CN111269153A - Synthesis method of α -difluoro- β -carbonyl sulfone compound - Google Patents
Synthesis method of α -difluoro- β -carbonyl sulfone compound Download PDFInfo
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- CN111269153A CN111269153A CN202010083958.7A CN202010083958A CN111269153A CN 111269153 A CN111269153 A CN 111269153A CN 202010083958 A CN202010083958 A CN 202010083958A CN 111269153 A CN111269153 A CN 111269153A
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 33
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims abstract description 16
- -1 aryl diazonium salt Chemical class 0.000 claims abstract description 15
- 239000012954 diazonium Substances 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 11
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 28
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 239000000460 chlorine Substances 0.000 claims description 17
- 239000003504 photosensitizing agent Substances 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- 239000012295 chemical reaction liquid Substances 0.000 claims description 7
- 238000004440 column chromatography Methods 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000003208 petroleum Substances 0.000 claims description 7
- 150000003254 radicals Chemical class 0.000 claims description 7
- 238000000926 separation method Methods 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 230000002950 deficient Effects 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000000010 aprotic solvent Substances 0.000 claims description 4
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 229910004879 Na2S2O5 Inorganic materials 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- VQGHOUODWALEFC-UHFFFAOYSA-N 2-phenylpyridine Chemical compound C1=CC=CC=C1C1=CC=CC=N1 VQGHOUODWALEFC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 239000012973 diazabicyclooctane Substances 0.000 claims description 2
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 claims description 2
- SEACYXSIPDVVMV-UHFFFAOYSA-L eosin Y Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C([O-])=C(Br)C=C21 SEACYXSIPDVVMV-UHFFFAOYSA-L 0.000 claims description 2
- 238000012544 monitoring process Methods 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 2
- 238000006555 catalytic reaction Methods 0.000 claims 2
- 125000001174 sulfone group Chemical group 0.000 claims 1
- 235000010262 sodium metabisulphite Nutrition 0.000 abstract description 14
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000002904 solvent Substances 0.000 abstract description 3
- 239000003513 alkali Substances 0.000 abstract description 2
- 125000000524 functional group Chemical group 0.000 abstract 1
- 239000000758 substrate Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 30
- 229940001584 sodium metabisulfite Drugs 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- 238000004293 19F NMR spectroscopy Methods 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 5
- 238000012512 characterization method Methods 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 3
- CIZVQWNPBGYCGK-UHFFFAOYSA-N benzenediazonium Chemical class N#[N+]C1=CC=CC=C1 CIZVQWNPBGYCGK-UHFFFAOYSA-N 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- PBFZWQBSVZTREH-UHFFFAOYSA-N 3,5-dimethylbenzenediazonium Chemical class CC1=CC(C)=CC([N+]#N)=C1 PBFZWQBSVZTREH-UHFFFAOYSA-N 0.000 description 1
- DBEQHSWUYRYJMT-UHFFFAOYSA-N 4-chlorobenzenediazonium Chemical class ClC1=CC=C([N+]#N)C=C1 DBEQHSWUYRYJMT-UHFFFAOYSA-N 0.000 description 1
- LWYMLCYZEMSNBK-UHFFFAOYSA-N 4-methylbenzenediazonium Chemical class CC1=CC=C([N+]#N)C=C1 LWYMLCYZEMSNBK-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- LTXREWWZJREOFH-UHFFFAOYSA-N difluoromethylsulfonyl(difluoro)methane Chemical compound FC(F)S(=O)(=O)C(F)F LTXREWWZJREOFH-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000005281 excited state Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of organic chemistry, in particular to a synthesis method of α -difluoro- β -carbonyl sulfone compounds, which takes acetonitrile as a solvent and consists of aryl diazonium salt, sodium pyrosulfite and 2, 2-difluoroenol silyl ether in Ru (bpy)3Cl2·6H2The synthesis method of the compound has the advantages that the aryl diazonium salt, the sodium pyrosulfite and the 2, 2-difluoroenol silyl ether which are easily obtained are used as raw materials, strong alkali, ultralow temperature and other harsh reaction conditions are not needed, the compound has the advantages of strong functional group compatibility, wide substrate application range and the like, and the synthesis method can realize the synthesis of the compoundThe high-efficiency synthesis of a series of α -difluoro- β -carbonyl sulfone compounds has good academic guidance significance and industrial application value.
