CN111978216B - Preparation method of beta-carbonyl sulfone compound - Google Patents
Preparation method of beta-carbonyl sulfone compound Download PDFInfo
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- CN111978216B CN111978216B CN202011001970.5A CN202011001970A CN111978216B CN 111978216 B CN111978216 B CN 111978216B CN 202011001970 A CN202011001970 A CN 202011001970A CN 111978216 B CN111978216 B CN 111978216B
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Abstract
The invention discloses a preparation method of a beta-carbonyl sulfone compound, belonging to the technical field of organic synthesis. Aiming at the problems of complex operation, narrow substrate range and poor functional group tolerance in the prior art, the invention provides a preparation method of a beta-carbonyl sulfone compound, which comprises the following steps: taking a compound of a formula I and a compound of a formula II as raw materials, taking copper salt as a catalyst, reacting in an organic solvent, and after the reaction is finished, carrying out post-treatment to obtain the beta-carbonyl sulfone compound. The method has the advantages of simple and convenient operation, mild reaction conditions, wide substrate range, good functional group tolerance, high yield up to 93 percent and remarkable reduction of the synthesis cost.
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Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a beta-carbonyl sulfone compound.
Background
The beta-carbonyl sulfone structural unit widely exists in various drug molecules and natural products, and the beta-carbonyl sulfone structural unit often has better biological activities such as anticancer, anti-tumor, antibacterial and anti-inflammatory activities, so that the construction of the beta-carbonyl sulfone structural unit has important application value in drug discovery and new drug development. In addition, as an organic synthesis intermediate, the beta-carbonyl sulfone compound can also be used for synthesizing an optically active beta-hydroxy sulfone compound, chiral lactone, tetrahydrofuran, gamma-butyrolactone, N-heterocyclic compounds and the like.
At present, the synthesis methods of beta-carbonyl sulfone compounds are mainly divided into two types: the traditional synthetic method mostly adopts sulfinic acid and salts thereof as a sulfone source to react with corresponding alpha-halogenated ketone, or is directly obtained by oxidizing beta-carbonyl thioether, beta-carbonyl sulfoxide or beta-hydroxy sulfone; and the oxygen sulphonation reaction based on the participation of free radicals is also widely applied to the synthesis of beta-carbonyl sulphone compounds recently. Although the currently known methods for the synthesis of β -carbonyl sulfones are various, these methods have some disadvantages, such as: raw materials are not easy to obtain, the operation is complicated, the reaction conditions are relatively harsh, the types of substrates are limited, the tolerance of functional groups is not good, and the like; furthermore, most reactions use sulfinic acids and their salts as sulfone sources, but sulfinic acids and their salt species are relatively rare.
CN108383763B discloses a synthetic method of a beta-carbonyl sulfone compound, which comprises the following steps: 1) Mixing a compound A shown in a formula A, a compound B shown in a formula B and an oxidant to obtain a mixed solution, adding a metal copper catalyst into the mixed solution, and adding the metal copper catalyst into the mixed solution for three times; 2) And treating the mixture after the reaction by a cation exchange membrane, and then performing post-treatment to obtain the beta-carbonyl sulfone compound shown in the formula C. The oxidant used in the method is peroxide, the operation is complicated (for example, the catalyst is added for three times and the cation exchange membrane treatment is needed before column chromatography), and the structure of the compound A is greatly limited, so that the substrate range is narrow.
Therefore, it is very important to develop a method for preparing the beta-carbonyl sulfone compound, which has the advantages of easily available raw materials, simple and convenient operation, wide substrate range and good functional group tolerance.
Disclosure of Invention
The invention aims to solve the problems of the existing preparation method of beta-carbonyl sulfone compounds and provides a synthesis method of beta-carbonyl sulfone compounds, which has the advantages of simple operation, mild reaction conditions, low cost, wide substrate range and good functional group tolerance.
The invention provides a synthesis method of beta-carbonyl sulfone compounds, which comprises the steps of taking 1,1-disubstituted olefin of a compound of formula I and sulfonyl hydrazide of a compound of formula II as raw materials, taking copper salt as a catalyst, reacting in an organic solvent, and after the reaction is finished, carrying out post-treatment to obtain the beta-carbonyl sulfone compounds shown in formula III;
wherein R is 1 Selected from substituted or unsubstituted C 6 ～C 10 Aryl, substituted or unsubstituted C 5 ～C 18 Heteroaryl, wherein the heteroatom of the heteroaryl is N, O or S, and the number of the heteroatoms is 1-3; r 1 In (b), said substituted C 6 ～C 10 Aryl or substituted C 5 ～C 18 The substituent of the heteroaryl group being C 1 ～C 8 Alkyl radical, C 3 ～C 8 Cycloalkyl radical, C 1 ～C 8 Alkoxy radical, C 1 ～C 8 Alkoxycarbonyl, C 1 ～C 8 Carbamoyl radical, C 1 ～C 8 Alkylcarbonyl, cyano, trifluoromethyl, halogen, nitro, phenyl or phenoxy;
R 2 is selected from C 1 ～C 18 Alkyl, substituted or unsubstituted C 6 ～C 10 Aryl, substituted or unsubstituted C 5 ～C 18 Heteroaryl, wherein the heteroatom of the heteroaryl is N, O or S, and the number of the heteroatoms is 1-3; r 2 In (b), said substituted C 6 ～C 10 Aryl or substituted C 5 ～C 18 The substituent of the heteroaryl group being C 1 ～C 8 Alkyl radical, C 3 ～C 8 Cycloalkyl radical, C 1 ～C 8 Alkoxy radical, C 1 ～C 8 Alkoxycarbonyl, C 1 ～C 8 Carbamoyl radical, C 1 ～C 8 Alkylcarbonyl, cyano, trifluoromethyl, halogen, nitro, phenyl or phenoxy;
R 3 and R 4 Independently selected from H, C 1 ～C 8 Alkyl, unsubstituted or substituted C 6 ～C 10 Aryl, hydroxy, C 1 ～C 8 Alkoxy, unsubstituted or substituted phenoxy, substituted acyloxy, substituted sulfonyloxy, mono-or disubstituted amino, azido, phosphono, sulphonyl, and R 3 And R 4 Not being H or R at the same time 3 、R 4 And the carbon to which they are attached to form a 3-to 8-membered alkyl ring or C 6 ～C 10 An aromatic ring; r 3 And R 4 In (b), said substituted C 6 ～C 10 The substituent of the aryl or substituted phenoxy group being C 1 ～C 8 Alkyl radical, C 1 ～C 8 Alkoxy radical, C 1 ～C 8 Alkoxycarbonyl, cyano, trifluoromethyl, halogen, phenoxy; r 3 And R 4 Wherein the substituent of said substituted acyloxy or substituted sulfonyloxy is unsubstituted or C 1 ～C 8 Alkyl substituted C 6 ～C 10 An aryl group; r 3 And R 4 In (1), the substituent of the mono-or di-substituted amino groupIs C 1 ～C 8 Alkyl radical, C 6 ～C 10 Aryl, acyl, sulfonyl;
R 5 selected from hydrogen or C 1 ～C 8 Alkyl, and when R 3 、R 4 And the carbon to which they are attached to form C 6 ～C 10 When it is aromatic, R 5 Is absent.
