Acetylvinyl Acrylates : New Captodative Olefins Bearing an Internal Probe for the Evaluation of the Relative Reactivity of Captodative against Electron-Deficient Double Bonds in Diels-Alder and Friedel-Crafts Reactions

As olefinas captodativas 3a e 3b derivadas dos ácidos metacrílico e trans-crotônico foram preparadas. A presença de uma segunda ligação dupla na molécula, atuando como marcador interno, permitiu-nos comparar sua reatividade relativa em reações de Diesl-Alder e Friedel-Crafts. A reatividade foi avaliada com ciclopentadieno (6) atuando como dieno em cicloadição Diels-Alder, e com furano (9) e tiofeno (10) como substratos heteroaromáticos Friedel-Crafts. Em ambos os processos, a ligação dupla da enona captodativa mostrou-se mais reativa que a do sistema acrílico. A teoria FMO considera essa quimiosseletividade como consequência da maior contribuição da enona ao orbital LUMO dessas moléculas. A pequena seletividade exo observada na cicloadição com 6 concorda com a maior estabilidade do estado de transição, de acordo com os resultados de cálculos B3LYP/6311G(d,p).


Introduction
The captodative olefins 1-acetylvinyl arenecarboxylates, 1a-1c, have proved to be as reactive in Diels-Alder additions as olefins substituted only with an electron-withdrawing group, such as methyl vinyl ketone (2). 1 They have also shown high regio-and stereoselectivities with unsymmetrically substituted dienes in these reactions. 2Moreover, in 1,3-dipolar cycloadditions with diverse nitrones, olefin 1a reacted faster than dipolarophile 2, with much higher regio-and stereoselectivities. 3 However, from a perturbational point of view, 4 captodative olefins should be less reactive and selective than alkenes substituted only with electronwithdrawing groups.Structural and theoretical studies of olefin 1a revealed that the delocalization of the oxygen lone pair of the electron-donor group toward the π-system was inhibited by conformational restrictions, 5 also suggesting a dominant effect of the acetyl electronwithdrawing group on the polarization of the double bond.Moreover, the regioselectivity shown in 1,3-dipolar additions toward nitrones and nitrile oxides was rationalized by the DFT/HSAB theory, 3 which showed the relevance of the electron-donor group in controlling the interaction of the cycloaddends.Therefore, it appears that electronic and structural factors might explain the reactivity and regiochemistry observed in both cycloaddition reactions.
In order to carry out a more profound evaluation of the effects involved in the control of the reactivity of captodative olefins, it would be interesting to design new captodative alkenes bearing a second activated double bond as an internal probe.It is likely that both double bond moieties would be subjected to similar solvent and reagent interactions, bearing out the relevant structural and electronic effects on the π orbital that control reactivity.Accordingly, we hereby describe the preparation of the novel olefins 3a and 3b, and their study as dienophiles in Diels-Alder additions, and as electrophiles in aromatic electrophilic substitution (AES), under Friedel-Crafts conditions.Hartree-Fock (HF/6-31G(d,p)) and DFT (B3LYP/6-311G(d,p)) calculations were carried out to determine the most stable conformers of 3a and 3b, and to evaluate the relative energies of the unoccupied MOs expected to be involved in the reactivity of these processes.In addition, in order to obtain a better understanding of the exo stereoselectivity commonly observed in the cycloaddition reactions of captodative olefins, we have determined (B3LYP/6-311G(d,p)) some of the possible transition states in the Diels-Alder reaction of 3a and 3b with cyclopentadiene (6).

