CN115057803B - S- (methyl-d) 3 ) Synthesis method and application of phenyl sulfide substance - Google Patents

S- (methyl-d) 3 ) Synthesis method and application of phenyl sulfide substance Download PDF

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CN115057803B
CN115057803B CN202210899216.0A CN202210899216A CN115057803B CN 115057803 B CN115057803 B CN 115057803B CN 202210899216 A CN202210899216 A CN 202210899216A CN 115057803 B CN115057803 B CN 115057803B
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邵欣欣
张燕
刘雯
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Hangzhou Normal University
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Abstract

The invention discloses S- (methyl-d) 3 ) A method for synthesizing phenyl sulfide substances and application thereof. Firstly, adding sodium sulfonate with different substituents into a container, and then adding D 3 P-toluenesulfonyl methyl ester and organic solvent react for 2 to 10 hours at normal temperature to obtain S- (methyl-d) 3 ) And (3) a phenyl sulfide substance. The invention also provides S- (methyl-d) 3 ) The application of phenyl sulfide as electrophilic tridentate methylating reagent with aryl iodide derivative or terminal alkyne derivative as substrate. The product of the invention is used as an electrophilic tridentate methylating reagent, has stable structure, easy storage and high reaction activity. The method has the advantages of good substrate solubility, wide applicability and high reaction yield. The method has few side reactions, green and high efficiency.

Description

S- (methyl-d) 3 ) Synthesis method and application of phenyl sulfide substance
Technical Field
The invention belongs to the technical field of chemistry, and relates to S- (methyl-d) 3 ) The synthesizing process and application of phenyl sulfide matter are applied in preparing thio-deuterated methylated product through reaction with different electrophiles and nucleophiles in the presence of different catalysts.
Background
Bioisosteres with deuterium atoms as hydrogen atoms are well known to various chemists for their wide application in drug discovery and development. The important characteristics of the method are that the bond length of the C-D bond is shorter, the vibration frequency is lower, and the dissociation energy is higher than that of the C-H bond, so that the absorption, distribution, metabolism and excretion of certain medicine molecules can be directly influenced, and the effectiveness, tolerance and safety of the medicine are improved. Therefore, deuterium atoms make minor modifications to the hydrogen-containing drug molecules to achieve reduced drug toxicity, altered pharmacokinetics, and enhanced desired biopharmaceutical or physical properties without altering the advantageous effects of the original drug. The thiodeuteromethyl group, which is an important member of the substituent group containing deuterium atoms, is widely present in numerous natural products and medicines and plays a vital role in improving the biological activity and physical properties of molecules. Due to the existence of deuterium atoms, and for molecules containing thiodeuteromethyl, the preparation of the compounds in high yield and the excellent deuteration rate (> 99%) are the difficulties and challenges existing in the field at present.
At present, the synthesis of organic molecules containing the thiodeuteromethyl is mainly carried out by reacting a highly toxic and malodorous thiophenol or thiol substrate with electrophilic deuteromethylation, and the strategy often needs a characteristic substrate, has poor functional group compatibility, and also has the defect of the variety of deuteromethylation reagents to limit the further application of the method (Wang, M.Y.; zhao, Y.F.; zhao.Y.; shi, Z.Z. science Adv,2020,6,1-7). The direct thio-deuterated methylation method overcomes the defects, and the universality of the substrate is greatly enhanced. In this strategy, the development and application of electrophilic deuterated methylating agents is an effective method, but the variety of highly efficient electrophilic agents is quite lacking, and the corresponding electrophilic deuterated methylating agents are prepared by deuterated DMSO or deuterated sodium borohydride, which requires about 40 equivalents of deuterated DMSO, and the cost is quite high, and the deuteration rate can only reach 97% at the highest. In the subsequent direct introduction of the thiodeuterated methyl group, the deuteration rate of the product was only 97% and could not meet the requirements of the relevant thiodeuterated drug (Huang, c.m.; li, j.; ai, j.j.; liu, x.y.; rao, w.d.; wamg, s.y. Org. Lett,2020, 22, 9128-9132). Deuterated methyl triflate prepared from inexpensive readily available deuterated methanol can be prepared as a "one pot" process with the addition of heat and additional additives to facilitate its synthesis (Xiao, huang, Y, q.; tian, h.y.; bai.j.; cheng, f.; wang.x.; ke, m.l.; chen, f.e. chem commun.2022, 58, 3015-3018.).
The synthesis method of the high-activity electrophilic deuteration reagent with adjustable structure and controllable activity is developed by taking the low-cost and easily-obtained deuterium source as the initial raw material, and meanwhile, the research and development of the compound have important significance in high-efficiency direct introduction of the deuteration group.
Disclosure of Invention
It is an object of the present invention to provide an S- (methyl-d) 3 ) A method for synthesizing phenyl sulfide substances.
First, D was prepared by the conventional method (patent number 201110064696.0) using deuterated methanol as the starting material 3 -p-toluenesulfonyl methyl ester; s- (methyl-d) is then synthesized 3 ) And (3) a phenyl sulfide substance.
Step (1) at normal temperature, sulfo groups with different substituents are addedAdding sodium acid into a container, and adding D 3 -p-toluenesulfonyl methyl ester and an organic solvent;
the sodium sulfonate is naphthalene-2-sodium thiosulfate, and the structural formula isOr sodium quinoline-8-thiosulfonate of the formula +.>Or the structural formula is->Wherein the substituent R 1 Is one of alkyl, nitro, cyano, halogen and trifluoromethyl, and the substitution position is 2 or 3 or 4;
the organic solvent is N, N-dimethylformamide solvent or N, N-dimethylacetamide solvent, and the concentration is 0.1-1M;
in the reaction system, sodium sulfonate and D are added 3 -molar ratio of p-toluenesulfonyl methyl ester of 1.5:1, D per mmol 3 1 to 10ml of organic solvent are added correspondingly to the tosyl methyl ester.
The reaction is carried out for 2 to 10 hours at normal temperature, and the steps are as follows:
s- (methyl-d) is obtained 3 ) Phenyl sulfide substance, R 2 Is->
Further, the reaction is carried out under nitrogen or argon.
Another object of the present invention is to provide S- (methyl-d) prepared by the above method 3 ) The application of phenyl sulfide as electrophilic tridentate methylating reagent with aryl iodide derivative or terminal alkyne derivative as substrate.
The aryl iodide derivative is 5-chloro-2-iodopyridine with a structural formula ofOr 6-iodoquinoline with the structural formula +.>Or 3-iodoquinoline with the structural formula +.>Or 5-iodo-1H-indole of formula +.>Or tert-butyl 5-iodo-1H-indole-1-carboxylate of the formula +.>Or 5-iodobenzofuran of formulaOr (E) -1- (2-iodovinyl) -4-methoxybenzene of the formula +.>
Or the structural formula isAryl iodide derivative of (2), wherein the substituent R 3 Is one of amino, hydroxyl, aldehyde, halogen, ester, tosyloxy, tertiary butyl dicarbonate and amido.
The terminal alkyne derivative is methyl but-3-alkyne-1-yl-2-thiophenecarboxylate, and the structural formula isOr 3-ethynyl thiophene with the structural formula +.>
Or the structural formula isTerminal alkyne derivatives of (2), wherein the substituents R 4 Is one of amino, methoxy, carbonyl, halogen and ester;
or the structural formula isTerminal alkyne derivatives of (2), wherein the substituents R 5 Is halogen.
The method overcomes the defects of expensive initial raw materials, complicated reagent synthesis and low reagent activity in the prior method, prepares the S-deuterated methyl-aryl sulfonyl thioester compound by taking low-cost and easily-obtained deuterated methanol as an initial material, and further realizes the regulation and control of the reaction activity of the electrophilic deuterated reagent by adjusting different groups in a reagent framework. Meanwhile, two reduction coupling reactions of the metal salt and aryl iodobenzene and cross coupling reactions of the metal salt and terminal alkyne are developed.
The invention has the following beneficial effects:
(1) The invention has low cost, and realizes the preparation of the deuterated thiomethyl reagent by starting from deuterated methanol and performing a simple two-step reaction at room temperature without adding additives and without complicated column chromatography separation.
(2) The invention prepares the deuterated thiomethyl reagent with different substituents introduced into the reagent skeleton, and realizes adjustable structure and controllable activity.
(3) The invention develops the reductive coupling reaction of the deuterated thiomethyl reagent and aryl iodobenzene under the action of nickel salt and ligand, thereby realizing C (sp 2 )-SCD 3 Constructing chemical bonds; develops the cross-coupling reaction of the deuterated thiomethyl reagent and the terminal alkyne under the action of copper salt and ligand, realizes C (sp 1 )-SCD 3 Construction of chemical bonds.
Detailed Description
The following examples are provided to further illustrate the preparation process and specific applications of the present invention, but are in no way limiting.
First, the prior method is adopted to prepare D 3 Para-toluenesulfonyl methyl ester, followed by preparation of S- (methyl-d) 3 ) And (3) a phenyl sulfide substance.
Preparation example 1.
