Contemporary Carbocation Chemistry: Applications in Organic Synthesis

Review pubs.acs.org/CR

Contemporary Carbocation Chemistry: Applications in Organic Synthesis Rajasekhar Reddy Naredla and Douglas A. Klumpp* Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, Illinois 60115, United States 3.3.1. Charge Migration and Remote Functionalization 3.3.2. Superelectrophilic Trihalomethyl Cations 3.3.3. Synthesis of Polycyclic Aromatic Compounds 3.3.4. Ammonium−Carbenium Dications 4. Carbocations in Classical Reactions 4.1. Friedel−Crafts Alkylation 4.1.1. Intramolecular Friedel−Crafts Reactions 4.1.2. Intermolecular Friedel−Crafts Reactions 4.2. Cationic Cyclization Cascades 4.3. SN1 and SN1′ Reactions 4.4. Wagner−Meerwein Rearrangements 4.5. Homoallylic−Cyclopropyl Carbinyl Carbocations 4.6. Ritter Reaction 4.7. Schmidt Reaction 4.8. Pinacol and Prins-Pinacol Rearrangements 4.9. Hydroamination 4.10. Nazarov Reaction 4.11. Propargylic and Allenyl Cations 5.0. Carbocations in Asymmetric Synthesis 5.1. General Aspects 5.2. Stereocontrol by Covalently Attached Groups: Chiral Carbocations 5.3. Stereocontrol by Use of Chiral Counter Ions 5.4. Stereocontrol by Reactions with Chiral Nucleophiles 6.0. Summary and Outlook Author Information Corresponding Author Notes Biographies Acknowledgments References

CONTENTS 1. Introduction 2. Carbocations: New Methods 2.1. Cation Pool 2.1.1. Diarylmethyl Cations 2.1.2. Oxidative Transformations 2.2. Internal Redox 2.2.1. Benzylidene Meldrum’s Acid 2.2.2. Iminium-Type Electrophile 2.2.3. Barbituric Acid Derivatives 2.3. New Leaving Groups 2.3.1. 1,3-Dicarbonyl Complexes 2.3.2. Aryl-λ3-Bromane Leaving Group 2.3.3. Alkoxide Activation 2.4. New Lewis Acids 2.4.1. Boronic Acids 2.4.2. Silicon-Based Lewis Acids 2.4.3. Alumenium-Based Lewis Acids 2.4.4. Friedel−Crafts Lewis Acids 2.5. New Brønsted Acids 2.5.1. Triflyl Derivatives 2.5.2. Carboranes and Related Acids 2.5.3. BF3 Conjugate Acids 2.5.4. Friedel−Crafts Brønsted Acids 3. Carbocations: Low to High Electrophilicity 3.1. Reactions of Highly Stabilized Systems 3.1.1. Reactions with Enols 3.1.2. Reactions with Enamines 3.1.3. Reactions with Other Nucleophiles 3.2. More Reactive Carbocations 3.2.1. Reactions of α-Carbonyl Carbocations 3.2.2. Reactions of Fluoro-Substituted Carbocations 3.2.3. Reactions of Trifluormethyl-Substituted Carbocations 3.3. Reactions of Superelectrophilic Carbocations © XXXX American Chemical Society

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1. INTRODUCTION The extraordinary instability of such an ‘ion’ accounts for many of the peculiarities of organic reactions.Frank C. Whitmore, 1932 The interesting statement by Whitmore came at a period of time when organic chemists were beginning to understand the importance of carbocations in chemical reactions.1 Prior to this period, a fairly large number of organic transformations had

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Figure 1. Early synthetic and mechanistic discoveries involving carbocations.

protonation,6 the carbocation was firmly established as one of the most important reactive intermediates in organic synthesis. As noted aptly by Stang in his historical perspective on carbocation chemistry, this period of time ushered in “the golden age of mechanistic organic chemistry” from about the 1940s through the mid-1970s.7 It was during this period that carbocations were thoroughly investigated, and this in turn led to the development of many new synthetic methodologies including those of heteroatom-stabilized carbocations, allylic and homoallylic cations, rearrangements, cycloadditions, cascade reactions, and others. Indeed, the “peculiarities of organic reactions” noted by Whitmore had become a valuable tool in the hands of synthetic organic chemists. This was succinctly stated by George Olah during his 1994 Nobel Prize (awarded to him “for his contribution to carbocation chemistry”) award address when he stated, “Knowledge about mechanisms makes it possible to develop better and less expensive methods to prepare products of technical importance.”8 The value of carbocationic synthetic chemistry cannot be overstated, as it continues to be a vital part of industrial and academic chemistry. For example, the petroleum industry uses alkylation unit chemistry (isobutylene or propene/isobutane/ acid) to produce more than 1.6 million barrels per day of highly branched hydrocarbons (i.e., 1) for use in transportation fuels (Scheme 1).9a The critical C−C bond-forming step involves the reaction of a carbocation with the alkene, followed by hydride transfer from the isobutane to the carbocation. Likewise, the majority of phenol is still produced using the oxidation of cumene and the subsequent Hock rearrangement.9b Cumene itself is formed by the Friedel−Crafts alkylation of benzene with propene, a reaction involving the 2-propyl cation. More recent technologies include the methanol-to-gasoline (MTG) and methanol-to-olefins (MTO) processes developed by

been reported in the literature, reactions that involved rearrangements, substitutions, eliminations, additions, and even polymerizations. However, these organic reactions exhibited baffling “peculiarities” which could not be explained with the bonding theories of the time. During the period 1901−1940, the peculiarities began to make sense. It was during this period of time that carbocations were discovered and they were understood to be reactive intermediates in many synthetic organic reactions. The discovery of the first carbocation is often attributed to Norris in the year 1901; however, an independent report by Kehrman and Wentzel was published the same year (Figure 1).2 Both papers described the ionization of substrates in sulfuric acid to give colored solutions, identified as solutions containing the triphenylmethyl cation. Other eminent chemists made contributions at this early date, including Stieglitz, Baeyer, and Gomberg.3 The discoveries of cationic species involving carbon were at first considered to be little more than laboratory curiosities, as it would be 20 years before carbocationic intermediates were proposed as intermediates chemical reactions. Thus, mechanistic advances were at least several decades behind the synthetic discoveries. By 1920, several notable carbocation-based reactions had been known for decades including the pinacol rearrangement, Friedel−Crafts alkylation, and acid-catalyzed polymerizations of olefins. However, there was no awareness of the carbocation reaction intermediates. A critical insight was made by Meerwein and Vam Emster in 1922, when they proposed “a rearrangement of the cation” for the acid-promoted isomerization of camphene hydrochloride (vide inf ra).4 This pioneering idea was soon followed by Ingold and Rothstein’s suggestion of an SN1 mechanism and Whitmore’s formal description of heterolytic bond cleavage at carbon.5,1 With further descriptions of alkene B


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Scheme 1

Scheme 3

Mobil.10 Solid-state NMR studies have suggested mechanisms involving a “hydrocarbon pool” within the channels of the acidic zeolite catalyst. The catalytic sites are shown to possess carbocationic intermediates, for example the 1,3-cyclopentadienyl cation (2) and 1,1,2,4,6-pentamethylbenzenium cation (3, Scheme 2).11 These carbocation intermediates are thought to be the basis for C−C bond forming reactions in the MTG and MTO processes.

2. CARBOCATIONS: NEW METHODS In recent years, several new approaches have been developed for the utilization of carbocations in organic synthesis. These include entirely new approaches to generating carbocations as reactive electrophiles, but also involve the development of novel acids for use in classical routes to carbocations.

Scheme 2

2.1. Cation Pool

A series of carbocationic reactions have been described by Yoshida’s group in which the “cation pool” strategy is used. While the electrochemical generation of carbocations has been known for some time,15 the cation pool method differs by its accumulation of the electrophilic species in solution (i.e., pooling the cations). This is accomplished through the use of irreversible, oxidative reactions under non-nucleophilic conditions. The carbocations then react with nucleophiles in a second step. This method is analogous to the preparation of carbanionic reagents such as Grignard or organolithium species, generally as a concentrated solution, and this is followed by electrophilic trapping of the carbanion. Besides the recent work with carbocations, the cation pool method has been effectively used to generate a variety of onium ions including iminium ions, N-acyliminium ions, carboxonium ions, and others. This chemistry has been recently reviewed.16 2.1.1. Diarylmethyl Cations. Using the cation pool method, oxidative C−H bond dissociation provides a good route to diarylmethyl carbocations (Scheme 4).17 Oxidation of the diarylmethane, at a potential of 1.96 V, leads to carbocation 8, which may be reacted with a variety of nucleophiles. Electrophilic aromatic substitution provides the triarylmethane (9) while allylation gives the alkene 10. With the ketene silyl acetal, the ester (11) is isolated in fair yield. 2.1.2. Oxidative Transformations. The Yoshida group has also developed a combined electrochemical−chemical oxidation route mediated by alkoxysulfonium ions.18 For example, the diarylmethanes are oxidized to the carbocations (i.e., 8) and trapped by dimethylsulfoxide (DMSO) to give the alkoxy sulfonium ions, such as 12 (Scheme 5). In this example of the “cation-pool” method, there is complete conversion of the starting material to the carbocation 8, which itself may be directly observed by NMR. Since the oxidation potential of DMSO is 1.76 V (vs SCE), the carbocation is initially formed in the absence of DMSO. Trapping of the carbocation, followed by reaction with base, leads to the oxidized product (13) in 91% yield. This study also demonstrated the utility of electrochemical oxidation of alkenes leading to synthetically useful conversions. Stilbenes are oxidized and trapped by 2 equiv of DMSO, providing access to benzils in fair to good yields. Other alkene substrates were shown to undergo

The diverse chemistry of carbocations has also received considerable attention from the academic community, with carbocation-based synthetic reactions being used in methodology development and targeted organic synthesis. Despite the long history of synthetic carbocation chemistry, this continues to be an area of intensive research. As described in the following review, new methodologies are being developed for C−C bond construction, functional group manipulation, activation of sp3 carbons, and rearrangements of carbon skeletons. Many of the classical organic reactions continue to be developed and applied to innovative synthetic conversions, including the total syntheses of natural products. Carbocations have also been used in several recent asymmetric synthetic methodologies. Although the physical organic chemistry of carbocations is also an active area of research, these types of studies are not discussed in this article, as this topic has been thoroughly reviewed.12 Likewise, many useful synthetic methods report the use of electrophiles such as carboxonium ions, sulfoxonium ions, iminium ions, N-acyl iminium ions, and related species. These reactions are also outside the scope of this review, but the interested reader is encouraged to examine Olah’s outstanding monograph on this subject.13 Finally, it is appropriate to discuss terminology. Using the convention put forth by Olah,14 the term carbocation encompasses two types of structures, the carbenium and carbonium ions (Scheme 3). Carbenium ions have been defined as the classical trivalent, sp2 hybridized carbocations (4−5), while carbonium ions are considered species with pentacoordinate (or higher) carbon having 3-center−2-electron bonding (6−7). Since the vast majority of cationic structures in this review are carbenium ions, these species will be referred to simply as “carbocations”. In accord with Olah’s designation, the examples of higher coordinate, nonclassical species will be referred to as “carbonium ions”. C


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Scheme 4

Scheme 5

Scheme 7

intramolecular nucleophilic attack, for example leading to substituted pyrrolidines (Scheme 6). Two-electron oxidation of

may be accomplished with stilbene derivatives (Scheme 8). Thus, oxidation of stilbene 19 is followed by hydrolysis to provide diol 20.

Scheme 6

Scheme 8

2.2. Internal Redox

A variety of novel cyclization reactions have been recently reported in which zwitterionic species are key intermediates in the transformations. Sometimes referred to as “internal redox reactions”, these transformations have generally involved zwitterionic structures composed of stabilized anionic centers paired with stabilized cationic centers. The electrophilic sites are most often iminium or carboxonium ion centers. Nevertheless, several reports have described reactions in which carbocationic centers are involved in the chemistry. 2.2.1. Benzylidene Meldrum’s Acid. Fillion and coworkers reacted the benzylidene Meldrum’s acid (21) with Sc(OTf)3 to obtain the carbocyclic product (23) in 90% yield (Scheme 9).20 Like other internal redox reactions, this

alkene 14 leads to cyclization and formation of the alkoxysulfonium ion (15). Final treatment with base leads to the pyrrolidine 16. Other intramolecular reactions were done with aryl, alkenyl, and hydroxyl nucleophiles. With hydrolysis of the alkoxysulfonium ion intermediates, alcohol products may be isolated.19 For example, toluene derivatives are selectively oxidized to the benzyl alcohols (i.e., 18, Scheme 7). Two-electron oxidation leads to formation of the benzylic carbocation which is trapped by DMSO. Hydrolysis of the alkoxysulfonium ion (17) provides access to the alcohol (18) in good yield. The authors suggest that overoxidation is prevented by a relatively high oxidation potential of the alkoxysulfonium ion (17). Similar chemistry D


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carbocation 27 (Scheme 11). A deuterium labeling study was done to show complete transfer of deuteride from the 3°

Scheme 9

Scheme 11

transformation is thought to involve an initial [1,5]-hydride transfer, generating the zwitterionic intermediate (22). Reaction of the anionic and cation sites then forms the new ring. An important aspect of this transformation is the stability of the carbocationic site, well-stabilized by the methoxyphenyl group. The cyclization products (i.e., 23) may be further reacted via intramolecular Friedel−Crafts acylation to provide tetracyclic ring systems. 2.2.2. Iminium-Type Electrophile. A similar strategy was used by Akiyama et al. to prepare 3-arylisoquinolines.21 The synthetic methodology begins with imine formation and the reaction with a Brønsted or Lewis acid (Scheme 10). Again, the

carbon to the benzylic position. In the case of compound 26, cyclization gives the tetraline 28 in good yield. It was also shown that a [1,6]-hydride shift could be accomplished. Compound 29 reacts to give the internal redox product, indane 30, in 91% yield. This system also forms the cyclopentyl carbocation. Curiously, the carbocationic center undergoes a Friedel−Crafts-type cyclization to form the indane 30 instead of reaction at the carbanion site. Under these conditions, similar internal redox reactions could not be accomplished with systems generating less stable 2° alkyl carbocations.

Scheme 10

2.3. New Leaving Groups

2.3.1. 1,3-Dicarbonyl Complexes. An innovative method for generating carbocations has been described by Li and coworkers in which 1,3-dicarbonyl groups are used as leaving groups. For example, diketone 31 is reacted with 5bromoindole in the presence of FeCl3 catalyst (Scheme 12).23 Activation of the C−C bond is achieved by complexation Scheme 12

key step involves a Sc(OTf)3-promoted 1,5-hydride shift from the benzylic carbon to the iminium carbon. The resulting carbocation (24) undergoes C−N bond formation to give the desired heterocyclic product (25). The methodology is shown to work best with electron-rich aryl groups capable of stabilizing the carbocation center. Other acids were found to catalyze the internal redox process, including FeCl3, TsOH, TfOH, and Yb(OTf)3. The synthetic methodology was used to prepare racemic tetrahydropalmatine, a biologically active natural product. 2.2.3. Barbituric Acid Derivatives. Akiyama also recently demonstrated the possibility of generating 3° alkyl carbocations by internal redox chemistry.22 Using barbituric acid derivatives (26), [1,5]-hydride transfer provides the 3° cyclopentyl

of the 1,3-dicarbonyl moiety, leading to formation of the stabilized enolate ion complex and the carbocation 32. A Friedel−Crafts reaction then provides the substituted indole (33) in 83% yield. Other nucleophiles were reacted with the formed carbocations, including alkene and alkyne nucleophiles. A somewhat related process was reported by Hu and coworkers showing that methylenecyclopropane (34) could be E


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reacted with Lewis acids to give indene products such as 35 (Scheme 13), formed by distal-bond cleavage and then

Scheme 15

Scheme 13

Scheme 16

cyclization (i.e., 36).24 A number of other useful synthetic methodologies have also been developed from acid-mediated reactions of methylenecyclopropanes, including conversions with carbocationic intermediates. This chemistry was recently reviewed.25 2.3.2. Aryl-λ3-Bromane Leaving Group. Ochiai and associates have utilized a bromane hyperleaving group to generate the highly strained cyclopentenyl vinyl cation (37, Scheme 14).26 Previous attempts to generate 37 were unsuccessful, either from the triflate (38)27 or the cyclopent1-enyl(phenyl)-λ3-iodane (39).28 Vinyl cations tend to favor sp hybridization and a bond angle around 180°. Cyclopentenyl vinyl cation (37) has a bond angle of about 141°, introducing a considerable amount of strain and inhibiting its formation. Using the more reactive cyclopent-1-enyl-λ3-bromane (40), however, provides a good yield of the solvolysis product 41. Carbocation 37 gives 1-chlorocyclopentene from alkyl chloride solvents, providing further evidence for the intermediacy of the cyclopentenyl vinyl cation, and vinyl ethers (i.e., 41) from alcohols. 2.3.3. Alkoxide Activation. The Kabilka group has sought to develop increasingly mild conditions for the generation of carbocationic intermediates for use in synthesis. They have reported several methodologies in which alkoxide ions are reacted with Lewis acids to form stabilized carbocations. For example, a series of carbocations (i.e., 43) were generated from alkoxide salts (42) and titanium(IV) halides (Scheme 15).29 These are shown to react efficiently with terminal alkynes, and the intermediate vinyl cations (44) are captured by chloride ion to provide trisubstituted (E)-alkenyl chlorides. Similar transformations were done with TiBr4 to give the alkenyl bromides. Another recent study demonstrated the use iron trichloride to effect C−O bond cleavage to carbocations.30 Thus, reactions of the lithium alkoxide (46) with FeCl3 provide the diarylmethyl carbocation (47) which may be trapped by allyl silane to give the substitution product 48 (Scheme 16). Good

yields of the substitution product were also obtained with BCl3, SnCl4, and AlCl3. A related study involved the allylation of propargyl alcohols using BCl3.31 Fuchter and Levy also reported a method for preparing allylic chlorides from carbonyl derivatives.32 The synthetic method involves SN1′ type reactions of magnesium allylic alkoxides. In clever use of cyclopropenium cations, Lambert and Kelly activated alcohols for substitution reactions (Scheme 17).33 Scheme 17

Thus, 2-phenylethanol reacts with the dichlorocyclopropene (49) to yield the alkoxycyclopropenium ion intermediate (51) which undergoes substitution to the alkyl chloride and the cyclopropenone 52. The authors suggest a process involving formation of an initial cyclopropenium cation (50) that reacts with the alcohol group. The formation of 51 was confirmed by NMR experiments.

Scheme 14

F


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2.4. New Lewis Acids

Scheme 20

A number of innovative Lewis acid systems have been reported recently, some of which promote the formation of carbocation intermediates in synthetic transformations. General reviews have been published on Lewis acid systems, including very thorough monographs.34 The use of hydrogen-bond-donor catalysts has seen numerous applications, and this chemistry has been recently reviewed.35 A very active area of Lewis acid research has involved the use of electrophilic metal catalysts, most notably those generated from the noble metals. The reactions of electrophilic silver,36 gold,37 and platinum38 species have also been well-reviewed in the literature. Although many of these reactions doubtless proceed through carbocationic intermediates, their chemistry is not discussed. 2.4.1. Boronic Acids. Electron-deficient, boron-centered Lewis acids, such as B(C6F5)3, have been extremely useful in organic synthesis.39 Recent work has likewise shown that electron-deficient boronic acids are effective reagents for the generation of carbocationic species under fairly mild conditions. For example, Hall and co-workers have described the use of pentafluorophenyl boronic acid (55) and related boronic acids in substitution reactions (Scheme 18).40 Reaction of the allylic

reactions using benzylic alcohols and boronic acid catalysts.42 As in the case of the allylic alcohols, the reactions with benzylic alcohol are thought to proceed through stabilized carbocationic intermediates. Finally, it must be noted that the electrondeficient boronic acids have the potential to exhibit both Lewis and Brønsted acidity. This aspect may be important in the catalytic activities of these reagents. 2.4.2. Silicon-Based Lewis Acids. Since the early work of Vorbrügen and Noyori,43 the Lewis acid catalytic activities of silyl triflates have been very well-developed. Several new generation silyl-based Lewis acids have been reported, and they have exhibited exceptionally high reactivities. These Lewis acids range from covalent silyl derivatives (59−60) to species approaching trivalent silicon cations (61−63; Scheme 21). Scheme 21

Scheme 18

Both silyl derivatives 59 and 60 have been shown to be capable of ionizing allylic alcohols to carbocations. The silylium ion salts (61−63) have all shown activity in hydrodefluorination reactions. For example, Ozerov designed a catalytic process for generating the silylium salt 61 during a hydrodefluorination reaction (Scheme 22).44 The trityl salt is reacted with

alcohol 53 and catalyst 55 leads to the N-heterocyclic product (54) in good yield. An SN1′ mechanism is suggested for the conversion, with carbocation 56 triggering the cyclization. A wide variety of cyclizations were accomplished, including Friedel−Crafts cyclizations, a polyolefin cyclization, a phenol cyclization, heterocyclizations with alcohols, and a spiroketalization (Scheme 19).

