An efficient ZnO-catalyzed synthesis of novel indole-annulated thiopyrano-chromene derivatives via Domino Knoevenagel-hetero-Diels-Alder reaction

Article abstract of DOI:10.1016/j.tetlet.2009.09.106

An efficient synthesis of pentacyclic indole derivatives is achieved via domino Knoevenagel-hetero-Diels-Alder reactions of indolin-2-thiones and O-propargylated salicylaldehyde derivatives in CH₃CN in the presence of 10 mol % of ZnO as a heter

Full text of DOI:10.1016/j.tetlet.2009.09.106

Tetrahedron Letters 50 (2009) 6723–6727
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Tetrahedron Letters
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An efficient ZnO-catalyzed synthesis of novel indole-annulated
thiopyrano-chromene derivatives via Domino
Knoevenagel-hetero-Diels–Alder reaction
*
Mostafa Kiamehr, Firouz Matloubi Moghaddam
Laboratory of Organic Synthesis and Natural Products, Department of Chemistry, Sharif University of Technology, PO Box 11155-9516 Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 July 2009
Revised 5 September 2009
Accepted 21 September 2009
Available online 24 September 2009
An efficient synthesis of pentacyclic indole derivatives is achieved via domino Knoevenagel-hetero-Diels–
Alder reactions of indolin-2-thiones and O-propargylated salicylaldehyde derivatives in CH3CN in the
presence of 10 mol % of ZnO as a heterogeneous catalyst. The products are formed in good to excellent
yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Knoevenagel reaction
Hetero-Diels–Alder reaction
Indolin-2-thione
O-propargylated salicylaldehyde
ZnO
The indole moiety is frequently encountered in medicinal
chemistry and is considered to be a privileged scaffold.1 Several
compounds possessing an indole moiety show antitumor activity,2
and can lead to inflammation and vessication of human skin.3
Compounds containing a thiopyranoindole moiety are important
because of their biological activity,4 and various pentacyclic indole
alkaloids such as reserpine, rauniticine, yohimbine, and aspido-
spermine show extensive bioactivity profiles.5
There are several examples of the synthesis of benzopyran and
pyranobenzopyran moieties while those of their sulfur-containing
analogs are rare.6 A literature survey revealed that there are only a
few reports on the synthesis of polycyclic pyranothiopyrans.7
An important objective in organic synthesis is the development
of highly efficient synthetic procedures toward complex molecules.
The hetero-Diels–Alder reaction represents an effective method for
the synthesis of heterocyclic compounds, especially natural prod-
ucts.8 In recent years, intramolecular-hetero-Diels–Alder reactions
have been widely used in numerous reactions in organic synthesis,
because of their economical and stereocontrolled nature.9 These
reactions allow the formation of two or more rings at once, avoid-
ing sequential chemical transformations. However, it is a prerequi-
site that activating groups have to be built into dienophiles to
achieve the desired reactivity.10
these reactions, the domino Knoevenagel-hetero-Diels–Alder reac-
tion is a very efficient process, especially in the area of heterocycles
and natural products.12
For a long time, the use of alkynes in hetero-Diels–Alder reac-
tions was limited because of the lower reactivity of unactivated al-
kynes compared to the corresponding alkenes. The use of different
Lewis acids13 provides new opportunities for various catalytic al-
kyne reactions. Furthermore, the surface of metal oxides exhibit
both Lewis acid and Lewis base characters. This is typical of many
metal oxides, especially TiO2, Al2O3, and ZnO. They are excellent
adsorbents for a wide variety of organic compounds, and increase
the reactivity of the reactants.14 ZnO is a very interesting metal
oxide as it has surface properties which potentially favor diverse
organic chemistry.15
Balalaie et al. recently described the domino Knoevenagel-
hetero-Diels–Alder reaction (DKHDA) of several 1,3-dicarbonyl
R2
CHO
ZnO/ 3 h
CH3CN/ reflux
+
O
A
C
R2
O
N
S
N
B
R1
R1
Recently, domino reactions have been used as highly efficient
S
processes for the improvement of reaction efficiency.11 Among
1
2
3a-j
R1= Ph, Et, Me
R2= H, Br, OMe, NO2
* Corresponding author. Tel.: +98 21 66165309; fax: +98 21 66012983.
E-mail address: matloubi@sharif.edu (F.M. Moghaddam).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.106

