Synthetic and mechanistic studies on the solvent-dependent copper-catalyzed formation of indolizines and chalcones

Article abstract of DOI:10.1021/acscatal.5b00417

Copper nanoparticles supported on activated carbon have been found to catalyze the multicomponent synthesis of indolizines from pyridine-2-carbaldehyde derivatives, secondary amines, and terminal alkynes in dichloromethane; in the absence of solvent, howe

Full text of DOI:10.1021/acscatal.5b00417

Research Article
pubs.acs.org/acscatalysis
Synthetic and Mechanistic Studies on the Solvent-Dependent
Copper-Catalyzed Formation of Indolizines and Chalcones
María Jose Albaladejo,† Francisco Alonso,* and María Jose Gonzalez-Soria
́
́
́
Departamento de Química Organ
99, E 03080 Alicante, Spain
́ ́
ica, Facultad de Ciencias and Instituto de Síntesis Organica (ISO), Universidad de Alicante, Apdo.
S
* Supporting Information
ABSTRACT: Copper nanoparticles supported on activated
carbon have been found to catalyze the multicomponent
synthesis of indolizines from pyridine-2-carbaldehyde deriva-
tives, secondary amines, and terminal alkynes in dichloro-
methane; in the absence of solvent, however, heterocyclic
chalcones are formed. We provide compelling evidence that
both processes take place through aldehyde−amine−alkyne
coupling intermediates. In contrast to other well-known mechanisms for chalcone formation from aldehydes and alkynes, a new
reaction pathway involving propargyl amines as intermediates that do not undergo rearrangement is presented. The formation of
indolizines or chalcones is driven by inductive and solvent effects, with a wide array of both being reported. In both reactions, the
nanoparticulate catalyst has been shown to be superior to some commercially available copper catalysts, and it could be recycled
in the case of the chalcone synthesis.
KEYWORDS: chalcones, copper nanoparticles, indolizines, multicomponent reactions, nitrogen heterocycles, propargylamines,
reaction mechanisms
position. Some methods based on two-component annulations
catalyzed by copper have also been reported.9 However, the
multicomponent reaction of 2-pyridinecarbaldehyde derivatives,
secondary amines, and terminal alkynes has emerged as a
powerful tool whereby the synthesis of indolizines can be
attained in a single operation and atom-efficient manner.
Catalytic processes with gold,10 silver,11 iron,12 copper,13 and
zinc14 have been described for this purpose.
INTRODUCTION
■
Indolizines1 and chalcones2 share a large variety of pharmaco-
logical activities, including anticancer, antibacterial, antifungal,
anti-inflammatory, antitubercular, antioxidant, or analgesic
activity, among others (Chart 1). In particular, some
Chart 1. Structure of Some Bioactive Indolizines and
Heterocyclic Chalcones
Chalcone synthesis is normally accomplished following the
classical Claisen−Schmidt condensation between aromatic
ketones and aldehydes (Scheme 1, eq 1);15a other methods,
such as the Suzuki coupling, Friedel−Crafts acylation, or Julia-
Kocienski olefination, have been also practiced.15b Propargyl
alcohol derivatives16 have been used as chalcone precursors by
isomerization to the corresponding enones (Scheme 1, eq
2)16a−c,e or through the Meyer−Schuster rearrangement17
(Scheme 1, eq 3).16d,f More interesting is the direct reaction
of aromatic aldehydes and alkynes to furnish chalcones.
