Efficient nickel-catalysed: N -alkylation of amines with alcohols

Article abstract of DOI:10.1039/c8cy01200h

The selective N-alkylation of amines with alcohols via the borrowing hydrogen strategy represents a prominent sustainable catalytic method, which produces water as the only by-product and is ideally suited for the catalytic transformation of widely available alcohol reaction partners that can be derived from renewable resources. Intensive research has been devoted to the development of novel catalysts that are mainly based on expensive noble metals. However, the availability of homogeneous or heterogeneous non-precious metal catalysts for this transformation is very limited. Herein we present a highly active and remarkably easy-to-prepare Ni based catalyst system for the selective N-alkylation of amines with alcohols, that is in situ generated from Ni(COD)₂ and KOH under ligand-free conditions. This novel method is very efficient for the functionalization of aniline and derivatives with a wide range of aromatic and aliphatic alcohols as well as diols and exhibits excellent functional group tolerance including halides, benzodioxane and heteroaromatic groups. Several TEM measurements combined with elemental analysis were conducted in order to gain insight into the nature of the active catalyst and factors influencing reactivity.

Full text of DOI:10.1039/c8cy01200h

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Efficient nickel-catalysed N-alkylation of amines
with alcohols†
Cite this: Catal. Sci. Technol., 2018,
8, 5498
a
a
ab
Anastasiia Afanasenko,
Saravanakumar Elangovan,
Marc C. A. Stuart,
c
a
Giuseppe Bonura,
Francesco Frusteric and Katalin Barta
*
The selective N-alkylation of amines with alcohols via the borrowing hydrogen strategy represents a prom-
inent sustainable catalytic method, which produces water as the only by-product and is ideally suited for
the catalytic transformation of widely available alcohol reaction partners that can be derived from renew-
able resources. Intensive research has been devoted to the development of novel catalysts that are mainly
based on expensive noble metals. However, the availability of homogeneous or heterogeneous non-
precious metal catalysts for this transformation is very limited. Herein we present a highly active and re-
markably easy-to-prepare Ni based catalyst system for the selective N-alkylation of amines with alcohols,
that is in situ generated from NiIJCOD)2 and KOH under ligand-free conditions. This novel method is very
efficient for the functionalization of aniline and derivatives with a wide range of aromatic and aliphatic alco-
hols as well as diols and exhibits excellent functional group tolerance including halides, benzodioxane and
heteroaromatic groups. Several TEM measurements combined with elemental analysis were conducted in
order to gain insight into the nature of the active catalyst and factors influencing reactivity.
Received 8th June 2018,
Accepted 11th September 2018
DOI: 10.1039/c8cy01200h
rsc.li/catalysis
formed carbonyl compound reacts with the amine to form
the corresponding imine, which is reduced to the alkylated
Introduction
Amines are centrally important compounds in the bulk and
fine chemical industry since they are frequently encountered
scaffolds in agrochemicals, dyes, natural products and phar-
maceutically active compounds1,2 (Fig. 1a). Conventional
methods to access amines include the nucleophilic substitu-
tion of halides3 as well as reductive alkylation4 processes.
However, these methods suffer from low atom-economy and
E factor due to the formation of stoichiometric amounts of
waste5 and may face limitations in selectivity as well as sub-
strate cost or availability. Therefore, special attention has to
be devoted to the development of novel catalytic methods6–11
that would allow the selective and environmentally-friendly
synthesis of amines.12
amine by means of the metal hydride generated during the
first dehydrogenation step (Fig. 1b).14 This atom-economic
transformation represents a prime example in green chemis-
try since it only produces water as by-product and uses widely
available alcohol reaction partners that can also be poten-
tially derived from renewable resources.15–17
Following the remarkable progress in this field using pre-
cious metals,12,13,18 novel methods that utilize inexpensive
and widely abundant metals19 such as Fe,20,21 Co,22 Mn23
and Ni24,25 have recently emerged.26 Thus, there is tremen-
dous potential for the development of novel methods using
non-precious metals and great demand for improving reac-
tion scope, substrate compatibility and catalyst stability as
well as decreasing catalyst loading.
