Mild and efficient synthesis of secondary aromatic amines by one-pot stepwise reductive amination of arylaldehydes with nitroarenes promoted by reusable nickel nanoparticles

Article abstract of DOI:10.1016/j.mcat.2019.110507

The one-pot stepwise reductive amination of arylaldehydes with nitroarenes is described, using reusable nickel nanoparticles (Ni-pol) as catalyst and NaBH₄ as mild, inexpensive, and safe reducing agent. The proposed catalytic system holds several advantages such as the use of a non-precious and earth-abundant metal, the facile separation of the catalyst from the reaction mixture by centrifugation, excellent stability towards air and moisture, very mild reaction conditions, good recyclability, broad substrate scope with good to excellent yields, and easy scalability (up to 1.0 g). FESEM analyses indicate that the active species are cubic nanocrystals of Ni in the average cross section value of 35 nm with a quite narrow (25–45 nm) and monomodal distribution, which becomes bimodal with the recycling reactions but without agglomeration.

Full text of DOI:10.1016/j.mcat.2019.110507

MolecularCatalysis476(2019)110507
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Molecular Catalysis
journal homepage: www.elsevier.com/locate/mcat
Mild and efficient synthesis of secondary aromatic amines by one-pot
stepwise reductive amination of arylaldehydes with nitroarenes promoted
by reusable nickel nanoparticles
Ambra Maria Fiorea, Giuseppe Romanazzia,⁎, Maria Michela Dell’Annaa,⁎, Mario Latronicoa,
Cristina Leonellib, Matilda Malia, Antonino Rizzutia, Piero Mastrorillia
a DICATECh, Politecnico di Bari, via Orabona 4, 70125, Bari, Italy
b Dipartimento di Ingegneria "Enzo Ferrari", Università di Modena e Reggio Emilia, via Vignolese 905, 41125, Modena, Italy
A R T I C L E I N F O
A B S T R A C T
Keywords:
Reductive amination
Ni catalyst
Polymer supported nanoparticles
Recyclability
Secondary amines
The one-pot stepwise reductive amination of arylaldehydes with nitroarenes is described, using reusable nickel
nanoparticles (Ni-pol) as catalyst and NaBH4 as mild, inexpensive, and safe reducing agent. The proposed
catalytic system holds several advantages such as the use of a non-precious and earth-abundant metal, the facile
separation of the catalyst from the reaction mixture by centrifugation, excellent stability towards air and
moisture, very mild reaction conditions, good recyclability, broad substrate scope with good to excellent yields,
and easy scalability (up to 1.0 g). FESEM analyses indicate that the active species are cubic nanocrystals of Ni in
the average cross section value of 35 nm with a quite narrow (25–45 nm) and monomodal distribution, which
becomes bimodal with the recycling reactions but without agglomeration.
1. Introduction
nitroarene is, in principle, attractive as it removes another hydro-
genation step, saving both time and costs considering that nitro aro-
Secondary aromatic amines are important intermediates and
building blocks for the production of several agrochemicals, additives,
drugs, dyes, herbicides, pharmaceuticals, pigments, and other fine-
chemicals [1,2]. However, the development of a facile, efficient and
low-cost approach to their preparations remains a great challenge from
a synthetic point of view [3–5]. By far, the most general synthetic ap-
proaches to obtain secondary aromatic amines are the direct alkylation
of anilines with alkyl halides [4,6], the N-alkylation of anilines with
alcohols [7–9], Buchwald–Hartwig [10–12] or Ullman-type CeN cross-
couplings [13,14], and the amine-carbonyl reductive amination
[15–21]. The latter strategy seems the most preferable one, because of
the easily availability of the substrates and high atom-economy.
