2022, Vol.51, No.1


Colloidal metal nanoparticles were examined for reductive amination of phenol by ammonia under mild reaction conditions. The results showed that Rh-PVP was the most active catalyst for reductive amination reaction. Linear, cyclic, and amino alcohols were used as nucleophiles and converted to primary/secondary/tertiary amines. Using this strategy, the synthesis of an industrially important chemical, N-cyclohexyl-2-pyrrolidone was explored.

Cyclohexylamine is an important intermediate for the synthesis of pharmaceuticals, agrochemicals electronic materials, vulcanization accelerators and polymers.1 Conventionally, cyclohexylamine is produced via a two-step procedure that involves hydrogenation of nitrobenzene to aniline28 followed by hydrogenation of aniline to cyclohexylamine.913 The starting material for this procedure, nitrobenzene, is generally generated via nitration of benzene; however this requires the use of copious amount of acids, which creates environmental issues and safety concerns. Thus, an atom-economical and environmentally sustainable method for producing cyclohexylamine is needed.

Biomass-derived phenols are cheap and readily available and can be used for cyclic C-6 feedstock. Recently, various catalytic methods have been studied for the synthesis of cyclohexanone and cyclohexanol produced from biomass-derived phenols.1422 Reductive amination of cyclohexanone by ammonia/amines can produce cyclohexylamine/N-substituted cyclohexylamine. Recently, Li and the Vaccaro group developed a simple and efficient method for the synthesis of N-substituted cyclohexylamine using Pd/C catalyst.2325 However, these methods require large amounts of catalyst, have low atom-economy and require use of an organic solvent. Furthermore, these methods can only be used to produce secondary or tertiary cyclohexylamine derivatives. The synthesis of cyclohexylamine was challenging because of the low stability of cyclohexylamine. De Vos et al. reported a Rh/C catalyst for the synthesis of cyclohexylamine using a large amount of ammonia (7 equivalent) and high temperature (100 °C).26 Later, the same group explored the first non-noble catalyst (Ni/Al2O3) for a similar transformation using relatively harsh reaction conditions (10 mol % catalyst and 160 °C).27 Thus, in consideration of green chemistry, solvent-free conditions are the most favourable to minimize the costs and waste (Scheme 1).

In recent years, colloidal metal nanoparticles have received more attention because of their high activity and selectivity for the desired product. Previously, our group prepared PVP stabilized Rh nanoparticles by using a microwave-assisted polyol reduction method which provides a simple, fast and efficient method for preparing Rh nanoparticles, and we found that this catalyst demonstrated excellent activity for synthesis of secondary imine from nitriles.28 Later, we studied selective hydrogenation of benzoic acid derivatives and quinolines under solvent-free conditions by Rh-PVP.29 As part of our continuing interest in the applications of the Rh nanoparticles, we report herein Rh nanoparticles catalyzed reductive amination of phenol by ammonia/amines under solvent-free conditions.

Initially, we examined reductive amination of phenol by aqueous ammonia as a model reaction for optimization of metal catalysts. As summarized in Table 1, the reactions were performed under mild reaction conditions (5 bar H2 and 40 °C) without reaction solvent. Among tested catalysts, Rh-PVP catalyst afforded the highest yield (96%) of cyclohexylamine (Entry 1). Ru-PVP and Pt-PVP catalysts delivered low yields of cyclohexylamine but Ru-PVP afforded a high yield of cyclohexanol and Pt-PVP afforded cyclohexanol and dicyclohexylamine. Pd-PVP and Ir-PVP catalysts showed low conversion of phenol (Entries 4 and 5). Next, we compared the activity of Rh-PVP with previously reported Rh/C and Pd/C catalysts. Both (Rh/C and Pd/C) catalysts were purchased from Tokyo Chemical Industry Co. Ltd. Rh/C gave full phenol conversion and 87% yield of cyclohexylamine. The mild conditions (40 °C, NH3 aq and neat) with Rh/C catalyst were more favorable for the synthesis of cyclohexylamine than previously reported conditions (140 °C, NH3 in methanol and 2-propanol).26 On the other hand, dicyclohexylamine was obtained as product in presence of Pd/C catalyst (Entry 6 and 7). No product formation was observed in the absence of catalyst (Entry 8).

