CN116102584A - 3, 3-gem difluoro allyl compound, preparation method and application thereof - Google Patents

3, 3-gem difluoro allyl compound, preparation method and application thereof Download PDF

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Publication number
CN116102584A
CN116102584A CN202211091590.4A CN202211091590A CN116102584A CN 116102584 A CN116102584 A CN 116102584A CN 202211091590 A CN202211091590 A CN 202211091590A CN 116102584 A CN116102584 A CN 116102584A
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formula
substituted
compound
alkyl
difluoroallyl
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张新刚
饶娜
闵巧桥
张大伟
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Shanghai Institute of Organic Chemistry of CAS
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

The invention discloses a 3, 3-gem difluoroallyl compound, a preparation method and application thereof. The invention provides a 3, 3-gem difluoro allyl borane, silane or stannane compound shown in a formula A; the invention provides a 3, 3-gem difluoro allyl borane, silane or stannane compound which can be highThe method for effectively preparing various difluoroalkyl compounds with various structures has very wide application prospect in medicines, pesticides and materials.

Description

3, 3-gem difluoro allyl compound, preparation method and application thereof
Technical Field
The invention relates to a 3, 3-gem difluoro allyl compound, a preparation method and application thereof; in particular to 3, 3-gem difluoro alkene compound-based borane, silane or stannane compound, a preparation method and application thereof.
Background
The alpha-aryl, heteroaryl, alkenyl, alkynyl, alkyl-alpha, alpha-difluoroallyl structural compound and the derivative building blocks thereof have wide application in the aspects of biological medicine, pesticide, material science and the like. For example: some important fluorine-containing drugs KAG-308, glecarprevir, taflupirest, etc. contain an alpha, alpha-difluoroallyl structure.
However, conventional methods of synthesizing α -aryl, heteroaryl, alkenyl, alkynyl, alkyl- α, α -difluoroalkyl blocks are generally made from carbonyl groups by DAST or Deoxofluor (e.g., markovsi, l.n.; pahinnik, v.e.; kirsanov, a.v. synthesis 1973,787. (b) Middleton, w.j.j. Org. chem.1975,40,574. (c) Lal, g.s.; pez, g.p.; pesarei, r.j.; prozonic, f.m.; cheng, h.j. Org. Chem.1999,64,7048.). However, these methods generally have disadvantages such as lengthy reaction steps, poor functional group compatibility, and the necessity of using highly toxic fluorinating agents for some reactions.
The block synthesis of transition metal catalyzed α -aryl, heteroaryl or alkenyl- α, α -difluoroalkyl structural compounds and derivatives thereof developed in the last two decades ((a) schwanebe, m.k., mcCarthy, j.r., whitten, j.p. tetrahedron lett.2000,41,791 (b) Feng, z., chen, f., zhang, x.org. lett.2012,14,1938 (c) Belhomme, m. -c., poisson, t., pannecke, x.org. lett.2013,15,3428 (d) Taguchi, t., kitagawa, o, morikawa, t., uihara, h., endo, h. koyashison, y. Let.35, tm., 35, tm, 35, 6, tm, 35, d, tm, 35, d, d., of the same kind of compounds were synthesized by the compounds. However, these methods still exist such as: the compatibility of the functional group is poor, the catalyst usage is high, the reaction condition is harsh, and the like.
In 2014, the palladium-catalyzed coupling reaction of nucleophiles with electrophilic α -bromo- α, α -difluoroallyl reagents (j.am.chem. Soc.2014,136,1230; ZL 2013 1 0658890.0) simplified the synthesis of α -aryl, heteroaryl, alkenyl- α, α -difluoroallyl structures, but the reaction still had the following limitations: 1. the structural diversity of the product is still to be further broken through under the restriction of synthesis of the alpha-bromo-alpha, alpha-difluoroallyl reagent; 2 some arylboronic acid nucleophilic reagents need to be prepared in advance, which is not beneficial to the mass preparation of the structure; 3 the compatibility of the reaction to most aryl boric acid nucleophilic reagents of heterocycles is poor, and the synthesis requirement of various alpha-heterocycles-alpha, alpha-difluoroallyls structures is difficult to meet.
For the reactions of alpha, alpha-difluoroallylation in which nucleophiles participate, other types of alpha, alpha-difluoroallylic reagents (Synlett.1996, 4,371; chem.Pharm. Bull.1985,33 (11), 5137), the preparation process is often cumbersome, and the reactions involved tend to be regioselective, difficult to control, defluorinated side reactions occur, harsh reaction conditions, limited reaction substrates and types, etc., making it difficult to achieve broad-spectrum, efficient preparation of the desired product structure, especially for heterocyclic aromatic nucleophiles.
On the other hand, 3-gem-difluoroalkenylboranes, silanes or stannanes as nucleophilic alpha, alpha-gem-difluoroallylation can likewise be coupled with widely available electrophiles of the aryl halide type in the presence of a catalyst (chem.Commun.2019, 55,3705-3708; angew.chem., int.ed.,2018,57,7196). However, the conventional preparation process of 3, 3-difluoro alkenyl borane, silane or stannane compounds has the problems of difficult acquisition of raw materials, high catalyst dosage (5% -100%), expensive ligand, difficult mass preparation or acquisition and the like, so that the large-scale preparation and wide application of the reagent are limited.
Therefore, a new method for preparing 3, 3-gem difluoro alkenyl borane, silane or stannane compounds as nucleophilic alpha, alpha-gem difluoro allylation test by using cheap fluorine-containing industrial raw materials through a high-efficiency, simple and low-cost method is developed, and the reagent is applied to the application of synthesizing alpha-heterocycle-alpha, alpha-gem difluoro allylation compounds in a broader spectrum and high efficiency, thereby having remarkable significance.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects of larger structural limitation, low reaction activity controllability, limited substrate applicability and the like of the alpha, alpha-gem-difluoroallylation reagent in the prior alpha, alpha-gem-difluoroallylation reaction. The invention aims to provide 3, 3-gem difluoro alkenyl borane, silane or stannane compounds which are used as nucleophilic alpha, alpha-gem difluoro allylation tests, and various difluoro alkyl compounds with various structures can be efficiently prepared.
The invention solves the technical problems through the following technical proposal.
The invention also provides a preparation method of the 3, 3-difluoroallyl compound shown in the formula F, which comprises the following steps: in an organic solvent, in the presence of alkali and a copper catalyst, carrying out the following reaction between a compound shown in a formula A and a compound shown in a formula B to obtain a 3, 3-gem-difluoroallyl compound shown in a formula F; the organic solvent is a mixture of one or more of halogenated aromatic hydrocarbon solvents, ether solvents and ester solvents and amide solvents;
Figure BDA0003837221440000031
wherein R and R' are
Figure BDA0003837221440000032
R 'and R' are H, C 1 -C 20 Is or are R a Substitution C 1 -C 20 Alkyl, 5-7 membered heterocycloalkyl, or by one or more R b Substituted 5-7 membered heterocycloalkyl, C 1 -C 20 Is/are R c Substituted C 1 -C 20 alkyl-O-, C 6 -C 20 Is or are R d Substituted C 6 -C 20 Is aryl, 5-14 membered heteroaryl, substituted with one or more R e The heteroatoms in the substituted 5-14 membered heteroaryl, the 5-7 membered heterocycloalkyl, and the 5-14 membered heteroaryl are independently selected from one or more of N, O and S;
z is Si or Sn;
R 1 and R is 1’ H, C independently 1 -C 20 Is or are R a Substituted C 1 -C 20 Alkyl of (a);
alternatively, R 1 And R is 1’ Connected to and connected to
Figure BDA0003837221440000041
Together form: 5-7 membered heterocycloalkyl, or by one or more R b Substituted 5-7 membered heterocycloalkyl; wherein the hetero atoms of the 5-7 membered heterocycloalkyl are B and O;
R 2 、R 3 and R is 4 Independently is halogen, C 1 -C 20 Is or are R c Substituted C 1 -C 20 Alkyl, C of (2) 1 -C 20 Is/are R d Substituted C 1 -C 20 alkyl-O-, C 6 -C 20 Is or are R e Substituted C 6 -C 20 Aryl of (a);
alternatively, R 2 、R 3 And R is 4 Any 2 of which are linked together with the linked Z to form: 5-7 membered heterocycloalkyl, or by one or more R f Substituted 5-7 membered heterocycloalkyl; wherein the hetero atom of the 5-7 membered heterocycloalkyl group is Si or Sn;
R a 、R b 、R c 、R d 、R e and R is f Independently is halogen, C 1 -C 20 Alkyl, C of (2) 1 -C 20 alkyl-O-C (=o) -, C 1 -C 20 alkyl-O-or C 6 -C 20 When C is aryl 6 -C 20 Is singly linked or is connected with the 5-7 membered heterocyclic alkyl in a parallel ring.
In certain preferred embodiments of the present invention, certain groups in the 3, 3-difluoroallyl compounds of formula F are defined below, and the groups not mentioned are as described in any of the embodiments of the present application (hereinafter referred to as "in certain embodiments of the present invention"), the preparation process is as follows,
Figure BDA0003837221440000042
Wherein,,
r is
Figure BDA0003837221440000043
Z is Si or Sn;
R 1 and R is 1’ H, C independently 1 -C 20 Is or are R a Substituted C 1 -C 20 Alkyl of (a);
alternatively, R 1 And R is 1’ Connected to and connected to
Figure BDA0003837221440000044
Together form: 5-7 membered heterocycloalkyl, or by one or more R b Substituted 5-7 membered heterocycloalkyl; wherein the hetero atoms of the 5-7 membered heterocycloalkyl are B and O;
R 2 、R 3 and R is 4 Independently is halogen, C 1 -C 20 Is or are R c Substituted C 1 -C 20 Alkyl, C of (2) 1 -C 20 Is one or more of alkyl-O-, andr is a number of d Substituted C 1 -C 20 alkyl-O-, C 6 -C 20 Is or are R e Substituted C 6 -C 20 Aryl of (a);
alternatively, R 2 、R 3 And R is 4 Any 2 of which are linked together with the linked Z to form: 5-7 membered heterocycloalkyl, or by one or more R f Substituted 5-7 membered heterocycloalkyl; wherein the heteroatom of the 5-7 membered heterocycloalkyl is Si or Sn;
R a 、R b 、R c 、R d and R is f Independently is halogen, C 1 -C 20 Alkyl, C of (2) 1 -C 20 alkyl-O-C (=o) -or C 6 -C 20 When C is aryl 6 -C 20 Is singly linked or is connected with the 5-7 membered heterocyclic alkyl in a parallel ring.
