N-Alkylation of amines with phenols over highly active heterogeneous palladium hydride catalysts

Abstract

Phenols are directly converted to secondary amines in considerable yield via hydrogenation and amination tandem reaction over Al₂O₃ supported palladium hydride (PdH_x) bi-functional catalyst. Note that this system proceeds efficiently with mild conditions under H₂ atmosphere, which was difficult to achieve in previous reports. The catalyst and the mechanism of reaction are both studied. Furthermore, various secondary amines can be formed in good yields under this conversion system.

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Secondary amine compounds are important moieties in pharmaceuticals, agrochemicals, and materials.^1,2 The synthesis of secondary amines was investigated extensively in laboratory studies and industrial operations.³ The traditional synthesis methods of secondary amines are via coupling amines with alcohols,⁴ organic halides,⁵ and carbonyl compounds.⁶ However, toxic and unstable agents (such as alkyl halides, aldehydes, phosphine ligands) are widely used in the traditional syntheses, which always result in environment problems.^4–6

Recently, as the valorization of renewable and green resources in organic synthesis getting popular, synthetic methods of secondary amine compounds based on renewable and abundant substrates have received extensive attentions. For instances, reductive alkylation of amine with abundant and cheap carbon dioxide has been reported by Cantat and Beller respectively.⁷ In our previous report, formic acid and other alkyl carboxylic acids, which are less toxic, easy to store and transport, and available from biomass in part, have also been demonstrated to be capable in the synthesis of substituted amines.⁸ Lately our attentions were drawn to lignin-derived phenols, a new renewable carbon resource. Based on the reports about the depolymerisation of lignin, production of phenols (like cresol, 4-propylphenol, guaiacol) from lignin in large scale may be possible in the future.⁹ Lignin-derived phenols were newly proved to be another promising substrate in the synthesis of secondary amines by Li and co-workers.¹⁰ This method derives from the reductive alkylation of amines with cyclohexanone, but it is more practical and straightforward. Soon after Li's report, Taddiei and his colleagues reported that microwave (MW) heating was more conducive to the reductive amination of phenols.¹¹ While, in above reports, sodium formate was used as hydrogen resources to reduce phenols via the catalytic hydrogen transfer reaction. Catalytic hydrogenation with molecule hydrogen for the reductive amination reaction seemed to be difficult at low temperature in above reported reactions. Accordingly, highly efficient catalytic hydrogenation systems for the reductive amination of phenols with molecule hydrogen are still necessary to develop.

In order to improve the catalytic activity of Pd catalysts, palladium hydride drawn our attention. Palladium hydride (PdH_x), which is widely investigated as an excellent hydrogen storage material,¹² is newly proved that would improve the catalytic activity of supported Pd catalyst.¹³

Herein, we report a catalyzed hydrogenation and amination tandem process for the production of secondary amine from lignin-derived phenols over PdH_x/Al₂O₃ bi-functional catalyst under H₂ atmosphere (shown in Scheme 1). The reaction could be operated under mild conditions with high yield of target amine. Compared with previous reports,^10,11 this is the most moderate conditions for the reductive amination of phenols under hydrogen atmosphere. The catalyst could maintain good activity after 5 times using. Additionally, various phenols and amines were used to synthesize different secondary amines and their related steric effects were also investigated. Finally, the mechanism of tandem reaction was proposed based on the kinetic study.

Scheme 1 Reductive amination of lignin-derived phenols over PdH_x/Al₂O₃ catalyst.

Initially, various Pd catalysts were synthesized and tested in the reductive amination reaction to find the superior one (Table S1, in ESI†). All the Pd catalysts were characterized by XRD (Fig. S1, in ESI†). In the catalyst screening, most of the supported Pd catalysts preformed low catalytic activity for this conversion except Pd/Al₂O₃ catalyst. Besides, we also tested the catalytic activity for the hydrogenation of phenols with those Pd catalysts. Contrary to our expectation, the Pd catalysts showed good and similar catalytic performs for the hydrogenation of phenol to cyclohexanone in the tests (Table S2, in ESI†). Hence, the low catalytic activity of Pd catalysts in reductive amination was due to the poisoning effects of p-toluidine. Finally, Al₂O₃ was chosen as support for PdH_x catalyst synthesis. The PdH_x/Al₂O₃ catalyst was prepared via reported methods,¹⁴ and characterized by TEM, XPS and XRD (shown in Fig. 1). TEM results reflected that PdH_x nanoparticles were about 4.7 nm. Comparing with the XPS of Pd/Al₂O₃, Pd peak on PdH_x/Al₂O₃ shifted to 0.28 eV higher binding energy. Besides, in XRD patterns, a new peak at lower angle (θ = 39.4°) appeared in the PdH_x/Al₂O₃ catalyst, when the peak of Pd(0) (θ = 40.0°) decreased. The peaks shifting in XPS and XRD characterizations are attributed to the forming of PdH_x species, that are similar to the previous reports.^13,14 From the above results, PdH_x/Al₂O₃ was prepared successfully.