Scheme 22

Scheme 19

triethylsilane to give the silylium salt 61 and triphenylmethane. The extraordinary Lewis acidity of the triethylsilyl cation and the strength of the Si−F bond provide the driving force for abstraction of the fluoride from perfluoroalkyl groups. In the case of α,α,α-trifluorotoluene, fluoride abstraction gives the benzylic cation 64 and fluorotriethylsilane. Subsequent hydride abstraction, either from excess triethylsilane or triphenylmethane, completes the hydrodefluorination step and continues the catalytic cycle. The process then repeats for the remaining C−F bonds in greater than 99% efficiency. The catalytic reaction exhibits a TON of 71. The same catalytic system was also shown to hydrodefluorinate 1-fluoropentane with quantitative reduction of the C−F bond. Ozerov’s group also

Previous work by McCubbin demonstrated the value of this approach in Friedel−Crafts chemistry.41 Allylic alcohols (i.e., 57) were shown to react efficiently with electron-rich arenes in the presence of pentafluorophenyl boronic acid, leading to Friedel−Crafts products (i.e., 58) such as that from 2methylfuran (Scheme 20). The chemistry was shown to work with indole, pyrrole, aryl ethers, and phenolic nucleophiles. The mild reaction conditions exhibited reasonably good functional group tolerance. In comparisons with other catalysts, similar yields were obtained with BF3·OEt2 and AuCl3 catalysts, but significantly lower yields of product were obtained with FeCl3 and TsOH. The same research group described Friedel−Crafts G


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which the alumenium cation, Me2Al+, abstracts fluoride to provide the carbocation 71. Subsequent steps involve cyclization to the indane or direct alkylation from the Me3Al. Further ionization of the C−F bonds, and alkylation of the incipient carbocations, provides the observed alkylative defluorination products 69 and 70. 2.4.4. Friedel−Crafts Lewis Acids. There is also a continued demand for improved Friedel−Crafts alkylation catalysts, and a variety of new Lewis acid catalytic systems have been recently reported. These include the following: nanoscopic inorganic fluorides,49 high surface area SiO2−ZnO2 mixed oxides,50 Fe-MCM-41 nanoparticles,51 and mesoporous Nb−Mo oxide nanoparticles.52

designed a system involving silylium-carborane catalysts, including salt 63.45 In this study, it was demonstrated that defluorination could also be accompanied by Friedel−Crafts reactions and alkyl group isomerization, two characteristic reactions of carbocations. A related set of catalytic reactions was described by Müller and co-workers (Scheme 23).46 The hydrogen bridged disilyl Scheme 23

2.5. New Brønsted Acids

Because of their importance in many areas of synthetic chemistry, the development of new Brønsted acids has always been an important goal. Depending on the specific use of the acid, the new Brønsted acids must have properties, including thermal stability, an appropriate level of acidity, good catalytic activity, ease of preparation/handling, and low environmental impact. Several general reviews on Brønsted acids have been published in recent years.53 2.5.1. Triflyl Derivatives. The Yamamoto group has recently developed a number of very useful, strong, Brønsted acids, such as the pentafluorophenylbis(triflyl)methane (72) (Scheme 26).54 Pentafluorophenylbis-(triflyl) methane (72) was first prepared in 2001, and among its reactions,33 it found use in conversions involving carbocations.55 More recently, it was shown that the bulky nature of its counterion may be important in its chemistry.56 In an effort to enhance its practical value, polymer-bound (polystyrene) derivatives and fluoroustagged derivatives of 72 have also been prepared.55 In typical acid-catalyzed reactions (Fischer esterification, Friedel−Crafts acylation, acetal formation), the polymer bound derivative exhibits chemical reactivity comparable to the solid, perfluororesin sulfonic acid catalyst, Nafion SAC-13. This same research group has prepared a valuable series of chiral phosphoramide catalysts (73),57 and these acids have been shown to be useful in carbocationic reactions, some of which are described later. There have been several recent reviews describing chiral Brønsted acids.58 In addition to the oxophosphoramide, chiral N-triflyl thio- and seleno-phosphoramides were also prepared.59 Yamamoto and Cheon also described the preparation and use of bis-N-trifluoromethanesulfonyl squaramide (74).60 This novel acid was shown to catalyze Mukaiyama aldol and Michael reactions, but its use in carbocation forming reactions has yet to be demonstrated. 2.5.2. Carboranes and Related Acids. A rather extraordinary series of acids and superacids have been developed by Reed and co-workers: the carborane

cation salt (62) was generated by hydride abstraction from a naphthyl silane using a trityl cation salt. In reactions with 1fluorodecane, complete hydrodefluorination is observed in 30 min at room temperature. A catalytic process is suggested involving the bridged disilyl cation salt (62) and the corresponding bridged disilyl fluoride salt (66). The bridged silyl cation 62 abstracts fluoride to generate the carbocationic intermediate, which immediately reacts with compound 65 to yield the hydrocarbon product. This leads to the formation of the bridged disilyl fluoride salt (66). Further reaction of the silane reducing agent completes the catalytic cycle. Remarkably, silylium carboranes have even abstracted fluoride from fluorobenzene.47 It was shown that reaction of salt 63 with fluorobenzene provides an 80% yield of the isomeric chloronium carboranes 67 and 68 (Scheme 24). As noted by the authors, compounds 67 and 68 are those expected from the generation of the phenyl cation. 2.4.3. Alumenium-Based Lewis Acids. The Ozerov group has examined alumenium catalysis as a means alkylating aliphatic C−F bonds.48 The alkylative defluorinations are accomplished through the use of Me3Al (or Et3Al) and catalytic dialkylalumenium cations paired with the hexabromocarborane anion. In one transformation, (3,3,3)-trifluoropropyl)benzene is found to give two products (69 and 70) from alkylative defluorination (Scheme 25). A mechanism is proposed in Scheme 24

H


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Scheme 25

nanotubes,66 methanetrisulfonic acid,67 and silicomolybdic acid within mesoporous silica hollow spheres.68

Scheme 26

3. CARBOCATIONS: LOW TO HIGH ELECTROPHILICITY 3.1. Reactions of Highly Stabilized Systems

It is not surprising that the first carbocation to be discovered was the triphenylmethyl cation, described in 1901 by Norris, Kehrman, and Wentzel.2 As a carbocation benefitting from resonance with three phenyl rings and considerable protection by steric effects, it is a relative stable ion. It forms easily by the ionization of triphenylmethanol, or the analogous halide precursors, using mildly acidic conditions. Less stable carbocations were thought to be involved in numerous synthetic organic transformations, but they were not generally persistent species or easily observed like the triarylmethyl cations. Olah’s ingenious use of stable ion conditions (highly acidic conditions with solvents of low nucleophility) substantially increased the lifetimes of the ions, preventing reactions with nucleophiles and bases.7b This enabled less stable carbocations to be observed directly by NMR and other methods. These studies also opened the door to many useful superacid-catalyzed reactions involving unstable carbocationic intermediates.65 The relative stabilities of carbocations have been a subject of study for decades. Among the methods of characterizing the stabilities of carbocations, Lossing’s measurements of gas-phase hydride affinities69 and Arnett’s calorimetric measurements70 in solution-phase (superacid) have been particularly useful. More recently, Mayr and co-workers have conducted extensive kinetics studies in estimating the electrophilicities and nucleophilicities of a wide variety of reactants.71 Using the equation log k(20 °C) = s(N + E), the rate constants k for nucleophile−electrophile reactions may be calculated from three parameters (N the nucleophilicity parameter, E the electrophilicity parameter, and s the nucleophile-dependent slope parameter). By analyzing pseudo-first-order rate constants with various types of nucleophiles, the electrophilicities of many cationic and neutral species have been established, including carbocations. The relative reactivities of carbocations are clearly apparent, for example, with diarylmethyl cations where the electrophilicity parameters and relative reactivities vary by at

(CH2B11R5X6; R = H, Me, Cl, Br; X = Cl, Br) and boron acids (H2B12X12, X = Cl, Br).61 Although very little work has been done to demonstrate their abilities to catalyze synthetic organic transformations, the remarkably high acidity has enabled the Reed group to prepare stable solutions of carbocations such as alkyl cations, protonated arenes, and even protonated C60. Consequently, it is expected that the catalytic activity of the carborane and boron acids should parallel other exceptionally strong Brønsted acids such as HF−BF3, CF3SO3H, FSO3H, and magic acid. The chemistry of these acids has been reviewed recently.61 2.5.3. BF3 Conjugate Acids. Olah and co-workers have described the Brønsted acid system, H2O−BF3, which is low cost, readily prepared, and highly acidic.62 Its ability to generate carbocationic intermediates may be inferred by the synthetic transformations it promotes.62 For example, this acid catalyst was used in Olah’s preparation of fluorine-containing pesticides, compounds structurally related to DDT [1,1,1-trichloro-2,2bis(p-chlorophenyl)ethane].63 The chemistry involves gemdiols and hemiacetals in reactions with arenes (hydroxyalkylation), and one of the electrophilic aromatic substitution steps occurs through formation of the benzylic carbocation. Recent work has also shown H2O−BF3 to catalyze electrophilic aromatic substitution reactions (halogenation, hydroxyalkylation, nitration), the Fries rearrangement, and thioacetalization of ketones. A similar Lewis acid conjugate has also been described with CF3CH2OH−BF3.64 These acids have been described in Olah’s recent monograph on superacid chemistry.65 2.5.4. Friedel−Crafts Brønsted Acids. There is also a continued demand for improved Friedel−Crafts alkylation catalysts, and a variety of new Brønsted acid catalytic systems have been reported. These include protonated titanate I


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least 15 orders of magnitude (Scheme 27).70 For synthetic applications, these data allow the relative reactivities of

cases, they are capable of reacting with the enols of aldehydes, ketones, and related compounds. These reactions lead to αfunctionalized products from carbonyl compounds. For example, Kobayashi has described a series of nucleophilic substitution reactions done in water and catalyzed by a surfactant-type Brønsted acid.74 Cyclohexanone is alkylated with alcohol 78 by the action of dodecylbenzenesulfonic acid in water (Scheme 28). Similar reactions were accomplished with

Scheme 27

Scheme 28

nucleophiles to be compared with the relative reactivities of the carbocations, and the respective reaction rates may be estimated. Thus, a successful reaction must utilize an electrophile and nucleophile with complementary reactivities, a concept beautifully described by Mayr (Figure 2).72 An active area of research involves the generation of relatively stable carbocations for use in synthetic methodologies. According to Mayr’s data on nucleophilicities, stabilized carbocations, such as 76 or 77, should react readily with good π-donor nucleophiles such as olefins, allyl silanes, enol silyl ethers, and enamines. Since stabilized carbocations may be generated using mild reaction conditions, this methodology has been the subject of several recent reports. It was also the subject of a brief review.73 3.1.1. Reactions with Enols. The tautomerization of carbonyl compounds leads to the formation of enols, and the nucleophilic character of the enols is well-known from reactions such as α-halogenation of aldehydes/ketones/esters. Stabilized carbocations may be formed as persistent species, and in some

other nucleophiles, such as diketones, thiols, indoles, and furans. Several Friedel−Crafts type reactions were reported, suggesting the involvement of carbocationic intermediates in the transformations. Despite the nucleophilic character of water, the carbocationic intermediate is sufficiently persistent to react with the nucleophilic reagents. For comparison, Mayr estimated water nulceophilicity to be 5.20 and ethyl vinyl ether to be 3.92, using reactions with diarylmethyl carbocations.75 This suggests that enols react via low concentrations of the carbocation intermediates. Cozzi has developed a novel set of carbocationic reactions conducted in water without the presence of acidic reagents.76 By generating highly stabilized carbocations, the carbocations are sufficiently long-lived for reactions with nucleophiles such indole, pyrrole, and acetylacetone. For example, the ferrocenyl alcohol 79 is suspended/floated in water with acetylacetone, and the substitution product (81) is formed in good yield

Figure 2. Estimated reaction rates, kcalcd’s, using nucleophilicity parameter N and electrophilicity parameter E. J


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(Scheme 29). It is suggested that ionization leads to formation of the stabilized ferrocenyl carbocation 80. Ionization is likely

Scheme 31

Scheme 29

facilitated by hydrogen bonding effects at the oil−water interface, as the mixture forms an emulsion or biphasic solution. Other stabilized carbocations gave similar results, while less stable cationic systems were unreactive under these conditions. Reactions of stabilized diarylmethyl cations have been used to provide functionalized oxazolones and related heterocycles.77 Thus, reaction of the oxazolone and alcohol provide the functionalized heterocycle 82 in quantitative yield (Scheme 30). Although the reaction was also shown to proceed with the

suggest the L-proline carboxylic acid group serves an important role in the catalytic reaction by generating the chiral enamine. Xiao recently described a stereoselective α-alkylation of aldehydes using a chiral diarylprolinol silyl ether (Scheme 32).82 Coupled with a reduction step, the alcohol product (86) Scheme 32

Scheme 30

is formed in good yield and enantioselectivity from n-butanal. In some systems, IrCl3 or IrBr3 performed better than CuCl as the Lewis acid catalysts, with typical loading of 10−20 mol %. Asymmetric alkylation of ketones and aldehydes has also been accomplished with pyrrolidine-derived chiral ionic liquids.83 A series of ionic liquid catalysts, amines, and pyrrolidines were compared in a test reaction involving the SN1-type alkylation of cyclohexanone imines with bis[4(dimethylamino)phenyl]methanol (Scheme 33). The experiments showed the highest degree of enantioselectivity with ionic liquid 87, as the alkylation product was obtained in 79% ee. With a substituted cyclohexanone (89), alkylation is accomplished with fair enantioselectivity and excellent diastereoselectivity. In addition to the substitution product 89, a substantial amount of the enantioenriched starting material is recovered. The diaseteroselectivity can be understood as a result of the preferred axial attack of the carbocation at the enamine (90). In another recent report,84 a thioxotetrahydropyrimidinonesubstituted pyrrolidine was used in the α-alkylation of cyclic ketones with stabilized carbocations. MacMillan catalysts were found to be particularly effective in promoting the asymmetric alkylation of aldehydes via stabilized carbocations.85 A series of proline and imidazolidinone catalysts were screened in a model reaction between n-octanal and bis(4dimethylaminophenyl)methanol. The imiadazolidinone 91 was found to have the highest activity, and in a series of SN1-type alkylations, it provided good yields of the alkylation products (i.e., 92, Scheme 34). Depending on the substrates, enantioselectivities were typically around 70−90% ee. For

use of a thiourea organocatalyst, trifluoroacetic acid (20 mol %) gave the optimum results. Similar alkylation products were obtained with 2-oxindole, pyrazolone, and benzofuranone heterocycles. A related series of conversions were reported by Chi and co-workers in which diarylmethanols are ionized by ptoluenesulfonic acid.78 The resulting carbocations alkylate aldehydes in good yields. 3.1.2. Reactions with Enamines. With the advent of proline, imidazolidinone, and other organocatalysts, many new synthetic methods have been developed utilizing enamine nucleophiles and related species.79 Some of these methodologies have provided outstanding levels of asymmetric induction from chiral catalyst systems.79 As moderately strong nucleophiles (N ∼ 11−16),80 enamines should react readily with stabilized carbocations, if the proper conditions can be developed wherein both the carbocation and enamine are generated. Melchiorre and co-workers demonstrated that arylsulfonyl indoles provide stabilized carbocations for α-alkylation of aldehydes (Scheme 31).81 Sulfoxide 83 undergoes KFpromoted elimination, and with reprotonation, the electrophilic carbocation 85 is formed. Product 84 results from a reaction of the carbocation and the isovaleraldehyde-based enamine. Good yields and stereoselectivities were observed with several other aldehydes and arylsulfonyl indoles. Other pyrollidine and imidazolidinone organocatalysts were also studied, but only proline gave the desired alkylation product. The authors K


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Scheme 33

Scheme 34

Scheme 35

more highly substituted aldehydes, the reaction exhibited modest diastereoselectivities (d.r., 1.5−3.0:1.0). The reaction is thought to involve formation of the enamine 93 which reacts with the carbocation 94. It is suggested that the stereochemical outcome is determined by the carbocation approaching from the least hindered side of the enamine. The resulting iminium complex (95) is then hydrolyzed to generate the product and catalyst 91. Four other stabilized carbocations were shown to enantioselectively alkylate aldehydes. In an elegant application of organocatalysts, Jacobson’s group used aminothioureas to catalyze the enantioselective αalkylation of aldehydes with a stabilized carbocation (Scheme 35).86 The chemistry involves reaction of benzhydryl bromide (97) with 2-phenylpropionaldehyde in the presence of an aminothiourea catalyst (96). A mechanism is proposed for the conversion wherein compound 96 acts as a bifunctional catalyst, forming an enamine with the aldehyde and acting as Lewis acid to promote ionization of the alkyl halide. With hydrogen bond stabilization of the bromide ion, complex 99 is formed, and the enamine reacts with the carbocation. A secondary kinetic isotope effect was measured (kH/kD = 1.12), from deuterium-substitution at the benzhydryl carbon, and it is consistent with ionization of the sp3 center to form the carbocation and an sp2 carbon. Carbon−carbon bond

formation arises from reaction of the benzhydryl cation and the enamine. 3.1.3. Reactions with Other Nucleophiles. As an approach to β-arylpropionic acids, Martin and co-workers reported a reaction of heterocyclic alcohols (and acetates) with silyl ketene acetals.87 Ionization of the alcohol (100) by TMSOTf leads to the carbocation (101) and a reaction with the silyl ketene acetal gives the ester (102) in good yield (Scheme 36). These results are in accord with calculated nucleophilicities, in which silyl ketene acetals (N ∼ 8−10) are only slightly less reactive than enamines (N ∼ 11−16).70 Scheme 36

L


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Jiao’s group was able to develop a method by which stabilized benzylic cations couple with terminal alkynes (Scheme 37).88 For example, diphenylmethanol reacts with

Scheme 39

Scheme 37

phenyl acetylene through the use of TfOH and Fe(OTf)3 catalysts. It is suggested that the iron triflate complexes to the alkyne and the carbocation intermediate reacts with this complex. A final deprotonation step gives the substitution product (103). Phenylacetylene is a considerably less reactive nucleophile (N = 0.34) than enamines or silyl ketene acetals,89 so more reactive carbocations are used in this coupling reaction. Mayr’s electrophilicity measurement assigns the diphenylmethyl cation a value of E = 5.90.70 Dehydrative coupling reactions, such as one in Scheme 37, were recently the subject of a comprehensive review.90 Recent work by Najera and Baeza has demonstrated the reaction of allylic alcohols with nucleophiles such as arenes, sulfonamides, amides, and 1,3-dicarbonyl compounds.91 The reactions are promoted by fluorinated alcohols (trifluoroethanol, pKa 23.5, and hexafluoroisopropanol, pKa 18.2),92 and the allylic cations are formed. For example, alcohol 104 is reacted with the allylsilane to form the diene product 106 (Scheme 38).

