Versatile routes for synthesis of diarylamines through acceptorless dehydrogenative aromatization catalysis over supported gold-palladium bimetallic nanoparticles

Article abstract of DOI:10.1039/c6sc04455g

Diarylamines are an important class of widely utilized chemicals, and development of diverse procedures for their synthesis is of great importance. Herein, we have successfully developed novel versatile catalytic procedures for the synthesis of diarylamines through acceptorless dehydrogenative aromatization. In the presence of a gold-palladium alloy nanoparticle catalyst (Au-Pd/TiO₂), various symmetrically substituted diarylamines could be synthesized starting from cyclohexylamines. The observed catalysis of Au-Pd/TiO₂ was heterogeneous in nature and Au-Pd/TiO₂ could be reused several times without severe loss of catalytic performance. This transformation needs no oxidants and generates molecular hydrogen (three equivalents with respect to cyclohexylamines) and ammonia as the side products. These features highlight the environmentally benign nature of the present transformation. Furthermore, in the presence of Au-Pd/TiO₂, various kinds of structurally diverse unsymmetrically substituted diarylamines could successfully be synthesized starting from various combinations of substrates such as (i) anilines and cyclohexanones, (ii) cyclohexylamines and cyclohexanones, and (iii) nitrobenzenes and cyclohexanols. The role of the catalyst and the reaction pathways were investigated in detail for the transformation of cyclohexylamines. The catalytic performance was strongly influenced by the nature of the catalyst. In the presence of a supported gold nanoparticle catalyst (Au/TiO₂), the desired diarylamines were hardly produced. Although a supported palladium nanoparticle catalyst (Pd/TiO₂) gave the desired diarylamines, the catalytic activity was inferior to that of Au-Pd/TiO₂. Moreover, the activity of Au-Pd/TiO₂ was superior to that of a physical mixture of Au/TiO₂ and Pd/TiO₂. The present Au-Pd/TiO₂-catalyzed transformation of cyclohexylamines proceeds through complex pathways comprising amine dehydrogenation, imine disproportionation, and condensation reactions. The amine dehydrogenation and imine disproportionation reactions are effectively promoted by palladium (not by gold), and the intrinsic catalytic performance of palladium is significantly improved by alloying with gold. One possible explanation of the alloying effect is the formation of electron-poor palladium species that can effectively promote the β-H elimination step in the rate-limiting amine dehydrogenation.

Full text of DOI:10.1039/c6sc04455g

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Versatile routes for synthesis of diarylamines through acceptorless
dehydrogenative aromatization catalysis over supported gold–palladium
bimetallic nanoparticles†
Kento Taniguchi,a Xiongjie Jin,a Kazuya Yamaguchi,*a Kyoko Nozakib and Noritaka Mizuno*a
a
Department of Applied Chemistry, School of Engineering, The University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku,
Tokyo
113-8656,
Japan.
E-mail:
tmizuno@mail.ecc.u-tokyo.ac.jp;
kyama@appchem.t.u-tokyo.ac.jp; Fax: +81-3-5841-7220
b
Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
Abstract
Diarylamines are an important class of widely utilized chemicals, and development of diverse
procedures for their synthesis is of great importance. Herein, we have successfully developed novel
versatile catalytic procedures for the synthesis of diarylamines through acceptorless dehydrogenative
aromatization. In the presence of a gold–palladium alloy nanoparticle catalyst (Au–Pd/TiO2), various
symmetrically substituted diarylamines could be synthesized starting from cyclohexylamines. The
observed catalysis of Au–Pd/TiO2 was heterogeneous in nature and Au–Pd/TiO2 could be reused
several times without severe loss of catalytic performance. This transformation needs no oxidants
and generates molecular hydrogen (three equivalents with respect to cyclohexylamines) and
ammonia as the side products. These features highlight the environmentally benign nature of the
present transformation. Furthermore, in the presence of Au–Pd/TiO2, various kinds of structurally
diverse unsymmetrically substituted diarylamines could successfully be synthesized starting from
various combinations of substrates such as (i) anilines and cyclohexanones, (ii) cyclohexylamines
and cyclohexanones, and (iii) nitrobenzenes and cyclohexanols. The role of the catalyst and the
reaction pathways were investigated in detail for the transformation of cyclohexylamines. The
catalytic performance was strongly influenced by the nature of the catalyst. In the presence of a
supported gold nanoparticle catalyst (Au/TiO2), the desired diarylamines were hardly produced.
1

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Although a supported palladium nanoparticle catalyst (Pd/TiO2) gave the desired diarylamines, the
catalytic activity was inferior to that of Au–Pd/TiO2. Moreover, the activity of Au–Pd/TiO2 was
superior to that of a physical mixture of Au/TiO2 and Pd/TiO2. The present Au–Pd/TiO2-catalyzed
transformation of cyclohexylamines proceeds through complex pathways comprising amine
dehydrogenation, imine disproportionation, and condensation reactions. The amine dehydrogenation
and imine disproportionation reactions are effectively promoted by palladium (not by gold), and the
intrinsic catalytic performance of palladium is significantly improved by alloying with gold. One
possible explanation of the alloying effect is the formation of electron-poor palladium species that
can effectively promote the β-H elimination step in the rate-limiting amine dehydrogenation.
Introduction
Diarylamines are very important compounds and core structural motifs frequently utilized for
pharmaceuticals, agricultural chemicals, dyes, radical-trapping antioxidants, and electroluminescent
materials.1 From the viewpoint of starting materials, the previously developed synthetic methods for
diarylamines are roughly divided into four categories; namely (i) arylation of anilines using aryl
halides (Fig. 1, eqn (1)),2,3 (ii) arylation of anilines using aryl metal or metalloid species (Fig. 1,
eqn (2)),4,5 (iii) arylation of anilines involving directing-group assisted aromatic C–H bond activation
(Fig. 1, eqn (3)),6 and (iv) dehydrogenative aromatization (Fig. 1, eqn (4)).7
The research groups of Buchwald and Hartwig have independently established the potent
palladium-catalyzed cross-coupling reaction between anilines and aryl halides (Buchwald–Hartwig
coupling, Fig. 1, eqn (1)).2 Arylation of ammonia using aryl halides is included in this category.3 As
for arylation of anilines with aryl metal or metalloid species, the Chan–Lam coupling between
anilines and arylboronic acids (or arylboronates) is undoubtedly one of the most powerful and
versatile reactions,4 and the C–N cross-coupling reactions of anilines (or aniline surrogates) with aryl
metal species, such as magnesium-, zinc-, nickel-, and gold-based reagents, have also been reported
(Fig. 1, eqn (2)).5 These cross-coupling methodologies exhibit wide substrate scopes and are
2

