Photochemically induced radical reactions with furanones

Introduction

Photochemical reactions considerably enlarge the spectrum of reactions which can be carried out within a compound family [1–4]. This behavior is due to the change of electronic configuration upon electronic excitation by light absorption [5, 6]. Many photochemical reactions fulfill requirements of sustainable chemistry [7–10]. Often, activation can be carried out without chemical reagents, only by absorption of light [11]. Photochemical reactions have likewise been studied in the framework of process intensification [12]. In this context, continuous flow microreactors have found widespread applications in organic synthesis [13–15]. Their transparent reactor bodies with thin reaction channels enable high transmission of light and subsequently superior photonic efficiencies [16, 17]. These features make continuous flow devices attractive for photochemical applications [18–22]. Flow operation likewise limits the risk of photodecompositions or secondary photoreactions due to the removal of photoproducts from the light source. Many laboratory systems use commercially available ‘embedded’ flow reactors, pumping systems and light sources [23–26]. Due to their flexible design, microcapillary reactors have recently become more widespread [27–32].

Intermolecular radical addition as a standard reaction to evaluate and compare different photochemical reactor systems

The addition of ketyl radicals to α,β-unsaturated carbonyl or carboxyl compounds can be carried out in a very efficient way, especially when the ketyl radical intermediates are produced by hydrogen abstraction from secondary alcohols and when ketones are used as sensitizer [33–37]. Such an efficient reaction is depicted in Scheme 1 [38]. Isopropanol is added to the chiral furanone 1 in high yield and complete diastereoselectivity. The adduct 2 was transformed into (–)-terebic acid. Acetone was used as sensitizer. Although the absorption of this ketone is low at wavelengths > 300 nm, sensitization is efficient when it is added in higher concentrations or as co-solvent. The efficiency of this reaction is also explained by the fact that a radical chain mechanism is involved. After photochemical excitation of acetone and hydrogen abstraction, two identical ketyl radicals 3 are generated. These nucleophilic radicals easily add to the furanone 1 leading to the oxoallyl radical 4. After hydrogen abstraction from isopropanol by this intermediate, the final product 2 is formed and the hydroxyisopropyl radical 3 is regenerated. The radical chain process is very efficient and the termination step, the reaction of the radical intermediate 4 with hydroxyisopropyl radicals 3, plays only a minor role. In the case of the addition of isopropanol, the usage of acetone as sensitizer avoids the formation of different ketyl radicals form the secondary alcohol and the sensitizer. Furthermore, side product formation by photoreduction of the sensitizer is also avoided. Such a reaction is frequently observed with aromatic ketones that are often used as sensitizer in such transformations [39]. Similar reactions have been carried out with ketyl radical intermediates which have been produced via photochemical electron transfer [40].

Scheme 1

Acetone sensitized radical addition of isopropanol to furanones.

Due to its efficiency, the acetone sensitized addition of secondary alcohols to furanones was used as a model reaction to characterize and to compare different photochemical microreactor systems [41, 42]. In order to be able to achieve more coherent results, 4,4′-dimethoxybenzophenone (DMBP) was used as a more effective sensitizer. Its absorption spectrum better overlaps with the emission spectrum of the various UVA light sources used (Fig. 1) [42]. Such electron donor substituted aromatic ketones have also been applied successfully to the photochemically induced radical addition of tertiary amines to electron deficient alkenes [43, 44]. Thus the 4,4′-dimethoxybenzophenone (DMBP) photosensitized addition of secondary alkohols to a series of furanones was selected as a model transformation for a detailed reactor comparison study (Scheme 2) [41, 42, 45, 46].

Fig. 1

Absorption spectrum of 4,4′-dimethoxybenzophenone (DMBP) and emission spectra of different light sources.

Scheme 2

DMBP-sensitized isopropanol addition to furanones.

