New 3-vinylation products of indole and investigation of its Diels-Alder reactivity: synthesis of unusual Morita-Baylis-Hillman-type products

Article abstract of DOI:10.1016/j.tet.2010.02.081

3-Vinylindoles as precursors of carbazole and bis-indole derivatives were synthesized. Then, to form new carbazoles, Diels-Alder reactivity of these vinylindoles was studied with various dienophiles. During the cycloaddition reaction, unusual Morita-Baylis-Hillman-type products were observed. The structure and the formation mechanism of the products is discussed.

Full text of DOI:10.1016/j.tet.2010.02.081

Tetrahedron 66 (2010) 3214–3221
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New 3-vinylation products of indole and investigation of its Diels–Alder
reactivity: synthesis of unusual Morita–Baylis–Hillman-type products
,
Ali Enis Sadak a, Tayfun Arslan b, Neslihan Celebioglu a, Nurullah Saracoglu a
*
a Department of Chemistry, Faculty of Sciences, Atatu¨rk University, Erzurum 25240, Turkey
b Department of Chemistry, Faculty of Arts and Sciences, Giresun University, Giresun 28049, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
3-Vinylindoles as precursors of carbazole and bis-indole derivatives were synthesized. Then, to form new
carbazoles, Diels–Alder reactivity of these vinylindoles was studied with various dienophiles. During the
cycloaddition reaction, unusual Morita–Baylis–Hillman-type products were observed. The structure and
the formation mechanism of the products is discussed.
Received 1 December 2009
Received in revised form
22 January 2010
Accepted 22 February 2010
Available online 25 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
H
N
The indole (1) and carbazole (2) moieties occur widely in syn-
thetic and natural products.1–6 Due to a wide range of biological
activities, the synthesis of carbazoles and bis-indole alkaloids has
received considerable interest. Ever since the first isolation of
a simple carbazole alkaloid, murrayanine (3), organic chemists have
been interested in the synthesis of carbazole alkaloids.7 An indo-
locarbazole alkaloid staurosporine (4) has very interesting
biological activities such as antimicrobial, hypotensive, cytotoxic
properties, inhibition of protein kinase C, and platelet aggregation
inhibition.8–10 Vinblastine (5) isolated from Catharanthus roseus,
a more complex annulated system containing the indole ring, has
been widely used as an agent for cancer chemotherapy (Fig. 1).11–13
Vinylindoles have been shown to act as heterocyclic dienes in
HOMOdiene-controlled Diels–Alder reactions, and therefore, as
valuable synthons in highly functionalized carbazole ring systems,
indole alkaloids, and carbolines.14–26 The Michael addition is one of
the most important carbon–carbon and carbon-heteroatom bond-
forming reactions in organic synthesis.27–38 For the synthesis of
carbazoles and bis-indoles, we are examining the synthesis of new
3-vinylindoles 6–9 and investigating their Diels–Alder reactivity.
Our retro-synthetic approach to carbazoles and bis-indoles was
delineated through the retro-synthetic analysis depicted in
Figure 2, which identifies the key step as well as vinylindoles 6–9.
Thus, bis-indole 10 could be accessed through the Fisher indoliza-
tion of the cyclic ketone 11. The carbazole derivative 11 could be
derived from vinylindole 6 by [4þ2]-cycloaddition.
O
R2
N
N
N
H
N
H
R1
O
1
2 R1=R2=H
H3C
MeO
3 R1=OMe, R2=CHO
OH
NHMe
4
N
H
N
H
N
MeO2C
MeO
H
OH
N
OAc
5
H
Me
CO2Me
Figure 1. Some indoles and carbazoles.
2. Results and discussions
First, we prepared Michael adduct 13 from the Bi(NO3)3$5H2O-
catalyzed conjugate addition reaction between indole 1 and
cyclopent-2-enone 12 (Scheme 1).39 Reaction of the Michael
addition product 13 with 2,3-dichloro-5,6-dicyanobenzoquinone
(DDQ) yielded vinylindole 6, an
Although vinylindole was prepared by a similar strategy,
molecules 7 and 9 could be synthesized via different routes.
a,b-unsaturated ketone (Scheme 1).
8
* Corresponding author. Tel.: þ90 442 231 4425; fax: þ90 442 236 0948.
E-mail address: nsarac@atauni.edu.tr (N. Saracoglu).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.081

A.E. Sadak et al. / Tetrahedron 66 (2010) 3214–3221
3215
formation of bromo-compound 24 as a single product (Scheme 3).
The configuration of bromine atom and indole ring in 24 was de-
termined by the coupling constants of the relevant protons as well as
the calculated optimized molecule geometry. The vicinal coupling
O
O
n(CH2)
N
constant (3J¼2.5 Hz) for a methine proton (a doublet at
¼5.02 ppm)
d
H
6-9
bonding to the bromine atom confirms the cis position of the indole
ring and the bromine. The calculated dihedral angle (60.50ꢀ) by the
AM1 method is in agreement with the proposed structure 24. The
reaction of 24 with LiCl was carried out in DMF at 160 ꢀC for 3 h to
provide a mixture of three products, which contained vinylindole 9,
isomerization product 25, and rearrangement product 26. The mix-
ture was submitted to silica gel column chromatography. Following
chromatography, we managed to separate the two vinylindoles, 9
and 26. Furthermore, isomerization product 25 could be isolated as
a mixture with vinylindole 9. While vinylindoles 9 and 26 were
initial products, isomer 25 was formed by isomerization of 9. To test
this isomerization, the reaction of pure 9 with lithium chloride in
DMF under the same reaction conditions gave a mixture of 9 and 25
in a ratio of 7:3. Independently, when pure 9 was heated in DMF
without base, no isomerization was observed. Product 26 was an
unexpected elimination product. For the formation of 26, we suggest
that the mechanism involves a carbene rearrangement via a geminal
hydrogen halide elimination as depicted in Scheme 4. The structure
of rearrangement product 26 was determined by 1H- and 13C NMR
spectroscopy. The most conspicuous feature in the 1H NMR spectra of
26 was a triplet (3J¼5.9 Hz) at 6.41 ppm, which corresponds to the
olefinic proton in the cyclooctene ring. The C3-H proton in the
pyrrole ring of indole skeleton resonates as a doublet (3J¼2.9 Hz) at
6.98 ppm. The sixteen carbon resonance signals support the
suggested structure.
n=1,2,3,4
ketone unit
for bis-indoles
O
NH
x
x
x
x
N
H
6
N
H
N
H
diene unit
for carbazoles
X=X : dienophile
10
11
Figure 2. Retro-synthetic approach to carbazoles and bis-indoles.
Scheme 1.
Due to the formation of tris-indole 1640 as well as Michael
adduct 1541 from indole 1 and cyclohex-2-enone 14, we first
synthesized bromo compounds 1742 and 18. The ZrCl4-catalyzed
reaction of a mixture of bromo compounds 17 and 18 gave a mix-
ture of Michael adducts 19 and 20 (Scheme 2). After reduction of 19
and 20 with Zn–AcOH, DDQ-oxidation of 15 gave vinylindole 7.43–45
Structure analysis of vinylindole 7 showed that cisoid (C) conformer
7C is in equilibrium with transoid (T) conformer 7T. The coupling
constant for C3-H and nuclear Overhauser enhancement (NOE)
experiments for both C3-H in the indole ring and olefinic alpha
proton in cyclohexen-2-one of 7 were completely in agreement
with the structures depicted in Scheme 2.
O
O
21
9
.
Bi(NO3)3 5H2O
CH2Cl2, rt
76%
N
H
N
H
1
22
O
Br
ZrCl4
CH2Cl2
35%
23
O
O
O
O
LiCl
Br
+
+
DMF
N
N
H
N
H
N
H
160 o
C
H
9 (15%)
26 (2.3%)
24
25
LiCl
DMF, 160 o
C
Scheme 3.
Scheme 4.
Scheme 2.