Moreover, such reaction is referred to as direct reductive amination,
when the amine and the carbonyl compound are mixed together with
the proper reducing agent without prior formation of the intermediate
imine (or iminium salt) and stepwise (or indirect) reductive amination,
when it involves the preformation of the intermediate imine followed
by reduction in a separate step [22]. When the reductive amination uses
as nitrogen source the anilines, these can be easily synthesized in ad-
vance by the hydrogenation of the corresponding nitroarene deriva-
tives. Thus, a direct or indirect reductive amination starting from a
matic compounds are cheaply available starting materials in organic
synthesis [23]. In the last decade several efforts have been addressed to
develop an efficient heterogeneous catalytic version of this one-pot
direct or indirect reductive amination promoted by supported nano-
particles or nanocomposites of metals such as Ag [24], Au [25–27], Co
[28–36], Cu [37,38], Fe [39,40], Ni [41,42], Pd [43–57], Pt [58–60],
Rh [61], Ru [62], as well as by heterobimetallic systems such as AgPd
[63–65], AuPd [66,67], CoRh [68,69], and NiPd [70]. We also con-
tributed to this field reporting the catalytic activity and recyclability of
a polymer supported Pd nanoparticles (Pd-pol) obtained by copoly-
merization of Pd(AAEMA)2 [AAEMA− = deprotonated form of 2-
(acetoacetoxy) ethyl methacrylate] with methacrylic comonomers [51].
Pd-pol also proved to accelerate other kinds of chemical reactions such
as reductions, oxidations and esterifications [71–76]. However, aiming
to replace noble metals with earth abundant first-row transition metals
[77,78], and continuing our studies on metal-containing polymers to be
used as heterogenous catalysts [79,80], we synthesized more recently
the nickel homologue (Ni-pol) of Pd-pol by copolymerizing Ni
(AAEMA)2 with N,N-dimethylacrylamide and N,N’-methylenebisacry-
lamide and submitting it to calcination at 300 °C under N2 (Scheme 1)
[81].
⁎ Corresponding authors.
E-mail addresses: giuseppe.romanazzi@poliba.it (G. Romanazzi), mariamichela.dellanna@poliba.it (M.M. Dell’Anna).
https://doi.org/10.1016/j.mcat.2019.110507
Received 8 April 2019; Received in revised form 10 July 2019; Accepted 11 July 2019
2468-8231/©2019PublishedbyElsevierB.V.

A.M. Fiore, et al.
MolecularCatalysis476(2019)110507
Scheme 1. Synthesis of Ni-pol.
Scheme 2. Synthesis of N-benzylaniline (3aa) through hydrogenation of nitrobenzene (1a) and reductive amination of benzaldehyde (2a).
Table 1
Preliminary tests to achieve the best reaction conditionsa.
Entry
Molar Ratio NaBH4/1a (step A)
Solvent
Time Reaction (step A + B+C)
HCOOH Addition in step B (2 equiv)
Isolated Yield of 3aa (%)c
1
2
3
4
20b
3b
H2O/Et2O (1:1, v/v)
“
“
2 h + 40 min + 3 h
3 h + 40 min + 3 h
3 h + 40 min + 3 h
3 h + 40 min + 3 h
No
No
Yes
Yes
40
47
61
96
3b
3b
MeOH
a
Reaction conditions: 0.50 mmol of nitrobenzene (1a), 0.70 mmol of benzaldehyde (2a), Ni 2.0 mol% (11.0 mg of Ni-pol) with respect to 1a, 5.0 ml solvent, room
temperature.
b
c
3.0 mmol NaBH4 were added after step B (see Scheme 2).
based on nitrobenzene.
Ni-pol was found a very active, selective, recoverable and reusable
towards halo-anilines [81], avoiding the hydro-dehalogenation side-
product formation typical for noble metal catalysed reductions. Here
we describe the catalytic activity and recyclability of Ni-pol towards
one-pot stepwise reductive amination of arylaldehydes with nitroarenes
in the presence of NaBH4 as mild reducing agent, which is well-known
to have broad applications in organic and inorganic synthesis for its
ready availability, moderate cost and ease of handling with respect to
reducing reagents [82–85].
catalyst for the reduction of several functionalized nitroarenes to cor-
responding aromatic amines in a biphasic H2O/Et2O medium at room
temperature in the presence of NaBH4 as reducing agent [81] and we
deemed it worthwhile to check whether Ni-pol could be an effective
catalyst also for promoting the reductive amination reaction. The
reason of studying the catalytic activity of Ni-pol in the aforementioned
reaction stands both in the cheapness of the metal employed, and in the
selectivity already observed towards the reduction of halo-nitroarenes
2

A.M. Fiore, et al.
