Transition Metal Vinylidene- and Allenylidene-Mediated Catalysis in

Review Cite This: Chem. Rev. XXXX, XXX, XXX−XXX

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Transition Metal Vinylidene- and Allenylidene-Mediated Catalysis in Organic Synthesis Sang Weon Roh, Kyoungmin Choi, and Chulbom Lee*

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Department of Chemistry, Seoul National University, Seoul 08826, Republic of Korea ABSTRACT: With their mechanistic novelty and various modalities of reactivity, transition metal unsaturated carbene (alkenylidene) complexes have emerged as versatile intermediates for new reaction discovery. In particular, the past decade has witnessed remarkable advances in the chemistry of metal vinylidenes and allenylidenes, leading to the evolution of a diverse array of new catalytic transformations that are mechanistically distinct from those developed in the previous two decades. This review aims to provide a survey of the recent achievements in the development of organic reactions that make use of transition metal alkenylidenes as catalytic intermediates and their applications to organic synthesis.

CONTENTS 1. Introduction 2. Stoichiometric Reactions of Unsaturated Carbenes 2.1. Metal-Free Vinylidenes 2.2. Metal Vinylidene Complexes 2.3. Metal Allenylidene Complexes 3. Catalytic Reactions of Metal-Complexed Alkenylidenes: Carbon−Heteroatom Bond Formation 3.1. Anti-Markovnikov Hydrofunctionalization 3.1.1. Acid Nucleophiles 3.1.2. Hydration 3.1.3. Oxygen-Centered Neutral Nucleophiles 3.1.4. Amine, Imine, and Hydrazine Nucleophiles 3.1.5. Thiols, Phosphines, Silanes, and Boranes 3.1.6. Reactions Involving Acyl Complexes 3.2. Atom-Transfer Reactions 3.2.1. Oxygen and Nitrogen Transfer 3.2.2. Hydrogen Transfer 4. Catalytic Reactions of Metal-Complexed Alkenylidenes: Carbon−Carbon Bond Formation 4.1. Nucleophilic Addition 4.1.1. Enols and Enamines 4.1.2. Alkenes and Arenes 4.2. Pericyclic Reactions 4.2.1. Electrocyclization 4.2.2. Cycloaddition 4.2.3. Sigmatropic Rearrangement 4.3. Disubstituted Alkenylidenemetals 4.3.1. Rh− and Re−Alkenylidenes 4.3.2. Au−Alkenylidenes 4.4. Alkyne−Alkyne Coupling © XXXX American Chemical Society

5. Catalytic Reactions of Metal-Complexed Allenylidenes 5.1. Heteroatom Nucleophiles 5.1.1. Oxygen and Phosphorus Nucleophiles 5.1.2. Nitrogen Nucleophiles 5.1.3. Enantioselective Propargylic Substitution with O- and N-Nucleophiles 5.2. Carbon Nucleophiles 5.2.1. Enols and Enamines 5.2.2. Alkenes and Arenes 5.2.3. Other Nucleophiles 6. Conclusion Associated Content Special Issue Paper Author Information Corresponding Author ORCID Notes Biographies Acknowledgments Abbreviations References

A B B D G H H H K N S T U W W Y Z Z Z AB AD AD AE AG AI AI AJ AM

AN AN AN AP AP AR AR AU AW AX AX AX AX AX AX AX AX AY AY AY

1. INTRODUCTION Unsaturated carbenes constitute a class of reactive intermediates whose structures are characterized by the attachment of the carbene center to an unsaturated (sp2 or sp) carbon atom through a π-bond.1 These carbenes, also termed alkenylidenes, are highly unstable and have found limited use in organic synthesis due to the difficulties associated with Received: September 15, 2018

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DOI: 10.1021/acs.chemrev.8b00568 Chem. Rev. XXXX, XXX, XXX−XXX

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contexts. While it is beyond the scope of this review to cover in detail the many facets of metal alkenylidene carbene chemistry, a number of excellent reviews are available. Earlier reviews have covered the chemistry of free1,11−17 and metal-complexed unsaturated carbenes in stoichiometric settings.18−37 Catalysis involving metal alkenylidenes has also been covered by a number of previous reviews, which have focused on specific metal systems,38−40 the transformations enabled by their catalysis such as anti-Markovnikov addition,41 cycloisomerization,42 pericyclic,43 metathesis reactions,44,45 as well as their applications in organic synthesis.46,47 Particularly notable is the book by Bruneau and Dixneuf published in 2008, which comprehensively surveys metal vinylidenes and allenylidenes in catalysis covering the literature of the first two decades since the inception of the field.48 For the catalysis of ruthenium alkenylidenes, an area that has seen the most extensive development, a review by Saá and co-workers covers the literature up to 2013.38 However, considerable advances remain unaddressed, particularly those that culminated in the recent emergence of new catalyst systems, reactions, and applications based on conceptually distinct approaches. This review aims to offer an updated overview on metal alkenylidene-mediated catalysis for use in organic synthesis, highlighting the newest reactions and applications in complex synthetic settings.

access. In contrast, transition metal-complexed unsaturated carbenes are much more stable and may be readily prepared from alkynes via metal activation.2 These metal-complexed carbenes enable geminal functionalization of alkynes in which bond formation takes place at the carbon atom bound to the metal center in contrast with the more common vicinal addition mediated by π-alkynemetals (Scheme 1). Since the Scheme 1. Free and Metal-Complexed Unsaturated Carbenes and Their Access from Alkynes

2. STOICHIOMETRIC REACTIONS OF UNSATURATED CARBENES Free, organic vinylidenes and their corresponding metal complexes share a range of similarities in their reactions from the viewpoint of structural transformations effected. However, vast differences exist in their respective reaction pathways, arising from the coordinative interaction between the carbene ligand and a metal center. Compared with their alkylidene analogs, metal alkenylidenes display a broader spectrum of reactivity due to the two π-systems present in the carbon−carbon and carbon−metal double bonds. As shown in the following archetypal reactions of organic vinylidenes and metal-bound vinylidenes, rich chemistry is manifested in these stoichiometric transformations, some of which have been translated into catalytic settings.

report of the first metal vinylidene species,3,4 a large body of work has been carried out on both metal vinylidene and allenylidene species to reveal their structure, reactivity, and modes of formation. While early studies were focused on stoichiometric systems, recognition of the potential of a metal vinylidene to mediate catalysis changed the initial notion that the carbon−metal double bond might be too stable and devoid of catalytic reactivity. Furthermore, the facile access from alkynes under simple and mild conditions and the feasibility of modulating reactivity by metal templation have rendered the metal alkenylidene an attractive intermediate to target for new reaction discovery. Indeed, remarkable progress has been made over the last three decades, leading to the development of a variety of reactions making use of metal alkenylidenes as catalytic species. In particular, the past decade has witnessed the evolution of a diverse array of new transformations that greatly expand the scope and utility of metal alkenylidenemediated catalysis in organic synthesis to the extent that some of the reactions have been employed as strategic steps in the context of complex organic synthesis. The purpose of this review is to provide a compilation of the recent advances in the chemistry of transition metal unsaturated carbene complexes. With a brief survey of the reactions of free carbenes for comparison with those of their metal-coordinated counterparts, the discussion will focus mainly on the catalytic processes mediated by metal alkenylidene species that have been extensively developed during the past decade. In addressing these processes on the basis of types of reactions and bonds formed therefrom, particular emphasis has been placed on both the mechanistic modalities and the synthetic applications. Propargylic substitution reactions enabled by metal allenylidene-mediated catalysis have been discussed in a separate section, as they share a nearly uniform mode of reactivity.5−10 These restrictions unfortunately leave out a substantial body of early work performed both in organic and in organometallic

2.1. Metal-Free Vinylidenes

Vinylidenes undergo an array of reactions that are typically observed with their saturated analogs, alkylidene carbenes, e.g., insertion to C−H, O−H, and N−H bonds, addition to πbonds, and 1,2-migration. A notable difference in their reactivity is the more pronounced tendency of vinylidenes toward 1,2-migration, which results in the formation of alkynes.17 Vinylidenes exist as a singlet state in which the electron pair occupies an sp-hybridized orbital with an empty perpendicular p-orbital. The simplest vinylidene, :CCH2, is higher in energy than its acetylene tautomer by 44 kcal/mol.49 Computational studies have also shown that this vinylidene constitutes a local minimum of the energy surface, where there is an approximately 3 kcal/mol energy barrier to return to acetylene (Scheme 2).50 In sharp contrast, transition-metal-bound vinylidenes, depending on the nature of metal and ligand, can be more stable than metal η2-alkynes. For example, isomerization of RuCl2(PH3)2(η2-HCCH) to RuCl2(PH3)2(CCH2) was calculated to be exothermic with an energy change of 19 kcal/ mol.51 B


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concerted reaction pathway for the insertion process of vinylidenes. The C−H insertion of vinylidenes effecting stereospecific alkenylation renders this chemistry a powerful tool for use in complex total synthesis. For example, the site-selective C−H insertion of vinylidene 10 generated from the reaction of ketone 9 with lithiated diazotrimethylsilylmethane led to efficient construction of a bridgehead, quaternary stereocenter of the key intermediate 11 en route to platensimycin (Scheme 5).57,58

Scheme 2. Vinylidene−Acetylene Tautomerization in the Absence or Presence of a Transition Metal

Alkyl substitution is believed to increase the half-life of vinylidenes, permitting the carbene to engage in reactions other than 1,2-migration. The first example of such a reaction was reported in 1977 by Dreiding and co-workers. Flash vacuum pyrolysis (FVP) of cyclohexene oxide 1 produced a number of rearrangement products among which the peculiar bicyclic compound 2 was isolated in 2% yield (Scheme 3a).52

Scheme 5. Vinylidene C−H Insertion Reaction En Route to Platensimycin

Scheme 3. Flash Vacuum Pyrolysis (FVP) of Ynones and C−H Insertions of Vinylidenes

Vinylidenes readily engage in [2 + 1] cycloaddition with a tethered π-bond. Through a cascade of reactions involving a sequence of ring opening, extrusion of dinitrogen and styrene, and rearrangement, vinylidene 15 was produced from αepoxyhydrazone 13 under toluene reflux. The resultant vinylidene added to an alkene to give the highly strained cyclopropane 16 which was rapidly converted to trimethylenemethane (TMM) diyl radical 17. Subsequently, [3 + 2] cycloaddition of the diyl radical with the remaining alkene ensued, affording the tricyclic core 14 of triquinanes (Scheme 6).59

For the origin of bicycle 2, cyclohexene oxide 1 was postulated to undergo rearrangement to ynone 3 (X = H). It was demonstrated that ynone 3 was indeed the intermediate leading to the formation of bicyclo[3.3.0]octane 5 presumably via C−H insertion of a vinylidene.53 It was also observed that the cyclopentenone product could be generated from the reactions of deuterium-labeled (X = D) and trimethylsilylsubstituted (X = TMS) alkynes (Scheme 3b). The migration of deuterium and silicon is most likely to be a consequence of the involvement of a vinylidene intermediate, and this 1,2migration has long been used as a mechanistic probe in vinylidene chemistry. Access to vinylidenes is efficiently achieved through the reactions accompanying extrusion of dinitrogen that compensates for the energy required to generate these highly reactive intermediates. When methyl ketone 6 was exposed to Seyferth−Gilbert conditions,54,55 cyclopentene 8 was produced in good yield with excellent enantiospecificity (Scheme 4).56 The reaction occurs through C−H insertion of a vinylidene intermediate generated from diazoalkene 7 with extrusion of nitrogen. The retention of stereochemistry indicates a

Scheme 6. Sequential [2 + 1]/[3 + 2] Cycloaddition Reactions of Vinylidenes

Scheme 4. Retention of Stereochemistry in C−H Insertion Reactions of Vinylidenes Vinylidenes can be generated through 1,1-elimination of 1metallo-1-halo-alkenes.13 It was this α-elimination making use of the acidity of an alkenyl hydrogen that produced the requisite vinylidene intermediate in Taber’s total synthesis of (−)-morphine (Scheme 7).60 Upon treatment with KHMDS, alkenyl bromide 18 went through a sequence of α-elimination and benzylic C−H insertion of the resultant vinylidene 21 to C


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Scheme 7. Vinylidene Generation via 1,1-Elimination from Alkenyl Halides

afford the cis-fused cyclopentene 19 with exclusive diastereoselectivity. An interesting example of O−Si insertion was observed when a vinylidene was formed in close proximity to a silylether (Scheme 8).61 Addition of a sulfinate to alkynyliodonium(III) Scheme 8. Formal O−Si Insertion of Vinylidenes Figure 1. Simplified description of frontier molecular orbitals for d8metal vinylidene complex.

coordination, many diverse types of reactions are observed with the metal vinylidene complexes, not limited to those based on electrophilicity. Transition metal vinylidene complexes can be accessed from a wide variety of organometallic species such as metal π-alkyne, σ-alkynyl, carbyne, and acyl complexes. Discussed in this section are a series of archetypal reactions that have been well established with stoichiometric metal-complexed vinylidene systems. This brief survey will serve to highlight the reactivity of metal-complexed vinylidenes and underline points of contrast with their metal-free counterparts. The most general way to access metal vinylidenes is through isomerization of π-alkyne complexes derived from terminal alkynes (Scheme 9). In the conversion of mononuclear η2complex 27 to vinylidene η1-complex 29, three pathways have been known to play varying roles depending on the nature of the metal center and ligand. For midtransition metals, e.g., Mn(I),63 and Ru(II),51,64,65 a mechanism involving direct 1,2-

22 induced elimination of iodobenzene to give rise to dihydrofuran 23 as the major product. As established well by a series of early studies on the reactions of alkynyliodonium(III) salts,11,14 vinylidene 25 is the likely intermediate in this formal O−Si insertion process. It has been proposed that direct addition of the ether oxygen to the carbene center gives the zwitterionic intermediate 26, which undergoes Stevenstype 1,2-rearrangement to furnish 2-silyl-3-sulfonyldihydrofuran 23. 2.2. Metal Vinylidene Complexes

While the ability to react with a silyl ether attests to the strong electrophilic character of an organic vinylidene, the high reactivity is significantly mitigated upon coordination with transition metals. As predicted by the MO model for the bonding with a metal, the singlet vinylidene serves as a ligand capable of both σ-donating and π-accepting, leading to significant stabilization of the carbene center. According to simple frontier orbital analysis, about 25% of the HOMO (π3) is localized on the β-carbon atom whereas the π-antibonding orbital, an energetically isolated LUMO (π4), is about 60% localized on the α-carbon of the vinylidene ligand (Figure 1).62 On the basis of this MO profile, it is expected that nucleophilic addition will occur at the α-carbon atom of the metal vinylidene while electrophiles will react with the β-carbon atom. Owing to the electronic balance available upon

Scheme 9. General Mechanisms for the Formation of Metal Vinylidene Complexes

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deprotonation. Upon increasing the temperature, the resultant allyl vinyl ether 40 underwent Claisen rearrangement, giving acyliron complex 41 in good yield.77 While addition of oxygen nucleophiles is most common, nitrogen nucleophiles have also been known to attack the αcarbon of vinylidene complexes. In a study with tungsten complex 42, pyrrolidine and other related amine nucleophiles were found to be capable of undergoing such an addition process to give rise to the aminocarbene complexes such as pyrrolidinylcarbene 43 (Scheme 12a).78 Interestingly, addition

hydrogen shift has been suggested, which is induced by agostic interaction between the metal center and the alkynyl C−H bond (cf. 28). On the other hand, metal−hydrido complex 30 formed via oxidative addition can be an intermediate en route to the vinylidene complex. In this stepwise pathway likely to be operative with late transition metals, e.g., Rh(I),66,67 Ir(I),68 and Co(I),69 1,3-hydrogen shift may occur through an inter-67 or intramolecular70,71 mechanism. A two-step process involving a metal alkenyl intermediate (cf. 31) is also feasible for the generation of a metal vinylidene. In this case, the alkenylmetal species arising from hydrometalation is converted to the metal vinylidene via α-hydrogen elimination.72−74 As predicted by the MO model and paralleled in metal-free organic vinylidenes, nucleophilic addition to the α-carbon of metal vinylidene has been observed with a number of complexes. For example, [CpRu(PPh3)2(CCHPh)]PF6 (32) undergoes hydroalkoxylation with methanol, providing Fischer carbene 33 as the product (Scheme 10a). Similarly,

Scheme 12. Addition of Nitrogen Nucleophiles to Metal Vinylidene Complexes

Scheme 10. Addition of Oxygen Nucleophiles to Metal Vinylidene Complexes

of dimethylhydrazine to iron vinylidene 44 generated acetonitrile complex 45 (Scheme 12b).79 It is proposed that subsequent to the formation of Fischer carbene 46 via hydrazine addition, a sequence of proton shuffling and N−N bond cleavage gives rise to dimethylamine and acetonitrile complex 45. It is worthy of note that in this process the αcarbon of the vinylidene is oxidized by hydrazine, while the oxidation state of the metal center remains unchanged. A distinct feature of the reactivity of transition metal vinylidenes vis-à-vis metal-free unsaturated carbenes is that both the metal−carbon and carbon−carbon double bonds can participate in cycloaddition processes. Upon coordination of allyldiphenylphosphine, indenylruthenium 48 was rapidly converted to ruthenacycle 49 via [2 + 2] cycloaddition (Scheme 13a).80 Noteworthy is the facility with which the two alkenes participate in this thermally forbidden process. As noted in analogous reactions of allenes, 81 electronic perturbation brought about by metal coordination may be responsible for the enhanced reactivity of the π-system. When coordinative vacancy is generated at the metal center, the [2 + 2] cycloaddition can also involve the metal−carbon double bond as shown in the formation of titanacyclobutane 52 (Scheme 13b).82 Titanium vinylidene 51 is proposed as an intermediate, which is produced from the geminal-dimetallic alkene 50 through elimination of AlMe2Cl induced by HMPA. The [2 + 1] cycloaddition, a type of reactivity commonly displayed by carbenoid intermediates, is also observed with metal vinylidene complexes. When reacted with diiron nonacarbonyl (53), the 14-membered silacycle 54 was converted to methylenecyclopropene complex 55 (Scheme 14).83 In this novel transannular process, the two alkynes

addition of water to complex 32 resulted in the formation of acylruthenium intermediate 34, which, upon subsequent decarbonylation, gave ruthenium carbonyl 35.75 When the more electron-deficient complex 36 was subjected to the same hydration conditions, acyl complex 37 could be isolated without decarbonylation (Scheme 10b).76 The Fischer carbene emanating from a metal vinylidene can engage in further reactions (Scheme 11). Addition of an allylic alcohol to vinylideneiron complex 38 produced Fischer carbene 39, which was converted into alkenyliron 40 by Scheme 11. Claisen Rearrangement of a Fischer Carbene Derived from an Iron Vinylidene

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Scheme 13. Cycloaddition Reactions Involving CαCβ and MCα Double Bonds

Scheme 15. Electrocyclization of Metal Vinylidenes and Subsequent [4 + 2] Cycloaddition

