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Cite This: Acc. Chem. Res. 2018, 51, 1667−1680

Recent Advances in Transition-Metal-Catalyzed/Mediated Transformations of Vinylidenecyclopropanes Song Yang§ and Min Shi*,†,‡,§ †

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State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, P. R. China ‡ State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. China § Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, 130 MeiLong Road, Shanghai 200237, P. R. China S Supporting Information *

CONSPECTUS: Vinylidenecyclopropanes (VDCPs), having an allene moiety connected to a highly strained cyclopropyl group, have attracted a substantial amount of attention since they are fascinating building blocks for organic synthesis. During recent years, the reactions of VDCPs in the presence of a Lewis acid or a Brønsted acid and those induced by heat or light have experienced significant advancements due to the unique structural and electronic properties of VDCPs. Transition-metal-catalyzed reactions of VDCPs were not intensely investigated until the last 5 years. Recently, significant progress has been made in transition-metalcatalyzed transformations of VDCPs, and they have emerged as a new direction for the chemistry of strained small rings, especially when new types of functionalized vinylidenecyclopropanes (FVDCPs) are used as substrates. To date, many interesting transformations have been explored using these novel VDCPs under the catalysis of transition metals, such as gold, palladium, or rhodium, and various novel and useful heterocyclic or polycyclic compounds have been generated. These new findings have enriched the chemistry of strained small carbocycles. This Account will describe the transition-metal-catalyzed transformations of VDCPs recently developed in our laboratory and by other groups. The chemistry of Au-catalyzed VDCPs has been enriched and extensively developed by our group. In this respect, a new process for generating gold carbenes from VDCPs has been disclosed. The reactivity of these new gold carbenoid species was fully investigated, and many novel reaction modes based on these new gold carbenoid species were explored, including oxidation reactions, intramolecular cyclopropanations, C(sp3)−H bond functionalizations, and C−O bond cleavage reactions. Rh-catalyzed reactions of VDCPs are another key field of transition-metal-catalyzed reactions of VDCPs. In particular, rhodium-catalyzed cycloadditions, Pauson−Khand reactions, and C−H bond activations of FVDCPs have been explored in detail by our group. A new trimethylenemethane rhodium (TMM−Rh) complex generated from VDCPs was discovered and utilized as an electrophilic Rh−π-allyl precursor. Moreover, some unprecedented highly regio- and enantioselective asymmetric allylic substitutions via this novel TMM−Rh complex were developed with different kinds of nucleophiles. This Account will also summarize the recent advances in palladium-, copper-, and iron-catalyzed cycloisomerization reactions of VDCPs reported by our group and others. These reactions always afford the desired products with excellent chemo-, regio-, diastereo-, and enantioselectivities, which will make them highly valuable for the synthesis of key scaffolds in natural products and pharmaceutical molecules in the future.

1. INTRODUCTION Cyclopropane was first discovered by Freund in 1882. Since then, an increasing number of organic chemists have been attracted by this fascinating, small three-membered carbocycle.1 The functionalized cyclopropanes known as vinylidenecyclopropanes (VDCPs), which have an allene moiety

Scheme 1. Vinylidenecyclopropanes (VDCPs)

Received: April 17, 2018 Published: June 29, 2018 © 2018 American Chemical Society

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DOI: 10.1021/acs.accounts.8b00171 Acc. Chem. Res. 2018, 51, 1667−1680

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Accounts of Chemical Research Scheme 2. Cycloisomerization of Yne-VDCPs 1 and 2 Catalyzed by Gold

Scheme 3. Proposed Mechanism for the Gold-Catalyzed Cycloisomerization of Yne-VDCPs

