A method for synthesizing 4-benzyl-5-hydroxy-1-phenyl-1-alken-3-one compounds

Abstract

The application relates to the technical field of organic synthesis, and discloses a method for synthesizing 4-benzyl-5-hydroxy-1-phenyl-1-en-3-ketone compounds. In the application, silane is used as a reducing agent, organic phosphine is used as a ligand, a dibenzylideneacetone compound (I) and an aldehyde compound (II) are subjected to a conjugate reduction / aldol addition series reaction under the catalysis of Cu to obtain a 4-benzyl-5-hydroxy-1-phenyl-1-en-3-ketone compound (III). The method carries out two-step series reactions in the same reaction container, does not need to separate reaction intermediates, reduces the operation process of separation and purification, and is simple in operation. The reaction condition is mild, and the reaction can be carried out at normal temperature. The copper catalyst is a non-noble metal catalyst, and has the advantages of wide source and low price.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for synthesizing 4-benzyl-5-hydroxy-1-phenyl-1-en-3-one compounds. Background Technology

[0002] These compounds have broad application prospects in fields such as drug synthesis, materials science, and organic chemical engineering. For example, they can serve as key intermediates for certain drugs, used in the synthesis of compounds with specific biological activities.

[0003] Currently, the synthesis of 4-benzyl-5-hydroxy-1-phenyl-1-en-3-one compounds is as follows:

[0004]

[0005] There are various methods for processing these compounds, but they generally suffer from several problems, such as cumbersome reaction steps, difficulty in obtaining raw materials, harsh reaction conditions, and low yields. These problems not only increase production costs but also limit the industrial application of these compounds.

[0006] For example, some existing synthetic methods require the use of expensive catalysts, such as Rh catalysts. [1-2] Or special reaction conditions, such as reaction at low temperature -50℃. [3-4] Or requires heating [5] This not only increases production costs but also adds to operational complexity and safety risks. Furthermore, some methods require raw materials that are difficult to obtain, necessitating multi-step synthesis or purification, which further increases production time and costs.

[0007] Some methods require multiple reaction steps and complex separation and purification operations, such as multiple column chromatography separations, and the product selectivity is not high. This not only reduces production efficiency but may also cause environmental pollution.

[0008] Therefore, developing a synthetic method for 4-benzyl-5-hydroxy-1-phenyl-1-en-3-one compounds that uses readily available raw materials, operates under mild conditions, is simple to operate, and yields high amounts has significant practical importance and application value. This will not only help reduce production costs and improve production efficiency, but also promote the widespread application of these compounds in more fields.

[0009] This invention uses readily available and inexpensive dibenzylpyrone compounds, silanes, and aldehydes as raw materials to generate 4-benzyl-5-hydroxy-1-phenyl-1-en-3-one compounds via a non-precious metal Cu catalytic reaction. This reaction method is a conjugate reduction-aldol addition tandem reaction, reducing intermediate purification and separation steps and simplifying the operation. The reaction can be carried out at room temperature and pressure under mild conditions.

[0010] References

[0011] [1] Jung C-K., Krische M.J. Asymmetric Induction in Hydrogen-Mediated Reductive Aldol Additions to r-Amino Aldehydes Catalyzed by Rhodium: Selective Formation of syn-Stereotriads Directed by Intramolecular Hydrogen-Bonding[J]. J. Am. Chem. Soc. 2006, 128, 17051–17056.

[0012] [2] Bee C., Han S.B., Hassan A., H. Iida, M.J. Krische. Diastereo- and Enantioselective Hydrogenative Aldol Coupling of Vinyl Ketones: Design of Effective Monodentate TADDOL-Like Phosphonite Ligands[J]. J. Am. Chem. Soc. 2008, 130, 2746–2747.

[0013] [3] Chuzel O., Deschamp J., Chausteur C., Riant O. Copper(I)-Catalyzed Enantio- and Diastereoselective Tandem Reductive Aldol Reaction. Org. Lett. 2006, 8, 5943-5946. [4] Deschamp J., Riant O. Efficient Construction of Polycyclic Derivatives via a Highly Selective CuI-Catalyzed Domino Reductive-Aldol Cyclization. Org. Lett. 2009, 11, 1217-1220.

[0014] [5]Shiomi T.,Adachi T.,Ito Ji.,Nishiyama H.IntermolecularAntiselective and Enantioselective Reductive Coupling of Enones and AromaticAldehydes with Chiral Rh(Phebox)Catalysts[J].Org.Lett.2009,11,1011-1014. Summary of the Invention

[0015] To overcome the shortcomings of existing technologies, this invention provides a method for synthesizing 4-benzyl-5-hydroxy-1-phenyl-1-en-3-one compounds with mild reaction conditions and high cost-effectiveness, achieved through the following technical solution:

[0016] This invention utilizes silane as a reducing agent in the catalytic action of a copper salt-phosphine ligand to perform a conjugated reduction-aldol addition tandem reaction of dibenzylpyridinium acetone (Ⅰ) and an aldehyde (Ⅱ) to yield a 4-benzyl-5-hydroxy-1-phenyl-1-en-3-one (Ⅲ). This method involves two tandem reactions in the same reaction vessel, eliminating the need to separate reaction intermediates, reducing separation and purification processes, and simplifying the operation. Furthermore, the reaction conditions are mild and can be carried out at room temperature. Copper, as a non-precious metal catalyst, has the advantages of being widely available and inexpensive.

