N-Alkylation of amines through hydrogen borrowing over a heterogeneous Cu catalyst

Article abstract of DOI:10.1039/c3ra44364g

Substitution of alkylhalides for the synthesis of amines is a relevant target for synthetic chemists. Secondary amines can be obtained in a one pot-one step reaction from secondary and benzylic alcohols and aniline over a heterogeneous copper catalyst. The process does not require any additive, is intrinsically safe and produces no waste.

Full text of DOI:10.1039/c3ra44364g

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N-Alkylation of amines through hydrogen
borrowing over a heterogeneous Cu catalyst†
Cite this: RSC Adv., 2014, 4, 2596
*
Federica Santoro, Rinaldo Psaro, Nicoletta Ravasio and Federica Zaccheria
Received 14th August 2013
Accepted 31st October 2013
DOI: 10.1039/c3ra44364g
www.rsc.org/advances
Substitution of alkylhalides for the synthesis of amines is a relevant as hydrogen acceptor due to high activity in both alcohol dehy-
target for synthetic chemists. Secondary amines can be obtained in a drogenation and activated C]C bond hydrogenation reactions.5,6
one pot-one step reaction from secondary and benzylic alcohols and
Results obtained in the alkylation of aniline with different
aniline over a heterogeneous copper catalyst. The process does not alcohols are reported in Table 1. The reaction of primary
require any additive, is intrinsically safe and produces no waste.
alcohols was quite selective but very slow. Aer 24 h reaction
only about 60% conversion was observed (entries 1–3). On the
contrary reaction of secondary and benzylic alcohols was faster
although with variable selectivity. The only by-product formed
was the corresponding carbonyl compound. Only in a few
cases some aldol condensation product was identied, namely
in entry 2 (12.7%) entry 8 (1.4%) and entry 9 (traces). Tertiary
amines were never identied in the reaction mixture.
Secondary alcohols with the cyclohexanol structure gave
the corresponding amine with high selectivity (entries 4–5),
while cyclooctanol and cyclododecanol produced the amine in
a lower yield although the only byproduct was the corre-
sponding ketone. a-Methyl-benzyl alcohols also reacted fast
but when the aromatic ring was unsubstituted unselective
process were obtained whereas reaction of 1(p-methoxy-
phenyl)-ethanol gave the corresponding amine with 93% yield
(entry 9). Linear secondary alcohols also gave very selective
reactions (Table 1, entry 10). Allylic alcohols gave mixture of
products due to competition of the C]C double bond for
hydrogenation (not reported for the sake of clarity), whereas,
much to our surprise, primary benzylic ones gave the corre-
sponding amines with yield up to 99% for electrondonor para
substituents (Table 2).
This result was quite unexpected as the previously reported
alcohol transfer dehydrogenation reaction never went to
completion with primary benzylic alcohols.5 This was shown to
be due to competition between the aldehyde formed and the
hydrogen acceptor, namely styrene. The aldehyde was hydro-
genated instead of styrene giving back the alcohol with an
apparent uncomplete transformation of the alcohol itself. The
high yield in amine obtained in this paper with electron rich
benzylic alcohols (up to 99%, Table 2, entry 4) suggests that the
imine formed through condensation of the aldehyde with
aniline is a better acceptor than styrene. This was indeed
Amines are key moieties in both pharmaceutically and biolog-
ically active molecules and natural products.1
In the last few years there has been a renaissance in the
search for new synthetic methods for the synthesis of amines
owing to the need for substituting N-alkylation of amines with
toxic alkylhalides due to both environmental concerns and low
selectivity of the process.
Direct reductive amination (DRA) of ketones or aldehydes,
that is the reaction in which the carbonyl compound and the
amine react in the presence of a reducing agent is of course a
very valuable alternative, but it is most oen carried out with
hydride donors resulting in the production of large amounts of
waste and inorganic salts.2
We recently reported on the DRA of ketones in the presence of
a heterogeneous supported Cu/SiO2 catalyst.3 The method is very
effective for aromatic ketones, that is for the synthesis of ben-
zylidene amines, that are not easily obtained when using hydride
reagents. However, the catalytic amination of alcohols by the
“borrowing hydrogen” methodology is by far one of the most
appealing technique from the environmental point of view,4
therefore we looked for the activity of Cu/Al2O3 catalysts for this
reaction.
