Spirosilanes Activate Gold(I)-Catalysts in Cycloisomerization and Intermolecular Reactions.

Gold‐catalyzed reactions have established as a powerful tool in organic synthesis, offering efficient pathways to construct diverse molecular structures and notably scaffolds with high complexity. Most processes rely on the use of LAuCl precatalysts, which are generally activated, i.e., cationized, by silver salts. In this work, we explore the role of silicon‐based Lewis acids based, such as spirosilane, derivatives as alternative activators in lieu of silver salts. It was found that Martin spirosilanes mediate the activation of gold precatalysts, facilitating diverse cyclization and cycloisomerization reactions as well as intermolecular reactions. NMR studies and computational investigations suggest that no real cationization, i.e., formation of an ionic pair, takes place, but rather activation through weak interaction between silicon and the chlorine atom of LAuCl. This preserves the Au─Cl bond and ultimately enables the LAuCl complex to be recovered. On the same line, the LAuCl–silane interaction has also proven to be beneficial for asymmetric catalysis. This work significantly contributes to the expansion of gold‐catalyzed transformations by opening up the prospect of a more sustainable gold catalysis. It also opens perspectives on the use of silicon‐based Lewis acids as versatile cooperative agents in organometallic chemistry.

A comprehensive study on the asymmetric gold-catalyzed cycloisomerization reaction of heteroatom tethered 1,6-enynes is described. The cycloisomerization reactions were conducted in the presence of the chiral cationic Au(I) catalyst consisting of (R)-4-MeO-3,5-(t-Bu)2-MeOBIPHEP-(AuCl)2 complex and silver salts (AgOTf or AgNTf2) in toluene under mild conditions to afford functionalized bicyclo[4.1.0]heptene derivatives. The reaction conditions were found to be highly substrate-dependent, the best results being obtained in the case of oxygen-tethered enynes. The formation of bicyclic derivatives, including cyclopropyl pentasubstituted ones, was reported in moderate to good yields and in enantiomeric excesses up to 99%.

Carbon is a primary element to constitute organic molecules, while metal catalysis is a basic tool in organic synthesis. The establishment of a link between the ubiquitous carbon bonding and metal catalysis is thus a fundamentally important problem. However, there is yet no experimental example to introduce the role of carbon bonding in a metal catalysis process. Herein, we merged the topics of carbon bonding and metal catalysis together and demonstrated that a supramolecular carbon-bonding metal complex can not only give rise to catalytic activity but, more remarkably, direct structural-isomer selection events in gold-catalyzed reactions. The experimental results unveil the fact that the imposing of weak carbon-bonding interactions on a gold complex can alter the carbene as well as the Lewis acid property of these catalysts. These results illustrate a non-negligible role of weak carbon-bonding interactions in the modulation of metal catalysis. As such, carbon-bonding metal catalysis is suggested to be used as a routine tool not only in the development of reactions but more frequently in analyzing reaction processes in metal catalysis.

Communicating Chemistry in “Chemistry”

A simple and efficient access to a new P‐chiral, but so far racemic ligand class featuring ortho‐trityl and ortho‐biaryl motifs is reported. The phosphines are prepared by efficient three‐ to four‐step modular syntheses from simple branched alkyl(diphenyl)phosphine oxides in 52–63% overall yield. They form stable gold complexes, which were characterized by X‐ray crystallography and spectroscopic methods. Fundamental catalytic properties of the complexes were studied in 1,6‐enyne cycloisomerization reactions of achiral substrates to benchmark their activity against the efficient achiral catalyst (JohnPhos)AuCl. The results show that the new complexes can be applied in amounts down to 100 ppm allowing the cycloisomerization reactions to be performed with turnover frequencies of 20000 h−1 and turnover numbers of up to 10000 h−1.magnified image

