CN106146454A - The method of polyfluoro biaryl compounds is prepared in Negishi coupling - Google Patents

The method of polyfluoro biaryl compounds is prepared in Negishi coupling Download PDF

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CN106146454A
CN106146454A CN201610511926.6A CN201610511926A CN106146454A CN 106146454 A CN106146454 A CN 106146454A CN 201610511926 A CN201610511926 A CN 201610511926A CN 106146454 A CN106146454 A CN 106146454A
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polyfluoro
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biaryl compounds
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黄治炎
王俊亚
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Shaanxi Normal University
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Abstract

The invention discloses a kind of method that polyfluoro biaryl compounds is prepared in Negishi coupling, the method is with alkyl Grignard reagent or lithium alkylide as activator, and under equivalent zinc halide assists, the complex using nickel source and biphosphine ligand to be formed is catalyst, realize the cross-coupling between polyfluoro aromatic hydrocarbons and halogenated aryl hydrocarbon or aromatic yl sulphonate, thus obtain polyfluoro biaryl.Compared with existing synthetic method, the present invention uses Negishi coupling to prepare polyfluoro biaryl compounds first, coupling involved by the method occurs site accurate, highly controllable, target product productivity is high and selectivity is excellent, productivity is between 85%～99%, single arylated products ratio is up to more than 99%, have low in raw material price, substrate functional group better tolerance, substrate applicability is wide, reaction condition is gentle, simple to operate, post processing easy, pollute the advantages such as little, demonstrates higher social value and commercial introduction prospect simultaneously.

Description

The method of polyfluoro biaryl compounds is prepared in Negishi coupling
Technical field
The invention belongs to synthesize polyfluoro biaryl compounds technical field, be specifically related to one and select in a mild condition The method of property arylation polyfluoro aromatic hydrocarbons.
Background technology
Coupling reaction is to prepare one of polyfluoro maximally effective means of biaryl compounds.From Takashi in 2005 The Sakai report many fluorobenzoic boric acids of palladium chtalyst and aryl halides cross-coupling prepare polyfluoro biaryl (Takashi Sakai.Org.Lett.2005,7,4915) since, the cross-coupling reaction based on palladium chtalyst is developed rapidly.Especially It is the direct cross-coupling (J.Am.Chem.Soc.2006,128,8574 with polyfluoro aromatic hydrocarbons as raw material；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), related chemistry reaction equation is as follows:
Make a general survey of these report documents, it is seen that, present direct cross-coupling mostly there is problems in that
1, arylation productivity is low, especially runs into phenyl tetrafluoride and this kind of substrate containing multiple equivalent activity hydrogen of trifluoro-benzene Time, in addition to single arylated products, also can additionally generate bis-arylation even triaryl product.The existence of these by-products is not only Directly results in the reduction (< 75%) of single arylation principal product productivity, return and follow-up isolated and purified bring extreme difficulties.
2, the existing direct coupling method of many fluorobenzene, is required for greatly the harsh conditions such as high temperature (90～120 DEG C), and this is further Add the difficulty of reaction industry.
3, existing catalysis pattern mostly uses the palladium catalytic system of costliness, and this makes reaction cost be greatly improved.
Within 2016, execute Zhang Jie report nickel, copper syncatalytic many fluorobenzene arylation reaction (Org.Lett.DOI: 10.1021/acs.orglett.6b00819), this reaction achieves the direct friendship with nickel as catalyst, with many fluorobenzene as substrate Fork coupling reaction, but there is also following defect: 1) reaction needs nickel, two kinds of metal co-catalysis of copper to complete；2) this reaction exists Completing under the harsh conditions of 120 DEG C of high temperature, operation easier is bigger；3) the many fluorobenzene participation coupling containing multiple acid c h bonds is anti- Answer selectivity low (2.1: 1).Related chemistry reaction equation is as follows:
Summary of the invention
It is efficiently single that the technical problem to be solved is to overcome existing arylation method to be difficult to polyfluoro aromatic hydrocarbons Arylation and a difficult problem for severe reaction conditions, it is provided that a kind of simple to operate, with low cost, reaction condition is gentle, high selectivity and The method of high yield synthesis polyfluoro biaryl compounds.
Solve the technical scheme that above-mentioned technical problem used to be made up of following step:
1, under the conditions of anhydrous and oxygen-free, with oxolane as solvent, by the polyfluoro aromatic hydrocarbons shown in Formulas I and alkyl Grignard reagent Stir 2～18 hours at 0～50 DEG C or that the polyfluoro aromatic hydrocarbons shown in Formulas I and lithium alkylide are stirred at-20～0 DEG C 2～18 is little Time, it is subsequently adding zinc halide, stirring at normal temperature 1～2 hours.
