Mild Hydrogenation of Amides to Amines over a Platinum-Vanadium Bimetallic Catalyst

Article abstract of DOI:10.1002/anie.201704199

Hydrogenation of amides to amines is an important reaction, but the need for high temperatures and H₂ pressures is a problem. Catalysts that are effective under mild reaction conditions, that is, lower than 30 bar H₂ and 70 °C, have not yet been reported. Here, the mild hydrogenation of amides was achieved for the first time by using a Pt-V bimetallic catalyst. Amide hydrogenation, at either 1 bar H₂ at 70 °C or 5 bar H₂ at room temperature was achieved using the bimetallic catalyst. The mild reaction conditions enable highly selective hydrogenation of various amides to the corresponding amines, while inhibiting arene hydrogenation. Catalyst characterization showed that the origin of the catalytic activity for the bimetallic catalyst is the oxophilic V-decorated Pt nanoparticles, which are 2 nm in diameter.

Full text of DOI:10.1002/anie.201704199

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Mild Hydrogenation of Amides to Amines over Platinum-
Vanadium Bimetallic Catalyst
Authors: Takato Mitsudome, Kazuya Miyagawa, Zen Maeno, Tomoo
Mizugaki, Koichiro Jitsukawa, Jun Yamasaki, Yasutaka
Kitagawa, and Kiyotomi Kaneda
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201704199
Angew. Chem. 10.1002/ange.201704199
Link to VoR: http://dx.doi.org/10.1002/anie.201704199
http://dx.doi.org/10.1002/ange.201704199

10.1002/anie.201704199
Angewandte Chemie International Edition
Mild Hydrogenation of Amides to Amines
over Platinum–Vanadium Bimetallic Catalyst
Takato Mitsudome, Kazuya Miyagawa, Zen Maeno, Tomoo Mizugaki,
Koichiro Jitsukawa, Jun Yamasaki, Yasutaka Kitagawa, Kiyotomi Kaneda*
[*]Dr. T. Mitsudome, K. Miyagawa, Dr. Z. Maeno, Dr. T. Mizugaki, Dr. Y. Kitagawa, Prof. Dr.
K. Jitsukawa, Prof. Dr. K. Kaneda
Department of Materials Engineering Science, Graduate School of Engineering Science, Osaka
University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan
Fax: (+81) 6-6850-6260, E-mail: kaneda@cheng.es.osaka-u.ac.jp
Dr. J. Yamasaki
Research Center for Ultra-High Voltage Electron Microscopy, Osaka University, 7-1,
Mihogaoka, Ibaraki, Osaka 567-0047, Japan
Prof. Dr. K. Kaneda
Research Center for Solar Energy Chemistry, Osaka University,
1-3, Machikaneyama, Toyonaka, Osaka 560-8531, Japan
[**]This work was supported by JSPS KAKENHI Grant Nos. 17H03457, 26289303,
26105003 and 24246129. This work was also supported by the Program for Creating
Future Wisdom, Osaka University. We thank Dr. Uruga, Dr. Ina, Dr. Nitta, and Dr. Honma
(SPring-8) for XAFS measurements. The TEM experiments were performed at the
Research Center for Ultra-high Voltage Electron Microscopy, Osaka University.
Keywords: amide, heterogeneous catalyst, hydrogenation, platinum, vanadium
Abstract: Hydrogenation of amides to amines is an important reaction, but the need for high
temperatures and H2 pressures is a problem. No catalysts that are effective under mild conditions,
i.e., lower than 30 bar H2 and 70 °C, have yet been reported. Here, the mild hydrogenation of
amides was achieved for the first time, using a Pt–V bimetallic catalyst. Amide hydrogenation
under just 1 bar H2 at 70 °C or 5 bar H2 at room temperature was achieved using the bimetallic
1
This article is protected by copyright. All rights reserved.