Since carbazoles also represent an important family of alkaloids,
For the synthesis of vinylindole 9, the Michael adduct 22 was
prepared from indole 1 and cyclooct-2-en-1-one 21 (Scheme 3).46
Oxidation of this compound with DDQ gave a complex reaction
mixture. Therefore, indole 1 was treated with vinyl bromide 2310 in
dichloromethane at room temperature, which resulted in the
we turned out our attention to the synthesis of carbazole
derivatives and studied the cycloaddition reactions of vinylindoles
6–9. First, the Diels–Alder reactivity of vinylindole 6 was carried out
with dieoniphiles such as maleic anhydride, dimethyl acetylene-
dicarboxylate (DMAD), tetracyanoethylene (TCE), naphthoquinone,

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A.E. Sadak et al. / Tetrahedron 66 (2010) 3214–3221
and p-benzoquinone under different conditions. However,
unreacted starting material was recovered in every case.
and the aromatic proton at 7.85 ppm. While the OCH neighbouring
to the phenolic group for unusual product 43 resonates as a singlet
at 6.96 ppm, the olefinic proton in eight-member ring appears the
triplet at 6.25 ppm. For the unusual product 44, whilst the singlet of
olefinic proton resonances at 6.55 ppm, the OCH proton appears as
a triplet at 5.91 ppm. The resonances of the alkoxy carbons for both
compound 43 and 44 are at 86.6 ppm and at 84.6 ppm, respectively.
Later, vinylindole 6 was reacted with N-phenyltriazolinedione
(PTAD; 29), to yield 30 as the only product (Scheme 5). The isolated
product was not the expected cycloadduct 31 or possible Michael-
type product 32. A careful examination of the 1H and 13C NMR
spectra of the product revealed an exclusive formation of Aza-
Baylis–Hillman-type product 30. The Aza-Baylis–Hillman reaction,
a variation of the Morita–Baylis–Hillman, describes the reaction of
an electron-deficient alkene, usually an a,b-unsaturated carbonyl
compound with an imine in the presence of a nucleophile to give an
allylic amine.47–51 We observed a similar behavior when the
reactivity of vinylindoles 7–9 with PTAD was investigated. All
vinylindoles provided Aza-Baylis–Hillman-type products 33–35 as
the sole product (Fig. 3). The structures of the products were de-
termined by 1H NMR, 13C NMR, IR, and elemental analysis. The
unusual Morita–Baylis–Hillman-type product 30 was characterized
by the presence of NH signals (
d
¼11.09 ppm and 12.30 ppm), aro-
matic ten protons (
d
¼8.41–7.18 ppm) and the AA0BB0 system arising
from CH2 protons. In particular, the coupling constant (3J¼3.3 Hz)
between the olefinic C2-H (doublet at 8.41 ppm) and NH protons in
the pyrrole moiety show that the phenyl-urazole ring was joined to
the
a
-position of the cyclopenten-2-one ring.
Scheme 6.
O
O
Cl
Cl
CN
CN
O
O
O
36
O
O
CN
OH
CN
OH
+
CH2Cl2
5 day, rt
N
H
N
H
N
H
Cl
Cl
CN
CN
9
43
44
Cl
Cl
(40%)
(21%)
Scheme 7.
For the formation of Aza-Baylis–Hillman-type products 30,
33–35, we suggest that the reaction involves two mechanisms both
an ionic and neutral, as described below (Scheme 8). Firstly, reso-
nance (R) structure 6R of vinylindole 6 adds to the double bond of
N]N in the PTAD molecule to furnish intermediate 45a. The
mechanism results in bond tautomerization and proton shift. The
second mechanism initiates an ene-reaction between PTAD and
Scheme 5.
the double bond of the
a
,b
-unsaturated ketone and continues as
keto–enol tautomerization.
O-
O
O
N-
N
H
N
N
O
O
N
Ph
O
O
N
H
N
H
N
H
N
Ph
29
6
6R
45a
Figure 3. Aza-Morita–Baylis–Hillman-type products.
PTAD
ene-reaction
Next, our experiments focused on the cycloaddition of vinyl-
O
H
indoles 6–9 with DDQ 36. The reaction of both 6 and 7 with 1 equiv
DDQ in methylene chloride gave a single reaction product, which
was the Morita–Baylis–Hillman-type products 37–39, not the
expected cycloadducts 40–42 (Scheme 6). While the reaction of
vinylindole 8 with DDQ allowed us to isolate product 37 together
with two products as yet uncharacterized, the reaction of 9 in the
presence of DDQ resulted in the formation of two new unusual
products 43–44, which were purified via silica gel thin-layer
chromatography (Scheme 7). The structures of these compounds
were elucidated on the basis of 1H-, and 13C NMR spectroscopic
data, extensive double resonance, and NOE experiments. For
example, irradiation of the NH proton at 11.91 ppm of molecule 38
caused an enhancement of the C2-H in the pyrrole ring at 7.99 ppm
O
H
H
N-
N
N
N
N
O
O
O
N
O
N
Ph
N
H
O
O
N
H
Ph
46a
45b
OH
H
O
H
N
N
N
H-shift
O
N
N
Ph
O
N
H
N
H
Ph
46b
30
Scheme 8.

A.E. Sadak et al. / Tetrahedron 66 (2010) 3214–3221
3217
A similar formation mechanism is proposed for Morita–Baylis–
Hillman-type-products 37–39 of DDQ (Scheme 9). However,
according to the suggested mechanism, 1 mole of HCl was elimi-
nated during product formation.
spectrophotometer. 1H NMR and 13C NMR spectra were recorded on
200 (50) and 400 (100)-MHz Varian spectrometer and are reported
in d units with SiMe4 as internal standard. Elemental analyses were
carried out on a Leco CHNS-932 instrument. All optimized geom-
etries were determined using SPARTAN04 software for Windows
(version 1.0.0) as the semi-empirical AM1.52–55
4.1.1. 3-(1H-indol-3-yl)cyclopentanone (13). A solution of indole (1)
(2.85 g, 24.36 mmol), cyclopenten-2-one (12; 2 g, 24.39 mmol), and
Bi(NO3)3$5H2O (85 mg, 0.18 mmol) in acetonitrile (20 mL) was
placed in a glass tube. The tube was sealed and was heated at 70–
80 ꢀC for two days. After cooling the mixture to room temperature,
the mixture is filtered and the filtrate was washed with CH2Cl2
(50 mL). The organic layer was washed with saturated NaHCO3
(2ꢁ25 mL), water (2ꢁ25 mL), dried over MgSO4 and the solvent
was evaporated. The crude product was recrystallized from CH2Cl2/
hexane (3.91 g, 82%, red crystals from CH2Cl2/n-hexane, mp 108–
109 ꢀC); 1H NMR (400 MHz, CDCl3):
d 8.18 (m, NH, 1H), 7.65
(d, J¼7.7 Hz,]CH, 1H), 7.38 (d, J¼7.7 Hz,]CH, 1H), 7.25
(t, J¼7.7 Hz,]CH, 1H), 7.17 (t, J¼7.7 Hz,]CH, 1H), 6.96 (d,
J¼2.2 Hz,]CH, 1H), 3.73 (p, J¼7.3 Hz, CH, 1H), 2.77 (dd, J¼17.8 Hz,
Scheme 9.
A mechanism for the formation of the products 43 and 44 from 9
and DDQ is given in Scheme 10. The reaction mechanism involves
a Diels–Alder cycloaddition step giving rise to primary cycloadduct
49, that is, rearranged through a hydrogen shift and bond break
towards the more stable phenol structure 43 (Scheme 10). The key
step is the behavior of the carbonyl group of DDQ as a dienophile to
give products 43 and 44. We assume that vinylindole 9 isomerizes
to vinylindole 25 in the reaction medium. A similar mechanism
could also be proposed to yield product 44 with the cycloaddition
reaction between vinylindole 25 and DDQ.
7.3 Hz, CH2, 1H), 2.58–2.29 (m, CH2, 4H), 2.19–2.09 (m, CH2, 1H). 13
C
NMR (100 MHz, CDCl3):
d 210.0, 137.0, 126.9, 122.6, 120.3, 119.7,
119.3, 118.8, 111.7, 45.6, 38.4, 34.0, 30.1. Anal. Calcd for C13H13NO: C,
78.36; H, 6.58; N, 7.03. Found: C, 78.69; H, 6.42; N, 7.12.
