Heterogeneous copper-catalyzed coupling of amines: a possible way for the preparation of imines

Article abstract of DOI:10.1007/s00706-016-1784-9

Copper(II) on 4-? molecular sieves is an efficient catalyst for the preparation of imines from benzylamines under simple reaction conditions. No oxidative atmosphere or oxidizing agents are required. Preparative experiments showed that no aldehyde intermediate can be detected even under ambient atmospheric conditions. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-016-1784-9

Monatsh Chem
DOI 10.1007/s00706-016-1784-9
ORIGINAL PAPER
Heterogeneous copper-catalyzed coupling of amines: a possible
way for the preparation of imines
1
Agnes Magyar Zoltan Hell
1
´
•
´
Received: 23 March 2016 / Accepted: 17 May 2016
Ó Springer-Verlag Wien 2016
˚
Abstract Copper(II) on 4-A molecular sieves is an effi-
compounds and natural products. Imines contain a reactive
C=N double bond, which can easily undergo various types
of transformations, such as addition, reduction, and
cyclization reactions (yielding aziridines, ß-lactams, and so
on) [1, 2].
cient catalyst for the preparation of imines from
benzylamines under simple reaction conditions. No
oxidative atmosphere or oxidizing agents are required.
Preparative experiments showed that no aldehyde inter-
mediate can be detected even under ambient atmospheric
conditions.
Traditionally, imines can be prepared by the condensa-
tion of primary amines and carbonyl compounds, i.e.,
aldehydes or ketones [3–6]. This method has some disad-
vantages; the aldehydes are generally sensitive to oxidation
by the air, thus their handling and storage are more diffi-
cult, and/or they usually need purification before use. The
condensation is an acid-catalyzed method that can result
problems if an acid sensitive compound should be trans-
formed. As water is formed in the reaction, this also can
induce problems in the case of water-sensitive compounds.
Another way for the preparation of imines is the oxi-
dation of a secondary amine. Several methods were
described using, e.g., Au [7, 8], Cu [8], or transition metals
[8] as catalyst, generally in oxygen atmosphere.
Graphical abstract
NH2
CH(R')-R''
Cu2+/4A
N
120 ° 14 h
C,
neat
+
H
2N-CH(R')-R''
Keywords Imines Á Amines Á Copper Á
˚
4-A molecular sieves Á Heterogeneous catalysis
Recently, catalytic oxidative self- and cross-coupling of
amines to imines using a suitable metal catalyst and/or
stoichiometric amount of an oxidant has received much
attention as a greener route of imine synthesis. Several
methods with different catalysts have been published,
among others CuCl [9], CuI [10] or CuBr2 [11] and
TEMPO, Ru-complex [12, 13], Au powder [14, 15], gold
supported on alumina [15], magnetic gold nanoparticles
[16], Au–Pd nanoparticles [17], Fe/CCl4 [18], Co-porphyrin
complex [19], the heteropolyacid NPV6Mo6 [20], VO(Hh-
pic)2 [21] under aerobic conditions, V2O5/H2O2 [22], AIBN
and oxygen [23], TiO2 as photocatalyst [24–26], or TBHBQ
[27] have been described. Several other metals were also
used in photocatalytic reactions [28].
Introduction
Imines represent an important class of useful synthetic
intermediates for the preparation of N-heterocycles, many
of which are important synthons of pharmaceutically active
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-016-1784-9) contains supplementary
material, which is available to authorized users.
´
& Zoltan Hell
zhell@mail.bme.hu
1
Department of Organic Chemistry and Technology, Budapest
The disadvantages of these methods are that they gen-
erally require toxic reagents, expensive precious metal
}
University of Technology and Economics, Muegyetem rkp.
3, H-1111 Budapest, Hungary
123

´
A. Magyar, Z. Hell
complex systems, or large excess amount of an oxidant, or
pure oxygen as oxidant. Thus, the development of a sim-
pler method involving simpler conditions may have
synthetic importance.
without solvent weak conversion was observed (entry 8),
even as with Cu0/4A in acetonitrile (entry 5).