Description
Technical Field
The invention belongs to the technical field of organic chemistry, and particularly relates to a synthesis method of α -difluoro- β -carbonyl sulfone compounds
Background
α -difluoro- β -carbonyl sulfone is a common sulfonyl compound containing a difluoromethyl structure, and in the field of organic synthesis, α -difluoro- β -carbonyl sulfone compounds can be used as key intermediates to participate in nucleophilic addition, cycloaddition and self-synthesisThe fluorine-containing compound with important biological activity is constructed by radical reaction. [ C.Ni, L.Zhang, J.Hu, J.org.chem.2009,74,3767; (b) ye, l.zhang, c.ni, j.rong, j.hu, chem.commun.,2014,50,10596.]In pharmaceutical chemistry, the use of difluoromethyl as a structural mimic of hydroxyl groups in bioactive molecules has also attracted considerable attention, and the introduction of difluoromethyl into bioactive molecules can significantly improve their metabolic stability and oral bioavailability, etc. [ Y.Zafrani, G.Sod-Moriah, D.Yeffet, A.Berlinier, D.Amir, D.Marciano, S.Elias, S.Katalan, N.Ashkenazi, M.Madmon, E.Gershonov, S.Saphier, J.Med.Chem.2019,62,5628; (b) x. s.hu, j. -s.yu, j.zhou, chem.commun, 2019,55,13638.]At present, the synthesis method of α -difluoro- β -carbonyl sulfone compounds is very rarely reported, 2009, Hu group reports methyl benzoate and difluoromethyl sulfone (PhSO)2CF2H) To synthesize α -difluoro- β -carbonyl sulfone compounds [ C.Ni, L.Zhang, J.Hu, J.org.chem.2009,74,3767]The method needs to be carried out under strong alkali LHMDS and ultralow temperature (-98 ℃), and further application of the method is limited, so that the development of the method for efficiently synthesizing the α -difluoro- β -carbonyl sulfone compound, which has the advantages of easily obtained raw materials, mild conditions and simple and convenient operation, has good economic prospect and application value.
In recent years, the solid sulfur dioxide substitute is used as a source of sulfur dioxide, and a molecule of sulfur dioxide is inserted into an organic molecule, so that a novel synthesis strategy which is widely concerned is formed, and the quick and efficient synthesis of sulfonyl compounds is realized. [ (a) a.s.Deeming, E.j.emmett, C.s.Richards-Taylor, M.C.Willis, Synthesis 2014,2701; (b) liu, c.fan, j.wu, org.biomol.chem.2015,13,1592; (c) emmett, m.c. willis, Asian j.org.chem.2015,4,602; (d) g.qiu, k.zhou, l.gao, j.wu, org.chem.front.2018,5,691; (e) k.hofman, n. -w.liu, g.manolikakes, chem.eur.j.2018,24,11852; (f) g.qiu, l.lai, j.cheng, j.wu, chem.commun.,2018,54, 10405; (g) g.qiu, k.zhou, j.wu, chem.commun.,2018,54, 12561; (h) s.ye, g.qiu and j.wu, chem.commun.,2019,55,1013 ]
Disclosure of Invention
The invention aims to provide a simple and efficient synthesis method of α -difluoro- β -carbonyl sulfone compounds.
The synthesis method of the α -difluoro- β -carbonyl sulfone compound provided by the invention is characterized in that aryl diazonium salt, sodium pyrosulfite and 2, 2-difluoroenol silyl ether are used as raw materials, and the α -difluoro- β -carbonyl sulfone compound is efficiently constructed through reaction under the irradiation conditions of a photosensitizer and blue light.