4.1.2. 3-(1H-indol-3-yl)cyclopent-2-enone (6). A solution of 13
(392 mg, 1.97 mmol) and DDQ (447 mg, 1.97 mmol) in dry benzene
(10 mL) was stirred at room temperature for 90 min. After the
benzene was evaporated, the residue was dissolved by with CH2Cl2
(50 mL) and washed with saturated NaHCO3 (2ꢁ50 mL), water
(2ꢁ25 mL), dried over MgSO4 and the solvent was evaporated. The
crude product was recrystallized from CH2Cl2/hexane (110 mg, 28%,
green dust, mp 207–208 ꢀC); 1H NMR (400 MHz, DMSO-d6):
d 11.93
(m, NH,1H), 8.05 (d, J¼2.9 Hz,]CH, 1H), 7.88 (d, J¼7.9 Hz,]CH, 1H),
7.47 (d, J¼7.9 Hz,]CH, 1H), 7.21–7.15 (m,]CH, 2H), 6.47 (s,]CH,
1H), 3.10–3.08 (m, AA0 part of AA0BB0 system, CH2, 2H), 2.38–2.35
(m, BB0 part of AA0BB0 system, CH2, 2H). 13C NMR (100 MHz, DMSO-
d6): d 208.7, 169.7, 138.0, 130.2, 125.6, 123.2, 122.1, 121.9, 120.9, 113.1,
112.6, 34.4, 29.8. IR (KBr, cmꢂ1) 3218, 2919, 1727, 1650, 1567, 1432,
1236, 1191, 743. Anal. Calcd for C13H11NO: C, 79.16; H, 5.62; N, 7.10.
Found: C, 78.90; H, 5.70; N, 7.21.
4.1.3. Bromination of cyclohexen-1-one (14). To
a solution of
Scheme 10.
cyclohexen-1-one (14; 2 g, 20.83 mmol) in CH2Cl2 (50 mL) was
dropped a solution of Br2 (3.32 g, 20.75 mmol) in CH2Cl2 (25 mL) at
0 ꢀC and the mixture stirred for 45 min. After the addition of Br2,
the mixture is stirred at the same temperature for 90 min. Later,
NEt3 (3.54 g, 35.00 mmol) was added dropwise to the reaction
mixture at room temperature. After stirring for 90 min, the mixture
was washed with brine (100 mL) and HCl (3%, 2ꢁ50 mL). The or-
ganic layer was dried over MgSO4, and the solvent was removed
under vacuum. The crude product was crystallized from ethanol to
give a mixture product of 17 and 18 (3.90 g). The 1H NMR in-
tegration ratio of the mixture showed that the formation of 17/18
(67:33). For the mixture of 17 and 18; 1H NMR (200 MHz, CDCl3):
3. Conclusions
In conclusion, we have described the synthesis of new 3-vinyl-
indole derivatives. These vinyl groups are in a,b-unsaturated cyclic
ketones. The results of the present study demonstrate that
attempted Diels–Alder reactions of vinylindoles with various dien-
ophiles mainly provided unusual Morita–Baylis–Hillman-type
products. In the case of 9, the secondary products were isolated
through primary [4þ2]-cycloaddition products. The formation of
these unusual products can be attributed to the cyclic structure and
ketone functionality of the vinyl group, which changes the geometry
and electron density. Due to the unexpected behaviors of this type of
3-vinylindoles, the chemistry of 2-vinylindoles is in progress.
d
7.43 (t, J¼4.4 Hz,]CH, 1H), 2.66–2.50 (m, CH2, 2H), 2.50–2.41 (m,
CH2, 2H), 2.14–2.04 (m, CH2, 2H). 13C NMR (50 MHz, CDCl3):
153.0, 125.9, 40.4, 30.4, 24.7.
d 193.1,
4. Experimental section
4.1. General methods
4.1.4. Michael addition reaction of indole (1) and a mixture of 17/18
with ZrCl4-catalyzed. A solution of indole (1) (606 mg, 5.18 mmol)
and a mixture of 17/18 (950 mg; 67:33) and ZrCl4 (23 mg, 0.20%
mmol) in CH2Cl2 (10 mL) was stirred for 3 h at room temperature.
Then, the mixture was filtered on a short silica gel column (5 g)
eluting with CH2Cl2 (200 mL). After the solvent was evaporated,
Melting points were determined on Buchi 539 capillary melting
apparatus. Infrared spectra were recorded on a Mattson 1000 FTIR

3218
A.E. Sadak et al. / Tetrahedron 66 (2010) 3214–3221
crude product gave a mixture of Michael adducts 19/20 (1.20 g).
Since the isomers were not subjected to the purification procedure,
the spectral data was not obtained.
thin layer (50 g) eluting with ethyl acetate/hexane (10%) gave
36 mg (30%) of 8, which was crystallized from CH2Cl2/hexane
(30 mg, 25%, yellow crystals, mp: 80–81 ꢀC); 1H NMR (400 MHz,
CDCl3):
d
8.51 (m, NH, 1H), 7.93 (d, J¼8.1 Hz,]CH, 1H), 7.47 (d,
4.1.5. 3-(1H-indol-3-yl)cyclohexanone (15). To a magnetically stir-
red mixture of glacial acetic acid (10 mL) and Zn (1.62 g,
25.00 mmol) at room temperature, a solution of a mixture (1.10 g)
of Michael adduct 19/20 was dropwise. After addition was com-
pleted, the temperature was raised to and maintained at 70 ꢀC for
20 h. Then, the reaction mixture was cooled and treated with ether
(150 mL), and the zinc residue was filtered. The ethereal layer was
washed with a saturated NaHCO3 (3ꢁ50 mL) to remove acetic acid,
and dried over MgSO4. The solvent removed under reduced pres-
sure. The reduction product 15 was recrystallized from CH2Cl2/
hexane (723 mg, 83%, yellow crystals, mp 103–104 ꢀC; Lit.41 106–
J¼2.6 Hz,]CH, 1H), 7.41 (dd, J¼7.9, 0.9 Hz,]CH, 1H), 7.36–7.19
(m,]CH, 2H), 6.60 (s,]CH, 1H), 2.97–2.94 (m, CH2, 2H), 2.73–2.70
(m, CH2, 2H), 2.17–1.88 (m, CH2, 4H). 13C NMR (100 MHz, CDCl3):
d
204.9, 153.1, 137.3, 127.2, 125.3, 125.1, 123.4, 121.5, 121.2, 119.2,
111.9, 42.0, 32.1, 25.2, 21.4. IR (KBr, cmꢂ1) 3345, 2926, 2855, 1586,
1457, 1240, 739. Anal. Calcd for C15H15NO: C, 79.97; H, 6.71; N, 6.22.
Found: C, 80.11; H, 6.40; N, 6.12.
4.1.9. 3-(1H-indol-3-yl)cycoloctanone (22). A solution of indole (1)
(106 mg, 0.90 mmol), cycloocten-2-one (112 mg, 0.90 mmol), and
Bi(NO3)3$5H2O (32 mg, 0.065 mmol) in CH2Cl2 (10 ml) was stirred
as magnetically at room temperature for two days. After the solvent
was removed, the residue was dissolved in ethyl acetate (50 mL).
The organic layer was washed with water (3ꢁ30 mL), dried over
Na2SO4 and the solvent was evaporated. The crude product was
recrystallized from CH2Cl2/hexane (164 mg, 76%, orange powder,
107 ꢀC); 1H NMR (200 MHz, CDCl3):
d 8.17 (m, NH, 1H), 7.65 (d,
J¼7.4 Hz,]CH, 1H), 7.38 (d, J¼8.2 Hz,]CH, 1H), 7.27–7.11 (m,]CH,
2H), 6.98 (d, J¼2.4 Hz,]CH, 1H), 3.47 (m, CH, 1H), 2.85
(dd, J¼14.1 Hz, 4.6 Hz, A part of AB system, CH2, 1H), 2.65 (dd,
J¼14.1 Hz, 10.4 Hz, B part of AB system, CH2, 1H), 2.50–2.10 (m, CH2,
2H), 2.09–1.81 (m, CH2, 2H). 13C NMR (50 MHz, CDCl3):
d
213.9,
mp 119–120 ꢀC); 1H NMR (400 MHz, CDCl3):
d 8.27 (m, NH,1H), 7.73
138.5, 128.2, 124.2, 122.4, 121.7, 121.4, 121.0, 113.4, 50.1, 43.6, 38.0,
33.8, 26.9. Anal. Calcd for C14H15NO: C, 78.84; H, 7.09; N, 6.57.
Found: C, 78.99; H, 6.87; N, 6.33.
