Microwave assisted InCl3 mediated regioselective synthesis of highly functionalized indolylpyran under solvent-free condition and its chemical transformation to indolyltriazolylpyran hybrids

Article abstract of DOI:10.1016/j.tetlet.2014.04.104

A series of novel, highly functionalized indolylpyrans has been synthesized via InCl₃ catalyzed microwave irradiation of 3-cyanoacetylindoles, aromatic aldehydes with NMSM under solvent- free condition. Further, the synthesized azidoindolylpyrans undergo [3+2] cycloaddition reaction with different phenyl acetylenes to give indolyltriazolylpyran hybrids in excellent yields. This domino transformation, generating CC, CC, CO, CN, and NN bonds with a stereo center in minimum reaction steps. In particular the attractive feature of this approach is the synthesis of three important bioactive heterocyclic frameworks, indole-pyran-triazole hybrids, under mild reaction conditions, making this novel strategy highly useful in our diversity oriented synthesis (DOS).

Full text of DOI:10.1016/j.tetlet.2014.04.104

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave assisted InCl3 mediated regioselective synthesis of highly
functionalized indolylpyran under solvent-free condition and its
chemical transformation to indolyltriazolylpyran hybrids
⇑
Jayabal Kamalraja, Paramasivan Thirumalai Perumal
Organic Chemistry Division, CSIR-Central Leather Research Institute, Adyar, Chennai 600020, Tamilnadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel, highly functionalized indolylpyrans has been synthesized via InCl3 catalyzed microwave
irradiation of 3-cyanoacetylindoles, aromatic aldehydes with NMSM under solvent- free condition. Fur-
ther, the synthesized azidoindolylpyrans undergo [3+2] cycloaddition reaction with different phenyl
acetylenes to give indolyltriazolylpyran hybrids in excellent yields. This domino transformation, generat-
ing CAC, C@C, CAO, CAN, and N@N bonds with a stereo center in minimum reaction steps. In particular
the attractive feature of this approach is the synthesis of three important bioactive heterocyclic frame-
works, indole–pyran–triazole hybrids, under mild reaction conditions, making this novel strategy highly
useful in our diversity oriented synthesis (DOS).
Received 3 March 2014
Revised 28 April 2014
Accepted 29 April 2014
Available online xxxx
Keywords:
InCl3
NMSM
Michael addition
Ó 2014 Elsevier Ltd. All rights reserved.
Regioselective
Indolylpyran and indolyltriazolylpyran
hybrids
Multi-component reactions (MCR) have emerged as a powerful
tool for delivering the highly functionalized small organic mole-
cules1 mimicking privileged natural products that are promising
candidates in chemical and drug development. MCRs provide a
huge number of small molecules by generating multiple bonds
and stereocentres by the single operation under mild reaction con-
ditions, lesser reaction times, and minimal waste.
Indole ring system is probably the most pervasive heterocycle
in nature and an important structural component in many pharma-
ceutical agents.2 Furthermore, indoles substituted with heterocy-
clic rings at the 3-position have been found in a fascinating array
of bioactive natural products and pharmaceutical compounds
(Fig. 1). For example, nortopsentins A–C exhibit in vitro cytotoxic-
ity against P388 cells;3 hamacanthin B reveals cytotoxic activities
against a wide range of human tumor cell lines with GI50 values
at micromolar concentration;4 meridianins A–E show cytotoxicity
toward murine tumor cell lines and have potent inhibition against
several protein kinases.5 So exploration of more general methods
for the synthesis of indole motif is highly desirable.
H
N
O
Br
Br
N
HN
NH
Heterocyclic motify
Hamacanthin B
X
H2N
N
N
R
N
H
R1
R
N
N
R2
R3
HN
H
N
H
NH
3-substituted indole
Nortopsentins A-C
R4
Meridianins A-E
Figure 1. Representatives of important indol-3-yl substituted heterocycles.
moieties in a single molecule often enhances the biocidal profile
remarkably. This encouraged us to focus on Target Oriented Syn-
thesis (TOS) in this area to design new heterocyclic systems con-
taining both indole and pyran moieties. The wide application of
these heteroaromatic compounds has made them popular syn-
thetic targets.
In addition, multi-functionalized 4H-pyrans are an important
class of compounds present in several natural or synthetic com-
pounds with important biological and pharmacological activities.6
Usually, the manifestation of two or more different heterocyclic
Ambiphilic synthons which hold both nucleophilic and
electrophilic sites have great potential in developing a novel syn-
thetic strategy. (E)-N-Methyl-1-(methylthio)-2-nitroethenamine
⇑
Corresponding author. Tel.: +91 44 24437130; fax: +91 44 24911589.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
http://dx.doi.org/10.1016/j.tetlet.2014.04.104
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kamalraja, J.; Perumal, P. T. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.104