In this context and continuing our interest in developing
N-alkylation reactions using earth abundant metals,20,21 we
sought to develop an efficient catalytic system based on
nickel. Searching for a catalytic system that would be conve-
nient to prepare, and afford lower catalyst loading without
the need of any organic ligand, we have turned our attention
to Ni nanoparticle (NiNP) chemistry. Due to the pioneering
work of Yus and others, much progress has been made in
this area, especially related to transfer hydrogenation chemis-
try, typically using 2-pronanol.27 As a specific example,
2-propanol was used as hydrogen source in the reductive
amination of aldehydes and ketones catalyzed by NiNP.28
The N-alkylation of amines with alcohols via the borrowing
hydrogen approach has emerged as a very attractive and
waste-free alternative to provide N-alkylated amines.13,14 More
specifically, the hydrogen borrowing strategy begins with the
metal-catalysed dehydrogenation of an alcohol. Further, the
a Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747
AG Groningen, The Netherlands. E-mail: k.barta@rug.nl
b Electron Microscopy, Groningen Biomolecular Sciences and Biotechnology
Institute, University of Groningen, 9747 AG Groningen, The Netherlands
c CNR-ITAE “Nicola Giordano”, Via S. Lucia Sopra Contesse, 5, 98126 Messina,
Italy
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8cy01200h
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Fig. 1 (a) Representative examples of pharmaceuticals comprising an N-alkyl amine moiety; (b) general mechanism of the ‘borrowing hydrogen’
strategy.
Furthermore, NiNP catalyst enabled the activation of primary
alcohols for reductive aza-Wittig reaction.29 Interestingly,
NiNP chemistry has recently found application in the chemis-
try of renewable resources. Hartwig and coworkers discovered
that in situ generated NiNP are highly active for the scission
of phenyl ether bonds in simple lignin model compounds,30
while Luque and coworkers have reported on microwave
assisted preparation of Ni nanoparticles stabilized by ethyl-
ene glycol for the hydrogenolysis of benzyl-phenyl ether.31
Surprisingly, the efficient N-alkylation of amines has not
yet been realized with any NiNP system.
Herein, we describe the N-alkylation of amines via the hy-
drogen borrowing mechanism, to the best of our knowledge,
yet unprecedented by Ni nanoparticles generated in situ. This
catalyst is conveniently prepared from NiIJCOD)2 in the pres-
ence of sub-stoichiometric amount of base and shows versa-
tility in the selective monoalkylation of various aniline deriva-
tives with a broad range of alcohols.
18 hours). The reaction mixture was cooled down to room
temperature. After taking a sample (app. 0.5 mL) for GC anal-
ysis, the crude mixture was filtered through silica gel, eluted
with ethyl-acetate, and concentrated in vacuo. The residue
was purified by flash column chromatography to provide the
pure amine product.
Representative procedure for generating TEM specimens
After reaction, according to the Representative Procedure
above indicated, the Schlenk vessel was cooled to room tem-
perature and the solvent was evaporated under vacuum for at
least 1 h. Then, the concentrated solution was taken by
means of a 1 mL glass syringe and resuspended into 1 mL of
toluene by discharging two droplets through the septum of
the polypropylene screw-thread cap of a 2 mL Amber vial. Af-
ter sonication for 15 min, two drops from the solution were
sequentially placed onto a TEM grid, which was allowed to
dry in the glovebox for 1 h prior to analysis.
