Current Organic Synthesis, 2005, 2, 281-299 281 Oxyfunctionalization of Alkenes by Dye-Sensitized Intrazeolite Photooxygenation

Manolis Stratakis*

Department of Chemistry, University of Crete, 71409 Iraklion, Greece Abstract: This review focuses on the recent achievements towards the selective formation of allylic 1 hydroperoxides by the reaction of singlet molecular oxygen ( O2) with alkenes adsorbed in the cavities of zeolite Na-Y. The product distribution by zeolite confinement is often dramatically different compared to the photooxygenation reaction in a homogeneous medium. Cation – π interactions and cation – singlet oxygen interactions, in the rate-limiting transition states, are most likely responsible for the changes in product selectivity within Na-Y. Keywords: Singlet oxygen, allylic hydroperoxides, regioselectivity, diastereoselectivity, zeolite Na-Y, cation – π interactions.

STRUCTURAL FEATURES OF FAUJASITES The faujasite framework consists of two main cages, the supercage, and the sodalites (Fig. 1). The supercage results Zeolites are crystalline aluminosilicates whose primary from the assembly of the smaller sodalite cages. The access 4- 5- structure is formed by SiO4 and AlO4 tetrahedra sharing to the supercages occurs by four 12-membered ring the edges [1]. Their tertiary structure forms strictly uniform “windows”, of approximately 7-8 Å in diameter. channels and cavities of molecular dimensions that are repeated along the zeolite lattice. Due to the lower valence of The “windows” are tetrahedrally distributed around the centre of the supercages, which are approximately 13 Å in the aluminum relative to silicon, the excess negative charge diameter. The charge-compensating cations in faujasites (one per Al atom) is balanced by alkali metal cations, occupy three different positions as shown in Fig. 1, namely mainly Na+. The cations are placed in the interior of cavities and can be easily exchanged. The cation-exchange process Type I-III [3]. Only cations at sites II and III can interact to leads to new type of materials having interesting properties the hosted organic compounds. Depending on the size of the [2], and it is expected in the near future that the metal- cation, the supercages in the alkali metal exchanged Y supported zeolites will find significant applications in zeolites (M-Y) have enough net volume to host relatively applied chemistry. large organic molecules. For example, Na-Y can adsorb molecules even of the size of a steroid. On the other hand, An important class of the zeolite family are the for type X faujasites, the free volume of the supercages is faujasites, known as zeolites X and Y, which have the more limited due to the extra compensating cations, and typical composition for the unit cell as follows: finds less applications in organic chemistry.

Type Na-X Na86(AlO2)86(SiO2)106 · x H2O The performance of organic reactions in organized media, Type Na-Y Na (AlO ) (SiO ) · x H O e.g. by zeolite confinement [4-6], and the use of zeolites as 56 2 56 2 136 2 selective and “green” catalysts [7] for organic transformations has been popularized in recent years. The main advantage of the zeolites to be tested as media or catalysts for carrying out organic reactions, is the so called “shape selectivity” [8]. The shape selectivity can be categorized into 3 types: (i) Reactant selectivity; from a mixture of reactants only the molecules with the appropriate shape can be adsorbed into the cavities. (ii) Product selectivity; only those products, produced from the intrazeolite reaction, having the appropriate shape can diffuse out of the pores, and (iii) Transition state shape selectivity; due to the zeolite confinement, the relative stability of transition states for the possible reaction pathways can be significantly altered. Fig. (1). Structure of the faujasite supercage assembled by the sodalite cages (the arrows indicate the positions of the cations). PHOTOOXYGENATION REACTIONS IN ORGANIZED MEDIA *Address correspondence to these authors at the Department of Chemistry, University of Crete, 71409 Iraklion, Greece; E-mail: The partial exchange of the Na+ cations within the zeolite [email protected] Na-Y supercages by dye molecules that have the structure of

1570-1794/05 $50.00+.00 © 2005 Bentham Science Publishers Ltd. 282 Current Organic Synthesis, 2005, Vol. 2, No. 2 Manolis Stratakis organic cations (e.g. methylene blue, thionin, etc.) [9] For the achievement of mass balances in intrazeolite triggered the interest to examine the dye-sensitized photooxygenation reaction >80%, loading levels of 0.1-0.3 photooxygenation of organic compounds within the confined adsorbed molecules per zeolite supercage have been environment of the faujasite Y cavities. The reaction of successfully used in the past. However, the recent singlet oxygen with organic compounds has attracted a observation by Clennan and Pace [19], that replacing the significant attention in the scientific community, not only solvent hexane with perfluorohexane was very crucial for the because of their biological role [10], but also due to their efficiency of the reaction, allowed the zeolite medium to be mechanistic interest and the valuable synthetic applications used for preparative scale photooxygenation reactions (500 as well [11]. The study of singlet oxygen reactions with mgr of alkene), without loss of the product selectivity or the alkenes using alternative supramolecular systems as reduction of the mass balance. The fluorophobicity of microreactors [12], such as pentasil zeolites [13], nafion alkenes in perfluorohexane allows the facile migration of the membranes [14] and surfactant vesicles [15], has also reactant molecules into the zeolite cavities. In hexane, on the attracted a considerable attention recently, but will not be other hand, the affinity of a simple alkene such as 2-methyl- presented in the present review article. 2-heptene for entering into the interior of Na-Y decreases by For the success of the dye-sensitized singlet oxygen ~50% relative to the fluorinated solvent. In the same study, 1O lifetime reactions within zeolite Na-Y, the loading level of the dye the authors extrapolated the upper limit for the 2 within Na-Y to be 7.5 µs. Based on this value, it was and the water content [16] in the interior of zeolite are estimated that singlet oxygen can migrate through 5,000 crucial. At increased loading levels, the dye tend to dimerize 3 1 supercages, before it deactivates to O2 or react with the and do not emit [17], thus, inefficiently producing O2 upon excitation by energy transfer to the triplet molecular oxygen. adsorbed substrate. At an approximate loading level of 1 thionin cation per 100 zeolite supercages, irradiation under a constant flow of COMPLEXITIES OF THE INTRAZEOLITE oxygen gas produces singlet oxygen efficiently, leading to PHOTOOXYGENATION REACTIONS rapid oxidation of tri- and tetrasubstituted alkenes to form ene allylic hydroperoxides [18] as shown for the It is well-known that faujasites (Na-Y or Na-X) contain photooxygenation of tetramethylethylene (1) in Scheme 1. small concentration of both Brönsted [20] and Lewis acid sites [21]. The acidic sites may cause significant problems, H C CH 3 3 Thionin/Na-Y H2C CH3 such as the decomposition or rearrangement of product and OOH reactants, giving often poor reaction mass balances. Acid- H CCH hv/O 3 3 2 H3CCH3 sensitive alkenes, such as terpenes, upon adsorption within 1 Na-Y undergo isomerization and skeletal rearrangements. Scheme 1. Ene hydroperoxidation of tetramethylethylene within Ramamurthy and co-workers have reported such problems in thionin-supported Na-Y. the intrazeolite photooxygenation of limonene [16]. In addition, tertiary allylic hydroperoxides, formed in the