Ytterbium(III) triflate,18a Amberlyst-15,18b or graphite oxide18c
have been found to promote the latter transformation with
rearrangement (Scheme 1, eq 4), whereas the solid base
Cs2CO3/Al2O319a or the quaternary ammonium hydroxide base
Triton B19b produced the nonrearranged products (Scheme 1,
eq 5). More recently, propargyl amines derived from
fluorinated aldehydes, m- and p-nitroaniline, and phenyl-
acetylene gave the rearranged chalcone when irradiated with
heterocyclic chalcones have been recently shown to possess
prominent antibacterial activity.3 The indolizine system is also
an important scaffold in natural product synthesis,4 whereas in
recent years, chalcones have been studied in materials science
because of their interesting photophysical properties.5
Indolizines have been synthesized following classical
methods6 or by iodine-mediated7 and transition-metal-
catalyzed8 cycloisomerization of pyridines bearing alkynyl,
propargyl, allenyl, or cyclopropenyl substituents at the 2
Received: February 26, 2015
Revised: April 24, 2015
© XXXX American Chemical Society
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Scheme 1. Different Methods for Chalcone Synthesis
microwaves in the presence of montmorillonite doped with
copper(I) chloride (Scheme 1, eq 6).20 It was considered that
the nitroaniline moiety acted as a good leaving group,
generating allenic cation species that led to the chalcone after
reaction with water, in a manner similar to that which was
invoked for propargyl alcohol derivatives (Scheme 1, eq
3).16d,f,17
In organic chemistry, selective transformations of the same
starting materials into two or more different products can be
done by the choice of the catalyst.21 More challenging is to
reach the same objective conversely, by deploying a single
catalyst but different solvent systems. Owing to our interest in
metal colloids22 and the application of supported copper
nanoparticles (CuNPs) in organic chemistry,23 we have
recently communicated the multicomponent synthesis of
indolizines from pyridine-2-carbaldehyde derivatives, secondary
amines, and terminal alkynes catalyzed by copper nanoparticles
on activated carbon in dichloromethane (Scheme 2).24
reduction of anhydrous copper(II) chloride with lithium metal
and a catalytic amount of 4,4′-di-tert-butylbiphenyl (DTBB, 10
mol %) in THF at room temperature;26 the supported catalysts
were not subjected to any treatment prior to use.
Synthesis of Indolizines. The metal support, solvent and
conditions were previously optimized using pyridine-2-
carbaldehyde (1a), piperidine (2a) and phenylacetylene (3a)
as model compounds; oxidized copper nanoparticles (Cu2O
and CuO) on activated carbon (CuNPs/C) was found to be
the catalyst of choice in dichloromethane at 70 °C.24 With the
optimized conditions in hand, a wide range of indolizines were
synthesized in modest-to-high isolated yields by using low
catalyst loading (0.5 mol %) (Table 1). Pyridine-2-carbalde-
hyde (1a) was successfully combined with six different
secondary amines (2a−f) and seven aryl acetylenes containing
electron-neutral, -withdrawing, or -releasing substituents (3a−
g). Aliphatic alkynes (3h, 3i) were found to be more reluctant
to react, leading to the expected indolizines (4afh, 4afi, 4ach)
in relatively lower yields (42−64%) because of partial
decomposition during chromatographic purification. Likewise,
reactions with pyridine-2-carbaldehydes substituted at the 6
position (1b−d) required prolonged heating, probably for
steric reasons. Poor yield was noted for the 5-bromoindolizine
4bfa as a result of the major formation of the A3 coupling
product; however, we could make use of this result to prove the
reaction mechanism (vide infra). This methodology was also
effectual when applied to quinoline-2-carbaldehyde (1e), giving
the corresponding pyrrolo[1,2-a]quinolines 4eaa−eag in good-
to-high isolated yields (72−92%). Unfortunately, this catalyst,
which showed good recycling properties in other multi-
component reactions,25 could not be efficiently recycled in
the present case (40% yield in a second cycle). The substantial
metal leaching observed, together with the possible catalyst
poisoning, could account for this behavior. This fact is not so
important if we take into account that the copper loading used
in these experiments is low.
Scheme 2. Synthesis of Indolizines and Chalcones Catalyzed
by CuNPs/C
Interestingly, the same starting materials (with piperidine as
the secondary amine) and catalyst used for this purpose gave
rise to heterocyclic chalcones in the absence of solvent, with
this representing the first copper-catalyzed synthesis of
chalcones (without rearrangement) from aromatic aldehydes
and alkynes. We wish to present herein a complete study, which
includes the scope of this methodology more focused on the
synthesis of chalcones and, most importantly, our endeavor to
understand mechanistically the formation of both the
indolizines and chalcones.
