A facile access to substituted indoles utilizing palladium catalyzed annulation under microwave enhanced conditions

Article abstract of DOI:10.1016/j.tetlet.2013.07.073

A facile access to differently substituted indoles using palladium catalyzed annulation reactions under microwave enhanced conditions has been achieved. A highly active and efficient catalytic system PdCl ₂/(A-taphos) for the synthesis of indole via palladium catalyzed ring annulation of ortho iodo anilines and aldehydes has been developed.

Full text of DOI:10.1016/j.tetlet.2013.07.073

Tetrahedron Letters 54 (2013) 5126–5129
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A facile access to substituted indoles utilizing palladium catalyzed
annulation under microwave enhanced conditions
Ranjith P. Karuvalam , Karickal R. Haridas , Ayyiliath M. Sajith , Arayambath Muralidharan b
a
a,
⇑
b
a
School of Chemical Sciences, Kannur University, Payyanur Campus, Edat PO 670327, Kannur, Kerala, India
School of Chemical Sciences, Organic Chemistry Division, Kannur University, Nehru Arts and Science College, Kerala, India
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile access to differently substituted indoles using palladium catalyzed annulation reactions under
Received 22 May 2013
Revised 9 July 2013
Accepted 10 July 2013
Available online 17 July 2013
microwave enhanced conditions has been achieved. A highly active and efficient catalytic system PdCl
A-taphos) for the synthesis of indole via palladium catalyzed ring annulation of ortho iodo anilines and
aldehydes has been developed.
2
/
(
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Indole
PdCl
2
A-taphos
Microwave
Palladium catalyzed cross-coupling reactions have evolved as
one of the efficient and robust methods in the field of organic syn-
thesis for construction of diverse heterocycles. This is largely
attributed to the fact that it provides a more general and applicable
cores.9,10 As a part of our research oriented toward microwave
mediated palladium catalyzed cross-coupling reactions in the syn-
1
1
thesis of nitrogen heterocycles and biologically active mole-
1
2
cules, we were interested in the synthesis of some indole based
1
method for the construction of biaryls, synthesis of various het-
2
erocycles which are found in polymers, biologically relevant mol-
R3
3
ecules, ligands, and various materials. The importance of nitrogen
I
O
based heterocycles as indicated by its role in many aspects
prompted us to design more efficient synthetic protocols for a fac-
ile access to diverse nitrogen heteroaraomatics. The use of palla-
dium catalyzed cross-coupling reactions in building the
heterocyclic core itself was studied in detail by various researchers.
Also, the use of heterocyclic fragment as one of the reaction com-
ponents to access diverse analogues utilizing palladium mediated
cross-coupling reactions has also been well explored. Despite these
advancements in this field, there still remains a need for an effi-
cient protocol employing low catalyst loadings for the carbon–car-
bon bond forming reactions of nitrogen derived heteroaromatics.
The synthesis and functionalization of indole based structures have
R1
R1
+
R3
PdCl2/(A-taphos)
Cesium acetate
microwave, 120 oC
R2
H
N
N
H
Dioxane
R2
1
(a-q)
2(a-q)
3(a-q)
Scheme 1. Synthesis of substituted indoles utilizing palladium catalyzed annula-
tion reactions under microwave enhanced conditions.
PPh2
PCy
2
PPh2
i-Pr
i-Pr
Fe
PPh
2
4
–8
been an area of major focus for synthetic organic chemists.
Due
PPh2
i-Pr
to the wide medicinal relevance of the analogues based on this het-
erocyclic core, there is always a need for developing efficient syn-
thetic protocols through which diversity oriented synthesis can be
employed in generating various analogues. A number of methods
are available in the literature in accessing these heterocyclic
(rac)-BINAP
XPhos
DPPF
P
P
P
PPh2
PPh2
O
N
⇑
Corresponding author. Tel./fax: +91 497 2806402.
E-mail addresses: pkranjith@redifmail.com (R.P. Karuvalam), krharidas2001@ya-
DPPP
Ataphos
Xantphos
hoo.com (K.R. Haridas).
Figure 1. Structures of the ligands used for screening the ring annulation.
0
040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.073