Batch reactions were conducted in a test tube using a conventional chamber reactor (Rayonet) fitted with 16 × 8 W UVA fluorescent tubes. For the reactions under microflow conditions, three different reactor types were investigated (Fig. 2, Table 1). The UV-LED driven microchip reactor achieved high conversion rates of 89–100 % after just 2.5 min. The dwell device, the microcapillary tower and the batch system needed 5 min of irradiation in order to reach high to quantitative conversions. The superior performance of the microchip system was associated with its favorable design features, which furthermore resulted in improved energy efficiencies and space-time-yields (STY) [47]. Although microchips are interesting devices for early R&D processes, their productivity rates are limited due to their small inner volumes. In contrast, ‘open’ capillary reactors allow easy modifications and flexible designs. The capillary reactor concept was thus advanced into a novel multi-microcapillary flow reactor (MμCFR) for 10 parallel photochemical runs (Fig. 3) [48]. The design features of this advanced microflow reactor system are summarized in Table 2.

Fig. 2

Microreactor setups. Front: mikroglas dwell device (left) and Micronit microchip (right). Back: syringe pump (left) connected to a dual microcapillary tower unit equipped with a single 8 W UV-fluorescent tube (right).

Fig. 3

Multi-microcapillary flow reactor (MμCFR).

The reactor was subsequently applied to process optimization, process validation, scale-up and parallel library synthesis [49–51]. DMBP, xanthone, 4-benzoylbenzoic acid and benzophenone were initially identified as suitable sensitizers, with DMBP yielding the highest conversion rate. The concentrations of DMBP and furanone were optimized in independent runs and were subsequently used for validation and scale-up studies. The multicapillary reactor was furthermore utilized for the synthesis of a small 3 × 3 product library using three furanones and three alcohols. The corresponding addition products were isolated from two successive runs in good to excellent yields of 57–94 % after column chromatography.

In the previously discussed reaction, the radical chain reaction is started by hydrogen abstraction by the electronically excited sensitizer from the secondary alcohol. Such reactions have successfully been carried out with a large variety of ketones as sensitizer. As already briefly mentioned above, in the case of the addition of tertiary amines only electron donor substituted aromatic ketones such as DMBP were particularly efficient. A typical example is depicted in Scheme 3 [52–54]. The addition of N-methylpyrrolidine 9 to the chiral furanone 8 was highly efficient when electron donor substituted aromatic ketones were used as sensitizer. The main difference between these two radical additions is that in the case of the tertiary amines, the starting reaction is a two step procedure. First, an electron is transferred from the tertiary amine to the electronically excited sensitizer, leading to the formation of a radical ion pair 11 and 12. In a second step, an acid base reaction, the neutral radical intermediates 13 and 14 are generated. The nucleophilic α-aminoalkyl radical easily adds to the electron deficient double bond of the furanone. More complex tandem addition cyclization reactions have also been successfully performed with these sensitizers [55–57]. The reactions were much less efficient with benzophenone or acetophenone. Initially, it was assumed that the difference in reactivity may be attributed to different excited states of the aromatic ketones. While benzophenone or acetophenone possess T₁ states with nπ* character, those T₁ states of electron donor substituted aromatic ketones have ππ* or even CT character [58]. A more profound study, however, revealed that both types of ketones possess very similar physico-chemical properties [59]. Thus, the quenching rate of the triplet states by electron transfer is very similar. Consequently, no further optimization by modification of the ketone sensitizer seemed to be possible. The reason for the successful application of these compounds as sensitizer is most probably due to the high stability of the corresponding ketyl radicals 13. Further extension of the scope of the reaction was accomplished by influencing the steps of the radical chain mechanism. This was done by addition of thiocarbonyl compounds to the reaction mixture [60–62]. These compounds are able to add reversibly to radical intermediates [63, 64].

Scheme 3

Photosensitized radical addition of tertiary amines to an electron deficient double bond.

The same transformations were successfully performed using heterogeneous photocatalysis. In this case, inorganic semiconductors such as TiO₂ or ZnS were used as sensitizers [65–67].

