Synthesis of novel pentacyclic thiopyrano indole-annulated benzo-δ-sultone derivatives via a domino Knoevenagel-hetero-Diels-Alder reaction in water

Article abstract of DOI:10.1016/j.tetlet.2013.03.070

An efficient synthesis of novel pentacyclic thiopyrano indole-annulated benzo-δ-sultone derivatives is achieved via intramolecular domino Knoevenagel-hetero-Diels-Alder reaction of 2-formylphenyl (E)-2-phenylethenyl sulfonates and indoline-2-thiones in aq

Full text of DOI:10.1016/j.tetlet.2013.03.070

Tetrahedron Letters 54 (2013) 2685–2689
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Synthesis of novel pentacyclic thiopyrano indole-annulated
benzo-d-sultone derivatives via a domino Knoevenagel-hetero-Diels–Alder
reaction in water
Firouz Matloubi Moghaddam a, , Mohammad Reza Khodabakhshi a, Mostafa Kiamehr a,b
,
⇑
Zahra Ghahremannejad a
a Laboratory of Organic Synthesis and Natural Products, Department of Chemistry, Sharif University of Technology, Azadi Street, PO Box 11155-9516, Tehran, Iran
b Department of Chemistry, Faculty of Science, University of Qom, Qom, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of novel pentacyclic thiopyrano indole-annulated benzo-d-sultone derivatives is
achieved via intramolecular domino Knoevenagel-hetero-Diels–Alder reaction of 2-formylphenyl
(E)-2-phenylethenyl sulfonates and indoline-2-thiones in aqueous medium. The products are formed
in good yields with high regio- and stereoselectivity.
Received 11 November 2012
Revised 5 March 2013
Accepted 13 March 2013
Available online 24 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Knoevenagel-hetero-Diels–Alder
Domino reaction
Indoline-2-thiones
Aqueous medium
Benzo-d-sultones
Thiopyrano indole
The hetero-Diels–Alder reaction is a powerful and efficient reac-
tion for the synthesis of heterocycle-containing compounds includ-
ing natural products.1 The intramolecular hetero-Diels–Alder
reaction has been widely used in organic synthesis because of its
economical and stereoselective nature.2 Tietze et al. have reported
the domino Knoevenagel-hetero-Diels–Alder reaction of unsatu-
rated aromatic and aliphatic aldehydes with various 1,3-dicarbonyl
compounds for the synthesis of polycyclic compounds possessing a
pyran ring.3
Indole derivatives are widespread in nature and compounds
possessing this ring system have various biological activities,4 such
as antitumor5 and topical anti-inflammatory activity.6 Thiopyrano
indole-annulated compounds are important because of their broad
pharmacological and medicinal activity.7 Some [6,6] fused penta-
cyclic indole alkaloids such as aspidospermine, rauniticine, reser-
pine, and yohimbine show extensive bioactivity.8
metathesis,13 and Pd-catalyzed intramolecular cyclizations.14 Bio-
logical studies on sultones are mainly concerned with their toxico-
logical, skin sensitization,15 and antiviral activity.16
To the best of our knowledge, there are no examples of domino
Knoevenagel-hetero-Diels–Alder reactions using thioamides,
particularly
indoline-2-thiones
with
2-formylphenyl
(E)-2-phenylethenyl sulfonates in the literature, and especially so
for indoline-2-thione with 2-formylphenyl (E)-2-phenylethenyl
sulfonates. In continuation of our research in the area of domino
Knoevenagel-hetero-Diels–Alder reactions,17 and the synthesis of
indole-containing heterocycles with biological significance,18 we
herein report a new and highly efficient reaction for the preparation
of thiopyranoindole-annulated benzo-d-sultones 3a–l and 4a–l
based on the reaction of 2-formylphenyl (E)-2-phenylethenyl sulfo-
nates 1 and indoline-2-thiones 2 (Scheme 1).
The 2-formylphenyl (E)-2-phenylethenyl sulfonate substrates
1a–c were prepared in high yields from the corresponding substi-
tuted salicylaldehydes 5a-c and (E)-2-phenylethenylsulfonyl chlo-
ride (6) using K2CO3 in dry acetone at room temperature
(Scheme 2).
Sultones are cyclic sulfonate esters of a sulfonic acid and are
usually considered as alkylation agents, due to their easy reactions
with a variety of nucleophiles.9 The most important methods for
the preparation of sultones are C–H insertion reactions,10
Diels–Alder reactions,11 olefin sulfination reactions,12 ring-closing
To optimize the conditions, the reaction of compound 1a with
2a was used as a model system and the effects of the solvent and
catalyst were studied. When water was used as the solvent in
the absence of a catalyst under reflux conditions for 4 h, products
⇑
Corresponding author. Tel.: +98 21 66165309; fax: +98 21 66012983.
E-mail address: matloubi@sharif.edu (F.M. Moghaddam).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.070