3.2. More Reactive Carbocations

Barring the influence of steric effects, the stabilities of carbocations depend largely on the ability of substituent groups to donate electron density to the carbocation center. Conversely, carbocations having electron-withdrawing groups tend to be destabilized, and they may exhibit enhanced reactivities.96 For example, it was shown that the solvolysis of allylic mesylates (92% acetone−water) is greatly inhibited by CF3 group substitution (Scheme 40).97 Scheme 40

Scheme 38

This may be interpreted to mean that compound 110 gives an allylic cation (110+) which is roughly 5 orders of magnitude more reactive toward a mesylate nucleophile than is allylic cation 109+. The greater electrophilic reactivity of 110+ is obviously a consequence of the electron-withdrawing properties of CF3 group. This type of structure−activity relationship in carbocations has been the subject of extensive studies in physical organic chemistry.96 However, the activated carbocations have also seen considerable use in synthetic methodology. Recent examples are described in the following sections. 3.2.1. Reactions of α-Carbonyl Carbocations. It has been long recognized that α-carbonyl carbocations are very reactive electrophiles, and as such, they may be exploited in synthetic reactions.98 The α-carbonyl carbocations have been most often generated by ionization of α-hydroxy or α-bromo ketones, aldehydes, esters, and amides. This chemistry has been used in several routes to functionalized 2-oxyindoles. For example, reaction of a 3-hydroxyoxindole (111) with a Lewis acid provides the diaryl 2-oxyindole from N-methylindole (112, Scheme 41).99 Similarly, the 3-hydroxyoxindole (113) reacts in superacid to form products from Freidel−Crafts chemistry, such as the ethyl salicylate derivative (114).100 Both conversions involve ionization of the alcohol, providing the mono- and dicationic electrophiles (115 and 116, respectively). Zhou et al. recently described the preparation of functionalized 2-oxyindoles through the use of the Ritter reaction.101 3Hydroxy-2-oxindoles are reacted with HClO4 (10−20 mol %)

The intermediate allyl cation 105 has an estimated electrophilicity parameter E = 2.70.93 Given the weak nucleophilic reactivity of the allyl silane (N = 1.79),88 the reactive allylic cation helps facilitate this conversion. Allyl stannanes are also relatively good nucleophiles (N ∼ 3− 7) and react with many types of electrophilic species.70 Qin and co-workers recently generated a pyrroloindoline carbocation in order to prepare functionalized pyrroloindolines.94 In a key step in the synthesis of the natural product, (−)-ardeemin, the pyrroloindoline carbocation was reacted with prenyl tributyl stannane (Scheme 39). Thus, silver-promoted bromide abstraction leads to formation of the chiral carbocation 107. Alkylation occurs in good yield and perfect stereoselectivity to provide the pyrroloindoline 108. This synthetic intermediate was then converted to (−)-ardeemin. In the case of Qin’s syntheses of pyrroloindoline derivatives, a benzylic carbocation is utilized in the methodology. According to Mayr’s reactivity scales, benzylic carbocations, stabilized by a single aryl ring, are fairly reactive electrophiles (E > 4).95 This makes possible an extensive set of reactions, including those with significantly weaker nucleophiles. M


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Scheme 41

Scheme 43

3.2.2. Reactions of Fluoro-Substituted Carbocations. Previously, the hydrodefluorination and alkylative defluorination reactions of fluoroalkanes, trifluoromethyl-substituted arenes, and fluorobenzene were described.44−49 These remarkable processes were initiated by exceptionally powerful Lewis acids, such as the silylium cations, to abstract fluoride and create a new carbocationic site. In most of these processes, the carbocationic intermediates were simply reduced with excess triethylsilane or reacted with a trialkylaluminum. However, fluoro-substituted carbocations may also be useful electrophiles in synthetic reactions, and several recent studies have utilized these reactive intermediates in synthetic methods. For example, a novel method for the synthesis of polycyclic aromatic hydrocarbons has been described in which fluorinesubstituted carbocations are involved.104 The 1,1-difluoro-1alkene (126) is reacted in superacid to provide the cyclized compound in good yield (Scheme 45). Following the initial cyclization, the C−F bond is cleaved either through protolysis or by the action of the Lewis acid SbF5. The initial product 127 may then be oxidized to the benzochrysene. Although fluorosubstituted carbocations are not as well-stabilized as those having strong electron donating groups, the fluorine-substituted carbocation (128) does benefit from modest n→p donation. In a comparison of difluoro (130), dichloro (131), and carboxylic acid (132) groups, only the 1,1-difluoro-1-alkene (130) provides the desired hydrocarbon cyclization product in a model study.105 Recently, the Hu and Klumpp groups described the protolysis of trifluoromethyl groups as a means of generating carbocations.106,107 Despite being one of the strongest covalent bonds, the C−F bond is cleaved by the action of Brønsted superacids to give fluorine-stabilized carbocations. These carbocations are shown to be useful in Freidel−Crafts and other reactions (Scheme 46). 3.2.3. Reactions of Trifluormethyl-Substituted Carbocations. The effects of trifluoromethyl and other perfluoroalkyl groups on electrophilic sites (i.e., carbonyl groups) have been well-documented. Likewise, trifluoromethyl-substituted carbocations also show high electrophilic reactivities and pronounced charge delocalization. For example, perfluoroalkyl groups have a striking effect in the 1,3 γ-silyl elimination toward bicyclobutane

in the presence of alkyl, vinyl, or aryl nitriles to give amides of 3-amino-2-oxindole (Scheme 42). Ionization of compound 117 leads to formation of the α-carbonyl carbocation, and nucleophilic attack by the nitrile gives the Ritter reaction product 118. Scheme 42

Recently, two synthetic approaches leading to functionalized benzolactones have likewise employed α-carbonyl carbocation reactions. Nicolaou’s group used an intramolecular Friedel− Crafts reaction in their synthesis of the natural products, hopeanol and hopeahainol A.102 After completing model studies with analogous Freidel−Crafts reactions, the α-hydroxy ester 119 was prepared and subjected to the BF3−OEt2 catalyst reaction (Scheme 43). Although the α-carbonyl carbocation 120 is stabilized by two electron-rich aryl groups, it is sufficiently reactive to undergo the intramolecular reaction to give the benzolactone product (121) in good yield. Further synthetic steps provided the natural products hopeanol and hopeahainol A (122). The latter compound has been shown to be a potent acetylcholinesterase inhibitor and a possible antiAlzheimer’s disease drug. In another recent study, α-hydroxyesters were utilized in tandem Friedel−Crafts/lactonization reactions to provide benzofuranones (Scheme 44).103 Presumably, ionization of the α-hydroxyester 123 leads to a carbocation that undergoes the Friedel−Crafts reaction with resorcinol. The intermediate 124 subsequently forms the lactone ring of product 125. An alternative process could involve ester formation first and then the intramolecular Friedel−Crafts reaction. N


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Scheme 44

stereoisomer in 83% yield (Scheme 48).109 The observed stereochemistry suggests conformer 138 is strongly preferred

Scheme 45

Scheme 48

and dictates the stereochemical outcome of the reaction (cyclization into either of the adjacent phenyl rings will give the observed syn stereochemistry). Evidently, the trifluoromethyl group leads to significant charge delocalization of the carbocation into the phenyl group, leading to π-stacking with the adjacent phenyl group(s), and this stabilizes conformer 138.

Scheme 46

3.3. Reactions of Superelectrophilic Carbocations

During the 1970s, several literature reports described the reactions of monocationic electrophiles with greatly enhanced reactivities in superacidic media. Olah was the first to suggest the concept of superelectrophilic activation or protosolvation of the electrophiles.110 In the case of the nitronium cation (139), superelectrophilic activation involves partial or complete protonation of the oxygen lone pair electrons, and the ion develops increasingly positive charge (Scheme 49). Alter-

products (Scheme 47).108 Reaction of cyclobutane 133 provides the bicyclobutane 134 in about 90% (estimated by Scheme 47

Scheme 49

natively, the ion may interact with excess Lewis acid, and the same result is achieved. The increased positive charge greatly enhances the reactivity of the electrophile. In the case of the protonitronium dication (140 or 141), this species has been shown to react with alkanes and strongly deactivated arenes, both exceptionally weak nucleophiles. Since Olah’s seminal reports, a variety of carbocation-based superelectrophiles have been described, including the protosolvated tert-butyl dication (142),111 various ethylene dications (143), the carboxonium− carbenium dication (144),112 the ammonium−carbenium dication (145),113 and others (Scheme 50). The chemistry of superelectrophiles has been reviewed,114 and several more recent studies are described below.

NMR) along with the byproduct silyl ether and silanol. Without the trifluoromethyl substituent, the reaction gives bicyclobutane in just 2% yield. It is suggested that the trifluoromethyl substituent enhances the neighboring group interaction of the silyl group and this leads to ionization. The resulting carbocation (135) is strongly stabilized by γ-silyl interaction, and reaction with water or TFE then gives the final bicyclobutane 134. Perfluoroalkyl groups have also been shown to influence the stereoselectivity of intramolecular Friedel−Crafts reactions. When the 1,3-diketone (136) is reacted with benzene in CF3SO3H, the substituted indane (137) is formed as a single O


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Scheme 50

Scheme 52

3.3.1. Charge Migration and Remote Functionalization. Superelectrophiles often carry two or three positive charges on a relatively small molecular framework. Among the various reactions of superelectrophiles, many of the conversions involve processes in which the positive charges are separated, dispersed, or jettisoned.115 For example, Shudo and Ohwada studied superelectrophilic electrocyclizations and found that energy barriers were 6 to 17 kcal/mol lower for dicationic transition states versus monocationic transition states.116 It was suggested that charge−charge repulsive effects enhance the delocalization of electrons, a necessary condition for a pericyclic reaction. In recent work from our research group, we found examples in which tricationic superelectrophiles exhibit charge delocalization, and this enabled remote functionalization of the carbocationic intermediate (Scheme 51). Ionization of the

should be reasonably stable species due to n→π donation, and he suggested the possibility of superelectrophilic activation by interaction with excess Lewis acid (Scheme 53).121 Akhrem and Scheme 53

co-workers have utilized CBr4·2AlBr3 in several recent examples of alkyl group oxidations. These transformations amply demonstrate how CBr4·2AlBr3 earned the title as an “aprotic superacid”. The superelectrophilic trihalomethyl cations are capable of abstracting hydride from alkyl groups. Moreover, the resulting carbocations are utilized in synthetic methodologies by nucleophilic trapping. For example, 2-nonanone reacts to provide the dicationic intermediate (154) from hydride abstraction (Scheme 54).122,123 Hydride abstraction occurs regioselectively at C-8

Scheme 51

Scheme 54

triarylmethanol 146 in superacid leads to trication 147.117 Charge−charge repulsive effects tend to separate the positive charge centers, leading to positive charge formation at the remote site of the phenyl group (148). Nucleophilic attack at the para-position gives the arylated product (149) in good yield and regioselectivity. Remote functionalization has also been accomplished with trifluoromethyl-substituted carbodications.118 In other studies, it has been shown that charge centers can migrate through saturated carbon chains.119 Reaction of the hetrocyclic alcohol 150 with benzene in superacid leads to a nearly quantitative yield of the Friedel−Crafts product 153. This product is formed by ionization to carbocation 151, charge migration to carbocation 152, and reaction with benzene leading to product 153 (Scheme 52). Due to charge−charge repulsive effects, the 1,6-dication is favored over the 1,5dication. Deuterium labeling experiments suggested that charge migration occurs through deprotonation−reprotonation steps. 3.3.2. Superelectrophilic Trihalomethyl Cations. The powerful carbocationic oxidizing agent, CX3+ (X = Cl, Br; often combined with excess Lewis acid), was first described by Badger and Bach.120 Sommer noted that trihalomethyl cations

in order to minimize charge−charge repulsive effects. Isomerization leads to the tertiary carbocation 155 which is efficiently trapped by carbon monoxide to form the corresponding acyl cation (not shown). It was demonstrated that the resulting acyl cation reacts in good yield with alcohol and arene nucleophiles. With isopropanol, the ester (5) is formed in 78% yield. The same superelectrophilic system has also been used to produce 1,3-dicarbonyl adamantanes from adamantane and other carbonylated products from saturated hydrocarbons.124,125 Recent work has also shown the utility of HF− SbF5−CCl4 in C−H bond activation.126 Thibaudeau et al. have functionalized alkyl amides, ketones, and nitriles, by analogous superelectrophilic chemistry. Some of the proposed dicationic intermediates were observed by low temperature NMR spectroscopy. 3.3.3. Synthesis of Polycyclic Aromatic Compounds. In several recent reports, Klumpp and Li have described superelectrophilic condensation reactions leading to polycyclic P


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Scheme 55

aromatic compounds, including heterocyclic products.119,127 The chemistry involves two novel aspects: charge−charge repulsive effects within the dicationic intermediates and the role of benzene as a leaving group. For example, reaction of the styryl-functionalized substrate (157) gives 2-nitrochrysene (158) in good yield (Scheme 55).127 As noted above, charge−charge repulsive effects are important in multiply charged cationic species, a topic that was recently reviewed.115 In the present case, protonation of the styryl group occurs regioselectively to give dication 159 in order to maximize the distance between cationic charges and give the more stable benzylic carbocationic center. Cyclization is followed by an aromatization that occurs through the elimination of benzene. Although the phenyl group is not generally considered a good leaving group, ipso protonation generates the arenium ion 160 and benzene elimination occurs to give the chrysene aromatic ring system. A similar reaction may be accomplished with heterocyclic alcohols, such as pyridine 161 (Scheme 56).128 Ionization in superacid gives the dication 162, and subsequent ring-closing and ring-opening steps lead to the functionalized benzo[f ]quinoline (163).

Scheme 57

reactions have generated heterocyclic superelectrophiles. For example, the imidazolium−carbenium dication 168 was formed from double protonation (Scheme 58). Cyclization then provides compound 169 in modest yield.131 Scheme 58

An interesting example of superelectrophilic carbocation chemistry involves the anti-Markovnikov addition of Nallylanilines.132 When aniline 170 is reacted with HF−SbF5 (21 mol % SbF5), the tetrahydroquinoline 171 is isolated in good yield (Scheme 59). To account for nucleophilic attack at

Scheme 56

Scheme 59

3.3.4. Ammonium−Carbenium Dications. Several recent studies have demonstrated the synthetic utility of ammonium−carbenium dications. Thibaudeau has shown that β-fluoroamines (i.e., 166) may be prepared from unsaturated amines (i.e., 164) using HF−SbF5 (Scheme 57).129 Diprotonation leads to formation of the superelectrophilic species 165, which is sufficiently electrophilic to abstract fluoride from its (SbF5)n complex. It was also shown that N-allylic sulfonamides gave similar reactive carbocations, leading to intramolecular reactions with aryl groups or fluorination products depending on the reaction conditions.130 Other superacid-promoted

the terminal carbon, a mechanism is suggested involving the tricationic superelectrophile 172 with the three-center−twoelectron bond (formally a carbonium ion center). The aryl ring then reacts with terminal carbon of superelectrophile 172 providing the tetrahydroquinoline ring system. In support of the proposed mechanism, compound 170 was reacted with HF−SbF5 in the presence of C6D12, a potential deuteride donor, and products 173 and 174 were isolated (173:174, 31:5 ratio). Product 174 is notable because it indicates that a significant amount of positive charge resides at the terminal Q


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carbon. This type of charge distribution is consistent with the ring closure reaction leading to product 171.

Scheme 61

4. CARBOCATIONS IN CLASSICAL REACTIONS 4.1. Friedel−Crafts Alkylation

The first examples of Friedel−Crafts alkylation were reported in the late 1800s.133 While it is now recognized that these early examples involved carbocationic intermediates, it would be several decades before carbocations were suggested in mechanistic proposals.134 Friedel and Crafts initially suggested that their reactions occurred by formation of an aluminum chloride−arene complex followed by reaction with the alkyl halide. In papers by Klipstein and Meerwein, carbocations were first suggested as intermediates in Friedel−Crafts alkylation.135 The role of carbocation intermediates became firmly established by subsequent studies from others. Besides mechanistic considerations, the synthetic value of Friedel− Crafts alkylation cannot be overstated, as it is used in numerous industrial processes, pharmaceutical syntheses, and fine chemical preparations.136 Synthetic chemists continue to develop new methods and catalysts for Friedel−Crafts alkylation reactions, and as described below, it is a reaction used in the synthesis of various natural products. 4.1.1. Intramolecular Friedel−Crafts Reactions. As a route to ring-fused arenes, intramolecular Friedel−Crafts reactions have a long and successful history. Previously, intramolecular Friedel−Crafts reactions were discussed in the conversions of reactive and superelectrophilic carbocationic systems (vide supra). The intramolecular reactions of carbocations continue to provide new methods of carbocycle synthesis. For example, a series of substituted indenes were prepared by a superacid-catalyzed cyclization aryl-1,3-dienes (Scheme 60).137 Protonation of the diene 175 occurs

An intramolecular Friedel−Crafts reaction has been accomplished to give spirofurooxindoles.140 Ionization of alcohol 178 leads to the diarylmethyl carbocation 179 (Scheme 62). Nucleophilic attack at the furan ring carbon then leads to the observed spirocyclic product 180. In an effort to prepare novel derivatives of podophyllotoxin, a potent insecticide and antifungal agent, the Xu group has conducted an unusual intramolecular Friedel−Crafts reaction leading to the ring-fused bicyclo[2,2,2]octane product 181 (Scheme 63).141 Ionization of the ester group (Ar = p-tolyl) leads to the benzylic carbocation and cyclization gives compound 181. An intramolecular Friedel−Crafts reaction was used by Heo and co-workers in their recent synthesis of the natural product, laetevirenol A (184).142 Reaction of the alcohol (182) with pTsOH gives the advanced synthetic intermediate 183 in fair yield and excellent diastereoselectivity (Scheme 64). Global demethylation then provides laetevirenol A. The conversion is thought to occur by an equilibration of two carbocations (185− 186), with the less stable benzylic carbocation (186) leading to the cyclization product 183. Both enantiomers of aphanorphine have been prepared by Friedel−Crafts cyclizations involving chiral 3-pyrrolidinols (Scheme 65).143 (−)-Aphanorphine was synthesized by the reaction of 3-pyrrolidinol (187) with AlCl3 to obtain the tricyclic intermediate (189), a cyclization involving the chiral carbocation 188. Further synthetic steps then provided the natural product 190. A similar Lewis acid-catalyzed transformation was described recently by the Lautens group as an efficient route cis-hexahydrobenzophenanthridines and related tetracyclic compounds.144 Acid-catalyzed ring-opening reactions of cyclic ethers are general routes to carbocations, and it is common in both organic and biosynthetic chemistry. Epoxide ring-opening is often used in the carbocationic cyclization cascades of polyolefins (vide inf ra), but it has also been useful in Friedel−Crafts alkylation. For example, Qu and Li recently described a series of stereoselective intramolecular Friedel− Crafts reactions involving the ring-opening of epoxides with perfluorinated alcohols.145 In another study, highly functionalized isochroman and dioxabicyclooctane derivatives were prepared in good yields by the Lewis acid promoted ringopening reactions of dihydropyrans (Scheme 66).146 For example, the substituted dihydropyran 191 reacts with Sc(OTf)3 (20 mol %), and ring-opening leads to the stabilized allylic carbocation (192). A Friedel−Crafts type reaction then provides the mixture of regioisomers 193a and 193b. In order to account for the observed stereoselectivity, a mechanism is proposed in which the hydroxysilyl ether and the styryl

Scheme 60

regioselectively to provide carbocation 176, and cyclization provides the indene 177 in nearly quantitative yield. Regioselective protonation leads to cyclization at the more electron-rich aryl ring. Alternatively, the cyclization of 176 may be more closely related to a 4π-electrocyclization. Experimental and theoretical results from a similar reaction are consistent with an electrocyclization mechanism.138 Yang and co-workers used the protonation of stilbene derivatives and carbocation intermediates to access dibenzo[a,d]cycloheptanes.139 The chemistry was applied to the synthesis of natural products (±)-ampelopsin B and diptoindonesin D (Scheme 61). Thus, reaction of (±)-εviniferin (prepared by the dimerization of resveratrol) with triflic anhydride leads to formation of (±)-ampelopsin B. A mechanism is suggested involving olefin protonation and cyclization to the natural product. R


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Scheme 62

Scheme 63

Scheme 65

substitutuents reside in pseudoequatorial positions of the intermediate carbocation 192. An allylic carbocation cyclization was also used in Harmata’s recent synthesis of elisapterosin B precursors and related tetralin derivatives (Scheme 67).147 Using Hg(OTf)2, the allylic alcohol 194 is ionized in benzene or toluene, and the cyclization product is obtained in 73% yield as a mixture of stereoisomers. The trans isomer of 195 is formed with a modest degree of selectivity, though bulkier allylic groups showed greater diastereoselectivity. Recently, Frontier and Eisenberg described a novel rearrangement and cyclization of a heterocyclic enone catalyzed by an iridium(III) catalyst.148 Thus, compound 196 is reacted to provide the spirocyclic compound 197 in good yield (Scheme 68). The reaction involves formation of the iridium(III) catalyst by silver-promoted bromide abstraction. Complexation with the 1,3-dicarbonyl group leads to positive

charge formation at the β-carbon with a subsequent hydride shift leading to carbocation 198. This intermediate then undergoes an intramolecular Friedel−Crafts reaction to give the final product 197. 4.1.2. Intermolecular Friedel−Crafts Reactions. Even with the rapid growth of transition-metal-catalyzed reactions, Friedel−Crafts reactions are still perhaps the most important route to functionalized aromatic compounds. A substantial number of intermolecular Friedel−Crafts alkylations are described in the research literature each year, as alkylbenzenes and other functionalized arenes are extremely useful feedstock chemicals. Recent applications of intermolecular Friedel−Crafts reactions are described below.

