HETEROCYCLES

Paper | Regular issue | Vol. 83, No. 3, 2011, pp. 591-607
Received, 14th December, 2010, Accepted, 31st January, 2011, Published online, 9th February, 2011.
DOI: 10.3987/COM-10-12122

■ Synthesis and Transformations of Novel Benzo[c]furans

Roberta Palkó, Zsuzsanna Riedl, Sándor Sólyom, István Pallagi, Tibor András Rokob, Orsolya Egyed, and György Hajós*

Institute of Biomolecular Chemistry, Chemical Research Center, Hungarian Academy of Sciences, H-1025 Budpest, Pusztaszeri út 59, P.O. Box 17, Hungary

Abstract

Some novel 1-cyanoisobenzofurans have been synthesized by a convenient ring closure methodology. The new products easily reacted with electron-deficient olefins and acetylenes to yield Diels-Alder products. Theoretical calculations satisfactorily support the quinonoide character of the new isobenzofuran derivatives.

INTRODUCTION
In the course of earlier studies of one of the authors on 2,3-benzodiazepines with non-competitive AMPA antagonist activity, pharmacophore modelling studies1 and considerations on possible metabolic transformations suggested that 5-hydroxylated 2,3-benzodiazepines of type A would be a promising candidate in this area. In order to justify this hypothesis, elaboration of a synthetic route to A seemed of interest. For this purpose, the retrosynthetic analysis A ⇒ B was considered (Scheme 1) and, thus, efforts have been made for the synthesis of the possible precursor B.

In contrast to these expectations, all efforts for preparation of cyanohydrins B as a candidate starting compound for the target ring system A failed and, instead, 1-cyanobenzo[c]furans as stable substances have been obtained as the result of accomplishment of the designed synthetic route. In this paper we report on this recently elaborated pathway to benzo[c]furans.

RESULTS AND DISCUSSION
Considerations of the possible access to the originally planned cyanohydrin B revealed that ketoaldehyde 3 could be an obvious source to this compound. Inspection of the pertinent literature, furthermore, revealed that a two-step protocol can conveniently be applied for the synthesis of 3 (Scheme 2). Accordingly, substituted salicylaldehydes (1) were first converted to N-benzoylhydrazones (2)2 and, subsequently, this compound, when treated with lead tetraacetate, underwent rearrangement to give the ketoaldehyde (3).3 Although several reaction conditions for this rearrangement have been published,4 the lead tetraacetate method gave the best results in our hands.

Transformation of 3 to the original target (B) was tried by treatment with trimethylsilyl cyanide and subsequent acidic hydrolysis. When this reaction was carried out in dichloromethane, an oily colourless product was formed first, which, upon treatment with hydrochloric acid, was converted to a yellow product in a fast reaction. The appearance of an sp2 quaternary carbon instead of the sp3 CH carbon in the 13C NMR spectrum, the yellow colour and the 1H NMR assignment altogether supported the conclusion that B was not formed and, instead, a ring closure occurred to yield a benzo[c]furan derivative (5).

The first step in the course of this transformation is obviously formation of an O-trimethylsilylcyanohydrin (4) intermediate, which is followed by cyclization to the bicyclic product (5). This step is initiated by acidic desilylation and nucleophilic attack of the intermediate hydroxyl-oxygen atom on the carbonyl carbon atom activated by the strongly acidic medium. Finally, elimination of water can yield the product (5).

While synthesis of great number of symmetrically substituted benzo[c]furans has been published,5,6 relatively few papers appeared on asymmetrically substituted derivatives.7 In particular, only a few derivatives of 1-cyano-3-arylbenzo[c]furans have been described.8,9 It is also important to note that in these syntheses potassium cyanide/acetic acid was used for the cyclization to derivatives of 5, whereas in our procedure trimethylsilyl cyanide of markedly higher safety is applied for this purpose. In contrast to the relative instability of numerous benzo[c]furan derivatives, the obtained 1-cyano substituted compounds proved to be stable and can be stored without any precaution under normal conditions.

This experience prompted us to investigate the electronic distribution of these compounds in order to assess if the presence of the cyano group exerts any influence on the quinonoide character represented by the neutral chemical structure (Figure 1, structure a). In other words, consideration of contribution of the possible dipolar valence bond mesomeric structure (structure b) with a dipolar valence bond seemed of particular interest.

A simple yet effective way to estimate relative weight of resonance forms is to examine computed bond lengths of the molecules of interest. Density functional calculations at the M06-2X/6-31G* level10-13 were used to compare equilibrium geometries of benzo[b]furan (Figure 2, d), benzo[c]furan (e), and 1-cyano-3-(p-nitrophenyl)-benzo[c]furan (f), as well as the structurally related compounds butadiene (a), divinylether (b), and acrolein (c).

It is apparent that benzo[c]furan (e and f), unlike benzo[b]furan (d), has markedly alternating C–C bond lengths in the aromatic ring, pointing to significant quinonoide character. Importantly, there are only very slight changes in the geometry upon the substitution of the electron withdrawing cyano group (i.e. f vs. e), which underlines the dominant role of the quinonoide structure also for the cyano substituted compounds discussed in the present work. This finding is also consistent with the properties of frontier molecular orbitals of the species of interest (Figure 3). The shape of the HOMO and the energy gap between the HOMO and the HOMO-1 are in agreement with a polyene character of f similar to e.

