CN111269074A - Preparation method of α -halogenated trifluoromethyl substituted alkane - Google Patents

Abstract

The invention relates to a preparation method of α -halogenated trifluoromethyl substituted alkane, which aims to achieve the purpose of efficiently constructing α -halogenated trifluoromethyl substituted alkane and adopts the technical scheme that an olefin compound, an oxidant, sodium trifluoromethyl sulfinate and trihaloacetic acid are added into an organic solvent and react for 24 hours at room temperature to obtain α -halogenated trifluoromethyl substituted alkane.

Description

Preparation method of α -halogenated trifluoromethyl substituted alkane

Technical Field

The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of α -halogenated trifluoromethyl substituted alkane.

Background

The trifluoromethyl group is a very important group in the fields of medicinal chemistry and material chemistry because of its chemical stability, strong electrophilicity, metabolic stability and unique hydrophobicity. Therefore, the introduction of trifluoromethyl groups into organic compounds is of great research value. The trifluoromethyl compound has wider application in the fields of medicine, pesticide and novel polymer. According to the literature, about 15% to 20% of new drugs contain fluorine atoms, which can significantly change the physicochemical properties and biological activity of the compounds.

In 2015, Jung and Han subjects published halotrifluoromethylation of non-activated olefins promoted by halosulfino (CuX). The optimum reaction conditions determined by the authors were: 1.5 equivalents of haloidenone (CuX) as promoter and halogen source, non-activated olefin as substrate, S- (trifluoromethyl) dibenzothiophene tetrafluoroborate reagent (Umemoto reagent) as trifluoromethyl source, pinacol ester diborate (B)₂pin₂) And potassium monohydrogen phosphate (K)₂HPO₄) As an additive, under the protection of argon (Ar), acetonitrile (MeCN) is used as a solvent, and the reaction is carried out for 22 hours at 65 ℃, and the reaction formula is as follows:

in 2015, Jr topic group proposed Cu (dap)₂Cl photosensitive compounds catalyze the chlorotrifluoromethylation of olefinic substrates. Authors expressed in Cu (dap)₂Cl as catalyst, trifluoromethanesulfonyl Chloride (CF)₃SO₂Cl) as a trifluoromethyl source and a chlorine source, potassium monohydrogen phosphate (K)₂HPO₄) 1, 2-Dichloroethane (DCE) as an additive is used as a solvent and is reacted for 24 hours at normal temperature under the irradiation of visible lightObtaining chloro trifluoromethyl product with the following reaction formula:

trifluoromethyl is an important structural unit of a plurality of natural products and compounds with biological activity, and the synthesis of trifluoromethyl compounds has important research significance for expanding molecules with special chemical functions (including medicines, pesticides, fine chemicals and intermediates thereof and the like). Development of a research work for initiating the double functionalization of inactive olefins and activated olefins by trifluoromethyl radicals can efficiently synthesize halogenated trifluoromethylated products.

Disclosure of Invention

The invention aims to provide a preparation method for constructing α -halogenated trifluoromethyl substituted alkane efficiently, which is realized by the following technical scheme that an olefin compound with a structural formula shown in (I), an oxidant, sodium trifluoromethyl sulfinate and trihaloacetic acid are added into an organic solvent to react for 24 hours at room temperature to obtain α -halogenated trifluoromethyl substituted alkane shown in (II), wherein the reaction formula is as follows:

wherein R is¹、R²、R³、R⁴Is alkyl or hydrogen atom, and X is bromine atom or chlorine atom;

wherein the molar ratio of the olefin compound to the oxidant to the sodium trifluoromethanesulfonate to the trihaloacetic acid is 1:3:1.5: 2;

wherein the organic solvent is 1, 2-Dichloroethane (DCE), and the oxidant is manganese triacetate dihydrate.

The reaction firstly comprises oxidizing sodium trifluoromethyl sulfonate and trihaloacetic acid by manganese triacetate dihydrate, respectively obtaining trifluoromethyl free radicals and halogen free radicals, carrying out free radical addition reaction on the trifluoromethyl free radicals and double bonds of olefin compounds to obtain carbon free radicals, and finally capturing by the halogen free radicals to obtain α -halogenated trifluoromethylated products.