Conjugate Addition Reactions in Organic Synthesis

C,C-Palladacycles are an important class of organometallic compounds in which palladium is σ-bonded to two carbon atoms. They have three notable features that make them attractive in organic synthesis and organometallic chemistry: (1) C,C-Palladacycles are reactive intermediates that can be accessed via Pd(0)-catalyzed C-H activation of organic halides. Compared to Pd(II)-catalyzed heteroatom-directed C-H activation, C-H activation catalyzed by Pd(0) has some distinct advantages. In this type of catalytic reaction, the halo groups of readily available organic halides act as traceless directing groups. Furthermore, this strategy avoids the use of stoichiometric external oxidants. (2) C,C-Palladacycles have differentiated reactivities from common open-chain Pd(II) species. In particular, C,C-palladacycles have high reactivity toward electrophiles including alkyl halides. This unique reactivity can be utilized to develop novel reactions. (3) C,C-Palladacycles have two C-Pd bonds, providing a unique platform for developing novel reactions.Although a number of reactions of C,C-palladacycles had been developed prior to our work, the scope was largely limited to intramolecular cyclization reactions. Although Catellani reactions are intermolecular reactions of C,C-palladacycles, only one of the C-Pd bonds is functionalized. Our laboratory has sought to develop intermolecular difunctionalization reactions of C,C-palladacycles that exploit their unique reactivity and open new possibilities in organic synthesis. Aiming to develop synthetically useful reactions, we primarily focus on ring-forming reactions. In this Account, we summarize our laboratory's efforts to exploit intermolecular difunctionalization reactions of C,C-palladacycles that are obtained through Pd(0)-catalyzed C-H activation. We have developed a wide array of new reactions that represent facile and efficient methods for the synthesis of cyclic organic compounds, including functional materials and drug molecules. A range of C,C-palladacycles have been studied, including C(aryl),C(aryl)-palladacycles from 2-halobiaryls, C(aryl),C(alkyl)-palladacycles from ortho-iodo-tert-butylbenzenes or ortho-iodoanisole derivatives, and those obtained by cascade reactions. C,C-Palladacycles have been found to react with a variety of oxidants to furnish Pd(IV) intermediates, such as alkyl halides, aryl halides, diazo compounds, and N,N-di-tert-butyldiaziridinone, ultimately affording various cyclic structures, including 5-10-membered rings, carbo- and azacycles, spirocycles, and fused rings. Furthermore, novel reactivity of C,C-palladacycles has been discovered. For example, we found that C,C-palladacycles have unusually high reactivity toward disilanes, which can be leveraged to disilylate a variety of C,C-palladacycles with very high efficiency. These results should provide inspiration to develop other C-Si bond-forming reactions in the future. We hope that this Account will stimulate further research into the rich chemistry of C,C-palladacycles, in particular reactions that find practical applications in the synthesis of bioactive and functional molecules and those that advance the state of the art in C-H functionalization.

Our research focus is on applying two long range electrostatic interactions – coulombic interaction between ion pairs and hydrogen bonding—to two tasks: exploring counterion effects in gold catalysis and utilizing hydrogen bonding for fluorinating reagent development. Cationic gold catalysis is considered one of the most important breakthroughs in organic synthesis over the past two decades. A wealth of empirical information on counterion effects is now available regarding homogeneous gold catalysis. However, the rational understanding of the counterion effect on reactivity is still elusive. We proposed a widely applicable model to rationalize the kinetic effect in gold catalyzed reaction. We first solved the problem of the silver effect that existed in gold catalyst and provided a more stable gold catalyst preparation protocol. We discovered that the presence of silver activators almost always had adverse effects in many gold catalyzed reactions. However, using a pre-formed L-Au+X- complex by removing excess AgX before the reaction avoided this problem. The deleterious silver effect may be caused by the interaction of silver salts with key gold intermediates like vinyl gold complex in the gold catalytic cycle. With the new method of catalyst preparation, we investigated the counterion effect in various cationic gold catalyzed reactions. We found that gold affinity and hydrogen bonding basicity of counterions play critical roles in the reactivity of cationic gold catalysts. The impact of our studies may not be limited to gold catalysis but may also provide guidance in transition metal catalysis in general. We then applied the hydrogen bonding basicity scale of different anions for the development of a new generation of HF-based reagents. We utilized a novel acidic but strong hydrogen bonding acceptor as a stabilizer to fixate gaseous and toxic hydrogen fluoride as liquid. This new reagent has several advantages such as being inexpensive, easily handled, and more acidic than other commercially available HF reagent. We then utilized this HF reagent on the hydrofluorination of various highly functionalized alkenes. The excellent functional group tolerance, exclusive Markovnikov addition regioselectivity and high atom economy may facilitate the preparation of other fluorinated products at both the lab and industrial scale.