Specifically, the method of the invention is carried out by reacting aryl diazonium salt, sodium pyrosulfite and 2, 2-difluoroenol silyl ether in Ru (bpy) in an organic solvent (such as acetonitrile)3Cl2·6H2Under the condition of taking O as a photosensitizer, placing the O under the irradiation of blue light to react, generating aryl sulfonyl free radicals by aryl diazonium salt and sodium metabisulfite under the action of the blue light and the photosensitizer, then carrying out addition on 2, 2-difluoroenol silyl ether to obtain a free radical intermediate, and carrying out single electron oxidation on the intermediate and the excited photosensitizer to obtain α -difluoro- β -carbonyl sulfone compounds, wherein the reaction formula is as follows:
in the formula, Ar is a phenyl or heterocyclic substituent substituted by electron-withdrawing or electron-donating groups, the electron-withdrawing groups are any one of fluorine, chlorine, bromine, trifluoromethyl, acyl and ester group substituents, the electron-donating groups are alkyl or alkoxy substituent groups, and the heterocyclic rings are electron-deficient or electron-rich heterocyclic rings.
R is a phenyl or heterocyclic substituent substituted by an electron withdrawing group or an electron donating group, the electron withdrawing group is any one of fluorine, chlorine, bromine, iodine and acyl substituent, the electron donating group is alkyl or alkoxy substituent, and the heterocycle is an electron-deficient or electron-rich heterocycle.
The method comprises the following specific steps:
(1) to the reaction tube were added, in this order, an aryl diazonium salt (0.3mmol), sodium metabisulfite (0.4mmol), 2-difluoroenolsilyl ether (0.2mmol) and Ru (bpy) at room temperature3Cl2·6H2O (0.004mmol), plugging the reaction tube by a plug, placing the reaction tube in high-purity nitrogen or argon for three times, adding acetonitrile (2mL) after the system is in an anaerobic condition, placing the system under 15W blue light irradiation, and stirringStirring until complete reaction;
(2) and after TLC monitoring complete reaction, directly carrying out reduced pressure concentration on the reaction liquid, carrying out column chromatography separation, and taking a mixed system of petroleum ether and ethyl acetate as a mobile phase to obtain the corresponding sulfonyl acetonitrile compound.
The yield of the reaction can reach 25-80%.
The structure of the compound is shown in the specification1H NMR、13C NMR, HRMS and the like.
In the invention, the electron-withdrawing group or electron-donating group substituted phenyl or heterocyclic substituent group, the electron-withdrawing group is any one of fluorine, chlorine, bromine, trifluoromethyl, acyl and ester group substituent groups, the electron-donating group is alkyl or alkoxy substituent group, and the heterocycle is electron-deficient or electron-rich heterocycle.
In the invention, the solid substitute of sulfur dioxide is Na2S2O5The second alternative may be DABCO.(SO2)2Or K2S2O5. The reaction yield is reduced to a certain extent when replacing the sulfur dioxide solid substitute.
In the invention, R is a phenyl or heterocyclic substituent substituted by electron-withdrawing or electron-donating groups, the electron-withdrawing groups are any one of fluorine, chlorine, bromine, iodine and acyl substituents, the electron-donating groups are alkyl or alkoxy substituents, and the heterocyclic rings are electron-deficient or electron-rich heterocyclic rings.
In the present invention, the photosensitizer used is Ru (bpy)3Cl2·6H2O, alternative Ir (ppy)3、Eosin-Y、Eosin Y-Na2And fluoroescein, etc. are commonly used as commercial photosensitizers. The reaction yield is reduced to a certain extent when the photosensitizer is replaced.
In the present invention, the organic solvent used is preferably acetonitrile, and less preferred solvents are aprotic solvents such as 1, 2-dichloroethane, dichloromethane, tetrahydrofuran, and 1, 4-dioxane. The reaction yield is reduced in the above solvents.
In the invention, the usage of sodium metabisulfite is preferably 2.0 equivalents, and the alternative usage is 1.0-3.0 equivalents based on 1.0 equivalent of 2, 2-difluoroenol silyl ether; the aryl diazonium salt is 1.5 equivalent, and the alternative dosage is 1.0.0-3.0 equivalent. The above substitution causes a certain reduction in the reaction yield.
