Selective synthesis of secondary amines via N-alkylation of primary amines and ammonia with alcohols by supported copper hydroxide catalysts

Article abstract of DOI:10.1246/cl.2010.1182

The N-alkylation of primary amines and ammonia (in situ generated from urea or aqueous ammonia) with alcohols to secondary amines was efficiently promoted by supported copper hydroxide catalysts, Cu(OH)_xAl₂O ₃ and Cu(OH)_x/TiO₂. The observed catalysis was truly heterogeneous, and the catalysts could be reused without an appreciable loss of catalytic performance.

Full text of DOI:10.1246/cl.2010.1182

doi:10.1246/cl.2010.1182
1182
Published on the web October 16, 2010
Selective Synthesis of Secondary Amines via N-Alkylation of Primary Amines
and Ammonia with Alcohols by Supported Copper Hydroxide Catalysts
Jinling He, 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
(Received September 6, 2010; CL-100767; E-mail: tmizuno@mail.ecc.u-tokyo.ac.jp)
Table 1. The N-alkylation of 1a with 2a by various catalystsa
The N-alkylation of primary amines and ammonia (in situ
cat.
generated from urea or aqueous ammonia) with alcohols to
+
n-C7H15
N
H
Ph +
n-C7H15
N
Ph
Ph
OH
NH2
n-C7H15
secondary amines was efficiently promoted by supported copper
hydroxide catalysts, Cu(OH)x/Al2O3 and Cu(OH)x/TiO2. The
observed catalysis was truly heterogeneous, and the catalysts
could be reused without an appreciable loss of catalytic
performance.
1a
2a
Catalyst
3a
3a'
Yield/%
Entry
3a
3a¤
1
2b
3
4
5c
6
7
8
9
10
11
12
13
14
15c
16
Cu(OH)x/Al2O3
Cu(OH)x/TiO2
CuCl2/Al2O3
85
80
ndf
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
3
4
6
10
9
7
9
6
6
7
7
8
6
8
5
10
The N-alkylation of primary amines to secondary ones is of
great importance because the products have been utilized as
important synthons for pharmaceuticals, agricultural chemicals,
and bioactive compounds.1 Frequently, alkylhalides have been
utilized for the N-alkylation with stoichiometric amounts of
inorganic bases.1 However, the reaction with alkylhalides
produces large amounts of inorganic salts as wastes.1
Cu(OH)2
Cu(OH)2 + Al2O3
CuCl2¢2H2O
Cu(NO3)2¢3H2O
Cu(CH3COO)2¢H2O
Cu(PhCOO)2
Cu(CF3SO3)2
An alternative environmentally-friendly approach is the N-
alkylation with alcohols as alkylating reagents in the presence of
appropriate transition-metal catalysts, so-called “borrowing
hydrogen strategy” (or “hydrogen autotransfer strategy”):2 The
dehydrogenation of an alcohol initially proceeds to afford an
aldehyde (more electrophilic than an alcohol), followed by the
dehydrative condensation with an amine to produce an imine.
Then, the imine is hydrogenated by the transitory formed metal
hydride species, giving the desired N-alkylated amine. Although
many homogeneous catalysts, in particular platinum group metal
complexes, have been reported to be active for the N-alkylation
with alcohols,2,3 these systems have shortcomings of the
recovery and reuse of expensive catalysts and/or the indispen-
sable use of co-catalysts such as bases and stabilizing ligands.
The development of easily recoverable and recyclable hetero-
geneous catalysts can solve the problems of the homogeneous
systems and has received a particular research interest.4,5
In this paper, we report that easily prepared inexpensive
supported copper hydroxides, Cu(OH)x/Al2O3 and Cu(OH)x/
TiO2,6 can act as efficient heterogeneous catalysts for the N-
alkylation of primary amines and ammonia (in situ generated
from urea or aqueous ammonia) with alcohols. Generally,
copper-catalyzed N-alkylation reactions require high H2 pres-
sures (²100 atm), high reaction temperatures (²160 °C), and/or
stoichiometric amounts of bases (e.g., K2CO3) to attain high
yields of desired amines.5 In contrast, the present N-alkylation
with supported copper hydroxide catalysts efficiently proceeded
under relatively mild reaction conditions (1 atm of Ar, 135 °C)
without any co-catalysts.7
d
Cu(acac)2
e
[Cu(®-OH)(tmen)]2Cl2
CuCl
[Cu(C¸CPh)]n
Al2O3
None
aReaction conditions: Catalyst (Cu: 0.04 mmol), 1a (0.5
mmol), 2a (2 mmol), mesitylene (2 mL), 135 °C, 65 min, under
1 atm of Ar. Yields (based on 1a) were determined by GC
analyses. b60 min. cAl2O3 (200 mg). dacac: acetylacetonato.