Upon the above theoretical conclusion the new compounds were considered as reactive candidates as dienes in Diels-Alder reactions. Such conversions with isobenzofurans of different substitution pattern have already been reported.7b These cycloadditions have been carried out with three different dienophiles: dimethyl acetylene dicarboxylate (DMAD), N-phenylmaleimide (Scheme 3), and ethyl acrylate (Scheme 4).
In all cases, these reactions took place in toluene under reflux conditions in medium to high yields. Thus, reaction with DMAD gave the diesters 6, whereas cycloadditions with N-phenylmaleimide yielded the tetracyclic derivatives 7.

The NMR spectra of this compound did not allow unambiguous determination of which of the possible diastereomer of 7 was formed in these cycloadditions concerning the position of the bridged oxygen containing ring and the pyrrole ring. However, DFT calculations15 on 7a carried out to identify the stereochemical preference revealed that the transition state leading to endo-7a is 2.2 kcal/mol lower in free energy than that leading to exo-7a (see structures on Figure 4). Relative stability of the products parallels that of the TSs, but the difference is smaller (0.7 kcal/mol).

Transformations with ethyl acrylate resulted in formation of mixtures of regioisomers 8 and 9 (Scheme 4). Thorough NMR analysis of the mixture 8b+9b revealed that the two isomers are present in a ratio of roughly 3:1. The main product 8b was separated by chromatography, and the pure compound was analyzed by spectroscopy. Predominance of 8 in the reaction mixtures seems to be in accordance with the expected polarization of the two reaction partners (Figure 1).

It is interesting to note that because of the resulting chiral centers in these products, pairs of diastereomers – major (M) and minor (m) ones - should be formed for both regioisomers 8 and 9 according to the relative positions of the ester and the cyano groups. Thus, four sets of signals were supposed to appear which were indeed observed in the 1H-NMR spectrum of the 8c+9c and 8d+9d mixtures. Product ratios were as follows: 8cM/8cm: 55 mol%/22 mol%; 9cM/9cm: 16mol %/7 mol%; 8dM/8dm: 50 mol%/25 mol%; 9dM/9dm: 16 mol%/9 mol%. The regioisomeric ratios of 8c:9c and 8d:9d were 77:23 and 75:25, respectively. Comparison of the steric structures of isomers 8d M, 8d m, 9d M, and 9d m are shown in Figure 5.

These experimental findings reveal that the elaborated synthetic route provides a relatively easy access to stable isobenzofurans. These compounds – in accordance with the theoretical considerations – possess quinonoide character, which enables their easy conversion with dienophiles to give cycloadducts in good yield.

EXPERIMENTAL
General: Melting points were determined on a Kofler apparatus and are uncorrected. The IR spectra were recorded on a Thermo Nicolet Avatar 320 FT-IR spectrometer. NMR experiments were performed on Varian INOVA-200 or Varian INOVA-400 spectrometer equipped with a 5 mm inverse detection z-gradient probe. 1H and 13C NMR spectra were measured at room temperature (25 oC) in an appropriate solvent. 1H and 13C chemical shifts are expressed in ppm (δ) referenced to residual solvent signals. The elemental analysis has been carried out with an Elementar Vario EL III apparatus. Chromatographic separations were carried out on Merck Kieselgel 60 (230-400 mesh). Reactions were monitored with Merck Kieselgel 60 F254-precoated TLC plates (0.25 mm thickness). All chemicals and solvents were used as supplied.

Compounds 2a-d were synthesized analogously to the literature procedure published for related compounds.4a

(Z)-N'-(2-Hydroxybenzylidene)-4-nitrobenzohydrazide (2a): This compound has been reported in the literature.2a, 3b, 18 Colourless crystals, mp 288-293 °C. (lit., mp 280-283 °C2a; 277-279 °C3b; 291-292 °C14).

(Z)-4-Bromo-N'-(2-hydroxybenzylidene)benzohydrazide (2b): Colourless crystals 4.29 g (90%), mp 225-230 °C. IR (KBr, cm-1): 3221, 3064, 1645, 1483, 1297, 1152, 1010, 748; 1H NMR δ (DMSO-d6): 6.92 (t, 2H), 7.31 (t, 1H), 7.56 (d, 1H), 7.76 (d, 2H), 7.89 (d, 2H), 8.64 (s, 1H), 11.2 (s, 1H), 12.1 (s, 1H). 13C NMR δ (DMSO-d6): 116.4, 118.7, 119.4, 125.8, 129.5, 129.7, 131.6, 131.9, 148.6, 157.5, 161.9. Anal. Calcd for C14H11BrN3O4 (318.00): C, 52.69; H, 3.47; N, 8.78. Found: C, 53.08; H, 3.41; N, 8.73.

(Z)-N'-(2-Hydroxy-4-methoxybenzylidene)-4-nitrobenzohydrazide (2c): Although synthesis of this compound has been reported2b no characterization has yet been described. Yellow crystals 4.5 g (98%), mp 218-220 °C. IR (KBr, cm-1): 3550, 3203, 3024, 1656, 1516, 1351, 1282, 831, 709; 1H NMR δ (DMSO-d6): 3.78 (s, 1H), 6.53 (d, 2H), 7.47 (d, 2H), 8.15 (d, 2H), 8.37 (d, 2H), 8.58 (s, 1H), 11.44 (s, 1H), 12.26 (s, 2H). 13C NMR δ (DMSO-d6): 55.2, 101.1, 106.5, 111.6, 123.5, 129.0, 130.9, 138.5, 149.2, 149.5, 159.4, 160.8, 162.2. Anal. Calcd for C15H13N3O5 (315.09): C, 57.14; H, 4.16; N, 13.33. Found: C, 57.35; H, 4.31; N, 13.56.