Wherein, the product obtained by the reaction is processed, and then quenching, extraction, organic phase washing, drying and column chromatography separation are carried out in sequence.

Quenching: quenching with an aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium carbonate;

and (3) extraction: ethyl acetate was used as extractant.

Washing: the mixture was washed with saturated brine.

And (3) drying: dried over anhydrous magnesium sulfate.

And (3) column chromatography separation: 300-400 mesh silica gel chromatographic column, wherein the eluent is a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 10: 1.

The invention has the beneficial effects that:

1. manganese triacetate dihydrate, sodium trifluoromethanesulfonate and trihaloacetic acid used in the preparation method of the trifluoromethylated product are all easily available products and are easy to store.

2. The α position of the trifluoromethylated product obtained by the reaction has halide which is easy to be substituted by other functional groups, thus providing a new method for synthesizing various active natural products and medicaments.

3. The reaction is carried out at normal temperature and normal pressure, the required conditions are simple, the reaction is stable, the yield is good, the application range is wide, and the method has good application prospect for synthesizing natural products or medicines containing trifluoromethyl groups.

Detailed Description

The technical solutions in the embodiments of the present invention are clearly and completely described below. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those specifically described and will be readily apparent to those of ordinary skill in the art without departing from the spirit of the present invention, and therefore the present invention is not limited to the specific embodiments disclosed below.

Example one

A dry reaction tube was taken and weighed into the olefin shown in the reaction scheme (95.1mg,0.5mmol), manganese acetate dihydrate (402.2mg,1.5mmol), sodium trifluoromethylsulfinate (117.0mg,0.75mmol), tribromoacetic acid (296.7mg,1mmol), and then 6mL1, 2-Dichloroethane (DCE) was added. After the reaction was stirred at room temperature for 24 hours, 10mL of an aqueous sodium thiosulfate solution and a saturated aqueous sodium carbonate solution were added, respectively, and the mixture was quenched, extracted three times with ethyl acetate (10mL), combined, and the organic phases were washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The organic solvent was removed using a rotary evaporator until no solvent was distilled off, and finally separated by column chromatography on silica gel (300-400 mesh) (eluent: petroleum ether/ethyl acetate in a volume ratio of 100/1) to give 139.1mg of a colorless liquid in a yield of 82%.

Characterization data-nuclear magnetic product analysis:

¹HNMR(500MHz,Chloroform-d)δ7.34(d,J＝5.7Hz,4H),7.31–7.25(m,1H),4.50(s,2H),4.17–4.10(m,1H),3.48(t,J＝5.8Hz,2H),2.82–2.72(m,1H),2.71–2.61(m,1H),1.94–1.81(m,2H),1.72–1.52(m,4H).13CNMR(126MHz,Chloroform-d)δ138.5,128.4,127.7,127.6,125.4(q,1J(C,F)＝278.0Hz),73.0,69.9,44.9(q,2J(C,F)＝2.9Hz),43.1(q,3J(C,F)＝28.4Hz),38.3,28.9,24.1.

example two

A dry reaction tube was taken and weighed into the olefin shown in the reaction scheme (126.7mg,0.5mmol), manganese acetate dihydrate (402.2mg,1.5mmol), sodium trifluoromethylsulfinate (117.0mg,0.75mmol), tribromoacetic acid (296.7mg,1mmol), and then 6mL1, 2-Dichloroethane (DCE) was added. After the reaction was stirred at room temperature for 24 hours, 10mL of an aqueous sodium thiosulfate solution and a saturated aqueous sodium carbonate solution were added, respectively, and the mixture was quenched, extracted three times with ethyl acetate (10mL), combined, and the organic phases were washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The organic solvent was removed using a rotary evaporator until no solvent was evaporated, and finally column chromatography on silica gel (300-400 mesh) was carried out (eluent: petroleum ether/ethyl acetate in a volume ratio of 10/1) to give 191.1mg of a colorless liquid in a yield of 95%.

