Designing a Potential Pathway for the Catalytic Synthesis of 1,3-Cyclohexanediamine

Abstract

Cyclohexylamines are important and valuable key intermediates in the chemical industry, playing a crucial role in the synthesis of a variety of compounds. Developing a low-cost and efficient synthesis route for these chemicals is highly desirable but also presents significant challenges due to the complexity of the reactions involved. Herein, we designed three pathways for the production of 1,3-cyclohexanediamine (1,3-CHDA), including the one-pot reductive amination of resorcinol (RES) with ammonia and molecular hydrogen, the reductive amination of 1,3-cyclohexandione (1,3-CHD) with ammonia, and the oximation–hydrogenation of 1,3-CHD. Through systematical investigation, we finally developed a low-cost, simple operation and an efficient methodology for the synthesis of 1,3-CHDA as follows: RES was firstly hydrogenated in H₂O over Raney Ni to obtain 1,3-CHD, and then the obtained liquid reaction mixture was used directly for the subsequent oximation with hydroxylamine hydrochloride without further purification to form the oxime intermediate, followed by the hydrogenation of the oxime in methanol over Raney Ni to achieve the target product 1,3-CHDA with a high yield.

1. Introduction

Primary amines are known to be key compounds in agricultural, pharmaceutical, textile, and personal care industries [1]. Due to their importance, much effort has been devoted to developing various approaches for the synthesis of primary amines, such as the N-alkylation of ammonia with haloalkanes [2], the reduction of nitriles [3], the hydrocyanation and reduction of alkenes [4], the hydroamination of olefins [5], and the reductive amination of hydroxyl or carbonyl compounds [6]. In regard to our target chemical, i.e., 1,3-cyclohexanediamine (1,3-CHDA), which is widely used as a significant intermediate in the chemical industry, one possible synthesis pathway is the hydrogenation of the benzene ring in m-phenylenediamine. For example, Yang et al. [7] investigated the hydrogenation of m-phenylenediamine over Ru/g-C₃N₄ catalysts at 130 °C and 5 MPa H₂, and achieved a 73% yield of 1,3-CHDA after 24 h. Tomkins and Müller [8] studied the hydrogenation of the benzene ring in the methyl-phenylenediamines (o- and m- diamines) over LiOH-treated Ru/CNT catalysts, obtaining the corresponding methyl-cyclohexanediamines with yields not exceeding 54%. The authors attributed the relatively lower yields of alicyclic amines to the competition adsorption of amino groups with the benzene ring on metal active sites, which hinders the hydrogenation of the benzene ring. Considering that the aniline derivatives are industrially produced by the hydrogenation of nitro groups [9], an ambitious strategy to produce alicyclic amines is the one-pot process by the simultaneous hydrogenation of both the nitro groups and the benzene ring. Unfortunately, the ever reported yield of 2-methyl-1,3-cyclohexanediamine by this method over LiOH-treated Ru/CNT was only 48% [8]. Although cyclohexanamine is easily achieved in high yields (exceeding 90%) from aniline or nitrobenzene [10,11], the direct hydrogenation of m-phenylenediamine or m-dinitrobenzene does not seem to achieve satisfactory 1,3-CHDA yields, mainly due to the effects of mutual electron transfer and steric hindrance between the substitute groups on the benzene ring in addition to the influence of the competition adsorption of amino groups, which is similar to our previous study on the selective hydrogenation of biphenols to the corresponding cyclohexanediones [12,13].

Another strategy to synthesize 1,3-CHDA is by the reductive amination or oximation–hydrogenation of 1,3-cyclohexandione (1,3-CHD). The former involves the condensation of carbonyl groups with ammonia to form imines, followed by the hydrogenation of the C=N bond to 1,3-CHDA.In our previous work, 1,3-cyclohexanediamine [14] and 3-aminocyclohexanone [15] have been prepared by the reductive amination of 1,3-cyclohexanedione. The latter involves the oximation of 1,3-CHD with hydroxylamine salts to oxime, and then oxime is hydrogenated to 1,3-CHDA [16]. G. Merling [17] reports on a systematic study of the synthesis, structural characterization, and chemical properties of dihydroresorcin with the aim of revealing its reciprocal isomeric behavior and the differences in its reactions with related compounds. The study’s exploration of the underlying chemical reaction mechanism provides us with a guide for the subsequent design of reaction routes for industrial applications.