Using the best reaction conditions (neat, 120 °C, 14 h),
we examined the catalyst Cu2?/4A in different hetero-
coupling reactions of benzylamine with alkyl- and aralky-
lamines (Table 2). The crude reaction mixtures were
Solid acid catalyzed methods have also been described,
thus K-10 montmorillonite alone [29] or in combination of
microwave irradiation [30], as well as Al grafted MCM-41
[31] under ambient atmospheric conditions.
1
examined by H NMR spectroscopy. In all cases, benzy-
lamine consumed completely (lack of the signal at about
3.8 ppm), and the mixtures of the desired hetero-coupled
imine and the homo-coupled 2 were formed. We found that
with increasing number of carbon atoms between the aro-
matic ring and the amine function, the yield of the hetero-
coupled product slightly decreased, while the amount of the
self-coupled 2 increased. Thus, ß-phenylethylamine (3) and
3-phenylpropylamine (5) gave the desired products 4 and 6
with 70 and 65 % yield, respectively (entries 2, 3). With
(S)-a-methylbenzylamine (7, entry 4), 66 % of the desired
8 was obtained. The same yield was obtained when the
amount of 7 was increased to 1.3 equiv. (S)-Phenylglycinol
(9) failed to react (entry 5), tryptamine (11) in boiling
toluene gave the hetero-coupled 12 with 50 % yield (entry
6). Aliphatic amines were also tested. Butylamine (13,
entry 7) alone gave no product, while in the butylamine–
benzylamine mixture only the homo-coupled N-benzyli-
denebenzylamine (2) could be detected. Hexylamine (15)
and decylamine (17) gave the hetero-coupled products 16
and 18 with 42 and 70 % yield, respectively. These results
can be explained by the boiling point of the respective
amine. Aniline (21) and cyclohexylamine (23) showed
moderate reactivity, from the NMR spectra of the reaction
Results and discussion
We examined the reaction of different amines in the
presence of copper(II) on 4-A molecular sieves (Cu2?/4A),
˚
which has successfully been applied earlier in the prepa-
ration of propargylamines [32], as well as in the
N-arylation of different heterocycles [33]. We found that
benzylamine at 120 °C, without solvent, under ambient
atmosphere, in the presence of Cu2?/4A gave N-benzyli-
denebenzylamine (2) with excellent yield. Only ca. 1 % of
nitrile, the known by-product [6] of the reaction, was
detected by GC–MS. To determine the optimal reaction
conditions, other supported metal catalysts as well as dif-
ferent solvents were examined in the reaction. The results
are presented in Table 1.
When solvent was used, the yield was very low (entry
5), or no product was observed. In the presence of the
˚
untreated 4-A molecular sieves (4A), moderate yield was
obtained (entry 1). Co2?/4A and Ti4?/4A in toluene gave
no product (entries 6, 7), in the presence of Ti4?/4A
Table 1 Self-coupling of benzylamine in the presence of different catalysts and solvents
N
NH
2
2
1
Entry
Catalyst
Solvent
Reaction time/h
Yield/%a
1
2
3
4
5
6
7
8
4A
Neat
14
26
12
14
24
9
35
0
Cu2?/4A
Cu2?/4A
Cu2?/4A
Cu0/4A
Co2?/4A
Ti4?/4A
Ti4?/4A
Toluene
Acetonitrile
Neat
0
97b
16
0
Acetonitrile
Toluene
Toluene
Neat
9
0
14
25
1-mmol benzylamine, 0.05-g catalyst, at 120 °C or in boiling solvent
a
1
Based on the H NMR spectra of the product
b
Isolated yield
123

Heterogeneous copper-catalyzed coupling of amines: a possible way for the preparation of imines
Table 2 Hetero-coupling between benzylamine and different ara-
lkyl- and alkylamines
Table 2 continued
Entry
Amine
Product
Yield /%
0c
N
R
Cu2+/4A
NH2
+
H2NR
N
120°C
neat
NH2
7
13
14
N
Entry
1
Amine
Product
Yield /%
97a
NH2
N
4
NH2
8
9
42b
70b
15c
4
15
1
2
16
N
NH2
N
4
N
2
3
4
70b
65b
66b
8
NH2
NH2
8
3
5
17
18
NH2
N
OH
10
OH19
6
20
NH2
NH2
N
N
11
~60b
~60b
7
8
21
22
OH
OH
NH2
N
NH2
5
6
0c
N
12
9
10
23
24
NH
NH2
N
50b, d
a
b
c
d
N
H
Isolated yield
1
11
Determined by H NMR
Determined by GC–MS
In refluxing toluene
12
mixture, the starting amine could be shown together with
the desired product and 2 (entries 11, 12).
