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Abstract
A novel type of yne-vinylidenecyclopropanes (VDCPs) has been synthesized and applied in gold-catalyzed cycloisomerization reactions. It was found that these compounds can undergo an intramolecular cycloisomerization and perform as a three-carbon synthon for [3+2] cycloaddition under gold catalysis to give fused [4.3.0] and [5.3.0] bicyclic derivatives and VDCP rearranged products in moderated to good yields under mild conditions. The substrate scope of these novel transformations has been explored and plausible reaction mechanisms have been presented on the basis of deuterium labeling experiments and DFT calculations.
The data on the reactions of various classes of functionalized alkynyl cyclopropanes that proceed with simultaneous participation of triple bond, three-membered ring, and functional group at a cyclopropane ring are systematized. The syntheses of polysubstituted and fused furans and indoles based on electrophile-induced and catalytic transformations of alkynyl cyclopropyl carbonyl compounds and their derivatives are considered separately. The methods for isomerization of 1-alkynyl cyclopropanols and their ethers to 3-methylenecyclobutanones are described. Information on the reactions of other types of alkynyl cyclopropanes containing one or more functional groups at three-membered ring leading to different acyclic, carbo-, and heterocyclic compounds is given. Transformations of alkynyl cyclopropanes lacking the functional groups, which simultaneously involved the cyclopropane ring and the alkynyl fragment, are also discussed.
In this paper, we report a gold(I)‐catalyzed cascade cyclization of N ‐ or O ‐nucleophile tethered‐vinylidenecyclopropanes (VDCPs), resulting in the synthesis of pyrrole, furan, pyrrolidine, and piperidine skeletons in 30%‐98% yields. Depending on the carbon chain length connecting the nucleophile and VDCPs, two reaction pathways are available, leading to different products. Both α‐amino VDCPs and α‐hydroxyl VDCPs, where nucleophiles and VDCPs are connected by a methylene group, undergo intramolecular nucleophilic addition and aromatization, followed by ring‐opening of the cyclopropane unit to produce substituted pyrroles and furans. By extending the chain length to three or four carbons, it becomes possible to form pyrrolidines and piperidines with a cyclobutene moiety via ring expansion of the cyclopropane unit, accompanied by gold carbene induced vinylogous nucleophilic addition.
A gold(I)-catalyzed intramolecular cyclization of alcohol or amine tethered-vinylidenecyclopropanes via carbene or non-carbene process was developed to afford functionalized morpholines, piperazines and oxazepanes in good yields under mild conditions with...
Data on methods for the synthesis of various classes of functionalized alkynylcyclopropanes (FACPs) reported in the last two decades are systematized. Synthetic routes to FACPs based on cyclopropanation of unsaturated compounds with various carbenes, carbenoids, and ylides are considered separately. Methods for introducing functional groups into the three-membered ring of alkynylcyclopropanes via metalation and elimination—addition processes as well as other synthetic routes to functionalized cyclopropanes are discussed.
The past decade has witnessed the golden age of homogeneous gold-catalyzed reactions, especially those that involve the transformation of highly strained molecules into complex molecular architectures. Gold catalysts, with unique electronic properties and catalytic abilities, have elevated versatile reaction modes through π-interaction induced activation. On the basis of increasing research interest in this topic, together with the significant development of various ligands, including phosphine ligands and azacyclic or noncyclic carbene ligands, the understanding of the catalytic function of gold catalysts has become much deeper and more comprehensive. Different reaction needs thus could be adapted by a novel gold catalyst with a diversified ligand selection. Furthermore, the whole evolution of the gold catalysis on synthetic methodologies has realized and expanded its application into natural product synthesis as well as the potentiality of drug discovery, which endows this ancient metal with a magnificent renaissance. The reactivity of strained small ring molecules with high tension has always been an important research topic in organic chemistry. When the highly strained small ring is linked with a π-electron rich moiety or contains a heteroatom, the gold activation of the π-system or coordination with the heteroatom can initiate a cascade reaction, usually followed by ring opening or expansion. These processes can result in the rapid construction of complex and distinct molecular structures, many of which feature in biologically important molecules. In this review, we will mainly summarize the advances on diverse reaction types and molecular constructions accomplished by homogeneous gold catalysis using highly strained substrates, including methylenecyclopropanes (MCPs), vinylidenecyclopropanes (VDCPs), cyclopropenes as well as aziridine- and epoxide-containing molecules, focusing on the last 10 years. For functionalized alkynyl cyclopropanes, several early inspiring and elegant examples will be described in this review for systematically understanding these transformations.
We report herein an oxidization reaction of enones with Cu(II) complex that leads to a regioselective [3+2] cycloaddition to furnish highly functionalized cyclopentenes and spirocyclic compounds in fair‐to‐good yields, disclosing a new type of [3+2] cycloaddition. This cycloaddition reaction occurred via formation of γ‐enone radical, providing a rarely explored reactivity pattern for enones.
In organic synthesis, the synthetic methodology of using cyclopropanes for cycloadditions has witnessed significant progress over the past several years. A series of cyclopropane-related cycloaddition reactions via organic or metal-catalyzed/mediated pathways has been exploited in constructing cyclic frameworks such as polycycles, bridged-ring carbocycles, and heterocycles. Moreover, this synthetic chemistry has also recently blossomed in the pursuit of highly efficient asymmetric cycloadditions, C–H bond-activated cycloadditions, photoredox catalysis-cooperated cycloadditions, and several other unique reaction processes. Although numerous cyclopropane-based cycloaddition reactions have been reported, the newly explored cycloadditions have not yet been reviewed. Herein, we present recent progress in cyclopropane-related cycloadditions over the past 6 years.