In principle, any laboratory-made catalyst should be more
efficient than commercially available catalysts used for the same
purpose. Otherwise, it is difficult to economically justify the
time, materials and human resources employed during its
preparation. Taking into account this premise, we undertook a
comparative study on the reactivity of CuNPs/C with that of
some commercial copper catalysts. The standard conditions
were applied to the model reaction of pyridine-2-carbaldehyde
(1a), piperidine (2a), and phenylacetylene (3a). As shown in
RESULTS AND DISCUSSION
■
All the supported copper catalysts used in this study were
prepared by adding a variety of supports to a recently prepared
suspension of the CuNPs,25 readily generated, in turn, by
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a
Table 1. Multicomponent Synthesis of Indolizines Catalyzed by CuNPs/C
a
Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), 3 (0.5 mmol), CuNPs/C [20 mg, ∼0.5 mol %, determined from the Cu content (1.4 wt %) and
b
the Cu2O/CuO area from XPS (∼1:1)], CH2Cl2 (1 mL), 70 °C; reaction time and isolated yield in parentheses. The propargylamine 5bfa was the
major product (72%). NMR yield based on the starting aldehyde.
c
Table 2, the best performance was attained with CuNPs/C
(entry 11) in terms of catalyst loading, reaction time, and
conversion. The kinetic profile for the synthesis of 4aaa shows
almost a linear increase in the conversion within the first 3 h
(up to 92%), being nearly quantitative after 4 h (98%) (Figure
1). For this particular reaction, TON and TOF of up to 200
and 65 h−1, respectively, have been recorded.
on other methodologies,10−13 we can propose a reaction
mechanism for this multicomponent synthesis of indolizines,
including (a) CuNPs-mediated enhancement of the alkyne
acidity by coordination to the carbon−carbon triple bond,27
enabling the formation of the corresponding copper(I)
acetylide; (b) addition of the latter to the in situ-generated
iminium ion derived from the aldehyde and the secondary
amine; (c) copper-promoted cycloisomerization of the resulting
propargylamine (A3 product) through a 5-endo-dig and
On the basis of our previous mechanistic studies on the
aldehyde−amine−alkyne coupling (A3 coupling),23b as well as
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on the low indolizine conversion recorded for some 6-
bromopyridin-2-carbaldehyde derivatives and managed to
isolate propargylamine 5bfa. Subsequent treatment of 5bfa
with CuNPs/C in dichloromethane furnished the expected
indolizine 4bfa after prolonged heating (Scheme 4). These
results distinctly unveil that 2-pyridinyl propargyl amines are
the precursor intermediates of indolizines.
Table 2. Comparison of CuNPs/C with Commercial Copper
Catalysts
a
Synthesis of Chalcones. We discovered that the reaction
of pyridine-2-carbaldehyde (1a), piperidine (2a), and phenyl-
acetylene (3a) catalyzed by CuNPs/C, when performed in the
absence of solvent, mainly led to the corresponding chalcone
(6aa). We considered it convenient to optimize the copper
catalyst to get the best possible conversion into the desired
chalcones. The aforementioned substrates were used in a model
reaction, carried out with CuNPs on diverse supports at 70 °C
in the absence of solvent (Table 3). In a control experiment, we
confirmed the necessity of copper for the reaction to take place
(Table 3, entry 1). Among the different catalysts tested,
NPsCu/C and NPsCu/graphite gave the highest conversions,
with the former reaching a higher one with lower metal content
(Table 3, entries 2 and 3). Other supports based on metal
oxides or microporous or organic materials were not effective in
this transformation (Table 3, entries 5−12). The introduction
of a second metal in the catalyst supported on carbon had a
deleterious effect in the conversion (Table 3, entries 13−16).
