A method for synthesizing oxime compounds

Abstract

The invention belongs to the technical field of synthesis of organic intermediates, and specifically relates to a method for synthesizing oxime compounds. The method adopts a novel, inexpensive, and widely applicable alcohol deoxygenation activation strategy, utilizes a hydroxyl activation reagent to in-situ convert the alcohol into an intermediate, realizes the deoxygenation free radical coupling reaction of the sulfonyl oxime compound and the alcohol under visible light photooxidation-reduction catalysis, and constructs an oxime compound with important medical value. The preparation method of the invention has the characteristics of low energy consumption, no pollution, high reaction efficiency, good functional group tolerance, wide substrate range, diversified product derivation, etc., and provides an efficient and universal platform for the deoxygenation free radical conversion of most alcohols.

Description

Technical Field

[0001] The invention belongs to the technical field of synthesis of organic intermediates, and more specifically, relates to a method for preparing oxime compounds. Background Art

[0002] Oximes and oxime ethers are present in many biologically and pharmaceutically active compounds, including antibiotics such as streptomycin, chloramphenicol, and vancomycin, polypeptide hormones such as auxin and cortisol, as well as anti-tumor drugs, antiviral drugs, and anti-AIDS drugs. Oximes are also widely used in the synthesis of drugs, dyes, and pesticides. In addition, they are versatile building blocks that can be easily converted into amines, hydroxylamines, ketones, and nitriles. Therefore, the development of efficient synthetic methods for oximes and oxime ethers has attracted widespread attention from chemists.

[0003] Different from the classical methods for preparing oxime ethers based on the reaction of carbonyl compounds, recent research results on the radical-mediated substitution functionalization of sulfonyl oxime ethers provide a powerful platform for constructing oxime ethers from different radical precursors through C–C bond formation. The pioneering work of Kim and co-workers revealed the radical coupling reaction between sulfonyl oxime ethers and alkyl halides, which provided oxime ethers by using stoichiometric organotin and other radical initiators (J.Am.Chem.Soc.,1996,Vol.118,No.21,5138-5139). However, this method was plagued by stoichiometric toxic organotin reagents or relatively high reaction temperatures. Subsequently, sulfonyl oxime ethers were used as radical acceptors to carry out carboximation reactions of various radical precursors, including alkenes, alkanes, alkyl halides, aliphatic carboxylic acids, sulfones, and amines under transition metal-catalyzed and photocatalytic conditions. In this regard, the application of alcohols with diverse structures and wide sources as radical precursors has also attracted much attention. Recently, Jiao Ning's group reported an ingenious silver-catalyzed carbonylation of the δ-C–H bond of alcohols. This strategy allows the free radical coupling of unactivated fatty alcohols with sulfonyl oxime ethers via 1,5-hydrogen atom transfer of alkoxy groups (Nat. Commun., 2018, Vol. 9, No. 1, 2625). Zhao Yu et al. successfully developed a silver-catalyzed ring-opening coupling reaction of cyclopropanols with sulfonyl oxime ethers to provide γ-keto oxime ethers (Org. Biomol. Chem., 2020, Vol. 18, No. 19, 3734-3739). However, there is still a lack of efficient methods for the deoxy radical coupling of alcohols with sulfonyl oxime ethers via C–O bond cleavage. In the past decade, the development of visible light photoredox chemistry has provided an excellent means for the deoxy radical functionalization of alcohols. Currently, chemists have developed many methods to achieve the C(sp) deoxy radical functionalization of alcohols under photoredox catalysis. 3)–O bond homolysis. However, these methods still have the following problems: (1) they are not suitable for the generation of non-stabilized alkyl radicals from primary alcohols; (2) they are heavily dependent on precious metal photocatalysts. Therefore, it is still very necessary to further explore an efficient and low-cost method to obtain oxime ethers with important pharmaceutical value. Summary of the invention

[0004] In view of the above defects or improvement needs of the prior art, the present invention provides a method for synthesizing oxime compounds, which adopts a novel, inexpensive and widely applicable alcohol deoxygenation activation strategy, uses benzo-1,3-dithiolane (BDT) as an activating group, and obtains an alkyl radical intermediate through oxidation, deprotonation and β-cleavage of the sulfur atom in the molecule, thereby realizing a visible light-driven deoxygenation cross-coupling reaction of alcohol and sulfonyl oxime ether, constructing oxime compounds with important medical value, and solving the technical problem that it is difficult to generate oxime compounds by deoxygenation of alcohol under mild conditions.

[0005] To achieve the above object, according to one aspect of the present invention, a method for synthesizing oxime compounds from alcohols by promoting visible light is provided, the method comprising the following steps:

[0006] (1) adding a reactant alcohol, a hydroxyl activating agent, a first base and a first organic solvent to a dry reaction bottle, and placing the reaction bottle at 10-40° C. and stirring continuously to allow the reactant alcohol and the hydroxyl activating agent to generate an intermediate in situ, and then removing the first organic solvent;

[0007] (2) adding a sulfonyl oxime compound, a photocatalyst, a second organic solvent and a second base to the reaction bottle after the first solvent is removed under a protective gas atmosphere and starting the reaction, wherein the intermediate obtained in step (1) is used as an alkyl radical precursor;

[0008] (3) placing the reaction system in a constant temperature water bath at 10-40° C. and stirring, and continuously irradiating with visible light after the stirring begins, so that the alkyl radical precursor and the sulfonyl oxime compound undergo a free radical coupling reaction under the irradiation of visible light to obtain an oxime compound.

[0009] Preferably, the hydroxyl activating reagent in step (1) can be one of 1,3-benzodithiopyrrole tetrafluoroborate, 1,3-benzodithiopyrrole hexafluorophosphate, 1,3-benzodithiopyrrole trifluoromethanesulfonate, and 1,3-benzodithiopyrrole perchlorate, and the intermediate is 1,3-dithiapentane (BDT).

[0010] Preferably, the reactant alcohol in step (1) is a primary, secondary or tertiary alcohol.

[0011] Preferably, the reactant alcohol in step (1) is an alcohol compound containing ether, amide, trifluoromethyl, thioether, fluoride, or aromatic heterocycle.

[0012] Preferably, the first organic solvent in step (1) is one of tetrahydrofuran, isopropyl ether, ethyl ether, dichloromethane, petroleum ether, n-pentane, n-hexane and cyclohexane.

[0013] Preferably, the first base in step (1) is one of pyridine, 2,4,6-trimethylpyridine, 2,6-dimethylpyridine, 4-methoxypyridine, potassium dihydrogen phosphate, disodium hydrogen phosphate, sodium bicarbonate, potassium acetate, sodium acetate, potassium benzoate, sodium benzoate, and potassium tert-butoxide.

[0014] Preferably, the second organic solvent in step (2) is at least one of dichloromethane, n-hexane, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, trifluorotoluene, and benzonitrile.

[0015] Preferably, the second base in step (2) is one of pyridine, 2,4,6-trimethylpyridine, 2,6-dimethylpyridine, 4-methoxypyridine, potassium dihydrogen phosphate, disodium hydrogen phosphate, sodium bicarbonate, potassium acetate, sodium acetate, potassium benzoate, sodium benzoate, and potassium tert-butoxide.