A cationic Rh(I) complex catalyzed intramolecular cycloaddition reaction of ene-vinylidenecyclopropanes to produce bicyclo[4.3.0] skeletons containing a quaternary all carbon center at the ring juncture has been successfully established. The reaction could afford a range of desired bicyclic products in good yields with a broad substrate scope and good functional-group tolerance. The asymmetric variant of this cycloaddition could also be achieved by using chiral bisphosphine ligands to give the desired products in high ee values. Furthermore, the exclusive production of endo- and exocyclic double bond products could be achieved when the substituent at the quaternary carbon center is a methyl group. The synthetic utility of the obtained product has been demonstrated by several transformations of the obtained bicyclic products. The reaction mechanism and product selectivity were studied by control experiments, and plausible reaction mechanisms have been proposed.
A cationic Rh(I) complex-catalyzed intramolecular [3+2] cycloaddition reaction of newly developed yne-vinylidenecyclopropanes (VDCPs) has been established, affording an efficient synthesis of fused [6.5]-bicyclic structures in moderate to good under mild...
Vinylidenecyclopropanes (VDCPs), having an allene moiety connected to a highly strained cyclopropyl group, have attracted a substantial amount of attention since they are fascinating building blocks for organic synthesis. During recent years, the reactions of VDCPs in the presence of a Lewis acid or a Brønsted acid and those induced by heat or light have experienced significant advancements due to the unique structural and electronic properties of VDCPs. Transition-metal-catalyzed reactions of VDCPs were not intensely investigated until the last 5 years. Recently, significant progress has been made in transition-metal-catalyzed transformations of VDCPs, and they have emerged as a new direction for the chemistry of strained small rings, especially when new types of functionalized vinylidenecyclopropanes (FVDCPs) are used as substrates. To date, many interesting transformations have been explored using these novel VDCPs under the catalysis of transition metals, such as gold, palladium, or rhodium, and various novel and useful heterocyclic or polycyclic compounds have been generated. These new findings have enriched the chemistry of strained small carbocycles.
Gold- and silver-catalyzed intramolecular annulation and rearrangement of aniline-linked 1,6-enyens containing methylenecyclopropane have been reported in this paper, affording the corresponding 1,2-dihydroquinolines containing a cyclobutene moiety as the major products upon gold catalysis and the corresponding 1,2-dihydroquinolines containing a methylenecyclopropane moiety as a single product upon silver catalysis in moderate to good yields under mild conditions. In the gold-catalyzed cycle, the formation of 1,2-dihydroquinolines containing a cyclobutene moiety may undergo twice cyclopropyl gold-carbene intermediate
Gold(I) catalyzed cycloisomerization reaction is one of the key transformations that remain underexplored to build molecular diversity and complexity. In this review, we summarize synthesis endeavors where enyne cycloisomerization chemistry was utilized to form structurally intriguing as well as biologically relevant heterocyclic scaffolds. To this goal, most of the efforts tend to exploit gold carbene type intermediates, often supporting a cyclopropane ring and transform them into new scaffolds. Various examples have been grouped together to highlight the role of presence or absence of external heteroatom nucleophiles in modulating reactive intermediates into novel molecular frameworks. The last section is devoted to the emerging role of gold(I) catalyzed cycloisomerization reactions in driving the divergent synthesis approaches wherein a common substrate can be transformed into distinct molecular scaffolds by merely varying reaction conditions or gold complexes.
This chapter contains sections titled: Pericyclic Reactions Claisen Cope Electrocyclization and Cyclo-revision Sigmatropic Shifts Addition Reactions Ene Reactions Rearrangements Acid-catalysed Reactions Ring-opening Reactions Rearrangement Reactions Addition–Cyclization Reactions Pinacol and Benzidine Rearrangements Hydride Shifts Halogen-induced Reactions Boron, Phosphrpous, and Silicon Reactions Thermal Reactions Carbene Reactions Oxidation and Reduction Metathesis Named Reactions Anion-induced Reactions Aromatic Reactions Sugar Reactions Metal-induced Reactions Copper Gold Indium Iridium Iron Nickel Rhodium Ruthenium Palladium Platinum Silver Tin Ytterbium Zinc Miscellaneous Reactions References The diastereoselective Ireland-Claisen rearrangement of a range of substituted allyl –amino esters has been reported to give enantiopure –substituted––amino esters diastereoselectively. A review of the application of divinylcyclopropane-cycloheptadiene rearrangement in synthesis has been reported, as well as of the orthoester Johnson-Claisen rearrangement and analogous reactions. Kinetic investigations of substituent effects in the thermal rearrangement of bis-vinyl ether substrates differ from that for analogous [3,3]–sigmatropic rearrangement of allyl vinyl ethers, and a dissociative transition state with significant dipolar character is suggested. A subsequent intramolecular addition of the enolate to an alkyne gives 3,4–dihydro–2–quinolones, which rearrange on heating to 2– quinolones. Au-catalysed cycloisomerization of aryl propargyl ethers followed by a Petasis-Ferrier rearrangement/aromatization cascade results in functionalized naphthalenes. An allylic gold(I) cation intermediate in the gold-promoted rearrangement of 1,5–enynes has been characterized by NMR spectroscopy. Computational studies indicate that the transformation occurs through an uncommon rearrangement.