3-Pyrroline structure is a common scaffold in natural products and synthetic bioactive molecules. 3-Pyrroline derivatives are also important intermediates in organic synthesis. The synthetic study of 3-pyrroline compounds has therefore always attracted great attention. Tertiary enamides are a class of unique and versatile synthons. They are able to participate in intramolecular and intermolecular reactions with various electrophiles, affording diverse nitrogen-containing heterocyclic compounds. Recently, we attempted the Heck reaction of the five-membered cyclic tertiary enamides and discovered the formation of alpha-arylated product with the double bond being shifted. We then envisioned a tandem diarylation reaction to synthesize 2,5-disubstituted-3-pyrroline derivatives. Herein, we reported the investigation of the Heck reaction of cyclic tertiary enamides, a simple and convenient approach to trans-2,5-disubstituted-3-pyrrolines. Silver salts were found to be effective additives to accelerate the reaction, while PdCl2(PPh3)(2) appeared as the best catalyst to improve the regioselectivity. Under the optimized conditions, a variety of differently substituted aryl iodides reacted smoothly with N-benzoyl-2,3-dihydro-1H-pyrrole 2a to afford the desired products 4a similar to 4k in moderate to high yields. Other N-substituted enamide substrates 2b similar to 2e underwent similar tandem reactions to give the corresponding products in moderate chemical yields. A representative procedure for this reaction is as follows: to an oven-dried Schlenk tube was successively added PdCl2(PPh3)(2) (18 mg, 0.025 mmol, 5 mol%), AgNO3 (177 mg, 1.05 mmol, 2.1 equiv.), DABCO (168 mg, 1.5 mmol, 3.0 equiv.) and dry DMA (1.0 mL) under argon atmosphere. After stirring for 5 min at room temperature and the mixture turned black, aryl iodides 1a similar to 11(1.05 mmol) in DMA (1.0 mL) was introduced into the tube, following the addition of substrate 2a similar to 2f (0.50 mmol) in DMA (1.0 mL). The resulting mixture was stirred at 80 degrees C until starting enamides and mono-arylated compounds were consumed, which was monitored by TLC analysis. After filtration, extraction and concentration in vacuo, the reaction residue was flash chromatographed on a silica gel column eluted with a mixture of petroleum ether and ethyl acetate (V: V=6 :1) to give the pure product 4a similar to 4p. The resulting trans-2,5-diphenyl-3-pyrroline was converted to pyrrole and pyrrolidine derivative, respectively, by oxidation and reduction.

Speech The innovative area of homogeneous gold catalysis so far has mainly focused on alkylgold, vinylgold and gold carbenoid intermediates. A new class of gold-catalyzed reactions, proceeding via gold(I) vinylidene complexes, will be presented. A full-scope study of these new catalytic cycles, involving the principle of “dual activation” of the substrate by two gold centers, gold vinylidene intermediates and an efficient ”catalyst transfer” will be presented. In addition to experimental insights this includes studies of the new steps by computational chemistry. Furthermore, new intermolecular reactions and extensions of these principles will be reported. This includes C-H activation at room temperature. Even sp-C-H-bonds can be activated in a positional selective manner. Improved catalysts for these reactions base on an innovative new one-step synthesis of NHC-gold(I) complexes. Vinyl iodides are accessible this way, too. This shows the orthogonality of gold catalysis and palladium catalysis in organic synthesis. It is possible to conduct a goldcatalyzed reaction at a halogenated substrate without addressing the halide at all, and then a subsequent palladium-catalyzed reaction with the organic halide can be done. Some of the reactions allow the isolation of gem-diaurated species, interesting organometallic intermediates. These could be characterized by a number of X-ray single crystal structure analyses.

During the last decade, gold-catalyzed reactions have become a tour de force in organic synthesis. Recently, the gold-, Brønsted acid- or Lewis acid-catalyzed oxygen transfer from carbonyl to carbon–carbon triple bond, the so-called alkyne–carbonyl metathesis, has attracted much attention because this atom economical transformation generates α,β-unsaturated carbonyl derivatives which are of great interest in synthetic organic chemistry. This mini-review focuses on the most recent achievements on gold-catalyzed oxygen transfer reactions of tethered alkynones, diynes or alkynyl epoxides to cyclic enones. The corresponding mechanisms for the transformations are also discussed.

