CN107759443B - Aryl high-iodine trifluoromethyl reagent, preparation and application thereof - Google Patents
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- CN107759443B CN107759443B CN201711253540.0A CN201711253540A CN107759443B CN 107759443 B CN107759443 B CN 107759443B CN 201711253540 A CN201711253540 A CN 201711253540A CN 107759443 B CN107759443 B CN 107759443B
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Abstract
The invention discloses an aryl high-iodine trifluoromethyl reagent and a preparation method thereof, wherein the reagent adopts high-iodide ArIY2With TMSCF3The aryl trifluoromethyl high-iodine substance is prepared by direct anion ligand exchange reaction and developed into a high-efficiency trifluoromethylation reagent. Can directly, simply and efficiently prepare the high-iodine trifluoromethyl reagent. The reagent is stable and high in reaction activity, can be used for various trifluoromethylation reactions, and does not need a catalyst (the Togni trifluoromethyl reagent needs to be activated when in use). Solves the problem of high-iodine trifluoromethyl in the prior artThe non-cyclic aryl trifluoromethyl high-iodine trifluoromethyl reagent has the defects of few types of reagents, single structure, complicated synthesis steps and the like, and the non-cyclic aryl trifluoromethyl high-iodine trifluoromethyl reagent has various structures and a direct and simple preparation method.
Description
Technical Field
The invention discloses an aryl high-iodine trifluoromethyl reagent, also provides a preparation method of the reagent, further discloses application of the reagent in the field of organic synthesis methodology, and belongs to the technical field of organic synthesis chemistry.
Background
The compound containing trifluoromethyl has obviously enhanced physical and chemical properties and bioactivity, and is widely applied to the fields of medicines, pesticides, dyes, energy sources, materials and the like. Particularly in the medical field, the fluorine-containing drugs account for nearly 30%, for example, 17 of the fluorine-containing drugs approved in nearly three years are fluorinated aromatic hydrocarbons, and 6 contain trifluoromethyl.
Arylperfluoroalkyl periododides (ArI (C)nF2n-1) X) is a highly efficient electrophilic perfluoroalkyl transfer reagent. Among the simplest perfluoroalkyl groups are the high iodine analogs of trifluoromethyl (ArICF)3X), but is extremely challenging with respect to its preparation. Since 1978, Yagupolski and Umemoto have been devoted to the synthesis of this trifluoromethyl iodide, and later, the Togni group and the Qingfeng solitary group have tried to synthesize or detect this compound, but both failed. Preparation of ArICF3The instability of the intermediates involved in X, as well as its own instability, is believed to be a major reason for the inability to obtain such materials. Thus, the Togni group designed and synthesized two cyclic aryl trifluoromethyl homoiodides in 2006. The existence of five-membered ring skeleton successfully stabilizes trifluoromethyl high-iodine species, so that the trifluoromethyl high-iodine species becomes the electrophilic trifluoromethylating reagent which is most widely applied at present.
At present, the electrophilic trifluoromethyl reagent has few types, and the preparation of the simple aryl trifluoromethyl periodate with adjustable structure is still lack of a direct and effective method. In view of this, the development of a direct and simple method for synthesizing aryl trifluoromethyl high-iodine reagent with rich structure and developing the aryl trifluoromethyl high-iodine reagent into a high-efficiency new trifluoromethyl reagent is a technical problem which needs to be solved urgently in the current research field.
Disclosure of Invention
The purpose of the invention is: provides electrophilic trifluoromethylating reagents with adjustable structures, has simple and direct preparation method, has a structure different from the prior aryl high-iodine trifluoromethylating reagent with a ring structure, namely a Togni reagent, and develops the application of the reagents in trifluoromethyl transfer reaction.
