Hydroxyl-substituted alkane compounds and methods of electrochemically reducing a couple to form a hydroxyl-substituted alkane compound

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to a hydroxyl-substituted alkane compound and a method for electrochemically reducing coupling to synthesize the hydroxyl-substituted alkane compound. The hydroxyl-substituted alkane compound includes an alpha-trifluoromethyl alcohol compound and a ketone carbonyl derivative hydroxyl alkylate. The structural general formula of the alpha-trifluoromethyl alcohol compound is CF3-C(OH)(R1)-CH(R5)-R2. The structural general formula of the ketone carbonyl derivative hydroxyl alkylate is R3-C(OH)(R4)-CH(R5)-R2. R1 is an aryl group, a heteroaryl group or a C1-C4 alkyl group. R2 is an aryl group, a fused ring group or an alkenyl group. R3 is a cyano group or a C1-C4 alkoxycarbonyl group. R4 is a phenyl group or a C1-C4 alkyl group. R5 is H or a C1-C4 alkyl group. The hydroxyl-substituted alkane compound and the synthesis method provided by the application have mild reaction conditions and simple operation.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing hydroxyl-substituted alkane compounds by electrochemical reduction coupling. Background Technology

[0002] In the fields of organic synthesis, medicinal chemistry, and materials science, hydroxyl-containing alkanes are an important building block in organic synthesis. Among them, α-trifluoromethyl alcohol, due to the unique electronic, spatial, and hydrophobic properties of the trifluoromethyl group (-CF3), can significantly enhance the lipophilicity, metabolic stability, and bioavailability of drugs, and is widely found in drugs such as flutial and lansoprazole. At the same time, other hydroxyl-substituted alkanes (such as cyano and ester-substituted hydroxyalkanes) are also key intermediates in the fields of fine chemicals and agrochemicals, and have irreplaceable value in drug development, materials synthesis, and other fields.

[0003] Currently, conventional methods for preparing hydroxylated alkanes mainly involve ionic reactions, including the addition of nucleophiles to carbonyl compounds and the alkylation of ketones by organometallic reagents. These methods have clear pathways, but they have limitations such as harsh reaction conditions, reagent excess, numerous byproducts, low atom economy, complex operation, high cost, and potential environmental pollution.

[0004] In recent years, photo-redox catalysis-based radical coupling strategies have been gradually applied to the synthesis of these compounds. For example, patent CN108774121A discloses a method for the visible light catalysis preparation of α-aryl-β-trifluoromethyl ketones, the products of which can be further converted into α-trifluoromethyl alcohol derivatives. However, such methods often require noble metal catalysts or special photosensitizers, increasing costs and making product separation more difficult, thus limiting large-scale application.

[0005] Biocatalytic reduction is also used for the synthesis of chiral hydroxyalkanes (especially chiral α-trifluoromethyl alcohols). For example, patent CN121538277A uses imine reductase AtRedAm to prepare chiral α-trifluoromethyl alcohols, which can solve the problem of chiral isomer separation. However, it has problems such as difficult catalyst preparation, narrow substrate applicability, slow reaction rate and poor enzyme stability.

[0006] The journal *Angewandte Chemie International Edition* (2025, 64 (4):e202415218, DOI: 10.1002 / anie.202415218) reported that trifluoromethylthiophene salt was used as the trifluoromethyl source. After electrochemical reduction, CF3 radicals were generated. After addition to unactivated olefins, the carbon radicals were reduced to carbanions by a secondary cathodic reduction. The reaction was then terminated by solvent protonation. MgBr2 was used as a sacrificial reducing agent. Combined with cyclic voltammetry, high selectivity was achieved, and the functional group tolerance was excellent.

[0007] Despite the abundance of existing synthetic methods and significant progress in trifluoromethylation of organic electrosynthesis, the electrochemical synthesis of hydroxylated alkanes still has shortcomings: direct synthesis methods are few, some require specific sacrificial reagents or electrolytes, resulting in high costs and operational complexity; substrate applicability is narrow, making it difficult to be compatible with redox-sensitive heterocyclic compounds; and there is still room for improvement in reaction efficiency, yield, and selectivity, making it difficult to meet the needs of large-scale industrial production and drug development. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to overcome the above-mentioned defects of the prior art and provide a method for synthesizing hydroxy-substituted alkane compounds by electrochemical reduction coupling. The reaction conditions are mild, the operation is simple, the environment is friendly, and the functional group compatibility is good. It can simultaneously synthesize α-trifluoromethyl alcohols and ketone carbonyl derivative hydroxyalkylates, filling the gap in the prior art.