[0017] A method for synthesizing 4-benzyl-5-hydroxy-1-phenyl-1-en-3-one compounds, the specific synthetic route is as follows:

[0018]

[0019] The specific synthesis method is as follows: copper salt and phosphine ligand are added to Hullinger flask 1. Under Ar2 atmosphere, anhydrous reaction solvent is added to Hullinger flask 1 and stirred for 30 min. Then, silane is added to Hullinger flask 1 and stirred for 15 min. Compound of formula I is added to Hullinger flask 2. Under Ar2 atmosphere, anhydrous reaction solvent is added to Hullinger flask 2 and stirred to dissolve. The solution in Hullinger flask 2 is added to Hullinger flask 1. Then, compound of formula II is added to Hullinger flask 1 and stirred to react, thereby synthesizing compound of formula III, 4-benzyl-5-hydroxy-1-phenyl-1-en-3-one.

[0020] Furthermore, the R in the compound of formula I and the compound of formula III 1 It is a C1-C4 straight-chain alkyl group or a halogroup, and the substituent can be located at the ortho, meta, or para positions; the R in the compound of formula II and the compound of formula III 2It is one of the C1-C4 straight-chain alkyl or phenyl groups.

[0021] Furthermore, the phosphine ligand is one of the phosphine compounds L1-L4 with the following structures.

[0022]

[0023] Furthermore, the copper salt is one of [CuF(PPh3)3]·2MeOH and Cu(OAc)2;

[0024] Furthermore, the silane is either PMHS or methyldiethoxysilane.

[0025] Furthermore, the reaction solvent is one of tetrahydrofuran, toluene, and diethyl ether.

[0026] Furthermore, the initial concentration of the compound of formula I / reaction solvent is 0.3 mol / L.

[0027] Furthermore, the molar ratio of the copper salt, phosphine ligand, silane, compound I, and compound II is 0.01:0.01:4:1:1-4.5.

[0028] Furthermore, during the reaction, the temperature inside the Huylenk flask was 0-30°C.

[0029] Compared with the prior art, the beneficial effects of the present invention are:

[0030] A method for synthesizing 4-benzyl-5-hydroxy-1-phenyl-1-en-3-one compounds is provided, using bis(α,β-unsaturated carbonyl) dibenzylideneacetone compounds as substrates. The reaction is conducted at ambient temperature and pressure under mild conditions. The catalyst used is the inexpensive, non-precious metal Cu, and the starting materials are readily available and inexpensive. The synthetic method is a conjugate reduction-aldol addition tandem reaction carried out in the same reaction vessel, eliminating the need to separate reaction intermediates and reducing the cumbersome steps involved in stepwise reactions. This method offers advantages such as rapid reaction and high yield. Attached Figure Description

[0031] Figure 1 The syn-product in Example 1 1 H NMR spectrum;

[0032] Figure 2 The syn-product in Example 1 13 C NMR spectrum;

[0033] Figure 3 For the syn-products in Examples 2, 3, 4, and 5 1 H NMR spectrum;

[0034] Figure 4 For the syn-products in Examples 2, 3, 4, and 5 13 C NMR spectrum;

[0035] Figure 5 The anti-products in Examples 2, 3, 4, and 5 1 H NMR spectrum;

[0036] Figure 6 The anti-products in Examples 2, 3, 4, and 5 13 C NMR spectrum;

[0037] Figure 7 The syn-product in Example 6 1 H NMR spectrum;

[0038] Figure 8 The syn-product in Example 6 13 C NMR spectrum;

[0039] Figure 9 The anti-product in Example 6 1 H NMR spectrum;

[0040] Figure 10 The anti-product in Example 6 13 C NMR spectrum;

[0041] Figure 11 The anti-product in Example 7 1 HNMR spectrum;

[0042] Figure 12 The anti-product in Example 7 13 C NMR spectrum;

[0043] Figure 13 The syn-product in Example 8 1 H NMR spectrum;

[0044] Figure 14 The syn-product in Example 8 13 C NMR spectrum;

[0045] Figure 15 The anti-product in Example 8 1 H NMR spectrum;

[0046] Figure 16 The anti-product in Example 8 13 C NMR spectrum;

[0047] Figure 17 The anti-product in Example 91 H NMR spectrum;

[0048] Figure 18 The anti-product in Example 9 13 C NMR spectrum;

