CN111269153B - Synthetic method of alpha, alpha-difluoro-beta-carbonyl sulfone compound - Google Patents
Synthetic method of alpha, alpha-difluoro-beta-carbonyl sulfone compound Download PDFInfo
- Publication number
- CN111269153B CN111269153B CN202010083958.7A CN202010083958A CN111269153B CN 111269153 B CN111269153 B CN 111269153B CN 202010083958 A CN202010083958 A CN 202010083958A CN 111269153 B CN111269153 B CN 111269153B
- Authority
- CN
- China
- Prior art keywords
- alpha
- electron
- beta
- difluoro
- photosensitizer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000010189 synthetic method Methods 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000003504 photosensitizing agent Substances 0.000 claims abstract description 18
- 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
- 239000012954 diazonium Substances 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 12
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- 150000003254 radicals Chemical class 0.000 claims abstract description 9
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 9
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 8
- 230000009471 action Effects 0.000 claims abstract description 4
- 230000003647 oxidation Effects 0.000 claims abstract description 4
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 4
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims abstract description 3
- 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
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 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 10
- 239000007787 solid Substances 0.000 claims description 10
- 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
- 239000000543 intermediate Substances 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000003208 petroleum Substances 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 class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 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
- 238000001308 synthesis method Methods 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
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 229910052740 iodine Inorganic materials 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
- 239000000126 substance Substances 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
- 150000001989 diazonium salts Chemical class 0.000 claims 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 2
- 239000000203 mixture Substances 0.000 claims 2
- 238000006555 catalytic reaction Methods 0.000 claims 1
- 150000002170 ethers Chemical class 0.000 claims 1
- 235000010262 sodium metabisulphite Nutrition 0.000 abstract description 14
- -1 aryl diazonium salts Chemical class 0.000 abstract description 13
- 229940001584 sodium metabisulfite Drugs 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000003513 alkali Substances 0.000 abstract description 2
- 125000000524 functional group Chemical group 0.000 abstract 1
- 239000004296 sodium metabisulphite Substances 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
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy 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
- 125000001424 substituent group Chemical group 0.000 description 4
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 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
- 239000002904 solvent Substances 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
- 239000002253 acid Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-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
- 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
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 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
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
Landscapes
- 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, and particularly relates to a synthetic method of an alpha, alpha-difluoro-beta-carbonyl sulfone compound. The method of the invention is to use acetonitrile as a solventFrom aryl diazonium salts, sodium metabisulphite and 2, 2-difluoroenolsilyl ether in Ru (bpy)3Cl2·6H2And (2) under the condition of taking O as a photosensitizer, reacting under the irradiation of blue light, generating aryl sulfonyl free radicals by using aryl diazonium salt and sodium metabisulfite 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 excited photosensitizer to obtain the alpha, alpha-difluoro-beta-carbonyl sulfone compound. The synthetic method of the compound has the advantages that the aryl diazonium salt, the sodium pyrosulfite and the 2, 2-difluoroenol silyl ether which are simple and easy to obtain are used as raw materials, harsh reaction conditions such as strong alkali and ultralow temperature are not needed, the advantages of strong functional group compatibility, wide substrate application range and the like are achieved, the high-efficiency synthesis of a series of alpha, alpha-difluoro-beta-carbonyl sulfone compounds can be realized, and the synthetic method 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 synthetic method of an alpha, alpha-difluoro-beta-carbonyl sulfone compound
Background
Alpha, alpha-difluoro-beta-carbonyl sulfone is a common sulfonyl compound containing a difluoromethyl structure. In the field of organic synthesis, alpha-difluoro-beta-carbonyl sulfone compounds can be used as key intermediates to participate in nucleophilic addition, cycloaddition and free radical reaction to construct fluorine-containing compounds with important biological activity. [ 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, reports about synthetic methods of alpha, alpha-difluoro-beta-carbonyl sulfone compounds are extremely rare. In 2009, the Hu group reported methyl benzoate and difluoromethyl sulfone (PhSO)2CF2H) To synthesize the alpha, alpha-difluoro-beta-carbonyl sulfone compound. [ C.Ni, L.Zhang, J.Hu, J.org.chem.2009,74,3767]The method needs to be carried out under the conditions of strong alkali LHMDS and ultralow temperature (-98 ℃), and further application of the method is limited. Therefore, the method for efficiently synthesizing the alpha, alpha-bis has the advantages of easily obtained raw materials, mild conditions and simple and convenient operationThe method for preparing the fluorine-beta-carbonyl sulfone compound 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, convenient and efficient synthesis method of alpha, alpha-difluoro-beta-carbonyl sulfone compounds.
