Facile access to: N -substituted anilines via dehydrogenative aromatization catalysis over supported gold-palladium bimetallic nanoparticles

Article abstract of DOI:10.1039/c5cy01908g

N-Substituted anilines are widely utilized important compounds, and the development of their diverse synthetic procedures is of great significance. Herein, we have successfully developed a widely applicable powerful catalytic route to N-substituted anilines. In the presence of a gold-palladium alloy nanoparticle catalyst (Au-Pd/Al₂O₃) and styrene, various kinds of structurally diverse N-substituted anilines (twenty three examples) could be synthesized starting from cyclohexanones and amines (including aliphatic primary and secondary amines and anilines). The catalytic performance was strongly influenced by the nature of the catalyst. A supported gold catalyst (Au/Al₂O₃) was completely inactive for the present transformation. Although a supported palladium catalyst (Pd/Al₂O₃) gave the desired N-substituted anilines to some extent, the performance was inferior to that of Au-Pd/Al₂O₃. The catalytic activity of the palladium species in Au-Pd/Al₂O₃ was at least ca. three times higher than that in Pd/Al₂O₃. Moreover, the performance of Au-Pd/Al₂O₃ was superior to that of a physical mixture of Au/Al₂O₃ and Pd/Al₂O₃. Thus, palladium was intrinsically effective for the present transformation (dehydrogenative aromatization) and its performance was improved by alloying with gold. The present transformation proceeds through a sequence of the dehydrative condensation of cyclohexanones and amines to produce enamines (or ketimines), followed by the dehydrogenative aromatization to produce the corresponding N-substituted anilines. In the aromatization step, styrene could act as an effective hydrogen acceptor to selectively produce the desired N-substituted anilines without catalyzing the disproportionation of the enamine intermediates. The observed catalysis using Au-Pd/Al₂O₃ was truly heterogeneous in nature, and Au-Pd/Al₂O₃ could be reused.

Full text of DOI:10.1039/c5cy01908g

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Facile access to N-substituted anilines via dehydrogenative aromatization
catalysis over supported gold–palladium bimetallic nanoparticles†
Kento Taniguchi, Xiongjie Jin, Kazuya Yamaguchi and Noritaka Mizuno*
Department of Applied Chemistry, School of Engineering, The University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
Email: tmizuno@mail.ecc.u-tokyo.ac.jp
Abstract
N-Substituted anilines are widely utilized important compounds, and the development of their
diverse synthetic procedures is of great significance. Herein, we have successfully developed a
widely applicable powerful catalytic route to N-substituted anilines. In the presence of a
gold‒palladium alloy nanoparticles catalyst (Au–Pd/Al2O3) and styrene, various kinds of structurally
diverse N-substituted anilines (twenty three examples) could be synthesized starting from
cyclohexanones and amines (including aliphatic primary and secondary amines and anilines). The
catalytic performance was strongly influenced by the nature of catalyst. A supported gold catalyst
(Au/Al2O3) was completely inactive for the present transformation. Although a supported palladium
catalyst (Pd/Al2O3) gave the desired N-substituted anilines to some extent, the performance was
inferior to that of Au–Pd/Al2O3. The catalytic activity of the palladium species in Au‒Pd/Al2O3 was
at least ca. three times higher than that in Pd/Al2O3. Moreover, the performance of Au–Pd/Al2O3 was
superior to that of a physical mixture of Au/Al2O3 and Pd/Al2O3. Thus, palladium was intrinsically
effective for the present transformation (dehydrogenative aromatization), and its performance was
improved by alloying with gold. The present transformation proceeds through the sequence of the
dehydrative condensation of cyclohexanones and amines to produce enamines (or ketimines),
followed by the dehydrogenative aromatization to produce the corresponding N-substituted anilines.
In the aromatization step, styrene could act as the effective hydrogen acceptor to selectively produce
the desired N-substituted anilines without catalyzing the disproportionation of the enamine
intermediates. The observed catalysis of Au–Pd/Al2O3 was truly heterogeneous in nature, and
Au–Pd/Al2O3 could be reused.
1

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Introduction
Anilines and their N-substituted derivatives are an important class of chemicals that have widely
been utilized as pharmaceuticals, agricultural chemicals, bioactive compounds, dyes, and color
pigments, for example.1 Aniline has industrially been produced by the reduction of nitrobenzene.1
With regard to N-substituted anilines, a number of synthetic procedures have been developed up to
the present.2–7 N-Alkylation of anilines remains one of the most frequently utilized synthetic
procedures for N-alkyl anilines, and alkyl halides have traditionally been utilized as alkylating
reagents.2 However, the selectivity to the desired mono- or disubstituted anilines is low in some cases.