MolecularCatalysis476(2019)110507
Table 2
Reductive amination of benzaldehyde (2a) with different nitroaromatics (1b-j)a.
Entry
1
Nitroarene
Product
Time Reaction (step A + B+C)
3 h + 40 min + 3 h
IsolatedYield (%)b
97
2
3
4
5 h + 40 min + 3 h
6 h + 40 min + 3 h
5 h + 40 min + 3 h
85
80
50
5
6
2 h + 40 min + 3 h
2 h + 40 min + 3 h
98
97
7
8
10 h + 40 min + 3 h
2 h + 40 min + 3 h
93
98
9
2 h + 40 min + 3 h
97
a
Reaction conditions: 0.50 mmol of nitroaromatics (1b-j) 0.70 mmol of benzaldehyde (2a), Ni 2.0 mol% (11.0 mg of Ni-pol) with respect to 1b-j, 5.0 ml solvent,
room temperature.
b
based on corresponding nitroarene.
2. Experimental
using standard Schlenk techniques unless otherwise specified. Ni-pol
was prepared as reported in ref. [81]. Nickel content (5.35%W) in Ni-
pol was assessed after sample mineralization by Graphite Furnace
Atomic Absorption Spectroscopy (GFAAS; PerkinElmer 3110 appa-
ratus). Mineralization of Ni-pol prior to Ni analyses was carried by
microwave irradiation with an ETHOS E-TOUCH Milestone applicator,
after addition of HCl/HNO3 (3:1 v/v) solution (12 mL) to each weighted
2.1. Materials, methods and instrumentations
Nitrobenzene was distilled under inert atmosphere before use, while
all other reagents/reactants and solvents were used as received. All
manipulations were carried out under inert dinitrogen atmosphere
3

A.M. Fiore, et al.
MolecularCatalysis476(2019)110507
Table 3
Reductive amination of different arylaldehydes (2b-n) with nitrobenzene (1a)a.
Entry
1
Arylaldehyde
Product
Time Reaction (step A + B+C)
3 h + 40 min + 3 h
Isolated Yield (%)b
80
2
3 h + 40 min + 3 h
73
3
4
5
3 h + 40 min + 3 h
3 h + 40 min + 3 h
3 h + 40 min + 3 h
98
72
93
6
7
3 h + 40 min + 3 h
3 h + 40 min + 3 h
96
98
8
9
3 h + 40 min + 3 h
3 h + 40 min + 4 h
95
96
10
11
3 h + 40 min + 3 h
3 h + 40 min + 3 h
96
98
12
a
3 h + 40 min + 5 h
93
Reaction conditions: 0.50 mmol of nitrobenzene (1a), 0.70 mmol of arylaldehydes (2b-n), Ni 2.0 mol% (11.0 mg of Ni-pol) with respect to 1a, 5.0 ml solvent,
room temperature.
b
based on nitrobenzene.
4

A.M. Fiore, et al.