[0009] I. Hydroxyl-substituted alkanes

[0010] The hydroxylated alkane compounds of this invention include α-trifluoromethyl alcohols and hydroxyalkylated ketone carbonyl derivatives, with the following structural formulas:

[0011] 1. The general structural formula of the α-trifluoromethyl alcohol compounds is: CF3-C(OH)(R1)-CH(R5)-R2;

[0012] 2. The general structural formula of the ketone carbonyl derivative hydroxyalkylated compound is: R3-C(OH)(R4)-CH(R5)-R2;

[0013] Wherein, R1 is aryl, heteroaryl, or C1-C4 alkyl;

[0014] R2 can be aryl, fused ring group, or alkenyl group;

[0015] R3 is a cyano or a C1-C4 alkoxycarbonyl group;

[0016] R4 is a phenyl or a C1-C4 alkyl group;

[0017] R5 is H or a C1-C4 alkyl group.

[0018] Preferably, the aryl group is phenyl, C1-C4 alkyl-substituted phenyl, C1-C4 alkoxy-substituted phenyl, halophenyl, cyano-substituted phenyl, naphthyl, phenanthryl, or [1,1'-biphenyl]-4-yl; the heteroaryl group is furanyl, thienyl, or benzothienyl; the fused ring group is 9H-fluorenyl; and the alkenyl group is allyl or cinnamyl.

[0019] Preferably, the α-trifluoromethyl alcohol compound is 1,1,1-trifluoro-2,3-diphenylpropane-2-ol, 1,1,1-trifluoro-2-phenyl-3-(p-tolyl)propane-2-ol, 1,1,1-trifluoro-3-(4-fluorophenyl)-2-phenylpropane-2-ol, 2-(4-bromophenyl)-1,1,1-trifluoro-3-phenylpropane-2-ol, 1,1,1-trifluoro-2-(furan-2-yl)-3-phenylpropane-2-ol, 1,1,1-trifluoro-2-phenyl-3-(4-(trifluoromethyl)phenyl)propane-2-ol, methyl 4- (3,3,3-trifluoro-2-hydroxy-2-phenylpropyl)benzoate, 3-(2-fluorophenyl)-1,1,1-trifluoro-2-phenylpropane-2-ol, 2-([1,1'-biphenyl]-4-yl)-1,1,1-trifluoro-3-phenylpropane-2-ol, 1,1,1-trifluoro-2,3-diphenylbutane-2-ol, 2-(9H-fluorene-9-yl)-1,1,1-trifluoro-1-phenylethane-1-ol, 1,1,1-trifluoro-2,5-diphenylpent-4-en-2-ol or 1,1,1-trifluoro-2-phenylpent-4-en-2-ol.

[0020] Preferably, the ketone carbonyl derivative hydroxyalkylate is 2-hydroxy-2,3-diphenylpropionitrile or ethyl 2-hydroxy-2-methyl-3-phenylpropionate.

[0021] II. Electrochemical Reduction Coupling Synthesis Method

[0022] The method for electrochemical reduction coupling to synthesize hydroxylated alkane compounds according to the present invention includes the following steps: using carbonyl compounds and alkyl halides as reactants, in the presence of organic solvents and electrolytes, an electric current is passed through an unseparated electrolytic cell to carry out an electrolytic reaction, and after separation and purification, hydroxylated alkane compounds are obtained.

[0023] (a) Reactants

[0024] 1. Carbonyl compounds: including trifluoromethyl ketones, arylformyl cyanides, and oxocarboxylic acid esters.

[0025] The structural formula of trifluoromethyl ketone compounds is: CF3-CO-R1 (R1 is defined as above).

[0026] The preferred formaldehyde cyanide is benzoyl cyanide, and the oxocarboxylic acid ester is ethyl 2-oxopropionate.

[0027] Preferred trifluoromethyl ketone compounds are trifluoromethyl acetophenone, 4-methyltrifluoromethyl acetophenone, 4-tert-butyltrifluoromethyl acetophenone, 4-methoxytrifluoromethyl acetophenone, 4-phenyltrifluoromethyl acetophenone, 4-fluorotrifluoromethyl acetophenone, 4-chlorotrifluoromethyl acetophenone, 4-bromotrifluoromethyl acetophenone, 4-cyanotrifluoromethyl acetophenone, 3-chlorotrifluoromethyl acetophenone, 3-methyltrifluoromethyl acetophenone, 2-naphthyltrifluoromethyl acetophenone, 3,5-dimethyltrifluoromethyl acetophenone, 2-furanyltrifluoromethyl acetophenone, 2-thienyltrifluoromethyl acetophenone, 3-benzothienyltrifluoromethyl acetophenone, or 1,1,1-trifluoro-2-butanone.

[0028] 2. Alkyl halides: The structural formula is: R2-CH(R5)-X (R2 and R5 are defined as above), where X is a halogen, preferably bromine.

[0029] Preferred alkyl halides are benzyl bromide, 4-methylbenzyl bromide, 4-tert-butylbenzyl bromide, 4-phenylbenzyl bromide, 4-fluorobenzyl bromide, 4-chlorobenzyl bromide, 4-bromobenzyl bromide, 4-trifluoromethylbenzyl bromide, 4-methoxycarbonylbenzyl bromide, 3-chlorobenzyl bromide, 3-methylbenzyl bromide, 2-fluorobenzyl bromide, 2-cyanobenzyl bromide, 3,5-dimethylbenzyl bromide, 2-naphthylbenzyl bromide, (1-bromoethyl)benzene, (bromomethylene)diphenyl, 9-bromofluorene, cinnamyl bromide, or allyl bromide.