(dd, J¼7.8, 1.1 Hz,]CH, 1H), 7.36 (dd, J¼7.8, 1.1 Hz,]CH, 1H), 7.23
(td, J¼7.8, 1.1 Hz,]CH, 1H), 7.17 (td, J¼7.8, 1.1 Hz,]CH, 1H), 6.95 (d,
J¼2.2 Hz,]CH, 1H), 3.65–3.59 (m, CH, 1H), 3.00–2.94 (m, CH2, 1H),
2.74–2.70 (m, CH2, 1H), 2.69–2.62 (m, CH2, 1H), 2.52–2.46 (m, CH2,
1H), 2.17–2.01 (m, CH2, 2H), 2.00–1.95 (m, CH2, 1H), 1.83–1.75 (m,
4.1.6. 3-(1H-indol-3-yl)cyclohex-2-enone (7). A solution of 15
(440 mg, 2.06 mmol) and DDQ (468 mg, 2.06 mmol) in dry benzene
(10 mL) was stirred at 0 ꢀC for 1 h. Then, the stirring was continued
at room temperature for 12 h. After the benzene was evaporated,
the residue was dissolved by with CH2CL2 (100 mL) and washed
with saturated NaHCO3 (3ꢁ20 mL), water (50 mL), dried over
MgSO4 and the solvent was evaporated. The crude product was
recrystallized from acetone (200 mg, 46%, yellow dust, mp 166–
CH2,1H),1.67–1.52 (m, CH2, 3H). 13C NMR (100 MHz, CDCl3):
d 217.3,
136.7, 126.4, 122.3 (CH), 121.4, 120.3 (CH), 119.5 (CH), 119.2 (CH),
111.7 (CH), 48.4 (CH2), 43.3 (CH2), 35.9 (CH), 34.3 (CH2), 28.0 (CH2),
25.1 (CH2), 24.6 (CH2). IR (KBr, cmꢂ1) 3392, 3055, 2928, 2859, 1709,
1619, 1458, 1421, 1338, 1313, 1259, 1229, 1170, 1142, 1126, 1100, 1077,
1047, 1011, 932. Anal. Calcd for C16H19NO: C, 79.63; H, 7.94; N, 5.80.
Found: C, 79.53; H, 7.82; N, 5.67.
167 ꢀC); 1H NMR (200 MHz, CDCl3):
d 9.05 (m, NH, 1H), 7.97
(d, J¼7.4 Hz,]CH, 1H), 7.57 (d, J¼2.6 Hz,]CH, 1H), 7.44 (d,
J¼6.5 Hz,]CH, 1H), 7.40–7.22 (m,]CH, 2H), 6.74 (s,]CH, 1H), 2.84
(t, J¼6.2 Hz, CH2, 2H), 2.54 (t, J¼6.2 Hz, CH2, 2H), 2.17 (p, J¼6.2 Hz,
4.1.10. 2-Bromo-2-cyclooctenone (23). To a solution of cycloocten-
2-one (1 g, 8.06 mmol) in CH2Cl2 (25 mL) at 0 ꢀC, a solution of Br2
(1.29 g, 8.06 mmol) in CH2Cl2 (25 mL) was added dropwise for
45 min. After the addition was completed, the reaction mixture was
stirred at room temperature for 90 min. Then, NEt3 (0.822 mg,
8.06 mmol) was added dropwise to the reaction mixture at room
temperature. After stirring for 90 min, the mixture was washed
with brine (100 mL) and HCl (3%, 2ꢁ50 mL). The organic layer was
dried over MgSO4, and the solvent was removed under vacuum. The
crude product was obtained as dark yellow colored liquid (1.20 g,
CH2, 2H). 13C NMR (50 MHz, CDCl3):
d 201.7, 157.3, 139.3, 127.9,
126.9, 125.2, 124.2, 123.6, 123.1, 118.5, 113.8, 39.4, 30.7, 24.7. IR (KBr,
cmꢂ1) 3384, 2924, 2852, 1695, 1606, 1583, 1561, 1510, 1485, 1449,
1348, 1331, 1292, 1189, 1078, 967, 876, 822, 738. Anal. Calcd for
C14H13NO: C, 79.59; H, 6.20; N, 6.63. Found: C, 79.28; H, 6.13; N,
6.67.
4.1.7. 3-(1H-indol-3-yl)cycloheptanone. A solution of indole (1)
(59 mg, 0.50 mmol), cyclohepten-2-one (56 mg, 0.50 mmol), and
Bi(NO3)3$5H2O (18 mg, 0.036 mmol) in CH2Cl2 (10 mL) was stirred
as magnetically at room temperature for two days. The mixture was
diluted with CH2Cl2 (50 mL). The organic layer was washed with
water (3ꢁ30 mL), dried over Na2SO4 and the solvent was evapo-
rated. The crude product was recrystallized from CH2Cl2/hexane
(83 mg, 73%, red powder, mp 105–106 ꢀC); 1H NMR (400 MHz,
73%); 1H NMR (400 MHz, CDCl3):
(t, J¼6.9 Hz, CH2, 2H), 2.46–2.42 (m, CH2, 2H), 1.89–1.83 (m, CH2,
2H), 1.67–1.56 (m, CH2, 4H). 13C NMR (100 MHz, CDCl3):
207.7,
d
6.81 (t, J¼6.9 Hz,]CH, 1H), 2.72
d
140.7, 121.2, 41.6, 30.5, 26.1, 22.7. Anal. Calcd for C8H11BrO: C, 47.32;
H, 5.46. Found: C, 47.51; H, 5.41.
4.1.11. (2S(R),3R(S))-2-Bromo-3-(1H-indol-3-yl)cyclooctanone
(24). A solution of indole (1) (750 mg, 6.38 mmol), 2-bromo-2-
cyclooctenone (23; 1.30 g; 6.38 mmol), and ZrCl4 (32 mg,
0.02 mmol) in CH2Cl2 (15 mL) was stirred at room temperature for
1 h. After the solvent was removed, the residue was dissolved with
ethyl acetate (50 mL).The organic layer was washed with water
(3ꢁ20 mL), dried over MgSO4 and the solvent was evaporated.
Chromatography of the residue on silica gel (20 g) eluting with
ethyl acetate/hexane (10:90) furnished the compound 24 (0.72 mg,
35%): (dark brown powder from CH2Cl2/hexane; mp 130–131 ꢀC);
CDCl3):
d
8.22 (m, NH, 1H), 7.64 (d, J¼8.1 Hz,]CH, 1H), 7.34 (d,
J¼8.1 Hz,]CH, 1H), 7.22–7.12 (m,]CH, 2H), 6.91 (d, J¼1.5 Hz,]CH,
1H), 3.30–3.24 (m, CH, 1H), 3.01–2.94 (m, CH2, 1H), 2.89–2.84 (m,
CH2, 1H), 2.67–2.63 (m, CH2, 2H), 2.33–2.28 (m, CH2, 1H), 2.09–2.00
(m, CH2, 2H), 1.86–1.72 (m, CH2, 2H), 1.64–1.57 (m, CH2, 1H). 13C
NMR (100 MHz, CDCl3):
d 214.8, 136.7, 126.3, 122.3, 121.6, 120.0,
119.5, 119.2, 111.6, 50.8, 44.3, 38.4, 34.2, 29.5, 24.6. IR (KBr, cmꢂ1
)
3385, 2928, 1693, 1458, 1372, 741. Anal. Calcd for C15H17NO: C,
79.26; H, 7.54; N, 6.16. Found: C, 79.03; H, 7.41; N, 6.28.