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frequently utilized as reliable choices for diarylamine synthesis; however, they require
pre-functionalized substrates, such as aryl halides and aryl metal species, which inevitably cause the
concurrent formation of (super)stoichiometric amounts of waste. Although arylation of anilines with
arenes through directing group-assisted aromatic C–H bond activation has recently been developed
(Fig. 1, eqn (3)),6 most of the reported systems require (super)stoichiometric amounts of organic
reagents or metal-based oxidants, and exhibit a limited scope of substrates.
Recently, dehydrogenative aromatization has emerged as an attractive strategy for synthesis of
various aromatic compounds (Fig. 1, eqn (4)).7,8 For example, cyclohexanones and cyclohexanols are
converted into the corresponding phenols,8a–h and the reaction of cyclohexanones in the presence of
amines gives the corresponding N-substituted anilines.7 Various kinds of oxidants (hydrogen
acceptors), such as molecular oxygen, 1-octene, styrene, tert-butyl peroxybenzoate,
2,3-dichloro-5,6-dicyanobenzoquinone, and molecular iodine, have been utilized for
dehydrogenative aromatization,7,8 and acceptorless dehydrogenative aromatization of
cyclohexanones into phenols has also been reported.8f The acceptorless dehydrogenation with a
release of molecular hydrogen is more desirable reaction from the viewpoint of high atom economy,
increasing environmental concerns, and hydrogen recycling.9 Meanwhile, we have recently reported
gold–palladium bimetallic nanoparticles catalyze oxidative dehydrogenation reactions to afford
N-substituted anilines7i and phenols8g using molecular oxygen as the sole oxidant.
As a continuation of our interest in the development of efficient catalytic dehydrogenation
reactions, we report herein for the first time “acceptorless dehydrogenative aromatization” reactions
to give symmetrically substituted diarylamines starting from cyclohexylamines (Fig. 1, eqn (5)), and
unsymmetrically substituted diarylamines using various combinations of substrates such as anilines
and cyclohexanones (Fig. 1, eqn (6)), cyclohexylamines and cyclohexanones (Fig. 1, eqn (7)), and
nitrobenzenes and cyclohexanols (Fig. 1, eqn (8)). The substrates used in this study are summarized
in Fig. 2. These reactions proceed without the use of oxidants under an Ar atmosphere and typically
concurrently produce molecular hydrogen as a coproduct (no hydrogen evolution for eqn (8)).
3

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Additionally, catalysis using Au–Pd/TiO2 for the present dehydrogenative aromatization was truly
heterogeneous and Au–Pd/TiO2 was easily recoverable and reusable without severe loss of catalytic
performance.
Results and discussion
Effect of catalysts
First, we carried out the dehydrogenative aromatization of 4-isopropylcyclohexylamine (1a) into
4-(1-methylethyl)-N-[4-(1-methylethyl)phenyl]benzenamine (2a) in the presence of various
supported metal nanoparticles catalysts (gold, palladium, and gold–palladium on metal oxide
supports; given in the format: metal/support, see in the Experimental section and ESI† for their
preparation and characterization). The reactions were typically carried out at 160 °C in mesitylene
under an Ar atmosphere (1 atm) without oxidants and additives. The reaction profiles are shown in
Fig. 3. Gold–palladium bimetallic nanoparticles supported on TiO2 (Au–Pd/TiO2) showed excellent
catalytic performance for acceptorless dehydrogenative aromatization. We prepared four kinds of
Au–Pd/TiO2 catalysts with the different Au/Pd molar ratios (Au/Pd = 76/24, 58/42, 35/65, and 14/86)
and carried out the reaction of 1a using these four catalysts under the conditions described in
Table S1. Although the Au–Pd/TiO2 catalyst with the Au/Pd ratio of 58/42 (average particle size
(dav): 3.3 nm, standard deviation (σ): 1.0 nm) gave the slightly better result than the others, the effect
of the Au/Pd ratios was not so significant (Table S1, entries 1 and 9–11, ESI†). When using the best
Au–Pd/TiO2 catalyst (Au/Pd = 58/42), the yield of 2a reached 88% under the conditions described in
Fig. 3 for 24 h (Fig. 3a, Table S1, entry 2, ESI†). In this reaction, we also confirmed the
coproduction of ca. three equivalents (2.8 mmol) of hydrogen gas and ca. one-half equivalents
(0.3 mmol) of ammonia gas with respect to 1a (1.0 mmol). In contrast, the desired diarylamine 2a
was not produced at all in the presence of Au/TiO2 (dav: 1.9 nm, σ: 0.5 nm) (Fig. 3b, Table S1,
entries 3 and 4, ESI†), thus showing that gold is completely inactive for the aromatization. When
using Pd/TiO2 (dav: 2.0 nm, σ: 0.8 nm), 2a was produced in 44% yield (Fig. 3c, Table S1, entry 6,
4

