Formal [4+1] Annulation Reactions in the Synthesis of Carbocyclic and

Review pubs.acs.org/CR

Formal [4+1] Annulation Reactions in the Synthesis of Carbocyclic and Heterocyclic Systems Jia-Rong Chen,* Xiao-Qiang Hu, Liang-Qiu Lu, and Wen-Jing Xiao* Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, Hubei 430079, China 7.1. With Aldehydes, Ketones, and Esters 7.2. With Unsaturated Imines 7.3. With Nitroolefins 8. Miscellaneous Formal [4+1] Annulation 8.1. Transition Metal-Catalyzed Formal [4+1] Annulation 8.1.1. Alkynes-Based Formal [4+1] Annulation 8.1.2. Alkenes-Based Formal [4+1] Annulation 8.1.3. Methylenecyclopropanes-Based Formal [4+1] Annulation 8.1.4. Aldehydes and Ketones-Based Formal [4+1] Annulation 8.2. Organocatalytic Formal [4+1] Annulation 8.2.1. Electron-Deficient Acetylenes and Allenes-Based Formal [4+1] Annulation 8.2.2. Aldehyde and Ketone-Based Formal [4+1] Annulation 8.3. Vinylcyclopropane Rearrangement-Based Formal [4+1] Annulation 9. Conclusions Author Information Corresponding Authors Notes Biographies Acknowledgments Abbreviations References

CONTENTS 1. Introduction 2. Carbon Monoxide-Based Formal [4+1] Annulation 2.1. With Allenyl and Dienyl Derivatives 2.2. With α,β-Unsaturated Imines 2.3. With Enynes 2.4. With Amides 3. Nucleophilic Carbenes-Based Formal [4+1] Annulation 3.1. With Vinyl and Aryl Isocyanates 3.2. With Vinyl Ketenes 3.3. With Dienes and Azadienes 4. Diazo Reagents-Based Formal [4+1] Annulation 4.1. With Ketenes 4.2. With α,β-Unsaturated Ketones 4.3. With Other Four-Atom Fragments 5. Fischer Carbene Complexes-Based Formal [4+1] Annulation 5.1. With 1,3-Dienes 5.2. With α,β-Unsaturated Systems 5.3. With Cyclobutenediones 6. Isocyanides-Based Formal [4+1] Annulation 6.1. With α,β-Unsaturated Ketones and Imines 6.2. With Nitroolefins 6.3. With Vinyl Isocyanates 6.4. Isocyanide Insertion-Based Formal [4+1] Annulation 6.4.1. With Aryl Bromides Bearing Pendent Nucleophiles 6.4.2. With Bisnucleophiles 6.5. With 1,4-Zwitterionic Species 6.6. Isocyanides-Based Radical Formal [4+1] Annulation 7. Ylides-Based Formal [4+1] Annulation © XXXX American Chemical Society

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1. INTRODUCTION The development of new strategies and chemical reactions continues to be a major focus of research efforts in the modern synthetic organic community.1 Of the various types of reactions that have been discovered over the past 90 years, cyclization and cycloaddition reactions have been established as the most synthetically useful and theoretically and mechanistically investigated transformations.2−4 Impressive developments have been achieved in this field, and a variety of powerful strategies have been established for the construction of structurally complex and diversely functionalized carbocycles and heterocycles due to their predominance in natural products and pharmaceuticals. For example, representative methodologies for the formation of small- and medium-sized rings include [2+1],5 [2+2],6 [3+2],7 [4+2],8 [4+3],9 and [5+2]10 cycloaddition reactions. In addition, the most of these reactions have been extensively discussed in many comprehensive

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Received: December 15, 2014

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DOI: 10.1021/cr5006974 Chem. Rev. XXXX, XXX, XXX−XXX

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y13a,b,e and other researchers15 have extensively compiled important advances in this active area. Therefore, only certain recent studies in this field and certain miscellaneous examples are discussed in section 8 of this Review. Wherever possible, working models and catalytic enantioselective versions are emphasized. To calibrate the reasonable scope of this survey, this Review is accordingly organized by the different types of C1 synthons. Other analogous formal [4+1] annulation reactions with hetero one-atom fragments, such as nitrogen, sulfur, and selenium, will not be considered in this Review and are directed to some recent literature.16 The literatures has been scanned mainly from 1980 to December of 2014 by SciFinder search. We hope that this Review will be useful for medicinal and synthetic organic chemists and will also inspire further interesting reaction design and developments in this area.

reviews and monographs, including a special issue of Chemical Reviews.11 In this context, the synthesis of five-membered carbocyclic and heterocyclic compounds, especially compounds based on cyclization and cycloaddition reactions, has attracted considerable attention from synthetic chemists. The majority of the accepted processes have been generally based on the [3+2] cycloaddition,7 the Pauson−Khand [2+2+1] cyclization,12 and the vinylcyclopropane-cyclopentene rearrangement (Scheme 1).13 In contrast, the otherwise inaccessible modality, the Scheme 1. General Cycloaddition Strategies for the Synthesis of Five-Membered Carbocyclic and Heterocyclic Architectures

2. CARBON MONOXIDE-BASED FORMAL [4+1] ANNULATION Carbon monoxide (CO) is an important type of C1 feedstock, and transition metal-catalyzed carbonylative cycloadditions have provided tremendous methods for an extensive variety of diversely functionalized carbocyclic and heterocyclic carbonyl compounds.12e,17 Over the past several decades, significant progress, including enantioselective variants, has been achieved in this field. Particularly, the transition metal-catalyzed carbonylative [4+1] cycloaddition of CO with conjugated systems has provided a powerful approach to the synthetically useful and biologically important cyclic carbonyl compounds, such as the γ-lactones, γ-lactams, and cyclopentenones (Scheme 2).3b,h,18 In this section, representative examples are discussed

formal [4+1] annulation, such as the reaction between fouratom conjugated systems and C1 sources, provides an alternative and versatile approach to these compounds because of their distinct synthetic advantages and the immediate availability of the preliminary materials. Therefore, a variety of conceptually new strategies have been realized over recent decades. The chemistry of the [4+1] annulation reaction is enjoying a renaissance and has become the primary focus of numerous research groups. Although a significant number of reviews about the synthesis of small- and medium-sized ring systems based on the cyclization and cycloaddition strategy have been published, only small subsets of the literature on the formal [4+1]annulation reactions have been surveyed. Certain examples on the metal-mediated [4+1] cycloaddition have been summarized by Lautens3a and Frühauf.3b Several CO-based formal [4+1] annulation reactions for the synthesis of cyclopentenones are also discussed in certain recent monographs12e and reviews.3 A recent review by Gevorgyan on the transition metal-mediated synthesis of monocyclic aromatic heterocycles surveyed certain literature sources for [4+1] cycloaddition reactions.14 However, these reviews only addressed a limited number of studies on the formal [4+1] annulations. No comprehensive review has been devoted to this topic. In this Review, we highlight recent advances in the identification of various suitable C1 synthons and their application in the development of efficient [4+1] annulation reactions along with the synthesis of related natural and biologically active compounds. Note that the rearrangement of the vinylcyclopropanes and their analogues, which involves cyclopropanation of the dienes and the sequential rearrangement, can be considered to be another powerful formal [4+1] annulation for the preparation of five-membered carbocyclic and heterocyclic compounds. Excellent reviews by Hudlick-

Scheme 2. CO-Based Formal [4+1] Annulation Strategy for the Synthesis of Five-Membered Carbo- and Heterocyclic Carbonyl Compounds

according to the different types of conjugated systems, such as the 1,4-dipole equivalents. Certain related plausible mechanisms are also presented. 2.1. With Allenyl and Dienyl Derivatives

Five-membered carbocyclic rings are frequently encountered in important pharmaceuticals and bioactive natural products and are useful building blocks in organic and diversity-oriented synthesis. Transition metal-mediated cyclization has offered an efficient methodology for the synthesis of these compounds. In 1992, Eaton’s group disclosed the first transition metalcatalyzed [4+1] cycloaddition reaction. Conjugated diallenes of type 1 underwent highly stereoselective [4+1] cycloadditions with CO catalyzed by Fe(CO)5 or Fe2(CO)9 under mild conditions, which afforded an extensive range of 2,5dialkylidenecyclopentenones 2 in consistently satisfactory yields (Scheme 3).19 On the basis of careful kinetic studies, the authors have proposed a possible mechanism for this reaction, B


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underwent the η2-complex 3A, which maintains equilibrium with the metallocycle 3B to form the corresponding carbonylative cycloadduct 4e (Scheme 6).22

Scheme 3. Iron-Catalyzed [4+1] Cycloaddition between Conjugated Diallenes and CO

Scheme 6. Proposed Mechanism

as shown in Scheme 4. Initially, the presence of substrate diallene 1a accelerated the CO exchange in Fe(CO)5 to yield Scheme 4. Proposed Mechanism

Mechanistically, allenyl imines such as 5 should be capable of undergoing a similar [4+1] cycloaddition with CO. As shown in Scheme 7, the Fe(CO)5-catalyzed under photochemical Scheme 7. Iron-Catalyzed [4+1] Cycloaddition of Allenyl Imines with CO

the complex 1A followed by the formation of metallacyclopentene 1B by η4-coordination. Next, a sequential CO insertion and reductive elimination of 1C generated the corresponding product 2a with release of the catalyst for the next catalytic cycle.20 Eaton and his co-workers have also successfully extended this strategy to the allenyl ketones and aldehydes.21 Analogous to the diallenes, Eaton and Kubiak discovered that allenyl ketones and aldehydes 3 smoothly reacted with CO in the iron-catalyzed [4+1] cycloaddition to form a variety of diversely functionalized α-alkylidenebutenolides 4 with acceptable yields and stereoselectivities (Scheme 5). Low-temperature Fourier transform infrared spectroscopy (FTIR) studies and kinetic experiments demonstrated that the reaction possibly

conditions [4+1] cycloaddition between allenyl imine 5 and CO furnished the corresponding 3-alkylidene-4-pyrrolin-2-one derivatives 6 in reasonable yields with excellent E/Z ratios.23 The structural diversity of the conjugated diene-transition metal complex has attracted significant attention due to the variable coordination mode. For example, the coordination of unsaturated systems to rhodium through the η4 complex mode has provided another entry to the design of new [4+1] cycloaddition reactions (Scheme 8). For example, in 1996, Ito, Scheme 8. Carbonylative [4+1] Cycloaddition between η4Bound (Vinylallene) Rhodium Complex and CO

Scheme 5. Iron-Catalyzed [4+1] Cycloaddition of Allenyl Ketones and Aldehydes with CO

Murakami, and their co-workers disclosed that the stable σ2bonded (vinylallene)rhodium complex 11, which can be easily prepared from vinylallene 10 and RhCl(PPh3)3, smoothly underwent carbonylative [4+1] cycloaddition in 1 atm of CO atmosphere to form cyclopentenone 13 in a yield of 96%, which was most likely isomerized from cyclopentenone 9.24 C


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vinylallenes were well tolerated to generate the corresponding products in reasonable yields and enantioselectivities. The carbonylative cycloaddition of vinylallenes 18, which bear an ester group, resulted in significantly improved enantioselectivities, and the successive reduction of the cyclopentenones 19 produced the exclusive formation of ciscyclopentenols 20 in generally high yields (Scheme 11).27 The use of the platinum complex, which was formed in situ from [Pt(cod)2] and (R,R)-Me-DuPHOS, afforded the cyclization products with opposite configuration of the products from the rhodium-catalyzed reactions, which highlighted the synthetic utility of this strategy. The Lewis acid-promoted decomplexation of the tricarbonyl iron/1,3-diene complexes represents another alternative [4+1] annulation for the preparation of the cyclopenten-2-ones. As illustrated in Scheme 12, Frank-Neumann and his co-workers

Additional mechanistic studies identified that the complex [Rh(cod)(dppbe)]OTf demonstrated high functional tolerance with respect to the vinylallenes. The mechanistic studies suggested that the ring flipping of the η4 complex 7 into the stable planar metallacyclopentene complex 9 allowed for the Rh(I)-catalyzed formal [4+1] annulation reactions between vinylallenes and CO. A possible reaction pathway that is similar to the Fe(CO)5-catalyzed [4+1] cycloaddition of conjugated diallenes has also been proposed (Scheme 9).25 The Pt(cod)2/ dppbe complex can also catalyze the [4+1] cycloaddition of vinylallenes as efficiently as rhodium. Scheme 9. Proposed Mechanism

Scheme 12. Formal [4+1] Carbonylative Cyclization of 1,3Dienes with CO via Tricarbonyl Iron Complexes

From a mechanistic viewpoint, asymmetric induction can be achieved when the chiral rhodium complex was employed in the carbonylative cyclization of vinylallenes. Ito and his coworkers have developed the first example of a catalytic asymmetric [4+1] cycloaddition of vinylallenes 16 with CO by combining rhodium and a chiral bisphosphine ligand to furnish the chiral 5-substituted 2-alkylidene-3-cyclopentenones 17 with satisfactory to excellent enantioselectivities (Scheme 10).26 The chiral rhodium complex, which was generated in situ

discovered that the tricarbonyl iron complexes of the 1,1,3- and 1,1,2,3-multisubstituted 1,3-dienes (22 and 25) were smoothly decomplexed using AlCl3 (1.0 equiv) or AlBr3 (1.0 equiv) in a CO atmosphere, which affords the corresponding spirocyclic or cyclocondensed cyclopentenones, 23 and 26, in adequate yields.28 The reaction was proposed to proceed through an acyl π-ally complex after CO insertion in a relatively stereoselective manner. The reaction with optically pure η4-diene iron carbonyl complex 25 produced the chiral product 26 in 70% yield with 9/1 dr. The catalytic version of this reaction remains unknown. In 2000, Larock’s group was the first to report that the palladium-catalyzed cyclocarbonylation of o-halobiaryls 27 with CO provided an efficient route to the biologically important and synthetically useful fluorenones 28 (Scheme 13).29 In an optimal set of reaction conditions, including Pd(PCy3)2 (5 mol %), anhydrous CsPiv (2.0 equiv), and DMF as the solvent at 110 °C, an extensive range of substituted 2-bromo and 2iodobiaryls 27, which bear electron-donating or electronwithdrawing groups, were well tolerated and afford the corresponding flourene-9-ones 28 in high yields. In addition, polycyclic fluorenones and isoquinoline-, indole-, pyrrole-, and thiophene-fused fluorenones can also be successfully constructed via this methodology. A possible mechanism involving

Scheme 10. Rhodium-Catalyzed Enantioselective [4+1] Cycloaddition between Vinylallenes and CO

from [Rh(cod)2]PF6 (5 mol %) and (R,R)-Me-DuPHOS (6 mol %), showed the best results, and an extensive variety of

Scheme 11. Rhodium-Catalyzed Asymmetric [4+1] Cycloaddition between Ester-Containing Vinylallenes and CO

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Scheme 13. Palladium-Promoted Cyclocarbonylation of oHalobiaryls with CO

and insertion of CO then produced the acylpalladium intermediate 29B. The reaction of acylpalladium with the neighboring olefin followed by the elimination and readdition of the reversible palladium β-H produced the palladium enolate 29F. The protonation of 29F by H2O furnished the corresponding final product 30 and released the Pd(II) salt, which was reduced to Pd(0) for the next catalytic cycle. 2.2. With α,β-Unsaturated Imines

The catalytic carbonylative [4+1] cycloaddition of α,βunsaturated imines with CO is a challenging but synthetically useful method for the construction of γ-lactam skeletons, which are commonly found in numerous alkaloids and pharmaceutically promising compounds. Murai and his co-workers developed the first example of a [4+1] cycloaddition of structurally simple α,β-unsaturated imines 31 with CO catalyzed by Ru3(CO)12 (Scheme 16).32 These authors noted

the formation of acylpalladium 27A and the key intermediate 27B was proposed for this cyclocarbonylation reaction. Inspired by Negishi’s pioneering study on the palladiumcatalyzed carbonylative cyclizations of the 1-iodo-1,4-alkadienes and o-iodostyrenes with CO for the preparation of cyclic ketones,30 Larock’s group has also indicated that an extensive range of unsaturated aryl iodides and dienyl iodides, bromides, and triflates 29 smoothly underwent carbonylative [4+1] cyclization under optimal conditions involving Pd(OAc)2 (10 mol %), pyridine (2.0 equiv), nBu4NCl (2.0 equiv), and 1 atm of CO at 100 °C, which provides the corresponding diversely substituted indanones and 2-cyclopentenones 30 in generally acceptable yields (Scheme 14).31 The reaction with substrates that contain an internal olefin failed to yield the expected products.

Scheme 16. Catalytic Carbonylative [4+1] Cycloaddition of α,β-Unsaturated Imines with CO

Scheme 14. Palladium-Catalyzed Carbonylative Cyclization of Unsaturated Aryl Iodides and Dienyl Derivatives with CO

that the selection of tBu group of the nitrogen atom and the use of 10 atm of CO at 180 °C were critical for the reaction efficiency. Under the optimal conditions, an extensive array of α,β-unsaturated imines 31 efficiently underwent cyclization to yield the unsaturated γ-lactam derivatives 32 with reasonable yields (70−94%). Although this catalytic system proved to be inappropriate for the aromatic imines, this reaction represents

On the basis of the control and deuteration experiments, a commonly accepted mechanism for this transformation has also been proposed (Scheme 15). Pd(OAc)2 was initially reduced to the active Pd(0) species, which underwent an oxidative addition with substrates 29 to yield intermediate 29A. The coordination

Scheme 15. Proposed Mechanism for Palladium-Catalyzed Carbonylative Cyclization

E


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the first example of a catalytic carbonylative [4+1] cycloaddition of the simple 1,3-diene systems. A possible reaction pathway was also proposed for the reaction. As shown in Scheme 17, the coordination of the

Scheme 19. Possible Mechanism

Scheme 17. Proposed Reaction Pathway

nitrogen atom of α,β-unsaturated imine 31a to ruthenium enabled the formation of complex 31aA, which was easily converted to metallacycle 31aB via an oxidative cyclization. An insertion of CO and reductive elimination of the ruthenium complex afforded the cycloadduct 31aD. In the case of imines that bear a β-hydrogen, the resultant 32a′ can be easily transformed into the thermally more stable α,β-unsaturated γlactam, such as 32a.

Concurrently, Tang and his co-workers also demonstrated that 3-acyloxy-1,4-enynes 36 underwent a [4+1] cycloaddition reaction with CO, which was initiated by the Rh-catalyzed 1,3acyloxy migration. In contrast to Fukuyama’s study, in the case of trisubstituted olefins, Tang and his co-workers revealed that products 37 were exclusively formed without the detection of any isomers 38, when the crude products from the Rh-catalyzed carbonylative cycloaddition were treated with 2.0 equiv of triethylamine (Scheme 20).36 The current methodology

2.3. With Enynes

Transition metal-catalyzed cycloisomerization reactions of the 1,n-enynes have emerged as conceptually and chemically attractive processes for organic synthesis and have enabled the synthesis of various types of carbocyclic and heterocyclic systems in a highly efficient manner.33 In this field, the Rhcatalyzed and acyloxy migration initiated the [4+1] cycloaddition of 1,4-enyne or 1,3-enyne esters with CO to provide a convenient method for construct diversely functionalized cyclopentenone derivatives.34 For example, Fukuyama, Ryu, Fensterbank, Malacria, and their co-workers recently discovered that the enyne esters 33, which bear an alkyl substituent on the alkyne terminus, underwent a [4+1]-type cycloaddition with CO that was smoothly catalyzed by 5 mol % of [RhCl(cod)]2 (Scheme 18).35 Despite the use of 60 atm of CO, the reaction

Scheme 20. Rh-Catalyzed [4+1] Cycloaddition between 3Acyloxy-1,4-enynes and CO

Scheme 18. Rh-Catalyzed [4+1] Annulation between 1,4Enyne Esters and CO exhibited a relatively broader substrate scope and a higher Z/ E ratio of the desired products. Given the simple purification procedure, mild reaction conditions, and immediate availability of the 3-acyloxy-1,4-enynes, this protocol has significant potential for the synthesis of biologically active and synthetically useful monocyclic and bicyclic cyclopentenones. Recently, Yu, Pu, and their co-workers reported that 5acyloxy-1,3-enynes 41 that were readily prepared from 2methyl-but-1-en-3-yne 39 and aldehydes 40 can also efficiently undergo [4+1] cycloaddition with CO in the presence of [RhCl(CO)2]2 in refluxing 1,2-dichloroethane to obtain cyclopentenones 42 in moderate to high yields (Scheme 21).37 Reasonable stereoselectivities were achieved for the enyne substrates that bear an electron-deficient or o-substituted aromatic ring at the propargylic carbon (R = aryl). The immediate availability of the preliminary material and the operationally simple procedure rendered this strategy as an attractive complementary method for the construction of highly functionalized cyclopentenones. To account for the stereoelectronic effects of the substrates on the stereoselectivities, a plausible mechanism was also

exhibited a broad substrate scope with respect to the enyne esters, and the resultant cyclopentenones 34 and isomerized products 35 were obtained in satisfactory yields with moderate to moderate ratios of 34 to 35. A possible mechanism for this [4+1] cycloaddition reaction is shown in Scheme 19. For example, the initial electrophilic activation of the alkyne moiety of 33a by the rhodium complex resulted in the formation of π-complex 33aA. Next, a nucleophilic attack of an ester group via the migration of 1,3acyloxy yielded zwitterionic vinyl-rhodium species 33aB, which was subsequently converted to rhodacyclopentadiene 33aC. The successive carbonyl insertion and the reductive elimination of intermediate 33aD afforded the final cycloadduct cyclopentenone 34a. F


