A chiral selenium / sulfur-based catalyst based on a phox ligand skeleton, a synthesis method and application thereof

Abstract

The present application relates to a kind of chiral selenium / sulfur catalyst based on PHOX ligand skeleton and its synthesis method and application.The catalyst is based on PHOX ligand skeleton selenium or sulfide, synthesis method is from PHOX ligand skeleton substrate as raw material, after separation, purification, different chiral selenium / sulfur catalyst based on PHOX ligand skeleton is obtained after one step derivatization.The catalyst is applied to organic chiral catalytic reaction, specifically for generating arylthio product with quaternary carbon center.Compared with prior art, the present application has the advantages of simple reaction steps, mild conditions, easy to buy raw materials, high yield, rich product variety, good economy and the like.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis technology, specifically to a chiral selenium / sulfur catalyst based on a PHOX ligand framework, its synthesis method, and its application. Background Technology

[0002] David Crich's group first synthesized the PHOX ligand skeleton in 1989 (Tetrahedron Letters. 1989, 30, 475.). At that time, the synthesis of the PHOX ligand skeleton was limited to racemic products and was synthesized as intermediates in reactions with low yields. In 2019, Glünter Helmchen's group (Tetrahedron Letters. 1993, 34, 1769.) first used the PHOX ligand skeleton as a chiral catalyst, which could increase the ee value of the product of the asymmetric allylation reaction to 99%. Jonathan MJ Williams' group increased the yield of the chiral PHOX ligand skeleton to 92% in 1994.

[0003] In 2003, Richard C. Bunt's research group (Organic Letters, 2003, 5, 2279) applied chiral PHOX ligand skeleton molecules to palladium-catalyzed allylic substitution reactions, achieving an ee value as high as 93% for the corresponding products. In 2013 (J. Org. Chem. 2012, 77, 1477), Christoph Schneider's research group reacted these PHOX ligands with metallic iridium to catalyze hydrogenation reactions. In the same year, Fan Qinghua's research group (Chem. Asian J. 2013, 8, 1101) again utilized these PHOX ligands with metallic iridium as ligands to catalyze asymmetric hydrogenation reactions, achieving an ee value as high as 97% for the corresponding products. In 2021, Scott E. Denmark synthesized a series of PHOX ligand backbone molecules via 1,2-oxoamineization of alkenes (J.Am.Chem.Soc.2021,143,13408), with an ee value as high as 96%, and then carried out a series of derivatizations on these PHOX ligand backbone molecules.

[0004] Currently, PHOX ligands have not been well applied in the construction of chiral sulfur- or selenium-containing compounds. Therefore, this application, based on the understanding of the chiral construction of sulfur- or selenium-containing compounds, attempts to construct new PHOX catalysts for sulfur or selenium oxidation and apply them to the construction of sulfur-containing chiral compounds, thus expanding the catalytic range of PHOX ligands. Summary of the Invention

[0005] The purpose of this invention is to overcome at least one of the defects of the prior art and provide a chiral selenium / sulfur catalyst based on the PHOX ligand framework, its synthesis method, and its application, which has a simple reaction step, mild conditions, readily available raw materials, high yield, rich product variety, and good economic efficiency.

[0006] The objective of this invention can be achieved through the following technical solutions:

[0007] In this application, based on the PHOX ligand molecule as the basic framework, chiral catalysts with different selenium / sulfur oxidation PHOX ligand molecule backbones were further constructed. These ligands were applied to small organic molecule catalytic reactions and exhibited certain catalytic activity. The specific scheme is as follows:

[0008] A chiral selenium / sulfur catalyst based on a PHOX ligand framework, wherein the catalyst is a selenium or sulfide based on a PHOX ligand framework, comprising the following structural formula:

[0009]

[0010] Furthermore, the structural formula of the catalyst is as follows:

[0011]

[0012] A method for synthesizing chiral selenium / sulfur catalysts based on the PHOX ligand framework as described above. This method uses PHOX ligand framework substrates as raw materials, undergoes a one-step derivatization, followed by separation and purification to obtain different chiral selenium / sulfur catalysts based on the PHOX ligand framework. The specific preparation route is as follows:

[0013]

[0014] Furthermore, the method specifically involves dissolving different PHOX ligand substrates in a solvent, adding selenium powder or sulfur powder to carry out the reaction, monitoring the completion of the reaction using TLC, and then purifying the reaction by vacuum distillation and column chromatography to obtain different derivatized selenium / sulfur catalysts based on the PHOX ligand framework.