Scheme 64

S


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as a mixture of diastereomers. The strong preference for the syn stereoisomer may be rationalized by formation of the carbocation 201 and diastereofacial differentiation based on the relative sizes of the ester group and oxy group. It is noted that diastereoselectivity is greatest with increasing size of the ester alkoxy group and stabilization of the carbocation center (via electron donating substituents). Huo and Wang recently described a series of novel Friedel− Crafts reactions with chalcone epoxides.149 Their chemistry involves generation of a distonic radical cation intermediate from oxidative ring-opening of the epoxide and subsequent nucleophilic reaction at the carbocationic center (Scheme 70).

Scheme 66

Scheme 70

Scheme 67

Using tris(4-bromophenyl)aminium hexachloroantimonate (TBPA+SbCl6−), the chalcone epoxide (202) gives the Friedel−Crafts product 203 in 67% yield as the mixture of stereoisomers. Overall, the conversion is catalytic, as 5 mol % of the one electron oxidant is used in the conversion. An analogous reaction was done with 2-naphthols, and subsequent cyclization/oxidation steps provided good yields of polysubstituted naphtha[2,1-b]furans.150 Synthetic approaches to α-aryl carbonyl compounds are extremely useful, as this substructure is present in a number of clinically useful drugs. There have been several recent reports describing the use of α-carbonyl carbocations in Freidel−Crafts reactions as an approach to these types of products. For example, Johnson and Smith utilized α-keto phosphates (204) as precursors to acyl-substituted carbocations, and these were successfully trapped with aryl (Scheme 71), enol silyl ether, azide, and other n-type nucleophiles.151 Taylor and co-workers arylated a series of compounds by ionization of α-bromo esters (i.e., 205) and amides.152 This study also demonstrated the application toward intramolecular Freidel−Crafts reactions.

Scheme 68

As a means of preparing 3,3-diaryl-2-hydroxypropionates, Bach and Wilke carried out Friedel−Crafts reactions with 3arylglycidates (i.e., 199, Scheme 69). For example, epoxide ring-opening with Sc(OTf)3 provides the arylated product 200 Scheme 69

T


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(OTf)2 all provided yields of 210 greater than 85%. Subsequent steps then gave the desired tetracyclic ring system (i.e., 211). The Lautens group recently described the diastereoselective arylation of amino-substituted tetralins (Scheme 74).154 For

Scheme 71

Scheme 74

As a method for preparing pyrroloindoline derivatives, Qin and co-workers have utilized silver-promoted Friedel−Crafts reactions. Functionalized pyrroloindolines are known for diverse biological activities, including some promising results against multidrug resistant pathogens and cancers. Thus, the bromide 206 is reacted with AgBF4 in the presence of an arene nucleophile (Scheme 72). The resulting benzylic carbocation

example, reaction of the amino alcohol 212 with excess aluminum chloride provides the Friedel−Craft product 213 in excellent yield and diastereoselectivity. Lower yields were obtained with decreasing amounts of acid, suggesting formation of the dicationic, superelectrophilic intermediate (214). The chemistry was also accomplished with alkylbenzenes, aryl ethers, thiophenes, furan, indole, and pyrrole.

Scheme 72

4.2. Cationic Cyclization Cascades

The cationic cyclizations of polyterpenes and olefins have been intensively studied for more than 70 years. Nature exhibits exquisite regio- and stereocontrol in cyclization cascades, and synthetic organic chemists have long sought to use similar chemistry to prepare target molecules and develop new methodologies.155 In recent years, synthetic methods have been developed for cationic cyclization cascades with novel substrates and new catalysts or reagents. Although cation-π cyclizations of polyprenoids have been promoted by a variety of electrophilic reagents and acids, very little progress has been made with halonium-induced cyclizations. However, such reactions are well-known in nature leading to halogenated natural products. Two recent studies have demonstrated the viability of cation-π cyclization cascades using halonium-type reagents.156 The Snyder group described the use of Et2SBr·SbBrCl5 to effect polyene cyclizations.156a,b For example, olefin 215 was reacted with Et2SBr·SbBrCl5, and the cyclization product 216 was obtained in 75% yield (Scheme 75). This method was compared to similar reactions with Br2/AgBF4, NBS/PPh3, and 2,4,4,6-tetrabromocyclohexa-2,5-cyclohexadienone, but Et2SBr·SbBrCl5 was found to give the highest yields for cation-π cyclizations. Ishihara and co-workers described a method for enantioselective halocyclization utilizing N-iodosuccinimide and a chiral phosphoramidite (Scheme 75).156c Reaction of olefin 217 leads to the cyclization product 218 in modest yield and 91% ee, following a secondary reaction with ClSO3H. It is proposed that the reactive electrophile is the chiral phosphonium salt 219 (X = succinimide anion). It is also suggested that the bulky triphenylsilyl groups play a crucial role in the facial selectivity at the achiral olefin 217, with delivery of the iodonium preferred on the si-face.

(207) reacts with good positional selectivity in conversions with substituted arenes. As described previously, carbocation 207 was also used in the synthesis of (−)-ardeemin.87 Bisai and co-workers conducted Friedel−Crafts reactions with 3-hydroxy-2-oxindoles in order to access the core structure of the azonazine indole alkaloids (Scheme 73).153 A variety of Lewis acids were shown to ionize compound 209 leading to the Fridel−Crafts product; In(OTf)3, Cu(OTf)3, Bi(OTf)3, SnScheme 73

U


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Scheme 75

Scheme 77

example, Lewis-acid-promoted epoxide ring-opening with epoxide 226 gives product 227 by a pair of carbocationic ring closure reactions (Scheme 78). The reaction was also catalyzed Scheme 78

The Corey group has utilized epoxide-initiated cation−olefin polyannulation as an approach to pentacyclic triterpenes, including enantioselective access to the natural product germanicol.157 Starting from farnesyl acetate, epoxide 220 was prepared and subjected to Lewis acid-catalyzed epoxide ringopening, followed by treatment with polyphosphoric acid (Scheme 76). The penetacyclic synthetic intermediate 221 is isolated in 33% yield, and subsequent steps provide germanicol (222). The biomimetic synthetic chemistry begins with Lewisacid-promoted epoxide ring-opening, carbocation formation, and then a cascade of bond forming reactions (223). A similar synthetic method was used by Corey’s group to prepare the naturally occurring nor-triterpenes, aegiceradienol,158,159 as well as related pentacyclic triterpenes. A tetracyclization was also utilized in the enantioselective synthesis of (+)-α-onocerin.160 Shaw’s research group has recently described the first cationic cyclization cascade promoted by sulfur- and selenium-based electrophiles that produces heterocyclic structures.161 For example, diene 224 reacts with phenylselenium chloride and Sc(OTf)3 to give the heterocyclic product 225, following deprotection of the amine (Scheme 77). It is suggested that the active catalyst is a protic acid generated from Sc(OTf)3 and adventitious moisture. With exclusive formation of the trans-fused product, the cyclizations likely occur through the “chair−chair” conformation. The cyclization of olefinic epoxides has also provided a route to indole mono-, sesqui-, and diterpene alkaloids.162 For

by BF3−Et2O, MeAlCl2, and SnCl4 Lewis acids. Larger systems (228) were also cyclized, although the yields decrease and isomeric products were formed. In the biosynthetic pathways involving polyisoprenes, there are two modes of carbocationic cyclization: head-to-tail and tailto-head. Shenvi and Pronin recently demonstrated a rare example of tail-to-head cyclization, and it has been applied to the synthesis of naturally occurring terpenes (Scheme 79).163 For example, reaction of epoxide 229 with EtAlCl2 provides the carbon framework for cumacrene (232) and dunnienoic acids in 40% yield. The authors propose a key aspect involving sequestration of the counteranion away from the carbocation. Thus, ring-opening leads to the allylic carbocation 230 and then to intermediate 231. Because the counteranion is distant from carbocation site, this allows the slow cyclization to occur, as opposed to deprotonation of 231 to an undesirable alkene.

Scheme 76

V


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Scheme 79

4.3. SN1 and SN1′ Reactions

Scheme 81

SN1 reactions have been the subject of numerous synthetic and physical organic chemistry studies since the early 1900s. Through the pioneering mechanistic work of Ingold, Hughes, Winstein, Olah, and many others, the roles of carbocation intermediates were firmly established.164 Recent synthetic studies have used this venerable reaction to prepare novel products.165 For example, Mead and co-workers have utilized SN1 chemistry as a synthetic approach to a pyranochromene ring system.166 When diol 233 is ionized with p-TsOH, carbocation 234 is generated (Scheme 80). The new pyran ring Scheme 80

functionalized dihydropyrans (240) were synthesized (Scheme 82).169 The preference for syn stereochemistry was explained by Scheme 82

is formed by diastereoselective reaction of the alcohol group with the carbocation, and product 235 is formed in 81% yield. As an explanation for the facial selectivity at the carbocation reaction, the authors suggest π-stacking between the benzylic carbocation and the adjacent methoxyphenyl group. This proposal is supported by further experimental work as well as computational studies. The chemistry provides access to pyranochromene ring system common to natural products calyxin I, calyxin J, and epicalyxin J. As a synthetic approach to the dalesconol natural product ring system, a carbocation-mediated dearomatization reaction was developed by Shi and co-workers.167 Thus, reaction of substrate 236 in silica gel provides the carbocation 237 which attacks the ipso position of the adjacent aryl group (Scheme 81). Desilylation also occurs to give the synthetic intermediate 238 in good yield. Carbocationic intermediates have been effectively used in the preparation of cyclic ethers. For example, a Ca(NTf2) 2 catalyzed hydroalkoxylation was reported leading to good yields of tetrahydrofurans and tetrahydropyrans from unsaturated alcohols.168 In another study, Hanessian utilized BF3·OEt2 to ionize allylic alcohols (i.e., 239), and a series of

favored attack from the re-face of the carbocation center (241). It was suggested that si-face attack requires a conformation with unfavorable eclipsing interactions. Through the use of a novel SN1 reaction, Liu has developed an asymmetric synthetic approach to the sesquiterpene, epiheliannuol E (Scheme 83).170 Ionization of the alcohol 242 leads to the cyclization product 244 as the exclusive diastereomer in 86% yield. It is suggested that an initial 3° carbocation undergoes acetate migration to the 2° carbocation (243) which is rapidly captured by the phenolic hydroxyl group. The observed stereoselectivity may be explained by a conformation (245) in which the bulky substituents reside in pseudoequatorial positions. W


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Scheme 83

promoted ring-opening, followed by a 4π electrocyclization ring closure to give 251 (vide inf ra). Compound 251 was successfully converted to the functionalized cyclopentyl amine 254, a substance shown to have hNK1 inhibitory activity in biological studies. A similar set of intramolecular reactions has also been reported by the same research group. The chemistry has been applied to the synthesis of a novel series of aza-spirocycles and spirocyclic ethers.173,174 For example, compound 255 is ionized to the carbocation 256, and cyclization leads to the intermediate product 257 (Scheme 86). The spirocyclic ether

In a study related to the mechanism of the Prins cyclization, Alder and co-workers generated the 2-oxa-5-adamantyl carbocation (246) and used it in the preparation of functionalized oxo-adamantanes (247−249; Scheme 84).171 Scheme 84

Starting from 5-bromo-2-oxoadamantane, reaction with AgSbF6 provides cation 246. Further reaction with TMSN3 gives the azide 247, or water gives the alcohol 248. Ritter reaction conditions provide the amide (249). Recently, several reports have described the use of diaryl carbocations bearing the furyl group, as an entry into the Piancatelli rearrangement. For example, Read de Alaniz and coworkers showed that ionization of the alcohol (250) with lanthanide triflates in the presence of anilines provides the rearrangement product (251) in good yield (Scheme 85).172 Related systems gave similar products in fair to excellent yields (52−92%). The reaction involves ionization to the benzylic carbocation 252 and nucleophilic attack at the furan ring to provide the intermediate product 253. Compound 253 undergoes the Piancatelli rearrangement by Lewis-acid-

Scheme 86

product (259) is formed in good yield by the ring-opening− ring-closing sequence (257 → 259) of the Piancatelli rearrangement. Yin and co-workers have described another series of Lewis-acid-catalyzed reactions of furandiols, but under their reaction conditions, ring-fused cyclopentenones are formed.175 Several recent studies have demonstrated the utility of ionic liquid systems in carbocation-based substitutions. Many ionic liquids possess high levels of Brønsted or Lewis acidity, and thus, they are capable of generating carbocations from suitable precursors.176 Creary and co-workers have also shown that the strong ionizing power of nonacidic ionic liquids can lead to carbocationic intermediates from ionization of organo trifluoroacetates and triflates.177 The resulting carbocations give products from elimination, rearrangement, or substitution reactions.

Scheme 85

4.4. Wagner−Meerwein Rearrangements

The Wagner−Meerwein rearrangement is a historically important reaction in organic chemistry. In 1899, Wagner discovered the interconversion of camphene hydrochloride, isobornyl chloride, and camphene. Shortly thereafter, Meerwein X


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to yield ketone 268 in 54% yield. Further ring-construction steps provide the desired tricyclic terpenoid core. The Wagner−Meerwein rearrangement has also been used to prepare the B/C/D rings of C19-diterpenoid alkaloids, aconitine, talatizamine, and chasmanine.182 Thus, heating of compound 269 leads to the Wagner−Meerwein rearrangement and formation of cation 270 (Scheme 89). Cation 270 reacts with DMSO, and a base-promoted elimination gives compound 271 in good yield.

and Vam Emster observed solvent effects for the camphene hydrochloride isomerization, and the solvent effects were strikingly similar to those previously reported in the ionization of triphenylmethyl chloride.4 This prompted Meerwein to propose “a rearrangement of the cation”, a landmark suggestion that an organic reaction occurs with involvement of a carbocationic species. The contemporary description of Wagner−Meerwein rearrangements includes 1,2-cationic migrations of alkyl and aryl groups as well as hydride. Review articles describing the Wagner−Meerwein rearrangement have appeared regularly.178 Recent synthetic studies have described both novel skeletal rearrangements of carbocations and the use of Wagner− Meerwein rearrangements in targeted syntheses. For example, a Wagner−Meerwein rearrangement is involved in the rearrangement perhydro-3a,6; 4,5-diepoxyisoindoles (Scheme 87).179

Scheme 89

Scheme 87

Steroidal epoxides are well-known for their tendencies to undergo acid-promoted ring-opening and isomerization through Wagner−Meerwein rearrangements. Recently, it was shown that ionic liquids promote these conversions with good yields and selectivity.183 Heating epoxide 272 in 1-butyl-3methylimidazolium hexafluorophosphate, [bmim]+[PF6]−, leads to a quantitative conversion to the 13-epi-18-nor-16-one derivative 273 (Scheme 90). On the basis of earlier NMR Thus, reaction of diepoxide 260 with BF3·Et2O and acetic anhydride provides the tricyclic product 263 in good yield. The proposed mechanism involves epoxide ring-opening to carbocation 261 and a Wagner−Meerwein rearrangement leading to cation 262 and the final product 263. A similar rearrangement was reported earlier which involved 2,11cepoxyoxireno[6,7]isoindolo[1,2-a]isoquinolines.180 The Wicha group has utilized the Wagner−Meerwein rearrangement to elegantly prepare the dicyclopenta[a,d]cyclooctane ring system of fusicoccins and ophiobolins natural products (Scheme 88).181 The epoxide 264 is reacted with BF3−OEt2, which undergoes ring-opening to the carbocation 265. Following a Wagner−Meerwein rearrangement, carbocation 266 reacts through a pair diastereoselective hydride shifts

Scheme 90

Scheme 88 studies showing epoxide ring-opening, the authors suggest a similar mechanism involving structure 274. Ring-opening is followed by migration of the methyl group, hydride shift, and ketone formation. Recently, Katoh and co-workers reported the enantioselective total synthesis of (+)-stachyflin, a potent antiviral compound.184 The key step of their synthesis involves ringopening of the epoxide 275 (Scheme 91). Formation of an intermediate carbocation is followed by a Wagner−Meerwein rearrangement with a 1,2-hydride shift to form carbocation 276. The resulting carbocation is then trapped by the phenolic hydroxyl group, which provides the required cis-ring junction between the A and B rings of (+)-stachyflin. Oxidation provides the pentacyclic ketone 277 in 71% yield. Y


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Scheme 91

Scheme 93

Scheme 94

An interesting oxidative Wagner−Meerwein transposition has been developed by Canesi and co-workers.185 For example, phenol 278 is reacted with the hypervalent iodine reagent to generate the carbocationic intermediate 279 (Scheme 92).

example, a tandem ring-opening and ring-closing sequence has been used to prepare dihydropyrrole-based chromophores.189 The 1-cyclopropylindene (286) reacts with acetonitrile, and the dihydropyrrole 287 is formed in good yield (Scheme 95). A

Scheme 92

Scheme 95

Migration of the allyl group and deprotonation gives the highly functionalized cyclohexadienone 280. It was also shown that alkyl, aryl, and vinyl groups will undergo transposition, and a ring contraction was also accomplished. 4.5. Homoallylic−Cyclopropyl Carbinyl Carbocations

The equilibrium between the cyclopropyl carbinyl, homoallylic, and cyclobutyl carbocations has been extensively described from mechanistic studies.186 Additionally, this carbocationic system has been utilized in numerous synthetic studies. In a recent application, the homoallylic carbocation rearrangement was used by Tian and co-workers to prepare the bridged [10]annulene structure of Rp(−)-spiniferin-1, a natural product with planar chirality.187 Their approach involved preparation of perfluoroalkylsulfonate ester (281) from an alcohol precursor with concomitant formation of the homoallylic carbocation (282; Scheme 93). Rearrangement then provides Rp(−)spiniferin-1. Utilizing the cyclopropyl ring-opening rearrangement, the bromide 283 was converted to the homoallylic bromide 285 in 77% yield (Scheme 94).188 Presumably, the rearrangement involves ionization to the cyclopropyl carbinyl dication 284. The product 285 is then converted to a lycorine-type alkaloid product. Besides targeted synthetic reactions, this carbocationic system has been used in methodology development. For

mechanism is proposed involving protonation of the indene giving the carbocation 288 while subsequent ring-opening and nucleophilic attack provides the nitrilium ion 289. Ring-closure and deprotonation then gives the final product 287. In another new methodology, Honda and co-workers have obtained 3-phenylselenohomoallylic products (i.e., 292) from reaction of the corresponding cyclopropane (290, Scheme 96).190 The preference for the Z-stereoisomer may be explained by the preferred conformation of carbocation 291. Functionalized allenes could then be prepared by oxidative elimination of the phenylselenyl group. A previous study from this group described similar chemistry with cyclopropylsilylmethanols leading to Z-homoallyl derivatives.191 The Yadav and France groups have recently described homoNazarov cyclization involving cationic cyclopropyl ring-openings. For example, the functionalized indole (293) is reacted with SnCl4, and the ring-fused product 295 is formed in good Z


