Regio-and Stereoselectivity in the Paternò-Büchi Reaction on Furan Derivatives

The photochemical coupling reaction between 2,3-dihydrofuran and benzaldehyde was studied by using DFT/B3LYP/6 − 31G + (d, p) method. The regiocontrol of the attack of the benzaldehyde on the double bond is related to the different stabilities of the biradical intermediates. The endo stereoselectivity of the reaction depends on the superposition between HSOMO and LSOMO in the biradical intermediate. In the photochemical reaction between furan and benzaldehyde also the regiocontrol depends on the relative stability of the possible biradical intermediates. The exo stereoselectivity of the coupling reaction depends on the superposition between the HSOMO and LSOMO of the biradical intermediate. The reaction of chiral phenylglyoxylates with furan gave the corresponding adducts with de = 15–95%. The stereocontrol can be explained considering the energy gap between the biradical intermediates in the coupling reaction. When the reaction was performed in the presence of zeolite, the diastereoisomeric excess increased. The reaction of benzoin and 2-phenylpropiophenone with furan gave the cycloadduct with high diastereocontrol. All the products were obtained with de > 98%. The Paterrnò-Büchi reaction between 2-furylmethanols with aromatic carbonyl compounds also showed high regioand stereocontrol. On the contrary, when 5-methyl derivatives were used, a lack of regiocontrol was observed. Furthermore, with aliphatic carbonyl compounds, no diastereoselectivity was observed. These results were explained assuming the attack of the excited carbonyl compound on the same side as the hydroxyl group, through the formation of a hydrogen bond or of a complex. This type of attack gave the biradical intermediate in preferential conformations. The relative energies of these conformers account for the observed diastereoselectivity.


INTRODUCTION
[2 + 2]-cycloadditions are one of the most important reactions in organic photochemistry.Several applications in organic synthesis have been described [1].The Patern ò-Büchi reaction is a [2 + 2]-cycloaddition reaction between a carbonyl compound and an alkene (Scheme 1(a)).The regiochemistry of this reaction appeared to be a difficult problem to solve from the first.Patern ò performed a reaction between 2-methyl-2-butene and benzaldehyde, and he could not assign the exact structure of the product.He was not able to distinguish between 1 and 2 (Scheme 1(b)) [2].Büchi solved the problem showing that 1 was the actual product [3].Furthermore, in this reaction the stereocontrol was not examined, but several stereoisomers could be obtained.
Regio-and stereocontrol of the Patern ò-Büchi reaction was not always understood.For several years the comprehension level of these two factors resembled the description of some problems connected with the evolution of photo-chemistry made by Ciamician in 1912: "in ordinary organic chemistry the reactions often take place in some definite way; but the photochemical reactions often furnish surprises and proceed along quite different lines" [4].
The Patern ò-Büchi reaction is a photocycloaddition of an n, π * carbonyl compound in either its S 1 or the T 1 state to an alkene in its ground state.In a theoretical study the authors showed that there are two conical intersection points located near the C−C and C−O bonded biradical regions of the ground state [5].Furthermore, for C−O attack, the triplet surface must cross the singlet to reach a diradicaloid minimum.
For C−C attack, the triplet state biradical minimum is located at the same geometry as the conical intersection between the two singlet states, and the efficiency of the intersystem crossing will be determined by the nature of the spinorbit coupling.Thus, for the triplet, the reaction path can be predicted by the most stable biradical rule [5] and electron-rich alkenes has been determined by using laser flash photolysis [6,7].A conformational analysis of the biradicals has been published [8].
Furan derivatives can give the Patern ò-Büchi reaction reacting with carbonyl compounds.This reaction has been used extensively in the synthesis of natural products [9,10].
In order to explain both regio-and stereocontrol of the Patern ò-Büchi reaction on furan derivatives, we used the pattern represented in the Scheme 2 on the basis of the work of Scharf [11].We assumed that the formation of the possible biradicals is reversible.The consequence of this hypothesis is, in agreement with the theoretical study, that the formation of the more stable intermediate is preferred, while all the other isomers undergo retrocleavage.The following ring closure is an irreversible step, determined by spin-orbit coupling [12][13][14], that usually allowed the formation of the more stable compound [15].
Obviously, in the presence of achiral precursors, k 1 = k 2 as well as k 3 = k 4 .In the presence of chiral reagents or in a chiral environment, we can observe k 1 = k 2 and k 3 = k 4 .
We examined the regiochemistry of the reaction, and we tested the possibility that the regiochemical behaviour of the reaction is determined by the formation of the more stable biradical intermediate.We performed DFT/B3LYP calcula-tions using 6 − 31G + (d, p) basis set on Gaussian 03.We examined the structures M and N (Figure 1).
