CN114478150B - S-deuterated methyl-aryl sulfonyl thioester compound and synthetic method and application thereof - Google Patents

S-deuterated methyl-aryl sulfonyl thioester compound and synthetic method and application thereof Download PDF

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CN114478150B
CN114478150B CN202210075728.5A CN202210075728A CN114478150B CN 114478150 B CN114478150 B CN 114478150B CN 202210075728 A CN202210075728 A CN 202210075728A CN 114478150 B CN114478150 B CN 114478150B
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陈芬儿
肖霄
黄印秋
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Zhejiang University of Technology ZJUT
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Abstract

The invention discloses an S-deuterated methyl-aryl sulfonyl thioester compound and a synthesis method and application thereof, wherein the synthesis method is that deuterated methanol shown in a formula (1) is used in an organic wayForming an intermediate shown in a formula (2) with an electrophile in a solvent under the environment of alkali and nitrogen; the intermediate shown in the formula (2) and aryl thiosulfonic acid sodium salt shown in the formula (3) react under the action of a phase transfer catalyst to obtain the S-deuterated methyl-aryl sulfonyl thioester compound, wherein the reaction process is as follows:wherein R is 1 Selected from phenyl, substituted phenyl or condensed rings, and the substituent on the substituted phenyl is methyl, methoxy, tertiary butyl or halogen. The method has the advantages of mild reaction conditions, cheap and easily obtained raw materials, simple reaction operation, higher yield, economy, practicability and environmental friendliness; the reaction efficiency is high after the reaction amplification, and the prepared S-deuterated methyl-aryl sulfonyl thioester compound can be used for further synthesizing deuterated thiomethyl compounds containing C-S, P-S, N-S bonds.

Description

S-deuterated methyl-aryl sulfonyl thioester compound and synthetic method and application thereof
Technical Field
The invention belongs to the technical field of organic compound synthesis, and particularly relates to an S-deuterated methyl-aryl sulfonyl thioester compound and a synthesis method and application thereof, belonging to the technical field of organic compound process application.
Background
Methyl groups are ubiquitous as the simplest functional groups in numerous natural products and drugs, and play a critical role in improving the physical properties and biological activity of compounds. Among them, the compounds with thiomethyl, methyl sulfoxide and methyl sulfone are more important basic stones of modern pharmaceutical chemistry. Such as thiocolchicine, an inhibitor of tubulin polymerization with a thiomethyl structure, and the antipsychotic agent thioridazine; sulconazole which is an anti-cardiovascular disease drug and sulindac which is a non-steroidal anti-inflammatory drug with a methyl sulfoxide structure; a non-steroidal anti-inflammatory drug, namely, a non-rocoxib drug with a methylsulfone structure and a vitamin E Ji drug for treating basal cell carcinoma;
in addition, deuterium atoms can be used as bioisosteres of hydrogen atoms and can be used as trace atoms to study metabolic pathways of drugs in the human body. Since the bond dissociation energy of the carbon-deuterium bond is higher than that of the carbon-hydrogen bond, the introduction of deuterium atoms to replace hydrogen atoms at the metabolic sites of some drugs may have a significant effect on the pharmacokinetic properties. Over the past few decades, a number of deuterated drug candidates entered the clinical trial phase, and in 2017, the FDA approved the first deuterated drug, antitant, to be marketed. In addition to the application in pharmaceutical chemistry, deuterated labeled compounds are widely used as a tool for the mechanism research of chemical reactions and the identification research of products, and in view of the importance of deuterated compounds, it is necessary to develop a practical and highly versatile preparation method.
In summary, the deuterated thiomethyl structure with a thiomethyl skeleton and deuterium hydrogen is a group with a certain patent drug potential, but in the prior art, the traditional method for constructing the deuterated thiomethyl skeleton on the drug structure is mainly carried out by deuterated iodomethane or deuterated dimethyl sulfate with larger toxicity, which has a certain harm to human body, so that the method is limited. In recent years, the method for introducing deuterated thiomethyl through deuterated DMSO or deuterated sodium borohydride needs to use a large amount of deuterated reagent as a substrate or a solvent, so that the cost is high, and the application of the method on an industrial scale is limited.
It is therefore particularly important to find a non-toxic deuterium source capable of synthesizing deuterated thiomethylating agents starting at 1 equivalent and to explore the coupling method of such deuterating agents with nucleophilic products.
Disclosure of Invention
The invention overcomes a plurality of defects of the traditional construction of deuterated thiomethyl skeleton reaction, and innovatively develops a method for directly obtaining the universal deuterated methyl thiolation reagent by using deuterated methanol as 1 equivalent under mild conditions through a one-pot method. In view of this, the present invention devised a reaction method for preparing S-deuterated methyl-arylsulfonyl thioesters with an arylthiosulfonic acid sodium salt in an organic solvent under the action of a phase transfer catalyst by using an electrophile and a base-activated deuterated methanol.
S-deuterated methyl-aryl sulfonyl thioester compound with structural formula shown in formula (4), wherein R 1 Selected from phenyl groupsSubstituted phenyl or condensed rings, the substituents on substituted phenyl being methyl, methoxy, tert-butyl or halogen
A synthetic method of S-deuterated methyl-aryl sulfonyl thioester compounds comprises the following steps:
1) Deuterated methanol shown in a formula (1) is used for forming an intermediate shown in a formula (2) with an electrophile in an alkali and nitrogen environment in an organic solvent;
2) Reacting an intermediate shown in a formula (2) with aryl sodium thiosulfate shown in a formula (3) under the action of a phase transfer catalyst to obtain a compound shown in a formula (4), wherein the reaction process is as follows:
wherein R is 1 Selected from phenyl, substituted phenyl or condensed rings, and the substituent on the substituted phenyl is methyl, methoxy, tertiary butyl or halogen.
Further, the condensed ring is naphthalene ring, and halogen is fluorine, chlorine or bromine.
Further, the electrophile is trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride or methanesulfonic anhydride, preferably trifluoromethanesulfonic anhydride, and the amount of the electrophile is 1.05 to 5.0 equivalents, preferably 1.1 equivalents, of deuterated methanol represented by formula (1).
Further, the base is 2, 6-lutidine or triethylamine, preferably 2, 6-lutidine, and the base is used in an amount of 1.0 to 5.0 equivalents, preferably 1.2 equivalents, of deuterated methanol represented by formula (1).
Further, the organic solvent is N, N-dimethylformamide or acetonitrile, preferably N, N-dimethylformamide.
Further, the phase transfer catalyst is used in an amount of 2.5 to 100mol%, preferably 5mol%, of deuterated methanol represented by formula (1).
Further, the molar ratio of deuterated methanol represented by formula (1) to arylthiosulfonate represented by formula (3) is 1.0:1.0-1.0:5.0, preferably 1.0:1.5.
Further, the reaction temperature of step 1) is-20 to 0 ℃, preferably 0 ℃; the reaction temperature in step 2) is 30-100℃and preferably 60 ℃.
Further, the reaction time of step 1) is 1 to 4 hours, preferably 1.5 hours; the reaction time in step 2) is 4 to 12 hours, preferably 6 hours.
The application of the S-deuterated methyl-aryl sulfonyl thioester compound, in particular to the application in the synthesis of aryl deuterated methyl phenyl sulfide compound, the application in the synthesis of C-S bond-containing compound, the application in the synthesis of P-S bond-containing compound, the application in the synthesis of N-S bond-containing compound and the application in the synthesis of disulfide compound.
The invention has the beneficial effects that:
1) 1 equivalent of deuterated methanol is adopted, the deuterated methanol is activated by an electrophile, and finally, the deuterated methanol is coupled with aryl sodium thiosulfate under the action of phase transfer catalysis, and the reaction is carried out at the temperature of 30-100 ℃, so that the adverse conditions that the reaction conditions of the former are harsh, a large amount of deuterium sources are needed, and the like are overcome, and the reaction for synthesizing the deuterated thiomethyl reagent is developed more efficiently, green and convenient;
2) The preparation of the compound realizes gram-scale reaction, has practicability and wide application prospect, and is suitable for industrial scale production.
3) The invention has the advantages of high reaction efficiency, high yield, simple and stable preparation, no pungent smell and mild reaction conditions.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples, to which the present invention is not limited. Variations and advantages that would occur to one skilled in the art are included in the invention without departing from the spirit and scope of the inventive concept, and the scope of the invention is defined by the appended claims. The procedures, conditions, reagents, experimental methods, etc. for carrying out the present invention are common knowledge and common knowledge in the art, except for those specifically mentioned below, and the present invention is not particularly limited. The data presented in the examples below include specific operations and reaction conditions and products. The purity of the product was identified by nuclear magnetism.
