A method for the asymmetric allylic alkylation of racemic allylic alcohol with 1,3-diketone by heterogeneous catalysis

Abstract

The invention relates to a method for asymmetric allylic alkylation of racemic allyl alcohol and 1,3-diketone by heterogeneous catalysis. The allyl alcohol and the 1,3-diketone undergo an asymmetric allylic alkylation reaction under the catalytic action of an asymmetric catalyst loaded with metal rhodium in a polymer. The structural formula of the asymmetric catalyst loaded with metal rhodium in a polymer is: wherein n1 is an integer of 10-100, n2 is an integer of 1-10, and n3 is 1. The method utilizes an asymmetric catalyst loaded with metal rhodium in a polymer to cause an allylic alkylation reaction of the allyl alcohol and the 1,3-diketone. The asymmetric catalyst loaded with metal rhodium in a polymer not only has excellent reaction activity and enantioselectivity, but also has the advantages of catalyst recyclability, no metal leaching, simple separation, and the like.

Description

Technical Field

[0001] The invention relates to the field of asymmetric allylic alkylation, and in particular to a method for asymmetric allylic alkylation of racemic allylic alcohol and 1,3-diketone using heterogeneous catalysis. Background Art

[0002] Asymmetric allylic alkylation is an important method for constructing chiral carbon-carbon bonds. With its advantages of good atom economy, excellent asymmetric selectivity, broad functional group tolerance and product scalability, asymmetric allylic alkylation has become a research frontier and hotspot in the field of chiral asymmetric catalysis. At the same time, this chiral asymmetric catalytic method also provides important technical support for the synthesis of chiral molecules in the fields of medicine, pesticides, functional materials and specialty chemicals.

[0003] However, from the perspective of the current industrial application in this field, there are still some problems in the asymmetric allylic alkylation reaction, such as the expensive catalysts used in the reaction process, the difficulty in recycling, the metal residues, the difficulty in separation and the resulting decrease in yield, etc., which limit the industrial application of asymmetric allylic alkylation-related reactions. Therefore, it is particularly important to find a mild and efficient asymmetric allylic alkylation reaction method. Summary of the invention

[0004] In view of the prior art, the present invention develops a method for heterogeneously catalyzing the asymmetric allylic alkylation of racemic allylic alcohol with 1,3-diketone. The method utilizes an asymmetric catalyst loaded with metal rhodium in a polymer to cause the allylic alcohol and 1,3-diketone to undergo an allylic alkylation reaction. The asymmetric catalyst loaded with metal rhodium in a polymer not only has excellent reaction activity and enantioselectivity, but also has the advantages of catalyst recyclability, no metal leaching, and simple separation.

[0005] Based on this, the present invention provides a method for heterogeneously catalyzing the asymmetric allylic alkylation of racemic allyl alcohol and 1,3-diketone, wherein the allyl alcohol and the 1,3-diketone undergo an asymmetric allylic alkylation reaction under the catalytic action of an asymmetric catalyst loaded with metal rhodium in a polymer, and the structural formula of the asymmetric catalyst loaded with metal rhodium in a polymer is: Wherein, n1 is an integer from 10 to 100, n2 is an integer from 1 to 10, and n3 is 1.

[0006] More specifically, the preparation method of the polymer-supported rhodium asymmetric catalyst is as follows:

[0007] Step 1, (S)-binaphthol and pivaloyl chloride undergo a monoesterification reaction under the action of an alkaline catalyst to obtain an intermediate (S)-1; Step 2, the intermediate (S)-1 undergoes a bromine substitution reaction with liquid bromine at the 6' position of another naphthol ring of the (S)-binaphthol, and then a NaHSO3 aqueous solution is added to quench, and after the quenching is completed, the organic phase is extracted and concentrated, and the concentrate is subjected to an ester hydrolysis reaction to obtain an intermediate (S)-2; Step 3, the intermediate (S)-2 undergoes a 4-vinylphenyl coupling reaction with (4-vinylphenyl)boric acid at the 6' bromine substituent position reaction to obtain intermediate (S)-3; step 4, intermediate (S)-3, iminostilbene, and phosphorus trichloride undergo a phosphoramidation reaction under the action of an alkaline catalyst to obtain monomer 1; step 5, monomer 1 and (1,5-cyclooctadiene)chlororhodium (I) dimer undergo a complexation reaction, and the reaction liquid after the reaction is filtered to obtain a monomer 2 solution; step 6, the monomer 2 solution undergoes a copolymerization reaction with styrene and divinylbenzene under the action of a copolymerization catalyst and an initiator, and after the reaction is completed, the reaction product is filtered, washed, and dried to obtain the polymer-loaded metal rhodium asymmetric catalyst.

