A method for synthesizing alpha-substituted arylacetamides

Abstract

The application discloses a synthesis method of alpha-substituted arylacetamide compounds. The method is based on a light-driven iron-catalyzed decarboxylative arylalkylation reaction system of ligand-metal charge transfer (LMCT) mechanism, can efficiently couple readily available N-arylacrylamide with commercial and various carboxylic acids, and can prepare a series of alpha-substituted arylacetamide compounds containing acyclic quaternary carbon stereogenic centers with high chemical selectivity. The system is suitable for various carboxylic acid substrates, including primary, secondary and tertiary alkyl carboxylic acids and complex biological active carboxylic acid molecules.

Description

Technical Field

[0001] This application belongs to the field of organic synthesis methodology technology, specifically relating to a method for synthesizing α-substituted arylacetamide compounds. Background Technology

[0002] α-substituted aryl acetamides possess a wide range of biological activities. For example, US4453975A, JPS5942303A, JPS59048403A, and JPS60136546A disclose a series of α-substituted aryl acetamides as herbicidal active ingredients, exhibiting excellent selective biological activity against plants. Particularly when used as herbicides in paddy fields, they do not cause any significant phytotoxicity to beneficial crops and show strong herbicidal and growth-inhibiting activity against competing weeds such as barnyard grass. US4582934A reports that α-substituted aryl acetamides possess insecticidal activity, showing very high control efficacy against harmful insects such as diamondback moth and thrips. Furthermore, existing technologies such as CN101896461A report that aryl acetamides can treat diseases such as Alzheimer's disease by regulating γ-secretase.

[0003] Existing methods for synthesizing α-substituted arylacetamides are quite limited. For example, WO2017141512A1 reports a condensation reaction of benzylamine compounds with carboxylic acids, which requires a specific borate ester catalyst. CN115304505A reports a method for synthesizing amides via olefin carbonylation, which requires an expensive palladium-catalyzed reaction system. Therefore, research into the synthesis of α-substituted arylacetamides is of great significance. Summary of the Invention

[0004] The purpose of this invention is to provide a universally applicable method for synthesizing α-substituted arylacetamide compounds. This method is based on a photo-driven iron-catalyzed decarboxylation arylalkylation reaction system with a ligand-metal charge transfer (LMCT) mechanism. It can efficiently couple readily available N-arylacrylamides with commercially available, structurally diverse carboxylic acids to prepare a series of α-substituted arylacetamide compounds containing acyclic quaternary carbon stereocenters with high chemoselectivity. This system is applicable to a variety of carboxylic acid substrates, including primary, secondary, and tertiary alkylcarboxylic acids, as well as structurally complex bioactive carboxylic acid molecules.

[0005] A method for synthesizing α-substituted arylacetamide compounds according to the present invention includes the following steps: An N-aryl-N-arylsulfonylacrylamide compound (Formula 1), a carboxylic acid compound (Formula 2), a ferrous salt catalyst, an organic base, and an organic solvent were added to a reactor. The reaction was then stirred under ambient temperature (room temperature to 50°C), light, and an inert atmosphere. After complete reaction, the mixture was purified to obtain an α-substituted arylacetamide compound (Formula 3). The reaction formula is as follows: ;;

[0006] In the above reaction formula, Ar1 and Ar2 are independently selected from substituted or unsubstituted C atoms. 6-20 Aryl, C 2-20 Heteroaryl; wherein the substituent is selected from halogens, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups; R1 is hydrogen, C 1-6 alkyl; R2-R4 are independently hydrogen, substituted or unsubstituted C atoms. 1-6 Alkyl, C 3-12 cycloalkyl, C 6-20 Aryl, C 6-20 aryloxy group, C 1-6 alkoxycarbonyl; and / or any two of R2-R4 linked together to form C 3-12 cycloalkyl, C 3-12 Heterocyclic alkyl or C 3-12 The other is an unsaturated cyclic hydrocarbon group, and the other is hydrogen or C. 1-6 Alkyl or C 6-20 Aryl groups; and / or R2-R4 groups together constitute an adamantyl group; wherein the substituents are selected from halogens, C 1-6 Alkyl, C 6-12 Aryl, ethynyl, C 1-6 Alkoxycarbonyl, C 6-12 Arylformyl, C 6-12 Aryloxy group; and wherein the arylformyl group and aryloxy group are optionally C 1-6 Alkyl, C 1-6 Alkoxy groups are substituted; the cycloalkyl, heteroalkyl, and unsaturated cycloalkyl groups optionally have =O substituents.

[0007] Preferably, Ar1 and Ar2 are independently selected from substituted or unsubstituted phenyl, naphthyl, thiophene, furanyl, benzothiophene, and benzofuranyl groups; wherein the substituents are selected from fluorine, chlorine, bromine, iodine, -CN, -NO2, methyl, methoxy, and trifluoromethyl groups. R1 is hydrogen or methyl; R2-R4 are independently hydrogen, substituted or unsubstituted C atoms. 1-6Alkyl, cyclopentyl, phenyl, phenoxy, methoxycarbonyl; and / or any two of R2-R4 linked together to form cyclopropyl, cyclohexyl, tetrahydropyranyl, cyclohexenyl, cyclopentenyl, cyclobutanone, and the other being hydrogen, methyl, or phenyl; and / or R2-R4 together constitute an adamantyl group; wherein the substituents are selected from fluorine, chlorine, bromine, iodine, methyl, phenyl, ethynyl, methoxycarbonyl, benzoyl, and phenoxy; and wherein the benzoyl and phenoxy groups are optionally substituted with methyl or methoxy groups.