Preferably, in the above process for preparing a β -carbonyl sulfone compound, R 1 Selected from substituted or unsubstituted C 6 ～C 10 Aryl, substituted or unsubstituted C 5 ～C 11 A heteroaryl group; r 1 Wherein the heteroatom of the heteroaryl is N, O or S, and the number of the heteroatoms is 1-3; r 1 In (b), said substituted C 6 ～C 10 Aryl or substituted C 5 ～C 11 The substituent of the heteroaryl group being C 1 ～C 4 Alkyl radical, C 1 ～C 4 Alkoxy radical, C 1 ～C 4 Alkoxycarbonyl, C 1 ～C 4 Carbamoyl radical, C 1 ～C 4 Alkylcarbonyl, cyano, trifluoromethyl, fluoro, chloro, bromo, nitro, phenyl or phenoxy.
Preferably, in the above process for preparing a β -carbonyl sulfone compound, R 2 Is selected from C 1 ～C 8 Alkyl, substituted or unsubstituted C 6 ～C 10 Aryl, substituted or unsubstituted C 5 ～C 11 A heteroaryl group; r 2 Wherein the heteroatom of the heteroaryl is N, O or S, and the number of the heteroatoms is 1-3; r 2 In (b), said substituted C 6 ～C 10 Aryl or substituted C 5 ～C 11 The substituent of the heteroaryl group being C 1 ～C 4 Alkyl radical, C 1 ～C 4 Alkoxy radical, C 1 ～C 4 Alkoxycarbonyl, C 1 ～C 4 Carbamoyl radical, C 1 ～C 4 Alkylcarbonyl, cyano, trifluoromethyl, fluoro, chloro, bromo, nitro, phenyl or phenoxy.
More preferably, in the preparation method of β -carbonyl sulfone compound, the compound of formula I is selected from:
more preferably, in the preparation method of β -carbonyl sulfone compound, the compound of formula II is selected from:
in the preparation method of the beta-carbonyl sulfone compound, the molar ratio of the compound shown in the formula I, the compound shown in the formula II and the copper salt is 1:1.0 to 4.0:0.01 to 0.20.
Preferably, in the preparation method of the β -carbonyl sulfone compound, the molar ratio of the compound of formula I, the compound of formula II and the copper salt is 1:2.0:0.05.
in the preparation method of the beta-carbonyl sulfone compound, the copper salt is any one of copper trifluoromethanesulfonate, copper acetate, copper acetylacetonate, ketone bromide, copper fluoride, copper nitrate trihydrate, copper sulfate, copper oxide, cuprous iodide, cuprous chloride, cuprous acetate or elemental copper.
Preferably, in the preparation method of the β -carbonyl sulfone compound, the copper salt is copper trifluoromethanesulfonate.
In the preparation method of the beta-carbonyl sulfone compound, the organic solvent is at least one of acetonitrile, tetrahydrofuran, 1,4-dioxane, N-dimethylformamide, ethanol, chloroform, dichloromethane, ethyl acetate, diethyl ether, ethylene glycol dimethyl ether, acetone, dimethyl sulfoxide, N-methylpyrrolidone, N-dimethylacetamide or water.
Preferably, in the preparation method of the β -carbonyl sulfone compound, the organic solvent is acetonitrile and water at a volume ratio of 9: 1.
In the preparation method of the beta-carbonyl sulfone compound, the reaction is carried out at 40-80 ℃.
Preferably, in the preparation method of the β -carbonyl sulfone compound, the reaction temperature is 65 ℃.
In the preparation method of the beta-carbonyl sulfone compound, the reaction time is 4-24 h.
Preferably, in the preparation method of the β -carbonyl sulfone compound, the reaction time is 12 hours.
In the preparation method of the beta-carbonyl sulfone compound, the reaction is carried out under the air or oxygen.
Preferably, in the preparation method of the β -carbonyl sulfone compound, the reaction is performed under oxygen.
Further, the beta-carbonyl sulfone compound with the following structure can be prepared by adopting the preparation method of the beta-carbonyl sulfone compound:
the invention has the beneficial effects that:
the products prepared by the method are characterized by nuclear magnetic spectrum, and the synthesized compounds are confirmed to be beta-carbonyl sulfone compounds. The method takes 1,1-disubstituted alkene and sulfonyl hydrazide as raw materials, uses oxygen as an oxidant and an oxygen source of carbonyl, has the advantages of simple and convenient operation, mild reaction conditions, stable process conditions, easy purification of products, wide substrate range and good functional group tolerance, obviously reduces the preparation cost, has the yield up to 93 percent, and is suitable for large-scale production.