2
J. Kamalraja, P. T. Perumal / Tetrahedron Letters xxx (2014) xxx–xxx
R2
Table 1
R2
Optimization of reaction conditions for the synthesis of 4a
Entry
Solvent
Condition
Yieldd (%)
InCl3 (20 mol%)
2
e
EtOHa
rt, 24 h
—
R1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
O
EtOHb
Reflux, 10 h
Reflux, 8 h
Reflux, 8 h
100 °C, 10 h
100 °C, 10 h
Reflux, 10 h
100 °C, 6 h
MW, 5 min
MW, 7 min
MW, 7 min
MW, 7 min
MW, 10 min
MW, 8 min
65
56
50
30
O
NC
NO2
NH
MW, 3 - 7 min, SFC
MeOHb
CH3CNb
DMFb
R1
CN
NO2
NH
O
N
Tolueneb
Waterb
—
e
4
HN
S
H
1
58
45
70
55
61
45
3
c
—
EtOHf
Scheme 1. Synthesis of highly functionalized indolylpyrans 4.
MeOHf
CH3CNf
DMFf
(NMSM) is one such versatile intermediate,7 which contains four
active sites with three functional groups on an ethene motif and
it is used in the synthesis of antiulcer drugs such as ranitidine8
and nizatidine.9 Based on these key features herein, we demon-
strate the use of the special reactivity of NMSM, for convenient
combinatorial synthesis of alkylamino-3-nitro-4H-pyranylindoles.
Recently, the utility of indium(III) Lewis acids10 in organic syn-
thesis has received much attention due to eco-compatible princi-
ple, such as relatively low toxicity, stability in air and water, and
recyclability. Very few methods for the preparation of indole
substituted heterocyclic compounds have been reported. However,
these methods suffer from tedious synthetic routes; longer reac-
tion time, drastic reaction conditions, as well as narrow substrate
scope.11–13 In continuation of our research on the development of
new synthetic methods for 3-substituted indoles and use of green
chemical techniques,14 application of InCl3 in organic synthesis15
and utilizing of NMSM,16 herein, we disclose microwave assisted
chemo and regioselective synthesis of 3-pyranyl indole derivatives
by one-pot three-component coupling of NMSM, aromatic alde-
hydes, and 3-cyanoacetyl indole with InCl3 as a catalyst (Scheme 1).
The reactions were completed within 3–7 min and the pure prod-
ucts could be isolated in high yields simply by the addition of eth-
anol to the reaction mixture and filtration. The synthetic route is
convergent, and allows easy placement of a variety of substituents
around the periphery of the heterocyclic ring system.
Toluenef
Waterf
—
e
65
a
b
c
d
e
f
Reaction performed at room temperature.
Reaction performed at thermal condition.
Reaction performed at solvent free condition.
Isolated yield.
No reaction.
Reaction performed at MW condition.
Table 2
Catalyst screening for the synthesis of 4a under solvent free condition in MW
irradiationa
Entry
Catalystb
Time (min)
Yieldc (%)
1
2
3
Piperidine
Et3N
8
6
10
63
75
55
L
-Proline
4
5
6
7
8
9
DBU
4
3
5
8
10
6
65
93
40
65
25
30
InCl3
p-TSA
Cu(TfO)3
FeCl3
I2
a
b
c
All microwave reactions performed at 450 W.
Catalyst used 20 mol (%).
Isolated yield.
In our initial endeavor to optimize the reaction conditions, 3-
cyanoacetyl indole (1.0 mmol), 4-bromobenzaldehyde (1.0 mmol),
and NMSM (1.0 mmol) were selected as test substrates. Initially,
the above three-component coupling was carried out in EtOH at
room temperature in the absence and presence of catalytic amount
of piperidine and there was no formation of the product even after
24 h of stirring. Next, the test reaction was investigated in the pres-
ence of various solvents such as EtOH, MeOH, CH3CN, DMF, tolu-
to 93%. With this optimized reaction condition in our hand, the
scope and generality of this protocol were next examined by
employing various aromatic aldehydes and substituted 3-cyano-
acetyl indoles. No obvious electronic effects due to the substituent
groups on the aldehyde were observed, and the products were
obtained in high yields (Scheme 1, Table 3).
ene, water and various catalysts such as piperidine, Et3N, DBU, L-
proline and Lewis acid such as p-TSA, InCl3, Cu(TfO)3, FeCl3, and
I2 under reflux condition, but we did not obtain the appreciable
yield.
Taking into consideration the entire outcome, a plausible mech-
anistic pathway for the domino coupling is depicted in Scheme 2.
Initially 3-cyanoacetylindole 1 undergoes keto-enol tautomeriza-
tion to give 10. This 10 undergoes Knoevenagel condensation with
aromatic aldehyde 2 to give adduct 6 in presence of InCl3, which
acts as a Michael acceptor. The adduct 6 immediately undergoes
Michael-type addition with NMSM 3 to generate the open-chain
intermediate 7. Intermediate 7 undergoes intramolecular O-cycli-
zation via path I to give compound 4 with the elimination of MeSH.
Intermediate 7 may exist in another rotameric form 70, which could
undergo N-cyclization via path II to give compound 40. During our
investigations, we did not observe even traces of 40 and only 4 was
obtained exclusively, suggesting O-cyclization through the route I,
making the protocol highly chemo and regioselective.
Microwave assisted organic synthesis has revolutionized new
synthetic path of modern organic chemistry due to the energy
saving, shortened reaction time, and less side products.17 In view
of these advantages on the use of microwave irradiation, initially,
the above cited one pot reaction was investigated using domestic
microwave oven at 300 W in a sealed tube by using InCl3 in cata-
lytic amount which led to formation of Knoevenagel product. Next
we tried 450 W and the product 4a, was obtained in 70% yield
under ethanol as solvent. Further increment of radiation power
to 600 W led to a decrease in yield. Hence, we selected 450 W for
all subsequent reactions.
Next we optimized the reaction conditions for obtaining the
good yield by using catalyst and solvents mentioned above and sol-
vent-free conditions (Tables 1 and 2). To our delight, the product
was obtained in 82% yield with InCl3 in catalytic amount under
SFC. Further increment of catalyst to 20 mol % enhanced the yield
One interesting application of this methodology is the ready
access to hitherto unreported, new hybrids of indolyltriazolylpyran
derivatives with the ‘click reaction’.18 We focused our attention on
the copper promoted CAN bond formation based protocols.19
Huisgen [3+2] cycloaddition20 has several advantages like rapid,
Please cite this article in press as: Kamalraja, J.; Perumal, P. T. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.104

