Synthesis of pyrano[3,2-b]indole derivatives based on intramolecular hetero-Diels-Alder of 2-benzylidene-2,3-dihydro-1H-indol-3-ones

Article abstract of DOI:10.1002/hlca.200390218

Pyrano[3,2-b]indole derivatives 2-6 were synthesized in good yields from 1-acetyl-2-benzylidene-2,3-dihydro-1H-indol-3-ones 8 and 13-15 by an intramolecular hetero-Diels-Alder reaction. The structures of compounds 2a, 3a, 4, 5, and 6 were unambiguously es

Full text of DOI:10.1002/hlca.200390218

Helvetica Chimica Acta Vol. 86 (2003)
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Synthesis of Pyrano[3,2-b]indole Derivatives Based on Intramolecular
Hetero-DielsÀAlder of 2-Benzylidene-2,3-dihydro-1H-indol-3-ones
by Yann Daviona), BenoÓt Josepha)1), Vale¬rie Be¬ne¬teaua), Jean-Michel Le¬gerb), Christian Jarryb),
and Jean-Yves Me¬rour*a)
a
¬
¬
) Institut de Chimie Organique et Analytique, UMR-CNRS 6005, Universite d×Orleans, BP 6759, F-45067
¬
Orleans Cedex 2 (fax: (33)2-38-41-70-81; e-mail: jean-yves-merour@univ-orleans.fr)
b
¬
) EA 2962, Pharmacochimie, Universite Victor Segalen Bordeaux II, F-33076 Bordeaux Cedex
Pyrano[3,2-b]indole derivatives 2 6 were synthesized in good yields from 1-acetyl-2-benzylidene-2,3-
dihydro-1H-indol-3-ones 8 and 13 15 by an intramolecular hetero-DielsÀAlder reaction. The structures of
compounds 2a, 3a, 4, 5, and 6 were unambiguously established by X-ray analysis. Compounds 4 and 5 were
further aromatized to the corresponding derivatives 16 and 17, respectively.
1. Introduction. The hetero-DielsÀAlder reaction has been developed in the last
decade because of its elegant, economical, and stereocontrolled application in the
synthesis of polycyclic skeletons of natural products [1]. Thus, Tietze and co-workers
have performed hetero-DielsÀAlder reactions of 1-oxa-1,3-butadiene as a powerful
method for the synthesis of the pyran moiety [2]. By a similar approach, Dehaen and
co-workers [3] have prepared in a diastereoselective manner polycyclic heterocycles
with fused pyrano and thiopyrano rings. Under microwave irradiation conditions,
Raghunathan and co-workers [4] have reported the synthesis of pyranoquinolinone by
DielsÀAlder methodology with a high degree of chemoselectivity. A limited number of
benzylidenedihydroindol-2- or -3-ones have been reported to behave as dienophiles in
DielsÀAlder reactions. To the best of our knowledge, Desimoni and co-workers have
described the preparation of pyrano[2,3-b]indole derivatives from benzylidenedihy-
droindol-2-one in good yields via this approach [5]. Among our research projects, the
reactivity of 1-acetyl-2,3-dihydro-1H-indol-3-one (1a) was investigated in order to
prepare new heterocyclic compounds through cycloaddition reactions [6]. Thus, we
have already reported a convenient methodology for the preparation of pyrano[3,2-
b]indole derivatives [7]. Following this preliminary communication, we herein describe
the complete synthetic work with the corresponding structural analysis of the new
pentacyclic derivatives 2 6.
Results and Discussion. First, we investigated the synthesis of pyrano[3,2-b]indole
derivatives 2 and 3 (Scheme 1). Aldol condensation of 1-acetyl-2,3-dihydro-1H-indol-
3-one (1a) or 1-acetyl-2,3-dihydro-5-methoxy-1H-indol-3-one (1b) and 2-[(3-methyl-
but-2-enyl)oxy]benzaldehyde (7a) [8] or ethyl (E)-4-(2-formylphenoxy)but-2-enoate
1
¬
Present address: Laboratoire de Chimie Organique 1, Universite Claude Bernard Lyon 1, UMR-CNRS
)
√
5622, CPE - Batiment 308, 43 Boulevard du 11 Novembre 1918, F-69622 Villeurbanne Cedex

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Helvetica Chimica Acta Vol. 86 (2003)
(7b) [9], respectively, gave compounds 8a 8c in good yields (except 8c) as (E)/(Z)
diastereoisomer mixtures [10]. The intramolecular DielsÀAlder reaction was first
carried out with derivative 8a ((E)/(Z) ratio 17:83). The reaction was performed in a
sealed tube in toluene at 1408 for 3 days to afford, after a chromatographic separation,
the cis- and trans-pyrano[3,2-b]indole derivatives 2a and 3a, respectively, in 62%
overall yield.
Scheme 1. Synthesis of Compounds 2 and 3
The cyclization gave predominantly the cis-product (cis/trans ratio 76 :24) [10]. The
ratio did not exactly match the (E)/(Z) ratio of the starting heterodiene due to a partial
isomerization of the mixture during the cyclization reaction. The cis-configuration of
2a was supported by the coupling constant J(6a,13b) ˆ 4.4 Hz (trans-isomer 3a:

Helvetica Chimica Acta Vol. 86 (2003)
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J(6a,13b) ˆ 12.0 Hz) consistent with a trans-diaxal relationship and 2D-NOESY
experiments (connectivities were observed between HÀC(6a) and HÀC(13b)). In
addition, X-ray crystal-structure analyses of 2a and 3a were performed (Figs. 1 and 2),
and the cis- and trans-configurations, respectively, were unambigously established.
