Article pubs.acs.org/IECR
Cite This: Ind. Eng. Chem. Res. 2017, 56, 14766−14770
Mild and Selective Synthesis of Secondary Amines Direct from the Coupling of Two Aldehydes with Ammonia Ziliang Yuan, Peng Zhou, Xixi Liu, Yanxin Wang, Bing Liu,* Xun Li, and Zehui Zhang Key Laboratory of Catalysis and Materials Sciences of the Ministry of Education, South-Central University for Nationalities, Wuhan, 430074, People’s Republic of China
ABSTRACT: Synthesis of secondary amines direct from the coupling of two aldehydes was first reported in the presence of NH3 and H2 molecules. A magnetic material supported palladium catalyst (γ-Fe2O3@HAP-Pd) was found to be active for this transformation at room temperature and atmospheric hydrogen pressure, providing structurally diverse secondary amines with good to excellent yields (70.0−92.3%).
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INTRODUCTION Secondary amines have been considered to be one kind of the important motifs in organic compounds, because they have been widely present in numerous bioactive molecules and because of their widespread pharmaceutical applications.1 Currently, several methods have been reported for the synthesis of secondary amines, mainly including amine−carbonyl reductive amination,2 alkylation of amines with alkyl halides,3 direct N-alkylation of amines with alcohols,4 reductive coupling of nitroarenes with organohalides,5 and Buchwald−Hartwig6,7 as well as Ullman-type carbon−nitrogen cross-coupling reactions.8,9 Although these methods could produce good to high yields of secondary amines, some of these methods are limited to practical applications, due to the inherent drawbacks such as the difficulty in the recycling of homogeneous catalysts, the release of highly toxic wastes, and the harsh reaction conditions. Reductive amination of carbonyl compounds with ammonia as a nitrogen source has recently been explored in the synthesis of primary amines over either homogeneous or heterogeneous catalysts.10,11 For example, Zhang and co-workers recently reported that the partially reduced Ru/ZrO2 could catalyze the reductive amination of carbonyl compounds with aqueous ammonia with high yields at 85 °C (Scheme 1).10 However,
this method required the use of a large amount of aqueous ammonia (14 equiv) and high hydrogen pressure (20 bar).10 The as-formed primary amines can be further transformed into the secondary amines via the reductive amination with carbonyl compounds in the presence of reducing agent.12,13 The pursuit of sustainable chemistry has required the development of new strategies to access organic compounds in a safe, compact, and energy-efficient manner.14 Thus, it is reasonable to develop a one-pot strategy for the synthesis of secondary amines direct from the coupling of two carbonyl compounds with ammonia (Scheme 1). In our previous work, a magnetic γ-Fe2O3@HAP-Pd catalyst was prepared by the following steps including the encapsulation of γ-Fe2O3 by hydroxyapatite (HAP) to get core−shell structured γ-Fe2O3@HAP, the exchange of Pd2+ with Ca2+ in γ-Fe2O3@HAP, followed by the reduction of the Pd2+ to metallic Pd nanoparticles, and this catalyst showed high catalytic activity for the oxidation of 5-hydroxymethylfurfural into 2,5-furandicarboxylic acid.15 As palladium catalysts have also been widely used as the catalysts to activate molecular H2 for reductive chemical reactions,16,17 it is expected that this catalyst is active for the selective synthesis of secondary amines directly from two aldehydes in the presence of NH3 and H2 molecules.
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EXPERIMENTAL SECTION Materials. All of the solvents were purchased from Sinopharm Chemical Reagent Co., Ltd. (Shanghai, China). All of the chemicals were purchased from Aladdin Chemicals Co. Ltd. (Beijing, China). All of the solvents and the chemicals were used directly without purification.