Scheme 14. [2 + 1] Cycloaddition of Metal Vinylidenes

Scheme 16. Disubstituted Alkenylidenemetals from Alkynylmetals

embedded within the ring system engage one another upon metal complexation. By analogy with a related Mn(II) case, which led to isolation of a manganese alkenylidene species,84 it has been proposed that silyl 1,2-migration of the initial πcomplex 56 generates iron vinylidene 57, which then undergoes a [2 + 1] cycloaddition with the transannular alkyne. In studies on the reactions involving stoichiometric metalbound vinylidene systems, tungsten and related Group 6 transition metals have been most widely employed. One interesting example employing a tungsten carbonyl complex showed that Fischer carbene 60 could be prepared through cyclization of arylalkyne 58, which was effected by the reaction between the α-carbon of vinylidene 59 and the intramolecular ketone oxygen (Scheme 15).85,86 While this C−O bondforming ring closure proceeded presumably via 6π-electrocyclization, the transiently dearomatized tungsten carbene 60 was found to be capable of undergoing [4 + 2] cycloaddition with the electron-rich alkenes to produce naphthalene derivatives 62 and 64 after subsequent processes involving a retro-Diels−Alder reaction. Metal vinylidene complexes can arise from alkynylmetal species through bond formation at the β-carbon. While protonation of the β-carbon of metal alkynyl σ-complexes or protonation at the metal center followed by 1,3-shift is prevalent, examples have also been reported in which the generation of a metal-bound vinylidene is accompanied by C− C bond formation (Scheme 16). Tungsten alkynyl complex 65 reacts with benzaldehyde in the presence of a Lewis acid, giving metal alkenylidene complex 68 through a carbonyl addition process. The resulting vinylidene 68 undergoes cyclization with the intramolecular alcohol and elimination to

give Fischer carbene 70, which participates in an array of reactions such as Grignard addition and hydrolysis.87 In addition to aldehydes, other electrophiles can be applied in initial C−C bond-forming step such as acetals,88 oxiranes,89,90 aziridines,91 and N-acyl iminium ions.92 Nitrogen nucleophiles, instead of alcohols, can also trap metal vinylidene intermediates such as 68.93 These methods have been applied to syntheses of a number of lactone natural products such as (+)-blastmycinone, (−)-litsenolide C1, (−)-epilitsenolide C2, and (−)-isodihydromahubanolide B.94,95 The SN2-type displacement of alkyl halides by metal alkynyl complexes is among the most straightforward means to access disubstituted alkenylidene complexes. For example, ruthenium complex 71 gave rise to ruthenium alkynyl complex 72 on treatment with basic alumina, which slowly cyclized to disubstituted alkenylidene complex 73 (Scheme 17).96 A number of intermolecular variants were reported in stoichioScheme 17. Disubstituted Alkenylidenemetals via Intramolecular Substitution Reaction

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Scheme 20. Nucleophilic Addition to α- and γ-Carbon in Metal Allenylidenes

metric reactions using more activated electrophiles (e.g., methyl iodide, ethyl iodide,96 methyl triflate,97 methyl fluorosulfonate,98 and iodoacetonitrile99). Recent studies have shown that 1,2-migration of a carbon substituent is a viable pathway to access disubstituted alkenylidene complexes from internal alkynes (Scheme 18).100−110 For example, Cp*−Ir complex 74 reacts with Scheme 18. Disubstituted Alkenylidenemetals via 1,2Carbon Migration

lectivity was noted in the reactions of trimethylindenylruthenium allenylidene 84. While the reaction with methanol gave Fischer carbene 85 through an α-addition, the γ-addition was the dominant pathway when sodium methoxide was employed as the nucleophile, affording alkynylruthenium 86 (Scheme 20b).114 Due to the presence of two electrophilic centers, metal allenylidenes can engage in multiple reactions with nucleophiles. Examples based on this line of reactivity often employ ambident nucleophiles, thus effecting ring closure. When Nhydroxymethylamine was added to tungsten allenylidene 87, cyclic Fischer carbene 88 was produced (Scheme 21a).115 In

propiolate 75 to afford alkenyliridium 76 on exchange of one chloride ligand with a noncoordinating anion.110 The more electron-withdrawing substituent, the carbethoxy group in this case, has higher migratory aptitude during the formation of the β,β-disubstituted alkenylidenemetal.103−108 Subsequently, iridium alkenylidene 78 is proposed to undergo α-migration or external attack of a chloride to the alkenylidene center to furnish iridacycle 76. 2.3. Metal Allenylidene Complexes

Allenylidene, :CCCH2, is a homologated variant of vinylidene, belonging to the class of unsaturated carbenes termed cumulenylidenes, :C(C)nCH2. Metal allenylidenes can be readily prepared from propargylic alcohols via metal vinylidene intermediates.111 For example, dehydration from ruthenium vinylidene 80 results in the allenylidene complex 81 (Scheme 19).112

Scheme 21. Tandem α- and γ-Addition to Metal Allenylidenes

Scheme 19. Preparation of Allenylidene Complexes from Propargyl Alcohols

Metal allenylidene complexes exhibit a pattern of reactivity similar to that of metal vinylidene complexes, which is governed by partial positive and negative characters of the αand β-carbons, respectively. Additional electrophilic reactivity is manifested at the γ-carbon atom as expected from the resonance contribution of a propargylic cation within the structure of a metal alkynyl complex. Therefore, nucleophilic addition can take place at both the α- and the γ-positions of allenylidene complexes. It has been found that the selectivity between α- and γ-addition depends on the nature of the metal complex as well as the nucleophile employed. For example, ruthenium allenylidene 81 produced a mixture of α-adduct 82 and γ-adduct 83 upon treatment with a lithium acetylide nucleophile (Scheme 20a).113 By contrast, exclusive regiose-

another example employing ruthenium allenylidene 81, treatment with an acetone enolate led to C−C bond formation at the γ-carbon to give rise to alkynylruthenium 89, which, upon protonation, was converted to dihydropyran 91 via cyclization of ruthenium vinylidene 90 (Scheme 21b).113 As noted in the reactions of metal-complexed vinylidenes, the cumulated π-systems of allenylidene complexes lend G


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themselves to cycloaddition. In an early example employing rhodium allenylidene 92, the MCα bond was found to engage in a facile reaction with phenylacetylene (Scheme 22).116 In this process giving alkenylidene π-allyl complex 94

Scheme 25. Ruthenium Allenylidenes as Metathesis Catalyst Precursor

Scheme 22. [2 + 2] Cycloaddition of MCα Bond

as the product, rhodacyclobutene 93 is proposed to be the intermediate, which arises from [2 + 2] cycloaddition and then undergoes rearrangement via migration of the phosphine ligand. Flanked by two π-systems, the CαCβ bond can undergo [2 + 2] cycloaddition with a tethered alkene in an analogous manner to that of vinylidene complexes. The reaction of ruthenium complex 95 with diphenylpropargyl alcohol in refluxing THF furnished cycloadduct 97 (Scheme 23).117

dealing with the chemistry of metal allenylidenes in metathesis reactions.38,44−46 From a structural vantage point, metal allenylidenes can be considered as “extended” metal vinylidenes. However, the crucial difference lies in the unique ability of metal allenylidenes to mediate nucleophile addition at the γ-position. This reactivity along with facile access to metal allenylidene complexes from propargylic alcohol derivatives has been translated into the development of catalytic propargylic substitution reactions, which will be discussed in section 5. Catalysis effecting the reactions at the α-carbon, though mediated by a metal allenylidene species, will be presented alongside catalysis involving metal vinylidenes in order to highlight the underlying mechanism shared by these metal complexes.

Scheme 23. [2 + 2] Cycloaddition of CαCβ Bond

When the reaction was performed in DCM solvent, ruthenium allenylidene 96 was produced without cyclization. Subsequent refluxing of this allenylidene complex in THF resulted in the formation of the same cyclobutane 97, supporting the mechanism involving [2 + 2] cycloaddition of a ruthenium allenylidene intermediate. The CβCγ bond of metal allenylidene complexes has also been shown to be a competent participant in cycloaddition. For example, when ruthenium allenylidene 81 was treated with excess isoprene, a Diels−Alder reaction took place slowly to give [4 + 2] cycloadduct 98 in excellent yield (Scheme 24).118 Overall, every unsaturation on the metal allenylidene framework has been shown to possess the potential to undergo a cycloaddition reaction.

3. CATALYTIC REACTIONS OF METAL-COMPLEXED ALKENYLIDENES: CARBON−HETEROATOM BOND FORMATION 3.1. Anti-Markovnikov Hydrofunctionalization

3.1.1. Acid Nucleophiles. Among the diverse reactions observed with stoichiometric metal vinylidene complexes, most notable is the process involving addition of heteroatom nucleophiles. It is this reactivity, based upon the electrophilicity of the α-carbon, that has been first translated into catalysis. In 1986, Dixneuf and Sasaki reported the rutheniumcatalyzed anti-Markovnikov addition of carbamic acids to terminal alkynes (Scheme 26).124 In this seminal report, a mechanism involving a transition metal vinylidene as a catalytic intermediate was proposed for the novel reaction that generated alkenyl carbamates from terminal alkynes, amines, and carbon dioxide with high anti-Markovnikov selectivity. The proposed catalytic cycle of the three-component coupling reaction starts with reversible formation of ruthenium vinylidene 108 from 1-hexyne (106). Subsequent to the nucleophilic addition of the in situ generated N,Ndiethylcarbamate at the α-carbon, protonation of the resulting alkenylruthenium 109 and 110 yields the carbamate product 107 with anti-Markovnikov selectivity while regenerating the ruthenium catalyst. Although the yield and E/Z selectivity were rather low, the reaction demonstrated the possibility of utilizing a metal vinylidene as a catalytic intermediate.

Scheme 24. [4 + 2] Cycloaddition of CβCγ Bond

The group of Fürstner and Dixneuf has demonstrated that allenylidene ruthenium 100 (X = PF6) could serve as a metathesis precatalyst,119 which was later proved to be more effective with a triflate counteranion (X = OTf) (Scheme 25).120,121 Mechanistic studies have revealed the catalytic species to be 14-electron ruthenium carbene 104, which is generated through a sequence involving intramolecular Friedel−Crafts-type cyclization, cymene dissociation, and metathesis with 99.122,123 Several reviews have been published H


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Scheme 26. First Metal Vinylidene-Mediated Catalysis: The Dixneuf Reaction

Scheme 27. Anti-Markovnikov Addition of Carboxylic Acids to Terminal Alkynes

half-sandwich complexes ligated with a Cp, Tp, or p-cymene group, as well as NHC and cationic complexes (Chart 1).134−142 The reaction also found applications in the context of lactonization135 and dienyl ester synthesis for use as monomers in atom transfer radical polymerization (ATRP) processes.142 Chart 1. Ruthenium-Based Catalysts for Hydrocarboxylation

On examination of the mechanism, the stereochemistry of the alkenylruthenium species arising from the nucleophilic addition to the vinylidene complex is expected to favor an (E)configuration on steric grounds; the sterically more demanding carbon−ruthenium bond is preferentially positioned anti to the butyl chain. Upon stereoretentive protodemetalation (or reductive elimination via a metal hydride), the (E)-organometallic intermediate (cf. 109) is transformed into a (Z)alkenyl carbamate product. The preference for the (Z)-alkene formation serves as a primary indicator for the metal vinylidene mechanism along with the anti-Markovnikov regioselectivity and has been frequently observed in hydrofunctionalization of terminal alkynes with heteroatom nucleophiles. The Dixneuf group further probed an array of mononuclear ruthenium complexes for their effectiveness as catalysts. Among the various ruthenium complexes examined were RuCl3·3H2O,125 RuCl2(pyr)2(nbd), RuCl2(CH3CN)(p-cymene), [RuCl(CH3CN)2(p-cymene)]BF4, RuCl2(PMe3)(p-cymene), and RuCl2(PMe3)(C6Me6),126,127 with the last complex derived from hexamethylbenzene to be most effective. A ruthenium catalyst complexed with a P,P-ligand, such as (η3-2methylallyl)2Ru(dppe), was also found to be potent for the three-component coupling.128 Recently, improvements have been made using supercritical CO2 or a ruthenium(arene)(dppe)-type catalyst.129,130 The anti-Markovnikov hydrofunctionalization of terminal alkynes has also been reported using carboxylic acids. While a literature example of this reaction dates back to 1983,131 welldefined ruthenium systems operating through vinylidenemediated catalysis have led the way to major development in this area. Compared with the carbamate addition, the reaction with carboxylic acids may be carried out under milder conditions with a broader reaction scope. In an early example employing a Ru(dppb) catalyst, a variety of structurally diverse alkyl-, aryl-, and silylacetylenes underwent the coupling reaction with alkyl-, alkenyl-, and arylcarboxylic acids to afford alkenyl carboxylates 111 with predominantly (Z)-selectivity (Scheme 27).132,133 A number of ruthenium catalyst systems have since been developed for this process. Examples include ruthenium−arene

The extension of the reaction to propargylic alcohol substrates led to formation of formal Meyer−Schuster rearrangement products (Scheme 28). Addition of benzoic Scheme 28. Anti-Markovnikov Addition of Carboxylic Acids to Propargyl Alcohols

acid to propargyl alcohol 120 under ruthenium catalysis gave alkenyl benzoate 121, which was then promptly converted to enal 122 upon treatment with an acid.143 The synthesis of enals can be accomplished in a single operation by running the ruthenium-catalyzed reaction at elevated temperatures.144 In addition to the ruthenium complexes, catalyst systems based on rhodium have also been used in the hydrocarboxylation of terminal alkynes. Breit and co-workers reported a rhodium species, complexed with P,N-ligand 123, to be highly efficient in promoting the coupling of carboxylic acids and terminal alkynes (Scheme 29).145 Both high yields I


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limited to terminal alkynes. In a recent report, the reaction of alkynyliodonium(III) 128 with benzoic acid in the presence of a Pd(II) catalyst resulted in 1,1-addition of the acid to the alkyne with concomitant 1,2-shift of the iodine(III) group (Scheme 31).149 It has been proposed that the reaction takes

Scheme 29. Rhodium-Catalyzed Hydrocarboxylation of Terminal Alkynes

Scheme 31. Hydrocarboxylation of Alkynyliodoniums through 1,2-Iodine(III) Shift

and excellent (Z)-selectivity were attained with a wide variety of substrates including sterically demanding tert-butylacetylene. More recently, the characterization of the active catalytic species has been performed through a series of mechanistic studies, which led to the identification of a more reactive catalyst system that completed the reaction with a much faster rate.146 When combined with asymmetric hydroformylation, the rhodium-catalyzed hydrocarboxylation with high (Z)- and antiMarkovnikov selectivity provides expeditious access to enantioenriched α-hydroxyaldehyde from terminal alkynes. In the total synthesis of (+)-patulolide C by Risi and Burke, hydroformylation of (Z)-alkenyl acetate 125, obtained from terminal alkyne 124, gave aldehyde 126 which was then subjected to a sequence of Wittig and macrolactonization reactions (Scheme 30).147 Similar strategies, making use of ruthenium catalysis for the enol acetate synthesis, have been applied to the syntheses of (+)-decarestrictine L and (−)-pyrenophorol.148 The hydrocarboxylation via metal vinylidene-mediated catalysis may be carried out with disubstituted alkynes, not

place through the catalytic cycle involving generation of palladium vinylidene 131 via 1,2-shift of the iodine(III) group, migration of the carboxylate ligand on the palladium center to the α-carbon, and protodepalladation of the resulting alkenylpalladium 132. Notable in this reaction is the utilization of a palladium catalyst and 1,2-shift of an iodine(III) group in the generation of a metal-bound vinylidene, both of which constitute a rare example. The anti-Markovnikov hydrofunctionalization of terminal alkynes has been extended to amides and related nitrogen nucleophiles. Under the catalysis of a ruthenium methallyl complex, the addition of primary amides 133 to alkynes furnished (Z)-vinylamides 134 as products (Scheme 32a).150 For efficient conversion, ytterbium(III) triflate was required as a cocatalyst. It is proposed that the Lewis acid additive renders the amide hydrogen more acidic, promoting facile protonation and removal of the methallyl group from the ruthenium center, to which the amide nucleophile coordinates. The reaction gave (Z)-vinylamide 134 as the kinetic product with a Z/E ratio of up to 40:1, which was reversed to 1:20 upon thermal isomerization. The Ru/Yb bimetallic system was also applicable to secondary amide nucleophiles, giving the products with (Z)-selectivity.151 It was found that RuCl3 could be conveniently used as a precatalyst for this reaction.152 Interestingly, when tributylphosphine was used as the ligand instead of bis(dicyclohexylphosphino)methane, (E)-vinylamides 137 were obtained as the major products (Scheme 32b).153 The formation of vinylamide products with (E)selectivity was also noted in the reactions with imide 138 (Scheme 32c) and thioamide 140 (Scheme 32d).154,155 The Goossen group performed comprehensive experimental and in silico mechanistic studies to suggest a catalytic cycle for the formation of vinyl amides, consisting of a series of steps mediated by ruthenium hydride species. (Scheme 32e).74 In

Scheme 30. Application of (Z)-Selective Hydrocarboxylation in Target-Oriented Synthesis

J


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Scheme 32. Ruthenium-Catalyzed Anti-Markovnikov Addition Reactions of Various Amide Derivatives

the initial phase of the proposed catalytic cycle, alkyne 106 forms π-complex 145 with the octahedral hydrido complex 144 generated from oxidative addition to the N−H bond. Subsequently, tandem β-insertion and α-elimination processes involving ruthenium hydride species convert the η2-alkyne to η1-vinylidene complex 147. This isomerization, known to be a pathway to metal vinylidenes, seems more likely with acidic nucleophiles and may be promoted by exchange of the ancillary ligands PBu3 and DMAP. Finally, migration of the amide ligand to the vinylidene center followed by C−H reductive elimination provides vinyl amide product 150. In this last stage, the formation of a C−N bond occurs through migration of the amide group anti to the butyl chain, in contrast to the hydrocarboxylation where the C−O bond is formed with syn selectivity. A similar N-alkenylation of γlactam 143 has also been shown to be feasible using a rhenium catalyst (Scheme 33).156

Scheme 34. Ruthenium-Catalyzed Intramolecular AntiMarkovnikov Addition Using Amides

The nitrogen atom of a carbamate is also capable of undergoing nucleophilic addition to a ruthenium vinylidene. Haak reported formation of α,β-unsaturated imines from the reaction of propargylic alcohol 155 and isocyanates, in which the in situ generated carbamate acted as an N-nucleophile (Scheme 35).158 After intramolecular addition of the carbamate to ruthenium vinylidene 158, decarboxylation and protodemetalation gives N-phenylimine 157. In contrast, when performed with boron trifluoride, the ruthenium-catalyzed reaction of 3-methyl-1-butyn-3-ol (120) with phenylisocyanate furnished allene 161 presumably via 162 that arose from addition of the carbonyl oxygen to a ruthenium vinylidene intermediate (cf. 158).159 3.1.2. Hydration. Despite its readily conceivable synthetic potential, the anti-Markovnikov addition of water to terminal alkynes had long been elusive. In 1998, Wakatsuki and Tokunaga reported the first example of a catalytic hydration process (Scheme 36).160 In the presence of a complex derived from an arene−ruthenium and an electron-deficient phosphine, the reaction of terminal alkynes with water gave aldehydes 163 as the major product along with methyl ketone 165 and alkene 170 as minor products (vide infra). Through a continuing study, the same group identified a Cp-bound ruthenium species complexed with a dppm ligand to be an excellent catalyst for the hydration reaction, affording the aldehyde

Scheme 33. Rhenium-Catalyzed Anti-Markovnikov Addition of Lactams

The anti-Markovnikov addition of amide nucleophiles to terminal alkynes has been practiced intramolecularly to give rise to cyclic enamides (Scheme 34).157 Treatment of amide and sulfonamide 153 with a Cp−Ru catalyst in pyridine led to 6-endo ring closure, affording the cyclic amides 154, presumably through a Dixneuf-type mechanism involving direct N-addition to the α-carbon of the ruthenium vinylidene intermediate. K


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Scheme 35. N-Alkenylcarbamate Intermediate in Ruthenium Vinylidene Catalysis

be responsible for the production of the alkene byproduct 170 via β-hydride elimination. As seen in the metal vinylidene-mediated hydrocarboxylation−hydrolysis, anti-Markovnikov hydration of propargylic alcohols produces α,β-unsaturated aldehydes (Scheme 37a).162,163 While this Meyer−Schuster rearrangement may Scheme 37. Anti-Markovnikov Hydration of Propargyl Alcohols

occur through a hydration−dehydration sequence mediated by a metal vinylidene, an alternative dehydration−hydration pathway involving a metal allenylidene species is also possible. The cationic dinuclear complex 175 possessing a thiolate bridge was also found to be effective in catalyzing the propargyl alcohol to enal transformation (Scheme 37b).164 The reaction could be performed without external water, and α,βunsaturated ketone 176 was obtained after aldol condensation of the initial enal products with acetone solvent. Significant advances in anti-Markovnikov alkyne hydration have come from the use of custom-made catalysts (Scheme 38).165−178 Most of the tailored catalysts were developed by

