Gold-nanoparticle-catalyzed synthesis of propargylamines: The traditional A3-multicomponent reaction performed as a two-step flow process

Article abstract of DOI:10.1002/chem.201002043

The alkyne, aldehyde, amine A³-coupling reaction, a traditional multicomponent reaction (MCR), has been investigated as a two-step flow process. The implicated aminoalkylation reaction of phenylacetylene with appropriate aldimine intermediates

Full text of DOI:10.1002/chem.201002043

FULL PAPER
DOI: 10.1002/chem.201002043
Gold-Nanoparticle-Catalyzed Synthesis of Propargylamines: The Traditional
A3-Multicomponent Reaction Performed as a Two-Step Flow Process
Lahbib Abahmane, J. Michael Kçhler, and G. Alexander Groß*[a]
Abstract: The alkyne, aldehyde, amine
A3-coupling reaction, a traditional mul-
ticomponent reaction (MCR), has been
investigated as a two-step flow process.
The implicated aminoalkylation reac-
tion of phenylacetylene with appropri-
ate aldimine intermediates was cata-
lyzed by gold nanoparticles impregnat-
ed on alumina. The aldimine formation
was catalyzed by Montmorillonite K10
beforehand. The performance of the
process has been investigated with re-
spect to different reaction regimes.
Usually, the A3-multicomponent reac-
tion is performed as a “one-pot” pro-
cess. Diversity-oriented syntheses using
MCRs often have the shortcoming that
only low selectivity and low yields are
achieved. We have used a flow-chemis-
try approach to perform the A3-MCR
in a sequential manner. In this way, the
reaction performance was significantly
enhanced in terms of shortened reac-
tion time, and the desired propargyl-
amines were obtained in high yields.
Keywords: flow chemistry · gold ·
multicomponent reactions · nano-
particles · packed-bed capillary re-
actor · propargylamines
Introduction
Hence, catalyzed one-pot strategies will only be successful if
the applied catalysts are compatible with all intermediate re-
action steps. The immobilization of catalysts on solid sup-
ports enables heterogeneous catalyzed reactions to be con-
ducted even in flow processes.[7] A great variety of catalysts
and support materials is available. Flow chemistry uses
micro reaction technologies to carry out chemical reactions
under controlled-flow conditions.[8] The sequential applica-
tion of different heterogeneous catalysts in a continuous-
flow system allows MCRs to be conducted in a stepwise
manner without a change of solvent. In this way, different
catalysts can be applied for the individual reaction steps
without detrimental influence on previous or subsequent re-
action steps. Solutions of building blocks can be introduced
into the flow system just before the catalyst. Side reactions
by interference of unreacted building blocks with other reac-
tion intermediates can also be circumvented by adopting
this approach. The application of a micro flow system ena-
bles fast temperature changes so that different temperatures
can be applied for each reaction step. Individual optimiza-
tion of the reaction selectivity and kinetics of each step can
improve the efficiency of the overall MCR sequence.[9]
Some examples of MCRs in micro flow-through reactors
have been described previously.[10] However, the solvent and
energy consumptions of sequential MCR processing appear
to be comparable to those of the equivalent batch processes.
Nevertheless, in terms of green chemistry aspects, the flow-
chemistry approach seems to be advantageous because the
overall reaction yields may be considerably enhanced.
Multicomponent reactions (MCRs), such as the A3-reac-
tion,[1] enable the formation of complex molecules in just
one reaction step. High molecular diversity can thereby be
obtained because different building block combinations
enable easy variation of the moieties on the final molecule.[2]
MCRs[3] such as the Ugi reaction,[4] the Mannich reaction,[5]
or the Biginelli reaction,[6] for example, offer great potential
for diversity-oriented synthesis. However, the mechanisms
of MCRs involve different intermediate states that have to
be traversed sequentially en route to the final product. The
consequent complexity of the reaction sometimes results in
low yields and low selectivity in favor of the desired prod-
uct, thus necessitating the application of costly separation
procedures. The intensification of MCRs by heating to im-
prove the kinetics is difficult because the reaction selectivity
of the involved intermediate states may get lost. Carrying
out the desired reaction steps by the sequential addition of
the building blocks to the reaction flask can help to over-
come this problem. In such “one-pot” reactions, a necessary
catalyst for one reaction step cannot be kept apart from sub-
sequent reaction steps that may be disturbed by this catalyst.