Preparation of the captodative olefins 1-acetylvinyl acrylates 3a and 3b
The method used previously 1 for the preparation of compounds 1 was applied to the synthesis of captodative olefins 3a and 3b, providing the expected products, although in very low yields (<10%).The reaction conditions were improved by addition of the acryloyl chloride, 5a or 5b, to the solution of butane-2,3-dione (4) at -50 °C, and maintaining the reaction at room temperature for 24 h (Scheme 1).Although the NMR spectra of the reaction crude showed only traces of byproducts, the yields of the purified compounds were low (3a, 26%; 3b, 33%).This was probably due to their instability to the purification process.Although different column chromatography supports (alumina, silica gel, florisil), and radial chromatography were tried, the best way to purify these compounds was by flash column chromatography through silica gel.Olefin 3c was also obtained, as shown by 1 H NMR of the corresponding reaction mixture, but it was not stable to purification conditions.Olefins 3a and 3b were fully characterized by spectroscopy and HRMS.
We have recently reported experimental and theoretical studies that confirm a planar conformation for the conjugated enone moiety of olefin 1a, which can adopt the two possible s-cis and s-trans conformations. 5lthough the latter was found to be more stable, in both cases the conjugated aroyloxy group adopts an orthogonal conformation with respect to the plane of the enone. 5Our ab initio calculations (B3LYP/6-311G(d,p)) of the four possible s-cis/s-trans conformers of olefin 3a show that the most stable geometry corresponds to that in which the enone fragment (a) adopts the s-cis conformation, while the methacrylate moiety (b) has the s-trans geometry.On the other hand, in the most stable conformer of olefin 3b, the preferred conformation is the s-cis for both conjugated fragments (Figure 1).For both olefins, 3a and 3b, the Scheme 1. conjugated moieties (a) and (b) were, nevertheless, perpendicular to each other, paralleling the preferred conformations found for 1a and other captodative olefins. 6he four possible s-cis/s-trans conformers of both alkenes had similar energies, spanning a small energy range (0.42 kcal mol -1 for 3a, and 1.16 kcal mol -1 for 3b; Table 1).Although these energy differences are not large enough to claim that one of the conformers is totally favored in the gas phase, it has been established that, for analogous small energy differences, the solid-state conformation of the conjugated acrylate system of alkene 1d, shows good agreement with the calculated gas phase structure. 6

Diels-Alder and Friedel-Crafts reactions of olefins 3a and 3b
The reactivity and selectivity of these olefins in Diels-Alder reactions were evaluated under thermal and catalytic conditions, using cyclopentadiene (6) as the diene (Table 2).Both exo and endo stereoisomers, 7 and 8, were obtained under mild thermal conditions (Scheme 2), showing a small preference for the exo isomers 7a and 7b (Table 2, entries 1 and 11).The structure of the major stereoisomers was established by NMR spectroscopy, and by comparison with spectroscopic data of the unambiguously established structures of adducts of olefin 1a. 7The exo stereoselectivity was slightly improved by adding Lewis acid catalysts, although it depended on the type and amount of the catalyst used.For instance, for dienophile 3a, the best results were obtained with 1.0 mol equiv. of aluminum chloride or titanium chloride (Table 2, entries 2 and 7); while for 3b, only the former catalyst and ZnI 2 were able to slightly enhance the exo selectivity with respect to the thermal trial (Table 2, entries 12 and 14).The exo selectivity obtained for dienophiles 3a and 3b was similar to that shown by captodative olefins 1a-1c, 1 and by other captodative olefins. 8t is worth noticing that, in all cases, the addition took place only at the enone double bond, even in the catalyzed trials.This chemoselectivity indicates a higher reactivity of this double bond in comparison with that of the acrylate moiety, under Diels-Alder conditions.This behavior is not unexpected, considering that the ester carbonyl group has a lesser electron-withdrawing effect than the ketone carbonyl group. 6This would support the hypothesis that the reactivity of this kind of captodative olefins is controlled mainly by the electronic effect of the electronwithdrawing group. 5lefin 1a reacts with furan (9) under Lewis acid catalysis to give the Friedel-Crafts product, the aromatic electrophilic substitution taking place at the C-2 carbon of the heterocycle. 9 strong electron-withdrawing effect is required in the Michael acceptors for an efficient Friedel-Crafts reaction. 10ence, this reaction could be a sensitive method to evaluate the reactivity of the potential Michael bis-acceptors 3a and 3b.Thus, under Lewis acid catalysis (BF3.Et 2 O) at low temperature (-78 °C), alkene 3a reacted with 9 to give a single product (11a), arising from addition to the enone double bond (Scheme 3).Again, the acrylic double bond was reluctant to undergo the addition, even for acceptor 3b, since the Friedel-Crafts reaction with 9 provided the product of addition to the enone 11b (Scheme 3).A similar behavior was found for both alkenes 3a and 3b when the electrophilic substitution was performed on thiophene (10).As in the case of 9, the incoming Michael acceptor was directed to the C-2 position of the heterocycle (Scheme 3).The 1 H NMR analysis of reaction crudes did not show any product arising from the Friedel-Crafts reaction at the acryloxy double bond (b).The moderate yields of the adducts were due to their low stability under the column chromatography carried out on silica gel.