[0008] Most preferably, Ar1 is selected from phenyl, p-tolyl, p-methoxyphenyl, p-chlorophenyl, p-fluorophenyl, p-iodophenyl, benzothiophene, p-methylphenyl, m-methylphenyl, o-methylphenyl, and p-trifluoromethylphenyl; Ar2 is selected from phenyl, p-tolyl, p-cyanophenyl, thiophenl, and naphthyl; R1 is hydrogen or methyl; R2-R4 are independently hydrogen, methyl, phenyl, benzyl, cyclopentyl, isopropyl, acetophenone, diphenylmethane, p-methoxyacetophenone, methoxycarbonyl, propargyl, butylyn, phenoxy, ; and / or any two of R2-R4 are linked together to form cyclopropyl, cyclohexyl, tetrahydropyranyl, cyclohexenyl, cyclopentenyl, cyclobutanone, and the other is hydrogen, methyl, or phenyl; and / or the three of R2-R4 together constitute adamantyl.

[0009] According to the aforementioned synthesis method of the present invention, the ferrous salt catalyst is selected from one or a mixture of several of Fe(OAc)2, Fe(OTf)2, FeBr2, and FeCl2; preferably Fe(OAc)2.

[0010] According to the aforementioned synthesis method of the present invention, the organic base is any one or a mixture of several of triethylenediamine (DABCO), 2,4,6-trimethylpyridine, 2,6-dimethylpyridine, and pyridine; preferably triethylenediamine (DABCO).

[0011] According to the aforementioned synthesis method of the present invention, the organic solvent is any one or a mixture of several of dichloromethane, dichloroethane, chloroform, tetrahydrofuran, acetonitrile, toluene, and chlorobenzene; preferably dichloromethane.

[0012] According to the synthesis method described above, the light source is provided by a 5-36W, preferably 18W, blue LED lamp, and the blue light wavelength is preferably 420-480nm, and most preferably 456nm.

[0013] According to the synthesis method described above, the inert atmosphere is a nitrogen atmosphere or an argon atmosphere, preferably an argon atmosphere.

[0014] According to the aforementioned synthesis method of the present invention, the reaction is preferably carried out at room temperature; the reaction time is 8-24 hours, preferably 12-16 hours.

[0015] According to the aforementioned synthetic method of the present invention, the purification process is as follows: After the reaction is completed, the reaction mixture is concentrated under vacuum, diluted with diethyl ether, and washed with saturated brine. The organic phases are combined, dried over anhydrous sodium sulfate, and concentrated again under vacuum. The resulting crude product is purified by silica gel column chromatography to obtain compound 3.

[0016] Compared with existing technologies, the method of the present invention has the following advantages: This invention reports for the first time a photo-driven iron-catalyzed decarboxylation arylalkylation reaction system based on the ligand-metal charge transfer (LMCT) mechanism. This system enables the efficient coupling of readily available N-arylacrylamides with commercially available, structurally diverse carboxylic acids, resulting in the highly chemoselective preparation of a series of α-substituted arylacetamide compounds containing acyclic quaternary carbon stereocenters. This system is applicable to a variety of carboxylic acid substrates, including primary, secondary, and tertiary alkylcarboxylic acids, as well as structurally complex bioactive carboxylic acid molecules.

[0017] The synthetic method of the present invention has broad substrate applicability, mild and simple reaction conditions, and can prepare various desired α-substituted arylacetamide compounds in moderate to good yields. Detailed Implementation

[0018] The present invention will be further described in detail below with reference to specific embodiments. Unless otherwise specified, the methods used herein are conventional methods in the art, and the reagents used are all obtained through conventional commercial channels.

[0019] Preparation of raw materials The preparation of the raw materials follows a known method in the prior art, and the specific synthetic route is as follows: . Example 1

[0020] To a Srank tube, 0.2 mmol of N-phenyl-N-benzenesulfonylmethacrylamide (Formula 1a), 0.3 mmol of neopentanoic acid (Formula 2a), 5 mol% ferrous acetate, 0.4 mmol of DABCO (Formula 2a), and 2.0 mL of dichloromethane were added. The reaction tube was then purged three times with argon and placed in a fan-cooled environment at room temperature. The mixture was stirred for 12 hours under 18 W blue LED light (approximately 2.0 cm from the light source), and the reaction mixture was monitored by thin-layer chromatography and / or gas chromatography-mass spectrometry until the reactants were completely consumed. After the reaction, the reaction mixture was concentrated under vacuum, diluted with diethyl ether, and washed with saturated brine. The combined organic phases were dried over anhydrous sodium sulfate and concentrated again under vacuum. The crude product was purified by silica gel column chromatography to give 51.4 mg of the target product (Formula 3aa) in 87% yield. (White solid) 1 H NMR (400 MHz, Chloroform- d )δ (ppm) 7.48 - 7.45 (m, 2H), 7.41 - 7.34 (m, 3H), 7.34 - 7.29 (m, 2H), 7.28- 7.25 (m, 2H), 7.08 - 7.02 (m, 1H), 6.81 (s, 1H), 2.35 (d, J = 14.8 Hz, 1H), 2.15 (d, J = 14.4 Hz, 1H), 1.78 (s, 3H), 0.89 (s, 9H); 13 C NMR (100 MHz, Chloroform- d ) δ (ppm) 175.7, 145.0, 138.1, 129.0, 128.8, 127.3, 127.1, 124.1,119.7, 51.9, 50.5, 32.0, 31.8, 25.2.

[0021] Example 2-14 Reaction Condition Optimization Experiment Using Example 1 as a template, the effects of different factors such as catalyst, organic base, solvent, light source, and temperature on the reaction were investigated. The results are shown in Table 1. Table 1:

[0022] Substrate Expansion Example 1 Under the reaction conditions of Example 1, different N-aryl-N-arylsulfonylacrylamide compounds were reacted with neopentanoic acid to prepare a series of α-substituted arylacetamide compounds. The reaction formulas and results are as follows:

[0023] .