[0008] The process control of the monoesterification reaction is as follows: (S)-binaphthol and an alkaline catalyst are dissolved in a solvent, pivaloyl chloride is added dropwise at -5 to 5°C, and the temperature is raised to 20 to 30°C for reaction for 4 to 6 hours after the addition is completed; wherein the molar ratio of (S)-binaphthol to pivaloyl chloride is 1:(1.0 to 1.01).

[0009] The process control of the bromine substitution reaction is as follows: dissolving the intermediate (S)-1 in a solvent, adding liquid bromine at -5 to 5°C, and keeping the reaction warm for 3 to 4 hours after the addition; wherein the molar ratio of the intermediate (S)-1 to the liquid bromine is 1:(1.8 to 2.2).

[0010] The process control of the ester hydrolysis reaction is as follows: adding a solvent and a strong alkaline solution to the concentrate and mixing them evenly, reacting at 20-30° C. for 2-3 hours, and then acidifying with a strong acid to a pH of 1-2.

[0011] The strong alkali solution is at least one of potassium hydroxide, sodium hydroxide, sodium acetate, potassium acetate, sodium carbonate, sodium bicarbonate, and lithium hydroxide solution; the concentration of the strong alkali solution is 5-6 mol / L.

[0012] The strong acid solution is at least one of hydrochloric acid, sulfuric acid and nitric acid; and the concentration of the strong acid solution is 3N.

[0013] The process control of the coupling reaction is: the intermediate (S)-2, (4-vinylphenyl)boric acid, Pd(PPh3)4, K2CO3 and the solvent are mixed evenly, and heated to reflux for reaction for 20 to 24 hours under nitrogen protection; wherein the molar ratio of the intermediate (S)-2, (4-vinylphenyl)boric acid, K2CO3, and Pd(PPh3)4 is 1:(1.2 to 1.3):(2.5 to 3.5):0.03.

[0014] The process control of the phosphoramidation reaction is as follows: dissolve the alkaline catalyst and PCl3 in a solvent, add iminostilbene dropwise at -5 to 5°C, react at 20 to 30°C for 3 to 4 hours, then add the intermediate (S)-3 at -5 to 5°C, and react at 20 to 30°C for 18 to 20 hours; wherein the molar ratio of the intermediate (S)-3, iminostilbene, PCl3, and alkaline catalyst is 1:(3.5 to 4.0):(1 to 1.05):(5 to 7).

[0015] The process control of the complex reaction is as follows: the solvent, monomer 1 and (1,5-cyclooctadiene)chlororhodium (I) dimer are uniformly mixed under nitrogen protection, and reacted at 20-30° C. for 2-3 hours to obtain a monomer 2 solution; wherein the molar ratio of monomer 1 to (1,5-cyclooctadiene)chlororhodium (I) dimer is 1:(5-5.2).

[0016] The process control of the copolymerization reaction is as follows: after the monomer 2 solution, divinylbenzene, azobisisobutyronitrile, styrene and solvent are uniformly mixed, the temperature is raised to 55-65° C., and the mixture is reacted for 24-26 hours under stirring at 500-700 rpm; wherein the molar ratio of monomer 2, divinylbenzene and styrene is 1:(1-10):(10-100), and the molar amount of azobisisobutyronitrile is 1-5% of the molar amount of monomer 2.

[0017] The alkaline catalyst is at least one of Et3N, N,N-diisopropylethylamine, pyridine and piperidine.

[0018] The solvent is at least one of acetonitrile, toluene, dichloromethane, tetrahydrofuran, acetone, ethyl acetate, methanol, ethanol and petroleum ether.

[0019] Furthermore, the method for asymmetric allylic alkylation comprises the following steps: under the protection of an inert gas, the polymer-loaded metal rhodium asymmetric catalyst is uniformly mixed in a solvent, the allyl alcohol, the 1,3-diketone, and trifluoroacetic acid are added at room temperature, and the reaction is completed for 24 to 25 hours; after the reaction is completed, the product is filtered and concentrated to obtain the product.

[0020] Further, the reaction equation of the asymmetric allylic alkylation reaction is:

[0021]

[0022] Among them, R 1 , R 2 is any one of phenyl, methyl and ethyl; R 3 It is any one of hydrogen, methyl and chlorine.

[0023] Furthermore, the allyl alcohol is any one of 1a to 1k, and the molecular structural formulas of 1a to 1k are as follows:

[0024]

[0025] Furthermore, the 1,3-diketone is any one of 2a to 2d, and the molecular structure of 2a to 2d is as follows:

[0026]

[0027] Furthermore, the molar amount of the polymer-supported metal rhodium asymmetric catalyst is 0.001 to 0.2 times the molar amount of the allyl alcohol.