In one embodiment of the invention, R e Is halogen, C 1 -C 20 Alkyl, C of (2) 1 -C 20 alkyl-O-C (=o) -, C 1 -C 20 alkyl-O-or C 6 -C 20 When C is aryl 6 -C 20 Is singly linked or is connected with the 5-7 membered heterocyclic alkyl in a parallel ring.
In one embodiment of the invention, R and R' are defined as the same.
Wherein the ester solvent can be ethyl acetate; the halogenated aromatic solvent can be chlorobenzene or fluorobenzene; the ether solvent can be one or more of diethylene glycol dimethyl ether DME, dioxane and tetrahydrofuran THF; the amide solvent can be one or more of dimethylacetamide DMA, N-dimethylformamide DMF, N-methylpyrrolidone NMP and N, N-dimethylpropenyl urea DMPU; preferably tetrahydrofuran, diethylene glycol dimethyl ether, dioxane, ethyl acetate or chlorobenzene, and dimethylacetamide. The volume ratio of the total volume of one or more of the halogenated aromatic solvents, ether solvents, and ester solvents to the amide solvents in the mixture may be from 100:1 to 1:100, such as 7.2:1, 3.2:1, 2.4:1, 2:1, 1.6:1, 1:1, 1:1.25, 1:2.5.
The amount of the organic solvent is not particularly limited so as not to affect the reaction; in the present invention, the mass volume ratio of the compound represented by the formula A to the organic solvent is preferably 0.01mol/L to 2mol/L (for example, 0.15mol/L to 1 mol/L).
The molar ratio of the compound shown in the formula A to the compound shown in the formula B can be 1:1.5 to 2:1; for example 1.5:1 to 2:1.
The compounds of formula A may be added using conventional solutions, for example in dimethylacetamide DMA solutions, and for example 1.2M in DMA. Alternatively, the compound shown in the formula A can be added in a gaseous form and reacted; the gas pressure may be 1atm.
The alkali can be alcohol alkali metal alkali or alkali metal hydroxide; such as one or more of sodium hydroxide, potassium hydroxide, lithium t-butoxide, sodium t-butoxide, potassium t-butoxide, sodium methoxide, potassium methoxide, and lithium methoxide; preferably one or more of lithium t-butoxide, potassium methoxide and lithium methoxide.
The molar ratio of the base to the compound of formula a may be 1.5:1 to 3:1; for example 2:1 to 2.5:1.
The copper catalyst may be a copper salt catalyst, such as cuprous halide, and also such as cuprous chloride.
The molar ratio of the copper catalyst to the compound of formula a may be from 0.00001:1 to 0.1:1; for example 0.00001:1, 0.0001:1, 0.0002:1, 0.001, 0.01:1, 0.05:1; the amount can be significantly reduced as the scale of the reaction is increased.
Preferably, the reaction is carried out under an inert atmosphere, which may be argon or nitrogen.
The reaction may also be carried out in the presence of a ligand which may be selected from: 1, 3-bis (diphenylphosphine) propane dppp, 1-bis (diphenylphosphine) ethane dppe, 1-bis (diphenylphosphine) methane dppm, bis (2-diphenylphosphine phenyl) ether DPEphos, (R) - (+) -DM- (i.e., (R) - (+) -DM-SegPhos), bpy, 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene Xantphos
Figure BDA0003837221440000061
One or more of the following; preferably (R) - (+) -DM- (i.e., (R) - (+) -DM-SegPhos), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthenes Xantphos.
The molar ratio of the ligand to the compound of formula a may be 1.5:1 to 3:1; for example 2:1 to 2.5:1.
In one scheme of the preparation method, the reaction raw materials comprise the alkali, a copper catalyst, a compound shown as a formula A, a compound shown as a formula B and the organic solvent.
In one scheme of the preparation method, the reaction raw materials comprise the alkali, a copper catalyst, a compound shown as a formula A, a compound shown as a formula B, the ligand and the organic solvent.
The temperature of the reaction may be 10 to 80 ℃; for example 10 to 35 ℃.
The progress of the reaction may be monitored by conventional monitoring methods in the art (e.g., TLC or NMR), typically at the end of the reaction when the compound of formula a is lost or no longer reacted.
In one embodiment of the invention, R ", R'", R 1 、R 1’ 、R 2 、R 3 、R 4 、R a 、R b 、R c 、R d 、R e And R is f In (C) 1 -C 20 Alkyl, substituted C 1 -C 20 C in the alkyl group of (2) 1 -C 20 The alkyl groups of (a) are independently C 1 -C 10 Alkyl radicals of (2), e.g. C 1 -C 6 Also, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In one embodiment of the invention, R e In R 'and R', C is as described 1 -C 20 Alkyl, substituted C 1 -C 20 C in the alkyl group of (2) 1 -C 20 The alkyl groups of (a) are independently C 1 -C 10 Alkyl radicals of (2), e.g. C 1 -C 6 Also, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In one embodiment of the invention, R 1 、R 1’ 、R 2 、R 3 、R 4 、R a 、R b 、R c 、R d And R is f In (C) 1 -C 20 Alkyl, substituted C 1 -C 20 C in the alkyl group of (2) 1 -C 20 The alkyl groups of (a) are independently C 1 -C 10 Alkyl radicals of (2), e.g. C 1 -C 6 Also, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In one embodiment of the invention, R e In R 'and R', C is as described 1 -C 20 alkyl-O-, substituted C 1 -C 20 C in alkyl-O-of (C) 1 -C 20 The alkyl groups of (a) are independently C 1 -C 10 Alkyl radicals of (2), e.g. C 1 -C 6 Also, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In one embodiment of the invention, R 2 、R 3 、R 4 、R a 、R b 、R c 、R d And R is f In (C) 1 -C 20 alkyl-O-, substituted C 1 -C 20 C in alkyl-O-of (C) 1 -C 20 The alkyl groups of (a) are independently C 1 -C 10 Alkyl radicals of (2), e.g. C 1 -C 6 Also, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In one embodiment of the invention, R e Wherein the halogen is F, cl or Br.
In one embodiment of the invention, R 2 、R 3 、R 4 、R a 、R b 、R c 、R d And R is f Wherein the halogen isF、Cl、Br。
In one embodiment of the invention, R 1 And R is 1’ Connected to and connected to
Figure BDA0003837221440000081
Together form: 5-7 membered heterocycloalkyl, or by one or more R b In the substituted 5-7 membered heterocycloalkyl, the 5-7 membered heterocycloalkyl is
Figure BDA0003837221440000082
In one embodiment of the invention, R ", R'", R 2 、R 3 、R 4 、R a 、R b 、R c 、R d And R is f In (C) 6 -C 20 Aryl, substituted C 6 -C 20 C in aryl of (C) 6 -C 20 Is independently phenyl.
In one embodiment of the invention, R e In R 'and R', C is as described 6 -C 20 Aryl, substituted C 6 -C 20 C in aryl of (C) 6 -C 20 Is independently phenyl.
In one embodiment of the invention, R 2 、R 3 、R 4 、R a 、R b 、R c 、R d And R is f In (C) 6 -C 20 Aryl, substituted C 6 -C 20 C in aryl of (C) 6 -C 20 Is independently phenyl.
In one embodiment of the invention, R 2 、R 3 、R 4 、R a 、R b 、R c 、R d 、R e And R is f Independently H, cl, methyl, ethyl, n-butyl, methyl-O-, me-O-C (=o) -or phenyl.
In one embodiment of the invention, R 2 、R 3 And R is 4 Independently Cl, methyl, ethyl, phenyl, methyl-O-, n-butyl.
In one embodiment of the invention, R 'and R' are independently H, phenyl,
Figure BDA0003837221440000083
Figure BDA0003837221440000084
In one embodiment of the invention, R' "is independently H or
Figure BDA0003837221440000085
In one embodiment of the invention, R a Independently phenyl.
In one embodiment of the invention, R b Independently H, methyl, me-O-C (=o) -or phenyl.
In one embodiment of the invention, R d Is independently H, cl, methoxy or-COOMe.
In one embodiment of the invention, R and R' are
Figure BDA0003837221440000091
Figure BDA0003837221440000092
In one embodiment of the present invention, the 3, 3-difluoroallyl compound represented by formula F has any one of the following structures:
Figure BDA0003837221440000093
the invention provides a 3, 3-difluoroallyl compound, which has any one of the following structures:
Figure BDA0003837221440000094
/>
Figure BDA0003837221440000101
the invention also provides an application of the 3, 3-difluoroallyl compound shown in the formula F, wherein the 3, 3-difluoroallyl compound shown in the formula F is used as an alpha, alpha-gem difluoroallylation reagent,
Figure BDA0003837221440000102
Wherein R, R "and R'" are as defined above.
In one scheme, the 3, 3-difluoroallyl compound shown as the formula F is
Figure BDA0003837221440000103
Wherein R and R' are as defined above.
In one scheme, the 3, 3-difluoroallyl compound shown as the formula F is
Figure BDA0003837221440000104
Wherein R is defined as above.
In one aspect, the application may be: taking the 3, 3-difluoroallyl compound shown as a formula F as an alpha, alpha-gem difluoroallylation reagent, and carrying out suzuki coupling reaction (suzuki reaction) with halogenated aromatic hydrocarbon or halogenated heteroaromatic hydrocarbon compound to prepare alpha, alpha-gem difluoroallyl substituted aromatic hydrocarbon or heteroaromatic hydrocarbon compound;
for example, it comprises the steps of:
in an organic solvent, in the presence of a catalyst and alkali, carrying out a suzuki coupling reaction (suzuki reaction) on a 3, 3-difluoroallyl compound shown as a formula F and a halogenated aromatic hydrocarbon or halogenated heteroaromatic hydrocarbon compound to prepare the alpha, alpha-gem difluoroallyl substituted aromatic hydrocarbon or heteroaromatic hydrocarbon compound.
The suzuki coupling reaction formula is as follows:
Figure BDA0003837221440000111
preferably is
Figure BDA0003837221440000112
More preferably
Figure BDA0003837221440000113
Wherein R, R "and R'" are as defined above;
X is halogen in the halogenated aromatic hydrocarbon or halogenated heteroaromatic hydrocarbon compound, and the alpha, alpha-gem difluoroallyl substituted aromatic hydrocarbon or heteroaromatic hydrocarbon compound contains fragments shown in a formula III.