The synthesis reaction of the S-deuterated methyl-aryl sulfonyl thioester compound comprises the following reaction processes:
example 1
Synthesis of S-deuterated methyl-4-benzenesulfonyl thioester:
CD was added to a dry schlenk tube under nitrogen atmosphere 3 OD (36.07 mg,1.0mmol, 1.0 equiv.), 2, 6-lutidine (128.6 mg,1.2mmol,1.2 equiv.) and anhydrous DMF (2.0 mL), followed by dropwise addition of Tf at 0deg.C 2 O (310.3 mg,1.1mmol,1.1 equiv.) after 90min of reaction, sodium salt of phenylthiosulfonate (293.9 mg,1.5mmol,1.5 equiv.) TBAI (18.47 mg,0.05mmol,5 mol%) was added to the reaction system and reacted at 60℃for 6 hours, followed by quenching with water, extraction with ethyl acetate, separation of the organic phase, removal of the solvent under reduced pressure, purification by column chromatography to give product 4a (151.1 mg,80%, deuteration rate)>99%) (eluent polarity: PE: EA 20:1).
1 H NMR(400MHz,CDCl 3 )δ7.92(d,J＝7.7Hz,2H),7.68–7.62(m,1H),7.61 –7.51(m,2H)； 13 C NMR(100MHz,CDCl 3 )δ143.5,133.6,129.2,127.0.HRMS (ESI)for C 7 H 5 D 3 O 2 S 2 [M+Na] + calcd 214.0046,found 214.0046.
Example 2
Synthesis of S-deuterated methyl-4-methylbenzenesulfonyl thioester:
under nitrogen atmosphere, underCD addition to a dried schlenk tube 3 OD (36.07 mg,1.0mmol, 1.0 equiv.), 2, 6-lutidine (128.6 mg,1.2mmol,1.2 equiv.) and anhydrous DMF (2.0 mL), followed by dropwise addition of Tf at 0deg.C 2 O (310.3 mg,1.1mmol,1.1 equiv.) after 90min of reaction, 4-methylbenzothiosulfonic acid sodium salt (315.4 mg,1.5mmol,1.5 equiv.) TBAI (18.47 mg,0.05mmol,5mol%) was added to the reaction system and reacted at 60℃for 6 hours, followed by water quenching, extraction with ethyl acetate, separation of the organic phase, removal of the solvent under reduced pressure, column chromatography purification to give product 4b (172.2 mg,84%, deuteration rate)>99%) (eluent polarity: PE: EA 60:1).
1 H NMR(400MHz,CDCl 3 )δ7.81(d,J＝8.2Hz,2H),7.35(d,J＝8.2Hz,2H), 2.45(s,3H). 13 C NMR(100MHz,CDCl 3 )δ144.9,141.1,129.9,127.3,21.8.MS(EI) m/z 205.03(M + ).mp:(56.5–57.4℃).
Example 3
Synthesis of S-deuterated methyl-4-methylbenzenesulfonyl thioester:
CD was added to a dry schlenk tube under nitrogen atmosphere 3 OD (36.07 mg,1.0mmol, 1.0 equiv.), 2, 6-lutidine (128.6 mg,1.2mmol,1.2 equiv.) and anhydrous acetonitrile (2.0 mL), followed by dropwise addition of Tf at 0deg.C 2 O (310.3 mg,1.1mmol,1.1 equiv.) after 90min of reaction, 4-methylbenzothiosulfonic acid sodium salt (315.4 mg,1.5mmol,1.5 equiv.) TBAI (18.47 mg,0.05mmol,5mol%) was added to the reaction system and reacted at 60℃for 6 hours, followed by water quenching, extraction with ethyl acetate, separation of the organic phase, removal of the solvent under reduced pressure, column chromatography purification to give product 4b (155.8 mg,76%, deuteration rate)>99%) (eluent polarity: PE: EA 60:1).
1 H NMR(400MHz,CDCl 3 )δ7.81(d,J＝8.2Hz,2H),7.35(d,J＝8.2Hz,2H), 2.45(s,3H). 13 C NMR(100MHz,CDCl 3 )δ144.9,141.1,129.9,127.3,21.8.MS(EI) m/z 205.03(M + ).mp:(56.5–57.4℃).
Example 4
Synthesis of S-deuterated methyl-4-methylbenzenesulfonyl thioester:
CD was added to a dry schlenk tube under nitrogen atmosphere 3 OD (1.80 g,50mmol,1.0 equiv.), 2, 6-lutidine (6.42 g,60mmol,1.2 equiv.) and anhydrous DMF (2.0 mL) followed by dropwise addition of Tf at 0deg.C 2 O (15.51 g,55mmol,1.1 equiv.) after 90min of reaction, 4-methylbenzothiosulfonic acid sodium salt (15.77 g,75mmol,1.5 equiv.) is added to the reaction system, TBAI (0.92 g,2.5mmol,5 mol%) and reacted at 60℃for 6 hours, the reaction is quenched with water, extracted with ethyl acetate, the organic phase is separated, the solvent is removed under reduced pressure, and the product 4b (8.71 g,85%, deuteration rate) is purified by column chromatography>99%) (eluent polarity: PE: EA 60:1).
1 H NMR(400MHz,CDCl 3 )δ7.81(d,J＝8.2Hz,2H),7.35(d,J＝8.2Hz,2H), 2.45(s,3H). 13 C NMR(100MHz,CDCl 3 )δ144.9,141.1,129.9,127.3,21.8.MS(EI) m/z 205.03(M + ).mp:(56.5–57.4℃).
Example 5
Synthesis of S-deuterated methyl-4-methoxybenzene sulfonyl thioester:
CD was added to a dry schlenk tube under nitrogen atmosphere 3 OD (36.07 mg,1.0mmol, 1.0 equiv.), 2, 6-lutidine (150.0 mg,1.4mmol,1.4 equiv.) and anhydrous DMF (2.0 mL), followed by dropwise addition of Tf at 0deg.C 2 O (338.5 mg,1.2mmol,1.2 equiv.) after 90min of reaction, sodium 4-methoxythiophenesulfonate (338.9 mg,1.5mmol,1.5 equiv.) is added to the reaction, TBAI (18.47 mg,0.05mmol,5 mol%) is reacted at 60℃for 6 hours, the reaction is quenched with water, extracted with ethyl acetate, the organic phase is separated, the solvent is removed under reduced pressure, and the product 4c (185.6 mg,84%, deuterated) is obtained by column chromatography purificationRate of>99%) (eluent polarity: PE: EA 20:1).
1 H NMR(400MHz,CDCl 3 )δ7.91–7.71(m,2H),7.09–6.85(m,2H),3.87(s, 3H)； 13 C NMR(100MHz,CDCl 3 )δ163.5,135.1,129.2,114.2,55.6.HRMS(ESI) for C 8 H 7 D 3 O 3 S 2 [M+Na] + calcd 244.0152,found 244.0155.
Example 6
Synthesis of S-deuterated methyl-4-tert-butylbenzenesulfonyl thioester:
CD was added to a dry schlenk tube under nitrogen atmosphere 3 OD (36.07 mg,1.0mmol, 1.0 equiv.), 2, 6-lutidine (150.0 mg,1.4mmol,1.4 equiv.) and anhydrous DMF (2.0 mL), followed by dropwise addition of Tf at 0deg.C 2 O (338.5 mg,1.2mmol,1.2 equiv.) after 90min of reaction, sodium 4-tert-butylthiophenesulfonate (378.0 mg,1.5mmol,1.5 equiv.) is added to the reaction system, TBAI (18.47 mg,0.05mmol,5 mol%) is reacted at 60℃for 6 hours, the reaction is quenched with water, extracted with ethyl acetate, the organic phase is separated, the solvent is removed under reduced pressure, and the product 4d (183.1 mg,74%, deuteration rate) is obtained by column chromatography purification>99%) (eluent polarity: PE: EA 20:1).
1 H NMR(400MHz,CDCl 3 )δ7.81(d,J＝8.2Hz,2H),7.54(d,J＝8.1Hz,2H), 1.32(s,9H)； 13 C NMR(100MHz,CDCl 3 )δ157.5,140.6,126.7,126.1,35.1,30.8. HRMS(ESI)for C 11 H 13 D 3 O 2 S 2 [M+Na] + calcd 270.0672,found 270.0672.
Example 7
Synthesis of S-deuterated methyl-4-fluorobenzenesulfonyl thioester:
under nitrogen atmosphere, under dry schlenCD addition to the k tube 3 OD (36.07 mg,1.0mmol, 1.0 equiv.), 2, 6-lutidine (150.0 mg,1.4mmol,1.4 equiv.) and anhydrous DMF (2.0 mL), followed by dropwise addition of Tf at 0deg.C 2 O (338.5 mg,1.2mmol,1.2 equiv.) after 90min of reaction, sodium 4-fluorobenzylthiosulfonate (320.9 mg,1.5mmol,1.5 equiv.) TBAI (18.47 mg,0.05mmol,5mol%) was added to the reaction system and reacted at 60℃for 6 hours, followed by water quenching, extraction with ethyl acetate, separation of the organic phase, removal of the solvent under reduced pressure, column chromatography purification to give product 4e (165.3 mg, 79%, deuteration rate)>99%) (eluent polarity: PE: EA 20:1).