23

Na - Y

45

9

67 8

monoterpene

Scheme 2. Transformation of monoterpenes to p-cymene within Na-Y under thermal conditions. Oxyfunctionalization of Alkenes by Dye-Sensitized Intrazeolite Photooxygenation Current Organic Synthesis, 2005, Vol. 2, No. 2 283 photooxygenation of trisubstituted alkenes do not persist benzene binding enthalpy is roughly equivalent to the + within the Na-Y cages [18]. The unwanted side-reactions and binding enthalpy between Na and H2O. The adsorption of complexities, attributable to acid catalysis can be minimized alkenes or arenes into the interior of the zeolites is mainly or completely suppressed by treatment of the zeolite with driven by their quadrupolar interaction with the alkali metal bases such as pyridine or triethylamine for a few minutes cations present in the cages. Haw and co-workers [26] have prior to the photooxygenation reaction. presented experimental evidence for the Li+ - benzene interaction within zeolite LiZSM-5 using solid state NMR. We studied [22] the fate of several monoterpenes within Cations not only play a significant role in the adsorption thionin-supported Na-Y under thermal conditions, and found efficiency of the porous materials, but they have also that the intrazeolite transformations of the adsorbed proposed [27] to play a major role in intrazeolite reactions molecules are most probably consonant with an electron by affecting the relative energies of the possible transition transfer pathway subordinated to the presence of the acidic states through substrate binding [28]. To have a deep sites. For example, upon loading of several monoterpenes knowledge of the factors affecting the product distribution in within thionin-supported Na-Y (monocyclic, bicyclic or intrazeolite photooxygenation reactions, it was necessary to acyclic), in the absence of oxygen or visible light irradiation, perform theoretical calculations on the interaction of alkali immediate isomerization takes place with main formation of metal cations with olefins. We [29] and others [30] α-terpinene (2), isoterpinolene (5) and p-cymene (9). The performed a systematic study on the interaction of Na+ and aromatic component p-cymene, was postulated to arise from Li+ with several alkenes in the gas phase using the DFT and the dehydrogenation of the monoterpenes, initiated by the MP2 method or Ab initio calculations. formation of their radical cations [23] (Scheme 2). In addition, the initially formed isomeric terpenes such as 2 or Two predominant binding trends were mainly 5, finally transform to 9 after prolonged intrazeolite recognized. The first was that for the majority of the alkenes, treatment (1-2 hours). The formation of radical ion pairs the cations do not bind on top of the π system, but close to under thermal conditions within Na-Y is more likely it. Thus, for trisubstituted alkenes, the binding site resides associated with the presence of acidic sites [24]. Pyridine or either towards the more or the less substituted side of the triethylamine most probably react with the acidic sites, and olefin. A typical example is trimethylethylene, whose therefore destroy the “electron holes” that initiate the electron interaction with Li+ was calculated to give the two almost transfer-induced pathway. isoenergetic minima presented in Fig. 2. This unexpected type of interaction was found even with highly symmetric CATION - π INTERACTIONS WITHIN Na-Y alkenes such as tetramethylethylene. The second trend was that there is a relatively strong interaction for both cations Alkali metal cations have been known to bind strongly (Li+ or Na+) to the alkyl chains of the double bond, at the to the π face of aromatics [25]. For example, the Na+ - homoallylic position. A typical example is cis-3-hexene

Fig. (2). Local minima structures of Li+ binding to trimethylethylene at the B3LYP/6-31G* level of theory.

Fig. (3). Local minima structures of Li+ binding to cis-3-hexene at the B3LYP/6-31G* level of theory. 284 Current Organic Synthesis, 2005, Vol. 2, No. 2 Manolis Stratakis

(Fig. 3), in which the structure where the Li+ interacts with The mechanism of this reaction has been extensively studied both alkyl chains is more stable compared to the structure in the past [35], and found to proceed via formation of an where it sits at the antiperiplanar position by 3.0 kcal/mol. intermediate perepoxide. The energy profile of the reaction The two binding trends of the alkali metal cations to alkenes depends on the degree of the alkyl substitution. Recent were rationalized taking into account the polarization of the theoretical and experimental work by Singleton and co- double bond by the cation, polarization of the alkyl chains workers [36], however, proposed a two step no-intermediate and steric effects as well. Recently, Gal and coworkers [31] mechanism, with a rate-limiting transition state resembling reported a similar alkyl chain - Li+ attraction in that for the formation of a perepoxide in the initially alkylbenzenes, namely the “scorpion effect”. proposed stepwise process. Photooxygenation of the isomeric cis, trans and gem- MECHANISM OF THE ENE tetramethylethylenes-d6 (1-d6) is an ideal tool (Stephenson’s HYDROPEROXIDATION IN THE DYE-SENSITIZED isotope effect test) [37] to study the mechanism of ene-type INTRAZEOLITE PHOTOOXYGENATION OF reactions. For cis-1-d6 Clennan and Sram [38] had reported a ALKENES negligible isotope effect of kH/kD = 1.04 for the intrazeolite 1 reaction with O2 within methylene blue-supported Na-Y. Ene type allylic hydroperoxides can be formed in We performed the thionin-sensitized intrazeolite photooxygenation reactions by two alternative pathways, photooxygenation of trans-1-d6 and gem-1-d6, and found namely the Type I and Type II processes [32]. Type I [39] for the trans-1-d6 a kH/kD = 1.52 ± 0.05, whereas for involves formation of a radical ion pair between the alkene the gem-1-d6 it was kH/kD = 1.62 ± 0.05 (Scheme 4). The and molecular oxygen, while in Type II photooxygenation measured intrazeolite isotope effects were very similar to 1 process, singlet oxygen ( O2) is the reacting species. Type I those reported for the photooxygenation in solution [37], intrazeolite photooxygenation of alkenes has been reported and therefore, consonant with a Type II photooxygenation by Frei [33] and others [34] to give mainly allylic process for tetrasubstituted alkenes, in which singlet oxygen hydroperoxides (Scheme 3). In this process, the charge forms irreversibly a perepoxide or a perepoxide-type transfer band of the alkene - O2 complex within Na-Y was intermediate in the rate-limiting step of the reaction. A irradiated to form the alkene radical cation and superoxide scenario, involving radical ion pairs as precursors of the ene ion. The radical ion pair in turn gives the allylic allylic hydroperoxides is unlikely to occur upon visible light hydroperoxides via an allylic radical intermediate. On the irradiation within the thionin-supported Na-Y. other hand, for the Type II pathway, singlet molecular In addition, to elucidate the energy reaction profile in the 1 oxygen ( O2) is produced by energy transfer from the triplet intrazeolite photooxygenation of trisubstituted alkenes, the 3 excited state of a photosensitizer to O2 [32]. Singlet oxygen competing photooxygenation of 1-phenyl-3-methyl-2-butene is a highly reactive enophile that reacts with alkenes and its deuterated at the geminal methyl analog (Scheme 5) possessing allylic hydrogens to form allylic hydroperoxides.