etmen: N,N,N¤,N¤-tetramethylethylenediamine. fnd: not de-
tected (<1%).
selectivities to the secondary amine 3a (Entries 1 and 2). No
formation of 3a was observed in the absence of the catalysts
(Entry 16) or in the presence of Al2O3 (Entry 15). The catalyst
precursor CuCl2¢2H2O and commonly utilized copper salts and
complexes such as Cu(NO3)2¢3H2O, Cu(CH3COO)2¢H2O,
Cu(PhCOO)2, Cu(CF3SO3)2, Cu(acac)2, [Cu(®-OH)(tmen)]2Cl2,
CuCl, and [Cu(C¸CPh)]n were not effective (Entries 6-14). The
catalytic activities of supported copper hydroxides were much
higher than those of unsupported Cu(OH)2 (Entry 4) and a
physical mixture of Cu(OH)2 and Al2O3 (Entry 5). The reaction
hardly proceeded in the presence of the copper chloride species
supported on Al2O3 prepared without the base pretreatment
(CuCl2/Al2O3, Entry 3, see Supporting Information11 for prep-
aration). These results suggest that the generation of the highly
dispersed “copper hydroxide species” on the surface of supports
is very important to achieve the high catalytic activity and
selectivity.7
The catalytic activities for the reaction of n-octylamine (1a)
with benzyl alcohol (2a) to form N-benzyloctylamine (3a) were
compared (Table 1). Among various catalysts tested, supported
copper hydroxide catalysts such as Cu(OH)x/Al2O3 and
Cu(OH)x/TiO2 (see Supporting Information11 for preparation
and characterization) showed the highest catalytic activities and
The Cu(OH)x/Al2O3-catalyzed reaction of 1a with 2a was
carried out under the conditions described in Table 1, and the
catalyst was removed from the reaction mixture by hot filtration
at ca. 50% yield of 3a. After removal of the catalyst, the reaction
Chem. Lett. 2010, 39, 1182-1183
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1183
Table 2. The synthesis of various secondary aminesa
experiment that the oxidative dehydrogenation of alcohols and
the hydrogenation of imines to amines in the presence of
alcohols efficiently proceeded with the Cu(OH)x/Al2O3 catalyst
(Figure S1).11 Thus, the present N-alkylation likely proceeds via
the following three sequential reactions. First, the dehydrogen-
ation of an alcohol to a carbonyl compound proceeds with the
transitory formation of the copper hydride species. 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
corresponding secondary amine.
R
N
H
R'
R'
N
H
R'
NH
2
+
NH3 +
R'
R
OH
OH
R'
or
NH
2
X = H (1b), o-OCH3 (1c),
p-OCH3 (1d), p-CH3 (1e)
1a NH
2
X
O
NH
NH3 28% aq. solution
2
1g
1f
H N
NH
2
1h
2
OH
OH
X = H (2a), p-OCH3 (2b),
Y
p-CH3 (2c), m-CH3 (2d), o-CH3 (2e)
2f
Entry
N Source
Alcohol
Time/min
Yield/%
1
2
3
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
1g
1g
1g
1g
1h
2a
2b
2c
2c
2f
2c
2a
2a
2a
2a
2a
2c
2d
2e
2a
65
60
60
85
84
81
75
87
91
79
70
83
93
85
95
91
98
80
This work was supported in part by the Global COE
Program (Chemistry Innovation through Cooperation of Science
and Engineering), Japan Chemical Innovation Institute (JCII),
and Grants-in-Aid for Scientific Researches from Ministry of
Education, Culture, Sports, Science and Technology.
4b
5
75
780
105
90
90
360
70
480
480
900
1500
720
6
7
8
9
References and Notes
1
a) R. N. Salvatore, C. H. Yoon, K. W. Jung, Tetrahedron 2001, 57,
7785. b) B. R. Brown, The Organic Chemistry of Aliphatic Nitrogen
Compounds, Oxford University Press, New York, 1994. c) M. B.
Smith, J. March, March’s Advanced Organic Chemistry: Reactions,
Mechanisms, and Structure, 6th ed., John Wiley & Sons, Inc.,
Hodoken, New Jersey, 2007.
10
11
12c
13c
14c
15
2
3
a) M. H. S. A. Hamid, P. A. Slatford, J. M. J. Williams, Adv. Synth.
Catal. 2007, 349, 1555. b) G. Guillena, D. J. Ramón, M. Yus, Chem.