Moreover, alkyl halides are toxic, and their use for the N-alkylation produces large amounts of
wastes. Therefore, much attention has recently been paid to the use of environmentally-friendly
alkylating reagents, e.g., alcohols, for N-alkylation of anilines through a ‘‘borrowing hydrogen’’
strategy.3 Reductive amination of carbonyl compounds is also a powerful synthetic procedure for
N-substituted anilines, and in some catalytic systems, nitrobenzenes can directly be utilized as the
starting materials.4 The Buchwald‒Hartwig coupling5 and the Chan‒Lam coupling6 are two of the
most versatile cross-coupling methodologies for synthesis of N-substituted anilines (including N-aryl
anilines). Although these cross-coupling methodologies can precisely design N-substituted aniline
scaffolds, they should utilize pre-activated substrates, which concurrently generate
(super)stoichiometric amounts of wastes.
Recently, dehydrogenative (oxidative) aromatization has emerged as a reliable procedure for
synthesis of various aromatic compounds.7–9 By the dehydrogenative aromatization protocol utilizing
palladium-based catalysts (homogeneous catalysts in most cases), N-substituted anilines can be
synthesized starting from cyclohexanones and amines.7a–c In the immediate past, we reported a novel
"dehydrogenative self-coupling aromatization route" to N-cyclohexylanilines or symmetrically
substituted diarylamines starting from cyclohexylamines using O2 (air) as the hydrogen acceptor
(oxidant) (Scheme 1a and S1, ESI†).9 This transformation proceeds through the following sequential
pathway (Scheme S1, ESI†).9 Initially, aerobic dehydrogenation of cyclohexylamine proceeds to give
2

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cyclohexylimine (step 1 in Scheme S1, ESI†). Then, nucleophilic addition of another
cyclohexylamine molecule to the cyclohexylimine intermediate takes place to afford
N-cyclohexylidenecyclohexylamine (step 2 in Scheme S1, ESI†). Finally, disproportionation and/or
aerobic dehydrogenation of the N-cyclohexylidenecyclohexylamine proceeds to give the
corresponding N-cyclohexylaniline as the final product with the concurrent formation of
cyclohexylamine and dicyclohexylamine (step 3 in Scheme S1, ESI†). These amines formed in the
aromatization step can again aerobically be oxidized, and thus it can be considered that O2 is
formally the terminal oxidant (step 4 in Scheme S1, ESI†). For this transformation, the effect of
catalysts is very crucial. Various cyclohexylamines can be converted into the corresponding
N-cyclohexylanilines in high yields when using a supported gold‒palladium bimetallic catalyst
(Au‒Pd/Al2O3), whereas Au/Al2O3, Pd/Al2O3, and a physical mixture of Au/Al2O3 and Pd/Al2O3
hardly afford the desired products (Scheme 1a).9 In this transformation, gold and palladium mainly
catalyze the amine oxidation and the aromatization, respectively, and by alloying gold and palladium,
the intrinsic abilities of gold and palladium for these transformations are possibly improved by
electronic ligand effects.10
If the gold‒palladium bimetallic catalyst is effective for aniline synthesis starting from various
kinds of structurally diverse cyclohexanones and amines, the system will be a powerful procedure.
And so, in order to synthesize N,N-disubstituted anilines, we performed several reactions using
cyclohexanones and ‘‘secondary’’ amines in the presence of Au‒Pd/Al2O3 using O2 (air) as the
hydrogen acceptor. Although the desired N,N-disubstituted anilines could be obtained to some extent,
the concurrent formation of N,N-disubstituted cyclohexylamines was inevitable, resulting in low
selectivities to the desired N,N-disubstituted anilines (Scheme 1b, discuss later in more detail). One
possible explanation of the low selectivities is that O2 is the poor hydrogen acceptor, and
consequently the aromatization partly proceeds through the disproportionation of the enamine
intermediates generated by the dehydrative condensation of cyclohexanones and secondary amines.
Moreover, once N,N-disubstituted cyclohexylamines are formed, their dehydrogenation is quite
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difficult (discuss later in more detail). With this situation in mind, we considered to explore the
suitable hydrogen acceptors (instead of O2) for the Au‒Pd/Al2O3-catalyzed dehydrogenative
aromatization starting from cyclohexanones and amines in order to avoid the formation of the
undesired cyclohexylamine by-products.
Herein, we disclose for the first time that styrene can act as the effective hydrogen acceptor for
the Au–Pd/Al2O3-catalyzed selective production of N-substituted anilines starting from
cyclohexanones and amines (Scheme 1c). The present Au‒Pd/Al2O3-catalyzed system with styrene
as the hydrogen acceptor is applicable to a variety of substituted cyclohexanones and amines
(including aliphatic primary and secondary amines and anilines), selectively affording the
corresponding N-substituted anilines in moderate to high yields (twenty three examples). The
observed catalysis is truly heterogeneous in nature, and the Au‒Pd/Al2O3 catalyst can be reused.