[0028] Furthermore, the molar amount of the 1,3-diketone is 0.5 to 3.0 times the molar amount of the allyl alcohol.

[0029] Furthermore, the molar amount of the trifluoroacetic acid is 0.01 to 3 times the molar amount of the allyl alcohol.

[0030] Furthermore, the solvent is at least one of toluene, dichloromethane, ethyl ether, tetrahydrofuran, p-xylene, acetonitrile, and methyl tert-ether.

[0031] Furthermore, the asymmetric allylic alkylation method may also be a continuous flow method, and the specific steps include:

[0032] S1, filling the asymmetric catalyst of the polymer-supported metal rhodium into a solid support bed, connecting the solid support bed to a continuous flow device, and purging the pipeline of the continuous flow device with nitrogen;

[0033] S2. Dissolve the allyl alcohol, the 1,3-diketone and trifluoroacetic acid in a solvent respectively, inject the three solutions into a continuous flow device at a constant flow rate using a syringe pump to react, collect the effluent after the reaction, concentrate under reduced pressure and then use column chromatography to obtain the product.

[0034] In summary, the present invention has the following beneficial effects:

[0035] The present invention utilizes a polymer-loaded metal rhodium asymmetric catalyst to cause allyl alcohol and 1,3-diketone to undergo an allylic alkylation reaction. The polymer-loaded metal rhodium asymmetric catalyst not only has excellent reaction activity and enantioselectivity, but also has the advantages of catalyst recycling, no metal leaching, and simple separation. DETAILED DESCRIPTION

[0036] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0037] The experimental methods in the following examples are conventional methods unless otherwise specified. The experimental materials and reagents used in the following examples are commercially available unless otherwise specified. The quantitative tests in the following examples were repeated three times, and the data are the average or average ± standard deviation of the three repeated experiments.

[0038] In addition, the "and / or" in the full text includes three solutions. Taking A and / or B as an example, it includes technical solution A, technical solution B, and a technical solution that satisfies both A and B. In addition, the technical solutions between the various embodiments can be combined with each other, but it must be based on the fact that ordinary technicians in the field can implement it. When the combination of technical solutions is contradictory or cannot be implemented, it should be deemed that such a combination of technical solutions does not exist and is not within the protection scope required by the present invention.

[0039] The invention provides a method for asymmetric allylic alkylation of racemic allyl alcohol and 1,3-diketone by heterogeneous catalysis. The allyl alcohol and the 1,3-diketone undergo an asymmetric allylic alkylation reaction under the catalytic action of an asymmetric catalyst loaded with metal rhodium in a polymer.

[0040] Among them, the structural formula of the asymmetric catalyst of polymer-supported metal rhodium is: n1 is an integer from 10 to 100, n2 is an integer from 1 to 10, and n3 is 1.

[0041] Meanwhile, the allyl alcohol used in the embodiments of the present invention is any one of 1a to 1k, and the molecular structures of 1a to 1k are as follows:

[0042]

[0043] Furthermore, the 1,3-diketone used in the embodiments of the present invention is any one of 2a to 2d, and the molecular structures of 2a to 2d are as follows:

[0044]

[0045] Example 1

[0046] In this embodiment, allyl alcohol is 1a, 1,3-diketone is 2a,

[0047] Asymmetric catalyst of polymer-supported metal rhodium, n1=50, n2=5, n3=1.

[0048] The specific reaction steps are as follows:

[0049] Asymmetric catalyst (60 mg, 3 mmol%) of polymer-supported metal rhodium was added to a dry schlenk tube equipped with a stirring bar, and Ar was replaced three times with a vacuum pump. Under Ar protection, toluene (2.0 mL) was added, and allyl alcohol 1a (0.2 mmol), 1,3-diketone 2a (0.4 mmol), and trifluoroacetic acid (25 mmol%) were added, stirred at room temperature for 24 h, filtered and concentrated under reduced pressure. The product was purified by silica gel column chromatography, recorded as A1, with a yield of 95% and an ee value of 90%.

[0050] The analytical test of product A1 is as follows:

[0051] Colorless oil, 41.0mg, 95% yield, 90%ee [Daicel Chiralpak IC (0.46cmx25cm), n-hexane / 2-propanol=95 / 5, v=1.0mL·min -1 ,λ=210nm, t(minor)=7.197min, t(major)=7.590min].

