Synthesis of indolizines and heterocyclic chalcones catalyzed by supported copper nanoparticles

Article abstract of DOI:10.1002/chem.201204305

Solvent decides: Versatile copper nanoparticles (Cu NPs) on activated carbon have been found to catalyze the multicomponent synthesis of indolizines in dichloromethane and the synthesis of heterocyclic chalcones in the absence of solvent, in both cases, f

Full text of DOI:10.1002/chem.201204305

DOI: 10.1002/chem.201204305
Synthesis of Indolizines and Heterocyclic Chalcones Catalyzed by Supported
Copper Nanoparticles
Marꢀa Josꢁ Albaladejo, Francisco Alonso,* and Miguel Yus[a]
Dedicated to Professor Irina P. Beletskaya on the occasion of her 80th birthday
The indolizine ring system is an important skeleton in
natural-product synthesis,[1] as well as in pharmaceutics, in
which it is associated with a wide range of biological activi-
ties including anticancer, antibacterial, antifungal, anti-
inflammatory, anticholinergic, antihistaminic, antimicrobial,
anticonvulsant, antitubercular, antioxidant, or analgesic ac-
tivity, among others.[2] In recent years, to obtain the indoli-
zine moiety, besides the classical synthetic methods,[3] the
iodine-mediated[4] and transition-metal catalyzed[5] ap-
proaches by carbon–nitrogen bond-forming reactions have
attracted the interest of different groups. In particular, the
transition-metal catalyzed cycloisomerization of pyridines
containing alkynyl, propargyl, allenyl, or cyclopropenyl sub-
stituents at the 2 position, developed by Gevorgyan et al.,
are praiseworthy.[5b] Several methodologies based on two-
component annulations catalyzed by copper have also been
described recently.[6] On the other hand, the multicompo-
nent synthesis of heterocycles is a powerful tool, which
allows structural diversity and complexity in a single opera-
tion and atom-efficient manner.[7] In this context, the multi-
component synthesis of indolizines from 2-pyridinecarbalde-
hyde derivatives, secondary amines, and terminal alkynes
has been reported under gold,[8] silver,[9] and iron[10] catalysis.
But to the best of our knowledge, this type of reaction has
never been studied under copper catalysis.[11] Herein, we
present the first methodology for the copper-catalyzed mul-
ticomponent synthesis of indolizines from 2-pyridinecarb-
The copper catalysts were prepared by addition of a varie-
ty of supports to a suspension of the recently prepared
CuNPs, readily generated in turn from anhydrous copper(II)
chloride, lithium metal, and a catalytic amount of 4,4’-di-
tert-butylbiphenyl (DTBB, 10 mol%) in THF at room tem-
perature;[13] the supported catalysts were not subjected to
any treatment prior to use. A screening was carried out to
optimize the catalyst support, solvent, and conditions, by re-
acting pyridine-2-carbaldehyde (1a), piperidine (2a), and
phenylacetylene (3a; Table 1). THF, H2O, MeOH, EtOH,
PhMe, CHCl3, ClCH2CH2Cl, or MeCN were found to be in-
appropriate solvents, with only CH2Cl2 providing variable
Table 1. Screening of the catalysts in the synthesis of 4aaa.[a]
Entry
Catalyst
Conversion [%][b]
1
2
3
4
5
6
7
8
none
1
CuNPs/C[c]
CuNPs/graphite
CuNPs/MWCNT[d]
CuNPs/SiO2
CuNPs/TiO2
CuNPs/MgO
CuNPs/ZnO
CuNPs/zeolite Y
CuNPs/montmorillonite K10
CuNPs/cellulose
CuNPs/chitosan
CuNPs[e]
92 (3)
72
84
57
68 (2)
15 (21)
57
65 (13)
21
85 (72)
65
4
60
27
55
28
ACHTUNGTRENNUNGaldehyde derivatives, secondary amines, and terminal al-
kynes, as part of our ongoing interest in the application of
supported copper nanoparticles (CuNPs) in organic chemis-
try.[12] Interestingly, the same starting materials and catalyst
used for this purpose gave heterocyclic chalcones in the ab-
sence of solvent. Moreover, the highly diastereoselective
transformation of indolizines into indolizidines by catalytic
hydrogenation is also presented.
9
10
11
12
13
14
15
16
17
18
19
20
CuNPs
CuCl
CuCl2
CuBr
CuI
CuO
Cu2O
50
55
57
[a] M. J. Albaladejo, Dr. F. Alonso, Prof. M. Yus
Departamento de Quꢀmica Orgꢁnica
Facultad de Ciencias and Instituto de Sꢀntesis Orgꢁnica (ISO)
Universidad de Alicante, Apdo. 99, 03080 Alicante (Spain)
Fax : (+34)965 903549
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), 3a (0.5 mmol),
catalyst (20 mg, entries 2–12; 10 mol%, entries 13 and 14; 1 mol%,
entries 13–18), CH2Cl2 (1 mL), 708C (reaction at 508C in parentheses),
20 h. [b] Conversion into 4aaa was determined by GC. [c] 0.5 mol%, 3h
reaction time. [d] Multi-walled carbon nanotube. [e] THF (1 mL) as
solvent.
E-mail: falonso@ua.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204305.
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Chem. Eur. J. 2013, 19, 5242 – 5245