Scheme 4. Gold-Catalyzed Oxidative Ring Expansion of VDCPs 10

connected to the highly strained cyclopropyl group (Scheme 1), are thermally stable and reactive substances, making them fascinating building blocks for organic synthesis, and thus, they have attracted the attention of many organic chemists.2 For years, the classical investigations of VDCPs mainly focused on the photo- and heat-induced and acid-catalyzed transformations of VDCPs.2b However, in the past decade the development of transition-metal-catalyzed transformations of VDCPs has attracted much attention and undergone significant advances. Currently, it has emerged as a new direction in the chemistry of strained small rings, especially the use of new types of functionalized vinylidenecyclopropanes (FVDCPs) as substrates. Many interesting transformations have been explored using these novel VDCPs and transition metal catalysts, such as those with gold, palladium, or rhodium, and these reactions can generate useful and novel heterocyclic or polycyclic compounds, which have expanded the chemistry of strained small carbocycles. This Account will mainly highlight the recently developed chemical transformations of VDCPs involving transition metal catalysts reported by our group and other groups since 2010. It is hoped that this Account will satisfy the expectations of the general communities who are interested in the transition-metal-

catalyzed transformations of VDCPs and related cyclopropanes.

2. TRANSITION-METAL-CATALYZED/MEDIATED TRANSFORMATIONS OF VINYLIDENECYCLOPROPANES 2.1. Gold-Catalyzed Transformations of VDCPs

The field of gold catalysis has undergone significant advances in recent years.3 The exploration of new reaction modes in this arena has reached the forefront of current research. New goldcatalyzed transformations of VDCPs have been extensively investigated by our group during the last several years.4 More recently, new gold-catalyzed cycloisomerizations of VDCPs and new processes for generating gold carbenes from VDCPs have been disclosed by our group.5 2.1.1. Gold-Catalyzed Cycloisomerization of VDCPs. A novel intramolecular cycloisomerization of yne-VDCPs 1 and 2 catalyzed by a gold(I) complex was reported in 2014 (Scheme 2).6 The length of the carbon chain connecting the alkynyl anchor with the VDCP moiety was identified as being critical to the reaction outcome. When n = 1, the reactions proceeded smoothly and gave cycloisomerized bicyclic compounds 3 as 1668


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Accounts of Chemical Research Scheme 5. Representative Examples of Gold(I)-Catalyzed Cycloisomerizations of VDCPs 14

the major products in the presence of Au catalyst I. When n = 2, the VDCP-rearranged products 4 were the major products, and they were generated in moderate yields using the optimal conditions with slight modifications. A plausible mechanism for this cycloisomerization is depicted in Scheme 3 and is based on isotope labeling experiments and previous reports.7 As shown in path a, coordination of the terminal alkyne in VDCP 1 or 2 with the AuI catalyst initially affords gold species 5, which undergoes a 6-exo-dig cyclization to generate equilibrating intermediates 6 and 7. Vinylgold intermediate 6 subsequently undergoes an intramolecular cyclization to generate the corresponding products 3 with release of the AuI catalyst, which is the major process when n = 1. When n = 2, gold species 5 undergoes a 5-exo-dig cyclization to give vinylgold species 8 (Scheme 3, path b). Then intermediate 8 undergoes an intramolecular cyclization of the nucleophilic vinylgold moiety to afford cyclobutene-containing bicyclic intermediate 9 together with concomitant release of the gold catalyst, which generates the corresponding products 4 through a cyclobutene ring-opening process. This is a major process when n = 2. 2.1.2. Gold Carbene Intermediates Generated via VDCPs and Their Reactivity. In 2012, we presented a novel oxidative ring expansion of VDCPs 10 with pyridine N-oxide 12 catalyzed by Ph3PAuCl in the presence of AgSbF6. This transformation could be considered the first example confirming that gold carbenoid intermediates can be generated from VDCPs with a gold catalyst (Scheme 4).8 Notably, theoretical calculations indicated that cyclobutylgold carbene

