Photocycloadditions of benzene derivatives and their systematic application to organic synthesis

Introduction

Photochemical reactions of simple compounds can generate a high degree of molecular complexity and diversity which is of high interest, for example, for the search of new biologically active compounds.^[1] The photochemical reactivity of organic compounds is significantly different from their ground state reactivity. This is due to the fact that photochemical or electronic excitation modifies the electronic configuration of such compounds.^[2,3] New compounds or compound families become easily available that cannot, or only with difficulty, be synthesised by more conventional methods of organic synthesis. Consequently, these reactions have become an important tool in organic synthesis.^[4–7] During recent years, photochemical reactions became also particularly attractive in chemical and pharmaceutical industries when searching for new biologically active compounds.^[8,9] Photocycloadditions of alkenes with electronically excited benzene derivatives are typical examples. While ground state reactions of such compounds are often characterised by a high tendency to regenerate aromaticity in the products, photochemical reactions are frequently characterised by a high tendency to loose aromatic character in the products. In this context, it should also be mentioned that photochemical excitation significantly affects the aromatic or anti-aromatic character.^[10–13] Thus benzene derivatives become anti-aromatic when they are photochemically excited. Consequently, the reactivity is significantly increased. For the same reason, product formation at the excited state potential energy surface is directed to structures which are less stable at the ground state potential energy surface. Thus, a high degree of molecular complexity is generated in one step with relatively simple starting compounds. In the context of sustainable chemistry, it should be pointed out that in these reactions the concept of the photon as a traceless reagent is realised.^[14]

Three different modes of photocycloaddition are possible between ground state alkenes and electronically excited benzene type compounds (Scheme 1). They provide efficient access to complex non-aromatic polycyclic compounds. Ortho ([2 + 2]) photocycloadditions lead to bicyclo[4.2.0]octa-2,4-dienes, meta ([2 + 3]) photocycloadditions generate tricyclo[3.3.0.0]octa-3-enes and para ([2 + 4]) photocycloadditions give rise to bicyclo[2.2.2]octa-2,5-dienes.

Scheme 1. 

Three modes of photocycloadditions of alkenes to electronically excited benzene derivatives.

Despite promising recent studies,^[15–17] para photocycloadditions are rarely observed for benzene-like aromatic compounds. Ortho and meta photocycloadditions have been studied much more intensively since their discoveries, respectively, in 1957^[18,19] and 1966.^[20,21] However, many aspects, such as the competition between these modes, still need intensive investigation. Also, the influence of substituents or the influence of the spin multiplicity on this competition are not yet well understood. These are important topics when the reactions are systematically applied to organic synthesis. Mechanisms based on the formation of an exciplex have been proposed to explain the selectivity.^[22,23] The selectivity is strongly influenced by the nature of the substituents because they affect the electron-donating and accepting properties of the partners. A large electronic difference between the partners induced by the substituents directs the reaction towards the ortho photocycloaddition whereas a small difference favours the meta photocycloaddition.^[22,24] The substitution pattern may also cause an exergonic photochemical electron transfer between the reaction partners leading to non-cyclisation products. A common intermediate for all three photocycloadditions was later found in a computational study.^[25] It is easily accessible from the S₁ state and corresponds to a conical intersection between the S₁ and S₀ surfaces. Over the years, numerous reviews have described many aspects of these reactions, ranging from experimental conditions and mechanistic descriptions to applications in total synthesis.^[26–30] The present article gives an overview of historical and recent applications in total syntheses. Topological aspects are detailed as they are crucial for the planning of total syntheses. Furthermore, new insights on the competition between ortho and meta photocycloadditions at their singlet excited state are highlighted.

Meta photocycloaddition at the singlet state

It was early established that the meta photocycloaddition occurs at the singlet excited state, based on the observed retention of configuration of the alkene partner and quenching experiments.^[31] The mechanism of the meta photocycloaddition is detailed for the intramolecular version in Scheme 2. The intramolecular [2 + 3] cycloaddition of the aromatic compound 1 excited to the singlet state to the alkene function can either occur at positions 1,3 or 2,6, to lead to intermediates 2 or 3 respectively. They also possess zwitterionic character due to the singlet multiplicity.^[32] After this initial formation of two σ-bonds, the charge or radical combination leads to two different products for each intermediate depending on the generated cyclopropane. The more common intermediate 2 usually yields angular triquinanes 4 or linear triquinanes 5. Intermediate 3 gives structures 6 or 7. Due to the zwitterionic character of the intermediates, electronic properties of substituent X have an influence on the regioselectivity. If X is electron-donating, it directs the addition towards positions 1,3 to form intermediate 2, while positions 2,6 and intermediate 3 are preferred when X is electron-withdrawing.^[20,33,34] In the case of the absence of a strong donor or acceptor substituent X, compelling evidence showed the biradical nature of these intermediates.^[35,36]

Scheme 2. 