10.1002/anie.201704199
Angewandte Chemie International Edition
catalyst. The mild reaction conditions enabled highly selective hydrogenation of various amides
to the corresponding amines, while inhibiting arene-hydrogenation. Catalyst characterization
showed that the origin of the bimetallic catalyst’s activity is oxophilic V-decorated Pt
nanoparticles of diameter 2 nm.
Main text: Amide reduction is an important and straightforward method for the production of
amines. Amines are ubiquitous in biological systems and essential in various materials such as
dyes, drugs, polymers, and solvents.1,2 However, the reduction of amides to amines is among the
most difficult reductions of carboxylic acid derivatives because amides are the least reactive
motifs. Laboratory-scale amide reductions are commonly performed using stoichiometric
amounts of metal hydrides such as LiAlH4, NaBH4, and iBu2AlH.3,4 However, the use of such
reactions in industrial-scale synthesis is restricted because they generate large amounts of metal
wastes and are operationally difficult. Alternatively, catalytic reduction of amides via
hydrosilylation has been developed.5 Despite the wide applicability for functionalized amides, the
use of silane reagents inevitably causes low atom-efficiency.
The most environmentally benign method is direct hydrogenation because theoretically water is
the only by-product. This therefore represents a promising route for the sustainable production of
amines. Over the past 100 years, much effort has been made to improve catalytic performances
in amide hydrogenation. However, the available catalysts have inadequate efficiencies and
drawbacks such as the need for high H2 pressures and temperatures, difficulties in catalyst reuse,
and low selectivities for amines. The development of high performance catalysts for the
hydrogenation of amides is therefore an important objective.6 The achievement of hydrogenation
of amides under mild conditions, ideally lower than 30 bar H2 and 70 °C,6 is listed as a leading
candidate in 12 key innovative research areas for the future sustainable production of
pharmaceuticals.7
In early studies of the hydrogenation of amides, Co,8 Ni,9 copper–chromium oxide,10 and Re11
catalysts were found to be effective, but required harsh reaction conditions, namely 200–370 bar
2
This article is protected by copyright. All rights reserved.

10.1002/anie.201704199
Angewandte Chemie International Edition
H2 and 200–300 °C. In 1988, Dobson reported a catalyst with much improved efficiency, namely
a bimetallic Pd/Re catalyst enabled amide hydrogenation at 130 bar H2 and 200 °C.12 Fuchikami
et al. and Whyman et al. also developed bimetallic catalysts consisting of Ru/Re, Ru/Mo, Rh/Re
and Rh/Mo, which facilitated hydrogenation under milder conditions (Ru/Re 50–100 bar H2, 150–
160 °C; Ru/Mo 20–100 bar H2, 130–160 °C).11-16 Recently, other Re-based multi-metallic
catalytic systems such as Pt/Re/In,17 Pt/Re/TiO2,18 and Pd/Re/carbon19 have enabled the use of
lower H2 pressures (5–70 bar) and temperatures (120–160 °C). An alternative approach using
homogeneous Ru-based catalysts at 10–80 bar H2 and 80–220 °C has important practical
drawbacks such as difficulty of catalyst reuse, the need for synthetically complex ligands, and
low selectivities arising from unavoidable by-production of alcohols through C–N bond cleavage
with decreasing reaction temperature.20-22 Consequently, despite much effort, no catalysts for the
hydrogenation of amides to amines under acceptably mild conditions, i.e., lower than 30 bar H2
and 70 °C, have yet been developed. The development of catalysts for mild hydrogenation of
amides is therefore still a great challenge.
Here, we report the first example of the highly efficient hydrogenation of amides to amines under
mild conditions, i.e., lower than 30 bar H2 and 70 °C. This was achieved using a bimetallic
heterogeneous catalyst consisting of V-decorated Pt nanoparticles. This new green catalytic
system, which works under mild conditions, enables the selective hydrogenation of various
functionalized amides to amines. The bimetallic catalyst can be separated from the reaction
mixture and reused without loss of efficiency.
Initially, bimetallic catalysts consisting of group 8–10 metals and group 5–7 metals were
synthesized by impregnation of on hydroxyapatite (HAP), which is a promising support because
it is chemically and thermally stable, and its nonporous structure can address mass-transfer
limitation problems.23 The prepared heterogeneous catalysts were evaluated in the hydrogenation
of N-acetylmorpholine (1) as a model substrate under mild reaction conditions (30 bar H2, 70 °C).
3
This article is protected by copyright. All rights reserved.

