Thermal [4 + 2] Cycloadditions of 3-Acetyl-, 3-Carbamoyl-, and 3-Ethoxycarbonyl-Coumarins with 2,3-Dimethyl-1,3-butadiene under Solventless Conditions: A Structural Study

The thermal [4+2] cycloadditions of 3-acetyl-, 3-carbamoyl, and 3-ethoxy-carbonylcoumarins with 2,3-dimethyl-1,3-butadiene under solvent free conditions are reported, as well as the epoxidation reactions of some adducts. Discussion is focused on the structural features of the Diels-Alder adducts and their epoxides, based upon NMR, X-ray, and mass spectral data, and supported by ab initio theoretical calculations.


Introduction
Coumarins are widely known to undergo pericyclic reactions like photodimerization [1]. On this topic and in the context of crystal engineering, our group has reported the solid state photodimerization of ethyl coumarin-3-carboxylate (1a) and its 6-Cl and 6-Br derivatives 1b and 1c [2]. In contrast, the use of coumarins as 2 components in Diels-Alder (DA) cycloadditions has been less studied due to OPEN ACCESS their low reactivity in these reactions. Only 3-substituted coumarins with electron-withdrawing groups like COOEt [3], NO 2 [4], SO 2 Ph, or heterocyclic rings [5], and very recently with CN [6], have been reported to undergo DA reactions under high pressure conditions.

Results and Discussion
The synthesis of the cycloadducts was performed, starting from coumarins 1-5, in a sealed glass ampoule with an excess of the diene (6 equivalents) at 160 ºC, to give the corresponding DA cycloadducts 6-10, in moderate to good yields (60-85%). The isolated yield of the adduct 6a (80%), after purification by column chromatography, is lower than that reported in CH 2 Cl 2 at high pressure [5] or under SFC in the presence of catalysts [7], but higher than that reported in water at 150 ºC (58%) [5]. The cycloadduct 7a was obtained in 85% yield, which is higher than the reported value (76%) using toluene as solvent [7].
In all cases racemic mixtures of the cis fused rings were formed, except in the case of 8a which was synthesized using enantiopure (R)-1-phenylethylamine to generate coumarin 3a. Thus, it is assumed that 8a was obtained as a 60:40 mixture of (6aS,10aS,1'R) and (6aR,10aR,1'R) diastereomers, respectively. For this mixture, two sets of signals in the 1 H-NMR spectrum are clearly observed at  5.89, 1.21 (major) and 5.82, 1.37 (minor). They are doublets assigned to the NH and CH 3 protons of the amide moiety, respectively. In the former set, the signal for the CH 3 protons appears shielded because of the effect exerted by the coumarin aromatic ring diamagnetic currents. The ab initio calculated molecular geometry of (6aS,10aS,1'R) and (6aR,10aR,1'R) diastereomers predicts that the CH 3 protons, in the former, are in the appropriate position to be shielded by diamagnetic currents of the aromatic ring, with 1.24 kcal mol -1 in favour of the (6aS,10aS,1'R) diatereomer. These results are in agreement with the preference of the diene approach to the less hindered face of the starting coumarin 3a (Figure 1). However, the asymmetric induction of the chiral amine pendant group is poor in comparison with the results obtained for bulkier 3-alkoxides [10], because of its relatively long distance from the reactive double bond. In order to test the stereofacial selectivity of the addition reaction on the cyclohexene ring, the epoxidation of compounds 6a-10a and 10d,f,i with m-chloroperbenzoic acid (m-CPBA) was performed. The reaction proceeded in moderate 70-80% (11a-15a) to very good yields 90-96% (15d,f,i). The X-ray data (vide infra) show that the oxygen atom is stereoselectively added to the less hindered face of the cyclohexene ring, opposite to the benzopyrone ring. Therefore, the racemic mixture (6aR,7aR,8aS,9aR) and (6aS,7aS, 8aR,9aS) is formed except in the case of compound 13a, which was obtained as a 60:40 mixture of diastereomers because of the presence of the amine moiety stereocentre. Thus, the original diastereomeric ratio of the starting adduct 8a is preserved (vide supra).
The molecular structure in solution was analyzed by 1 H-and 13 C-NMR, the numbering scheme is given in Figure 1. Several differences in the 1 H-NMR spectra appear as a consequence of the cycloaddition. The H-4 signal in coumarins 1-5 usually appears as a singlet between 8.0 and 8.4 ppm [11], whereas in the cycloadducts 6-10 it becomes H-10a and appears as a doublet of doublets, by coupling with H 2 -10, in the range 3.36-3.65 ppm. Irradiation of H-10a signal gave NOEs with H-1, H eq -10, and alkyl protons of the R group, confirming the cis fusion between dihydropyrone and cyclohexene rings. Besides NOE experiments, the assignments of all 1 H signals were achieved through COSY experiments. The mean values of the coupling constants of H-10a with H ax -10 (11.0-12.6 Hz) and H eq -10 (5.0-6.5 Hz), suggest a pseudo axial-axial and pseudo axial-equatorial relationship, respectively, and thus an anchored conformation for the cyclohexene ring. The nature of the carbonyl group at the 6a position exerts influence on the chemical shift of H-10a: for COOEt and COMe, H-10a appears in the range of 3.36-3.47 ppm whereas for CONHR it appears more deshielded, in the range 3.58-3.65 ppm, due to the effect of the amide mesomerism. The chemical shift of H ax -7 in the acetylated adducts 10 appears at higher field (2.04-2.38 ppm) than in the carbamoyl and ethoxycarbonyl adducts 6a-8a (2.47-2.50 ppm). This trend could be explained by a syn or anti conformational preference of the 3-CO with respect to the lactone carbonyl moiety. In compounds 6a-8a the most populated conformer on the 1 H-NMR time scale is the anti one with the 3-CO group appropriately positioned to exert a deshielding effect on H ax -7, whereas the syn conformer is the predominant form in adducts 10a-i. The chemical shift of H ax -7, in the adduct 9a, is out of range ( 2.30) because of the protective effect exerted by the phenyl ring of the 2-phenylethyl amine residue. Finally, the chemical shift of H eq -7 is in the range of 2.78 to 2.91 ppm, due to the deshielding effect of the dihydropyrone carbonyl moiety.
The change in the hybridization of C-3 and C-4 from sp 2 in coumarins 1-5 to sp 3 character in adducts 6-10 shifts the corresponding carbon atoms C-6a and C-10a, to lower frequencies, from 118-125 to 54-61 and from 147-149 to 36-37 ppm, respectively. The nature of the 3-substituent influences the chemical shift of the carbon atom carrying the substituent: thus C-6a appears in the range of 54-55 ppm for amide and ester adducts 6a-9a and at 60-61 ppm for the acetylated adducts 10a-i. The difference in chemical shifts is preserved from the starting coumarins: C-3 resonates at 118-120 ppm in compounds 1a-4a 9 and at 124-125 ppm in 5a-i.
Epoxidation changes the hybridation of C-8 and C-9 atoms from sp 2 in the cycloadducts 6-10 to sp 3 character in epoxides 11a-15a and 15d,f,i, shifting the corresponding C-7a and C-8a carbon atoms approximately by 62 ppm to lower frequencies. Subtle changes are also observed in the 1 H-NMR spectra: the oxirane methyl protons, H ax -7, and H ax -9 (these last H ax -10 before the epoxidation) are shifted to low frequencies by approximately 0.3 ppm, owing to the effect of the steric compression exerted by the new formed three-membered ring. The molecular structures of cycloadduct 10b and epoxide 15i, obtained by X-ray diffraction, are shown in Figure 2. Selected bond lengths and angles are listed in Table 1. In consequence of the transformation of C3-C4 double bond in coumarins to the single bond C6a-C10a in the adducts, this bond length enlarges by 0.18(2) Å, from 1.359(2) in 5a [12] to 1.538(3) in 10b. Epoxidation of adducts also changes the hybridation of C8 and C9 atoms enlarging C8-C9 bond length by 0.13(1) Å, in agreement with their new sp 3 character, from 1.331(3) in 10b to 1.462 (7) in 15i (C7A-C8A), respectively. Table 1. Selected bond lengths and angles from X-ray data of compounds 10b and 15i.