Intramolecular meta photocycloaddition.

Applications of meta photocycloadditions in total syntheses

The meta photocycloaddition gives access to many different scaffolds depending on the opening of the cyclopropane ring (Scheme 3). A topological analysis is helpful for a targeted application to the synthesis of natural compounds. On the one hand, cleavage of the external allylic σ-bond (blue) leads to either angular triquinanes like isocomene, or linear triquinanes like hirsutene. On the other hand, cleavage of the internal allylic σ-bond (red) gives sesquiterpenoids like α-cedrene. From this type of product, another internal σ-bond (green) can be cleaved leading to other polycyclic structures like rudmollin.

Scheme 3. 

Natural products synthesis by different cyclopropane openings. A topological analysis.

The pioneer work of Wender and Howbert displayed many applications of the meta photocycloaddition in total syntheses of natural products.^[37] In this first of a large series of articles, in 1981, they described their strategy considering the mode of addition (ortho, meta, para), regioselectivity, endo/exo selectivity and stereochemistry. First, they pointed out that the intramolecular reaction drastically reduces the number of possible cycloadducts compared to the intermolecular version. Then they adjusted the substituents and their electronic properties to favour the meta mode and to direct the regioselectivity. Finally, the endo/exo selectivity and stereochemistry were explained by looking at the conformations of the exciplexes. Some of these syntheses will now be briefly discussed focusing on the crucial steps of meta photocycloaddition and cyclopropane opening.

In the total synthesis of isocomene, the meta photocycloaddition of the aromatic compound 8 gives both the linear and angular cycloadducts 9 and 10 (Scheme 4).^[38] It should be pointed out that the reaction was stereospecific with respect to the chiral centre in 8 which is explained by an allylic 1,3-strain effect.^[39] This was observed in many similar reactions. The linear adduct 10 was transformed into the angular one (9) by a thermal vinyl cyclopropane rearrangement. Conveniently, this process also leads to the opening of the cyclopropane by a 1,5-hydrogen transfer to yield product 11. Isocomene was then obtained by a regioselective catalytic hydrogenation.

Scheme 4. 

Total synthesis of isocomene.

In the synthesis of hirsutene, the meta photocycloaddition was less efficient (Scheme 5).^[40] It was improved by adding an acetyl function on the lateral chain of substrate 12. Treating the meta adduct 13 with 10-camphor-sulfonic acid then led to intermediate A with a tertiary allylic positive charge that was neutralised by an E₁ elimination to yield product 14. Hirsutene was then obtained after four additional steps.

Scheme 5. 

Total synthesis of hirsutene.

The enantioselective total syntheses of penifulvins A, B and C were developed more recently by Gaich and Mulzer using a similar methodology (Scheme 6).^[41,42] The stereogenic quaternary carbon centres in position 6 of adducts 16 and 18 were set by the trisubstituted E/Z double bonds of substrates 15 and 17 respectively. Due to the fact that the photocycloadditions occur at the singlet excited state, no long living radical intermediates are generated enabling E/Z isomerisation. It should be pointed out that such reactions can be carried out with compounds possessing non-protected hydroxy functions.

Scheme 6. 

Total syntheses of penifulvins B and C in analogy to the synthesis of penifulvin A.

In the synthesis of α-cedrene, the meta photocycloaddition of compound 19 led to a mixture of products 20 and 21 (Scheme 7). These two adducts converged into product 22 when the internal allylic σ-bond was cleaved by an addition of Br₂ followed by radical debromination using tributyltin hydride. α-Cedrene was finally obtained with 58% yield by a Wolff–Kishner reduction of product 22.

Scheme 7. 

Total synthesis of α-cedrene.

