CuCl catalyzed green and efficient one-pot synthesis of aminoindolizine frameworks via three-component reactions of aldehydes, secondary amines, and terminal alkynes in PEG

Article abstract of DOI:10.1016/j.tetlet.2012.07.113

CuCl catalyzes efficient synthesis of aminoindolizine scaffolds by one-pot reactions in PEG of pyridine- or quinoline-2-carboxaldehydes with secondary amines and terminal alkynes via tandem C-H activation, coupling, and cyclization reactions. The reaction

Full text of DOI:10.1016/j.tetlet.2012.07.113

Tetrahedron Letters 53 (2012) 5483–5487
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
CuCl catalyzed green and efficient one-pot synthesis of aminoindolizine
frameworks via three-component reactions of aldehydes, secondary amines,
and terminal alkynes in PEG
⇑
Sarita Mishra, Bikramaditya Naskar, Rina Ghosh
Department of Chemistry, Jadavpur University, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
CuCl catalyzes efficient synthesis of aminoindolizine scaffolds by one-pot reactions in PEG of pyridine- or
quinoline-2-carboxaldehydes with secondary amines and terminal alkynes via tandem C–H activation,
coupling, and cyclization reactions. The reactions are easy to perform, atom-economic, environment
friendly, broad in scope, and allow the generation of a number of biologically potent aminoindolizine
frameworks from readily accessible starting materials.
Received 14 June 2012
Revised 23 July 2012
Accepted 26 July 2012
Available online 7 August 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
PEG
Heterocycles
Cyclization
Coupling
Aminoindolizidines
The demand for protocol efficiency and green credentials in or-
ganic synthesis can only be met through innovative research. Reac-
tion procedures are expected to comprehensively address the
issues of atom-economy, number of steps, and the avoidance of
auxiliary chemicals.1 Multi component reaction protocols in envi-
ronmentally benign solvents coupled with the use of catalytic re-
pid peroxidase inhibition),7f calcium entry blocker,7g histamine
H3 receptor antagonist,7h and 5-HT1A receptor ligand.7i The nu-
cleus has also been shown to have senescence delaying proper-
ties,8a anti-HIV8b and anti-herpes8c activities. It even shows
active cardiovascular properties8d and is a CNS depression agent.8e
Indolizines have the ability to reverse multi-drug resistance8f and
induce apoptosis through a mitochondrial pathway against a broad
range of cancer cell lines.8g
Given the amount of applicability this framework commands on
both medicinal as well as industrial aspects. It is hardly an exagger-
ation to state that considerable effort has already been devoted to-
ward efficient synthesis of this nucleus. In this connection the
synthesis of amino indolizines has attracted much attention. Sev-
eral synthetic protocols for the synthesis of indolizines have been
reported in the literature.9 Some of the methods worth noting
are Chichibabin reaction of 1-(ethoxycarbonylmethyl)-2-meth-
ylpyridinium chloride;9a 1,3 dipolar cycloaddition of a reactive
agent systems offer
a suitable strategy to meet the green
requirements while developing libraries of medicinal scaffolds.2
Polyethylene glycol happens to be one such solvent which meets
the aforesaid requirements. This is on account of the fact that it
is water soluble, thermally stable over a wide range of tempera-
ture, insensitive to variation in catalytic systems, non-volatile
and non-explosive by nature, commercially available, immiscible
with a number of organic solvents, and non-toxic.3 As a result
numerous organic reactions utilizing PEG as solvent medium
may be found in the literature pertaining to synthetic
methodology.4
The indolizine nucleus is a noteworthy motif because it is found
as a key constituent in many bioactive compounds, some of which
are naturally occurring5,6 while others are only synthetically acces-
sible. Besides, the indolizine nucleus has already established itself
as a potent pharmacophore exhibiting multiple pharmacological
properties7 (Fig. 1) like anti-inflammatory,7a anti-convulsant,7b
anti-tubercular,7c anti-leishmanial,7d herbicidal,7e anti-oxidant (li-
H
Me
N
O
CN
N
N
N
N
O
MeO
N
N
5-HTIA receptor antagonist
O
O
N
O
O
O
N
N
Anticonvulsant and
O
histamine H3 receptor antagonist
antiinflammatory activity
PDE5A inhibitor
⇑
Corresponding author. Fax: +91 033 2414 6266.
E-mail addresses: ghosh_rina@hotmail.com, ghoshrina@yahoo.com (R. Ghosh).