Fig. 1. ORTEP Drawing of the crystal structure of compound 2a with atom numbering (ellipsoids at 50%
probability)
Fig. 2. ORTEP Drawing of the crystal structure of compound 3a with atom numbering (ellipsoids at 50%
probability)

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All attempts to improve the yield of the intramolecular cyclization and the
diastereoselectivity failed. Addition of a Lewis acid into the medium accelerates the
reaction but decreases the yield (15 23%) by degradation of the starting material. In
addition, no ene product was obtained in our different attempts at intramolecular
cyclization.
The intramolecular-cyclization conditions (sealed tube, 1408, 3 days, toluene) were
applied to the derivatives 8b ((E)/(Z) ratio 19 :81) and 8c ((E)/(Z) ratio 40 :60). The
first one gave 2b (cis isomer, J(6a,13b) ˆ 5.4 Hz) and 3b (trans-isomer, J(6a,13b) ˆ
10.7 Hz) in moderate yield (36%) with a cis/trans diastereoisomer ratio of 69 :31.
Similarly from 8c, compounds 2c (cis-isomer, J(6a,13b) ˆ 4.7 and J(6a,7) ˆ 11.3 Hz)
and 3c (trans-isomer J(6a,13b) ˆ 9.8 and J(6a,7) ˆ 10.3 Hz) were obtained in 57% yield
(cis/trans ratio 63 :37). For the compounds 2c and 3c, the trans-configuration, observed
in compound 8c between the H-atoms Hb and Hc, was also conserved i.e., between
HÀC(6a) and HÀC(7)).
On the basis of these successful results, we investigated the intramolecular hetero-
DielsÀAlder reaction of substituted 1-acetyl-2-benzylidene-2,3-dihydro-1H-indol-3-
ones (13, 14, and 15 obtained from 1a and tert-butyl N-(2-formylphenyl)-N-(3-
methylbut-2-enyl)carbamate (11a), 2-(4-methylpent-3-enyl)benzaldehyde (11b) [11],
or 2-[(3-methylbut-2-enyl)sulfanyl]benzaldehyde (11c) [12], respectively, in the
presence of piperidine in 78 80% yield as a mixture of diastereoisomers (13: (E)/
(Z) 49 :5 1;14: (E)/(Z) 7 :93; 15: (E)/(Z) 21:79). It should be noted that starting
material 11c was prepared from 2-sulfanylbenzoic acid (9) [13] by a reduction/
alkylation sequence, followed by MnO2 oxidation (Scheme 2). Alkylation [14][15] with
1-bromo-3-methylbut-2-ene must be performed on the 2-sulfanylbenzyl alcohol rather
than 2-sulfanylbenzaldehyde in order to prevent dimerization.
Scheme 2. Preparation of Sulfonyl-Substituted Benzaldehyde 11c
Hetero-DielsÀAlder reactions were performed on 13 15 in a sealed tube (1408,
24 h) to afford exclusively the cis-diastereoisomers 4 6, respectively, in 86, 71, and
57% yield (Scheme 3).
The structures were again deduced from the 1H-NMR coupling constants of the ring
H-atoms HÀC(6a) and HÀC(13b) (4: J(6a,13b) ˆ 7.0 and 5: J(6a,13b) ˆ 6.3 Hz) and
2D-NOESY experiments. X-Ray crystal-structure analyses were also performed for
compounds 4 6 (see Fig. 3 for compound 4) indicating inter alia the cis-configuration.
In all cases studied, the cis-annelated products were predominantly or exclusively
obtained from benzylidenedihydroindol-2-ones. As already described by Tietze et al.
[12], under kinetic control, the endo-transition state A, leading to the cis-adduct, is
energetically more favorable than the exo-transition state B. The presence of a
heteroatom (XˆO, NÀPiv, S) instead of a CH2 group in the chain adjacent to the aryl

Helvetica Chimica Acta Vol. 86 (2003)
Scheme 3. Synthesis of Compounds 4
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6
Fig. 3. ORTEP Drawing of the crystal structure of compound 4 with atom numbering (ellipsoids at 50%
probability)

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Helvetica Chimica Acta Vol. 86 (2003)
moiety has no product-determining influence on the conformation of the transition
state (Fig. 4).
Fig. 4. endo- and exo-Transition states A and B, respectively
When compound 4 was treated with N-bromosuccinimide (NBS; 1.1 equiv.),
followed by reflux in basic medium, a satisfying 75% yield of the corresponding
aromatized derivative 16 was obtained. Similarly, the same conditions applied to 5
afforded derivative 17 in 50% yield (Scheme 4).
Scheme 4. Aromatization
In this study, new intramolecular DielsÀAlder adducts 2 6 have been obtained
from judiciously prepared substituted benzylidene-2,3-dihydro-1H-indol-3-ones. The
method described is useful to synthesize polycyclic derivatives with potential
pharmaceutical properties.
Experimental Part
General. All reactions requiring anh. conditions were conducted in flame-dried apparatus. Petroleum ether
(b.p. 40 608) was used as chromatographic eluent. 2-[(3-methylbut-2-enyl)oxy]benzaldehyde (7a) [8], ethyl 4-
(2-formylphenoxy)but-2-enoate (7b) [9], and 2-(4-methylpent-3-enyl)benzaldehyde (11b) [11] were prepared in
good yields according to literature procedures. TLC: on precoated silica-gel plates (Merck 60F254); visualization
with an UV lamp. Flash chromatography (FC): on a column with flash silica gel 60 Merck (40 63 mm) as the
stationary phase. M.p.: B¸chi capillary instrument; uncorrected. IR Spectra: Perkin-Elmer FTIR paragon 1000
spectrometer. NMR Spectra: at 300 K in CDCl3, with Bruker Avance DPX-250 spectrometer; chemical shifts in
ppm relative to Me4Si (TMS). MS: Perkin-Elmer SCIEX API-300; ion-spray methodology.
