A method for the synthesis of chiral alpha-aryl ketones

Abstract

The application discloses a synthesis method of chiral alpha-aryl ketone and belongs to the field of organic synthesis. According to the method, an asymmetric decarboxylative acylation reaction is carried out in a protective atmosphere by taking a redox active ester derived from alpha-aryl carboxylic acid and a fatty carboxylic acid as reaction substrates, under irradiation of visible light and in the presence of a nickel salt, a chiral ligand, a photocatalyst, a carboxylic acid activator, an organic reducing agent and a solvent, so that an enantiomerically enriched alpha-aryl ketone compound is efficiently obtained.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for synthesizing chiral α-aryl ketones. Background Technology

[0002] α-Aryl ketones are widely found in natural products, drug molecules, and bioactive molecules, and are also important synthetic intermediates for constructing various oxygen- or nitrogen-containing chiral compounds such as alcohols, amines, amides, and oximes. In particular, α-aryl ketones with chiral centers are prone to racemization or side reactions during synthesis due to the adjacency of their α-position stereocenter to the carbonyl group. Therefore, their asymmetric synthesis has always been an important research topic in the field of organic synthesis. Existing asymmetric synthetic methods for α-aryl ketones mainly include transition metal-catalyzed coupling reactions, reductive acylation reactions, olefin hydroacylation reactions, and radical acylation reactions. However, the above methods generally have the following drawbacks: First, some methods require the prior preparation of organometallic reagents such as organozinc, organomagnesium, or organoboron, involving numerous raw material preparation steps and being sensitive to water, air, or functional groups. Second, some methods require substrates with high reactivity but relatively poor stability, such as acyl chlorides, activated carboxylic acids, or aldehydes, limiting their application in the later stages of complex molecule modification. Third, some reductive coupling systems require the use of stoichiometric metal reducing agents, such as zinc or manganese powder, which may lead to issues related to metal waste disposal and functional group compatibility. Fourth, existing photochemical asymmetric acylation methods often require the use of noble metal photocatalysts or special free radical precursors, resulting in high costs and limited substrate sources. Carboxylic acid compounds are widely available, stable, and readily available, and are widely found in natural products, pharmaceutical molecules, and bulk chemicals. If α-aryl carboxylic acid derivatives and aliphatic carboxylic acids could be directly used as coupling agents to construct α-aryl ketone skeletons via decarboxylation, it would have high synthetic value. However, when two different carboxylic acid derivatives participate in cross-coupling in the same system, problems such as reductive decarboxylation, homocoupling, competition for side reactions, and difficulty in controlling selectivity easily arise. Therefore, developing a mild, highly selective, and functional group-tolerant method for the synthesis of α-aryl ketones is of great significance. Summary of the Invention

[0003] The purpose of this invention is to provide a method for synthesizing chiral α-aryl ketones, in order to solve the problems in the prior art where the asymmetric synthesis of α-aryl ketones depends on organometallic reagents, acyl chlorides or stoichiometric metal reducing agents, and has limited substrate applicability and functional group tolerance.

[0004] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0005] The present invention provides a method for synthesizing chiral α-aryl ketones. Using a photo-redox / nickel dual-catalysis strategy, redox-active esters and aliphatic carboxylic acids derived from α-aryl carboxylic acids are used as reaction substrates. Under visible light irradiation and in the presence of nickel salts, chiral ligands, photocatalysts, carboxylic acid activators, organic reducing agents, and solvents, an asymmetric decarboxylation acylation reaction occurs in a protective atmosphere, thereby efficiently obtaining enantiomeric α-aryl ketone compounds.

[0006] The general structural formula of the redox-active ester derived from α-aryl carboxylic acid is shown below:

[0007] .

[0008] Among them, R 1 R 2 Each of the following is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, halogen, substituted or unsubstituted aryl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, cyano, and alkyloxycarbonylalkyl.

[0009] The substituents used for substitution are selected from one or more of C1-C6 alkyl, halogen, aryl, trifluoromethyl, heteroatom (O, N, S, etc.), and cyano substitution.

[0010] The general structural formula of the fatty carboxylic acid is:

[0011] .