The invention relates to an aryl high-iodine trifluoromethyl reagent, which has the structural general formula as follows:
wherein X is Cl; r is H; then phenyl trifluoromethyl iodine chloride; the molecular formula is as follows: c7H5IF3Cl；
Or X is Cl; r is F; then 4-fluorophenyl trifluoromethyl iodine chloride; the molecular formula is as follows: c7H4IF4Cl；
Or X is F; r is H; then phenyl trifluoromethyl iodine fluoride; the molecular formula is as follows: c7H5IF4；
Or X is Br; r is H; then is phenyltrifluoromethyl iodine bromide; the molecular formula is as follows: c7H5IF3Br；
Or X is F3COCO; r is H; then is phenyl trifluoromethyl trifluoroacetic acid iodine; the molecular formula is as follows: c9H5IF6O2。
The preparation method of the aryl trifluoromethyl high-iodine compound comprises the following steps:
1) adding an aryl periodide and a metal fluoride which are initial raw materials into a nitrile organic solvent under the nitrogen atmosphere; the molar ratio of the metal fluoride to the aryl periodide is 1.0-2.0, and the concentration of a reaction system is as follows: the volume ratio of the mole number of the aryl periodide to the nitrile organic solvent is 0.25-1.0 mmol/mL;
2) adding TMSCF under the stirring condition of minus 20 ℃ to minus 45 DEG C3Carrying out the reaction for 8-24 hours; TMSCF3The molar ratio of the aryl monoiodide to the aryl monoiodide is 1.0-2.0;
3) after the reaction is finished, moving the reaction system to 0 ℃, adding a mixture of alkali metal salt aqueous solution and acetone, and extracting by using dichloromethane; the volume ratio of the mixture of the alkali metal salt aqueous solution and the acetone is 1.0-3.0;
4) concentrating to obtain the aryl trifluoromethyl high iodine derivative.
The nitrile organic solvent in step 1) of the invention is selected from: acetonitrile, propionitrile, butyronitrile.
The aryl periododides described in step 1) of the present invention are selected from: ArI (OCOCOCF)3)2、ArICl2。
The metal fluoride in step 1) of the present invention is selected from: KF. CsF.
The alkali metal salt in step 3) of the present invention is selected from: NaCl, NaBr and KF.
The preparation method of the phenyl trifluoromethyl iodine chloride comprises the following steps:
1) under the nitrogen atmosphere, adding di (trifluoroacetic acid) iodobenzene and potassium fluoride into a nitrile organic solvent; the molar ratio of the potassium fluoride to the di (trifluoroacetic acid) iodobenzene is 1.0-2.0, and the concentration of a reaction system is as follows: the volume ratio of the mole number of the bis (trifluoroacetic acid) iodobenzene to the nitrile organic solvent is 0.25-1.0 mmol/mL;
2) adding TMSCF under the stirring condition of minus 20 ℃ to minus 45 DEG C3Carrying out the reaction for 8-24 hours; TMSCF3The molar ratio of the compound to bis (trifluoroacetic acid) iodobenzene is 1.0-2.0;
3) after the reaction is finished, moving the reaction system to 0 ℃, adding a mixture of sodium chloride aqueous solution and acetone, and extracting by dichloromethane; the volume ratio of the mixture of the sodium chloride aqueous solution and the acetone is 1.0-3.0;
4) concentrating to obtain the final product.
The preparation method of 4-fluorophenyl trifluoromethyl iodine chloride comprises the following steps
1) Under the nitrogen atmosphere, adding bis (trifluoroacetic acid) 4-fluoroiodobenzene and potassium fluoride into a nitrile organic solvent; the molar ratio of the potassium fluoride to the bis (trifluoroacetic acid) 4-fluoroiodobenzene is 1.0-2.0, and the concentration of a reaction system is as follows: the volume ratio of the mole number of the bis (trifluoroacetic acid) 4-fluoroiodobenzene to the nitrile organic solvent is 0.25-1.0 mmol/mL;
2) adding TMSCF under the stirring condition of minus 20 ℃ to minus 45 DEG C3Carrying out the reaction for 8-24 hours; TMSCF3The molar ratio of the non-cyclic high iodide to the non-cyclic high iodide is 1.0-2.0;
3) after the reaction is finished, moving the reaction system to 0 ℃, adding a mixture of sodium chloride aqueous solution and acetone, and extracting by dichloromethane; the volume ratio of the mixture of the sodium chloride aqueous solution and the acetone is 1.0-3.0;
4) concentrating to obtain the final product.