Drawings
FIG. 1 shows NMR of the compound prepared in example 1 1 And H, spectrum.
FIG. 2 shows NMR of the compound prepared in example 1 13 And C, spectrum.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with figures are described in detail below. It should be understood that the preparation of the examples of the present invention are intended to be illustrative only and not limiting.
Example 1: 2-p-toluenesulfonylacetophenone
2,3-diphenyl-1-propene (97mg, 0.5 mmol), p-toluenesulfonylhydrazide (186mg, 1.0 mmol), copper trifluoromethanesulfonate (9mg, 0.025 mmol) and acetonitrile/water (V: V = 9. After the reaction was completed, the solvent was removed under reduced pressure, and the product was isolated by column chromatography (100 to 200 mesh, petroleum ether: ethyl acetate = 8:1) (white solid, yield 93%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ8.00–7.89(m,2H),7.82–7.71(m,2H),7.68–7.57(m,1H),7.53–7.43(m,2H),7.40–7.29(m,2H),4.72(s,2H),2.44(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ188.19,145.41,135.77,134.36,129.87,129.35,128.86,128.63,63.58,21.74。
example 2:1- (4-methylphenyl) -2-p-toluenesulfonyl ethanone
The reaction operation was carried out in the same manner as in example 1 except for using 2-p-tolyl-3-phenyl-1-propene (104mg, 0.5mmol) instead of 2,3-diphenyl-1-propene to obtain a product (white solid, yield 62%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ7.85(d,J＝8.2Hz,2H),7.76(d,J＝8.3Hz,2H),7.34(d,J＝8.0Hz,2H),7.28(d,J＝8.5Hz,2H),4.69(s,2H),2.45(s,3H),2.43(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ187.65,145.59,145.31,135.65,133.28,129.80,129.54,129.50,128.58,63.52,21.80,21.73。
example 3:1- (biphenyl-4-yl) -2-p-toluenesulfonyl ethanone
The reaction was carried out in the same manner as in example 1 except for using 2- (biphenyl-4-yl) -3-phenyl-1-propene (135mg, 0.5 mmol) in place of 2,3-diphenyl-1-propene to obtain a product (white solid, yield 83%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ8.03(d,J＝8.4Hz,2H),7.78(d,J＝8.2Hz,2H),7.71(d,J＝8.4Hz,2H),7.63(d,J＝7.2Hz,2H),7.49(t,J＝7.3Hz,2H),7.45–7.40(m,1H),7.35(d,J＝8.0Hz,2H),4.75(s,2H),2.45(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ187.68,147.05,145.45,139.44,135.65,134.43,130.04,129.89,129.06,128.64,128.62,127.47,127.35,63.70,21.78。
example 4:1- (4-methoxyphenyl) -2-p-toluenesulfonyl ethanone
The reaction was carried out in the same manner as in example 1 except for using 2- (4-methoxyphenyl) -3-phenyl-1-propene (112mg, 0.5 mmol) in place of 2,3-diphenyl-1-propene, thereby obtaining the product (white solid, yield 79%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ7.95(d,J＝8.9Hz,2H),7.75(d,J＝8.2Hz,2H),7.34(d,J＝8.0Hz,2H),6.95(d,J＝8.9Hz,2H),4.67(s,2H),3.89(s,3H),2.45(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ186.36,164.56,145.32,135.67,131.97,129.83,128.86,128.60,114.08,77.37,77.26,77.05,76.74,63.57,55.67,21.77。
example 5:1- (4-phenoxyphenyl) -2-p-toluenesulfonyl ethanone
The reaction was carried out in the same manner as in example 1 except for using 2- (4-phenoxyphenyl) -3-phenyl-1-propene (143mg, 0.5mmol) instead of 2,3-diphenyl-1-propene, thereby obtaining the product (white solid, yield 83%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ7.94(d,J＝8.9Hz,2H),7.76(d,J＝8.2Hz,2H),7.43(t,J＝7.9Hz,2H),7.35(d,J＝8.0Hz,2H),7.25(t,J＝8.6Hz,1H),7.09(d,J＝7.7Hz,2H),7.00(d,J＝8.9Hz,2H),4.67(s,2H),2.45(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ186.46,163.29,154.83,145.41,135.63,131.95,130.20,129.87,128.60,125.13,120.57,117.14,63.61,21.79。
example 6:1- (4-bromophenyl) -2-p-toluenesulfonyl ethanone
The reaction was carried out in the same manner as in example 1 except for using 2- (4-bromophenyl) -3-phenyl-1-propene (137mg, 0.5 mmol) instead of 2,3-diphenyl-1-propene, thereby obtaining the product (white solid, yield 51%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ7.83(d,J＝8.6Hz,2H),7.74(d,J＝8.3Hz,2H),7.64(d,J＝8.6Hz,2H),7.35(d,J＝8.1Hz,2H),4.68(s,2H),2.46(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ187.29,145.65,135.41,134.42,132.24,130.86,130.04,129.95,128.58,63.71,21.80。
example 7:1- (4-chlorophenyl) -2-p-toluenesulfonyl ethanone
The reaction operation was carried out in the same manner as in example 1 except for using 2- (4-chlorophenyl) -3-phenyl-1-propene (114mg, 0.5 mmol) in place of 2,3-diphenyl-1-propene to obtain a product (white solid, yield 63%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ7.91(d,J＝8.5Hz,2H),7.74(d,J＝8.1Hz,2H),7.46(d,J＝8.5Hz,2H),7.35(d,J＝8.1Hz,2H),4.69(s,2H),2.45(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ187.08,145.63,141.13,135.46,134.03,130.82,129.95,129.23,128.57,63.69,21.79。
example 8:1- (4-fluorophenyl) -2-p-toluenesulfonyl ethanone
The reaction operation was carried out in the same manner as in example 1 except for using 2- (4-fluorophenyl) -3-phenyl-1-propene (106mg, 0.5 mmol) in place of 2,3-diphenyl-1-propene (2,3-diphenyl-1-propene), so as to obtain the product (white solid, yield 43%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ8.01(dd,J＝8.8,5.3Hz,2H),7.75(d,J＝8.2Hz,2H),7.35(d,J＝8.0Hz,2H),7.16(t,J＝8.6Hz,2H),4.70(s,2H),2.45(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ186.58,166.44(d,J＝257.7Hz),145.54,135.46,132.27(d,J＝9.7Hz),132.16(d,J＝2.9Hz),129.89,128.53,116.10(d,J＝22.1Hz),63.67,21.74； 19 F NMR(376MHz,CDCl 3 )δ-102.33。