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Scheme 21. Rh(I)-Catalyzed [4+1] Cycloaddition between Alkenyl Propargyl Acetates and CO


postulated on the basis of Murakami and Ito’s model.24,26 As shown in Scheme 22, the coordination of the triple bond of the substrate 41 to the Rh(I) generated complex 41A, which underwent a 1,3-acyloxy migration to yield the allene intermediates 41B-1 and 41B-2. The increased steric interaction between the o-substituted phenyl ring of 41B-1 and the ligands of the Rh complex may cause the preferential formation of 41B-2. The η4 complexes 41B-1 and 41B-2 were converted to the metallacyclopentenes 41C-1 and 41C-2, respectively. The π−π interaction between the electrondeficient phenyl ring and the acetate group favors the formation of intermediate 41C-2, which underwent a successive CO insertion and reductive elimination to yield the final product E42 as the major isomer. The development of new reactions for the efficient construction of diversely functionalized furans has attracted extensive research due to their significant presence as core structures in natural products and pharmaceuticals.38 Recently, Zhang’s group documented a highly regio- and stereoselective carbonylative cyclization of the 2-substituted or 2,3-disubstituted 1-(1-alkynyl)-cyclopropyl ketones 43, which was initiated by the Rh(I)-catalyzed activation/cleavage of the carbon− carbon σ-bond of the cyclopropane ring (Scheme 23).39 Under the optimal conditions (5 mol % of [Rh(CO)2Cl]2 in refluxing 1,2-dichloroethane), the reaction smoothly proceeded to produce an extensive range of 1,3,5-tri- and 1,3,5,6-tetrasubstituted 5,6-dihydrocyclopenta[c]furan-4-ones 44 in reasonable yields. Interestingly, it was also found that the trisubstituted furans 45 were also isolated in a range of 20−40% yields as a mixture of E/Z isomers. A plausible reaction pathway was postulated, as shown in Scheme 24. For example, the regioselective oxidative addition

Scheme 23. Rh(I)-Catalyzed Carbonylative Cyclization of 1(1-Alkynyl)-cyclopropyl Ketones with CO

of the C1−C2 bond of cyclopropane (1R,2R)-43a via rhodium catalysis generated rhodacyclobutane 43aA, followed by a rapid cycloisomerization to form the fused furan-derived rhodacyclopentane 43aB. An insertion of CO then formed the furan-fused rhodacyclohexanone 43aC, and the subsequent reductive elimination furnished the final carbonylative cycloadduct 44a. Surprisingly, the reaction with diastereoisomer (1R,2S)-43a only produced the trisubstituted furan 45a. Although a precise mechanism was still unknown, it was postulated that the initially formed rhodacyclobutane intermediate 43aA′ might afford the 1,2-allenyl ketone 43aB′ through a sequential β-H elimination/reductive elimination/isomerization process. Finally, the 1,2-allenyl ketone 43aB′ underwent a further Rh(I)-catalyzed cycloisomerization to yield trisubstituted furan 45a. The highly strained epoxides have been extensively used as building blocks in organic synthesis via a C−O bond cleavage/ ring opening, which provide a powerful platform for the development of new chemical transformations.40 On the basis of the structural properties of these three-membered ring systems, Zhang and his co-workers continued to develop an elegant rhodium-catalyzed tandem heterocyclization/formal G


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Scheme 24. Plausible Mechanism

with CO for the synthesis of five-membered benzolactams,43 the carbonylation of aromatic or aliphatic amides via the transition metal-catalyzed activation of the C−H and N−H bonds and carbonylation has been established as an efficient entry to five-membered nitrogen-containing heterocycles. In 2009, Chatani and his co-workers developed an interesting Ru-catalyzed formal [4+1] annulation reaction of aromatic amides 51 with CO, in which the bidendate pyridine-2ylmethyamine moiety served as the directing group for the Rucatalyzed cyclocarbonylation (Scheme 27).44 The reaction

[4+1] cycloaddition reaction of 1-(1-alkynyl)oxiranyl ketones 46 involving an unexpected C−C bond cleavage of the epoxide moiety (Scheme 25).41 The use of [Rh (cod)Cl]2/SPhos 47 in Scheme 25. Rh(I)-Catalyzed Tandem Cyclization/Formal [4+1] Annulation between 1-(1-Alkynyl)oxiranyl Ketones and CO

Scheme 27. Ruthenium-Catalyzed Carbonylative [4+1] Cyclization of Aromatic and Aliphatic Amides with CO

refluxing 1,2-dichloroethane in 1 atm of CO achieved the best results, and an extensive variety of heavily functionalized furo[3,4-b]furan-3(2H)-ones 48 were obtained in generally satisfactory yields. Using routine manipulation, the cyclization products 48 can be easily transformed into other synthetically useful heterocyclic systems (Scheme 26). A possible pathway that is similar to their previously reported Rh(I)-catalyzed carbonylation of 1(1-alkynyl)cyclopropyl ketones was proposed for the present reaction.39

tolerated an extensive range of functional groups on the aromatic rings and furnished corresponding phthalimide derivatives 52 in consistently acceptable yields. The control experiments with a different benzyl amide also confirmed the critical role of the pyridine-2-ylmethyamine in the desired reaction, which provides a new process for the engineering C− H functionalization reaction. Recently, the Chatani group also extended this unique bidendate-assisted mode to the formal [4+1] annulation between aliphatic amides and CO for the synthesis of highly functionalized succinimide derivatives.45 The limitation of Chatani’s strategy is the requirement of 10 atm of CO. In contrast to Chatani’s strategy, in 2010 Yu’s group disclosed a Pd(II)-catalyzed and monodentate CONHC6H5directed carbonylation of β-C(sp3)−H and cyclization of Narylamides 53 in 1 atm of CO to form the corresponding succinimide derivatives 54 in moderate to excellent yields, which can be easily hydrolyzed into the corresponding synthetically useful 1,4-dicarbonyl compounds (Scheme 28).46 The mild reaction conditions tolerated a diverse set of substituents in the substrates. In addition to the

Scheme 26. Synthetic Applications

2.4. With Amides

The transition metal-catalyzed and chelation-assisted C−H bond activation/functionalization is one of the most powerful methods for the formation of various new chemical bonds in organic synthesis.42 Pioneered by Orito’s inspiring work on Pd(OAc)2-catalyzed direct carbonylation of benzylic amines H


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Scheme 28. Pd(II)-Catalyzed Carbonylative Cyclization of N-Arylamides with CO


CONHC6H5-directing group, the privileged sulfonamide pharmacophore can also serve as a competitive directing group for the Pd(II)-catalyzed cyclocarbonylation reaction to access an extensive variety of otherwise unavailable celecoxib analogues, potential cyclooxygenase-II inhibitors.47 Recently, Rovis and his co-workers developed a Rh(III)catalyzed oxidative cyclocarbonylation of N-alkyl aromatic amides 55 via C−H and C−N bond activation to afford the formal [4+1] annulation products, phthalimides 56, in moderate yields (Scheme 29).48 In contrast to Yu’s approach, the N-aryl benzamides proved to be unreactive in optimal conditions, and the amide substrates with electron-withdrawing groups resulted in relatively lower yields. On the basis of the experimental mechanistic studies with the incorporation of deuterium, a plausible catalytic cycle was also proposed for this reaction (Scheme 30). Initially, the precatalyst Rh(III)Cp*(MeCN)3(ClO4)2 was transformed into the active species Rh(III)Cp*CO3(ClO4). The coordination of the amide N−H and the C−H activation yielded the rhodacycle 55A intermediate. The coordination of a molecular unit of CO and insertion of CO resulted in the formation of six-membered rhodacycle 55C, which underwent reductive elimination to produce the desired phthalimide product 56 and a Rh(I) species. Oxidation of the Rh(I) species by Ag2CO3 regenerated the catalytically active Rh(III) complex for the next catalytic cycle. A Pd(II)-catalyzed cyclocarbonylation of the Nalkoxybenzamides with CO to access diversely substituted phthalimides was simultaneously noted by Lloyd-Jones, Booker-Milburn, and their co-workers.49 In addition, Daugulis’ group recently disclosed that a combination of Co(acac)2 (20 mol %) and Mn(OAc)·3H2O (1.0 equiv) also enabled mild and efficient cyclocarbonylation of the aminoquinoline amides

with CO (1 atm) with 8-aminoquinoline as the directing group, which affords the corresponding substituted phthalimide derivatives in generally satisfactory yields.50 Despite the central role of gaseous CO in carbonylation chemistry, some major disadvantages, such as high pressure, toxicity, and inconvenient storage and transport, have encouraged chemists to develop various CO surrogates for carbonylation transformations.51 In this context, Shi’s group has recently reported an efficient Pd(OAc)2-catalyzed hydroesterification of alkenylphenols utilizing phenyl formate as the CO surrogate (Scheme 31).52 The reaction tolerated an extensive range of alkenylphenols to furnish the corresponding formal [4+1] annulation products, benzofuran-2(3H)-ones 59, with yields above the range of 79−99% with high regioselectivity. The configuration of the alkene moiety of the disubstituted substrates has no detrimental effect on the reaction efficiency and regioselectivity.

3. NUCLEOPHILIC CARBENES-BASED FORMAL [4+1] ANNULATION Singlet carbenes that bear one or two π-donor heteroatoms, such as oxygen, sulfur, and nitrogen, frequently exhibit ambiphilic or nucleophilic properties and have attracted considerable attention over recent decades.53 These unusual properties result from the resonance stabilization of the carbene singlet state by the conjugate donation of electron density from the heteroatoms into the formally vacant p-orbital of the carbene carbon (Scheme 32). These important characteristics render these carbenes as ideal carbonyl 1,1-dipolar equivalents for the development of new and synthetically useful [4+1] cycloaddition reactions.54

Scheme 29. Rh(III)-Catalyzed Formal [4+1] Annulation between N-Alkyl Aromatic Amides and CO Involving C−H/C−N bond Activation and Carbonylation

I


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Scheme 31. Pd(OAc)2-Catalyzed Hydroesterification of Alkenylphenols

Scheme 32. Nucleophilic Carbenes-Based [4+1] Annulation for the Synthesis of Five-Membered Carbocyclic and Heterocyclic Compounds

Scheme 34. [4+1] Cycloaddition between Vinyl Isocyanates and Dimethoxycarbene

3.1. With Vinyl and Aryl Isocyanates

In the chemistry of nucleophilic carbenes, the pioneering introduction of the thermal transformation of 2,2-disubstituted Δ3-1,3,4- oxadiazolines into these species as a mild, clean, and safe alternative method by Warkentin has stimulated considerable interest in these reactive intermediates (Scheme Scheme 33. Generation of Nucleophilic Carbenes

steps from the commercially available piperonyl alcohol 65 in an 11% total yield.58 The azepinoindole scaffold is commonly identified in a number of biologically active Stemona alkaloids, such as stenine 73 and neotuberostemonine 74. On the basis of their own strategy, Rigby and his co-workers described the rapid construction of these azepinoindole subunits using the [4+1] cycloaddition between vinyl isocyanate 62 and Warkentin’s oxadiazoline 63-derived dimethoxy carbene as the main transformation (Scheme 36).59 The bis(alkylithio)carbene species, such as 76, comprise another type of useful carbonyl 1,1-dipole equivalent (Scheme 37).60 For example, dithiocarbene 76, which derived in situ from dithiooxadiazoline 75, reacts smoothly with the vinyl isocyanates in a manner that is similar to dimethoxycarbene, and affords a variety of interesting adducts 77. The heavily functionalized adducts 77 enabled a range of synthetically useful functional group interchanges to produce valuable building blocks for alkaloid synthesis. For example, dithiocarbene, which is thermally generated from dithiooxadiazoline 75, underwent a formal [4+1] cycloaddition with β-aryl-substituted vinyl isocyanate 78 to afford the corresponding hydroindolone 79 with the assembly of the highly congested quaternary center at C3a (Scheme 38).61 The Ra−Ni-mediated reductive desulfurization followed by a series of routine operations then yielded the target (±)-mesembrine 80 with reasonable efficiency. Note that the six- and seven-membered cyclic dithiocarbenes can also react well with various vinyl isocyanates to produce the corresponding pyrrolidone derivatives in satisfactory yields.62 Rigby’s group successfully extended this methodology to the aryl isocyanates. For example, the thermally induced [4+1] cycloaddition of bis(alkylthio)carbene with substituted aryl

33).55 In this context, these nucleophilic carbenes have been identified as versatile carbonyl 1,1-dipole equivalents in [4+1] cycloaddition reactions with various 1,4-dipoles, such as the vinyl isocyanates, vinyl ketenes, and dienes.54a Inspired by the propensity of the vinyl isocyanates to function as 1,4-dipolar equivalents in the (4+2) and [4+1] cyclization reactions,56 Rigby and his co-workers initially developed a [4+1] cycloaddition of vinyl isocyanate with dimethoxycarbene.57 As shown in Scheme 34, the reaction with vinyl isocyanate 62 and 2,2-dimethoxy Δ3-1,3,4-oxadiazolines 63 worked very well in refluxing xylene to afford 2:1 carbene/ isocyanate adducts 64a in a yield of 80% after the [4+1] annulations and addition of a second carbene via a rapid NH insertion. A range of structurally diverse vinyl isocyanates were tolerated in this process to form the corresponding hydroindolones 64b−64d in generally reasonable yields. To illustrate the synthetic utility of this [4+1] cycloaddition reaction, Rigby’s group also applied this methodology as a critical step in the total synthesis of Amaryllidaceae alkaloid, (±)-tazettine 69. As shown in Scheme 35, the [4+1] cycloaddition between β-aryl vinyl isocyanate 67, which derived from acyl azide 66, and dimethoxycarbene, which derived from Warkentin’s oxadiazoline 63, resulted in a rapid assembly of the [2]benzopyrano[3,4-c]hydroindole core structure 68 of (±)-tazettine. A set of additional routine functional group manipulations provided the racemic target molecule 69 in 16 J


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Scheme 35. Total Synthesis of (±)-Tazettine

Scheme 36. Synthetic Application: Assembly of the Core Azepinoindole Tricycle of Stemona Alkaloids

proceeds via a highly organized transition state, the use of chiral carbenes may result in the formation of the corresponding products in a highly enantioselective manner. Thus, Ribgy and his co-workers initially applied the chiral oxadiazoline 85, which was prepared from (1R,2S)-ephedrine, to the cycloaddition with acyl azide 84 to obtain the corresponding adduct 86 in 44% yield, which was easily transformed into the enantiomerically enriched (−)-hydroisatin 87 with 80% ee (Scheme 40).64 The fused pyrroloindole scaffold 88 frequently occurs over a range of biologically active compounds, including natural products and designed medicinal agents (Scheme 41). Therefore, the development of more practical and efficient procedures for the construction of these structural motifs remains an area of intensive research. Thus, the nucleophilic dimethoxycarbene and bis(propylthio)carbene were also extended to the [4+1] cyclization reaction of indole isocyanates 89 by Rigby’s group, which generated the corresponding 2:1 adducts 90 and 91 in generally satisfactory yields (Scheme

Scheme 37. [4+1] Cycloaddition between Bis(alkylthio)carbenes and Vinyl Isocyanates

isocyanates 82 provided efficient access to a variety of isatin derivatives in acceptable yields (Scheme 39).63 This process is generally inaccessible with dimethoxycarbene. Considering that the reaction pathway in which the final ring-closing step of this [4+1] cycloaddition most likely Scheme 38. Total Synthesis of (±)-Mesembrine

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Scheme 39. Formal [4+1] Cyclization between Aryl Isocyanates and Bis(alkylthio)carbenes

Scheme 40. Asymmetric [4+1] Cycloaddition between Vinyl Isocyanates and Chiral Nucleophilic Carbenes

acetylcholine blocking agent, (±)-phenserine 95 (Scheme 42).66 N-Heterocyclic carbenes (NHC) have been extensively applied as versatile ligands in transition-metal catalysis and organocatalysts.67 Rigby and his co-workers disclosed that these nucleophilic NHCs of type 97, which are immediately and thermally formed from 2-trichloromethyl-1,3-imidazoline 96, can also undergo the [4+1] cycloaddition with a variety of vinyl isocyanates (Scheme 43).68 The reaction showed a different

Scheme 41. Formal [4+1] Annulation between Indole Isocyanates and Nucleophilic Carbenes

Scheme 43. Formal [4+1] Cycloaddition between Vinyl Isocyanates and N-Heterocyclic Carbenes

41).65 Indole substrates that bear isocyanate substituents in the 4−6 positions were well tolerated in the reaction, which provided a new structural platform for the construction of isomeric pyrroloindole motifs that were also prevalent in many biologically important compounds. Given the functional and abundantly fused pyrroloindole that was formed in the process, the formal [4+1] cyclization reaction of indole isocyanate 92 with bis(propylthio)carbene 76 was also employed as the main step in the total synthesis of the

reactivity profile as compared to the O- and S-substituted carbenes and delivered the corresponding highly functionalized hydroindolones 98 in acceptable yields. 3.2. With Vinyl Ketenes

Trialkylsilyl vinyl ketenes have been determined to smoothly react as 1,4-dipole equivalents with nucleophilic carbenes in a

Scheme 42. Total Synthesis of (±)-Phenserine

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yields (Scheme 45a).70 The reactions with electron-rich dienes, such as vinylcyclohexene and Danishefsky’s diene, did not occur in these conditions. The intramolecular version of this cycloaddition reaction with oxadiazolines 104a and 104b formed the bicyclic adducts 105 and 106 in improved yields with superior diastereoselectivities (Scheme 45b). Enone 107 can also serve as a 1,4equivalent to undergo an intramolecular cyclization to yield the bicyclic ortho ester 108 with an 82% yield (Scheme 45c). Spin, Legault, and their co-workers completely examined the scope of this reaction and discovered that a variety of other electrondeficient dienes with various substitution patterns can also participate in the intramolecular [4+1] cycloaddition to form the 5−5, 6−5, and 7−5 fused O-heterocyclic compounds in satisfactory yields with moderate to high diastereoselectivities.71 Regarding the mechanisms of the [4+1] cycloaddition of the nucleophilic carbenes with electron-deficient dienes, three possible mechanistic portraits were proposed by Spino and Legault based on the stereochemical outcome of the related reactions and the computational calculations, including a concerted [4+1]-cycloaddition, a cyclopropanation-vinylcyclopropane rearrangement, and an ionic stepwise pathway.72 In 1999, Liu and co-workers suggested that the arylchlorocarbenes, such as 110, which derived from arylchlorodiazirines 109 via thermolysis or photolysis, can undergo a formal [4+1] annulation with 1-azabuta-1,3-dienes 111 (Scheme 46).73 The

manner similar to the vinyl cyanates, which caused the formation of highly substituted five-membered carbocyclic products. For example, Rigby and his co-workers demonstrated that the O-, S-, and N-based nucleophilic carbenes underwent efficient formal [4+1] cycloadditions with an extensive range of trialkylsilyl vinyl ketenes 99 to produce the corresponding highly substituted cyclopentenones 100 in satisfactory yields (Scheme 44).69 Scheme 44. [4+1] Annulation between Vinyl Ketenes and Nucleophilic Carbenes for Synthesis of Highly Functionalized Cyclopentenones

Scheme 46. Formal [4+1] Annulation between the 1Azabuta-1,3-dienes and Arylchlorocarbenes

3.3. With Dienes and Azadienes

The [4+1] annulations of dienes with carbenes can be considered to be the five-membered ring equivalent of the Diels−Alder reaction (eq 1). However, successful examples of

these reactions have remained elusive because the common carbenes and carbenoids are prone to undergo cyclopropanation with alkenes and 1,3-dienes. Recently, Spino and his coworkers reported that dialkoxycarbenes, which are generated from the thermal decomposition of oxadiazolines 63 or 101, efficiently added to the electron-poor diene 102 to deliver the corresponding cyclopentenes 103a or 103b in satisfactory

reaction smoothly proceeded to afford 1,2,3-trisubstituted pyrroles 113 in moderate to excellent yields after elimination of HCl from the initially formed formal [4 + 1] adducts, dihydropyrroles 112. The reaction proceeded through the formation of azomethine ylide by the attack of the nitrogen of the 1-azabuta-1,3-dienes on the vacant 2p-orbital of the singlet carbene and an intramolecular ring-closing step. This formal

Scheme 45. Inter- and Intramolecular Formal [4+1] Annulation of Electron-Poor Dienes with Electron-Rich Carbenes

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[4+1] annulation strategy with the nucleophilic carbenes has also been successfully extended to the 2-vinylpyridine and pyridyl-hydrazone derivatives by Liu74 and Behbehani,75 respectively.

Scheme 49. Formal [4+1] Annulation of (Trialkylsilyl)vinylketenes with Diazomethanes

4. DIAZO REAGENTS-BASED FORMAL [4+1] ANNULATION Diazo compounds represent a valuable class of nucleophilic carbenoid reagents and have been extensively applied in formal [4+1] annulations (Scheme 47). A variety of four-atom Scheme 47. Diazo Reagent-Based Formal [4+1] Annulation

pentenones with cis dispositions of the R2 and R3 substituents. The substrates 119, which are stable silyl vinylketenes, can be easily prepared from the thermal reaction of TIPS- or TBSprotected alkynes with the Fischer carbene complexes.80 This methodology was also successfully applied as the main step for the efficient construction of the tricyclic skeleton of the biologically important natural product rocaglamide, beginning with the benzofuran-substituted silyl vinylketene and phenyldiazomethane.81 The substrate scope of the formal [4+1] annulation strategy was also extended to trialkylsilyl-arylketenes 122 by Danheiser and his co-workers (Scheme 51).82 The reaction exhibited a high functional tolerance regarding the arylketene components, and the desired 2-indanones 123 with desilylation of TMS were generally obtained in satisfactory yields. The TAS-arylalkenes were conveniently prepared from the corresponding diazo ketones using a two-step process that involved silylation and the Wolff rearrangement. Mechanistic studies have identified two possible pathways for the reaction in which both of the key intermediates 122B and 122C were probably formed from the initially formed (Z)-enolate 122A via ionization and internal displacement, respectively. A rearrangement of 122B or the 4πelectrocyclic closure of 122C followed by isomerization and desilylation then formed the final products 123.

fragments, such as the stabilized ketene derivatives and the α,β-unsaturated ketones, react very well with the substituted diazomethanes in a formal [4+1] annulation manner to produce the corresponding five-membered carbocyclic and heterocyclic rings. 4.1. With Ketenes

Tidwell and their co-workers noted that TMS-stabilized bisketenes 114 smoothly underwent a formal [4+1] cycloaddition with substituted diazomethanes 115 to yield cyclopentene-1,3-diones 116 in moderate to excellent yields (Scheme 48).76 The formation of these products was proposed to proceed via a nucleophilic addition of diazomethane to the more reactive ketenyl group and a ring closure of the resultant zwitterions intermediate 114A.77 Analogous to the bisketenes, vinylketenes can also serve as versatile four-atom fragments to react with the diazomethanes to form the corresponding highly functionalized five-membered cycles. For example, Danheiser’s group noted that TMSvinylketenes 117 underwent an efficient formal [4+1] annulation with diazo compounds 115 to furnish the expected cyclopentenone products 118 in high yields (Scheme 49).78 The transition metal-stabilized vinylketenes have also proved to be viable four-carbon synthons in formal [4+1] annulation reactions. For example, Moser’s group indicated that silyl vinylketenes 119 that bear the Cr(CO)3 moiety efficiently underwent a formal [4+1] annulation with diazomethanes 115 to afford the corresponding highly functionalized cyclopentenones in generally excellent yields with complete stereoselectivity (Scheme 50).79 For all products 120, the Cr(CO)3 fragment was easily removed after treatment with CAN or hydrolysis to furnish the corresponding cyclopentenones 121 in quantitative yields. The reaction with (Z)silyl vinylketenes and phenyldiazomethane produced an acceptable yield of the remaining diastereomeric cyclo-

4.2. With α,β-Unsaturated Ketones

Diazo compounds have also been highly exploited as a carbene source in transition-metal catalysis and can undergo a variety of transformations, such as insertion and cycloaddition via transient metal-associated carbonyl ylides.83 In this context, the transition metal-catalyzed formal [4+1] annulation reaction of the diazo compounds with α,β-unsaturated carbonyl compounds has been established for efficient access to various biologically interesting and synthetically useful dihydrofuran derivatives.