of oxidizing agents, the formation of aldehydes has been
expected from the amines, and this aldehyde would con-
densate with the amines [9, 29]. Another proposition was
the oxidation of the amine first to hydroxylamine, and its
transformation into aldehyde [29].
The homo-coupling of different benzylamine derivatives
were also tested. In these cases, the desired products were
obtained generally with excellent isolated yield. The con-
versions were complete, and no by-products were found.
The results are shown in Table 3.
The other possible way is the transformation of the
amine into imine, which would react with the amine in a
condensation reaction yielding ammonia as by-product.
This was expected both under normal [10] and inert [13]
atmosphere. In both mechanisms, the role of the metal is
assumed to form a complex with the amine to facilitate the
reaction.
The competitive reaction of different benzylamines was
tested with benzylamine (1) and piperonylamine (25). GC–
MS examination of the reaction mixture showed the pres-
ence of three from the four possible products, 2, 33, and 34
in a ratio 13:23:18. This means that the electronic factors of
the aromatic ring do not play important role in the reaction.
Surprisingly, instead of the homo-coupled product of
piperonylamine (26) only its reduced derivative 35 could
be detected (Scheme 1).
We examined the reaction of benzylamine both under
ambient and argon atmosphere. The same yields were
obtained in the reactions. When the reaction was stopped
after 5 h and a sample was examined by NMR spec-
troscopy, no signal of aldehyde was observed, and only
In the literature, there are two pathways described for
the reactions. Under aerobic conditions or in the presence
123

´
A. Magyar, Z. Hell
Table 3 Homo-coupling of different benzylamine derivatives
Scheme 1
N
Yieldb
/%
Entry
1
Amine
Product
2
O
O
O
O
O
O
NH2
N
+
70
95
98
NH2
25
26
O
N
NH2
N
O
1
33
2
3
Cu2+/4A
14 h
O
O
O
27
29
28
+
120°C,
neat
+
O
O
NH2
O
H2N
N
N
Cl
Cl
Cl
O
30
34
25
NH2
N
+
O
O
O
4
85
N
H
31
32
O
35
a
Reaction conditions: 120 °C, 14 h, no solvent, 2-mmol amine, 0.05-
g catalyst
b
Isolated yield
another amine yielding the product. Recently, we
observed that dihydrobenzimidazoles transformed spon-
taneously to benzimidazoles in the presence of a
microporous zeolite [34]. The hydrogen formed could
not be shown; either it was adsorbed by the zeolite, or it
was chemically transformed in the pores of the zeolit. A
similar process can be imagined with the hydrogen
formed in the first step in this reaction, particularly if
this hydrogen forms as a proton, since the support has
basic properties.
the signals of the starting amine as well as the product
were detected. GC–MS analysis of the reaction mixture
also showed the absence of aldehyde. The gases evolved
from the reaction mixture were detected by IR spec-
troscopy, and we found that only ammonia was formed
(Fig. 1). No water was observed at all in the gas phase.
Thus, we can conclude that in the presence of our cat-
alyst the transformation occurs rather via the formation
of benzylimine (Scheme 2), and this will react with
Fig. 1 FT-IR analysis of the gases evolved from the reaction
123

Heterogeneous copper-catalyzed coupling of amines: a possible way for the preparation of imines
room temperature for 12 h. Then, the solid was filtered out,
Scheme 2
washed with deionized water and then with acetone, and
dried in an oven at 120 °C for 1 h. Based on the ICP-OES
results, the copper content of this catalyst was 5.8 wt%.