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M. Kiamehr, F. M. Moghaddam / Tetrahedron Letters 50 (2009) 6723–6727
Table 1
compounds with O-propargylated salicylaldehyde derivatives for
the synthesis of tetracycles with a pyran ring,16 however, to the
best of our knowledge, there is no report on the domino Knoevena-
gel-intramolecular-hetero-Diels–Alder reaction of indolin-2-thi-
ones with O-propargylated salicylaldehydes. In the context of our
general interest in ZnO-catalyzed organic synthesis,17 and the
synthesis of heterocyclic compounds using thioamides,18 we here-
in report a highly efficient strategy for the preparation of polycyclic
compounds 3a–j, which consist of an indole ring (A), a dihydro-
thiopyran ring (B) annulated to a dihydrochromene ring (C)
(Scheme 1).
The O-propargylated salicylaldehydes 2a–d were prepared from
the corresponding substituted salicylaldehydes in good to excel-
lent yields via Williamson ether synthesis.19 The reaction of com-
pound 1a with 2a was used as a model to optimize the reaction
conditions. The experimental results are summarized in Table 1.
Effect of catalyst and solvent on the domino Knoevenagel-hetero-Diels–Alder reaction
of 1a and 2a
Entry
Catalyst
Solvent
Temperature
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
—
—
—
—
PhMe
CH3CN
H2O
rt
rt
rt
80 °C
80 °C
Reflux
Reflux
Reflux
Reflux
Reflux
48
48
48
5
5
3
3
3
3
3
33
35
0
38
42
10
40
90
90
90
PhMe
—
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CuIb (100%)
ZrOCl2 (100%)
ZnO (100%)
ZnO (50%)
ZnO (10%)
10
a
Yield of isolated product.
Decomposition of 1a took place in the presence of CuI.
b
Table 2
Domino Knoevenagel-hetero-Diels–Alder reactions of 1a–c with 2a–da
Entry
Aldehyde
Indolin-2-thione
Product
Yieldb (%)
CHO
O
S
S
S
O
N
1
90
N
S
2a
1a
3a
O
N
2
2a
85
N
S
1b
1c
3b
O
N
3
2a
88
N
S
3c
Br
Br
CHO
O
4
1a
95
O
N
S
2b
3d
Br
O
5
1b
2b
90
N
S
3e

M. Kiamehr, F. M. Moghaddam / Tetrahedron Letters 50 (2009) 6723–6727
6725
Table 2 (continued)
Entry
Aldehyde
Indolin-2-thione
Product
Yieldb (%)
Br
O
6
7
8
9
1c
2b
88
85
85
95
95
N
S
3f
OMe
CHO
O
O
1a
1b
1a
1c
N
OMe
S
2c
3g
OMe
O
2c
N
S
3h
O2N
O
O2N
CHO
O
N
S
2d
3i
O2N
O
10
2d
N
S
3j
a
All reactions were carried out at reflux in CH3CN with ZnO (10 mol %) for 3 h.
Isolated yield.
b
When the reaction was carried out at room temperature using
analyses.20 The characteristic signals for 3a–j in the 1H NMR spec-
tra were an AB quartet for the –OCH2 group between 4.60 and
5.05 ppm, a singlet for the aliphatic CH group at 5.17–5.46 ppm,
and another singlet for the SCH@ group at 6.00–6.34 ppm. The
diastereotopic nature of the two protons of the OCH2 group is
due to the helical shape of rings A–C in products 3a–j.16 The cor-
responding signals of the –OCH2 and aliphatic CH groups in the
13C NMR spectra appeared at 73.0–73.8 ppm and 36.0–36.5 ppm,
respectively.
A plausible mechanism for the reaction is shown in Scheme 2.
The initial step is a Knoevenagel condensation between indolin-
2-thiones 1a–c and aldehydes 2a–d in which the aldehyde function
may be activated by ZnO to facilitate the condensation. Next, the
1a (0.5 mmol, 1 equiv) and 2a (0.5 mmol, 1 equiv) in toluene or
CH3CN, the reaction rate was slow and the product was obtained
in only 33% or 35% yield after 48 h, (entries 1 and 2). Running
the reaction in water did not provide the desired product (entry
3). When the reaction was carried out under refluxing conditions
using 1a (0.5 mmol, 1 equiv), 2a (0.5 mmol, 1 equiv) and ZnO
(100 mol %) in CH3CN the reaction time was reduced to 3 h afford-
ing 3a in 90% yield (entry 8). Decreasing the ratio of ZnO to
10 mol % afforded the same result, but with 5 mol % of ZnO, the
reaction took longer. Hence, the conditions used in entry 10 are
optimal. Using the optimized conditions, we studied the domino
Knoevenagel-hetero-Diels–Alder reactions of compounds 1a–c
and 2a–d to give products 3a–j in high yields (85–95%) (Table 2).
The structures of the products were established from their
NMR spectroscopic data (1H NMR, 13C NMR, DEPT) and elemental
triple bond is activated with ZnO through formation of a
p-com-
plex and provides the necessary conditions for the subsequent
intramolecular-hetero-Diels–Alder reaction.