10.1002/anie.201704199
Angewandte Chemie International Edition
Table 1. Hydrogenation of 1 using supported metal catalysts
under the mild conditions.
It was found that Pt/V/HAP was active, giving the desired amine 2 in high yield without the
formation of any by-products (Table 1, entries 1 and 2). Other Pt- (Table 1, entries 6–8) and V-
based (Table 1, entries 9–11) bimetallic catalysts, and the single-metal catalysts Pt/HAP and
V/HAP (Table 1, entries 12 and 13) were hardly active, clearly showing the specific bimetallic
effect of Pt and V. Pt/V/HAP even catalyzed hydrogenation at room temperature, affording 2 in
excellent yield (Table 1, entry 3). A high yield of 2 was also obtained at room temperature at a
lower H2 pressure, i.e., 5 bar (Table 1, entry 4). Furthermore, the hydrogenation proceeded
efficiently under atmospheric pressure of H2 at 70 °C (Table 1, entry 5). To the best of our
knowledge, this Pt/V bimetal is the first example of a catalyst that works at ambient temperature
4
This article is protected by copyright. All rights reserved.

10.1002/anie.201704199
Angewandte Chemie International Edition
or just 1 bar of H2. The high activity of the Pt/V bimetal did not depend significantly on the type
of support; Pt/V deposited on typical supports gave similarly moderate yields of 2, showing a
potential of Pt/V catalysts for wide availability (Table 1, entries 14–17).
We then investigated the substrate scope of Pt/V/HAP in hydrogenation under mild conditions.
Pt/V/HAP showed high activity for various amides (Table 2). A wide range of secondary and
tertiary aliphatic amides were successfully hydrogenated, giving the desired amines as the sole
product in excellent yields (Table 2, entries 1–15). Pt/V/HAP could promote hydrogenation of an
amide bearing adamantyl moiety under just 1 bar of H2 (Table 1, entry 11). Previously reported
metal nanoparticle catalysts for the hydrogenation of aromatic amides require harsh reaction
conditions, inevitably causing concomitant reduction of aromatic rings.14-16,18,19 In sharp contrast
to reported heterogeneous catalysts, Pt/V/HAP enabled the highly chemoselective hydrogenation
of various aromatic amides without arene-hydrogenation to afford the corresponding amines in
excellent yields (Table 2, entries 16–22). This is the first example of a heterogeneous catalyst for
hydrogenation of amides to amines, while inhibiting arene-hydrogenation.24 Furthermore, the
mild reaction condition (30 bar H2, r.t.) also allowed selective amide hydrogenation with halogen
group remaining intact (Table 2, entries 17). Pt/V/HAP did not show activity for primary amides
under these mild conditions (Table 2, entries 23 and 24).25
After hydrogenation of 1, the used Pt/V/HAP catalyst was readily separated from the reaction
mixture by filtration and reusable without any loss of its high activity even after the 10th recycling
run (Table 2, entry 2). Inductively coupled plasma atomic emission spectroscopy (ICP-AES)
showed the absence of Pt and V species in the filtrate, indicating that no metal leaching occurred
during the reaction. Pt/V/HAP is highly reusable unlike reported heterogeneous catalysts which
suffer from a decrease in activity during recycling.19
5
This article is protected by copyright. All rights reserved.

10.1002/anie.201704199
Angewandte Chemie International Edition
Table 2. Hydrogenation of various amides using Pt/V/HAP
under the mild reaction conditions.
6
This article is protected by copyright. All rights reserved.

10.1002/anie.201704199
Angewandte Chemie International Edition
To elucidate the reasons for high activity of Pt/V/HAP, we characterized Pt/V/HAP using
electron microscopy and X-ray absorption fine structure (XAFS) analysis. A representative
secondary-electron image of Pt/V/HAP after treatment with H2 under reaction conditions (30 bar
H2, 70 °C) shows the formation of Pt nanoparticles of mean diameter 2.2 nm on the HAP surface
(Fig. 1a). Well-defined lattice fringes with d-spacings attributed to Pt nanoparticles are observed
(Fig. S1). The elemental distributions of Pt and V on HAP were determined using annular dark-
field scanning transmission electron microscopy (ADF-STEM) coupled with energy-dispersive
X-ray spectroscopy (EDX) (Fig. 1b–f). Elemental mapping of Pt/V/HAP reveals that V (shown
in green in Fig. 1d) and Pt (shown in red in Fig. 1e) are highly dispersed on HAP and, importantly,
that V surrounds Pt. EDX line analysis also shows the coexistence of Pt and V, confirming that
the Pt nanoparticles are decorated with V species (Fig. S2).
Figure 1. (a) Secondary-electron image of Pt/V/HAP treated with H2. (b) ADF-STEM image
of Pt/V/HAP treated with H2. Elemental mapping images of (c) Ca, (d) V, and (e) Pt. f)
Composite overlay image formed from (c), (d), and (e).
7
This article is protected by copyright. All rights reserved.