Results and discussion
To begin with, we carried out the dehydrogenative aromatization of cyclohexanone (1a) with
morpholine (2a) to produce 4-phenylmorpholine (3aa) in the presence of various hydrogen acceptors
and supported metal catalysts (Table 1). The reaction was typically carried out at 100 °C in toluene
for 6 h. In the absence of hydrogen acceptors under Ar atmosphere (1 atm), the
Au–Pd/Al2O3-catalyzed dehydrogenative aromatization of 1a with 2a gave a ca. 1:2 mixture of the
desired aniline 3aa (34% yield) and the undesired cyclohexylamine 4aa (64% yield) (Table 1,
entry 1). This result indicates that the aromatization proceeds through the ‘‘disproportionation’’ of the
enamine intermediate 5aa formed through the dehydrative condensation of 1a and 2a, that is, 5aa
itself acts as the hydrogen acceptor in this case. Under air atmosphere (1 atm), the
Au–Pd/Al2O3-catalyzed dehydrogenative aromatization gave the desired aniline 3aa in 41% yield
with the concurrent formation of a significant amount of the cyclohexylamine by-product 4aa (46%
yield) (Table 1, entry 2), and thus the disproportionation of 5aa inevitably occurred even when using
O2 as the hydrogen acceptor. In the separate experiment, we confirmed that the desired aniline 3aa
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was not formed at all when the reaction was carried out using the cyclohexylamine 4aa as the
starting material (Scheme 2a). Therefore, once 4aa was formed through the disproportionation of the
enamine intermediate 5aa, the dehydrogenation of 4aa hardly proceeded under the present reaction
conditions even in the presence of hydrogen acceptors, resulting in the low selectivity to the desired
aniline. When benzoquinone was utilized as the hydrogen acceptor, not only the substrates but also
benzoquinone were mostly converted into unidentified by-products, and the desired 3aa was
obtained in only 5% yield (Table 1, entry 7). Thus, benzoquinone was not suitable for the present
system. When utilizing styrene as the hydrogen acceptor under Ar atmosphere (1 atm), the desired
aniline 3aa was selectively obtained without the formation of the undesired cyclohexylamine 4aa
(Table 1, entry 3). When the reaction time was prolonged to 18 h for the Au–Pd/Al2O3-catalyzed
dehydrogenative aromatization using styrene, the yield of 3aa reached up to 76%, and 4aa was not
produced at all also in this case (Table 1, entry 4). Although other alkenes, such as 1-octene and
cyclooctene, were utilized as the hydrogen acceptors, the disproportionation of 5aa could not be
avoided, resulting in the formation of 4aa (Table 1, entries 5 and 6).
Next, the Au‒Pd/Al2O3-catalyzed hydrogenation of alkene hydrogen acceptors, such as styrene,
1-octene, cyclooctene, and 5aa, was carried out in order to explain the above-mentioned effect of
hydrogen acceptors. In the presence of Au‒Pd/Al2O3 and H2 (1 atm) under the conditions described
in Table S1, styrene was quantitatively converted into ethylbenzene (Table S1, entry 1, ESI†). While
other alkenes, such as 5aa, 1-octene, and cyclooctene, were also hydrogenated to the corresponding
alkanes, their reaction rates were lower than that of styrene (Table S1, entries 1‒4, ESI†). The results
of the competitive hydrogenation reactions summarized in Scheme 3 are of extreme importance to
understand the effect of hydrogen acceptors. When the Au‒Pd/Al2O3-catalyzed competitive
hydrogenation of an equimolar mixture of styrene and 5aa was carried out, styrene was preferentially
hydrogenated to afford ethylbenzene in 77% yield without occurring the hydrogenation of 5aa
(Scheme 3a). On the other hand, such preferential hydrogenation phenomena were not observed
when using 1-octene and cyclooctene. When the competitive hydrogenation of an equimolar mixture
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of 1-octene and 5aa was carried out, a ca. 1:1 mixture of n-octane (63% yield) and 4aa (67% yield)
was obtained (Scheme 3b). In the case of the competitive hydrogenation of cyclooctene and 5aa, the
hydrogenation of 5aa rather preferentially occurred to give 4aa in 76% yield, and cyclooctane was
obtained in only 6% (Scheme 3c). From these competitive hydrogenation reactions, we consider that
the ability as the hydrogen acceptor for the present Au‒Pd/Al2O3-catalyzed dehydrogenative
aromatization increased in the order of cyclooctene < 1-octene ≈ 5aa << styrene, which is in good
agreement with the results indicated in Table 1. It is known that the palladium
nanoparticles-catalyzed hydrogenation of C=C double bonds of alkenes undergoes through the
formation of di-σ-bonded intermediates on the palladium surface and that the interaction between
alkene substrates and the palladium surface is very important.11 One possible explanation of the
above competitive hydrogenation reactions is as follows: The p orbitals and planar geometry of the
aromatic ring of styrene can assist the formation of the di-σ-bond, which is preferable to
hydrogenation, while the relatively sterically bulky alkyl groups in 1-octene, cyclooctene, and 5aa do
not positively contribute to but rather hinder the formation of the di-σ-bond in comparison with
styrene.11a For that reason, it is likely that styrene showed the excellent performance as the hydrogen
acceptor for the present Au–Pd/Al2O3-catalyzed dehydrogenative aromatization system, and 1-octene
and cycloocetene were not effective hydrogen acceptors (Table 1, entries 3–6).
