Thiolate-protected gold nanoclusters Au25(phenylethanethiol)18: An efficient catalyst for the synthesis of propargylamines from aldehydes, amines, and alkynes

Article abstract of DOI:10.1246/cl.160813

In this study, we report a thiolate-protected Au nanocluster, Au₂₅(phenylethanethiol)₁₈ [Au₂₅(PET)₁₈], which serves as an efficient catalyst by a three-component coupling reaction (A³ reaction) of ald

Full text of DOI:10.1246/cl.160813

Advance Publication Cover Page
Thiolate-Protected Gold Nanoclusters Au25(phenylethanethiol)18: an Efficient Catalyst for
the Synthesis of Propargylamines from Aldehydes, Amines, and Alkynes
Yurina Adachi, Hideya Kawasaki, Tatsuki Nagata, and Yasushi Obora*
Advance Publication on the web October 4, 2016
doi:10.1246/cl.160813
© 2016 The Chemical Society of Japan
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1
Thiolate-Protected Gold Nanoclusters Au25(phenylethanethiol)18: an Efficient Catalyst for the
Synthesis of Propargylamines from Aldehydes, Amines, and Alkynes
Yurina Adachi, Hideya Kawasaki, Tatsuki Nagata, Yasushi Obora*
Department of Chemistry and Materials Engineering, Faculty of Chemistry,
Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan
(E-mail: obora@kansai-u.ac.jp)
In this study, we report thiolate-protected Au nanocluster,
The catalytic activity of the Pd1Au24/CNTs in the oxidation of
alcohols was higher than that of Au25/CNTs. In 2008, Jin and
co-workers reported the synthesis and separation of
phenylethanethiol-protected AuNCs [Au25(PET)18] using a
size-focusing method.15a In 2012, they reported metal oxide-
supported Au25(PET)18 as a heterogeneous catalyst for the
Ullmann homocoupling of phenols and aryl iodides.15b
AuNCs enable the use of reduced catalyst loadings; this
increases the specific surface area and improves the catalytic
activity, and reduces costs. Although the activity of supported
Au25(PET)18 has been well explored,16 its use in colloidal form
(homogeneous catalysis) has not been exploited.15b,c
Homogeneous catalysts show high activity under mild
conditions because of their large surface areas. Recently,
unsupported (homogeneous) colloidal NPs have been used as
catalysts, and we have developed dimethylformamide (DMF)-
stabilized colloidal Pd and Cu NPs using a DMF reduction
method.17 These catalysts have high catalytic activities in
Mizorok–Heck,17a Suzuki–Miyaura,17a and Ullmann coupling
reactions.17b
In this study, we used thiolate-protected colloidal
AuNCs [Au25(PET)18] as an efficient catalyst for synthesizing
propargylamine derivatives from aldehydes, amines, and
alkynes using an environmentally friendly, low-toxicity A3
reaction. We also investigated the behaviour of Au25(PET)18
in solution and its function as an unsupported homogeneous
catalyst.
First, we investigated the behaviour of Au25(PET)18 in
various solutions, as it is important to understand any solvent-
dependent behaviour. Au25(PET)18 is highly soluble in DMF,
dichloroethane, and dioxane, but complete dissolution in
dichloromethane (DCM) takes a long time. Au25(PET)18 is
insoluble in hexane.
Au25(phenylethanethiol)18 [Au25(PET)18] serves as an efficient
catalyst by a three-component coupling reaction (A3 reaction)
of aldehydes, amines, and alkynes to give the corresponding
propargylamines in good to excellent yields.
Keywords: gold nanocluster catalyst, propargylamine, amine,
alkyne
Amines are fundamental and important substrates in
organic transformations.1 The conversion of amines to more
complex functionalized amines containing unsaturated
substructures is valuable.2 In particular, propargylamine
derivatives, amines containing a C≡C bond, are important
nitrogen-containing scaffolds in organic transformations.3
Some examples of metal-catalysed synthesis of
propargylamine derivatives have been reported.3 In particular,
three-component coupling reactions (A3 reactions), i.e. one-
pot synthesis of propargylamine derivatives from amines,
aldehydes, and alkynes, have been achieved using various
metal catalysts such as Cu, Ag, and Au species.4 This method
has been proceeded by the use of immobilized supported
catalyst systems.5
Au is an effective low-toxic catalyst for organic
synthesis, and much research has focused on their use as
nanocatalysts.6 Au nanoparticles (AuNPs) are used in a range
of applications, e.g. emitting materials,7 inks,8 and biomedical
materials.9 Au nanoclusters (AuNCs), which are aggregates of
Au atoms, of size less than 2 nm, have received particular
attention as new nanocatalysts because of their high catalytic
activity.10–16 The size-dependent-structures and discrete
electronic states in metal nanoclusters can be used to catalyse
various reactions, e.g. oxidation and hydrogenation.10
In 1987, Haruta and co-workers first showed that CO
could be oxidized using small (<2 nm) AuNCs supported on
metal oxides.11 As a result of this work, heterogeneously
supported AuNC-catalysed reactions have received
considerable attention.12
Many approaches have been used for the atomically
precise synthesis of AuNCs. Some groups have synthesized
thiol-protected AuNCs with precise size control.13 Tsukuda
and co-workers first reported the preparation of precisely
sized thiol-protected AuNCs [Au25(SR)18] on hydroxyapatite,
and used them to catalyse styrene epoxidation.14a In 2012,
they converted Au25(SR)18 to Pd1Au24(SR)18.14b Here, the
metallic part (Pd1Au24) was immobilized on multi-walled
carbon nanotubes (CNTs) by calcination (Pd1Au24/CNTs).
Next, Au25(PET)18 oxidation was investigated by stirring
under O2 in the desired solvent. In 2008, Jin and co-workers
observed structural changes in Au25(PET)18 under O2 in DCM
using ultraviolet-visible spectroscopy.18 We observed similar
changes in the absorption patterns of Au25(PET)18 at 400, 450,
and 670, and 700 nm under O2 in toluene, DCM, and
tetrachloroethane (TCE), indicating oxidation of Au25(PET)18
[see the Supporting Information (SI)].
Based on the solution behaviour, we performed an A3
homogeneous catalytic reaction of an aldehyde, amine, and
alkyne in toluene.