Experimental
Results and discussions
Representative procedure for catalytic N-alkylation of aniline
Establishing an active NiNP catalyst system for N-alkylation
with benzyl alcohol
of amines
An oven-dried 20 mL Schlenk tube, equipped with a stirring
bar, was charged with aniline (0.5 mmol, 1 equiv.), benzyl al-
cohol (0.75 mmol, 1.5 equiv.), NiIJCOD)2 (0.015 mmol, 3
mol%), KOH (0.15 mmol, 0.3 equiv., 30 mol%) and cyclo-
pentyl methyl ether (solvent, 2 mL). The solid materials were
weighed into the Schlenk tube under air, NiIJCOD)2 was
weighed in the glovebox; then the Schlenk tube was removed
from the glovebox, subsequently connected to an argon line
and vacuum–argon exchange was performed three times. Liq-
uid starting materials and solvent were charged under an ar-
gon stream. The Schlenk tube was capped and the mixture
was rapidly stirred at room temperature for 1 min, then was
placed into a pre-heated oil bath at the appropriate tempera-
ture (typically 140 °C) and stirred for a given time (typically
In order to establish the desired full hydrogen borrowing cy-
cle (Fig. 1b) that involves alcohol dehydrogenation, as well as
imine hydrogenation, we selected benzyl alcohol and aniline
as model substrates. Initially, the reaction was conducted
with various Ni precursors (Table 1, entries 1–4, Table S1†) in
the range of 120–140 °C under an argon atmosphere. While
relatively low conversion was obtained with precursors
NiIJOTf)2 and NiBr2, a high conversion value was detected
with NiIJCOD)2, which can be attributed to the ease of NiNP
generation from this Ni(0) precursor at 140 °C even in the ab-
sence of hydrogen gas. Selecting NiIJCOD)2 for further study,
the effect of various bases was evaluated (Table 1, entries 1,
5–8, Table S2†) with significant variation in substrate conver-
sion and product selectivity. Interestingly, with KOH a perfect
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Table 1 Optimization of the reaction conditions for amination of benzyl alcohol (1a) with aniline (2a′)
Entry
Alcohol (equiv.)
Base (equiv.)
Precatalyst (mol%)
Temp [°C]
Conv. [%]
Sel. of 3a [%]
Sel. of 3a′ [%]
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
2
2
2
2
1.2
2
KOH (0.5)
KOH (0.5)
KOH (0.5)
KOH (0.5)
LiOH (0.5)
NaOH (0.5)
KOtBu (0.5)
K2CO3 (0.5)
KOH (0.5)
KOH (0.5)
KOH (0.1)
KOH (0.3)
—
KOH (0.5)
KOH (0.3)
KOH (0.3)
KOH (0.3)
KOH (0.3)
KOH (0.3) + Hg (30)
KOH (0.3)
NiIJCOD)2 (5)
NiCl2IJdme) (5)
NiIJOTf)2 (5)
NiBr2 (5)
NiIJCOD)2 (5)
NiIJCOD)2 (5)
NiIJCOD)2 (5)
NiIJCOD)2 (5)
NiIJCOD)2 (5)
NiIJCOD)2 (5)
NiIJCOD)2 (3)
NiIJCOD)2 (3)
NiIJCOD)2 (5)
—
NiIJCOD)2 (3)
Ni(COD)2 (3)
NiIJCOD)2 (3)
NiIJCOD)2 (3)
NiIJCOD)2 (3)
NiIJCOD)2 (3)
140
140
140
140
140
140
140
140
100
120
140
140
140
140
140
140
140
140
140
140
>99
86
73
99
79
63
70
7
10
87
0
16
19
30
92
48
1
91
>99
95
93
20
0
1
7
10
5
74
90
3
7
7
9
30
2
22
6
5
<1
5
7
78
>99
>99
90
10
23
31
67
94
73
9
10
11
12
13
14
15a
16
17b
18c
19
20d
2
7
1.5
1.5
1.5
1.5
1.5
1.5
>99
>99
>99
>99
25
5
16
16
General reaction conditions: general procedure (see ESI, page S5–S9), 0.6–1 mmol of 1a, 0.5 mmol of 2a′, NiIJCOD)2 (0.015–0.025 mmol, 3–5
mol%), KOH (0.05–0.25 mmol, 10–50 mol%), 100–140 °C, 2 mL CPME, 18 h. Conversion and selectivity were determined by GC-FID using dec-
a
ane as an internal standard. At the beginning of the reaction NiNP were generated from NiIJCOD)2 (0.015 mmol, 3 mol%) and 2 mL CPME (as
a solvent) at 140 °C during 30 min, later KOH (0.15 mmol, 30 mol%), 1a (0.75 mmol), 2a′ (0.5 mmol) were added and the reaction mixture was
b
c
stirred and heated at 140 °C for 18 h. Reaction performed with freshly distilled benzyl alcohol. Reaction performed under non-inert condi-
tions. d Used pentylamine (0.5 mmol) instead of aniline (2a′).