Figure 1. Pharmacologically potent indolizine scaffolds.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.113

5484
S. Mishra et al. / Tetrahedron Letters 53 (2012) 5483–5487
R1
N
CuCl in polyethylene glycol (PEG), and the results are summarized
in Scheme 1, Tables 1 and 2.
R2
R1
R2
CHO
+
10 mol % CuCl
PEG, 90 0C
3-4 h, N2
R3
Keeping the coupling of pyridine-2-carboxaldehyde, morpho-
line, and phenylacetylene as our model reaction a series of exper-
iments were carried out with the aim of devising an improved
catalyst system to reach the desired 1-aminoindolizine scaffold.
We screened quite a few metal catalysts which included FeCl3, In(-
OTf)3, and some salts of copper (I and II) such as its triflate, acetate,
halides, and oxide (Table 1, entries 1–15). While FeCl3 in toluene
(entry 1) altogether failed to yield the desired target, and In(OTf)3
in toluene afforded the corresponding product in 50% yield (Table 1,
entry 2), Cu(OTf)2 and CuCl proved promising in their catalytic
activity keeping toluene as the reaction medium. In between the
two aforesaid copper salts Cu(OTf)2 was found to give better yields
of 1-aminoindolizine. In order to give due regard to the green cre-
dentials as well as to the eco safety of the protocol we shifted our
solvent from toluene to PEG. We observed quite interestingly, that
CuCl surpassed Cu(OTf)2 in terms of the yield of the product gener-
ated (entries 4 and 7). Alternative solvents like CH3CN and DCE
(Table 1, entries 13 and14) were also tested (for the model reac-
tion) but better results were obtained using 10 mol % of CuCl in
PEG medium (entries 7 and 12–17). However, CuCl could not cat-
alyze our model reaction at room temperature. Decreasing the cat-
alyst load of CuCl from 10 to 5 mol % decreases the yield of 4b
considerably (Table 1, entry 16).
Thus, under the optimized reaction condition pyridine-2-car-
boxaldehyde (1a, 1.0 mmol), morpholine (1.2 mmol), and phenyl-
acetylene (1.5 mmol) in the presence of 10 mol % of CuCl in PEG
at 90 °C afforded the corresponding 1-aminoindolizine product
(4a) in excellent yield (Table 2, entry 1). With the optimized
reaction conditions in hand, the generality of the protocol was
assessed by the synthesis of diversely substituted 1-aminoindoli-
zines. This was achieved through variations (in the starting
materials) between pyridine-2-carboxaldehyde (1a) and quino-
line-2-carboxaldehyde (2b) and their reactions with various sec-
ondary amines and a number of different terminal alkynes.
Initially, keeping the first two components pyridine-2-carboxal-
NH
2
+
N
N
R3
3
1
4a-4o
(63-96 %)
Scheme 1. One-pot multicomponent synthesis of 1-aminoindolizines.
dipole prepared from a substituted pyridinium salt and alkyne;9b
silver catalyzed cycloisomerization of propargyl heterocycles;9c
gold catalyzed migratory cycloisomerization of propargyl ether
into various types of 1,2-disubstituted N-fused heterocycles;9d
Pd-mediated coupling of aryl halide with propargylic esters or
ethers followed by cyclization;9e Cu-catalyzed reaction of pyridine
and alkenyldiazoacetates;9f low temperature organo-copper medi-
ated cross coupling/cycloisomerization of heterocyclic propargyl
mesylates;9g Pd/Cu activated sequential cross coupling/cycloiso-
merization reactions of propargyl amines or amides with hetero-
aryl bromide;9h Pd catalyzed intramolecular carbopalladation/
cyclization of propargylic ethers or esters;9i microwave assisted
three-component reaction of acyl bromide, pyridine, and acety-
lene9j and three-component coupling of pyridine-2-carboxalde-
hyde, amine, and terminal alkyne (Au,10a AgBF4
or Fe(acac)3/
10b
TBAOH10c-catalyzed). One of the most convenient approaches
amongst the aforesaid methods that attracted our attention was
the three-component coupling of aldehydes, amines, and terminal
acetylenes to form the highly potent aminoindolizines developed
by Yan and Liu10a since such compounds are yet underexplored
in terms of biological activities. It is indeed worth noting at this
point that Cu-catalyzed reactions4f,11,12b have generated consider-
able interest over the past decade for three-component coupling/
cyclization of aldehydes, amines, and alkynes. In continuation of
our work on synthesis of heterocycles12 we report herein, an effi-
cient, green, one pot method for the synthesis of 1-aminoindoli-
zines and analogs via three-component coupling/cyclization of
aldehydes, secondary amines, and terminal alkynes catalyzed by
Table 1
Screening of the catalyst and solvent in one-pot synthesis of 1-morpholinylindolizine
O
O
N
CHO
Catalyst
+
+
Ph
N
N
H
Solvent
N
Temp.