1H NMR (400 MHz, CDCl3):
d 8.25 (m, NH, 1H), 7.63 (d,
J¼7.6 Hz,]CH, 1H), 7.42 (d, J¼7.6 Hz,]CH, 1H), 7.26–7.16 (m,]CH,
3H), 5.02 (d, J¼2.4 Hz, CHBr, 1H), 4.25 (td, J¼5.0, 2.4 Hz, CH, 1H),
3.07–3.00 (m, CH2, 1H), 2.81–2.76 (m, CH2, 1H), 2.34–2.27 (m, CH2,
1H), 2.07–1.75 (m, CH2, 5H), 1.56–1.52 (m, CH2, 1H), 1.28–1.21 (m,
4.1.8. 3-(1H-indol-3-yl)cyclohept-2-enone (8). A solution of 3-(1H-
indol-3-yl)cycloheptanone (120 mg, 0.53 mmol) and DDQ (120 mg,
0.53 mmol) in dry benzene (15 mL) was stirred at 0 ꢀC for 3 h. After
the solvent was evaporated, the residue was filtered on a silica gel
CH2, 1H). 13C NMR (100 MHz, CDCl3):
d 207.8, 136.2, 126.2, 122.9

A.E. Sadak et al. / Tetrahedron 66 (2010) 3214–3221
3219
(CH), 122.5 (CH), 119.9 (CH), 118.0 (CH), 117.9, 111.9 (CH), 68.0
(CHBr), 39.4 (CH2), 36.7 (CH), 30.7 (CH2), 29.6 (CH2), 26.3 (CH2),
24.6 (CH2). IR (KBr, cmꢂ1) 3392, 3055, 2928, 2859, 1709, 1619, 1458,
1421, 1338, 1313, 1259, 1229, 1170, 1142, 1126, 1100, 1077, 1047, 1011,
932. Anal. Calcd for C16H18BrNO: C, 60.01; H, 5.67; N, 4.37. Found: C,
59.86; H, 5.84; N, 4.30.
(31 mg, 33%, mp 290–291 ꢀC); 1H NMR (400 MHz, DMSO-d6):
d
12.30 (d, J¼2.8 Hz, NH, 1H), 11.09 (m, NH, 1H), 8.41 (d,
J¼2.8 Hz,]CH, 1H), 7.58–7.40 (m,]CH, 5H), 7.39–7.38 (m,]CH,
1H), 7.25–7.18 (m,]CH, 2H), 3.40–3.38 (m, AA0 part of AA0BB0 sys-
tem, CH2, 2H), 2.55–2.53 (m, BB0 part of AA0BB0 system, CH2, 2H). 13C
NMR (100 MHz, DMSO-d6): d 201.2, 168.4, 153.3, 152.8, 137.5, 133.2,
132.6, 129.5, 128.5, 127.0, 126.7, 126.2, 123.2, 122.3, 121.4, 113.4,
109.6, 32.8, 28.3. IR (KBr, cmꢂ1) 3260, 2919, 1760, 1704, 1588, 1502,
1424, 1235. Anal. Calcd for C21H16N4O3: C, 67.73; H, 4.33; N, 15.05.
Found: C, 67.48; H, 4.46; N, 15.30.
4.1.12. The reaction of (2S(R),3R(S))-2-bromo-3-(1H-indol-3-yl)cy-
clooctanone (24) with LiCl. A solution of (2S(R),3R(S))-2-brom-3-
(1H-indol-3-yl)cyclooctanone (24) (5.51 g, 17.21 mmol) and LiCl
(1.09 g, 25.70 mmol) in 50 mL of dimethylformamide (DMF) was
stirred at 160 ꢀC for 3 h. The mixture was cooled, and DMF was
removed under reduced pressure. The mixture was dissolved with
ethyl acetate (50 mL), the organic layer was washed with water
(3ꢁ20 mL) and dried over MgSO4. The residue (3.38 g) was
chromatographed over thin-layer silica gel with ethyl acetate/
hexane (10:90). The first fraction was identified as the mixture of
25 and 26 (2.50 g). The second fraction gave the mixture of 9 and
25 (100 mg). The last fraction furnished (E)-3-(1H-indol-3-yl)cy-
clooct-2-enone (9) (650 mg, 15%; yellow crystals from CH2Cl2/
hexane, mp 69–70 ꢀC). A sample of the first fraction (300 mg) was
subjected to thin-layer silica gel chromatography with ethyl ace-
tate/hexane (25:75). The third band gave (Z)-2-(1H-indol-3-
yl)cyclooct-2-enone (26), which was crystallized from ether/hex-
ane (95 mg, 2.3%, pale brown crystals, mp 103–104 ꢀC). For 9; 1H
4.1.14. 1-(2-(1H-Indol-3-yl)-6-oxocyclohex-1-enyl)-4-phenyl-1,2,4-
triazolidine-3,5-dione (33). A solution of 7 (100 mg, 0.47 mmol) and
PTAD (82.5 mg, 0.47 mmol) in 10 mL of dry CHCl3 was stirred at
room temperature for 5 min. After the reaction was completed, the
formed precipitate was filtered through filter paper. The residue
was purified by crystallization from acetone (80 mg, 45%, yellow
powder, mp 168–170 ꢀC); 1H NMR (400 MHz, DMSO-d6):
d 10.99
(m, NH, 1H), 9.36 (m, NH, 1H), 8.04 (d, J¼2.9 Hz,]CH, 1H), 7.87 (d,
J¼8.1 Hz,]CH,1H), 7.58–7.48 (m,]CH, 5H), 7.41–7.37 (m,]CH,1H),
7.24–7.14 (m,]CH, 2H), 3.42 (dt, J¼11.7, 6.0 Hz, A part of AB system,
CH2, 1H), 3.10 (dt, J¼11.7, 6.0 Hz, B part of AB system, CH2,1H), 2.62–
2.58 (m, CH2, 2H), 2.23–2.17 (m, CH2, 2H). 13C NMR (100 MHz,
DMSO-d6): d 193.0, 159.2, 154.5, 153.1, 137.5, 132.8, 129.7 (CH), 129.6
(CH), 128.5 (CH), 126.8, 126.7 (CH), 126.2, 122.8 (CH), 121.5 (CH),
121.4 (CH), 113.2 (CH), 112.0, 37.7 (CH2), 32.1 (CH2), 22.7 (CH2). IR
(KBr, cmꢂ1) 3252, 2950, 1768, 1704, 1588, 1502, 1424, 1371, 1330,
1240,1188, 1138,1023. Anal. Calcd for C22H18N4O3: C, 68.38; H, 4.70;
N, 14.50. Found: C, 68.47; H, 4.62; N, 14.31.
NMR (400 MHz, CDCl3):
d
9.15 (m, NH, 1H), 7.95 (d, J¼8.1 Hz,]CH,
1H), 7.46 (d, J¼2.9 Hz,]CH, 1H), 7.40 (d, J¼8.1 Hz,]CH, 1H), 7.26–
7.15 (m,]CH, 2H), 6.96 (s,]CH, 1H), 3.17 (t, J¼7.0 Hz, CH2, 2H),
2.97 (t, J¼7.3 Hz, CH2, 2H), 1.84–1.75 (m, CH2, 4H), 1.69–1.64 (m,
CH2, 2H). 13C NMR (100 MHz, CDCl3):
d 203.5, 149.6, 137.5, 129.1
(CH), 126.3 (CH), 125.1, 123.2 (CH), 121.5 (CH), 121.2 (CH), 119.3,
112.2 (CH), 42.8 (CH2), 32.2 (CH2), 25.5 (CH2), 23.7 (CH2), 23.2
(CH2). IR (KBr, cmꢂ1) 3241, 2928, 2851, 1706, 1582, 1517, 1430,
1344, 1255, 1236, 1203, 1157, 1123. Anal. Calcd for C16H17NO: C,
80.30; H, 7.16; N, 5.85. Found: C, 80.23; H, 6.95; N, 5.93. For
4.1.15. (Z)-1-(2-(1H-Indol-3-yl)-7-oxocyclohept-1-enyl)-4-phenyl-
1,2,4-triazolidine-3,5-dione (34). A solution of
8
(110 mg,
0.48 mmol) and PTAD (86 mg, 0.48 mmol) in 15 mL of dry CHCl3
was stirred at room temperature for 5 min. After completion of the
reaction, the formed precipitate was filtered through filter paper
and dissolved in acetone. After acetone was removed, residue was
purified by crystallization from CH2Cl2/hexane (87 mg, 45%, yellow
mixture of 9 and 25;1H NMR (400 MHz, CDCl3):
d 8.80 (m, NH,
1H), 8.31 (m, NH, 1H), 7.97 (d, J¼7.7 Hz,]CH, 1H), 7.88 (d,
J¼8.1 Hz,]CH, 1H), 7.45 (d, J¼3.0 Hz,]CH, 1H), 7.40 (d,
J¼8.1 Hz,]CH, 1H), 7.38 (d, J¼8.6 Hz,]CH, 1H), 7.37–7.15 (m,]CH,
5H), 6.93 (s,]CH, 1H), 6.34 (t, J¼8.6 Hz,]CH, 1H), 3.63 (s, CH2,
2H), 3.18 (t, J¼6.8 Hz, CH2, 2H), 2.96 (t, J¼7.3 Hz, CH2, 2H), 2.58–
2.56 (m, CH2, 2H), 2.46–2.41 (m, CH2, 2H), 1.90–1.72 (m, CH2, 8H),
powder, mp 233–234 ꢀC); 1H NMR (400 MHz, DMSO-d6):
d 11.77
(m, NH, 1H), 10.75 (m, NH, 1H), 7.83 (d, J¼2.9 Hz,]CH, 1H), 7.62 (d,
J¼7.7 Hz,]CH, 1H), 7.49–7.38 (m,]CH, 3H), 7.37–7.34 (m,]CH,
3H), 7.18–7.14 (m,]CH, 1H), 7.11–7.07 (m,]CH, 1H), 3.10 (m, CH2,
2H), 2.69 (m, CH2, 2H), 1.91–1.87 (m, CH2, 4H). 13C NMR (100 MHz,
1.70–1.64 (m, CH2, 2H). 13C NMR (100 MHz, CDCl3):
d
213.7, 203.3,
DMSO-d6): d 198.7, 155.4, 153.7, 152.5, 137.5, 132.7, 129.9, 129.7,
149.1, 137.4, 137.1, 129.9, 129.4 (CH), 126.8 (CH), 125.9 (CH), 125.3,
125.2, 123.3 (CH), 122.6 (CH), 122.3 (CH), 121.5 (CH), 121.3 (CH),
120.7 (CH), 120.4 (CH), 119.6, 119.2, 112.0 (CH), 111.7 (CH), 47.0
(CH2), 42.8 (CH2), 41.9 (CH2), 32.3 (CH2), 28.8 (CH2), 27.9 (CH2),
25.5 (CH2), 25.3 (CH2), 23.7 (CH2), 23.2 (CH2). (Note: The signals of
25 are underline). For (Z)-2-(1H-indol-3-il)cyclooct-2-enone (26)
129.6, 128.4, 126.6, 126.2, 122.6, 120.9, 120.7, 114.3, 113.0, 32.1, 31.4,
24.4, 20.6. IR (KBr, cmꢂ1) 3283, 2935, 1762, 1698, 1500, 1428, 1245.