intermediates 11 are much more stable than all of the other possible reaction intermediates. Intermediates 11 are oxidized by 12 to provide the corresponding alkylidenecyclobutanone derivatives 13. To demonstrate that this method of generating gold carbenoid intermediates from VDCPs is useful for other transformations, we designed and synthesized ene-VDCP derivatives 14 and anticipated that the in situ-generated gold carbenoid intermediates could be captured by the allyloxyl group via a cyclopropanation. Interestingly, we achieved cyclopropanation and allyl transfer through controllable carbene- and non-carbene-related processes, respectively (Scheme 5).9 Moreover, the chiral gold(I) complex could catalyze this reaction and give the corresponding cyclopropanation products 15 in good yields with 80−87% ee (Scheme 5, eq 1). In general, when the ortho substituent of VDCPs 14 was a H or F atom, cyclopropanation products 15 were acquired in good to excellent yields (Scheme 5, eq 2). However, when R3 was a sterically bulky substituent such as Cl, Br, or tBu, allyl transfer products 16 and 17 were obtained in good yields depending on the steric environment surrounding the alkene moiety along with moderate ee values using a chiral gold(I) complex (Scheme 5, eqs 3 and 4). Plausible mechanisms based on previous literature and preliminary density functional theory calculations for the goldcatalyzed cycloisomerizations of ene-VDCP derivatives via carbene- and non-carbene-related processes are shown in Scheme 6. When the ortho position has a H or F substituent, the reaction proceeds through a carbene. Upon coordination of 1669


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Accounts of Chemical Research Scheme 6. Proposed Mechanism for the Formation of 15a, 16g, and 17k

Scheme 7. Gold Carbene-Induced C(sp3)−H Functionalization

a gold catalyst with VDCP 14a, intermediate 18 is generated, which undergoes a ring expansion to afford gold-stabilized cationic intermediate 19 and carbenoid species 20. Subsequent cyclopropanation forms polycyclic product 15a. When R3 = Me, Cl, Br, or tBu at the ortho position on the benzene ring, the oxygen atom in 14g attacks the middle carbon of the allenyl moiety in intermediate 21, probably because of the increased nucleophilicity of the oxygen atom, affording the corresponding oxonium intermediate 22, which undergoes an SE′ allyl transfer to generate product 16g via intimate ion pair 23. For 14k, the oxygen atom exclusively attacks the terminal carbon at the allene moiety of the VDCP in intermediate 24 to form oxonium intermediate 25, presumably because of the steric bulk at the alkene site, and 25 similarly undergoes an allyl transfer to give 17k via intimate ion pair 26. Finally, the

gold species is quenched by the allylic cation to afford the allyltransferred product. Gold(I)-catalyzed redox-neutral C−H bond functionalization reactions are one of the most challenging problems in the field of homogeneous gold catalysis.10 In 2016, a novel stereoselective gold-catalyzed C(sp3)−H bond functionalization was achieved, giving benzoxepine derivatives 28 in moderate to good yields with high ee values by means of this new process for generating gold carbenes (Scheme 7).11 This was the first example of an asymmetric gold carbeneinitiated C(sp3)−H bond functionalization. A plausible mechanism for this gold-catalyzed stereoselective C(sp3)−H bond functionalization is shown in Scheme 8. Coordination of the cationic Au(I) complex to the allene moiety of VDCP 27a gives intermediate 29, which undergoes a 1670


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allene motif in VDCP 32a is activated by a cationic gold species to produce gold carbene 38 via intermediates 36 and 37. The intramolecular nucleophilic attack of the methoxymethyl group to the carbene center subsequently affords seven-membered oxonium intermediate 39. The C−O bond is then cleaved along with dearomatization to give intermediate 40. Cyclobutanone intermediate 42 is produced upon hydrolysis and keto−enol tautomerization. Finally, the gold complex serves as a Lewis acid and promotes the aromatization along with a 1,5-H transfer to afford product 35a.

