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-ethoxycarbonylcoumarins 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.

1. 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 n class="Chemical">ethyl coumarin-3-carboxylate (1a) and its 6-Cl and 6-Br derivatives 1b and 1c [2]. In contrast, the use of coumarins as 2π components in Diels-Alder (DA) cycloadditions has been less studied due to their low reactivity in these reactions. Only 3-substituted coumarins with electron-withdrawing groups like COOEt [3], NO2 [4], SO2Ph, or heterocyclic rings [5], and very recently with CN [6], have been reported to undergo DA reactions under high pressure conditions.

The DA reaction of 1a with 2,3-dimethyl-1,3-butadiene was realized in n class="Chemical">water alone and in CH2Cl2 under 9 kbar pressure [5]. The use of HfCl4·2THF as catalyst, and solvent free conditions (SFC) significantly improve selectivity and yields [7]. However, independent results, obtained from our group, indicate that this reaction can be performed without catalyst under SFC [8]. Thus, in this work the synthesis of the (6aR,10aR)-rel-6a,7,10,10a-tetrahydro-8,9-dimethyl-6-oxodibenzo[b,d]pyran derivatives 6-10 from the DA reaction of 3-acetyl-, 3-carbamoyl-, and 3-ethoxycarbonyl-coumarins 1-5 with 2,3-dimethyl-1,3-butadiene under SFC as well as the synthesis of some of their epoxides 11-15 is reported (Scheme 1). The molecular structure of the compounds obtained is discussed on the basis of their NMR and X-ray data.

Scheme 1

Synthesis scheme and numbering.

2. 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 CH2Cl2 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 n class="Chemical">(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 1H-NMR spectrum are clearly observed at δ 5.89, 1.21 (major) and 5.82, 1.37 (minor). They are doublets assigned to the NH and CH3 protons of the amide moiety, respectively. In the former set, the signal for the CH3 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 CH3 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.

Figure 1

Calculated molecular structures of the (6aS,10aS,1’R) and (6aR,10aR,1’R) diastereomers of the cycloadduct 8a. In the former (left) the methyl protons of the chiral amine residue lie in the shielding cone of the coumarin benzenoid ring.

Calculated molecular structures of the (6aS,10aS,1’R) and (6aR,10aR,1’R) diastereomers of the cycloadduct 8a. In the former (left) the methyl protons of the chiral n class="Chemical">amine residue lie in the shielding cone of the coumarin benzenoid ring.

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 n class="Chemical">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 1H- and n class="Chemical">13C-NMR, the numbering scheme is given in Figure 1. Several differences in the 1H-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 H2-10, in the range 3.36–3.65 ppm. Irradiation of H-10a signal gave NOEs with H-1, Heq-10, and alkyl protons of the R group, confirming the cis fusion between dihydropyrone and cyclohexene rings. Besides NOE experiments, the assignments of all 1H signals were achieved through COSY experiments. The mean values of the coupling constants of H-10a with Hax-10 (11.0–12.6 Hz) and Heq-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 Hax-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 1H- NMR time scale is the anti one with the 3-CO group appropriately positioned to exert a deshielding effect on Hax-7, whereas the syn conformer is the predominant form in adducts 10a-i. The chemical shift of Hax-7, in the adduct 9a, is out of range (δ 2.30) because of the protective effect exerted by the phenyl ring of the 2-phenylethyl amine residue. Finally, the chemical shift of Heq-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 n class="Gene">C-3 and C-4 from sp in coumarins 1-5 to sp 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-4a9 and at 124–125 ppm in 5a-i.

Epoxidation changes the hybridation of C-8 and C-9 atoms from sp in the cycloadducts 6-10 to sp 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 1H-NMR spectra: the oxirane methyl protons, Hax-7, and Hax-9 (these last Hax-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 n class="Chemical">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 character, from 1.331(3) in 10b to 1.462(7) in 15i (C7A―C8A), respectively.

Figure 2

Molecular structure of cycloadduct 10b and 15i. Thermal ellipsoids drawn at the 50% probability level.

Table 1

Selected bond lengths and angles from X-ray data of compounds 10b and 15i.

Atoms	10b (X = Cl)	15i (X = Br)
Bond lengths/Å
O(5)C(6)	1.373(3)	1.364(6)
O(6)C(6)	1.190(3)	1.195(6)
C(6)C(6A)	1.526(3)	1.522(7)
C(6A)C(7)	1.536(3)	1.541(6)
C(6A)C(10A)	1.538(3)	1.551(6)
C(6A)C(13)	1.537(3)	1.527(6)
C(7)C(8)	1.509(3)
C(7)C(7A)		1.501(7)
C(8)C(9)	1.331(3)
C(7A)C(8A)		1.462(7)
C(9)C(10)	1.500(3)
C(8A)C(9)		1.505(6)
C(10)C(10A)	1.530(3)
C(9)C(9A)		1.523(6)
XC(2)a	1.742(2)	1.900(5)
Bond angles/º
C(4A)O(5)C(6)	120.94(16)	120.2(4)
C(6A)C(7)C(8)	115.64(18)	117.2(4)
C(9)C(10)C(10A)	112.61(18)
C(8A)C(9)C(9A)		113.7(4)
O(13)C(13)C(6A)	120.30(19)	121.1(5)
XC(2)C(1)a	119.68(15)	119.1(4)
Torsion angles/º
C(6)O(5)C(4A)C(10B)	20.4(3)	23.2(6)
C(7)C(6A)C(6)O(5)	166.50(17)	163.0(4)
O(5)C(6)C(6A)C(13)	74.9(2)	77.6(5)
C(6)C(6A)C(13)O(13)	15.2(3)	2.6(6)
O(13)C(13)C(6A)C(7)	104.8(2)	116.7(5)
O(8)C(9)C(10)C(10A)	23.4(3)
O(8)C(8A)C(9)C(9A)		-42.6(5)
C(10A)C(10B)C(4A)O(5)	-3.2(3)
C(9A)C(9B)C(4A)O(5)		-1.6(7)
C(7)C(8)C(9)C(10)	0.4(3)
C(7)C(7A)C(8A)C(9)		0.9(7)
C(9B)C(1)C(2)X	179.04(13)	177.9(3)

The X-ray structures of compounds 10b and 15i show that the CO of the acetyl group is pointing towards the lactone ring [C(7)C(6A)C(13)O(13) torsion angles of -104.8(2), -and -116.7(5)º for 10b and 15i, respectively. Thus, the n class="Gene">syn conformation between both carbonyls is the preferred in the solid state, the same conformational preference being observed in solution by NMR (vide supra). The torsion angles C(10A)C(10B)C(4A)O(5) (10b) and C(9A)C(9B)C(4A)O(5) (15i) in dihydropyrone ring, and C(7)C(8)C(9)C(10) (10b) and C(7)C(7A)C(8A)C(9) (15i) in cyclohexene ring, take values near to zero, in agreement with a distorted twisted boat conformation for both rings. Epoxydation has a negligible influence on the conformation of the cyclohexane ring as observed in compound 15i.