General methods
All chemicals and solvents were of reagent grade and used as received. Melting points were measured on an Electrothermal IA 9100 apparatus and were uncorrected. IR spectra were recorded in KBr disks using a Perkin-Elmer 16F PC IR spectrophotometer. Mass spectra were obtained in a GC/MS system (Varian) with an electron ionization mode. Elemental analyses (EA) were performed on a Perkin-Elmer 2400 elemental analyzer. 1 H-and 13 C-NMR spectra were recorded on a Varian Mercury 300 ( 1 H, 300.08; 13 C, 75.46 MHz) instrument in CDCl 3 solutions, unless otherwise specified, measured with SiMe 4 as the internal reference, are in ppm and coupling constants n J in Hz. 1 H-and 13 C-NMR assignments were achieved on the basis of NOE, COSY and HETCOR experiments. Singlecrystal X-ray diffraction data for molecules 10b and 15i were collected on a Bruker Apex II area detector diffractometer at 100 and 293 K, respectively, with Mo K radiation,  = 0.71073 Å. A semiempirical absorption correction was applied using SADABS [18], and the program SAINT [18] was used for integration of the diffraction profiles. The structures were solved by direct methods using SHELXS97 [19] program of WinGX package [20]. The final refinement was performed by full-matrix least-squares methods on F 2 with SHELXL97 [19] program. H atoms on C, N and O were positioned geometrically and treated as riding atoms, with C-H = 0.93-0.98 Å, and with Uiso(H) = 1.2Ueq(C). Mercury was used for visualization, molecular graphics and analysis of crystal structures [21], software used to prepare material for publication was PLATON [22]. Crystallographic data (excluding structure factors) for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication CCDC numbers 735605 (10b) and 721872 (15i). Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (Fax: +44-01223-336033 or E-Mail: deposit@ccdc.cam.ac.uk). Crystals suitable for X-ray analysis were obtained from saturated CHCl 3 solutions. The program GAUSSIAN98 [23] was used to perform the ab initio molecular orbital calculations at RHF-631G** level of theory.

Conclusions
The thermal reactions of ethyl coumarin-3-carboxylate (1a), 3-carboxyamides 2a-4a and 3-acetylcoumarins 5a-i with 2,3-dimethyl-1,3-butadiene under SFC yielded the corresponding DA adducts in 60 to 85%, as a racemic mixture of the cis fused rings. Poor asymmetric induction is observed when the enantiopure compound 3a was used. Epoxidation of DA cycloadducts 6a-10a proceeded in 70-80% yield, whereas starting from 10d, 10f, and 10i, the isolated yields were in the 90-96% range. NMR and X-ray data demonstrated that the oxygen atom is stereoselectively added to the less hindered face of the cyclohexene ring, opposite to the benzopyrone ring fusion. 1 H-NMR and X-ray data supported an anchored twisted boat conformation for both dihydropyrone and cyclohexene rings. Data on the supramolecular structure of DA adducts and epoxides is scarce, although it is directed by CH···A (A = O, ) and, in the case of 15i, also by Br···Br interactions.