Discussion
FMO theory has predicted correctly the difference in reactivity for Diels-Alder additions of captodative olefin 1a with respect to olefin 1d. 2,5,6Thus, for the energetically more favorable HOMO-diene/LUMO-dienophile gap, the LUMO energy for 1a was lower than that of 1d, predicting a faster addition towards a diene such as 6 for the former alkene, which agrees with experimental results.Furthermore, the relative FMO energies of 1a fit well the experimental values of ionization energies (IE) and electron affinities (EA). 5,6Therefore, considering that in alkenes 1a and 1d the electron-donating group is the same, and the steric interactions are similar, one can consider that the double bond in the enone frame is more reactive than that of the acrylate moiety.
Consequently, for alkene 3a, the enone system (a) should be more reactive than the acrylate fragment (b), regardless of the effect of the electron-donating group.This should be detected by comparison of the coefficient contributions of both moieties to the LUMO.We calculated the FMO energies and coefficients (HF/6-31G(d,p)) for the most stable geometries of 3a and 3b (Table 3).The LUMO energies of both systems are quite similar, being that of 3a lower.The atomic wave function coefficients of the LUMOs are localized mainly at the double bond of the enone moiety, and not at the acrylate double bond.The main contribution of the latter fragment is found in the next unoccupied orbitals (LUMO+1) in both, 3a and 3b (Table 3).
If we consider that 3a is a bis-captodative olefin, from the point of view of the electron donor groups, the methyl a All under N 2 atmosphere, using CH 2 Cl 2 as solvent, with 1.3 mol equiv. of diene 6. Thermal trials in the presence of 1-2% hydroquinone; b Proportions as determined by 1 H NMR of the crude reaction mixtures; c As a mixture of isomers after purification by column chromatography.

