Direct reductive amination of carbonyl compounds with primary/secondary amines using recyclable water-soluble FeII/EDTA complex as catalyst

Article abstract of DOI:10.1016/j.tetlet.2007.12.023

Direct reductive amination of aliphatic, aromatic and heterocyclic carbonyl compounds with primary/secondary amines is reported with water-soluble Fe^II/EDTA complex as a catalyst using low-pressure molecular hydrogen in a biphasic media. The catalyst is highly selective, recyclable and is an excellent replacement for expensive noble metal catalysts or stoichiometric reducing agents.

Full text of DOI:10.1016/j.tetlet.2007.12.023

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 965–969
Direct reductive amination of carbonyl compounds with
primary/secondary amines using recyclable water-soluble
FeII/EDTA complex as catalyst
Malhari D. Bhor, Mayur J. Bhanushali, Nitin S. Nandurkar, Bhalchandra M. Bhanage *
Department of Chemistry, Institute of Chemical Technology, University of Mumbai, N. Parekh Marg, Matunga, Mumbai 400019, India
Received 15 October 2007; revised 24 November 2007; accepted 5 December 2007
Available online 8 December 2007
Abstract
Direct reductive amination of aliphatic, aromatic and heterocyclic carbonyl compounds with primary/secondary amines is reported
with water-soluble FeII/EDTA complex as a catalyst using low-pressure molecular hydrogen in a biphasic media. The catalyst is highly
selective, recyclable and is an excellent replacement for expensive noble metal catalysts or stoichiometric reducing agents.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Water-soluble catalyst; Imines; Hydrogenation; Biphasic catalysis
Amines and their derivatives are used as versatile building
blocks for organic compounds, precursors to biologically
active compounds, pharmaceuticals,1 such as tolterodine
and agrochemicals.2 They are synthesized using various
methods including arylation of amines,3 hydroamination
of olefins,4 reductive amination of carbonyl compounds,5
nitro reduction followed by reductive amination,6 hydro-
cyanation of imines,7 etc. Direct reductive amination
(DRA) of carbonyl compounds with amines is an elegant
and powerful method for producing substituted amines. It
is commonly carried out using borohydride based reducing
agents such as NaBH4,8 NaBH3CN,9 NaBH(OAc)3,10 py-
cal and ecological points of view. DRA is normally carried
out using heterogeneous catalysts,14 however, a few
homogeneous catalysts have been reported.15 Bo¨rner and
co-workers16 and Beller and co-workers17 independently
reported the first homogeneously catalyzed reductive ami-
nation of carbonyl compounds with amines using Rh(I)
complexes as catalysts and Rh/TPPTS catalyst in organic
solvents for the synthesis of primary amines using aq ammo-
nia. Also, Nait Ajjou and Robichaud demonstrated the first
example of DRA of aldehydes with amines using water-sol-
uble transition metal catalysts18 (Pd, Pt, Ir, Rh) along with
water-soluble ligands such as TPPTS and BQC.
ridine–BH3,11 ZnBH4–ZnCl2 and silica gel–ZnBH4.13
Recently, Chaudhari and co-workers19 reported chemo-
selective hydrogenation of nitroaromatics using novel
water-soluble Fe complex catalysts. The catalyst has sev-
eral advantages including lower cost, high TON value
and is an efficient alternative to stoichiometric reductions
using metal catalysts for hydrogenation of nitroaromatics.
Also, Casey and Guan20 reported a chemoselective Fe
catalyst for hydrogenation of ketones. In continuation
of our work on amine synthesis via N-arylation,21 DRA
using Cu(PPh3)2BH4 as the reducing agent in the presence
of sulfamic acid22 and chemoselective hydrogenation of
12
However, most of these methods suffer from the major
drawback of requiring stoichiometric reductant. Also, the
use of NaBH3CN has a risk of residual cyanide; pyridine
borane is thermally unstable and involves handling risks.
Hence, use of a cheaper reductant like molecular hydrogen,
that is, catalytic hydrogenation is attractive from economi-
*
Corresponding author. Tel.: +91 22 24145616; fax: +91 22 24145614.
E-mail address: bhalchandra_bhanage@yahoo.com (B. M. Bhanage).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.023