2, under the conditions of anhydrous and oxygen-free, nickel source, biphosphine ligand are added in oxolane, stirring at normal temperature 30 minutes；Wherein Described nickel source is double (1,5-cyclo-octadiene) nickel, nickel acetate, trifluoracetic acid nickel, nickel acetylacetonate, trifluoromethanesulfonic acid nickel, chlorinations Any one in nickel, nickelous bromide, glycol dimethyl ether Nickel dichloride., glycol dimethyl ether nickelous bromide；Described biphosphine ligand Structural formula is as follows:
It prepares according to following method: with oxolane as solvent, is 1.1 in molar ratio by halogenated aryl hydrocarbon and Mg powder : 1 back flow reaction is wholly absent to Mg powder, after being cooled to-78 DEG C, is slowly dropped into the oxolane of double (2-dichloride phosphine) phenylate Solution, the most double (2-dichloride phosphine) phenylate is 1: 8 with the mol ratio of magnesium powder, is slowly increased to room temperature, continues to stir after dropping Mix 8 hours；Reactant liquor is cooled to-20 DEG C, is slowly added to methanol cancellation reaction, isolated and purified product, obtains biphosphine ligand, tool Body synthetic route is as follows:
In formula, Ar represents phenyl, C1～C6Alkyl-substituted phenyl, C1～C6Alkoxy substituted phenyl, difluorophenyl, fluoroform Any one in base phenyl, naphthyl, furyl, siloxy phenyl, X1Represent Cl, Br or I.
3, under the conditions of anhydrous and oxygen-free, step (1) and (2) gained reactant liquor are mixed, and adds the halo shown in Formula II Aromatic hydrocarbons or aromatic yl sulphonate, at 0～50 DEG C after stirring extremely reaction completely, add methanol cancellation reaction, isolated and purified product, obtain Polyfluoro biaryl compounds shown in formula III.
In above-mentioned Formulas I～III, R1～R4The most independent representative H, F, C1～C10Alkyl, C1～C6Alkoxyl, phenyl, C1 ～C6Alkyl-substituted phenyl, C1～C4Alkoxy substituted phenyl, pi-allyl, cinnamyl, trifluoromethyl, benzyl, silica-based, siloxy In any one, and R1～R4In at least one be that F, R represent H, C1～C10Alkyl, C1～C6Alkoxyl, phenyl, C1～C6 Alkyl-substituted phenyl, C1～C4Alkoxy substituted phenyl, ester group, F, Cl, CF3, any one in CN, X represent Br, I orR ' represents CF3、CH3Or p-CH3-C6H4, Y represents C, O, N or S, and when Y represents C, Z=1, n=1 or 2, Y represents During N, Z=1 or 0, n=1 or 2, when Y represents O, S, Z=0, n=1 or 2.
Above-mentioned R1～R4The most independent representative H, F, C1～C6Alkyl, C1～C4Alkoxyl, phenyl, pi-allyl, meat Gui Ji, trifluoromethyl, benzyl, C1～C4Alkyl replace silica-based in any one, and R1～R4In at least one be F；R is excellent Choosing represents H, C1～C4Alkyl, C1～C2Alkoxyl, phenyl, formic acid C1～C6Alkyl ester group, C1～C4 alkyl acyl, F, Cl, CF3, any one in CN.
Above-mentioned halogenated aryl hydrocarbon or aromatic yl sulphonate, nickel source, biphosphine ligand, polyfluoro aromatic hydrocarbons, alkyl Grignard reagent or alkyl Lithium, the mol ratio of zinc halide are 1: 0.05～0.2: 0.05～0.2: 1.2～5.0: 1.0～3.0: 1.0～3.0, preferably halo The mol ratio of aromatic hydrocarbons or aromatic yl sulphonate, nickel source, biphosphine ligand, polyfluoro aromatic hydrocarbons, alkyl Grignard reagent or lithium alkylide, zinc halide is 1∶0.08∶0.10∶2.4∶2.0∶2.2。
Above-mentioned zinc halide is any one in zinc chloride, zinc bromide, zinc iodide, and alkyl Grignard reagent is methyl chloride Magnesium, ethylmagnesium chloride, n-pro-pyl magnesium chloride, isopropylmagnesium chloride, methyl-magnesium-bromide, ethylmagnesium bromide, n-pro-pyl magnesium bromide, different Any one in propyl group magnesium bromide, lithium alkylide is any one in lithium methide, n-BuLi, tert-butyl lithium.
Above-mentioned nickel source is preferably double (1,5-cyclo-octadiene) nickel, and Ar preferably represents 3,5-dimethyl-4-methoxyphenyl, Any one in phenyl, 3,4-Dimethoxyphenyl, naphthyl.
Single arylation reaction of polyfluoro aromatic hydrocarbons is split into three steps and carries out by the present invention, and the first step uses alkyl Grignard reagent or alkane Base lithium reagent activation polyfluoro aromatic hydrocarbons obtains corresponding many fluoro aryls azoviolet (i.e. polyfluoro aryl grignard reagent)；Second step adds halogen Change zinc, swap with magnesium salt, generate polyfluoro arylzinc reagent；3rd step in oxolane with common nickel source and biphosphine ligand Between the complex that formed be catalyst, intersect idol between catalysis polyfluoro arylzinc reagent and halogenated aryl hydrocarbon (or aromatic yl sulphonate) Connection (i.e. Negishi cross-coupling reaction), it is achieved under temperate condition, polyfluoro biaryl compounds efficiently synthesizes.The present invention adopts With one pot of strategy of three steps, solve in a mild condition polyfluoro biaryl compounds product structure be difficult to control to, functional group resistance to By the difficult problem that property is bad.