2
Table 1. Optimization of Au25(PET)18 catalyzed A3 reactiona
reaction proceeded smoothly under O2 and Ar. It is therefore
assumed that Au25 species are involved in the reaction, but
−
we could not clearly discuss the difference in the catalytic
activity between the anionic Au and the neutral Au clusters.
This reaction proceeded even in the presence of small
amounts of catalyst, i.e. 0.01 mol% (68% yield) and 0.001
mol% (14% yield).
H
N
CHO
N
Ph
cat. Au25(PET)18 (0.1 mol %)
Toluene (1 mL)
60 C, 24 h
under O2 (1 atm)
1 mmol
1a
1 mmol
2a
1 mmol
3a
4a
Table 2. Scope of aldehydes, amines, and alkynes applicable to
Au25(PET)18 catalyzed A3 reaction reactiona
Entry
Conditions
Yield/%b
1
Standard conditions
56
R2
R3
cat. Au25(PET)18
N
2
DMF-protected AuNCs used as catalyst
DMF-protected PdNCs used as catalyst
DCM as solvent
n.d.c
n.d.c
2
R1CHO R2R3NH
R4
+
+
R1
3
4d
Toluene
80 C, 24 h
under Ar
R4
1
2
3
4
5
TCE as solvent
1
6
DMF as solvent
26
7
THF as solvent
22
N
N
N
8
DMA as solvent
15
9
Ratio of 1a
Ratio of 1a
Ratio of 1a
Ratio of 1a
:
:
:
:
2a
2a
2a
2a
:
:
:
:
3a=1:1:2
3a=1:2:3
3a=1:3:3
3a=1:3:2
76
Ph
89%
R1
R1= H (4b)
10
11
12
13
14
95(93)
56
94% (4d)
93% (4e)
R1= OMe (4c) 97%
14
1a:
2a:
3a=1:2:3, under Ar, 80 °C
>99
R2 R3
N
N
1a:
2a:
3a=1:2:3, Au25(PET)18(0.01 mol %)
68
N
a Standard conditions: 1a (1 mmol), 2a (1 mmol) and 3a (1 mmol)
in toluene (1 mL) with Au25(PET)18 (0.1 mol %) at 60 °C. bGC
yields. The number in parenthesis shows isolated yield. cNot
detected by GC. dAt 35 °C, 6 h.
R2= R3= Et (4g)
89%
85% (4f)
82% (4i)
R2= nBu, R3= Me (4h) 97%
The reaction of tolualdehyde (1a), piperidine (2a), and
phenylacetylene was selected as a test reaction and was
performed under various conditions (Table 1), with
Au25(PET)18 as an unsupported homogeneous catalyst. The
standard A3 reaction gave the desired propargylamine
derivative 4a in in 56% yield (entry 1). This reaction did not
proceed with DMF-protected metal NCs (Au and Pd), which
were previously reported by our group (entries 2 and 3).17a,19
Thiolate ligands strongly bind on Au, which is an advantage
the Au25(PET)18 cluster over the DMF-protected Au NCs with
regard to retain the cluster’s stability in the catalytic
conditions.19 In addition, it is reported that the single crystal
X-ray analysis of the Au25(PET)18 clusters possesses open
sites, unblocked by thiolates. The open sites might serve as an
active sites in the catalytic reactions.15,20 Next, the effect of
the solvent was examined. The reaction was sluggish in DCM
and TCE (entries 4 and 5). The yield of 4a was more than
halved when solvents other than DMF (entry 6) were used,
with tetrahydrofuran (THF) and dimethylacetamide (DMA)
giving 4a in 15% (entry 7) and 22% (entry 8), yields,
respectively.
N
N
N
Ar
SiMe3
60% (4m)b
Ar= p-anisyl (4k) 98%
Ar= pyridinyl (4l) 89%
98% (4j)
a Conditions: 1 (0.5 mmol), 2 (1 mmol) and 3 (1.5 mmol) in toluene
(0.5 mL) with Au25(PET)18 (0.1 mol %) at 80 °C. All yields are
isolated yields. b At 50 °C.
We investigated the range of substrates that can be used
in this reaction. The aldehyde was varied first. The desired
products 4b–4e and 4i were obtained in good to excellent
yields from benzaldehyde (4b) and anisaldehyde (4c). o-
Tolualdehyde (4d) gave an excellent yield, despite the
increased steric hindrance. Valeraldehyde (4e), an aliphatic
aldehyde, also gave an excellent yield. Ketones were also
tested instead of aldehydes. The corresponding product 4f was
obtained in excellent yield from a cyclic ketone, namely
cyclohexanone, but acetophenone gave only a trace of the
desired product. However, the reaction of diethyl ketone
under these conditions did not give the product. Next, the
amine was varied. Aliphatic amines, i.e. diethylamine, N-
methylbutylamine, and dibutylamine, gave the desired
products 4g, 4h, and 4i, respectively, in good to excellent
yields The reaction with aniline, diphenylamine, and N-
methylaniline were unsuccessful and gave no product. It is
important to use secondary amines. When the reaction was
attempted with primary amines such as hexylamine or
The effect of the initial substrate ratios was examined
(entries 9–12). The yield improved with increasing amount of
alkyne. In contrast, increasing the amount of amine inhibited
the
reaction.
The
best
substrate
ratios
were
aldehyde:amine:alkyne = 1:2:3 (entry 10). This reaction may
need excess alkyne to compensate for slow activation through
reaction of the alkyne and Au25(PET)18 active sites. The amine
is needed for enamine formation and alkyne activation (see
the SI). This reaction gave an excellent yield (>99%) under Ar
at 80 C (entry 13). As shown in entries 10 and 13, this