With CuNPs/C as the catalyst of choice, we undertook the
optimization of the base, amount of catalyst, and reaction
temperature (Table 4). The results obtained were found to be
crucial to understanding the reaction pathway (vide infra). For
instance, tertiary amines, such as Et3N, pyridine, DABCO, (i-
Pr)2NEt, N,N-dimethylaniline, N-methylpiperidine, or
TMEDA, were found to be ineffective, with no trace of
chalcone 6aa being detected. The reaction was also unfruitful
with the inorganic bases NaHCO3 or K2HPO4 (<1% and 0%
conversion, respectively). Bases such as Et2NH, t-BuOK, or
Cs2CO3 led to poor conversions of ∼10% (Table 4, entries 1−
3), whereas a better one was recorded with pyrrolidine (Table
4, entry 4). Piperidine was found to be the best base, even
though a stoichiometric amount was required to achieve high
conversion (Table 4, entries 5−8). Other amounts of catalyst or
reaction temperatures gave conversions <60% (Table 4, entries
9−15). The kinetic profile for the synthesis of 6aa shows a
conversion of up to 82% within the first 3 h, to reach a
maximum fixed at 85% after prolonged heating (Figure 2).
The optimized reaction conditions (Table 4, entry 8) were
extended to the reaction of a variety of aldehydes and alkynes
(Table 5). Pyridine-2-carbaldehyde (1a) and its derivatives
substituted at the 6 position (1b,c,f) were reacted with several
phenylacetylenes, producing the corresponding chalcones in
modest-to-good yields (40−77%). In general, the 6-substituted
carbaldehydes were found to be less reactive than the
unsubstituted counterparts. This method was also applicable
to other heteroaromatic aldehydes, such as quinoline-2-
carbaldehyde (1e), 1-methyl-1H-imidazole-2-carbaldehyde
(1g), and thiazole-2-carbaldehyde (1h), with a scanty
conversion being obtained in the latter case. We sought to
extend this procedure to nonheteroaromatic aldehydes by
combining different p-substituted benzaldehydes (1i−k) with
phenylacetylene (1a) and p-(trifluoromethyl)phenylacetylene
(1c). The electron-withdrawing effect exerted by the CF3 group
in the alkyne improved the yield with respect to the
unsubstituted phenylacetylene. It is worth noting that the
presence of electron-withdrawing groups, either (or both) in
b
entry
catalyst
CuCl
mol %
t (h)
conv (%)
1
2
1
20
20
20
20
20
20
20
20
20
20
4
27
55
28
50
55
57
23
24
40
42
98
CuCl2
1
3
CuBr
1
4
CuI
1
5
CuO
1
6
Cu2O
1
7
Cu(OAc)2
CuOAc
CuBr·SMe2
CuOTf
CuNPs
1
8
1
9
1
10
11
1
0.5
a
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), 3a (0.5 mmol),
catalyst, CH2Cl2 (1 mL), 70 °C. Conversion into 4aaa was
b
determined by GC.
Figure 1. Plot showing the evolution of the synthesis of 4aaa catalyzed
by CuNPs/C.
aromatization processes; and (d) protonolysis of the inter-
mediate copper indolizide (Scheme 3). The participation of
propargyl amines as indolizine precursors has been often
postulated,10−14 but to the best of our knowledge, never
demonstrated. These pyridinyl propargyl amines must be rather
elusive intermediates that, once generated in the reaction
medium, rapidly cyclize to the corresponding indolizines. It is
noteworthy that tiny peaks attributable to propargylamines
were detected by GC/MS (same m/z as that of indolizines) in
some of the reaction crudes derived from pyridine-2-
carbaldehyde (1a). Notwithstanding the limitations to isolate
a pyridinyl propargylamine and transform it into the