The synthesis method of the alpha, alpha-difluoro-beta-carbonyl sulfone compound provided by the invention uses aryl diazonium salt, sodium pyrosulfite and 2, 2-difluoroenol silyl ether as raw materials, and the alpha, alpha-difluoro-beta-carbonyl sulfone compound is efficiently constructed by 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)3Cl2·6H2And (2) under the condition of taking O as a photosensitizer, reacting under the irradiation of blue light, generating aryl sulfonyl free radicals by using aryl diazonium salt and sodium metabisulfite 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 excited photosensitizer to obtain the alpha, alpha-difluoro-beta-carbonyl sulfone compound. 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 the irradiation of 15W blue light, and stirring until the reaction is completed;
(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. Replacing sulfur dioxide solid substituteThe yield is somewhat reduced.
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)3Cl2·6H2O as photosensitizer reacts under the irradiation of blue light to generate aryl sulfonyl radical under the action of blue light and photosensitizerAnd (3) adding the silyl ether to obtain a free radical intermediate, and performing single electron oxidation on the intermediate and an excited photosensitizer to obtain the alpha, alpha-difluoro-beta-carbonyl sulfone compound. The sulfur dioxide solid substitutes used in the method are all abundant and easily-obtained chemical raw materials, so that the use of strong acid raw materials in the traditional sulfonyl compound synthesis is avoided, a new way is provided for the efficient synthesis of a series of alpha, alpha-difluoro-beta-carbonyl sulfone compounds, and the method has important research and application values.
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 temperature3Cl2·6H2O (0.004mmol), plugging the reaction tube with 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 stirring until the TLC monitors complete reaction. And (3) directly concentrating the reaction solution 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 alpha, alpha-difluoro-beta-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 temperature3Cl2·6H2O (0.004mmol), plugging the reaction tube with 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 stirring until the TLC monitors complete reaction. And (3) directly concentrating the reaction solution 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 alpha, alpha-difluoro-beta-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 temperature3Cl2·6H2O (0.004mmol), plugging the reaction tube with 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 stirring until the TLC monitors complete reaction. The reaction liquid is directly decompressed and concentrated, and a mixed system of petroleum ether and ethyl acetate is used as a mobile phase for column chromatography separation, so that the corresponding alpha, alpha-difluoro-beta-carbonyl sulfone compound example 3 can be obtained.
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).13C NMR(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 the reaction tube with 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 stirring until the TLC monitors complete reaction. And (3) directly concentrating the reaction solution 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 alpha, alpha-difluoro-beta-carbonyl sulfone compound example 4.
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 temperature3Cl2·6H2O (0.004mmol), plugging the reaction tube by a plug, placing the reaction tube in high-purity nitrogen for three times, and making the system be in a state of noAfter oxygen, acetonitrile (2mL) was added and stirred under 15W blue light until TLC monitored complete reaction. And (3) directly concentrating the reaction solution 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 alpha, alpha-difluoro-beta-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 (5)
1. A synthetic method of alpha, alpha-difluoro-beta-carbonyl sulfone compounds is characterized in that diazonium salts, sulfur dioxide solid substitutes and 2, 2-difluoroenol silyl ether derivatives are placed in an aprotic solvent under the catalysis of a photosensitizer and are irradiated by blue light to react, the diazonium salts and the sulfur dioxide solid substitutes generate aryl sulfonyl free radicals under the action of the blue light and the photosensitizer, then the 2, 2-difluoroenol silyl ether derivatives are added to obtain free radical intermediates, and the free radical intermediates and the excited photosensitizer are subjected to single electron oxidation to obtain the alpha, alpha-difluoro-beta-carbonyl sulfone compounds, wherein the reaction formula is as follows:
in the formula (I), the compound is shown in the specification,
ar is an electron-withdrawing group or electron-donating group-substituted phenyl or heterocyclic substituent, the electron-withdrawing group is any one of fluorine, chlorine, bromine, trifluoromethyl, acyl and ester group substituent, the electron-donating group is an alkyl or alkoxy substituent, and the heterocycle is an electron-deficient or electron-rich heterocycle;
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 an alkyl or alkoxy substituent, and the heterocycle is an electron-deficient or electron-enriched heterocycle;
the specific reaction steps are as follows:
(1) adding a certain amount of diazonium salt, a sulfur dioxide solid substitute, a 2, 2-difluoroenol silyl ether derivative 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 a corresponding alpha, alpha-difluoro-beta-carbonyl sulfone compound;
wherein the content of the first and second substances,
the solid substitute of sulfur dioxide is Na2S2O5、DABCO·(SO 2)2And K2S2O5Any one of the above;
the photosensitizer used is Ru (bpy)3Cl2·6H2O、Ir(ppy)3、Eosin-Y、Eosin Y-Na2And fluoroescein;
the aprotic solvent is any one of acetonitrile, 1, 2-dichloroethane, dichloromethane, tetrahydrofuran and 1, 4-dioxane.