The method specifically comprises the following steps:
a100 mL round-bottomed flask, which had been baked in an oven at 120℃for 1-2 hours, was cooled, then placed in a magnet, and air was purged three times under nitrogen or argon atmosphere, then 37.5mmol of 4-toluene-thiosulfonic acid sodium salt was addedAir was extracted three times under nitrogen or argon atmosphere, 25.0mmol of the reagent and 50mL of super-dry N, N-dimethylformamide solvent were added, the reaction was stirred at room temperature for 6 hours, the reaction solution was poured into 50mL of water, the organic phase was extracted with ethyl acetate (50 mL. Times.3), the combined organic phases were back-extracted with water 5 times, then dried with anhydrous sodium sulfate for 15 minutes, then filtered with a sand core funnel, the organic phases were combined, and the solvent was removed by spin evaporation. Finally, the crude product is subjected to silica gel column chromatography to obtain a white solid target product with 94 percent of separation yield and deuteration rate>99％。 1 H NMR(400MHz，CDCl 3 )δ7.79(2H，d，J＝8.3Hz)，7.34(2H，d，J＝8.4Hz)，2.44(3H，s)； 13 CNMR(101MHz，CDCl 3 )δ144.9，140.9，129.9，127.2，21.7，17.9–17.1(m，C-D 3 )。
Preparation example 2.
The product isThe method specifically comprises the following steps:
sealing the tube with 25.0mL which has been baked in an oven at 120deg.C for 1-2 hours, cooling, adding the magnet, pumping out the gas three times under nitrogen atmosphere, adding 4.5mmol of 4-nitrothiosulfate sodium saltThree times of air extraction under nitrogen or argon atmosphere, 3.0mmol of reagent and 30.0mL of super-dry N, N-dimethylformamide solvent are added, the reaction is stirred at room temperature for 2h, the reaction solution is poured into 30mL of water, the organic phase is extracted with ethyl acetate (30 mL. Times.3), the combined organic phases are back extracted with water for 3 times, then dried with anhydrous sodium sulfate for 15min, then filtered with a sand core funnel, the organic phases are combined, and the solvent is removed by spin evaporation. Finally, the crude product is subjected to silica gel column chromatography to obtain a light yellow solid target product with a separation yield of 75 percent and deuteration rate>99％。M.p.＝94.6–95.9℃；IR(thin film)1526(s)，1333(m)，1142(s)，1078(m)，855(m)，732(s)，681(s)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ8.42(2H，d，J＝8.9Hz)，8.12(2H，d，J＝8.9Hz)； 13 C NMR(101MHz，CDCl 3 )δ150.6，148.8，128.4，124.8，18.2–17.4(m，C-D 3 )；HRMS(ESI+)[M+H]Calculated +C 7 H 5 D 3 NO 4 S 2 :237.0078, found: 237.0078.
preparation example 3.
The product isThe method specifically comprises the following steps:
sealing the tube with 25.0mL which has been baked in an oven at 120deg.C for 1-2 hours, cooling, adding the magnet, pumping out the gas three times under nitrogen atmosphere, adding 4.5mmol of 4-cyano sodium thiosulfateThree times of air extraction under nitrogen or argon atmosphere, 3.0mmol of reagent and 15.0mL of super-dry N, N-dimethylacetamide solvent are added, the reaction is stirred at room temperature for 3 hours, the reaction solution is poured into 30mL of water, the organic phase is extracted with ethyl acetate (30 mL×3), the combined organic phases are back extracted with water for 3 times, then dried with anhydrous sodium sulfate for 15 minutes, then filtered with a sand core funnel, the organic phases are combined, and the solvent is removed by spin evaporation. Finally, the crude product can obtain a white solid target product with 83 percent of separation yield through silica gel column chromatography, and the deuteration rate is high>99％。M.p.＝91.9–92.7℃；IR(thin film)1325(m)，1142(s)，1075(m)，834(m)，783(w)，622(s)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ8.04(2H，d，J＝8.6Hz)，7.88(2H，d，J＝8.6Hz)； 13 C NMR(101MHz，CDCl 3 )δ147.4，133.3，127.7，117.4，117.1，18.5–17.4(m，C-D 3 )；HRMS(ESI+)[M+H]Calculated +C 8 H 5 D 3 NO 2 S 2 :217.0179, found: 217.0185.
preparation example 4.
The product isThe method specifically comprises the following steps:
sealing the tube with 25.0mL which has been baked in an oven at 120deg.C for 1-2 hours, cooling, adding the magnet, pumping out the gas three times under nitrogen atmosphere, adding 4.5mmol of 4-chlorothiosulfonic acid sodium saltThree times of air extraction under nitrogen or argon atmosphere, 3.0mmol of reagent and 10.0mL of super-dry N, N-dimethylformamide solvent are added, the reaction is stirred at room temperature for 4 hours, the reaction solution is poured into 30mL of water, the organic phase is extracted with ethyl acetate (30 mL. Times.3), the combined organic phases are back extracted with water for 3 times, then dried with anhydrous sodium sulfate for 15 minutes, then filtered with a sand core funnel, the organic phases are combined, and the solvent is removed by spin evaporation. Finally, the crude product can obtain a white solid target product with a separation yield of 81% through silica gel column chromatography, and the deuteration rate is high>99％。M.p.＝34.7–35.9℃；IR(thin film)1576(m)，1473(m)，1394(m)，1321(s)，1820(m)，1142(s)，1076(s)，1012(m)，824(m)，747(s)，699(m)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ7.85(2H，dd，J＝8.7，2.0Hz)，7.53(dd，J＝8.7，1.9Hz，2H)； 13 C NMR(101MHz，CDCl 3 )δ142.1，140.4，129.7，128.6，18.1–17.2(m，C-D 3 )；HRMS(ESI+)[M+Na]Calculated +C 7 H 4 D 3 ClO 2 S 2 Na:247.9656; actual measurement value: 247.9665.
preparation example 5.
The product isThe method specifically comprises the following steps:
sealing the tube with 25.0mL which has been baked in an oven at 120deg.C for 1-2 hours, cooling, adding the magnet, pumping out the gas three times under nitrogen atmosphere, adding 4.5mmol of 4-fluorobenzene sulfosulfonic acid sodium saltThree times of air extraction under nitrogen or argon atmosphere, 3.0mmol of reagent and 6.0mL of super-dry N, N-dimethylformamide solvent are added, the reaction is stirred at room temperature for 6 hours, the reaction solution is poured into 30mL of water, the organic phase is extracted with ethyl acetate (30 mL. Times.3), the combined organic phases are back extracted with water for 3 times, then dried with anhydrous sodium sulfate for 15min, then filtered with a sand core funnel, the organic phases are combined, and the solvent is removed by spin evaporation. Finally, the crude product is subjected to silica gel column chromatography to obtain a white solid target product with 80 percent of separation yield and deuteration rate>99％。M.p.＝45.8–46.5℃；IR(thin film)1584(m)，1489(m)，1325(m)，1290(m)，1229(m)，1137(s)，1098(m)，836(s)，1137(s)，708(m)，654(s)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ7.98–7.94(2H，m)，7.28–7.23(2H，m)； 13 C NMR(101MHz，CDCl 3 )δ165.6(d，J C-F ＝257.8Hz)，139.8(d，J C-F ＝3.1Hz)，130.0(d，J C-F ＝9.6Hz)，116.6(d，J C-F ＝22.8Hz)，18.0–17.2(m，C-D 3 )； 19 F NMR(471MHz，CDCl 3 )δ-102.95–-102.99(1F，m).HRMS(ESI+)[M+H]Calculated +C 7 H 5 D 3 ClO 2 S 2 :210.0133, found: 210.0128.
preparation example 6.
The product isThe method specifically comprises the following steps:
the mixture was baked in an oven at 120℃for 25 hours and 1-2 hours.Sealing the tube by 0mL, cooling, putting a magnet, pumping out the gas three times under the nitrogen atmosphere, and adding 4.5mmol of 4-trifluoromethyl phenylthio sodium sulfonateThree times of air extraction under nitrogen or argon atmosphere, 3.0mmol of reagent and 6.0mL of super-dry N, N-dimethylacetamide solvent are added, the reaction is stirred at room temperature for 6 hours, the reaction solution is poured into 30mL of water, the organic phase is extracted with ethyl acetate (30 mL×3), the combined organic phases are back extracted with water for 3 times, then dried with anhydrous sodium sulfate for 15min, filtered with a sand core funnel, the organic phases are combined, and the solvent is removed by spin evaporation. Finally, the crude product can be separated by silica gel column chromatography to obtain a colorless oily liquid target product with the isolation yield of 79 percent and the deuteration rate>99％。IR(thin film)1404(w)，1320(s)，1131(s)，1107(m)，1081(m)，1061(s)，1016(m)，843(m)，709(s)，611(s)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ8.06(2H，d，J＝8.2Hz)，7.84(2H，d，J＝8.3Hz)； 13 C NMR(101MHz，CDCl 3 )δ146.9，135.1(q，J C-F ＝33.2Hz)，127.6，126.6(q，J C-F ＝3.6Hz)，123.1(q，J C-F ＝274.1Hz)，18.1–17.2(m，C-D 3 )； 19 F NMR(471MHz，CDCl 3 )δ-63.2.HRMS(ESI+)[M+H]Calculated +C 8 H 5 D 3 F 3 O 2 S 2 :260.0101, found: 260.0105.
preparation example 7.
