Process for the synthesis of deuterium labeled substances containing deuterium atom building blocks

Abstract

The present application relates to a synthesis method of deuterium-labeled substances containing deuterium atom structural units, which comprises mixing aryl chloride with deuterium water in an organic solvent, adding a catalyst of ethylene glycol dimethyl ether-nickel dichloride and a ligand of 2,9-dimethyl-1,10-phenanthroline, and then reacting under the condition of zinc powder and nitrogen protection to obtain the deuterium element labeled compound. The present application uses ethylene glycol dimethyl ether-nickel dichloride as a catalyst, and aryl chloride can react with deuterium water to generate deuterium atom substitution products under the condition of nitrogen at normal temperature and pressure. The reaction condition is simple and mild. Meanwhile, the range of alternative substrates is more extensive, and the use of inexpensive nickel as a catalyst has higher economic value compared with the previous reports.

Description

Technical Field

[0001] This invention relates to a method for synthesizing deuterium-labeled substances containing deuterium atom structural units under normal pressure, belonging to the field of organic synthesis technology. Background Technology

[0002] Deuterium is a stable, non-radioactive isotope of hydrogen, exhibiting chemical properties comparable to hydrogen in certain reactions. Deuterated compounds have wide applications in various research fields, including isotope labeling, quantitative analysis, and pharmacokinetic analysis. Therefore, compounds containing deuterium labeling represent an important class of structural units, and the introduction of this group has significant research implications.

[0003] The promising prospects of deuterated drug molecules have attracted the attention of numerous research groups. Among these methods, the dehalogenation of aryl halides has become the preferred method for preparing deuterated products. With the development of cross-coupling reactions, the introduction of transition metals has facilitated the breaking of the CX bond. Improvements in dehalogenation reactions over the past five years have primarily involved using deuterated water as the deuterium source to achieve relatively mild dehalogenation of halides under photocatalytic or electrocatalytic conditions. For example, L. Lu, H. Li, Y. Zheng, F. Bu, A. Lei, Facile and Economical Electrochemical Dehalogenative Deuteration of (Hetero)Aryl Halides. CCS Chem., 2021, 3, 2669. provides a detailed report on the synthesis methods of these compounds. However, these methods have the following limitations: 1. Limited substrate applicability; 2. Use of expensive platinum as an electrode; 3. Incompatibility with sensitive substituents containing active hydrogen, etc.

[0004] Furthermore, CN115745720A discloses a method for the dehalogenation and deuteration of deuterated aromatic compounds. This method uses aromatic compounds as raw materials, palladium acetate, palladium chloride, palladium bromide, and palladium iodide as catalysts, heavy water, deuterated methanol, deuterated ethanol, and deuterated acetone as deuterium source reagents, and magnesium, aluminum, and zinc as reducing agents. The reaction is carried out by mechanical grinding. After the reaction, the product is separated and purified to obtain the deuterated compound. This method has advantages such as high operability, good deuteration effect, fast reaction rate, and solvent-free operation. However, this method has disadvantages such as poor functional group compatibility, and cannot perform dehalogenation and deuteration reactions on aryl halides containing active hydrogen functional groups such as amino and hydroxyl groups. Also, it mainly focuses on the dehalogenation and deuteration process of aryl bromide raw materials, with few reports on aryl chlorides. CN114054046A discloses the preparation and application of an Au / CdS composite photocatalytic material, using sodium sulfite as a sacrificial agent, water and acetonitrile (v:v = 1:1) as solvents, and Au / CdS as a catalyst, to carry out a deuteration reaction under an inert atmosphere and light irradiation (λ > 400 nm). CN115322065A discloses a method for the industrial production of deuterated pharmaceutical intermediate D using a combination of supported nickel and organic base catalysis. However, the use of relatively hazardous deuterium gas as a deuterium source poses safety challenges, and the high price of deuterium gas greatly limits the industrial-scale application of this method; furthermore, this method can only achieve deuteration at specific sites, which is limited compared to dehalogenation deuteration. CN111233716A discloses a nickel-catalyzed method for the preparation of α-deuterated chiral sulfonamide compounds. However, the main limitation of this method is that it can only perform deuteration at specific sites of the imine structure, resulting in a narrow substrate range for the deuteration reaction. Summary of the Invention

[0005] In view of the aforementioned state of the prior art, the technical problem to be solved by the present invention is to overcome the shortcomings of the prior art, which generally involves deuteration reactions under high conditions such as heating or high pressure, resulting in a narrow range of substrates that can be selected for deuteration reactions, and the need to further improve the deuteration rate and yield. The purpose of the present invention is to provide a method for synthesizing deuterated labeled substances containing deuterium atomic structural units that has a high yield, simple conditions, low waste emissions, simple reaction equipment, and is easy to industrialize.

[0006] The technical solution for achieving the above-mentioned objectives can be summarized as follows:

[0007] The method for synthesizing deuterium-labeled substances containing deuterium atom structural units includes the following steps:

[0008] Aryl chloride (I) was mixed with deuterated water in an organic solvent, and the catalyst ethylene glycol dimethyl ether-nickel dichloride and the ligand 2,9-dimethyl-1,10-o-phenanthroline were added. The mixture was then reacted in the presence of zinc powder and under nitrogen protection to prepare deuterium-labeled compound (II).

[0009] (I) is for Where R 1 It is selected from hydrogen, alkyl, alkoxy, aromatic, substituted aromatic, heterocyclic aromatic, hydroxyl, amino, aldehyde, ester, carbonyl, and / or cyano.

[0010] According to the present invention, preferably, the organic solvent is dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone.

[0011] According to the present invention, preferably, the reaction temperature is 15°C to 40°C, and more preferably 20°C to 35°C.

[0012] According to the present invention, preferably, the reaction pressure is 1 atm to 3 atm, more preferably 1 atm to 1.5 atm.

[0013] According to the present invention, preferably, the molar ratio of aryl chloride to deuterated water is 1:3 to 1:20, more preferably 1:5 to 1:10.

[0014] According to the present invention, preferably, the molar ratio of aryl chloride to ethylene glycol dimethyl ether-nickel dichloride is 1:1 to 20:1, more preferably 5:1 to 20:1.

[0015] According to the present invention, preferably, the molar ratio of aryl chloride to 2,9-dimethyl-1,10-o-phenanthroline is 1:1 to 10:1, more preferably 1:1 to 5:1.

[0016] According to the present invention, preferably, the molar ratio of aryl chloride to zinc powder is 1:1 to 1:5, more preferably 1:2 to 1:3.

[0017] According to the present invention, preferably, after the reaction is completed, ethyl acetate is added to quench the reaction. Preferably, the reaction further includes a separation and purification step:

[0018] After quenching the reaction, the product was washed with brine to separate the organic phase. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and separated by column chromatography to obtain the target product.

[0019] According to the present invention, preferably, the deuterium-labeled compound (II) is selected from at least one of the following compounds:

[0020]

[0021] The beneficial effects of this invention are as follows:

[0022] 1. This invention uses ethylene glycol dimethyl ether-nickel dichloride as a catalyst, enabling the reaction of aryl chlorides with deuterated water to generate deuterated products under nitrogen atmosphere, ambient temperature and pressure. The reaction conditions are simple and mild. Furthermore, it allows for a wider range of substrate choices and uses inexpensive nickel as a catalyst, making it more economically valuable than previously reported methods.

[0023] 2. Compared with traditional synthesis methods, the method of the present invention has many advantages such as high yield, simple conditions, low waste discharge, simple reaction equipment, and easy industrial production. Detailed Implementation

[0024] The present invention provides a method for synthesizing deuterium-labeled substances containing deuterium atom structural units, comprising the following steps:

[0025] Aryl chloride (I) was mixed with deuterated water in an organic solvent, and the catalyst ethylene glycol dimethyl ether-nickel dichloride and the ligand 2,9-dimethyl-1,10-o-phenanthroline were added. The mixture was then reacted in the presence of zinc powder and under nitrogen protection to prepare deuterium-labeled compound (II).