1 H NMR(400MHz,CDCl 3 )δ8.07–7.85(m,2H),7.31–7.21(m,2H)； 13 C NMR(100MHz,CDCl 3 )δ165.5(d, 1 J C-F ＝1020Hz),139.7(d, 4 J C-F ＝16Hz),129.9 (d, 3 J C-F ＝40Hz),116.5(d, 2 J C-F ＝92Hz)； 19 F NMR(376MHz,CDCl3)δ 103.0.HRMS(ESI)for C 7 H 4 D 3 FO 2 S 2 [M+Na] + calcd 231.9952,found 231.9953.
Example 8
Synthesis of S-deuterated methyl-4-chlorobenzenesulfonyl thioester:
CD was added to a dry schlenk tube under nitrogen atmosphere 3 OD (36.07 mg,1.0mmol, 1.0 equiv.), 2, 6-lutidine (150.0 mg,1.4mmol,1.4 equiv.) and anhydrous DMF (2.0 mL), followed by dropwise addition of Tf at 0deg.C 2 O (338.5 mg,1.2mmol,1.2 equiv.) after 90min of reaction, 4-chlorobenzenesulfonic acid sodium salt (344.9 mg,1.5mmol,1.5 equiv.) TBAI (18.47 mg,0.05mmol,5mol%) was added to the reaction system and reacted at 60℃for 6 hours, followed by water quenching, extraction with ethyl acetate, separation of the organic phase, removal of the solvent under reduced pressure, purification by column chromatography to give the product 4f (180.6 mg,80%, deuteration rate)>99%) (eluent polarity: PE: EA 20:1).
1 H NMR(400MHz,CDCl 3 )δ7.93–7.80(m,2H),7.59–7.47(m,2H)； 13 C NMR(100MHz,CDCl 3 )δ142.1,140.3,129.5,128.4；HRMS(ESI)for C 7 H 4 D 3 ClO 2 S 2 [M+Na] + calcd 247.9656,found 247.9655.
Example 9
Synthesis of S-deuterated methyl-4-bromobenzenesulfonyl thioester:
CD was added to a dry schlenk tube under nitrogen atmosphere 3 OD (36.07 mg,1.0mmol, 1.0 equiv.), 2, 6-lutidine (150.0 mg,1.4mmol,1.4 equiv.) and anhydrous DMF (2.0 mL), followed by dropwise addition of Tf at 0deg.C 2 O (338.5 mg,1.2mmol,1.2 equiv.) after 90min of reaction, 4-chlorobenzenesulfonic acid sodium salt (410.8 mg,1.5mmol,1.5 equiv.) TBAI (18.47 mg,0.05mmol,5mol%) was added to the reaction system and reacted at 60℃for 6 hours, followed by water quenching, extraction with ethyl acetate, separation of the organic phase, removal of the solvent under reduced pressure, purification by column chromatography to give 4g (210.8 mg,78%, deuteration rate)>99%) (eluent polarity: PE: EA 20:1).
1 H NMR(400MHz,CDCl 3 )δ7.78(d,J＝8.7Hz,2H),7.70(d,J＝8.7Hz, 2H)； 13 C NMR(100MHz,CDCl 3 )δ142.6,132.5,128.8,128.5.HRMS(ESI)for C 7 H 4 D 3 BrO 2 S 2 [M+Na] + calcd 291.9151,found 291.9155.
Example 10
Synthesis of S-deuterated methyl-2-naphthalene sulfonyl thioester:
CD was added to a dry schlenk tube under nitrogen atmosphere 3 OD (36.07 mg,1.0mmol, 1.0 equiv.), 2, 6-lutidine (150.0 mg,1.4mmol,1.4 equiv.) and anhydrous DMF (2.0 mL), followed by dropwise addition of Tf at 0deg.C 2 O (338.5 mg,1.2mmol,1.2 equiv.) after 90min of reaction, 2-naphthalenethiosulfonyl sodium salt (369.0 mg,1.5mmol,1.5 equiv.) is added to the reaction system, TBAI (18.47 mg,0.05mmol,5 mol%) is reacted at 60℃for 6 hours, the reaction is quenched with water, extracted with ethyl acetate, the organic phase is separated, the solvent is removed under reduced pressure, and the product is purified by column chromatography to give 4h (185.8 mg,77%, deuteration rate)>99%) (eluent polarity: PE: EA 20:1).
1 H NMR(400MHz,CDCl 3 )δ8.46(s,1H),8.04–7.98(m,2H),7.96–7.88(m, 2H),7.72–7.60(m,2H)； 13 C NMR(100MHz,CDCl 3 )δ140.1,135.1,131.6,129.8, 129.5,129.4,128.6,127.9,127.8,121.9.HRMS(ESI)for C 11 H 7 D 3 O 2 S 2 [M+Na] + calcd 262.0203,found 262.0200.
Example 11
[1,1' -Biphenyl]-4-yl (methyl-d) 3 ) Synthesis of thioether:
s-deuterated methyl-4-methylbenzenesulfonyl thioester prepared by example 2 (1.64 g,8mmol,1 equiv.) 5a (12 mmol,2.38g,1.5 equiv.) and anhydrous methanol (40.0 mL) were added to the system under nitrogen atmosphere in a dry schlenk tube 4 (0.4mmol,63.8mg,0.05equiv.), NaHCO 3 (16 mmol,1.34g,2 equiv.) and stirring at room temperature for 24h, after the reaction, adding water to the reaction system, quenching, extracting with dichloromethane, collecting the organic phase, removing the solvent under reduced pressure, purifying by column chromatography to obtain the product 6a (1.40 g,86%, deuteration rate)>99%) (eluent polarity: PE).
1 H NMR(400MHz,CDCl 3 )δ7.59(d,J＝8.2Hz,2H),7.54(d,J＝8.2Hz,2H), 7.48–7.42(m,2H),7.39–7.32(m,3H)； 13 C NMR(100MHz,CDCl 3 )δ140.7,138.1, 137.7,128.9,127.6,127.3,127.1,127.0.MS(EI)m/z 203.08(M + ).mp:(88.7- 90.1℃).
Example 12
(3- (benzyloxy) phenyl) (methyl-d 3 ) Synthesis of thioether:
s-deuterated methyl-4-methylbenzenesulfonyl thioester prepared by example 2 (0.2 mmol,41.0g,1 equiv.) 5b (0.3mmol,68.4mg,1.5 equiv.), anhydrous methanol (2.0 mL) was added to the system under nitrogen atmosphere in a dry schlenk tube 4 (0.01mmol,1.6mg,0.05equiv.), NaHCO 3 (0.4 mmol,33.6mg,2 equiv.) and stirred at room temperature for 24h, after the reaction was completed, water was added to the reaction system, and extraction was performed with dichloromethane. The organic phase was collected, the solvent was removed under reduced pressure, and purified by column chromatography to give product 6b (38.7 mg,83%, deuteration rate)>99%) (eluent polarity: PE).
1 H NMR(400MHz,CDCl 3 )δ7.47–7.31(m,5H),7.23–7.18(m,1H),6.91– 6.84(m,2H),6.78–6.74(m,1H),5.06(s,2H). 13 C NMR(100MHz,CDCl 3 )δ159.2, 140.0,136.9,129.8,128.7,128.1,127.6,119.2,113.2,111.4,70.13.HRMS (ESI-TOF)m/z:[M+H] + Calcd for C 14 H 12 D 3 OS 234.1032；Found 234.1035.
Example 13
(methyl-d) 3 ) Synthesis of (4- (phenoxy) phenyl) sulfide:
s-deuterated methyl-4-methylbenzenesulfonyl thioester prepared by example 2 (0.2 mmol,41.0g,1 equiv.) 5c (0.3mmol,64.2mg,1.5 equiv.), anhydrous methanol (2.0 mL) was introduced into a dry schlenk tube under nitrogen atmosphere, and CuSO was added to the system 4 (0.01mmol,1.6mg,0.05equiv.), NaHCO 3 (0.4 mmol,33.6mg,2 equiv.) and stirring at room temperature for 24h, after the reaction, adding water to the reaction system, quenching, extracting with dichloromethane, collecting the organic phase, removing the solvent under reduced pressure, and then, columnChromatography purification gave product 6c (32.8 mg,75%, deuteration rate)>99%) (eluent polarity: PE).