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ESI†), thus indicating that palladium is essential for the transformation and that Au–Pd/TiO2 has a
superior catalytic activity relative to Pd/TiO2. A physical mixture of Au/TiO2 and Pd/TiO2 gave 2a in
69% yield (Fig. 3d, Table S1, entry 8, ESI†), lower than that obtained with Au–Pd/TiO2.
High-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) and
energy dispersive X-ray spectroscopy (EDS) analyses of Au–Pd/TiO2 revealed that random
gold–palladium alloy nanoparticles were formed on TiO2 (Fig. S1, ESI†). The catalytic activity of
the palladium species (based on the yield of 2a) in Au–Pd/TiO2 (88% yield, Table S1, entry 2, ESI†)
was at least twice that of Pd/TiO2 (44% yield, Table S1, entry 6, ESI†), clearly indicating that the
intrinsic catalytic activity of palladium for the reaction was improved by alloying with gold. The
enhancement in catalytic activity is likely due to an electronic ligand effect; such alloying effects are
frequently observed for several oxidation reactions using gold–palladium alloy catalysts such as
alcohol oxidation and hydrogen oxidation (H2O2 production).10 Also, in our previous study on
Au–Pd/LDH-catalyzed (LDH = Mg–Al-layered double hydroxide) oxidative dehydrogenation of
cyclohexanols and cyclohexanones to phenols using molecular oxygen as the oxidant, the
improvement of palladium catalysis by alloying with gold was crucial.8g The role of the metal
species and the alloying effect will be discussed in additional detail below.
Next, the effect of supports was examined. Gold–palladium bimetallic nanoparticles, supported
on TiO2, Al2O3, MgO, and CeO2, exhibited catalytic activities for the dehydrogenative aromatization
of 1a, and TiO2 was the best support among them (Table S1, entries 1, 12–14, ESI†). When using
SiO2 as the support, 2a was hardly produced (Table S1, entry 15, ESI†), indicating that acidic
supports are not suitable for the present transformation. Thus, we hereafter mainly utilize the most
active Au–Pd/TiO2 catalyst (Au/Pd = 58/42) for further detailed investigations.
Heterogeneous catalysis and catalyst reuse
To verify whether the observed catalysis with Au–Pd/TiO2 was truly heterogeneous, the following
control experiments were carried out. The reaction of 1a to produce the corresponding diarylamine
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2a was carried out under conditions described in Fig. 4, and Au–Pd/TiO2 was removed from the
reaction mixture by hot filtration after 3 h, then the filtrate was heated at 160 °C. In this case, no
further
production
of
2a
and
no
further
consumption
of
4-(1-methylethyl)-N-[4-(1-methylethyl)cyclohexyl]benzeneamine
(3a)
and
4-(1-methylethyl)benzenamine (4a) were observed, as shown in Fig. 4. 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.11 These results clearly indicate that the observed
Au–Pd/TiO2-catalyzed dehydrogenative aromatization is truly heterogeneous in nature.11
After the reaction was complete, the Au–Pd/TiO2 could easily be retrieved from the reaction
mixture by simple filtration with >90% recovery. We performed repeated reuse experiments for the
transformation of 1a under the standard reaction conditions using the retrieved catalyst. Although
Au–Pd/TiO2 could be reused several times, the catalytic activity gradually decreased during the
repeated reuse experiments; 90% yield of 2a for the reaction of 1a with the fresh catalyst, 86% yield
for the first reuse, 82% yield for the second reuse, and 71% yield for the third reuse (Fig. 5).
Transmission electron microscopy (TEM) analysis confirmed that the average particle size of
gold–palladium alloy nanoparticles gradually increased during repeated reuse experiments; the
average particle size in the fresh Au–Pd/TiO2 catalyst was 3.3 nm and increased to 4.4 nm after the
third reuse experiment (Fig. S1, ESI†). HAADF-STEM and EDS analyses of Au–Pd/TiO2 used after
the third reuse experiment revealed that random gold–palladium alloy nanoparticles were kept on
TiO2 (Fig. S1, ESI†). Therefore, the gradual deactivation is likely caused by the increase in particle
size.
Substrate scope
In this section, we examined the substrate scope for Au–Pd/TiO2-catalyzed dehydrogenative
aromatization. The substrates used in this study are summarized in Fig. 2. As shown in Fig. 5, under
optimized reaction conditions, various kinds of structurally diverse cyclohexylamines could be
6

