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Progress in the Synthesis and Transformations of Alkylidenecyclopropanes and Alkylidenecyclobutanes Alberto Brandi,* Stefano Cicchi, Franca M. Cordero, and Andrea Goti Dipartimento di Chimica “Ugo Schiff”, Università degli Studi di Firenze, Via della Lastruccia 13, I-50019-Sesto Fiorentino, Italy 3.5.2. Ring Enlargements 3.5.3. Pericyclic Rearrangements 3.5.4. Isomerizations 3.5.5. Miscellaneous Transformations 4. Concluding Remarks Author Information Corresponding Author Notes Biographies References

CONTENTS 1. Introduction 2. Alkylidenecyclopropanes 2.1. Syntheses of Methylene- and Alkylidenecyclopropanes (MCPs and ACPs) 2.1.1. Formation of the Cyclopropane Ring 2.1.2. From Preformed Cyclopropanes 2.1.3. From Preformed Methylene- and Alkylidenecyclopropanes 2.2. Reactions 2.2.1. Reactions of the CC Double Bond with Conservation of the Ring 2.2.2. Rearrangements 2.2.3. Reactions Involving Cyclopropane RingOpening 2.3. Naturally Occurring and Biologically Active Alkylidenecyclopropanes 2.4. Theoretical Studies 3. Alkylidenecyclobutanes 3.1. Introduction 3.2. Synthesis of Alkylidenecyclobutanes by Ring Formation 3.2.1. By Allene−Alkene [2+2] Cycloaddition 3.2.2. By Metal-Catalyzed Cyclization 3.2.3. Miscellaneous 3.3. By Ring Enlargement of Cyclopropane Compounds 3.3.1. Thermally Induced 3.3.2. Induced by Acids and Electrophiles 3.3.3. Metal-Catalyzed 3.3.4. Miscellaneous 3.4. Synthesis of Alkylidenecyclobutanes from Preformed Four-Membered Ring Compounds 3.4.1. From Cyclobutanones or Ketones 3.4.2. HX Eliminations 3.4.3. XY Eliminations 3.4.4. Isomerization Reactions 3.5. Selected Rearrangements of Alkylidenecyclobutanes 3.5.1. Ring-Openings © 2014 American Chemical Society

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1. INTRODUCTION Methylene- and alkylidenecyclopropanes (MCPs and ACPs, 1, Figure 1) and -cyclobutanes (MCBs and ACBs, 2, Figure 1) are

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Figure 1. General structures of MCPs1 and MCBs.2

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highly strained molecules, but at the same time most of them are surprisingly stable to allow their use in many synthetic applications. Being multifunctional reagents with high energy, they envision an enormous potential in organic syntheses. Indeed a real explosion of investigations on the synthesis and transformations of these compounds has been observed in the last 20 years. This flourishing of new reactivity has been documented in the literature by a large number of reviews, albeit mainly related to methylene- and alkylidenecyclopropanes (1).1 Methyleneand alkylidenecyclobutanes (2) have received much more scarce attention in the same period.2 The purpose of this Review is to describe recently published literature on the synthesis and reactivity of alkylidenecyclopropanes (1) and to introduce the chemistry of methylene- and alkylidenecyclobutanes (2), materials that have received much less attention. The part devoted to alkylidenecyclopropanes (1) is mainly aimed to gather recently published literature on their synthesis and reactivity as an extension to the articles by Pellissier.1h,j The analysis of the recent literature was particularly focused on the

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Received: December 6, 2013 Published: June 13, 2014

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reactions involving catalysis by metals, which represent the field of major development in recent years.

Scheme 2. Simmons−Smith Reaction for the Cyclopropanation of Allenes4

2. ALKYLIDENECYCLOPROPANES 2.1. Syntheses of Methylene- and Alkylidenecyclopropanes (MCPs and ACPs)

Despite the inherent simplicity of the methylenecyclopropane (MCP) moiety, its peculiar reactivity, and its consequent application in a large number of synthetic applications, requires the availability of MCP derivatives bearing a wide variety of substituents, also in enantiomerically pure form. This has given origin to a great number of synthetic approaches and kept the attention of research groups in developing new ones. This variety can be rationalized in a few general approaches as was reported in our previous review.1e Pellissier has confirmed such organization of the material in a more recent review.1h For these reasons, while keeping the division of the subjects, we will limit our description to some of the noteworthy works that appeared since 1998 and focus on articles that appeared recently in the literature. 2.1.1. Formation of the Cyclopropane Ring. 2.1.1.1. Carbene and Carbenoid Additions. The addition of carbenes 4 to allenes 5 or alkylidenecarbenes 7 to alkenes 6 (Scheme 1) is the most straightforward approach to MCPs and alkylidenecyclopropanes (ACPs) 3 and has found wide applications since its first description in the early 1960s.3

Scheme 3. Mechanism of Reaction of a Diaryallene with Dibromocarbene5

Scheme 1. Addition of Carbenes to Allenes or Alkylidenecarbenes to Alkenes3

Scheme 4. Reaction of Diarylvinylidenecyclopropanes with Dibromocarbene5

The various synthetic approaches differ in the way the carbenoid species is produced. The Simmons−Smith reaction for the cyclopropanation of allenes, using zinc carbenoids, is a well-established method, widely discussed1e and applied also to the production of enantiopure compounds. In a work focused on the production of spiro[2.2]pentanes 11 and 13, an attempted double cyclopropanation of α-substituted allenamides 8 and 9 also gives synthetically useful amounts of methylenecyclopropane derivatives 10 and 12 (Scheme 2).4 Halocarbenes, produced by alkaline treatment of CHCl3, CHBr3, or alkyl halides, cycloadd to allenes to produce 1,1dihalo-2-alkylidenecyclopropanes.1e However, (dibromomethylene)cyclopropane 17 is obtained when the substrate is a diarylallene such as 14. The suggested mechanism involves the homolytic cleavage of the distal carbon−carbon bond of the cyclopropane ring and subsequent rearrangement (Scheme 3).5 When the same approach is applied to diarylvinylidenecyclopropanes, like compound 18, the reaction affords the corresponding 1-(dihalomethylene)spiropentane 19 in a reaction that occurs at room temperature (Scheme 4).5 1,1-Difluoro-2-methylenecyclopropane backbones are easily accessible by reaction of a difluorocarbene source with allenes. Trimethylsilyl fluorosulfonyldifluoroacetate (FO2SCF2CO2SiMe3, TFDA) is a good precursor of difluorocarbene and reacts with allenes to afford the expected substituted MCPs. The thermal rearrangement of substituted

1,1-difluoromethylenecyclopropanes affords new MCP derivatives. The reaction becomes selective and more useful when using sulfonylallenes, such as 20. In this case, the carbene derivative attacks preferentially the electron-rich double bond to afford the MCP derivative 21 (Scheme 5).6 Scheme 5. Reaction of Sulfonylallenes with TFDA6

Compounds 21 can be subsequently modified to produce new ACPs through known procedures such as the Heck reaction or reaction with electrophiles after lithiation of the double bond.6 The thermal isomerization of compound 21 (R1, R2 = Me) affords two new difluorinated MCP derivatives 22 and 23 (Scheme 6).7 The metal-mediated addition of a carbene species, obtained from a diazo compound, to double bonds is the main synthetic approach for the synthesis of cyclopropanes and has been 7318


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Scheme 6. Thermal Isomerization of 216

Scheme 8. Effect of the Silyl Group on the Rh-Catalyzed Cyclopropanation of Allenes9

thoroughly applied to the production of ACPs.1e The enantioselective cyclopropanation of allenes mediated by rhodium has been demonstrated to be an effective method. The use of a rhodium complex, Rh2(S-DOSP)4 (26), with an aryldiazoacetate 25 and allenes 24 affords the expected ACP derivatives 27 in good yields and with high enantiomeric excesses (Scheme 7).8 Scheme 7. Enantioselective Cyclopropanation of Allenes Mediated by Rhodium8

two different products: while the Rh catalyst promotes selectively a C−H insertion process, the Cu(I) salt induces the cyclopropanation reaction (Scheme 9).10 Scheme 9. Intramolecular Rh-Catalyzed Cyclopropanation of Allenes10

Worth of noting is that, although toluene is a common solvent for cyclopropanation reactions, in this case it caused side reactions presumably due to the lower reactivity of allenes with respect to monosubstituted alkenes. The authors also reported a more than 10-fold increase in reactivity of silyl substituted allenes with respect to alkyl-substituted ones and justified the result with the hyperconjugation of the silicon atom stabilizing a partial positive charge buildup on C-2 of the allene group during the cyclopropanation. The same research group studied the substituent effects on the rates of rhodiumcatalyzed allene cyclopropanation through a series of competition reactions of phenylallene 24 (R1 = Ph, R2 = H) versus substituted allenes.9 Electronic effects can influence the reactivity of allenes, although only a small effect can be attributed to resonance, due to the cumulene structure of the allene. The presence of a silyl group, attached to the nonreacting π-bond, has a strong β-silicon effect accelerating the reaction on the other π-bond. This makes feasible the enantioselective synthesis of ACPs from 1,3-disubstituted allenes. While the 1,3-dialkylsubstituted allene 28 reacts with diazoacetate 29 in the presence of Rh2(S-DOSP)4 to afford a mixture of compounds 30 and 31, under the same conditions, 1-(trimethylsilyl)-1,2-butadiene (32) affords only ACP 33 with excellent enantiomeric excess, but yields were not reported (Scheme 8). The lower reactivity of allenes toward carbenes or carbenoid species with respect to double bonds is confirmed by the study of an intramolecular process. Starting from the same substrate of general structure 34, the use of Rh2(OAc)4 or CuI affords

Very recently, Charette11 proposed a new protocol for the enantioselective synthesis of diacceptor ACPs, that is, ACPs bearing two electron-withdrawing substituents on the same C atom of the ring, like compound 39. The carbene obtained from α-cyano diazo esters 37 in the presence of a Rh(II) catalyst performed very nicely (Scheme 10). Scheme 10. Enantioselective Synthesis of Diacceptor ACPs11

The presence of one CN group in the diazo compound is mandatory for a positive outcome of the reaction. The authors justify this requisite with the inherent in-plane conformation of the linear CN group that maximizes the electrophilicity of the metal−carbene species. On the contrary, other electronwithdrawing groups (EWG) adopt preferentially an out-ofplane conformation that makes the carbene less electrophilic (Figure 2). 7319


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Scheme 13. Use of Aliphatic Ketones for the Synthesis of 7Methylenenorcaranes14

A carbenoid chain process is proposed for the alkylative carbocyclization of ω-iodoalkynyl tosylates with alkynyllithium compounds. The slow addition of a THF solution of iodobutynyl tosylates of general structure 53 to a solution of 1-alkynyllithium 54, at 0 °C, affords the iodinated ACP derivatives 55 (Scheme 14).15

Figure 2. Conformations of substituted metal−carbene species.11

This protocol was extended to the enantioselective synthesis of ACPs using rhodium complexes bearing chiral azetidinated ligands (S-IBAZ) 41. This is the first example of an enantioselective synthesis of ACPs bearing two EWGs, like compound 42 (Scheme 11).

Scheme 14. Alkylative Carbocyclization of ω-Iodoalkynyl Tosylates15

Scheme 11. Enantioselective Synthesis of ACPs Bearing Two EWGs11

The RuCl(cod)Cp* (45) catalyst precursor in the presence of N2CHSiMe3 (44) promotes the regioselective transformation of allenynes 43 and 47 into the new alkylidenebicyclo[3.1.0]hexane derivatives 46 and 48 containing an adjacent Z-alkenyl group (Scheme 12).12

The proposed reaction mechanism is a combination of Knorr’s type process, proposed for the formal substitution of a vinyl bromide by an organolithium compound,16 and the process proposed by the authors for a cyclization reaction of ωiodoalkynes.17 The I/Li exchange reaction of iodoalkyne 56 with RLi affords the corresponding lithium acetylide 57, which undergoes an exo-trig cyclization followed by a vinylic substitution of the cycloalkylidenecarbenoid to produce the alkenyllithium intermediate 59. I/Li exchange furnishes the final product 60 (Scheme 15).

Scheme 12. Transformation of Allenynes into the Alkylidenebicyclo[3.1.0]hexane Derivatives12

Scheme 15. Proposed Mechanism for the Alkylative Carbocyclization15

Concerning the complementary synthetic approaches, that is, the addition of alkylidenecarbene or carbenoid species to alkenes, although the alkylidenecarbenes have been studied thoroughly in the past,13 their application to the synthesis of ACP or MCP has not produced notable examples other than those discussed previously.1e An exception is represented by the work of Aoyama and Shioiri in which the alkylidenecarbenes are prepared by the reaction of aliphatic ketones 49 with TMSC(Li)N2 (51) and subsequently reacted in situ with alkenes. This reaction produces a series of substituted 7methylenenorcaranes 52 (Scheme 13).14

2.1.1.2. Eliminations. The parent MCP 1 (R1 = R2 = R3 = H) has always been a challenging product due to its volatility. Since the first synthesis, the elimination route turned out to be the best approach.1e More recently, Binger has optimized the synthetic procedure starting from methallyl chloride and using NaN(SiMe3)2 as the base. The reaction affords a mixture of MCP and 1-methylcyclopropene. Pure MCP is obtained bubbling the mixture through a DMSO solution of t-BuOK.18 Analogously, vinyl-substituted MCP 62 can be obtained by 7320


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treatment of the 4-chloromethyl-2,4-dienyl carbamate 61 with BuLi and a diamine. The use of (−)-sparteine allows the synthesis of enantioenriched 62, whose absolute configuration was, however, not determined (Scheme 16).19

Scheme 19. Synthesis of a Cyclopropylsulfone and Its Conversion in an ACP Derivative22

Scheme 16. Synthesis of an Enantioenriched MCP19

Allenes bearing a good leaving group can also be used for the synthesis of ACP derivatives through an elimination step. The leaving group can be a bromide20 or a selenonium ion (Scheme 17).21 Scheme 17. Use of Allenes with Good Leaving Groups for the Synthesis of ACP Derivatives20,21 Scheme 20. Reaction of 1,1-Dibromocyclobutanes with MeLi24

A common mechanism can be proposed in which the enolate 65, produced by deprotonation of malonate with NaH, attacks the central carbon atom of the allene moiety 63, and the adduct, after a proton transfer, cyclizes to form the ACP derivative 64 (Scheme 18).

Scheme 21. Reactivity of Cyclobutylmagnesium Carbenoids25

Scheme 18. Mechanism of the Reaction of a Malonate with Allenes with Good Leaving Group20,21

The carbanions of 3-halopropylpentachlorophenyl sulfones (69) cyclize to afford the cyclopropylsulfone 70. The use of an excess of base and of aromatic aldehydes or ketones affords, through a Julia−Kocienski olefination reaction, benzylidenecyclopropane derivatives 73 (Scheme 19).22 A well-studied synthetic procedure for the synthesis of ACP is the extrusion of N2 from pyrazolines, which usually affords mixture of products due to the formation of diradical resonating species. The reaction has been studied thoroughly in the past, and many examples have previously been reported,1e whereas it has very rarely found a recent application.23 2.1.1.3. Rearrangements. Cyclobutyl carbenes 75, generated by the reaction of 1,1-dibromocyclobutanes 74 with MeLi at low temperature, afford with good selectivity the corresponding ACPs 76 by rearrangement (Scheme 20).24 A new multistep synthesis of ACPs was developed starting from ketones and exploiting the reactivity of cyclobutylmagnesium carbenoids in the last step. The magnesium carbenoids 79, formed in situ, undergo a rearrangement of the ensuing carbene affording the alkylidenecyclopropane derivatives 80 (Scheme 21).25

The use of an optically active sulfoxide, like 81, afforded the optically active derivative 82 with high enantioselectivity (Scheme 22). A novel dithiamethylenecyclopropane, 86, was synthesized by the reaction of dithiolactone 83 with benzyne.26 In analogy with other substrates, the cycloaddition of benzyne (obtained Scheme 22. Synthesis of an Optically Active ACP25

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94 is provided by the Pd-catalyzed reaction of propargylsubstituted malonate esters 93 with aryl halides. The selectivity of the reaction is remarkable: the aromatic substituent, introduced by the reaction, is always located trans to the quaternary carbon bearing the two carboxyl groups (Scheme 26).28

from 84 by treatment with TBAF) produced the sulfonium ylide 85, which further rearranged to the ACP derivative 86 (Scheme 23). Scheme 23. Reaction of a Dithiolactone with Benzyne26

Scheme 26. Pd-Catalyzed Reaction of Propargyl-Substituted Malonate Esters with Aryl Halides28

Whereas dimethyl-substituted vinylidenecyclopropane derivatives 87 (R2 = Me) undergo smooth oxidation with tetrapropylammonium perruthenate (TPAP) and N-methylmorpholine-N-oxide (NMO) to give the corresponding aldehydes 88, the diaryl derivatives 87 (R2 = Ar) afford the unexpected dialkylidenecyclopropane compounds 89 (Scheme 24).27

The mechanism proposed for this reaction involves the deprotonation of the π-complex 96 of the Pd species with the alkyne. The subsequent cyclopropane ring closure affords the final product (Scheme 27).

Scheme 24. Reactivity of Dimethyl- and Diaryl-Substituted (2-Vinylidene-cyclopropyl)-methanols toward Oxidation27

Scheme 27. Mechanism of the Pd-Catalyzed Reaction of Propargyl-Substituted Malonate Esters with Aryl Halides28

The mechanism proposed for this transformation is based on the reactivity of the alkoxyperruthenate 90, which, after a fast proton migration, rearranges to the final product (Scheme 25). 2.1.1.4. Metal-Mediated Formation of the Cyclopropane Ring. An easy and straightforward access to substituted ACPs

A detailed study of the metal-catalyzed reactivity of hydroxylated 1,5-allenynes 98 was performed to demonstrate the influence of the substituents and of the catalyst involved in the transformation. Compounds 98 underwent a smooth and efficient transformation into 6-methylenebicyclo[3.1.0]hexan-3one derivatives 99 employing PtCl4, or PtCl2, as the catalyst. The use of [AuCl(PPh3)] changed the outcome of the reaction into 2-ethynyl-3,6-dihydro-2H-pyran derivatives 100. Thus, hydroxylated 1,5-allenynes behave like hydroxylated 1,5-enynes, or β-hydroxyallenes, depending on the reaction conditions. However, despite potential competition between the two nucleophilic sites (i.e., the OH group and the internal allene double bond), only chemospecific transformations were found in which [Au(PPh3)]+ selectively activated the allene moiety, whereas PtClx (x = 2,4) activates only the triple bond (Scheme 28).29

Scheme 25. Mechanism of the Diaryl-Substituted (2Vinylidene-cyclopropyl)-methanols Oxidation27

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Scheme 28. Different Reactivity of Hydroxylated 1,5Allenynes toward Pt and Au Catalysis29

Scheme 30. [2+1] Cycloaddition Reactions of Phenylacetylene to Strained Double Bonds31

A very important contribution to the development of a new synthetic approach to ACPs is the one provided by Buono’s group.30,31 The development of new Pd and Pt complexes 101−105 (Figure 3), based on the use of secondary phosphine

allowed the assignment of the E configuration to the product (Scheme 31).32 Scheme 31. Enantioselective [2+1] Cycloaddition Reaction of Phenylacetylene to Norbornadiene32

Figure 3. Pd and Pt complexes for the [2+1] cycloaddition of terminal alkynes to strained double bonds.30,31

oxides, also in the enantiopure form, allowed the synthesis of ACP derivatives by a formal [2+1] cycloaddition of terminal alkynes to norbornadiene derivatives and strained double bonds. In the first work of the series, complex 101, produced in situ from Pd(OAc)2 and the corresponding ligand, was used in the reaction of norbornadiene (106) with terminal alkynes that occurred under mild conditions affording norbornene-annelated ACPs 108 in good yields (Scheme 29).30

Very recently, the same group extended the procedure to the use of ynamides. For this purpose, the most active catalytic species is the phosphapalladacycle complex 125 that afforded a number of tricyclic ACP derivatives 126 (Scheme 32).33 2.1.2. From Preformed Cyclopropanes. 2.1.2.1. Elimination. 1-Alkyl-1-halo-substituted cyclopropanes 127 easily undergo elimination of HX by treatment with a base affording the corresponding ACPs 80. This procedure was applied by de Meijere’s group to the efficient production of bicyclopropylidene (BCP, 129) starting from 128 (Scheme 33).34−36

Scheme 29. [2+1] Cycloaddition Reactions of Terminal Alkynes to Norbornadiene30

Scheme 32. [2+1] Cycloaddition Reactions of Ynamides to Norbornadiene Derivatives33

The reaction was later extended, using Pt(II) complexes 103 and 104, to a small library of strained alkenes (Scheme 30).31 The availability of enantiopure secondary phosphine oxides prompted the study of the enantioselectivity of the process. The use of enantiopure complex 104 together with mandelic acid as additive (10 mol %) afforded enantioenriched adduct (E)-110 as a rare example of E−Z enantiomerism. Computational results and vibrational circular dichroism spectrum 7323


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Scheme 33. Synthesis of ACPs by HX Elimination34−36

Scheme 36. Selenoxide Elimination Reaction for the Synthesis of ACPs44

The formal elimination of three molecules of p-toluenesulfonic acid is necessary for the transformation of tris-tosylate 141 into the corresponding exotic tris(methylene)cyclopropane ([3]radialene) 142 (Scheme 37).45 This was achieved by A one-pot alkylation elimination procedure has been used widely for the preparation of biologically active ACP derivatives. Several derivatives of ciclopropavir (see section 2.3) have been synthesized starting from MCP derivatives 132,37,38 and a multigram synthesis of the useful intermediate 13339 has been described (Scheme 34).