The preparation method of the phenyl trifluoromethyl iodine fluoride comprises the following steps:
1) under the nitrogen atmosphere, adding di (trifluoroacetic acid) iodobenzene and potassium fluoride into a nitrile organic solvent; the molar ratio of the potassium fluoride to the di (trifluoroacetic acid) iodobenzene is 1.0-2.0, and the concentration of a reaction system is as follows: the volume ratio of the mole number of the bis (trifluoroacetic acid) iodobenzene to the nitrile organic solvent is 0.25-1.0 mmol/mL);
2) adding TMSCF under stirring at-20 deg.C3Carrying out the reaction for 8-24 hours; TMSCF3The molar ratio of the compound to bis (trifluoroacetic acid) iodobenzene is 1.0-2.0;
3) after the reaction is finished, moving the reaction system to 0 ℃, adding a mixture of a potassium fluoride aqueous solution and acetone, and extracting by using dichloromethane; the volume ratio of the mixture of the potassium fluoride aqueous solution and the acetone is 1.0-3.0;
4) concentrating to obtain the final product.
The preparation method of the phenyl trifluoromethyl iodine bromide comprises the following steps:
1) under the nitrogen atmosphere, adding di (trifluoroacetic acid) iodobenzene and potassium fluoride into a nitrile organic solvent; the molar ratio of the potassium fluoride to the di (trifluoroacetic acid) iodobenzene is 1.0-2.0, and the concentration of a reaction system is as follows: the volume ratio of the mole number of the bis (trifluoroacetic acid) iodobenzene to the nitrile organic solvent is 0.25-1.0 mmol/mL;
2) adding TMSCF under the stirring condition of minus 20 ℃ to minus 45 DEG C3Carrying out the reaction for 8-24 hours; TMSCF3The molar ratio of the compound to bis (trifluoroacetic acid) iodobenzene is 1.0-2.0;
3) after the reaction is finished, moving the reaction system to 0 ℃, adding a mixture of sodium bromide aqueous solution and acetone, and extracting by using dichloromethane; the volume ratio of the mixture of the sodium bromide aqueous solution and the acetone is 1.0-3.0;
4) concentrating to obtain the final product.
The preparation method of the phenyl trifluoromethyl trifluoroacetic acid iodine comprises the following steps:
1) under the nitrogen atmosphere, adding starting raw materials of bis (trifluoroacetic acid) iodobenzene and potassium fluoride into a nitrile organic solvent; the molar ratio of the potassium fluoride to the di (trifluoroacetic acid) iodobenzene is 1.0-2.0, and the concentration of a reaction system is as follows: molar number of iodobenzene bis (trifluoroacetic acid): the volume of the nitrile organic solvent is equal to 0.25-1.0 mmol/mL);
2) adding TMSCF under the stirring condition of minus 20 ℃ to minus 45 DEG C3Carrying out reaction for 8-24 hours to obtain the product; TMSCF3The molar ratio of the compound to bis (trifluoroacetic acid) iodobenzene is 1.0-2.0.
The aryl trifluoromethyl high-iodine compound synthesized by the invention can be used as an electrophilic trifluoromethylating reagent to carry out trifluoromethylation reaction on various organic matters.
The invention has the advantages that: with aryl-periodicides ArIY2With TMSCF3The aryl trifluoromethyl high-iodine substance is prepared by direct anion ligand exchange reaction and developed into a high-efficiency trifluoromethylation reagent. The trifluoromethylation reagent, the preparation method and the application are provided, and the high-iodine trifluoromethylation reagent can be directly, simply and efficiently prepared. The reagent is stable and high in reaction activity, can be used for various trifluoromethylation reactions, and does not need a catalyst (the Togni trifluoromethyl reagent needs to be activated when in use). The defects that the high-iodine trifluoromethyl reagent in the prior art is few in types, single in structure, complicated in synthesis steps and the like are overcome, and the acyclic aryl high-iodine trifluoromethyl reagent which is diverse in structure and direct and simple in preparation method is provided.