The supramolecular structure of DA adduct 10b and epoxide 15i is organized by weak CH···A (A = O, π) interactions. Nevertheless, they are scarce in comparison with those encountered in the crystal packing of the starting n class="Chemical">coumarins [12]. Thus, compound 15i is worthy to mention, since its crystal network is organized by several CH···O and Br···Br polarization-induced interactions, in the bc plane [Figure 3(a)], and CH···π bifacial contacts developing the third dimension along the (7 0 3) direction [(Figure 3(b)]. The Br···Br distance of 3.496(6) Å (symmetry code: (i) 1-x, 1-y, 2-z) is shorter than the reported value of 3.618(4) Å for 6-bromo-N-(2-hydroxyethyl)-2-oxo-2H-1-benzopyran-3-carboxamide [13]. The geometric parameters associated with non covalent interactions are listed in Table 2, C—H···O [14] and C—H···π [15] interactions are in agreement with accepted criteria and particularly with values reported for other coumarins [12,16].

Figure 3

Supramolecular structure of compound 15i. (a) View in the bc plane showing CH···O and Br···Br contacts. (b) View of bifacial CH···π contacts developing the third dimension along the (7 0 3) direction. Dashed lines represents intermolecular CH···A (A = O, π) contacts.

Table 2

Geometric parameters associated with intermolecular hydrogen interactions in compounds 10b and 15i.

Compound	D―H···A (symmetry code)	D―H/Å	H···A/Å	D···A/Å	D―H···A/°
10b	C(14)―H14B··· Cg(2) (x, y+1, z)		2.66	3.626(2)	169
	C(10)―H(10)···O(13) (x, ½-y, z+½)		2.37	3.199(2)	140
15i	C(1)―H(1)···O(8) (-x, 1-y, 1-z)	0.93	2.56	3.317(6)	139
	C(9)―H(10A)···O(8) (-x, 1-y, 1-z)	0.98	2.59	3.491(6)	153
	C(14)―H(14A)···O(8) (-x, 1-y, 1-z)	0.96	2.51	3.421(7)	160
	C(9)―H(9A)···O(6) (1-x, 2-y, 1-z)	0.97	2.51	3.428(6)	157
	C(14)―H(14C)··· Cg(3)a (x-1, y, z)		2.76	3.603(6)	147
	C(15)―H(15A)··· Cg(3)a (1-x, 2-y, 2-z)		2.92	3.764(6)	148

a Cg(3) is the centroid of the benzenoid ring (C1-C4/C4a/C9B).

The molecular peaks of 3-acetylcoumarin adducts 10 and their n class="Chemical">epoxides 15a,d,f,i are barely observed (1%) by mass spectrometry. Nevertheless all compounds are cleaved and rearranged following the typical fragmentation path depicted in Scheme 2. Cycloadducts and epoxides give the corresponding fragments, m/z 227 for 6a-10a and 243 for 11a-15a, by the loss of 3-ethoxycarbonyl, 3-carbamoyl, or 3-acetyl angular groups. The species derived from 6-10 are further broken by the loss of CO and rearranged to the 2,3-dimethyl-1,4,4a,9b-tetrahydro-dibenzofuran ion (m/z 199) or by the loss of dimethylacetylene (m/z 54) to form the oxacyclobutanaphtalene species (m/z 173). The species derived from epoxides 11-15 mainly rearrange to the corresponding dibenzofuran (m/z 225) or chromene species (m/z 211) after the loss of water or O2, respectively. Both fragmentation paths are in agreement with those found for other coumarins [17]. It is worthy to mention that retro-DA conversion was observed only in compound 10e.

Scheme 2

Typical fragmentation path of DA adducts 6a-10ai and epoxides 11a-15a-i by mass spectrometry.

3. Experimental

3.1. 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. n class="Chemical">1H- and 13C-NMR spectra were recorded on a Varian Mercury 300 (1H, 300.08; 13C, 75.46 MHz) instrument in CDCl3 solutions, unless otherwise specified, measured with SiMe4 as the internal reference, δ are in ppm and coupling constants nJ in Hz. 1H- and 13C-NMR assignments were achieved on the basis of NOE, COSY and HETCOR experiments. Single-crystal 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 Kα radiation, λ = 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 F2 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 CHCl3 solutions. The program GAUSSIAN98 [23] was used to perform the ab initio molecular orbital calculations at RHF-631G** level of theory.

3.2. General synthetic procedure for coumarins

The starting coumarins 1a-4a were n class="Gene">synthesized according with the methodology reported elsewhere [11,16,24]. 6-Substituted acetyl coumarins 5a-i were synthesized by Knoevenagel condensation of ethyl acetoacetate and the corresponding 5-substituted 2-hydroxybenzaldehyde, the spectroscopic data of 5a-d are in agreement with literature [25].

3-Acetyl-6-methoxy-2H-1-benzopyran-2-one (5e). Prepared from 0.41 mL (3.3 mmol) of 2-hydroxy-5-methoxybenzaldehyde and 0.42 mL (3.3 mmol) of ethyl acetoacetate. Yellow solid 89% yield, mp 180–183 ºC. IR ν(cm-1): 1723 (OC=O), 1677 (C=O), 1226, 1197 (C-O). 1H-NMR: 8.44 (s, 1H, H4), 7.28 (d, 1H, 3J = 9.1, H8), 7.20 (dd, 1H, 3J = 9.1, 4J = 2.9, H7), 7.02 (d, 1H, 4J = 2.6, H5), 3.85 (s, 3H, OCH3), 2.70 (s, 3H, CH3); 13C-NMR: 195.9 (CO), 159.7 (OCO), 156.6 (C6), 150.1 (C10), 147.6 (C4), 124.8 (C3), 123.2 (C7), 117.9 (C5), 118.7 (C9), 111.3 (C8), 56.1 (OCH3), 30.9 (CH3); EA (%) calculated for C12H10O4: 66.05 C, 4.62 H; found: 66.04 C, 4.61 H.

3-Acetyl-8-methoxy-2H-1-benzopyran-2-one (5f). Prepared from 0.5 g (3.3 mmol) of 2-hydroxy-3-methoxybenzaldehyde and 0.42 mL (3.3 mmol) of ethyl acetoacetate. Yellow solid, 88% yield, mp 171–174 °C. IR ν(cm-1): 1727 (OC=O), 1682 (C=O), 1278, 1197 (C-O). 1H-NMR: 8.42 (s, 1H, H4), 7.25 (d, 1H, 4J = 1.1, 3J = 5.7, H7), 7.14 (d, 1H, 4J = 2.0, 3J = 5.7, H5), 7.18 (t, 1H, 3J = 5.5, 4J = 2.0, H6), 3.94 (s, 3H, OCH3), 2.68 (s, 3H, CH3); 13C-NMR: 195.8 (CO), 158.9 (OCO), 145.1 (C10), 147.9 (C4), 147.2 (C8), 125.0 (C5), 124.8 (C3), 121.5 (C6), 116.0 (C7), 118.9 (C9), 56.5 (OCH3), 30.8 (CH3); EA (%) calculated for C12H10O4: 66.05 C, 4.62 H; found: 66.15 C, 4.60 H.