[0015] Furthermore, the molar ratio of PHOX ligand substrate to selenium powder or sulfur powder is 1:(2.5-3.5), the reaction time is 40-50 h, and the solvent is DCM.

[0016] Furthermore, the molar ratio of PHOX ligand substrate to selenium powder or sulfur powder is 1:3, and the reaction time is 2 days.

[0017] Application of a chiral selenium / sulfur catalyst based on a PHOX ligand framework as described above, which is used in organic chiral catalytic reactions.

[0018] Furthermore, this catalyst was applied to generate aryl thiolated products with quaternary carbon centers, and the synthetic route is as follows:

[0019]

[0020] Further, the specific synthesis method is as follows: the substrate ethyl 2-diazo-2-phenylacetate, aryl sulfide reagent, catalyst and tetraethyl cyanophosphate are added to the reaction tube, solvent is added, and the reaction is carried out in an inert atmosphere. During the reaction, the reaction is monitored by TLC plate. After separation and purification, a chiral compound with a quaternary carbon center and aryl sulfide substitution is obtained.

[0021] Furthermore, the molar ratio of the substrate, aryl sulfide reagent, catalyst, and tetraethyl cyanophosphate copper hexafluorophosphate is 0.05:(0.05-0.07):(0.005-0.006):(0.004-0.006); the solvent is toluene.

[0022] Compared with the prior art, the present invention has the following characteristics:

[0023] (1) The method of the present invention has for the first time achieved the synthesis of selenium / sulfur catalysts based on PHOX ligand frameworks with different selenium / sulfur substitutions using the same type of PHOX ligand substrates;

[0024] (2) The method of the present invention uses a simple and easy-to-operate one-step method to prepare chiral selenium / sulfur catalysts based on the PHOX ligand framework, avoiding complex synthetic routes;

[0025] (3) The product of the method of the present invention has universality. Depending on the different substituted PHOX ligand substrates, a variety of derived chiral catalysts with selenium / sulfur substitution can be synthesized and have certain catalytic activity. Detailed Implementation

[0026] The embodiments of the present invention are described in detail below. These embodiments are implemented based on the technical solution of the present invention, and provide detailed implementation methods and specific operation processes. However, the scope of protection of the present invention is not limited to the following embodiments.

[0027] A synthetic method for selenium / sulfur catalysts based on PHOX ligand frameworks is proposed. This method starts with PHOX ligand framework substrates and generates different chiral selenium / sulfur catalysts based on PHOX ligand frameworks through further derivatization.

[0028] The proton nuclear magnetic resonance spectra (¹H NMR, ¹³C NMR) of the compounds were determined using a Bruker AVANCE III HD400 in deuterated chloroform. Chemical shifts (δ) are expressed in ppm, with tetramethylsilane as an internal standard. Multiplicity is as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplyt.

[0029] The catalyst in the synthesis method of the present invention comprises:

[0030]

[0031] For catalytic applications of this type of PHOX ligand, a synthetic method for preparing an aryl sulfur-substituted product with a quaternary carbon center is provided, specifically including the following steps:

[0032] The synthetic route of the above method is as follows:

[0033]

[0034] The method of the catalyst used in this invention is designed to use economically available ethyl 2-diazo-2-phenylacetate and aryl sulfide reagent as raw materials. Under the action of the catalyst and copper tetraethyl cyanophosphate, the reaction is carried out at room temperature and in an argon atmosphere for a period of time. After separation and purification, the aryl sulfide product with a quaternary carbon center is obtained.

[0035] The present invention will be further illustrated below through embodiments, the purpose of which is solely to provide a better understanding of the invention. Therefore, the scope of protection of this patent is not limited to these embodiments.