The present invention utilizes New Nickel catalyst system and catalyzing to achieve polyfluoro arenes selectivity list arylation under zinc assists.With existing Technology is compared, and beneficial effects of the present invention is as follows:
1, this method achieve first zincon participate in Negishi coupling prepare polyfluoro biaryl compounds, success Being prepared for structure height controlled polyfluoro this target product of biaryl, productivity is up to more than 85%.
2, the present invention solves the coupling selectivity of the many fluorobenzene (phenyl tetrafluoride, trifluoro-benzene etc.) containing multiple hydrogen of equal value and asks Topic, its single arylated products ratio is up to 99%, and productivity is up to more than 85% simultaneously.
The more weak many fluorobenzene of the hydracids such as 3, the present invention solves trifluoro-benzene, difluorobenzene are difficult to activation and participate in the difficulty of coupling Topic.
4, present invention, avoiding and directly use aryl grignard reagent participation coupling reaction to cause sensitive the asking of substrate functional group Topic, expands the scope of application of substrate.Simultaneous reactions is carried out in oxolane single solvent, simplifies reaction.
5, catalyst of the present invention is the nickel composite being easy to get, and compares palladium catalytic system or the bimetallic catalytic body altogether of costliness System, nickel catalysis low cost, pollute little, there is high economic worth and social value.
6, reaction condition of the present invention is gentle, easy and simple to handle, and reaction is the most at room temperature carried out, and compares existing palladium chtalyst skill Art needs the harsh conditions of high temperature, and the present invention has high IP prospecting.
Accompanying drawing explanation
Below in conjunction with embodiment, the present invention is described in more detail, but protection scope of the present invention is not limited only to these in fact Execute example.
Double (2-bis-(3,5-dimethyl-4-methoxyphenyl) phosphine) phenylate of biphosphine ligand used in example below according to Following method prepares:
1.89g (8.8mmol) 3,5-dimethyl-4-methoxybromobenzene gram and 192mg (8mmol) magnesium powder are placed in 40mL do In dry oxolane, back flow reaction 2 hours, magnesium is wholly absent, and then at-78 DEG C, is slowly dropped to and is dissolved with 372mg (1.0mmol), in the 20mL tetrahydrofuran solution of double (2-dichloride phosphine) phenylates, it is slowly increased to room temperature after dropping, continues to stir Mix 8 hours；Reactant liquor being cooled to-20 DEG C, is slowly added to methanol cancellation reaction, is slowly increased to room temperature after cancellation, reactant liquor is used Saturated aqueous ammonium chloride washs 3 times, and is extracted with ethyl acetate, and merges organic facies, dried with anhydrous sodium sulfate, crosses and filters Go sodium sulfate, filtrate decompression to be evaporated, through silica gel chromatography column chromatography for separation, obtain double (2-bis-(3,5-dimethyl-4-methoxybenzenes Base) phosphine) phenylate, its productivity is 62%, and structural characterization data are:1H NMR(400MHz,CDCl3): δ 7.11 (td, J=7.6, 1.6Hz, 4H), 6.95-6.90 (m, 10H), 6.83 (ddd, J=7.6,4.2,1.6Hz, 2H), 6.52 (dd, J=8.1, 3.5Hz,2H),3.68(s,12H),2.19(s,24H)。
By above-mentioned 3,5-dimethyl-4-methoxybromobenzene is replaced with equimolar 2-bromonaphthalene, i.e. can get structural formula such as Under double (2-bis-(2-naphthyl) phosphine) phenylate of biphosphine ligand:
Its productivity is 55%, and structural characterization data are:1H NMR(600MHz,CDCl3): δ 7.73 (d, J=8.0Hz, 4H), 7.64 (d, J=8.3Hz, 4H), 7.61 (d, J=8.0Hz, 4H), 7.55 (d, J=8.3Hz, 4H), 7.45 (td, J=7.5, 1.1Hz, 4H), 7.41 (td, J=7.5,1.1Hz, 4H), 7.23 (dt, J=7.8,1.4Hz, 2H), 7.15 (t, J=7.0Hz, 4H), 6.92 (t, J=7.2Hz, 2H), 6.87 (dd, J=8.0,4.1Hz, 2H), 6.81 (ddd, J=7.5,4.1,1.5Hz, 2H)。
By above-mentioned 3,5-dimethyl-4-methoxybromobenzene is with equimolar 3, and 4-dimethoxy bromobenzene is replaced, To double (2-bis-(3,4-Dimethoxyphenyl) phosphine) phenylate of the biphosphine ligand that structural formula is following:
Its productivity is 39%, and structural characterization data are:1H NMR(400MHz,CDCl3): δ 7.20 (td, J=7.7, 1.5Hz, 2H), 6.96 (td, J=7.4,0.6Hz, 2H), 6.78-6.71 (m, 16H), 3.86 (s, 12H), 3.72 (s, 12H).