Scheme 1. Synthesis of Secondary Amines via the Coupling of Two Aldehydes with Ammonia
Received: Revised: Accepted: Published: © 2017 American Chemical Society
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September 19, 2017 November 20, 2017 November 21, 2017 November 21, 2017 DOI: 10.1021/acs.iecr.7b03887 Ind. Eng. Chem. Res. 2017, 56, 14766−14770
Article
Industrial & Engineering Chemistry Research General Procedures of the Synthesis of Secondary Amines. Typically, the γ-Fe2O3@HAP-Pd catalyst (20 mg), isopropanol (10 mL), benzaldehyde (1 mmol), and 26 wt % aqueous ammonia solution (0.3 mL, 4.2 mmol) were charged into the reactor. The air in the reactor was expelled from the reactor by the purge of H2 five times. Then the reactor was charged with 1 bar H2 at room temperature and then sealed. Then the reactions were carried out at a desired temperature for a certain time with magnetic stirring at 1000 rpm. After reaction, the autoclave was depressurized. The reaction mixture was analyzed by gas chromatography (GC). Analytical Methods. Product analysis was performed on an Agilent 7890A GC with an autosampler and a flame ionization detector (FID). The products were separated by a HP-5 capillary column (30 m × 530 μm × 1.5 μm). The temperature of the column was initially kept at 80 °C for 3 min, and then increased at a rate of 20 °C min−1 to 220 °C. The temperatures of the FID and the injector were set to be 270 and 300 °C, respectively. Products were identified by the comparison of the retention time with the authentic chemicals, and further confirmed by GC−MS (Agilent 7890A GC/5973 MS, HP-5 column). The amounts of products were determined based on GC data using the internal standard method using toluene and phenyl ether as double internal standards to quantify primary amines, imines, and secondary amines, respectively.
mediate). As shown in Table 1, both benzaldehyde conversion and product distribution were greatly affected by the solvents. Generally speaking, low to moderate benzaldehyde conversions and low selectivity of N-dibenzylamine were observed in nonpolar or weaker polar solvents (Table 1, entries 1−4). Higher benzaldehyde conversions and higher selectivity of Ndibenzylamine were attained in solvents with stronger polarity such as tetrahydrofuran (THF), methanol, and isopropanol (Table 1, entries 5−7). The main reason should be the polarity of the reaction solvents. The nonpolar or weak polar solvents showed poor solubility for the aqueous ammonia solution, and the γ-Fe2O3@HAP-Pd catalyst also had a poor dispersion in those solvents. Insolubility or poor solubility of aqueous ammonia solution in the nonpolar or weaker polar solvents made it difficult for the condensation between ammonia molecules and benzaldehyde, which is the first step in the onepot synthesis of N-dibenzylamine from benzaldehyde, and results in the low selectivity for N-dibenzylamine (Table 1, entries 1−4). The poor dispersion of α-Fe2O3@HAP-Pd catalyst should be one of the reasons for the lower conversion. Therefore, reactions in those solvents were much more sluggish. For all cases, benzylamine was not detected, because of the fast condensation of benzylamine with benzaldehyde to produce the other intermediate N-benzylidenebenzylamine. In addition, the reaction in water showed poor selectivity of Ndibenzylamine (Table 1, entry 8). Isopropanol was proved to be the best solvent for this reaction, which gave 100% benzaldehyde conversion and the highest N-dibenzylamine selectivity of 50.4% (Table 1, entry 7). However, benzyl alcohol was still produced with a selectivity of 49.6% (Table 1, entry 7). Then the amount of catalyst was optimized and the results are shown in Figure 1. As the amount of catalyst increased from
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RESULTS AND DISCUSSION Optimization of the Reaction Conditions for the Synthesis of N-Dibenzylamine from Benzaldehyde. Synthesis of N-dibenzylamine directly from benzaldehyde was used as the model reaction. First, the reaction was performed in different solvents at 25 °C, as different solvents have different properties, which would influence the catalyst performance, and the results are listed in Table 1. Three products including NTable 1. Results of the Synthesis of N-Dibenzylamine from Benzaldehyde in Different Solventsa
selectivity (%) entry
solvent
conv (%)
1
2
1 2 3 4 5 6 7 8
hexane dichloromethane ethyl acetate p-xylene THF methanol isopropanol H2O
48.0 26.2 30.7 65.1 93.8 100 100 100
91.6 96.8 97.4 77.4 55.2 58.2 49.6 67.2
8.4 − − 22.6 43.8 41.8 50.4 14.0
Figure 1. Effect of amount of catalyst on the reaction. Reaction conditions: i-PrOH (10 mL), 20 bar H2, and 25 °C for 2 h.