3-Acetyl-6,8-dichloro-2H-1-benzopyran-2-one (5g). Prepared from 0.5 g (2.6 mmol) of 3,5-dichlorosalicylaldehyde and 0.33 mL (2.6 mmol) of ethyl acetoacetate. White solid in 48% yield, mp 172–175 ºC. IR ν(cm-1): 1749 (OC=O), 1676 (C=O), 1217 (C-O), 769 (C-Cl). 1H-NMR: 8.37 (s, 1H, H4), 7.54 (d, 1H, 4J = 2.4, H7), 7.66 (d, 1H, 4J = 2.4, H5), 2.71 (s, 3H, CH3); 13C-NMR 194.8 (CO), 157.7 (OCO), 149.7 (C10), 145.4 (C4), 122.9 (C8), 127.8 (C5), 126.2 (C3), 130.5 (C6), 134.2 (C7), 120.1 (C9), 30.7 (CH3); EA (%) calculated for C11H6O3Cl2: 51.39 C, 2.35 H; found: 51.53 C, 2.42 H.

3-Acetyl-8-bromo-6-chloro-2H-1-benzopyran-2-one (5h). Prepared from 0.5 g (2.1 mmol) of 3-bromo-5-chloro-salicylaldehyde and 0.27 mL of ethyl acetoacetate (2.1 mmol). Yellow solid in 60% yield, mp 192–196 ºC. IR ν(cm-1): 1740 (OC=O), 1675 (C=O), 1202 (C-O), 760 (C-Cl), 556 (C-Br). 1H-NMR (DMSO-d6): 8.55 (s, 1H, H4), 8.05 (d, 1H, 4J = 2.2, H7), 8.12 (d, 1H, 4J = 2.2, H5), 2.56 (s, 3H, CH3); 13C-NMR: 195.4 (CO), 158.0 (OCO), 150.7 (C10), 146.1 (C4), 110.5 (C8), 129.8 (C5), 126.6 (C3), 129.5 (C6), 136.5 (C7), 121.1 (C9), 30.7 (CH3); EA (%) calculated for C11H6O3ClBr: 43.82 C, 2.01 H; found: 43.70 C, 2.12 H.

3-Acetyl-6-bromo-8-methoxy-2H-1-benzopyran-2-one (5i). Prepared from 0.5 g (2.2 mmol) de 5-bromo-2-hydroxy-3-methoxybenzaldehyde and 0.28 mL of ethyl acetoacetate (2.2 mmol). Yellow solid in 89% yield, mp 215–218 ºC. IR ν(cm-1): 1735 (OC=O), 1674 (C=O), 1235, 1128 (C-O), 662 (C-Br). 1H-NMR: 8.36 (s, 1H, H4), 7.24 (d, 1H, 4J = 2.1, H7), 7.34 (d, 1H, 4J = 2.1, H5), 3.96 (s, 3H, OCH3), 2.71 (s, 3H, CH3); 13C-NMR: 195.1 (CO), 158.0 (OCO), 144.0 (C10), 146.3 (C4), 147.6 (C8), 123.1 (C5), 125.5 (C3), 117.1 (C6), 118.8 (C7), 119.7 (C9), 56.5 (OCH3), 30.5 (CH3); EA (%) calculated for C12H9O4Br: 48.5 C, 3.1 H; found: 48.45 C, 2.95.

3.3. General synthetic procedure for DA adducts

1 mmol (typically 100–300 mg) of the corresponding coumarin 1-5 and the appropriate volume equivalent to 6 mmol of n class="Chemical">2,3-dimethyl-1,3-butadiene (typically 0.3–1.0 mL) were placed in a glass ampoule; the sealed ampoule was placed inside a metallic capsule and heated in a sand bath at 160 ºC for a period of 24 hours. The ampoule content was dissolved in CHCl3 and evaporated to dryness. The resultant solid was washed with hot hexane and the insoluble solid was purified by CC in SiO2–gel, using CHCl3 as eluent. Cycloadducts 6a [5], 7a [9] are reported elsewhere.

(6aR,10aR)- and (6aS,10aS)-N-[(R)-1-Phenylethyl]-6a,7,10,10a-tetrahydro-8,9-dimethyl-6-oxo-dibenzo[b,d]pyran-6a-carboxamide (8a). White crystalline solid in 77% yield, mp 168.9–171.4 °C. IR/ν (cm-1): 3312 (NH), 1784 (OC=O), 1629 (NC=O), 1532 (C=C), 1222 (N-C), 1146 (C-O). 1H- NMR: 7.30 (m, 1H, H3), 7.26 (t, 2H, 3J = 7.3 and 7.7, Hm), 7.13 (t, 1H, 3J = 7.3, Hp), 7.14 (d, 2H, 3J = 7.3, Ho), 7.07 (t, 1H, 3J = 8.1 and 8.4, H2), 7.00 (d, 1H, 3J = 8.1, H1), 6.83 (dd, 1H, 3J = 5.3, 4J = 2.2, H4), 5.89, 5.82 (d, 1H each, 3J = 7.5, N-H), 4.88 (dq, 1H, 3J = 7.3, CH3), 3.58 (m, 1H, H10a), 2.90 (t, 1H, 3J = 18.3, Heq-7), 2.49 (d, 1H, 3J = 17.4, Hax-7), 2.32 (t, 1H, 3J = 18.7 and 12.3, Heq-10), 2.02 (m, 1H, Hax-10), 1.67, 1.60 (s, 3H each, 2CH3), 1.37, 1.21 (d, 3H, 3J = 7.0, CH3); 13C-NMR: 170.6, 170.5 (NCO), 167.6, 167.4 (OCO), 150.2 (C4a), 142.5, 142.2 (Ci), 129.0 (C3), 128.7, 128.6 (Cm), 128.5, 128.4 (C1), 128.1 (C10b), 128.0, 127.7 (C2), 127.4, 126.1 (Cp), 125.5, 125.7 (Co), 123.5, 123.6 (C9), 123.2, 123.3 (C8), 116.8, 116.7 (C4), 55.0, 54.8 (C6a), 49.5, 49.2 (NCH), 37.0, 36.9 (C7), 36.8, 36.8 (C10), 36.3 (C10a), 21.6, 21.4 (CH3CH), 18.8, 18.8 (CH3); GC/MS m/z (%): 375 (M+, 24), 281 (38), 227 (100), 211 (5), 199 (3), 105 (29), 79 (12), 44 (5).

(6aR,10aR)-rel-N-(2-Phenylethyl)-6a,7,10,10a-tetrahydro-8,9-dimethyl-6-oxodibenzo[b,d]pyran-6a-carboxamide (9a). White crystalline powder in 84% yield, mp 138.6–140.0 °C. IR/ν (cm-1): 3333 (NH), 1771 (OC=O), 1634 (NC=O), 1546 (C=C), 1222 (C–O), 1144 (C–N). 1H-NMR: 7.25 (t, 2H, 3J = 7.3, Hm), 7.27 (d, 1H, 3J = 7.3, H1), 7.21 (dt, 1H, 7.0 Hz, H3), 7.11 (ddt, 1H, 3J = 7.2 and 7.7, 4J = 1.3, H2), 7.05 (dd, 2H, 3J = 7.1, Ho), 7.00 (dd, 1H, 3J = 7.5, H4), 5.79 (t, 1H, 3J = 5.4, NH), 3.58 (dd, 1H, 3J = 11.7 and 11.7, H10a), 3.34 (dt, 2H, 3J = 7.2 and 7.2, 4J = 2.0, NCH2), 2.79 (d, 1H, 3J = 17.1, Heq-7), 2.61 (m, 2H, CH2), 2.30 (d, 1H, 3J = 16.7, Hax-7), 2.26 (d, 1H, Heq-10), 2.00 (dd, 1H, 3J = 15.5 and 12.0, Hax-10), 1.58, 1.65 (s, 3H, 2CH3); 13C-NMR: 170.4 (NC=O), 168.4 (OC=O), 150.0 (C4a), 138.4 (Ci), 129.0 (C10b), 128.9 (Co,m), 128.6 (Cp), 128.4 (C3), 127.9 (C1), 126.8 (C3), 125.4 (C2), 123.7 (C9), 123.1 (C8), 116.8 (C4), 41.3 (NCH2), 37.3 (C7), 36.5 (C10a), 36.3 (C13), 35.5 (CH2), 18.8, 18.7 (CH3); GC/MS m/z (%): 375 (M+, 20), 227 (100), 199 (3), 173 (7); EA (%) calculated for C24H25O3N: 76.77 C, 6.71 H, 3.73 N; found: 76.70C, 6.72 H, 3.82 N.

