CN110872206A - Reduction coupling method for synthesizing 1, 1-difluoroethyl aromatic compound - Google Patents

Reduction coupling method for synthesizing 1, 1-difluoroethyl aromatic compound Download PDF

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CN110872206A
CN110872206A CN201911209464.2A CN201911209464A CN110872206A CN 110872206 A CN110872206 A CN 110872206A CN 201911209464 A CN201911209464 A CN 201911209464A CN 110872206 A CN110872206 A CN 110872206A
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difluoroethyl
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aromatic compound
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李新进
刘健昌
张继达
李相晔
刘河甫
刘会
李月云
董云会
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Shandong University of Technology
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Abstract

The invention particularly relates to a synthetic method for synthesizing a 1, 1-difluoroethyl aromatic compound by a reduction coupling strategy, belonging to the technical field of organic compound process application. The introduction of 1, 1-difluoroethyl can improve the metabolic stability of biomolecules, so that the development of a new 1, 1-difluoroethylation method is of great significance. The present invention utilizes 1, 1-difluoromonochloroethane (CH) which is an inexpensive industrial raw material3CF2Cl, commonly called freon R142b, 1kg/50 yuan) is a difluoroethylation reagent, realizes the 1, 1-difluoroethylation reaction of halogenated aromatic hydrocarbon under the catalytic action of transition metal nickel, and has higher yield. Provides a new method for simply and efficiently realizing the synthesis of the 1, 1-difluoroethyl aromatic compound.

Description

Reduction coupling method for synthesizing 1, 1-difluoroethyl aromatic compound
Technical Field
The invention particularly relates to a synthetic method for synthesizing a 1, 1-difluoroethyl aromatic compound by a reduction coupling strategy, which realizes 1, 1-difluoroethylation by utilizing 1, 1-difluoromonochloroethane and halogenated aromatic hydrocarbons (chlorine, bromine and iodo aromatic hydrocarbons), and belongs to the technical field of organic compound process application.
Background
Aryl ethers have an important role in modulating the properties of bioactive scaffold molecules. The biological metabolic stability of aryl ether has limitation, so that the aryl ether has higher metabolic stability and has biological electron equivalenceAnalogs of lipids have important research significance. Difluoromethyl blocks (-CF) are known2-) is an electron equivalent of an oxygen atom, and the introduction of a fluorine atom increases the metabolic stability of the biomolecule. Thus, 1, 1-difluoroethyl (CF)2CH3) Is an ideal substitute of methoxy (OMe), and has important significance for developing efficient 1, 1-difluoroethylation reaction.
Currently, there are several methods for achieving 1, 1-difluoroethylation.
(1) The synthesis of 1, 1-difluoroethyl compounds was achieved by activating the benzyl C-H bond under the action of electrophilic fluorinating reagents (j.b. Xia, c. Zhu and c. Chen,J Am Chem Soc, 2013, 135, 17494；P. Xu, S.Guo, L. Wang and P. Tang,Angew Chem Int Ed, 2014, 53, 5955.）。
(2) 1, 1-difluoroethylation was achieved by reacting CH3CF2Br with a grignard reagent (y. Ohtsuka and t. yamakawa,J. Fluorine Chem,2016, 185, 96.）。
(3) fluorinating a terminal aryne compound under the catalytic action of a gold complex to obtain a 1, 1-difluoroethylated aromatic compound (O.E. Okoromoba, J. Han, G.B. Hammond and B.xu,J Am Chem Soc, 2014,136, 14381.）。
(4) 1, 1-difluoromonochloroethane and arylboronic acid under nickel catalysis to give 1, 1-difluoroethylaromatic compounds (J.Liu, J.Zhang, C.Wu, H.Liu, F.Sun, Y.Li, Y.Liu, Y.Dong and X.Li,RSC Adv, 2019, 9, 28409.）
these methods have certain limitations, or require the participation of noble metals, or expensive reactants, or poor substrate universality.
Disclosure of Invention
The invention relates to a method for preparing 1, 1-difluoroethyl aromatic compound, which comprises the steps of utilizing 1, 1-difluoromonochloroethane and halogenated aromatic hydrocarbon (chlorine, bromine and iodoaromatic hydrocarbon) to react for 10 hours at 110 ℃ by adding a transition metal nickel catalyst, a ligand, an additive, a reducing agent and a solvent to obtain the 1, 1-difluoroethyl aromatic compound, wherein the reaction equation is shown in figure 1.
In the invention, the catalyst is bis (tricyclohexylphosphine) nickel dichloride.
In the invention, the ligand is 4,4 '-diamino-2, 2' -bipyridine.
In the invention, the additive is 4-dimethylamino pyridine and magnesium chloride.
In the invention, the reducing agent is zinc powder.
In the present invention, the solvent is dimethyl sulfoxide (DMSO).