6726
M. Kiamehr, F. M. Moghaddam / Tetrahedron Letters 50 (2009) 6723–6727
R2
R2
O
CHO
ZnO
+
CH3CN
reflux
O
R2
O
N
R1
hetero-Diels-Alder
N
S
R1
S
S
N
R1
1a-c
2a-d
3a-j
4
Scheme 2. A plausible mechanism for the formation of compounds 3a–j.
Ezpeleta, J. M. J. Org. Chem. 2002, 67, 2131; (h) Osborn, H. M. I.; Coisson, D. Mini-
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56, 5259.
In summary, we have described a ZnO-catalyzed domino Knoe-
venagel-intramolecular-hetero-Diels–Alder reaction, which pro-
vides an efficient route for the formation of polycyclic indole
derivatives in a single step. The major advantage of this reaction
is the ease of the work-up during which the products can be iso-
lated without chromatography. This method also offers other
advantages such as clean reactions, low loading of catalyst, high
yields of products, short reaction times, and the use of ZnO as a
non-toxic, non-corrosive, commercially available, and inexpensive
heterogeneous catalyst, which make it a useful and attractive strat-
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ones and indolin-2-ones in domino Knoevenagel-intramolecular-
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Acknowledgment
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2008, 38, 2043; (c) Moghaddam, F. M.; Saeidian, H.; Mirjafary, Z.; Sadeghi, A.
Lett. Org. Chem. 2007, 4, 576; (d) Moghaddam, F. M.; Saeidian, H.; Mirjafary, Z.;
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Synlett 2005, 1612; (f) Moghaddam, F. M.; Zali Boinee, H. Tetrahedron 2004, 60,
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20. To a stirred suspension of ZnO (10 mol %) in CH3CN (10 ml) were added
indolin-2-thione 1a–c (0.5 mmol) and O-propargylated salicylaldehyde
derivative 2a–d (0.5 mmol). The reaction mixture was stirred at reflux for
3 h and the progress of the reaction was monitored by TLC. After completion of
the reaction, the mixture was poured onto ice-cold water and stirred for
10 min, which resulted in the precipitation of the product 3a–j. The solid
precipitate was filtered, dried, washed with petroleum ether to remove any
residual starting material and after drying, recrystallized from ethanol.
Selected spectroscopic data: 9-Phenyl-9,13c-dihydro-6H-chromeno[40,30:4,5]-
thiopyrano[2,3-b]indole (3a): 90%; pale-white solid, mp 138–141 °C; dH
(500 MHz, CDCl3) 4.80 (1H, d, J 11.9 Hz, CH), 4.99 (1H, d, J 11.9 Hz, CH), 5.46
(1H, s, CH), 6.19 (1H, s, @CH), 6.82 (1H, t, J 7.5 Hz, HAr), 6.90 (1H, d, J 8.1 Hz,
HAr), 7.13–7.19 (2H, m, HAr), 7.22–7.24 (2H, m, HAr), 7.30–7.32 (1H, m, HAr),
7.46–7.50 (3H, m, HAr), 7.56–7.62 (3H, m, HAr); dC [125 MHz, CDCl3/DMSO-d6
(10%)] 36.5 (CH), 73.1 (CH2), 105.0 (C), 110.0 (CH), 111.3 (CH), 117.4 (CH),
118.5 (CH), 121.0 (CH), 121.1 (CH), 122.5 (CH), 126.4 (C), 127.0 (CH), 127.1 (C),
We would like to acknowledge the help rendered by the Islamic
Development Bank (IDB) for granting a loan in 1993 for purchasing
a 500 MHz Bruker NMR spectrometer.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.09.106.
References and notes
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M. Kiamehr, F. M. Moghaddam / Tetrahedron Letters 50 (2009) 6723–6727
6727
127.4 (CH), 128.3 (CH), 128.6 (CH), 128.8 (C), 129.1 (C), 129.8 (C), 130.1 (CH),
136.9 (C), 154.2 (C). Anal. Calcd for C24H17NOS: C, 78.44; H, 4.66; N, 3.81.
Found: C, 77.84; H, 4.61; N, 3.77.
(1H, d, J 8.1 Hz, HAr), 7.06 (1H, d, J 7.6 Hz, HAr), 7.15–7.20 (2H, m, HAr), 7.27 (1H,
d, J 8.1 Hz, HAr), 7.38 (1H, d, J 8.2 Hz, HAr), 7.56 (1H, d, J 7.8 Hz, HAr); dC
(125 MHz, CDCl3) 15.6 (CH3), 36.5 (CH), 39.5 (NCH2), 73.4 (CH2), 103.3 (C),
108.9 (CH), 110.4 (CH), 117.1 (CH), 118.6 (CH), 120.2 (CH), 121.1 (CH), 121.8
(CH), 125.2 (C), 127.1 (CH), 127.7 (C), 128.2 (CH), 128.7 (C), 129.4 (C), 137.2 (C),
154.2 (C). Anal. Calcd for C20H17NOS: C, 75.20; H, 5.36; N, 4.39. Found: C, 74.53;
H, 5.28; N, 4.32.
9-Ethyl-9,13c-dihydro-6H-chromeno[40,30:4,5]thiopyrano[2,3-b]indole (3b):
85%; pale-white solid, mp 118–121 °C; dH (500 MHz, CDCl3) 1.43 (3H, t, J
7.2 Hz, CH3), 4.15–4.17 (2H, m, NCH2), 4.80 (1H, d, J 11.9 Hz, CH), 4.99 (1H, d, J
11.7 Hz, CH), 5.41 (1H, s, CH), 6.24 (1H, s, @CH), 6.78 (1H, t, J 7.5 Hz, HAr), 6.89