A gold(I)-catalyzed cycloisomerization/ring expansion sequence allows the highly enantioselective synthesis of 2-oxocyclobutylcyclopentane derivatives from cyclopropyl-substituted enynes. The bimetallic [(R)-MeO-DTBM-BIPHEP-(AuCl)2] complex was found to be the best precatalyst, affording the desired cyclobutanones in high yields and enantioselectivities (up to 99% ee). The usefulness of the method was further demonstrated by preparing the tricyclic core scaffold of russujaponol D.
A rhodium/silver synergistic catalysis has been established, enabling cycloisomerization/cross coupling of keto-vinylidenecyclopropanes with terminal alkynes toward the regio- and enantioselective formation of diversified tetrahydropyridin-3-ol tethered 1,4-enynes in good yields and high ee values. In this synergistic catalysis, Rh(I) and Ag(I) catalysts selectively activate keto-VDCP substrates and terminal alkynes to generate -allyl Rh(III) complex of oxa-rhodacyclic intermediate and Ag alkynyl intermediate, respectively. The rapid transmetalation of alkynyl groups from Ag to Rh is proposed to play a key role to realize the regioselective cleavage of distal bond of the three-membered ring in this transformation.
1‐Alkynylcyclopropyl tosylates react with alkylmagnesium halides in the presence of catalytic ferric acetylacetonate [Fe(acac) 3 ] under net propargylic substitution; allene formation, which is the prevalent reactivity mode of propargylic substrates otherwise, was noticed as a side reaction only when branched alkyl‐ or aryl‐Grignard reagents were used. These transformations represent the first successful iron‐catalyzed cross‐coupling reactions of tert ‐alkyl electrophiles.
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A novel and convenient Pd-initiated radical cascade stereoselective iodofluoroalkylation/cycloisomerization of ene-vinylidenecyclopropanes with fluoroalkyl iodides has been developed. The reaction proceeds under mild reaction conditions with high atom economy and stereoselectivity, thereby allowing an efficient access to a variety of difluoromethylated or perfluoroalkylated pyrrolidines tethered with an alkyl iodide. Two plausible radical pathways for the transformation have been proposed on the basis of the results of control experiments and relevant literature, in one of which Pd(0) was thought as an initiator rather than a catalyst.
An efficient and highly regioselective synthetic method has been developed for the preparation of novel cyclobutene-containing spiro[2.3]hexenes fused with six or seven-membered carbo- or hetero-cycles in good to excellent yields following a thermal induced intramolecular [2+2] cycloaddition of alkynone-vinylidenecyclopropanes or a sequential oxidation/thermal induced intramolecular [2+2] cycloaddition process of propynol-vinylidenecyclopropanes under metal-free conditions. (C) 2015 Published by Elsevier Ltd.
The generation of 3-(pyrazolo[5,1-a]isoquinolin-1-yl)propanoic acids via a silver(I)-catalyzed three-component reaction of 2-alkylenecyclobutanone and N′-(2-alkynylbenzylidene)hydrazide with water is reported. This unexpected transformation proceeds through 6-endo cyclization, [3 + 2] cycloaddition, and rearrangement, leading to 3-(pyrazolo[5,1-a]isoquinolin-1-yl)propanoic acids in good yields.
A novel iron(III)-catalyzed intramolecular cycloisomerization of acetal–vinylidenecyclopropanes to afford a series of halogenated 1,2-disubstituted cyclobutenes tethered with a tetrahydropyrrole has been developed. The reaction is thought to proceed through a formal iron-catalyzed Prins cyclization followed by a ring-enlarging rearrangement of the methylenecyclopropane carbocation. The present protocol provides an alternative route to functionalized disubstituted cyclobutenes and the corresponding products could be successfully transformed into eight-membered oxacyclic products.
One-pot synthesis of highly substituted norbornadienes/norbornenes via gold-catalysed dehydrative cyclisation of alkynyldienols, followed by intermolecular [4 + 2] cycloaddition of in situ generated cyclopentadiene and activated alkynes/alkenes is described. The precursors, alkynyldienols, are obtained via sequential Sonogashira cross-coupling of 3-bromoenals, alkyne addition and reduction. Yields of the enynals and multisubstituted norbornadienes in all the cases are good to excellent. This journal is
Two new gold(I)-catalyzed cascade reactions of 4-hydroxy- and 4-silyloxy-1,5-allenynes are disclosed, offering access to a variety of mono- and bicyclic, polyunsaturated carbonyl compounds. The diverse reactivity observed for the investigated allenyne system is controlled by the nature of the unsaturated substrate: Allenynes bearing a free hydroxyl group engage in what is likely an oxycyclization/allene-ene carbocyclization cascade, while their silylated analogues are converted through a carbocyclization/pinacol-type rearrangement process.
Phosphane and N-heterocyclic carbene ligated gold(I) chlorides can be effectively activated by Na[Me3 NB12 Cl11 ] (1) under silver-free conditions. This activation method with a weakly coordinating closo-dodecaborate anion was shown to be suitable for a large variety of reactions known to be catalyzed by homogeneous gold species, ranging from carbocyclizations to heterocyclizations. Additionally, the capability of 1 in a previously unknown conversion of 5-silyloxy-1,6-allenynes was demonstrated.
