Three-component coupling of aldehydes, amines, and alkynes catalyzed by oxidized copper nanoparticles on titania

Article abstract of DOI:10.1002/ejoc.201200090

Copper nanoparticles (mainly as Cu₂O) on titania have been shown to catalyze the multicomponent synthesis of propargylamines from aldehydes, amines, and alkynes (A³ coupling) effectively at 70 °C under solvent-free conditions. Both aromatic and aliphatic aldehydes and alkynes have been combined with secondary amines to provide a wide range of propargylamines in moderate to excellent yields. Two examples of ketone/amine/alkyne (KA ²) coupling are also included. The catalyst is easy to prepare, reusable at a low copper loading (0.5 mol-%), and exhibits higher catalytic activity than some commercially available copper sources. Some mechanistic aspects of the reaction have also been examined, which have unveiled the participation of copper(I) acetylides in a heterogeneous process. Copyright

Full text of DOI:10.1002/ejoc.201200090

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FULL PAPER
DOI: 10.1002/ejoc.201200090
Three-Component Coupling of Aldehydes, Amines, and Alkynes Catalyzed by
Oxidized Copper Nanoparticles on Titania
María José Albaladejo,[a] Francisco Alonso,*[a] Yanina Moglie,[a] and Miguel Yus[a]
Dedicated to the memory of Professor Balbino Mancheño
Keywords: Multicomponent reactions / Nanoparticles / Copper / Alkynes / Aldehydes / Amines
Copper nanoparticles (mainly as Cu2O) on titania have been
shown to catalyze the multicomponent synthesis of prop-
ples of ketone/amine/alkyne (KA2) coupling are also in-
cluded. The catalyst is easy to prepare, reusable at a low cop-
argylamines from aldehydes, amines, and alkynes (A3 cou- per loading (0.5 mol-%), and exhibits higher catalytic activity
pling) effectively at 70 °C under solvent-free conditions. Both
aromatic and aliphatic aldehydes and alkynes have been
combined with secondary amines to provide a wide range of
than some commercially available copper sources. Some
mechanistic aspects of the reaction have also been examined,
which have unveiled the participation of copper(I) acetylides
propargylamines in moderate to excellent yields. Two exam- in a heterogeneous process.
(A3 coupling) has emerged as a powerful tool that enables
Introduction
the direct addition of alkynes to imines (generated in situ)
in a multicomponent and more efficient manner.[7]
Propargylamines are a versatile class of compounds ex-
tensively applied as precursors in the synthesis of heterocy-
clic compounds such as quinolines,[1a] phenanthrolines,[1b]
pyrroles,[1c] pyrrolidines,[1d] indolizines,[1e] or oxazolidin-
ones,[1f] among others.[2] They have also been utilized as in-
termediates in the total synthesis of some natural and phar-
maceutical products.[3] Moreover, some propargylamine de-
rivatives have been confirmed to be potent anti-apoptotic
agents that protect neurons against cell death in cellular and
animal models of neurodegenerative disorders. Indeed, they
have been shown to delay the need for symptomatic therapy
in untreated Parkinson’s disease patients, results consistent
with a neuroprotection role for compounds of this type.[4]
Conventional methods for the formation of the prop-
argylamine moiety include direct amination of propargyl
halides,[5a] triflates,[5b] phosphates, or acetates,[5c] or the
more widely practiced addition of alkynylmetal reagents to
imines.[6] The latter approach, normally involving stoichio-
metric amounts of lithium or magnesium acetylides, re-
quires strict control of the reaction conditions and lacks
atom economy, and its application is precluded in the pres-
ence of the more reactive functional groups. In recent years,
metal-catalyzed coupling of aldehydes, amines, and alkynes
The catalytic activation of the C–H bond of terminal al-
kynes has been primarily achieved with complexes or salts
of the late transition metals (e.g., Ir, Zn, Fe, Co, Ni, Ag,
Au, Ir, Ru, but also In), but by far the most studied metal
has been copper, especially with secondary amines.[7] How-
ever, the majority of the catalytic systems are homogeneous,
making the recovery and recycling of the catalyst trouble-
some. Nowadays, nanocatalysis is considered a sustainable
and competitive alternative to conventional catalysis, be-
cause the metal nanoparticles possess a high surface-to-vol-
ume ratio, which enhances their activity and selectivity, at
the same time maintaining the intrinsic features of a hetero-
geneous catalyst.[8] In particular, the immobilization of
metal nanoparticles on high-surface-area inorganic sup-
ports allows better stability and dispersity of the particles
as well as a further exploitation of the special activity and
recycling properties of the catalyst.[9]
To the best of our knowledge there are two reports that
describe the use of copper nanoparticles (CuNPs) in A3
coupling: a) Cu0NPs (18Ϯ2 nm), prepared in the aqueous
core of reverse micellar droplets, were applied at 15 mol-%
in MeCN at 100–110 °C under nitrogen and were reutilized
five times (94–61%),[10a] and b) nanocrystalline CuO was
used at 10 mol-% in toluene at 90 °C and reutilized four
times (82–76%).[10b] Although the heterogeneous catalysts
studied in A3 coupling generally exhibit good reuse capa-
bility, there are still some drawbacks that limit their accept-
ance, such as the high prices of the catalysts (especially
[a] Departamento de Química Orgánica, Facultad de Ciencias and
Instituto de Síntesis Orgánica (ISO), Universidad de Alicante,
Apdo. 99, 03080 Alicante, Spain
Fax: +34-965903549
E-mail: falonso@ua.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200090.
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M. J. Albaladejo, F. Alonso, Y. Moglie, M. Yus
FULL PAPER
those derived from noble metals) and their tedious prepara- tile and reusable catalyst, consisting of oxidized copper
tion. In addition, some protocols involve environmentally nanoparticles on activated carbon (0.5 mol-% CuNPs/C),
unfriendly solvents, harsh conditions, long reaction times, for the multicomponent synthesis of 1,2,3-triazoles from or-
and the need for inert atmospheres. The quest for new and ganic halides, aryldiazonium salts, anilines, and epoxides in
more efficient catalysts for the synthesis of propargylamines water.[14] A catalyst based on oxidized copper nanoparticles
based on A3 coupling is therefore still a subject of interest on titania (1 mol-% CuNPs/TiO2) for the homocoupling of
in synthetic organic chemistry.
terminal alkynes in THF or under solventless conditions at
As a part of our investigations into the reactivity of 65 °C in the presence of piperidine (30 mol-%) as a base
active metals and nanoparticles,[11] a form of active copper has recently been reported.[15] As part of our research into
was obtained from CuCl2·2H2O, lithium metal, and a cata- organic reactions promoted by CuNPs, here we wish to
lytic amount of 4,4Ј-di-tert-butylbiphenyl (DTBB) in THF present our results on the performance and scope of sup-
at room temperature and applied in reductions of a range ported CuNPs in the three-component coupling of alde-
of organic functionalitites.[12] We discovered that copper hydes, amines, and alkynes under solvent-free conditions
nanoparticles (CuNPs) were formed either from CuCl2· (Scheme 1).
2H2O or from anhydrous CuCl2 under these conditions.
Unsupported CuNPs, generated from anhydrous CuCl2,
were found to catalyze 1,3-dipolar cycloadditions of organic
azides and terminal alkynes in remarkably short reaction
Results and Discussion
times.[13] A second generation of catalysts was introduced
Preparation and Screening of the Catalysts
through the immobilization of the CuNPs on different inor-
ganic supports. In particular, we developed a highly versa-
The copper catalysts were prepared by addition of a vari-
ety of inorganic 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 DTBB (10 mol-%) in THF at room temperature. The
supported catalysts were not subjected to any treatment
prior to use. Firstly, a screening was carried out in order to
optimize the catalyst support, solvent, and conditions, with
the coupling of benzaldehyde (1a), piperidine (2a), and
phenylacetylene (3a) as a model reaction (Table 1). A con-
trol experiment at 70 °C in the absence of catalyst did not
give the expected product, irrespective of the solvent used
(Table 1, Entry 1). In general, all the catalysts were quite
effective in CH2Cl2, with the exception of CuNPs/TiO2
(Table 1, Entry 5/CH2Cl2). The best results were achieved
with CuNPs/C (Table 1, Entry 2/CH2Cl2), either at 70
Scheme 1. Homocoupling of phenylacetylene and A3 coupling cat-
alyzed by CuNPs/TiO2.
Table 1. Optimization of the support, solvent, and reaction conditions.[a]
Entry
Catalyst[b]
THF
H2O
EtOH
PhMe
CH2Cl2
MeCN
Acetone
Neat
1
2
3
4
5
6
7
8
9
10
none
CuNPs/C
CuNPs/G
CuNPs/ZY
CuNPs/TiO2
CuNPs/ZnO
CuNPs/MK
CuNPs/SiO2
CuNPs/MS
CuNPs/MgO
–
–
7
6
2
7
11
–
6
4
3
–
23
8
–
24
–
–
–
4
2
32
8
21
21
13
7
–
–
–
5
3
–
–
18
4
42
6
–
–
–
–
–
–
–
–
–
–
3
82
51
70
25
25
22
14
–
32
38
3
98 [90][c]
96 [47][c]
92 [89][c]
27
60
98 [35][d]
94 [75][c]
85
72
48
57
–
8
31
44
12
92 [47][c]
86
87 [47][c]
75
[a] Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), 3a (1.0 mmol), CuNPs/support (20 mg), solvent (2 mL), 70 °C; numbers in each
solvent column refer to conversion into 4aaa after 24 h, determined by GC. [b] C = activated carbon, G = graphite, ZY = sodium
zeolite Y, MK = montmorillonite K-10, MS = molecular sieves (4 Å). [c] Reaction at 40 °C in brackets. [d] Reaction at room temperature
in brackets.
