Synthesis of some novel and complex thiopyrano indole derivatives from simple oxindole via intramolecular domino hetero Diels-Alder reactions

Article abstract of DOI:10.1016/j.tetlet.2011.10.133

Some novel polycyclic thiopyrano[2,3-b]indole derivatives 7 were synthesized from simple oxindole 1 by exploring intramolecular domino hetero Diels-Alder reactions strategy.

Full text of DOI:10.1016/j.tetlet.2011.10.133

Tetrahedron Letters 53 (2012) 137–140
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Tetrahedron Letters
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Synthesis of some novel and complex thiopyrano indole derivatives from
simple oxindole via intramolecular domino hetero Diels–Alder reactions
⇑
Swarup Majumder , Pulak J. Bhuyan
Medicinal Chemistry Division, North East Institute of Science & Technology, Jorhat 785006, Assam, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Some novel polycyclic thiopyrano[2,3-b]indole derivatives 7 were synthesized from simple oxindole 1 by
exploring intramolecular domino hetero Diels–Alder reactions strategy.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 8 September 2011
Revised 21 October 2011
Accepted 23 October 2011
Available online 4 November 2011
Keywords:
Thiopyrano[2,3-b]indole
Oxindole
1,3-Dimethyl barbituric acid
a-Halo aldehyde
Intramolecular domino hetero Diels–Alder
reactions
Indole nucleus is a prominent structural subunit present in
numerous natural products and synthetic compounds with vital
medicinal value.1 The poly cyclic annulated indole compounds
continue to be of extensive synthetic interest, partly because there
are many biologically active natural products of this type, and also
because the polycyclic frameworks lead to relatively rigid struc-
tures that might be expected to show substantial selectivity in
their interactions with enzymes or receptors.2 Thus, pentacyclic
indole alkaloids such as reserpine, rauniticine, yohimbine, and
aspidospermine show extensive bioactivity profiles.3 Thiopyrane
annelated heterocyclic compounds are important due to their bio-
logical activity.4 There are several examples of the synthesis of
benzopyran and pyrano-benzopyran moieties while those of their
sulphur-containing analogs are rare.5 A literature survey revealed
that there are only a few reports on the synthesis of polycyclic
pyranothiopyrans.6
As part of our continued interest on indole and synthesis of di-
verse heterocyclic compounds of biological significance,10 recently
we reported an efficient method for the synthesis of
a-carbolines
from oxindole by exploring a ‘three-component reaction in one
pot’.11 In the present Letter, we report the synthesis of some novel
complex thio pyrano[2,3-b]indole from simple oxindole via intra-
molecular domino hetero Diels–Alder reaction using ethylenedia-
mine diacetate (EDDA) as catalyst.
Oxoindole 1, on treatment with Vielsmeier reagent afforded
the key
a
-halo aldehyde intermediate 2 (Scheme 1).12 The Boc-
protected indole 3 was prepared in high yields by employing
standard Boc protection protocol using di-tert-butyl dicarbonate
(Boc2O).13 The unsaturated side chain was smoothly introduced
in the 2-chloro-3-formyl indole 2 by a nucleophilic substitution
In recent years, intramolecular-hetero-Diels–Alder reactions
have been widely used in numerous reactions in organic synthesis,
because of their economical and stereo controlled nature.7 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.8 The domino-Knoevenagel hetero
Diels–Alder reaction represents one of the most powerful and effi-
cient reactions for the synthesis of natural products and other het-
erocyclic compounds of biological significance.9
CHO
Boc-anhydride
DMF+ POCl3
Cl
O
N
H
1
N
H
2
CHO
Cl
CHO
S
(NH2)2CS, NaOH,
N
1-Bromo- 3-methyl-
2-butene
N
H
Boc
3
4
⇑
Corresponding author. Fax: +91 376 2370011.
E-mail address: majumderswar@yahoo.co.in (S. Majumder).