selectivity and conversion was achieved at 140 °C, while the
use of K2CO3 gave much poorer results. The optimum reac-
tion temperature was found to be 140 °C as shown by the
lower conversion values in experiments conducted at lower
temperature range (Table 1, entries 9 and 10, Table S4†).
Without Ni precursor, only traces of product were observed
in the presence of base (Table 1, entry 14). Importantly, the
catalyst loading could be lowered to 3 mol% and loading of
base to 0.3 equivalents (Table 1, entry 16). Further, in order
to exclude the possibility for small amounts of aldehyde or
other impurities in the alcohol starting material to exhibit
catalytic activity,32 we have conducted an experiment with
freshly distilled benzyl alcohol, with unchanged results (entry
17 versus entry 16; see also ESI,† Note 3). Importantly, we also
successfully carried out an experiment under non-inert condi-
tions during which all starting materials were handled under
air (entry 18, see also ESI,† Note 4).
try 15), comparable to a regular reaction when typically, sol-
vent and all substrates were added at the same time. Further-
more, when the reaction was conducted in the presence of
mercury (Table 1, entry 19), which is a well-known poison for
heterogeneous catalysts, inhibition of the catalysis took
place.35,36 When the poisoning test was repeated in a differ-
ent fashion, namely initially the reaction was conducted for 1
h and analysed, after mercury was added and the reaction
was continued for 1 h and analysed again, the two samples
taken showed practically identical results, indicating an inhi-
bition of catalytic activity upon addition of mercury (see ESI†
Table S7). At this point it is worth to mention that although
the mercury poisoning test is indicative for a reaction operat-
ing with heterogeneous catalyst, it does not exclude processes
related to catalyst modification in situ such as leaching of sol-
uble monometallic species, or formation of smaller set of
clusters of metal particles in solution during catalysis. As de-
scribed in the excellent review of Ananikov and co-workers,34
several catalytic systems using metal nanoparticles33 rely on
dynamic processes involving a homogeneous or heteroge-
neous pre-catalyst.
Characterization and nature of the catalyst
To gain additional proof of the heterogeneous nature of the
Ni catalyst in situ obtained from NiIJCOD)2, we conducted sev-
eral experiments. When we subjected NiIJCOD)2 to thermal de-
composition in CPME, in the absence of the substrates,
followed by the addition of all reactants and base, we
obtained 99% of conversion and 91% of product (Table 1, en-
Recycling experiments were successfully conducted, albeit
the results showed gradually declining substrate conversion
over four consecutive runs (Fig. S1 and Table S8†).
Next, a series of TEM measurements were conducted in or-
der to determine the nature and size distribution of the in
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Fig. 2 TEM micrographs of the in situ generated Ni-NPs under various reaction conditions and particle size distribution of the investigated sam-
ples: a) Ni precursor only; b) Ni precursor in presence of KOH; c) Ni precursor in presence of K2CO3; d) Ni precursor in presence of benzyl alcohol;
e) Ni precursor in presence of KOH and benzyl alcohol; f) Ni precursor in presence of KOH, benzyl alcohol and aniline.