[a] L. Abahmane, J. M. Kçhler, Dr. G. A. Groß
Institute for Micro- and Nanotechnology
Department of Physical Chemistry and Micro Reaction Technology
Ilmenau University of Technology
Weimarerstrasse 32, 98693 Ilmenau (Germany)
E-mail: alexander.gross@tu-ilmenau.de
Propargylamine derivatives (5) are interesting molecules
for drug screening, useful intermediates for heterocycle syn-
thesis, and are involved in many different synthetic strat-
egies.[11] The three-component coupling reaction of aldehyde
(1), amine (2), and alkyne (4) building blocks furnishes
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002043: Preparative proce-
dure for Au nanoparticles; details of the packed-bed capillary reac-
tors and flow-reaction procedure; full spectroscopic data of all prod-
ucts.
Chem. Eur. J. 2011, 17, 3005 – 3010
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step individually. For the initial
condensation reaction, Mont-
morillonite K-10 (MM K-10)
was used to produce the ald-
AHCTUNGTRENNUNG
a
combined Brønsted and Lewis
acidic activity, and has been
used previously as a catalyst for
various reactions.[20] For the
subsequent alkyne addition
step, Au nanoparticles support-
Scheme 1. Aminoalkylation of alkynes (4) by the aldimine intermediate 3 in a two-step reaction sequence.
Two different heterogeneous catalysts (Montmorillonite K-10, Au-NP@Al2O3) were applied sequentially at dif-
ferent reaction temperatures.
propargylamine derivatives of type 5 (Scheme 1). The neces-
sary two-step pathway for this reaction involves addition of
the alkyne (4) to an aldimine intermediate (3). Hence, the
initial reaction step involves the formation of the aldimine
(3) intermediate by condensation of an aldehyde (1) and an
amine (2) prior to addition of the alkyne (4). The initial con-
densation can be promoted by Lewis or Brønsted acids,
whereas the second reaction step needs transition metal cat-
ed on Al2O3 (Au-NP@Al2O3) were used. To this end, Au
nanoparticles of about 2 nm diameter were prepared.[21]
Basic alumina powder was then impregnated with these
nanoparticles according to a literature procedure[22] (see the
Supporting Information). The resulting catalysts were used
as obtained, without further calcination or redox activation.
Both catalyst materials were used as packed-bed capillary
reactors (PBCR) assembled in a bench-top micro flow
system (Scheme 2). PBCR1 was filled with MM K-10, and
PBCR2 was filled with Au-NP@Al2O3. This combination of
catalysts has previously been used to good effect for the syn-
thesis of pyridine and polypyridine derivatives.[22,23]
alysis. Several catalysts have been employed to assist the
3
À
A -reaction by C H activation. Various metal ions, such as
FeIII,[12] CuI,[13] AgI, and AuI/AuIII,[14] as well as Ir, In, and
Zn[15] compounds, have been investigated as effective cata-
lysts. Various nanoparticular metals[16] and metal oxides[17]
have also been investigated as
catalysts for the A3-reaction.
Colloidal nanoparticles of Ni,
Cu, Ag, and Au were investi-
gated by Kindwai et al.[16,18] Au
nanoparticles were found to be
highly active. Zhou et al. made
use of silver oxide nanoparticles
supported on different materi-
als, such as multiwalled nano-
tubes, diatomite, silica, and alu-
mina.[17b] Superior catalytic per-
formance was observed for the
alumina support, but the au-
thors noted a decrease in reac-
tivity after repeated use. Chng
et al. made use of Au nanopar-
ticles supported on quantum
dots.[19] However, most of the
described catalysts need several
hours to yield high conver-
sion.[18a,19] To the best of our
knowledge, alumina-supported
Au nanoparticles have not hith-
erto been investigated as a cata-
lyst for the A3-reaction.