[2+2+2] Cycloadditions can be applied to specifically build up derivatives of benzene and cyclohexadiene and, therefore, have attracted much attention. Herein, we present an intramolecular [2+2+2] cycloaddition of triynes catalyzed by the first-generation Grubbs ruthenium complex (Ru gen-1), which can efficiently afford benzene derivatives in good yields under mild conditions. Moreover, we also report on a novel tandem cross-metathesis transformation of intramolecular enediynes also catalyzed by Ru gen-1, which has not been observed previously in related reports. On the basis of deuterium labeling experiments, a possible reaction mechanism is presented.
Cascade transformation: A highly regioselective and stereoselective synthesis of polyfunctional indoles from isatin derivatives and allenic esters is disclosed. The novel cascade transformation is a direct and rapid entry to polycyclic indoles through sequential catalysis of rearrangement and [4+2] cycloaddition under very mild conditions bearing various substituents at many positions.
We report a gold-catalyzed [2+2+2]-cycloaddition of 1,7-enynes with carbonyl species; our experimental data suggest that the resulting oxacyclic cycloadducts arose from an interception of gold-containing cyclobutenium intermediates with carbonyl species.
Cycloisomerization of 1,n-enynes and diynes is a powerful method in organic synthesis to access heterocyclic compounds and has drawn increasing attention from organic chemists. In this paper, we attempted to summarize our recent results on the transition metal-catalyzed cycloisomerization to synthesize five or six-membered heterocyclic compounds using 1,n-enynes and diynes having a propargylic ester moiety. First, we will describe the synthesis of 2,3-disubstituted 3-pyrrolines via gold catalyzed cycloisomerization of 1,6-diynes. In addition, we will also disclose a novel silver catalyzed tandem 1,3-acyloxy migration/Mannich-type addition/elimination of the sulfonyl group of N-sulfonylhydrazone-propargylic esters to 5,6-dihydropyridazin-4-one derivatives. Furthermore, we will introduce three interesting examples of the synthesis of bicyclic compounds via titanium or rhodium catalyzed carbocyclization of enynes. In this context, we have presented that 1,n-enynes and diynes containing propargylic esters are highly reactive and useful starting materials for the cycloisomerization catalyzed by a transition metal catalyst.
1-Alkenyl-2-(2′,2′-diphenylethenylidene)cyclopropanes thermally rearranged to 4-(diphenylethenylidene)cyclopent-1-enes at relatively low temperature (≤373 K). Measurement of activation parameters revealed that the reactivity and mode of the reaction largely depend on structures of starting materials and products.
Der andere Hang des Bergrückens: Eine Änderung des Gerüsts von Diinsystemen eröffnet neue Cyclisierungsmodi für die duale Goldkatalyse. Anstelle einer 5‐endo‐Cyclisierung unter Bildung von Vinylidengoldverbindungen führt eine 6‐endo‐Cyclisierung zu goldstabilisierten Carbenen als Schlüsselintermediaten für selektive C‐H‐Insertionen (siehe Bild).
Alkylsubstituierte Diine liefern in goldkatalysierten Reaktionen Benzofulvene. Der Katalysezyklus dieser einzigartigen Reaktionssequenz beinhaltet die Bildung von Goldacetyliden durch Alkinyl‐C‐H‐Aktivierung, die Bildung einer Vinyliden‐Gold(I)‐Zwischenstufe durch duale Aktivierung und eine Alkyl‐C‐H‐Aktivierung durch die Vinyliden‐Gold(I)‐Spezies. gem‐Diaurierte Spezies, die aus den Katalysereaktionen erhalten wurden, erwiesen sich als hochaktive Katalysatoren für diese Umsetzungen.
Nichtaktivierte Alkane reagieren in intermolekularen C(sp3)‐H‐Insertionen mit hoch reaktiven Goldvinyliden‐Spezies, die außerdem als Synthone für Alkyliden‐Carbene betrachtet werden können. Beginnend mit einer Cyclopropanierung durch die Vinyliden‐Spezies/das Alkyliden‐Carbenoid, werden interessante Cyclobutenderivate über eine diastereoselektive Ringerweiterungskaskade in nur einem Syntheseschritt gebildet.
Ring-opening reaction of vinylidenecyclopropanediesters catalyzed by Re2(CO)10 or Yb(OTf)3 afforded 2H-pyran-2-one derivatives or α,β-unsaturated ketones in moderate to good yields through a highly regioselective carbon–carbon bond cleavage pathway. The substituents at the cyclopropane mainly determine the regioselectivity of the carbon–carbon bond cleavage, providing different products of tandem ring-opening and rearrangement reactions.
Goldene Zeiten: Jüngste Entwicklungen im Bereich der Goldkatalyse ermöglichen die Verwendung von Alkinen als Carbonyläquivalente in der Synthese von komplexen und empfindlichen Naturstoffen und bringen dadurch Flexibilität in die Syntheseplanung. Das Verständnis der Reaktion und ein neues Katalysatordesign schaffen Bedingungen, die auch für Intermediate im späten Stadium geeignet sind.