Scheme 3.
group of the acrylate moiety of this compound would be less electron-donating (by hyperconjugation of the C-H bonds) than the oxygen atom (by conjugation of the electron-lone pairs) on the other captodative double bond.Hence, one could expect a higher reactivity of the acrylic double bond with reagents such as cyclopentadiene (6) in Diels-Alder additions, and with heterocycles in Friedel-Crafts reactions.In contrast to this expectation, the additions to the methacrylic double bond were not observed.This might be ascribed to the following effects: (i) the inhibition of conjugation of the lone pairs of the oxygen atom in the captodative enone moiety due to the conformational preference, which impedes an efficient overlapping between these electrons and the π orbital of the double bond; 5 and (ii) the inductive electronwithdrawing effect of the enol ester. 1 It is interesting to notice that the largest coefficient in the unoccupied MOs, involving the double bonds of the enone and acrylate fragments, is found at the beta terminal carbon for both alkenes 3a and 3b, as observed for the captodative double bond of alkenes 1.
The major atomic coefficient contributions of the enone double bond (a) to the LUMO of olefins 3a and 3b, indicate that this double bond should be the one mostly involved in the Diels-Alder reaction, as experimentally observed.A similar suggestion could also be made for the chemoselectivity associated to observed in the Friedel-Crafts reaction, since the π electron density of the benzene ring, playing the role of the nucleophile (interacting through the HOMO), would react with the best Michael acceptor as the electrophile (interacting through the LUMO). 11 obvious reason can account for the slight exo stereoselectivity displayed in the cycloaddition of olefins 3 to cyclopentadiene (6), nor for the lack of significant changes on this selectivity by modifying the reaction conditions from thermal to catalytic, due to the large number of possible stabilizing and destabilizing interactions between diene and dienophile at the transition state. 6,12Therefore, we have undertaken the calculation of the transition states (TS) using the hybrid DFT method B3LYP/6-311G(d,p) for the cycloaddition of diene 6 to the enone double bond of alkenes 3a and 3b.Taking into consideration the small energy differences among the conformers of both alkenes (Table 1), and the fact that not necessarily the most stable conformers of the reactants lead to the most stable transition states, we determined eight possible transition states for each alkene.We considered only the endo and exo approaches of 6 to the face of the enone double bond opposite to the carbonyl of the ester, on the grounds that this face would be the one with the least steric interactions (Figure 2).The determination of these endo and exo transition states was carried out for each one of the four conformers of 3a and 3b.At the same time, we obtained the geometries and energies of the products derived from each one of the transition states.The results are summarized in Tables 4 and 5.
It is worth noticing that for both alkenes the most stable transition states (Tables 4 and 5) are those arising from the exo approach of 6 to the lowest-energy conformer of the captodative olefin (Figure 2), in agreement with the experimental results.In addition, the lowest-energy endo transition states also correspond to the approach of the a These are the values of the pz coefficients, the relative pz' contributions are analogous; b Energy of the HOMOs of olefins 3a and 3b, with the coefficient contributions located at the enone moiety (a).The energy and coefficients of the acrylate moiety (b) correspond to those found at the HOMO-1 orbitals; c Energies of the LUMOs of olefins 3a and 3b, with coefficient contributions located at the enone (a) moiety.The energies and coefficients of olefins 3a and 3b for the acrylate moiety (b) correspond to those found at the LUMO+1 orbitals; d For the most stable nonplanar s-cis/s-trans conformation of the (a) and (b) moieties of olefin 3a, and the s-cis/s-cis conformation of the (a) and (b) moieties of olefin 3b (Table 1).
diene to the most stable conformers of the 3a and 3b.The quasi-orthogonal conformation of the acrylate electrondonating group with respect to the enone π-plane is maintained at the transition state.The preference for the scis conformation of the enone at both endo and exo TSs has been attributed to its greater electrophilicity. 13ven though the energy differences shown in Tables 4  and 5 (∆E or ∆E 0 ) are relatively small between the exo/ endo TSs, they reflect the small ratios of the corresponding adducts 7/8 for the thermal experimental trials (Table 3, entries 1 and 11).However, there is no significant correspondence between these energy differences and the higher exo preference (exo/endo, 69:31) for dienophile 3a with respect to that found for dienophile 3b (exo/endo, 59:41), since the energy difference (∆∆E 0 ) between the lowest-energy exo and endo transition states is 0.77 kcal mol -1 stereoselectivity for 3a and 0.89 kcal mol -1 for 3b.
Analysis of the relative energies (∆E or ∆E 0 ) of all possible adducts of 7 and 8 shows that the exo adducts 7a and 7b are quite more stable than the endo adducts 8a and 8b, respectively (Tables 4 and 5).Therefore, for these cycloadditions, the major exo adducts 7 seem to be both the thermodynamic and kinetic products.
For both additions between diene 6 and olefins 3a and 3b, of the two σ bonds being formed in all endo and exo transition states, a much stronger interaction is found between carbon C-1 of the diene and the terminal carbon C-1 of the dienophile, since it presents a more developed σ bond than the σ bond between carbon C-4 of the diene and C-2 of the olefin (Figure 2), as suggested by the internuclear distances measured between these reaction centers (the internuclear distances shown in Figure 2 are very similar to those measured in all the other TSs).The slightly higher stability of the exo transition state may be the result of a delicate balance between steric and electronic interactions between the substituents of the dienophile, the methylene bridge, 8,14 and the π system of the diene. 15

Conclusions
The new bis-captodative olefin 3a and captodative olefin 3b have been prepared from biacetyl (4) and the corresponding acryloyl chlorides 5a and 5b.Highly chemoselective Diels-Alder cycloadditions and Friedel-Crafts reactions were observed when olefins 3 reacted with cyclopentadiene (6) and heterocycles 9 and 10, respectively, showing exclusive addition to the enone moiety.FMO calculations, in agreement with these experimental results, indicate a significant π contribution of the enone double bond to the LUMO, suggesting that the addition reactions should take place there, and not on the acrylic double bond of the captodative olefins 3.
The exo stereoselectivity shown by olefins 3 with diene 6 was accounted for by the lower energy calculated for the exo transition states, in comparison with the endo.Additional calculations at the ground state showed that the exo adducts 7 were also the thermodynamic products.

