Carbon dioxide promoted reductive amination of aldehydes in water mediated by iron powder and catalytic palladium on activated carbon

Article abstract of DOI:10.1016/j.cattod.2016.01.048

A mixture of iron powder and catalytic palladium on activated carbon has been developed for reductive amination of various aromatic aldehydes, including 2-pyridinecarboxaldehyde, in water under CO₂ atmosphere. The reversible reaction of CO₂ with water could form carbonic acid and hydrogen transfer from water to Pd(0) took place with the presence of iron powder, leading to formation of high-active Pd hydrides for the reductive amination process. On the other hand, the reaction system could be inherently neutralized by ready removal of CO₂, thus resulting in facile post-processing.

Full text of DOI:10.1016/j.cattod.2016.01.048

G Model
CATTOD-10020; No. of Pages5
ARTICLE IN PRESS
Catalysis Today xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Catalysis Today
journal homepage: www.elsevier.com/locate/cattod
Carbon dioxide promoted reductive amination of aldehydes in water
mediated by iron powder and catalytic palladium on activated carbon
Ran Maa, Yue-Biao Zhoua, Liang-Nian Hea,b,∗
a State Key Laboratory and Institute of Elemento-Organic Chemistry, China
b Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin 300071, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A mixture of iron powder and catalytic palladium on activated carbon has been developed for reduc-
tive amination of various aromatic aldehydes, including 2-pyridinecarboxaldehyde, in water under CO2
atmosphere. The reversible reaction of CO2 with water could form carbonic acid and hydrogen transfer
from water to Pd(0) took place with the presence of iron powder, leading to formation of high-active Pd
hydrides for the reductive amination process. On the other hand, the reaction system could be inherently
neutralized by ready removal of CO2, thus resulting in facile post-processing.
Received 22 October 2015
Received in revised form
27 December 2015
Accepted 19 January 2016
Available online xxx
© 2016 Elsevier B.V. All rights reserved.
Keywords:
Palladium on activated carbon
Reductive amination
Water
In situ carbonic acid
Iron powder
1. Introduction
improvement in terms of environmentally benign hydrogen source
and easily operated processes with less expensive and less toxic
Preparation of functionalized amines in an effective way has
always been necessary especially in medicinal chemistry and mod-
ern organic synthesis. In this context, direct reductive amination
of carbonyl compounds represents a powerful tool for the prepara-
tion of amine derivatives, which generally includes two steps: the
formation of imines via the reaction of aldehydes or ketones with
amines and subsequent hydrogenation [1–3]. Ecological and eco-
nomic benefits of this kind protocol are obvious since the amount of
solvents, reagents and energy consumption would be dramatically
reduced compared with the stepwise processes. However, despite
being a reaction of proven efficiency, it presents a large drawback
related with the handling of hydrogen gas (flammable and explo-
sive). For this reason, numerous alternative reducing agents that
are mainly rely on precious metals (e.g., Ir, Pt, Rh, Ru) have been
developed, such as active boranes or tin compounds, iso-propanol,
formates, silanes, and so-called Hanztsch esters [4–8]. Recently,
Beller et al. reported the nanostructured iron-catalyst for the tan-
dem reductive amination between nitroarenes and aldehydes using
hydrogen as reductant [9]. While, there is still much room for
metals.
The efficient reduction of water for generation of hydrogen
is one of the most challenging transformations in chemistry and
wateris theultimatehydrogensource, beingbothsafeandplentiful.
In the CO2–H2O two phase system, water is thought to behave as the
terminal hydrogen source with the presence of the reducing metal
such as Fe or Zn because the reversible reaction between CO2 and
H2O could form the carbonic acid with a pH value as low as 3 [10].
And this CO2/H2O system could be inherently neutralized by read-
ily remove of CO2. As an extension of our previous works on the use
of in situ carbonic acid-promoted organic reactions [11], we herein
would like to apply such self-neutralizing acid for the synthesis of
various amine derivatives by the direct reductive amination of alde-
hydes, thus avoiding isolating the imines intermediate (Scheme 1).
Pd/C and iron powder mixture in the CO2/H2O system has been
revealed to be an efficient methodology for the reductive amina-
tion process and satisfactory yields of the one-pot formed amines
were achieved with facilitated post-processing procedures.
2. Experimental
Aldehydes and amines were purchased from Aladdin Reagent
Inc. Pd/C and iron powder was purchased from Alfa Aesar China
Co., Ltd. Distilled water and all other reagents were obtained
∗
Corresponding author at: State Key Laboratory and Institute of Elemento-
Organic Chemistry, China. Fax. +86 2223503878.
E-mail addresses: heln@nankai.edu.cn, helnnk@126.com (L.-N. He).
http://dx.doi.org/10.1016/j.cattod.2016.01.048
0920-5861/© 2016 Elsevier B.V. All rights reserved.
Please cite this article in press as: R. Ma, et al., Carbon dioxide promoted reductive amination of aldehydes in water mediated by iron
powder and catalytic palladium on activated carbon, Catal. Today (2016), http://dx.doi.org/10.1016/j.cattod.2016.01.048