966
M. D. Bhor et al. / Tetrahedron Letters 49 (2008) 965–969
1
3
conditions using toluene/water as a solvent gave a 60%
yield but with a slower reaction rate without affecting the
selectivity and supports the literature report that the reac-
tion rate is lower in biphasic systems than the respective
homogeneous systems.24 In this context, we preferred not
to use another solvent. In the current system, the reagents
were added to the water phase directly containing the Fe/
EDTA complex. Since, the reagents are liquid and insolu-
ble in the aqueous phase, they form small droplets sus-
pended in a continuous aqueous catalyst phase. This is
typical of biphasic catalysis wherein the catalyst phase acts
as a continuous phase and the reactants form another
phase in the form of small-suspended droplets.25 Due to
elimination of the organic solvent phase, an increased con-
centration of reagents can be achieved leading to a higher
reaction rate.26 The products remained insoluble after reac-
tion and could be separated by simple phase separation or
using extraction techniques. The catalyst phase could be
recycled (Table 1, entry 5). The role of temperature on
the reductive amination was studied (entries 7 and 8). It
was observed that at 100 °C and 120 °C, the reaction rate
was much slower leading to just 62% and 79% yields of
N-benzylaniline, respectively, whereas a better yield of
90% was obtained at 150 °C. EDTA is a well-known
N-containing hexadentate chelating ligand, similarly the
Fe(II) complex of the O-containing chelating ligand
2,2,6,6,-tetramethyl-3,5-heptanedione (TMHD)21a was also
tested. The efficiency of the Fe/EDTA catalyst was also
compared with the conventional Pd/C catalyst and found
to give comparable results (entry 10).5b The best reaction
conditions for DRA were 1 mol % of FeSO4Á7H2O and
EDTA-Na2Á2H2O as ligand (Fe/EDTA ratio of 1:5), which
gave a 90% yield of N-benzylaniline (entry 4).
II
R
N
R
O
1 mol% Fe /EDTA-Na
2
H
N
+
H O
2
+
4
3
2
1
2
4
R
R
R
R
R
R
water,400 psi H , 150 °C,
2
(80-90%)
12 h, 500 rpm
OH
3
(5-10%)
II
1 mol%Fe /EDTA-Na
2
4
1
2
3
4
R , R , R , R = alkyl, aryl, het.
R
R
Scheme 1. DRA of carbonyl compounds with amines catalyzed by FeII/
EDTA.
a,b-unsaturated nitriles,23 we herein report a novel metho-
dology for DRA of carbonyl compounds with primary
and secondary amines using water-soluble FeII/EDTA-Na2
complex as catalyst with molecular hydrogen (Scheme 1).
The reaction was carried out in water as a solvent and
using molecular hydrogen. Moreover, the catalyst is air
stable due to the absence of conventional air sensitive phos-
phine based ligands as in TPPTS.24 Initially, DRA of
benzaldehyde with aniline was chosen as a model reaction
to test the catalytic activity of the water-soluble Fe/EDTA
catalysts. The results are summarized in Table 1, which
show the selective formation of N-benzylaniline. Forma-
tion of a small quantity of benzyl alcohol along with unre-
acted imine accounted for the products obtained indicating
excellent material balance.
When Fe salts such as FeNO3Á9H2O and FeSO4Á7H2O
were used as catalysts without any ligand, low yields of
amine (52% and 66%, respectively) and reduced selectivity
towards the amine as 10–15% of benzyl alcohol was also
observed as a hydrogenation product of benzaldehyde.
The use of ethylenediaminetetraacetic acid disodium salt
dihydrate (EDTA-Na2Á2H2O) as a ligand in combination
with Fe salts led to a significant increase in both selectivity
and yields of amine. Reductive amination under biphasic
The present water-soluble catalyst system was applicable
for DRA of a variety of aliphatic, aromatic and heterocy-
clic aldehydes as well as aliphatic and cyclic ketones with
primary and secondary amines (Table 2).27 Substituted
benzaldehydes (4-methoxy, 4-chloro, 4-cyano) were reduc-
tively aminated with aniline to give N-alkylated amines in
81–84% yields. Formation of dechlorinated or cyano
reduced products were not observed. The catalyst system
was also effective for reductive amination of benzaldehyde
with an aliphatic amine (entry 2) and substituted anilines
(4-methoxy and 3-trifluoromethyl) resulting in N-alkylated
amines in 78%, 86% and 82% yields, respectively. DRA of
benzaldehyde with secondary amines such as piperidine,
morpholine and N-benzylpiperazine was carried out using
the Fe/EDTA catalyst and molecular hydrogen in good
yields (70–74%, entry 5). Aliphatic aldehydes such as pen-
tanal, hexanal and heptanal were found to undergo reduc-
tive amination with aniline with good selectivity towards
amines (entry 6). Similarly, aliphatic or cyclic ketones were
reductively aminated with aniline leading to good yields of
amines (entries 7 and 8). N-Alkylated amines containing a
heterocycle could also be obtained in moderate to good
yields via reductive amination of furfural or thiophene-2-
carboxaldehyde with aniline (entry 9) and benzaldehyde
Table 1
Reductive amination of aniline (A) with benzaldehyde (B)a
Entry
Catalyst
Ligand
Conversion
Yield
Aa
Ba
Cg
Dg
1
2
3
FeNO3Á9H2O
FeSO4Á7H2O
FeNO3Á9H2O
FeSO4Á7H2O
FeSO4Á7H2O
FeSO4Á7H2O
FeSO4Á7H2O
FeSO4Á7H2O
Fe(II)TMHD
10% Pd/C
—
—
99
99
99
99
97
99
95
99
99
99
98
98
98
98
96
97
93
97
96
99
52
66
72
90
85
60
62
79
58
94
15
12
9
EDTA-Na2
EDTA-Na2
EDTA-Na2
EDTA-Na2
EDTA-Na2
EDTA-Na2
—
4
5
5b
6c
7d
8e
9f
10h
a
4
4
3
4
8
4
—
Aniline (A = 5 mmol), benzaldehyde (B = 6 mmol), catalyst
(0.05 mmol), ligand (0.25 mmol), water (20 ml), H2 (400 psi), 150 °C,
500 rpm, 12 h.
b
3rd recycle.
c
Biphasic conditions (toluene 10 ml: water 10 ml).
At 100 °C.
At 120 °C.
Toluene (20 ml) as a solvent.
GC yields of C = N-benzyl aniline; D = benzyl alcohol.
Reaction condition as given in Ref. 5b.
d
e
f
g
h