Table 1. Screening of noble catalyst for reductive amination of phenol by ammoniaa
Table 1. Screening of noble catalyst for reductive amination of phenol by ammoniaa
entry catalyst particle size (nm) conv.
GC yield
1 Rh-PVP 6.5 ± 1.8 99 96:3:1
2 Ru-PVP 3.8 ± 1.1 99 33:54:0
3 Pt-PVP 3.9 ± 0.4 36 8:13:6
4 Pd-PVP 4.8 ± 0.7 10 1:0:0
5 Ir-PVP 1.7 ± 0.4 10 0:2:1
6b Pd/C 99 0:0:91
7b Rh/C 99 87:1:1
8 No catalyst 0 0:0:0

aReaction conditions: phenol (1 mmol), NH3 (aq) (1.2 mmol), catalyst (2 mol %), H2 (5 bar), 40 °C, 24 h. bPurchased from Tokyo Chemical Industry CO. LTD.

We also examined the effects of different solvents on reductive amination by ammonia in presence of Rh-PVP (Figure 1). When toluene or 2-propanol was used as reaction solvent, a high (88%) and moderate (67%) yield of cyclohexylamine was obtained respectively. Surprisingly, the reaction using water afforded cyclohexanol as the major product. This result was consistent with previous report by the Yan group.30 Reductive amination of cyclohexanone by gaseous NH3 in water also showed cyclohexanol as a major product. Water can act as a hydrogen donor which favors hydrogenation of C=O double bonds.31 Overall, Rh-PVP was found to be an active catalyst for reductive amination of phenol by phenol under solvent-free conditions.

The general applicability of Rh-PVP catalyst was examined for the reductive amination of phenol using various amines as the N-source (Table 2). High to moderate yield of corresponding secondary amines were obtained from linear amine (Entry 1 and 2). Aminol alcohol was transformed with high yield (91%) without decomposing the C-O bond (Entry 4). Cyclic amines such as pyrrolidone were selectively converted to the tertiary amine. The reaction with cyclohexylmethyl-amine and 2-phenylethylamine afforded moderate to low yield of the corresponding amine (Entries 6 and 7).

Table 2. Reductive amination of phenol by various amines over Rh-PVPa
Table 2. Reductive amination of phenol by various amines over Rh-PVPa

Next, we expanded the general applicability of Rh-PVP for the reductive amination of substituted phenols by ammonia as N-source under modified reaction conditions (40 °C and 7 bar H2) and ammonia as the N-source. A methyl substituent on the phenol ring affected the rate of reaction of o- and p-toluidine (Table 3); the electron donating inductive effect (+I) might be responsible for that phenomenon. When phenol with a bulky group was used, the conversion of phenol was low but the selectivity of corresponding cyclohexylamines was not affected. Biomass-derived lignin contains three types of C-O crosslinks: α-O-4, β-O-4 and 4-O-5 linkage of C-O bond. Among these, the diphenyl ether of 4-O-5 (BDE = 314 kJ mol−1) is stronger than the aliphatic ether bond of α-O-4 (BDE = 218 kJ mol−1) and β-O-4 (BDE = 289 kJ mol−1).32 We, therefore, increased the reaction temperature and pressure (100 °C and 20 bar H2) for reductive amination of diphenyl ether and 70% yield primary amine was obtained with 4% yield of (cyclohexyloxy)benzene (Scheme S1).

Table 3. Reductive amination of substituted phenols by ammonia over Rh-PVPa
Table 3. Reductive amination of substituted phenols by ammonia over Rh-PVPa

Table S1 shows the comparative study between previously reported catalysts and Rh-PVP catalyst for reductive amination of phenol by ammonia/amines. Rh-PVP catalyst showed 95% yield of the products and turnover number (TON) of 46 under mild reaction conditions. This TON is 2 and 4 times higher than reported Rh/C and Ni/Al2O3 catalyst respectively.26,27 When HCOONa and NaBH4 were used as hydrogen sources, carbon-supported Pd catalytic systems showed TON of 32, 13 and 0.008.2325 These results clearly demonstrate the high catalytic efficiency of the present system.