Detailed Description
Example 1
Preparation of phenyltrifluoromethyl iodide chloride:
in a 15 mL round bottom flask, 0.5 mmol of bis (trifluoroacetic acid) iodobenzene was added, and under anhydrous nitrogen atmosphere, 0.75 mmol of potassium fluoride and 1.0 mL of MeCN were added, and at-45 ℃ 0.75 mmol of trifluoromethyltrimethylsilane was added. After stirring for 21 hours, the reaction mixture was poured into a mixed solution of 20 mL of a 15% aqueous sodium chloride solution and 10 mL of acetone at 0 ℃. The mixed solution was extracted with methylene chloride (20 mL, 3 times), and the organic phases of the extracted mixed solution were combined and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the crude product was washed with petroleum ether to give a white solid, phenyltrifluoromethyl iodochloride, in 86% yield.
Nuclear magnetic and mass spectral characterization of phenyltrifluoromethyl iodide chloride:1H NMR (600 MHz, DMSO-d6) δ 8.31 (d, J = 8.4 Hz, 2H), 7.72 (t, J = 7.5 Hz, 1H), 7.57 (t, J = 7.8 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 136.4 (2C), 132.7 (1C), 132.1 (2C), 120.2 (1C), 109.6 (q, J = 393 Hz, 1C). 19F NMR (565 MHz, DMSO-d6) δ -35.7 (s). HRMS (ESI) Calc¢d for C7H5F3I [M-Cl]+: 272.9383; found 272.9382。
example 2
Preparation of 4-fluorophenyl trifluoromethyl iodine chloride
In a 15 mL round bottom flask, 0.5 mmol of 4-fluoro-di (trifluoroacetic acid) iodobenzene was added, and under anhydrous nitrogen atmosphere, 0.75 mmol of potassium fluoride and 1.0 mL of acetonitrile were added, and at-20 ℃ 0.75 mmol of trifluoromethyltrimethylsilane was added. After stirring for 21 hours, the reaction mixture was poured into a mixed solution of 20 mL of a 15% aqueous sodium chloride solution and 10 mL of acetone at 0 ℃. Extracted with dichloromethane (20 mL, 3 times). The organic phases of the extracted mixed solution were combined and dried over anhydrous magnesium sulfate. Dried over anhydrous magnesium sulfate. After evaporation of the solvent, the crude product was washed with petroleum ether to give a white solid as 4-fluorophenyl trifluoromethyl iodochloride in 65% yield.
Nuclear magnetic resonance of fluorophenyl trifluoromethyl iodide chlorideAnd (3) mass spectrum characterization:1H NMR (600 MHz, CDCl3, δ): 8.14~8.11 (m, 2H), 7.72 (t, J = 8.4 Hz, 2H). 13C NMR (151 MHz, DMSO-d6, δ): 164.4 (d, J = 251.7 Hz, 1C), 139.5 (d, J = 7.9 Hz, 2C), 119.5 (d, J = 22.8 Hz, 2C), 114.9 (d, J = 3.2 Hz, 1C), 109.7 (q, J = 392.8 Hz, 1C). 19F NMR (565 MHz, CDCl3, δ): -34.9 (s, 3F),-103.2 (s, 1F). HRMS (ESI) Calc¢d for C7H4F4I [M-Cl]+: 290.9374; found 290.9378。
example 3
Preparation of phenyl trifluoromethyl iodine fluoride
In a 15 mL round bottom flask, 0.5 mmol of bis (trifluoroacetic acid) iodobenzene was added, and under anhydrous nitrogen atmosphere, 0.75 mmol of potassium fluoride and 1.0 mL of MeCN were added, and at-45 ℃ 0.75 mmol of trifluoromethyltrimethylsilane was added. After stirring for 24 hours, the reaction mixture was poured into a mixed solution of 20 mL of a 15% aqueous potassium fluoride solution and 10 mL of acetone at 0 ℃. Extracted with dichloromethane (20 mL, 3 times). The organic phases of the extracted mixed solution were combined and dried over anhydrous magnesium sulfate. Dried over anhydrous magnesium sulfate. After the solvent was distilled off, the crude product was washed with petroleum ether to give a white solid which was phenyltrifluoromethyl iodofluoride in 56% yield.