[0016] Preferably, the first base in step (1) and the second base in step (2) are the same or different, more preferably the same.

[0017] Preferably, the photocatalyst is 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (4-CzIPN), 3,4,5,6-tetrakis(9-carbazolyl)-ophthalonitrile (4-CzPN), 2,3,5,6-tetrakis(9-carbazolyl)-terephthalonitrile (4-CzTPN), Ir[dF(CF3)ppy]2(dtbbpy)PF6, Ir[dF(CF3)2ppy]2(b py)PF6, Ir[dF(F)ppy]2(dtbbpy)PF6, [Ir(dFppy)2(dtbbpy)]PF6, Ir[pF(Me)ppy]2(dtb bpy)PF6, Ir[FCF3(CF3)ppy]2(dtbbpy)PF6, Ir[dF(CF3)2ppy]2(5,5'-CF3-bpy)PF6.

[0018] Preferably, the sulfonyl oxime is (phenylsulfonyl)methane O-benzyl oxime, ((4-fluorophenyl)sulfonyl)methane O-benzyl oxime, ((4-methoxyphenyl)sulfonyl)methane O-benzyl oxime, ((4-(tert-butyl)phenyl)sulfonyl)methane O-benzyl oxime, 2,2,2-trifluoro-1-(phenylsulfonyl)ethane-1-one O-benzyl oxime, N-(benzyloxy)-1 -(phenylsulfonyl)formamidocyanide, N-((4-chlorobenzyl)oxy)-1-(phenylsulfonyl)formamidocyanide, N-((4-bromobenzyl)oxy)-1-(phenylsulfonyl)formamidocyanide, N-ethoxy-1-(phenylsulfonyl)formamidocyanide, and ethyl 2-(((cyano(phenylsulfonyl)methylene)amino)oxy)acetate.

[0019] Preferably, the sulfonyl oxime has a leaving group, and the leaving group of the sulfonyl oxime may be one of a benzenesulfonyl group, a p-methoxybenzenesulfonyl group, a p-fluorobenzenesulfonyl group, and a p-tert-butylbenzenesulfonyl group.

[0020] Preferably, the molar ratio of the sulfonyl oxime compound to the intermediate is 1.2-3.0.

[0021] Preferably, the molar ratio of the alcohol, the intermediate, the first base, the second base and the photocatalyst is 1.2:2.0:1.0:(1.0-3.0):(0.01-0.03), preferably 1.2:2.0:1.0:1.2:0.02.

[0022] In general, the above technical solution conceived by the present invention has the following technical advantages compared with the prior art:

[0023] (1) The synthesis method of the present invention adopts a novel, inexpensive and widely applicable alcohol deoxygenation activation strategy. A hydroxyl activation reagent is used to react the reactant alcohol with an in situ generated alkyl radical precursor. A photocatalyst is used to drive the deoxygenation cross-coupling reaction between the alcohol and the sulfonyl oxime ether under visible light, thereby constructing oxime compounds with important medical value. The problem of high energy consumption in the deoxygenation of alcohol to generate oxime compounds is solved, and the use of environmentally polluting, toxic and harmful reagents such as carbon disulfide and trivalent phosphine in the previously reported alcohol deoxygenation conversion method is avoided. The method is not only suitable for the conversion of primary, secondary and tertiary alcohol compounds, but also suitable for alcohol compounds containing functional groups such as ether, amide, trifluoromethyl, thioether, fluoride and aromatic heterocycles such as thiophene and pyrazole, thereby successfully expanding the substrate range.

[0024] (2) The second base used in the present invention, such as 2,4,6-trimethylpyridine, can effectively promote the deprotonation process of the intermediate. The photocatalyst used, such as 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile, can efficiently transfer single electrons with the intermediate under visible light irradiation. The second organic solvent used, such as MeCN, can completely dissolve sulfonyl oxime and the intermediate. The selection of the above substances can greatly improve the reaction efficiency.

[0025] (3) The present invention also studies the molar ratio of alcohol, intermediate, first base, second base and photocatalyst. Within the preferred molar ratio range of the present invention, the hydrogen abstraction rate of the intermediate and the conversion rate of oxime compounds are significantly improved, which greatly improves the reaction efficiency and yield.

[0026] (4) The present invention realizes the efficient and chemically selective deoxy radical transformation of primary alcohols, secondary alcohols and tertiary alcohols driven by visible light through a one-pot process, and synthesizes a series of valuable oxime compounds with excellent yields. The preparation method of the present invention has the characteristics of high reaction efficiency, good functional group tolerance, wide substrate range, and diversified product derivatization, and provides an efficient and universal platform for the deoxy radical transformation of most alcohols. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of 2-cyclohexylacetaldehyde O-benzyl oxime in Example 1 of the present invention.

[0028] Figure 2 This is the carbon nuclear magnetic resonance spectrum of 2-cyclohexylacetaldehyde O-benzyl oxime in Example 1 of the present invention.

[0029] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde O-benzyl oxime in Example 2 of the present invention.

[0030] Figure 4 This is the carbon nuclear magnetic resonance spectrum of 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde O-benzyl oxime in Example 2 of the present invention.

[0031] Figure 5 This is the hydrogen nuclear magnetic resonance spectrum of tert-butyl 4-(3-((benzyloxy)imino)propyl)piperidine-1-carboxylate in Example 3 of the present invention.

[0032] Figure 6 This is the carbon nuclear magnetic resonance spectrum of tert-butyl 4-(3-((benzyloxy)imino)propyl)piperidine-1-carboxylate in Example 3 of the present invention. DETAILED DESCRIPTION

[0033] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention. In addition, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0034] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific implementation described herein is only used to explain the present invention and is not intended to limit the present invention. In addition, the technical features involved in each embodiment of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0035] The preparation method of the oxime compound of the present invention can be represented by the following chemical formula:

[0036]

[0037] Among them, R 1 is alkyl, benzyl;

[0038] R 2 is a hydrogen atom, a cyano group, or a trifluoromethyl group;

[0039] R 3 It is an ester group, an aryl group or an alkyl group.

[0040] The oxime compounds prepared by the present invention include but are not limited to compounds with structures shown in any one of the following formulas 1-23, wherein the E / Z in brackets below the compound is defined as the ratio of the amount of the compound between the E-configuration isomer and the Z-configuration isomer.

[0041]

[0042] The operation of the technical solution of the present invention is described in detail by the following example:

[0043] Example 1

[0044] In a nitrogen-filled glove box, cyclohexylmethanol (27 mg, 0.24 mmol), 1,3-benzodithiopyrrole tetrafluoride boron salt (BDTF) (48 mg, 0.2 mmol), 2,4,6-trimethylpyridine (49 mg, 0.4 mmol) and tetrahydrofuran (2.0 mL) were added to a reaction bottle equipped with a magnetic stirrer. The reaction mixture was stirred at 20°C for 30 minutes, and then the tetrahydrofuran was removed under reduced pressure. The reaction system after the solvent was removed was transferred to a glove box, and ((4-fluorophenyl)sulfonyl)methane O-benzyl oxime (117 mg, 0.4 mmol), 4-CzIPN (3 mg, 2 mol%), 2,4,6-trimethylpyridine (29 mg, 0.24 mmol) and MeCN (4.0 mL) were added in sequence. The reaction system was stirred in a 30°C water bath for 12 hours and irradiated with a 20W blue LED lamp (about 0.6 cm away). The solvent acetonitrile was removed under reduced pressure, and the residue was separated and purified by column chromatography to obtain an oxime compound of formula I-1 in a yield of 89%. The product was a colorless liquid with E / Z=1.4:1.