R. P. Karuvalam et al. / Tetrahedron Letters 54 (2013) 5126–5129
5127
Table 1
analogues utilizing microwave assisted, metal mediated cross-cou-
pling processes.
a
Effect of catalyst in synthesis of indoles via palladium catalyzed ring annulation
S. no.
Catalyst
Yield (%)
Microwave assisted organic synthesis (MAOS) plays a vital
role in the design of new molecule as well as in the drug discov-
1
2
3
4
5
6
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
2
2
2
2
2
2
/BINAP
/DPPF
/DPPP
/Xphos
/Xantphos
/A-taphos
22
38
20
41
30
53
1
3–15
ery laboratories.
Microwave heating has been shown to dra-
matically reduce reaction times, increase the product yields and
enhance the product purities by reducing unwanted side reac-
tions compared to conventional heating methods. The short reac-
tion times provided by microwave synthesis make it ideal for
rapid reaction scouting and optimization of reaction conditions.
The use of microwave assisted palladium catalyzed cross-cou-
pling reactions to access various hereto aromatic substrates is
nowadays well studied.
a
Reaction conditions: 1n (0.10 mmol), 2n (0.16 mmol), PdCl
10 mol %), Cs
0 min.
2
(5 mol %), ligand
(
4
2
CO
3
(0.20 mmol), and DMF, microwave irradiated at 120 °C for
Table 2
Effect of base in synthesis of indoles via palladium catalyzed ring annulation
In an attempt to synthesize differently substituted indoles uti-
lizing palladium mediated cross-coupling reactions, we herein de-
scribe a highly efficient protocol for variously substituted indoles
a
S. no.
Base
KOH
Yield
(
Scheme 1). In order to set the reaction parameters, a model sys-
tem and a range of conditions were explored. ortho iodo aniline
1n) reacted efficiently with an aldehyde (2n) in the presence of
palladium catalyst (PdCl /xantphos) and cesium carbonate as a
1
2
3
4
5
6
7
5
K
K
Cs
CH
2
CO
PO
CO
COOCs
3
35
49
53
72
30
28
3
4
(
2
3
2
3
base in DMF. It was heated via microwave irradiation at 120 °C
to afford product in 30% yield. The products formed were purified
by flash column chromatography. Next we focused on screening
various ligand (Fig. 1) combinations with cesium carbonate as a
base and palladium chloride as the catalyst. Different ligands were
explored along with palladium precursor to find an optimum true
catalyst which will facilitate the formation of indoles with high
yields (Table 1). The unique effect of cesium salts in palladium cat-
DBU
DABCO
a
Reaction conditions: 1n (0.10 mmol), 2n (0.16 mmol), PdCl
10 mol %), base (0.20 mmol), and DMF, microwave irradiated at 120 °C for 40 min.
2
(5 mol %), A-taphos
(
Table 3
a
Effect of solvent in synthesis of indoles via palladium catalyzed ring annulation
1
6,17
S. no.
Solvent
Yield
alyzed cross-coupling reactions
ties of cesium cation like very large ionic radius, low charge density
and high polarizability. From Table 1 it is clear that the PdCl /A-ta-
arises from the special proper-
1
2
3
4
5
Toluene
THF
DME
DMF
Dioxane
25
42
35
30
70
2
phos combination provided an effective catalytic system which en-
hanced the formation of indoles in 53% yield. This could be
attributed to the fact that this catalytic combination provided a
a
18
Reaction conditions: 1n (0.10 mmol), 2n (0.16 mmol), PdCl
10 mol %), and CH COOCs (0.20 mmol), solvent, microwave irradiated at 120 °C for
3
0 min.
2
(5 mol %), A-taphos
highly active catalytic species which was instrumental for the
(
4
better conversions to products. Now that we have found an effec-
tive catalytic system, we were interested in screening different
Table 4
Synthesis of indoles via palladium catalyzed ring annulation of ortho iodoaniline and aldehydes
a
S. no.
ortho iodoaniline (1)
Aldehyde (2)
Product (3)
Yieldb (%)
72
Cl
I
O
H
Cl
a
NH2
N
H
Cl
I
O
H
Cl
b
c
80
69
N
H
N
F3CO
I
O
H
F
F
O
F
N
H
N
H
Cl
I
O
H
Cl
d
e
f
70
64
66
NH2
N
H
Cl
I
O
H
Cl
N
H
N
F3CO
I
O
H
F3CO
N
H
N
H
I
O
H
O
O
O
NH2
O
75
g
N
H
O
O
(
continued on next page)