1. DielsÀAlder Reactions: Typical Procedure. In a sealed tube, a soln. of 8 (1.0 mmol) or 13 15 (1.0 mmol)
in toluene (10 ml) was stirred at 1408 for 3 or 4 d for 8 and 24 h for 13 15. After cooling, toluene was removed in
vacuo, the crude residue was purified by CC (silica gel; AcOEt/petroleum ether 2 :8) to give 2 and 3 except for
4
6 (AcOEt/petroleum ether 1:9). The diastereoisomers 2 and 3 were separated by CC.

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1-(6a,7,13,13b-Tetrahydro-7,7-dimethyl-6H-[1]benzopyrano[4',3':4,5]pyrano[3,2-b]indol-13-yl)ethan-1-one
(2a and 3a) [7]. Time 3 d; 62% yield (cis/trans 76 :24). cis-Isomer 2a: m.p. 165 166 8 (AcOEt/hexane). trans-
Isomer 3a: m.p. 195 197 8 (AcOEt/hexane).
1-(6a,7,13,13b-Tetrahydro-10-methoxy-7,7-dimethyl-6H-[1]benzopyrano[4',3':4,5]pyrano[3,2-b]indol-13-
yl)ethan-1-one (2b and 3b). Time 4 d; 36% yield (cis/trans 69 :31).
cis-Isomer 2b: oil. IR (film): 3059, 2926, 1691, 1615, 1489, 1135, 1033, 757. 1H-NMR (250 MHz, CDCl3): 7.77
(d, J ˆ 9.1, 1 arom. H); 7.17 (d, J ˆ 7.7, 1 arom. H); 7.09 (t, J ˆ 7.7, 1 arom. H); 7.03 (d, J ˆ 2.6, 1 arom. H); 6.95
(dd, J ˆ 2.6, 9.1, 1 arom. H); 6.83 (td, J ˆ 1.1, 7.7, 1 arom. H); 6.73 (dd, J ˆ 1.1, 7.7, 1 arom. H); 5.03 (d, J ˆ 5.4,
HÀC(13b)); 4.58 (dd, J ˆ 5.0, 12.1, 1 H, CH2); 4.42 (dd, J ˆ 3.1, 12.1, 1 H, CH2); 3.89 (s, Me); 2.78 (s, Me); 2.46
2.44 (m, HÀC(6a)); 1.61 (s, Me); 1.12 (s, Me). 13C-NMR (62.90 MHz, CDCl3): 169.3 (CO); 156.1 (C); 154.0 (C);
138.6 (C); 129.1 (CH); 129.0 (CH); 127.8 (CH); 124.9 (C); 123.0 (C); 120.9 (CH); 117.8 (C); 116.1 (CH); 115.9
(CH); 113.7 (CH); 100.3 (C); 78.7 (C); 66.1 (CH2); 55.7 (Me), 40.6 (C(13b)); 33.4 (C(6a)); 28.2 (Me); 27.2
‡
(Me); 23.0 (Me). MS: 378 ([M ‡ 1] ). Anal. calc. for C23H23NO4: C 73.19, H 6.14, N 3.71; found: C 72.81,
H 5.98, N 3.91.
trans-Isomer 3b: oil. IR (film): 3059, 2926, 1691, 1615, 1489, 1135, 1033, 757. 1H-NMR (250 MHz, CDCl3):
8.08 (d, J ˆ 9.0, 1 arom. H); 7.18 7.16 (m, 2 arom. H); 7.05( d, J ˆ 2.6, 1 arom. H); 7.00 (dd, J ˆ 2.6, 9.0,
1 arom. H); 6.92 (dd, J ˆ 1.1, 7.7, 1 arom. H); 6.87 (t, J ˆ 7.7, 1 arom. H); 4.44 (dd, J ˆ 6.3, 9.7, 1 H, CH2); 4.42
(d, J ˆ 10.7, HÀC(13b)); 4.18 (dd, J ˆ 9.7, 12.3, 1 H, CH2); 3.90 (s, Me); 2.61 (s, Me); 2.27 2.21 (m, HÀC(6a));
1.52 (s, Me); 1.39 (s, Me). 13C-NMR (62.90 MHz, CDCl3): 169.5 (CO); 156.3 (C); 153.8 (C); 140.4 (C); 129.7
(C); 128.8 (CH); 128.0 (CH); 124.7 (CH); 124.5(C); 121.1 (CH); 117.1 (CH); 116.7 (CH); 115.3 (C); 114.2
(CH); 100.1 (C); 77.1 (C); 69.0 (CH2); 55.8 (Me); 47.5 (C(13b)); 35.5 (C(6a)); 27.3 (Me); 26.4 (Me); 18.4 (Me).
‡
MS: 378 ([M ‡ 1] ). Anal. calc. for C23H23NO4: C 73.19, H 6.14, N 3.71; found: C 72.94, H 6.31, N 3.76.
Ethyl 13-Acetyl-6a,7,13,13b-tetrahydro-6H-[1]benzopyrano[4',3':4,5]pyrano[3,2-b]indole-7-carboxylate (2c
and 3c). Time 24 h; 57% yield (cis/trans 60 :40).
