Thiolate-Protected Au 25 (SC 2 H 4 Ph) 18 Nanoclusters as a Catalyst for Intermolecular Hydroamination of Terminal Alkynes

Article abstract of DOI:10.1055/s-0037-1610671

Au ₂₅ (SC ₂ H ₄ Ph) ₁₈ nanoclusters have high catalytic activity for hydroamination of terminal alkynes. This reaction proceeds under O ₂ or air. The presence of molecular oxygen has a profound effect

Full text of DOI:10.1055/s-0037-1610671

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
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T. Nagata et al.
Letter
Synlett
Thiolate-Protected Au25(SC2H4Ph)18 Nanoclusters as a Catalyst for
Intermolecular Hydroamination of Terminal Alkynes
Tatsuki Nagata
cat.Au25(SC2H4Ph)18
R1
Yurina Adachi
Au
SC2H4Ph
Yasushi Obora*
NH2
N
neat
70 °C
under O2
+
Department of Chemistry and Material Engineering, Faculty
of Chemistry, Materials and Bioengineering, Kansai University,
Suita, Osaka 564-8680, Japan
R1
R2
R2
obora@kansai-u.ac.jp
R1 = H, OMe, tBu, F, Br
R
2 = H, OMe, tBu, F, Br
12 examples
Yield 37–82%
Received: 12.09.2018
Accepted after revision: 15.10.2018
Published online: 16.11.2018
Mizushima, Hayashi, Tanaka
NAr
DOI: 10.1055/s-0037-1610671; Art ID: st-2018-u0587-l
cat.Ph3PAuMe
Ar NH2
R1
R2
R2
+
(1)
(2)
R1
acidic promotor
Abstract Au25(SC2H4Ph)18 nanoclusters have high catalytic activity for
hydroamination of terminal alkynes. This reaction proceeds under O2 or
air. The presence of molecular oxygen has a profound effect on the
Au25(SC2H4Ph)18 reactivity. The catalysts can be separated from the
mixture after the reaction and reused.
He and Brouer
NHCbz
cat.Ph3PAuOTf
CbzNH2
+
Key words hydroamination, gold nanocluster, imines, gold catalyst,
reusing catalyst
Kitahara and Sakurai
NH2
H
N
cat.Au:PVP
air
Imines are attractive building blocks for a variety of
organic reactions. They have high reactivity toward various
nucleophiles, such as in asymmetric hydrogenation, aza-
Henry or Mannich-type reactions, cycloaddition, and nucleo-
philic addition.1 Nitrogen-containing products are widely
used as the scaffolds of synthetic drugs or natural products.
Traditional imine synthesis is an equilibrium reaction, and
hydroamination is one of the most atom economical and
sustainable imine formation methods.2
(3)
(4)
Ph
Ph
Ph
Ph
This work
Ar NH2
Ar
N
cat.Au25(SC2H4Ph)18
under O2
+
Ar
Ar
Scheme 1 Hydroamination of multiple bonds activated by gold
catalysts
In late-transition-metal-catalyzed (Pd, Ru, Ir, Rh, Pt, and
Au) hydroamination of alkynes, C–C triple bond activation
is generally the key step.2,3 Au(I) catalysts have π-acidic
properties, and various gold-activated reactions have been
investigated for hydroamination.4 Tanaka and Mizushima
reported intermolecular hydroamination of alkynes with
acidic promoters (Scheme 1, eq 1).5a He and Brouwer re-
ported hydroamination of 1,3-dienes. The noncoordinating
anion effect was observed (Scheme 1, eq 2).5b Generation of
more electrophilic gold active species is necessary. Co-acidic
and stable counteranions are required for application of the
catalysts. Additives that can be easily removed from the de-
sired products are desirable.
Among the attempts to activate gold, considerable at-
tention has been focused on gold nanoparticles owing to
their unique properties.6 Haruta found significant differ-
ences in the catalytic activities of bulk metals and small
particles.7 Ligand-protected nanoclusters, such as thiolate-,
phosphine-, and dendrimer-protected clusters, have been
studied in detail, and they are suitable as models for cata-
lytic reaction investigation because it is easy to produce
nanoparticles of a specific size.8 Atomically precise gold
nanoclusters with very small particle sizes (1–2 nm) are
known to have high catalytic activity9 for CO oxidation, C–C
bond formation, hydrogenation, styrene or alcohol oxida-
tion, and hydroamination reactions. In 2010, Sakurai and
Kitahara reported gold nanoclusters (NCs) stabilized by
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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T. Nagata et al.