[0049] Figure 19 The syn-product in Example 10 1 H NMR spectrum;

[0050] Figure 20 The syn-product in Example 10 13 C NMR spectrum;

[0051] Figure 21 The anti-product in Example 10 1 H NMR spectrum;

[0052] Figure 22 The anti-product in Example 10 13 C NMR spectrum;

[0053] Figure 23 The syn-product in Example 11 1 H NMR spectrum;

[0054] Figure 24 The syn-product in Example 11 13 C NMR spectrum;

[0055] Figure 25 The anti-product in Example 11 1 HNMR spectrum;

[0056] Figure 26 The anti-product in Example 11 13 C10 NMR spectrum. Specific implementation methods

[0057] The present invention is described in detail below through embodiments, but the present invention is not limited to the embodiments described below. Unless otherwise specified, the experimental methods used in the present invention are all conventional methods, and the experimental equipment, materials, reagents, etc. used can be obtained commercially.

[0058] Example 1

[0059] At room temperature, [CuF(PPh3)3]·2MeOH (5.6 mg) and L1 (3.2 mg) were added to Hurricane flask 1. Tetrahydrofuran (2 mL) was then added as the reaction solvent and stirred for 15 min. Finally, 4 equiv... PMHS was added to Hurricane flask 1 and stirred for 30 min. 1 equiv of dibenzyl acetone (140.6 mg) was added to Hurricane flask 2, and under Ar2 atmosphere, tetrahydrofuran (2 mL) was added to Hurricane flask 2 and stirred to dissolve. The solution from Hurricane flask 2 was added to Hurricane flask 1, and 4.5 equiv of acetaldehyde (0.15 mL) was added to Hurricane flask 1. The mixture was stirred for 1 h, quenched with ammonium fluoride solution (10 mL, 0.15 mol / L, methanol:water = 3:1), filtered, separated, and extracted three times with dichloromethane (5 mL). The organic phases were collected, and the diastereomeric ratios were obtained by HPLC separation. Column chromatography yielded the product 4-benzyl-5-hydroxy-1-phenylhex-1-en-3-one (151 mg, yield 90%, dr value 1:1.22, conversion 100%).

[0060] The NMR spectrum of the diastereomer syn-product in this embodiment is shown in the attached figure. Figure 1 and Figure 2 .

[0061]

[0062] 1 HNMR (500MHz, CDCl3) δ7.36-7.33(m,2H),7.28-7.22(m,4H),7.17-7.11(m,4H),7.08(d,J=7.2Hz,1H),6.52(d,J=1 6.0Hz, 1H), 3.88 (dd, J=6.5, 4.3Hz, 1H), 3.08 (dt, J=7.3, 4.0Hz, 1H), 2.92 (d, J=6.9Hz, 2H), 1.16 (d, J=6.6Hz, 3H).

[0063] 13 C NMR (126MHz, CDCl3) δ204.74,143.77,139.05,134.25,130.81,129.13,128.95,128.57,128.53,126.86,126.50,68.45,57.43,36.04,22.01.

[0064] Example 2

[0065] At room temperature, [CuF(PPh3)3]·2MeOH (5.6 mg) and L3 (3.3 mg) were added to Huyrank flask 1. Tetrahydrofuran (2 mL) was then added as the reaction solvent and stirred for 15 min. Finally, 4 equiv... PMHS was added to Hurricane flask 1 and stirred for 30 min. 1 equiv of dibenzyl acetone (140.6 mg) was added to Hurricane flask 2, and under Ar2 atmosphere, tetrahydrofuran (2 mL) was added to Hurricane flask 2 and stirred to dissolve. The solution from Hurricane flask 2 was added to Hurricane flask 1, followed by 4.5 equiv of propionaldehyde (0.2 mL). The mixture was stirred for 1.5 h, and ammonium fluoride solution (10 mL, 0.15 mol / L, methanol:water = 3:1) was added. The mixture was filtered, separated, and extracted three times with dichloromethane (5 mL). The organic phases were collected and separated by HPLC to obtain the diastereomer ratios. Column chromatography yielded the product 4-benzyl-5-hydroxy-1-phenylhept-1-en-3-one (162 mg, yield 92%, dr value 1:2.33, conversion 100%).

[0066] Example 3

[0067] At room temperature, Cu(OAc)₂ (2.2 mg) and L₂ (1.6 mg) were added to Huyranco flask 1. Then, 2 mL of diethyl ether (the reaction solvent) was added to Huyranco flask 1 and the mixture was stirred for 15 min. Finally, 4 equiv of [amount missing] was added. PMHS was added to Hurricane flask 1 and stirred for 30 min. 1 equiv of dibenzyl acetone (140.6 mg) was added to Hurricane flask 2, and under Ar2 atmosphere, 2 mL of diethyl ether (the reaction solvent) was added to Hurricane flask 2 and stirred to dissolve. The solution from Hurricane flask 2 was added to Hurricane flask 1, and 4.5 equiv of propionaldehyde (0.2 mL) was added to Hurricane flask 1. The mixture was stirred for 1.5 h, and ammonium fluoride solution (10 mL, 0.15 mol / L, methanol:water = 3:1) was added. The mixture was filtered, separated, and extracted three times with dichloromethane (5 mL). The organic phases were collected, and the diastereomeric ratios were obtained by HPLC separation. Column chromatography yielded the product 4-benzyl-5-hydroxy-1-phenylhept-1-en-3-one (156 mg, yield 89%, dr value 1:1.27, conversion 100%).