Scheme 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.133

138
S. Majumder, P. J. Bhuyan / Tetrahedron Letters 53 (2012) 137–140
at the 2-position of the compound by prenyl thiolate. The prenyl
thiolate was prepared by the decomposition of S-prenyl isothiou-
rea salt with sodium hydroxide to which 1-Boc-2-chloro-3-for-
mylindole 3 was added and refluxed for half an hour. After
work-up, S-alkenyl aldehyde 4 was obtained 72% yield where
Boc was deprotected (Scheme 1). This type of Boc deprotection
under basic condition is well documented.14
A plausible mechanism for the formation of indolo-S-alkenyl
aldehyde 4 15 is outlined in Scheme 2. 2-Thioprenyl indolo-3-carb-
aldehyde 4 was then reacted with N,N-dimethylbarbituric acid 5a
in the presence of EDDA (20 mol %) at reflux using CH3CN as sol-
vent (Scheme 3). The intermediate Knoevenagel adduct 6a was ob-
served by TLC control and appearance of the yellow-orange colour
within 15 min. It was not isolated and allowed to cyclise which
after 3–4 h refluxing gave the cis fused pentacyclic thio-pyr-
ano[2,3-b]indole derivative 7a in high yield (75%) and with diaste-
reoselectivity (>99%).
O
N
CHO
S
CH3CN
Reflux
N
+
O
O
N
H
4
5a
O
N
O
N
O
N
N
O
EDDA
O
O
Ha
Hb
Hetero Diels-
Alder
S
S
N
N
H
H
6a
7a
The reaction was then studied under microwave irradiation
Scheme 3.
and the product was obtained in 69% yield along with 15% of
16
the Knoevenagel condensed product 6a.
When the reaction
of 4 and 5a was carried out in toluene under reflux condition
in the absence of catalyst for 12 h afforded the desired product
in low yield 7a (50%) along with some red coloured side product.
However, when EDDA (20 mol %) was employed as a catalyst, the
desired product 7a was obtained 65% yield after refluxing for
3 h. EDDA first catalysed the Knoevenagel condensation and then
may have activated the double bonds to provide the necessary
conditions for the subsequent intra molecular-hetero-Diels–Alder
reaction. Increasing the amount of catalyst (30 mol %) or the
reaction time decreased the yield of the product 7a. The reaction
was also carried out in the presence of triethyl amine and
piperidine but no satisfactory results were obtained. Among
the various conditions employed, the reaction in the presence
EDDA in acetonitrile was found to give the best results. The
effect of solvent was also studied by carrying out the reaction
at various solvents such as toluene, ethanol, MeCN, and H2O.
Running the reaction in water did not provide the desired
product. Our observations are recorded in Table 1.
The structures of the compounds were ascertained from the
spectroscopic data. 1H NMR spectra of 7a showed the absence
of the prenylic protons at d 3.57 (d, J = 7.8 Hz, 2H), 5.26–5.31
(m, 1H) and the presence of two other N-Me protons at d 3.30
and 3.36 as singlets. The cis-fusion at the ring junction of 7a is
ascertained from the coupling constant of 4.7 Hz between the
two hydrogens Ha and Hb in the 1H NMR spectrum. The charac-
teristic signals for 7a in the 1H NMR spectra was the singlet for
O–C(CH3)2 group 1.32 ppm, multiplet for two hydrogen at S–
CH2 group at d 3.49–3.55 ppm. The reaction was then studied
by utilizing other cyclic dicarbonyl compounds viz barbituric acid
(5b), Meldrum’s acid (5c), dimedone (5d), 1,3-indanedione (5e)
and 3-methyl-1-phenyl-2-pyrazolin-5-one (5f) to generate the
Table 1
Optimization for the formation of indole derivatives
conditions
7 under various reaction
Entry Catalyst (20 mol %) Temperature (°C) Solvent
Time (h) Yd.
1
2
3
4
5
6
7
8
—
—
—
—
rt
Reflux
rt
Reflux
rt
rt
Reflux
Reflux
Reflux
MW
MW
MW
Reflux
Toluene 24
45
50a
51
35
42
54
75
65
61
69
62
44b
NRc
Tolune
Ethanol
Ethanol
CH3CN
CH3CN
CH3CN
Toluene
Ethanol
_
12
24
12
24
12
3
3
3
2 min
2 min
4 min
24
—
EDDA
EDDA
EDDA
EDDA
EDDA
EDDAd
EDDA
EDDA
9
10
11
12
13
_
_
water
a
b
c
Decomposed.