MolecularCatalysis476(2019)110507
were introduced in the vessel and the reaction mixture was stirred for
further 40 min (step B). Then, 3.0 mmol of NaBH4 was added under
stirring, leaving the system to react for due time (step C). The reaction
mixture was then diluted with 5.0 ml of methanol and filtered. The solid
(Ni-pol) was washed with methanol (3 × 5.0 mL) and the combined
organic layers were dried (Na2SO4) and concentrated under reduced
pressure to get the crude product, which was then purified by column
chromatography using a short plug of silica gel and eluted with the
appropriate solvent mixture. Evaporation of solvents afforded the de-
sired secondary amines. All secondary amines, except for 3al and 3am,
are compounds already known in the literature and were characterized
by comparison with their 1H NMR and MS (EI, 70 eV) data. Amines 3al
and 3am were characterized by 1H and 13C{1H} NMR, MS (EI, 70 eV),
and elemental analysis. N-(thiophen-3-ylmethyl)aniline (3al) was eluted
from silica gel using petroleum ether 40-60 °C/dichloromethane in a
volume ratio of 7:4 (Rf = 0.36) affording the title compound as a yellow
oil. 1H NMR (400 MHz, CDCl3, δ): 7.32 (m, 1 H), 7.24-7.16 (m, 3 H),
7.09 (d, J = 5.0 Hz, 1 H), 6.75 (t, J = 7.3 Hz, 1 H), 6.67 (d, J = 7.3 Hz,
2 H), 4.35 (s, 2 H), 3.52 (br s, 1H, NH). 13C{1H} NMR (100.6 MHz,
CDCl3, δ): 148.2, 140.6, 129.4, 127.3, 126.3, 121.9, 117.9, 113.1, 43.9.
EI/MS m/z (%): 189 (63) [M+], 97 (100), 77 (21), 65 (14). Anal. calcd
for C11H11NS: C, 69.80; H, 5.86; N, 7.40; S, 16.94; found: C, 69.44; H
5.63; N, 7.37. N-((5-bromothiophen-2-yl)methyl)aniline (3am) was
eluted from silica gel using petroleum ether bp 40–60 °C/di-
chloromethane in a volume ratio of 7:3 (Rf = 0.30) affording the title
compound as a pale yellow oil. 1H NMR (400 MHz, CDCl3, δ): 7.20 (t,
J = 8.0 Hz, 2 H), 6.91 (d, J = 3.6 Hz, 1 H), 6.80-6.74 (m, 2 H), 6.66 (d,
J = 8.0 Hz, 1 H), 4.45 (s, 2 H), 4.06 (br s, 1H, NH). 13C{1H} NMR
(100.6 MHz, CDCl3, δ): 147.3, 145.2, 129.7, 129.3, 125.2, 118.5, 113.3,
111.1, 43.9. EIMS m/z (%): 267 (37) [M+], 175 (100), 96 (33), 77 (21),
65 (15). Anal. calcd for C11H10BrNS: C, 49.27; H, 3.76; Br, 29.80; N,
5.22; S, 11.96; found: C, 49.11; H 3.69; N, 5.30.
Fig. 1. Recyclability of Ni-pol in the reductive amination of benzaldehyde (2a)
with nitrobenzene (1a) to give N-benzylaniline (3aa).
sample. Column chromatography was performed using Merck® Kie-
selgel 60 (230–400 mesh) silica gel. 1H NMR and 13C{1H} NMR were
recorded on a Bruker Avance 400 MHz and are reported in ppm relative
to tetramethylsilane. Elemental analyses were obtained on a EuroVector
CHNS EA3000 elemental analyser using acetanilide as analytical stan-
dard material. Gas chromatography (GC) data were acquired on a HP
6890 instrument equipped with a FID detector and a HP-1 (Crosslinked
Methyl Siloxane) capillary column (60.0 m x0.25 mm x1.0 μm). Gas
chromatography–mass spectrometry (GC–MS) data (EI, 70 eV) were
acquired on a HP 6890 instrument using a HP-5MS cross-linked 5% PH
ME siloxane (30.0 m ×0.25 mm × 0.25 μm) capillary column coupled
with a mass spectrometer HP 5973. Surface morphology was in-
vestigated on high resolution Field Emission Scanning Electron Micro-
scopy (FESEM) (Nova NanoSEM 450 manufactured by FEI Company,
USA) equipped with Energy Dispersive X-ray Spectroscopy (X-EDS;
Bruker QUANTAX-200) and Electron Backscatter Diffraction (EBSD)
detectors (Nordlys with Channel 5 software). Each dried sample of Ni-
pol was finely ground and a suspension in water of the fine powder was
dropped on common Formvar® coated copper grids. To enhance the
resolutions of the scanning micrograph obtained, each grid was coated
with gold-palladium alloy (sputtering machine: K550, Emitech Ltd,
United Kingdom). The coating thickness was set-up to about 8 nm to
avoid alteration of the sample morphology. The stability of the spe-
cimen material under the scanning electron beam of the Scanning
Transmission Electron Detector (STEM) mode was checked comparing
the surface morphology before and after the focusing process; this as-
sured that the originality of the structure, pattern, contour and texture
of the catalyst were not affected by any physical and chemical distor-
tion before and during the FESEM analysis, since low voltage (30 kV)
STEM mode was adopted. The STEM allowed transmission images to be
taken at a resolution of about 1 nm @300,000x in our samples when
observed in high vacuum mode.