Type I

3 H2C CH3 H3C CH3 hv/ O2 O2 H CCH H3CCH3 Na-Y 3 3

H2 C CH3 H2C CH3 OOH + HOO H3 CCH3 H3CCH3

Type II

3 hv O2 3 1 sensitizer sensitizer* O2

CH3 O H3C CH3 1O H2C CH3 2 CH3 O OOH H3CCH3 H3CCH3 H3 C CH3

Scheme 3. Type I and Type II intrazeolite photooxygenation processes. Oxyfunctionalization of Alkenes by Dye-Sensitized Intrazeolite Photooxygenation Current Organic Synthesis, 2005, Vol. 2, No. 2 285

H3C CD3 hv/O2 H2C CD3 H3C CD2 OOH + DOO k /k = 1.62 thionin/Na-Y H D H3CCD3 H3CCD3 H3CCD3

gem-1-d6 kH kD

H C CH H3C CH3 hv/O2 H2C CH3 3 3 OOH + DOO kH/kD = 1.04 D3CCD3 thionin/Na-Y D3CCD3 D3CCD2

cis-1-d6 kH kD

D C CH D3C CH3 hv/O2 D2C CH3 3 2 HOO OOD + kH/kD = 1.52 H3CCD3 thionin/Na-Y H3CCD3 H3CCD3

trans-1-d6 kH kD Scheme 4. Intrazeolite photooxygenation of the isomeric tetramethylethylenes-d6. was studied [39]. A negligible intermolecular isotope effect almost independent ratio of secondary to tertiary allylic of kH/kD = 1.03 ± 0.02 indicated that also for trisubstituted hydroperoxides ~ 1/1 [40]. In addition, for the case of 1- alkenes, formation of a perepoxide-type transition state is the methyl-1-cycloalkenes [41], such as 14 and 15, the more rate-limiting step. substituted side of the alkene is the more reactive (“cis effect” selectivity). Ramamurthy and Li reported [42] that in H3C CH3 D3CCD3 hv/O contrast to the reaction in solution, the thionin-sensitized versus 2 kH/kD = 1.03 intrazeolite photooxygenation of trisubstituted alkenes is thionin/Na-Y highly regioselective, giving the secondary allylic Ph Ph hydroperoxide as the major or only product (Table 1). k kH D Furthermore, 1-methyl-1-cycloalkenes give mainly ene Scheme 5. Intermolecular kinetic isotope effect in the product with hydrogen atom abstraction from the methyl intrazeolite photooxygenation of 1-phenyl-3-methyl-2-butene. group. The regioselectivity was significantly affected by the size REGIOSELECTIVITY IN THE INTRAZEOLITE of the cation present in the supercage (Table 2) [43]. For PHOTOOXYGENATION OF TRISUBSTITUTED example, in the photooxygenation of 13 within Li-Y, the ALKENES secondary hydroperoxide was formed in 100% relative yield, while in Cs-Y, the ratio secondary to tertiary hydroperoxide For geminal dimethyl trisubstituted alkenes, such as 10 was 66/34, very close to what is found in solution. It was or 13, photooxygenation in solution gives a nearly solvent

Table 1. Intrazeolite Photooxygenation of Trisubstituted Alkenes (the Values in Parentheses Indicate the Relative Reactivity of the Ene Reaction in Solution)

CH3 CH3 100 (50) 72 (50) H3 C CH3 CH3 0 (50) 28 (50) 10 11

CH3 CH3 100 (46) 85 (40) CH3 Ph CH3 0 (54) 15 (60)

12 13

10 (45) CH 88 (40) 0 (45) 3 CH3 100 (6)

2 (15) 0 (48) 14 15 286 Current Organic Synthesis, 2005, Vol. 2, No. 2 Manolis Stratakis

Table 2. Cation-Dependent Regiochemical Control in the Intrazeolite Photooxygenation of 1- Phenyl-3-methyl-2-butene CH CH HOO 3 3 hv/O2 CH3 OOH + Ph CH3 Ph CH3 thionin/M-Y Ph CH2 13 13a 13b

M 13a (%) 13b (%)

Li 100 0 Na 85 15 Rb 80 20 Cs 66 34 postulated that the cation-dependent change in the the more substituted carbon atom bears a partial positive 1 regioselectivity is proportional to the magnitude of the charge (Model B). Thus, the electrophilic O2 attacks the cation – π interactions. Li+ being the smallest alkali metal more nucleophilic monosubstituted olefinic carbon atom, cation is expected to bind the substrate very strong and affect and allylic hydrogen abstraction occurs from the alkyl the relative energy of the transition states leading to the substituents at the geminal disubstituted site. For alkene 13 secondary or tertiary allylic hydroperoxides. For the case of (Table 1) in which R = Ph, we proposed [45] a simultaneous the largest Cs+, cation – π interactions are less important, interaction of the cation with the phenyl group and the and product distribution is zeolite-unaffected. alkene double bond, that results in a conformation in which To shed light to the factors affecting the product none of the allylic hydrogen atoms at the benzylic position distribution of the ene reaction, it was necessary to measure are perpendicular to the olefinic plane to become reactive for 1O (Model C). Later, however, Ramamurthy the regioselectivity for the hydrogen atom abstraction from abstraction by 2 and co-workers performed theoretical calculations and each of two geminal methyl groups (twin or twix) [44] in suggested [48] that for the phenyl-substituted alkenes at the trisubstituted alkenes such as 10-13. This was accomplished lone position, simultaneous interaction of the cation to the by stereoselective deuterium labelling of the twin methyl phenyl group and to alkene double bond as well is unlikely group. Independent studies by us [43] and Clennan’s group to occur. According to the regioselectivity results from the [45] revealed that the so-called “cis effect” [46] selectivity photooxygenation of some tetrasubstituted alkenes, Clennan found in solution, no longer operates within the zeolite. As and Sram [38] proposed the mechanistic Model D. They seen in Table 3, for the case of 16-19, the twin methyl group argued that the alkali-metal cation forms a complex with the reactivity increases up to 14 times (see substrate 18) by pendant oxygen in the intermediate perepoxide, which leads zeolite confinement. to a greater positive charge on the carbon framework, while Several models were invoked to explain the low steric interactions between the cation and the alkyl intrazeolite reactivity of the allylic hydrogen atoms at the substituents affect the stability of thetransition states that lone position, and the increased reactivity of the twin methyl lead to the intermediate. In the perepoxide intermediate of group as well (Scheme 6). Originally, Ramamurthy and co- Model D, the C-O bonds are highly unsymmetrical due to workers proposed [42,43] that steric effects inside the cavity polarization effects and therefore, accounts for the place the bulkier alkyl group (R) at the lone position away Markovnikov-type selectivity. Finally, based on theoretical from the cation; therefore, the methylene hydrogen atoms calculations of the interaction of the Li+ and Na+ to 2- cannot react with the electrophile (Model A). Later, it was methyl-2-hexene at the B3LYP/6-31G* level of theory [29], postulated [18] that polarization of the alkene by interaction we postulated that cation – π interactions place the alkyl of the double bond with the cation occurs in such a way that group R towards the cation (scorpion effect [31], Model E).

Table 3. Regioselectivity in the Intrazeolite Photooxygenation of Deuterium Labeled Trisubstituted Alkenes (the Values in Parentheses Indicate the Relative Reactivity in Solution)

CD3 42 (14) CD3 33 (8) H3C CH3 58 (36) H3C CH3 61 (48) 6 (44) 0 (50) 16 17

CD3 37 (8) CD3 57 (4)

CH3 41 (38) Ph CH3 33 (36) 10 (60) 22 (54)

18 19 Oxyfunctionalization of Alkenes by Dye-Sensitized Intrazeolite Photooxygenation Current Organic Synthesis, 2005, Vol. 2, No. 2 287

Model A Model B Model C innapropriate 1 1 O2 1 conformation for O2 O2 abstraction

R R H H H H H H Na Ph H3 C Na H C H3C CH 3 CH 3 CH3 3 Na

Model D Model E innapropriate 1O conformation for δ+ O δ 2 O - abst racti on

R H H H C Na 3 Na R CH3 H3C CH3 Scheme 6. Proposed models for the intrazeolite photooxygenation of trisubstituted alkenes.