Ph
Entry
Catalysta
Solvent
Condition
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
FeCl3
Toluene
Toluene
Toluene
PEG
PEG
PEG
PEG
PEG
PEG
PEG
Reflux
Reflux
Reflux
90 °C
90 °C
90 °C
90 °C
90 °C
90 °C
90 °C
90 °C
Reflux
Reflux
Reflux
rt
12
12
3
3
3
3
3
3
3
6
4
4
4
4
24
4
—
50
75
82
80
80
96
82
70
—
61
62
65
50
—
In(OTf)3
Cu(OTf)2
Cu(OTf)2
CuSO4
CuI
CuCl
CuBr
CuCl2
CuO
Cu(OAc)2
CuCl
PEG
Toluene
CH3CN
DCE
PEG
PEG
CuCl
CuCl
CuCl
CuClc
CuCl
90 °C
90 °C
70
45
H2O
3
a
b
c
10 mol % of all the catalysts was used.
Standardization of reaction conditions: Pyridine-2-carboxaldehye (1.0 mmol), morpholine (1.2 mmol), and phenylacetylene (1.5 mmol) under N2 atmosphere.
5 mol % CuCl was used.

S. Mishra et al. / Tetrahedron Letters 53 (2012) 5483–5487
5485
Table 2
One-pot synthesis of aminoindolizines13,14
R1
N
R2
R1
R2
CHO
+
10 mol % CuCl
PEG, 90 0
3-4 h, N2
R3
NH
+
N
N
C
R3
3
2
1
4
Entry
1
Aldehyde
Amine
Alkyne
Product
Time (h)
3
Yielda,b (%)
O
Ph
4a
96 (96,10a 91,10b 8310c
)
N
1a
CHO
N
2a
H
2
3
4
5
6
1a
2a
4-Me-Ph
4-F-Ph
4-Cl-Ph
Biphenyl
C6H13
4b
4c
4d
4e
4f
3
3
3
4
4
92 (90,10b 8310c
)
1a
1a
1a
1a
2a
2a
2a
2a
85
89
78
73
7
8
1a
1a
4-Cl-Ph
C6H13
4g
4h
3
3
85 (88,10a 7210c
)
N
2b
H
2b
70 (6610a
85
)
9
1a
Ph
4i
3
N
H
2d
Ph
10
11
1a
1a
Ph
4j
4
4
71 (2810a
81
)
2e
NH
Me
2e
4-Me-Ph
4k
NH
HN
12
1ac
Ph
4ld
3
63 (52,10a 5710c
)
g
2
O
13
14
15
Ph
4m
4n
4o
4
3
4
90 (8810b
92
)
N
CHO
N
H
2a
2a
1b
1b
1b
4-Me-Ph
Ph
90 (74,10a 7010c
)
N
H
2b
a
b
c
Yield of isolated pure product.
Yield of reported compounds are listed in the parentheses with corresponding references.
1a (2 equiv), 2g (1.2 equiv), and phenylacetylene (1.5 equiv).
Bis-indolizine.
d
dehyde and morpholine of our model reaction intact, we varied
the substitution pattern on the phenyl group of the phenylacet-
ylene. It was found that groups having +I effect (entry 2) or +R
effects (Table 2, entries 3 and 4) as well as ÀI effect (entry 5)
led to the corresponding products in good to excellent yields.
