Reduction of imines with a reusable bimetallic PdCo–Fe3O4 catalyst at room temperature under atmospheric pressure of H2

Bimetallic nanocatalysts have been used for the development of organic reactions, owing to the synergistic effect between the transition metals. A new procedure for synthesizing amines by the reduction of imines with H2 at atmospheric pressure and room temperature in the presence of PdCo–Fe3O4 nanoparticles is reported. The straightforward procedure, mild reaction conditions, high turnover number, and recyclability extend the scope of this reaction to practical applications.


Introduction
Amines are versatile organic molecules found in various natural products, 1 drug molecules, 2 and dyes. 3 Of particular interest is a large number of pharmaceuticals, such as profenamine (antidyskinetic), 4 promazine (antiemetic), 5 ciprooxacin (antibiotic), 6 imipramine (antidepressant), 7 and propiomazine (antipsychotic agent), 8 which all contain the amine functionality (Scheme 1). In this context, research to develop continually mild and convenient synthetic procedures for synthesizing amines from various precursors remains highly relevant to the present pharmaceutical industry. 9 Among many established procedures, the reduction of imines is one of the most straightforward methods, owing to the fact that imines can be readily produced from precursor amines and carbonyl compounds. 10 Although the reduction of imines can be facilitated by adding stoichiometric hydride reagents, such as NaBH 4 , 11 NaBH 3 CN,12 or NaBH(OAc) 3 , 13 catalytic processes are preferred for a large-scale production. Various homogeneous transition metal catalysts such as Pd, 14a Ir, 15a Ru, 16a,b Mn, 17a and Mo 18 have been employed in the reduction of imines using H 2 . Drawbacks associated with reactions on these catalysts include high temperature and high H 2 pressure required to achieve high turnover numbers (TON). In the meantime, heterogeneous catalysis employing transition metals have been gaining increasing attention as an alternative to homogeneous catalysis, owing to the usability and recyclability. 19 For the purpose of overcoming the shortcomings mentioned above, efforts have been concentrated on recycling the catalyst, thereby allowing repeated applications aer the hydrogenation process. 14b-e,15b,c,16c,17b Therefore, we envisioned that further development of the catalytic reaction reduction of imines under mild reaction conditions, i.e., room temperature and at atmospheric pressure of H 2 , with a high turnover number, and good catalyst reusability is still in need (Table 1).
There has been increasing interest in bimetallic heterogeneous catalysts because they oen exhibit a synergistic effect between two types of metals, which is not observed in metals of single type. 20 A series of bimetallic heterogeneous catalysts, supported on iron oxide (Fe 3 O 4 ) nanoparticles (NPs), have recently been developed for application in the development of various organic reactions. This included the development of PdPt-Fe 3 O 4 NPs that have been employed in nitroarene reduction, 21 arylsilylation, 22 as well as secondary amine synthesis from benzonitriles and nitroarenes. 23 Additionally, AuPd-Fe 3 O 4 NP catalysts have been developed for reductive amination, 24 oxidation of furan-2,5-dimethylcarboxylate, 25 and N-formylation of secondary amines. 26 However, all these catalysts employed expensive, precious metals (Pd and Pt, Au and Pd) among the transition metal element group. Further research therefore focused on the development of a bimetallic nanocatalyst that incorporated at least one inexpensive transition metal. Accordingly, PdCo bimetallic catalysts were identied as a promising alternative, with applications in various organic transformations. 27 These include the development of a PdCo catalyst for the transfer hydrogenation of carbonyl compounds by Kumar et al.,27a while Wang group employed a PdCo electrocatalyst for the reduction of oxygen and the oxidation of ethanol. 27b Chen group also successfully employed a PdCo alloy for oxygen reduction, 27c while Salmeron group investigated the effect of a PdCo nanocatalyst in CO oxidation. 27d A PdCo bimetallic catalyst has, however, not yet been employed in imine reduction. In the present study, we have developed PdCo-Fe 3 O 4 as a recyclable bimetallic nanocatalyst for the reduction of imines (Scheme 2) under very mild conditions.

