Iodine-catalyzed [3+2] cyclization of 2-pyridylesters and chalcones: metal-free approach for the synthesis of substituted indolizines

Article abstract of DOI:10.1016/j.tetlet.2016.05.083

A transition metal-free iodine catalyzed synthesis of indolizine derivatives through [3+2] cyclization of 2-pyridylesters and chalcones has been described. The method is efficient to synthesize a variety of substituted indolizines including hetero aromati

Full text of DOI:10.1016/j.tetlet.2016.05.083

Accepted Manuscript
Iodine–catalyzed [3+2] cyclization of 2-pyridylesters and chalcones: Metal-free
approach for the synthesis of substituted indolizines
N. Naresh Kumar Reddy, Ramachandra Reddy Donthiri, Chitrakar Ravi,
Subbarayappa Adimurthy
PII:
S0040-4039(16)30616-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.083
TETL 47702
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 April 2016
17 May 2016
21 May 2016
Please cite this article as: Naresh Kumar Reddy, N., Donthiri, R.R., Ravi, C., Adimurthy, S., Iodine–catalyzed [3+2]
cyclization of 2-pyridylesters and chalcones: Metal-free approach for the synthesis of substituted indolizines,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.05.083
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Graphical Abstract
Iodine–catalyzed [3+2] cyclization of 2-
pyridylesters and chalcones: Metal-free
approach for the synthesis of substituted
indolizines
Leave this area blank for abstract info.
N. Naresh Kumar Reddy, Ramachandra Reddy Donthiri, Chitrakar Ravi, and Subbarayappa Adimurthy*

1
Tetrahedron Letters
Iodine–catalyzed [3+2] cyclization of 2-pyridylesters and chalcones: Metal-free
approach for the synthesis of substituted indolizines
N. Naresh Kumar Reddy, Ramachandra Reddy Donthiri, Chitrakar Ravi, and Subbarayappa Adimurthy*
Academy of Scientific & Innovative Research, CSIR–Central Salt & Marine Chemicals Research Institute, G.B. Marg, Bhavnagar-364 002. Gujarat (INDIA);
adimurthy@csmcri.org
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A transition metal-free iodine catalyzed synthesis of indolizine derivatives through [3+2]
cyclization of 2-pyridylesters and chalcones has been described. The method is efficient to
synthesize variety of substituted indolizines including hetero aromatic indolizines. Mechanistic
studies reveal that, the reaction follows the radical pathway.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
2-pyridylesters
Chalcones
Di-tert-butyl peroxide
Iodine
Indolizines
our efforts to the development of metal-free conditions for this
particular transformation (Scheme 2). Our previous experience
Introduction
on the synthesis of azaheterocycles14 and by considering the
advantages of iodine or their derivatives as an alternative to
transition metal catalysis in organic transformations,15 we
described herewith the iodine-catalyzed synthesis of indolizines
by [3+2] cyclization of 2-pyridylesters with chalcones.
The construction of azaheterocycles through direct
functionalization of C−H bonds with simple and readily available
starting substrates is of considerable interest in organic synthesis.
This process accomplished under metal-free conditions becomes
an advantageous, because it avoids the metal contamination in
the final product. Among the azaheterocycles, the construction of
indolizine derivatives are of significant importance due to their
presence in a large variety of biologically active molecules,1
naturalproducts,2 and synthetic pharmaceuticals.3 Many synthetic
and naturally occurring indolizine derivatives found to exhibit
outstanding biological activity for example; anti-inflammatory,
antiviral, anti-bacterial, cardiovascular agents, anti-cancer and
CNS depression agents (Scheme 1).4, Owing to their unique
5
photo physical properties of substituted indolizines, they are used
as organic materials for various applications.6 Therefore, the
development of synthetic methods to access indolizines paid
much attention.
Scheme 2
To check our hypothesis, we initially performed a reaction with
2-ethylpyridylacetate (0.4 mmol) 1a, chalcone (0.2 mmol) 2a and
I2 (0.05mmol) in DMF at 110 ºC for 24 h. To our delight, the
Scheme 1
expected
product
ethyl-3-benzoyl-2-phenylindolizine-1-
To our knowledge many reported methods involve transition
metal catalyzed intra and/or inter molecular cyclisation of
pyridine derivatives.7-12 Recently we reported the synthesis of
indolizine derivatives from 2-pyridylesters with chalcones, in
which we used Cu(OAc)2 as a catalyst and excess amount of
FeCl2 as an oxidant.13 To avoid the use of metal, we continued
carboxylate 3a was obtained in 11% yield (Table 1, entry 1). On
the basis of these initial findings we screened with other solvents
such as DMSO, NMP, 1,2-dichlorobenzene (DCB) and toluene.
A considerable improvement in the yield of 3a was observed
when DCB was used as a solvent (Table 1, Entry 2−5). Further,
addition of DTBP (Di-tert-butyl peroxide) to the reaction mixture