The product isThe method specifically comprises the following steps:
sealing the tube with 25.0mL which has been baked in an oven at 120deg.C for 1-2 hours, cooling, adding the magnet, pumping out the gas three times under nitrogen atmosphere, adding 4.5mmol of 3-chlorobenzenesulfonic acid sodium saltAir was purged three times under nitrogen or argon atmosphere, 3.0mmol of the reagent and 5.0mL of ultra-dry N were added,the N-dimethylformamide solvent was stirred at room temperature for 7 hours, the reaction solution was poured into 30mL of water, the organic phase was extracted with ethyl acetate (30 mL. Times.3), the combined organic phases were back-extracted 3 times with water, then dried over anhydrous sodium sulfate for 15min, then filtered with a sand core funnel, the organic phases were combined, and the solvent was removed by rotary evaporation. Finally, the crude product can obtain a yellow oily liquid target product with a separation yield of 72 percent by silica gel column chromatography, and the deuteration rate is high>99％。IR(thin film)1460(w)，1409(w)，1327(m)，1143(s)，1075(m)，788(m)，666(s)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ7.90(1H，s)，7.81(1H，d，J＝7.9Hz)，7.61(1H，d，J＝8.1Hz)，7.54–7.50(1H，m)； 13 C NMR(101MHz，CDCl 3 )δ145.2，135.6，134.0，130.7，127.2，125.2，18.0–17.5(m，C-D 3 )；HRMS(ESI+)[M+H]Calculated +C 7 H 5 D 3 ClO 2 S 2 :225.9837, found: 225.9847.
preparation example 8.
The product isThe method specifically comprises the following steps:
sealing the tube with 25.0mL which has been baked in an oven at 120deg.C for 1-2 hours, cooling, adding the magnet, pumping out the gas three times under nitrogen atmosphere, adding 4.5mmol of 2-fluorobenzene sulfosulfonic acid sodium saltThree times of air extraction under nitrogen or argon atmosphere, 3.0mmol of reagent and 6.0mL of super-dry N, N-dimethylformamide solvent are added, the reaction is stirred at room temperature for 6 hours, the reaction solution is poured into 30mL of water, the organic phase is extracted with ethyl acetate (30 mL. Times.3), the combined organic phases are back extracted with water for 3 times, then dried with anhydrous sodium sulfate for 15min, then filtered with a sand core funnel, the organic phases are combined, and the solvent is removed by spin evaporation. Finally, the crude product can be subjected to silica gel column chromatography to obtain a colorless oily liquid target product with a separation yield of 78 percent and deuteration rate>99％。IR(thin film)1596(w)，1473(s)，1328(s)，1266(m)，1227(w)，1144(s)，1120(s)，1067(m)，826(m)，762(s)，712(m)，685(s)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ7.92–7.87(1H，m)，7.69–7.63(1H，m)，7.34–7.25(2H，m)； 13 C NMR(101MHz，CDCl 3 )δ158.8(d，J C - F ＝259.6Hz)，136.2(d，J C-F ＝8.3Hz)，131.7(d，J C-F ＝13.3Hz)，129.8，124.4(d，J C-F ＝4.2Hz)，117.9(d，J C-F ＝21.1Hz)，18.2–17.6(m，C-D 3 )； 19 F NMR(471MHz，CDCl 3 )δ-106.95–-107.0(1F，m).HRMS(ESI+)[M+H]Calculated +C 7 H 5 D 3 FO 2 S 2 :210.0133; actual measurement value: 210.0142.
preparation example 9.
The product isThe method specifically comprises the following steps:
sealing the tube with 25.0mL which has been baked in an oven at 120deg.C for 1-2 hours, cooling, adding the magnet, pumping out the gas three times under nitrogen atmosphere, adding 4.5mmol of sodium naphthalene-2-thiosulfateThree times of air extraction under nitrogen or argon atmosphere, 3.0mmol of reagent and 6.0mL of super-dry N, N-dimethylformamide solvent are added, the reaction is stirred at room temperature for 6 hours, the reaction solution is poured into 30mL of water, the organic phase is extracted with ethyl acetate (30 mL. Times.3), the combined organic phases are back extracted with water for 3 times, then dried with anhydrous sodium sulfate for 15min, then filtered with a sand core funnel, the organic phases are combined, and the solvent is removed by spin evaporation. Finally, the crude product can obtain the colorless oily liquid target product with 84 percent of separation yield through silica gel column chromatography, and the deuteration rate>99％。IR(thinfilm)1318(s)，1142(s)，1124(s)，1066(m)，852(w)，822(m)，750(m)，652(s)，636(m)，611(m)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ8.46(1H，s)，8.02–7.99(2H，m)，7.95–7.90(2H，m)，7.71–7.63(2H，m)； 13 C NMR(101MHz，CDCl 3 )δ140.3，135.2，131.8，130.0，129.6，129.5，128.7，128.0，128.0，122.0，17.9–17.4(m，C-D 3 )；HRMS(ESI+)[M+H]Calculated +C 11 H 8 D 3 O 2 S 2 :242.0383; actual measurement value: 242.0392.
preparation example 10.
The product isThe method specifically comprises the following steps:
sealing the tube with 25.0mL which has been baked in an oven at 120 ℃ for 1-2 hours, cooling, putting the tube into a magnet, pumping out the gas three times under nitrogen atmosphere, adding 4.5mmol of 3-trifluoromethyl phenylthiosulfonic acid sodium saltThree times of air extraction under nitrogen or argon atmosphere, 3.0mmol of reagent and 3.0mL of super-dry N, N-dimethylacetamide solvent are added, the reaction is stirred at room temperature for 10 hours, the reaction solution is poured into 30mL of water, the organic phase is extracted with ethyl acetate (30 mL×3), the combined organic phases are back extracted with water for 3 times, then dried with anhydrous sodium sulfate for 15 minutes, then filtered with a sand core funnel, the organic phases are combined, and the solvent is removed by spin evaporation. Finally, the crude product can obtain a colorless oily liquid target product with 80 percent of separation yield through silica gel column chromatography, and deuteration rate>99％。IR(thin film)1323(s)，1127(s)，1099(s)，1069(s)，805(m)，719(m)，692(m)，651(m)，638(s)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ8.18(1H，s)，8.12(1H，d，J＝8.0Hz)，7.91(1H，d，J＝7.8Hz)，7.76–7.72(1H，m)； 13 C NMR(101MHz，CDCl 3 )δ144.8，132.0(q，J C-F ＝33.9Hz)，130.4(q，J C-F ＝3.5Hz)，130.3，130.2，124.1(q，J C-F ＝3.9Hz)，123.0(q，J C - F ＝274.1Hz)，18.1–17.2(m，C-D 3 )； 19 F NMR(471MHz，CDCl 3 )δ-62.9.HRMS(ESI+)[M+H]Calculated +C 8 H 5 D 3 F 3 O 2 S 2 :260.0101, found: 260.0106.
preparation example 11.
The product isThe method specifically comprises the following steps:
sealing the tube with 25.0mL which has been baked in an oven at 120deg.C for 1-2 hours, cooling, adding the magnet, pumping out the air three times under nitrogen atmosphere, adding 4.5mmol of quinoline-8-sodium thiosulfateThree times of air extraction under nitrogen or argon atmosphere, 3.0mmol of reagent and 6.0mL of super-dry N, N-dimethylformamide solvent are added, the reaction is stirred at room temperature for 6 hours, the reaction solution is poured into 30mL of water, the organic phase is extracted with ethyl acetate (30 mL. Times.3), the combined organic phases are back extracted with water for 3 times, then dried with anhydrous sodium sulfate for 15min, then filtered with a sand core funnel, the organic phases are combined, and the solvent is removed by spin evaporation. Finally, the crude product is subjected to silica gel column chromatography to obtain a white solid target product with 62 percent of separation yield and deuteration rate>99％。M.p.＝116.6–117.7℃；IR(thin film)1493(w)，1312(s)，1160(w)，1115(s)，830(s)，787(s)，762(m)，669(s)，629(s)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ9.15(1H，dd，J＝4.3，1.8Hz)，8.43(1H，dd，J＝7.4，1.4Hz)，8.27(1H，dd，J＝8.3，1.8Hz)，8.10(1H，dd，J＝8.2，1.4Hz)，7.65(1H，dd，J＝8.2，7.4Hz)，7.58(1H，dd，J＝8.3，4.2Hz)； 13 C NMR(101MHz，CDCl 3 )δ151.2，143.0，140.4，136.5，134.5，130.6，129.1，124.9，122.3，19.2–18.4(m，C-D 3 )；HRMS(ESI+)[M+H]Calculated +C 10 H 7 D 3 NO 2 S 2 :243.0336; actual measurement value: 243.0330.
preparation example 12.
The product isThe method specifically comprises the following steps:
sealing 25.0mL which has been baked in an oven at 120deg.C for 1-2 hoursThe tube was cooled and then placed in a magnet, and the air was evacuated three times under nitrogen atmosphere, and 4.5mmol of 3-fluorobenzene thiosulfonic acid sodium salt was addedThree times of air extraction under nitrogen or argon atmosphere, 3.0mmol of reagent and 6.0mL of super-dry N, N-dimethylformamide solvent are added, the reaction is stirred at room temperature for 6 hours, the reaction solution is poured into 30mL of water, the organic phase is extracted with ethyl acetate (30 mL. Times.3), the combined organic phases are back extracted with water for 3 times, then dried with anhydrous sodium sulfate for 15min, then filtered with a sand core funnel, the organic phases are combined, and the solvent is removed by spin evaporation. Finally, the crude product can obtain a colorless oily liquid target product with 73 percent of separation yield through silica gel column chromatography, and deuteration rate>99％。IR(thin film)1591(w)，11471(m)，1425(w)，1324(s)，1304(m)，1268(w)，1224(m)，1132(s)，1081(m)，1000(w)，885(m)，867(m)，800(m)，690(m)，672(m)，612(m)cm- 1 ； 1 H NMR(400MHz，CDCl 3 )δ7.72(1H，d，J＝7.9Hz)，7.63–7.61(1H，m)，7.59–7.54(1H，m)，7.38–7.33(1H，m)； 13 C NMR(101MHz，CDCl 3 )δ162.3(d，J C-F ＝254.0Hz)，145.4(d，J C - F ＝6.7Hz)，131.2(d，J C-F ＝7.5Hz)，122.9(d，J C-F ＝3.6Hz)，121.1(d，J C-F ＝21.4Hz)，114.4(d，J C - F ＝24.9Hz)，18.1–17.2(m，C-D 3 )； 19 FNMR(471MHz，CDCl 3 )δ-108.7–-108.8(1F，m).HRMS(ESI+)[M+H]Calculated +C 7 H 5 D 3 FO 2 S 2 :210.0133; actual measurement value: 210.0125.
s- (methyl-d) prepared according to the method of examples 1-12 3 ) The application of phenyl sulfide as electrophilic tridentate methylating reagent with aryl iodide derivative or terminal alkyne derivative as substrate.