Scheme 8. Proposed Mechanism for Gold-Catalyzed C(sp3)−H Bond Functionalization

2.2. Rhodium-Catalyzed Reactions of VDCPs

Organorhodium chemistry has been recognized as a powerful synthetic tool in organic chemistry and other related fields for many years. In particular, rhodium-catalyzed cycloadditions, Pauson−Khand reactions, and asymmetric allylic substitutions have received a substantial amount of attention from organic chemists because of their convenience, relatively low environmental impact, and good atom economy.13 2.2.1. Rhodium-Catalyzed Cycloadditions of VDCPs. In 2010, a new, efficient catalytic system was established for the intramolecular Rh-catalyzed cycloaddition of VDCPs 43 (Scheme 11).14 In this new system, MeCN was identified as being critical for the formation of bicyclo[5.1.0]octylene derivatives 44. Alternatively, a catalytic system consisting of [RhCl(CO)2]2 and toluene without MeCN led to [2 + 2] cycloaddition adducts 45. On the basis of previous work and results of control experiments, we proposed that coordination of MeCN and the tethered terminal alkene to the Rh(I) metal center generated intermediate 46 in situ. Next, oxidative addition of the rhodium(I) complex into the neighboring allylic C−H bond affords π-allyl rhodium−hydrogen species 47, which undergoes intramolecular cycloaddition to the allene moiety to form seven-membered carbocyclic rhodium−hydrogen species 48. Finally, reductive elimination affords product 44 with regeneration of the Rh(I) catalyst. In 2011, we developed another example of intramolecular cycloadditions of yne-VDCPs and ene-VDCPs catalyzed by rhodium(I); these reactions provide functionalized polycyclic products in moderate to good yields with high regio- and diastereoselectivities.15 In this cycloaddition reaction of yneVDCPs 49, coordination of the internal double bond of the allene and alkyne moiety to the rhodium(I) complex forms

ring expansion to give gold carbene species 30 because of its amphiphilic character. A C(sp3)−H bond functionalization subsequently occurs in intermediate 31 to give the corresponding benzoxepine product 28a with elimination of the cationic gold(I) catalyst. To further investigate the electrophilic properties of these new gold carbene species and expand their reaction modes, we developed a novel C−O bond cleavage process using VDCPs as starting materials (Scheme 9). Upon gold(I) catalysis, the gold carbenes generated in situ from VDCPs 32 could undergo an intramolecular nucleophilic attack to afford C−O bond cleavage products 34 or 35 in the presence of water in good yields.12 In addition, the stereochemistry of products 34 and 35 could be controlled by utilizing different ligands on the gold catalyst. We speculated that the steric bulkiness of the ligands on the gold(I) catalyst could control the Z/E configuration to give products 34 or 35. However, at the present stage we have not found any straightforward experimental evidence to explain this finding. On the basis of control experiments, a plausible mechanism for the generation of 35 is proposed in Scheme 10. First, the

Scheme 9. Gold Carbene-Induced Intramolecular Carbon−Oxygen Bond Cleavage Reaction

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Accounts of Chemical Research Scheme 10. Plausible Mechanism for Gold Carbene-Induced Intramolecular Carbon−Oxygen Bond Cleavage

Scheme 11. Intramolecular Cycloaddition of VDCPs 43 Catalyzed by Rhodium

Scheme 12. Intramolecular [2 + 2] Cycloaddition of VDCPs 49 Catalyzed by Rh(I)

Scheme 13. Rhodium-Catalyzed Intramolecular Cycloaddition of VDCPs 53

intermediate 51 (Scheme 12). Subsequently, cyclometalation/ reductive elimination provides corresponding polycyclic products 50. For the rhodium-catalyzed intramolecular cycloaddition of ene-VDCPs 53, π-allyl rhodium hydride species 55 is produced after oxidative addition of the rhodium(I) catalyst onto the neighboring allylic C−H bond with the assistance of MeCN (Scheme 13). Subsequently, intramolecular insertion into the

internal double bond of the allene moiety leads to rhodium hydride species 56, which undergoes reductive elimination to afford products 54. Unexpectedly, when ene-VDCPs 53 having a methyl group at the terminal position or the internal position of the alkene moiety are used as substrates, different azacyclooctene derivatives 57 can be obtained in yields of 29−38% through rhodium(I)-catalyzed activation of a C(sp3)−H bond following a cyclopropane ring-opening process (Scheme 14). 1672