[0052] 1 H NMR(400MHz,Chloroform-d)δ7.40–7.30(m,2H),7.28–7.15(m,3H),5.90(ddd,J=17.2,10.2,7.7Hz,1H),5.12(d,J= 10.5Hz,1H),5.09(d,J=3.7Hz,1H),4.30(d,J=11.7Hz,1H),4.21(dd,J=11.7,7.7Hz,1H),2.29(s,3H),1.92(s,3H). 13C NMR(101MHz,Chloroform-d)δ202.99,202.89,139.89,138.07,129.01,127.99,127.30,116.60,74.31,49.86,30.17,29.63.

[0053] HRMS(ESI)calcd for C 14 H 17 O2[M+H] + :217.1223.Found:217.1220.

[0054] The difference between Example 2 and Example 1 is that the allyl alcohol is 1b and the product is recorded as A2.

[0055] The analytical test of product A2 is as follows:

[0056] Colorless oil, 42.8 mg, 93% yield, 90% ee [Daicel Chiralpak IC (0.46cmx25cm), n-hexane / 2-propanol=97 / 3, v=1.0mL·min -1 ,λ=210nm, t(minor)=8.803min, t(major)=9.430min].

[0057] 1 H NMR(400MHz,Chloroform-d)δ7.13(q,J=8.2Hz,4H),5.88(ddd,J=17.0,10.2,7.7Hz,1H),5.11(d,J=13.1Hz,1H),5 .07(d,J=6.3Hz,1H),4.28(d,J=11.7Hz,1H),4.17(dd,J=11.7,7.8Hz,1H),2.33(s,3H),2.28(s,3H),1.93(s,3H). 13 C NMR(101MHz,Chloroform-d)δ203.14,203.01,138.29,136.93,136.83,129.70,127.81,116.34,74.37,49.52,30.13,29.66,21.09.

[0058] HRMS(ESI)calcd for C 15 H 19 O2[M+H] + :231.1380.Found:231.1381.

[0059] The difference between Example 3 and Example 1 is that the allyl alcohol is 1c and the product is recorded as A3.

[0060] The analytical test of product A3 is as follows:

[0061] White solid, 49-52℃, 45.3mg, 92% yield, 90%ee [Daicel Chiralpak IC (0.46cm x 25cm), n-hexane / 2-propanol=97 / 3, v=1.0mL·min -1 ,λ=210nm, t(minor)=13.050min, t(major)=14.240min].

[0062] 1 H NMR (400MHz, Chloroform-d) δ7.13(d,J=8.7Hz,2H),6.86(d,J=6.7Hz,2H),5.87(ddd,J=17.4,10.3,7.6Hz,1H),5.08(d,J=6. 8Hz,1H),5.05(d,J=1.0Hz,1H),4.24(d,J=11.7Hz,1H),4.15(dd,J=11.8,7.6Hz,1H),3.79(s,3H),2.26(s,3H),1.91(s,3H). 13 C NMR(101MHz,Chloroform-d)δ203.10,203.05,158.65,138.35,131.78,129.00,116.18,114.34,74.45,55.26,49.03,30.18,29.62.

[0063] HRMS(ESI)calcd for C 15 H 19 O3[M+H] + :247.1329.Found:247.1329.

[0064] The difference between Example 4 and Example 1 is that the allyl alcohol is 1d and the product is recorded as A4.

[0065] The analytical test of product A4 is as follows:

[0066] Colorless oil, 46.3 mg, 96% yield, 92% ee [Daicel Chiralpak IC (0.46cmx25cm), n-hexane / 2-propanol=95 / 5, v=1.0mL·min -1 ,λ=210nm, t(minor)=37.890min, t(major)=39.900min].

[0067] 1 H NMR(400MHz,Chloroform-d)δ7.62(d,J=8.3Hz,2H),7.34(d,J=8.3Hz,2H),5.88–5.78(m,1H) ,5.15(d,J=4.4Hz,1H),5.11(d,J=11.2Hz,1H),4.28–4.26(m,2H),2.26(s,3H),1.95(s,4H). 13 C NMR(101MHz,Chloroform-d)δ201.90,201.80,145.64,136.62,132.75,128.89,118.57,118.00,111.21,73.83,49.37,30.18,29.54.

[0068] HRMS(ESI)calcd for C 15 H 16 NO2[M+H] + :242.1176.Found:242.1178.

[0069] The difference between Example 5 and Example 1 is that the allyl alcohol is 1e and the product is recorded as A5.

[0070] The analysis and test of product A5 are as follows:

[0071] Colorless oil, 51.1 mg, 90% yield, 92% ee [Daicel Chiralpak IC (0.46cmx25cm), n-hexane / 2-propanol=99 / 1, v=1.0mL·min -1 ,λ=210nm, t(minor)=9.507, t(major)=9.800.