Embodiment 1
2-methyl-5-(2 ', 3 ', 5 ', the 6 '-tetrafluoro phenyl) thiophene that composite structure formula is following
1, under the conditions of anhydrous and oxygen-free, 360mg (2.4mmol) 1,2,4,5-phenyl tetrafluoride is dissolved in 1mL oxolane, so The tetrahydrofuran solution of rear addition 1mL 2mol/L isopropylmagnesium chloride, stirring at normal temperature is reacted 12 hours, is subsequently adding 2.2mL The tetrahydrofuran solution of 1mol/L zinc chloride, room temperature continues stirring 2 hours.
2, under the conditions of anhydrous and oxygen-free, in 1mL oxolane, 20.6g (0.08mmol) double (1,5-cyclo-octadiene) is added Nickel, 53.9mg (0.1mmol) double (2-diphenylphosphine) phenylate, stirring at normal temperature 30 minutes.
3, under the conditions of anhydrous and oxygen-free, step 1 and step 2 gained reactant liquor are mixed, and adds 224mg (1.0mmol) 2-methyl-5-iodothiophen, stirring at normal temperature 12 hours, TLC detection reaction completely, adds 0.5mL methanol and stirs 10 minutes, question response After cancellation completely, reactant liquor 0.1mol/L salt acid elution, and be extracted with ethyl acetate, acetic acid ethyl acetate extract anhydrous slufuric acid Sodium is dried, and evaporated under reduced pressure, then through silica gel chromatography column chromatography for separation, obtains 2-methyl-5-(2 ', 3 ', 5 ', 6 '-phenyl tetrafluoride Base) thiophene, its productivity is 92%, and structural characterization data are: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
4-(2 ', 3 ', 5 ', the 6 '-tetrafluoro phenyl) 1-Phenylethanone. that composite structure formula is following
In the step 2 of embodiment 1, will double (2-diphenylphosphine) phenylates with equimolar pair (2-bis-(3,5-dimethyl- 4-methoxyphenyl) phosphine) phenylate replacement, in step 3, by 2-methyl-5-iodothiophen with equimolar to acetylphenyl three Fluorine methanesulfonates is replaced, and other steps are same as in Example 1, obtain 4-(2 ', 3 ', 5 ', 6 '-tetrafluoro phenyl) 1-Phenylethanone., and it produces Rate is 98%, and structural characterization data are: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 fluoro-1,1 '-biphenyl of 2,3,5,6-tetra-that composite structure formula is following
In the step 2 of embodiment 1, will double (2-diphenylphosphine) phenylates with equimolar pair (2-bis-(3,5-dimethyl- 4-methoxyphenyl) phosphine) phenylate replacement, in step 3,2-methyl-5-iodothiophen is replaced with equimolar iodobenzene, reaction temperature Degree rises to 50 DEG C, and other steps are same as in Example 1, obtain 2, and 3,5,6-tetra-fluoro-1,1 '-biphenyl, its productivity is 85%, structure Sign data are:1H NMR(400MHz,CDCl3): δ 7.54-7.44 (m, 5H), 7.13-7.01 (m, 1H).
Embodiment 4
The following 2-methyl of composite structure formula-2 ', 3 ', 5 ', 6 '-four fluoro-1,1 '-biphenyl
In the step 2 of embodiment 1, will double (2-diphenylphosphine) phenylates with equimolar pair (2-bis-(3,5-dimethyl- 4-methoxyphenyl) phosphine) phenylate replaces, in step 3, by 2-methyl-5-iodothiophen with equimolar o-tolyl fluoroform Sulphonic acid ester is replaced, and reaction temperature rises to 50 DEG C, and other steps are same as in Example 1, obtain 2-methyl-2 ', 3 ', 5 ', 6 '-four Fluoro-1,1 '-biphenyl, its productivity is 87%, and structural characterization data are:1H NMR(400MHz,CDCl3): δ 7.42-7.22 (m, 4H),7.15-7.6(m,1H),2.22(s,1H)。
Embodiment 5
The fluoro-3 '-methoxyl group of 2,3,5,6-tetra--1,1 '-biphenyl that composite structure formula is following
In the step 3 of embodiment 1, by 2-methyl-5-iodothiophen by equimolar m-methoxyphenyl trifluoromethanesulfonic acid Ester is replaced, and other steps are same as in Example 1, obtain 2,3,5,6-tetra-fluoro-3 '-methoxyl group-1,1 '-biphenyl, and its productivity is 87%, structural characterization data are:1H NMR(400MHz,CDCl3): δ 7.41 (t, J=8.0Hz, 2H), 7.09-6.99 (m, 4H), 3.85(s,1H)。
Embodiment 6
The fluoro-4 '-methoxyl group of 2,3,5,6-tetra--1,1 '-biphenyl that composite structure formula is following
In the step 2 of embodiment 1, incite somebody to action equimolar double (2-bis-(3, the 4-dimethoxys of double (2-diphenylphosphine) phenylates Phenyl) phosphine) phenylate replaces, in step 3, by 2-methyl-5-iodothiophen by equimolar p-methoxyphenyl trifluoromethanesulfonic acid Ester is replaced, and reaction temperature rises to 40 DEG C, and other steps are same as in Example 1, obtain 2,3,5,6-tetra-fluoro-4 '-methoxyl group-1, 1 '-biphenyl, its productivity is 85%, and structural characterization data are:1H NMR(400MHz,CDCl3): δ 7.41 (d, J=8.0Hz, 2H), 7.02 (d, J=8.8Hz, 2H), 3.87 (s, 1H).