Thus, the allylic methylene hydrogens have inappropriate dramatic increase in the reactivity of the sulfide functionality conformations for abstraction since they cannot adopt relative to an alkene double in substrates containing both the perpendicular orientations with respect to plane of the double sulfide and olefinic linkages [51]. An electrostatic interaction bond. In fact, Model E resembles Model C, which is between Na+ and the negatively charged oxygen of the applicable to phenyl-substituted alkenes such as 13. persulfoxide intermediate [52] was invoked by Clennan and Generally, all models are working hypotheses, and further co-workers (Scheme 8). experimental results are necessary to tune the role of the zeolite medium in the regioselectivity of the ene reaction. O 1O O + S 2 Na To explain the enhanced reactivity of the allylic hydrogen R R' S atoms at the less substituted side of the trisubstituted Na-Y R R' alkenes (twin position), it was proposed [45,46] that the Na+ - persulfoxide interaction electrostatic interaction of the pendant negatively charged oxygen atom in the intermediate perepoxide with an alkali metal cation within the cages of Na-Y stabilizes the S O R R' transition state in which the oxygen is directed towards the 2 S less substituted side of the alkene (Scheme 7). In the absence R R' of the cation-stabilizing interaction, the intermediate in Scheme 8. Cation-stabilizing persulfoxide intermediate within which oxygen can interact only with one allylic hydrogen Na-Y. atom (twin-oriented perepoxide) is not favorable due to entropic reasons, as has been suggested by Schuster and co- workers (cis-effect selectivity) [49]. INTRAZEOLITE ASYMMETRIC PHOOTOXYGE- δ- NATION OF ALKENES δ+ O O D2CCH3 The confined spaces of Na-Y may induce enantioselective D reactions if appropriately modified with chiral inductors

H3C [53]. By suitably mixing chiral compounds such as (-)- R OOD ephedrine, (-)-pseudoephedrine or (-)-norephedrine, a “chiral R H Na zeolite” can be produced. Ramamurthy and co-workers have twin selectivity successfully used this approach to perform a variety of Scheme 7. Cation-directing twin regioselectivity in the enantioselective photochemical reactions with Na-Y, intrazeolite photooxygenation of trisubstituted alkenes. obtaining remarkable enantioselectivities in certain cases [54]. The attempts to achieve an enantioselective Despite the complexity of the proposed heuristic models, photooxygenation within a chirally-modified zeolite Na-Y it is widely accepted that cation – oxygen interaction is are very limited. Only the photooxygenation of 1-phenyl-3- significant for the intrazeolite singlet oxygen ene reactions methyl-2-butene (13) was studied within thionin-supported with olefins. It has been proposed that cations play a major zeolite Na-Y modified by (+)-ψ-ephedrine, to give [55] role in the rate acceleration and product distribution for the approximately 15% e.e. for the formation of the major intrazeolite photooxygenation of sulfides [50], or the secondary allylic hydroperoxides (Scheme 9). 288 Current Organic Synthesis, 2005, Vol. 2, No. 2 Manolis Stratakis

HOO CH3 CH3 CH3 OOH hv/O2 + Ph CH3 Ph CH2 Ph CH3 thionin/Na-Y (+ )-ψ-e phedrine 13 15% e.e

Scheme 9. Asymmetric photooxygenation of an alkene in a chirally-modified zeolite Na-Y.

It might be tempting to examine the photooxygenation 10, with [A] > [B]). The Na+ - bound alkenes are expected of alkenes bearing polar substituents in such chirally- to be highly unreactive due to the electron depletion from modified media. The expected stronger interactions between the double bond. Assuming that the dynamic equilibrium the polar substituents of the substrates and the chiral between the Na+ complexed or uncomplexed species is fast, inductors in the confined environment of Na-Y, might lead and applying the Curtin-Hammett principle, the reaction is to increased enantioselectivity for the formation of the chiral expected to occur mainly via the uncomplexed alkene, allylic hydroperoxides. therefore, similar regioselectivity results are expected to those found in solution [57]. On the other hand, if the carbonyl functionality is shifted from the α- to the γ- INTRAZEOLITE PHOTOOXYGENATION OF position with respect to the double bond (substrate 23), the ELECTRON-POOR ALKENES alkenes give the expected regiochemical outcome (predominant formation of the secondary allylic Clennan and co-workers [56] reported that the intrazeolite hydroperoxides), as found in the intrazeolite environment is unable to influence the regiochemistry in the α β photooxygenation of non-functionalized trisubstituted photooxygenation of electron-poor alkenes such as , - alkenes [39]. unsaturated carbonyl compounds, relative to the photooxygenation in solution. The regioselectivity results are presented in Table 4. To explain the lack of changes in REMOTE SUBSTITUENT EFFECTS IN THE the regioselectivity on going to the zeolite environment, it REGIOSELECTIVITY OF TRISUBSTITUTED was suggested that only the alkenes, which were not ALKENES complexed to the cation, are reactive, although they are the minor component in a dynamic equilibrium involving Due to the confined environment and cation – π uncomplexed and complexed substrates (A and B in Scheme interactions within the zeolite cavities as well, it is expected

Table 4. Regiochemistry in the Intrazeolite Photooxygenation of Electron-Poor Alkenes (the Values in Parentheses Indicate the Relative Reactivity in Solution)

MeO 6 (3) MeO MeO H C O O H3 C O 3 29(15) H CCH H3CCH3 CH3 3 3 6 (2) 94 (98) 94 (97) 71 (85) 20 21 22

15 (47) H3C 85 (53) O H3C H3 C 23

Complex A Complex B Uncomplexed substrate Na + Na + MeO MeO R COOM e R1 O 1 R1 O R CH R2 CH3 2 3 R2 CH3