Scheme 37. Synthesis of Tris(methylene)cyclopropane45

Scheme 34. Synthesis of ACPs by HBr Elimination37,38

transforming the tris-tosylate 141 into the tris-iodide with sodium iodide in acetone and subsequently running the trisiodide as an ethereal solution under reduced pressure through a column of potassium hydroxide pellets heated at 150 °C. A similar procedure has been used also for dehydromesylation.46 Elimination of a bromine molecule or a bromo-acetoxy elimination, both mediated by Zn, has also been described39 The elimination of siloxanes mediated by TBAF as described in Scheme 38 allows the efficient synthesis of difluorosubstituted MCPs 144.47 Scheme 38. Elimination Reaction of Siloxanes for the Synthesis of Difluorosubstituted MCPs47

Enantiopure MCP-diol derivatives were produced through enzymatic resolution of the diol 137. Using PFL (Pseudomonas fluorescens lipase AK) or PPL (porcine pancreas lipase), the monoacetate 138 was obtained in excellent yield and with very high enantiomeric excess (Scheme 35).40 Scheme 35. Enantiopure MCPs through Enzymatic Resolution40

The reaction of 1-silylcyclopropyl bromides 145 with dichloromethyl methyl ether in the presence of an excess of butyllithium affords silyl-substituted ACPs 149. In the proposed reaction mechanism, the carbene 147, derived from the reaction of dichloromethyl methyl ether with butyllithium, reacts with the cyclopropyllithium derivative 146. Elimination of lithium chloride from the resulting carbenoid 148 and subsequent or simultaneous 1,2-shift of the silyl group affords the final products 149 (Scheme 39).48,49 An enantioselective organocatalytic approach to alkylidenecyclopropanes has been developed using the Michael addition to nitroalkenes 151 of a cyclopropane-containing aldehyde 150, obtained by a Kulinkovich reaction of ethyl 3,3-diethoxypropanoate and subsequent acetylation. The reaction requires the use of an enantiopure diphenylprolinol silyl ether 152 and an acid cocatalyst, 4-nitrophenol, to furnish acceptable yields and excellent enantiomeric excesses of ACP 153 (Scheme 40).50 2.1.2.2. Reactions with Double Bond Shift. 2.1.2.2.1. Nucleophilic Displacement. Substituted cyclopropenes are easily available, chiral ones also in enantiopure form, through the cyclopropanation of alkynes,51 and can be efficiently transformed into ACPs. Arylmethylenecyclopropenes 154, obtained

The same authors, more recently, used compound 138 as an intermediate toward the synthesis of nucleobase-substituted, biologically active, MCPs.41 The selenoxide elimination from cyclopropylmethyl selenoxides is another useful synthetic approach to ACPs and has found application in the preparation of biologically active MCPs.42,43 As an example, the synthesis of the constrained αamino acid 140, which is also an irreversible inhibitor of a bacterial enzyme, is described (Scheme 36).44 7324


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Scheme 39. Synthesis of Silyl-Substituted ACPs48,49

Scheme 42. Synthesis of ACPs by Treatment of Cyclopropene Derivatives with Grignard Reagents52,53

Scheme 40. Enantioselective Organocatalytic Approach to ACPs50

recently, the same research group extended this procedure to the preparation of highly substituted MCPs 160 containing quaternary centers.53 The study shows how the selectivity can be switched using two different catalysts: the use of CuI or CuBr·SMe2 favors the formation of the syn adduct 160a, while the use of Fe(acac)3, in some examples, favors the formation of the anti adduct 160b (Scheme 42). The utility of this synthetic approach is further increased by a subsequent transformation. Heating adducts 163 induces a rearrangement of the backbone with formation of new ACPs 164. 54 The process is stereospecific, and the use of enantioenriched cyclopropenes affords enantioenriched ACPs with complete conservation of stereochemical integrity. The limit of the process is the mandatory presence of an aromatic substituent on the cyclopropyl ring (Scheme 43). The nature of substituents on the aromatic ring influences the rate of the reaction: the presence of a MeO-substituted aromatic ring enhances the reactivity and the reaction goes to completion in 4 h, while the presence of a fluorine atom slows the reaction so that it needs 16 h to be completed. The proposed reaction mechanism involves the intermediate 165, greatly stabilized by the aromatic substituent. The overall process can be performed in a one-pot procedure without isolation of the intermediate MCP 163 (Scheme 43). Marek’s group has shown that cyclopropenyl carbinols 166 react with lithium aluminum hydride to afford the reduced cyclopropylcarbinols 167.55 However, upon addition of 20 mol % of CuI to the reaction mixture, ACPs 80 are produced. The proposed mechanism foresees the in situ formation of CuH that performs a formal SN2′ reaction (Scheme 44).56

by Rh-catalyzed cyclopropanation of alkynes with diazo compounds, can easily be transformed into the corresponding ACPs 155 by treatment with 3 equiv of DBU (Scheme 41). Scheme 41. Transformation of Substituted Cyclopropenes into ACPs by Treatment with DBU51

The presence of an arylmethylene group is mandatory for the completion of the reaction, regardless of the nature of the substituents on the aromatic ring. Fox’s group developed other interesting approaches to these compounds. When the cyclopropene derivatives 156, bearing an hydroxymethyl group on C-3 and a leaving group in the allylic position, were treated with a Grignard reagent, a regioselective carbomagnesiation with the alkylation of the ring on C-2 and subsequent elimination of MgBrOR2 occurred to produce the double bond shift to the exocyclic position (Scheme 42).52 The use of at least 5 equiv of Grignard reagent is mandatory to obtain a good yield, and the authors hypothesize a high order dependence on its concentration. A plausible mechanism suggests the double role of the Grignard reagent: as alkylating agent and as a Lewis acid (reactive intermediate 158). Very 7325


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Scheme 43. Rearrangements of ACPs upon Heating54

transformation into the corresponding acetates or diphenylphosphinites.59 The acetates of general structure 171 were transformed into the corresponding ACPs 172 simply by filtration through a silica gel column or by treatment with Amberlyst-15. The observed high selectivity toward the E isomer was justified with a chairlike transition state 173 in which the R1 substituent is in a pseudoequatorial position (Scheme 46). Scheme 46. [3,3]-Sigmatropic Rearrangement of Cyclopropenylcarbinolacetate into ACPs59

Scheme 44. Treatment of Cyclopropylcarbinols with LiAlH4 and Grignard Reagents55−58

The rearrangement of the corresponding phosphinites proceeds similarly in excellent yields although with a lower E/Z selectivity. The extension of this reactivity to more highly substituted cyclopropenylcarbinols is not trivial. As a matter of fact, compound 174 does not rearrange even after prolonged heating in refluxing toluene (Scheme 47).60 Scheme 47. Absence of Reactivity of Substituted Cyclopropylcarbinolphosphinites60

However, when the phosphinylation reaction occurs in the presence of a tertiary amine, the crude reaction mixture contains traces of the rearrangement products. A screening of tertiary bases revealed that DBU is the most efficient for promoting the transformation that now can be performed in a one-pot fashion (Scheme 48).60

Such copper-catalyzed SN2′ reaction can also be used for the addition of Grignard reagents to unprotected cyclopropenylcarbinols 166 to create a new quaternary carbon center in the cyclopropane ring of ACP 168. The reaction is efficient, and the stereoselectivity depends on the nature of the Grignard reagent (Scheme 44).57,58 The use of enantiopure cyclopropenylcarbinols 169 allows the synthesis of highly enantioenriched ACPs 170 with high selectivity (Scheme 45).57 2.1.2.2.2. Rearrangements. Cyclopropenylcarbinols 166 undergo [3,3]- and [2,3]-sigmatropic rearrangements upon

Scheme 48. Reactivity of Cyclopropylcarbinolphosphinites in the Presence of DBU60

Scheme 45. Synthesis of Enantioenriched ACPs from Enantiopure Cyclopropenylcarbinols57

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It is noteworthy that the diastereoselectivity is a function of the electron density on the phosphorus atom and of the electronic nature of the substituent in the para position of the aromatic ring. The authors suggest the formation of the zwitterionic intermediate 178 to account for the catalytic activity of DBU (Scheme 49).

Scheme 51. Possible Pd-Catalyzed Transformation of Allylcyclopropanes

Scheme 49. Proposed Mechanism of the Rearrangement60

A [2,3]-sigmatropic rearrangement is responsible for the transformation of diselenides 179 into new ACP derivatives 182. Compounds of general structure 179 are obtained upon treatment of the corresponding vinylidenecyclopropane with diphenyldiselenide in the presence of AIBN. Treatment of 179 with H2O2, in the presence of pyridine, and subsequent heating at 80 °C causes the formation of the bis-selenoxides 180, which undergo the final rearrangement as described in Scheme 50 for the major diastereomer.61

Scheme 52. N-Tosylamino Acid Esters as Nucleophiles in Pd-Catalyzed Transformations62

Scheme 50. [2,3]-Sigmatropic Rearrangement of Diselenides into ACPs61

2.1.2.3. Wittig and Related Reactions. The Wittig reaction turned out to be useful for the synthesis of ACPs despite the limitations due to the unavailability of cyclopropanones and the low reactivity of its synthetic equivalents.1e Only a limited number of reports can be found in the recent literature. Among the most important and original advances in the application of this reaction is that by Zemlicka et al., who treated the enantiopure oxaphospholane 190 with formaldehyde to afford the corresponding MCP 192 (Scheme 53). The availability of the two enantiomers of phospholane 190 allows the synthesis of both enantiomers of 192.66 Scheme 53. Wittig Reaction of an Oxaphospholane with Formaldehyde66

2.1.2.2.3. Through Transition Metal−Allyl Complexes. The palladium-catalyzed transformation of allyl derivatives represents a useful synthetic approach to produce new ACPs. Scheme 51 summarizes the reactivity and shows the scope of the reaction. A variety of soft carbon nucleophiles (stabilized carbanions) gives substitution to the terminal position of the π-allyl system with good to excellent yields (Scheme 51, route b), in contrast to hard nucleophiles, which add preferentially to the cyclopropane terminus (route a).1e Despite the great potential and the works published before 1998, since then a limited number of examples have been described. N-Tosylamino acid esters 188 were found to be good nucleophiles, giving exclusively the attack at the terminal position (Scheme 52).62 Also, anilines turned out to be good substrates. 63 Alternatively, diethylzinc,63 dimethyl malonate, and sodium formate64 acted as efficient nucleophiles. Recently, Carreira used this method to obtain an intermediate in the total synthesis of (±)-gelsemoxonine.65

Ring-fused ACPs 195 can be synthesized starting from N,Ohemiacetals of bicyclo[n.1.0]alkanones 193 in the presence of an aluminum silicon oxide (Kyowaad 700) as a promoter (Scheme 54).67 In a Wittig-type reaction, gem-dichlorocyclopropanes 196 react with ketones in the presence of the titanocene bis(triethylphosphite) complex 197. The reaction is very wide Scheme 54. Use of N,O-Hemiacetals in the Wittig Reaction67

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Recently, this approach has been extended to the use of αsulfonylallyllithium compound 209 to produce allylidenecyclopropanes 210 (Scheme 58).71

in scope and can be applied also to esters and lactones (Scheme 55).68 Scheme 55. Titanocene Bis(triethylphosphite) as Catalyst in a Wittig-type Reaction68

Scheme 58. Allylidenecyclopropanes from Cyclopropylidenoids and α-Sulfonylallyllithium Compounds71

2.1.2.4. Miscellaneous. A remarkable dimerization of cyclopropylcarbenoids catalyzed by CuCl2 was described by de Meijere’s group.69 The copper carbenoid precursors are prepared in situ by halogen-lithium exchange on gemdibromocyclopropanes 199 and 201 (Scheme 56).

New examples of substituted 3-radialenes have been synthesized with the aim to introduce electron-withdrawing substituents. Using the known Fukunaga method,72 that is, treatment of stabilized carbanions with tetrachlorocyclopropene, the syntheses of compounds 211−213 were readily achieved (Figure 4).73

Scheme 56. Dimerization of Cyclopropylcarbenoids Catalyzed by CuCl269

Figure 4. Substituted 3-radialenes.

2.1.3. From Preformed Methylene- and Alkylidenecyclopropanes. In a seminal work, de Meijere’s group demonstrated the versatility of bicyclopropylidene (BCP, 129) in the production of new, variously substituted, ACPs involving palladium catalysis.74 Treatment of BCP with iodobenzene 214, under typical Heck conditions, gives the corresponding 1-phenylallylidenecyclopropane (217) in 78% yield. The mechanism involves carbopalladation of the double bond of 129 by phenylpalladium iodide followed by a cyclopropylmethyl/homoallyl rearrangement and, finally, by β-hydride elimination (Scheme 59). The use of vinyl iodide (218) or cyclohexenyl iodide (220) gives access to new dendralenes 219 and 221. This reaction works also with 2-bromo-1,6-enynes.75 BCP itself reacts, under catalysis of Pd(OAc)2, to form allylidenecyclopropane 222, which oligomerizes to form a mixture of compounds 223−225. Using Pd(dba)2 as a catalyst, a distal bond cleavage occurs followed by dimerization to afford compound 226 (Scheme 60). Moreover, nucleophiles can trap the π-allylpalladium intermediate. Several kinds of nucleophiles have been used, ranging from acetate to malonate enolates, primary and secondary amines.76 In these reactions, the use of trifuranylphosphane (TFP) as ligand, retarding the β-elimination process, is mandatory to obtain good yields of the substituted ACPs (Scheme 61).

Magnesium cyclopropylidenoids are stable at low temperature (−60 °C) and react with nucleophiles, such as lithiumsulfonyl carbanions, to give ACPs in good yields. The synthetic procedure starts from cyclopropyl sulfides 203 that are oxidized and chlorinated to afford the precursors 204, which was, finally, treated with an excess of i-PrMgCl to produce the Mg cyclopropylidenoids 205. These reagents are treated at −78 °C with the lithium-sulfonyl carbenoids 206 to give ACPs 208 (Scheme 57).70 Scheme 57. Magnesium Cyclopropylidenoids as Precursors of ACPs70

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Scheme 59. Reaction of BCP To Afford ACPs74

The same reaction can also be used for the production of silylated ACPs by addition of disilanes, silylboranes, silylstannanes, and silyl cyanides to the double bond of BCP to afford compounds of general structure 232 (Figure 5).77

Figure 5. Compounds obtained from BCP.77

The Heck reaction can also be applied to alkenylidenecyclopropanes with similar results.78 Shi’s group has proposed several transformations of vinylidenecyclopropanes (VCPs) into substituted ACPs. Treating VCPs of general structure 18 with 2,3-dihydrophthalazine-1,4-dione (233) in the presence of iodosobenzene diacetate affords new heterocycle-annelated ACPs 235 in good yields. In a plausible reaction mechanism, the iodosobenzenediacetate oxidizes 233 to phthalazine-1,4dione 234, which is an equivalent of a 1,3-dipole reacting with the highly strained double bond of VCPs (Scheme 62).79

Scheme 60. Reaction of BCP under the Catalysis of Pd(OAc)2 and Pd(dba)275

Scheme 62. Oxidation of 2,3-Dihydrophthalazine-1,4-dione and Formation of the Adduct with VCP79

Scheme 61. Use of Different Nucleophiles To Trap the πAllylpalladium Complex of BCP76

The same group proposed also a Pd-catalyzed coupling reaction of 2-iodophenol and N-(2-iodophenyl)-4-methylbenzenesulfonamide with VCPs 236. The two different substrates required different, individually optimized, reaction conditions to afford ACPs 237 and 238, respectively (Scheme 63).80 When VCPs 236 react with ethyl (arylimino)acetates 239 in the presence of a Lewis acid, the outcome of the reaction is a 1,2,3,4-tetrahydroquinoline derivative 240 bearing an MCP Scheme 63. Reactions of VCP with 2-Iodophenol and N-(2Iodophenyl)-4-methylbenzenesulfonamide under Pd Catalysis80

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2.2. Reactions

moiety on C-3. The presence of an electron-donating group on the aryl ring of the imine is mandatory for the efficiency of the reaction (Scheme 64).81

2.2.1. Reactions of the CC Double Bond with Conservation of the Ring. Several reactions of highly strained MCPs proceed with opening of the three-membered ring (see section 2.2.3), but, under suitable conditions, addition reactions across the C−C double bond of the MCPs are also possible with conservation of the cyclopropyl unit. In some cases, especially in nitrone 1,3-dipolar cycloadditions (1,3-DC), the reactivity of the strained small ring in the initial product increases leading to new interesting compounds through a spontaneous, or thermally induced, opening of the cyclopropane ring. Recent examples of all of these kinds of reactions are illustrated in this paragraph. In methanol solution, bromine addition to unsubstituted MCP, bicyclopropylidene (129), methylenespiropentane (244), and (dicyclopropylmethylene)cyclopropane (257) occurs predominantly with retention of all three-membered rings. The rate of this reactions as well as those of the bromine addition to mono- and bisbisspiropropanated bicyclopropylidene as well as bis-spirocyclopropanated MCP have been determined.85 Addition of bromine, by way of pyridinium tribromide, to the double bond of MCP 248 gave 249 in good yield (80%) (Scheme 68).86 The 1-bromo-1-bromomethylcyclopropane

Scheme 64. Formation of 1,2,3,4-Tetrahydroquinoline Derivatives from VCP81

The 1,3-dipolar cycloaddition of nitrones 242 to VCPs 241 gives new classes of ACPs 243, in which the double bond is substituted by an isoxazolidine ring. The reaction affords mixtures of diastereoisomers, which can be separated by crystallization (Scheme 65).82 Scheme 65. 1,3-Dipolar Cycloaddition of Nitrones with VCPs82

Scheme 68. Addition of Bromine to the Double Bond of MCPs86 MCP derivatives can undergo thermal and photochemical rearrangements to afford new ACP or MCP derivatives. It is known that BCP (129) undergoes thermal rearrangement at high temperature to produce methylenespiropentane 244 along with [4] rotane 245. The relative ratio is dependent on the reaction temperature (Scheme 66). Scheme 66. Thermal Rearrangement of BCP83

249 reacted with nucleobases such as adenine and 2-amino-6chloropurine through an alkylation-elimination process to afford ACPs 250 that were used as synthetic precursors of fluorinated analogues of cyclopropavir (see section 2.3). 1′-Aryl-2-aminomethyl-substituted ACPs 251 react with iodine in the presence of K2CO3, and with PhSeBr to give the bicyclic derivatives 252 and 253, respectively, by an intramolecular nucleophilic trapping of an intermediate cyclopropylmethyl cation. Both the iodo- and the selenidocyclization are highly stereoselective, affording exclusively the trans stereoisomers (Scheme 69).87

Recently, de Meijere’s group studied the rate constant of this transformation and that of methylenespiropentane at elevated temperature.83 An interesting example of photochemical rearrangement has been described by Creary’s group. Upon irradiation with UV light (350 nm), some 3,3-dimethyl-2-acylmethylenecyclopropanes, like 246, undergo rearrangement to afford isopropylidenecyclopropanes like 247 (Scheme 67).84

Scheme 69. Reaction of 1′-Aryl-2-aminomethyl-Substituted ACPs with I2 or PhSeBr87

Scheme 67. Photochemical Rearrangement of 3,3-Dimethyl2-benzoylmethylenecyclopropane84

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Scheme 72. Aminochlorination of MCPs91

1′-Methoxy-1′-trimethylsilylmethylenecyclopropanes 149 (see Scheme 39) slowly hydrolyzed to cyclopropyl silyl ketones during chromatography on silica gel. The E-2-phenyl derivative 255 was completely converted into a diastereomeric mixture of the cyclopropyl ketone 256 (X = H) by treatment with sulfuric acid in methanol at 30 °C in 0.5 h (73% yield, trans:cis ratio = 64:36). Various electrophiles were used to trap methylenecyclopropanes 149 in situ without isolation. The results of the three-step one-pot procedure starting from 254 are summarized in Scheme 70 (see also Scheme 39).49,88 Scheme 70. Hydrolysis of 1′-Methoxy-1′trimethylsilylmethylenecyclopropanes with Electrophiles49,88

give intermediate 265 (Scheme 73).92 The homologous monoarylmethylenecyclobutanes undergo the same reaction affording the corresponding cyclobutyl ketones. Scheme 73. Reaction of 1′-Aryl-Substituted Methylenecyclopropanes with HOBt92 The Brønsted acid NH4Cl catalyzes a chemoselective hydration and hydroamination of (dicyclopropylmethylene)cyclopropane (257) by H2O and basic amines, respectively, with conservation of all three cyclopropane rings (Scheme 71).89 No conversion of 257 was accomplished with benzyl Scheme 71. Hydrolysis and Aminolysis of (Dicyclopropylmethylene)cyclopropane89 A reactivity study of 2,2-difluoro-3,3-dialkyl-(1′tosylmethylene)cyclopropanes under different reaction conditions has been reported. Distal and proximal bonds of the ring can be selectively broken by radicals and amines, respectively (see sections 2.2.3.5 and 2.2.3.4). The dimethyl derivative 267 reacted with nucleophiles such as sodium salts of ethanol, phenol, thiophenol, and diethyl malonate enolate to give the addition products 268 with conservation of the cyclopropyl unit (Scheme 74).93

alcohol or amines such as aniline or secondary dibenzylamine. Other MCP derivatives failed to give the same reaction. The unique reactivity of this MCP derivative was ascribed to the extraordinary stability of the tricyclopropylcarbenium ion initially formed upon protonation of 257. The Lewis acid FeCl3 catalyzes the aminochlorination of MCPs by N,N-dichloro-p-toluenesulfonamide (p-TsNCl2) in acetonitrile at room temperature.90 The same products 261 can be achieved under CO2 pressure (50 atm) in the absence of any metal catalyst and solvent. Lower yields or no products at all were obtained, respectively, under air or an Ar atmosphere at the same pressure. In some cases, the formation of a minor amount of the ring-opening product 262 was observed (Scheme 72).91 1′-Aryl-substituted methylenecyclopropanes 263 react with 2 equiv of 1-hydroxybenzotriazole (HOBt) to give the cyclopropyl ketones 266 in good yields. The reaction mechanism has not been completely elucidated. Some experimental evidence suggests that the reaction could proceed through epoxidation of the double bond by the HOBt tautomer (1H-benzo[d][1,2,3]triazole 3-oxide) followed by nucleophilic addition of HOBt to

Scheme 74. Reactivity of 2,2-Difluoro-3,3-dialkyl-(1′tosylmethylene)cyclopropanes with Nucleophiles93

Michael adducts obtained from methyl 2-chloro-2-cyclopropylidene-acetate (269) with appropriate nucleophiles can react by nucleophilic substitution of the chlorine atom adjacent to the cyclopropyl group affording spirocyclopropane-heterocycles. de Mejere et al.94 exploited this chemistry to prepare spiro[cyclopropane-1,4′-oxazoline] and 5-oxopiperazine derivatives 270 and 273. In the first case, the addition of arenecarboxamides in the presence of sodium hydride to the 7331


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Michael acceptor 269 was followed by an intramolecular nucleophilic substitution to yield 270 (Scheme 75). In the

77). The mode of reactivity, which involves (cyclopropylcarbinyl)-metal intermediates, is very sensitive to the substitution

Scheme 75. Reaction of 2-Chloro-2-cyclopropylideneacetate with Nucleophiles94,95

Scheme 77. Addition of o-C−H Bond of Pyridyl-Substituted Benzenes to ACPs97

second case, the unstable adducts of primary amines to 269 were directly acylated with an α-bromoacetic acid chloride under modified Schotten−Baumann conditions, and the dihalo derivatives 271 were cyclized to 273 with a second set of primary amines (Scheme 75).95 Triallylindium reacts with the methyl ester or ketone 274 affording the corresponding Michael adducts 275. Allylation of the ketone 274-COMe with allylindium sesquiiodide, diiodide, and allylmagnesium bromide occurs with the opposite regioselectivity (1,2-addition) to give the corresponding tertiary allyl alcohol. In MCPs 276, the chelating group CH2OH on C2 induces a selective allylation at the exocyclic Csp2, and cyclopropanes 277 were obtained as single trans-stereoisomers (Scheme 76).96

pattern, and in several cases the ring-opening of the cyclopropane was observed (see Scheme 180, section 2.2.3.6.2). A palladium-catalyzed addition of silyl−silyl and silyl−stannyl bonds to bicyclopropyliene (129) with retention of both rings has also been observed.77 A regio- and stereoselective hydroalkynylation of MCPs with retention of the cyclopropane ring was accomplished in the presence of Ni(cod)2 and NiCl2(dme)/Zn with PMePh2 as phosphine ligand. The introduction of the alkynyl group took place exclusively at the endocyclic carbon atom of the CC bond on the less sterically hindered face affording cyclopropanes 285 as single diastereomers (Scheme 78).98 Scheme 78. Hydroalkynylation of MCPs98

Scheme 76. Triallylindium and Allylindium Sesquiiodide Reactions with ACPs96

Analogous regio- and stereoselectivity were observed in the nickel-catalyzed reductive coupling of MCPs 286 with aldehydes and triethylborane (Scheme 79).99 Various aromatic, heteroaromatic, and aliphatic aldehydes, including ferrocenecarboxyaldehyde, were used. Under the same reaction conditions, monosubstituted and trans-2,3-dialkylsubstituted MCPs gave the corresponding ring-opened hydroacylation products (see section 2.2.3.6.2).100 Treatment of cyclopropylidenediphenylmethane (288) with an excess of lithium and naphthalene as the catalyst at −20 °C causes the opening of the ring with formation of a dianion that can react with different electrophiles. The same reaction carried out at −78 °C in the presence of a catalytic amount of 4,4′-di-