[0036] Example 1: Preparation of compound A

[0037]

[0038] Under anhydrous and oxygen-free conditions, 0.12 mmol A-0 (CAS No.: 148461-15-8) was dissolved in ultra-dry DCM (0.5 mL), and 0.36 mmol of selenium powder was added at room temperature. The reaction was stirred at room temperature for 2 days, and the reaction was monitored by TLC. After the reaction was completed, the solution was filtered through diatomaceous earth, concentrated using a rotary evaporator, and then evaporated to dryness. The crude product was purified by silica gel (1:3 EtOAc: petroleum ether) to give a white solid compound A in 99% yield.

[0039] 1H NMR(400MHz,Chloroform-d)δ7.99(dd,J=7.7,4.3Hz,1H),7.92–7.69(m,4H),7.58–7.35(m,8H),7.35– 7.25(m,3H),7.25–7.15(m,3H),4.98(t,J=9.8Hz,1H),4.21(dd,J=10.2,8.2Hz,1H),4.02–3.70(m,1H); 13 C NMR (101MHz, CDCl3) δ164.64,164.61,141.66,134.34,134.24,132.85,132 .73,132.60,132.50,132.32,132.27,132.21,132.17,132.14,132.09,132. 07,131.95,131.43,131.40,131.26,131.23,131.19,131.16,130.43,130.31,128.45,128.43,128.39,128.30,128.26,127.34,126.89,74.39,69.89.

[0040] Example 2: Preparation of compound B

[0041]

[0042] Under anhydrous and oxygen-free conditions, 0.12 mmol of A-O (CAS No.: 148461-15-8) was dissolved in 0.5 mL of ultra-dry DCM. 0.36 mmol of sulfur powder was added at room temperature, and the reaction was stirred at room temperature for 2 days. The reaction was monitored by TLC to indicate completion. After completion, the mixture was filtered through diatomaceous earth, concentrated using a rotary evaporator, and then evaporated to dryness. The crude product was purified by silica gel (1:3 EtOAc: petroleum ether) to give a white solid compound B in 99% yield.

[0043] 1 H NMR(400MHz,Chloroform-d)δ7.98(dd,J=7.8,4.2Hz,1H),7.86–7.75(m,4H),7.58–7.36(m,9H),7.3 5–7.26(m,2H),7.23(m,3H),4.99(t,J=9.8Hz,1H),4.20(dd,J=10.2,8.2Hz,1H),3.96–3.74(m,1H); 13C NMR (101MHz, CDCl3) δ164.97,164.93,141.71,134.26,134.15,134.05,133.97,1 33.45,133.19,133.11,132.64,132.15,132.13,132.10,132.06,131.99,131.86, 131.81,131.75,131.71,131.41,131.38,131.24,131.21,131.17,131.14,130.39,130.27,128.47,128.44,128.39,128.31,128.26,127.38,126.95,74.59,69.98.

[0044] Example 3: Preparation of compound C

[0045]

[0046] Under anhydrous and oxygen-free conditions, 0.12 mmol C-O (CAS No.: 201409-47-4) was dissolved in ultra-dry DCM (0.5 mL), and 0.36 mmol of selenium powder was added at room temperature. The reaction was stirred at room temperature for 2 days, and the reaction was monitored by TLC. After the reaction was completed, the solution was filtered through diatomaceous earth, concentrated using a rotary evaporator, and then evaporated to dryness. The crude product was purified by silica gel (1:2 EtOAc: petroleum ether) to give a white solid compound C in 99% yield.