Application example 1.
The method specifically comprises the following steps:
25.0mL of the reaction mixture, which had been baked in an oven at 120℃for 1-2 hours, was capped, cooled and then placed in a magnet, and under a nitrogen atmosphere, was evacuated three times, 0.375mmol of deuterated reagent, 0.25mmol of 4-iodoanisole, 0.00625mmol of nickel acetate, 0.0075mmol of 2, 2-bipyridine and 0.5mmol of zinc powder were added, and evacuated three times under a nitrogen or argon atmosphere, 1.25mL of ultra-dry methanol was added, and the reaction mixture was stirred at 60℃for 2 hours, and was poured into 30mL of water, the organic phase was extracted with ethyl acetate (30 mL. Times.3), the combined organic phases were back-extracted with water 3 times, and then dried with anhydrous sodium sulfate for 15 minutes, and then filtered with a sand core funnel, the organic phases were combined, and the solvent was removed by spin evaporation. Finally, the crude product can obtain a colorless oily liquid target product with 93 percent of separation yield through silica gel column chromatography, and deuteration rate>99％。 1 H NMR(400MHz，CDCl 3 )δ7.26(2H，d，J＝8.9Hz)，6.84(2H，d，J＝8.1Hz)，3.77(3H，s)； 13 C NMR(101MHz，CDCl 3 )δ158.2，130.2，128.7，114.7，55.4，17.8–17.0(m，C-D 3 )。
Application example 2.
The method specifically comprises the following steps:
25.0mL of the reaction mixture, which had been baked in an oven at 120℃for 1-2 hours, was capped, cooled and then placed in a magnet, and under a nitrogen atmosphere, was evacuated three times, 0.375mmol of deuterated reagent, 0.25mmol of methyl 4-iodobenzoate, 0.00625mmol of nickel acetate, 0.0075mmol of 2, 2-bipyridine and 0.5mmol of zinc powder were added, and evacuated three times under a nitrogen or argon atmosphere, 1.25mL of ultra-dry methanol was added, and the reaction mixture was stirred at 60℃for 2 hours, the reaction mixture was poured into 30mL of water, the organic phase was extracted with ethyl acetate (30 mL. Times.3), the combined organic phases were back-extracted with water 3 times, and then dried with anhydrous sodium sulfate for 15min, and then filtered with a sand core funnel, the organic phases were combined, and the solvent was removed by rotary evaporation. Finally, the crude product can obtain a white solid target product with 89 percent of separation yield through silica gel column chromatography, and the deuteration rate>99％。M.p.＝79.4–81.4℃；IR(thin film)1706(s)，1593(m)，1434(m)，1402(m)，1187(m)，1114(s)，1011(m)，967(m)，837(m)，757(s)，670(m)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ7.92(2H，d，J＝8.5Hz)，7.23(2H，d，J＝8.4Hz)，3.88(3H，s)； 13 C NMR(101MHz，CDCl 3 )δ166.9，145.5，129.9，126.3，124.9，52.1，14.6–13.8(m，C-D 3 )；HRMS(ESI+)[M+H]Calculated +C 9 H 8 D 3 O 2 S:186.0663, found: 186.0665.
application example 3.
The method specifically comprises the following steps:
25.0mL of the reaction mixture, which had been baked in an oven at 120℃for 1-2 hours, was sealed, cooled and then placed in a magnet, and under a nitrogen atmosphere, was evacuated three times, 0.375mmol of deuterated reagent, 0.25mmol of (E) -1- (2-iodophor) -4-methoxybenzene, 0.00625mmol of nickel acetate, 0.0075mmol of 2, 2-bipyridine and 0.5mmol of zinc powder were added, and evacuated three times under a nitrogen or argon atmosphere, 1.25mL of ultra-dry methanol was added, and the reaction mixture was stirred at 60℃for 2 hours, and the reaction mixture was poured into 30mL of water, and the organic phase was extracted with ethyl acetate (30 mL. Times.3), and the combined organic phases were back-extracted with water 3 times, and then dried with anhydrous sodium sulfate for 15 minutes, and then filtered with a sand core funnel, and the solvent was removed by spin evaporation. Finally, the crude product can obtain a white solid target product with 77 percent of separation yield through silica gel column chromatography, and deuteration rate>99％。M.p.＝67.0–69.2℃；IR(thin film)1593(m)，1508(s)，1464(w)，1305(w)，1258(s)，1238(m)，1176(m)，1032(s)，928(s)，837(s)，785(s)，743(w)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ7.14(2H，d，J＝8.60Hz)，6.75(2H，d，J＝8.6Hz)，6.52(1H，d，J＝15.4Hz)，6.20(1H，d，J＝15.4Hz)，3.70(3H，s)； 13 C NMR(101MHz，CDCl 3 )δ158.7，130.2，126.7，124.9，123.3，114.2，55.4，14.8–14.1(m，C–D 3 )；HRMS(ESI+)[M+H]Calculated +C 10 H 10 D 3 OS:184.0870, found: 184.0863.
application example 4.
The method specifically comprises the following steps:
25.0mL of the reaction mixture, which had been baked in an oven at 120℃for 1-2 hours, was capped, cooled and then placed in a magnet, and under a nitrogen atmosphere, was evacuated three times, 0.375mmol of deuterated reagent, 0.25mmol of 4-iodobenzene toluene, 0.00625mmol of nickel acetate, 0.0075mmol of 2, 2-bipyridine and 0.5mmol of zinc powder were added, and evacuated three times under a nitrogen or argon atmosphere, 1.25mL of ultra-dry methanol was added, and the reaction mixture was stirred at 60℃for 2 hours, the reaction mixture was poured into 30mL of water, the organic phase was extracted with ethyl acetate (30 mL. Times.3), the combined organic phases were back-extracted with water 3 times, and then dried with anhydrous sodium sulfate for 15 minutes, and then filtered with a sand core funnel, the organic phases were combined, and the solvent was removed by spin evaporation. Finally, the crude product can obtain a colorless oily liquid target product with 73 percent of separation yield through silica gel column chromatography, and deuteration rate>99％。IR(thin film)2917(m)，1697(s)，1592(s)，1561(m)，1216(m)，1171(m)，1095(s)，966(s)，911(m)，833(s)，812(s)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ9.91(1H，s)，7.76(2H，d，J＝8.5Hz)，7.31(2H，d，J＝8.4Hz)； 13 C NMR(101MHz，CDCl 3 )δ191.4，148.0，133.0，130.1，125.3，13.9–14.3(m，C-D 3 )；HRMS(ESI+)[M+H]Calculated +C 8 H 5 D 3 NaOS:178.0376, found: 178.0369.
application example 5.
The method specifically comprises the following steps:
25.0mL of the tube was sealed after being baked in an oven at 120℃for 1-2 hours, cooled, put into a magnet, evacuated three times under nitrogen atmosphere, added with 0.375mmol of deuterated reagent, 0.25mmol of 1-chloro-4-iodobenzene, 0.00625mmol of nickel acetate, 0.0075mmol of 2, 2-bipyridine and 0.5mmol of zinc powder, evacuated three times under nitrogen or argon atmosphere, and added with 1.25mL of ultra-dry methanol was reacted at 60℃with stirring for 2 hours, the reaction solution was poured into 30mL of water, the organic phase was extracted with ethyl acetate (30 mL. Times.3), the combined organic phases were back-extracted 3 times with water, then dried over anhydrous sodium sulfate for 15min, then filtered with a sand core funnel, the organic phases were combined, and the solvent was removed by rotary evaporation. Finally, the crude product can obtain a colorless oily liquid target product with 80 percent of separation yield through silica gel column chromatography, and deuteration rate>99％。 1 H NMR(400MHz，CDCl 3 )δ7.24(2H，d，J＝8.6Hz)，7.16(2H，d，J＝8.7Hz)； 13 C NMR(101MHz，CDCl 3 )δ137.1，130.9，129.0，128.0，15.0–15.9(m，C-D 3 )。
Application example 6.
The method specifically comprises the following steps:
25.0mL of the reaction mixture, which had been baked in an oven at 120℃for 1-2 hours, was sealed, cooled and then placed in a magnet, the mixture was evacuated three times under a nitrogen atmosphere, 0.375mmol of deuterated reagent, 0.25mmol of 2- (4-iodophenyl) -4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde, 0.00625mmol of nickel acetate, 0.0075mmol of 2, 2-bipyridine and 0.5mmol of zinc powder were added, the mixture was evacuated three times under a nitrogen or argon atmosphere, 1.25mL of ultra-dry methanol was added, the reaction mixture was stirred at 60℃for 2 hours, the reaction mixture was poured into 30mL of water, the organic phase was extracted with ethyl acetate (30 mL. Times.3), the combined organic phase was back extracted 3 times with water, and then dried with anhydrous sodium sulfate for 15 minutes, then filtered with a sand funnel, the organic phase was combined, and the solvent was removed by spin evaporation. Finally, the crude product can obtain the target product of colorless oily liquid with 61 percent of separation yield through silica gel column chromatography, and deuteration rate>99％。IR(thin film)2977(w)，1597(m)，1394(m)，1357(s)，1144(m)，1102(s)，1015(w)，962(w)，858(m)，818(m)，727(w)，652(m)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ7.71(2H，d，J＝8.3Hz)，7.22(2H，d，J＝8.4Hz)，1.34(12H，s)； 13 C NMR(101MHz，CDCl 3 )δ142.7，135.2，130.0，125.1，83.9，14.7–14.3(m，C-D 3 )；HRMS(EI+)[M+H]Calculated +C 13 H 17 D 3 BO 2 S:254.1460, found: 254.1461.
application example 7.