Results and Discussion
Scheme 2. Flow chemistry set-up schemes for the different reaction regimes A–C. P1, P2 pumps; P(1) pressure
sensor; T(1), T(2) temperature sensors; PBCR1 (Montmorillonite K-10) and PBCR2 (Au-NP@Al2O3):
We have used two different ma-
terials to catalyze each reaction packed-bed capillary reactors; BPR: back-pressure regulator.
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Chem. Eur. J. 2011, 17, 3005 – 3010

Propargylamine Synthesis by a Two-Step Flow Process
FULL PAPER
To investigate the performance of the process, the reac-
tion sequence was carried out under different regimes:
A) the catalytic potentials of PBCR1 and PBCR2 for the
three-component reaction were investigated independently
of one another; B) solutions of all three building blocks
were mixed and fed sequentially through PBCR1 and
PBCR2 at different temperatures; C) the aldehyde and
amine building block solutions were mixed and fed through
PBCR1, and then the alkyne solution was added to the in-
termediate product stream before implementation of
PBCR2. These set-up modes are illustrated in Scheme 2. In
the case of regime C, each solution was fed at the same flow
rate. However, the flow rate for PBCR2 was twice that for
PBCR1. In other words, the residence time in PBCR2 was
half of that in PBCR1.
small amounts at about 1208C (Table 1, entries 5 and 6).
Hence, the catalytic capabilities of both catalysts were low
or absent when they were used independently. Reaction
regime B involved subjecting the premixed building blocks
to both catalysts sequentially, which enabled the formation
of intermediate 3 under MM K-10 catalysis in the presence
of phenylacetylene (4). When the intermediate reaction mix-
ture passed the second PBCR2, formation of the desired
propargylamine (5) under Au-NP@Al2O3 catalysis was an-
ticipated. However, the observed process performance was
low, with only 13% conversion to 5 (Table 1, entry 7). When
the reaction was investigated under flow regime C, the de-
sired product was obtained in a fair yield of about 40%
(Table 1, entry 8). Hence, regime C clearly gave the best re-
action performance.
The product profiles generated under the different reac-
tion regimes were analyzed by LC-MS and studied for par-
ticular combinations of building blocks. The regime giving
the best reaction performance was optimized in greater
detail. Therefore, different reaction temperatures, residence
times (flow rates), stoichiometries, and solvents were investi-
gated. The optimized conditions were applied to produce
about 25 representative propargylamines using different
building blocks.
The conditions for the different reaction regimes were op-
timized using benzaldehyde (1a), piperidine (2a), and phe-
nylacetylene (4). For reaction regimes A–C, 0.5 molLÀ1
ethanolic solutions of these compounds were applied at
50 mLminÀ1. The obtained results are summarized in
Table 1. The thermal reaction under regime A without any
We further optimized the reaction regime C by tuning the
reaction conditions for both PBCRs separately. First, the ini-
tial condensation reaction was investigated. To this end, a
premixed ethanolic solution of benzaldehyde (1a) and piper-
idine (2a) was fed through the first PBCR1 and the inter-
mediate reaction product 3 was analyzed by GC-MS. Reac-
tant concentrations of 0.5 molLÀ1 were used. The reaction
profile of the intermediate aldimine (3) was analyzed with
respect to the flow rate and the temperature. It was found
that near-quantitative conversion was achieved at ambient
temperature (about 258C) and 60 min residence time
(50 mLminÀ1) (Figure 1a). Elevated temperatures (40–
1008C) led to significantly decreased yields. Hence, PBCR1
was used at ambient temperature.