1 1 1O O2 O2 2

High population Low population Low population (less reactive) (le ss reactive) (more reactive) Scheme 10. Multicomplexation model for the intrazeolite photooxygenation of electron-poor alkenes. Oxyfunctionalization of Alkenes by Dye-Sensitized Intrazeolite Photooxygenation Current Organic Synthesis, 2005, Vol. 2, No. 2 289 that the regioselectivity in the photooxygenation of It was proposed [39] that the changes in the ene reactivity trisubstituted alkenes might be influenced by remote at the lone position for the phenyl-substituted alkenes are substituents relative to the reaction center (alkene double controlled by cation - π interactions and conformational bond) specially if they can strongly bind to the cation. We effects within the Na-Y supercages. Depending on the performed [39] the intrazeolite photooxygenations in a series remoteness of the phenyl ring from the reaction centre, of deuterium-labeled gem-dimethyl trisubstituted alkenes, by simultaneous coordination of the Na+ with the phenyl ring varying the position of a phenyl or a cyclohexyl substituent and the alkene double bond, probably places the allylic at the end of the alkyl chain at the lone position. We chose methylene hydrogen atoms in a favorable (perpendicular to the phenyl and cyclohexyl groups as substituents because the double bond) or unfavorable position for ene reaction they have similar steric demands, but different electronic (Scheme 11). For the cyclohexyl-substituted alkenes, character. The phenyl group can strongly coordinate to the however, coordination of the Na+ to the alkene double bond Na+ cations within the Na-Y supercages. The regioselectivity affords similar conformations for the allylic methylene results are presented in Table 5. For the phenyl-substituted hydrogen atoms and, therefore, they are approximately alkenes 18 and 24-26, there is a significant variation of the equally reactive. This is also corroborated by the fact that the reactivity at the allylic positions (twin, twix or lone) by twix/twin reactivity ratio is the same for all cyclohexyl- changing the length of the phenyl-substituted alkyl chain. substituted alkenes, while for the phenyl-substituted For example, the reactivity at the lone position is 10% for compounds it changes remarkably. 18, slightly drops to 7% for 24, then increases significantly appropriate or innapropriate 1 to 44% in 25 and finally drops to 22% in 26. Similarly, O2 conformation for allylic hydrogen significant variations were found for the ratio of twin/twix atom abstraction allylic hydroperoxides. While for 18 twin/twix = 63/37, by H increasing the length of the alkyl chain the ratio drops to H 30/70 in 24, to 32/68 in 25, and finally for alkene 26 it is 50/50. Contrary, for the cyclohexyl-substituted alkenes 19 n Ph and 27-28, the intrazeolite variation of the lone/twin/twix H3C reactivity ratio is quite similar (approximately 22/37/41). On CH3 Na the other hand, the regioselectivity results for the photooxygenation of all alkenes (phenyl or cyclohexyl- Scheme 11. Possible interaction of Na+ to phenyl-substituted substituted) in solution, is quite similar (lone/twin/twix ~ alkenes within Na-Y. 50/5/45). The novel feature of the intrazeolite regioselectivities for the phenyl-substituted alkenes is that INTRAZEOLITE PHOTOOXYGENATION OF the lone and the twin/twix reactivity ratios depend ISOBUTENYLARENES AND STILBENES significantly on the position of phenyl group. This effect is absent for the case of the cyclohexyl-substituted alkenes. Photooxygenation of 1-aryl-2-methylpropenes in solution proceeds slowly, and affords a complex mixture of products

Table 5. Substituent Effects in the Intrazeolite Photooxygenation of Trisubstituted Alkenes (the Values in Parentheses Indicate the Relative Reactivity in Solution)

CD3 57 (4) CD3 37 (8)

Ph CH3 33 (36) CH3 41 (38) 10 (60) 22 (54) 18 19

CD3 28 (5) Ph CD3 35 (5) CH3 65 (49) 7 (46) CH3 40 (46) 25 (49) 24 27

CD3 18 (5) CD3 37 (7) Ph CH CH3 38 (47) 3 42 (42) 44 (48) 21 (51) 25 28

CD3 39 (4)

Ph CH3 39 (51) 22 (45)

26 290 Current Organic Synthesis, 2005, Vol. 2, No. 2 Manolis Stratakis

O O CH 3 1 O HOO CH2 H 2 O CH3 + CH O Ph CH solvent O 3 + + 3 Ph CH3 Ph CH3 CH 29 OO OO 3

major

CH3 CH2 H3C CH3 HOO CH CH CHO 3 O 3 1 O2 O + + solvent

30 major

Scheme 12. Photooxygenation of isobutenylarenes in solution. arising mainly from [4+2] or [2+2] addition to the double Similarly, for 1-(2-methylpropenyl)naphthalene (30), apart bond [58]. The ene pathway is less favorable or even absent. from the minor ene product, an 1,4-endoperoxide is mainly For example, β,β-dimethylstyrene (29) affords the ene adduct formed [59]. in approximately 20% yield, benzaldehyde (from a [2+2] The intrazeolite photooxygenation in a series of pathway), and mainly two diastereomeric di-endoperoxides isobutenylarenes [60], bearing either electron-withdrawing or (from a [4+2] pathway) in a ratio 2/1 (Scheme 12). electron-deficient substituents on the aryl ring affords rapidly

Table 6. Photooxygenation of Isobutenylarenes within the Thionin-Supported Zeolite Na-Y

CH 1 HOO CH 3 O2 2

Ar CH3 Na-Y Ar CH3 >85% relative yield

CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3

29 30 31 H3 C 32

CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3

CH3 H C 3 F C MeO 353 36 33 CH3 34

CH 3 CH3 CH3 CH 3 CH3 CH3

CF 3 F CF 3 37 38 39 Oxyfunctionalization of Alkenes by Dye-Sensitized Intrazeolite Photooxygenation Current Organic Synthesis, 2005, Vol. 2, No. 2 291 the ene allylic hydroperoxides as the major or even exclusive Similarly, for the o-CF3 substituted styrene 45, in solution products (Table 6). The relative yield of the ene adduct was twin/twix = 77/23, while within Na-Y, twin/twix = 32/68. always higher than 85%. It is remarkable that Again, for the naphthyl-substituted alkene 42, the reaction in isobutenylarenes whose photooxygenation in solution zeolite is twin selective, however, in solution is twix requires many hours to go to completion, only requires 3-5 selective (twin/twix = 82/18). minutes to react to same extend in the confined space of the The unexpected increased reactivity of the twix methyl zeolite (for the same amount of reactants). For example, the group for the photooxygenation of β,β-dimethyl styrenes in ortho-CF3 substituted styrene 38 gives after 4 minutes of solution has been rationalized [58,63] in terms of attractive intrazeolite photooxygenation the ene product in >97% arene-oxygen interactions in the transition state for the relative yield. In contrast, photooxygenation in solution formation of the twix-oriented intermediate. For the proceeds at a remarkably slow rate (less than 5% conversion intrazeolite photooxygenation reactions, cation – π after 45 min of irradiation) with formation of a complex interactions have been primarily examined as the major reaction mixture. reason to dictate the site selectivity for the ene pathway. To explain the remarkable chemoselectivity, two possible DFT calculations at the B3LYP/6-31G* level of theory intermediates were invoked, the perepoxide [58], that leads revealed that the binding site of Na+ to the substrates of to ene product and the open 1,4-zwitterionic intermediate Table 7 is controlled significantly by the presence of [61], which gives the [4+2] or [2+2] adducts. Na+-binding substituents capable of interacting to the cation via non- to the aryl ring within Na-Y, destabilizes the open bonded electron pairs (e.g. fluorine or oxygen atoms). The zwitterionic intermediate (ZI), because upon cation Na+ - F interaction, for example, is highly exothermic and is complexation the aryl ring is losing electron density and is the driving force for the facile adsorption of fluorinated less capable to stabilize the positive charge at the benzylic compounds within Na-Y [64]. Although for the parent β,β- position (Scheme 13). On the other hand, for the perepoxide dimethyl styrene 29, the cation binds approximately in the intermediate, complexation of the aryl ring to the cation is middle and on top of the phenyl ring, for the para-CF3 expected to cause significantly less destabilization compared substituted styrene 36, binding occurs in between the middle to the open zwitterion. An alternative explanation for the of the aryl ring and the fluorine atoms (Fig. 4). For the lack of Diels-Alder cycloadduct formation, could be that encapsulation of the alkene within the zeolite, places the aryl group at an inappropriate conformation for a concerted [4+2] reaction to take place (s-cis conformation between the alkene double bond and the aryl ring). This rationalization, 1 however, requires a synchronous mechanism for the O2 addition to the arylalkene, which is unlikely [61] to occur. δ- δ+ O O H2 C CH3 Ar

Na Ar OOH H3 C CH3 ene product perepoxide (PE)