example 9:4- (2-p-toluenesulfonylacetyl) benzonitrile
The reaction was carried out in the same manner as in example 1 except for using 4- (3-phenylprop-1-en-2-yl) benzonitrile (110mg, 0.5 mmol) in place of 2,3-diphenyl-1-propene, thereby obtaining a product (white solid, yield 37%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ8.08(d,J＝8.3Hz,2H),7.80(d,J＝8.3Hz,2H),7.74(d,J＝8.1Hz,2H),7.36(d,J＝8.0Hz,2H),4.72(s,2H),2.47(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ187.15,145.86,138.52,135.33,132.62,130.03,129.78,128.51,117.58,117.48,63.90,21.76。
example 10:4- (2-p-toluenesulfonylacetyl) benzoic acid methyl ester
The reaction was carried out in the same manner as in example 1 except for using methyl 4- (3-phenylprop-1-en-2-yl) benzoate (126mg, 0.5 mmol) in place of 2,3-diphenyl-1-propene to obtain a product (white solid, yield 39%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ8.14(d,J＝8.4Hz,2H),8.01(d,J＝8.4Hz,2H),7.75(d,J＝8.2Hz,2H),7.35(d,J＝8.1Hz,2H),4.74(s,2H),3.96(s,3H),2.45(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ187.84,165.90,145.62,138.77,135.54,134.85,129.96,129.92,129.25,128.58,63.85,52.63,21.73。
example 11:1- (3-methoxyphenyl) -2-p-toluenesulfonyl ethanone
The reaction was carried out in the same manner as in example 1 except for using 2- (3-methoxyphenyl) -3-phenyl-1-propene (112mg, 0.5 mmol) in place of 2,3-diphenyl-1-propene, thereby obtaining the product (white solid, yield 73%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ7.77(d,J＝8.3Hz,2H),7.52(d,J＝7.7Hz,1H),7.45–7.43(m,1H),7.39(t,J＝8.0Hz,1H),7.34(d,J＝8.0Hz,2H),7.16(dd,J＝8.2,1.8Hz,1H),4.71(s,2H),3.84(s,3H),2.45(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ187.96,159.86,145.37,136.99,135.69,129.82,128.59,122.20,121.17,112.85,63.61,55.49,21.72。
example 12:1- (3-fluorophenyl) -2-p-toluenesulfonyl ethanone
The reaction operation was carried out in the same manner as in example 1 except for using 2- (3-fluorophenyl) -3-phenyl-1-propene (106mg, 0.5 mmol) in place of 2,3-diphenyl-1-propene (2,3-diphenyl-1-propene), so as to obtain a product (white solid, yield 35%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ7.78–7.74(m,3H),7.62(d,J＝9.0Hz,1H),7.52–7.45(m,1H),7.38–7.30(m,3H),4.70(s,2H),2.46(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ187.10(d,J＝2.3Hz),162.78(d,J＝249.0Hz),145.65,137.69(d,J＝6.5Hz),135.45,130.61(d,J＝7.7Hz),129.95,128.60,125.39(d,J＝3.0Hz),121.52(d,J＝21.5Hz),115.85(d,J＝22.8Hz),63.73,21.78； 19 F NMR(376MHz,CDCl 3 )δ-110.99。
example 13:1- (2-methoxyphenyl) -2-p-toluenesulfonyl ethanone
The reaction was carried out in the same manner as in example 1 except for using 2- (2-methoxyphenyl) -3-phenyl-1-propene (112mg, 0.5 mmol) in place of 2,3-diphenyl-1-propene, thereby obtaining the product (white solid, yield 70%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ7.75(d,J＝8.2Hz,2H),7.66(dd,J＝7.8,1.6Hz,1H),7.52–7.47(m,1H),7.29(d,J＝8.0Hz,2H),6.99(t,J＝7.5Hz,1H),6.90(d,J＝8.4Hz,1H),4.93(s,2H),3.88(s,3H),2.42(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ189.24,158.96,144.84,136.56,135.26,131.27,129.55,128.55,126.22,120.97,111.67,67.45,55.69,21.71； 19 F NMR(376MHz,CDCl 3 )δ-108.90。
example 14:1- (2-fluorophenyl) -2-p-toluenesulfonyl ethanone
The reaction operation was carried out in the same manner as in example 1 except for using 2- (2-fluorophenyl) -3-phenyl-1-propene (106mg, 0.5 mmol) in place of 2,3-diphenyl-1-propene (2,3-diphenyl-1-propene), so as to obtain the product (white solid, yield 44%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ7.77–7.67(m,3H),7.53–7.47(m,1H),7.25(d,J＝8.0Hz,2H),7.19–7.14(m,1H),7.04(dd,J＝11.4,8.4Hz,1H),4.72(s,2H),2.36(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ185.10(d,J＝3.1Hz),160.85(d,J＝255.3Hz),144.25,135.08(d,J＝9.5Hz),134.99,130.11(d,J＝1.7Hz),128.73,127.52,123.78(d,J＝3.5Hz),123.43(d,J＝11.2Hz),115.80(d,J＝23.8Hz),66.05(d,J＝8.8Hz),20.68； 19 F NMR(376MHz,CDCl 3 )δ-108.90。
example 15:1- (naphthalen-1-yl) -2-p-toluenesulfonyl ethanones
The reaction was carried out in the same manner as in example 1 except for using 2- (naphthalen-1-yl) -3-phenyl-1-propene (122mg, 0.5 mmol) in place of 2,3-diphenyl-1-propene to obtain the product (white solid, yield 81%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ8.56(d,J＝8.3Hz,1H),8.05(t,J＝8.0Hz,2H),7.89(d,J＝8.4Hz,1H),7.74(d,J＝8.2Hz,2H),7.62–7.49(m,3H),7.28(d,J＝8.2Hz,2H),4.85(s,2H),2.43(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ190.54,145.34,135.72,134.69,133.91,133.34,130.93,130.37,129.85,128.79,128.62,126.88,125.57,124.30,66.31,21.75。
example 16:1- (furan-3-yl) -2-p-toluenesulfonyl ethanone
The reaction was carried out in the same manner as in example 1 except for using 2- (furan-3-yl) -3-phenyl-1-propene (92mg, 0.5 mmol) in place of 2,3-diphenyl-1-propene (2,3-diphenyl-1-propene), so as to obtain the product (white solid, yield 43%).