The biradical N is more stable than M by 1.49 kcal mol −1 .This result is in agreement with the experimental result.On the basis of this result the stability of the biradical intermediates can account for the regiochemical behaviour of the reaction.
We can see also why the endo isomer is favoured in the reaction.In Figure 2 we have depicted the HSOMO and the LSOMO of the biradical N. The HSOMO is mainly localized on the aromatic ring and it is extended on the benzylic radical site.The LSOMO is mainly localized on the dihydrofuran ring.The coupling between the radical carbons in these two orbitals is possible (the atomic orbitals involved can superimpose themselves) only if the endo isomer is formed (Figure 3).
We also examined for this case the regioisomeric biradical intermediates O and P resulting from the head-to-head and the head-to-tail addition, respectively (Figure 4).
The biradical O is more stable than P by 16.5 kcal mol −1 .The biradical O exists as two conformers and we considered only that conformer able to give the ring closure.The HSOMO and LSOMO of the biradical O are reported in Figure 5.
Also in this case the HSOMO is mainly localized on the benzaldehyde fragment of the biradical while the LSOMO is mainly localized on the furanoid part of the molecule.The coupling between the radical carbons in these two orbitals, considering that the atomic orbitals involved can superimpose themselves, can give only the exo isomer, in agreement with the experimental results (Figure 6).
All the reactions gave in good yields the corresponding oxetanes.Considering the stereocontrol of the reaction, while the reaction with 8-phenylmenthol glyoxylate gave a high di- astereoisomeric excess, the reaction with the glyoxylate ester 7 gave only 15% de and the reaction with the glyoxylate ester 8 resulted in no diastereoselectivity (Figure 7).The best results in order to justify the observed stereoselectivity can be obtained considering the energy of the triplet biradical intermediates in the reaction of 7-9 with furan (Figure 8).
Calculations on these biradical intermediates showed that Qa (the precursor of 10) was more stable than Qb by 0.73 kcal mol −1 .Furthermore, Ra and Rb differed by only 0.02 kcal mol −1 , in agreement with the observed lack of stereoselectivity of the reaction.Finally, the biradical intermediate Sa showed to be more stable than Sb by 21.9 kcal mol −1 : also this result is in agreement with the observed high diastereoisomeric excess.
In conclusion, the stereocontrol of the Patern ò-Büchi reaction between 7-9 and furan can be explained considering the relative stability of the possible biradical intermediates.
To improve diastereoselectivity, we tried to carry out a reaction in an organized medium (zeolite).Selective absorption on the surface of the solid (NaY) could improve diastereoselectivity.We obtained the adducts 10-12.It is noteworthy that this type of procedure allowed us to improve diastereoselectivity: while, in the reaction in solution, 10 was obtained with de = 15%, the reaction in an organized medium gave de = 37%.While 11 was obtained as a mixture of diastereoisomers, the use of the zeolite allowed to reach 18% diastereoisomeric excess.Also in the case of 12, obtained in solution with de = 95%, the use of the zeolite increases the diastereoisomeric excess reaching the value of 98%.If the chiral center is near the reaction site, the diastereoselectivity increases.Benzoin (13) reacted with furan to give the corresponding adduct 14 in acceptable yield (56%) and de > 98% (Figure 9) [27].
Also in this case we calculated the energy of the intermediates Ta and Tb for the reaction of benzoin with furan.The structures are depicted in Figure 10.The biradical Ta was more stable than Tb for 3.66 kcal mol −1 , in agreement with the observed stereoselectivity.
When chiral ketones were used as substrates we obtained products deriving from the Norrish Type II raction.In order to avoid Norrish Type II reaction we used a substrate without γ-hydrogen.We used the phenyl derivative 16 (Figure 11).In this case we observed the formation of the corresponding adduct [28].
The NMR data for the compound 16 are in agreement for an exo position for the phenyl group at C−6. Chiral HPLC (Chiralcel OJ, λ = 235 nm, 99 : 1 n-hexane/isopropanol) showed a de > 98%.
We calculated the total energy of the possible intermediates in the reaction of 15 with furan.The structures of these compounds (Ua, 1Ub) are showed in Figure 12.The R, S conformer Ub is more stable than the S, S one by 1.1 kcal mol −1 and this difference can account for the observed diastereoselectivity.
Furthermore, the analysis of the HSOMO and LSOMO in this biradical intermediate (Figure 13) shows that the coupling can occur to give the product with the phenyl group in the exo configuration.

Photoaddition of carbonyl compounds to chiral furans
The diastereoselectivity of the Patern ò-Büchi reaction can be determined in the presence of some substituents, that is, the presence of chiral substituents on the alkene.Adam showed that allylic alcohols 17 reacted with benzophenone to give the corresponding adducts 18 and 19 with high region-and diastereoselectivity (Scheme 5) [29][30][31][32].
