Synthesis and transformations of novel benzo[C]furans

Article abstract of DOI:10.3987/COM-10-12122

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. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-12122

HETEROCYCLES, Vol. 83, No. 3, 2011
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HETEROCYCLES, Vol. 83, No. 3, 2011, pp. 591 - 607. © The Japan Institute of Heterocyclic Chemistry
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,a Zsuzsanna Riedl,a Sándor Sólyom,b István Pallagi,b
Tibor András Rokob,a,c Orsolya Egyed,a and György Hajósa*
aChemical Research Center of the Hungarian Academy of Sciences, H-1025
Budapest, Pusztaszeri út 59-67, Hungary
bUbichem Ltd., H-1097 Budapest, Illatos út 33, Hungary
cPresently at the Institute of Chemistry and Biochemistry, AS CR, Flemingovo
nám. 2, 16610 Prague, Czech Republic
E-mail: ghajos@chemres.hu
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.
HO
O
OH
N R'
CN
N
R
O
R
X
X
B
A
Scheme 1. Retrosynthetic analysis A  B

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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
1
13C NMR spectrum, the yellow colour and the H 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.

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593
H
C N
NH
CHO
OH
4-X-C6H4CONHNH2
R
OH
X
O
R
1
2
NC OSiMe3
H
CHO
B
O
Me3SiCN, ZnI2
CH2Cl2
Pb(OAc)4
HCl/H2O
O
R
R
CN
O
R
X
3
X
4
X
X
R
5
NO2
Br
a
b
c
d
H
H
NO2 OMe
OMe
Br
Scheme 2. Four-step synthesis of 1-cyanoisobenzofurans
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.
CN
O
CN
O
Ar
Ar
a
b
Figure 1. Some of the mesomeric structures of 1-cyano-3-arylbenzo[c]furan

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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).
Figure 2. Calculated bond lengths (in angstroms) of benzofuran isomers and of some simple compounds
treated as reference. Ar = p-nitrophenyl
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).

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595
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.
Figure 3. Frontier molecular orbitals of benzofuran isomers. Atom coloring: carbon-green, oxygen-red,
nitrogen-blue, hydrogen-white. Surfaces were drawn with a cutoff of 0.05 atomic units.14 Orbital
energies in hartrees are also shown.
Scheme 3. Diels-Alder cyclizations with 1-cyanoisobenzofurans

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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).
Figure 4. M06-2X/6-31G* optimized geometries of the transition states leading to endo and exo isomers
of 7a. Selected distances are given in angstroms.
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).
CN
O
CN
O
CO2Et
CO2Et
+
5
R
R
CO2Et
X
X
8
9
Scheme 4. Formation of regioisomeric cycloadducts in reaction of cyanoizobenzofurans with acryl ester

HETEROCYCLES, Vol. 83, No. 3, 2011
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Figure 5. Comparison of structures of the diastereomeric isomer pairs (M and m) of regioisomers 8d and
9d. M stands for major diastereomer, m for minor diastereomer. The arrows indicate the relevant, rather
weak NOE-s for distinguishing the diastereomers. The NOE enhancements (1% - 4%) were determined
from selective 1D-NOESY experiments.
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
1
which were indeed observed in the H-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.

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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
1
13
solvent. H and C 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
1
225-230 C. IR (KBr, cm-1): 3221, 3064, 1645, 1483, 1297, 1152, 1010, 748; H NMR  (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  (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%),
1
mp 218-220 C. IR (KBr, cm-1): 3550, 3203, 3024, 1656, 1516, 1351, 1282, 831, 709; H NMR 
(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  (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 
(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,

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1H), 12.04 (s, 1H). 13C NMR  (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  (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  (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,
1
1106, 962, 847; H NMR  (CDCl3): 3.90 (s, 3H), 6.91 (s, 1H), 7.12 (d, 1H), 7.61 (q, 4H), 7.94 (d, 1H),
13
9.82 (s, 1H). C NMR  (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.