In the invention, the concentrations of the 1, 1-difluoro monochloroethane, the halogenated aromatic hydrocarbon, the bis (tricyclohexylphosphine) nickel dichloride, the 4,4 '-diamino-2, 2' -bipyridine, the 4-dimethylaminopyridine, the magnesium chloride and the zinc powder in the dimethyl sulfoxide are as follows in sequence: 0.7M, 0.2M, 0.02M, 0.04M, 0.6M, 0.4M.
Specifically, the synthesis method comprises the steps of adding reactants 2 halogenated aromatic hydrocarbon (0.2 mmol), bis (tricyclohexylphosphine) nickel dichloride (10 mol%), 4,4 '-diamino-2, 2' -bipyridine (10 mol%), 4-dimethylaminopyridine (20 mol%), magnesium chloride (3 equivalent) and zinc powder (2 equivalent) into a 10ml Schlenk reaction tube, vacuumizing and changing nitrogen, dissolving reactant 1 in DMSO solution (prepared before the reaction starts, slowly introducing reactant 1 into DMSO until the total volume is not increased, and performing the steps of19F NMR 0.7 mol/L) was added to the solution, and the reaction was carried out at 110 ℃ for 10 hours. After the reaction is finished, detecting the reaction by TLC, and carrying out column chromatography separation to obtain a target product 3.
In the invention, the synthetic method of the synthesized 1, 1-difluoroethyl aromatic compound provides a widely applicable synthetic method for 1, 1-difluoroethylation modification of bioactive molecules.
The invention discloses a method for preparing 1, 1-difluoroethyl aromatic compound by using commercial 1, 1-difluoromonochloroethane and halogenated aromatic hydrocarbon as reactants. The reaction operation is simple, the reactants are cheap and easy to obtain, the yield is high, and the method is suitable for large-scale production.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples, but the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive conceptVariations and advantages that may occur to those skilled in the art are intended to be included within the invention and the scope of the appended claims. The procedures, conditions, reagents, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited. The data given in the examples below include specific operating and reaction conditions and products. The product structure is determined by nuclear magnetic resonance (1H NMR，19F NMR，13C NMR) and low resolution (GC-MS) identification.
Example 1, 4- (1, 1-difluoroethyl) -1,1' -biphenyl (FIG. 2).
To a 10ml Schlenk reaction tube, 4-bromobiphenyl (4-chlorobiphenyl or 4-iodobiphenyl) (0.2 mmol), bis (tricyclohexylphosphine) nickel dichloride (10 mol%), 4,4 '-diamino-2, 2' -bipyridine (10 mol%), 4-dimethylaminopyridine (20 mol%), magnesium chloride (3 eq), and zinc powder (2 eq) were added, vacuum was applied to exchange nitrogen gas, a DMSO solution in which reactant 1 was dissolved was added (prepared before the reaction started, reactant 1 was slowly passed through DMSO until the total volume did not increase, and the reaction was passed through19F NMR 0.7 mol/L) was added to the solution, and the reaction was carried out at 110 ℃ for 10 hours. After the reaction is finished, detecting the reaction by TLC, and separating by column chromatography to obtain the target product (4-bromobiphenyl 72%, 4-chlorobiphenyl 49%, 4-iodobiphenyl 74%).1H NMR (400 MHz, CDCl3): δ 7.65(d,J= 8.3 Hz, 2H), 7.60 (t,J= 6.8 Hz, 4H), 7.47 (t,J= 7.5 Hz, 2H), 7.40(t,J= 7.4 Hz, 1H), 1.97 (t,J= 18.2 Hz, 3H).19F NMR(376MHz, CDCl3): δ -87.30 (q,J= 18.0 Hz, 2F).GC-MS (m/z): 218 (M+), 203 (M+-CH3), 153 (M+-CF2-CH3)。
Example 2,3- (1, 1-difluoroethyl) -1,1' -biphenyl (FIG. 3).
To a 10ml Schlenk reaction tube were added 3-bromobiphenyl (0.2 mmol), bis (tricyclohexylphosphine) nickel dichloride (10 mol%), 4,4 '-diamino-2, 2' -bipyridine (10 mol%), 4-dimethylaminopyridine (20 mol%), magnesium chloride(3 equiv.) and Zinc powder (2 equiv.), vacuumizing and changing nitrogen, then adding DMSO solution (prepared before reaction, slowly introducing reactant 1 into DMSO until total volume is not increased, passing through19F NMR 0.7 mol/L) was added to the solution, and the reaction was carried out at 110 ℃ for 10 hours. After the reaction is finished, detecting the reaction by TLC, and separating by column chromatography to obtain the target product (40%).1H NMR(400 MHz, CDCl3): δ 7.73 (s, 1H), 7.67-7.64 (m, 1H), 7.60 (d,J= 7.6 Hz,2H), 7.50-7.45 (m, 4H), 7.38 (t,J= 7.4 Hz, 1H), 1.97 (t,J= 18.2Hz, 3H).19F NMR(376MHz, CDCl3): δ -87.6 (q,J= 18.2 Hz, 2F).GC-MS (m/z): 218 (M+),203 (M+-CH3), 153 (M+-CF2-CH3)。
Example 3, 5'- (1, 1-difluoroethyl) -1, 1': 3', 1' ' -terphenyl (FIG. 4).