Furthermore, it may be possible to synthesize 1,3-CHDA by the one-pot reductive amination of the phenolic hydroxyl compound resorcinol (RES), an inexpensive by-product from the coal carbonization industry. As we know, the reductive amination of alcohols generally includes the dehydrogenation of the alcoholic hydroxyl group into the carbonyl group via a ‘borrowing hydrogen mechanism’, which is generally regarded as the rate-controlling step, and then is followed by the reductive amination of the formed carbonyl group with amine reagents [18]. Differently from the reductive amination of alcohols, the reductive amination of RES involves the partial reduction of RES firstly to enol structures, which undergo enol–keto tautomerization to 1,3-CHD, thereby avoiding the challenging dehydrogenation step of the hydroxyl groups [19]. Therefore, it seems an exciting pathway for the synthesis of 1,3-CHDA.

The present work focused on developing a potential industrial process for the production of 1,3-CHDA. Considering the infeasibility of the aforementioned hydrogenation pathway of m-phenylenediamine or m-dinitrobenzene, we prefer the synthesis pathways involving reductive amination or oximation–hydrogenation. As shown in Scheme 1, the following three synthesis pathways have been proposed for the production of 1,3-CHDA by changing the substrate and the amine reagents. (1) The one-pot pathway: In this pathway, we tried to use RES as the substrate to form the target product 1,3-CHDA via one-pot reductive amination with ammonia and H₂ gas. (2) The ammonia pathway: In this pathway, we used 1,3-CHD instead of RES as the substrate for the reductive amination process, while 1,3-CHD can be obtained from the hydrogenation of RES over Pd or Ni catalysts [12]. And (3) the hydroxylamine hydrochloride pathway: In this route, 1,3-CHD and hydroxylamine salt firstly undergo the oximation reaction to form the intermediate 1,3-cyclohexandione dioxime (1,3-CHDO), and then 1,3-CHDO is hydrogenated to 1,3-CHDA. We established and optimized the reaction conditions for each pathway to achieve the highest yield of 1,3-CHDA, and finally developed a competitive route for the synthesis of 1,3-CHDA.

2. Results and Discussion

2.1. Synthesis of 1,3-CHDA by One-Pot Reductive Amination of RES

Inspired by our previous work on the reductive amination of 5-hydroxymethylfurfural into 2,5-bisaminomethylfuran [20,21], we thought that the most exciting pathway for the production of 1,3-CHDA would be the one-pot reductive amination of RES with ammonia, by which after the benzene ring of RES is first partially hydrogenated by the hydrogen atoms over metal catalysts, the formed enol intermediate isomerizes rapidly to 1,3-CHD, followed by the reductive amination of carbonyl groups with ammonia and molecular hydrogen to form the final product 1,3-CHDA. This idea is also supported by Cuypers et al. [19], who obtained a 99% yield of cyclohexylamine via the reductive amination of phenol with ammonia over Ni/Al₂O₃ catalysts. We replicated the reductive amination of phenol over the industrial Raney Ni catalyst with a cyclohexylamine yield of 91.3% (entry 1,

Table 1. Reductive amination of phenol and benzenediols.

Entry	Substrate	Reaction Conditions	Product (Yield)
1		0.5 MPa NH3, 2 MPa H2
			91.3
2		0.5 MPa NH3, 2 MPa H2
			58.5%
3		0.5 MPa NH3, 2 MPa H2
			63.2%		<1.0%
4		0.5 MPa NH3, 2 MPa H2
			38.0%		<1.0%
5		0.63 g NH3OH∙HCl, 0.40 g NaOH, 2 MPa H2
			23.5%	15.0%		<1.0%

Reaction conditions: substrate 0.50 g, H₂O 15 mL, Raney Ni 0.20 g, 170 °C, 10 h.