Scheme 36. Anti-Markovnikov Hydration of Terminal Alkynes

Scheme 38. Ligands Used for Ruthenium-Catalyzed Hydration

products in significantly higher yield (81−94%) from a range of alkyl- and aryl-substituted terminal alkynes.161 The proposed mechanism involves a variety of processes mediated by ruthenium complexes, in which the methyl ketone byproduct 165 arises from a competing Markovnikov addition of water to π-complex 164 while ruthenium vinylidene 166 existing in equilibrium with 164 leads to the anti-Markovnikov hydration pathway. In a more detailed mechanistic study carried out with calculations and labeling experiments, it was proposed that the conversion of η2-alkyne to η1-vinylidene complex might involve an alkenylruthenium(IV) species (cf. 171) which could be formed via protonation of 164 and underwent α-hydrogen elimination.73 Following addition of water and tautomerization of the resultant Fischer carbene 167 to ruthenium acyl complex 168, reductive elimination gives the aldehyde product 163. The acyl intermediate can also undergo decarbonylation, providing carbonyl complex 169 which may

replacing one or two phosphine ligands with nitrogencontaining ligands for the Cp−ruthenium(II) center. The evolution of effective catalyst systems began with the use of P,N-type ligands. Marked rate enhancement was noted in the reactions employing pyridylphosphines 177 and 178165 and the related imidazole ligand 181.166 With a ruthenium catalyst derived from ligand 178, terminal alkynes were cleanly hydrated within 3 h to give the aldehyde products with the ratio of aldehyde to methyl ketone products reaching up to 10 000 to 1. The self-assembled ligand 183 also displayed comparable efficiency and selectivity.167,168 An interesting aspect of this paired system is that the catalyst with heteroleptic ligands is superior to the homoleptic catalyst composed of only single-type ligands; the reactions using L


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either the pyridylphosphine or benzopyridonylphosphine resulted in compromised yield and selectivity. To explain the efficiency of the P,N-ligands, it has been suggested by the Grotjahn group based on computational studies that the ligand might play an additional role as a general acid−base catalyst (Scheme 39).169,170 The nitrogen

Scheme 41. CpRu−AZARYPHOS-Catalyzed Hydration of Terminal Alkynes

Scheme 39. Role of Nitrogen Heterocycles in Alkyne Hydration

The catalytic hydration reaction could be carried out with various alkyl (cf. 194) and arylalkynes (cf. 195), including steroidal 197 and peptidyl substrates 198 bearing additional functional groups. In addition to P,N-ligands, N,N-ligands have also proved highly efficient in the ruthenium-catalyzed alkyne hydration. In particular, the ruthenium catalyst complexed with electrondeficient bipyridine 199 catalyzed the reaction at ambient temperature (Scheme 42).179 The catalyst system composed of

atom of the ligand assists conversion of the initial alkyne πcomplex 184 to vinylidene complex 186 via alkynyl σ-complex 185, through deprotonation and reprotonation (depicted in red). Subsequently, analogous proton shuttling facilitates both the water addition (depicted in blue) and tautomerization (depicted in green). Recently, yet more elaborate P,N-type ligands 179 and 180 called AZARYPHOS (aza−aryl−phosphane) have been reported as efficient catalyst systems for the hydration of terminal alkynes.171,172 Employing AZARYPHOS ligands, the ruthenium-catalyzed hydration of (homo)propargylic alcohols and propargylic amines gave rise to β-hydroxy-,173 γhydroxy-,174 and β-aminoaldehyde175 derivatives. For example, hydration reaction of propargyl amine 192, obtained from acetylide addition to imine 190, gave β-aminoaldehyde product 193 in the presence of a Cp−Ru−naphthalene precatalyst and AZARYPHOS ligand 180 (Scheme 40).

Scheme 42. Hydration of Terminal Alkyne at Ambient Temperature

a Cp−Ru complex and ligand 199 was found to be amenable for performing hydration−reductive amination and hydration− oxidation tandem reactions without isolating the aldehyde.180 The electronic nature of bipyridine ligands was found to exert a great influence on the reactivity of the ruthenium complex. For example, the ruthenium complex ligated with 1,1′-bipyridine not only catalyzed the alkyne hydration but also promoted hydrogenation of the resulting aldehyde in the presence of formic acid, thus providing alcohol product 203 (Scheme 43).178 Noteworthy is the large discrepancy between the rates of each step to the degree that little or no reduction takes place prior to the completion of the hydration step. The temporal separation of the two steps, both mediated by a single catalyst, allowed interception of aldehyde intermediate 202 by the stabilized Wittig reagent 204. In this case, hydrogenation reaction occurred at the conjugated alkene, giving the threecomponent coupling product 206 in excellent yield. A specialized catalyst with an N,N,N-type ligand was found to be potent for the tandem alkyne hydration and carbonyl reduction (Scheme 44).181 The hemilability of the pendent amine ligand of 207 plays critical roles: upon protonation, it creates a vacant coordination site to set the vinylidene catalysis in motion and acts as an activator of formic acid to produce the formate complex 208 and enhance the catalytic performance in the second step. Thus, the overall reaction could take place under mild conditions, typically at ambient temperature.

Scheme 40. Synthesis of β-Aminoaldehyde through Imine Alkynylation/Alkyne Hydration

Thus, with aldehyde or imine substrates, the sequence of acetylide addition and hydration serves as an effective surrogate for the aldol or Mannich reaction of acetaldehyde, a difficult process to perform using an enolate anion as a nucleophile. It has been found that in situ ligand exchange is feasible, allowing convenient procedures to be applied using commercial CpRu(PPh3)2Cl as the ruthenium source (Scheme 41).176 M


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Scheme 43. Tandem Hydration/Transfer Hydrogenation Reactions Using a Single Catalyst

Scheme 45. Application of Tandem Alkyne Hydration/ Transfer Hydrogenation

Scheme 44. Tandem Hydration/Transfer Hydrogenation at Ambient Temperature

Scheme 46. Intramolecular Addition of Alcohols

tested, molybdenum was most effective, although the turnover numbers were low. When the reactions were carried out in the presence of Bu3SnOTf, 2-stannylated dihydrofuran 216 was produced, indicating the feasibility of intercepting the Fischer carbene intermediate with an electrophile other than proton.185 The alkynol cyclization was extended to include 1-butyn-3,4diol substrates (Scheme 47).186 In this reaction catalyzed by

The anti-Markovnikov alkyne hydration engendering a polar functional group from the nonpolar C−C triple bond via mild catalysis is strategically attractive in the context of complex total synthesis. In the total synthesis of (+)-batzelladine B, the anchoring alcohol of the eastern fragment was masked as a terminal alkyne. The ruthenium-catalyzed hydration−reduction reaction performed at room temperature revealed the primary alcohol, while the preceding Mannich reaction, acidic hydrolysis, and amide coupling were all tolerant of the terminal alkyne functionality (Scheme 45).182 3.1.3. Oxygen-Centered Neutral Nucleophiles. Catalysis involving addition to metal vinylidenes has also been reported using alcohols as well as amines and phosphines. These heteroatom nucleophiles display lower reactivity as compared with those possessing an acidic hydrogen atom. Thus, the most frequently observed reaction mode involving these nucleophiles is that of intramolecular addition, with the exception of allylic alcohols which participate in intermolecular processes quite well, likely due to their ability to interact with the metal center through alkene coordination.134,183 In 1993, the McDonald group reported the cycloisomerization of homopropargylic alcohol 212 to dihydrofuran 214 enabled by metal vinylidene intermediacy (Scheme 46).184 Among the Group 6 metal (Cr, Mo, W) carbonyl complexes

Scheme 47. Synthesis of Furans from Butynediols

dinuclear ruthenium complex 218, the alcohol at the propargylic position served as a leaving group for formation of ruthenium allenylidene intermediate 220, while the homopropargylic alcohol acted as a nucleophile. The application of the Group 6 metal carbonyl complexes to the synthesis of dihydropyran systems has also been reported.187−189 While a preformed metal carbonyl catalyst, prepared by carbon monoxide removal with trimethylamine Noxide (TMNO), was effective for dihydrofuran synthesis N


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saccharosamine glycal 235, desosamine 236, disaccaride subunit 237 of altromycin, stavudine 238, and cordycepin 239 (Chart 2).194−198

(Scheme 46), the corresponding 6-membered ring formation required irradiation at elevated temperatures (Scheme 48a).190 Scheme 48. Cycloisomerization for 6- and 7-Membered Oxacycles

Chart 2. Applications of Alkynol Cycloisomerization in Target-Oriented Synthesis

In addition to simple cycloisomerization, intramolecular alcohol addition to a metal-bound vinylidene may lead to further cyclization (Scheme 50). In these examples, a tethered alkene in alkynol 240 participated in [2 + 1] cycloaddition with the tungsten Fischer carbene 241, furnishing bicyclo[5.1.0]octane 242.199,200 In combination with the acid-catalyzed glycosylation of glycals, reiterative application of the tungsten-catalyzed cycloisomerization offered a powerful strategy for the de novo synthesis of 3-deoxysaccharides.191 The tungsten-catalyzed reaction was also found to be feasible for 7-endo cyclization of 1-alkyn-6-ols when a conformational constraint such as an acetonide was present in the tether (Scheme 48b).192 The tungsten-catalyzed cycloisomerization exhibited divergent regiochemical preference depending on the propargylic substituent of 1-alkyne-5-ol substrates (Scheme 49).193 The O-

Scheme 50. Tandem Cyclization/Cyclopropanation

In 1999, Trost and Rhee reported a ruthenium-catalyzed oxidative endo cyclization of alkynols that gave rise to γbutyrolactone products (Scheme 51).201 In the presence of the stoichiometric oxidant N-hydroxysuccinimide, Fischer carbene intermediate 248, resulting from cyclization of ruthenium vinylidene 247, undergoes an oxidative process through attack at the α-carbon rather than reductive elimination via the tautomeric ruthenium alkenyl 249. The oxidative endo cyclization competed with simple hydroalkoxylation when applied to 6-membered ring synthesis (Scheme 52).202 It was found that choice of the ligand was crucial for selectivity. While the reaction using an electron-rich ligand favored oxidative cyclization to form δ-valerolactone 253, the use of an electron-deficient ligand reoriented the reaction toward cycloisomerization. The electron-rich ligand has been proposed to favor the formation of Fischer carbene 256 that undergoes oxidative decomplexation, while alkenylruthenium 255 gives dihydropyran product 254 on the use of an electron-deficient ligand. In both cases, employment of excess phosphine ligand was required to prevent 5-exo cycloisomerization. Trost and Rhee utilized the oxidative cyclization to accomplish a concise synthesis of (−)-muricatacin from allylic bromide 257 in three steps (Scheme 53a).201 The reaction was tolerant of the 4-hydroxy group and gave cleanly the 5membered cyclization product, (−)-muricatacin. The cyclo-

Scheme 49. Endo- and Exo-Cycloisomerizations of BisHomopropargyl Alcohols

triisopropylsilyl ether 228 underwent 6-endo cyclization to afford dihydropyran 230, whereas 5-exo ring closure was the major outcome for the same reaction employing the O-benzyl ether 231. The disparity was proposed to be due to the chelating ability of the benzylic ethereal oxygen atom (cf. 232), which slowed the rate of vinylidene formation. The 5- and 6-endo cycloisomerization of various 1-alkyn-4ols and 1-alkyn-5-ols under Group 6 metal carbonyl-mediated catalysis has been extensively used in the synthesis of their respective furanoses and pyranoses. Various carbohydrates have been synthesized such as vancosamine glycal 234, O


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Scheme 51. Oxidative Cyclization of Homopropargyl Alcohols

Scheme 53. Ruthenium-Catalyzed Cyclization of Alkynols in Target-Oriented Synthesis

Scheme 52. Divergent Pathways in Cyclization of Bishomopropargylic Alcohols

alkynols.207 The synthesis of benzo-fused ring ethers via endo cyclization was also feasible with Cp−Ru208 and Cp−Os209 catalysts, which gave rise to benzopyran and benzoxepine, respectively. A rhodium catalyst system with an electron-deficient phosphine ligand has been reported, which promotes the cycloisomerization of homo- and bis-homopropargylic alcohols to give dihydrofuran and dihydropyran products (Scheme 56).210 In these reactions, the use of excess phosphine was required in order to suppress the competing alkyne dimerization processes. A similar rhodium catalyst system has been found to be effective for 7-endo cycloisomerization (Scheme 57). In the total synthesis of (−)-acetylaranotin by the Reisman group, the pivotal tetrahydrooxepine intermediate 288 was constructed in high yield through hydroalkoxylation of propargylic alcohol 287.211 It has been shown that the high ligand loading required for the rhodium-catalyzed cycloisomerization can be avoided by using a bidentate phosphine ligand (Scheme 58).212 The catalyst derived from a 1:1 complex of rhodium and bisphosphine 291 induced cyclization of bisalkyne 290 while avoiding the often problematic alkyne dimerization. In this example where two terminal alkyne units could participate in the reaction, 6-endo cyclization took place in preference to a 7endo process, thus providing dihydropyran 292 en route to the anticancer agent, laulimalide.213 As seen in the ruthenium-catalyzed cycloisomerization (Scheme 54), 6-endo cyclization of an alcohol was also favored over 5-endo cyclization of a carbamate in the rhodium catalysis (Scheme 59). Using Wilkinson’s catalyst, alkyne 293 was transformed to the glycal subunit 295 of lomaiviticins, kedarcidin, and yokonolide.214

isomerization was applied to the synthesis of narbosine B, wherein the disaccharide was efficiently constructed by iterative glycal formation and propargyl alcohol glycosylation (Scheme 53b).202 Cycloisomerization producing dihydropyran systems has been applied to the synthesis of forosamine and DPP4 inhibitor 270 (Scheme 54).203,204 In both cases, commercially available CpRu(PPh3)2Cl catalyst promoted 6-endo cyclization with high selectivity. In contrast, the use of a tungsten Fischer carbene catalyst for the reaction of 267 led to 5-endo ring closure exclusively, affording tungsten amino−carbene complex 273. Ruthenium catalysts with P,N-ligands were shown to be efficient for endo cyclization of alkynols producing 5- to 8membered oxacycles (Scheme 55). A broad range of dihydrofurans, -pyrans, and -oxepines were prepared in good yield using Ru−PN3 catalyst 275.205,206 Similarly, Ru−P2N2 catalyst 278 promoted cycloisomerization of aryl-tethered P


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Scheme 54. Chemoselectivity in Cycloisomerization of Aminoalcohols

Scheme 55. Alkynol Cycloisomerizations for 5-, 6-, 7-, and 8-Membered Oxacycles

Scheme 56. Rhodium-Catalyzed Cycloisomerization of Homo- and Bis-homopropargylic Alcohols Phenols proved to be suitable nucleophiles for the metal vinylidene-mediated endo-selective cyclization. Under the catalysis of CpRu(PPh3)2Cl, 2-ethynylphenol 296 underwent 5-endo cyclization, in preference to the 5-exo or 6-endo ring closure involving the benzyl alcohol, producing benzofuran 297 (Scheme 60a).208 The Cp−ruthenium complex with bifunctional P,N-ligand 178, which showed high catalytic activity in alkyne hydration, efficiently promoted both the cyclization and the hydration of bisalkyne 298 (Scheme 60b).215 A cyclization via phenol addition has recently been practiced using internal alkyne substrates (Scheme 61). Under the catalysis of a cationic rhodium complex ligated with BINAP, a variety of alkynes 301 flanked by aryl and silyl groups were converted to 3-silylbenzofuran products 301 in high yield.216 It was proposed that 1,2-migration of the silyl, rather than aryl, group occurred during the formation of rhodium vinylidene intermediate 304, which might be assisted by the phenolic oxygen. Despite the success of the anti-Markovnikov addition to alkynes using carboxylic acid, carbamate, and amide nucleophiles, the intermolecular hydroalkoxylation has been achieved only in limited settings. While early studies have shown that allylic alcohols intercept a metal-complexed vinylidene more readily than saturated alcohols, hydroalkoxylation typically requires the use of alcohol nucleophiles

Scheme 57. Rhodium-Catalyzed Alkynol Cycloisomerization in the Synthesis of Acetylaranotin

in large excess. For example, the ruthenium-catalyzed reaction of phenylacetylene (305) with allyl alcohol (5.7 equiv) produced (Z)-vinyl ether 306 along with aldehyde 307, which presumably arose from the Claisen rearrangement of 306 (Scheme 62).134 Q


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Scheme 58. Improved Ligand Stoichiometry Using Bidentate Phosphine

Scheme 62. Intermolecular Hydroalkoxylation Using an Allyl Alcohol

Scheme 63. Intermolecular Hydroalkoxylation Using Simple Alcohols

Scheme 59. Chemoselectivity in Rhodium-Catalyzed Alkynol Cycloisomerization

Scheme 60. Ruthenium-Catalyzed Cycloisomerization of Ethynylphenols

effective for the conversion of phenylacetylene to methyl vinyl ether 308. Ethanol and isopropanol participated in this reaction as well, albeit providing lower yield after prolonged reaction times. Other rhodium catalysts based on semicorrin (311)218 and NHC (312)219 ligands were also reported to promote the hydroalkoxylation of arylalkynes with methanol and ethanol. It has been suggested that the anionic phenoxy and amido ligands of the rhodium catalyst may facilitate the necessary deprotonation−protonation steps required during the course of alkoxide addition to the rhodium vinylidene. Interestingly, the reaction with 311 produces enol ether products with (E)-preference, which is proposed to arise from methanol addition anti to the aryl group followed by rapid reductive elimination from an alkenylrhodium (cf. 313). In contrast, tautomerization of the alkenylrhodium to a rhodium carbene (cf. 314) reorients selectivity to (Z)-preference in the reaction with 310.220 In addition to alcohols, epoxide and carbonyl groups have been reported to be capable of intercepting metal vinylidene intermediates. When ethynylepoxide 315 was treated with pentacarbonylmolybdenum in the presence of TEA, furan 316 was isolated in good yield (Scheme 64a).221 The same cyclization could be carried out under catalysis of a Tp−Ru complex with lower catalyst loadings (Scheme 64b).222 The result of deuterium-labeling experiments lent support to the mechanism involving direct rearrangement of metal vinylidene 317 to Fischer carbene 318 rather than an allenylidene pathway. Carbonyl groups, when placed in close proximity to alkynes, have been known to intercept metal vinylidenes in stoichiometric as well as catalytic processes. An interesting cascade reaction was reported, which combined ketone or

Scheme 61. Cycloisomerization of Ethynylphenols: Synthesis of Silylbenzofurans

Intermolecular alkyne hydroalkoxylation with simple alcohols has been reported by the Kakiuchi group using rhodium catalyst 310 bearing an 8-hydroxyquinoline ligand (Scheme 63).217 The reaction in a methanol−DMA cosolvent was R


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Scheme 64. Cycloisomerization of Ethynyloxiranes