2
Tetrahedron Letters
Table 1: Optimization of reaction conditions for 3aa
reaction under argon atmosphere does not have considerable
effect on the overall yield of the product (scheme 4. eq. 1). It
indicates the molecular oxygen is not the driving force for this
reaction. The addition of radical trapping reagent TEMPO to the
reaction, it does not leads to the formation of 3a or TEMPO
Table 2: Scope of indolizines from 2-pyridylesters and
chalconesa
a
Reaction conditions: 1a (0.4 mmol), 2a (0.2 mmol), catalyst, oxidant,
solvent (1.0 mL), 24 h, isolated yield.
showed significant improvement in the yield of the product 3a,
whereas TBHP (tert-Butyl Hydroperoxide) and oxygen
atmosphere were found inefficient oxidants for this
transformation (Table 1, entries 6-9). The maximum yield of 3a,
(87 %) was observed at 120 ºC reaction temperature with two
equivalents of DTBP as an oxidant w.r.t. 2a (Table 1, entry 10).
Increase in the amount of iodine (even more than stoichiometric
amount w.r.t. 2a) in absence of DTBP was found not efficient
than the catalytic amount of iodine with DTBP (Table 1, entry
11&12). Finally the optimized conditions considered for this
transformation are as follows: 1a (0.4 mmol), 2a (0.2 mmol),
iodine (0.05 mmol), DTBP (0.4 mmol) and 1mL of DCB as a
solvent at 120 ºC.
a
2-Pyridylester 1a (0.4 mmol), chalcone 2a (0.2 mmol), I2 (0.05 mmol),
DTBP (0.4 mmol), DCB (1.0 mL) in an oil bath at 120 ºC, for 24 h, isolated
yields.
With the optimized conditions, the substrate scope of this
iodine-catalyzed reaction was tested (Table 2). Different 2-
pyridylesters (–COOnBu, –COOiPr, –COOcy and –COOMe
groups) reacted well with chalcone 2a and produced the
corresponding indolizine esters 3b-3e in moderate to good yields.
Then, the reaction was extended to substituted chalcones with 1a,
both electron–donating and –withdrawing substituted groups
containing chalcones were well tolerated under the optimized
reaction conditions. The reaction of (1a) with electron donating
groups (such as –OMe, –Et, –Me, –SMe) at para position of
phenyl ring of chalcone provided the corresponding products 3f-
3i in good to excellent yields (80–89 %). The halogen (–F and –
Cl) and nitro (–NO2) substituted chalcones also underwent to the
present transformation and gave the products 3j−3l in good
yields (65–82 %). Notably, hetero aromatic ring containing
chalcones also well reacted under these conditions with 1a and
provided the corresponding products 3m−3t with moderate to
good yields (40–86 %). However the present conditions are not
suitable for the reactants such as 2-(pyridin-2-yl) acetonitrile, N-
methyl-N-phenylcinnamamide and ethylcinnamate to obtain
corresponding products.
adduct, instead a keto product 4a was isolated in 72 % yield
(Scheme 4. eq. 2). Next 1a was subjected to the optimized
conditions without chalcone, only 17 % of 4a was isolated
(Scheme 4. eq. 3). Further, conducting the reaction of 1a under
argon atmosphere, the decomposition of 1a was observed
(Scheme 4. eq. 4). Reaction of 1a with TEMPO under the
optimized conditions, 92 % of 4a was isolated (scheme 4. eq. 5).
These experiments suggests the oxidation of 1a to 4a is efficient
Scheme 3. Gram scale preparation of 3a
To validate the applicability of the present transformation in
gram-scale preparation, we performed a gram scale reaction of 1a
and 2a under the optimized conditions and the product 3a was
isolated in 81 % yield (Scheme 3).
only in presence of TEMPO. To confirm the role of the TEMPO,
1a was treated with TEMPO under argon atmosphere, 20 % of
TEMPO-adduct 5a and 25 % of 4a were isolated along with
inseparable mixture of 4a and 5a (Scheme 4. eq. 6). Therefore,
the formation of 5a suggests the reaction may proceed through a
radical intermediate I.
To get insight in to the reaction mechanism, additional
experiments were performed (Scheme 4). It was observed that the

3
INDUS MAGIC (CSC-0123) and DST, Government of India
(SR/S1/OC-13/2011) and for financial support.
Based on experimental observations and reported literature a
radical mechanism has been proposed.15g Initially 1a in presence
of DTBP forms a radical intermediate I and I up on reaction with
2a, generate another radical intermediate II. This undergoes intra
molecular radical addition followed by oxidation to yield
intermediate IV. Proton elimination from IV and its subsequent
aromatization yield the final product 3a.
Supplementary Material
Supplementary data (detailed experimental procedure and
spectroscopic data) associated with this article can be found,
in the online version, at
References and notes
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In conclusion we have developed a transition metal-free
indolizine synthesis through [3+2] cyclisation of 2-pyridylesters
and chalcones using iodine as a catalyst. Wide range of
substituted indolizines efficiently synthesized including hetero
aromatic ring containing products. Mechanistic studies support a
radical mechanism for the present transformation.
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Acknowledgments
CSIR-CSMCRI Communication No. 038/2016. N.N.K.R and
R.R.D. and C.R. are thankful to AcSIR for their Ph.D. enrolment
and the “Analytical Discipline and Centralized Instrumental
Facilities” for providing instrumentation facilities. R.R.D. is also
thankful to UGC, New Delhi for his fellowship. We thank CSIR-

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Tetrahedron Letters
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5
Iodine–catalyzed [3+2] cyclization of 2-
pyridylesters and chalcones: Metal-
free approach for the synthesis of
substituted indolizines
N. Naresh Kumar Reddy, Ramachandra Reddy
Donthiri, Chitrakar Ravi, and Subbarayappa
Adimurthy*
Academy of Scientific & Innovative Research,
CSIR–Central Salt & Marine Chemicals Research
Institute, G.B. Marg, Bhavnagar-364 002. Gujarat
(INDIA); adimurthy@csmcri.org
Highlights:
Transition metal-free,
Iodine catalyzed,
Efficient Synthesis of indolizines,
Wide substrate scope,
Mild conditions