Heterogeneously catalyzed selective N-alkylation of aromatic and heteroaromatic amines with alcohols by a supported ruthenium hydroxide

Article abstract of DOI:10.1016/j.jcat.2009.01.020

The N-alkylation of aromatic and heteroaromatic amines with alcohols could efficiently be promoted by an easily prepared supported ruthenium hydroxide catalyst Ru(OH)_x/Al₂O₃. A variety of aromatic and heteroaromatic amines were selectively converted into the corresponding secondary amines in moderate to excellent yields without any co-catalysts such as bases and stabilizing ligands. The observed catalysis was intrinsically heterogeneous and the Ru(OH)_x/Al₂O₃ catalyst recovered after the reaction could be reused without an appreciable loss of its high catalytic performance for the N-alkylation.

Full text of DOI:10.1016/j.jcat.2009.01.020

Journal of Catalysis 263 (2009) 205–208
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Research Note
Heterogeneously catalyzed selective N-alkylation of aromatic and heteroaromatic
amines with alcohols by a supported ruthenium hydroxide
Jung Won Kim a, Kazuya Yamaguchi a,b, Noritaka Mizuno a,b,∗
a
Department of Applied Chemistry, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan
b
a r t i c l e i n f o
a b s t r a c t
Article history:
The N-alkylation of aromatic and heteroaromatic amines with alcohols could efficiently be promoted by
an easily prepared supported ruthenium hydroxide catalyst Ru(OH)x/Al2O3. A variety of aromatic and
heteroaromatic amines were selectively converted into the corresponding secondary amines in moderate
to excellent yields without any co-catalysts such as bases and stabilizing ligands. The observed catalysis
was intrinsically heterogeneous and the Ru(OH)x/Al2O3 catalyst recovered after the reaction could be
reused without an appreciable loss of its high catalytic performance for the N-alkylation.
© 2009 Elsevier Inc. All rights reserved.
Received 16 December 2008
Revised 28 January 2009
Accepted 28 January 2009
Available online 13 February 2009
Keywords:
Alcohols
Amines
Heterogeneous catalysis
N-alkylation
Ruthenium hydroxide
1. Introduction
secondary amines. This is because it proceeds via a completely dif-
ferent mechanism [4–8]. In addition, the reaction produces only
water as a byproduct [Eq. (2)]:
The N-alkylation of primary amines to secondary amines is of
fundamental importance because secondary amines have widely
been used as synthetic intermediates for pharmaceuticals, agro-
chemicals, bioactive compounds, polymers, and dyes [1,2]. In par-
ticular, the N-alkylation of aromatic amines is very important in
industries [1,2]. The most frequently used procedure for the N-al-
kylation is the reaction of amines with alkyl halides in the pres-
ence of stoichiometric amounts of inorganic bases [1–3] [Eq. (1)]:
Until now, many homogeneous transition metal
R–NH2 +
→
+ H2O
(2)
catalysts, especially ruthenium- and iridium-based catalysts, have
been reported to be active for the N-alkylation with alcohols [4–8].
However, these systems have disadvantages of the recovery and
reuse of expensive catalysts and/or the indispensable use of co-
catalysts such as bases and stabilizing ligands [4–8]. The develop-
ment of easily recoverable and recyclable heterogeneous catalysts
can solve the problems of the homogeneous systems and has re-
ceived a particular research interest [16–20]. Although there are
several reports on the N-alkylation using heterogeneous catalysts
such as solid acids and transition metal-based catalysts, most of
them require high reaction temperatures, the scope of substrates is
limited, and turnover frequency (TOF) and turnover number (TON)
are low [9–15]. Therefore, the development of widely usable het-
erogeneously catalyzed selective N-alkylation systems is still chal-
lenging.
Herein, we report the selective N-alkylation of aromatic and
heteroaromatic amines with alcohols by an easily prepared sup-
ported ruthenium hydroxide catalyst Ru(OH)x/Al2O3 [21–24]. The
present system has the following significant advantages: (i) appli-
cability to various aromatic and heteroaromatic amines, (ii) higher
catalytic activity and selectivity than those of the previously re-
ported heterogeneous systems [9–15], (iii) no use of co-catalysts,
ꢀ
ꢀ
R–NH2 + R –X → RR NH + HX
(1)
(X=Cl,Br,I)
However, the selectivity to the desired secondary amines is gen-
erally low in the N-alkylation with alkyl halides because the nu-
cleophilicity of amines is increased by the N-alkylation, resulting
in the formation of undesired tertiary amines and alkylammonium
halides as byproducts [1–3]. In addition, the above reaction pro-
duces large amounts of inorganic salts as wastes [1–3].
An alternative environmentally-benign approach to the syn-
thesis of secondary amines is the N-alkylation with alcohols as
alkylating reagents in the presence of transition metal catalysts
[4–15]. The advantage of the procedure in comparison with the N-
alkylation with alkyl halides is the high selectivity to the desired
Corresponding author at: Department of Applied Chemistry, School of Engineer-
ing, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan. Fax:
+81 3 5841 7220.
*
E-mail address: tmizuno@mail.ecc.u-tokyo.ac.jp (N. Mizuno).
0021-9517/$ – see front matter © 2009 Elsevier Inc. All rights reserved.
doi:10.1016/j.jcat.2009.01.020