Conservation of the cyclopropane unit in transition metalcatalyzed reactions of MCPs is rather unusual (see section 2.2.3.6), but some cases have been described. During the study of a ruthenium-catalyzed hydroarylation of MCP derivatives, Ackermann et al.97 found that the o-C−H bond of pyridylsubstituted benzenes 278 adds to the CC double bond of BCP (129) and 2-phenylmethylenecyclopropane (281) in a highly regioselective manner affording compounds 279−280 and 282 with conservation of all cyclopropane rings (Scheme 7332


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Scheme 79. Nickel-Catalyzed Reductive Coupling of MCPs with Aldehydes and Triethylborane99

Scheme 82. Formation and Rearrangement of Pt Complexes with Allylidenecyclopropanes103

2,2-Difluoro-(1′-tosylmethylene)cyclopropanes 21 react with dienes such as cyclopentadiene and furan in the ionic liquid butylmethylimidazolium hexafluorophosphate ([BMIm][PF6]) to give the Diels−Alder adducts 297 (Scheme 83).104 The

tert-butylbiphenyl (DTBB) afforded, after hydrolysis, the dimer 289 with conservation of the cyclopropyl units. Under Barbiertype conditions, cyclopropyl derivatives 290 were obtained by treatment with aniline and 3-pentanone (Scheme 80).101

Scheme 83. Diels−Alder Adducts of 2,2-Difluoro-(1′tosylmethylene)cyclopropanes104

Scheme 80. Reaction of Cyclopropylidenediphenylmethane with Li and Naphthalene Followed, or Not, by Addition of Electrophiles101

Spiro[2.3]hexanes 292 were prepared by a one-pot two-step process consisting of Zr-catalyzed cycloalumination of MCPs 284 with Et3Al (Dzhemilev reaction) followed by Pd-catalyzed carbocyclization of the aluminacyclopentane intermediates 291 with allyl chloride (Scheme 81).102 Deuterolysis of 291

cycloaddition with 2-substituted furans was completely regioand stereoselective and afforded compounds 297a each as a single isomer. Furan adducts 297 (X = O) underwent cycloreversion reaction at 100 °C with regeneration of MCPs 21 in good yield. 3-Spirocyclopropane-tetrahydroquinolines 300 were obtained by acid-catalyzed aza-Diels−Alder cycloaddition of ACPs 298 with (arylimino)acetate 299. Both Lewis and Brønsted acids catalyze this reaction, but the best results were obtained with trifluoromethanesulfonic acid (TfOH) and solid acidic montmorillonite K-10 (mont. K-10) (Scheme 84).105 At room temperature, 1′,1′-disubstituted MCPs 260 react with heterodienes 302 in the presence of a catalytic amount of a Lewis acid (LA), such as Sc(OTf)3 or BF3·Et2O, to afford chromene derivatives 305 in good yields (61−80%). The proposed mechanism involves a LA-catalyzed regioselective hetero-Diels−Alder cycloaddition followed by isomerization of the primary adduct 304 with opening of the cyclopropyl ring. Upon heating, 2-H-chromenes 305 (R1 = 4-XC6H4) undergo a LA-catalyzed transformation to indene derivatives 303, which could be directly obtained by heating the mixture of 302 and MCPs 260 (R1 = 4-XC6H4) at 60 °C for 10 h (Scheme 85).106 Nitrone 1,3-DCs of MCP derivatives have been thoroughly studied and continue to be an area of intense interest either for

Scheme 81. Preparation of Spiro[2.3]hexanes102

revealed that cycloalumination of 284 (R = C5H11) afforded a mixture of 2- and 3-spirofused aluminacyclopentanes, whereas the phenyl derivative 284 (R = Ph) gave exclusively the 2spirofused regioisomer. A range of diphosphine platinum complexes with η2methylenecyclopropane and η2-bicyclopropylidene ligands such as [Pt(MCP)(dppp)] and [Pt(BCP)(dppp)] 294 were synthesized by addition of the free alkene to ethene precursor complexes. The corresponding complex with allylidenecyclopropane was unstable and slowly rearranged into the metallacyclopentene complex 295 (Scheme 82).103 7333


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into piperidones 311 and/or dihydropyridones 316 through a complementary two-step process consisting of N−O hydrogenolysis to amino alcohols 315 followed by Pd-catalyzed cyclizations.107 A different transformation of 5-spirocyclopropaneisoxazolidines 306, that is, an acid-mediated thermal rearrangement (ATR), is known. In the presence of an acid, these isoxazolidines undergo a ring contraction to azetidinones 317 with concomitant elimination of an alkene (Scheme 86).107,108 In some cases, depending on the nature of the substrates, it can be convenient to perform the two-step processes 1,3-DC/TR and 1,3-DC/ATR in a domino fashion without isolation of adducts 306. This reaction is peculiar for MCP adducts, and the corresponding MCB derivatives and other isoxazolidines undergo unselective fragmentation under the ATR conditions.110 Both TR and ATR of 5-spirocyclopropaneisoxazolidines are quite general processes, but the chemistry of these spiro-fused isoxazolidines is very rich and far from being fully understood, as shown by the new possible transformations recently described in the literature. The latest achievements in this area are shown below. The two-step sequence 1,3-DC/TR was applied to the synthesis of the two aza-analogues of terpenoid ketones 321. Sterically congested cyclic nitrones 318 required harsh conditions to react with MCPs 319 and afforded adducts 320 with complete regioselectivity in moderate yields. Isoxazolidines 320 were relatively stable and isomerized at 450 °C under flash vacuum thermolysis (FVT) conditions affording trimethyloctahydroquinolizin-2-ones 321 as single isomers (Scheme 87).111 1,3-DC of the fluorinated MCP 267 with N-methyl-Cphenylnitrone (322, Ar = Ph) was found to be more efficient and selective when petroleum ether was used as the solvent. At 50 °C, MCP 267 reacted with acyclic nitrones 322 to give

Scheme 84. Aza-Diels−Alder Cycloaddition Reactions of ACPs105

the peculiarities of MCPs as dipolarophiles, the regio- as well as stereochemical aspects of the cycloaddition, and the value of adducts as synthetic intermediates.107 Actually, 5-spirocyclopropaneisoxazolidines 306 can be easily transformed into structurally differentiated compounds exploiting the presence of a relatively weak N−O bond adjacent to the strained small ring.108 Adducts 306 undergo a Brandi−Guarna thermal rearrangement (TR)109 with ring expansion to selectively substituted 4-piperidones 311 through the intermediate formation of diradicals 309 and 310 (Scheme 86). Depending on the nature of the nitrone substituents, a competitive formation of TR byproducts such as open-chain enaminones 313 and benzazocinones 314 can also occur. Analogously to 5spirocyclopropaneisoxazolidines, the corresponding monounsatured adducts of nitrile oxides and MCP derivatives, that is, 5spirocyclopropaneisoxazolines, undergo TR to dihydropyridones.107 Spiro-fused isoxazolidines 306 can also be converted Scheme 85. Reaction of ACPs with Heterodienes106

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Scheme 86. 1,3-Dipolar Cycloaddition Reactions of ACPs with Nitrones and Subsequent Transformations107−110

Scheme 87. Synthesis of Two Aza-Analogues of Terpenoids111

Scheme 88. 1,3-DC of a Fluorinated MCP with N-Methyl-Cphenylnitrone112

difluoro-substituted 5-spirocyclopropaneisoxazolidines 323 with complete regioselectivity, high diastereoselectivity, and in good yield. At 100 °C, the same mixtures of nitrones 322 and dipolarophile 267 were directly converted into 5-[(4methylphenyl)sulfonyl]-tetrahydro-4-pyridinols 325 through a domino two-step sequence 1,3-DC/TR. As well as the cycloaddition step, the rearrangement was completely regioselective, and the 3,3-difluoro-2,2-dimethyl derivatives 325 were obtained as the only products through the intermediate formation of diradicals 324 (Scheme 88).112 Bicyclopropylidene (BCP, 129) reacts with nitrones to afford 4,5-bis-spirocyclopropanated isoxazolidines. These adducts experience the opening of only the 5-spirofused cyclopropane under the Brandi−Guarna rearrangement conditions affording

valuable spirocyclopropanated piperidinones. For example, treatment of the bicyclic nitrone 326 with BCP in xylenes at 125 °C for 64 h afforded spiro[cyclopropanepyrido[2,1a]isoquinolinone] 328 along with a minor amount of the open-chain isomer 329. The 1,3-DC/TR domino process applied to the enantiopure pyrroline N-oxide 330 and BCP (129) afforded as the main product 8-spirocyclopropaneindolizidinone 332a, which originated from the favored anti-(3-tBuO) adduct 311a (Scheme 89).113 4,5-Bis-spirocyclopropanated isoxazolidines could be isolated by performing the reaction at lower temperature for longer time. For instance, isoxazolidine 334 was obtained in 45% yield along with a minor amount of the rearranged products 335 and 7335


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Scheme 89. 1,3-DC of BCP and Subsequent Transformations113

hexahydropyrrolo[1,2-b]isoxazoles 338, 341, 343, 331, and 345 could be synthesized in good yields starting from BCP and a suitable cyclic nitrone (Scheme 90).114−116 Analogously, 1,3-DC of the enantiopure pyrroline N-oxide 346 and ethoxycarbonyl-methylenecyclopropane 347 afforded a diastereomeric mixture of 5-spirocyclopropaneisoxazolidines 348 with complete regioselectivity (Scheme 91).116

336 by heating a mixture of BCP (129) and the nitrone 322 at 110 °C for 5 d, but it was recovered as the only product in 90% yield after 20 d at 60 °C (Scheme 90).114 The temperature Scheme 90. 1,3-DC of BCP and Subsequent Transformations114−116

Scheme 91. 1,3-DC of Ethoxycarbonylmethylenecyclopropane with a Cyclic Nitrone116

A two-step alternative method to convert 4,5-bis-spirocyclopropanated isoxazolidines into 3-spirocyclopropane-4-pyridine derivatives was also studied. In particular, isoxazolidines were selectively reduced by SmI2 to bicyclopropyl 1,3-amino alcohols that underwent a Pd(II)-catalyzed cascade rearrangement to 3spirocyclopropanedihydro- and -tetrahydropyrid-4-ones upon heating at 80 °C under a pressure of O2 in the presence of pyridine and Pd(OAc)2. Some results obtained with this method and, for comparison, those derived from the corresponding TRs are shown in Scheme 92.114 Upon heating in the presence of trifluoroacetic acid (TFA), adducts of MCP derivatives and pyrroline-N-oxides, that is, 3′H-spiro[cyclopropane-1,2′-pyrrolo[1,2-b]isoxazoles], directly afford N-trifluoroacetyl-β-homoprolines, probably because the carbapenam skeleton of the initially formed ATR products is not stable under the reaction conditions, and undergoes opening of the β-lactam ring followed by acylation of the nitrogen atom (Scheme 93). Analogously, bis-spirocyclopropanated pyrrolo[1,2-b]isoxazolidines afford N-trifluoroacetyl-αcyclopropyl-β-homoprolines. Examples are shown in Scheme 93. The substituted homoprolines could be coupled with natural α-amino acids to give α/β/α-tripeptides.115,116 Esters of Feist’s acid 365 were shown to be less reactive as dipolarophiles than the parent compound MCP. In fact, the photoelectron spectrum of the diethyl ester 365 (E = CO2Et) indicates that the electron-withdrawing groups cause a significant lowering of the HOMO energy (0.93 eV). MCPs 365 react with acyclic aldonitrones (C,N-disubstituted nitrones) and ketonitrones (C,C,N-trisubstituted nitrones) affording, respectively, 4-spiro- and 5-spirocyclopropane-isoxazolidines.117 The inversion of regioselectivity is probably caused by steric factors; however, preliminary calculations on 1,3-DC of 365 with C,N-diphenylnitrone (364, R1 = R2 = Ph) did not fit the

necessary to trigger the rearrangement of 5-spirocyclopropanated isoxazolidine strongly depends on the nature of substituents. For example, adduct 338 (E = CO2Me) was synthesized at 60 °C, whereas the corresponding tert-butyl derivative 338 (E = CO2t-Bu) underwent TR at 40 °C showing a surprising thermal instability.115 By choosing an appropriate cycloaddition temperature, the bis-spirocyclopropanated 7336


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Scheme 92. Two-Step Method To Convert 4,5-Bis-spirocyclopropanated Isoxazolidines into 3-Spirocyclopropane-4-pyridine Derivatives114a

Reaction conditions: (a) TR, xylenes, 125 °C, 12 h; (b) SmI2, THF, room temperature, 2 h; (c) Pd(OAc)2 (10 mol %), O2 (5 atm), py (2 equiv), toluene, 80 °C, 3 h. a

Scheme 94. 1,3-DC of Esters of Feist’s Acid with Nitrones117

Scheme 93. Transformations of Adducts of ACPs with Pyrroline-N-oxides in Acid Conditions115,116a

Scheme 95. 1,3-DC of Feist’s Acid Methyl Ester with NMethyl-C,C-bis(methoxycarbonyl)nitrone118 Reaction conditions: (a) TFA (1.5 equiv), CH3CN, 70 °C (MW), 2 min; (b) TFA (1.5 equiv), CH3CN, 70 °C (MW), 15 min; (c) TFA (1.5 equiv), toluene, 110 °C, 10 min. a

observed regioselectivity with aldonitrones. The reaction with nitrones 364 required elevated temperatures (80−110 °C) and long reaction times to afford 4-spirocyclopropaneisoxazolidines 366, which were isolated as single isomers in moderate yields (17−59%) (Scheme 94). The reaction of 365 (E = CO2Me) with N-methyl-C,Cbis(methoxycarbonyl)nitrone (367) afforded mainly the 5spirocyclopropaneisoxazolidine primary adduct 368 that was totally converted to the expected pyridine derivative 369 by TR in refluxing xylene (Scheme 95). 1,3-DC of 365 (E = CO2Me) with N-arylnitrones 370 gave the 5-spirocyclopropanated adducts 371 that could not be isolated, because they spontaneously evolved into 373 and 374 under the cycloaddition conditions (Scheme 96).118 Azeto[1,2-a]quinolines 373 likely derive from transannular cyclization of the corresponding benzazocinones initially formed by TR of 371 (Scheme 96, see also Scheme 86).

The reaction of the methyl ester of the Feist’s acid (365, E = CO2Me) with cyclic aldonitrones 375 and 377 and ketonitrone 337 (E = CO2Me) at 80 °C afforded diastereomeric mixtures of 5-spirocyclopropaneisoxazolidines 376, 378, and 381, respectively (Schemes 97 and 98). Both diastereomers 378 undergo the Brandi−Guarna rearrangement in refluxing xylene affording a mixture of the pyrido-[2,1-a]isoquinoline 379 and the bicyclic enaminone 380. Under the same conditions, the isolated adduct 381a was selectively converted into a single indolizidine 382, whose relative configuration was not established (see also Scheme 86).119 7337


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Scheme 96. 1,3-DC of Feist’s Acid Methyl Ester with N-ArylC,C-bis(methoxycarbonyl)nitrone and Subsequent Transformations

Scheme 98. 1,3-DC of Feist’s Acid Methyl Ester with Cyclic Ketonitrone and Subsequent Transformations119

Scheme 99. Reaction of Benzylidenecyclopropane-1,1dicarboxylates with Acyclic Nitrones120

Analogously to Feist’s esters, benzylidenecyclopropane-1,1dicarboxylates react with acyclic aldonitrones and ketonitrones with opposite regioselectivity. 1,3-DC of benzylidenecyclopropane 383 with C-aryl and C-amido nitrones afforded 4spirocyclopropane isoxazolidines 384 with complete regio- and stereoselectivity, and in good yields (56−89%) (Scheme 99).120 The 1′,1′-diphenyl derivative 385 was less reactive as dipolarophile than 383 and required longer reaction times to react with C-amido nitrones 364 (Scheme 100).117b In contrast to aldonitrones 364, ketonitrones 370 reacted with benzylidenecyclopropanes 387 to afford pyrrolo[1,2a]quinolines 392 in moderate to good yields (32−81%) (Scheme 101). Compounds 392 are likely formed through a domino process consisting of a regioselective 1,3-DC to 5spirocyclopropaneisoxazolidines 388, TR to benzazocines 389, transannulation to azetoquinolines 390, azetidine ring-opening, and cyclocondensation (see also Schemes 86 and 96).118 2-Alkynylbenzaldoximes 393 react with arylidenecyclopropanes 263 in the presence of a catalytic amount of AgOTf at 75 °C to afford benzo-7-azabicyclo[4.2.2]dec-7-en-4-ones 398 in good yields. The proposed mechanism involves silver(I)catalyzed 6-endo cyclization to isoquinoline-N-oxides 394 followed by 1,3-DC of 394 with 263 to give spirocyclopropanated isoxazolidines 395. Under the reaction conditions, the adducts 395 undergo homolytic cleavage of the N−O bond,

Scheme 100. Reaction of 1′,1′Diphenylbenzylidenecyclopropane-1,1-dicarboxylates with Acyclic Nitrones117b

followed by opening of the cyclopropyl ring and intramolecular radical cyclization to form 398 (Scheme 102).121

Scheme 97. 1,3-DC of Feist’s Acid Methyl Ester with Cyclic Aldonitrones and Subsequent Transformations119

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Scheme 101. Reactions of Acyclic Ketonitrones with Benzylidenecyclopropanes118

Scheme 102. Reactivity of Arylidenecyclopropanes with 2Alkynylbenzaldoximes121

Scheme 103. Reactions of Bis(methylene)cyclopropanes with C,N-Diaryl Nitrones122

The reactions of bis(methylene)cyclopropanes 399 with C,N-diaryl nitrones 242 and nitrile oxides generated in situ from hydroxymoyl chlorides 404 afforded, respectively, the TR products 402, 403, and 407 in moderate yields (Schemes 103 and 104). The addition of dipolarophiles occurred only at the less substituted double bond of 399 with selective formation of 5-spirocyclopropanated adducts 400 and 405 that spontaneously rearranged under the reaction conditions. In both cases, only the hexahydro- and tetrahydro-2,2-dimethylpyridines were formed by cyclization of the diradical intermediates 401 and 406.122 The alkylidenecyclopropane nitrile oxide 409, generated from the nitroalcohol 408, underwent a spontaneous intramolecular 1,3-DC at room temperature to smoothly afford the tricyclic isoxazoline 410 in 79% yield (Scheme 105).65 The spirocyclopropanated isoxazoline 410 was converted into the highly functionalized isoxazolidine 411 with conservation of the spirocyclopropane moiety. The isoxazolidine 411 was then treated with TFA at 80 °C to trigger the ring contraction to the bicyclic β-lactam 412 (see also Scheme 86) that was used in a total synthesis of the alkaloid (±)-gelsemoxonine. 1,3-DC of ethyl cyclopropylideneacetate (347) with azomethine ylides generated from 413 in the presence of the catalyst Cu(I)/(S)-TF-BipharmPhos (414) afforded 3-spirocyclopropanated pyrrolidines 415 with high enantio- and diastereoselectivity (Scheme 106).123 Thermally induced intramolecular [2+2] cycloaddition of allenyl-substituted arylidenecyclopropanes 416 afforded MCB derivatives 417 in good yields with conservation of the cyclopropane ring. The cycloaddition was completely diaster-

eoselective in favor of the cis-fused adducts 417. The strained cyclopropane ring was necessary for the cycloaddition to occur under the reported conditions (140 °C, 8 h). DFT calculations indicated that the reaction is a concerted process (Scheme 107).124 2.2.2. Rearrangements. In this section, reactions involving the ACP moiety, which lead to isomerized products as a consequence of a skeletal rearrangement, are covered. Reactions that afford formally rearranged products, but follow more recognizable reaction pathways, for example, intramolecular cycloaddition reactions, are discussed in the appropriate chapters. 2.2.2.1. Thermal Rearrangements. 2-(Phenylthiomethyl)arylidenecyclopropanes 419a and the corresponding selenides 419b, obtained from hydroxymethyl-ACPs 418 by mesylation 7339


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Scheme 104. Reactions of Bis(methylene)cyclopropanes with Nitrile Oxides122

Scheme 107. Thermally Induced Intramolecular [2+2] Cycloaddition of Allenyl-Substituted Arylidenecyclopropanes124

Scheme 105. Intramolecular 1,3-DC of an Alkylidenecyclopropane Nitrile Oxide in the Total Synthesis of (±)-Gelsemoxonine65 and nucleophilic substitution, undergo a thermal ring-opening rearrangement to dienes 420 on heating in refluxing THF (Scheme 108).125 The sulfides and selenides 420 are obtained Scheme 108. Thermal Rearrangement of Phenylthiomethyland Phenylselenomethyl-Substituted ACPs125

Scheme 106. Enantioselective 1,3-DC of Ethyl Cyclopropylideneacetate with Azomethine Ylides123

generally in good yields (74−97%) as E/Z mixtures (2−5:1), and the process can be carried out in a one-pot manner by direct heating of the ACPs 419, often obtained already in mixtures together with 420. The rearrangement is believed to occur through an intermediacy of radical species by homolytic C−X bond cleavage, followed by ring-opening and final radical recombination. However, the radical pair rearrangement should occur very fast, because the process is unaffected by the addition of radical trapping agents, and no mixed products were formed in crossover experiments. The corresponding halide derivatives failed to give the analogous rearrangement, except to a limited extent for the iodide. MCP is known to undergo a degenerate rearrangement through orthogonal trimethylenemethane (TMM) diradical intermediates (or dipolar, depending on the nature of the substrates) derived from cleavage of the ring 2,3-C−C bond when heated at higher temperatures. The same process occurs reversibly also in MCP and ACP derivatives, with the equilibrium being shifted toward the formation of the more stable product.126 Properly substituted ACPs have recently been employed to generate TMM species under diverse irradiation conditions to study electroluminescent, fluorescence, and thermoluminescent effects of the produced biradicals, their excited form, or related radical cation species.127 From the preparative point of view, this rearrangement may be used for accessing isomerized ACP derivatives from a previously synthesized alkylidenecyclopropane. 7340


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observed stereoselectivity (Scheme 110).130 In contrast to the related ester derivatives (430, R2 = OEt), which were

This concept has been used in the isomerization of difluoroalkylidenecyclopropane 21104,112 (see Scheme 6, section 2.1.1.1), taking advantage of the relatively mild conditions7 required for the rearrangement as a consequence of the difluorosubstitution.128 An ACP rearrangement is also believed to be responsible for the isomerization of diones 421 to spirocyclopropanepyrans 422, obtained unexpectedly instead of the products of a Cope rearrangement (see below), and formed by 6π-electrocyclization of the isomerized intermediate ACPs 423 (Scheme 109).129 This reaction can be carried out also in a domino