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Scheme 96

Scheme 99

the spirocyclic product 301 in good yield. Other Lewis acids TiCl4, InCl3, and ZnCl2 also promoted the reaction. In another recent study, it has also been demonstrated that cyclopropyl carbinyl cations may react with nitrogen-centered nucleophiles, providing a route to N-heterocycles.197 An unusual example of the cyclopropyl carbinyl−cyclobutyl cation interconversion was observed in the PPh3 reduction of endoperoxides (Scheme 100).198 When peroxide 302 is reacted

yield (Scheme 97).192 Complexation of the carbonyl group by the Lewis acid leads to ring-opening and generation of the βScheme 97

Scheme 100

with PPh3 in AcOH, the bicyclic product 305 is formed as a minor byproduct (13% yield). The conversion involves heterolysis of the peroxide bond and formation of the carbocation 303. Ring expansion leads to the bridgehead carbocation 304 which is then trapped by acetate. Carbocation 303 also reacts with acetate to give ca. 50% yield of the corresponding hydroxyl acetates (cis and trans).

silyl-stabilized homoallylic cation (294). A Friedel−Crafts-type reaction then provides the ring-fused product (295). A similar ring-forming strategy was described by using In(OTf)3 catalyst and TsOH.193,194 Aryl-stabilized homoallylic cations were involved in the conversions. Chan’s group has used cyclopropyl methanol to generate homoallylic products for use in halocyclizations (Scheme 98).195 For example, reaction of alcohol 296 leads to the

4.6. Ritter Reaction

The Ritter reaction was first described in 1948, and it has found general use in the preparation of N-alkylamides from carbocation intermediates.199 The chemistry continues to be an active area of investigation. Among the recent work, Baran and co-workers developed a method by which unactivated sp3 C−H bonds are aminated via the Ritter reaction (Scheme 101).200 Their work is based in part on an earlier study by Banks et al. describing the C−H functionalization of alcohols, in which F-TEDA-BF4 (Selectfluor) leads to low yields of Ritter

Scheme 98

Scheme 101

product of rearrangement 297, presumably through the cyclopropyl carbinyl cation. Further reaction with N-iodosuccinimide provides the iodocyclization product 298 in excellent yield. An interesting series of reactions were described by Yeh and co-workers in which homoallylic cations react with an adjacent tethered alkyne (Scheme 99).196 Thus, alcohol 299 is reacted with FeCl3, and cationic ring-opening leads to the homoallylic cation 300. Subsequent ring-closure and chloride trapping gives AA


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reaction byproducts.201 As an example of the new methodology, menthol (306) is reacted with F-TEDA-PF6 and catalytic quantities of CuBr2 and Zn(OTf)2 in acetonitrile. The amide (309) is formed in 91% yield. In the proposed mechanism, hydrogen atom abstraction and oxidation lead to the carbocation 307 which undergoes the Ritter reaction and cyclization to give heterocycle 308. Hydrolysis then gives the final product 309. Similar amidations were accomplished with ketones and even cycloalkanes. Although the vast majority of Ritter reactions involve nonstereoselective reactions at carbocations, several diastereoselective reactions have recently been reported. For example, Lepore demonstrated the stereoretentive synthesis of amides from cyclic alcohols (Scheme 102).202 The alcohols (i.e., 310)

Scheme 103

Scheme 102 Scheme 104

are initially converted to the chlorosulfites, and these are reacted with the nitrile−TiF4 complex. A mechanism is proposed in which the chlorosulfite complex 311 is formed. This undergoes dissociation (312), and the cation is trapped by a front-side nucleophilic attack. Hydrolysis then provides the amide 313 with retention of the stereochemsitry. The authors suggest that the stereochemical outcome may be the result of a pyramidal carbocation center. Another approach to the diasteroselective Ritter reaction was described by Bach, and it utilizes an adjacent stereocenter to control facial selectivity of nucleophilic attack at the carbocation center.203 Chiral secondary benzylic alcohols were reacted with aliphatic and aromatic nitriles in strongly acidic media, and following aqueous workup, the amide products were obtained (Scheme 103). In the case of alcohol 314, the product 315 is formed in good yield, with excellent diastereoselectivity with the anti diastereomer being strongly preferred. The stereoselectivity is explained by nucleophilic attack occurring from the si face of the planar carbocation (316) due to the larger size of the methyl group (A = 1.74) compared to the methoxycarbonyl group (A = 1.2). An intramolecular Ritter reaction has also been accomplished with excellent diastereoselectivity.204 Reaction of the 1-indanol derivative (317) in methanesulfonic acid provides the heterocycle (318) in good yield exclusively as the cis-ring-fused product (Scheme 104). Ionization leads to carbocation 319, followed by internal nucleophilic attack by the cyano group. The facial selectivity is largely controlled by the geometric constraints of the adjacent carbon. The synthetic methodology was developed in an approach to compounds such as the cisfused hexahydro-4aH-indeno[1,2-b]pyridine (320), a potential nonpeptide NK1-antagonist.

Heteropoly acids were evaluated as catalysts for Ritter reactions (Scheme 105).205 In an interesting example with Scheme 105

camphene (321), phosphotungstic acid is shown to promote the Wagner−Meerwein rearrangement of the carbocation 322, followed by a Ritter reaction with cation 323. Amide 324 is formed as the exclusive product, suggesting that the rate of the Wagner−Meerwein rearrangement far exceeds the rate of Ritter reaction with carbocation 322. A Wagner−Meerwein−Ritter sequence was also used in a recent synthesis of amantadine derivatives, some of which showed promising activity against influenza virus strains.206 Thus, the noradamantyl alcohol 325 is reacted with H2SO4 in the presence of chloroacetonitrile, and the chloroacetamide (326) is formed in good yield (Scheme 106). The adamantyl cage is formed by isomerization of carbocation 327 to the relatively stable 3° bridgehead carbocation 328. The Ritter reaction provides compound 326 AB


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4-cyanopyridine in the presence of the ionic liquid, [BMIM](SO3H)[TfO], and the resulting amide is isolated in 70% yield (entry 4). Amgen researchers recently described a convenient method for preparing tert-butyl amides with the use of tert-butyl acetate (entry 5).211 This method is considered more convenient for large-scale Ritter reactions preparing tert-butyl amides, as it avoids the use of isobutylene or tert-butanol. The method has been demonstrated with aryl, vinyl, and alkyl nitriles. As described previously, Zhou and co-workers have used the Ritter reaction to prepare functionalized 2-oxyindoles by the Ritter reaction.101

Scheme 106

4.7. Schmidt Reaction

During the 1990s, Pearson’s group demonstrated the general utility of the Schmidt reaction between carbocationic centers and alkyl azides. Both inter- and intramolecular reactions were shown to be effective. In 2000, the reaction was used to prepare the natural product, gephyrotoxin.212 More recent studies have also used the intramolecular Schmidt reaction to prepare alkaloid products. For example, the indolizadine ring system may be accessed by an epoxide-initiated cyclization (Scheme 107).213 The conversion involves epoxide ring-opening to

(the amide group may be cleaved to the amantadine derivative by reaction with thiourea). Among the recently developed synthetic methodologies, various substrates, acids, and conditions have been used in the Ritter reaction (Table 1). A photochemical approach was used by Song and co-workers (entry 1),207 producing a relatively stable benzylic carbocation which could be trapped by acetonitrile. Table 1. Various Ritter Reaction Methodologies

Scheme 107

generate the carbocationic site (331), and nucleophilic attack by the azide is followed by extrusion of N2 along with bond migration. Intermediate 332 is produced, and reduction with hydrolysis provides indolizadine 330. Compound 330 was then converted to indolizadine alkaloids 167B and 209D. The Schmidt reaction is a well-established route to imines, but recently it was shown that unsaturated imines could also be prepared from allyl cations (Scheme 108).214 Using either allylic alcohol or ethers, intramolecular Schmidt reactions provide α,β-unsaturated cyclic imines in fair to good yields (35−83%, 13 examples). The chemistry was applied to the synthesis of a Costa Rica ant venom alkaloid (335). Thus, reaction of ether 333 with TMSOTf leads to the allylic carbocation 334 and the Schmidt reaction product 335. 4.8. Pinacol and Prins-Pinacol Rearrangements

The pinacol rearrangement dates to the middle 1800s, and it has been used in many synthetic applications.215,216 In recent use, George and co-workers utilized a pinacol rearrangement in the synthesis of (+)-liphagel, a marine natural product exhibiting potent anticancer activities.217 The key step of their synthesis involves the reaction of diol 336 with CF3CO2H (Scheme 109). Ionization provides the chiral, benzylic carbocation 337, which undergoes ring expansion to the carboxonium ion 338. Dehydration occurs readily in the acidic conditions, and the benzofuran product 339 is formed in 74%

Likewise, Yadav’s group obtained amide products from the reactions of styrenes and related olefins with HBF4−OEt2 and nitriles (entry 2).208 Cossy and co-workers have sought to develop environmentally benign catalyst systems, and they found FeCl3·6H2O effectively promotes the Ritter reaction (entry 3).209 Benzylic alcohols and tertiary-alkyl acetates were used as the carbocation source. Laali et al. have described an efficient methodology using acidic ionic liquids to promote Ritter reactions.210 For example, 1-adamantanol is reacted with AC


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Scheme 108

approach was recently described for the preparation 2oxasprio[m,n]alkanes, a structural motif found in several natural products (Scheme 111).219 Reaction of diol 343 with

Scheme 109

Scheme 111

overall yield. Formylation and demethylation steps then provide (+)-liphagel. Suzuki and co-workers have developed an isoxazole-directed pinacol rearrangement that was used to generate quaternary carbon centers in a stereoselective manner.218 For example, diol 340 was reacted with BF3−OEt2 (20 mol %), and the rearrangement product 342 was isolated in 94% and 98% ee (Scheme 110). The mechanism involves regioselective

acetaldehyde leads to formation of the carboxonium ion 344 which undergoes the Prins reaction leading to carbocation 345. Ring contraction and deprotonation then give the final tricyclic product 346. Overman and Velthuisen have described a Prins-pinacol reaction involving the preparation of chiral attached ring systems.220 As an example, compound 347 was reacted with SnCl4, and the attached ring product 348 was obtained in 82% yield (Scheme 112). Significantly, the reaction occurs with

Scheme 110

Scheme 112

ionization of the bridgehead hydroxyl group to form carbocation 341, followed by stereospecific migration of the prenyl group. It was suggested that the isoxazole ring effectively stabilizes the carbocation center and this is the basis for regioselective ionization. Other groups were also shown to undergo 1,2-migration, including aryl, heteroaryl, vinyl, and alkynyl groups. Besides ionization of 1,2-diols, the carbocation intermediates may be generated by other means. A particularly useful method has been through the Prins reaction. An example of this

enantioselective construction of two adjacent stereocenters. This is considered to be a consequence of stereoelectronic effects in the Prins reaction (349) and rapid pinacol rearrangement (350), prior to conformational equilibration of the cyclohexyl cation ring. Subsequent studies by the same research group showed that the Prins-pinacol rearrangement AD


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can also be used toward the stereocontrolled synthesis of 12oxatricyclo[6.3.1.02,7]dodecane ring systems.221 Recently, their work with this chemistry culminated in the total synthesis of (+)-sieboldine (354, Scheme 113).222 Reaction of the acetal

Scheme 114

Scheme 113

benzofulvene 359 in good yield (Scheme 115).228 Good yields of product 359 were also obtained with AuClPPh3, and H3PMo12O40 catalysts.

351 with TiCl4 provides the carbocation 352 via the Prins reaction. A subsequent pinacol rearrangement gives the bicyclic product 353 in 70% yield. Further synthetic steps gave the unusual N-hydroxyazacyclononane ring system of (+)-sieboldine (354).

Scheme 115

4.9. Hydroamination

Hydroamination combines an olefin with an amine or related compound, a reaction having 100% atom economy. There have been significant advances in transition-metal-catalyzed hydroamination chemistry,223 but fewer examples are known utilizing Lewis and Brønsted acid catalysts.224 In one recent example, Li et. al have developed Lewis-acid-catalyzed (FeCl3, ZrCl4, BiCl3, and AlCl3) hydroamination, and a mechanism is proposed in which the amine−Lewis acid complexes protonate the alkenes to form carbocationic intermediates.225 Nucleophilic reaction with free amines (anilines) or group transfer from the Lewis acid then provides the hydroamination product (ca. 50−95% yields). A cyclization cascade was used by Knight and Haskins to prepare (±)-α-cyclopiazonic acid, a toxic biproduct from the fungus Penicillin cyclopium Westling. The synthesis begins with the preparation of the silyl ether 355 in several steps from indole-4-methanol (Scheme 114). Reaction of 355 with CF3SO3H leads to the tetracyclic intermediate 357 in 74% yield. The conversion is thought to involve cyclization through the benzylic carbocation 356. Further steps then provide (±)-α-cyclopiazonic acid.

A similar type of cyclization has been described recently, though not formally a Nazarov cyclization, in which allylic alcohols undergo FeCl3-catalyzed cyclizations to functionalized indenes (Scheme 116).229 Reaction of alcohol 361 with FeCl3 (10 mol %) leads to formation of the allylic carbocation 362, and cyclization to carbocation 363, and deprotonation gives indene 364 in good yield. Compound 364 was then converted to the natural product, jungianol. Scheme 116

4.10. Nazarov Reaction

The Nazarov reaction was first described in the 1940s, and it has become a valuable transformation in synthetic organic chemistry.226 The Nazarov reaction has been the subject of numerous review articles and accounts, as the chemistry has been widely studied over the years.227 Moreover, it has been used in several natural product synthetic routes. Many Nazarov reactions begin with the formation of a carboxonium ion and they often form a new ring by a 4π-electrocyclization reactions. As a reaction with carboxonium ion intermediates, this chemistry is outside the scope of the present review article. Nevertheless, some carbocation-based Nazarov-type reactions have been reported. For example, reaction of the allenic alcohol 358 with Brønsted or Lewis acids provides the AE


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In some Nazarov reactions, the intermediate oxyallyl cation may participate in secondary reactions. As described in many previous reports, the oxyallyl cation may be trapped by nucleophiles or rearrange through carbocationic pathways.230 Several recent investigations have sought to further explore this area of synthetic carbocation chemistry. For example, Frontier and co-workers have described a novel series of synthetic reactions leading to spirocyclic cyclopentenones (Scheme 117).231 Thus, reaction of compound 365 with the Lewis

Scheme 118

Scheme 117

Table 2. Products and Yields from the Reactions of Oxyallyl Cation 374 with π-Nucleophiles

acid 369 gives the product cyclopentenone 366 in 91% yield. This transformation is thought to occur via the Nazarov reaction intermediate 367, which itself undergoes a Wagner− Meerwein shift and styryl migration (368). Dissociation of the Lewis acid (369) then provides the cyclopentenone product. Recent progress in oxyallyl cation chemistry includes reactions with amine nucleophiles. The Tius group has prepared a variety of amine-functionalized cyclopentenones by this chemistry, including optically active products.232 The propargyl vinyl ketone (370) was prepared with a camphorderived chiral auxiliary group, and reaction with activated florisil leads to the oxyallyl cation 371 (Scheme 118). Stereoselective reaction of phenethylamine at the si face of the carbocation leads to the cyclopentenone 372. Similar reactions without the chiral auxiliary were described in an earlier paper.233 Burnell and Marx have developed methodologies for generating new carbon−carbon bonds by nucleophilic reactions at the oxyallyl cation.234 π-Nucleophiles such as furan, cyclohexadiene, and enol ethers provide the respective products (375−377) in good yields (Table 2). While reactions with allylsilanes also gave some of the desired C-allylated product, the conversions often gave mixtures of products.

Scheme 119

Perhaps the most well-known of these reactions is the Meyer−Schuster rearrangement,236 in which water reacts at the allenyl cation site and an α,β-unsaturated carbonyl compound is formed. The Meyer−Schuster rearrangement and related processes continue to be used in new synthetic methodologies. For example, the Liang group has utilized this chemistry to convert hydroxylated enynes to functionalized heterocycles (Scheme 120).237 Thus, enyne 379 is converted to the 2,3dihydropyrrole 380 with the use of catalytic CF3SO3H. The reaction involves formation of cation 381 and subsequent ring formation. The use of the Meyer−Schuster rearrangement in heterocyclic synthesis has also been recently reviewed.238

4.11. Propargylic and Allenyl Cations

The ionization of propargylic alcohols leads to an extremely useful carbocationic intermediate.235 The carbocation generally has both the character of a propargylic cation 378a and an allenyl carbocation 378b (Scheme 119), opening up a diverse set of available synthetic transformations. AF


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Scheme 120

Scheme 122

Wang and Lu have utilized the allenyl cations (i.e., 383) to prepare a variety of products. This includes functionalized allenes,239 indenes,240 and 4-methylene-4,5-dihydro-1H-pyrazoles (Scheme 121).241 Compound 384 was prepared in 75% yield with Yb(OTf)3 while compounds 385 and 386 were prepared in 72% and 50%, respectively, with BF3·OEt2. A recent report has also demonstrated the use of cation 383, and related allenyl cations, in the synthesis of 2,5-dihydroisoxazoles by reactions with N-tosyl hydroxylamine.242 In another heterocycle synthesis, a three-component reaction was developed to give functionalized dihydroazepines.243 A mechanism is proposed involving reaction of the allenic carbocations with in situ formed enamine nucleophiles. Liu and co-workers have utilized allenyl cations in a preparation of dihydro-β-carbolines (Scheme 122).244 For example, ionization of the α-indolyl propargylic alcohol (387) gives the allenyl cation 388. Reaction of the nitrone, with subsequent rearrangement, gives the final dihydro-β-carboline 389. Besides triflic acid, Sc(OTf)3 was also found to be an effective catalyst for the reaction. The Zhan group has developed a method of preparing acrylonitriles via a domino reaction involving propargylic substitution and rearrangement (Scheme 123).245 For example, reaction of alcohol 390 with p-tosylhydrazide in the presence of FeCl3 (10 mol %) gives the acrylonitrile 391 in good yield. A mechanism is proposed in which the propargylic cation reacts with p-tosylhydrazide leading to intermediate 392. In some cases, the intermediate substitution products (i.e., 392) could be isolated, and mechanistic studies showed that these intermediates reacted further to provide the expected acrylonitrile products. This suggests an isomerization, referred to as an aza-Meyer−Schuster rearrangement, leads to the allene intermediate 393. Further tautomerization to 394 and

Scheme 123

elimination of TsNHTMS provides the final product 391. The methodology works best with diarylpropargylic alcohols although several aryl alkyl-substituted alcohols, such as 390, were successfully converted to the acrylonitriles. Dehydrative propargylation has been demonstrated for a variety of nucleophiles,246 and the conversions often proceed through the propargyl cation. Several recent reports have described Friedel−Crafts-type propargylation reactions,247

Scheme 121

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including several methodologies used to prepare functionalized indoles (Scheme 124). Among the new methods for the

Scheme 126

Scheme 124

5.0. CARBOCATIONS IN ASYMMETRIC SYNTHESIS 5.1. General Aspects

Asymmetric synthesis has become an important part of nearly all areas of organic synthesis, including the chemistry of carbocations. This area of carbocation chemistry has been particularly active over the past several years. Useful synthetic methodologies have been developed which exploit the inherent reactivities of carbocationic intermediates. The utility of this chemistry has also been demonstrated in its application toward natural product syntheses. As generally a planar structure, carbocations may react with nucleophiles at either of two faces. If a new stereocenter is being formed, then facial selectivity of nucleophilic attack becomes the key aspect in asymmetric synthesis with carbocations. There have been three basic strategies for controlling facial selectivity in reactions at carbocations (Figure 3). First, chiral directing groups and auxiliaries have been

propargylation of indole, catalytic p-toluenesulfonic acid248 and aluminum triflate249 are shown to provide good conversions. Use of catalytic amounts of the rhenium complex [ReBr(CO)3(thf)]2 facilitates the propargylation of indole.250 This catalytic system is also shown to couple the propargylic system to 1,3-diketones, β-ketoesters, enol silyl ethers, alcohols, thiols, and electron-rich arenes. A novel method of coupling has been described by Rao and Venkateswarlu, in which DDQ reacts at an sp3 carbon to initiate the coupling reaction.251 Although no mechanism is proposed for the conversion, it likely involves hydride abstraction to form the propargylic cation. Hall and co-workers have developed a novel catalyst for the Meyer−Schuster rearrangement, electron-deficient boronic acids.252 As described previously, the electron-deficient boronic acids catalyze a variety of SN1 and SN1′ reactions. Accordingly, reaction of the propargylic alcohol 395 with the boronic acid 396 leads to the unsaturated ester 397 in good yield (Scheme 125). It was shown that less-substituted propargylic alcohols Scheme 125

were significantly less reactive in the conversion, suggesting the involvement of the propargylic carbocations in the initial reaction steps. The West group has recently described an interesting series of VO(acac)2 catalyzed Meyer−Schuster rearrangements involving propargyl bis(allylic) alcohols.253 For example, reaction of alcohol 398 leads to carbocation formation (399) and subsequent steps to give the cross-conjugated triene 400 (Scheme 126). Other common catalysts gave little (GaCl3, AuCl3) or no (TsOH, PtCl4) triene product.