Fig. 1 (a) TEM picture of PdH_x/Al₂O₃; (b) Pd 3d XPS spectrums of PdH_x/Al₂O₃ and Pd/Al₂O₃; (c) XRD patterns for PdH_x/Al₂O₃ and Pd/Al₂O₃.

Consistent with our expectations, fresh PdH_x/Al₂O₃ catalyst showed a higher catalytic activity than Pd/Al₂O₃ in the reductive amination reaction (entry 1–2, Table 1). The high activity would be due to the species of PdH_x. In contrast, the yield of 3a was only 8% when PdH_x/C was used in the reaction (entry 3, Table 1). That means support is another important role in the catalytic activity. Additionally, PdH_x/Al₂O₃ catalyst showed good stability. After 5 times using, 71% yield of 3a was still observed (entry 5, Table 1). No targeted product was detected when this reaction was carried out under Ar atmosphere, confirming there was no NaBH₄ left in the PdH_x/Al₂O₃ catalyst (Table S1, in ESI†). Besides, the solvent effect was also investigated (Table S3, in ESI†). Non-polar solvent (such as hexane, toluene) were more benefit for this conversion than polar solvent (such as alcohols, γ-valerolactone, acetonitrile, N,N-dimethylformamide and 1,4-dioxane). But, 47% yield of 3a was observed when water was used as solvent. In the Sheldon's hot filtration test, the reaction stopped completely after filtrating out the solid catalysts. Just trace of leached Pd cations (0.0025 mg Pd) was detected via ICP test in the solvent (Table S4, in ESI†).

Table 1 Catalyst screening for the reductive amination^a

Entry	Catalyst	Conversion (%)	3a yield (%)
a Reaction conditions: 0.2 mmol phenol and 0.4 mmol p-toluidine are added into 2 mL hexane with 40 mg catalyst under 1 atm H2 atmosphere, 50 °C for 3 hours.b Reaction time is extended to 5 hours.c Catalyst was used 5^th, the yield is confirmed by GC with p-tertbutylbenzene as internal standard.
1	5% Pd/Al2O3	57	45
2	5% PdHx/Al2O3	75	70
3	5% PdHx/C	9	8
4^b	5% PdHx/Al2O3	95	94
5^c	5% PdHx/Al2O3	80	71

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To investigate the properties of Al₂O₃ carriers, the fresh and used PdH_x/Al₂O₃ catalysts were characterized by FT-IR (shown in Fig. 2). The bands at 598 cm⁻¹, 800 cm⁻¹ are attributed to Al–O–Al bond stretching.¹⁵ The water molecules coordinated on Al₂O₃ are corresponded to absorption bands located in the 1415 and 1630 cm⁻¹ regions.¹⁵ The adsorbed water molecule may act as an acid proton donor, it promoted the hydrogenation of phenol to cyclohexanone.¹⁶ The infrared absorption features in 3450 cm⁻¹ and 3558 cm⁻¹ regions are attributed to the stretching of O–H bond on the Al₂O₃ surface.¹⁵ New peaks at 1157 cm⁻¹ and 1234 cm⁻¹, observed in the IR spectra of used PdH_x/Al₂O₃ catalyst, are caused by adsorbed phenol and intermediate cyclohexanone on the surface used PdH_x/Al₂O₃.¹⁶ Meanwhile, the decreasing of infrared absorptions at 1415 cm⁻¹ in the used catalyst was attributed to the reducing of adsorbed water on Al₂O₃. Those observations reflected that the phenols were adsorbed and replaced the absorbed water molecule over the surface of Al₂O₃. Next to the adsorption, the absorbed phenol was hydrogenated to cyclohexanone over PdH_x/Al₂O₃ (shown in Scheme 2). This process was consistent with Slowing's work.¹⁶ The adsorbed phenol and cyclohexanone hindered the adsorption of the soluble p-toluidine over the surface of catalyst and prevented the catalyst from poisoning.