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butylamine, the reaction did not reach completion because the
enamine intermediate was too stable and the reaction
terminated at this step. Finally, a number of alkynes were
tested. Functionalized aromatic alkynes, namely 4-
ethynyltoluene and 4-ethynylanisole, gave the corresponding
products 4j and 4k in excellent yields. 3-Ethynylpyridine, an
alkyne containing a heterocycle, gave the corresponding
product 4l in good yield. In contrast, 1-decyne, an aliphatic
alkyne, gave the desired product in only 8% yield, and
trimethylsilylalkyne gave the desired product 4m in 60%
yield.
Next, we investigated the turnover number (TON) of
Au25(PET)18 in this reaction. The catalyst loading was reduced
in stages (entry 15) to determine its effects. The TON rose
gradually to a maximum of 1.4 × 104.
We investigated catalyst reuse. The catalyst was placed
in toluene under O2 at 60 C; it did not aggregate after 24 h
(Table 1, entry 9). After reaction, the solvent was evaporated
from the quenched mixture, and hexane (about 7 mL) was
added to form a solid. The recovered catalyst was filtered off
and redissolved in toluene for reuse. This material was used in
the A3 model reaction and gave 64% yield.
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In conclusion, we have shown that thiolate-protected
AuNCs, Au25(PET)18, have high catalytic activity in the
production of propargylamine derivatives from aldehydes,
amines, and alkynes by a three-component coupling reaction.
Further studies to achieve a detailed understanding of the
reaction and its overall scope are currently underway in our
laboratory.
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