[0026] (I) is for Where R 1 It is selected from hydrogen, alkyl, alkoxy, aromatic, substituted aromatic, heterocyclic aromatic, hydroxyl, amino, aldehyde, ester, carbonyl, and / or cyano.

[0027] According to the present invention, the deuteration reaction is carried out in an organic solvent. The highest deuteration rate and yield are achieved with N,N-dimethylacetamide, followed by N,N-dimethylformamide. The yields and deuteration rates of N-methylpyrrolidone and dimethyl sulfoxide are lower than those of the aforementioned two solvents. Furthermore, these solvents are readily soluble in water, offering advantages over existing technologies such as simplified operation and purification.

[0028] In one or more preferred embodiments, the organic solvent is dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, or N-methylpyrrolidone.

[0029] According to the present invention, the deuteration reaction can be carried out at room temperature and pressure, without the need for higher temperatures and pressures. Compared with the prior art, the reaction conditions are milder. At higher temperatures and pressures, no significant increase in reaction yield and deuteration rate was observed.

[0030] In one or more preferred embodiments, the reaction temperature is 15°C to 40°C, preferably 20°C to 35°C.

[0031] In one or more preferred embodiments, the reaction pressure is 1 atm to 3 atm, preferably 1 atm to 1.5 atm.

[0032] According to the present invention, the catalyst for the deuteration reaction is ethylene glycol dimethyl ether-nickel dichloride, with 2,9-dimethyl-1,10-o-phenanthroline as a ligand. As a catalyst, ethylene glycol dimethyl ether-nickel dichloride coordinates and activates with 2,9-dimethyl-1,10-o-phenanthroline in the reaction system to form a key nickel intermediate, which will be used to catalyze subsequent reaction processes.

[0033] According to the present invention, zinc powder is used as a reducing agent in the reaction system to complete the reduction process of the nickel catalyst.

[0034] According to the present invention, regarding the proportions of the various materials, a higher deuteration rate and yield can be obtained when the molar ratio of aryl chloride to deuterated water is 1:5. When the molar ratio of deuterated water is further increased, the deuteration rate and yield of the reaction will not show a significant increase. Furthermore, when the molar ratio of ethylene glycol dimethyl ether-nickel dichloride, 2,9-dimethyl-1,10-o-phenanthroline, or zinc powder is further increased, the deuteration rate and yield of the reaction will not change significantly.

[0035] In one or more preferred embodiments, the molar ratio of aryl chloride to deuterated water is 1:3 to 1:20, preferably 1:5 to 1:10.

[0036] In one or more preferred embodiments, the molar ratio of aryl chloride to ethylene glycol dimethyl ether-nickel dichloride is 1:1 to 20:1, preferably 5:1 to 20:1.

[0037] In one or more preferred embodiments, the molar ratio of aryl chloride to 2,9-dimethyl-1,10-o-phenanthroline is 1:1 to 10:1, preferably 1:1 to 5:1.

[0038] In one or more preferred embodiments, the molar ratio of aryl chloride to zinc powder is 1:1 to 1:5, preferably 1:2 to 1:3.

[0039] According to the present invention, the above-mentioned deuteration reaction system has better operability due to its milder reaction temperature and simpler reaction conditions compared to previous reports. Since the relevant reaction proceeds via a reductive coupling mechanism, the reaction route has good compatibility with substituent groups.

[0040] According to the present invention, after the reaction is completed, the process further includes quenching the reaction and separation and purification steps:

[0041] The reaction was quenched by adding ethyl acetate, washed with brine, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate, the organic phases were combined, and the target product was obtained by column chromatography.

[0042] The present invention will be described in detail below through specific embodiments, but is not limited thereto.

[0043] The room temperature mentioned in the embodiment is 15℃~35℃, and the atmospheric pressure is 1atm.

[0044] Example 1: Synthesis of 5-d-1,3-dimethoxybenzene

[0045]

[0046] a): Take a 25 mL Schlenk reaction tube, add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 35 mg of 1-chloro-3,5-dimethoxybenzene, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. Under nitrogen protection, stir at room temperature for 12 hours. After the reaction is complete, add 10 mL of ethyl acetate to quench the reaction, wash with 5 mL of brine, separate the organic phase, extract the aqueous phase three times with ethyl acetate, combine the organic phases, and separate by column chromatography to obtain 26 mg of pure 5-d-1,3-dimethoxybenzene, with a yield of 95% and a deuteration rate greater than 99%.

[0047] b): Take a 25 mL Schlenk reaction tube, add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 35 mg of 1-chloro-3,5-dimethoxybenzene, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. Under nitrogen protection, stir at room temperature for 12 hours. After the reaction is complete, add 10 mL of ethyl acetate to quench the reaction, wash with 5 mL of brine, separate the organic phase, extract the aqueous phase three times with ethyl acetate, combine the organic phases, and separate by column chromatography to obtain 25 mg of pure 5-d-1,3-dimethoxybenzene, with a yield of 91% and a deuteration rate of 98%.

[0048] c): Take a 25 mL Schlenk reaction tube, add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 35 mg of 1-chloro-3,5-dimethoxybenzene, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. Under nitrogen protection, stir at room temperature for 12 hours. After the reaction is complete, add 10 mL of ethyl acetate to quench the reaction, wash with 5 mL of brine, separate the organic phase, extract the aqueous phase three times with ethyl acetate, combine the organic phases, and separate by column chromatography to obtain 24 mg of pure 5-d-1,3-dimethoxybenzene, with a yield of 89% and a deuteration rate greater than 99%.

[0049] d): Take a 25 mL Schlenk reaction tube, add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 35 mg of 1-chloro-3,5-dimethoxybenzene, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. Under nitrogen protection, stir at room temperature for 12 hours. After the reaction is complete, add 10 mL of ethyl acetate to quench the reaction, wash with 5 mL of brine, separate the organic phase, extract the aqueous phase three times with ethyl acetate, combine the organic phases, and separate by column chromatography to obtain 25 mg of pure 5-d-1,3-dimethoxybenzene, with a yield of 91% and a deuteration rate of 96%.

[0050] e): Take a 25 mL Schlenk reaction tube, add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 35 mg of 1-chloro-3,5-dimethoxybenzene, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. Under nitrogen protection, stir at room temperature for 12 hours. After the reaction is complete, add 10 mL of ethyl acetate to quench the reaction, wash with 5 mL of brine, separate the organic phase, extract the aqueous phase three times with ethyl acetate, combine the organic phases, and separate by column chromatography to obtain 23 mg of pure 5-d-1,3-dimethoxybenzene, with a yield of 86% and a deuteration rate of 98%.

[0051] f): Take a 25 mL Schlenk reaction tube, add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 35 mg of 1-chloro-3,5-dimethoxybenzene, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. Under nitrogen protection, stir at room temperature for 12 hours. After the reaction is complete, add 10 mL of ethyl acetate to quench the reaction, wash with 5 mL of brine, separate the organic phase, extract the aqueous phase three times with ethyl acetate, combine the organic phases, and separate by column chromatography to obtain 20 mg of pure 5-d-1,3-dimethoxybenzene, with a yield of 72% and a deuteration rate of 95%.

[0052] g): Take a 25 mL Schlenk reaction tube, add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 35 mg of 1-chloro-3,5-dimethoxybenzene, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. Under nitrogen protection, stir at room temperature for 12 hours. After the reaction is complete, add 10 mL of ethyl acetate to quench the reaction, wash with 5 mL of brine, separate the organic phase, extract the aqueous phase three times with ethyl acetate, combine the organic phases, and separate by column chromatography to obtain 19 mg of pure 5-d-1,3-dimethoxybenzene, with a yield of 71% and a deuteration rate of 92%.

[0053] h): Take a 25 mL Schlenk reaction tube, add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 35 mg of 1-chloro-3,5-dimethoxybenzene, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. Under nitrogen protection, stir at room temperature for 12 hours. After the reaction is complete, add 10 mL of ethyl acetate to quench the reaction, wash with 5 mL of brine, separate the organic phase, extract the aqueous phase three times with ethyl acetate, combine the organic phases, and separate by column chromatography to obtain 25 mg of pure 5-d-1,3-dimethoxybenzene, with a yield of 91% and a deuteration rate of 96%.

