CN108373461B - A kind of method that light/nickel concerted catalysis prepares fluoro biaryl - Google Patents

A kind of method that light/nickel concerted catalysis prepares fluoro biaryl Download PDF

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CN108373461B
CN108373461B CN201810397024.3A CN201810397024A CN108373461B CN 108373461 B CN108373461 B CN 108373461B CN 201810397024 A CN201810397024 A CN 201810397024A CN 108373461 B CN108373461 B CN 108373461B
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nickel
fluoro
biaryl
light
concerted catalysis
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CN108373461A (en
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黄治炎
解昆
孟鸽
马俊杰
王俊亚
薛东
杨俊�
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Shaanxi Normal University
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Abstract

The invention discloses the methods that a kind of light/nickel concerted catalysis prepares fluoro biaryl, this method is using cheap metal nickel salt as catalyst, without additional ligand, Negishi cross-coupling occurs between trace photosensitizer concerted catalysis fluorinated aryl zincon and aryl halides under visible light illumination, prepares fluoro biaryl hydrocarbon compound.Coupling reaction functional group tolerance is good, and substrate applicability is wide, closely at room temperature to obtain a variety of fluoro biaryl hydrocarbon compounds (80%~96%) in high yield.Compared with palladium catalytic system reported in the literature, light used by the method for the present invention/nickel concerted catalysis system photosensitizer dosage is low, and Raney nickel is cheap, and the ligand without additional valuableness, has environmentally protective, economical and practical advantage；In conjunction with flowing synthetic technology, the present invention important fluoro biaryl hydrocarbon compound of Fully automated synthesis easy to accomplish.

Description

A kind of method that light/nickel concerted catalysis prepares fluoro biaryl
Technical field
The invention belongs to fluoro biaryl synthesis technical fields, and in particular to one kind prepares fluorine by light/nickel concerted catalysis For the method for biaryl.
Background technique
Fluoro biaryl is one of the important skeleton of drug molecule, functional material molecule, and cross-coupling reaction is to prepare this The important means of the fluorine-containing biaryl hydrocarbon compound of class.The method of document or patent report synthesizing fluoro biaryl is mainly wrapped at present It includes: the Suzuki coupling reaction (Takashi Sakai.Org.Lett.2005,7,4915) of palladium chtalyst, palladium chtalyst polyfluoro aromatic hydrocarbons Direct arylation reaction (be shown in: ChemCatChem 2014,6,1824 by summary；Representative paper is shown in: J.Am.Chem.Soc.2006,128,8574；Org.Lett.2009,11,3346；Org.Lett.2010,12,2116； J.Am.Chem.Soc.2010,132,16377；Org.Lett.2011,13,276；J.FluorineChem.2013,151,50； Appl.Organometal.Chem.2014,28,180；Tetrahedron.Lett.2015,56,123；), nickel catalysis polyfluoro virtue The nickel catalysis Kumada coupling that the direct arylation reaction of hydrocarbon (Org.Lett.2016,18,2548) and inventor report recently is anti- Answer (ACS Catal.2017,7,7421；CN 106146454A；CN 106187656A).The common ground of these methods are as follows: need Additional Phosphine ligands and Metal Palladium or nickel form active catalyst, are catalyzed between halogenated aryl hydrocarbon and fluorinated aromatic hydrocarbon nucleopilic reagent and hand over Fork coupling reaction prepares fluoro biaryl.Further, since the strong electronegativity of fluorine atom, so that coupling reaction is more difficult, first three Kind method, which generally requires high temperature, effectively to be carried out.It can be seen that the synthetic technology of fluoro biaryl is still in period of expansion, wound The synthetic technology for building economical and efficient needs new idea and method.
Summary of the invention
It is a kind of in nearly room temperature and without outside plus under conditions of ligand technical problem to be solved by the present invention lies in providing, pass through The method that light/nickel concerted catalysis efficiently prepares serial fluoro biaryl.