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converted into the corresponding symmetrically substituted diarylamines in the presence of
Au–Pd/TiO2. The reaction of cyclohexylamine and its derivatives with a methyl group at each
position of the cyclohexane rings (1a–1e) efficiently proceeded to afford the corresponding
diarylamines. Cyclohexylamines with other alkyl groups at their 4-position, such as ethyl (1f),
n-propyl (1g), n-butyl (1h), sec-butyl (1i), tert-butyl (1j), and n-pentyl (1k) groups, could also be
converted into the corresponding symmetrically substituted diarylamines. Notably, a larger scale
reaction was also successful; even when a gram-scale (10 mmol-scale) acceptorless dehydrogenative
aromatization of 1a was performed, 2a was obtained in 94% yield (Fig. 6).
Various kinds of basic chemicals, such as cyclohexylamine, aniline, nitrobenzene, cyclohexanone,
and cyclohexanol, are now industrially produced from benzene in large quantities.12 These basic
chemicals and their derivatives are readily available, and thus the development of efficient catalytic
transformations for production of profitable compounds directly utilizing them or their derivatives as
starting materials is a very important subject. Therefore, to further explore the practical utility of the
Au–Pd/TiO2-catalyzed acceptorless dehydrogenative aromatization system, we next attempted to
synthesize unsymmetrically substituted diarylamines starting from various combinations of
substrates such as (i) anilines and cyclohexanones (Fig. 7), (ii) cyclohexylamines and
cyclohexanones (Fig. 8), and (iii) nitrobenzenes and cyclohexanols (Fig. 9).
As described in Fig. 7, various combinations of anilines and cyclohexanones (Fig. 2) successfully
afforded the corresponding unsymmetrically substituted diarylamines in the presence of Au–Pd/TiO2.
These reactions efficiently proceeded using equimolar mixtures of anilines and cyclohexanones.
Anilines with alkyl groups (4b–4f) efficiently reacted with cyclohexanone (5a), giving the
corresponding diarylamine derivatives. Anilines with various substituents, such as methoxy (4g),
fluoro (4h), dimethylamino (4i), and ester (4j) groups, could be applied to the present system.
1-Naphthylamine (4k) could also be utilized in this reaction. Cyclohexanones possessing various
substituents at each position, such as 4-methylcyclohexanone (5b), 3-methylcyclohexanone (5c),
2-methylcyclohexanone (5d), 3,4-dimethylcyclohexanone (5e), 3,5-dimethylcyclohexanone (5f),
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4-ethylcyclohexanone (5g), 4-propylcyclohexanone (5h), 4-tert-butylcyclohexanone (5i), ethyl
4-oxocyclohexanonecarboxylate (5j), and 4-phenylcyclohexanone (5k), could successfully be
utilized as coupling partners for aniline (4l) in the Au–Pd/TiO2-catalyzed system. The
dehydrogenative aromatization of β-tetralone (5l) with 4l afforded N-phenyl-β-naphthylamine (6o),
which is one of the most important radical-trapping antioxidants.13
As shown in Fig. 8, unsymmetrically substituted diarylamines could also be synthesized starting
from equimolar mixtures of cyclohexylamines and cyclohexanone (Fig. 2) through
Au–Pd/TiO2-catalyzed acceptorless dehydrogenative aromatization. Through reactions with 1b,
cyclohexanones with various alkyl groups, such as 4-methyl (5b), 3-methyl (5c), 4-ethyl (5g),
4-propyl (5h), and 4-tert-butyl (5i), could be converted into the corresponding diarylamines.
Disubstituted cyclohexanones, such as 5e and 5f, could also be used as substrates. The reaction of 5k
and 4-ethoxycyclohexanone (5m) with 1b gave the corresponding diarylamines. Various
cyclohexylamines, such as 1c, 1d, and 1j, were also good coupling partners for 5a, giving the
corresponding diarylamine derivatives．
Notably, we could successfully synthesize unsymmetrically substituted diarylamines starting
from nitrobenzenes (7a–7c) and cyclohexanols (8a and 8b) in the presence of Au–Pd/TiO2 (Fig. 9).
In this reaction, hydrogen formed in the alcohol dehydrogenation and aromatization steps is all
effectively utilized for the selective six-electron reduction of nitrobenzenes. Therefore, the reaction
efficiently proceeded using equimolar mixtures of nitrobenzenes and cyclohexanols. The reaction of
nitrobenzenes and cyclohexanols to produce diarylamines has never been reported to date, to the best
of our knowledge.
Reaction pathways
In this section, the reaction pathways for Au–Pd/TiO2-catalyzed transformation of 1a to 2a are
discussed in detail. As shown in Fig. 3a, the reaction profile for the transformation of 1a shows that
3a and 4a were initially produced followed by their conversion into the desired diarylamine 2a. In a
8