2
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Cu-Catalyzed Three-Component Coupling Reactions
(98%) or at 40 °C (90%), although the level of conversion leading to 4aaa and 4aba in high yields, and 4aca in moder-
with CuNPs on zeolite Y at 40 °C (89%) is also worthy of ate yield, respectively. Propargylamine 4ada, derived from
mention (Table 1, Entry 4/CH2Cl2). Acetone, THF, H2O, 2-methylpiperidine (2d), required prolonged heating and
EtOH, PhMe, or MeCN were shown to be inappropriate was obtained with moderate diastereoselectivity, whereas N-
solvents, with only THF providing a moderate degree of methylbenzylamine (2e) reacted more rapidly and with
conversion into 4aaa in the presence of CuNPs/C (Table 1, higher conversion into 4aea.
Entry 2/THF). All the catalysts were tested in the absence
of solvent, with the observation of no conversion for
CuNPs/MS, modest levels of conversion for CuNPs/G,
CuNPs/ZY, CuNPs/MK, and CuNPs/SiO2, moderate to
good levels of conversion for CuNPs/C, CuNPs/ZnO, and
CuNPs/MgO, and excellent levels of conversion for CuNPs/
TiO2 (Table 1, neat). Unfortunately, low levels of conversion
were observed in the latter case when the reaction was car-
ried out at room temperature (Table 1, Entry 5/neat). Be-
cause solvent-free organic synthesis is one of the most
promising steps for waste prevention and environmental
protection,[16] we selected CuNPs/TiO2 at 70 °C under sol-
vent-free conditions as the catalyst of choice, to the detri-
ment of the potentially good performance of CuNPs/C in
CH2Cl2 at 40 °C.
Next, the nature of the alkyne was modified with the
aldehyde and the amine kept constant. Arylacetylenes bear-
ing either electron-donating (4aab) or electron-withdrawing
groups (4aac) were examined, with the latter giving some
side reactions; cyclohexylacetylene furnished 4aad in a yield
intermediate between those of 4aab and 4aac. The structure
of the aldehyde seemed to have more pronounced effects
both on the reaction time and on the isolated yield. Longer
reaction times and lower yields were observed for the deriv-
atives of 4-methoxybenzaldehyde (4baa) and 2-napththal-
dehyde (4eaa), for instance, whereas much better results
were achieved with 2-iodobenzaldehyde (4caa), 3-nitrobenz-
aldehyde (4daa), and benzofuran-2-carbaldehyde (4faa).
Several aliphatic aldehydes were then subjected to the A3
coupling. Decanal (4g) and cyclohexanecarbaldehyde (4h),
when coupled with piperidine (2a) and phenylacetylene
(3a), afforded the propargylamines 4gaa and 4haa in high
yields, though the reaction time was much shorter in the
second case. N-Methylaniline (2f) and N-methyl-α-methyl-
benzylamine (2g) behaved similarly in reactions with cyclo-
hexanecarbaldehyde (4h) and phenylacetylene (3a), with the
products 4hfa and 4hga being obtained in good yields but
with low diastereoselectivity in the latter case. An alkyl- and
cycloalkyl-substituted propargylamine (4hae) could be also
prepared in high yield. We were delighted to see that even
the simplest aldehyde, formaldehyde (1i, 37% in H2O/
MeOH solution), reacted nicely with diethylamine (2h) and
Characterization of the Catalyst[15]
The CuNPs/TiO2 catalyst had previously been charac-
terized by different means including TEM, X-ray photo-
electron spectroscopy (XPS), and powder XRD, among
others. Analysis by TEM revealed the presence of well-de-
fined and dispersed spherical nanoparticles with diameters
of ca. 1.0Ϯ0.4 nm on the titania. Auger analysis comple-
mented the data obtained from XPS, denoting primarily the
presence of Cu2O. A copper content of 3.0 wt.-% in the
catalyst was determined by inductively coupled plasma
mass spectrometry (ICP-MS). This content corresponds to
1 mol-% Cu with respect to the substrates in the A3 cou-
pling, but only 0.47 mol-% (ca. 0.5 mol-%) with allowance
for the fact that the copper is mainly in the form of cop-
per(I) oxide. This catalyst loading is considerably lower
than those previously reported with other catalytic systems
based on CuNPs (10–15 mol-%).[10]
phenylacetylene (3a), thus giving access to
a prop-
argylamine unsubstituted at the propargyl position (4iha).
(S)-(–)-Citronellal (4j) was coupled with piperidine (2a) and
phenylacetylene (3a), with the expected product 4jaa being
obtained in a relatively short reaction time, in a high yield,
and with some diastereoselectivity. In this case, the two dia-
stereoisomers could be separated by column chromatog-
raphy.
In view of the low to moderate diastereoselectivities ob-
served for 2-methylpiperidine (2d) and N-methyl-α-methyl-
benzylamine (2g), we speculated that use of proline deriva-
tives might give better results. Indeed, (R)-2-(methoxy-
methyl)pyrrolidine (2i, Scheme 2) afforded the benzalde-
Three-Component Coupling of Aldehydes, Amines, and
Alkynes Catalyzed by CuNPs/TiO2
All reactions were performed with ca. 0.5 mol-% CuNPs/ hyde derivative 4aia in 84% yield and 94:6 dr, this ratio
TiO2 at 70 °C in the absence of solvent. A control experi- matching the values obtained for ent-4aia with other meth-
ment under the above conditions but in the presence only of odologies.[17] A slightly lower isolated yield and diastereo-
titania (without copper) gave no trace of the corresponding selectivity were recorded when decanal was used as the alde-
propargylamine after 24 h. This result confirms the essen- hyde (Scheme 2, compound 4gia). In this case, the relative
tial role of copper and practically rules out any catalytic (R,R) stereochemistry assigned for the major diastereoiso-
effect of the support.
mer was established by correlation of the chemical shifts of
A series of commercially available aldehydes, secondary the NCH propargylic hydrogen atoms in the two diastereo-
amines, and alkynes were subjected to the title reaction isomers with those of 4aia. Finally, it is noteworthy that the
(Table 2). Firstly, benzaldehyde (1a) and phenylacetylene coupling of benzaldehyde (1a), piperidine (2a), and phenyl-
(3a) were coupled with different cyclic amines such as piper- acetylene (3a) was demonstrated to be scalable to 5 mmol,
idine (2a), morpholine (2b), and 4-methylpiperidine (2c), giving rise to propargylamine 4aaa in 67% isolated yield.
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Table 2. Three-component coupling of aldehydes, amines, and alkynes catalyzed by CuNPs/TiO2.[a,b]
[a] Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), 3 (1.0 mmol), CuNPs/TiO2 (0.5 mol-%), neat, 70 °C. [b] Isolated yield. [c] Dia-
stereomeric ratio measured by GC from the reaction crude.
Stability and Recycling of the Catalyst
performance in the coupling of benzaldehyde (1a), piperi-
dine (2a), and phenylacetylene (3a) was observed over four
The catalyst could be handled in air and all the experiments consecutive cycles (Figure 1).
were carried out without air exclusion; these are advantages
The copper level in the aqueous solution between cycles
that make the process operationally simple. It is worth men- was detected to be 40 ppb (ICP-MS), which practically rules
tioning that, despite the fact of the small amount of catalyst out any loss of catalytic activity through metal leaching.
utilized (20 mg), it could easily be recovered by filtration More probably, loss of catalyst mass during filtration
(after addition of diethyl ether) and reused. Good catalyst (through a fritted glass filter) could account for the decreas-
4
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Cu-Catalyzed Three-Component Coupling Reactions
were the best commercial catalysts, although prolonged
heating was necessary and the levels of conversion were not
as high as desirable (Table 3, Entries 4 and 6). The levels of
conversion for CuCl and CuCl2 dropped when the catalyst
loading was reduced to 1 mol-%, with concomitant forma-
tion of the diyne derived from 3a (Table 3, Entries 5 and 7).
A similar trend was observed for CuBr and CuI at 1 mol-
% (Table 3, Entries 8 and 9). Therefore, the nanosized char-
acter of our catalyst and its distribution on the support
seem to play decisive roles in its higher performance
(Table 3, Entry 10). Furthermore, the easy catalyst prepara-
tion, lower metal loading, lower reaction temperature, lack
of requirement for an inert atmosphere, and absence of sol-
vent are some clear advantages with respect to other cata-
lysts based on CuNPs[10] or other heterogeneous cata-
lysts.[7d]
Scheme 2. Diastereoselective synthesis of propargylamines 4aia and
4gia.
Table 3. Synthesis of propargylamine 4aaa catalyzed by different
copper catalysts.[a]
Entry Cu catalyst
[Mol-%]
t [h]
Conversion [%][b]
1
2
3
4
5
6
7
8
9
Cu
CuO
Cu2O
CuCl
CuCl
CuCl2
CuCl2
CuBr
CuI
10
10
10
10
1
10
1
1
1
0.5
24
24
24
24
24
24
24
24
24
7
49
55
63
80
63[c]
76
Figure 1. Recycling of CuNPs/TiO2 in the synthesis of prop-
argylamine 4aaa.
64[c]
51[d]
62[d]
98
10
CuNPs/TiO2
ing tendency in the conversion observed in the recycling
experiments. Although the above analysis points to a pro-
cess that is heterogeneous in nature, we cannot in principle
dismiss the possibility that the support acts as a reservoir
for metal species that leach into solution and readsorb. Pro-
cesses of this kind, however, have mainly been shown to
occur for nanoparticle suspensions of the catalytically
active group VIII transition metals.[18]
[a] Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), 3a
(1.0 mmol), catalyst, neat, 70 °C. [b] Levels of conversion deter-
mined by GC. [c] A 31% yield of the diyne derived from 3a was
obtained. [d] 15–26% yields of the diyne derived from 3a were ob-
tained.