Scheme 66. Rhodium-Catalyzed Hydroamination of Terminal Alkynes

Scheme 67. Rhodium-Catalyzed Hydroamination Using Secondary Amines

oxime addition to a metal vinylidene and cyclopropane ring opening under tungsten catalysis (Scheme 65).223 Upon Scheme 65. Tandem Cycloisomerization/Ring-Opening Reactions

rhodium catalyst 331 with CuBr cocatalyst induced tandem addition of amine and alkyne to furnish propargylic amine product 332 (Scheme 67b).226 The formation of the 2:1 alkyne−amine coupling product presumably resulted from the copper-catalyzed alkynylation of an iminium intermediate arising from the initial hydroamination product (cf. 329). It has been suggested that dirhodium vinylidene 334, an isolable intermediate, is a catalyst resting state and exists in equilibrium with the mononuclear vinylidene complex 333 that enters into the catalytic cycle.227 Another intermolecular hydroamination reaction employing a W(CO)4(piperidine)2 catalyst has been reported producing enamine products with good yield.228 Hydrazines can add to terminal alkynes to yield hydrazones through metal vinylidene-mediated catalysis (Scheme 68). Various N-alkyl- and N,N-dialkyl-substituted hydrazones have been prepared in good to excellent yield by using a Tp−Rh catalyst in the presence of P(2-furyl)3 ligand.229 Pyrazole and benzotriazole have been found to be suitable nucleophiles for alkyne hydroamination (Scheme 69). N-

treatment with a catalytic tungsten carbonyl complex at room temperature, the 6,3-fused ethynylcyclohexane 321 was smoothly isomerized to the 6,5-fused heterocyclic products 322. The proposed mechanism involved addition of the carbonyl oxygen or oxime nitrogen to the tungsten vinylidene, cyclopropane ring opening of the tricyclic intermediate, and aromatization. 3.1.4. Amine, Imine, and Hydrazine Nucleophiles. The intermolecular addition of amines to metal vinylidene intermediates has been much less explored as compared with the corresponding processes of amides, possibly due to catalyst deactivation by basic amine substrates. An additional factor to be considered is that the mechanistic distinction between the 1,1-addition and the 1,2-addition is not always clear, since both pathways can lead to anti-Markovnikov hydroamination of terminal alkynes via metal vinylidene and π-alkyne intermediates. Recently, several examples have been reported invoking a vinylidene mechanism. A Tp−Rh catalyst has proved to be effective for hydroamination of aliphatic terminal alkynes with both primary and secondary amines, giving rise to the imine and enamine products, respectively (Scheme 66).224 A rhodium catalyst ligated with a P,N,O-ligand system has been shown to be effective for secondary amine addition to phenylacetylene (305) at room temperature producing (E)enamine 329 in excellent yield (Scheme 67a).225 While the same reaction with alkylalkynes gave poor results, the use of

Scheme 68. Anti-Markovnikov Addition of Hydrazine to Terminal Alkyne

S


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Alkenyl 1,2-diazole products were formed in high yield from the reaction of various alkyl- and arylalkynes with diazoles using only 0.5 mol % of a cationic ruthenium complex.230

Scheme 71. Carbon 1,2-Migration in Vinylidene Catalysis: Synthesis of Indoles

Scheme 69. Ruthenium-Catalyzed Azole Vinylation

Aromatic and aliphatic amines have been shown to be competent nucleophiles capable of intercepting metal vinylidene intermediates generated from aryl-tethered terminal alkynes (Scheme 70). Various 2-ethynylanilines were cyclized

rhodium-catalyzed pyrrole synthesis from terminal alkyne 330 and alkenylimine 348 (Scheme 72).235 The proposed

Scheme 70. Cycloisomerization of Arylalkynes with Nitrogen Nucleophiles

Scheme 72. Synthesis of Pyrroles from Terminal Alkynes and Imines

mechanism involved capture of rhodium vinylidene 350 with the imine nitrogen followed by cyclization of the zwitterionic intermediate to form the formal [4 + 1] cycloadduct 353, which upon protodesilylation gave pyrrole 349. 3.1.5. Thiols, Phosphines, Silanes, and Boranes. Thiols are among the least explored nucleophiles for the reaction with metal vinylidenes, possibly due to catalyst poisoning by the substrates. While cyclization of 1-butyn-4-mercaptan to dihydrothiophene has been shown to be feasible by mediation of a stoichiometric Group 6 metal vinylidene,236 an example of anti-Markovnikov thiol addition to a terminal alkyne has been reported using the thiolate-bridged dinuclear ruthenium catalyst 355 (Scheme 73).237

to indole products by using rhodium and ruthenium catalysts.157,215,231 Dihydroisoquinoline 342 was also prepared from the ruthenium-catalyzed cyclization of sulfonamide 341.157,232 The intramolecular hydroamination could be extended to 7-endo ring closure making use of a Cp−Os catalyst and the homobenzylic secondary amine substrate 343, producing 3-benzazepine 344.233 While the substrates for metal vinylidene-mediated catalysis have been limited to terminal alkynes and a few heteroatomsubstituted internal alkynes, the use of internal alkynes bearing two carbon substituents has recently been reported (Scheme 71).234 Upon heating with catalytic CpRu(dppe)Cl, N-acyl-2alkynylanilines 345 cycloisomerized to 3-substitued indoles 346 in good to excellent yield. An array of alkyl-, aryl-, and carbonyl-substituted alkynes was found to generate the β,βdisubstituted alkenylidenemetal intermediate 347 via 1,2carbon migration. In a stoichiometric experiment, one specific intermediate (347; R1 = Ph, R2 = Ph) was isolated and shown to furnish the corresponding indole product upon heating. This remarkable transformation attests to feasibility of implementing catalysis based on the 1,2-carbon migration observed in stoichiometric systems (cf. Scheme 18). Similar to carbonyl groups, sp2 -hybridized nitrogen nucleophiles have been used to intercept metal vinylidene intermediates. Iwasawa and co-workers reported a novel

Scheme 73. Anti-Markovnikov Hydrothiolation

Serving as ligands for the metal center, phosphines can add to a vinylidene moiety within the same metal complex. This type of C−P bond formation via α-migratory insertion has been reported to take place in a ruthenium-catalyzed hydrophosphination, which generates alkenyl phosphine 357 in good yield with modest (Z)-selectivity (Scheme 74).238 The 1,2-migration of a metal ligand to the carbene center constitutes an efficient pathway for intercepting a metal vinylidene intermediate with non-nucleophilic boranes and T


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Scheme 74. Anti-Markovnikov Hydrophosphination

Scheme 77. Reconstitutive Addition of Allylic Alcohol to Terminal Alkyne

silanes. In an early example, pinacolborane and catecholborane were added to various terminal alkynes under rhodium catalysis to give (Z)-alkenylborane in good yield (Scheme 75).239 [Ir(cod)Cl]2 was shown to be comparable in catalyzing Scheme 75. Formal trans-Hydroboration of Terminal Alkynes

report, terminal alkyne 365 and allylic alcohol 366 were reconstitutively coupled under ruthenium catalysis to furnish β,γ-unsaturated ketone 367. The proposed catalytic cycle involves intermolecular addition of allylic alcohol 366 to ruthenium vinylidene 368, an otherwise difficult process without facilitation by the coordination of the alkene. Fischer carbene 370 then undergoes a metallo-Claisen rearrangement to give acylruthenium 371, which finally yields ketone 367 via reductive elimination. The reconstitutive addition has been performed taking advantage of both metal vinylidene and allenylidene intermediates. In the presence of allylic alcohol 366, subjection of diol 373 to the conditions for ruthenium-catalyzed propargylic substitution produced 374 (Scheme 78).244 The catalytic cycle

the formal trans-hydroboration giving (Z)-alkenylborane products, substrates synthetically useful for subsequent crosscoupling reactions. More recently, the Leitner group reported a highly efficient formal trans-hydroboration reaction using a ruthenium catalyst containing a P,N,P-type pincer ligand (Scheme 76).240 In the Scheme 76. Formal trans-Hydroboration and Hydrosilylation of Terminal Alkynes

Scheme 78. Tandem Propargylic Substitution/ Reconstitutive Addition Reactions

presence of only 0.2 mol % of ruthenium complex 362, various aryl and alkylalkynes reacted at room temperature with pinacolborane to afford alkenylboranes in good yield with excellent (Z)-selectivity. It has been suggested that an in situ formed H−Ru−Bpin species may be involved in the generation of a ruthenium vinylidene intermediate, from which the C−B bond emanates via α-migration.241 This catalytic system was effective for trans-hydrosilylation that furnished alkenylsilane 364 with high (Z)-selectivity, although only aliphatic alkynes could be employed.242 3.1.6. Reactions Involving Acyl Complexes. In 1990, shortly after the first report of metal vinylidene-mediated catalysis, Trost and co-workers reported the first example of a catalytic C−C bond-forming reaction making use of a metal vinylidene intermediate (Scheme 77).183,243 In this seminal

is initiated by the formation of ruthenium allenylidene intermediate 375. Subsequent to intramolecular etherification, the resulting THF−vinylidene 376 engaged in the reconstitutive addition reaction with alcohol 366 to give rise to ketone 374. The reconstitutive addition, occurring through the catalysis mediated by ruthenium alkenylidene species, has been applied to the synthesis of a number of targets, including functionU


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alized steroid 377,245 rosefuran (378),246 and calyculin subunit 379 (Chart 3a).247 The development of an enantioselective

(Scheme 81).252 In the proposed mechanism, allenylidene 392, formed from propargylic alcohol 390, undergoes α-hydration

Chart 3. Applications of Reconstitutive Addition Reactions

Scheme 81. Decarbonylative C−C Bond Cleavage Reaction of Propargyl Alcohols

to give acylruthenium 393. Subsequently, deinsertion followed by reductive elimination provides the CO extrusion product 391. Decarbonylative cyclization of ynals has been reported, wherein a C−C bond is formed between terminal alkyne and tethered aldehyde moieties with extrication of CO (Scheme 82).253 Treatment of ynal 394 with a Cp−Ru catalyst in acetic

variant of the reaction has been pursued by the Trost and Hidai groups using various chiral Cp−Ru catalysts 380−382, but only modest success has been achieved (Chart 3b).248,249 The anti-Markovnikov hydration of terminal alkynes involves a metal acyl intermediate that may be exploited for C−C bond formation. On the basis of this strategy, hydrative carbocyclization has been realized under ruthenium catalysis (Scheme 79).250 Subjection of terminal alkyne 383, possessing

Scheme 82. Decarbonylative Carbocyclization of Alkynals

Scheme 79. Hydrative Carbocyclization of Alkynyl Enones

a tethered α,β-unsaturated ketone, to the conditions for antiMarkovnikov hydration using a trinuclear [Ru3Cl5(dppm)3]PF6 catalyst resulted in the formation of cyclopentanone 384. Hydrative alkyne addition can occur in an intermolecular fashion using excess (5 equiv) methyl vinyl ketone (MVK) acceptor (Scheme 80).251 The three-component coupling of alkyne, water, and MVK afforded 1,4-diketone 389 in good yield under the catalysis of RuCl2(CH3CN)2(dppm). Decarbonylation of acylruthenium intermediates can be purposedly exploited for carbon−carbon triple bond cleavage

acid gave cyclopentene 395 in excellent yield. While carbonyl addition of the acetic acid adduct 402 has been originally proposed to be a pathway for ring closure, further studies suggest ruthenium hydroxycarbene 398, formed from oxetylidene complex 397, to be a key intermediate. Acetic acid plays a crucial role acting as a proton shuttle in the generation and tautomerization of 398 to acylruthenium(IV) 400. Subsequent to ligand dissociation and CO deinsertion, alkenylruthenium 401 furnishes the decarbonylative cyclization product 395.254 The decarbonylative cyclization, occurring through C−C bond formation at the β-carbon of terminal alkynes, is also viable for 1,6-diyne substrates (Scheme 83).255 Under the same conditions for ynal cyclization (cf. Scheme 82), diyne

Scheme 80. Intermolecular Hydrative Three-Component Coupling Reaction

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additional alkyne, reductive elimination, and hydrolysis to furnish the alkyne-water 2:1 adducts 409 and 410. Upon addition to metal vinylidene intermediates, nucleophiles containing a metal-binding moiety often generate metal chelates that engage in C−C bond-forming migratory insertion processes rather than produce simple adducts. The reaction of alkyne 106 with allylamine in the presence of Wilkinson’s catalyst gave cyclic imine 417 as the product (Scheme 85).257

Scheme 83. Decarbonylative Carbocyclization of 1,6-Diynes

Scheme 85. Three-Component Coupling of Terminal Alkyne and Allylamine 403 gave rise to methylenecyclopentane 404. The key C−C bond-forming event has been proposed to be the [3 + 2] cycloaddition of the internal alkyne with the alkenyl complex 406 derived from ruthenium vinylidene 405 and acetic acid. Ruthenacycle 407 then undergoes a series of processes involving deacetylation, decarbonylation, and reductive elimination to give the carbocyclic product 404. Metal imidoyl complexes derived from metal vinylidenes have also been utilized for C−C bond formation. In the presence of Wilkinson’s catalyst and 2-amino-3-picoline, the reaction of alkyne 330 with water yielded a mixture of two isomeric enones, 409 and 410, as products (Scheme 84).256

In this three-component 2:1 coupling reaction, the Fukumoto group proposes that the initial amine adduct 418 undergoes a series of hydro- and carbometalation steps to provide dihydropyrrole 417.

Scheme 84. Chelation-Assisted Hydrative Dimerization of Terminal Alkynes

3.2. Atom-Transfer Reactions

3.2.1. Oxygen and Nitrogen Transfer. The carbon− metal bond of a vinylidene complex can be directly oxidized or reduced via atom- or group-transfer reactions. In 2002, Fukumoto et al. reported the ruthenium-catalyzed reaction of terminal alkynes with hydrazines that provided nitrile products (Scheme 86).258 In this process effecting an “N−H” transfer Scheme 86. Nitrogen Transfer to Terminal Alkynes

from a hydrazine to an alkyne, metallohydrazone 422, a tautomer of the Fischer carbene 421 arising from addition of N,N-dimethylhydrazine to the ruthenium vinylidene intermediate, undergoes N−N bond cleavage to afford nitrile products. For the reaction of hindered alkyne substrates bearing a tertiary alkyl substituent, the use of tertbutylhydrazine under rhodium catalysis was found to be more effective by minimizing simple anti-Markovnikov addition giving hydrazone products.259 The oxygen atom of epoxides may be transferred to the carbene center of a metal vinylidene complex to produce a metalloketene species that can enter electrophilic reaction

Rhodium imidoyl 413 is proposed as the key intermediate, which arose from pyridyl nitrogen-assisted addition of 2amino-3-picoline to vinylidene 411 and subsequent tautomerization of Fischer carbene 412. This rhodium imidoyl 413 then undergoes a sequence of migratory insertion with an W


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pathways. In 2004, Liu and co-workers reported an interesting cycloisomerization reaction involving oxygen translocation (Scheme 87).260,261 Treatment of epoxyalkyne 425 with the

Scheme 90. Intermolecular Oxygen Transfer Using Picoline N-Oxides

Scheme 87. Intramolecular Oxygen Transfer of Epoxyalkynes

nucleophilic addition (Scheme 91). The intermediacy of a metalloketene species was supported by the observation of Scheme 91. Mechanism of the Oxygenative Addition Tp−Ru catalyst led to formation of 2-naphthol product 426 in high yield. In contrast, trisubstituted epoxide 430 gave 2indanone 431 under the same reaction conditions (Scheme 88). The dichotomy is rationalized by differential reactivity of Scheme 88. Inversion of Regioselectivity in the Cyclization of Metalloketenes

formation of aldehyde 447 from the reactions with a poor nucleophile or no nucleophile, which occurred through oxygenation of alkylidene complex 446 arising from CO deinsertion of the rhodium ketene complex 442. Recently, the vinylidene-to-ketene conversion enabled by rhodium catalysis has been used as a powerful means for macrolactonization of alkynols (Scheme 92). The use of a cationic rhodium catalyst in combination with catalytic ytterbium triflate proved efficient in effecting the macrocycle formation without requiring high dilution.264

the alkenes toward the ketene intermediate formed from transfer oxygenation; disubstituted alkene 429 engages in electrocyclization, whereas trisubstituted alkene 432 undergoes cationic cyclization. Nitrones can also participate in redox reactions with alkynes, where N-to-C oxygen transfer is mediated by a metal vinylidene intermediate. Heating of alkynyl nitrone 434 in the presence of a Tp−Ru catalyst led to cycloisomerization to isoquinolone 435 (Scheme 89).262 Scheme 89. Oxygen Transfer Reaction of Nitrones

Scheme 92. Macrolactonization Enabled by Oxygenation of Rhodium Vinylidene

Catalytic generation of ketene intermediates has been realized using an external oxygen transfer agent (Scheme 90).263 While sulfoxides were found to be effective only in an intramolecular setting, pyridine N-oxides proved efficient for the rhodium-catalyzed oxygenative functionalization of terminal alkynes. Thus, this reaction catalytically renders terminal alkynes into acyl donors, able to form esters, amides, and carboxylic acids in excellent yield upon reacting with alcohols, amines, and water. The mechanism of the oxidative addition to alkynes involves oxygenation of the metal vinylidene intermediate 440 to metalloketene 441, which yields the acyl products on

The possibility of oxygenating metal vinylidene intermediates has provided the opportunity to make use of terminal alkynes as ketene equivalents. A recent example reported by the Li group describes an application of the process to coumarine synthesis (Scheme 93). The reaction of phenylacetylene (305) and salicylaldehyde (450) in the presence of Wilkinson’s catalyst and 4-picoline N-oxide afforded coumarine 451 in excellent yield through a tandem sequence involving ketene generation, phenol addition, and intramolecular aldol condensation.265 X


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facile conversion of the initial zwitterionic adduct 463 to the more stable (E)-isomer 464 prior to the conrotatory electrocyclic ring closure. A cyclization of sulfoxyenynes has been reported making use of a ketene intermediate generated by intramolecular transfer oxygenation (Scheme 96).268 Under the catalysis of a Cp−Ru

Scheme 93. Tandem Oxygenative Addition/Aldol Condensation Reactions

Scheme 96. Oxygenative [2 + 2] Cycloaddition Reaction of Terminal Alkyne with Intramolecular Alkene

The metalloketene intermediate was shown to be capable of participating in electrocyclization (Scheme 94).266 The arylcomplex with the P,N-ligand AZARYPHOS, sulfoxyenyne 465 was cycloisomerized to fused bicycle 467 in high yield through [2 + 2] cycloaddition of ketene 466 with the tethered alkene. An interesting rearrangement takes place when this ruthenium-catalyzed internal redox reaction is carried out with propargylic sulfoxides (Scheme 97).269 Under the

Scheme 94. Oxygenative Cycloaromatization of Dienynes

Scheme 97. Oxygen Transfer and Rearrangement of Propargylic Sulfoxide

tethered enyne 454 was converted to naphthol 455 under rhodium catalysis in the presence of stoichiometric pyridine Noxide. On the basis of the feasibility of trapping the rhodiumbound ketene intermediate 457 with ethanol, the authors suggest that oxygenation precedes the C−C bond-forming electrocyclization. The alkyne-to-ketene catalytic conversion has also been applied in the Staudinger β-lactam synthesis. Terminal alkyne 459 was found to participate well in the rhodium-catalyzed oxygenative cycloaddition with imine 460 to afford β-lactam product 461 (Scheme 95).267 A stepwise [2 + 2] cycloaddition mechanism has been proposed, in which metalloketene intermediate 462, generated by oxygenation of the vinylidene complex, undergoes sequential imine addition and 4π-electrocyclization. In contrast to the classical Staudinger reaction producing cis-β-lactams, the rhodium-catalyzed process exhibited high trans selectivity, probably as a consequence of

catalysis of a Cp−Ru complex ligated with AZARYPHOS ligand 179, 2,6-dimethylphenyl sulfoxide 468 underwent redox isomerization to afford thioester 469 in high yield. It has been suggested that the double migration is a consequence of S-to-C transfer oxygenation induced by ruthenium vinylidene formation followed by 1,3-translocaton of the aryl sulfide group via a ketene intermediate. 3.2.2. Hydrogen Transfer. The metal-complexed unsaturated carbenes catalytically generated from alkynes have been shown to participate in hydrogen transfer processes, effecting reduction at the carbon−carbon triple bond. In particular, internal redox exchange via transfer hydrogenation has been frequently observed in the ruthenium-catalyzed reaction of propargylic substrates (Scheme 98).270 When diyne 473, containing a propargyl benzyl ether moiety, was heated in the presence of a cationic TpRu(PPh3) catalyst, dienyne 474 was generated with the internal alkyne intact. A mechanism involving ruthenium allenylidene 475 has been suggested, in which the rebound of benzyl alcohol on to the α-carbon produces Fischer carbene 476, setting the stage for an intramolecular hydride shift that leads to formation of the diene product with concomitant release of benzaldehyde as the byproduct.