[0030] (ii) Reaction conditions

[0031] 1. Molar ratio: The molar ratio of carbonyl compound to alkyl halide is 1:2 to 3, preferably 1:3, based on the molar amount of carbonyl compound. This ratio ensures that the alkyl halide fully participates in the coupling reaction and improves the conversion rate of carbonyl compound.

[0032] 2. Electrolyte: It is a quaternary ammonium salt or lithium salt, and can be one or more of tetrabutylammonium bromide, tetrabutylammonium perchlorate, tetrabutylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, lithium tetrafluoroborate, or lithium perchlorate. Tetrabutylammonium bromide is preferred because it has good conductivity, excellent compatibility with the reaction system, and can effectively promote the electrolysis reaction. The amount of electrolyte used is 0.5 to 1.0 times that of tetrabutylammonium bromide, preferably 0.5 times that of tetrabutylammonium bromide, based on the molar amount of carbonyl compound. This reduces the amount of electrolyte used while ensuring reaction efficiency and lowering costs.

[0033] 3. Organic solvent: one or more of acetonitrile, N,N-dimethylacetamide or N,N-dimethylformamide, preferably anhydrous acetonitrile, which has good solubility and high electrochemical stability, can ensure that the reactants and electrolytes are fully dissolved, and does not participate in side reactions; the amount of solvent used must ensure that the reactants are completely dissolved, usually 4 mL of anhydrous acetonitrile is used for every 0.2 mmol of carbonyl compound.

[0034] 4. Electrode and Electrolysis Parameters: The anode of the electrolysis reaction is a tin electrode, and the cathode is a copper electrode. This electrode combination can achieve efficient reduction coupling of carbonyl compounds and alkyl halides, avoid unnecessary side reactions, and improve the yield and selectivity of the target product. The electrolysis reaction is carried out under a constant current of 5-15 mA, preferably 10 mA. The electrolysis reaction time is 1-3 hours, preferably 2 hours. The reaction is carried out at room temperature and in an air atmosphere, without the need for inert gas protection, which simplifies the operation and reduces the equipment requirements and operational difficulty of the reaction.

[0035] (III) Separation and purification

[0036] After the electrolysis reaction is completed, the pure product can be obtained by conventional separation and purification methods. The typical post-processing operation is as follows: pour the reaction solution into water, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry with anhydrous magnesium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography to obtain hydroxylated alkanes.

[0037] (iv) Reaction Mechanism

[0038] The reaction mechanism of this invention is as follows: At the cathode, the carbonyl compound undergoes single-electron reduction to generate a carbonyl radical anion intermediate; simultaneously, the alkyl halide is also reduced at the cathode to generate an alkyl radical; the two radical intermediates undergo efficient cross-coupling on or near the cathode surface to generate the target hydroxyl-substituted alkane compound. Oxidation occurs at the anode via a sacrificial tin electrode or oxidation by electrolyte anions, achieving efficient reaction without the need for a separate electrolytic cell. Taking trifluoromethyl ketone and benzyl bromide as examples, the mechanism is as follows: Figure 41 As shown.

[0039] Compared with the prior art, the beneficial effects of the present invention are:

[0040] (1) This invention discloses for the first time a set of hydroxy-substituted alkanes covering α-trifluoromethyl alcohols and hydroxyalkylated ketone carbonyl derivatives, and provides a method for synthesizing such compounds using a single electrochemical reduction coupling system, filling the technological gap in this field and providing a new green route for the synthesis of two important organic intermediates;

[0041] (2) The method of the present invention uses electrons as a cleaning reducing agent, which completely avoids the use of quantitative metal reducing agents (such as zinc and magnesium) and Lewis acids in traditional methods, conforms to the concept of green chemistry and sustainable development, and greatly reduces the generation of waste.

[0042] (3) The reaction of the present invention is carried out at room temperature, normal pressure and air atmosphere, without the need for inert gas protection, the operation is extremely simple, the equipment requirements are low, and it is suitable for laboratory and industrial production.

[0043] (4) The substrates of the present invention have a wide range of applications and good functional group compatibility. They have good tolerance to sensitive groups such as halogen, cyano, ester, and heterocyclic groups. They can cover substrates with various substitution forms such as aryl, heteroaryl, fused ring group, and alkenyl. The yield of the target product is moderate to excellent.