Mobiler Acylrest: Die Titelreaktion liefert diastereomerenreine 3,4‐disubstituierte Pyrrolidin‐2‐one, die sehr wichtige Strukturmotive in Naturstoffen sind, in guten bis ausgezeichneten Ausbeuten. Mechanistische Untersuchungen weisen darauf hin, dass die Transformation über eine Tandem‐1,3‐Acyloxywanderung und eine nachfolgende 1,5‐Acyloxywanderung verläuft.
AbstractA series of easily accessible arene‐1,2‐diynes, bearing one aryl substituent on one of the alkynyl groups, is readily converted to dibenzopentalenes in good yields by gold(I) catalysts. The participation of gold acetylides could be proven by the direct conversion to the corresponding gem‐diaurated dibenzopentalenes with a gold catalyst. From an experiment with a gold acetylide complex and stoichiometric amounts of the gold “catalyst” the corresponding gem‐diaurated complex of a dibenzopentalene could be obtained and characterized by X‐ray crystal structure analysis. Labelling studies with deuterated alkynes show the expected deuteration of the two remaining positions of the pentalene core. All this provides evidence for a dual activation mode of the reaction and gold(I) vinylidene complexes as intermediates of the catalytic cycle.
The intermediacy of gold acetylides in the gold(I)-catalyzed cycloisomerization of enynes was questioned. While dinuclear gold complexes are observed under electrospray ionization conditions, the solution reactivity of gold acetylides also leads to the conclusion of their high affinity for the second coordination of a gold moiety, leading to dinuclear gold complexes. However, the involvement of gold acetylides and the corresponding diaurated species in the elementary steps of cycloisomerization mechanisms of enynes appears unlikely.
Ring-expansion reactions of bicyclic vinylidenecyclopropanes in the presence of Lewis acid was investigated, providing an efficient method for the synthesis of naphthalenes with annulated carbocycles of various ring sizes in good to excellent yields under mild conditions.
The oxidation of (diphenylethenylidene) cyclopropanes and (dialkylethenylidene) cyclopropanes with m-chloroperbenzoic acid gave respectively 2-(diphenylethylidene) cyclobutan-1-ones and cyclopropyl keto esters with high selectivity.
Photoisomerization of cis- and trans-1-diarylvinylidene-2,3-dimethylcyclopropanes is described. The formation of different photostationary state mixtures of cis and trans isomers generated by direct and triplet-sensitized photoreactions clearly shows that the photoisomerization proceeds via their excited singlet and triplet states, respectively.
This review highlights the synthesis of heterocycles via cascade reactions that involve the activation of an alkyne using carbophilic Lewis acids. Primarily guided by the type of reactivity evolving from the alkyne activation, such key steps are categorized as the addition of simple heteroatom nucleophiles, intramolecular carboalkoxylations, addition of carbonyl nucleophiles, rearrangement of propargylic esters, and enyne cycloisomerizations. Additionally, the functionalization of existing heterocycles is discussed.
1 Introduction
2 Functionalization of Existing Heterocycles
3 Synthesis of Heterocycles through Cyclization Reactions
3.1 Intramolecular Addition of Simple Heteroatom Nucleophiles
3.2 Intramolecular Carboalkoxylations and Carboaminations
3.3 Carbonyls and Imines as Nucleophiles
3.4 Propargylic Esters
3.5 Enyne Cycloisomerizations
4 Miscellaneous Reactions
5 Conclusions
Exposure of alpha-ene-VCPs to catalytic [Rh(dppm)]SbF(6) led to the discovery of a novel Rh(I)-catalyzed [3+2] reaction, which was shown to be efficient for the construction of 5/6- and 5/7-bicyclic compounds rather than the anticipated type II [5+2] products.
The oxidation of (diphenylethenylidene) cyclopropanes and (dialkylethenylidene) cyclopropanes with m-chloroperbenzoic acid gave respectively 2-(diphenylethylidene) cyclobutan-1-ones and cyclopropyl keto esters with high selectivity.
Vinylidenecyclopropanes undergo ring-opening reactions with xanthydrol in the presence of BF3·OEt2 or with xanthene in the presence of DDQ at 0°C in 1,2-dichloroethane to give the corresponding conjugate triene derivatives in moderate to good yields. Plausible reaction mechanisms have been discussed on the basis of previous literature and the control experiments. The further transformation of these trienes has been disclosed in DCE in the presence of BF3·OEt2 along with a plausible reaction mechanism.
Gold-catalyzed reactions of C–H bonds, with a particular emphasis on C–C, C–O, and C–N bond formations, are reviewed.Figure optionsView in workspaceDownload full-size imageDownload as PowerPoint slide
Hong C. Shen was born in Chengdu, China in 1974. In 1997, he received his B.S. degree in Chemistry from Peking University under the guidance of Professor Yunhua Ye. Hong Shen subsequently moved to University of Minnesota, where he developed a formal [3+3] cycloaddition under the direction of Professor Richard Hsung, and obtained his M.S. degree in 1998. Hong Shen then joined the research group of Professor Barry Trost at Stanford University. His work spanned from Ru- and Pd-catalyzed reactions to their applications in total syntheses of natural products. After having his Ph.D. degree in 2003, Hong Shen became a medicinal chemist at Merck Research Laboratories, Rahway, New Jersey. He is currently a research fellow working on the discovery of novel drugs for the treatment of cardiovascular and metabolic diseases. He has authored over 24 papers and 8 patents.
