Zinc iodide: A mild and efficient catalyst for one-pot synthesis of aminoindolizines via sequential A3 coupling/cycloisomerization

Article abstract of DOI:10.1039/c3ra46513f

ZnI₂ was found to be an efficient catalyst for the synthesis of indolizine derivatives by a three-component coupling of pyridine-2- carboxaldehyde/quinoline-2-carboxaldehyde, secondary amines, and terminal alkynes in high yields. This protocol

Full text of DOI:10.1039/c3ra46513f

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Zinc iodide: a mild and efficient catalyst for one-pot
synthesis of aminoindolizines via sequential A3
coupling/cycloisomerization†
Cite this: RSC Adv., 2014, 4, 6672
Subhajit Mishra,a Avik Kumar Bagdi,a Monoranjan Ghosh,a Subrata Sinhab
Received 8th November 2013
Accepted 23rd December 2013
a
*
and Alakananda Hajra
DOI: 10.1039/c3ra46513f
www.rsc.org/advances
ZnI2 was found to be an efficient catalyst for the synthesis of indolizine compounds, some of them are naturally occurring,5 while
derivatives by a three-component coupling of pyridine-2-carbox- others are only synthetically accessible and also important in
aldehyde/quinoline-2-carboxaldehyde, secondary amines, and pharmaceuticals. Indolizines and their derivatives have been
terminal alkynes in high yields. This protocol is compatible with a wide allied with a broad range of biological activities such as anti-
range of substrates and is expected to find broad applications due to bacterial, antiviral, anti-inammatory6 and central nervous
its operational simplicity, shorter reaction time and low cost. A system (CNS) depressant activity.7 They also serve as phospha-
preliminary photophysical study showed that synthesized morpholi- tase inhibitors,8 aromatase inhibitors,9 antioxidant reagents,10
nopyrrolo[1,2-a]quinolines represent a new class of fluorophore with and calcium entry blockers11 (Fig. 1).
high quantum yield.
As a consequence, great attention has been drawn to the
synthesis of indolizine derivatives and a number of elegant
methods have been developed in recent years.12 In most of the
cases, transition metals are used to synthesize these moieties
via C–C and C–N bond forming reactions. Three-component
coupling reaction of 2-pyridine carboxaldehyde, secondary
amine, and terminal alkyne (A3) is one of the efficient strategies
for the synthesis of these scaffolds.13 However only few meth-
odologies have been reported based on A3 coupling reactions.
But coinage metal based catalysts are used in almost all case-
s.13a,b,d,e Moreover, gold and silver catalysts are very expensive
and additionally, sometimes inert atmosphere is required to
carry out these transformations. Therefore, nding a new
methodology for the synthesis of indolizines in terms of effi-
ciency, operational simplicity and economic practicability is
highly desirable.
Introduction
One-pot catalytic conversion of organic reactions with readily
available, non-toxic, and inexpensive reagents has attracted
signicant research attention in recent years. Multicomponent
reactions (MCRs) involve simple and exible combination of
three or more building units in a accessible one-pot reaction to
form a product containing substantial elements of all the
reactants.1 The multicomponent synthesis of heterocycles
allows structural diversity and complexity in a single operation
and atom-efficient manner. So the MCRs become an important
tool for both combinatorial chemistry and diversity-oriented
synthesis (DOS), and play a signicant role in the development
of methodology for drug discovery.2,3
Zinc salts are abundant, cheap, non-toxic, and exhibit envi-
ronmentally benign properties. Therefore, organic chemists
have been interested in using zinc salts as catalysts during the
Indolizine is an important heterocycle, composed of an
electron-rich pyrrole and an electron-poor pyridine, which has
drawn considerable attention in past few years.4 The indolizine
nucleus is an important skeleton for many bioactive
aDepartment of Chemistry, Visva-Bharati (A Central University), Santiniketan 731235,
India. E-mail: alakananda.hajra@visva-bharati.ac.in; Fax: +91 3463 261526; Tel: +91
3463 261526
bIntegrated Science Education and Research Centre, Visva-Bharati, Santiniketan 731
235, India
† Electronic supplementary information (ESI) available: Experimental procedure,
characterization data, and NMR spectra for all compounds. See DOI:
10.1039/c3ra46513f
Fig. 1 Pharmacologically potent indolizine derivatives.
