Supported gold(III) catalysts for highly efficient three-component coupling reactions

Article abstract of DOI:10.1002/anie.200800098

(Chemical Equation Presented) Charged gold species stabilized on nanocrystalline CeO₂ or ZrO₂ are highly active catalysts for the one-pot, three-component coupling of aldehydes, amines, and alkynes/N-protected ethynylaniline, which yields multifunctionalized propargylamines and indoles in good to excellent yields (see picture; Ts=toluene-4-sulfonyl).

Full text of DOI:10.1002/anie.200800098

Communications
DOI: 10.1002/anie.200800098
Supported Catalysts
Supported Gold(III) Catalysts for Highly Efficient Three-Component
Coupling Reactions**
Xin Zhang and Avelino Corma*
Over the past few years gold has emerged as a source of
effective heterogeneous[1] and homogeneous catalysts,[2] rep-
resented by supported gold nanoparticles and gold salts/
complexes, respectively. Both these types of catalyst have
their advantages and disadvantages.[2,3] Attempts to bridge the
gap between homogeneous and heterogeneous gold catalysis
will lead to more efficient and environmentally friendly
methods for chemical synthesis.[4] Our group has recently
been carrying out comparative studies on homogeneous and
heterogeneous gold catalysts for a series of reactions.[1e,4b,5] This
methodology, combined with theoretical calculations,[5f] has
allowed us to design effective gold catalysts and rationalize the
nature of different catalytic sites present on supported gold
nanoparticles. We have noticed, however, that although
catalytic multicomponent reactions for efficient organic syn-
thesis are recognized as an atom-economic route to green
chemistry, the possibilities offered by supported gold catalyst
have scarcely been explored to date.[6] We show herein that the
appropriate choice of heterogeneous gold catalysts offers
unique possibilities for multicomponent reactions.
Propargylamines are versatile synthetic intermediates in
organic synthesis and are also important structural elements
in natural products and therapeutic drug molecules.[7a–c] These
compounds have traditionally been synthesized by nucleo-
philic attack of lithium acetylides or Grignard reagents on
imines or their derivatives.[7d,e] However, these reagents must
be used in stoichiometric amounts, are highly moisture-
sensitive, and require strictly controlled reaction conditions.
An alternative atom-economical approach to their synthesis is
achieving a sustainable catalytic process, the rapid reduction
of cationic gold species into inactive metallic atoms is
unavoidable when gold salts activate alkynes/alkenes.[2b,c,3]
Heterogeneous catalysts may therefore be an attractive
solution to this problem, although the very limited number
of examples reported for the A3 coupling thus far show very
low activity (turnover number (TON) ꢀ 33).[6,12] Since catal-
ysis with gold salts/complexes indicates that AuIII and AuI
could be the most active species,[9] we have prepared
supported gold catalysts in which partially charged and
electron-deficient gold atoms are stabilized and show that
Au nanoparticles supported on nanocrystalline ZrO2 and
CeO2 are highly active, selective, and recyclable catalysts for
the A3 coupling reaction with water as solvent. The direct
synthesis of functionalized indoles by three-component
coupling and cyclization is also presented.
Benzaldehyde, piperidine, and phenylacetylene were used
as model substrates to study the catalytic activity of the
different supported gold catalysts. The results of these studies
(Table 1) show that gold supported on SiO2 or carbon leads to
low conversion (ꢀ 13%). The Au/TiO2 and Au/Fe2O3 catalysts
supplied by the World Gold Council show moderate activity,
while gold (2–5 nm) supported on nanocrystalline CeO2
(approx. 5 nm) and ZrO2 (5–10 nm) give the highest con-
version (ꢁ 95%), with yields of isolated product of between
93 and 100%. No conversion was found in the absence of
catalyst under identical conditions.