[0044] (5) The reaction of the present invention is carried out in an undivided electrolytic cell, which simplifies the reaction apparatus, and the electrolyte and organic solvent are easy to select and obtain, thus reducing the reaction cost;

[0045] (6) The method of the present invention is easy to scale up, can achieve gram-scale preparation, and has a stable yield of the target product, and has good prospects for industrial application. Attached Figure Description

[0046] Figure 1 The hydrogen NMR spectrum of the product of Example 1 of this invention;

[0047] Figure 2 The carbon NMR spectrum of the product in Example 1 of this invention;

[0048] Figure 3 The NMR fluorine spectrum of the product of Example 1 of this invention;

[0049] Figure 4 The hydrogen NMR spectrum of the product in Example 2 of this invention;

[0050] Figure 5 The carbon NMR spectrum of the product in Example 2 of this invention;

[0051] Figure 6 The NMR fluorine spectrum of the product in Example 2 of this invention;

[0052] Figure 7The hydrogen NMR spectrum of the product in Example 3 of this invention;

[0053] Figure 8 The carbon NMR spectrum of the product in Example 3 of this invention;

[0054] Figure 9 The NMR fluorine spectrum of the product in Example 3 of this invention;

[0055] Figure 10 The hydrogen NMR spectrum of the product in Example 4 of this invention;

[0056] Figure 11 The carbon NMR spectrum of the product in Example 4 of this invention;

[0057] Figure 12 The NMR fluorine spectrum of the product in Example 4 of this invention;

[0058] Figure 13 The hydrogen NMR spectrum of the product in Example 5 of this invention;

[0059] Figure 14 The carbon NMR spectrum of the product in Example 5 of this invention;

[0060] Figure 15 The NMR fluorine spectrum of the product in Example 5 of this invention;

[0061] Figure 16 The hydrogen NMR spectrum of the product in Example 6 of this invention;

[0062] Figure 17 The carbon NMR spectrum of the product in Example 6 of this invention;

[0063] Figure 18 The NMR fluorine spectrum of the product in Example 6 of this invention;

[0064] Figure 19 The hydrogen NMR spectrum of the product in Example 7 of this invention;

[0065] Figure 20 The carbon NMR spectrum of the product in Example 7 of this invention;

[0066] Figure 21 The NMR fluorine spectrum of the product in Example 7 of this invention;

[0067] Figure 22 The hydrogen NMR spectrum of the product in Example 8 of this invention;

[0068] Figure 23 The carbon NMR spectrum of the product in Example 8 of this invention;

[0069] Figure 24 The NMR fluorine spectrum of the product in Example 8 of this invention;

[0070] Figure 25The hydrogen NMR spectrum of the product in Example 9 of this invention;

[0071] Figure 26 The carbon NMR spectrum of the product in Example 9 of this invention;

[0072] Figure 27 The NMR fluorine spectrum of the product in Example 9 of this invention;

[0073] Figure 28 The hydrogen NMR spectrum of the product in Example 10 of this invention;

[0074] Figure 29 The carbon NMR spectrum of the product in Example 10 of this invention;

[0075] Figure 30 The NMR fluorine spectrum of the product in Example 10 of this invention;

[0076] Figure 31 The hydrogen NMR spectrum of the product of Example 11 of this invention;

[0077] Figure 32 The carbon NMR spectrum of the product in Example 11 of this invention;

[0078] Figure 33 The NMR fluorine spectrum of the product of Example 11 of this invention;

[0079] Figure 34 The hydrogen NMR spectrum of the product in Example 12 of this invention;

[0080] Figure 35 The carbon NMR spectrum of the product in Example 12 of this invention;

[0081] Figure 36 The NMR fluorine spectrum of the product in Example 12 of this invention;

[0082] Figure 37 The hydrogen NMR spectrum of the product in Example 13 of this invention;

[0083] Figure 38 The carbon NMR spectrum of the product in Example 13 of this invention;

[0084] Figure 39 The hydrogen NMR spectrum of the product in Example 14 of this invention;

[0085] Figure 40 The carbon NMR spectrum of the product in Example 14 of this invention;

[0086] Figure 41 This is a schematic diagram of the reaction mechanism of the present invention, using trifluoromethyl ketone and benzyl bromide as an example. Detailed Implementation

[0087] The present invention will be further described below with reference to specific embodiments.

[0088] Unless otherwise specified, the raw materials used in the embodiments are all commercially available conventional raw materials; unless otherwise specified, the process methods used in the embodiments are all conventional methods in the art.

[0089] Example 1

[0090] This invention synthesizes 1,1,1-trifluoro-2,3-diphenylpropane-2-ol, with the following structural formula:

[0091] .

[0092] The specific synthesis method is as follows: In a 25 mL unseparated electrolytic cell, trifluoromethylacetophenone (0.2 mmol, 34.8 mg), benzyl bromide (0.6 mmol, 102.6 mg), and tetrabutylammonium bromide (0.1 mmol, 32.2 mg) were added sequentially. Anhydrous acetonitrile (4 mL) was added using a syringe. A polished tin electrode (20 mm x 10 mm x 0.5 mm) was used as the anode, and a copper electrode (20 mm x 10 mm x 0.2 mm) was used as the cathode, inserted into the reaction mixture. Electrolysis was performed at a constant current of 10 mA for 2 h at room temperature and in air atmosphere. After electrolysis, the reaction mixture was poured into water (60 mL), filtered with diatomaceous earth, and extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1 v / v) to give a colorless oily product (45.3 mg, yield 85%, purity ≥95%). The proton, carbon, and fluorine spectra of the product are shown below. Figure 1-3 As shown. Characterization data:

[0093] 1 HNMR (400MHz, CDCl3) δ7.53(d,J=6.8Hz,2H),7.39-7.31(m,3H),7.22-7.15(m,3H),7.01-6.92(m,2H),3.50-3.35(m,2H),2.44(s,1H).