(Z)-4-Bromo-N'-(2-hydroxy-4-methoxybenzylidene)benzohydrazide (2d): Colourless crystals 4.78 g (91%), mp 196-199 °C. IR (KBr, cm-1): 3424, 3252, 3063, 1627, 1507, 1352, 1278, 835, 806; 1H NMR δ (DMSO-d6): 3.77 (s, 3H), 6.51 (m, 2H), 7.44 (d, 1H), 7.75 (d, 2H), 7.87 (d, 2H), 8.54 (s, 1H), 11.55 (s, 1H), 12.04 (s, 1H). 13C NMR δ (DMSO-d6): 55.3, 101.1, 106.5, 111.7, 125.6, 129.6, 131.1, 131.5, 132.0, 149.0, 159.4, 161.6, 162.1. Anal. Calcd for C15H13BrN2O3 (348.01): C, 51.60; H, 3.75; N, 8.02. Found: C, 51.42; H, 3.47; N, 7.89.

Compounds 3a-d were synthesized according to the published procedure3a using lead tetraacetate.

2-(4-Nitrobenzoyl)benzaldehyde (3a): This compound has been reported in the literature.2a, 3b Yellow crystals, mp 152-156 °C. (lit., mp 151-152 °C2a; 153-155 °C3b).

2-(4-Bromobenzoyl)benzaldehyde (3b): This compound has been described in the literature.9 Colourless crystals, mp 112-115 °C. (lit., mp 110-113 °C9).

2-(4-Nitrobenzoyl)-4-methoxybenzaldehyde (3c): This compound has been described in the literature.19 Starting from 2c (1 g) yellow crystals were obtained, 0.35 g (39%), mp 135-140 °C. IR (KBr, cm-1): 3206, 2919, 2850, 1602, 1519, 1347, 1283, 1219, 1109, 965, 850, 832; 1H NMR δ (CDCl3): 3.93 (s, 3H), 6.95 (s, 1H), 7.19 (d, 1H), 7.92 (t, 3H), 8.26 (d, 2H), 9.80 (s, 1H). 13C NMR δ (CDCl3): 55.9, 114.4, 115.3, 123.7,128.0, 130.0, 134.8, 141.3, 141.8, 150.3, 164.1, 189.0, 194.9. Anal. Calcd for C15H11NO5 (285.06): C, 63.16; H, 3.89; N, 4.91. Found: C, 63.03; H, 3.86; N, 5.24.

2-(4-Bromobenzoyl)-4-methoxybenzaldehyde (3d): Starting from 2d (1 g) brown crystals were obtained, 0.41 g (47%), mp 97-100 °C. IR (KBr, cm-1): 3090, 2945, 2857, 1665, 1562, 1396, 1294, 1218, 1106, 962, 847; 1H NMR δ (CDCl3): 3.90 (s, 3H), 6.91 (s, 1H), 7.12 (d, 1H), 7.61 (q, 4H), 7.94 (d, 1H), 9.82 (s, 1H). 13C NMR δ (CDCl3): 56.1, 114.2, 115.5, 128.3, 129.1, 131.2, 132.2, 133.8, 135.8, 143.1, 164.0, 189.1, 195.6. Anal. Calcd for C15H11BrO3 (317.99): C, 56.45; H, 3.47. Found: C, 56.15; H, 3.27.

General Procedure for preparation of isobenzofurans 5a-d: To a stirred solution of the appropriate aldehyde (2 mmol, 3a-d) in CH2Cl2 (6 mL) trimethylsilyl cyanide (338 mg, 3.4 mmol) and few crystals of ZnI2 were added. The reaction mixture was stirred at rt for 24 h and evaporated to dryness in vacuum. The residue was mixed with water (4 mL) and conc. hydrochloric acid (4 mL) and stirred at 40 °C for 1 h. The resulting solution was cooled down to rt, and was extracted with Et2O (3x30 mL) and chloroform (5x20 mL). The combined organic solution was dried over Na2SO4 and evaporated to dryness to give solid product, which was treated with ethanol and filtered off to give 5a-d.

3-(4-Nitrophenyl)isobenzofuran-1-carbonitrile (5a): Brown crystals, 0.211 g (40%), mp 227-231 °C. IR (KBr, cm-1): 3081, 2920, 2850, 2206, 1592, 1509, 1341, 1107, 854, 743; 1H NMR δ (DMSO-d6): 7.37 (1H, dd, J = 8.0, 7.7 Hz, H5), 7.45 (1H, dd, J = 7.9, 7.7 Hz, H6), 7.74 (1H, d, J = 7.9 Hz, H7), 8.22 (1H, d, J = 8.0 Hz, H4), 8.29 (2H, m, H3’ + H5’), 8.36 (2H, m, H2’ + H6’). 13C NMR δ (DMSO-d6): 112.6 (CN), 117.9 (C1), 121.0 (C4), 122.0 (C3a), 125.1 (C2’ + C6’), 127.2 (C3’ + C5’), 128.6 (C5), 130.5 (C6), 133.4 (C7a), 134.7 (C1’), 147.5 (C4’), 148.5 (C3). Anal. Calcd for C15H8N2O3 (264.24): C, 68.18; H, 3.05; N, 10.60. Found: C, 68.11; H, 3.02; N, 10.56.

3-(4-Bromophenyl)isobenzofuran-1-carbonitrile (5b): Yellow crystals, 0.326 g (55%), mp 125-130 °C. IR (KBr, cm-1): 3082, 2923, 2205, 1454, 1435, 1404, 1070, 1005, 829, 740; 1H NMR δ (CDCl3): 7.22 (m, 2H), 7.60 (m, 3H), 7.82 (m, 3H). 13C NMR δ (CDCl3): 112.5, 117.6, 120.3, 126.5, 127.3, 128.0, 128.6, 129.0, 131.7, 132.4, 133.6, 149.6. Anal. Calcd for C15H8BrNO (296.98): C, 60.43; H, 2.70; N, 4.70. Found: C, 60.06; H, 2.56; N, 4.53.