1 H NMR(400MHz,CDCl 3 )δ7.38–7.30(m,2H),7.30–7.24(m,2H),7.15– 7.07(m,1H),7.03–6.98(m,2H),6.98–6.94(m,2H)； 13 C NMR(100MHz,CDCl 3 ) δ157.4,155.3,132.3,129.9,129.2,123.4,119.7,118.8.HRMS(EI-TOF)m/z Calcd for C 13 H 9 D 3 S 219.0797[M] + ,Found 219.0802.
Example 14
(methyl-d) 3 ) Synthesis of (2- (phenoxy) phenyl) sulfide:
s-deuterated methyl-4-methylbenzenesulfonyl thioester prepared by example 2 (0.2 mmol,41.0g,1 equiv.) 5d (0.3mmol,64.2mg,1.5 equiv.), anhydrous methanol (2.0 mL) was introduced into a dry schlenk tube under nitrogen atmosphere, and CuSO was added to the system 4 (0.01mmol,1.6mg,0.05equiv.), NaHCO 3 (0.4 mmol,33.6mg,2 equiv.) and stirring at room temperature for 24h, after the reaction, adding water to the reaction system, quenching, extracting with dichloromethane, collecting the organic phase, removing the solvent under reduced pressure, purifying by column chromatography to obtain product 6d (31.9 mg,73%, deuteration rate)>99%) (eluent polarity: PE).
1 H NMR(400MHz,CDCl 3 )δ7.36–7.30(m,2H),7.29–7.25(m,1H),7.18– 7.11(m,2H),7.11–7.06(m,1H),7.00–6.96(m,2H),6.92–6.88(m,1H). 13 C NMR(100MHz,CDCl 3 )δ157.3,153.6,130.8,129.8,126.8,126.0,124.5,123.1, 119.4,118.0.HRMS(EI-TOF)m/z Calcd for C 13 H 9 D 3 S 219.0797[M]+,Found 219.0793.
Example 15
(methyl-d) 3 ) Synthesis of (naphthalen-2-yl) sulfide:
s-deuterated methyl-4-methylbenzenesulfonyl thioester prepared by example 2 (0.2 mmol,41.0g,1 equiv.) 5e (0.3mmol,51.6mg,1.5 equiv.), anhydrous methanol (2.0 mL) was introduced into a dry schlenk tube under nitrogen atmosphere, and CuSO was added to the system 4 (0.01mmol,1.6mg,0.05equiv.), NaHCO 3 (0.4 mmol,33.6mg,2 equiv.) and stirred at room temperature for 24h, after the reaction was completed, water was added to the reaction system, and extraction was performed with dichloromethane. The organic phase was collected, the solvent was removed under reduced pressure, and purified by column chromatography to give product 6e (28.6 mg,81%, deuteration rate)>99%) (eluent polarity: PE).
1 H NMR(400MHz,CDCl 3 )δ7.80(d,J＝8.1Hz,1H),7.76(d,J＝8.4Hz,2H), 7.62(d,J＝1.2Hz,1H),7.52–7.46(m,1H),7.46–7.38(m,2H)； 13 C NMR(100 MHz,CDCl 3 )δ136.2,134.0,131.1,128.3,127.8,126.9,126.7,125.8,125.3,123.5. MS(EI)m/z 177.07[M] + .mp:(55.4–56.7)℃
Example 16
(methyl-d) 3 ) Synthesis of (phenanthren-9-yl) sulfide:
s-deuterated methyl-4-methylbenzenesulfonyl thioester prepared by example 2 (0.2 mmol,41.0g,1 equiv.) 5f (0.3mmol,66.6mg,1.5 equiv.), anhydrous methanol (2.0 mL) was added to the system under nitrogen atmosphere in a dry schlenk tube 4 (0.01mmol,1.6mg,0.05equiv.), NaHCO 3 (0.4 mmol,33.6mg,2 equiv.) and stirring at room temperature for 24h, after the reaction, adding water to the reaction system, quenching, extracting with dichloromethane, collecting the organic phase, removing the solvent under reduced pressure, purifying by column chromatography to obtain product 6f (32.2 mg,71%, deuteration rate)>99%) (eluent polarity: PE).
1 H NMR(400MHz,CDCl 3 )δ8.74–8.67(m,1H),8.67–8.60(m,1H),8.43– 8.36(m,1H),7.86–7.79(m,1H),7.74–7.66(m,2H),7.64–7.56(m,3H)； 13 C NMR(100MHz,CDCl 3 )δ134.5,132.1,130.6,130.4,129.0,127.7,127.1,127.0, 126.9,126.2,125.0,123.4,123.2,122.7.mp:(91.8–93.7)℃.HRMS(EI-TOF)m/zCalcd for C 15 H 9 D 3 S 227.0848[M] + ,Found 227.0844.
Example 17
(methyl-d) 3 ) Synthesis of (pyren-4-yl) thioether:
s-deuterated methyl-4-methylbenzenesulfonyl sulfide prepared by example 2 (0.2 mmol,41.0g,1 equiv.) and 5g (0.3mmol,73.8mg,1.5 equiv.) (2.0 mL) of dry methanol were introduced into a dry schlenk tube under nitrogen atmosphere, and CuSO was added to the system 4 (0.01mmol,1.6mg,0.05equiv.), NaHCO 3 (0.4 mmol,33.6mg,2 equiv.) and stirring at room temperature for 24h, after the reaction, adding water to the reaction system to quench, extracting with dichloromethane, collecting the organic phase, removing the solvent under reduced pressure, purifying by column chromatography to obtain 6g (35.1 mg,70% deuteration rate)>99%) (eluent polarity: PE).
1 H NMR(400MHz,CDCl 3 )δ8.56(d,J＝9.2Hz,1H),8.20–8.09(m,4H), 8.04–7.97(m,4H)； 13 C NMR(100MHz,CDCl 3 )δ133.2,131.6,131.2,129.5,129.4, 127.7,127.4,127.0,126.3,125.4,125.2,125.1,124.7,123.9.HRMS(ESI-TOF)m/z: [M+H] + Calcd for C 17 H 10 D 3 S 252.0926；Found 252.0921.mp:(69.9–71.0)℃.
Example 18
(4-chlorophenyl) (methyl-d) 3 ) Synthesis of thioether:
s-deuterated methyl-4-methylbenzenesulfonyl thioester prepared by example 2 (0.2 mmol,41.0g,1 eq) was introduced into a dry schlenk tube under nitrogen atmospherev.), 5h (0.3mmol,46.8mg,1.5 equiv), anhydrous methanol (2.0 mL), and CuSO was added to the system 4 (0.01mmol,1.6mg,0.05equiv.), NaHCO 3 (0.4 mmol,33.6mg,2 equiv.) and stirring at room temperature for 24h, after the reaction, adding water to the reaction system, quenching, extracting with dichloromethane, collecting the organic phase, removing the solvent under reduced pressure, purifying by column chromatography to obtain the product 6h (24.5 mg,76%, deuteration rate)>99%) (eluent polarity: PE).
1 H NMR(400MHz,CDCl 3 )δ7.25(d,J＝8.7Hz,2H),7.18(d,J＝8.7Hz,2H)； 13 C NMR(100MHz,CDCl 3 )δ137.1,131.0,129.0,128.1.MS(EI)m/z 161.01[M] +
Example 19
(4-bromophenyl) (methyl-d) 3 ) Synthesis of thioether:
s-deuterated methyl-4-methylbenzenesulfonyl thioester prepared by example 2 (0.2 mmol,41.0g,1 equiv.) 5i (0.3mmol,60.0mg,1.5 equiv.), anhydrous methanol (2.0 mL) was introduced into a dry schlenk tube under nitrogen atmosphere, and CuSO was added to the system 4 (0.01mmol,1.6mg,0.05equiv.), NaHCO 3 (0.4 mmol,33.6mg,2 equiv.) and stirring at room temperature for 24h, after the reaction, adding water to the reaction system, quenching, extracting with dichloromethane, collecting the organic phase, removing the solvent under reduced pressure, purifying by column chromatography to obtain product 6i (29.5 mg,72%, deuteration rate)>99%) (eluent polarity: PE).
1 H NMR(400MHz,CDCl 3 )δ7.39(d,J＝8.6Hz,2H),7.11(d,J＝8.6Hz,2H)； 13 C NMR(100MHz,CDCl 3 )δ137.8,131.9,128.2,118.7.MS(EI)m/z 204.96[M] + .