Anal. Calcd for C23H20N4O3: C, 68.99; H, 5.03; N, 13.99. Found: C,
69.13; H, 5.01; N, 13.78.
4.1.16. (Z)-1-(2-(1H-Indol-3-yl)-8-oxocyclooct-1-enyl)-4-phenyl-
1H NMR (400 MHz, CDCl3):
d
8.54 (m, NH, 1H), 7.84 (dd, J¼6.6,
1,2,4-triazolidine-3,5-dione (35). A solution of
9
(100 mg,
1.8 Hz,]CH, 1H), 7.31 (dd, J¼6.6, 1.8 Hz,]CH, 1H), 7.21–7.16
(m,]CH, 2H), 6.98 (d, J¼2.9 Hz,]CH, 1H), 6.41 (t, J¼5.9 Hz,]CH,
1H), 2.61–2.58 (m, CH2, 2H), 2.47–2.42 (m, CH2, 2H), 2.00–1.98 (m,
CH2, 2H), 1.78–1.74 (m, CH2, 4H). 13C NMR (100 MHz, CDCl3):
0.42 mmol) and PTAD (72 mg, 0.42 mmol) in 10 mL of CHCl3 was
stirred at room temperature for five days. After removal of the
solvent, the residue was chromatographed on thin-layer silica gel
eluting with acetone/hexane (30:70). The brown band was
extracted with ethyl acetate (50 mL), and the solvent was removed.
Residue was crystallized from acetone/hexane (82 mg, 49%, pale
brown powder, mp 207–208 ꢀC); 1H NMR (400 MHz, DMSO-d6):
d
213.8, 137.0, 134.7, 128.5, 125.7, 123.2, 122.6, 120.4, 120.2, 113.0,
111.9, 44.9, 29.7, 29.2, 24.1, 23.1. IR (KBr, cmꢂ1) 3283, 2896, 2821,
1648, 1553, 1482, 1338,1300, 1210, 1196, 1144,1068, 977. Anal.
Calcd for C16H17NO: C, 80.30; H, 7.16; N, 5.85. Found: C, 80.06; H,
6.98; N, 6.01.
d
11.66 (d, J¼2.6 Hz, NH, 1H), 10.69 (m, NH, 1H), 7.75 (d,
J¼2.6 Hz,]CH, 1H), 7.63 (d, J¼7.7 Hz,]CH, 1H), 7.49–7.43 (m,]CH,
3H), 7.38–7.33 (m,]CH, 3H), 7.16–7.12 (m,]CH, 1H), 7.09–7.05
(m,]CH, 1H), 3.30–3.36 (m, CH2, 2H), 2.98–2.95 (m, CH2, 2H), 1.80–
1.78 (m, CH2, 2H), 1.72–1.65 (m, CH2, 4H). APT 13C NMR (100 MHz,
4.1.13. 1-(2-(1H-Indol-3-yl)-5-oxocyclopent-1-enyl)-4-phenyl-1,2,4-
triazolidine-3,5-dione (30). A solution of 6 (50 mg, 0.25 mmol) and
PTAD (44 mg, 0.25 mmol) in dry CHCl3 (10 mL) was stirred at room
temperature for 5 min. After the reaction was completed, the
formed precipitate was filtered through filter paper, and washed
with acetone. The product 30 was obtained as a grey powder
d6-DMSO):
d 197.2 (CO), 154.0, 152.5 (2C), 137.3, 132.8, 131.7, 129.5
(CH), 129.2 (CH), 128.3 (CH), 126.5 (CH), 126.3, 122.4 (CH), 120.7
(CH), 120.5 (CH), 115.1, 113.0 (CH), 42.7 (CH2), 33.7 (CH2), 25.3 (CH2),
23.7 (CH2), 23.6 (CH2). IR (KBr, cmꢂ1) 3288, 2900, 2856, 1940, 1765,

3220
A.E. Sadak et al. / Tetrahedron 66 (2010) 3214–3221
1690, 1550, 1430, 1257, 1210, 1158. Anal. Calcd for C24H22N4O3: C,
69.55; H, 5.35; N, 13.52. Found: C, 69.70; H, 5.23; N, 13.37.
products was determined in both the first precipitate and first
band. But, the structures of these products were yet not
characterized.