Some Mechanistic Aspects
Tentative mechanisms for copper-catalyzed A3 coupling
have been proposed. They normally invoke the participa-
tion of copper acetylides, which react with the iminium ions
Comparison with Other Catalysts
Any laboratory-made catalyst should, as a matter of generated in situ from the aldehydes and secondary amines
principle, be more efficient than commercially available cat- to give the corresponding propargylamines.[19] This class in-
alysts used for the same purpose, and so we undertook a cludes the mechanism reported by Lakshmi Kantam et al.
comparative study of the reactivity of CuNPs/TiO2 with when nanocrystalline CuO was used as catalyst.[10b] The
those of different commercially available copper sources mechanism depicted by Kidwai et al. however, is somewhat
(Table 3). The standard conditions were applied to the reac- dubious because, on one hand, Cu0NPs seem to undergo
tion of benzaldehyde (1a), piperidine (2a), and phenyl- oxidative addition to the alkyne to give a mixed copper hy-
acetylene (3a) at different catalyst loadings. Copper metal, dride acetylide, followed by deprotonation to afford the
CuO, and Cu2O (10 mol-%) gave rise to the expected pro- copper acetylide.[10a] On the other hand, though, the au-
pargylamine 4aaa with moderate levels of conversion thors suggested that the reaction might proceed through a
(Table 3, Entries 1–3). CuCl and CuCl2 (both at 10 mol-%) free radical mechanism.
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M. J. Albaladejo, F. Alonso, Y. Moglie, M. Yus
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We performed different experiments in order to gain an anchored to the heterogeneous catalyst (5a/TiO2); some
inside into the reaction mechanism of the A3 coupling cata- Cu–O bonding between Cu atoms and the O of TiO2 has
lyzed by CuNPs. We observed that the addition of radical been reported on specific surfaces.[21] When 5a/TiO2 was
traps such as norbornene, cumene, or 2,6-di-tert-butylphen- washed with diethyl ether, in order to remove any trace of
ol did not inhibit the standard reaction, and no products phenylacetylene, and warmed to 70 °C, the corresponding
originated from their reaction with alkynyl radicals were diyne 6a was formed and the yellow color on the solid van-
detected. Use of TEMPO led to some side reactions, al- ished. Addition of benzaldehyde (1a) and piperidine (2a) to
though its coupling with the alkyne moiety was not ob- that solid furnished the A3 product 4aaa together with a
served either. Because the presence of free radicals might minor amount of diyne 6a. These experiments therefore im-
compromise the existence of the (originally) formyl hydro- ply that copper(I) acetylides are the true intermediates in
gen atom in the product (tertiary benzylic and propargylic this methodology and suggest a process that is hetero-
N–C–H), two deuterium-labeling experiments were con- geneous in nature.
ducted (Scheme 3). The reaction of benzaldehyde (1a) with
piperidine (2a) and deuterated phenylacetylene (D1-3a) did
not show any incorporation of deuterium into the product
4aaa (Scheme 3, a), whereas the coupling of deuterated
benzaldehyde (D1-1a) with piperidine (2a) and phenyl-
acetylene (3a) yielded the propargylamine D1-4aaa with
quantitative deuterium incorporation (Scheme 3, b). These
results indicate that the reaction mechanism of the A3 cou-
pling catalyzed by CuNPs very likely does not involve free
radicals.
Scheme 4. Formation of copper(I) phenylacetylide from CuNPs/
TiO2.
On the basis of the experiments described above and our
previous experience in acetylene chemistry and CuNPs, we
propose an ionic reaction mechanism (Scheme 5) that in-
cludes: a) coordination of the alkyne to the CuNPs with
concomitant activation of the C–H bond, b) formation of
the corresponding copper(I) acetylide on the titania sup-
port (the acetylenic hydrogen might form a hydroxy group
with a surface oxygen atom or might be attached to a bridg-
ing oxygen of the support),[22] and c) addition of the cop-
per(I) acetylide to the iminium ion generated in situ from
Scheme 3. Deuterium-labeling experiments in the CuNPs/TiO2-cat-
alyzed A3 coupling.
the aldehyde and the amine, with the subsequent formation
of the propargylamine, water, and regeneration of the cata-
lytically active species.
We have recently experimentally demonstrated that cop-
per(I) acetylides are the true intermediate species in copper-
catalyzed azide/alkyne cycloadditions involving unsup-
ported CuNPs in the presence of triethylamine and THF as
The Ketone/Amine/Alkyne (KA2) Coupling
Ketones are much more reluctant than aldehydes to react
solvent.[13b] We also showed that, in the absence of base, in the three-component reaction. In fact, the KA2 coupling
CuNPs enhance the acidity of a terminal alkyne in water, remained unknown until the recent discovery by the group
by coordination to the carbon–carbon triple bond, thus en- of Van der Eycken, in which microwave irradiation was
abling the formation of the corresponding copper(I) acet- found to assist this process with CuI catalysis (20 mol-%)
ylide. When phenylacetylene was allowed to react with the at 100 °C in the absence of solvent.[23] Only cyclohexanone
CuNPs/TiO2 catalyst at 70 °C a yellow color attributable to and its derivatives were reported to be reactive enough to
copper(I) phenylacetylide (5a) appeared over the support produce the expected propargylamines in moderate to good
(Scheme 4).[20] This organocopper compound displayed yields. More recently, a wider substrate scope has been
great stability and insolubility, not undergoing any notice- achieved with the aid of gold catalysis.[24] We studied the
able change after exposure to air for several weeks. It is CuNPs/TiO2-catalyzed KA2 coupling of cyclohexanone
generally recommended that copper acetylides be preserved (1k, Scheme 6) with piperidine (2a) and phenylacetylene
under inert atmosphere in the dark, so we cannot rule out (3a) and observed that, under the above solvent-free condi-
a stabilization effect arising from the fact that 5a remains tions, maximum yields of ca. 35% were recorded. The yields
6
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Cu-Catalyzed Three-Component Coupling Reactions
and cycloalkyl-substituted substrates. The catalyst could be
recycled, with negligible leaching (40 ppb), and reused over
four cycles, providing excellent to good yields of the prod-
uct (98–79%). Moreover, higher catalytic activity with less
byproduct formation was observed for CuNPs/TiO2 than
for some commercial copper sources. In addition, two ex-
amples of ketone/amine/alkyne coupling have been re-
ported, in this case in the presence of dichloromethane as
solvent. Finally, different experiments ruled out a free-radi-
cal mechanism and unveiled the participation of copper(I)
acetylides as reaction intermediates in a process that is
heterogeneous in nature.
Experimental Section
General: Anhydrous copper(II) chloride (97%, Aldrich), lithium
powder (MEDALCHEMY S. L.), and DTBB (4,4Ј-di-tert-butylbi-
phenyl, Aldrich) were commercially available. Degussa P25 TiO2
(60% anatase, 40% rutile) with a surface area of 50 m2 g–1 was used
as support, after being calcined in air at 500 °C for 5 h. All the
starting materials and other reagents were commercially available
of the best grade (Aldrich, Acros, Alfa Aesar) and were used with-
out further purification. 1-Deuterio-2-phenylacetylene (D1-3a) was
prepared by stirring phenylacetylene (3a) and D2O at 70 °C over-
night, followed by a standard extraction workup.[14c] 1-Deuterio-
Scheme 5. Proposed reaction mechanism for the A3 coupling cata-
lyzed by CuNPs/TiO2.
could be substantially improved [also in the case of N-meth-
ylbenzylamine (2e)] by use of dichloromethane as solvent
(Scheme 6). In contrast, pentan-3-one could be coupled
with N-methylbenzylamine and phenylacetylene in only
30% yield, even with use of dichloromethane as solvent.
1-phenylmethanone (D1-1a) was obtained from ethyl benzoate by
[25]
reduction with LiAlD4
(THF, 0 °C, 4 h, room temp.) and oxi-
dation with Dess–Martin’s reagent (CH2Cl2, 2 h, room temp.).
THF was dried in a Sharlab PS-400-3MD solvent purification sys-
tem with an alumina column. All reactions were carried out with
a multireactor apparatus and the corresponding reactor tubes.
Melting points were obtained with a Reichert Thermovar appara-
tus. Optical rotations were measured with a Perkin–Elmer 341 po-
larimeter with a thermally jacketed 5-cm cell at approximately
20 °C. Concentrations (c) are given in g/100 mL and [α] values are
given in units of 10–1 deg cm2 g–1. NMR spectra were recorded with
Bruker Avance 300 and 400 spectrometers (300 and 400 MHz for
1H NMR; 75 and 100 MHz for 13C NMR); peak assignments were
achieved on the basis of DEPT experiments and estimation with
the ACD/Laboratories 6.0 program; chemical shifts (δ) are given in
parts per million and coupling constants (J) in Hertz. Infrared
analysis was performed with a Jasco 4100LE (Pike MIRacle ATR)
spectrophotometer; wavenumbers (ν) are given in cm–1. Mass spec-
˜
tra (EI) were obtained at 70 eV with an Agilent 5973 spectrometer;
fragment ions in m/z with relative intensities (%) in parentheses.
HRMS analyses were also carried out in the electron impact mode
(EI) at 70 eV with a Finnigan MAT95S spectrometer. The purities
of volatile compounds and the chromatographic analyses (GLC)
were determined with a Hewlett–Packard HP-5890 instrument and
an Agilent 5973 GC–MS apparatus. Retention times (tR) were ob-
tained with the latter under the following conditions: HP5MS cap-
illary column (30 m, 0.25 mm diameter, 0.25 μm film thickness)
with helium (54.1 mLmin–1) as carrier gas, Tinjector = 250 °C,
Tcolumn = 60 °C (3 min) and 60–270 °C (15 °Cmin–1). Column
chromatography was performed with silica gel 60 of 40–60 microns
(hexane/EtOAc as eluent).