The method specifically comprises the following steps:
25.0mL of the reaction mixture which had been baked in an oven at 120℃for 1-2 hours was sealed, cooled and then placed in a magnet, the mixture was evacuated three times under a nitrogen atmosphere, 0.375mmol of deuterated reagent, 0.25mmol of 5-iodo-1H-indole, 0.00625mmol of nickel acetate, 0.0075mmol of 2, 2-bipyridine and 0.5mmol of zinc powder were added, the mixture was evacuated three times under a nitrogen or argon atmosphere, 1.25mL of ultra-dry methanol was added, the reaction mixture was stirred at 60℃for 2 hours, the reaction mixture was poured into 30mL of water, the organic phase was extracted with ethyl acetate (30 mL. Times.3), the combined organic phase was back-extracted 3 times with water, then dried with anhydrous sodium sulfate for 15 minutes, then filtered with a sand core funnel, the organic phase was combined, and the solvent was removed by spin evaporation. Finally, the crude product is subjected to silica gel column chromatography to obtain a yellow oily liquid target product with a separation yield of 83 percent, and the deuteration rate is high>99％。IR(thin film)3409(w)，1453(m)，1412(w)，1307(m)，1094(w)，890(w)，799(w)，757(s)，722(s)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ8.08(1H，brs)；7.64(1H，s)；7.26(1H，d，J＝8.4Hz)，7.21(1H，d，J＝8.5Hz)，7.14(1H，s)，6.48(1H，s)； 13 C NMR(101MHz，CDCl 3 )δ134.5，128.7，127.9，125.0，124.0，121.2，117.7，102.2，18.4–17.6(m，C-D 3 )；HRMS(ESI+)[M+H]Calculated +C 9 H 7 D 3 NS:167.0717, found: 167.0736.
application example 8.
The method specifically comprises the following steps:
sealing the tube with 25.0mL which has been baked in an oven at 120deg.C for 1-2 hours, cooling, adding the magnet, pumping out the air three times under nitrogen atmosphere, adding 0.375mmolDeuterated reagent, 0.25mmol of tert-butyl 5-iodo-1H-indole-1-carboxylate, 0.00625mmol of nickel acetate, 0.0075mmol of 2, 2-bipyridine and 0.5mmol of zinc powder are pumped three times under nitrogen or argon atmosphere, 1.25mL of ultra-dry methanol is added, the reaction is stirred at 60 ℃ for 2H, the reaction solution is poured into 30mL of water, the organic phase is extracted with ethyl acetate (30 mL×3), the combined organic phases are back-extracted with water 3 times and then dried with anhydrous sodium sulfate for 15min, then filtered with a sand core funnel, the organic phases are combined and the solvent is removed by spin evaporation. Finally, the crude product can obtain a colorless oily liquid target product with 91 percent of separation yield through silica gel column chromatography, and deuteration rate>99％。IR(thin film)1730(s)，1450(s)，1364(s)，1340(s)，1277(m)，1247(s)，1158(s)，1133(s)，1085(s)，1022(s)，854(w)，790(w)，761(s)，721(m)，613(w)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ8.07(1H，d，J＝7.4Hz)，7.59(1H，d，J＝3.2Hz)，7.50(1H，d，J＝1.6Hz)，7.29(1H，dd，J＝1.8，8.7Hz)，6.51(1H，d，J＝3.6Hz)，1.68(9H，s)； 13 C NMR(101MHz，CDCl 3 )δ149.7，133.5，131.7，131.4，126.6，124.8，120.1，115.6，106.8，83.9，28.3，17.1–16.7(m，C-D 3 )；HRMS(ESI+)[M+H]Calculated +C 14 H 14 D 3 NNaO 2 S:289.1061, found: 289.1067.
application example 9.
The method specifically comprises the following steps:
25.0mL of the reaction mixture which had been baked in an oven at 120℃for 1-2 hours was sealed, cooled and then placed in a magnet, under a nitrogen atmosphere, the gas was evacuated three times, 0.375mmol of deuterated reagent, 0.25mmol of 1-chloro-4-iodobenzene, 0.00625mmol of nickel acetate, 0.0075mmol of 2, 2-bipyridine and 0.5mmol of zinc powder were added, under a nitrogen or argon atmosphere, the gas was evacuated three times, 1.25mL of ultra-dry methanol was added, stirring was performed at 60℃for 2 hours, the reaction mixture was poured into 30mL of water, the organic phase was extracted with ethyl acetate (30 mL. Times.3), the combined organic phase was back-extracted 3 times with water, and then dried with anhydrous sodium sulfate for 15 minutes,the organic phases were then combined and the solvent was removed by rotary evaporation. Finally, the crude product can obtain a white solid target product with a separation yield of 81% through silica gel column chromatography, and the deuteration rate is high>99％。 1 H NMR(400MHz，CDCl 3 )δ7.83(1H，s)，7.42(2H，d，J＝8.6Hz)，7.19(2H，d，J＝8.6Hz)，2.14(3H，s)； 13 C NMR(101MHz，CDCl 3 )δ168.7，135.6，133.6，127.9，120.8，24.6。
Application example 10.
The method specifically comprises the following steps:
25.0mL of the reaction mixture, which had been baked in an oven at 120℃for 1-2 hours, was capped, cooled and then placed in a magnet, and under a nitrogen atmosphere, was evacuated three times, 0.375mmol of deuterated reagent, 0.25mmol of 5-iodobenzofuran, 0.00625mmol of nickel acetate, 0.0075mmol of 2, 2-bipyridine and 0.5mmol of zinc powder were added, and evacuated three times under a nitrogen or argon atmosphere, 1.25mL of ultra-dry methanol was added, and the reaction mixture was stirred at 60℃for 2 hours, the reaction mixture was poured into 30mL of water, the organic phase was extracted with ethyl acetate (30 mL. Times.3), the combined organic phases were back-extracted with water 3 times, and then dried with anhydrous sodium sulfate for 15 minutes, and then filtered with a sand core funnel, the combined organic phases were spin-distilled off. Finally, the crude product can obtain a colorless oily liquid target product with 89% of separation yield through silica gel column chromatography, and deuteration rate>99％。IR(thin film)1447(s)，1261(m)，1173(s)，1132(m)，1110(s)，1030(s)，874(m)，802(m)，760(s)，731(s)，697(m)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ7.62(1H，d，J＝2.2Hz)，7.56(1H，d，J＝1.9Hz)，7.44(1H，d，J＝8.6Hz)，7.28(1H，dd，J＝2.0，8.6Hz)，6.72(1H，dd，J＝1.0，2.2Hz)； 13 CNMR(101MHz，CDCl 3 )δ153.6，145.8，131.9，128.4，125.2，120.8，111.9，106.3，17.6–17.2(m，C-D 3 )；HRMS(ESI+)[M+H]Calculated +C 9 H 7 D 3 NS:168.0557, found: 168.0555.
application example 11.
The method specifically comprises the following steps:
25.0mL of the reaction mixture, which had been baked in an oven at 120℃for 1-2 hours, was capped, cooled and then placed in a magnet, and under a nitrogen atmosphere, was evacuated three times, 0.375mmol of deuterated reagent, 0.25mmol of 3-iodoquinoline, 0.00625mmol of nickel acetate, 0.0075mmol of 2, 2-bipyridine and 0.5mmol of zinc powder were added, and evacuated three times under a nitrogen or argon atmosphere, 1.25mL of ultra-dry methanol was added, and the reaction mixture was stirred at 60℃for 2 hours, the reaction mixture was poured into 30mL of water, the organic phase was extracted with ethyl acetate (30 mL. Times.3), the combined organic phases were back-extracted with water 3 times, and then dried with anhydrous sodium sulfate for 15 minutes, and then filtered with a sand core funnel, the combined organic phases were spin-distilled off. Finally, the crude product is subjected to silica gel column chromatography to obtain a yellow solid target product with 65 percent of separation yield and deuteration rate>99％。M.p.＝38.9–40.2℃；IR(thin film)1706(s)，1593(m)，1434(m)，1402(m)，1187(m)，1114(s)，1011(m)，967(m)，837(m)，757(s)，670(m)cm- 1 ； 1 H NMR(400MHz，CDCl 3 )δ8.79(1H，d，J＝2.4Hz)，8.05(1H，d，J＝8.4Hz)，7.87(1H，d，J＝2.2Hz)，7.71(1H，d，J＝8.4Hz)，7.65–7.61(1H，m)，7.54–7.50(1H，m)； 13 C NMR(101MHz，CDCl 3 )δ150.0，145.9，132.7，131.2，129.3，128.7，128.4，127.3，126.8，15.6–15.0(m，C-D 3 )；HRMS(ESI+)[M+H]Calculated +C 10 H 7 D 3 NS:179.0717, found: 179.0710.
application example 12.