[0045] The following are the test results of this compound:

[0046] E isomer: 1 H NMR(400MHz, CDCl3)δ7.47(t,J=6.6Hz,1H),7.41–7.27(m,5H),5.07(s,2H),2.09(t,J= 6.8Hz,2H),1.74–1.63(m,5H),1.52–1.42(m,1H),1.28–1.12(m,3H),1.01–0.90(m,2H). 13 C{ 1 H}NMR(101MHz, CDCl3)δ151.0,137.8,128.5,128.3,127.9,75.6,37.0,36.3,33.1,26.4,26.3.Z isomer: 1 H NMR (400MHz, CDCl3) δ7.41–7.27(m,5H),6.72(t,J=5.6Hz,1H),5.11(s,2H),2.28(t,J= 6.4Hz,2H),1.74–1.63(m,5H),1.52–1.42(m,1H),1.28–1.12(m,3H),1.01–0.90(m,2H). 13 C{ 1H}NMR(101MHz, CDCl3)δ151.7,138.3,128.5,128.0,127.8,75.8,35.8,33.5,33.3,26.4,26.3.IR:ν=1628cm -1 .HRMS(EI):m / z[M+H] + Calculate for C 15 H 22 NO:232.1696,found:232.1697.

[0047] Example 2

[0048] This example and Example 1 adopt the same method to synthesize oxime compounds, and the difference from Example 1 is that:

[0049] The raw alcohol added was (tetrahydro-2H-pyran-4-yl)methanol (28 mg, 0.24 mmol), and the sulfonyl oxime added was ((4-fluorophenyl)sulfonyl)methane O-benzyl oxime (117 mg, 0.4 mmol). The oxime compound of formula I-2 was obtained in a yield of 87% by column chromatography separation and purification, and the product was a colorless liquid with E / Z=2:1.

[0050] The following are the test results of this compound:

[0051] E isomer: 1 H NMR(400MHz, CDCl3)δ7.46(t,J=6.4Hz,1H),7.39–7.27(m,5H),5.07(s,2H),4.00–3.88(m,2H),3 .42–3.29(m,2H),2.15(t,J=6.4Hz,2H),1.78–1.66(m,1H),1.64–1.53(m,2H),1.40–1.26(m,2H). 13 C{ 1 H}NMR(101MHz,CDCl3)δ149.7,137.7,128.5,128.3,127.9,75.7,67.9,36.5,33.4,32.8.Z isomer: 1 H NMR (400MHz, CDCl3) δ7.39–7.27(m,5H),6.72(t,J=5.8Hz,1H),5.11(s,2H),4.00–3.88(m,2H),3 .42–3.29(m,2H),2.34(t,J=6.4Hz,2H),1.78–1.66(m,1H),1.64–1.53(m,2H),1.40–1.26(m,2H).13 C{ 1 H}NMR(101MHz, CDCl3)δ150.3,138.1,128.5,128.0,127.9,75.9,67.9,36.5,33.1,32.9.IR:ν=1624cm -1 .HRMS(EI):m / z[M+H] + Calculate for C 14 H 20 NO2:234.1489,found:234.1488.

[0052] Example 3

[0053] This example and Example 1 adopt the same method to synthesize oxime compounds, and the difference from Example 1 is that:

[0054] The raw alcohol added was N-Boc-4-piperidineethanol (55 mg, 0.24 mmol), the sulfonyl oxime added was ((4-fluorophenyl)sulfonyl)methane O-benzyl oxime (117 mg, 0.4 mmol), the reaction mixture was stirred at 30° C., and the constant temperature water bath temperature was 40° C. The oxime compound of formula I-3 was obtained with a yield of 82% by column chromatography separation and purification, and the product was a colorless liquid with E / Z=1:1.

[0055] The following are the test results of this compound:

[0056] E isomer: 1 H NMR(400MHz, CDCl3)δ7.43(t,J=6.2Hz,1H),7.38–7.27(m,5H),5.05(s,2H),4.15–3.96(m,2H),2.70–2.5 6(m,2H),2.43–2.35(m,1H),2.25–2.16(m,1H),1.67–1.59(m,2H),1.47–1.37(m,12H),1.12–1.00(m,2H). 13 C{ 1 H}NMR(101MHz, CDCl3)δ155.0,151.3,138.2,128.5,128.1,127.9,79.4,75.9,44.0,35.5,32.9,32.0,28.6,23.2.Zisomer: 1H NMR (400MHz, CDCl3) δ7.38–7.27(m,5H),6.66(t,J=5.6Hz,1H),5.10(s,2H),4.15–3.96(m,2H),2.70–2.5 6(m,2H),2.43–2.35(m,1H),2.25–2.16(m,1H),1.67–1.59(m,2H),1.47–1.37(m,12H),1.12–1.00(m,2H). 13 C{ 1 H}NMR(101MHz, CDCl3)δ155.0,152.2,137.8,128.5,128.3,127.9,79.4,75.7,44.0,35.8,33.2,32.0,28.6,26.9.IR:ν=1693cm -1 .HRMS(EI):m / z[M+H] + Calculate for C 20 H 31 N2O3:347.2329,found:347.2328.

[0057] Example 4

[0058] This example and Example 1 adopt the same method to synthesize oxime compounds, and the difference from Example 1 is that:

[0059] The raw alcohol added was (4,4-difluorocyclohexyl)methanol (36 mg, 0.24 mmol), and the sulfonyl oxime added was ((4-fluorophenyl)sulfonyl)methane O-benzyl oxime (117 mg, 0.4 mmol). The oxime compound of formula I-4 was obtained in a yield of 75% by column chromatography separation and purification. The product was a colorless liquid with E / Z=1.1:1.

[0060] The following are the test results of this compound:

[0061] E isomer: 1 H NMR (400MHz, CDCl3) δ7.46 (t, J=6.4Hz, 1H), 7.39–7.26 (m, 5H), 5.07 (s, 2H), 2.16 (t, J= 6.6Hz,2H),2.11–2.02(m,2H),1.81–1.72(m,3H),1.69–1.54(m,2H),1.36–1.27(m,2H). 13 C{ 1H}NMR(101MHz, CDCl3)δ149.8,137.7,128.5,128.4,128.0,123.4(t,J=241. 9Hz), 75.8, 35.4 (d, J = 2.6Hz), 34.2, 33.4 (t, J = 25.2Hz), 28.8 (d, J = 9.6Hz). 19 F NMR (376MHz, CDCl3) δ-91.9 (d, J = 239.1Hz).Z isomer: 1 H NMR (400MHz, CDCl3) δ7.39–7.26(m,5H),6.71(t,J=5.8Hz,1H),5.11(s,2H),2.35(t,J= 6.4Hz,2H),2.11–2.02(m,2H),1.81–1.72(m,3H),1.69–1.54(m,2H),1.36–1.27(m,2H). 13 C{ 1 H}NMR(101MHz, CDCl3)δ150.4,138.1,128.5,128.1,127.9,123.4(t,J=241. 9Hz), 76.0, 33.9, 33.4 (t, J = 25.2Hz), 31.8 (d, J = 2.8Hz), 28.9 (d, J = 9.4Hz). 19 F NMR (376MHz, CDCl3) δ-101.9 (d, J = 250.0Hz). IR: ν = 1731cm -1 .HRMS(EI):m / z[M+H] + Calculate for C 15 H 20 F2NO:268.1507,found:268.1505.