And (3) product characterization: 1 HNMR(400MHz,CDCl 3 )δ7.76(d,J＝8.2Hz,2H),7.62(s,1H),7.37–7.31(m,3H),6.62–6.57(m,1H),4.57(s,2H),2.45(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ175.88,151.85,148.11,145.40,135.60,129.85,128.55,120.47,113.21,63.60,21.73。
example 17:2- (4-methoxybenzenesulfonyl) acetophenone
The reaction operation was carried out in the same manner as in example 1 except for using 4-methoxybenzenesulfonylhydrazide (202mg, 1.0 mmol) in place of the p-toluenesulfonylhydrazide to obtain a product (white solid, yield 83%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ7.95(d,J＝7.7Hz,2H),7.81(d,J＝8.8Hz,2H),7.63(t,J＝7.4Hz,1H),7.49(t,J＝7.7Hz,2H),6.99(d,J＝8.8Hz,2H),4.72(s,2H),3.88(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ188.34,164.14,135.74,134.37,130.90,130.08,129.35,128.87,114.38,63.73,55.74。
example 18:2- (4-bromophenylsulfonyl) acetophenone
The reaction operation was carried out in the same manner as in example 1 except for using 4-bromobenzenesulfonyl hydrazide (251mg, 1.0 mmol) in place of the p-toluenesulfonyl hydrazide to obtain a product (white solid, yield 69%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ7.93(d,J＝7.3Hz,2H),7.76(d,J＝8.7Hz,2H),7.69(d,J＝8.7Hz,2H),7.64(t,J＝7.4Hz,1H),7.50(t,J＝7.8Hz,2H),4.74(s,2H)； 13 C NMR(101MHz,CDCl 3 )δ187.87,137.62,135.58,134.55,132.53,130.21,129.78,129.25,128.95,63.32。
example 19:2- (4-Chlorophenylsulfonyl) acetophenone
The reaction operation was carried out in the same manner as in example 1 except for using 4-chlorobenzenesulfonyl hydrazide (207mg, 1.0 mmol) in place of the p-toluenesulfonyl hydrazide to obtain a product (white solid, yield 64%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ7.94(d,J＝7.4Hz,2H),7.83(d,J＝8.6Hz,2H),7.64(t,J＝7.4Hz,1H),7.56–7.45(m,4H),4.74(s,2H)； 13 C NMR(101MHz,CDCl 3 )δ186.88,140.10,136.06,134.56,133.52,129.15,128.51,128.22,127.93,62.32。
example 20:2- (4-fluorobenzenesulfonyl) acetophenone
The reaction operation was carried out in the same manner as in example 1 except for using 4-fluorobenzenesulfonyl hydrazide (190mg, 1.0 mmol) (104mg, 0.5 mmol) in place of the p-toluenesulfonyl hydrazide to obtain a product (white solid, yield 45%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ7.97–7.89(m,4H),7.64(t,J＝7.4Hz,1H),7.50(t,J＝7.8Hz,2H),7.22(t,J＝8.5Hz,2H),4.74(s,2H)； 13 C NMR(101MHz,CDCl 3 )δ187.98,166.15(d,J＝257.4Hz),135.62,134.67(d,J＝3.3Hz),134.53,131.67(d,J＝9.7Hz),129.26,128.94,116.55(d,J＝22.7Hz),63.46； 19 F NMR(376MHz,CDCl 3 )δ-102.38。
example 21:4- (2-Oxophenylethanesulfonyl) benzonitrile
The reaction operation was carried out in the same manner as in example 1 except for using 4-cyanobenzenesulfonyl hydrazide (197mg, 1.0 mmol) in place of the p-toluenesulfonyl hydrazide to obtain a product (white solid, yield 74%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ8.04(d,J＝8.3Hz,2H),7.93(d,J＝7.7Hz,2H),7.86(d,J＝8.3Hz,2H),7.66(t,J＝7.2Hz,1H),7.52(t,J＝7.7Hz,2H),4.78(s,2H)； 13 C NMR(101MHz,CDCl 3 )δ187.66,142.62,135.37,134.81,132.89,129.53,129.18,129.07,117.98,117.04,62.95。
example 22:2- (4-trifluoromethylbenzenesulfonyl) acetophenone
The reaction operation was carried out in the same manner as in example 1 except for using 4-trifluoromethylbenzenesulfonylhydrazide (240mg, 1.0 mmol) in place of the p-toluenesulfonylhydrazide to give a product (white solid, yield 81%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ8.05(d,J＝8.1Hz,2H),7.92(d,J＝7.7Hz,2H),7.81(d,J＝8.1Hz,2H),7.63(t,J＝7.3Hz,1H),7.48(t,J＝7.6Hz,2H),4.80(s,2H)； 13 C NMR(101MHz,CDCl 3 )δ187.77,142.15,135.77(q,J＝33.1Hz),134.65,135.48,129.39,129.17,128.99,126.32(q,J＝3.7Hz),123.06(q,J＝273.2Hz),63.04； 19 F NMR(376MHz,CDCl 3 )δ-63.25。