[0054] i): Take a 25 mL Schlenk reaction tube, add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 35 mg of 1-chloro-3,5-dimethoxybenzene, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. Under nitrogen protection, stir at room temperature for 12 hours. After the reaction is complete, add 10 mL of ethyl acetate to quench the reaction, wash with 5 mL of brine, separate the organic phase, extract the aqueous phase three times with ethyl acetate, combine the organic phases, and separate by column chromatography to obtain 17 mg of pure 5-d-1,3-dimethoxybenzene, with a yield of 61% and a deuteration rate of 90%.

[0055] j): Take a 25 mL Schlenk reaction tube, add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 35 mg of 1-chloro-3,5-dimethoxybenzene, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. Under nitrogen protection, stir at room temperature for 12 hours. After the reaction is complete, add 10 mL of ethyl acetate to quench the reaction, wash with 5 mL of brine, separate the organic phase, extract the aqueous phase three times with ethyl acetate, combine the organic phases, and separate by column chromatography to obtain 14 mg of pure 5-d-1,3-dimethoxybenzene, with a yield of 52% and a deuteration rate of 81%.

[0056] k): Take a 25 mL Schlenk reaction tube, add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 35 mg of 1-chloro-3,5-dimethoxybenzene, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. Under nitrogen protection, stir at room temperature for 12 hours. After the reaction is complete, add 10 mL of ethyl acetate to quench the reaction, wash with 5 mL of brine, separate the organic phase, extract the aqueous phase three times with ethyl acetate, combine the organic phases, and separate by column chromatography to obtain 27 mg of pure 5-d-1,3-dimethoxybenzene, with a yield of 98% and a deuteration rate of 96%.

[0057] l): Take a 25 mL Schlenk reaction tube, add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 35 mg of 1-chloro-3,5-dimethoxybenzene, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. Under nitrogen protection, stir at room temperature for 12 hours. After the reaction is complete, add 10 mL of ethyl acetate to quench the reaction, wash with 5 mL of brine, separate the organic phase, extract the aqueous phase three times with ethyl acetate, combine the organic phases, and separate by column chromatography to obtain 26 mg of pure 5-d-1,3-dimethoxybenzene, with a yield of 96% and a deuteration rate of 99%.

[0058] m): Take a 25 mL Schlenk reaction tube, add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 35 mg of 1-chloro-3,5-dimethoxybenzene, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. Under nitrogen protection, stir at room temperature for 12 hours. After the reaction is complete, add 10 mL of ethyl acetate to quench the reaction, wash with 5 mL of brine, separate the organic phase, extract the aqueous phase three times with ethyl acetate, combine the organic phases, and separate by column chromatography to obtain 26 mg of pure 5-d-1,3-dimethoxybenzene, with a yield of 95% and a deuteration rate of 98%.

[0059] n): Take a 25 mL Schlenk reaction tube, add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 35 mg of 1-chloro-3,5-dimethoxybenzene, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. Under nitrogen protection, stir at room temperature for 12 hours. After the reaction is complete, add 10 mL of ethyl acetate to quench the reaction, wash with 5 mL of brine, separate the organic phase, extract the aqueous phase three times with ethyl acetate, combine the organic phases, and separate by column chromatography to obtain 25 mg of pure 5-d-1,3-dimethoxybenzene, with a yield of 91% and a deuteration rate of 94%.

[0060] o): Take a 25 mL Schlenk reaction tube, add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 35 mg of 1-chloro-3,5-dimethoxybenzene, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. Under nitrogen protection, stir at room temperature for 12 hours. After the reaction is complete, add 10 mL of ethyl acetate to quench the reaction, wash with 5 mL of brine, separate the organic phase, extract the aqueous phase three times with ethyl acetate, combine the organic phases, and separate by column chromatography to obtain 24 mg of pure 5-d-1,3-dimethoxybenzene, with a yield of 86% and a deuteration rate of 92%.

[0061] p): In a 25 mL Schlenk reaction tube, add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 35 mg of 1-chloro-3,5-dimethoxybenzene, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. Stir at room temperature for 12 hours under nitrogen protection. After the reaction is complete, add 10 mL of ethyl acetate to quench the reaction, wash with 5 mL of brine, separate the organic phase, and extract the aqueous phase three times with ethyl acetate. Combine the organic phases and separate by column chromatography to obtain 25 mg of pure 5-d-1,3-dimethoxybenzene (90% yield, 99% deuteration).

[0062] 1 H NMR (500MHz, CDCl3) δ6.52–6.51(m,2H),6.48–6.47(m,1H),3.79(s,6H); 13 CNMR(125MHz, CDCl3)δ160.78,129.58(t,J=27.5Hz),105.97,100.35,55.22; HRMS(ESI)m / z([M+H] + )Calcd.for C8H 10 DO2 139.0744, found:139.0741.

[0063] Example 2: Synthesis of 1-d-naphthalene

[0064]

[0065] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 35 mg of 1-chloronaphthalene, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 24 mg of pure 1-d-naphthalene, with a yield of 91% and a deuteration rate of 90%.

[0066] 1 H NMR (500MHz, CDCl3) δ7.85–7.83(m,3.1H),7.49–7.46(m,4H); 13 C NMR (125MHz, CDCl3) δ 133.37, 133.30, 127.84, 127.80, 127.52 (t, J = 24.5Hz), 125.79, 125.70; HRMS (ESI) m / z ([M+H]+ )Calcd.for C 10 H8D 130.0762, found:130.0768.

[0067] Example 3: Synthesis of 9-d-phenanthrene

[0068]

[0069] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 43 mg of 9-chlorophenanthrene, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, and column chromatography was used to separate 27 mg of pure 9-d-phenanthrene, with a yield of 75% and a deuteration rate of 96%.

[0070] 1 H NMR (500MHz, CDCl3) δ8.67(d,J=8.0Hz,2H),7.87(d,J=8.0Hz,2H),7.72(s,1H),7.63(t,J=7.0Hz,2H),7.58(t,J=7.0Hz,2H).; 13 C NMR (125MHz, CDCl3) δ 132.02, 131.96, 130.27, 128.54, 128.48, 126.76, 126.57 (t, J = 24.0Hz), 126.52, 122.63.; HRMS (ESI) m / z ([M+H] + )Calcd.for C 14 H 10 D 180.0918, found: 180.0916.

[0071] Example 4: Synthesis of 1-d-2-methoxynaphthalene

[0072]

[0073] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 38 mg of 1-chloro-2-naphthyl methyl ether, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, and column chromatography was used to obtain 31 mg of pure 1-d-2-methoxynaphthalene, with a yield of 96% and a deuteration rate of 99%.

[0074] 1 H NMR (500MHz, CDCl3) δ7.68–7.63(m,3H),7.36–7.32(m,1H),7.26–7.22(m,1H),7.07–7.05(m,1H),3.81(s,3H).; 13 C NMR (125MHz, CDCl3) δ 157.46, 134.43, 129.33, 128.86, 127.61, 126.63, 126.32, 123.53, 118.69, 105.32 (t, J = 24.0Hz), 55.22.; HRMS (ESI) m / z ([M+H] + )Calcd.for C 11 H 10 DO 160.0867, found:160.0869.

[0075] Example 5: Synthesis of 4-d-benzyloxybenzene

[0076]

[0077] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 44 mg of 4-benzyloxychlorobenzene, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 30 mg of pure 4-d-benzyloxybenzene, with a yield of 82% and a deuteration rate of 90%.