The second reaction step catalyzed by Au-NP@Al2O3 was
investigated with respect to the reaction temperature, flow
rate, and catalyst loading. Motivated by literature reports,
we carried out the reaction with 1.5 equivalents of phenyla-
cetylene (4) at 808C. The obtained conversions are shown in
Figure 1b. It was found that complete conversion could not
be achieved within 30 min residence time (PBCR2) at a cat-
alyst loading of about 1.25 wt.% Au. However, a loading of
about 2.5 wt.% Au led to full conversion of the aldehyde
(1a) within 30 min (Table 1, entry 9). Variation of the reac-
tion temperature led to lower performance at both loading
levels (Figure 2). That is to say, the best yield of the desired
propargylamine (5) was obtained at 808C. Finally, we sought
to ascertain whether a 1.5-fold stoichiometric excess of phe-
nylacetylene (4), as mentioned in many literature reports,
was in fact necessary. Reduction of the 1.5 equivalent excess
to a stoichiometric ratio proved to have no influence; con-
versions of about 97% were observed in both cases. Differ-
ent solvents (methanol, acetonitrile, toluene, water) were
also tested for the overall process, but ethanol was found to
be the most effective. In previous studies, the lifetime per-
formance of the Au-NP@Al2O3 catalyst was investigated
over 48 h. A marginal decrease in the catalytic performance
was observed after 12 h of continuous use.[22] Hence, we re-
newed the catalyst in PBCR2 after 12 h of operation time.
To identify any leaching of the Au catalyst, a batch of about
1 mmol of propargylamine (5a) was synthesized using fresh-
ly prepared catalyst. The crude product was concentrated in
Table 1. Reaction performance in dependence on the reaction regime as
shown in Scheme 2 at constant flow rate (0.5 mol LÀ1, ethanolic solution,
50 mLminÀ1 per feed[a], 1.25 wt.% Au-NP@Al2O3).
Entry
Reaction
regime
Catalyst
Temp.
[8C]
Conv.
[%][b]
AHCTUNGTRENNUNG
1
2
3
4
5
6
80
150
25
80
25
80
25
80
25
80
25
80
0
0
0
0
0
5
A
A
A
B
C
C
no catalyst
MM K-10
1.25% Au-NP@Al2O3
MM K-10
1.25% Au-NP@Al2O3
MM K-10
1.25% Au-NP@Al2O3
MM K-10
2.5% Au-NP@Al2O3
7
8
9
13
44
97
[a] Fluidic residence times: PBCR1 60 min; PBCR2 30 min. [b] Calculat-
ed for benzaldehyde.
catalytic support was attempted at up to 1508C (Table 1, en-
tries 1 and 2), but the desired propargylamine (5a) was not
observed. The use of Montmorillonite K-10 alone under
regime A did not yield the desired product either (Table 1,
entries 3 and 4). The use of Au-NP@Al2O3 alone (at a load-
ing of 1.25wt.% Au) yielded the desired product in very
Chem. Eur. J. 2011, 17, 3005 – 3010
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3007

G. A. Groß et al.
vacuum at 1808C overnight and the residue was investigated
by EDX analysis. However, no trace of Au was observed.
To demonstrate the potential of the optimized process,
different building block combinations were used. The ob-
tained conversions and yields are shown in Table 2. Fair to
Table 2. Results for various building blocks using reaction regime C
(Scheme 1).
Entry
Aldehyde
Amine
2
Product
Conv.
[%][a]
Yield
[%][b]
1
5
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
1c
1c
1c
1c
1d
1d
1d
1d
1d
1e
1e
1e
1e
1e
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
5a
5b
5c
5d
5e
5 f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
97
54
95
91
88
99
85
97
88
92
70
43
53
70
56
99
99
93
99
99
92
80
99
99
99
96
52
92
89
83
99
80
95
86
88
66
40
49
65
53
99
88
90
97
98
89
76
90
94
93
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Figure 1. a) Conversion of benzaldehyde (1a) to the intermediate aldi-
mine (3) determined by GC-MS for PBCR1 (258C, flow rates 50–
500 mLminÀ1), b) total product formation determined by HPLC analysis
after application of both catalysts according to regime C (PBCR2, 808C,
flow rates 100–1000 mLminÀ1).