). Unfortunately, when we changed the raw materials from phenol to benzenediols, the main products were not always the expected cyclohexanediamines (entries 2–4, Table 1). Only 1,4-benzenediol was mainly converted into the expected 1,4-CHDA in a 58.5% yield via one-pot reductive amination (entry 2, Table 1). Using 1,2-benzenediol and 1,3-benzenediol (i.e., RES) as the substrates, however, less than 1.0% of the corresponding cyclohexanediamines were obtained, but with a 63.2% yield of decahydrophenazine and a 38.0% yield of 3-amino-2-ene-cyclohexanone, respectively (entries 3 and 4, Table 1). Replacing NH₃ with hydroxylamine hydrochloride as a stronger nucleophilic reagent still obtained less than a 1.0% yield of 1,3-CHDA, but a 15% yield of cyclohexanol and a 23.5% yield of cyclohexylamine, respectively (entry 5, Table 1), indicating that dehydroxylation mostly occurred during the reductive amination of RES. The variation in commercially available catalysts or other reaction conditions was also not helpful for improving the 1,3-CHDA yield. As aforementioned, we attribute the discrepancy to the neglective effect of the functional group at the o- and m-positions. In our previous study on the hydrogenation of RES, a satisfactory yield of 1,3-CHD (e.g., >60%) seemed not possible from the hydrogenation of RES over commercially available Pd- or Ni-based catalysts except when an alkaline additive such as NaOH or tributylamine is introduced to stabilize the enol intermediate [12].

2.2. Synthesis of 1,3-CHDA by Ammonia Pathway from 1,3-CHD

To achieve a high yield of 1,3-CHDA, we attempted to carry out the reductive amination of 1,3-CHD with NH₃ over various commercially available metal hydrogenation catalysts. During the reductive amination process, unexpected side reactions occurred, and multiple by-products were generated, including cyclohexylamine II, intermediate product 3-amino-2-enone cyclohexanone III, 3-aminocyclohexanone IV, 3-amino cyclohexanol V, cyclohexanol VI, and other by-products (mainly polymerized secondary and tertiary amines). As shown in

Table 2. Reductive amination of 1,3-CHD with NH₃ over different commercial metal catalysts.

Entry	Catalyst	Conv. (%)	Yield (%)
						Others
			(I)	(II)	(III)
1	Pd/C	100	-	25.1	68.3	6.60
2	Pt/C	100	0.63	2.11	91.5	5.76
3	Ru/C	100	-	-	96.4	3.60
4	Rh/C	100	-	1.90	87.0	11.1
5	Raney Ni	100	37.5	26.8	20.1	15.6
6	Raney Ni a	97.5	-	0.10	94.6	2.80
7	Raney Ni b	80.5	26.9	37.6	-	16.0

Reaction conditions: 1,3-CHD 0.10 g (0.89 mmol), 1,4-dioxane 15 mL, catalyst 0.05 g, 0.50 MPa NH₃, 2.0 MPa H₂, 150 °C, 4 h. ^a 5 min. ^b 0.10 g III as the substrate, 4 h.

, noble metal catalysts Pd/C, Pt/C, Ru/C, and Rh/C resulted in only a trace of 1,3-CHDA, with the main product being III (Entries 1–4, Table 2). It is surprising that when using Raney Ni as the catalyst for the reductive amination of 1,3-CHD (Entry 5, Table 2), a 37.5% yield of the target product 1,3-CHDA was achieved, along with major by-products II (26.8%) and III (17.1%). When reducing the reaction time to 5 min, the Raney Ni-catalyzed reductive amination of 1,3-CHD gave a 97.5% conversion of 1,3-CHD and a 97.0% yield of the intermediate III (Entry 6, Table 2). Simultaneously, by using III as the substrate and Raney Ni as the catalyst (Entry 7, Table 2), it was observed that the distribution of reaction products in the reductive amination of III was essentially consistent with that in the reductive amination of 1,3-CHD (Entry 7 vs. 5, Table 2). This indicates that in the reductive amination of 1,3-CHD, one carbonyl group in the 1,3-CHD molecule is first attacked by ammonia, and, after a dehydration process, the carbon–carbon and carbon–oxygen double bonds form a stable p-π conjugation, resulting in the production of III, and other products are presumed to be generated through its further reactions [22].

Solvents are considered to have a significant influence on the reductive amination reaction [23]. Therefore, the effect of solvents on the reductive amination of 1,3-CHD with NH₃ was investigated. As shown in

Table 3. Solvent effect on the reductive amination of 1,3-CHD with NH₃ over Raney Ni.