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separate experiment, we confirmed that N-cyclohexylanilines were efficiently converted into the
corresponding diarylamines under the same reaction conditions in the presence of Au–Pd/TiO2.
Furthermore, when the Au–Pd/TiO2-catalyzed reaction of 1a was carried out in the presence of
p-toluidine (4b), significant amounts of amine–aniline cross-coupling products 6q and 3q were
produced (Fig. 10). These results indicate that both N-cyclohexylanilines (3) and anilines (4) are
possible intermediates for diarylamines.
The present Au–Pd/TiO2-catalyzed dehydrogenative aromatization is likely initiated by the
dehydrogenation of cyclohexylamine substrates (1) to cyclohexylimines (9). We hypothesize that the
present diarylamine production is mainly made up of two routes (Fig. 11). In Route A, after the
initial formation of 9, the condensation of
9
and
1
gives the corresponding
N-cyclohexylidenecyclohexanamines (10) followed by dehydrogenation to afford 3. The
dehydrogenation of 3 then takes place to give the corresponding N-phenylcyclohexylimines (11),
followed by aromatization to afford the desired diarylamines 2. In Route B, the further
dehydrogenation of 9 produces 4. After condensation of 9 and 4 aromatization occurs. The reaction
profile in Fig. 3a shows that the concentration of 3a was significantly higher than that of 4a during
the reaction. Therefore, we considered that Route A is the major pathway for the present diarylamine
production. In addition, the dehydrogenation of 3 (N-arylated secondary amines) is much slower than
that of 1 (primary amines), as can be seen from Fig. 3a.
As above-mentioned, palladium was intrinsically effective for the transformation of
cyclohexylamine 1a, whereas gold was not effective (Fig. 3). In addition, the catalytic activity of
palladium was significantly improved by alloying with gold (Fig. 3). In order to reveal the effect of
the catalyst on the aromatization step in Route A in detail, we next carried out the reaction of
N-cyclohexylaniline (3b) using Au–Pd/TiO2, Au/TiO2, Pd/TiO2, and a mixture of Au/TiO2 and
Pd/TiO2. In the presence of Au–Pd/TiO2, the reaction efficiently proceeded to afford the
corresponding diarylamine 2b (Fig. 12a). When using Au/TiO2, almost no conversion of 3b was
observed (Fig. 12b), indicating gold is completely inactive for dehydrogenation of this type of amine.
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In the presence of Pd/TiO2, 2b was produced in significant amounts (Fig. 12c), showing that
palladium is essential for the transformation. The catalytic activity of a simple mixture of Au/TiO2
and Pd/TiO2 was almost the same as that of Pd/TiO2, and much lower than that of Au–Pd/TiO2
(Fig. 12d). Therefore, the effect of alloying palladium with gold is crucial for the transformation of 3.
We also performed the reaction of N-cyclohexylidenebenzenamine (11b). In the presence of
Au–Pd/TiO2, 11b was quantitatively converted into a ca. 1:2 mixture of 2b and 3b in the initial stage
of the reaction (within 10 min) (Fig. 13a). After that, 11b was hardly detected throughout the reaction
(Fig. 13a). In addition, 11b was not observed for the reaction starting from 3b (Fig. 12a). These time
courses clearly revealed that the desired diarylamine 2b was produced through the disproportionation
of 11b without evolution of hydrogen gas and that the disproportionation was much faster than the
dehydrogenation of 3b to 11b. Pd/TiO2 was also effective for the disproportionation, whereas
Au/TiO2 was not (Fig. 13b), indicating that palladium is essential for the disproportionation.
On the basis of the above-mentioned pieces of experimental evidence, we concluded that
Au–Pd/TiO2-catalyzed dehydrogenative aromatization proceeds through complex pathways
composed of several amine dehydrogenation, imine disproportionation, and condensation reactions
(Fig. 11). These amine dehydrogenation and imine disproportionation reactions are effectively
promoted by palladium (not by gold), and the intrinsic catalytic performance of palladium is
significantly improved by alloying with gold. The reaction is initiated by the acceptorless
dehydrogenation of 1 to 9 with concomitant formation of hydrogen gas. In Route A (major route), the
condensation of 9 and 1 takes place to give 10. The disproportionation of 10 then takes place in
which 10 itself, 9, and 11 possibly act as the hydrogen acceptors, producing one molecule of 3 and
two molecules of amines from three molecules of imines (one molecule of 10 + two molecules of 10,
9, and/or 11). The amines formed in the disproportionation step are again dehydrogenated to the
corresponding imines by Au–Pd/TiO2. When 10 itself acts as the hydrogen acceptor for the
disproportionation, dicyclohexylamine (12) is produced. We confirmed, in a separate experiment,
that the desired diarylamine could efficiently be produced starting from 12 in the presence of
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Au–Pd/TiO2 (Fig. S2, ESI†). The dehydrogenation of 3 proceeds to give 1D1OI:f1o0.l1l0o3w9/Ce6dSC0b44y55G
disproportionation to afford the desired diarylamines 2 with concomitant formation of amines, as
with the reaction of 10. In Route B (minor route), 9 is further dehydrogenated to 4, possibly via
disproportionation, which readily reacts with 9 to form 11. Finally, the disproportionation of 11
affords the desired diarylamines 2. Regardless of Route A or Route B, the reaction theoretically
produces three equivalents of hydrogen gas and one-half equivalents of ammonia gas with respect to
1, which agrees well with the above-mentioned experimental result; the reaction of 1a gave 2a in
88% yield with concomitant formation of ca. three equivalents (2.8 mmol) of hydrogen gas and ca.
one-half equivalents (0.3 mmol) of ammonia gas with respect to 1a (1.0 mmol) (Table S1, entry 2,
ESI†).
In the reactions demonstrated in Fig. 7 and Fig. 8, the condensation of substrates (anilines +
cyclohexanones or cyclohexylamines + cyclohexanones) initially takes place followed by the
pathways indicated in Fig. 11. The reaction demonstrated in Fig. 9 is initiated by the
dehydrogenation of cyclohexanols to cyclohexanones.14 Then, nitrobenzenes are reduced to the
corresponding anilines by using the hydrogen formed (or transiently formed metal hydride species
directly) in the initial alcohol dehydrogenation and dehydrogenative aromatization steps. The
reaction then proceeds through the pathways shown in Fig. 11, giving the desired unsymmetrically
substituted diarylamines 6 (Fig. S3, ESI†).
Quite recently, we reported an efficient aerobic oxidative dehydrogenation of cyclohexanols
and cyclohexanones to phenols catalyzed by Au–Pd/LDH.8g We revealed in the previous study that
gold in Au–Pd/LDH plays an important assisting role on the β-H elimination from palladium-enolate
species in the dehydrogenation of cyclohexanones to cyclohexenones by palladium, likely via an
electronic ligand effect.8g The greater electronegativity of gold compared to that of palladium has
been reported to cause a net electron transfer from palladium to gold, thus resulting in the formation
of more electron-poor palladium species.10,15 Consequently, the β-H elimination step using
Au–Pd/LDH becomes more favorable in comparison to Pd/LDH.8g
11

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We measured the XPS spectra of Au–Pd/TiO2 and Au/TiO2 around Au 4f compDoOnI:e1n0.t1s03(9F/Ci6gS.CS0444,55G
ESI†).16 The two peaks in each spectrum observed around 83 eV and 87 eV are attributed to Au 4f7/2
and 4f5/2, respectively. The Au 4f peaks of Au–Pd/TiO2 were observed at more negative binding
energies in comparison with those of Au/TiO2. These significant negative shifts indicate the net
electron-transfer from palladium to gold occurs to form electron-rich gold and electron-poor
palladium species in Au–Pd/TiO2.10,15 As above-mentioned, the dehydrogenation of 3 is the
rate-limiting reaction for the present Au−Pd/TiO2-catalyzed aromatization. The amine
dehydrogenation possibly includes a β-H elimination step; it has been reported that the
dehydrogenation of amines on the surface of palladium-based nanoparticles proceeds through the
formation of palladium–amide species followed by β-H elimination.17 At this stage, our one possible
explanation of the alloying effect is the formation of electron-poor palladium species by alloying
with gold that can effectively promote the β-H elimination step in the rate-limiting amine
dehydrogenation.
Conclusion
We have successfully developed novel widely applicable synthetic procedures for formation of
diarylamines. In the presence of a supported gold–palladium alloy nanoparticle catalyst
(Au–Pd/TiO2), various kinds of structurally diverse symmetrically and unsymmetrically substituted
diarylamines could be synthesized through acceptorless dehydrogenative aromatization starting from
various substrate combinations. The observed catalysis was truly heterogeneous, and the Au–Pd/TiO2
catalyst could be reused. Owing to the practical and environmentally benign nature, we hope that the
catalytic transformations developed in this study will find wide applications for the synthesis of
diarylamine derivatives and their related compounds.
12