example 23:2- (4-Nitrobenzenesulfonyl) acetophenone
The reaction operation was carried out in the same manner as in example 1 except for using 4-nitrophenylsulfonyl hydrazide (217mg, 1.0 mmol) in place of the p-toluenesulfonyl hydrazide to obtain a product (white solid, yield 42%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ8.40(d,J＝8.9Hz,2H),8.12(d,J＝8.9Hz,2H),7.93(d,J＝8.5Hz,2H),7.67(t,J＝7.4Hz,1H),7.52(t,J＝7.8Hz,2H),4.81(s,2H)； 13 C NMR(101MHz,CDCl 3 )δ187.60,151.07,144.03,135.33,134.86,130.34,129.19,129.09,124.31,63.01。
example 24:2- (3-bromobenzenesulfonyl) acetophenone
The reaction operation was carried out in the same manner as in example 1 except for using 3-bromobenzenesulfonyl hydrazide (251mg, 1.0 mmol) in place of the p-toluenesulfonyl hydrazide to obtain the product (white solid, yield 64%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ8.04(t,J＝1.6Hz,1H),7.97–7.90(m,2H),7.84(d,J＝7.9Hz,1H),7.78(d,J＝8.0Hz,1H),7.64(t,J＝7.4Hz,1H),7.50(t,J＝7.8Hz,2H),7.43(t,J＝7.9Hz,1H),4.75(s,2H)； 13 C NMR(101MHz,CDCl 3 )δ187.70,140.48,137.31,135.58,134.58,131.50,130.67,129.23,128.96,127.31,123.19,63.28。
example 25:2- (2-bromophenylsulfonyl) acetophenone
The reaction operation was carried out in the same manner as in example 1 except for using 2-bromobenzenesulfonyl hydrazide (251mg, 1.0 mmol) in place of the p-toluenesulfonyl hydrazide to obtain a product (white solid, yield 63%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ8.05–7.97(m,1H),7.87(d,J＝7.6Hz,2H),7.74–7.67(m,1H),7.54(t,J＝7.4Hz,1H),7.46–7.36(m,4H),5.01(s,2H)； 13 C NMR(101MHz,CDCl 3 )δ187.81,138.16,135.80,135.38,135.11,134.43,132.48,129.15,128.90,128.04,120.90,60.54。
example 26:2- (naphthalene-1-sulfonyl) acetophenone
The reaction operation was carried out in the same manner as in example 1 except for using naphthalene-1-sulfonylhydrazide (222mg, 1.0 mmol) in place of p-toluenesulfonylhydrazide to obtain a product (white solid, yield 59%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ8.71(d,J＝8.6Hz,1H),8.15(d,J＝7.4Hz,1H),8.05(d,J＝8.2Hz,1H),7.90(d,J＝8.2Hz,1H),7.79(d,J＝7.3Hz,2H),7.67(t,J＝8.3Hz,1H),7.56(t,J＝7.5Hz,1H),7.49(t,J＝7.4Hz,1H),7.46(t,J＝7.8Hz,1H),7.33(t,J＝7.8Hz,2H),4.82(s,2H)； 13 C NMR(101MHz,CDCl 3 )δ186.78,134.85,134.79,133.20,133.15,132.84,130.39,128.45,128.18,128.06,127.76,127.71,126.11,123.28,122.69,61.84。
example 27:2- (pyridine-3-sulfonyl) acetophenone
The reaction operation was carried out in the same manner as in example 1 except for using pyridine-3-sulfonylhydrazide (173mg, 1.0 mmol) in place of the p-toluenesulfonylhydrazide to obtain a product (white solid, yield 48%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ9.14–9.10(m,1H),8.89(d,J＝4.0Hz,1H),8.23(d,J＝8.0Hz,1H),7.94(d,J＝7.6Hz,2H),7.65(t,J＝7.4Hz,1H),7.55–7.48(m,3H),4.83(s,2H)； 13 C NMR(101MHz,CDCl 3 )δ187.79,154.61,149.53,136.81,135.34,135.21,134.73,129.14,129.02,123.68,63.25。
example 28:2- (thiophene-2-sulfonyl) acetophenone
The reaction operation was carried out in the same manner as in example 1 except for using thiophene-2-sulfonylhydrazide (178mg, 1.0mmol) in place of the p-toluenesulfonylhydrazide to obtain a product (white solid, yield 65%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ7.95(d,J＝7.3Hz,2H),7.74(dd,J＝4.9,1.2Hz,1H),7.70(dd,J＝3.8,1.2Hz,1H),7.63(t,J＝7.4Hz,1H),7.49(t,J＝7.8Hz,2H),7.13(dd,J＝4.8,3.9Hz,1H),4.83(s,2H)； 13 C NMR(101MHz,CDCl 3 )δ187.81,139.38,135.62,135.49,135.00,134.46,129.22,128.90,127.94,64.34。
example 29:2- (Butanesulfonyl) acetophenone
The reaction operation was carried out in the same manner as in example 1 except for using n-butylsulfonyl hydrazide (152mg, 1.0 mmol) in place of the p-toluenesulfonyl hydrazide to obtain a product (white solid, yield 90%).