cis-Isomer 2c: M.p. 197 1988 (AcOEt/hexane). IR (KBr): 2973, 2925, 1746, 1635, 1489, 1461, 1373, 1030,
755. 1H-NMR (250 MHz, CDCl3): 7.81 (d, J ˆ 8.3, 1 arom. H); 7.59 (d, J ˆ 7.6, 1 arom. H ) ; 7.40 7.25
(m, 2 arom. H); 7.14 7.08 (m, 2 arom. H); 6.86 6.79 (m, 2 arom. H); 5.24 (d, J ˆ 4.7, HÀC(13b)); 4.71
(d, J ˆ 11.3, HÀC(7)); 4.45 4.41 ( m, CH2); 4.39 (q, J ˆ 7.1, CH2); 2.88 (s, Me); 2.75 2.68 ( m, HÀC(6a));
1.40 (t, J ˆ 7.1, Me ) . 13C-NMR (62.90 MHz, CDCl3): 169.6 (CO); 169.5(CO); 152.2 (C); 138.5(C); 134.0 (C);
130.3 (CH); 128.3 (CH); 125.4 (CH); 123.4 (CH); 123.0 (C); 122.9 (C); 121.3 (CH); 118.9 (C); 118.4 (CH); 117.0
(CH); 115.0 (CH); 74.1 (C(7)); 65.9 (CH2); 62.0 (CH2); 34.0 (C(13b)); 33.8 (C(6a)); 27.8 (Me); 14.3 (Me). MS:
‡
392 ([M ‡ 1] ). Anal. calc. for C23H21NO5: C 70.58, H 5.41, N 3.58; found: C 70.87, H 5.61, N 3.56.
trans-Isomer 3c: M.p. 217 2188 (AcOEt/hexane). IR (KBr): 2973, 2925, 1746, 1635, 1489, 1461, 1373, 1030,
755. 1H-NMR (250 MHz, CDCl3): 8.13 (d, J ˆ 8.3, 1 arom. H); 7.67 (d, J ˆ 7.8, 1 arom. H); 7.41 (t, J ˆ 7.8,
1 arom. H); 7.31 (t, J ˆ 7.6, 1 arom. H); 7.16 (t, J ˆ 7.6, 1 arom. H); 7.09 (d, J ˆ 7.6, 1 arom. H); 6.93 6.84
(m, 2 arom. H); 4.58 (d, J ˆ 9.8, HÀC(13b)); 4.49 (d, J ˆ 10.3, HÀC(7)); 4.40 4.35( m, 2 CH2); 2.66 (s, Me);
2.55 2.48 (m, HÀC(6a)); 1.37 (t, J ˆ 7.1, Me ) . 13C-NMR (62.90 MHz, CDCl3): 169.9 (CO); 168.2 (CO); 154.3
(C); 141.7 (C); 134.8 (C); 128.5(CH); 128.2 (C); 126.1 (CH); 124.1 (CH); 123.6 (CH); 122.5(C); 121.5(CH);
118.1 (CH); 117.4 (CH); 115.9 (C); 115.5 (CH); 76.6 (C(7)); 68.0 (CH2); 62.2 (CH2); 41.9 (C(6a)); 38.2
‡
(C(13b)); 26.8 (Me); 14.3 (Me). MS: 392 ([M ‡ 1] ). Anal. calc. for C23H21NO5: C 70.58, H 5.41, N 3.58; found:
C 70.25, H 5.45, N 3.43.
1-(13-Acetyl-5,6,6a,7,13,13b-hexahydro-7,7-dimethylindolo[2',3':5,6]pyrano[3,4-c]quinolin-5-yl)-2,2-di-
methylpropan-1-one (4). According to the procedure for the synthesis of 2 and 3, compound 4 was prepared
from 13. Time 24 h; 86% yield; cis-isomer exclusively; m.p. 225 226 8 (CH2Cl2/hexane).
1-(5,6,6a,7,13,13b-Hexahydro-7,7-dimethylbenzo[5,6][2]benzopyrano[4,3-b]indol-13-yl)ethan-1-one (5).
According to the procedure for the synthesis of 2 and 3, compound 5 was prepared from 14 in 24 h; yield
71%; cis-isomer exclusively. M.p. 173 1758 (AcOEt/petroleum ether). IR (KBr): 3027, 2902, 1686, 1623, 1485,
1455, 1126, 753. 1H-NMR (250 MHz, CDCl3): 8.13 (d, J ˆ 8.2, 1 arom. H); 7.60 (br. d, J ˆ 7.5, 1 arom. H); 7.39
7.24 (m, 2 arom. H); 7.16 7.00 (m, 4 arom. H); 4.39 (d, J ˆ 7.0, HÀC(13b)); 2.75 2.64 ( m, CH2, HÀC(6a));
2.55 (s, Me); 2.40 2.29 (m, 1 H, CH2); 1.37 (s, Me); 1.23 1.07 (m, 1 H, CH2); 0.66 (s, Me). 13C-NMR
(62.90 MHz, CDCl3): 169.3 (CO); 139.3 (C); 139.2 (C); 138.7 (C); 134.7 (C); 126.5(CH); 126.4 (CH); 126.3
(2 CH); 125.2 (CH); 124.0 (C); 123.1 (CH); 117.7 (CH); 115.9 (CH); 115.8 (C); 80.0 (C); 41.4 (C(13b)); 36.6
‡
(C(6a)); 28.4 (CH2); 28.1 (Me); 26.6 (Me); 25.3 (CH2); 19.8 (Me). MS: 346 ([M ‡ 1] ). Anal. calc. for
C23H23NO2: C 79.97, H 6.71, N 4.05; found: C 79.75, H 6.89, N 3.91.