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Table 2 Amination of various alcohols with aniline
3a, 90%
3b, 85%
3c, 84%
3d, 98%
3h, 51%
3g, 62%
3f, 72%
3e, 92%
3j, 38%a,b
3k, 69%b
3l, 90%
3i, 69%
3m, 89%
3q, 88%
3ua, 63%
3n, 87%
3r, 85%
3o, 89%
3s, 90%
3va, 67%
3p, 89%
3t, 12%
3ub, 18%a
3vb, 28%
General reaction conditions: general procedure (see ESI, page S13–S15), 1.5 mmol of 1a–v, 1 mmol of aniline, NiIJCOD)2 (0.03 mmol, 3 mol%),
a
b
KOH (0.3 mmol, 30 mol%), 140 °C, 2 mL CPME, 18 h. Yield was calculated based on GC-FID. 1 mL of methanol or ethanol, 1 mmol of
aniline, NiIJCOD)2 (0.1 mmol, 10 mol%), KOH (1 mmol), 150 °C, 2 mL CPME, 48 h. For details see ESI, Table S9.
situ generated NiNP. To gain more insight into the possible
structural changes imparted by the various components of
this peculiar system, a number of experiments were carried
out by systematic variation of the base, alcohol and amine
and the corresponding TEM images were recorded (Fig. 2).
The first sample (Fig. 2a), prepared by heating NiIJCOD)2 in
CPME showed Ni oxide clusters of ca. 20 nm in large regions
with agglomerated particles sized in the range of 2–5 nm, as
expected in the absence of the base and any substrates present.
The same sample, however in the presence of KOH (30 mol%)
(Fig. 2b), displayed larger Ni oxide clusters (50–100 nm) formed
by nanoparticles still of 2–5 nm (Fig. 2b) surrounded by potas-
sium. Caubère,37,38 and Hartwig30 have previously indicated
that base can stabilize nickel nanoparticles and this phenome-
non is observed in our system as well. In contrast to KOH, the
specimen obtained using K2CO3 showed particles with mark-
edly different morphology, with more agglomeration and poor
dispersion (≈2%) of Ni nanoparticles (Fig. 2c). This is a likely
explanation for the lower catalytic activity of this system
(Table 1 entry 1 versus entry 8 and ESI† Table S2 entry 1 versus
entry 5). Next, the influence of the benzyl alcohol was investi-
gated. Isolated Ni oxide clusters of ca. 25 nm (Fig. 2d) with well
dispersed nanoparticles (average size 4 nm) were obtained in
presence of 1.5 equivalents of benzyl alcohol that confirmed
our assumption of a possible stabilization of metal particles by
benzyl alcohol, supporting the alcohol–Ni interaction that is
necessary for the dehydrogenation reaction. This effect was
even more pronounced in the presence of KOH. The mixture
containing benzyl alcohol and KOH after 20 min (Fig. 2e)
showed no visible nickel particles at low magnification. How-
ever, at higher magnification, very regularly and finely distrib-
uted metal Ni nanoparticles of ca. 2 nm were observed,
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Table 3 N-alkylation of various aniline with n-butanol
5a, 78%
5b, 77%
5d, 32%
5c, 53%
5e, 70%
5f, 86%
5i, 72%
5g, 65%
5h, 42%b
5k, 36%
5j, 62%
5n, 32%a
5l, 64%
5m, 72%b
5pa, 32%b
5ob, 39%b
5oa, 25%b
b
5pb, 43%
5q, 32%b
5r, 57%c
General reaction conditions: general procedure (see ESI, page S15–S18), 1.5 mmol of n-butanol (4a), 1 mmol of 2a–r, NiIJCOD)2 (0.03 mmol, 3
mol%), KOH (0.3 mmol, 30 mol%), 140 °C, 2 mL CPME, 18 h. a Yield was calculated based on GC-FID. b 3 mmol of n-butanol, 1.5 mmol of cor-
c
responding amine, NiIJCOD)2 (0.03 mmol, 3 mol%), KOH (0.3 mmol, 30 mol%), 140 °C, 2 mL CPME, 48 h. 3 mmol of n-butanol, 1.5 mmol of
corresponding amine, NiIJCOD)2 (0.05 mmol, 5 mol%), KOH (0.5 mmol, 50 mol%), 140 °C, 2 mL CPME, 72 h. For details see ESI, Table S10.