[0072] 1H NMR(400MHz,Chloroform-d)δ7.59(d,J=8.0Hz,2H),7.35(d,J=8.0Hz,2H),5.93–5.80( m,1H),5.15(s,1H),5.12(d,J=6.2Hz,1H),4.35–4.24(m,2H),2.28(s,3H),1.96(s,3H). 13 C NMR(101MHz,Chloroform-d)δ202.24,202.12,144.16,137.14,129.54(q,J=32.4Hz),128.40,125 .94(q,J=3.9Hz),124.02(q,J=272.1Hz).128.30–119.72(m),117.54,74.10,49.30,30.11,29.50. 19 F NMR(376MHz,Chloroform-d)δ-62.55.

[0073] HRMS(ESI)calcd for C 15 H 16 F3O2[M+H] + :285.1097.Found:285.1099.

[0074] The difference between Example 6 and Example 1 is that the allyl alcohol is 1f and the product is recorded as A6.

[0075] The analysis and test of product A6 are as follows:

[0076] Colorless oil, 44.5mg, 95% yield, 91%ee [Daicel Chiralpak IC (0.46cmx25cm), n-hexane / 2-propanol=97 / 3, v=1.0mL·min -1 ,λ=210nm, t(minor)=7.043, t(major)=7.470.

[0077] 1 H NMR(400MHz,Chloroform-d)δ7.21–7.13(m,2H),7.00(t,J=8.7Hz,2H),5.90–5.79( m,1H),5.09(s,1H),5.08–5.02(m,1H),4.25–4.11(m,2H),2.25(s,3H),1.91(s,3H). 13C NMR(101MHz,Chloroform-d)δ202.61,202.56,163.05,160.61,137.87,135.67(d,J =3.2Hz),129.55(d,J=8.1Hz),116.71,115.94,115.72,74.37,48.86,30.13,29.52. 19 F NMR (376MHz, Chloroform-d) δ-115.18 (q, J=7.6, 7.0Hz).

[0078] HRMS(ESI)calcd for C 14 H 16 FO2[M+H] + :235.1129.Found:235.1132.

[0079] The difference between Example 7 and Example 1 is that the amount of allyl alcohol is 1 g and the product is recorded as A7.

[0080] The analysis and test of product A7 are as follows:

[0081] White solid, 72-75℃, 53.5mg, 91% yield, 92%ee [Daicel Chiralpak IC (0.46cm x 25cm), n-hexane / 2-propanol=99.5 / 0.5, v=1.0mL·min -1 ,λ=210nm, t(minor)=24.183, t(major)=26.960.

[0082] 1 H NMR(400MHz,Chloroform-d)δ7.46(d,J=8.4Hz,2H),7.10(d,J=8.4Hz,2H),5.85(ddd,J=16.7,10.5,7.3Hz,1H),5 .12(s,1H),5.09(d,J=7.8Hz,1H),4.24(d,J=11.7Hz,1H),4.18(dd,J=11.7,7.3Hz,1H),2.27(s,3H),1.95(s,3H). 13 C NMR(101MHz,Chloroform-d)δ202.46,202.38,138.99,137.46,132.08,129.71,121.15,117.07,74.18,49.00,30.15,29.50.

[0083] HRMS(ESI)calcd for C 14 H 16 BrO2[M+H] + :295.0328.Found:295.0330.

[0084] The difference between Example 8 and Example 1 is that the allyl alcohol is 1h and the product is recorded as A8.

[0085] The analysis and test of product A8 are as follows:

[0086] White solid, 131-133℃, 50.8mg, 87% yield, 85%ee [Daicel Chiralpak AD-H (0.46cm x 25cm), n-hexane / 2-propanol=97 / 3, v=1.0mL·min -1 ,λ=210nm, t(minor)=9.880, t(major)=9.043.

[0087] 1 H NMR (400MHz, Chloroform-d) δ7.59(t,J=8.2Hz,4H),7.47(t,J=7.6Hz,2H),7.38(t,J=7.3Hz,1H),7.31(d,J=8.2Hz,2H),5.94(d dd,J=17.5,10.2,7.6Hz,1H),5.20–5.11(m,2H),4.35(d,J=11.7Hz,1H),4.27(dd,J=11.7,7.6Hz,1H),2.31(s,3H),1.99(s,3H). 13 C NMR(101MHz,Chloroform-d)δ202.91,202.85,140.55,140.15,138.97,138.01 ,128.87,128.39,127.70,127.45,127.07,116.74,74.32,49.50,30.23,29.65.

[0088] HRMS(ESI)calcd for C 20 H 21 O2[M+H] + :293.1536.Found:293.1533.

[0089] The difference between Example 9 and Example 1 is that the allyl alcohol is 1i and the product is recorded as A9.

