Domino-Knoevenagel-hetero-Diels-Alder reactions: an efficient one-step synthesis of indole-annulated thiopyranobenzopyran derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.04.054

Rapid one-step synthesis of hitherto unreported indole-annulated pentacyclic heterocycles containing oxygen, nitrogen, and sulfur has been described by domino-Knoevenagel-hetero-Diels-Alder reaction. The reaction sequence provides a route to the synthesis of a novel type of polyheterocycles in excellent yields with high stereoselectivity.

Full text of DOI:10.1016/j.tetlet.2009.04.054

Tetrahedron Letters 50 (2009) 3889–3891
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Tetrahedron Letters
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Domino-Knoevenagel-hetero-Diels–Alder reactions: an efficient one-step
synthesis of indole-annulated thiopyranobenzopyran derivatives
*
K. C. Majumdar , Abu Taher, Krishanu Ray
Department of Chemistry, University of Kalyani, Kalyani 741 235, WB, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Rapid one-step synthesis of hitherto unreported indole-annulated pentacyclic heterocycles containing
oxygen, nitrogen, and sulfur has been described by domino-Knoevenagel-hetero-Diels–Alder reaction.
The reaction sequence provides a route to the synthesis of a novel type of polyheterocycles in excellent
yields with high stereoselectivity.
Received 3 March 2009
Revised 11 April 2009
Accepted 15 April 2009
Available online 18 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Domino-intramolecular
Knoevenagel-hetero-Diels–Alder reactions
O-Allylated salicylaldehydes
1-Methylindoline-2-thione
One-step synthesis
Indole nucleus is an important subunit present in many biolog-
ically active natural products.1 Compounds possessing indole moi-
ety show antitumor activity,2 cause inflammation, and vessication
to human skin.3 Compounds containing thiopyranoindole moiety
are important because of their biological activity.4 Some [6,6]-
fused pentacyclic indole alkaloids such as reserpine, rauniticine,
yohimbine, and aspidospermine show extensive bioactivity.1b,f
These extensive bioactivities of various indole derivatives
prompted us to undertake a study on the synthesis of [6,6]-fused
pentacyclic indole derivatives in which bioactive thiopyrano indole
moiety is fused with a benzopyran moiety.
There are several examples for the synthesis of benzopyrans
and pyranobenzopyrans moieties while those of their sulfur con-
taining analogs are rare.5 Literature survey reveals that there are
few reports for the synthesis of polycyclic pyranothiopyrans.6 We
have reported coumarin- and pyrone-annulated [6,6]-fused pyra-
nothiopyran ring systems using sequential Claisen rearrange-
ment6d and tributyltinhydride-mediated radical cyclization,6c
respectively. However, applying the same methodology upon ind-
oline-2-thione derivatives we could not obtain the expected [6,6]-
fused pyranothiopyran ring rather, [6,5]-fused pyranothiofurans7
and a spiro compound8 were obtained. More reports on the syn-
thesis of furanothiopyran moieties are available.9 However, the
scope of these protocols is limited by number of steps, by harsh
reaction conditions, and by stoichiometric amounts of reagents.10
Till now there are no reports for the synthesis of indole-annulated
[6,6]-fused pentacyclic pyranothiopyran system. We, therefore,
attempted to find an efficient and convenient synthetic methodol-
ogy for the synthesis of such sulfur containing polycyclic
compounds.
The hetero Diels–Alder reaction is one of the most efficient and
powerful synthetic tool for the synthesis of heterocycles, including
natural products.11 Tietze et al. extensively described the domino-
Knoevenagel-hetero-Diels–Alder reaction (DKHDA) of unsaturated
aromatic and aliphatic aldehydes with several 1,3-dicarbonyl
compounds for the synthesis of tetracycles with a pyran ring.12
Desimoni et al. have reported a comparative study between het-
ero-Diels–Alder and intramolecular ene reaction upon (E)-1-acet-
yl-3-arylideneindolin-2-one.13 During the last few years there are
several reports by the application of this methodology.6a,b,14 Here-
in, we report the results of our present investigation applying
DKHDA strategy.
The required precursors 2a–g were prepared in very good yields
by refluxing aromatic hydroxyl-aldehydes 1a–g with allyl or crotyl
bromide in dry acetone in the presence of anhydrous K2CO3 and a
catalytic amount of NaI15 (Scheme 1).
To examine the Knoevenagel-hetero-Diels–Alder reaction of 1-
methylindoline-2-thione (3) with O-allyl aromatic aldehydes (2)
we first used O-allyl salicylaldehyde as a precursor of the hetero-
diene. When the reaction was carried out at room temperature
using 3 (0.613 mmol, 1 equiv), 2a (0.613 mmol, 1 equiv), and
NEt3 (1 equiv) in acetic acid, the reaction rate was slow and the
product was obtained in only 15% yield after 24 h. But when the
reaction was carried out at refluxing condition using
(0.613 mmol, 1 equiv), 2a (0.613 mmol, 1 equiv), and NEt3
3
* Corresponding author. Tel.: +91 033 25827521; fax: +91 033 2582 8282.
E-mail address: kcm_ku@yahoo.co.in (K.C. Majumdar).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.054