Co2?/4A and Ti4?/4A were prepared analogously using
CoCl2Á6H2O and TiCl4, respectively. Cu0/4A was prepared by
the reduction of Cu2?/4A as described in [33]; Cu2?/4A (5 g)
was reduced with 6.13 cm3 hydrazine hydrate (80 % aqueous
solution) in 50 cm3 ethanol for 3 h at room temperature. The
solid was filtered, and washed with ethanol. The material
obtained was stored under nitrogen atmosphere.
NH2
Cu2+/4A
NH
-
2 H
1
1
NH2
-NH3
N
N
H
2
Samples were heating at120 °C for 1 h beforethe reaction.
General procedure for the preparation of imines
Conclusion
The mixture of the appropriate amines (2 mmol in the
case of homo-coupling and 1 mmol in the case of hetero-
coupling) and Cu2?/4A (0.05 g) were stirred at 120 °C
for 14 h. The mixture was left to cool down to room
temperature, diluted with 10 cm3 diethyl ether, then the
solid was filtered, and the filtrate was evaporated. The
material thus obtained has been characterized. Based on
XRF examinations, some copper dissolved from the cat-
alyst during the reaction (leaching). The amount of this
copper depended on the nature of the amine. To remove
this metal contaminant, the product was dissolved in
˚
Copper(II) on 4-A molecular sieves is an efficient catalyst for
the preparation of imines from benzylamine and different
aralkyl- and alkylamines. With aralkylamines, the yield
drops slightly with increasing number of carbon atoms
between the aromatic ring and the amine function. The
reactivity of aliphatic amines depends on the number of
carbon atoms, probably on the boiling point of these amines.
There was no oxidative transformation of the amine to
aldehyde or hydroxylamine observed even under ambient
atmospheric conditions. The substituents of benzylamine do
not influence the reaction significantly, when two benzy-
lamine derivatives were reacted, the possible homo- and
hetero-coupled products were formed in near equal amount.
˚
diethyl ether, MS 4 A was added, and the mixture was
stirred at room temperature for 30 min. Then, the solid
was filtered, and the filtrate was evaporated.
In the case of homo-coupling, no appreciate amount of
by-product was obtained; the yields described in Table 3
can be considered as isolated yield. In the case of hetero-
Experimental
1
coupling, the yields given in Table 2 are based on the H
GC–MS measurements were performed on an Agilent 6890
NMR spectra of the crude product, calculating based on the
intensities of the CH=N signals appeared between 8.1 and
8.5 ppm. The respective signals for the individual com-
pounds are shown in Table S1 in Supplementary Material.
The recyclability of the catalyst has been tested in the
homo-coupling of benzylamine. Thus, after the first reac-
tion, the filtered catalyst was dried at 120 °C for an hour
then used in the second reaction. The yield obtained after
the second run was exactly the same as in the first reaction.
FT-IR analysis of the gases: the gas cell of the IR
spectrophotometer was flushed several times with argon.
Then, it was attached to the reaction vessel and the reaction
was continued for 4 h. Then, the collected gases were
measured by the spectrophotometer.
N-GC-5973
N-MSD
chromatograph,
using
a
30 m 9 0.25 mm Restek, Rtx-5SILMS column with a film
layer of 0.25 lm. The initial temperature of column was
45 °C for 1 min, followed by programming at 10 °C/min up
to 310 °C and a final period at 310 °C (isothermal) for
17 min. The temperature of the injector was 250 °C. The
carrier gas was He, and the operation mode was splitless. 1H
NMR spectra were made on BRUKER Avance-300 instru-
ment using TMS as an internal standard (d = 0 ppm) in
CDCl3. FT-IR spectra were measured on a Bruker Tensor 37
instrument equipped with DTGS detector, between 400 and
4000 cm-1, with 4 cm-1 resolution. All compounds and
solvents were purchased from Merck Hungary Ltd.