In a first approximation, the differences in the catalytic
activity observed might appear to be correlated with the
to perform this type of reaction by a catalytic coupling of
3
À
alkyne, aldehyde, and amine (A coupling) by C H activa-
Table 1: Three-component coupling of benzaldehyde, piperidine, and
tion, where water is the only theoretical by-product.[8] Recent
progress in this area has been reported using homogeneous
catalysts such as gold salts (AuBr3 or AuCl),[9a] organic gold
complexes,[9b] silver salts,[10] copper salts,[11a–c] Hg2Cl2,[11d] and a
Cu/RuII bimetallic system,[11e] among which the cationic gold
species showed the highest catalytic activity.[9] However,
besides the potential limitations of homogeneous catalysis for
phenylacetylene with supported gold catalysts.[a]
[b]
EntryCataslty
Gold [mol%] Conv.[c] [%] Yield[d] [%] TON[e]
1
2
3
4
5
6
0.2% Au/SiO2
3.0% Au/C
1.5% Au/TiO2
4.5%Au/Fe2O3
2.8% Au/ZrO2
2.5% Au/CeO2
0.013
0.081
0.075
0.247
0.142
0.127
<5
13
35
40
95
–
n.d.
n.d.
n.d.
93
–
[*] Dr. X. Zhang, Prof. Dr. A. Corma
Instituto de Tecnología Química, UPV-CSIC
Universidad PolitØcnica de Valencia
Avda. de los Naranjos s/n, 46022 Valencia (Spain)
Fax: (+34)96-3877809
161
464
162
668
788
100
>99
E-mail: acorma@itq.upv.es
[**] This work was supported bythe Spanish government (project MAT
2006-14274-C02-01). X. Zhang thanks the ITQ for a scholarship. The
experimental assistance of S. Carrettin, . Cantín, J. Gaona, and P.
Serna is acknowledged.
[a] Reaction conditions: benzaldehyde (1.0 mmol), piperidine
(1.2 mmol), and phenylacetylene (1.3 mmol), H2O (MiliQ, 1.0 mL),
6 h, 1008C. [b] The number (e.g. 0.2%) is the mass weight of gold loaded
on the support (e.g. SiO2). [c] Determined byGC analsyis based on
aldehyde. [d] Yields of isolated product based on benzaldehyde; n.d. not
determined. [e] Calculated on the basis of total weight of gold.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Angewandte
Chemie
nano-size effect of the gold. This effect can easily be ruled out
with our catalysts since, although the gold particles supported
on TiO2, Fe2O3, carbon, ZrO2, and CeO2 supports are similar
in size (2–5 nm; see Figure S1 and Table S1 in the Supporting
Information), their catalytic activity is quite different. It must
therefore be concluded that there is no direct correlation
between the size of the gold particles of the supported
catalysts and the activity observed for the A3 coupling
reaction. This conclusion agrees very well with the work of
Kidwai et al.,[12a] who found that unsupported gold nano-
particles with average sizes of 10, 20, or 30 nm gave very
similar conversions (approx. 90%).
In an attempt to explain the catalytic activity of the
different supported gold catalysts, we considered that cationic
gold could be the active species, as is the case with
homogeneous gold catalysis. If this is so, and taking into
account that XPS, FTIR, and EXAFS studies and theoretical
calculations have indicated that cationic gold species can be
stabilized on CeO2[5,13] and ZrO2[14,15] but not on silica, carbon
(NaBH4 reduction of a gold precursor), or the gold reference
catalysts (calcination at 4008C in air results in the reduction of
cationic gold species to the metal),[16] it can be assumed that
the high catalytic activity observed for Au/ZrO2 and Au/CeO2
is due to the presence of positively charged gold species.
To check the validity of this assumption, we prepared a
series of Au/CeO2 and Au/ZrO2 samples in which the AuIII/
AuT (AuT: total amount of gold) and AuI/AuT ratios were
varied by reducing the sample with H2 at 100 and 3008C for
3 h, respectively. The results, which are presented in Figure 1a
and Table S2 in the Supporting Information, show a direct
correlation between the concentration of AuIII species and the
catalytic activity; no clear correlation was found between the
catalytic activity and the concentration of AuI or Au0
(Table S2). Although it is not possible to discard some
catalysis by AuI and Au0, their catalytic activity should be
much lower than that of AuIII.