accounting for a metal dispersion as high as 50% (for EDX
analysis of this sample see ESI† Fig. S4) – signifying the active
system prior to the addition of aniline. The actual reaction mix-
ture, after 20 minutes reaction time showed similar finely dis-
persed particles (see ESI† Fig. S3a), while the reaction mixture
imaged after 18 hours (Fig. 2f) still showed well dispersed Ni°
nanoparticles, although slightly larger than those observed in
the initial phase of the reaction. Interestingly, when the Ni par-
ticles were generated in presence of pentylamine (see ESI† Fig.
S3c) the TEM images showed that the particles were completely
besieged by the amine, whereas in the presence of aniline (see
ESI† Fig. S3b) they were well dispersed. A reaction mixture
comprising benzyl alcohol and pentylamine showed similar be-
haviour (Fig. S3d†). This can be explained by a stronger coordi-
nation of the more basic (aliphatic) amines to the nickel parti-
cles and likely the cause of the poor conversion values obtained
in the presence of pentylamine (Table 1, entry 20) and similar
substrates (ESI† Table S10, entries 28–31).
N-Alkylation of aniline with a wide range of alcohols
To demonstrate the general applicability of the catalytic sys-
tem, various (hetero)aromatic and aliphatic alcohols, includ-
ing diols, were evaluated in the catalytic N-alkylation of ani-
line under optimized conditions (Table 2). Electron-donating
and electron-withdrawing substituted benzyl alcohols were
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successfully used in the selective mono-alkylation of aniline
(Table 2). Notably, benzyl alcohols (1a–1e) with electron-
donating substituents, including the sterically more hindered
2-methoxy benzyl alcohol (1c) reacted smoothly with aniline,
resulting in very good to excellent (84–98%) isolated yields of
3a–e (Table 2). When benzyl alcohols bearing the electron-
withdrawing groups –NO2, –CN, –CH3COOCH3, –CF3 were
employed, much lower reactivity was observed (Table S9, en-
tries 23–26, in the ESI†). Furthermore, the important building
block piperonyl alcohol (1g) was transformed to the desired
product 3g with 62% isolated yield. Interestingly, hetero-
aromatic alcohols such as the biomass-derived furfuryl alco-
hol and 2-(hydroxymethyl)pyridine were alkylated selectively,
albeit with moderate yields (Table 2, 3h and i, respectively).
Next, aliphatic alcohols as reaction partners in the
N-alkylation of aniline were investigated. Gratifyingly, short
and long chain aliphatic alcohols (1k–s) readily afforded the
lic nanoparticles42 and RANEY®-nickel43 are known for the
amination of alcohols. Besides this, a few homogeneous cata-
lytic systems using nickel for alkylation of amines24,25 and
N-alkylation of hydrazides and arylamines with racemic alco-
hols44 were very recently reported, but to the best of our
knowledge, the system described above is the first example
where in situ generated Ni nanoparticles act as highly effi-
cient catalysts for the attractive N-alkylation of amines. Clear
advantages are the Ni loading being as low as 3%, and there
is no catalyst preparation or any ligand required. Therefore,
we believe our system to be a valuable addition to these ex-
amples of Ni catalysts that are either homogeneous or
supported heterogeneous in nature. This is an excellent
starting point for establishing robust, highly active and recy-
clable Ni catalyst in the future, for example by using polyeth-
ylene glycol (PEG)45 or ionic liquids.46
corresponding desired amine product (3k–s, 69–90%) under Conclusion
optimized conditions. It was even possible to achieve
In summary, we have developed a simple and highly active
N-alkylation with methanol, but only 38% GC yield of
N-methylated product was seen even at high catalyst/base
loading. Notably, when 1,5- and 1,6-diols were examined, the
mono-alkylated amino alcohols (3ua) and (3va) were obtained
in 63% and 67% isolated yield, respectively, and minor
amounts of cyclic products were observed (Table 2).