Jacques Muzart was born in 1946, in Vienne la Ville, a small village in the Argonne area, 200 km east of Paris. He studied chemistry at the Université de Champagne-Ardenne and received his degrees (Doctorat de 3ème cycle—1972, Doctorat d'Etat—1976) for his work with Jean-Pierre Pète on photochemical rearrangements of α,β-epoxyketones and β-diketones. He was appointed at the Centre National de la Recherche Scientifique (CNRS) in 1971 as Stagiaire de Recherche and spent 15 months (1977–1978) as a postdoctoral fellow of National Science Foundation working with Elias J. Corey at Harvard University on natural product synthesis. On his return to Reims, he mainly studied the photoreactivity of η3-allylpalladium complexes and anionic activation by supported reagents. In 1988, he was promoted to Directeur de Recherche CNRS. His research interests concentrate on transition-metal catalysis with particular emphasis on oxidations, asymmetric reactions, C–H activations and mechanisms. Since a few years, he is also involved in the valorisation of agricultural by-products and in the use of water and molten salts as solvents for Organic Synthesis.
The palladium-tetraphosphine catalyzed arylation of an alkylidenecyclopropane gives a simple and direct access to 1-aryl-2-methyl-1-(2,2,3,3-tetramethylcyclopropylidene)propenes. This reaction tolerates several functional groups on the aryl bromides. Even heteroaryl bromides have been used successfully. This reaction probably proceeds via a classical oxidative addition of the aryl bromide to palladium, insertion of the C=CMe2 bond in the Ar-Pd bond followed by beta-elimination to give the dienes.
The cis–trans photoisomerization of 1-bis(4-methoxyphenyl)vinylidene-2,3-dimethylcyclopropanes in aerated acetonitrile was sensitized by 9,10-dicyanoanthracene and chloranil in the presence of an additive via an electron-transfer chain process, in which the cation radicals generated from the vinylidenecyclopropanes were involved as chain carriers.
Hong C. Shen was born in Chengdu, China in 1974. In 1997, he received his B.S. degree in chemistry from Peking University under the direction of Professor Yunhua Ye. Hong C. Shen subsequently moved to University of Minnesota, where he developed a formal [3+3] cycloaddition with Professor Richard Hsung, and obtained his M.S. degree in 1998. Hong Shen then joined the research group of Professor Barry Trost at Stanford University. His work spanned from Ru- and Pd-catalyzed reactions to their applications in total syntheses of natural products. After obtaining his Ph.D. degree in 2003, Hong C. Shen assumed a senior research chemist position at Merck Research Laboratories, Rahway, New Jersey. He is currently a research fellow working on the discovery of novel drugs for treatment of cardiovascular and metabolic diseases. He has authored close to 30 publications and 9 patents.
CuCl-catalyzed cyclization-dimerization reactions of 3-cyclopropylideneprop-2-en-1-ones provide an interesting route to benzofuran-7(3aH)-one derivatives with one highly strained three-membered ring and one four-membered ring via intramolecular cycloisomerization, sequential bimolecular [4 + 2] cycloaddition, opening of the oxa-bridge, and ring contraction. Furthermore, the reaction was monitored by NMR experiments to unveil some key intermediates.
The other side of the mountain: Changing the framework of diyne systems opens up new cyclization modes for dual gold catalysis. Instead of a 5-endo cyclization and gold vinylidenes a 6-endo cyclization gives rise to gold-stabilized carbenes as key intermediates for selective CH insertions.
Mobile: The title reaction affords diastereomerically pure 3,4-disubstituted pyrrolidin-2-ones, which are important structural motifs in natural products, in good to high yields. Mechanistic investigations suggest the transformation proceeds through a tandem 1,3-acyloxy migration and a subsequent 1,5-acyloxy migration. DCE=1,2-dichloroethane, IPr=1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene.
An intramolecular Pauson-Khand type cycloaddition reaction of ene-vinylidenecyclopropanes with carbon monoxide has been established by using [Rh(COD)Cl](2) as the catalyst. The reaction was found to be highly efficient in solvents of 1,2-dichloroethane and 1,1,2,2-tetrachloroethane to give excellent yields of 90-99%. The reaction provides easy access to a series of fused 6,5-ring structures containing spiro-cyclopropane units that are useful for drug design and development. A mechanism of this cycloaddition process has been proposed accounting for structures of resulting products that were unambiguously assigned by X-ray diffractional analysis.
The PtCl2-mediated intramolecular cycloisomerization of 1,6-enynes functionalized at propargylic positions shows a high versatility and can give rise to a variety of products with potential synthetic applications. A broad computational study at the DFT level is reported to provide a better mechanistic understanding of these reactions and of the factors that control the course of these processes. For every type of cycloisomerization, several reasonable pathways have been proposed and evaluated. The results suggest that these reactions probably share common steps and could proceed through the formation of cyclopropyl platinum carbenes by endo- or by exo-cyclization routes. The role of the propargylic substituent and the additional alkene chain for dienyne precursors is also discussed. The metathesis process involves an initial 5-exo cyclopropanation path, in common with the formation of polycyclic adducts, but it is retarded or inhibited by the presence of an additional alkene chain.