Scheme 6. KA2 coupling catalyzed by CuNPs/TiO2.
Conclusions
A series of catalysts composed of copper nanoparticles
on different supports have been tested in three-component
couplings of aldehydes, secondary amines, and terminal al-
kynes. The CuNPs/TiO2 catalyst, in which copper is present
mainly as Cu2O, manifested the best performance in this
reaction at 70 °C under solvent-free conditions. An array of
structurally different propargylamines has been synthesized,
in moderate to excellent yields (52–99%) and with low
Typical Procedure for the Preparation of CuNPs/TiO2: Anhydrous
copper(II) chloride (135 mg, 1 mmol) was added at room tempera-
ture under argon to a suspension of lithium (14 mg, 2 mmol) and
4,4Ј-di-tert-butylbiphenyl (DTBB, 27 mg, 0.1 mmol) in THF
metal loadings (0.5 mol-%), from all sorts of aryl-, alkyl-, (2 mL). The reaction mixture, which was initially dark blue, rapidly
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Pages: 13
M. J. Albaladejo, F. Alonso, Y. Moglie, M. Yus
FULL PAPER
changed to black, indicating that the suspension of copper nano-
particles had been formed. This suspension was diluted with THF
(18 mL) followed by addition of TiO2 (1.28 g). The resulting mix-
ture was stirred for 1 h at room temperature and filtered, and the
solid was washed with THF (20 mL) and dried under vacuum.
(2ϫm, 6 H, CH2CH2CH2CH), 2.14–2.37, 2.41–2.51 (2ϫm, 2 H,
NCH2), 2.53–2.75 (m, 1 H, CHCH3), 5.31 (s, 1 H, NCH), 7.20–
7.40, 7.44–7.57, 7.58–7.74 (3ϫm, 10 H, 10ϫArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 20.9 (CH3), 25.2, 26.4, 35.7 (3ϫCH2), 47.0
(NCH2), 55.3 (NCH), 56.2 (CHCH3), 85.1 (CHCϵC), 88.3
(CHCϵC), 123.6, 139.8 (2ϫArC), 127.3, 128.0, 128.2, 128.3,
General Procedure for the A3 Coupling Catalyzed by CuNPs/TiO2:
The aldehyde 1 (1.0 mmol), amine 2 (1.0 mmol), and alkyne 3
(1.0 mmol) were placed in a reactor tube containing CuNPs/TiO2
(20 mg, ca. 0.5 mol-%) without solvent. The reaction mixture was
warmed to 70 °C without exclusion of air and monitored by TLC
and/or GLC until total conversion of the starting material. EtOAc
(2 mL) was added to the resulting mixture, followed by filtration
through celite and washing with additional EtOAc (4 mL). The
crude reaction product was purified by column chromatography
(silica gel, hexane/EtOAc), except for compounds 4haa and 4iha,
which were obtained in suitably pure states, to give the correspond-
ing propargylamines 4.
128.4, 128.6, 131.9, 132.0 (10ϫArCH) ppm. IR (neat): ν = 3055,
˜
3025, 2929, 1598, 1489, 1448, 754, 722, 690 cm–1. MS (70 eV): m/z
(%) = 289 (18) [M]+, 275 (33), 274 (100), 212 (46), 192 (76), 191
(100), 190 (14), 189 (56), 165 (19), 115 (11).
1
Selected data for the minor diastereoisomer: tR = 17.18. H NMR
(300 MHz, CDCl3): δ = 1.07–1.15 (d, J = 6.3 Hz, 3 H, CH3CH),
3.05–3.23 (m, 1 H, CHCH3), 5.06 (s, 1 H, NCH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 26.7, 34.9 (2ϫCH2), 54.5 (NCH), 58.6
(CHCH3) ppm. MS (70 eV): m/z (%) = 289 (5) [M]+, 274 (41), 212
(18), 192 (26), 191 (100), 189 (20).
N-Benzyl-N-methyl-1,3-diphenylprop-2-yn-1-amine (4aea):[27] Yel-
low oil. Rf = 0.64 (hexane/EtOAc 9:1). tR = 17.82. 1H NMR
(400 MHz, CDCl3): δ = 2.24 (s, 3 H, CH3), 3.68 (AB system, J =
13.2 Hz, 2 H, CH2), 4.92 (s, 1 H, NCH), 7.22–7.44 (m, 11 H,
11ϫArH), 7.53–7.61 (m, 2 H, 2ϫArH), 7.65–7.71 (m, 2 H,
2ϫArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 38.2 (CH3), 59.1
(CH2), 59.7 (NCH), 84.9 (CHCϵC), 88.8 (CHCϵC), 123.4 (ArC),
127.2, 127.6, 128.3, 128.5, 129.2, 132.0 (15ϫArCH), 139.2, 139.5
1-(1,3-Diphenylprop-2-yn-1-yl)piperidine (4aaa):[26] Yellow solid. Rf
= 0.44 (hexane/EtOAc 9:1); m.p. 65.9–66.4 °C. tR = 16.90. 1H
NMR (300 MHz, CDCl3): δ = 1.35–1.49 (m, 2 H, CH2CH2CH2N),
1.50–1.67 (m, 4 H, 2ϫCH2CH2N), 2.55 (t, J = 5.4 Hz, 4 H,
2ϫNCH2), 4.79 (s, 1 H, NCH), 7.23–7.39 (m, 6 H, 6ϫArH), 7.48–
7.55 (m, 2 H, 2ϫArH), 7.60–7.68 (m, 2 H, 2ϫArH) ppm. 13C
NMR (75 MHz, CDCl3): δ = 24.6, 26.3, 50.8 (5ϫCH2), 62.5
(NCH), 86.2 (CHCϵC), 87.9 (CHCϵC), 123.5 (ArC), 127.6, 128.2,
(2ϫArC) ppm. IR (neat): ν = 3060, 3028, 2842, 2791, 1598, 1489,
˜
1450, 1326, 1274, 1017, 754, 734, 690 cm–1. MS (70 eV): m/z (%) =
311 (14) [M]+, 234 (41), 220 (13), 192 (22), 191 (100), 189 (21), 91
(25).
128.4, 128.7, 131.9 (10ϫArCH), 138.7 (ArC) ppm. IR (neat): ν =
˜
3060, 2934, 2923, 2114, 1596, 1487, 1447, 1299, 1273, 1200, 757,
724, 693 cm–1. MS (70 eV): m/z (%) = 275 (45) [M]+, 274 (29), 232
(15), 199 (27), 198 (100), 192 (48), 191 (100), 190 (13), 189 (59),
165 (19), 115 (24).
1-[3-(4-Methoxyphenyl)-1-phenylprop-2-yn-1-yl]piperidine (4aab):[26]
Yellow oil. Rf = 0.42 (hexane/EtOAc 9:1). tR = 17.93. 1H NMR
(300 MHz, CDCl3): δ = 1.37–1.48 (m, 2 H, CH2CH2CH2N), 1.51–
1.69 (m, 4 H, 2ϫCH2CH2N), 2.55 (t, J = 5.3 Hz, 4 H, 2ϫNCH2),
3.81 (s, 3 H, CH3), 4.77 (s, 1 H, NCH), 6.81–6.91 (m, 2 H,
2ϫArH), 7.22–7.38 (m, 3 H, 3ϫArH), 7.42–7.49 (m, 2 H,
2ϫArH), 7.60–7.66 (m, 2 H, 2ϫArH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 24.6, 26.3, 50.8 (5ϫCH2), 55.5 (OCH3), 62.6 (NCH),
84.7 (CHCϵC), 87.7 (CHCϵC), 114.0, 127.5, 128.1, 128.7, 133.3
4-(1,3-Diphenylprop-2-yn-1-yl)morpholine (4aba):[26] Yellow oil. Rf
= 0.16 (hexane/EtOAc 9:1). tR = 16.40. 1H NMR (400 MHz,
CDCl3): δ = 2.50–2.78 (m, 4 H, 2ϫOCH2), 3.60–3.85 (m, 4 H,
2ϫNCH2), 4.79 (s, 1 H, NCH), 7.24–7.41 (m, 6 H, 6ϫArH), 7.46–
7.56 (m, 2 H, 2ϫArH), 7.58–7.70 (m, 2 H, 2ϫArH) ppm. 13C
NMR (100 MHz, CDCl3): δ = 50.0 (2ϫNCH2), 62.2 (NCH), 67.3
(2ϫOCH2), 85.2 (CHCϵC), 88.7 (CHCϵC), 123.1 (ArC), 127.9,
128.3, 128.5, 128.7, 131.9 (10ϫArCH), 137.9 (ArC) ppm. IR
(9ϫArCH), 115.6, 138.9, 159.5 (3ϫArC) ppm. IR (neat): ν =
˜
3059, 3028, 2932, 2218, 1604, 1508, 1491, 1450, 1289, 1271, 1244,
830, 805, 740, 699 cm–1. MS (70 eV): m/z (%) = 305 (23) [M]+, 304
(13), 228 (38), 222 (38), 221 (100), 207 (15), 179 (10), 178 (28).
(neat): ν = 3059, 3029, 2853, 2820, 2361, 2331, 1597, 1489, 1450,
˜
1284, 1245, 1114, 754, 724, 690 cm–1. MS (70 eV): m/z (%) = 277
(15) [M]+, 200 (21), 191 (100), 189 (25).