[0068] Example 4

[0069] At 10°C, [CuF(PPh3)3]·2MeOH (5.6 mg) and L4 (2.4 mg) were added to Huyrank flask 1. Tetrahydrofuran (2 mL) was added as the reaction solvent and stirred for 15 min. Then, 4 equiv of methyldiethoxysilane was added to Huyrank flask 1 and the mixture was stirred for 30 min. In Huyrank flask 2, 1 equiv of dibenzyl acetone (140.6 mg) was added. Under an Ar2 atmosphere, 2 mL of tetrahydrofuran was added as the reaction solvent and stirred to dissolve the solution. The solution in Huyrank flask 2 was then... Add to Hurricane flask 1, then add 4.5 equiv propionaldehyde (0.2 mL) to Hurricane flask 1, stir and react for 1.5 h, add ammonium fluoride solution (10 mL, 0.15 mol / L, methanol:water = 3:1), filter, separate the layers, extract three times with dichloromethane (5 mL), separate the layers, collect the organic phase, and obtain the diastereomeric ratio after HPLC separation. After column chromatography, the product 4-benzyl-5-hydroxy-1-phenylhept-1-en-3-one (158 mg, yield 90%, dr value 1:1.22, conversion 98%) was obtained.

[0070] Example 5

[0071] At room temperature, [CuF(PPh3)3]·2MeOH (5.6 mg) and L1 (3.2 mg) were added to Huyranco flask 1. Toluene (2 mL) was then added as the reaction solvent and stirred for 15 min. Finally, 4 equiv... PMHS was added to Hurricane flask 1 and stirred for 30 min. 1 equiv of dibenzyl acetone (140.6 mg) was added to Hurricane flask 2. Under Ar2 atmosphere, toluene (2 mL) was added to Hurricane flask 2 and stirred to dissolve. The solution in Hurricane flask 2 was added to Hurricane flask 1, and 3 equiv of propionaldehyde (0.13 mL) was added to Hurricane flask 1. The mixture was stirred for 1.5 h. Ammonium fluoride solution (10 mL, 0.15 mol / L, methanol:water = 3:1) was added. The mixture was filtered, separated, and extracted three times with dichloromethane (5 mL). The organic phases were collected and separated by HPLC to obtain the diastereomer ratio. After column chromatography, the product 4-benzyl-5-hydroxy-1-phenylhept-1-en-3-one (128 mg, yield 73%, dr value 1:1.33, conversion 97%) was obtained.

[0072] The NMR spectra of the products from Examples 2, 3, 4, and 5 are shown in the attached figures. Figure 3 , Figure 4 , Figure 5 and Figure 6 .

[0073]

[0074] 11H NMR (500 MHz, CDCl3) δ 7.47 - 7.40 (m, 3H), 7.39 - 7.33 (m, 3H), 7.28 - 7.20 (m, 5H), 6.62 (d, J = 16.0 Hz, 1H), 3.63 (tt, J = 8.8, 4.6 Hz, 1H), 3.24 (td, J = 7.4, 3.8 Hz, 1H), 3.05 (d, J = 7.5 Hz, 2H), 1.52 (dddd, J = 14.4, 8.5, 5.5, 3.1 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H).

[0075] 13 13C NMR (126 MHz, CDCl3) δ 205.36, 143.92, 139.16, 134.26, 130.94, 129.21, 129.03, 128.66, 128.63, 126.90, 126.56, 74.11, 55.47, 36.35, 29.10, 10.72.

[0076]

[0077] 1 1H NMR (500 MHz, CDCl3) δ 7.35 - 7.29 (m, 5H), 7.24 - 7.18 (m, 3H), 7.17 - 7.10 (m, 3H), 6.45 (d, J = 16.0 Hz, 1H), 3.84 (dt, J = 8.5, 4.4 Hz, 1H), 3.22 (dt, J = 10.0, 4.2 Hz, 1H), 3.09 - 3.00 (m, 2H), 1.65 - 1.52 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H).

[0078] 13 13C NMR (126 MHz, CDCl3) δ 204.32, 143.71, 139.87, 134.35, 130.78, 129.14, 128.97, 128.64, 128.55, 126.62, 126.41, 73.46, 56.38, 33.29, 27.63, 10.65.