Letter
Synlett
poly(N-vinyl-2-pyrrolidone) (Au:PVP NCs, mean size = 1.3 nm)
as versatile catalysts for intramolecular cycloaddition of
primary amines to unactivated alkenes (Scheme 1, eq 3).10
They proposed that O2 is initially adsorbed on the gold sur-
face to form electron-deficient reactive sites. From the re-
sults of density functional theory calculations, absorption
of O2 provides superoxo-like species and Lewis acidic sites
for Au NCs. Substrate alkene activation is favorable, whereas
a high activation barrier prevents amine activation. Corma
reported that nanogold supported on chitosan is an effi-
cient catalyst for hydroamination of terminal alkynes in the
absence of an acid promoter. Nanocatalysts possess the
potential to replace conventional reaction promoters.11 Thio-
late-protected Au NCs catalyze the C–N bond formation re-
action. Jin et al. reported that the thiolate-protected Au NCs
Au38(SC2H4Ph)24 catalyzes three-component (amine, alde-
hyde, and alkyne, A3) coupling reactions.12 Recently, our re-
search group reported that Au25(SC2H4Ph)18 gives the corre-
sponding propargylamines in good to excellent yields under
O2.12b However, the A3-coupling reaction mechanism has
not been well-explored.
and remaining starting material was recovered. The highest
catalytic activity and yield of 3a were achieved when the
reaction was performed in the absence of a solvent. The use
of representative nonpolar and polar solvents was ineffec-
tive under these conditions. (Table 1, entries 1–3). Reaction
of 1a with 2a at a 1a/2a molar ratio of 3:1 gave 3a in high
yield (54%, Table 1, entry 5). However, reaction with equi-
molar amounts of 1a and 2a gave in the higher yield (62%,
Table 1, entry 4). The use of excess amine resulted in a de-
crease in the catalytic activity (Table 1, entry 5). The reac-
tion proceeded under open air and argon atmospheres (Ta-
ble 1, entries 6 and 7). However, the catalytic reaction per-
formed better with O2 rather than with air or inert gas. An
amount of O2 in the system gave a good yield (Figure 1).
In this study, we propose Au25(SC2H4Ph)18 as an efficient
catalyst for hydroamination of alkynes. Notably, the hydro-
amination yield is different under oxygen and argon atmo-
spheres. Au25(SC2H4Ph)18 NCs are activated under an oxygen
atmosphere and catalyze intermolecular hydroamination.
The reaction of aniline (1a, 0.5 mmol) with phenylacet-
ylene (2a, 1.5 mmol) was performed in the presence of
Au25(SC2H4Ph)18 (0.1 mol %) under an oxygen balloon at 70
°C for 24 h, giving 3a in 80% NMR yield and 63% isolated
yield (Table 1, entry 1). Side reactions were not observed
Figure 1 Plots of the reaction yields under (a) O2 (black curve), (b) air
(blue curve), and (c) argon (orange curve) atmospheres
Table 1 Au25(SC2H4Ph)18-Catalyzed Hydroamination of Terminal
Alkynes
The results of hydroamination of terminal alkynes un-
der the standard conditions using various substituted ani-
lines and phenylacetylenes are given in Scheme 2. Using an-
ilines bearing electron-rich substituents gave the corre-
sponding ketimines 3b–d in good to moderate yields.
Anilines bearing fluoro/chloro substituents were found to
be less effective. Anilines bearing methoxy and tert-butyl
groups gave the corresponding imines 3g and 3h in good
yields. Heteroaromatic terminal alkynes were also tolerated
in this reaction (3k and 3l). The use of 3-aminopridine with
phenylacetylene was not suitable for this reaction, and the
desired product was obtained only in low yield (<10%) un-
der these conditions. The reaction of 1a with terminal ali-
phatic alkyne such as 1-octyne was sluggish. Unfortunately,
aliphatic amines (e.g., hexylamine, cyclohexylamine) and
internal alkynes (diphenylacetyrene, 4-octyne) did not give
the desired products, and starting materials were recov-
ered.