10.1002/anie.201704199
Angewandte Chemie International Edition
Pt L3-edge and V K-edge X-ray absorption near edge structure (XANES) spectra of Pt/V/HAP
before and after treatment under 30 bar H2 and 70 °C are depicted in Fig. 2. The white line from
Pt decreased in intensity after treatment with H2, indicating the formation of metallic Pt (Fig. 2A).
The absorption edge in the V K-edge XANES spectrum of Pt/V/HAP prior to the treatment was
similar to that of V2O5, suggesting that V is present as V5+ species [Fig. 2B(a) and 2B(b)]. After
H2 treatment, the intensity of the pre-edge peak derived from the V=O moiety significantly
decreased and the absorption edge shifted toward lower energy, similarly to that of V(acac)3,
indicating in situ generation of reduced V3+ species [Fig. 2B(c) and 2B(d)]. A peak shift was not
observed for V/HAP (i.e., in the absence of Pt) after treatment with H2, clearly showing that the
V5+ species in Pt/V/HAP were reduced in situ to V3+ by adjacent metallic Pt species with H2.
Figure 2. (A) Pt L3-edge XANES spectra of (a) PtCl2, (b) Pt/V/HAP, (c) Pt/V/HAP treated with
H2, and (d) Pt foil. (B) V K-edge XANES spectra of (a) V2O5, (b) Pt/V/HAP, (c) Pt/V/HAP
treated with H2, and (d) V(acac)3.
Based on the specific bimetallic effect and close interactions between Pt and V, we propose
cooperative catalysis by Pt and V atoms, as follows. During hydrogenation, V=O (V5+) species
deposited on Pt nanoparticles are reduced by Pt surface atoms to form V3+ species. Next, the
8
This article is protected by copyright. All rights reserved.

10.1002/anie.201704199
Angewandte Chemie International Edition
coordinatively unsaturated sites at the V species generated in situ activate C=O amide bonds and
the adjacent Pt species cooperatively hydrogenate the activated C=O moieties, giving the
corresponding amine (Scheme S2). The key interaction of oxophilic V3+ with the C=O amide
bond was well supported by FT-IR spectroscopy and density functional theory (DFT) calculations
(Figs. S4 and S5). Similar bimetallic effects between hydrogenation catalysts and Lewis acid
catalysts have been reported.26,27 Furthermore, we previously found that amides were activated by
atomically dispersed V species on supports.28 These results clearly show that cooperative action
between Pt and the adjacent V species plays a crucial role in the mild hydrogenation of amides
through activation of the C=O amide bond by the oxophilic V3+ species generated in situ, followed
by C=O hydrogenation by adjacent Pt species.
In conclusion, a hydrogenation of amides to amines under mild conditions was achieved using a
V-decorated Pt bimetallic catalyst. The Pt/V catalyst promoted amide hydrogenation to amines at
ambient temperature or just 1 bar of H2 for the first time. Various amides, including aromatic ones,
were converted to the corresponding amines in high yields without arene-hydrogenation. This
catalytic system has the significant advantages of mild operating conditions, simple work-up
procedures, high catalyst reusability, and a broad substrate scope, enabling green sustainable
hydrogenation of amides to amines. Characterization of the Pt/V catalyst and DFT calculations
showed a cooperative catalysis between V for activation of the C=O amide bond, and adjacent Pt
for the C=O hydrogenation.
9
This article is protected by copyright. All rights reserved.