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DOI: 10.1039/C6SC04455G
Experimental section
Instruments and reagents
GC analyses were performed on Shimadzu GC-2014 equipped with a flame ionization detector (FID)
using a capillary column (InertCap5) for liquid phase analysis and Shimadzu GC-8A equipped with a
thermal conductivity detector (TCD) using a glass tube column (5 Å molecular sieve) for gas phase
analysis. GC-MS spectra were recorded on Shimadzu GCMSQP2010 equipped with a capillary
1
13
column (InertCap5) at an ionization voltage of 70 eV. Liquid-state H and C NMR spectra were
recorded on JEOL JNM-ECA 500 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 a 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 then dried in air. XPS
analyses were performed using a JEOL JPS-9000 under Mg Kα radiation (hν = 1253.6 eV, 8 kV,
10 mA). The peak positions were calibrated with respect to the Ti 2p3/2 peak (459.4 eV).18 TiO2 (BET
surface area: 316 m2 g−1, cat. no. ST-01, Ishihara Sangyo Kaisya), SiO2 (BET surface area:
274 m2 g−1, cat. no. CARiACT Q-10 (75−150 m), Fuji Silysia Chemical Ltd.), Al2O3 (BET surface
area: 160 m2 g−1, cat. no. KHS-24, Sumitomo Chemical), CeO2 (BET surface area: 111 m2 g−1, cat.
no. 544841-25G, Aldrich), and MgO (BET surface area: 36 m2 g−1, cat. no. NO-0012-HP, Ionic
Liquids Technologies), were commercially available. Solvents and substrates were obtained from
Kanto Chemical, TCI, Wako, or Aldrich (reagent grade), and purified prior to use, if necessary.19
Preparation of catalysts
Au–Pd/TiO2 (Au/Pd = 58/42) was prepared as follows. First, an aqueous solution of HAuCl4·4H2O
(5.0 mM), PdCl2 (3.3 mM), and KCl (two equivalents with respect to PdCl2, 6.7 mM) containing
TiO2 (2.0 g) was vigorously stirred at room temperature for 15 min. Then, the pH of the solution was
adjusted to 10.0 using an aqueous solution of NaOH (1.0 M, ca. 1.5 mL). The resulting slurry was
then further stirred for 24 h at room temperature giving 2.0 g of the hydroxide precursor. By the
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reduction of the hydroxide precursor using hydrogen (1 atm) at 150 °C for 30 min, the supported
gold–palladium bimetallic nanoparticle catalyst Au–Pd/TiO2 was obtained. The contents of gold and
palladium in Au–Pd/TiO2 were 0.134 mmol g−1 and 0.095 mmol g−1, respectively (determined by
ICP-AES), and the average particle size (dav) was 3.3 nm (standard deviation (σ): 1.0 nm).
Au–Pd/TiO2 (Au/Pd = 76/24, Au: 0.150 mmol g−1, Pd: 0.046 mmol g−1), Au–Pd/TiO2 (Au/Pd = 35/65,
Au: 0.078 mmol g−1, Pd: 0.144 mmol g−1), Au–Pd/TiO2 (Au/Pd = 14/86, Au: 0.031 mmol g−1, Pd:
0.188 mmol g−1), and other supported catalysts were prepared essentially by the same manner as that
for Au–Pd/TiO2 (Au/Pd = 58/42) (for the preparation of Au–Pd/MgO, an aqueous solution of NaOH
was not used); Au/TiO2 (Au: 0.149 mmol g−1, dav: 1.9 nm, σ: 0.5 nm), Pd/TiO2 (Pd: 0.250 mmol g−1,
dav: 2.0 nm, σ: 0.8 nm), Au–Pd/SiO2 (Au: 0.026 mmol g−1, Pd: 0.048 mmol g−1, dav: 6.4 nm, σ:
7.7 nm), Au–Pd/Al2O3 (Au: 0.111 mmol g−1, Pd: 0.090 mmol g−1, dav: 3.7 nm, σ: 1.1 nm),
Au–Pd/CeO2 (Au: 0.128 mmol g−1, Pd: 0.086 mmol g−1, dav: 3.2 nm, σ: 1.1 nm), and Au–Pd/MgO
(Au: 0.074 mmol g−1, Pd: 0.062 mmol g−1, dav: 5.1 nm, σ: 1.9 nm).
Catalytic reactions
Catalytic reactions were typically carried out according to the following procedure. Into a Schlenk
flask reactor (volume: ca. 20 mL) were successively placed Au–Pd/TiO2 (Au: 1.45 mol%, Pd:
1.05 mol% with respect to the cyclohexylamine), cyclohexylamine (1, 1.0 mmol), n-hexadecane
(0.1 mmol, internal standard), mesitylene (2 mL), and a Teflon-coated magnetic stir bar, and then the
mixture was stirred at 160 °C under Ar (1 atm). Substrate conversions and product yields were
determined by GC analysis using n-hexadecane as an internal standard. As for isolation of the
products, the internal standard was not used. After the reaction, the catalyst was removed by simple
filtration (>90% catalyst recovery) and the filtrate was concentrated by evaporation of the mesitylene
solvent. The crude product was subjected to column chromatography on silica gel (typically using
chloroform/hexane as an eluent), giving the pure diarylamine product. The products were confirmed
13
by comparison of their GC retention times, GC-MS spectra, and/or NMR (1H and C) spectra with
14

