Metal-free synthesis of indolizines through oxidative C–C and C–N bond formations of C (sp3) –H bonds

Article abstract of DOI:10.1016/j.tetlet.2016.01.082

Iodine catalyzed synthesis of indolizine-1-carboxylates through oxidative C–C and C–N bond formations by the reaction of 2-pyridyl acetates with alkynes and alkenes without metal, oxidant, and base. This procedure is compatible with a broad range of functional groups in both alkynes and alkenes with good yields. The reaction proceeds through a tandem C–C bond formation followed by an intramolecular cyclization.

Full text of DOI:10.1016/j.tetlet.2016.01.082

Accepted Manuscript
Metal–free Synthesis of Indolizines through Oxidative C–C and C–N Bond
Formations of C (sp3) –H Bonds
N. Naresh Kumar Reddy, Darapaneni Chandra Mohan, Subbarayappa
Adimurthy
PII:
S0040-4039(16)30080-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.01.082
TETL 47246
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 November 2015
20 January 2016
22 January 2016
Please cite this article as: Naresh Kumar Reddy, N., Mohan, D.C., Adimurthy, S., Metal–free Synthesis of Indolizines
through Oxidative C–C and C–N Bond Formations of C (sp3) –H Bonds, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.01.082
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Metal–free Synthesis of Indolizines through
Oxidative C–C and C–N Bond Formations of
C (sp3) –H Bonds
N. Naresh Kumar Reddy, Darapaneni Chandra Mohan and Subbarayappa Adimurthy*

Tetrahedron Letters
journal homepage: www.els evier.com
Metal–free Synthesis of Indolizines through Oxidative C–C and C–N Bond
Formations of C (sp3) –H Bonds
N. Naresh Kumar Reddy, Darapaneni Chandra Mohan and Subbarayappa Adimurthy*
Academy of Scientific & Innovative Research, CSIR–Central Salt & Marine Chemicals Research Institute, G.B. Marg, Bhavnagar-364 002. Gujarat (INDIA).
* E-mail: adimurthy@csmcri.org
ARTICLE INFO
ABSTRACT
Article history:
Received
Iodine catalyzed synthesis of indolizine-1-carboxylates through oxidative C–C and C–N bond
formations by the reaction of 2–pyridyl acetates with alkynes and alkenes without metal, oxidant
and base. This procedure is compatible with a broad range of functional groups in both alkynes
and alkenes with good yields. The reaction proceeds through a tandem C–C bond formation
followed by an intramolecular cyclization.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
2–pyridyl acetates
Alkenes
Alkynes
Indolizines
Iodine
In recent years, cross dehydrogenative coupling (CDC)
reactions have emerged as powerful tools for the wide range of
organic transformations like synthesis of various biological
active compounds, natural products, agrochemicals, functional
materials and polymers via C–C and C–hetero bond formations.
The main advantage of this (CDC) system is the direct utilization
of two or more reaction substituents involved without
prefunctionalization to construct new bonds (C-X; X= C, N, S, O,
& P etc.).1 However, most of these reactions requires transition
metal catalysts like Cu, Fe, Pd, Ni, Rh, Ru, Co, and V which may
pose difficulties for their recovery from the effluent or leaching,
contamination of traces of these metals in the product, in
particularly pharmaceutical products.1,2 Therefore, the
proven to be an efficient catalysts for the CDC reactions for the
synthesis variety of heterocyclic compounds.3,4 Iodine being less
toxic, metal-free and abundantly available.
Indolizines are a class of bridged head azaheterocycles also
they are indole isosteres and exhibit a wide range of interesting
biological
Additionally,
and
pharmacological
derivatives
properties
showed
(Fig.1).5-7
efficient
indolizine
fluorescence and luminescence properties.8 Due to their
importance, various synthetic methods have been developed
which includes cyclocondensation method, [3+2] cycloadditions,
cycloadditions, A3 coupling and cycloisomerizations.9-11
Recently, Agrawal and Pan groups simultaneously reported the
synthesis of indolizines with more than stoichiometric excess of
silver salts and bases [Scheme 1, eq. 1.].12 More recently we
reported copper-catalyzed oxidative synthesis of indolizines from
pyridine derivatives [Scheme 1, eq. 2].13 However, purification of
such biological and pharmaceutically active products requires
extreme care due to the possible contamination of metal residues
in the target compounds. Hence, we became interested to develop
transition metal-free routes for the synthesis of indolizines which
can be able to access by the annulation of pyridine derivatives.
Herein we describe the direct synthesis of substituted indolizines
from commercially accessible 2-pyridyl acetates with alkynes
(sp) and alkenes (sp2) through oxidative coupling reactions
without metal, base and oxidant [Scheme 1, eq-3].14
O
MeO
O
HO
O
OMe
Ph
NH2
NC
NC
N
N
N
Ph
Ph
Anti-Fungal
Anti-microbial
Anti-cancer
O
OMe
CN
F
N
N
O
Ph
HN
Cl
Initially, based on our previous works on synthesis of
bridged head azaheterocyclic compounds,15 we have chosen
pyridyl acetate with alkyne/alkene as starting substrates which
are commercially available. We started the optimization of
conditions for the synthesis of indolizine (3a) by the reaction of
pyridyl ester 1a with phenyl acetylene (2a) (Table 1). With the
catalytic amount of copper(I) iodide in acetonitrile as a solvent at
O
Anti-convulsant
Endothelial growth factor (VEGF)
Figure 1. Biologically active indolizine derivatives
development of alternative catalysts for these reactions are highly