[0024] Structural characterization of the product: Compound 3ba: R f = 0.3 (PE / EA = 20 : 1); 1 H NMR (400 MHz, Chloroform- d ) δ (ppm) 7.48- 7.43 (m, 2H), 7.39 - 7.34 (m, 2H), 7.31 - 7.26 (m, 1H), 7.25 - 7.20 (m,2H), 7.09 - 7.04 (m, 2H), 6.75 (s, 1H), 2.34 (d, J = 14.8 Hz, 1H), 2.27 (s,3H), 2.13 (d, J = 14.8 Hz, 1H), 1.77 (s, 3H), 0.88 (s, 9H); 13 C NMR (100 MHz, Chloroform- d ) δ (ppm) 175.6, 145.2, 135.5, 133.8, 129.5, 128.8, 127.1, 119.8,51.8, 50.5, 32.0, 31.8, 25.2, 20.9.

[0025] Compound 3ca: R f = 0.3 (PE / EA = 10 : 1); 1 H NMR (400 MHz, Chloroform- d ) δ (ppm) 7.48- 7.44 (m, 2H), 7.40 - 7.34 (m, 2H), 7.31 - 7.26 (m, 1H), 7.26 - 7.21 (m,2H), 6.83 - 6.77 (m, 2H), 6.73 (s, 1H), 3.76 (s, 3H), 2.34 (d, J = 14.8 Hz, 1H), 2.13 (d, J = 14.4 Hz, 1H), 1.77 (s, 3H), 0.88 (s, 9H); 1313C NMR (100 MHz, Chloroform- d ) δ (ppm) 175.6, 156.3, 145.2, 131.2, 128.8, 127.2, 127.1, 121.6, 114.1, 55.6, 51.7, 50.5, 32.0, 31.8, 25.2。

[0026] Compound 3da: R f = 0.3 (PE / EA = 20 : 1); 1 1H NMR (400 MHz, Chloroform- d ) δ (ppm) 7.48 - 7.44 (m, 2H), 7.41 - 7.35 (m, 2H), 7.32 - 7.26 (m, 3H), 6.98 - 6.91 (m, 2H), 6.79 (s, 1H), 2.33 (d, J = 14.4 Hz, 1H), 2.14 (d, J = 14.4 Hz, 1H), 1.78 (s, 3H), 0.88 (s, 9H); 13 13C NMR (100 MHz, Chloroform- d ) δ (ppm) 175.7, 159.3 (d, J = 242 Hz), 144.9, 134.1 (d, J = 3 Hz), 128.9, 127.3, 127.1, 121.6 (d, J = 8 Hz), 115.6 (d, J = 22 Hz), 51.8, 50.5, 32.0, 31.8, 25.1; 19 19F NMR (376 MHz, Chloroform-d) δ (ppm) -118.3。

[0027] Compound 3ea: R f = 0.3 (PE / EA = 20 : 1); 1 1H NMR (400 MHz, Chloroform- d) δ (ppm) 7.47- 7.42 (m, 2H), 7.41 - 7.35 (m, 2H), 7.33 - 7.26 (m, 3H), 7.24 - 7.18 (m,2H), 6.79 (s, 1H), 2.32 (d, J = 14.8 Hz, 1H), 2.14 (d, J = 14.8 Hz, 1H), 1.77(s, 3H), 0.87 (s, 9H); 13 C NMR (100 MHz, Chloroform- d ) δ (ppm) 175.8, 144.8,136.6, 129.1, 128.9, 128.9, 127.4, 127.1, 121.0, 52.0, 50.4, 32.0, 31.8,25.1.

[0028] Compound 3fa: R f = 0.3 (PE / EA = 20 : 1); 1 H NMR (400 MHz, Chloroform- d ) δ (ppm) 7.57- 7.52 (m, 2H), 7.46 - 7.41 (m, 2H), 7.40 - 7.34 (m, 2H), 7.32 - 7.27 (m,1H), 7.15 - 7.10 (m, 2H), 6.77 (s, 1H), 2.31 (d, J = 14.4 Hz, 1H), 2.14 (d, J = 14.8 Hz, 1H), 1.76 (s, 3H), 0.87 (s, 9H); 13 C NMR (100 MHz, Chloroform- d ) δ(ppm) 175.8, 144.8, 137.8, 128.9, 127.4, 127.0, 121.6, 87.2, 52.0, 50.4,32.0, 31.8, 25.1.

[0029] Compound 3ga: R f = 0.3 (PE / EA = 20 : 1); 1 H NMR (400 MHz, Chloroform-d ) δ (ppm) 8.06 (d, J J = 2.0 Hz, 1H), 7.71 (d, J J = 8.8 Hz, 1H), 7.51 - 7.47 (m, 2H), 7.43 - 7.37 (m, 3H), 7.33 - 7.28 (m, 1H), 7.26 - 7.23 (m, 1H), 7.14 - 7.09 (m, 1H), 6.94 (s, 1H), 2.38 (d, J = 14.8 Hz, 1H), 2.17 (d, J = 14.8 Hz, 1H), 1.81 (s, 3H), 0.91 (s, 9H); 13 C NMR (100 MHz, Chloroform- d ) δ (ppm) 175.8, 145.2, 140.2, 135.4, 134.9, 128.9, 127.5, 127.3, 127.1, 124.0, 122.6, 117.6, 114.4, 52.0, 50.6, 32.0, 31.8, 25.2。

[0030] Compound 3ha: R f = 0.3 (PE / EA = 20 : 1); 1 H NMR (400 MHz, Chloroform- d ) δ (ppm) 7.37 - 7.31 (m, 2H), 7.25 - 7.21 (m, 2H), 7.20 - 7.15 (m, 2H), 7.09 - 7.03 (m, 2H), 6.80 (s, 1H), 2.36 (s, 3H), 2.33 (d, J J = 14.8 Hz, 1H), 2.28 (s, 3H), 2.12 (d, J J = 14.8 Hz, 1H), 1.75 (s, 3H), 0.89 (s, 9H); 13 C NMR (100 MHz, Chloroform- d) δ (ppm) 175.8, 142.1, 136.8, 135.6, 133.7, 129.5, 129.4, 127.0,119.8, 51.5, 50.5, 32.0, 31.8, 25.3, 21.0, 20.9.

