CN117402092A - Green synthesis method of gamma-carbonyl sulfone compound - Google Patents
Green synthesis method of gamma-carbonyl sulfone compound Download PDFInfo
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- CN117402092A CN117402092A CN202311305845.7A CN202311305845A CN117402092A CN 117402092 A CN117402092 A CN 117402092A CN 202311305845 A CN202311305845 A CN 202311305845A CN 117402092 A CN117402092 A CN 117402092A
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 63
- 230000005496 eutectics Effects 0.000 claims abstract description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims abstract description 13
- DOUHZFSGSXMPIE-UHFFFAOYSA-N hydroxidooxidosulfur(.) Chemical compound [O]SO DOUHZFSGSXMPIE-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 13
- 239000011734 sodium Substances 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 10
- 238000003756 stirring Methods 0.000 claims abstract description 8
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims abstract description 7
- 239000007858 starting material Substances 0.000 claims abstract description 5
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims abstract 5
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 claims description 21
- 235000019743 Choline chloride Nutrition 0.000 claims description 21
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical compound [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 claims description 21
- 229960003178 choline chloride Drugs 0.000 claims description 21
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 claims description 10
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 claims description 10
- 229960003237 betaine Drugs 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 239000012046 mixed solvent Substances 0.000 claims description 8
- -1 sulfinic acid sodium salt Chemical class 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000003480 eluent Substances 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 5
- 238000002390 rotary evaporation Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 150000001299 aldehydes Chemical class 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 150000001345 alkine derivatives Chemical class 0.000 description 9
- 230000000694 effects Effects 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 6
- 235000005513 chalcones Nutrition 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 5
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 description 5
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 150000003457 sulfones Chemical class 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- KFZUDNZQQCWGKF-UHFFFAOYSA-M sodium;4-methylbenzenesulfinate Chemical compound [Na+].CC1=CC=C(S([O-])=O)C=C1 KFZUDNZQQCWGKF-UHFFFAOYSA-M 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N trimethylsilyl-trifluoromethansulfonate Natural products C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- VEOWIIWGSZYCNY-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-(4-methylphenyl)sulfonyl-3-phenylpropan-1-one Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C=1C=CC=CC=1)CC(=O)C1=CC=C(Cl)C=C1 VEOWIIWGSZYCNY-UHFFFAOYSA-N 0.000 description 1
- JVTCRBRRWDUIEM-UHFFFAOYSA-N 3-(4-methoxyphenyl)sulfonyl-1,3-diphenylpropan-1-one Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)C(C=1C=CC=CC=1)CC(=O)C1=CC=CC=C1 JVTCRBRRWDUIEM-UHFFFAOYSA-N 0.000 description 1
- IKHGPWHRYZYOKP-UHFFFAOYSA-N 3-(4-methylphenyl)sulfonyl-1,3-diphenylpropan-1-one Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C=1C=CC=CC=1)CC(=O)C1=CC=CC=C1 IKHGPWHRYZYOKP-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000002429 anti-coagulating effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 150000001789 chalcones Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000005489 p-toluenesulfonic acid group Chemical group 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000001699 photocatalysis Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- KVCGISUBCHHTDD-UHFFFAOYSA-M sodium;4-methylbenzenesulfonate Chemical compound [Na+].CC1=CC=C(S([O-])(=O)=O)C=C1 KVCGISUBCHHTDD-UHFFFAOYSA-M 0.000 description 1
- CHLCPTJLUJHDBO-UHFFFAOYSA-M sodium;benzenesulfinate Chemical compound [Na+].[O-]S(=O)C1=CC=CC=C1 CHLCPTJLUJHDBO-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 238000010490 three component reaction Methods 0.000 description 1
- 238000007039 two-step reaction Methods 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 discloses a green synthesis method of gamma-carbonyl sulfone compounds, and belongs to the technical field of compound synthesis. The method is characterized in that aldehyde and aryne are used as starting materials of the reaction, sulfonic acid type eutectic/water is used as a solvent, stirring reaction is carried out for 1-3 hours at the temperature of 25-40 ℃, sodium sulfinate is added after the reaction is finished, and stirring reaction is continued for 1-2 hours to obtain the gamma-carbonyl sulfone compound. The method has the advantages of mild reaction conditions, convenient raw material sources, high yield and green reaction system.