[0090] The analysis and test of product A9 are as follows:

[0091] White solid, 75-78℃, 48.4mg, 91% yield, 90%ee [Daicel Chiralpak IC (0.46cm x 25cm), n-hexane / 2-propanol=97 / 3, v=1.0mL·min -1 ,λ=210nm, t(minor)=10.860, t(major)=11.837.

[0092] 1 H NMR(400MHz,Chloroform-d)δ7.87–7.79(m,3H),7.68(d,J=1.8Hz,1H),7.60–7.45(m,2H),7.37(dd,J=8.5,1. 8Hz,1H),5.98(ddd,J=17.0,10.2,6.7Hz,1H),5.20–5.11(m,2H),4.47–4.35(m,2H),2.33(s,3H),1.93(s,3H). 13 C NMR(101MHz,Chloroform-d)δ202.94,202.80,137.98,137.33,133.56,132.59,128.84 ,127.85,127.72,126.81,126.40,126.07,125.95,116.90,74.26,49.87,30.16,29.69.

[0093] HRMS(ESI)calcd for C 18 H 19 O2[M+H] + :267.1380.Found:267.1385.

[0094] The difference between Example 10 and Example 1 is that the allyl alcohol is 1j and the product is recorded as A10.

[0095] The analysis and test of product A10 are as follows:

[0096] Colorless oil, 39.5mg, 89% yield, 91%ee [Daicel Chiralpak IC (0.46cmx25cm), n-hexane / 2-propanol=97 / 3, v=1.0mL·min -1,λ=210nm, t(minor)=9.240, t(major)=9.800.

[0097] 1 H NMR (400MHz, Chloroform-d) δ7.20 (dd, J=5.1, 1.2Hz, 1H), 6.94 (dd, J=5.1, 3.5Hz, 1H), 6.85 (d, J=3.1Hz, 1H), 5.88 (ddd, J= 17.1,10.1,8.0Hz,1H),5.20–5.11(m,2H),4.53(dd,J=11.4,8.0Hz,1H),4.24(d,J=11.4Hz,1H),2.25(s,3H),2.04(s,3H). 13 CNMR(101MHz,Chloroform-d)δ202.46,202.25,143.13,137.55,127.07,125.15,124.58,117.13,75.09,44.74,30.07,29.63.

[0098] HRMS(ESI)calcd for C 12 H 15 O2S[M+H] + :223.0787.Found:223.0785.

[0099] The difference between Example 11 and Example 1 is that allyl alcohol is 1k and the product is recorded as A11.

[0100] The analysis and test of product A11 are as follows:

[0101] Colorless oil, 42.9 mg, 88% yield, 93% ee [Daicel Chiralpak IC (0.46cmx25cm), n-hexane / 2-propanol=99 / 1, v=1.0mL·min -1 ,λ=210nm, t(minor)=17.017, t(major)=15.300.

[0102] 1H NMR(400MHz,Chloroform-d)δ7.34–7.28(m,2H),7.22(t,J=7.4Hz,1H),7.17(d,J=6.7Hz, 2H),5.58(ddd,J=17.0,10.3,9.3Hz,1H),5.25–5.15(m,2H),3.73(d,J=10.6Hz,1H),2.94 (qd,J=10.4,3.0Hz,1H),2.72(ddd,J=14.4,10.0,4.8Hz,1H),2.52(ddd,J=13.8,9.9,7.0 Hz,1H),2.15(s,3H),2.13(s,3H),1.72–1.60(m,1H),1.51(dtd,J=13.4,10.2,4.9Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ203.66,203.51,141.57,137.58,128.50,128.47,126.06,118.58,74.69,44.06,34.34,33.12,30.05,29.69.

[0103] HRMS(ESI)calcd for C 16 H 21 O2[M+H] + :245.1536.Found:245.1538.

[0104] The difference between Example 12 and Example 1 is that the 1,3-diketone is 2b and the product is recorded as A12.

[0105] The analysis and test of product A12 are as follows:

[0106] Colorless oil, 44.9 mg, 92% yield, 86% ee [Daicel Chiralpak IC (0.46cmx25cm), n-hexane / 2-propanol=90 / 10, v=1.0mL·min -1 ,λ=210nm, t(minor)=5.427, t(major)=6.620.

[0107] 1H NMR(400MHz,Chloroform-d)δ7.35–7.29(m,2H),7.26–7.17(m,3H),5.89(ddd,J=17.1,10.3,7.1Hz,1H),5.10(d,J=8.4Hz,1H),5.06(s,1H),4.32– 4.19(m,2H),2.62(qd,J=7.2,1.6Hz,2H),2.29(dq,J=18.5,7.2Hz,1H),2 .11(dq,J=18.5,7.2Hz,1H),1.05(t,J=7.2Hz,3H),0.75(t,J=7.2Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ205.45,140.15,138.24,128.90,128.01,127.18,116.49,73.01,49.92,36.39,35.72,7.43,7.21.