Solving technical solution used by above-mentioned technical problem is: under the conditions of anhydrous and oxygen-free, by the virtue of neighbour's fluorine shown in Formulas I Halogenated aryl hydrocarbon shown in base zincon, Formula II, Raney nickel, photosensitizer are added in organic solvent, reaction solution is heated to 40~ It 60 DEG C, is stirred to react under light illumination, after fully reacting, methanol quenching reaction is added, isolates and purifies, obtains fluorine shown in formula III For biaryl, reactional equation is as follows:
R in formula1~R4It is independent to represent H or F；Ar represents phenyl, thienyl, naphthalene, pyridyl group, indyl, benzo Furyl, benzothienyl, any one in quinolyl or C1~C6Alkyl, C1~C6Alkoxy, trifluoromethyl, formic acid second Phenyl, the thienyl, naphthalene, pyridyl group, indyl, benzofuran that ester group, methyl formate base, any one in acetyl group replace Base, benzothienyl or quinolyl and its analogue；X represent Cl, Br, I, methylsulphur acidic group, trifluoromethanesulfonate, to methyl Benzene sulfonic acid base, trifluoroacetic acid base.
In above-mentioned preparation method, the preferably described halogenated aryl hydrocarbon and adjacent fluoro aryl zincon, Raney nickel, photosensitizer mole Than for 1:2~3:0.05~0.20:0.0005~0.0020.
Above-mentioned Raney nickel be bis- (1,5- cyclo-octadiene) nickel, nickelous bromide (glycol dimethyl ether) complex compound, nickel chloride, Nickelous bromide, nickel iodide, nickel acetate, any one in trifluoromethanesulfonic acid nickel.
Above-mentioned photosensitizer is any one in following compound a~m or its analog:
Wherein photosensitizer a~h is commercially produced product, and the synthetic route and synthetic method of photosensitizer i~m is as follows:
It (1) is in molar ratio 1:8~20 by BODIPY 2 and aryl grignard reagent using anhydrous methylene chloride as solvent, 1.0mol/L hydrochloric acid is used after having reacted, and is extracted with dichloromethane, methylene chloride in back flow reaction 6~12 hours at 50 DEG C After extract liquor anhydrous sodium sulfate drying, evaporated under reduced pressure, silica gel column chromatography separation obtains BODIPY 3, wherein described Aryl grignard reagent is phenyl-magnesium-bromide, 2- naphthyl-magnesium bromide, any one in 3,5- di-tert-butyl-phenyl magnesium bromide.
It (2) is in molar ratio 1:3~5 by BODIPY 3 and N- N-iodosuccinimide using anhydrous methylene chloride as solvent, Reaction 10 minutes is stirred at room temperature, adds water quenching to go out after react, and is extracted with dichloromethane, dichloromethane extract is with anhydrous After sodium sulphate is dry, evaporated under reduced pressure, silica gel column chromatography separation obtains BODIPY4.
(3) under nitrogen atmosphere, Isosorbide-5-Nitrae-dioxane is added in BODIPY 4, aryl boric acid and ethyl alcohol, water volume ratio is The in the mixed solvent of 2:1:1, is then added K3PO4, four (triphenyl phosphorus) palladiums, wherein BODIPY 4 and aryl boric acid, K3PO4, four The molar ratio of (triphenyl phosphorus) palladium is 1:3~5:5~7:0.05~0.2, and back flow reaction 12 hours at 90 DEG C add after having reacted Water quenching is gone out, and is extracted with dichloromethane, after dichloromethane extract anhydrous sodium sulfate drying, evaporated under reduced pressure, and silica gel column chromatography Chromatography obtains photosensitizer, wherein the aryl boric acid is phenyl boric acid or 2- naphthalene boronic acids.
The present invention is using cheap halogenated aryl hydrocarbon and the fluorinated aryl zincon being prepared in situ as coupled substrate, using simple Nickel compound is metallic catalyst, and Negishi occurs between trace photosensitizer concerted catalysis substrate under visible light action and intersects Coupling, the important fluoro biaryl hydrocarbon compound of preparation series.Compared with prior art, beneficial effects of the present invention are as follows:
1, the present invention does not need extra ligand using common nickel compound as catalyst.