Catalyst preparation
Characterization of the products
The catalyst was prepared according to the method described
in [32]. Thus, 2 g of support and 0.34 g (2 mmol) of
CuCl2Á2H2O in 200 cm3 deionized water were stirred at
N-Benzylidene-benzylamine (2)
Yellowish oil; 1H NMR (300 MHz) corresponds to the data
described in [10]; 13C NMR (75 MHz) corresponds to the
123

´
A. Magyar, Z. Hell
data described in [10]; GC: tR = 15.30 min; MS: m/z
(%) = 194 (M?-1), 117, 91 (100), 77.
N-(4-Methoxybenzylidene)-4-methoxybenzylamine (28)
Yellowish oil; 1H NMR (300 MHz) corresponds to the data
described in [11].
N-Benzylidene-2-phenylethylamine (4)
Yellowish waxy solid; m.p.: 29–30 °C (Ref. [39, 40]
N-(4-Chlorobenzylidene)-4-chlorobenzylamine (30)
m.p.: 56–57 °C (Ref. [41] 58–60 °C); 1H NMR (300 MHz)
corresponds to the data described in [11].
1
33–34 °C); H NMR (300 MHz) corresponds to the data
described in [35], no signal was observed at 8.40 ppm (CH
of N-2-phenylethenyl-benzylamine [36]).
N-[4-(tert-Butyl)benzylidene]-4-(tert-butyl)benzylamine
N-Benzylidene-3-phenylpropylamine (6)
1
(32)
Yellowish oil; 1H NMR (300 MHz) corresponds to the data
described in [24].
Yellowish oil; H NMR (300 MHz): d = 2.05 (m, 2H),
2.71 (q, 2H), 3.64 (t, 2H), 7.18–7.42 (m, 10H), 8.27 (s, 1H)
ppm; 13C NMR (75 MHz): d = 32.2, 33.4, 60.8, 125.6,
125.7, 127.9, 128.2, 130.6, 141.8, 161.1 ppm; GC:
tR = 19.84 min; MS: m/z (%) = 223 (M?), 194, 146,
132, 119 (100), 104, 91.
N-Benzylidene-piperonylamine (33)
GC: tR = 22.22 min; MS: m/z (%) = 239 (M?), 135(100),
105, 90, 77.
N-Piperonylidene-benzylamine (34)
GC: tR = 22.34 min; MS: m/z (%) = 239 (M?), 135, 117,
105, 91, 77.
(S)-N-Benzylidene-1-phenylethylamine (8)
1
Yellow oil; H NMR (300 MHz) corresponds to the data
described in [27].
Bis(3,4-methylenedioxybenzyl)amine (35)
GC: tR = 26.66 min; MS: m/z (%) = 283 (M??1), 161,
135 (100), 121, 105, 77.
N-Benzylidene-tryptamine (12)
Yellowish oil; 1H NMR (300 MHz) corresponds to the data
described in [37].
´
Acknowledgments A. M. is grateful to Chinoin Pharmaceuticals Ltd.
N-Benzylidene-hexylamine (16)
1H NMR (300 MHz) corresponds to the data described in
[38].
for the financial support. This work was financially supported by the
´
´
New Szechenyi Development Plan (TAMOP-4.2.1/B-09/1/KMR-
2010-0002).
N-Benzylidene-decylamine (18)
1H NMR (300 MHz): d = 0.87 (t, 3H), 1.26 (m, 14H),
1.69 (m, 2H), 3.60 (m, 2H), 7.26-7.39 (m, 3H), 7.70 (m,
2H), 8.26 (s, 1H) ppm; 13C NMR (75 MHz): d = 14.2,
22.8, 27.5, 29.4, 29.5, 29.6, 28.7, 31.0, 32.0, 61.9, 128.1,
128.6, 130.5, 136.4, 160.8 ppm; GC: tR = 19.87 min;
MS: m/z (%) = 244 (M?-1), 230, 216, 202, 188, 174,
160 (100), 146, 132, 118, 104, 91, 77 (corresponds
completely to the spectrum given in spectrum library of
the apparatus).
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