AreneâAlkene Cycloaddition - Chemical Reviews (ACS Publications)

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Arene−Alkene Cycloaddition Richard Remy and Christian G. Bochet* Department of Chemistry, University of Fribourg, Chemin du Musée 9, CH-1700 Fribourg, Switzerland ABSTRACT: Cycloadditions are among the most efficient chemical processes, combining atom economy, stereospecificity, and the ability to generate molecular complexity in a single step. Aromatic rings would in principle be ideal reaction partners, as they contain, at least from the topological point of view, both olefinic and diene subunits; however, the stability of the conjugated aromatic system would be broken by cycloaddition reactions, which are therefore rarely applied, because kinetics and thermodynamics hinder the process. From that aspect, photochemical activation opens interesting perspectives, as one can selectively provide excess energy to one of the reactants but not to the product, thus preventing thermal back reaction. Indeed, aromatic rings show a rich photochemistry, ranging from isomerizations, substitutions, and additions to cycloadditions. In this review, we will focus on cycloadditions, covering literature from early observations up to the present.

CONTENTS

References

1. 2. 3. 4. 5.

Introduction Experimental Considerations Photophysics and Photochemistry of Benzene Mechanistic Considerations Ortho Cycloaddition 5.1. Ortho Cycloaddition with Benzene-like Aromatics 5.1.1. Intermolecular 5.1.2. Intramolecular 5.2. Ortho Cycloaddition with Polycyclic Aromatics 5.3. Ortho Cycloaddition with Heteroaromatics 6. Meta Cycloaddition 6.1. Meta Cycloaddition with Benzene-like Aromatics 6.1.1. Intermolecular 6.1.2. Intramolecular 6.2. Meta Cycloaddition with Chiral Induction 6.3. Meta Cycloaddition with Naphthalene Derivatives 7. Para Cycloaddition 7.1. Para Cycloaddition with Benzene-like Aromatics 7.1.1. Intermolecular 7.1.2. Intramolecular 7.2. Para Cycloaddition with Naphthalene Derivatives 7.3. Para Cycloaddition with Heteroaromatics 8. Other Types of Cycloadditions 9. Conclusion Author Information Corresponding Author Notes Biographies Acknowledgments © XXXX American Chemical Society

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1. INTRODUCTION Cycloadditions are among the most efficient chemical processes, combining atom economy, stereospecificity, and the ability to generate molecular complexity in a single step. It is thus not surprising that they have become increasingly popular among synthetic chemists, and a very large fraction of complex (natural) products syntheses include cycloadditions, often as the key step. Particular members of the cycloaddition family are [2 + 2], [3 + 2], and [4 + 2] variants, respectively adding two, three, or four carbon atoms to an olefinic partner. The [2 + 2] cycloaddition is forbidden by Woodward−Hoffmann rules in the thermal mode. A stepwise version using particular promoters, such as Lewis acids, is possible, but it is allowed by photochemical activation. Overall, this reaction remained quite restricted to a few particular cases. On the other hand, [3 + 2] and [4 + 2] cycloadditions are thermally allowed by the symmetry of the frontier orbitals of the reactants, and they are both very widely used. Aromatic rings would in principle be ideal reaction partners, as they contain, at least from the topological point of view, both olefinic and diene subunits; however, the stability of the conjugated aromatic system would be broken by cycloaddition reactions, which are therefore rarely applied, because kinetics and thermodynamics hinder the process. Even if the kinetic barrier can be overcome, the reversibility of these reactions usually gives back the starting materials. Even cycloadditions with less aromatic reactants such as furans are notoriously difficult. From that aspect, photochemical activation opens interesting perspectives, as one can selectively provide excess energy to one of the reactants but not to the product, thus preventing thermal back reaction.

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Special Issue: Photochemistry in Organic Synthesis Received: January 4, 2016

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DOI: 10.1021/acs.chemrev.6b00005 Chem. Rev. XXXX, XXX, XXX−XXX

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pressure Hg lamps emit a few additional lines, mainly at 315 and 365 nm. On the other hand, high-pressure Hg lamps emit continuously from 254 nm up to the visible. These lamps are typically packaged as immersion lamps, which should be placed at the center of a double- or triple-mantel reactor; the reaction solution is placed in the outer mantel, so that it can be irradiated from the inside with a large exposure surface. Water circulation is possible, to cool either the reaction or the lamp. Filters can be fitted around the lamps. An experimentally attractive alternative is the Rayonet reactor, which looks like a metallic cylinder (with a typical diameter of a few dozen centimeters, of which the internal periphery is equipped with several (typically 8 or 16) Hg lamps with an appropriate pressure and a fluorescent coating delivering the desired wavelengths (typically 254, 300, 350, and 420 nm). The monochromaticity is modest (except for 254 nm), typically more than 20 nm of line width, but most of the time sufficient for organic reactions. Other setups are available for Hg lamps, such as projector-style housings, with focusing or collimating optics, and a filter chamber. The most commonly found filters are cutoff filters, allowing transmission of light longer than a specified threshold; for example, Vycor (λ > 230 nm) or Pyrex (λ > 285 nm). Quartz is essentially transparent above 200 nm. Liquid filters are also frequently used, such as copper sulfate aqueous solutions (transparent between 340 and 540 nm) and water (cutting off infrared).15 Even if, technically, any filter could be used with any source, some combinations do not make sense, and this is sometimes the source of failure. For example, one should never user a low-pressure Hg lamp (254 nm) with a Pyrex filter (cutoff at 285 nm): in such a setup, no light at all will go through the filter. Using glassware made out the particular type of glass may replace the need for dedicated filters. In recent years, light-emitting diode (LED)-based reactors have become increadingly popular. Among the clear advantages are the availability of almost every wavelength in 5 nm increments, good monochromaticity (10 nm), little heating, and much longer lifetime (20 000 h vs 1000 h for Hg lamps). The major drawbacks for the moment are very low intensities for short wavelengths and high cost. Another important factor to consider is the light intensity, which can vary greatly between different lamp types and manufacturers. Thus, reaction times quoted in the literature cannot be compared unless exactly the same conditions are used. Shape of the reactor, exposure surface, and distance between lamp and sample have a massive impact on the effective intensity reaching the sample. Thus, the best parameter to describe the efficiency of a photochemical reaction remains the quantum yield, the ratio between formed product and number of absorbed photons. Finally, a well-defined temperature can be difficult to maintain and to measure, and many publications fail to report this important parameter (or room temperature is quoted, but the gradual heating of the light source is not taken into consideration). Low-temperature irradiation can pose some experimental difficulties, as condensation of moisture between light source and sample may change the amount of light effectively available. In this article, we have tried to report as accurately as possible the experimental conditions used, but in many cases, the original publications are quite vague and experimental parts are missing.