Scheme 48. Formal [4+1] Cycloaddition Reactions of TMS-Stabilized Bisketenes with Diazomethanes

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Scheme 50. Formal [4+1] Annulation of Silyl Vinylketenes with Diazomethanes

Scheme 53. Formal [4+1] Annulation of α,β-Enones with Dimethyl Diazomalonate

Scheme 51. Formal [4+1] Annulation of the (Trialkylsilyl)arylketenes with TMS-Diazomethane for the Synthesis of the 2-Indanes

Scheme 54. Reaction between (Z)-Enones and Dimethyl Diazomalonate: A Formal [3+2] Cycloaddition

In 1967, Spencer and his co-workers discovered a pioneering formal [4+1] cyclization between β-methoxy-α,β-unsaturated ketone 124 and ethyl diazoacetate 125 in the presence of a catalytic amount of CuSO4, which afford furans 127 with moderate yield after the spontaneous elimination of methanol from the initially formed 2,3-dihydrofuran 126 (Scheme 52).84 The reaction was proposed to proceed via an initial attack of the carbonyl oxygen on the copper-carbenoid reagent to obtain the carbonyl ylide intermediate, which underwent further 1,5cyclization to form the final product.85 However, this interesting study has not attracted significant interest from the synthetic community for nearly 30 years. This strategy was recently extended by Anac’s group to the reactions of the simple linear s-cis-α,β-unsaturated ketones, such as α-ionone, β-ionone, and benzalacetone, with dimethyl diazomalonate and ethyl acetodiazoacetate using Cu(acac)2 as the catalyst (Scheme 53).86 Because these α,β-unsaturated ketone substrates 128 did not possess any methanol-like leaving group, the reaction primarily afforded the densely functionalized dihydrofurans 131 in moderate yields. The conformations of the α,β-enones have a significant influence on the reaction pathway. For example, the reaction of (Z)-enones 132 and 134 with dimethyl diazomalonate produced the formal [3+2] adducts, ioxole derivatives 133 and 135, respectively (Scheme 54).87 Note that Rh(II) acetate can also catalyze this type of [4+1] annulation of the electron-

rich 1,3-dienes and acetyl-acetone with the diazocompounds.88 In addition, the readily available N-substituted azetidines can undergo a Cu(acac)2-catalyzed ring expansion with the diazocarbonyl compounds to furnish the formal [4+1] annulation products, the pyrrolidines, in generally acceptable yields.89 Despite these impressive achievements, the catalytic asymmetric version has remained less explored. In 2007, Fu’s group reported the first example of the copper/(−)-bpy*catalyzed enantioselective [4+1] cycloaddition between enones 136 and diazocompounds 137 (Scheme 55).90 The stereoselectivity and chemical yield were substantially dependent on the steric demand of the diazoester component, and the reaction with bulky 2,6-diisopropyl phenyl ester 137 yielded the best results. In optimal conditions, a variety of aromatic groups with variable electronic properties and substitution patterns, as well as heteroaromatic and aliphatic substituents, were well

Scheme 52. Formal [4+1] Cycloaddition of β-Methoxy-α,β-Unsaturated Ketone with Ethyl Diazoacetate

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realized an asymmetric catalytic version using their side armmodified chiral ligand 144 and corresponding optically active multiple-substituted dihydrofurans 145 were obtained in acceptable yields with excellent stereoselectivities (up to 99/1 dr, 96% ee).93 Recently, Favi and his co-workers disclosed that the inexpensive CuCl2 also enabled an efficient formal [4+1] annulation reaction between the highly reactive 1,2-diaza-1,3dienes, which were generated in situ from the α-halo N-acyl hydrazones, and the diazo esters, and furnish the corresponding pharmaceutically important and diversely substituted 4,5dihydropyrazole-5-carboxylic in moderate to excellent yields.94

Scheme 55. Cu-Catalyzed Enantioselective Formal [4+1] Cycloadditions between the Enones and Diazocompounds

4.3. With Other Four-Atom Fragments

By employing the nucleophilicity of the diazo carbon and the leaving property of the diazo group, in 2008, Wang’s group devised a Tf2O-promoted formal [4+1] annulation of Narylamides 147 with ethyl diazoacetate 125 for the efficient and concise synthesis of 2,3-disubstituted indole derivatives 148 in the presence of 2-chloropyridine and 2,6-dichloropyridine as the bases (Scheme 57).95 This mild approach tolerated an

tolerated in the enone components 136 and furnish the expected densely functionalized 2,3-dihydrofurans 139 in typically reasonable yields with excellent diastereo- and enantioselectivities. This strategy was also utilized in an expeditious synthesis of the medicinally important and optically active deoxy-C-nucleoside 140. Liang’s group independently and simultaneously discovered a CuI-catalyzed formal [4+1] annulation between the α,β-acetylenic ketones and the diazoacetates, which provides an efficient entry to the highly substituted furans with typically satisfactory yields and regioselectivity.91 In 2011, Tang, Yu, and their co-workers noted an interesting copper-catalyzed cycloaddition reaction between α-benzylidene-β-ketoesters 141 and diazoacetate 137 (Scheme 56).92 The product distribution was significantly dependent on the nature of the ligands. For example, the use of less bulky ligand 142 furnished the corresponding formal [4+1] cycloadducts, the highly substituted dihydrofurans 145, with satisfactory yields with excellent diastereoselectivities, while sterically hindered ligand 143 resulted in the preferential formation of the seven-membered ring dihydrobenzoxepines 146 in moderate to superior yields with 85/15 to 95/5 dr. Extensive discrete Fourier transform (DFT) calculation studies showed that these two possible competitive reaction pathways were influenced by the steric properties of the nitrogen ligands. Considering the mild conditions and high functional tolerance, this methodology provides an efficient and practical approach to optically active polysubstituted 2,3-dihydrofurans and dihydrobenzoxepines. Subsequently, the same group also

Scheme 57. Formal [4+1] Annulation between N-Aryl Amides and Ethyl Diazoacetate for Indole Synthesis

extensive range of aryl and alkyl groups on the acyl moiety. The reaction presumably proceeded via an electrophilic activation of the N-arylamides in the presence of pyridine derivatives toward the nucleophilic attack of ethyl diazoacetate and an intramolecular electrophilic substitution as the main steps. In addition to the N-arylamides, the 2-aminoaryl and alkyl ketones have also been demonstrated as suitable four-atom fragments to undergo formal [4+1] annulation reactions with diazo reagents. For example, Reddy and his co-workers have developed a Cu(OTf)2-catalyzed formal [4+1] annulation between 2-aminoaryl ketones 149 and α-diazoketones 150, which generated efficient access to 2,3-disubstituted indole derivatives 151 in generally acceptable yields (Scheme 58).96 The Lewis acid Cu(OTf)2 coordinated with the carbonyl group to facilitate the nucleophilic addition of the α-diazoketone

Scheme 56. Cycloadditions between α-Benzylidene-β-ketoester and Diazoacetates

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Scheme 58. Cu(OTf)2-Catalyzed Formal [4+1] Annulation between 2-Aminoaryl or Alkyl Ketones and α-Diazoketones

followed by the replacement of N2 by an amine and dehydration to afford the final indoles 151. This methodology was also successfully applied as the main step in the formal total synthesis of homofascaplysin C. Recently, a Rh2(OAc)4-catalyzed formal [4+1] annulation that involves the generation of ammonium ylide and an intramolecular aldol-type cyclization between the (E)-styrenyland alkyl-substituted 2-aminoaryl ketones was also devised by Hu, which resulted in the formation of an extensive variety of highly functionalized 3-hydroxy-2,2,3-trisubstituted indole derivatives in satisfactory yields with excellent diastereoselectivities.97 Hu and his co-workers successfully extended this Rh2(OAc)4-catalyzed formal [4+1] annulation strategy to the amine-substituted enones, which generated 2,2,3-trisubstituted indoline derivatives in generally satisfactory yields with excellent diastereoselectivities.98 The addition of BINOL phosphoric acid (20 mol %) as an additive was critical for trapping the in situ-formed ammonium ylides, and the use of chiral phosphoric acid resulted in a moderate yield and enantioselectivity. The transition-metal-mediated C−C bond cleavage of the benzocyclobutenols provides another class of useful fourcarbon synthons for cycloaddition reactions due to their unique reactivity profile.15b,99 Wang and his co-workers recently demonstrated that the Rh(I) catalyst promoted an efficient insertion of the diazoester-derived carbenes into the C−C bond of benzocyclobutenols 153 in toluene at 100 °C (Scheme 59).100 The reaction accommodated an extensive variety of benzocyclobutenols 153 and diazoesters 154 to furnish the corresponding formal [4+1] cycloaddition products, highly substituted indanol derivatives 155 that bear an all-carbon quaternary center with generally high yields with excellent regioselectivity and diastereselectivity. The reaction proceeded via the initial formation of arylrhodium species 153B by βcarbon elimination followed by rhodium carbene generation, migratory insertion, and an intramolecular aldol reaction sequence to yield the final products. The complete diastereoselectivity for the cis-configuration was attributed to the highly stereoselective intramolecular aldol reaction step. Subsequently, the Murakami group reported an enantioselective version of the Rh(I)-catalyzed formal [4+1] annulation between various cyclobutanols and diazo compounds, which were generated in situ from the aldehydes-derived tosylhydrazones.101 Using (R)-SEGPHOS or (R,S)-PPF-PtBu2 as the chiral ligands, both of the diastereomers of the corresponding cyclopentanols can be obtained in a highly enantioselective manner.

Scheme 59. Rh(I)-Catalyzed Formal [4+1] Annulation between Benzocyclobutenols and Diazoesters

In 2013, Rovis’ group developed an interesting formal [4+1] annulation of O-pivaloyl benzohydroxamic acids 156 with the donor/acceptor diazo compounds 157 via the Rh(III)-catalyzed C−H activation strategy (Scheme 60).102 The donor/acceptor diazo compounds 157 were utilized to prevent their potential Scheme 60. Rh(III)-Catalyzed Oxidative Formal [4+1] Annulation between Benzohydroxamic Acids and Diazo Compounds

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dimerization, and the directing group N-OPiv moiety also proved to be critical for the desired reaction. In optimal conditions, an extensive range of diversely substituted benzohydroxamic acids and heterocyclic substrates were well tolerated to produce the corresponding isoindolones 158 in generally high yields. The reaction also demonstrated a broad scope and high functional tolerance with respect to the diazo compounds. A series of aryl, heteroaryl, alkyl-substituted, and cyclic diazo compounds, as well as the 1-aryl-substituted 2,2,2trifluoro diazoethane, were well accommodated. Subsequently, Yu and his co-workers noted a similar Rh(III)-catalyzed oxidative formal [4+1] annulation between the O-acetyl benzohydroxamic acids and the α-diazoesters for the efficient synthesis of the highly functionalized benzolactam derivatives.103 On the basis of the isolation and X-ray crystal structure analysis of the five-membered rhodacyclic complex, a plausible mechanism that involves the directing group-assisted rhodacycle formation, the Rh-carbene generation and its migratory insertion, and the final reductive elimination was proposed.

Scheme 62. Formal [4+1] Cycloaddition between Methyl Sorbate and Fischer Carbene Complexes

5. FISCHER CARBENE COMPLEXES-BASED FORMAL [4+1] ANNULATION Since their initial discovery in 1964 by Fischer,104 the stable metal carbene complexes (CO)nMC(XR′)R have been well established as extraordinarily versatile reagents with extensive application in organic synthesis, particularly in the field of cycloaddition and cyclization chemistry.105 Using different Fischer carbene complexes and fine-tuning the reaction parameters, a plethora of different-sized carbo- and heterocycles can be efficiently constructed with high selectivity.106 Among these processes, the Fischer carbene complexes typically serve as the C1, C2, and C3 units. Some Fischer carbene complexes can also serve as the C1 unit to undergo a formal [4+1] annulation reaction with suitable four-atom components to form diversely substituted five-membered ring systems. In this section, the major representative advances in this field are discussed according to the different types of C4 units in the processes (Scheme 61).

Scheme 63. Formal [4+1] Cycloaddition of 1,3-Diamino-1,3dienes and Fischer Carbene Complexes

and his co-workers documented the efficient reaction of 1,3diamino-1,3-diene 162 with aryl and cycloalkenylmethoxycarbene chromium complexes 163 in toluene at room temperature, which affords the formal [4+1] cycloadducts 164 in moderate to excellent yields (Scheme 63).108 In the case of the

aryl-substituted carbene complex, a small amount of the typical cyclopropanation product was also detected. In contrast, the 2aza-1,3-dienes reacted well with the aryl and heteroarylmetal carbenes in a formal [4+1] cycloaddition manner, which provides the corresponding pyrrolidone derivatives in generally acceptable yields.109 Aznar and his co-workers revealed that 1-amino-1,3-dienes 165 also underwent a similar formal [4+1] annulation with furyl and β-substituted alkenylcarbene complexes 166 with high efficiency, which facilitated the formation of densely functionalized cyclopentenamine derivatives 167 with suitable yields and diastereoselectivities (Scheme 64). The reaction is proposed to occur by a 1,2-addition leading to intermediate 165A and its intramolecular cyclization process.110 In contrast, the reaction with the arylcarbene chromium complex and the α,β-disubstituted alkenylcarbene tungsten complex yielded the formal [2+1], [3+2], and [4+3] carbocyclization products. The simple 1,3-dienes have consistently undergone the formal [2+1] and [4+2] cycloadditions with the alkoxy(alkyl/ aryl) carbene complexes and the alkoxy(alkenyl) carbene complexes of the group 6 metals.111 During their investigation into the [3+2] cycloaddition of the alkenyl carbene complexes and unactivated 1,3-butadienes, Barluenga and his co-workers revealed that the reaction pathway can be changed to the formal [4+1] annulation process by selecting a suitable reaction

Scheme 61. Fischer Carbene Complexes-Based Formal [4+1] Annulation

5.1. With 1,3-Dienes

In 1993, Hegedus’ group noted that the thermal reaction between electron-deficient methyl sorbate 159 and chromium carbene complex 160 occurred via a formal [4+1] cycloaddition and yielded the corresponding trisubstituted cyclopentene 161 with a 34% yield (Scheme 62). The reaction was proposed to proceed through a sequential 1,6-addition and reductive elimination. Although the reaction outcome is highly substrate-dependent, this transformation represents the first example of a formal [4+1] annulation between a chromium carbene complex and a diene.107 The nature of the Fischer carbene complexes and the substitution patterns served an important role in their reaction modes, which provides a powerful platform for the development of new formal [4+1] reactions. For example, Barluenga R


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Scheme 64. Formal [4+1] Annulation between 4Unsubstituted 1-Amino-1,3-dienes and Fischer Carbene Complexes

Scheme 66. Formal [4+1] Annulation between 1-Azadienes and Chromium Carbene Complex

media and temperature (Scheme 65).112 For example, performing the reaction of 1,3-dienes 168 and alkenylcarbene

alkenyl chromium carbene complexes.116 These strategies provided an efficient and promising entry to five-membered nitrogen heterocycles. The reaction of enones and enals with alkoxycarbene complexes consistently produced complicated reaction mixtures. However, an extensive study by Barluenga and his coworkers recently demonstrated that the reaction pathways of the alkoxy(alkenyl)carbene complexes can be fine-tuned by varying the reaction parameters.117 As shown in Scheme 67, the thermal reaction between the α,β-unsaturated ketones and the aldehydes 174 and the alkenyl- and aryl-substituted methoxycarbene complexes 163 exclusively proceeded through a formal [4+1] annulation pathway in THF at 100 °C, which furnished the corresponding highly substituted 2,3-dihydrofurans 175 in moderate to excellent yields. The reaction exhibited a high functional tolerance regarding the alkenylcarbene complexes and enones and enals. Additional treatment of the 2,3-dihydrofurans 175 with HBF4 in the presence of silica gel in Et2O caused the efficient conversion into furans 176. The experimental observation from the reaction with the cyclic alkenylcarbene complex and methyl vinylketone showed that the formation of the 2,3-dihydrofurans may result from a tandem process, which involved an initial [2+1] cyclopropanation between the carbene carbon and the CC bond and a subsequent ring rearrangement.

Scheme 65. Formal [4+1] Annulation Reaction of Unactivated 1,3-Dienes with Alkoxy(alkenyl)carbene Chromium Complexes

chromium complex 169 in THF at 120 °C yielded the formal [4+1] cycloadduct cyclopentenes 170 in moderate yields. The low yield was attributed to the formation of a considerable amount of unidentified side products. The reaction was rationalized to proceed via a metal-Diels−Alder reaction of the CrC dienophile and a reductive elimination of the chromium moiety. An intramolecular variant of this formal [4+1] annulation of the chromium aminocarbenes was also achieved by Spino’s group to obtain an efficient entry to a variety of bicyclic N-heterocyclic compounds with acceptable yields, which are commonly detected in many natural alkaloids.113

5.3. With Cyclobutenediones

Herndon and co-workers noted that an extensive range of alkoxy- and alkyl-substituted cyclobutenediones 177 may undergo a formal [4+1] annulation with a variety of alkylcarbene complexes 178 to obtain cyclopentenediones 179 and 180 in moderate yields (Scheme 68).118 However, the reaction with the alkoxyarylcarbene complexes caused the formation of 5-alkylidenefuranones 181 as the major products. Because cyclobutenediones are liable to a C−C bond insertion, a possible mechanism that involves an oxidative addition of chromium into the acyl−acyl bond/carbene insertion (177A to 177B)/reductive elimination process was proposed for this interesting reaction. Cyclopentenediones 180 may result from the low-valent chromium-induced reduction of the initially formed products 179. The formation of 5-alkylidenefuranones 181 may be formed by O-acylation of the enolates 177D, which is formed by ionization of the C−Cr bond via intermediate 177C.

5.2. With α,β-Unsaturated Systems

The thermal reaction between the Fischer carbene complexes and the simple imines typically generates a complicated mixture of products. In 1994, Danks’ group was the first group to report that the α,β-unsaturated imines of type 171 smoothly reacted with chromium carbene complex 172 in refluxing toluene, which afforded the 1,2,3-trisubstituted pyrroles 173 in a 50− 60% yield (Scheme 66).114 This formal [4+1] annulation reaction was proposed to proceed through the initial formation of intermediate cyclopropane A and a rearrangement to 2,3dihydropyrrol B. The loss of ethanol yielded the final products 173. Similar reaction outcomes have also been observed by Barluenga and his co-workers.115 The indicated that small amounts of the formal [4+1] adducts, the vinylpyrroles, were formed (25−28% yields) in the formal [3+2] cycloaddition reaction between the α,β-unsaturated hydrazones and the S


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Scheme 67. Formal [4+1] Cycloaddition of α,β-Unsaturated Carbonyl Compounds with Fischer Carbene Complexes

Scheme 68. Formal [4+1] Cycloaddition between Cyclobutenediones and Fischer Carbene Complexes

6. ISOCYANIDES-BASED FORMAL [4+1] ANNULATION Isocyanides represent a family of versatile organic molecules that bear unique electronic properties and have been extensively applied in organic synthesis, particularly in the synthesis of nitrogen-containing molecules and natural and drug-like products with potential bioactivities.119 For example, the isocyanides exhibit a reactivity profile similar to that of CO to a certain extent and can serve as valuable one-atom units to undergo imidoylative reactions and a formal [4+1] annulation with appropriate four-atom fragments (Scheme 69). This type

catalyzed imidoylative reactions has been discussed in recent excellent reviews,120 no special-purpose reviews on the applications of isocyanides as C1 synthons in formal [4+1] annulations have been performed. Therefore, this section focuses on recent progress in isocyanides-based formal [4+1] annulation reactions and their applications in the synthesis of complex carbocyclic and heterocyclic compounds. Certain recent isocyanide insertion-initiated formal [4+1] annulation reactions will also be discussed. 6.1. With α,β-Unsaturated Ketones and Imines

The formal [4+1] annulations between isocyanides and 1,3conjugated systems are significant for the synthesis of fivemembered carbocyclic and heterocyclic compounds. Intrigued by the synthetically and biologically important ring-fused γbutyrolactone motifs, Saegusa and his co-workers developed an Et2AlCl-promoted [4+1] annulation of the α,β-unsaturated ketones and aldehydes 182 with isocyanides 183, which provides an efficient approach to ring-fused γ-butyrolactones 184 in a highly stereoselective manner (Scheme 70).121 The reaction showed a high functional tolerance regarding the cisoid-configured α,β-unsaturated ketones. The resultant unsaturated iminolactones 184 are easily transformed into γbutyrolactones 185 via hydrogenation and hydrolysis. This strategy has also been successfully applied to other heterodienes, such as the azadienes,122 the diazadienes,123 2,4diones,124 and the α-thioxothioamides.125

Scheme 69. Isocyanides-Based Formal [4+1] Annulation for the Synthesis of Five-Membered Ring Systems

of one-atom unit has shown certain advantages over CO because it is easily handled and nongaseous and its structure can be simply modified. Although the use of isocyanides in multicomponent reactions and Lewis acid- or transition metal-

Scheme 70. Lewis Acid-Promoted [4+1] Annulation between α,β-Unsaturated Ketones and Aldehydes and Isocyanides

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Scheme 71. Formal [4+1] Annulation of 2-Acetyl-1,4-benzoquinone with Isocyanides