5 to 20 mg, the conversion of the reaction increased gradually and reached 100% when 20 mg of catalyst was used. This is because of more catalytic active sites as the amount of catalyst increased. However, when the amount of catalyst increased to 25 mg, no more effect on the conversion or selectivity on the reaction was found. Moreover, the amount of catalyst showed no effect on the selectivity on N-dibenzylamine. Therefore, the optimized amount of catalyst is 20 mg. With the aim to improve the selectivity of N-dibenzylamine in isopropanol, other reaction conditions were further optimized (Table 2). The selectivity of N-dibenzylamine greatly increased from 50.4% at 25 °C to 87.0% at 0 °C
Reaction conditions: benzaldehyde (1 mmol), solvent (10 mL), NH3· H2O (2.8 mmol), catalyst (20 mg), 20 bar H2, and temperature (25 °C) for 2 h. a
benzylidenebenzylamine, N-dibenzylamine, and benzyl alcohol were detected for the reaction of benzaldehyde in the presence of ammonia and hydrogen molecules in the presence of the γFe2O3@HAP-Pd catalyst. Obviously, benzyl alcohol was generated from the hydrogenation of benzaldehyde. NDibenzylamine was the end product, which was formed from the hydrogenation of N-benzylidenebenzylamine (the inter14767
DOI: 10.1021/acs.iecr.7b03887 Ind. Eng. Chem. Res. 2017, 56, 14766−14770
Article
Industrial & Engineering Chemistry Research
yield of 96.6% at 0 °C and 1 bar H2 with 4.2 equiv of NH3. Moreover, this reaction showed no conversion without catalyst or with γ-Fe2O3@HAP as catalyst (Table 2, entries 12 and 13), indicating that Pd catalyst is needed in this transformation. To the best of our knowledge, this is the first time for the synthesis of secondary amines directly from the coupling of two carbonyl compounds under such mild conditions. The high activity at low temperature and atmospheric H2 pressure enables the use of common glass reactors, demonstrating a promising potential in industrial application from an economical, environmental, and safe viewpoint. Reaction Pathway of the Transformation of Benzaldehyde into N-Dibenzylamine. To better understand the reaction process, the time course of the reaction pathway was recorded. The reaction was performed at a lower temperature of −10 °C and 1 bar H2 with the aim to give more information about the reaction intermediate. As shown in Figure 2, the
Table 2. Optimization of the Reaction Conditions for the Synthesis of N-Dibenzylaminea
selectivity (%) entry
T (°C)
H2 (bar)
NH3·H2O (mmol)
conv (%)
1
2
1 2 3 4 5 6 7 8 9 10 11b 12c 13d
25 0 −10 0 0 0 0 0 0 0 0 0 0
20 20 20 10 7.5 5 2.5 1 1 1 1 1 1
2.8 2.8 2.8 2.8 2.8 2.8 2.8 2.8 1.4 4.2 4.2 4.2 4.2
100 87.1 53.4 88.1 73.8 55.2 46.1 38.1 30.0 52.9 100 0 0
49.6 13.0 0 10.2 11.2 14.6 12.4 11.2 53.8 2.0 3.4 0 0
50.4 87.0 98.0 89.8 88.2 85.4 87.6 88.8 46.2 98.0 96.6 0 0
a
Reaction conditions: benzaldehyde (1 mmol), isopropanol (10 mL), catalyst (2.5 wt % Pd, 20 mg), 2 h. bThe reaction time was 6 h. cNo catalyst was added. dγ-Fe2O3@HAP was added as catalyst.