3-(4-Nitrophenyl)-5-methoxyisobenzofuran-1-carbonitrile (5c): Orange crystals, 0.153 g (26%), mp 223-228 °C. IR (KBr, cm-1): 2924, 2853, 2209, 1594, 1519, 1346, 1265, 1231, 1103, 1014, 845, 814; 1H NMR δ (CDCl3): 3.87 (s, 3H), 6.95 (t, 2H), 7.45 (d, 1H), 7.95 (d, 2H), 8.30 (d, 2H). 13C NMR δ (CDCl3): 55.9, 94.4, 97.4, 111.8, 119.2, 124.6, 125.5, 126.1, 130.7, 135.6, 159.4. Anal. Calcd for C16H10N2O4 (294.06): C, 65.31; H, 3.43; N, 9.52. Found: C, 65.56; H, 3.45; N, 9.54.

3-(4-Bromophenyl)-5-methoxyisobenzofuran-1-carbonitrile (5d): Brown crystals, 0.566 g (89%), mp 169-174 °C. IR (KBr, cm-1): 3083, 2942, 2201, 1642, 1558, 1476, 1434, 1260, 1227, 1178, 1073, 1008, 823; 1H NMR δ (CDCl3): 3.89 (s, 3H), 6.95 (t, 2H), 7.46 (d, 1H), 7.65 (m, 4H). 13C NMR δ (CDCl3): 55.4, 94.7, 112.5, 118.8, 120.9, 122.8, 125,7, 126.9, 129.0, 122.8, 125,7, 126.9, 129.0, 130.9, 131.8, 132.4, 147.6, 158.2. Anal. Calcd for C16H10BrNO2 (328.16): C, 58.56; H, 3.07; N, 4.27. Found: C, 58.16; H, 3.39; N, 4.08.

General procedure for preparation of cycloadducts 6a-d: To a solution of the appropriate isobenzofuran derivative (5a-d, 1 mmol) in toluene (20 mL) DMAD (2 mmol) was added, and this mixture was refluxed for 24 h. After evaporation of the reaction mixture the residue was treated with cold EtOH to give colourless crystals, which were filtered off and recrystallized from EtOH.

Dimethyl 1-cyano-4-(4-nitrophenyl)-1,4-dihydro-1,4-epoxynaphthalene-2,3-dicarboxylate (6a): Colourless crystals, 0.284 g (70%), mp 159-163 °C. IR (KBr, cm-1): 2962, 2919, 2850, 1729, 1715, 1515, 1353, 1293, 1133, 1020, 1003, 853; 1H NMR δ (CDCl3): 3.76 (s, 3H), 3.87 (s,3H), 7.42 (m, 2H), 7.68 (m, 2H), 7.85 (d, 2H), 8. 37 (d, 2H). 13C NMR δ (CDCl3): 53.0, 53.1, 94.5, 112.6, 121.0, 121.8, 124.0, 127.4, 127.6, 127.7, 137.9, 144.6, 145.6, 148.6, 155.2, 160.0, 163.1. Anal. Calcd for C21H14N2O7 (406.08): C, 62.07; H, 3.47; N, 6.89. Found: C, 62.24; H, 3.47; N, 6.50.

Dimethyl 1-cyano-4-(4-bromophenyl)-1,4-dihydro-1,4-epoxynaphthalene-2,3-dicarboxylate (6b): Colourless crystals, 0.263 g (60%), mp 112-114 °C. IR (KBr, cm-1): 2954, 1737, 1728, 1638, 1439, 1312, 1242, 1126, 1012, 973, 827; 1H NMR δ (CDCl3): 3.73 (3H, s, COOCH3”’), 3.84 (3H, s, COOCH3”), 7.22 (2H, m, H7 + H8), 7.41 (1H, m, H6), 7.48 (2H, m, H2’ + H6’), 7.62 (2H, m, H3’ + H5’), 7.63 (1H, m, H5). 13C NMR δ (CDCl3): 52.9 (COOCH3”’), 53.0 (COOCH3”), 79.7 (C4), 95.3 (C1), 112.9 (CN), 120.8 (C5), 122.4 (C6), 124.3 (C4’), 127.1 (C7), 127.6 (C8), 128.5 (C2’ + C6’), 130.2 (C1’), 132.2 (C3’ + C5’), 145.0 + 145.1 (C4a + C8a), 145.6 (C2), 155.9 (C3), 160.2 (COOCH3”), 163.5 (COOCH3”’). Anal. Calcd for C21H14BrNO5 (439.01): C, 57.29; H, 3.21; N, 3.18. Found: C, 57.43; H, 3.07; N, 3.07.

Dimethyl 1-cyano-4-(4-nitrophenyl)-6-methoxy-1,4-dihydro-1,4-epoxynaphthalene-2,3-dicarbox- ylate (6c): Yellow crystals, 0.235 g (54%), mp 152-155 °C. IR (KBr, cm-1): 3006, 2964, 1727, 1525, 1350, 1259, 1220, 1128, 1006, 856; 1H NMR δ (CDCl3): 3.75 (s, 3H), 3.80 (s, 3H), 3.86 (s, 3H), 6.67 (d, 1H), 6.98 (s, 1H), 7.55 (d, 1H), 7.82 (d, 2H), 8.37 (d, 2H). 13C NMR δ (CDCl3): 53.0, 53.1, 55.9, 94,3, 109.4, 111.5, 112.7, 121.7, 124.0, 127.5, 135.8, 137.9, 146.2, 146.5, 148.5, 154.5, 159,3, 160.1, 163.2. Anal. Calcd for C22H16N2O8 (436.09): C, 60.55; H, 3.70; N, 6.42. Found: C, 60.38; H, 3.54; N, 6.11.