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Table 1 Optimization of the reaction conditionsa
Entry
Catalyst
Mol%
Solvent
Temp. (ꢀC)
Yieldb (%)
1
2
3
4
5
6
7
8
ZnI2
ZnI2
ZnI2
ZnI2
ZnCl2
ZnBr2
Zn(OTf)2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
FeCl3
AlCl3
10
10
10
10
10
10
10
10
10
10
10
10
10
15
5
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Ethanol
Acetonitrile
1,4-Dioxane
THF
DMF
DMSO
Toluene
Toluene
Toluene
Toluene
60
80
100
Reux
100
62
75
92
82
72
75
73
—
Scheme 1 Zn-catalyzed A3 coupling reactions.
100
100
last three decades.14 Various multicomponent reactions
involving alkynes have been carried out employing zinc salts in
recent times.15 Kantam et al.15a reported a one-pot synthesis of
propargylamines catalyzed by Zn-dust (Scheme 1, eq. A). Ma
et al.15b reported ZnI2-mediated synthesis of disubstituted
allenes by a three-component coupling reaction involving
alkynes, amines and aldehydes (Scheme 1, eq. B). Few cyclo-
isomerization reactions catalyzed by Zn have also been reported
for the synthesis of varieties of heterocycles.16 Moreover, our
own research found that Zn-salts are to be very efficient catalysts
in promoting various chemical transformations.17 Based on our
own research experiences in Zn catalysis and C–H bond func-
tionalization,18 we thought that Zn could catalyze the three-
component coupling and subsequent cycloisomerization to
provide indolizine moiety. Herein we are pleased to report a
simple and convenient approach to synthesize 1-amino-
indolizines by a three-component coupling (A3) of 2-pyridine
carboxaldehyde, secondary amines,ꢀand terminal alkynes using
ZnI2 as a catalyst in toluene at 100 C (Scheme 1, eq. C).
Reux
Reux
100
Reux
100
100
100
100
100
9
—
10
11
12
13
14
15
16
17
Trace
Trace
<5
<5
90
78
—
—
10
10
100
a
Reaction conditions: 1 mmol of 1a, 1.1 mmol of 2a and 1.2 mmol of 3a
b
in the presence of catalyst in solvent (3 mL) for 1 h. Isolated yields.
amount of catalyst and increasing the amount of catalyst
(15 mol%) did not improve the yield, (Table 1, entry 14) whereas
decreasing the amount of catalyst (5 mol%) decreased the yield
(Table 1, entry 15). Use of inert atmosphere was not benecial
for this transformation. However other Lewis acids such as
anhydrous AlCl3 (10 mol%) and FeCl3 (10 mol%) (Table 1,
entries 16, and 17) did not afford the corresponding products.
Finally optimized reaction conditions was achieved using pyri-
dine-2-carboxaldehyde (1 mmol), morpholine (1.1 mmol) and
Results and discussion
We started our study by choosing pyridine-2-carboxaldehyde phenylacetylene (1.2 mmol) in presence of 10 mol% of zinc
(1a), morpholine (2a), and phenylacetylene (3a) as the model iodide in toluene at 100 ꢀC (Table 1, entry 3) under ambient air.
substrates for this cascade reaction using 10 mol% ZnI2 as the
Keeping the optimized reaction conditions in hand a series
catalyst in toluene for 1 hour at 60 ꢀC. To our delight, the of experiments were performed to verify the general applica-
desired product was obtained in 62% yield. Inspired by this bility of the present methodology, which are summarized in
result, we carried out the reaction employing various zinc salts Table 2. Various phenylacetylene having different substituents
in different solvents as well as varying temperature and the such as –Me (4aab, 4aeb, 4bab), –OMe (4aac, 4bac), –F (4aae) led
results are summarized in Table 1. When the temperature was to the corresponding products in good to excellent yields.