The effect of catalysts was also very significant. As above-mentioned, the
Au–Pd/Al2O3-catalyzed dehydrogenative aromatization of 1a with 2a using styrene selectively gave
3aa in good yields (Table 1, entries 3 and 4).12 On the other hand, the desired 3aa was not produced
at all in the presence of Au/Al2O3, thus showing that gold is completely inactive for the
dehydrogenative aromatization (Table 1, entry 8). In the presence of Pd/Al2O3, 3aa was produced to
some extent (20% yield, Table 1, entry 9), thus indicating that palladium is essential for the
dehydrogenative aromatization and that Au–Pd/Al2O3 has the superior catalytic activity to Pd/Al2O3.
The physical mixture of Au/Al2O3 and Pd/Al2O3 gave 3aa in 33% yield (Table 1, entry 10), and the
yield was lower than that obtained with Au–Pd/Al2O3 (Table 1, entry 3). It was revealed by the
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high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) and
energy dispersive X-ray spectroscopy (EDS) analyses of Au–Pd/Al2O3 that gold–palladium alloy
nanoparticles were formed on Al2O3 (Fig. 1b–d). Thus, the catalytic performance of the palladium
species in Au‒Pd/Al2O3 was at least ca. three times higher than that in Pd/Al2O3, clearly indicating
that the intrinsic catalytic performance of palladium for the dehydrogenative aromatization was
improved by alloying with gold. This is likely due to the electronic ligand effect, and such effects are
frequently observed for several oxidation reactions using gold–palladium alloy catalysts, e.g.,
alcohol oxidation and H2O2 production.10 Thus, we hereafter utilized the most active Au–Pd/Al2O3
catalyst and the most effective styrene hydrogen acceptor for further investigation of the
dehydrogenative aromatization.
To verify whether the observed catalysis was truly caused by ‘‘solid’’ Au–Pd/Al2O3 or
‘‘leached’’gold and/or palladium species, the following control experiments were carried out. The
reaction of 1a with pyrrolidine (2b) to produce the corresponding aniline 3ab was carried out under
the conditions described in Fig. 2, and the Au–Pd/Al2O3 catalyst was removed from the reaction
mixture by hot filtration at ca. 30% yield of 3ab. Then, the filtrate was again heated at 80 °C. In this
case, no further production of 3ab was observed, as shown in Fig. 2. In addition, it was confirmed by
inductively coupled plasma atomic emission spectroscopy (ICP-AES) analysis that no gold and
palladium species were detected in the filtrate. These results clearly indicate that the observed
catalysis for the present Au–Pd/Al2O3-catalyzed dehydrogenative aromatization is truly
heterogeneous in nature.13 After the reaction was completed, Au–Pd/Al2O3 could easily be retrieved
from the reaction mixture by simple filtration with >90% recovery. We performed the repeated reuse
experiments using the retrieved catalyst. Unfortunately, the catalytic performance of Au–Pd/Al2O3
gradually decreased during the repeated reuse experiments; 76% yield of 3aa for the reaction with
the fresh catalyst, 67% yield for the first reuse, and 49% for the second reuse for the reaction of 1a
with 2a; 87% yield of 3ab for the reaction with the fresh catalyst and 67% yield for the first reuse for
the reaction of 1a with 2b under the conditions described in Fig. 3. We confirmed by the TEM
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analyses that the average particle size gradually increased during the repeated reuse experiments; the
average particle size in the fresh Au–Pd/Al2O3 was 2.9 nm and increased up to 4.3 nm after the first
reuse (Table S2, Fig. S1, ESI†). Therefore, the deactivation is likely caused by the increase in the
particle size.
The scope of the present Au–Pd/Al2O3-catalyzed dehydrogenative aromatization was next
examined. With the optimized reaction conditions in hand, various kinds of structurally diverse
N-substituted anilines could be synthesized starting from substituted cyclohexanones and amines
(including aliphatic primary and secondary amines and anilines) (Fig. 3 and S2, ESI†). The reaction
of cyclohexanone (1a) with secondary amines, such as morpholine (2a) and pyrrolidine (2b),
efficiently proceeded to afford the corresponding N-substituted aniline derivatives in high yields. By
the reaction with cyclohexanones, aliphatic primary amines, such as cyclohexylamine (2c) and
n-octylamine (2d), could also be converted into the corresponding N-substituted anilines. Besides
aliphatic amines, aniline (2e) and its derivatives, such as 4-methoxyaniline (2f) and 4-methylaniline
(2g), could be applied to the present system, affording the corresponding unsymmetrically
substituted diaryl amines. Cyclohexanones possessing various substituents at each position, such as
4-methylcyclohexanone (1b), 3-methylcyclohexanone (1c), 4-ethylcyclohexanone (1d), and
4-phenylcyclohexanone (1e), could successfully be utilized as the coupling partners for secondary
amines (2a and 2b), primary amines (2c and 2d), and anilines (2e–2g) in the present
Au–Pd/Al2O3-catalyzed system. Interestingly, we found for the first time that Au–Pd/Al2O3 could
catalyze the tandem 1,4-addition/1,2-addition/dehydrogenative aromatization reaction starting from
cyclohex-2-en-1-one (1f) and pyrrolidine (2b), giving the corresponding 1,3-diaminobenzene (3fb)
in a high yield (Scheme 4).