[0031] Compound 3ia: R f = 0.3 (PE / EA = 20 : 1); 1 H NMR (400 MHz, Chloroform- d ) δ (ppm) 7.37- 7.33 (m, 2H), 7.26 - 7.24 (m, 1H), 7.21 - 7.17 (m, 2H), 7.15 - 7.10 (m,2H), 6.91 - 6.82 (m, 2H), 2.38 - 2.32 (m, 4H), 2.30 (s, 3H), 2.14 (d, J =14.8 Hz, 1H), 1.77 (s, 3H), 0.90 (s, 9H); 13 C NMR (100 MHz, Chloroform- d ) δ(ppm) 175.9, 142.0, 138.9, 138.1, 136.9, 129.5, 128.8, 127.0, 124.9, 120.4,116.8, 51.6, 50.5, 32.0, 31.8, 25.3, 21.5, 21.1.

[0032] Compound 3ja: R f = 0.3 (PE / EA = 20 : 1); 1 H NMR (400 MHz, Chloroform- d ) δ (ppm) 7.93- 7.86 (m, 1H), 7.43 - 7.36 (m, 2H), 7.23 - 7.14 (m, 3H), 7.05 (s, 1H), 7.01- 6.94 (m, 1H), 6.75 (s, 1H), 2.41 - 2.35 (m, 4H), 2.18 (d, J = 14.8 Hz, 1H), 1.81 (s, 3H), 1.80 (s, 3H), 0.88 (s, 9H);13 C NMR (100 MHz, Chloroform- d ) δ(ppm) 176.1, 141.8, 137.0, 136.2, 130.3, 129.5, 127.8, 127.2, 126.8, 124.4,121.7, 51.8, 49.9, 32.0, 31.9, 24.9, 21.0, 17.1。

[0033] Compound 3ka: R f = 0.3 (PE / EA = 20 : 1); 1 H NMR (400 MHz, Chloroform- d ) δ (ppm) 7.52 - 7.48 (m, 2H), 7.48 - 7.44 (m, 2H), 7.35 - 7.30 (m, 2H), 7.21 - 7.16 (m,2H), 6.96 (s, 1H), 2.36 (s, 3H), 2.30 (d, J = 14.8 Hz, 1H), 2.13 (d, J = 14.4Hz, 1H), 1.76 (s, 3H), 0.88 (s, 9H); 13 C NMR (100 MHz, Chloroform- d ) δ (ppm)176.3, 141.5, 141.2, 137.2, 129.7, 126.9, 126.2 (q, J = 3.8 Hz), 119.2, 51.8,50.4, 32.0, 31.8, 25.2, 21.0; 19 F NMR (376 MHz, Chloroform-d) δ (ppm) -62.0.。

[0034] Compound 3la: R f = 0.3 (PE / EA = 10 : 1); 1 H NMR (400 MHz, Chloroform- d) δ (ppm) 7.64 - 7.60 (m, 2H), 7.60 - 7.56 (m, 2H), 7.40 - 7.36 (m, 2H), 7.30 - 7.26 (m, 2H), 7.12 - 7.05 (m, 1H), 6.98 (s, 1H), 2.36 (d, J = 14.4 Hz, 1H), 2.04 (d, J = 14.4 Hz, 1H), 1.79 (s, 3H), 0.93 (s, 9H); 13 C NMR (100 MHz, Chloroform - d ) δ(ppm) 173.8, 151.2, 137.7, 132.5, 129.1, 127.6, 124.7, 120.2, 118.7, 111.0, 52.0, 51.0, 32.1, 31.7, 24.7。

[0035] Compound 3ma: R f = 0.3 (PE / EA = 20 : 1); 1 H NMR (400 MHz, Chloroform - d ) δ (ppm) 7.40 - 7.36 (m, 2H), 7.31 - 7.26 (m, 3H), 7.26 - 7.25 (m, 1H), 7.10 - 7.05 (m, 2H), 7.04 - 7.00 (m, 1H), 2.45 (d, J = 14.8 Hz, 1H), 2.08 (d, J = 14.4 Hz, 1H), 1.85 (s, 3H), 0.96 (s, 9H); 13 C NMR (100 MHz, Chloroform - d ) δ (ppm) 174.0, 150.8, 137.9, 129.0, 127.2, 125.0, 124.9, 124.3, 119.9, 52.3, 50.5, 32.2, 31.5, 26.0。

[0036] Compound 3na: R f = 0.3 (PE / EA = 20 : 1); 1H NMR (400 MHz, Chloroform- d ) δ (ppm) 7.95 (d, J = 2 Hz, 1H), 7.91 - 7.87 (m, 1H), 7.87 - 7.82 (m, 2H), 7.58 - 7.52 (m,2H), 7.52 - 7.50 (m, 1H), 7.35 - 7.30 (m, 2H), 7.26 - 7.21 (m, 2H), 7.10 -6.99 (m, 1H), 6.84 (s, 1H), 2.45 (d, J = 14.8 Hz, 1H), 2.29 (d, J = 14.4 Hz,1H), 1.90 (s, 3H), 0.92 (s, 9H); 13 C NMR (100 MHz, Chloroform- d ) δ (ppm) 175.6,142.6, 138.1, 133.4, 132.5, 129.0, 128.6, 128.2, 127.7, 126.6, 126.4, 126.1,125.2, 124.2, 119.8, 52.1, 50.2, 32.1, 31.8, 25.2.

[0037] Compound 3oa: Rf = 0.3 (PE / EA = 20 : 1); 1H NMR (400 MHz, Chloroform-d) δ (ppm)7.47 - 7.38 (m, 3H), 7.38 - 7.32 (m, 3H), 7.31 - 7.26 (m, 2H), 7.25 - 7.21(m, 2H), 7.04 (t, J = 7.6 Hz, 1H), 3.62 - 3.54 (m, 1H), 2.53 - 2.43 (m, 1H),1.70 - 1.63 (m, 1H), 0.91 (s, 9H);13C NMR (100 MHz, Chloroform-d) δ (ppm)172.2, 141.7, 138.1, 129.1, 129.0, 127.9, 127.3, 124.3, 119.9, 51.1, 46.8, 31.1, 29.7.