A similar strategy was applied to the synthesis of rudmollin. This synthesis required the cleavage of two σ-bonds of the cyclopropane (Scheme 8).^[43] Irradiation of substrate 23 yielded a mixture of meta adducts 24 and 25. As for α-cedrene, the cleavage by electrophilic activation of the internal allylic σ-bond of the two products 24 and 25 led to a unique product 26. Compound 27 was obtained after eight additional steps; its geometry allowed the cleavage of another σ-bond originating from the initial cyclopropane. Mesylation of the alcohol, followed by addition of lithium aluminium hydride, induced fragmentation to give product 28. Rudmollin was then obtained after six additional steps.

Scheme 8. 

Total synthesis of rudmollin.

Asymmetric induction of meta photocycloadditions

High diastereoselectivities were observed by Sugimura and co-workers by introducing a chiral tether (Scheme 9). Irradiation of substrate 29 yielded predominantly adduct 31 (70%) and traces of product 30 (<2%).^[44,45]

Scheme 9. 

Diastereoselective meta photocycloaddition using a chiral tether.

Several photochemical reactions have been carried out with cyclodextrin (CD) inclusion complexes in order to induce chirality by the host structure.^[46,47] Moderate enantioselectivities were obtained by Vízvárdi and co-workers by complexation of the substrates in CDs (Scheme 10).^[48] The irradiation of a β-CD complex of substrate 32 yields products 33 and 34 in a 1:3 ratio with an enantiomeric excess (ee) of 2 and 17% respectively. The difference of ee was explained by comparing the approaches leading to each product in the CD cavity. The stereodifferentiation in approach (ii) is more expressed than in approach (i), the facial enantioselectivity is thus higher for product 34 than for product 33.

Scheme 10. 

Enantioselective meta photocycloaddition by irradiating a β-CD complex.

Competition between [2 + 2] and [2 + 3] photocycloadditions at the singlet and triplet excited state

The intramolecular ortho photocycloaddition gives access to interesting tricyclic structures that often rearrange into more stable products. Selective ortho photocycloaddition is usually induced by placing an electron-withdrawing substituent on the aromatic ring. Furthermore, acetophenone derivatives give exclusively ortho photocycloadditions since they react at the triplet excited state. In accordance with the El Sayed rules,^[2,49] this is due to the facile intersystem crossing from the n–π* singlet excited state to π–π* triplet excited state of the aromatic ketones.^[50] In this case, the primary adduct 37 of ortho photocycloaddition is formed via a biradical intermediate^[51] 36 that combines after intersystem crossing (Scheme 11). The initial ortho photocycloaddition adducts 37 then undergo a spontaneous thermal disrotatory ring opening. Finally, a photochemical disrotatory cyclisation of cyclooctatriene 38 leads to the stable product 39.^[52]

Scheme 11. 

Ortho photocycloaddition of acetophenone derivative 35.

Cosstick et al. observed the same consecutive rearrangements of the primary ortho adduct 41 when irradiating benzonitrile derivative 40 in acetonitrile (Scheme 12).^[53] This study opened the question of singlet or triplet intermediates for these derivatives because they noticed that the reaction rate was not affected when irradiating solutions saturated by xenon.^[54] In such conditions, xenon induces an increased spin-orbit coupling by a heavy atom effect. Later, the authors performed more quenching experiments.^[55] First, they compared the intensity of fluorescence of compounds bearing an alkene on the side chain with the saturated analogues. The fluorescence was quenched by 50% for the derivatives with alkenes, proving that there is an interaction between the singlet excited state aromatic and ground state alkene. However, they noted that the quenching was less pronounced compared to aromatic compounds known to react at the singlet excited state. Then they observed that the formation of the cyclooctatriene 42 was quenched by 50% in the presence of a low concentration of 2,5-dimethylhexa-2,4-diene or 2,3-dimethylbuta-1,3-diene. As these dienes are triplet quenchers, the result may indicate that the first step of the ortho photocycloaddition occurs at the triplet state, but the possibility of side reactions with the dienes was not ruled out. Nevertheless, in this experiment the photocyclisation to form final product 43 was not affected, they thus concluded that the last step of photocyclisation of the cyclooctatriene takes place at the singlet excited state in acetonitrile as solvent.

Scheme 12. 

Ortho photocycloaddition of benzonitrile derivative 40.

Following this work, Wagner et al. performed the irradiation of the same compound in acetone in a larger study investigating the effect of triplet sensitisation.^[56] The triplet reaction in acetone yielded a different product 44. Triplet sensitisation did not impact the first step of the ortho photocycloaddition. However, it caused a different electrocyclisation of the cyclooctatriene 42, confirming that the product 43 is obtained from a photocyclisation at the singlet excited state.