Description
Technical Field
The invention belongs to the technical field of compound synthesis, and particularly relates to a green synthesis method of gamma-carbonyl sulfone compounds.
Background
Meanwhile, the ketone sulfone compound with carbonyl and sulfonyl has wide application in pharmacy and functional materials. Among these, gamma-carbonyl sulfones have a wide range of biological properties, such as anticancer, antibacterial and anticoagulant properties. In addition, carbonyl and sulfonyl groups can also be converted to other important organic functional groups by conventional reactions, and therefore, gamma-carbonyl sulfones are of great importance in organic synthesis.
Currently, the traditional synthesis of gamma-carbonyl sulfones is mainly carried out by reacting aromatic thiophenols with chalcones, followed by oxidation of sulfides to sulfones. This step requires the use of a large amount of an oxidizing agent, is poor in atomic economy, and is serious in odor of the aromatic thiophenol. Sreehar et al synthesized gamma-carbonyl sulfone in methylene chloride using sodium p-toluene sulfinate and chalcone as raw materials, ferric chloride as a catalyst, and trimethylsilicon chloride as an additive (Synlett 2018, 1949-1952). The application range of the reaction system substrate is narrow, and the problem of heavy metal residue exists, so that the application of the reaction system substrate in the field of medicine synthesis is limited.
Liu Guoping et al carried out the above reaction in the aqueous phase using hydrochloric acid as the promoter (ACS Sustainable chem. Eng.2016,4, 1804-1809). The reaction requires the use of equivalent amounts of hydrochloric acid, which is more contaminated. Similarly, N-p-toluenesulfonylhydrazone (J.org.chem.2014, 79, 441-445) and p-toluenesulfonimide (Angew.chem.int.ed.2013, 52, 12354-12358) may also be reacted with chalcone under the action of a base or carbene catalyst to give the corresponding gamma-carbonyl sulfones. The raw materials of the method need to be synthesized through multiple steps, and expensive catalysts are needed, so that the reaction cost is high. The sulfonyl chloride may be reacted with chalcone under photocatalytic conditions, however, the process requires the use of expensive iridium catalysts (angelw. Chem. Int. Ed.2020,59, 11620-11626).
As is clear from the above background documents, the synthesis method of γ -carbonyl sulfone is mainly to use different sulfonyl compounds (sodium benzene sulfinate, sulfonyl hydrazone, sulfonyl hydrazide, sulfonyl chloride, etc.) to react with chalcone. It is noted that both part of the sulfonyl compound and chalcone with different substituents are required to be subjected to multiple reaction and purification steps, and that the commercially available starting materials only involve starting materials with simple substituents. In addition, these reaction processes have disadvantages such as unsatisfactory yields, narrow substrate ranges, long reaction times, and the need to use environmentally unfriendly organic solvents. Therefore, in view of the important activity of the gamma-carbonyl sulfone compound, it is necessary to develop a general and green synthesis method with simple raw materials, convenient sources, mild reaction conditions, simple reaction system, high yield and low price.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a green synthesis method of gamma-carbonyl sulfone compounds, which has the advantages of mild reaction conditions, convenient raw material sources, high yield and green reaction system.
In order to achieve the above purpose, the invention adopts the technical scheme that:
a green synthesis method of gamma-carbonyl sulfone compounds comprises the following steps:
aldehyde and aryne are used as starting materials of the reaction, sulfonic acid type eutectic/water is used as a solvent, the mixture is stirred in a flask for reaction for 1 to 3 hours at the temperature of between 25 and 40 ℃, sodium sulfinate is added after the reaction is finished, and the stirring reaction is continued for 1 to 2 hours to prepare the gamma-carbonyl sulfone compound.
The reaction route is as follows:
in the gamma-carbonyl sulfone compound of the invention, R 1 ，R 2 And R is 3 The substituent type and position are not limited. R is R 1 May be alkyl, and benzene rings having different substituents. R is R 2 The substituent may be hydrogen, methyl, methoxy, halogen, etc., and the position of the substituent is not limited, and may be ortho, meta, para. R is R 3 Can be phenyl, p-methylphenyl, methyl and other substituents.
In the sulfonic acid type eutectic (deep eutectic solvents, DES), the hydrogen bond acceptor comprises one of choline chloride and betaine; the hydrogen bond donor comprises one of p-toluenesulfonic acid and trifluoromethanesulfonic acid; the molar ratio of the hydrogen bond acceptor to the hydrogen bond donor is 1:1-3.