3890
K. C. Majumdar et al. / Tetrahedron Letters 50 (2009) 3889–3891
Figure 1. Single-crystal X-ray structure of compound 4a.
a. R1 = R2 = R3 = H
b. R1 = OMe, R2 = R3 = H
c. R1 = Br, R2 = R3 = H
Table 1
OH
Results of domino-Knoevenagel-hetero-Diels–Alder reactions of substrate 3a
R3
O
CHO
R2
(i)
CHO
R2
Entry
Aromatic aldehyde (2)
Product (4)
Yieldb (%)
d. R1 = Me, R2 = R3 = H
e. R1 = Cl, R2 = Me, R3 = H
f. R1 = R2 = H, R3 = Me
O
R1
R1
O
H
g. R1, R2 = 5,6-C4H4 (phenylene), R3 = H
1a-g
2a-g
H
1
96
CHO
S
Scheme 1. Reagents and conditions: (i) allyl bromide, anhydrous K2CO3, acetone,
2a
N
4a
NaI, reflux.
O
O
MeO
(1 equiv) in acetic acid the reaction time was drastically reduced to
2 h affording 4a in 96% yield (Scheme 2).
The reaction is highly stereoselective affording exclusively the
cis-[6,6]-fused thiopyranobenzopyran derivatives. The structure
and stereochemistry of the product 4a have been determined by
spectral analysis16 and single-crystal XRD data17 (Fig. 1).
H
H
2
3
4
5
6
92
89
86
85
90
92
MeO
CHO
2b
S
N
O
4b
O
H
Br
In order to extend the utility of this methodology, we have fur-
ther carried out the reaction by using several different O-allylated
aromatic aldehydes (2b–g). The results are listed in Table 1. Reac-
tion of 3 with 1 equiv of 2b and 1 equiv of NEt3 in refluxing acetic
acid gave product 4b in 92% yield (entry 2). When the same reac-
tion was carried out with 2c and 2d, the desired products 4c and 4d
were obtained in 89 and 86% yields, respectively (entries 3 and 4),
85% yield of the product was obtained when the reaction was car-
ried out with 2e (entry 5). Similarly treatment of 2f with 3 under
the same reaction condition afforded product 4f in 90% yield (entry
6), whereas that of 2g gave product 4g in 92% yield (entry 7). In all
the cases the reactions were carried out for 2 h and the structures
of the products were determined by comparison of their spectral
data with those of the product 4a. In all the cases the stereochem-
istry of the ring juncture protons was found to be cis.
H
Br
CHO
S
2c
N
O
4c
O
H
Me
H
Me
CHO
S
2d
N
O
4d
O
H
Cl
H
Cl
CHO
2e
Me
S
Me
O
N
H
4e
The stereochemistry of the final product of Diels–Alder reaction
depends on the endo- and exo-orientation of the dienophile in the
transition state. We were unable to isolate the intermediate hete-
rodiene 5. However, a probable explanation for the cis-stereo-
O
H
CHO
2f
S
4f
N
O
O
O
H
O
CHO
(i)
H
S
H
+
H
7
CHO
N
S
S
2g
N
4g
N
3
2a
4a
a
All reactions are carried out in refluxing AcOH for 2 h.
Isolated yields.
Scheme 2. Reagents and conditions: (i) 1 equiv 3, 1 equiv 2a, 1 equiv NEt3, AcOH,
reflux.
b