[0108] HRMS(ESI)calcd for C 16 H 21 O2[M+H] + :245.1536.Found:245.1533.

[0109] The difference between Example 13 and Example 1 is that the 1,3-diketone is 2c and the product is recorded as A13.

[0110] The analysis and test of product A13 are as follows:

[0111] Colorless oil, 43.5 mg, 87% yield, 90% ee [Daicel Chiralpak OD-H (0.46cmx 25cm), n-hexane / 2-propanol=99 / 1, v=1.0mL·min -1 ,λ=210nm, t(minor)=6.773, t(major)=7.407.

[0112] 1 H NMR(400MHz,Chloroform-d)δ7.40–7.27(m,5H),6.18(ddd,J=17.1,10.4,7.5Hz,1H),5.25 (d,J=10.3Hz,1H),5.18(d,J=17.1Hz,1H),4.63(d,J=7.6Hz,1H),2.34(s,3H),1.96(s,3H). 13C NMR (101MHz, Chloroform-d) δ201.33,198.51,137.21,135.44,130.12,128.50,127.83,119.30,87.19,53.96,27.91,27.72.

[0113] HRMS(ESI)calcd for C 14 H 16 ClO2[M+H] + :251.0833.Found:251.0831.

[0114] The difference between Example 14 and Example 1 is that the 1,3-diketone is 2d and the product is recorded as A14.

[0115] The analysis and test of product A14 are as follows:

[0116] White solid,87-90℃ 50mg,90%yield,87%ee,1.5:1d.r.[DaicelChiralpak AD-H(0.46cm x 25cm),n-hexane / 2-propanol=99.5 / 0.5,v=1.0mL·min -1 ,λ=225nm,t A (minor A)=64.483,t A (major A)=23.867.t B (minor B)=23.127,t B (majorB)=40.967.

[0117] 1 H A NMR(400MHz,Chloroform-d)δ7.89(d,J=7.9Hz,2H),7.44–7.37(m,3H),7.26(d,J=25.0Hz,3H),7.22(s,1H),7.16 –7.08(m,1H),6.04(ddd,J=16.8,10.2,8.6Hz,1H),5.29–5.13(m,3H),4.47(dd,J=11.3,8.6Hz,1H),2.27(s,3H). 13 C ANMR(101MHz,Chloroform-d)δ203.24,194.37,140.48,138.17,136.94,133.70,128.76,128.73,128.66,127.95,126.95,116.74,69.36,50.11,27.70. 1 H B NMR(400MHz,Chloroform-d)δ8.13(d,J=6.9Hz,2H),7.64(t,J=7.6Hz,1H),7.54(t,J=7.6Hz,3H),7.36–7.32(m,3H ),7.20(s,1H),5.87(ddd,J=17.3,10.2,7.2Hz,1H),5.13–4.95(m,3H),4.53(dd,J=11.4,7.2Hz,1H),1.99(s,3H). 13 C B NMR(101MHz,Chloroform-d)δ202.68,194.39,139.75,138.47,137.16,133.92,129.02,128.98,128.95,128.39,127.37,116.41,68.28,50.08,28.11.

[0118] HRMS(ESI)calcd for C 19 H 19 O2[M+H] + :279.1380.Found:279.1382.

[0119] Specifically, the structural formulas of products A1 to A12 are as follows:

[0120]

[0121] Embodiment 15

[0122] Experimental study on the recovery and application of asymmetric catalysts supported by polymers with metal rhodium

[0123] The filter cake after filtration in Example 1 was collected, washed with ethanol, acetone and petroleum ether in sequence, and dried under vacuum at 40° C. for 1 h to recover the asymmetric catalyst loaded with metal rhodium in a polymer.

[0124] The recovered polymer-loaded rhodium asymmetric catalyst is reused, and the synthesis steps of Example 1 are repeated, the product mixture is filtered, and the above operation is repeated to obtain the product and recover the polymer-loaded rhodium asymmetric catalyst.

[0125] The cycle was repeated four times, and the yield and ee value of each cycle are shown in Table 1.

[0126] Table 1 Yield and ee value of four cycles

[0127]

[0128]

[0129] It can be seen from Table 1 that the asymmetric catalyst of polymer-supported metal rhodium can stably maintain the reaction activity and enantioselectivity.

