Hydrogen-transfer reductive amination of aldehydes catalysed by nickel nanoparticles

Article abstract of DOI:10.1055/s-2008-1072748

Nickel nanoparticles have been found to catalyse the reductive amination of aldehydes by transfer hydrogenation with isopropanol at 76°C. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072748

LETTER
1289
Hydrogen-Transfer Reductive Amination of Aldehydes Catalysed by Nickel
Nanoparticles
R
eductive Am
r
ination
o
a
f
A
ldehyde
n
s
cisco Alonso,* Paola Riente, Miguel Yus*
Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Química Orgánica (ISO), Universidad de Alicante, Apdo. 99,
03080 Alicante, Spain
Fax +34(96)5903549; E-mail: falonso@ua.es; E-mail: yus@ua.es
Received 12 February 2008
Dedicated to Professor Dieter Seebach on the occasion of his 70th birthday
O
OH
Ni nanoparticles (20 mol%)
i-PrOH, 76 °C
Abstract: Nickel nanoparticles have been found to catalyse the re-
ductive amination of aldehydes by transfer hydrogenation with iso-
propanol at 76 °C.
R1
R2
R1
R2
30–90%
R1 = aryl; R2 = H, alkyl, vinyl
R1, R2 = alkyl
R1–R2 = cycloalkyl fragment
Key words: reductive amination, aldehydes, imines, nickel nano-
particles, hydrogen transfer, amines
Scheme 1 Hydrogen-transfer reduction of carbonyl compounds ca-
talysed by nickel nanoparticles
The reduction of imines is a very useful transformation in
organic synthesis since the resulting amines have wide-
spread applications in industry and in synthetic organic
chemistry. Three general methods for this reaction can be
highlighted involving the use of (a) metal hydrides, (b)
dissolving metals, and (c) catalytic hydrogenation.1 The
reductive amination of aldehydes and ketones, an impor-
tant transformation in biological systems, is, however, a
more direct and convenient route to amines.2 The reduc-
tive amination with metal hydrides3 or by catalytic
hydrogenation4 are the most practiced methods, whereas
transfer hydrogenation is more restricted to the reduction
of preformed imines.5
Hydrogen-transfer reactions6 are advantageous with re-
spect to other reduction methods for several reasons: (a)
the hydrogen donor is easy to handle (no gas containment
or pressure vessels are necessary), cheap and environmen-
tally friendly (e.g., isopropanol), (b) possible hazards are
minimized, (c) the mild reaction conditions applied can
afford enhanced selectivity, and (d) catalytic asymmetric
transfer hydrogenation can be applied in the presence of
chiral ligands.7 These reactions are mostly performed un-
der homogeneous conditions in the presence of noble-
metal complexes, whereas less attention has been paid to
processes under heterogeneous conditions or involving
non-noble metals.
imines. Reductive aminations involving nickel were per-
formed with hydrazine using borohydride exchange res-
in–nickel acetate11 (for primary amines) or with
stoichiometric nickel boride in methanol.12 On the other
hand, the transfer hydrogenation of preformed imines was
carried out with isopropanol and excess aluminum isopro-
poxide in the presence of Raney nickel (the reaction failed
in the absence of aluminum isopropoxide),13 or with sodi-
um isopropoxide catalysed by a nickel(0)–N-heterocyclic
carbene complex.14 However, to the best of our knowl-
edge, nickel-mediated reductive amination reactions by
transfer hydrogenation have never been reported.
We want to report herein the first application of nickel, in
the form of nanoparticles, to the hydrogen-transfer reduc-
tive amination of aldehydes, using isopropanol as the hy-
drogen source in the absence of any added base.