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ring structures in good to excellent yields (Scheme 16).17 Initially, cyclometalation of 62 with a Rh(I) catalyst gives rhodacyclic intermediate 64. Insertion of CO into 64 provides two regioisomers, 65 and 66, which undergo reductive elimination to produce the corresponding cycloadducts 63. 2.2.3. Rhodium-Catalyzed C−H Bond Activation Reactions of VDCPs. In recent years, C−H bond functionalization has been established as a powerful tool for organic synthesis.18 In 2017, we demonstrated switchable C− H bond functionalizations of benzamides and VDCPs 67 through variation of the directing group from C(O)NH−OPiv to C(O)NH−OBoc, providing products 69 or 70, respectively, under mild conditions (Scheme 17).19 Several possible reaction pathways have been proposed, as shown in Scheme 18. Under the catalysis of Cp*Rh(III), substrates 68a and 68b undergo direct C−H bond activation to form intermediates 71. Insertion of VDCP 67a into 71 forms intermediate 72 when the directing group is C(O)NH− OPiv. Subsequent reductive elimination along with internal oxidation results in C−N bond formation/N−O bond cleavage to afford product 69a with release of the Rh(III) catalyst (cycle A). When substrate 68 has a C(O)NH−OBoc protecting group, the insertion of 67a into 71 gives intermediate 73, and then N−Rh bond cleavage gives intermediate 74. Subsequent β-C elimination affords intermediate 75, which undergoes N− Rh bond re-formation to afford intermediate 76 (cycle B, path a). Alternatively, intermediate 73 may undergo β-C elimination of the cyclopropane to generate intermediate 76 (cycle B, path b). Similarly, reductive elimination and internal oxidation leading to C−N bond formation/N−O bond cleavage occur to give product 70a and release the Rh(III) catalyst. 2.2.4. Rhodium-Catalyzed Asymmetric Allylic Substitutions of VDCPs. Asymmetric allylic substitution is one of the most important strategies for stereoselective carbon− carbon and carbon−heteroatom bond formation and has many applications in the synthesis of biologically interesting compounds.20 We recently found that cationic Rh(I) complexes could insert into the weaker distal C−C bond of cyclopropane rings and then rearrange to give a new type of trimethylenemethane−rhodium (TMM−Rh) complex (78, Scheme 19). In contrast to traditional TMM−metal complexes,21 this new type of TMM−Rh species includes an inner olefinic moiety that can react with a carbonyl group to generate electrophilic Rh−π-allyl intermediate 79, which can serve as an efficient electrophile for allylic substitution. Very recently, we demonstrated a synergistic rhodium/silver dual-catalyzed cycloisomerization/cross-coupling of ketoVDCPs 81 with terminal alkynes, and these reactions afford a series of highly functional six-membered ring products with high regio- and enantioselectivities (Scheme 20).22 A wide substrate scope was tolerated by this new cycloisomerization/ cross-coupling reaction, which allowed the preparation of a range of six-membered ring derivatives 83 including multiple functional groups such as tertiary hydroxyl groups and alkenyl and alkynyl moieties in good to excellent yields with outstanding ee values. On the basis of the results of control experiments, a plausible mechanism for this rhodium/silver dual-catalyzed cycloisomerization/cross-coupling of keto-VDCPs with terminal alkynes is proposed as depicted in Scheme 21. Initially, TMM−Rh complex 84 is generated from the oxidative addition of the weaker distal C−C bond following a rearrangement. Subsequent ketone carbometalation generates

Scheme 14. Rhodium-Catalyzed C(sp3)−H Bond Activation of VDCPs 53

Scheme 15. Rhodium-Catalyzed Pauson−Khand Reaction of VDCPs 53

Scheme 16. Rhodium-Catalyzed Pauson−Khand Reaction of VDCPs 62

2.2.2. Rhodium-Catalyzed Pauson−Khand Reactions of VDCPs. In 2012, we explored a Pauson−Khand-type [3 + 2 + 1] cycloaddition reaction of ene-VDCPs 53 with CO under rhodium catalysis, and the reaction provided a series of aza- or oxabicyclic products 58 in moderate to good yields with high regio- and diastereoselectivities (Scheme 15).16 Oxidative addition of the distal C−C bond of cyclopropane along with isomerization generates rhodacyclobutane intermediate 59, which undergoes migratory insertion and insertion of CO to give intermediate 60 or 61. Then products 58 can be obtained from 60 or 61 via reductive elimination along with regeneration of the rhodium(I) catalyst. A highly efficient Rh(I)-catalyzed Pauson−Khand-type [2 + 2 + 1] cycloaddition of ene-VDCPs 62 with CO was achieved by our group, and the reaction generated a range of fused 6,51673