To a 10ml Schlenk reaction tube, 3, 5-diphenylbromobenzene (0.2 mmol), bis (tricyclohexylphosphine) nickel dichloride (10 mol%), 4,4 '-diamino-2, 2' -bipyridine (10 mol%), 4-dimethylaminopyridine (20 mol%), magnesium chloride (3 eq), and zinc powder (2 eq) were added, vacuum was applied to exchange nitrogen, and a DMSO solution in which reactant 1 was dissolved was added (prepared before the reaction started, reactant 1 was slowly introduced into DMSO until the total volume was not increased, after that19F NMR 0.7 mol/L) was added to the solution, and the reaction was carried out at 110 ℃ for 10 hours. After the reaction is finished, the TLC detection reaction is carried out, and the column chromatography separation is carried out to obtain the target product (39%).1H NMR (400 MHz, CDCl3): 7.86 (s, 1H), 7.71 (s, 2H), 7.66 (d,J= 7.8Hz, 4H), 7.49 (t,J= 7.5 Hz, 4H), 7.40 (t,J= 7.3 Hz, 2H), 2.02 (t,J=18.2 Hz, 3H).19F NMR(376MHz, CDCl3): δ -87.6 (q,J= 18.2 Hz, 2F).GC-MS (m/z): 294(M+), 279 (M+-CH3)。
Example 4, (1, 1-difluoroethyl) benzene (FIG. 5).
To a 10ml Schlenk reaction tube, 3, 5-diphenylbromobenzene (0.2)mmol), bis (tricyclohexylphosphine) nickel dichloride (10 mol%), 4,4 '-diamino-2, 2' -bipyridine (10 mol%), 4-dimethylaminopyridine (20 mol%), magnesium chloride (3 eq), zinc powder (2 eq), evacuating and changing nitrogen, then dissolving reactant 1 in DMSO solution (prepared before reaction starts, slowly introducing reactant 1 into DMSO until the total volume is not increased, passing through19F NMR 0.7 mol/L) was added to the solution, and the reaction was carried out at 110 ℃ for 10 hours. After the reaction is finished, the reaction kettle is used for reaction,19f NMR detection gave the desired product (42%).19F NMR(376MHz, CDCl3): δ -86.3 (q,J= 18.2 Hz, 2F).GC-MS (m/z): 142 (M+), 127 (M-CH3)+, 77 (M-CF2-CH3)+, 65 (CF2CH3)+。
Example 5, 4- (1, 1-difluoroethyl) -4 '-ethyl-1, 1' -biphenyl (FIG. 6).
To a 10ml Schlenk reaction tube, 4-bromo-4 ' -ethylbiphenyl (0.2 mmol), bis (tricyclohexylphosphine) nickel dichloride (10 mol%), 4,4' -diamino-2, 2' -bipyridine (10 mol%), 4-dimethylaminopyridine (20 mol%), magnesium chloride (3 eq), and zinc powder (2 eq) were added, vacuum was applied to exchange nitrogen, and a DMSO solution in which reactant 1 was dissolved (prepared before the reaction started, reactant 1 was slowly introduced into DMSO until the total volume did not increase, followed by19F NMR 0.7 mol/L) was added to the solution, and the reaction was carried out at 110 ℃ for 10 hours. After the reaction is finished, the TLC detection reaction is carried out, and the column chromatography separation is carried out to obtain the target product (58%).1H NMR (400 MHz, CDCl3): δ 7.63 (d,J= 8.2 Hz, 2H), 7.56 (d,J= 8.2Hz, 2H), 7.52 (d,J= 8.0 Hz, 2H), 7.30 (d,J= 7.9 Hz, 2H), 2.71 (q,J= 7.6Hz, 2H), 1.96 (t,J= 18.2 Hz, 3H), 1.29 (t,J= 7.6 Hz, 3H).19F NMR(376MHz,CDCl3): δ -87.2 (q,J= 18.0 Hz, 2F).GC-MS (m/z): 246 (M+), 231 (M+-CH3), 181(M+-CF2-CH3), 65 (CF2CH3 +)。
Example 6, 1- (4- (1, 1-difluoroethyl) phenyl) ethan-1-one (FIG. 7).
