Naphthyl modified ChiraPhos type diphosphine ligand as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of organic synthesis, and particularly discloses a modified ChiraPhos type diphosphine ligand and a preparation method and application thereof.The modified ChiraPhos type diphosphine ligand is modified on the basis of a ChiraPhos ligand, naphthyl is introduced into the structure, the chiral recognition effect of a catalyst formed by the naphthyl and rhodium is better, and the catalytic activity of the catalyst is improved. A higher ee value can be induced to be generated in synthesis of an L-menthol key intermediate (R)-citronellal. The invention further provides a specific preparation method of the modified ChiraPhos type diphosphine ligand, and the modified ChiraPhos type diphosphine ligand is obtained from cheap and easily available raw materials through simple and convenient operation. The diphosphine ligand is used for a reaction for preparing (R)-citronellal through asymmetric hydrogenation of citral under rhodium catalysis, the (R)-citronellal with the ee value higher than that of a traditional rhodium catalysis system can be obtained through citral (E / Z = 90: 10) with cis-trans isomers mixed, and a certain foundation is laid for further reducing the industrial production cost of the (R)-citronellal.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and relates to the development of bisphosphine ligands, particularly to a naphthyl-modified ChiraPhos-type bisphosphine ligand and its preparation method, as well as its application in the catalytic asymmetric hydrogenation of citral to prepare (… R Applications of citronellol. Technical Background

[0002] Menthol, scientifically known as 2-isopropyl-5-methylcyclohexanol, is a cyclic monoterpene compound commonly found in plants such as mint and sage. Structurally, menthol contains three chiral centers, resulting in eight isomers. Figure 1 .), of which only L Menthol has antibacterial, antipruritic, cooling, and analgesic effects, and has a strong minty aroma. Therefore, L Menthol is widely used in food, daily fine chemicals, and pharmaceuticals, with annual consumption exceeding 40,000 tons, making it one of the world's best-selling flavoring monomers (Liding Industry Research Center, *China*). L - "Analysis of Supply and Demand Status and Market Trend Research Report of Menthol Industry", 2022.

[0003] Due to the influence of factors such as climate and human intervention, naturally extracted... L The yield and quality of menthol are difficult to guarantee. BASF in Germany has developed a direct asymmetric hydrogenation synthesis method via citral. R )-Citronellol is then synthesized L - The route for menthol synthesis, using commercially available raw materials, is currently the most widely used industrial asymmetric synthesis method. L - The simplest and most economical process for producing menthol. The key to this entire process lies in ( R Efficient asymmetric synthesis of citronellol.

[0004] That is: a policy developed by BASF in 2008 based on ( Z )-Citral and ( E The synthesis of )-citral via asymmetric hydrogenation as the key chiral control step L -The route of menthol ( Figure 2 .), and achieve industrialized production ( ( a ) Jakel, C.;Paciello, R. CN pat, 101039894A, 2005. ( b ) Jakel, C.; Paciello, R.; SaintLaumer, J. CN pat, 101675020A, 2008. ( c(Heydrich, G.; Gralla, G.; Rauls, M.; Schmidt-Leithoff, J.; Ebel, K.; Krause, W.; Oehlenschlaeger, S.; Jakel, C.; Friedrich, M.; Bergner, EJ; Kashani-Shirazi, N.; Paciello, R. CN pat,101932543A, 2008.). First, Z / E Mixed citral is distilled and separated into ( Z )-Citral and ( E )-citral, which were then subjected to asymmetric catalytic hydrogenation to obtain ( R )-Citronellol, which then undergoes a carbonyl-olefin reaction to give the cyclized product. L -Isomentheptyl, finally hydrogenated from the C=C double bond to obtain... L - Menthol.