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Accounts of Chemical Research Scheme 17. Rhodium(III)-Catalyzed C−H Bond Functionalization of Benzamides and VDCPs 67

Scheme 18. Proposed Mechanisms for Rh(III)-Catalyzed C−H Bond Functionalization of Benzamides and VDCPs

Scheme 19. VDCP as a Precursor To Generate a New Type of TMM−Rh Complex

followed by reductive elimination and double-bond isomerization via intermediate 89 produces corresponding lactone derivative 90. The isolation of 90 provides evidence for the intermediacy of oxa-rhodacyclic species 85. We recently demonstrated another unprecedented example of hydroamination and hydroindolation of keto-VDCPs 81 via a TMM−Rh intermediate with high regio- and enantioselec-

intermediate 85. Meanwhile, terminal alkyne 82a reacts with AgX (X = NTf2) to provide alkynyl-Ag intermediate 86, which can rapidly undergo transmetalation to Rh to give intermediate 87. Reductive elimination from intermediate 87 gives the corresponding alkoxy-Rh intermediate 88. Protonolysis of intermediate 88 gives the final cycloisomerization/crosscoupling product 83aa. Carbonylation of intermediate 85 1674


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Scheme 20. Highly Enantioselective Cycloisomerization/Cross-Coupling of VDCPs 81 with Terminal Alkynes 82 Catalyzed by Rhodium/Silver

2.3. Palladium-Catalyzed or Palladium-Initiated Reactions of VDCPs

Scheme 21. Proposed Mechanism for Rh/Ag-Catalyzed Enantioselective Cycloisomerization/Cross-Coupling of VDCPs with Terminal Alkynes

In 2012, Wu’s group demonstrated a PdCl2-catalyzed oxidative cycloisomerization of VDCPs 94 to yield furan-fused cyclobutenes 95, which were versatile intermediates for further transformations (Scheme 23).24 Functionalized 2-alkylidenecyclobutanones 96 could be generated with high selectivity in the presence of PdCl2 and Dess−Martin periodinane (DMP). Furthermore, in the presence of TfOH (30 mol %), 2alkylidenecyclobutanones 96 underwent a ring-contraction rearrangement reaction to give spirocyclopropane derivatives 97. Our group also developed a novel Pd-catalyzed intramolecular rearrangement of VDCPs 98 to yield functionalized dimethylenecyclopropanes 99 in moderate to high yields through a C−C bond activation utilizing the weak coordination of a sulfonamide directing group (Scheme 24).25,26 A plausible reaction mechanism is shown in Scheme 24. A sulfonamide group with a N−H moiety may serve as a weakly coordinating group for Pd(II) to generate intermediate 100. The three-membered ring subsequently opens, and intramolecular attack by the sulfonamide moiety affords the corresponding allylic Pd intermediate 101 involving an aziridine moiety. Next, the central carbon of the previous allene moiety attacks the aziridine moiety to give intermediate 102, and subsequent protonation yields the final product 99. Organofluorine compounds are frequently used in medicine, agriculture, and life and materials sciences because of their unique metabolic stability, lipophilicity, and biological properties.27 It is very important to develop new synthetic methods to access organofluorine compounds.28 In 2016, we developed a new, efficient Pd-catalyzed radical cascade iodofluoroalkyla-

tivities (Scheme 22).23 A variety of secondary amines could undergo this reaction with 81 to give hydroamination products 91 in good to excellent yields with outstanding ee values. Highly enantioselective allylic alkylation at both C3 and N1 of indoles can be achieved either by directly using indoles as nucleophiles or by a one-pot asymmetric hydroamination and subsequent oxidative dehydroaromatization of the indolines.