[0038] Substrate Expansion Example 2 Under the reaction conditions of Example 1, different carboxylic acid compounds were reacted with N-phenyl-N-benzenesulfonylmethacrylamide compounds to prepare a series of α-substituted arylacetamide compounds. The reaction formulas and results are as follows: ;

[0039]

[0040] Structural characterization of the product: Compound 3ab: Compound 3ac: Rf = 0.3 (PE / EA = 20 : 1); 1H NMR (400 MHz, Chloroform-d) δ (ppm)7.43 - 7.34 (m, 5H), 7.34 - 7.31 (m, 2H), 7.29 - 7.24 (m, 4H), 7.21 - 7.11(m, 13C NMR (100 MHz, Chloroform-d) δ (ppm) 175.2, 143.5, 142.1, 138.0, 129.1, 129.0, 128.5, 128.4, 127.4, 127.0, 125.9, 124.2, 119.8, 51.6, 38.4, 36.3, 26.2, 24.0.

[0041] Compound 3ad: Rf = 0.3 (PE / EA = 20 : 1); 1H NMR (400 MHz, Chloroform-d) δ (ppm) 7.44 - 7.38 (m, 4H), 7.38 - 7.34 (m, 2H), 7.34 - 7.29 (m, 1H), 7.29 - 7.24 (m, 2H), 7.10 - 7.02 (m, 1H), 6.81 (s, 1H), 2.18 - 2.02 (m, 2H), 1.81 - 1.71 (m, 3H), 1.63 (s, 3H), 1.59 - 1.45 (m, 4H), 1.33 - 1.26 (m, 1H), 1.20 - 1.10 (m, 1H), 1.10 - 0.96 (m, 2H); 13C NMR (100 MHz, Chloroform-d) δ (ppm) 175.4, 143.9, 138.1, 129.0, 129.0, 127.3, 127.0, 124.2, 119.8, 51.6, 40.6, 38.1, 32.8, 32.7, 30.8, 25.3, 24.0。

[0042] Compound 3ae: Rf = 0.3 (PE / EA = 20 : 1); 1H NMR (400 MHz, Chloroform-d) δ (ppm) 7.44 - 7.41 (m, 2H), 7.41 - 7.38 (m, 2H), 7.38 - 7.34 (m, 2H), 7.34 - 7.29 (m, 1H), 7.28 - 7.24 (m, 2H), 7.09 - 7.02 (m, 1H), 6.80 (s, 1H), 2.18 - 2.01 (m, 2H), 1.63 (s, 3H), 1.59 - 1.49 (m, 1H), 1.23 - 1.11 (m, 1H), 1.06 - 0.96 (m, 1H), 0.88 (dd, J = 6.8, 6.8 Hz, 6H); 13C NMR (100 MHz, Chloroform-d) δ (ppm) 175.4, 143.8, 138.1, 129.0, 129.0, 127.3, 127.0, 124.2, 119.8, 51.6, 36.7, 33.4, 28.6, 23.9, 22.7, 22.6。

[0043] Compound 3af: Rf = 0.3 (PE / EA = 20 : 1); 1H NMR (400 MHz, Chloroform-d) δ (ppm)7.41 - 7.37 (m, 2H), 7.36 - 7.32 (m, 5H), 7.30 - 7.26 (m, 3H), 7.25 - 7.19(m, 5H), 7.19 - 7.14 (m, 4H), 7.11 - 7.05 (m, 1H), 6.73 (s, 1H), 3.90 (t, J =7.2 Hz, 1H), 2.16 - 2.05 (m, 3H), 1.98 - 1.88 (m, 1H), 1.66 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ (ppm) 175.0, 144.9, 144.7, 143.5, 138.0, 129.1,129.0, 128.6, 128.6, 127.9, 127.9, 127.5, 127.0, 126.3, 124.2, 119.8, 51.8,51.6, 37.3, 30.5, 24.0. HRMS m / z (ESI) calcd for C30H29NO([M+H]+) 420.2322, found 420.2323. Compound 3ag: Rf = 0.3 (PE / EA = 10 : 1); 1H NMR (400 MHz, Chloroform-d) δ (ppm) 7.96 - 7.91 (m, 2H), 7.58 - 7.53 (m, 1H), 7.50 - 7.42 (m, 6H), 7.41 - 7.34 (m, 3H), 7.32 - 7.26 (m, 3H), 7.10 - 7.04 (m, 1H), 3.02 (t, J = 7.2 Hz, 2H), 2.26 - 2.15 (m, 1H), 2.15 - 2.05 (m, 1H), 1.85 - 1.74 (m, 1H), 1.70 (s, 3H), 1.66 - 1.56 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ (ppm) 200.2, 175.0, 143.7, 138.2, 136.9, 133.2, 129.0, 129.0, 128.7, 128.1, 127.4, 126.8, 124.2, 120.0, 51.7, 38.6, 38.5, 23.9, 19.3。

[0044] Compound 3ah: Rf = 0.3 (PE / EA = 5 : 1); 1H NMR (400 MHz, Chloroform-d) δ (ppm) 7.92(m, 1H), 7.91 - 7.89 (m, 1H), 7.57 (s, 1H), 7.54 - 7.50 (m, 2H), 7.44 - 7.40(m, 2H), 7.39 - 7.34 (m, 2H), 7.30 - 7.26 (m, 3H), 7.10 - 7.03 (m, 1H), 6.93- 6.89 (m, 2H), 3.84 (s, 3H), 2.95 (t, J = 6.8 Hz, 2H), 2.24 - 2.13 (m, 1H),2.11 - 2.02 (m, 1H), 1.81 - 1.73 (m, 1H), 1.69 (s, 3H), 1.66 - 1.58 (m, 1H);13C NMR (100 MHz, Chloroform-d) δ (ppm) 198.9, 175.0, 163.6, 144.0, 138.3,130.4, 130.0, 129.0, 128.9, 127.3, 126.8, 124.2, 120.1, 113.8, 55.6, 51.7,38.7, 38.1, 23.9, 19.5.。