Figure 3. Methods for stereocontrol at carbocations. AH


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shown to control the preferred route of nucleophilic attack.204 These are reaction involving chiral carbocations. Usually this involves an adjacent stereocenter blocking either the re or the si face of the carbocation. It may also involve geometric constraints in ring-forming reactions. A second strategy involves the use of a chiral counterion that associates with the (typically) achiral carbocation.254 This synthetic method has become increasingly useful with the development of new types of chiral Brønsted acids. Intimate ion pairing creates the chiral environment around the achiral carbocation resulting in stereoselective reactions with nucleophiles. A third type of asymmetric synthesis involves the use of chiral nucleophiles in reactions with achiral carbocations.255 This strategy has been useful with various organocatalysts, for example in the reactions of chiral enamines. In the following section, recent examples of asymmetric synthesis with carbocations will be discussed.

anti-selectivity was observed for the CO2Me, NO2, OH, CN, Cl, and CCTMS substitutents, while syn-selectivity was observed for the SO2Et, SO3Et, and PO(OEt)2 substituents. These observations are consistent with A-values or the relative sizes of the groups at the adjacent stereocenter. In another study from the Bach group, various Lewis acids were compared and AuCl3 (10 mol %) was found to be an effective catalyst for the ionization of benzyl acetates, giving Friedel−Crafts products.257 The reactions lead to products in good diastereoselectivities. Besides arene nucleophiles, the diastereoselective substitution reactions are demonstrated with allyltrimethylsilane, trimethylsilylcyanide, acetylacetone, and enolsilyl ethers. Though similar reactions were demonstrated with FeCl3 and Bi(OTf)3, the authors note better functional group tolerance with the gold catalyst. Using similar chemistry, a chiral benzylic carbocation has been generated and used in the synthesis of (−)-podophyllotoxin (408), a biologically active member of the lignane class of natural products.258 The required alcohol substrate (405) was prepared from the Taniguchi lactone (404) by an aldol reaction (Scheme 128). Though several catalytic systems were

5.2. Stereocontrol by Covalently Attached Groups: Chiral Carbocations

Similar to the reactions of other trigonal planar groups (enolates, aldehydes/ketones, alkenes), asymmetric reactions of carbocations involve facial control of reactant delivery. This is often done through the influence of an adjacent stereocenter. Several of these types of systems have already been discussed, as these chiral carbocations have been used in stereoselective Friedel−Crafts, SN1 and SN1′, Wagner−Meerwein rearrangement, Ritter, pinacol rearrangement, and Nazarov reactions. While diastereoselective intramolecular reactions of carbocations have been known for some time, only recently have intermolecular reactions been described. An early series of studies were done by the Bach group in which chiral benzylic cations were generated and trapped with arene, silyl enol ether, and other nucleophiles (Scheme 127).256 The benzylic cations

Scheme 128

Scheme 127

examined, FeCl3 provided the best yield and stereoselectivity for the Friedel−Crafts reactions. Reaction of the alcohol 405 leads to the chiral benzylic carbocation 406 which gives product 407 from the 1,3-benzodioxole. Subsequent reaction steps provide (−)-podophyllotoxin (408) in 35% overall yield from the Taniguchi lactone 404. Seeking an efficient route to 1,1,2-triarylalkanes for a drug development program, Merck researchers described the use of chiral benzylic carbocations in diastereoselective Friedel−Crafts reactions.259 For example, the optically active 1-pentanol (409) is reacted with the protected indole (410) in CF3CO2H, and the substitution products (411/412) are formed in 92% yield (Scheme 129). This system provided the highest diastereoselectivity (94:6, anti/syn) and yield, as the authors examined the effects of aryl substitutents (adjacent to carbocation and on the arylsulfonyl group), acid catalyst, and alcohol chain length. The best diastereoselectivities were achieved with the 1-pentanol system (anti/syn, ∼10:1), while an analogous 1-propanol system exhibited little diastereoselectivity (anti:syn, ∼2:1). From the optically active alcohol 409 (99% ee), the anti product 411 is formed in 98% ee, an indication that the stereochemical integrity was retained at the α-carbon. The

are ideal substrates for stereoselective reactions, as they are relatively stable and conformationally well-defined due to 1,3allylic strain. Thus, the enantiomerically enriched alcohol 401 reacts with 2-methylthiophene in the presence of HBF4·OEt2 to give the substitution product 402 in 93% yield and excellent diastereoselectivity. The reaction involves formation of the resonance-stabilized carbocation 403 (R = CO2Me) and strong preference for the anti-substitution product 402. The diastereofacial selectivity can be understood by assuming the nucleophile approaches from the less-hindered face of the carbocation, the side bearing the methoxycarbonyl substituent. Other carbocations (403) were generated with a variety of substituents, and all showed good reactivities in Friedel−Crafts reactions with electron-rich arenes. Good to excellent levels of diastereoselectivities were observed for all carbocations. The AI


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Scheme 129

Scheme 130

synthesized from the tris(2,6-dimethoxyphenyl)methyl cation (Scheme 131). Carbocation 419 is highly stabilized (pKR+ ∼

observed stereoselectivity is explained by nucleophilic attack from the same face as the α-phenyl group (413). Besides these synthetic applications, there has also been some effort to directly observe and characterize chiral, carbocationic intermediates. Using stable ion conditions, the chiral carbocations may be directly observed by low temperature NMR spectroscopy (Scheme 130).260 For example, ionization of alcohol 414 in superacidic FSO3H provides the chiral carbocation 415, which was fully characterized using oneand two-dimensional NMR spectroscopic experiments (DEPT, COSY, NOESY, HMQC, HMBC). Chemical shift values for the carbocationic center and the methoxy-substituted carbon suggest a substantial degree of charge delocalization. Cation 415 may be trapped, albeit in low yield, to provide the substitution product 416 with good diastereoselectivity. Using a stronger acid (magic acid, FSO3H/SbF5), the dicationic species (418) was also observed by NMR. The strongly deshielded carbocation site is consistent with the weaker stabilizing ability of the p-tolyl substitutent, while the deshielded ester carbonyl carbon is consistent with its protonation in magic acid. Carbocation 418 is considered an example of a chiral superelectrophile. In a study by Lacour and co-workers, an unusual series of diastereoselective reactions were reported with carbocations possessing helical chirality.261 Carbocationic [4]helicenes were prepared; for example, the quinacridinium derivative (419) was

Scheme 131

19), and due to steric effects, a helical conformation is generated with an inner pitch of about 2.7 Å. This stereochemical element leads to diastereotopic facial discrimination in reactions with both hydride and organolithium reagents. Reaction with phenyllithium results in the formation of the diastereoselective product 420 via re face attack. Since the methoxy groups reside almost exactly above and below each other, nucleophilic attack from beneath (si face attack) would force the methoxy groups into each other, disfavoring this reaction course. The degree of diasteroeselectivity was found to be highly dependent on the size of the nucleophile and the nature of the N-substituents. AJ


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5.3. Stereocontrol by Use of Chiral Counter Ions

In a combined intra- and intermolecular reaction, You and co-workers used chiral N-triflyl phosphoramide catalysts in enantioselective syntheses of aryl-substituted fluorenes (426 → 427; Scheme 133).264 In an optimized procedure, the 9phenanthryl-substituted N-triflyl phosphoramide (425) was found to give the best yields and enantioselectivities. There were 11 chiral N-triflyl phosphoramides examined. The condensation is thought to involve formation of the carbocation with coordination of the chiral counterion (428), leading to the enantioselective ring closure. A similar series of reactions were also reported with the use of chiral phosphoric acids.255 The Rueping group described the use of chiral Brønsted acids to promote a catalytic asymmetric allylic substitution, a reaction utilized in the synthesis of chromenes (Scheme 134).265 Thus, alcohol 430 is reacted with the chiral N-triflyl

The development of chiral Brønsted acids and related conjugate Lewis-Brønsted acids has led to many new stereoselective synthetic methodologies involving electrophilic species.262 In some of these reactions, the stereoselectivity originates from tight ion pairing between an achiral electrophile and the chiral conjugate base or anion. In other cases, the reaction may be initiated by stereoselective delivery of a proton or electrophile to an alkene or other group. As a recent example of this strategy, Corey and Surendra used a conjugate Brønsted−Lewis acid system to initiate a highly enantioselective polycyclization.263 Reaction of polyenes with the SbCl5-dichloro-BINOL acid system (421) leads to polycyclic products (Scheme 132). For example, triene 422 Scheme 132

Scheme 134

provides the tetracyclic product 423 in good yield and enantioselectivity. The authors propose a mechanism involving π-face-selective protonation with the developing carbocation center being stabilized by a naphthyl ring (424). The high enantioselectivity can be attributed to the rapid cyclization steps involved in the formation of 423. The tin complex was found to be superior to similar acids with In(III), Al(III), or Ti(IV) metal centers.

phosphoramide (429) in toluene, and the product chromene (431) is formed in 84% yield with 93% ee. The authors attempted a similar conversion with other N-triflyl phosphoramides, and the stereoselectivities varied from 12% to 92% ee (10 acids). Similar yields and enantioselectivities were obtained from substrates having varied aryl substituents. It is suggested that enantioselectivity is the direct result of formation of a

Scheme 133

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Scheme 135

Scheme 136

contact ion pair between the chiral counteranion and achiral carbocation (432). A highly enantioselective alkylation of enamides has been reported (Scheme 135). For example, Guo and co-workers have shown that enamides are alkylated in good enantioselectivities (88−96% ee) with stabilized benzylic carbocations in the presence of chiral phosphoric acids.266 The optimized procedure utilized the H8-BINOL-based phosphoric acid (433), and in the case of enamide 434, alkylation with alcohol 435 provides alkylation product 436 following hydrolytic workup. The alkylation product is formed in 80% yield and 89% enantioselectivity. In an attempt to carry out enantioselective Friedel−Crafts reactions, chiral phosphoric acids (i.e., 437) were used to ionize benzylic alcohols 438, and the resulting carbocation intermediates were trapped with indole nucleophiles (Scheme 136).267 Although modest, the stereocontrol is thought to arise from ion pairing between the carbocation and the chiral phosphate counterion. The phosphoric acids were not sufficiently reactive to ionize alcohols, such as 1-phenyl-2,2dimethyl-1-propanol, which give less stabilized carbocations.

Figure 4. Chiral enamines shown to react enantioselectively with carbocations.

general strategy, reacting an achiral electrophile with a chiral nucleophile, is a well-established approach in asymmetric synthesis. Despite the achievements made with organocatalysts and chiral enamines, this area of carbocation chemistry has seen relatively little development. The chiral enamine chemistry has been illustrated nicely by the recent study from Kokotos.256 Using the chiral thioxotetrahydropyrimidinone-substituted pyrrolidine catalyst (445), cyclohexanone is enantioselectively alkylated to give product 446 (Scheme 137). With ionization of the benzhydrol, nucleophilic attack by the enamine forms the new carbon− carbon bond (447) and stereocenter. It is proposed that the thioxotetrahydropyrimidinone ring assists in the delivery of the carbocation to the re-face of the enamine.

5.4. Stereocontrol by Reactions with Chiral Nucleophiles

As described previously, highly stabilized carbocations may be generated under the same reaction conditions in which some organocatalysts are used. With the use of chiral organocatalysts, such as L-proline, pyrrolidines, imidazolidinones, and aminothioureas, enantioselective synthetic strategies have been developed for the alkylation of aldehydes and ketones with carbocations. These methodologies involve the formation of chiral enamines (93, 440−443; vide supra) as the nucleophiles (Figure 4). In such reactions, facial selectivity at the enamine is controlled by the chiral auxiliary group, and attack by the achiral carbocation generates the new stereocenter. This AL


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Scheme 137

Scheme 138

nucleophile (450). Product 451 is formed in 90% yield with reasonably good diastereoselectivity.

A variation of this approach was reported by Melchiorre and co-workers.268 Asymmetric γ-alkylation of enals has been achieved through the use of stabilized carbocations and organocatalysts. For example, reaction of the enal (448) with the alcohol in the presence of a primary amine catalyst (cinchona alkaloid) and chiral phosphoric acid leads to γalkylation of the cyclohexene ring (Scheme 138). As with similar conversions with aldehydes and ketones, the reaction is thought to involve dienamine formation and ionization of the alcohol to the carbocation. Martin has described a unique coupling reaction between an achiral carbocation and a chiral nucleophile.269 A diastereoselective reaction was developed through the use of an oxazolidinone chiral auxiliary group (Scheme 139). Thus, reaction of the indole alcohol with CF3SO3Si(CH3)3 provides the carbocation 452, which reacts then with the chiral π-

6.0. SUMMARY AND OUTLOOK In the 112 years since the carbocation was discovered, organic chemists have developed a vast array of synthetic methodologies based on carbocationic intermediates. Older synthetic conversions, such as the Friedel−Crafts reaction, are constantly evolving. New approaches, catalysts, and substrates continue to be developed. Moreover, these classical reactions are being utilized in state-of-the-art total syntheses projects, a testimony to the value and scope of these carbocation-based reactions. We also continue to see synthetic organic chemists develop new and innovative methods for generating carbocations, especially those produced in a chiral environment. In the years ahead, challenges will include advancing the asymmetric synthetic methodologies, developing more robust catalysts, and finding more environmentally friendly conditions for carbocationic reactions. Norris, Kehrman, and Wentzel could not have imagined the growth that would come from their unusual, yellow sulfuric acid solutions. Perhaps similar to an acorn being planted in the dirt, with time bringing forth a trunk and the enormous branches of an oak tree, the discovery of the carbocation has led to the development of major areas in organic chemistry and many useful synthetic organic transformations.

Scheme 139

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. AM


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Notes

REFERENCES

The authors declare no competing financial interest.

(1) Whitmore, F. C. J. Am. Chem. Soc. 1932, 54, 3274. (2) (a) Norris, J. F. Am. Chem. J. 1901, 25, 117. (b) Kehrman, F.; Wentzel, F. Chem. Ber. 1901, 34, 3815. (3) (a) Stieglitz, J. Am. Chem. J. 1899, 21, 101. (b) Baeyer, A.; Villiger, V. Chem Ber. 1902, 35 (1189), 3013. (c) Gomberg, M. Chem. Ber. 1902, 35, 2397. (4) Meerwein, H.; Van Emster, K. Chem. Ber. 1922, 55, 2500. (5) Ingold, C. K.; Rothstein, E. J. Chem. Soc. 1928, 1217. (6) Whitmore, F. C. Ind. Eng. Chem. 1934, 26, 94. (7) (a) Stang, P. J. In Carbocation Chemistry; Olah, G. A., Prakash, G. K. S., Eds.; Wiley: Hoboken, NJ, 2004; pp 1−6. (b) Olah, G. A. J. Org. Chem. 2001, 66, 5943. (c) For an excellent historical account of the development of carbocation chemistry, see: Nenitzescu, C. D. In Carbonium Ions; Olah, G. A., Schleyer, P. v. R., Eds.; Wiley: New York, 1968; Vol. 1, pp 1−76. (8) Olah, G. A. My Search for Carbocations and Their Role in Chemistry. In Nobel Lectures, Chemistry 1991−1995; Malmström, B. G., Ed.; World Scientific Publishing Co.: Singapore, 1997. (9) (a) Olah, G. A.; Molnar, A. Hydrocarbon Chemistry; Wiley: Hoboken, NJ, 2003; pp 215−220. (b) Olah, G. A.; Molnar, A. Hydrocarbon Chemistry; Wiley: Hoboken, NJ, 2003; p 513. (10) (a) McCann, D. M.; Lesthaeghe, D.; Kletnieks, P. W.; Guenther, D. R.; Hayman, M. J.; Van Speybroeck, V.; Waroquier, M.; Haw, J. F. Angew. Chem., Int. Ed. 2008, 47, 5179. (b) Li, J.; Wei, Y.; Chen, J.; Tian, P.; Su, X.; Xu, S.; Qi, Y.; Wang, Q.; Zhou, Y.; He, Y.; Liu, Z. J. Am. Chem. Soc. 2012, 134, 836. (11) (a) Mota, C. J. A.; Rosenbach, N., Jr. J. Braz. Chem. Soc. 2011, 22, 1197. (b) Stavitski, E.; Pidko, E. A.; Kox, M. H. F.; Hensen, E. J. M.; van Santen, R. A.; Weckhuysen, B. M. Chem.Eur. J. 2010, 16, 9340. (12) (a) McClelland, R. A. Org. React. Mech. 2012, 257. (b) Aue, D. H. Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2011, 1, 487. (c) Okulik, N. B.; Jubert, A. H.; Castro, E. A. Trends Org. Chem. 2011, 15, 51. (d) O’Ferrall, R. M. Adv. Phys. Org. Chem. 2010, 44, 19. (e) Tantillo, D. J. Chem. Soc. Rev. 2010, 39, 2847. (e) Reddy, V. P.; Prakash, G. K. S. Adv. Phys. Org. Chem. 2009, 43, 219. (f) Laali, K. K.; Borosky, G. L. Adv. Phys. Org. Chem. 2009, 43, 135. (g) Tantillo, D. J. J. Phys. Org. Chem. 2008, 21, 561. (h) Shubin, V. G. Russ. Chem. Bull. 2008, 57, 761. (i) Siehl, H.-U. Adv. Phys. Org. Chem. 2008, 42, 125. (j) Carbocation Chemistry; Olah, G. A., Prakash, G. K. S., Eds.; Wiley: Hoboken, NJ, 2004. (13) Olah, G. A.; Laali, K. K.; Wang, Q.; Prakash, G. K. S. Onium Ions; Wiley: Hoboken, NJ, 1998. (14) Olah, G. A. J. Am. Chem. Soc. 1972, 94, 808. (15) (a) Utley, J. Chem. Soc. Rev. 1997, 26, 157. (b) Moinet, C.; Hurvois, J.-P.; Jutland, A. Adv. Org. Synth. 2005, 1, 403. (16) Yoshida, J.-i. In Developments in Carbocation and Onium Ion Chemistry; Laali, K., Ed.; ACS Symposium Series 395; American Chemical Society: Washington, DC; 2007; pp 184−209. (17) Okajima, M.; Soga, K.; Nokami, T.; Suga, S.; Yoshida, J. Org. Lett. 2006, 8, 5005. (18) Ashikari, Y.; Nokami, T.; Yoshida, J. J. Am. Chem. Soc. 2011, 133, 11840. (19) Ashikari, Y.; Nokami, T.; Yoshida, J. Org. Lett. 2012, 14, 938. (20) Mahonet, S. J.; Moon, D. T.; Hollinger, J.; Fillion, E. Tetrahedron Lett. 2009, 50, 4706. (21) Mori, K.; Kawasaki, T.; Akiyama, T. Org. Lett. 2012, 14, 1436. (22) Mori, K.; Sueoka, S.; Akiyama, T. J. Am. Chem. Soc. 2011, 133, 2424. (23) Li, H.; Li, W.; Liu, W.; He, Z.; Li, Z. Angew. Chem., Int. Ed. 2011, 50, 2975. (24) Hu, B.; Xing, S.; Wang, Z. Org. Lett. 2008, 10, 5481. (25) Shi, M.; Lu, J.-M.; Wei, Y.; Shao, L.-X. Acc. Chem. Res. 2012, 45, 641. (26) Miyamoto, K.; Shiro, M.; Ochiai, M. Angew. Chem., Int. Ed. 2009, 48, 8931.