Cycloisomerizations of enynes are probably the most representative carbon–carbon bond forming reactions catalyzed by electrophilic metal complexes. These transformations are synthetically useful because chemists can use them to build complex architectures under mild conditions from readily assembled starting materials. However, these transformations can have complex mechanisms. In general, gold(I) activates alkynes in the presence of any other unsaturated functional group by forming an (η2-alkyne)–gold complex. This species reacts readily with nucleophiles, including electron-rich alkenes. In this case, the reaction forms cyclopropyl gold(I) carbene-like intermediates. These can come from different pathways depending on the substitution pattern of the alkyne and the alkene. In the absence of external nucleophiles, 1,n-enynes can form products of skeletal rearrangement in fully intramolecular reactions, which are mechanistically very different from metathesis reactions initiated by the [2 + 2] cycloaddition of a Grubbs-type carbene or other related metal carbenes.In this Account, we discuss how cycloisomerization and addition reactions of substituted enynes, as well as intermolecular reactions between alkynes and alkenes, are best interpreted as proceeding through discrete cationic intermediates in which gold(I) plays a significant role in the stabilization of the positive charge. The most important intermediates are highly delocalized cationic species that some chemists describe as cyclopropyl gold(I) carbenes or gold(I)-stabilized cyclopropylmethyl/cyclobutyl/homoallyl carbocations. However, we prefer the cyclopropyl gold(I) carbene formulation for its simplicity and mnemonic value, highlighting the tendency of these intermediates to undergo cyclopropanation reactions with alkenes.We can add a variety of hetero- and carbonucleophiles to the enynes in the presence of gold(I) in intra- or intermolecular reactions, leading to the corresponding adducts with high stereoselectivity through stereospecific anti-additions. We have also developed stereospecific syn-additions, which probably occur through similar intermediates. The attack of carbonyl groups at the cyclopropyl carbons of the intermediate cyclopropyl gold(I) carbenes initiates a particularly interesting group of reactions. These trigger a cascade transformation that can lead to the formation of two C–C and one C–O bonds. In the fully intramolecular process, this stereospecific transformation has been applied for the synthesis of natural sesquiterpenoids such as (+)-orientalol F and (−)-englerin A.Intra- and intermolecular trapping of cyclopropyl gold(I) carbenes with alkenes leads to the formation of cyclopropanes with significant increase in the molecular complexity, particularly in cases in which this process combines with the migration of propargylic alkoxy and related OR groups. We have recently shown this in the stereoselective total synthesis of the antiviral sesquiterpene (+)-schisanwilsonene by a cyclization/1,5-acetoxy migration/intermolecular cyclopropanation. In this synthesis, the cyclization/1,5-acetoxy migration is faster than the alternative 1,2-acyloxy migration that would result in racemization.

A series of water-soluble encapsulated copper(I), silver(I) or gold(I) complexes based on NHC-capped permethylated cyclodextrins (ICyDMe ) were developed and used as catalysts in pure water for hydration, lactonization, hydroarylation and cycloisomerization reactions. ICyDMe ligands gave cavity-based high regioselectivity in hydroarylations, and high enantioselectivities in gold-catalyzed cycloisomerizations reactions giving up to 98 % ee in water. These ICyDMe are therefore useful ligands for selective catalysis in pure water.

Exposure of enynes containing a hydroxyl group at one of the propargylic positions to catalytic amounts of either PtCl2 or (PPh3)AuCl/AgSbF6 results in a selective rearrangement with formation of bicyclo[3.1.0]hexan-3-one derivatives. The same products are obtained by a "one-pot" process on treatment of an alkynal with allylchlorodimethylsilane (4) and PtCl2 via a reaction cascade involving an initial platinum-catalyzed allylation followed by the cycloisomerization of the homoallylic alcohol formed in situ. This novel skeletal reorganization process was implemented into a concise total synthesis of the terpenes sabinone (18) and sabinol (19). Furthermore it is shown that conversion of the hydroxylated enynes into the corresponding acetates followed by reaction with a cationic gold catalyst formed from (PPh3)AuCl and AgSbF6 opens entry into isomeric products bearing the ketone function at the C-2 position of the bicyclo[3.1.0]hexane skeleton. The outcome of a deuterium labeling experiment and the analysis of the stereochemical course of the cycloisomerization reaction are consistent with the formation of cyclopropylmethyl platinum carbene species as reactive intermediates.

A concise synthesis of the tricyclic skeleton of crotobarin and crotogoudin via a gold-catalyzed 1,6-enyne cycloisomerization reaction is reported.