Scheme 110. Thermal Rearrangement of Alkenyl-Substituted ACPs130,131

Scheme 109. Domino Condensation/Thermal Rearrangement of Formyl-Substituted ACPs with 1,3Diones129

unreactive, the diesters 432 also gave cyclopentenes 433, but simple acyclic diesters afforded low yields, furnishing as major products isomeric cyclopentenes 434 (Scheme 110).131 These compounds differed both from the Cope rearrangement products 431 and from the products of the ACP rearrangement/6π-electrocyclization process occurring with the related diones 421. However, the homolytic ring cleavage with formation of a diradical species and subsequent coupling of the radical stabilized by the two ester groups may account for their formation. Accordingly, the radical trapping agent TEMPO suppressed this alternative route. It has been reported that compounds 431 may be obtained also in a one-pot process starting from aldehydes 424 through a Wittig alkenation/ rearrangement sequence, albeit in lower yields.130 In contrast, the one-pot process has been found to occur very efficiently with benzylidene derivatives 437 formed in situ from the phosphonium salt 435. In this case, using n-BuLi as the base, the succeding Cope sigmatropic rearrangement occurred under surprisingly mild conditions, affording trans-disubstituted cyclopentenes 436 in moderate to good yields even at room temperature in only 3 h (Scheme 110).131 The release of the high strain energy content associated with the alkylidenecyclopropane moiety should be responsible for the uncommonly mild conditions required for these Cope rearrangements. An analogous condensation/rearrangement process was achieved for the synthesis of N-amino pyrrole derivatives 439 on reacting the aldehydes 424 with hydrazines 438 (Scheme 111).132 The reaction likely involves an aza Cope rearrange-

fashion, which is particularly successful with cyclic diones, starting from ACP aldehydes 424 and diketones 425 to give spiro compounds 426 under similar reaction conditions in the presence of catalytic L-proline to promote the condensation reaction. Spirocyclopropanated pyrans 422 and 426 are obtained as cis/trans diastereomeric mixtures with low selectivity (1:1.2−2.7). When cyclopentane-1,2-dione (427) is used in the condensation/rearrangement process, small amounts of isomers 428, formally derived from an alternative [3,5]-sigmatropic shift of 429, were also isolated besides predominating pyrans 426 (Scheme 109).129 Shi et al. had previously found that the parent monoketone derivatives 430 afforded the trans-disubstituted methylenecyclopentenes 431 and proposed a Cope rearrangement of the 1,5-diene unit in 430 without involvement of the carbonyl group to occurr through a chairlike TS, which accounts for the 7341


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the methylenecyclopropane and reclosure by attack of the amide nitrogen atom at the exomethylene carbon. Similarly, Lautens et al. reported earlier an efficient MgI2promoted ring expansion of amides 448 to α,β-unsaturated lactams 449 (Scheme 113).134 During the course of that study,

Scheme 111. Domino Condensation/Thermal Rearrangement of Formyl-Substituted ACPs with Hydrazines132

Scheme 113. MgI2-Promoted Rearrangement of MCP Carboxamides134,135

ment of the primary hydrazone intermediates 440 to give methylenepyrrolines 441, which readily aromatize to the final products. Interestingly, the process profited from the presence of H2O liberated in the condensation step, because the addition of drying agents rendered the reaction sluggish; analogously, isomerization of 440 was faster and more efficient when H2O (2 equiv) was added. 2.2.2.2. Lewis Acid-Induced Rearrangements. The related tosylhydrazones 442 derived from MCP ketones were found to undergo a different rearrangement on heating at 120 °C in DME in the presence of 10 mol % MgCl2 and TMEDA (1 equiv), furnishing dihydropyridazines 443 in good yields and with good selectivities, with the azadienes 444 as side-products (Scheme 112).133 However, the 443/444 ratio proved to be Scheme 112. Mg Salts-Induced Rearrangement of Hydrazones and Oximes of 2-Acyl-Substituted MCPs133

the isomeric β,γ-unsaturated lactams 450 were also isolated as side-products in low yields. Because these methylenepyrrolidinones are useful intermediates for which no general synthetic method had been available, further studies were carried out to shift the selectivity toward their formation. It was found that use of high dilution and substoichiometric amounts of MgI2 favors the exomethylene isomer: under these conditions, a series of azoles and azines gave excellent yields of lactams 450 with good selectivity, which appeared sensitive to electronic factors (Scheme 113).135 Interestingly, in contrast to 3isoxazolyl derivatives, a 5-isoxazolyl substrate turned out to be unreactive. It was speculated that the presence of an αnitrogen atom is essential for prerequisite chelation, upon which magnesium releases an iodide ion, which attacks the

strongly dependent on the Lewis acid used, and it was possible to achieve a complete reversal of the selectivity in favor of 443 when MgI2 was used in the presence of N-benzylidene toluenesulfonamide. Extendibility to the corresponding oximes 445, which gave good yields of the oxazines 446 and 447 with poor selectivity, was demonstrated (Scheme 112).133 On the basis of mechanistic studies, the authors proposed an initial activation of the hydrazone by coordination to the metal followed by heterolytic cleavage of the distal 2,3 C−C bond of 7342


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cyclopropane initiating the rearrangement process. Compatibility of substitution at both exomethylene and the cyclopropane ring of the MCP moiety was ascertained with the 2pyridyl amides 451, which afforded methylenepyrrolidinones 452 in moderate to good yields and with excellent selectivities. In the course of studies aimed at the synthesis of N-aminopyrroles 439 reported above (Scheme 111), Shi et al. reported that analogous thermal reactions of aldehydes 424 with simple monosubstituted hydrazines (eg, phenylhydrazine) or primary amines were unsuccessful.132 However, Ma reported that related ACP ketones 453 afford 2,3,4-trisubstituted pyrroles 455 when treated with an excess (4 equiv) of an amine 454 in refluxing acetonitrile in the presence of MgSO4 (Scheme 114).136 The process may be rationalized by initial formation of

Scheme 115. Au-Catalyzed Cope Rearrangement of an ACP Embedded into a 1,5-Dienyl Moiety140

product with much less substituted double bonds (a terminal alkene and a 1,1-disubstituted in 459 vs two trisubstituted alkenes in 458). An analogous example is the thermal rearrangement of 1,4-dicyclopropylidenebutane to 1,1′-divinylbicyclopropyl.141 The reason for the higher thermodynamic stability of the product with less substituted double bonds rests in the release of the incremental strain energy of the ACP moiety in 458. Following this finding, studies have been carried out to assess the generality of the process, subjecting a series of ACPs 460, obtained in moderate yields by Wittig reaction of cyclopropyltriphenylphosphonium bromide with the corresponding aldehydes in the presence of NaH,142 to the rearrangement under gold catalysis. Moreover, because this unique reaction affords valuable chiral vinylcyclopropanes 461 from achiral dienes 460, it lent itself to develop the first enantioselective methodology for a Cope rearrangement with the use of chiral catalysts (Scheme 116). After extensive experimentation with ACP 460 (R1 = Me, R2 = Bn) as a model substrate, it was found that the paracyclophane complex 462 performed much better in terms of enantioselectivity than other gold complexes with chiral diphosphines, which exhibited high asymmetric induction in other Au(I)-catalyzed reactions. Under the optimal conditions shown in Scheme 116, ACPs 460 afforded the corresponding vinylcyclopropane rearrangement products 461 generally in good to excellent yields and with high enantiomeric excesses.140 Only ACP 472 failed to give the rearranged vinylcyclopropane, probably due to unfavorable thermodynamics for the loss of extended conjugation. Free OH groups were tolerated, albeit compound 470 was obtained in lower yield than its protected derivatives 468 and 469. The low yield of vinylcyclopropane 471 derived from a concomitant reaction, reminiscent of a Pt-catalyzed isomerization previously reported by Fürstner (see below),143 which furnished the cyclobutene 473 in 23% yield as a side-product.140 DFT calculations allowed one to locate along the reaction coordinate the carbenium ion intermediate 476, the formation of which from the equilibrium mixture of the complexed model compound 474−475 (L = PMe3) required only ∼15 kcal/mol, thus lowering the activation barrier by about 20 kcal/mol as compared to the uncatalyzed rearrangement (Scheme 117).140 The computations also confirmed that the driving force for this otherwise unfavorable conversion to a less substituted product is the relief of ring strain, with a gain in ΔG of 4−7 kcal/mol on passing from ACPs 460 to vinylcyclopropanes 461. Consistent with this conclusion was the failure of the rearrangement reaction when the cyclopropylidene group was replaced with a cyclopentylidene or with two methyl groups. To extend the above rearrangement to the synthesis of spirocyclopropanated medium size carbocycles 478, Gagné et al. subsequently studied the Au-catalyzed reaction of cycloalkylidenecyclopropanes 479, with the chain connecting the two double bonds of the 1,5-diene moiety included into a five-

Scheme 114. Magnesium Sulfate-Promoted Domino Condensation/Rearrangement of Acyl-Substituted ACPs with Amines136

imines 456 (facilitated by removal of H2O with magnesium sulfate) followed by isomerization via ring enlargement through cleavage of the distal C−C bond of the ACP and subsequent H shift, albeit direct attack of the amine to the unsubstituted carbon atom of the ACPs 453 cannot be ruled out. 2.2.2.3. Transition Metal-Catalyzed Rearrangements. It is known that Cope [3,3]-sigmatropic rearrangements can be promoted by the action of transition metal derivatives, and the first Pd-catalyzed Cope rearrangement of acyclic 1,5-dienes has been reported by Overman.137 Under electrophilic metal catalysis, the rearrangement may require far milder conditions than the harsh thermal conditions commonly needed (150− 200 °C), occurring at room temperature or even below. Mechanistically, lowering of the activation energy is achieved by transforming the pericyclic synchronous reaction into a stepwise process through the formation of a cyclic metalcarbenium ion intermediate (which sometimes is not localized as a relative minimum energy point, thus maintaining the concerted process feature).138 During the course of studies aimed at developing novel goldcatalyzed cationic cascade processes leading to polycyclic skeletons, Gagné et al. found that ACP 458 gives the Cope rearrangement product 459 in excellent yield under Au catalysis139 rather than the expected tricyclic derivative (Scheme 115).140 The Cope rearrangement converts a 1,5diene into a different 1,5-diene; thus, thermodynamic factors drive the direction of the process, typically converting less substituted alkenes into more highly substituted ones. The reaction in Scheme 115 is remarkable, in that it affords a 7343


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Scheme 116. Au-Catalyzed Enantioselective Cope Rearrangement of ACPs Embedded into a 1,5-Dienyl Moiety140

Scheme 118. Au-Catalyzed Rearrangement of AlkenylSubstituted Cyclohexylidenecyclopropanes144

Cope rearrangement as a consequence of the strain introduced by the additional ring. Another gold-catalyzed process involving ACPs, the cycloisomerization of cyclopropylidene enynes, was reported by Toste et al. to furnish the bicyclo[4.2.0]octane skeleton (Scheme 119).146 The Au-catalyzed cycloisomerization of 1,6enynes has emerged recently as one of the most effective strategies for the construction of complex polycyclic structures,147 with the cascade sequence typically involving an initial 5-exo-dig or 6-endo-dig cyclization of the double bond electron pair to the complexed alkyne. Toste et al. found that substitution of the double bond of the enyne system with a terminal cyclopropylidene moiety shifted the reaction of ACPs 483 to a 6-exo-dig cyclization mode and proposed this change to reflect the higher stability of the derived cyclopropylmethyl cationic intermediate 484. This primary intermediate would readily undergo a ring expansion to an Au(I)-stabilized cyclobutyl cation 485, which finally affords a mixture of the observed dienes 487/488 by a 1,2-hydrogen shift (Scheme 119).146 Under the reaction conditions, the kinetic product 487 appears to isomerize to the thermodynamically more stable diene 488, which predominates at longer reaction times. When the triple bond in 483 is substituted with an aryl ring (and consequently the H atom for the final 1,2-hydrogen shift is lacking), the intermediate cation 485 gets involved in a Nazarov-type electrocyclization, thus affording in moderate to excellent yields the tetracyclic products 489. When the sterically congested ortho-iodophenyl-substituted ACP 483 (R = 2-IC6H4) was treated with 5 mol % of the (R)-Au complex 490 with a chiral bisphosphine ligand, the corresponding product 489 was obtained enantioselectively (82% ee) in high yield. Yet another pathway was followed, when the R substituent contained a nucleophilic atom at a proper distance to favor an intramolecular attack at the carbocationic center, as is the case of the hydroxybutyl-substituted 483 (R = CH2CH2CH2CH2OH). In this case, the primary intermediate 484 was intercepted by internal attack of the hydroxy group to afford the tetrahydropyranyl-substituted spirocyclopentane 486 (Scheme 119).146 In contrast to these results, Shi et al. reported that similar substrates 491, differing from 483 only by replacement of the malonate fragment with a nitrogen (substituted with a sulfonyl group) or oxygen heteroatom in the chain connecting the two unsaturations, gave spiropentane-annelated heterocycles 492 in good to excellent yields (Scheme 120).148 Among several Au(I)

Scheme 117. Mechanism Proposed for the Au-Catalyzed Cope Rearrangement Involving ACPs140

to seven-membered ring, obtained again from the corresponding ketones 480 by the above-mentioned Wittig methodology (Scheme 118).144 Most of the substrates employed in the reaction, cyclopentylidene and cycloheptylidene derivatives and more highly substituted cyclohexylidenes, gave intractable mixtures of compounds with the use of different solvents, catalysts, and activating agents. Only the two cyclohexylidenecyclopropanes 481a,b, when treated with the Gagosz catalyst,145 gave a clean reaction, affording however the tricyclic compounds 482a,b instead of the expected cyclooctenes 478 (n = 2) (Scheme 118).144 DFT calculations suggested that the tricycle 482 may arise either on initially formed Cope rearrangement product 478 by a subsequent cyclization or directly from the Au(I)-complexed substrates by a cyclization/ rearrangement cascade. The cyclization pathways become viable due to the higher activation energy required for the 7344


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Scheme 119. Au-Catalyzed Cycloisomerization of Cyclopropylidene Enynes Tethered by a Malonate Moiety146

Scheme 120. Au-Catalyzed Rearrangement of Nitrogen- and Oxygen-Tethered Cyclopropylidene Enynes148

Fensterbank and Malacria et al. observed that the reaction outcome was strongly dependent on the substrate structure, and particularly on the length of the alkyl chain connecting the alcohol moiety with the cyclopropane ring in the bicyclic ACPs 497 (Scheme 121), obtained by cycloisomerization of 1,5Scheme 121. Au-Catalyzed Rearrangement of Bicyclic ACPs Bearing a Hydroxyalkyl Substituent29

catalysts tested, the tBuXPhos catalyst 494 gave the best results, and the reaction turned out to be of broad scope; however, increasing the length of the linking chain in 1,7-enynes resulted in no reaction. The outcome of the reaction was rationalized as deriving from an initial 6-endo-dig cyclization on the Au(I)complexed alkyne, analogous to that observed with the corresponding derivatives possessing a dimethyl substitution instead of the cyclopropyl group, to give the cationic intermediate 493, which experiences goldcarbenoid stabilization; then, a 1,2-H shift and subsequent protodeauration affords the final tricycles 492. Only in the case of the unsubstituted enyne 495 was a different product obtained deriving from a cycloisomerization, which was ascribed to a preferred 5-exo-dig ring closure (Scheme 120).148 Another Au(I)-catalyzed cascade of ACPs bearing a terminal hydroxy group led to oxygen heterocycles, as in the case of product 492 reported above, through intramolecular nucleophilic attack at a cationic gold complex. Interestingly,

allenynes catalyzed by PtCl4 (see section 2.1.1.4).29 With an alkyl chain long enough to form an unstrained cycle as in 497 (n = 3), a preferred attack at the ipso carbon atom of the cyclopropane ring was observed under catalysis with AuCl leading to the spiroannelated tetrahydrofuran 498, while for the lower homologue 497 (n = 2) the intramolecular nucleophilic attack occurred at the exo carbon atom of the alkene affording the tricyclic fused tetrahydropyran 499. Under gold/silver cocatalysis, the hydroxymethyl-substituted 497 (n = 1) with a 7345


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yet shorter chain led to ring expansion of the bicyclo[3.1.0]hexane system and concomitant dehydration to yield the cyclodienone 500 (Scheme 121).29 Following a previously developed strategy for accessing allenylcyclobutanols by Lewis acid-induced intermolecular reaction of propargyl alcohols with MCPs,149 Shi et al. devised that the intramolecular version could afford bicyclic allenycyclolbutanols. Indeed, upon treatment with Lewis acids, the ether-linked ACP enynes 501 gave the expected tetrahydropyran-annelated allenylcyclobutanols 502 (Scheme 122).150

Scheme 123. Au-Catalyzed Rearrangement/Aromatization of Cyclohexylidenecyclopropanes151

conditions, as presented in Scheme 123, were quite critical for the reaction; other Lewis acid catalysts were able to trigger this transformation, but performed less efficiently. The reaction worked better with an aryl substituent on the cyclohexane ring, thus affording biphenyl derivatives; however, it has a broader scope and was successful also with an n-butyl group. The presence of both the cyclopropylidene and the cyclohexylidene group is mandatory: no reaction occurred when the former was replaced with a cyclobutylidene or the latter with a cyclopentylidene. During the reaction, three hydrogen atoms are formally transferred from the cyclohexane to the C3 fragment deriving from cyclopropane. Labeling experiments showed that the hydrogen transfer occurs mostly, but not exclusively, intramolecularly, and DFT calculations suggested that successive activations of allylic C−H bonds were involved.151 Similar 4-arylcyclohexylidenecyclopropanes 506 gave a related dehydrogenative aromatization to 4-isopropenylbiphenyls 507 on treatment with palladium acetate (Scheme 124),152

Scheme 122. Au- and Ag-Catalyzed Rearrangement of ACPs Tethered to a Propargyl Alcohol Moiety150

Scheme 124. Pd-Catalyzed Rearrangement/Aromatization of Cyclohexylidenecyclopropanes152

Among a large variety of Lewis and Brønsted acids tested, silver triflate turned out to perform as the best, albeit still giving only moderate yields, in the presence of a small amount of water. The presence of aryl groups at the carbinol center is essential, because the corresponding dimethyl-substituted alcohol failed to give the rearrangement. Allenyl alcohols 502 underwent a cyclobutanol to cyclopentanone ring enlargement under Au(I) catalysis, affording the alkenyl-substituted bicyclo[3.2.1]octanones 503 with a quaternary bridgehead carbon (Scheme 122).150 Interestingly, because the actual catalyst was formed in situ in the presence of AgOTf, these same reaction conditions were able to trigger the cascade conversion of ACP 501 (R = Ar = Ph) to the corresponding final bicycle 503, albeit in modest yield, but better anyway than the overall yield in the two-step sequence. Mechanistically, the process was proposed to be initiated by formation of an allenyl cation in a Meyer−Schuster type rearrangement followed by cyclization and cyclopropylmethyl to cyclobutyl cation rearrangement. Final attack of water would lead to the allenecyclobutanols 502; then, coordination of allene by gold would induce the ring expansion and final protodeauration to furnish products 503. Shi and Li et al. have reported yet another ring-opening reaction of ACPs catalyzed by Au(I) complexes, the transformation of cyclohexylidenecyclopropanes 504 to propylbenzenes 505 (Scheme 123).151 Formally, this is not a simple rearrangement because the primary rearranged products undergo a final dehydrogenation under the reaction conditions (which is not catalyzed by the metal) to gain aromatic stabilization. The process is very interesting and intriguing, representing a rare case of activation of both C−C and C−H bonds in a single cascade sequence. The best reaction

which apparently induced cleavage of the distal C−C bond of the methylenecyclopropane moiety instead of the proximal as occurred with gold. The efficiency of the catalytic process was low, and a considerable amount of Pd(OAc)2 was required to obtain acceptable yields. Moreover, the process was strictly limited to substrates 506: any structural variation (replacement of the aryl group with H or alkyl, aryl at C-2 or C-3 instead of at C-4, replacement of cyclohexylidene or cyclopropylidene with cyclopentylidene or cyclobutylidene, respectively) afforded only complex mixtures of products. A related Pd-catalyzed rearrangement, which involved both C−C and C−H activation, was reported by Huang et al. for diarylmethylenecyclopropanes 508, which delivered dihydronaphthalenes 509 (Scheme 125).153 Palladium acetate alone was unable to induce any reaction, but when an NHC ligand was added, compounds 509 were formed in poor yields. Improvement in the process was achieved when a preformed Pd−NHC complex and additional NHC ligand was used, with the combination 511/512 giving optimal results. Under these conditions, moderate to fair yields of dihydronaphthalenes 509 were obtained, and only in a few cases were dienes 510 isolated in low yields as minor byproducts (Scheme 125).153 The diaryl substitution at the double bond appeared essential, because benzylidenecyclopropane was unreactive and a methyl-aryl7346


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Scheme 125. Pd-Catalyzed Rearrangement of Diarylmethylenecyclopropanes153

Scheme 126. Rh-Catalyzed Rearrangement of ACPs Tethered to Indole Moieties155

disubstituted ACP gave mostly a trimer. An ACP with different aryl substituents afforded a mixture of both possible cyclized products. The outcome of the reaction was rationalized according to an initial hydropalladation of the double bond followed by rearrangement to a homoallyl-Pd species by cleavage of the cyclopropane proximal C−C bond. This species may give a β-hydride elimination to dienes 510;154 the NHC ligands make this reaction less favorable, thus allowing the alkyl-Pd species to add to the vicinal arene. Final β-hydride elimination to products 509 restores aromatic stabilization. A cyclopropane ring-opening rearrangement to the corresponding diene has recently been observed by Shi et al. on ACPs substituted with an indole moiety at the end of the carbon chain. Thus, indole 513, upon treatment with a catalytic amount of the Rh(I) complex [Rh(cod)(IPr)Cl], afforded the diene 514 in 76% yield (Scheme 126).155 Remarkably, when the above catalyst was replaced with Wilkinson’s catalyst (5 mol %) and triphenylphosphine added as a ligand, the reaction gave a different product 515 deriving from a cycloisomerization process, which involved a ring fusion to the five-membered ring of indole to afford a β-carboline, a motif widely found in natural alkaloids and pharmaceuticals. It was proved that Wilkinson catalyst was able to promote the conversion of diene 514 to the tricycle 515, a Pictet−Spengler-like reaction that can be induced also by Brønsted acids such as trifluoroacetic acid. Therefore, it is likely that the diene is the primary reaction product of the rearrangement, and the Rh complex behaves as a Lewis acid catalyzing the subsequent cyclization of the indole. The scope of this novel cycloisomerization process was then addressed with a series of indole-substituted ACP derivatives 516, varying substitution at the indole benzenoid ring and in the chain, length of the tether, and sulfonate substituent at nitrogen atom. The reaction showed broad tolerance to substitution, affording valuable tetrahydro-β-carboline derivatives 517 independent of electronic effects. Only when the tethering nitrogen atom was replaced with a dimethyl malonate carbon did the reaction stop at the stage of the diene derivative. The terminal ACP moiety was crucial for the reaction to occur efficiently, because a substrate lacking the cyclopropane ring gave the cyclized product only to a marginal extent. The synthetic usefulness of product 515 was demonstrated by its elaboration into tetracyclic indole derivatives by application of different transition metal-catalyzed reactions. The outcome of

the reaction and isotopic labeling experiments prompted the authors to propose a mechanism, supported also by DFT calculations, which involves the alkylidenerhodacyclobutane species 518, formed by oxidative addition with insertion into the distal cyclopropane C−C bond, followed by isomerization through a TMM-like TS to methylenerhodacyclobutane 519, which undergoes β-H elimination to the σ-allyl/π-allyl species 520/521. The latter complex then undergoes reductive elimination regenerating the catalytically active Rh(I) and affording the diene 514 (Scheme 126).155 The subsequent cycloisomerization to 515 then occurs likely by direct attack of C-2 of the indole to the diene, because a related 2-methylindole ACP failed to give any cyclization, furnishing only the diene derivative in 38% yield. 7347