1-{1-Phenyl-3-[4-(trifluoromethyl)phenyl]prop-2-yn-1-yl}piperidine
(4aac): Yellow oil. Rf = 0.54 (hexane/EtOAc 9:1). tR = 16.68. 1H
NMR (300 MHz, CDCl3): δ = 1.38–1.51 (m, 2 H, CH2CH2CH2N),
1.51–1.68 (m, 4 H, 2ϫCH2CH2N), 2.55 (t, J = 5.3 Hz, 4 H,
2ϫNCH2), 4.80 (s, 1 H, NCH), 7.26–7.41 (m, 3 H, 3ϫArH), 7.55–
7.65 (m, 6 H, 6ϫArH) ppm. 13C NMR (75 MHz, CDCl3): δ =
24.6, 26.3, 50.9 (5ϫCH2), 62.5 (NCH), 86.7 (CHCϵC), 89.1
1-(1,3-Diphenylprop-2-yn-1-yl)-4-methylpiperidine (4aca):[27] Yellow
oil. Rf = 0.78 (hexane/EtOAc 8:2). tR = 17.42. 1H NMR (300 MHz,
CDCl3): δ = 0.89 (d, J = 6 Hz, 3 H, CH3), 1.07–1.22 (m, 1 H,
CHCH3), 1.29–1.45, 1.49–1.74 (2ϫm, 4 H, 2ϫCH2CH2N), 2.18
(td, J = 11.7, 2.7 Hz, 1 H, NCHH), 2.50 (td, J = 11.1, 2.7 Hz, 1
H, NCHH), 2.59–2.72 (m, 1 H, NCHH), 2.88–3.01 (m, 1 H,
NCHH), 4.81 (s, 1 H, NCH), 7.24–7.42 (m, 6 H, 6ϫArH), 7.47–
7.55 (m, 2 H, 2ϫArH), 7.59–7.68 (m, 2 H, 2ϫArH) ppm. 13C
NMR (75 MHz, CDCl3): δ = 22.1 (CH3), 30.9 (CHCH3), 34.5,
34.9, 47.6, 52.8 (4ϫCH2), 62.2 (NCH), 86.2 (CHCϵC), 87.9
(CHCϵC), 123.5 (ArC), 127.6, 128.2, 128.4, 128.6, 131.9
1
3
(CHCϵC), 124.1 (q, JC,F = 1083 Hz, CF3), 125.3 (q, JC,F = 15;
2 HzϫArCH), 127.3 (ArC), 127.8, 128.3, 128.6, 132.2 (7ϫArCH),
2
129.9 (q, JC,F = 129 Hz, ArC), 138.3 (ArC) ppm. IR (neat): ν =
˜
2934, 1614, 1450, 1321, 1125, 1065, 929, 840, 807, 744 cm–1. MS
(70 eV): m/z (%) = 343 (24) [M]+, 342 (15), 267 (15), 266 (93), 260
(34), 259 (100), 191 (14), 189 (22). HRMS (EI): m/z calcd. for
C21H20F3N 343.1548; found 343.1537.
(10ϫArCH), 138.8 (ArC) ppm. IR (neat): ν = 3059, 3029, 2947,
˜
2920, 1489, 1449, 1321, 1273, 754, 722, 690 cm–1. MS (70 eV): m/z
(%) = 289 (22) [M]+, 288 (16), 213 (14), 212 (80), 192 (32), 191
(100), 189 (24), 115 (10).
1-(3-Cyclohexyl-1-phenylprop-2-yn-1-yl)piperidine (4aad):[26] Yellow
oil. Rf = 0.48 (hexane/EtOAc 9:1). tR = 15.63. 1H NMR (300 MHz,
CDCl3): δ = 1.26–1.60 (m, 12 H, 6ϫCH2), 1.67–1.90 (m, 4 H,
2ϫCH2), 2.38–2.58 (m, 5 H, 2ϫCH2, CHCH2), 4.55 (d, J =
1.8 Hz, 1 H, NCH), 7.22–7.37 (m, 3 H, 3ϫArH), 7.53–7.59 (m, 2
H, 2ϫArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 24.7, 24.9,
1-(1,3-Diphenylprop-2-yn-1-yl)-2-methylpiperidine (4ada):[28] Dia-
stereoisomer mixture (5.9:1). Brown oil. Rf = 0.45, 0.55 (hexane/
EtOAc 9:1).
Major diastereoisomer: tR = 16.98. 1H NMR (300 MHz, CDCl3): δ
= 1.18–1.28 (d, J = 6.0 Hz, 3 H, CH3CH), 1.30–1.54, 1.57–1.79 26.1, 26.3, 33.3, 50.6 (10ϫCH2), 29.3 (CHCH2), 62.0 (NCH), 76.0
8
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Eur. J. Org. Chem. 0000, 0–0

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Cu-Catalyzed Three-Component Coupling Reactions
(CHCϵC), 92.4 (CHCϵC), 127.3, 127.9, 128.7 (5ϫArCH), 139.5 5.3 Hz, 4 H, 2ϫNCH2), 5.01 (d, J = 0.9 Hz, 1 H, NCH), 6.91 (t,
(ArC) ppm. IR (neat): ν = 3060, 3027, 2928, 2852, 2237, 1491,
J = 0.9 Hz, 1 H, ArH), 7.18–7.38 (m, 5 H, 5ϫArH), 7.49–7.60 (m,
4 H, 4ϫArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 24.4, 26.1,
50.8 (5ϫCH2), 57.2 (NCH), 83.5 (CHCϵC), 87.1 (CHCϵC),
106.5, 111.7, 121.0, 122.9, 124.3, 128.4, 128.5, 132.0 (10ϫArCH),
˜
1448, 1297, 1268, 988, 727, 696 cm–1. MS (70 eV): m/z (%) = 281
(10) [M]+, 205 (16), 204 (100), 141 (12), 115 (17), 91 (13).
1-[1-(4-Methoxyphenyl)-3-phenylprop-2-yn-1-yl]piperidine (4baa):[26]
Yellow oil. Rf = 0.35 (hexane/EtOAc 8:2). tR = 18.20. 1H NMR
(400 MHz, CDCl3): δ = 1.38–1.49 (m, 2 H, CH2CH2CH2N), 1.51–
1.67 (m, 4 H, 2ϫCH2CH2N), 2.46–2.63 (m, 4 H, 2ϫNCH2), 3.81
(s, 3 H, OCH3), 4.73 (s, 1 H, NCH), 6.85–6.93 (m, 2 H, 2ϫArH),
7.28–7.37 (m, 3 H, 3ϫArH), 7.47–7.58 (m, 4 H, 4ϫArH) ppm.
13C NMR (100 MHz, CDCl3): δ = 24.6, 26.3, 50.7 (5ϫCH2), 55.4
(OCH3), 61.9 (NCH), 86.6 (CHCϵC), 87.7 (CHCϵC), 113.5,
128.1, 128.4, 129.7 (9ϫArCH), 123.5, 130.8 (2ϫArC), 131.9
128.1, 154.7, 155.4 (4ϫArC) ppm. IR (neat): ν = 2936, 2799, 2094,
˜
1313, 1295, 1255, 985, 762, 753, 743, 695 cm–1. MS (70 eV): m/z
(%) = 315 (15) [M]+, 232 (32), 231 (100), 202 (17), 102 (10). HRMS
(EI): m/z calcd. for C22H21NO 315.1623; found 315.1660.
1-(1-Phenyldodec-1-yn-3-yl)piperidine (4gaa): Yellow oil. Rf = 0.44
1
(hexane/EtOAc 8:2). tR = 16.90. H NMR (400 MHz, CDCl3): δ =
0.88 (t, J = 6.8 Hz, 3 H, CH3), 1.23–1.77 (m, 22 H, 11ϫCH2),
2.43–2.56, 2.63–2.77 (2ϫm, 4 H, 2ϫNCH2), 3.41–3.55 (m, 1 H,
(ArCH), 159.1 (ArCOCH ) ppm. IR (neat): ν = 3054, 2931, 1609,
˜
NCH), 7.26–7.32 (m,
3 H, 3ϫArH), 7.40–7.48 (m, 2 H,
3
1584, 1508, 1488, 1441, 1272, 1244, 1168, 1035, 754, 690 cm–1. MS
2ϫArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.3 (CH3), 22.8,
24.7, 26.4, 27.1, 29.5, 29.6, 29.7, 32.1, 33.6 (13ϫCH2), 58.8 (NCH),
85.7 (CHCϵC), 88.4 (CHCϵC), 123.8 (ArC), 127.9, 128.3, 131.9
(70 eV): m/z (%) = 305 (16) [M]+, 222 (23), 221 (100), 178 (15).
1-[1-(2-Iodophenyl)-3-phenylprop-2-yn-1-yl]piperidine (4caa): Yellow
oil. Rf = 0.79 (hexane/EtOAc 7:3). tR = 18.48. 1H NMR (400 MHz,
CDCl3): δ = 1.39–1.62 [m, 6 H, (CH2)3CH2N], 2.44–2.72 (m, 4 H,
2ϫNCH2), 4.83 (s, 1 H, NCH), 7.26 (s, 1 H, ArH), 7.29–7.38 (m,
4 H, 4ϫArH), 7.47–7.54 (m, 2 H, 2ϫArH), 7.70–7.75 (dd, J =
10.8, 1.6 Hz, 1 H, ArH), 7.85–7.92 (dd, J = 10.4, 2.4 Hz, 1 H,
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.7, 26.2, 60.6
(5ϫCH2), 65.9 (NCH), 85.6 (CHCϵC), 88.8 (CHCϵC), 101.6
(CI), 123.3 (ArC), 127.6, 128.3, 128.4, 129.3, 130.3, 131.9, 140.2
(5ϫArCH) ppm. IR (neat): ν = 3064, 3025, 2924, 2853, 1488, 1465,
˜
1098, 754, 689 cm–1. MS (70 eV): m/z (%) = 325 (0.15) [M]+, 199
(15), 198 (100), 115 (11). HRMS (EI): m/z calcd. for C23H35N
325.2770; found 325.2731.