And (3) product characterization: 1 H NMR(400MHz,CDCl 3 )δ8.02(d,J＝7.4Hz,2H),7.66(t,J＝7.4Hz,1H),7.53(t,J＝7.7Hz,2H),4.57(s,2H),3.29–3.23(m,2H),1.93–1.84(m,2H),1.56–1.45(m,2H),0.98(t,J＝7.4Hz,3H)； 13 C NMR(101MHz,CDCl 3 )δ189.31,135.77,134.63,129.32,128.99,59.53,53.48,23.88,21.64,13.54。
example 30: 2-p-toluenesulfonylacetophenone
The same operation as in example 1 was repeated except for using 3-methyl-2-phenyl-3- (4-methoxyphenyl) -1-propene (119mg, 0.5mmol) in place of 2,3-diphenyl-1-propene to obtain the same product as in example 1 (white solid, yield 63%).
Example 31: 2-p-toluenesulfonylacetophenone
The same procedures used in example 1 were repeated except for using 3,3-dimethyl-2-phenyl-3- (4-methoxyphenyl) -1-propene (126mg, 0.5 mmol) in place of 2,3-diphenyl-1-propene (all: s.) to give the same product as in example 1 (white solid, yield 58%).
Example 32: 2-p-toluenesulfonylacetophenone
The same procedures used in example 1 were repeated except for using (3-methoxyprop-1-en-2-yl) benzene (74mg, 0.5 mmol) in place of 2,3-diphenyl-1-propene (2,3-diphenyl-1-propene), to obtain the same product as in example 1 (white solid, yield 59%).
Example 33: 2-p-toluenesulfonylacetophenone
The same operation as in example 1 was carried out using N- (2-phenylallyl) aniline (105mg, 0.5 mmol) in place of 2,3-diphenyl-1-propene and the like to obtain the same product as in example 1 (white solid, yield 65%).
Example 34: 2-p-toluenesulfonylacetophenone
The same reaction procedure as in example 1 was conducted except that acetonitrile/water (V: V = 9:1) was replaced with acetonitrile, to give the same product as in example 1 (white solid, yield 51%).
Example 35: 2-p-toluenesulfonylacetophenone
The same reaction procedure as in example 1 was repeated except that acetonitrile/water (V: V = 5:1) was used instead of acetonitrile/water (V: V = 9:1), to obtain the same product as in example 1 (white solid, yield 86%).
Example 36: 2-p-toluenesulfonylacetophenone
The same reaction procedure as in example 1 was repeated except that dimethyl sulfoxide/water (V: V = 5:1) was used instead of acetonitrile/water (V: V = 9:1), to obtain the same product as in example 1 (white solid, yield 58%).
Example 37: 2-p-toluenesulfonylacetophenone
The reaction operation was carried out in the same manner as in example 1 except that acetonitrile/water (V: V = 5:1) was used instead of acetonitrile/water (V: V = 9:1) and copper bromide (6 mg, 0.025mmol) was used instead of copper trifluoromethanesulfonate, to obtain the same product as in example 1 (white solid, yield 55%).
Example 38: 2-p-toluenesulfonylacetophenone
The same operation as in example 1 was carried out except that 65 ℃ was replaced by 50 ℃, to obtain the same product (white solid, yield 54%) as in example 1.
Example 39: 2-p-toluenesulfonylacetophenone
The same reaction operation as in example 1 was carried out except that 80 ℃ was used instead of 65 ℃, whereby the same product as in example 1 was obtained (white solid, yield 46%).
Example 40: 2-p-toluenesulfonylacetophenone
The same operation as in example 1 was carried out except that air was used instead of oxygen, to obtain the same product as in example 1 (white solid, yield 31%).
Claims (17)
1. The preparation method of the beta-carbonyl sulfone compound is characterized by comprising the following steps: the method comprises the following steps:
reacting 1,1-disubstituted olefin of a compound of a formula I and sulfonyl hydrazide of a compound of a formula II in an organic solvent by using copper salt as a catalyst, and after the reaction is finished, carrying out post-treatment to obtain a beta-carbonyl sulfone compound shown in a formula III; the reaction is carried out under air or oxygen;
wherein R is 1 Selected from substituted or unsubstituted C 6 ～C 10 Aryl, substituted or unsubstituted C 5 ～C 18 Heteroaryl, wherein the heteroatom of the heteroaryl is N, O or S, and the number of the heteroatoms is 1-3; r 1 In (b), said substituted C 6 ～C 10 Aryl or substituted C 5 ～C 18 The substituent of the heteroaryl group being C 1 ～C 8 Alkyl radical, C 3 ～C 8 Cycloalkyl radical, C 1 ～C 8 Alkoxy radical, C 1 ～C 8 Alkoxycarbonyl, C 1 ～C 8 Alkylcarbamoyl, C 1 ～C 8 Alkylcarbonyl, cyano, trifluoromethyl, halogen, nitro, phenyl or phenoxy;
R 2 is selected from C 1 ～C 18 Alkyl, substituted or unsubstituted C 6 ～C 10 Aryl, substituted or unsubstituted C 5 ～C 18 Heteroaryl, wherein the heteroatom of the heteroaryl is N, O or S, and the number of the heteroatoms is 1-3; r 2 In (b), said substituted C 6 ～C 10 Aryl or substituted C 5 ～C 18 The substituent of the heteroaryl group being C 1 ～C 8 Alkyl radical, C 3 ～C 8 Cycloalkyl radical, C 1 ～C 8 Alkoxy radical, C 1 ～C 8 Alkoxycarbonyl, C 1 ～C 8 Alkylcarbamoyl, C 1 ～C 8 Alkylcarbonyl, cyano, trifluoromethyl, halogen, nitro, phenyl or phenoxy;
R 3 and R 4 Independently selected from H, C 1 ～C 8 Alkyl, unsubstituted or substituted C 6 ～C 10 Aryl, hydroxy, C 1 ～C 8 Alkoxy, unsubstituted or substituted phenoxy, substituted acyloxy, substituted sulfonyloxy, mono-or disubstituted amino, azido, phosphono, sulphonyl, and R 3 And R 4 Not being H or R at the same time 3 、R 4 And the carbon to which they are attached to form a 3-to 8-membered alkyl ring or C 6 ～C 10 An aromatic ring; r 3 And R 4 In (b), said substituted C 6 ～C 10 The substituent of the aryl or substituted phenoxy group being C 1 ～C 8 Alkyl radical, C 1 ～C 8 Alkoxy radical, C 1 ～C 8 Alkoxycarbonyl, cyano, trifluoromethyl, halogen or phenoxy; r 3 And R 4 Wherein the substituent of said substituted acyloxy or substituted sulfonyloxy is unsubstituted or C 1 ～C 8 Alkyl substituted C 6 ～C 10 An aryl group; r 3 And R 4 Wherein the substituent of the mono-or di-substituted amino is C 1 ～C 8 Alkyl radical, C 6 ～C 10 Aryl, acyl, or sulfonyl;
R 5 selected from hydrogen or C 1 ～C 8 Alkyl, and when R 3 、R 4 And the carbon to which they are attached to form C 6 ～C 10 When it is aromatic, R 5 Is absent.