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equally efficient independently of the configuration of the double bond in the substrate, because both E and Z isomers afforded the same product with comparable yield and diastereoselectivity. These results followed previous findings from the same authors, who employed the same substrates in [3+2+2] cycloaddition processes with the involvement of an external alkyne (see section 2.2.3.6.3). On the basis of their mechanistic hypothesis, they envisaged that the proposed intermediate 527 (or the corresponding η3-allyl complex), formed by oxidative addition onto the Rh catalyst of the distal cyclopropane C−C bond cleavage to yield 525, subsequent isomerization to 526, and carbometalation, in the absence of an external alkyne may undergo a β-H elimination to 528 instead of a further carbometalation reaction, thus affording an enecycloisomerization process. These rhodium hydride intermediates then would produce the final dienes 523 (Y = H) or the enol tautomer of the observed aldehydes 524 (Y = OH) by reductive elimination (Scheme 127). The synthetic usefulness of this novel rearrangement was demonstrated by a straightforward total synthesis of kainic acid in eight synthetic steps from the commercially available oxazolidinone 529 in 17% overall yield. The key step of the strategy was the completely diastereoselective Rh-catalyzed cycloisomerization of ACP 529, synthesized in turn by the Pd-catalyzed nucleophilic displacement of 1-vinylcyclopropyl tosylate developed by Salaün and de Meijere et al.,157 to aldehyde 530.156 Ma et al. employed ACPs 532, several of which have been shown above as precursors of pyrroles after derivatization to the corresponding imines (Scheme 114), for a ring-opening/ cyclization to furans 533 under catalysis of Pd(0) (Scheme 128).158,159 The best reactivity and selectivity were achieved

Another Rh(I)-catalyzed cycloisomerization was reported by Evans and Inglesby, who obtained products of a formal enecycloisomerization reaction with concomitant cyclopropane ring-opening from alkenylidenecyclopropanes. On treatment with [Rh(cod)Cl]2 in the presence of phosphite ligands at 100 °C in toluene, ACPs 522 gave the dienes 523 (Y = H) or aldehydes 524 (Y = OH) in excellent yields and with complete diastereoselectivity (>19:1) in favor of the cis-3,4-disubstituted derivative (Scheme 127).156 The reaction showed a broad scope, working either with an all-carbon linker or with a chain containing an oxygen or nitrogen heteroatom, thus securing access to cyclopentanes or tetrahydrofuran and pyrrolidine derivatives, respectively. It is noteworthy that the process was Scheme 127. Rh-Catalyzed Rearrangement of ACPs Tethered to Alkene and Allylic Alcohol Moieties156

Scheme 128. Sodium Iodide and Pd-Catalyzed Rearrangement of Acyl-Substituted ACPs158

with the use of Pd(PPh3)4 as the catalyst. The reaction is believed to produce primarily the isomeric methylenedihydrofurans 534, and the process was stopped at this stage when the reaction mixture was directly subjected to chromatographic purification without acidic treatment with HCl. The authors also found that a similar rearrangement is induced by iodide ion, which gave, however, the isomeric furan derivatives 535 and 536 under catalytic and stoichiometric conditions (with or without addition of catalytic (MeCN)2PdCl2), respectively (Scheme 128).158 Albeit involving obviously different mecha7348


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however, preformed Pd(0) complexes failed to trigger the rearrangement because a base was proposed to be necessary for deprotonating the initial palladacyclobutane intermediate, formed by oxidative insertion into the proximal C−C bond of MCP. Under Pd(II) catalysis and in the presence of water, (arylmethylene)cyclopropylketones 540 underwent a different transformation to afford, as formal hydration products, the saturated acyclic diketones 542 (Scheme 130).160 Similarly, the (arylmethylene)cyclopropylmethanols 418 under Pd(0) catalysis in the absence of oxygen at room temperature gave the rearranged allylic alcohols 543, while on heating at 80 °C in toluene they afforded the isomerized γ,δunsaturated aldehydes 544.161 The best conditions for the formation of aldehydes were found with the use of a molar equivalent of acetic acid and addition of triphenylarsine as a ligand. It was proved for one allylic alcohol 543 (Ar = Ph) that the same reaction conditions caused its isomerization to the corresponding aldehyde 544. Under oxidative conditions in the presence of air, ACPs 418 underwent a rearrangement accompanied by formal dehydrogenation to the acyclic conjugated aldehydes 545, with Pd(II) likely catalyzing the final oxidation step from the alcohols 543 (Scheme 131).162 Under PdCl2 catalysis and with an excess of CuBr2 under air atmosphere, electron-withdrawing substituted ACPs 418 gave a brominative ring enlargement to the dihydro- and tetrahydrofuran derivatives 546/547 (Scheme 131).163 Interestingly,

nisms, both of the rearrangements went through cleavage of the distal C−C bond of the MCP moiety. With Pd(0), initial oxidative addition by insertion of Pd into this bond was proposed, while iodide could attack the less substituted terminus of the cyclopropane moiety and cleave the same bond to stabilize into an enolate ion. These intermediates would then evolve by cyclization of the oxygen onto different carbon atoms leading to the observed products. In contrast, when a Pd(II) catalyst was used with the same substrates 532, six-membered oxygen heterocycles 537 were obtained in good yields (Scheme 129).158 The best catalyst was Scheme 129. Pd(II)-Catalyzed Rearrangement of AcylSubstituted ACPs158a

PdCl2(MeCN)2, which worked very efficiently affording the dihydropyrans 537 in very short times at room temperature in acetone, CH2Cl2, or benzene. In this case, initial chloropalladation of the double bond followed by cyclopropylmethyl-Pd to homoallyl-Pd rearrangement caused the cleavage of the proximal C−C bond in MCP, thus allowing for subsequent cyclization to a six-membered heterocycle. When cyclohexylidenecyclopropane 538 was used, the spirocyclohexaneannelated 2H-pyran 539 was isolated in excellent yield (Scheme 129).158a Related (arylmethylene)cyclopropylketones 540 were reported to undergo a Pd-catalyzed rearrangement to acyclic conjugated ketones 541 (Scheme 130).160 Both E and Z diastereoisomers of an alkylidenecyclopropane were also demonstrated to undergo this rearrangement. The actual catalyst for the reaction was a Pd(0) species formed in situ from palladium acetate in the presence of triphenylphosphine;

Scheme 131. Pd- and Pd/Cu-Catalyzed Rearrangement and Rearrangement/Hydrohalogenation of (Arylmethylene)cyclopropylmethanols161−163

Scheme 130. Pd-Catalyzed Rearrangement and Rearrangement/Hydration of (Arylmethylene)cyclopropylketones160

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coupled to other metal-catalyzed conversions in one-pot processes, with a ROM/RCM cascade when a suitable allyloxy-substituted arene was used and a Grubbs catalyst added to the reaction mixture. A plausible mechanism for this rearrangement, which also accounts for the results obtained in labeling studies, involves the ring expansion of the metal complex 551 to the metalcarbene-stabilized 552, which, after 1,2-hydride shift to 553, affords the final cyclobutenes 550 (Scheme 132).143,163 With the use of (arylmethylene)cyclopropylmethanols 418 (Scheme 131),163 Shi et al. demonstrated that the rearrangement can be applied also to ACPs substituted at the cyclopropane ring. This subject was exploited by Marek et al., who employed gem-disubstituted ACPs 170 under both Shi’s and Fürstner’s conditions to achieve an efficient access to enantiomerically pure (or enriched) chiral cyclobutenes possessing a quaternary stereogenic center, for which general synthetic methods are lacking. Both methods worked well to furnish the desired products 554/555 in satisfactory yields (Scheme 133).165 As observed with substrates 418, the reaction

when a catalytic amount of CuBr2 was used under anaerobic conditions and at lower temperature, electron-donating substituted ACPs 418 afforded smoothly the cyclobutenylmethanols 548/549, with electron-poor arylidenes reacting only sluggishly (Scheme 131).163 Similar conditions had already been reported to furnish cyclobutenes from unfunctionalized ACPs (see below) but required much longer reaction times. It had been speculated that coordination of the free hydroxy group to Pd accelerates the reaction, with donor groups on the arene stabilizing the incipient positive charge at the benzylic position required for ring expansion to a cyclobutene. In contrast, electron-withdrawing groups may favor alternative pathways, such as ring-opening of the cyclopropane by attack of a bromide ion when excess CuBr2 is present. Because this pathway finally generates a palladium hydride species that evolves to Pd(0) via reductive elimination, the need for reoxidation to Pd(II) accounts for the required excess of Cu(II) and air. The metal-catalyzed (arylmethylene)cyclopropane to arylcyclobutenyl rearrangement has been reported in 2006 independently by Shi et al.164 with Pd(II) and shortly before by Fürstner et al. with Pt(II).143 Shi found optimal conditions for the conversion of (arylmethylene)cyclopropane 76 into arylcyclobutenes 550 with the use of Pd(OAc)2 /CuBr2 cocatalysis (Scheme 132).164 Electron-rich arenes reacted

Scheme 133. Pt- and Pd/Cu-Catalyzed Rearrangement of Chiral gem-Disubstituted ACPs to Cyclobutenes165

Scheme 132. Pt- and Pd/Cu-Catalyzed Rearrangement of ACPs to Cyclobutenes143,164

was highly regioselective, affording the 3,3-disubstituted cyclobutenes 554 preferentially (often exclusively) with respect to their 4,4-disubstituted isomers 555. The reason for the observed regioselectivity was ascribed to a preferential cleavage of the C1−C3 proximal bond in the cyclopropane ring (path a) over the alternative C1−C2 proximal bond (path b) due to the partial carbanionic character of the migrating carbon atom, which is better accommodated when it is less substituted (Scheme 133). Consequently, formation of the metalcarbene 557, which then leads to cyclobutenes 554, is predominant over its isomer 558 leading to 555. According to this hypothetical mechanism, cyclobutenes 554 were predicted to maintain the enantiomeric composition of their precursors 170, because the stereogenic center is not involved during the whole process. To prove this assumption, one enantiomerically pure (98% ee) substrate 170 (R1 = CH2CH2Ph, R2 = Et) was prepared58 and subjected to the rearrangement in the presence of PtCl2. The

smoothly at room temperature in dichloroethane, while unsubstituted or electron-poor arenes required higher temperatures and longer reaction times, leading to incomplete conversions and moderate yields even after 24 h at 80 °C. Alkylidenecyclopropanes were unable to undergo the rearrangement. The conditions reported by Fürstner et al. (catalytic PtCl2) appear to offer a broader scope, because either electronpoor or -rich (arylmethylene)cyclopropanes and alkylidenecyclopropanes 76 proved to be suitable substrates for the reaction (Scheme 132).143 An atmosphere of CO was reported to accelerate the reaction, probably forming a more active catalytic species. It was also proved that this reaction may be efficiently 7350


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pyridine-directed activation of alkene C−H bonds166 and the activation of aldehyde C−H bonds for hydroacylation processes.167 In the first approach, ACPs 565 and 567 possessing a vinylpyridine moiety linked to the exomethylene carbon of the ACP through a C2 unit of a saturated chain or of an aryl ring, respectively, afforded cycloheptenes 566 and 568 when treated with Wilkinson’s catalyst in the presence of AgSbF6 at 120 °C in THF in a sealed tube (Scheme 135).168

corresponding cyclobutenes 554 and 555 were obtained in 60% yield and in a ratio of 88:12 (Scheme 133).165 The major isomer 554 was formed with the same enantiomeric purity as the starting ACP 170 (98% ee, measured after oxidative ringopening of the cyclobutene to the corresponding diketone). In contrast, the minor cyclobutene 555 was obtained with only 14% ee, showing that a high degree of racemization occurs, when the carbon stereogenic center is the migrating atom. Yet another transformation was observed when the PtCl2 catalysis conditions were applied to (arylmethylene)cyclopropanes 559 possessing very electron-rich aryl groups. These substrates gave cyclobutenes 550 when employed in diluted solutions (c = 0.02 M), but afforded dimeric products 560 at higher concentrations (Scheme 134).143 Their formation

Scheme 135. Rh-Catalyzed Rearrangement of ACPs Tethered to a 2-Alkenylpyridine Moiety168

Scheme 134. Pt-Catalyzed Rearrangement of Electron-Rich (Arylmethylene)cyclopropanes143

The mechanistic interpretation, consistent with findings of deuterium labeling studies, assumes that the initially formed alkenylrhodium hydride 569 adds to the ACP double bond to give the rhodacyclopentane 570, which in turn forms the rhodacyclooctene 571 by ring expansion. Final reductive elimination affords the isolated cycloheptenes 566 and 568 and regenerates the catalytically active Rh(I) species. In the second approach, both aryl- and ethyl-linked ACP aldehydes 572 and 574, respectively, were activated by the use of Rh(I) complexes in the presence of a phosphine and ethylene in dichloroethane at 120 °C in a sealed tube and afforded good yields of cycloheptenones 573 and 575.168 As in the previous reaction, initial C(O)−H activation by oxidative addition is thought to be followed by hydrometalation of the MCP double bond to give a rhodacyclopentanone. These species often experience a decarbonylation process, which is slowed by ethylene or an alkene,169 but in this case the proximity of the ACP moiety offers a low activation energy alternative with formation of a rhodacyclooctenone via a cyclopropylmethyl-Rh to homoallyl-Rh rearrangement, which is advantageous due to release of strain energy of the cyclopropane, and finally produces cycloheptenones 573 and 575 by reductive elimination. Interestingly, enantiomerically pure substituted ACPs 576 and 578 afforded regioisomeric cyclo-

was rationalized on the basis of the usual rearrangement leading to the cyclobutene 550; however, in this case the more electron-rich double bond favors the attack of cyclobutene 550 (or its precursor 553) on the complex 561, affording the cyclobutyl cation 562 stabilized by the aryl group. An intramolecular Friedel−Crafts reaction with attack on the vicinal activated arene with formation of the five-membered ring followed by final protodemetalation leads to the isolated dimeric cyclobutanes 560. The Friedel−Crafts step accounts for the formation of regioisomeric products, when more than one ortho position in the arene ring can be attacked, as in the case of 560b. The less activated ACP 563 did not undergo the Friedel−Crafts reaction and furnished the different cyclobutene dimer 564 directly deriving from intermediate 562. Other rearrangements involving the ring-opening of an MCP moiety were conceived by combining known metal-catalyzed C−H activation methods with cycloisomerization chemistry of a vicinal MCP in a cascade process. Fürstner et al. applied this concept utilizing two different Rh(I)-catalyzed reactions, the 7351


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octenones 577 and 579, respectively, both obtained with complete retention of configuration (Scheme 136).168 The

Scheme 137. Rh-Catalyzed Rearrangement of ACPs Tethered to an α,α′-Disubstituted Aldehyde Moiety171

Scheme 136. Rh-Catalyzed Rearrangement of ACPs Tethered to an Aldehyde Moiety168

MCPs, of general structure 586, upon reaction with aldehydes produce imines 587, which, upon heating, undergo an intramolecular formal [3+2] cycloaddition to produce pyrrolo[1,2-a]indoles 588. The reaction proceeds smoothly with aromatic as well as heteroaromatic aldehydes and formaldehyde (Scheme 138).172

outcome of these reactions infers that the proximal C−C bond of the ACP cis to the aryl group is selectively cleaved independently of the degree of substitution, as a consequence of a strict conformational requirement for the ring expansion step. Moreover, stereoconservation in the formation of 577, where the stereogenic center was the migrating carbon atom, suggests complete retention of configuration in both C−C bond cleavage and reductive elimination steps. ̈ et al. have extended the studies on Rh(I)-catalyzed Aissa intramolecular hydroacylations of ACPs to the α,α′-disubstituted aldehydes 580, in continuation of studies carried out on analogous alkylidenecyclobutanes and alkylideneazetidines, which gave access to cyclooctenes and azocinones, respectively (see below).170 It was found that all of the substrates underwent smooth rearrangements to cycloheptenones 581 under milder conditions, when a different Rh(I) complex was used in the presence of bidentate BINAP ligand (Scheme 137).171 Noticeably, the ACP moiety was the preferred site for hydroacylation when an unsaturated allyl (substituted or not) or propargyl group was introduced in the substrate. Alkynecontaining ACPs 580 showed incomplete conversion and sidereactions, but the desired reactivity was restored on replacing the BINAP ligand with dppf. Diols 582 and 584, in a two-step process without purification of the intermediate unstable aldehydes, obtained by Dess−Martin periodinane (DMP) and Swern oxidation, respectively, efficiently gave spiro[4.6]undecenedione 583 and spiro[6.6]tridecadienedione 585, in the latter case by a 2-fold hydroacylation. 2.2.3. Reactions Involving Cyclopropane Ring-Opening. 2.2.3.1. Thermal Reactions. Properly aniline-substituted

Scheme 138. Formal [3+2] Cycloaddition of Imines172

The 1,1-dialkoxy-2-methylenecyclopropane 589 (Scheme 139) acts as a masked and stabilized dipole, which, upon heating, undergoes [3+2] cycloaddition reactions with several dipolarophiles. The cycloaddition of 589 with substituted cyclohexenones and cyclopentenones, of general structure 591, provides access to mixtures of hexahydroindanone and bicycle[3.3.0]octanone derivatives 592 and 593 by cycloaddition to the double bond, Scheme 139. 1,1-Dialkoxy-2-methylenecyclopropane as Masked Dipole

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as well as oxaspiro[4.5]decene byproducts 594 by cycloaddition to the CO bond (Scheme 140).173 Hexahydroindanes of type 592 were utilized for the synthesis of illudine type compounds.

Scheme 141. Reactions of Triflic Acid with ACP Alcohols with Two Aromatic Substituents175

Scheme 140. Cycloaddition of 1,1-Dialkoxy-2methylenecyclopropane to Cyclohexenones and Cyclopentenones173

Scheme 142. Reactions of Triflic Acid with ACP Alcohols with One or No Aromatic Substituents175

2.2.3.2. Reactions with Electrophiles and Lewis AcidCatalyzed Reactions. Like many other alkenes, ACPs easily undergo reactions with electrophiles, but, due to the presence of the strained cyclopropane ring, the large variety of products that can be obtained is peculiar for these compounds. Likewise, the action of Lewis acids is a powerful trigger to promote useful transfromations of ACPs in which the cyclopropyl moiety can be preserved (see section 2.2.1), expanded or opened. The simple addition of HX (X = halide) to MCPs at 120 °C affords open-chain alkenes. The reaction has been improved using halide salts in AcOH.174 Other Brønsted acids can be used to promote transformations of ACPs. The reaction of triflic acid with ACP alcohols 595 induces rearrangements with formation of new bicyclic compounds, the structure of which is, again, dependent on the nature of the carbinol substituents. The presence of two phenyl rings (Scheme 141) favors the cyclopropane ring cleavage. Subsequent ring closure of 598 produces the naphthyl derivative 596.175 On the other hand, when at least one of the two substituents is not aromatic (600, R1 = alkyl, H; R2 alkyl, aryl), the outcome of the reaction is a methylenecyclobutane 601 produced by a ring enlargement process and quenching of the intermediate carbocation 604 by a water molecule (Scheme 142).175 The dimethylenecyclopropanes of general structure 606 react smoothly with TfOH in toluene to undergo a ring enlargement

of the three-membered ring to form dihydroindene derivatives 607 (Scheme 143).27 Halogenes add very easily to ACPs, affording mainly openchain products. For example, the addition of I2 to ACPs affords 2,4-diiodo-1-butenes when the reaction is carried out in dichloroethane.176 When the reaction is performed on ACPs bearing two substituents on the double bond, in acetone/H2O the main products are iodocyclopropylmethanols (see section 2.2.1).177 Other strongly electrophilic fluorinated reagents, like N-fluorobenzensulfonimide (NFSI) or 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor), react with MCP derivatives affording open-chain fluorinated products. The reaction with NFSI affords fluorinated alkenes 608 bearing the benzenesulfonimido group (Scheme 144).178,179 The use of Selectfluor and a nitrile as solvent gives rise to the formation of fluorinated alkenes 609 substituted with amido groups (Scheme 145).178 7353


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Scheme 143. Ring Enlargement Mediated by TfOH27

inducing a ring enlargement. The reaction gives rise to mixtures of the diastereoisomeric compounds 618 in good overall yields (Scheme 147).180 Scheme 147. Reaction of ACPs with 3-Amino-2-ethyl-4(3H)quinazolinone in the Presence of Iodosobenzenediacetate180

Scheme 144. Reaction of MCPs with NFluorobenzensulfonimide178,179

Scheme 145. Reaction of MCPs with Selectfluor and Nitriles178 Phenylsulfenyl chloride and phenylselenyl chloride add to ACPs affording mixtures of substituted cyclobutenes 620 and open-chain homoallylic compounds 621 in ratios depending on solvent and structure of the substrates. Using alkyl-substituted ACPs 622, allylcyclopropane derivatives 623 are obtained (Scheme 148).181 The proposed mechanism involves the addition of phenylsulfenyl chloride or phenylselenyl chloride to ACPs to afford the corresponding episulfonium or episelenium ion 624, which leads to the intermediate carbonium ion 625 (Scheme 149). The subsequent nucleophilic attack by chloride furnishes the ring-opened products 621 (path a, Scheme 149). The

In an attempt to produce fluorinated MCPs, compound 610 was treated with diethylaminosulfur trifluoride (DAST). Unexpectedly, the reaction afforded the fluorinated methylenecyclobutane 614, presumably through the formation of the carbocation 612 that gives ring enlargement to the cyclobutane derivative (Scheme 146).86 A nitrene equivalent can be produced by reaction of 3amino-2-ethyl-4(3H)-quinazolinone (Q-NH2, 615) with iodosobenzenediacetate (PIDA) in the presence of Na2CO3. This electrophilic species reacts with alkylidenecyclopropanes

Scheme 148. Phenylsulfenyl Chloride and Phenylselenyl Chloride Additions to ACPs181

Scheme 146. Reactions of MCP Derivatives with DAST86

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Scheme 149. Proposed Mechanism for the Addition of Phenylsulfenyl Chloride or Phenylselenyl Chloride to ACPs181

Scheme 151. Lewis Acid-Mediated Reaction of ACP with Diarylpropenols184

competitive rearrangement of carbonium ion 625 gives ringexpanded cyclobutyl cation 626, which affords products 620 via a β-proton elimination (path b). If one of the two substituents is an alkyl group, the immediate β-elimination is the favorite process to afford compounds 623 (Scheme 149). If the addition of selenyl electrophiles is mediated by Lewis acids, the reaction outcome is different. 1,2-Diphenyldiselane, with the catalysis of Lewis acids, adds to ACPs very efficiently. The reaction product is a 1,1-diphenylselenyl cyclobutane 630, formed through an electrophilic addition of phenyl selenium cation (PhSe+) to the double bond followed by ring enlargement (Scheme 150).182

Scheme 152. Reaction of Methylenecyclopropylcarbinols with Acetals of Aromatic Aldehydes with the Catalysis of Sc(OPf)3185