As above-mentioned, for the Au–Pd/Al2O3-catalyzed reaction of 1a and 2a, a significant amount
of the enamine intermediate 5aa was observed at 6 h, but not at 18 h (Table 1, entries 3 and 4). In the
separate experiments, we confirmed that the desired aniline 3aa was produced when the reaction was
carried out using 5aa as the starting material (Scheme 2b and c). Furthermore, as above-described,
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the dehydrogenative aromatization of cyclohexylamine 4aa hardly proceeded even inDtOhI:e10p.1r0e3s9/eCn5cCYe01o9f08G
styrene as the hydrogen acceptor (Scheme 2a). Based on these experimental results, we here propose
a possible reaction pathway for the present Au–Pd/Al2O3-catalyzed dehydrogenative aromatization
reaction (Scheme 5). Initially, the condensation of cyclohexanone (1) with an amine (2) proceeds to
give an enamine intermediate (5) with the concomitant formation of water (step 1 in Scheme 5).
Then, the palladium-catalyzed dehydrogenation of 5 proceeds to give the corresponding diene
intermediate 6 using styrene as the hydrogen acceptor with the concurrent formation of ethylbenzene
(step 2 in Scheme 5). Finally, the dehydrogenation of 6 proceeds to give the desired N-substituted
aniline 3 using styrene as the hydrogen acceptor with the concurrent formation of ethylbenzene
(step 3 in Scheme 5). The desired N-substituted aniline 3 is selectively obtained in the present
Au–Pd/Al2O3-catalyzed dehydrogenative aromatization system when utilizing styrene as the
hydrogen acceptor. As above-mentioned, styrene could act as the suitable hydrogen acceptor, and the
hydrogen accepting ability was superior to that of 5 (Scheme 3a). In contrast, the hydrogen accepting
abilities of common alkenes, such as 1-octene and cyclooctene, were similar to or lower than that of
5 (Scheme 3b and c). Therefore, in the absence of styrene, the enamine intermediate 5 itself works as
the hydrogen acceptor to concurrently afford the undesired cyclohexylamine 4 through
disproportionation.
Conclusion
We have successfully developed the widely applicable synthetic procedure for N-substituted anilines.
In the presence of a supported gold and palladium alloy nanoparticles catalyst (Au–Pd/Al2O3) and
styrene as the hydrogen acceptor, various kinds of structurally diverse N-substituted anilines could be
synthesized through dehydrogenative aromatization reaction of cyclohexanones with amines. The
observed catalysis was truly heterogeneous, and the Au–Pd/Al2O3 catalyst could be reused.
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Experimental section
Instruments and reagents
GC analyses were performed on Shimadzu GC-2014 with a FID detector equipped using a InertCap5
or a Stabilwax capillary column. GC-MS spectra were recorded on Shimadzu GCMS-QP2010
1
equipped with a InertCap5 capillary column at an ionization voltage of 70 eV. Liquid-state H and
1
13
13C NMR spectra were recorded on JEOL JNM-ECA 500. H and C NMR were measured at 500
and 125 MHz, respectively, with TMS as an internal standard (δ = 0 ppm). ICP-AES analyses were
performed on Shimadzu ICPS-8100. TEM measurements were performed on JEOL JEM-2010HC.
HAADF-STEM and EDS images were obtained using JEOL JEM-ARM 200F operating at 200 kV.
TEM and STEM samples were prepared by placing a drop of the suspension on carbon-coated Cu
grids and dried in air. XPS analyses were performed using JEOL JPS-9000 under Mg Kα radiation
(hν = 1253.6 eV, 8 kV, 10 mA). The peak positions were calibrated by the Al 2p3/2 peak (74.0 eV).
Al2O3 (160 m2 g–1, Cat. No. KHS-24, Sumitomo Chemical) and TiO2 (316 m2 g–1, Cat. No. ST-01,
Ishihara Sangyo Kaisya) were commercially available. Solvents and substrates (cyclohexanones and
amines) were obtained from Kanto Chemical, TCI, Wako, or Aldrich (reagent grade), and purified
prior to the use, if necessary.14
Preparation of catalysts
Au–Pd/Al2O3 was prepared as follows.15 An aqueous solution of HAuCl4·4H2O and K2PdCl4
(4.2 mM each, 60 mL) containing Al2O3 (2.0 g) was vigorously stirred at room temperature for
15 min. Then, the pH of the solution was adjusted to 10.0 by using an aqueous solution of NaOH
(1.0 M). Then, the resulting slurry was further stirred for 24 h at room temperature, giving 2.0 g of
the hydroxide precursor. By the reduction of the hydroxide precursor using H2 (1 atm) at 150 °C for
30 min, the supported gold–palladium bimetallic nanoparticles catalyst, Au–Pd/Al2O3, was obtained.