In the invention, the used light source is blue light, and the secondary options can be visible light sources such as white light, green light and the like. The above substitution causes a certain reduction in the reaction yield.
In the invention, the blue light power is 15W, the secondary option can be 3W-100W, and the change of the blue light power in the range has no obvious influence on the reaction yield.
In the present invention, the reaction temperature is preferably room temperature, and the alternative temperature is 50 ℃, and changing the reaction temperature within the above range has no significant effect on the reaction yield.
The method of the invention is carried out by reacting aryl diazonium salt, sodium pyrosulfite and 2, 2-difluoroenol silyl ether in Ru (bpy) in organic solvent (such as acetonitrile)3Cl2·6H2The method comprises the steps of placing O as a photosensitizer, reacting under the irradiation of blue light, generating aryl sulfonyl free radicals by aryl diazonium salt and sodium pyrosulfite under the action of the blue light and the photosensitizer, adding 2, 2-difluoroenol silyl ether to obtain a free radical intermediate, and carrying out single electron oxidation on the intermediate and the photosensitizer in an excited state to obtain the α -difluoro- β -carbonyl sulfone compound.
Detailed Description
The invention is further described below by means of specific examples.
Example 1
To a dry reaction tube were added p-tolyl diazonium salt (0.3mmol), sodium metabisulfite (0.4mmol), 2-difluoroenolsilyl ether (0.2mmol), and Ru (bpy) in this order at room temperature3Cl2·6H2And O (0.004mmol), plugging the reaction tube by using a plug, placing the reaction tube in high-purity nitrogen for three times, adding acetonitrile (2mL) after the system is in an anaerobic condition, placing the system under 15W blue light irradiation, stirring the mixture until the TLC monitors complete reaction, directly decompressing and concentrating the reaction liquid, and performing column chromatography separation by using a mixed system of petroleum ether and ethyl acetate as a mobile phase to obtain the corresponding α -difluoro- β -carbonyl sulfone compound example 1.
Structural characterization of compound example 1:1H NMR(400MHz,CDCl3)δ8.18(d,J＝7.8Hz,1H),7.90(d,J＝7.7Hz,1H),7.70(t,J＝7.4Hz,1H),7.54(t,J＝7.5Hz,1H),7.44(d,J＝7.8Hz,1H),2.50(s,2H).13C NMR(100MHz,CDCl3)δ184.0(t,J＝23.1Hz),147.7,135.3,132.1,130.9,130.8(t,J＝3.1Hz),130.2,129.4,128.8,116.5(t,J＝300.7Hz),21.9.19F NMR(376MHz,CDCl3)δ-101.7.
example 2
To a dry reaction tube were added phenyl diazonium salt (0.3mmol), sodium metabisulfite (0.4mmol), 2-difluoroenolsilyl ether (0.2mmol), and Ru (bpy) in this order at room temperature3Cl2·6H2And O (0.004mmol), plugging the reaction tube by using a plug, placing the reaction tube in high-purity nitrogen for three times, adding acetonitrile (2mL) after the system is in an anaerobic condition, placing the system under 15W blue light irradiation, stirring the mixture until the TLC monitors complete reaction, directly decompressing and concentrating the reaction liquid, and performing column chromatography separation by using a mixed system of petroleum ether and ethyl acetate as a mobile phase to obtain the corresponding α -difluoro- β -carbonyl sulfone compound example 2.
Structural characterization of compound example 2:1H NMR(400MHz,CDCl3)δ8.18(d,J＝7.6Hz,1H),8.04(d,J＝7.6Hz,1H),7.82(t,J＝7.4Hz,1H),7.74-7.63(m,2H),7.55(t,J＝7.5Hz,1H).13C NMR(100MHz,CDCl3)δ183.7(t,J＝23.2Hz),136.0,135.4,132.6,132.0,130.9,130.8(t,J＝3.1Hz),129.5,128.9,116.5(t,J＝301.2Hz).19F NMR(376MHz,CDCl3)δ-101.5.