Indeed, aromatic rings show a rich photochemistry, ranging from isomerizations, substitutions, and additions to cycloadditions. In this review, we will focus on cycloadditions, covering literature from early observations up to the present. While very detailed reviews on particular modes of photocycloaddition have been published previously (some of them in this journal), we have nevertheless included many early examples in order to give a sufficiently large overview of these reactions. We have covered the various modes of cycloadditions in separate sections; however, as many of these reactions give mixtures of products, it is sometimes difficult to label them with a unique descriptor. We have arbitrarily decided to consider the major product to determine where to cite them. The field has already been surveyed on several occasions, starting with an excellent early review by one of the pioneers in the field, Gilbert,1 where he clearly explained the fundamentals of the possible reactions and the factors governing the ortho, meta, or para mode of cycloaddition. About 20 years later, Cornelisse and de Haan2 wrote a very detailed review on ortho cycloaddition. In the same book, Mizuno et al.3 reviewed photocycloadditions of hetero- and polyaromatics. In the same year, Wagner4 reviewed ortho cycloadditions of triplet benzenes with olefins. A few years later, Chappell and Russell5 reviewed the applications of meta cycloaddition. The same topic was also reviewed on several occasions by Wender et al.,6,7 pioneers in meta cycloadditions. Cornelisse8 also published a systematic review on meta cycloaddition. More general reviews9−11 covering all types of arene photocycloadditions were also published, such as the one from Hoffmann.12 Shortly after, Hoffmann13 reviewed photochemical key steps in natural product synthesis, and a large section is devoted to arene− alkene cycloadditions. Monographs, textbooks, and large reference series also covered the field, the latest being by Gaich.14

2. EXPERIMENTAL CONSIDERATIONS Excitation of a chromophore requires photons with exactly the energy corresponding to the energy difference between excited Scheme 1. Photochemistry of Benzene

and ground states. Thus, the wavelength of the light used for photochemical reactions is of critical importance. Unfortunately, types and specifications of light sources are quite diverse, and they are sometimes difficult to acquire at a reasonable cost. Changing one type to another is in principle possible, provided that the wavelength and intensity are comparable, but this makes the reproducibility of published photochemical reactions challenging. Among the most widely used UV-light sources are mercury lamps, but even those come in various versions. Low-pressure Hg lamps have a single emission at 254 nm, whereas mediumB


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Scheme 2. Modes of Photocycloaddition of Benzene with Various Olefinic Partners According to Their Orbital Symmetry

3. PHOTOPHYSICS AND PHOTOCHEMISTRY OF BENZENE In the absence of additional reactants, benzene itself can undergo various photochemical reactions, mainly isomerizations. Thus, irradiation of benzene in the gas phase at 185 nm leads to the formation of fulvene (Scheme 1), together with an unidentified product, possibly the acyclic 1,3-hexadiene-5-yne.16 On the other hand, photolysis of liquid benzene at 254 nm leads first to benzvalene, before the concentration of fulvene increases;17 it has been initially hypothesized that benzene is a precursor to fulvene, and this was confirmed a few years later.18 Interestingly, Dewar benzene is not produced photochemically from benzene itself but from the photolysis of cis-1,2-dihydrophthalic acid followed by oxidative decarboxylation.19 However, 1,2,4-tri-(tbutyl)benzene most probably leads to the correspondingly substituted Dewar benzene.20 It was found later that populating higher excited states of benzene with shorter wavelength irradiation (either 206 or 160−220 nm), namely S2 and S3, actually leads directly to Dewar benzene.21,22 Bryce-Smith23 analyzed the possibility of photochemical reactions of benzene with different olefins in terms of orbital symmetry (Scheme 2). Interestingly, at this stage, the possibility of para adducts was predicted, but no experimental observation had been done yet.

Scheme 3. Modes of Photocycloaddition of Benzene Derivatives

• The two incoming carbon atoms connect to two carbons separated by two additional atoms. This is called 1,4- or para cycloaddition (C, Scheme 3). In early papers, in particular on meta cycloadditions, the way the three-membered ring is linked in the product with respect to the original aromatic compound is also numbered (see Scheme 3), and this may cause some confusion. In those cases, the mode of addition is usually denoted with the ortho, meta, or para descriptor. The structures of ortho and para adducts are quite straightforward in terms of locating the original positions of the reactants in the product. On the other hand, the meta adduct may be ambiguous, in particular when the aromatic substrate is substituted, and several isomers are possible. Structure B is very often represented as a typical bicyclo[3.3.0]octene with an additional bond, showing more clearly that it is actually a dihydrosemibullvalene. It was recognized already in the 1970s that the difference in electron-donating and -accepting ability between reaction partners (which can be expressed in the Rehm−Weller equation) dictates the reaction mode (Scheme 4). A large difference (with

4. MECHANISTIC CONSIDERATIONS Cycloaddition of a benzene-type aromatic and a two-carbon unsaturated system (mainly olefins and acetylenes) can proceed in three topological ways: • The two incoming carbon atoms connect to two adjacent carbon atoms of the aromatic compound. This is called 1,2- or ortho cycloaddition (A, Scheme 3). • The two incoming carbon atoms connect to two carbons separated by another atom. This is called 1,3- or meta cycloaddition (B, Scheme 3). C


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Scheme 4. Photoreactivity of Benzene Derivatives with Olefins As Predicted by Their Difference in Ionization Potential

Scheme 6. Reaction Mechanism between Excited Benzene and Ethylene As Predicted by Computation

intersection (CI) between the S1 and S0 surfaces. From that perspective, all three possible photocycloaddition products are accessible. No transition states (and thus no activation barriers) were detected, and it is the dynamics that dictates which of these products is formed. Substituents, of course, have an impact on the location of this CI and may drive the reaction in favor of one or the other photoproduct.

Scheme 5. Orientation of Olefin with Respect to Substitutents on the Benzene Ring

5. ORTHO CYCLOADDITION 5.1. Ortho Cycloaddition with Benzene-like Aromatics

5.1.1. Intermolecular. One of the first occurrences of ortho cycloaddition was reported by Angus and Bryce-Smith in 1959,32 Scheme 7. Ortho Adducts between Benzene and Maleic Anhydride

as the product of irradiation of benzene with maleic anhydride. In fact, ortho adduct 1 was postulated only as an intermediate, because the diene formed by the initial reaction reacts further with another equivalent of maleic anhydride in a classical Diels− Alder reaction, leading to 2 (Scheme 7); a para adduct like 3 was excluded, as it would not add to a second anhydride unit. A thermal pathway was experimentally excluded. Bicyclic cyclohexadienes containing an element of strain are known to spontaneously undergo electrocyclic ring opening, and structures like 1 would be typical examples. Thus, it is quite common that primary adducts are not observed, as later examples will show. A few years later, Büchi and co-workers33 isolated in good yield the ortho adduct between benzonitrile and 2-methyl-2-butene (63%); the addition of benzophenone perturbed the process and only 0.05% of product was isolated (however, 54% of the Paternò−Bü chi adduct with benzophenone was isolated instead). Also, benzonitrile reacted in the same way with alkynes, but the adducts spontaneously rearranged to cyclooctatetraenes. Ortho addition of benzene with cis- and trans-butene by irradiation at 254 nm is stereospecific, as shown by Wilzbach and Kaplan.34 The ortho cycloadducts can be photolabile, as it was