Catalyst characterization
Here, bimetallic PdCo-Fe 3 O 4 NPs were synthesized through the modication of an existing synthetic procedure for AuPd-Fe 3 O 4 . 24 Sequentially adding palladium(II) chloride (PdCl 2 ) in ethylene glycol (EG), cobalt(II) chloride hexahydrate (CoCl 2 -$6H 2 O) in water, and aqueous sodium borohydride solution dropwise to a Fe 3 O 4 solution in water followed by stirring under 60 C for 24 h afforded PdCo-Fe 3 O 4 NPs. The synthesized nanocatalyst was characterized employing various techniques. Scanning electron microscopy (SEM) images ( Fig. 1a and S1 †) were obtained using a JSM-7800F Prime microscope (JEOL Ltd., Tokyo, Japan). High-resolution transmission electron microscopy (HR-TEM) images (Fig. 1b, S4 and S6 †) were obtained using a JEM-3010 microscope (JEOL Ltd., Tokyo, Japan), indicating successful deposition of Pd and Co atoms on the Fe 3 O 4 support. Scanning transmission electron microscopy images (STEM, Fig. 2 and S5 †) were obtained using a JEM-ARM200F microscope (JEOL Ltd., Tokyo, Japan), while energy-dispersive X-ray spectroscopy (EDS) images ( Fig. S2 and S3 †) were obtained using a JSM-7800F Prime Field Emission Scanning Electron Microscope (JEOL Ltd., Tokyo, Japan), showing that Pd and Co were randomly distributed. The electron energy loss spectroscopy (EELS) was performed using a Themis Z STEM (ThermoFisher, MA, USA), where the high-energy loss spectrum images indicated that the Co lines are located at 780-800 eV (Fig. S7 †). In addition, the X-ray diffraction (XRD) data obtained using a D8 Advance XRD (Bruker, Billerica, MA, USA) indicated that the diffraction peaks at $40 and 46-47 2q were shied. This suggested that PdCo-Fe 3 O 4 is made up with Pd-Co bimetallic alloy (Fig. S8 †). 27h X-ray photoelectron spectroscopy (XPS) data were obtained using a SIGMA PROBE XPS (ThermoFisher Scientic, UK) and provided information on the electronic states of the catalyst (Fig. S9 †). Here, rst major peaks at the Pd 3d 5/2 and Pd 3d 3/2 energy levels were observed at 335.35 and 340.61 eV, respectively, which correspond to metallic Pd(0) species. 28 In addition, rst major peaks at the Co 2p 3/2 and Co 2p 1/2 energy levels were observed at 779.84 and 795.64 eV, respectively, corresponding to metallic Co(0) species. 29 Finally, an OPTIMA 8300 inductively coupled plasma-atomic emission spectrometer (ICP-AES) (PerkinElmer, Waltham, MA, USA), was

Reaction optimization
For the initial screening study, N-benzylideneaniline (1a) was selected as a representative substrate and N,N-dimethylacetamide (DMA) as the solvent. Various reaction conditions were examined, with the results presented in Tables 2 and S1-S4. † When the reaction was carried out with only Fe 3 O 4 as a catalyst under 1.0 atm of H 2 , the reaction did not proceed and 1a remained unchanged (entry 1). Although the reaction resulted in hydrogenolysis side products when Pd/C was employed as a catalyst, none of the desired product was produced (entry 2). However, employing 4.0 mol% of Pd-Fe 3 O 4 resulted in a 60% yield of the desired product 2a, while catalysis employing Co-Fe 3 O 4 alone did not produce any 2a (entries 3 and 4, respectively). Finally, employing the PdCo-Fe 3 O 4 bimetallic catalyst resulted in a 95% yield, indicating an outstanding synergistic effect between Pd and Co (entry 5). To conrm this synergy, the reaction yields of several substrates from the reactions employing monometallic catalysts were compared (Table S6 †).
Here, the reaction yields using PdCo-Fe 3 O 4 were higher than those obtained when Pd-Fe 3 O 4 or Co-Fe 3 O 4 was used independently. The initial kinetics associated with employing either monometallic catalysts or PdCo-Fe 3 O 4 catalyst were also investigated ( Fig. S17 †). An enhanced reaction rate was observed for the reaction when the PdCo-Fe 3 O 4 catalyst was employed, demonstrating an additional benet associated with the use of the bimetallic catalyst. The effect of other solvents was also evaluated. Here, employing methanol and N,N-dimethylformamide (DMF) (entries 6 and 7), resulted in lower yields when compared to yields obtained with DMA. Reactions with other reducing agents such as phenylsilane (entry 8), ammonia borane (entry 9), and sodium borohydride (entry 10) also resulted in lower product yields. Ultimately, approximately quantitative yields were obtained (entries 11 and 12, respectively) even when the catalyst loading was reduced from 2.0 mol% to 1.0 or 0.50 mol%, respectively. Furthermore, the turnover number (TON) of the catalyst could be higher than 1500 even when the catalyst loading was low, demonstrating the efficiency of the catalyst to facilitate imine reduction (entry 13).