corresponding indolizine, we turned our attention to the 6-
substituted pyridine-2-carbaldehyde derivatives. The steric
hindrance arisen between the 6-substituent of the pyridine
and the alkyne substituent prior to ring closure could be a
chance to isolate the pursued propargylamine. We capitalized
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Scheme 3. Reaction Mechanism Proposed for the Three-Component Synthesis of Indolizines Catalyzed by CuNPs/C
Scheme 4. Transformation of Propargylamine 5bfa into
Indolizine 4bfa
Table 4. Optimization of the Reaction Conditions in the
Chalcone Synthesis
a
b
Table 3. Optimization of the Copper Catalyst in the
Chalcone Synthesis
entry
base (equiv)
T (°C)
conv (%)
a
1
2
Et2NH (1.0)
70
70
70
70
70
70
70
70
70
70
70
rt
10
10
10
40
5
t-BuOK (1.0)
3
Cs2CO3 (1.0)
pyrrolidine (1.0)
piperidine (0.3)
piperidine (0.4)
piperidine (0.5)
piperidine (1.0)
4
5
6
8
7
32
85
0
b
c
8
entry
catalyst
% wt Cu
conv (%)
c
9
piperidine (1.0)
1
2
none
0
0
85
70
26
39
45
39
57
47
49
53
<4
22
27
0
d
10
11
12
13
14
15
piperidine (1.0)
piperidine (1.0)
piperidine (1.0)
piperidine (1.0)
piperidine (1.0)
piperidine (1.0)
2
NPsCu/C
1.4
e
60
0
3
NPsCu/graphite
NPsCu/MWCNT
NPsCu/TiO2
NPsCu/MgO
NPsCu/ZnO
2.3
d
4
2.4
60
80
100
10
34
56
5
3.0
6
1.5
7
1.8
a
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), 3a (0.5 mmol),
CuNPs/C (20 mg), neat, 20 h. Conversion into 6aa was determined
8
NPsCu/zeolite Y
3.7
b
e
9
NPsCu/MK-10
1.8
c
d
e
by GC. 5 mg CuNPs/C. 10 mg CuNPs/C. 30 mg CuNPs/C.
10
11
12
13
14
15
16
NPsCu/cellulose
NPsCu/chitosan
NPsCu/Al silicate
NPsCu-Co/C
NPsCu-Ni/C
2.9
2.5
the aldehyde or (and) the alkyne, was fundamental for the
chalcones being formed. In fact, pyridine-2-carbaldehyde (1a)
did not react with phenylacetylenes containing electron-
donating groups, such as 4-methoxyphenylacetylene (3f) or
4-N,N-(dimethylamino)phenylacetylene (3e), to form the
expected chalcones, but the corresponding indolizines in
variable amounts (2% 4aaf, 16 h; 77% 4aae, 17 h);
quinoline-2-carbaldehyde (1e) and 4-methoxyphenylacetylene
(3f) gave indolizine 4eaf (18%, 17 h) and the corresponding
chalcone in only 7% conversion. Likewise, the reaction of
1.2
0.6 (0.9)
0.9 (0.9)
0.4 (1.2)
1.4 (0.8)
NPsCu-Fe/C
NPsCu-Zn/C
50
a
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), 3a (0.5 mmol),
b
catalyst (20 mg), neat, 70 °C, 20 h. Cu % wt in the catalyst; second
metal % wt in parentheses. Conversion into 6aa was determined by
GC. Multiwalled carbon nanotube. Montmorillonite K-10.
c
d
e
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ucts derived from the A3 coupling or alkyne homocoupling
were detected. Aliphatic alkynes as well as aliphatic aldehydes
did not react toward the formation of the enones in any case.
Other nonheteroaromatic aldehydes, such as 4-methylbenzal-
dehyde, 4-methoxybenzaldehyde, 4-N,N-dimethylaminobenzal-
dehyde, 4-bromobenzaldehyde, or piperonal, reacted with
phenylacetylene to give the A3 and alkyne homocoupling
products.
Despite the fact that this methodology is not high-yielding, it
is worthy of note that, under the same conditions, the alkyne
homocoupling23a and A3 coupling23b (or indolizine formation)
can take place and compete with the chalcone formation.
Nevertheless, efficient chalcone synthesis was achieved in some
cases by using a minute catalyst loading (0.03 mol %, TON
2367, TOF 197 h−1) (Scheme 5).