[0078] 1H NMR (500MHz, CDCl3) δ7.36–7.35(m,2H),7.31–7.28(m,2H),7.25–7.24(m,1H),7.22–7.20(m,2H),6.91–6.89(m,2H),4.98(s,2H).; 13 C NMR (125MHz, CDCl3) δ 158.73, 137.02, 129.34, 128.54, 127.90, 127.45, 120.62 (t, J = 24.5Hz), 114.78, 69.85.; HRMS (ESI) m / z ([M+H] + )Calcd.for C 13 H 12 DO 186.1024, found:186.1031.

[0079] Example 6: Synthesis of 4-d-acetophenone

[0080]

[0081] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-phenanthroline, 31 mg of 4-chloroacetophenone, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 21 mg of pure 4-d-acetophenone, with a yield of 86% and a deuteration rate of 99%.

[0082] 1 H NMR (500MHz, CDCl3) δ7.97–7.96(m,2H),7.48–7.46(m,2H),2.61(s,3H).; 13 CNMR (125MHz, CDCl3) δ198.14, 137.07, 132.77 (t, J = 24.5Hz), 128.42, 128.27, 26.60.; HRMS (ESI) m / z ([M+H] + )Calcd.for C8H8DO 122.0711,found:122.0713.

[0083] Example 7: Synthesis of 4-d-3-methylacetophenone

[0084]

[0085] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 34 mg of 4-chloro-3-methylacetophenone, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 25 mg of pure 4-d-3-methylacetophenone, with a yield of 94% and a deuteration rate of 99%.

[0086] 1 H NMR (500MHz, CDCl3) δ7.69–7.66(m,2H),7.27–7.25(m,2H),2.50(s,3H),2.32(s,3H).; 13 C NMR (125MHz, CDCl3) δ198.33, 138.16, 137.03, 133.45 (t, J = 24.5Hz), 128.70, 128.24, 125.49, 26.60, 21.19.; HRMS (ESI) m / z ([M+H] + )Calcd.for C9H 10 DO 136.0867, found:136.0870.

[0087] Example 8: Synthesis of 4-d-benzophenone

[0088]

[0089] A 25 mL Schlenk reaction tube was used to add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-phenanthroline, 43 mg of 4-chlorobenzophenone, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was complete, 10 mL of ethyl acetate was added to quench the reaction. The mixture was washed with 5 mL of brine, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 34 mg of pure 4-d-benzophenone, with a yield of 94% and a deuteration rate of 90%.

[0090] 1 H NMR (500MHz, CDCl3) δ7.74–7.73(m,4H),7.54–7.50(m,1.1H),7.43–7.40(m,4H).; 13C NMR (125MHz, CDCl3) δ196.74, 137.57, 132.39, 132.09 (t, J = 25.0Hz), 130.04, 128.25, 128.14.; HRMS (ESI) m / z ([M+H] + )Calcd.for C 13 H 10 DO 184.0867, found:184.0869.

[0091] Example 9: Synthesis of 5-d-1-indanone

[0092]

[0093] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 33 mg of 5-chloro-1-indanone, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, and column chromatography was used to separate 25 mg of pure 5-d-1-indanone, with a yield of 92% and a deuteration rate of 91%.

[0094] 1 H NMR (500MHz, CDCl3) δ7.76(d,J=7.5Hz,1H),7.59(t,J=7.5Hz,0.09H),7.48(s,1H),7.37(d,J=7.5Hz,1H),3.16–3.14(m,2H),2.71–2.58(m,2H).; 13 C NMR (125MHz, CDCl3) δ207.02, 155.12, 137.06, 134.25 (t, J = 24.0Hz), 127.13, 126.55, 123.68, 36.19, 25.77.; HRMS (ESI) m / z ([M+H] + )Calcd.for C9H8DO 134.0711,found:134.0716.

[0095] Example 10: Synthesis of 4-d-benzaldehyde

[0096]

[0097] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 28 mg of p-chlorobenzaldehyde, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 25 mg of pure 4-d-benzaldehyde, with a yield of 87% and a deuteration rate of 99%.

[0098] 1 H NMR (500MHz, CDCl3) δ10.03 (s, 1H), 7.89 (d, J = 8.0Hz, 2H), 7.55 (d, J = 8.0Hz, 2H).; 13 C NMR (125MHz, CDCl3) δ192.38, 136.39, 134.45 (t, J = 25.0Hz), 129.73, 128.87.; HRMS (ESI) m / z ([M+H] + )Calcd.for C7H6DO 108.0554,found:108.0552.

[0099] Example 11: Synthesis of 2-d-3-hydroxybenzaldehyde

[0100]

[0101] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 40 mg of 2-bromo-3-hydroxybenzaldehyde, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, and column chromatography was used to obtain 21 mg of pure 2-d-3-hydroxybenzaldehyde, with a yield of 85% and a deuteration rate of 99%.

[0102] 1 H NMR (500MHz, CDCl3) δ9.96 (s, 1H), 7.46–7.41 (m, 2H), 7.13 (m, 1H), 5.79 (s, 1H); 13 C NMR(125MHz, CDCl3)δ192.27,156.38,137.81,130.35,123.35,122.01,114.77.; HRMS(ESI)m / z([M+H]+ )Calcd.for C7H6DO2 124.0503,found:124.0500.

[0103] Example 12: Synthesis of methyl 4-d-phenylacetate

[0104]

[0105] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-phenanthroline, 37 mg of methyl 4-chlorophenylacetate, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 25 mg of pure methyl 4-d-phenylacetate, with a yield of 83% and a deuteration rate of 96%.

[0106] 1 H NMR (500MHz, CDCl3) δ7.31 (d, J = 8.0Hz, 2H), 7.28 (s, J = 8.0Hz, 2H), 3.68 (s, 3H), 3.62 (s, 2H).; 13 C NMR (125MHz, CDCl3) δ171.96, 133.91, 129.18, 128.40, 126.75 (t, J = 24.5Hz), 51.97, 41.14.; HRMS (ESI) m / z ([M+H] + )Calcd.for C9H 10 DO2 152.0816,found:152.0817.

[0107] Example 13: Synthesis of dimethyl 5-d-isophthalate

[0108]

[0109] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 46 mg of dimethyl 5-chloroisophthalate, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 29 mg of pure dimethyl 5-d-isophthalate, with a yield of 75% and a deuteration rate of 90%.

[0110] 1 H NMR (500MHz, CDCl3) δ8.61–8.60(m,1H),8.15–8.14(m,2H),7.46(t,J=9.5,0.1H),3.87(m,6H).; 13 C NMR (125MHz, CDCl3) δ166.16, 133.63, 130.62, 130.46, 128.28 (t, J = 27.0Hz), 52.32.; HRMS (ESI) m / z ([M+H] + )Calcd.for C 10 H 10 DO4 196.0715,found:196.0719.

[0111] Example 14: Synthesis of methyl 2-d-benzoate

[0112]

[0113] A 25 mL Schlenk reaction tube was used to add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-phenanthroline, 34 mg of methyl 2-chlorobenzoate, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was complete, 10 mL of ethyl acetate was added to quench the reaction. The mixture was washed with 5 mL of brine, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 23 mg of pure methyl 2-d-benzoate, with a yield of 85% and a deuteration rate of 98%.

[0114] 1 H NMR (500MHz, CDCl3) δ7.99–7.96(m,1H),7.50–7.46(m,1H),7.38–7.35(m,2H),3.84(s,3H).; 13 C NMR (125MHz, CDCl3) δ167.06, 132.87, 130.01, 129.51, 129.24 (t, J = 24.5Hz), 128.31, 128.19, 52.06.; HRMS (ESI) m / z ([M+H] + )Calcd.for C8H8DO2 138.0660,found:138.0668.

[0115] Example 15: Synthesis of methyl 3-d-2-methylbenzoate

[0116]

[0117] A 25 mL Schlenk reaction tube was used to add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 37 mg of methyl 3-chloro-2-methylbenzoate, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was complete, 10 mL of ethyl acetate was added to quench the reaction. The mixture was washed with 5 mL of brine, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 27 mg of pure methyl 3-d-2-methylbenzoate, with a yield of 90% and a deuteration rate of 99%.