increased to 80 ꢀC and 100 ꢀC, the yields of the reaction Aliphatic alkyne like 1-octyne gave the corresponding indoli-
increased to 75% and 92% respectively (Table 1, entries 2, and zines with moderate yields (4aad, 4abd). It might be due to the
3). However, further increasing the temperature (under reux) instability of the compounds which decomposed quickly during
the yield of the reaction decreased to 82% (Table 1, entry 4). column chromatography. Heteroaryl alkyne, 3-ethynyl thio-
This may be due to the decomposition of the product at higher phene (4aaf) also reacted under the present reaction conditions
temperature. Other Zn salts like ZnCl2, ZnBr2 and Zn(OTf)2 were without any difficulties. Various cyclic and acyclic secondary
not so effective like ZnI2 (Table 1, entries 5–7). Toluene amines, such as piperidine (4abd), dibenzylamine (4ada), and
appeared to be the best choice among the common solvents N-methylaniline (4aca) successfully gave the desired product
such as EtOH, CH3CN, 1,4-dioxane, THF, DMF, DMSO (Table 1, with moderate to excellent yields. Interestingly, thiomorpholine
entries 8–13). 10 mol% ZnI2 was necessary as the optimum afforded the indolizine derivatives (4aea, 4aeb) in high yields
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Table 2 ZnI2-catalyzed synthesis of aminoindolizinesa
Scheme 2 Proposed mechanism.
Fig. 2 Absorbance and fluorescence emission spectra of 4bac in
various solvents (concentration ꢁ 10ꢂ4 mol Lꢂ1). Hex ¼ hexane, Ben ¼
benzene, CB ¼ chlorobenzene, ACN ¼ acetonitrile.
organic light emitting devices (OLEDs). On seeing the long
conjugation of pyrrolo[1,2-a]quinoline moiety, we took interest
in doing photophysical study. Therefore, a preliminary survey of
the photophysical activity of few compounds (4aaa, 4bab, 4bac)
was carried out (see, ESI†). The absorption spectra and emission
spectra of 4bac were recorded in various solvents (Fig. 2). In
absorption spectra, there is no signicant shiing. The char-
acteristic emission band was observed with the maximum
varying between 514 and 541 nm. This morpholinopyrrolo[1,2-a]-
quinoline uorophore exhibited high quantum yield (0.47) in
chlorobenzene and also showed large Stokes shi which is an
attractive property for biological probes. Moreover a distinct
bathochromic (red) shi of the emission maxima was observed
with increasing the polarity of the solvents. This solvatochromic
behaviour which results from the stabilization of polar emitting
state by polar solvents is characteristic for molecules showing
internal charge transfer on excitation.22
a
Reactions conditions: 1 mmol of 1, 1.1 mmol of 2 and 1.2 mmol of 3 in
the presence of ZnI2 (10 mol%) in 3 mL of toluene at 100 ꢀC for 1 h.
Isolated yields.
without deactivation of catalyst. Moreover, quinoline-2-carbox-
aldehyde was also reacted successfully under the optimized
reaction conditions to give the corresponding pyrrolo[1,2-a]-
quinoline derivatives (4bab, 4bac).
A proposed mechanism for this cyclization reaction is rep-
resented in Scheme 2. The rst step is the A3 coupling of pyri-
dine-2-carboxaldehyde, morpholine and phenylacetylene in
presence of catalytic amount of zinc iodide to form the corre-
sponding propargylic pyridine 5 through the iminium inter-
mediate.15b Zn co-ordinates with the triple bond of alkyne to
enhance the electrophilicity. As a result nucleophilic attack by
Conclusions
lone pair on nitrogen atom takes place resulting the formation In summary, we have developed a facile and economic protocol
of 6 which on subsequent deprotonation and demetallation for the one-pot synthesis of the biologically potent indolizine
giving rise to the corresponding 1-amino indolizine.
derivatives by a three-component coupling of pyridine-2-car-
Organic compounds exhibiting intense uorescence are boxaldehyde/quinoline-2-carboxaldehyde, secondary amines,
always in demand as these are used as biological markers,19 and terminal alkynes. The key features of the present protocol
functional organic devices and sensors,20 dyes21 as well as in are wide substrate scope, operational simplicity, shorter
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reaction times, low cost of the catalyst and good to excellent
isolated yields. We believe that our present protocol is the
simplest and a convenient way to synthesize indolizine scaf-
folds. Furthermore, morpholinopyrrolo[1,2-a]quinolines repre-
sent a new class of uorophore with high quantum yields.
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Acknowledgements
A. H. acknowledges the nancial support from the Department
of Science and Technology, Govt. of India (Grant no. SR/S5/GC-
´
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