Example 4
Preparation of phenyltrifluoromethyl iodine bromide
In a 15 mL round bottom flask, 0.5 mmol of bis (trifluoroacetic acid) iodobenzene was added, and under anhydrous nitrogen atmosphere, 0.75 mmol of potassium fluoride and 1.0 mL of acetonitrile were added, and 0.75 mL of trifluoromethyltrimethylsilane was added at-45 ℃. After stirring for 24 hours, the reaction mixture was poured into a mixed solution of 20 mL of a 15% aqueous sodium bromide solution and 10 mL of acetone at 0 ℃. Extracted with dichloromethane (20 mL, 3 times). The organic phases of the extracted mixed solution were combined and dried over anhydrous magnesium sulfate. Dried over anhydrous magnesium sulfate. After the solvent was distilled off, the crude product was washed with petroleum ether to give a white solid, phenyltrifluoromethyl iodobromide, in 70% yield.
Process for preparing phenyl trifluoromethyl iodine bromideNuclear magnetic and mass spectral characterization:1H NMR (600 MHz, CDCl3, δ): 8.12 (d, J = 7.8 Hz, 2H), 7.71 (t, J = 7.5 Hz, 1H), 7.53 (t, J = 7.8 Hz, 2H). 13C NMR (151 MHz, DMSO-d6, δ): 136.6 (2C), 132.7 (1C), 132.1 (2C), 119.2 (1C), 105.6 (q, J = 400.6 Hz, 1C). 19F NMR (565 MHz, CDCl3, δ): -35.5 (s). HRMS (ESI-TOF) Calc’d for C7H5F3I [M-Br]+: 272.9383; found 272.9462。
example 5
Preparation of phenyl trifluoromethyl trifluoroacetic acid iodine
In a 15 ml round bottom flask, 215 mg (0.5 mmol) of iodobenzene bis (trifluoroacetic acid) was added, 43.5 mg (0.75 mmol) of potassium fluoride and 1.0 ml of acetonitrile (ultra-dry) were added under anhydrous nitrogen atmosphere, and 111. mu.l (0.75 mmol) of trifluoromethyltrimethylsilane was added at-45 ℃. After stirring for 24 hours, the reaction mixture was stored at-45 ℃ with a yield of > 99%.
Test example 1
Preparation of compound alpha-trifluoromethyl-alpha-acetyl dithioketene dimer
Adding 0.11 mmol of phenyltrifluoromethyl iodochloride, 0.1mmol of alpha-acetyl dithioketene chloride and a magnetic stirrer into a 10 mg Schlenk sealed tube, adding 1 mL of dry dichloromethane under the nitrogen protection environment, stirring for 8 hours at 30 ℃, and adding 10 mu L of benzotrifluoride as an internal standard19F NMR spectrum, calculating fluorine spectrum integral to obtain nuclear magnetic yield of alpha-trifluoromethyl-alpha-acetyl ketene disulfide>99 percent. The reaction mixture was isolated and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 15/1) to give 21 mg of a pale yellow solid, isolated in 92% yield. Characterization of the compound α -trifluoromethyl- α -acetyldithioketene:1H NMR (500 MHz, CDCl3) δ 3.41 (t, J = 7.5 Hz, 2H), 3.33 (t, J = 7.5 Hz, 2H), 2.38 (q, J = 2.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 190.9, 174.9, 124.7 (q, J = 272.0 Hz), 115.5 (q, J = 31.0 Hz), 37.6, 36.7 (q, J = 3.4 Hz), 28.5 (q, J = 4.4 Hz); 19F NMR (470 MHz, CDCl3) δ -55.7 (s, 3F)。
if the phenyltrifluoromethyl iodide chloride in the above experimental procedure was replaced with the Togni reagent as the trifluoromethylating reagent, no reaction occurred, and it was thus found that phenyltrifluoromethyl iodide chloride had higher reactivity than the Togni reagent.