Entry	Solvent	Conv. (%)	Yield (%)
									Others
			(I)	(II)	(III)	(IV)	(V)	(VI)
1	H2O	100	0.51	-	79.5	18.8	0.32	0.12	0.75
2	Methanol	100	5.00	-	68.0	27.0	-	-	-
3	1-Butanol	100	14.7	17.5	36.3	20.4	8.67	1.31	1.12
4	Isopropanol	100	12.9	27.7	16.7	13.1	25.1	4.50	-
5	Toluene	100	34.4	30.6	13.0	5.84	4.16	6.87	5.13
6	Cyclohexane	100	34.3	13.4	-	2.20	31.2	4.50	14.4
7	1,4-Dioxane	100	37.5	26.8	20.1	1.05	10.4	4.02	0.13
8	1,4-Dioxane a	100	53.1	30.6	0.46	2.04	8.41	1.39	4.00

Reaction conditions: 1,3-CHD 0.10 g (0.89 mmol), solvent 15 mL, Raney Ni 0.05 g, 0.50 MPa NH₃, 2.0 MPa H₂, 150 °C, 4 h. ^a 170 °C, 3 h.

, in the highly polar solvents water and alcohols (Entries 1–4, Table 3), only yields of 1,3-CHDA less than 15% were obtained, and the main products were the intermediate III and its C=C bond hydrogenation product IV, which may be due to the fact that polar solvents can stabilize the enamine structure [24]. In low- or non-polar solvents such as toluene and cyclohexane (Entries 5 and 6, Table 3), the reaction rate was faster, but significantly more by-products of secondary and tertiary amines were produced. The main reason is considered to be their lower ammonia solubility, and thus the ammonia in the system is not sufficient to suppress further reactions between the primary amine and carbonyl groups [25]. The reductive amination reaction in the solvent 1,4-dioxane showed the best results with a 37.5% yield of 1,3-CHDA (Entry 7, Table 3), mainly owing to its moderate polarity and sufficient ammonia solubility. By further optimizing other reaction conditions including reaction temperature, reaction time, ammonia pressure, and hydrogen pressure (Table S1), a higher 1,3-CHDA yield of 53.1% (the ratio of cis–trans isomers was 17:83) was obtained, with II as the main by-product (Entry 8, Table 3). Using other moderately polar oxygen-containing organic solvents (Table S2), the yields of 1,3-CHDA and the distribution of by-products were similar to the results in 1,4-dioxane. The significant production of the deamination by-product II may be due to the instability of such cyclic vicinal structures in the hydrogenation environment, and meanwhile the reductive amination reaction requires a higher reaction temperature, making it prone to losing a functional group [26].

2.3. Synthesis of 1,3-CHDA by Hydroxylamine Hydrochloride Pathway from 1,3-CHD

Due to the relatively low yield of 1,3-CHDA in the above-mentioned ammonia pathway, we designed a hydroxylamine hydrochloride pathway using 1,3-CHD as the raw material to further improve the yield of 1,3-CHDA. In this synthetic strategy, 1,3-CHD and hydroxylamine salt firstly undergo the oximation reaction to produce the key intermediate 1,3-CHDO, and then 1,3-CHDO is hydrogenated to 1,3-CHDA. In comparison to NH₃, the nitrogen in hydroxylamine exhibits stronger nucleophilic activity due to the electron-donating effect of the hydroxyl group [27]. Consequently, carbonyl groups are more facile to form oximes by nucleophilic addition with hydroxylamine than to form imines with NH₃. For the same reason, the presence of the hydroxyl group in C=N increases the electron cloud density of the C=N bond in an oxime, making the electrophilic addition of hydrogen to the C=N bond in oximes much easier than that to the only C=N bond in imines [28]. Additionally, the N-O bond in oximes is easy to cleave under the hydrogenation conditions to produce primary amines [29]. In this pathway, the rational design and optimization for the high-yield production of 1,3-CHDA is significant but challenging.