Moreover, contrary to the behavior observed for CuNPs/C
in the synthesis of indolizines, when recovered by filtration or
centrifugation, the catalyst could be reused over four cycles in
the synthesis of chalcone 6ia using low loading (0.13 mol %)
with a decrease in the catalytic activity (Figure 3). Attempts to
reutilize the catalyst in the synthesis of heterocyclic chalcone
6aa were unfruitful, which was ascribed to the known tendency
Figure 2. Plot showing the evolution of the synthesis of 6aa catalyzed
by CuNPs/C.
benzaldehyde with phenylacetylenes bearing any kind of
substituents led to 10−38% chalcone conversion [4-bromo-
phenylacetylene (10%), methyl 4-ethynylbenzoate (22%), 4-
methylphenylacetylene (34%), 4-methoxyphenylacetylene
(38%) and 4-ethynyl-N,N-dimethylaniline (12%)]; side prod-
a
Table 5. Synthesis of Chalcones from Aldehydes and Alkynes Catalyzed by CuNPs/C
a
Reaction conditions: 1 (0.5 mmol), 2a (0.5 mmol), 3 (0.5 mmol), CuNPs/C (20 mg, 0.5 mol %), 70 °C; reaction time and isolated yield in
parentheses.
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was obtained in <50% conversion in all cases, with the
exception of CuI (Table 6, entry 4); moderate conversion was
obtained with the latter, though a larger amount of this
nonrecyclable catalyst and a longer reaction time were required
than with CuNPs/C (Table 6, entry 12). Moreover, an increase
in the amount of CuI had a detrimental effect on the
conversion (Table 6, entry 5).
Scheme 5. Synthesis of Chalcone 6ia Using Very Low
Catalyst Loading
From a structural point of view, we must underline that all
chalcones were obtained as single E diastereoisomers, showing
typical values of trans-coupled vinylic protons (3JH−H = 15.7−
16.4 Hz). The regiochemistry of the products was originally
proposed by comparison of the NMR chemical shifts with
those in the literature (Figure 4)29 and unequivocally
established by X-ray crystallographic analysis of chalcone 6fc
(Figure 5).30 This information proves that no rearrangement is
involved in the chalcone formation.
Figure 4. Comparison of the chemical shifts of 6aa and its
regioisomer.29
Figure 3. Reutilization of the catalyst in the synthesis of the chalcone
6ia using 0.13 mol % CuNPs/C.
of this type of compounds to form stable complexes with
copper,28 in this case with a poisoning effect.
As previously studied for the synthesis of indolizines, we
compared the performance of CuNPs/C with that of some
commercial copper catalysts in the synthesis of chalcones
(Table 6). Chalcone 6aa was used as the model target, which
Table 6. Comparison of CuNPs/C with Commercial Copper
a
Catalysts
Figure 5. Plot showing the X-ray structure and atom numbering for
compound 6fc; 50% disorder was observed for the CF3 group.30
To gain insight into the reaction mechanism of the chalcone
formation, three isotopic-labeling experiments were conducted
(Scheme 6) using deuterated pyridine-2-carbaldehyde [(D1)-
1a, eq 1], piperidine [(D1)-2a, eq 2], and phenylacetylene
[(D1)-3a, eq 3]. The deuterium incorporation was estimated by
integrating the triplet signals of the H−D coupling relative to
those of the H−H coupling (Figure 1, Supporting Informa-
tion). The corresponding chalcone 6aa was formed with
different degrees of deuterium incorporation at the α and β
positions with respect to the carbonyl group. The low
deuteration degree achieved in all cases suggests a favored
D−H exchange for the three reagents in play. This behavior
was somewhat expected for phenylacetylene (D1)-3a and
piperidine (D1)-2a beause of the acidity of the acetylenic D and
N-D, respectively. The scarce deuterium incorporation also
observed in the case of pyridine-2-carbaldehyde (D1)-1a points
to a new mechanism different from those previously
published.16−19 The kH/kD = 0.47 determined for eq 1 in
Scheme 6 reveals the absence of a primary kinetic isotopic
effect and rules out the cleavage of the formyl group C−H as
b
entry
catalyst
CuCl
mol %
t (h)
conv (%)
1
2
1
1
20
20
20
20
20
20
20
20
20
20
20
9
47
33
44
70
18
2
CuCl2
CuBr
3
1
4
CuI
1
5
CuI
10
1
6
CuO
7
Cu2O
1
25
10
4
8
Cu(OAc)2
CuOAc
CuBr·SMe2
CuOTf
CuNPs
1
9
1
10
11
12
1
18
28
85
1
0.5
a
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), 3a (0.5 mmol),
Cu catalyst, neat, 70 °C. Conversion into 6aa was determined by GC.