4.1.17. 4-(2-(1H-Indol-3-yl)-5-oxocyclopent-1-enyl)-5-chloro-3,6-di-
oxocyclohexa-1,4-diene-1,2-dicarbonitrile (37). A solution of
6
4.1.20. Reaction of (E)-3-(1H-indol-3-yl)cyclooct-2-enone (9) with
DDQ. A solution of 9 (220 mg, 0.92 mmol) and DDQ (208 mg,
0.92 mmol) in CHCl3 (20 mL) was placed in a glass tube. The tube
was sealed and was heated at 50 ꢀC for three days. The solvent was
concentrated under vacuum. The crude products were submitted to
thin-layer silica gel chromatography eluting with acetone/hexane
(30:70). The first band extracted with ethyl acetate (50 mL) gave 43
(170 mg, 40%), which was recrystallized from methanol (yellow
crystals, mp 153–154 ꢀC). The second fraction extracted with ethyl
acetate (50 mL) afforded 44 as yellow oil (90 mg, 21%). (Z)-3-(2-
(1H-Indol-3-yl)-8-oxocyclooct-2-enyloxy)-4,5-dichloro-6-hydroxy-
(100 mg, 0.50 mmol) and DDQ (115 mg, 0.50 mmol) in CH2Cl2
(15 mL) was placed in a glass tube. The tube was sealed and was
heated at 55–60 ꢀC for three days. The reaction mixture was cooled
and diluted with CH2Cl2 (50 mL). The organic layer was washed
with water (3ꢁ30 mL) and dried over Na2SO4. Then, the solvent
was evaporated and the residue was crystallized from acetone/
hexane (45 mg, 23%, green powder, mp 250–251 ꢀC); 1H NMR
(400 MHz, DMSO-d6):
d
12.15 (d, J¼2.7 Hz, NH, 1H), 8.24 (d,
J¼2.7 Hz,]CH, 1H), 7.94 (d, J¼7.8 Hz,]CH, 1H), 7.51 (d,
J¼7.8 Hz,]CH, 1H), 7.24–7.14 (m,]CH, 2H), 3.25–3.23 (m, AA0 part
of AA0BB0 system, CH2, 2H), 2.51–2.48 (m, BB0 part of AA0BB0 system,
phthalonitrile (43): 1H NMR (400 MHz, DMSO-d6):
d 11.12 (m, NH,
CH2, 2H). 13C NMR (100 MHz, DMSO-d6):
d
197.4, 155.4, 150.7, 148.4,
1H), 7.41 (d, J¼2.6 Hz,]CH, 1H), 7.26 (d, J¼7.6 Hz,]CH, 1H), 7.04 (t,
J¼7.6 Hz,]CH, 1H), 6.96 (t, J¼7.6 Hz,]CH, 1H), 6.25 (t,
J¼8.7 Hz,]CH, 1H), 6.19 (s, OCH, 1H), 2.83–2.76 (m, CH2, 1H), 2.48–
2.29 (m, CH2, 3H), 1.93–1.92 (m, CH2, 2H), 1.70–1.51 (m, CH2, 1H),
142.9, 137.4, 132.6, 131.8, 129.7, 126.2, 123.2, 121.9, 121.6, 114.2, 113.3,
113.2,109.9,106.4,102.0, 32.3, 25.3. IR (KBr, cmꢂ1) 3394, 2918, 2555,
2314, 2079, 1589. Anal. Calcd for C21H10ClN3O3: C, 65.04; H, 2.60, N,
10.84. Found: C, 65.16; H, 2.58; N, 11.03.
1.49–1.48 (m, CH2, 1H). APT 13C NMR (100 MHz, DMSO-d6):
d 208.1
(CO), 154.4, 149.6, 136.8, 134.1 (CH), 134,0, 129.0, 128.6, 125.4, 124.1
(CH),122.2 (CH),119.9 (CH),119.3 (CH),115.8,114.1,114.0,112.2 (CH),
109.1, 102.0, 86.9 (OCH), 39.0 (CH2), 27.4 (CH2), 27.1 (CH2), 26.4
(CH2). IR (KBr, cmꢂ1) 3669, 2935, 2863, 2235,1707,1560,1440,1420,
1357, 1230, 1129, 1089, 1011, 949, 933. Anal. Calcd for
C24H17Cl2N3O3: C, 61.82; H, 3.67; N, 9.01. Found: C, 62.01; H, 3.92; N,
8.97.
4.1.18. 4-(2-(1H-Indol-3-yl)-6-oxocyclohex-1-enyl)-5-chloro-3,6-di-
oxocyclohexa-1,4-diene-1,2-dicarbonitrile (38). A solution of
7
(100 mg, 0.46 mmol) and DDQ (104 mg, 0.46 mmol) in CH2Cl2
(10 mL) was placed in a glass tube. The tube was sealed and was
heated at 55–60 ꢀC for three days. The reaction mixture was cooled
and the solvent was evaporated and the residue was crystallized
from CH2Cl2/hexane (106 mg, 57%, brown powder, mp 185–186 ꢀC);
1H NMR (400 MHz, DMSO-d6):
d
11.91 (m, NH, 1H), 7.99
4.1.21. (Z)-3-(2-(1H-Indol-3-yl)-4-oxocyclooct-2-enyloxy)-4,5-di-
(d, J¼3.1 Hz,]CH, 1H), 7.85 (d, J¼7.3 Hz,]CH, 1H), 7.46
(d, J¼7.3 Hz,]CH, 1H), 7.17 (t, J¼7.3 Hz,]CH, 1H), 7.11
(t, J¼7.3 Hz,]CH, 1H), 3.21–3.20 (m, CH2, 2H), 2.55–2.51 (m, CH2,
chloro-6-hydroxyphthalonitrile (44). 1H NMR (400 MHz, DMSO-d6):
d
11.70 (d, J¼2.6 Hz, NH, 1H), 7.80 (d, J¼2.6 Hz,]CH, 1H), 7.74 (d,
J¼7.3 Hz,]CH, 1H), 7.43 (d, J¼7.3 Hz,]CH, 1H), 7.17–7.09 (m,]CH,
2H), 6.55 (s,]CH, 1H), 5.91 (t, J¼8.3 Hz, OCH, 1H), 2.84–2.78 (m,
CH2, 1H), 2.67–2.64 (m, CH2, 1H), 2.14–2.12 (m, CH2, 1H), 1.76–1.52
2H), 2.14–2.09 (m, CH2, 2H). 13C NMR (100 MHz, DMSO-d6):
d 190.9,
153.9, 150.3, 143.4, 141.3, 137.3, 131.4 (CH), 131.3, 130.1, 126.3, 122.8
(CH), 122.2 (CH), 121.3 (CH), 114.2, 113.6, 113.1 (CH), 111.3, 102.7,
102.6, 37.4 (CH2), 30.9 (CH2), 22.5 (CH2). IR (KBr, cmꢂ1) 2490, 2227,
1692, 1628, 1580, 1549, 1506, 1484, 1410, 1354, 1299, 1257, 1224,
1193, 1124, 1063, 1015, 915. Anal. Calcd for C22H12ClN3O3: C, 65.76;
H, 3.01; N, 10.46. Found: C, 66.99; H, 2.90; N, 10.63.
(m, CH2, 4H). 13C NMR (100 MHz, DMSO-d6):
d 201.1, 165.1, 146.9,
141.3, 137.1, 133.2, 132.5, 129.4, 128.4, 126.0, 122.6, 121.1, 120.3, 118.7,
116.1, 112.9, 112.2, 107.5, 96.3, 84.6, 43.6, 31.8, 23.0, 22.8. APT 13C
NMR (100 MHz, DMSO-d6):
d 201.1 (CO), 165.1, 146.9, 141.3, 137.1,
133.2, 132.5, 129.4 (CH), 128.4 (CH), 126.0, 122.6 (CH), 121.1 (CH),
120.3 (CH), 118.7, 116.1, 112.9 (CH), 112.2, 107.5, 96.4, 84.6 (OCH),
43.6 (CH2), 31.2 (CH2), 23.0 (CH2), 22.8 (CH2). IR (KBr, cmꢂ1) 3665,
2930, 2850, 2235,1607,1557,1443,1430,1351,1238,1110,1050, 920.
Anal. Calcd for C24H17Cl2N3O3: C, 61.82; H, 3.67; N, 9.01. Found: C,
66.99; H, 3.90; N, 9.93.
4.1.19. The reaction of (E)-3-(1H-indol-3-yl)cyclohept-2-enone (8)
with DDQ. A solution of 8 (330 mg, 1.46 mmol) and DDQ (333 mg,
1.46 mmol) in CHCl3 (25 mL) was stirred at room temperature for
five days. The precipitate was separated via filtration. After the
filtration solvent was concentrated under vacuum, suspended in
chloroform (15 mL), and filtered through filter paper. The
precipitate afforded 43 as yellow powder (157 mg, 24%, mp 239–
240 ꢀC). The filtrate was submitted to thin-layer silica gel chro-
matography eluting with acetone/hexane (20:80). The first band
extracted with ethyl acetate (50 mL) gave 44 as yellow oil (165 mg,
25%). The remaining band was extracted by ethyl acetate (50 mL),
the solvent was removed. Recrystallization of the combined resi-
dues from ethyl acetate/hexane gave 39 as yellow powder (158 mg,
26%, mp 179–180 ꢀC); (E)-4-(2-(1H-indol-3-yl)-7-oxocyclohept-
1-enyl)-5-chloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile
Acknowledgements
We are greatly indebted to The Scientific and Technical Research
Council of Turkey (TUBITAK, Grant No. TBAG-107T073) for their
financial support for this work.
Supplementary data
Supplementary data includes 1H and 13C NMR spectra of com-
pounds. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2010.02.081.