The nickel nanoparticles (NiNPs) were generated from
anhydrous nickel(II) chloride, lithium powder, and a cat-
alytic amount of DTBB (4,4¢-di-tert-butylbiphenyl, 5
mol%) in THF at room temperature. A preliminary study
was carried out using benzaldehyde and aniline as model
substrates in order to optimise the amount of catalyst and
compare with other nickel catalysts (Table 1). A 1:1
NiNPs/substrate molar ratio showed to be very effective
with a fast and high conversion into the product N-benzyl-
aniline (entry 1). A 1:5 NiNPs/substrate molar ratio (20
mol% Ni) showed a similar conversion to that in the sto-
ichiometric reaction though longer time was needed (en-
try 2), whereas the yield dropped drastically by using a
1:10 NiNPs/substrate molar ratio (10 mol% Ni). It is note-
worthy that under the same conditions as in entry 2, the
commercially available Raney nickel (entry 4) and Ni/
Al2O3 (entry 5) led to the formation of the corresponding
imine, which did not undergo reduction at all. The imine
was also the only reaction product when the reaction was
carried out in the absence of any catalyst (entry 6). In view
of the above results, we decided that the reaction condi-
tions involving 20 mol% NiNPs were the most convenient
In this sense, and due to our ongoing interest on the reac-
tivity of active metals,8 we have recently reported the first
application of well-defined nickel(0) nanoparticles9 to the
transfer hydrogenation with isopropanol of a variety of
carbonyl compounds in the absence of any added base at
76 °C (Scheme 1).10 It is noteworthy that, in contrast with
other transition metals, nickel has been scarcely used in
reductive aminations or in the transfer hydrogenation of
SYNLETT 2008, No. 9, pp 1289–1292
x
x.
x
x.
2
0
0
8
Advanced online publication: 07.05.2008
DOI: 10.1055/s-2008-1072748; Art ID: D05308ST
© Georg Thieme Verlag Stuttgart · New York

1290
F. Alonso et al.
LETTER
NiNPs (20 mol%)
i-PrOH, 76 °C
Table 1 Hydrogen-Transfer Reductive Amination of Benzaldehyde
with Aniline in the Presence of Different Nickel Catalysts
R2
R1CHO
+
R2NH2
R1
N
H
Ni catalyst
Ph
Scheme 2 Reagents and conditions: aldehyde (5 mmol), amine (5
mmol), NiNPs (1 mmol), i-PrOH (10 mL), 76 °C.
+
Ph
N
PhCHO
PhNH2
H
i-PrOH, 76 °C
Entry
Ni catalyst/substrate (mmol)
NiNPs 1:1
Time (h) Yield (%)a
to study the scope of this reductive amination (Scheme 2
and Table 2).
1
2
3
4
5
6
1
96
91
8
The optimised reaction conditions were first applied to the
reductive amination of benzaldehyde with different kinds
of primary amines (Table 2).15 Moderate-to-excellent
yields of the corresponding N-benzylanilines were ob-
tained for aniline as well as for para-, ortho- or meta-sub-
stituted anilines (entries 1–4). The primary alkyl amine
octan-1-amine led to N-benzyloctan-1-amine in high yield
(entry 5), whereas phenethylamine reacted in a modest
yield (entry 6). Two benzylic amines were also studied,
the more hindered a-methylbenzylamine (entry 8) show-
ing a better performance than benzylamine (entry 7).
NiNPs 1:5
9
NiNPs 1:10
24
24
24
24
Raney Ni 1:5
Ni/Al2O3 1:5
none
0b
0b
0b
a GLC yield.
b The corresponding imine was obtained.
Table 2 Reductive Amination of Aldehydes by Hydrogen Transfer with Isopropanol Catalysed by Nickel Nanoparticles
Entry
1
Aldehyde
PhCHO
Amine
PhNH2
Time (h)
9
Producta
Yield (%)b
73
Ph
Ph
Ph
Ph
N
H
NH2
2
3
PhCHO
PhCHO
10
12
65
N
H
NH2
99c
N
H
OMe
MeO
NH2
4
5
PhCHO
PhCHO
8
80
Ph
Ph
N
H
OMe
OMe
NH2
10
90c
NH2
N
H
7
7
Ph
6
7
PhCHO
PhCHO
24
8
43
77
Ph
Ph
N
H
Ph
Ph
N
H
Ph
Ph
NH2
8
9
PhCHO
12
4
92c
97c
Ph
N
H
Ph
NH2
CHO
CHO
CHO
Ph
N
H
PhNH2
85c
87
N
H
10
11
6
7
NH2
7
N
H
10
NH2
CHO
Ph
N
H
NH2
12
24
80
Ph
Synlett 2008, No. 9, 1289–1292 © Thieme Stuttgart · New York

LETTER
Reductive Amination of Aldehydes
1291
Table 2 Reductive Amination of Aldehydes by Hydrogen Transfer with Isopropanol Catalysed by Nickel Nanoparticles (continued)
Entry
13
Aldehyde
Amine
Time (h)
24
Producta
Yield (%)b
40
CHO
N
H
Ph
Ph
Ph
NH2
CHO
N
H
14
15
PhNH2
6
8
44
MeO
MeO
MeO
CHO
NH2
98c
N
H
MeO
MeO
CHO
CHO
36d
99c
N
H
16
17
6
7
NH2
7
MeO
MeO
Ph
N
H
12
NH2
Ph
MeO
O
H
N
18
19
20
48
48
12
30
NH2
CHO
7
O
7
H
PhNH2
PhNH2
30d
70
N
CHO
Ph
8
8
CHO
Ph
N
H
a All isolated products were ≥ 95% pure (GLC and/or 1H NMR).
b Isolated yield after column chromatography unless otherwise stated.
c Crude yield.
d GLC yield.