206
J.W. Kim et al. / Journal of Catalysis 263 (2009) 205–208
(iv) simple workup procedure, namely catalyst/product separation,
(v) reusability of the Ru(OH)x/Al2O3 catalyst, and (vi) use of an
easily prepared Ru(OH)x/Al2O3 catalyst.
Table 1
N-alkylation of aniline (1a) with benzyl alcohol (2a) by various catalysts:a
catalyst
−−−−→
2. Experimental
2.1. General
GC analyses were performed on Shimadzu GC-2014 using a
flame ionization detector equipped with a TC-5 (internal diame-
ter = 0.25 mm, length = 60 m) or a DB-WAX capillary column
(internal diameter = 0.25 mm, length = 30 m). NMR spectra were
recorded on JEOL JNM-EX-270. 1H and 13C NMR spectra were mea-
sured at 270 and 67.8 MHz, respectively, in CDCl3 with TMS as an
internal standard. 2H NMR spectra were measured at 41.25 MHz
using C6D6 as an external standard. Mass spectra were recorded
on Shimadzu GCMS-QP2010 equipped with a TC-5HT capillary col-
umn (internal diameter = 0.25 mm, length = 30 m). The ICP-AES
analyses were performed with Shimadzu ICPS-8100. Reagents and
substrates were commercially obtained from Tokyo Kasei, Aldrich,
and Fluka (reagent grade), and purified before the use [25]. Al2O3
(KHS-24, BET surface area: 160 m2 g−1) was obtained from Sumit-
omo Chemical. Ru/C (Ru metal on active carbon, 5 wt%) and RuHAP
[26] (Ru–Cl species on hydroxyapatite, 9.1 wt%) were purchased
from NE Chemcat and Wako, respectively. The supported ruthe-
nium hydroxide catalyst Ru(OH)x/Al2O3 was prepared according
to the procedure reported previously (see Supporting information)
[21–24].
Entry
Catalyst
Conversion
of 1a (%)
Yield (%)
ꢀ
3a
ꢀꢀ
3a
3a
1
2
3
4
5
6
7
8
Ru(OH)x/Al2O3
RuClx/Al2O3
Ru/C
RuHAP
RuO2 (anhydrous)
Ru(OH)x
RuCl3·nH2O
RuCl2(PPh3)3
[RuCl2(p-cymene)]2
Ru(acac)3
96
55
88
13
2
78
22
50
nd
nd
nd
nd
66
3
nd
3
nd
nd
nd
18
23
21
13
2
2
3
11
6
2
nd
nd
nd
nd
nd
nd
nd
5
nd
nd
nd
nd
nd
nd
b
2
12
84
12
5
15
1
9
10
11
12c
13c
14
Ru3(CO)12
Al2O3
12
1
1
d
Al2O3
1
<1
None
nd
a
Reaction conditions: 1a (0.25 mmol), 2a (0.375 mmol), catalyst (Ru: 5 mol%),
◦
mesitylene (1 mL), 132 C, 5 h, under 1 atm of Ar. Conversion and yield were based
on 1a and determined by GC. nd = not detected.
b
Prepared without base pretreatment.
60 mg.
Prepared by the treatment with an aqueous NaOH solution (0.1 M).
c
d
2.2. Procedure for the N-alkylation
All operations for the N-alkylation were carried out in a glove
box under Ar. A typical example is as follows. Into a Pyrex-glass
vial were successively placed Ru(OH)x/Al2O3 (Ru: 5 mol%), aniline
(1a, 0.25 mmol), benzyl alcohol (2a, 0.375 mmol), and mesity-
lene (1 mL). A Teflon-coated magnetic stir bar was added and
try 2). This is likely because of the generation of the active ruthe-
nium hydroxide species on the surface of Al2O3 by the reaction of
ruthenium chloride species with NaOH [21–24].
In order to verify whether the observed catalysis is derived
from solid Ru(OH)x/Al2O3 or leached ruthenium species, the N-
alkylation of 1a with 2a was carried out under the conditions
described in Table 1 and the Ru(OH)x/Al2O3 catalyst was removed
from the reaction mixture by filtration at ca. 50% conversion of 1a.
After removal of the catalyst, the reaction was again carried out
with the filtrate under the same conditions. In this case, the reac-
tion was completely stopped (Fig. S1). It was confirmed by ICP-AES
analysis that no ruthenium was detected in the filtrate (below de-
tection limit of 7 ppb). All these facts can rule out any contribution
to the observed catalysis from ruthenium species that leached into
the reaction solution and the observed catalysis is intrinsically het-
erogeneous [27].
◦
the reaction mixture was vigorously stirred (800 rpm) at 132 C
under 1 atm of Ar. The conversion and yield(s) were periodi-
cally determined by GC analyses. After the reaction was completed
(11 h), the spent Ru(OH)x/Al2O3 catalyst was separated by filtra-
tion, washed with an aqueous solution of NaOH (0.1 M) and water,
and then dried in vacuo prior to being recycled. The product 3a
was isolated by a silica gel column chromatography (89% isolated
yield).
3. Results and discussion
First, the catalytic activity and selectivity for the N-alkylation of
1a with 2a to the corresponding secondary amine 3a were com-
pared among various catalysts (Table 1). Ru(OH)x/Al2O3 showed
the highest catalytic activity and gave the corresponding secondary
amine 3a in 78% yield under the present conditions (entry 1).
Next, the scope of the present Ru(OH)x/Al2O3-catalyzed N-al-
kylation was examined (Table 2). Various combinations of sub-
strates (six amines and four alcohols) have been investigated and
all reactions efficiently proceeded to give the corresponding sec-
ondary amines in moderate to excellent yields without any co-
catalysts such as bases and stabilizing ligands.1 Especially, the
reaction of aniline derivatives (1a–1c) with benzylic alcohols (2a
and 2b) efficiently proceeded; the reaction of 1a with 2a gave 3a
in 89% isolated yield (99% conversion of 1a) under the present
ꢀꢀ
In this case, no formation of the tertiary amine 3a was ob-
served. The reaction hardly proceeded in the absence of the cat-
alyst, or in the presence of Al2O3 or Al2O3 treated with an aque-
ous NaOH solution (entries 12–14). In the presence of the cata-
lyst precursor of RuCl3·nH2O, the desired secondary amine 3a was
not produced (entry 7). Also, complexes of [RuCl2(p-cymene)]2,
Ru(acac)3, and Ru3(CO)12 were not effective for the N-alkylation
under the present conditions (entries 9–11). Although RuCl2(PPh3)3
conditions, for example. In this case, the TOF (based on the ini-
−1
tial rate) and the TON reached up to 4 h
and 18, respec-
tively, and these values were higher than those of the previously
reported heterogeneous systems so far (TOF: 0.1–0.9 h−1, TON:
0.2–9.1) [9–15]. Not only aniline derivatives but also heteroaro-
matic amines (1d and 1f) gave high yields of the corresponding
ꢀꢀ
gave 66% yield of 3a, the undesirable tertiary amine 3a was
also produced to some extent (entry 8) [8]. The catalytic activity
of Ru(OH)x/Al2O3 was higher than those of other heterogeneous
catalysts such as Ru/C, RuHAP, RuO2 anhydrous, and Ru(OH)x (en-
tries 3–6). The base pretreatment of the catalysts (see Supporting
information) significantly increased the activity (entry 1 vs en-
1
The N-alkylation of tert-butylamine with 2a gave the corresponding secondary
amine in 60% yield for 11 h under the conditions described in Table 2.