As a preferred embodiment, the eutectic is selected from choline chloride/p-toluenesulfonic acid, choline chloride/trifluoromethanesulfonic acid, betaine/p-toluenesulfonic acid, betaine/trifluoromethanesulfonic acid. The preferable choline chloride/p-toluenesulfonic acid eutectic consists of choline chloride and p-toluenesulfonic acid according to a molar ratio of 1:1-3. The preferred choline chloride/trifluoromethanesulfonic acid eutectic consists of choline chloride and trifluoromethanesulfonic acid in a molar ratio of 1:1-2. The preferable betaine/p-toluenesulfonic acid eutectic consists of betaine and p-toluenesulfonic acid according to a molar ratio of 1:1-3. The preferable betaine/trifluoromethanesulfonic acid eutectic consists of betaine and trifluoromethanesulfonic acid according to the mol ratio of 1:1-2. The gamma-carbonyl sulfone compounds in the several kinds of eutectic can be smoothly generated, the yield of the target product is more than 75%, and the choline chloride/trifluoromethanesulfonic acid is the optimal eutectic for the reaction, especially when the choline chloride/trifluoromethanesulfonic acid is composed of the two materials according to the molar ratio of 1:1.5, the yield of the obtained target product reaches the optimal, and the yield is as high as 92%.
The solvent is a mixed solvent of sulfonic acid type eutectic and water, and the volume ratio of the solvent to the mixed solvent is 1:0.2-1. The amount of the mixed solvent to be used is in accordance with the addition amount of a conventional solvent, for example, aldehyde is used as a standard substrate, and the concentration thereof in the mixed solvent is 0.05 to 0.2mol/L, preferably 0.05 to 0.1mol/L.
The molar ratio of the aldehyde to the aryne to the sulfinic acid sodium salt is 1:1.2 to 1.5:1.5 to 2.
The reaction time is 1-3 hours of the reaction time of the first aldehyde and the aryne, and then sodium sulfinate is added for continuous reaction for 1-2 hours.
After the two-step reaction is finished, extracting by adopting an organic solvent, separating residues by column chromatography to obtain a gamma-carbonyl sulfone compound, wherein the organic solvent such as ethyl acetate and the like is a mixture of petroleum ether and ethyl acetate, and the volume ratio of the column chromatography eluent is 5:1. the raffinate is eutectic, water and a small amount of residual sodium sulfinate, and can be directly reused without additional treatment.
The invention has the advantages and beneficial effects that:
1. the invention provides a general synthesis method of gamma-carbonyl sulfone compounds, which lays a foundation for the convenient synthesis of the compounds.
2. The synthesis method of the gamma-carbonyl sulfone compound provided by the invention has the advantages that no catalyst is needed, few byproducts are basically nontoxic, the reaction is carried out in two steps under the room temperature condition, no intermediate purification step is needed, the process is simple and convenient, the environment is protected, and the atom economy is high.
3. The invention provides a synthesis method of gamma-carbonyl sulfone compounds, which takes eutectic and water as solvents. The eutectic is a novel solvent with excellent physical and chemical properties, formed by quaternary ammonium salt and acid, is basically nontoxic, low in steam pressure, biodegradable and reusable, and the preparation process only needs stirring, so that the atomic utilization rate reaches 100%, and the eutectic is the best substitute of the traditional organic solvent with high toxicity and easy volatilization.
4. The synthesis method of the gamma-carbonyl sulfone compound provided by the invention takes the commercial aldehyde, alkyne and sulfinic acid sodium salt as raw materials, and has the advantages of convenient raw material source, low price, simple reaction condition, short reaction time and high yield; the reaction can be carried out in the air, the post-treatment is simple and convenient, and the purification and the large-scale production of the product are facilitated.
Description of the drawings:
FIG. 1 is a synthetic reaction scheme for gamma-carbonyl sulfones of the invention;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of a gamma-carbonyl sulfone compound 4a in example 1 of the present invention;
FIG. 3 is a nuclear magnetic resonance spectrum of a gamma-carbonyl sulfone compound 4a in example 1 of the present invention.