Biographies

Rajasekhar Reddy Naredla was born in Andhra Pradesh, India, in 1984. He received his B.Sc. in chemistry in 2004 from Andhra Loyola College, Vijayawada, India, and M.Sc. in organic chemistry in 2007 from National Institute of Technology, Tiruchirappalli, India. After receiving his masters he moved to National Tsing Hua University, Taiwan, where he worked as a research fellow in the laboratories of Professor Reuben Jih-Ru Hwu (2007−2009). He is currently a fourth year Ph.D. student Professor Klumpp’s laboratory at Northern Illinois University. His current research is focused on the application of superelectrophiles to novel organic reactions and new method development.

Douglas Klumpp was born and raised near Chicago, Illinois. He completed a B.S. degree in chemistry at the University of Oklahoma and a Ph.D. degree in organic chemistry at Iowa State University. Following this, he was awarded a postdoctoral fellowship to conduct research in the laboratories of Professor George A. Olah at the University of Southern California. His independent academic career began in 1996 with a junior faculty appointment at California State Polytechnic Institute in Pomona, California. Since 2003, he has been a faculty member at Northern Illinois University, where he is a full professor. His research interests involve synthetic and mechanistic studies of electrophilic species, including carbocations.

ACKNOWLEDGMENTS The financial support of the NIH-National Institute of General Medical Sciences (GM085736-01A1) is gratefully acknowledged. AN


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(59) Cheon, C. H.; Yamamoto, H. Org. Lett. 2010, 12, 2476. (60) Cheon, C. H.; Yamamoto, H. Tetrahedron Lett. 2009, 50, 3555. (61) Reed, C. A. Acc. Chem. Res. 2010, 43, 121. (62) Prakash, G. K. S.; Panja, C.; Shakhmin, A.; Shah, E.; Mathew, T.; Olah, G. A. J. Org. Chem. 2009, 74, 8659. (63) Prakash, G. K. S.; Paknia, F.; Mathew, T.; Mloston, G.; Joschek, J. P.; Olah, G. A. Org. Lett. 2011, 13, 4128. (64) Prakash, G. K. S.; Mathew, T.; Marinez, E. R.; Esteves, P. M.; Rasul, G.; Olah, G. A. J. Org. Chem. 2006, 71, 3952. (65) Olah, G. A.; Prakash, G. K. S.; Molnar, A.; Sommer, J. Superacid Chemistry, 2nd ed.; Wiley: New York, 2009. (66) Kitan, M.; Wada, E.; Nakajima, K.; Hayashi, S.; Miyazaki, S.; Kobayashi, H.; Hara, M. Chem. Mater. 2013, 25, 385. (67) Bonrath, W.; Aquino, F.; Haas, A.; Hoppmann, S.; Netscher, T.; Pace, F.; Pauling, H. Sustainability 2009, 1, 161. (68) Dou, J.; Hua, C. J. Am. Chem. Soc. 2012, 134, 16235. (69) Lossing, F. P.; Holmes, J. L. J. Am. Chem. Soc. 1984, 106, 6917. (70) Arnett, E. M.; Pienta, N. J. J. Am. Chem. Soc. 1980, 102, 3329. (71) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66. (72) Figure 2 adapted from Lucius, R.; Loos, R.; Mayr, H. Angew. Chem., Int. Ed. 2002, 41, 92. (73) Cozzi, P. G.; Benfatti, F. Angew. Chem., Int. Ed. 2010, 49, 256. (74) Shirakawa, S.; Kobayashi, S. Org. Lett. 2007, 9, 311. (75) (a) Burfeindt, J.; Patz, M.; Müller, M.; Mayr, H. J. Am. Chem. Soc. 1998, 120, 3629. (b) Minegishi, S.; Kobayashi, S.; Mayr, H. J. Am. Chem. Soc. 2004, 126, 5174. (76) Cozzi, P. G.; Zoli, L. Angew. Chem., Int. Ed. 2008, 47, 4162. (77) Alba, A.-N. R.; Calbet, T.; Font-Bardia, M.; Moyano, A.; Rios, R. Eur. J. Org. Chem. 2011, 2053. (78) Xing, C.; Sun, H.; Zhang, J.; Li, G.; Chi, Y. R. Chem.Eur. J. 2011, 17, 12272. (79) Asymmetric Organocatalysis. Science of Synthesis; List, B., Maruoka, K., Eds.; Georg Thieme Verlag: Stuttgart, Germany, 2012. (80) Kempf, B.; Hampel, N.; Ofial, A. R.; Mary, H. Chem.Eur. J. 2003, 9, 2209. (81) Shaikh, R. R.; Mazzanti, A.; Petrini, M.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2008, 47, 8707. (82) Xiao, J. Org. Lett. 2012, 14, 1716. (83) (a) Zhang, L.; Cui, L.; Li, X.; Li, J.; Luo, S.; Cheng, J.-P. Chem.Eur. J. 2010, 16, 2045. (b) Zhang, L.; Cui, L.; Li, X.; Li, J.; Luo, S.; Cheng, J.-P. Eur. J. Org. Chem. 2010, 4876. (84) Trifonidou, M.; Kokotos, C. G. Eur. J. Org. Chem. 2012, 1563. (85) Cozzi, P. G.; Benfatti, F.; Zoli, L. Angew. Chem., Int. Ed. 2009, 48, 1313. (86) Brown, A. R.; Kuo, W.-H.; Jacobson, E. N. J. Am. Chem. Soc. 2010, 132, 9286. (87) Fu, T.-h.; Bonaparte, A.; Martin, S. F. Tetrahedron Lett. 2009, 50, 3253. (88) Xinag, S.-K.; Zhanng, L.-H.; Jiao, N. Chem. Commun. 2009, 6487. (89) Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker, B.; Kempf, B.; Loos, R.; Ofial, A. R.; Remennikov, G.; Schimmel, H. J. Am. Chem. Soc. 2001, 123, 9500. (90) Kumar, R.; Van der Eycken, E. V. Chem. Soc. Rev. 2013, 42, 1121. (91) Trillo, P.; Baeza, A.; Najera, C. J. Org. Chem. 2012, 77, 7344. (92) Both values measured in DMSO, see: Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456. (93) Troshin, K.; Schindele, C.; Mayr, H. J. Org. Chem. 2011, 76, 9391. (94) Wang, Y.; Kong, C.; Du, Y.; Song, H.; Zhang, D.; Qin, Y. Org. Biomol. Chem. 2012, 10, 2793. (95) Ammer, J.; Mayr, H. Macromolecules 2010, 43, 1719. (96) (a) Creary, X. Chem. Rev. 1991, 91, 1625. (b) Gassman, P. G.; Tidwell, T. T. Acc. Chem. Res. 1983, 16, 279. (97) Poulter, C. D.; Satterwhite, D. M.; Rilling, H. C. J. Am. Chem. Soc. 1976, 98, 3376. (98) Begue, J. P.; Charpentier-Morize, M. Acc. Chem. Res. 1980, 13, 207.

(27) Pfeifer, W. D.; Bahn, C. A.; Schleyer, P. v. R.; Bocher, S.; Harding, C. E.; Hummel, K.; Hanack, M.; Stang, P. J. J. Am. Chem. Soc. 1971, 93, 1513. (28) Okuyama, T.; Takino, T.; Sueda, T.; Ochiai, M. J. Am. Chem. Soc. 1995, 117, 3360. (29) Yao, M.-L.; Quick, T. R.; Wu, Z.; Quinn, M. P.; Kabalka, G. W. Org. Lett. 2009, 11, 2647. (30) Kabalka, G. W.; Yao, M.-L.; Borella, S.; Goins, L. K. Organometallics 2007, 26, 4112. (31) Kabalka, G. W.; Yao, M.-L.; Borella, S. J. Am. Chem. Soc. 2006, 128, 11320. (32) Fuchter, M. J.; Levy, J.-N. Org. Lett. 2008, 10, 4919. (33) Kelly, B. D.; Lambert, T. H. J. Am. Chem. Soc. 2009, 131, 13930. (34) (a) Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.; WileyVHC: Weinheim, Germany, 2000. (b) Rueping, M.; Koenigs, R. M.; Atodiresei, I. Chem. Soc. Rev. 2011, 40, 4539. (c) Antoniotti, S.; Poulain-Martini, S.; Dunach, E. Synlett 2010, 2973. (35) (a) Schenker, S.; Zamfir, A.; Freund, M.; Tsogoeva, S. B. Eur. J. Org. Chem. 2011, 2209. (b) Lu, H.-H.; Tan, F.; Xiao, W.-J. Curr. Org. Chem. 2011, 15, 4022. (36) (a) Li, Z.; He, C. Eur. J. Org. Chem. 2006, 4313 and references cited therein. (b) Yanagisawa, A. Silver, Gold, and Palladium Lewis Acids; Wiley-VHC: Weinheim, Germany, 2004. (37) Modern Gold Catalyzed Synthesis; Hashmi, A. S. K., Toste, D. F., Eds.; Wiley-VHC: Weinheim, Germany, 2009. (38) Iwasa, S.; Nishiyama, H. In Lewis Acids in Organic Synthesis; Yamamoto, H., Kündig, E. P., Saudan, C. M., Eds.; Wiley-VHC: Weinheim, Germany, 2008; Chapter 14. (39) Erker, G. Dalton Trans. 2005, 1883. (40) Zheng, H.; Ghanbari, S.; Nakamura, S.; Hall, D. G. Angew. Chem., Int. Ed. 2012, 51, 6187. (41) McCubbin, J. A.; Hosseini, H.; Krokhin, O. V. J. Org. Chem. 2010, 75, 959. (42) McCubbin, J. A.; Krokhin, O. V. Tetrahedron Lett. 2010, 51, 2447. (43) Noyori, R.; Murata, S.; Suzuki, M. Tetrahedron 1981, 37, 3899. (44) Scott, V. J.; Celenligil-Cetin, R.; Ozerov, O. V. J. Am. Chem. Soc. 2005, 127, 2852. (45) Douvris, C.; Ozerov, O. V. Science 2008, 321, 1188. (46) Panisch, R.; Bolte, M.; Müller, T. J. Am. Chem. Soc. 2006, 128, 9676. (47) Duttwyler, S.; Douvris, C.; Fackler, N. L. P.; Tham, F. S.; Reed, C. A.; Baldridge, K. K.; Siegel, J. S. Angew. Chem., Int. Ed. 2010, 49, 7519. (48) Gu, W.; Haneline, M. R.; Douvris, C.; Ozerov, O. V. J. Am. Chem. Soc. 2009, 131, 11203. (49) Candu, N.; Wuttke, S.; Kemnitz, E.; Coman, S. M.; Parvulescu, V. I. Appl. Catal., A 2011, 391, 169. (50) Kaper, H.; Bouchmella, K.; Mutin, P. H.; Goettmann, F. ChemCatChem 2012, 4, 1813. (51) Jiang, Y.; Lin, K.; Zhang, Y.; Liu, J.; Li, G.; Sun, J.; Xu, X. Appl. Catal., A 2012, 445−446, 172. (52) Okumura, K.; Ishida, S.; Kinoshita, Y.; Sanada, T.; Iida, K.; Katada, N. Chem. Lett. 2012, 41, 947. (53) (a) Acid Catalysis in Modern Organic Synthesis; Yamamoto, H., Ishihara, K., Eds.; Wiley-VHC: Weinheim, Germany, 2008. (b) Cheon, C. H.; Yamamoto, H. Chem. Commun. 2011, 47, 3043. (c) Rueping, M.; Nachtsheim, B. J.; Ieawsuwan, W.; Atodiresei, I. Angew. Chem., Int. Ed. 2011, 50, 6706. (d) Rueping, M.; Kuenkel, A.; Atodiresei, I. Chem. Soc. Rev. 2011, 40, 4539. (54) Ishihara, K.; Hasegawa, A.; Yamamoto, H. Angew. Chem., Int. Ed. 2001, 40, 4077. (55) Hasegawa, A.; Ishihara, K.; Yamamoto, H. Angew. Chem., Int. Ed. 2003, 42, 5731. (56) Payette, J. N.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 3043. (57) Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 9626. (58) (a) Ref 53. (b) You, S.-L.; Cai, Q.; Zeng, M. Chem. Soc. Rev. 2009, 38, 2190. AO


Chemical Reviews

Review

(99) Zhou, F.; Cao, Z.-Y.; Zhang, J.; Yang, H. B.; Zhou, J. Chem. Asian J. 2012, 7, 233. (100) Naredla, R. R.; Raja, E. K.; Klumpp, D. A. Tetrahedron Lett. 2013, 54, 3245. (101) Zhou, F.; Ding, M.; Zhou, J. Org. Biomol. Chem. 2012, 10, 3178. (102) Nicolaou, K. C.; Kang, Q.; Wu, T. R.; Lim, C. S.; Chen, D. Y.K. J. Am. Chem. Soc. 2010, 132, 7540. (103) Chen, L.; Zhou, F.; Shi, T. D.; Zhou, J. J. Org. Chem. 2012, 77, 3454. (104) Ichikawa, J.; Yokota, M.; Kudo, T.; Umezaki, S. Angew. Chem., Int. Ed. 2008, 47, 4870. (105) Fuchibe, K.; Jyono, H.; Fujiwara, M.; Kudo, T.; Yokota, M.; Ichikawa, J. Chem.Eur. J. 2011, 17, 12175. (106) Wang, F.; Hu, J. Chin. J. Chem. 2009, 27, 27. (107) Kethe, A.; Tracy, A. F.; Klumpp, D. A. Org. Bioorg. Chem. 2011, 9, 4545. (108) Kelly, C. B.; Colthart, A. M.; Constant, B. D.; Corning, S. R.; Dubois, L. N. E.; Genovese, J. T.; Radziew, J. L.; Sletten, E. M.; Whitaker, K. R.; Tilley, L. J. Org. Lett. 2011, 13, 1646. (109) O’Connor, M. J.; Boblak, K. N.; Topinka, M. J.; Kindelin, P. J.; Briski, J. M.; Zheng, C.; Klumpp, D. A. J. Am. Chem. Soc. 2010, 132, 3266. (110) Olah, G. A.; Germain, A.; Lin, H. C.; Forsyth, D. J. Am. Chem. Soc. 1975, 97, 2928. (111) Olah, G. A.; Hartz, N.; Rasul, G.; Prakash, G. K. S. J. Am. Chem. Soc. 1993, 115, 6985. (112) Rendy, R.; Zhang, Y.; McElrea, A.; Gomez, A.; Klumpp, D. A. J. Org. Chem. 2004, 69, 2340. (113) Klumpp, D. A.; Beauchamp, P. S.; Sanchez, G. S., Jr.; Aguirre, S.; de Leon, S. Tetrahedron Lett. 2001, 42, 5821. (114) Olah, G. A.; Klumpp, D. A. Superelectrophiles and Their Chemistry; Wiley & Sons: New York, 2008. (115) Klumpp, D. A. Chem.Eur. J. 2008, 14, 2004. (116) Ohwada, T.; Suzuki, T.; Shudo, K. J. Am. Chem. Soc. 1998, 110, 4629. (117) Naredla, R. R.; Zheng, C.; Nilsson Lill, S. O.; Klumpp, D. A. J. Am. Chem. Soc. 2011, 133, 13169. (118) O’Connor, M. J.; Boblak, K. N.; Topinka, M. J.; Kindelin, P. J.; Briski, J. M.; Zheng, C.; Klumpp, D. A. J. Am. Chem. Soc. 2010, 132, 3266. (119) Li, A.; Kindelin, P. J.; Klumpp, D. A. Org. Lett. 2006, 8, 1233. (120) Bach, R. D.; Badger, R. C. Synthesis 1979, 529. (121) Sommer, J.; Bukula, J. Acc. Chem. Res. 1993, 26, 370. (122) Akhrem, I. S.; Afanas’eva, L. V.; Kagramanov, N. D.; Petrovskii, P. V. Tetrahedron Lett. 2012, 53, 4221. (123) Orlinkov, A. V.; Kagramanov, N. D.; Petrovskii, P. V.; Akhrem, I. S. Tetrahedron Lett. 2010, 51, 259. (124) Akhrem, I. S.; Avetisyan, D. V.; Afanas’eva, L. V. Tetrahedron Lett. 2012, 53, 3493−3496. (125) Akhrem, I. S.; Avetisyan, D. V.; Kagramanov, N. D.; Petrovskii, P. V.; Mysova, N. E. Mendeleev Commun. 2010, 20, 257. (126) Martin-Mingot, A.; Compain, G.; Liu, F.; Jouannetaud, M.-P.; Bachmann, C.; Frapper, G.; Zunino, F.; Thibaudeau, S. J. Fluorine Chem. 2012, 134, 56. (127) (a) Li, A.; T. M. Gilbert, T. M.; Klumpp, D. A. J. Org. Chem. 2008, 73, 3654. (b) Li, A.; DeSchepper, D.; Klumpp, D. A. Tetrahedron Lett. 2009, 50, 1924. (128) Kethe, A.; Li, A.; Klumpp, D. A. Tetrahedron 2012, 68, 3357. (129) (a) Thibaudeau, S.; Martin-Mingot, A.; Jounnetaud, M.-P.; Karam, O.; Zunino, F. Chem. Commun. 2007, 3198. (b) Liu, F.; Martin-Mingot, A.; Jounnetaud, M.-P.; Karam, O.; Thibaudeau, S. Org. Biomol. Chem. 2009, 7, 4789. (130) Liu, F.; Martin-Mingot, A.; Jounnetaud, M.-P.; Zunino, F.; Thibaudeau, S. Org. Lett. 2010, 12, 868. (131) Sheets, M. A.; Li, A.; Bower, E. A.; Weigel, A. R.; Abbott, M. P.; Gallo, R. M.; Mitton, A. A.; Klumpp, D. A. J. Org. Chem. 2009, 73, 2502.

