Method for preparing trans-4-methylcyclohexanol with high selectivity

Abstract

The invention belongs to the field of organic synthesis, and discloses a method for preparing trans-4-methylcyclohexanol with high selectivity. The preparation method comprises the following steps: stirring nickel salt and a ligand in an organic solvent I to react under an inert gas condition to obtain a nickel catalyst; wherein the ligand is at least one of L1, L2 and L3; and (2) adding the nickel catalyst prepared in the step (1) and 4-methylphenol into a solvent II, and carrying out hydrogenation reaction to obtain trans-4-methylcyclohexanol. The method is mild in reaction condition and high in product yield (91%), and 4-methylcyclohexanol with high trans ratio is obtained with high selectivity. The used nickel catalyst has higher activity and lower cost, so that the method is expected to be widely applied to synthesis of trans-4-methylcyclohexanol.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, and particularly relates to a method for preparing trans-4-methylcyclohexanol. Background Technology

[0002] 4-Methylcyclohexanol is a high-boiling-point solvent and fragrance raw material with excellent performance, good solubility, unique aroma quality, and good safety. As a moderately polar solvent, compared with some traditional chlorinated hydrocarbons or strongly polar solvents, this compound has lower toxicity and irritation, making it safer to use and store. It has good solubility for resins, oils, and waxes, and its moderate evaporation rate is beneficial for coating leveling and reduces evaporation loss during use, while also being environmentally friendly and economical. In terms of aroma characteristics, it presents a mild and long-lasting woody / camphor-like scent, suitable for soaps, detergents, and home fragrance products. It can be used as a fixative and blending fragrance, effectively enhancing the overall fragrance quality and longevity. trans-4-methylcyclohexanol is a compound with a single stereostructure and uniform chemical properties. It can be used as a chiral structural unit in pharmaceuticals, materials, pesticides, and other fields. In particular, as a fragrance, it has a more unique aroma than 4-methylcyclohexanol. Therefore, the development of trans-4-methylcyclohexanol synthesis research is of great significance.

[0003] 4-Methylcyclohexanol is generally synthesized from 4-methylphenol via hydrogenation. The hydride reduction or catalytic hydrogenation of 4-methylphenol typically produces a mixture of cis- and trans-4-methylcyclohexanols. Subsequent methods such as recrystallization and column chromatography are needed to separate the isomers to obtain either cis-4-methylcyclohexanol or trans-4-methylcyclohexanol. The main drawbacks of this method are: the reaction conditions are relatively harsh, requiring high temperatures and pressures, demanding sophisticated equipment and consuming significant energy; the catalysts used are often noble or transition metals, making them expensive and susceptible to deactivation due to impurities, hindering recovery and reuse; and the biggest challenge lies in the lack of stereoselectivity, simultaneously generating a mixture of cis- and trans-4-methylcyclohexanol isomers. Because the two are similar in physicochemical properties, subsequent separation and purification steps are complex, yields are limited, and costs are significantly increased, making it difficult to efficiently obtain a high-purity product with a single configuration. This, to some extent, restricts its widespread application in fine chemicals requiring specific stereostructures (such as high-end fragrances). Therefore, it is of great significance to develop a simple, low-cost method for the one-step hydrogenation synthesis of trans-4-methylcyclohexanol from 4-methylphenol with high selectivity for trans products. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention proposes a method for the highly selective preparation of trans-4-methylcyclohexanol.

[0005] To achieve the above objectives, the technical solution of the present invention is implemented as follows:

[0006] A method for highly selectively preparing trans-4-methylcyclohexanol, comprising the following steps:

[0007] (1) Under inert gas conditions, nickel salt and ligand are reacted in organic solvent I with stirring to obtain a nickel catalyst; wherein the ligand is at least one of L1, L2 and L3:

[0008] ;

[0009] (2) The nickel catalyst and 4-methylphenol prepared in step (1) are added to solvent II, hydrogen gas is introduced, and trans-4-methylcyclohexanol is obtained by hydrogenation reaction.

[0010] The specific reaction formula is as follows:

[0011] .

[0012] In step (1) above, the molar ratio of nickel salt to ligand is 1:1-1.6. The stirring reaction is carried out at a temperature of 60-120℃ for 5-12 h.