Substrate scope
The reduction of several imines with various substituents on the aromatic ring was subsequently evaluated at the optimized conditions, employing a 0.20 M substrate concentration for a period of 18 h. Here, as shown in Scheme 3, the reduction of N-benzylideneaniline, with no substituent on the aniline or benzene ring, proceeded smoothly, and a 91% yield of the desired product (2a) could be isolated. Substrates with a methyl group on the aniline moiety resulted in moderate to good yields (76% and 82% for 2b and 2c, respectively), while the reaction of a substrate with a single methyl group at position 2 of the aromatic ring did not have an impact on the yield (2c). However, substitution with two methyl groups at positions 2 and 6 resulted in a low yield (2d), demonstrating the inuence of steric hindrance. Strong electron-donating methoxy group on the aromatic ring was well tolerated (2e). The reduction of substrates with strong electron-withdrawing groups, such as uorine, were associated with high yields (94% and 83% for 2f and 2g, respectively). The reduction of an imine containing a relatively bulky triuoromethyl group at position 2 of the aniline ring provided a 73% yield (2h). For the reduction of substrates containing a halogen such as Cl, Br, and I, the use of  PdCo-Fe 3 O 4 was not appropriate, because substrate dehalogenation occurred. 30 It was therefore hypothesized that reducing the content of Pd relative to that of Co to a minimum, may suppress dehalogenation while maintaining the synergy between Pd and Co. This was conrmed as the reaction with Pd 0.05 Co 1 -Fe 3 O 4 proceeded successfully without knocking out the chloride group at position 4 of the aniline ring, resulting in a 74% yield obtained within 30 h (2i). Various substrates with substituents on the benzyl ring were further tested. Here, the reaction of a substrate containing a methoxy group at position 3 provided a 71% yield (2j), while a good yield (75%, 2k) was also obtained using a 3-hydroxy substituted substrate. The reaction of a substrate with multiple hydroxyl groups at positions 2 and 3 on the benzyl ring also resulted in a high yield (94%, 2l).
Similarly, when a substrate possessing uoro or triuoromethyl group on the benzyl ring was employed in the reaction, high yields (90%, 85% and 84% for 2m, 2n and 2o, respectively) could be obtained under similar conditions. Reduction of a substrate containing a heteroaromatic ring, such as pyridine was also well tolerated, resulting in an 80% yield (2p). Finally, an 87% yield was obtained when a substrate with an acetamide group on the benzyl ring was employed in the reaction. In this instance, the amide functionality was intact (2q).

Effect of Pd : Co ratio and various supports
Based on the results from Table 2, the role of Co in the PdCo bimetallic catalyst appeared to accelerate hydrogenation since the bimetallic catalyst works more efficiently than either of the monometallic catalyst. Therefore, we were curious whether any differences in catalytic activity could be attributed to the composition of the two metals in the catalyst. Catalysts with various Pd : Co ratios were therefore prepared (Fig. S12 †) and tested under the same reaction conditions ( Table 3, entries 1-6).
Here, the experimental data indicated that the yields were excellent regardless of the Pd : Co molar ratios. Reaction using the catalyst with 0.04 : 1 molar ratio of Pd : Co resulted in 91% yield in 18 h (

Recycling test
Considering that heterogeneous catalysts are oen employed based on their convenient recovery and the possibility to reuse the catalyst, the recyclability of various Pd x Co y -Fe 3 O 4 NPs was tested under optimized conditions ( Fig. 3 and S13 †). PdCo-  PdCo-C 6 3 Fe 3 O 4 NPs were used as a representative catalyst, aer being recovered using a small magnet and washed with MeOH several times. In the recycling experiment with 1a, a consistent catalytic activity was observed for 12 cycles. However, starting from the 13th cycle, a reduction in reactivity was observed. Evaluation of the SEM and HR-TEM images of the catalyst aer the 14th cycle indicated that the used PdCo particles exhibited a high degree of agglomeration as well as detachment of metal atoms from the Fe 3 O 4 support ( Fig. S14 and S15 †). Additionally, ICP-AES analysis of the used catalyst showed a reduction in both Pd and Co contents, from 7.49 wt% to 1.69 wt% for Pd and from 3.89 wt% to 0.28 wt% for Co, respectively (Fig. S11 †), reecting the decreased reactivity aer the repeated catalytic cycles.