[0012] Among them, R 3 It is selected from any one of substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, cyano, and alkyloxycarbonylalkyl.

[0013] The substituents used for substitution are selected from one or more of C1-C6 alkyl, halogen, aryl, trifluoromethyl, heteroatom (O, N, S, etc.), and cyano substitution.

[0014] The general structural formula of the target product is:

[0015] .

[0016] The nickel salt is a nickel(II) chloride-ethylene glycol dimethyl ether complex.

[0017] The structure of the chiral ligand is shown below:

[0018] .

[0019] The photocatalyst is 4CZIPN, and its structure is shown below:

[0020] .

[0021] The carboxylic acid activator is dimethyl carbonate (DMDC), whose structure is shown below:

[0022] .

[0023] The organic reducing agent is hesperidin (HE), and its structure is shown below:

[0024] .

[0025] The selected solvent is chosen from one of isopropyl acetate, ethylene glycol dimethyl ether, tetrahydrofuran, and ethyl acetate, with isopropyl acetate being preferred.

[0026] The protective atmosphere is an inert gas, such as argon.

[0027] The reaction temperature is 0-30 ℃, and more preferably 10 ℃.

[0028] The reaction time is 6-24 hours, and more preferably 12 hours.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] 1. This invention uses carboxylic acid compounds as coupling raw materials, which are widely available, stable and readily available, thus avoiding the use of organometallic reagents and acyl chloride substrates.

[0031] 2. This invention uses a dual catalytic system composed of organic photocatalyst 4CzIPN and nickel catalyst, eliminating the need for precious metal photocatalysts and reducing reaction costs.

[0032] 3. This invention does not require the addition of stoichiometric metal reducing agents, thus avoiding the side reactions and waste disposal problems caused by metal reducing agents such as zinc powder and manganese powder.

[0033] 4. This invention has a wide range of applicable substrates and is well tolerant to functional groups such as aryl, alkyl, alkenyl, halogen, trifluoromethyl, ether, ester, ketone, heterocyclic and sulfonamide.

[0034] 5. The α-aryl ketone products obtained by this invention can be further converted into chiral alcohols, amides, and other structures, and have high synthetic application value. Attached Figure Description

[0035] Figure 1 (S)-1,4-diphenylpentan-3-one prepared in Example 1 of this invention1 H NMR spectrum.

[0036] Figure 2 (S)-1,4-diphenylpentan-3-one prepared in Example 1 of this invention 13 C NMR spectrum Detailed Implementation

[0037] The present invention will be further described below with reference to embodiments. It should be understood that the following embodiments are for illustrative purposes only and are not intended to limit the scope of protection of the present invention. Any equivalent substitutions or conventional adjustments made based on the technical solutions of the present invention should fall within the scope of protection of the present invention.

[0038] The compounds and their derivatives involved in the embodiments of this invention are all named according to the IUPAC (International Union of Pure and Applied Chemistry) nomenclature system.

[0039] Example 1:

[0040] In a dried 10 mL Schlenk tube equipped with a Teflon stir bar, 4CzIPN (0.004 mmol, 3.2 mg), nickel(II)-ethylene glycol dimethyl ether complex (0.02 mmol, 4.4 mg), and L8 (0.03 mmol, 18.0 mg) were added together with 1.0 mL of anhydrous isopropyl acetate under argon atmosphere. The reaction mixture was stirred at room temperature for 30 minutes. Subsequently, hemisyl ester HE (0.3 mmol, 76.0 mg) was added. 1.0 mL of isopropyl acetate solution containing 1,3-dioxoisoindoline-2-yl 2-phenylpropionic acid (0.2 mmol, 1.0 eq), 3-phenylpropionic acid (0.4 mmol, 2.0 eq), and dimethyl carbonate (0.60 mmol, 64.0 μL) was added via a 1.0 mL syringe. Subsequently, the Schlenk tubes were tightly sealed with a sealing film stopper and irradiated and stirred at 10°C with a 40-watt blue LED lamp (Kessil PR160L, 427nm) for 12 hours. After irradiation, the lamp was turned off. The reaction solution was diluted with 15 mL of diethyl ether and washed three times with 1 M hydrochloric acid and 1 M anhydrous potassium carbonate solution, respectively. The organic layer was washed with brine (2 × 10 mL), dried on anhydrous sodium sulfate, and concentrated under reduced pressure. The acylated product was obtained by purification of the residues by preparative thin-layer chromatography. The yield was 80%, with an enantiomer excess of 96%. The synthetic route is as follows:

[0041]

[0042] Product: (S)-1,4-diphenylpentan-3-one

[0043] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR(400 MHz, CDCl3) δ 7.32 – 7.27 (m, 2H), 7.26 –7.18 (m, 3H), 7.18 – 7.11 (m, 3H), 7.06 (ddt, J = 7.5, 1.4, 0.7 Hz, 2H), 3.70(q, J = 6.9 Hz, 1H), 2.89 – 2.74 (m, 2H), 2.73 – 2.63 (m, 2H), 1.37 (d, J =7.0 Hz, 3H).

[0044] Carbon NMR characterization: 13 C NMR (151 MHz, CDCl3) δ 209.86, 141.05, 140.47,128.94, 128.39, 128.27, 127.88, 127.14, 126.00, 53.21, 42.58, 29.98, 17.32.

[0045] Example 2:

[0046] The preparation method is the same as that in Example 1 for (S)-1,4-diphenylpentan-3-one, except that acetic acid is used instead of 3-phenylpropionic acid. The yield of the target product is 68%, with an enantiomeric excess of 93%. The synthetic route is as follows:

[0047]

[0048] Product: (S)-3-phenylbutane-2-one

[0049] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (600 MHz, CDCl3) δ 7.38 – 7.34 (m, 2H), 7.31 –7.27 (m, 1H), 7.24 (dd, J = 7.5, 2.0 Hz, 2H), 3.77 (q, J = 7.0 Hz, 1H), 2.07(s, 3H), 1.42 (d, J = 7.0 Hz, 3H).

[0050] Carbon NMR characterization: 13 C NMR (151 MHz, CDCl3) δ 208.85, 140.63, 128.96, 127.84, 127.19, 53.77, 28.36, 17.22.

[0051] Example 3:

[0052] The preparation method is the same as that in Example 1 for (S)-1,4-diphenylpentan-3-one, except that undecanoic acid is used instead of 3-phenylpropionic acid. The yield of the target product is 68%, with an enantiomeric excess of 93%. The synthetic route is as follows:

[0053]

[0054] Product: (S)-2-Phenylacetetane-3-one

[0055] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (600 MHz, CDCl3) δ 7.35 (t, J = 7.6 Hz, 2H), 7.27 (d, J = 7.2 Hz, 1H), 7.25 – 7.21 (m, 2H), 3.77 (q, J = 7.0 Hz, 1H), 2.36 (td,J = 7.6, 3.3 Hz, 2H), 1.49 (ddt, J = 21.8, 14.7, 7.1 Hz, 2H), 1.41 (d, J =7.0 Hz, 3H), 1.30 – 1.17 (m, 14H), 0.90 (t, J = 7.1 Hz, 3H).

[0056] Carbon NMR characterization: 13 C NMR (151 MHz, CDCl3) δ 211.09, 140.80, 128.86,127.90, 127.06, 52.97, 41.07, 31.88, 29.53, 29.43, 29.32, 29.29, 29.07,23.88, 22.67, 17.47, 14.11.

[0057] Example 4:

[0058] The preparation method is the same as that in Example 1 for (S)-1,4-diphenylpentan-3-one, except that 4-phenylbutyric acid is used instead of 3-phenylpropionic acid. The yield of the target product is 57%, with an enantiomeric excess of 97%. The synthetic route is as follows:

[0059]

[0060] Product: (S)-2,6-diphenylhexane-3-one

[0061] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR(600 MHz, CDCl3) δ 7.35 (t, J = 7.6 Hz, 2H), 7.30– 7.22 (m, 5H), 7.20 – 7.16 (m, 1H), 7.10 – 7.01 (m, 2H), 3.75 (q, J = 7.0Hz, 1H), 2.55 (dt, J = 14.5, 7.5 Hz, 1H), 2.49 – 2.44 (m, 1H), 2.44 – 2.33(m, 2H), 1.88 – 1.80 (m, 2H), 1.41 (d, J = 7.0 Hz, 3H).