1-(6a,7,13,13b-tetrahydro-7,7-dimethyl-6H[1]benzothiopyrano[4',3':4,5]pyrano[3,2-b]indol-13-yl)ethan-1-
one (6). According to the procedure for the synthesis of 2 and 3, compound 6 was prepared from 15 ((E)/(Z)

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mixture). Time 24 h; 57% yield; cis-isomer exclusively. Brown solid. M.p. 2128. IR (KBr): 3054, 2982, 2932,
1
1704, 1633, 1480, 1459, 1445, 1416, 1370. H-NMR (250 MHz, CDCl3): 8.19 (d, J ˆ 8.1, 1 arom. H); 7.61 (d, J ˆ
7.1, 1 arom. H); 7.44 (d, J ˆ 7.7, 1 arom. H); 7.37 (t, J ˆ 8.1, 1 arom. H); 7.29 (t, J ˆ 7.7, 1 arom. H); 7.21 7.05
(m, 3 arom. H); 4.50 (d, J ˆ 6.3, HÀC(13b)); 3.20 3.05( m, CH2); 2.41 (s, MeCO); 2.39 2.31 (m, HÀC(6a));
1.39 (s, Me); 0.81 (s, Me). 13C-NMR (62.90 MHz, CDCl3): 169.1 (CO); 140.4 (C); 139.4 (C); 136.5(C); 134.8
(C); 129.5(CH); 127.6 (CH); 127.0 (CH); 126.5(CH); 125.4 (CH); 123.4 (C); 123.1 (CH); 117.5(CH); 116.0
(CH); 114.5(C); 79.3 (C); 47.5(CH); 39.1 (CH); 31.8 (CH 2); 28.3 (Me); 26.2 (Me); 19.9 (Me). MS: 364 ([M ‡
‡
1] ). Anal. calc. for C22H21NO2S: C 72.70, H 5.82, N 3.85; found: C 73.07, H 5.99, N 3.97.
2. General Procedure for the Aldolization Reaction. A soln. of 1 (1.0 mmol), 7 (1.5mmol), and piperidine
(0.25ml) in toluene (25ml) was stirred at 110 8 for a given time. After cooling and evaporation of toluene, the
crude residue was purified by CC (silica gel; AcOEt/petroleum ether 1 :9 for 8a and 8b and 2 :8 for 8c) to give 8.
1-Acetyl-2,3-dihydro-2-(1-{2-[(3-methylbut-2-enyl)oxy]phenyl}methylidene)-1H-indol-3-one (8a). Time
1 h; yield 83% ((Z)/(E) 83 :17). Oil.
(Z)-Isomer: IR (film): 3070, 2926, 1713, 1602, 1487, 1486, 1456, 1004, 755. 1H-NMR (250 MHz, CDCl3): 8.32
(d, J ˆ 8.4, 1 arom. H); 7.84 (d, J ˆ 7.3, 1 arom. H); 7.63 (d, J ˆ 7.3, 1 arom. H); 7.52 (s, Ha); 7.46 (d, J ˆ 7.3,
1 arom. H); 7.38 7.24 (m, 2 arom. H); 7.01 6.93 (m, 2 arom. H); 5.45 (br. t, J ˆ 6.5, Hb); 4.58 (d, J ˆ 6.2, CH2);
1.89 (s, Me); 1.74 (s, Me); 1.70 (s, Me). 13C-NMR (62.90 MHz, CDCl3): 185.9 (CO); 170.4 (CO); 157.6 (C); 150.1
(C); 138.1 (C); 136.2 (CH); 134.9 (C); 131.5(CH); 131.0 (NC ˆCHC6H4); 124.7 (CH); 124.2 (CH); 123.9 (C);
123.5(C); 120.9 (CH); 119.4 (Me 2CˆC); 118.7 (CH); 117.7 (CH); 112.5(CH); 65.5(CH 2); 25.8 (Me), 25.0
‡
(Me), 18.4 (Me). MS: 348 ([M ‡ 1] ). Anal. calc. for C22H21NO3: C 76.06, H 6.09, N 4.03; found: C 75.82,
H 5.91, N 3.85.
1-Acetyl-2,3-dihydro-5-methoxy-2-(1-{2-[(3-methylbut-2-enyl)oxy]phenyl}methylidene)-1H-indol-3-one
(8b). Time 4.5h; yield 86% (( Z)/(E) 81 :19). Oil.
(Z)-Isomer: IR (film): 3078, 2931, 1687, 1629, 1486, 1132, 1027, 753. 1H-NMR (250 MHz, CDCl3): 8.25
(d, J ˆ 9.0, 1 arom. H); 7.52 (s, Ha); 7.47 7.17 (m, 5arom. H); 7.04 6.89 ( m, 1 arom. H); 5.45 (t, J ˆ 6.4, Hb);
4.58 (d, J ˆ 6.3, CH2); 3.85( s, Me); 1.87 (s, Me); 1.75( s, Me); 1.71 (s, Me). 13C-NMR (62.90 MHz, CDCl3): 186.0
(CO); 170.2 (CO); 157.7 (C); 157.1 (C); 144.8 (C); 138.1 (C); 135.5 (C); 131.6 (CH); 131.0 (NCˆCHC6H4);
124.9 (C); 124.5(CH); 123.6 (CH); 120.9 (CH); 119.4 (C); 119.2 (CH); 119.0 (Me CˆC); 112.5(CH); 105.8
2
‡
(CH); 65.6 (CH2); 56.0 (Me), 25.9 (Me); 24.9 (Me); 18.4 (Me). MS: 378 ([M ‡ 1] ). Anal. calc. for C23H23NO4:
C 73.19, H 6.14, N 3.71; found: C 72.87, H 6.30, N 3.56.
Ethyl (E)-4-{2-[(1-Acetyl-2,3-dihydro-3-oxo-1H-indol-2-ylidene)methyl]phenoxy)}but-2-enoate (8c). Time
8 h; yield 37% ((Z)/(E) 60 :40). Oil.