[0013] Furthermore, in step (1) above, the nickel salt is at least one selected from Ni(acac)2, NiCl2, NiBr2, NiI2, Ni(NTf2)2, Ni(BF4)2, Ni(OAc)2•4H2O, Ni(NO3)2, NiSO4, Ni(OTs)2, and Ni(ClO4)2. The organic solvent I is any one selected from tetrahydrofuran, benzene, toluene, p-xylene, 1,4-dioxane, dimethyl sulfoxide, 1,2-dichloroethane, diethyl ether, cyclohexane, chloroform, dichloromethane, and petroleum ether.

[0014] In step (2) above, the amount of nickel catalyst added is 5-60% of the mass of 4-methylphenol. Solvent II is any one of tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, and diethyl ether.

[0015] Furthermore, in step (2) above, the pressure of hydrogen is 3-4 MPa. The temperature of the hydrogenation reaction is 100-130℃, and the time is 5-12 h.

[0016] trans-4-methylcyclohexanol was prepared using the above-described highly selective method for preparing trans-4-methylcyclohexanol.

[0017] In the nickel-catalyzed hydrogenation of 4-methylphenol, the high selectivity of trans-4-methylcyclohexanol stems from the specific interaction between the nickel catalyst and the reactants. 4-Methylphenol is immobilized through π-π interactions within the aromatic ring and coordination of the phenolic hydroxyl oxygen atom with nickel; this two-site adsorption locks the conformation of the nickel catalyst-substrate complex. Subsequently, the Ni-H species generated by the catalyst activation with hydrogen stepwise hydrogenates the benzene ring. Under the combined effect of the catalyst's conformational locking of the substrate and the steric effect of the methyl group on the substrate ring, hydrogen atoms tend to add from the opposite side of the ring plane, providing stereochemical induction in the crucial unsaturated intermediate stage, ultimately placing the methyl and hydroxyl groups on opposite sides of the trans-addition on the cyclohexane ring. Simultaneously, the spatial structure and electronic properties of the nickel catalyst further stabilize the trans-addition transition state, ultimately leading to the highly selective formation of trans-4-methylcyclohexanol under the combined influence of kinetic control and thermodynamic stability.

[0018] The beneficial effects of this invention are:

[0019] (1) This invention provides a method for highly selectively preparing trans-4-methylcyclohexanol. Trans-4-methylcyclohexanol is obtained by reacting 4-methylphenol as a raw material under the action of hydrogen and nickel catalyst. The reaction conditions are mild, the product yield is high (91%), and high trans-proportion 4-methylcyclohexanol can be obtained without isomer separation of the product.

[0020] (2) The nickel catalyst used in this invention includes nickel salts and ligands (any one or a combination of L1, L2 and L3), which have significant advantages: high efficiency in hydrogenation reactions, low cost, good stability and controllability, and easy recycling. Therefore, this method is expected to be widely used in trans-4-methylcyclohexanol. Attached Figure Description

[0021] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0022] Figure 1 The cis-4-methylcyclohexanol of this invention 1 H NMR spectrum.

[0023] Figure 2 The cis-4-methylcyclohexanol of this invention 13 C10 NMR spectrum.

[0024] Figure 3 The present invention relates to trans-4-methylcyclohexanol. 1 H NMR spectrum.

[0025] Figure 4 The present invention relates to trans-4-methylcyclohexanol. 13 C10 NMR spectrum.

[0026] Figure 5 The 4-methylcyclohexanol (cis:trans ratio of 1:9) prepared in Example 1 of this invention 1 H NMR spectrum.

[0027] Figure 6 The 4-methylcyclohexanol (cis:trans ratio of 1:9) prepared in Example 1 of this invention 13 C10 NMR spectrum. Detailed Implementation

[0028] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0029] Example 1

[0030] This embodiment provides a highly selective method for preparing trans-4-methylcyclohexanol, comprising the following steps:

[0031] (1) Synthesis of ligand L1

[0032] Under anaerobic and anhydrous conditions, 0.121 g of pyridine-2-boric acid (0.55 mmol), 0.176 g of compound I (0.5 mmol), 0.029 g of tetra(triphenylphosphine)palladium (0.025 mmol), and 0.207 g of potassium carbonate (1.5 mmol) were added sequentially to a dried reaction vessel that had undergone a three-cycle vacuum-nitrogen exchange. Using dimethylformamide (10 mL) as solvent, the mixture was first stirred at room temperature for 20 minutes, then heated to 150 °C and reacted for 10 hours. After the reaction was completed and cooled to room temperature, a mixture of ammonium hydroxide (5 mL), tetrahydrofuran (10 mL), and water (5 mL) was added. The mixture was stirred at room temperature for 16 hours, then extracted with ethyl acetate (15 mL × 3). The combined organic phases were then subjected to saturated brine (10 mL × ... Wash with 2 mL of the product, dry with anhydrous sodium sulfate, filter, remove solvent by vacuum distillation, and purify the crude product by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1 to 2:1 gradient) to obtain 0.102 g of L1, with a yield of 92%. 1H NMR δ 8.74 (dd, J = 4.1, 1.7 Hz, 1H), 8.70-8.63 (m, 2H), 8.41 (dd, J = 8.1, 1.3 Hz, 1H), 8.15 (dd, J = 7.2, 1.5 Hz, 1H), 7.82 (td, J = 7.2, 1.7 Hz, 1H), 7.71 (ddd, J = 8.1, 7.2, 1.7 Hz, 1H), 7.32-7.25 (m, 2H). 13 C NMR δ 151.78, 151.01, 149.23, 149.07, 147.67, 141.84, 136.75,136.73, 128.87, 124.75, 122.54, 121.76, 119.29.

[0033] The reaction formula is as follows:

[0034]

[0035] (2) Preparation of nickel catalyst

[0036] In a Shrek flask under nitrogen protection, 0.511 g (2.3 mmol) of L1 ligand and 20 mL of dehydrated tetrahydrofuran were added, and the mixture was stirred until the ligand dissolved. Then, 0.255 g (2.0 mmol) of anhydrous nickel chloride was slowly added, and the reaction mixture was refluxed in an oil bath at 60 °C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered to remove any possible insoluble matter, and the filtrate was concentrated under reduced pressure to approximately 5 mL. 30 mL of n-hexane was slowly added dropwise to the concentrate, precipitating a solid precipitate. The solid was collected by centrifugation, washed 2-3 times with a small amount of cold n-hexane, and dried in a vacuum oven at 40 °C for 8 hours to obtain 0.633 g of the L1 nickel complex (structural formula below), with a yield of 90%.

[0037]

[0038] (3) Synthesis of trans-4-methylcyclohexanol

[0039] Under nitrogen protection, a reaction glass flask equipped with a magnetic stirrer was placed in a 300 mL high-pressure reactor. The system was first purged with nitrogen three times to remove air. 0.5 mmol of 4-methylcresol (approximately 0.054 g), 0.025 mmol of nickel catalyst obtained in step (2) (approximately 0.0089 g), 10 mL of dehydrated tetrahydrofuran, and 5 mL of deionized water were added sequentially to the reaction flask. The flask was then sealed with the stopper. After closing the reactor, the inside was flushed three times with hydrogen to remove residual gas, and then hydrogen was introduced until the pressure inside the reactor reached 3 MPa. The reactor was placed in an oil bath and heated to 100°C. Magnetic stirring was turned on (500 r / min), and the reaction was carried out at a constant temperature for 12 hours. After the reaction was completed, the heating device was turned off, and the reactor was allowed to cool to room temperature. The hydrogen pressure was then slowly released. The reaction solution was transferred to a separatory funnel and extracted with diethyl ether (20 mL each time, three times in total). The organic phases were combined and dried with anhydrous sodium sulfate for 2 hours. The desiccant was removed by filtration, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1), and the target fraction was collected and the eluent was removed by distillation to give 0.050 g of 4-methylcyclohexanol, with a yield of 87%. The cis:trans ratio was 10:90.

[0040] NMR of cis-4-methylcyclohexanol 1 H NMR δ 3.93 (tt, J = 4.9, 3.0 Hz, 1H, cis-CHOH), 1.81 (s, 1H), 1.76-1.64 (m, 2H), 1.55 (ddt, J = 13.9, 11.2, 3.4 Hz, 2H), 1.45 (td, J = 7.3, 6.8, 3.9 Hz, 3H), 1.39- 1.27 (m, 2H), 0.91 (d, J =6.2 Hz, 3H), such as Figure 1 As shown; 13 C NMR δ 66.88, 32.17, 31.10, 28.98, 21.61, as shown Figure 2 As shown.