J. Kamalraja, P. T. Perumal / Tetrahedron Letters xxx (2014) xxx–xxx
3
Table 3
The copper(I) catalyzed 1,2,3-triazole formation from azides
and terminal acetylenes is a particularly powerful linking reaction,
due to its high degree of dependability, complete specificity, and
the bio-compatibility of the reactants.21 The triazole products are
more than just passive linkers; they readily associate with biolog-
ical targets, through hydrogen bonding and dipole interactions. A
demonstration of the synthetic utility of this method is shown in
Scheme 3.
Three-component reaction of highly functionalized indolylpyrans hybridsa
Entry
Product
R1
R2
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
H
H
Br
H
H
Br
H
Br
H
H
H
4-Br
3
5
4
3
5
3
7
4
5
6
4
5
3
3
5
6
93
90
88
91
86
93
85
84
89
90
92
87
90
88
87
86
4-Me
4-Me
4-NO2
4-Cl
4-NO2
4-OMe
4-F
2,4-Cl
3-NO2
2-F
2-N3
4-Br
In this regard we have attempted the [3+2] cycloaddition
reaction between phenyl acetylene and the synthesized poly
substituted indolylpyran with 20 mol % of Cu(I) catalyst. Further,
H
Br
Br
OMe
OMe
Table 4
Synthesis of highly functionalized indolyltriazolylpyran hybridsa 5a–d
4-Me
4-Br
4-Me
Entry
Product
R1
Time (h)
Yieldb (%)
1
2
3
4
5a
5b
5c
5d
H
1.5
78
80
81
83
a
All the reaction were carry out in 1 mmol scale.
Isolated yield.
Br
Me
F
1.75
1.25
1.0
b
a
Reaction performed room temperature.
Isolated yield.
selective, high-yield, and broad scope for carbon–nitrogen bond
forming reactions in the synthesis of N-substituted 1,2,3-triazoles.
b
2
R
1
Michael
R
NO
NH
NC
2
addition
2
R
H
Knoevenagel
condensation
S
O
6
3
1
R
H
HN
NC
NO
N
2
InCl
3
O
InCl
InCl
3
3
S
H
O
O
Concerted
path
HN
7
O-attack
path I
1
CN
R
2
R
2
R
-MeSH
2
2
N
R
H
1'
1
R
H
H
NC
7'
NO
S
2
keto-enol
R
InCl
1
3
tautomerisation
NC
NO
2
O
H
N
O
HN
O
4
N
H
In Cl
3
1
CN
R
HN
2
N-attack
R
path II
N
H
1
1
R
-H O
2
NC
NO
S
2
N
4'
HN
Scheme 2. Plausible reaction scenario for the formation of 4.
N
R1
N
N3
N
NC
NO2
NC
NO2
(20 mol %) CuI
ACN:H2O (1:1)
R1
O
4
NH
O
NH
HN
HN
5
Scheme 3. Synthesis of indolyltriazolylpyrans 5.
Please cite this article in press as: Kamalraja, J.; Perumal, P. T. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.104