Scheme 22. Rhodium-Catalyzed Asymmetric Hydroamination and Hydroindolation of VDCPs 81

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Accounts of Chemical Research Scheme 23. Palladium-Catalyzed Oxidative Cycloisomerization of VDCPs 94

Scheme 24. Palladium-Catalyzed Intramolecular Rearrangement of VDCPs 98

Scheme 26. Proposed Mechanism for the PalladiumCatalyzed Radical Cascade Iodofluoroalkylation/ Cycloisomerization of VDCPs

molecular radical rearrangement, and ring opening of the cyclopropane gives radical intermediate 108, which is able to abstract the iodide from LnPd(I)I, forming the final products and regenerating the Pd(0) species. Another plausible pathway (path b) is also proposed and shown in Scheme 26. Alternatively, the same intermediate (108) may react with Rf−I again, generating the Rf· radical and directly producing products 104 or 105. In 2008, Buono’s group reported a [2 + 1] cycloaddition of norbornene derivatives 109 with tertiary propargylic acetates 110 to access VDCPs 111 by utilizing Pd(OAc)2 and secondary phosphine oxides (Scheme 27).30 In addition, when the [2 + 1] cycloaddition was performed at 60 °C in toluene instead of THF, novel bicyclo[3.2.1]octadiene derivatives 112 were acquired. It is worth noting that VDCPs 113 are intermediates in the synthesis of 112.

tion/cycloisomerization reaction of ene-VDCPs 103 with fluoroalkyl iodides that afforded a variety of difluoromethylated or perfluoroalkylated pyrrolidines tethered to alkyl iodide derivatives 104 and 105 in high yields (Scheme 25).29 The reactions proceeded under mild conditions with high atom economy and provided efficient access to difluoromethylated or perfluoroalkylated pyrrolidines. On the basis of the results of control experiments, possible reaction mechanisms for the formation of 104 and 105 are outlined in Scheme 26. In path a, a single electron transfer between Rf−I and Pd(0) generates a fluoroalkyl radical, Rf·. Next, addition of Rf· to the double bond of VDCP 103 produces another radical intermediate, 106. Subsequent 5-exotrig cyclization gives methylenecyclopropane (MCP) radical intermediate 107. Intermediate 107 undergoes an intra-

Scheme 25. Palladium-Catalyzed Radical Cascade Iodofluoroalkylation/Cycloisomerization of VDCPs 103

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Accounts of Chemical Research Scheme 27. Synthesis of VDCPs 111 and Their Ring Expansion via Palladium-Catalyzed [2 + 1] Cycloaddition

Scheme 28. Palladium-Catalyzed [2 + 1] Cycloadditions for the Synthesis of VDCPs and Further Transformations

Scheme 31. Proposed Mechanism for the Fe(III)-Catalyzed Cycloisomerization of VDCPs

Scheme 29. Cu(I)-Catalyzed Cyclizations of VDCPs 94

acids 115 under palladium catalysis to generate oxabicyclo[3.2.1]oct-2-ene derivatives 116. 2.4. Copper-Catalyzed Reactions of VDCPs

In 2013, Wu’s group developed interesting cyclization− dimerization reactions of VDCPs 94 catalyzed by CuCl to access benzofuran-7(3aH)-one derivatives 117, which have one highly strained three-membered ring and one fourmembered ring (Scheme 29, eq 1).33 In 2014, Ren’s group reported another Cu-mediated electrophilic cyclization reaction of VDCPs 94 to efficiently synthesize highly substituted furan derivatives 118 (Scheme 29, eq 2).34