[0079] Example 6

[0080] At room temperature, [CuF(PPh3)3]·2MeOH (5.6 mg) and L2 (1.6 mg) were added to Hurricane flask 1. Tetrahydrofuran (2 mL) was then added as the reaction solvent and stirred for 15 min. Finally, 4 equiv... PMHS was added to Hurricane flask 1 and stirred for 30 min. In Hurricane flask 2, 1 equiv of dibenzyl acetone (140.6 mg) was added, and under Ar2 atmosphere, tetrahydrofuran (2 mL) was added to Hurricane flask 2 and stirred to dissolve. The solution from Hurricane flask 2 was added to Hurricane flask 1, followed by 2 equiv of butyraldehyde (0.10 mL). The mixture was stirred for 2 h, and ammonium fluoride solution (10 mL, 0.15 mol / L, methanol:water = 3:1) was added. The mixture was filtered, separated, and extracted three times with dichloromethane (5 mL). The organic phases were collected and separated by HPLC to obtain the diastereomer ratios. Column chromatography yielded the product 4-benzyl-5-hydroxy-1-phenylnon-1-en-3-one (144 mg, yield 78%, dr value 1.17:1, conversion 100%). The NMR spectrum of the product in this example is shown in the attached figure. Figure 7 ,and Figure 8 , Figure 9 and Figure 10 .

[0081]

[0082] 1 H NMR (500MHz, CDCl3) δ7.46-7.40(m,3H),7.37(d,J=7.2Hz,2H),7.24(q,J=7.7Hz,5H),7.17(t,J=7.1Hz,1H),6.61(d,J=16.0H z,1H),3.73(dq,J=8.8,4.3Hz,1H),3.21(td,J=7.5,3.9Hz,1H),3.11-3.05(m,2H),1.52-1.32(m,4H),0.88(t,J=7.2Hz,3H).

[0083] 13 C NMR (126MHz, CDCl3) δ205.12,143.69,139.04,134.17,130.73,129.04,128.8 6,128.48,128.46,126.80,126.39,72.32,55.75,38.19,36.20,19.32,13.94.

[0084]

[0085] 1H NMR (500MHz, CDCl3) δ7.35-7.29(m,5H),7.24-7.09(m,6H),6.45(d,J=16.0Hz,1H),3.93(dt,J=8.5, 3.9Hz,1H),3.19(dt,J=8.4,4.2Hz,1H),3.08-2.97(m,2H),1.62-1.43(m,4H),0.93(t,J=7.2Hz,3H).

[0086] 13 C NMR (126MHz, CDCl3) δ204.30,143.68,139.93,134.44,130.77,129.16,128.9 9,128.65,128.56,126.72,126.42,71.79,56.84,36.89,33.39,19.45,14.15.

[0087] Example 7

[0088] At room temperature, [CuF(PPh3)3]·2MeOH (5.6 mg) and L1 (3.2 mg) were added to Hurricane flask 1. Tetrahydrofuran (2 mL) was added as the reaction solvent and stirred for 15 min. Then, 4 equiv of methyldiethoxysilane was added to Hurricane flask 1 and the mixture was stirred for 30 min. In Hurricane flask 2, 1 equiv of dibenzyl acetone (140.6 mg) was added. Under an Ar2 atmosphere, 2 mL of tetrahydrofuran was added as the reaction solvent and stirred to dissolve the solution. The solution in Hurricane flask 2 was then... Add to Hurricane flask 1, then add 1 equiv benzaldehyde (0.06 mL) to Hurricane flask 1, stir and react for 3 h, add ammonium fluoride solution (10 mL, 0.15 mol / L, methanol:water = 3:1), filter, separate the layers, extract three times with dichloromethane (5 mL), separate the layers, collect the organic phase, and obtain the diastereomeric ratio after HPLC separation. After column chromatography, the product 4-benzyl-5-hydroxy-1,5-diphenylpent-1-en-3-one (88 mg, yield 43%, dr value 1:1.22, conversion 91%) was obtained.

[0089] The NMR spectrum of the anti-product in this embodiment is shown in the attached figure. Figure 11 and Figure 12 .

[0090]

[0091] 1H NMR (500MHz, CDCl3) δ7.34(d,J=10.5Hz,9H),7.29-7.21(m,7H),7.14(d,J=7.8Hz,3H),6.44(d,J=16.0Hz,1H),5 .30(s,1H),4.93(d,J=4.4Hz,1H),3.56(dt,J=8.9,5.9Hz,1H),3.03-2.97(m,1H),2.87(dd,J=13.6,6.0Hz,1H).

[0092] 13 C NMR (126MHz, CDCl3) δ204.15,143.55,142.59,138.77,134.29,130.64,129.02, 128.82,128.55,128.47,127.81,127.03,126.52,126.20,75.27,58.14,36.45.