[0005] In this industrial synthesis route, the reaction product ( R Citronellol mainly comes from ( E )-Citral, ( S Citronellol mainly comes from ( Z )-citral, in order to obtain higher enantioselectivity ( R )-Citronellol, often requires ( E / Z )-Citral was separated into trans-citral by distillation. E Citral, also known as geranialdehyde, is then asymmetrically hydrogenated using a chiral catalyst containing rhodium to obtain ( R )-Citronellol. The synthesis process is simple, but it is sensitive to ( E / Z The process of distilling citric acid to obtain a single component requires sophisticated production equipment, involves significant separation challenges, and is costly. Furthermore, the rhodium / chiraphos catalytic system used only yields 90% of the desired product. ee Enantiomerism ( Figure 3 .), resulting in the income ( R Citronellol has low chiral purity, and further chiral enrichment to 99% is needed during subsequent application and conversion processes. ee Only then can the usage requirements be met.

[0006] To avoid ( R The increased cost due to insufficient chiral purity of citronellol necessitates the development of new catalytic systems that enable one-step catalytic hydrogenation to achieve higher chiral purity when using citral with a single configuration as the substrate. R Citronellol has significant value. Summary of the Invention

[0007] To address the shortcomings of existing technologies, the present invention aims to provide a naphthyl-modified ChiraPhos-type bisphosphine ligand and a method for synthesizing this bisphosphine ligand. The modified bisphosphine ligand of the present invention exhibits better chiral recognition performance with rhodium in the catalyst formation process, and compared to the standard ChiraPhos ligand, it can induce higher levels of... ee value ( R )-citronellol.

[0008] This invention is achieved through the following technical solution: A naphthyl-modified ChiraPhos-type bisphosphine ligand has the following structure: .

[0009] A further improvement to the present invention is as follows: A method for preparing a naphthyl-modified ChiraPhos-type bisphosphine ligand includes the following steps: (1) Grignard reagent B was prepared by reacting compound A with metallic Mg. Diethyl phosphite reacted with the obtained Grignard reagent B in a substitution reaction to generate compound C. (2) To reduce compound C to form compound D; (3) Compound E undergoes a substitution reaction with methanesulfonyl chloride to generate compound F; (4) Compound D undergoes a substitution reaction with compound F, and then reacts with BH3•THF to obtain compound G; (5) Compound G undergoes a deborane reaction to yield ligand H; The reaction route is shown below:

[0010] Furthermore, in the above preparation method: The reaction in step (1) uses THF as solvent, and the molar ratio of compound A:Mg:diethyl phosphite is 1:1-1.5:0.3-0.4. The reaction described in step (2) is carried out in the presence of PhSiH3 in the solvent of toluene. The molar ratio of compound C to PhSiH3 is 1:4-6. The reaction described in step (3) is carried out in the presence of NEt3 with DCM as solvent. The molar ratio of compound E: methanesulfonyl chloride: NEt3 is 1:2-5:2-5. The reaction described in step (4) uses tetrahydrofuran as a solvent. n The reaction is carried out under the action of BuLi, and the compounds F and D are reacted in terms of molar amount: nBuLi: BH3•THF = 1: 2-5: 2-5: 4-6; The reaction in step (5) uses ethanol as a solvent.

[0011] Furthermore, in the above preparation method: Step (1) Prepare a suitable reagent and react it at 40-70 °C for 2-4 h. The substitution reaction is carried out at room temperature for 4 h-12 h. The reaction described in step (2) is carried out at 115-135 °C for 10-14 h. The reaction described in step (3) is carried out at room temperature for 10-14 h. The reactions described in step (4) are all carried out at room temperature, with the substitution reaction taking 10-14 h and the reaction with BH3•THF taking 20-40 min. The reaction in step (5) is carried out at 90-110 °C for 10-14 h.

[0012] Furthermore, each step in the above preparation method also includes a separation and purification step.

[0013] A further improvement to the present invention is as follows: The above-mentioned naphthyl-modified ChiraPhos-type bisphosphine ligands were used in the catalytic asymmetric hydrogenation of citral to prepare ( R The application of citronellol is characterized in that the bisphosphine ligand reacts with Rh(CO)₂acac to form a complex catalyst, and the molar ratio of citral to the complex catalyst is 1:0.001-0.003; the citral... E / Z = 90:10; the reaction temperature is 35-45℃, and the time is 6-14 h.