In the oximation reaction of 1,3-CHD, hydroxylamine hydrochloride was chosen as the hydroxylamine salt to save costs. The reaction of 1,3-CHD and hydroxylamine hydrochloride is reversible. Therefore, an excess of hydroxylamine hydrochloride is necessary to perform an efficient oximation reaction. Meanwhile, a base is needed to neutralize and release hydroxylamine for further reaction with 1,3-CHD [30]. Firstly, using triethylamine (TEA) as a base, the reaction solvent was optimized. As shown in

Table 4. Results of the oximation of 1,3-CHD with hydroxylamine hydrochloride.

Entry	Solvent	Base	n (NH3OH·HCl: 1,3-CHD)	n (Base: NH3OH·HCl)	pH Value	Yield (%)
1	Methanol	TEA	2.50	1.20	-	85.5
2	Methanol–H2O a	TEA	2.50	1.20	-	54.2
3	H2O	TEA	2.50	1.20	5.00	88.3
4	H2O	Pyridine	2.50	1.20	4.50	88.4
5	H2O	Na2CO3	2.50	1.20	7.00	71.9
6	H2O	NaOH	2.50	1.20	7.67	64.5
7	H2O	NaOH	2.50	1.30	10.93	26.9
8	H2O	NaOH	2.50	1.10	6.90	68.4
9	H2O	NaOH	2.50	1.05	6.60	73.3
10	H2O	NaOH	2.25	1.05	7.07	78.1
11	H2O	NaOH	2.20	1.05	6.58	92.1
12	H2O	NaOH	2.10	1.05	6.27	91.1
13	H2O b	NaOH	2.20	1.05	6.58	97.5

Reaction conditions: 1,3-CHD 2.24 g (20 mmol), solvent 15 mL, 25 °C, 3 h; ^a v (methanol-to-H₂O) = 1:1. ^b 5 °C, 3 h.

, a higher 1,3-CHDO yield (88.3%) was achieved in H₂O than in methanol or a methanol–water mixture (Entry 3 vs. entries 1, 2, Table 4). 1,3-CHDO has good crystallinity [31]. It is insoluble in water and could be easily obtained by simple filtration. Considering the cost-effectiveness, environmental friendliness, and simplicity of product separation, water was chosen as the reaction solvent for the oximation of 1,3-CHD. Next, four different bases were selected for the neutralization of hydroxylamine hydrochloride, and the initial pH values of the reactions were recorded to investigate the influence of pH on the reaction. Using TEA and pyridine as the bases, the initial pH values were 5.00 and 4.50, respectively, and high yields of 1,3-CHDO (88.3% and 88.4%) were obtained (Entries 3, 4, Table 4). Na₂CO₃ gave a 71.9% yield of 1,3-CHDO (Entry 5, Table 4). NaOH, being a stronger base, gave a 64.5% yield of 1,3-CHDO in the same reaction conditions (Entry 6, Table 4). From a cost perspective, NaOH was chosen as the base for the following optimization. When increasing the amount of NaOH, the pH value exceeded 10, and 1,3-CHDO yield was only 26.9% (Entry 7, Table 4), indicating that an excessively high pH value is not conducive to the oximation of 1,3-CHD. It can be noted that, with the decrease in the amount of NaOH, the pH value decreased to nearly neutral, and the 1,3-CHDO yield increased (Entries 8 and 9, Table 4). Remarkably, a high 1,3-CHDO yield of 92.1% was achieved under nearly neutral conditions by adjusting the ratio of NH₃OH·HCl to 1,3-CHD (Entry 11, Table 4). By the further optimization of the reaction temperature and time (Table S3), the highest 1,3-CHDO yield of 97.5% was achieved (Entry 13, Table 4).

Subsequently, the hydrogenation of 1,3-CHDO to 1,3-CHDA over the non-noble catalyst Raney Ni was investigated. The hydrogenation of 1,3-CHDO follows a comparable reaction pathway, initially undergoing dehydration to form imine, which is then hydrogenated to form 1,3-CHDA, with the production of by-products such as cyclohexanol and cyclohexylamine being related to the hydrolysis and deamination of the imine [32]. It can be seen from

Table 5. Optimization of the hydrogenation of 1,3-CHDO to 1,3-CHDA.