Intramolecular radical addition with electronically excited furanones

Photochemical radical additions have also been carried out without sensitization. In such reactions photochemically induced hydrogen transfer plays an important role. In the present context two types of mechanisms are frequently discussed. A hydrogen atom may be transferred form a hydrogen donor to a photochemically excited species in one step (Fig. 4, eq. 1), i.e., the electron and the proton are transferred simultaneously. In a second mechanism, the electron is transferred first and a radical ion pair is subsequently generated (eq. 2). In a second step, the proton follows and the same neutral radical intermediates are generated. In the latter case, the photochemical electron transfer and the following acid/base reaction are exothermic. In the first mechanism the photochemical electron transfer is endothermic while the formation of the neutral radical intermediates is exothermic. This mechanistic feature may also be discussed in the context of proton coupled electron transfer [68–72]. In contrast to many reactions in this domain, both particles are transferred from the same molecular site of the hydrogen donor to the same site of the acceptor. In a narrow definition, this is called “hydrogen atom transfer” (HAT) [72, 73].

Fig. 4

Two mechanisms for hydrogen transfer from a donor to an electronically excited acceptor.

The way in which the hydrogen is transferred has a significant influence on the outcome of the reaction. With the following examples, the influence on the regioselectivity is discussed. The two step mechanism is operating in the reaction of α,β-unsaturated ketones with tertiary amines (Scheme 4). After photochemical excitation of the enone 16, an electron transfer occurs form the tertiary amine 17 to the electronically excited species leading to the radical ion pair 18, 19 [74–76]. In the next step, a proton is transferred from the radical cation 19 to the radical anion 18. It is transferred onto the oxygen atom since the charge density is high in this position. It is this site of the molecule where basicity is located. The hydoxyallyl radical 20 and the α-amino alkyl radical 21 are generated as neutral intermediates. Radical combination leads to the final product 22. Thus, a C–C bond is formed in the β-position of enone 16. The same reaction was also carried out in an intramolecular way. Under the same reaction conditions, compounds 23 and 25 were transformed into 24 and 26, respectively [76, 77]. It must be pointed out that C–C bond formation always occurs in the β-position even in the case of the reaction of 25 where a quaternary carbon center is formed (26). Due to steric hindrance, the formation of such centers is difficult.

Scheme 4

Photochemical addition of tertiary amines to α,β-unsaturated ketones.

Acetales derived from aldehydes are also suitable hydrogen donors. In α,β-unsaturated lactones (furanones) such as 27, the amine was replaced by such a function (Scheme 5) [78]. The furanone is electronically excited by triplet sensitization with acetone. Spirocyclic compound 28a, b are obtained in which a C–C bond is formed exclusively in the α-position of the α,β-unsaturated lactones. The regioselectivity contrasts with the selectivity observed in the previous reaction with tertiary amines as hydrogen donors (Scheme 4). It also contrasts with the Michael type addition of nucleophilic radicals depicted in Schemes 1–3. The formation of compounds 28a, b is explained by the following mechanism. Electronic excitation occurs via triplet energy transfer from ³nπ* excited acetone to the furanone 27. The vibrationally relaxed T₁ state 29 possessing ππ* character, is further characterized by the suppression the C–C π-bond and a high spin density in the β position. For this reason, hydrogen abstraction according to eq. 1 in Fig. 4 occurs in this position. Thus the biradical intermediate 30 is formed [79, 80]. Radical combination leads to the final products 28a, b. If a two step mechanism would take place, an intramolecular radical ion pair 31 with a high charge density at the carbonyl oxygen would be formed. The proton would be transferred from the acetale moiety to the enolate leading to the intermediate 32. Radical combination would furnish compounds 33a, b with the formation of a C–C bond in the β position of the furanone part. These products are not observed. The oxidation of acetales is indeed difficult [81]. Photochemical electron transfer with acetales is only possible with very electron poor acceptors [82].

Scheme 5

Photosensitized intramolecular radical addition of an acetale function to a furanone moiety.

In the present case, hydrogen transfer only occurs from the acetal position (2′ position). However, the transfer may also occur from the 6′ position of the tetrahydropyranyl substituent. The competition of these two reactions was observed when an alkyl substituent was attached to the side chain of the furanone derivative 34 (Scheme 6) [78]. A 1:1 mixture of diastereoisomers of 34 (center 2′ of the tetrahydropyranyl group with respect to the center 5 of the furanone moity) was transformed. The spirocyclic compound 35 and the macrocyclic compound 36 were obtained. Only one diastereoisomer, the lk or S*S* diasteroisomer of 35 was isolated. This latter diastereoselectivity is also influenced by the radical combination in the diradical intermediate 37 which is related to particular properties of such intermediates [83, 84]. In this step, an intersystem crossing form the triplet state of 37 to the singlet state of 35 is involved [85–90]. Hydrogen abstraction in position 6′ is observed in the case of the ul (S*R*) diastereoisomer. Two diastereomeric diradical intermediates 39 and 40 may be generated by such a reaction step. However, radical combination leading to the final product 36 was only observed in the case of compound 34 possessing the ul (S*R*) relative configuration. Hydrogen abstraction in the 6′ position is also favored by an endocyclic anomeric effect [91–99].