(Z)-Isomer: IR (film): 3078, 2931, 1704, 1487, 1462, 1031, 756. 1H-NMR (250 MHz, CDCl3): 8.26 (d, J ˆ 8.4,
1 arom. H); 7.83 (d, J ˆ 7.5, 1 arom. H); 7.62 (d, J ˆ 7.5, 1 arom. H); 7.51 (s, Ha); 7.47 (d, J ˆ 8.5, 1 arom. H);
7.39 7.22 (m, 2 arom. H); 7.08 6.98 (m, 2 arom. H); 6.87 6.83 (m, Hb); 6.06 (d, J ˆ 15.6, EtOCOCH); 4.75
(m, CH2); 4.15( q, J ˆ 7.1, CH2); 1.88 (s, Me); 1.25( t, J ˆ 7.1, Me ) . 13C-NMR (62.90 MHz, CDCl3): 182.8 (CO);
170.2 (CO); 165.9 (CO); 156.4 (C); 150.0 (C); 141.4 (CH); 137.9 (C); 136.4 (CH); 135.1 (C); 131.8 (CH); 131.1
(CH); 129.1 (CH); 124.8 (CH); 124.3 (CH); 122.7 (NCˆCHC6H4); 122.5(C); 121.7 (CH); 117.6 (CH); 112.2
‡
(CHˆCHCH2); 67.0 (CH2), 60.7 (CH2), 24.9 (Me), 14.3 (Me). MS: 392 ([M ‡ 1] ). Anal. calc. for C23H21NO5:
C70.58, H 5.41, N 3.58; found: C 70.77, H 5.57, N 3.45.
N-(2-Formylphenyl)-2,2-dimethyl-N-(3-methylbut-2-enyl)propanamide (11a). To a soln. of N-(2-formyl-
phenyl)-2,2-dimethylpropanamide (2.6 g, 12.5mmol) in dry DMF (25ml) was added portionwise NaH (607 mg,
15.4 mmol, 60% in dispersion) at 08. Then, 2-methyl-4-bromobut-2-ene (2.8 g, 18.8 mmol) dissolved in DMF
(25ml) was added dropwise at 0 8. The final mixture was stirred for 5h at r.t. The mixture was poured into H 2O
(100 ml) and then extracted with AcOEt (2 Â 40 ml). The org. layer was washed with brine, then dried
(MgSO4), and evaporated in vacuo. The crude residue was purified by CC (silica gel; petroleum ether/AcOEt
95:5) to afford 11a (2.2 g, 65%). Oil. IR (film): 3088, 2994, 2870, 1688, 1638, 1597, 1394, 1356, 1172, 751.
1H-NMR (250 MHz, CDCl3): 10.09 (s, CHO); 7.96 (dd, J ˆ 1.6, 7.7, 1 arom. H); 7.63 (dt, J ˆ 1.6, 7.7, 1 arom. H);
7.48 (t, J ˆ 7.7, 1 arom. H); 7.24 (d, J ˆ 7.7, 1 arom. H); 5.27 (t, J ˆ 7.0, ˆCH); 4.33 (dd, J ˆ 7.1, 13.9, 1 H, CH2);
4.15( dd, J ˆ 8.1, 13.9, 1 H, CH2); 1.61 (s, Me); 1.15( s, Me); 1.03 (s, 3 Me). 13C-NMR (62.90 MHz, CDCl3): 189.3
(CO); 177.2 (CO); 145.2 (C); 138.2 (C); 134.5(CH); 133.6 (C); 131.1 (CH); 128.5(CH); 128.4 (CH); 117.9
‡
(CH); 50.8 (CH2); 41.1 (C); 29.2 (3 Me); 25.4 (Me); 17.1 (Me). MS: 274 ([M ‡ 1] ). Anal. calc. for C17H23NO2:
C 74.69, H 8.48, N 5.12; found: C 74.35, H 8.38, N 4.95.
N-{2-[(1-Acetyl-2,3-dihydro-3-oxo-1H-indol-2-ylidene)methyl]penyl}-2,2-dimethyl-N-(3-methylbut-2-
enyl)propanamide (13). According to the procedure for the synthesis of 8, 13 was prepared from 1a and 11a.
Time 3 h; 78% yield ((Z)/(E) 51:49). Oil. IR (film): 3062, 2967, 1690, 1639, 1480, 1381, 1361, 1276, 757. 1H-NMR

Helvetica Chimica Acta Vol. 86 (2003)
2695
(250 MHz, CDCl3): (E)-Isomer: 8.21 (br. d, J ˆ 8.3, 1 arom. H); 8.10 8.05( m, 1 arom. H); 7.87 (dd, J ˆ 1.0, 7.5,
1 arom. H); 7.72 7.68 (m, 1 arom. H, Ha); 7.43 7.40 (m, 2 arom. H); 7.35 7.24 ( m, 1 arom. H); 7.23 7.19
(m, 1 arom. H); 5.36 5.23 (m, Hb); 4.66 (dd, J ˆ 6.1, 14.3, 1 H, CH2); 3.90 3.68 (m, 1 H, CH2); 2.63 (s, Me);
1.66 (s, Me); 1.38 (s, Me); 1.13 (s, 3 Me). 1H-NMR (250 MHz, CDCl3): (Z)-Isomer: 8.21 (br. d, J ˆ 8.3,
1 arom. H); 8.07 8.05( m, 1 arom. H); 7.76 (dd, J ˆ 1.0, 7.5, 1 arom. H); 7.67 7.63 (m, 1 arom. H, Ha); 7.39
7.37 (m, 2 arom. H); 7.35 7.24 ( m, 1 arom. H); 7.16 7.13 (m, 1 arom. H); 5.36 5.23 (m, Hb); 4.39 (dd, J ˆ 6.1,
14.3, 1 H, CH2); 3.90 3.68 (m, 1 H, CH2); 2.12 (s, Me); 1.5 6 (s, Me); 1.23 (s, Me); 1.05( s, 3 Me). 13C-NMR
(62.90 MHz, CDCl3): (E)/(Z)-mixture: 185.5 (CO): 182.6 (CO); 178.0 (CO); 177.8 (CO); 169.9 (CO); 168.9
(CO); 150.1 (C); 148.3 (2 C); 144.3 (C); 142.7 (C); 136.4 (C); 136.3 (CH); 135.5 (C); 135.2 (C); 132.9 (C); 132.2
(CH); 130.9 (2 CH); 130.3 (CH); 130.2 (CH); 130.1 (CH); 128.0 (CH); 127.2 (CH); 126.0 (CH); 125.1 (CH);
124.7 (CH); 124.3 (2 CH); 124.0 (2 C); 119.0 (CH); 118.9 (CH); 117.7 (CH); 117.5(CH); 117.3 (2 CH); 50.5
(CH2); 41.2 (C); 41.0 (C); 29.2 (3 Me); 26.6 (Me); 25.8 (Me); 25.7 (Me); 25.2 (Me); 17.7 (Me); 17.5 (Me). MS:
‡
431 ([M ‡ 1] ). Anal. calc. for C27H30N2O3: C 75.32, H 7.02, N 6.51; found: C 75.15, H 7.20, N 6.50.
