Microwave assisted synthesis of indole-annulated dihydropyrano[3,4-c] chromene derivatives via hetero-Diels-Alder reaction

Article abstract of DOI:10.1016/j.tetlet.2011.06.052

An efficient two-step synthesis of indole-annulated dihydropyrano[3,4-c] chromene derivatives is achieved via Knoevenagel condensation of O-propargylated salicylaldehyde derivatives with indolin-2-ones followed by a microwave-assisted intramolecular-heter

Full text of DOI:10.1016/j.tetlet.2011.06.052

Tetrahedron Letters 52 (2011) 4337–4341
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Tetrahedron Letters
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Microwave assisted synthesis of indole-annulated dihydropyrano[3,4-c]
chromene derivatives via hetero-Diels–Alder reaction
⇑
Mukund Jha , Stephanie Guy, Ting-Yi Chou
Department of Biology and Chemistry, Nipissing University, North Bay, ON, Canada P1B 8L7
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient two-step synthesis of indole-annulated dihydropyrano[3,4-c]chromene derivatives is achieved
via Knoevenagel condensation of O-propargylated salicylaldehyde derivatives with indolin-2-ones
followed by a microwave-assisted intramolecular-hetero-Diels–Alder reaction of the resulting (Z)-3-(2-
(prop-2-ynyloxy)benzylidene)indolin-2-ones in the presence of 20 mol % CuI in acetonitrile.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 17 May 2011
Revised 10 June 2011
Accepted 11 June 2011
Available online 4 July 2011
Keywords:
Indole
Indolin-2-one
Dihydropyran
Chromene
Benzopyran
Hetero-Diels–Alder
Knoevenagel reaction
Introduction
acids, especially CuI, has provided the opportunity for an efficient
hetero-Diels–Alder reaction-involving alkynes.7–9
Heterocyclic compounds attract special attention in chemical
literature because of their abundance in natural products and the
diverse biological properties associated with them. There are a
large variety of heterocycles known and among them indole and
pyran ring systems are of particular importance. Numerous inter-
esting arrays of biological activities have been linked to natural
and unnatural compounds possessing a substituted indole nucleus,
making it a suitable building block for many therapeutic agents.1
The pyran ring, on the other hand, is among one of the most widely
investigated heterocycles.2 The benzopyran or chromene core con-
taining chemicals are prevalent in compounds with proven phar-
macological properties.3 Fused chromenes (polycyclic pyrans) are
also of interest because of their well-documented antibacterial
and novobiocin activities.4 Thus, the need for the development of
efficient and practical syntheses of novel heterocycles with these
ring systems is of great significance.
The domino Knoevenagel–hetero-Diels–Alder reaction is a very
efficient process in organic synthesis because it allows multiple
transformations in a single pot. This reaction provides a valuable
method for the construction of polyheterocyclic compounds.5 Over
the past few years, syntheses of several complex annulated dihy-
dropyrans have been achieved using the domino Knoevenagel–
hetero-Diels–Alder reaction.5,6 More recently, the use of Lewis
To combine the interesting and remarkable biological activities
of both indole and polycyclic pyrans we sought a synthesis of in-
dole-annulated dihydropyrano[3,4-c]chromene skeleton 4 (Scheme
1). Literature survey disclosed three recent reports describing the
synthesis of closely related sulfur-containing analogs of 4.10–12
However, to the best of our knowledge the synthesis of chromene
4 has not been reported. Herein, we disclose a Cu-catalyzed micro-
wave-assisted synthesis of indole-annulated dihydropyrano[3,4-
c]chromene derivatives.
A retrosynthetic analysis of 4 is depicted in Scheme 1. The
dihydropyranopyran ring of 4 can be assembled from alkyne 3,
which could be synthetically accessible via a Knoevenagel reaction
of O-propargylated salicylaldehyde derivatives 2 with indolin-2-
ones 1.
Two types of precursors indolin-2-ones, acetyl (1a and b) and
methyl (1c) substituted were chosen to carry out the desired intra-
molecular Knoevenagel–hetero-Diels–Alder reaction. 1-Acetylindo-
lin-2-one (1a) and 1-acetyl-6-chloroindolin-2-one (1b) were
prepared from commercially available indolin-2-one and 6-chloro-
indolin-2-one using a published procedure.13 The methylation of
isatin and its subsequent reduction using hydrazine hydrate
resulted in 1-methylindolin-2-one (1c).14 The O-propargylated sali-
cylaldehyde derivatives 2a–e were synthesized in high yields
(>85%) by reacting substituted salicylaldehydes with propargyl ben-
zenesulfonate analogous as per previously reported procedure using
potassium carbonate in DMF.9
⇑
Corresponding author.
E-mail address: mukundj@nipissingu.ca (M. Jha).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.052