1-(1-Cyclohexyl-3-phenylprop-2-yn-1-yl)piperidine (4haa):[26] Brown
oil. Rf = 0.48 (hexane). tR = 16.26. 1H NMR (400 MHz, CDCl3): δ
= 0.87–1.09 (m, 2 H, CH2), 1.13–1.81 (m, 13 H, 5ϫCH2, 2ϫCHH,
CHCH2), 2.03, 2.10 (2ϫd, J = 13.2, 11.2 Hz, 2 H, 2ϫCHH), 2.35–
2.45, 2.57–2.68 (2ϫm, 4 H, 2ϫNCH2), 3.10 (d, J = 9.6 Hz, 1 H,
(9ϫArCH), 140.9 (ArC) ppm. IR (neat): ν = 3055, 2930, 1562,
˜
1488, 1461, 1451, 1434, 1298, 1266, 1203, 753, 742, 689 cm–1. MS
(70 eV): m/z (%) = 401 (30) [M]+, 400 (24), 318 (42), 317 (61), 274
(13), 199 (16), 198 (100), 191 (43), 190 (23), 189 (88), 188 (12),
187 (10), 165 (12), 115 (11). HRMS (EI): m/z calcd. for C20H20IN
401.0640; found 401.0610.
NCH), 7.21–7.32 (m,
3 H, 3ϫArH), 7.39–7.48 (m, 2 H,
2ϫArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.9, 26.2, 26.4,
26.9, 30.6, 31.5 (8ϫCH2), 39.7 (CHCH2), 50.9 (2ϫNCH2), 64.5
(NCH), 86.3 (CHCϵC), 87.9 (CHCϵC), 123.9, 127.7, 128.3, 131.8
(5ϫArCH) ppm. IR (neat): ν = 3054, 3025, 2926, 2849, 1597, 1488,
˜
1443, 1102, 996, 753, 689 cm–1. MS (70 eV): m/z (%) = 281 (0.08)
1-[1-(3-Nitrophenyl)-3-phenylprop-2-yn-1-yl]piperidine
(4daa):[29]
[M]+, 199 (16), 198 (100), 115 (18).
Yellow oil. Rf = 0.27 (hexane/EtOAc 9:1). tR = 20.15. 1H NMR
(400 MHz, CDCl3): δ = 1.38–1.49 (m, 2 H, CH2CH2CH2N), 1.52–
1.70 (m, 4 H, 2ϫCH2CH2N), 2.35–2.73 (m, 4 H, 2ϫNCH2), 4.87
(s, 1 H, NCH), 7.30–7.42, 7.47–7.61 (2ϫm, 6 H, 6ϫArCH), 8.01
(d, J = 7.7 Hz, 1 H, ArCH), 8.15 (d, J = 7.7 Hz, 1 H, ArCH), 8.55
(s, 1 H, ArCH) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.4, 26.3,
50.8 (5ϫCH2), 61.8 (NCH), 84.3 (CHCϵC), 89.2 (CHCϵC),
122.7, 123.5, 128.5, 128.6, 129.1, 132.0, 134.6 (9ϫArCH), 122.8,
N-(1-Cyclohexyl-3-phenylprop-2-yn-1-yl)-N-methylaniline (4hfa):[30]
Yellow oil. Rf = 0.85 (hexane/EtOAc 8:2). tR = 17.98. 1H NMR
(400 MHz, CDCl3): δ = 1.06–1.34 (m, 4 H, 2ϫCH2), 1.65–1.93 (m,
6 H, 3ϫCH2), 2.16–2.18 (m, 1 H, CHCH2), 2.91 (s, 3 H, CH3),
4.34 (d, J = 12.8 Hz, 1 H, NCH), 6.72–6.79 (m, 1 H, ArH), 6.84–
6.92 (m, 2 H, 2ϫArH), 7.23–7.30 (m, 5 H, 5ϫArH), 7.36–7.43
(m, 2 H, 2ϫArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 26.1,
26.3, 26.6, 30.3, 30.8 (5ϫCH2), 33.6 (CHCH2), 41.5 (CH3), 58.9
(NCH), 85.4 (CHCϵC), 87.6 (CHCϵC), 111.8, 114.4, 117.7, 128.0,
128.3, 129.2, 131.8 (10ϫArCH), 123.5, 150.7 (2ϫArC) ppm. IR
141.5, 148.4 (3ϫArC) ppm. IR (neat): ν = 3074, 2934, 2848, 2808,
˜
1736, 1528, 1346, 1091, 754, 727, 690 cm–1. MS (70 eV): m/z (%) =
320 (20) [M]+, 319 (12), 277 (10), 236 (45), 199 (18), 198 (100), 190
(26), 189 (48), 115 (13).
(neat): ν = 3058, 3030, 2850, 1596, 1502, 1489, 1275, 750, 689 cm–1.
˜
MS (70 eV): m/z (%) = 303 (6) [M]+, 301 (12), 290 (13), 280 (11),
221 (18), 220 (100), 218 (13), 208 (14), 207 (56), 204 (20), 191 (11),
179 (11), 177 (16), 167 (16), 165 (14), 152 (12), 141 (12), 115 (20),
107 (22), 106 (28), 105 (32), 104 (25), 103 (10), 102 (11), 91 (17),
79 (15), 78 (20), 77 (50), 75 (14), 67 (13), 55 (11), 54 (11), 51 (21).
1-[1-(Naphthalen-2-yl)-3-phenylprop-2-yn-1-yl]piperidine (4eaa):[26]
Beige solid. Rf = 0.50 (hexane/EtOAc 9:1); m.p. 126.4–127.9 °C.
1
tR = 21.44. H NMR (300 MHz, CDCl3): δ = 1.36–1.50 (m, 2 H,
CH2CH2CH2N), 1.52–1.71 (m, 4 H, 2ϫCH2CH2N), 2.60 (s, 4 H,
2ϫNCH2), 4.94 (s, 1 H, NCH), 7.32–7.40 (m, 3 H, 3ϫArH), 7.44–
7.52 (m, 2 H, 2ϫArH), 7.53–7.61 (m, 2 H, 2ϫArH), 7.73–7.79
(m, 1 H, ArH), 7.80–7.92 (m, 3 H, 3ϫArH), 8.08 (s, 1 H,
ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 24.6, 26.3, 60.0
(5ϫCH2), 62.7 (NCH), 86.2 (CHCϵC), 88.2 (CHCϵC), 123.5
(ArC), 126.0, 126.1, 126.8, 127.4, 127.7, 127.9, 128.2, 128.5, 132.0
1-Cyclohexyl-N-methyl-3-phenyl-N-(1-phenylethyl)prop-2-yn-1-
amine (4hga): Diastereoisomer mixture (1:0.80). Yellow solid. Rf =
0.85 (hexane/EtOAc 8:2); m.p. 83.8–86.4 °C. tR = 17.96 and 18.15.
1H NMR (300 MHz, CDCl3): δ = 0.59–1.30, 1.38–1.88, 1.91–2.03
(3ϫm, 20 H, 10ϫCH2), 1.33–1.37 (d,
J = 6.6 Hz, 6 H,
(12ϫArCH), 133.1, 133.2, 136.4 (3ϫArC) ppm. IR (neat): ν =
˜
2ϫCH3CH), 2.05, 2.31 (2ϫs, 6 H, 2 ϫNCH3), 2.09–2.25 (m, 2 H,
2ϫCHCH2), 3.07, 3.59 (2ϫd, J = 10.2 Hz, 2 H, 2ϫNCH), 3.61,
3.69 (2ϫq, J = 6.6 Hz, 2 H, 2ϫCHCH3), 7.15–7.52 (m, 20 H,
20ϫArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.5, 22.1
(2ϫCH3CH), 26.1, 26.2, 26.4. 26.8, 30.3, 31.4, 31.6 (10ϫCH2),
33.0, 35.0 (2ϫCHCH2), 40.2, 40.4 (2ϫNCH3), 57.8, 60.0
3055, 2934, 2356, 1596, 1507, 1488, 1445, 1435, 1266, 784, 762,
695. MS (70 eV): m/z (%) = 325 (14) [M]+, 242 (47), 241 (100), 240
(12), 239 (33), 198 (18).
1-[1-(Benzofuran-2-yl)-3-phenylprop-2-yn-1-yl]piperidine (4faa): Yel-
low solid. Rf = 0.48 (hexane/EtOAc 9:1); m.p. 93.5–96.9 °C. tR
=
20.13. 1H NMR (300 MHz, CDCl3): δ = 1.38–1.52 (m, 2 H, (2ϫNCH), 63.1, 63.2 (2ϫCHCH3), 86.3, 86.5 (2ϫCHCϵC),
CH2CH2CH2N), 1.53–1.79 (m, 4 H, 2ϫCH2CH2N), 2.66 (t, J = 87.6, 87.9 (2ϫCHCϵC), 123.9, 124.0, 126.7, 126.9, 127.5, 127.7,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O20090
/KAP1
Date: 15-03-12 10:53:47
Pages: 13
M. J. Albaladejo, F. Alonso, Y. Moglie, M. Yus
FULL PAPER
127.8, 128.3, 128.4, 131.8, 131.9 (20ϫArCH), 146.1, 146.9
(2R)-1-[(1R)-1,3-Diphenylprop-2-yn-1-yl]-2-(methoxymethyl)-
pyrrolidine (4aia): Diastereoisomer mixture (15:1). Major dia-
(2ϫArC) ppm. IR (neat): ν = 3061, 3027, 2930, 2847, 2359, 2342,
˜
1596, 1488, 1449, 753, 700, 689 cm–1. MS (70 eV) (tR = 17.96): m/z
stereoisomer: Pale yellow oil. Rf = 0.24 (hexane/EtOAc 9:1). [α]2D0
=
(%) = 331 (0.07) [M]+, 249 (10), 248 (100), 144 (58), 115 (14), 105
+89.8 (c = 1.0, CHCl3) [ref.[17a] –107.8 (c 0.34, CHCl3), ent-4aia].