[0041] NMR of trans-4-methylcyclohexanol 1 H NMR δ 3.59-3.45 (m, 1H, trans-CHOH), 1.99-1.87 (m, 2H), 1.75-1.64 (m, 2H), 1.59 (s, 1H), 1.38-1.18 (m, 3H), 1.05-0.91 (m, 2H), 0.88 (d, J = 6.5 Hz, 3H), as Figure 3 As shown; 13C NMR (101 MHz, Chloroform-d) δ70.95, 35.63, 33.34, 31.77, as shown Figure 4 As shown.

[0042] 4-Methylcyclohexanol with a cis:trans ratio of 10:90 1 H NMR δ 3.93 (tt, J = 4.9, 3.0 Hz, 0.1H, cis-CHOH), 3.53 (tt, J = 10.9, 4.3 Hz, 0.9H, trans-CHOH), 2.02-1.88 (m, 2H), 1.81-1.63 (m, 3H), 1.41-1.18 (m, 3H), 1.06-0.83 (m, 5H). Such as Figure 5 As shown, 13 C NMR δ 70.91, 35.60, 33.33, 32.19, 31.77, 28.98, 21.92. (e.g.) Figure 6 As shown.

[0043] Example 2

[0044] This embodiment provides a highly selective method for preparing trans-4-methylcyclohexanol, comprising the following steps:

[0045] (1) Synthesis of ligand L2

[0046] Under nitrogen protection, 15 mL of anhydrous diethyl ether was added to a dry 50 mL three-necked flask, a magnetic stir bar was placed in, and the flask was cooled in an ice bath at 0 °C. A 2.5 mmol solution of magnesium methyl bromide in diethyl ether (3 M, 0.83 mL) was slowly added dropwise through a constant-pressure dropping funnel, and the mixture was stirred for 5 minutes to ensure homogeneity. Then, 1 mmol of 2-(methylsulfinyl)quinoline was dissolved in 5 mL of anhydrous diethyl ether and transferred to another constant-pressure dropping funnel. This solution was then slowly added dropwise to the reaction mixture at 0 °C, and the mixture was stirred at 0 °C for 30 minutes after the addition was complete. The ice bath was then removed, and the reaction was allowed to proceed at room temperature with stirring for 2 hours. After the reaction was complete, 20 mL of saturated ammonium chloride aqueous solution was slowly added dropwise under ice bath cooling (the dropping rate was controlled to avoid bumping), and the mixture was stirred for 10 minutes until the layers separated. The mixture was transferred to a separatory funnel and extracted three times with 20 mL of anhydrous diethyl ether. The organic phases were combined, and the mixture was dried over anhydrous sodium sulfate for 2 hours. The desiccant was removed by filtration, and the ether was removed by vacuum distillation (35℃, 0.08 MPa) to obtain a pale yellow crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1), and the target fraction was collected and the solvent was removed to obtain 0.126 g of colorless crystalline ligand L2, with a yield of 98%. 1H NMR δ 9.17 (d, J = 2.1 Hz, 1H), 8.35 (d, J = 8.5 Hz,1H), 8.30 (d, J = 2.0 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.98-7.90 (m, 4H),7.73 (td, J = 7.8, 1.2 Hz, 1H), 7.58-7.49 (m, 3H). 13 C NMR δ 155.76, 155.45,151.17, 147.24, 137.98, 136.76, 129.97, 129.90, 129.25, 128.35, 128.28,127.98, 127.77, 127.51, 126.48, 126.39, 120.20, 120.09.

[0047] The reaction formula is as follows:

[0048]

[0049] (2) Preparation of nickel catalyst

[0050] In a Shrek flask under nitrogen protection, 0.256 g of L2 ligand (0.001 mol) and 20 mL of dehydrated tetrahydrofuran were added, and the mixture was stirred until the ligand dissolved. Then, 0.218 g of anhydrous nickel bromide (0.001 mol) was slowly added, and the reaction mixture was refluxed in an oil bath at 75 °C for 8 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered to remove any possible insoluble matter, and the filtrate was concentrated under reduced pressure to approximately 5 mL. 30 mL of n-hexane was slowly added dropwise to the concentrate, causing a solid precipitate to form. The solid was collected by centrifugation, washed 2-3 times with a small amount of cold n-hexane, and dried in a vacuum oven at 50 °C for 6 hours to obtain 0.399 g of the L2 nickel complex (structural formula below), with a yield of 84%.