[0045] Compound 3ai: Rf = 0.3 (PE / EA = 10 : 1); 1H NMR (400 MHz, Chloroform-d) δ (ppm)7.42 - 7.39 (m, 4H), 7.37 - 7.31 (m, 3H), 7.29 - 7.24 (m, 2H), 7.09 - 7.04(m, 1H), 6.84 (s, 1H), 3.61 (s, 3H), 2.48 - 2.38 (m, 2H), 2.36 - 2.27 (m,1H), 2.26 - 2.15 (m, 1H), 1.65 (s, 3H);13C NMR (100 MHz, Chloroform-d) δ(ppm) 174.5, 173.9, 142.6, 137.9, 129.2, 129.0, 127.8, 127.0, 124.4, 119.9,51.7, 51.0, 34.1, 29.8, 23.7。

[0046] Compound 3aj: Rf = 0.3 (PE / EA = 20 : 1); 1H NMR (400 MHz, Chloroform-d) δ (ppm) 7.43 - 7.40 (m, 2H), 7.40 - 7.39 (m, 2H), 7.37 - 7.34 (m, 2H), 7.33 - 7.29 (m, 1H), 7.29 - 7.24 (m, 2H), 7.08 - 7.03 (m, 1H), 6.81 (s, 1H), 2.19 - 2.14 (m, 2H), 2.14 - 2.01 (m, 2H), 1.89 (t, J = 2.8 Hz, 1H), 1.65 (s, 3H), 1.59 - 1.51 (m, 2H), 1.45 - 1.36 (m, 1H), 1.27 - 1.20 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ (ppm) 175.2, 143.5, 138.0, 129.1, 129.0, 127.5, 127.0, 124.3, 119.8, 84.4, 68.5, 51.6, 38.4, 28.9, 23.9, 23.6, 18.3。

[0047] Compound 3ak: Rf = 0.3 (PE / EA = 10 : 1); 1H NMR (400 MHz, Chloroform-d) δ (ppm) 7.49 - 7.41 (m, 4H), 7.41 - 7.34 (m, 3H), 7.32 - 7.23 (m, 4H), 7.12 - 7.06 (m, 1H), 6.99 - 6.89 (m, 2H), 6.84 - 6.79 (m, 2H), 4.05 - 3.95 (m, 2H), 2.73 - 2.62 (m, 1H), 2.61 - 2.51 (m, 1H), 1.80 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ (ppm) 174.7, 158.7, 143.1, 137.9, 129.5, 129.2, 129.0, 127.7, 126.9, 124.4, 120.8, 120.0, 114.6, 64.7, 50.6, 38.3, 24.3。

[0048] Compound 3al: Rf = 0.3 (PE / EA = 20 : 1); 1H NMR (400 MHz, Chloroform-d) δ (ppm)7.46 - 7.42 (m, 2H), 7.42 - 7.37 (m, 2H), 7.37 - 7.33 (m, 2H), 7.33 - 7.28(m, 1H), 7.28 - 7.23 (m, 2H), 7.10 - 7.01 (m, 1H), 6.83 (s, 1H), 2.11 (dd, J= 5.6, 5.6 Hz, 1H), 2.02 (dd, J = 5.6, 5.6 Hz, 1H), 1.67 (s, 4H), 0.94 (d, J= 6.4 Hz, 3H), 0.76 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, Chloroform-d) δ(ppm) 175.4, 144.2, 138.1, 129.0, 128.9, 127.4, 127.1, 124.2, 119.8, 51.7,47.4, 24.9, 24.8, 24.7, 24.3.

[0049] Compound 3am: Rf = 0.3 (PE / EA = 20 : 1); 1H NMR (400 MHz, Chloroform-d) δ (ppm) 7.45 - 7.41 (m, 2H), 7.41 - 7.36 (m, 2H), 7.36 - 7.33 (m, 2H), 7.32 - 7.24 (m, 3H), 7.05 (t, J = 7.2 Hz, 1H), 6.82 (s, 1H), 2.07 (dd, J = 5.2, 5.2 Hz, 1H), 1.98 (dd, J = 5.2, 5.2 Hz, 1H), 1.72 - 1.61 (m, 5H), 1.58 - 1.50 (m, 2H), 1.44 - 1.30 (m, 2H), 1.21 - 0.97 (m, 4H), 0.94 - 0.85 (m, 1H); 13C NMR(100 MHz, Chloroform-d) δ (ppm) 175.4, 144.3, 138.1, 129.0, 128.9, 127.3, 127.0, 124.2, 119.8, 51.7, 46.1, 35.4, 35.3, 34.1, 26.5, 26.5, 26.3, 24.4.