The contents of gold and palladium in Au–Pd/Al2O3 were 0.070 mmol g–1 and 0.109 mmol g–1,
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respectively (determined by ICP-AES). HAADF-STEM and EDS mapping analyses indicated that
alloyed gold–palladium bimetallic nanoparticles were formed on the Al2O3 support (Fig. 1). It was
confirmed by the TEM analysis that the average particle size of gold–palladium alloy nanoparticles
was 2.9 nm (standard deviation: 1.0 nm, Fig. 1). The size distribution was determined by using 200
particles in the TEM images. Other supported catalysts, such as Au/Al2O3 (Au: 0.158 mmol g–1,
average size: 3.2 nm, standard deviation: 1.1 nm, Fig. S3, ESI†), Pd/Al2O3 (Pd: 0.237 mmol g–1,
average size: 2.2 nm, standard deviation: 0.5 nm, Fig. S4, ESI†), and Au–Pd/TiO2 (Au:
0.070 mmol g–1, Pd: 0.118 mmol g–1, average size: 1.8 nm, standard deviation: 0.4 nm, Fig. S5,
ESI†) were prepared by the same manner as that for Au–Pd/Al2O3.
Catalytic reaction
The catalytic reaction was typically carried out according to the following procedure. Into a Schlenk
flask reactor (volume: ca. 20 mL) were successively placed Au–Pd/Al2O3 (Au: 1.4 mol%, Pd:
2.2 mol% with respectively to an cyclohexanone), cyclohexanone (1, 0.5 mmol), amine (2,
1.0 mmol), styrene (1.0 mmol), n-decane (0.1 mmol, internal standard), toluene (2 mL), and a
Teflon-coated magnetic stir bar, and then the mixture was stirred at 100 °C under Ar (1 atm). The
conversions and product yields were determined by GC analysis using n-decane as an internal
standard. As for isolation of products, an internal standard was not used. After the reaction, the
catalyst was removed by simple filtration (>90% catalyst recovery), and then the filtrate was
concentrated by evaporation of the toluene solvent. The crude product was subjected to column
chromatography on silica gel (typically using n-hexane/diethyl ether as an eluent), giving the pure
N-substituted aniline product. The products were confirmed by the comparison of their GC retention
times, GC-MS spectra, and/or NMR (1H and 13C) spectra with those of the authentic data. As for the
reuse experiment, Au–Pd/Al2O3 was retrieved by filtration, washed with a mixed solvent of methanol
and dichloromethane. The retrieved Au–Pd/Al2O3 was dried at 100 °C in air, and activated at 150 °C
in 1 atm of H2 prior to being used for the reuse experiment.
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Acknowledgements
We thank Mr. H. Oshikawa (The University of Tokyo) for his help with HAADF-STEM and EDS
analyses. This work was supported in part by JSPS KAKENHI Grant Numbers 15H05797 and
15J09227. A part of this work was conducted in Research Hub for Advanced Nano Characterization,
The University of Tokyo, under the support of ‘‘Nanotechnology platform’’ (project No. 12024043,
MEXT). K. T. was supported by JSPS through Program for Leading Graduate Schools (MERIT
program) and Research Fellowship for Young Scientists.
Notes and references
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12 One referee asked us to examine the effect of supports. Thus, according to the comment, we
prepared the Au–Pd/TiO2 catalyst by the same manner as that for Au–Pd/Al2O3 (Au:
0.070 mmol g–1, Pd: 0.118 mmol g–1), and the catalytic performance was examined. It was
revealed by the HAADF-STEM and EDS analyses of Au–Pd/TiO2 that Au–Pd alloy nanoparticles
were formed on TiO2 (Fig. S5b–d, ESI†). The TEM analysis revealed that the average size of the
alloy nanoparticles was 1.8 nm (Fig. S5a, ESI†) and smaller than that in Au–Pd/Al2O3. When the
dehydrogenative aromatization of 1a with 2a was carried out using the Au–Pd/TiO2 catalyst
14

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under the conditions described in Table 1, the desired aniline 3aa was produced in 84% yield (cf.
59% yield using Au–Pd/Al2O3; Table 1, entry 3). The average particle sizes of Au–Pd/Al2O3 and
Au–Pd/TiO2 were 2.9 nm and 1.8 nm, respectively. From these average particle sizes and the
palladium contents, we estimated the numbers of the surface exposed palladium atoms in
Au‒Pd/Al2O3 and Au–Pd/TiO2.15 Assuming that the nanoparticles are homogeneous and that the
sizes are unchanged during the reaction, the turnover numbers (TONs) based on the surface
exposed palladium atoms were calculated to be 98 for Au‒Pd/Al2O3 and 86 for Au–Pd/TiO2 and
almost the same to each other. Therefore, we consider that the high performance of Au–Pd/TiO2
is possibly due to the small average particle size rather than the electronic effect from the
support.
13 R. A. Sheldon, M. Wallau, I. W. C. E. Arends and U. Schuchardt, Acc. Chem. Res., 1998, 31, 485.
14 W. L. F. Armarego and C. L. L. Chai, Purification of Laboratory Chemicals,
Butterworth-Heinemann, Oxford, 5th edn, 2003.
15 The numbers of the surface exposed metal atoms were estimated by using the model cluster with
fcc structure according to the following literatures: (a) N. Toshima, M. Harada, Y. Yamazaki and
K. Asakura, J. Phys. Chem., 1992, 96, 9927; (b) M. Harada, K. Asakura and N. Toshima, J. Phys.
Chem., 1993, 97, 5103; (c) Y. Shiraishi, D. Ikenaga and N. Toshima, Aust. J. Chem., 2003, 56,
1025; (d) H. Zhang, T. Watanabe, M. Okumura, M. Haruta and N. Toshima, Nat. Mater., 2012, 11,
49.