[0118] 1 H NMR (500MHz, CDCl3) δ7.82(d,J=7.5Hz,1H),7.30(d,J=7.5Hz,1H),7.15(t,J=7.5Hz,1H),3.80(s,3H),2.51(s,3H).; 13 C NMR (125MHz, CDCl3) δ167.00, 140.03, 131.77, 131.29 (t, J = 24.5Hz), 130.50, 129.50, 125.61, 51.71, 21.58.; HRMS (ESI) m / z ([M+H] + )Calcd.for C9H 10 DO2 152.0816,found:152.0824.

[0119] Example 16: Synthesis of ethyl 3,5-d2-benzoate

[0120]

[0121] A 25 mL Schlenk reaction tube was used to add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 44 mg of ethyl 3,5-dichlorobenzoate, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was complete, 10 mL of ethyl acetate was added to quench the reaction. The mixture was washed with 5 mL of brine, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 24 mg of pure ethyl 3,5-d2-benzoate, with a yield of 80% and a deuteration rate of 99%.

[0122] 1H NMR (500 MHz, CDCl3) δ8.51 (s, 2H), 7.55 (s, 1H), 4.38 (q, J = 7.0 Hz, 2H), 1.40 (t, J = 7.0 Hz, 2H).; 13 C NMR (125 MHz, CDCl3) δ 166.60, 132.54, 130.46, 129.38, 127.97 (t, J = 24.0Hz), 60.91, 14.30.; HRMS (ESI) m / z ([M+H] + )Calcd.for C9H9D2O2 153.0879,found:153.0886.

[0123] Example 17: Synthesis of 4-(4-d-phenyl)morpholine

[0124]

[0125] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 46 mg of 4-(4-chlorophenyl)morpholine, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 30 mg of pure 4-(4-d-phenyl)morpholine, with a yield of 90% and a deuteration rate of 99%.

[0126] 1 H NMR (500 MHz, CDCl3) δ7.29 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.5 Hz, 2H), 3.87–3.85 (m, 4H), 3.16–3.15 (m, 4H).; 13 C NMR (125 MHz, CDCl3) δ151.23, 129.04, 119.75 (t, J = 24.5Hz), 115.67, 66.91, 49.34.; HRMS (ESI) m / z ([M+H] + )Calcd.for C 10 H 13 DNO 165.1133,found:165.1130.

[0127] Example 18: Synthesis of 4-d-phenylacetonitrile

[0128]

[0129] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 28 mg of p-chlorobenzonitrile, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 17 mg of pure 4-d-phenylacetonitrile, with a yield of 94% and a deuteration rate of 90%.

[0130] 1 H NMR (500MHz, CDCl3) δ7.67 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 0.1H), 7.48 (d, J = 8.0 Hz, 2H).; 13 C NMR (125MHz, CDCl3) δ132.64 (t, J = 24.5Hz), 132.13, 128.98, 118.83, 112.43.; HRMS (ESI) m / z ([M+H] + )Calcd.for C7H5DN 105.0558,found:105.0564.

[0131] Example 19: Synthesis of 4-dN,N-dimethylaniline

[0132]

[0133] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 31 mg of 4-chloro-N,N-dimethylaniline, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 22 mg of pure 4-dN,N-dimethylaniline, with a yield of 89% and a deuteration rate of 99%.

[0134] 1 H NMR (500MHz, CDCl3) δ7.24(m,2H),6.75(m,2H),2.94(s,6H).; 13C NMR(125MHz, CDCl3)δ150.58,128.92,116.63,112.64,40.62.; HRMS(ESI)m / z([M+H] + )Calcd.for C8H 11 DN123.1027, found:123.1020.

[0135] Example 20: Synthesis of 4-d-phenylmethyl sulfone

[0136]

[0137] A 25 mL Schlenk reaction tube was used to add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 38 mg of 4-chlorophenylmethyl sulfone, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was complete, 10 mL of ethyl acetate was added to quench the reaction. The mixture was washed with 5 mL of brine, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 27 mg of pure 4-d-phenylmethyl sulfone, with a yield of 87% and a deuteration rate of 96%.

[0138] 1 H NMR (500MHz, CDCl3) δ7.88 (d, J = 7.5Hz, 2H), 7.51 (d, J = 7.5Hz, 2H), 3.00 (s, 3H).; 13 C NMR (125MHz, CDCl3) δ140.38, 133.37 (t, J = 24.5Hz), 129.20, 127.26, 44.42.; HRMS (ESI) m / z ([M+H] + )Calcd.for C7H8DO2S158.0381,found:158.0384.

[0139] Example 21: Synthesis of 4-d-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzene

[0140]

[0141] A 25 mL Schlenk reaction tube was used to add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 48 mg of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)chlorobenzene, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was complete, 10 mL of ethyl acetate was added to quench the reaction. The mixture was washed with 5 mL of brine, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 38 mg of pure 4-d-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzene, with a yield of 92% and a deuteration rate of 99%.

[0142] 1 H NMR (500MHz, CDCl3) δ7.74 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 1.27 (s, 12H).; 13 C NMR (125MHz, CDCl3) δ 134.69, 130.94 (t, J = 30.0Hz), 127.57, 83.73, 24.84.; HRMS (ESI) m / z ([M+H] + )Calcd.for C 12 H 17 DBO2 206.1457,found:206.1454.

[0143] Example 22: Synthesis of 2-dN-phenylaniline

[0144]

[0145] A 25 mL Schlenk reaction tube was used to add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 46 mg of 2-chloro-N-phenylaniline, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was complete, 10 mL of ethyl acetate was added to quench the reaction. The mixture was washed with 5 mL of brine, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 32 mg of pure 2-dN-phenylaniline, with a yield of 80% and a deuteration rate of 99%.

[0146] 1H NMR(500MHz,DMSO-d6)δ10.25(s,H),7.98–7.96(m,2H),7.71–7.79(m,1H),7 .61–7.58(m,1H),7.55–7.52(m,2H),7.38–7.35(m,2H),7.12–7.09(m,1H).; 13 C NMR(125MHz,DMSO-d6)δ166.02,139.58,135.47,131.97,129.04,128.94,12 8.82,128.11,124.09,120.81,120.55(t,J=25.0Hz).;HRMS(ESI)m / z([M+H] + )Calcd.for C 13 H 11 DNO199.0976, found:199.0979.

[0147] Example 23: Synthesis of phenyl 2-d-benzoate

[0148]

[0149] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 64 mg of phenyl 2-iodobenzoate, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 36 mg of pure phenyl 2-d-benzoate, with a yield of 89% and a deuteration rate of 99%.

[0150] 1 H NMR (500MHz, CDCl3) δ8.21–8.19(m,2H),7.62–7.59(m,1H),7.50–7.47(m,2H),7.43–7.39(m,2H),7.27–7.23(m,1H),7.22–7.20(m,1H).; 13 C NMR(125MHz, CDCl3)δ165.07,150.88,133.48,130.08,129.54,129.40,129.30,128.49,125.79,121.63,121.37(t,J=25.0Hz).; HRMS(ESI)m / z([M+H] + )Calcd.for C13 H 10 DO2 200.0816,found:200.0821.

[0151] Example 24: Synthesis of 5-d-1-methyl-1H-indole

[0152]

[0153] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 33 mg of 5-chloro-1-methyl-1H-indole, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 24 mg of pure 5-d-1-methyl-1H-indole, with a yield of 90% and a deuteration rate of 99%.

[0154] 1 H NMR (500MHz, CDCl3) δ7.56–7.54(m,1H),7.25–7.23(m,1H),7.15–7.13(m,1H),6.96(d,J=7.0Hz,1H),6.41(dd,J=7.0Hz,1H),3.70(s,3H).; 13 C NMR (125MHz, CDCl3) δ 136.65, 128.72, 128.42, 121.33, 120.70, 118.94 (t, J = 24.5Hz), 109.12, 100.84, 32.76.; HRMS (ESI) m / z ([M+H] + )Calcd.for C9H9DN 133.0871,found:133.0877.