The method specifically comprises the following steps:
sealing a tube with 25.0mL which has been baked in an oven at 120deg.C for 1-2 hours, cooling, adding a magnet, pumping out and deflating three times under nitrogen atmosphere, adding 0.375mmol of deuteration reagent, 0.25mmol of 6-iodoquinoline, 0.00625mmol of nickel acetate, 0.0075mmol of 2, 2-couplingPyridine and 0.5mmol zinc powder were extracted three times under nitrogen or argon atmosphere, 1.25mL of ultra-dry methanol was added, the reaction was stirred at 60 ℃ for 2h, the reaction solution was poured into 30mL of water, the organic phase was extracted with ethyl acetate (30 ml×3), the combined organic phases were back extracted 3 times with water, then dried over anhydrous sodium sulfate for 15min, then filtered with a sand funnel, the organic phases were combined, and the solvent was removed by rotary evaporation. Finally, the crude product can obtain a yellow solid target product with a separation yield of 42% by silica gel column chromatography, and deuteration rate>99％。M.p.＝43.1–43.8℃；IR(thinfilm)1584(w)，1484(w)，1343(w)，1187(w)，1123(w)，1070(w)，1034(w)，867(m)，830(s)，798(m)，770(w)cm- 1 ； 1 H NMR(400MHz，CDCl 3 )δ8.82(1H，d，J＝3.0Hz)，8.03(1H，d，J＝8.2Hz)，7.98(1H，d，J＝8.9Hz)，7.58(1H，dd，J＝1.96，8.8Hz)，7.51(1H，d，J＝1.8Hz)，7.38–7.35(1H，m)； 13 C NMR(101MHz，CDCl 3 )δ149.6，146.6，137.6，134.9，129.7，129.1，128.9，122.4，121.8，15.5–14.8(m，C-D 3 )；HRMS(ESI+)[M+H]Calculated +C 10 H 7 D 3 NS:179.0717, found: 179.0721.
application example 13.
The method specifically comprises the following steps:
25.0mL of the reaction mixture, which had been baked in an oven at 120℃for 1-2 hours, was sealed, cooled and then placed in a magnet, and under a nitrogen atmosphere, was evacuated three times, 0.375mmol of deuterated reagent, 0.25mmol of 4-iodophenyl-4-toluenesulfonate, 0.00625mmol of nickel acetate, 0.0075mmol of 2, 2-bipyridine and 0.5mmol of zinc powder were added, and evacuated three times under a nitrogen or argon atmosphere, 1.25mL of ultra-dry methanol was added, and stirred at 60℃for 2 hours, the reaction mixture was poured into 30mL of water, the organic phase was extracted with ethyl acetate (30 mL. Times.3), the combined organic phases were back-extracted 3 times with water, and then dried with anhydrous sodium sulfate for 15 minutes, and then filtered with a sand core funnel, the organic phases were combined, and the solvent was removed by spin evaporation. The final crude product was obtained by silica gel column chromatography in 89% isolation yieldTo a white solid target product, and deuteration rate>99％。M.p.＝78.2–79.0℃；IR(thin film)1488(m)，1372(s)，1176(s)，1155(s)，1091(m)，1012(w)，859(m)，841(m)，816(s)，750(m)，686(m)，666(m)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ7.68(2H，d，J＝7.8Hz)，7.30(2H，d，J＝8.0Hz)，7.12(2H，d，J＝8.7Hz)，6.88(2H，d，J＝8.8Hz)，2.44(3H，s)； 13 C NMR(101MHz，CDCl 3 )δ147.0，145.5，137.7，132.2，129.8，128.6，127.3，122.8，21.8，15.6–14.8(m，C-D 3 )；HRMS(ESI+)[M+H]Calculated +C 14 H 12 D 3 O 3 S 2 :298.0645, found: 298.0650.
application example 14.
The method specifically comprises the following steps:
25.0mL of the reaction mixture, which had been baked in an oven at 120℃for 1-2 hours, was capped, cooled and then placed in a magnet, and under a nitrogen atmosphere, was evacuated three times, 0.375mmol of deuterated reagent, 0.25mmol of 4-iodophenol, 0.00625mmol of nickel acetate, 0.0075mmol of 2, 2-bipyridine and 0.5mmol of zinc powder were added, and evacuated three times under a nitrogen or argon atmosphere, 1.25mL of ultra-dry methanol was added, and the reaction mixture was stirred at 60℃for 2 hours, the reaction mixture was poured into 30mL of water, the organic phase was extracted with ethyl acetate (30 mL. Times.3), the combined organic phases were back-extracted with water 3 times, and then dried with anhydrous sodium sulfate for 15 minutes, and then filtered with a sand core funnel, the combined organic phases were spin-distilled off. Finally, the crude product can obtain the colorless oily liquid target product with 84 percent of separation yield through silica gel column chromatography, and the deuteration rate>99％。 1 H NMR(400MHz，CDCl 3 )δ7.22(2H，d，J＝8.7Hz)，6.79(2H，d，J＝8.6Hz)，4.79(H，s)； 13 C NMR(101MHz，CDCl 3 )δ154.1，130.4，128.9，116.2，17.8–17.0(m，C-D 3 )。
Application example 15.
The method specifically comprises the following steps:
25.0mL of the reaction mixture, which had been baked in an oven at 120℃for 1-2 hours, was sealed, cooled and then placed in a magnet, and under a nitrogen atmosphere, was evacuated three times, 0.375mmol of deuterated reagent, 0.25mmol of 5-chloro-2-iodopyridine, 0.00625mmol of nickel acetate, 0.0075mmol of 2, 2-bipyridine and 0.5mmol of zinc powder were added, and evacuated three times under a nitrogen or argon atmosphere, 1.25mL of ultra-dry methanol was added, and the reaction mixture was stirred at 60℃for 2 hours, the reaction mixture was poured into 30mL of water, the organic phase was extracted with ethyl acetate (30 mL. Times.3), the combined organic phases were back-extracted with water 3 times, and then dried with anhydrous sodium sulfate for 15 minutes, and then filtered with a sand funnel, the organic phases were combined, and the solvent was removed by rotary evaporation. Finally, the crude product is subjected to silica gel column chromatography to obtain a yellow oily liquid target product with a separation yield of 70 percent and deuteration rate>99％。IR(thin film)1568(m)，1451(s)，1354(m)，1122(s)，1005(m)，818(m)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ8.37(1H，d，J＝2.4Hz)，7.43(1H，d，J＝7.4，13.4Hz)，7.10(1H，d，J＝8.6Hz)； 13 C NMR(101MHz，CDCl 3 )δ158.2，148.1，135.7，127.6，122.2，13.4–12.5(m，C-D 3 )；HRMS(ESI+)[M+H]Calculated +C 6 H 3 D 3 ClNS:163.0171, found: 163.0181.
application example 16.
The method specifically comprises the following steps:
sealing a tube with 25.0mL which has been baked in an oven at 120deg.C for 1-2 hours, cooling, placing in a magnet, pumping out the gas three times under nitrogen atmosphere, adding 0.375mmol of deuterated reagent, 0.25mmol of 1- (allyloxy) -4-iodobenzene, 0.00625mmol of nickel acetate, 0.0075mmol of 2, 2-bipyridine and 0.5mmol of zinc powder, pumping out the gas three times under nitrogen or argon atmosphere, adding 1.25mL of ultra-dry methanol, stirring at 60deg.C for reacting for 2 hours, pouring the reaction solution into 30mL of water, extracting the organic phase with ethyl acetate (30 mL×3), and collecting the combined organic phaseBack-extracting with water for 3 times, drying with anhydrous sodium sulfate for 15min, filtering with a sand core funnel, mixing organic phases, and removing solvent by rotary evaporation. Finally, the crude product can obtain the yellow oily liquid target product with 37 percent of separation yield through silica gel column chromatography, and the deuteration rate>99％。IR(thin film)1595(w)，1492(s)，1279(m)，1239(s)，1176(m)，996(m)，927(m)，821(m)cm -1 ； 1 HNMR(400MHz，CDCl 3 )δ7.28–7.24(2H，m)，6.89–6.85(2H，m)，6.10–6.00(1H，m)，5.41(1H，dd，J＝1.6，17.2Hz)，5.29(1H，dd，J＝1.5，10.6Hz)，4.52(2H，d，J＝5.3Hz)； 13 C NMR(101MHz，CDCl 3 )δ157.2，133.2，130.1，129.0，117.9，115.5，69.0，17.7–16.9(m，C-D 3 )；HRMS(ESI+)[M+H]Calculated +C 10 H 9 D 3 OS:184.0870, found: 184.0879.
application example 17.
The method specifically comprises the following steps:
25.0mL of the reaction mixture, which had been baked in an oven at 120℃for 1-2 hours, was sealed, cooled and then placed in a magnet, and under a nitrogen atmosphere, was evacuated three times, 0.375mmol of deuterated reagent, 0.25mmol of 4-iodoaniline, 0.00625mmol of nickel acetate, 0.0075mmol of 2, 2-bipyridine and 0.5mmol of zinc powder were added, and evacuated three times under a nitrogen or argon atmosphere, 1.25mL of ultra-dry methanol was added, and the reaction mixture was stirred at 60℃for 2 hours, the reaction mixture was poured into 30mL of water, the organic phase was extracted with ethyl acetate (30 mL. Times.3), the combined organic phases were back-extracted with water 3 times, and then dried with anhydrous sodium sulfate for 15 minutes, and then filtered with a sand core funnel, the combined organic phases were spin-distilled off. Finally, the crude product can obtain the yellow oily liquid target product with the separation yield of 79 percent by silica gel column chromatography, and the deuteration rate>99％。IR(thin film)3347(w)，1619(m)，1494(s)，1276(m)，1178(w)，819(m)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ7.18(2H，d，J＝8.4Hz)，6.63(2H，d，J＝8.4Hz)，3.65(2H，brs)； 13 C NMR(101MHz，CDCl 3 )δ145.2，131.1，125.7，115.8，18.7–17.7(m，C-D 3 )；HRMS(ESI+)[M+H]Calculated +C 7 H 6 D 3 NS:143.0717, found: 143.0725.
application example 18.