Embodiment 7
2-(2 ', 3 ', 5 ', the 6 '-tetrafluoro phenyl) naphthalene that composite structure formula is following
In the step 2 of embodiment 1, incite somebody to action equimolar double (2-bis-(2-naphthyl) phosphine) benzene of double (2-diphenylphosphine) phenylates Ether is replaced, and in step 3, is replaced with equimolar 2-iodonaphthalene by 2-methyl-5-iodothiophen, and reaction temperature rises to 50 DEG C, its His step is identical with embodiment 1, obtains 2-(2 ', 3 ', 5 ', 6 '-tetrafluoro phenyl) naphthalene, and productivity is 95%, structural characterization data For:1H NMR (400MHz,CDCl3): δ 7.98-7.90 (m, 4H), 7.60-7.57 (m, 3H), 7.07-7.15 (m, 1H).
Embodiment 8
1-(2 ', 3 ', 5 ', the 6 '-tetrafluoro phenyl) naphthalene that composite structure formula is following
In the step 2 of embodiment 1, will double (2-diphenylphosphine) phenylates with equimolar pair (2-bis-(3,5-dimethyl- 4-methoxyphenyl) phosphine) phenylate replacement, in step 3,2-methyl-5-iodothiophen is replaced with equimolar 2-iodonaphthalene, instead Answering temperature to rise to 50 DEG C, other steps are same as in Example 1, obtain 1-(2 ', 3 ', 5 ', 6 '-tetrafluoro phenyl) naphthalene, and its productivity is 86%, structural characterization data are:1H NMR(400MHz,CDCl3): δ 8.02 (d, J=8.0Hz, 1H), 7.96 (d, J=8.0Hz, 1H),7.62-7.48(m,5H),7.25-7.16(m,1H)。
Embodiment 9
2,3,5,6-tetra-that composite structure formula is following is fluoro-1,1 '-4 ', 1 "-terphenyl
In the step 3 of embodiment 1, by 2-methyl-5-iodothiophen by equimolar 4-phenyl triflate Replacing, reaction temperature rises to 50 DEG C, and other steps are same as in Example 1, obtain 2,3,5,6-tetra-fluoro-1,1 '-4 ', 1 "-three connection Benzene, its productivity is 88%, and structural characterization data are:1H NMR(400MHz,CDCl3): δ 7.75 (d, J=8.4Hz, 2H), 7.67 (d, J=7.2Hz, 2H), 7.57 (d, J=8.0Hz, 2H), 7.45 (t, J=7.6Hz, 2H), 7.41 (t, J=7.2Hz, 1H), 7.13-7.05(m,1H)。
Embodiment 10
Composite structure formula following 2,3,4 ', the fluoro-1,1 '-biphenyl of 5,6-five
In the step 3 of embodiment 1, fluorophenyl triflate is replaced by 2-methyl-5-iodothiophen with equimolar Changing, reaction temperature rises to 40 DEG C, and other steps are same as in Example 1, obtain 2, and 3,4 ', 5,6-five fluoro-1,1 '-biphenyl, it produces Rate is 87%, and structural characterization data are:1H NMR(400MHz,CDCl3): δ 7.47-7.44 (m, 2H), 7.21-7.17 (m, 2H), 7.12-7.03(m,1H)。
Embodiment 11
The fluoro-4 '-Trifluoromethyl-1 of 2,3,5,6-tetra-that composite structure formula is following, 1 '-biphenyl
In the step 3 of embodiment 1, methyl bromobenzene trifluoride is replaced by 2-methyl-5-iodothiophen with equimolar, other Step is same as in Example 1, obtains 2,3,5,6-tetra-fluoro-4 '-Trifluoromethyl-1s, 1 '-biphenyl, and its productivity is 86%, structural table Levying data is: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 12
6-(2 ', 3 ', 5 ', 6 '-tetrafluoro phenyl)-2-naphthonitrile that composite structure formula is following
In the step 3 of embodiment 1, by 2-methyl-5-iodothiophen by equimolar 6-cyano group-2-naphthyl trifluoromethanesulfonic acid Ester is replaced, and other steps are same as in Example 1, obtain 6-(2 ', 3 ', 5 ', 6 '-tetrafluoro phenyl)-2-naphthonitrile, and its productivity is 86%, structural characterization data are:1H NMR(400MHz,CDCl3): δ 8.30 (S, 1H) 8.04-7.98 (m, 3H), 7.69 (d, J= 8.0Hz,2H),7.20-7.11(m,1H)。
Embodiment 13
4-(2 ', 3 ', 5 ', 6 '-tetrafluoro phenyl)-ethyl benzoate that composite structure formula is following
In the step 3 of embodiment 1, by 2-methyl-5-iodothiophen with equimolar to carbethoxy phenyl fluoroform sulphur Acid esters is replaced, and other steps are same as in Example 1, obtain 4-(2 ', 3 ', 5 ', 6 '-tetrafluoro phenyl)-ethyl benzoate, its productivity Being 93%, structural characterization data are: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 14
2-(2 ', 3 ', 4 ', the 6 '-tetrafluoro phenyl) naphthalene that composite structure formula is following
In the step 1 of embodiment 1, by 1,2,4,5-phenyl tetrafluorides are replaced, in step with equimolar 1,2,3,5-phenyl tetrafluorides In rapid 3,2-methyl-5-iodothiophen is replaced by equimolar 2-naphthyl triflate, other steps and embodiment 1 phase With, obtaining 2-(2 ', 3 ', 4 ', 6 '-tetrafluoro phenyl) naphthalene, its productivity is 96%, and structural characterization data are:1H NMR(400MHz, CDCl3): δ 7.95-7.89 (m, 4H), 7.57-7.50 (m, 3H), 6.95-6.88 (m, 1H).