The diastereoselectivity dropped drastically in the presence of the protic solvent methanol and totally disappeared for the corresponding silyl ethers.These data are in agreement with the presence of a hydroxyl directing effect in the Patern ò-Büchi reaction.The threo isomer can be favoured through the formation of a hydrogen bond between triplet excited benzophenone and the substrate in the exciplex, while the formation of the erythro stereoisomer would be less favoured due to allylic strain (Scheme 6).
The formation of a hydrogen bond directing the Patern ò-Büchi reaction has been considered by other researchers.Diastereoselective cycloaddition has been obtained using chiral enamide [33,34], or in the reaction of allylic alcohols with naphthalene rings [35].When unsymmetrical carbonyl partners such as acetophenone or benzaldehyde were used, high diastereoselectivity was observed to give the corresponding cis isomer.The regioselectivity was high with acetophenone but lower with benzaldehyde [30].
Cis diastereoselectivity can be explained by using the Griesbeck rule on the possible triplet biradicals formed in the reaction.Steric interactions are minimized when the biradical assumes the optimal conformation and this conformation accounts for the formation of the observed stereoisomer [32].
When chiral allylic alcohols were used as substrates in the reaction, cis diastereoisomers were formed.Also in this case, a pronounced threo diastereoselectivity was observed, in agreement with a less pronounced hydroxyl directing effect when acetophenone and benzaldehyde were used [30,32].A chiral allyl ether gave the corresponding adduct with high diastereoselectivity [36].
The reaction of allylic alcohols with carbonyl compounds was tested also on a particular type of allylic alcohol such as 2-furylmethanol derivatives.While the reaction of 2furylmethanol with benzophenone showed low regioselectivity, the presence of larger substituents on the carbon bearing the alcoholic function allows a high regioselectivity (Scheme 7) [37].Furthermore, when 2-furylethanol (20) was used as substrate, a 1 : 1 mixture of stereoisomers was obtained, while, when 1-(2-furyl)-benzylic alcohol (21) was the substrate, only one diastereoisomer was obtained.The high diastereoselectivity observed was confirmed using optically active 21.
The regioselectivity of the reaction was explained on the basis of the relative stability of the biradical intermediates.A theoretical study (DFT) showed that the biradical obtained on the most hindered side of the molecule was more stable than the other [38].The nature of the intermediate was in agreement with the observed ρ value in a Hammett free energy correlation.
When 5-methyl-2-furyl derivatives were used as substrates, a different regioselectivity was observed.Compound 22 gave a 1 : 1 mixture of regioisomers 25 and 26, when irradiated in the presence of benzophenone, and a single regioisomer 27 in the presence of benzaldehyde on the side bearing the methyl group (Scheme 7) [38].In agreement with the results obtained with 2-furyl derivatives, the products deriving from the attack on the side bearing the alcoholic function were obtained as a single diastereoisomer, while those deriving from the attack on the side bearing the methyl group were obtained as a mixture of diastereoisomers.Then, the hydroxyl group near the reaction center is needed to have diastereoselectivity.
The reaction of 2-furylmethanol derivatives with aliphatic aldehydes and ketones gave the corresponding adducts with high regioselectivity but no diastereoselectivity (Scheme 7) [39].
The observed diastereoselectivity in the reaction with aromatic carbonyl compounds clearly shows that it increases in relation to the nature of the substituents on the carbon bearing the alcoholic function as described by Adam.However, while Adam considers the allylic strain with a methyl group as the driving force for the diastereoselectivity [29][30][31], in this case, the methyl group is not present.Therefore, the allylic strain cannot be used to explain diastereoselectivity.
In order to have more data to explain the observed stereoselectivity we studied the photochemical behaviour or tertiary 2-furylcarbinols [40].The photochemical reaction of 1methyl-1-phenyl-1-(2-furyl)methanol 28 with benzaldehyde gave a mixture of two regioisomeric products 29 and 30.
The regioisomer on the most hindered side of the molecule was obtained in low yield but it showed a complete diastereoisomeric control.On the contrary the main product was a mixture of four diastereoisomeric products (Scheme 8).The reaction of the same compound 28 with benzophenone gave only the product deriving from the attack on the most hindered double bond of molecule 31.This compound was obtained with 48% diastereoisomeric excess.
The reaction of 1-methyl-1-t-butyl-1-(2-furyl)methanol (32) with benzaldehyde and benzophenone showed complete regioselectivity.In all the experiments only the products deriving from the attack of the carbonyl compound on the most hindered double bond of the substrate were observed (Scheme 9).