[0062] Carbon NMR characterization: 13 C NMR (151 MHz, CDCl3) δ 210.59, 141.67, 140.64,128.92, 128.42, 128.30, 127.90, 127.13, 125.83, 53.02, 40.18, 34.93, 25.31,17.43.

[0063] Example 5:

[0064] The preparation method is the same as that in Example 1 for (S)-1,4-diphenylpentan-3-one, except that 4-phenoxybutyric acid is used instead of 3-phenylpropionic acid. The yield of the target product is 77%, with an enantiomeric excess of 97%. The synthetic route is as follows:

[0065]

[0066] Product: (S)-6-phenoxy-2-phenylhexane-3-one

[0067] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR(600 MHz, CDCl3) δ 7.35 – 7.31 (m, 2H), 7.29 –7.20 (m, 5H), 6.94 (tt, J = 7.3, 1.1 Hz, 1H), 6.85 – 6.80 (m, 2H), 3.91 (ddd,J = 9.3, 1.97 (dtd, J =14.1, 7.0, 1.5 Hz, 1H), 1.43 (d, J = 7.0 Hz, 3H).

[0068] Carbon NMR characterization: 13 C NMR (151 MHz, CDCl3) δ 210.31, 158.79, 140.59,129.39, 128.94, 127.85, 127.17, 120.64, 114.45, 66.64, 53.13, 37.32, 23.54,17.39.

[0069] Example 6:

[0070] The preparation method is the same as that in Example 1 for (S)-1,4-diphenylpentan-3-one, except that 4,4,4-trifluorobutyric acid is used instead of 3-phenylpropionic acid. The yield of the target product is 62%, with an enantiomeric excess of 93%. The synthetic route is as follows:

[0071]

[0072] Product: (S)-6,6,6-trifluoro-2-phenylhexane-3-one

[0073] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (600 MHz, CDCl3) δ 7.42 – 7.34 (m, 2H), 7.33 –7.29 (m, 1H), 7.26 – 7.19 (m, 2H), 3.79 (q, J = 6.9 Hz, 1H), 2.69 – 2.57 (m,2H), 2.47 – 2.36 (m, 1H), 2.33 – 2.24 (m, 1H), 1.45 (d, J = 7.0 Hz, 3H).

[0074] Carbon NMR characterization: 13 C NMR (151 MHz, CDCl3) δ 207.21, 139.94, 129.15, 127.77, 127.51, 53.08, 33.30, 33.28, 28.23, 28.03, 17.31.

[0075] Example 7:

[0076] The preparation method is the same as that in Example 1 for (S)-1,4-diphenylpentan-3-one, except that 6-chlorohexanoic acid is used instead of 3-phenylpropionic acid. The yield of the target product is 51%, with an enantiomeric excess of 95%. The synthetic route is as follows:

[0077]

[0078] Product: (S)-8-chloro-2-phenyloctane-3-one

[0079] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (600 MHz, CDCl3) δ 7.38 – 7.33 (m, 2H), 7.30 –7.27 (m, 2H), 7.26 – 7.20 (m, 2H), 3.77 (q, J = 7.0 Hz, 1H), 3.48 (t, J = 6.7Hz, 2H), 2.44 – 2.34 (m, 2H), 1.72 – 1.66 (m, 2H), 1.57 – 1.48 (m, 2H), 1.42(d, J = 7.0 Hz, 3H), 1.32 (dt, J = 15.4, 6.9 Hz, 2H).

[0080] Carbon NMR characterization: 13 C NMR (151 MHz, CDCl3) δ 210.57, 140.63, 128.94,127.87, 127.17, 53.09, 44.79, 40.66, 32.29, 26.27, 23.02, 17.39.