the consequence of exergonic electron transfer) leads to substitution, whereas an endergonic process leads to cycloaddition. Within the latter, it was noted that a small difference favors the meta mode, whereas larger differences favor the ortho mode. A typical cutoff value of ΔIP = 0.6 eV was proposed.24,25 This model was later refined by Mattay and co-workers.26−28 In order to rationalize the impact of polar substituents on the aromatic ring, Mattay et al.29 hypothesized that an exciplex was involved: “In conclusion one can say: though the existence of an exciplex is not conclusively proven in most cases of meta photocycloadditions, the assumption of an exciplex-like arrangement of the reactants as a necessary step is the best model to predict the stereochemistry of the products.” (see Scheme 5). Endo orientation of the alkene is usually preferred. Robb and co-workers30,31 studied computationally the reaction between benzene and ethylene. They concluded that, of all the intermediate species in Scheme 6, only one (VII) is energetically accessible from S1, and it corresponds to a conical D


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Scheme 8. Adducts between Hexafluorobenzene and Cyclooctene

Scheme 9. Ortho Adducts between Benzene and Electronpoor Olefins

Scheme 11. Photocycloaddition between Benzene and a Chlorouracil Derivative

Scheme 12. Intramolecular Ortho Photocycloaddition with an Alkyne

Scheme 10. Ortho Photocycloaddition between Benzene and Alkynes

Scheme 13. Intramolecular Ortho Photocycloaddition between Aryl Ketone and Alkene, Followed by Consecutive Electrocyclic Reactions

observed that, in the course of irradiation, the amount of ortho adduct decreases in favor of meta and para adducts. Solvent polarity effects were identified, and ortho addition was favored when the olefin was significantly electron-rich or electron-poor; when that was not the case, meta adduct was observed predominantly.24 These features are also seen in solvent effects: meta addition is insensitive to the nature of the solvent, whereas ortho addition is favored by polar solvents. Cyclic carbonates also react in an ortho fashion with benzene, but the product rapidly isomerizes to the para adduct under the reaction conditions (with acetophenone sensitization).35 A similar reaction between hexafluorobenzene and cyclooctenes gave interesting mechanistic insight,36 showing that the product distribution is time-dependent, eventually reaching a

photostationary state. In particular, 6 (as a mixture of isomers amounting to 24%) is absent before the equilibrium (Scheme 8). Meta adducts 4 and 5 (60%) are thus slightly more favored than the ortho adduct (combined yield of 40%). On the other hand, contrary to the reaction with benzene, hexafluorobenzene failed to give any of the expected products with tetramethylethylene; polar addition products with concomitant loss of hydrogen fluoride were observed. With enol ethers, it was found that the ortho cycloadduct is the one formed with the highest quantum yield (>0.7), but its further E


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Hoffmann and Pete and co-workers48−50 later showed that phenol derivatives also give ortho adducts, which rearrange in situ under acidic catalysis into benzocyclobutane derivatives (Scheme 15). Interestingly, the benzocyclobutanes were later exploited in thermal generation of orthoquinodimethane and subsequent trapping with a dienophile.51 The regiochemistry gives predominantly the meta, para cyclobutane over its ortho, meta isomer, irrespective of the presence of a preexisting substituent ortho to the phenol; also, both tetrahydrofuran and tetrahydropyran rings were formed in comparable yields. On the other hand, with a longer tether (n = 3), seven-membered rings were not formed. Similar observations were reported by De Keukeleire and coworkers,52,53 where photolysis of 41 gave predominantly ortho adducts (or their subsequent reaction products). For example, photolysis of 41d led to the following distribution of products, as determined by HPLC analysis: 42d (30%), 44d (10%), 45d (43%), and 43d (5%), together with 12% unreacted 41d (Scheme 16). Related processes were observed in minor products of cascade reactions by Penkett and Woolford54 (vide infra and Scheme 17). Interestingly, with particular substitution patterns, counterintuitive regioselectivities were observed (Scheme 18).55,56 Here again, the tetrahydropyran ring is hydrolyzed in acidic medium, and a dienone enol ether is obtained. In a series of articles, Wagner et al.57,58 showed that the parasubstituted analogues also reacted in a similar way (Scheme 19). The ratio of the final product regioisomers (58 vs 60) is likely to be correlated with the preferred exciplex conformation, giving a preference to the kinetically favored 57 (anti) over its diastereoisomer 56 (syn). The radical nature of the mechanism was later confirmed by the opening of a cyclopropyl-derived alkene.59 In order to show the influence of the difference in donor− acceptor properties of the substrate, Nuss et al.60 showed the switch from the normally obtained meta to ortho adducts by polarizing the double bond with a nitrile (Scheme 20). The reaction can lead to interesting cores, which could be the starting point toward the synthesis of complex natural products, as shown by Banerji and co-workers61 (Scheme 21).

Scheme 14. Intramolecular Ortho Photocycloaddition between Aryl Ester and Alkene, Followed by Consecutive Electrocyclic Reactions

photodecomposition leads to a poor chemical yield, thus limiting the synthetic usefulness.37 Electron-rich arenes were also reported to react with electronpoor alkenes (Scheme 9).38 Hanzawa and Paquette39 also reported the initial ortho addition of alkynes with benzene, which react further upon prolonged photolysis to give the intricate polycyclic structure 16. A radical cyclization mechanism through intermediates 18 and 19 was invoked (Scheme 10). Seki and co-workers40 reported the addition of benzene to 6chloro-1,3-dimethyluracil, leading to a cyclooctatetraene after elimination of hydrochloric acid and electrocyclic ring opening (Scheme 11). Pressure seems to have an effect on the reaction, as the rate of ortho cycloaddition between benzene and acrylonitrile increased by a factor 6.5 under a pressure of 500 bar. The authors could deduce a “pseudoactivation volume” of −31 cm3·mol−1 in acetonitrile. With reverse electron demand pairs, that is, the reaction between benzene and dihydropyrane, there was an acceleration in apolar solvent but a slowdown in acetonitrile.41 5.1.2. Intramolecular. Contrary to the intermolecular case, Gilbert and co-workers42 studied a version where benzene and olefin are tethered. The reaction yielded mainly isomers of meta adducts, and no ortho adducts were observed. In stark contrast, alkynes added in an ortho fashion but only as a transient species, as rapid electrocyclic ring opening yielded cyclooctatetraenes (Scheme 12).43 A few years later, Wagner and Nahm44,45 observed nevertheless that intramolecular cycloaddition of acetophenone derivatives can lead to ortho adducts, with a relatively high quantum yield (up to 0.3; Scheme 13). The reaction was proposed to arise from a ketone-facilitated n−π* singlet to π−π* triplet-state transition. Gilbert and co-workers46 later made similar observations. Hoffmann and Pete47 published a related example with benzoic acid esters; the reversible series of pericyclic processes, carried out in methanol, can be stopped by formation of a ketal in acidic medium (Scheme 14).