[0051]

[0052] (3) Synthesis of trans-4-methylcyclohexanol

[0053] Under nitrogen protection, a reaction glass bottle equipped with a magnetic stirrer was placed in a 300 mL high-pressure reactor. The system was first purged with nitrogen three times to remove air. 0.5 mmol of 4-methylcresol (approximately 0.054 g), 0.025 mmol of nickel catalyst obtained in step (2) (approximately 0.0119 g), 10 mL of dehydrated tetrahydrofuran, and 5 mL of deionized water were added sequentially to the reaction bottle. The stopper was then tightened and the reactor was sealed. After closing the reactor, it was flushed three times with hydrogen to remove residual gas, and then hydrogen was introduced until the pressure inside the reactor reached 3.5 MPa. The reactor was placed in an oil bath and heated to 110°C. Magnetic stirring was turned on (500 r / min), and the reaction was carried out at a constant temperature for 9 hours. After the reaction was completed, the heating device was turned off, and the reactor was allowed to cool to room temperature. The hydrogen pressure was then slowly released. The reaction solution was transferred to a separatory funnel and extracted with diethyl ether (20 mL each time, three times in total). The organic phases were combined and dried with anhydrous sodium sulfate for 2 hours. The desiccant was removed by filtration, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1), and the target fraction was collected and the eluent was removed by distillation to give 0.045 g of 4-methylcyclohexanol, with a yield of 82%. The cis:trans ratio was 16:84.

[0054] Example 3

[0055] This embodiment provides a highly selective method for preparing trans-4-methylcyclohexanol, comprising the following steps:

[0056] (1) Synthesis of ligand L3

[0057] Under dry conditions, 10 mmol of ethylenediamine (approximately 0.60 g), 20 mmol of benzaldehyde (approximately 2.12 g), and 20 mL of anhydrous benzene were added to a round-bottom flask, and the mixture was stirred at room temperature for 5 hours to induce a condensation reaction. Subsequently, the reaction mixture was placed in an ice bath, and 30 mL of anhydrous methanol was added. Then, 25 mmol of sodium borohydride (approximately 0.94 g) was added in portions, and the mixture was stirred at room temperature for 12 hours after the addition was complete. After the reaction was completed, excess sodium borohydride was slowly quenched with water, and benzene and methanol were removed by vacuum distillation. The residue was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain 2.09 g of the target product L3, with a yield of 87%. 1 H NMR δ7.36-7.21 (m, 1H), 3.86 (dt, J = 5.3, 1.1 Hz, 1H), 2.77-2.70 (m, 1H). 13 C NMRδ 139.61, 128.52, 128.33, 127.51, 52.72, 46.67.

[0058] The reaction formula is as follows:

[0059]

[0060] (2) Preparation of nickel catalyst

[0061] In a Shrek flask under nitrogen protection, 2.40 g of L3 ligand (0.01 mol) and 20 mL of dehydrated tetrahydrofuran were added, and the mixture was stirred until the ligand dissolved. Then, 3.12 g of anhydrous nickel iodide (0.01 mol) was slowly added, and the reaction mixture was refluxed in an oil bath at 80 °C for 6 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered to remove any possible insoluble matter, and the filtrate was concentrated under reduced pressure to approximately 5 mL. 30 mL of n-hexane was slowly added dropwise to the concentrate, causing a solid precipitate to form. The solid was collected by centrifugation, washed 2-3 times with a small amount of cold n-hexane, and dried in a vacuum oven at 60 °C for 5 hours to obtain 4.81 g of the L3 nickel complex, with a yield of 87%.

[0062]

[0063] (3) Synthesis of trans-4-methylcyclohexanol

[0064] Under nitrogen protection, a reaction glass flask equipped with a magnetic stirrer was placed in a 300 mL high-pressure reactor. The system was first purged with nitrogen three times to remove air. 0.5 mmol of 4-methylcresol (0.054 g), 0.015 mmol of nickel catalyst (0.0083 g) obtained in step (2), 10 mL of dehydrated tetrahydrofuran, and 5 mL of deionized water were added sequentially to the reaction flask. The flask was then sealed with the stopper. After closing the reactor, it was flushed three times with hydrogen to remove residual gas, and then hydrogen was introduced until the pressure inside the reactor reached 4 MPa. The reactor was placed in an oil bath and heated to 130°C. Magnetic stirring was turned on (500 r / min), and the reaction was carried out at a constant temperature for 5 hours. After the reaction was completed, the heating device was turned off, and the reactor was allowed to cool to room temperature. The hydrogen pressure was then slowly released. The reaction solution was transferred to a separatory funnel and extracted with diethyl ether (20 mL each time, 3 times in total). The organic phases were combined and dried with anhydrous sodium sulfate for 2 hours. The desiccant was removed by filtration, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1), and the target fraction was collected and the eluent was removed by distillation to give 0.050 g of 4-methylcyclohexanol, with a yield of 88%. The cis:trans ratio was 13:87.