catalytic system for efficient and selective N-alkylation of
amines with alcohols that can be conveniently prepared
using a catalytic amount (as low as 3 mol%) of NiIJCOD)2 and
sub-stoichiometric amount of KOH under ligand-free condi-
tions. The described system is tolerant to a variety of func-
tional groups such as halides, benzodioxane and hetero-
aromatic groups present in either the alcohol or the amine
substrate. In order to gain further insight into the nature of
the active catalytic system and influence of reaction parame-
ters on catalyst morphology, a series of TEM measurements
combined with elemental analysis were performed that found
finely dispersed in situ generated metal particles in the
catalysed reaction. Additional studies revealed that potassium
hydroxide is uniquely suited for the stabilization of Ni nano-
particles and that the alcohol substrate also has a stabilizing
role. Furthermore, clear differences in the morphology of the
particles were seen in the presence of aromatic versus ali-
phatic amine, the latter leading to poor reactivity due to
stronger amine coordination. The substrate scope was well in
line with these findings, where the nature of the alcohol reac-
tion partner could be broadly varied (benzyl alcohol, short or
long chain aliphatic alcohol, diol) while aniline derivatives
were better suited substrates than aliphatic amines. To the
best of our knowledge this is the first, very simple yet highly
active and selective NiNP catalyst system for the N-alkylation
of amines with alcohols that operates via the hydrogen bor-
rowing strategy.
N-Alkylation of a variety of amines with 1-butanol
Further expanding the scope of the reaction, n-butanol was
chosen as coupling partner to a series of diversely substituted
aniline derivatives, bearing electron-donating (2a–e) and
electron-withdrawing (2i–l) groups as well as sterically hindered
amines (2f–g), and diamines (2m, 2o–q), which were selectively
alkylated. More specifically, there was no significant difference
in the reactivity of p-methoxy-aniline (2a) compared to
p-methyl-aniline (2b), however a gradual decrease of product
yield was observed (77% for 5b, 53% for 5c, 32% for 5d) when
the substrate was changed to the meta- and ortho-substituted
analogues. A similar behavior was observed for fluoro-anilines
2i, 2j and 2k. Interestingly, pyrrole substituted aniline
furnished 57% isolated yield of 5r. Aromatic amines bearing
the electron-withdrawing groups –CN, –CH3COOCH3 and –CF3
showed low reactivity with 1-butanol, namely only minor
amounts of products were observed (Table S10, entries 19–21,
in the ESI†). Next, when aromatic diamines were used as a sub-
strate, the corresponding mono and di-N-alkylated amines were
isolated (Table 3, 5oa–5ob and 5pa–5pb). When aliphatic amine
cyclohexylamine was used, it gave 32% GC yield of desired
product 5n and 67% of imine (5n′). Other aliphatic amines
(benzylamine, pentylamine and morpholine) did not afford any
products under the optimized reaction conditions (Table S10,
entries 28–30, in the ESI†), in accordance with previous TEM
investigation that shows stronger coordination of aliphatic
amines to the Ni particles likely leading to diminished activity.
Examples of heterogeneous catalysts comprising nickel on
alumina39,40 or silica,41 γ-Al2O3 supported Ni and Cu bimetal-
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
K. B. is grateful for financial support from the European Re-
search Council, ERC Starting Grant 2015 (CatASus) 638076.
This work is part of the research program Talent Scheme
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(Vidi) with project number 723.015.005 (K. B.), which is partly
financed by the Netherlands Organization for Scientific Re-
search (NWO).
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