Dimethyl 1-cyano-4-(4-bromophenyl)-6-methoxy-1,4-dihydro-1,4-epoxynaphthalene-2,3-dicarbox- ylate (6d): Colourless crystals, 0.257 g (55%), mp 136-138 °C. IR (KBr, cm-1): 3000, 2948, 2836, 1707, 1630, 1473, 1439, 1292, 1217, 1012, 823; 1H NMR δ (CDCl3): 3.74 (s, 3H), 3.80 (s, 3H), 3.84 (s, 3H), 6.64 (d, 1H), 7.00 (s, 1H), 7.50 (t, 3H), 7.62 (d, 2H). 13C NMR δ (CDCl3): 53.1, 53.2, 56.1, 95.3, 109.5, 112.1, 113.2, 121.6, 124.4, 128.7, 130.4, 136.7, 146.4, 147.2, 155.4, 159.5, 160.5, 163.7. Anal. Calcd for C22H16BrNO6 (469.02): C, 56.19; H, 3.43; N, 2.98. Found: C, 56.23; H, 3.21; N, 2.98.

General procedure for preparation of 7a-d: A solution of the appropriate isobenzofuran derivative (5a-d, 1 mmol) in toluene (20 mL) N-phenylmaleimide (2 mmol) was added and this mixture was refluxed for 8 h. After evaporation of the reaction mixture the residue was treated with cold ethanol to give white crystals, which was filtered off and recrystallized from EtOH.

9-(4-Nitrophenyl)-1,3-dioxo-2-phenyl-1,2,3,3a,9,9a-hexahydro-4H-4,9-epoxybenzo[f]isoindole-4-car-bonitrile (7a): Colourless crystals, 0.357 g (86%), mp 245-249 °C. IR (KBr, cm-1): 3119, 3092, 1783, 1715, 1527, 1353, 1291, 1183, 1016, 789; 1H NMR δ (CDCl3+DMSO-d6): 4.22 (d, 1H), 4.52 (d, 1H), 6.46 (dd, 2H), 7.02 (d, 1H), 7.31 (d, 3H), 4.74 (tt, 2H), 7.61 (d, 1H), 8.16 (d, 2H), 8.37 (d, 2H). 13C NMR δ (CDCl3+DMSOd6): 52.1, 54,1, 91.5, 113.6, 120.5, 120.7, 125.7, 127.6, 128.7, 129.1, 129.8, 130.0, 137.6, 140.7, 141.0, 148.0, 169.6, 171.4. Anal. Calcd for C25H15N3O5 (437.10): C, 68.65; H, 3.46; N, 9.61. Found: C, 68.34; H, 3.27; N, 9.43.

9-(4-Bromophenyl)-1,3-dioxo-2-phenyl-1,2,3,3a,9,9a-hexahydro-4H-4,9-epoxybenzo[f]isoindole-4- carbonitrile (7b): Colourless crystals, 0.434 g (92%), mp 245-250 °C. IR (KBr, cm-1): 3086, 2919, 1781, 1712, 1496, 1383, 1181, 1007, 787; 1H NMR δ (CDCl3): 4.11 (1H, d, J = 8.7 Hz, H3a), 4.35 (1H, d, J = 8.7 Hz, H9a), 6.44 (2H, m, H2” + H6”), 7.00 (1H, ddd, J = 7.3, 1.0, 0.9 Hz, H5), 7.27 (3H, m, H3” + H4” + H5”), 7.38 (1H, ddd, J = 7.4, 7.3, 1.2 Hz, H6), 7.45 (1H, ddd, J = 7.6, 7.4, 1.0 Hz, H7), 7.59 (1H, ddd, J = 7.6, 1.2, 0.9 Hz, H8), 7.64 (2H, m, H3’ + H5’), 7.78 (2H, m, H2’ + H6’). 13C NMR δ (CDCl3): 52.3 (C3a), 54.6 (C9a), 77.2 (C9), 92.5 (C4), 114.1 (CN), 120.8 (C8), 121.3 (C5), 123.8 (C4’), 126.0 (C2” + C6”), 128.6 (C2’ + C6’), 129.1 (C3” + C4” + C5”), 129.3 (C7), 130.1 (C6), 130.4 (C1”), 132.1 (C3’ + C5’), 133.3 (C1’), 138.0 (C8a), 141.9 (C4a), 169.9 (C1); 171.7 (C3). Anal. Calcd for C25H15BrN2O3 (470.03): C, 63.71; H, 3.21; N, 5.94. Found: C, 63.71; H, 3.25; N, 5.61.