Scheme 6

Intramolecular radical addition of an acetale function to a furanone moiety carrying an alkyl substituent at the side chain.

These results indicate that the regioselectivity of hydrogen abstraction is influenced by the stereochemistry of the starting products. Two stereochemical elements mainly contribute to the outcome of the reaction (Scheme 7): (1) the relative configuration at the acetale center with respect to the chiral center at the furanone moiety (42), (2) the axial or the equatorial orientation of the substituent at the six membered ring of the tetrahydropyranyl moiety. In order to characterize the influence of each one, the glucosyl derivatives 43, 44, 45 and 46 have been prepared and transformed under the same conditions. In these compounds, the axial (α anomer) and the equatorial (β anomer) orientations are logged. Furthermore, the two diastereoisomers 5R and 5S for each anomer were synthesized.

Scheme 7

Stereochemical elements determining the regioselectivity of hydrogen abstraction and structures used to detect the influence of each of them.

The glucosyl derivatives 43, 44, 45 and 46 have been subjected to the same reaction conditions (Scheme 8). The αR diatstereoisomer 45 as well as the βR diastereoisomer 43 react via hydrogen abstraction at the anomeric center leading to the spirocyclic compounds 47a, b. The diastereomeric ratio is comparable for both transformations. In the case of the β anomer 43, the yield is higher. In this case, the hydrogen is orientated in the axial position. Hydrogen abstraction from such a position is generally more efficient than that from an equatiorial orientated hydrogen atom in a corresponding α anomer [100]. The αS diatstereoisomer 46 selectively reacts via hydrogen abstraction in the 5′ position of the glucosyl moiety leading to the macrocyclic compound 48 in relatively high yield. In the case of the reaction of the corresponding βS diastereoisomer 44, again spicrocyclic compounds 49a, b are formed via hydrogen abstraction at the anomeric center. However, considerable amounts of the macrocyclic compound 48 are also isolated. Since this compound possesses α configuration at the anomeric center, an epimerization must also take place during the reaction.

Scheme 8

Stereoselective triplet sensitized transformation of glucosyl derivatives of an α,β-unsaturated lactone.

A more detailed investigation confirmed the formation and the transformation of different radical intermediates which can best be illustrated for the reaction of isomer 44 (Scheme 9). After photochemical excitation by triplet sensitization, hydrogen abstraction occurs at the anomeric center and the diradical intermediate 50 is generated. This intermediate is in equilibrium with the corresponding α conformer 51. Radical combination yields the spirocyclic compounds 49a, b. In the axial conformer 51, hydrogen can be transformed back from the furanone moiety to the glucosyl part. Thus, the αS diastereoisomer 46 is generated. It has been detected in considerable amounts in the reaction mixture after a 50 % transformation of the isomer 44. Upon electronic excitation, this isomer selectively yields the macrocyclic compound 48via hydrogen abstraction in position 5′ and formation of the diradical intermediate 53.

Scheme 9

Radical steps in the stereoselective triplet sensitized reaction of the α,β-unsaturated lactone derivative 44.

DFT calculations have been performed in order to get a deeper insight into the regioselectivity of the hydrogen abstraction. The influence of an alkyl substituent at the side chain is well understood. The ³ππ* excited and vibrationally relaxed state of the furanone moieties has been modeled with structures 54 and 55 (Scheme 10) [78]. Transition states for the hydrogen abstraction at the anomeric center (2′ position) leading to structure 56 and at the 6′ position leading to structure 57 have been calculated. Selected results are summarized in Table 3. The difference of the free enthalpy of activation (ΔΔG^≠) for hydrogen abstraction in position 2′ and 6′ in model structures 54 and at 55 is reported. In the case of the lk isomer 54, hydrogen abstraction is favored in the 2′ position and it takes place in the β anomer. In the case of the ul isomer 55, hydrogen abstraction is favored in the 6′ position and it takes place in the α anomer. Thus the experimental results (Scheme 6) are confirmed by the computational study. Similar calculations also verified the results depicted in Schemes 5 and 8 concerning the hydrogen abstraction step.