COMMUNICATION
degree of conversion into 4aaa depending on the support
(Table 1). A control experiment at 708C in the absence of
catalyst gave a trace of the expected product (Table 1,
entry 1), whereas CuNPs on different carbon supports and
cellulose gave the best results, with the latter showing good
performance even at 508C (Table 1, entries 2, 3, 4, and 11).
CuNPs/C (CuNPs on activated carbon) was the catalyst of
choice due to its best performance also in the synthesis of
chalcones (see below) and to the fact that it was previously
fully characterized.[13] The supported nanostructured catalyst
exhibited superior behavior in the synthesis of indolizine
4aaa compared with unsupported CuNPs (Table 1, en-
tries 13 and 14) or commercial bulk copper catalysts
(Table 1, entries 15–20).
The optimized conditions were extended to the synthesis
of a wide range of indolizines in moderate-to-high yields
(59–93%) by using low catalyst loading (0.5 mol%)
(Table 2). Pyridine-2-carbaldehyde (1a) was successfully
combined with different secondary amines (2a–e) and phe-
nylacetylene (3a), as well as with piperidine (2a), and a va-
riety of aryl acetylenes containing either electron-withdraw-
ing or -releasing substituents (4aab–aag). However, aliphatic
alkynes were somewhat reluctant to react (4ach). The meth-
odology was proven to be equally effective for quinoline-2-
carbaldehyde (1b) to give the corresponding pyrrolo
ACHTUNGTRENNUNG[1,2-a]-
AHCTUNGTRENNUNG
havior observed for CuNPs/C in other multicomponent re-
actions,[13] in the present case, reutilization was inefficient
due to leaching and/or catalyst poisoning.[14] This fact is not
so important, if we take into account the low copper loading
used in the experiments.
Furthermore, we discovered that the standard procedure
for the synthesis of indolizines, in the presence of the amine
and the absence of solvent, produced the heterocyclic chal-
cones 5 in moderate yields with exclusive E stereochemistry
(see some selected examples in Table 3). It has been recent-
ly disclosed that pyridin-2-yl chalcones possess strong anti-
bacterial activity against both susceptible and resistant
Staphylococcus aureus strains.[15] The synthesis of hetero-
AHCTUNGTREGcNNUN yclic chalcones from pyridin-2-carbaldehyde derivatives
Table 2. Multicomponent synthesis of indolizines catalyzed by CuNPs/C.[a]
[a] Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), 3 (0.5 mmol), CuNPs/C (20 mg, 0.5 mol%), CH2Cl2 (1 mL), 708C; reaction time and isolated yield
in parentheses; Bn=benzyl.
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F. Alonso et al.
Table 3. Synthesis of heterocyclic chalcones 5 catalyzed by CuNPs/C.[a]
tions. Apparently, this is the first time that copper has been
shown to catalyze these two processes. In addition, we have
devised a route to a new type of indolizidines by combining
the multicomponent synthesis of indolizines with a highly
diastereoselective catalytic hydrogenation. Further research
on the scope and mechanism[18] of the copper-catalyzed reac-
tions, as well as on the scope of the catalytic hydrogenation,
are under way.
Acknowledgements
This work was generously supported by the Spanish Ministerio de Econo-
mꢀa y Competitividad (MINECO; CTQ2007-65218, CTQ2011-24151, and
Consolider Ingenio 2010-CSD2007-00006), the Generalitat Valenciana
(GV; PROMETEO/2009/039), and FEDER. Y.M. acknowledges the ISO
of the Universidad de Alicante for a grant.
Keywords: chalcones
·
copper
·
indolizines
·
multicomponent reactions
heterocycles
·
nanoparticles
·
nitrogen
[a] Reaction conditions:
1 (0.5 mmol), 3 (0.5 mmol), piperidine (2a,
0.5 mmol) CuNPs/C (20 mg, 0.5 mol%), neat, 708C; reaction time and
isolated yield in parentheses.
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In short, we have unveiled CuNPs/C as a versatile cata-
lyst, which allowed the multicomponent synthesis of indoli-
zines (from pyridine-2-carbaldehyde derivatives, secondary
amines, and terminal alkynes) in dichloromethane and the
synthesis of heterocyclic chalcones under solvent-free condi-
which the reaction of trimethylsilylACTHNUGTRNEUNG(phenyl)acetylene (an internal
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Synthesis of Indolizines and Heterocyclic Chalcones
COMMUNICATION
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(aldehyde–amine–alkyne) coupling, giving
a propargyl amine
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[14] In a second cycle: 40% yield. Reutilization of any of the catalysts in
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Received: December 4, 2012
Revised: February 8, 2013
Published online: March 7, 2013
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