[0014] Compared with the prior art, the beneficial effects of the present invention are as follows: Compared to the standard ChiraPhos ligand, this invention modifies the ChiraPhos ligand with a naphthyl group, resulting in better chiral recognition and the induction of higher product yields. ee value.

[0015] The synthetic method of this invention starts from inexpensive, commercially available raw materials and can synthesize modified bisphosphine ligands. The resulting new ligands can achieve citral ( Z / E The asymmetric hydrogenation of citral ligands (= 10 / 90) yields chiral products with high stereoselectivity. This invention provides a novel synthetic method with inexpensive and readily available starting materials and convenient operation. The bisphosphine ligands obtained by this method exhibit good chiral induction effects, and compared with currently known methods, can improve the chiral efficiency of citral (= 10 / 90) to a certain extent.E / Z The stereoselectivity of asymmetric hydrogenation (90:10) points the way for further experimental investigations. Attached Figure Description

[0016] Figure 1 These are eight isomers of menthol; Figure 2 Synthesis of direct asymmetric hydrogenated citral L -The process route for menthol; Figure 3 Prepared for BASF ( R Synthetic route of citronellol; Figure 4 The image shows the 1H NMR spectrum of catalyst L. Figure 5 This is a 3D dynamic simulation diagram of a single crystal of compound G. Detailed Implementation

[0017] The present invention will now be described in detail with reference to specific embodiments.

[0018] Example 1: Preparation of naphthyl-modified ChiraPhos-type bisphosphine ligands Synthesis Step 1:

[0019] Weigh Mg scrap (35 mmol, 867 mg) into a 500 mL three-necked flask. Repeat the purging of argon atmosphere three times with a vacuum line, and use a diaphragm pump to evacuate the system. Heat to 200℃ for 2-4 hours to activate. After activation, maintain vacuum and allow to cool naturally to room temperature, then purge with argon. Heat to 40-70℃, add THF to the flask, and dissolve A (28 mmol) in THF. First, use a constant pressure dropping funnel to add 5 mL of the solution to the system. Observe that dense bubbles emerge and the color of the system changes from colorless to dark. Then, slowly add the remaining solution to the system, and the reaction system gradually turns black. After the addition is complete, continue the reaction at 40℃-70℃ for 2-4 hours. Diethyl phosphite (10 mmol, 1.3 mL) was dissolved in THF and slowly added dropwise to the system in an ice-water bath. Upon addition, a portion of the solution turned gray, then rapidly black. After the addition was complete, the mixture was stirred in the ice-water bath for 30 min. The ice-water bath was then removed, and the mixture was stirred at room temperature for 4-12 h, during which time the system changed from a black to a dark gray suspension. The reaction was quenched by slowly adding 1 M dilute hydrochloric acid in an ice-water bath, and the system rapidly turned into a white suspension. With continued addition, the white suspension gradually dissolved. Upon standing, the system separated into two layers: a colorless aqueous phase at the bottom and a pale yellow organic phase at the top. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous MgSO4, and evaporated to dryness to obtain a pale yellow solid. Most impurities were removed using pure DCM and DCM / MeOH to obtain a white solid. The solid was then pulped using PE / EA to obtain C, a white solid, with a yield of 65%. Melting point: 98.1-99.4℃.

[0020] 1 H NMR (400 MHz, CDCl3): 8.39 (d, 2H), δ 8.35 (d, J = 481.2 Hz, 1H), 7.94 - 7.86 (m, 6H), 7.66 - 7.55 (m, 6H). 31 P NMR (162 MHz, CDCl3): δ 21.72. Synthesis Step 2:

[0021] Weigh C (10 mmol) into a 25 mL sealed tube, repeat the gas replacement three times, add PhSiH3 (50 mmol) and toluene solution, heat the oil bath to 115℃-135℃, react overnight, and the reaction is confirmed to be complete by NMR phosphorus spectrum. The solution is removed by vacuum pump and dried to obtain D, a white solid with a yield of 96%.