under the same reaction conditions, albeit the conversion of benzaldehyde decreased from 100% to 87.1% after 2 h (Table 2, entries 1 and 2). These results suggested that the hydrogenation of benzaldehyde into benzyl alcohol was highly sensitive to the reaction temperature. Furthermore, the hydrogenation of benzaldehyde into benzyl alcohol was completely inhibited at −10 °C, but the conversion of benzaldehyde continuously decreased to 53.4% after 2 h (Table 2, entry 3). Taking the conversion of benzaldehyde and the selectivity of N-dibenzylamine into account, the reaction temperature was set at 0 °C, as it can produce both high conversion and high selectivity of N-dibenzylamine. Furthermore, the effects of hydrogen pressure and the amount of ammonia amount on this reaction were investigated. It was noted that benzaldehyde conversion gradually increased with the increase of the hydrogen pressure from 1 to 10 bar, and then almost remained stable at 20 bar (Table 2, entries 2 and 4−8). The increase of benzaldehyde conversion at higher hydrogen pressure was due to the increase of the hydrogen concentration in the reaction solution, and it can be considered that hydrogen concentration in the reaction solution was almost constant with the hydrogen pressure beyond 10 bar. Interestingly, the product selectivity at 0 °C was almost not influenced by the hydrogen pressure (Table 2, entries 2 and 4− 8). The effect of ammonia amount was also studied. It was noted that both benzaldehyde conversion and N-dibenzylamine selectivity increased with the increase of ammonia amount (Table 2, entries 2 and 8−10). For example, benzaldehyde conversion increased from 30.0% with 1.4 equiv of NH3 to 52.9% with 4.2 equiv of NH3 after 2 h at 0 °C and 1 bar H2, and the formation of benzyl alcohol was greatly inhibited with 4.2 equiv of NH3. This is due to the higher concentration of ammonia that promoted the condensation step of benzaldehyde with ammonia, and thus inhibited the hydrogenation of benzaldehyde into benzyl alcohol. By prolonging the reaction time to 6 h, N-dibenzylamine was produced in an excellent
Figure 2. Time course of the product distribution for the synthesis of N-dibenzylamine from benzaldehyde. Reaction conditions: γ-Fe2O3@ HAP-Pd (20 mg), benzaldehyde (1 mmol), NH3·H2O (4.2 mmol), −10 °C, isopropanol (10 mL), H2 (1 bar).
concentration of benzaldehyde gradually decreased during the reaction process, and the concentration of N-dibenzylamine gradually increased. Furthermore, the concentrations of Nbenzylidenebenzylamine and benzylamine gradually increased at an early reaction stage, and then decreased at the late reaction stage. Therefore, both N-benzylidenebenzylamine and benzylamine were the intermediates for the transformation of benzaldehyde into N-dibenzylamine. Benzylamine should be produced from the condensation of benzaldehyde with NH3 to generate phenylmethanimine (compound A, Scheme 2) and the subsequent hydrogenation of phenylmethanimine.17,18 However, phenylmethanimine was not detected due to its instability.18,19 The as-formed benzylamine underwent condensation with benzaldehyde to generate the other intermediate N-benzylidenebenzylamine (compound B, Scheme 2), which was a very fast step. Thus, the concentration of benzylamine was very low during the reaction process. NBenzylidenebenzylamine was further reduced to the final product of N-dibenzylamine (compound C, Scheme 2). After 10 h, N-dibenzylamine was produced in a high yield of 95.6% with benzaldehyde conversion of 100% at −10 °C and 1 bar H2. Substrate Scope of the Developed Method. The substrate scope of the developed method was finally studied (Table 3). The γ-Fe2O3@HAP-Pd catalyst was active not only 14768
DOI: 10.1021/acs.iecr.7b03887 Ind. Eng. Chem. Res. 2017, 56, 14766−14770
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Industrial & Engineering Chemistry Research Scheme 2. Reaction Pathway for the Synthesis of N-Dibenzylamine
Table 3. Substrate Scope of the Developed Catalytic Systema