Example 20
(4-iodophenyl) (methyl-d 3 ) Synthesis of thioether:
s-deuterated methyl-4-methylbenzenesulfonyl thioester prepared by example 2 (0.2 mmol,41.0g,1 equiv.) 5j (0.3mmol,74.3mg,1.5 equiv.), absolute ethanol (2.0 mL) was added to the system under nitrogen atmosphere in a dry schlenk tube 4 (0.01mmol,1.6mg,0.05equiv.), NaHCO 3 (0.4 mmol,33.6mg,2 equiv.) and stirring at room temperature for 24h, after the reaction, adding water to the reaction system, quenching, extracting with dichloromethane, collecting the organic phase, removing the solvent under reduced pressure, purifying by column chromatography to obtain the product 6j (35.4 mg,70%, deuteration rate)>99%) (eluent polarity: PE).
1 H NMR(400MHz,CDCl 3 )δ7.39(d,J＝8.6Hz,2H),7.11(d,J＝8.6Hz,2H)； 13 C NMR(100MHz,CDCl 3 )δ137.8,131.9,128.2,118.7.MS(EI)m/z 204.96[M] + . mp:(34.7–36.2)℃.
Example 21
4- ((methyl-d) 3 ) Thio) synthesis of methyl benzoate:
s-deuterated methyl-4-methylbenzenesulfonyl thioester prepared by example 2 (0.2 mmol,41.0g,1 equiv.) 5k (0.3mmol,54.0mg,1.5 equiv.), absolute ethanol (2.0 mL) was added to the system under nitrogen atmosphere in a dry schlenk tube 4 (0.01mmol,1.6mg,0.05equiv.), NaHCO 3 (0.4 mmol,33.6mg,2 equiv.) and stirring at room temperature for 24h, after the reaction, adding water to the reaction system, quenching, extracting with dichloromethane, collecting the organic phase, removing the solvent under reduced pressure, purifying by column chromatography to obtain product 6k (28.9 mg,78%, deuteration rate)>99%) (eluent polarity: PE: ea=10/1).
1 H NMR(400MHz,CDCl 3 )δ7.86(d,J＝8.5Hz,2H),7.17(d,J＝8.5Hz,2H), 3.82(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ170.0,145.5,130.0,126.4,125.0,52.1. HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 9 H 8 D 3 O 2 S 186.0668；Found 186.0666.
Example 22
4- ((methyl-d) 3 ) Thio) synthesis of ethyl benzoate:
s-deuterated methyl-4-methylbenzenesulfonyl sulfide (0.2 mmol,41.0g,1 equiv.) obtained by example 2, 5l (0.3mmol,58.2mg,1.5 equiv.), anhydrous methanol (2.0 mL) were charged into a dry schlenk tube under nitrogen atmosphere, and CuSO was added to the system 4 (0.01mmol,1.6mg,0.05equiv.), NaHCO 3 (0.4 mmol,33.6mg,2 equiv.) and stirring at room temperature for 24h, after the reaction, adding water to the reaction system, quenching, extracting with dichloromethane, collecting the organic phase, removing the solvent under reduced pressure, purifying by column chromatography to obtain 6l (31.8 mg,80% deuteration rate)>99%) (eluent polarity: PE: ea=20/1).
1 H NMR(400MHz,CDCl 3 )δ7.94(d,J＝8.5Hz,2H),7.25(d,J＝8.5Hz,2H), 4.36(q,J＝7.1Hz,2H),1.39(t,J＝7.1Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ 166.5,145.3,130.0,126.8,61.0.MS(EI)m/z 199.07[M] + .
Example 23
(methyl-d) 3 ) Synthesis of (4-nitrophenyl) sulfide:
s-deuterated methyl-4-methylbenzenesulfonyl sulfide (0.2 mmol,41.0g,1 equiv.), 5m (0.3mmol,50.1mg,1.5 equiv.), anhydrous methanol (2.0 mL) obtained by example 2 was charged into a dry schlenk tube under nitrogen atmosphere, and CuSO was added to the system 4 (0.01mmol,1.6mg,0.05equiv.), NaHCO 3 (0.4 mmol,33.6mg,2 equiv.) and stirring at room temperature for 24h, after the reaction, adding water quench, extracting with dichloromethane, collecting the organic phase, and reducing the pressureAfter removal of the solvent under the column chromatography purification gives the product 6m (26.8 mg,78%, deuteration rate)>99%) (eluent polarity: PE: ea=50/1).
1 H NMR(400MHz,CDCl 3 )δ8.13(d,J＝9.1Hz,2H),7.28(d,J＝9.1Hz, 2H)； 13 C NMR(100MHz,CDCl 3 )δ148.9,144.9,125.1,124.0.MS(EI)m/z 172.04 [M] + .mp:(62.4-64.1)℃.
Example 24
3- ((methyl-d) 3 ) Thio) synthesis of benzonitrile:
s-deuterated methyl-4-methylbenzenesulfonyl thioester prepared by example 2 (0.2 mmol,41.0g,1 equiv.) 5n (0.3mmol,44.1mg,1.5 equiv.), absolute ethanol (2.0 mL) was added to the system under nitrogen atmosphere in a dry schlenk tube 4 (0.01mmol,1.6mg,0.05equiv.), NaHCO 3 (0.4 mmol,33.6mg,2 equiv.) and stirring at room temperature for 24h, after the reaction, adding water to the reaction system, quenching, extracting with dichloromethane, collecting the organic phase, removing the solvent under reduced pressure, purifying by column chromatography to obtain product 6n (19.8 mg,65%, deuteration rate)>99%) (eluent polarity: PE: ea=10/1).
1 H NMR(400MHz,CDCl 3 )δ7.47–7.34(m,4H)； 13 C NMR(100MHz, CDCl 3 )δ141.0,130.6,129.4,129.0,128.4,118.6,113.3.HRMS(ESI-TOF)m/z:[M +H] + Calcd for C 8 H 5 D 3 NS 153.0566；Found 153.0560.
Example 25
(4- ((methyl-d) 3 ) Thio) phenyl) methanol synthesis:
s-deuterated methyl-4-methylbenzenesulfonic acid prepared by example 2 was introduced into a dry schlenk tube under nitrogen atmosphereAcyl thioester (0.2 mmol,41.0g,1 equiv.), 5o (0.3mmol,45.6mg,1.5 equiv.), absolute ethanol (2.0 mL), and CuSO were added to the system 4 (0.01mmol,1.6mg,0.05equiv.), NaHCO 3 (0.4 mmol,33.6mg,2 equiv.) and stirring at room temperature for 24h, after the reaction, adding water to the reaction system, quenching, extracting with dichloromethane, collecting the organic phase, removing the solvent under reduced pressure, purifying by column chromatography to obtain product 6o (23.4 mg,75%, deuteration rate)>99%) (eluent polarity: PE: ea=5/1).
1 H NMR(400MHz,CDCl 3 )δ7.29(d,J＝8.5Hz,2H),7.25(d,J＝8.5Hz,2H), 4.65(s,2H),1.68(brs,1H)； 13 C NMR(100MHz,CDCl 3 )δ137.9,137.8,127.8, 127.0,65.1.HRMS(EI-TOF)m/z Calcd for C 8 H 7 D 3 OS 157.0641[M] + ,Found 157.0638.
Example 26
(2- ((methyl-d) 3 ) Thio) phenyl) methanol synthesis:
s-deuterated methyl-4-methylbenzenesulfonyl thioester prepared by example 2 (0.2 mmol,41.0g,1 equiv.) 5p (0.3mmol,45.6mg,1.5 equiv.), anhydrous methanol (2.0 mL) was introduced into a dry schlenk tube under nitrogen atmosphere, and CuSO was added to the system 4 (0.01mmol,1.6mg,0.05equiv.), NaHCO 3 (0.4 mmol,33.6mg,2 equiv.) and stirring at room temperature for 24h, after the reaction, adding water to the reaction system, quenching, extracting with dichloromethane, collecting the organic phase, removing the solvent under reduced pressure, purifying by column chromatography to obtain product 6p (23.4 mg,75%, deuteration rate)>99%) (eluent polarity: PE: ea=4/1).
1 H NMR(400MHz,CDCl 3 )δ7.38–7.34(m,1H),7.29–7.24(m,2H),7.19– 7.14(m,1H),4.74(s,2H),2.43(brs,1H)； 13 C NMR(100MHz,CDCl 3 )δ139.0, 136.8,128.5,128.2,126.7,125.6,63.7.HRMS(EI-TOF)m/z Calcd for C 8 H 7 D 3 OS 157.0641[M] + ,Found 157.0642.
Example 27
4- ((methyl-d) 3 ) Thio) phenol synthesis:
s-deuterated methyl-4-methylbenzenesulfonyl thioester prepared by example 2 (0.2 mmol,41.0g,1 equiv.) 5q (0.3mmol,41.4mg,1.5 equiv.), anhydrous methanol (2.0 mL) were introduced into a dry schlenk tube under nitrogen atmosphere, and CuSO was added to the system 4 (0.01mmol,1.6mg,0.05equiv.), NaHCO 3 (0.4 mmol,33.6mg,2 equiv.) and stirring at room temperature for 24h, after the reaction, adding water to the reaction system, quenching, extracting with dichloromethane, collecting the organic phase, removing the solvent under reduced pressure, purifying by column chromatography to obtain product 6q (20.8 mg,73%, deuteration rate)>99%) (eluent polarity: PE: ea=5/1).