5.2. Ortho Cycloaddition with Polycyclic Aromatics

Perfluoronaphthalene was found to react photochemically with indene to give all three possible modes but with a marked preference for ortho (55%), with a ratio 76:77:78:79 of 39:16:10:35 (Scheme 22).62 Cyanonaphthalene was also studied, and ortho cycloadditions were observed, together with polar reaction products, depending on the structure of the aromatics.63,64 In the same study, the intramolecular mode was shown to also give cycloadduct isomers 81 and 82, in a 20:1 ratio (unfortunately, no chemical yield was provided) (Scheme 23). Döpp et al.65 studied the reaction of cyanonaphthalene with 1,1-disubstituted olefins. Monosubstituted naphthalenes also underwent intramolecular cycloaddition with enol ethers, but the

Scheme 15. Intramolecular Ortho Photocycloaddition between Phenol and Alkene, without Consecutive Electrocyclic Reactions

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Scheme 16. Intramolecular Ortho Photocycloaddition of Unsubstituted Phenol Ethers

Scheme 17. Intramolecular Ortho Photocycloaddition of an Anisole Derivative

Scheme 18. Effect of Substituents on Intramolecular Ortho Photocycloaddition Regioselectivity

Scheme 19. Stepwise Formation of Intramolecular Ortho Adducts

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excited carbonyl groups, and this was indeed observed in the following attempt to obtain ortho adducts (Scheme 26).75 Cyclohexadiene reacts cleanly in an ortho fashion with 1cyanonaphthalene, whereas 2-cyanonaphthalene also gives para adducts and polyaddition products; the possibility of a Cope-like rearrangement complicates the analysis of what is the primary photoproduct (Scheme 27).76 A similar reaction was also performed with furan, and to a certain extent, an initial [4 + 4] cycloaddition product is thermally converted into an apparent ortho adduct.77 Kohmoto et al.78 reported an intramolecular reaction giving ortho, para, and other products in various yields, but sometimes with the ortho product as the major one (up to 82%; Scheme 28). Condensed polyaromatics also have a relatively rich cycloaddition photochemistry. Mizuno and co-workers79 reported an intramolecular reaction with pyrene derivatives (Scheme 29). A similar but intermolecular version (Scheme 30) was also reported in what looks like a stereospecific process (in the specific example with a cis-alkene, two diastereosiomers are obtained, both of them retaining the initial alkene cis configuration).80 Less symmetrical polyaromatics were also investigated, and substituted styrenes were shown to react regioselectively with chrysene (Scheme 31).81 Hoffmann82 reported intramolecular cycloaddition of resorcinol derivative 112, leading first to an ortho adduct 113, which then rearranges into naphthalene 114 in acidic medium (Scheme 32).

Scheme 20. Forcing the Ortho Photocycloaddition Mode by Electronically Biasing the Olefinic Partner

Scheme 21. Exploitation of Intramolecular Ortho Photocycloaddition in Synthesis of Complex Products

5.3. Ortho Cycloaddition with Heteroaromatics

Pyridine itself does not undergo photocycloaddition with olefins,83 but its pentafluoro derivative gives the ortho adduct 116 in the presence of ethylene (Scheme 33).84 The latter thermally adds a second ethylene molecule at 40 °C, giving 117. Sakamoto et al.85 reported an unprecedented photochemical dimerization, presumably originating from ortho adduct 119 (Scheme 34). A similar reaction was also observed with 1-cyanonaphthalene, together with the above-mentioned dimer. Depending on the substituents on pyridine, various ratios of cycloadducts and dimers were isolated (Scheme 35).86 Interestingly, 2-cyanonaphthalene did not react under the same conditions. On the other hand, in the presence of alkenes, the pyridine derivative 121 gave a series of products (Scheme 36).87 Compound 123 presumably arises from a Dewar pyridine intermediate, whereas 125 is the hydrolysis product of 124. The latter is an initial ortho adduct, which underwent an electrocyclic ring opening and subsequent reclosing. Interestingly, pyrazines add to allysilanes in an apparent meta reaction; however, it was in fact shown to be an initial ortho addition, followed by a rearrangement (Scheme 37).88 Oxazolopyridines also react in an ortho fashion, as shown by Donati et al.89 (Scheme 38). In the absence of an alkene, 131 is photostable, but it reacts readily when irradiated in the presence of acrylonitrile. The initial adducts were, however, not directly isolated, as they spontaneously either rearranged into the eightmembered rings 132 and 134 (in relative yields of 45% and 42%) or further reacted in a Diels−Alder reaction (133, 13%). Booker-Milburn et al.90 reported the photoreaction of maleimide with benzotriazole in moderate yield (Scheme 39). Nonbenzenoid aromatics of course also have a rich photochemistry, but they tend to behave more like regular dienes or olefins and have been deliberately omitted here. Typically, furans

position of the tether had a strong influence on reactivity.66 Depending on the substituent, various ratios of ortho and para products were obtained, and a triplet biradical mechanism was proposed.67,68 Wagner and Sakamoto69 reported similar reactions (Scheme 24). Sensitizing experiments confirmed that the reaction occurs from the triplet state, and a radical-type addition of a biradical to the alkene was proposed. The effect of complexation with metallic cations and Eu(III) favored the formation of product 88 over 89. In fact, 88 is invariably the kinetically controlled product (in benzene, 2 h), and equimolar amounts of 88 and 89 were obtained only after longer irradiation (benzene, 20 h). In the presence of Eu(III) salt, the amount of 88 was even higher (Scheme 25).70 Both triplet sensitizers and quenchers had no apparent effect on the reaction’s course. Solvent and additive effects were studied, in particular from the perspective of solvent/exciplex interactions.71,72 Hydrogen bonds were shown to have a directing effect on a related intermolecular reaction;73 the reaction was also performed in a microreactor.74 One should, however, not overlook the other classical photochemical reactions, such as hydrogen abstraction by H


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Scheme 22. Double Ortho Photocycloaddition of Perfluoronaphthalene with Indene

Scheme 23. Intramolecular Ortho Photocycloaddition of a Cyanonaphthalene Derivative

Scheme 24. Intramolecular Ortho Photocycloaddition of Naphthalene Derivatives

Scheme 25. Effects of Complexation with Cations on Intramolecular Ortho Photocycloaddition of Naphthalene Derivatives

other photoprocesses such as the Paternò−Büchi reaction.91−93 With pyrones and pyridones, furans tend to react in [4 + 4]

react either as the olefinic partner with excited benzenes (and these examples will be cited in the relevant section) or undergo I


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Scheme 26. Side Reaction in Intramolecular Ortho Photocycloaddition of Naphthalene Derivatives