[0062] Example 5

[0063] This example and Example 1 adopt the same method to synthesize oxime compounds, and the difference from Example 1 is that:

[0064] The raw alcohol added was 4,4,4-trifluorobutanol (31 mg, 0.24 mmol), the sulfonyl oxime added was ((4-fluorophenyl)sulfonyl)methane O-benzyl oxime (117 mg, 0.4 mmol), the reaction mixture was stirred at 30° C., and the constant temperature water bath temperature was 40° C. The oxime compound of formula I-5 was obtained in a yield of 65% by column chromatography separation and purification, and the product was a colorless liquid with E / Z=1.2:1.

[0065] The following are the test results of this compound:

[0066] E isomer: 1 H NMR (400MHz, CDCl3) δ7.44(t,J=5.8Hz,1H),7.39–7.30(m,5H),5.07(s,2H),2.32–2.25(m,2H),2.14–2.05(m,2H),1.82–1.73(m,2H). 13 C{ 1 H}NMR(101MHz, CDCl3)δ149.5,137.7,128.5,128.44,128.41(q,J=281.6Hz),128.0,75.9,33.1(q,J=28.9Hz),28.6,19.0(q,J=3.1Hz). 19 FNMR(376MHz, CDCl3)δ-66.4(t,J=10.8Hz).Zisomer: 1 H NMR (400MHz, CDCl3) δ7.39–7.30(m,5H),6.69(t,J=5.6Hz,1H),5.13(s,2H),2.49–2.42(m,2H),2.14–2.05(m,2H),1.82–1.73(m,2H). 13 C{ 1 H} NMR (101MHz, CDCl3) δ150.4, 137.9, 128.5, 128.4 (q, J = 281.6Hz), 128.1, 128.0, 76.1, 33.5 (q, J = 28.9Hz), 24.9, 18.9 (q, J = 3.2Hz). 19 F NMR (376MHz, CDCl3) δ-66.4 (t, J = 10.8Hz). IR: ν = 1642cm - 1 .HRMS(EI):m / z[M+H] + Calculate for C 12 H 15 F3NO:246.1100,found:246.1099.

[0067] Example 6

[0068] This example and Example 1 adopt the same method to synthesize oxime compounds, and the difference from Example 1 is that:

[0069] The raw alcohol added was 4-(methylthio)butanol (29 mg, 0.24 mmol), the sulfonyl oxime added was ((4-fluorophenyl)sulfonyl)methane O-benzyl oxime (117 mg, 0.4 mmol), the reaction mixture was stirred at 25° C., and the constant temperature water bath temperature was 35° C. The oxime compound of formula I-6 was obtained with a yield of 81% by column chromatography separation and purification, and the product was a colorless liquid with E / Z=1.3:1.

[0070] The following are the test results of this compound:

[0071] E isomer: 1 H NMR(400MHz, CDCl3)δ7.45(t,J=6.2Hz,1H),7.39–7.27(m,5H),5.05(s,2H),2.53– 2.45(m,2H),2.43–2.35(m,1H),2.25–2.19(m,1H),2.08(s,3H),1.65–1.55(m,4H). 13 C{ 1 H}NMR(101MHz, CDCl3)δ151.1,137.8,128.5,128.3,127.9,75.7,33.9,29.2,28.5,25.8,15.6.Z isomer: 1 H NMR (400MHz, CDCl3) δ7.39–7.27(m,5H),6.68(t,J=5.6Hz,1H),5.11(s,2H),2.53– 2.45(m,2H),2.43–2.35(m,1H),2.25–2.19(m,1H),2.08(s,3H),1.65–1.55(m,4H). 13 C{ 1 H}NMR(101MHz, CDCl3)δ152.0,138.2,128.5,128.0,127.9,75.9,33.9,28.8,25.5,25.4,15.6.IR:ν=1625cm -1 .HRMS(EI):m / z[M+H] + Calculate for C 13 H 20 NOS:238.1260,found:238.1260.

[0072] Example 7

[0073] This example and Example 1 adopt the same method to synthesize oxime compounds, and the difference from Example 1 is that:

[0074] The raw alcohol added was 3-(2-thienyl)-1-propanol (34 mg, 0.24 mmol), and the sulfonyl oxime added was ((4-fluorophenyl)sulfonyl)methane O-benzyl oxime (117 mg, 0.4 mmol). The oxime compound of formula I-7 was obtained in a yield of 78% by column chromatography separation and purification. The product was a colorless liquid with E / Z=1.5:1.

[0075] The following are the test results of this compound:

[0076] E isomer: 1 H NMR(600MHz, CDCl3)δ7.48(t,J=6.0Hz,1H),7.41–7.29(m,5H),7.16–7.11(m,1H),6.95–6.90(m ,1H),6.81–6.76(m,1H),5.08(s,2H),2.90–2.84(m,2H),2.30–2.24(m,2H),1.92–1.85(m,2H). 13 C{ 1 H}NMR(151MHz, CDCl3)δ150.8,144.4,137.8,128.5,128.4,128.0,126.9,124.6,123.3,75.7,29.3,29.0,28.7.Z isomer: 1 H NMR (600MHz, CDCl3) δ7.41–7.29(m,5H),7.16–7.11(m,1H),6.95–6.90(m,1H),6.81–6.76(m,1H ),6.72(t,J=5.5Hz,1H),5.13(s,2H),2.90–2.84(m,2H),2.49–2.43(m,2H),1.92–1.85(m,2H). 13 C{ 1 H}NMR (151MHz, CDCl3) δ151.6,144.4,138.2,128.5,128.1,127.9,126.9,124.5,123.3,75.9,29.6,28.4,25.4.IR:ν=1645,1598,1542cm -1 .HRMS(EI):m / z[M+H] + Calculate for C 15 H 18 NOS:260.1104,found:260.1102.

[0077] Example 8

[0078] This example and Example 1 adopt the same method to synthesize oxime compounds, and the difference from Example 1 is that:

[0079] The raw alcohol added was 3-(1-1H-pyrazolyl)-1-propanol (30 mg, 0.24 mmol), and the sulfonyl oxime added was ((4-fluorophenyl)sulfonyl)methane O-benzyl oxime (117 mg, 0.4 mmol). The oxime compound of formula I-8 was obtained in a yield of 73% by column chromatography separation and purification, and the product was a colorless liquid with E / Z=1:1.