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Table 1 Dehydrogenative aromatization of 1a with 2a using various hydrogenDOaI:c1c0e.1p03t9o/rCs5CYa0n19d08G
catalystsa
H
N
O
O
O
O
N
N
N
+
+
+
O
1a
2a
3aa
4aa
5aa
Entry
Catalyst
Hydrogen acceptor
Yield (%)
3aa
34
41
59
76
51
41
5
4aa
64
46
<1
<1
47
56
<1
<1
<1
<1
5aa
<1
13
12
<1
<1
<1
<1
40
12
48
1
Au–Pd/Al2O3
Au–Pd/Al2O3
Au–Pd/Al2O3
Au–Pd/Al2O3
Au–Pd/Al2O3
Au–Pd/Al2O3
Au–Pd/Al2O3
Au/Al2O3
none
O2 (air)
styrene
styrene
1-octene
cyclooctene
benzoquinone
styrene
styrene
styrene
2b
3
4c
5
6
7d
8e
9f
10g
<1
20
33
Pd/Al2O3
Au/Al2O3 + Pd/Al2O3
a Reaction conditions: catalyst (Au: 1.4 mol%, Pd: 2.2 mol% with respect to 1a), 1a (0.5 mmol), 2a
(1.0 mmol), hydrogen acceptor (1.0 mmol), toluene (2 mL), 100 °C, Ar (1 atm), 6 h. Yields (based on
b
1a) were determined by GC analysis using n-decane as an internal standard. Open air (1 atm).
d
e
c 18 h. Substrates and benzoquinone were mostly converted into unidentified by-products. Au:
f
g
1.4 mol% with respect to 1a. Pd: 2.2 mol% with respect to 1a. A physical mixture of Au/Al2O3
and Pd/Al2O3 (Au: 1.4 mol%, Pd: 2.2 mol% with respect to 1a).
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(a)
40
30
20
10
0
0
2
4
6
8
10
20 nm
size (nm)
5.0 nm
5.0 nm
5.0 nm
(c)
(d)
(b)
Fig. 1 (a) TEM image of Au–Pd/Al2O3 and the size distribution of bimetallic nanoparticles (average:
2.9 nm, : 1.0 nm). The size distribution was determined using 200 particles. (b) HAADF-STEM
image of Au–Pd/Al2O3. (c) EDS images (Au element) of Au–Pd/Al2O3. (d) EDS images (Pd element)
of Au–Pd/Al2O3.
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H
N
O
N
+
1a
100
2b
3ab
80
60
40
20
0
Removal of the catalyst
0
1
2
3
4
5
6
Time (h)
Fig. 2 The effect of removal of the Au–Pd/Al2O3 catalyst (verification of heterogeneous catalysis).
Reaction conditions: Au–Pd/Al2O3 (Au: 1.4 mol%, Pd: 2.2 mol% with respect to 1a), 1a (0.5 mmol),
2b (1.0 mmol), styrene (1.0 mmol), toluene (2 mL), 80 °C, Ar (1 atm). Yields (based on 1a) were
determined by GC analysis using n-decane as an internal standard.
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R2
R2
R3
O
O
N
R3
AuPd/Al2O3
+
HN
R1
R1
1
2
3
H
N
H
N
N
N
3aa,a 76% (75%)b
3ab,c 87%b
3ac, 95% (78%)
3ad, 69%
H
N
H
N
H
N
OMe
Me
3ae, 91% (80%)
3af, 87%
3ag, 73%
O
O
O
N
N
Me
N
N
Me
Et
3ba,a 85%
3ca,a 83%
3da,a 64%
O
N
N
Me
N
Ph
Me
Et
3ea,a 35%
3bb,c 71%
3cb,c 77%
3db,c 73%
H
N
H
N
N
Me
Ph
Me
3eb,c 77%
3bc, 68%
3cc, 74%
H
N
H
N
H
N
Et
Ph
Et
Me
3dc, 77%
3ec, 80%
3be, 60%
H
N
H
N
H
N
Me
Ph
3ce, 83%
3de, 44%
3ee, 50%
Fig. 3 Scope of the present Au–Pd/Al2O3-catalyzed dehydrogenative aromatization of
cyclohexanones with amines. Reaction conditions: Au–Pd/Al2O3 (Au: 1.4 mol%, Pd: 2.2 mol% with
respect to 1), 1 (0.5 mmol), 2 (1.0 mmol), styrene (1.0 mmol), mesitylene (2 mL), 130 °C, Ar (1 atm),
24 h. Yields (based on 1) were determined by GC analysis using n-decane or naphthalene as an
internal standard. a Toluene (2 mL), 100 °C, 18 h. b The values in the parentheses indicate the
isolated yields. c Toluene (2 mL), 80 °C, 6 h.