[0081] Example 8:

[0082] The preparation method is the same as that in Example 1 for (S)-1,4-diphenylpentan-3-one, except that hepta-6-enoic acid is used instead of 3-phenylpropionic acid. The yield of the target product is 64%, with an enantiomeric excess of 85%. The synthetic route is as follows:

[0083]

[0084] Product: (S)-2-Phenylon-8-en-3-one

[0085] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (600 MHz, CDCl3) δ 7.39 – 7.32 (m, 2H), 7.28 –7.26 (m, 1H), 7.25 – 7.19 (m, 2H), 5.75 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.00 – 4.89 (m, 2H), 3.77 (q, J = 7.0 Hz, 1H), 2.42 – 2.32 (m, 2H), 1.97 (dtd, J = 7.4, 6.1, 1.4 Hz, 2H), 1.56 – 1.48 (m, 2H), 1.41 (d, J = 7.0 Hz,3H), 1.32 – 1.23 (m, 2H).

[0086] Carbon NMR characterization: 13 C NMR (101 MHz, CDCl3) δ 210.77, 140.73, 138.49,128.86, 127.86, 127.07, 114.48, 52.98, 40.77, 33.39, 28.24, 23.29, 17.41.

[0087] Example 9:

[0088] The preparation method is the same as that in Example 1 for (S)-1,4-diphenylpentan-3-one, except that 4-ethoxy-4-oxobutyric acid is used instead of 3-phenylpropionic acid. The yield of the target product is 59%, with an enantiomeric excess of 95%. The synthetic route is as follows:

[0089]

[0090] Product: Ethyl (S)-4-oxo-5-phenylhexanoate

[0091] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR(600 MHz, CDCl3) δ 7.39 – 7.31 (m, 2H), 7.30 –7.27 (m, 1H), 7.27 – 7.23 (m, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.82 (q, J = 7.0Hz, 1H), 2.74 – 2.64 (m, 2H), 2.63 – 2.56 (m, 1H), 2.46 (dt, J = 17.0, 6.5Hz, 1H), 1.45 (d, J = 7.0 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H).

[0092] Carbon NMR characterization: 13 C NMR (151 MHz, CDCl3) δ 209.05, 172.76, 140.54,128.96, 127.91, 127.22, 60.57, 52.98, 35.64, 28.24, 17.39, 14.16.

[0093] Example 10:

[0094] The preparation method is the same as that in Example 1 for (S)-1,4-diphenylpentan-3-one, except that 4-oxopentanoic acid is used instead of 3-phenylpropionic acid. The yield of the target product is 50%, with an enantiomeric excess of 99%. The synthetic route is as follows:

[0095]

[0096] Product: (S)-6-phenylheptane-2,5-dione

[0097] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (600 MHz, CDCl3) δ 7.35 (dd, J = 8.2, 6.9 Hz,2H), 7.28 – 7.27 (m, 1H), 7.26 – 7.23 (m, 2H), 3.84 (q, J = 7.0 Hz, 1H), 2.78– 2.68 (m, 2H), 2.60 – 2.53 (m, 2H), 2.18 (s, 3H), 1.43 (d, J = 7.0 Hz, 3H).

[0098] Carbon NMR characterization: 13 C NMR(151 MHz, CDCl3) δ 209.57, 207.21, 140.65,128.93, 127.91, 127.19, 52.98, 37.19, 34.72, 29.91, 17.39.

[0099] Example 11:

[0100] The preparation method is the same as that in Example 1 for (S)-1,4-diphenylpentan-3-one, except that 3-(thiophene-3-yl)propionic acid is used instead of 3-phenylpropionic acid. The yield of the target product is 66%, with an enantiomeric excess of 96%. The synthetic route is as follows:

[0101]

[0102] Product: (S)-4-phenyl-1-(thien-3-yl)pentane-3-one

[0103] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (600 MHz, CDCl3) δ 7.33 (dd, J = 8.2, 6.7 Hz,2H), 7.29 – 7.25 (m, 1H), 7.23 – 7.15 (m, 3H), 6.87 – 6.79 (m, 2H), 3.74 (q,J = 6.9 Hz, 1H), 2.92 – 2.80 (m, 2H), 2.75 – 2.64 (m, 2H), 1.41 (d, J = 7.0Hz, 3H).

[0104] Carbon NMR characterization: 13 C NMR (151 MHz, CDCl3) δ 209.78, 141.23, 140.45,128.96, 128.05, 127.87, 127.17, 125.40, 120.38, 53.18, 41.70, 24.37, 17.34.