NH2
cat.Au25(SC2H4Ph)18
N
neat,
70 °C, 24 h
1a
2a
3a
Entry
Conditionsa
Yield (%)b
1
2
3
4
5
6
7
standard
80 (63)
trace
42
toluene solvent
acetonitrile solvent
ratio of 1a/2a = 1:1
ratio of 1a/2a = 3:1
under air (balloon)
under Ar (balloon)
62
54
58
52
a Standard conditions: 1a (0.5 mmol) was allowed to react with 2a
(1.5 mmol) in the presence of the Au25(SC2H4Ph)18 catalyst (0.1 mol %
based on the amount of 1a) at 70 °C for 24 h.
b NMR yields based on 1a. The isolated yield is given in parenthesis.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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T. Nagata et al.
Letter
Synlett
R1
cat.Au25(SC2H4Ph)18
(0.1 mol%)
NH2
N
+
neat,
70 °C, 24 h,
under O2
R1
R2
R2
1a–e
2a–e
3b–l
tBu
OMe
X
N
N
N
N
N
MeO
3b (82%)
3c (79%)
3d (48%)
3e (X = Br 37%)
3f (X = F 38%)
3g (72%)
N
N
N
N
tBu
N
X
S
3h (66%)
3i (X = Br 52%)
3j (X = F 60%)
3k (42%)
3l (65%)
Scheme 2 Reaction of various anilines and phenylacetylenes.a aReaction conditions: 1a–e (0.5 mmol), 2a–e (1.5 mmol), and Au25(SC2H4Ph)18 catalyst
(0.1 mol % based on 1) at 70 °C for 24 h. The values in parentheses are the isolated yields.
A plausible reaction mechanism based on the most gen-
eral pathway is shown in Scheme S1.2 Initially,
Au25(SC2H4Ph)18 NCs generate Lewis acidic sites. Terminal
alkynes are activated by electron-deficient (Lewis acidic)
sites. An oxygen atmosphere results in nanoclusters oxida-
tion.13 Au25(SC2H4Ph)18 has an electron-rich Au13 core and
delocalized valence electrons. The Au12 shell is positively
charged owing to electron transfer from gold to sulfur. In
the presence of molecular oxygen, it has been proposed
that electron transfer from the Au13 core to absorbed oxy-
gen occurs.14 This coordination of dioxygen has been well
investigated by research of CO oxidation and the olefin
epoxidation mechanism.15 Overall, cationic activated
Au25(SC2H4Ph)18 promotes activation of the alkyne triple
bond. After attack of the aniline, the hydroamination prod-
uct is released from the enamine intermediate.
nm) were found after the fifth run (Figure 3). The decrease
in the yield can be attributed to gradual decomposition of
Au25(SC2H4Ph)18. A study of the stability of Au25(SR)18 agrees
with our results.17
Figure 2 Reusing of the Au25(SC2H4Ph)18 catalyst five times
The catalyst recyclability is important for its use in in-
dustrial and chemical research. Metal nanoparticles are
possible recoverable and recyclable catalysts.16 We investi-
gated the reusability of the catalyst. The reaction was per-
formed under the standard conditions. Catalyst separation
and recovery were performed by filtration and extraction
(Figure S1). For five reusing experiments, the desired prod-
uct 3a was obtained in 38–78% yield (Figure 2). The catalyst
tolerated multiple cycles. To understand the significant loss
in the catalytic activity, the particle size was measured by
dynamic light scattering (DLS). After the 1st run, the parti-
cles retained their size (1–2 nm). Aggregated clusters (210
In conclusion, we have demonstrated that the
Au25(SC2H4Ph)18 catalyst has high catalytic activity for
hydroamination of terminal alkynes.18,19 Abundant molecu-
lar oxygen plays an important role in gold activation. This
catalytic system can be easily separated from the product
and provides access to imines. The Au25(SC2H4Ph)18 catalyst
can be reused. Further investigation of Au25(SC2H4Ph)18 and
metal nanoparticles as catalysts is in progress.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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Figure 3 DLS average Au NCs sizes before the reaction (red curve),
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Reference and Notes
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(18) Preparation of the Au25(SC2H4Ph)18 Catalyst
The Au25(SC2H4Ph)18 nanoclusters were synthesized according
to a previously reported method.20 HAuCl4·4H2O (2 mmol, 0.8 g)
was dissolved in 150 ml tetrahydrofuran (THF) solution con-
taining tetraoctylammonium bromide (2.4 mmol, 1.3 g) at room
temperature. After stirring for 15 min, 2-phenylethanethiol (10
mmol, 1.4 g) was added, and the solution was stirred for 15 min
2 h. A cold aqueous solution (25 ml) containing NaBH4 (20
mmol, 0.8 g) was then rapidly added to the solution, and the
solution was then stirred at room temperature. After 15 h, the
THF solvent was evaporated, and the remaining red brown
powder was washed with methanol to remove excess thiol and
other byproducts. The Au25(SC2H4Ph)18 clusters were extracted
from the dried sample using acetonitrile.