[0080] The following are the test results of this compound:

[0081] E isomer: 1 H NMR (600MHz, CDCl3) δ7.52–7.49(m,1H),7.41(t,J=5.8Hz,1H),7.38–7.32(m,4H),7.32–7.25(m ,2H),6.23–6.20(m,1H),5.06(s,2H),4.14–4.09(m,2H),2.17–2.13(m,2H),2.10–2.01(m,2H). 13 C{ 1 H}NMR(151MHz, CDCl3)δ149.8,139.5,137.8,129.4,128.5,128.3,128.0,105.3,75.7,50.9,27.1,26.6.Z isomer: 1 H NMR (600MHz, CDCl3) δ7.52–7.49(m,1H),7.38–7.32(m,4H),7.32–7.25(m,2H),6.63(t,J=5.6Hz ,1H),6.23–6.20(m,1H),5.10(s,2H),4.14–4.09(m,2H),2.38–2.33(m,2H),2.10–2.01(m,2H). 13 C{ 1 H}NMR(151MHz, CDCl3)δ150.6,139.5,137.9,129.2,128.5,128.1,127.9,105.4,75.9,51.5,27.1,23.2.IR:ν=1647,1596cm -1 .HRMS(EI):m / z[M+H] + Calculate for C 14 H 18 N3O:244.1444,found:244.1446.

[0082] Example 9

[0083] This example and Example 1 adopt the same method to synthesize oxime compounds, and the difference from Example 1 is that:

[0084] The raw alcohol added was benzyl alcohol (26 mg, 0.24 mmol), the sulfonyl oxime added was ((4-fluorophenyl)sulfonyl)methane O-benzyl oxime (117 mg, 0.4 mmol), the reaction mixture was stirred at 15° C., and the constant temperature water bath temperature was 25° C. The oxime compound of formula I-9 was obtained in a yield of 66% by column chromatography separation and purification, and the product was a colorless liquid with E / Z=1.2:1.

[0085] The following are the test results of this compound:

[0086] E isomer: 1 H NMR (400MHz, CDCl3) δ7.55(t,J=6.6Hz,1H),7.41–7.17(m,10H),5.11(s,2H),3.53(d,J=6.6Hz,2H). 13 C{ 1 H}NMR(101MHz,CDCl3)δ149.9,137.8,136.4,128.9,128.8,128.5(2C),128.0,126.9,75.8,36.0.Z isomer: 1 H NMR (400MHz, CDCl3) δ7.41–7.17(m,10H),6.86(t,J=5.4Hz,1H),5.18(s,2H),3.73(d,J=5.4Hz,2H). 13 C{ 1 H}NMR(101MHz, CDCl3)δ150.4,138.0,137.0,128.9,128.8,128.4,128.1,126.7,76.1,32.7.IR:ν=1603cm -1 .HRMS(EI):m / z[M+H] + Calculate for C 15 H 16 NO:226.1226,found:226.1227.

[0087] Example 10

[0088] This example and Example 1 adopt the same method to synthesize oxime compounds, and the difference from Example 1 is that:

[0089] The raw alcohol added was cyclohexanol (24 mg, 0.24 mmol), the sulfonyl oxime added was ((4-fluorophenyl)sulfonyl)methane O-benzyl oxime (117 mg, 0.4 mmol), the reaction mixture was stirred at 10° C., and the constant temperature water bath temperature was 20° C. The oxime compound of formula I-10 was obtained with a yield of 90% by column chromatography separation and purification, and the product was a colorless liquid with E / Z=4:1.

[0090] The following are the test results of this compound:

[0091] E isomer: 1 H NMR (400MHz, CDCl3) δ7.41–7.27(m,6H),5.06(s,2H),2.30–2.17(m,1H),1.81–1.62(m,5H),1.33–1.18(m,5H). 13 C{ 1 H}NMR (101MHz, CDCl3) δ155.6,137.8,128.5,128.4,127.9,75.6,38.6,30.5,25.9,25.5.Zisomer: 1 H NMR (400MHz, CDCl3) δ7.39–7.27(m,5H),6.51(d,J=7.4Hz,1H),5.10(s,2H),3.02–2.88(m,1H),1.81–1.62(m,5H),1.33–1.18(m,5H). 13 C{ 1 H}NMR (101MHz, CDCl3) δ156.5,137.8,128.5,128.4,127.7,75.7,34.6,29.7,26.0,25.4.

[0092] Embodiment 11

[0093] This example and Example 1 adopt the same method to synthesize oxime compounds, and the difference from Example 1 is that:

[0094] The raw alcohol added was tetrahydropyran-4-ol (25 mg, 0.24 mmol), and the sulfonyl oxime added was ((4-fluorophenyl)sulfonyl)methane O-benzyl oxime (117 mg, 0.4 mmol). The oxime compound of formula I-11 was obtained in a yield of 88% by column chromatography separation and purification, and the product was a colorless liquid with E / Z=6:1.

[0095] The following are the test results of this compound:

[0096] E isomer: 1H NMR (400MHz, CDCl3) δ7.40–7.27(m,6H),5.06(s,2H),4.00–3.91(m,2H),3.49–3.37(m,2H),2.54–2.41(m,1H),1.73–1.54(m,4H). 13 C{ 1 H}NMR(101MHz,CDCl3)δ153.5,137.6,128.5,128.4,128.0,75.8,67.2,35.9,30.1.Z isomer: 1 H NMR(400MHz, CDCl3)δ7.40–7.27(m,5H),6.54(d,J=6.9Hz,1H),5.10(s,2H), 4.00–3.91(m,2H),3.49–3.37(m,2H),3.24–3.11(m,1H),1.73–1.54(m,4H). 13 C{ 1 H}NMR (101MHz, CDCl3) δ154.4,138.0,128.5,128.0,127.9,75.9,67.1,32.0,29.3.

[0097] Example 12

[0098] This example and Example 1 adopt the same method to synthesize oxime compounds, and the difference from Example 1 is that:

[0099] The raw alcohol added was tetrahydro-2H-thiopyran-4-ol (28 mg, 0.24 mmol), and the sulfonyl oxime added was ((4-fluorophenyl)sulfonyl)methane O-benzyl oxime (117 mg, 0.4 mmol). The oxime compound of formula I-12 was obtained in a yield of 79% by column chromatography separation and purification, and the product was a colorless liquid with E / Z=10:1.

[0100] The following are the test results of this compound:

[0101] E isomer: 1 H NMR (400MHz, CDCl3) δ7.40–7.27(m,6H),5.06(s,2H),2.73–2.60(m,4H),2.36–2.23(m,1H),2.12–2.04(m,2H),1.73–1.61(m,2H). 13 C{ 1H}NMR(101MHz,CDCl3)δ153.9,137.6,128.5,128.4,127.9,38.2,31.2,27.8.Z isomer: 1 H NMR (400MHz, CDCl3) δ7.40–7.27(m,6H),5.10(s,2H),2.73–2.60(m,4H),2.36–2.23(m,1H),2.12–2.04(m,2H),1.73–1.61(m,2H). 13 C{ 1 H}NMR(101MHz, CDCl3)δ153.9,137.6,128.5,128.4,127.9,75.9,34.2,30.3,27.6.IR:ν=1630,1604cm -1 .HRMS(EI):m / z[M+H] + Calculate for C 13 H 18 NOS:236.1104,found:236.1103.