Thus, Cu/Al2O3 was found to be a very active catalyst in the
transfer dehydrogenation of secondary alcohols by using styrene
CNR ISTM, via C. Golgi 19, 20133 Milan, Italy. E-mail: n.ravasio@istm.cnr.it; Fax:
+390250314405; Tel: +390250314382
† Electronic supplementary information (ESI) available: Catalysts preparation and
activation, experimental procedure, spectral data, copies of 1H and 13C spectra,
copies of EI mass spectra. See DOI: 10.1039/c3ra44364g
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Table 1 Catalytic amination of different alcohols with aniline over Cu/ Table 2 Catalytic amination of different benzylic alcohols with aniline
a
a
Al2O3
over Cu/Al2O3
Entry
1
Alcohol
t (h)
Conv. (%)
52.7
A (%)
85.4
B (%)
15.1
Entry
1
Alcohol
t (h)
Conv. (%)
100
A (%)
84.6
B (%)
13.7
24
5
2
3
24
24
56.8
63.1
76.9
90.8
0.84
9.2
2
1
100
94.2
5.8
3
12
85.9
93.4
14.1
6.6
3
4
5
6
7
8
100
100
100
100
94.3
88.2
4
4
100
95
0.5
3
12
76.5
99.6
21.5
0.4
2
12
85.5
89.4
14.4
10.6
5
6
3
6
100
100
95
0.7
9.0
5
5
78.8
73.7
78.7
18.8
25.4
18.0
72.6
7
2
99
62.6
0.9
12
8
3
6
100
100
59.1
93.1
10.2
9
12
63.1
32.8
64.3
a
Reaction conditions: alcohol (0.65 mmol), aniline (0.65 mmol), Cu/SiO2
catalyst (100 mg), xylene (8 mL), N2 (1 atm), 130 ꢁC (oil bath temp.),
stirring (1000 rpm). Reaction mixtures were analysed by GC-MS (5%-
phenyl-methyl polysiloxane capillary column length 30 m, injection
T ¼ 60 ꢁC) with n-dodecane as internal standard, and by 1HNMR and
13CNMR spectroscopy.
9
—
10
12
24
96.8
71.5
94.7
73.8
—
For electrondonor para substituents the plot of log(kX/kH)
versus the Brown–Okamoto s+ series of different benzylic alco-
hols was found to be linear with a slope corresponding to a
Hammett r+ value of ꢀ0.68 (r2 ¼ 0.99) showing development of
a positive charge in the intermediate just as reported in the case
of dehydrogenation with an almost coincident r+ value (ꢀ0.69).5
When the substituent electrondonor character decreases
also the imine hydrogenation rate decreases and it begins to
accumulate in the reaction mixture. In particular for p-NO2 and
m-NO2 benzylic alcohols no amine was formed. The relative
position of the substituents had almost no inuence on the
reaction in agreement with the results obtained in the prepa-
11
11.5
a
Reaction conditions: alcohol (0.65 mmol), aniline (0.65 mmol), Cu/
Al2O3 catalyst (100 mg), xylene (8 mL), N2 (1 atm), 130 ꢁC (oil bath
temp.), stirring (1000 rpm), main byproduct the corresponding
carbonyl compound. Reaction mixtures were analysed by GC-MS (5%-
phenyl-methyl polysiloxane capillary column length 30 m, injection
T ¼ 60 ꢁC) with n-dodecane as internal standard, and by 1HNMR and
13CNMR spectroscopy.
conrmed by competitive hydrogenation of p-methoxy-benzal- ration of imines over CuO supported on magnetite.7 It is also
dehyde vs. N-(4-methoxybenzylidene)aniline, showing the last worth noting that no dehalogenation took place under the
one being hydrogenated much faster (Fig. 1).
reaction conditions used (Table 2, entries 6–9).
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One of the best catalytic system is represented by Cu-Al
hydrotalcite with more than stoichiometric amount of K2CO3,
but also this method fails with aliphatic secondary alcohols.12
To the best of our knowledge the only system able to convert
secondary alcohols into amines in one step is Ni/q-Al2O3.13
However, the Ni based system requires a 20% excess of alcohol
and a higher temperature (155ꢁ oil bath T) and moreover it is
much more active for primary alcohols due to the hydride
transfer mechanism suggested. Thus, the Ni/q-Al2O3 system is
not able to hydrogenate the imine under the same experimental
conditions.
This observation and the high yields in amine obtained in the
one pot N-alkylation reaction prompted us to investigate the
activity of Cu/Al2O3 in the direct hydrogenation of different
aldimines, a reaction that has been recently mentioned among
the ones of interest to the pharmaceutical industry needing a
green chemistry approach.14 Several methods have been
proposed for the transfer hydrogenation of imines15–18 but due to
the relevance of chiral amines in pharma products mainly pro-
chiral ketimines have been considered. For this last reaction
hydrogenation with H2 in the presence of non-noble metals has
been scarcely explored. Fe complexes19 or Zn(OTf)2 can be used20
under 50–80 bar of H2 while the use of Raney Nickel requires a
high catalyst loading as well as special handling to remove water
from the pyrophoric catalyst to minimize hydrolysis of the imine
substrate. Several ketimines could be hydrogenated by a Pd-Cu/C
catalyst at room T and 1.7 bar of H2.21
Fig. 1 Competitive hydrogenation of p-methoxy-benzaldehyde vs. N-
(4-methoxybenzylidene)aniline, 130 ꢁC, 1 bar H2, xylene.