60 °C in open air for 24 h, trace amount of 3a was observed
(Table 1, entry 1).
proceed efficiently (Table 1, entries 3–7). Surprisingly NMP as a
solvent under the same conditions, 18% of (3a) was isolated
(Table 1, entry 8). With the motivation of this result, we have
varied the temperature and different iodine sources (NIS, TBAI),
however no improvement was observed (Table 1, entries 10 and
11). Further increase of temperature from 80 °C to 100 °C and
120 °C,
Table 2 Substrate scope of various pyridyl esters with
different alkynesa
Scheme 1. Synthetic strategies for indolizines
Instead of acetonitrile, the reaction performed with toluene as
solvent under the same conditions, no product formation was
observed (Table 1, entry 2). Using iodine in place CuI and
different solvents like polar and nonpolar solvents (acetonitrile,
DMF, DMSO, and triethylamine) in all these conditions reaction
did not
Table 1 Optimization of condition for 3aa
CO2Et
conditions
Ph
H
+
CO2Et
N
N
1a
2a
3a
Ph
Entry
1
Solvent
Catalyst
Time(h)
Yieldb
Trace
Temp ( C)
CuI (10 mol%)
24
24
24
24
24
60
60
60
60
60
60
60
ACN
toloune
toloune
2
3
4
5
6
7
CuI (10 mol%)
I2(50 mol%)
I2(50 mol%)
I2(50 mol%)
I2(50 mol%)
I2(50 mol%)
nr
Trace
Trace
Trace
Trace
nr
ACN
DMF
DMSO
TEA
a Conditions: 1a (0.4 mmol), 2a (0.2 mmol), solvent (2 mL), in an oil bath, 10
h, isolated yield.
24
24
8
9
10
11
12
I2(50 mol%)
I2(50 mol%)
NIS(50 mol%)
TBAI(50 mol%)
I2(50 mol%)
24
24
24
24
24
18
21
20
nr
30
NMP
NMP
NMP
NMP
NMP
60
80
80
80
100
120
120
(3a) was obtained in 21%, 30% and 36% yield respectively
(Table 1, entries 12 and 13). The yield of the reaction was
improved by decreasing of the catalyst loading (50-10 mol %)
(Table 1, entries 14-17). Further decrease of catalyst from 10
mol% to 5 and 2.5 mol %, yield of (3a) was also decreased
(Table 1, entries 18 and 19).
13
14
I2(50 mol%)
I2(30 mol%)
24
24
36
45
NMP
NMP
15
16
17
I2(20 mol%)
I2(10 mol%)
I2(10 mol%)
I2(5 mol%)
I2(2.5 mol%)
I2(10 mol%)
I2(10 mol%)
120
120
120
120
120
120
120
24
24
5
5
5
5
5
49
57
68
53
35
75
76
NMP
NMP
NMP
NMP
NMP
NMP
NMP
Finally, by tuning the substrate concentration (entries 20 and
21) and reaction time, 78% of (3a) was obtained (Table 1, entry
22). No reaction was observed without catalyst under the same
reaction conditions (entry 23) and at room temperature (entry
24). Hence the conditions of entry 22 was chosen as the best
suitable for the present transformation to study further scope of
the methodology.
18
19
20c
21d
22d
23d
24d
I2(10 mol%)
120
120
rt
10
10
10
78
nr
nr
NMP
NMP
NMP
--
With the optimization condition in hand, we have explored the
substrate scope for the synthesis of variety of indolizines from
different pyridyl esters with alkyne derivatives and the result are
summarised in table 2. Initially, we performed the reaction of
phenyl acetylene with various pyridyl esters such as –COOEt, –
I2(10 mol%)
aConditions: 1a (0.2 mmol), 2a (0.3 mmol), catalyst, additive, solvent (0.5
mL), in an oil bath 10 h. under argon atmosphere. bIsolated yield. c2a used as
(0.4 mmol). d1a used as (0.4 mmol).