Wherein, the mol ratio of the 3, 3-difluoroallyl compound shown in the formula F to the halogenated aromatic or heteroaromatic compound can be 1.5:1 to 1:1.5.
The solvent can be one or more of ether solvents, amide solvents, nitrile solvents, halogenated aromatic solvents and ester solvents; for example, one or more of an ether solvent, a halogenated aromatic hydrocarbon solvent and an ester solvent; the ether solvent can be dioxane, tetrahydrofuran or ethylene glycol dimethyl ether DME; such as dioxane, ethylene glycol dimethyl ether; the amide solvent can be one or more of N, N-dimethylformamide and N, N-dimethylacetamide; the nitrile solvent can be acetonitrile; the halogenated aromatic solvent can be chlorobenzene; the ester solvent may be ethyl acetate.
The amount of the organic solvent is not particularly limited so as not to affect the reaction; in the present invention, the mass volume ratio of the compound represented by the formula F to the organic solvent is preferably 0.01mol/L to 2mol/L (e.g., 0.1mol/L to 0.375 mol/L).
Preferably, the compound of formula F is added as a mixture with the solvent, wherein the concentration of the compound of formula F in the mixture may be 3M.
The catalyst may be a Pd catalyst, for example selected from: pd (PPh) 3 ) 4 、PdCl 2 (dppf)、PdBr 2 、Pd(acac) 2 、PdCl 2 (PhCN) 2 、PdCl 2 (PPh 3 ) 2 、PdCl 2 (CH 3 CN) 2 、PdCl 2 (PCy 3 ) 2 、Pd(OAc) 2 、Pd(CF 3 COO) 2 、PdCl 2 、PdI 2 、PdCl 2 (dppb)、Pd 2 (dba) 3 、PdCl 2 (dppp)、Pd(DPPF)Cl 2 、
Figure BDA0003837221440000121
Figure BDA0003837221440000122
For example Pd (PPh) 3 ) 4 、PdCl 2 (dppf)、PdBr 2 、Pd(acac) 2 、PdCl 2 (PhCN) 2 、PdCl 2 (PPh 3 ) 2 、PdCl 2 (CH 3 CN) 2 、PdCl 2 (PCy 3 ) 2 、Pd(OAc) 2 、Pd(CF 3 COO) 2 、PdCl 2 、PdI 2 、PdCl 2 (dppb)、Pd 2 (dba) 3 And PdCl 2 (dppp); also e.g. PdBR 2 、PdCl 2 (PhCN) 2 、PdCl 2 (CH 3 CN) 2 。
The molar ratio of the catalyst to the 3, 3-difluoroallyl compound shown as the formula F can be 0.0002:1 to 0.2:1; for example 0.01, 0.0375:1, 0.05:1, 0.001:1, 0.0002:1.
The alkali can be one or more of alkali metal fluoride, alkali metal hydroxide, alkali metal alkoxide, alkali metal carbonate and alkali metal phosphate; for example, one or more of alkali metal fluoride, alkali metal hydroxide, alkali metal alkoxide, and alkali metal carbonate; the alkali metal fluoride may be LiF, csF or KF, such as LiF, csF; the alkali metal hydroxide can be NaOH, and the alkali metal alcoholThe compound may be Meona, meoli or t-Buona, for example Meona, and the alkali carbonate may be K 2 CO 3 、Cs 2 CO 3 For example K 2 CO 3 The alkali metal phosphate can be K 3 PO 4 The method comprises the steps of carrying out a first treatment on the surface of the The base is preferably CsF.
The molar ratio of the alkali to the 3, 3-difluoroallyl compound shown in the formula F can be 1.5:1 to 3:1; for example 2.25:1.
The reaction is preferably carried out under an inert atmosphere, which may be argon or nitrogen.
The suzuki coupling reaction may be carried out in the presence of a ligand selected from the group consisting of: triphenylphosphine PPh 3 1, 2-bis (diphenylphosphine) benzene dppbz, 1' -bis (diphenylphosphine) ferrocene dppf, 1, 3-bis (diphenylphosphine) propane dppp, 1-bis (diphenylphosphine) ethane dppe, 1-bis (diphenylphosphine) methane dppm, bis (2-diphenylphosphine phenyl) ether DPEphos, (R) - (+) -DM- (i.e., (R) - (+) -DM-SegPhos), bpy, and 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene Xantphos; for example PPh 3 。
The molar ratio of the ligand to the catalyst may be from 1:1 to 5:1, for example from 2:1 to 3.7:1.
The temperature of the reaction may be 10 to 100 ℃, for example 60 to 80 ℃.
The progress of the reaction may be monitored by conventional monitoring methods in the art (e.g., TLC or NMR), typically by taking the compound of formula F or the vanishing or halogenated heteroaromatics as the end point of the reaction when they are no longer reacted.
In one embodiment, the halogen in the halogenated aromatic or heteroaromatic compound and the alpha, alpha-gem difluoroallyl substituted aromatic or heteroaromatic compound thereof may be F, cl, br, I; such as Cl, br, I.
In one embodiment, the halogenated aromatic hydrocarbon compound and the alpha, alpha-gem-difluoroallyl substituted aromatic hydrocarbon compound thereof can be Ar-X and Ar-X
Figure BDA0003837221440000131
The alpha, alpha-gem-difluoroallyl-substituted aromatic compounds are preferably
Figure BDA0003837221440000132
Wherein Ar is C substituted or unsubstituted by a substituent 6 -C 14 Aryl radicals, e.g. C substituted or unsubstituted by substituents 6 -C 14 An aryl group; x is the halogen; the number of X may be 1 or more, for example 1, 2; the C is 6 -C 14 The aromatic ring may be a benzene ring or a naphthalene ring; the substituents may be: halogen (e.g. F, br, cl), -CN, -NO 2 Methyl, trifluoromethyl, methyl-O-, bz, OBn, =s, =o, aldehyde, -NH 2 、-NMe 2 、-COOMe、-COOEt、-COOH、-OTBS、-Ts、
Figure BDA0003837221440000141
For example halogen (e.g. F, br, cl), -CN, -NO 2 Methyl, trifluoromethyl, methyl-O-, bz, OBn, =s, =o, aldehyde, -NH 2 、-NMe 2 、-COOMe、-COOEt、-COOH、-OTBS、-Ts、/>
Figure BDA0003837221440000142
Figure BDA0003837221440000143
/>
In one scheme, the halogenated heteroarene compound and the alpha, alpha-geminal difluoroallyl substituted heteroarene compound thereof are hetAr-X and
Figure BDA0003837221440000144
the alpha, alpha-gem-difluoroallyl-substituted heteroarenes are preferably +.>
Figure BDA0003837221440000145
Wherein HetAr is a 5-14 membered heteroaryl substituted or unsubstituted with a substituent; x is the halogen; the number of X may be 1 or more, for example 1, 2; the heteroatom in HetAr may be selected from one or more of N, O and S; for example furan Radicals (e.g.)>
Figure BDA0003837221440000146
) Thienyl (e.g.)>
Figure BDA0003837221440000147
) Pyridyl (e.g
Figure BDA0003837221440000148
Figure BDA0003837221440000149
For example->
Figure BDA00038372214400001410
) Pyrimidinyl (e.g.)>
Figure BDA00038372214400001411
) Pyrazinyl (e.g.)>
Figure BDA00038372214400001412
) Pyrazolo [3,4-b]Pyridyl (e.g.)>
Figure BDA00038372214400001413
) Indazolyl (e.g
Figure BDA00038372214400001414
) Benzothiazolinyl (e.g.)>
Figure BDA00038372214400001415
) Pyrrolo [2,3-b]Pyridyl (e.g
Figure BDA0003837221440000151
) Benzo [ d ]]Thiazolyl (e.g., quinolinyl (e.g.)>
Figure BDA0003837221440000152
Figure BDA0003837221440000153
For example->
Figure BDA0003837221440000154
) Isoquinolinyl (e.g.)>
Figure BDA0003837221440000155
Figure BDA0003837221440000156
For example->
Figure BDA0003837221440000157
) Quinazolinyl (e.g.)>
Figure BDA0003837221440000158
) Quinoxalinyl (e.g
Figure BDA0003837221440000159
) Bipyridyl (e.g.)>
Figure BDA00038372214400001510
) Benzothienyl (e.g.)>
Figure BDA00038372214400001511
For example->
Figure BDA00038372214400001512
) Pyrazolyl (e.g.)>
Figure BDA00038372214400001513
) Dibenzothienyl (e.g
Figure BDA00038372214400001514
) Benzofuranyl (e.g.)>
Figure BDA00038372214400001515
Figure BDA00038372214400001516
) Benzothiazolonyl (e.g.)>
Figure BDA00038372214400001517
) The method comprises the steps of carrying out a first treatment on the surface of the For example, furyl (e.g.)>
Figure BDA00038372214400001518
) Thienyl (e.g.)>
Figure BDA00038372214400001519
) Pyridyl (e.g.)>
Figure BDA00038372214400001520
Figure BDA00038372214400001529
) Pyrimidinyl (e.g.)>
Figure BDA00038372214400001521
) Pyrazinyl (e.g.)>
Figure BDA00038372214400001522
) Pyrazolo [3,4-b]Pyridyl (e.g.)>
Figure BDA00038372214400001523
) Indazolyl (e.g.)>
Figure BDA00038372214400001524
) Benzo [ d ]]Thiazolyl (e.g.)>
Figure BDA00038372214400001525
) Pyrrolo [2,3-b]Pyridyl (e.g.)>
Figure BDA00038372214400001526
) Benzo [ d ]]Thiazolyl (e.g
Figure BDA00038372214400001527
) Quinolinyl (e.g.)>
Figure BDA00038372214400001528
) Different typesQuinolinyl (e.g.)>
Figure BDA0003837221440000161
) Quinazolinyl (e.g.)>
Figure BDA0003837221440000162
) Quinoxalinyl (e.g.)>
Figure BDA0003837221440000163
) Benzothienyl (e.g.)>
Figure BDA0003837221440000164
) Pyrazolyl (e.g.)>
Figure BDA0003837221440000165
) The method comprises the steps of carrying out a first treatment on the surface of the The substituents may be: halogen (e.g. F, br, cl), -CN, -NO 2 Methyl, trifluoromethyl, methyl-O-, ethyl-O-, phO-, boc-, bz, OBn, =s, =o, aldehyde, -NH 2 、-NMe 2 、-COOMe、-COOEt、-COOH、-OTBS、-Ts、/>
Figure BDA0003837221440000166
Figure BDA0003837221440000167
For example halogen (e.g. F, br, cl), -CN, -NO 2 Methyl, trifluoromethyl, methyl-O-, bz, OBn, =s, =o, aldehyde, -NH 2 、-NMe 2 、-COOMe、-COOEt、-COOH、-OTBS、-Ts、/>
Figure BDA0003837221440000168
In one scheme, the halogenated heteroarene compound and the alpha, alpha-geminal difluoroallyl substituted heteroarene compound thereof are X-HetAr-X and
Figure BDA0003837221440000169
for example, -HetAr-is bipyridyl, for example
Figure BDA00038372214400001610
In one embodiment, the halogenated aromatic or heteroaromatic compound and the corresponding α, α -gem difluoroallyl substituted aromatic or heteroaromatic compound may be any one of the following groups:
Figure BDA00038372214400001611
Figure BDA0003837221440000171
/>
Figure BDA0003837221440000181
/>
Figure BDA0003837221440000191
/>
Figure BDA0003837221440000201
/>
Figure BDA0003837221440000211
unless otherwise specified, all technical and scientific terms used herein have the standard meaning of the art to which the claimed subject matter belongs. In case there are multiple definitions for a term, the definitions herein control.