The regiocontrol was explained, as described above, considering the relative stability of the biradical intermediates.In this case, in the reaction of the 1-methyl-1-phenyl-1-(2-furyl)methanol with benzaldehyde the biradical obtained from attack on the less hindered double bond of the substrate was more stable than the other one by 18.03 kJ mol −1 .
On the basis of these results we can attempt an explanation of the stereocontrol.1-Methyl-1-phenyl-1-(2-furyl)methanol may exist in three conformations (Figure 14).All three conformers were in the range of 1.97 kJ mol −1 and they did not show a preference.
To solve the problem we tested the following hypothesis: the directing effect exerted by the hydroxyl group is either due to the formation of a hydrogen bond between the hydroxyl group and the oxygen of the excited carbonyl compound, or it is due to the formation of a complex.This type of interaction could favour the formation of a preferential conformation in the biradical intermediate where the hydroxyl group and the oxygen of the carbonyl compound are near.These conformations could have different energies for different diastereoisomeric biradicals, giving an explanation of the observed behaviour.The above hypothesis requires that the biradical intermediates have a very short life enabling them to equilibrate to the most stable one.In the case of 1-methyl-1-phenyl-1-(2-furyl)methanol, if the hydroxyl group drives the attack of the oxygen of the carbonyl group, we obtained the conformations of the biradical intermediate represented in Figure 14.
We can observe that AB and AD are the preferred conformations.Calculations on these conformations showed that there is a difference of 13.26 kJ mol −1 between the energies of these two conformations (AD is the most stable one).This difference can account for the observed complete diastereoselectivity of the reaction.In the reaction of the same substrate with benzophenone the corresponding conformers AB and AD show an energy difference of 7.79 kJ mol −1 : this difference is in agreement with the observed diastereoselectivity.
On the basis of these conformers, if the attachment of the excited carbonyl compound occurs on the prochiral face of the furan ring where the hydroxyl group is present, the conformers in Figure 15 can be obtained.
The conformers of Figure 15 differ by 6.90 kJ mol −1 , in agreement with the observed diastereoisomeric excess.
To test the above-described hypothesis we examined also the results obtained on 2-furylmethanol derivatives.The reaction of 2-furylphenylmethanol gave complete diastereoisomeric control when it reacted with benzophenone [37].The conformers of this substrate are reported in Figure 16.The conformers deriving from the attack of the excited carbonyl compound on the prochiral face of the furan ring where the hydroxyl group is present are described in Figure 16.
AI is the most stable conformer of the (RR) * biradical, while AL represents the most stable conformer of (RS) The same approach can be used to justify the stereocontrol of the reaction of allylic alcohols with benzophenone [41].

CONCLUSION
In conclusion we have shown that the regiocontrol of the attack of the benzaldehyde on the double bond is related to the different stability of the biradical intermediates.The endo stereoselectivity of the reaction depends on the superposition between HSOMO and LSOMO in the biradical intermediate.The regiocontrol depends on the relative stability of the possible biradical intermediates.The exo stereoselectivity of the coupling reaction depends on the superposition between the HSOMO and LSOMO of the biradical intermediate.The stereocontrol in the reaction between furan and chiral phenylglyoxylates can be explained considering the energy gap between the biradical intermediates in the coupling reaction.When the reaction was performed in the presence of zeolite, the diastereoisomeric excess increased.The reaction of benzoin and 2-phenylpropiophenone with furan gave the corresponding adduct with high diastereocontrol.
The Patern ò-Büchi reaction between 2-furylmethanols with aromatic carbonyl compounds showed high regio-and stereocontrol.The results were explained assuming the attack of the excited carbonyl compound on the same side as the hydroxyl group, through the formation of a hydrogen bond or of a complex.This type of attack gave the biradical intermediate in preferred conformations.The relative energies of these conformers account for the observed diastereoselectivity.
The above-reported discussion of the state of art points out some arguments that can be the object of future work in this field: some hypotheses able to explain the simple stereoselectivity observed in the reaction between furan and benzaldehyde have been reported.This selectivity has to be confirmed studying the photochemical behavior of other carbonyl compounds, in particular heterocyclic carbonyl compounds.We have only very few data on furan-and thiophene-2-carbaldehyde [42][43][44].In particular, the possible role of the excited singlet state in this reaction has to be explained, and some heterocyclic aldehydes have a long half-life.
Diastereoselective synthesis has been performed by using chiral substrates.It is not clear if this behaviour is a general character of this reaction: we need to test this behavior on a large number of chiral ketones.
High stereoselectivity was observed in the reaction between 2-furylmethanol derivatives and carbonyl compounds.We do not know the photochemical behaviour of 3-furylmethanol derivatives.

Figure 7 :
Figure 7: The reaction of chiral phenylglyoxylates with furan.