J.W. Kim et al. / Journal of Catalysis 263 (2009) 205–208
207
Table 2
Scope of the present Ru(OH)x/Al2O3-catalyzed N-alkylation.a
Entry
1
Amine
Alcohol
Time (h)
11
Product
Conv. of amine (%) (Yield (%))
1a
1a
1a
1a
2a
2a
2a
2b
3a
3a
3a
99 (89b)
2c
3d
4d
11
98 (87)
98 (98)
ꢀ
0.17
11
3b
>99 (90)
5
6
1a
1a
2c
24
24
3c
>99 (95b)
89 (75)
2d
3d
7
8
1b
1c
2a
2a
24
11
3e
3f
>99 (83)
95 (76)
9
1d
1d
1e
2a
2d
2a
24
24
24
3g
3h
3i
>99 (99)
66 (60)
98 (96)
10
11
12
1f
1f
2a
2d
24
24
3j
98 (90)
66 (65)
13
3k
a
◦
Reaction conditions: Amine (0.25 mmol), alcohol (0.375 mmol), Ru(OH)x/Al2O3 (Ru: 5 mol%), mesitylene (1 mL), 132 C, under 1 atm of Ar. Conversion and yield were
based on the starting amine and determined by GC and 1H NMR.
b
Isolated yield.
Recycling experiment.
Under 1 atm of O2.
c
d
secondary amines. Benzylic (2a and 2b) as well as heteroaromatic
(2c) and aliphatic alcohols (2d) worked well as reaction partners of
aromatic and heteroaromatic amines. After the reaction was com-
pleted, the Ru(OH)x/Al2O3 catalyst could be easily recovered by
filtration and the spent catalyst could be reused without an appre-
ciable loss of its high catalytic performance (entry 2 in Table 2).
The reaction profiles for the Ru(OH)x/Al2O3-catalyzed N-alkyla-
that the hydrogenation of imines to amines in the presence of
alcohols (MPV-type reduction [23,24]) efficiently proceeded with
the Ru(OH)x/Al2O3 catalyst; the hydrogenation of 3a readily pro-
ceeded to give 3a in 77% yield in the presence of 2a as a hydrogen
donor [Eq. (3)]:
Therefore, the
ꢀ
ꢀ
tion of 1a with 2a (Fig. 1) showed that 3a was initially formed
Ru(OH)x/Al2O3 (5 mol%)
followed by the formation of 3a. Under aerobic conditions, the re-
−−−−−−−−−−−−−−−−−−−−−→
(3)
ꢀ
2a (0.375 mmol), mesitylene (1 mL),
action of 1a with 2a exclusively gave 3a without the formation of
◦
132 C, 9.5 h, Ar (1 atm)
3a (entry 3 in Table 2). It was confirmed in a separate experiment
ꢀ
3a, 77% yield
3a (0.25 mmol)