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3-(4-Nitrophenyl)isobenzofuran-1-carbonitrile (5a): Brown crystals, 0.211 g (40%), mp 227-231 C.
1
IR (KBr, cm-1): 3081, 2920, 2850, 2206, 1592, 1509, 1341, 1107, 854, 743; H NMR  (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
13
(1H, d, J = 8.0 Hz, H4), 8.29 (2H, m, H3’ + H5’), 8.36 (2H, m, H2’ + H6’). C NMR  (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  (CDCl3): 7.22 (m,
13
2H), 7.60 (m, 3H), 7.82 (m, 3H). C NMR  (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
1
223-228 C. IR (KBr, cm-1): 2924, 2853, 2209, 1594, 1519, 1346, 1265, 1231, 1103, 1014, 845, 814; H
NMR  (CDCl3): 3.87 (s, 3H), 6.95 (t, 2H), 7.45 (d, 1H), 7.95 (d, 2H), 8.30 (d, 2H). 13C NMR  (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  (CDCl3): 3.89 (s, 3H), 6.95 (t, 2H), 7.46 (d, 1H), 7.65 (m, 4H). 13C NMR  (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.

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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  (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  (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  (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  (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  (CDCl3): 3.75 (s, 3H), 3.80 (s, 3H), 3.86 (s, 3H), 6.67 (d,
13
1H), 6.98 (s, 1H), 7.55 (d, 1H), 7.82 (d, 2H), 8.37 (d, 2H). C NMR  (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,
1
1630, 1473, 1439, 1292, 1217, 1012, 823; H NMR  (CDCl3): 3.74 (s, 3H), 3.80 (s, 3H), 3.84 (s, 3H),
13
6.64 (d, 1H), 7.00 (s, 1H), 7.50 (t, 3H), 7.62 (d, 2H). C NMR  (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

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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,
1
1715, 1527, 1353, 1291, 1183, 1016, 789; H NMR  (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
 (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  (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
13
= 7.6, 1.2, 0.9 Hz, H8), 7.64 (2H, m, H3’ + H5’), 7.78 (2H, m, H2’ + H6’). C NMR  (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]iso-
indole-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  (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 
(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  (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).

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603
13C NMR  (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  (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  (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  (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,
1
1010, 827; H NMR  (CDCl3): 1.02 (3H, t, J = 6.8Hz, COOCH2-CH3), 2.44 (1H, dd, J = 11.7, 3.6 Hz,

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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  (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-tetra-
hydro-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  (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,  (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).

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13C NMR data of 9cM,  (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  (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  (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  (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

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(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.
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J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani,
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14. Molecular graphics were drawn using Molekel. P. Flükiger, H. P. Lüthi, S. Portmann, and J. Weber,
MOLEKEL 4.3; Swiss National Supercomputing Centre CSCS: Manno, Switzerland, 2000.
15. Solvent-phase free energies are reported, calculated using M06-2X/6-311++G(2df,2pd) single-point
electronic energies,16 with geometries and frequencies for thermal corrections (298.15 K) determined
at the M06-2X/6-31G* level. Solvent effects of toluene were computed on gas-phase geometries
using the SMD model17 at the latter level of theory.
16. For the 6-311++G(2df,2pd) basis set, see: (a) K. Raghavachari, J. S. Binkley, R. Seeger, and J. A.
Pople, J. Chem. Phys., 1980, 72, 650; (b) T. Clark, J. Chandrasekhar, G. W. Spitznagel, and P. v. R.
Schleyer, J. Comp. Chem., 1983, 4, 294; (c) M. J. Frisch, J. A. Pople, and J. S. Binkley, J. Chem.
Phys., 1984, 80, 3265.
17. For the SMD solvation model, see: A. V. Marenich, C. J. Cramer, and D. G. Truhlar, J. Phys. Chem.
B, 2009, 113, 6378.
18. H. T. Diem Phan, B. Kim, and Vy M. Dong, J. Am. Chem. Soc., 2009, 131, 15608.
19. Schering AG, U.S. patent, 6 600 036 B2. 2003.