5s
5t
5u
5v
5w
5x
5y
[a] Determined by HPLC. [b] Yield of isolated product after flash chro-
matography.
excellent yields were obtained. Previously published meth-
ods for A3-coupling have been largely limited to aromatic
aldehydes and cyclic aliphatic amines. However, we ob-
served excellent conversions of the investigated aliphatic al-
dehydes (Table 2, entries 16–25). Cyclic aliphatic amines
with five-, six-, and seven-membered rings have been suc-
cessfully used in previous work. However, acyclic aliphatic
amines have only rarely been used for the A3-reaction and
they seem to be difficult building blocks.[10f] We chose two
acyclic aliphatic amines: diethylamine (2b) and N-methyl-2-
ethanolamine. In both cases, fair to good yields were ob-
tained. The hydroxyl groups of the obtained propargylamine
compounds (5e, 5j, 5o, 5t, and 5y) were found to be unaf-
fected. Excellent yields of the desired propargylamine deriv-
Figure 2. Conversion of benzaldehyde (1a) according to regime C deter-
mined by HPLC for different reaction temperatures (total flow rate
50 mLminÀ1).
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Propargylamine Synthesis by a Two-Step Flow Process
FULL PAPER
atives (5) were obtained even when acyclic amines were
used in combination with aliphatic aldehydes (Table 2, en-
tries 17, 20, 22, and 25). The flow regime clearly had a signif-
icant influence on the reaction performance. Neither cata-
lyst was able to catalyze the multicomponent reaction inde-
pendently (Table 1, entries 1–5). Even the serial arrange-
ment of the catalysts under flow regime B showed only a
low reaction performance (Table 1, entry 7). Only flow
regime C was able to exploit the full potential of both cata-
lysts. Significant reaction intensification in terms of reduced
reaction times (60 min for the first step, 30 min for the
second step), as well as good conversion of demanding
building blocks, was achieved by utilization of the flow-
chemistry technique.
Experimental Section
General procedure for the flow-through preparation of propargylamines
(5): The respective aldehydes (1a–e) (1.0 mmol, 1.0 equiv), amines (2a–
e) (1.0 mmol, 1.0 equiv), and phenylacetylene (4) (1.0 mmol, 1.0 equiv)
were each dissolved in aliquots of anhydrous ethanol (2 mL). PBCR1
(L1=50 cm, ID=1.0 mm) was filled with Montmorillonite K-10 powder
(Fluka) (400 mg) and 3 ꢁ molecular sieve beads (Alfa Aesar) (40 mg).
PBCR2 (L1=50 cm, ID=1.0 mm) was packed with Au-NP@Al2O3 cata-
lyst (380 mg). The continuous-flow reaction system was primed with an-
hydrous ethanol (20 mL) before use. The ethanolic aldehyde and amine
solutions were mixed and fed through PBCR1 at 50 mLminÀ1. The phe-
nylacetylene (4) solution was added at 50 mLminÀ1 to the intermediate
product stream immediately before PBCR2. The crude reaction mixture
was collected and analyzed by LC-MS. After evaporation of the solvent
under vacuum, the product was purified by flash chromatography.
Conclusion
Acknowledgements
MCRs are usually carried out as one-pot reactions. Thereby,
detrimental interferences between the different reaction in-
termediates and the catalysts or other building blocks often
lead to low selectivity and poor yields. Serial performance
of the respective reaction steps by means of flow chemistry
enables processing under reaction regimes that prevent such
detrimental interferences between reagents and catalysts.
Each reaction step can be optimized separately and finally
arranged as a flow-through system without a change of sol-
vent. We have verified this recent concept for the traditional
A3-MCR.
Financial support from the Stiftung fꢂr Technologie, Innovation und For-
schung, STIFT-Thꢂringen and the Deutsche Forschungsgemeinschaft
(DFG) (FKZ: KO 1403/22–1) is gratefully acknowledged. The sedulous
support for compound analysis from S. Gꢂnther, K. Risch, and U. Ritter
is gratefully acknowledged. The authors thank S. Schneider for the flow
set-up realization and software development and S. Singh for helpful dis-
cussions.
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Received: July 19, 2010
Revised: October 7, 2010
Published online: January 31, 2011
3010
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