Definition of groups
The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, chemical elements are in accordance with CAS version of the periodic Table of the elements, and handbook of chemistry and physics, 75 th edition, 1994. In addition, general principles of organic chemistry may be referenced to the descriptions in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato:1999, and "March's Advanced Organic Chemistry" by Michael b.smith and Jerry March, john Wiley & Sons, new york:2007, the entire contents of which are incorporated herein by reference.
In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds. When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left.
Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, C 1 -C 6 Alkyl refers to an alkyl group as defined below having a total of 1, 2, 3, 4, 5 or 6 carbon atoms. The total number of carbon atoms in the reduced notation does not include carbon that may be present in a substituent of the group.
In this context, a numerical range as defined in substituents, such as 0 to 4, 1-4, 1 to 3, etc., indicates an integer within the range, such as 1-6 is 1, 2, 3, 4, 5, 6.
In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings indicated below, unless specifically indicated otherwise.
The term "comprising" is an open-ended expression, i.e. including what is indicated by the invention, but not excluding other aspects.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, provided that the valence of the particular atom is normal and the substituted compound is stable.
In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a specific substituent. Further, when the group is substituted with 1 or more of the substituents, the substituents are independent of each other, that is, the 1 or more substituents may be different from each other or the same. Unless otherwise indicated, a substituent group may be substituted at each substitutable position of the substituted group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position.
In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. The term "C x -C y Alkyl "refers to a straight or branched chain saturated hydrocarbon containing from x to y carbon atoms. For example, the term "C 1 ～C 6 Alkyl "or" C 1-6 Alkyl "means in particular methyl, ethyl, C independently disclosed 3 Alkyl, C 4 Alkyl, C 5 Alkyl and C 6 An alkyl group; "C 1-4 Alkyl "refers specifically to independently disclosed methyl, ethyl, C 3 Alkyl (i.e. propyl, including n-propyl and isopropyl), C 4 Alkyl (i.e., butyl, including n-butyl, isobutyl, sec-butyl, and tert-butyl).
The terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" as used herein refer to a particular fragment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities that are embedded or attached to a molecule.
When none of the recited substituents indicates through which atom it is attached to a chemical structural formula (including but not specifically mentioned compounds), such substituents may be bonded through any atom thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
When any variable (e.g. R a ) In the definition of a compound, the definition of each position of the variable is independent of the definition of the other positions, and the meanings of the variable are independent and do not influence each other. Thus, if a group is substituted with 1, 2 or 3R a The radical is substituted, that is to say, it may be substituted by up to 3R a Substituted, at position R a Definition of (d) and the remaining position R a Are defined independently of each other. In addition, substituents And/or combinations of variables are allowed only if the combination yields a stable compound.
Where no substituent is explicitly indicated in a recited group, such a group is merely unsubstituted. For example when "C 1 -C 4 Alkyl "not previously" substituted or unsubstituted "refers only to" C 1 -C 4 Alkyl "as such or" unsubstituted C 1 -C 4 An alkyl group.
In the various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable enumerates an "alkyl" group, it will be understood that the "alkyl" represents a linked alkylene group.
In some specific structures, when an alkyl group is explicitly represented as a linking group, then the alkyl group represents a linked alkylene group, e.g., the group "halo-C 1 -C 6 C in alkyl' 1 -C 6 Alkyl is understood to mean C 1 -C 6 An alkylene group.
The term "halogen" means fluorine, chlorine, bromine or iodine, in particular F or Cl.
In this application, as part of a group or other group (e.g., as used in haloalkyl, deuterated alkyl, etc.), the term "alkyl" is meant to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms, consisting only of carbon atoms and hydrogen atoms, and being attached to the remainder of the molecule by a single bond. For example having from 1 to 20 (preferably from 1 to 10, more preferably from 1 to 6, more preferably from 1 to 4) carbon atoms. Wherein propyl is C 3 Alkyl (including isomers such as n-propyl or isopropyl); butyl is C 4 Alkyl (including isomers such as n-butyl, sec-butyl, isobutyl, or tert-butyl); pentyl is C 5 Alkyl (including isomers such as n-pentyl, 1-methyl-butyl, 1-ethyl-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, isopentyl, t-pentyl or neopentyl); hexyl isC 6 Alkyl (including isomers such as n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2-dimethylpropyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, nonyl, decyl and the like.
In the present application, the term "alkylene" as part of a group or other group means a saturated divalent hydrocarbon group resulting from the removal of two hydrogen atoms from a saturated straight or branched hydrocarbon group; i.e. one hydrogen in the alkyl group is substituted, the definition of alkyl group being as described above. Examples of alkylene groups include methylene (-CH) 2 (-), ethylene { including-CH 2 CH 2 -or-CH (CH) 3 ) - } isopropylidene { including-CH (CH) 3 )CH 2 -or-C (CH) 3 ) 2 - }, and the like.
In this application, the term "alkoxy" as part of a group or other group refers to an-O-alkyl group, the definition of alkyl being as described above.
In the present application, as part of a group or other group, the term "alkenyl" refers to a straight or branched hydrocarbon chain radical having at least one double bond, consisting of carbon and hydrogen atoms only, and being linked to the remainder of the molecule by a single bond. For example having from 2 to 20 (preferably from 2 to 10, more preferably from 2 to 6, most preferably from 2 to 4) carbon atoms, including for example, but not limited to, vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, sec-butenyl, tert-butenyl, n-pentenyl, 2-methylbutenyl, 2-dimethylpropenyl, n-hexenyl, heptenyl, 2-methylhexenyl, 3-methylhexenyl, octenyl, nonenyl, decenyl and the like.
In this application, as part of a group or other group, the term "cycloalkyl" means a saturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more bridged, fused or spiro ring system) carbocyclic substituent, and which may be attached to the remainder of the molecule via any suitable carbon atom by a single bond. For example, a 3-20 membered cycloalkyl group having 3 to 20 carbon atoms, preferably a 3-10 membered cycloalkyl group having 3 to 10 carbon atoms, more preferably a 3-7 membered cycloalkyl group having 3 to 7 carbon atoms, most preferably a 3-6 membered cycloalkyl group having 3 to 6 carbon atoms. In one embodiment, a typical monocyclic cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
In the present application, the term "heterocycloalkyl" as part of a group or other group means a group having a heteroatom or heteroatom group consisting of carbon atoms and 1 or more heteroatoms selected from O, S, N (in the form of tertiary amine moieties), B, P, sn or Si (e.g. C (=o), S (=o) 2 、P(＝O)、P(＝O) 2 The method comprises the steps of carrying out a first treatment on the surface of the The a-terminal represents the attachment position). For example from 2 to 20 (preferably 2 to 6) carbon atoms and 1 to 6 are selected from C (=o), S, S (=o), S (=o) 2 、O、N、Si、P、P(＝O)、P(＝O) 2 And B is a stable 3 to 26 membered (preferably 3 to 20 membered, more preferably 4 to 10 membered, most preferably 3 to 7 membered) saturated heterocyclic hydrocarbon group consisting of heteroatoms or heteroatom groups; preference is given to heterocyclic hydrocarbon radicals having 1, 2 or 3 ring heteroatoms independently selected from N, O and S, which are saturated, 4-to 10-membered, mono-or polycyclic (e.g. bicyclic, tricyclic or more bridged, fused or spiro ring systems). The ring system of the heterocycloalkyl bicyclic ring may include one or more heteroatoms in one or both rings; and is saturated. In some embodiments, "heterocycloalkyl" is a 5-to 7-membered monocyclic heterocycloalkyl, a 6-to 8-membered ring-attached heterocycloalkyl, a 6-to 8-membered bridged ring-attached heterocycloalkyl, or a 7-to 10-membered spiro-attached heterocycloalkyl.
In this application, the term "aryl" as part of a group or other group means a conjugated hydrocarbon ring system group that satisfies the 4n+2 rule. For example, a conjugated hydrocarbon ring system group having 6 to 20 carbon atoms (preferably having 6 to 10 carbon atoms) satisfying the 4n+2 rule. For the purposes of the present invention, aryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl groups as defined above, provided that the aryl groups are linked to the rest of the molecule via atoms on the aromatic ring by single bonds. In one embodiment, the term "aryl" refers to an aromatic group consisting of carbon atoms, each ring having aromaticity. Examples of aryl groups include, but are not limited to, phenyl, naphthyl.
In the present application, the term "heteroaryl" as part of a group or other group means a conjugated ring system group having carbon atoms and 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur within the ring. Unless otherwise specifically indicated in the present specification, heteroaryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and when they are bicyclic, tricyclic or more bicyclic (fused) rings, they may also include being fused to cycloalkyl or heterocycloalkyl groups as defined herein, provided that heteroaryl groups are linked to the rest of the molecule by a single bond via an atom on an aromatic ring. Preferably a 5-14 membered heteroaryl group comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, more preferably a 5-6 membered heteroaryl group comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoxazolyl, thiadiazolyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxazolyl, cinnolinyl, quinazolinyl, indolizinyl, phenanthridinyl, isoxazolyl, phenoxazinyl, phenothiazinyl, benzoxazolyl, or benzisoxazolyl.