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M. Jha et al. / Tetrahedron Letters 52 (2011) 4337–4341
Scheme 1. Retrosynthetic analysis of indole-annulated dihydropyrano[3,4-c]chromene.
Table 1
step and increase the efficiency we decided to use Et3N in dichloro-
methane and 72 h stirring at room temperature to carry out the
synthesis of 3-(2-(prop-2-ynyloxy)benzylidene)indolin-2-one
derivatives 3a–j.18 The pure products 3a–j were obtained in excel-
lent yields (>85%) upon crystallization using acetonitrile. Synthesis
of methyl substituted 3-(2-(prop-2-ynyloxy)benzylidene)indolin-
2-one analog 3j was achieved under similar conditions starting
with 1-methyl indolin-2-one (1c).
Optimization of intramolecular-hetero-Diels–Alder reaction conditions
Next, the intramolecular Cu-catalyzed hetero-Diels–Alder reac-
tion on 3a was attempted to obtain the desired indole-annulated
dihydropyrano[3,4-c]chromene derivatives under microwave irra-
diation as well as conversational refluxing conditions. A 25 min
microwave irradiation at 200 °C in dry acetonitrile in the presence
of 10 mol % CuI resulted in the formation of desired 4a in low yield
(30%). However, the conventional refluxing condition failed to
yield the desired product even after 72 h of heating. Thus, we set-
tled with the microwave conditions and attempted to further opti-
mize the reaction parameters to maximize the yield of desired
dihydropyrano[3,4-c]chromene derivatives. The reaction was car-
ried out in the presence of four different concentrations of CuI
(10, 20, 30, and 40 mol %). As indicated in Table 1, the best conver-
sion of 3a to the cyclized product 4a was obtained in the presence
of 20 mol % of CuI with 5 min of irradiation at 200 °C.18 Lowering
the reaction temperature resulted in lower yield (Table 1, entry
7). Furthermore, running the reactions in solvents other than ace-
tonitrile led to either lower yields (dioxane, entry 8) or no product
at all (DMF and water, entries 9 and 10).
Subsequently, using the optimized reaction conditions, the in-
dole-annulated dihydropyrano[3,4-c]chromene derivatives 4a–i
were synthesized in 60–71% yields (Table 2). The structures of
the products were confirmed using spectroscopic and HRMS data.
The characteristic IH NMR signals of AB quartet for O–CH2 and sin-
glet for OCH groups for the dihydropyrano[3,4-c]chromene ring
system were observed in between 4.8–5.1 ppm and 6.6–7.0 ppm,
respectively. Interestingly, a mixture of orange-colored non-polar
compounds appeared in all of the hetero-Diels–Alder reactions as
side-products, which could be attributed to the loss in the yields
of the desired compounds. The side-products appeared as a single
spot on TLC, but the NMR data indicated it to be mixture of com-
pounds. Repeated attempts to isolate and characterize these side-
products were unsuccessful in our hands, mainly due to their
non-polar nature. Their separation using silica based column chro-
matography proved to be quite challenging as they were eluting
together even with hexanes. We are currently investigating this
further.
Entry Catalyst
(mol %)
Solvent
Temperature
(°C)
Time
(min)
Yield
(%)
1
2
3
4
5
6
7
8
9
10
10
20
20
10
30
40
20
20
20
20
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
200
200
200
200
200
200
150
25
25
5
5
5
5
5
10
10
10
30
38
65
35
60
55
40
20
0
Dioxane 130a
DMF
Water
200
190a
0
a
Highest temperature achieved in microwave.
Similar to previous reports of hetero-Diels–Alder reactions
involving unreactive terminal alkynes,9 we pursued a one-step syn-
thesis of dihydropyrano[3,4-c]chromene derivatives under domino
Knoevenagel–hetero-Diels–Alder reaction conditions. Using indo-
lin-2-one 1a and salicylaldehyde derivative 2a as model reactants,
the single-pot condensation–cyclization reaction was attempted
in the presence of 20 mol % CuI and (NH4)2HPO4 in refluxing aceto-
nitrile.9 Unfortunately, the desired product 4a was not obtained
even after refluxing for up to 72 h. Instead, the condensation prod-
uct 3a was isolated in low yield (<20%) along with the recovery of
unreacted starting materials. Subsequently, the same reaction
was carried out under microwave irradiation (200 °C), and a similar
observation was recorded. Efforts to synthesize 4a analogous to
other known domino Knoevenagel–hetero-Diels–Alder reaction
conditions of substituted alkynes8,15 were also unsuccessful. These
repeated failures prompted us to first synthesize and isolate the
Knoevenagel condensation intermediates 3a–i and subsequently
try the intermolecular hetero-Diels–Alder cyclization on them to
obtain the desired indole-annulated dihydropyranopyrans. The
Knoevenagel condensation to synthesize compounds 3a–i was tried
in dichloromethane analogous to previously reported similar con-
densations using two different bases, Et3N16 and ethylenedia-
mine-N,N0-diacetic acid (EDDA).17 Although the time required for
the reaction to undergo completion was longer in the case of Et3N
(72 h) compared to EDDA (8 h), the product yields were signifi-
cantly higher with Et3N. In contrast, the condensation catalyzed
with EDDA, despite being rapid, resulted in the hydrolysis of the
N-acetyl group giving a mixture of 3a and its deacetylated analog
in almost 1:1 ratio. To eliminate the chromatographic purification
As shown in Table 2, no significant aromatic substitution effect
on the intramolecular-hetero-Diels–Alder reaction was observed in
the formation of the cyclized products 4a–i. It was interesting to
note that relatively bulky naphthalene based indole-annulated
dihydropyrano[3,4-c]chromene 4i was successfully obtained using
this methodology. In contrast to acetyl-substituted compounds
3a–i, the intramolecular-hetero-Diels–Alder cyclization of 1-
methyl substituted 3j under the optimized reaction condition
was unsuccessful (Table 2).