1-Acetyl-2,3-dihydro-2-{[2-(4-methylpent-3-enyl)phenyl]methylidene}-1H-indol-3-one (14). According to
the procedure for the synthesis of 8, 14 was prepared from 1a and 11b [11]. Time 9 h; yield 80% ((Z)/(E) 93 :7).
Oil.
(Z)-Isomer: IR (film): 3061, 2927, 1697, 1459, 1008, 758. 1H-NMR (250 MHz, CDCl3): 8.31 (d, J ˆ 8.2,
1 arom. H); 7.83 (d, J ˆ 7.6, 1 arom. H); 7.63 (t, J ˆ 8.2, 1 arom. H); 7.50 (s, Ha); 7.44 (d, J ˆ 7.3, 1 arom. H);
7.31 7.18 (m, 4 arom. H); 5.19 (br. t, J ˆ 6.1, Hb); 2.79 (t, J ˆ 7.4, CH2); 2.33 (q, J ˆ 7.4, CH2); 1.80 (s, MeCO);
1.69 (s, Me); 1.5 9 (s, Me). 13C-NMR (62.90 MHz, CDCl3): 185.5 (CO); 170.1 (CO); 150.1 (C); 142.5 (C); 136.3
(CH); 135.4 (C); 132.9 (C); 132.8 (C); 130.3 (CH); 129.8 (CH); 128.9 (CH); 126.6 (CH); 124.8 (CH); 124.1
(CH); 123.7 (C); 123.0 (CH); 120.4 (CH); 117.7 (CH); 33.8 (CH2); 29.2 (CH2); 25.7 (Me); 25.0 (Me); 17.7 (Me).
‡
MS: 346 ([M ‡ 1] ). Anal. calc. for C23H23NO2: C 79.97, H 6.71, N 4.05; found: C 80.18, H 6.67, N 4.19.
1-Acetyl-2,3-dihydro-2-{2-[(3-methylbut-2-enyl)sulfanyl]benzylidene}-1H-indol-3-one (15). According to
the procedure for the synthesis of 8, 15 was prepared from 1a and 11c [12][14] in 4 h; yield 78% ((Z)/(E)
79 :21). Yellow oil. IR (film): 3056, 2974, 2930, 1694, 1634, 1459, 1365, 1311, 1277, 1188. 1H-NMR (250 MHz,
CDCl3): (E)-Isomer: 8.23 (d, J ˆ 8.3, 1 arom. H); 7.84 (d, J ˆ 7.6, 1 arom. H); 7.77 (s, Ha); 7.73 (d, J ˆ 7.6,
1 arom. H); 7.63 (t, J ˆ 7.1, 1 arom. H); 7.46 7.21 (m, 4 arom. H); 5.25 (br. t, J ˆ 7.8, Hb); 3.50 (d, J ˆ 7.8, CH2);
2.68 (s, MeCO); 1.66 (s, Me); 1.5 4 (s, Me). 1H-NMR (250 MHz, CDCl3): (Z)-Isomer: 8.30 (d, J ˆ 8.3,
1 arom. H); 7.86 (d, J ˆ 7.6, 1 arom. H); 7.65( t, J ˆ 7.9, 1 arom. H); 7.61 (s, Ha); 7.44 7.18 (m, 5arom. H); 5.33
(br. t, J ˆ 7.6, Hb); 3.63 (d, J ˆ 7.6, CH2); 1.80 (s, MeCO); 1.74 (s, Me); 1.69 (s, Me). 13C-NMR (62.90 MHz,
CDCl3): (Z)-Isomer: 185.4 (CO); 170.2 (CO); 150.0 (C); 139.1 (C); 137.5 (C); 136.3 (CH); 135.8 (C); 134.1 (C);
129.7 (CH); 129.1 (CH); 129.0 (CH); 126.0 (CH); 124.8 (CH); 124.1 (CH); 123.7 (C); 119.9 (CH); 118.2 (CH);
‡
117.7 (CH); 31.8 (CH2); 25.6 (Me); 24.8 (Me); 17.8 (Me). MS: 386.5 ([M ‡ Na] ). Anal. calc. for C22H21NO2S:
C 72.70, H 5.82, N 3.85; found: C 72.42, H 5.67, N 3.74.
1-(7,13-Dihydro-7,7-dimethylindolo[2',3':5,6]pyrano[3,4-c]quinolin-13-yl)ethan-1-one (16). To a soln. of 4
(133 mg, 0.31 mmol) in CCl4 (10 ml) at reflux was added N-bromosuccinimide (NBS; 55 mg, 0.31 mmol). The
final mixture was stirred for 45min at reflux. After cooling, the solvent was removed in vacuo, and CH2Cl2 was
added (10 ml). Then,Et3N (0.5ml, 3.6 mmol) was added, and the soln. was stirred for 2 h at reflux. The latter was
poured into H2O (10 ml). The medium was acidified with 37% HCl (1 ml) and extracted twice with CH2Cl2 (2 Â
10 ml). The org. layer was washed with brine, then dried (MgSO4), and evaporated in vacuo. The crude residue
was purified by CC (silica gel; petroleum ether/AcOEt 8 :2) to afford 16 (79 mg, 75%) as an oil [7].