We next studied the reactivity of substituted benzalde- fer reductive amination in good isolated yield (entry 20).
hydes with different amines under the above reaction con- Unfortunately, any attempt to reuse the nickel nanoparti-
ditions. 4-Methylbenzaldehyde reacted nicely with cles failed.16
aniline (entry 9) or with the alkanamines octan-1-amine
In conclusion, we have demonstrated for the first time that
(entry 10), 2-methylpropan-1-amine (entry 11), and phen-
nickel, in the form of nanoparticles, can catalyse the re-
ethylamine (entry 12). The reaction of this substrate with
ductive amination of aldehydes by transfer hydrogena-
benzylamine was, however, rather limited (entry 13). It is
tion, using isopropanol as the hydrogen source in the
noteworthy that aniline and octan-1-amine, which gave
absence of any added base. The process is especially ef-
good results in the reaction with 4-methylbenzaldehyde,
fective in the reductive amination of aromatic aldehydes,
led to much lower yields in the reaction with 4-methoxy-
most of the corresponding secondary amines being ob-
benzaldehyde (compare entries 9 and 10 with 14 and 16,
tained in good-to-excellent yields. The application to ali-
respectively). On the other hand, 4-methylaniline and
phatic aldehydes is, however, more limited. In general,
phenethylamine provided the corresponding secondary
this methodology is advantageous because (a) the prepa-
ration step of the imine is avoided, aldehydes and amines
amines in excellent yields (entries 15 and 17).
Some other aldehydes showed to be more reluctant to un- being directly used as starting materials, (b) the source of
dergo the title reaction. For instance, the reductive amina- hydrogen is isopropanol, a cheap and environmentally
tion of furfural with octan-1-amine proceeded in rather friendly solvent, and (c) the nickel nanoparticles have
low yield (entry 18). A similar behaviour was observed been shown to be superior to other nickel catalysts in this
for linear alkyl-substituted aldehydes such as decanal (en- reaction.
try 19). In these two examples, as well as in most of the
products in which the yields were moderate to low, the
secondary amines were accompanied by variable amounts
Acknowledgment
This work was generously supported by the Spanish Ministerio de
Educación Ciencia (MEC; grants CTQ2004-01261 and
CTQ2007-65218; Consolider Ingenio 2010-CSD2007-00006) and
the Generalitat Valenciana (GV; grants GRUPOS03/135 and
GV05/005). P.R. thanks the MEC for a predoctoral grant.
of the corresponding precursor imines. Nonetheless, sep-
aration of the desired amine could be easily accomplished
by column chromatography. Finally, cyclohexanecarbox-
aldehyde underwent the nickel-catalysed hydrogen-trans-
y
Synlett 2008, No. 9, 1289–1292 © Thieme Stuttgart · New York

1292
F. Alonso et al.
LETTER
dibenzylamine, and N-benzyl-1-phenylethanamine were
References and Notes
characterized by comparison of their physical and
spectroscopic analyses with those of commercially available
samples (Aldrich). N-Benzyl-4-methylaniline,17 N-benzyl-
2-methylaniline,17 N-benzyl-3,5-dimethoxyaniline,18 N-
benzyloctan-1-amine,19 N-(4-methylbenzyl)aniline,20 N-(4-
methylbenzyl)octan-1-amine,21 N-(4-methylbenzyl)-2-
phenylethanamine,22 N-benzyl-4-methylbenzylamine,23 N-
(4-methoxybenzyl)aniline,24 N-(4-methoxybenzyl)-4-
methylaniline,25 N-(4-methoxybenzyl)octan-1-amine,21 N-
(4-methoxybenzyl)-2-phenylethanamine,26 N-[(furan-2-
yl)methyl]octan-1-amine, N-(n-decyl)aniline,27 and N-
(cyclohexylmethyl)aniline28 were characterised by
comparison of their physical and spectroscopic data with
those described in the literature.