Scheme 27. Ortho Photocycloaddition between Cyanonaphthalene and Cyclohexadiene

Scheme 30. Intermolecular Ortho Photocycloaddition of Pyrene Derivatives

Scheme 28. Reversible Intramolecular Photocycloaddition of Naphthalene Derivatives

Scheme 31. Intermolecular Ortho Photocycloaddition of Chrysene Derivatives

Scheme 29. Intramolecular Ortho Photocycloaddition of Pyrene Derivatives

benzene with cis-cyclooctene gave one major adduct (85%), which was identified as 137 (Scheme 40). Prolonged irradiation led to compounds incorporating a second cyclooctene unit. Naphthalene was shown to react in a similar manner, giving 138. Without further details, it was indicated in this work that alkynes react in the same way. It was also shown that cyclooctene inhibits the formation of fulvene by photoisomerization of benzene (vide supra) and that fulvene itself does not react to give 137. Simultaneously, the same reaction was reported with cisbutene by Wilzbach and Kaplan,102 and it was described as the addition of an olefin to the cyclopropane ring of benzvalene. The stereospecificity, together with kinetic measurements and quenching experiments, suggested a singlet-based mechanism.103 Srinivasan104 reported the meta cycloaddition with cyclobutene. A few years later, Srinivasan and co-workers105 published detailed work on the reaction with cyclopentene and assigned

cycloadditions.94−96 Indoles, on the other hand, react with alkenes in [2 + 2]97−99 or Diels−Alder cycloadditions.100

6. META CYCLOADDITION 6.1. Meta Cycloaddition with Benzene-like Aromatics

6.1.1. Intermolecular. One of the earliest explicit reports of a meta addition dates back to 1966,101 where irradiation of J


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Scheme 32. Intramolecular Ortho Photocycloaddition between Two Aromatics, Followed by Rearrangement

Scheme 33. Ortho Photocycloaddition of Pentafluoropyridine with Ethylene

Scheme 34. Photodimerization of a Pyridine Derivative

Scheme 35. Ortho Photocycloaddition between Naphthalene and Pyridine Derivatives

Scheme 37. Initial Ortho Photocycloaddition between Pyrazine and Allylsilane Derivatives, Followed by Rearrangement

Scheme 36. Ortho Photocycloaddition between Pyridine and Acrylonitrile Derivatives

consistently good yields but also because subsequent acidic hydrolysis allows to access versatile cores, ready for further functionalization (Scheme 42). Cyclopentene reacts with o-methylanisole (Scheme 43) to yield a meta adduct in 70% yield (based on unreacted starting material), giving a 1:1 ratio of 145 to 146.107 These isomers arise from two possible recombinations, forming bond a (145) or bond b (146). The opposite electronic combination is also possible, and, benzene gave meta adducts with enol ethers upon irradiation at 254 nm.37 The amount of meta adduct increases with time, suggesting once again the reversibility of an initial ortho cycloaddition. The same observation is also true for the reaction between benzene and vinyl acetate: an initial ortho/meta ratio of 7:1 increased to 9:1 upon prolonged irradiation. The quantum yields actually show the same kinetic 7:1 ratio (Φortho = 0.01, Φmeta = 0.22). Chemical yields were not reported, as both

the structures 139 and 140 (Scheme 41). Low yields of 5% and 1% were quoted due to experimental difficulties in the isolation, but it was estimated that a 10-fold increase was likely. Anisole was also tested with a dozen acyclic or cyclic olefins, and the meta adducts were usually obtained as the major products, almost always as endo isomers. Chemical yields between 20% (cyclohexene) and 85% (cyclopentene) were obtained, with quantum yields ranging from 2% (cyclohexene) to 21% (cycloheptene).106 Anisole was interesting not only for its K


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Scheme 38. Ortho Photocycloaddition between Oxazolopyridine and Acrylonitrile Derivatives

Scheme 42. Meta Photocycloadducts between Anisole and Cyclopentene

Scheme 43. Isomers in Meta Photocycloaddition between oMethylanisole and Cyclopentene

ortho position of the bridge with respect to the substituent is also called 2,6-addition; likewise meta−meta (3,5), ortho−para (2,4 or 4,6), and meta−ipso (1,3 or 1,5). With R being an electrondonating group, the ortho−ortho orientation is favored, whereas when R is an electron-withdrawing group, the ortho−para orientation predominates, which is in line with what was shown earlier. Cornelisse and co-workers110 also studied the intermolecular reaction with cyclopentene in terms of isotope effects. The inherent strain in the meta cycloadducts can be released by various mechanisms, and the resulting structures are also of high interest in the synthesis of particular scaffolds. For example, Fenton and Gilbert111 heated the cycloadducts in an acidic medium (Scheme 46). The mechanism starts with protonation of the double bond at C-4, which provokes the rupture of the three-membered ring, thus restoring a double bond; final trapping with water leads to one of the two alcohols (the ratios of which depend on the substrate substituent). Gilbert et al.112 also studied the regio- and stereoselectivity of benzene and substituted derivatives with trans-dichloroethylene in detail. Despite the radical nature of the “intermediate”, the trans relationship between the two chlorine atoms was retained in all the products. Sheridan113 performed a very elegant experiment, aiming at proving that the biradical 152 was indeed an intermediate in the meta photocycloaddition between xylene and cyclopentene (Scheme 47) leading to a mixtures of 153, 154, and 155. Thus, 156 was attempted to be independently prepared by thermolysis of the corresponding diazo precursor. Surprisingly, the thermolysis of two possible precursors 156 and 157 led to two different isomers 153 and 154; although the result regarding 152 were inconclusive, the involvement of diazo biradicals was by itself a highly interesting result, prompting caution when investigating biradicals (Scheme 48). Two years later, however, Reedich and Sheridan114 indeed showed compelling evidence for the involvement of a biradical, replacing the diazo thermolysis by photolysis (Scheme 49). In the following case, 162a reacted with 163a and 163c (ca. 65% yield in both cases), and 162b reacted with 163c (giving

Scheme 39. Ortho Photocycloaddition between Benzotriazole and Maleimide

Scheme 40. Early Reports on Meta Photocycloadducts of Benzene and Naphthalene with Cyclooctene

Scheme 41. Meta Photocycloadducts between Benzene and Cyclopentene

reactants were used neat and the products were isolated after evaporation.108 As mentioned earlier, the position of polar substituents has an impact on regio- and stereoselectivity, as shown in the study by Mattay and co-workers28 with a benzene derivative bearing two electron-withdrawing groups (Scheme 44). Cornelisse and co-workers109 studied systematically the orientation effect of one substituent (Scheme 45). The ortho− L


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Scheme 44. Isomers in Meta Photocycloaddition between Cyclopentene and m-Ditrifluoromethylbenzene

Scheme 45. Various Regioselectivities in Meta Photocycloaddition of Monosubstituted Benzene Derivatives