9-(4-Nitrophenyl)-7-methoxy-1,3-dioxo-2-phenyl-1,2,3,3a,9,9a-hexahydro-4H-4,9-epoxybenzo[f]isoindole-4-carbonitrile (7c): Light brown crystals, 0.294 g (63%), mp 206-210 °C. IR (KBr, cm-1): 3086, 2986, 1782, 1713, 1522, 1347, 1195, 1012, 731; 1H NMR δ (CDCl3): 3.73 (s, 3H), 4.11 (d, 1H), 4.37 (d, 1H), 6.52 (d, 3H), 6.94 (d, 1H), 7.32 (s, 3H), 7.50 (d, 1H), 8.14 (d, 2H), 8.38 (d, 2H). 13C NMR δ (CDCl3): 52.5, 54.8, 55.9, 92.0, 107.6, 109.7, 113.9, 114.3, 122.0, 124.1, 125.9, 127.9, 129.1, 129.2, 129.7, 130.3, 140.9, 143.1, 148.5, 161.5, 169.8, 171.6. Anal. Calcd for C26H17N3O6 (467.11): C, 66.81; H, 3.67; N, 8.99. Found: C, 66.45; H, 3.60; N, 8.78.

9-(4-Bromophenyl)-7-methoxy-1,3-dioxo-2-phenyl-1,2,3,3a,9,9a-hexahydro-4H-4,9-epoxybenzo[f]isoindole-4-carbonitrile (7d): Colourless crystals 0.445 g (89%), mp 245-248 °C. IR (KBr, cm-1): 3092, 2983, 2936, 1785, 1722, 1593, 1496, 1371, 1282, 1182, 1005, 830; 1H NMR δ (CDCl3): 3.72 (s, 3H), 4.09 (d, 1H), 4.33 (d, 1H), 6.52 (m, 3H), 6.91 (d, 1H), 7.30 (s, 3H), 7.46 (d, 1H), 7.65 (d, 2H), 7.78 (d, 2H). 13C NMR δ (CDCl3): 52.3, 54.9, 55.9, 92.5, 107.7, 114.2, 121.8, 123.8, 126.0, 127.9, 128.6, 129.0, 129.9, 130.5, 132.0, 133.2, 134.1, 143.7, 161.4, 170.0, 171.6. Anal. Calcd for C26H17BrN2O4 (500.04): C, 62.29; H, 3.42; N, 5.59. Found: C, 62.02; H, 3.39; N, 5.65.

General procedure for cycloadditions of isobenzofurans 5a-d with ethyl acrylate to yield cycloadducts 8 and 9: A solution of the appropriate isobenzofuran derivative (5a-d, 1 mmol) in toluene (20 mL) ethyl acrylate (2 mmol) was added and the mixture was refluxed for 24 h. After evaporation of the reaction mixture, the oil was purified by column chromatography (silica, eluent: hexane: EtOAc= 2:1).

Formation of the mixture of ethyl 1-(4-nitrophenyl)-4-cyano-1,2,3,4-tetrahydro-1,4-epoxynaphtha- lene-2-carboxylate (8a) and ethyl 4-(4-nitrophenyl)-1-cyano-1,2,3,4-tetrahydro-1,4-epoxynaphtha- lene-2-carboxylate (9a): Colourless crystals, 0.229 g (63%), mp 130-132 °C. IR (KBr, cm-1): 3112, 3080, 2983, 1740, 1712, 1521, 1350, 1279, 1052, 1041, 977. 1H NMR δ (CDCl3): 1.03 (3H, t, J = 7.0 Hz, CH3 {8a}), 1.28 (3H, t, J = 7.0 Hz, CH3 {9a}), 2.49 (1H, dd, J = 11.5, 3.8 Hz, H3b{8a}), 2.57 (1H, dd, J = 12.0, 10.5 Hz H3a{9a}), 2.62 (1H, dd, J =12.0, 4.4 Hz, H3b{9a}), 2.95 (1H, dd, J = 11.5, 10.7 Hz, H3a{8a}); 3.77 (1H, m,H2{9a}), 3.78 (1H, dd, J = 10.7, 3.8 Hz, H2{8a}), 3.71-3.77 (2*3H, OCH3 {8a, 9a}), 3.9-4.1 (2*2H, CH2 {8a, 9a}), 6.92(1H, d, J = 8.0 Hz, H5{9a}), 7.00 (1H, d, J = 8.1 Hz, H8{8a}), 7.33 (2*1H, t, J = 8.0 Hz, H7{9a}+ H6{8a}), 7.36 (1H, t, J = 8.0 Hz, H6{9a}), 7.42 (1H, t, J = 8.1 Hz,H7{8a}), 7.48 (1H, d, J = 8.0 Hz, H8{9a}); 7.57 (1H, d, J = 8.1 Hz, H5{8a}), 7.70 (2H, m, H2’+H6’{9a}), 7.96 (2H, m, H2’+H6’{8a}), 8.34 (2*2H, m, H3’+H5’{8a, 9a}).

13C NMR δ (CDCl3) of 8a: 13.9 (CH3), 39.7(C3), 48.5 (C2), 61.6 (CH2CH3), 75.9 (C4), 91.2 (C1), 115.5 (CN), 118.7 (C5), 121.4 (C8), 123.5 (C3’+C5’), 128.6 (C6), 128.8 (C7), 129.0 (C2’+C6’), 130.3 (C1’), 141.8 (C4a), 142.3 (C8a), 148.3 (C4’), 169.4 (C=O). 13C NMR δ (CDCl3) of 9a: 14.1 (CH3), 35.8 (C3), 51.7 (C2), 61.9 (CH2CH3), 77.0 (C1), 90.3 (C4); 115.5 (CN), 119.0 (C8), 120.3 (C5), 124.0 (C2’+C6’), 126.9 (C3’+C5’), 128.0 (C7), 129.4 (C6), 130.2 (C1’), 141.8 (C8a), 142.3 (C4a), 148.2 (C4’), 169.2 (C=O). Anal. Calcd for C20H16N2O5 (364.11): C, 65.93; H, 4.43; N, 7.69. Found: C, 65.83; H, 4.18; N, 7.42.