(39): 1H NMR (400 MHz, Acetone-d6):
d 10.81 (m, NH, 1H), 7.82 (d,
J¼1.8 Hz,]CH, 1H), 7.79 (d, J¼7.7 Hz,]CH, 1H), 7.47 (dd, J¼7.9,
1.1 Hz,]CH, 1H), 7.18–7.10 (m,]CH, 2H), 3.21–3.18 (m, CH2, 2H),
2.73–2.72 (m, CH2, 2H), 2.14–2.00 (m, CH2, 4H). 13C NMR (100 MHz,
References and notes
1. Kno¨lker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303–4427.
2. Jones, R. A. In Comprehensive Heterocyclic Chemistry; Katritzky, R. A., Reese, W.,
Eds.; Pergamon: New York, NY, 1984; Vol. 4, p 201.
3. Hesse, M. Indolalkaloide; Chemie: Weinheim, 1974.
4. Sundberg, R. J. In The Chemistry of Indoles; Blomquist, A. T., Ed.; Academic: New
York, NY, 1970.
Acetone-d6):
d 195.5, 146.4, 139.4, 137.0, 136.9, 128.1, 128.0, 126.5,
122.1, 121.1, 120.3, 114.1, 112.2, 112.1, 102.7, 40.4, 30.4, 24.2, 20.4
(Note: The four resonance signals of quaternary carbons are co-
inciding in the olefinic area). IR (KBr, cmꢂ1) 3339, 2924, 2218, 1641,
1583. Anal. Calcd for C23H14ClN3O3: C, 66.43; H, 3.39; N, 10.11.
Found: C, 66.31; H, 3.48; N, 10.01. The existence of two different
5. Remers, W. A. In The Chemistry of Heterocyclic Compounds; Houlihan, W. J., Ed.;
Wiley-Interscience: New York, NY, 1973; Vol. 25,, Part I, Chapter 1.

A.E. Sadak et al. / Tetrahedron 66 (2010) 3214–3221
3221
6. Hibino, S.; Choshi, T. Nat. Prod. Rep. 2001, 18, 66–87.
7. Chakraborty, D. P.; Barman, B. K.; Bose, P. K. Tetrahedron 1965, 21, 681–685.
8. Pindur, U.; Kim, Y. S.; Mehrabani, F. Curr. Med. Chem. 1999, 6, 29–69.
9. Steglich, W.; Steffan, B.; Kopanski, K.; Eckhardt, G. Angew. Chem., Int. Engl. 1980,
19, 459–460.
31. Yadav, J. S.; Abraham, S.; Reddy, B. V. S.; Sabitha, G. Synthesis 2001, 2165–2169.
32. Bandini, M.; Melchiorre, P.; Melloni, A.; Umani-Ronchi, A. Synthesis 2002, 1110–
1114.
33. Agnusdei, M.; Bandini, M.; Melloni, A.; Umani-Ronchi, A. J. Org. Chem. 2003, 68,
7126–7129.
10. Hilger, T.; Kuniyoshi, M. J. Toxicol. Toxin Rev. 2000, 19, 119–137.
11. Noble, R. L.; Beer, C. T.; Cutts, J. H. Ann. N.Y. Acad. Sci. 1958, 76, 882–894.
12. Svoboda, G. H.; Neuss, N.; Gorman, M. J. Am. Pharm. Assoc. Sci. Ed.1959, 48, 659–666.
13. Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.; Tokuyama, H.;
Fukuyama, T. Pure Appl. Chem. 2003, 75, 29–38.
14. Zhang, Y. Tetrahedron 2006, 62, 3917–3927.
15. Joseph, B.; Da Costa, H.; Merour, J.-Y.; Leonce, S. Tetrahedron 2000, 56, 3189–
3196.
16. Pindur, U.; Pfeuffer, L.; Kim, M.-H. Helv. Chim. Acta 1989, 72, 65–72.
17. Lopez-Alvarado, P.; Alonso, M. A.; Avendano, C.; Menendez, J. C. Tetrahedron
Lett. 2001, 42, 7971–7974.
18. Alonso, M. A.; Lopez-Alvarado, P.; Avendano, C.; Menendez, J. C. Tetrahedron
2003, 59, 2821–2830.
19. Eitel, M.; Pindur, U. J. Org. Chem. 1990, 55, 5368–5374.
20. Pindur, U.; Kim, M.-H. Tetrahedron Lett. 1988, 29, 3927–3928.
21. Pindur, U.; Eitel, M. J. Heterocycl. Chem. 1991, 28, 951–954.
22. Alonso, M. A.; Lopez-Alvarado, P.; Avendano, C.; Menendez, J. C. Lett. Org. Chem.
2004, 1, 20–22.
34. Bandini, M.; Fagioli, M.; Melloni, A.; Umani-Ronchi, A. Synthesis 2003, 397–402.
35. Yadav, J. S.; Reddy, B. V. S.; Swamy, T. Synthesis 2004, 106–110.
36. Alam, M. M.; Varala, R.; Adapa, S. R. Tetrahedron Lett. 2003, 44, 5115–5119.
37. Cavdar, H.; Saracoglu, N. Tetrahedron 2005, 61, 2401–2405.
38. Cavdar, H.; Saracoglu, N. J. Org. Chem. 2006, 71, 7793–7799.
39. Bandini, M.; Cozzi, P. G.; Giacomini, M.; Melchiorre, P.; Selva, S.; Umani-Ronchi,
A. J. Org. Chem. 2002, 67, 3700–3704.
40. Ko, S.; Lin, C.; Tu, Z.; Wang, Y.-F.; Wang, C.-C.; Yao, C.-F. Tetrahedron Lett. 2006,
47, 487–492.
41. Bartoli, G.; Bartolacci, M.; Bosco, M.; Foglia, G.; Giuliani, A.; Marcantoni, E.;
Sambri, L.; Torregiani, E. J. Org. Chem. 2003, 68, 4594–4597.
42. Kowalski, C. J.; Weber, A. E.; Fields, K. W. J. Org. Chem. 1982, 47, 5088–5093.
43. Arcadi, A.; Alfonsi, M.; Bianchi, G.; D’Anniballe, G.; Marinelli, F. Adv. Synth. Catal.
2006, 348, 331–338.
44. Chakrabarty, M.; Kundu, T.; Harigaya, Y. J. Chem. Res., Synop. 2004, 778–780.
45. Banerjı, J.; Saha, M.; Chakrabarti, R.; Kanrar, S.; Chatterjee, A.; Budzikiewicz, H.;
Prange, T.; Neuman, A. J. Chem. Res., Synop. 1993, 320–321.
46. Moran, J.; Suen, T.; Beauchemin, A. M. J. Org. Chem. 2006, 71, 676–679.
47. Matsui, K.; Takizawa, S.; Sasai, H. J. Am. Chem. Soc. 2005, 127, 3680–3681.
48. Baylis, A.B.; Hillman, M.E.D. German Patent 21,55,113, 1972.
49. Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41 2815–2815.
50. You, J.; Xu, J.; Verkade, J. G. Angew. Chem., Int. Ed. 2003, 42, 5054–5056.
51. Yu, C.; Hu, L. J. Org. Chem. 2002, 67, 219–223.
23. Pindur, U. In Advances in Nitrogen Heterocycles; Moody, C. J., Ed.; JAI: Greenwich,
1995; Vol. 1, pp 121–172.
24. Pindur, U.; Eitel, M. Helv. Chim. Acta 1988, 71, 1060–1064.
25. Padwa, A.; Lynch, S. M.; Mejia-Oneto, J. M.; Zhang, H. J. Org. Chem. 2005, 70,
2206–2218.
26. Rosillo, M.; Dominguez, G.; Casarrubios, L.; Amador, U.; Perez-Castells, J. J. Org.
Chem. 2004, 69, 2084–2093.
52. Spartan v. 5.0; Wave function, Inc.: 18401 Von Karman Avenue, Suite 370,
Irvine, CA, 92612, 2003.
27. Lewandowska, E. Tetrahedron 2006, 63, 2107–2122.
28. Saracoglu, N. Top. Heterocycl. Chem. 2007, 11, 1–61.
29. Harrington, P.; Kerr, M. A. Synlett 1996, 1047–1048.
30. Harrington, P.; Kerr, M. A. Can. J. Chem. 1998, 76, 1256–1265.
53. Parr, R. G.; Yang, W. Density-Functional Theory of Atoms and Molecules; Oxford
University Press: New York, NY, 1994.
54. Becke, A. D. J. Chem. Phys. 1993, 98, 1372–1377.
55. Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789.