b
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Scheme 6. Deuterium-Labeling Experiments in the Synthesis of Chalcone 6aa Catalyzed by 0.5 mol % CuNPs
being the determining step of the reaction (Figure 2,
Supporting Information). This number is closer to that of an
inverse secondary kinetic isotopic effect, implying a sp2-to-sp3
rehybridization of the carbonyl group of 1a during the
reaction.31
Therefore, copper seems to be essential to obtain the A3
coupling product but not to transform it into the chalcone.
The fact that no D−H exchange was detected in (D1)-5laa
supports a type of irreversible process driven to the formation
of the chalcone.
The fact that the chalcone 6aa was not formed in the
presence of tertiary amines and that the best conversions were
achieved with the secondary amines piperidine and pyrrolidine
(Table 4, entries 4 and 8, respectively), led us to conceive the
reaction taking place through the A3 coupling product. It is
well-known that this coupling is especially favored when using
piperidine as the secondary amine and involves a sp2−sp3
rehybridization as commented above. In this sense, piperidine-
derived propargyl amine (D1)-5laa was subjected to the
reaction with piperidine (2a) in the presence of CuNPs/C
and water under prolonged heating (Scheme 7). It was
On the basis of all the aforementioned experiments, we can
propose a mechanism for the copper-catalyzed synthesis of
chalcones from aldehydes and alkynes, including (a) the
formation of the piperidine-derived propargylamine catalyzed
by CuNPs/C, in the terms shown in Scheme 3 and previously
published by our group;23b (b) piperidine-promoted isomer-
ization of the propargylamine to the corresponding allenyl-
amine; and (c) hydrolysis of the allenylamine to the E chalcone
(Scheme 8). There are several features in this mechanism that,
in our opinion, play a decisive role in the outcome of the
reaction. First, the acidity of the propargylic hydrogen; we
believe that this hydrogen atom is particularly acid because it is
at the same time propargylic, benzylic, and at the α-position
with respect to the nitrogen. This acidity might also be
enhanced in certain cases by coordination of the CuNPs to the
carbon−carbon triple bond. Up to this point, the scenario is the
same as previously described for the A3 coupling or the
multicomponent synthesis of indolizines. However, it is the
absence of solvent, in conjunction with the presence of
electron-withdrawing groups in the starting materials, that really
makes a difference in the pathway toward the synthesis of
chalcones. We believe that piperidine plays a double role, acting
as both a component in the A3 coupling and as a base; the
unsolvated piperidine would manifest a more effective basic
power, deprotonating the propargyl hydrogen atom and driving
the course of the reaction on the chalcone formation. The
negative inductive effect caused by the presence of electron-
withdrawing groups would work in the same direction:
increasing the acidity of the propargylic hydrogen atom and
stabilizing the negative charge generated after deprotonation in
the propargyl-to-allenyl amine isomerization. This explanation
is concordant with the observation that the synthesis of
chalcones from aromatic aldehydes or alkynes with electron-
donating substituents is troublesome.
Scheme 7. Experimental Evidence on Propargyl Amines
Acting As Chalcone Precursors
gratifying to observe the formation of the corresponding
chalcone (6la), albeit the conversion was low, in agreement
with the absence of electron-withdrawing groups in the
aldehyde and alkyne components, as noted above. In contrast,
the propargyl amine 5lac,32 bearing the electron-withdrawing
trifluoromethyl group, led to the expected chalcone 6lc in
either the presence or the absence of the copper catalyst.