(1) For monographs and reviews, see: (a) Comprehensive
Organic Synthesis, Vol. 8; Trost, M. B.; Fleming, I., Eds.;
Pergamon: Oxford, 1991. (b) Hudlický, M. Reductions in
Organic Chemistry, 2nd ed.; ACS: Washington, D. C.,
1996. (c) Singaram, B.; Goralski, C. T. In Transition Metals
for Organic Synthesis, Vol. 2; Beller, M.; Bolm, C., Eds.;
Wiley-VCH: Weinheim, 1998, 147.
(2) For reviews, see: (a) Tarasevich, V. A.; Kozlov, N. G. Russ.
Chem. Rev. 1999, 68, 55. (b) Gomez, S.; Peters, J. A.;
Maschmeyer, T. Adv. Synth. Catal. 2002, 344, 1037.
(3) For reviews, see: (a) Baxter, E. W.; Reitz, A. B. Org. React.
2002, 59, 1. (b) Abdel Magid, A. F.; Mehrman, S. J. Org.
Process Res. Dev. 2006, 10, 971.
(4) For reviews, see: (a) Tararov, V. I.; Kadyrov, R.; Riermeier,
T. H.; Dingerdissen, U.; Boerner, A. Org. Prep. Proced. Int.
2004, 36, 99. (b) Tararov, V. I.; Boerner, A. Synlett 2005,
203.
(5) For a review, see: Roszkowski, P.; Czarnocki, Z. Mini-Rev.
Org. Chem. 2007, 4, 190.
(6) For reviews, see: (a) Johnstone, R. A. W.; Wilby, A. H.
Chem. Rev. 1985, 85, 129. (b) Kellogg, R. M. In
Comprehensive Organic Synthesis, Vol. 8; Trost, B. M.;
Fleming, I., Eds.; Pergamon: Oxford, 1991, Chap. 1.3.
(c) Bäckvall, J. E. J. Organomet. Chem. 2002, 652, 105.
(7) For reviews, see: (a) Blaser, H.-U.; Spindler, F. In
Comprehensive Asymmetric Catalysis, Vol. 1; Jacobsen, E.
N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer: Berlin, 1999,
247. (b) Ohkuma, T.; Noyori, R. In Comprehensive
Asymmetric Catalysis, Suppl. 1; Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Eds.; Springer: Berlin, 2004, 43.
(8) For reviews, see: (a) Alonso, F.; Yus, M. Chem. Soc. Rev.
2004, 33, 284. (b) Alonso, F.; Yus, M. Pure Appl. Chem.
2008, 80, 1005.
(9) (a) Alonso, F.; Calvino, J. J.; Osante, I.; Yus, M. Chem. Lett.
2005, 34, 1262. (b) Alonso, F.; Calvino, J. J.; Osante, I.;
Yus, M. J. Exp. Nanosci. 2006, 1, 419.
(10) (a) Alonso, F.; Riente, P.; Yus, M. Tetrahedron 2008, 64,
1847. (b) Alonso, F.; Riente, P.; Yus, M. Tetrahedron Lett.
2008, 49, 1939.
Spectroscopic Data of New Compounds
N-(4-Methylbenzyl)-2-methylpropan-1-amine
Yellow oil; Rf = 0.18 (hexane–EtOAc, 1:1). IR (neat): 3345
cm–1. 1H NMR (300 MHz, CDCl3): d = 0.91 (d, J = 6.7, 6 H,
2 × CH3CH), 1.69 (br s, 1 H, NH), 1.76–1.85 (m, 1 H,
CHCH3), 2.34 (s, 3 H, CH3C), 2.42 (d, J = 7.0, 2 H, CH2CH),
3.71 (s, 2 H, CH2C), 7.15, 7.19 (AB system, J = 8.2, 4 H,
ArH). 13C NMR (75 MHz, CDCl3): d = 20.2, 20.8 (3 × CH3),
27.5 (CHCH3), 53.1, 56.6 (2 × CH2), 128.0, 129.0 (4 ×
ArCH), 136.0, 137.0 (2 × ArC). MS (70 eV): m/z = 177
[M+], 134, 106, 105, 77. HRMS: m/z [M+] calcd for C12H19N:
177.1517; found: 177.1516.