[0102] Embodiment 13

[0103] This example and Example 1 adopt the same method to synthesize oxime compounds, and the difference from Example 1 is that:

[0104] The raw alcohol added was N-Boc-4-hydroxypiperidine (48 mg, 0.24 mmol), and the sulfonyl oxime added was ((4-fluorophenyl)sulfonyl)methane O-benzyl oxime (117 mg, 0.4 mmol). The oxime compound of formula I-13 was obtained in a yield of 75% by column chromatography separation and purification, and the product was a colorless liquid with E / Z=7:1.

[0105] The following are the test results of this compound:

[0106] E isomer: 1 H NMR (400MHz, CDCl3) δ7.38–7.27(m,6H),5.04(s,2H),4.15–3.94(m,2H),2.86–2. 70(m,2H),2.43–2.30(m,1H),1.77–1.70(m,2H),1.45(s,9H),1.44–1.36(m,2H).Z isomer: 1H NMR (400MHz, CDCl3) δ7.38–7.27(m,6H),5.09(s,2H),4.15–3.94(m,2H),2.86–2. 70(m,2H),2.43–2.30(m,1H),1.77–1.70(m,2H),1.45(s,9H),1.44–1.36(m,2H). 13 C{ 1 H}NMR (101MHz, CDCl3) δ154.8,153.5,137.6,128.5,128.4,128.0,79.6,75.9,43.3,36.9,29.4,28.6.

[0107] Embodiment 14

[0108] This example and Example 1 adopt the same method to synthesize oxime compounds, and the difference from Example 1 is that:

[0109] The raw alcohol added was 4-hydroxycyclooctene (30 mg, 0.24 mmol), and the sulfonyl oxime added was ((4-fluorophenyl)sulfonyl)methane O-benzyl oxime (117 mg, 0.4 mmol). The oxime compound of formula I-14 was obtained in a yield of 85% by column chromatography separation and purification, and the product was a colorless liquid with E / Z=16:1.

[0110] The following are the test results of this compound: 1 H NMR (400MHz, CDCl3) δ7.43–7.24(m,6H),5.75–5.58(m,2H),5.04(s,2H),2 .45–2.29(m,2H),2.23–2.08(m,3H),1.76–1.64(m,3H),1.55–1.40(m,3H). 13 C{ 1 H}NMR(101MHz, CDCl3)δ156.4,137.8,130.5,129.7,128.5,128.4,127.9,75.6,38.4,33.0,30.3,27.7,26.0,24.5.IR:ν=1650,1629cm -1 .HRMS(EI):m / z[M+H] + calcdfor C 16 H 22 NO:244.1696,found:244.1698.

[0111] Embodiment 15

[0112] This example and Example 1 adopt the same method to synthesize oxime compounds, and the difference from Example 1 is that:

[0113] The raw alcohol added was tert-butyl alcohol (18 mg, 0.24 mmol), the sulfonyl oxime added was ((4-fluorophenyl)sulfonyl)methane O-benzyl oxime (117 mg, 0.4 mmol), the reaction mixture was stirred at 15° C., and the constant temperature water bath temperature was 25° C. The oxime compound of formula I-15 was obtained in a yield of 51% by column chromatography separation and purification, and the product was a colorless liquid.

[0114] The following are the test results of this compound: 1 H NMR (400MHz, CDCl3) δ7.44–7.30(m,6H),5.09(s,2H),1.13(s,9H). 13 C{ 1 H}NMR (101MHz, CDCl3) δ158.8,137.8,128.5,128.4,127.9,75.7,33.8,27.7.

[0115] Example 16

[0116] This example and Example 1 adopt the same method to synthesize oxime compounds, and the difference from Example 1 is that:

[0117] The raw alcohol added was tert-amyl alcohol (21 mg, 0.24 mmol), and the sulfonyl oxime added was ((4-fluorophenyl)sulfonyl)methane O-benzyl oxime (117 mg, 0.4 mmol). The oxime compound of formula I-16 was obtained in a yield of 63% by column chromatography separation and purification, and the product was a colorless liquid.

[0118] The following are the test results of this compound: 1 H NMR (400MHz, CDCl3) δ7.41–7.29(m,6H),5.08(s,2H),1.43(q,J=7.6Hz,2H),1.08(s,6H),0.84(t,J=7.6Hz,3H). 13 C{ 1 H}NMR(101MHz, CDCl3)δ158.4,137.9,128.5,128.4,127.9,75.7,36.9,33.7,25.0,8.8.IR:ν=1602cm - 1 .HRMS(EI):m / z[M+H] + Calculate for C 13 H 20NO:206.1539,found:206.1538.

[0119] Embodiment 17

[0120] This example and Example 1 adopt the same method to synthesize oxime compounds, and the difference from Example 1 is that:

[0121] The alcohol added was dimethylbenzyl alcohol (36 mg, 0.24 mmol), the sulfonyl oxime added was ((4-fluorophenyl)sulfonyl)methane O-benzyl oxime (117 mg, 0.4 mmol), the reaction mixture was stirred at 15° C., and the constant temperature water bath temperature was 25° C. The oxime compound of formula I-17 was obtained in a yield of 54% by column chromatography separation and purification, and the product was a colorless liquid.

[0122] The following are the test results of this compound: 1 H NMR (600MHz, CDCl3) δ7.48(s,1H),7.44–7.34(m,5H),7.33–7.26(m,3H),7.16–7.12(m,2H),5.11(s,2H),2.76(s,2H),1.15(s,6H). 13 C{ 1 H}NMR(151MHz, CDCl3)δ158.0,138.0,137.7,130.7,128.4(2C),128.0,127.8,126.3,75.7,47.4,37.8,25.4.

[0123] Embodiment 18

[0124] This example and Example 1 adopt the same method to synthesize oxime compounds, and the difference from Example 1 is that:

[0125] The raw alcohol added was cyclohexanol (24 mg, 0.24 mmol), the sulfonyl oxime added was 2,2,2-trifluoro-1-(benzenesulfonyl)ethane-1-one O-benzyl oxime (137 mg, 0.4 mmol), the reaction mixture was stirred at 15° C., and the constant temperature water bath temperature was 25° C. The oxime compound of formula I-18 was obtained in a yield of 65% by column chromatography separation and purification, and the product was a colorless liquid with E / Z>20:1.

[0126] The following are the test results of this compound: 1H NMR (600MHz, CDCl3) δ7.40–7.32(m,5H),5.21(s,2H),2.95–2.88(m,1H),1.80–1.73(m,4H),1.70–1.60(m,3H),1.30–1.18(m,3H). 13 C{ 1 H}NMR(151MHz, CDCl3)δ152.1(q,J=29.5Hz),136.8,128.6,128.3(2C),121.3(q,J=275.9Hz),77.7,36.9,28.0,26.4,25.8. 19 F NMR (376MHz, CDCl3) δ-66.6.