example 3
To a dry reaction tube were added p-chlorophenyl diazonium salt (0.3mmol), sodium metabisulfite (0.4mmol), 2-difluoroenolsilyl ether (0.2mmol), and Ru (bpy) in this order at room temperature3Cl2·6H2And O (0.004mmol), plugging the reaction tube by using a plug, placing the reaction tube in high-purity nitrogen for three times, adding acetonitrile (2mL) after the system is in an anaerobic condition, placing the system under 15W blue light irradiation, stirring the mixture until the TLC monitors complete reaction, directly decompressing and concentrating the reaction liquid, and performing column chromatography separation by using a mixed system of petroleum ether and ethyl acetate as a mobile phase to obtain the corresponding α -difluoro- β -carbonyl sulfone compound example 3.
Structural characterization of compound example 3:1H NMR(400MHz,CDCl3)δ8.17(d,J＝7.8Hz,1H),7.97(d,J＝8.0Hz,1H),7.72(t,J＝7.4Hz,1H),7.64(d,J＝7.9Hz,1H),7.56(t,J＝7.6Hz,1H).13CNMR(100MHz,CDCl3)δ183.6(t,J＝23.0Hz),143.3,135.5,132.3,131.9,131.0,130.7(t,J＝3.2Hz),123.0,128.9,116.4(t,J＝301.6Hz).19F NMR(376MHz,CDCl3)δ-101.3.
example 4
To a dry reaction tube were added 3, 5-xylyldiazonium salt (0.3mmol), sodium metabisulfite (0.4mmol), 2-difluoroenolsilyl ether (0.2mmol), and Ru (bpy) in this order at room temperature3Cl2·6H2O (0.004mmol), plugging a reaction tube by a plug, placing in high-purity nitrogen for three times, adding acetonitrile (2mL) after the system is in an anaerobic condition, placing in 15W blue light for irradiation, stirring until TLC (thin layer chromatography) monitors complete reaction, directly decompressing and concentrating the reaction liquid, and performing column chromatography separation by using a mixed system of petroleum ether and ethyl acetate as a mobile phase to obtain a corresponding α -difluoro- β -carbonyl sulfone compound4。
Structural characterization of compound example 4:1H NMR(400MHz,CDCl3)δ8.19(d,J＝7.9Hz,1H),7.70(t,J＝7.4Hz,1H),7.63(s,1H),7.55(t,J＝7.5Hz,1H),7.41(s,1H),2.44(s,1H).13C NMR(100MHz,CDCl3)δ183.8(t,J＝23.0Hz),139.7,137.8,135.3,132.2,132.1,130.8(t,J＝3.2Hz),128.8,128.3,116.6(t,J＝301.0Hz),21.1.19F NMR(376MHz,CDCl3)δ-101.5.
example 5
To a dry reaction tube were added phenyl diazonium salt (0.3mmol), sodium metabisulfite (0.4mmol), 2-difluoroenolsilyl ether (0.2mmol), and Ru (bpy) in this order at room temperature3Cl2·6H2And O (0.004mmol), plugging the reaction tube by using a plug, placing the reaction tube in high-purity nitrogen for three times, adding acetonitrile (2mL) after the system is in an oxygen-free condition, placing the mixture under the irradiation of 15W blue light, stirring the mixture until the TLC monitors complete reaction, directly concentrating the reaction liquid under reduced pressure, and performing column chromatography separation by using a mixed system of petroleum ether and ethyl acetate as a mobile phase to obtain the corresponding α -difluoro- β -carbonyl sulfone compound example 5.
Structural characterization of compound example 5:1H NMR(400MHz,CDCl3)δ8.08(d,J＝8.1Hz,1H),8.03(d,J＝7.7Hz,1H),7.80(t,J＝7.5Hz,1H),7.65(t,J＝7.8Hz,1H),7.34(d,J＝8.2Hz,1H),2.45(s,1H).13C NMR(100MHz,CDCl3)δ183.0(t,J＝22.8Hz),146.9,135.8,132.5,130.9,130.8,129.5,129.4,116.5(t,J＝301.1Hz),21.8.19F NMR(376MHz,CDCl3)δ-101.4.
it will be appreciated by persons skilled in the art that the above examples are illustrative only and not intended to be limiting of the invention, and that modifications to the above described embodiments will fall within the scope of the appended claims provided they fall within the true spirit of the invention.