[0065] Example 4

[0066] This embodiment provides a highly selective method for preparing trans-4-methylcyclohexanol, comprising the following steps:

[0067] (1) The synthesis method of ligand L2 is the same as that in Example 2.

[0068] (2) Preparation of nickel catalyst

[0069] In a Shrek flask under nitrogen protection, 0.256 g of L2 ligand (0.001 mol) and 20 mL of dehydrated tetrahydrofuran were added, and the mixture was stirred until the ligand dissolved. Then, 0.218 g of anhydrous nickel bromide (0.001 mol) was slowly added, and the reaction mixture was refluxed in an oil bath at 120 °C for 8 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered to remove any possible insoluble matter, and the filtrate was concentrated under reduced pressure to approximately 5 mL. 30 mL of n-hexane was slowly added dropwise to the concentrate, causing a solid precipitate to form. The solid was collected by centrifugation, washed 2-3 times with a small amount of cold n-hexane, and dried in a vacuum oven at 60 °C for 5 hours to obtain 0.432 g of the L2 nickel complex, with a yield of 91%.

[0070]

[0071] (3) Synthesis of trans-4-methylcyclohexanol

[0072] Under nitrogen protection, a reaction glass bottle equipped with a magnetic stirrer was placed in a 300 mL high-pressure reactor. The system was first purged with nitrogen three times to remove air. 0.5 mmol of 4-methylcresol (approximately 0.054 g), 0.025 mmol of nickel catalyst obtained in step (2) (approximately 0.0119 g), 10 mL of dehydrated tetrahydrofuran, and 5 mL of deionized water were added sequentially to the reaction bottle. The stopper was then tightened and the reactor was sealed. After closing the reactor, it was flushed three times with hydrogen to remove residual gas, and then hydrogen was introduced until the pressure inside the reactor reached 3 MPa. The reactor was placed in an oil bath and heated to 120°C. Magnetic stirring was turned on (500 r / min), and the reaction was carried out at a constant temperature for 7 hours. After the reaction was completed, the heating device was turned off, and the reactor was allowed to cool to room temperature. The hydrogen pressure was then slowly released. The reaction solution was transferred to a separatory funnel and extracted with diethyl ether (20 mL each time, 3 times in total). The organic phases were combined and dried with anhydrous sodium sulfate for 2 hours. The desiccant was removed by filtration, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1), and the target fraction was collected and the eluent was removed by distillation to give 0.049 g of 4-methylcyclohexanol, with a yield of 90%. The cis:trans ratio was 8:92.

[0073] Example 5

[0074] This embodiment provides a highly selective method for preparing trans-4-methylcyclohexanol, comprising the following steps:

[0075] (1) The synthesis method of ligand L2 is the same as that in Example 2.

[0076] (2) Preparation of nickel catalyst

[0077] In a Shrek flask under nitrogen protection, 0.0016 mol of L2 ligand and 20 mL of dehydrated tetrahydrofuran were added, and the mixture was stirred until the ligand dissolved. Then, 0.218 g of anhydrous nickel bromide (0.001 mol) was slowly added, and the reaction mixture was refluxed in an oil bath at 120 °C for 5 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered to remove any possible insoluble matter, and the filtrate was concentrated under reduced pressure to approximately 5 mL. 30 mL of n-hexane was slowly added dropwise to the concentrate, causing a solid precipitate to form. The solid was collected by centrifugation, washed 2-3 times with a small amount of cold n-hexane, and dried in a vacuum oven at 60 °C for 5 hours to obtain 0.408 g of the L2 nickel complex, with a yield of 86%.