[0105] Example 12:

[0106] The preparation method was the same as that in Example 1 for (S)-1,4-diphenylpentan-3-one, except that 1,3-dioxoisoindoline-2-yl ester (0.2 mmol, 1.0 eq) was replaced with 2-(p-tolyl)propionic acid-1,3-dioxoisoindoline-2-yl ester. The yield of the target product was 71%, with an enantiomeric excess of 96%. The synthetic route is as follows:

[0107]

[0108] Product: (S)-1-Phenylon-4-(p-Tolyl)pentane-3-one

[0109] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (600 MHz, CDCl3) δ 7.24 (dd, J = 8.3, 6.8 Hz,3H), 7.20 – 7.15 (m, 1H), 7.13 (d, J = 7.9 Hz, 2H), 7.11 – 7.02 (m, 4H), 3.69(q, J = 7.0 Hz, 1H), 2.87 (ddd, J = 14.9, 9.0, 6.5 Hz, 1H), 2.79 (ddd, J =14.3, 9.2, 6.0 Hz, 1H), 2.74 – 2.62 (m, 2H), 2.35 (s, 3H), 1.38 (d, J = 7.0Hz, 3H).

[0110] Carbon NMR characterization: 13 C NMR (151 MHz, CDCl3) δ 210.09, 141.12, 137.47,136.80, 129.61, 128.37, 128.28, 127.74, 125.97, 52.80, 42.49, 30.00, 21.03,17.34.

[0111] Example 13:

[0112] The preparation method is the same as that of (S)-1,4-diphenylpentan-3-one in Example 1, except that 2-(4-methoxyphenyl)propionic acid-1,3-dioxoisoindoline-2-yl ester is used instead of 2-phenylpropionic acid-1,3-dioxoisoindoline-2-yl ester. The yield of the target product was 75%, with an enantiomeric excess of 91%. The synthetic route is as follows:

[0113]

[0114] Product: (S)-4-(4-methoxyphenyl)-1-phenylpentan-3-one

[0115] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR(600 MHz, CDCl3) δ 7.23 (q, J = 6.8 Hz, 2H), 7.19– 7.15 (m, 1H), 7.09 (dd, J = 8.0, 5.3 Hz, 4H), 6.88 – 6.84 (m, 2H), 3.81 (s,3H), 3.67 (q, J = 7.0 Hz, 1H), 2.92 – 2.85 (m, 1H), 2.80 (ddd, J = 14.4, 8.9,6.3 Hz, 1H), 2.73 – 2.64 (m, 2H), 1.40 – 1.36 (m, 3H).

[0116] Carbon NMR characterization: 13 C NMR (151 MHz, CDCl3) δ 209.81, 158.86, 141.14,132.59, 128.80, 128.31, 128.21, 125.91, 114.42, 55.23, 52.33, 42.29, 30.04,17.25.

[0117] Example 14:

[0118] The preparation method is the same as that in Example 1 for (S)-1,4-diphenylpentan-3-one, except that 2-(4-fluorophenyl)propionic acid-1,3-dioxoisoindoline-2-yl ester is used instead of 2-phenylpropionic acid-1,3-dioxoisoindoline-2-yl ester. The yield of the target product is 65%, with an enantiomeric excess of 87%. The synthetic route is as follows:

[0119]

[0120] Product: (S)-4-(4-fluorophenyl)-1-phenylpentan-3-one

[0121] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (600 MHz, CDCl3) δ 7.24 (t, J = 7.5 Hz, 2H), 7.20– 7.15 (m, 1H), 7.16 – 7.11 (m, 2H), 7.11 – 7.06 (m, 2H), 7.04 – 6.93 (m,2H), 3.71 (q, J = 7.0 Hz, 1H), 2.93 – 2.78 (m, 2H), 2.74 – 2.64 (m, 2H), 1.39 (dd, J = 7.0, 0.9 Hz, 3H).

[0122] Carbon NMR characterization: 13 C NMR (151 MHz, CDCl3) δ 209.25, 162.84, 161.21,140.94, 136.15, 136.13, 129.31, 129.26, 128.35, 128.20, 126.00, 115.75,115.61, 52.34, 42.45, 29.96, 17.36.