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those of the authentic data. The detection of hydrogen and ammonia in the gas-phaseDwOIa: 1s0.c10a3r9r/iCe6dSCo04u4t55G
with GC (with a TCD detector) and GC-MS analyses. The quantification of hydrogen gas formation
was performed by measurement of the evolved gas volume after ammonia trapping using aqueous
HCl, and the quantification of ammonia formation was performed by titration of the aqueous HCl
solution using aqueous NaOH. As for the reuse experiment, Au–Pd/TiO2 was retrieved by filtration
and washed with a mixed solvent of methanol and dichloromethane. The retrieved Au–Pd/TiO2 was
activated at 150 °C in 1 atm of hydrogen prior to being used for the reuse experiment.
Acknowledgments
We thank Mr. H. Oshikawa (The University of Tokyo) for his help with the HAADF-STEM and EDS
analyses. This work was supported in part by JSPS KAKENHI Grant No. 15H05797 in “Precisely
Designed Catalysts with Customized Scaffolding” and 15J09227. A part of this work was conducted
in the 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 the
JSPS through the Program for Leading Graduate Schools (MERIT program) and the Research
Fellowship for Young Scientists.
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Notes and references
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11 We also confirmed by hot-filtration experiments that the observed catalyses of Au/TiO2, Pd/TiO2,
and the physical mixture of Au/TiO2 and Pd/TiO2 for the reaction of 1a were truly heterogeneous:
R. A. Sheldon, M. Wallau, I. W. C. E. Arends and U. Schuchardt, Acc. Chem. Res., 1998, 31, 485.
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14 It has been reported that Au–Pd alloy nanoparticle catalysts are effective for alcohol
dehydrogenation.10 In addition, we have reported that Au–Pd alloy nanoparticle catalysts showed
high performance for the dehydrogenation of cyclohexanols to cyclohexanones.8g
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16 We also attempted to confirm the peak shifts of Pd 3d components in Au–Pd/TiO2. However, it
was very difficult to confirm that because the peak due to Pd 3d5/2 was overlapped with that of
4f5/2 and the intensity of the peak attributed to Pd 3d3/2 was very low.
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Butterworth-Heinemann, Oxford, 5th edn, 2003.
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(a) Previous works
H
N
NH2
X
(1)
+
R
R
R
R
R'
R'
R'
R'
R
R'
X = halogen
H
N
NH2
M
(2)
(3)
+
R
R'
M = metal, B(OH)2, etc.
H
N
NH2
H
+
DG
R
R'
DG = directing group
H
N
O
NH2
(4)
+
R
R'
(b) This work
H
NH2
N
+ NH3 + 6H2
+ H2O + 2H2
(5)
(6)
2
R
R
R
R
H
N
O
O
NH2
+
+
+
R'
R
R
R
R'
R'
R'
H
N
NH2
NO2
(7)
(8)
+ H2O + 5H2
R
R
R'
R'
H
N
HO
+ 3H2O
Fig. 1 Synthetic procedures for diarylamines.
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Cyclohexylamines (1)
NH2
DOI: 10.1039/C6SC04455G
NH2
NH2
NH2
NH2
NH2
1a
1b
1c
NH2
1d
1e
1f
NH2
NH2
NH2
NH2
1g
1h
1i
1j
1k
Anilines (4)
NH2
NH2
NH2
NH2
NH2
NH2
O
4g
4b
4c
4d
4e
NH2
4f
NH2
NH2
NH2
NH2
O
N
F
O
4h
4i
4j
4k
4l
Cyclohexanones (5)
O
O
O
O
O
O
O
5a
5b
5c
5d
5e
5f
5g
O
O
O
O
O
O
O
O
O
5h
5i
5j
5k
5l
5m
Nitrobenzenes (7)
Cyclohexanols (8)
HO HO
NO2
NO2
NO2
O
7a
7b
7c
8a
8b
Fig. 2 Substrates used in this study. 1a, 1c–1k, 5e, 5f, and 8b are mixtures of cis-trans isomers.
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H
N
H
N
NH2
NH2
1a
2a
3a
4a
100
80
60
40
20
0
100
(a) AuPd/TiO2
(b) Au/TiO2
80
60
40
20
0
2a
3a
4a
2a
3a
4a
0
6
12
18
24
0
6
12
18
24
Time [h]
Time [h]
100
80
60
40
20
0
100
80
60
40
20
0
(d) Au/TiO2 + Pd/TiO2 (Physical mixture)
(c) Pd/TiO2
2a
3a
4a
2a
3a
4a
0
6
12
18
24
0
6
12
18
24
Time [h]
Time [h]
Fig. 3 Reaction profiles for the acceptorless dehydrogenative aromatization of 1a using various catalysts.
Reaction conditions: Catalyst (Au: 1.45 mol%, Pd: 1.05 mol%), 1a (1.0 mmol), mesitylene (2 mL), 160 °C, Ar
(1 atm). Yields were determined by GC analysis using n-hexadecane as an internal standard. (a) Au–Pd/TiO2.
(b) Au/TiO2. (c) Pd/TiO2. (d) Au/TiO2 + Pd/TiO2 (physical mixture).
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H
N
H
N
NH2
NH2
1a
2a
3a
4a
100
80
60
40
20
0
removal of the catalyst
2a
3a
4a
0
6
12
18
24
Time [h]
Fig. 4 Effect of removal of Au–Pd/TiO2 (verification of heterogeneous catalysis). Reaction conditions:
Au–Pd/TiO2 (Au: 1.45 mol%, Pd: 1.05 mol%), 1a (1.0 mmol), mesitylene (2 mL), 160 °C, Ar (1 atm). Yields
were determined by GC analysis using n-hexadecane as an internal standard. The arrow indicates the removal
of Au–Pd/TiO2 by hot filtration.
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H
N
NH2
AuPd/TiO2
mesitylene (2 mL)
Ar (1 atm), 160 oC, 24 h
R
R
R
1
2
H
H
N
H
N
N
2a, 90%
2b, 78%
2c, 82%
86% (1st reuse)
82% (2nd reuse)
71% (3rd reuse)
H
N
H
N
H
N
2d, 80%
2e, 19%
2f, 77%
H
N
H
N
H
N
2g, 75% (75%)
2h, 70% (69%)
2i, 87% (84%)
H
N
H
N
2j, 86%
2k, 55% (49%)
Fig. 5 Scope of the Au–Pd/TiO2-catalyzed acceptorless dehydrogenative aromatization of cyclohexylamines.
Reaction conditions: Au–Pd/TiO2 (Au: 1.45 mol%, Pd: 1.05 mol%), 1 (1.0 mmol), mesitylene (2 mL), 160 °C,
Ar (1 atm), 24 h. Yields were determined by GC analysis using n-hexadecane as an internal standard. The
values in the parentheses indicate the isolated yields.
24