4
J. Kamalraja, P. T. Perumal / Tetrahedron Letters xxx (2014) xxx–xxx
(3.75, s, 55.5)
(8.86, s, 128.5)
H3C
O
H
(6.93, d, = 8.4 Hz, 114.4)
J
H
H
(7.81, d, J = 7.6 Hz)
(5.20, s, 29.5
(7.30, d, J = 8.4 Hz, 129.3)
(4.85, s, 40.4, Stereocentre)
NO2
N
Stereocentre)
N
N
118.4
NC
H
(7.25, d, = 6.8 Hz)
J
H
H
H
NC
NO2
H
(10.28, d, J = 3.2 Hz)
O
N H
CH3
(7.19, t, J = 6.8 Hz)
O
N H
CH3
(10.39, q, J = 5.2 Hz)
H
HN
(2.93, s, 27.2)
HN
(12.06, d,
J = 2 Hz)
H
(12.04, s)
(3.18, d, J = 5.2 Hz, 29.1)
(7.54, d, J = 8 Hz)
H
(8.13, s, 128.7)
(8.08, d, J = 2.8 Hz, 130.2)
Compound 5a
Compound 4g
Figure 2. 1H and 13C NMR assignment of compounds 4g and 5a as representative examples.
5. (a) Jiang, B.; Yang, C. G.; Xiong, W. N.; Wang, J. Bioorg. Med. Chem. 2001, 9, 1149;
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the ortho-substituted azido-pyrans is treated with various para-
substituted phenyl acetylenes in 1:1 mixture of acetonitrile
and water with CuI as catalyst to afford the expected 1,4-disub-
stituted 1,2,3-triazole derivative 5a–d in good yield by simple
work-up (Scheme 3 and Table 4). For all these reactions, the con-
ventional chromatographic purification or recrystallization was
not required.
The main advantage of this procedure is simple work-up. Iso-
lation of the product was achieved in high purity simply by fil-
tration. The structures of 4 and 5 were easily deduced using IR,
Mass, elemental analysis, and NMR spectroscopy (Fig. 2) tech-
niques. The spectral data are in good agreement with the pro-
posed structures.
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In summary, we have developed a hitherto unreported conve-
nient, efficient, microwave assisted chemoselective, and regiose-
lective synthesis of several 3-pyranyl indole derivatives in the
presence of InCl3 under SFC. The synthesized azido indolylpyrans
were successfully transformed into N-substituted 1,2,3-triazole
derivatives by [3+2] cycloaddition with different phenyl acety-
lenes. In this simple process, we adapted three biologically
important core moieties (pyran–indole–triazole) in the single
compound with a stereocenter with all reactants efficiently uti-
lized. Further synthetic applications and functional group trans-
formations of these entities are currently in progress in our
laboratory.
Acknowledgment
14. (a) Thirumurugan, P.; Perumal, P. T. Tetrahedron 2009, 65, 7620; (b) Praveen, C.;
Karthikeyan, K.; Perumal, P. T. Tetrahedron 2009, 65, 9244; Shanthi, G.;
Perumal, P. T. Tetrahedron Lett. 2007, 48, 6785; (d) Thirumurugan, P.; Perumal,
P. T. Tetrahedron Lett. 2009, 50, 4145; (e) Thirumurugan, P.; Nandakumar, A.;
Muralidharan, D.; Perumal, P. T. J. Comb. Chem. 2010, 12, 161; (f) Lakshmi, N. V.;
Thirumurugan, P.; Perumal, P. T. Tetrahedron Lett. 2010, 51, 1064; (g)
Nandhakumar, A.; Thirumurugan, P.; Perumal, P. T.; Vembu, P.; Ponnusamy,
M. N.; Ramesh, P. Bioorg. Med. Chem. Lett. 2010, 20, 4252; (h) Lakshmi, N. V.;
Thirumurugan, P.; Noorulla, K. M.; Perumal, P. T. Bioorg. Med. Chem. 2010, 20,
5054.
15. (a) Babu, G.; Perumal, P. T. Tetrahedron Lett. 1997, 38, 5025; (b) Babu, G.;
Perumal, P. T. Tetrahedron 1998, 54, 1627; (c) Babu, G.; Nagarajan, R.;
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Subbulakshmi, G.; Perumal, P. T. Tetrahedron 2007, 63, 2057.
16. (a) Kamalraja, J.; Muralidharan, D.; Perumal, P. T. Synlett 2012, 2894; (b)
Kamalraja, J.; Perumal, P. T. Tetrahedron Lett. 2010, 55, 2010.
J.K. is grateful to the Council of Scientific and Industrial
Research (CSIR), New Delhi, India for providing financial assistance
to carryout doctoral research programme.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
04.104.
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Please cite this article in press as: Kamalraja, J.; Perumal, P. T. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.104