[0127] Embodiment 19

[0128] This example and Example 1 adopt the same method to synthesize oxime compounds, and the difference from Example 1 is that:

[0129] The raw alcohol added was cyclohexanol (24 mg, 0.24 mmol), the sulfonyl oxime added was N-(benzyloxy)-1-(phenylsulfonyl)carboximide cyanide (120 mg, 0.4 mmol), the reaction mixture was stirred at 10° C., and the constant temperature water bath temperature was 20° C. The oxime compound of formula I-19 was obtained in a yield of 78% by column chromatography separation and purification, and the product was a colorless liquid with E / Z>20:1.

[0130] The following are the test results of this compound: 1 H NMR (400MHz, CDCl3) δ7.42–7.29(m,5H),5.23(s,2H),2.50–2.37(m,1H),1.92–1.76(m,5H),1.46–1.19(m,5H). 13 C{ 1 H}NMR (101MHz, CDCl3) δ137.4,136.3,128.6,128.5,128.4,110.0,77.7,40.9,30.0,25.5(2C).

[0131] Embodiment 20

[0132] This example and Example 1 adopt the same method to synthesize oxime compounds, and the difference from Example 1 is that:

[0133] The raw alcohol added was cyclohexanol (24 mg, 0.24 mmol), the sulfonyl oxime added was N-((4-chlorobenzyl)oxy)-1-(phenylsulfonyl)carboximide cyanide (134 mg, 0.4 mmol), the reaction mixture was stirred at 15° C., and the constant temperature water bath temperature was 25° C. The oxime compound of the structure of formula I-20 was obtained with a yield of 81% by column chromatography separation and purification, and the product was a colorless liquid with E / Z=15:1.

[0134] The following are the test results of this compound: 1 H NMR(600MHz, CDCl3)δ7.36–7.26(m,4H),5.18(s,2H),2.45–2.38(m,1H),1.90–1.77 (m,4H),1.72–1.67(m,1H),1.44–1.35(m,2H),1.34–1.26(m,2H),1.24–1.19(m,1H). 13 C{ 1 H}NMR(151MHz, CDCl3)δ137.8,134.8,134.4,129.9,128.8,109.9,76.8,41.0,30.0,25.5(2C).

[0135] Embodiment 21

[0136] This example and Example 1 adopt the same method to synthesize oxime compounds, and the difference from Example 1 is that:

[0137] The raw alcohol added was cyclohexanol (24 mg, 0.24 mmol), and the sulfonyl oxime added was N-((4-bromobenzyl)oxy)-1-(phenylsulfonyl)carboximide cyanide (152 mg, 0.4 mmol). The oxime compound of formula I-21 was obtained in a yield of 83% by column chromatography separation and purification, and the product was a colorless liquid with E / Z>20:1.

[0138] The following are the test results of this compound: 1 H NMR(600MHz, CDCl3)δ7.52–7.46(m,2H),7.25–7.19(m,2H),5.16(s,2H),2.46–2.38(m,1H),1 .89–1.77(m,4H),1.72–1.66(m,1H),1.44–1.35(m,2H),1.33–1.26(m,2H),1.23–1.19(m,1H). 13 C{ 1H}NMR (151MHz, CDCl3) δ137.8,135.3,131.8,130.1,122.5,109.8,76.8,40.9,30.0,25.5,25.4.

[0139] Embodiment 22

[0140] This example and Example 1 adopt the same method to synthesize oxime compounds, and the difference from Example 1 is that:

[0141] The raw alcohol added was cyclohexanol (24 mg, 0.24 mmol), the sulfonyl oxime added was N-ethoxy-1-(phenylsulfonyl)carboximide cyanide (95 mg, 0.4 mmol), the reaction mixture was stirred at 10° C., and the constant temperature water bath temperature was 20° C. The oxime compound of formula I-22 was obtained in a yield of 73% by column chromatography separation and purification, and the product was a colorless liquid, E / Z=20:1.

[0142] The following are the test results of this compound: 1 H NMR (400MHz, CDCl3) δ4.25 (q, J = 7.2Hz, 2H), 2.47–2.37 (m, 1H), 1.90–1.77 (m, 4H), 1.72–1.66 (m, 1H), 1.44–1.18 (m, 8H). 13 C{ 1 H}NMR (101MHz, CDCl3) δ136.4,110.1,71.7,40.9,30.1,25.5(2C),14.4.

[0143] Embodiment 23

[0144] This example and Example 1 adopt the same method to synthesize oxime compounds, and the difference from Example 1 is that:

[0145] The raw alcohol added was cyclohexanol (24 mg, 0.24 mmol), the sulfonyl oxime added was ethyl 2-(((cyano(benzenesulfonyl)methylene)amino)oxy)acetate (119 mg, 0.4 mmol), the reaction mixture was stirred at 15° C., and the constant temperature water bath temperature was 25° C. The oxime compound of formula I-23 was obtained in a yield of 76% by column chromatography separation and purification, and the product was a colorless liquid, E / Z=8:1.

[0146] The following are the test results of this compound: 1H NMR (400MHz, CDCl3) δ4.70 (s, 2H), 4.21 (q, J = 7.2Hz, 2H), 2.49–2.39 (m, 1H), 1.91–1.76(m,4H),1.71–1.64(m,1H),1.46–1.35(m,2H),1.34–1.19(m,6H). 13 C{ 1 H}NMR (101MHz, CDCl3) δ168.7,138.9,109.5,71.6,61.4,40.9,29.9,25.5,25.4,14.3.

[0147] The present invention also explores the conditions of the reaction. First, the effects of different photoredox catalysts on the oximation reaction were investigated. The results are shown in the following table. When 4-CzIPN organic photocatalyst is used, the oximation reaction can obtain the target compound with a yield of 53%. When polyfluoroiridium photocatalysts such as Ir[dFCF3ppy]2(bpy)PF6 are used, the reaction yields are 25%-47%. However, when Rhodamin B, fac-Ir(ppy)3 and [Mes - Acr-Ph + When ](BF4) is used as the photocatalyst, no product is generated, which proves that there are both organic non-metallic photocatalysts and noble metal photocatalysts that are not suitable for this system. The preliminary screening data show that 4-CzIPN is selected as the best photocatalyst for the reaction of the present invention under the current conditions.

[0148]

[0149] Table 1 Effect of different photocatalysts on the oximation reaction efficiency

[0150]

[0151] The present invention also investigates different second reaction solvents. When the reaction solvent is replaced with a highly polar solvent such as DMF, DMSO, etc., the efficiency of the oximation reaction decreases slightly. When ether solvents such as 1,4-dioxane and DME are used, the reaction only obtains products with a yield of 17% and 36%. When benzene solvents such as trifluorotoluene and benzene or halogenated solvents such as DCE are used, the yield is not improved. Therefore, MeCN is finally selected as the best second solvent for the oximation reaction of the present invention.

[0152]

[0153] Table 2 Effect of the second solvent on the oximation reaction efficiency

[0154]

[0155] The present invention also investigates the effect of the second base in the reaction system on the reaction efficiency. When tertiary amines such as triethylenediamine are used instead of 2,4,6-trimethylpyridine, the reaction does not proceed. At the same time, the effect of the electronic effect on pyridine on the reaction is explored. When pyridine has no substituent or an electron-donating substituent, the reaction efficiency is slightly reduced. When pyridine has an electron-withdrawing substituent, the yield is greatly reduced. Inorganic bases also have a certain reactivity in this system. Unlike inorganic acid bases such as potassium phosphate and potassium carbonate, which have no promoting effect on the oximation reaction, organic acid bases such as potassium benzoate and sodium acetate have a slight advantage in reaction efficiency, but still do not exceed pyridine. When sodium fluoride is used, the reaction only obtains the product at a yield of 28%. Therefore, 2,4,6-trimethylpyridine is selected as the best second base used in the present invention.