Embodiment 15
2-that composite structure formula is following (4 '-methoxyl group-2 ', 3 ', 5 ', 6 '-tetrafluoro phenyl) naphthalene
In the step 1 of embodiment 1, by 2.4mmol 1,2,4,5-phenyl tetrafluorides with equimolar 3-methoxyl group-1,2,4, 5-phenyl tetrafluoride is replaced, and in step 3, is replaced by equimolar 2-naphthyl triflate by 2-methyl-5-iodothiophen, other Step is same as in Example 1, obtains 2-(4 '-methoxyl group-2 ', 3 ', 5 ', 6 '-tetrafluoro phenyl) naphthalene, and its productivity is 88%, structure Sign data are:1H NMR(400MHz,CDCl3): δ 7.96-7.89 (m, 4H), 7.58-7.51 (m, 3H), 4.15 (s, 3H).
Embodiment 16
2-that composite structure formula is following (4 '-methyl-2 ', 3 ', 5 ', 6 '-tetrafluoro phenyl) naphthalene
In the step 1 of embodiment 1, by 2.4mmol 1,2,4,5-phenyl tetrafluorides with equimolar 3-methyl isophthalic acid, 2,4,5- Phenyl tetrafluoride is replaced, and in step 3, is replaced by equimolar 2-naphthyl triflate by 2-methyl-5-iodothiophen, other steps The most same as in Example 1, obtain 2-(4 '-methyl-2 ', 3 ', 5 ', 6 '-tetrafluoro phenyl) naphthalene, its productivity is 98%, structural characterization Data are:1H NMR(400MHz,CDCl3): δ 7.96-7.89 (m, 4H), 7.56-7.53 (m, 3H), 2.35 (s, 3H).
Embodiment 17
2-that composite structure formula is following (4 '-methoxy-2 ', 3 ', 5 ', 6 '-tetrafluoro phenyl) naphthalene
In the step 1 of embodiment 1, by 1,2,4,5-phenyl tetrafluorides with equimolar to methoxymethylphenyl fluoroform sulphur Acid esters is replaced, and in step 3, is replaced by equimolar 2-naphthyl triflate by 2-methyl-5-iodothiophen, other steps Same as in Example 1, obtain 2-(4 '-methoxy-2 ', 3 ', 5 ', 6 '-tetrafluoro phenyl) naphthalene, its productivity is 87%, structure Sign data are:1H NMR(400MHz,CDCl3): δ 7.97-7.89 (m, 4H), 7.59-7.53 (m, 3H), 4.66 (s, 2H), 3.46(s,3H)。
Embodiment 18
2-that composite structure formula is following (4 '-benzyl-2 ', 3 ', 5 ', 6 '-tetrafluoro phenyl) naphthalene
In the step 1 of embodiment 1, by 1, benzyl phenyl triflate is replaced by 2,4,5-phenyl tetrafluorides with equimolar Change, in step 3,2-methyl-5-iodothiophen is replaced by equimolar 2-naphthyl triflate, other steps and enforcement Example 1 is identical, obtains 2-(4 '-benzyl-2 ', 3 ', 5 ', 6 '-tetrafluoro phenyl) naphthalene, and its productivity is 85%, and structural characterization data are:1H NMR(400MHz,CDCl3): δ 7.95-7.88 (m, 4H), 7.56-7.52 (m, 3H), 7.35-7.26 (m, 5H), 4.16 (s, 2H)。
Embodiment 19
2-(2 ', 4 ', the 5 '-trifluorophenyl) naphthalene that composite structure formula is following
In the step 1 of embodiment 1, by the 1 of 2.4mmol, 1,3, the 5-phenyl tetrafluorides of 2,4,5-phenyl tetrafluoride 3.0mmol replace Changing, isopropylmagnesium chloride is replaced with equimolar ethylmagnesium chloride, and reaction temperature rises to 50 DEG C, in step 3, by 2-methyl- 5-iodothiophen is replaced by equimolar 2-naphthyl triflate, and other steps are same as in Example 1, obtain 2-(2 ', 4 ', 5 '-trifluorophenyl) naphthalene, its productivity is 89%, and structural characterization data are:1H NMR(400MHz,CDCl3): δ 7.96-7.89 (m, 4H),7.56-7.52(m,3H),6.84-6.80(m,1H)。
Embodiment 20
2-that composite structure formula is following (4 '-bis-methyl tertbutyls silica-based-2 ', 3 ', 5 ', 6 '-tetrafluoro phenyl) naphthalene
In the step 1 of embodiment 1, by 1,2,4, the 5-phenyl tetrafluorides double methyl tertbutyl silica-based-2,3 of equimolar 4-, 5,6-phenyl tetrafluorides are replaced, and in step 3, are replaced by equimolar 2-naphthyl triflate by 2-methyl-5-iodothiophen, Other steps are same as in Example 1, obtain 2-(4 '-bis-methyl tertbutyls silica-based-2 ', 3 ', 5 ', 6 '-tetrafluoro phenyl) naphthalene, and it produces Rate is 85%, and structural characterization data are:1H NMR(400MHz,CDCl3): δ 8.00-7.87 (m, 4H), 7.58-7.50 (m, 3H), 0.99(s,9H),0.44(s,6H)。