[0123] Example 15:

[0124] The preparation method is the same as that of (S)-1,4-diphenylpentan-3-one in Example 1, except that 1,3-dioxoisoindoline-2-yl 4-chloro-2-phenylbutyrate is used instead of 1,3-dioxoisoindoline-2-yl 2-phenylpropionic acid. The yield of the target product was 78%, with an enantiomeric excess of 92%. The synthetic route is as follows:

[0125]

[0126] Product: (S)-6-chloro-1,4-diphenylhexane-3-one

[0127] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (600 MHz, CDCl3) δ 7.37 – 7.28 (m, 3H), 7.27 –7.21 (m, 2H), 7.22 – 7.14 (m, 3H), 7.08 (d, J = 7.5 Hz, 2H), 3.95 (t, J = 7.3Hz, 1H), 3.50 (dt, J = 11.5, 5.9 Hz, 1H), 3.34 (ddd, J = 11.0, 8.0, 5.2 Hz, 1H), 2.90 (dt, J = 14.7, 7.6 Hz, 1H), 2.81 (dt, J = 14.4, 7.4 Hz, 1H), 2.72(t, J = 7.6 Hz, 2H), 2.50 (dq, J = 13.8, 6.6 Hz, 1H), 2.19 – 2.10 (m, 1H).

[0128] Carbon NMR characterization: 13 C NMR (151 MHz, CDCl3) δ 208.23, 140.78, 137.52,129.11, 128.39, 128.35, 128.16, 127.59, 126.00, 55.65, 43.19, 42.76, 34.54,29.90.

[0129] Example 16:

[0130] This embodiment is an optimization screening experiment of chiral ligands. The operation process is similar to that of Example 1, except that ligand L8 is replaced with other ligands. The reaction effects are compared as shown below.

[0131]

[0132] Example 17:

[0133] This example is an optimization screening experiment on carboxylic acid activators. The operation process is similar to that in Example 1, except that isopropyl acetate is replaced with other solvents. The reaction effects are compared in Table 1 below.

[0134] Table 1

[0135]

[0136] Application Example 1:

[0137] This application example relates to an application transformation of the product (S)-3-phenylbutane-2-one from Example 2. (S)-3-phenylbutane-2-one (0.2 mmol, 32.0 mg) was added to a flame-dried Schlenk tube equipped with a stir bar and dissolved in methanol (2 ml). Sodium borohydride (40 equivalents) was added, and the reaction mixture was stirred at −78°C for 5 hours until the reaction was complete as monitored by thin-layer chromatography. The reaction was then quenched with a saturated aqueous solution of ammonium chloride (10 ml). The reaction mixture was heated to room temperature and extracted with ethyl acetate (10 ml × 3). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography to give (2S,3S)-3-phenylbutane-2-ol (78% yield, diastereomeric excess >20:1), a key intermediate in the synthesis of erythro-3-phenyl-2-butyl azide in organic synthesis (J. Med. Chem. 1973, 16, 1, 14–18). The synthetic route is as follows:

[0138]

[0139] Product: (2S,3S)-3-phenylbutane-2-ol.

[0140] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR(600 MHz, CDCl3) δ 7.29 (ddd, J = 51.1, 20.7, 7.0Hz, 12H), 3.71 (dd, J = 10.1, 5.6 Hz, 1H), 1.74 – 1.65 (d, 3H), 1.31 (d, J =6.8 Hz, 3H).

[0141] Carbon NMR characterization: 13 C NMR (151 MHz, CDCl3) δ 143.3, 142.3, 128.6, 128.5, 128.4, 128.2, 126.8, 125.8, 75.4, 46.3.