(132) Compain, G.; Martin-Mingot, A.; Frapper, G.; Bachmann, C.; Jouannetaud, M.-P.; Thibaudeau, S. Chem. Commun. 2012, 48, 5877. (133) Olah, G. A. In Friedel-Crafts and Related Reactions; Olah, G. A., Ed.; Wiley & Sons: New York, 1963; Vol. 1, pp 1−16. (134) (a) Calloway, N. O. Chem. Rev. 1935, 17, 327. (b) Fairbrother, F. Trans. Faraday Soc. 1941, 37, 763. (135) (a) Klipstein, K. H. Ind. Eng. Chem. 1926, 18, 1328. (b) Meerwein, H. Ann. Chem. 1927, 455, 227. (136) Rueping, M.; Nachtsheim, B. J. Beil. J. Org. Chem. 2010, 6 (6), DOI: 10.3762/bjoc.6.6. (137) Eom, D.; Park, S.; Park, Y.; Ryu, T.; Lee, P. H. Org. Lett. 2012, 14, 5392. (138) Smith, C. D.; Rosocha, G.; Mui, L.; Batey, R. A. J. Org. Chem. 2010, 75, 4716. (139) Wang, G.-W.; Wang, H.-L.; Capretto, D. A.; Han, Q.; Hu, R.B.; Yang, S.-D. Tetrahedron 2012, 68, 5216. (140) Yin, B.-L.; Lai, J.-Q.; Zhang, Z.-R.; Jiang, H.-F. Adv. Synth. Catal. 2011, 353, 1961. (141) Guo, Y.; Fan, L.; Wang, J.; Yang, C.; Qu, H.; Xu, H. Tetrahedron 2013, 69, 774. (142) Choi, Y.; Kim, B. T.; Heo, J.-N. J. Org. Chem. 2012, 77, 8762. (143) Medjahdi, M.; Gonzalez-Gomez, J. C.; Foubelo, F.; Yus, M. Eur. J. Org. Chem. 2011, 2230. (144) Liebert, C.; Brinks, M. K.; Capacci, A. G.; Fleming, M. J.; Lautens, M. Org. Lett. 2011, 13, 3000. (145) Li, G.-X.; Qu, J. Chem. Commun. 2010, 46, 2653. (146) Medeiros, M.; Narayan, R. S.; McDougal, N. T.; Schaus, S. E.; Porco, J. A., Jr. Org. Lett. 2010, 12, 3222. (147) Ying, W.; Barnes, C. L.; Harmata, M. Tetrahedron Lett. 2011, 52, 177. (148) Vaidya, T.; Manbeck, G. F.; Chen, S.; Frontier, A. J.; Eisenberg, R. J. Am. Chem. Soc. 2011, 133, 3300. (149) Huo, C.; Xu, X.; Jia, X.; Wang, X.; An, J.; Sun, C. Tetrahedron 2012, 68, 190. (150) Huo, C.; Xu, X.; An, J.; Jia, X.; Wang, X.; Wang, C. J. Org. Chem. 2012, 77, 8310. (151) Smith, A. G.; Johnson, J. S. Org. Lett. 2010, 12, 1784. (152) Lai, P.-S.; Dubland, J. A.; Sarwar, M. G.; Chudzinski, M. G.; Taylor, M. S. Tetrahedron 2011, 67, 7586. (153) Ghosh, S.; Kinthada, L. K.; Bhunia, S.; Bisai, A. Chem. Commun. 2012, 48, 10132. (154) Devoust, M.; Kitching, J. A.; Fleming, M. J.; Lautens, M. Chem.Eur. J. 2010, 16, 50. (155) (a) Yoder, R. A.; Johnston, J. N. Chem. Rev. 2005, 105, 4730. (b) Tantillo, D. J. Nat. Prod. Rep. 2011, 28, 1035. (156) (a) Snyder, S. A.; Treitler, D. S.; Schall, A. Tetrahedron 2010, 66, 4796. (b) Snyder, S. A.; Treitler, D. S. Org, Synth. 2011, 88, 54. (c) Sakakura, A.; Ukai, A.; Ishihara, K. Nature 2007, 445, 900. (157) Surendra, K.; Corey, E. J. J. Am. Chem. Soc. 2008, 130, 8865. (158) Huang, A. X.; Xiong, Z.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 9999. (159) Corey, E. J.; Lee, J. J. Am. Chem. Soc. 1993, 115, 8873. (160) Mi, Y.; Schreiber, J. V.; Corey, E. J. J. Am. Chem. Soc. 2002, 124, 11290. (161) Moore, J. T.; Soldi, C.; Fettinger, J. C.; Shaw, J. T. Chem. Sci. 2013, 4, 292. (162) Isaka, T.; Hasegawa, M.; Toshima, H. Biosci. Biotechnol. Biochem. 2011, 11, 2213. (163) Pronin, S. V.; Shenvi, R. A. Nat. Chem. 2012, 4, 915. (164) Nenitzescu, C. D. In Carbonium Ions; Olah, G. A., Schleyer, P. v. R., Eds.; Wiley & Sons, 1968; Vol. 1, pp 59−63. (165) For a recent review, see: Emer, E.; Sinisi, R.; Capdevila, M. G.; Petruzzillo, D.; De Vincentiis, F.; Cozzi, P. G. Eur. J. Org. Chem. 2011, 647. (166) Cakir, S. P.; Stokes, S.; Sygula, A.; Mead, K. T. J. Org. Chem. 2009, 74, 7529. (167) Fan, Y.; Feng, P.; Liu, M.; Pan, H.; Shi, Y. Org. Lett. 2011, 13, 4494. AP


Chemical Reviews

Review

(168) Diba, A. K.; Begouin, J.-M.; Niggemann, M. Tetrahedron Lett. 2012, 53, 6629. (169) Hanessian, S.; Focken, T.; Oza, R. Tetrahedron 2011, 67, 9870. (170) Liu, Y.; Huang, C.; Liu, B. Tetrahedron Lett. 2011, 52, 5802. (171) Alder, R. W.; Carta, F.; Reed, C. A.; Stoyanova, I.; Willis, C. L. Org. Biomol. Chem. 2010, 8, 1551. (172) Veits, G. K.; Wenz, D. R.; Read de Alaniz, J. Angew. Chem., Int. Ed. 2010, 49, 9484. (173) Palmer, L. I.; Read de Alaniz, J. Angew. Chem., Int. Ed. 2011, 50, 7167. (174) Palmer, L. I.; Read de Alaniz, J. Org. Lett. 2013, 15, 476. (175) Yin, B.-L.; Wu, Y.-L.; Lai, J. Q. Eur. J. Org. Chem. 2009, 2695. (176) (a) Aschauer, S.; Schilder, L.; Korth, W.; Fritschi, S.; Jess, A. Catal. Lett. 2011, 141, 1405. (b) Zhu, A.; Li, L.; Wang, J.; Zhuo, K. Green Chem. 2011, 13, 1244. (c) Laali, K. K. In Ionic Liquids in Organic Synthesis; ACS Symposium Series 950; American Chemical Society: Washington, DC, 2007; pp 144−159. (177) (a) Creary, X.; Willis, E. D.; Gagnon, M. J. Am. Chem. Soc. 2005, 127, 18114. (b) See also: Bini, R.; Chiappe, C.; Pieraccini, D.; Piccioli, P.; Pomelli, C. S. Tetrahedron Lett. 2005, 46, 6675. (178) (a) Mullins, R. J.; Grote, A. L. In Name Reactions for Homologations; Li, J. J., Ed.; 2009; Part 2, pp 373−394. (b) Schreiber, P. Chem.-Ztg., Chem. Appar. 1969, 93, 957. (179) Zubkov, F. I.; Zaytsev, V. P.; Nikitina, E. V.; Khrustalev, V. N.; Gozun, S. V.; Boltukhina, E. V.; Varlamov, A. V. Tetrahedron 2011, 67, 9148. (180) Zubkov, F. I.; Ershova, J. D.; Orlova, A. A.; Zaytsev, V. P.; Nikitina, E. V.; Peregudov, A. S.; Gurbanov, A. V.; Borisov, R.; Khrustalev, V. N.; Maharramov, A. M.; Varlamov, A. V. Tetrahedron 2009, 65, 3789. (181) Michalak, M.; Michalak, K.; Urbanczyk-Lipkowska, Z.; Wicha, J. J. Org. Chem. 2011, 76, 7497. (182) Cheng, H.; Xu, L.; Chen, D.-L.; Chen, Q.-H.; Wang, F.-P. Tetrahedron 2012, 68, 1171. (183) Horvath, A.; Szajli, A.; Kiss, R.; Koti, J.; Maho, S.; SkodaFoldes, R. J. Org. Chem. 2011, 76, 6048. (184) Sakurai, J.; Kikuchi, T.; Takahashi, O.; Watanabe, K.; Katoh, T. Eur. J. Org. Chem. 2011, 2948. (185) Guerard, K. C.; Chapelle, C.; Giroux, M.-A.; Sabot, C.; Beaulieu, M.-A.; Achache, N.; Canesi, S. Org. Lett. 2009, 11, 4756. (186) Olah, G. A.; Reddy, V. P.; Prakash, G. K. S. Chem. Rev. 1992, 92, 69. (187) (a) Ding, K.; Sun, Y.-s.; Tian, W.-S. J. Org. Chem. 2011, 76, 1495. (b) Sun, Y.-s.; Ding, K.; Tian, W.-S. Chem. Commun. 2011, 47, 10437. (188) Liu, D.; Chen, J.; Ai, L.; Zhang, H.; Liu, J. Org. Lett. 2013, 15, 410. (189) Zaniroato, V.; Pollini, G. P.; De Risi, C.; Valente, F.; Melloni, A.; Fusi, S.; Barbetti, J.; Olivucci, M. Tetrahedron 2007, 63, 4975. (190) Honda, M.; Nishizawa, T.; Nishii, Y.; Funjinami, S.; Segi, M. Tetrahedron 2009, 65, 9403. (191) Honda, M.; Yamamoto, Y.; Tsuchida, H.; Segi, M.; Nakajima, T. Tetrahedron Lett. 2005, 46, 6465. (192) Yadav, V. K.; Kumar, N. V. Chem. Commun. 2008, 3774. (193) Phun, L. H.; Patil, D. V.; Cavitt, M. A.; France, S. Org. Lett. 2011, 13, 1952. (194) De Simone, F.; Saget, T.; Benfatti, F.; Almeida, S.; Waser, J. Chem.Eur. J. 2011, 17, 14527. (195) Mothe, S. R.; Kothandaraman, P.; Rao, W.; Chan, P. W. H. J. Org. Chem. 2011, 76, 2521. (196) Yeh, M.-C. P.; Liang, C.-J.; Fan, C.-W.; Chiu, W.-H.; Lo, J.-Y. J. Org. Chem. 2012, 76, 9707. (197) Kothandaraman, P.; Huang, C.; Susanti, D.; Rao, W.; Chan, P. W. H. Chem.Eur. J. 2011, 17, 10081. (198) Erden, I.; Gartner, C.; Azimi, M. S. Org. Lett. 2009, 11, 3986. (199) (a) Guerinot, A.; Reymond, S.; Cossy, J. Eur. J. Org. Chem. 2012, 2012, 19. (b) Brewer, A. R. E. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; Wiley: Hoboken, NJ,

2007; pp 471−476. (c) Krimen, L. I.; Cota, D. J. Org. React. 1969, 17, 213. (200) Michaudel, Q.; Thevenet, D.; Baran, P. S. J. Am. Chem. Soc. 2012, 134, 2547. (201) Banks, R. E.; Lawrence, N. J.; Besheesh, M. K.; Popplewell, A. L.; Pritchard, R. G. Chem. Commun. 1996, 1629. (202) Mondal, D.; Bellucci, L.; Lepore, S. D. Eur. J. Org. Chem. 2011, 7057. (203) (a) Rubenbauer, P.; Bach, T. Chem. Commun. 2009, 2130. (b) Stadler, D.; Bach, T. Chem.Asian J. 2008, 3, 272. (204) Emelen, K. V.; De Wit, T.; Hoornaert, G. J.; Compernolle, F. Org. Lett. 2000, 2, 3083. (205) Kartashov, V. R.; Arkhipova, A. V.; Malkova, K. V.; Sokolova, T. N. Russ. Chem. Bull. 2006, 55, 387. (206) Torres, E.; Fernandez, R.; Miquet, S.; Font-Bardia, M.; Vanderlinden, E.; Naesens, L.; Vazquez, S. ACS Med. Chem. Lett. 2012, 3, 1065. (207) Bi, N. M.; Ren, M. G.; Song, Q. H. Synth. Commun. 2010, 40, 2617. (208) Reddy, B. V. S.; Reddy, N. S.; Madan, Ch.; Yadav, J. S. Tetrahedron Lett. 2010, 51, 4827. (209) Anxionnat, B.; Guerinot, A.; Reymond, A.; Cossy, J. Tetrahedron Lett. 2009, 50, 3470. (210) Kalkhambkar, R. G.; Waters, S. N.; Laali, K. K. Tetrahedron Lett. 2011, 52, 867. (211) Baum, J. C.; Milne, J. E.; Murry, J. A.; Thiel, O. R. J. Org. Chem. 2009, 74, 2207. (212) Pearson, W. H.; Fang, W.-k. J. Org. Chem. 2000, 65, 7158. (213) Reddy, P. G.; Baskaran, S. J. Org. Chem. 2004, 69, 3093. (214) Hayashi, K.; Tanimoto, H.; Zhang, H.; Morimoto, T.; Nishiyama, Y.; Kakiuchi, K. Org. Lett. 2012, 14, 5728. (215) Butlerov, A. Justus Liebigs Ann. Chem. 1873, 170, 151. (216) Kirsch, S. F. Nachr. Chem. 2008, 56, 1228. (217) George, J. H.; Baldwin, J. E.; Adington, R. M. Org. Lett. 2010, 12, 2394. (218) Suzuki, K.; Takikawa, H.; Hachisu, Y.; Bode, J. W. Angew. Chem., Int. Ed. 2007, 46, 3252. (219) Chaver, S. N.; Ullapu, P. R.; Min, S. J.; Lee, K. J.; Pae, A. N.; Kim, Y.; Cho, Y. S. Org. Lett. 2009, 11, 3834. (220) Overman, L. E.; Velthuisen, E. J. J. Org. Chem. 2006, 71, 1581. (221) Overman, L. E.; Tains, P. S. J. Org. Chem. 2010, 75, 455. (222) Canham, S. M.; France, D. J.; Overman, L. E. J. Org. Chem. 2013, 78, 9. (223) Crozet, D.; Urrutigoity, M.; Kalck, P. ChemCatChem 2011, 3, 1102. (224) (a) Dion, I.; Beauchemin, A. M. Angew. Chem., Int. Ed. 2011, 50, 8233. (b) Taylor, J. G.; Adrio, L. A.; Hii, K. K. Dalton Trans. 2010, 39, 1171. (225) Cheng, X.; Xia, Y.; Wei, H.; Xu, B.; Zhang, C.; Li, Y.; Qian, G.; Zhang, X.; Li, K.; Li, W. Eur. J. Org. Chem. 2008, 1929. (226) Nazarov, I. N.; Zaretskaya, I. I. Izv. Akad. Nauk. SSSR, Ser. Khim. 1941, 211. (227) Vaidya, T.; Eisenberg, R.; Frontier, A. J. ChemCatChem 2011, 3, 1531. (228) Corider, P.; Aubert, C.; Malacria, M.; Lacote, E.; Gandon, V. Angew. Chem., Int. Ed. 2009, 48, 8757. (229) Dethe, D. H.; Murhade, G. Org. Lett. 2013, 15, 429. (230) (a) Frontier, A. J.; Collison, C. Tetrahedron 2005, 61, 7577. (b) Pellisier, H. Tetrahedron 2005, 61, 6479. (c) Huang, J.; Lebœuf, D.; Frontier, A. J. J. Am. Chem. Soc. 2011, 133, 6307 and references cited therein. (231) Huang, J.; Frontier, A. J. J. Am. Chem. Soc. 2007, 129, 8060. (232) Dhoro, F.; Kristensen, T. E.; Stockmann, V.; Yap, G. P. A.; Tius, M. A. J. Am. Chem. Soc. 2007, 129, 7256. (233) Dhoro, F.; Tius, M. A. J. Am. Chem. Soc. 2005, 129, 12472. (234) Marx, V. M.; Burnell, D. J. J. Am. Chem. Soc. 2010, 132, 1685. (235) Miyake, Y.; Uemura, S.; Nishibayashi, Y. ChemCatChem 2009, 1, 342. AQ


Chemical Reviews

Review

(236) (a) Mullins, R. J.; Collins, N. R. In Name Reactions for Hologations, Part 2; John Wiley & Sons: Hoboken, NJ; 2009; pp 305− 318. (b) Engel, D. A.; Dudley, G. B. Org. Biomol. Chem. 2009, 7, 4149. (237) Ji, K.-G.; Chen, J.; Zhu, H. T.; Yang, F.; Shaukat, A.; Liang, Y.M. Chem.Eur. J. 2011, 17, 305. (238) Wen, J.-J.; Zhu, Y.; Zhan, Z.-P. Asian J. Org. Chem. 2012, 1, 108. (239) Yin, G.; Zhu, Y.; Zhang, L.; Lu, P.; Wang, Y. Org. Lett. 2010, 13, 940. (240) Zhu, Y.; Yin, G.; Hong, D.; Lu, P.; Wang, Y. Org. Lett. 2011, 14, 1024. (241) Zhu, Y.; Wen, S.; Yin, G.; Hong, D.; Lu, P.; Wang, Y. Org. Lett. 2011, 14, 3553. (242) Zhu, Y.; Yin, G.; Sun, L.; Lu, P.; Wang, Y. Tetrahedron 2012, 68, 10194. (243) Yin, G.; Zhu, Y.; Lu, P.; Wang, Y. J. Org. Chem. 2011, 76, 8922. (244) Wang, L.; Xie, X.; Liu, Y. Org. Lett. 2012, 14, 5848. (245) Hao, L.; Wu, F.; Ding, Z.-C.; Xu, S.-X.; Ma, Y.-L.; Chen, L.; Zhan, Z.-P. Chem.Eur. J. 2012, 18, 6453. (246) For a general review, see: Kumar, R.; Van der Eycken, E. V. Chem. Soc. Rev. 2013, 42, 1121. (247) (a) Niggemann, M.; Meel, M. J. Angew. Chem., Int. Ed. 2010, 49, 3684. (b) Kennedy-Smith, J. J.; Young, L. A.; Toste, F. D. Org. Lett. 2004, 6, 1325. (c) Li, Y.; Kim, Y. J.; Kim, A. Y.; Lee, K.; Jung, M. H.; Hur, N. H.; Park, K. H.; Seo, W. S. Chem. Mater. 2011, 23, 5398. (248) Sanz, R.; Miguel, D.; Alvarez-Gutierrez, J. M.; Rodriguez, F. Synlett 2008, 975. (249) Gohain, M.; Marais, C.; Bezuidenhoudt, B. C. B. Tetrahedron Lett. 2012, 53, 4704. (250) Kuniobu, Y.; Ueda, H.; Takai, K. Chem. Lett. 2008, 37, 878. (251) Damu, G. L. V.; Selvam, J. J. P.; Vankata Rao, C.; Venkateswarlu, Y. Tetrahedron Lett. 2009, 50, 6154. (252) Zheng, H.; Lejkowski, M.; Hall, D. G. Chem Sci. 2011, 2, 1305. (253) Reider, C. J.; Winberg, K. J.; West, F. G. J. Org. Chem. 2011, 76, 50. (254) For example, see: Sun, F.-L.; Zeng, M.; Gu, Q.; You, S.-L. Chem.Eur. J. 2009, 15, 8709. (255) Trifonidou, M.; Kokotos, C. G. Eur. J. Org. Chem. 2012, 1563. (256) (a) Mühlthau, F.; Schuster, O.; Bach, T. J. Am. Chem. Soc. 2005, 127, 9348. (b) Stadler, D.; Mühlthau, F.; Rubenbauer, P.; Herdtweck, E.; Bach, T. Synlett 2006, 16, 2573. (c) Stadler, D.; Bach, T. Chem.Asian J. 2008, 3, 272. (257) Rubenbauer, P.; Bach, T. Adv. Synth. Catal. 2008, 350, 1125. (258) Stadler, D.; Bach, T. Angew. Chem., Int. Ed. 2008, 47, 7557. (259) (a) Chung, J. Y.; Mancheno, D.; Dormer, P. G.; Variankaval, N.; Ball, R. G.; Tsou, N. N. Org. Lett. 2008, 10, 3037. (b) Chung, J. Y.; Steinhuebel, D.; Krska, S. W.; Hartner, F. W.; Cai, C.; Rosen, J.; Mancheno, D. E.; Pei, T.; DiMichele, L.; Ball, R. G.; Chen, C.-y.; Tan, L.; Alorati, A. D.; Brewer, S. E.; Scott, J. P. Org. Process Res. Dev. 2012, 16, 1832. (260) Stadler, D.; Goeppert, A.; Rasul, G.; Olah, G. A.; Prakash, G. K. S.; Bach, T. J. Org. Chem. 2009, 74, 312. (261) Guin, J.; Besnard, C.; Pattison, P.; Lacour, J. Chem. Sci. 2011, 2, 425. (262) Zeng, M.; You, S.-L. Synlett 2010, 1289. (263) Surendra, K.; Corey, E. J. J. Am. Chem. Soc. 2012, 134, 11992. (264) Wang, S.-G.; Han, L.; Zeng, M.; Sun, F.-L.; Zhang, W.; You, S.L. Org. Biomol. Chem. 2012, 10, 3202. (265) Rueping, R.; Uria, U.; Lin, M.-Y.; Atodiresei, I. J. Am. Chem. Soc. 2011, 133, 3732. (266) Guo, Q.-X.; Peng, Y.-G.; Zhang, J.-W.; Song, L.; Feng, Z.; Gong, L.-Z. Org. Lett. 2009, 11, 4620. (267) Wilcke, D.; Herdtweck, E.; Bach, T. Synlett 2011, 1235. (268) Bergonzini, G.; Vera, S.; Melchiorre, P. Angew. Chem., Int. Ed. 2010, 49, 9685. (269) Fu, T.-h.; Bonaparte, A.; Martin, S. F. Tetrahedron Lett. 2009, 50, 3253.

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