(6aR,10aR)-rel-6a-Acetyl-6a,7,10,10a-tetrahydro-8,9-dimethyl-6-oxodibenzo[b,d]pyran (10a). White crystalline powder in 83% yield, mp 86–88 ºC. IR/ν(cm-1): 1763 (OC=O), 1702 (C=O), 1159, 1140 (C-O). 1H-NMR: 7.25 (m, 1H, H3), 7.22 (dd, 1H, 3J = 12.1, 4J = 1.8, H1), 7.10 (td, 1H, 3J = 7.3, 4J = 1.2, H2), 7.03 (dd, 1H, 3J = 7.9, 4J = 1.1, H4), 3.47 (dd, 1H, 3J = 11.2 and 11.4, H10a), 2.87 (d, 1H, 3J = 17.3, Heq-7), 2.31 (dd, 1H, 3J = 18.0, Hax-7), 2.24 (d, 1H, 3J = 12.0, Heq-10), 2.12 (s, 3H, CH3), 2.06 (dd, 1H, Hax-10), 1.70, 1.62 (s, 3H, CH3); 13C-NMR 204.1 (CO), 168.6 (OCO), 150.4 (C4a), 128.9 (C3), 127.6 (C1), 127.5 (C10b), 125.1 (C2), 123.5 (C9), 122.8 (C8), 117.2 (C4), 60.6 (C6a), 36.8 (C10a), 35.9 (C10), 34.8 (C7), 26.2 (C14), 18.8, 18.9 (CH3); GC/MS m/z (%): 270 (M+, 4), 227 (100), 199 (8), 185 (7), 173 (10), 43 (22); EA (%) calculated for C17H18O3: 75.53 C, 6.73 H; found: 75.50, 6.70 H.

(6aR,10aR)-rel-6a-Acetyl-2-chloro-6a,7,10,10a-tetrahydro-8,9-dimethyl-6-oxodibenzo[b,d]pyran (10b). Pale yellow solid in 50% yield, mp 102–106 ºC. IR/ν(cm-1): 1781 (OC=O), 1699 (C=O), 1212, 1139 (C-O), 814 (C-Cl). 1H-NMR: 7.27 (dd, 1H, 3J = 8.0, 4J = 1.98, H3), 7.19 (d, 1H, 4J = 2.0, H1), 6.94 (d, 1H, 3J = 8.0 Hz, H4), 3.43 (dd, 1H, 3J = 6.2, 11.3, H10a), 2.86 (d, 1H, 2J = 16.0, Heq-7), 2.28 (dd, 1H, 2J = 18.3, 3J = 6.2, Heq-10), 2.13 (d, 1H, 2J = 16.0, Hax-7), 2.11 (s, 3H, H14), 2.02 (dd, 1H, 2J = 18.3, 3J = 11.3, Hax-10), 1.67 (s, 3H, CH3), 1.59 (s, 3H, CH3); 13C-NMR: 203.5 (CO), 167.9 (OCO), 148.9 (C4a), 130.1 (C10b), 129.3 (C2), 128.8 (C3), 127.6 (C1), 123.8 (C9), 122.9 (C8), 118.5 (C4), 60.2 (C6a), 36.6 (C10a), 35.7 (C10), 34.8 (C7), 26.3 (C14), 18.8, 18.9 (CH3); GC/MSm/z (%): 306 (M+, 1), 261 (100), 233 (11), 219 (11), 207 (10), 165 (5), 70 (7), 43 (26); EA (%) calculated for C17H17O3Cl-0.4H2O: 65.45 C, 5.75 H; found 65.58 C, 5.79 H.

(6aR,10aR)-rel-6a-Acetyl-2-bromo-6a,7,10,10a-tetrahydro-8,9-dimethyl-6-oxodibenzo[b,d]pyran (10c). Pale yellow solid in 55% yield, mp 50–54 °C. IR/ν(cm-1): 1773 (OC=O), 1711 (C=O), 1205, 1138 (C-O), 821 (C-Br). 1H-NMR: 7.30 (dd, 1H, 3J = 7.2, 4J = 1.7, H3), 7.27 (d, 1H, 4J = 1.7 Hz, H1), 6.86 (d, 1H, 3J = 7.2, H4), 3.41 (dd, 1H, 3J = 6.4, 11.4 Hz, H10a), 2.83 (d, 1H, 2J = 16.8, Heq-7), 2.14 (dd, 1H, 2J = 16.9, 3J = 11.4, Heq-10), 2.09 (s, 3H, H14), 2.04 (d, 1H, 2J = 16.9, Hax-7), 1.92 (dd, 1H, 2J = 16.8, 3J = 6.4, Hax-10), 1.57 (s, 3H, CH3), 1.66 (s, 3H, CH3);13C-NMR: 203.6 (CO), 167.9 (OCO), 149.4 (C4a), 130.4 (C1), 131.8 (C3), 129.6 (C2), 123.4 (C9), 122.8 (C8), 118.9 (C4), 117.7 (C10b), 60.3 (C6a), 36.5 (C10a), 35.7 (C10), 34.7 (C7), 26.2 (C14), 18.8, 18.9 (CH3); GC/MS m/z (%): 348 (M+, 1), 305 (100), 277 (5), 251 (6), 198 (10), 165 (10), 43 (58); EA (%) calculated for C17H17O3Br: C 58.47 C, 4.91 H; found: C 58.43 C, 4.82 H.

(6aR,10aR)-rel-6a-Acetyl-6a,7,10,10a-tetrahydro-8,9-dimethyl-2-nitro-6-oxodibenzo[b,d]pyran (10d). Pale yellow powder in 81% yield, mp 142–147 C. IR/ν(cm-1): 1782 (OC=O), 1726 (C=O), 1525 (NO2), 1339, 1230 (C-O). 1H-NMR: 8.16 (d, 1H, 4J = 2.5, H1), 8.14 (dd, 1H, 3J = 9.3, 4J = 2.5, H3), 7.15 (d, 1H, 3J = 9.3, H4), 3.60 (dd,1H, 3J = 6.4, 11.1, H10a), 2.90 (d, 1H, 2J = 17.3, Heq-7), 2.38 (d, 1H, 2J = 17.3, Hax-7), 2.27 (dd, 1H, 2J = 16.7, 3J = 6.2, Heq-10), 2.15 (s, 3H, H14), 2.05 (dd, 1H, 2J = 16.7, 3J = 11.1, Hax-10), 1.62 (s, 3H, CH3), 1.71 (s, 3H, CH3); 13C-NMR: 202.7 (CO), 166.9 (OCO), 154.7 (C4a), 144.6 (C2), 128.9 (C10b), 124.8 (C3), 123.6 (C1), 123.3 (C9), 122.9 (C8), 118.1 (C4), 60.1 (C6a), 36.5 (C10a), 35.6 (C10), 34.6 (C7), 26.1 (C14), 18.8, 18.9 (CH3); GC/MS m/z (%): 315 (M+, 1), 272 (100), 244 (8), 230 (8), 218 (8), 204 (6), 67 (7), 43 (25); EA (%) calculated for C17H17O5N: 64.75 C, 5.43 H, 4.44 N; found 65.10 C, 5.65 H, 4.20 N.