Scheme 46. Reactivity of Meta Photocycloadducts in Acidic Medium

Table 1. Intramolecular Meta Photocycloaddition of Monosubstituted Benzene Derivatives There was also an effect of pressure on meta cycloadditions, with a rate increase and a pseudo volume of activation of ca. −30 cm3·mol−1, but only a moderate effect on regio- or stereoselectivity for apolar substrates. On the other hand, vinyl ethers showed a stronger sensitivity to pressure.41 Substituents on the aromatic ring with a 1,3-relationship may mutually interact at the transition state, thus influencing the overall regioselectivity. For example, a trifluoromethyl group and a hydroxymethyl group influenced the meta cycloaddition outcome by hydrogen bonding.122 This reaction was exploited in the total synthesis of natural products. Wender and Dreyer123 converted a meta cycloadduct 168 into a [3.3.3]propellane core 169, en route to the synthesis of (±)-modhephene 171 (Scheme 52). Very few additional steps were necessary: namely, saponification and oxidation of the acetate, base-promoted trialkylation of the ketone, addition of a cuprate to the cyclopropane, and two reductions led to the target compound. The regiochemistry of the cycloaddition involves addition of vinyl acetate across the 1,3-carbon atoms; the major isomer connects the unsubstituted terminus of the olefin to the most substituted aromatic position, but it is the ultimate recombination that discriminates between the angular triquinane 167 (C2−C6; minor isomer) and the propellane 168 (C2−C4; major isomer). Starting from slightly different precursors (benzene and vinyl acetate), a synthesis of (±)-isoiridomyrmecin 175 was achieved (Scheme 53).124 The photocycloaddition was based on earlier

90% of 164 and 165). All other combinations were unsuccessful (Scheme 50).115 Furan reacts with substituted benzenes, but frequently as mixtures, and which mode predominates is not directly linked to the electron density of the arene. In fact, if the alkene is part of a conjugated diene, many additional reaction modes can then occur,116−118 such as the meta 1,4, as seen in the reaction of furan with toluene (Scheme 51):119−121 M


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Scheme 47. Hypothesis of the Radical Nature of Meta Photocycloaddition

Scheme 48. Initial Mechanistic Study To Confirm the Radical Nature of Meta Photocycloaddition

Scheme 50. Meta Photocycloaddition between Bicyclic Benzene Derivatives and Cyclic Olefins

Scheme 51. Meta Photocycloaddition between Toluene and Furan

work by Gilbert and Bin Samsudin,108 but it was reported as “low yielding”. 6.1.2. Intramolecular. The first report of an intramolecular meta cycloaddition came almost immediately after the initial account, by Morrison and Ferree,125 with the irradiation of 6phenylhex-2-ene. No unambiguous structure was assigned, but all the possible isomers compatible with the analytical data were meta adducts (Scheme 54). The exact nature of the isomers was disclosed a few years later.126 As will be seen in a later section, phenethyl vinyl ether gave a meta adduct as a minor product.127A systematic study of the

latter reaction with tethers of various lengths was performed (Table 1).128,129 The intramolecular reaction with an oxygen-containing tether was examined in great detail by De Keukeleire and coworkers,130,131 including the endo/exo preference of the substituents in the meta cycloadducts. Likewise, Cornelisse and co-workers132−134 studied effects of substitution on the tether of 5-phenylpent-1-ene derivatives 180−182(Scheme 55).

Scheme 49. Mechanistic Study Confirming the Radical Nature of Meta Photocycloaddition

N


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Scheme 52. Total Synthesis of (±)-Modhephene by Wender and Dreyer123

Scheme 53. Total Synthesis of (±)-Isoiridomyrmecin by Wender and Dreyer124

the olefinic partner reduced the total number of possible photocycloadducts from 168 to only 2. The meta adducts 186 and 187 were then further transformed into (±)-α-cedrene 189, in what the synthetic community considers one of the most elegant and efficient total syntheses ever (Scheme 56).135 One of the striking features of this synthesis is the convergent conversion of both isomeric meta cycloadducts into a single product, by treatment with molecular bromine and radical debromination. Electrophilic activation of the double bond and presence of the methoxy group provoked the rupture of the three-membered ring. A final Wolff−Kischner reduction led directly to the targeted product 189. Wender and co-workers systematically explored all the possible variations of cycloadditions and how to convert the adducts into natural products, in an impressive series of natural products syntheses. Opening the cyclopropane ring is certainly the most intuitive (and thermodynamically favored) step, and all three ruptures led to different types of scaffold, including linear triquinanes (such as hirsutene) and angular triquinanes (such as isocomene). It is also very interesting to note where the subsituents end up in the product, with respect to the reactant (colored spheres, Scheme 57). The synthesis of cedrene in Scheme 56 involved the rupture of bond b. Instead of electrophilic opening of the three-membered ring as seen above, pyrolysis of the meta adduct 191 induced a [1,5]sigmatropic shift, paving the way for an also extremely efficient synthesis of (±)-isocomene 194 (Scheme 58). In this case, bond c of the cyclopropane is broken.136 Here again, a mixture of the cycloadducts can be used, although the yields were higher if one started with one of the meta products. Rupture of the third side of the cyclopropane ring in 196 (bond a) leads to a different fused-bridged system, part of the structure of hirsutene 202 (Scheme 59).137 In this case, installation of a leaving group vicinal to the cyclopropane provokes the dehydrative rupture. Two diastereoisomers 196 and 197 and one regioisomer 198 of the meta adducts were obtained, and the elaboration toward hirsutene required isolation

Scheme 54. Meta Photocycloadducts of 6-Phenylhex-2-ene

Scheme 55. Effects of Substituents on the Tether of 5Phenylpentene Derivatives

Scheme 56. Total Synthesis of (±)-α-Cedrene by Wender and Howbert135

The real potential of this reaction was uncovered by the sensational publication of Wender and Howbert in 1981,135 where the constraints imposed by the difference in ionization potential between the electron-rich arene (specifically a dialkylanisole), length of the tether, and substitution degree of O


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Scheme 57. Polycyclic Ring Systems Accessible by Meta Photocycloaddition

steps, namely, addition of a thiol to the exocyclic olefin, reduction of the remaining double bond by catalytic hydrogenation, elimination of a sulfoxide, and final ozonolysis. Reminiscent of the synthesis of hirsutene, the linear triquinane core of coriolin 208 was generated by conjugate addition of a thiol directly on the meta cycloadduct 204, leading to rupture of a bond of the cyclopropane (Scheme 60).138 Also exploiting the meta cycloaddition toward triquinanes, the synthesis of silphiperfols (Scheme 61) converts the angular triquinane adduct 212 by bromination.139 In this case, the linear and angular triquinane initial cycloadducts mutually interconvert by photolysis with less energetic light (Pyrex filtering). In the synthesis of rudmollin 217 (Scheme 62), a similar mode of opening of the cyclopropane in 214 and 215 as for cedrene is used, this time by electrophilic activation with mercuric acetate.140 Rudmollin includes a bicyclo[3.5.0]decane ring system, common to numerous biologically active natural products, such as phorbol. Thus, the precursor 213 was converted into a 2.3:1 mixture of isomers 214 and 215 by irradiation with a medium-pressure Hg lamp at room temperature. [Note that there is an apparent discrepancy in ref 140