[0155] Example 25: Synthesis of 4-d-indole

[0156]

[0157] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 30 mg of 4-chloroindole, 18 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, and column chromatography was used to separate 17 mg of pure 4-d-indole, with a yield of 70% and a deuteration rate of 73%.

[0158] 1 H NMR (500MHz, CDCl3) δ7.99(s,1H),7.65(d,J=8.0Hz,0.27H),7.33(d,J=8.0Hz,1H),7.20–7.17(m,1H),7.13–7.10(m,2H),6.54–6.53(m,1H); 13 C NMR (125MHz, CDCl3) δ 135.68, 127.66, 124.11, 121.90, 120.66, 120.37 (t, J = 25.5Hz), 119.74, 119.62.; HRMS (ESI) m / z ([M+H] + )Calcd.for C8H7DN 119.0714,found:119.0723.

[0159] Example 26: Synthesis of 5-d-indole

[0160]

[0161] A 25 mL Schlenk reaction tube was used to add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 30 mg of 5-chloroindole, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was complete, 10 mL of ethyl acetate was added to quench the reaction. The mixture was washed with 5 mL of brine, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 17 mg of pure 5-d-indole, with a yield of 72% and a deuteration rate of 80%.

[0162] 1H NMR (500MHz, CDCl3) δ8.05 (s, 1H), 7.65 (d, J = 8.0Hz, 1H), 7.36 (s, 1H), 7.21–7. 18(m,0.2H),7.15(t,J=3.0Hz,1H),7.12(d,J=8.0Hz,1H),6.55–6.54(m,1H).; 13 C NMR (125MHz, CDCl3) δ135.69, 127.64, 124.10, 121.64 (t, J = 25.0Hz), 120.67, 119.04, 110.88, 102.52.; HRMS (ESI) m / z ([M+H] + )Calcd.for C8H7DN 119.0714,found:119.0721.

[0163] Example 27: Synthesis of 2-d-thioxanthone

[0164]

[0165] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-phenanthroline, 49 mg of 2-chlorothioxanthone, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 38 mg of pure 2-d-thioxanthone, with a yield of 90% and a deuteration rate of 90%.

[0166] 1 H NMR (500MHz, CDCl3) δ8.63–8.61(m,2H),7.63–7.56(m,4H),7.50–7.46(m,1.1H).; 13 C NMR (125MHz, CDCl3) δ 179.92, 137.23, 132.22, 132.12, 129.82, 129.71, 129.18, 126.26, 125.98 (t, J = 25.5Hz), 125.94.; HRMS (ESI) m / z ([M+H] + )Calcd.for C 13 H8DOS214.0431,found:214.0427.

[0167] Example 28: Synthesis of 4-d-aniline

[0168]

[0169] A 25 mL Schlenk reaction tube was used to add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 26 mg of 4-chloroaniline, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was complete, 10 mL of ethyl acetate was added to quench the reaction. The mixture was washed with 5 mL of brine, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 16 mg of pure 4-d-aniline, with a yield of 87% and a deuteration rate of 80%.

[0170] 1 H NMR (500MHz, CDCl3) δ7.17–7.14(m,2H),6.76(t,J=7.0Hz,0.2H),6.69(m,2H),3.61(s,2H).; 13 C NMR (125MHz, CDCl3) δ146.27, 129.26, 129.14, 118.29 (t, J = 24.5Hz), 115.08.; HRMS (ESI) m / z ([M+H] + )Calcd.for C6H7DN 95.0714,found:95.0711.

[0171] Example 29: Synthesis of 3-d-aniline

[0172]

[0173] A 25 mL Schlenk reaction tube was used to add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 26 mg of 3-chloroaniline, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was complete, 10 mL of ethyl acetate was added to quench the reaction. The mixture was washed with 5 mL of brine, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 15 mg of pure 3-d-aniline, with a yield of 82% and a deuteration rate of 76%.

[0174] 1 H NMR (500MHz, CDCl3) δ7.15 (t, J=7.5Hz, 1.24H), 6.75 (d, J=7.5Hz, 1H), 6.69–6.67 (m, 2H), 3.44 (s, 2H).; 13C NMR (125MHz, CDCl3) δ146.30, 129.23, 128.95 (t, J = 23.5Hz), 118.40, 115.07, 114.97.; HRMS (ESI) m / z ([M+H] + )Calcd.for C6H7DN 95.0714,found:95.0720.

[0175] Example 30: Synthesis of 2-d-aniline

[0176]

[0177] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 26 mg of 2-chloroaniline, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, and column chromatography was used to obtain 17 mg of pure 2-d-aniline in 88% yield with a deuteration rate of 99%.

[0178] 1 H NMR (500MHz, CDCl3) δ7.10–7.06(m,2H),6.68(t,J=7.0Hz,1H),6.66–6.60(m,1H),3.37(s,2H).; 13 C NMR (125MHz, CDCl3) δ146.26, 129.24, 129.14, 118.53, 115.09, 114.80 (t, J = 24.0Hz).; HRMS (ESI) m / z ([M+H] + )Calcd.for C6H7DN 95.0714,found:95.0715.

[0179] Example 31: Synthesis of 2-d-4-chloroaniline

[0180]

[0181] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 51 mg of 2-iodo-4-chloroaniline, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 18 mg of pure 2-d-4-chloroaniline, with a yield of 71% and a deuteration rate of 99%.

[0182] 1 H NMR (500MHz, CDCl3) δ7.03–7.00(m,2H),6.53–6.51(m,1H),3.48(br,2H).; 13 CNMR (125MHz, CDCl3) δ144.85, 129.06, 128.97, 123.11, 116.20, 115.91 (t, J = 24.0Hz).; HRMS (ESI) m / z ([M+H] + )Calcd.for C6H6DClN 129.0324,found:129.0321.

[0183] Example 32: Synthesis of 2-d-4-bromoaniline

[0184]

[0185] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 51 mg of 2-iodo-4-bromoaniline, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, and column chromatography was used to obtain 26 mg of pure 2-d-4-bromoaniline, with a yield of 74% and a deuteration rate of 99%.

[0186] 1 H NMR (500MHz, CDCl3) δ7.16–7.14(m,2H),6.48–6.46(m,1H),3.48(br,2H).; 13CNMR (125MHz, CDCl3) δ145.31, 131.94, 131.85, 116.66, 116.38 (t, J = 24.0Hz), 110.12.; HRMS (ESI) m / z ([M+H] + )Calcd.for C6H6DBrN 172.9819,found:172.9826.

[0187] Example 33: Synthesis of 4-d-phenol

[0188]

[0189] A 25 mL Schlenk reaction tube was used to add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 44 mg of 4-iodophenol, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was complete, 10 mL of ethyl acetate was added to quench the reaction. The mixture was washed with 5 mL of brine, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 18 mg of pure 4-d-phenol, with a yield of 92% and a deuteration rate of 86%.

[0190] 1 H NMR (500MHz, CDCl3) δ7.22(d,J=8.0Hz,2H),6.92(t,J=8.0Hz,0.14H),6.83(d,J=8.0Hz,2H),5.76–5.71(br,1H).; 13 C NMR (125MHz, CDCl3) δ155.29, 129.54, 120.79, 120.52 (t, J = 25.5Hz), 115.32.; HRMS (ESI) m / z ([M+H] + )Calcd.for C6H6DO 96.0554,found:96.0559.

[0191] Example 34: Synthesis of 2-d-phenol

[0192]

[0193] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 44 mg of 2-iodophenol, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 18 mg of pure 2-d-phenol, with a yield of 93% and a deuteration rate of 99%.

[0194] 1 H NMR (500MHz, CDCl3) δ7.24–7.21(m,2H),6.94–6.90(m,1H),6.84–6.82(m,1H),5.67(br,1H).; 13 C NMR (125MHz, CDCl3) δ155.32, 129.63, 129.54, 120.75, 115.33, 115.06 (t, J = 24.0Hz).; HRMS (ESI) m / z ([M+H] + )Calcd.for C6H6DO 96.0554,found:96.0552.