2.3. Recycling of the catalyst
Ni-pol (66.0 mg, Ni %w = 5.35, 60.0 μmol of Ni), nitrobenzene 3a
(3.0 mmol), methanol (30.0 mL) and NaBH4 (9.0 mmol) were in-
troduced in a 100 ml three-necked round flask (equipped with a mag-
netic stirrer and a gas bubbler), and the mixture was stirred under
magnetic stirring at 25 °C until aniline I quantitatively formed (2 h, step
A). Then, 240 μl (ca. 6.0 mmol) of formic acid and benzaldehyde 2a
(4.2 mmol) were introduced in the vessel and the reaction mixture was
stirred for futher 40 min (step B). Then, maintaining the stirring, NaBH4
(18.0 mmol) was added leaving the system to react for 3 h (step C). The
reaction mixture was then diluted with 20.0 ml of methanol and cen-
trifugated for separating Ni-pol, which was washed with methanol
(3 × 25.0 mL), water (2 x 25.0 mL) and rinsed in n-hexane (20 mL). The
methanol phase was dried (Na2SO4) and concentrated under reduced
pressure to get the crude product, which was then purified by column
chromatography using a short plug of silica gel and eluted with pet-
roleum ether 40–60 °C/dichloromethane in a volume ratio of 7:3 and
evaporation of solvents afforded the desired amine 3aa. The recovered
Ni-pol was dried in air at 60 °C for 2 h, and then brought to room
temperature, re-weighed and used for the subsequent catalytic cycle.
Iteration of this procedure was repeated for four reuses of the catalyst.
2.2. General experimental procedure for one-pot stepwise reductive
amination of aromatic aldehydes with nitroarenes
3. Result and discussion
Ni-pol (11.0 mg, Ni %w = 5.35, 10.0 μmol of Ni), the desired ni-
troarene (0.50 mmol), methanol (5.0 mL) and NaBH4 (1.5 mmol) were
introduced in a 25 ml three-necked round flask (equipped with a
magnetic stirrer and a gas bubbler to discharge the dihydrogen excess
produced during reaction), and the mixture was stirred under magnetic
stirring at 25 °C for the time necessary to form the corresponding ani-
lines (step A, monitoring by TLC and/or GC and GC–MS). Then, 40 μl
(ca. 1.0 mmol) of formic acid and the desired arylaldehyde (0.70 mmol)
3.1. Optimal reaction conditions for the one-pot stepwise reductive
amination
To evaluate the catalytic activity of Ni–pol, the reductive amination
starting from nitrobenzene (1a) and benzaldehyde (2a) to afford N-
benzylaniline (3aa) was chosen as the benchmark reaction (Scheme 2).
We first carried out this reaction in a direct fashion (i.e. one-pot, one
step), stirring 1a (0.50 mmol), 2a (0.70 mmol) and Ni-pol (2.0% mol/
5

A.M. Fiore, et al.
MolecularCatalysis476(2019)110507
Scheme 3. General accepted reaction pathways for the reduction of nitrobenzene (1a) to aniline (I).