Scheme 58. Total Synthesis of (±)-Isocomene by Wender and Dreyer136

of one of the adducts (in order to have the appropriate orbital alignment between leaving group, broken bond, and the proton to be lost). The final product was obtained with few additional

Scheme 59. Total Synthesis of (±)-Hirsutene by Wender and Howbert137

P


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Scheme 60. Total Synthesis of (±)-Coriolin by Wender and Howbert138

Scheme 61. Total Synthesis of Silphiperfols by Wender and Singh139

Scheme 62. Total Synthesis of Rudmollin by Wender and Fisher140

single meta cycloadduct 223. Using a medium-pressure Hg lamp with a Vycor filter led only to low conversion (ca. 30%), mainly due to the filtering effect of the products also absorbing the incident light. However, adding a bismuth chloride filter significantly improved the conversion (80%) and allowed the isolation of crystalline 223 in 51% yield (64% based on recovered 222). A few subsequent steps led to the target compound 224, bearing a fenestrane skeleton. Another way of opening the cyclopropane ring is the addition of cyanomethyl radical, as shown in the synthesis of subergorgic acid (Scheme 64).142 Addition of a radical to the double bond leads to a cyclopropylmethyl radical, which spontaneously opens. Thus, exposure of 225 to Vycor-filtered light from a mediumpressure Hg lamp gave a 1.8:1 mixture of linear and angular triquinanes 226 and 227 in 42% yield (61% based on recovered

about the ratio of isomers, between what is stated in the text and in the schemes. We quote here the ratio from the text.] Regioand stereochemistry is explained by an exciplex derived from conformation 213. Both isomers can be converted into 216 by reaction with mercuric acetate, in slightly different yields (respectively 58% and 71%). The synthesis of laurenene 224 (Scheme 63) departs from the previous cases, as several steps were carried out before the cycloaddition, thus presenting an already quite functionalized starting material.141 The precursor 222 was assembled by Diels− Alder reaction between o-methylbenzyne and cycloheptadiene and a few functional group interconversions. Another interesting feature is the length of the tether, apparently carrying one carbon less than in the previous examples; it is in fact distant from the arene by the same number of atoms. Photolysis of 222 gave a Q


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Scheme 63. Total Synthesis of (±)-Laurenene by Wender et al.141

Scheme 64. Total Synthesis of Subergorgic Acid by Wender and deLong142

Scheme 65. Total Synthesis of Retigeranic Acid by Wender and Singh143

Scheme 66. Effect of Olefinic Substituents on the Ring System Obtained by Meta Photocycloaddition

R


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Scheme 67. Synthesis of Fenestranes by Keese and Co-workers145−147

Scheme 68. Synthesis of Fenestranes by Wender at al.148

[5.5.5.5]fenestradiene, but unfortunately, a different isomer was obtained instead by thermolysis. This route remains, however, remarkably efficient to form fenestrane-type skeletons, and it was subsequently used by other groups. Thus, Wender et al.148 prepared a cis,cis,cis,trans-[5.5.5.5]fenestrane derivative by meta cycloaddition, followed by a radical cascade, initiated by addition of the cyanomethyl radical (Scheme 68). Penkett et al.149 also assembled the fenestrane core but in a single step (Scheme 69). Photolysis (4 h) of the difunctionalized precursor 254 in cyclohexane gave an initial product distribution where the linear meta adduct was the major product (23%), together with a small amount of its angular isomer (3.5%) and a series of rearranged ortho adducts. A longer photolysis time (16 h) gave directly 8% of fenestrane 261. Mechanistic studies with deuterium labeling showed that a photochemical reopening of the initial meta cycloadduct is involved. An aza version was also successful.150 Along those lines, the tertiary alcohol analogue 46 was subjected to similar conditions, and the intermediate meta (263−265) and ortho (47) adducts were observed (Scheme 70).54 However, unlike in the previous case, further irradiation failed to provide a fenestrane core. The presence of the tertiary alcohol provides an additional thermal decomposition pathway to the meta cycloadducts. Consistent with an elimination reaction, ketone-bearing side products were isolated. It was

starting material). The photoadducts are themselves photolabile, and it was found to be beneficial to stop the reaction before complete conversion (ca. 66%). The isomers were separated, and the angular isomer 227 was further elaborated toward the target compound. In the synthesis of retigeranic acid 235 (Scheme 65), the cyclopropane in 231 is also opened by a radical process, initiated by addition of the photochemically generated aminoformyl radical.143 Photolysis of 230 gave a 1:2 mixture of angular and linear triquinanes 231 and 232 (72% combined yield). These isomers are actually interconvertible photochemically, exploiting the rearrangement of the vinylcyclopropane substructure. The final structure is assembled by a very elegant intramolecular Diels−Alder reaction. Cosstick and Gilbert144 designed an interesting way of selecting the linear versus angular triquinane mode (Scheme 66). With very similar precursors, differing only by the position of a halogen atom, either the angular or the linear triquinane core is the major product of the meta cycloaddition. Keese and co-workers145−147 used this reaction to assemble fenestrane cores (Scheme 67). Compound 244 can be explained by an initial ortho cycloaddition (which also leads to a fenestrane but of the [4.5.5.6] type), followed by a series of electrocyclic ring opening/closures, as we have seen earlier. The two other isomers are meta adducts, originating from a common 1,3-biradical. A [1,5] sigmatropic shift from 246 could, in principle, have led to a S


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Scheme 69. Synthesis of Fenestranes by Penkett et al.149

Scheme 71. Side Reactions in Intramolecular Meta Photocycloaddition

Scheme 72. Consecutive Photochemical Reaction in Assembly of Complex Structures

In some cases, other photoinduced processes can compete with photocycloadditions; for example, the unusual ene reaction shown in Scheme 71 was observed, as an additional product in the photolysis of 266, where the expected linear triquinane remained the major product. Interestingly, none of the ene product was detected in substrates containing a substituent (methyl or methoxy) in position 2 of the aromatic ring; regular ortho cycloadducts were isolated instead. It is thus legitimate to hypothesize that 268 may arise from subsequent photochemical decomposition of an initial ortho adduct. However, the 267:268 ratio does not evolve significantly with time, and the ene reaction remains a reasonable explanation.151 In another example, by De Keukeleire and He,152 an initial Norrish-type I reaction was followed by meta cycloaddition with the newly formed olefin. Thus, the transformation 272 → 273 → 274 was performed by a single irradiation at 300 nm in 34% yield (Scheme 72). The intramolecular cycloaddition of 3-benzyloxyprop-1-ene gives preferentially a linear triquinane (such as 276) over its angular isomer (such as 277). On the other hand, replacing the oxygen by a nitrogen atom in the tether is detrimental to the reaction, as electron transfer from the electron-rich nitrogen atom to the excited benzene predominates. However, when electron-withdrawing substituents limit the donating ability of the nitrogen and electron-donating groups on the arene limit the accepting ability, modest to very good yield of meta cycloadducts were obtained (Scheme 73).153 Only linear triquinanes were observed. Interestingly, inclusion of a silicon atom in the tether leads to a highly selective and high-yield meta cycloaddition (85% of a single isomer) (Scheme 74).154,155 A synthesis of ceratopicanol 290 was performed by Chanon and co-workers156 (Scheme 75). In a very expeditious route, the