K. C. Majumdar et al. / Tetrahedron Letters 50 (2009) 3889–3891
3891
O
O
O
NEt3
S
+
S
S
N
AcOH,
CHO
N
N
3
2
5
exo
5a
endo
path b
path a
O
O
H
H
H
H
S
S
N
N
6
4
Scheme 3. Probable explanation for the stereochemistry of the compounds 4.
Ghosh, S. K.; Biswas, P. Tetrahedron 2003, 59, 2151; (g) Majumdar, K. C.;
Mukhopadhyay, P. P. Synthesis 2003, 97.
chemistry of the product (4) is given in Scheme 3. The intermediate
5 may undergo rotation around single bond to assume the struc-
ture 5a which may then undergo cyclization via endo selectivity
of the hetero-Diels–Alder reaction (path b). The reaction does not
occur via exo selectivity to afford the product 6 perhaps due to
the sp2- geminal effect of 1,3-allylic strain.18
6. (a) Jayashankaran, J.; Manian, R. D. R. S.; Raghunathan, R. Tetrahedron Lett.
2006, 47, 2265; (b) Matiychuk, V. S.; Lesyk, R. B.; Obushak, M. D.; Gzella, A.;
Atamanyuk, D. V.; Ostapiuk, Y. V.; Kryshchyshyn, A. P. Tetrahedron Lett. 2008,
49, 4648; (c) Majumdar, K. C.; Muhuri, S. Synthesis 2006, 2725; (d) Majumdar,
K. C.; Kundu, U. K.; Ghosh, S. K. Org. Lett. 2002, 4, 2629.
7. Majumdar, K. C.; Alam, S. J. Chem. Res. 2006, 281.
8. Majumdar, K. C.; Alam, S. Org. Lett. 2006, 8, 4059.
Inconclusion, wehavedemonstratedanefficientandsimplestrat-
egy for the synthesis of indole annulated-[6,6]-thiopyranobenzopy-
rans in excellent yields by domino-Knoevanagal-hetero-Diels–
Alder reactions. The reaction is a general one and highly stereoselec-
tive leading to cis-annulated polyheterocycles in a single step.
9. (a) Majumdar, K. C.; Islam, R.; Alam, S. Synth. Commun. 2008, 38, 754; (b)
Majumdar, K. C.; Chattopadhyay, S. K. Can. J. Chem. 2006, 84, 469; (c)
Majumdar, K. C.; Samanta, S. K. Synth. Commun. 2006, 36, 1299; (d)
Majumdar, K. C.; Kundu, U. K.; Mukhopadhyay, P. P.; Ghosh, S. Arkivoc 2003,
47; (e) Majumdar, K. C.; Bandopadhyay, A.; Biswas, A. Tetrahedron 2003, 59,
5289; (f) Majumdar, K. C.; Kundu, U. K.; Ghosh, S. Perkin Trans. 1 2002, 2139.
10. (a) For a detailed report on the toxicity of tin reagents, see Occupational
Exposure to Organotin Compounds, US Department of Health, Education and
Welfare, Washington, Nov. 1976.; (b) Boyer, I. J. Toxicology 1989, 55, 253.
11. (a) Yadav, J. S.; Reddy, B. V. S.; Sadashiv, K.; Padmavani, B. Adv. Synth. Catal.
2004, 346, 607; (b) Yamanaka, M.; Nishida, A.; Nakagana, M. Org. Lett. 2000, 2,
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Acknowledgments
We thank the CSIR (New Delhi) and the DST (New Delhi) for
financial assistance. We thank Professor A. T. Khan, Indian Institute
of Technology, Guwahati, for the XRD data of compound 4a. Two of
us (A.T. and K.R.) are grateful to the CSIR (New Delhi) for their
fellowships.
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16.
A
mixture of 1-methylindoline-2-thione (3)(1 equiv) and O-allyl
salicylaldehyde (2a)(1 equiv) was refluxed in acetic acid in the presence of
triethylamine (1 equiv) for 2 h. After completion of the reaction as monitored
by TLC the reaction mixture was cooled and diluted with water (50 mL). This
was extracted with ethylacetate (3 Â 25 mL). The combined organic extract
was washed with saturated solution of sodium bicarbonate followed by brine
solution and dried over anhydrous Na2SO4. The solvent was distilled off. The
resulting product was purified by column chromatography over silica gel (60–
120 mesh) using petroleum ether–ethyl acetate (97:3) mixture as eluent to
give compounds (4a). Yield: 96%, colorless solid; mp 162–164 °C; IR (neat):
m
max = 1274, 1466, 1485, 2876 cmÀ1 1H NMR (CDCl3, 300 MHz): dH = 2.45 (dq,
;
J = 2.1, 9.3 Hz, 1H), 2.97 (d, J = 12.9 Hz, 1H), 3.35 (t, J = 12.3 Hz, 1H), 3.62 (s, 3H),
4.41 (dd, J = 2.1, 11.1 Hz, 1H), 4.52 (dd, J = 2.1, 11.4 Hz, 2H), 6.72–6.80 (m, 2H),
7.06 (t, J = 7.2 Hz, 1H), 7.16–7.20 (m, 1H), 7.28–7.32 (m, 3H), 7.60–7.63 (m, 1H)
ppm. 13C NMR (100 MHz): 26.1, 30.1, 32.1, 32.7, 70.3, 108.0, 108.4, 116.5,
117.0, 119.8, 120.5, 121.1, 125.1, 127.9, 129.2, 129.5, 130.2, 137.3, 151.9 ppm.
HRMS: m/z calcd for C19H17NOS [M+H]+: 308.1104; found; 308.1094.
17. CCDC reference no. for the CIF file of compound 4a: CCDC 719681.
18. Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.