[0022] 1 H NMR(400 MHz, CDCl3) δ 8.03 (d, 2H), 7.75-7.82 (m, 6H), 7.45-7.55(m, 6H), 5.21 (d, J = 173.3 Hz, 1H). 31 P NMR (162 MHz, CDCl3) δ -39.8. Synthesis Step 3:

[0023] E (5 mmol) was dissolved in 10 mL of DCM. After adding NEt3 (3.0 equivalents), the solution was cooled to 0 °C, and MsCl (3.0 equivalents) was slowly added. The addition was exothermic, accompanied by the precipitation of a white precipitate. The reaction was slowly brought back to room temperature with stirring, and monitored by TLC (PE / EA = 1:1, phosphomolybdic acid plate analysis). After the reaction was complete, the organic phase was washed with dilute hydrochloric acid, and the aqueous phase was extracted three times with DCM. The organic phases were combined and washed with saturated brine, dried over anhydrous MgSO4, and the solvent was evaporated to obtain a pale yellow, fine granular solid with a pungent odor (containing unreacted MsCl). Purification by column chromatography yielded pure F as a white solid, in 86% yield.

[0024] Synthesis Step 4:

[0025] Weigh D (3.0 equivalents) into a 100 mL Schlenk flask, dissolve it in cryogenically degassed tetrahydrofuran, and slowly add n-butyllithium (3.0 equivalents, 1.8 min) dropwise at 0°C. n After the addition of hexane was complete, the mixture was allowed to return to room temperature naturally. The mixture was stirred at room temperature for 3-5 hours. F (5 mmol) was dissolved in freeze-degassed ultra-dry tetrahydrofuran. The bis(methanesulfonyl) intermediate solution was slowly added dropwise to the system at 0°C. After the addition was complete, the mixture was allowed to return to room temperature naturally. The reaction was allowed to proceed overnight at room temperature, and the reaction was monitored by TLC. After complete substrate conversion, the mixture was placed in an ice-water bath, and BH3•THF solution (1 M in THF) was added dropwise. The mixture was then stirred at room temperature for approximately 30 minutes. The mixture was quenched with methanol in the ice-water bath, resulting in bubbling. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and evaporated to dryness. The mixture was then subjected to rapid column chromatography using PE / EA / DCM (silica gel may promote borane decomposition), yielding a white solid product G in 33% yield.

[0026] 1H NMR (400 MHz, CDCl3) δ 8.39 - 8.30 (m, 2H), 8.23 ​​- 8.14 (m, 2H), 7.87 - 7.74 (m, 8H), 7.72 - 7.64 (m, 4H), 7.60 - 7.48 (m, 10H), 7.39 (m, 2H),3.41 (m 2H), 1.31 (q, J = 7.3 Hz, 6H), 1.19 - 0.02 (m, 6H). 31 P NMR (162 MHz, CDCl3) δ 26.90. 13 C NMR (101 MHz, CDCl3) δ 135.52, 134.28, 132.73, 128.81, 128.57, 128.21, 127.74, 127.50, 127.15, 126.96, 43.37, 10.91. HRMS(ESI): calcd for C 44 H 42 B2P2Na [M+Na] + 677.2840, found 677.2848. Single-crystal X-ray diffraction data:

[0027] G: (CCDC No: 2502695) The specific single-crystal data is as follows:

[0028] Synthesis Step 5:

[0029] Compound G (1 mmol) was weighed into a 200 mL Schlenk flask, ethanol was added and the mixture was allowed to react overnight in an oil bath at 100 °C. The reaction was detected by NMR and the reaction was complete. The solution was removed by vacuum pump and the mixture was dried to give a white solid H. The yield was 67%.