Scheme 72. One-Pot Three-Component Process Involving Formal [4+1] Annulation of Quinine Methides with Cyclohexyl Isocyanide

Shaabani and his co-workers also discovered that 2-acetyl1,4-benzoquinone 186 reacted well with isocyanides 183 in a formal [4+1] annulation manner to afford the N-substituted iminolactone 187 without any catalyst, which underwent a smooth isomerization to provide isobenzofuran-4,7-quinones 188 in high yields (Scheme 71).126 Another analogous methodology that involves a one-pot formal [4+1] annulation between quinone methides 191, which was generated in situ from 4-hydroxycoumarin 189, various aldehydes 190, and cyclohexyl isocyanide, was reported by Nair et al. (Scheme 72).127 The reaction tolerated an extensive range of aromatic aldehydes and provided an efficient and practical route to furocoumarins 193 and furoquinlones 194 and 195 with generally adequate yields. The o-thioquinones, which derived in situ from o-hydroxyphenylthiophthalimides, also efficiently underwent this formal [4+1] cycloaddition with isocyanides to produce the 2-imino-1,3-oxathioles in high yields.128 Chatani and his co-workers reported the first example of a catalytic formal [4+1] annulation between α,β-unsaturated ketones 196 and aryl isocyanides 197 using a catalytic amount of GaCl3, which furnished an extensive array of diversely functionalized iminolactones 198 with high yields (Scheme 73).129 The aromatic isocyanides that bear sterically demanding or electron-withdrawing substituents yielded better results, whereas the aliphatic isocyanides proved to be ineffective under the standard conditions. This catalytic system showed a broad substrate scope regarding the α,β-unsaturated ketones. A possible stepwise mechanism was proposed for the reaction, in which the GaCl3 catalyst served a critical role in promoting the E/Z isomerization of intermediate 196B cyclization, and the release of GaCl3 was attributed to its lower oxophilicity. This mechanism was also supported by computational calculation studies.130

Scheme 73. Catalytic Formal [4+1] Annulation between the α,β-Unsaturated Ketones and Aryl Isocyanides

The cycloaddition reaction of the imine derivatives with the isocyanides provides another powerful entry to the fivemembered N-heterocyclic compounds. For example, Deyrup’s group developed a pioneering example of the formal [4+1] cycloaddition between N-acylimines 199 and t-butyl isocyanide to afford acceptable yields of the 5-iminooxazoline derivatives by acid catalysis (Scheme 74).131 Note that the reaction did not occur without an acid catalyst. The reaction was applicable to hexafluoroacetone or the methyl 3,3,3-trifluoropyruvate derived N-acylimines.132 This protocol was recently extended to the [4+1] annulation of cyclohexyl isocyanide and the Z-α-benzoyl amino-acrylic acid esters by Esmaeili for the preparation of the U


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isocyanides, in which the initial protonation of iminium with HCl was critical to the success of the reaction (Scheme 76).137 This reaction provided an unprecedented and useful direct access to 2-aminopyrrole derivatives 208. Using this strategy, the 5-aminoisoxazole and 5-aminopyrazole derivatives were also conveniently prepared through the isocyanide-based [4+1] cycloaddition of the α-bromoketone oximes and the αhalogenoketone hydrazones, respectively.138 Recently, Li’s group has reported a mild silver-promoted radical formal [4+1] annulation between a diverse set of α-halo ketoximes and 1,3-dicarbonyl compounds, which provide efficient access to the Δ2-isoxazoline synthesis.139 The development of convenient and efficient methods for the construction of unsymmetrical polysubstituted aminopyrroles continues to be an attractive but challenging task for synthetic chemists. Zhu and Masson recently reported a highyielding formal [4+1] cycloaddition between α,β-unsaturated imidoyl cyanides 209 and the isocyanides promoted by a catalytic amount of AlCl3 (Scheme 77).140 Interestingly, the

Scheme 74. Acid-Catalyzed Formal [4+1] Cycloaddition of N-Acyl Imines with tButyl Isocyanides

highly functionalized 5-iminooxazolines, which can be conveniently transformed into the valuable α,α-disubstituted αamino acid amides.133 The in situ-generated enyne-isonitrile was also determined to undergo this reaction in an intramolecular manner.134 The formal [4+1] annulation of the conjugated CN−C N bond system with the isocyanides provides a versatile platform for the generation of fused heterocyclic systems. For example, Groebke’s group reported an efficient one-pot threecomponent reaction for the preparation of the imidazo[1,2-a]fused heterobicyclic compounds from 2-amino-pyridine, pyrazine, and pyrimidine (Scheme 75).135 The reaction can

Scheme 77. AlCl3-Catalyzed Formal [4+1] Annulation between α,β-Unsaturated Imidoyl Cyanides and Isocyanides

Scheme 75. One-Pot Three-Component Reaction Involving [4+1] Annulation for Synthesis of Fused 3-Aminoimidazole Derivatives

AlCl3 proved to be superior over GaCl3 for this reaction, which was previously employed for the [4+1] cycloaddition of the α,β-unsaturated carbonyl compounds with the isocyanides.129a The reaction proved to be relatively general regarding the α,βunsaturated imidoyl cyanides and the isocyanides. A possible mechanism that involves a formal [4+1] annulation and a [1,3]H-shift was postulated for the reaction. The nitrile group was also important for the reaction by stabilizing the enamine intermediate 209B and preventing side reactions. The aliphatic isocyanides can also participate in a sequential Knoevenagel condensation/[4+1] cycloaddition reaction for the facile synthesis of the pyrrolo[1,2-a]benzimidazoles.141 Recently, Ukaji, Soeta, and their co-workers disclosed that the in situ-derived N-acyl and N-thioacyl imines 211 may serve as a class of unique 1,4-dipoles to undergo formal [4+1] annulation with the isocyanides (Scheme 78).142 The reaction

be considered to proceed via a formal [4+1] cycloaddition of the in situ-generated iminium intermediate 201A with the isocyanides followed by the rearomatization of 201C and a 1,3H shift. The reaction proved to be relatively general regarding the aldehydes 201 and isocyanides 183, and the corresponding heterobicyclic products 203−205 were obtained in moderate to excellent yields. Note that Bienaymé’s group and Tsai’s group simultaneously and independently documented this multicomponent reaction using HClO4 and Sc(OTf)3, respectively.136 Bienaymé’s group successfully applied this strategy to the library synthesis by conveniently generating 30 000 different compounds. Morel and his co-workers described a formal [4+1] cycloaddition of the α,β-unsaturated imine salts 206 with the

Scheme 76. Synthesis of 2-Aminopyrrole Derivatives by [4+1] Cycloaddition of Iminium Hydrochlorides 206 with Isocyanides

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Scheme 78. [4+1] Cycloaddition of in Situ-Generated N-Acyl and N-Thioacyl Imines with Isocyanides

can be changed using the α-substituted β-nitroolefins. For example, a formal [4+1] annulation of nitroolefins 216 with isocyanides 217 initially afforded the isoxazoline N-oxides 216B. Intermediate 216B then underwent a sequential ring opening/H-shift/intramolecular cyclization to produce the final 1-hydroxyindoles 218 in moderate to excellent yields (Scheme 80).146 This strategy showed a high functional tolerance and can be applied to the preparation of various fused 1hydroxypyrrole derivatives.

tolerated an extensive variety of N-acyl and N-thioacyl N,Oacetals 211 and isocyanides 183 using TMSOTf or TMSCl as the promoters to furnish the corresponding highly substituted bioactive oxazoles and thiazoles 212 in generally moderate to high yields. A plausible mechanism that involves the sequential organosilane-assisted formation of N-acylimine derivatives 211A and their formal [4+1] cycloaddition with the isocyanides via nitrilium intermediate 211C was proposed. 6.2. With Nitroolefins

Similar to the N-acyl imines, aza dienes, and α,β-unsaturated carbonyl compounds, Saegusa and his co-workers determined that nitroolefins of type 213 can also react well with isocyanides 214 in a formal [4+1] cycloaddition manner to produce the unstable isoxazoline N-oxides 213A, which can undergo an additional ring opening/H-shift/reduction sequence to afford the final α-cyano-α-substituted acetamides 215 via the key nitrile oxide intermediates 213B and 213C (Scheme 79).143

Scheme 80. Formal [4+1] Annulation between Nitroolefins and Isocyanides

Scheme 79. Reactions of β-Substituted Nitroolefins with Isocyanides

Wróbel and his co-workers noted that the readily available Naryl-2-nitrosoanilines that bear an electrophilic nitroso and a nucleophilic amine moiety can serve as suitable four-atom synthons to undergo a formal [4+1] annulation with the isocyanoacetic esters and benzylic aryl sulfones, respectively, and provide an efficient route to the biologically important 2aminobenzimidazole and 1,2-diaryl-1H-benzimidazole derivatives.147

The nitrile oxide intermediate 213C can be successfully trapped by an intramolecular 1,3-dipolar cycloaddition reaction with the alkenes to synthesize more complex fused carbocyclic and heterocyclic compounds.144 Parsons and his co-workers also developed an intermolecular variant.145 Parson’s group discovered that the highly reactive intermediate nitrile oxides, which are generated by the reaction of functionalized isonitriles with nitroolefins, smoothly reacted with methyl arylate to form a variety of functionally rich isoxazoline derivatives. In contrast, Foucaud and co-workers revealed that the pathway of evolution of the isoxazoline N-oxide intermediates

6.3. With Vinyl Isocyanates

Vinyl isocyanates represent a class of versatile reagents with extensive application in the synthesis of nitrogen-containing heterocycles due to their unique reactivity patterns (refer to section 3.1). For example, Rigby’s group determined that the vinyl isocyanates 219 can serve as four-atom units in a [4+1] annulation with cyclohexyl isocyanide without any catalyst (Scheme 81).148 The reaction showed a broad scope regarding W


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Scheme 81. Formal [4+1] Annulation between Vinyl Isocyanates and Cyclohexyl Isocyanide

Scheme 83. Formal [4+1] Annulation between TIPSVinylketenes and tert-Butyl Isocyanide

precursors for the construction of the biologically active aminocyclopentitol derivatives.151 6.4. Isocyanide Insertion-Based Formal [4+1] Annulation

Isocyanides have also been extensively utilized as CO equivalents in transition-metal-catalyzed isocyanide insertion reactions.120 In this context, this strategy has recently been extended to the formal [4+1] annulation for the construction of diverse carbocycles and heterocycles using finely designed fouratom fragment components. Several powerful catalytic systems for this transformation have been documented in the past decade; these results will be discussed in the following section based on the different types of four-atom fragments. 6.4.1. With Aryl Bromides Bearing Pendent Nucleophiles. Whitby’s group noted the first example of a palladiumcatalyzed insertion of isocyanide into 2-bromobenzylamine 229, which formed a formal [4+1] adduct amidine 230 with a yield of 64% (Scheme 84a).152 This strategy can be successfully extended to 2-bromobenzylalcohols 231. An extensive range of aliphatic isocyanides were well tolerated, and the corresponding benzo-fused cyclic imidates 232 were obtained in moderate to excellent yields (Scheme 84b). In 2012, Ji, Zhu, and their co-workers described a highyielding palladium-catalyzed tert-butyl isocyanide insertion into 2-bromo-substituted aryl alky ketones 233 (Scheme 85).153 The reaction exhibited a broad scope for the ketone components, and the resultant benzo-fused cyclic imidates 234 were conveniently transformed into highly functionalized lactones 235 with a Z-configuration by simple acid hydrolysis.

the vinyl isocyanate components and furnished the corresponding pyrrolinone derivatives 220 with generally satisfactory yields. In certain cases, the reaction directly afforded the hydrolysis products, such as hydroindolones 220f. The vinyl isocyanates can be conveniently prepared from the related α,βunsaturated carboxylic acids by the Curtius rearrangement, which enabled a one-pot process. Note that the non-hydrogen group at the α-position of the vinyl isocyanate was critical to the reaction. Given the immediate availability of the preliminary material and the operational simplicity, this methodology should have significant potential in alkaloid synthesis. For example, Rigby has successfully applied this strategy to a concise and formal total synthesis of erysotrine alkaloid 226 (Scheme 82). This reaction was also employed as the main step in the total synthesis of another erythrinan alkaloid, (±)-2-epi-erythrinitol.149 Analogous to the vinyl isocyanates, the TIPS-vinylketenes of type 227 can also efficiently undergo a formal [4+1] annulation with tert-butyl isocyanide without any catalyst, which affords the corresponding highly functionalized cyclopentenones 228 with generally acceptable yields (Scheme 83).150 The Cr(CO)3 motif in the products also provided a handle for additional structural elaborations. These products can serve as the main

Scheme 82. Concise Formal Total Synthesis of Erysotrine Alkaloid

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Scheme 84. Palladium-Catalyzed Isocyanide Insertion: Synthesis of Benzo-Fused Amidines and Imidates


A plausible mechanism was also postulated (Scheme 86). First, oxidative addition of 233 to the Pd(0) catalyst generated complex 233A, which underwent the isocyanide insertion into the palladium−carbon bond to obtain the imidoyl palladium intermediate 233B. The coordination of oxygen of the carbonyl group in enolic form may accelerate the formation of the sixmembered oxopalladacyclic intermediate 233C. The intermediate 233C underwent a reductive elimination to form imidates 234 with the release of Pd(0) catalyst. A routine acid hydrolysis produced the final lactones 235. This strategy was recently applied to the palladium-catalyzed insertion of isocyanides into amides for the construction of diversely substituted isoindolinone derivatives.154 In the cyclization reactions that involve palladium-catalyzed isocyanide insertion, the formation of the main heteropalladacyclic intermediate serves an important role in the formation of the new heterocyclic compounds. In 2011, Murakami and his co-workers disclosed an alternative palladium-catalyzed isocyanide insertion reaction of 236 initiated by the extrusion of N2 (Scheme 87).155 This group determined that the resultant azapalladacyclic intermediate 236A, which was generated by the oxidation addition of triazinone to Pd(0) and N2 extrusion, efficiently reacted with a variety of aryl and aliphatic isocyanides to form the corresponding 3-imino-substituted isoindolin-1ones and thiaisoindolines with consistently excellent yields. Inspired by Curran and Larock’s pioneering studies on the cyclization of the imidoyl palladium complex,156 Chatani and his co-workers recently documented an efficient palladiumcatalyzed formal [4+1] annulation between the 2-halobiaryls and the isocyanides by combining isocyanide insertion and C− H bond activation/functionalization strategies (Scheme 88).157 The protocol also tolerated a variety of 2-bromo-substituted heterobiaryls 238 and 2-bromostyrenes to produce the expected fluorenone imines in moderate to excellent yields. Interestingly, only sterically demanding aromatic isocyanides proved to be suitable for this reaction. Mechanistic studies that examined the intramolecular kinetic isotope effect revealed that the formation of the critical intermediate palladacycle 238A via

Scheme 87. Palladium-Catalyzed Denitrogenation/ Isocyanide Insertion

Scheme 88. Palladium-Catalyzed Cyclization of 2Halobiaryls with Isocyanides by Combining Isocyanide Insertion and C−H Bond Activation Strategies

palladium-catalyzed isocyanide insertion and C−H bond activation was critical to the success of this reaction. Zhu’s group reported an unprecedented Rh(III)-catalyzed formal [4+1] annulation between N-benzoylsulfonamides 240 and isocyanides 183 (Scheme 89).158 In the presence of [RhCl2Cp*]2 as the catalyst and Cu(OAc)2·H2O as the oxidant,

Scheme 85. Efficient Synthesis of Phthalides by Sequential Palladium-Catalyzed tert-Butyl Isocyanide Insertion and Acid Hydrolysis

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prepare acceptable yields of 2-aminobenzoxazoles and 2aminobenzothiazoles. A possible mechanism was proposed for this reaction (Scheme 91). Pd(OAc)2(tBuNC)2 catalyst initially reacted with bisnucleophilic diamine to generate intermediate 242A, which underwent isocyanide insertion to obtain the sixmembered azapalladacyclic species 242B. A final reductive elimination resulted in the release of the catalyst Pd0(tBuNC)2 species and the formation of the corresponding final product 243 after isomerization. The authors also applied this strategy as the main step in efficient formal total synthesis of the antihistamines, norastemizole, and astemizole (Scheme 92). Considering the immediate availability of the substrates and the extensive functional group compatibility, this protocol should have significant synthetic potential in the construction of structurally diverse five-membered heterocycles. The palladium and cobalt-catalyzed insertion of the isocyanides into the o-phenylenediamines, 2-aminophenols, and 2-aminobenzenethiols was also recently described by Jiang, Wang, and Ji, respectively.161 Interestingly, Jiang’s group noted that the 2-aminobenzenethiols can undergo a similar formal [4+1] annulation with nitriles catalyzed by Cu(OAc)2.162 Using the strategy of transition-metal-catalyzed isocyanide insertion, Xu and his co-workers recently disclosed a highly applicable synthesis of biologically and synthetically valuable 2amino-1,3,4-oxadiazoles 248 and 2-imino-1,3,4-oxadiazolines 249 using a palladium-catalyzed oxidative formal [4+1] annulation between hyrazides 247 and isocyanides 183 (Scheme 93).163 The reaction of the benzoylhydrazides with acetyl as the leaving group afforded the corresponding 2-amino1,3,4-oxadiazoles in moderate to excellent yields, whereas the use of N-aryl or naphthyl-substituted benzohydrazides led to the formation of the 2-imino-1,3,4-oxadiazolines with comparable yields.

Scheme 89. Rhodium-Catalyzed Formal [4+1] Annulation between N-Benzoylsulfonamides and Isocyanides

an extensive range of N-benzolysulfonamides with various electronic properties and substitution patterns smoothly reacted with bulky aromatic and aliphatic isocyanides to obtain the corresponding 3-(imino)isoindolinones 241 with acceptable yields and moderate Z/E ratios. The reaction was relatively sensitive to the N−H acidity; the Ts group was the best selection. Analogous to the palladium-catalyzed isocyanide insertion, the formations of the five-membered ring rhodacycle 240A by the C−H bond activation and intermediate 240B via the isocyanide insertion were considered as critical steps. Recently, Yu, Dai, and their co-workers also disclosed an interesting Pd2(dba)3-catalyzed and CONHOMe-directed formal [4+1] annulation of the N-methoxybenzamides, which bear various heteroatoms with t-BuNC by the C−H functionalization strategy and provide an operationally simple and versatile approach to the 3-(imino)isoindolinones with high efficiency and positional selectivity.159 6.4.2. With Bisnucleophiles. The highly functionalized benzimidazoles, benzoxazoles, and benzothiazoles are a class of privileged heterocyclic scaffolds with an extensive occurrence in numerous bioactive natural products and medicinally relevant molecules. The transition-metal-catalyzed insertion of isocyanides into bisnucleophiles, such as the o-phenylenediamines, 2aminophenols, and 2-aminobenzenethiols, represents one of the most efficient and atom-economic methods for the synthesis of these heterocyclic compounds. Maes, Orru, Euijter, and their co-workers have recently disclosed an interesting and practical palladium-catalyzed insertion of the isocyanides into bisnucleophilic o-phenylenediamines, 2-aminophenols, and 2-aminobenzenethiols (Scheme 90).160 Using of only 1 mol % of Pd(OAc)2 as the catalyst under O2, an extensive array of aromatic and heteroaromatic bisnucleophilic o-phenylenediamines 242 and aliphatic isocyanides were well suited to furnish the corresponding products 243 in generally high yields. This reaction was successfully extended to the 2-aminophenols and 2-aminobenzenethiols to

6.5. With 1,4-Zwitterionic Species

The formal [4+1] annulation reactions of the 1,4-zwitterionic species with the isocyanides, particularly the enantioselective variants, constitute another attractive but challenging platform for the construction of diversely functionalized five-membered carbocyclic and heterocyclic compounds. Hayashi, Shintani, and their co-workers recently described interesting Pd(0)-catalyzed decarboxylative annulations between γ-methylidene-δ-valerolactones 250 and the isocyanides, which afforded a variety of highly substituted conjugated cyclopentenimines 252 in excellent yields (Scheme 94).164 The reaction showed a high functional tolerance for the α-(hetero) aryl-γ-methylidene-δvalerolactones. Under the standard conditions, the diversely substituted aromatic isocyanides worked well, whereas the aliphatic isocyanides resulted in moderate yields. A possible mechanism was also proposed for this reaction, which involves the formation of the main reactive 1,4-zwitterionic species 250A by an oxidative addition/decarboxylation and addition/ cyclization sequence of intermediate 250B. An enantioselective variant of this reaction was also achieved using (R)-DTMBSegphos as the chiral ligand (81% ee).

Scheme 90. Palladium-Catalyzed Isocyanide Insertion into Bisnucleophiles

6.6. Isocyanides-Based Radical Formal [4+1] Annulation

The unique properties of isocyanides also enable the radicalbased annulation reaction using suitable reagents for the construction of polycyclic compounds.18a,165 Curran and coworkers described the first example of a formal [4+1] annulation of 1-substituted 5-iodo-1-pentynes with aryl isocyanides under sunlamp irradiation in the presence of Z


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Scheme 92. Formal Total Synthesis of Norastemizole and Astemizole

Scheme 93. Pd-Catalyzed Oxidative Formal [4+1] Annulation between Hydrazides and Isocyanides

Scheme 94. Formal [4+1] Annulation between γ-Methylidene-δ-valerolactones and Isocyanides

hexamethylditin (Scheme 95).166 The reaction showed considerable generality for the iodopentynes and isocyanides, which afforded the corresponding cyclopenta-fused quinolines 254 in moderate to excellent yields. A possible mechanism that involves the formal [4+1] radical annulation and radical ring closure was also proposed, including (a) the photopromoted

formation of radical 253A and its addition to isocyanide, (b) the intramolecular annulation of the resultant imidoyl radical 253B to an alkyne, and (c) the final ring closing addition of vinyl radical 253C to the aryl group and rearomatization. This strategy was also successfully applied to the formal total synthesis of antitumoral (±)-camptothecin, in which the formal AA


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Scheme 95. Formal [4+1] Annulation between 5-Iodo-1pentynes and Aryl Isocyanides

Scheme 97. Formal [4+1] Annulation of Cyano-Substituted Alky and Sulfanyl Radicals with Isocyanides

[4+1] annulation of pyridone radical 255A with phenyl isocyanide and the following ring closure afforded the product 256 (Scheme 96).167 Similarly, the enantioselective synthesis of (20S)-camptothecin and its analogues, such as topotecan, irinotecan, and GI-147211C, were also successfully achieved by this protocol beginning with the optically pure main pyridone lactone 258.168 The synthetic potential of this cascade radical reaction was also demonstrated in the formal total synthesis of (S)-mappicine, (20R)-homocamptothecin, homosilatecans, and luotonin A, as well as their analogues and related natural products.169 Nanni and his co-workers discovered another type of radical annulation reaction of aryl isocyanides with cyano-substituted alkyl and sulfanyl radicals under sunlamp irradiation, which formed the corresponding cyclopentaquinoxalines 260 and thienoquinoxalines 262, respectively, in fair yields (Scheme 97).170 In this reaction, disulfide proved to be superior to its related thiol counterparts. On the basis of a semiempirical calculation study, a cascade [4+1] annulation/ring closure pathway that is similar to Curran’s mode was also proposed.167a In addition to the aromatic isocyanides, Smith and Lenoir documented that the vinyl isocyanides 263 can undergo the previously mentioned cascade radical formal [4+1] annulation/ intermolecular cyclization (Scheme 98).171 Under previously developed standard conditions by Curran, a variety of linear and cyclic vinyl isocyanides reacted well with the substituted iodoalkynes and iodonitriles to furnish the expected pyridines and pyrazines 264 in moderate to excellent yields. In 2006, Studer’s group observed that the C-centered radical, which was generated by the thermal C−O bond homolysis

Scheme 98. Radical Annulation between the Vinyl Isocyanides and Iodoalkynes and Iodonitriles

from alkene-terminated alkoxamines 265, can also undergo the [4+1] annulation and the subsequent cyclization with aryl isocyanides (Scheme 99).172 The reaction demonstrated a large scope for both components, and a variety of quinoline derivatives were obtained in moderate to high yields.