[0078]

[0079] (3) Synthesis of trans-4-methylcyclohexanol

[0080] Under nitrogen protection, a reaction glass bottle equipped with a magnetic stirrer was placed in a 300 mL high-pressure reactor. The system was first purged with nitrogen three times to remove air. 0.5 mmol of 4-methylcresol (approximately 0.054 g), 0.0324 g of nickel catalyst obtained in step (2), 10 mL of dehydrated tetrahydrofuran, and 5 mL of deionized water were added sequentially to the reaction bottle. The stopper was then tightened and the reactor was sealed. After closing the reactor, it was flushed three times with hydrogen to remove residual gas, and then hydrogen was introduced until the pressure inside the reactor reached 3 MPa. The reactor was placed in an oil bath and heated to 120°C. Magnetic stirring was turned on (500 r / min), and the reaction was carried out at a constant temperature for 7 hours. After the reaction was completed, the heating device was turned off, and the reactor was allowed to cool to room temperature. The hydrogen pressure was then slowly released. The reaction solution was transferred to a separatory funnel and extracted with diethyl ether (20 mL each time, three times in total). The organic phases were combined and dried with anhydrous sodium sulfate for 2 hours. The desiccant was removed by filtration, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1), and the target fraction was collected and the eluent was removed by distillation to give 0.048 g of 4-methylcyclohexanol, with a yield of 88%. The cis:trans ratio was 10:90.

[0081] Example 6

[0082] This embodiment provides a highly selective method for preparing trans-4-methylcyclohexanol, comprising the following steps:

[0083] (1) The synthesis method of ligand L2 is the same as that in Example 2.

[0084] (2) Preparation of nickel catalyst

[0085] In a Shrek flask under nitrogen protection, 0.256 g of L2 ligand (0.001 mol) and 20 mL of dehydrated tetrahydrofuran were added, and the mixture was stirred until the ligand dissolved. Then, 0.218 g of anhydrous nickel bromide (0.001 mol) was slowly added, and the reaction mixture was refluxed in an oil bath at 120 °C for 8 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered to remove any possible insoluble matter, and the filtrate was concentrated under reduced pressure to approximately 5 mL. 30 mL of n-hexane was slowly added dropwise to the concentrate, causing a solid precipitate to form. The solid was collected by centrifugation, washed 2-3 times with a small amount of cold n-hexane, and dried in a vacuum oven at 60 °C for 5 hours to obtain 0.432 g of the L2 nickel complex, with a yield of 91%.

[0086]

[0087] (3) Synthesis of trans-4-methylcyclohexanol

[0088] Under nitrogen protection, a reaction glass flask equipped with a magnetic stirrer was placed in a 300 mL high-pressure reactor. The system was first purged with nitrogen three times to remove air. 0.5 mmol 4-methylcresol (0.054 g), 0.0027 g mmol nickel catalyst obtained in step (2), 10 mL dehydrated tetrahydrofuran, and 5 mL deionized water were added to the reaction flask in sequence. The flask was then sealed with a stopper. After closing the reactor, the inside was flushed with hydrogen three times to remove residual gas, and then hydrogen was introduced until the pressure inside the reactor reached 3 MPa. The reactor was placed in an oil bath and heated to 120°C. The magnetic stirrer was turned on (500 r / min) and stirred at a constant temperature for 7 hours. After the reaction was completed, the heating device was turned off, and the reactor was allowed to cool to room temperature. The hydrogen pressure was then slowly released. The reaction solution was transferred to a separatory funnel and extracted with diethyl ether (20 mL each time, 3 times in total). The organic phases were combined and dried with anhydrous sodium sulfate for 2 hours. The desiccant was removed by filtration, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1), and the target fraction was collected and the eluent was removed by distillation to give 0.047 g of 4-methylcyclohexanol, with a yield of 86%. The cis:trans ratio was 15:85.

[0089] Comparative Example 1

[0090] The preparation method of 4-methylcyclohexanol in this comparative example includes the following steps:

[0091] Under nitrogen protection, a reaction glass flask equipped with a magnetic stirrer was placed in a 300 mL high-pressure reactor. The system was first purged with nitrogen three times to remove air. 0.5 mmol of 4-methylcresol (approximately 0.054 g), 0.025 mmol of 5% Pd / C (approximately 0.0532 g), 10 mL of dehydrated tetrahydrofuran, and 5 mL of deionized water were added sequentially to the flask. The flask was then tightly sealed. After closing the reactor, it was flushed three times with hydrogen to remove residual gases, and then hydrogen was introduced until the pressure inside the reactor reached 3 MPa. The reactor was placed in an oil bath and heated to 120 °C. Magnetic stirring was started (500 r / min), and the reaction was carried out at a constant temperature and with stirring for 7 hours. After the reaction was completed, the heating device was turned off, and the reactor was allowed to cool to room temperature. The hydrogen pressure was then slowly released. The reaction mixture was transferred to a separatory funnel and extracted with diethyl ether (20 mL each time, three times in total). The organic phases were combined and dried over anhydrous sodium sulfate for 2 hours. The desiccant was removed by filtration, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1), and the target fraction was collected and the eluent was removed by distillation to give 0.0517 g of 4-methylcyclohexanol, with a yield of 95%. The cis:trans ratio was 74:26.