The "-" at the end of a group means that the group is attached to other fragments in the molecule through that site.
As used herein, the singular forms "a", "an", and "the" are understood to include plural referents unless the context clearly dictates otherwise.
The term "one(s)" or "one(s) or two or more" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.
Unless otherwise indicated, the present invention employs conventional methods of mass spectrometry, elemental analysis, and the various steps and conditions are referred to in the art by conventional procedures and conditions.
The present invention employs, unless otherwise indicated, standard nomenclature for analytical chemistry, organic synthetic chemistry and optics, and standard laboratory procedures and techniques. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and light emitting device performance detection.
In addition, unless explicitly indicated otherwise, the description of the invention as "…" independently is to be understood broadly as meaning that each individual described may be independent of the other, and may be the same or different. In more detail, the description "… is independently" may mean that specific options expressed between the same symbols in different groups do not affect each other; it may also be expressed that specific options expressed between the same symbols in the same group do not affect each other.
Those skilled in the art will appreciate that, in accordance with convention used in the art, the present application describes the structural formula of a group as used in
Figure BDA0003837221440000271
Is->
Figure BDA0003837221440000272
It means that the corresponding group R is linked to other fragments, groups in the compound through this site.
Those skilled in the art will appreciate that, in accordance with convention used in the art, the present application describes the structural formula of a group as used in
Figure BDA0003837221440000273
Represents a single bond or a double bond.
Unless otherwise specified, all technical and scientific terms used herein have the standard meaning of the art to which the claimed subject matter belongs. In case there are multiple definitions for a term, the definitions herein control.
The above preferred conditions can be arbitrarily combined to obtain the preferred examples of the present invention without departing from the common sense in the art
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: (1) The method provided by the invention uses cheap trifluoropropene as a raw material and a cheap catalyst (copper catalyst such as copper salt catalyst and copper chloride) to prepare nucleophilic alpha, alpha-gem difluoroallylation reagent with high efficiency under the condition of no ligand (the copper catalyst content can be as low as one thousandth to one thousandth), and the preparation process has potential industrial application value; (2)
The prepared 3, 3-difluoro alkenyl borane, silane or stannane can be used for efficiently preparing various difluoro alkyl compounds with various structures, and the prepared various difluoro alkyl compounds have very wide application prospects in medicines, pesticides and materials.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
In the invention, room temperature refers to the ambient temperature, which is 10-35 ℃. Overnight means 8-15 hours. Reflux refers to the reflux temperature of the solvent at atmospheric pressure.
Example 1
Investigation of ligand Effect
Figure BDA0003837221440000281
Weighing ligand (10 mol%), B 2 Pin 2 (1.5 eq) was put into a glove box to be called cuprous chloride (10 mol%), lithium t-butoxide (3.0 eq), double rows were connected, argon was exchanged three times, 1.5mL of THF was added, stirring was performed for 15 minutes, trifluoropropene (0.25mmol,1.2M in DMA) was added, and the reaction was performed at room temperature for 4 hours. 50. Mu.L of fluorobenzene was added thereto, stirred for two minutes, and then left to stand, and the supernatant was aspirated to confirm a fluorine signal.
Figure BDA0003837221440000282
Figure BDA0003837221440000291
Figure BDA0003837221440000292
The reaction time is shortened to 1-2h, and other operations and conditions are the same.
Figure BDA0003837221440000293
Example 2
Investigation of alkali effect:
Figure BDA0003837221440000294
weighing ligand Xantphos (10 mol%), B 2 Pin 2 (1.5 eq) was put into a glove box and weighed as cuprous chloride (10 mol%), lithium t-butoxide (x eq), double rows were connected, argon was exchanged three times, 1.5mL THF was added, stirring was performed for 15 minutes, trifluoropropene (0.25mmol,1.2M in DMA) was added, and the reaction was performed at room temperature for 4 hours.
50. Mu.L of fluorobenzene was added thereto, stirred for two minutes, and then left to stand, and the supernatant was aspirated to confirm a fluorine signal.
Figure BDA0003837221440000301
Example 3
Investigation of solvent Effect
Figure BDA0003837221440000302
Weighing ligand (10 mol%), B 2 Pin 2 (1.5 eq) was put into a glove box and was named cuprous chloride (10 mol%), lithium t-butoxide (2 eq), the double rows were connected, argon was exchanged three times, 1.5mL of solvent was added, stirring was performed for 15 minutes, trifluoropropene (0.25mmol,1.2M in DMA) was added, and the reaction was performed at room temperature for 5 hours. 50. Mu.L of fluorobenzene was added thereto, stirred for two minutes, and then left to stand, and the supernatant was aspirated to confirm a fluorine signal.
Figure BDA0003837221440000303
Figure BDA0003837221440000311
Example 4
B 2 Pin 2 Investigation of the amount:
Figure BDA0003837221440000312
weighing B 2 Pin 2 (y eq) into a glove box, namely cuprous chloride (10 mol%), lithium tert-butoxide (2 eq), connecting double rows, pumping argon three times, adding 1.5mL THF, stirring for 15 minutes, adding trifluoropropene (0.25mmol,1.2M in DMA), and reacting for 5 hours at room temperature. 50. Mu.L of fluorobenzene was added thereto, stirred for two minutes, and then left to stand, and the supernatant was aspirated to confirm a fluorine signal.
Figure BDA0003837221440000313
Example 5
Investigation of alkali at optimal ratio:
Figure BDA0003837221440000321
weighing B 2 Pin 2 (0.25 mmol), put into a glove box and called cuprous chloride (10 mol%), alkali (2 eq), connect double rows, pump argon three times, add 1.5mL THF, stir for 15 minutes, add trifluoropropene (1.5eq,1.2M in DMA), react for 5h at room temperature. 50. Mu.L of fluorobenzene was added thereto, stirred for two minutes, and then left to stand, and the supernatant was aspirated to confirm a fluorine signal.
Figure BDA0003837221440000322
Example 6
Optimization of catalyst dosage:
weighing B 2 Pin 2 (x mmol), put into a glove box, call cuprous chloride (z mol%), meOLi (2 eq), connect double rows, pump argon three times, add THF, stir for 15 minutes, add trifluoropropene (1.5eq,1.2M in DMA), and react overnight at room temperature. 50. Mu.L of fluorobenzene was added thereto, stirred for two minutes, and then left to stand, and the supernatant was aspirated to confirm a fluorine signal.
6-1：
Figure BDA0003837221440000331
6-2：
Figure BDA0003837221440000332
6-3：
Figure BDA0003837221440000333
6-4: preliminary investigation of 1% catalyst amplification reaction:
Figure BDA0003837221440000334
example 7
Investigation of 1atm trifluoropropene gas atmosphere:
Figure BDA0003837221440000335
weighing B 2 Pin 2 (25.4 g,100 mmol), was put into a glove box and weighed cuprous chloride (0.1 mmol,10 mg), meOLi (3.8 g,200 mmol), connected in double rows, argon was exchanged three times, freshly distilled anhydrous THF (40 mL) and ultra-dry DMF (40 mL) were added, stirred at room temperature for 15 minutes, then trifluoropropene gas was slowly bubbled in, and the reaction was carried out at room temperature for 48 hours. Adding fluorobenzene internal standard, stirring for two minutes, standing, and sucking the supernatant to confirm the nuclear magnetic yield. The obtained reaction mixed solution is added with 500mL of normal hexane for dilution and beating for 2 hours, then is kept still, supernatant is sucked out (repeated 3-5 times for beating with 500mL of normal hexane), water is added for dilution after the last beating is finished, and 250mL of normal hexane is used for extraction. The resulting organic phases were combined and washed three times with saturated saline to remove water-soluble THF and DMF. After drying the n-hexane phase with anhydrous sodium sulfate, the resulting mixture was rapidly filtered through a 2-4 cm pad of silica gel. N-hexane is recovered by distillation and concentration under normal pressure, the mixture obtained after decompression and concentration is recrystallized by a proper amount of n-pentane at the temperature of minus 78 ℃ to obtain n-pentane solution (which can be directly used for subsequent reaction) of the expected target product, 17.4g of pure product can be obtained by further distillation and concentration under normal pressure, and the separation yield is 85 percent.
Example 8
Investigation of 1atm trifluoropropene gas atmosphere:
Figure BDA0003837221440000341
weighing B 2 Pin 2 (100 g, 390 mol) and put into a glove box to be chloridizedCuprous (0.390 mmol,39.4 mg) and MeOLi (29.9 g,8mol,2 eq) were connected in double rows, argon was exchanged three times, freshly distilled anhydrous THF (160 mL) and ultra-dry DMF (160 mL) were added, stirred at room temperature for 15 minutes, then trifluoropropene gas was bubbled slowly, and the reaction was carried out at room temperature for 48 hours. Adding fluorobenzene internal standard, stirring for two minutes, standing, and sucking the supernatant to confirm that the nuclear magnetic yield is 99%. The obtained reaction mixed solution is added with 800mL of normal hexane for dilution and pulping for 2 hours, then is kept still, supernatant is sucked out (repeated 3-5 times for pulping with 800mL of normal hexane), water is added for dilution after the last pulping is finished, and 500mL of normal hexane is used for extraction. The resulting organic phases were combined and washed three times with saturated saline to remove water-soluble THF and DMF. After drying the n-hexane phase with anhydrous sodium sulfate, the resulting mixture was rapidly filtered through a 2-4 cm pad of silica gel. N-hexane is recovered by distillation and concentration under normal pressure, the mixture obtained after decompression and concentration is recrystallized by a proper amount of n-pentane at the temperature of minus 78 ℃ to obtain n-pentane solution (which can be directly used for subsequent reaction) of the expected target product, 64.3g of pure product can be obtained by further distillation and concentration under normal pressure, and the separation yield is 80 percent.