[0050] Compound 3an: Rf = 0.3 (PE / EA = 5:1); 1H NMR (400 MHz, Chloroform-d) δ (ppm) 7.44 - 7.37 (m, 4H), 7.36 - 7.30 (m, 3H), 7.28 - 7.23 (m, 2H), 7.08 - 7.03 (m, 1H), 6.89 (s, 1H), 3.88 - 3.72 (m, 2H), 3.34 - 3.13 (m, 2H), 2.18 - 1.98 (m, 2H), 1.69 (s, 3H), 1.62 - 1.48 (m, 2H), 1.41 - 1.32 (m, 1H), 1.26 - 1.16 (m, 2H); 13C NMR (100 MHz, Chloroform-d) δ (ppm) 175.2, 143.9, 138.0, 129.0, 129.0, 127.6, 127.0, 124.3, 119.9, 68.1, 68.0, 51.4, 45.9, 34.9, 34.8, 31.6, 24.4。

[0051] Compound 3ao: Rf = 0.3 (PE / EA = 20:1); 1H NMR (400 MHz, Chloroform-d) δ (ppm) 7.44 - 7.37 (m, 4H), 7.37 - 7.30 (m, 3H), 7.29 - 7.25 (m, 2H), 7.09 - 7.03 (m, 1H), 6.79 (s, 1H), 5.64 - 5.58 (m, 1H), 5.58 - 5.53 (m, 1H), 2.55 - 2.35 (m, 2H), 2.35 - 2.26 (m, 1H), 2.25 - 2.12 (m, 2H), 2.07 - 1.98 (m, 1H), 1.87 - 1.75 (m, 1H), 1.68 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ (ppm) 175.5, 143.9, 138.0, 130.2, 130.1, 129.0, 129.0, 127.5, 127.2, 124.2, 119.7, 52.0, 45.4, 40.7, 40.5, 35.0, 24.3。

[0052] Compound 3ap: Rf = 0.3 (PE / EA = 20 : 1); 1H NMR (400 MHz, Chloroform-d) δ (ppm) 7.47 - 7.42 (m, 2H), 7.42 - 7.38 (m, 2H), 7.37 - 7.31 (m, 3H), 7.29 - 7.24 (m, 2H), 7.09 - 7.03 (m, 1H), 6.86 (d, J = 6.0 Hz, 1H), 5.82 - 5.47 (m, 2H), 2.21 - 1.79 (m, 5H), 1.79 - 1.71 (m, 1H), 1.69 (d, J = 3.6 Hz, 3H), 1.68 - 1.51 (m, 2H), 1.46 - 1.30 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ (ppm) 175.4, 175.4, 144.1, 144.0, 138.0, 129.0, 127.5, 127.4, 127.1, 127.0, 126.9, 126.9, 126.7, 124.2, 119.9, 51.7, 51.7, 45.7, 45.6, 33.8, 33.7, 30.9, 30.7, 30.1, 30.1, 25.4, 25.4, 24.5, 24.3。

[0053] Compound 3aq: Rf = 0.3 (PE / EA = 4:1); 1H NMR (400 MHz, Chloroform-d) δ (ppm) 7.43 - 7.38 (m, 4H), 7.37 - 7.32 (m, 3H), 7.30 - 7.26 (m, 2H), 7.10 - 7.04 (m, 1H), 6.82 (s, 1H), 3.11 - 2.99 (m, 1H), 2.86 - 2.74 (m, 1H), 2.74 - 2.65 (m, 1H), 2.51 - 2.31 (m, 4H), 1.70 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ (ppm) 208.1, 174.9, 142.6, 137.8, 129.2, 129.1, 127.9, 127.1, 124.4, 119.8, 53.9, 53.5, 51.8, 45.7, 23.9, 20.6.

[0054] Compound 3ar: Rf = 0.3 (PE / EA = 20:1); 1H NMR (400 MHz, Chloroform-d) δ (ppm) 7.28 - 7.25 (m, 6H), 7.25 - 7.23 (m, 2H), 7.23 - 7.18 (m, 3H), 7.13 - 7.08 (m, 2H), 7.07 - 7.00 (m, 2H), 6.73 (s, 1H), 2.81 (d, J = 14.4 Hz, 1H), 2.48 (d, J = 14.4 Hz, 1H), 1.51 (s, 3H), 0.85 - 0.77 (m, 2H), 0.71 - 0.65 (m, 1H), 0.54 - 0.47 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ (ppm) 175.3, 144.9, 143.6, 138.0, 129.5, 128.9, 128.6, 128.0, 127.3, 127.1, 125.8, 124.1, 119.8, 52.6, 48.0, 23.9, 22.8, 13.8, 13.4.

[0055] Compound 3as: Rf = 0.3 (PE / EA = 20 : 1); 1H NMR (400 MHz, Chloroform-d) δ (ppm) 7.50 - 7.44 (m, 2H), 7.40 - 7.33 (m, 4H), 7.32 - 7.24 (m, 3H), 7.09 - 7.01 (m, 1H), 6.82 (s, 1H), 2.18 (d, J = 14.8 Hz, 1H), 2.01 (d, J = 14.8 Hz, 1H), 1.88 - 1.82 (m, 3H), 1.80 (s, 3H), 1.66 - 1.55 (m, 6H), 1.55 - 1.51 (m, 6H); 13C NMR (100 MHz, Chloroform-d) δ (ppm) 175.7, 145.4, 138.1, 129.0, 128.8, 127.2, 127.0, 124.1, 119.8, 52.2, 51.6, 44.0, 36.9, 34.3, 28.9, 25.9。

[0056] Compound 3at: Rf = 0.3 (PE / EA = 20 : 1); 1H NMR (400 MHz, Chloroform-d) δ (ppm)7.54 - 7.50 (m, 2H), 7.44 - 7.39 (m, 3H), 7.38 - 7.32 (m, 2H), 7.32 - 7.27(m, 2H), 7.11 - 7.06 (m, 1H), 7.05 (m, 1H), 6.90 (s, 1H), 6.70 (dd, J = 1.6,1.6 Hz, 1H), 6.63 (d, J = 1.6 Hz, 1H), 3.87 (t, J = 6.4 Hz, 2H), 2.46 (d, J =14.8 Hz, 1H), 2.36 (s, 3H), 2.24 - 2.19 (m, 4H), 1.89 - 1.77 (m, 5H), 1.50 -1.37 (m, 2H), 0.97 (s, 3H), 0.89 (s, 3H);13C NMR (100 MHz, Chloroform-d) δ(ppm) 175.7, 157.2, 145.2, 138.1, 136.5, 130.4, 129.0, 128.9, 127.4, 127.1,124.2, 123.7, 120.7, 119.9, 112.1, 68.6, 51.9, 48.4, 41.4, 34.3, 28.9, 28.7, 25.2, 24.5, 21.6, 16.0.