(52), 77 (9). MS (70 eV) (tR = 18.15): m/z (%) = 331 (0.09) [M]+, tR = 17.41. H NMR (300 MHz, CDCl3): δ = 1.56–1.76, 1.88–2.02
1
249 (20), 248 (100), 144 (61), 115 (15), 105 (56), 77 (10). HRMS
(EI): m/z calcd. for C24H29N 331.2300; found 331.2331.
(2 ϫ m, 4 H, CH2CH2CH), 2.52–2.64, 2.68–2.81 (2 ϫ m, 2 H,
NCH2), 3.24–3.36 (m, 1 H, CHCH2), 3.42 (s, 3 H, OCH3), 3.43–
3.58 (m, 2 H, CH2O), 5.33 (s, 1 H, NCH), 7.24–7.38, 7.47–7.54,
7.60–7.67 (3ϫm, 10 H, ArH) ppm. 13C NMR (75 MHz, CDCl3):
δ = 23.2, 28.8 (CH2CH2CH), 48.1 (NCH2), 57.6, 59.3, 60.3 (NCH,
OCH3, CHCH2), 77.16 (CH2O), 86.3 (CHCϵC), 87.7 (CHCϵC),
123.5 (ArC), 127.4, 128.1, 128.2, 128.3, 128.4, 131.9 (10ϫArCH),
1-(1-Cyclohexylnon-2-yn-1-yl)piperidine (4hae):[31] Yellow oil. Rf =
0.79 (hexane/EtOAc 9:1). tR = 15.68. 1H NMR (400 MHz, CDCl3):
δ = 0.89 (t, J = 6.9 Hz, 3 H, CH3), 1.02–1.82 (m, 23 H, 11ϫCH2,
CHCH2), 1.88–2.08 (m, 2 H, CH2), 2.19–2.24 (td, J = 6.9, J =
2.1 Hz, 2 H, CϵCCH2), 2.25–2.35 (m, 2 H, CH2), 2.48–2.57 (m, 2
H, CH2), 2.84 (dt, J = 9.7, J = 1.8 Hz, 1 H, NCH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 14.2 (CH3), 18.8, 22.8, 24.9, 26.3, 26.4,
26.9, 28.7, 29.4, 30.6, 31.3, 31.5 (13ϫCH2), 39.8 (CHCH2), 50.7
(2ϫCH2), 64.1 (NCH), 77.5 (CHCϵC), 85.9 (CHCϵC) ppm. IR
139.9 (ArC) ppm. IR (neat): ν = 3059, 3028, 2871, 1598, 1489,
˜
1448, 1104, 1070, 754, 725, 690 cm–1. MS (70 eV): m/z (%) = 305
(0.20) [M]+, 261 (16), 260 (82), 192 (54), 191 (100), 189 (36), 165
(12). HRMS (EI): m/z calcd. for C21H23NO 305.1780; found
305.1785.
(neat): ν = 2924, 2851, 1449, 1299, 1261, 1230, 1156, 1102,
˜
996 cm–1. MS (70 eV): m/z (%) = 289 (0.21) [M]+, 207 (31), 206
(2R)-2-(Methoxymethyl)-1-[(3R)-1-phenyldodec-1-yn-3-yl]pyrrol-
idine (4gia): Diastereoisomer mixture (10:1). Major diastereoisomer:
Yellow oil. Rf = 0.16 (hexane/EtOAc 9:1). [α]2D0 = 71.9 (c = 1.0,
(100).
N,N-Diethyl-3-phenylprop-2-yn-1-amine (4iha):[32] Yellow oil. Rf =
0.42 (hexane/EtOAc 8:2). tR = 16.31. 1H NMR (300 MHz, CDCl3):
δ = 1.14 (t, J = 7.2 Hz, 6 H, 2ϫCH3), 2.67 (q, J = 6.8 Hz, 4 H,
2ϫCH2CH3), 3.68 (s, 2 H, CH2N), 7.26–7.32 (m, 3 H, 3ϫArH),
7.39–7.46 (m, 2 H, 2ϫArH) ppm. 13C NMR (75 MHz, CDCl3): δ
= 12.5 (2ϫCH3), 41.4 (2ϫCH2CH3), 47.4 (CH2CϵC), 83.9
(CHCϵC), 85.4 (CHCϵC), 123.3, 128.1, 128.4 (5ϫArCH), 131.8
1
CHCl3). tR = 18.53. H NMR (400 MHz, CDCl3): δ = 0.88 (t, J =
6.8 Hz, 3 H, CH3CH2), 1.22–1.37, 1.39–1.95 (2ϫm, 20 H,
10ϫCH2), 2.74 (q, J = 8.4 Hz, 1 H, NCHAHB), 2.89–2.97 (m, 1
H, NCHAHB), 3.07–3.16 (m, 1 H, CHCH2O), 3.28–3.44 (m, 2 H,
CH2O), 3.37 (s, 3 H, CH3O), 3.90 (t, J = 7.4 Hz, 1 H, NCH),
7.25–7.31, 7.39–7.45 (2ϫm, 5 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 14.3 (CH3CH2), 22.8, 23.3, 26.9, 28.5, 29.5, 29.6, 29.7,
32.1, 35.3, 47.8 (11ϫCH2), 53.9 (NCH), 59.3 (OCH3), 60.6
(CHCH2O), 76.5 (CH2O), 85.2 (CHCϵC), 88.9 (CHCϵC), 123.7
(ArC) ppm. IR (neat): ν = 3079, 3056, 2969, 2818, 1597, 1488,
˜
1321, 1068, 754, 690 cm–1. MS (70 eV): m/z (%) = 187 (10) [M]+,
172(49), 116 (13), 115 (100).
(ArC), 127.9, 128.3, 131.9 (5ϫArCH) ppm. IR (neat): ν = 3055,
˜
1-[(5S)-5,9-Dimethyl-1-phenyldec-8-en-1-yn-3-yl]piperidine (4jaa):
Diastereoisomer mixture (2.5:1) separated by column chromatog-
raphy.
3035, 2922, 2853, 1597, 1488, 1457, 1441, 1106, 754, 722, 690 cm–1.
MS (70 eV): m/z (%) = 355 (0.19) [M]+, 311 (29), 310 (100), 229
(10), 228 (65), 143 (13), 129 (16), 128 (20), 117 (19), 115 (28), 95
(13), 91 (26), 70 (49). HRMS (EI): m/z calcd. for C24H37NO
355.2875; found 355.2895.
Major diastereoisomer: Yellow oil. Rf = 0.61 (hexane/EtOAc 9:1).
[α]2D0 = –9.1 (c = 1.0, CHCl3). tR = 17.20. 1H NMR (400 MHz,
CDCl3): δ = 0.96 (d, J = 6.4 Hz, 3 H, CHCH3), 1.09–1.28 (m, 1 H,
CHCH3), 1.36–1.49, 1.50–1.84 (2ϫm, 16 H, 5ϫCH2, 2ϫCH3),
1.90–2.11 (m, 2 H, CHCH2CH2), 2.39–2.53, 2.59–2.74 (2ϫm, 4 H,
2ϫNCH2), 3.51–3.63 (dd, J = 8.4, 6.8 Hz, 1 H, NCH), 5.06–5.16
[td, J = 6.4, J = 1.5 Hz, 1 H, CHC(CH3)2], 7.22–7.33 (m, 3 H,
3ϫArH), 7.38–7.46 (m, 2 H, 2ϫArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 17.8, 20.1, 25.9 (3ϫCH3), 24.8, 25.6, 26.4, 36.7, 40.5,
50.7 (8ϫCH2), 29.8 (CHCH3), 56.4 (NCH), 85.6 (CHCϵC), 88.6
(CHCϵC), 123.8 (ArC), 125.0 (C=CH), 127.8, 128.3, 131.8
1-(1-Deuterio-1,3-diphenylprop-2-yn-1-yl)piperidine
(D1-4aaa):[33]
Yellow solid. Rf = 0.42 (hexane/EtOAc 9:1); m.p. 55.7–57.6 °C. tR
= 16.82. 1H NMR (300 MHz, CDCl3): δ = 1.30–1.42 (m, 2 H,
CH2CH2CH2N), 1.42–1.62 (m, 4 H, 2ϫCH2CH2N), 2.49 (t, J =
5.3 Hz, 4 H, 2ϫNCH2), 7.16–7.32 (m, 6 H, 6ϫArH), 7.40–7.49
(m, 2 H, 2ϫArH), 7.52–7.60 (m, 2 H, 2ϫArH) ppm. 13C NMR
1
(75 MHz, CDCl3): δ = 24.6, 26.3, 50.8 (5ϫCH2), 62.1 (t, JC,D
=
84 Hz, NCD), 86.1 (CHCϵC), 88.0 (CHCϵC), 123.5 (ArC), 127.6,
128.2, 128.4, 128.7, 131.9 (10ϫArCH), 138.6 (ArC) ppm. IR
(5ϫArCH), 131.3 (C=CH) ppm. IR (neat): ν = 2929, 2852, 1488,
˜
(neat): ν = 3052, 3016, 2934, 2923, 2366, 1953, 1596, 1487, 1446,
˜
1452, 1441, 1155, 1101, 754, 690 cm–1. MS (70 eV): m/z (%) = 323
(0.29) [M]+, 199 (17), 198 (100), 138 (17), 115 (18), 102 (9). HRMS
(EI): m/z calcd. for C23H33N 323.2613; found 323.2586.
1103, 757, 718, 693 cm–1. MS (70 eV): m/z (%) = 277 (10)
[M + 1]+, 276 (50) [M]+, 275 (22), 200 (26), 199 (100), 193 (43),
192 (100), 191 (12), 190 (40), 189 (11), 166 (12), 116 (17).
Minor diastereoisomer: Yellow oil. Rf = 0.45 (hexane/EtOAc 9:1).