Fig. 2. STEM micrographs and associated size distribution (on the right) of matrix polymer embedded Ni nanoparticles: (a) Ni-pol recovered after the first run of the
model reaction and (b) its size distribution; (c) Ni-pol recovered after five subsequent runs of the model reaction and (d) its size distribution.
mol ratio relative to the limiting reagent) at room temperature in a
mixture (5.0 mL) of equal volumes of diethyl ether (Et2O) and water,
and NaBH4 (10 mmol). However, monitoring the reaction progress by
GC–MS, revealed that within 2 h the conversion of 1a was complete but
the main products were anyline (intermediate I) and benzyl alcohol
(by-product II) due to the simultaneous reduction of 1a and 2a, with
negligible amounts (1–2 %) of imine (intermediate III) and target N-
benzylaniline (3aa).
the direct reaction but adding the benzaldehyde after step A (Scheme 2)
resulted in only a 16% yield of imine (intermediate III in Scheme 2)
with no formation of the desired amine 3aa. However, the addition of
further 3.0 mmol NaBH4 during step C (a practice that was followed for
all reactions described herein) allowed to reach a 40% yield of 3aa
within 3 h (entry 1 of Table 1). This result points out that, in our system,
the imine formation is sluggish and most NaBH4 is wasted. Among the
factors influencing the equilibrium between imine III and its corre-
sponding precursors (I and 2a) (solvent, concentration, pH, tempera-
ture, electronic and steric effects) [17,19] we focused on pH, well aware
that the hydrolysis of NaBH4 in the first step gives rise to an alkaline
We then passed to verify whether Ni-pol could be an effective
catalyst for promoting the indirect reductive amination (i.e. one-pot,
stepwise) [86]. Carrying out the reaction in the conditions described for
6

A.M. Fiore, et al.
MolecularCatalysis476(2019)110507
reaction medium [87–90], and that, conversely, the imine formation
requires a pH value ranging from 4 to 6 [91–93]. A first attempt to
reduce the pH of the medium was made by reducing the amount of
NaBH4 in step A, with all other parameters unchanged. Unfortunately,
using a three-fold excess of NaBH4 (which was found to be the
minimum amount required to preserve an acceptable reaction time, 3 h)
in step A resulted in only a slightly improved yield (47%, entry 2 of
Table 1) of 3aa. Given that Brønsted acids are known to facilitate the
formation of Schiff bases [94–96] we tested several carboxylic acids as
additives for our reaction. The best result (61% yield of 3aa, entry 3 of
Table 1) was achieved by using two equiv of HCOOH (1.0 mmol) with
respect to I in the step B. A satisfying yield of 96% (entry 4 of Table 1)
was obtained when the benchmark reaction was carried out in me-
thanol, a solvent that, besides ensuring hydrogen production through
methanolysis of NaBH4 [97–99], facilitates the formation of the imine
[17,19]. In this regard, very recently Yan and coworkers indicated
methanol as the most suitable solvent for the reductive amination of
ketones catalyzed by Ru/C, Rh/C, Pd/C and Pt/C systems [100].
By carrying out all the reactions reported in Table 1 in the absence
of Ni-pol, the conversion of nitrobenzene was negligible.
substituted benzaldehydes (2f-i, Table 3, entry 5–8), some of which
being sterically demanding reactants (2f and 2i), excellent yields were
achieved for the corresponding target secondary amines 3af (93%), 3ag
(96%), 3ah (98%) and 3ai (95%) without lowering of the overall re-
action time. When an arylaldehyde with a potential reducible group
such as p-formylbenzonitrile (2j) was screened, a 96% isolated yield
was obtained in the corresponding amine 3aj even if in step C a longer
reaction time (4 h) was necessary (Table 3, entry 9). Finally, hetero-
aromatic aldehydes such as furfural (2k), 3-thiophenecarboxaldehyde
(2l), and 5-bromo-2-thiophenecarboxaldehyde (2k) were tested, and
excellent yields of corresponding amines 3ak (96%), 3al (98%), 3am
(93%) were achieved (Table 3, entries 9–11). Thiophene based amines
3al and 3am required a longer time reaction in step C (4 and 5 h, re-
spectively) but it is worth noting that in the case of 3am no debromi-
nation was observed.
3.3. Recycling of the catalyst, heterogeneity test and scale up
The recyclability of Ni-pol in the reductive amination of benzal-
dehyde (2a) with nitrobenzene (1a) was next considered. From the
handling point of view and for reducing loss of catalyst between dif-
ferent cycles, the benchmark reaction was scaled up to 3.0 mmol of 1a.