1-(7,13-Dihydro-7,7-dimethylbenzo[5,6][2]benzopyrano[4,3-b]indol-13-yl)ethan-1-one (17). According to
the procedure for the synthesis of 16, 17 was prepared from 5 in 50% yield. Oil. IR (film): 3057, 2929, 1701, 1453,
1277, 1107, 751. 1H-NMR (250 MHz, CDCl3): 8.45 8.39 ( m, 2 arom. H); 7.80 (br. d, J ˆ 7.8, 1 arom. H); 7.73
(d, J ˆ 8.5, 1 arom. H); 7.65 (br. d, J ˆ 7.0, 1 arom. H); 7.56 7.41 (m, 4 arom. H); 7.35( t, J ˆ 7.5, 1 arom. H); 2.16
(s, Me); 2.03 (s, Me); 1.66 (s, Me). 13C-NMR (62.9 MHz, CDCl3): 172.7 (CO); 144.1 (C); 138.0 (C); 133.6 (C);
133.5(C); 128.6 (CH); 127.4 (CH); 127.0 (CH); 126.9 (CH, C); 126.2 (CH); 125.1 (CH); 123.9 (CH); 122.5(C);
122.4 (C); 121.8 (CH); 120.3 (C); 118.0 (CH); 116.3 (CH); 81.9 (C); 27.4 (Me); 27.3 (Me); 24.6 (Me). MS: 342
‡
([M ‡ 1] ). Anal. calc. for C23H19NO2: C 80.92, H 5.61, N 4.10; found: C 81.27, H 5.43, N 3.95.
Crystallographic data for the structures 2a, 3a, and 4 (Table) have been deposited with the Cambridge
Crystallographic Data Centre as deposition No CCDC-203686, CCDC-203687, and CCDC-203688. Copies of the
data can be obtained, free of charge, on application to the CCDC, 12 Union Road, Cambridge CB21EZ (fax:
‡44(1223)336033; e-mail: ccdc.cam.ac.uk).
¬
The authors gratefully acknowledge the technical assistance of Ms. Amelie Tessier.

2696
Helvetica Chimica Acta Vol. 86 (2003)
Table 1. Crystallographic Data of Compounds 2a, 3a, and 4
Parameters
2a
3a
4
Empirical formula
Formula weight [g ¥ molÀ1
Temp. [K]
C22H21N2O3
347.40
296(2)
C22H21N2O3
347.40
296(2)
C27H30N2O3
450.53
296(2)
]
Crystal size [mm]
Wavelength [ä]
Crystal system
Space group
Goodness-of-fit on F2
Unit-cell parameters
0.50 Â 0.37 Â 0.250.37
 0.10  0.050.30
 0.15  0.10
1.54178
1.54178
1.54180
triclinic
P1
monoclinic
P21/c
1.049
monoclinic
P21/n
1.049
≈
1.035
a ˆ 8.793(2) ä
b ˆ 15.462(4) ä
c ˆ 12.743(8) ä
a ˆ 908
a ˆ 10.523(3) ä
b ˆ 17.839(2) ä
c ˆ 10.586(3) ä
a ˆ 908
a ˆ 11.063(1) ä
b ˆ 11.138(2) ä
c ˆ 11.222(1) ä
a ˆ 103.88(1)8
b ˆ 90.98(1)8
g ˆ 119.26(1)8
1156.3(3)
2, 1237 mg/m3
0.641 mmÀ1
460
b ˆ 91.39(3)8
g ˆ 908
b ˆ 116.06(2)8
g ˆ 908
Volume [ä3]
Z, calc. density
Absorption coefficient
F(000)
1732.0(12)
4, 1.332 mg/m3
0.711 mmÀ1
736
1785.2(7)
4, 1293 mg/m3
0.689 mmÀ1
736
q Range for data collection
Index ranges
4.50 to 64.928
À 10 ꢀ h ꢀ 10
0 ꢀ k ꢀ 18
0 ꢀ l ꢀ 14
4.94 to 54.948
À 11 ꢀ h ꢀ 10
0 ꢀ k ꢀ 18
0 ꢀ l ꢀ 11
4.11 to 54.958
À 11 ꢀ h ꢀ 11
À 11 ꢀ k ꢀ 11
0 ꢀ l ꢀ 11
Reflections coll.
2898
2230
2890
Max. and min. transmission 0.8424 and 0.7177
0.9663 and 0.78450.9387 and 0.8310
Refinement method
full-matrix
full-matrix
full-matrix
east-squares on F2
least-squares on F2
2230, 3, 246
R1 ˆ 0.0535,
wR2 ˆ 0.1085
R1 ˆ 0.1046,
wR2 ˆ 0.1349
0.0039(4)
least-squares on F2
2890, 0, 302
R1 ˆ 0.0433,
wR2 ˆ 0.1000
R1 ˆ 0.0776,
wR2 ˆ 0.1196
0.0108(7)
Data, restraints, parameters 2898, 0, 248
Final R indices
R1 ˆ 0.0570,
wR2 ˆ 0.1420
R1 ˆ 0.0906,
wR2 ˆ 0.1691
0.0095(10)
R Indices (all data)
Extinction coefficient
Largest diff. peak and hole
0.235and À0.239 e ¥ äÀ3 0.158 and À0.179 e ¥ äÀ3 0.217 and À0.149 e ¥ äÀ3
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Helvetica Chimica Acta Vol. 86 (2003)
2697
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1
[10] Determined by H-NMR.
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Received March 7, 2003