The method specifically comprises the following steps:
25.0mL of the reaction mixture, which had been baked in an oven at 120℃for 1-2 hours, was capped, cooled and then put into a magnet, the mixture was evacuated three times under a nitrogen atmosphere, 0.75mmol of deuterated reagent, 0.50mmol of 1-ethynyl-4-methoxybenzene, 0.025mmol of cuprous iodide, 0.03mmol of 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene and 0.75mmol of potassium carbonate were added, the mixture was evacuated three times under a nitrogen or argon atmosphere, 5.0mL of ultra-dry dimethyl sulfoxide was added, the reaction mixture was stirred at room temperature for 24 hours, the reaction mixture was poured into 30mL of water, the organic phase was extracted with ethyl acetate (30 mL. Times.3), the combined organic phase was back-extracted with water 5 times, and then dried with anhydrous sodium sulfate for 15 minutes, and then filtered with a sand core funnel, the organic phase was combined, and the solvent was removed by spin evaporation. Finally, the crude product can obtain a colorless oily liquid target product with a separation yield of 90% by silica gel column chromatography, and deuteration rate>99％。IR(thin film)1604(m)，1505(s)，1288(m)，1245(s)，1171(s)，1106(m)，1030(s)，829(s)，781(m)(s)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ7.37(2H，d，J＝8.8Hz)，6.82(2H，d，J＝8.8Hz)，3.79(3H，s)； 13 C NMR(101MHz，CDCl 3 )δ159.6，133.4，115.5，113.9，91.5，79.0，55.3，19.5–18.2(m，C-D 3 )；HRMS(ESI+)[M+H]Calculated +C 10 H 8 D 3 OS:182.0713, found: 182.0716.
application example 19.
The method specifically comprises the following steps:
sealing the tube with 25.0mL which has been baked in an oven at 120deg.C for 1-2 hours, cooling, and placing intoThe magneton was purged three times under nitrogen atmosphere, 0.75mmol of deuterated reagent, 0.50mmol of 1-bromo-4-acetylenyl, 0.025mmol of cuprous iodide, 0.03mmol of 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene and 0.75mmol of potassium carbonate were added, the gas was purged three times under nitrogen or argon atmosphere, 5.0mL of ultra-dry dimethyl sulfoxide was added, the reaction was stirred at room temperature for 24 hours, the reaction solution was poured into 30mL of water, the organic phase was extracted with ethyl acetate (30 ml×3), the combined organic phase was back extracted with water 5 times, then dried with anhydrous sodium sulfate for 15min, then filtered with a sand core funnel, the organic phase was combined, and the solvent was removed by spin evaporation. Finally, the crude product can obtain a colorless oily liquid target product with a separation yield of 85% by silica gel column chromatography, and deuteration rate>99％。IR(thin film)2165(m)，1483(s)，1240(w)，1069(m)，1009(m)，820(s)，768(m)cm -1 ； 1 HNMR(400MHz，CDCl 3 )δ7.41(2H，d，J＝8.5Hz)，7.25(2H，d，J＝8.5Hz)； 13 C NMR(101MHz，CDCl 3 )δ132.9，131.6，122.4，122.3，90.8，82.5，19.2–18.3(m，C-D 3 )；HRMS(ESI+)[M+H]Calculated +C 9 H 5 D 3 BrS:229.9713, found: 229.9701.
application example 20.
The method specifically comprises the following steps:
25.0mL of the reaction mixture is sealed after being baked in an oven at 120 ℃ for 1-2 hours, cooled and placed into a magnet, the mixture is pumped out and deflated three times under the nitrogen atmosphere, 0.75mmol of deuterated reagent, 0.50mmol of 1-chloro-4-ethynylbenzene, 0.025mmol of cuprous iodide, 0.03mmol of 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene and 0.75mmol of potassium carbonate are added, the mixture is pumped out and inflated three times under the nitrogen or argon atmosphere, 5.0mL of ultra-dry dimethyl sulfoxide is added, the mixture is stirred and reacted at room temperature for 24 hours, the reaction mixture is poured into 30mL of water, the organic phase is extracted with ethyl acetate (30 mL multiplied by 3), the combined organic phase is back extracted with water for 5 times, then dried with anhydrous sodium sulfate for 15 minutes, then the mixture is filtered by a sand core funnel, the organic phase is combined, and the solvent is removed by spin evaporation. Finally, the crude product is passed through a silica gel columnChromatography can obtain the target product as colorless oily liquid with 83% separation yield and deuteration rate>99％。 1 HNMR(400MHz，CDCl 3 )δ7.33(2H，d，J＝8.6Hz)，7.26(2H，d，J＝8.6Hz)； 13 C NMR(101MHz，CDCl 3 )δ134.1，132.7，128.7，122.0，90.8，82.3，19.1–18.4(m，C-D 3 )。
Application example 21.
The method specifically comprises the following steps:
25.0mL of the reaction mixture, which had been baked in an oven at 120℃for 1-2 hours, was sealed, cooled and then placed in a magnet, the mixture was evacuated three times under a nitrogen atmosphere, 0.75mmol of deuterated reagent, 0.50mmol of 1- (4-ethylphenyl) ethan-1-one, 0.025mmol of cuprous iodide, 0.03mmol of 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene and 0.75mmol of potassium carbonate were added, the mixture was evacuated three times under a nitrogen or argon atmosphere, 5.0mL of ultra-dry dimethyl sulfoxide was added, the reaction mixture was stirred at room temperature for 24 hours, the reaction mixture was poured into 30mL of water, the organic phase was extracted with ethyl acetate (30 mL. Times.3), the combined organic phase was back-extracted with water 5 times, then dried with anhydrous sodium sulfate for 15 minutes, then filtered with a sand core funnel, the organic phase was combined, and the solvent was removed by spin evaporation. Finally, the crude product can obtain a yellow solid target product with a separation yield of 88.2% by silica gel column chromatography, and the deuteration rate is high>99％。M.p.＝51.5–52.4℃；IR(thin film)2162(w)，1674(s)，1596(m)，1402(m)，1354(m)，1265(m)，1180(m)，959(m)，830(s)，724(m)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ7.84(2H，d，J＝8.5Hz)，7.41(2H，d，J＝8.5Hz)，2.55(3H，s)； 13 CNMR(101MHz，CDCl 3 )δ197.3，135.7，131.0，128.3，128.3，91.5，85.6，26.6，19.2–18.3(m，C-D 3 )；HRMS(ESI+)[M+H]Calculated +C 11 H 8 D 3 OS:194.0713, found: 194.0708.
application example 22.
The method specifically comprises the following steps:
25.0mL of the reaction mixture, which had been baked in an oven at 120℃for 1-2 hours, was capped, cooled and then put into a magnet, the mixture was evacuated three times under a nitrogen atmosphere, 0.75mmol of deuterated reagent, 0.50mmol of methyl 4-ethynylbenzoate, 0.025mmol of cuprous iodide, 0.03mmol of 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene and 0.75mmol of potassium carbonate were added, the mixture was evacuated three times under a nitrogen or argon atmosphere, 5.0mL of ultra-dry dimethyl sulfoxide was added, the reaction mixture was stirred at room temperature for 24 hours, the reaction mixture was poured into 30mL of water, the organic phase was extracted with ethyl acetate (30 mL. Times.3), the combined organic phase was back-extracted with water 5 times, and then dried with anhydrous sodium sulfate for 15 minutes, then filtered with a sand core funnel, the organic phase was combined, and the solvent was distilled off. Finally, the crude product can obtain a white solid target product with a separation yield of 90% by silica gel column chromatography, and deuteration rate>99％。M.p.＝96.2–96.7℃；IR(thin film)2158(w)，1706(s)，1600(m)，1435(m)，1309(w)，1275(s)，1194(m)，1176(m)，1111(m)，1001(w)，960(w)，853(m)，768(s)，698(m)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ7.95(2H，d，J＝8.4Hz)，7.42(2H，d，J＝8.5Hz)，3.90(3H，s)； 13 C NMR(101MHz，CDCl 3 )δ166.5，130.8，129.5，129.0，128.1，91.4，85.0，52.2，19.2–18.3(m，C-D 3 )；HRMS(ESI+)[M+H]Calculated +C 11 H 8 D 3 OS:210.0656, found: 210.0663.
application example 23.
The method specifically comprises the following steps:
sealing a tube with 25.0mL which has been baked in an oven at 120 ℃ for 1-2 hours, cooling, putting a magnet, pumping out and deflating three times under nitrogen atmosphere, adding 0.75mmol of deuterated reagent, 0.50mmol of 4-ethynylaniline, 0.025mmol of cuprous iodide, 0.03mmol of 4, 5-diphenylphosphine-9, 9-dimethylxanthene and 0.75mmol of potassium carbonate, pumping out and deflating under nitrogen or argon atmosphereThree times, add 5.0mL of ultra-dry dimethyl sulfoxide, stir at room temperature for 24h, pour the reaction solution into 30mL of water, extract the organic phase with ethyl acetate (30 ml×3), strip the combined organic phases with water 5 times, then dry with anhydrous sodium sulfate for 15min, then filter with a sand core funnel, combine the organic phases, spin-evaporate to remove the solvent. Finally, the crude product can obtain the yellow oily liquid target product with 89 percent of separation yield through silica gel column chromatography, and the deuteration rate>99％。IR(thin film)3371(w)，1603(s)，1508(s)，1287(m)，1175(m)，1003(w)，827(s)cm -1 ； 1 HNMR(400MHz，CDCl 3 )δ7.23(2H，dd，J＝8.7，2.0Hz)，6.55(2H，dd，J＝8.6，2.0Hz)，3.81(2H，brs)； 13 C NMR(101MHz，CDCl 3 )δ146.9，133.5，114.7，112.5，92.3，77.8，19.4–18.6(m，C-D 3 )；HRMS(ESI+)[M+H]Calculated +C 9 H 7 D 3 NS:167.0717, found: 167.0711.
application example 24.