N-Cyclohexyl-2-pyrrolidone (CHP) is used an important solvent for photoresist stripper in the electronics industry, as a chemical polisher in circuit board fabrication and as a dye carrier in aramid fabrics.3335 In previous reports, the synthesis of CHP has been achieved using [BMIM]BF4 catalyzed lactamization of cyclohexylamine with γ-butyrolactone,36 Cu-catalyzed N-alkylation of 2-pyrrolidone by cyclohexyl bromide,37 and Rh-catalyzed cyclization of N-prop-2-enyl cyclohexyl-amine.38 However, these methods require high temperature (200 °C), functionalized and toxic reactants and alkyl halides that produce copious amount of salt waste. Initially we carried out reaction of phenol and 4-amino butyric acid using Rh-PVP catalyst but a low yield (41%) of CHP was obtained (Table S2). In previous reports, tin (Sn) has generally been used for the activation of carboxylic acid via interaction between carbonyl oxygen and the Lewis acid sites of Sn. Therefore, the addition of Sn to a catalytic system can enhance the selectivity of desired product.39 With considering this fact, we prepared 5 wt % Rh-PVP-5 wt % Sn/TiO2 catalyst using impregnation and evaluated it for one-pot synthesis of CHP from phenol and 4-aminobutyric acid (Scheme 2). This catalyst afforded the moderate yield (60%) of CHP synthesized from cyclohexanol (40%). Note that this was the first example for the synthesis of CHP from phenol and 4-aminobutyric acid under mild reaction conditions.

The recyclability of Rh-PVP catalysts was also investigated under optimized reaction conditions for reductive amination of phenol by aqueous ammonia. After the first cycle, the catalyst was washed with acetone, separated by centrifugation and dried at 80 °C for 12 h under vacuum. As shown Figure 2, Rh-PVP catalyst was reused with minor loss in the yield of cyclohexylamine with increase in the yield of cyclohexanol. Furthermore, the morphology of recovered catalyst was examined using scanning transmission electron microscopy (STEM). The surface of Rh-PVP catalyst was slightly aggregated after the first cycle. Probably, such aggregation in Rh metal might be responsible for increased yield of cyclohexanol in the second and third cycle (Figure S1).


Figure S2 shows the time-yield course of cyclohexylamine for reductive amination of phenol by NH3 under optimized reaction conditions. In this profile, a consecutive reaction mechanism was observed; the intermediate (cyclohexanone) was converted to cyclohexylamine in presence of ammonia. On the other side, the intermediate (cyclohexanone) was transformed to cyclohexanol in absence of ammonia (Figure S3). However, reductive amination of phenol by NH3 in water gave cyclohexanol as the major product.

In a plausible reaction mechanism, phenol is converted to cyclohexanone in the presence of [Rh-PVP]/[H]. Then, cyclohexanone undergoes condensation with ammonia to cyclohexanimine (eq 1). We investigated the possibility of non-catalytic condensation reaction of cyclohexanone and ammonia. No formation of cyclohexanimine was observed in the absence of catalyst (eq 2). Finally, hydrogenation of imine produces the desired product, cyclohexylamine in the presence of [Rh-PVP] (Scheme 3).

In summary, we have developed an efficient catalytic method for reductive amination of phenol by ammonia. Rh-PVP catalyst was able to synthesize cyclohexylamines under mild reaction conditions (40 °C and 5 bar H2). In addition, we found that our approach could be used for the synthesis of industrially important chemicals such as N-cyclohexyl-2-pyrrolidone from phenol.

This work was partly supported by Advanced Characterization Platform of the Nanotechnology Platform Japan (JPMXP09-A-20-KU-0356) sponsored by the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. We are grateful to T. Toriyama, Dr. T. Yamamoto, and Prof. S. Matsumura of Kyushu University for his helpful support in the analysis with scanning transmission electron microscopy (STEM) images. This research was supported by the ACCEL program, Japan Science and Technology Agency (JST), JPMJAC1501.

Supporting Information is available on https://doi.org/10.1246/cl.210574.