Decomposed.
No reaction occurs.
30 mol %.
d
oxabutadiene system which after cyclisation resulted the product
7b–f (Table 2).
The sulphur atom is less electronegative and has high polariz-
ability compared to other hetero atoms. Besides, two methyl
groups are present in terminal position of thioprenyl which facili-
tated the hetero Diels–Alder reaction. It is confirmed by the fact
that, when 2-N-allylmethylamino-3-formyl indole 8 (prepared by
nucleophilic substitution at the 2-position of the compound 3 by
N-allylmethyl amine) reacted with 5a gave simply the Knoevena-
gel condensed product without any cyclised compound 9 even in
the presence of EDDA catalyst (Scheme 4).
In conclusion, we have demonstrated a simple and efficient
NH
2
strategy for the synthesis of some novel thiopyrano indole deriva-
_
SNa
Excess
NaOH
S
NH
2
+
17
tives
from simple oxindole via intramolecular domino hetero
+
_
NH
Br
S
2
Diels–Alder reactions in 62–75% yields. The reaction also demon-
strates an efficient synthesis for Boc deprotection in basic condi-
tions without disturbing aldehyde functionality. The method also
offers other advantages such as clean reactions, low loading of cat-
alyst, high yields of products, and short reaction times for the syn-
thesis of pentacyclic indole derivatives. This reaction, which can be
further utilised in the synthesis of many other heterocyclic com-
pounds of biological importance is a valuable addition to the chem-
istry of indole in particular and heterocyclic compounds as a
whole. Further study of the reaction is in progress.
NH Br
2
Ethanol/
Reflux
CHO
CHO
Cl
+
S
N
N
H
Boc
_
4
NaS
Scheme 2.

S. Majumder, P. J. Bhuyan / Tetrahedron Letters 53 (2012) 137–140
139
Table 2
Synthesis of Pentacyclic indoles 7 via [4+2] hetero Diels–Alder reaction
Acknowledgments
Aromatic aldehyde
Active methylene compound
Product
The authors thank DST, New Delhi, for the financial support.
S.M. thanks CSIR for a Senior Research Fellowship & Director, NE-
IST, Jorhat for providing the facilities to perform the work.
O
O
N
N
N
N
O
O
References and notes
O
O
4
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Nat. Prod. Rep. 2000, 17, 175.
S
5a
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1985, 50, 1695; (c)Hetero Diels–Alder Methodology in Organic Synthesis; Boger,
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N
H
7a
O
O
NH
HN
HN
O
O
O
N
H
O
4
S
N
H
5b
O
7b
O
O
O
O
O
O
O
O
4
5c
S
N
H
7c
O
O
8. (a) House, H. O.; Cronin, T. H. J. Org. Chem. 1965, 30, 1061; (b) Roush, W. R. J. Am.
Chem. Soc. 1978, 100, 3599; (c) Roush, W. R.; Peseckis, S. M. J. Am. Chem. Soc.
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9. (a) Tietze, L. F.; Rackelman, N. In Multicomponent Reactions; Zhu, J., Bienayme,
H., Eds.; Wiley-VCH: Weinheim, 2005; pp 121–167; (b) Tietze, L. F.;
Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967; (c) Tietze, L. F.; Rackelmann,
N.; Müller, I. Chem. Eur. J. 2004, 10, 2722; (d) Tietze, L. F.; Modi, A. Med. Res. Rev.
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Majumder, S.; Baruah, B.; Bhuyan, P. J. Synthesis 2010, 929; (c) Deb, M. L.;
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O
4
4
4
5d
S
N
H
7d
O
O
O
O
O
12. Lu, S. C.; Duan, X. Y.; Shi, B. L.; Ren, Y. W.; Zhang, W.; Zhang, Y. H.; Tu, Z. F. Org.
Lett 2009, 11, 3902.
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5e
S
N
H
7e
14. Jacquemard, U.; Be´ne´teau, V.; Lefoix, M.; Routier, S.; Me´rour, J.-Y.; Coudert, G.
Tetrahedron 2004, 60, 10039.