[0047] 1 H NMR(400MHz,Chloroform-d)δ7.88–7.69(m,5H),7.53–7.26(m,10H),7.19(dt,J=7.3,3.8Hz,2H),7.13(m ,1H),5.30(d,J=8.0Hz,1H),4.90(t,J=7.3Hz,1H),3.13(dd,J=18.0,6.8Hz,1H),2.84(d,J=18.0Hz,1H); 13CNMR(101MHz,CDCl3)δ163.92,163.89,141.47,140.03,134.38,134.28,132.97, 132.91,132.70,132.59,132.44,132.33,132.19,132.14,132.12,132.07,131.9 8, 131.96, 131.30, 131.27, 131.26, 131.24, 131.22, 131.15, 131.12, 130.28, 130.16, 128.42, 128.29, 128.24, 128.16, 127.22, 125.45, 125.20, 83.59, 76.59, 38.6

[0048] Example 4: Preparation of Compound D

[0049]

[0050] Under anhydrous and oxygen-free conditions, 0.12 mmol C-O (CAS No.: 201409-47-4) was dissolved in ultra-dry DCM (0.5 mL), and 0.36 mmol of sulfur powder was added at room temperature. The reaction was stirred at room temperature for 2 days, and the reaction was monitored by TLC. After the reaction was completed, the mixture was filtered through diatomaceous earth, concentrated using a rotary evaporator, and then evaporated to dryness. The crude product was purified by silica gel (1:2 EtOAc: petroleum ether) to give a white solid compound D in 99% yield.

[0051] 1 H NMR(400MHz,Chloroform-d)δ7.89–7.66(m,5H),7.58–7.28(m,10H),7.24–7.07(m,3H),5.29 (d,J=8.0Hz,1H),4.87(t,J=7.2Hz,1H),3.13(dd,J=18.0,6.8Hz,1H),2.88(d,J=17.9Hz,1H); 13C NMR (101MHz, CDCl3) δ164.09,164.06,141.43,140.02,134.21,134.20,134.11 ,134.04,133.33,133.22,133.18,132.41,132.18,132.12,132.02,131.89,131 .79,131.23,131.20,131.17,131.09,131.06,130.18,130.06,128.38,128.38,128.25,128.24,128.21,128.11,127.16,125.41,125.16,83.64,76.63,38.67.

[0052] Example 5: Preparation of compound E

[0053]

[0054] Under anhydrous and anaerobic conditions, 0.13 mmol of E-0 (CAS No.: 148461-14-7) was dissolved in 0.5 mL of ultradry DCM. 0.39 mmol of selenium powder was added at room temperature, and the reaction was stirred at room temperature for 2 days. The reaction was monitored by TLC to indicate completion. After completion, the mixture was filtered through diatomaceous earth, concentrated using a rotary evaporator, and then evaporated to dryness. The crude product was purified by silica gel (1:2 EtOAc: petroleum ether) to obtain a white solid compound E in 99% yield.

[0055] 1 H NMR(400MHz,Chloroform-d)δ8.35–7.63(m,5H),7.61–6.91(m,9H),3.80(dd,J=9.8,8.2Hz, 1H),3.66(t,J=8.6Hz,1H),3.51(q,J=9.1Hz,1H),1.59(m,1H),0.79(dd,J=33.5,6.7Hz,6H); 13C NMR (101MHz, CDCl3) δ163.00,162.97,134.46,134.35,132.90,132.76,13 2.59,132.51,132.48,132.21,132.13,132.10,131.98,131.79,131.70,13 1.61,131.32,131.29,131.14,131.11,131.06,131.04,131.01,130.11,12 9.99,128.32,128.29,128.19,128.17,73.06,70.73,32.51,19.34,18.79.

[0056] Example 6: Preparation of compound F

[0057]

[0058] Under anhydrous and oxygen-free conditions, 0.13 mmol of E-O (CAS No.: 148461-14-7) was dissolved in 0.5 mL of ultradry DCM. 0.39 mmol of sulfur powder was added at room temperature, and the reaction was stirred at room temperature for 2 days. The reaction was monitored by TLC to indicate completion. After completion, the mixture was filtered through diatomaceous earth, concentrated using a rotary evaporator, and then evaporated to dryness. The crude product was purified by silica gel (1:2 EtOAc: petroleum ether) to give a white solid compound F in 99% yield.