[0094] 13 CNMR(101MHz,CDCl3)δ137.1,133.1,130.8,128.5,128.4,128.3,127.5,126.4,125.6(q,J=287.2Hz),77.1(q,J=27.9Hz),41.9.

[0095] 19 FNMR (376MHz, CDCl3) δ -78.2.

[0096] HRMS(ESI)m / z:[M+Na]+calcdforC15H13F3NaO+289.0811; found289.0800.

[0097] Example 2

[0098] This invention synthesizes 1,1,1-trifluoro-2-phenyl-3-(p-tolyl)propane-2-ol, with the following structural formula:

[0099] .

[0100] The synthesis method involved replacing the benzyl bromide in Example 1 with an equimolar amount of 4-methylbenzyl bromide, with the remaining operations identical to those in Example 1. A colorless oily product was obtained (50.5 mg, yield 90%, purity ≥95%). The 1H, 1C, and fluorine spectra of the product are shown below. Figure 4-6 As shown. Characterization data:

[0101] 1 HNMR (400MHz, CDCl3) δ7.41(d,J=8.0Hz,2H),7.24-7.11(m,5H),7.05-6.92(m,2H),3.47-3.34(m,2H),2.38(s,1H),2.348(s,3H).

[0102] 13 CNMR(101MHz, CDCl3)δ138.4,134.1,133.2,130.8,129.0,128.5,127.5,126.4,125.6(q,J=286.6Hz),77.0(q,J=27.7Hz),41.7,21.1.

[0103] 19 FNMR (376MHz, CDCl3) δ-78.4.

[0104] Example 3

[0105] This invention synthesizes 1,1,1-trifluoro-3-(4-fluorophenyl)-2-phenylpropane-2-ol, with the following structural formula:

[0106] .

[0107] The synthesis method involved replacing the benzyl bromide in Example 1 with an equimolar amount of 4-fluorobenzyl bromide, with the remaining operations identical to those in Example 1. A colorless oily product was obtained (46.6 mg, yield 82%, purity ≥95%). The proton, carbon, and fluorine spectra of the product are shown below. Figure 7-9 As shown. Characterization data:

[0108] 1HNMR (400MHz, CDCl3) δ7.51(dd,J=8.8,5.6Hz,2H),7.24-7.17(m,3H),7.05(t,J=8.8Hz,2H),6.99-6.92(m,2H),3.45-3.35(m,2H),2.45(s,1H).

[0109] 13 CNMR(101MHz, CDCl3)δ162.8(d,J=248.8Hz),132.83(d,J=3.3Hz),132.79,130.7,128.6,128.5( dq,J=3.2,1.8Hz),127.7,125.4(q,J=287.4Hz),115.2(d,J=21.6Hz),76.8(q,J=28.1Hz),41.8.

[0110] 19 FNMR (376MHz, CDCl3) δ-78.5,-113.6.

[0111] Example 4

[0112] This invention synthesizes 1,1,1-trifluoro-2-(furan-2-yl)-3-phenylpropane-2-ol, with the following structural formula:

[0113] .

[0114] The synthesis method involved replacing the trifluoromethylacetophenone in Example 1 with an equimolar amount of 2-furanyltrifluoromethyl ketone, with the remaining operations identical to those in Example 1. A colorless oily product was obtained (24.6 mg, yield 48%, purity ≥95%). The proton, carbon, and fluorine spectra of the product are shown below. Figure 10-12 As shown. Characterization data:

[0115] 1 HNMR(400MHz, CDCl3)δ7.47(dd,J=1.6,1.2Hz,1H),7.25-7.19(m,3H),7.04-6.95(m, 2H),6.43-6.29(m,2H),3.52(d,J=13.6Hz,1H),3.26(d,J=13.6Hz,1H),2.60(s,1H).

[0116] 13 CNMR(101MHz, CDCl3)δ149.6,142.9,133.0,130.6,128.4,127.5,124.5(q,J=286.7Hz),110.9,110.0,75.4(q,J=29.6Hz),39.5.

[0117] 19 FNMR (376MHz, CDCl3) δ-80.0.

[0118] Example 5

[0119] This invention synthesizes 1,1,1-trifluoro-2-phenyl-3-(4-(trifluoromethyl)phenyl)propane-2-ol, with the following structural formula:

[0120] .