2, photosensitizer dosage used in the present invention is low, and reaction temperature is close to room temperature.
3, the present invention can be used for synthesizing the key intermediate of a variety of important drugs.
Specific embodiment
Below with reference to embodiment, the present invention is described in more detail, but protection scope of the present invention is not limited only to these realities Apply example.
Embodiment 1
Composite structure formula following 2- methyl -5- (2 ', 3 ', 5 ', 6 '-tetrafluoro phenyl) thiophene
Under the conditions of anhydrous and oxygen-free, 1.0mL tetrahydrofuran, 2.0mL N, N- dimethyl formyl are successively added into reaction tube Amine, 7.7mg (0.025mmol) nickelous bromide (glycol dimethyl ether) complex compound, 88mg (0.5mmol) 2- methyl -5- bromothiophene, THF solution, 1.0mL 1.0mol/L (1mmol) 2,3,5,6- phenyl tetrafluoride of 100 μ L 10mmol/L (0.001mmol) photosensitizer i The tetrahydrofuran solution of base zincon, reaction tube is placed in white light, and (5W is stirred at 50 DEG C away under reaction tube 1cm) illumination Reaction 12 hours after having reacted, is added 0.5mL methanol and stirs 10 minutes, be quenched wait react completely, by reaction solution saturated common salt It is extracted with ethyl acetate three times after water dilution, acetic acid ethyl acetate extract is dry with anhydrous sodium sulfate, evaporated under reduced pressure, silica gel chromatographic column Chromatography is to get sterling 2- methyl -5- (2 ', 3 ', 5 ', 6 '-tetrafluoro phenyl) thiophene 192mg, yield 92%, structural characterization Data are as follows:1H NMR(600MHz,CDCl3): δ 7.42 (d, J=3.6Hz, 1H), 6.99-6.93 (m, 1H), 6.85 (d, J= 3.0Hz,1H),2.56(s,3H)。
Embodiment 2
The following 4- of composite structure formula (2 ', 3 ', 5 ', 6 '-tetrafluoro phenyl) acetophenone
In the present embodiment, with the 2- methyl -5- bromothiophene in equimolar parabromoacetophenone alternative embodiment 1, Qi Tabu It is rapid same as Example 1, obtain 4- (2 ', 3 ', 5 ', 6 '-tetrafluoro phenyl) acetophenone, yield 98%, structural characterization data Are as follows:1H NMR(400MHz,CDCl3): δ 8.08 (d, J=8.4Hz, 2H), 7.58 (d, J=8.0Hz, 2H), 7.15-7.10 (m, 1H),2.66(s,3H)。
Embodiment 3
The following fluoro- 1,1 '-biphenyl of 2,3,5,6- tetra- of composite structure formula
In the present embodiment, with the 2- methyl -5- bromothiophene in equimolar bromobenzene alternative embodiment 1, other steps and reality It is identical to apply example 1, obtains 2,3,5,6- tetra- fluoro- 1,1 '-biphenyl, yield 98%, structural characterization data are as follows:1H NMR (400MHz,CDCl3):δ7.54-7.44(m,5H),7.13-7.01(m,1H)。
Embodiment 4
The following fluoro- 3'- methoxyl group -1,1'- biphenyl of 2,3,5,6- tetra- of composite structure formula
In the present embodiment, with the 2- methyl -5- bromothiophene in equimolar 3- bromoanisole alternative embodiment 1, Qi Tabu It is rapid same as Example 1, obtain 2,3,5,6- tetra- fluoro- 3'- methoxyl group -1,1'- biphenyl, yield 93%, structural characterization number According to are as follows:1H NMR(400MHz,CDCl3): δ 7.41 (t, J=8.0Hz, 2H), 7.09-6.99 (m, 4H), 3.85 (s, 1H).