To a 10ml Schlenk reaction tube, 4-acetylbromobenzene (0.2 mmol), bis (tricyclohexylphosphine) nickel dichloride (10 mol%), 4,4 '-diamino-2, 2' -bipyridine (10 mol%), 4-dimethylaminopyridine (20 mol%), magnesium chloride (3 eq), zinc powder (2 eq) were added, vacuum was applied to exchange nitrogen gas, and a DMSO solution in which reactant 1 was dissolved (prepared before the reaction started, reactant 1 was slowly passed through DMSO until the total volume was not increased, followed by19F NMR 0.7 mol/L) was added to the solution, and the reaction was carried out at 110 ℃ for 10 hours. After the reaction is finished, the TLC detection reaction is carried out, and the column chromatography separation is carried out to obtain the target product (78%).1H NMR (400 MHz, CDCl3): δ 8.01 (d,J= 8.2 Hz, 2H), 7.60 (d,J= 8.2 Hz, 2H),2.63 (s, 3H), 1.93 (t,J= 18.2 Hz, 3H).19F NMR(376MHz, CDCl3): δ -88.8 (q,J= 18.2 Hz, 2F). GC-MS (m/z):: 184 (M+), 169 (M+-CH3), 141 (M+-COMe)。
Example 7, 1- (1, 1-difluoroethyl) -4- (methylsulfonyl) benzene (FIG. 8).
To a 10ml Schlenk reaction tube, 4-bromobenzenesulfone (0.2 mmol), bis (tricyclohexylphosphine) nickel dichloride (10 mol%), 4,4 '-diamino-2, 2' -bipyridine (10 mol%), 4-dimethylaminopyridine (20 mol%), magnesium chloride (3 equivalents), and zinc powder (2 equivalents) were added, vacuum was applied to exchange nitrogen, and a DMSO solution in which reactant 1 was dissolved was added (prepared before the reaction started, reactant 1 was slowly introduced into DMSO until the total volume was not increased, followed by19F NMR 0.7 mol/L) was added to the solution, and the reaction was carried out at 110 ℃ for 10 hours. After the reaction is finished, detecting the reaction by TLC, and separating by column chromatography to obtain the target product (80%).1HNMR (400 MHz, CDCl3):δ 7.95 (d,J= 8.2 Hz, 2H), 7.65 (d,J= 8.2 Hz, 2H),3.01 (s, 3H), 1.87 (t,J= 18.2 Hz, 3H).19F NMR(376MHz, CDCl3): δ -89.1 (q,J= 18.3 Hz, 2F).13C NMR (100 MHz, CDCl3):δ 143.5 (t,2 J C-F= 27.2 Hz), 141.9 (t,4 J C-F= 1.6 Hz), 127.8, 125.9 (t,3 J C-F= 6.0 Hz), 123.0 (t,1 J C-F= 240.4 Hz),44.4, 26 (t,2 J C-F= 29.2 Hz). GC-MS (m/z): 220 (M+), 205 (M+-CH3), 141 (M+-SO2CH3), 65 (CF2CH3 +)。
Example 8, 5- (1, 1-difluoroethyl) -2, 3-dihydro-1H-indan-1-one (FIG. 9).
To a 10ml Schlenk reaction tube, 5-bromoindanone (0.2 mmol), bis (tricyclohexylphosphine) nickel dichloride (10 mol%), 4,4 '-diamino-2, 2' -bipyridine (10 mol%), 4-dimethylaminopyridine (20 mol%), magnesium chloride (3 eq), zinc powder (2 eq) were added, vacuum was applied to exchange nitrogen gas, and a DMSO solution in which reactant 1 was dissolved (prepared before the reaction started, reactant 1 was slowly passed through DMSO until the total volume did not increase, after that19F NMR 0.7 mol/L) was added to the solution, and the reaction was carried out at 110 ℃ for 10 hours. After the reaction is finished, the TLC detection reaction is carried out, and the column chromatography separation is carried out to obtain the target product (83%).1H NMR(400 MHz, CDCl3): δ 7.73 (d,J= 8.0 Hz, 1H), 7.56 (s, 1H), 7.43 (d,J= 8.0Hz, 1H), 3.12 (t,J= 5.8 Hz, 2H), 2.67 (t,J= 5.8 Hz, 2H), 1.87 (t,J=18.2 Hz, 3H).19F NMR(376MHz, CDCl3): δ -88.5 (q,J= 18.2 Hz, 2F).13C NMR (100MHz, CDCl3): δ 206.2, 155.3, 144.2 (t,2 J C-F= 26.1 Hz), 138.1, 124.04 (t,3 J C-F= 5.6 Hz), 124.0, 123 (t,3 J C-F= 6.3 Hz), 121.4 (t,1 J C-F= 238.8 Hz), 36.4,26.1 (t,2 J C-F= 29.4 Hz), 25.9. GC-MS (m/z): 196 (M+), 153 (M+-COCH2), 65(CF2CH3 +)。
Example 9, 4- (1, 1-difluoroethyl) phenyl) (phenyl) methanone (figure 10).