[0142] Application Example 2:

[0143] This application example relates to an application transformation of the product (S)-1,4-diphenylpentan-3-one from Example 1. In a 10 mL Schlenk tube equipped with a magnetic stirrer, sodium acetate (4 mmol) and hydroxylamine hydrochloride (3 mmol) were added, followed by a solution of compound 1 (2 mmol) in ethanol / water (volume ratio = 4:1). The reaction mixture was heated to reflux until thin-layer chromatography showed complete consumption of the ketone starting material. After reflux, the reaction was cooled to room temperature. Excess ethanol was removed to obtain a crude product, which was then added to water (20 mL). The resulting aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL) and brine (1 × 20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting oxime was used directly in the next reaction step. 2,4,6-trichloro-1,3,5-triazine (36.6 mg, 0.2 mmol) was added to N,N-dimethylformamide (0.1 mL) and stirred at 25°C. After a white solid was formed, the synthesized (R)-1,4-diphenylpentan-3-one oxime was dissolved in N,N-dimethylformamide (1 mL) and added to the reaction mixture. The reaction was stirred at room temperature and monitored by thin-layer chromatography until completion (5 h). Water (15 mL) was then added, and the aqueous phase was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with saturated sodium carbonate solution (20 mL), followed by washing with 1 N hydrochloric acid and brine. The organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by preparative thin-layer chromatography to give 3-phenyl-N-((R)-1-phenylethyl)propionamide (68% yield, 94% enantiomeric excess). This compound can serve as a key raw material for the synthesis of β-substituted secondary amides ((R)-3-phenyl-N-((R)-1-phenylethyl)butyramide) in organic synthesis, and is also a key intermediate in the synthesis of the biomass chemical derivative (4R,5S)-4,5-diphenyldihydrofuran-2(3H)-one (J. Org. Chem. 1998, 63, 2-3). Its synthetic route is shown below:

[0144]

[0145] Product: 3-Phenylacetyl-N-((R)-1-phenylethyl)propionamide.

[0146] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR(600 MHz, CDCl3) δ 7.35 – 7.19 (m, 11H), 5.12 (p,J = 7.1 Hz, 1H), 2.99 (t, J = 7.5 Hz, 2H), 2.50 (td, J = 7.5, 1.7 Hz, 2H), 1.43 (d, J = 6.9 Hz, 3H).

[0147] Carbon NMR characterization: 13 C NMR (151 MHz, CDCl3) δ 171.1, 143.0, 140.8, 128.6, 128.6, 128.4, 127.3, 126.3, 126.2, 48.6, 38.7, 31.7, 21.6.

Claims

1. A method for synthesizing a chiral α-aryl ketone, characterized in that: By employing a photo-oxidation-reduction / nickel dual-catalysis strategy, using redox-active esters and aliphatic carboxylic acids derived from α-aryl carboxylic acids as reaction substrates, an asymmetric decarboxylation acylation reaction is carried out under a protective atmosphere in the presence of visible light irradiation and nickel salts, chiral ligands, photocatalysts, carboxylic acid activators, organic reducing agents, and solvents, thereby efficiently obtaining enantiomeric enriched α-aryl ketone compounds. The general structural formula of the redox-active ester derived from α-aryl carboxylic acid is shown below: ； Among them, R 1 R 2 Each of the following is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, halogen, substituted or unsubstituted aryl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, cyano, and alkyloxycarbonylalkyl. The general structural formula of the fatty carboxylic acid is: ； Among them, R 3 It is selected from any one of substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, cyano, and alkyloxycarbonylalkyl. The general structural formula of the α-aryl ketone compound is: 。 2. The synthesis method according to claim 1, characterized in that: The nickel salt is a nickel(II) chloride-ethylene glycol dimethyl ether complex.

3. The synthesis method according to claim 1, characterized in that: The structure of the chiral ligand is shown below: 。 4. The synthesis method according to claim 1, characterized in that: The photocatalyst is 4CZIPN, and its structure is shown below: 。 5. The synthesis method according to claim 1, characterized in that: The carboxylic acid activator is dimethyl carbonate, and its structure is shown below: 。 6. The synthesis method according to claim 1, characterized in that: The organic reducing agent is hansyl ester, and its structure is shown below: 。 7. The synthesis method according to claim 1, characterized in that: The selected solvent is chosen from one of isopropyl acetate, ethylene glycol dimethyl ether, tetrahydrofuran, and ethyl acetate.

8. The synthesis method according to claim 1, characterized in that: The reaction temperature is 0-30 ℃, and the reaction time is 6-24 hours.

9. The synthesis method according to claim 8, characterized in that: The reaction temperature was 10 ℃ and the reaction time was 12 hours.

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