Scheme 95. Oxygenative [2 + 2] Cycloaddition Reaction of Terminal Alkynes with Imines

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Scheme 98. Reduction of Metal Vinylidene Complexes through Hydrogen Transfer

Scheme 100. Propargylic Reduction Using Isopropanol as an External Reductant

Scheme 101. Hydrogenolysis via a Metal Vinylidene Intermediate

The application of the metal allenylidene-mediated hydrogen transfer approach to cyclic ether 479 led to intramolecular redox isomerization (Scheme 99).271 The reaction of 2-ethynyl

4. CATALYTIC REACTIONS OF METAL-COMPLEXED ALKENYLIDENES: CARBON−CARBON BOND FORMATION

Scheme 99. Redox Isomerization and Oxidation of Propargylic Ethers

4.1. Nucleophilic Addition

4.1.1. Enols and Enamines. As with the reactions involving heteroatom nucleophiles, carbon-centered nucleophiles can also add to the electrophilic α-carbon of metalcomplexed vinylidenes, enabling construction of carbon− carbon bonds. An early example was reported in 1997, which described the reaction of ω-alkynylmalonate 491 in the presence of a molybdenum complex to give cyclopentene 492 through C−C bond formation between the stabilized enolate and the vinylidene center of intermediate 493 (Scheme 102).275 Despite the high catalyst loading, this example Scheme 102. Cycloisomerization of ω-Alkynyl Malonates

tetrahydropyran 479 with a Tp−Ru catalyst resulted in ring opening to give ketodiene 480. Taking advantage of the C−O bond cleavage entailed in the metal allenylidene mechanism, the reaction can be used for oxidative cleavage of propargylic ethers as exemplified by the generation of phenyl ketone 482 from propargyl ether 481.272 Utilizing an external reductant such as isopropyl alcohol, the hydrogen transfer reaction has been applied to regioselective reduction of propargylic alcohols (Scheme 100).273 Treatment of alcohol 155 with the dinuclear ruthenium catalyst 483 possessing P,S-ligand at 60 °C led to clean deoxygenation to give propargylbenzene (484). The direct reduction of metal vinylidene intermediates has also been reported using dihydrogen (Scheme 101).274 Various alkynes substituted with a tributylstannyl group underwent the ruthenium-catalyzed hydrogenation to furnish 1,1-disubstituted alkene products, likely through hydrogenolysis of the ruthenium vinylidene intermediate generated by 1,2-stannyl migration. While the reaction of alkylalkynes was carried out with PBu3 ligand, P,N-ligand 489 was found to be efficient for hydrogenation of arylalkynes.

demonstrated the potential of metal vinylidene-mediated catalysis to be expanded to include various types of carbon nucleophiles. The addition of carbonyl-derived nucleophiles to a metal vinylidene intermediate has recently been demonstrated to be feasible in an intermolecular setting. Under rhenium catalysis, tertiary nucleophiles possessing an acidic C−H bond undergoes anti-Markovnikov addition to aliphatic alkynes (Scheme 103).276 For instance, 1-dodecyne and trimethyl methanetricarboxylate gave alkene 495 in excellent yield. While 2phenylmalonate proved to be competent nucleophiles, no reaction took place using an unsubstituted malonate (cf. 497). Various 1,3-dicarbonyl compounds were later found to be Z


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Scheme 103. Anti-Markovnikov Addition of Methanetricarboxylates to a Terminal Alkyne

Scheme 105. Divergent Selectivity in Tungsten-Catalyzed Carbocyclizations

suitable for the reaction using ReBr(CO)3(THF)2 as the catalyst with an amine base such as DIPEA.277 In addition to stabilized enolates and enols, silyl enol ethers have been exploited as nucleophiles in reactions with metal vinylidene intermediate (Scheme 104).278 The reaction of silyl Scheme 104. Intramolecular Endo-Cyclization of Silyl Enol Ethers with Tethered Alkynes

Scheme 106. Rhodium-Catalyzed Cycloisomerization of NPropargylenamines enol ether 498 using a tungsten catalyst induced C−C bondforming annulation to provide cyclopentene 500. After cyclization of tungsten vinylidene 499, the water added to the reaction mixture presumably promoted desilylation and protodemetalation, thereby effecting catalyst turnover. The strategy using silyl enol ether nucleophiles has been shown to be effective for the preparation of tetrahydroindanones (cf. 501),279 decalinones (cf. 502),280,281 and bicyclo[3.3.1]nonanones and bicyclo[5.3.1]undecanones (cf. 503 and 504).282 Divergent selectivity was observed in the carbocyclization of the dienyl propargyl amine 505 (Scheme 105).283 Treatment of 505 with catalytic hexacarbonyltungsten led to [4 + 1] cycloaddition giving 1-azabicyclo[3.3.0]octane 506. However, use of the same conditions with the addition of tributylamine resulted in cycloisomerization to yield the 2-aza isomer 507. It has been proposed that the in situ formed tungsten− pentacarbonyl serves as a π-acid under the base free conditions, converting 508 to 510 through tandem 5-endo cyclizations. In contrast, the reaction in the presence of tributylamine commences with formation of tungsten vinylidene 511, which undergoes a series of reactions involving double cyclization with the dienol silyl ether, followed by skeletal rearrangement from a bridged to a fused ring system on 1,2migration of tungsten carbene 513. Enamines are capable of capturing metal vinylidene intermediates to bring about C−C bond formation (Scheme 106).284 Under rhodium catalysis, N-benzoyl- and N-tosylenamines 515 were cycloisomerized to dihydropyridines 516 and 517, respectively. The formation of exo-enamine 516 has been ascribed to the facile intramolecular deprotonation of Ha by

the carbonyl oxygen of 519, while N-sulfonyliminium 521 is believed to give the more stable conjugated diene 517 as the product via deprotonation of Hb. Indoles have displayed anti-Markovnikov reactivity as a carbon nucleophile in metal-catalyzed addition to terminal alkynes. Employing Re(CO)5Br as a catalyst, the reaction of alkyne 523 with N-methylindole 524 gave the bis-indole adduct 525 as the product (Scheme 107).285 While 40% AA


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Scheme 107. Anti-Markovnikov Addition of Indoles to Terminal Alkynes

Scheme 109. Carbocyclization of Ethynylstilbenes

deuterium incorporation observed from a labeling experiment suggested the involvement of a rhenium vinylidene intermediate, running the same reaction without solvent reoriented the selectivity to the formation of a Markovnikov bis-adduct, indicating subtle mechanistic balance existing in the process. The anti-Markovnikov addition of HCN to alkynes has recently been reported using a rhodium catalyst (Scheme 108).286 In this process employing cyanohydrin 526 as the

naphthalene 536, presumably via electrocyclization followed by demetalation induced by 1,2-migration of the iodo group (Scheme 110). Scheme 110. Carbocyclization of Iodostyrenes

Scheme 108. Anti-Markovnikov Addition of Hydrogen Cyanide to Terminal Alkynes

A cycloisomerization with a more complicated skeletal rearrangement was observed from the reaction of 2alkynylstyrene 539 (Scheme 111).288 An initial cyclization, catalyzed by a Tp−Ru complex, is proposed to form indenyl cation 542, which gives rise to cyclopropane 544 upon rearrangement and demetalation (first cycle). The highly

source of HCN, the conversion of terminal alkynes to βsubstituted acrylonitriles 527 took place with predominantly (E)-selectivity. The use of a DPEphos gave better yields and selectivity for aliphatic alkynes. However, optimal outcomes for the reactions with aromatic alkynes were observed using dppf as the ligand. 4.1.2. Alkenes and Arenes. Alkenes and arenes have been shown to be reactive toward the electrophilic carbene center of metal-complexed vinylidenes. Most of the reactions are, however, limited to intramolecular settings due to the rather weak nucleophilicity of these π-systems. Skeletal rearrangements are common in these reactions, as addition of πnucleophile to the metal vinylidene engenders carbocation intermediates. In 2003, Liu and co-workers reported the cycloisomerization of 2-alkynyl stilbene 531 to naphthalene 532, which took place via ruthenium-mediated catalysis (Scheme 109).287 The reaction is proposed to be initiated by the generation of ruthenium vinylidene 533 and then proceed through a cationic cyclization pathway. The formation of the five-membered ring intermediate 534, in preference to a six-membered carbocycle, is likely due to the cation stabilizing effect of the pmethoxyphenyl group. After 1,2-migration of the aryl group, aromatization gives the 1-aryl-substituted naphthalene 532 as the product. It has been found, however, that the nature of the alkene profoundly affects the mode of ring closure. In contrast to the π-cyclization of the diaryl-substituted alkene 531 triggered by electrophilicity of the ruthenium vinylidene, the reaction of iodostyrene 535 resulted in cycloisomerization to

Scheme 111. Carbocyclization of Ethynylstryenes Involving a Series of Rearrangement

AB


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strained alkylidenecyclopropane 544 then undergoes further isomerization to indene 540 via ring-opening and H-shift processes that are possibly assisted by the ruthenium catalyst (second cycle). Endo-selective cycloisomerization via metal vinylidenemediated catalysis is possible with a terminal alkyne tethered to an electronically biased alkene. The reaction of 1,5-enyne 549 in the presence of a diruthenium catalyst gave rise to cyclohexadiene 550 in excellent yield (Scheme 112).289 Similarly, oxirane-tethered 1,5-enynes gave phenol products under a ruthenium catalysis.290

Scheme 114. Arylative Carbocyclization of Gold Vinylidenes from Bis-Iodoalkynes

Scheme 112. Cycloisomerization of 1,5-Enynes

Scheme 115. Carboxylative Carbocyclization of 1,6-Diynes The use of arenes as nucleophiles in the addition to metal vinylidenes can furnish C−H vinylation products. An intramolecular Friedel−Crafts alkenylation has been achieved, which brings about the cycloisomerization of alkynylarenes (Scheme 113).291 Upon treatment with a gold catalyst, Scheme 113. Friedel−Crafts-Type Carbocyclization of Iodoalkynes

which then undergoes outer-sphere nucleophilic addition of a benzoate anion. Metal vinylidene complexes may induce mechanistically distinct carbocyclization featuring a radical intermediate. Enediyne 561 generated silacycle 562 when heated in the presence of a rhodium complex with an electron-rich phosphine (Scheme 116).297 The proposed mechanism

iodoalkyne 551 undergoes cyclization to give dihydrobenzoquinolines 552 and 553 in excellent yield as a 4:1 regioisomeric mixture. An arylalkyne with an oxygen tether, instead of an N-tosyl group, also underwent the reaction to yield a 3-iodo-2H-chromene.292 These results suggest that both gold vinylidene and π-alkyne complexes are generated under the reaction conditions and subsequently participate in electrophilic aromatic substitution. In a related example making use of the same gold catalyst, bis(iodoalkyne) 554 was converted to diiodonaphthalene 555 through successive π-addition processes initiated by the electrophilic gold vinylidene moiety of 556 (Scheme 114).293 Although incorporation of the deuterium label at the 3 position is supportive for the vinylidene mechanism, the authors do not exclude an alternative scenario involving cyclization of a gold π-alkyne intermediate, followed by protonation and 1,2-iodine migration. Difficulty associated with the mechanistic distinction has been noted in another gold catalysis, while calculation studies support the latter scenario.294,295 Lee and co-workers reported an interesting rutheniumcatalyzed reaction effecting carboxylative cyclization of 1,6diynes (Scheme 115).296 In this addition−cyclization reaction, the two alkynes of 557 are incorporated into the cyclic product 558 as endo- and exo-alkene moieties with concomitant addition of benzoic acid with exclusive (E)-stereoselectivity. The ruthenium complex 559, possessing both vinylidene and π-alkyne ligands, has been proposed as the key intermediate,

Scheme 116. Cyclization of an Enediyne via a Radical Intermediate

involves rhodium vinylidene intermediate 563, which engages in a Myers−Saito-type cyclization to form diyl radical 564. Subsequent hydrogen abstraction followed by rebound of the α-silyl radical to the rhodium center produces rhodacycle 566, which undergoes reductive elimination to provide silacycle 562. When the TMS group is replaced with a simple alkyl chain, alkene products are formed through β-hydride elimination instead of reductive elimination to provide a silacycle as in product 562.298 The electron-rich catalyst, AC


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processes prior to furnishing 573 via aromatization− demetalation. Iodo- and silylalkynes are viable substrates for electrocyclization mediated by metal vinylidene species. Facile benzannulation was observed when 2-ethynylstyrene 579 was treated with a tungsten carbonyl catalyst in THF at room temperature (Scheme 119).282,304,305 Similarly, the reaction of

CpRu(PMe3)2Cl, has also been shown to be capable of generating diradical intermediate from terminal alkynes.299 4.2. Pericyclic Reactions

4.2.1. Electrocyclization. The two π-bonds in metal vinylidene complexes confer more dimensions of pericyclic reactions to alkynes. In 1996, the Merlic group reported the first example of metal vinylidene-mediated cycloisomerization of dienynes, a substrate type otherwise incapable of participating in electrocyclization due to the linear alkyne structure (Scheme 117). In the presence of a ruthenium−

Scheme 119. Tungsten-, Rhodium-, and RutheniumCatalyzed Cycloisomerization of Ethynylstyrenes

Scheme 117. Cycloisomerization of Dienynes

cymene catalyst, dienyne 567 undergoes benzannulation to afford benzofuran 568 in high yield. It is noteworthy that the alkyne-to-vinylidene conversion, enabled by a ruthenium catalyst, set the stage for facile electrocyclization under DCM reflux.300 Various coronenes and corannulenes have been synthesized under similar ruthenium catalysis.301,302 Electrocyclization of a metal vinylidene intermediate may lead to skeletal rearrangement of the resulting alkylidene carbene. The ruthenium-catalyzed reaction of dienyne 572 under toluene reflux gave the tetracyclic product 573 (Scheme 118).303 The authors proposed that the initial electrocyclization product 575, with no hydrogen available for demetalation, goes through a series of alkyl migration

silylalkyne 582 using a rhodium catalyst produced naphthalene 584.306 Recently, it has been shown that this type of cycloisomerization could also accompany 1,2-carbon migration.307 Under the catalysis of a Cp−Ru complex, internal alkyne 585 was transformed into 1-phenylnaphthalene (62). The diaryl-substituted ruthenium alkenylidene intermediate 586 could be isolated at 75 °C and, upon elevation of the temperature, gave rise to 62, lending support to the proposed mechanism. Regiodivergency has been observed in the cyclization of haloalkynes using different catalysts (Scheme 120).308,309 Fürstner and co-workers reported that the gold-catalyzed cyclization of haloalkyne 587 (X = Br, I) gave 9halophenanthrene 588, whereas 10-halophenanthrene 589 was instead produced under indium catalysis. Similar outcomes were seen in the cyclization of selenoalkyne (cf. 587, X = SePh), which gave the 1,2-selenium-migrated product under

Scheme 118. Skeletal Rearrangements in Ruthenium Vinylidene-Mediated Cycloisomerization

Scheme 120. Cycloisomerization Reactions for the Synthesis of Halophenanthrenes

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gold catalysis and the simple cycloisomerization product with In(OTf)3.310 Employing 6π-systems, comprising a CN double bond within a 1,5-enyne, electrocyclization reactions have been reported to provide pyridine products. In the presence of a tungsten carbonyl catalyst, N-phenylalkynylimine 590 undergoes cycloisomerization to furnish quinoline 592 (Scheme 121).311 Addition of NMO prior to workup improved the yield of 592, presumably by aiding the removal of a tungsten carbonyl unit bound to the product.

Scheme 123. [2 + 2] Cycloaddition and Cycloreversion

Scheme 121. Tungsten-Catalyzed Electrocyclization of Ethynylimines The CC double bond of a metal vinylidene can serve as a part of a diene in the [4 + 2] cycloaddition. In the presence of a rhodium porphyrin catalyst, ethynylalkyne 601 dimerized through the intermediacy of a rhodium vinylidene species 604 (Scheme 124).314 Due to the susceptibility of the ethynylimine moiety toward nucleophiles, silyl-substituted alkynylimines have been employed as more reliable substrates for metal-catalyzed cyclization (Scheme 122).312 Alkynylimine 594 prepared

Scheme 124. Dimerization via [4 + 2] Cycloaddition

Scheme 122. Synthesis of Quinolines from N-Arylamides

from the corresponding amide 593 undergoes electrocyclization via a ruthenium vinylidene intermediate to furnish quinoline 595. The authors proposed that the trimethylsilyl group is removed after electrocyclization via protodesilylation by ammonium hexafluorophosphate. 4.2.2. Cycloaddition. Both points of unsaturation in vinylidenemetals, CC and MC double bonds, can participate in various cycloaddition reactions. In particular, the electronic perturbation imparted to the CC double bond on metal complexation allows for metal-complexed vinylidene species to participate in symmetry-forbidden [2 + 2] cycloaddition under mild thermal conditions. An example of this [2 + 2] cycloaddition of a metal vinylidene complex is shown in Scheme 123.313 In the presence of a ruthenium− cymene catalyst, diyne 596 was cyclized to ethynylphenanthrene 597 at room temperature. In this metathesis-type reaction, the CαCβ bond of ruthenium vinylidene 598 is proposed to undergo [2 + 2] cycloaddition with the pendent alkyne, forming cyclobutene 599. Subsequent cycloreversion leads to formation of the new ruthenium vinylidene species 600, which gives rise to alkyne 597 upon decomplexation. It is noteworthy that ruthenium vinylidene 598 undergoes ringforming metallotropic shift to 600, even though it has the potential to undergo an electrocyclization process, as depicted in Scheme 120.