[0057] The embodiments described above are merely preferred embodiments of the present invention, and not an exhaustive list of all possible implementations 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 α-substituted arylacetamide compounds, characterized in that, Includes the following steps: An N-aryl-N-arylsulfonylacrylamide compound (Formula 1), a carboxylic acid compound (Formula 2), a ferrous salt catalyst, an organic base, and an organic solvent were added to a reactor. The reaction was then stirred under ambient temperature (room temperature to 50°C), light, and an inert atmosphere. After complete reaction, the mixture was purified to obtain an α-substituted arylacetamide compound (Formula 3). The reaction formula is as follows: ； In the above reaction formula, Ar1 and Ar2 are independently selected from substituted or unsubstituted C atoms. 6-20 Aryl, C 2-20 Heteroaryl; wherein the substituent is selected from halogens, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups; R1 is hydrogen, C 1-6 alkyl; R2-R4 are independently hydrogen, substituted or unsubstituted C atoms. 1-6 Alkyl, C 3-12 cycloalkyl, C 6-20 Aryl, C 6-20 aryloxy group, C 1-6 alkoxycarbonyl; and / or any two of R2-R4 linked together to form C 3-12 cycloalkyl, C 3-12 Heterocyclic alkyl or C 3-12 The other is an unsaturated cyclic hydrocarbon group, and the other is hydrogen or C. 1-6 Alkyl or C 6-20 Aryl groups; and / or R2-R4 groups together constitute an adamantyl group; wherein the substituents are selected from halogens, C 1-6 Alkyl, C 6-12 Aryl, ethynyl, C 1-6 Alkoxycarbonyl, C 6-12 Arylformyl, C 6-12 Aryloxy group; and wherein the arylformyl group and aryloxy group are optionally C 1-6 Alkyl, C 1-6 Alkoxy groups are substituted; the cycloalkyl, heteroalkyl, and unsaturated cycloalkyl groups optionally have =O substituents; The ferrous salt catalyst is selected from one or a mixture of several of Fe(OAc)2, Fe(OTf)2, FeBr2, and FeCl2; the organic base is any one or a mixture of several of triethylenediamine (DABCO), 2,4,6-trimethylpyridine, 2,6-dimethylpyridine, and pyridine.

2. The synthesis method according to claim 1, characterized in that, Ar1 and Ar2 are independently selected from substituted or unsubstituted phenyl, naphthyl, thiophene, furanyl, benzothiophene, and benzofuranyl groups; wherein the substituents are selected from fluorine, chlorine, bromine, iodine, -CN, -NO2, methyl, methoxy, and trifluoromethyl groups; R1 is hydrogen or methyl; R2-R4 are independently hydrogen, substituted or unsubstituted C atoms. 1-6 Alkyl, cyclopentyl, phenyl, phenoxy, methoxycarbonyl; and / or any two of R2-R4 linked together to form cyclopropyl, cyclohexyl, tetrahydropyranyl, cyclohexenyl, cyclopentenyl, cyclobutanone, and the other being hydrogen, methyl, or phenyl; and / or R2-R4 together constitute an adamantyl group; wherein the substituents are selected from fluorine, chlorine, bromine, iodine, methyl, phenyl, ethynyl, methoxycarbonyl, benzoyl, and phenoxy; and wherein the benzoyl and phenoxy groups are optionally substituted with methyl or methoxy groups.

3. The synthesis method according to claim 2, characterized in that, Ar1 is selected from phenyl, p-tolyl, p-methoxyphenyl, p-chlorophenyl, p-fluorophenyl, p-iodophenyl, benzothiophene, p-methylphenyl, m-methylphenyl, o-methylphenyl, and p-trifluoromethylphenyl; Ar2 is selected from phenyl, p-tolyl, p-cyanophenyl, thiophenl, and naphthyl; R1 is hydrogen or methyl; R2-R4 are independently hydrogen, methyl, phenyl, benzyl, cyclopentyl, isopropyl, acetophenone, diphenylmethane, p-methoxyacetophenone, methoxycarbonyl, propargyl, butylyn, phenoxy, ; and / or any two of R2-R4 are linked together to form cyclopropyl, cyclohexyl, tetrahydropyranyl, cyclohexenyl, cyclopentenyl, cyclobutanone, and the other is hydrogen, methyl, or phenyl; and / or the three of R2-R4 together constitute adamantyl.

4. The synthesis method according to any one of claims 1-3, characterized in that, The ferrous salt catalyst is selected from Fe(OAc)2.

5. The synthesis method according to any one of claims 1-3, characterized in that, The organic base mentioned is triethylenediamine (DABCO).

6. The synthesis method according to any one of claims 1-3, characterized in that, The organic solvent is any one or a mixture of several of dichloromethane, dichloroethane, chloroform, tetrahydrofuran, acetonitrile, toluene, and chlorobenzene; preferably dichloromethane.

7. The synthesis method according to any one of claims 1-3, characterized in that, The light source is provided by a 5-36W, preferably 18W, blue LED lamp, with the blue light wavelength preferably 420-480nm, and most preferably 456nm.

8. The synthesis method according to any one of claims 1-3, characterized in that, The inert atmosphere is a nitrogen atmosphere or an argon atmosphere, preferably an argon atmosphere.

9. The synthesis method according to any one of claims 1-3, characterized in that, The reaction is preferably carried out at room temperature; the reaction time is 8-24 hours, preferably 12-16 hours.

10. The synthesis method according to any one of claims 1-3, characterized in that, The purification process described herein is as follows: After the reaction is complete, the reaction mixture is concentrated under vacuum, diluted with diethyl ether, and washed with saturated brine. The organic phases are combined, dried over anhydrous sodium sulfate, and concentrated again under vacuum. The crude product is purified by silica gel column chromatography to obtain compound 3.

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