[0156]

[0157] Table 3 Effect of the second base on the oximation reaction efficiency

[0158]

[0159] The present invention also optimizes the leaving group type of sulfonyl oxime and the dosage of sulfonyl oxime. In the initial trial stage, p-methoxybenzenesulfonyl was selected, but after screening, it was found that p-fluoro and p-tert-butylbenzenesulfonyl had better reaction effects, and the products were obtained with yields of 73% and 65% respectively, while the effect of benzenesulfonyl was average. Subsequently, an attempt was made to increase the dosage of sulfonyl oxime to improve the reaction efficiency, and it was found that when two equivalents of sulfonyl oxime were added, the reaction yield could reach 93%.

[0160]

[0161] Table 4 Effect of leaving group type and sulfonyl oxime dosage on oximation reaction efficiency

[0162]

[0163]

[0164] The present invention also optimizes the ratio of the second base and the photocatalyst. As can be seen from the table below, when the amount of alcohol, intermediate, and first base remains unchanged (the molar ratio of the three is 1.2:1.0:2.0), a good yield of the target product is shown in the range of (1.0-3.0):(0.01-0.03) of the second base and the photocatalyst, wherein the yield of the oximation reaction increases first and then decreases with the increase in the amount of 2,4,6-trimethylpyridine, and the best effect is achieved at 1.2 equiv. The best effect is achieved when the amount of the photocatalyst 4-CzIPN is 2 mol%, that is, the best material ratio under this condition is 1.2:1.0:2.0:1.2:0.02 for alcohol, intermediate, first base, second base, and photocatalyst.

[0165]

[0166] Table 5 Effect of the ratio of the second base and the photocatalyst on the oximation reaction efficiency

[0167]

[0168] It will be easily understood by those skilled in the art that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing an oxime compound, characterized in that: The method comprises the following steps: (1) adding a reactant alcohol, a hydroxyl activating reagent, a first base and a first organic solvent to a dry reaction bottle, and placing the reaction bottle at 10-30° C. and stirring continuously to allow the reactant alcohol and the hydroxyl activating reagent to generate an intermediate in situ, and then removing the first organic solvent; (2) adding a sulfonyl oxime compound, a photocatalyst, a second organic solvent and a second base to a reaction flask after removing the first organic solvent under a protective gas atmosphere, and starting the reaction, wherein the intermediate obtained in step (1) is used as an alkyl radical precursor; (3) placing the reaction system in a 20-40° C. water bath and stirring, and continuously irradiating with visible light after the stirring begins, so that the alkyl radical precursor and the sulfonyl oxime compound undergo a free radical coupling reaction under the irradiation of visible light to obtain an oxime compound; The hydroxyl activating agent in step (1) is one of 1,3-benzodithiopyrrole tetrafluoroborate, 1,3-benzodithiopyrrole hexafluorophosphate, 1,3-benzodithiopyrrole trifluoromethanesulfonate, and 1,3-benzodithiopyrrole perchlorate; The second base in step (2) is one of pyridine, 2,4,6-trimethylpyridine, 2,6-dimethylpyridine, 4-methoxypyridine, diisopropylethylamine, tetramethylguanidine, potassium phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, potassium carbonate, sodium bicarbonate, potassium acetate, sodium acetate, potassium benzoate, sodium benzoate, potassium tert-butoxide, and cesium fluoride; The photocatalyst is one of 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile, 3,4,5,6-tetrakis(9-carbazolyl)-ophthalonitrile, 2,3,5,6-tetrakis(9-carbazolyl)-terephthalonitrile, Ir[dF(CF3)ppy]2(dtbbpy)PF6, Ir[dF(CF3)2ppy]2(bpy)PF6, Ir[dF(F)ppy]2(dtbbpy)PF6, [Ir(dFppy)2(dtbbpy)]PF6, Ir[pF(Me)ppy]2(dtbbpy)PF6, Ir[FCF3(CF3)ppy]2(dtbbpy)PF6, and Ir[dF(CF3)2ppy]2(5,5'-CF3-bpy)PF6; The sulfonyl oxime compound is one of (benzenesulfonyl)methane O-benzyl oxime, ((4-fluorophenyl)sulfonyl)methane O-benzyl oxime, ((4-methoxyphenyl)sulfonyl)methane O-benzyl oxime, ((4-(tert-butyl)phenyl)sulfonyl)methane O-benzyl oxime, 2,2,2-trifluoro-1-(benzenesulfonyl)ethane-1-one O-benzyl oxime, N-(benzyloxy)-1-(benzenesulfonyl)formamidocyanide, N-((4-chlorobenzyl)oxy)-1-(benzenesulfonyl)formamidocyanide, N-((4-bromobenzyl)oxy)-1-(benzenesulfonyl)formamidocyanide, N-ethoxy-1-(benzenesulfonyl)formamidocyanide, and ethyl 2-(((cyano(benzenesulfonyl)methylene)amino)oxy)acetate.

2. The method according to claim 1, characterized in that The reactant alcohol in step (1) is a primary, secondary or tertiary alcohol.

3. The method according to claim 1, characterized in that: The first organic solvent in step (1) is one of tetrahydrofuran, isopropyl ether, ethyl ether, dichloromethane, petroleum ether, n-pentane, n-hexane and cyclohexane.

4. The method according to claim 1, characterized in that: The first base in step (1) is one of pyridine, 2,4,6-trimethylpyridine, 2,6-dimethylpyridine, 4-methoxypyridine, diisopropylethylamine, tetramethylguanidine, potassium phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, potassium carbonate, sodium bicarbonate, potassium acetate, sodium acetate, potassium benzoate, sodium benzoate, potassium tert-butoxide, and cesium fluoride.

5. The method according to claim 4, characterized in that The first base and the second base are the same.

6. The method according to claim 1, characterized in that The second organic solvent in step (2) is one of dichloromethane, 1,2-dichloroethane, n-hexane, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether, tetrahydrofuran, toluene, trifluorotoluene, benzonitrile, and 1,4-dioxane.

7. The method according to claim 1, characterized in that The molar ratio of the intermediate to the sulfonyl oxime compound is 1.2-3.

8. The method according to any one of claims 1 to 5, characterized in that: The molar ratio of the alcohol, 1,3-benzodithiopyrrole tetrafluoride boron salt, the first base, the sulfonyl oxime compound, the second base and the photocatalyst is 1.2: 2.0: 1.0: (1.0-3.0): (0.01-0.03).

9. The method according to claim 8, characterized in that The molar ratio of the alcohol, 1,3-benzodithiopyrrole tetrafluoride boron salt, the first base, the sulfonyl oxime compound, the second base and the photocatalyst is 1.2:2.0:1.0:1.2:0.02.

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