1 H NMR(400MHz,CDCl 3 )δ7.21(d,J＝8.6Hz,2H),6.78(d,J＝8.6Hz,2H), 5.04(brs,1H). 13 C NMR(100MHz,CDCl 3 )δ154.2,130.5,128.9,116.2.HRMS (EI-TOF)m/z Calcd for C 7 H 5 D 3 OS 143.0484[M] + ,Found 143.0482.
Example 28
(4- ((methyl-d) 3 ) Thio) phenyl) synthesis of tert-butyl carbamate:
s-deuterated methyl-4-methylbenzenesulfonyl thioester prepared by example 2 (0.2 mmol,41.0g,1 equiv.) 5r (0.3mmol,71.1mg,1.5 equiv.), anhydrous methanol (2.0 mL) was introduced into a dry schlenk tube under nitrogen atmosphere, and CuSO was added to the system 4 (0.01mmol,1.6mg,0.05equiv.), NaHCO 3 (0.4 mmol,33.6mg,2 equiv.) and stirring at room temperature for 24h, after the reaction, adding water to the reaction system, quenching, extracting with dichloromethane, collecting the organic phase, removing the solvent under reduced pressure,column chromatography purification gave product 6r (41.6 mg,86%, deuteration rate)>99%) (eluent polarity: PE: ea=10/1).
1 H NMR(400MHz,CDCl 3 )δ7.33(d,J＝8.7Hz,2H),7.25(d,J＝8.7Hz,2H), 6.52(s,1H),1.54(s,9H). 13 C NMR(100MHz,CDCl 3 )δ152.8,136.3,131.9,128.7, 119.3,80.7,28.4.HRMS(ESI-TOF)m/z:[M+Na] + Calcd for C 12 H 14 D 3 NO 2 S265.1066；Found 265.1063.
Example 29
5- ((methyl-d) 3 ) Thio) benzo [ d ]][1,3]Synthesis of dioxane:
s-deuterated methyl-4-methylbenzenesulfonyl sulfide (0.2 mmol,41.0g,1 equiv.) obtained by example 2, 5S (0.3mmol,49.8mg,1.5 equiv.), anhydrous methanol (2.0 mL) and CuSO were added to the system in a dry schlenk tube under nitrogen atmosphere 4 (0.01mmol,1.6mg,0.05equiv.), NaHCO 3 (0.4 mmol,33.6mg,2 equiv.) and stirring at room temperature for 24h, after the reaction, adding water to the reaction system, quenching, extracting with dichloromethane, collecting the organic phase, removing the solvent under reduced pressure, purifying by column chromatography to obtain product 6s (28.0 mg,82%, deuteration rate)>99%) (eluent polarity: PE).
1 H NMR(400MHz,CDCl 3 )δ6.84–6.73(m,3H),5.94(s,2H). 13 C NMR (100MHz,CDCl 3 )δ148.2,146.3,130.6,122.0,109.5,108.9,101.3.HRMS(EI-TOF) m/z Calcd for C 8 H 5 D 3 O 2 S 171.0433[M] + ,Found 171.0434.
Example 30
4- ((methyl-d) 3 ) Thio) dibenzo [ b, d]Furan:
s-deuterated methyl-4-methylbenzenesulfonyl sulfide (0.2 mmol,41.0g,1 equiv.), 5t (0.3mmol,63.6mg,1.5 equiv.), anhydrous methanol (2.0 mL) obtained by example 2 was charged into a dry schlenk tube under nitrogen atmosphere, and CuSO was added to the system 4 (0.01mmol,1.6mg,0.05equiv.), NaHCO 3 (0.4 mmol,33.6mg,2 equiv.) and stirring at room temperature for 24h, after the reaction, adding water to the reaction system, quenching, extracting with dichloromethane, collecting the organic phase, removing the solvent under reduced pressure, purifying by column chromatography to obtain the product 6t (29.5 mg,68%, deuteration rate)>99%) (eluent polarity: PE).
1 H NMR(400MHz,CDCl 3 )δ7.94(d,J＝7.6Hz,1H),7.79(d,J＝7.6Hz,1H), 7.65(d,J＝8.2Hz,1H),7.50–7.44(m,1H),7.40–7.33(m,2H),7.33–7.28(m, 1H). 13 C NMR(100MHz,CDCl 3 )δ156.1,154.2,127.4,126.1,124.2,123.4,123.0, 121.5,120.9,118.2,112.1.HRMS(EI)m/z Calcd for C 13 H 7 D 3 OS 217.0644[M] + , Found 217.0641.
Example 31
1, 4-bis ((methyl-d) 3 ) Thio) benzene synthesis:
s-deuterated methyl-4-methylbenzenesulfonyl sulfide (0.35 mmol,71.8mg,2.3 equiv.) obtained by example 2, 5u (0.15mmol,49.8mg,1 equiv.), anhydrous methanol (2.0 mL) and CuSO were added to the system in a dry schlenk tube under nitrogen atmosphere 4 (0.01mmol,1.6mg,0.05equiv.), NaHCO 3 (0.3 mmol,25.2mg,2 equiv.) and stirring at room temperature for 24h, after the reaction, adding water to the reaction system, quenching, extracting with dichloromethane, collecting the organic phase, removing the solvent under reduced pressure, purifying by column chromatography to obtain the product 6t (17.9 mg,68%, deuteration rate)>99%) (eluent polarity: PE).
1 H NMR(400MHz,CDCl 3 )δ7.20(s,4H). 13 C NMR(100MHz,CDCl 3 )δ 135.2,127.8.HRMS(EI-TOF)m/z Calcd for C 8 H 4 D 6 S 2 176.0601[M] + ,Found 176.0599.
Example 32
2- ((methyl-d) 3 ) Synthesis of thio) -1-oxo-2, 3-dihydro-1H-indene-2-carboxylic acid methyl ester:
s-deuterated methyl-4-methylbenzenesulfonyl thioester prepared by example 2 (61.5 mg,0.3mmol,1.5 equiv.) 5v (38.0mg,0.2mmol,1 equiv.), cs are introduced into a dry schlenk tube under nitrogen atmosphere 2 CO 3 (97.7 mg,0.3mmol,1.5 equiv.) and 1, 2-dichloroethane (1 ml), the reaction system was reacted at room temperature for 12 hours, after the completion of the reaction, water was added to the reaction system, the mixture was quenched, extracted with methylene chloride, the organic phase was collected, the solvent was removed under reduced pressure, and then purified by column chromatography to give the product 6v (43.0 mg,90% deuteration rate)>99%) (eluent polarity: PE: ea=20/1).
1 H NMR(400MHz,CDCl 3 )δ7.83(d,J＝7.8Hz,1H),7.66–7.60(m,1H), 7.46–7.40(m,2H),3.89(d,J＝17.8Hz,1H),3.80(s,3H),3.14(d,J＝17.8Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ196.3,169.9,150.5,135.5,134.0,128.4,126.3,125.7, 58.0,53.4,40.1.HRMS(ESI-TOF)m/z:[M+Na] + Calcd for C 12 H 9 D 3 O 3 SNa 262.0588；Found 262.0590.
Example 33
2- ((methyl-d) 3 ) Synthesis of tert-butyl thio) -1-oxo-2, 3-dihydro-1H-indene-2-carboxylate:
s-deuterated methyl-4-methylbenzenesulfonyl thioester prepared by example 2 (61.5 mg,0.3mmol,1.5 equiv.) and 5w (46.4mg,0.2mmol,1 equiv.), cs were added to a dry schlenk tube under nitrogen atmosphere 2 CO 3 (97.7mg,0.3mmol,1.5equiv(IV) and 1, 2-dichloroethane (1 ml), reacting the reaction system at room temperature for 12 hours, adding water to quench the reaction system after the completion of the reaction, extracting with methylene chloride, collecting an organic phase, removing the solvent under reduced pressure, and purifying by column chromatography to obtain a product 6w (53.3 mg, 95% deuteration rate)>99%) (eluent polarity: PE: ea=15/1).