2686
F. M. Moghaddam et al. / Tetrahedron Letters 54 (2013) 2685–2689
R2
R2
O
O
R1
R1
R1
CHO
O
SO2
Hb
Ph
Ha
SO2
Hb
Ph
Ha
H2O, 4 h
reflux
+
Ph
S
+
Hc
Hc
S
N
O
R3
O
R2
S
S
R1= H, Br
R2= H, OMe
R3= Me, Et, Ph, H
N
N
R3
R3
major
3a-l
minor
4a-l
1a-c
2a-d
Scheme 1. Synthesis of thiopyrano indole-annulated benzo-d-sultone derivatives 3a–l and 4a–l.
SO2Cl
R1
CHO
OH
R1
CHO
O
R1
H
Yield (%)
R2
H
acetone
+
1a
1b
1c
96
93
S
K2CO3, 8h
O
R2
O
R2
Br
H
H
R1=H, Br
92
R2=H, OMe
OMe
6
1a-c
5a-c
Scheme 2. Synthesis of 2-formylphenyl (E)-2-phenylethenyl sulfonates 1a–c.
Table 1
Effect of the solvents and catalyst on the yield and selectivity of products
O
O
CHO
SO2
H
Ph
H
SO2
H
Ph
H
O
+
Ph
S
+
H
H
S
N
Me
O
O
S
S
N
Me
N
Me
2a
1a
4a
3a
Entry
Solvent
Catalyst
Temp
Ratio of 1a:2a
Time (h)
Yielda (%)
Ratio of 3a:4ab
1
2
3
4
5
6
7
8
H2O
–
Reflux
Reflux
Reflux
Reflux
rt
Reflux
Reflux
Reflux
1:1
1:1
1:1
1:1
4
4
6
8
10
4
60
57
42
31
39
80
63
78
67:33
64:36
70:30
55:45
76:24
68:32
65:35
61:39
AcOH
CH3CN
CH3CN
CH3CN
H2O
Et3N
EDDA
ZnO
EDDA
–
1:1
1:1.2
1.2:1
1:1.4
H2O
H2O
–
–
4
4
a
Yield of isolated product.
Based on the 1H NMR spectrum of the crude product.
b
3a and 4a were obtained in 60% overall yield in a ratio of 67:33.
When the reaction was carried out in the presence of triethylamine
(1 equiv) in AcOH (Table 1, entry 2) for 4 h or ethylenediammoni-
um diacetate (EDDA, 0.2 equiv) in CH3CN (Table 1, entry 3) for 6 h,
the desired products 3a and 4a were obtained in 57% and 42%
yields, respectively.
The structures and the ratios of compounds 3 and 4 were deter-
mined from their spectroscopic data and by elemental analysis.19
The relative configurations were established from the coupling
constants of the appropriate H-atoms. For example, the 1H NMR
spectrum of compound 3a showed a doublet of doublets (J = 10.8,
4.5 Hz) at d 4.57 for the Hb proton, and two doublets: J = 10.7 at
d 4.62 for Ha in trans-relationship with Hb, and J = 4.5 at d 4.57
for Hc in cis-relationship with Hb. In contrast, compound 4a
showed a doublet of doublets (J = 10.6, 11.5 Hz) at d 4.19 for the
Hb proton and two doublets: J = 10.6 and J = 11.5 at d 4.77 and d
5.16 for Ha and Hc, both of which were in a trans relationship
with Hb.
A plausible mechanism for the formation of products 3a–l and
4a–l is outlined in Scheme 3. Indoline-2-thiones 2 undergo a Knoe-
venagel condensation with 2-formylphenyl (E)-2-phenylethenyl
sulfonates 1 in H2O at reflux to afford an alkene intermediate,
which was not isolated. This intermediate can potentially follow
two pathways for the hetero-Diels–Alder reaction. The endo transi-
tion state (path a) leading to the cis-trans annulated cycloadduct, is
more favorable than the exo transition state (path b) due to an sp2-
geminal effect based on the phenomenon of 1,3-allylic strain.20
According to our previous report,17c the effect of ZnO as a Lewis
acid was also studied, and we observed that in this case the yield of
the product decreased to 31% yield (entry 4). In an attempt to im-
prove the selectivity of the reaction (i.e., the ratio of cis/trans prod-
ucts), we used ethylenediammonium diacetate as the catalyst in
acetonitrile at room temperature, but found that the selectivity
was not increased considerably (entry 5). Finally, we concluded
that adding a catalyst had no beneficial effect, therefore using
H2O as a green solvent, we investigated using different ratios of
substrates 1a and 2a. The best results were obtained using a ratio
(1a:2a) of 1:1.2 (entry 6).
We next studied the domino Knoevenagel-hetero-Diels–Alder
reaction of 2-formylphenyl (E)-2-phenylethenyl sulfonate deriva-
tives 1a–c and indoline-2-thiones 2a–d. The results are shown in
Table 2.