Detailed Description
The present invention is not limited to the following embodiments, and those skilled in the art can implement the present invention in various other embodiments according to the present invention, or simply change or modify the design structure and thought of the present invention, which fall within the protection scope of the present invention. It should be noted that, without conflict, the embodiments of the present invention and features of the embodiments may be combined with each other.
Comparative examples:
the following reaction formula is three-component reaction (as standard reaction) of benzaldehyde, phenylacetylene and sodium p-methylbenzenesulfinate in a eutectic/water mixed solvent under optimal conditions:
substrate 1a (0.5 mmol), phenylacetylene 2a (0.6 mmol), choline chloride/trifluoromethanesulfonic acid (ChCl/TfOH, 1:1.5,4 mL) and water (1 mL) were sequentially added to a clean, dry 10mL Schlenk reaction tube and the reaction stirred at 25 ℃ for 3 hours; then, sodium p-toluenesulfonate 3a (0.75 mmol) was added to the reaction tube and stirring was continued for 2h. After the reaction, 5mL of ethyl acetate was added for extraction, the organic phase was separated, the solvent was spin-dried by a rotary evaporator, and the residue obtained was purified by column chromatography using petroleum ether and ethyl acetate as eluent (volume ratio 5:1) and silica gel (200-300 mesh sieve).
The following control experimental groups 1 to 16 are comparative illustrations with reference to standard reaction conditions:
| experimental group | Difference from standard reaction conditions | Yield rate |
| 1 | No difference | 92％ |
| 2 | Choline chloride/p-toluenesulfonic acid substituted choline chloride/trifluoromethanesulfonic acid | 80％ |
| 3 | Betaine/p-toluenesulfonic acid instead of choline chloride/trifluoromethanesulfonic acid | 83％ |
| 4 | Betaine/trifluoromethanesulfonic acid instead of choline chloride/trifluoromethanesulfonic acid | 85％ |
| 5 | Choline chloride: trifluoromethanesulfonic acid=1:1 | 80％ |
| 6 | Choline chloride: trifluoromethanesulfonic acid=1:2 | 75％ |
| 7 | n (aldehyde): n (alkyne): n (sodium sulfinate) =1: 1.5:1.5 | 91％ |
| 8 | n (aldehyde): n (alkyne): n (sodium sulfinate) =1: 1.2:2 | 88％ |
| 9 | V (ChCl/TfOH): v (water) =8ml 2ml | 86％ |
| 10 | V (ChCl/TfOH): v (water) =2ml:0.5 ml | 81％ |
| 11 | V (ChCl/TfOH): v (water) =2.5 ml:2.5ml | 70％ |
| 12 | V (ChCl/TfOH): v (water) =3.33 ml 1.67ml | 83％ |
| 13 | V (ChCl/TfOH): v (water) =3.75 ml 1.25ml | 85％ |
| 14 | V (ChCl/TfOH): v (water) =4.17 ml:0.83ml | 90％ |
| 15 | No water is added | 54％ |
| 16 | Reaction without step by step | 62％ |
The influence of different acid eutectic matters on the reaction is examined by experimental groups 1-4 in the table, and experimental data show that the 4 acid eutectic matters have better catalytic activity on the reaction, the yield is more than 80%, the reaction effect is optimal in ChCl/TfOH, and the yield is as high as 92%.
Experimental groups 5 and 6 examined the effect of the molar composition ratio of choline chloride and trifluoromethanesulfonic acid in ChCl/TfOH on the reaction, with the best effect and 92% yield for experimental group 1 of choline chloride and trifluoromethanesulfonic acid at a molar composition ratio of 1:1.5; when the molar composition ratio of the choline chloride to the trifluoromethanesulfonic acid is 1:1 or 1:2, the yield of the target product is greatly reduced. This is because trifluoromethane sulfonic acid in the eutectic is an active catalytic center of the reaction, and the too small amount is unfavorable for the reaction; and excessive acid is easy to cause the generation of byproducts, so that the yield of target products is greatly reduced.
Experimental groups 7 and 8 examined the effect of the molar ratio of aldehyde, alkyne and sodium sulfinate on the reaction. When n (aldehyde): n (alkyne): n (sodium sulfinate) =1: 1.5:1.5, the reaction yield was 91%; when n (aldehyde): n (alkyne): n (sodium sulfinate) =1: 1.2:2, the reaction yield was 88%. Description when n (aldehyde): n (alkyne): n (sodium sulfinate) =1: 1.2:1.5, the reaction condition is optimal, the reaction is insufficient due to the reduced consumption, other byproducts are generated due to the excessive consumption, and the yield of the target product is reduced.