(6aR,10aR)-rel-6a-Acetyl-6a,7,10,10a-tetrahydro-2-methoxy-8,9-dimethyl-6-oxodibenzo[b,d]pyran (10e). Pale yellow solid in 55% yield, m.p 44–46 ºC. IR/ν(cm-1): 1761 (OC=O) 1710 (C=O) 1190, 1147 (C-O). NMR: 1H-NMR: 6.89 (d, 1H, 4J = 3.5, H1), 6.87 (d, 1H, 3J = 6.5, H4), 6.68 (dd, 1H, 3J = 6.5, 4J = 3.2, H3), 3.71 (s, 3H, OCH3), 3.36 (dd,1H, 3J = 6.5, 11.0, H10a), 2.78 (d, 1H, 2J = 16.7, Heq-7), 2.19 (dd, 1H, 2J = 18.2, 3J = 6.5, Heq-10), 2.06 (s, 3H, H14), 2.09 (d, 1H, 2J = 16.7, Hax-7), 2.00 (dd, 1H, 2J = 18.2, 3J = 11.0, Hax-10), 1.59 (s, 3H, CH3), 1.63 (s, 3H, CH3); 13C-NMR: 203.7 (CO), 168.3 (OCO), 156.2 (C2), 143.8 (C4a), 128.0 (C3), 123.0 (C9), 122.4 (C8), 117.5 (C1), 113.2 (C10b), 112.3 (C4), 60.0 (C6a), 55.4 (OCH3), 36.7 (C10a), 35.4 (C10), 34.4 (C7), 25.9 (C14), 18.4, 18.5 (CH3); GC/MS m/z (%): 300 (M+, 1), 218 (80), 190 (5), 175 (15); EA (%) calculated for C18H20O4: 71.98 C, 6.71 H; found: 71.91 C, 6.65 H.

(6aR,10aR)-rel-6a-Acetyl-6a,7,10,10a-tetrahydro-4-methoxy-8,9-dimethyl-6-oxodibenzo[b,d]pyran (10f). Pale yellow powder 85% yield, mp 115–119 ºC. IR ν(cm-1): 1769 (OC=O), 1706 (C=O), 1196, 1095 (C-O). 1H-NMR: 7.03 (dd, 1H, 3J = 8.4, 7.7 H2), 6.82 (d, 1H, 3J = 8.4, Hz, H1), 6.78 (d, 1H, 3J = 7.7, H3), 3.85 (s, 3H, OCH3), 3.44 (dd, 1H, 3J = 6.4, 11.4, H10a), 2.88 (d, 1H, 2J = 16.7, Heq-7), 2.21 (dd, 1H, 2J = 18.2, 3J = 6.4, Heq-10), 2.12 (s, 3H, H14), 2.11 (d, 1H, 2J = 16.7, Hax-7), 2.03 (dd, 1H, 2J = 18.5, 3J = 11.4, Hax-10), 1.68 (s, 3H, CH3),1.59 (s, 3H, CH3); 13C-NMR: 203.9 (CO), 167.9 (OCO), 147.8 (C10), 139.9 (C8), 128.7 (C9), 125.2 (C6), 123.5 (C9), 122.8 (C8), 119.1 (C7), 111.6 (C5), 60.4 (C6a), 56.2 (OCH3), 36.9 (C10a), 35.8 (C10), 34.9 (C7), 26.4 (C14), 18.8, 18.9 (CH3); GC/MS m/z (%): 300 (M+, 1), 257 (100), 229 (7), 203 (8), 105 (2), 105 (2), 91 (4), 77 (4), 43 (17); EA (%) calculated for C18H20O4: 71.98 C, 6.71 H; found: 72.25 C, 6.80 H.

(6aR,10aR)-rel-6a-Acetyl-2,4-dichloro-6a,7,10,10a-tetrahydro-8,9-dimethyl-6-oxodibenzo[b,d]pyran (10g). Pale yellow powder in 71% yield, mp 148–151 ºC. IR/ν(cm-1): 1787 (OC=O), 1703 (C=O), 1233, 1192 (C-O), 810 (C-Cl). 1H-NMR: 7.28 (d, 1H, 4J = 2.4, H3), 7.11 (d, 1H, 4J = 2.4, H1), 3.47 (dd, 1H, 3J = 6.2, 11.5, H10a), 2.89 (d, 1H, 2J = 17.0, Heq-7), 2.28 (dd, 1H, 2J = 17.9, 3J = 6.2, Heq-10), 2.17 (d, 1H, 2J = 18.7, Hax-7), 2.14 (s, 3H, H14), 1.97 (dd, 1H, 2J = 18.9, 3J = 9.3, Hax-10), 1.69 (s, 3H, CH3), 1.59 (s, 3H, CH3); 13C-NMR: 202.8 (CO), 166.8 (OCO), 144.9 (C4a), 130.7 (C4), 130.1 (C2), 129.2 (C3), 126.1 (C1), 123.3 (C9), 122.9 (C8), 60.1 (C6a), 36.9 (C10a), 35.5 (C10), 34.9 (C7), 26.5 (C14), 18.8, 18.9 (CH3); GC/MSm/z (%): 339 (M+, 1), 296 (100), 268 (9), 253 (12), 241 (12), 232 (9), 91 (5), 67 (8), 43 (37); EA (%) calculated for C17H16O3Cl2: 60.19 C, 4.75 H; found 60.15 C, 4.85 H.

(6aR,10aR)-rel-6a-Acetyl-4-bromo-2-chloro-6a,7,10,10a-tetrahydro-8,9-dimethyl-6-oxodibenzo[b,d]pyran (10h). Pale yellow powder in 62% yield, mp 152–155 ºC. IR ν(cm-1): 1785 (OC=O), 1703 (C=O), 1232, 1131 (C-O), 787 (C-Cl), 524 (C-Br). 1H-NMR: 7.45 (d, 1H, 4J = 2.4, H1), 7.15 (d, 1H, 4J = 2.4, H3), 3.46 (dd,1H, 3J = 6.4, 11.4, H10a), 2.89 (d, 1H, 2J = 17.1, Heq-7), 2.31 (dd, 1H, 2J = 17.6, 3J = 6.4, Heq-10), 2.19 (d, 1H, 2J = 16.9, Hax-7), 2.14 (s, 3H, H14), 1.99 (dd, 1H, 2J = 17.6, 3J = 11.4, Hax-10), 1.69 (s, 3H, CH3), 1.60 (s, 3H, CH3); 13C-NMR: 202.8 (CO), 166.9 (OCO), 146.1 (C4a), 132.0 (C3), 130.6 (C2), 130.4 (C4), 126.8 (C1), 123.3 (C9), 122.9 (C8), 111.4 (C10b), 60.1 (C6a), 37.0 (C10a), 35.5 (C10), 34.9 (C7), 26.6 (C14), 18.8, 18.9 (CH3); GC/MSm/z (%): 384 (M+, 1), 341 (100), 325 (5), 313 (6), 287 (10), 232 (15), 67 (16), 43 (27); EA (%) calculated for C17H16O3ClBr: 53.22 C, 4.2 H; found 53.60 C, 4.25 H.