Scheme 30. Iron(III)-Catalyzed Cycloisomerizations of VDCPs 119

2.5. Iron-Catalyzed Reactions of VDCPs

Compared with traditional transition-metal catalysis, iron catalysts have many advantages, such as lower costs and toxicity and improved stability and operational simplicity; thus, these catalysts have emerged as powerful tools in organic synthesis in recent years.35 In 2015, we developed a novel intramolecular cycloisomerization of acetal-VDCPs 119 catalyzed by Fe(III) under mild conditions, providing a range of halogenated 1,2-disubstituted cyclobutene tethered to tetrahydropyrrole derivatives 120 in moderate to good yields (Scheme 30).36 A plausible mechanism for the Fe(III)-catalyzed cycloisomerization is proposed in Scheme 31. Initially, FeCl3 abstracts a methoxy moiety from 119a to generate an anionic

Very recently, Buono and Clavier reported another efficient catalytic system for [2 + 1] cycloadditions of oxanorbornene derivatives 113 and tertiary propargyl esters 110, and the reaction gives a variety of VDCPs 114 (Scheme 28).31,32 Furthermore, VDCPs 114 can react with a series of carboxylic 1677



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FeCl3(OMe)− species and oxocarbenium intermediate 121. Next, a Prins-type 5-exo-trig cyclization occurs to give cationic MCP intermediate 122, which undergoes a ring expansion rearrangement to afford intermediate 123. Nucleophilic attack of a chloride anion from MeCOCl to intermediate 123 yields the desired product 120a.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.accounts.8b00171.

3. CONCLUSION In this Account, we have summarized the recent advances in transition-metal-catalyzed reactions of vinylidenecyclopropanes

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General procedures for the synthesis of vinylidenecyclopropanes (PDF)

AUTHOR INFORMATION

Corresponding Author

Scheme 32. Tendency and Challenges in the Development of Chemical Transformations of VDCPs

*E-mail: [email protected]. ORCID

Min Shi: 0000-0003-0016-5211 Notes

The authors declare no competing financial interest. Biographies Dr. Song Yang received his B.S. from East China University of Science and Technology in 2013 and his Ph.D. from East China University of Science and Technology in 2018 under the direction of Professor Min Shi. Dr. Prof. Min Shi received his B.S. in 1984 from the Institute of Chemical Engineering of East China (now named East China University of Science and Technology) and his Ph.D. in 1991 from Osaka University in Japan. He completed his postdoctoral research experience with Prof. Kenneth M. Nicholas at the University of Oklahoma (1995−1996) and worked as an ERATO Researcher at the Japan Science and Technology Agency (1996−1998). He is currently a group leader of the State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences.

(VDCPs). The different types of easily prepared functionalized vinylidenecyclopropanes (FVDCPs) generated via transition metal catalysis demonstrate the diversity of the products, which are useful substrates in organic synthesis. These newly developed synthetic methodologies provide a powerful protocol for accessing many novel carbocyclic, heterocyclic, or polycyclic structures with different-sized skeletons. As heterocyclic and polycyclic structures widely exist in biologically active natural products, organic materials, agrochemicals, and pharmaceuticals, the preparation of heterocycles and polyheterocycles and their transformations are undoubtedly at the foundation of organic synthesis.37 These VDCP-derived heterocyclic and polycyclic compounds, such as polycyclic indoles, benzoxepines, difluoromethylated or perfluoroalkylated pyrrolidines, and highly substituted furan derivatives, have many applications in the synthesis of natural products and drug-like substances. Although significant advances in this area have been made by us and other groups, there are still challenges that remain to be solved in this field (Scheme 32). For example, the current discoveries have not included significant synthetic applications, especially in the synthesis of targeted natural products and bioactive substances. Second, although gold-, rhodium-, and palladium-catalyzed reactions of VDCPs have been scrutinized, transformations of VDCPs catalyzed by other transition metals are still insufficient. In addition, increased effort should be made to design and synthesize more novel types of FVDCPs and explore their reactivities. We expect that this Account will attract the attention of the community and serve as an entry point for reaction discovery in the near future.

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ACKNOWLEDGMENTS We are grateful for funding from the National Basic Research Program of China (973 Program) (2015CB856603), the National Natural Science Foundation of China (20472096, 21372241, 21572052, 20672127, 21421091, 21372250, 21121062, 21302203, 20732008, 21772037, and 21772226), and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB20000000 and sioczz201808).

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