Fig. 2 FT-IR spectra of flesh PdH_x/Al₂O₃ and used PdH_x/Al₂O₃ catalysts.

Scheme 2 The proposed mechanism for the phenol adsorption over PdH_x/Al₂O₃ and the hydrogenation of phenol in reaction.

With the kinetics study (Fig. S6 in ESI†), two possible reaction pathways were proposed in Scheme 3. In the major pathway, phenol was converted to cyclohexanone (m1), and then m1 was coupled with p-toluidine over acid sites of Al₂O₃. Formed imine (m2) was reduced to product (3a) over PdH_x/Al₂O₃ catalyst. In the minor pathway, p-toluidine was hydrogenated into enamine intermediate. Whereafter, the unstable intermediate enamine yielded p-methylcyclohexanone (sm1) via hydrolysis. Following conversion was similar with the major pathway. Similar process was in previous reports.¹⁷ Remarkably, the ratio of cis/trans forms of 3d confirmed that the hydrogenation process was mainly carried out on the plane of catalyst.

Scheme 3 Two possible pathways for the reductive amines reaction.

To extend the scope of this conversion system, various phenols and substituted amines were inspected with the modified reaction conditions. The results in Table 2 showed that most of reductive amination products would be formed in good yield. In general, the steric effect of the substitutes on phenols showed remarkable negative influence on reaction efficiency. For example, ortho-substituted cresol showed nearly no conversion (3b, Table 2). However, under the same reaction condition, meta- and para-substituted cresol gained 74% and 88% yield of product respectively (3c and 3d, Table 2). The desired products decreased from 36% to 15% with the increase of the steric hindrance in para-position (3e–3g, Table 2). Interestingly, the site of substituted methyl group on aniline did not remarkably impact the yields of N-alkylation products (3h–3k, Table 2). Nevertheless, anilines with large substituted groups at ortho sites were inert for this conversion (3l and 3m, Table 2). Furthermore, the anilines bearing electron-drawing groups and electron-donating groups were also compatible in this conversion (3n–3r, Table 2). It was notable that dehalogenation process would happen when 4-chloro-aniline and 4-bromo-aniline were used as substrates (Scheme S1, in ESI†). Pyridine-2-amine, a heterocyclic amine, had shown no reaction over PdH_x/Al₂O₃ catalyst (3s, Table 2). Furthermore, the reactivity of alkylamines was also considered, and target products were observed and confirmed by GC-MS (3t–3v, Table 2) (Fig. S7–S9 in ESI†). Notably, during the process of tertiary amine formation, cyclohexanol was observed in the reaction system as intermediate which was not observed in the reductive amination process. This result is possibly due to the different mechanisms of the formation of secondary and tertiary amines.

Table 2 Substrate scope of reductive amination^a

a Reaction conditions: 0.2 mmol phenol and 0.4 mmol amine are added into 2 mL hexane with 40 mg catalyst under 1 atm H₂ atmosphere, 70 °C for 10 hours. The yield is confirmed by GC with p-tertbutylbenzene as internal standard.b The reaction time is extended to 20 hours.c The products were confirmed by GC-MS.

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In summary, we have developed a high active PdH_x/Al₂O₃ catalyst for reductive coupling of lignin-derived phenols with amines in high yield and good stereoselectivity under mild conditions. The superior performance of the PdH_x/Al₂O₃ catalyst is likely due to the high reactivity of PdH_x species and the activation of phenol by Al₂O₃ support. The promising results present a great potential in the application of lignin as a renewable reagent for fine chemical preparation in the future.

Acknowledgements

This work was supported by the 973 Program (2012CB215306), NSFC (21325208, 21402181, 21572212), IPDFHCPST (2014FXCX006) CAS (KFJ-EW-STS-051, YZ201563), FRFCU and PCSIRT.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra22383d

‡ The authors contributed equally to this work.

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