Page 25 of 32
Chemical Science
H
N
View Article Online
DOI: 10.1039/C6SC04455G
NH2
AuPd/TiO2 (1.1 g)
mesitylene (10 mL)
Ar (1 atm), 160 oC, 24 h
1a (10 mmol)
2a, 94% yield
Fig. 6 Larger scale acceptorless dehydrogenative aromatization of 1a. Reaction conditions: Au–Pd/TiO2 (Au:
1.45 mol%, Pd: 1.05 mol%), 1a (10.0 mmol), mesitylene (10 mL), 160 °C, Ar (1 atm), 24 h.
25

Chemical Science
Page 26 of 32
View Article Online
DOI: 10.1039/C6SC04455G
H
N
O
NH2
AuPd/TiO2
+
mesitylene (2 mL)
Ar (1 atm), 160 oC, 24 h
R
R'
R
R'
4
5
6
H
N
H
N
H
H
N
N
6d, 99%
6a, 85%
6b, 79%
6c, 81%
H
N
H
N
H
N
H
N
N
F
O
6e, 83%
6i,b 48%
6f,a 91%
6g, 99%
6h, 53%
H
N
H
N
H
N
H
N
O
O
6j,c 60%
6a, 91%
6b, 88%
H
H
H
N
N
N
6c, 50%
6d, 98% (94%)
6k, 96%
H
N
H
N
H
N
6l, 93%
6m, 91% (88%)
6e, 98%
H
N
H
N
H
N
O
O
6i, 59%
6n, 72% (67%)
6o, 66%
Fig. 7 Scope of the Au–Pd/TiO2-catalyzed synthesis of diarylamines starting from cyclohexanones with
anilines. Reaction conditions: Au–Pd/TiO2 (Au: 2.9 mol%, Pd: 2.1 mol%), 4 (0.5 mmol), 5 (0.5 mmol),
mesitylene (2 mL), 160 °C, Ar (1 atm), 24 h. Yields were determined by GC analysis using n-hexadecane or
biphenyl as an internal standard. The values in the parentheses indicate the isolated yields. aAu–Pd/TiO2 (Au:
b
c
1.45 mol%, Pd: 1.05 mol%), 12 h. Au–Pd/TiO2 (Au: 0.73 mol%, Pd: 0.52 mol%). 4k (2.0 mmol), 5a
(0.5 mmol).
26

Page 27 of 32
Chemical Science
View Article Online
DOI: 10.1039/C6SC04455G
H
N
O
NH2
AuPd/TiO2
+
mesitylene (2 mL)
Ar (1 atm), 160 oC, 24 h
R
R'
R
R'
1
5
6
H
N
H
H
N
H
N
N
6a, 66%
6b, 75%
6l, 77%
6m, 70%
H
N
H
N
H
N
H
N
O
6e, 59%
6d, 58%
6k, 65%
6p, 43%
H
H
N
N
H
N
H
N
6n, 54%
6a, 58%
6b, 71%
6e, 63%
Fig. 8 Scope of the Au–Pd/TiO2-catalyzed synthesis of diarylamines starting from cyclohexanones and
cyclohexylamines. Reaction conditions: Au–Pd/TiO2 (Au: 2.9 mol%, Pd: 2.1 mol%), 1 (0.5 mmol), 5
(0.5 mmol), mesitylene (2 mL), 160 °C, Ar (1 atm), 24 h. Yields were determined by GC analysis using
n-hexadecane as an internal standard.
27

Chemical Science
Page 28 of 32
View Article Online
DOI: 10.1039/C6SC04455G
H
NO2
HO
HO
N
+
O
O
7a
7b
8a
8a
6f, 99% yield
H
N
NO2
AuPd/TiO2
+
+
mesitylene (2 mL)
Ar (1 atm), 150 oC, 24 h
6a, 76% yield
H
N
NO2
HO
7c
8b
6a, 81% yield
Fig. 9 Scope of the Au–Pd/TiO2-catalyzed synthesis of diarylamines starting from tandem dehydrogenation
aromatization of nitrobenzenes and cyclohexanols. Reaction conditions for the upper reaction: Au–Pd/TiO2
(Au: 5.8 mol%, Pd: 4.2 mol%), 7a (0.25 mmol), 8a (0.25 mmol), mesitylene (2 mL), 150 °C, Ar (1 atm), 24 h.
Reaction conditions for the middle reaction: Au–Pd/TiO2 (Au: 2.9 mol%, Pd: 2.1 mol%), 7b (0.5 mmol), 8a
(0.5 mmol), mesitylene (2 mL), 150 °C, Ar (1 atm). Reaction conditions for the bottom reaction: Au–Pd/TiO2
(Au: 2.9 mol%, Pd: 2.1 mol%), 7c (0.5 mmol), 8b (2.0 mmol), mesitylene (2 mL), 150 °C, Ar (1 atm). Yields
were determined by GC analysis using n-hexadecane as an internal standard.
28

Page 29 of 32
Chemical Science
View Article Online
DOI: 10.1039/C6SC04455G
H
N
H
N
NH2
NH2
NH2
+
1a
4b
4a (10% yield)
3a (16% yield)
2a (32% yield)
H
H
N
N
6q (27% yield)
3q (2% yield)
Fig. 10 Acceptorless dehydrogenative aromatization of 1a in the presence of 4b. Reaction conditions:
Au–Pd/TiO2 (Au: 1.45 mol%, Pd: 1.05 mol% to 1a), 1a (1.0 mmol), 4b (1.0 mmol), mesitylene (2 mL),
160 °C, Ar (1 atm), 24 h. Yields were determined by GC analysis using n-hexadecane as an internal standard.
29