[0121] The synthesis method involved replacing the benzyl bromide in Example 1 with an equimolar amount of 4-trifluoromethylbenzyl bromide, with the remaining operations identical to those in Example 1. A colorless oily product was obtained (46.8 mg, yield 70%, purity ≥95%). The proton, carbon, and fluorine spectra of the product are shown below. Figure 13-15 As shown. Characterization data:

[0122] 1 HNMR (400MHz, CDCl3) δ7.56-7.49(m,2H),7.46(d,J=8.0Hz,2H),7.43-7.36(m,3H),7.12(d,J=8.4Hz,2H),3.54-3.42(m,2H),2.49(s,1H).

[0123] 13 CNMR(101MHz, CDCl3)δ137.6,136.3,16131.1,129.6(d,J=32.4Hz),128.8,128.4,126.6(d,J=14 9.6Hz), 126.2(q,J=1.4Hz), 125.0(q,J=3.6Hz), 123.4(d,J=125.6Hz), 77.4(q,J=28.5Hz), 41.6.

[0124] 19 FNMR (376MHz, CDCl3) δ-62.6,-78.5.

[0125] Example 6

[0126] This invention synthesizes methyl 4-(3,3,3-trifluoro-2-hydroxy-2-phenylpropyl)benzoate, with the following structural formula:

[0127] .

[0128] In Example 1, benzyl bromide was replaced with an equimolar amount of 4-methoxycarbonylbenzyl bromide, and the remaining procedures were the same as in Example 1. A colorless oily product was obtained (38.9 mg, yield 60%, purity ≥95%). The 1H, 1C, and fluorine spectra of the product are shown below. Figure 16-18 As shown. Characterization data:

[0129] 1 HNMR (400MHz, CDCl3) δ7.83(d,J=8.4Hz,2H),7.51-7.44(m,2H),7.39-7.32(m,3H),7.04(d,J=8.0Hz,2H),3.87(s,3H),3.46(s,2H),2.54(s,1H).

[0130] 13 CNMR (101 MHz, CDCl3) δ 166.9, 138.8, 136.4, 130.8, 129.4, 129.2,128.7, 128.4, 126.2, 125.5 (q, J = 287.3 Hz), 77.8 (q, J = 28.1 Hz), 52.1,41.8.

[0131] 19 FNMR (376MHz, CDCl3) δ-78.4.

[0132] Example 7

[0133] This invention synthesizes 3-(2-fluorophenyl)-1,1,1-trifluoro-2-phenylpropane-2-ol, with the following structural formula:

[0134] .

[0135] In Example 1, benzyl bromide was replaced with an equimolar amount of 2-fluorobenzyl bromide, and the remaining operations were the same as in Example 1. A colorless oily product was obtained (40.4 mg, yield 71%, purity ≥95%). The proton, carbon, and fluorine spectra of the product are shown below. Figure 19-21 As shown. Characterization data:

[0136] 1 HNMR(400MHz, CDCl3)δ7.57-7.47(m,2H),7.39-7.30(m,3H),7.21-7.13(m,1H),6.99(t,J=9.2Hz,1H),6.89(t,J =8.0Hz,1H),6.81(td,J=7.6,2.0Hz,1H),3.59(d,J=14.0Hz,1H),3.35(d,J=14.4Hz,1H),2.73(d,J=4.0Hz,1H).

[0137] 13 CNMR(101MHz, CDCl3)δ161.7(d,J=245.2Hz),136.2,132.6(d,J=4.1Hz),129.1(d,J=8.6Hz),128.5,128.2,126.3(d,J= 1.8Hz),125.6(q,J=287.2Hz),123.8(d,J=3.5Hz),120.7(d,J=15.0Hz),115.2(d,J=23.0Hz),77.4(q,J=28.0Hz),34.9.

[0138] 19 FNMR (376MHz, CDCl3) δ-78.9,-116.5.

[0139] Example 8

[0140] This invention synthesizes 2-([1,1'-biphenyl]-4-yl)-1,1,1-trifluoro-3-phenylpropane-2-ol, with the following structural formula:

[0141] .

[0142] In Example 1, trifluoromethylacetophenone was replaced with an equimolar amount of 4-phenyltrifluoromethylacetophenone, and the remaining procedures were the same as in Example 1. A white solid product was obtained (53.4 mg, yield 78%, purity ≥95%). The proton, carbon, and fluorine spectra of the product are shown below. Figure 22-24 As shown. Characterization data:

[0143] 1 HNMR(400MHz, CDCl3)δ7.57(d,J=7.6Hz,2H),7.55-7.48(m,2H),7.46-7.36(m,7 H),7.33(t,J=5.2Hz,1H),7.04(d,J=8.4Hz,2H),3.54-3.40(m,2H),2.46(s,1H).

[0144] 13 CNMR (101MHz, CDCl3) δ140.4,140.3,137.1,132.1,131.2,128.8,128.6,128.3,127. 4,127.1,127.0,126.5(d,J=1.6Hz),125.1(q,J=287.0Hz),77.4(q,J=28.3Hz),41.5.