Entry	Solvent	Cat. Dosage (g)	Conv. (%)	Yield (%)
							Others
1	Methanol	0.06	100	60.0	2.10	8.30	29.6
2	Methanol	0.1	100	79.0	7.15	4.92	8.93
3	Methanol	0.3	100	87.4	6.06	4.34	2.20
4	N-Methyl-pyrrolidone	0.3	100	52.6	47.4	-	-
5	H2O	0.3	84.1	-	44.2	39.9	-
6	1-Butanol	0.3	100	92.7	3.52	3.36	0.42
7	Isopropanol	0.3	100	92.3	5.10	0.27	2.33
8	1,4-dioxiane	0.3	98.7	92.8	1.68	0.74	3.48

Reaction conditions: 1,3-CHDO 0.20 g (1.4 mmol), catalyst Raney Ni, solvent 15 mL, 1.0 MPa H₂, 50 °C, 4 h.

that Raney Ni exhibited good performance for the hydrogenation reaction. Under reaction conditions of 0.06 g catalyst, 1.0 MPa H₂, and 50 °C for 4 h, the hydrogenation of 1,3-CHDO in methanol gave a 60.0% yield of 1,3-CHDA with the complete conversion of 1,3-CHDO (Entry 1, Table 5). Increasing the catalyst dosage resulted in an increase in the yield of 1,3-CHDA, and an 87.4% yield of 1,3-CHDA was achieved when the catalyst dosage was 0.3 g (Entries 2,3, Table 5). Moreover, the hydrogenation of 1,3-CHDO was affected by the solvents. Due to its high polarity, 1,3-CHDO is poorly soluble in non-polar solvents such as toluene and cyclohexane, making hydrogenation reactions challenging in these solvents. Various solvents with moderate polarity were chosen for the hydrogenation of 1,3-CHDO. In N-methyl-pyrrolidone, the yield of 1,3-CHDA was only 52.6%, and the main by-product was cyclohexylamine. In water, a large number of the by-products cyclohexanol and cyclohexylamine were obtained, resulting from the hydrolysis and deamination of the imine. Higher 1,3-CHDA yields were obtained when 1,3-CHDO was hydrogenated in alcoholic solvents and 1,4-dioxane, with 1,3-CHDA yields around 90%. Considering that 1,3-CHDO showed a good solubility in methanol (Table S4), methanol was chosen as the reaction solvent, which not only allows for a reduction in solvent usage and energy consumption by increasing the substrate concentration but also lowers costs due to the affordability of methanol. Figure 1a demonstrates the effect of H₂ pressure on the hydrogenation of 1,3-CHDO. At 1.0 MPa H₂, the yield of 1,3-CHDA reached 87.4%, and the highest 1,3-CHDA yield of 90% was given at 2.0 MPa. Further increasing the H₂ pressure did not significantly improve the yield. As shown in Figure 1b, when the substrate concentration was in the range of 0.013–0.04 g/mL, the yield of 1,3-CHDA reached around 90%. However, continuing to increase the substrate concentration led to a gradual decrease in the yield of 1,3-CHDA. Hence, the optimal substrate concentration for the hydrogenation of 1,3-CHDO was controlled between 0.013 and 0.04 g/mL. Meanwhile, the hydrogenation of 1,3-CHDO was obviously affected by temperature and reaction time (Figure 1c,d). At room temperature for 4 h, only a 43.8% yield of 1,3-CHDA was obtained. With the increase in the temperature to 50 °C, a complete conversion of 1,3-CHDO and a maximum 1,3-CHDA yield of 90% (the ratio of cis–trans isomers was 41:59) was achieved after 4 h of reaction, which was much higher than that obtained by the above ammonia pathway. The excessive reaction temperature (>80 °C) and time (>4 h) decreased the yield of 1,3-CHDA and noticeably increased the by-products cyclohexylamine and cyclohexanol.

Moreover, we applied our developed methodology to the transformation of various cyclohexanones to form the corresponding cyclohexylamines under the optimum reaction conditions for the oximation–hydrogenation of 1,3-CHD to 1,3-CHDA (Table S5). It can be seen that high yields (80–93%) of the corresponding oximes in the oximation step and high yields (76–100%) of the corresponding cyclohexylamines in the hydrogenation step were achieved, respectively, in all the cases tested. These results indicate that we provided an efficient methodology for the oximation–hydrogenation of cyclohexanones to the corresponding cyclohexylamines.