Although it may well be plausible that the hydrolysis step
leading to the chalcone takes place in situ, it is important not to
overlook the possibility that this step occurred during the
workup. With this aim, we studied by NMR the progress of the
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Research Article
Scheme 8. Reaction Mechanism Proposed for the Synthesis of Chalcones from Aldehydes and Alkynes Catalyzed by CuNPs/C
reaction of 2-pyridinecarbaldehyde (1a), piperidine (2a), and
phenylacetylene (3a) under solvent-free conditions at 70 °C;
DMSO-d6 was used as an external reference. It is noteworthy
that the formation of the chalcone 6aa was observed at an early
stage (∼1 h), as proven by the coupling constant of the two
in agreement with the fact that catalyst reutilization was more
effective in the later than in the former and also suggest that the
leached species into solution are catalytically inactive, thus
pointing to a catalysis of heterogeneous nature.
1
CONCLUSIONS
vinylic protons (J = 16.1 Hz) in H NMR and the chemical
■
shift of CO (180.2 ppm) in 13C NMR (Figure 4, Supporting
Information). This lends weight to the argument that
hydrolysis of the chalcone precursor occurs to some extent in
the reaction medium, involving the in situ-formed water,
although probably not fast enough to allow piperidine to work
catalytically.
Nature of the Catalysis. The following experiments were
implemented in order to ascertain the nature of the catalysis:
the standard indolizine (4aaa) and chalcone (6aa) syntheses
were run up to 42% and 38% conversion (referred to the
starting aldehyde), respectively. The catalyst was removed by
filtration, and the filtrates were subjected to additional heating
for a total reaction time of 5 h (40% and 37% conversion,
respectively) and 10 h. After the latter time, 54% conversion
was recorded in the indolizine synthesis, albeit to the detriment
of the indolizine (15% 4aaa + 39% byproducts), and 34%
conversion in the chalcone synthesis. Apparently, decom-
position of the indolizine occurs in the absence of the
supported catalyst after prolonged heating.
The multicomponent synthesis of a series of indolizines and
pyrrolo[1,2-a]quinolines has been effectively accomplished
from pyridine-2-carbaldehyde derivatives, secondary amines,
and alkynes using CuNPs/C as catalyst in dichloromethane.
The methodology has been applicable to a variety of amines
and alkynes, with the latter including aryl alkynes (bearing
electron-neutral, -releasing, and -withdrawing groups) as well as
aliphatic alkynes (42−93%). Interestingly, the same procedure,
when applied in the absence of solvent using piperidine as the
secondary amine, has led to heterocyclic chalcones as major
products in modest-to-good yields (40−77%). Nonheterocyclic
chalcones have also been obtained, although the presence of
electron-withdrawing groups is crucial for their formation. In
both processes, the catalyst was shown to be superior to some
commercially available copper catalysts, and it could be reused
in the chalcone synthesis over four cycles with a decrease in
activity (85−64% conversion). Reaction mechanisms have been
proposed for the indolizine and chalcone formation, based on
the strong experimental evidence of participation of propargyl
amines as intermediates in both cases. To the best of our
knowledge, there is only one example in the literature in which
propargyl amines have been used as chalcone precursors, albeit
On the other hand, ICP-OES analyses of the filtrates showed
substantial Cu leaching in the indolizine synthesis (39.7%) and
some leaching in the chalcone synthesis (1.4%). These data are
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Research Article
the rearranged products are obtained [Scheme 1, eq 6].20 It can
be inferred, therefore, that the synthesis of chalcones from aryl
aldehydes and alkynes disclosed herein and the corresponding
mechanism are unprecedented. On the basis of leaching studies,
both the indolizine and chalcone syntheses are suggested to
proceed under heterogeneous catalysis.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.5b00417.
Procedures, characterization data, NMR spectra, kinetic
isotope effect graphic (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
*Phone. +34-965909614. Fax: +34-965903549. E-mail:
falonso@ua.es.
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Present Address
†(M.J.A.) Sharda Cropchem Espana S. L., Carril Condomina
̃
(Atalaya Business Center), 30006 Murcia, Spain.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This work was generously supported by the Spanish Ministerio
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