As reported in Fig. 1, the catalyst was tested up to five cycles. In each
catalytic cycle, Ni-pol was easily recovered by centrifugation, washed
and rinsed with solvents, dried under air for 2 h at 60 °C, and then
employed for a new run. After a slight decrease of isolated yield of 3aa
in the second run (87% with respect to 96%), in the subsequent cycles
the isolated yield remained almost constant at values above 80%.
Aiming at checking if the catalytic cycle occurred in heterogeneous
or homogeneous phase, the activity of the mother liquor in step A of the
benchmark reaction was analyzed. Ni-pol was filtered off after 15 min
of reaction step A, when 85% conversion of 1a was reached and the
reaction mixture analyzed by GC (internal standard method) reported a
yield in aniline equal to 31%, while the yields in diazobenzene and
diazoxybenzene were 17% and 40%, respectively. Scheme 3 reports the
general accepted reaction pathways (direct and condensation routes)
with relative intermediates for the reduction of nitrobenzene (1a) to
aniline (I) [101–105], explaining the presence of diazo- and diazoxy-
products.
After 2 h 45 min stirring in the absence of Ni-pol, GC analysis of the
reaction mixture revealed that the composition of the reaction mixture
did not change. This observation suggests that Ni-pol works as real
heterogeneous catalyst as also confirmed by graphite furnace atomic
absorption spectroscopy (GFAAS). Ni-pol removed from the mother
liquor after 15 min and Ni-pol re-used for five reaction cycles were
mineralized and analyzed by GFAAS revealing that, within the instru-
mental error, the nickel content of used material was the same of the
pristine catalyst.
3.2. Substrate scope
With the optimized reaction conditions in our hand, we passed to
explore the scope and general applicability of the present catalytic
system, using various combinations of arylaldehydes and nitroarenes.
Results obtained in the reductive amination of benzaldehyde (2a) with
different nitroaromatics (1a-j) and in the reductive amination of dif-
ferent arylaldehydes (2b-n) with nitrobenzene (1a) are reported in
Tables 2 and 3, respectively.
In the reductive amination of 2a, nitroarenes (1b-j) bearing both
electron-donating groups and electron-withdrawing groups were
screened. Among p-halo-nitroarenes (1b-e), an effect of the substituent
on the reaction time of step A and yield of target secondary amines was
observed. Amine 3ba bearing fluorine (Table 2, entry 1) was obtained
in excellent yield (97%) while amines 3ca and 3 da (Table 2, entries
2–3) bearing chlorine and bromine, respectively, were achieved in
slightly lower yields (85% for 3ca and 80% for 3da) after longer re-
action times in step A. The slight decrease of yields was due to a partial
dehalogenation of both intermediate imine and target amine during
step C, as revealed by monitoring the reaction course via GCeMS.
Unfortunately, for amine 3ea bearing iodine (Table 2, entry 4) a severe
dehalogenation was observed, resulting in a moderate yield (50%) in
3 da. In the transformation of nitrotoluenes (Table 2, entries 5–7), no
significant steric effect was observed on the yield of target molecules.
The para (3fa), the meta (3ga) and the ortho (3ha) derivatives were
obtained in 98, 97, and 93% yield respectively. However, amine 3ha
bearing o-methyl group needed a longer reaction time (10 h) for ac-
complishing step A with respect to 2 h necessary for 3fa and 3ga. The
same trend was observed in the transformation of methoxy ni-
trobenzenes (Table 2, entries 8 and 9): high yields were achieved for
amines 3ia (98%) and 3ja (97%).
Finally, we also studied the scalability on one-gram scale of our
developed protocol for the reductive amination. Carrying out the
benchmark reaction on 6.0 mmol of 1a, 1.02 g (93%) of 3aa was iso-
lated, therefore confirming that our protocol is reliably scalable.