COOMe, –COOiPr, –COOnBu, and –COOCy. All the esters
reacted smoothly and produced the corresponding indolizine
derivatives (3a–3e) in moderate to good yields. Next, we have
performed the reaction of pyridin-2-yl acetate (1a), with different
phenyl acetylenes and the reaction found to be very facile with
both electron rich and electron deficient phenyl acetylenes. The
presence of, electron rich and deficient groups at para-position of
for further functionalization. Further the present system also
applicable to indene and 1, 2-dihydronaphthalene under typical
conditions, to afford the desired products 5n and 5o in moderate
yields. However, no desired product formation was observed
with aliphatic olefins (1-decene and 1-octene) which were not
included in Table-3.
To understand the reaction mechanism we performed some
control experiments (Scheme 2). When the reaction of 2-(pyridin-
2-yl)-acetonitrile (6) and 2-ethnylpyridine (8) (instead of 1a)
were reacted with 2a under the optimized conditions, no product
formation was observed in both the cases. These two experiments
indicates the presence of ester group is essentially for the present
transformation. When the reaction was carried out in presence of
1, 2-diphenylethyne (10) with 1a, it resulted <5% yield of
product (11). It indicates that, the reaction may be going through
a tandem C–C bond formation followed by cyclization. Further
the reaction was checked in presence of radical scavengers
(TEMPO and BQ) under optimized conditions to ascertain the
reaction pathway, no product formation was observed. It clearly
indicates that the reaction goes via radical pathway. However
without any oxidant, the catalytic amount of iodine is generated
for the oxidative formation indolizine in moderate to good yields
is not known at this point. Hence we are unable to propose a
likely reaction mechanism due to miscellaneous results observed
with control experiments. Some control experiments are under
way in our laboratory to establish the mechanism.
n
phenyl acetylene (Me, Pr, Br, and F) gave the desired products
(3f-3i) in good yields (73–87%). Substituent’s at ortho(-OMe)
and meta(-Cl) position of phenyl acetylene and bicyclic alkynes
also reactive and produced the corresponding products (3j- 3l) in
good yields (67–82%). It may be noted that, halide (Cl, Br and F)
substituted indolizine derivatives were well tolerated and which
could be further applied in traditional cross–coupling reactions.
Additionally, we evaluated the substrate scope of substituted
pyridyl esters with various phenyl acetylenes. Pyridyl esters, like
methyl, isopropyl, n-butyl, and cyclohexyl reacted smoothly with
phenyl acetylenes and afforded the desired products (3m–3r) in
moderate to good yields. However, no product (3s) formation
was observed with 2-ethynylpyridine in this case starting
substrates were decomposed.
Table 2 Substrate scope of pyridyl ester with different
alkenesa
CN
CN
I2 (10 mol %)
NMP, Ar
Ph
H
+
N
N
7; nr
6
2a
I2 (10 mol %)
NMP, Ar
Ph
H
+
N
N
9; nr
8
2a
COOEt
Ph
COOEt
I2 (10 mol %)
NMP, Ar
Ph
+
N
N
11;
<5%
1a
10
COOEt
Ph
COOEt
I2 (10 mol %)
NMP, Ar
H
+
N
N
TEMPO (1.5 equiv.)
or
BQ (1.5 equiv.)
3a; nr
Additionally, we examined the reaction of alkenes instead of
alkynes with pyridyl ester (1a) under the optimized conditions of
table 2, and the results are included in Table 3.16 Initially, the
reaction of (1a) with styrene (4a) produced the desired product
(5a) in 59% yield without any oxidant. Based on this exciting
result, we performed the reaction of substituted styrene such as
methyl (para, meta and ortho) position, p-tert-butyl, and p-
phenyl with 1a and produced the corresponding indolizine
derivatives (5b–5f) in moderate to good yields. However with 2,
4-dimethyl styrene gave the low yield (35%) of desired product
5g, it might be due to steric effect of two methyl groups. The
electron withdrawing substituent like -F, (para, meta) -Cl, (para,
meta & ortho) and Br (ortho) reacted efficiently and gave the
moderate yields of (5h–5m) products, which could be employed
1a
2a
Scheme 2. Control experiments
In conclusion, we have developed a metal/oxidant/base-free
direct synthesis of substituted indolizines from commercially
accessible 2-pyridyl acetates with alkynes (sp) and alkenes (sp2)
using iodine as a catalyst. This methodology is applicable for the
synthesis of functionalized indolizines in moderate to good yields
via oxidative C–C and C–N bond formations.
Acknowledgments

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