affording high yields of the corresponding secondary amines. For the less active aliphatic aldehydes, the reactions were performed at 25 °C, affording the corresponding secondary amine in good yield (Table 3, entry 16). Unfortunately, we failed to extend our method to ketones because of the higher steric effect. Recycling of the γ-Fe2O3@HAP-Pd Catalyst. The recycling experiments of the Fe2O3@HAP-Pd catalyst were finally studied. The transformation of benzaldehyde into Ndibenzylamine was used as the model reaction, and the reaction was performed at 0 °C for 6 h. After reaction, the γ-Fe2O3@ HAP-Pd catalyst was easily recovered from the reaction mixture with the assistance of an external magnet, and then it was washed with a large amount of water and ethanol, respectively. The content of Pd in the reaction mixture was not detected with inductively coupled plasma mass spectrometry (ICP-MS). Furthermore, the filtered solution did not exhibit any further reactivity. Then the recovered γ-Fe2O3@HAP-Pd catalyst was dried in a vacuum oven overnight. The spent catalyst was reused for the second run, and the reaction conditions were the same as the first run. As shown in Figure 3, the γ-Fe2O3@HAP-
Reaction conditions: substrate (1 mmol), isopropanol (10 mL), γFe2O3@HAP-Pd (2.5 wt % Pd, 20 mg), 26.5 wt % NH3·H2O (300 μL, 4.2 mmol), 6 h, 1 bar H2. bThe reaction was conducted at 25 °C. a
for the aromatic aldehydes (Table 3, entries 1−14), but also for the less reactive cyclohexanecarboxaldehyde and aliphatic carbonyl compounds, affording good to excellent secondary amines (Table 3, entries 15 and 16). The activities of the aromatic aldehydes were affected by the substituted groups and steric effect. First, substrates with electron-withdrawing groups were less active than those with electron-donating groups. For example, no conversions were observed for the substrates of 4fluorobenzaldehyde and 4-(trifluoromethyl)benzaldehyde with stronger electron-withdrawing groups at 0 °C and good yields can be attained with a reaction temperature of 25 °C (Table 3, entries 1 and 2). However, dehalogenation was observed for 4bromobenzaldehyde (Table 3, entry 3), which produced a 78% yield of benzaldehyde and a 22% yield of N-benzylidenebenzylamine. Then, substrates with more steric groups were less active than those with less steric effect. For example, 4-methylbenzaldehyde shown a higher conversion and yields compared with 3- methylbenzaldehyde, and for more steric 2-methylbenzaldehyde they become even lower. To our pleasure, the γFe2O3@HAP-Pd catalyst was tolerant to other functional groups such as esters (Table 3, entry 9) and the carboxylic group (Table 3, entry 10). This catalytic system was also effective for the heterocyclic aldehydes (Table 3, entries 11− 13) and fused-ring aromatic aldehyde (Table 3, entry 14),
Figure 3. Recycling experiments of the γ-Fe2O3@HAP-Pd catalyst. Reaction conditions: benzaldehyde (1 mmol), isopropanol (10 mL), γFe2O3@HAP-Pd (20 mg), 26.5 wt % NH3·H2O (300 μL, 4.2 mmol), 0 °C, 6 h, 1 bar H2.
Pd catalyst can be reused six times without the loss of its catalytic activity. As shown in Figure 3, the yields remained over 90% and the catalytic activity of the γ-Fe2O3@HAP-Pd catalyst was fully restored without apparent loss of activity and selectivity during the recycling experiments.
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CONCLUSION In conclusion, an unprecedented method was developed for the one-pot synthesis of secondary amines directly via the coupling of two carbonyl compounds in the presence of NH3 and H2 over the magnetic γ-Fe2O3@HAP-Pd catalyst. This method produced the structurally diverse secondary amines with good to excellent yields from the readily available carbonyl compounds under very mild conditions. Furthermore, the γ14769
DOI: 10.1021/acs.iecr.7b03887 Ind. Eng. Chem. Res. 2017, 56, 14766−14770
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nanostructures encapsulated in metal−organic frameworks. Chem. Commun. 2017, 53, 1184−1187. (17) Ide, M. S.; Hao, B.; Neurock, M.; Davis, R. J. Mechanistic insights on the hydrogenation of α, β-unsaturated ketones and aldehydes to unsaturated alcohols over metal catalysts. ACS Catal. 2012, 2, 671−683. (18) Xu, X.; Li, Y.; Gong, Y.; Zhang, P.; Li, H.; Wang, Y. Synthesis of Palladium nanoparticles supported on mesoporous N-doped carbon and their catalytic ability for biofuel upgrade. J. Am. Chem. Soc. 2012, 134, 16987−16990. (19) Gomez, S.; Peters, J. A.; van der Waal, J. C.; Zhou, W.; Maschmeyer, T. Preparation of benzylamine by highly selective reductive amination of benzaldehyde over Ru on an acidic activated carbon support as the catalyst. Catal. Lett. 2002, 84, 1−5.
Fe2O3@HAP-Pd catalyst was highly stable without the loss of its catalytic activity during the recycling experiments.
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AUTHOR INFORMATION
Corresponding Author
*Tel.: +86-135-4529-5675. E-mail:
[email protected]. ORCID
Peng Zhou: 0000-0002-3317-3747 Bing Liu: 0000-0001-8451-695X Zehui Zhang: 0000-0003-1711-2191 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (21203252).
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