Characterization data-nuclear magnetic product analysis:

¹HNMR(500MHz,Chloroform-d)δ7.77(d,J＝8.1Hz,2H),7.31(d,J＝8.0Hz,2H),5.15(t,J＝6.2Hz,1H),4.08–4.01(m,1H),2.94(q,J＝6.3Hz,2H),2.78–2.68(m,1H),2.67–2.56(m,1H),2.43(s,3H),1.86–1.70(m,2H),1.58–1.36(m,4H).13CNMR(126MHz,Chloroform-d)δ143.5,136.9,129.8,127.1,125.3(q,1J(C,F)＝278.0Hz),44.6(q,2J(C,F)＝2.9Hz),42.9(q,3J(C,F)＝28.5Hz),42.8,37.9,28.7,24.1,21.5.IR(KBr):3273,2946,2866,2360,2342,1600,1434,1321,1268,1159,1086,812,687,550cm-1.

EXAMPLE III

A dry reaction tube was taken, and the olefin shown in the reaction formula (107.6mg,0.5mmol), manganese acetate dihydrate (402.2mg,1.5mmol), sodium trifluoromethanesulfonate (117.0mg,0.75mmol), trichloroacetic acid (163.4mg,1mmol) and 6mL1, 2-Dichloroethane (DCE) were weighed in. After the reaction was stirred at room temperature for 24 hours, 10mL of an aqueous sodium thiosulfate solution and a saturated aqueous sodium carbonate solution were added, respectively, and the mixture was quenched, extracted three times with ethyl acetate (10mL), combined, and the organic phases were washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The organic solvent was removed using a rotary evaporator until no solvent was distilled off, and finally column chromatography on silica gel (300-400 mesh) was carried out (eluent: petroleum ether/ethyl acetate in a volume ratio of 10/1) to give 79.9mg of a colorless liquid in a yield of 50%.

Characterization data-nuclear magnetic product analysis:

¹HNMR(500MHz,Chloroform-d)δ7.86(dd,J＝5.5,3.1Hz,2H),7.74(dd,J＝5.5,3.1Hz,2H),4.32(dd,J＝14.8,9.3Hz,1H),4.08–4.02(m,1H),3.25–3.15(m,1H),1.90(s,3H),1.78(s,3H).13CNMR(126MHz,Chloroform-d)δ167.7,134.2,131.8,126.1(q,1J(C,F)＝283.4Hz),123.4,66.9,50.9(q,2J(C,F)＝23.8Hz),35.8,33.5,30.3(q,3J(C,F)＝2.6Hz).IR(KBr):2978,2360,2342,1773,1717,1402,1368,1255,1139,725,610cm--1.

it is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Claims (3)

1. A preparation method of α -halogenated trifluoromethyl substituted alkane is characterized in that an olefin compound with a structural formula shown in (I), an oxidant, sodium trifluoromethyl sulfinate and trihaloacetic acid are added into an organic solvent, a final product mixture is obtained after reaction for 24 hours at room temperature, and then α -halogenated trifluoromethyl substituted alkane shown in a formula (II) is obtained after purification treatment, wherein the reaction formula is as follows:

the structural formula of the trihaloacetic acid is as follows:

wherein R is¹、R²、R³、R⁴Is alkyl or hydrogen atom, and X is bromine atom or chlorine atom;

wherein the molar ratio of the olefin compound to the oxidant to the sodium trifluoromethanesulfonate to the trihaloacetic acid is 1:3:1.5: 2;

wherein the organic solvent is 1, 2-Dichloroethane (DCE), and the oxidant is manganese triacetate dihydrate.

2. The method of claim 1, wherein the purification comprises quenching, extracting, washing the organic phase, drying, and separating by column chromatography.

3. The method according to claim 2, wherein the at least one α -halogeno-trifluoromethyl-substituted alkane is a halogenated compound,

quenching: quenching with an aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium carbonate;

and (3) extraction: ethyl acetate was used as extractant;

washing: washing with saturated saline water;

and (3) drying: drying with anhydrous magnesium sulfate;

and (3) column chromatography separation: 300-400 mesh silica gel chromatographic column, wherein the eluent is a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 10: 1.