The method specifically comprises the following steps:
25.0mL of the tube was sealed after having been baked in an oven at 120℃for 1-2 hours, cooled and then put into a magnet, the gas was evacuated three times under a nitrogen atmosphere, 0.75mmol of deuterated reagent, 0.50mmol of ethyl but-3-yn-1-yl 4-bromobenzoate, 0.025mmol of cuprous iodide, 0.03mmol of 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene and 0.75mmol of potassium carbonate were added, the gas was evacuated three times under a nitrogen or argon atmosphere, 5.0mL of ultra-dry dimethyl sulfoxide was added, the reaction was stirred at room temperature for 24 hours, the reaction solution was poured into 30mL of water, the organic phase was extracted with ethyl acetate (30 mL. Times.3), the combined organic phase was back-extracted with water 5 times, then dried with anhydrous sodium sulfate for 15 minutes, then filtered with a sand core funnel, the organic phase was combined, and the solvent was removed by spin evaporation. Finally, the crude product can obtain a colorless oily liquid target product with a separation yield of 66% by silica gel column chromatography, and deuteration rate>99％。IR(thin film)1720(s)，1590(m)，1397(w)，1265(s)，1173(m)，1102(s)，1068(m)，1011(s)，847(m)，754(s)，682(w)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ7.91(2H，d，J＝8.6Hz)，7.59(2H，d，J＝8.6Hz)，4.40(2H，t，J＝6.8Hz)，2.77(2H，t，J＝6.9Hz)； 13 C NMR(101MHz，CDCl 3 )δ165.7，131.9，131.3，129.0，128.4，88.3，72.6，63.1，20.7，19.0–18.6(m，C-D 3 )；HRMS(ESI+)[M+H]Calculated +C 12 H 9 D 3 BrO 2 S 2 :301.9924, found: 301.9921.
application example 25.
The method specifically comprises the following steps:
25.0mL of the tube was sealed after having been baked in an oven at 120℃for 1-2 hours, cooled and then put into a magnet, the gas was evacuated three times under a nitrogen atmosphere, 0.75mmol of deuterated reagent, 0.50mmol of ethyl but-3-yn-1-yl 4-iodobenzoate, 0.025mmol of cuprous iodide, 0.03mmol of 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene and 0.75mmol of potassium carbonate were added, the gas was evacuated three times under a nitrogen or argon atmosphere, 5.0mL of ultra-dry dimethyl sulfoxide was added, the reaction was stirred at room temperature for 24 hours, the reaction solution was poured into 30mL of water, the organic phase was extracted with ethyl acetate (30 mL. Times.3), the combined organic phase was back-extracted with water 5 times, then dried with anhydrous sodium sulfate for 15 minutes, then filtered with a sand core funnel, the organic phase was combined, and the solvent was removed by spin evaporation. Finally, the crude product can be subjected to silica gel column chromatography to obtain a colorless oily liquid target product with a separation yield of 62 percent and deuteration rate>99％。IR(thin film)1717(s)，1585(m)，1393(m)，1263(s)，1176(m)，1101(s)，1006(s)，845(m)，751(s)，682(m)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ7.79(2H，d，J＝8.5Hz)，7.73(2H，d，J＝8.6Hz)，4.38(2H，t，J＝6.8Hz)，2.75(2H，t，J＝6.8Hz)； 13 C NMR(101MHz，CDCl 3 )δ165.9，137.8，131.1，129.5，101.0，88.3，72.6，63.1，20.7，18.9–18.1(m，C-D 3 )；HRMS(ESI+)[M+H]Calculated +C 12 H 9 D 3 IO 2 S：349.9786，Actual measurement value: 349.9786.
application example 26.
The method specifically comprises the following steps:
25.0mL of the tube was sealed after being baked in an oven at 120℃for 1-2 hours, cooled and then placed in a magnet, the gas was extracted three times under nitrogen atmosphere, 0.75mmol of deuterated reagent, 0.50mmol of methyl but-3-yn-1-yl-2-thiophenecarboxylate, 0.025mmol of cuprous iodide, 0.03mmol of 4, 5-diphenylphosphine-9, 9-dimethylxanthene and 0.75mmol of potassium carbonate were added, the gas was extracted three times under nitrogen or argon atmosphere, 5.0mL of ultra-dry dimethyl sulfoxide was added, the reaction was stirred at room temperature for 24 hours, the reaction solution was poured into 30mL of water, the organic phase was extracted with ethyl acetate (30 mL. Times.3), the combined organic phase was back extracted 5 times with water, then dried with anhydrous sodium sulfate for 15 minutes, then filtered with a sand core funnel, the organic phase was combined, and the solvent was removed by spin evaporation. Finally, the crude product can obtain a colorless oily liquid target product with 60 percent of separation yield through silica gel column chromatography, and deuteration rate>99％。IR(thin film)1705(s)，1524(w)，1417(m)，1357(w)，1255(s)，1094(s)，860(w)，747(s)，719(s)(m)cm -1 ； 1 H NMR(400MHz，CDCl 3 )δ7.81(1H，dd，J＝3.8，1.2Hz)，7.57(1H，dd，J＝5.0，1.3Hz)，7.10(1H，dd，J＝5.0，3.8Hz)，4.37(2H，t，J＝7.0Hz)，2.75(2H，t，J＝7.0Hz)； 13 C NMR(101MHz，CDCl 3 )δ162.0，133.8，133.5，132.7，127.9，88.2，72.6，63.0，20.7，18.8–18.3(m，C-D 3 )；HRMS(ESI+)[M+H]Calculated +C 10 H 8 D 3 O 2 S 2 :230.0383, found: 230.0384.
application example 27.
The method specifically comprises the following steps:
sealing tube with 25.0mL baked in oven at 120deg.C for 1-2 hr, cooling, adding magnet, and coolingUnder nitrogen atmosphere, the gas was evacuated three times, 0.75mmol of deuterated reagent, 0.50mmol of 3-ethynylthiophene, 0.025mmol of cuprous iodide, 0.03mmol of 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene and 0.75mmol of potassium carbonate were added, the gas was evacuated three times under nitrogen or argon atmosphere, 5.0mL of ultra-dry dimethyl sulfoxide was added, the reaction solution was stirred at room temperature for reaction for 24 hours, poured into 30mL of water, the organic phase was extracted with ethyl acetate (30 ml×3), the combined organic phases were back extracted with water 5 times, then dried with anhydrous sodium sulfate for 15min, then filtered with a sand core funnel, the organic phases were combined, and the solvent was removed by spin evaporation. The final crude product was purified by silica gel column chromatography to give a colorless oily liquid product in 92% isolation yield with deuteration rate>99％。IR(thin film)2923(w)，1354(w)，1004(w)，957(w)，871(w)，837(m)，778(s)，690(w)，624(m)cm- 1 ； 1 H NMR(400MHz，CDCl 3 )δ7.47(1H，dd，J＝3.0，1.2Hz)，7.28(1H，dd，J＝4.8，1.8Hz)，7.13(1H，dd，J＝5.0，1.2Hz)； 13 C NMR(101MHz，CDCl 3 )δ130.2，129.3，125.3，122.5，86.7，80.4，19.1–18.6(m，C-D 3 )；HRMS(ESI+)[M+H]Calculated +C 7 H 4 D 3 S 2 :158.0172, found: 158.0175.

Claims (3)

  1. s- (methyl-d) 3 ) The synthesis method of the phenyl sulfide substance is characterized by comprising the following steps:
    at normal temperature, adding sodium sulfonate into a container, and then adding D 3 -p-toluenesulfonyl methyl ester and an organic solvent;
    the sodium sulfonate has the structural formulaWherein the substituent R 1 Methyl, the substitution position is 4;
    the concentration of the organic solvent is 0.1-1M;
    in the reaction system, sodium sulfonate and D are added 3 The molar ratio of p-toluenesulfonyl methyl ester is 1.5:1, D per mmol 3 1 to 1 of p-toluenesulfonyl methyl ester is correspondingly added0ml of organic solvent;
    the reaction is carried out for 2 to 10 hours at normal temperature, and the reaction equation is as follows:
    s- (methyl-d) is obtained 3 ) Phenyl sulfide substance, R 2 Is->
  2. 2. S- (methyl-d) as defined in claim 1 3 ) The synthesis method of the phenyl sulfide substance is characterized by comprising the following steps: the organic solvent is N, N-dimethylformamide solvent or N, N-dimethylacetamide solvent.
  3. 3. S- (methyl-d) as defined in claim 1 3 ) The synthesis method of the phenyl sulfide substance is characterized by comprising the following steps: the reaction is carried out under the protection of nitrogen or argon.
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CN114478150A (en) * 2022-01-22 2022-05-13 浙江工业大学 S-deuterated methyl-aryl sulfonyl thioester compound and synthesis method and application thereof
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