Test example 2
Preparation of compound alpha-trifluoromethyl-acetophenone
Adding 0.15 mmol of phenyltrifluoromethyl iodine chloride and a magnetic stirring bar into a 10 mL Schlenk sealed tube, adding a mixed solution of 0.2 mmol of 1-phenyl-1-trimethylsiloxy-ethylene and 1 mL of dried DMF under the nitrogen protection environment, stirring for 15 hours at 50 ℃, and adding 10 mu L of benzotrifluoride as an internal standard19F NMR spectrum, calculating fluorine spectrum integral to obtain nuclear magnetic yield of alpha-trifluoromethyl-acetophenone>99 percent. The reaction mixture was isolated and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 50/1) to give 26 mg of a white solid in an isolated yield of 92%. Characterization of the compound α -trifluoromethyl-acetophenone:1H NMR (CDCl3, 400 MHz): δ = 3.78 (q, J = 10.2 Hz, 2H), 7.48−7.51 (m, 2H), 7.60−7.64 (m, 1H), 7.91−7.93 (m, 2H); 13C NMR (CDCl3, 100 MHz): δ 189.7 (q, J= 2.8 Hz), 135.7, 134.1, 128.9, 128.3, 124.0 (q, J = 276.7 Hz), 41.9 (q, J = 28.3 Hz). 19F NMR (CDCl3, 376 MHz): δ = −62.1 (t, J = 10.2 Hz)。
if Togni's reagent is used as trifluoromethylating agent instead of phenyltrifluoromethyliodonium chloride in the above experimental procedure, CuSCN is used as catalyst.
Claims (2)
1. A preparation method of 4-fluorophenyl trifluoromethyl iodine chloride comprises the following steps:
1) under the nitrogen atmosphere, adding bis (trifluoroacetic acid) 4-fluoroiodobenzene and potassium fluoride into a nitrile organic solvent; the molar ratio of the potassium fluoride to the bis (trifluoroacetic acid) 4-fluoroiodobenzene is 1.0-2.0, and the volume ratio of the mole number of the bis (trifluoroacetic acid) 4-fluoroiodobenzene to the nitrile organic solvent is 0.25-1.0 mmol/mL;
2) adding TMSCF under the stirring condition of-20 to-45 DEG C3Carrying out the reaction for 8-24 hours; TMSCF3The molar ratio of the compound to bis (trifluoroacetic acid) 4-fluoroiodobenzene is 1.0-2.0;
3) after the reaction is finished, moving the reaction system to 0 ℃, adding a mixture of sodium chloride aqueous solution and acetone, and extracting by dichloromethane; the volume ratio of the mixture of the sodium chloride aqueous solution and the acetone is 1.0-3.0;
4) concentrating to obtain the final product;
the structural formula of the 4-fluorophenyl trifluoromethyl iodine chloride is as follows:
2. a preparation method of phenyl trifluoromethyl trifluoroacetic acid iodine comprises the following steps:
1) under the nitrogen atmosphere, adding starting raw materials of bis (trifluoroacetic acid) iodobenzene and potassium fluoride into a nitrile organic solvent; the molar ratio of the potassium fluoride to the di (trifluoroacetic acid) iodobenzene is 1.0-2.0, and the molar number of the di (trifluoroacetic acid) iodobenzene is as follows: the volume of the nitrile organic solvent is equal to 0.25-1.0 mmol/mL;
2) adding TMSCF under the stirring condition of-20 to-45 DEG C3Carrying out reaction for 8-24 hours to obtain the product; TMSCF3The molar ratio of the compound to bis (trifluoroacetic acid) iodobenzene is 1.0-2.0;
the structural formula of the phenyl trifluoromethyl trifluoroacetic acid iodine is as follows:
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| A new method of perfluoroalkylation;L.M.Yagupol.skii et al.;《Communications》;19781130;第837页左栏第7段,右栏第一段 * |
| In site generation of PhI+CF3 and transition-metal-free oxidative sp2 C-H trifluoromethylation;Cong Xu et al.;《Chemistry A European journal》;20130618;第19卷;文献support information第5页第2段 * |
| P. K. Sajith et al..Quantification of the trans influence in hypervalent lodine complexes.《Inorganic Chemistry》.第967-977页,2011,第51卷 * |
| Quantification of the trans influence in hypervalent lodine complexes;P. K. Sajith et al.;《Inorganic Chemistry》;第967-977页;20111228;第51卷;第969页表1序号4，第972页表5序号38，第973页表6序号14 * |
| Synyhesis of chloro（phenyl）trifluoromethyliodane and catalyst-free electrophilic trifluoromethylstions;Cong Xu et al.;《Organic Letters》;20180620;第20卷;第3933-3937页 * |
| 苯基三氟甲基-λ3-碘烷的合成及烯的三氟甲基化碳环化反应研究;郭佳;《中国博士学位论文全文数据库 工程科技I辑》;20190915;全文 * |
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