(6aR,10aR)-rel-6a-Acetyl-2-bromo-6a,7,10,10a-tetrahydro-4-methoxy-8,9-dimethyl-6-oxodibenzo-[b,d]pyran (10i). Pale yellow powder in 83% yield, mp 160–164 ºC. IR/ν(cm-1): 1769 (OC=O), 1706 (C=O), 1275, 1196 (C-O), 506 (C-Br). 1H-NMR: 6.94 (s, 1H, H1), 6.94 (s, 1H, H3), 3.84 (s, 3H, OCH3), 3.41(dd, 1H, 3J = 6.2, 11.3, H10a), 2.88 (d, 1H, 2J = 16.9, Heq-7), 2.36 (dd, 1H, 2J = 17.0, 3J = 6.2, Heq-10), 2.18 (d, 1H, 2J = 16.9, Hax-7), 2.13 (s, 3H, H14), 1.97 (dd, 1H, 2J = 17.0, 3J = 11.3, Hax-10), 1.68 (s, 3H, CH3), 1.59 (s, 3H, CH3); 13C-NMR: 203.4 (C=O), 167.4 (OCO), 148.4 (C4a), 138.5 (C4), 130.3 (C2), 123.4 (C9), 122.8 (C8), 121.9 (C3), 117.6 (C10b), 114.9 (C1), 60.2 (C6a), 56.5 (s, 3H, OCH3), 36.7 (C10a), 35.6 (C10), 34.9 (C7), 26.4 (C14), 18.8, 18.8 (CH3); GC/MS m/z (%): 380 (M+, 1), 337 (100), 309 (4), 283 (8), 256 (8), 228 (14), 115 (5), 91 (5), 43 (31); EA (%) calculated for C18H19O4Br: 57.01 C, 5.05 H; found 57.20 C, 5.06 H.

3.4. General synthetic procedure for epoxides

Prepared from 200 mg of compounds 6-10 and two equivalents of m-CPBA dissolved in CHCl3 (25 mL) and refluxed for 24 h. The CHCl3 solution was extracted with an aqueous saturated NaHCO3 solution. The organic layer was dried with Na2SO4, then filtered and concentrated.

Ethyl (6aR,7aR,8aS,9aR)-rel-6a,7,7a,8a,9,9a-hexahydro-7a,8a-dimethyl-6-oxo-5,8-dioxacyclopropa-[b]phenantrene-6a(6H)-carboxylate (11a). White crystalline solid in 73% yield, mp 79.8–82.5 °C. IR/ν (cm-1): 1772 (OC=O), 1735 (EtOC=O), 1248, 1230, 1150 (C-O). 1H-NMR: 7.19 (ddd, 1H, 3J = 7.7, 7.7, 4J = 1.8 Hz, H3), 7.09 (dd, 1H, 3J = 7.5, 4J = 1.8, H1), 7.03 (dd, 1H, 3J = 7.5, 4J = 1.1, H2), 6.98 (d, 1H, 3J = 8.6, H4), 3.87 (m, 2H, OCH2), 3.36 (dd, 1H, 3J = 12.4 and 5.5, H9a), 2.83 (d, 1H, 3J = 15.2, Heq-7), 2.24 (d, 1H, 3J = 15.4, Hax-7), 2.21 (dd, 1H, 3J = 10.3 and 5.5, Heq-9), 1.60 (dd, 1H, 3J = 15.6 and 12.5, Hax-9), 1.40, 1.24 (s, 3H c/u, 2CH3), 0.83 (t, 3H, CH3-CH2). 13C-NMR: 169.9 (OCO), 167.4 (OCO lactone), 150.9 (C4a), 129.1 (C1), 127.8 (C3), 126.4 (C9b), 125.1 (C2), 117.0 (C4), 62.3 (CH2-O), 61.7 (C8a), 60.3 (C7a, 53.3 (C6a), 35.6 (C9a), 34.5 (C9), 34.4 (C7), 21.0 (CH3-C8a), 19.2 (CH3-C7a), 13.9 (CH3-CH2); GC/MS m/z (%): 316 (M+, 2), 259 (38), 243 (100), 225 (50), 214 (34), 199 (24), 145 (11), 115 (17), 91 (6), 43 (52); EA (%) calculated for C18H20O5: 68.34 C, 6.37 H; found: 68.35 C, 6.32 H.

(6aR,7aR,8aS,9aR)-rel-N-benzyl-6a,7,7a,8a,9,9a-hexahydro-7a,8a-dimethyl-6-oxo-5,8-dioxacyclo-propa[b]phenantrene-6a(6H)-carboxamide (12a). White crystalline solid in 78% yield, mp 205.4–207 °C. IR/ν (cm-1): 3342 (NH), 1773 (OC=O), 1637 (NC= O), 1538 (C=C), 1234 (C-O), 1152 (C-N). 1H- NMR: 7.27 (m, 1H, H3), 7.21 (m, 5H, 5H-C6H5), 7.12 (t, 1H, 3J =7.4, H6), 7.01 (d, 1H, 3J = 8.0, H5), 6.82 (m, 1H, H4), 5.82 (t, 1H, NH), 4.22 (m, 2H, AA’BB’, NCH2), 3.52 (dd, 1H, 2J = 12.5, 3J = 5.3, H9a), 2.94 (d, 1H, 2J = 15.5, Heq-7), 2.32 (dd, 1H, 2J = 15.5, 3J = 5.2, Heq-9), 2.27 (d, 1H, 2J = 15.5, Hax-7), 1.69 (dd, 1H, 2J = 15.6, 3J = 12.7, Hax-9), 1.43 (s, 3H, CH3), 1.30 (s, 3H, CH3); 13C-NMR: 169.4 (NCO), 168.0 (OCO lactone), 150.3 (C4a), 137.4 (Ci), 128.9 (C-m and C1), 128.0 (C3), 127.8 (Cp), 127.5 (Co), 127.0 (C9b), 125.6 (C2), 117.0 (C4), 61.8 (C8a), 60.5 (7a), 54.6 (C6a), 43.9 (NCH2), 36.0 (C9a), 35.7 (C9), 34.7 (C8a), 21.0 (CH3-C8a), 19.1 (CH3-C7a); GC/MS m/z (%): 377 (M+, 2), 318 (10), 243 (40), 227 (15), 225 (30), 211 (32), 199 (8), 173 (8), 150 (100), 131 (10), 91 (95), 43 (30); EA (%) calculated for C23H23O4N: 73.19 C, 6.14 H; found: 73.09 C, 6.14 H.