F. M. Moghaddam et al. / Tetrahedron Letters 54 (2013) 2685–2689
2687
Table 2
Results obtained for the domino Knoevenagel-hetero-Diels–Alder reactions of 1a–c with 2a–d
Entry
Sulfonate
Indolin-2-thione
Products
Yield (%)a
Ratio of 3:4b
O
O
S
N
Me
SO2
H
SO2
H
H
H
Ph
Ph
H
2a
1
1a
80
67:33
H
S
S
N
N
Me
3a
Me
4a
O
O
Br
Br
SO2
H
SO2
H
H
H
Ph
Ph
H
2
1b
2a
88
69:31
H
S
S
N
N
Me
3b
Me
4b
OMe
OMe
O
O
SO2
H
SO2
H
H
H
3
1c
2a
75
77:23
Ph
Ph
H
H
S
S
N
N
Me
3c
Me
4c
O
O
S
N
Et
SO2
H
SO2
H
H
H
Ph
Ph
H
2b
4
1a
75
78:22
H
S
S
N
N
Et
3d
Et
4d
O
O
Br
Br
SO2
H
SO2
H
H
H
Ph
Ph
H
5
1b
2b
85
80:20
H
S
S
N
N
Et
Et
3e
4e
OMe
OMe
O
O
SO2
H
SO2
H
H
H
6
1c
2b
80
67:33
Ph
Ph
H
H
S
S
N
N
Et
Et
3f
4f
O
O
S
N
Ph
SO2
H
SO2
H
H
H
Ph
Ph
H
2c
7
1a
72
79:21
H
S
S
N
N
Ph
3g
Ph
4g
(continued on next page)