[0145] 19FNMR (376MHz, CDCl3) δ-78.3.

[0146] Example 9

[0147] This invention synthesizes 1,1,1-trifluoro-2,3-diphenylbutane-2-ol, with the following structural formula:

[0148] .

[0149] In Example 1, benzyl bromide was replaced with an equimolar amount of (1-bromoethyl)benzene, and the remaining procedures were the same as in Example 1. A colorless oily product was obtained (44.8 mg, yield 80%, diastereomer mixture, purity ≥95%). The 1H, 1C, and fluorine spectra of the product are shown below. Figure 25-27 As shown. Characterization data:

[0150] 1 HNMR (400MHz, CDCl3) δ7.65(d,J=7.6Hz,2H),7.46-7.40(m,2H),7.39-7.30(m,6H),3.67(q,J=7.2Hz,1H),2.62(s,1H),1.03(d,J=6.8Hz,3H).

[0151] 13 CNMR(101MHz, CDCl3)δ140.5,137.1,128.8,128.7,128.4,128.3,127.6,125.8(q,J=1.7Hz),125.6(q,J=288.7Hz),79.7(q,J=26.3Hz),44.5,16.1.

[0152] 19 FNMR (376MHz, CDCl3) δ-71.3.

[0153] Example 10

[0154] This invention synthesizes 1-(9H-fluorene-9-yl)-2,2,2-trifluoro-1-phenylethane-1-ol, with the following structural formula:

[0155] .

[0156] In Example 1, benzyl bromide was replaced with an equimolar amount of 9-bromofluorene, and the remaining procedures were the same as in Example 1. A yellow solid product was obtained (56.5 mg, 83%, purity ≥95%). The proton, carbon, and fluorine spectra of the product are shown below. Figures 28-30 As shown. Characterization data:

[0157] 1HNMR(400MHz, CDCl3)δ7.67(t,J=6.8Hz,2H),7.62(d,J=7.2Hz,1H),7.54-7.46(m,2H),7.44-7.35(m, 4H),7.34-7.23(m,2H),6.98(td,J=7.6,1.2Hz,1H),6.34(d,J=8.0Hz,1H),4.77(s,1H),2.27(s,1H).

[0158] 13 CNMR(101MHz, CDCl3)δ142.8,142.3,141.0,139.8,137.4,128.8,128.5,128.3,128.2,127.9(q,J=3.2Hz),1 26.6(d,J=5.7Hz),126.5,126.4(d,J=1.7Hz),125.7(q,J=288.5Hz),119.7,119.6,79.7(q,J=27.9Hz),54.1.

[0159] 19 FNMR (376MHz, CDCl3) δ-71.3.

[0160] Example 11

[0161] This invention synthesizes 1,1,1-trifluoro-2,5-diphenylpent-4-en-2-ol, with the following structural formula:

[0162] .

[0163] In Example 1, benzyl bromide was replaced with an equimolar amount of cinnamyl bromide, and the remaining procedures were the same as in Example 1. A colorless oily product was obtained (43.8 mg, yield 75%, purity ≥95%). The proton, carbon, and fluorine spectra of the product are shown below. Figures 31-33 As shown. Characterization data:

[0164] 1 HNMR(400MHz, CDCl3)δ7.60(d,J=7.2Hz,2H),7.44-7.34(m,3H),7.29-7.18(m,5H),6.56(dt,J=2.4,1 .2Hz,1H),5.97-5.85(m,1H),3.11(dd,J=14.4,6.8Hz,1H),3.01(dd,J=14.0,8.0Hz,1H),2.65(s,1H).

[0165] 13CNMR (101MHz, CDCl3) δ137.0,136.8,136.4,128.7,128.6,128.5,128.0,126. 5(d,J=1.4Hz),126.4,125.4(q,J=286.6Hz),121.3,76.2(q,J=28.2Hz),39.7.

[0166] 19 FNMR (376MHz, CDCl3) δ -78.9.

[0167] Example 12

[0168] This invention synthesizes 1,1,1-trifluoro-2-phenylpent-4-en-2-ol, with the following structural formula:

[0169] .

[0170] In Example 1, benzyl bromide was replaced with an equimolar amount of allyl bromide, and the remaining operations were the same as in Example 1. A colorless oily product was obtained (29.4 mg, 68%, purity ≥95%). The proton, carbon, and fluorine spectra of the product are shown below. Figures 34-36 As shown. Characterization data:

[0171] 1 HNMR(400MHz, CDCl3)δ7.58(d,J=7.6Hz,2H),7.46-7.32(m,3H),5.62-5.48(m,1H),5.3 1-5.20(m,1H),2.99(dd,J=14.0,6.4Hz,1H),2.85(dd,J=14.4,8.0Hz,1H),2.61(s,1H).

[0172] 13 CNMR(101MHz, CDCl3)δ136.8,130.4,128.6,128.4,126.5,125.3(q,J=286.6Hz),122.1,75.8(q,J=28.4Hz),40.3.