10.1002/anie.201704199
Angewandte Chemie International Edition
References
1. A. Ricci, Modern Amination Methods (Wiley, New York, 2000)
2. J. S. Carey, D. Laffan, C. Thomson, M. T. Williams, Org. Biomol. Chem. 2006, 4, 2337.
3. H. C. Brown, P. Hein, J. Org. Chem. 1973, 38, 912.
4. W. G. Gribble, Chem. Soc. Rev. 1998, 27, 395.
5. For reviews of amine synthesis via hydrosilylation of amides, see a) A. Volkov, F. Tinnis, T.
Slagbrand, P. Trillo, H. Adolfsson, Chem. Soc. Rev. 2016, 45, 6685; b) B. Li, J. B. Sortaisa,
C. Darcel, RSC Adv. 2016, 6, 57603; c) D. Addis, S. Das, K. Junge, M. Beller, Angew. Chem.
Int. Ed. 2011, 50, 6004; Angew. Chem. 2011, 123, 6128.
6. A. M. Smith, R. Whyman, Chem. Rev. 2014, 114, 5477.
7. D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey, H. L. Leazer, Jr., R. J.
Linderman, K. Lorenz, J. Manley, B. A. Pearlman, A. Wells, A. Zaks, T. Y. Zhang, Green
Chem. 2007, 9, 411.
8. Anon. (to I. G. Farbenindustrie Akt.-Ges.) German Patent DE 667627, 1938.
9. A. Guyer, A. Bieler, G. Gerliczy, Helv. Chim. Acta 1955, 38, 1649.
10. H. J. Schneider, H. Adkins, S. M. McElvain, J. Am. Chem. Soc. 1952, 74, 4287.
11. H. S. Broadbent, W. J. Bartley, J. Org. Chem. 1963, 28, 2345.
12. I. A. Dobson (BP Chemicals Limited), EP 0286280, 1988.
13. C. Hirosawa, N. Wakasa, T. Fuchikami, Tetrahedron Lett. 1996, 37, 6749.
14. G. Beamson, A. J. Papworth, C. Philipps, A. M. Smith, R. Whyman, J. Catal. 2010, 269, 93.
15. G. Beamson, A. J. Papworth, C. Philipps, A. M. Smith, R. Whyman, Adv. Synth. Catal. 2010,
352, 869.
16. G. Beamson, A. J. Papworth, C. Philipps, A. M. Smith, R. Whyman, J. Catal. 2011, 278,
228.
17. A. A. Smith, P. Dani, P. D. Higginson, A. J. Pettman (Avantium International B.V.), WO
2005066112, 2005.
18. R. Burch, C. Paun, X.-M. Cao, P. Crawford, P. Goodrich, C. Hardacre, P. Hu, L. McLaughlin,
10
This article is protected by copyright. All rights reserved.

10.1002/anie.201704199
Angewandte Chemie International Edition
J. Sá, J. M. Thompson, J. Catal. 2011, 283, 89.
19. M. Stein, B. Breit, Angew. Chem. Int. Ed. 2013, 52, 2231; Angew. Chem. 2013, 125, 2287.
20. E. Balaraman, B. Gnanaprakasam, L. J. W. Shimon, D. Milstein, J. Am. Chem. Soc. 2010,
132, 16756.
21. J. M. John, S. H. Bergens, Angew. Chem. Int. Ed. 2011, 50, 10377; Angew. Chem. 2011, 123,
10561.
22. M. Ito, T. Ootsuka, R. Watari, A. Shiibashi, A. Himizu, T. Ikariya, J. Am. Chem. Soc. 2011,
133, 4240.
23. K. Kaneda, T. Mizugaki, ACS Catal. 2017, 7, 920.
24. The hydrogenation of amides to amines without arene-hydrogenation using homogeneous
catalysts is reported. See J. Coetzee, D. L. Dodds, J. Klankermayer, S. Brosinski, W. Leitner,
A. M. Z. Slawin, D. J. Cole-Hamilton, Chem. Eur. J. 2013, 19, 11039.
25. The chemoselective hydrogenations of amides bearing ester or olefinic group using
Pt/V/HAP did not proceed. See Scheme S1 in the supporting information for details.
26. J. R. Cabrero-Antonino, E. Alberico, K. Junge, H. Junge, M. Beller, Chem. Sci. 2016, 7,
3432.
27. M. Yuan, J. Xie, S. Zhu, Q. Zhou, ACS Catal. 2016, 6, 3665.
28. S. Sueoka, T. Mitsudome, T. Mizugaki, K. Jitsukawa, K. Kaneda, Chem. Commun. 2010, 46,
8243.
11
This article is protected by copyright. All rights reserved.

10.1002/anie.201704199
Angewandte Chemie International Edition
COMMUNICATION
Takato Mitsudome, Kazuya Miyagawa,
Zen Maeno, Tomoo Mizugaki, Koichiro
Jitsukawa, Jun Yamasaki, Yasutaka
Kitagawa, Kiyotomi Kaneda*
Page No. – Page No.
Hydrogenation of amides to amines under mild conditions, i.e., lower than 30 bar H2
Mild Hydrogenation of Amides to
and 70 °C, using a reusable Pt–V bimetallic catalyst is reported. This Pt–V bimetal
Amines over Platinum–Vanadium
is the first example of a catalyst that works at ambient temperature or 1 bar of H2.
Bimetallic Catalyst
12
This article is protected by copyright. All rights reserved.