CN114276223B - Synthetic method of alpha-iodine-alpha-trifluoromethyl arylethanone - Google Patents
Synthetic method of alpha-iodine-alpha-trifluoromethyl arylethanone Download PDFInfo
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Abstract
The invention discloses a synthetic method of alpha-iodine-alpha-trifluoromethyl arylethanone, belonging to the field of organic chemistry. The method adopts cheap and easily-obtained sodium trifluoromethanesulfonate as a trifluoromethyl source and diiodo pentoxide as an oxidant and an iodine source, and has the advantages of wide applicability of substrates, simple and easily-obtained raw materials and low economic cost. In addition, the method realizes the synthesis of the target product in one step, can obtain the target product with better yield only by reacting for 8-24 hours, and has quick and high-efficiency reaction. The synthesis method converts simple and easily-obtained aryl ethylene into the alpha-iodine-alpha-trifluoromethyl aryl ethanone compound under simpler conditions, realizes iodination, trifluoromethylation and carbonylation of aryl ethylene in one step, and has wide application of target compounds in the fields of medicines, pesticides, petrochemical industry and the like.
Description
Technical Field
The invention particularly relates to a synthesis method of alpha-iodine-alpha-trifluoromethyl arylethanone, belonging to the field of organic chemistry.
Background
Since the 50 s of the 20 th century, it was discovered that introduction of fluorine atoms into specific sites of drug molecules could improve their biological activity, and a large number of fluorine-containing drugs began to emerge as spring shoots after rain. From 1970, it has only accounted for 2% of the pharmaceutical market, to date reaching about 20%. 35 chemicals were co-approved by the U.S. Food and Drug Administration (FDA) for marketing in 2019, 14 of which contained fluorine atoms and 7 contained trifluoromethyl groups. In the past decades, a great deal of research into CF has been conducted 3 A new strategy for introducing groups into organic molecules. More recently, the development of new and more recently developed devicesSince iodides have a very important role in nucleophilic substitution and cross-coupling reactions, the bifunctionalization involving unsaturated bonds, the halogenation, trifluoromethylation and especially the iodination and trifluoromethyl difunctionalization of alkenes and alkynes, has attracted considerable attention over the last few years.
Disclosure of Invention
The invention develops a new method for iodination, trifluoromethylation and carbonylation of aryl ethylene, namely a synthetic method of an alpha-iodo-alpha-trifluoromethyl arylethanone compound. According to the invention, aryl ethylene reacts with sodium trifluoromethanesulfonate under the catalysis of silver salt, three-functionalization of aryl ethylene is carried out in one step, and the alpha-iodine-alpha-trifluoromethyl arylethanone compound is synthesized, so that iodination, trifluoromethylation and carbonylation of aryl ethylene can be conveniently, quickly and efficiently realized.
The invention aims to provide a method for synthesizing an alpha-iodine-alpha-trifluoromethyl arylethanone compound, which comprises the steps of taking an aryl ethylene compound shown in a formula (1) and sodium trifluoromethyl sulfinate shown in a formula (2) as reactants in an organic solvent, and carrying out a functional group reaction under the action of silver salt and an iodine source to synthesize the alpha-iodine-alpha-trifluoromethyl arylethanone compound shown in the formula (3);
wherein R is selected from H and C 1 -C 8 Alkyl radical, C 1 -C 8 Haloalkyl, aryl, halogen (F, cl, br), cyano, nitro, C 1 -C 8 Alkoxy, acyl, and amide groups;
the iodine source is any one or more of diiodo, potassium iodate and potassium periodate.
In one embodiment of the invention, acyl is-C (O) R ', R' is selected from C1-C8 alkyl.
In one embodiment of the invention, the amide group is-C (O) -NR a R b ，R a 、R b Each independently selected from C1-C8 alkyl, or-NR a R b Is composed of
n =1 or 2.
In one embodiment of the present invention, the aryl group includes a substituted or unsubstituted benzene ring, a naphthalene ring; the substitution may be one to three; the substituted group is selected from halogen, C 1 -C 8 Alkyl radical, C 1 -C 8 An alkoxy group.
In one embodiment of the present invention, the organic solvent comprises acetonitrile (CH) 3 CN), N-Dimethylformamide (DMF), N-dimethylacetamide (DMAc) and Dimethylsulfoxide (DMSO). DMSO is preferred.
In one embodiment of the invention, the silver salt is any one or more of silver nitrate, silver carbonate, silver fluoride and silver sulfate. Silver fluoride and silver sulfate are preferable.
In one embodiment of the invention, the molar ratio of the arylalkene compound to the silver in the silver salt is 1 (1.0-4.0).
