dichloromethanes is broadened and displaced downfield relative to those of the initial compounds.     

Photoactivated hydrosilylation reaction of alkynes

The photoactivated (350 nm) hydrosilylation of alkynes by silanes catalyzed by platinum(II) bis(acetylacetonato) has been studied. Platinum(II) bis(acetylacetonato) is an efficient catalyst. High yields of adducts (>98% for terminal alkynes) can be obtained in 2–3 h after a short induction period with a catalyst–reactant molar ratio of 10⁻³/1. The reaction rate depends on the choice of silane, irradiation time and the concentration of catalyst. The major product is the β-trans adduct. Minor products are the α isomer with a trace of β-cis isomer. Comparisons of hydrosilylation reactions of alkynes with hydrosilylation reactions of alkenes are reported.     

Room-temperature phosphorescence of a supercooled liquid: kinetic stabilisation by desymmetrisation

Achieving organic room-temperature phosphorescence (RTP) in a solvent-free liquid state is a challenging task because the liquid state provides a less rigid environment than the crystal. Here, we report that an unsymmetrical heteroaromatic 1,2-diketone forms an organic RTP liquid. This diketone exists as a kinetically stable supercooled liquid, which resists crystallisation even under pricking or shearing stresses, and remains as a liquid for several months. The unsymmetrical diketone core is flexible, with eight distinct conformers possible, which prevents nucleation and growth for the liquid–solid transition. Interestingly, the thermodynamically stable crystalline solid-state was non-emissive. Thus, the RTP of the diketone was found to be liquiefaction-induced. Single-crystal X-ray structure analysis revealed that the diminished RTP of the crystal is due to insufficient intermolecular interactions and restricted access to an emissive conformer. Our work demonstrates that flexible unsymmetrical skeletons are promising motifs for bistable liquid–solid molecular systems, which are useful for the further development of stimuli-responsive materials that use phase transitions.

Metal-free, single-component, unsymmetrical 1,2-diketone exhibits liquefaction-induced room-temperature phosphorescence. Desymmetrisation provides the supercooled liquid with notable kinetic stability and phase-dependent phosphorescence properties.     

Direct growth of crystalline triazine-based graphdiyne using surface-assisted deprotection–polymerisation

Graphdiyne polymers have interesting electronic properties due to their π-conjugated structure and modular composition. Most of the known synthetic pathways for graphdiyne polymers yield amorphous solids because the irreversible formation of carbon–carbon bonds proceeds under kinetic control and because of defects introduced by the inherent chemical lability of terminal alkyne bonds in the monomers. Here, we present a one-pot surface-assisted deprotection/polymerisation protocol for the synthesis of crystalline graphdiynes over a copper surface starting with stable trimethylsilylated alkyne monomers. In comparison to conventional polymerisation protocols, our method yields large-area crystalline thin graphdiyne films and, at the same time, minimises detrimental effects on the monomers like oxidation or cyclotrimerisation side reactions typically associated with terminal alkynes. A detailed study of the reaction mechanism reveals that the deprotection and polymerisation of the monomer is promoted by Cu(ii) oxide/hydroxide species on the as-received copper surface. These findings pave the way for the scalable synthesis of crystalline graphdiyne-based materials as cohesive thin films.

We present a one-pot deprotection/polymerisation protocol for the synthesis of crystalline graphdiynes on top of a copper surface starting with stable trimethylsilylated alkyne monomers.      

Selective propargylic C(sp3)–H activation of methyl-substituted alkynes versus [2 + 2] cycloaddition at a titanium imido template

The reaction of the titanium imido complex 1b with 2-butyne leads to the formation of the titanium azadiene complex 2a at ambient temperature instead of yielding the archetypical [2 + 2] cycloaddition product (titanaazacyclobutene) which is usually obtained by combining titanium imido complexes and internal alkynes. The formation of 2a is presumably caused by an initial propargylic C(sp³)–H activation step and quantum chemical calculations suggest that the outcome of this unexpected reactivity is thermodynamically favored. The previously reported titanaazacyclobutene I (which is obtained by reacting 1b with 1-phenyl-1-propyne) undergoes a rearrangement reaction at elevated temperature to give the corresponding five-membered titanium azadiene complex 2b.

An unexpected reactivity between a titanium imido complex and internal alkynes was unveiled yielding titanaazacyclobutenes instead of the expected [2 + 2] cycloaddition products.     

Ritter-type iodo(iii)amidation of unactivated alkynes for the stereoselective synthesis of multisubstituted enamides

The Ritter reaction, Brønsted- or Lewis acid-mediated amidation of alkene or alcohol with nitrile via a carbocation, represents a classical method for the synthesis of tertiary amides. Although analogous reactions through a vinyl cation or a species alike may offer a route to enamide, an important synthetic building block as well as a common functionality in bioactive compounds, such transformations remain largely elusive. Herein, we report a Ritter-type trans-difunctionalization of alkynes with a trivalent iodine electrophile and nitrile, which affords β-iodanyl enamides in moderate to good yields. Mediated by benziodoxole triflate (BXT), the reaction proves applicable to a variety of internal alkynes as well as to various alkyl- and arylnitriles. The benziodoxole group in the product serves as a versatile handle for further transformations, thus allowing for the preparation of various tri- and tetrasubstituted enamides that are not readily accessible by other means.

Ritter-type trans-selective iodo(iii)amidation of internal alkynes with benziodoxole triflate and various nitriles has been achieved for the stereocontrolled synthesis of multisubstituted enamides.