Embodiment 5
The following 2- of composite structure formula (2', 3', 5', 6'- tetrafluoro phenyl) naphthalene
In the present embodiment, with the 2- methyl -5- bromothiophene in equimolar 2- naphthalene bromide alternative embodiment 1, other steps It is same as Example 1, obtain 2- (2', 3', 5', 6'- tetrafluoro phenyl) naphthalene, yield 99%, structural characterization data are as follows:1H NMR (400MHz,CDCl3):δ7.98-7.90(m,4H),7.60-7.57(m,3H),7.07-7.15(m,1H)。
Embodiment 6
The following fluoro- 4'- Trifluoromethyl-1 of 2,3,5,6- tetra- of composite structure formula, 1'- biphenyl
It is other with the 2- methyl -5- bromothiophene in equimolar 4- 5 bromine benzotrifluoride alternative embodiment 1 in the present embodiment Step is same as Example 1, obtains 2,3,5,6- tetra- fluoro- 4'- Trifluoromethyl-1s, 1'- biphenyl, yield 92%, structure table Levy data are as follows:1H NMR(400MHz,CDCl3): 7.77 (d, J=8.4Hz, 2H), 7.60 (d, J=8.0Hz, 2H), 7.18- 7.09(m,1H)。
Embodiment 7
The following 4- of composite structure formula (2', 3', 5', 6'- tetrafluoro phenyl)-ethyl benzoate
In the present embodiment, with the 2- methyl -5- bromothiophene in equimolar 4- bromobenzoic acid ethyl ester alternative embodiment 1, Its step is same as Example 1, obtains 4- (2', 3', 5', 6'- tetrafluoro phenyl)-ethyl benzoate, yield 98%, structure Characterize data are as follows:1H NMR(400MHz,CDCl3): 8.17 (d, J=8.4Hz, 2H), 7.55 (d, J=8.4Hz, 2H), 7.14- 7.09 (m, 1H), 4.19 (q, J=7.2Hz, 2H), 1.42 (t, J=7.2Hz, 3H).
Embodiment 8
The following 3- of composite structure formula (2', 3', 5', 6'- tetrafluoro phenyl)-thiophene -2-carboxylic acid methyl esters
In the present embodiment, the nickelous bromide (ethylene glycol in equimolar bis- (1,5- cyclo-octadiene) nickel alternative embodiments 1 will be used Dimethyl ether) complex compound, with the 2- methyl-in equimolar thiophene -2-carboxylic acid methyl esters -3- triflate alternative embodiment 1 5- bromothiophene, other steps are same as Example 1, obtain 3- (2', 3', 5', 6'- tetrafluoro phenyl)-thiophene -2-carboxylic acid methyl esters, Its yield is 97%, structural characterization data are as follows:1H NMR(400MHz,CDCl3): 7.63 (d, J=5.2Hz, 1H), 7.15-7.06 (m,2H),3.81(s,3H)。
Embodiment 9
The following 2- of composite structure formula (2', 3', 4', 6'- tetrafluoro phenyl) naphthalene
In the present embodiment, with 2,3,5,6- tetra- in equimolar 2,3,4,6- tetrafluoro phenyl zincon alternative embodiments 1 Fluorophenyl zincon, with the 2- methyl -5- bromothiophene in equimolar 2- naphthalene bromide alternative embodiment 1, other steps and implementation Example 1 is identical, obtains 2- (2', 3', 4', 6'- tetrafluoro phenyl) naphthalene, yield 96%, structural characterization data are as follows:1H NMR (400MHz,CDCl3):δ7.95-7.89(m,4H),7.57-7.50(m,3H),6.95-6.88(m,1H)。
Embodiment 10
The following 2- of composite structure formula (2', 4', 5'- trifluorophenyl) naphthalene
In the present embodiment, with 2,3,5,6- tetrafluoros in equimolar 2,4,6- tetrafluoro phenyl zincon alternative embodiments 1 Phenyl zincon substitutes white light with blue light with the 2- methyl -5- bromothiophene in equimolar 2- naphthalene bromide alternative embodiment 1, Its step is same as Example 1, obtains 2- (2', 4', 5'- trifluorophenyl) naphthalene, yield 89%, structural characterization data are as follows:1H NMR(400MHz,CDCl3):δ7.96-7.89(m,4H),7.56-7.52(m,3H),6.84-6.80(m,1H)。
Embodiment 11
The following 2- of composite structure formula (2 ', 6 '-difluorophenyl) naphthalene
In the present embodiment, with 2,3,5,6- phenyl tetrafluorides in equimolar 2,6- difluorophenyl zincon alternative embodiment 1 Base zincon substitutes white light with blue light with the 2- methyl -5- bromothiophene in equimolar 2- naphthalene bromide alternative embodiment 1, other Step is same as Example 1, obtains 2- (2', 4', 5'- trifluorophenyl) naphthalene, yield 83%, structural characterization data are as follows: 1H NMR (600MHz, CDCl3): δ 8.01 (s, 1H), 7.96 (d, J=8.4Hz, 1H), 7.92-7.91 (m, 2H), 7.61 (dd, J= 8.4,1.2Hz, 1H), 7.57-7.53 (m, 2H), 7.35-7.30 (m, 1H), 7.05 (t, J=7.9Hz, 2H).