[0173] 19 FNMR (376MHz, CDCl3) δ-79.2.

[0174] Example 13

[0175] This invention synthesizes 2-hydroxy-2,3-diphenylpropionitrile, with the following structural formula:

[0176] .

[0177] In Example 1, trifluoromethylacetophenone was replaced with an equimolar amount of benzoyl cyanide, and the remaining operations were the same as in Example 1. A colorless oily product was obtained (18.3 mg, yield 41%, purity ≥95%). The proton and carbon spectra of the product are shown below. Figures 37-38 As shown. Characterization data:

[0178] 1 HNMR (400MHz, CDCl3) δ8.03-8.00(m,2H),7.56(t,J=7.6,1H),7.46(t,J=8.0,2H),7.37-7.30(m,2H),7.30-7.21(m,3H),4.29(s,2H).

[0179] 13 CNMR (101MHz, CDCl3) δ197.6,136.7,134.6,133.2,129.5,128.69,128.66,128.6,126.9,45.5.

[0180] Example 14

[0181] This invention synthesizes ethyl 2-hydroxy-2-methyl-3-phenylpropionate, with the following structural formula:

[0182] .

[0183] In Example 1, trifluoromethylacetophenone was replaced with an equimolar amount of ethyl 2-oxopropionate, and the remaining procedures were the same as in Example 1. A colorless oily product was obtained (19.6 mg, yield 47%, purity ≥95%). The proton and carbon spectra of the product are shown below. Figures 39-40 As shown. Characterization data:

[0184] 1 HNMR(400MHz, CDCl3)δ7.32-7.25(m,3H),7.24-7.17(m,2H),4.32-4.02(m,2H ),3.10(s,1H),3.02(d,J=13.6Hz,2H),1.5222(s,3H),1.29(t,J=7.2Hz,3H).

[0185] 13 CNMR (101MHz, CDCl3) δ176.1,136.0,130.1,128.2,126.9,75.1,61.8,46.4,25.9,14.2.

[0186] Example 15

[0187] Scale-up reaction experiment of Example 1 of the present invention:

[0188] In a 100 mL unseparated electrolytic cell, trifluoromethylacetophenone (1.04 g, 6 mmol), benzyl bromide (3.08 g, 18 mmol), and tetrabutylammonium bromide (0.97 g, 3 mmol) were added. Anhydrous acetonitrile (80 mL) was added. A tin anode (4.0 cm × 4.0 cm × 0.05 cm) and a copper cathode (4.0 cm × 4.0 cm × 0.02 cm) were inserted. The electrolysis was carried out at 10 mA / cm² at room temperature. 2 Constant current density electrolysis with an electrode area of ​​2 cm² 2 The charge was increased to 6.0 F / mol. After electrolysis, the product (1.13 g, yield 71%, purity ≥95%) was obtained by the post-processing method in Example 1.

Claims

1. A method for electrochemical reduction coupling to synthesize hydroxylated alkane compounds, characterized in that, The process includes the following steps: using carbonyl compounds and alkyl halides as reactants, an electrolytic reaction is carried out in an unseparated electrolytic cell in the presence of an organic solvent and an electrolyte, with an electric current flowing through the reaction. After separation and purification, hydroxylated alkane compounds are obtained. The anode of the electrolytic reaction is a tin electrode, and the cathode is a copper electrode. The electrolytic reaction is carried out under a constant current of 5–15 mA for 1–3 hours. The reaction is carried out at room temperature in an air atmosphere. The carbonyl compounds include trifluoromethyl ketones, arbutin cyanides, and oxocarboxylic acid esters. The structural formula of the trifluoromethyl ketone compound is CF3-CO-R1. The arbutin cyanide is benzoyl cyanide, and the oxocarboxylic acid ester is ethyl 2-oxopropionate. The alkyl halide has the structural formula: R2-CH(R5)-X, where X is a halogen; The structural formula of the compound is: , , , , , , , , , , , , , .

2. The method for electrochemical reduction coupling to synthesize hydroxylated alkane compounds according to claim 1, characterized in that: The electrolyte is a quaternary ammonium salt or a lithium salt.

3. The method for electrochemical reduction coupling to synthesize hydroxylated alkane compounds according to claim 1, characterized in that: The organic solvent is one or more of acetonitrile, N,N-dimethylacetamide, and N,N-dimethylformamide.

4. The method for electrochemical reduction coupling to synthesize hydroxylated alkane compounds according to claim 1, characterized in that: The molar ratio of carbonyl compound to alkyl halide is 1:2 to 3, based on the molar amount of carbonyl compound.

5. The method for electrochemical reduction coupling to synthesize hydroxylated alkane compounds according to claim 1, characterized in that: The specific separation and purification operation is as follows: the reaction solution is poured into water, extracted with ethyl acetate, the organic phases are combined and washed with saturated brine, dried with anhydrous magnesium sulfate, filtered, concentrated, and the residue is purified by silica gel column chromatography to obtain hydroxylated alkane compounds.

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