Our recent results give new insights on the nature of the excited state involved in the first step of ortho photocycloaddition of benzonitrile derivatives (Scheme 13).^[57] The irradiation of benzonitrile derivative 45 bearing a methoxy substituent revealed that the singlet excited state prevails by direct absorption in acetonitrile. On the one hand, the major products 46 and 47 are the result of a singlet state meta photocycloaddition. Their formation is favoured by the methoxy substituent that stabilises the zwitterionic intermediate (see meta photocycloadditions section). Compound 46 was completely transformed into 47 by prolonged irradiation. On the other hand, the regioselectivity of the [2 + 2] addition served as a support that the ortho adduct 50 is formed at the singlet excited state. The irradiation in acetonitrile yielded product 50 resulting from the known rearrangements of adduct 48 which is formed by an ortho photocycloaddition on positions 1,2. After complete conversion of 45 and prolonged irradiation, its 15% portion of the product mixture didn’t change. In contrast, triplet sensitisation by irradiation in an acetonitrile/acetone mixture yielded product 53 resulting from an ortho photocycloaddition on positions 1,6. No product was isolated when irradiations were carried out in pure acetone, indicating that the photocyclisation of cyclooctatrienes 52 is not effective at the triplet state. The reaction is only possible in an acetonitrile/acetone mixture that permits the triplet ortho photocycloaddition by sensitisation of substrate 45 as well as the singlet photocyclisation by direct absorption of cyclooctatriene 52. A typical triplet-excited state reaction of a cyclooctatriene intermediate is reported in Ref. [58].

Scheme 13. 

Meta and ortho photocycloadditions of benzonitrile derivative 45 bearing a methoxy substituent. Singlet and triplet excited state reactivity.

Applications of ortho photocycloaddition in total syntheses

An early example of application of ortho photocycloadditions was the synthesis of compounds 57 and 58 (Scheme 14)^[59,60] that are 5,5-dialkylcyclohexane-1,3-dione analogues of known herbicides.^[61–64] The irradiation of the 3,5-dihydroxy derivative 54 gave product 56 via a tautomerisation of the primary ortho adduct 55. The final products 57 and 58 were obtained after a ring opening induced by methanol addition under acidic conditions.

Scheme 14. 

Synthesis of compounds 57 and 58 analogues of known herbicides.

Resorcinol derivatives such as 59 possess low photo-reactivity when irradiated under standard conditions due to the reversibility of the reaction (Scheme 15). When irradiated in an acidic medium, product 62 was isolated.^[65,66] Under these acidic conditions, the tetrahydrofuran moiety of the primary ortho adduct 60 is protonated. Subsequent opening of the tetrahydrofuran ring then leads to product 62. This type of benzocyclobutenes are valuable synthesis intermediates.^[67] Product 63 was obtained after eight steps, and it was efficiently transformed into product 64 via a thermal rearrangement. Removal of the methyl carbamate protecting group finally gave benzooctahydroisoquinoline 65.^[68,69] This compound is a rigidified structural analogue of dopamine and has a selective affinity to certain dopamine receptors.

Scheme 15. 

Synthesis of benzooctahydroisoquinoline 65 as a dopamine analogue.

More recently, Zech and Bach have revisited the ortho photocycloadditions on salicylic acid derivatives.^[70] In prevision of total syntheses,^[71] gradual changes to the substrate structures were performed in order to study the selectivity of the reaction (Scheme 16).^[72] For example, an additional oxygen atom in the side chain (66a) gave product 69 as expected, after the known rearrangements of primary adduct 67 and cyclooctatriene 68. However, a methyl substituent (66b, R═Me) yielded a different regioisomer (70) after photocyclisation of the cyclooctatriene 68.

Scheme 16. 

Regioselectivity depending on the substitution pattern on the aromatic compound.

In their strategy for the total synthesis of atlanticone C, this methyl group had to be introduced before the photochemical step so they replaced the ester function with a cyclic ketone (71) to force the formation of the desired regioisomer 72 (Scheme 17).^[72] To prevent undesired photochemical reactivity of the α,β-unsaturated carbonyl function, an aqueous solution of Fe₂(SO₄)₃ was used to absorb light below λ = 350 nm. Synthesis of atlanticone C from product 72 was completed by modifications of the oxidation state of several carbon atoms and introduction of a stereogenic centre. It was performed in nine steps with an overall yield of 6%.