Aliphatic terminal alkyne like 1-octyne was found to react
uneventfully with pyridine-2-carboxaldehyde (1a) and morpho-
line generating the corresponding product in 73% yield (Table 2,
entry 6). Cyclic amines like piperidine coupled with pyridine-2-
carboxaldehyde (1a) and terminal alkynes like 4-chlorophenyl-
acetylene (entry 7) and 1-octyne (entry 8) to give the respective
products, 4g in comparable yield to that reported earlier10a and
4h in much improved yield in comparison to the reported one.10c
Both dicyclohexylamine (2d, entry 9) and methylphenylamine
(2e, entry 10) reacted fruitfully with pyridine-2-carboxaldehyde
(1a) and phenylacetylene pair to afford the corresponding prod-
ucts in good yields; it is worthy to note that product 4j (entry
10) was obtained in much better yield (71%) compared to that
(28%) obtained before.10a Methylphenylamine (2e) also reacted
successfully with pyridine-2-carboxaldehyde and 4-methyl phen-
ylacetylene to produce the corresponding product in high yield
(Table 2, entry 11). Of specific note was the coupling of pipera-
zine with 1a and phenylacetylene resulting in the corresponding
bis-indolizine moiety 4l in good yield (entry 12) which was bet-
ter than those reported earlier.10a,c Similarly, quinoline-2-carbox-
aldehyde was also coupled fruitfully under the optimized
protocol with morpholine/piperidine (Table 2, entry 13/15) in
the presence of phenylacetylene to give the corresponding prod-
ucts, 4m in comparable yield (entry 13) with respect to that pro-
duced by the reported method based on morpholine10b but 4o in
much better yield (entry 15) compared to those reported before
based on piperidine.10a,c The yield of the product was not af-
fected upon shifting to 4-methylphenylacetylene (Table 2, entry
14).
Single crystal X-ray analysis conclusively confirmed the struc-
ture of the isolated 1-aminoindolizine (4b) product.15 An ORTEP
diagram of 4b is shown in Figure 2.
The formation of aminoindolizine can be explained by a tenta-
tive mechanism (Scheme 2) in which probably the activation of
C–H bond of phenylacetylene by CuCl is taking place and the cop-

5486
S. Mishra et al. / Tetrahedron Letters 53 (2012) 5483–5487
Acknowledgments
S.M. (SRF) and B.N. (JRF) are grateful to UGC and CSIR, India,
respectively for their research fellowships. CAS-UGC and FIST-
DST, New Delhi, India are acknowledged for supporting research
facilities to the Department of Chemistry, Jadavpur University.
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O
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CuCl
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A
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B
H2O
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Cyclisation
-
O
Cl
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N
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N
H
-H+
Cu
Ph
N
+
D
N
CuCl
+H+
Ph
Ph
H
4a
3a
Scheme 2. Proposed mechanism.
per acetylide intermediate A is generated. A reacts with iminium
ion B, in situ generated by the reaction of pyridine-2-carboxalde-
hyde (1a) with morpholine (2a), producing the corresponding
propargylamine C. It then undergoes cyclization (5 endo-dig) to
give finally 1-morpholinylindolizine product (4a).
In summary, a facile, economic, and green protocol for a one-pot
multicomponent synthesis of the biologically potent indolizine
scaffold has been described by the reaction of pyridine-2-carboxal-
dehyde/quinoline-2-carboxaldehyde, secondary amines, and ter-
minal alkynes. The salient features in favor of the present
procedure being greater operational simplicity, low reaction time,
and general high isolated yields of products. In addition, the use
of a non-toxic and inexpensive catalytic system and a non-hazard-
ous solvent system greatly augments the green credentials of the
present protocol for its further ramification for large scale produc-
tion of these pharmacologically potent heterocyclic compounds.
Biological screening of some of the tailor-made aminoindolizines
and analogs is underway for future publication.
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1H NMR (500 MHz, C6D6): d 7.72 (d, J = 7.0 Hz, 1H), 7.44 (d, J = 9.0 Hz,1H), 7.07
(dd, J = 5.5 Hz, 8.0 Hz, 2H), 6.83 (d, J = 5.1 Hz, 2H), 6.55 (s, 1H), 6.36 (dd,
J = 6.5 Hz, 8.5 Hz, 1H), 6.06 (t, J = 6.5 Hz, 1H), 3.77 (t, J = 4.5 Hz, 4H), 2.88 (t,
J = 4.5 Hz, 4H). 13C NMR (125 MHz, C6D6): d = 130.3, 129.8, 129.7, 128.84,
128.82, 125.8, 121.6, 121.4, 118.0, 115.9, 115.8, 114.7, 111.0, 106.2, 67.3, 54.5.
IR (KBr) (m
max/cmÀ1): 2978, 2863, 2826, 1627, 1517, 1451, 1431, 1306, 1222,
1111. ESI-HRMS: Calcd for C18H18FN2O [M+H]+: 297.1403. Found: 297.1398.
3-(Biphenyl)-1-(morpholin-4-yl)indolizine (4e): Yellow solid, mp 168–169 °C.