Scheme 150. Addition of Selenyl Electrophiles to ACPs Mediated by Lewis Acids182

In the proposed reaction mechanism, the Lewis acid induces the formation of the mixed acetal 639 and its transformation into the oxonium ion 640, which is responsible for the ring enlargement (Scheme 153). Scheme 153. Proposed Reaction Mechanism for the Catalysis of Sc(OPf)3 Very similar results were also obtained, in the same work, using 1,2-di-p-tolyldisulfane. A more recent report demonstrates that TiCl4 can be conveniently substituted by FeCl3 (20 mol %). In this new protocol, the reaction occurs at room temperature.183 The use of Lewis acids as catalysts opens a wide range of new ACPs reactivity. BF3·Et2O catalyzes the intermolecular reaction of arylmethylenecyclopropanes with triaryl propenols 632. The reaction outcome depends upon the nature of the substituents on the methylenecyclopropane moiety (Scheme 151). When the two substituents are both aromatic, the final compound is the triene 633 (with, in some cases minor amounts of alcohol 634); when one of the substituents is a methyl group, the main products are alkylidenecyclobutanes 635 (Scheme 151).184 The methylenecyclopropylcarbinol 637 reacts with acetals of aromatic aldehydes with the catalysis of Sc(OPf)3 (OPf = C8F17SO3) to afford tetrahydrofuran derivatives 638. The reaction is fairly stereoselective affording exclusively the trans product 638a in most of the reported examples (Scheme 152).185

Acyl chlorides react with (E)-2-(arylmethylene)cyclopropanaldehyde 424 in the presence of ZnCl2 (1 equiv) to afford substituted alkylidenecyclobutane derivatives 643 in a stereoselective process. The double bond geometry of the starting material has a fundamental role in determining the nature of the final products. While E-424 affords exclusively the expected cyclobutanes 643, the Z-424 isomers undergo the cyclopropyl ring-opening through a distal bond cleavage that affords dienes 644 (Scheme 154).186 Several intramolecular transformations can be catalyzed by Lewis acids. TiCl4 can mediate an intramolecular ring 7355


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disubstituted with EWGs, like in compound 651, the Lewis acid induces a distal bond ring-opening to give a stable 1,3dipole that reacts with nucleophiles. If the nucleophilic attack occurs intramolecularly, the products obtained depend upon the distance between the two reacting centers and on the nature of the Lewis acid. Scheme 157 summarizes the transformations of aryl-substituted dimethyl methylenecyclopropane-1,1-dicarboxylate 651.188 In an intermolecular process, if the nucleophile is a propargylic alcohol, the product is the corresponding allyl propargyl ether 658, which can be a suitable substrate for an intramolecular Conia-ene reaction. This two-step transformation can be performed in a one-pot process with moderate overall yield to produce tetrahydropyranyl derivatives 659 using another Lewis acid catalyst mixture (Scheme 158).189 In a more recent report, a new protocol that uses methanol as the solvent has been developed by which the double bond configuration was preserved. If the counter reagent is panisaldehyde, the reaction product is a substituited tetrahydrofuran 661 (Scheme 159).28 EWG gem-disubstituted MCPs react with nitrones 364 to produce 1,2-oxazinanes 663 by a formal [3+3] cycloaddition. The reaction is regio- and stereoselective, affording in all cases only one isomer, in good yields and under mild reaction conditions. In one case leading to 1,2-oxazinane 664, the reaction could be carried out in a three-component one-pot process, starting from benzaldehyde and N-phenylhydroxylamine, as precursors of the nitrone, and MCP 383 in the presence of 30 mol % of Yb(OTf)3 (Scheme 160).190 2.2.3.3. Reactions with Bases. The d imethyl (arylmethylene)cyclopropane-1,1-dicarboxylates, of general structure 387, undergo an unexpected ring-opening rearrangement when treated with n-BuLi. The result is a mixture of Z/Econfigured buta-1,3-dienes 665 in which the Z isomer is the most abundant (Scheme 161).191 The scope of this reaction is limited by the necessity of one aromatic substituent on the double bond. The proposed reaction mechanism justifies the preponderance of the Z isomer, because of steric hindrance in the allene intermediates 668a and 668b (Scheme 162). 2.2.3.4. Reactions with Nucleophiles. Methylenecyclopropanes bearing an EWG group (in this case an amido group as in compound 671) on the ring, upon reaction with MgI2, undergo a distal bond cleavage due to the nucleophilic attack of iodide. This process forms the iodinated magnesium enolate 673 that reacts with N-p-toluensulfinimines 674 to produce substituted pyrrolidines 676 in a highly stereoselective manner (Scheme 163).192 The use of deuterated starting material, and stereoelectronic arguments, support the SN2−SN2 mechanism versus an SN2′− SN2′ mechanism that would involve the exocyclic double bond. The scope of the reaction is wide, and it can be applied to aromatic, heteroaromatic, and α,β-unsaturated sulfonimines. With few exceptions, the reaction produces a single diasteroisomer through a proposed transition state in which the magnesium ion chelates the two reagents.192 The presence of two fluorine substituents on the cyclopropane ring activates the methylenecyclopropane 267 toward nucleophilic attack by primary and secondary amines followed by a proximal C−C bond cleavage to form enamines 677 (Scheme 164).93 Benzylamines react at 0 °C with methyl 2-chloro-2cyclopropylideneacetate (269) to trigger the cyclopropyl ring

Scheme 154. Reaction of Acyl Chlorides with (E)-2(Arylmethylene)cyclopropanaldehyde in the Presence of ZnCl2186

enlargement of MCPs 645 having a propargylic ester group. This reaction affords bicyclic compounds 646 in good yields (Scheme 155).187 Scheme 155. Intramolecular Ring Enlargement Mediated by TiCl4187

The mechanism proposed involves the nucleophilic intramolecular addition of the pendant methylenecyclopropane to the alkyne moiety, activated by the Lewis acid, along with the formation of the carbocation 648, which induces the cyclopropane ring enlargement to give 649 and the subsequent attack on the allene moiety (Scheme 156). Scheme 156. Proposed Mechanism for the Intramolecular Ring Enlargement Mediated by TiCl4187

An analogous transformation occurs with the carbinol 501; however, the presence of water and AgOTf as the Lewis acid drives the reaction to produce compound 502 (see Scheme 122).150 Attention has been paid to the special reactivity of ACPs bearing two electron-withdrawing groups (EWGs) on the cyclopropane ring. When the cyclopropane ring is gem7356


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Scheme 157. Intramolecular Reactivity of ACPs Bearing Two Electron-Withdrawing Groups with Lewis Acids188

Scheme 160. Reaction of EWG gem-Disubstituted MCPs with Nitrones190

Scheme 158. Intermolecular Reactivity of ACPs Bearing Two Electron-Withdrawing Groups with Propargylic Alcohol and Subsequent Reactivity189

Scheme 161. Reaction of EWG gem-Disubstituted MCPs with BuLi191

Scheme 159. Intermolecular Reactivity of ACPs Bearing Two Electron-Withdrawing Groups with an Aromatic Aldehyde28

reactions involving ACPs will be discussed.1j These reactions can be initiated by addition of a radical species to the C−C double bond of an MCP (usually, albeit not exclusively, evolving with cyclopropane ring-opening) or directly at the cyclopropane ring. In addition, reactions that occur via radicals generated by an SET mechanism with either reducing or oxidizing reagents will be presented. 2.2.3.5.1. Additions of Preformed Radicals. In contrast to previous findings that had shown a preferred cleavage of the proximal bond in the bromination of diarylmethylenecyclopro-

expansion and final elimination of HCl to afford cyclobutenamines 678. The lability of 678 toward hydrolysis was circumvented by its deprotonation and trapping with Boc2O (Scheme 165).193 2.2.3.5. Attack by Radicals. In this section, the few examples that have been added in recent years to the portfolio of radical 7357


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Scheme 166. Radicals Addition to gem-Difluorosubstituted ACPs92

Scheme 162. Proposed Mechanism of the Reaction of EWG gem-Disubstituted MCPs with BuLi191

Scheme 163. Ring Enlargement Mediated by MgI2192 compounds such as ICl, prone to generate electrophilic halogen species rather than radicals, were unreactive. de Meijere et al. reported on the facile addition of thiols to the double bond of bicyclopropylidene (129) and other MCPs with retention of the three-membered rings.195 Subsequently, Huang has reported the radical additions to (arylmethylene)cyclopropanes of phenylthiol196 and diethyl phosphate,197 which promoted the cyclopropane ring-opening and afforded dihydronaphthalene derivatives. More recently, Huang et al. extended these studies to the addition of selenium reagents to (arylmethylene)cyclopropanecarbaldehydes 682.198 Interestingly, a different reactivity was found depending on the radical or electrophilic nature of the selenium reagents, with the former leading to naphthalenes 683 and the latter to cyclopropaneannelated tetrahydrofurans 684 (Scheme 167).199 Persulfate generates the phenylselenyl radical from N-(phenylseleno)phthalimide: this adds to the C−C double bond to give the cyclopropylmethyl radical 685, which in turn rearranges to the homoallyl radical 686 stabilized by a formyl group. This latter intermediate evolves to the final product 683 on cyclization followed by dehydrogenation. On the contrary, the phenylselenyl cation generated from PhSeBr adds to the double bond to form seleniranium ion 687, which undergoes intramolecular nucleophilic attack of the aldehyde oxygen, induced by addition of water, to afford the final tetrahydrofuran 684 (Scheme 167). Baba et al.200 reported a unique addition of a tin-centered radical to the central carbon atom of an MCP. Indeed, the tributyltin radical, formed by activation of tributyltin hydride with triethylborane, added to the terminal carbon of the double bond of MCP 688, leaving the cyclopropane unaffected to give 689 (Scheme 168).201 On the other hand, activation by Pd(0) catalysis furnished the open-chain homoallyltin derivative 690 with cleavage of the proximal C−C bond of 688 with the unsubstituted carbon atom.202 In contrast, when the MCP 281 was treated with iododibutyltin hydride and a catalytic amount of triethylborane, only alkenyltin iodide 691, derived from cleavage of the proximal C−C bond of the MCP at the substituted bond, was obtained in elevated yield, and 688 behaved analogously (Scheme 168).200 Albeit the reason for this shift in regioselectivity has not been elucidated, it is apparent that the Bu2ISn radical attacks the central atom of MCP to generate the cyclopropylmethyl radical 692, which rearranges to the homoallyl radical 693 as the precursor of the observed product 691. Because the products of this addition are alkenyltin derivatives, which are suitable substrates for Stille-type crosscoupling reactions, and in addition showed limited stability to

Scheme 164. Reaction of Fluorine-Substituted MCPs with Amines93

Scheme 165. Reaction of Benzylamine with Methyl 2Chloro-2-cyclopropylideneacetate193

panes under radical conditions,194 Xiao reported that the gemdifluorosubstitution in ACPs 21 favored direct attack of radicals on the electron-deficient carbon of the cyclopropane with subsequent homolytic cleavage of the distal C−C bond and formation of a stabilized allyl radical intermediate. Thus, reagents capable to form radicals, such as halogens and tin hydrides under thermal activation, gave functionalized difluorinated compounds 680 and 681, respectively (Scheme 166).93 In the case of halogenations, addition of radical inhibitors affected the reaction negatively; moreover, interhalogen 7358


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and PPh3 to afford in a one-pot operation the cross-coupled pnitrostyrenes 695 in good yields (Scheme 169).200 The process

Scheme 167. Addition of Selenylating Reagents to (Arylmethylene)cyclopropanecarbaldehydes198

Scheme 169. One-Pot Addition of Tin Hydrides/Stille Cross-Coupling of MCPs196,203

was also coupled with an intramolecular radical cyclization onto an alkene placed at a suitable distance203 in the MCP 696 to furnish directly a more elaborated cross-coupled tetrahydrofuran 697 as a mixture of cis/trans diastereoisomers. 2.2.3.5.2. SET Reactions. Early studies on the lithiation of ACPs followed by quenching of the organometal intermediates with electrophiles were carried out by Maercker et al. and suggested the formation of dilithiated intermediates at the C−C double bond, which may undergo subsequent rearrangements including cyclopropane ring-opening and transfer of the lithium to more stabilized carbanion centers.204 Recent findings reported by Yus documented a change in regioselectivity, when the dilithiated species were generated according to the arene-catalyzed lithiation technology205 instead of with Li metal only. Indeed, treatment of 2,2-diphenylmethylenecyclopropane (688) with excess lithium metal, or also with lithium in the presence of catalytic naphthalene at room temperature, followed by quenching with water, furnished 4,4-diphenylbut1-ene (699), apparently derived from the dilithiobutene 698 formed by cleavage of the proximal C−C bond with the substituted carbon of 688. In contrast, when the lithiation was carried out in the presence of catalytic 4,4′-di-tert-butylbiphenyl (DTBB) at low temperature and followed by quenching with several electrophiles of the organolithium intermediates, only products 702 and 703 derived from cleavage of the distal C−C bond were obtained (Scheme 170).206 These products apparently originated from the corresponding equilibrating allyl-dilithiated species 700 and 701, respectively. Only when a very reactive electrophile such as water was used, was the isomer 702 observed; in all other cases except for a biselectrophile, the more highly substituted alkene 703 was formed exclusively. Maercker et al. reported that lithiation of (diphenylmethylene)cyclopropane (288) with lithium at −20 °C to room temperature and subsequent reaction with electrophiles gave products 710 functionalized at one of the arenes, apart from very reactive electrophiles such as H2O and dimethyl sulfate, which gave the isomeric 709 (Scheme

Scheme 168. Addition of Tin Hydrides to MCPs196,201,202

purification procedures, they were directly subjected to Pd(0)catalyzed coupling with aryl iodides. Thus, to the crude reaction mixtures derived from treatment of MCPs 694 with Bu2SnIH and Et3B as above were added p-nitroiodobenzene, Pd2(dba)3, 7359


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Scheme 170. Arene-Catalyzed Lithiation of ACPs100,200,206

oxidizing species such as manganese triacetate. Suitable nucleophiles can then intercept the transient cationic center, and the radical undergoes a rearrangement. Thus, cyclopropanaphthalenes 711 gave 1,2-benzanthracenes 712 in excellent yields when treated with Mn(OAc)3 in acetic acid, via the radical cation 713 (Scheme 171).207 Nucleophilic attack, Scheme 171. Reaction of (Diarylmethylene)cyclopropa[b]naphthalenes with Mn(OAc)3207

radical rearrangement with cyclopropane ring-opening, and intramolecular arylation with hydrogen radical abstraction would produce the observed products 712. Other one-electron metal oxidants, such as Cu(OAc)2 and (NH4)2Ce(NO3)6, gave only traces of products. Different solvents were also ineffective, indicating that the solvent mostly acts as the nucleophile. Indeed, when acetic acid was replaced with other carboxylic acids (hexanoic, benzoic) as solvent or by THF, the corresponding phenolic esters were obtained. It was also possible to introduce different nucleophiles, such as benzenesulfinate and azide, when the corresponding sodium salts were added to the reaction mixture. The synthetic usefulness of compounds 712 was demonstrated by their direct use in Nicatalyzed or in Pd-catalyzed cross-coupling reactions after their transformation into the corresponding triflates, which led to valuable intermediates for new materials. 2.2.3.6. Reactions Induced by Transition Metals. In the past decade, the development of new transformations induced by the use of transition metal derivatives has been undoubtedly the most prolific area of research involving ACPs, and several accounts on specific subjects have been published. Although already broadly addressed since the pioneering studies by Noyori et al. and Binger et al. in the 1970s,208 this subject has witnessed continued increase since then and is further flourishing in this century. Many new metal complexes have been considered to achieve unknown reaction modes and new or better selectivities. Concerning the metal, Pd remains the metal most intensively employed, but Ni, and then Rh, have experienced much increased interest and follow closely. More limited examples have been documented with the use of Pt, Ru, Os, Au, and Cu. In this section, the most recent findings will be presented, apart from those concerning simple rearrangement reactions of the substrates, already addressed in section 2.2.2.3, and those not involving the cyclopropane ring-opening, treated in section 2.2.1. To rationalize its presentation, the subject has been

170).204a Likely, the radical species 704/705 initially formed by an SET process undergo further lithiation to 706, which experiences (it or its radical precursor 705) a cyclopropylmethyl to homoallyl rearrangement to give the dilithiated 707. This intermediate has a short lifetime and readily isomerizes at room temperature to the more stabilized dilithio compound 708, which accounts for the formation of alkenes 710. Yus et al. found that isomerization of 707 to 708 can be suppressed if the lithiation of 288 is performed at low temperature in the presence of naphthalene as the catalyst. Under these conditions, only difunctionalized alkenes 709, in several cases accompanied by monofunctionalized products, have been obtained (Scheme 170).101 Conversely, (diarylmethylene)cyclopropa[b]naphthalenes furnish a radical cation by releasing one electron from the exomethylene double bond when treated with a single electron 7360


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further divided into five sections, regarding the stoichiometric use of transition metals with ACPs for the synthesis of metal complexes, and their catalytic use in addition, cycloaddition, cyclodimerization, and polymerization reactions, respectively. 2.2.3.6.1. Stoichiometric Formation of Metal Complexes. As compared to the multitude of reports published on transformations of ACPs induced by transition metal derivatives, relatively scarce efforts have been devoted to the isolation of transition metal complexes from reactions involving alkylidenecyclopropanes. Nevertheless, a few examples have been reported for the formation of different types of complexes, belonging at least to the following five categories: (i) η2alkylidenecyclopropanes and 1,3-diene derivatives formed via ring-opening isomerization,209 (ii) alkylidenemetallacyclobutanes,209f,210 (iii) η4-trimethylenemethanes,211 (iv) metallacyclopentanes resulting from the oxidative coupling of the C−C double bond with that of an alkene,209f,212 and (v) ring expanded homoallyl type metallacycles.209f The isolation and characterization of these different types of complexes is remarkable, because each of them has been proposed as an intermediate along some of the transformation pathways of metal-catalyzed reactions of ACPs. In addition to the complexes mentioned above, during his studies on the chloropalladation of ACPs, Hughes et al. reported the formation of allyl−Pd complexes derived from nucleophilic ring-opening of MCP when a palladium derivative with nucleophilic ligands, such as chloride, was used.213 They observed that isopropylidenecyclopropane did not form complexes and undergo the chloropalladation reaction, while unsubstituted MCPs did. In contrast, Shi et al. reported that (1′,1′-diarylmethylene)cyclopropanes undergo the chloropalladation reaction, and they recently isolated complexes 716 by treatment of ACPs 619 with stoichiometric amounts of PdCl2 or PdBr2 (Scheme 172).214

Scheme 173. Reaction of ACPs with Pt(0) Complexes102

indeed, it was found that several Pt(0) complexes, including Pt(cod)2, Pt(C2H4)3, and Pt(norbornene)3, catalyzed the isomerization of BCP (129) into allylidenecyclopropane (222).103 Complexes 720 were observed to have limited stability in solution and slowly rearranged to the spirocyclopropanated platinacyclopentenes 721. Unprecedented coordination modes of reorganized ACP backbones resulting from reactions of ACPs with Os(II) or Ru(II) complexes have been discovered recently and described in a series of papers by Esteruelas et al. The reactions of (2pyridyl)methylenecyclopropane 723 with the cyclopentadienylosmium complex 722 and with hydridotris(pyrazolyl)borate Os or Ru complexes 725 in dichloromethane at room temperature afforded novel cyclobutylidenemetal complexes 724 and 726, respectively, by displacement of the two acetonitrile or acetone ligands (Scheme 174). 215 The complexes were isolated as crystalline compounds and characterized by spectroscopic methods and by X-ray structural studies. The vicinal pyridine nitrogen coordination site was necessary for formation of the complexes, because ACPs lacking a chelation assistant failed to give the ring expansion to a four-membered ring. Other coordinating groups were able to trigger the rearrangement, as demonstrated by formation of complex 729 in the reaction of the osmium complex 725a with ethyl cyclopropylideneacetate (347); in this case, spectroscopic evidence for formation of the intermediate complex 728 with the ACP chelated to Os was collected in CD2Cl2 solution (Scheme 174).215 The ACPs 76 lacking an additional coordinating group gave yet another unprecedented transformation upon reaction with the Os complex 725a in fluorobenzene at room temperature, leading to a unique cleavage of both proximal C−C bonds of the MCP moiety. The two originating fragments, that is, ethylene and a carbene, both occupied a coordination site at osmium affording the ethyleneosmiumvinylidene complexes 727 (Scheme 174).216 The same complexes were obtained by successive addition of the corresponding terminal alkyne, which experienced a tautomerization,217 and ethylene (or vice versa) to 725a.