Gram scale reaction
The scalability of the reaction (Scheme 4) was further investigated, and at a 6.0 mmol scale, the reaction of 1a resulted in an 80% yield of 2a, demonstrating its potential suitability in organic synthesis applications.

Conclusions
In summary, a new catalytic system was developed for the synthesis of amines via the reduction of imines. Utilizing a PdCo bimetallic nanocatalyst, various imines could be reduced to amines at room temperature and under 1.0 atm of H 2 . This process therefore allowed the catalytic reduction of imines to amines without the use of toxic or polluting stoichiometric reducing agents. Furthermore, the catalytic performance of the bimetallic PdCo-Fe 3 O 4 NPs was superior to that of monometallic NPs, such as Pd-Fe 3 O 4 and Co-Fe 3 O 4 . This indicated the existence of a synergistic effect between Pd and Co. The application scope of the reaction was broad, and it could tolerate substrates with various functional groups. The reduction reaction was further shown to be independent of the Pd : Co ratio, while the Fe 3 O 4 NPs were proven to be a more effective support material than other supporting materials such as TiO 2 , CeO 2 , and C. The PdCo-Fe 3 O 4 NPs could be used in more than 10 cycles without a signicant loss of catalytic activity. Moreover, it was possible to run the reaction on a gram scale. The high turnover number combined with the simple experimental procedure overcomes the limitations associated with previous approaches such as high reaction temperatures, high H 2 pressures, as well as the use of expensive transition metal precursors. This catalyst will be investigated further to expand its potential applications in organic chemistry.

Materials
All commercially available chemicals were purchased from Acros Organics (Pittsburgh, PA, USA), Sigma-Aldrich Aldrich (St. Louis, MO, USA), Alfa Aesar (Ward Hill, MA, USA), Tokyo Chemical Industry (Tokyo, Japan), and used without further purication. Imine substrates were synthesized by a known procedure. 31

Synthesis of PdCo-Fe 3 O 4 NPs
Initially, 88.7 mg (0.50 mmol) of PdCl 2 and 1.00 g of PVP (M w $ 10 000 g mol À1 , 0.10 mmol) were placed in 20 mL of ethylene glycol (EG) in a 100 mL round-bottom ask. This mixture was sonicated for 10 min and stirred for 1 h at 100 C in an oil bath. In a separate 100 mL round-bottom ask, 119.0 mg (0.50 mmol) of CoCl 2 $6H 2 O and 500 mg of PVP (0.050 mmol) were added to 20 mL of water. This mixture was sonicated for 10 min and stirred for 30 min at 60 C in an oil bath. Meanwhile, 500 mg of Fe 3 O 4 NPs were added to 150 mL of water in a two-necked 500 mL round-bottom ask and then sonicated for 10 min. Catalyst characterization SEM images were obtained using JSM-7800F Prime (JEOL Ltd., Tokyo, Japan) and MERLIN Compact (ZEISS, Oberkochen, Germany). HR-TEM images were obtained using JEM-3010 (JEOL Ltd., Tokyo, Japan). STEM images were obtained using JEM-ARM200F (JEOL Ltd., Tokyo, Japan). XPS data were obtained using SIGMA PROBE (ThermoVG, U.K). ICP-AES data were obtained using OPTIMA 8300 (PerkinElmer, Waltham, MA, USA). The machines mentioned above are installed at the National Center for Inter-University Research Facilities (NCIRF) at Seoul National University. EELS images were obtained using Themis Z (Thermo Fisher, MA, USA) installed at the Research Institute of Advanced Materials at Seoul National University.
The powder X-ray diffraction (XRD) was performed using a D8 Advance (Bruker, Billerica, MA, USA) installed at the National Instrumentation Center for Environmental Management (NICEM) at Seoul National University. Fourier-transform infrared spectroscopy images were obtained using Spectrum Two (PerkinElmer, Waltham, MA, USA) installed at Seoul National University.
General procedure of the synthesis of amines A glass vial (10 mL) were charged with an imine (0.20 mmol), PdCo-Fe 3 O 4 (2.0 mol%), and N,N-dimethylacetamide (1.0 mL). The mixture was sonicated for 1 min and stirred at room temperature. Next, the vial was purged with H 2 using a balloon lled with H 2 for 1 min and stirred for 18 h at room temperature. The reaction mixture was extracted by ethyl acetate and the organic layer was ltered through a layer of Celite® and magnesium sulfate. The crude product was puried by column chromatography.

Conflicts of interest
There are no conicts to declare.