[0030] 1H NMR (400 MHz, CDCl3) δ 7.99 (d, 2H), 7.89 (d, 2H), 7.83 (d, 2H), 7.76 (d, 2H), 7.73 - 7.67 (m, 4H), 7.65 -7.56 (m, 4H), 7.53 (t, 2H), 7.49 -7.40 (m, 8H), 7.31- 7.27 (m, 2H), 2.85 (m, 2H), 1.33 (dd, J = 14.0, 6.9 Hz, 6H). 31 P NMR (162 MHz, CDCl3) δ -8.05. Example 2: Preparation of complex catalyst

[0031]

[0032] Rh(CO)₂acac (0.2 mmol, 51.6 mg) was weighed into a 25 mL single-necked flask inside a glove box. 2 mL of degassed ultra-dry toluene was added, followed by ligand H (0.4 mmol). Within a short time, vigorous bubbling occurred, the solution turned orange-yellow, and insoluble matter was present. The mixture was stirred at room temperature for 1 h. Subsequently, the mixture was removed from the glove box, and n-pentane was added to the system, resulting in the precipitation of a large amount of yellow flocculent material. The mixture was filtered through a funnel, washed again with n-pentane, and the solid was transferred to a flask. The solvent was removed under vacuum, yielding a yellow powder, denoted as catalyst L, with a yield of 94%.

[0033] 1 H NMR (400 MHz, CDCl3) δ 8.18 (s, 4H), 7.88 (s, 4H), 7.70 - 7.46 (m,16H), 7.43 - 7.32 (m, 32H), 2.20 (s, 4H), 0.73 (s, 12H). 13 C NMR (101 MHz, CDCl3) δ 135.43, 133.64, 130.00, 129.03, 128.61,127.85, 127.78, 127.39, 126.99,123,61, 37.83, 13.80. 31 P NMR (162 MHz, CDCl3) δ 63,32, 62,51. The metal precursor Rh(CO)₂acac and the prepared ligand H need to be stored in a glove box, otherwise they are prone to oxidation and deterioration. Through the above complexation treatment, the complexed catalyst is more stable and can be stored in air for a long time without deterioration, making operation more convenient.

[0034] Example 3: Preparation of citral by hydrogenation ( R )-Citronellol

[0035] The complexed catalyst L (0.01 mmol, 0.2 mol%) prepared in Example 3 was weighed into the hydrogenation tube, sealed with a sealing film, and placed into an autoclave. After purging the autoclave to an Ar atmosphere, 1 mL of degassed ultra-dry tetrahydrofuran was added through the feed inlet. The autoclave was purged three times with CO / H2 = 1:1 syngas, and then 10 atm was introduced. The autoclave was then placed in a 60 °C oil bath and stirred for 3 h for activation. After depressurization, the catalyst was injected through the feed inlet. E / Z = 90:10 citral (760 mg, 5 mmol), after purging the gas in the autoclave three times, H2 (50 atm.) was introduced, and then the autoclave was placed in a 40 °C oil bath with stirring for 12 h. After cooling, H2 was slowly released, the autoclave was opened, and the crude product was filtered through a short silica gel column. n-Tetane was added to the filtrate as an internal standard, and after thorough mixing, GC samples were prepared. The reaction results were detected by GC. GC analysis conditions: Beta-Dex 225 TM Injector temperature 250 °C, detector temperature 250 °C, split ratio 20:1, column flow rate 1 mL / min, column oven temperature 100 °C (60 min) - 5 °C / min - 220 °C (0 min), retention time: ( S )-Citronellol was 43.535 min, ( R Citronellol was 43.961 min, and n-tetane was 50.799 min. Z The concentration of citral was 69.567 min. E The conversion time for citral was 72.696 min. The citral conversion rate was 100%, yielding ( R Citronellol purity 99%, yield 98%, enantioselectivity 77% ee .

[0036] Comparative Example 1

[0037] In this comparative example, the complex catalyst M was prepared using the unmodified ChiraPhos ligand, following the same method as in Example 3. The resulting complex catalyst was then used for the hydrogenation of citral to prepare ( R Citronellol was prepared using a method similar to that in Example 3, which will not be repeated here. The conversion rate of citral was 100%, yielding ( R Citronellol purity 99%, yield 98%, enantioselectivity 70% ee .