benzaldehyde conversion increases continuously up to 99%
with Au/CeO2 over 12 h. This result indicates that AuCl3 is
deactivated in the first 2 h and is decomposed or reduced into
metallic gold,[2b,c,3] whereas no significant deactivation of Au/
CeO2 is found. The turnover frequencies (TOFs) calculated
on the basis of total gold (1645 hÀ1) and AuIII ions (5674 hÀ1)
are significantly higher than that of AuCl3 (635 hÀ1) when
working at low levels of benzaldehyde conversion (ꢀ 31% at
0.17 h); the maximum TONs calculated on the basis of total
gold (3120) and AuIII ions (10760) of Au/CeO2 are one and
two orders of magnitude higher than that of AuCl3 (273),
respectively (see Table S3). Although 100% conversion has
also been reported with much larger amounts of AuBr3 under
similar reaction conditions,[9a] our results indicate that the
TON and TOF obtained with Au/ZrO2 and Au/CeO2 are
much higher than those of gold salts/complexes, copper/silver
salts, and others (TON ꢀ 100).[9–11] It has also been reported
that unsupported Au and Ag nanoparticles (TON ꢀ 10),[12a,b]
gold on layered double hydroxide (LDH-AuCl4, TON ꢀ 33),[6]
or hydroxyapatite-supported Cu (TON ꢀ 8)[12c] are active
catalysts for the A3 coupling reaction. However, the results
presented above clearly show that the activity of our Au/ZrO2
and Au/CeO2 catalysts is two orders of magnitude higher than
those of these previously reported solid catalysts.[6,12]
It should be noted that these Au/ZrO2 and Au/CeO2
catalysts can work in a variety of organic solvents (methanol
and tetrahydrofuran), where they lead to more than 80%
conversion. Nevertheless, the reaction in water is very clean
and this is the solvent of choice. In contrast to homogeneous
gold, silver, copper, or unsupported Au nanoparticles,[9–12] Au/
CeO2 and Au/ZrO2 do not require an inert atmosphere.
To examine the scope of the A3 coupling reaction with Au/
CeO2 and Au/ZrO2, we extended our studies to different
combinations of aldehydes, amines, and alkynes. As depicted
in Table 2, aromatic aldehydes give excellent yields in the A3
coupling reaction (entries 1–7). Benzaldehydes with electron-
donating groups react smoothly (entries 2–4), while substitu-
tion of electron-withdrawing groups on the benzene ring
decreases the reactivity (entries 5–7). High yields are still
generally obtained in the latter case except for with 4-
nitrobenzaldehyde, which contains a strongly electron-with-
drawing group (entry 8), although longer reaction times are
needed. Notably, aliphatic aldehydes such as cyclohexanecar-
boxaldehyde, butylaldehyde, and octylaldehyde also display
very high activity, with yields of 99, 85, and 95%, respectively
(entries 9–11). While unwanted trimerization of aliphatic
aldehydes is a major limitation of the A3 coupling reactions
catalyzed by homogeneous catalysts,[9–11] no trimer could be
detected with the supported gold catalyst.
Considering that AuIII is the most active catalytic species
when the A3 coupling reaction is carried out in a homoge-
neous phase, we compared the catalytic activity of Au/CeO2
and AuCl3 under the same reaction conditions. It can be seen
from Figure 1b and Table S3 that benzaldehyde conversion
with AuCl3 is higher than with Au/CeO2 in the first 2 h and the
maximum conversion (80%) is obtained at 2 h, while
The reaction with secondary amines proceeded smoothly
to afford the corresponding propargylamines (Table 2,
entries 12–15). The reactions with piperidine and pyrrolidine
resulted in complete benzaldehyde conversion with a yield
higher than 99%. The A3 coupling reactions with chiral
amines were also successful, with yields of more than 97%
and excellent diastereoselectivities (up to 99:1) obtained with
(S)-(+)-2-pyrrolidinemethanol and (S)-(+)-2-(methoxyme-
thyl)pyrrolidine (entries 16–18). (S)-(+)-2-methylpiperidine
afforded up to 87% yield with good diastereoselectivity
III
T
~
Figure 1. A) Correlation between the Au /Au ratio of Au/CeO2 ( ) and
&
Au/ZrO2 ( ) and the TON calculated on the basis of total gold.
b) Comparison of the catalytic activity of AuCl3 ( ) and Au/CeO2 (&)
catalysts under identical reaction conditions (benzaldehyde
(2.0 mmol), piperidine (2.4 mmol), and phenylacetylene (2.6 mmol),
H2O (1.0 mL), 1008C; Au/CeO2: 5 mg; AuCl3: 1.8 mg).