Scheme 96. Formal Total Synthesis of (±)-Camptothecin

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Scheme 99. Tandem Cyclization between Alkoxyamines and Isocyanides

Scheme 100. Proposed Reaction Pathway

Interestingly, the reactions with R1 as the aryl group in alkoxyamines 265 predominately afforded the products 266, whereas CO2Me and CN as R1 resulted in the formation of the tautomerized products 267. Microwave irradiation can substantially accelerate the reaction. A possible mechanism that involves a 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO)-mediated cascade radical cyclization was also postulated (Scheme 100). Considering the accessibility of the preliminary material, the simple operational procedure, and no requirement for toxic tin reagents, this strategy provides an efficient and complementary entry to fused carbocyclic and heterocyclic compounds. Nitriles can also serve as C1 fragments to undergo Ti(IV)mediated formal [4+1] cycloaddition reactions with 1,3-dienes, homoallylic Grignard reagents, and Cu(II)-catalyzed [4+1] cycloaddition with ethylenediamine to furnish a diverse set of five-membered carbocycles and nitrogen-containing heterocycles with acceptable chemical yields and efficiency.173

Scheme 101. Ylides-Based Formal [4+1] Annulation for the Synthesis of Five-Membered Carbocyclic and Heterocyclic Compounds

(one-atom fragments) to react with 1,3-conjugated systems (four-atom fragments) in a formal [4+1]-annulation manner to furnish the corresponding diversely functionalized five-membered carbocycles and heterocycles. Certain products were also conveniently transformed into natural products and their analogues. However, to the best of our knowledge, the general reviews devoted to this field remain lacking.175 Therefore, major recent advances in the use of ylides in formal [4+1] annulation reactions for the synthesis of five-membered carbocycles and heterocycles will be discussed in this section according to the different four-atom fragments, including aldehydes, ketones, esters, imines, and nitroolefins.

7. YLIDES-BASED FORMAL [4+1] ANNULATION Ylides, as exemplified by phosphine, nitrogen, and sulfur ylides that bear nucleophilic sites and leaving groups, represent a family of unique versatile reagents that can efficiently react with various CX (e.g., X = C, N, O) double bonds via a nucleophilic addition/intramolecular substitution sequence.174 Using this reactivity, these reagents have been extensively utilized for the preparation of a substantial variety of biologically important and synthetically useful olefins and small ring systems, such as cyclopropanes, epoxides, and aziridines. A recent investigation of the heteroatoms and structural modifications of the ylides has demonstrated that these reagents can also be successfully applied to the construction of five- and six-membered compounds beyond the classic three-membered rings (Scheme 101). For example, rationally designed ylides can be used as 1,1-dipolar synthons

7.1. With Aldehydes, Ketones, and Esters

Vinylketenes have been established as a class of versatile fouratom building blocks with extensive applications in annulation reactions for the synthesis of various carbocyclic compounds.77,176 Using the unique reactivity of the vinylketenes, Danheiser and co-workers developed a formal [4+1] annulation of (trialkylsilyl)vinylketenes 117 (“TAS-vinylketenes”) with sulfur ylides 268 to provide a powerful route to the functionalized 2-cyclopentenones 269 with excellent transselectivity (Scheme 102).78 The incorporation of the bulky trialkylsilyl group was critical for the stabilization of the ketenes by suppressing side reactions, such as dimerization and [2+2] cyclization. Diazomethane and the TMS-diazomethanes also AC


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Scheme 102. Formal [4+1] Annulation of (Trialkylsilyl)vinyl Ketenes with Sulfur Ylides

Scheme 104. Enantioselective Synthesis of 2,3-Disubstituted Tetrahydrofurans

proved to be suitable for this annulation. The stereochemistry of the products showed that this reaction can proceed via a nucleophilic addition/ionization/4π-electrocyclic closure sequence. Another alternative pathway that involves the nucleophilic addition/internal displacement sequence was also possible. This pioneering study provided a new fruitful platform for devising other vinyl ketene-based [4+1] annulation reactions. The silyl vinylketene substrates that contain an arene chromium tricarbonyl moiety can also undergo this formal [4+1] annulation with moderate to excellent yields.79 In addition to sulfur ylides and diazo compounds, Danheiser’s group also observed that the α-benzotriazolyl organolithium salt of type 270, which is easily accessed from the corresponding benzotriazole precursors,177 can serve as a suitable “carbenoid” reagent to smoothly undergo a formal [4+1] annulation with TAS-vinylketenes 117 catalyzed by the Lewis acid ZnBr2 and furnish a variety of diversely functionalized cyclopentenones 269 (Scheme 103).178 The reaction

iodide using NaH as the base, underwent an efficient formal [4+1] annulation with the α,α-dialkyl β-oxo amides and provided easy access to the highly substituted β-hydroxy-γlactam derivatives.180 Payne,181 Piras,182 Cao,183 and other researchers184 documented that ylides (e.g., sulfonium, arsonium, and ammonium ylides) can react with α,β-unsaturated carbonyl compounds in a formal [4+1] annulation manner to form highly substituted dihydrofuran derivatives as compared to cyclopropanes. However, the general asymmetric variants of these reactions using sulfur ylides remain ambiguous.185 Recently, Tang’s group described a highly diastereo- and enantioselective formal [4+1] annulation between α-ylidene-β-diketones 276 and the camphor-derived sulfur ylide 277, which provides easy access to the corresponding optically active trans-dihydrofurans 278 with moderate to high chemo-, diastereo-, and enantioselectivities (Scheme 105). 186 The selection of the base and the

Scheme 103. Formal [4+1] Annulation of (Trialkylsilyl)vinyl Ketenes with α-Benzotriazolyl Organolithium Salts

Scheme 105. Stereoselective Formal [4+1] Annulation of αYlidene-β-diketones with Sulfur Ylides

diastereoisomeric purity of sulfonium salt 277 proved to be important for the reaction efficiency, diastereo-, and enantioselectivities. The resulting D-camphor-derived sulfide was easily recovered. An analogous strategy that involves the formal [4+1] annulation between stabilized sulfur ylides and α,β-unsaturated thioamides was also developed by Samet et al. for the synthesis of the trans-dihydrothiophene derivatives.187 The in situ-generated o-quinone methides have emerged as a class of highly reactive and useful species with extensive application in cycloaddition and natural product synthesis.188 In this context, Zhou and his co-workers recently discovered a mild and general method for the efficient synthesis of trans-2,3dihydrobenzofurans using this type of intermediate (Scheme 106).189 They observed that o-quinone methides 280, which were generated in situ from 2-tosylalkylphenols 279, smoothly reacted with sulfur ylides in a [4+1] annulation manner to provide satisfactory yields (67−99%) of the corresponding products 283 with excellent diastereoselectivities (>20:1 dr). An extensive range of 2-tosylalkylphenols with diverse electronic properties and substitution patterns proved suitable for the reaction. Various stable sulfur ylides and the unstable trimethylsulfoxonium iodide can also smoothly participate in

displayed an extensive substrate scope, high chemical yields, and trans-selectivity. The products may also be conveniently transformed into synthetically valuable building blocks by elaborating the vinyl silane moiety. The sulfur ylide-based [4+1] annulation strategy was also successfully extended to an epoxide opening for the preparation of the synthetically useful and bioactive chiral tetrahydrofuran derivatives. In 2004, Borhan and his co-workers discovered that terminal epoxide 274, which is easily formed in situ from enantiomerically pure 2,3-epoxy alcohols 273 by the Payne rearrangement, can undergo a nucleophilic ring-opening/5exotet cyclization cascade with the in situ-generated dimethylsulfoxonium methylide (Corey−Chaykovsky reagent) 272 to afford the desired THF derivatives with good to high yields (Scheme 104).179 The reaction demonstrated a high functional tolerance and complete stereochemical fidelity. Considering the immediate availability of optically pure 2,3-epoxy-alcohols by the catalytically asymmetric Sharpless epoxidation and operational simplicity of the procedure, this methodology offers extensive applications in organic synthesis. Recently, Dong and his co-workers noted that this type of dimethylsulfoxonium methylide, which was derived in situ from trimethylsulfoxonium AD


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Scheme 106. Formal [4+1] Annulation of o-Quinone Methides and Sulfur Ylides

2-nitrobenzofuran derivatives in consistently moderate yields with a high functional group tolerance.194 In 2012, Sudalai and his co-workers described a tandem αamination/formal [4+1] annulation for the synthesis of the 4hydroxypyrazolidines.195 They found that the chiral amino aldehydes 286, which were generated in situ by the L-prolinecatalyzed α-amination of aldehydes 284, reacted well with sulfur ylide 272 in a formal [4+1] annulation pathway rather than via epoxidation (N-alkylation of 286A vs O-alkylation of 286B) (Scheme 107). The reaction furnished the corresponding synthetically and biologically important 4-hydroxypyrazolidine derivatives 287 in high yields with excellent diastereo- and enantioselectivities (75−98% ee). The products can be easily transformed into anti-1,2-aminoalcohols, which are common substructures in HIV protease inhibitors.196 In addition to the sulfur ylides, ammonium ylides are always considered to be another class of unique nucleophiles that possess a leaving group, which have also been extensively utilized as suitable reagents for the construction of fivemembered cyclic compounds. For example, Liang and his coworkers reported an efficient formal [4+1] annulation reaction between α,β-unsaturated ketenes and esters 290 and DABCOderived ammonium ylides 289, which can be easily generated in situ from quaternary ammonium salts 288 using K2CO3 as the base (Scheme 108).197 The reaction showed a high functional tolerance for both reaction components and furnished the corresponding 2,3-dihydrofuran derivatives 291 with high yields and trans-selectivities. No cyclopropanation product was detected in all cases. A rational mechanistic mode was suggested for the previously mentioned reaction based on Moorhoff’s model.198 This process can also be performed using a catalytic amount of 1,4-diazabicyclo[2.2.2]octane (DABCO) with no distinct effect on the reaction efficiency and stereoselectivities.199 This strategy was successfully extended to the reaction of pyridinium and imidazolium salts with enones for the synthesis of densely functionalized and fused 2,3dihydrofuran derivatives, such as furopyranone and the dihydrofuroquinolinone alkaloids.200 For the ammonium ylide-based formal [4+1] annulation reaction, a stoichiometric amount of quaternary ammonium salts is typically required, which resulted in certain limitations, such as toxicity and tedious workup procedures. In 2011, Tang and his co-workers reported a highly diastereoselective formal [4+1] annulation of α-ylidene-β-diketones 292 with the alkyl

the annulation reaction. A possible mechanism that involves the nucleophilic attack of sulfur ylide 282 on o-quinone methide 280 and the trans-elimination-cyclization of intermediate 280A was postulated for the reaction.190 However, the reaction using the camphor-derived chiral sulfur ylide only produced moderate enantioselectivity. Considering the accessibility of 2-tosylalkylphenols 279, the high yields and chemo- and diastereoselectivity, and the mild conditions, this protocol can provide a new reliable entry to diversely substituted benzofurans. Recently, the same group developed an alternative method for the generation of ortho-quinone methides in situ from 2alkyl-substituted phenols by Ag2O-mediated oxidation, which also reacted with sulfur ylides for the easy synthesis of heavily functionalized trans-2,3-dihydrobenzofurans in a more direct and atom-economical manner.191 Similarly, sulfur ylides 282 can also react well with the 2-N-phenylsulfonyl aminobenzaldehydes and salicyaldehydes to furnish satisfactory yields of the corresponding 2,3-dihydroindoles and 2,3-dihydrobenzofurans, respectively.192 A similar formal [4+1] annulation between the o-quinone methides and the pyridinium ylides was also developed by Osyanin’s group to provide efficient access to the biologically and synthetically important 1,2dihydronaphtho[2,1-b]furans and 2,3-dihydrobenzofurans with excellent diastereoselectivity.193 In addition to the sulfur ylides, Osyanin and his co-workers recently discovered that potassium trinitromethanide can serve as a suitable 1,1-ambiphilic synthon to react with the quaternary ammonium salt-derived o-quinone methides in a formal [4+1] annulation manner and provide the

Scheme 107. Enantioselective Synthesis of 4-Hydroxypyrazolidines by the Aldehyde-Based α-Amination/Formal [4+1] Annulation Sequence

AE


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Scheme 108. Formal [4+1] Annulation between α,β-Unsaturated Ketenes and Esters and in Situ-Generated Ammonium Ylides

diazoacetates mediated by a catalytic amount of pyridine and Fe(Tcpp)Cl (Scheme 109).201 This catalytic system proved to

Scheme 110. PPh3-Catalyzed [4+1] Annulation between 2,3Butadienoates and 1,1-Bisnucleophiles

Scheme 109. Pyridine/Iron-Catalyzed Formal [4+1] Annulation of α-Ylidene-β-diketones and α,β-Unsaturated Imines with Diazoacetates

suggested for this reaction. Subsequently, Reddy and his coworkers demonstrated that the MBH acetates of the acetylenic aldehydes can serve as C4 synthons to undergo the K2CO3promoted formal [4+1] annulation reaction with various 1,1′bisnucleophilic agents (e.g., ethyl cyanoacetate, diethyl malonate, ethyl nitroacetate, and 1-nitropropane) for the synthesis of arylidene cyclopentenes, which involves a sequential allylic substitution and 5-exo-dig-carbocyclization.207 The development of the nucleophilic phosphine-catalyzed asymmetric formal [4+1] annulation with 2,3-butadienoate as the C4 synthon remains a challenging task for organic chemists. Given the synthetic and pharmaceutical importance of the pyrazolone scaffold, Lu and his co-workers recently disclosed that 5-pyrazolones 300 are suitable C1 synthons for participation in an enantioselective formal [4+1] annulation reaction with 2,3-butadienoates 297, using their own Lthreonine-derived phosphine 301 as the catalyst (Scheme 111a).208 Under optimal conditions, an extensive range of Ntert-butyl-protected pyrozolones 300 that bear various electrondonating or electron-withdrawing groups at the aryl moiety were tolerated to produce the corresponding enantioenriched 4-spiro-5-pyrazolones 302 in acceptable yields with high ee values. Fu’s group also disclosed a highly efficient formal [4+1] annulation between 2,3-butadienoate 297 and a series of activated one-carbon coupling components 303 using the new chiral biphenyl-derived phosphepines (R)-304 or (R)-305 as nucleophilic catalysts, which caused the formation of the corresponding cyclopentane derivatives 306 with relatively superior enantioselectivities (Scheme 111b).209 For both of these groups, the presence of water was deleterious to the reaction efficiency and enantioselectivities. In 2010, Zhang’s group independently reported another type of formal [4+1] annulation between conjugated yne-enones 307 and allylic carbonates 308, in which the key zwitterionic

be tolerant of an extensive array of α-ylidene-β-diketone substrates, which provided the corresponding tetrasubstituted trans-dihydrofurans 293 with excellent yields (85−96%) and diastereoselectivities (>50:1). This reaction was also extended to α,β-unsaturated imines to obtain the trans-dihydropyrrole derivatives 296 in high yields with >50/1 dr. A plausible mechanism that involves the sequential formation of iron carbenoid/pyridinium ylide and a formal [4+1] annulation was suggested. As compared to sulfur and nitrogen ylides, the in situgenerated phosphorus ylides have rarely been utilized in ylidebased cyclization reactions, particularly the formal [4+1] annulation due to the poor leaving ability of the phosphonium motif and their preference for the Wittig reaction. Recently, Lu, Kwon, and other researchers established that the nucleophilic phosphine can react with the 2,3-butadienoates to form versatile dipolar-type intermediates, which have been extensively employed in annulation reactions, such as the [3+2],202 [4+2],203 and [3+3]204 cycloadditions via an addition/ elimination process for the construction of various carbocycles and heterocycles.205 In 2010, Tong and his co-workers described a formal [4+1] annulation reaction between 2,3-butadienoates 297 and 1,1bisnucleophiles 298 catalyzed by PPh3 to provide a variety of densely functionalized cyclopentenes in moderate to excellent yields (Scheme 110).206 The reaction showed a high functional tolerance for the bisnucleophiles 298. The incorporation of an acetate substituent into the β′-position of 297 was critical in the reaction. A possible mechanism that involves the formation of electrophilic intermediate 297B via 297A and its subsequent [4+1] annulation with 1,1-bisnucleophilic 298A was also AF


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Scheme 111. Chiral Phosphine-Catalyzed Enantioselective Formal [4+1] Annulation between 2,3-Butadienoates and Pyrazolones

Scheme 112. PPh3-Catalyzed Formal [4+1] Annulation of Conjugated Yne-enones with Allylic Carbonates

Scheme 113. Enantioselective Formal [4+1] Annulation between Isatin-Derived α,β-Unsaturated Ketones and MBH Carbonates by Phosphine Catalysis

keto esters by Huang211 and was recently expanded to the 3acyl-2H-chromen-2-ones by Shi.212 Using a chiral binaphthyl framework-derived bifunctional thiourea-phosphine 312 as the organocatalyst, Shi and his coworkers have developed a highly enantioselective formal [4+1] annulation reaction between an extensive variety of activated α,β-unsaturated ketones 310 and MBH carbonates 311 (Scheme 113).213 The reaction exhibited a high functional group tolerance for both components and provided the

intermediate ylide 308A formed from PPh3 and allylic carbonates served as a one-carbon unit (Scheme 112).210 The reaction smoothly proceeded with a wide range of conjugated yne-enones 307 to furnish the corresponding tetra-substituted dihydrofurans 309 in satisfactory yields with excellent diastereoselectivities. Other types of enones also proved to be competent for this annulation reaction. For example, this [4+1] annulation strategy, which involves allylic carbonates 308 as the C1 synthons, was recently expanded to the β,γ-unsaturated αAG


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Scheme 114. Formal [4+1] Annulation between 4,4-Dicyano-2-methylenebut-3-enoates and Maleimides by Phosphine Catalysis

Scheme 115. Enantioselective [4+1] Annulation of α,β-Unsaturated Imines with Sulfur Ylides

deuterium-labeling experiments and successful isolation of the stable zwitterions 314A and 314A′ (R1 = 4-MeC6H4, R2 = Me), which were initially formed from tertiary phosphine and 314, implied that these species are possible intermediates for this [4+1] annulation. The use of chiral phosphine organocatalyst 317 only resulted in 11% ee. He’s group simultaneously observed a similar PPh3/PhCO2H-catalyzed [4+1] annulation between the 4,4-dicyano-2-methylenebut-3-enoates and the 1,3azadienes and maleimides.216

corresponding heavily functionalized and biologically important spirooxindole derivatives 313, which bear two adjacent quaternary carbon stereocenters with moderate yields and excellent enantioselectivities. Despite moderate diastereoselectivities, two diastereoisomers can be easily separated by simple column chromatography in the majority of cases. In addition, the same group also developed the first example of the organocatalytic asymmetric formal [4+1] annulation between the dicyano-2-methylenebut-3-enoates and the Morita−Baylis− Hillman acetates using chiral thiourea-phosphine as the catalyst to furnish the corresponding densely functionalized chiral cyclopentenes with one quaternary carbon stereocenter in acceptable yields with high enantioselectivities.214 In addition to the MBH carbonates, Shi’s group recently revealed that maleimides 315 can serve as the C1 synthon to undergo an interesting formal [4+1] annulation with 4,4dicyano-2-methylenebut-3-enoates 314 by nucleophilic phosphine catalysis (Scheme 114).215 Using 10 mol % of PPh3 as the organocatalyst in toluene at 60 °C, the reaction with various aryl and heteroaryl-substituted 4,4-dicyano-2-methylenebut-3enoates 314 and aryl or alkyl-bearing maleimides 315 smoothly proceeded to furnish the corresponding highly functionalized spirocyclic compounds 316 in generally acceptable yields. The

7.2. With Unsaturated Imines

Multisubstituted chiral pyrroline and its derivatives are frequently encountered in a significant number of biologically active natural products, synthesized pharmaceuticals, and asymmetric synthesis. Thus, the development of catalytic asymmetric methodologies for the synthesis of these compounds is important for organic and medicinal chemistry. As compared to the traditional [3+2] cycloaddition, Xiao’s group developed an enantioselective formal [4+1] annulation of α,βunsaturated imines 318 with stable chiral sulfur ylides 319 to provide efficient access to the optically active highly functionalized pyrrolines 320 with excellent yields (83−99%) and diastereo- and enantioselectivities(>95/5 dr, 82−98% ee) (Scheme 115).217 The products can also be easily transformed AH