Palladium catalyzed intramolecular [3 + 2] cycloadditions of diastereomerically pure methylenecyclopropanes MCPs have been investigated. The reaction was found to be stereospecific and occurred with retention of configuration at the carbon center undergoing reaction. A variety of substitution patterns were tolerated on and around the MCP. Deuterium labeling studies have been conducted, and information about the rate of the reaction was obtained. A mechanism has been proposed involving π-allyl intermediates. Pd2(dba)3/P(OiPr)3 was a suitable catalyst for most cycloadditions, but molecular sieves or Pd(PPh3)4 improved the reaction with some substrates. 1,4-Addition of hydride or a carbanion to the enoate was achieved with high selectivity at the newly formed stereocenter. The allylic alcohol was selectively epoxidized with VO(acac)2/t-BuOOH.
Density functional theory has been used to investigate the reactions of 1,5 enynes with alcohols in the presence of a gold catalyst. We have compared the mechanism of the alcohol addition reaction for the enyne with that of the enyne where the carbon at position 3 is replaced with silicon. We find that different intermediates are present in both cases, and in the case of the silicon analogue, the intermediate that we find from the calculations is different from any that have previously been proposed in the literature. For the silicon analogue we have been able to rationalize the observed effects of alcohol concentration and nucleophilicity on the product distribution. For the carbon-based enyne we have shown why different products are observed depending on the substitution at position 3 of the enyne. Overall, we have provided for the first time a consistent explanation and rationalization of several different experiments that have been previously published in the literature. Our mechanism will assist in predicting the outcome of experimental reactions involving different alcohols, reagent concentrations, and substitution patterns of the 1,5 enynes.
Highly reactive gold vinylidene species are used for intermolecular C(sp(3) )H insertions into unactivated alkanes. In addition, they can be regarded as synthons for alkylidene carbenes. Initiated by cyclopropanation of the vinylidene species/alkylidene carbenoide, cyclobutene derivatives are formed in a diastereoselective fashion by a ring-enlargement cascade in only one step.
InCl(3) and other In(III) species have been widely applied as catalysts in many reactions. However, what are the real catalytic species of these reactions? Through DFT calculations and experimental investigation of the mechanism and regioselectivity of InCl(3)-catalyzed cycloisomerization reactions of 1,6-enynes (here all discussed 1,6-enynes are ene-internal-alkyne molecules), we propose that the catalytic species of this reaction is the in situ generated InCl(2)(+). Further electrospray ionization high-resolution mass spectroscopy (ESI-HRMS) supported the existence of InCl(2)(+) in acetonitrile solution. This finding of InCl(2)(+) as the catalytic species suggests that other reactions catalyzed by In(III) species could also have cationic In(III) species as the real catalysts. DFT calculations revealed that the catalytic cycle of the cycloisomerization of 1,6-enynes catalyzed by InCl(3) starts from InCl(2)(+) coordination to the alkyne of the substrate, generating a vinyl cation. Then nonclassical cyclopropanation of the vinyl cation to the alkene part of the substrate gives a homoallylic cation, which undergoes a novel homoallylic cation rearrangement involving a [1,3]-carbon shift to give the more stable homoallylic cation 15. Finally InCl(2)(+) cation coordination assisted nonconjugated [1,2]-hydride shifts deliver the final nonconjugated diene products. The preference of generating nonconjugated dienes instead of conjugated dienes in the cycloisomerization reaction is mainly due to two reasons: coordination of the InCl(2)(+) to the alkene part in [1,2]-H shift transition states disfavors the conjugated [1,2]-H shifts that generate cations adjacent to the positively charged alkene, and coordination of InCl(2)(+) to the nonconjugated diene product is stronger than coordination to the conjugated diene, making nonconjugated [1,2]-H shift transition states lower in energy than conjugated [1,2]-H shift transition states, on the basis of the Hammond postulate. DFT calculations predicted that the conjugated [1,2]-H shifts could become favored if the electron-donating methyl substituent in the alkyne moiety of the 1,6-enyne is replaced by a H atom. This prediction of producing a conjugated diene has been verified experimentally. Rationalization about why type II rather than type I products were obtained using InCl(3) as the catalyst in the cycloisomerization of 1,6-enynes has also been investigated computationally.
Three kinds of Lewis acid-mediated reactions of vinylidenecyclopropanes and aromatic aldehydes are disclosed in this paper, providing an efficient and selective synthesis of a variety of functionalized benzo[c]fluorene, furan and furo[2,3-b]furan derivatives.
Skeletal rearrangements of simple 1,6-enynes have been studied in order to determine the factors that control the formation of five- or six-membered rings. Simple 1,6-enynes substituted only at C-4 preferentially give six-membered rings on skeletal rearrangement in the presence of gold(I) catalysts, whereas increasing electron-withdrawing character of substituents at C-4 leads to five-membered rings. Reactions of these simple enynes in the presence of PtCl4 as catalyst give exclusively exo-double skeletal rearrangements. Enynes substituted at the alkyne also react with AuI catalysts to give exclusively products of exo-double rearrangement. The different mechanisms have been analyzed by DFT calculations. Although a pathway for the formation of six-membered rings involving two steps in a ring-expansion/ring-contraction process was found, the activation energy of the first step is too high. Instead, this skeletal rearrangement appears to follow an exo-single skeletal rearrangement in which the initial cyclopropyl gold carbene opens to form a six-membered ring. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)
Goldgräberstimmung: Die neuesten Entwicklungen in der stereoselektiven Goldkatalyse sind äußerst vielversprechend. Chiralitätstransfer oder die Bildung neuer stereogener Zentren aus prochiralen Substraten mit chiralen Goldkatalysatoren verlaufen mit exzellenten Enantioselektivitäten. Neue Konzepte, wie der Einsatz von Goldkatalysatoren mit chiralem Gegenion (siehe Schema; dppm=Bis(diphenylphosphanyl)methan), helfen, die Selektivtäten weiter zu verbessern.