G Model
CATTOD-10020; No. of Pages5
ARTICLE IN PRESS
2
R. Ma et al. / Catalysis Today xxx (2016) xxx–xxx
Scheme 1. Pd/C-catalyzed reductive amination of aldehydes with Fe in CO2/H2O system.
Table 1
Reductive amination with Fe in CO2/H2O systema.
Entry
Catal.
CO2 (MPa)
Conv.b (%)
Yield (%)
3ab
4ab
1
2
3
4
5
6
7
8
–
8
8
8
8
8
8
8
8
8
8
8
8
8
–
–
93
88
94
58
57
50
33
66
92
86
55
57
84
88
–
92
84
93
54
53
39
26
57
73
50
41
50
84
76
–
–
–
–
–
–
6
4
4
19
33
11
1
–
–
ZnCl2
FeCl2
FeBr3
RuCl3
Cu(OTf)2
RhCl3
IrCl3
PdCl2
Pd/C
PdBr2
Pd(OAc)2
Pd/C
9
10
11
12
13c
14
15d
Pd/C
Pd/C
–
a
Reaction conditions: benzaldehyde (1.1 mmol, 116.7 mg), aniline (1 mmol, 93.1 mg), catalyst 5 mol%, H2O (2 mL), Fe (2 mmol, 111.7 mg), 80 ◦C, 10 h.
Conversion and yield were relative to primary amine and determined by GC with biphenyl as the internal standard.
Without Fe.
H2 balloon, toluene was detected.
b
c
d
Table 2
commercially from Tianjin Guangfu Fine Chemical Research Insti-
tute and used without further purification. 1H NMR spectra was
recorded with a Bruker 400 spectrometer in CDCl3 and CDCl3
(7.26 ppm) was used as the internal reference. 13C NMR was
recorded at 100.6 MHz in CDCl3 and CDCl3 (77.0 ppm) was used as
the internal reference. GC–MS datas were collected on a Finnigan
HPG1800 A. GC analyses were performed on a Shimadzu GC-2014,
equipped with a capillary column (RTX-17, 30 m × 0.25 ␮m) using
a flame ionization detector.
Optimization of the reaction parametersa.
Entry
CO2 (MPa)
H2O (mL)
Temp. (◦C)
Conv.b (%)
Yield 4ab (%)
1
2
3
4
8
8
12
4
8
2
3
3
3
3
3
80
80
80
80
80
80
86
85
81
87
84
93
33
45
17
34
52
75
5c
6c,d
8
a
Unless otherwise stated, all the reactions were carried out with 1.1 mmol 1a and
1.0 mmol 2a in 2 mL solvent in the presence of Pd/C and Fe, at 80 ◦C for 10 h.
b
Conversion and yield were based on primary amines and determined by GC with
2.1. Reduction amination of aldehydes with Fe powder in
CO2/H2O
biphenyl as the internal standard.
c
Fe (3 mmol, 167.5 mg).
15 h.
d
A mixture of aldehyde (1.1 mmol), amine (1 mmol), Fe (3 mmol,
167.5 mg), Pd/C (Palladium on activated carbon 5% Pd, 106.4 mg),
H2O (3 mL) was placed in a 50 mL stainless steel autoclave equipped
with an inner glass tube at room temperature. The vessel was sealed
and CO2 was subsequently introduced into the autoclave, which
was then heated under the predetermined reaction temperature for
25 min to reach the equilibration. The final pressure was adjusted
to the desired pressure by introducing the correct amount of CO2.
After the reaction was finished, the vessel was cooled within an
ice-bath and the pressure was released slowly to atmospheric pres-
sure. The products were diluted with ethyl acetate and analyzed by
GC. The residue was purified by column chromatography on sil-
ica gel (200–300 mesh, eluting with n-hexane and ethyl acetate)
to afford the desired product. The isolated products were further
identified with NMR spectra and GC–MS, which are consistent with
those reported in the literature.
Please cite this article in press as: R. Ma, et al., Carbon dioxide promoted reductive amination of aldehydes in water mediated by iron
powder and catalytic palladium on activated carbon, Catal. Today (2016), http://dx.doi.org/10.1016/j.cattod.2016.01.048