Scheme 70. Attempted Synthesis of Fenestranes by a Double Photocycloaddition

also noted that isomer 264 could, to a certain extent, be converted into angular product 265. T


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Scheme 73. Intramolecular Meta Photocycloaddition with Oxygen- and Nitrogen-Containing Tethers

Other members of this family of natural products were prepared in a similar fashion, such as penifulvin B and C, where the gem-dimethyl group is monohydroxymethylated.160 These products are interesting targets, because they can serve as probes on whether the meta cycloaddition is a suprafacial process and whether the steps preceding ultimate formation of the cyclopropane are reversible. Thus, precursor 311 was subjected to the same treatment as in the previous synthesis, and the two regioisomers 312 and 313 were obtained in a 2:1 ratio, both of them as single diasteroisomers (Scheme 79). Interestingly, the two isomers are thermally interconvertible (by a vinylcyclopropane rearrangement), thus allowing recycling of the undesired linear triquinane 313. Angular isomer 312 was then converted in a few steps into penifulvin B. The suprafaciality of the process and the concerted formation of both bonds in the exciplex was confirmed by a similar sequence, starting with the geometric isomer 315, leading to penifulvin C 316. Chen and co-workers161,162 used it en route to lancifodilactone F (Scheme 80). Interestingly, the OTMS group proved crucial, as good yields were obtained, in contrast to the related structure lacking them, which gave only decomposition products. Compounds 318 and 319 were convergently elaborated further toward the lancifodilactone F core structure 324. Wegmann and Bach163 studied the effects of some substituents on the linear versus angular triquinane ratio resulting from intramolecular meta photocycloaddition of benzyloxypropenes (Scheme 81, Table 2) and noted that with electropositive groups (X = H, alkyl, silyl) the linear product was favored, whereas electronegative groups (X = OH, OAc, F) favored the angular product. Ground-state interactions between X and the olefin were proposed to alter the preferred conformation, leading to one or the other regioisomer. Aphidicolin core 331 was assembled similarly, starting from a relatively complex substrate (Scheme 82).164

Scheme 74. Intramolecular Meta Photocycloaddition with Silicon-Containing Tethers

meta cycloadduct 286 was opened by addition of a thiol. Reductive desulfuration, allylic oxidation, alkylation, and final reduction led to the target molecule. In the total synthesis of silphinane derivative 297 by Coates et al.157 (Scheme 76), a similar mixture of meta cycloadducts 292 and 293 was obtained (in ca. 1:1 ratio). In this case, the angular triquinane isomer is elaborated toward the target molecule, by reductive treatment, followed by epoxidation and reduction. Likewise, in the formal total synthesis of crinipellin B by Wender and Dore158 (Scheme 77), the meta cycloadducts 300 and 301 were opened by addition of a thiol. The angular triquinane 302 was then further transformed into 304 by transforming the thiophenol ether into a leaving group, followed by internal displacement by the primary alcohol. The fenestrane substructure is also part of natural products, such as penifulvin A 310. Gaich and Mulzer159 used a meta cycloaddition for its enantioselective synthesis. Optically pure precursor 305 could in principle react from two conformations, but it was envisioned that 305a would suffer from an A1,3 strain and that the exciplex 306 would be formed only from 305b. Indeed, photolysis of 305 in pentane at 22 °C led to a nearly equimolar mixture of linear and angular triquinanes, each of them as single diastereoisomers (Scheme 78). They were separated, and the angular isomer 307 was elaborated into the target compound.

Scheme 75. Total Synthesis of Ceratopicanol by Chanon and Co-workers156

U


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Scheme 76. Total Synthesis of a Silphinane Derivative by Coates et al.157

Scheme 77. Total Synthesis of Crinipellin B by Wender and Dore158

Scheme 78. Total Synthesis of Penifulvin A by Gaich and Mulzer159

Penkett and co-workers165 assembled the gelsemine skeleton by meta photocycloaddition, where the cyclopropane ring in 333 was cleaved by epoxidation (because the usual bromination gave the wrong regioselectivity) (Scheme 83). Photolysis of 332 led to additional isomers 334 and 335, arising from an initial ortho cycloadduct, undergoing first an electrocyclic ring opening into a cyclooctatriene and then reclosing by another electrocyclic process into a series of isomeric bicyclo[4.2.0]octenes. In building upon this strategy, a carbonate linker was tried, but unsuccessfully. An acetal linker gave modest yields of meta

cycloadducts (up to 17%). Similar to the above case with a silicon tether, a meta adduct was isolated but also in modest yields (Scheme 84).166 Cycloadducts were also opened by a Heck reaction (Scheme 85).167−170 Trifluoromethyl groups were included in the tether, without detrimental effects (Scheme 86). Interestingly, only angular triquinane cores were obtained when CF3 was on the chain, whereas mixtures were obtained when it was in the form of a trifluoroacetate. Regio- and stereoselectivity in the formation of V


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Scheme 79. Total Synthesis of Penifulvin B and C by Gaich and Mulzer160

Scheme 80. Synthesis of Lancifodilactone Core by Chen and Co-workers161,162

ortho, meta, or para position) in the aromatic ring revealed that, in all cases, both ortho and meta adducts were obtained, and the solvent had very little impact on the reaction. All the meta adducts occurred at the 2′,6′-position of the arene (Scheme 87).53 The diastereoselectivity of simple intramolecular meta photocycloaddition was studied. Irradiation of 351a and 351b led only

345a and 345b can be explained by an intramolecular hydrogen bond between the aromatic methoxy group and the alcohol. On the other hand, there is no obvious explanation why the absence of the trifluoromethyl group on the tether leads to a different product distribution.171 A systematic study on the positional effect of an ester group (either directly attached or through a methylene unit, in the W


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Scheme 81. Effect of Remote Substituents on Linear/Angular Ratio in Intramolecular Meta Photocycloadditions

Scheme 84. Synthesis of a More Substituted Core by Penkett et al.166

Table 2. Effect of Remote Substituents on Linear/Angular Ratio in Intramolecular Meta Photocycloadditions

Scheme 85. Functionalization of Meta Photocycloadduct by Heck Reaction

entry

X

2/3

yield (%)

1 2 3 4 5 6 7 8 9 10 11

H Me SiMe3 SiEt3 OTBS OH OMe CN OPiv OAc F

>95/5 >95/5 >95/5 87/13 44/56 22/75 41/59 40/60 33/67 16/84

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