Ph
N
15.
A solution of 1-bromo-3-methyl-2-butene (2 mmol, 0.298 g), thiourea
N
(3 mmol, 0.228 g) in ethanol (5 mL) was refluxed for 1 h. After addition of
sodium hydroxide (10 mmol, 0.40 g) in ethanol (5 mL) reflux was continued for
an additional hour and then 1-Boc-2-chloro-3-indolo carbaldehyde was added.
The mixture was refluxed for another half an hour and added 10 mL of water.
The mixture was extracted with dichloromethane (3 Â 20 mL). The combined
extracts were dried over anhydrous sodium sulphate, the solvent was
evaporated and the residue was purified by column chromatography using
petroleum ether/ethylacetate as eluent (7:3). Yield: 0.352 g (72%), mp 114–
N
Ph
N
O
5f
S
N
H
7f
115 °C. 1H NMR (300 MHz,CDCl3):
d 1.35 (s, 3H), 1.70 (s, 3H), 3.45 (d,
J = 8.04 Hz, 2H), 5.30–5.34 (m, 1H), 7.2–7.38 (m, 4H), 8.78 (s, br, 1H), 10.18 (s,
1H).
16. Typical experimental procedure for the synthesis of Knoevenagel condensation
product: Red solid: Yield: 0.057 g (20%), mp 165–166 °C. 1H NMR (300 MHz,
CDCl3):
d 1.32 (s, 3H), 1.71 (s, 3H), 3.32 (s, 3H), 3.46 (s, 3H), 3.57 (d,
J = 7.8 Hz, 2H), 5.26–5.31 (m, 1H), 7.05–7.26 (m, 4H), 8.78 (s, 1H), 9.58 (s, br,
1H).
O
5
O
N
N
17. General procedure for the intramolecular domino Knoevenagel hetero Diels–Alder
reaction: A solution of aldehyde (1 mmol), carbonyl compound (1 mmol) and
ethylene diammonium diacetate in acetonitrile was left for 30 min at room
temperature. The yellow-orange colour revealed the presence of the
knoevenagel condensation product. The mixture was refluxed for 3–5 h. The
solvent was evaporated and the residue was purified by column
chromatography using 3:7 ethyl acetate–petroleum ether as the eluent to get
pure desired compound.
N
N
O
O
O
CHO
N
O
N
N
N
Boc
Compound 7a: White solid. Yield: 0.287 g (75%), mp 205–206 °C. 1H NMR
(300 MHz, CDCl3): d 1.32 (s, 6H), 2.83–3.10 (m, 1H), 3.30 (s, 3H), 3.36 (s, 3H),
3.49–3.55 (m, 2H), 3.70 (d, J = 4.7 Hz, 1H), 7.18–7.99 (m, 4H), 8.53 (s, br, 1H).
13C NMR (75 MHz, CDCl3): d 24.27 (2C), 24.87, 28.54, 29.37, 31.56, 54.61, 85.88,
108.38, 126.55, 127.14, 127.77, 130.91, 138.03, 145.23, 150.14, 153.62, 154.43,
Boc
8
9
Scheme 4.

140
S. Majumder, P. J. Bhuyan / Tetrahedron Letters 53 (2012) 137–140
161.58, 166.50. MS (EI) 384.2 (M+H)+. CHN analyses Calcd: C, 62.66; H, 5.48; N,
13C NMR (75 MHz, CDCl3): d 25.26 (2C), 27.65, 29.24 (2C), 32.56, 39.78, 55.47,
85.59, 102.67, 109.62, 111.65, 118.96, 122.67, 123.24, 125.58, 129.36, 134.57,
139.72, 142.68, 159.60, 174.86. MS (EI) 368.3 (M+H)+. CHN analyses Calcd: C,
71.93; H, 6.81; N, 3.81%, (C22H25NO2S). Found: C, 71.40; H, 6.58; N, 3.74%.