[0130] Example 16

[0131] This example provides another method for synthesizing product A1, that is, using a continuous flow device, the specific process is as follows:

[0132] First, fill 300 mg of asymmetric catalyst (n1=50, n2=5, n3=1) of polymer-loaded metal rhodium into the solid support bed, connect the solid support bed to the continuous flow device, and purge the continuous flow device pipeline with nitrogen, and then use anhydrous toluene (or ether, tetrahydrofuran, ethylene glycol dimethyl ether, dichloromethane, etc.) to discharge the gas in the continuous flow device pipeline.

[0133] Prepare 40 mL of toluene solution (0.5 mol / L) of allyl alcohol 1a (20 mmol) and 1,3-diketone 2a (40 mmol), and 40 mL of toluene solution (0.5 mol / L) of trifluoroacetic acid (5 mmol), and inject the two solutions into the continuous flow system at a flow rate of 0.05 mL / min using a syringe pump. After all the solutions have been injected, use anhydrous toluene at the same flow rate to clean the pipeline. Collect the effluent, and concentrate the filtrate under reduced pressure. Column chromatography on silica gel is performed. 4.104 g of product A is obtained with a yield of 95% and an ee value of 90%.

[0134] In summary, the present invention utilizes a polymer-loaded metal rhodium asymmetric catalyst to cause allyl alcohol and 1,3-diketone to undergo an allylic alkylation reaction. The polymer-loaded metal rhodium asymmetric catalyst not only has excellent reaction activity and enantioselectivity, but also has the advantages of catalyst recyclability, no metal leaching, and simple separation.

[0135] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0136] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for the heterogeneous catalytic asymmetric allylic alkylation of racemic allylic alcohol with 1,3-diketone, characterized in that: The allyl alcohol and the 1,3-diketone undergo an asymmetric allylic alkylation reaction under the catalytic action of a polymer-supported metal rhodium asymmetric catalyst, and the structural formula of the polymer-supported metal rhodium asymmetric catalyst is: Wherein, n1 is an integer from 10 to 100, n2 is an integer from 1 to 10, and n3 is 1; The allyl alcohol is any one of 1a to 1k, and the molecular structural formulas of 1a to 1k are as follows: The 1,3-diketone is any one of 2a to 2d, and the molecular structure of 2a to 2d is as follows: Wherein, the asymmetric allylic alkylation reaction adopts a continuous flow method; The reaction equation of the asymmetric allylic alkylation reaction is:

2. The method for heterogeneously catalyzing the asymmetric allylic alkylation of racemic allylic alcohol with 1,3-diketone according to claim 1, characterized in that: The following steps are involved: Under the protection of inert gas, the polymer-loaded metal rhodium asymmetric catalyst is uniformly mixed in a solvent, and the allyl alcohol, the 1,3-diketone and trifluoroacetic acid are added at room temperature, and the reaction is carried out for 24 to 25 hours. After the reaction is completed, the product is filtered and concentrated to obtain the product.

3. The method for heterogeneously catalyzing the asymmetric allylic alkylation of racemic allylic alcohol with 1,3-diketone according to claim 2, characterized in that: The molar amount of the polymer-supported metal rhodium asymmetric catalyst is 0.001 to 0.2 times the molar amount of the allyl alcohol.

4. The method for heterogeneously catalyzing the asymmetric allylic alkylation of racemic allylic alcohol with 1,3-diketone according to claim 2, characterized in that: The molar amount of the 1,3-diketone is 0.5 to 3.0 times the molar amount of the allyl alcohol.

5. The method for heterogeneously catalyzing the asymmetric allylic alkylation of racemic allylic alcohol with 1,3-diketone according to claim 2, characterized in that: The molar amount of the trifluoroacetic acid is 0.01 to 3 times the molar amount of the allyl alcohol.

6. The method for heterogeneously catalyzing the asymmetric allylic alkylation of racemic allylic alcohol with 1,3-diketone according to claim 2, characterized in that: The solvent is at least one of toluene, dichloromethane, ethyl ether, tetrahydrofuran, p-xylene, acetonitrile and methyl tert-ether.

7. The method for heterogeneously catalyzing the asymmetric allylic alkylation of racemic allylic alcohol with 1,3-diketone according to claim 1, characterized in that: The asymmetric allylic alkylation method adopts a continuous flow method, and the specific steps include: S1, filling the asymmetric catalyst of the polymer-supported metal rhodium into a solid support bed, connecting the solid support bed to a continuous flow device, and purging the pipeline of the continuous flow device with nitrogen; S2. Dissolve the allyl alcohol, the 1,3-diketone and trifluoroacetic acid in a solvent respectively, inject the three solutions into a continuous flow device at a constant flow rate using a syringe pump to react, collect the effluent after the reaction, concentrate under reduced pressure and then use column chromatography to obtain the product.

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