[0195] Example 35: Synthesis of methyl 3-d-4-hydroxybenzoate

[0196]

[0197] A 25 mL Schlenk reaction tube was used to add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 56 mg of methyl 4-hydroxy-3-iodobenzoate, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was complete, 10 mL of ethyl acetate was added to quench the reaction. The mixture was washed with 5 mL of brine, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 27 mg of pure methyl 3-d-4-hydroxybenzoate, with a yield of 87% and a deuteration rate of 99%.

[0198] 1 H NMR (500MHz, CDCl3) δ7.88–7.86(m,2H),6.83–6.81(m,1H),6.73(s,1H),3.82(s,3H).; 13C NMR (125MHz, CDCl3) δ167.58, 160.40, 131.93, 131.84, 122.09, 115.31, 115.05 (t, J = 24.5Hz), 52.09.; HRMS (ESI) m / z ([M+H] + )Calcd.for C8H8DO3 154.0609,found:154.0616.

[0199] Example 36: Synthesis of 2-d-4-chlorophenol

[0200]

[0201] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 51 mg of 4-chloro-2-iodophenol, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 23 mg of pure 2-d-4-chlorophenol, with a yield of 90% and a deuteration rate of 99%.

[0202] 1 H NMR (500MHz, CDCl3) δ7.19–7.18(m,2H),6.78–6.76(m,1H),5.14(br,1H).; 13 CNMR (125MHz, CDCl3) δ154.28, 129.48, 129.40, 125.48, 116.72, 116.45 (t, J = 24.5Hz).; HRMS (ESI) m / z ([M+H] + )Calcd.for C6H5DClO 130.0164,found:130.0170.

[0203] Example 37: Synthesis of 2-d-4-bromophenol

[0204]

[0205] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 60 mg of 4-bromo-2-iodophenol, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 22 mg of pure 2-d-4-bromophenol, with a yield of 63% and a deuteration rate of 99%.

[0206] 1 H NMR (500MHz, CDCl3) δ7.27–7.24(m,2H),6.66–6.64(m,1H),5.01(br,1H).; 13 CNMR (125MHz, CDCl3) δ154.57, 132.44, 132.36, 117.19, 116.92 (t, J = 24.0Hz), 112.84.; HRMS (ESI) m / z ([M+H] + )Calcd.for C6H5DBrO 173.9659,found:173.9663.

[0207] Example 38: Synthesis of 2,6-d2-aniline

[0208]

[0209] A 25 mL Schlenk reaction tube was used to add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 50 mg of 2,6-dibromoaniline, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was complete, 10 mL of ethyl acetate was added to quench the reaction. The mixture was washed with 5 mL of brine, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 14 mg of pure 2,6-d2-aniline, with a yield of 73% and a deuteration rate of 93%.

[0210] 1 H NMR (500MHz, CDCl3) δ7.08 (d, J = 7.5Hz, 2H), 6.68 (t, J = 7.5Hz, 1H), 6.61 (d, J = 7.5Hz, 0.15H), 3.54 (br, 2H).; 13C NMR (125MHz, CDCl3) δ146.19, 129.13, 118.51, 115.07, 114.79 (t, J = 24.0Hz).; HRMS (ESI) m / z ([M+H] + )Calcd.for C6H6D2N 96.0777,found:96.0785.

[0211] Example 39: Synthesis of Isopropyl (Phenyl-3-d) Carbamate

[0212]

[0213] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 43 mg of chloraniline, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 31 mg of pure isopropyl (phenyl-3-d) carbamate, with a yield of 85% and a deuteration rate of 80%.

[0214] 1 H NMR (500MHz, CDCl3) δ7.39–7.38(m,2H),7.30–7.27(m,1.20H),7.05–7.03(m,1H),6.68(s,1H),1.29(s,6H).; 13 C NMR (125MHz, CDCl3) δ153.21, 138.06, 128.94, 128.66 (t, J = 24.5Hz), 123.14, 123.03, 118.51, 68.63, 22.04.; HRMS (ESI) m / z ([M+H] + )Calcd.forC 10 H 13 DNO2 181.1082,found:181.1089.

[0215] Example 40: Synthesis of ethyl 2-methyl-2-(phenoxy-4-d)propionate

[0216]

[0217] A 25 mL Schlenk reaction tube was used to add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 49 mg of chlorofibrate, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was complete, 10 mL of ethyl acetate was added to quench the reaction. The mixture was washed with 5 mL of brine, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 31 mg of pure ethyl 2-methyl-2-(phenoxy-4-d)propionate, with a yield of 75% and a deuteration rate of 99%.

[0218] 1 H NMR (500MHz, CDCl3) δ7.24(d,J=8.5Hz,2H),6.85(d,J=8.5Hz,2H),4.24(q,J=7.5Hz,2H),1.60(s,6H),1.24(t,J=7.5Hz,3H).; 13 C NMR (125MHz, CDCl3) δ174.32, 155.38, 128.99, 121.77 (t, J = 24.5Hz), 119.05, 78.99, 61.37, 25.35, 14.04.; HRMS (ESI) m / z ([M+H] + )Calcd.for C 12 H 16 DO3 210.1235,found:210.1234.

[0219] Example 41: Synthesis of isopropyl 2-(4-(benzoyl-4-d)phenoxy)-2-methylpropionate

[0220]

[0221] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 72 mg of isopropyl 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionate, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 45 mg of pure isopropyl 2-(4-(benzoyl-4-d)phenoxy)-2-methylpropionate, with a yield of 69% and a deuteration rate of 99%.

[0222] 1H NMR (500MHz, CDCl3) δ7.76(t,J=9.0Hz,4H),7.47(d,J=9.0Hz,2H),6.87(d,J=9.0Hz,2H),5.09(sept,J=8.0Hz,1H),1.66(s,6H),1.21(d,J=8.0Hz,6H).; 13 C NMR(125MHz, CDCl3)δ195.48,173.11,159.49,138.10,132.00,131.60(t,J=24.0Hz) ,130.55,129.68,128.03,117.11,79.32,69.26,25.33,21.48.;HRMS(ESI)m / z([M+H] + )Calcd.forC 20 H 22 DO4328.1654, found:328.1659.

[0223] Example 42: Synthesis of 2-(4-d-phenyl)-3-methyl-4H-1,3-tetrahydrothiazin-4-one-1,1-dioxide

[0224]

[0225] A 25 mL Schlenk reaction tube was used to add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 72 mg of phenanthroline, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was complete, 10 mL of ethyl acetate was added to quench the reaction. The mixture was washed with 5 mL of brine, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 38 mg of pure 2-(4-d-phenyl)-3-methyl-4H-1,3-tetrahydrothiazin-4-one-1,1-dioxide, with a yield of 78% and a deuteration rate of 99%.

[0226] 1 H NMR (500MHz, CDCl3) δ7.42(d,J=8.0Hz,2H),7.32(d,J=8.0Hz,2H),5.22(s,1H),3.29–3.25(m,1H),3.12–3.04(m,3H),2.90(s,3H).; 13C NMR (125MHz, CDCl3) δ166.11, 130.12 (t, J = 24.5Hz), 130.08, 129.15, 128.04, 80.57, 43.24, 36.20, 30.52.; HRMS (ESI) m / z ([M+H] + )Calcd.for C 11 H 13 DNO3S241.0752,found:241.0757.

[0227] Example 43: Synthesis of 5-((3,5-dimethylphenoxy-4-d)methyl)oxazoline-2-one

[0228]

[0229] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 51 mg of 5-((4-chloro-3,5-dimethylphenoxy)methyl)oxazoline-2-one, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 28 mg of pure 5-((3,5-dimethylphenoxy-4-d)methyl)oxazoline-2-one, with a yield of 62% and a deuteration rate of 99%.