M. Jha et al. / Tetrahedron Letters 52 (2011) 4337–4341
4339
Table 2
Synthesis of indole-annulated dihydropyrano[3,4-c]chromene derivatives 4a–i
Indolin-2-one 1a–c
Aldehyde 2a–e
Product 3a–j
Product 4a–i
Isolated yield (%) 4a–i
1a
65
66
71
2a
3a
3b
3c
4a
4b
4c
1a
2b
2c
1a
1a
63
2d
3d
4d
1b
64
2a
4e
3e
1b
64
2b
4f
3f
(continued on next page)

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M. Jha et al. / Tetrahedron Letters 52 (2011) 4337–4341
Table 2 (continued)
Indolin-2-one 1a–c
Aldehyde 2a–e
Product 3a–j
Product 4a–i
Isolated yield (%) 4a–i
1b
67
2c
4g
3g
1b
61
2d
4h
3h
1b
60
2e
4i
3i
1c
—
0
2a
3j
Scheme 2. A plausible mechanism for the formation of indole-annulated dihydropyrano[3,4-c]chromenes.
The mechanism of the cyclization appears to be in agreement
with the previously proposed mechanism of similar hetero-Diels–
Alder reactions on compounds possessing unreactive terminal
alkynes.8,9 The alkyne functionality is activated with CuI upon for-
but also added additional beneficial features to the reaction such
as shortened reaction time and low catalyst loading.
Acknowledgments
mation of a p-complex, which may be assisting in the subsequent
intramolecular-hetero-Diels–Alder reaction as depicted in Scheme
2. It has been recently reported in the synthesis of analogous in-
dole-annulated thiopyranobenaopyrans that the double bond of
fused thiopyran ring underwent migration when p-substituted
aldehydes were reacted with indoline-2-thione to afford products
with extended conjugation.11 However, we did not observe such
migration in our reactions.
Financial support from National Sciences and Engineering Re-
search Council of Canada (NSERC) and Nipissing University is
gratefully acknowledged. We would also like to thank Acadia Uni-
versity for granting access to its analytical facility.
References and notes
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Diels–Alder reaction for the synthesis of indole-annulated dihydro-
pyrano[3,4-c]chromene derivatives using CuI as the catalyst. The
use of microwave conditions not only made the reaction feasible