To a 10ml Schlenk reaction tube, 4-bromobenzoyl benzene (0.2 mmol), bis (tricyclohexylphosphine) nickel dichloride (10 mol%), 4,4 '-diamino-2, 2' -bipyridine (10 mol%), 4-dimethylaminopyridine (20 mol%), magnesium chloride (3 eq), zinc powder (2 eq) were added, nitrogen was exchanged by evacuation, and a DMSO solution in which reactant 1 was dissolved (prepared before the reaction started, reactant 1 was slowly passed through DMSO until the total volume did not increase, after that19F NMR 0.7 mol/L) was added to the solution, and the reaction was carried out at 110 ℃ for 10 hours. After the reaction is finished, the TLC detection reaction is carried out, and the target product (73%) is obtained by column chromatography separation.1H NMR (400 MHz, CDCl3):δ 7.76 (d,J= 8.1 Hz, 2H), 7.72 (d,J= 7.8 Hz, 2H),7.53 (t,J= 8.5 Hz, 3H), 7.41 (t,J= 7.6 Hz, 2H), 1.88 (t,J= 18.2 Hz,3H).19F NMR(376MHz, CDCl3): δ -88.5 (q,J= 18.2 Hz, 2F).13C NMR (100 MHz,CDCl3): δ 196.0, 141.8 (t,2 J C-F= 26.8 Hz), 138.8, 137.1, 132.8, 130.1, 130.1,128.4, 124.7 (t,3 J C-F= 6.0 Hz), 121.4 (t,1 J C-F= 239.7 Hz), 26.0 (t,2 J C-F=29.6 Hz). GC-MS (m/z): 246 (M+), 169 (M+-Ph), 141 (M+-COPh), 105 (COPh+) 77(Ph+), 65 (CF2CH3 +)。
Example 10, 6- (1, 1-difluoroethyl) isoquinoline (FIG. 11).
To a 10ml Schlenk reaction tube, add 6-bromine isoquinoline (0.2 mmol), bis (Tricyclohexyl phosphine) nickel dichloride (10 mol%), 4,4 '-diamino-2, 2' -bipyridine (10 mol%), 4-two amino pyridine (20 mol%), magnesium chloride (3 equiv.), zinc powder (2 equiv.), vacuum-pumping nitrogen gas, and then will dissolve reactant 1 DMSO solution (reaction starts before ready, reactant 1 slowly into DMSO, until the total volume is not increasing, through the process19F NMR 0.7 mol/L) was added to the solution, and the reaction was carried out at 110 ℃ for 10 hours. Reaction ofAfter completion, the reaction was checked by TLC and isolated by column chromatography to give the desired product (46%).1HNMR (400 MHz, CDCl3):δ 9.30 (s, 1H), 8.59 (d,J= 5.6 Hz, 1H), 8.04 (d,J=8.6 Hz, 1H), 7.98 (s, 1H), 7.70 (d,J= 6.0 Hz, 2H), 2.01 (t,J= 18.2 Hz,3H).19F NMR(376MHz, CDCl3): δ -88.5 (q,J= 18.2 Hz, 2F).13C NMR (100 MHz,CDCl3):δ 152.4, 143.9, 139.8 (t,2 J C-F= 26.7 Hz), 135.2, 128.4, 123.6 (t,3 J C-F= 5.2 Hz), 122.8 (t,3 J C-F= 6.9 Hz), 121.5 (t,1 J C-F= 239.8 Hz), 121.0, 26.0(t,2 J C-F= 29.5 Hz). GC-MS (m/z): 193 (M+), 179 (M+-N), 128 (M+- CF2CH3)。
Example 11, 6- (1, 1-difluoroethyl) quinoline (FIG. 12).
To a 10ml Schlenk reaction tube, 6-bromoquinoline (0.2 mmol), bis (tricyclohexylphosphine) nickel dichloride (10 mol%), 4,4 '-diamino-2, 2' -bipyridine (10 mol%), 4-dimethylaminopyridine (20 mol%), magnesium chloride (3 eq), zinc powder (2 eq) were added, vacuum was applied to exchange nitrogen gas, and a DMSO solution in which reactant 1 was dissolved (prepared before the reaction started, reactant 1 was slowly passed through DMSO until the total volume did not increase, after that19F NMR 0.7 mol/L) was added to the solution, and the reaction was carried out at 110 ℃ for 10 hours. After the reaction is finished, the TLC detection reaction is carried out, and the column chromatography separation is carried out to obtain the target product (44%).1H NMR(400 MHz, CDCl3):δ 8.98 (d,J= 4.0 Hz, 1H), 8.23 (d,J= 8.3 Hz, 1H), 8.17(d,J= 8.8 Hz, 1H), 8.00 (s, 1H), 7.82 (d,J= 8.8 Hz, 1H), 7.49-7.46 (m,1H), 2.03 (t,J= 18.0 Hz, 3H).19F NMR(376MHz, CDCl3): δ -87.65 (q,J= 18.1Hz).13C NMR (100 MHz, CDCl3): δ 151.5, 148.4, 136.7, 136.2 (t,2 J C-F= 26.7Hz), 130.1, 127.5, 125.8 (t,3 J C-F= 5.1 Hz), 124.1 (t,3 J C-F= 6.8 Hz), 121.8,121.6 (t,1 J C-F= 237.9 Hz), 26.0 (t,2 J C-F= 29.5 Hz). GC-MS (m/z): 193 (M+),179 (M+-N), 128 (M+- CF2CH3)。
Example 12, 2- (1, 1-difluoroethyl) dibenzo [ b, d ] thiophene (FIG. 13).