Ethyl 1-(4-bromophenyl)-4-cyano-1,2,3,4-tetrahydro-1,4-epoxynaphthalene-2-carboxylate (8b): Colourless crystals, 0.175 g (44%), mp 100-102 °C. IR (KBr, cm-1): 2983, 2903, 1730, 1460, 1263, 1041, 1010, 827; 1H NMR δ (CDCl3): 1.02 (3H, t, J = 6.8Hz, COOCH2-CH3), 2.44 (1H, dd, J = 11.7, 3.6 Hz, H3a), 2.91 (1H, dd, J = 11.7, 10.8 Hz, H3b), 3.77 (1H, dd, J = 10.8, 3.6 Hz, H2), 3.89 (2H, q, J = 6.8 Hz, COOCH2-CH3), 6.98 (1H, d, J = 7.4 Hz, H8), 7.27 (1H, dd, J = 7.7, 7.4 Hz, H7), 7.36 (1H, dd, J = 7.7, 7.5 Hz, H6), 7.52 (1H, d, J = 7.5 Hz, H5), 7.58 (4H, m, H2’ + H3’ + H5’ + H6’). 13C NMR δ (CDCl3): 13.9 (COOCH2-CH3), 39.7 (C3), 47.8 (C2), 61.3 (COOCH2-CH3), 75.6 (C4); 91.8 (C1), 115.8 (CN), 118.4 (C5), 121.6 (C8), 123.6 (C4’), 128.4 (C6); 128.5 (C7), 129.8 + 131.6 (C2’ + C3’ + C5’ + C6’), 133.7 (C1’), 142.3 (C8a), 142.6 (C4a), 169.7 (CO). Anal. Calcd for C20H16BrNO3 (397.03): C, 60.32; H, 4.05; N, 3.52. Found: C, 60.33; H, 3.86; N, 3.36.

Formation of the mixture of ethyl 1-(4-nitrophenyl)-4-cyano-7-methoxy-1,2,3,4-tetrahydro-1,4-epoxy-naphthalene-2-carboxylate (8c) and ethyl 4-(4-nitrophenyl)-1-cyano-6-methoxy- 1,2,3,4-tetrahydro-1,4-epoxynaphthalene-2-carboxylate (9c): Orange oil, 0.240 g (61%).

M stands for the major diastereomer, whereas m for the minor diastereomer. Thus, the four sets of signals can be assigned to the two pairs of diastereomers 8cM, 8cm, 9cM, 9cm.

1H NMR δ (CDCl3): 0.9 (3H, t, J = 7.0 Hz, CH3 {8cm}), 1.05 (3H, t, J = 7.0 Hz, CH3 {8cM}), 1.25 (3H, t, J = 7.0 Hz, CH3 {9cM}); 1.28 (3H, t, J = 7.0 Hz, CH3 {9cm}), 2.35 (1H, dd, J = 11.7, 8.7 Hz, H3a {8cm} ), 2.38 (1H, dd, J = 11.6, 8.6 Hz, H3a {9cm}), 2.49 (1H, dd, J = 11.6, 3.9 Hz, H3b {8cM}), 2.54 (1H, dd, J =12.0, 4.4 Hz, H3b {9cM}), 2.57 (1H, dd, J = 12.0, 10.5 Hz H3a {9cM}), 2.70 (1H, dd, J = 11.6, 4.7 Hz, H3b {9cm}), 2.93 (1H, dd, J = 11.6, 10.7 Hz, H3a {8cM}), 2.98 (1H, dd, J = 11.7, 4.9 Hz, H3b {8cm}), 3.07 (1H, dd, J = 8.6, 4.7 Hz, H2 {9cm}), 3.13 (1H, dd, J = 8.7, 4.9Hz, H2 {8cm}), 3.75 (1H, dd, J = 10.7, 3.9 Hz, H2 {8cM}), 3.85 (1H, dd, J = 10.5, 4.4 Hz, H2 {9cM}), 3.71-3.77 (4*3H, OCH3 {8cM, 8cm, 9cM, 9cm}), 3.9-4.1 (4*2H, CH2 {8cM, 8cm, 9cM, 9cm}), 6.38 (1H, d, J = 2.0 Hz, H5 {9cM}), 6.42 (1H, d, J = 2.0 Hz, H5 {9cm}), 6.48 (1H, d, J = 2.0 Hz, H8 {8cM}), 6.62 (1H, d, J = 2.0 Hz, H8 {8cm}), 6.77 (1H, dd, J = 8.1, 2.0Hz, H7 {9cM}); 6.82 (2*1H, m, H6 {8cm}+ H7 {9cm}), 6.86 (1H, dd, J = 8.1, 2.0Hz, H6 {8cM}), 7.34 (1H, d, J =8.1 Hz, H8 {9cM}), 7.40-7.43 (3*1H, m, H5 {8cM, 8cm}+H8{9cm}), 7.62-7.78 (3*2H, m, H2’+H6’ {8cM}), 7.94 (3*2H, m, H2’+H6’ {8cm, 9cM, 9cm}), 8.26-8.38 (4*2H, m, H3’+H5’ {8cM, 8cm, 9cM, 9cm}).