(6aR,7aR,8aS,9aR)- and (6aS,7aS,8aR,9aS)-6a,7,7a,8a,9,9a-hexahydro-7a,8a-dimethyl-6-oxo-N-[(R)-1-phenylethyl]-5,8-dioxacyclopropa[b]phenantrene-6a(6H)-carboxn class="Chemical">amide (13a). White crystalline powder in 78% yield, mp 163.9–165.0 °C; IR ν (cm-1): 3256 (NH), 1759 (OC=O), 1638 (NC=O), 1230, 1161, 1151 (C-O); GC/MS m/z (%) 391 (M+, 4), 332 (15), 243 (58), 227 (28), 225 (35), 211 (42), 199 (8), 173 (15), 105 (100), 43 (20). Minor (6aR,7aR,8aS,9aR) isomer 13a: 1H-NMR: 7.3–6.9 (m, 9H, ArH), 5.67 (d, 1H, 3J = 1.5, NH), 3.48 (dd, 1H, 3J = 5.1, 3J = 12.0, H9a), 2.92 (dd, 1H, 2J = 15.4, Heq-7), 2.27 (d, 1H, 2J = 15.6, Hax-7), 2.29 (m, 1H, Heq-9), 1.68 (dd, 1H, 2J = 15.6, 3J = 5.6, Hax-9), 4.84 (dq, 1H, 3J = 6.9, CHCH3), 1.43 and 1.30 (two s, 2 × 3H, 7a- and 8a-CH3), 1.26 (d, 3H, 3J = 7.0, CHCH3); 13C-NMR: 169.6 (NCO), 167.1 (C-6), 150.3 (C-4a), 142.0 (C-1’), 128.8 (C-3’,5’), 128.0 (C-1), no (C-3), 127.6 (C-9b), 127.0 (C-4’), 125.9 (C-2’,6’), 125.5 (C-2), 117.0 (C-4), 61.8 (C-8a), 60.6 (C-7a), 54.6 (C-6a), 49.1 (NCH), 35.9 (C-9a), 34.9 (C-9), 34.8 (C-7), 21.1, 21.0, and 19.1 (3 × CH3). Major (6aS,7aS,8aR,9aS) isomer 13a: 1H-NMR: 7.3–6.9 (m, 9H, ArH), 5.71 (d, 1H, 3J = 1.5, NH), 3.44 (dd, 1H, 3J = 5.1, 3J = 12.0, H-9a), 2.90 (dd, 1H, 2J = 15.4, Heq-7), 2.19 (d, 1H, 2J = 15.6, Hax-7), 2.29 (m, 1H, Heq-9), 1.68 (dd, 1H, 2J = 15.6, 3J = 5.6, Hax-9), 4.83 (dq, 1H, 3J = 6.9, CHCH3), 1.42 and 1.29 (two s, 2 × 3H, 7a- and 8a-CH3), 1.22 (d, 3H, 3J = 7.0, CHCH3); 13C-NMR: 169.3 (NCO), 167.1 (C-6), 150.4 (C-4a), 142.1 (C-1’), 129.0 (C-3’,5’), no (C-1), 127.9 (C-3), 127.7 (C-9b), 126.8 (C-4’), 126.1 (C-2’,6’), 125.5 (C-2), 117.0 (C-4), 61.8 (C-8a), 60.6 (C-7a), 54.5 (C-6a), 49.2 (NCH), 36.0 (C-9a), 35.5 (C-9), 34.8 (C-7), 21.1, 21.0, and 19.1 (3 × CH3).

(6aR,7aR,8aS,9aR)-rel-6a,7,7a,8a,9,9a-Hexahydro-7a,8a-dimethyl-6-oxo-N-(2-phenylethyl)-5,8-dioxacyclopropa[b]phenantrene-6a(6H)-carboxamide (14a). White crystalline powder in 78% yield, mp 189.4–191.6 °C. IR/ν (cm-1): 3322 (NH), 1789 (OC=O), 1640 (CONH), 1146 y 1129 (C-O). 1H- NMR: 7.25(m, 5H, Ph), 7.15 (dd, 1H, 3J = 7.4, 4J = 1.9, H3), 7.10 (dd, 1H, 3J = 7.4, 4J = 1.2, H2), 7.03 (d, 1H, 3J = 6.7, H1), 7.00 (d, 1H, 3J = 8.1, H4), 5.54 (a, 1H, NH), 3.48 (dd, 1H, 3J = 5.2, 3J = 12.6, H9a), 3.29 (q, 2H, 3J = 7.2, NCH2), 2.81 (d, 1H, 3J =5.5, Heq-7), 2.56 (t, 2H, 3J = 7.2, CH2), 2.28 (dd, 1H, 3J = 5.2, 2J = 15.7, Heq-9), 2.11 (d, 1H, 3J = 15.7, Hax-7), 1.65 (dd, 1H, 3J = 5.5 Hz, 3J= 12.6, Hax-9), 1.40, 1.29 (s, 3H c/u, 2CH3); 13C-NMR: 169.5 (NCO), 167.9 (OCO), 150.2 (C4a), 138.3 (Ci), 128.9 (Cm), 128.9 (Co), 128.8 (C1), 127.9 (C3), 126.9 (Cp), 125.7 (C2), 116.9 (C4), 127.1 (C9b), 61.8 (C8a), 60.5 (C7a), 54.4 (C6a), 41.2 (NCH2), 36.0 (CH2), 35.9 (C9a), 35.4 (C9), 34.5 (C7), 21.0 (CH3C8a), 19.1 (CH3C7a); GC/MS m/z (%) 391 (M+, 8), 332 (20), 243 (100), 227 (43), 225 (95), 211 (68), 173 (43); EA (%) calculated for C24H25O4N: 73.64 C, 6.44 H, 3.58 N; found: 73.27 C, 6.24 H, 3.44 N.

(6aR,7aR,8aS,9aR)-rel-6a-Acetyl-6a,7,7a,8a,9,9a-hexahydro-7a,8a-dimethyl-6-oxo-6H-5,8-dioxacyclopropa[b]phenantrene (15a). White crystalline powder in 70% yield, mp 125.6–126.9 °C. IR/ν (cm-1): 1772 (OC=O), 1699 (C=O), 1300, 1258, 1150 (C-O). 1H-NMR: 7.25 (dd, 1H, 3J = 7.6, 7.4, H2), 7.16 (d, 3J = 7.6, H1), 7.09 (dd, 1H, 3J= 7.4, 8.1, H3), 7.02 (d, 1H, 3J = 8.1, H4), 3.45 (dd, 1H, 3J = 12.2, 5.0, H9a), 2.83 (d, 1H, 2J = 15.0, Heq-7), 2.31 (dd, 1H, 2J = 15.4, 3J = 5.0, Heq-9), 2.08 (d, 1H, 2J = 15.0, Hax-7), 2.02 (s, 3H, CH3O), 1.68 (dd, 1H, 2J = 15.4, 3J = 12.2, Hax-9), 1.45, 1.31 (s, 3H c/u, 2CH3); 13C-NMR: 203.5 (COCH3), 170.4 (OCO), 150.6 (C4a), 134.9 (C9b), 130.5 (C1), 128.5 (C2), 125.4 (C3), 117.4 (C4), 62.0 (C8a), 60.4 (C7a), 60.3 (C6a), 35.9 (C9a), 34.3 (C9), 33.2 (C7), 25.5 (CH3CO), 21.0 (CH3C8a), 19.2 (CH3C7a); GC/MS m/z (%): 286 (M+, 1), 243 (16), 225 (28), 211 (100), 184 (14), 114 (17), 91 (9), 43 (60); EA (%) calculated for C17H18O4: 71.31 C, 6.34 H; found: 71.28 C, 6.44 H.