Example 9
Preparation of 600 hundred gram grade boron reagent:
Figure BDA0003837221440000351
weighing B 2 Pin 2 (1.02 kg,4 mol), into a glove box, cuprous chloride (0.8 mmol,80 mg) and Meoli (304 g,8mol,2 eq) were weighed, double rows were connected, argon was exchanged three times, freshly distilled anhydrous THF (800 mL) and ultra-dry DMF (400 mL) were added, stirred at room temperature for 15 minutes, and then trifluoropropene gas was slowly bubbled in and reacted at room temperature for 48 hours. Adding fluorobenzene internal standard, stirring for two minutes, standing, and sucking the supernatant to confirm that the nuclear magnetic yield is 95%. The obtained reaction mixed solution is added with 2L of normal hexane for dilution and pulping for 2 hours, then is kept still, supernatant is sucked out (3-5 times of pulping with 2L of normal hexane is repeated), water is added for dilution after the last pulping is finished, and 1L of normal hexane is used for extraction. The resulting organic phases were combined and washed three times with saturated saline to remove water-soluble THF and DMF. After drying the n-hexane phase with anhydrous sodium sulfate, the resulting mixture was rapidly filtered through a 2-4 cm pad of silica gel. Often timesThe normal hexane is recovered by distillation and concentration under reduced pressure, the mixture obtained after the concentration under reduced pressure is recrystallized by a proper amount of normal pentane at the temperature of minus 78 ℃ to obtain a normal pentane solution (which can be directly used for subsequent reaction) of the expected target product, 694g of pure product can be obtained by further distillation and concentration under normal pressure, and the separation yield is 85 percent. 1 H NMR(400MHz,Chloroform-d)δ4.20(dtd,J＝25.6Hz,8.0Hz,2.1Hz,2H),1.51(d,J＝8.0Hz,2H),1.25(s,12H). 19 F NMR(376MHz,Chloroform-d)δ-90.1(dd,J＝50.3Hz,1.3Hz,1F),-92.9(dd,J＝50.3Hz,25.6Hz,1F).
Example 10
Investigation of 1atm trifluoropropene gas atmosphere:
Figure BDA0003837221440000352
weighing B 2 Pin 2 (58.1 g,100 mmol), cuprous chloride (1 mmol,100 mg) and MeOLi (3.8 g,200 mmol) were weighed into a glove box, the double rows were connected, argon was exchanged three times, freshly distilled anhydrous THF (40 mL) and ultra-dry DMF (40 mL) were added, stirring was carried out at room temperature for 15 minutes, and then trifluoropropene gas was slowly bubbled and reacted at room temperature for 48 hours. Adding fluorobenzene internal standard, stirring for two minutes, standing, and sucking the supernatant to confirm the nuclear magnetic yield. The obtained reaction mixed solution is added with 500mL of normal hexane for dilution and beating for 2 hours, then is kept still, supernatant is sucked out (repeated 3-5 times for beating with 500mL of normal hexane), water is added for dilution after the last beating is finished, and 250mL of normal hexane is used for extraction. The resulting organic phases were combined and washed three times with saturated saline to remove water-soluble THF and DMF. After drying the n-hexane phase with anhydrous sodium sulfate, the resulting mixture was rapidly filtered through a 2-4 cm pad of silica gel. And distilling, concentrating and recycling normal hexane under normal pressure, decompressing and distilling the mixture obtained after decompressing and concentrating by an oil pump to obtain 25.0g of pure product, and separating and obtaining 68% of yield.
Example 11
Figure BDA0003837221440000361
Weighing [ Pd ], potassium carbonate and phenylboronic acid in a 500mL Schlenck bottle, connecting the two rows, pumping argon for three times, adding water, THF and bromotrifluoropropene, and stirring at 60 ℃ for 24 hours. Cool to room temperature and quench with water. PE extraction, spin drying and direct casting.
Figure BDA0003837221440000362
Weighing B 2 Pin 2 The cuprous chloride and the lithium methoxide are placed in a Schlenck bottle, double rows are connected, argon is pumped for three times, and the 2-phenyl trifluoropropene, THF and DMA which are the products of the previous reaction are added and stirred for one day at room temperature. Washing with water, and extracting with ethyl acetate. Spin drying and column passing. The product was obtained (94% yield, 95% purity). 1 H NMR(400MHz,CD 3 OD)δ7.40–7.28(m,4H),7.23(t,J＝7.1Hz,1H),1.96(s,2H),1.16(s,12H). 19 F NMR(376MHz,CD 3 OD)δ-90.8(dt,J＝45.4Hz,3.1Hz,1F),-92.2(d,J＝45.4Hz,1F).
Example 12
Figure BDA0003837221440000371
Weigh PdCl 2 (PPh 3 ) 2 Adding potassium carbonate and arylboronic acid into a 500mL solvent bottle, connecting the two rows, pumping argon for three times, adding water and tetrahydrofuran, stirring for 2 minutes, adding bromotrifluoropropene, heating and stirring for 24 hours at 60 ℃. And (5) recovering to room temperature, extracting by EA, washing by using brine, spin-drying, and passing through a column.
Weighing B 2 Pin 2 In a 250mL three-necked flask, cuCl and Meoli were placed in a flask, ar was exchanged, THF and DMA were added, the mixture was stirred for 2 minutes, the product of the previous reaction was added, and the mixture was stirred at room temperature overnight. The diatomite and the silica gel are filtered once, a large amount of DMA is removed by water washing, EA extraction, spin drying and column passing.
Figure BDA0003837221440000372
(two-step yield 55%, purity 95%)
1 H NMR(400MHz,CD 3 OD)δ7.33–7.26(m,2H),6.89–6.81(m,2H),3.80(s,3H),1.92(s,2H),1.16(s,12H). 19 F NMR(376MHz,CD 3 OD)δ-91.8(d,J＝48.0Hz,1F),-93.1(d,J＝48.0Hz,1F).
Figure BDA0003837221440000381
(two-step yield 58%, purity 95%)
1 H NMR(400MHz,CD 3 OD)δ7.24(t,1H),6.99–6.87(m,2H),6.83–6.72(m,1H),3.80(s,3H),1.94(s,2H),1.16(s,12H). 19 F NMR(376MHz,CD 3 OD)δ-90.3(dt,J＝44.5Hz,2.7Hz,1F),-91.3(d,J＝44.4Hz,1F).
Figure BDA0003837221440000382
(two-step yield 49%, purity 95%)
1 H NMR(400MHz,CD 3 OD)δ8.03(s,1H),7.91(d,J＝7.8Hz,1H),7.55(d,J＝9.0Hz,1H),7.39(t,J＝7.8Hz,1H),3.90(s,3H),1.95(s,2H),1.15(s,12H). 19 F NMR(376MHz,CD 3 OD)δ-89.8(dt,J＝43.7Hz,2.6Hz,1F),-91.3(d,J＝43.2Hz,1F).
Example 13
Figure BDA0003837221440000383
Weighing B 2 Pin 2 In a 500mL three-necked flask, cuCl and Meoli were placed in a flask, ar was exchanged, THF and DMA were added, the mixture was stirred for 2 minutes, the product of the previous reaction was added, and the mixture was stirred at room temperature for 2 days. (the fluorine spectrum shows that most of the starting material remains one day of reaction). The diatomite and the silica gel are filtered once, a large amount of DMA is removed by water washing, EA extraction, spin drying and column passing. PE→PE:EA 100: 1- & gt PE: EA 80: 1- & gt PE: EA 60:1 pass out. A pale yellow oily liquid was obtained, 8.0g, 37% yield in two steps.
Figure BDA0003837221440000391
1 H NMR(400MHz,CD 3 OD)δ7.32–7.26(m,2H),7.23–7.13(m,3H),2.60(t,J＝7.4Hz,2H),2.13–1.98(m,2H),1.73(p,J＝7.8Hz,2H),1.54(s,2H),1.23(s,12H). 19 F NMR(376MHz,CD 3 OD)δ-96.0(d,J＝59.4Hz,1F),-97.0(d,J＝59.3Hz,1F).
Example 14
Figure BDA0003837221440000392
Weighing [ Ni ] in a 100mL Schlenck bottle, connecting double rows, pumping argon for three times, adding chlorotrifluoropropene and dioxane, and dripping zinc reagent. Stirring for 2h at room temperature. Quenching with water, PE extraction, spin drying, and PE column chromatography to give 5.7g of crude product (impure, mixed with more by-products and agent) which is directly fed to the next step.
Figure BDA0003837221440000393
Weighing B 2 Pin 2 The cuprous chloride and the lithium methoxide are placed in a 50mL Schlenck bottle, double rows are connected, argon is pumped for three times, and the trifluoropropene compound, THF and DMA which are obtained in the previous step are added and stirred at room temperature overnight. Washing with water, extracting with ethyl acetate. Spin drying, passing through column, and passing out PE and EA 80:1. A viscous liquid, 5.8g, was obtained in 67% yield.
Figure BDA0003837221440000401
1 H NMR(400MHz,CD 3 OD)δ7.32–7.25(m,2H),7.19(t,J＝6.4Hz,3H),4.15(ddd,J＝25.8Hz,10.7Hz,2.7Hz,1H),2.72–2.50(m,2H),1.97–1.82(m,1H),1.78–1.53(m,3H),1.52–1.36(m,1H),1.25(s,12H). 19 F NMR(376MHz,CD 3 OD)δ-89.4(d,J＝49.9Hz,1F),-91.9(dd,J＝49.8Hz,25.8Hz,1F).
Application example 1
Palladium catalyzed geminal difluoroallylation of aryl heterocycles:
general procedure for the examples:
Figure BDA0003837221440000402
weighing bromoquinoline and PdCl 2 (dppf), base, and then argon was replaced three times in vacuo. Under argon, 1.5mL of solvent was added and stirred for 5 minutes. Allyl boron reagent (3M), 1.5mL solvent was added. Heating to 80 ℃ and stirring to react for 6h. The reaction mixture obtained was stirred for two minutes with fluorobenzene as an internal standard and then left to stand, and the supernatant was taken to examine the yield of the product.
Figure BDA0003837221440000403
Figure BDA0003837221440000411
Application example 2
Application examples 2-1 to 2-6 of bromoheterocycle:
weighing brominated heterocyclic raw materials and PdCl 2 (PhCN) 2 CsF, PPh 3 Argon was then replaced three times in vacuo. Under the protection of argon, 1.5mL of dioxane was added and stirred for 5 minutes. Allyl boron reagent (3M), 1.5mL solvent was added. Heating to 80 ℃ and stirring to react for 8h. The reaction mixture obtained was stirred for two minutes with fluorobenzene as an internal standard and then left to stand, and the supernatant was taken to examine the yield of the product.
Figure BDA0003837221440000412
(the product is the corresponding geminal difluoroallylated structure).