To a 10ml Schlenk reaction tube, 2-bromodibenzothiophene (0.2 mmol), bis (tricyclohexylphosphine) nickel dichloride (10 mol%), 4,4 '-diamino-2, 2' -bipyridine (10 mol%), 4-dimethylaminopyridine (20 mol%), magnesium chloride (3 eq), zinc powder (2 eq) were added, vacuum was applied to exchange nitrogen gas, and a DMSO solution in which reactant 1 was dissolved (prepared before the reaction started, reactant 1 was slowly passed through DMSO until the total volume did not increase, followed by19F NMR 0.7 mol/L) was added to the solution, and the reaction was carried out at 110 ℃ for 10 hours. After the reaction is finished, the TLC detection reaction is carried out, and the column chromatography separation is carried out to obtain the target product (43%).1H NMR (400 MHz, CDCl3):δ 8.30 (s, 1H), 8.21-8.19 (m, 1H), 7.91-7.86 (m,2H), 7.59 (d,J= 8.3 Hz, 1H), 7.51-7.49 (m, 2H), 2.04 (t,J= 18.2 Hz, 3H).19F NMR(376MHz, CDCl3): δ -86.4 (q,J= 18.0 Hz).13C NMR (100 MHz, CDCl3):δ140.8 (t,4 J C-F= 1.5 Hz), 139.9, 135.5, 135.1, 134.7 (t,2 J C-F= 26.8 Hz),127.2, 124.7, 123.1 (t,3 J C-F= 5.7 Hz), 122.9, 122.2 (t,1 J C-F= 239.3 Hz),121.8, 117.8 (t,3 J C-F= 6.5 Hz), 26.4 (t,2 J C-F= 30.1 Hz). GC-MS (m/z): 248 (M+), 233 (M+-CH3), 183 (M+- CF2CH3)。
Example 13, 9- (4- (1, 1-difluoroethyl) phenyl) -9H-carbazole (fig. 14).
To a 10ml Schlenk reaction tube, 9- (4-bromophenyl) carbazole (0.2 mmol), bis (bTricyclohexylphosphine) nickel dichloride (10 mol%), 4,4 '-diamino-2, 2' -bipyridine (10 mol%), 4-dimethylaminopyridine (20 mol%), magnesium chloride (3 equivalents) and zinc powder (2 equivalents), vacuumizing and changing nitrogen, then adding DMSO solution (prepared before reaction, slowly introducing reactant 1 into DMSO until the total volume is not increased, and passing through19F NMR 0.7 mol/L) was added to the solution, and the reaction was carried out at 110 ℃ for 10 hours. After the reaction is finished, the TLC detection reaction is carried out, and the column chromatography separation is carried out to obtain the target product (54%).1H NMR (400 MHz, CDCl3): δ 8.16 (d,J= 7.7 Hz, 2H), 7.76 (d,J= 8.2Hz, 2H), 7.65 (d,J= 8.2 Hz, 2H), 7.46-7.41 (m, 4H), 7.34-7.30 (m, 2H), 2.04(t,J= 18.2 Hz, 3H).19F NMR(376MHz, CDCl3): δ -87.2 (q,J= 18.2 Hz, 2F).GC-MS (m/z): 307 (M+), 292 (M+-CH3), 242 (M+-CF2-CH3), 65 (CF2CH3 +)。
Example 14, ethyl 4- (4- (1, 1-difluoroethyl) phenyl) -4-oxobutanoate (FIG. 15).