Claims (10)
1. An α -difluoro- β -carbonyl sulfone compound is characterized in that sulfone groups and difluoromethyl groups are simultaneously introduced into molecules through visible light catalysis, and the molecular structural general formula of the compound is as follows:
in the formula (I), the compound is shown in the specification,
ar is a phenyl or heterocyclic substituent substituted by electron-withdrawing or electron-donating groups, the electron-withdrawing groups are any one of fluorine, chlorine, bromine, trifluoromethyl, acyl and ester group substituents, the electron-donating groups are alkyl or alkoxy substituent groups, and the heterocyclic rings are electron-deficient or electron-rich heterocyclic rings.
R is a phenyl or heterocyclic substituent substituted by an electron withdrawing group or an electron donating group, the electron withdrawing group is any one of fluorine, chlorine, bromine, iodine and acyl substituent, the electron donating group is alkyl or alkoxy substituent, and the heterocycle is an electron-deficient or electron-rich heterocycle.
2. The method for synthesizing α -difluoro- β -carbonyl sulfone compound as claimed in claim 1, wherein in an aprotic solvent, aryl diazonium salt, sulfur dioxide solid substitute and 2, 2-difluoroenol silyl ether are put under the catalysis of a photosensitizer and are irradiated by blue light to react, the aryl diazonium salt and the sulfur dioxide solid substitute generate aryl sulfonyl free radicals under the action of the blue light and the photosensitizer, then 2, 2-difluoroenol silyl ether is added to obtain a free radical intermediate, and the free radical intermediate and the excited photosensitizer undergo single electron oxidation to obtain α -difluoro- β -carbonyl sulfone compound, which comprises the following steps:
(1) adding a certain amount of aryl diazonium salt, a sulfur dioxide solid substitute, 2-difluoroenol silyl ether and a photosensitizer into a dry test tube at room temperature, plugging the reaction tube by using a plug, placing the reaction tube in high-purity nitrogen or argon for three times, adding a certain amount of aprotic solvent after the system is in an anaerobic condition, placing the mixture under 15W blue light irradiation, and stirring until the mixture is completely reacted;
(2) after TLC monitoring complete reaction, directly decompressing and concentrating the reaction liquid, carrying out column chromatography separation, and adopting a mixed system of petroleum ether and ethyl acetate as a mobile phase to obtain the corresponding α -difluoro- β -carbonyl sulfone compound.
3. A synthesis process according to claim 2, characterized in that the solid substitute for sulfur dioxide used is Na2S2O5、DABCO.(SO2)2And K2S2O5Any one of them.
4. A synthesis process according to claim 3, characterized in that the solid substitute for sulfur dioxide used is Na2S2O5。
5. The synthesis process as claimed in claim 2, wherein the photosensitizer used is Ru (bpy)3Cl2·6H2O、Ir(ppy)3、Eosin-Y、Eosin Y-Na2And fluoroescein.
6. The synthesis process as claimed in claim 5, wherein the photosensitizer used is Ru (bpy)3Cl2·6H2O。
7. The method according to claim 2, wherein the aprotic solvent is any one of acetonitrile, 1, 2-dichloroethane, dichloromethane, tetrahydrofuran and 1, 4-dioxane.
8. The synthesis method of claim 2, wherein the sulfur dioxide solid substitute is used in an amount of 1.0 to 3.0 equivalents based on 1.0 equivalent of 2, 2-difluoroenolsilyl ether; the aryl diazonium salt is 1.0.0-3.0 equivalent.
9. A method of synthesis as claimed in claim 2, characterised in that the light source used is any one of blue, white and green light.
10. The synthesis method according to claim 9, wherein the blue light power used is 3W-100W, and the reaction temperature is room temperature to 50 ℃.
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| CN112266345B (en) * | 2020-10-30 | 2022-05-13 | 四川大学 | Preparation method of alpha, alpha-difluoro-beta-ketone sulfone compound |
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