The heterogeneous nature of the catalyst was proved by the
hot ltration test (Fig. S1†): no increase in conversion was
observed aer catalyst removal. Reuse is also possible as shown
in Fig. 2 although both conversion and selectivity to the amine
decreased.
We therefore explored the activity of both Cu/Al2O3 and Cu/
SiO2, the catalyst that we already used for direct reductive
amination of ketones.3‡
Heterogeneous catalysts for the N-alkylation of amines with
alcohols are rare. Recently a Cu catalyst supported on hydrotalcite
has been reported,8 but a high yield in amine was reported only
ꢁ
Deep characterization of these two systems both in the
presence of solvent and in the gas phase by means of in situ
Attenuated Total Reection Infrared spectroscopy (ATR-IR) and
in situ X-ray Absorption Spectroscopy (XAS) in combination with
CO adsorption showed that the presence of the solvent allows
reduction of the copper constituent at lower temperatures than
in the gas phase. Reduction of the alumina supported catalyst
was favoured in the liquid phase whereas the contrary was true
in the gas phase. Moreover the reduction behaviour measured
in the presence of the solvent was found to be correlated to the
much higher activity of Cu/Al2O3 in the dehydrogenation of 3-
octanol.22 On the other hand the Cu/SiO2 catalyst has always
shown much higher activity in the direct hydrogenation of C]O
and C]C double bonds.23,24
for the reaction of benzyl alcohol with aniline at 180 C, while
Cu(OH)/Al2O3 was active only for aliphatic primary amines.9 Au/
ZrO2 was also found to be effective10 but catalytic tests were
carried out only on aniline alkylation with benzylic alcohol.
On the other hand Ag/Al2O3 has been shown to be active and
selective, but high yields of secondary amines were only
obtained in the presence of a base11 such as Cs2CO3 or K3PO4.
The base was found to be necessary for an efficient dehydro-
genation of the alcohol whereas the Cu/Al2O3 catalyst used
throughout the present work is very active in this reaction,
particularly for secondary alcohols, not requiring any additive.
According to these ndings aldimines can be reduced under
mild conditions with excellent selectivity over both catalysts,
although reactions in the presence of Cu/SiO2 are much faster.
Results are reported in Table 3.
The impact of this one pot transformation in the context of
green chemistry is worth underlining. Among the different
guidelines and metrics that have been proposed so far25–29 Reac-
tion Mass Efficiency (RME), combining key elements of chemistry
and processes, represents a simple, objective, easily derived and
understood metric.29 This metric, dened as the % ratio between
the mass of product and the mass of all reactants, takes into
account atom economy, yield and stoichiometry of reactants and
it is usually quite low for N-alkylation reactions. In particular,
Fig. 2 Recyclability of the Cu/Al2O3 catalyst in the amination of p-
methoxybenzyl alcohol.
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Table 3 Reduction of some benzyl iminesa
Conclusions
In conclusion the high activity of Cu/Al2O3 both in secondary
and benzylic alcohols dehydrogenation and in imine hydroge-
nation allowed us to set up a very clean method for the
heterogeneous N-alkylation of aniline.
Alcohol and amine are used in stoichiometric amounts, no
additives are needed, the catalyst is easily prepared by readily
available starting materials and it can also be reused. Current
efforts are focused on further extension of the reaction to
different amines.
Entry
A
t (h)
Conv. (%)
B (%)
1b
2c
0.5
3
100
100
93.5
100
Acknowledgements
3
1
95
95.6
Regione Lombardia is acknowledged for funding the Sus-
ChemLombardia project.
4
0.5
6
100
99.4
100
97.0
5c
Notes and references
‡ Cu/SiO2 and Cu/Al2O3 catalysts with a 8% Cu loading were prepared as already
reported30 by using SiO2 (BET ¼ 486 m2 gꢀ1; PV ¼ 1.75 mL gꢀ1, 63–200 m, from
Aldrich) and g-Al2O3 (BET ¼ 210 m2
g
ꢀ1; PV ¼ 1.15 mL gꢀ1, 30 m) from Sasol.
6
7
1.5
99.5
98.3
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