In the copper-catalyzed intramolecular [4 + 2] cycloaddition reaction of dienyne 605, Fürstner and Stimson suggest that copper vinylidene 608 might act as a dienophile (Scheme 125).315 While the significant rate enhancement attests to copper catalysis, copper vinylidene 608 is proposed to be involved, with the [4 + 2] cycloaddition of copper−acetylide 607 as an alternative possibility. The MCα double bond of a metal vinylidene complex can engage in the [2 + 2] cycloaddition with an alkene, generating Scheme 125. [4 + 2] Cycloaddition via a Copper Vinylidene Intermediate

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a metallacyclobutane intermediate. This mode of reactivity has been observed in the cycloisomerization of 1,6-enynes (Scheme 126). In the presence of a rhodium catalyst, refluxing

Scheme 128. Cycloaddition of Rhodium Vinylidene Generated from β-Carbon Elimination

Scheme 126. Cycloisomerization of 1,6-Enynes

using CpRu(PPh3)2Cl as the catalyst (Scheme 129a).319 The Murakami group proposed that the [2 + 2] cycloaddition of Scheme 129. Intermolecular Coupling Reaction of Terminal Alkynes and Terminal Alkenes

enyne 610 in acetonitrile yielded methylenecyclohexene 611. While a rhodium hydride mechanism involving trans-hydrometalation step was originally proposed for this novel cyclization (cf. 615 and 616),316 a series of mechanistic studies established a [2 + 2] cycloaddition mechanism involving rhodium vinylidene 612 to be more plausible.317 The evidence supporting a vinylidene mechanism arose from deuterium-labeling experiments (Scheme 127). On subjection Scheme 127. Deuterium-Labeling Experiments on the Cycloisomerization of 1,6-Enynes ruthenium vinylidene 630 with alkene 627, in a head-to-head or a head-to-tail orientation, leads to the formation of dienes 628 and 629, respectively. Preference for the (Z,E)-diene product 628 is ascribed to the head-to-head approach of the alkene to the ruthenium center, whereby an open coordination site is created on dissociation of PPh3 due to the steric repulsion exerted by the phenyl group (Scheme 129b). The (Z,E)-stereoselectivity of the enyne coupling offers an opportunity for preparing triene substrates suitable for electrocyclic ring closure (Scheme 130).320 The reaction of to the rhodium-catalyzed cycloisomerization, deuterioalkyne 617 gave the 1,2-deuterium-migrated product 618. Moreover, the alkenyl deuterium label at 619 was translocated to the endo-alkene of 620 as a result of the reaction, indicating the sequence involving β-hydride (cf. 613) and reductive (cf. 614) eliminations to be the most likely pathway. Recently, a distinct mode of metal vinylidene formation has been reported that involves C−C bond cleavage by taking advantage of ring strain. The Tanaka group demonstrated that, under the catalysis of a cationic rhodium complex, methylenecyclopropane 621 underwent [2 + 2 + 1] cycloaddition reaction with 1,6-diyne 622 furnishing fulvene 623 in good yield (Scheme 128).318 The authors have suggested cycloreversion of rhodacyclobutane 624 to be the key process for the generation of vinylidenerhodium 625, which participates in cycloaddition reaction with diyne 622. Ruthenium vinylidenes are also capable of participating in [2 + 2] cycloaddition. Dienes 628 and 629 were produced from the reaction of phenylacetylene (305) and 1-octene (627)

Scheme 130. Tandem Alkyne−Alkene Coupling/ Electrocyclization Reactions

enyne 633 with excess styrene using the same ruthenium catalyst system furnished triene 634, which underwent 6πelectrocyclization to give cyclohexadiene 635 in good yield. The CN bond of pyridine serves as a π-counterpart in [2 + 2] cycloadditions with the MCα double bond of a metal vinylidene species. Trimethylsilylphenylethyne (636) and pyridine were coupled under ruthenium catalysis to give the alkenylated pyridine 637 in excellent yield (Scheme 131). A number of aryl− and alkyl−alkynes were shown to take part in AF


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Metal vinylidene complexes derived from Group 8 metals have been shown to be capable of transferring a vinylidene unit to π-systems, thus producing [4 + 1] or [2 + 1] cycloadducts. In an early example using a nickel catalyst, the reaction of alkyne 636 and disilacyclobutane 650 furnished a mixture of [4 + 1] and [4 + 2] cycloadducts, 651 and 652; the former of which was postulated to proceed through intermediacy of vinylidenenickel 653 complexed with ortho-disilaxylylene (Scheme 133).324

Scheme 131. Alkenylation of Pyridines

Scheme 133. [4 + 1] Cycloaddition Reaction Mediated by a Nickel Vinylidene Complex

The [2 + 1] cycloaddition of alkenes with the vinylidenes and allenylidenes derived from terminal alkynes has been achieved using a palladium catalyst (Scheme 134). In the the reaction with 3- and 4-substituted pyridines. An initially proposed mechanism was similar to that of the previously described chemistry: [2 + 2] cycloaddition to ruthenaazetidine 645 followed by β-hydride and reductive eliminations.321 Recent computational studies, however, have suggested a C−H activation mechanism, where the C−H bond of pyridinium salt 641 is deprotonated after α-migration of pyridine to the vinylidene center of 639.322 Subsequently, cycloreversion affords 2-pyridylruthenium vinylidene 643, from which an additional α-migration brings about C−C bond formation to give 644. Overall, the N-pyridyl vinylidene complex 639 is converted into the 2-pyridyl vinylidene 644 via C−H activation of a 2-pyridyl C−H bond. The metallacycle intermediate resulting from [2 + 2] cycloaddition may give rise to a carbocyclic product in the presence of carbon monoxide rather than generate enyne or diene products. The ruthenium-catalyzed reaction of ferrocenyl diyne 646 under CO pressure yielded diketone 647 (Scheme 132).323 A sequence involving formation of ruthenium vinylidene 648 via silicon 1,2-migration, [2 + 2] cycloaddition with the alkyne, and double CO insertion was proposed as the mechanism.

Scheme 134. [2 + 1] Cycloaddition Reactions Mediated by Palladium Vinylidene Complexes

presence of a catalytic palladium ligated with cyclohexylphenylphosphine oxide, the reaction of phenylacetylene with norbornadiene took place at 25 °C to produce cyclopropylidene 654.325 A similar reaction employing propargylic acetate 655 afforded allenylidene cyclopropane 656 as the product.326 Related examples include a [2 + 1] cycloaddition under platinum catalysis327 and an enantioselective variant using a chiral phosphinous acid which provided products in moderate ee.328 Recently, novel bimetallic vinylidene species prepared from alkenyl gem-dichlorides have been reported, along with their use in catalytic [2 + 1] cycloaddition reactions (Scheme 135).329 Reductive generation of a nickel vinylidene species from 1,1-dihaloalkene 657 mirrors that of metal-free alkenylidenes (see Scheme 7). The cyclopropanation exhibited a broad substrate scope, including a variety of aryl- and alkylsubstituted dihaloalkenes, as well as counterpart alkenes. 4.2.3. Sigmatropic Rearrangement. The π-bonds contained within metal vinylidenes readily participate in [3,3]- and [1,5]-sigmatropic rearrangement processes. The cyclopropane-tethered ketoalkyne 665 was converted to

Scheme 132. Carbonylative Cyclization from Diynes

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Ru catalyst under benzene reflux, enyne 671 was converted to cyclopentadiene 672. For this cycloisomerization involving formal C−H activation, ruthenium vinylidene 673 is proposed to undergo 1,5-hydrogen shift (C1−H) and metalla-6πelectrocyclization to provide ruthenacycle 675, which then reductively liberates cyclopentadiene 676. In most cases, enyne substrates were designed to possess a substituent facilitating the H-shift, e.g., phenyl, furyl, and siloxy groups.332 Subsequent to the metal-mediated pericyclic processes, an additional series of 1,5-sigmatropic H-shift are believed to take place converting the initial cyclopentadiene 676 to the more stable isomer 672. The alkenylation via direct C−H insertion, rather than 1,5-H shift followed by electrocyclization, has been proposed as an alternative mechanism for the cycloisomerization (Scheme 138).333 Indene 679 was produced on heating aryl alkyne 677

Scheme 135. Reductive [2 + 1] Cycloaddition Reaction from Alkenyl Dichlorides

Scheme 138. Platinum-Catalyzed Carbocyclization Induced by 1,5-Hydrogen Shift

phenol 668 in high yield under the catalysis of a chromium or tungsten carbonyl complex (Scheme 136).330 A sequence Scheme 136. [3,3]-Sigmatropic Rearrangement from Alkynylketones

at 120 °C in the presence of catalytic PtBr2, while the corresponding internal alkynes remained unreactive. On the basis of DFT computational studies, the authors proposed concerted C−H insertion of platinum vinylidene 680 to be the mechanism for the formation of 679 (R = allyl). Further calculation studies suggested that for substrates not bearing an allyl group the reaction coordinate could involve a 1,5“hydride” shift, producing the vinyl−platinum intermediate 681 from which carbocyclization can take place through a transition state such as 682.334,335 The same type of alkenylative cyclization via C−H activation proved feasible with bromoalkyne substrates using PtCl2 or [Ru(CO)3Cl3]2 catalyst.336 The 1,5-hydride shift to a metal vinylidene center may be exploited to generate a metal alkylidene species capable of undergoing further reactions. Iwasawa and Sogo reported the novel fragmentation of propargylic ether 683, mediated by the hydride transfer of rhenium vinylidene 687 (Scheme 139).337 Rhenium carbene 686, arising from this retro-ene-type process, undergoes [2 + 1] cycloaddition with silyl enol ether 688 to provide cyclopropane 693. This cyclopropane then yields cycloheptadiene 690 after a [3,3]-sigmatropic rearrangement. In addition to cyclopropanation, the metal α,β-unsaturated carbene complexes, derived from a metal vinylidene species via 1,5-hydride transfer, can serve as electrophiles. Chen and Wu recently reported the rhenium-catalyzed allylation of indoles using propargyl benzyl ether 684, wherein protodemetalation of an alkenylrhenium resulting from 1,4-addition to 686 gives rise to the allylated product 691.338 More recently, the Iwasawa group described the novel hydropropargylation of silyl enol ethers taking advantage of reversibility of the 1,5-hydride transfer between alkenylrhenium 694 and rhenium vinylidene intermediate 695.339

involving formation of metal vinylidene 669, [3,3]-sigmatropic rearrangement to Fischer carbene 670, and hydrogen shift is proposed to lead to oxepine 666, which then undergoes thermal electrocyclization and epoxide-opening isomerization to give phenol 668 under the reaction conditions. Metal vinylidenes conjugated with an alkene have been found to engage in a series of pericyclic reactions leading to ring formation (Scheme 137).331 Upon treatment with a Tp− Scheme 137. Hydrogen Shift-Induced Carbocyclization of Enynes

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Scheme 139. Rhenium Alkylidenes Derived from Vinylidene Complexes and Their Use in Catalysis

Scheme 140. Combined Rhodium Alkynyl- and Alkenylidene Catalysis

Scheme 141. Synthesis of the Erythrina Alkaloid

4.3. Disubstituted Alkenylidenemetals

4.3.1. Rh− and Re−Alkenylidenes. The β-alkylation of a metal alkynyl σ-complex can provide access to metal-bound disubstituted vinylidenes in stoichiometric settings.87−99,340 However, catalysis making use of this process was slow to be implemented due to the difficulty associated with performing β-alkylation selectively in preference to other reactions mediated by the π-alkynyl−, σ-alkynyl−, and vinylidene− metal intermediates that might exist in dynamic equilibrium. Taking advantage of facile 5-membered ring closure as a means to implement the β-alkylation process in catalysis, the Lee group developed a tandem cyclization reaction (Scheme 140).341 In this reaction mediated by a single rhodium catalyst, enyne 696 was converted to the 5,6-fused bicyclic diene 697 in high yield via a sequence involving β-alkylation of rhodium alkynyl 698 and [2 + 2] cycloaddition of rhodium alkenylidene complex 700. Combined catalysis of rhodium alkynyl and rhodium alkenylidene complexes has been applied to the total synthesis of an erythrina alkaloid (Scheme 141). Subjection of iodoenyne 702 to the alkylative cyclization conditions gave tetracycle 703 en route to 3-demethoxyerthratidinone, whose total synthesis was accomplished in 7 steps with 41% overall yield.342 A novel cascade cyclization reaction has been reported, which involves formation of a disubstituted rhodium−vinylidene species and Friedel−Crafts cyclization. In this cycloisomerization, addition of rhodium alkynyl 706 to an allenyl sulfone gave rise to β,β-disubstituted vinylidene intermediate 707, which on intramolecular aromatic substitution afforded 7membered carbocycle 705 in good yield (Scheme 142).343

Scheme 142. Friedel−Crafts-Type Cyclization of Rhodium Alkenylidenes

The [2 + 2] cycloaddition of alkynes and alkenes has been reported making use of a rhodium alkenylidene intermediate, generated by intermolecular C−C bond formation at the βcarbon of a terminal alkyne. Employing a rhodium catalyst ligated with 8-hydroxyquinoline, Kakiuchi and co-workers demonstrated a formal [2 + 2] cycloaddition between 1-octyne and ethyl acrylate, producing cyclobutene 708 in high yield (Scheme 143).344 It has been proposed that rhodium AI


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Scheme 143. Intermolecular Formation and Cyclization of Rhodium Alkenylidenes

Scheme 145. Dual-Gold Catalysis for C−H Insertion via Gold Alkenylidenes

Both the Zhang and the Hashmi groups proposed an alkynyl gold species such as 722 to be the catalysis-initiating intermediate (Scheme 146). Subsequent to the 5-endo-dig

alkenylidene 710, generated from addition of rhodium alkynyl 709 to ethyl acrylate, undergoes cyclization to form cyclobutenyl rhodium 711 en route to cyclobutene 708. On the basis of computational studies, the proposed rhodium alkenylidene-mediated mechanism is suggested to be favored over an alternative oxidative cyclization pathway involving a rhodacyclopentene intermediate (cf. 712).345 Recently, Fukumoto and co-workers reported a novel rhenium-catalyzed ene-type reaction between a terminal alkyne and an imine (Scheme 144).346 Using a rhenium carbonyl

Scheme 146. Proposed Mechanism of the Dual-Gold Catalysis

Scheme 144. Rhenium Alkenylidene-Mediated Formal Ene Reaction

cyclization of 723 via β-attack of the alkynyl gold moiety at the internal alkyne coordinated with another cationic gold species, C−H activation in gold alkenylidene complex 724 through a concerted or stepwise pathway results in additional cyclization to give 726. Subsequent to monodeauration, alkenylgold 727, proposed to be in equilibrium with diaurated complex 728,349,350 liberates the indene-fused cyclopentene product 721 upon transauration regenerating alkynylgold 722. Hashmi and co-workers observed an induction period at the early stage of the reaction, which might be indicative of a slow rate in the generation of alkynylgold 722 from IPrAuNTf2. Indeed, the preformed digold complex, DAC-IPr-NTf, exhibited faster initiation and better performance (Scheme 147).351 The catalyst turnover effected by the alkenyl-toalkynyl transauration (cf. 727 to 722) was not limited to terminal alkyne substrates, as exemplified by the efficient cycloisomerization of iodoalkyne 729 to 730.352 In addition to

complex in the presence of an electron-deficient phosphine, the reaction of terminal alkyne 330 with imine 713 afforded the formal Alder−ene product 714. It has been proposed that the key C−C bond formation takes place via the addition of alkynylrhenium 715 to imine 713 at the β-position generating alkenylidene 716, which then undergoes a 1,5-hydride shift and protodemetalation to furnish the allylic amine product 714. 4.3.2. Au−Alkenylidenes. While examples of catalysis mediated by a gold vinylidene species have appeared sporadically in the literature, a burst of investigations was initiated in 2012 by Hashmi and Zhang, who independently demonstrated dual-gold catalysis effecting C−H insertion. Benzene-tethered diyne 718 gave rise to indenocyclopentene 719 when treated with [AuBrettPhos]NTf2 catalyst (Scheme 145a).347 Similarly, the double-cyclization product 721 was generated from the reaction of diyne 720 in the presence of [Au(I)−IPr]NTf2 catalyst (Scheme 145b).348 AJ


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Scheme 147. Fast-Initiating Gold Precatalyst

Scheme 150. Stereospecific C−H Insertion via Gold Alkenylidenes

o-dialkynylbenzenes, 1,2-bisethynyl-pyridine and -thiophene were shown to be viable substrates.353,354 The cyclization under dual-gold catalysis can also be practiced with diynes containing a nonarene tether. Diyne 731, prepared by Ugi four-component coupling, undergoes double cyclization under gold catalysis to provide bicyclic pyridone 732 (Scheme 148).355

Scheme 151. β-Halogenation of Alkynylgold and Subsequent C−H Insertion

Scheme 148. Gold-Catalyzed Cycloisomerization of Diynes

silylalkynone 741 with N-bromoacetamide.358 It has been suggested that gold alkenylidene intermediate 744 arises from β-halogenation of the in situ generated alkynylgold rather than through 1,2-halogen migration. In a more recent computational study, the C−H insertion step is suggested to take place in an asynchronous concerted manner with a π-donating substituent at the alkenylidene β-position (745, X = Br or OMe).359 The authors argue that the dual-gold catalysis/C−H insertion (cf. Scheme 145) may also follow a similar pathway due to the extended π-conjugation in 724. In the absence of such a resonance effect (e.g., X = H or CF3), the C−H insertion is proposed to proceed in three phases: hydride transfer, C−C bond formation, and σ-to-π rearrangement. The gold alkenylidene may be intercepted with an alkene to produce alkylidenecyclopropanes. In an early study on the dual-gold-catalyzed cyclization of diynes, Hashmi and coworkers observed a product derived from incorporation of the cyclohexene solvent (Scheme 152).360 It is proposed that gold alkenylidene intermediate 749, arising from diyne cyclization, undergoes [2 + 1] cycloaddition with cyclohexene to afford alkylidenecyclopropane 750. Subsequently, the rebound of the gold(I) catalyst to the highly strained intermediate 750 resulted in a series of Wagner−Meerwein-type rearrangements, giving rise to the cyclobutane-fused tetracyclic product 747. Due to their highly electrophilic character, cationic gold alkenylidene intermediates engage readily in the reaction with alkenes and arenes. For example, enediyne 754 was cyclized to fluorene (756) under gold catalysis (Scheme 153).361 The formation of fluorene is believed to be a consequence of dualgold-catalyzed diyne cyclization, followed by π-cyclization, rather than C−H insertion, of the resulting gold alkenylidene intermediate 755 with the neighboring alkene. The electrophilic carbene center of gold intermediates derived from diyne has been trapped with both internal and external aromatic rings. In refluxing benzene, treatment of odiethynylbenzene (757) with an IPrAuNTf2 catalyst in the presence of triethylamine gave rise to β-phenylnaphthalene

The cycloisomerization involving C−H insertion has been performed with allenyne substrates (Scheme 149).356 In this Scheme 149. Gold-Catalyzed Cycloisomerization of Allenynes

double-cyclization reaction, catalyzed by a gold(I) or gold(III) complex, ω-alkynylallene 733 was cycloisomerized to indene 734 at 0 °C. On the basis of computational studies, it has been proposed that the gold vinylidene intermediate 737, poised for C−H insertion, is generated by 1,4-hydride shift of 736, which arises from gold alkyne π-complex 735. The C−H insertion of a gold alkenylidene intermediate has been shown to be stereospecific (Scheme 150). When enantioenriched iodoalkyne 738 was heated at 80 °C in the presence of catalytic IPrAuNTf 2, iodoindene 740 was produced with 89% enantiospecificity via C−H insertion of gold alkenylidene 739 likely in a concerted fashion.357 A gold complex of a β-halo-β-ketoalkenylidene has been proposed as a catalytic species capable of undergoing C−H insertion under mild conditions (Scheme 151). Zhang and coworkers reported the formation of cyclopentenone 742 as a 4:1 diastereomeric mixture from the gold-catalyzed reaction of AK


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Scheme 152. [2 + 1] Cycloaddition of Gold Alkenylidenes Followed by Rearrangement

Scheme 155. Gold-Catalyzed Tandem Annulation of 1,5Diynes

reaction of diyne 764 possessing a 2,6-Me2C6H3 group afforded indene 765 as the product (Scheme 156).365 Gold Scheme 156. Decarbonylative Carbocyclization in DualGold Catalysis

Scheme 153. Gold-Catalyzed Cycloisomerization of Enediynes

acyl complex 767, arising from water addition to 766, has been proposed as an intermediate, which furnishes 768 after decarbonylation. In the case of a 3,5-Me2C6H3-substituted diyne, the gold alkenylidene species is believed to be trapped by the aryl group, inhibiting water attack. A soft nucleophile such as a sulfonate anion was found to be capable of adding to gold alkenylidene intermediates, as shown in the gold-catalyzed cycloisomerization of tosylate 769 reported by the Hashmi group (Scheme 157).366 The alkyl-

(758) via Friedel−Crafts-type phenylation of 759 followed by rearrangement (Scheme 154).350,362 Scheme 154. Friedel-Crafts Arylation of Gold Alkenylidenes

Scheme 157. Formation of Gold Alkenylidenes through 5Exo-tet Cyclization

Efficient tandem annulation was also feasible using 1,5diynes having nonarene tether (Scheme 155).363,364 In this cyclization mediated by a DAC-IPr-NTf2 catalyst, the fused tricyclic product 763 was formed through intramolecular Friedel−Crafts-type capture of the gold vinylidene arising from diyne cyclization. Water can be used to capture the gold alkenylidene intermediate generated during the course of diyne cyclization. When performed in the presence of water, the gold-catalyzed

to-alkenyl translocation of the tosylate with the ring formation is proposed to occur through recombination of the cationic alkenylidene 771 with a tosylate anion, which is displaced from 770 in the β-alkylation process. The ability of gold alkenylidene intermediates to undergo addition with heteroatom nucleophiles provides the opportunity to perform a cascade reaction incorporating a group transfer process. Under dual-gold catalysis, methoxydiyne 773 cyclized to cyclopentenone 774 in excellent yield (Scheme 158).367 The proposed mechanism involves a 1,4-methoxy migration in gold alkenylidene species 776 that leads to formation of 777. Subsequent to isomerization of 777, the resulting pentadienyl cation 778 undergoes Nazarov cyclization followed by deaurations to give enol ether 781, which then hydrolyzes to furnish enone 774. AL