Embodiment 21
2-that composite structure formula is following (4 '-cinnamyl-2 ', 3 ', 5 ', 6 '-tetrafluoro phenyl) naphthalene
In the step 1 of embodiment 1, by 1,2,4,5-phenyl tetrafluorides equimolar 4-cinnamyl-2,3,5,6-phenyl tetrafluorides replace Change；In step 3, being replaced by equimolar 2-naphthyl triflate by 2-methyl-5-iodothiophen, reaction temperature rises to 40 DEG C, other steps are same as in Example 1, obtain 2-(4 '-cinnamyl-2 ', 3 ', 5 ', 6 '-tetrafluoro phenyl) naphthalene, and its productivity is 81%, structural characterization data are:1H NMR(600MHz,CDCl3): δ 7.98-7.95 (m, 2H), 7.93 (d, J=8.3Hz, 2H), 7.56-7.55 (m, 3H), 7.38 (d, J=7.6Hz, 2H), 7.32 (t, J=7.6Hz, 2H), 7.24 (t, J=7.3Hz, 1H), 6.57 (d, J=15.8Hz, 1H), 6.33 (dt, J=15.8,6.7Hz, 1H), 3.71 (d, J=6.7Hz, 2H).
Embodiment 22
2-(2 ', the 6-difluorophenyl) naphthalene that composite structure formula is following
1, under anhydrous and oxygen-free, by 342mg (3.0mmol) 1,3-difluorobenzene is dissolved in 1mL oxolane, the most slowly adds Entering the hexane solution of 0.8mL 2.5mol/L n-BuLi ,-20 DEG C of stirrings are reacted 6 hours, are then slowly added into 2.2mL 1mol/ The tetrahydrofuran solution of L zinc chloride, is slowly increased to room temperature, continues stirring 2 hours.
2, under the conditions of anhydrous and oxygen-free, in 1mL oxolane, 20.6g (0.08mmol) double (1,5-cyclo-octadiene) is added Nickel, 53.9mg (0.1mmol) double (2-diphenylphosphine) phenylate, stirring at normal temperature 30 minutes.
3, under the conditions of anhydrous and oxygen-free, step 1 and step 2 gained reactant liquor are mixed, and adds 276mg (1.0mmol) 2-naphthyl triflate, stirring at normal temperature 12 hours, TLC detection reaction completely, adds 0.5mL methanol and stirs 10 minutes, treat After reaction cancellation completely, reactant liquor 0.1mol/L salt acid elution, and be extracted with ethyl acetate, acetic acid ethyl acetate extract nothing Aqueous sodium persulfate is dried, and evaporated under reduced pressure, then through silica gel chromatography column chromatography for separation, obtains 2-(2 ', 6-difluorophenyl) naphthalene, and it produces Rate is 83%, and structural characterization data are: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).
Double (1,5-cyclo-octadiene) nickel in above-described embodiment also can be with equimolar nickel acetate, trifluoracetic acid nickel, acetyl Acetone nickel, trifluoromethanesulfonic acid nickel, Nickel dichloride., nickelous bromide, glycol dimethyl ether Nickel dichloride., glycol dimethyl ether nickelous bromide are replaced； Biphosphine ligand also can be replaced, the most such as with other biphosphine ligands of equimolar: double (2-bis-(3,4-Dimethoxyphenyl) phosphine) phenylate, Double (2-bis-(3,5-3,5-dimethylphenyl) phosphine) phenylates etc., isopropylmagnesium chloride also can be with equimolar methyl-magnesium-chloride, ethyl chloride Change magnesium, n-pro-pyl magnesium chloride, methyl-magnesium-bromide, ethylmagnesium bromide, n-pro-pyl magnesium bromide or isopropyl magnesium bromide to replace, zinc chloride Also can replace with equimolar zinc bromide or zinc iodide, n-BuLi also can be replaced, all by equimolar lithium methide or tert-butyl lithium The purpose of the present invention can be realized, obtain the products collection efficiency close with above-described embodiment.