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is derived in situ from phthalimide, to provide an efficient entry to the α,α′-disubstituted oxathioles with reasonable yields.226 The indole moiety is a privileged heterocyclic scaffold that is common to a large family of biologically active natural products and pharmaceuticals.227 Therefore, the search for more practical and efficient processes for the synthesis of the indole moiety remains a research area of considerable interest.228 As a continuation of their ongoing program toward the synthesis of biologically important carbo- and heterocycles,229 Xiao and his co-workers recently disclosed a cyclization reaction of N-(orthochloromethyl) aryl amides 327 with sulfur ylides 282 to provide the N-unsubstituted indoles 330 in consistently high yields (up to 95%) (Scheme 117).230 The related sulfonium salts can also

into important building blocks, such as the 4,5-disubstituted proline derivatives 321 and 322. The control experiments demonstrated that both electron-withdrawing groups, TIPBs and esters, are critical for guiding the reaction pathway ([4+1] vs [2+1]) by accelerating the Michael addition step and stabilizing the anionic enamine intermediate 318A.218 A possible transition state 318-TS was also proposed to rationalize the observed stereochemistry based on NMR studies. The formal [4+1] annulations of dimethylsulfoxonium methylide with α,β-unsaturated carboxamides and conjugated nitroso compounds have also been employed to prepare nonchiral pyrrolidones and isoxazolines, respectively.219 The chiral dihydropyrazoles represent another class of important five-membered aza-heterocycles due to their prevalence as core structures in natural products and pharmaceutical lead compounds. Their synthesis continues to be an interesting challenge in organic synthesis.220 Of the known methods, the catalytic enantioselective [3+2] cycloaddition has been identified as one of the most prominent protocols for the construction of these molecules.221 Inspired by the versatility of sulfur ylides as 1,1′-dipolar synthons in the cyclization reaction, Bolm and co-workers described an interesting copper(II)/(R)-BINAP-catalyzed enantioselective formal [4+1] annulation of azoalkenes 325,222 which was generated in situ from hydrazones 324, with stable sulfur ylides 282 (Scheme 116).223 The reaction tolerated a variety of

Scheme 117. Cascade Reaction between N-(orthoChloromethyl)aryl Amides and Sulfur Ylides

Scheme 116. Enantioselective [4+1] Annulation of in SituDerived Azoalkenes with Sulfur Ylides be directly utilized in a one-pot procedure with high yields when 6.0 equiv of Cs2CO3 is employed. The detailed mechanistic studies demonstrated that the reaction most likely proceeded via a formal [4+1] annulation between in situderived aza-o-quinodimethanes 328 and sulfur ylides 282 followed by an elimination/aromatization sequence.231 The mild reaction condition, operational simplicity, and immediate availability of the preliminary materials render make this strategy an attractive method for the synthesis of functionalized indole derivatives. This methodology was successfully extended to the enantioselective construction of indolines 329 using a reduced amount of Cs2CO3 and BINOL-derived chiral sulfur ylides (maximum 93% yield and 91% ee).232 The development of the asymmetric formal [4+1] annulation of the sulfur ylides by transition-metal catalysis remains an ambiguous and challenging task. Inspired by the extensive application of γ-methylidene-δ-valerolactones as four-atom units in Pd-catalyzed decarboxylative cycoadditions,164b,233 Xiao, Lu, and their co-workers recently disclosed the first example of the Pd(0)-catalyzed asymmetric decarboxylation/ cycloaddition of vinyl benzoxazinanones 331 with sulfur ylides 282, which formed the corresponding formal [4+1] annulation adducts, the biologically and synthetically important 3-vinyl indoline derivatives, in generally acceptable yields with excellent diastereo- and enantioselectivities (Scheme 118).234 The optimal mild conditions that involve the use of Pd2(dba)3· CHCl3/chiral phosphoramidite 332 as the catalyst in CHCl3 at −40 °C demonstrated a large scope and tolerance for an extensive range of functional groups for both partners. The extensive mechanistic studies suggested that the enantioselective trapping of in situ-generated Pd-stabilized zwitterionic intermediate 331A with nucleophilic sulfur ylide assisted by the electrostatic interaction was critical in the reaction. The vinyl moiety in the indoline products 333 enabled the installation of

hydrazones and sulfur ylides to produce the corresponding enantioenriched dihydropyrazoles 326 with high yields (84− 97%) and enantioselectivities (42−94% ee). A possible activation and stereoinduction mode 324-TS was proposed on the basis of previous related studies.224 This reaction represents the first example of this type and provides a platform for the design of other new catalytic asymmetric annulations of sulfur ylides, which form chiral five-membered ring systems. Recently, the Glorius group developed an interesting sequential N-heterocyclic carbene-catalyzed Stetter reaction of the enalderived acyl anion to the in situ-formed 1,2-diaza-1,3-dienes and the TsOH-mediated intramolecular cyclization, which furnished useful formal [4+1] annulation products, the styryl pyrazoles, in moderate yields with a high functional group tolerance.225 In addition to serving as the four-atom fragment, the highly active 1,2-diaza-1,3-dienes with electron-withdrawing groups can serve as the C1 fragment to participate in an unusual formal [4+1] annulation with α,α′-dioxothione, which AI


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Scheme 118. Pd-Catalyzed Asymmetric Formal [4+1] Annulation of Vinyl Benzoxazinanones with Sulfur Ylides

obtain intermediate 338B via a hydrogen transfer. Last, an intramolecular aza-Michael-type addition of intermediate 338B and the elimination of PPh3 produced the expected product 339. This PPh3-catalyzed formal [4+1] annulation strategy was also recently applied by the He group to the reaction between the highly activated dienes and allylic acetate for the immediate synthesis of the highly substituted and functionalized cyclopentenes.236 In addition to the 1,3-conjugated systems, functional molecules that bear electrophilic and nucleophilic sites can efficiently undergo annulation with sulfur ylides to obtain the diversely functionalized five-membered carbocyclic and heterocyclic compounds. For example, by fine-tuning the steric effect on the imines to control the kinetic preference, Huang and his co-workers developed a formal [4+1] annulation between salicyl N-thiophosphinyl imines 340 and sulfonium salts 281. The selection of the base and ylides was critical to the reaction because the reaction with the P- and N-based ylides produced no expected products. The reaction showed a large scope for the salicyl N-thiophosphinyl imines and sulfonium salts, which affords the corresponding trans-2,3-dihydrobenzofuran derivatives 341 in high yields with excellent chem- and diastereoselectivities (Scheme 120).237 The control experiments demonstrated that the steric hindrance between the bulky thiophosphinyl and the ester group accelerated the Oalkylation of intermediate 340A by averting its N-alkylation, which caused the preferential formation of the trans-enriched 2,3-disubstituted dihydrobenzofurans 341 over the aziridines 342. However, the asymmetric version of this reaction with (−)-methyl ester-derived sulfur ylide salt formed the cyclized product with low diastereo- and enantioselectivity. In 2013, Xiao’s group achieved an enantioselective formal [4+1] annulation of salicyl aldimines 343 with camphor-derived sulfonium salts 344, which facilitated the synthesis of trans-2,3dihydrobenzofurans 345 in moderate to excellent yields (29− 78%) with reasonable diastereo- and enantioselectivities (>95/5 dr, 21−98% ee) (Scheme 121).238 Modification of the reaction

various valuable functional groups using olefin cross metathesis (e.g., compounds 334 and 335) and transformations into structurally complex polycyclic indoline derivatives by the Pauson−Khand reaction or intramolecular cyclization (e.g., compounds 336 and 337). This interesting study presented a new method for the design of other synthetically useful formal [4+1] annulation reactions with the sulfur ylides by exploration of suitable and highly reactive metal-stabilized four-atom units. He’s group recently disclosed a phosphine-catalyzed formal [4+1] annulation of α,β-unsaturated imines 338 and allylic carbonates 308, which provide an efficient and highly diastereoselective approach to the multisubstituted 2-pyrrolines 339 (80−99% yield, >20:1 dr) (Scheme 119).235 The reaction Scheme 119. PPh3-Catalyzed Formal [4+1] Annulation of α,β-Unsaturated Imines with Allylic Carbonates

tolerated an extensive array of (hetero) aryl-substituted imines 338 with various electronic properties and substitution patterns. A possible pathway was also proposed for this reaction. First, a sequential addition/elimination/deprotonation between PPh3 and allylic carbonate 308 resulted in the allylic phosphorus ylides 308A or 308B. Second, the γ-carbanion addition of intermediate 308A to 1,3-azadiene 338 furnished intermediate 338A, which can easily undergo isomerization to AJ


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Scheme 120. Domino Annulation between the NThiophosphinyl Imines and Sulfur Ylides

Scheme 122. Domino Aza-MBH/Umpolung Addition Reaction: Formal [4+1] Annulation of Salicyl NThiophosphinyl Imines with Allenic Esters

aromatic imines 346 and produced the expected and heavily functionalized trans-2,3-dihydrobenzofurans 350 with high yields (72−99%) and diastereoselectivities (up to 97/3). The sterically hindered allylic carbonates can also be successfully utilized in the reaction. However, the development of an asymmetric version of this type remains an attractive but challenging task.

parameters, such as high temperature and microwave irradiation, has also been utilized to change the kinetic preference for the transformations of the sulfur ylides to synthesize 2,3-disubstituted dihydrobenzofuran derivatives.239 Analogous to the sulfur ylides, the 2-halo-1,3-dicarbonyl compounds can also undergo a formal [4+1] annulation with salicylic aldehyde derivatives, such as the 2-hydroxyaryl-α,βunsaturated ketones, 2-hydroxyarylnitroalkenes, and 2-hydroxyarylimines, with K2CO3 as the base, to produce a range of highly functionalized 2,3-dihydrobenzofurans with moderate to excellent yields.240 The phosphine ylide, which is generated by the reaction of the nucleophilic phosphine with the electron-deficient allene, can also serve as a versatile 1,1-dipolar C1 fragment in a formal [4+1] annulation. For example, Huang and his co-workers have described a bifunctional phosphine LBBA-catalyzed formal [4+1] annulation reaction of salicyl N-thiophosphinyl imines 346 and allenic esters 347 (Scheme 122).241 Various electronwithdrawing and electron-donating groups were well tolerated at the aromatic ring of the imines, which resulted in the corresponding 2,3-dihydrobenzofurans 349 in generally high yields (65−95%) with excellent cis-selectivities. The reaction using other Lewis bases, such as PPh3, nBu3P, or DABCO, produced poor results. A possible reaction mechanism that involves the aza-MBH/proton transfer/umpolung addition sequence, in which the H-bonding interaction between the hydroxy of the LBBA catalyst and the nitrogen of the imine proved to be critical for the preferential formation of the cisisomers, was also proposed (Scheme 123). The allylic phosphine ylides of type 311A, which were formed from allylic derivatives 311 and PPh3 via the addition/ elimination/deprotonation, were also recently discovered by Huang’s group to smoothly react with salicyl N-thiophosphinyl imines 346 in a formal [4+1] annulation (Scheme 124).242 The authors documented that the reaction with 5 mol % of PPh3 as the catalyst in refluxing toluene displayed a large scope for

7.3. With Nitroolefins

The isoxazoline N-oxides and their derivatives comprise a class of useful building blocks with numerous applications in the synthesis of biologically active molecules243 and naturally occurring products.244 Therefore, the development of efficient protocols for their practical and asymmetric synthesis has attracted considerable interest. Although the annulation reaction of the sulfur ylides with nitroolefins245 has been previously established as one of the most powerful methods for their synthesis, the enantioselective versions with a large substrate generality remain limited.246 In 2008, Tang and his co-workers described a highly enantioselective [4+1] annulation of cinchonidine (cinchonine)-derived ammonium salts 351a and 2-substituted nitroolefins 350 using Cs2CO3 as the base in THF at 0 °C (Scheme 125).247 The reaction exhibited a broad generality, and a variety of β-aryl, β-heteroaryl, and β-alkyl nitroolefins were well tolerated, which resulted in the corresponding products isoxazoline N-oxides 352 with consistently acceptable yields and excellent diastereo- and enantioselectivities. In contrast to Gaunt and Ley’s study,248 the possible formation of the cyclopropanes was not observed in this reaction. The same reaction with cinchonine-derived salt 351b afforded the opposite enantiomer of the product with 99% ee. Considering the immediate availability of these cinchonidine and cinchonine-derived ammonium salts, this strategy offers significant application in the synthesis of optically active isoxazoline N-oxides, whereas the catalytic version requires additional efforts. Gaunt and Ley also disclosed that the dimethylsulfonium salt can undergo a formal [4+1] annulation

Scheme 121. Asymmetric Formal [4+1] Annulation of the Aldimines with Camphor-Derived Sulfonium Salts

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Scheme 124. Formal [4+1] Annulation of Salicyl N-Thiophosphinyl Imines 346 with Allylic Carbonates 311

Scheme 125. Formal [4+1] Annulation of Ammonium Salts with Nitroolefins: Enantioselective Synthesis of Optically Active Isoxazoline-N-oxides

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Scheme 126. Formal Total Synthesis of Dehydroclausenamide

Scheme 127. Cascade [4+1] Annulation/Rearrangement Reaction between Nitroolefins and Stable Sulfur Ylides

Scheme 128. Elaboration of Oxazolidin-2-one and the Total Synthesis of (±)-epi-Cytoxazone

with nitroolefins to generate isoxazoline N-oxides in acceptable yields but with low diastereo- and enantioselectivities.249 Dehydroclausenamide 357, which is isolated from the Chinese folk medicine Clausena lansium, has been identified as a potentially hepatoprotective amide.250 On the basis of their success on the formal [4+1] annulations of ammonium salts and 2-nitroolefins, Tang and his co-workers achieved the synthesis of key intermediate 356 in a highly enantioselective manner using the product isoxazoline N-oxide 352a as the main preliminary material, which can be conveniently employed for the formal total synthesis of dehydroclausenamide 357 (Scheme 126).249,251 Inspired by the versatile reactivity and synthetic utility of the sulfur ylides and nitroolefins,243 Xiao and his co-workers developed an unprecedented cascade [4+1] annulation/

rearrangement reaction between nitroolefins 357 and stable sulfur ylides 282, which were sequentially promoted by 1-(2chlorophenyl)thiourea and N,N′-dimethyalaminopyridine (DMAP) to afford the unexpected oxazolindin-2-ones 359 in generally satisfactory yields with excellent diastereoselectivities (Scheme 127).252 The separate use of thiourea or DMAP resulted in trace amounts of the desired product. Under optimal conditions, an extensive range of aromatic and aliphatic nitroolefins with various substituents and substitution patterns smoothly participated in the reaction. This reaction proved to be suitable for the diversely functionalized stable sulfur ylides, and the corresponding oxazolindin-2-ones were obtained with high yields and stereoselectivity. On the basis of the successful trapping of the formal [4+1] annulation product 358A with ethyl acrylate and the D- and 13C-labeling experimental results, AM


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methodology was also demonstrated by the concise synthesis of natural products, (+)-epi-cytoxazone 362 and the core structure of valinoctin A 364. A stereoinduction model via hydrogen-bonding synergistic catalysis has also been proposed for the reaction. This study presented a new method for the development of asymmetric cycloaddition reactions that involved sulfur ylides. On the basis of the mechanistic studies of the sulfur ylidebased cyclization reactions,252 Xiao and his co-workers finetuned a formal [4+1]/[3+2] cycloaddition cascade reaction between alkene-tethered β-nitroolefins 365 and stable sulfur ylides 282 without the addition of any catalyst (Scheme 130).254 The reaction enabled the efficient construction of various highly functionalized and fused heterocyclic systems 366 with excellent yields (75−99%) and stereoselectivities (>95/5 dr). Four new bonds, three rings, and five consecutive stereocenters, including one quaternary carbon center, were formed in the reaction. Simple synthetic manipulation of the products produced a high yield of the pyrroline-fused corresponding chroman derivatives. Encouraged by this achievement, Xiao and his co-workers continued to develop an enantioselective version of this cascade reaction using the (R)-BINOL-derived chiral sulfur ylides 319 based on the axialto-central chirality strategy.255 This enantioselective reaction also demonstrated a high functional tolerance, and the optically active products 366 with moderate to excellent diastereo- and enantioselectivities were obtained in high yields. Notably, >90% of the axially chiral sulfide were easily recovered after the reaction. Recently, this concept was successfully extended to the formal [4+1]/[3+2] cycloaddition cascade of α-acrylatetethered β-nitroolefins with BINOL-derived chiral sulfur ylides. The BINOL scaffold exhibited high levels of asymmetric induction and reaction efficiency (70−91% yield; >95/5 dr; 86−94% ee).256 In 2010, Shi’s group developed a Lewis base-catalyzed asymmetric formal [4+1] annulation of nitro-substituted dienes 369, which was generated in situ from nitroolefins and aldehydes, with chiral sulfonium salt 277 to provide efficient access to the heavily substituted isoxazoline N-oxides with high yields and excellent chemo- and enantioselectivities (Scheme 131).257 An extensive structural modification of the chiral auxiliaries determined camphor-derived sulfonium salt 277 as the best choice in terms of stereochemistry control. By

a possible mechanism that involves sequential acid catalysis and base catalysis was postulated for the reaction. The main intermediate isoxazoline N-oxide 358A was initially formed via the [4+1] annulation of nitroolefin 358 and stable sulfur ylide 282 catalyzed by thiourea. Then, intermediate oxaziridine 358B, which was reversibly formed from 358A, underwent a DMAP-catalyzed deprotonation/ring opening/Hofmann rearrangement sequence to form isocyanate 358F. An intramolecular ring closing of 358F and protonation formed the desired products 359 and released the DMAP for the next catalytic cycle. Oxazolidin-2-one can also be efficiently transformed into useful building blocks, such as 1,2-amino alcohol 360 and αhydroxy-β-amino acid 361, by routine manipulation. A sequential Baeyer−Villiger oxidation and reduction of 359a provided the natural product (±)-epi-cytoxazone 362 with a 55% total yield (Scheme 128). Subsequently, Xiao’s group developed a catalytic variant of the formal [4+1] annulation/rearrangement cascade reaction of nitroolefins 358 and stable sulfur ylides 282 using the C2symmetric hydrogen-bonding urea catalyst 363. The reaction facilitated moderate (65−96%) yields of optically active 4,5disubstituted oxazolidinones 359 with moderate to high diastereo- and enantioselectivities (maximum 95:5 dr and 94% ee) (Scheme 129).253 The synthetic utility of this Scheme 129. H-Bonding Promoted Enantioselective Formal [4+1] Annulation/Rearrangement Cascade Reaction of Nitroolefins with Stable Sulfur Ylides

Scheme 130. Formal [4+1]/[3+2] Cycloaddition Cascade Reaction of Stable Sulfur Ylides with Nitroolefins

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Scheme 131. Enantioselective Synthesis of Highly Functionalized Isoxazoline-N-oxides

Scheme 132. Gram-Scale Synthesis of Clausenamide Derivative

efficiently undergo the 1,3-dipolar cycloaddition with the electron-deficient alkene and alkyne dipolarophiles to form nitroso acetals that bear three fused ring systems in acceptable yields with moderate diastereoselectivities. Inspired by Sun and Yu’s study,258 Liu’s group successfully extended this type of [4+1] annulation to sulfur ylides 282. Conversely, Liu’s group determined that the reaction between the 2-nitroglycals and sulfur ylides efficiently proceeded via a [4+1] annulation/rearrangement cascade using 1-phenylthiourea as the catalyst, which resulted in isoxazolines 377 in high yields with excellent diastereoselectivities (Scheme 134).259 The major R-isomer isoxazoline 377 was formed via the ring opening of the isoxazoline N-oxide 374B, which was formed from isoxazoline N-oxide 374A by keto−enol tautomerization,

combining pyrrolidine and Cs2CO3, a vast range of nitroolefins were well tolerated in the reaction with minimal influence on the reaction efficiency and enantioselectivity. The reactions with electron-poor aldehydes typically produced the products in excellent yields with slightly decreased enantioselectivities. Sterically hindered aldehydes resulted in superior yields and stereoselectivities due to the improved spatial control in the transition state. The camphor auxiliary can be easily recovered during the purification step. This methodology was successfully applied toward the gram-scale synthesis of the natural product 3-ent-6-ent-Clausenamide 373 with an all-cis-substitution pattern on the γ-lactam ring, which is one of the most challenging isomers in the family of Clausenamide (Scheme 132). Bromomalonate has been shown to exhibit a reactivity profile that is similar to the reactivity profile of sulfur ylide in the cyclization reaction with nitroolefins. For example, Sun, Yu, and their co-workers noted that 2-nitroglycals smoothly reacted with bromomalonate in a [4+1] annulation manner in the presence of 1.2 equiv of DBU in CH2Cl2, which resulted in the corresponding sugar-fused isoxazoline N-oxides with acceptable yields (54−98%) (Scheme 133).258 The resulting N-oxides can

Scheme 134. Formal [4+1] Annulation/Rearrangement Cascade between the 2-Nitroglycals and Sulfur Ylides

Scheme 133. Formal [4+1] Condensation between 2Nitroglycals and Bromomalonates

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and the O-hemiacetalization of 374C. The reaction also showed highly functional tolerance for the sulfur ylide components. Despite these impressive advances, general approaches for the efficient synthesis of chiral isoxazoline-N-oxides based on the catalytic enantioselective formal [4+1] annulation strategy remain relatively rare. The 2-halo-1,3-dicarbonyl compounds, such as bromomalonate 375b, have been recently proven by Maruoka’s group to be suitable C1 fragments in the catalytic asymmetric formal [4+1] annulation with nitroolefins 378 in phase-transfer catalysis, which is composed of a conjugate addition and ring-closing O-alkylation (Scheme 135).260 The

ratio). The (hetero) aryl-substituted MBH carbonates resulted in a cis-selectivity in the majority of cases.

8. MISCELLANEOUS FORMAL [4+1] ANNULATION In addition to the previously described [4+1] annulation using CO, nucleophilic carbenes, diazo reagents, isocyanides, and ylides, the use of other C1 synthons for the construction of structurally diverse five-membered carbo- and heterocycles is summarized in this section by different catalytic modes. The vinylcyclopropane rearrangement that involves cyclopropanation of the dienes and a sequential rearrangement, a total formal [4+1] annulation, has also provided another powerful approach to the highly functionalized cyclopentene derivatives. Several excellent reviews by Hudlicky in 1989 and 2010 and other researchers have extensively compiled the important advances in this active area.13 Therefore, only certain recent studies on this topic are discussed in this section.