Metallkatalysierte Cycloisomerisierungen von 1,n-Eninen haben sich als konzeptionell und chemisch höchst attraktive Reaktionen erwiesen, da sie dem häufig geforderten Streben nach Atomökonomie nachkommen und neuartige Reaktionsverläufe ermöglichen. Seit den bahnbrechenden Arbeiten in der Gruppe von Barry Trost mit Palladium Mitte der 1980er Jahre wurden viele weitere Metalle als hervorragende Katalysatoren für Enin-Gerüstumlagerungen identifiziert. Zudem kann das Verhalten von 1,n-Eninen durch funktionelle Gruppen wie Alkohol-, Aldehyd-, Ether-, Alken- oder Alkineinheiten beeinflusst werden, wodurch die Komplexität der synthetisierten Verbindungen zunimmt. Neben den eigentlichen 1,n-Enin-Umlagerungen wurden mehrere Tandemreaktionen entdeckt, die intramolekulare Abfangreagentien oder intermolekulare Partner einbeziehen. Diese Übersicht will die wichtigsten Beiträge auf diesem Gebiet der Katalyse behandeln und die mechanistischen Erkenntnisse zu den neuesten Entdeckungen darlegen und kommentieren.
Unterstützung für die direkte Route: DFT-Rechnungen und kinetische Studien deuten an, dass Cyclobutene nicht notwendigerweise als Intermediate der Gerüstumlagerungen von Eninen auftreten. Die Cyclobutene können aus den entsprechenden syn-Cyclopropylgold(I)-Carbenen entstehen (siehe Schema).
Chloridliganden sind maßgeblich für die goldkatalysierte Cycloisomerisierung von Alleninen zu Hydrindienen wie 1. Diese formalen Produkte einer C-H-Aktivierung entstehen vollständig selektiv anstelle der üblichen Alder-En-Produkte (2; siehe Schema). Eine DFT-Studie zur elektrophilen metallkatalysierten Cycloisomerisierung von mehrfach ungesättigten Systemen erklärt den Effekt.
Rings of gold: Vinylidenecyclopropanes can undergo efficient oxidative ring enlargements under mild conditions to give the corresponding alkylidenecyclobutanone derivatives in good yields. A plausible mechanism for this transformation has been proposed, and a new Au(I) -N complex, which can be used as an efficient catalyst in this oxidation reaction, has been isolated.
Fields of gold: Recent developments in the field of gold catalysis, using an alkyne as a carbonyl equivalent is becoming an important chemical transformation, thus providing flexibility in synthetic planning of complex and sensitive natural products. Understanding of the reaction and new catalyst designs are providing new conditions that are amenable for late-stage synthetic intermediates.
Five alkenylidenecyclopropanes have been arylated using a catalytic amount of [Pd(C3H5)Cl]2 (0.004%) associated to the tetradentate ligand cis, cis, cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane or Tedicyp as the catalyst. The carbo-palladation step occurs on the terminal double bond of the vinylidenecyclopropanes, without interaction with the internal one. The addition of the complex PdArL2 corresponds to an electrophilic attack on the face of the double bond, syn to the best electron-donor cyclopropyl substituent.Graphical abstract
A variety of polysubstituted tetrahydrofuran and indene derivatives were prepared in moderate to excellent yields via the cycloadditions of vinylidenecyclopropanes with common aldehydes in the presence of Lewis acid. The polysubstituted tetrahydrofuran 3 could undergo further transformations to the indene product 4 and furan derivatives 5.
Going for gold: The title reaction has been developed and demonstrates a wide substrate scope with respect to the 1,6-enynes and nitrones (see scheme; DCE = 1,2-dichloroethane, Tf = trifluoromethanesulfonyl). The results for the enantioselective versions are also presented.
A palladium-catalyzed asymmetric [3 + 2] cycloaddition of a vinyl-substituted trimethylenemethane (TMM) donor with alpha,beta-unsaturated acyl imidazoles is described. A newly designed bisdiamidophosphite ligand derived from (S,S)-trans-1,2-cyclohexanediamine and (2R,4R)-pentanediol has been instrumental for the development of this process. This transformation generates tetrasubstituted cyclopentanes bearing three contiguous stereocenters in high yields, with good diastereo- and enantioselectivity.
An efficient and selective gold-catalyzed cascade reaction for the synthesis of oxanorbornenes and naphthalene derivatives from easily prepared hydroxy enynes has been developed. Divergent products could be obtained from the same substrates by different gold catalytic systems.
Gold nanoparticles supported on TiO(2) (1.2 mol %) catalyze, for the first time under heterogeneous conditions, the cycloisomerization of a series of 1,6-enynes in high yields. In several cases, the product selectivity differs significantly as compared to homogeneous Au(I)-catalysis. Based on product analysis and stereoisotopic studies it is proposed that the major or exclusive pathway involves a 5-exo cyclization mode to form stereoselectively gold cyclopropyl carbenes that undergo a single cleavage pathway, in contrast to homogeneous Au-catalysis where the double cleavage pathway operates substantially.