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(a)
H
N
NH2
catalyst
O2
2
R
R
R
AuPd/Al2O3: 95% yield
Au/Al2O3: <1% yield
Pd/Al2O3: <1% yield
limited substrate scope
(cyclohexylamines only)
×
Au/Al2O3 + Pd/Al2O3: 3% yield
(b)
R2
N
R2
N
R2
O
AuPd/Al2O3
R3
+
R3
+
HN
O2
R3
R1
R1
R1
inevitable formation of substituted cyclohexylamines
×
(c)
R2
R2
O
N
AuPd/Al2O3
R3
+
HN
styrene
R3
R1
R1
selective formation of desired anilines
wide substrate scope



reusable catalyst
Scheme 1 Heterogeneously catalyzed dehydrogenative aromatization routes to N-substituted
anilines. (a) Our recently reported Au–Pd/Al2O3-catalyzed system from cyclohexylamines (see ref. 9),
(b) Au–Pd/Al2O3-catalyzed aerobic routes from cyclohexanones and amines (see Table 1, entry 2),
and (c) the reactions utilizing styrene as the hydrogen acceptor.
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(a)
O
O
O
AuPd/Al2O3
N
N
N
+
+
+
styrene
4aa
5aa
<1% yield
3aa
<1% yield
(b)
(c)
O
O
O
O
O
O
AuPd/Al2O3
N
N
N
styrene
5aa
3aa
69% yield
4aa
<1% yield
AuPd/Al2O3
N
N
N
No acceptor
3aa
4aa
5aa
31% yield
61% yield
Scheme 2 (a) Dehydrogenative aromatization starting from 4aa. Reaction conditions: Au–Pd/Al2O3
(Au: 1.4 mol%, Pd: 2.2 mol% with respect to 4aa), 4aa (0.5 mmol), styrene (1.0 mmol), toluene
(2 mL), 100 °C, Ar (1 atm), 6 h. (b and c) Dehydrogenative aromatization starting from 5aa.
Reaction conditions: Au–Pd/Al2O3 (Au: 1.4 mol%, Pd: 2.2 mol% with respect to 5aa), 5aa
(0.5 mmol), hydrogen acceptor (0 or 1.0 mmol), toluene (2 mL), 100 °C, Ar (1 atm), 6 h. Yields
(based on 4aa or 5aa) were determined by GC analysis using n-decane as an internal standard.
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(a)
(b)
O
O
O
O
AuPd/Al2O3
N
N
+
+
+
+
+
5aa
4aa
<1% yield
77% yield
O
AuPd/Al2O3
N
N
C6H13
C6H13
5aa
4aa
67% yield
63% yield
(c)
O
AuPd/Al2O3
N
N
+
5aa
4aa
75% yield
6% yield
Scheme 3 Au–Pd/Al2O3-catalyzed hydrogenation of an equimolar mixture of hydrogen acceptor
(styrene, 1-octene, and cyclooctene) and 5aa. Reaction conditions: Au–Pd/Al2O3 (Au: 0.4 mol%, Pd:
0.6 mol% with respect to alkenes), hydrogen acceptor (1.0 mmol), 4aa (1.0 mmol), ethanol (2 mL),
room temperature, H2 (1 atm), 1 h. Yields (based on 5aa and hydrogen acceptor, respectively) were
determined by GC analysis using n-decane as an internal standard.
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H
N
O
AuPd/Al2O3
+
N
N
1f
2b
3fb, 85% yield
Scheme 4 Au–Pd/Al2O3-catalyzed tandem 1,4-addition/1,2-addition/dehydrogenative aromatization
reaction of 1f with 2b to 3fb. Reaction conditions: Au–Pd/Al2O3 (Au: 1.4 mol%, Pd: 2.2 mol% with
respect to 1f), 1f (0.5 mmol), 2b (2.0 mmol), styrene (1.0 mmol), toluene (2 mL), 50 °C, Ar (1 atm),
6 h. Yields (based on 1f) were determined by GC analysis using n-decane as an internal standard.
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(Step 1: Condensation of cyclohexanone with amine)
R2
N
R2
HN
R3
O
+
+
H2O
R3
R1
R1
1
2
5
(Step 2: Dehydrogenation of enamine)
R2
R2
N
Pd
N
R3
R3
+
+
R1
R1
5
6
(Sstteepp33): Dehydrogenation of diene)
R2
R2
N
(Pd)
N
R3
R3
+
+
R1
R1
3
6
Scheme 5 Possible reaction pathway for the present Au–Pd/Al2O3-catalyzed dehydrogenative
aromatization starting from cyclohexanones and amines to produce N-substituted anilines. When
using primary amines (R2 = H), the corresponding ketimines are formed as the intermediates.
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Graphical abstract
R2
R2
HN
R3
O
N
Au−Pd/Al2O3
R3
+
styrene
R1
R1
selective formation of desired anilines
wide substrate scope
ꢀ
ꢀ
ꢀ
reusable catalyst
In the presence of a gold–palladium alloy nanoparticles catalyst (Au–Pd/Al2O3) and
styrene, various kinds of structurally diverse N-substituted anilines (twenty three
examples) could be synthesized starting from cyclohexanones and amines.