Rev. 2010, 110, 1611, and references cited therein.
aReaction conditions: Catalyst (Cu: 0.04 mmol), N source
(amine: 0.5 mmol, urea: 0.25 mmol, or ammonia: 0.5 mmol),
alcohol (2 mmol), mesitylene (2 mL), 135 °C, under 1 atm of
Ar. Yields (based on the amounts of nitrogen in N sources)
a) R. Grigg, T. R. B. Mitchell, S. Sutthivaiyakit, N. Tongpenyai,
J. Chem. Soc., Chem. Commun. 1981, 611. b) Y. Watanabe, Y. Tsuji,
Y. Ohsugi, Tetrahedron Lett. 1981, 22, 2667. c) D. Hollmann, A.
Tillack, D. Michalik, R. Jackstell, M. Beller, Chem. Asian J. 2007,
2, 403. d) K.-I. Fujita, Y. Enoki, R. Yamaguchi, Tetrahedron 2008,
64, 1943. e) B. Blank, M. Madalska, R. Kempe, Adv. Synth. Catal.
2008, 350, 749. f) O. Saidi, A. J. Blacker, G. W. Lamb, S. P.
Marsden, J. E. Taylor, J. M. J. Williams, Org. Process Res. Dev.
2010, 14, 1046.
b
c
were determined by GC analyses. Reuse experiment. Alco-
hol (2.5 mmol).
was again carried out with the filtrate under the same conditions,
and no further reaction proceeded. In addition, it was confirmed
by inductively coupled plasma atomic emission spectroscopy
that no copper was detected in the filtrate (below detection limit
of 7 ppb). The catalyst retrieved after the N-alkylation could be
reused without significant loss of catalytic performance (Entry 4
in Table 2).8 All these results can rule out any contribution to the
observed catalysis from copper species that leached into the
reaction solution and the observed catalysis is truly heteroge-
neous.9
Next, the scope of the present Cu(OH)x/Al2O3-catalyzed N-
alkylation was examined (Table 2). Various combinations of
substrates (eight nitrogen sources and six alcohols) have been
investigated, and all reactions efficiently proceeded to afford the
corresponding unsymmetrically as well as symmetrically sub-
stituted secondary amines in high yields without any co-catalysts
such as bases. When urea (1g) was used as a nitrogen source, the
corresponding symmetrically substituted secondary amines
could be obtained in high yields through the N-alkylation of
in situ generated ammonia from 1g (Entries 11-14).4b,10 In
addition, aqueous ammonia could be directly utilized for the
present N-alkylation (Entry 15).
4
5
With supported noble metal catalysts: a) J. W. Kim, K. Yamaguchi,
N. Mizuno, J. Catal. 2009, 263, 205. b) K. Yamaguchi, J. L. He, T.
Oishi, N. Mizuno, Chem.®Eur. J. 2010, 16, 7199. c) A. Corma, T.
Ródenas, M. J. Sabater, Chem.®Eur. J. 2010, 16, 254.
With copper-based heterogeneous catalysts: a) E. J. Schwoegler, H.
Adkins, J. Am. Chem. Soc. 1939, 61, 3499. b) A. Baiker, W.
Richarz, Tetrahedron Lett. 1977, 18, 1937. c) J. Runeberg, A.
Baiker, J. Kijenski, Appl. Catal. 1985, 17, 309. d) R. Vultier, A.
Baikera, A. Wokaunb, Appl. Catal. 1987, 30, 167. e) P. R. Likhar, R.
Arundhathi, M. L. Kantam, P. S. Prathima, Eur. J. Org. Chem. 2009,
5383.
6
7
K. Yamaguchi, T. Oishi, T. Katayama, N. Mizuno, Chem.®Eur. J.
2009, 15, 10464.
The hydroxide catalysts possess both Lewis acid and Brønsted base
sites. The alcoholate formation step can be promoted by the
“concerted activation” of an alcohol by the Lewis acid and Brønsted
base. Thus, the hydroxide catalysts do not need additives such as
bases to promote the reaction: F. Nikaidou, H. Ushiyama, K.
Yamaguchi, K. Yamashita, N. Mizuno, J. Phys. Chem. C 2010, 114,
10873.
8
9
It was confirmed by the XPS analysis that the Cu(II) species in
Cu(OH)x/Al2O3 were partially reduced to Cu(I) species during the
N-alkylation.
R. A. Sheldon, M. Wallau, I. W. C. E. Arends, U. Schuchardt, Acc.
Chem. Res. 1998, 31, 485.
The reaction profiles for the Cu(OH)x/Al2O3-catalyzed N-
alkylation of 1a with 2a showed that 3a¤ was initially formed,
followed by the formation of 3a. Under aerobic conditions, the
reaction of 1a with 2a exclusively gave 3a¤ without the
formation of 3a (Figure S1).11 It was confirmed in a separate
10 It was confirmed by the separate experiments that 1g was hydro-
lytically decomposed to ammonia by the presence of Al2O3 or TiO2
under similar conditions described in Table 2.
11 Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.html.
Chem. Lett. 2010, 39, 1182-1183
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/