Application example 3
Figure BDA0003837221440000413
Weighing 3-bromopyridine and PdCl 2 (dppf), csF, and then argon was vacuum-replaced three times. Under argon, 1.5mL of solvent was added and stirred for 5 minutes. Allyl boron reagent (3M), 1.5mL solvent was added. Heating to 80 ℃ and stirring to react for 6h. The reaction mixture obtained was stirred for two minutes with fluorobenzene as an internal standard and then left to stand, and the supernatant was taken to examine the yield of the product.
Figure BDA0003837221440000414
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Figure BDA0003837221440000421
Application example 4
Investigation of catalyst types and equivalent weights
Figure BDA0003837221440000422
3-bromopyridine, catalyst, csF were weighed and then argon was purged three times in vacuo. Under argon, 1.5mL of solvent was added and stirred for 5 minutes. Allyl boron reagent (3M), 1.5mL solvent was added. Heating to 80 ℃ and stirring to react for 6h. The reaction mixture obtained was stirred for two minutes with fluorobenzene as an internal standard and then left to stand, and the supernatant was taken to examine the yield of the product.
Figure BDA0003837221440000423
Figure BDA0003837221440000431
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Figure BDA0003837221440000432
Weighing 3-bromopyridine, catalyst, csF and the mixtureBulk PPh 3 Argon was then replaced three times in vacuo. Under argon, 1.5mL of solvent was added and stirred for 5 minutes. Allyl boron reagent (3M), 1.5mL solvent was added. Heating to 80 ℃ and stirring to react for 6h. The reaction mixture obtained was stirred for two minutes with fluorobenzene as an internal standard and then left to stand, and the supernatant was taken to examine the yield of the product.
Figure BDA0003837221440000433
Figure BDA0003837221440000441
Application example 5
Concentration Effect investigation
Figure BDA0003837221440000442
Weighing 3-bromopyridine and PdCl 2 (PhCN) 2 CsF, PPh 3 Argon was then replaced three times in vacuo. Under argon, 1.5mL of solvent (is dioxane) was added and stirred for 5 minutes. Allyl boron reagent (3M), 1.5mL solvent was added. Heating to 80 ℃ and stirring to react for 3h. The reaction mixture obtained was stirred for two minutes with fluorobenzene as an internal standard and then left to stand, and the supernatant was taken to examine the yield of the product.
Figure BDA0003837221440000443
Application example 6
Investigation of solvent Effect
Figure BDA0003837221440000444
Weighing 3-bromopyridine and PdCl 2 (PhCN) 2 CsF, PPh 3 Argon was then replaced three times in vacuo. Under the protection of argon1.5mL of solvent was added and stirred for 5 minutes. Allyl boron reagent (3M), 1.5mL solvent was added. Heating to 80 ℃ and stirring to react for 6h. The reaction mixture obtained was stirred for two minutes with fluorobenzene as an internal standard and then left to stand, and the supernatant was taken to examine the yield of the product.
Figure BDA0003837221440000451
Application example 7
Further investigation of heterocyclic substrate adaptability:
Figure BDA0003837221440000452
(the product is a corresponding geminal difluoroallylated structure of bromo).
Application example 8
Investigation of other types of heterocycles:
Figure BDA0003837221440000461
(the product is a corresponding geminal difluoroallylated structure of bromo).
Application example 9
Application examples after further optimization of conditions:
Figure BDA0003837221440000462
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Figure BDA0003837221440000463
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Figure BDA0003837221440000471
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Figure BDA0003837221440000481
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Figure BDA0003837221440000491
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Figure BDA0003837221440000501
application example 10
Figure BDA0003837221440000502
Add B to 1000mL three-necked flask under air conditions 2 pin 2 (200 mmol,1.0 eq.) CuCl (0.2 mmol,0.1 mol%) and MeOLi (400 mmol,2.0 eq.) were added under argon, the three-necked flask was replaced with argon 3 times, then with 3, 3-trifluoropropene, after which tetrahydrofuran (200 mL) and N, N-dimethylformamide (200 mL) were added under argon, the reaction system was reacted at 0deg.C for 2h, then warmed to room temperature for 10h. And after the reaction is finished, diluting with n-pentane, adding a certain amount of fluorobenzene as an internal standard, and carrying out fluorine spectrum quantitative detection. The reaction was then filtered through celite, the filtrate was diluted with n-pentane, the organic phase was washed with water multiple times and once again through celite. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product as a pale yellow liquid. The crude product was distilled under reduced pressure (6 mbar,60 ℃) to give 29.2g of the desired product 2 as a colorless oil in 71% yield. 1 H NMR(400MHz,Chloroform-d)δ4.20(m,1H),1.51(d,J＝8.0Hz,2H),1.25(s,12H). 19 F NMR(376MHz,Chloroform-d)δ-90.1(d,J＝50.3Hz,1F),-92.71–-93.06(m,1F).
Figure BDA0003837221440000511
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To a Schlenk flask under air conditions were added (hetero) aryl bromide 1a (0.4 mmol,1.0 eq.) andP(t-Bu) 2 Ph·PdCl 2 (3 mol%). CsF (2.0 eq.) and 1, 4-dioxane (1.5 mL) were added under argon followed by difluoroallylboron 2 (0.44 mmol,1.1 eq.) and 1, 4-dioxane (0.5 mL) under argon. The reaction flask was capped and then reacted at 100℃for 2 hours. After the reaction is finished, adding 2mL of ethyl acetate into the reaction system for dilution, and adding a certain amount of fluorobenzene as an internal standard for quantitative fluorine spectrum detection. After the fluorine spectrum determines the yield, the reaction system is filtered and the filtrate is concentrated. And finally, carrying out column chromatography on the concentrated crude product to obtain the product 3a which is wanted by us.
Application example 11
Investigation of ligand Effect
Figure BDA0003837221440000512
Experimental procedure Using the same procedure as in Compound 3a of application example 10, compound 2 was prepared by using reaction example 10.
Figure BDA0003837221440000521
a Reaction conditions 1a (0.4 mmol,1.0 eq), 2 (0.44 mmol,1.1 eq), 1, 4-dioxane (2.0 mL). b By using fluorobenzene as internal standard 19 F NMR detection; the yield of 2 refers to the residual amount of compound 2 after the reaction. c Without PPh 3 .
Application example 12
Investigation of solvent Effect
Figure BDA0003837221440000522
Experimental procedure Using the same procedure as in Compound 3a of application example 10, compound 2 was prepared by using reaction example 10.
Figure BDA0003837221440000523
a Reaction conditions 1a (0.4 mmol,1.0 eq.) 2 (0.44 mmol,1.1 eq.). b By using fluorobenzene as internal standard 19 F NMR detection; the yield of 2 refers to the residual amount of compound 2 after the reaction.
Application example 13
Investigation of the alkali Effect
Figure BDA0003837221440000531
Experimental procedure Using the same procedure as in Compound 3a of application example 10, compound 2 was prepared by using reaction example 10.
Figure BDA0003837221440000532
a Reaction conditions 1a (0.4 mmol,1.0 eq), 2 (0.44 mmol,1.1 eq), 1, 4-dioxane (2.0 mL). b By using fluorobenzene as internal standard 19 F NMR detection; the yield of 2 refers to the residual amount of compound 2 after the reaction.
Application example 14
Temperature effect investigation
Figure BDA0003837221440000533
Experimental procedure Using the same procedure as in Compound 3a of application example 10, compound 2 was prepared by using reaction example 10.
Figure BDA0003837221440000541
a Reaction conditions 1a (0.4 mmol,1.0 eq), 2 (0.44 mmol,1.1 eq), 1, 4-dioxane (2.0 mL). b By using fluorobenzene as internal standard 19 F NMR detection; 2 yield refers to the post-reaction compound2, residual amount of the catalyst.
Application example 15
Investigation of the ratio of the reactants
Figure BDA0003837221440000542
Experimental procedure Using the same procedure as in Compound 3a of application example 10, compound 2 was prepared by using reaction example 10.
Figure BDA0003837221440000543
a Reaction conditions 1, 4-dioxane (2.0 mL). b By using fluorobenzene as internal standard 19 F NMR detection; the yield of 2 refers to the residual amount of compound 2 after the reaction.
Application example 16
Investigation of reaction time
Figure BDA0003837221440000551
Experimental procedure Using the same procedure as in Compound 3a of application example 10, compound 2 was prepared by using reaction example 10.
Figure BDA0003837221440000552
a Reaction conditions 1a (0.4 mmol,1.0 eq), 2 (0.44 mmol,1.1 eq), 1, 4-dioxane (2.0 mL). b By using fluorobenzene as internal standard 19 F NMR was examined and isolated yields are in brackets; the yield of 2 refers to the residual amount of compound 2 after the reaction.
Application example 17
Figure BDA0003837221440000553
To a Schlenk flask under air conditions were added (hetero) aryl bromide 1a (6.70 mmol,1.0 eq.) and P (t-Bu) 2 Ph·PdCl 2 (0.5 mol%). CsF (2.0 eq.) and 1, 4-dioxane (33 mL) were added under argon followed by difluoroallylboron 2 (7.40 mmol,1.1 eq.) under argon. The reaction flask was capped and then reacted at 100℃for 2 hours. After the reaction was completed, the mixture was filtered through celite, and the filtrate was concentrated. Finally, column chromatography (petroleum ether/ethyl acetate=20:1) of the concentrated crude product afforded 1.04g of the target product 3a as a yellow oil in 71% yield.
Application example 18
Examination of the adaptability of heterocyclic substrates
Preparation of 3a-3z,3aa,3ab,4a and 4b Compounds
3a-3z,3aa and 3ab are prepared by reacting the corresponding bromo compound with
Figure BDA0003837221440000561
The reaction was carried out under the same experimental conditions as in application example 10.
Preparation of Compounds 4a and 4b, etc. by
Figure BDA0003837221440000562
Respectively and->
Figure BDA0003837221440000563
The reaction was carried out under the same experimental conditions as in application example 10.