O O Ar [4+2] or [2+2] adducts Na H3C CH3

open zwitterion (ZI) Scheme 13. Destabilization of the zwitterionic intermediate by coordination to a Na+. The intrazeolite photooxygenation of some stereoselectively deuterium-labeled 1-aryl-2-methylpropenes, revealed that the site selectivity for the ene pathway (ratio twin/twix) is significantly affected by cation – arene interactions within the zeolite cavities. The site selectivity for some isobutenylarenes are presented in Table 7 [62]. It is evident that remarkable changes occur by zeolite confinement Fig. (4). Calculated minima structures for the Na+ interaction to relative to the reaction in solution. For example, for the p- β β p-and o-CF3 substituted , -dimethyl styrenes at the B3LYP/6- CF3 substituted styrene 43, although in solution the ratio twin/twix = 26/74, within Na-Y it becomes 82/18. 31G* level of theory. 292 Current Organic Synthesis, 2005, Vol. 2, No. 2 Manolis Stratakis ortho-CF3 substituted styrene 38, however, the binding site binding site closer to the CF3 functionality (see the changes dramatically, and resides closely to the alkene structures of Fig. 4). The distance between the Na+ and the double bond. double bond of the alkene is higher, therefore, the stabilizing electrostatic interaction between and the incoming oxygen For the intrazeolite photooxidation of the alkenylarenes, and the cation less important (transition state TS , Scheme we proposed [62] that the relative reactivity of the twin and 3 14). Therefore, transition state TS predominates (twin twix methyl groups for allylic hydrogen atom abstraction is 4 allylic hydrogen atom abstraction). For the case of the ortho- controlled: (i) by electrostatic interactions between Na+ and -styrene 45, binding of Na+ to the fluorine the styrenes, and (ii) by electrostatic interactions of the substituted CF3 atoms shifts the cation very close to the alkene double bond negatively charged oxygen of the intermediate perepoxide to (Fig. 4), thus favoring electrostatic interaction between Na+ the Na+. For the parent β,β-dimethyl styrene 40, the slight and the negatively charged oxygen atom of the twix-oriented preference for the twix product formation was attributed to perepoxide, which essentially leads to twix selectivity. In favorable electrostatic interaction between the negatively addition, binding of Na+ to the naphthyl (42) or p- charged oxygen of perepoxide and the cation (higher stability fluorophenyl-substituted (46) alkenes occurs at more remote of TS compared to the TS in Scheme 14). By placing a 1 2 position from alkene double bond, relative to the parent β,β- CF3 substituent at the para-position of 40, interaction of Na+ to the highly electronegative fluorine atoms shifts the dimethyl styrene, thus, a twin-selective reaction occurs.

Table 7. Site Selectivity for the Photooxygenation of Deuterium-Labeled Isobutenylarenes by Zeolite Confinement (the Values in Parentheses Indicate the Relative Reactivity in Solution)

1 DOO CD HOO CD3 CD3 O2 2 + Ar CH Ar CH3 ene pathway Ar CH3 2

twin twix

Substrate Ar Intrazeolite photooxidation (twin/twix) Photooxidation in solution (twin/twix)

40 42/58 37/63

41 43/57 45/55 H3C

42 61/39 18/82

43 82/18 26/74 F3C

F3 C 44 38/62 30/70

CF 3 45 32/68 77/23

46 F 60/40 32/68 Oxyfunctionalization of Alkenes by Dye-Sensitized Intrazeolite Photooxygenation Current Organic Synthesis, 2005, Vol. 2, No. 2 293

δ- δ+ O O TS1 HOO CD3

Ph CH2 D C 3 Na twix CH3

δ- δ TS2 O + O DOO CD2

Ph CH3 twin D3C Na CH3

δ δ- + O O TS 3 F HOO CD3 F F Ar CH2 D3 C Na twix CH3

TS 4 δ- O δ O + F DOO CD F 2

F Ar CH3 D3C Na twin CH3 Scheme 14. Postulated transition states controlling the site selectivity in the intrazeolite photooxygenation of isobutenylarenes.

Significant changes in the product distribution by zeolite significantly the diastereoselectivity in the photooxygenation confinement, were found in the photooxygenation of of chiral alkenes. Na+ - π interactions have been postulated 1 stilbenes. Reaction of O2 with trans-stilbene in solution as a major factor for the dramatic change in the π facial proceeds very slowly, to give mainly mono or di- photoreduction of some enone steroids [67] within zeolite endoperoxides [65] arising from a non-concerted [4+2] Na-Y, relative to the reaction in a homogeneous cycloaddition pathway. By contrast, it was reported by environment. Ramamurthy and Li [66], that the dye-sensitized intrazeolite 1 The diastereoselectivity in the ene reaction of O2 with photooxygenation of stilbenes 47 and 48 proceeds via a chiral alkenes bearing a stereogenic center at the α- position [2+2] pathway, to form labile 1,2-dioxetanes, which cleave with respect to the double bond has been extensively studied under thermal conditions to benzaldehydes (Scheme 15). The in solution [68]. Chiral alkenes which bear a substituent on preferential formation of the 1,2-dioxetanes within Na-Y was the asymmetric carbon atom other than the hydroxy or amine attributed to an electron transfer pathway. However, a singlet functionality afford predominately erythro allylic oxygen-involved mechanistic rationalization cannot be ruled hydroperoxides. The erythro selectivity was attributed to out. steric and electronic repulsions between the incoming oxygen and the substituents on the stereogenic carbon atom, DIASTEREOSELECTIVITY IN THE and to a preferable conformational arrangement to minimize INTRAZEOLITE PHOTOOXYGENATION OF the 1,3-allylic strain. For allylic alcohols and amines, the CHIRAL ALKENES threo diastereoselectivity was rationalized in terms of an oxygen - hydroxy/amine steering effect. The study of the diastereoselection in the electrophilic We examined [69] the regioselectivity and π addition of singlet oxygen to the phase of chiral alkenes is diastereoselectivity in the photooxygenation of some chiral of primary interest for the achievement of a selective alkenes, possessing a phenyl group and an alkyl group (R) oxyfunctionalization reaction. Zeolite confinement and of various size on the stereogenic carbon atom (R = methyl, π cation – interactions might be expected to affect 49; R = ethyl, 50 and R = cyclohexyl, 51). The reaction of 294 Current Organic Synthesis, 2005, Vol. 2, No. 2 Manolis Stratakis

R R

Thi onin/Na-Y O O

hv/O2 R = H (47) R= OM e (48) R R

1 O2 solvent

R

RCHO

O O R Scheme 15. Photooxygenation of stilbenes in solution and within Na-Y.