2. A synthesis process according to claim 1, characterized in that the solid substitute for sulfur dioxide used is Na2S2O5。
3. The method of synthesis according to claim 1, characterized in thatThe photosensitizer used is Ru (bpy)3Cl2·6H2O。
4. The synthesis method according to claim 1, wherein the sulfur dioxide solid substitute is used in an amount of 1.0 to 3.0 equivalents based on 1.0 equivalent of the 2, 2-difluoroenolsilyl ether derivative; the diazonium salt is 1.0-3.0 equivalents.
5. The synthesis method according to claim 1, wherein the reaction temperature is from room temperature to 50 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010083958.7A CN111269153B (en) | 2020-02-10 | 2020-02-10 | Synthetic method of alpha, alpha-difluoro-beta-carbonyl sulfone compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010083958.7A CN111269153B (en) | 2020-02-10 | 2020-02-10 | Synthetic method of alpha, alpha-difluoro-beta-carbonyl sulfone compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111269153A CN111269153A (en) | 2020-06-12 |
| CN111269153B true CN111269153B (en) | 2021-10-08 |
Family
ID=70993697
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010083958.7A Expired - Fee Related CN111269153B (en) | 2020-02-10 | 2020-02-10 | Synthetic method of alpha, alpha-difluoro-beta-carbonyl sulfone compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111269153B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112266345B (en) * | 2020-10-30 | 2022-05-13 | 四川大学 | Preparation method of alpha, alpha-difluoro-beta-ketone sulfone compound |
-
2020
- 2020-02-10 CN CN202010083958.7A patent/CN111269153B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN111269153A (en) | 2020-06-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107141248B (en) | A kind of method of visible light catalytic synthesis three ketene compound of 3- sulfuryl loop coil | |
| CN107141246A (en) | A kind of preparation method of Isatine derivatives | |
| CN108164475B (en) | Method for catalytic synthesis of difluoromethyl-substituted linear aryl hetero-ketone | |
| CN111269153B (en) | Synthetic method of alpha, alpha-difluoro-beta-carbonyl sulfone compound | |
| CN113264843B (en) | Synthetic method of 3-aminobicyclo [1.1.1] pentane-1-carboxylic ester derivative | |
| CN112321553B (en) | Method for synthesizing 3-position difluoromethyl substituted coumarin derivative from aryl alkyne acid ester | |
| CN111072605B (en) | Preparation method of fluoroalkyl-substituted benzofuran derivative or indole derivative | |
| CN115260135B (en) | Synthesis method of oxindole compound | |
| CN111269155B (en) | Method for synthesizing alkenyl sulfone compound under metal-free condition | |
| CN107522584A (en) | A kind of α trifluoromethyl ketones compound and preparation method thereof | |
| CN114573512B (en) | Method for synthesizing C2-difluoro alkyl benzimidazole derivative | |
| CN104447336B (en) | A kind of three dish ene derivatives and preparation method thereof | |
| CN113651788B (en) | 3-aminoalkylchromone compound and preparation method thereof | |
| CN106928142B (en) | The 1,3- isoquinolin derovatives and preparation method thereof replaced containing arylthio | |
| CN110734389B (en) | Preparation method of dialkyl sulfone compound | |
| CN112194608B (en) | Synthesis method of visible light promoted 3-methyl-3-difluoroethyl-2-oxindole compound | |
| CN110683971B (en) | Method for synthesizing aryl acetylene alkyl sulfone compounds based on Hantzsch esters | |
| CN109134320A (en) | A kind of synthetic method of the sulphonyl class compound replaced containing beta-hydroxy | |
| CN110698369B (en) | Method for synthesizing aryl acetylene alkyl sulfone compound based on alkyl fluoborate | |
| CN111517904B (en) | Preparation method of sulfonyl acetonitrile compound | |
| CN114989063A (en) | Synthesis method of beta-halopyrrole compound | |
| CN105061421A (en) | Method for preparing 2-chloro-1, 8-naphthyridine derivative | |
| CN108484650B (en) | 3, 5-dibenzoimidazolyl-8-p-methylphenyl fluoroboron fluorescent derivative and preparation method and application thereof | |
| CN112939891A (en) | Method for preparing biphenyl benzothiazole compound | |
| CN113214273B (en) | Synthesis method of tetrahydrofuran indole compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20211008 |