[0093] Example 8

[0094] At room temperature, [CuF(PPh3)3]·2MeOH (5.6 mg) and L2 (1.6 mg) were added to Huyrank flask 1. Tetrahydrofuran (2 mL) was added as the reaction solvent and stirred for 15 min. Then, 4 equiv PMHS were added to Huyrank flask 1 and the mixture was stirred for 30 min. In Huyrank flask 2, 1 equiv PM... 1,5-Bis(4-chlorophenyl)pentan-1,4-dien-3-one (182.4 mg) was dissolved in a Huyranoque flask 2 under an Ar2 atmosphere by adding 2 mL of tetrahydrofuran as the reaction solvent and stirring. The solution in Huyranoque flask 2 was then added to Huyranoque flask 1, followed by the addition of 0.2 mL of 4.5 equiv propionaldehyde. The mixture was stirred for 1.5 h, and then ammonium fluoride solution (10 mL, 0.15 mol / L, methanol:water = 3:1) was added. The mixture was filtered, separated, and extracted three times with dichloromethane (5 mL). The organic phases were collected and separated by HPLC to obtain the diastereomer ratio. Column chromatography yielded the product 4-(4-chlorobenzyl)-1-(4-chlorophenyl)-5-hydroxyhept-1-en-3-one (161 mg, yield 74%, dr value 1:1.04, conversion 81%).

[0095] The NMR spectrum of the product in this embodiment is shown in the attached figure. Figure 13 , Figure 14 , Figure 15 and Figure 16 .

[0096]

[0097] 1 1H NMR (500 MHz, CDCl3) δ 7.41 - 7.34 (m, 5H), 7.27 - 7.21 (m, 3H), 7.15 (d, J = 8.4 Hz, 2H), 6.58 (d, J = 16.0 Hz, 1H), 3.60 (s, 1H), 3.16 (h, J = 4.0 Hz, 1H), 3.00 (d, J = 7.6 Hz, 2H), 1.51 (p, J = 7.3 Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H).

[0098] 13 13C NMR (126 MHz, CDCl3) δ 204.46, 142.50, 137.61, 137.03, 132.74, 132.47, 130.62, 129.82, 129.43, 128.82, 127.09, 74.09, 55.90, 35.52, 29.0, 10.66. <000?311>

[0100] 1 1H NMR (500 MHz, CDCl3) δ7.29 (d, J = 27.6 Hz, 5H), 7.19 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 6.45 (d, J = 16.0 Hz, 1H), 3.84 (dt, J = 8.4, 4.6 Hz, 1H), 3.17 (dq, J = 7.2, 4.1 Hz, 1H), 3.0? (d, J = 7.3 Hz, 2H), 1.57 (h, J = 6.9 Hz, 2H), 1.01 (t, J = 7.4 Hz,?H).

[0101] 13 13C NMR (126 MHz, CDCl3) δ 203.23, 142.30, 138.36, 136.84, 132.78, 132.23, 130.54, 129.70, 129.35, 128.73, 126.78, 73.45, 56.90, 32.67, 27.74, 10.60.

[0102] Example 9

[0103] At room temperature, Cu(OAc)₂ (2.2 mg) and L₁ (3.2 mg) were added to Huyranco flask 1. Toluene (2 mL) was added as the reaction solvent and stirred for 15 min. Then, 4 equiv of PMHS was added to Huyranco flask 1 and the mixture was stirred for 30 min. In Huyranco flask 2, 1 equiv of PMHS was added... 1,5-Bis(2-chlorophenyl)pentan-1,4-dien-3-one (182.4 mg) was dissolved in a Huyranco flask 2 by adding toluene (2 mL) under an Ar2 atmosphere and stirring. The solution in Huyranco flask 2 was then added to Huyranco flask 1, followed by the addition of 4.5 equiv propionaldehyde (0.2 mL) to Huyranco flask 1. The mixture was stirred for 1.5 h, and then ammonium fluoride solution (10 mL, 0.15 mol / L, methanol:water = 3:1) was added. The mixture was filtered, separated, and extracted three times with dichloromethane (5 mL). The organic phases were collected and separated by HPLC to obtain the diastereomer ratio. After column chromatography, the product 4-(2-chlorobenzyl)-1-(2-chlorophenyl)-5-hydroxyhept-1-en-3-one (116 mg, yield 53%, dr value 1:2.33, conversion 68%) was obtained.

[0104] The NMR spectrum of the anti-product in this embodiment is shown in the attached figure. Figure 17 and Figure 18 .

[0105]

[0106] 1 H NMR (500MHz, CDCl3) δ7.71 (d, J = 16.2Hz, 1H), 7.41-7.34 (m, 2H), 7.32-7.25 (m, 2H ),7.20(t,J=6.9Hz,1H),7.15-7.12(m,1H),7.08(td,J=7.4,3.8Hz,2H),6.40(d, J=16.2Hz,1H),3.89(s,1H),3.60-3.55(m,1H),3.29(dd,J=13.5,4.1Hz,1H),3.0 9(dd,J=13.6,10.8Hz,1H),3.00(s,1H),1.70-1.60(m,2H),1.05(t,J=7.4Hz,3H).