2.4. Synthesis of 1,3-CHDA by Hydroxylamine Hydrochloride Pathway from RES

1,3-CHD is relatively expensive as a raw material, which is not the optimal substrate choice for the industrial production of 1,3-CHDA. As we know, 1,3-CHD can be synthesized from the aqueous phase catalytic hydrogenation of RES with a high yield [13]. Therefore, RES can be used as an alternative starting material due to its low cost. After the hydrogenation of RES, the reaction mixture is simply filtered to remove the solid catalyst, and the liquid phase can be used directly for the subsequent reaction to simplify the process and save costs. However, this process is not applicable to the production of 1,3-CHDA by the ammonia pathway, since the optimal solvent was 1,4-dioxane in the reductive amination step of 1,3-CHD (Table 3). And thus, the purification of 1,3-CHD is necessary in the ammonia pathway. It is worth noting that the above-mentioned process is suitable in the hydroxylamine hydrochloride pathway, where the solvent for the oximation reaction is also H₂O.

We firstly investigated and optimized four different reaction systems for the hydrogenation of RES, and achieved over 94% yields of 1,3-CHD (Table S6). To save costs and streamline the process, the NaOH–Raney Ni system was chosen for the hydrogenation of RES, which gave a 95% yield of 1,3-CHD under reaction conditions of 100 °C and 2 MPa H₂ for 3 h. After removing the Raney Ni catalyst by filtration, the reaction mixture of RES hydrogenation was added to an appropriate amount of NaOH and hydroxylamine hydrochloride, and the oximation reaction was carried out at 5 °C for 3 h, achieving an 83.6% yield of 1,3-CHDO (based on RES). The subsequent hydrogenation of 1,3-CHDO was performed under the optimized reaction conditions and achieved a 90% yield of 1,3-CHDA in this step.

In summary, through the optimization of the raw materials and reaction conditions, we ultimately developed an efficient methodology for the production of 1,3-CHDA (Scheme 2). We selected RES as the starting material and obtained 1,3-CHD by hydrogenation. Subsequently, we conducted oximation–hydrogenation to obtain the final product 1,3-CHDA with a total yield of 75.2%.

3. Experimental Section

3.1. Materials

1,3-CHD, RES and hydroxylamine hydrochloride were purchased from Macklin Reagent Co., Ltd. (Shanghai, China). Ammonia and hydrogen gases were supplied by Hangzhou Xiyate Gas Co., Ltd. (Hangzhou, China), with a purity exceeding 99.99%. Commercial catalysts 5 wt% Pd/C, 5 wt% Pt/C, 5 wt% Ru/C, 5 wt% Rh/C, and Raney Ni were purchased from Shaanxi Rock New Materials Co., Ltd. (Baoji, China). Other chemicals used were purchased from China National Pharmaceutical Group Corporation (Shanghai, China). All the chemicals used in this work were analytical reagents and were used directly without any treatment.

3.2. Synthesis Section

3.2.1. Synthesis of 1,3-CHD from Hydrogenation of RES

In a typical experiment, 2 g (18.2 mmol) of RES, 10 mL of H₂O, 0.80 g of sodium hydroxide, and 0.20 g of Raney Ni were introduced into a 50 mL stainless-steel autoclave equipped with magnetic stirring. After being sealed and purged by H₂ for 3 times, the reactor was pressurized with H₂ to the designated pressure with continuous stirring at 1000 rpm. Afterwards, the reactor was heated to the designated temperature to initiate the reaction. After the reaction, the reaction bulk was cooled down to room temperature, and the reaction products were separated from the catalyst by filtration and analyzed by GC or GC-MS.

3.2.2. Synthesis of 1,3-CHDA by Reductive Amination of RES (One-Pot Pathway)

In a typical experiment, 0.5 g (4.5 mmol) of RES, 15 mL of H₂O, and 0.20 g of Raney Ni were introduced into a 50 mL stainless-steel autoclave equipped with magnetic stirring. After being sealed and purged by H₂ for 3 times, the reactor was pressurized with NH₃ and H₂ to the designated pressure successively and separately with continuous stirring at 1000 rpm. Afterwards, the reactor was heated to the designated temperature to initiate the reaction. After the reaction, the reaction bulk was cooled down to room temperature, and the reaction products were separated from the catalyst by centrifugation and analyzed by GC or GC-MS.