General
Melting points (uncorrected) were determined with an electrothermal capillary melting point apparatus.IR spectra were recorded on a Perkin-Elmer 1600 spectrophotometer. 1 H (300 MHz) and 13 C (75.4 MHz) NMR spectra were recorded on a Varian Mercury instrument, in CDCl 3 as solvent and TMS as internal standard.Mass spectra (MS) and high resolution mass spectrometry (HRMS) were obtained, in electron impact (EI) (70 eV) and fast atom bombardment (FAB) modes, on a Hewlett-Packard 5971A, and on a Jeol JMS-AX 505 HA spectrometers.Microanalyses were performed by M-H-W Laboratories (Phoenix, AZ).Analytical thin-layer chromatography was performed using E. Merck silica gel 60 F254 coated 0.25 plates, visualizing by long-and short-wavelength UV lamps.Flash column chromatography was performed on silica gel (230-400 mesh, Natland Int.).Radial chromatography was performed on a Chromatotron of Harrison Research Instruments.All air moisture sensitive reactions were carried out under nitrogen using oven-dried glassware.THF was freshly distilled from sodium, and methylene chloride from calcium hydride, prior to use.Triethylamine was freshly distilled from NaOH.All other reagents were used without further purification.

General procedure for the preparation of olefins 3a and 3b
To a solution of 5.0 mL (0.036 mol) of triethylamine in dry THF (20 mL) and HMPA (1.0 mL), at -50 °C and under an N 2 atmosphere, the acryloyl chloride 5 diluted in dry THF (10 mL) was slowly added.Then, at the same temperature, 2.41 g (0.028 mol) of butane-2,3-dione (4) diluted in dry THF (10 mL) were added dropwise.After being stirred at room temperature for 24 h, the solvent was removed under vacuum, the residue was dissolved in CH 2 Cl 2 (50 mL), and an aqueous saturated solution of NH 4 Cl (100 mL) was added.The aqueous layer was extracted with CH 2 Cl 2 (3 x 50 mL).The combined organic extracts were dried (MgSO 4 ), and the solvent was evaporated under vacuum.The residue was successively purified by flash column chromatography on silica gel (20 g, hexane/EtOAc, 95:5), and by radial chromatography (hexane/EtOAc, 95:5), to give the corresponding olefins 3a and 3b.

Theoretical Calculations
The ab initio HF/6-31G(d,p) and DFT B3LYP/6-311G(d,p) calculations were carried out using GAUSSIAN94 16 (PC-Linux).Geometries were optimized at the HF/6-31G(d,p) level, and these were employed as starting point for optimizations at the B3LYP/6-311G(d,p) level.The coefficients of the frontier molecular orbitals were obtained from the HF/6-31G(d,p) optimized geometries, considering the stability results obtained at the higher level.The transition states and adducts were characterized by vibrational frequency analyses carried out at the optimized geometries.A single imaginary vibrational frequency was obtained for all TSs.

Figure 2 .
Figure 2. B3LYP/6-311G(d,p) geometries for: The lowest-energy conformers of 3a and 3b (above); the most stable transition states for the cycloaddition of 6 to 3a and 3b (middle); the most stable adducts of the cycloaddition of 6 to 3a and 3b (below).

Table 4 .
B3LYP/6-311G(d,p) electronic energies (Ee) and electronic + zero-point energies (ZPE) (E 0 ) (au), and relative energies (∆E) (kcal mol -1 ) a of the endo and exo TSs, and of the adducts 7 and 8, for the Diels-Alder cycloadditions of olefin 3a to cyclopentadiene(6) a Relative to the most stable TS or adduct.bStereochemistry of the TS or adduct/stereochemistry of the alkene conformer (as defined in Table1).

Table 5 .
B3LYP/6-311G(d,p) electronic energies (Ee) and electronic + zero-point energies (ZPE) (E 0 ) (au), and relative energies (∆E) a (kcal mol -1 ) of the endo and exo TSs, and of the adducts 7 and 8, for the Diels-Alder cycloadditions of olefin 3b to cyclopentadiene(6) a Relative to the most stable TS or adduct; b Stereochemistry of the TS or adduct/stereochemistry of the alkene conformer (as defined in Table1).