In one embodiment of the invention, the temperature of the reaction is from 25 ℃ to 120 ℃. Preferably 60 to 100 ℃; further preferably 70 to 80 ℃.
In one embodiment of the invention, the reaction time is from 8 to 24 hours. And particularly 12h can be selected.
In one embodiment of the present invention, the molar charge ratio of the aryl alkene compound to the sodium trifluoromethanesulfonate is 1: (0.8-3); preferably 1: (1.5-3) specifically, 1.
In one embodiment of the present invention, the silver salt is used in an amount of 1.0 to 2.0equiv (molar equivalent) relative to the arylvinyl compound.
In one embodiment of the invention, the molar ratio of the aryl alkene compound to the iodine source is 1 (1.0-3.0). Specifically, 1.
In one embodiment of the invention, the reaction concentration of the arylalkene compound is from 0.05 to 5mmol/mL. More preferably 0.1mmol/mL.
In one embodiment of the invention, the functionalization reaction is inertCarried out in an atmosphere. Such as: nitrogen (N) 2 ) And (4) atmosphere.
In one embodiment of the invention, the aryl alkene compound, CF 3 SO 2 The molar ratio of Na, silver and iodine source can be selected from 1.
In one embodiment of the present invention, a novel green and economical synthesis method comprises the following steps:
with aryl ethylene and CF 3 SO 2 Na is used as a raw material, silver salt and an iodine source are added, a reaction is carried out for a period of time under the stirring condition at the temperature of 25-120 ℃ to obtain a crude product of the alpha-iodine-alpha-trifluoromethyl arylethanone compound, and then the pure alpha-iodine-alpha-trifluoromethyl arylethanone compound is obtained through filtration, washing, reduced pressure distillation and column chromatography separation.
In one embodiment of the invention, the separation method adopts a flash column chromatography separation method to obtain the final product alpha-iodine-alpha-trifluoromethyl arylethanone compound.
In one embodiment of the invention, the method is preferably carried out by the following steps: aryl ethylene, CF 3 SO 2 Adding Na, silver and an iodine source into a reaction vessel containing a dimethyl sulfoxide solvent according to a molar ratio of 1.
In one embodiment of the present invention, the reaction mechanism of the present invention is as follows: CF (compact flash) 3 SO 2 Na is oxidized by diiodo pentaoxide to generate trifluoromethyl radical, and diiodo pentaoxide is reduced to I 2 The trifluoromethyl radical attacks aryl ethylene to form trifluoromethyl methylated benzyl radical, which reacts with oxygen source in diiodo pentaoxide to form alpha-trifluoromethyl arylethanone 2 And (4) substitution to generate alpha-iodine-alpha-trifluoromethyl aryl ethanone.
Has the advantages that:
the process of the invention is carried out under nitrogen (N) 2 ) In the atmosphere, aryl vinyl compound is taken as a substrate, CF 3 SO 2 Na is a trifluoromethyl reagent, and can realize iodination and trifluoromethyl of aryl ethylene in one step under the action of silver salt and oxidantCarrying out alkylation and carbonylation to obtain the target compound.
The method of the invention respectively uses cheap and easily obtained CF 3 SO 2 Na is a trifluoromethyl source, diiodo pentaoxide is an oxidant and an iodine source, the applicability of a substrate is wide, the raw materials are simple and easy to obtain, and the economic cost is low; in addition, the method can obtain the target product with better yield only by reacting for 8-24 hours, and is quicker and more efficient.
The synthesis method converts simple and easily-obtained aryl ethylene into the alpha-iodine-alpha-trifluoromethyl aryl ethanone compound under simpler conditions, realizes iodination, trifluoromethylation and carbonylation of aryl ethylene in one step, and has wide application of target compounds in the fields of medicines, pesticides, petrochemical industry and the like.
Drawings
FIG. 1 is a synthetic scheme of the process of the present invention.
Detailed Description
The following are specific embodiments of the present invention.
The synthesis route map of the embodiment of the invention is shown in fig. 1:
with aryl ethylene and CF 3 SO 2 Na is used as a raw material, diiodo pentaoxide is used as an oxidant and an iodine source, silver sulfate is used as a silver salt, the mixture is added into a reaction bottle containing dimethyl sulfoxide, and then the reaction bottle is placed into an oil bath kettle at the temperature of 25-100 ℃ to fully react for 8-24 hours. The reaction expression is shown in figure 1.