[0059] 1 H NMR(400MHz,Chloroform-d)δ7.89–7.69(m,5H),7.58–7.27(m,9H),3.78(dd,J=9.8,8.1Hz,1H),3.66(t,J= 8.6Hz, 1H), 3.52 (td, J = 9.3, 7.4Hz, 1H), 1.59 (h, J = 6.8Hz, 1H), 0.86 (d, J = 6.7Hz, 3H), 0.76 (d, J = 6.7Hz, 3H); 13C NMR (101MHz, CDCl3) δ163.26,163.22,134.28,134.17,134.06,133.98,133.20 ,133.11,133.09,132.52,132.45,132.28,132.06,132.04,131.93,131.68,13 1.57, 131.48, 131.28, 131.25, 131.10, 131.06, 131.00, 130.97, 130.94, 130.07, 129.95, 128.30, 128.28, 128.18, 128.15, 72.99, 70.76, 32.52, 19.31, 18.72.

[0060] Example 7: Preparation of compound G

[0061]

[0062] Under anhydrous and oxygen-free conditions, 0.13 mmol of G-0 (CAS No.: 148461-16-9) was dissolved in 0.5 mL of ultradry DCM. 0.39 mmol of selenium powder was added at room temperature, and the reaction was stirred at room temperature for 2 days. The reaction was monitored by TLC to indicate completion. After the reaction was complete, the mixture was filtered through diatomaceous earth, concentrated using a rotary evaporator, and then evaporated to dryness. The crude product was purified by silica gel (1:3 EtOAc: petroleum ether) to give a white solid compound G in 99% yield.

[0063] 1 H NMR (400MHz, Chloroform-d) δ7.92–7.68(m,5H),7.61–7.33(m,9H),3.82(t,J=8. 5Hz, 1H), 3.60 (dd, J=10.3, 8.3Hz, 1H), 3.47 (dd, J=10.3, 8.6Hz, 1H), 0.78 (s, 9H); 13 CNMR(101MHz,CDCl3)δ163.03,163.00,134.87,134.76,132.99,132.96,13 2.77,132.66,132.46,132.39,132.22,132.18,132.16,132.05,131.82,13 1.68,131.59,131.43,131.41,131.19,131.16,131.09,131.05,131.02,130.28,130.16,128.36,128.34,128.23,128.21,76.13,68.71,33.68,26.08.

[0064] Example 8: Preparation of compound H

[0065]

[0066] Under anhydrous and oxygen-free conditions, 0.13 mmol of G-O (CAS No.: 148461-16-9) was dissolved in 0.5 mL of ultra-dry DCM. 0.39 mmol of sulfur powder was added at room temperature, and the reaction was stirred at room temperature for 2 days. The reaction was monitored by TLC to indicate completion. After completion, the mixture was filtered through diatomaceous earth, concentrated using a rotary evaporator, and then evaporated to dryness. The crude product was purified by silica gel (1:3 EtOAc: petroleum ether) to give a white solid compound H in 99% yield.

[0067] 1 H NMR(400MHz,Chloroform-d)δ8.07–7.61(m,5H),7.61–7.20(m,9H),3.83(td,J=8.3,2. 3Hz, 1H), 3.57 (dd, J=10.3, 8.2Hz, 1H), 3.47 (ddd, J=10.0, 8.2, 1.3Hz, 1H), 0.79 (s, 9H); 13 C NMR (101MHz, CDCl3) δ163.25,163.22,134.47,134.36,134.05,133.18,133.05,132.32,132.25,132.12,132.01,131.55,131.53,131 .44,131.30,131.27,131.07,131.04,130.94,130.91,130.17,130.04,128.27,128.24,128.14,128.11,76.01,68.71,33.61,25.99.

[0068] Application examples

[0069]

[0070] At room temperature, 0.05 mmol of substrate I (CAS No.: 22065-57-2, 1.0 equiv), 0.06 mmol of allyloxythiophenol J (CAS No.: 5296-64-0, 1.2 equiv), 0.0055 mmol of catalyst H (0.11 equiv), and 0.005 mmol of tetraethyl cyanophosphate (CAS No.: 64443-05-6, 0.1 equiv) were added to a reaction tube, along with solvent (toluene, 0.5 mL). The reaction was carried out under an argon atmosphere for a period of time, and the reaction was monitored by TLC. The chiral compound K with a quaternary carbon center and aryl sulfide substitution was then purified by vacuum distillation and column chromatography to obtain compound K (yield: 47%, ee value: 4%).