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4341
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18. Procedure for the synthesis of (E)-1-acetyl-3-(2-(prop-2-ynyloxy)benzylidene)
indolin-2-one (3a): a mixture of 1-acetyl indolin-2-one (1a, 5.71 mmol, 1 g),
propagylated salicylaldehyde (2a, 5.71 mmol, 0.92 g) and triethylamine
(3.4 mmol, 0.35 g) was stirred in dichloromethane for 72 h. The excess of
dichloromethane was evaporated and solid residue was crystallized using
acetonitrile to give 3a in 92% yield. Melting point: 103–106 °C.1HNMR
(300 MHz, CDCl3): d 8.33 (d, J = 8 Hz, 1H), 8.03, (s, 1H), 7.72 (d, J = 8 Hz, 1H),
7.64 (d, J = 8 Hz, 1H), 7.46 (dd, J = 7.5, 7 Hz, 1H), 7.33 (t, J = 8 Hz, 1H), 7.18–7.02
(m, 3H), 6.09–6.82 (m, 2H), 4.79 (s, 2H), 2.79 (s, 3H), 2.55 (s, 1H).13CNMR
(75 MHz, CDCl3): d 170.9, 168.5, 156.1, 140.1, 134.9, 131.7, 130.0, 129.9, 126.0,
124.4, 124.0, 122.3, 122.1, 121.2, 116.6, 112.7, 78.0, 76.1, 56.2, 26.9.ESI-HRMS
(amu): calcd
Procedure for the synthesis of indole-annulated dihydropyrano[3,4-
c]chromene 4a: microwave glass vial with magnetic stirrer bar was
C
20H15NNaO3 [M+Na]+: 340.0944; found [M+Na]+: 340.0947.
A
a
charged with 3a (0.16 mmol, 50 mg) and CuI (20 mol %, 6 mg) in dry
acetonitrile. The vial was sealed and subjected to microwave irradiation for
5 min at 200 °C (Discover™ single mode cavity microwave synthesizer (CEM
Corp.). The reaction mixture was cooled and subjected to flash column
chromatography (ethylacetate/hexanes, 10:80) to give 4a in 65% yield. Melting
point: 167–169 °C. 1H NMR (300 MHz, CDCl3): d 8.49 (d, J = 8 Hz, 1H), 7.63 (d,
J = 7.5 Hz, 1H), 7.38–7.36 (m, 2H), 7.30 (s, 1H), 7.17 (dd, J = 8, 7.5 Hz, 1H), 6.89–
6.80 (m, 3H), 5.01 (s, 1H), 4.91 (d, J = 12 Hz, 1H), 4.76 (d, 1H), 2.67 (s,
3H).13CNMR (75 MHz, CDCl3): d 168.8, 153.4, 143.2, 135.3, 132.0, 128.3, 127.9,
126.5, 124.2, 124.1, 120.8, 118.2, 117.2, 116.5, 111.1, 93.0, 67.4, 31.6, 29.7,
10. Majumdar, K. C.; Taher, A.; Ponra, S. Tetrahedron Lett. 2009, 51, 147–150.
11. Majumdar, K. C.; Taher, A.; Ponra, S. Tetrahedron Lett. 2010, 51, 2297–
2300.
26.5. ESI-HRMS (amu): calcd
C
20H15NNaO3 [M+Na]+: 340.0944; found
[M+Na]+: 340.0933.
12. Kiamehr, M.; Moghaddam, F. M. Tetrahedron Lett. 2009, 50, 6723–6737.