Example 1: synthesis of alpha-iodine-alpha-trifluoromethyl p-tert-butyl acetophenone
Under the protection of nitrogen, p-tert-butylstyrene (160mg, 1mmol) and CF were reacted respectively 3 SO 2 Na (320mg, 2.0mmol), diiodo pentoxide (666mg, 2mmol), silver sulfate (310mg, 1.0mmol) and dimethyl sulfoxide (10 mL) were charged into a 25mL reaction tube equipped with a stirrer, and reacted sufficiently at 80 ℃ for 12 hours. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate and washed with distilled water and saturated sodium chloride solution, respectively, and the solvent was removed by vacuum concentration, and the objective compound was isolated and purified by column chromatography to obtain 255mg of the product with a yield of 69% (yield 77%).
1 H NMR(400MHz,CDCl 3 )δ7.82(d,J＝8.5Hz,2H),7.44(d,J＝8.5Hz,2H),5.62(q,J＝6.9Hz,1H),1.27(s,9H). 19 F NMR(376MHz,CDCl 3 )δ-64.45(s). 13 C NMR(101MHz,CDCl 3 )δ186.68(s),157.71(s),129.37(d,J＝1.7Hz),127.81(s),125.07(s),122.56(q,J＝277.6Hz),34.31(s),29.94(s),14.75(q,J＝30.1Hz).
Example 2: synthesis of alpha-iodine-alpha-trifluoromethyl-p-phenylacetophenone
Under the protection of nitrogen, p-phenylstyrene (180mg, 1mmol), CF are reacted separately 3 SO 2 Na (320mg, 2.0mmol), diiodo pentoxide (666mg, 2mmol), silver sulfate (310mg, 1.0mmol) and dimethyl sulfoxide (10 ml) were put into a 25ml reaction tube equipped with a stirrer, and reacted sufficiently at 80 ℃ for 12 hours. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate and washed with distilled water and saturated sodium chloride solution, respectively, and the solvent was removed by vacuum concentration, and the target product was separated and purified by column chromatography to obtain 273mg of the product with a yield of 70%.
1 H NMR(400MHz,CDCl 3 )δ7.93(d,J＝8.5Hz,2H),7.62(d,J＝8.5Hz,2H),7.57–7.49(m,2H),7.39(t,J＝7.3Hz,2H),7.33(t,J＝7.2Hz,1H),5.65(q,J＝6.9Hz,1H). 19 F NMR(376MHz,CDCl 3 )δ-64.35(s). 13 C NMR(101MHz,CDCl 3 )δ187.73(s),147.33(s),139.30(s),131.67(d,J＝1.8Hz),129.48(s),129.13(s),128.76(s),127.67(s),127.36(s),123.6(q,J＝278.8Hz),15.95(q,J＝30.2Hz).
Example 3: synthesis of alpha-iodine-alpha-trifluoromethyl p-methoxy acetophenone
Under the protection of nitrogen, p-methoxystyrene (134mg, 1mmol) and CF were reacted with each other 3 SO 2 Na (320mg, 2.0mmol), diiodo pentoxide (666mg, 2mmol), silver sulfate (310mg, 1.0mmol) and dimethyl sulfoxide (10 ml) were put into a 25ml reaction tube equipped with a stirrer, and reacted sufficiently at 80 ℃ for 12 hours. After the reaction is finished, cooling to room temperature, diluting with ethyl acetate, washing with distilled water and saturated sodium chloride solution respectively, vacuum concentrating to remove solvent, and separating and purifying the target by column chromatographyProduct 213mg was obtained in 62% yield.
1 H NMR(400MHz,CDCl 3 )δ7.94(d,J＝8.9Hz,2H),6.98(d,J＝8.9Hz,2H),5.66(q,J＝6.9Hz,1H),3.90(s,3H). 19 F NMR(376MHz,CDCl 3 )δ-64.45(s). 13 C NMR(101MHz,CDCl 3 )δ186.65(s),164.66(s),131.31(s),123.59(q,J＝277.6Hz),123.59(q,J＝277.6Hz),114.34(s),55.68(s),15.73(q,J＝30.0Hz).
EXAMPLE 4 Synthesis of alpha-iodo-alpha-trifluoromethyl-p-tert-butyl acetophenone from different silver salts
Referring to example 1, the silver salt was replaced from silver sulfate with silver nitrate, silver carbonate, silver fluoride (equal silver molar amount), and a set of experiments without any silver salt was added, and other conditions were not changed, to synthesize α -iodo- α -trifluoromethyl-p-tert-butyl acetophenone. Specific yield a The results are shown in Table 1.
TABLE 1 Effect of different silver salts on the Synthesis of alpha-iodo-alpha-trifluoromethyl-p-tert-butyl acetophenone a
| Silver salts | Yield (%) |
| Without adding | 0 |
| AgNO 3 | 48 |
| Ag 2 CO 3 | 30 |
| AgF | 70 |
| Ag 2 SO 4 | 77 |
a. The yield is the fluorine spectrum yield.