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J.W. Kim et al. / Journal of Catalysis 263 (2009) 205–208
4. Conclusion
The supported ruthenium hydroxide Ru(OH)x/Al2O3 could act as
an efficient heterogeneous catalyst for the N-alkylation of aromatic
and heteroaromatic amines with alcohols. The N-alkylation could
be performed with high conversion and selectivity, giving the cor-
responding secondary amines. Furthermore, the catalyst/product
separation could be easily carried out and the Ru(OH)x/Al2O3 was
recyclable.
Acknowledgments
This work was supported in part by the Global COE Program
(Chemistry Innovation through Cooperation of Science and Engi-
neering), the Core Research for Evolutional Science and Technology
(CREST) program of the Japan Science and Technology Agency (JST),
and Grants-in-Aid for Scientific Researches from Ministry of Edu-
cation, Culture, Sports, Science and Technology.
Supporting information
Fig. 1. Reaction profiles for the N-alkylation of 1a with 2a. Reaction conditions:
1a (0.25 mmol), 2a (0.375 mmol), Ru(OH)x/Al2O3 (Ru: 5 mol%), mesitylene (1 mL),
132 C, under 1 atm of Ar.
The online version of this article contains additional supporting
information.
◦
Please visit DOI: 10.1016/j.jcat.2009.01.020.
present N-alkylation likely proceeds via the following three se-
quential reactions. First, the oxidative dehydrogenation of an al-
cohol to a carbonyl compound proceeds2 with the transitory for-
mation of the ruthenium hydride species [4–8,21–24].3 Then, the
carbonyl compound readily reacts with a starting amine to form
the corresponding imine. Finally, the hydrogen transfer reaction
from the hydride species to the imine proceeds to afford the corre-
sponding secondary amine. In the present Ru(OH)x/Al2O3-catalyzed
N-alkylation, the formation of the imine intermediate is not pos-
sible starting from the secondary amine. Therefore, it seems that
the high selectivity toward the corresponding secondary amine is
a specific feature that derives from the above-mentioned reaction
mechanism.
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2
The corresponding aldehydes were detected in the present N-alkylation, albeit
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ꢀ
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−−−−−−−−−−−−−−−−−−−−−−−−→
(4)
◦
mesitylene (1 mL), 132 C, 24 h, Ar (1 atm)
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85% yield
D content at α-position: 58%