Embodiment 12
The following 6- of composite structure formula (2 '-fluorophenyl) pyridine -2- hexyl formate
In the present embodiment, with 2,3,5,6- tetrafluoro phenyl zinc in equimolar 2- fluorophenyl zincon alternative embodiment 1 Reagent, with the 2- methyl -5- bromothiophene in the bromo- 2 pyridine carboxylic acid methyl esters alternative embodiment 1 of equimolar 6-, with equimolar light Quick dose of l replaces photosensitizer i, and other steps are same as Example 1, obtains 6- (2 '-fluorophenyl) pyridine -2- hexyl formate, produces Rate is 88%, structural characterization data are as follows: 1H NMR (400MHz, CDCl3): δ 8.10 (d, J=1.2Hz, 1H), 8.07 (td, J= 8.0,2.0Hz, 1H), 7.97 (dm, J=8.0Hz, 1H), 7.90 (td, J=7.8,1H), 7.42-7.38 (m, 1H), 7.29 (td, J=7.6,1.2Hz, 1H), 7.16 (ddd, J=11.3,8.22,1.2Hz, 1H), 4.02 (s, 3H).
Embodiment 13
The following 5- of composite structure formula (2', 3', 5', 6'- tetrafluoro phenyl) indoles
In the present embodiment, with the 2- methyl -5- bromothiophene in equimolar 5- bromo indole alternative embodiment 1, other steps It is same as Example 1, obtain 5- (2', 3', 5', 6'- tetrafluoro phenyl) indoles, yield 82%, structural characterization data are as follows:1H NMR(600MHz,CDCl3): δ 8.23 (br, 1H), 7.78 (s, 1H), 7.48 (d, J=8.4Hz, 1H), 7.30-7.26 (m, 2H),7.09-7.01(m,2H),6.64(s,1H)。
Embodiment 14
The following 3- of composite structure formula (2', 3', 5', 6'- tetrafluoro phenyl) benzofuran
In the present embodiment, replaced with equimolar 3- bromobenzofuran by 2- methyl -5- bromothiophene, other steps and implementation Example 1 is identical, obtains 3- (2', 3', 5', 6'- tetrafluoro phenyl) indoles, yield 82%, and structural characterization data are as follows:1H NMR (600MHz,CDCl3): δ 7.91 (s, 1H), 7.60 (d, J=8.3Hz, 1H), 7.58 (d, J=7.7Hz, 1H), 7.40 (t, J= 7.7Hz, 1H), 7.30 (t, J=7.5Hz, 1H), 7.15-7.10 (m, 1H).