[0092] Comparative Example 2

[0093] The preparation method of 4-methylcyclohexanol in this comparative example includes the following steps:

[0094] Under nitrogen protection, a reaction glass flask equipped with a magnetic stirrer was placed in a 300 mL high-pressure reactor. The system was first purged with nitrogen three times to remove air. 0.5 mmol of 4-methylcresol (approximately 0.054 g), 0.025 mmol of Raney nickel (approximately 0.00214 g), 10 mL of dehydrated tetrahydrofuran, and 5 mL of deionized water were added sequentially to the reaction flask. The flask was then sealed tightly with the stopper. After closing the reactor, it was flushed three times with hydrogen to remove any residual gas, and then hydrogen was introduced until the pressure inside the reactor reached 3 MPa. The reactor was placed in an oil bath and heated to 120 °C. Magnetic stirring was started (500 r / min), and the reaction was carried out at a constant temperature and with stirring for 7 hours. After the reaction was complete, the heating device was turned off, and the reactor was allowed to cool to room temperature. The hydrogen pressure was then slowly released. The reaction mixture was transferred to a separatory funnel and extracted with diethyl ether (20 mL each time, three times in total). The organic phases were combined and dried over anhydrous sodium sulfate for 2 hours. The desiccant was removed by filtration, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1), and the target fraction was collected and the eluent was removed by distillation to give 0.0533 g of 4-methylcyclohexanol, with a yield of 98%. The cis:trans ratio was 68:32.

[0095] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for highly selectively preparing trans-4-methylcyclohexanol, characterized in that, The steps are as follows: (1) Under inert gas conditions, nickel salt and ligand are reacted in organic solvent I with stirring to obtain a nickel catalyst; wherein the ligand is at least one of L1, L2 and L3: ； (2) The nickel catalyst prepared in step (1) and 4-methylphenol are added to solvent II and hydrogenated to obtain trans-4-methylcyclohexanol.

2. The method for highly selective preparation of trans-4-methylcyclohexanol according to claim 1, characterized in that, In step (1), the molar ratio of nickel salt to ligand is 1:1-1.

6.

3. The method for highly selective preparation of trans-4-methylcyclohexanol according to claim 2, characterized in that, The temperature of the stirring reaction in step (1) is 60-120℃ and the time is 5-12 h.

4. The method for highly selective preparation of trans-4-methylcyclohexanol according to claim 1, characterized in that, In step (1), the nickel salt is at least one of Ni(acac)2, NiCl2, NiBr2, NiI2, Ni(NTf2)2, Ni(BF4)2, Ni(OAc)2•4H2O, Ni(NO3)2, NiSO4, Ni(OTs)2 and Ni(ClO4)2.

5. The method for highly selective preparation of trans-4-methylcyclohexanol according to claim 4, characterized in that, In step (1), the organic solvent I is any one of tetrahydrofuran, benzene, toluene, p-xylene, 1,4-dioxane, dimethyl sulfoxide, 1,2-dichloroethane, diethyl ether, cyclohexane, chloroform, dichloromethane, and petroleum ether.

6. The method for highly selective preparation of trans-4-methylcyclohexanol according to claim 5, characterized in that, In step (2), the amount of nickel catalyst added is 5-60% of the mass of 4-methylphenol.

7. The method for highly selective preparation of trans-4-methylcyclohexanol according to claim 6, characterized in that, In step (2), solvent II is any one of tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, and diethyl ether.

8. The method for highly selective preparation of trans-4-methylcyclohexanol according to claim 7, characterized in that, The hydrogenation reaction in step (2) is carried out at a temperature of 100-130℃ for 5-12 hours.

9. The method for highly selective preparation of trans-4-methylcyclohexanol according to claim 8, characterized in that, The pressure of hydrogen in step (2) is 3-4 MPa.

10. Trans-4-methylcyclohexanol prepared by the highly selective method for preparing trans-4-methylcyclohexanol according to any one of claims 1-9.

Images