[0107] 13C NMR (126MHz, CDCl3) δ204.61,139.51,137.11,135.54,134.09,132.55,131.98,131.51,13 0.28,129.75,129.13,128.08,127.62,127.12,127.03,73.66,52.15,31.26,27.55,10.70.

[0108] Example 10

[0109] At room temperature, [CuF(PPh3)3]·2MeOH (5.6 mg) and L1 (3.2 mg) were added to Huyrank flask 1. Tetrahydrofuran (2 mL) was added as the reaction solvent and stirred for 15 min. Then, 4 equiv PMHS were added to Huyrank flask 1 and the mixture was stirred for 30 min. 1 equiv PMHS was added to Huyrank flask 2. 1,5-Bis(3-chlorophenyl)pentan-1,4-dien-3-one (182.4 mg) was dissolved in a Huyranoque flask 2 under an Ar2 atmosphere by adding 2 mL of tetrahydrofuran as the reaction solvent and stirring. The solution in Huyranoque flask 2 was then added to Huyranoque flask 1, followed by the addition of 0.2 mL of 4.5 equiv propionaldehyde. The mixture was stirred for 1.5 h, and then ammonium fluoride solution (10 mL, 0.15 mol / L, methanol:water = 3:1) was added. The mixture was filtered, separated, and extracted three times with dichloromethane (5 mL). The organic phases were collected and separated by HPLC to obtain the diastereomer ratio. Column chromatography yielded the product 4-(3-chlorobenzyl)-1-(3-chlorophenyl)-5-hydroxyhept-1-en-3-one (129 mg, yield 59%, dr value 1.17:1, conversion 73%).

[0110] The NMR spectrum of the product in this embodiment is shown in the attached figure. Figure 19 , Figure 20 , Figure 21 and Figure 22 .

[0111]

[0112] 1 H NMR (500MHz, CDCl3) δ7.46 (s, 1H), 7.39-7.30 (m, 4H), 7.24-7.15 (m, 3H), 7.10 (d, J = 7.3Hz, 1H), 6.62 (d, J = 16.0Hz, 1H), 3.65-3.58 (m, 1H), 3.19 (h, J = 4.0Hz, 1H), 3.01 (d, J = 7.5Hz, 2H), 1.51 (p, J = 7.3Hz, 2H), 0.97 (t, J = 7.4Hz, 3H).

[0113] 13 C NMR (126 MHz, CDCl3) δ 204.14, 142.17, 141.04, 135.98, 135.02, 134.36, 130.71, 130.22, 129.86, 129.14, 128.09, 127.75, 127.41, 126.82, 126.79, 73.98, 55.68, 35.64, 28.92, 10.53.

[0114]

[0115] 1 H NMR (500 MHz, CDCl3) δ 7.46 (s, 1H), 7.42 (d, J = 6.7 Hz, 1H), 7.34 (q, J = 7.1 Hz, 4H), 7.27 - 7.19 (m, 3H), 7.11 (d, J = 7.3 Hz, 1H), 6.58 (d, J = 16.0 Hz, 1H), 5.37 (s, 1H), 3.93 (dt, J = 8.5, 4.6 Hz, 1H), 3.28 (td, J = 7.2, 4.0 Hz, 1H), 3.10 (d, J = 7.3 Hz, 2H), 1.67 (dt, J = 14.3, 6.9 Hz, 2H), 1.10 (d, J = 7.5 Hz, 3H).

[0116] 13 C NMR (126 MHz, CDCl3) δ 203.06, 142.13, 141.93, 136.16, 135.07, 134.42, 130.70, 130.28, 129.92, 129.24, 128.12, 127.57, 127.43, 126.84, 126.71, 73.42, 56.76, 32.94, 27.76, 10.61.

[0117] Example 11

[0118] At room temperature, [CuF(PPh3)3]·2MeOH (5.6 mg) and L1 (3.2 mg) were added to Huyrank flask 1. Tetrahydrofuran (2 mL) was added as the reaction solvent and stirred for 15 min. Then, 4 equiv PMHS were added to Huyrank flask 1 and the mixture was stirred for 30 min. 1 equiv PMHS was added to Huyrank flask 2. 1,5-Bis(4-Tolyl)pentan-1,4-dien-3-one (157.2 mg) was dissolved in a Huyranoque flask 2 under an Ar2 atmosphere by adding 2 mL of tetrahydrofuran as the reaction solvent and stirring. The solution in Huyranoque flask 2 was then added to Huyranoque flask 1, followed by the addition of 0.2 mL of 4.5 equiv propionaldehyde. The mixture was stirred for 1.5 h, and then ammonium fluoride solution (10 mL, 0.15 mol / L, methanol:water = 3:1) was added. The mixture was filtered, separated, and extracted with 5 mL of dichloromethane. The organic phases were collected and separated by HPLC to obtain the diastereomer ratio. Column chromatography yielded the product 4-(4-methylbenzyl)-1-(4-methylphenyl)-5-hydroxyhept-1-en-3-one (136 mg, yield 71%, dr value 1.04:1, conversion 85%).