M. D. Bhor et al. / Tetrahedron Letters 49 (2008) 965–969
967
Table 2
Reductive amination of carbonyl compounds with aminesa
Entry
Carbonyl compound
Amine
Product
Alkylated amine yield (%)
Alcohol yield (%)
CHO
88
84
83
81
5
6
6
5
NH
2
R
1
N
H
a: R = -H
b: R = 4 –OCH3
c: R = 4 –Cl
d: R = 4 –CN
R
CHO
NH
N
H
2
2
3
78
86
8
4
OCH
3
CHO
OCH
3
HN
HN
H N
2
NH
2
CHO
CHO
CF
3
4
82
5
CF
3
5
74
72
70
9
7
8
X
NH
a: X = CH2
b: X = O
X
N
c: X = N-Bz
CHO
n
NH
2
NH
a: n = 2
b: n = 3
c: n = 4
6
81
78
80
5
6
6
n
O
R
R
NH
2
NH
7
70
66
6
4
a: R = -CH3
b: R = -C2H5
O
NH
2
NH
8
62
65
6
6
n
n
a: n = 1
b: n = 2
(continued on next page)

968
M. D. Bhor et al. / Tetrahedron Letters 49 (2008) 965–969
Table 2 (continued)
Entry
Carbonyl compound
Amine
Product
Alkylated amine yield (%)
Alcohol yield (%)
CHO
NH
X
2
72
76
7
5
H
N
9
X
a: X = O
b: X = S
CHO
NH
2
NH
10
52
21
8
2
N
N
CHO
11
N
N
H
a
Reaction conditions: carbonyl comp. (6 mmol), amine (5 mmol), FeSO4Á7H2O (0.05 mmol), EDTA-Na2 (0.25 mmol), water (20 ml), H2 (400 psi),
150 °C, 500 rpm, 12 h.
8. Hutchins, R. O.; Natale, N. R. Org. Prep. Proced. Int. 1979, 11, 201.
9. Borch, R. F.; Bernstien, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971,
93, 2897.
21% yield of the corresponding tertiary amine (entry 11).
10. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.;
with 3-aminopyridine (entry 10). Reductive amination of
benzaldehyde with N,N-diisopropylamine gave only a
In conclusion, we have developed a simple and eco-
Shah, R. D. J. Org. Chem. 1996, 61, 3849.
friendly method for direct reductive amination of aliphatic,
aromatic and heterocyclic carbonyl compounds with
primary and secondary amines. The catalyst system is an
efficient alternative to the noble metal catalysts used in
hydrogenation reactions. The method gives amines selec-
tively and operates at a low pressure of molecular hydrogen
and utilizes environmentally benign water as a solvent.
11. (a) Bomann, M. D.; Guch, I. C.; DiMare, M. J. J. Org. Chem. 1995,
60, 5995; (b) Pelter, A.; Rosser, R. M.; Mills, S. J. Chem. Soc. Perkin
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Acknowledgement
The authors are thankful for financial assistance from
the University Grants Commission, India for a major
research project (Project No. 32-273/2006 (SR)).
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27. Typical procedure for reductive amination of aldehydes and ketones with
amines: To a 100 ml high pressure reactor were added aldehyde or
ketone (6 mmol) and amine (5 mmol) resulting in a white opaque
solution indicating the formation of an imine intermediate. In a 100 ml
beaker, 14 mg (0.05 mmol) of FeSO4Á7H2O (powder form) and 93 mg
(0.25 mmol) of EDTA-Na2Á2H2O were dissolved in water (20 ml). The
resulting clear light green solution was then transferred to the high
pressure reactor. The reaction was then pressurized to 400 psi of
hydrogen, heated to 150 °C and stirred for 12 h at 500 rpm. The
reactor was cooled to room temperature and the remaining hydrogen
was carefully vented and the reactor opened. Ethyl acetate (2 Â 15 ml)
was added to the reactor and the reaction stirred for 15 min to extract
the product. The aqueous layer containing the Fe/EDTA complex was
recycled for the next run after phase separation. The combined extracts
were dried over sodium sulfate and the solvent was evaporated in
vacuo. The reaction mixture was analyzed by GC and the products
were confirmed by GCMS. Compound 1a: 1H NMR (400 MHz,
CDCl3): d = 7.38 (m, 5H), 7.30 (m, 2H), 6.83 (t, J = 7.3 Hz, 1H), 6.74
(d, J = 7.7 Hz, 2H), 4.32 (s, 2H), 4.06 (s, 1H). MS m/z (EI): M+ 183
(68), 91 (100), 182 (28), 106 (20), 77 (19), 65 (18).