1H NMR (500 MHz, C6D6): d 7.98 (d, J = 7.0 Hz, 1H), 7.52 (q, J = = 8.0 Hz, 4H),
7.45 (d, J = 8.5 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.26 (t, J = = 7.5 Hz, 2H), 7.16–
7.18 (m, 1H), 6.72 (s, 1H), 6.36 (dd, J = 6.5 Hz, 8.5 Hz, 1H), 6.08 (t, J = 7.0 Hz,
1H), 3.76 (t, J = 4.5 Hz, 4H), 2.89 (t , J = 4.0 Hz, 4H). 13C NMR (125 MHz, C6D6): d
140.9, 139.7, 131.8, 130.6, 128.97, 128.3, 127.4, 127.1, 126.2, 122.5, 121.8,
118.1, 114.8, 111.0, 106.3, 63.4, 54.5. IR (KBr) (m
max/cmÀ1): 2948, 2976, 2863,
2806, 1608, 1527, 1432, 1258, 1111, 1074. ESI-HRMS: Calcd for C24H22N2O
[M]+: 354.1732. Found: 354.1733.
13. Typical experimental procedure: Pyridine-2-carboxaldehye (107.12 mg,
1.0 mmol), CuCl (9.9 mg, 0.1 mmol), morpholine (104.5 mg, 1.2 mmol), and
phenylacetylene (153.2 mg, 0.16 mL, 1.5 mmol) were sequentially taken in a
10 mL flask followed by PEG (2 mL). The resulting reaction mixture was then
stirred at 90 °C in oil bath under N2 atmosphere until completion of the
reaction (3 h, as monitored by TLC). Cold water (40 mL) was added to the
reaction mixture, and the product was extracted with ethyl acetate
(3 Â 20 mL). The organic layer was washed with water, dried over anhydrous
Na2SO4, and then the solvent was evaporated under vacuum. The crude
product obtained was purified by flash chromatography on silica gel column
(230–400 mesh) using ethyl acetate-petroleum ether as eluent to afford the
pure indolizine product (4a, 267 mg, 96% yield). Spectroscopic data (IR, 1H
NMR, 13C NMR and HRMS) are in good agreement with the product structure.
This procedure was followed for the synthesis of all other 1-amino indolizine
derivatives and their analogs (4b–4o), Table 2).
N-Methyl-N-phenyl-[3-(4-methylphenyl)-indolizin-1-yl]amine (4l): Yellow solid;
mp 91 °C 1H NMR (500 MHz, C6D6): d 7.96 (d, J = 7.5 Hz, 1H), 7.26 (d, J = 7.5 Hz,
2H), 7.17 (t, J = 7.8 Hz, 2H), 7.10 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 8.0 Hz, 2H), 6.82
(d, J = 8.0 Hz, 2H), 6.77 (t, J = 7.0 Hz, 1H), 6.68 (s, 1H), 6.26 (dd, J = 6.5 Hz,
8.5 Hz, 1H), 6.00 (t, J = 6.8 Hz, 1H), 3.11 (s, 3H), 2.12 (s, 3H). 13C NMR (125 MHz,
C6D6): d 150.5, 136.6, 129.62, 129.55, 129.0, 128.4, 128.1, 124.0, 123.3, 122.0,
117.6, 117.1, 116.2, 113.4, 111.9, 110.6, 40.4, 20.9. IR (KBr) (m
max/cmÀ1): 3098,
3058, 2994, 2806, 2363, 1925, 1596, 1523, 1499, 1432, 1345, 1297, 1109. ESI-
HRMS: Calcd for C22H20N2 [M]+: 312.1626. Found: 312.1627.
14. The aminoindolizines and analogs (4a–4o) were found to decompose at room
temperature, indicated by a change of coloration from yellow to brown when
exposed to air.
15. Crystallographic data (excluding structure factor) for 4b have been deposited
with the Cambridge Crystallographic Data Centre as Supplementary
Publication No. CCDC 886132. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 IEZ, UK (fax:
+44 (0) 1223336033 or e-mail: deposit@ccdc.cam.ac.UK).
Characterization data of some representative compounds:
3-(4-Flurophenyl)-1-(morpholin-4-yl)indolizine (4c): Yellow solid; mp 78–80 °C.