Scheme 10

Model structures for computational study of regioselective hydrogen abstraction in the triplet sensitized reaction of α,β-unsaturated lactone derivatives.

Similar reactions with α,β-unsaturated carbonyl compounds involving hydrogen abstraction and radical combination have been previously reported, often without considering them in a broader context of organic synthesis [79, 80, 101–113]. Acetone is frequently used as a sensitizer in photochemical reactions of α,β-unsaturated lactones. Triplet energy transfer is then often favored. On the other hand, in the ³nπ* state this ketone may undergo hydrogen abstraction as in the case of the reaction depicted in Scheme 1. Furthermore, substrates such a furanones possess hydrogen atoms, for example in allyl positions, which may easily be abstracted. The fact that reactions as they are shown in Schemes 5, 6 and 8 and as they have previously been reported are efficient, indicates that the triplet energy transfer from ³nπ* excited acetone to these compounds is generally favored over hydrogen abstraction. Only when an efficient hydrogen donor such as isopropanol is present in large amounts in the reaction mixture compared to the olefinic reaction partner, hydrogen abstraction becomes dominant. The competition between these two reaction modes may also be discussed in the transformation of the furanone derivative 58 (Scheme 11) [114]. When the photochemical transformation is carried out with acetone as sensitizer, the furanone moiety is electronically excited and hydrogen is transferred from the aldehyde function into the β position of the furanone moiety leading to the diradical intermediate 59. Radical combination leads to the final spirocyclic products 60a, b. This mechanism is also detailed in Schemes 5 and 9. When photochemical sensitization is carried out with benzophenone as sensitizer, the photochemically excited aromatic ketone abstracts hydrogen form the aldehyde moiety in 58, leading to the radical intermediate 61. Intramolecular 1,4-radical addition induces the formation of the bicyclic product 62. A similar reaction as the latter one has been reported with dioxinone derivatives [115]. Obviously, the triplet energy of benzophenone is not high enough for the excitation of the furanone 58. The triplet energy of acetone is 332 kJ/mol [116] and that one of benzophenone is 287 kJ/mol [117]. Due to a different reactivity of 58 in the presence of these two ketones, the triplet energy of compounds such as 58 should therefore be in between these two values.

Scheme 11

Regioselective hydrogen abstraction in triplet sensitized reaction of α,β-unsaturated lactone derivatives depending on the triplet energy of the sensitizer.

Conclusions

Furanones are interesting substrates for organic synthesis [118, 119]. Photochemical addition of radicals is carried out in a very convenient way and thus increases the interest in such compounds. Using photochemical sensitization with ketones, various radical species are generated by hydrogen abstraction. These radicals are added to the electron deficient bond of the furanone. In the case of tertiary amines as hydrogen donors, photochemical electron transfer is involved. The addition of secondary alcohols occurs by hydrogen abstraction. In these intramolecular reactions, the addition always occurs in the β position of the α,β-unsaturated carbonyl compound. The radical addition of secondary alcohols is particularly efficient. Therefore, it has been used to evaluate the efficiency of different continuous flow micro-photoreactors. The microchip model showed the best overall performance, however, its low productivity limits it to early lead finding applications. Bundling of microcapillaries enabled the construction of an efficient continuous flow module for parallel synthesis. This reactor was successfully utilized for process optimization, scale-up and library synthesis. Furanones and other α,β-unsaturated ketones also undergo intramolecular radical reactions when they are photochemically excited. In this case, direct hydrogen transfer from the donor molecule to the olefinic substrate plays an important role. Hydrogen may be transferred either in a one-step or in a two-step procedure. The mechanism of the hydrogen transfer has a significant influence on the regioselectivity of the radical addition.