1 chiral alkenes 49-51 with O2 in solution is regioselective allylic hydroperoxides were formed, however, with an with preferential formation of the secondary allylic inverse diastereoselection trend (Table 8). The threo hydroperoxides. Among the secondary hydroperoxides the diastereomer is now predominant, and the ratio threo/erythro erythro isomer prevails (Table 8). It is also notable, that the increases with increasing the size of the R group. A minor tertiary allylic hydroperoxides has always the (Z)- remarkable example is substrate 51, for which the geometrical configuration. For example, in the diastereoselection trend was completely reversed photooxygenation of 1-cyclohexyl-1-phenyl-3-methyl-2- (erythro/threo = 09/91 versus 82/18 in solution). Formation butene 51, the (Z)-tertiary allylic hydroperoxide was formed of the major erythro diastereomer for the photooxygenation in 14% relative yield, while for the predominant secondary of the chiral alkenes in solution was explained considering allylic hydroperoxides, the ratio erythro/threo = 82/18. the transition state shown in Scheme 16. The phenyl group is placed to the opposite plane of the double bond with The thionin-sensitized intrazeolite photooxygenation of respect to the attacking oxygen, due to the unfavorable the 49-51 is highly regioselective, since only the secondary

Table 8. Regioselectivity and Diastereoselectivity in the Photooxygenation of Chiral Alkenes within Zeolite Na-Y and in Solution (Values in Parentheses)

H3 C CH3 R = methyl (49) R = et hyl (50) R = cyclohexyl (51) R

Ph

1 O2

OOH H2C CH3 H2C CH3 H3 C CH3 + + Ph R R OOH OOH Ph R Ph (Z) erythro threo a b c

Alkene a (%) b (%) c (%)

49 >1 (6) 46 (72) 54 (22) 50 >1 (10) 23 (70) 77 (20) 51 >1 (14) 9 (71) 91 (15) Oxyfunctionalization of Alkenes by Dye-Sensitized Intrazeolite Photooxygenation Current Organic Synthesis, 2005, Vol. 2, No. 2 295

OOH O H2C CH3 H C CH O 3 3 HR R + OOH Ph Ph Ph R H3C CH3 erythro (Z)

Scheme 16. Erythro-forming transition state for the photooxygenation of the phenyl-substituted chiral alkenes in solution. oxygen - arene electronic repulsions. In addition, a low diastereoselectivity (~10% d.e.) was found for the minimum 1,3-allylic strain between the tertiary allylic formation of the secondary allylic hydroperoxides. By Na-Y hydrogen and the twix allylic methyl group dictates the confinement, however, the reaction is 94% regioselective in 1 preferential O2 approach. On the other hand, the remarkable favor of the secondary hydroperoxides and the diastereomeric change of the diastereoselection on going from the solution excess enhances to 44% d.e. (Scheme 18). It is likely that, to the confined environment of the zeolite was rationalized upon interaction of the alkene with a Na+ within the cage, taking into account the strong electrostatic interaction of the the substrate folds, and the chirality is “transferred” close to phenyl ring to the Na+ within the supercages. The alkene the reaction center (double bond). As a result, the most likely adopts the conformation shown in Scheme 17. distribution of the diastereomeric ene products is Preferential attack of singlet oxygen from the less hindered significantly affected. top phase leads to the major threo allylic hydroperoxides. CH3 As the size of the R group increases, the energy difference Ph 94 % d.e. 44% between the threo and erythro forming transition states is (47 % d.e. 10%) CH3 expected to increase, in favor of the threo isomer. H3C 6 (53) 1 O2 top attack: threo 52 (more favorable) Scheme 18. Regioselectivity/diastereoselectivity in the photooxygenation of 2-methyl-5-phenyl-2-hexene (the values in parentheses indicate the relative reactivity in solution). H3C H The intrazeolite photooxygenation of 2-methyl-5-phenyl-

H3 C Na 2-hexene (substrate 53), specifically labeled at the twin R methyl group was performed, to determine the degree of diastereoselection induced by abstraction of an allylic hydrogen atom either from the more (CH3) or the less (CD3) 1 substituted side of the double bond (Scheme 19). It was O2 bottom attack: erythro (l ess favorable) found that the diastereoselectivity depends on the position of the allylic hydrogen to be abstracted. The twix/twin methyl Scheme 17. Threo and eryhthro-forming transition states for the reactivity was found within Na-Y to be 70/30. Formation of photooxygenation of phenyl-substituted chiral alkenes by the double bond by reaction of the twin methyl group (D- zeolite confinement. abstraction) proceeds with moderate diastereoselectivity (18% d.e.), while hydrogen abstraction from the twix methyl DIASTEREOSELECTIVITY-INDUCED BY A group proceeds with 54% d.e. This site differentiation in the REMOTE CHIRAL SUBSTITUENT diastereoselection was rationalized as follows. Upon folding of the alkene within the zeolite cages, the stereogenic center Due to the adsorption of the reactant alkenes in confined most probably becomes closer to the more substituted side environment within the zeolite cavities, increased of the double bond, thus higher diastereoselectivity is diastereoselectivity might be expected in cases where a chiral expected if the reaction occurs by hydrogen atom abstraction center resides at a remote position with respect to the double from the twix methyl group. bond (enzyme-like activity). This aspect of enhancement the A remarkable enhanced diastereoselection for the ene diastereoselection of a reaction induced by a remote pathway was also reported by our group [73] in the stereogenic center within zeolite Na-Y has been elegantly photooxygenation of the monoterpene (R)-(-)-α-phellandrene shown [70] in the photochemical disrotatory electrocyclic (54). The oxygenated products for the reaction of 54 with 1 cyclization of a chiral tropolone ether by Ramamurthy and O 2 in solution [74] are the two diastereoisomeric co-workers. endoperoxides 54a and 54b (major products), while five For the photooxygenation of chiral alkenes in solution isomeric ene adducts (54c-g) are formed in various amounts bearing a stereogenic center at the β- or more remote position (Table 9). Within zeolite Na-Y, the relative ratio of the with respect to the double bond, low or negligible overall ene adducts increases (ene/[4+2] = 34/66 in solution diastereoselection is expected [71]. We studied [72] the versus ene/[4+2] = 52/48 in the zeolite). Comparing the photooxygenation of 2-methyl-5-phenyl-2-hexene 52, a Diels-Alder adducts, the diastereomeric ratio of 54a/54b chiral alkene that bears a stereogenic center at the β-position slightly increases in zeolite, while for the ene adducts, for with respect to the double bond. As expected, in solution a those where the double bond is formed in the interior of the ring, the predominant diastereomer in solution is also the 296 Current Organic Synthesis, 2005, Vol. 2, No. 2 Manolis Stratakis

H2CCD3 H2CCD3

twix H C H C 3 + 3 OOH OOH H- abstra ct ion Ph Ph

70% (d.e. 54%) twin 1 CD3 O2 Ph CH3 Na-Y H3 C 53 twix

H3C CD2 H3C CD2 twin H3C + H3C D- abstraction OOD OOD Ph Ph

30% (d.e. 18%)

Scheme 19. Site-dependent diastereoselectivity in the intrazeolite photooxygenation of 2-methyl-5-phenyl-2-hexene (53). Table 9. Photooxygenation of (R)-(-)-α-Phellandrene in Zeolite and in Solution