Experimental groups 9 and 10 examined the effect of the amount of mixed solvent on the reaction. Among them, chCl/TfOH/water is preferably used in an amount of 5mL, and the yield is preferably reduced by increasing the amount to 10mL or by decreasing the amount to 2.5mL, and the concentration of the reactant is preferably maintained within the concentration range of 0.05-0.1 mol/L.
Experimental groups 11-15 examine the influence of the volume ratio of ChCl/TfOH and water on the reaction, and increasing the water ratio easily leads to the reduction of the yield of the target product. This is because the increase in water makes the dissolution of organic matter in the solvent relatively poor; while without the addition of water, the yield drops drastically to 54%. This is because the addition of water can reduce the viscosity of the reaction system, and better accelerate the contact of the substrate.
Experiment group 16 examined the effect of the no-step experiment on the reaction. When 3 raw materials are simultaneously added into the reaction system, the yield is only 62% after 3 hours of reaction. This is because sodium sulfinate in the reaction system can react with alkyne, resulting in an increase in byproducts.
The following examples 1 to 5 were carried out according to the standard reactions described above:
aldehyde 1 (0.5 mmol), alkyne 2 (0.6 mmol), choline chloride/trifluoromethanesulfonic acid (ChCl/TfOH, 1:1.5,4 mL) and water (1 mL) were added sequentially to a clean dry 10mL Schlenk reaction tube and the reaction stirred at 25 ℃ for 3 hours; then, sodium sulfinate 3 (0.75 mmol) was added to the reaction tube and stirring was continued for 2h. After the reaction, 5mL of ethyl acetate was added for extraction, the organic phase was separated, the solvent was spin-dried by a rotary evaporator, and the residue obtained was purified by column chromatography using petroleum ether and ethyl acetate as eluent (volume ratio 5:1) and silica gel (200-300 mesh sieve).
Example 1
1, 3-diphenyl-3-p-toluenesulfonyl-1-propanone was 92% yield.
White solid, melting point: 175-177 ℃. 1 H NMR(500MHz,CDCl 3 )δ2.32(s,3H),3.89(dd,J＝18.0,9.5Hz,1H),4.07(dd,J＝17.5,3.5Hz,1H),4.87(dd,J＝9.5,3.5Hz,1H),7.09-7.20(m,7H),7.35-7.41(m,4H),7.49-7.52(m,1H),7.86(d,J＝8.0Hz,2H). 13 C NMR(125MHz,CDCl 3 )δ21.7,37.2,66.6,128.2,128.6,128.9(2C),129.2,129.5,129.9,132.8,133.7,134.2,136.3,144.8,195.1.
Example 2
1- (4-chlorophenyl) -3-phenyl-3-p-toluenesulfonyl-1-propanone was 90% yield.
White solid, melting point: 187-189 ℃. 1 H NMR(500MHz,CDCl 3 )δ2.41(s,3H),3.93(dd,J＝18.0,9.5Hz,1H),4.15(dd,J＝17.5,3.5Hz,1H),4.94(dd,J＝9.5,3.5Hz,1H),7.18-7.29(m,7H),7.42-7.47(m,4H),7.90(d,J＝8.5Hz,2H). 13 C NMR(125MHz,CDCl 3 )δ21.7,37.1,66.6,128.5,128.8,129.0,129.1,129.4,129.6,129.8,132.6,134.0,134.6,140.2,144.8,193.9.
Example 3
1, 3-diphenyl-3-p-methoxy benzenesulfonyl-1-propanone with a yield of 95%.
White solid, melting point: 157-159 ℃. 1 H NMR(500MHz,CDCl 3 )δ3.83(s,3H),3.96(dd,J＝17.5,9.5Hz,1H),4.15(dd,J＝18.0,3.5Hz,1H),4.92(dd,J＝9.5,3.5Hz,1H),6.84(d,J＝9.0Hz,2H),7.21-7.28(m,5H),7.45-7.48(m,4H),7.57-7.60(m,1H),7.94(dd,J＝8.4,1.2Hz,2H). 13 C NMR(125MHz,CDCl 3 )δ37.1,55.6,66.7,114.0,128.2,128.5,128.8,129.9,131.3,132.9,133.7,136.3,163.8,195.1.