3.2.3. Synthesis of 1,3-CHDA by Reductive Amination of 1,3-CHD (Ammonia Pathway)

In a typical experiment, 0.10 g (0.89 mmol) of 1,3-CHD, 15 mL of 1,4-dioxane, and 0.05 g of Raney Ni were introduced into a 50 mL stainless-steel autoclave equipped with magnetic stirring. After being sealed and purged by H₂ for 3 times, the reactor was pressurized with NH₃ and H₂ to the designated pressure successively and separately with continuous stirring at 1000 rpm. Afterwards, the reactor was heated to the designated temperature to initiate the reaction. After the reaction, the reaction bulk was cooled down to room temperature, and the reaction products were separated from the catalyst by centrifugation and analyzed by GC or GC-MS.

3.2.4. Synthesis of 1,3-CHDA by Oximation–Hydrogenation of 1,3-CHD (Hydroxylamine Hydrochloride Pathway)

Oximation of 1,3-CHD: in a typical experiment, 2.24 g (20 mmol) of 1,3-CHD, 20 mL of H₂O, 1.84 g (46 mmol) of sodium hydroxide, and 3.06 g (44 mmol) of hydroxylamine hydrochloride were introduced into a 100 mL round-bottom flask with a magnetic stirring bar. Afterwards, the flask was immersed in a cooling bath to maintain the reaction temperature with a stirring rate of 800 rpm. The product 1,3-CHDO, which is precipitated from the aqueous solution, was collected by filtration and vacuum-dried for use.

Hydrogenation of 1,3-CHDO: in a typical experiment, 0.20 g (1.4 mmol) of 1,3-CHDO, 15 mL of methanol, and 0.30 g of Raney Ni were introduced into a 50 mL stainless-steel autoclave equipped with magnetic stirring. After being sealed and purged by H₂ for 3 times, the reactor was pressurized with H₂ to the designated pressure with continuous stirring at 1000 rpm. Afterwards, the reactor was heated to the designated temperature to initiate the reaction. After the reaction, the reaction bulk was cooled down to room temperature, and the reaction products were separated from the catalyst by centrifugation and analyzed by GC or GC-MS.

3.3. Purification Procedure

Excess hydrochloric acid was added to the hydrogenation reaction solution of 1,3-cyclohexanedione dihydrazone to convert the product 1,3-cyclohexanediamine into its hydrochloride salt. After adding acetone, crystals of 1,3-cyclohexanediamine hydrochloride precipitated out, and the product was purified by recrystallization.

3.4. Analytical Method

The products were analyzed with an Agilent (Santa Clara, CA, USA) 8090A GC equipped with an HP-5 capillary column (30.0 m × 0.32 mm × 0.25 μm) and a flame ionization detector (FID) using N-methylpyrrolidone as an internal standard. In order to confirm the structure of the reaction components, spectral analysis was performed using gas chromatography–mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) spectroscopy. The GC-MS analyses were performed using an Agilent 6890 GC system and a mass spectrometer equipped with an Agilent 5973 quadrupole mass spectrometer. The structure of the compound was further confirmed by ¹H NMR and ¹³C NMR spectra recorded on a Bruker (Billerica, MA, USA) AVANCENEO 500 MHz spectrometer using deuterated water and deuterated dimethyl sulfoxide as solvents. The corresponding analytical data, including representative mass and NMR spectra (¹H, ¹³C), are presented in the Supplementary Material (Figures S1 and S2).

4. Conclusions

Aiming at establishing a potential industrial route for the production of 1,3-CHDA, three possible synthesis pathways were designed and investigated, involving the one-pot reductive amination of RES with ammonia and molecular hydrogen, the reductive amination of 1,3-CHD, and the oximation–hydrogenation of 1,3-CHD. Finally, a low-cost, simple operation with an efficient methodology for the synthesis of 1,3-CHDA was developed. In this pathway, RES was firstly hydrogenated in H₂O over Raney Ni to obtain 1,3-CHD, then the obtained liquid reaction mixture was used directly for the subsequent oximation with hydroxylamine hydrochloride to form the oxime intermediate 1,3-CHDO, and finally 1,3-CHDO was hydrogenated over Raney Ni to achieve 1,3-CHDA with a total yield exceeding 75%.