In the reductive amination of different arylaldehydes with 1a
(Table 3), we tested first benzaldehydes bearing a halogen (Table 3,
entry 1–4) and, in general, no lowering of the reaction rate was ob-
served. With m-chloro-benzaldehyde (2b) and m-bromo-benzaldehyde
(2c) the yields (Table 3, entries 1 and 2) into the corresponding target
secondary amines 3ab (80%) and 3ac (73%) were good but not ex-
cellent because of a slight partial dehalogenation in step C. On the other
hand, with fluoro-benzaldehydes no dehalogenation of the fluoro group
occured but, contrary to what might be expected, with 2-fluoro-ben-
zaldehyde (2d) a higher yield (93%) of the target secondary amine 3ad
(Table 3, entry 3) was achieved compared to that (72%) of amine 3ae
(Table 3, entry 4) derived from 4-fluoro-benzaldehyde (2e). This ob-
servation points out that, in our catalytic system, electronic effects are
dominating with respect to steric ones. In fact, with various methoxy
3.4. FESEM analyses
The pristine Ni-pol material, as well as the catalyst recovered after
the first and the fifth catalytic cycle, respectively, were inspected by
FESEM analyses with STEM mode, aiming at gaining insights into the
morphology and the dispersion of the nickel active species on the
polymeric support, checking if they change with the recycles.
As already discussed in a previous work [81], pristine Ni-pol sup-
ports Ni nanoparticles (NPs) with diameter comprising between 11 and
37 nm and a few quantity of Ni(0) nanocubes with a cube side of
85–200 nm. FESEM picture of Ni-pol recovered after the first run
(Fig. 2a) shows a homogenously distributed cubic crystals of Ni in the
average cross section value of 35 nm. The particle size distribution is
7

A.M. Fiore, et al.
MolecularCatalysis476(2019)110507
quite narrow (25–45 nm) and monomodal (Fig. 2b), and the crystalline
habitus is very uniform and characteristic of cubic lattice. As already
observed [106], the high degree of nanoparticle dispersion and the
absence of aggregation suggest that the polymer matrix has a strong
confinement effect and an efficient stabilizing feature towards Ni NPs.
Ni NPs in Ni-pol recovered after five cycles (Fig. 2c) are very similar
to those observed in Ni-pol employed in the first run (Fig. 2a), although
some of them start aggregating at the surface of the polymer flake,
explaining why the catalytic activity of the system slightly decreases
with the re-cycles (see Fig. 1). However, FESEM analyses revealed that
in Ni-pol used for five runs the number of small nanoparticles (8–10 nm
in diameter) is higher with respect to the catalyst employed in the first
run. In addition, the smaller the nanoparticles, the more irregular their
shape. These small Ni NPs are very uniformly distributed, as are the
biggest ones, thus generating a bimodal NPs size distribution (Fig. 2d).
The amount of the smallest nanoparticles increases with the re-uses,
presumably due to further formation of Ni NPs under reductive reaction
conditions, as already observed by us [81]. In fact, during thermal
calcination under inert atmosphere only a fraction of the whole amount
of Ni(II) centers passes from +2 to 0 oxidation state giving rise to metal
NPs. The reduction of the remaining quantity of Ni(II) centers to Ni NPs
occurs during duty, thus explaining the broader distribution of Ni NPs
compared to that of the catalyst before use.
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The one-pot stepwise reductive amination of arylaldehydes with
nitroarenes was studied employing reusable nickel nanoparticles sta-
bilized on insoluble acrylamide polymer (Ni-pol) as catalyst and NaBH4
as mild, inexpensive, and safe reducing agent. Although the synthetic
protocol is indirect, the developed catalytic system Ni-pol holds several
advantages such as the use of a non-precious metal catalyst, the facile
separation of the catalyst by centrifugation, an excellent stability to-
wards air and moisture, mild reaction conditions, good recyclability
and scalability as well as broad substrate scope. FESEM analyses
pointed out that in Ni-pol the active species are Ni NPs in the form of
cubic crystals having an average cross section of 35 nm with a quite
narrow (25–45 nm) and monomodal size distribution. Although such
distribution becomes bimodal with the recycling reactions, no ag-
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was preserved.
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