Embodiment 15
The following 3- of composite structure formula (2', 3', 5', 6'- tetrafluoro phenyl) benzothiophene
It is other with the 2- methyl -5- bromothiophene in equimolar 3- bromobenzothiophene alternative embodiment 1 in the present embodiment Step is same as Example 1, obtains 3- (2', 3', 5', 6'- tetrafluoro phenyl) benzothiophene, yield 91%, structural characterization Data are as follows:1H NMR(400MHz,CDCl3):δ7.97-7.93(m,1H),7.62(s,1H),7.58-7.55(m,1H), 7.45-7.41(m,2H),7.21-7.12(m,1H)。
Embodiment 16
The following 3- of composite structure formula (2', 3', 5', 6'- tetrafluoro phenyl) quinoline
In the present embodiment, with the 2- methyl -5- bromothiophene in equimolar 3- bromoquinoline alternative embodiment 1, other steps It is same as Example 1, obtain 5- (2', 3', 5', 6'- tetrafluoro phenyl) quinoline, yield 97%, structural characterization data are as follows:1H NMR(600MHz,CDCl3): δ 8.99 (s, 1H), 8.31 (s, 1H), 8.18 (d, J=8.4Hz, 1H), 7.90 (d, J=8.0Hz, 1H), 7.82 (t, J=7.6Hz, 1H), 7.63 (t, J=7.6Hz, 1H), 7.26-7.13 (m, 1H).
Bis- (1,5- cyclo-octadiene) nickel, chlorination can be used in nickelous bromide (glycol dimethyl ether) complex compound in above-described embodiment Nickel, nickelous bromide, nickel iodide, nickel acetate or the replacement of trifluoromethanesulfonic acid nickel；White light can be replaced with blue light or green light；Photosensitizer i can be used Any one in photosensitizer a~h or j~m is replaced；Isometric N, N- diethyl first can be used in solvent for use N,N-dimethylformamide Amide or DMAC N,N' dimethyl acetamide replacement；The purpose of the present invention can be achieved in the change of these conditions, obtains and above-mentioned implementation Product yield similar in example.

Claims (6)

1. the method that a kind of light/nickel concerted catalysis prepares fluoro biaryl, it is characterised in that: under the conditions of anhydrous and oxygen-free, by Formulas I Shown in neighbour's fluoro aryl zincon, aromatic hydrocarbons, Raney nickel shown in Formula II, photosensitizer be added in organic solvent, by reaction solution plus Heat is stirred to react under light illumination to 40~60 DEG C, after fully reacting, methanol quenching reaction is added, isolates and purifies, obtains formula III Shown in fluoro biaryl；
R in formula1~R4It is independent to represent H or F；Ar represents phenyl, thienyl, naphthalene, pyridyl group, indyl, benzofuran Base, benzothienyl, any one in quinolyl or C1~C6Alkyl, C1~C6Alkoxy, trifluoromethyl, Ethyl formate Phenyl, the thienyl, naphthalene, pyridyl group, indyl, benzofuran that base, methyl formate base, any one in acetyl group replace Base, benzothienyl or quinolyl；X represents Cl, Br, I, methylsulphur acidic group, trifluoromethanesulfonate, p-methyl benzenesulfonic acid base, trifluoro Any one in acetate.
2. the method that light according to claim 1/nickel concerted catalysis prepares fluoro biaryl, it is characterised in that: the virtue The molar ratio of hydrocarbon and adjacent fluoro aryl zincon, Raney nickel, photosensitizer is 1:2~3:0.05~0.20:0.0005~0.0020.
3. the method that light according to claim 1 or 2/nickel concerted catalysis prepares fluoro biaryl, it is characterised in that: described Raney nickel be bis- (1,5- cyclo-octadiene) nickel, nickelous bromide (glycol dimethyl ether) complex compound, nickel chloride, nickelous bromide, nickel iodide, Any one in nickel acetate, trifluoromethanesulfonic acid nickel.
4. the method that light according to claim 1 or 2/nickel concerted catalysis prepares fluoro biaryl, it is characterised in that described Photosensitizer is any one in following compound a~m:
。
5. the method that light according to claim 1/nickel concerted catalysis prepares fluoro biaryl, it is characterised in that: the light According to the light source used for white light, blue light or green light.
6. the method that light according to claim 1/nickel concerted catalysis prepares fluoro biaryl, it is characterised in that described organic Solvent is tetrahydrofuran and N,N-dimethylformamide or N, and base formamide or DMAC N,N' dimethyl acetamide volume ratio are N- bis- The mixed liquor of 1:1~2.
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