2. The method for preparing a β -carbonyl sulfone compound according to claim 1, wherein: r is 1 Selected from substituted or unsubstituted C 6 ～C 10 Aryl, substituted or unsubstituted C 5 ～C 11 A heteroaryl group; r 1 Wherein the heteroatom of the heteroaryl is N, O or S, and the number of the heteroatoms is 1-3; r is 1 In (b), said substituted C 6 ～C 10 Aryl or substituted C 5 ～C 11 The substituent of the heteroaryl group being C 1 ～C 4 Alkyl radical, C 1 ～C 4 Alkoxy radical, C 1 ～C 4 Alkoxycarbonyl, C 1 ～C 4 Alkylcarbamoyl, C 1 ～C 4 Alkylcarbonyl, cyano, trifluoromethyl, fluoro, chloro, bromo, nitro, phenyl or phenoxy;
R 2 is selected from C 1 ～C 8 Alkyl, substituted or unsubstituted C 6 ～C 10 Aryl, substituted or unsubstituted C 5 ～C 11 A heteroaryl group; r is 2 Wherein the heteroatom of the heteroaryl is N, O or S, and the number of the heteroatoms is 1-3; r 2 In (b), said substituted C 6 ～C 10 Aryl or substituted C 5 ～C 11 The substituent of the heteroaryl group being C 1 ～C 4 Alkyl radical, C 1 ～C 4 Alkoxy radical, C 1 ～C 4 Alkoxycarbonyl, C 1 ～C 4 Alkylcarbamoyl, C 1 ～C 4 Alkylcarbonyl, cyano, trifluoromethyl, fluoro, chloro, bromo, nitro, phenyl or phenoxy.
3. The method for producing a β -carbonyl sulfone compound according to claim 1 or 2, characterized in that: the compound of formula I is selected from:
4. the method for producing a β -carbonyl sulfone compound according to claim 1 or 2, characterized in that: the compound of formula II is selected from:
5. the method for preparing a β -carbonyl sulfone compound according to claim 1, wherein: the molar ratio of the compound of formula I, the compound of formula II and the copper salt is 1:1.0 to 4.0:0.01 to 0.20.
6. The method for preparing a β -carbonyl sulfone compound according to claim 5, wherein: the molar ratio of the compound of formula I, the compound of formula II and the copper salt is 1:2.0:0.05.
7. the method for preparing a β -carbonyl sulfone compound according to claim 1, wherein: the copper salt is any one of copper trifluoromethanesulfonate, copper acetate, copper acetylacetonate, copper bromide, copper fluoride, copper nitrate trihydrate, copper sulfate, cuprous iodide, cuprous chloride or cuprous acetate.
8. The method for preparing a β -carbonyl sulfone compound according to claim 7, wherein: the copper salt is copper trifluoromethanesulfonate.
9. The method for preparing a β -carbonyl sulfone compound according to claim 1, wherein: the organic solvent is at least one of acetonitrile, tetrahydrofuran, 1,4-dioxane, N-dimethylformamide, ethanol, chloroform, dichloromethane, ethyl acetate, diethyl ether, ethylene glycol dimethyl ether, acetone, dimethyl sulfoxide, N-methylpyrrolidone, N-dimethylacetamide or water.
10. The method for preparing a β -carbonyl sulfone compound according to claim 9, wherein: the organic solvent is acetonitrile and water with the volume ratio of 9: 1.
11. The method for preparing a β -carbonyl sulfone compound according to claim 1, wherein: the reaction temperature is 40-80 ℃.
12. The method for preparing a β -carbonyl sulfone compound according to claim 11, wherein: the temperature of the reaction was 65 ℃.
13. The method for preparing a β -carbonyl sulfone compound according to claim 1, wherein: the reaction time is 4-24 h.
14. The method for preparing a β -carbonyl sulfone compound according to claim 13, wherein: the reaction time was 12h.
15. The method for producing a β -carbonyl sulfone compound according to any one of claims 1 to 2 or 5 to 14, wherein: the reaction is carried out under oxygen.
16. The method for preparing a β -carbonyl sulfone compound according to claim 3, characterized in that: the reaction is carried out under oxygen.
17. The method for preparing a β -carbonyl sulfone compound according to claim 4, wherein: the reaction is carried out under oxygen.
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