To a 10ml Schlenk reaction tube, 4- (4-bromophenyl) -4-oxobutanoic acid ethyl ester (0.2 mmol), bis (tricyclohexylphosphine) nickel dichloride (10 mol%), 4,4 '-diamino-2, 2' -bipyridine (10 mol%), 4-dimethylaminopyridine (20 mol%), magnesium chloride (3 eq), zinc powder (2 eq), evacuated to exchange nitrogen gas, and DMSO solution in which reactant 1 is dissolved (prepared before the reaction starts, reactant 1 is slowly passed through DMSO until the total volume does not increase, followed by19F NMR 0.7 mol/L) was added to the solution, and the reaction was carried out at 110 ℃ for 10 hours. After the reaction is finished, the TLC detection reaction is carried out, and the column chromatography separation is carried out to obtain the target product (61%).1H NMR (400 MHz, CDCl3):δ 8.03 (d,J= 8.1 Hz, 2H), 7.61 (d,J= 8.1Hz, 2H), 4.16 (q,J= 7.1 Hz, 2H), 3.32 (t,J= 6.5 Hz, 2H), 2.77 (t,J= 6.5Hz, 2H), 1.93 (t,J= 18.2 Hz, 3H), 1.27 (t,J= 6.6 Hz, 3H).19F NMR(376MHz,CDCl3):δ -88.82 (q,J= 18.2 Hz, 2F).13C NMR (100 MHz, CDCl3): δ 197.6, 172.8,142.6 (t,2 J C-F= 26.7 Hz), 137.6, 128.2, 125.0 (t,3 J C-F= 5.9 Hz), 121.3 (t,1 J C-F= 238.2 Hz), 60.8, 33.6, 28.2, 25.9(t,2 J C-F= 29.4 Hz), 14.2. GC-MS (m/z): 270 (M+), 255 (M+-C2H5), 169 (M+-C2H4CO2C2H5), 101 (C2H4CO2C2H+).141(PhCF2CH3.+)。
Example 15, - (1, 1-difluoroethyl) -4'- (pentyloxy) -1,1' -biphenyl (FIG. 16).
To a 10ml Schlenk reaction tube, 4-bromo-4 ' - (pentyloxy) biphenyl (0.2 mmol), bis (tricyclohexylphosphine) nickel dichloride (10 mol%), 4,4' -diamino-2, 2' -bipyridine (10 mol%), 4-dimethylaminopyridine (20 mol%), magnesium chloride (3 eq), zinc powder (2 eq) were added, vacuum was applied to exchange nitrogen, and a DMSO solution in which reactant 1 was dissolved was added (prepared before the reaction started, reactant 1 was slowly introduced into DMSO until the total volume did not increase, after that19F NMR 0.7 mol/L) was added to the solution, and the reaction was carried out at 110 ℃ for 10 hours. After the reaction is finished, the TLC detection reaction is carried out, and the column chromatography separation is carried out to obtain the target product (56%).1H NMR (400 MHz, CDCl3):δ 7.63-7.48 (m, 6H), 6.98 (d,J= 8.6 Hz,2H), 4.00 (t,J= 6.6 Hz, 2H), 1.96 (t,J= 18.2 Hz, 3H), 1.87-1.74 (m, 2H),1.51-1.34 (m, 4H), 0.94 (t,J= 7.0 Hz, 3H).19F NMR(376MHz, CDCl3): δ -87.1(q,J= 18.2 Hz, 2F).GC-MS (m/z): 304(M+), 233 (M+-C5H11)。
Example 16, isopropyl 2- (4- (4- (4- (1, 1-difluoroethyl) benzoyl) phenoxy) -2-methylpropanoate (FIG. 17)
To a 10ml Schlenk reaction tube, fenofibrate (0.2 mmol), bis (tricyclohexylphosphine) Nickel dichloride (10 mol%), 4,4 '-diamino-2, 2' -bipyridine (10 mol%), 4-dimethylaminopyridine (20 mol%), magnesium chloride (3 eq), zinc powder (2 eq), evacuating and changing nitrogen, and then adding a DMSO solution (prepared before the reaction starts, and slowly introducing the reactant 1 into DMSO until the total volume is not increased, and then carrying out the steps of19F NMR 0.7 mol/L) was added to the solution, and the reaction was carried out at 110 ℃ for 10 hours. After the reaction is finished, the TLC detection reaction is carried out, and the column chromatography separation is carried out to obtain the target product (62%).1H NMR (400MHz, CDCl3):δ 7.69 (t,J= 9.0 Hz, 4H), 7.53 (d,J= 8.0 Hz, 2H), 6.79 (d,J= 8.6 Hz, 2H), 5.1-4.96 (m, 1H), 1.87 (t,J= 18.2 Hz, 3H), 1.58 (s, 6H),1.12 (d,J= 6.3 Hz, 6H).19F NMR(376MHz, CDCl3): δ -88.4 (q,J= 18.2 Hz,2F).13C NMR (100 MHz, CDCl3):δ 194.7 , 173.1 , 159.8 , 141.3 (t,2 J C-F= 26.8Hz), 139.4 , 132.1 , 130.1 , 129.8 , 124.6 (t,3 J C-F= 6.0 Hz), 121.4 (t,1 J C-F= 239.6 Hz), 117.2 , 79.4 , 69.4 , 26.0 (t,2 J C-F= 29.6 Hz), 25.4 , 21.5. GC-MS (m/z): 390(M+), 303 (M+-CO2C2H7), 169 (CF2CH3PhCO+), 87(CO2C2H7 +)。
Drawings
FIG. 1 is a general reaction scheme of the synthesis method.
FIG. 2 is 4- (1, 1-difluoroethyl) -1,1' -biphenyl.
FIG. 3 is 3- (1, 1-difluoroethyl) -1,1' -biphenyl.