5
128
R. P. Karuvalam et al. / Tetrahedron Letters 54 (2013) 5126–5129
Table 4 (continued)
S. no.
ortho iodoaniline (1)
Aldehyde (2)
Product (3)
Yieldb (%)
F
I
H
O
NH2
F
h
i
73
N
H
I
O
H
O N
2
56
50
O N
NH2
2
N
H
O
O
O
H
O
O
O
O
I
j
NH2
N
H
I
O
H
O
k
l
78
72
70
O
NH2
N
H
I
O
H
NH2
N
H
I
O
H
m
OH
OH
NH2
I
N
H
H
O
NH2
n
72
N
H
I
O
H
o
p
80
80
N
N
H
I
O
H
NH2
N
H
I
O
H
q
75
NH2
N
H
a
Reaction conditions: ortho Iodoaniline 1(a–q) (0.10 mmol), aldehyde 2(a–q) (0.16 mmol), PdCl
microwave irradiated at 120 °C for 40 min.
2
(5 mol %), A-taphos (10 mol %), CH
3
COOCs (0.20 mmol), and dioxane,
b
Isolated yield.
bases and solvents which can facilitate the reaction conditions.
Among the bases that were explored, we found that cesium acetate
resulted in better conversions to products (Table 2, entry 5). The
use of soluble amine bases like DABCO and DBU was also tried.
Both these bases lead to the formation of products, but the yields
were low compared to the inorganic bases (Table 2, entries 6 and
the scope of exploring these analogues which are known to have
potential medicinal relevance.
Acknowledgments
The authors are thankful to the Organic Chemistry Division,
School of Chemical Science department, Kannur University and
the Head of Chemistry Department, School of Chemical Sciences
for providing facilities and good support for research work.
7
). Among the solvents, dioxane (Table 3, entry 5) was found to
be a better choice and Table 3 shows the effect of solvents on the
cyclization reactions. We can see that cesium acetate as base and
dioxane as solvent were found to be better choices for this reac-
tion. Using these optimized conditions in our hand substrate scope
was studied in detail as shown in Table 4. From the table it is very
clear that various diversely substituted anilines and aldehydes
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
2
yielded the cyclized indoles in reasonable yields. The PdCl /A-ta-
phos catalytic system was found to be instrumental in driving
the reaction which led to better yields of the indole. We speculate
that imine formed initially isomerizes to enamine, which was fol-
lowed by the intramolecular Heck reaction to get the substituted
indoles.
0
7.073.
References and notes
1. Marie, K.; Orla, A. M.; David, M.; David, M. C.; Humphrey, A. M.; Kurt, T. L.;
A highly efficient protocol for the synthesis of variously substi-
Anita, R. M. Tetrahedron Lett. 2012, 53, 403.
2
3
.
.
Franssen, N. M. G.; Reeka, J. N. H.; de Bruin, B. Polym. Chem. 2011, 2, 422.
Anita, C.; Pierre, V.; Maxime, D. C.; Sebastien, H.; Pascal, R.; Patrice, V.; Nadine,
A. Eur. J. Med. Chem. 2012, 55, 315.
tuted indole utilizing PdCl
hanced conditions has been achieved. This protocol expands
2
and A-taphos under microwave en-
19

R. P. Karuvalam et al. / Tetrahedron Letters 54 (2013) 5126–5129
5129
4
5
6
7
8
9
.
.
.
.
.
.
Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875.
17. Ralph, N. S.; Advait, S. N.; Kyung, W. J. J. Org. Chem. 2002, 67, 674.
18. Sajith, A. M.; Muralidharan, A. Tetrahedron Lett. 2012, 53, 1036.
Tois, T.; Franzen, R.; Kiskinen, A. Tetrahedron 2003, 59, 5395.
Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045.
Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 2001, 2491.
Pindur, U.; Adam, R. J. Heterocycl. Chem. 1988, 25, 1.
19. General procedure for the preparation of derivatives 3(a–q):To ortho iodoaniline,
1(a–q) (0.10 mmol), in dioxane (5 mL) was added PdCl (5 mol %), A-taphos
(10 mol %). The solution was purged with nitrogen and stirred at room
temperature for 10 min and aldehyde (2a–q) (0.16 mmol), CH COOCs
2
Bing, Li.; John, D. W.; Norton, P. P. Tetrahedron Lett. 2013, 54, 3124.
3
1
1
1
0. Wei, Y.; Deb, I.; Yoshikai, N. J. Am. Chem. Soc. 2012, 134, 9098.
1. Sajith, A. M.; Muralidharan, A. Tetrahedron Lett. 2012, 53, 5206.
2. Ranjith, P. K.; Haridas, K. R.; Susanta, K. N.; Guru Row, T. N.; Rajeesh, P.;
Rishikesan, R.; Suchetha, N. K. Eur. J. Med. Chem 2012, 49, 172.
3. Nadeesha, R.; Graham, B. J. Bioorg. Med. Chem. Lett 2013, 23, 1740.
4. Sadler, S.; Moeller, A. R.; Jones, G. B. Expert Opin. Drug Disc. 2012, 7(12), 1107.
5. Alcazar, J.; Oehlrich, D. Future Med. Chem. 2010, 2, 169.
(0.20 mmol), were added. The reaction mixture was again purged with
nitrogen and heated in the microwave at 120 °C for 30–40 min. Reaction was
monitored by TLC. After the completion, reaction mixture was cooled to room
temperature and water was added to the reaction mixture. It was then
extracted with ethyl acetate (25 mL Â 2) and the separated organic layer was
1
1
1
1
2 4
dried over anhydrous Na SO . The organic layer was filtered and concentrated
under vacuum, and the residue was purified by flash column chromatography
on silica gel.
6. Eric, E. D.; Feixia, C.; Seok, I. K.; Kyung, W. J. Tetrahedron Lett. 1999, 40, 1843.