Claims (9)

1. the method that polyfluoro biaryl compounds is prepared in a Negishi coupling, it is characterised in that it comprises the steps:
(1) under the conditions of anhydrous and oxygen-free, with oxolane as solvent, by the polyfluoro aromatic hydrocarbons shown in Formulas I with alkyl Grignard reagent 0 ～stir 2～18 hours at 50 DEG C or the polyfluoro aromatic hydrocarbons shown in Formulas I and lithium alkylide are stirred 2～18 hours at-20～0 DEG C, It is subsequently adding zinc halide, stirring at normal temperature 1～2 hours；
(2) under the conditions of anhydrous and oxygen-free, nickel source, biphosphine ligand are added in oxolane, stirring at normal temperature 30 minutes；Wherein said Nickel source be double (1,5-cyclo-octadiene) nickel, nickel acetate, trifluoracetic acid nickel, nickel acetylacetonate, trifluoromethanesulfonic acid nickel, Nickel dichloride., Any one in nickelous bromide, glycol dimethyl ether Nickel dichloride., glycol dimethyl ether nickelous bromide；The structure of described biphosphine ligand Formula is as follows:
In formula, Ar represents phenyl, C1～C6Alkyl-substituted phenyl, C1～C6Alkoxy substituted phenyl, difluorophenyl, trifluoromethylbenzene Any one in base, naphthyl, furyl, siloxy phenyl；
(3) under the conditions of anhydrous and oxygen-free, step (1) and (2) gained reactant liquor are mixed, and adds the halogenated aryl hydrocarbon shown in Formula II Or aromatic yl sulphonate, at 0～50 DEG C after stirring extremely reaction completely, add methanol cancellation reaction, isolated and purified product, obtain formula Polyfluoro biaryl compounds shown in III；
In above-mentioned Formulas I～III, R1～R4The most independent representative H, F, C1～C10Alkyl, C1～C6Alkoxyl, phenyl, C1～C6 Alkyl-substituted phenyl, C1～C4In alkoxy substituted phenyl, pi-allyl, cinnamyl, trifluoromethyl, benzyl, silica-based, siloxy Any one, and R1～R4In at least one be that F, R represent H, C1～C10Alkyl, C1～C6Alkoxyl, phenyl, C1～C6Alkyl Substituted-phenyl, C1～C4Alkoxy substituted phenyl, ester group, F, Cl, CF3, any one in CN, X represent Br, I orR ' represents CF3、CH3Or p-CH3-C6H4, Y represents C, O, N or S, and when Y represents C, Z=1, n=1 or 2, Y represents During N, Z=1 or 0, n=1 or 2, when Y represents O, S, Z=0, n=1 or 2.
The method that polyfluoro biaryl compounds is prepared in Negishi coupling the most according to claim 1, it is characterised in that: Described R1～R4The most independent representative H, F, C1～C6Alkyl, C1～C4Alkoxyl, phenyl, pi-allyl, cinnamyl, fluoroform Base, benzyl, C1～C4Alkyl replace silica-based in any one, and R1～R4In at least one be F.
The method that polyfluoro biaryl compounds is prepared in Negishi coupling the most according to claim 1, it is characterised in that: Described R represents H, C1～C4Alkyl, C1～C2Alkoxyl, phenyl, formic acid C1～C6Alkyl ester group, C1～C4 alkyl acyl, F, Cl、CF3, any one in CN.
4. the method preparing polyfluoro biaryl compounds according to the Negishi coupling described in claims 1 to 3 any one, It is characterized in that: described halogenated aryl hydrocarbon or aromatic yl sulphonate, nickel source, biphosphine ligand, polyfluoro aromatic hydrocarbons, alkyl Grignard reagent or alkane Base lithium, the mol ratio of zinc halide are 1:0.05～0.2:0.05～0.2:1.2～5.0:1.0～3.0:1.0～3.0.
5. the method preparing polyfluoro biaryl compounds according to the Negishi coupling described in claims 1 to 3 any one, It is characterized in that: described halogenated aryl hydrocarbon or aromatic yl sulphonate, nickel source, biphosphine ligand, polyfluoro aromatic hydrocarbons, alkyl Grignard reagent or alkane Base lithium, the mol ratio of zinc halide are 1:0.08:0.10:2.4:2.0:2.2.
The method that polyfluoro biaryl compounds is prepared in Negishi coupling the most according to claim 1, it is characterised in that: Described zinc halide is any one in zinc chloride, zinc bromide, zinc iodide.
The method that polyfluoro biaryl compounds is prepared in Negishi coupling the most according to claim 1, it is characterised in that: Described alkyl Grignard reagent is methyl-magnesium-chloride, ethylmagnesium chloride, n-pro-pyl magnesium chloride, isopropylmagnesium chloride, methyl bromide Any one in magnesium, ethylmagnesium bromide, n-pro-pyl magnesium bromide, isopropyl magnesium bromide.
The method that polyfluoro biaryl compounds is prepared in Negishi coupling the most according to claim 1, it is characterised in that: Described lithium alkylide is any one in lithium methide, n-BuLi, tert-butyl lithium.
The method that polyfluoro biaryl compounds is prepared in Negishi coupling the most according to claim 1, it is characterised in that: Described nickel source is double (1,5-cyclo-octadiene) nickel, and Ar represents 3,5-dimethyl-4-methoxyphenyl, phenyl, 3,4-dimethoxy Any one in base phenyl, naphthyl.
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