[0230] 1 H NMR (500MHz, CDCl3) δ6.65(s,2H),6.11(s,1H),4.97–4.92(m,1H),4.10–4.09(m,2H),3.76(t,J=8.5Hz,1H),3.61–3.58(m,1H),2.34(s,6H).; 13 C NMR(125MHz, CDCl3)δ159.49,155.89,137.32,127.16,114.63,74.13,68.22,42.65,20.88.; HRMS(ESI)m / z([M+H] + )Calcd.for C 12 H 15 DNO3 223.1187,found:223.1190.

[0231] Example 44: Synthesis of 4-d-9-methoxy-7H-furano[3,2-g]dihydropyran-7-one

[0232]

[0233] A 25 mL Schlenk reaction tube was used to add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 59 mg of 4-bromo-9-methoxy-7H-furano[3,2-g]dihydropyran-7-one, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was complete, 10 mL of ethyl acetate was added to quench the reaction. The mixture was washed with 5 mL of brine, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 30 mg of pure 4-d-9-methoxy-7H-furano[3,2-g]dihydropyran-7-one, with a yield of 68% and a deuteration rate of 90%.

[0234] 1 H NMR (500MHz, CDCl3) δ7.77(d,J=4.7Hz,1H),7.69(d,J=1.3Hz,1H),7.35(s,0.1H),6.82(d,J=1.3Hz,1H),6.37(d,J=4.7Hz,1H),4.30(s,3H).; 13 C NMR (125MHz, CDCl3) δ160.39,147.70,146.60,144.24,142.99,132.77,126.00,11 6.39,114.71,112.88,112.59(t,J=25.5Hz),106.66,61.29.;HRMS(ESI)m / z([M+H] + )Calcd.for C 12 H8DO4218.0558,found:218.0563.

[0235] Example 45: Synthesis of 2-d-isopropyl 5-(2,5-dimethylphenoxy)-2,2-dimethylvalerate

[0236]

[0237] A 25 mL Schlenk reaction tube was used, and 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 90 mg of 2-iodoisopropyl5-(2,5-dimethylphenoxy)-2,2-dimethylvalerate, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was completed, 10 mL of ethyl acetate was added to quench the reaction, and the mixture was washed with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 41 mg of pure 2-d-isopropyl5-(2,5-dimethylphenoxy)-2,2-dimethylvalerate, with a yield of 62% and a deuteration rate of 99%.

[0238] 1 H NMR(500MHz, CDCl3)δ7.25–7.22(m,2H),7.10–7.07(m,1H),6.93–6.88(m,2H)6.56–6.5 2(m,2H),3.87–3.85(m,2H),2.20(s,3H),2.08(s,3H),1.78–1.77(m,4H),1.26(s,6H).; 13 C NMR (125MHz, CDCl3) δ176.16,156.80,150.91,136.33,130.27,129.24,129.14,125.52,123.51,121.42,121 .16(t,J=25.0Hz),120.69,111.88,67.69,42.31,37.08,25.20,25.06,21.31,15.71.;HRMS(ESI)m / z([M+H] + )Calcd.for C 21 H 26 DO3 328.2017,found:328.2020.

[0239] Example 46: Synthesis of 2-d-phenyl(S)-2-(6-methoxy-2-naphthalene)propionate

[0240]

[0241] A 25 mL Schlenk reaction tube was used to add 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 86 mg of 2-iodophenyl(S)-2-(6-methoxy-2-naphthalene)propionate, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was complete, 10 mL of ethyl acetate was added to quench the reaction. The mixture was washed with 5 mL of brine, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 43 mg of pure 2-d-phenyl(S)-2-(6-methoxy-2-naphthalene)propionate, with a yield of 70% and a deuteration rate of 99%.

[0242] 1 H NMR (500MHz, CDCl3) δ7.89–7.82(m,3H),7.63–7.61(m,1H),7.42–7.39(m,2H),7.29–7.2 3(m,3H),7.12–7.10(m,1H),4.20(q,J=7.0Hz,1H),3.97(s,3H),1.81(d,J=7.0Hz,3H).; 13 C NMR (125MHz, CDCl3) δ173.01,157.66,150.72,135.06,133.74,129.21,129.18,129.08,128.90,127.27,126. 03,126.00,125.60,121.28,121.00(J=25.0Hz),118.99,105.55,55.12,45.46,18.41.;HRMS(ESI)m / z([M+H] + )Calcd.for C 20 H 18 DO3308.1391,found:308.1400.

[0243] Example 47: Synthesis of 2-d-phenyl-4-(N,N-dipropylaminosulfonyl)phenyl ester

[0244]

[0245] A 25 mL Schlenk reaction tube was used, containing 2.2 mg of ethylene glycol dimethyl ether-nickel dichloride, 2.1 mg of 2,9-dimethyl-1,10-o-phenanthroline, 97 mg of 2-iodophenyl 4-(N,N-dipropylaminosulfonyl)phenyl ester, 36 μL of deuterated water, and 0.5 mL of N,N-dimethylacetamide. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was complete, 10 mL of ethyl acetate was added to quench the reaction, followed by washing with 5 mL of brine. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and separated by column chromatography to obtain 48 mg of pure 2-d-phenyl 4-(N,N-dipropylaminosulfonyl)phenyl ester, with a yield of 66% and a deuteration rate of 99%.

[0246] 1 H NMR (500MHz, CDCl3) δ8.22–8.20(m,2H),7.85–7.84(m,2H),7.35–7.32(m,2H),7.20–7. 17(m,1H),7.13–7.11(m,1H),3.05–3.02(m,4H),1.49–1.44(m,4H),0.80–0.77(m,6H).; 13 C NMR (125MHz, CDCl3) δ163.64,150.45,144.74,132.70,130.60,129.41,129.31,126. 99,126.03,121.31,121.05(t,J=25.0),49.80,21.78,11.00.;HRMS(ESI)m / z([M+H] + )Calcd.for C 19 H 23 DNO4S 363.1483,found:363.1488.

[0247] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A method for synthesizing deuterium-labeled substances containing deuterium atom structural units, comprising the following steps: Aryl chloride (I) was mixed with deuterated water in an organic solvent, and the catalyst ethylene glycol dimethyl ether-nickel dichloride and the ligand 2,9-dimethyl-1,10-o-phenanthroline were added. The mixture was then reacted in the presence of zinc powder and under nitrogen protection to prepare deuterium-labeled compound (II). Where R 1 Selected from hydrogen, alkyl, alkoxy, aromatic, substituted aromatic, heterocyclic aromatic, hydroxyl, amino, aldehyde, ester, carbonyl, and / or cyano; The deuterium-labeled compound (II) is selected from at least one of the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 2. The method for synthesizing deuterium-labeled substances containing deuterium atom structural units according to claim 1, characterized in that, The organic solvent is dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, or N-methylpyrrolidone.

3. The method for synthesizing deuterium-labeled substances containing deuterium atom structural units according to claim 1, characterized in that, The reaction temperature is 15℃~40℃.

4. The method for synthesizing deuterium-labeled substances containing deuterium atom structural units according to claim 1, characterized in that, The reaction pressure is 1 atm to 3 atm.

5. The method for synthesizing deuterium-labeled substances containing deuterium atom structural units according to claim 1, characterized in that, The molar ratio of aryl chloride to deuterated water is 1:3 to 1:

20.

6. The method for synthesizing deuterium-labeled substances containing deuterium atom structural units according to claim 1, characterized in that, The molar ratio of aryl chloride to ethylene glycol dimethyl ether-nickel dichloride is 1:1 to 20:

1.

7. The method for synthesizing deuterium-labeled substances containing deuterium atom structural units according to claim 1, characterized in that, The molar ratio of aryl chloride to 2,9-dimethyl-1,10-o-phenanthroline is 1:1 to 10:

1.

8. The method for synthesizing deuterium-labeled substances containing deuterium atom structural units according to claim 1, characterized in that, The molar ratio of aryl chloride to zinc powder is 1:1 to 1:

5.

9. The method for synthesizing deuterium-labeled substances containing deuterium atom structural units according to claim 1, characterized in that, After the reaction was completed, ethyl acetate was added to quench the reaction, followed by washing with brine to separate the organic phase. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and separated by column chromatography to obtain the target product.

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