[α]2D0 = –16.9 (c = 1.0, CHCl3). tR = 17.16. 1H NMR (400 MHz,
CDCl3): δ = 0.95 (d, J = 6.5 Hz, 3 H, CHCH3), 1.18–1.31 (m, 1 H,
CHCH3), 1.33–1.52, 1.53–1.86 (m, 16 H, 5ϫCH2, 2ϫCH3), 1.93–
2.09 (m, 2 H, CHCH2CH2), 2.40–2.57, 2.63–2.76 (2ϫm, 4 H,
2ϫNCH2), 3.53–3.63 (dd, J = 10.2, 4.6 Hz, 1 H, NCH), 5.05–5.18
[td, J = 6.4, 1.3 Hz, 1 H, CHC(CH3)2], 7.23–7.33 (m, 3 H,
3ϫArH), 7.39–7.47 (m, 2 H, 2ϫArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 17.8, 19.4, 25.8 (3ϫCH3), 24.8, 25.5, 26.4, 37.7, 40.4,
50.9 (8ϫCH2), 29.9 (CHCH3), 56.9 (NCH), 85.9 (CHCϵC), 88.2
(CHCϵC), 123.8 (ArC), 125.0 (C=CH), 127.9, 128.3, 131.8
General Procedure for the KA2 Coupling Catalyzed by CuNPs/TiO2:
Cyclohexanone (1k, 0.1 mL, 1.0 mmol), an amine 2 (1.0 mmol),
and phenylacetylene (3a, 0.1 mL, 1.0 mmol) were placed in a reac-
tor tube containing CuNPs/TiO2 (20 mg, ca. 0.5 mol-%) and
CH2Cl2 (2 mL). The reaction mixture was warmed to 70 °C with-
out exclusion of air and monitored by TLC and/or GLC until total
conversion of the starting materials. EtOAc (2 mL) was added to
the resulting mixture, followed by filtration through celite and
washing with additional EtOAc (4 mL). The crude reaction product
was purified by column chromatography (silica gel, hexane/EtOAc)
to give the corresponding pure propargylamines 4kaa and 4kea.
(5ϫArCH), 131.3 (C=CH) ppm. IR (neat): ν = 2929, 2852, 1488,
˜
1452, 1441, 1155, 1102, 754, 690 cm–1. MS (70 eV): m/z (%) = 323
1-[1-(Phenylethynyl)cyclohexyl]piperidine (4kaa):[24] Pale yellow so-
(0.25) [M]+, 199 (17), 198 (100), 138 (15), 115 (18), 102 (10). HRMS lid. Rf = 0.15 (hexane/EtOAc 9:1); m.p. 35.5–38.9 °C. tR = 15.99.
(EI): m/z calcd. for C23H33N 323.2613; found 323.2577.
1H NMR (300 MHz, CDCl3): δ = 1.07–1.79, 1.99–2.15, 3.58–3.78
10
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20090
/KAP1
Date: 15-03-12 10:53:47
Pages: 13
Cu-Catalyzed Three-Component Coupling Reactions
bohydr. Chem. 1990, 9, 767–770; c) I. Imada, M. Yuasa, I. Nak-
(3ϫm, 20 H, 10ϫCH2), 7.21–7.34, 7.38–7.48 (2ϫm, 5 H,
5ϫArCH) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.2, 24.9, 25.9,
26.8, 35.9, 47.3 (10ϫCH2), 59.4 (NC), 86.2 (CϵCAr), 90.9
(CϵCAr), 123.9 (ArC), 127.7, 128.3, 131.8 (5ϫArCH) ppm. IR
amura, S.-I. Murahashi, J. Org. Chem. 1994, 59, 2282–2284.
For reviews, see: a) R. Bloch, Chem. Rev. 1998, 98, 1407–1438;
b) V. V. Kouznetsov, L. Y. Vargas Méndez, Synthesis 2008, 491–
506; c) G. Blay, A. Monleón, J. R. Pedro, Curr. Org. Chem.
2009, 13, 1498–1539.
[6]
[7]
[8]
(neat): ν = 3055, 2986, 2920, 2851, 1709, 1488, 1443, 1291, 1092,
˜
759, 692 cm–1. MS (70 eV): m/z (%) = 267 (50) [M]+, 266 (20), 253
(15), 252 (80), 238 (25), 225 (41), 224 (100), 211 (15), 210 (41), 196
(10), 190 (27), 155 (15), 142 (10), 141 (43), 128 (25), 127 (17), 115
(40), 91 (11), 84 (23).
For reviews, see: a) C. Wei, Z. Li, C.-J. Li, Synlett 2004, 1472–
1483; b) L. Zani, C. Bolm, Chem. Commun. 2006, 4263–4275;
c) C.-J. Li, Acc. Chem. Res. 2010, 43, 581–590; d) W.-J. Yoo, L.
Zhao, C.-J. Li, Aldrichim. Acta 2011, 44, 43–51.
For recent reviews and monographs, see: a) Nanoparticles and
Catalysis (Ed.: D. Astruc), Wiley-VCH, Weinheim, Germany,
2008; b) M. Kidwai, in: Handbook of Green Chemistry (Eds.:
P. T. Anastas, R. H. Crabtree), Wiley-VCH, Weinheim, Ger-
many, 2009, vol. 2, pp. 81–92; c) N. Yan, C. Xiao, Y. Kou, Co-
ord. Chem. Rev. 2010, 254, 1179–1218; d) V. Polshettiwar, R. S.
Varma, Green Chem. 2010, 12, 743–754.
For recent reviews, see: a) J. Sun, X. Bao, Chem. Eur. J. 2008,
14, 7478–7488; b) R. J. White, R. V. Luque, L. Budarin, J. H.
Clark, D. J. Macquarrie, Chem. Soc. Rev. 2009, 38, 481–494; c)
J. M. Campelo, D. Luna, F. Luque, J. M. Marinas, A. A. Ro-
mero, ChemSusChem 2009, 2, 18–45; d) L. De Rogatis, M.
Cargnello, V. Gombac, B. Lorenzut, T. Montini, P. Fornasiero,
ChemSusChem 2010, 3, 24–42.
a) M. Kidwai, V. Bansal, N. K. Mishra, A. Kumar, S. Mozum-
dar, Synlett 2007, 1581–1584; b) M. Lakshmi Kantam, S. Laha,
J. Yadav, S. Bhargava, Tetrahedron Lett. 2008, 49, 3083–3086.
For reviews, see: a) F. Alonso, G. Radivoy, M. Yus, Russ. Chem.
Bull. Int. Ed. 2003, 52, 2563–2576; b) F. Alonso, M. Yus, Chem.
Soc. Rev. 2004, 33, 284–293; c) F. Alonso, M. Yus, Pure Appl.
Chem. 2008, 80, 1005–1012; d) F. Alonso, P. Riente, M. Yus,
Acc. Chem. Res. 2011, 44, 379–391.
N-Benzyl-N-methyl-1-(phenylethynyl)cyclohexanamine (4kea): Pale
yellow oil. Rf = 0.67 (hexane/EtOAc 9:1). tR = 18.23. 1H NMR
(400 MHz, CDCl3): δ = 1.24–1.42, 1.56–1.83, 2.03–2.14 (3ϫm, 10
H, 5ϫCH2), 2.20 (s, 3 H, CH3), 3.68 (s, 2 H, NCH2), 7.20–7.25
(m, 1 H, ArH), 7.26–7.35 (m, 5 H, 5ϫArH), 7.36–7.41 (m, 2 H,
2ϫArH), 7.45–7.52 (m, 2 H, 2ϫArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 23.0, 25.9, 36.8, 55.8 (6ϫCH2), 35.5 (CH3), 59.2 (NC),
85.66 (CϵCAr), 90.89 (CϵCAr), 123.9 (ArC), 126.7, 127.8, 128.3,
[9]
128.4, 128.9, 131.9 (10ϫArCH), 141.3 (ArC) ppm. IR (neat): ν =
˜
3028, 2929, 2853, 1597, 1489, 1443, 1290, 1057, 754, 735, 690 cm–1.
MS (70 eV): m/z (%) = 303 (23) [M]+, 302 (11), 288 (38), 274 (11),
261 (23), 260 (100), 247 (21), 246 (44), 226 (14), 142 (19), 141 (14),
128 (13), 127 (12), 115 (31), 102 (23), 91 (83), 77 (10), 68 (10), 65
(11). HRMS (EI): m/z calcd. for C22H25N 303.1987; found
303.1989.
[10]
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Acknowledgments
This work was generously supported by the Spanish Ministerio de
Ciencia e Innovación (MICINN) (grant numbers CTQ2007-65218,
CTQ2011-24151), Consolider Ingenio (grant number 2010-
CSD2007-00006), the Generalitat Valenciana (grant number PRO-
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Job/Unit: O20090
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Date: 15-03-12 10:53:47
Pages: 13
M. J. Albaladejo, F. Alonso, Y. Moglie, M. Yus
FULL PAPER
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Received: January 26, 2012
Published Online: ᭿
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www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20090
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Date: 15-03-12 10:53:47
Pages: 13
Cu-Catalyzed Three-Component Coupling Reactions
Multicomponent Reactions
M. J. Albaladejo, F. Alonso,* Y. Moglie,
M. Yus ............................................ 1–13
Three-Component Coupling of Aldehydes,
Amines, and Alkynes Catalyzed by Oxid-
ized Copper Nanoparticles on Titania
A3 coupling catalyzed by ultrafine copper
nanoparticles on titania under solvent-free
conditions is described. Some examples of
KA2 coupling are also reported. The cata-
lyst is reusable and exhibited better per-
formance than commercially available cop-
per catalysts. The participation of copper(I)
acetylides in a heterogeneous process has
been demonstrated.
Keywords: Multicomponent reactions
/
Nanoparticles / Copper / Alkynes / Alde-
hydes / Amines
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
13