Example 4
1-phenyl-3-p-toluenesulfonyl-1-hexanone was 88% yield.
Colorless liquid. 1 H NMR(500MHz,CDCl 3 )δ7.93-7.91(m,2H),7.81(d,J＝8.4Hz,2H),7.60(tt,J＝1.2,7.2Hz,1H),7.48(t,J＝8.0Hz,2H),7.35(d,J＝8.0Hz,2H),4.00-3.94(m,1H),3.67(dd,J＝4.4,18.0Hz,1H),3.17(dd,J＝7.2,18.0Hz,1H),2.45(s,3H),1.97-1.88(m,1H),1.65-1.56(m,1H),1.46-1.23(m,2H),0.86(t,J＝7.2Hz,3H). 13 C NMR(125MHz,CDCl 3 )δ195.7,144.8,136.1,134.8,133.6,129.9,128.8,128.7,128.1,59.6,37.0,31.1,21.6,20.0,13.9。
Example 5
1-phenyl-3-methylsulfonyl-1-pentanone was produced in 85% yield.
Colorless liquid. 1 H NMR(500MHz,DMSO-d 6 )δ8.03-8.01(m,2H),7.64(tt,J＝1.2,7.2Hz,1H),7.53(t,J＝8.0Hz,1H),3.93-3.87(m,1H),3.76(dd,J＝5.2,18.4Hz,1H),3.26(dd,J＝6.0,18.4Hz,1H),2.93(s,3H),2.12-2.03(m,1H),1.78-1.67(m,1H),1.56-1.39(m,2H),0.99(t,J＝7.6Hz,3H)；. 13 C NMR(125MHz,DMSO-d 6 )δ195.9,136.0,133.9,128.9,128.2,58.5,39.7,37.2,30.9,20.1,13.9.
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that it will be apparent to those skilled in the art that several modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the scope of the invention.
Claims (6)
1. The synthesis method of the gamma-carbonyl sulfone compound is characterized by comprising the following steps of: taking aldehyde and aryne as starting materials of the reaction, taking sulfonic acid type eutectic/water as a solvent, stirring and reacting for 1-3 hours at the temperature of 25-40 ℃, adding sodium sulfinate after the reaction is finished, and continuously stirring and reacting for 1-2 hours to obtain the gamma-carbonyl sulfone compound;
the structural formula of the gamma-carbonyl sulfone compound is
Wherein R is 1 Is alkyl, phenyl containing different substituents; r is R 2 Is hydrogen, methyl, methoxy and halogen, and the positions of the substituents are ortho-position, meta-position and para-position; r is R 3 Phenyl, p-methylphenyl, methyl.
2. The method for synthesizing gamma-carbonyl sulfones according to claim 1, wherein the hydrogen bond acceptor in the sulfonic acid type eutectic comprises one of choline chloride and betaine; the hydrogen bond donor comprises one of p-toluenesulfonic acid and trifluoromethanesulfonic acid; the molar ratio of the hydrogen bond acceptor to the hydrogen bond donor is 1:1-3.
3. The method for synthesizing the gamma-carbonyl sulfone compound according to claim 1, wherein the solvent is a mixed solvent consisting of sulfonic acid type eutectic and water according to a volume ratio of 1:0.2-1; the addition amount is calculated according to the use amount of aldehyde, and the concentration of the aldehyde in the mixed solvent is 0.05-0.2 mol/L.
4. The method for synthesizing gamma-carbonyl sulfones according to claim 1, wherein the molar ratio of aldehyde, aryne and sulfinic acid sodium salt is 1:1.2 to 1.5:1.5 to 2.
5. The method for synthesizing a gamma-carbonyl sulfone compound according to claim 1, wherein the steps further comprise: extracting with organic solvent, and separating residue after rotary evaporation by column chromatography to obtain gamma-carbonyl sulfone compound.
6. The method for synthesizing a gamma-carbonyl sulfone compound according to claim 5, wherein the organic solvent comprises ethyl acetate; the column chromatography eluent is a mixture of petroleum ether and ethyl acetate, and the volume ratio of the column chromatography eluent is 5:1.
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