G Model
CATTOD-10020; No. of Pages5
ARTICLE IN PRESS
R. Ma et al. / Catalysis Today xxx (2016) xxx–xxx
3
Table 3
Reductive amination of aromatic aldehydes with different aminesa.
Entry
Aldehyde
Amine
Product
Yield (%)b
1
2
75
82
3
4
74
60
5
44
6
7
60
63
8c
37
9
11
a
Reaction conditions: aldehyde (1.1 mmol), amine (1 mmol), Pd/C (Palladium on activated carbon, 5% Pd, 106.4 mg), Fe (3 mmol, 167.5 mg), H2O 3 mL, CO2 8 MPa, 80 ◦C,
15 h.
b
Yield was based on primary amines and determined by 1H NMR yield with 1,1,2,2-tetrachloroethane as the internal standard.
100 ◦C.
c
Scheme 2. Isotope labeling experiments.
3. Results and discussion
any catalyst, and imine 3a was obtained in high yield with or with-
out CO2 (entry 1) [12]. Then, a series of catalysts were screened. As a
result, Lewis acid catalysts such as zinc(II), iron(II) or iron(III), Ru(III)
salts were almost inactive for the formation of 4a, but were favor-
able for 3a formation in moderate to high yield (entries 2–5). The
In our initial investigation, the reductive amination of benzalde-
hyde 1a with aniline 2a in reversible CO2/H2O system was carried
out (Table 1). No desired product 4a was detected in the absence of
Please cite this article in press as: R. Ma, et al., Carbon dioxide promoted reductive amination of aldehydes in water mediated by iron
powder and catalytic palladium on activated carbon, Catal. Today (2016), http://dx.doi.org/10.1016/j.cattod.2016.01.048

G Model
CATTOD-10020; No. of Pages5
ARTICLE IN PRESS
4
R. Ma et al. / Catalysis Today xxx (2016) xxx–xxx
Scheme 3. Suggested mechanism for the reductive amination.
possible reason is that these Lewis acidic metal catalysts may have
an influence on the formation of imines from the primary amine and
aldehydes or promote the imine hydrolysis. Trace amount of 4a was
just detected when Cu(II), Rh(III) and Ir(III) salts were employed
(entries 6–8). Notably, surplus benzaldehyde was hydrogenated to
benzyl alcohol in this Fe/CO2/H2O system detected by GC–MS. [10a]
Pd catalysts such as Pd/C and PdCl2, gave the target amine 4a in sig-
nificant yields. Whereas, PdBr2 just exhibited poorer performance
and Pd(OAc)2 was inactive in terms of producing 4a (entries 9–12).
Control experiments were turned out to prove the synergistic effect
between the iron powder and carbonic acid in situ formed (entries
13–14). No amine product 4a was detected in the absence of either
iron powder or CO2, thus demonstrating the promotion effect of
CO2 and iron powder in the hydrogen transfer from water to imine
intermediate (entries 13–14). On the other hand, when H2 (balloon)
was used as direct hydrogen resource, only toluene was observed
as a hydrogenation product of benzaldehyde (entry 15).
Water was used as the terminal hydrogen source and solvent
in this CO2 promoted reductive amination process, and 3 mL of
water could reach an adequate point for better yield with suffi-
cient proton donor (Table 2, entries 1 vs 2). On the other hand, CO2
pressure certainly has a significant influence on the reduction reac-
tion through tuning the acidity of the CO2/H2O biphasic system
[13]. In this context, the optimal CO2 pressure was screened out
as listed in Table 2. As expected, lower CO2 pressure would cause
deficient proton concentration (entry 4) and an optimal productiv-
ity of 4a was attained at the supercritical state of 8 MPa. But further
pumping CO2 to 12 MPa would be unfavorable (entry 3), proba-
bly owing to the dilution effect by high density CO2, thereby would
cause inefficiency of reductive amination. Increasing the amount of
iron powder revealed feasible, leading to a remarkably enhanced
4a yield (entry 5). Finally, good yields (> 70%) of 4a was obtained
with the extending the reaction time to 15 h (entries 6).
(entry 6). Satisfactory yield of 4 g was obtained through reduc-
tive amination of benzaldehyde 1a with m-toluidine 2c (entry 7).
1-naphthylamine 2d showed poorer performance even at an ele-
vated temperature, providing low yield of 4 h (entry 8). While,
2,6-dimethylaniline only furnished 11% yield of 4i, probably due
to the steric hindrance (entry 9).
In order to illuminate the actual proton donator of water,
isotope-labeling experiment was run in D2O instead of H2O as
depicted in Scheme 2. The deuterium position at the C N double
bond of final hydrolytic product (NMR and MS, see supporting infor-
mation), suggesting the hydrogen transfer from water to the imine,
followed by solvolysis with a trace amount of water (m/z = 184).
At this point we can propose a mechanism in which water can
act as hydrogen donor in the presence of CO2 promoted reductive
amination with metals mixture Pd/C/Fe (Scheme 3). In this mech-
anism two sequential paths for the hydrogen transference from
water to imine intermediate are proposed. The first step implies a
hydrogen transfer from water to Pd(0), leading to the formation of
the high-active Pd hydrides (Scheme 1) [14]. Then, the generated Pd
hydrides are able to hydrogenate the imine intermediate to amine
product, accompanied by the regeneration of Pd(0) catalyst.
4. Conclusion
In summary, we have developed an effective process for the
reductive amination of aldehydes mediated by Pd/C/Fe mixture.
With the promotion of CO2, water serves as solvent and termi-
nal hydrogen source. The work-up process could be inherently
neutralized by simple depressurization. Various amine derivatives
were obtained in good to excellent yield through the reductive
amination of aromatic, 2-pyridinecarboxaldehyde with different
substituted aromatic amines. Accordingly, the findings uncovered
in the present study could provide an industrially feasible route for
amines, and would also broaden the application of CO2 in green
chemical processes as a reaction medium and promoter.
The generality and feasibility of the present protocol were then
evaluated by performing the reductive amination with a broad
range of aldehydes with various amines under optimal reaction
conditions. As shown in Table 3, a variety of substituted ben-
zaldehydes were smoothly aminated and hydrogenated in good to
excellent yields. Aldehydes with CH3 or OCH3 at para-position
successfully gave the amine 4b,c in up to 82% yield (Table 3, entries
2–3). Heteroaromatic aldehyde, i.e., 2-pyridinecarboxaldehyde was
also readily converted to the corresponding amines through the
reductive amination with aniline 2a or p-anisidine 2b (entries 4–5).
Then, the reductive amination of different aromatic amines with
benzaldehyde 1a was investigated. Aniline with electron-donating
group 2b was transformed into the desired amines in 60% yield
Acknowledgments
We are grateful to the National Natural Sciences Foundation of
China, the Specialized Research Fund for the Doctoral Program of
Higher Education (20130031110013), the MOE Innovation Team
(IRT13022) of China, and the “111” Project of Ministry of Education
of China (project No. B06005) for financial support.
Please cite this article in press as: R. Ma, et al., Carbon dioxide promoted reductive amination of aldehydes in water mediated by iron
powder and catalytic palladium on activated carbon, Catal. Today (2016), http://dx.doi.org/10.1016/j.cattod.2016.01.048