As a result, it was found that: without the addition of silver salt and with the substitution of silver nitrate, silver carbonate, silver fluoride for the silver sulfate as catalyst in example 1, the product yields obtained were inferior to example 1, with yields not exceeding 50%.
EXAMPLE 5 Synthesis of alpha-iodo-alpha-trifluoromethyl-p-tert-butyl acetophenone in different solvents
Referring to example 1, α -iodo- α -trifluoromethyl-p-tert-butyl acetophenone was synthesized by replacing the solvent with dimethyl sulfoxide with acetonitrile, N-dimethylformamide, N-dimethylacetamide, water, NMP, respectively, and the other conditions were not changed.
The specific yield results are shown in table 2.
TABLE 2 Effect of different solvents on the synthesis of alpha-iodo-alpha-trifluoromethyl-p-tert-butyl acetophenone a
| Solvent(s) | Yield (%) |
| DMSO | 77 |
| CH 3 CN | 14 |
| DMAc | 20 |
| DMF | 31 |
| NMP | trace |
| H 2 O | 0 |
a. The yield is the fluorine spectrum yield.
As a result, it was found that: acetonitrile, N-dimethylformamide, N-dimethylacetamide, NMP and water are used for replacing dimethyl sulfoxide in example 1 as a solvent, and the obtained product yield is worse than that of example 1 and does not exceed 31%.
EXAMPLE 6 Synthesis of alpha-iodo-alpha-trifluoromethyl-p-tert-butyl acetophenone at different reaction temperatures
Referring to example 1, α -iodo- α -trifluoromethyl-p-tert-butyl acetophenone was synthesized by changing the reaction temperature from 80 ℃ to 25 ℃, 60 ℃ and 100 ℃ respectively, while keeping the other conditions unchanged.
The specific yield results are shown in table 3.
TABLE 3 influence of different reaction temperatures on the synthesis of alpha-iodo-alpha-trifluoromethyl-p-tert-butyl acetophenone a
a. The yield is the fluorine spectrum yield.
As a result, it was found that: the product yields obtained by replacing 80 ℃ in example 1 with 25 ℃, 60 ℃ and 100 ℃ were all inferior to example 1, and did not exceed 56%.
Claims (7)
1. A synthetic method of an alpha-iodine-alpha-trifluoromethyl arylethanone compound is characterized in that in an organic solvent, aryl alkene compound shown in a formula (1) and sodium trifluoromethyl sulfinate shown in a formula (2) are used as reactants, and a functionalization reaction is carried out under the action of silver salt and an iodine source to synthesize the alpha-iodine-alpha-trifluoromethyl arylethanone compound shown in the formula (3);
wherein R is selected from H and C 1 -C 8 Alkyl radical, C 1 -C 8 Haloalkyl, aryl, F, cl, br, cyano, nitro, C 1 -C 8 Alkoxy, acyl, and amide groups;
the iodine source is diiodo pentoxide;
the organic solvent comprises any one or more of acetonitrile, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide;
the silver salt is any one or more of silver nitrate, silver carbonate, silver fluoride and silver sulfate;
the temperature of the reaction is 60-100 ℃.
2. The process of claim 1, wherein the molar ratio of the arylalkene compound to silver in the silver salt is 1 (1.0-4.0).
3. The method of claim 1, wherein the molar charge ratio of the aryl alkene compound to the sodium trifluoromethylsulfinate is 1: (0.8-3).
4. The method of claim 1, wherein the molar ratio of the aryl alkene compound to the iodine source is 1 (1.0-3.0).
5. The method of claim 1, wherein the reaction concentration of the arylalkene compound is 0.05 to 5mmol/mL.
6. The method of claim 1, wherein the functionalizing reaction is performed under an inert atmosphere.
7. The method of any one of claims 1-6, wherein acyl is-C (O) R ', R' is selected from C1-C8 alkyl; the amide group being-C (O) -NR a R b ，R a 、R b Each independently selected from C1-C8 alkyl, or-NR a R b Is composed of
n＝1、2。
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| CN111807938A (en) * | 2020-07-22 | 2020-10-23 | 盐城工学院 | (E) -1-chloro-2-iodoethylene compound and preparation method thereof |
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| CN104888852A (en) * | 2015-05-29 | 2015-09-09 | 华中科技大学 | Catalytic system for oxidation of olefins and application thereof |
| CN105037081A (en) * | 2015-07-14 | 2015-11-11 | 翁月林 | Trifluoromethylation method for biphenylyl olefin compound |
| CN108341755A (en) * | 2017-01-24 | 2018-07-31 | 中国科学院福建物质结构研究所 | A method of it prepares containing bifunctional compound |
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