[0119] The NMR spectrum of the product in this embodiment is shown in the attached figure. Figure 23 , Figure 24 , Figure 25 and Figure 26 .

[0120]

[0121] 1 H NMR (500MHz, CDCl3) δ7.42(d,J=16.0Hz,1H),7.36(d,J=7.9Hz,2H),7.18(d,J=7.7Hz,2H),7.12(d,J=7.8Hz,2H),7.08(d,J=7.6Hz,2H),6.59(d,J=16 .0Hz,1H),3.61(dt,J=8.8,4.4Hz,1H),3.19(h,J=3.7Hz,1H),3.03-2.96( m,2H),2.37(s,3H),2.28(s,3H),1.54-1.46(m,2H),0.95(t,J=7.4Hz,3H).

[0122] 13C NMR (126MHz, CDCl3) δ205.54,144.00,141.58,136.18,136.09,131.68,129.85,1 29.37,129.18,128.73,126.09,74.09,55.52,36.00,29.21,21.71,21.17,10.77.

[0123]

[0124] 1 H NMR (500MHz, CDCl3) δ7.31-7.24(m,3H),7.14(d,J=7.7Hz,2H),7.04(q,J=7.9Hz,4H),6.44(d,J=16.0Hz,1H),3.84(dt,J=8.6,4. 3Hz,1H),3.20(dt,J=8.9,4.3Hz,1H),3.01(t,J=7.2Hz,2H),2.35(s,3H),2.24(s,3H),1.66-1.53(m,2H),1.01(t,J=7.5Hz,3H).

[0125] 13 C NMR (126MHz, CDCl3) δ204.35,143.66,141.26,136.80,135.78,131.71,129.68,1 29.26,129.01,128.56,125.74,73.51,56.46,32.87,27.63,21.60,21.05,10.62.

[0126] The embodiments described above are merely preferred embodiments of the present invention, and not all feasible embodiments of the present invention. Any obvious modifications made by those skilled in the art without departing from the principles and spirit of the present invention should be considered to be included within the scope of protection of the claims of the present invention.

Claims

1. A method for synthesizing 4-benzyl-5-hydroxy-1-phenyl-1-en-3-one compounds, characterized in that, The specific synthetic route is as follows: R in the compounds of formula I and formula III 1 It is one of C1-C4 straight-chain alkyl or halogroup, and the substituent can be located in the ortho, meta, or para position; R in compounds of formula II and formula III 2 It is one of the C1-C4 straight-chain alkyl or phenyl groups; The copper salt mentioned is one of [CuF(PPh3)3]·2MeOH and Cu(OAc)2; The phosphine ligand is one of the phosphine compounds L1-L4 with the following structures: The silane mentioned is either PMHS or methyldiethoxysilane.

2. The method for synthesizing 4-benzyl-5-hydroxy-1-phenyl-1-en-3-one compounds as described in claim 1, characterized in that, The molar ratio of the copper salt, phosphine ligand, silane, compound I, and compound II is 0.01:0.01:4:1:1-4.

5.

3. The method for synthesizing 4-benzyl-5-hydroxy-1-phenyl-1-en-3-one compounds as described in claim 1, characterized in that, The specific synthesis method is as follows: copper salt and phosphine ligand are added to Hullinger flask 1. Under Ar2 atmosphere, anhydrous reaction solvent is added to Hullinger flask 1 and stirred for 30 min. Then, silane is added to Hullinger flask 1 and stirred for 15 min. Compound of formula I is added to Hullinger flask 2. Under Ar2 atmosphere, anhydrous reaction solvent is added to Hullinger flask 2 and stirred to dissolve. The solution in Hullinger flask 2 is added to Hullinger flask 1. Then, compound of formula II is added to Hullinger flask 1 and stirred to react, thereby synthesizing compound of formula III, 4-benzyl-5-hydroxy-1-phenyl-1-en-3-one.

4. The method for synthesizing 4-benzyl-5-hydroxy-1-phenyl-1-en-3-one compounds as described in claim 3, characterized in that, The reaction solvent is one of tetrahydrofuran, toluene, or diethyl ether.

5. The method for synthesizing 4-benzyl-5-hydroxy-1-phenyl-1-en-3-one compounds as described in claim 3, characterized in that, The initial concentration of the compound of formula I / reaction solvent is 0.3 mol / L.

6. The method for synthesizing 4-benzyl-5-hydroxy-1-phenyl-1-en-3-one compounds as described in claim 3, characterized in that, During the reaction, the temperature range inside the Hughes flask is 0℃~30℃.

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