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Scheme 158. Methoxy 1,4-Migration in Gold Alkenylidenes

Scheme 159. Metal Vinylidene-Mediated Dimerization of Terminal Alkynes

Scheme 160. Head-to-Head Dimerization and Stereoselectivities

4.4. Alkyne−Alkyne Coupling

Terminal alkynes are prone to dimerization under transition metal catalysis due to their ability to readily interact with the metal center through various modes of coordination. Indeed, dimerization is a competing and often dominant pathway in a range of metal-catalyzed reactions of terminal alkynes, including those mediated by metal vinylidene species. Nevertheless, the alkyne dimerization, in principle, can be utilized for the expeditious synthesis of conjugated enynes. The first example of a metal vinylidene-mediated dimerization of terminal alkynes was reported by Yamazaki, in which dimerization of tert-butylacetylene (151) to butatriene 782 was carried out under the catalysis of a ruthenium dihydrido complex (Scheme 159).368 A detailed mechanism was established by later studies, which suggested ruthenium vinylidene 784 to be a key intermediate, with dialkynyl complex 783 as the active catalyst.369 In the proposed mechanism, the C−C bond formation takes place via alkyne migration to the vinylidene center of 784, and catalyst turnover is achieved by protodemetalation of 786. Formation of 1,3-enynes, rather than 1,2,3-trienes, through head-to-head coupling is a more commonly observed outcome of metal-catalyzed alkyne dimerization processes. For example, the reaction of phenylacetylene using dialkynyl ruthenium complex 787 as the catalyst gave (Z)-enyne 788 predominantly (Scheme 160).370 The steric hindrance imposed by the ancillary phosphine is proposed to be responsible for orienting the alkene to the (Z)-configuration in 790. In a head-to-head alkyne dimerization using Cp*Ru(II) hydrido system, the influence of the ligand on the E/Z selectivity has been evaluated.371 The reaction of phenylacetylene (305) with PCy3 provided (Z)-enyne 788 as the major product in a 9:1 ratio, whereas the selectivity was reversed to favor (E)-enyne 789

using PMe3. The orientation of the phenyl group of the vinylidene ligand during the alkynyl migration process is proposed to determine the E/Z selectivity. A bulky ligand (L = PCy3) leads to preferential formation of the (Z)-isomer via 792, while the (E)-isomer arises from 791 by minimizing steric repulsion between the two phenyl groups when a small ligand (L = PMe3) is employed. A similar outcome was also observed in an iridium-catalyzed reaction (Scheme 161).372 In this case, however, the authors suggest that the divergent selectivity is due to a change of Scheme 161. Ligand Effect in Iridium Catalysis

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mechanism. A tripropylphosphine ligand system is believed to proceed via a vinylidene mechanism as described above, whereas its triphenylphosphine counterpart is proposed to go through carboiridation involving migratory insertion of η1alkynyl iridium to another alkyne affording (E)-isomer 795. The head-to-head homodimerization of terminal alkynes has been carried out using a variety of catalytic systems including ruthenium half-sandwich complexes,373−378 Grubbs’ catalyst,379 a thiolate-bridged dimeric ruthenium(III),380 a ruthenium-P,N system,381 ruthenium-P4 and osmium P4 systems, 382,383 ruthenium-P,O and osmium-P,O systems,384−386 a Rh(III) catalyst,387 and iridium systems (Chart 4).388,389

Scheme 162. Cross-Dimerization of Terminal Alkynes

Chart 4. Catalysts Used for Head-to-Head Dimerization of Terminal Alkynes

complex 797 (Scheme 162c).392 In this case, 811 acts as the fast-reacting alkyne to generate a ruthenium vinylidene intermediate via 1,2-migration of the stannyl group. The metal-catalyzed alkyne dimerization has been tested in the context of macrocyclization by Hidai and co-workers (Scheme 163).393 In this early study making use of a thiolatebridged diruthenium catalyst it was demonstrated that diyne 813 could be converted to macrocyclic enyne 814. Scheme 163. Macrocyclization through Intramolecular Dimerization of Diynes

The alkyne dimerization has been further developed into a synthetically more valuable cross-coupling process that can conjoin two different terminal alkynes. Using ruthenium catalyst 807, the reaction of phenylacetylene with trimethylsilylacetylene gave rise to enyne 808 with high (Z)-selectivity (Scheme 162a).390 The use of the silylalkyne in large excess (20 equiv) was necessary for efficient cross-coupling, whereas other catalyst systems such as Rh(PPh3)3Cl, Cp*Ru(PPh3)2Cl, and TpRu(PPh3)2Cl gave the homodimer product. The crosscoupling was also feasible with the silyalkyne as the limiting agent. The iridium-catalyzed reaction using a 2:1 mixture of 1ocytne and triisopropylsilylacetylene produced enyne 810 with exceedingly high (Z)-selectivity (Scheme 162b).391 It is worthy of note that these reactions invariably incorporate the silylalkyne as the “yne” unit of the 1,3-enyne product, implying that the other alkyne partner (cf. 305 and 330) is more able to form a vinylidene complex. An interesting example using internal alkynes as substrates has been reported in which stannyl alkyne 811 was coupled with phenylacetylene to produce enyne 812 under the catalysis of a ruthenium arene

Cycloisomerization of dialkynylsilanes has recently been reported by the Tanaka group, invoking a mechanism related to that of alkyne dimerization (Scheme 164).394 When treated with a cationic rhodium(I)−BIPHEP catalyst at room temperature, dialkynylsilane 815 was converted to cyclic enyne 816 in good yield. The authors propose that facile Cto-O silyl migration (815 to 817), induced by rhodium coordination, sets the stage for the generation of vinylidene intermediate 818, from which a sequence involving alkynyl addition and protodemetalation produces enyne 816.395

5. CATALYTIC REACTIONS OF METAL-COMPLEXED ALLENYLIDENES 5.1. Heteroatom Nucleophiles

5.1.1. Oxygen and Phosphorus Nucleophiles. As established in stoichiometric studies, the γ-selective nucleophilic addition to metal allenylidene intermediates offers a mechanistic motif for catalytic propargylic substitution. The AN


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Ru−Ru bond of the catalyst plays a critical role in lowering the energy barriers of the otherwise unfavorable catalytic steps.398 A related reaction using a mononuclear catalyst has also been reported, which requires more activated substrates such as diphenyl-substituted propargyl alcohols.399 The diruthenium catalyst has also been found to mediate substitution of an alkenyl substrate (Scheme 167).400 The

Scheme 164. Silicon and Carbon Migration of Diynes

Scheme 167. Alkenyl Substitution Mediated by Ruthenium Butatrienylidenes

first example was reported in 1992 by Trost and co-workers, which demonstrated the feasibility of C−O bond formation at a propargylic position using an intramolecular alcohol nucleophile (see Scheme 78). An intermolecular reaction has also been developed for propargylic etherification using the thiolate-bridged diruthenium catalyst 218 (Scheme 165).396,397 The Hidai group reaction of dimedone (826) with enol triflate 827 occurred at room temperature in 30 min to give bisenol ether 828 in high yield with excellent (E)-selectivity. It has been proposed that the ruthenium catalyst assists departure of the triflate group through formation of cumulenylidene intermediate 829, to which γ-addition of dimedone occurs. Convergence to the (E)alkenyl product regardless of the geometry of the starting alkene indicates the intermediacy of a cumulenylidene complex. In a recent report by the Nishibayashi group, it has been shown that in addition to propargylic alcohol derivatives, cyclopropane-substituted alkynes can also participate in the ruthenium allenylidene-mediated catalysis (Scheme 168).401 In the presence of boron trifluoride and ruthenium complex 218, alkynylcyclopropane 831 underwent [3 + 2] cycloaddition with benzaldehyde at room temperature to furnish tetrahydrofuran 832. Computational studies have suggested allenyli-

Scheme 165. Intermolecular Propargylic Substitution Reaction Using Alcohol Nucleophiles

reported that a range of primary and secondary aliphatic alcohols, as well as phenols, could be employed as nucleophiles in the reaction of propargylic alcohol 155 to form ether products. The proposed catalytic cycle involves cationic diruthenium species 821 which forms vinylidene 822 and then allenylidene 823 complexes. Following dehydration via ruthenium allenylidene formation is the microscopic reverse involving the γ-addition of the alcohol nucleophile that gives vinylidene 824. After isomerization of 824 to π-alkyne 825 complexes, the ether product 820 and catalyst 821 are released (Scheme 166). It has been proposed, based on in silico experiments, that the

Scheme 168. Formal [3 + 2] Cycloaddition Reaction of Ethynylcyclopropanes

Scheme 166. Proposed Mechanism for the Propargylic Substitution Reaction

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dene complex 834, arising from vinylidene complex 833 via C−C bond cleavage, to be the key intermediate which undergoes a sequence of intermolecular carbonyl addition and intramolecular etherification. A phosphorus nucleophile has proved active in rutheniumcatalyzed propargylic substitution reactions (Scheme 169).397,402,403 Using the dinuclear ruthenium catalyst

Scheme 171. Ring-Opening-Substitution Reaction via Ruthenium Allenylidenes

Scheme 169. Phosphinylation of Propargyl Alcohols

ruthenium catalyst 218 (See Scheme 170), propargylic substitution took place via simple displacement of the alcohol with an amine.397 5.1.3. Enantioselective Propargylic Substitution with O- and N-Nucleophiles. The tetrahedral-to-trigonal conversion of the propargylic carbon during the course of metal allenylidene generation lends itself to asymmetric induction via deracemization. Following early studies employing ruthenium catalysts, significant advances in asymmetric propargylic substitution have recently come from the use of various chiral copper catalysts. In general, propargylic alcohols are suitable for direct use in ruthenium catalysis, while copper catalysis is usually performed with propargylic esters and carbamates for generation of the requisite allenylidene intermediate. A mechanistic dichotomy between the two metals also exists in the tandem substitution−cyclization processes of ambident nucleophiles. Whereas propargylic substitution is followed by a metal vinylidene-mediated addition pathway under ruthenium catalysis, ring closure takes place typically via addition to a πalkyne complex in the cases of copper catalysts. While the first example of copper allenylidene-mediated propargylic amination was reported in 1994,406 its enantioselective variants was slow to evolve. In 2008, van Maarseveen407,408 and Nishibayashi409,410 independently reported copper-catalyzed enantioselective propargylic amination reactions employing chiral nitrogen and phosphorus ligands, respectively (Scheme 172). In the presence of a complex of copper iodide and Pybox ligand 848, propargylic acetate 847 reacted with aniline at −20 °C to furnish propargylic amine

[Cp*RuCl(μ2-SMe)]2, alcohol 155 was converted to a bisphophinylated product in high yield by the reaction with diphenylphosphine oxide.402 When the reaction was conducted at a room temperature, monophophinylated product 838 could be isolated in excellent yield without alkyne-to-allene isomerization.397 5.1.2. Nitrogen Nucleophiles. Nitrogen nucleophiles are suitable for the catalytic propargylic substitution mediated by ruthenium allenylidene complexes. In particular, weakly basic nitrogen-centered nucleophiles such as carboxamides, sulfonamide, and aryl amines have been found to be effective in reactions with propargylic alcohol derivatives. For example, isobutyramide (840) provides the corresponding substitution product 841 under the catalysis of diruthenium complex 218 (Scheme 170).397 It has also been demonstrated that the propargylic amide product 841 can be subjected to the in situ gold-catalyzed cycloisomerization to obtain oxazole 842.404 Scheme 170. Propargylic Amide Substitution and Tandem Cyclization

Scheme 172. First Cu-Catalyzed Enantioselective Propargylic Aminations

A novel substitution reaction of cyclopropyl alcohol 843 has been carried out using ruthenium allenylidene-mediated catalysis. Employing cationic diruthenium catalyst 844, the reaction of the cyclopropane-substituted propargylic alcohol 843 with aniline gave rise to homoallylic amine 845 as the product (Scheme 171).405 The formation of the ring-opening product was proposed to result from the nucleophilic addition of aniline at the cyclopropane rather than attack at the γ position of the ruthenium allenylidene intermediate. When propargylic alcohol substrates devoid of a cyclopropyl substituent were subjected to the reaction using the neutral AP


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amination took place to produce aminoalcohol 857 when epoxide 854 was reacted with aniline 855 in the presence of a copper catalyst complexed with the electron-rich BIPHEP ligand (entry 2).416 Propargylic carbamates have also been used as substrates for copper-catalyzed asymmetric substitution that gives propargylic amine with concomitant CO2 extrusion (entry 3).417 When bisfunctional nucleophiles are employed, further structural elaboration can be achieved by subsequent metalcatalyzed reactions of alkynes. The reaction of propargylic acetate 847 with N-pentadienylaniline 861 using a chiral copper catalyst underwent propargylic amination and subsequent [4 + 2] cycloaddition to produce bicyclic amine 862 in 82% yield and 88% ee (entry 4).418 Hydrazine can also react with propargylic acetate 847 in the presence of a copper P,N,N-ligand complex. In this case, propargylic substitution is followed by intramolecular anti-Markovnikov addition, furnishing pyrazoline 863 (entry 5).419 Similarly, tandem propargylic substitution and cyclization took place when acetate 847 was reacted with another ambident nucleophile, 2-aminophenol 864, using a similar copper catalyst (entry 6).420 In contrast to the reaction with a hydrazine, however, the second alkyne addition exhibited Markovnikov selectivity. An interesting cascade process has been observed from the reaction of cyclic carbamate 867 with indoline (868) in the presence of a copper catalyst ligated with bisoxazoline ligand 869 (Scheme 174).421 Upon treatment with the copper

849 in 94% yield and 87% ee. The aryl substituent was crucial for both the yield and the enantioselectivity, while anilines proved most efficient as the nucleophile. On the other hand, the Nishibayashi group reported asymmetric amination using chiral bisphosphine ligand 850. Propargylic acetate 847 underwent the amination with a range of primary and secondary aniline derivatives, affording propargylic amines in good yield and high enantioselectivity. The asymmetric propargylic amination making use of chiral copper catalysts has been extended to include other types of substrates.411−420 Using a copper−BINAP complex as a catalyst, the reaction of alkyl-substituted propargylic ester 852 with N-methylaniline gave the tertiary amine product 853 in 82% ee (Scheme 173, entry 1).415 A highly enantioselective Scheme 173. Cu-Catalyzed Enantioselective Propargylic Amination and Tandem Reactions

Scheme 174. Tandem Propargylic Amination/ Hydroamination Followed by Rearrangement

catalyst, cyclic carbamate 867 is converted into a copper allenylidene complex via extrusion of CO2, which is then attacked by indoline to generate N-tosylaniline 871. Subsequently, the initial substitution product 871 is cyclized to bisindoline 872, likely through 5-exo addition of the N-Ts group to a copper π-alkyne intermediate. After the coppercatalyzed reaction is complete, addition of an acid (BF3·OEt2) or a base (Cs2CO3) leads to [3,3]-sigmatropic rearrangement or internalization of the exo-alkene, giving indole product 873 or 874, respectively. AQ


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from the ruthenium center (Scheme 177).426 Structural analysis of allenylidene complex 882, derived from the chiral

The enantioselective propargylic substitution via copper allenylidene-mediated catalysis has also been performed with alcohol nucleophiles. In a recent report by Nishibayashi and co-workers, the copper−Pybox complex was shown to be efficient for propargylic etherification, thus converting racemic secondary propargylic alcohol derivatives to enantiomerically enriched propargylic ethers 877 under mild conditions (Scheme 175).422 While aliphatic alcohols were employed as solvents, phenols proved more reactive nucleophiles, providing aryl ether products in methanol solvent.

Scheme 177. Stereochemical Model of the Nishibayashi Catalyst in Propargylic Substitution

Scheme 175. Enantioselective Propargylic Etherification Using a Cu−Pybox Complex

thiolate-bridged ruthenium 881, indicated the presence of a C−H-π-interaction. On the basis of this analysis, the incoming nucleophile is proposed to approach from the face opposite to the aryl group to avoid the steric congestion by this bulky moiety. Enol ethers have been found to be efficient nucleophiles for capturing metal allenylidene intermediates. The reaction of 155 with ethyl vinyl ether in ethanol produced diethoxy acetal product 883 (Scheme 178).427 It is worthy of note that the ruthenium allenylidene intermediate reacted with ethyl vinyl ether in preference to the ethanol used as a solvent.

5.2. Carbon Nucleophiles

5.2.1. Enols and Enamines. The feasibility of C−C bond formation via metal allenylidene-mediated catalysis was first demonstrated in 2001 by the Hidai group, who reported the formation of alkynylketones 878 and 879 upon refluxing propargylic alcohol 155 in 2-butanone in the presence of catalytic [Cp*Ru(μ2-SMe)Cl]2 (Scheme 176a).423 Silyl enol

Scheme 178. Propargylic Substitution with Enol Ethers

Scheme 176. Thiolate-Bridged Diruthenium-Catalyzed αPropargylation of Ketones

The addition of a silyl enol ether to a copper allenylidene intermediate has led to a novel decarboxylative cycloaddition reaction. Using a copper catalyst complexed with chiral Pybox 885, the reaction of propargylic carbamate 867 with silyloxyfuran 884 furnished the fused lactone 886 with high enantio- and diastereoselectivity (Scheme 179).428 Copper allenylidene species 887, generated from 867 with extrusion of CO2, is proposed to be attacked by the C5 of furan 884 to form oxocarbenium 888, which, upon addition of the pendent tosylamine, afforded the formal [4 + 2] cycloadduct 886. Scheme 179. Decarboxylative [4 + 2] Cycloaddition of Propargylic Carbamates

ethers and 1,3-dicarbonyl compounds were also shown to be competent nucleophiles in DCE solvent. Since this seminal example establishing the reactivity between a metal allenylidene and enol derivatives, further developments have been made which include enantioselective variants using a chiral thiolate-bridged ruthenium catalyst (Scheme 176b)424 and furan synthesis by domino catalysis using [Cp*Ru(μ2-SMe)Cl]2 and PtCl2 catalysts.425 A stereochemical model was put forward to rationalize the outcome of the asymmetric reaction involving π-facial discrimination at the γ-position of the allenylidene, furthest AR


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895 also proved competent nucleophiles (entry 4),433 propargylic alkylation of benzofuran-3-ones 898 gave 900 with high enantio- and diastereoselectivity under the catalysis of a copper−Pybox 899 complex (entry 5).434 All reactions shown in Scheme 180 exhibited excellent yields and enantioselectivities via intermediacy of a chiral copper allenylidene complex and/or copper enolate. However, the reactions with alkyl-substituted propargylic substrates (R1 = alkyl) generally resulted in diminished yields (60−70%). In contrast to the copper-catalyzed processes, the corresponding propargylation of 1,3-diketones using a diruthenium catalyst led to [3 + 3] cycloadditions (Scheme 181).435 The

Stabilized enolates have been widely used as nucleophiles in the metal allenylidene-mediated catalysis effecting C−C bond formations. In particular, a number of asymmetric propargylic substitution reactions have been developed using these nucleophiles under the catalysis of copper complexes with chiral nitrogen ligands (Scheme 180). The Hu group reported Scheme 180. Cu-Catalyzed Propargylic Substitution Using Stabilized Enolates