Scheme 172. Halopalladation of (Diarylmethylene)cyclopropanes214

A few more examples of η2-alkylidenecyclopropane complexes, considered to be the first intermediates involved in many metal-catalyzed transformations of ACPs, have been reported in recent years. Particularly, tricoordinated Pt(0) complexes 718, 719, and 720 with a bidentate phosphine and MCP (1), BCP (129), and allylidenecyclopropane (222), respectively, have been synthesized by ligand exchange from the ethylene complex 717 (Scheme 173).103 Especially noteworthy were the syntheses of the first allylidenecyclopropane metal complexes 720 and those of BCP complexes 719, of which very limited examples with Ti or Co had been reported earlier.209g,h As a strong π-donor capable of effective back-donation, Pt(0) was an ideal metal for coordinating such ACPs. Other Pt(0) complexes have also been described with different types of ligands, such as those coordinating two MCP units and one monodentate phosphine. Remarkably, the allylidenecyclopropane complex 720 has been obtained also reacting the complex 717 with BCP (129) in the presence of Pt(cod)2 at 40 °C; 7361


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was envisaged that 732 with a chelating vinylphosphine ligand might offer alternative routes, including the alkene moiety to react intramolecularly thus trapping some reaction intermediates. The reaction of the Os complex 732 with the pyridylmethylenecyclopropane 723 occurred analogously to those of the complexes 725 affording the cyclobutylideneosmium complex 733 when carried out at room temperature, but at higher temperatures more complex reaction mixtures were obtained (Scheme 175).218 The maximum amount achievable

Scheme 174. Reaction of ACPs with Os(II) and Ru(II) Complexes215,216

Scheme 175. Reaction of (2-Pyridylmethylene)cyclopropane with Propenylphosphine-Os(II) Complex218

of 733 in the reaction mixture, ca. 70% of total Os, was observed after 10 h in CH2Cl2 at room temperature. Over time it rearranged into the cyclobutene complex 734, which amounted to ca. 50% after 40 h in acetone at room temperature. Formation of 734 is meaningful, because it is a firm proof of the viability of the ACP-TM to cyclobutylideneTM to cyclobutene-TM process with a late transition metal (TM), as postulated by Fürstner and Shi in the Pt- or Pdcatalyzed rearrangement of ACPs to cyclobutenes (Scheme 133).143,163 Another complex was also detected in small amounts, structurally assigned as the osmacyclopentane 737 with a tetradentate ligand, which became the main product after 40 h on heating in acetone at 45 °C. Its formation was taken as a proof of the involvement of osmaazacyclopentene intermediates such as 736 (and its precursor 735) in the rearrangement process, because 737 likely results from coupling of methylenecyclopropyl carbon atom adjacent to pyridine to the terminal carbon of the isopropenyl moiety in 736 (an overall reductive coupling of the two double bonds in 735). The complex 738 also made its appearance at 45 °C and increased in its amount to ca. 40%, when the acetone solution was heated at 75 °C (Scheme 175).218 At this temperature, the main product in solution (ca. 60%) was the metallacycle 739, diastereomeric to 737, with the phosphorus and nitrogen atoms disposed cisoid in the four-membered face of the four-legged piano-stool structure. Formation of 738 implied the cleavage of one of the proximal cyclopropane C−C bonds in the intermediate 736, resulting in the product of a formal oxidative

The observed methylenecyclopropane to cyclobutylidene rearrangement, for example, 725 to 726, has a particular impact on the understanding of related catalyzed rearrangements of ACPs to cyclobutenes (Scheme 133), which Fürstner et al. and Shi et al. postulated to involve cyclobutylideneplatinum or -palladium intermediates.142,162 Esteruelas et al. proposed the rearrangement to occur through a formal oxidative addition from the chelated pyridyl−ACP complex 730 to give a metallaazacyclopentene 731 that gives the final ring expansion to 726 by cleavage of the C−C bond accompanied by migration of CH2 and reduction of the metal center (Scheme 174). To gain further insight into the mechanism and to find out additional viable reaction pathways, other related Os complexes with different ligands were taken into account, and it 7362


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Scheme 176. Pd- and Pt-Catalyzed Silaboration of ACPs219

addition of the starting ACP 723 to Os. Its characterization and isolation (structures of complexes 734, 737, and 738 were firmly established by X-ray diffraction analyses) was also very relevant, being the first example of a 2-alkylidene-1-metallacyclobutane complex for a late transition metal formed from an ACP. Its detection supports the mechanistic proposals suggested for several Ni-catalyzed cycloadditions of ACPs in which these types of metallacyclobutanes were postulated as intermediates (see below). Results of DFT calculations were in agreement with the overall mechanistic picture, being able to localize the proposed intermediates and all of the reaction products as deriving from the common intermediate 736. The energy levels calculated for the different products and transition states were qualitatively consistent with the experimental observations. 2.2.3.6.2. Metal-Catalyzed Addition Reactions. The first examples of 1,3-silaboration with ring-opening for ACPs, a valuable process capable of placing simultaneously two different main group metals possessing differentiated reactivity on a functionalized carbon backbone, were reported independently by de Meijere et al. for bicyclopropylidene and Suginome et al. for alkylidene- and methylenecyclopropanes.77,219 The reaction was catalyzed by Pd or Pt complexes, and some interesting selectivities were observed depending on the type of catalyst and substrate used. For example, cyclohexylidenecyclopropane (740) reacted with the silylated pinacolboronate 741 affording isomeric allyl- or homoallylsilanes 742 and 743, respectively, derived from cleavage of the distal or proximal C−C bond of the cyclopropane depending on the use of Pd(dba)2 or Pt(dba)2 as the catalyst (Scheme 176).219 In contrast, MCPs and ACPs less substituted at the double bond gave preferential proximal C−C bond cleavage also with Pd-based catalysts. However, benzylidenecyclopropane (744) also showed a reversal in selectivity switching from Pd to Pt and afforded diastereomeric mixtures of homoallylsilanes 745 with opposite Z/E ratio. The cyclohexane-annelated MCP 746 afforded the isomeric 1,4-adduct 748, when the reaction was triggered by a Pt catalyst rather than the usual 1,3-adduct 747 obtained in the Pd-catalyzed reaction. More recently, Suginome et al. provided an enantioselective version of the silaboration of MCPs employing Pd(dba)2 in the presence of an equimolar amount (with respect to Pd) of an enantiopure phosphine ligand as the catalyst, which also allowed the reaction to be performed under milder conditions. A series of meso MCPs 286 were silylborylated with the reagent 749 (which reacted slightly more enantioselectively than 741), under catalysis of Pd(dba)2 and the binaphthylphosphine 750, which turned out to be the best ligand in terms of enantioselectivity, affording the desymmetrized alkenylboronates 751 with high enantiomeric excesses (Scheme 177).220 Mechanistically, the reaction was interpreted as a Pd-induced activation of the B−Si bond followed by regioselective boropalladation of the C−C double bond of the MCP with boron going to the more substituted carbon, cyclopropylmethyl-Pd to homoallyl-Pd rearrangement, and final reductive elimination with formation of the C−Si bond. The subject has been reviewed by the authors,221 who subsequently reported the kinetic resolution of chiral racemic 2alkylmethylenecyclopropanes based on this reaction and an improved method for achieving very high enantioselectivities in the desymmetrization of meso MCPs based on the use of polymer-supported phosphine ligands. With the aim to gain the advantages of polymer-supported catalysts (simple recovery, reusability) while simultaneously enhancing the catalyst activity

and enantioselectivity, chiral polymeric ligands in which the chiral environment relies largely on the polymer backbone were considered.222 Thus, the polymer-based chiral ligand PQXphos 752 and related polymers with similar phosphines, the chirality of which relies on a single handed helical structure of the poly(quinoxaline-2,3-diyl) backbone and which had already shown remarkable enantioselectivities in other Pd-catalyzed reactions,223 have been investigated in the silylboration of MCPs 286. Among the polymeric ligands tested, the righthanded helical (P)-(R,R)-PQXphos 752 performed best, producing a significant rate enhancement in the desymmetrization of 286 along with considerably higher enantiomeric excesses of the borasilylated products 751 (Scheme 177).224 The high activity of this catalyst system permitted one also to decrease the catalyst loading to 0.2 mol % Pd without any significant loss in yield, and to run the reaction at 20 °C, which further improved the enantioselectivity to 97% ee. Interestingly, these polymeric systems undergo reversible perfect switching of helical chirality depending on solvent effects;225 the left-handed helical (M)-(R,R)-PQXphos, obtained in 1,1,2-trichloroethane, afforded the enantiomeric homoallylsilane (ent)-751 [R-R = (CH2)4] in 80% yield and with 91% ee with only a slight decrease as compared to the right-handed 752, which gave the corresponding 751 in 84% yield and 96% ee, confirming that the helical chirality plays the main role in determining the 7363


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configured enantiomer favoring the alternative cleavage involving the substituted one. Related to the silaboration reaction are the hydrometalation processes developed by Marek et al. with several main group covalent metal hydrides (of boron, silicon, tin) employing ACPs 170 with the purpose of accessing acyclic carbon chains containing an all-carbon substituted quaternary stereocenter. While metal-catalyzed hydrosilylation and hydrostannylation reactions of ACPs had previously been studied,227 no example of a catalyzed hydroboration had been described.228 However, the hydroboration in the presence of Wilkinson catalyst worked fine, affording the desired homoallylboronates 756a, as did the hydrosilylation with the same catalyst and the hydrostannylation catalyzed by Pd(PPh3)4, which gave homoallylmetal derivatives 756b and 756c, respectively, in high yields (Scheme 178).229 Boronates 756a were unstable on attempted

Scheme 177. Pd-Catalyzed Enantioselective Silaboration of MCPs220,224,226

Scheme 178. Rh- and Pd-Catalyzed Hydroboration, Hydrosilylation, and Hydrostannylation of ACPs229

enantioselectivity of the process. The kinetic resolution of racemic MCPs 284 gave optimal results with the use of phosphoramidite 753 as a chiral ligand and a 3-fold excess of the methylenecyclopropane. Under these conditions, the two constitutional isomers 754 and 755 were obtained, with good enantiomeric excesses for the major products 754 (Scheme 177).226 The reason for the observed enantioselectivity accompanied by formation of two constitutional isomers (a sort of parallel kinetic resolution) was ascribed to an opposite preferential cleavage of each of the proximal C−C bonds of the MCP in the complexes formed from the two enantiomers, with the faster reacting (R)-configured enantiomer favoring cleavage involving the unsubstituted carbon atom and the (S)-

purification and were transformed into the corresponding primary alcohols 757 and analyzed as such. Formation of the expected metal derivatives 756 was rationalized on the basis of the mechanism reported in Scheme 178 with a catalytically active species undergoing oxidative addition, thus activating the M−H bond. Hydrometalation of the double bond of 170 then gives 758, which rearranges to 759 by cyclopropane ringopening. Final reductive elimination furnishes the reaction 7364


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products 756 and regenerates the active catalyst. Detection of homoallyl-metals 756 as the exclusive reaction products implies that all of the steps are highly selective; furthermore, the reaction is stereoselective, because hydrosilylation of diastereomeric mixtures of 170 afforded products 756b with the same E/Z ratio. Particularly meaningful is the selectivity of the rearrangement step of 758 to 759: in addition to being faster than the alternative possible direct reductive elimination, it occurred with exclusive cleavage of the proximal C−C bond to the unsubstituted cyclopropane carbon atom. This was the requisite for securing full preservation of the stereochemical information from the quaternary cyclopropane carbon atom of the ACP 170 to the final open-chain products. Indeed, when enantiomerically pure substrates 760 and 762 were used in the hydrometalation/rearrangement reactions, the alcohols 761 and 763 with very close enantiomeric excesses were obtained after oxidation of the primary organometallic products (Scheme 178),229 with the slight loss in ee’s being ascribed to incomplete separation of the E/Z mixtures of diastereomers, which possessed opposite configuration at the stereogenic center.58 A series of mechanistically related transition metal-catalyzed additions were able to place a carbon chain (or atom) directly at one of the carbon atoms of the rearranged MCP skeleton. Among these, examples of hydroformylation, hydroacylation, hydroalkylation, hydroalkynylation, hydroarylation, carbomagnesiation, and carboethylation reactions of ACPs have all been reported recently. The hydroformylation was achieved by using syngas and a carbonyl−Rh(I) as catalyst (Scheme 179).230 Crucial for the selective formation of open-chain aldehydes 764 was the use of (bis)diphenylphosphinoferrocene (dppf) as an added ligand, because other ligands gave mixtures of formylated products derived from an unrearranged and a rearranged MCP moiety, with Xantphos giving a faster carbonylation and favoring formation of cyclopropylethanal versus the open-chain product 764 (90:10). The proposed mechanism is analogous to that of the hydrometalations, with an additional carbonyl insertion step to account for the formylation. The selectivity was also similar, with exclusive cleavage of the proximal C−C bond with the methylene carbon atom. Aldehyde 765 with high enantiomeric purity was obtained from benzylidenecyclopropane (E,S)-762. The Ni-catalyzed hydroacylation reported by Suginome et al. is closely related and can be regarded as an intermolecular variant of the Rh-catalyzed rearrangements discussed in section 2.2.2.3 (Schemes 136 and 137). It afforded ketones stereoselectively by reaction of MCPs with aldehydes. The scope of the reaction was studied with meso-746; a series of aromatic and aliphatic aldehydes underwent addition with MCP ring-opening to afford cis-acylvinylcyclohexanes 766 (Scheme 179).100 In a single case, a hydroacylation product with a conserved cyclopropane ring was isolated. The reaction was stereospecific; cis- and trans-2,3-disubstituted MCP 767 gave the ketone 768 with exclusive anti and syn configurations, respectively, demonstrating that also the cyclopropane carbon atom that experiences bond cleavage and migrates to the metal retains its configuration. On the contrary, the regioselectivity for nonsymmetric MCPs was not complete, but again preference for cleavage of the proximal C−C bond with the less substituted carbon atom was observed. Thus, MCPs 694 reacted with benzaldehyde to afford a mixture of isomeric ketones 769 and 770 with moderate to excellent selectivity, with the former being the major product.

Scheme 179. Rh- and Ni-Catalyzed Hydroformylation and Hydroacylation of ACPs100,230

A Ru-catalyzed hydroarylation of ACPs has been reported by Ackermann et al. with 2-arylpyridines 771 in which the ortho C−H bond of the aryl group is internally activated by the presence of a chelating nitrogen atom of a heterocyclic group (section 2.2.1, Scheme 77).231 While the Ru complex in the presence of common triarylphosphane ligands initiated mostly rearrangement of ACPs to the corresponding dienes (or products derived from them, such as dimeric Diels−Alder adducts), more sterically demanding ligands afforded products of hydroarylation of the ACP. Mostly, simple hydroarylation of the double bond without cyclopropane ring-opening was observed, but in rare cases hydroarylation products formally derived from distal cyclopropane C−C bond cleavage were isolated. This was especially the case for (diphenylmethylene)cyclopropane (288), which gave a mixture of hydroarylated monoadducts 773a and 773b, along with ca. 10% of an o,o′diadduct (for unsubstituted 771) and other products derived from rearrangement of the ACP used in excess (dihydronaphthalenes, hydrochlorinated products), on treatment with 27365


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Scheme 181. Pd-Catalyzed Hydroalkynylation of ACPs233

arylpyridines 771 in the presence of catalytic amounts of [RuCl2(cod)]n and the phosphine ligand 772 (Scheme 180).97b Scheme 180. Ru-Catalyzed Hydroarylation of (Diphenylmethylene)cyclopropane97b

explain the complete regioselectivity observed in these unique cases. This hypothesis was supported by the analogous completely selective transformation of ethyl cyclopropylideneacetate (347) into enynes 777 (Scheme 181).233 Following the above findings on MCP hydroacylations (Scheme 179), Ogata et al. described a three-component reductive version in the presence of silanes, which ends up with products of a formal hydro(silyloxy)alkylation, that is, silylated alcohols. Interestingly, the reaction displayed again exclusive cleavage of the proximal C−C bond of the cyclopropane, but the addition occurred with opposite regioselectivity with the carbinol carbon atom being linked to the sp2 carbon and the hydrogen atom to the sp3 carbon. The optimal reaction conditions were screened employing MCP 746 as the substrate and Ni(cod) 2 as the catalyst; it was found that triisopropylsilane performed much better than other silanes, and the reaction occurred only in the presence of the NHC ligand 778, with other NHC ligands or phosphines being ineffective. Under these strict conditions, similar to those reported for the related reaction with alkynes,234 746 reacted at room temperature with a series of aromatic aldehydes and iPr3SiH to afford silyl ethers 779 in good to excellent yields (Scheme 182).235 Concerning the MCP substrate scope, several MCPs 780 gave the expected silylated allyl alcohols 781 when reacted with benzaldehyde; a monosubstituted MCP gave exclusively the product from cleavage of the less substituted proximal C−C bond, but in lower yield. To explain the different regioselectivity with respect to the hydroacylation reaction, initial activation of the MCP via the nickelacyclobutane 782 or, alternatively, via the oxanickelacyclopentane 783 was proposed. Each of these intermediates can evolve to 784 either by addition of aldehyde at the sp 2 carbon atom or by rearrangement, respectively. In turn, 784 would afford the final silyl ethers 781 via Si−H bond activation to 785 and final reductive elimination (Scheme 182). When different reducing agents and phosphine ligands were used in the same reaction, the reductive addition occurred

An unprecedented Pd-catalyzed hydroalkynylation with cyclopropane ring-opening, in contrast to the Ni-catalyzed one reported shortly earlier by Suginome that left the cyclopropane ring intact (section 2.2.1, Scheme 78),98 was described recently by Mascareñas and López et al. The reaction involved cleavage of the distal C−C bond of the cyclopropane ring and is therefore related to the Pd-catalyzed additions pioneered by Yamamoto et al., which accept a broad range of nucleophiles and have been already extensively reviewed.232 Several Pd and Ni complexes tested failed to give the addition (or the expected [3+2] cycloaddition, see section 2.2.3.6.3), furnishing mostly homocoupling products of the alkyne and rearranged dienes from the ACP. However, a Pd(0) catalyst formed from Pd2(dba)3 in the presence of phosphite 774 was found to be the best system for achieving the formal addition of a series of terminal alkynes across the distal C−C bond of 1′(2-pyridylmethylene)cyclopropane (723) to afford 1,4-enynes 775 in moderate to good yields (Scheme 181).233 Also, for this reaction, the presence of an assisting coordinating atom was important, not for allowing the reaction to occur, but for controlling its regioselectivity. Indeed, structurally similar ACPs such as benzylidenecyclopropane (744) and the 3- and 4pyridyl isomers of 723 performed well in the reaction, but afforded mixtures of two isomeric 1,4-enynes along with the 1,3-enyne. The authors proposed a catalytic cycle starting with activation of the C−H bond of the alkyne by oxidative addition followed by regioselective hydropalladation of the C−C double bond of the ACP and ring-opening to give a π-allylpalladium intermediate, which furnishes the final products by reductive elimination. Isomerization of the π-allyl intermediate would explain the formation of isomeric enynes, but would be prevented by formation of chelated intermediates like 776. Thus, the presence of coordinating atoms in the proximity may 7366


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Scheme 182. Three-Component Ni-Catalyzed Hydro(silyloxy)alkylation of MCPs235

Scheme 183. Three-Component Ni-Catalyzed Ethylalkylation of MCPs with α,β-Unsaturated Ketones or Aldehydes and Triethylborane238

across the C−C double bond without involving the cyclopropane ring rearrangement, and triethylborane was the best reducing agent for this transformation (section 2.2.1, Scheme 79).99 However, when the aromatic aldehyde was replaced with a conjugated carbonyl compound,236 including aldehydes, an alkylative addition reaction with cyclopropane ring-opening at the proximal C−C bond occurred again, placing simultaneously two carbon fragments at the 1,3-positions of the cyclopropane, an ethyl group at the sp3 carbon, and the β-carbon atom of the conjugated carbonyl at the sp2 carbon.237 This novel carboethylation process was first studied with MCP 787, which reacted at room temperature with a range of different α,β-unsaturated ketones 786 and 789 and aldehydes 791 to afford the corresponding γ,δ-unsaturated carbonyl compounds 788, 790, and 792 with retention of configuration (Scheme 183).238 The best conditions for the alkylative coupling were selected by using catalytic Ni(cod)2 and PPh3 as ligand and a 2fold excess of Et3B and MeOH, with the latter acting likely either as an activating agent for triethylborane or a ligand for Ni to slow possible β-hydrogen eliminations, which would favor reductive couplings.237 It is noteworthy that also aldehydes 791 gave the carboethylation products without any hydroacylation reaction product being detected. The scope of the reaction regarding the MCP counterpart was addressed reacting a series of MCPs 286 with methyl vinyl ketone (793); all of them gave the expected ketone 794 in good yield, with a monosubstituted MCP affording regioselectively the product deriving from cleavage of the unsubstituted cyclopropane C−C bond. Only 2,3-dipropylmethylenecyclopropane (767) gave a diene deriving from β-H elimination as the main reaction product. The mechanistic proposal involves initial reductive coupling of the double bonds of the reaction partners to the spirocyclopropa-

nated nickelacyclopentane 795, which would experience ring expansion to the nickelacyclohexane 796 (Scheme 183).238 The latter, through an oxaallyl intermediate and after B−C bond activation, would lead to the key intermediate 797, precursor of the reaction products via reductive elimination and hydrolysis of the boroenolate. Transition metal-catalyzed carbomagnesiation of unsaturated functionalities is a useful strategy for accessing structurally complex and highly reactive Grignard reagents. Terao et al. have recently developed a novel carbomagnesiation of MCPs, occurring with rearrangement of the cyclopropane ring, catalyzed by Ni derivatives. Interestingly, a reagent dependence on the modality of rearrangement was observed, with arylmagnesium bromides adding across the less substituted proximal C−C bond (mode a) and alkenylmagnesium chlorides across the distal C−C bond (mode b) of MCPs 281 and 284 (Scheme 184).239 Accordingly, products 799/802 and 801/804 were obtained selectively after quenching with several electrophiles, indicating formation of intermediate 7367


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Scheme 184. Ni-Catalyzed Carbomagnesiation of MCPs239

short reaction time at room temperature. With these substrates, cleavage of the proximal C−C bond was the obvious option, but a more subtle choice on the regioselectivity of addition was to be faced because both carbon atoms involved in the bond cleavage are sp2-hybridized. However, after quenching of the intermediate adduct with several electrophiles including Celectrophiles, naphthalenes 812 were formed with very high selectivity (>90:1) and isolated in excellent yields (Scheme 185).241 The reaction worked well with other aryl Grignard Scheme 185. Pd-Catalyzed Carbomagnesiation of Diarylmethylenecyclopropa[b]naphthalenes241

Grignard reagents of the homoallyl type such as 798 or allyl type such as 800, respectively. Additions of aryl Grignard reagents worked best with Ni(PPh3)2Cl2 as the catalyst, while use of NiCl2 under phosphine-free conditions was more efficient for reactions with alkenyl Grignard derivatives. The corresponding palladium salts were ineffective in both cases, and other Grignard reagents (methyl, allyl) also failed to react. Ni(0), formed in situ by action of the Grignard reagent on the Ni(II) salt, was proposed as the active catalytic species, which would afford the complex 805. This complex may evolve to methylenenickelacyclobutanes 806 or 808 with cleavage of the proximal and distal bond, respectively, which in turn would afford the observed products 802 and 804 after ring-opening to 807 and 809 and reductive elimination (Scheme 184). More recently, the carbomagnesiation reaction has been extended to diarylmethylenecyclopropa[b]naphthalenes, a peculiar class of ACPs, which are highly reactive yet thermally stable and readily accessible compounds.240 In contrast to the related carbomagnesiation of ACPs, Pd salts showed high efficiency, and diphenylmethylenecyclopropa[b]naphthalene (810) underwent carbomagnesiation catalyzed by Pd(PPh3)2Cl2 with the aryl Grignard reagent 811 in a very

reagents and cyclopropanaphthalenes 813, as shown by formation of the iodinated products 814 with similar yields and regioselectivity. The catalytic process is believed to involve formation of the palladacyclobutane 815,210b and the regioselectivity was rationalized on the basis of steric effects with the less sterically hindered orientation of Grignard reagent shown in Scheme 185 being preferred and leading to the arylmagnesium intermediate 816 as the precursor of the experimentally observed products 814. Another metal-catalyzed addition capable of placing two carbon atoms in 1,3-positions of ACPs with concomitant ringopening was reported by Inomata et al. and consists of a biscarboxymethylation, thus allowing a difunctionalization of a cyclopropane. The reaction worked best under PdCl2/CuCl cocatalysis in a CO/O2 atmosphere at normal pressure and with MeOH or THF/MeOH as solvent. Under these conditions, ACPs 260 reacted efficiently with exclusive clevage of the proximal C−C bond to afford arylmethylene- and alkylideneglutarates 817 (Scheme 186).242 Arylidenecyclopropanes showed a good diastereoselectivity in favor of Econfigured diesters 817 (80−93% ds), while alkylidenecyclopropanes reacted with poor selectivity, and disubstituted 7368


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efficient. The palladium complex 819 was isolated from the reaction mixture, and it proved to be a highly active catalytic species for this reaction. Thus, it was proposed that this complex is the prominent catalyst for the reaction under the optimal conditions, and the reaction evolves through the πallylpalladium iodide 820. The diacetoxylation product is then produced by nucleophilic substitution with acetate to 821 and a Pd(II)/Pd(IV) catalytic cycle with the reductive elimination step from 822 introducing the second acetate group (Scheme 187).243 The same transformation of ACPs 631 to diacetates 818 was achieved with the use of (Me3P)AuCl as the catalyst (Scheme 187, conditions B),244 and a similar catalytic cycle involving Au(I)/Au(III) species was invoked, in analogy to recent findings for gold catalysis in the presence of strong oxidants.245 A similar substrate scope as with palladium was established, with alkyl substitution at the exomethylene carbon not being tolerated, but also very electron-rich aryl groups as the 4-methoxy-substituted gave a different oxidative rearrangement leading to cyclopropyl ketones. The reaction under gold catalysis worked well using only a slight excess of iodosobenzene diacetate and needed acetic acid as the solvent, which worked also as the nucleophile. Indeed, replacing iodosobenzene diacetate with the dipivalate gave the same diacetates 818, while the corresponding dipropionates were obtained when the reaction was carried out in propionic acid as the nucleophilic solvent. 2.2.3.6.3. Metal-Catalyzed Cycloaddition Reactions. In this section, the most recent advancements on the formal cycloaddition reactions undergone by ACPs under transition metal catalysis will be illustrated. The term cycloaddition is used here, as usually done for these reactions, in a broad sense, irrespective of the mechanism of the addition process, which occurs stepwise with formation of metal intermediates, and obviously has nothing to do with a concerted pericyclic reaction. Cycloaddition is just intended to mean the formation of cyclic compounds, in which part of the ACP partner is included in the formed cycle and the cycloadduct conserves generally all of the atoms of the reacting molecules. These cycloadditions are usually categorized according to the connectivity of the reactive fragments of the partners, which end up in the newly constructed cycle, indicating in a square parentheses the number of the atoms coming from each reacting moiety. Accordingly, the different cycloaddition types will be treated in separate sections, with the first number in parentheses being referred to the atoms originally belonging to the ACP moiety. To a great extent, the ACP partner behaves in cycloadditions as a three-carbon atom fragment, no matter whether if a proximal C−C bond (a or b mode, Scheme 188)