N-[(Furan-2-yl)methyl]octan-1-amine
Yellow oil; Rf = 0.24 (hexane–EtOAc, 1:1). IR (neat): 3325
cm–1. 1H NMR (300 MHz, CDCl3): d = 0.86 (t, J = 6.2, 3 H,
CH3), 1.26 [br s, 10 H, (CH2)5CH3], 1.48 (m, 2 H,
CH2CH2N), 1.98 (br s, 1 H, NH), 2.59 (t, J = 6.9, 2 H,
CH2CH2N), 3.77 (s, 2 H, CH2C), 6.16, 6.30, 7.35 (3 s, 3 H,
ArH). 13C NMR (75 MHz, CDCl3): d = 14.0 (CH3), 22.6,
27.3, 29.2, 29.4, 29.9, 31.7, 46.2, 49.1 (8 × CH2), 106.7,
110.0, 142.0 (3 × ArCH), 154.0 (ArC). MS (70 eV):
m/z = 209 [M+], 110, 81. HRMS: m/z [M+] calcd for
C13H23NO: 209.1779; found: 209.1777.
(16) In principle, deactivation of the catalyst cannot be attributed
to particle agglomeration as confirmed by transmission
electron microscopy (TEM) analysis of a sample of the
reused suspension. Further studies to understand the
properties, reactivity, and deactivation mechanism of the
catalyst are under way.
(11) Nah, J. H.; Kim, S. Y.; Yoon, N. M. Bull. Korean Chem. Soc.
1998, 19, 269.
(12) Saxena, I.; Borah, R.; Sarma, J. C. J. Chem. Soc., Perkin
Trans. 1 2000, 503.
(13) Botta, M.; De Angelis, F.; Gambacorta, A.; Labbiento, L.;
Nicoletti, R. J. Org. Chem. 1985, 50, 1916.
(14) Khul, S.; Schneider, R.; Fort, Y. Organometallics 2003, 22,
4184.
(15) General Procedure for the Hydrogen-Transfer
Reductive Amination of Aldehydes Catalysed by Nickel
Nanoparticles
(17) Zhu, X.; Ma, Y.; Su, L.; Song, H.; Chen, G.; Liang, D.; Wan,
Y. Synthesis 2006, 3955.
(18) Yamazaki, S.; Yamamoto, M.; Morikawa, S. Heterocycles
2006, 67, 269.
(19) Cho, B. T.; Kang, S. K. Tetrahedron 2005, 61, 5725.
(20) Byun, E.; Hong, B.; De Castro, K. A.; Lim, M.; Rhee, H.
J. Org. Chem. 2007, 72, 9815.
(21) Reddy, P. S.; Kanjilal, S.; Sunitha, S.; Prasad, B. N.
Tetrahedron Lett. 2007, 48, 8807.
(22) Hamana, H.; Iwasaki, F.; Nagashima, H.; Hattori, K.;
Hagiwara, T.; Narita, T. Bull. Chem. Soc. Jpn. 1992, 65,
1109.
(23) Shi, M.; Shen, Y. M. Helv. Chim. Acta 2001, 84, 3357.
(24) Varma, R. S.; Dahiya, R. Tetrahedron 1998, 54, 6293.
(25) Sing, S.; Kaur, U. Indian J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem. 1987, 26, 199.
A solution of the aldehyde (5 mmol) and the amine (5 mmol)
was prepared in i-PrOH (10 mL) and stirred for about 1 h.
Meanwhile, NiCl2 (130 mg, 1 mmol) was added over a
suspension of lithium (14 mg, 2 mmol) and DTBB (13 mg,
0.05 mmol) in THF (2 mL) at r.t. under argon. The reaction
mixture, which was initially dark blue, changed to black
indicating that nickel(0) was formed. After 10 min, the
initially prepared solution of the aldehyde and amine was
added to the nickel suspension. The reaction mixture was
warmed up to 76 °C and monitored by GLC-MS. The
resulting suspension was filtered through a pad containing
Celite and the filtrate was dried over MgSO4. The residue
obtained after removal of the solvent (15 Torr), when
necessary, was purified by column chromatography (SiO2,
hexane–EtOAc) to give the pure secondary amine.
N-Benzylaniline, N-benzyl-2-phenylethanamine,
(26) Horrillo Martínez, P.; Hultzsch, K. C.; Gil, A.; Branchadell,
V. Eur. J. Org. Chem. 2007, 3311.
(27) Moglie, Y.; Alonso, F.; Vitale, C.; Yus, M.; Radivoy, G.
Tetrahedron 2006, 62, 2812.
(28) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;
Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849.
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