Scheme 181. Ru-Catalyzed Propargylic Substitution Using Stabilized Enolates

formation of oxacycle 902 appears to result from 6-endo cyclization of a vinylidene complex formed from the addition of 1,3-cyclohexadione (901) to the allenylidene intermediate, whereas 5-exo cyclization of a π-alkyne complex is the dominant pathway for the postallenylidene addition under copper catalysis (cf. Scheme 180, entries 1 and 2). A Ru/Cu bimetallic catalysis approach proved successful in the enantioselective propargylic alkylation of stabilized enolates (Scheme 182). Employing alcohol 903 rather than Scheme 182. Cooperative Catalysis for Enantioselective Propargylic Substitution

a series of enantioselective copper-catalyzed reactions of propargylic acetates employing β-keto-substituted ester 889, phosphonate 891, acid 893, and ketone 895 nucleophiles. In the presence of catalytic copper complexed with P,N,N-ligand 859, propargylic acetate was reacted with β-ketoester 889 and β-ketophosphonate 891 to give rise to dihydrofurans 890 and 892, respectively, presumably through substitution followed by 5-exo-dig cyclization (entries 1 and 2).429,430 On the other hand, the propargylation of β-ketocarboxylic acid 893 was accompanied by decarboxylation to afford alkynylketone 894 (entry 3),431,432 thus offering an alternative route for regioselective ketone propargylation to the one shown in Scheme 176. While 2-substituted 1,3-dicarbonyl compounds

an ester, as the propargyl donor, the reaction with ketoester 904 and ketophosphonate 907 under the cocatalysis of [Cp*Ru(μ2-Si-Pr)Cl]2 and Cu(OTf)2 ligated with bisoxazoline 905 led to formation of the propargylated products 906 and 908, respectively.436,437 The asymmetric induction is proposed to be a consequence of π-face discrimination at the chiral copper enolates by the selective approach of the achiral ruthenium allenylidene intermediate. Another interesting example of dual catalysis has recently been reported, which achieves enantioselective C−C bond formation through the reaction between chiral metal AS


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In addition to enols and stabilized enolates, enamines are also able to participate in metal allenylidene-mediated catalysis. The consecutive copper-catalyzed reaction of 847 with N-tosyl enamine 918 resulted in [3 + 2] annulation to furnish pyrrole 920 (Scheme 185).441

allenylidene and organocatalyst-derived enolate intermediates (Scheme 183).438 Treatment of propargylic carbamate 867 Scheme 183. Synergistic Catalysis for Decarboxylative [4 + 2] Cycloaddition

Scheme 185. Tandem Propargylation and Cycloisomerization of Enaminoesters

A range of chiral P,P- and P,N,N-ligands have been used for asymmetric propargylation of enamines (Scheme 186). The reaction of N,N-diethylenamine 923 with propargylic acetate Scheme 186. Enantioselective Propargylic Substitution Using Enamines and acid 909 with dehydrating agents (TsCl, DIPEA) in the presence of chiral copper−Pybox 910 and benzotetramisole (BTM, 911) catalysts afforded lactam 912 with high ee and dr. The decarboxylative and dehydrative [4 + 2] annulation is proposed to involve enantio- and diastereoselective C−C bond formation in the reaction between copper allenylidene species 913 with BTM−enolate 914. The excellent stereoselectivity was ascribed to the synergistic effect of the chiral influences exerted by each catalytic intermediate. In a related study using a similar catalyst system, (S,S)-Ph-pybox and (S)-Me-BTM instead of (S,S)-i-Pr-Pybox (910) and (R)-Ph-BTM (911), the major product was found to be of opposite absolute stereochemistry, indicating the strong influence of the BTM catalyst on the enantioselection.439 Recently, vinylogous propargylation of enoates has been shown to be feasible using a copper−P,N,N-ligand catalyst (Scheme 184).440 The copper-catalyzed reaction of propargylic acetate 847 with coumarine 916 in the presence of DIPEA afforded the γ-propargylated product 917 in excellent yield and ee. Notably, high levels of yield and ee were maintained in the reactions employing alkyl-substituted propargyl acetate substrates. Scheme 184. Vinylogous Propargylation of Stabilized Enolates

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in the presence of a catalytic copper diphosphine complex generated the homopropargylic ketone 924 (entry 1),442 offering yet another alternative to the ruthenium-catalyzed process using ketones and propargylic alcohols (cf. Scheme 176). The reaction with a catalyst bearing ferrocenyl−P,N,Nligand 925 induced comparable reactivity (entry 2).443 The Hu group extended the scope of enamine nucleophiles to include substituted and cyclic enamines, which underwent propargylic substitution with excellent enantio- and diastereoselectivity under copper catalysis using a P,N,N-ligand (entries 3 and 4).444,445 A copper-catalyzed reaction of cyclic enamines with propargyl esters has been reported, which constructs bicyclic [n.3.1] systems through novel [3 + 3] annulation (Scheme 187).446 In the presence of a catalytic copper complexed with

Scheme 188. Ruthenium Allenylidene and Enamine Dual Catalysis

reported employing a racemic Cu−BINAP catalyst and a chiral organocatalyst.448 When α,β-unsaturated enals were used as substrates, the dual catalysis gave rise to γpropargylation products.449 A highly engineered hybrid catalyst has been developed for the asymmetric propargylation of enamine nucleophiles. Using the dinuclear ruthenium catalyst, having a chiral phosphoramide attached to its bridged thiolate ligands, the reaction of otolyl propargyl alcohol 941 with enamide 942 took place with high enantio- and diastereoselectivity, furnishing alkynone 943 after hydrolytic workup (Scheme 189).450 It is proposed that

Scheme 187. Double Enamine Alkylation via Copper Allenylidene Complexes

Scheme 189. Hybridized Catalyst for Enantioselective Propargylation

P,N,N-ligand 925, treatment of a methanolic solution of cyclohexenenamine 931 and propargyl acetate 847 with DIPEA gave rise to highly enantioselective formation of the bridged bicyclic ketone 932, accomplishing C−C bond formations at both α and α′ positions of cyclohexanone. Interestingly, the same reaction using a morpholino enamine (cf. 928, X = CH2) yielded a simple propargylated product (930) rather than 932.445 The proposed mechanism involved tandem propargylation-alkenylation mediated respectively by copper allenylidene 933 and vinylidene 935 intermediates. Although 6-endo-dig cyclization of a copper π-alkyne could not be ruled out as a pathway for the second C−C bond formation, various aryl- and alkyl-substituted propargyl esters produced the bicyclic products in excellent yield and selectivity. Ruthenium allenylidene intermediates have been shown to engage in reactions with enamines generated under organocatalytic conditions. For example, alkynol 940 was produced in high yield and ee from the reduction of the propargylated aldehyde which arose from the reaction of alcohol 155 with aldehyde 938 in the presence of both a ruthenium catalyst and the proline-derived organocatalyst 939 (Scheme 188).447 A conceptually similar dual-catalytic reaction has also been

the hybrid catalyst, capable of hydrogen bonding with the nucleophile, renders the π-facial stereodiscrimination more pronounced. The bifunctional hybrid catalyst proved superior to a dual-catalytic system employing achiral [Cp*Ru(μ2SMe)Cl]2 in combination with a chiral phosphoramide, which gave 943 with an ee of only 4%. 5.2.2. Alkenes and Arenes. Metal allenylidenes are potent electrophiles capable of undergoing Friedel−Crafts-type reactions with arenes and heteroarenes. They serve as equivalents of metal-templated propargylic cations, thus offering opportunities for asymmetric induction through the employment of chiral ligands. For example, when thiophenetethered alcohol 945 was treated with a chiral thiolate-bridged diruthenium catalyst, a highly enantioselective intramolecular propargylation took place to give thiophene 946 (Scheme 190).451 Under similar ruthenium catalysis, intermolecular propargylation was feasible with furan and indole substrates.452−454 AU


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Scheme 190. Intramolecular Propargylation of Thiophenes

Scheme 192. Dearomative Propargylation of Indoles

The enantioselective aromatic propargylation is also feasible using copper catalysts (Scheme 191). Recently, the NishibayaScheme 191. Enantioselective Cu-Catalyzed Friedel−CraftsType Propargylic Substitutions catalyst and acetate 954 led to formation of furano- and pyrroloindole derivatives 956 with high enantio- and diastereoselectivity, likely through addition of the heteroatom nucleophile to the iminium intermediate 957 arising from the initial propargylation.458 Similarly, piperidinoindoline 960 was formed in high yield and stereoselectivity from the reaction of indole 958 with cyclic carbamate 867, in which both Biox 869 and Pybox 959 ligands proved efficient (Scheme 193).459,460 Scheme 193. Decarboxylative [4 + 2] Cycloaddition for Piperidinoindoline

The electrophilic aromatic substitution of β-naphthol (962) with a ruthenium allenylidene results in [3 + 3] annulation (Scheme 194).461,462 In an analogous fashion to the propargylation of 1,3-diketones (cf. Scheme 181), propargyl alcohol 961 reacts to form a ruthenium allenylidene, which then undergoes the initial C−C bond formation with β-

shi group reported the first example of a copper allenylidenemediated aromatic propargylation for the enantioselective construction of a quaternary stereocenter having a CF3 group (entry 1).455 Using Pybox ligand 948, the copper catalyst system promoted the reaction of indole 524 with propargylic benzoate 947 to afford C3-propargylated indole 949 with 95% ee. The Hu group showed that electron-rich phenols are also excellent substrates for the metal allenylidene-mediated propargylation. Using a copper complex containing P,N,Nligand 859 as the catalyst, the asymmetric propargylation of phenol 950 proceeded with high yield and ee to afford the ppropargylated phenol 951 (entry 2).456 When the para position was blocked, dearomative propargylation took place to furnish cyclohexadienone 953 (entry 3).457 The asymmetric propargylation has been applied to indole substrates effecting their 2,3-difunctionalization (Scheme 192). Subjection of indole 955, possessing a heteroatom-attached chain at C3, to the propargylation using a copper−Pybox 848

Scheme 194. Enantioselective [3 + 3] Cycloaddition of Propargyl Alcohols and Naphthols

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converting allenylidene 971 through to vinylidene 973, via alkynyl complex 972. The 1,5-enyne products resulting from the alkene propargylation are versatile substrates that may participate in a range of metal-catalyzed cyclization reactions. An example of domino cyclization was reported, in which aryl ether 974 was converted to tetracycle 976 under the catalysis of both ruthenium and platinum complexes (Scheme 197).467 This

naphthol to give ruthenium vinylidene 963. This then undergoes 6-endo cyclization to afford 964. In contrast with the ruthenium catalysis, the analogous copper-catalyzed process led to [3 + 2] annulation (Scheme 195). Using a copper catalyst ligated with 966, the reaction of Scheme 195. Enantioselective [3 + 2] Cycloaddition of Propargyl Acetates and Naphthols

Scheme 197. Tandem Ene-Type Cyclization/Enyne Cycloisomerization Reactions

triple cyclization is proposed to be a consequence of the serial catalysis, which is initiated by a ruthenium-catalyzed alkene propargylation and terminated by a platinum-catalyzed enyne cycloisomerization. A similar cascade cyclization was also observed in the reaction of the homologous alkenyl propargylic alcohol 977 using a cationic [CpRu(PPh 3 ) 2 (CH 3 CN)]PF 6 catalyst (Scheme 198).468 The authors suggested that alcohol 977

β-naphthol with silylalkyne 965 gave naphthodihydrofuran 968 in excellent yield and enantioselectivity, probably through copper allenylidene-mediated propargylation followed by 5-exo hydroalkoxylation of copper π-alkyne complex 967.463 It is noteworthy that the same reaction employing a terminal alkyne substrate, instead of 965, produced 968 in much lower yield (up to 31%), indicating the importance of scavenging the acetate leaving group as TMSOAc for the efficiency of the reaction. While the capture of metal allenylidene intermediates with alkene nucleophiles can be accomplished intermolecularly by using an excess alkene,464 the C−C bond formation between them can be performed more efficiently in intramolecular settings.465,466 When aryl ether 969, possessing both propargylic alcohol and alkene functionalities, was heated in the presence of a thiolate-bridged diruthenium catalyst, dehydrative cyclization took place to form dihydrochromene 970 with high ee and cis selectivity (Scheme 196). An enereaction-type mechanism is proposed for the generation of allyl−propargyl coupling product, which involves C−C bondforming cyclization and intramolecular proton migration,

Scheme 198. Tandem Cyclization Reactions via Ruthenium Allenylidenes and Vinylidenes

undergoes ruthenium allenylidene-mediated cyclization to produce vinylidene intermediate 980, which then cyclizes further via the reaction between the vinylidene center and the exo-alkene to furnish the fused bicyclo[4.3.1]decene 978. 5.2.3. Other Nucleophiles. Reductive dimerization has been observed from the reaction of propargylic alcohol 155 with pinacolborane under typical ruthenium-catalyzed conditions for the generation of allenylidene intermediates (Scheme 199).469 The proposed mechanism involves hydroboration at the CβCγ bond of ruthenium allenylidene 823, which triggers a series of radical reactions, ultimately giving rise to the propargyl homocoupling product 983. Ylides have recently been shown to be capable of intercepting metal allenylidene intermediates. Under the catalysis of a copper−Pybox complex, the reaction of propargylic carbamate 867 with sulfonium 986 in the presence of DIPEA led to decarboxylative [4 + 1] cycloaddition giving rise to indoline 987 in high yield and ee (Scheme 200).470 On

Scheme 196. Intramolecular Ene-Type Cyclization

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alkynes into metal vinylidene and allenylidene intermediates, a diverse range of catalytic reactions has been developed that enable the formation of many different types of carbon−carbon and carbon−heteroatom bonds using readily available alkyne and propargyl alcohols as substrates. The list of transformations and variety of molecular structures accessed by them are impressive. With a more sophisticated understanding of the chemistry of metal unsaturated carbenes, the past decade has seen remarkable advances in the development of new reactions that greatly expand their scope and utility in organic synthesis. In addition to the reactivity harnessed in various nucleophilic addition and pericyclic processes, the capacity of metal alkenylidenes to mediate C−H activation, transfer oxygenation, and carbene transfer has also been enlisted to render an array of new transformations with distinct mechanistic pathways. Particularly noteworthy is the substrate scope of these processes that extends beyond terminal alkynes as well as the numerous metals that can be used in this catalysis including earth-abundant copper. These features together with the newly established mechanistic modalities will likely encourage future explorations of this chemical space. Importantly, chiral catalyst systems have been employed in asymmetric propargylation mediated by metal allenylidene species, furnishing enantioenriched products with ee values routinely in excess of 90%. While efforts to develop asymmetric variants of other reactions certainly will follow, the highly enantioselective propargylation, together with tandem processes enabling multiple ring formations, is expected to find many applications in complex organic synthesis, a domain to which metal alkenylidene-mediated catalytic reactions have made their ways as strategy-level transformations. As is evident from this review, the potential of metal alkenylidene-mediated catalysis will surely continue to be explored, leading to the discovery of more efficient catalysts and new reactions. Thus, it should not be surprising if research in this area undergoes more extensive development over the years to come.

Scheme 199. Dimerization of a Propargyl Alcohol

Scheme 200. Sulfonium Ylides as Nucleophiles

the basis of the observed nonlinear effect, a copper−Pybox dimer was proposed to be involved in the generation of allenylidene 988, which reacts with a sulfonium ylide generated from 986 to forge geminal C−C and C−N bonds. Phosphorus ylides have also proven to be excellent participants in the reaction with metal allenylidene intermediates. When the copper-catalyzed reaction of acetate 847 and phosphonium 990 was carried out in the presence of DIPEA, followed by addition of formaldehyde, enyne 992 was formed in high yield and ee, likely through Wittig olefination of ylide 993 with formaldehyde subsequent to asymmetric propargylation (Scheme 201).471 The one-pot, three-component coupling was feasible with a variety of aldehydes, glyoxalates, and ketenes.

ASSOCIATED CONTENT Special Issue Paper

This paper is an additional review for Chem. Rev. 2018, volume 118, issue 19, “Carbene Chemistry”.

AUTHOR INFORMATION

6. CONCLUSION Over the past three decades, transition metal unsaturated carbene-mediated catalysis has emerged as a powerful strategy that can effect a variety of previously inaccessible or difficult transformations. Taking advantage of the facile conversion of

Corresponding Author

Scheme 201. Phosphonium Ylides as Nucleophiles

Notes

*E-mail: [email protected]. ORCID

Kyoungmin Choi: 0000-0002-2614-8340 Chulbom Lee: 0000-0001-9566-5977 The authors declare no competing financial interest. Biographies Sang Weon Roh was born in 1987 in the Republic of Korea. He received his B.S. and M.S. degrees in Chemistry from Seoul National University (SNU) under the supervision of Chulbom Lee. He is currently a Ph.D. candidate, working on the total synthesis of natural products making use of transition metal vinylidene-mediated catalysis. Kyoungmin Choi obtained his B.S. degree from SNU in 2013 and is currently carrying out Ph.D. studies in Chulbom Lee’s group. His research is focused on rhodium-catalyzed carbofunctionalization of alkynes. AX


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HMDS HMPA Ind LG Me Mes MO MOM MS Ms MVK nbd NHC NMO NMP Oct Ph Pin Piv PMP PTSA pyr TBAB TBDPS TBS TEA Teoc TES Tf THF TIPS TMNO TMS tol Tp Ts

Chulbom Lee attended SNU to receive his B.S. and M.S. degrees in Chemistry under the guidance of Prof. Eun Lee. After completing Ph.D. studies in the lab of Prof. Barry Trost at Stanford University in 1998, he moved to Memorial Sloan-Kettering Cancer Center to work with Prof. Samuel Danishefsky as a US Army Breast Cancer Research Postdoctoral Fellow. In 2001, he began his independent career at Princeton University as Assistant Professor of Chemistry. In 2008, he moved back to his alma mater, SNU, and has since remained there as Professor of Chemistry. He has a broad interest in synthetic organic, organometallic, and bioorganic chemistry. His group has developed a range of novel reactions that occur through transition metal vinylidene-mediated catalysis. His research is also concerned with the synthesis of natural products possessing complex molecular architecture and significant biological activity.

ACKNOWLEDGMENTS Financial support from the National Research Foundation of Korea (2017 R1A2B3002869) and Samsung Science and Technology Foundation (SSTF-BA1402-12) are gratefully acknowledged. We thank the Posco TJ Park Foundation (SWR) and Seoul National University (KC) for fellowships and Mr. Felix de Courcy-Ireland for useful discussions and helpful comments. ABBREVIATIONS Ac acetyl ATRP atom transfer radical polymerization BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl BIPHEP 2,2′-bis(diphenylphosphino)-1,1′-biphenyl bipy bipyridine Bn benzyl Boc tert-butyloxycarbonyl Bu butyl CAN ceric ammonium nitrate Cbz carboxybenzyl (benzyloxycarbonyl) cod 1,5-cyclooctadiene coe cyclooctene Cp cyclopentadienyl Cp* pentamethylcyclopentadienyl Cy cyclohexyl DABCO 1,4-diazabicyclo[2.2.2]octane DCE 1,2-dichloroethane DCM dichloromethane dcypb 1,4-bis(dicyclohexylphosphino)butane DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DHP dihydropyran DIPEA diisopropylethylamine DMAP 4-dimethylaminopyridine DMA N,N-dimethylacetamide DMB 2,4-dimethoxybenzyl DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DPP4 dipeptidyl peptidase 4 dppm bis(diphenylphosphino)methane dppe 1,2- bis(diphenylphosphino)ethane dppf 1,1′-bis(diphenylphosphino)ferrocene dppp 1,3- bis(diphenylphosphino)propane dppb 1,4- bis(diphenylphosphino)butane ee enantiomeric excess es enantiomeric specificity Et ethyl Hex hexyl

hexamethyldisilazide hexamethylphosphoramide indenyl leaving group methyl mesityl (1,3,5-trimethylphenyl) molecular orbital methoxymethyl molecular sieve methanesulfonyl methylvinylketone norbornadiene N-heterocyclic carbene N-methylmorpholine N-oxide N-methyl-2-pyrrolidone octyl phenyl pinacolato pivaloyl p-methoxyphenyl p-toluenesulfonic acid pyridine tetrabutylammonium bromide tert-butyldiphenylsilyl tert-butyldimethylsilyl triethylamine 2-(trimethylsilyl)ethoxycarbonyl triethylsilyl trifluoromethanesulfonyl tetrahydrofuran triisopropylsilyl trimethylamine N-oxide trimethylsilyl toluene trispyrazolylborate p-toluenesulfonyl

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