Scheme 17. 

Total synthesis of atlanticone C.

The research group later described the first enantioselective total synthesis of (+)-atlanticone C using a similar photochemical reaction cascade.^[73] A catalytic chiral resolution of the racemic photoproduct was enabled by an enantioselective Corey–Bakshi–Shibata reduction. This time, (+)-atlanticone C was prepared in 10 steps with 18% yield from the enantiomerically pure photoproduct.

When similar compounds to 71 were irradiated at λ = 350 nm, a new reactivity was observed.^[74] Rauscher and co-workers used this photochemical reaction cascade for the total synthesis of (+)-agarozizanol B (Scheme 18).^[75] In this reaction, irradiation of substrate 73 yields product 74 after the classical sequence of ortho photocycloaddition, ring opening and photocyclisation. Compound 74 absorbs light under these conditions and undergoes a di-π-methane rearrangement to give product 76 via the biradical intermediate 75. The overall yield for these four successive reactions is 62%. Product 77 was then obtained with an ee of 96% with the same process used in the (+)-atlanticone C synthesis.^[73] The oxazaborolidine 78 was used for a catalytic chiral resolution of the photoproduct 76 by a Corey–Bakshi–Shibata reduction.^[76] Finally, (+)-agarozizanol B was obtained from compound 77 after seven steps with an overall yield of 55%.

Scheme 18. 

Total synthesis of (+)-agarozizanol B.

The synthetic value of the ortho photocycloaddition is considerably increased when applied to hetero-aromatic substrates such a pentafluoropyridine,^[77] oxazolopyridine,^[78] benzotriazole,^[79] or even polycyclic aromatics like cyanonaphthalene.^[80] More complex alkene partners can also be considered like naphthalene^[81,82] or 1-cyanonaphthalene.^[83]

Chiral induction of ortho photocycloadditions

Wagner and McMahon performed diastereoselective ortho photocycloadditions by irradiating compounds bearing a chiral auxiliary (Scheme 19).^[58] Using (2R,5R)-(–)-2,5-dimethylpyrrolidine or (7R)-(–)-camphorsultam attached to substrate 79, the final product 84 was isolated with a diastereoisomeric excess of 90%. The only permanent stereogenic centre C8 is created during the first step of the ortho photocycloaddition. Compound 80 is formed with a low diastereoselectivity. It is then increased by a photo-epimerisation of cyclooctatriene 81. The authors suggested that this kinetic resolution is due to the intersystem crossing to the triplet state facilitated by the acetyl substituent. It leads to ring opening of cyclooctatriene 81 to the tetraene biradical 82 where the rotation of the σ-bond between the allyl and pentadienyl moieties leads to an epimerisation during ring closing to cyclooctatriene 83.

Scheme 19. 

Diastereostelective ortho photocycloaddition with chiral auxiliary.

Conclusion

Starting from relatively simple products, photocycloadditions of benzene derivatives with alkenes provide efficient access to compounds with a high degree of molecular complexity. Mainly [2 + 3] (meta) or [2 + 2] (ortho) photocycloaddition take place. In the latter case, photochemical and thermal rearrangements of the primary adducts are generally observed. The meta photocycloaddition occurs at the singlet excited state. The ortho addition, however, can take place either at the singlet or the triplet excited state. In this case, the spin multiplicity may have an influence on the regioselectivity of cycloaddition. In this context, more systematic and detailed studies of the influence of the substitution pattern on the regioselectivity and the cycloaddition mode is necessary. For example, recent findings suggest that the role of the singlet excited state in ortho photocycloadditions of nitrile and ester substituted aromatic compounds may have been overlooked.

The meta photocycloaddition has already proven to be a key step in many syntheses of natural products. A topological analysis is helpful in this regard. In this context, the ortho photocycloaddition was neglected in the past. However, recently, impressive syntheses have been published using this photocycloaddition as a key step. The application of photocycloadditions of benzene derivatives to organic synthesis can further be strengthened if challenges such as chiral induction or para photocycloadditions continue to be addressed.

Data availability

Data sharing is not applicable as no new data were generated or analysed during this study.

Conflicts of interest

The authors declare no conflicts of interest.

Declaration of funding

The authors thank the Communauté Urbaine du Grand Reims and the Université de Reims Champagne-Ardenne for financial support of their research in this domain.