Compound 7e: Pale brown solid: 0.261 g (70%), mp 215–217 °C. 1H NMR
(300 MHz, CDCl3): d 1.36 (s, 6H), 2.84–3.11 (m, 1H), 3.52–3.62 (m, 2H), 3.72 (d,
J = 4.7 Hz, 1H), 7.20–8.26 (m, 8H), 8.53 (s, br, 1H). 13C NMR (75 MHz, CDCl3): d
25.87 (2C), 26.81, 30.12, 57.01, 87.95, 101.82, 108.7, 110.8, 118.97, 121.64,
122.92, 123.07, 126.95, 127.79, 130.31, 130.60, 132.54,135.37, 135.69, 138.86,
155.14, 169.98. MS (EI) 374.5 (M+H)+. CHN analyses Calcd: C, 73.99; H, 5.09; N,
3.75%, (C23H19NO2S). Found: C, 73.39; H, 5.47; N, 3.20%.
10.96%, (C20H21N3O3S). Found: C, 62.45; H, 5.17; N, 10.38%.
Compound 7b: Light brown solid. Yield: 0.256 g (72%), mp 212–215 °C. 1H NMR
(300 MHz, CDCl3): d 1.35 (s, 6H), 2.85–3.09 (m, 1H), 3.52–3.62 (m, 2H), 3.71 (d,
J = 4.6 Hz, 1H), 7.20–8.42 (m, 4H), 8.53 (s, br, 1H). 13C NMR (75 MHz, CDCl3): d
25.58 (2C), 26.37, 32.58, 51.75, 86.61, 104.79, 119.57, 123.60, 124.64, 128.67,
136.53, 143.56, 149.94, 151.02, 155.13, 160.53, 165.78. MS (EI) 356.8 (M+H)+.
CHN analyses Calcd: C, 60.84; H, 4.78; N, 11.83%, (C18H17N3O3S). Found: C,
60.23; H, 4.45; N, 11.65%.
Compound 7c: Crimson solid. Yield: 0.256 g (69%), mp 209–210 °C. 1H NMR
(300 MHz, CDCl3): d 1.34 (s, 6H), 1.58 (s, 6H), 2.86–3.13 (m, 1H), 3.52–3.62 (m,
2H), 3.76 (d, J = 4.7 Hz, 1H), 7.20–7.86 (m, 4H), 8.52 (s, br, 1H). 13C NMR
(75 MHz, CDCl3): d 22.78, 26.60 (2C), 28.78 (2C), 33.56, 53.68, 69.43, 85.86,
108.30, 113.55, 122.14, 125.77, 131.91, 137.73, 142.85, 148.96, 154.14, 163.62,
166.50. MS (EI) 372.7 (M+H)+. CHN analyses Calcd: C, 64.69; H, 5.66; N, 3.77%,
(C20H21NO4S). Found: C, 64.49; H, 5.78; N, 3.84%.
Compound 7f: Yellowish brown solid: 0.248 g (62%), mp 196–197 °C. 1H NMR
(300 MHz, CDCl3): d 1.32 (s, 6H), 2.64 (s, 3H), 2.94–3.08 (m, 1H), 3.59–3.74 (m,
2H), 3.95 (d, J = 4.9 Hz, 1H), 7.13–8.06 (m, 9H). 8.57 (s, br, 1H). 13C NMR
(75 MHz, CDCl3): d 14.51, 25.22 (2C), 33.41, 39.45, 64.65, 86.11, 108.20, 121.31,
125.49, 126.10, 127.48, 127.79, 128.43, 129.53, 130.96, 137.65, 139.81, 140.12,
142.67, 145.67, 148.22, 153.47, 161.40. MS (EI) 402.8 (M+H)+. CHN analyses
Calcd: C, 71.82; H, 5.73; N, 10.47, (C24H23N3OS). Found: C, 71.24; H, 5.97; N,
10.76%.
Compound 7d: Light yellow solid: 0.245 g (67%), mp 221–222 °C. 1H NMR
(300 MHz, CDCl3): d 1.03 (s, 3H), 1.15 (s, 3H), 2.24–2.31 (m, 2H), 2.52 (s, 2H),
2.94–3.09 (m, 1H), 3.82 (d, J = 4.6 Hz, 1H), 7.17–8.22 (m, 4H), 8.56 (s, br, 1H).