FIG. 4 is 5'- (1, 1-difluoroethyl) -1, 1': 3', 1' ' -terphenyl.
FIG. 5 is (1, 1-difluoroethyl) benzene.
FIG. 6 is 4- (1, 1-difluoroethyl) -4 '-ethyl-1, 1' -biphenyl.
FIG. 7 is 1- (4- (1, 1-difluoroethyl) phenyl) ethan-1-one.
FIG. 8 is 1- (1, 1-difluoroethyl) -4- (methylsulfonyl) benzene.
Figure 9 is 5- (1, 1-difluoroethyl) -2, 3-dihydro-1H-indan-1-one.
Figure 10 is (4- (1, 1-difluoroethyl) phenyl) (phenyl) methanone.
FIG. 11 is 6- (1, 1-difluoroethyl) isoquinoline.
FIG. 12 is 6- (1, 1-difluoroethyl) quinoline.
FIG. 13 is 2- (1, 1-difluoroethyl) dibenzo [ b, d ] thiophene.
Figure 14 is 9- (4- (1, 1-difluoroethyl) phenyl) -9H-carbazole.
FIG. 15 is ethyl 4- (4- (1, 1-difluoroethyl) phenyl) -4-oxobutanoate.
FIG. 16 is 4- (1, 1-difluoroethyl) -4'- (pentyloxy) -1,1' -biphenyl.
Figure 17 is isopropyl 2- (4- (4- (4- (1, 1-difluoroethyl) benzoyl) phenoxy) -2-methylpropanoate.

Claims (8)

1. A1, 1-difluoroethyl aromatic compound is characterized by having R1-CF2CH3Structure (II) wherein R1The method comprises the following steps:
4-biphenyl, 3, 5-biphenyl, phenyl, quinoline, isoquinoline, 4' -ethylbiphenyl, 4-acetylbenzene, 4- (methylsulfonyl) benzene, indanone, dibenzothiophene, carbazole and other (hetero) aromatic rings.
2. The method for synthesizing 1, 1-difluoroethyl aromatic compound according to claim 1, wherein the 1, 1-difluoroethyl aromatic compound is prepared by reacting 1, 1-difluoromonochloroethane and halogenated aromatic hydrocarbon (chloro, bromo, iodo aromatic hydrocarbon) at 110 ℃ for 10h by adding transition metal nickel catalyst, ligand, additive, reducing agent and solvent.
3. A process for the synthesis of a 1, 1-difluoroethyl aromatic compound as claimed in claim 2, wherein the catalyst is bis (tricyclohexylphosphine) nickel dichloride.
4. The method of synthesizing a 1, 1-difluoroethyl aromatic compound of claim 2 wherein the ligand is 4,4 '-diamino-2, 2' -bipyridine.
5. The method of synthesizing a 1, 1-difluoroethyl aromatic compound as claimed in claim 2, wherein the additives are 4-dimethylaminopyridine and magnesium chloride.
6. The method of synthesizing a 1, 1-difluoroethyl aromatic compound as claimed in claim 2, wherein said reducing agent is zinc powder.
7. The method of synthesizing a 1, 1-difluoroethyl aromatic compound as claimed in claim 2, wherein the solvent is dimethyl sulfoxide (DMSO).
8. The method of synthesizing a 1, 1-difluoroethyl aromatic compound as claimed in claim 2, wherein the concentrations of 1, 1-difluoromonochloroethane, the halogenated aromatic hydrocarbon, bis (tricyclohexylphosphine) nickel dichloride, 4 '-diamino-2, 2' -bipyridine, 4-dimethylaminopyridine, magnesium chloride and zinc powder in dimethyl sulfoxide are, in order: 0.7M, 0.2M, 0.02M, 0.04M, 0.6M, 0.4M.
CN201911209464.2A 2019-12-01 2019-12-01 Reduction coupling method for synthesizing 1, 1-difluoroethyl aromatic compound Pending CN110872206A (en)

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Publication number Priority date Publication date Assignee Title
CN109704914A (en) * 2019-01-19 2019-05-03 山东理工大学 A kind of facile syntheesis new method of 1,1- bis-fluoro ethyls aromatic compound

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Publication number Priority date Publication date Assignee Title
CN109704914A (en) * 2019-01-19 2019-05-03 山东理工大学 A kind of facile syntheesis new method of 1,1- bis-fluoro ethyls aromatic compound

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* Cited by examiner, † Cited by third party
Title
JIE SHENG 等: "Nickel-Catalyzed Reductive Cross-Coupling of Aryl Halides with Monofluoroalkyl Halides for Late-Stage Monofluoroalkylation", 《ANGEW. CHEM. INT. ED.》 *
LIU, JIANCHANG 等: "1,1-Difluoroethyl chloride (CH3CF2Cl), a novel difluoroalkylating reagent for 1,1-difluoroethylation of arylboronic acids", 《RSC ADVANCES》 *

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