Scheme 135. Catalytic Enantioselective Formal [4+1] Annulation between Nitroolefins and Bromomalonate by Phase-Transfer Catalysis

8.1. Transition Metal-Catalyzed Formal [4+1] Annulation

Transition metal-catalyzed cycloisomerization and cycloaddition represents a useful and efficient method for the assembly of biologically active and structurally complex carbocyclic and heterocyclic compounds from readily available preliminary materials.263 In this field, the formal [4+1] cycloaddition of the four-atom fragment with one-atom synthons has emerged as an attractive method for the synthesis of five-membered heterocycles. Impressive advances have been achieved over the past decade; they are surveyed in this section. 8.1.1. Alkynes-Based Formal [4+1] Annulation. The transition metal-catalyzed alkylidenation of the four-atom fragment with alkynes provides an efficient entry to fivemembered molecular frameworks. Liebeskin reported the first example of a formal [4+1] annulation of cobaltacyclopentenedione with terminal alkynes for the formation of 5-alkylidene cyclopentenediones with moderate to excellent yields, which introduced a new use of alkynes as one-carbon synthons in cycloaddition reactions264 Recently, Matsubara and Kurahashi’s group noted a Ni(0)/PMe3/MAD-catalyzed decarbonylation/ alkylidenation sequence between phthalimides 383 and TMSsubstituted alkynes 384, which affords the corresponding formal [4+1] annulation products, isoindolinones 385, with moderate yields (Scheme 137).265 Notably, it was found that the silyl group of the alkynes and the Lewis acid MAD are critical for the reaction efficiency and excellent chemoselectivity. The catalytic cycle of the reaction was proposed to involve the initial formation of nickelacycle 383A by MADassisted oxidative addition and the coordination of alkyne 384. The nickel vinylidene complex 383C, which was via a [1,2]-silyl

mild reaction conditions with the C 2-symmetric chiral quaternary ammonium salt 379 as the catalyst accommodated a variety of functional groups with respect to nitroolefins 378 and furnished the corresponding enantioenriched isoxazolineN-oxides with satisfactory yields and enantiomeric excess. These products can be conveniently transformed into highly substituted oximes, isoxazolines, and lactams with no loss of enantiomeric purity. Subsequently, Xie, Zhu, and their coworkers disclosed that the Morita−Baylis−Hillman adducts derived from the nitroolefins can also undergo quinidinecatalyzed formal [4+1] annulation with the 2-halo-1,3dicarbonyl compounds to yield densely functionalized isoxazoline N-oxides in a highly diastereo- and enantioselective manner.261 Recently, He and his co-workers disclosed that the allylic phosphorus ylides 311A, which were generated in situ from MBH carbonates 311 and phosphane, can serve as dipolar C1 synthons to participate in the formal [4+1] annulation with nitroalkenes 381 under mild conditions (Scheme 136).262 The reaction demonstrated a high functional tolerance and a large scope for both components, and acceptable yields of the corresponding densely substituted isoxazoline N-oxides were obtained with high diastereoselectivities (up to 20:1 trans/cis

Scheme 136. Catalyzed Formal [4+1] Annulation of the Nitroolefins with the MBH Carbonates by Nucleophilic Phosphane Catalysis

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compounds, Cossy, Meyer, and their co-workers recently developed a copper-free sequential Sonogashira coupling/5exo-dig cyclization of cis-2-iodocyclopropanecarboxamides 389 with terminal alkynes or enynes 386, in which the alkynes contributed as C1 synthons (Scheme 139).267 The reaction tolerated an extensive variety of N-substituents of 389 and terminal aryl and heteroaryl alkynes 386 to afford the corresponding formal [4+1] adducts, 4-methylene-3-azabicyclo [3.1.0.] hexan-2-ones 390, with generally high yields. The enamide moieties in the products 390 can undergo a further Pictet−Spengler cyclization and ionic hydrogenation to provide structurally complex polycyclic and bicyclic systems.268 Subsequently, Nájera and Alonso’s group noted a similar Pdcatalyzed copper-free tandem Sonogashira coupling/hydroalkoxylation between 2-bromo- or chlorobenzylic alcohols and terminal alkynes in microwave irradiation, which provide efficient access to dihydroisobenzofurans.269 In contrast to Cossy and Meyer’s strategy, Kwon developed a sequential oxo-Michael addition/intramolecular Heck cyclization of o-iodobenzyl alcohols 391 with activated acetylenes 392 (Scheme 140).270 The multicatalytic system, which is

Scheme 137. Nickel-Catalyzed Decarbonylation/ Alkylidenation of Phthalimides with Alkynes

shift of intermediate 383B, underwent a vinylidene insertion and reductive elimination to form the final products 385. The β-TMS-substituted α,β-unsaturated imines 387 also underwent a rhodium(I)-catalyzed formal [4+1] cycloaddition reaction with terminal alkynes 386, which resulted in the corresponding diversely functionalized pyrrole derivatives 388 in moderate to excellent yields (Scheme 138).266 The reaction

Scheme 140. Phosphine/Palladium Sequentially Catalyzed Oxo-Michael Addition/Heck Cyclization between oIodobenzyl Alcohols and Acetylenes

Scheme 138. Rh(I)-Catalyzed Formal [4+1] Annulation between α,β-Unsaturated Imines and Terminal Alkynes

composed of PPh3 and Pd(OAc)2, tolerated a large spectrum of o-iodobenzyl alcohols and acetylenes to furnish the formal [4+1] cycloadducts and the highly substituted and functionalized (Z)-alkylidene phthalans 394, with moderate to excellent yields. The synthetic potential of this methodology has also been demonstrated in the concise total synthesis of certain natural fungal metabolites, such as 3-deoxyisoochracinic acid 395, isoochracinic acid 396, and isoochracinol 397, by routine manipulations (Scheme 141). Recently, You’s group disclosed the first example of a single copper-promoted formal [4+1] annulation that involves the sequential oxidative alkynylation/intramolecular cyclization between the N-(quinolin-8-yl) benzamides and terminal alkynes (Scheme 142).271 Although the 8-aminoquinoline moiety was required for the desired transformation, the simple

was considered to proceed through the initial formation of rhodium vinylidene complex 386A as a critical intermediate, followed by a sequential nucleophilic addition of imine/ cyclization/elimination to produce the corresponding products after desilylation or isomerization. The TMS group of the α,βunsaturated imine also proved to be essential for the reaction by preventing the formation of the undesired pyridines. Similarly, the in situ generated highly reactive chlorocarbenes can react with the 1-azabuta-1,3-dienes in a formal [4+1] annulation manner to form the highly substituted pyrrole derivatives.73 The diversely functionalized 3-azabicyclo [3.1.0] hexanes are frequently detected in numerous biologically active compounds and pharmaceutical drug candidates. For the synthesis of these

Scheme 139. Pd(II)-Catalyzed Copper-Free Sequential Sonogashira Coupling/5-Exo-dig Cyclization of cis-2Iodocyclopropanecarboxamides with Terminal Alkynes

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Scheme 141. Synthesis of 3-Deoxyisoochracinic Acid, Isoochracinic Acid, and Isoochracinol

and styrene 401 catalyzed by the Pd(OAc)2/Cu(OAc)2 system, which renders formal [4+1] cycloadducts, phthalide derivatives 402 or 403, in moderate to excellent yields (Scheme 143).273 The intramolecular cyclization may proceed via an oxidative Wacker-type cyclization or nucleophilic addition. Miura and Satoh also demonstrated that the Rh/Cu catalyst in air can efficiently catalyze a similar oxidative cross coupling/cyclization reaction.274 The substrate scope of this methodology has been successfully extended to the substituted acrylic acids for the preparation of the biologically interesting butenolide derivatives using Rh/Ag2CO3 as the catalytic system.275 Since these pioneering studies were performed, a series of transition metal-catalyzed and carboxylic acid-directed oxidative C−H bond alkenylation/cyclization reactions have been developed. For example, a Ru(II)-catalyzed sequential oxidative alkenylation/cyclization reaction of benzoic acids 404 and electron-poor alkenes 405 was initially developed by Ackermann’s group using water as the environmentally friendly and nontoxic medium and Cu(OAc)2 as the oxidant (Scheme 144).276 The catalytic system exhibited a high functional

Scheme 142. Copper-Mediated Formal [4+1] Annulation between N-(Quinolin-8-yl) Benzamides and Terminal Alkynes

reaction system has demonstrated a large scope for both partners and a high functional group tolerance, which provides an alternative and simple approach to the biologically important 3-methyleneisoindolin-1-one derivatives. 8.1.2. Alkenes-Based Formal [4+1] Annulation. Over the past decade, transition metal complex-promoted direct C− H bond activation/functionalization has emerged as one of the most powerful strategies for the construction of various complex frameworks.42 Particularly, the rational use of the appropriate directing groups and the subsequent transformations of these directing groups have provided a stepeconomic and operationally simple approach to an extensive variety of carbocycles and heterocycles.272 Therefore, recent advances in the application of this strategy to the assembly of structurally diverse five-membered carbocycles and heterocycles are discussed in this subsection according to the different directing groups. In 1998, Miura and his co-workers indicated that a number of benzoic and naphthoic acids 400 can undergo sequential crosscoupling/intramolecular cyclization with butyl acrylate ester

Scheme 144. Ru(II)-Catalyzed Oxidative C−H Alkenylation/Cyclization of Benzoic Acids with Alkenes

Scheme 143. Oxidative Coupling/Cyclization between Aromatic Carboxylic Acids and Alkenes

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Scheme 145. Transition Metal-Catalyzed Oxidative C−H Bond Alkenylation/Intramolecular Cyclization of Amides with Alkenes

bond alkenylation/aza-Michael addition of benzamides or heteroaryl carboxamides with electron-poor alkenes to obtain moderate yields of γ-lactams 410 (Scheme 145b).282 The Pd(II)-catalyzed C−H olefination/annulation strategy was successfully and independently extended to the N-acylsulfonamides and N-alkoxybenzamides by Zhu283 (Scheme 145c) and Booker-Milburn49 (Scheme 145d) for the efficient synthesis of isoindolinones 413 and alkylidene isoindolinones 415. Recently, Lee and co-workers discovered that arylphosphonic acid monoethyl esters, phosphonamides, and phosphinamides can undergo the Rh-catalyzed sequential oxidative C−H alkenylation/intramolecular Michael addition with various electron-deficient olefins to provide an extensive range of biologically important benzoxaphosphole 1-oxides and phosphaisoquinoli-1-oxides in moderate to excellent yields.284 A similar Rh(III)-catalyzed tandem oxidative alkenylation/cyclization reaction of the N-benzyltriflamides with n-butyl acrylate and related α,β-unsaturated systems has been developed by Kim’s group to synthesize the corresponding formal [4+1] products, the differently substituted isoindolines, in moderate to high yields.285 This strategy with the Rh(III)-catalyzed tandem oxidative alkenylation/cyclization was also recently extended to an extensive range of picolinamides and activated alkenes by Xi’s group, which resulted in the formal [4+1] annulation products, the pyrido pyrrolone derivatives, in satisfactory yields with excellent regioselectivity and stereoselectivity.286 Cui’s group recently disclosed an interesting Rh(III)-catalyzed formal [4+1] annulation between Nmethyoxy-1H-indole-1-carboxamide and 4-hydroxyphenylboronic acid, which obtained a moderate yield of the corresponding spiro-cyclohexadienone.287 Among these examples, the directing groups not only assisted the coordination of the transition metal for the C−H activation but also participated in the subsequent annulation procedure, which highlights the step- and atom-economic features of these methodologies. In addition to the tandem C−H functionalization/annulation strategy, the Pd-catalyzed aza-Wacker reaction/conjugate addition of bisnucleophiles with electron-deficient alkenes

tolerance and a large scope with respect to the benzoic acids. A large variety of diversely substituted benzoic acids demonstrated a superior reaction with the acrylic acid esters and acrylonitrile to obtain the biologically and synthetically valuable phthalide derivatives 406 in generally high yields. A possible reaction pathway that involves the sequential cross C−H alkenylation/intramolecular oxa-Michael addition was also proposed on the basis of isotopic labeling experiments. Satoh, Miura, and their co-workers have independently revealed a single example of the Ru(II)-catalyzed formal [4+1] annulation, which involves the oxidative C−H alkenylation of benzanilide and an aza-Michael addition for the bicyclic benzamide synthesis.277 This group successfully expanded this strategy to the rhodium- and ruthenium-catalyzed one-pot sequential ortho-alkenylation/cyclization of α,α-disubstituted benzylamines with acrylates to form the corresponding formal [4+1] annulation products, (isoindol-1-yl)acetic acid derivatives, in moderate to high yields.278 The reaction represents an example of a free amino group that functions as a directing group for C−H activation and regioselective control. Subsequently, the groups of Ackermann and Li independently disclosed the Ru(II)- and Rh(III)-catalyzed sequential oxidative ortho C−H alkenylation and intramolecular aza-Michael addition between the sulfonamides and acrylates, which formed the corresponding [4+1] annulation products, the biologically important sultams, in generally acceptable yields.279 Wang and his co-workers recently disclosed that the combination of [Ru(p-cymene)Cl2]2 with Cu(OAc)2 enabled an efficient tandem decarboxylative divinylation/cyclization between 2hydroxy-2-phenylacetic acid and the acrylates to furnish the corresponding phthalide derivatives in moderate to excellent yields.280 Analogous to the carboxylic acids, Yu and his co-workers noted that aliphatic carboxylic acid-derived amides can undergo the Pd(II)-catalyzed sp3 C−H bond alkenylation/1,4-conjugate addition with benzyl acrylate, which affords the corresponding densely functionalized lactam products 408 with consistently acceptable yields (Scheme 145a).281 In contrast to Yu’s study, Li’s group developed a Rh(III)-catalyzed oxidative aryl C−H AS


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facilitated the entry to the five-membered heterocycles. For example, Booker-Milburn, Lloyd-Jones, and their co-workers noted that the Ts- or Boc-protected aminoalcohol or diamine nucleophiles 416 can undergo the Pd-catalyzed aza-Wacker reaction and an off-cycle conjugate addition with the monosubstituted electron-deficient alkenes 417 (Scheme 146).288 The reaction afforded the formal [4+1] annulation products, the saturated oxazolidine and imidazolidine derivatives, with moderate to excellent yields.


Scheme 146. Pd-Catalyzed Aza-Wacker Reaction/ Cyclization of Aminoalcohols and Diamines with Alkenes

8.1.3. Methylenecyclopropanes-Based Formal [4+1] Annulation. Methylenecyclopropanes (MCPs) represent a class of unique synthetic building blocks that can undergo a range of cycloadditions due to their high ring strain energy of cyclopropane.289 In 2011, Matsubara, Kurahashi, and their coworkers disclosed the first example of a nickel-catalyzed formal [4+1] annulation of enones with methylenecyclopropanes to produce the corresponding highly substituted dihydrofurans 421 with moderate to excellent yields and diastereoselectivity (Scheme 147).290 The reaction demonstrated a large scope for the methylenecyclopropanes and the enones. On the basis of the deuterium labeling experiments, a possible mechanism was also proposed for the reaction (Scheme 148). The initial oxidative addition of nickel to the enone formed oxa-nickelacycle 419A and the subsequent insertion of methylenecyclopropane 420 and a ring expansion furnished the eight-membered oxa-nickelacycle 419C. The nickel-hydride intermediate 419D, which was generated by the β-hydride elimination of intermediate 419C, then underwent an intramolecular cyclization with the terminal olefin to afford the more stable six-membered nickelacycle 419E. A final reductive elimination produced the final formal [4+1] cycloadduct 421 with the regeneration of the Ni(0) species. They also noted that the nickel catalyst can catalyze the formal [4+1] annulation between the thiophthalic anhydrides and the methylenecyclopropanes for the efficient synthesis of the thiophthalides, in which the methylenecyclopropanes also served as C1 synthons.291 In addition, the methylenecyclopropanes can serve as four-carbon fragments to participate in the formal [4+1] cycloaddition. For example, Shi and his coworkers have demonstrated that a catalytic system composed of Au(PPh3)Cl and AgOTf can efficiently catalyze the ring-

opening/ring-closing sequence of the methylenecyclopropanes with the sulfonamides to afford the formal [4+1] cycloadducts, the pyrrolidine derivatives, with reasonable yields.292 Recently, Echavarren and his co-workers revealed that the highly reactive gold(I) carbenes 422A, which were generated in situ by the Au(I)-catalyzed retro-Buchner reaction from 7substituted 1,3,5-cycloheptatrienes 422, can serve as suitable C1 synthons to react with the methylenecyclopropanes 423 in a formal [4+1] annulation manner (Scheme 149).293 The standard conditions exhibited a large substrate scope for the 7-substituted 1,3,5-cycloheptatrienes and the methylenecyclopropanes with moderate to excellent yields of the corresponding substituted cyclopentenes 424. On the basis of the control experiments and deuterium labeling, it was postulated that the methylenecyclopropanes were initially isomerized into cyclobutenes 423A via gold(I) catalysis. These intermediates underwent a sequential cyclopropanation with gold(I) carbenes 422A and a ring-opening to form the final products. This strategy was directly applied to a diverse set of di- and trisubstituted cyclobutenes as C4 synthons. 8.1.4. Aldehydes and Ketones-Based Formal [4+1] Annulation. Recently, the combination of transition metalcatalyzed and directing group-assisted C−H activation/ acylation with an intramolecular cyclization has proven to be a powerful protocol for the synthesis of heterocyclic compounds from the readily accessible starting materials. Kim’s group was the first group to develop a sequential Rh(III)-catalyzed oxidative aryl C−H bond acylation/intramolecular cyclization between secondary benzamides 427 and aromatic aldehydes 368 (Scheme 150).294 Common functional groups, such as CO2Me, COMe, F, Cl, Br, and CN, were well

Scheme 147. Ni-Catalyzed Formal [4+1] Annulation of Enones with Methylenecyclopropanes

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Scheme 149. Au(I)-Catalyzed Formal [4+1] Annulation between 7-Substituted 1,3,5-Cycloheptatrienes and Methylenecyclopropanes

Scheme 150. Rh(III)-Catalyzed Oxidative C−H Acylation/ Intramolecular Cyclization between Benzamides and Aldehydes

Scheme 151. Rh(III)-Catalyzed Formal [4+1] Annulation between Azobenzenes and Aldehydes

tolerated with respect to the benzamides and aldehydes, which result in the corresponding biologically significant 3-hydroxyisoindolin-1-ones 428 with generally moderate yields. In contrast to Kim’s study, Zhao, Huang, and their co-workers discovered that a catalytic amount of Pd(OAc) 2 and inexpensive TBHP can efficiently catalyze the C−H functionalization/annulation reaction of N-alkoxy or N-alkyl-substituted benzamides with aliphatic and aromatic aldehydes to produce the diversely functionalized 3-hydroxyisoindolin-1-ones in moderate to excellent yields. The high reaction efficiency, mild conditions, and large scope rendered this strategy as an attractive method for organic and medicinal chemists.295 In addition to the amide group, the azo group has been identified as a competent directing group for Rh(III) or Pd(II)catalyzed C−H activation/cyclization. For example, Ellman, Lavis, and their co-workers recently reported a Rh(III)catalyzed tandem C−H bond functionalization/intramolecular cyclization/aromatization of azobenzenes 429 with aldehydes 368 (Scheme 151).296 The reaction was considered to proceed through the formation of alcohols 429B and an intramolecular nucleophilic substitution as the main steps. A diverse range of azobenzenes and aldehydes were well tolerated to form the formal [4+1] annulation products, the pharmaceutically significant N-aryl-2H-indazoles 430, in satisfactory yields. Additional oxidative cleavage of the N-4-hydroxy-3,5-dimethylphenyl group with ceric ammonium afforded generally satisfactory yields of the N-free indazoles 431. A two-step procedure for the indazole synthesis that begins with the azobenzenes and the aldehydes in a formal [4+1] annulation manner by the combination of Pd(OAc)2/TBHP and Zn/ NH4Cl has been independently developed by Wang’s research group.297 Recently, Ellman’s group disclosed a BF3·Et2O-

catalyzed sequential umpolung addition of the glyoxylates to the oxygen of the nitrosoarenes and a Friedel−Crafts cyclization/aromatization, which rendered the formal [4+1] annulation products, the valuable 2,1-benzisoxazoles, in moderate to excellent yields.298 Using the strategy of the transition-metal-catalyzed C−H activation/annulation, Zhao’s group developed the first example of a Pd(II)-catalyzed formal [4+1] annulation of Nphenoxyacetamides 432 with aldehydes 368, in which the O−N functionality served as a directing group for the C−H activation step (Scheme 152).299 The standard conditions, which consist of Pd(TFA)2 (10 mol %) and TBHP (2.5 equiv) in t-AmOH, exhibited a large substrate scope for the Nphenoxyacetamides and aldehydes and a high functional group tolerance. A diverse set of aromatic, heterocyclic, and aliphatic aldehydes and N-phenoxyacetamides that bear electronically deficient or abundant groups on the aromatic ring reacted well to afford the biologically important 1,2-benzisoxazoles in moderate to excellent yields. This methodology can be applied to the synthesis of pharmaceuticals, such as risperidone, paliperidone, and iloperidone, beginning with aldehyde 434. Khalafi-Nezhad and Panahi noted a mild ruthenium-catalyzed dehydrogenative formal [4+1] coupling of primary alcohols AU


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Scheme 152. Pd(II)-Catalyzed Formal [4+1] Annulation of N-Phenoxyacetamides with Aldehydes

Scheme 153. Ti(III)-Catalyzed Formal [4+1] Cycloaddition of 3-Aminopropanenitrile with Ketones