*
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Communications
Table 2: Coupling of an aldehyde, alkyne, and amine catalyzed by Au/
Table 3: Three-component coupling and cyclization of an aldehyde,
CeO2 and Au/ZrO2 in water.[a]
amine, and N-protected ethynylaniline.[a]
1
1-CHO
R2R3NH
T [h]
Yield[b]
EntryR
R2R3NH[b]
R4
T [h] Yield[c] (d.r.)[d]
EntryR
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Ph
4-MeC6H4
4-MeOC6H4 piperidine
3,4-MeOC6H4 piperidine
4-CNC6H4
2-BrC6H4
4-ClC6H4
4-NO2C6H4
Cyclohexyl
Propyl
Heptyl
Ph
Ph
Ph
Ph
Cyclohexyl
Heptyl
Heptyl
Cyclohexyl
Heptyl
Ph
piperidine
piperidine
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
6
6
8
>99%
90%
93%
90%
99%
95%
97%
26%
>99%
85%
95%
>99%
92%
93%
83%
1
2
3
4
5
6
(HCHO)n (R1 =H)
Heptyl
piperidine
piperidine
piperidine
pyrrolidine
morpholine
diethylamine
6
6
6
6
6
6
95
97
75
87
70
90
Cyclohexyl
(HCHO)n (R1 =H)
(HCHO)n (R1 =H)
(HCHO)n (R1 =H)
12
12
12
12
14
6
14
14
6
6
8
12
6
6
6
6
6
6
6
6
4
4
piperidine
piperidine
piperidine
piperidine
piperidine
piperidine
piperidine
pyrrolidine
[a] Aldehyde (0.20 mmol), amine (0.24 mmol), and N-protected ethyny-
laniline (0.26 mmol), gold (0.0007 mmol), dioxane (1.0 mL); Ts=tolu-
ene-4-sulfonyl. [b] Yields of isolated product based on aldehyde.
R2,R3 =PhCH2 Ph
octylaldehyde and cyclohexanecarboxaldehyde to give the
appropriate three-component coupling and cyclization prod-
ucts in good to excellent yields (Table 3, entries 2 and 3). The
reaction with pyrrolidine, morpholine, and diethylamine
using paraformaldehyde also goes smoothly to give the
respective functionalized indoles in up to 90% yield
(Table 3, entries 4–6). Considering that functionalized indoles
are prominent core frameworks in biologically active com-
pounds,[17] this atom-economical strategy towards functional-
ized indoles opens up a new application for supported gold
catalysts that is clearly superior to previously reported
reactions using homogeneous Cu and Pd catalysts,[17] at least
from a catalyst separation and reuse point of view.
The stability of Au/CeO2 was studied by separating and
recycling the Au/CeO2 catalyst. After three successive cycles
with intermediate extensive washing with acetone and water,
the catalyst activity decreases by around 20%. This decrease
is mainly due to the leaching of a small portion of the gold that
interacts only weakly with the nanocrystalline CeO2 support.
Further recycling does not produce any further decrease in
activity (see the Supporting Information).
R2,R3 =Allyl
morpholine
M1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
99% (99:1)
M1
M2
M3
M3
piperidine
piperidine
piperidine
piperidine
piperidine
piperidine
piperidine
piperidine
97% (99:1)
99% (99:1)
82% (82:18)
87% (84:16)
99%
77%
25%
85%
95%
4-MeOC6H4
4-ClC6H4
(CH3)3C
(CH3)3C
(CH3)3C
butyl
Ph
Ph
Cyclohexyl
Heptyl
Heptyl
Cyclohexyl
Cyclohexyl
4
4
4
90%
99%
88%
butyl
(CH3)3Si
[a] Reaction conditions: aldehyde (1.0 mmol), amine (1.2 mmol), and
alkyne (1.3 mmol), Au/CeO2 (gold: 0.00127 mmol for entries 1–15 and
21–23; 0.0025 mmol for entries 16–20), Au/ZrO2 (gold: 0.0025 mmol for
entries 24–28) H2O (MiliQ, 1.0 mL), 1008C (1208C for entries 24–28).