Scheme 186. Cu-Catalyzed Bis-carboxymethylation of ACPs242

methylenecyclopropanes gave predominantly the Z-configured diastereoisomer (83−84% ds). Interestingly, simple cyclopropane derivatives did not undergo the reaction at all. Recently, Shi et al. have developed two different methods for achieving another 1,3-difunctionalization of ACPs, a diacetoxylation reaction, which occurred instead upon cleavage of the distal cyclopropane C−C bond. Both methods employed iodosobenzene diacetate as the terminal oxidant and were catalyzed by Pd and Au, respectively. Both diarylmethyleneand monoarylmethylenecyclopropanes 631 furnished allyl bisacetates 818 on treatment with an excess of PhI(OAc)2 and catalytic amounts of Pd(OAc)2 in acetonitrile at 60 °C in the presence of an equimolar amount of tetrabutylammonium iodide (Scheme 187, conditions A).243 The electronic nature of Scheme 187. Pd- and Au-Catalyzed Diacetoxylation of ACPs243,244

Scheme 188. Modes for C−C Bond Cleavage in ACPs and Their Participation As a Three-Carbon Unit in Cycloaddition Reactions

the substituent(s) on the aryl group(s) did not significantly influence the reaction outcome, while substrates with two alkyl or one aryl and one alkyl groups on the exomethylene carbon of the ACP afforded complex mixtures. The ammonium iodide turned out to be essential for obtaining the diacetoxylation in satisfactory yields in its absence, 440 nm) of the 2,2-diaryl-3,3-dimethyl-4- methylenecyclobutanone 1362, with p-chloranil as a sensitizer, produced in a photoinduced electron-transfer (PET) process, besides the 2,2-diaryl-4-(dimethylmethylene)cyclobutanone isomer 1363, the ring-opened dienyl ester with p-chloranil 1364 in different ratios according to the solvent used (Scheme 297).527 Scheme 297. p-Chloranil-Sensitized PET Reactions527

Scheme 300. Asymmetric Epoxidation and Subsequent Epoxide Rearrangement of Arylmethylenecyclobutanes532

In contrast to a diarylmethylenecyclopropane, which upon lithiation with Li/naphthalenide undergoes ring-opening and reaction with electrophiles, the homologous diarylmethylenecyclobutane when submitted to the lithiation under the same conditions gave only the expected ring-opened product with proton (or deuterium) insertion. Trapping with any other electrophile, such as t-BuCHO, Et2CO, or Me3SiCl, failed. The result could indicate that the cyclobutane opening takes place during the final workup.101 A 3-lithiomethyl-methylenecyclobutane underwent ring-opening to the 2-methylene-4-pentenyllithium derivative with a rate constant of 4.9 × 10−4 at −7.7 °C.521 Danishefsky et al., in their total synthesis of Eleutherobin, utilized the cyclohexene-fused (dimethylaminomethylene)cyclobutanone 1365, which was opened in MeOH in the presence of p-TsOH·H2O, to give the key (2-methoxycarbonylcyclohexenyl)acetaldehyde 1366 intermediate (Scheme 298).528 3.5.2. Ring Enlargements. The most frequently exploited transformation of MCBs in synthesis is the acid-catalyzed ring enlargement to cyclopentanones 1368 after epoxidation of the

The sugar-derived enantiopure ketone 1372 was employed in 20 mol % as an efficient chiral auxiliary for the asymmetric epoxidation of 1369 at −10 °C via the intermediately formed dioxirane from 1372. Similarly cyclopentanone N-phthaloylimide 1375 can be obtained in 91% yield by the reaction of Naminophthalimide 1374 and diacetoxyiodosobenzene [PhI(OAc)2] with (1′,1′-diphenylmethylene)cyclobutane (1373) (Scheme 301).533 The formed nitrene equivalent mediated the metal-free ring expansion of (diphenylmethylene)cyclobutane 1373 likely through the corresponding aziridine. The same type of transformation was carried out using 2,4-dinitrophenylsulfenamide as the amide precursor.534 7405


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Scheme 303. Radical-Induced Ring Expansion of ωBromopropyl-Substituted MCB536

Scheme 301. Nitrene Equivalent-Mediated Metal-Free Ring Expansion of an Alkylidenecyclobutane533

Alkylidenecyclobutanes are able to afford also cyclohexanones, but by a different strategy involving sulfoxide derivatives and a radical process.535 The sulfoxide 1376, upon reaction in refluxing benzene with tributyltin hydride (1.5 equiv), afforded 3-phenylcyclohexanone 1377 in 66% yield (Scheme 302).

Scheme 304. Different Ring-Enlargement Processes of 8Methylenebicyclo[4.2.0]octane Ring Systems Mediated by Lewis Acids537

Scheme 302. Radical-Induced Cyclohexanone Ring Formation from ACBs Substituted with a Sulfoxide Group in Allylic Position535

1391 in excellent yield. The diastereomer 1392 with diethylaluminum bromide provided in 91% yield the allylic bromide 1393, the product of shifting the 6/4 fusion bond, containing the bicyclo[3.3.0]octane ring system. Another bicyclo[3.3.0]octane ring system was obtained by selective rearrangement of a 7-methylenebicyclo[3.2.0]heptan3-one derivative upon treatment with 45% HBr in AcOH.538 Addition of Hg(ClO4)2 to bicyclic 6/4 fused MCBs 1394 and 1398 led to mixtures of bridged bicyclic compounds, diastereomeric bicyclo[2.2.2]octanones 1395, 1396 and 1399, 1400, and bicyclo[3.3.l]nonanones 1397 and 1401 (Scheme 305), all formed via an intramolecular aldol condensation of an

In terms of the mechanism, the reaction involves a [2,3]sigmatropic shift of the sulfoxide group followed by homolytic cleavage of the S−O bond, ring-opening of the resulting 1vinylcyclobutyloxy radical 1383 to 1384, and 6-endo-trig cyclization of the latter. Exclusively in the case of 1376, also 19% of the cyclopentanone 1378 was obtained, as a result of a 5-exo-trig cyclization of 1384. Several bi- and tricyclic substrates were subjected to the same transformation with similar efficiency. In some cases, with not-symmetrically substituted methylenecyclobutanes, such as 1379, a mixture of regioisomeric ketones, 1380 and 1381, was obtained resulting from the two possible C−C bond cleavages in the cyclobutyloxy radical of type 1383 (Scheme 302, eq b). Bi- or tricyclic ring-fused methylenecyclobutanes with an ω-bromopropyl chain, like 1385, undergo ring expansion in high yield, leading to cis-fused methylenecycloheptanes like 1388 (Scheme 303).536 This type of ring expansion was carried out by slow addition (over 4−6 h) of 1.5 equiv of tri-n-butyltin hydride to a refluxing benzene solution of the substrate, using AIBN as radical initiator. Ring expansion products (five examples) were obtained in 60−86% yield, and only small amounts of reduction products, like 1389, were detected. The diastereomeric mesylates 1390 and 1391 underwent a different ring enlargement process under reaction with Lewis acids (Scheme 304).537 Reaction of mesylate 1390 with MeAlC12 proceeded by migration of the olefinic carbon to give the rearranged chloride

Scheme 305. Synthesis of Bicyclo[2.2.2]octanones and Bicyclo[3.3.1]nonanones by Hg(ClO4)2-Mediated Transformation of 8-Methylenebicyclo[4.2.0]octane Ring Systems539

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intermediate diketone.539 The bulkiness of the substituent in 1394 and 1398 favors the formation of the kinetic enolate that leads preferentially to the bicyclo[3.3.l]nonanones 1397 and 1401. The initial [2+2] cycloadducts of an arylthioallene onto pquinones under promotion of TiCl4/Ti(OiPr)4 undergo opening of the MCB moiety with subsequent closure onto the quinone oxygen to form benzofuranes as final products.540 A straightforward and efficient cyclopentenylation process by reaction of (diarylmethylene)cyclobutanes with acyl chlorides in the presence of AlCl3 has also been described (Scheme 306).541 The 3-acyl-1,2-diaryl-cyclopentenes 1403 were formed

Scheme 307. Synthesis of a 1,10-Spirobiindane Derivative by a Domino Reaction of a Methyl Cyclobutylideneacetate Initiated by Arylrhodium(I) Species546

Scheme 306. Reaction of (Diarylmethylene)cyclobutanes with Acyl Chlorides To Form Acylcyclopentenes541

via the putative acylation intermediate 1405, which undergoes ring enlargement to 1406 and successive 1,2-aryl migration through a phenonium ion. When the aryl substituents are different, mixtures of regioisomeric cyclopentenes 1403 are obtained. The cyclobutylidenecarbene, generated by different methods, either by treatment of (dibromomethylene)cyclobutane with nBuli,542 or from (bromocyclobutylidenemethyl)trimethylsilane and BnNMe3F, or from cyclobutylidenediazomethane,543 spontaneously rearranges to cyclopentyne, which is trapped in situ with alkenes to give [2+2] cycloaddition products. The carbanionic ring enlargement of (halomethylene)cyclobutanes to 1-halocyclopentenes, which occurs with the intermediacy of cyclopentyne, has been investigated to ascertain the mechanism of the process and its regioselectivity.544,545 Transition-metal catalysis coupled with the reactivity and strain of the MCBs give rise to interesting rearrangements. Indeed the reaction of methyl (3-arylcyclobutylidene)acetate 1408 with sodium tetraarylborate under the catalysis of [RhCl(cod)]2 led to the 1,10-spirobiindane derivative 1409 in high yield through the domino process initiated by the reactive arylrhodium(I) species 1410 (Scheme 307).546 It is remarkable that the spirobiindane skeleton 1409 was formed via wellordered sequential steps consisting of two 1,4-additions, two βeliminations, two 1,4-rhodium migrations, and a 1,2-addition to the carbonyl group in the case that an excess of the tetraphenylborate was used. Spirobiindanes substituted on the indanone moiety can be obtained with the use of sodium tetraaryl borates (six examples, yields 41−79%). A general method to form 2,3-disubstituted indoles from readily available β,β-disubstituted styryl azides catalyzed by dirhodium(II) complexes, when applied to (2-azidophenylmethylene)cyclobutane, afforded the fused 2,3-cyclopentane-

annelated indole in excellent 98% yield.547 The ring enlargement occurs by migration at the level of a spiro-indoline intermediate having a positive charge on the benzylic carbon. In analogy to the intramolecular hydroacylation of aldehydetethered alkylidenecyclopropanes168 catalyzed by Rh complexes, the extension to aldehyde-tethered alkylidenecyclobutanes 1417 provided an excellent method for the synthesis of eight-membered rings. Cyclooctenones 1418 were isolated in very good to excellent yields using either neutral or cationic rhodium catalysts (Table 2).170 Both E and Z isomers of substrate 1417 reported in Table 2, entries 8−11, were converted into the same cyclooctenone, however, with different efficiency, even with different catalysts. The lone pair of electrons on a nitrogen atom leads to irreversible trapping of the active catalyst. This problem can be solved using pyridinium salt derivatives as in entries 12,13 (Table 2). The 6-methylenebicyclo[3.2.0]heptane 1135 (R1 = Me; R2 = R3 = R4 = H) was shown to rearrange to the bicyclo[3.3.0]octane derivative under catalysis of gold(I) complexes with N-heterocyclic carbenes, albeit with loss of enantiopurity.361 The Co−salen complex 1420 catalyzed the enantioselective carbonyl-ene reaction of MCB (2) with ethyl glyoxylate (1419) affording the 2-hydroxy-3-cyclobutenylpropionate 1421 in good yield and with excellent enantiomeric excess (Scheme 308).548 3.5.3. Pericyclic Rearrangements. N-Phosphoryl-N-allylynamides undergo a thermal domino aza-Claisen carbocyclization affording α,β-unsaturated cyclopentenimines. The Nmethylcyclobutylidine substituent, as the allyl moiety, in 1422 ends up in a bicyclo[3.3.0]octene N-phosphoryl imine 1423 (Scheme 309).549 7407


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Scheme 309. Domino Aza-Claisen Carbocyclization of a NPhosphoryl-N-methylcyclobutylidine Ynamide549

Table 2. Rh-Catalyzed Intramolecular Hydroacylation of Aldehyde-Tethered Alkylidenecyclobutanes170

Suffert and co-workers550 have widely described electrocyclization processes of complex alkylidenecyclobutanes 1424, when submitted to selective hydrogenation of the triple bond under nickel catalysis with the mild reagent mixture [Ni(OAc)2· 4H2O, 1 equiv; NaBH4, 1 equiv; ethylenediamine, 3.5 equiv; H2 1 atm], leading to [4.6.4.6]fenestradienes 1425 or [4.6.4.6]fenestrenes (Scheme 310). The intermediate 1426 undergoes a conrotatory 8π-electrocyclization, and 1427 a disrotatory 6πelectrocyclic reaction to provide 1425. Scheme 310. Electrocyclic Processes of Polyenic Alkylidenecyclobutanes: Synthesis of [4.6.4.6]Fenestradienes550

a [Rh(nbd)2]BF4 (15 mol %), BINAP (15 mol %). b(1) AgBF4 (1 equiv); (2) [{Rh(coe)2Cl}2] (5 mol %), AgBF4 (10 mol %), P(4MeOC6H4)3 (20 mol %). c(1) AgBF4 (1 equiv); (2) [Rh(nbd)2]BF4 (10 mol %), BINAP (10 mol %).

Vinyl-substituted alkylidenecyclobutanes, obtained by reaction of allenes with a diene, undergo stereoselective [3,3]sigmatropic rearrangements to exomethylenecyclohexenes. For example, the alkylidenecyclobutane 1430, produced by the [2+2] cycloaddition of the silyloxydiene 1429 to ethyl methylallenecarboxylate 1428, undergoes a rearrangement to the cyclohexene 1432, formally the product of a [4+2] cycloaddition, with high stereoselectivity (Scheme 311, eq a).551 The trimethylsilyl cyclobutyl ether 1430, when desilylated to the corresponding cyclobutanol, upon treatment with LiHMDS at −78 °C, undergoes a base-promoted ringopening-intramolecular Michael cyclization to the diastereomeric cyclohexenones 1431, with preference for the diastereoisomer with the opposite configuration of that obtained in the thermal reaction (Scheme 311, eq a).551 The same process, applied to cyclic dienes like 1433 (Scheme 311, eq b), afforded a diastereomeric mixture of formal [4+2] cycloadducts like 1436. Compound 1436b, and others derived from the same strategy, were utilized for the total synthesis of diterpene natural products.552

Scheme 308. Enantioselective Carbonyl−Ene Reaction of MCB with Ethyl Glyoxylate Catalyzed by a Co−Salen Complex548

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explained by a fully stepwise, statistical model, through the diradical 1438, it was found that there could be a role also for a formally concerted Cope pathway. The product of the reaction of MCB with BuLi/tBuOK, potassium methylenecyclobutanide, reacted with dibutylboron chloride, or 9-bromo-9borabicyclo[3.3.1]nonane, to give mixtures of isomeric 2(dialkylboryl)-1-methylenecyclobutane and 1-((dialkylboryl)methyl)-1-cyclobutene in dynamic equilibrium between them.556 The thermolysis of methylenecyclobutane takes place through the formation of diradical species, like 1441 or 1444, which can recombine giving isomerization products, like 1442, or ring enlarged products like 1445. A study of the energy profile of the degenerate methylenecyclobutane rearrangement correlates the stereoselectivity in the methylenecyclobutane rearrangement with electronically less stabilizing substituents (R = Ph, Me) to the recombination enthalpy of the intermediate diradicals (Scheme 313).557

Scheme 311. Selective [3,3]-Sigmatropic Rearrangements of Vinyl-Substituted Alkylidenecyclobutanes551,552

Scheme 313. Diradical Species by Thermolysis of Substituted MCBs: Isomerization or Ring Enlargement End Product557

Analogous diradical species have been assumed to explain the isomerization of fluorenylallene dimers.341,558Also, in the thermal isomerization of methylenecyclobutanone adducts, obtained by cycloadditions of arylketenes with 1,1-dimethylallene, to yield 2-isopropylidenecyclobutanones, a diradical (or zwitterionic) intermediate is at work.559,560 A cyclobutylidenemethylenecyclopentane is unstable and easily isomerizes to the cyclobutenylcyclopentene isomer.561 3.5.5. Miscellaneous Transformations. Acyl 2-alkylidenecyclobutanones 1447, obtained as single Z isomers from cyclopropylideneprop-2-en-1-ones 1446 in the presence of PdCl2 and Dess−Martin periodinane (DMP), by acidic treatment (TfOH 30 mol %) at room temperature easily rearrange, with ring contraction to the spiro-cyclopropanated 2furanones 1448 in very good yields (Scheme 314).562 Cyclobuta[a]indane derivatives of pharmacological interest, analogues of atipamezole, were synthesized by stereoselective reduction of methylenecyclobutane precursors. In one case, the

1,2-Dimethylenecyclobutanes, generally synthesized by cyclodimerization of allenes or elimination reactions, were used in [4+2] cycloaddition processes.349a,485,511,553 The [4+4] cyclodimerization of 1-isopropylidene-2-methylene-3,3-diphenylcyclobutane under photosensitized electron-transfer (PET) conditions, with 9,10-dicyanoanthracene as the photosensitizer, have been reported. At 0.1 M concentration of the dimethylenecyclobutane in degassed dichloromethane or acetonitrile, mixtures of two [4+4] syn- and anti-cyclodimers were obtained in 54−59% yields, with the syn isomer by far predominating.554 3.5.4. Isomerizations. The thermal rearrangement of a bicyclic fused methylenecyclobutane, 6methylenebicyclo[3.2.0]hept-2-ene (1437), to 5-methylenenorbornene (1439) has been experimentally and computationally studied also with the help of deuterium labeling (Scheme 312).555 The fitting between experimental and computational data is fair. Whereas much of the observed selectivity can be

Scheme 314. Acid-Mediated Rearrangement of Acyl 2Alkylidenecyclobutanones to Spiro-Cyclopropanated 2Furanones562

Scheme 312. Dynamic Effects on [3,3] and [1,3] Shifts of 6Methylenebicyclo[3.2.0]hept-2-ene555

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Scheme 315. Intramolecular Rh-Catalyzed Hydrosilylation446 and Ring-Closing Methatesis447 of Methylenecyclobuta[a]indane Derivatives

reduction to obtain 1451 was carried out with an intramolecular hydrosilylation of 1449 catalyzed by Rh2(OAc)4 followed by removal of the silicon tether in 1450 (Scheme 315, a).446 To obtain products with the opposite configuration at the cyclobutanes ring like 1454, an alkylidenecyclobutane precursor obtained by ring-closing metathesis of 1452 was stereoselectively hydrogenated with H2/Pd to 1453 (Scheme 315, b).447 This represents the only example of a metathesis of methylenecyclobutanes reported to date.

Alberto Brandi is Full Professor of Organic Chemistry. He is Director of the Consorzio Interuniversitario Metodologie e Processi Innovativi di Sintesi (CINMPIS, Bari, Italy). He is Chairman of the Scientific Board of the Italian Chemical Society (SCI). He is Titular Member of the Organic and Biomolecular Chemistry Division (III) of IUPAC. His awards include “Prix Franco-Italien” of the French Chemical Society in 2005; Prize for Research of the Organic Chemistry Division of SCI in 2007; and Adolfo Quilico Medal of the Organic Chemistry Division of

4. CONCLUDING REMARKS The collection of recent synthetic methods and reaction modes involving alkylidenecyclopropanes and alkylidenecyclobutanes is an authentication of the relevant role and dynamism assumed by these compounds in organic syntheses. The combination of their wide accessibility with the strain incorporated in their ring system makes them excellent synthetic tools for the most diverse applications in organic synthesis, all the more through very modern domino methodologies. The catalysis of transition metals has expanded, particularly in the past decade, their chemistry, and we can only predict that this expansion will be vigorous also in the years to come, because of the inestimable possible combinations of metal catalysts, reaction conditions, and reagents.

SCI in 2012. He has published over 220 scientific papers, reviews, and book chapters, and three patents. Research interests deal with stereoselective 1,3-dipolar cycloadditions for the syntheses of alkaloids and azaheterocycles; asymmetric synthesis of biologically active compounds: glycosidase inhibitors, sugar mimetics, β-lactams, amino acids; peptidomimetics and peptides; chemistry of spirocyclopropane heterocycles; and synthesis of functionalized nanomaterials.

AUTHOR INFORMATION Corresponding Author

*E-mail: alberto.brandi@unifi.it. Notes

The authors declare no competing financial interest. Biographies Stefano Cicchi is Assistant Professor at the University of Firenze. He received his Laurea cum laude (1989) and his Ph.D Degree (1993) from the University of Firenze under the supervision of Prof. A. Brandi. In 1991 he spent a research period at the University of Basel in the group of Prof. Bernd Giese. In 1996 he became Assistant Professor at the University of Florence. In 2002 he spent a period as visiting researcher at the University of Zaragoza in the group of Prof. Pedro Merino. Recent interests of research focus on material chemistry, mainly in the synthesis and characterization of organogelators and functionalization of carbon nanotubes for biological and catalytic applications. 7410


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Franca M. Cordero is Associate Professor of Organic Chemistry at the University of Firenze. She received her Laurea cum laude (1988) and her Ph.D. Degree (1992) from the University of Firenze working in Prof. F. De Sarlo’s group. During her thesis she spent a research period at the University of Stanford (CS.) in Prof. B. M. Trost’s group (1991). In 1994 she became Researcher at the University of Firenze. During 1997, she spent a research period at the Universitè de ParisSud (France) in Prof. J. Salaün’s group. She was appointed Associate Professor in 2005. Her research interests lie in the development of the chemistry of nitrones and cyclopropane derivatives and in the application of new synthetic methods and strategies for the synthesis of biologically active azaheterocyclic compounds and peptidomimetics such as alkaloids, iminosugar mimetics, unnatural amino acids, and βlactams.

Andrea Goti is Full Professor of Organic Chemistry at the University of Firenze, where he has served as the President of Bachelor and Master courses in Chemistry and is currently the Coordinator of the Ph.D. courses in Chemical Sciences. He was awarded the Doctor degree in Chemistry in 1982 (supervisor, Prof. F. De Sarlo). He was a C.N.R. Postdoctor Fellow at Princeton University with Prof. M. F. Semmelhack (1987) and a Vigoni Visiting Researcher at the GeorgAugust University of Göttingen (Germany) with Prof. A. de Meijere (1994). From 1985 to 1998 he was a C.N.R. Researcher (Centro di Studio sulla Chimica e la Struttura dei Composti Eterociclici e loro Applicazioni) in Firenze. In 1998 he was appointed Associate Professor at the University of Firenze, and in 2002 he was nominated Full Professor. He has authored over 160 scientific papers and serves in the Editorial Board of several chemical journals. His research interests focus on stereoselective organic synthesis, synthesis of biologically active natural and non natural products, carbohydrate derivatives and mimetics, synthetic applications of organometallic derivatives, cycloaddition reactions, new oxidation methods, and green chemistry. 7411


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