H3C CH3 54 H3C

1 O2

CH3 CH3 H3C OOH HOO CH3

O ++++O O O

H3 C CH3 H3C CH3 H3C CH3 H3C CH3

54a 54b 54c 54d

CH2 CH2 CH3 HOO HOO OOH ++

H3C CH3 H3C CH3 H3C CH3

54e 54f 54g

Conditions 54a (%) 54b (%) 54c (%) 54d (%) 54e (%) 54f (%) 54g (%)

i-PrOH /RB 39 26 14 9 2 1.5 3 Thionin/Na-Y 33 15 12 5 5 30 <1 predominant one in the zeolite. On the other hand, the organic synthesis, since reduction of the major ene adduct, relative amount of the ene adducts 54e and 54f (exocyclic (1S,5R)-5-(1-methylethyl)-2-methylidene-3-cyclohexen-1-yl double bond) increases substantially within Na-Y (total 35% hydroperoxide (54f) with triphenylphosphine afforded the in zeolite, versus only 3.5% in solution), with a remarkable natural product trans-yabunikkeol. change in the diastereoselectivity. The ratio of 54e/54f is For the reaction in solution, the similar stereochemical 14/86 in Na-Y versus 58/42 in solution. This interesting outcome of the ene and the [4+2] adducts (cis diastereomers example of enhanced diastereoselection found application in Oxyfunctionalization of Alkenes by Dye-Sensitized Intrazeolite Photooxygenation Current Organic Synthesis, 2005, Vol. 2, No. 2 297

orientation facing the more substituted side of the alkene, it Favorable transition state in solution cannot interact with any axially-oriented allylic hydrogen O atom(s). H O As indicated earlier, remote substituents with respect to H H H the reaction centre can influence the regiochemistry [39] and 54a, 54c, 54e the diastereoselection [72] of the intrazeolite singlet oxygen CH3 H ene reactions. Recent work from our lab [75] has shown that a remote substituent with respect to the reacting double H CH3 bond, suitable for binding to the Na+, such as the acetate functionality, can dramatically affect the regiochemistry and Favorable transition state within zeolite the diastereoselectivity of the intrazeolite singlet oxygen ene reaction for the case of 4-substituted 1-methyl-1- CH 2 cyclohexenes. The intrazeolite photooxygenation of O HOO H3 C H O limonene (4) is highly regioselective [18], with exclusive H formation of the ene adducts resulting from allylic hydrogen H3 C abstraction from the methyl group, as generally found in the H intrazeolite photooxygenation of 1-methyl-1-cycloalkenes H [42]. On the other hand, limonene (4) exhibits little H H3C CH3 Na diastereoselectivity. By placing an acetate functionality at 54f the remote 8-position of the limonene skeleton (α-terpinyl acetate, 55), the reaction gives mainly one regiosomeric Scheme 20. Transition states leading the major ene adducts in adduct in >90% diastereomeric excess, resulting from allylic solution and within Na-Y. hydrogen atom abstraction from the more substituted side of the cycloalkene (Scheme 21). This regiochemistry trend is in > trans) was rationalized in terms of a common perepoxide contrast to what has been reported for the intrazeolite intermediate shown in Scheme 20, which leads either to the photooxygenation of 1-methyl-1-cycloalkenes. ene or to the Diels-Alder products. In that intermediate, The dramatic change in the regioselectivity can be singlet oxygen attacks the more reactive trisubstituted explained considering attractive singlet oxygen – cation double bond of the more stable conformation from the top interactions during the formation of the intermediate phase to interact with an axially oriented allylic hydrogen 1 perepoxide, that direct O2 to abstract preferentially an atom. For the intrazeolite reaction, cation binding to the allylic hydrogen atom from the more substituted side of the alkene was used to explain the stereochemical outcome of alkene (transition state of Scheme 22). Most probably, the the reaction. The major ene adduct was proposed to arise Na+ cation is bound close to the acetate functionality and at from the transition state shown in Scheme 20. Oxygen 1 the appropriate position to interact electrostatically with O2. attacks from the opposite face of the alkene with regard to The allylic hydrogen at the 3-position has the ideal geometry the bound cation, and is preferentially oriented towards the for abstraction (axial conformation), thus, mainly one less substituted side of the double bond, because in the diastereomer is formed.

OOH H2 C 1 H C O2 2 CH3 CH2 Na-Y H3 C H3C 4 >97% (d.e. <10%)

H3C 1 H3 C O2 OOH Ac O CH3 AcO CH H3 C Na-Y H3 C 3 55 87% (d.e. >98%)

Scheme 21. Changes in the regiochemistry and diastereoselection by zeolite confinement due to a remote substituent.

δ- O δ+ O H C AcO 3 OOH H AcO H C CH3 CH 3 H3C 3 3 H3C H

Scheme 22. Na+-directing regioselectivity and diastereoselection in the intrazeolite photooxygenation of α-terpinyl acetate. 298 Current Organic Synthesis, 2005, Vol. 2, No. 2 Manolis Stratakis

CONCLUDING REMARKS [18] Ramamurthy, V.; Lakshminarasimhan, P.; Grey, C.P.; Johnston, L.J. J. Chem. Soc., Chem. Commun. 1998, 2411. [19] Pace, A.; Clennan, E.L. J. Am. Chem. Soc. 2002, 124, 11236. The confined environment of the zeolite supercages can [20] Jayathirma Rao, V.; Perlstein, D.L.; Robbins, R.J.; significantly influence the product distribution of singlet Lakshminarasimhan, P.H.; Kao, H-M.; Grey, C.P.; Ramamurthy, oxygen-induced reactions and can lead to the development of V. J. Chem. Soc., Chem. Commun. 1998, 269. novel and stereoselective oxyfunctionalization pathways in [21] Herwijnen, van H.W.G.; Brinker, U.H. Tetrahedron 2002, 58, the photooxygenation of alkenes. The cations within the 4963. π [22] Stratakis, M.; Stavroulakis, M.; Sofikiti, N. J. Phys. Org. Chem. supercages are not just inert fillers, but through cation – 2003, 16, 16. interactions can dramatically influence reaction pathways. [23] Climent, M-J.; Miranda, M.A.; Roth, H.D. Eur. J. Org. Chem. The experimental results presented herein are an excellent 2000, 1563. basis for the development of models with predictive [24] Casades, I.; Alvaro, M.; Garcia, H.; Espla, M. J. Chem. Soc., 1 Chem. Commun. 2001, 982. capability, in order to tune the behavior of O2 reactions by [25] Ma, J.C.; Dougherty, D.A. Chem. Rev. 1997, 97, 1303. zeolite confinement. In addition, these results reveal clearly [26] Barich, D.H.; Xu, T.; Zhang, J.; Haw, J.F. Angew. Chem., Int. Ed. that zeolites can no longer be considered as “boiling stones” Engl. 1998, 37, 2530. or adsorbing molecular sieves but can find significant [27] Ramamurthy, V.; Shailaja, J.; Kaanumalle, L.S.; Sunoj, R.B.; applications in organic chemistry [76]. The environmentally Chandrasekhar, J. J. Chem. Soc. Chem. Commun. 2003; 1987. [28] Yamada, S.; Morita, C. J. Am. Chem. Soc. 2002, 124, 8184. benign nature of the zeolite medium justify further [29] Froudakis, G.E.; Stratakis, M. Eur. J. Org. Chem. 2003, 359. exploration towards new frontiers for selective organic [30] McMahon, T.B.; Ohanessian, G. Chem. Eur. J. 2000, 6, 2931. transformations in organized media. [31] Mo, O.; Yanez, M.; Gal, J-F.; Maria, P-C.; Decouzon, M. Chem. Eur. J. 2003, 9, 4330. [32] Wasserman, H.H.; Murray, R. W. Singlet Oxygen, Academic ACKNOWLEDGEMENTS Press, New York, 1979. [33] Blatter, F.; Sun, H.; Vasenkov, S.; Frei, H. Catal. Today 1998, 41, 297. I would like to thank the General Secretariat of Research [34] Xiang, Y.; Larsen, S.C.; Grassian, V.H. J. Am. Chem. Soc. 1999, and Technology and the Greek Ministry of Education 121, 5063. (ΕΠΕΑΕΚ program) for financial support during the past 4- [35] Orfanopoulos, M.; Smonou, I.; Foote, C.S. J. Am. Chem. Soc. 5 years of my research activities in the University of Crete. I 1990, 112, 3607. 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Received: October 8, 2003 Accepted: November 3, 2003