(6aR,7aR,8aS,9aR)-rel-6a-Acetyl-6a,7,7a,8a,9,9a-hexahydro-7a,8a-dimethyl-2-nitro-6-oxo-6H-5,8-dioxacyclopropa[b]phenantrene (15d). White solid in 96% yield, mp 216–220 °C. IR/ν(cm-1): 1786 (OC=O), 1700 (C=O), 1526 (NO2), 1338, 1237, 1142 (C-O). 1H-NMR: 8.18 (dd, 1H, 4J = 2.6, 3J = 8.8, H3), 8.15 (d, 1H, 4J = 2.6, H1), 7.18 (d, 1H, 3J = 8.8, H4), 3.63 (dd, 1H, 3J = 5.2, 12.1, H9a), 2.89 (d, 1H, 2J = 15.5, Heq7), 2.38 (dd, 1H, 2J = 15.5, 3J = 5.2, Heq-9), 2.15 (d, 1H, 2J = 15.5, Hax-7), 2.09 (s, 3H, H14), 1.70 (dd, 1H, 2J = 15.5, 3J = 12.1, Hax-9), 1.35 (s, 3H, CH3), 1.48 (s, 3H, CH3); 13C-NMR: 202.2 (CO), 166.8 (OCO), 154.8 (C4a), 144.7 (C2), 127.4 (C9b), 125.2 (C3), 123.6 (C1), 118.2 (C4), 61.6 (C6a), 60.0 (C8a), 59.9 (C7a), 35.6 (C9), 34.2 (C9a), 32.9 (C7), 25.4 (C14), 20.9, 19.0 (CH3); GC/MS m/z (%): 331 (M+, 1), 288 (19), 256 (100), 230 (26), 115 (5), 91 (4), 43 (78); EA (%) calculated for C17H17O6N: 61.63 C, 5.17 H, 4.23 N; found: 61.44 C, 5.25 H, 4.14 N.

(6aR,7aR,8aS,9aR)-rel-6a-Acetyl-6a,7,7a,8a,9,9a-hexahydro-4-methoxy-7a,8a-dimethyl-6-oxo-6H-5,8-dioxacyclopropa[b]phenantrene (15f). White solid in 92% yield, mp 188–192 °C. IR/ν(cm-1): 1764 (OC=O), 1702 (C=O), 1281, 1153, 1095 (C-O). 1H-NMR: 7.05 (t, 1H, H2, 3J = 7.9), 6.85 (dd, 1H, 3J = 7.9, H1), 6.74 (dd, 1H, 3J = 7.9, H3), 3.85 (s, 3H, OCH3), 3.44 (dd, 1H, 3J = 5.0, 12.3, H9a), 2.85 (d, 1H, 2J = 15.2, Heq-7), 2.31 (dd, 1H, 2J = 15.5, 3J = 5.0, Heq-9), 2.07 (d, 1H, 2J = 15.2, Hax-7), 2.04 (s, 3H, H14), 1.70 (dd, 1H, 2J = 15.5, 3J = 12.3, Hax-9), 1.45 (s, 3H, CH3), 1.31 (s, 3H, CH3); 13C-NMR: 203.4 (CO), 167.8 (OCO), 147.8 (C4a), 139.6 (C4), 127.2 (C9b), 125.5 (C2), 118.9 (C1), 111.9 (C3), 61.9 (C6a), 60.3 (C8a), 60.1 (C7a), 56.3 (OCH3), 35.6 (C9), 34.4 (C9a), 33.2 (C7), 25.6 (C14), 19.2, 21.0 (CH3); GC/MS m/z (%): 316 (M+, 1), 273 (53), 255 (100), 245(4), 241 (60), 211 (11), 115 (13), 91 (8), 43 (47); EA (%) calculated for C18H20O5: 68.34 C, 6.37 H; found: 64.83 C, 6.28 H.

(6aR,7aR,8aS,9aR)-rel-6a-Acetyl-2-bromo-6a,7,7a,8a,9,9a-hexahydro-4-methoxy-7a,8a-dimethyl-6-oxo-6H-5,8-dioxacyclopropa[b]phenantrene (15i). White powder in 95% yield, mp 169–172 °C. IR/ν(cm-1): 1768 (OC=O), 1702 (C=O), 1198, 1154, 1123 (C-O), 512 (C-Br). 1H-NMR: 6.97 (d, 1H, 4J = 2.1, H1), 6.91 (d, 1H, 4J = 2.1, H3), 3.86 (s, 3H, OCH3), 3.42 (dd, 1H, 3J = 5.0, 12.3, H9a), 2.85 (d, 1H, 2J = 15.5, Heq-7), 2.30 (dd, 1H, 2J = 15.5, 3J = 5.0, Heq-9), 2.07 (s, 3H, H14), 2.06 (d, 1H, 2J = 15.5, Hax-7), 1.68 (dd, 1H, 2J = 15.5, 3J = 12.3, Hax-9), 1.45 (s, 3H, CH3), 1.32 (s, 3H, CH3); 13C-NMR: 202.8 (CO), 167.2 (OCO), 148.5 (C4a), 138.7 (C4), 128.8 (C2), 121.7 (C3), 117.8 (C9b), 115.4 (C1), 61.7 (C8a), 60.2 (C7a), 59.9 (C6a), 56.4 (OCH3), 35.4 (C9), 34.3 (C9a), 33.2 (C7), 25.7 (C14), 20.9, 19.2 (CH3); GC/MS m/z (%): 395 (M+, 1), 351 (27), 334 (10), 321 (100), 255 (8), 240 (28), 115 (12), 91 (5), 43 (80); EA (%) calculated for C18H19O5Br: 54.70 C, 4.85 H; found: 54.26 C, 4.74 H.

3.5. Crystal structures

Compound 10b: C17H17C O3, colorless crystals, monoclinic, P21/c, Z = 4, a = 18.809(2) Å, b = 7.1461(9) Å, c = 11.4261(14) Å, α = 90º, β = 105.493(2)º, γ = 90º, V = 1480.0(3) Å3, Dcalcd = 1.368 g/cm3, μ = 0.265 mm-1, 10086 reflections collected, 2603 independent (Rint = 0.025), 2414 observed, R1 = 0.0411, wR2 = 0.1198 (I > 2σ(I)).

Compound 15i: C18H19BrO5, colorless crystals, triclinic, P-1, Z = 2, a = 7.3676(18) Å, b = 10.851(3) Å, c = 12.154(3) Å, α = 108.055(4)º, β = 97.784(4)º, γ = 106.789(4)º, V = 857.0(4) Å3, Dcalcd = 1.532 g/cm3, μ = 2.423 mm-1, 8373 reflections collected, 3017 independent (Rint = 0.046), 2455 observed, R1 = 0.0575, wR2 = 0.1149 (I > 2σ(I)).

4. Conclusions

The thermal reactions of ethyl coumarin-3-carboxylate (1a), n class="Chemical">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. 1H-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, π) and, in the case of 15i, also by Br···Br interactions.