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(19) General Procedure and the Analytical Data of some Typical
Compounds
The reaction of aniline (1a) with phenylacetylene (2a) was per-
formed as follows. The prepared 1 mM Au25(SC2H4Ph)18nano-
cluster solution in toluene (0.5 mL) was added to a Schlenk flask
and the solvent was evaporated. Then, 1a (0.5 mmol, 47 mg)
and 2a (1.5 mmol, 153 mg) were added, and the solution was
stirred for 24 h at 70 °C under O2 (balloon). The chemical yield
of imine 3a was determined by integrating the 1H NMR spec-
trum with respect to an internal standard (1,3,5-trimethoxy-
benzene). Compound 3a was isolated by column chromatogra-
phy (25 μm silica gel, n-hexane/ethyl acetate = 99:1). The yield
was 63% (61 mg).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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3a N-(1-Phenylethylidene)benzenamine
d, J = 7.2 Hz), 2.19 (3 H, s). 13C NMR (400 MHz CDCl3): δ = 166.42
(C), 147.93 (C), 139.20 (C), 134.15 (C), 130.64 (CH), 128.43 (CH),
127.94 (CH), 127.28 (CH), 126.08 (CH), 125.90 (C), 125.88 (CH),
125.37 (CH), 123.55 (CH), 123.21 (CH), 113.44 (CH), 17.66
(CH3); GC-MS (EI) m/z (relative intensity) = 246 (12), 245 (62)
[M]+, 231 (20), 230 (100), 128 (6), 127 (53).
Yellow solid; mp 40–41 °C. 1H NMR (400 MHz CDCl3): δ = 7.98–
7.96 (2 H, m), 7.45–7.44 (3 H, m), 7.34 (2 H, t, J = 7.7 Hz), 7.08 (1
H, t, J = 7.2 Hz), 6.79 (2 H, d, J = 7.9 Hz), 2.22 (3 H, s); 13C NMR
(100 MHz CDCl3): δ = 165.48 (C), 151.65 (C), 139.42 (C), 130.46
(CH), 128.94 (CH), 128.36 (CH), 127.14 (CH), 123.20 (CH),
119.36 (CH), 17.38 (CH3). GC-MS (EI): m/z (relative intensity) =
195 (53) [M]+, 180 (100), 118 (12).
(20) (a) Dharmaratne, A. C.; Krick, T.; Dass, A. J. Am. Chem. Soc. 2009,
131, 13604. (b) Yamazoe, S.; Takano, S.; Kurashige, W.;
Yokoyama, T.; Nitta, K.; Negishi, Y.; Tsukuda, T. Nat. Commun.
2016, 7, 10414.
3b N-(1-Phenylethylidene)-1-naphthalenamine
Yellow solid; mp 85–86 °C. 1H NMR (400 MHz CDCl3) δ = 8.12–
8.10 (2 H, m), 7.84–7.77 (2 H, m), 7.60–7.40 (7 H, m), 6.78 (1 H,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E