[b] Chiral amines denoted as M1, M2, M3 are (S)-(+)-2-pyrrolidineme-
thanol, (S)-(+)-2-(methoxymethyl)pyrrolidine, and (S)-(+)-2-methylpi-
perdine, respectively. [c] Yields of isolated product based on aldehyde.
[d] Determined by 1H NMR spectroscopyand/or GC; the absolute
configuration was not determined.
We speculate that the reaction mechanism of these
supported gold catalysts (Scheme 1) could be the same as
that with cationic gold and/or copper under homogeneous
(entries 19 and 20). Considering that chiral propargylamines
are present in many important bioactive compounds,[7] these
results open up new possibilities for the application of
supported gold catalysts to the synthesis of chiral compounds.
Good to excellent yields were generally obtained for aryl
alkynes (Table 2, entries 1–22), although the reactivity is a
little lower in the case of aliphatic alkynes. Yields of 85–95%
were obtained using cyclohexanecarboxaldehyde and octy-
laldehyde at 1208C, and excellent yields can also be obtained
with n-hexyne and (trimethylsilyl)acetylene in combination
with octylaldehyde and cyclohexanecarboxaldehyde at 1208C
(Table 2, entries 24–28).
conditions.[9,11b,17d] Thus, the C H bond of the alkyne is
À
activated by a AuIII species stabilized by nanocrystalline CeO2
or ZrO2 to give a gold acetylide intermediate (A), which
reacts with the immonium ion (B) generated in situ from the
aldehyde and secondary amine to give the corresponding
propargylamine (C) or indole (D), in the case of alkyne and
The selective synthesis of functionalized indoles by using
N-protected ethynylaniline instead of phenylacetylene and
paraformaldehyde as the aldehyde, in dioxane, gave the 2-
(aminomethyl)indole derivative in 95% yield with no for-
mation of the expected propargylamines (Table 3, entry 1).
Paraformaldehyde can be exchanged for aldehydes such as
Scheme 1. Tentative mechanism for the direct synthesis of functional-
ized propargylamines (C) and indoles (D) by nanocrystalline CeO2- or
ZrO2-stabilized AuIII-catalyzed three-component coupling reactions.
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Angewandte
Chemie
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In conclusion, a heterogeneous catalyst based on gold
supported on nanocrystalline CeO2 and ZrO2 has been
successfully developed for the A3 coupling reaction. The
catalytic activity (TON and TOF) of Au/CeO2 and Au/ZrO2 is
the highest reported so far for this reaction and the catalysts
are air stable and can readily be recovered and reused. The
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(with high diastereoselectivities for chiral amines) and
functionalized indoles in good to excellent yields from
alkynes and N-protected ethynylaniline, respectively.
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Experimental Section
Catalyst preparation: Au/CeO2 was prepared by precipitation of
HAuCl4 with NaOH following a procedure described elsewhere.[5c]
Details of the preparation and characterization of the supported gold
catalysts are given in the Supporting Information.
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General procedure for the three-component coupling reaction:
All commercially available reagents were purchased from Aldrich
and used as received. The desired amount of supported gold catalyst
was added to a mixture of aldehyde (1 mmol), amine (1.2 mmol), and
alkyne (1.3 mmol) in 1.0 mL of H2O (MilQ) with n-octane as an
internal standard. The A3 coupling reaction was performed in a closed
glass reactor (2.0 mL, SUPELCO) with rapid stirring (approx.
1000 rpm) at 1008C in air. After a given reaction time, the product
mixtures were cooled to room temperature and centrifuged. The
separated oil was analyzed by GC (the water phase was also analyzed)
to determine the aldehyde conversion. The pure product was
obtained by flash chromatography and identified by GC-MS and
1H NMR spectroscopy (see Supporting Information).
Received: January 9, 2008
Revised: March 17, 2008
Published online: April 25, 2008
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Keywords: alkynes · gold · homogeneous catalysis ·
multicomponent reactions · supported catalysts
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