Scheme 154. Bisphosphine-Catalyzed Formal [4+1] Annulation between Dinucleophiles and Activated Acetylenes

organocatalytic cycloaddition and cyclization reactions, as well as their asymmetric versions, have been developed for the synthesis of variously membered carbocyclic and heterocyclic compounds. Several recent comprehensive reviews by Hong, Moyano, Rios, and Pellissier have summarized the vast majority of the advances in this field.4a−c In this subsection, we discuss recent advances in organocatalytic formal [4+1] cycloaddition reactions according to different types of C1 synthons. 8.2.1. Electron-Deficient Acetylenes and AllenesBased Formal [4+1] Annulation. In 2007, Kwon’s group developed the first example of a diphenylphosphinopropane (dppp)-catalyzed double Michael addition of amino acidderived dinucleophiles 441 to electron-deficient acetylenes 392 (Scheme 154).303 The reaction tolerated an extensive range of dinucleophiles to afford the formal [4+1] cycloadducts, azolidines 442 (e.g., oxazolidines, thiozolidines, and pyrrolidines), with high yields and a cis-selectivity under mild conditions. The bisphosphine was critical for the desired pathway. Vinyl anion 392A, which was formed by an initial nucleophilic addition of bisphosphine to acetylenes 392, deprotonated dinucleophile 441 to facilitate its first Michael addition to 392B to yield intermediate 392C. The other phosphine group may stabilize the intermediate 392C, which underwent a final SN2 replacement to furnish the cyclized

with 2-aminophenol using the heterogeneous catalytic system of phosphine-functionalized magnetic nanoparticles and Ru2Cl4(CO)6 for the efficient synthesis of the benzoxazole derivatives, in which the ruthenium-catalyzed oxidation of the alcohols to aldehydes was proposed as the main step.300 In 2013, Streuff and co-workers developed a sequential ketimine formation/reductive nitrile coupling between 3aminopropanenitrile 437 with aryl ketones 438 using [TiCp*2Cl2]/Zn as the promoter, which affords the formal [4+1] cycloaddition products, the α-tetrasubstituted pyrrolidin3-one derivatives 440, with generally acceptable total yields (Scheme 153).301 The reductive umpolung coupling step was considered to proceed via a Ti(III)-catalyzed single-electron transfer process, in which Ti(III) was generated from Ti(IV) by Zn. The reaction tolerated a variety of alkyl and aryl groups at the α-position. The enantioselective variant of this methodology with the chiral Ti(IV) complex produced an enantiomeric excess of 19%. 8.2. Organocatalytic Formal [4+1] Annulation

The use of small organic molecules to promote chemical transformations, organocatalysis, has experienced a spectacular growth in modes of catalytic activation and reaction developments over the past decade.302 A significant number of AV


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product 442. By combining dppp with the AcOH/NaOAc additives, the scope of this methodology was successfully extended to the easy and modular synthesis of biologically and pharmaceutically important aniline-containing heterocyclic rings, such as indolines and benzimidazolines.304 However, the β-substituted activated acetylene proved to be unsuitable for these reactions. As compared to the β-substituted activated acetylenes, Kwon’s group noted that the diversely substituted allenes 444 exhibited superior reactivity and can undergo the PMe3mediated double Michael addition with dinucleophiles 443 to furnish several classes of C2-disubstituted benzannulated fivemembered heterocyclic rings 445 with generally acceptable yields (Scheme 155).305 The control experimental results

Scheme 157. Chiral Amine-Catalyzed Domino Michael Addition/Intramolecular Alkylation between ωIodonitroalkene and Aliphatic Aldehydes

enantioenriched products have been conveniently transformed into the synthetically and biologically important γ-amino acid with no loss of optical purity. Han and his co-workers disclosed that the aromatic and aliphatic aldehydes can function as C1 synthons to undergo a 4-methoxy-TEMPO-catalyzed aerobic oxidative cyclization with 2-amino-phenols, 2-amino-thiophenol, and o-phenylenediamine in a one-pot manner, which resulted in the corresponding formal [4+1] annulation products (2-substituted benzoxazoles, benzothiazoles, and benzimidazoles) in generally high yields.308 Chiba’s group disclosed a K2CO3-promoted highly diastereoselective formal [4+1] annulation of 6-bromo-2-hexenoates with active methylene systems (e.g., malononitrile, dimethyl malonate, and phenylsulfonyl acetonitrile), which provided efficient access to the heavily substituted cyclopentane derivatives.309 The chiral amine-catalyzed enantioselective formal [4+1] annulation strategy has been successfully extended to 2nitroacrylates 350 and α-iodoaldehydes 453 by Zhong’s group, which involves the tandem Michael addition/intramolecular O-alkylation reaction (Scheme 158).310 The (S)-2(azidodiphenylmethyl) pyrrolidine organocatalyst 454 exhibited the best catalytic performances and afforded the corresponding densely substituted cis-isoxazoline N-oxides 455 with acceptable yields and excellent stereoselectivities (up to >20:1 dr (cis/trans) and >99% ee). This methodology showed a significant functional tolerance and large substrate scope for the 2-nitroacrylates. The optically active [4+1] annulation products cis-455 can also be easily transformed into synthetically valuable heterocyclic molecules, such as completely substituted 2-amino-γ-lactone 456. In 2012, Smith and his co-workers developed a one-pot enantioselective electrocyclic cascade reaction between functionalized anilines 457 and α,β-unsaturated system-containing aldehydes 458 via a phase-transfer catalysis strategy (Scheme 159).311 The standard conditions involving the use of (8S,9R)N-benzylcinchonidinium chloride as the catalyst in the presence of K2CO3 or KOH as the base tolerated a range of substituents at the benzene ring, including anilines and electron-withdrawing groups, as the 1,4-acceptor moiety, which afford the corresponding polycyclic indolines 461 that bear acceptable yields of multiple stereocenters with excellent enantioselectiv-

Scheme 155. PMe3-Promoted Formal [4+1] Annulation with Allenes

suggested that the phosphonium enolate 444A, which is generated by the initial addition of PMe3 to the allenoate esters, may function as a general base to trigger the double Michael additions. The operational simplicity and mild reaction conditions make this strategy an attractive method for the selective monoketalization of the β-diketones. Recently, Wang and his co-workers developed an interesting pyrrolidine-catalyzed formal [4+1] annulation that involves double Michael additions of the N-Boc- or N-Ts-protected 2aminophenols 446 to ynals 447 by an iminium activation mode (Scheme 156).306 The mild reaction conditions exhibited a high functional tolerance and scope for the 2-aminophenols and ynals, which produced an extensive variety of biologically relevant and densely substituted benzoxazoles 448 in high yields. However, the use of commonly used chiral amine catalysts resulted in a low enantioselectivity. 8.2.2. Aldehyde and Ketone-Based Formal [4+1] Annulation. Using double enamine/enamine catalysis, Enders’ group reported a chiral amine-catalyzed formal [4+1] annulation between (E)-5-iodo-1-nitropent-1-enes 449 and aliphatic aldehydes 450, in which the aliphatic aldehydes serve as C1 fragments (Scheme 157).307 This group discovered that diphenylprolinol silyl ether 451 and PhCO2H as additives can tolerate a variety of aliphatic aldehydes to form the corresponding cyclic γ-nitroaldehydes 452, which contain a quaternary stereogenic center with moderate to excellent diastereoselectivities and excellent enantiomeric excess. The

Scheme 156. Pyrrolidine-Catalyzed Formal [4+1] Annulation between N-Protected-2-aminophenols and Ynals

AW


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Scheme 158. Chiral Amine-Catalyzed Formal [4+1] Annulation between 2-Nitroacrylates and α-Iodoaldehydes

Scheme 159. Enantioselective Electrocyclic Cascade between Anilines and Aldehydes by Phase-Transfer Catalysis

ities (up to >20:1 dr and >97% ee). The initially formed imines 459 underwent deprotonation to bind with cinchonidinium cation catalyst 460 at the enolate carbon. Then, a stereospecific electrocyclization of this intermediate occurred to form an indolinyl anion (formal [4+1] adduct), which underwent an intramolecular diastereoselective 1,4-addition to furnish the final products 461. This methodology is significant in natural product synthesis due to its simple generation of the topologically complex scaffold and all-carbon quaternary stereocenters.

Scheme 160. Pioneering Examples on [4+1] Cyclopentene Annulations

8.3. Vinylcyclopropane Rearrangement-Based Formal [4+1] Annulation

Vinylcyclopropanes and their heteroatom analogues represent an important and versatile category of reactive five-atom units; they can undergo a vast array of rearrangement and cycloaddition reactions to produce various carbo- and heterocyclic compounds.13,312 Pioneered by the groups of Jefford,313 Hudlicky,314 and Danheiser315 (Scheme 160), the sequential cyclopropanation of the 1,3-dienes/vinylcyclopropane-cyclopentene rearrangement constitutes another powerful formal [4+1] annulation approach to five-membered carbocyclic rings. However, inconvenient handling of carbenoid reagent or forcing reaction conditions is typically required. Certain excellent reviews by Hudlicky have extensively compiled the important advances in this active area.13a,b,e The strained vinylic heterocyclic compounds, such as the vinylic aziridines, oxiranes, and thiiranes, can also participate in the transition metalcatalyzed ring rearrangement, which facilitates access to N-, O-, and S-containing five-membered heterocycles.316 Two recent reviews from the Njardarson group highlighted various methodology developments and synthetic applications in this

vibrant area.15 Because our Review focuses on C1 synthonbased formal [4+1] annulations, only certain recent studies about the vinylcyclopropane-cyclopentene rearrangement are highlighted in this subsection. Inspired by Hudlicky and Danheiser’s strategy, Lambert disclosed a practical and mild intramolecular formal [4+1] annulation of 1,3-dienyl β-keto esters 472 (Scheme 161).317 The reaction involves Pd(OAc)2-catalyzed oxidative cyclopropanation and a Lewis acid MgI2-mediated vinylcyclopropane-cyclopentene rearrangement. In contrast to Hudlicky and Danheiser’s cyclopropanation protocol, the Pd(OAc)2-cataAX


Chemical Reviews

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Scheme 161. Pd(OAc)2 and MgI2-Promoted Intramolecular Formal [4+1] Annulation of 1,3-Dienyl β-Keto Esters


have enabled the efficient construction of a variety of structurally complex and densely functionalized five-membered carbocyclic and heterocyclic compounds. Several methodologies have been successfully applied to the total synthesis of biologically important natural products. Despite these impressive advances, several challenges are likely to be addressed in the future development of new efficient formal [4+1] annulation reactions. For example, as compared to the numerous mechanistic studies of traditional cycloaddition reactions, such as the [4+2] cycloaddition and the 1,3-dipolar [3+2] cycloaddition, few extensive mechanistic studies of the formal [4 + 1] annulation reaction have been performed. Regarding enantioselective synthesis, although certain examples of auxiliary-induced chirality transfers or asymmetric catalysis have been developed, related methodological developments remain highly desirable. The discovery of new suitable dipolar four-atom and one-carbon fragments and their equivalents by the exploration of new reactive intermediates and reagents can provide a fruitful platform for the development of new formal [4+1] annulation reactions. Thus, we can expect numerous developments of valuable formal [4+1] annulation reactions and their application to the construction of other synthetically important and medicinally active carbo-/heterocyclic systems and molecularly complex systems. We hope that this Review will prompt additional research studies in this field and provide insight into the reaction design and search for new chemical transformations.

lyzed oxidative cyclopropanation accommodates a number of functional groups at the 1,3-diene moiety to furnish the corresponding vinylcyclopropane adducts in satisfactory yields with excellent diastereoselectivities. However, the gem-dimethyl substitution in the γ- or δ-position is required for the desired reaction. Employing MgI2 in CH3CN produces a simple vinylcyclopropane-cyclopentene rearrangement of these intermediates to afford the final bicyclic cyclopentene derivatives 474−477 in good yields. It was hypothesized that the iodide ions of MgI2 underwent a homoconjugate ring-opening addition to the initially formed vinylcyclopropanes 473 to form the Mg(II) enolate intermediate 473A, which underwent an intramolecular SN2 alkylation to yield the cyclopentene 474 (Scheme 162). This two-step strategy introduced a new method for the development of a formal [4+1] cycloaddition for the construction of structurally complex carbocyclic compounds.

9. CONCLUSIONS As demonstrated in this Review, previous decades have witnessed a surge of studies about the formal [4+1] annulation, which has become an extremely active and original field in carbocyclic and heterocyclic system synthesis. This Review revealed that the formal [4+1] annulation reaction is more than a homologous version of the related [3+2], [2+2+1] cycloaddition reactions or cycloisomerizations. The intrinsic structural and functional features of the various C1-fragments AY


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AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies

Liang-Qiu Lu was born in 1982. In 2005, he received his B.Sc. in Applied Chemistry. Subsequently, he joined Prof. Wen-Jing Xiao’s group at Central China Normal University (CCNU) to obtain his Ph.D. degree. In July of 2011, Dr. Lu joined the College of Chemistry at CCNU as a lecturer. He was also a Humboldt Scholar (Prof. Matthias Beller’s group) at the Leibniz-Institut für Katalyse e.V. (Germany). In June of 2013, he returned to CCNU, where his research interests focus on the development of new reactions via metal- and organocatalysis.

Jia-Rong Chen was born in 1980. He received his B.Sc. in Chemistry from Central China Agricultural University in 2003 and completed his Ph.D. studies in 2009 under the direction of Prof. Wen-Jing Xiao at Central China Normal University. From 2011 to 2012, Dr. Chen worked as a Humboldt postdoctoral fellow with Prof. Carsten Bolm at the Rheinisch-Westfäishce Technische Hochscule (RWTH) Aachen University. He then returned to Central China Normal University, where he works as an associate professor. His current research interests include the development of new catalysts for asymmetric

Wen-Jing Xiao was born in 1965. He received his B.Sc. in chemistry in 1984 and his M.Sc. in 1990 under the supervision of Professor WenFang Huang from Central China Normal University (CCNU). In 2000, he received his Ph.D. under the direction of Professor Howard Alper at the University of Ottawa, Canada. After postdoctoral studies with Professor David W. C. MacMillan (2001−2002) at the California Institute of Technology in the CA in 2003, Dr. Xiao became a full professor at the College of Chemistry at CCNU, China. His current research interests include the development of new synthetic methodologies and the synthesis of biologically active compounds.

catalysis and cycloaddition reactions.

ACKNOWLEDGMENTS We are sincerely grateful to our collaborators and co-workers, whose names appear in the related references, for their significant contributions to our study. Our work in this area was sponsored by the National Natural Science Foundation of China (nos. 21272087, 21472058, 21472057, 21202053, and 21232003) and the National Basic Research Program of China (2011CB808603); their support is gratefully acknowledged. We also thank all of the anonymous referees for their invaluable suggestions on preparing this manuscript.

Xiao-Qiang Hu was born in 1988. He received his B.S. from Wuhan Polytechnic University in 2011. Subsequently, he began his Ph.D. studies under the supervision of Prof. Jia-Rong Chen and Wen-Jing Xiao at Central China Normal University. His research interests

ABBREVIATIONS acac acetylacetone

include asymmetric catalysis and heterocyclic compound synthesis. AZ


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Cycloaddition Reactions in Organic Synthesis; Wiley-VCH: New York, 2002. (c) Royer, J., Ed. Asymmetric Synthesis of Nitrogen Heterocycles; Wiley Online Library, 2009. (d) Ma, S.-M., Ed. Handbook of Cyclization Reactions; Wiley-VCH: New York, 2010. (e) Nishiwaki, N., Ed. Methods and Applications of Cycloaddition Reactions in Organic Syntheses; John Wiley & Sons: New York, 2014. (3) (a) Lautens, M.; Klute, W.; Tam, W. Transition Metal-Mediated Cycloaddition Reactions. Chem. Rev. 1996, 96, 49−92. (b) Frühauf, H.-W. Metal-Assisted Cycloaddition Reactions in Organotransition Metal Chemistry. Chem. Rev. 1997, 97, 523−596. (c) Gibson, S. E.; Lewis, S. E.; Mainolfi, N. Transition metal-mediated routes to cyclopentenones. J. Organomet. Chem. 2004, 689, 3873−3890. (d) Zeni, G.; Larock, R. C. Synthesis of Heterocycles via Palladium π-Olefin and π-Alkyne Chemistry. Chem. Rev. 2004, 104, 2285−2309. (e) Kurteva, V. B.; Afonso, C. A. M. Synthesis of Cyclopentitols by Ring-Closing Approaches. Chem. Rev. 2009, 109, 6809−6857. (f) Krause, N.; Winter, C. Gold-Catalyzed Nucleophilic Cyclization of Functionalized Allenes: A Powerful Access to Carbo- and Heterocycles. Chem. Rev. 2011, 111, 1994−2009. (g) Godoi, B.; Schumacher, R. F.; Zeni, G. Synthesis of Heterocycles via Electrophilic Cyclization of Alkynes Containing Heteroatom. Chem. Rev. 2011, 111, 2937−2980. (h) Wu, X.-F.; Neumann, H.; Beller, M. Synthesis of Heterocycles via Palladium-Catalyzed Carbonylations. Chem. Rev. 2013, 113, 1−35. (i) Garayalde, D.; Nevado, C. Gold-Containing and Gold-Generated 1,n-Dipoles as Useful Platforms toward Cycloadditions and Cyclizations. ACS Catal. 2012, 2, 1462−1479. (4) (a) Hong, B.-C. In Enantioselective Organocatalyzed Reactions II; Mahrwald, R., Ed.; Springer: Dordrecht, 2011; Chapter 3, pp 187− 244. (b) Moyano, A.; Rios, R. Asymmetric Organocatalytic Cyclization and Cycloaddition Reactions. Chem. Rev. 2011, 111, 4703−4832. (c) Pellissier, H. Asymmetric organocatalytic cycloadditions. Tetrahedron 2012, 68, 2197−2232. (d) Herchl, R.; Waser, M. Stereoselective cyclization reactions under phase-transfer catalysis. Tetrahedron 2014, 70, 1935−1960. (5) (a) Reissig, H. U.; Zimmer, R. Donor-acceptor-substituted cyclopropane derivatives and their application in organic synthesis. Chem. Rev. 2003, 103, 1151−96. (b) Lebel, H.; Marcoux, J. F.; Molinaro, C.; Charette, A. B. Stereoselective cyclopropanation reactions. Chem. Rev. 2003, 103, 977−1050. (c) Rubin, M.; Rubina, M.; Gevorgyan, V. Transition metal chemistry of cyclopropenes and cyclopropanes. Chem. Rev. 2007, 107, 3117−79. (6) (a) Schuster, D. I.; Lem, G.; Kaprinidis, N. A. New Insights Into an Old Mechanism: [2 + 2] Photocycloaddition of Enones to Alkenes. Chem. Rev. 1993, 93, 3−22. (b) Winkler, J. D.; Bowen, C. M.; Liotta, F. [2 + 2] Photocycloaddition/Fragmentation Strategies for the Synthesis of Natural and Unnatural Products. Chem. Rev. 1995, 95, 2003−2020. (c) Tam, W.; Goodreid, J.; Cockburn, N. Transition Metal-Catalyzed 2 + 2 Cycloaddition Reactions between Bicyclic Alkenes and Alkynes. Curr. Org. Synth. 2009, 6, 219−238. (d) Alcaide, B.; Almendros, P.; Aragoncillo, C. Exploiting [2 + 2] cycloaddition chemistry: achievements with allenes. Chem. Soc. Rev. 2010, 39, 783− 816. (7) (a) Padwa, A.; Pearson, W. H. Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry toward Heterocycles and Natural Products; Wiley-Interscience: New York, 2002. (b) Gothelf, K. V.; Jørgensen, K. A. Asymmetric 1,3-Dipolar Cycloaddition Reactions. Chem. Rev. 1998, 98, 863−910. (c) Coldham, I.; Hufton, R. Intramolecular Dipolar Cycloaddition Reactions of Azomethine Ylides. Chem. Rev. 2005, 105, 2765−2810. (d) Pandey, G.; Banerjee, P.; Gadre, S. R. Construction of Enantiopure Pyrrolidine Ring System via Asymmetric [3 + 2]Cycloaddition of Azomethine Ylides. Chem. Rev. 2006, 106, 4484− 4517. (e) Stanley, L. M.; Sibi, M. P. Enantioselective CopperCatalyzed 1,3-Dipolar Cycloadditions. Chem. Rev. 2008, 108, 2887− 2902. (f) Amblard, F.; Cho, J. H.; Schinazi, R. F. Cu(I)-Catalyzed Huisgen Azide−Alkyne 1,3-Dipolar Cycloaddition Reaction in Nucleoside, Nucleotide, and Oligonucleotide Chemistry. Chem. Rev. 2009, 109, 4207−4220. (g) Adrio, J.; Carretero, J. C. Novel dipolarophiles and dipoles in the metal-catalyzed enantioselective 1,3-dipolar cycloaddition of azomethine ylides. Chem. Commun. 2011,

Ar BHT Bn Boc Bpy Bu CAN cod coe Cp Cp* m-CPBA CSA Cy p-cyemene dba DBU DCE DCM DMAP DME DMF DMSO DPPA dppbe dppf Dppf DPPP dr ee equiv LAH MAD

aryl 2,6-di-tert-butyl-4-methylphenol benzyl tert-butoxycarbonyl 2,2′-bipyridine butyl ceric ammonium nitrate 1,5-cyclooctadiene cyclooctadiene cyclopentadiene 1,2,3,4,5-pentamethylcyclopentadienyl m-chloroperoxybenzoic acid camphorsulfonic acid cyclohexyl 1-methyl-4-(1-isopropyl) benzene dibenzylideneacetone 1,8-diazabicycloundec-7-ene 1,2-dichloroethane dichloromethane 4-dimethylaminopyridine 1,2-dimethoxyethane N,N-dimethylformamide dimethyl sulfoxide diphenylphosphoryl azide 1,2-bis(diphenylphosphino)benzene 1,1′-bis(diphenylphosphino) ferrocene 1,1′-bis(diphenylphosphino) ferrocene diphenylphosphinopropane diastereomeric ratio enantiomeric excess equivalents lithium aluminum hydride methylaluminum bis (2,6-di-tert-butyl-4methylphenoxide) (R,R)-Me-DuPHOS (R,R)-1,2-bis (2,5-dimethylphosphorano) benzene Me methyl MS molecular sieves OTf trifluoromethanesulfonate Ph phenyl Py pyridine rt room temperature SPhos 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl TBHP tert-butyl hydroperoxide TBS tert-butyldimethylsilyl TEA triethyl amine Tf trifluoromethanesulfonyl Tf2O trifluoromethanesulfonic anhydride THF tetrahydrofuran TMG 1,1,3,3-tetramethylguanidine TMS trimethylsilyl Ts p-toluenesulfonyl TsCl p-toluenesulfonyl chloride

REFERENCES (1) (a) Pignataro, B. New Strategies in Chemical Synthesis and Catalysis; Wiley-VCH: New York, 2012. (b) Noyori, R. Synthesizing our future. Nat. Chem. 2009, 1, 5−6. (c) Ding, K.-L., Dai, L.-X., Eds. Organic Chemistry-Breakthroughs and Perspectives; Wiley-VCH: Weinheim, 2012. (2) (a) Carruthers, W. Cycloaddition Reactions in Organic Synthesis; Pergamon: Oxford, 1990. (b) Kobayashi, S., Jorgensen, K. A., Eds. BA


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Formal [4+1] Annulation Reactions in the Synthesis of Carbocyclic and

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