[0038] The comparison results are shown in the table below: Serial number Catalyst Citral conversion rate / % ()-Citronellal purity / % ()-Citronellal yield / % ()-Citronellal enantioselectivity 1 L 100 99 98 77 2 M 100 99 98 70 In summary, this invention presents a method for preparing naphthyl-modified ChiraPhos-type bisphosphine ligands, and applies it to the catalytic asymmetric hydrogenation of citral, resulting in the production of ligands with higher chiral purity. R Citronellol, with the potential to improve high-purity ( R The industrial production process of citronellol further reduces... L - Production cost of menthol.

[0039] The above description of the embodiments is only for illustrating the technical concept and features of the present invention. Its purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly. Those skilled in the art can obviously easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative effort. Therefore, the above embodiments should not be used to limit the scope of protection of the present invention. All improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A naphthyl-modified ChiraPhos type bisphosphine ligand, characterized in that, The structure is shown as formula H: 。 2. A process for the preparation of a naphthyl-modified ChiraPhos type bisphosphine ligand as claimed in claim 1, characterized in that, The method comprises the following steps: (1) preparing a Grignard reagent B by using compound A and Mg, and then performing a substitution reaction between diethyl phosphite and the obtained Grignard reagent B to obtain compound C; (2) performing a reduction reaction on compound C to obtain compound D; (3) performing a substitution reaction between compound E and methyl sulfonyl chloride to obtain compound F; (4) performing a substitution reaction between compound D and compound F, and then performing a reaction with BH3•THF to obtain compound G; (5) performing a de-borination reaction on compound G to obtain ligand H; The reaction route is shown as follows: 。 3. The method of claim 2, wherein: In step (1), the reaction is performed in THF as a solvent, and the molar ratio of compound A, Mg and diethyl phosphite is 1:1-1.5:0.3-0.4; In step (2), the reaction is performed in toluene as a solvent in the presence of PhSiH3, and the molar ratio of compound O and PhSiH3 is 1:4-6; In step (3), the reaction is performed in DCM as a solvent in the presence of NEt3, and the molar ratio of compound E, methyl sulfonyl chloride and NEt3 is 1:2-5:2-5; And / or, the reaction described in step (4) is carried out in tetrahydrofuran as a solvent, in n The reaction is carried out under the action of BuLi, and the compounds F and D are reacted in terms of molar amount: n BuLi: BH3•THF = 1: 2-5: 2-5: 4-6; In step (5), the reaction is performed in ethanol as a solvent.

4. The method of claim 2, wherein: In step (1), the reaction of preparing a suitable reagent is performed at 40-70 ℃ for 2-4 h, and the substitution reaction is performed at room temperature for 4 h-12 h; In step (2), the reaction is performed at 115-135 ℃ for 10-14 h; In step (3), the reaction is performed at room temperature for 10-14 h; In step (4), the reaction is performed at room temperature, the substitution reaction is performed for 10-14 h, and the reaction with BH3•THF is performed for 20-40 min; In step (5), the reaction is performed at 90-110 ℃ for 10-14 h.

5. The method of claim 2, wherein: Each step further comprises a step of separation and purification.

6. Use of the naphthyl-modified ChiraPhos type bisphosphine ligand according to claim 1 for catalyzing the asymmetric hydrogenation of citral to prepare (R)-citronellal, characterized in that R - citronellal is catalyzed in the presence of a catalyst comprising the naphthyl-modified ChiraPhos type bisphosphine ligand according to claim 1. The biphosphine ligand is reacted with Rh(CO)2acac to form a complex catalyst, the molar ratio of citral to the complex catalyst is 1:0.001-0.003; the citral is E / Z = 90:10; the reaction temperature is 35-45 ℃, and the reaction time is 6-14 h.

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