G Model
CATTOD-10020; No. of Pages5
ARTICLE IN PRESS
R. Ma et al. / Catalysis Today xxx (2016) xxx–xxx
5
Appendix A. Supplementary data
[7] (a) M. Kitamura, D. Lee, S. Hayashi, S. Tanaka, M. Yoshimura, J. Org. Chem. 67
(2002) 8685–8687;
(b) R. Kadyrov, T.H. Riermeier, Angew. Chem. Int. Ed. 42 (2003) 5472–5474.
[8] (a) S. Hoffmann, M. Nicoletti, B. List, J. Am. Chem. Soc. 128 (2006)
13074–13075.
[9] T. Stemmler, A.-E. Surkus, M.-M. Pohl, K. Junge, M. Beller, ChemSusChem 7
(2014) 3012–3016.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.cattod.2016.01.
048.
[10] (a) G. Li, H. Jiang, J. Li, Green Chem. 3 (2001) 250–251.
[11] (a) R. Ma, A.-H. Liu, C.-B. Huang, X.-D. Li, L.-N. He, Green Chem. 15 (2013)
1274–1279.
References
[12] (a) K. Tanaka, R. Shiraishi, Green Chem. 2 (2000) 272–273.
[13] (a) K.L. Toews, R.M. Shroll, C.M. Wai, N.G. Smart, Anal. Chem. 67 (1995)
4040–4043;
(c) C. Roosen, M.A. Schumacher, T. Mang, W. Leitner, L. Greiner, Green Chem.
9 (2007) 455–458.
[14] B. Abarca, R. Adam, R. Ballesteros, Org. Biomol. Chem. 10 (2012) 1826–1833.
[1] J.F. Hartwig, Acc. Chem. Res. 41 (2008) 1534–1544.
[2] A.W. Czarnik, Acc. Chem. Res. 29 (1996) 112–113.
[3] H.-U. Blaser, C. Malan, B. Pugin, F. Spindler, H. Steiner, M. Studer, Adv. Synth.
Catal. 345 (2003) 103–151.
[4] (a) W. Tang, X. Zhang, Chem. Rev. 103 (2003) 3029–3070.
[5] P.S. Reddy, S. Kanjilal, S. Sunitha, R.B.N. Prasad, Tetrahedron Lett. 48 (2007)
8807–8810.
[6] (a) T. Suwa, I. Shibata, K. Nishino, A. Baba, Org. Lett. 1 (1999) 1579–1581.
Please cite this article in press as: R. Ma, et al., Carbon dioxide promoted reductive amination of aldehydes in water mediated by iron
powder and catalytic palladium on activated carbon, Catal. Today (2016), http://dx.doi.org/10.1016/j.cattod.2016.01.048