1 H NMR(400MHz,CDCl 3 )δ7.80(d,J＝7.5Hz,1H),7.62–7.58(m,1H), 7.43–7.38(m,2H),3.82(d,J＝17.7Hz,1H),3.08(d,J＝17.7Hz,1H),1.46(s,9H). 13 C NMR(100MHz,CDCl 3 )δ196.8,168.3,150.5,135.2,134.2,128.1,126.2, 125.4,83.2,58.6,40.1,28.0.HRMS(ESI-TOF)m/z:[M+Na] + Calcd for C 15 H 15 D 3 O 3 S304.1062；Found 304.1060。
Example 34
S- (methyl-d) 3 ) Synthesis of 4-chlorophenyl thioester:
into a round bottom flask was charged S-deuterated methyl-4-methylbenzenesulfonyl thioester prepared by example 2 (0.25 mmol,51.2mg,1.0 equiv.) 5x (52.5 mg,0.375mmol,1.5 equiv.) and CH 3 CN (2.5 mL) and then tert-butyl hydroperoxide (0.5 mmol,64.5mg,2.0 equiv., 70wt.% in H) 2 O), the reaction was stirred at 82℃under reflux for 24 hours, the solvent was removed under reduced pressure, and then purified by column chromatography to give 6X (33.1 mg,70%, deuteration rate)>99%) (eluent polarity: PE).
1 H NMR(400MHz,CDCl 3 )δ7.91(d,J＝8.6Hz,2H),7.43(d,J＝8.6Hz,2H). 13 C NMR(100MHz,CDCl 3 )δ191.4,139.8,135.5,129.1,128.6.HRMS(EI-TOF) m/z Calcd for C 8 H 4 D 3 ClOS 189.0094[M] + ,Found 189.0103.
Example 35
4- ((methyl-d) 3 ) Thio) carbonyl) methyl benzoate:
into a round bottom flask were charged the S-deuterated methyl-4-methylbenzenesulfonyl thioester prepared by example 2 (0.25 mmol,51.2mg,1.0 equiv.), 5y (61.5 mg,0.375mmol,1.5 equiv.) and CH 3 CN (2.5 mL) and then tert-butyl hydroperoxide (0.5 mmol,64.5mg,2.0 equiv., 70wt.% in H) 2 O), the reaction was stirred at 82℃under reflux for 24 hours, the solvent was removed under reduced pressure, and then purified by column chromatography to give 6y (30.8 mg,58%, deuteration rate)>99%) (eluent polarity: PE).
1 H NMR(400MHz,CDCl 3 )δ8.11(d,J＝8.4Hz,2H),8.02(d,J＝8.4Hz,2H), 3.95(s,3H). 13 C NMR(100MHz,CDCl 3 )δ192.1,166.3,140.5,134.2,130.0,127.2, 52.6.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 10 H 8 D 3 O 3 S 214.0617；Found 214.0615.
Example 36
(methyl-d) 3 ) Synthesis of (m-tolylethynyl) sulfane:
5z (0.2 mmol,23.2mg,1 equiv.) and anhydrous tetrahydrofuran (1 mL) were added to a dry schlenk tube under nitrogen atmosphere, the tube was placed in an ice bath at-78℃and LiHMDs (0.22 mL,1M in THF,1.1equiv.) were slowly added dropwise, after 15 minutes, S-deuterated methyl-4-methylbenzenesulfonyl thioester (0.22 mmol,45.1mg,1.1 equiv.) prepared by example 2 was dissolved in anhydrous tetrahydrofuran (0.22 mL), the solution was added dropwise to the tube, reacted under the same conditions for another 15 minutes, then the schlenk tube was left to react at room temperature for 12 hours, the reaction was quenched with saturated ammonium chloride, followed by extraction with methylene chloride, the organic phase was collected, and after removal of the solvent under reduced pressure, column chromatography was purified to give 6z (30.8 mg,87%, deuterated rate > 99%) (eluent polarity: PE).
1 H NMR(400MHz,CDCl 3 )δ7.26–7.09(m,4H),2.32(s,3H). 13 C NMR(100 MHz,CDCl 3 )δ138.1,132.2,129.1,128.6,128.3,123.3,92.0,80.5,21.3.HRMS (EI-TOF)m/z Calcd for C 10 H 7 D 3 S 165.0692[M] + ,Found 165.0688.
Example 37
((4-chlorophenyl) ethynyl) (methyl-d) 3 ) Synthesis of sulfane:
5aa (0.2 mmol,27.0mg,1 equiv.) and anhydrous tetrahydrofuran (1 mL) were added to a dry schlenk tube under nitrogen atmosphere, the tube was placed in an ice bath at-78℃and LiHMDs (0.22 mL,1M in THF,1.1equiv.) were slowly added dropwise, after 15 minutes, S-deuterated methyl-4-methylbenzenesulfonyl thioester (0.22 mmol,45.1mg,1.1 equiv.) prepared by example 2 was dissolved in anhydrous tetrahydrofuran (0.22 mL), the solution was added dropwise to the tube, reacted under the same conditions for another 15 minutes, then the schlenk tube was left to react at room temperature for 12 hours, the reaction was quenched with saturated ammonium chloride, followed by extraction with methylene chloride, the organic phase was collected, and after removal of the solvent under reduced pressure, column chromatography was purified to give 6aa (25.1 mg,68% deuterated rate > 99%) (eluent polarity: PE).
1 H NMR(400MHz,CDCl 3 )δ7.33(d,J＝8.6Hz,2H),7.26(d,J＝8.6Hz, 2H)； 13 C NMR(100MHz,CDCl 3 )δ134.1,132.7,128.7,122.0,90.7,82.2.HRMS (ESI-TOF)m/z:[M+H] + Calcd for C 9 H 5 D 3 ClS 186.0224；Found 186.0228.
Example 38
2, 5-dichloro-3- ((methyl-d) 3 ) Thio) thiophene synthesis:
5ab (76.5 mg, 0.5) was added to a dry Schlenk flask under nitrogen atmospheremmol,1 equiv.) then 1mL THL solution was added and cooled to the appropriate temperature. TMPMgCl.LiCl (0.55mL,1M in THF,1.1equiv) was slowly added dropwise at room temperature and stirred at room temperature for 30 minutes. Then, S-deuterated methyl-4-methylbenzenesulfonyl thioester prepared in example 2 (128.1 mg,0.625mmol,1.25 equiv.) was added and the reaction mixture was stirred at room temperature for 30 minutes. After the reaction, 50% NH was used 4 Quench the reaction mixture with aqueous Cl solution and use Et 2 O (3X 10 mL) extraction. The combined organic layers were treated with Na 2 SO 4 Dried and concentrated in vacuo. Flash column chromatography on silica gel gave 6ab (85.4 mg,85%, deuteration rate)>99%). (eluent polarity: PE)
1 H NMR(400MHz,CDCl3)δ6.74(m,1H)； 13 C NMR(100MHz,CDCl3)δ131.3, 127.2,126.5,123.9.HRMS(EI)m/z Calcd for C 5 HD 3 Cl 2 S 2 200.9320[M] + ,Found 200.9324.
Example 39
S- (methyl-d) 3 ) Synthesis of diphenyl thiophosphonate:
5ac (0.2 mmol,40.4mg,1 equiv.) and anhydrous dichloromethane (2 mL) were added to a dry schlenk tube under nitrogen atmosphere, the tube was placed in an ice bath at-78℃and LiHMDs (0.22 mL,1M in THF,1.1equiv.) were slowly added dropwise, after 15 minutes, S-deuterated methyl-4-methylbenzenesulfonyl thioester prepared by example 2 (0.22 mmol,45.1mg,1.1 equiv.) was added, the reaction was further carried out under the same conditions for 15 minutes, then the schlenk tube was left to stand at room temperature for 12 hours, the reaction was quenched with saturated ammonium chloride, followed by extraction with dichloromethane, the organic phase was collected, and after removal of the solvent under reduced pressure, column chromatography was purified to give 6ac (30.1 mg,60%, deuterated rate > 99%) (eluent polarity: PE: EA=5/1).
1 H NMR(400MHz,CDCl 3 )δ7.91–7.84(m,4H),7.56–7.51(m,2H),7.50– 7.44(m,4H)； 13 C NMR(100MHz,CDCl 3 )δ132.8(d, 1 J C-P ＝106.7Hz),132.5(d, 4 J C-P ＝3.0Hz),131.6(d, 3 J C-P ＝10.5Hz),128.8(d, 2 J C-P ＝13.0Hz)； 31 P NMR(162 MHz,CDCl 3 )δ44.30.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 13 H 11 D 3 OPS 252.0686；Found 252.0686.
Example 40
S- (methyl-d) 3 ) -synthesis of N, N-diphenyl thiol hydroxylamine:
5ad (0.15 mmol,25.4mg,1 equiv.) and anhydrous tetrahydrofuran (1 mL) were added to a dry Schlenk tube under nitrogen, the tube was placed in an ice bath at 0deg.C, n-butyllithium (0.165 mmol,2.5M in THF,1.1equiv.) was slowly added dropwise, after 1 hour the tube was brought to room temperature and stirred for another 1 hour, then S-deuteromethyl-4-methylbenzenesulfonyl sulfide (0.22 mmol,45.1mg,1.1 equiv.) prepared by example 2 was added, and reacted under the same conditions for another 12 hours, after completion of the reaction, the reaction was quenched with saturated ammonium chloride, followed by extraction with dichloromethane, the organic phase was collected, and after removal of the solvent under reduced pressure, column chromatography was purified to give 6ad (16.3 mg,50%, deuteration > 99%) (eluent polarity: PE).