2688
F. M. Moghaddam et al. / Tetrahedron Letters 54 (2013) 2685–2689
Table 2 (continued)
Entry
Sulfonate
Indolin-2-thione
Products
Yield (%)a
Ratio of 3:4b
O
O
Br
Br
SO2
H
SO2
H
H
H
Ph
Ph
H
8
1b
2c
80
65:35
H
S
S
N
N
Ph
3h
OMe
Ph
4h
OMe
O
O
SO2
H
SO2
H
H
H
9
1c
2c
76
73:27
Ph
Ph
H
H
S
S
N
N
Ph
Ph
3i
4i
O
O
S
SO2
H
SO2
H
N
H
H
H
Ph
Ph
2d
10
1a
74
64:36
H
H
S
S
N
N
H
H
3j
4j
O
O
Br
Br
SO2
H
SO2
H
H
H
Ph
Ph
H
11
1b
2d
74
66:34
H
S
S
N
N
H
H
3k
4k
OMe
OMe
O
O
SO2
H
SO2
H
H
H
12
1c
2d
70
85:15
Ph
Ph
H
H
S
S
N
N
H
H
3l
4l
a
Yield of isolated product.
b
Based on the 1H NMR spectrum of the crude products.
R2
R3
O
R1
N
SO2
path a
H
S
R1
CHO
O
H
O2
Ph
S
Ph
O
H
S
S
O
Ph
N
R3
O
R2
R2
cis-trans
endo-E-syn
3a-l
R1
(major)
1a-c
H2O
reflux
+
R2
R3
N
O
R1
S
SO2
H
N
R3
Ph
S
H
Ph
R1
path b
H
2a-d
S
SO2
N
R3
O
trans-trans
R2
exo-E-anti
4a-l
(minor)
Scheme 3. A plausible mechanism for the formation of compounds 3 and 4.

F. M. Moghaddam et al. / Tetrahedron Letters 54 (2013) 2685–2689
2689
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In conclusion, we have developed
a novel and efficient
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procedure for the synthesis of pentacyclic thiopyrano indole-annu-
lated benzo-d-sultone derivatives via intramolecular domino
Knoevenagel hetero-Diels–Alder reactions of indoline-2-thiones
and 2-formylphenyl (E)-phenylethenyl sulfonate derivatives. The
reaction was performed in aqueous medium which is environmen-
tally friendly, and has other advantages such as high yields of prod-
ucts, ease of work-up, and proceeds via a catalyst-free procedure,
which should make it a useful and attractive procedure for the
synthesis of these types of compound.
Acknowledgment
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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.
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Majumdar, K. C.; Chattopadhyay, B.; Sinha, B. Synthesis 2008, 3857.
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Supplementary data
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S.; Saeidian, H. Tetrahedron 2010, 66, 8615; (b) Moghaddam, F. M.; Kiamehr,
M.; Taheri, S.; Mirjafary, Z. Helv. Chim. Acta 2010, 93, 964; (c) Kiamehr, M.;
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Supplementary data associated with this article can be found, in
theonlineversion,athttp://dx.doi.org/10.1016/j.tetlet.2013.03.070.
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19. General procedure for the synthesis of compounds 3a–l and 4a–l: a mixture of
2-formylphenyl (E)-2-phenylethenyl sulfonate 1 (0.5 mmol) and indoline-2-
thione derivative 2 (0.6 mmol) in H2O (6 ml) was stirred at reflux temperature.
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7-phenyl-6a,7,9,13c-tetrahydro[1,2]benzoxathiino[40,30:4,5]thiopyrano[2,3-
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.
1H NMR (500 MHz, CDCl3): d = 3.68 (3H, s, NMe), {for 4a, 3.74 (3H, s, NMe)},
4.57 (1H, dd, J = 4.5, 10.8 Hz, CHSO3), {for 4a, 4.19 (1H, dd, J = 10.6, 11.5 Hz,
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CDCl3): d = 27.6, 38.8, 45.5, 62.0, 107.6, 116.9, 118.6, 119.3, 121.0, 121.4, 121.5,
125.7, 126.9, 127.4, 127.7, 127.8, 128.2, 128.7, 129.0, 129.4, 130.5, 137.3. Anal.
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