[0071] The NMR data for product K can be found in the literature (Journal of Organic Chemistry, 2020, 85, 11882. This invention uses different catalytic methods to construct chiral products, which, although known, still verify the catalytic activity of the catalyst of this invention). Separation of enantiomers by HPLC. Column AD-H, 30℃, n-hexane:i-PrOH=99:1, 1mL / min, minor retention time: 8.60min, major retention time: 7.61min, er=48:52.

[0072] In this invention, a new PHOX-type catalyst for the oxidation of sulfur or selenium is prepared through a one-step oxidation process. Based on the existing PHOX ligands, a new interaction site between the PHOX-type catalyst and the substrate is added. Furthermore, through the weak interaction between sulfur atoms and selenium atoms, the construction of chiral compounds containing sulfur or selenium can be further controlled.

[0073] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention in any other way. Any person skilled in the art may make changes or modifications to the above-disclosed technical content to create equivalent embodiments. However, any simple modifications, equivalent changes, and modifications made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the protection scope of the present invention.

Claims

1. A chiral selenium / sulfur catalyst based on a PHOX ligand framework, characterized in that, The catalyst is a PHOX ligand-based selenium or sulfide, including the following structural formula: 。 2. The chiral selenium / sulfur catalyst based on a PHOX ligand framework according to claim 1, characterized in that, The structural formula of the catalyst is: 。 3. A method for synthesizing a chiral selenium / sulfur catalyst based on a PHOX ligand framework as described in claim 1 or 2, characterized in that, This method uses PHOX ligand-based substrates as raw materials, undergoes a one-step derivatization, followed by separation and purification, to obtain different chiral selenium / sulfur catalysts based on the PHOX ligand framework. The specific preparation route is as follows: ,or ,or ,or ,or ,or ,or .

4. The method for synthesizing a chiral selenium / sulfur catalyst based on a PHOX ligand framework according to claim 3, characterized in that, The method specifically involves dissolving different PHOX ligand substrates in a solvent, adding selenium powder or sulfur powder to carry out the reaction, monitoring the completion of the reaction using TLC, and then purifying the catalysts by vacuum distillation and column chromatography to obtain different derivatized chiral selenium / sulfur catalysts based on the PHOX ligand framework.

5. The method for synthesizing a chiral selenium / sulfur catalyst based on a PHOX ligand framework according to claim 3, characterized in that, The molar ratio of PHOX ligand substrate to selenium powder or sulfur powder is 1:(2.5-3.5), the reaction time is 40-50 h, and the solvent is DCM.

6. The method for synthesizing a chiral selenium / sulfur catalyst based on a PHOX ligand framework according to claim 5, characterized in that, The molar ratio of PHOX ligand substrate to selenium powder or sulfur powder is 1:3, and the reaction time is 2 days.

7. An application of a chiral selenium / sulfur catalyst based on a PHOX ligand framework as described in claim 1 or 2, characterized in that, This catalyst is used in organic chiral catalytic reactions; This catalyst was used to generate aryl thioproducts with quaternary carbon centers, and the synthetic route is as follows: 。 8. The application of the chiral selenium / sulfur catalyst based on the PHOX ligand framework according to claim 7, characterized in that, The specific synthesis method is as follows: the substrate 2-diazo-2-phenylethyl acetate, allyloxybenzylthiophenol, catalyst and tetraethyl cyanophosphate copper hexafluorophosphate are added to the reaction tube, solvent is added, and the reaction is carried out in an inert atmosphere. During the reaction, the reaction is monitored by TLC plate. After separation and purification, a chiral compound with a quaternary carbon center and aryl sulfur substitution is obtained. The structural formula of the chiral compound having a quaternary carbon center and aryl sulfide substitution is: 。 9. The application of a chiral selenium / sulfur catalyst based on a PHOX ligand framework according to claim 8, characterized in that, The molar ratio of substrate, allyloxythiophenol, catalyst, and tetraethyl cyanophosphate was 0.05: (0.05-0.07): (0.005-0.006): (0.004-0.006); the solvent was toluene.

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