1 H NMR(400MHz,DMSO)δ7.35–7.29(m,2H),7.16–7.12(m,2H),7.09–7.01(m,1H)； 13 C NMR(100MHz,CDCl 3 )δ148.2,129.4,122.9,121.9.HRMS (ESI-TOF)m/z:[M+H] + Calcd for C 13 H 11 D 3 NS 219.1030；Found 219.1032.
Example 41
1-dodecyl-2- (methyl-d) 3 ) Synthesis of disulfane:
s-deuterated methyl-4-methylbenzenesulfonyl thioester prepared by example 2 (0.22 mmol,45.1mg,1.1 equiv.) was dissolved in a dry Schlenk tube under nitrogen and 1mL of anhydrous methylene chloride was added. Then 5ae (40.5 mg,0.2mmol,1 equiv.), triethylamine (20.2 mg,28.0 μl,0.2mmol,1 equiv.) and 0.5mL of anhydrous dichloromethane were formulated into a solution, which was slowly dropped into Schlenk tube. The reaction was stirred at room temperature for 4 hours, and after removal of the solvent under reduced pressure, column chromatography was performed to give 6ae (35.6 mg,71%, deuteration > 99%) (eluent polarity: PE).
1 H NMR(400MHz,CDCl 3 )δ2.69(q,J＝8.0Hz,2H),1.73–1.64(m,2H), 1.45–1.34(m,2H),1.27(s,16H),0.88(t,J＝6.8Hz,3H)； 13 C NMR(100MHz, CDCl 3 )δ39.3,38.5,32.1,29.8,29.7,29.6,29.5,29.4,29.3,28.7,22.8,14.2.HRMS (ESI-TOF)m/z:[M+H] + Calcd for C 13 H 26 D 3 S 2 252.1899；Found 252.1890.
Example 42
1- ((methyl-d) 3 ) Synthesis of sulfoxide) -4-nitrobenzene:
s-deuterated methyl-4-methylbenzenesulfonyl thioester prepared by example 2 (0.22 mmol,45.1mg,1.1 equiv.) was dissolved in dry Schlenk tube under nitrogen atmosphere, 1mL of anhydrous methylene chloride was added, and then 5af (31.0 mg,0.2mmol,1 equiv.), triethylamine (20.2 mg, 28.0. Mu.L, 0.2mmol,1 equiv.) and 0.5mL of anhydrous methylene chloride were formulated into a solution, which was slowly dropped into Schlenk tube, and after the solvent was removed under reduced pressure at room temperature under stirring for 4 hours, column chromatography was purified to give 6af (32.6 mg,80%, deuteration > 99%) (eluent polarity: PE).
1 H NMR(400MHz,CDCl 3 )δ8.19(d,J＝9.0Hz,2H),7.65(d,J＝9.0Hz, 2H). 13 C NMR(100MHz,CDCl 3 )δ146.6,146.4,125.9,124.3.HRMS(EI-TOF)m/z Calcd for C 7 H 4 D 3 NO 2 S 2 204.0107[M] + ,Found 204.0104.
Example 43
4- ((methyl-d) 3 ) Synthesis of sulfonyl) -1,1' -biphenyl:
6a (0.2 mmol,40.6mg,1 equiv.) and m-chloroperoxybenzoic acid (81.2 mg,85% by mass) were dissolved in dichloromethane (2.0 mL) in a Schlenk tube under air atmosphere, reacted at room temperature under stirring for 12 hours, and after removal of the solvent under reduced pressure, column chromatography was purified to give 7a (43.7 mg,93%, deuteration > 99%) (eluent polarity: PE: ea=1:1).
1 H NMR(400MHz,CDCl 3 )δ8.01(d,J＝8.5Hz,2H),7.77(d,J＝8.5Hz,2H), 7.63–7.59(m,2H),7.52–7.47(m,2H),7.46–7.41(m,1H)； 13 C NMR(100MHz, CDCl 3 )δ146.9,139.3,139.2,129.2,128.8,128.1,128.0,127.5.HRMS(ESI-TOF) m/z:[M+H] + Calcd for C 13 H 10 D 3 O 2 S 236.0825；Found 236.0823.mp:(132.0– 133.2)℃.
Example 44
4- ((methyl-d) 3 ) Synthesis of sulphoxide) -1,1' -biphenyls:
6a (0.2 mmol,40.6mg,1 equiv.) and sodium periodate (51.3 mg,0.24mmol,1.2 equiv.) are dissolved in methanol: water=1:1 (2.0 mL) under air in a Schlenk tube and heated at 50 ℃ for 6 hours, after the reaction is completed, the solvent is removed under reduced pressure, and column chromatography is performed to give 7b (36.4 mg,83%, deuteration > 99%) (eluent polarity: EA).
1 H NMR(400MHz,CDCl 3 )δ7.74(d,J＝8.6Hz,2H),7.70(d,J＝8.6Hz,2H), 7.62–7.58(m,2H),7.49–7.44(m,2H),7.42–7.36(m,1H)； 13 C NMR(100MHz, CDCl 3 )δ144.4,144.2,139.8,129.1,128.2,128.1,127.3,124.1.HRMS(ESI-TOF) m/z:[M+H] + Calcd for C 13 H 10 D 3 OS 220.0875；Found 220.0870.mp:(137.4– 139.0)℃.
Example 45
(Z) -N- ([ 1,1' -biphenyl)]-4-yl (methyl-d) 3 )-λ 4 -sulfoxide group) cyanamide synthesis:
6a (0.1 mmol,20.3mg,1.1 equiv.) was introduced into NCNH in a Schlenk tube under nitrogen atmosphere 2 (5.0mg,0.12mmol,1.2equiv.),PhI(OAc) 2 (35.4 mg,0.11mmol,1.1 equiv.) acetonitrile (2.0 mL) was added thereto, the mixture was stirred at 0℃for 12 hours, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography to give 7c (21.9 mg,90% deuteration rate)>99%) (eluent polarity: EA).
1 H NMR(400MHz,CDCl 3 )δ7.86(d,J＝8.6Hz,2H),7.79(d,J＝8.6Hz,2H), 7.60–7.55(m,2H),7.52–7.46(m,2H),7.46–7.40(m,1H)； 13 C NMR(100MHz, CDCl 3 )δ146.5,139.0,134.6,129.3,129.0,128.9,127.4,126.7,124.1.HRMS (ESI-TOF)m/z:[M+Na]+ Calcd for C 14 H 9 D 3 N 2 S266.0802；Found 266.0807。

Claims (5)

1. The method comprises the following steps ofSThe synthetic method of the deuterated methyl-aryl sulfonyl thioester compound is characterized in that the structural formula is shown as a formula (4),
，
wherein R is 1 A substituent selected from substituted phenyl or naphthalene ring, wherein the substituent on the substituted phenyl is tert-butyl, fluorine, chlorine or bromine;
the synthesis method comprises the following steps:
1) In an organic solvent, deuterated methanol shown in the formula (1) reacts with an electrophile in the environment of alkali and nitrogen to generate an intermediate shown in the formula (2);
2) Reacting an intermediate shown in a formula (2) with aryl sodium thiosulfate shown in a formula (3) under the action of a phase transfer catalyst to obtain a compound shown in a formula (4), wherein the reaction process is as follows:
；
the organic solvent isN,N-dimethylacetamide or acetonitrile, the phase transfer catalyst being tetrabutylammonium iodide, the phase transfer catalyst being used in an amount of 2.5 to 100mol% of deuterated methanol represented by formula (1);
the electrophile is trifluoro methanesulfonic anhydride, trifluoro methanesulfonyl chloride or methanesulfonic anhydride, and the base is 2, 6-dimethyl pyridine or triethylamine; the reaction temperature of the step 1) is-20-0 ℃; the reaction temperature of the step 2) is 30-100 ℃.
2. The method of synthesis of claim 1, wherein the electrophile is used in an amount of 1.05 to 5.0 equivalents of deuterated methanol of formula (1).
3. The method of synthesis of claim 1, wherein the base is used in an amount of 1.0 to 5.0 equivalents of deuterated methanol of formula (1).
4. The method of synthesis of claim 1, wherein the molar ratio of deuterated methanol of formula (1) to arylthio sulfonate of formula (3) is 1.0:1.0 to 1.0:5.0.
5. The synthetic method of claim 1 wherein the reaction time of step 1) is from 1 to 4 h; the reaction time of step 2) is 4-12 h.
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