13C NMR data of 8cM, δ (CDCl3): 13.9 (CH3), 40.0 (C3), 48.5 (C2), 55.7 (OCH3), 61.5 (CH2CH3), 75.6 (C4), 91.3 (C1), 108.4 (C8), 113.0 (C6), 115.6 (CN), 120.0 (C5), 123.6 (C3’+C5’), 129.1 (C2’+C6’), 131.5 (C1’), 134.5 (C4a), 141.7 (C4’), 143.7 (C8a), 160.2 (C7), 169.4 (C=O).
13C NMR data of 9cM, δ (CDCl3): 14.1 (CH3), 35.8 (C3), 52.0 (C2), 55.8 (OCH3), 61.8 (CH2CH3), 77.3 (C1), 90.3 (C4), 105.9 (C5), 112.5 (C7), 115.4 (CN), 121.2 (C8), 123.6 (C3’+C5’), 127.2 (C2’+C6’), 131.0 (C1’), 131.1 (C8a), 143.2 (C4’), 146.9 (C4a), 160.8 (C6), 168.2 (C=O).
Diastereomeric ratios: 8cM 55 mol%, 8cm 22 mol%; 9cM 16mol%, 9cm 7 mol%. Regioisomeric ratio 8c:9c = 77:23.

Formation of the mixture of ethyl 1-(4-bromophenyl)-4-cyano-7-methoxy-1,2,3,4- tetrahydro-1,4-epoxynaphthalene-2-carboxylate (8d) and ethyl 4-(4-bromophenyl)-1-cyano-6- methoxy-1,2,3,4-tetrahydro-1,4-epoxynaphthalene-2-carboxylate (9d): Yellow oil 0.205 g (48%).

M stands for the major diastereomer, whereas m for the minor diastereomer. Thus, the four sets of signals can be assigned to the two pairs of diastereomers 8dM, 8dm, 9dM, 9dm.

1H NMR δ (CDCl3): 0.9 (3H, t, J = 7.0 Hz, CH3 {8dm}), 1.03 (3H, t, J = 7.0 Hz, CH3 {8dM}), 1.28 (3H, t, J = 7.0 Hz, CH3 {9dM}), 1.35(3H, t, J = 7.0 Hz, CH3 {9dm}), 2.27 (1H, dd, J = 11.3, 8.0 Hz, H3a {9dm}), 2.30 (1H, dd, J = 11.3, 8.1 Hz, H3a {8dm} ), 2.43 (1H, dd, J =11.3, 3.6 Hz, H3b {9dM}), 2.45 (1H, dd, J = 11.3, 3.6 Hz, H3b {8dM}), 2.57 (1H, dd, J = 11.3, 10.1 Hz H3a {9dM}), 2.70 (1H, dd, J = 11.3, 4.0 Hz, H3b {9dm}), 2.87 (1H, dd, J = 11.3, 10.1 Hz, H3a {8dM}), 2.95 (1H, dd, J = 11.5, 4.4 Hz, H3b {8dm}), 3.04 (1H, dd, J = 8.0, 4.0 Hz, H2 {9dm}), 3.05 (1H, dd, J = 8.1, 4.4Hz, H2 {8dm}), 3.77 (1H, dd, J = 10.1, 3.6 Hz, H2 {8dM}), 3.82 (1H, dd, J = 10.1, 3.6 Hz, H2 {9dM}), 3.71-3.77 (4*3H, OCH3 {8dM, 8dm, 9dM, 9dm}), 3.9-4.1 (4*2H, CH2 {8dM, 8dm, 9dM, 9dm}), 6.40(1H, d, J = 2.0 Hz, H5 {9dM}), 6.42 (1H, d, J = 2.0 Hz, H5 {9dm}), 6.48 (1H, d, J = 2.0 Hz, H8 {8dM}), 6.64 (1H, d, J = 2.0 Hz, H8 {8dm}), 6.75 (1H, dd, J = 8.1, 2.0 Hz, H6 {8dm}), 6.79 (2*1H, dd, J = 8.1, 2.0 Hz, H7 {9dM}+ H7{9dm}), 6.84 (1H, dd, J = 8.1, 2.0 Hz, H6 {8dM}), 7.36 (1H, d, J =8.1 Hz, H8 {9dM}), 7.42 (1H, d, J =8.1 Hz, H8 {9dm}), 7.40 (2*1H, m, H5 {8dM, 8dm}); 7.56-760 (4*4H, m, H2’+H3’+H5’+H6’ ({8dM, 8dm, 9dM, 9dm}).

13C NMR data of 8dM δ (CDCl3): 13.9 (CH3), 40.0 (C3), 47.9 (C2), 55.7 (OCH3), 61.3 (CH2CH3), 75.3 (C4), 91.9 (C1), 108.5 (C8), 112.9 (C6), 115.8 (CN), 119.6 (C5), 123.6 (C4’), 129.9 (C2’+C6’), 131.5 (C3’+C5’), 132.0 (C1’), 134.2 (C4a), 144.2 (C8a), 160.1 (C7), 169.6 (C=O).

13C NMR data of 9dM δ (CDCl3): 13.7 (CH3), 35.4 (C3), 52.1 (C2), 55.8 (OCH3),61.2 (CH2CH3), 77.3 (C1), 90.7 (C4), 106.2 (C5), 112.4 (C7), 115.8 (CN), 123.0 (C4’), 127.4 (C8), 129.9 (C2’+C6’), 131.6 (C3’+C5’), 131.7 (C8a), 131.9 (C1’), 146.0 (C4a), 160.3 (C6), 170.8 (C=O).

Diastereomeric ratios: 8dM 50 mol%, 8dm 25 mol%; 9dM 16mol%, 9dm 9 mol%. Regioisomeric ratio 8d:9d = 75:25.

ACKNOWLEDGEMENTS
Financial supports OTKA 77784, GVOP-3.2.1-2004-04-0311/3.0 and GVOP-3.2.1-2004-04-0210/3.0 are cordially acknowledged.

References

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