Figure BDA0003837221440000564
When R' is H, compound 2 is used to make 3a-3z,3aa and 3ab;
r' is
Figure BDA0003837221440000565
Compound 2 was used to prepare 4a and 4b. />
Figure BDA0003837221440000571
After the reaction, the reaction was carried out using fluorobenzene as an internal standard 19 F NMR detection measures isolated yields. The nuclear magnetic data of the above compounds are as follows:
Figure BDA0003837221440000572
compound (3 a) column chromatography (petroleum ether/ethyl acetate=20:1) gave 67mg of a yellow oil in 81% yield. 1 H NMR(400MHz,Chloroform-d)δ8.04(s,1H),7.79(s,1H),7.68(d,J＝8.4Hz,2H),7.47(t,J＝7.8Hz,2H),7.33(t,J＝7.8Hz,1H),6.32–6.15(m,1H),5.70(dt,J＝17.2,2.8Hz,1H),5.54(d,J＝10.8Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-85.9(dd,J＝9.4,3.0Hz,1H,2F). 13 C NMR(101MHz,Chloroform-d)δ139.59,138.73(t,J＝3.8Hz),133.26(t,J＝29.9Hz),129.50,127.19,125.75(t,J＝4.9Hz),120.75(t,J＝32.7Hz),120.12(t,J＝8.9Hz),119.43,116.78(t,J＝233.7Hz).MS(FI):m/z(％)220(M) + HRMS theoretical value C 12 H 10 N 2 F 2 220.0807; found 220.0810.
Figure BDA0003837221440000581
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Compound (3 b) column chromatography (petroleum ether/ethyl acetate=20:1) gave 80mg of a colorless oil in 97% yield. 1 H NMR(400MHz,Chloroform-d)δ8.99(d,J＝2.0Hz,1H),8.28(s,1H),8.14(d,J＝8.4Hz,1H),7.85(d,J＝8.4Hz,1H),7.77(t,J＝7.4Hz,1H),7.58(t,J＝7.4Hz,1H),6.23(dq,J＝17.6,10.1Hz,1H),5.64(dt,J＝17.2,2.8Hz,1H),5.57(d,J＝11.2Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-93.2(dd,J＝9.8,2.6Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ148.44,147.40(t,J＝5.0Hz),133.33(t,J＝6.1Hz),132.99(t,J＝5.0Hz),130.74,129.31,128.96(t,J＝5.0Hz),128.31,127.41,126.66,120.93(t,J＝9.2Hz),118.60(t,J＝239.3Hz).MS(ESI):m/z(％)206.1(M+H) + HRMS theoretical value C 12 H 10 NF 2 206.0776; found 206.0777.
Figure BDA0003837221440000582
Compound (3 c) column chromatography (petroleum ether/ethyl acetate=20:1) gave 90mg of a colorless oil in 74% yield. 1 H NMR(400MHz,Chloroform-d)δ8.28(d,J＝8.4Hz,1H),8.18(d,J＝8.5Hz,1H),7.86(d,J＝8.0Hz,1H),7.80–7.70(m,2H),7.61(t,J＝7.4Hz,1H),6.51(dq,J＝17.6,10.9Hz,1H),5.81(dt,J＝17.2,2.4Hz,1H),5.60(d,J＝11.2Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-97.2(dd,J＝10.9,2.6Hz,2F). 13 C NMR(101MHz,Chloroform-d)δ154.53(t,J＝30.6Hz),147.22,137.51,132.34(t,J＝27.4Hz),130.12,129.91,128.16,127.67,127.57,120.15(t,J＝9.2Hz),117.46(t,J＝240.9Hz),117.16(t,J＝3.4Hz).MS(EI):m/z(％)205(M) + HRMS theoretical value C 12 H 9 NF 2 205.0698; found 205.0701.
Figure BDA0003837221440000591
Compound (3 d). Column chromatography (petroleum ether/ethyl acetate=20:1) gave 86mg of a yellow oil in 90% yield. 1 H NMR(400MHz,Chloroform-d)δ8.85(d,J＝4.4Hz,1H),8.41(s,1H),8.19(d,J＝9.2Hz,1H),7.90–7.81(m,1H),7.56(d,J＝4.8Hz,1H),6.25(dq,J＝17.2,10.0Hz,1H),5.66(dt,J＝17.2,2.6Hz,1H),5.58(d,J＝11.2Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-93.6(dd,J＝9.4,2.6Hz,2F). 13 CNMR(126MHz,Chloroform-d)δ151.10,149.38,143.3,135.44(t,J＝27.9Hz),133.22(t,J＝29.9Hz),130.51,127.34(t,J＝4.7Hz),125.88,121.96,121.68(t,J＝6.7Hz),120.64(t,J＝9.1Hz),118.94(t,J＝239.8Hz).MS(EI):m/z(％)239(M) + HRMS theoretical value C 12 H 8 ClNF 2 239.0308; found 239.0307.
Figure BDA0003837221440000592
Compound (3 e) column chromatography (petroleum ether/ethyl acetate=3:1) gave 59mg of a colorless oil in 72% yield. 1 H NMR(400MHz,Chloroform-d)δ9.33(s,1H),8.76(s,1H),8.15(d,J＝8.4Hz,1H),8.04(d,J＝8.0Hz,1H),7.77(ddd,J＝10.0,6.8,1.6Hz,1H),7.67(t,J＝7.6Hz,1H),6.44–6.32(m,1H),5.65–5.56(m,2H). 19 F NMR(376MHz,Chloroform-d)δ-89.8(d,J＝9.4Hz,2F). 13 C NMR(101MHz,Chloroform-d)δ155.57,141.31(t,J＝9.1Hz),133.20(t,J＝29.1Hz),132.34(t,J＝1.5Hz),131.20,128.53,128.36,127.53,124.58(t,J＝3.3Hz),121.55(t,J＝9.4Hz),119.73(t,J＝239.5Hz).MS(FI):m/z(％)205(M) + HRMS theoretical value C 12 H 9 NF 2 205.0698; found 205.0701.
Figure BDA0003837221440000601
Compound (3 f) column chromatography (petroleum ether/ethyl acetate=2:1) gave 67mg of a yellow oil in 82% yield. 1 H NMR(400MHz,Chloroform-d)δ9.35(s,1H),8.62(s,1H),8.10–7.96(m,2H),7.80–7.65(m,2H),6.22(dq,J＝17.2,10.1Hz,1H),5.64(dt,J＝17.2,2.8Hz,1H),5.57(d,J＝10.8Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-94.3(d,J＝10.5Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ152.39,143.89,138.00(t,J＝27.7Hz),135.13,133.21(t,J＝29.7Hz),128.73,128.26,124.23(t,J＝4.8Hz),123.80(t,J＝6.6Hz),120.99,120.62(t,J＝9.2Hz),118.92(t,J＝239.7Hz).MS(EI):m/z(％)205(M) + HRMS theoretical value C 12 H 9 NF 2 205.0698; found 205.0701.
Figure BDA0003837221440000602
Compound (3 g) column chromatography (petroleum ether/ethyl acetate=20:1) gives 50mg of a colourless oil in 62% yield. 1 H NMR(400MHz,Chloroform-d)δ8.99(d,J＝5.6Hz,1H),8.39(d,J＝2.0Hz,1H),8.12(dd,J＝5.2,2.0Hz,1H),6.33(dq,J＝17.6,11.2Hz,1H),5.83(dt,J＝17.6,2.6Hz,1H),5.64(d,J＝11.2Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-98.2(dd,J＝11.3,2.6Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ157.86(t,J＝31.9Hz),154.63,151.96,131.16(t,J＝26.9Hz),121.26(t,J＝9.2Hz),117.36,116.43(t,J＝241.6Hz),113.25(t,J＝4.4Hz).MS(FI):m/z(％)200(M) + HRMS theoretical value C 8 H 6 O 2 N 2 F 2 200.0392; found 200.0393.
Figure BDA0003837221440000603
Compound (3 h) column chromatography (petroleum ether/ethyl acetate=15:1) gave 73mg of a colorless oil in 81% yield. 1 H NMR(400MHz,Chloroform-d)δ9.24(s,1H),8.41(dd,J＝8.0,2.0Hz,1H),7.73(d,J＝8.0Hz,1H),6.32(dq,J＝17.6,10.9Hz,1H),5.76(dt,J＝17.2,2.4Hz,1H),5.57(d,J＝11.2Hz,1H),4.43(q,J＝7.1Hz,2H),1.41(t,J＝7.2Hz,3H). 19 F NMR(376MHz,Chloroform-d)δ-98.7(dd,J＝10.9,2.6Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ164.48,157.96(t,J＝31.9Hz),150.55,138.36,131.79(t,J＝27.2Hz),127.16,120.59(t,J＝9.2Hz),119.60(t,J＝4.0Hz),116.93(t,J＝240.7Hz),61.73,14.20.MS(FI):m/z(％)227(M) + HRMS theoretical value C 11 H 11 O 2 NF 2 227.0752; found 227.0755.
Figure BDA0003837221440000611
Compound (3 i). Column chromatography (petroleum ether/ethyl acetate=3:1) gave 63mg of a colorless oil in 85% yield. 1 H NMR(400MHz,Chloroform-d)δ8.36(d,J＝12.4Hz,2H),7.31–7.27(m,1H),6.21–6.08(m,1H),5.61(dt,J＝17.6,2.8Hz,1H),5.55(d,J＝10.8Hz,1H),3.89(s,3H). 19 F NMR(376MHz,Chloroform-d)δ-93.7(dd,J＝9.8,3.0Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ155.32,139.37(t,J＝1.8Hz),139.22(t,J＝6.1Hz),132.85(t,J＝29.4Hz),132.56,120.74(t,J＝9.2Hz),118.18(t,J＝239.7Hz),117.27(t,J＝5.6Hz),55.68.MS(EI):m/z(％)185(M) + HRMS theoretical value C 9 H 9 ONF 2 185.0647; found 185.0649.
Figure BDA0003837221440000612
Compound (3 j). Column chromatography (petroleum ether/ethyl acetate=7:1) gave 60mg of a colorless oil in 83% yield. 1 H NMR(400MHz,Chloroform-d)δ10.17(s,1H),9.16(s,1H),8.99(s,1H),8.28(s,1H),6.17(dq,J＝17.6,10.3Hz,1H),5.70–5.58(m,2H). 19 F NMR(376MHz,Chloroform-d)δ-94.23(dd,J＝10.2,2.6Hz,2F). 13 CNMR(101MHz,Chloroform-d)δ189.77,152.97,151.93(t,J＝5.6Hz),133.17(t,J＝5.5Hz),132.32(t,J＝29.1Hz),130.87,121.49(t,J＝9.3Hz),117.86(t,J＝240.8Hz).MS(FI):m/z(％)183(M) + HRMS theoretical value C 9 H 7 ONF 2 183.0490; found 183.0493.
Figure BDA0003837221440000621
Compound (3 k). Column chromatography (petroleum ether/ethyl acetate=20:1) gave 67mg of a colorless oil in 91% yield. 1 H NMR(400MHz,Chloroform-d)δ8.22(d,J＝5.2Hz,1H),6.95(d,J＝5.2Hz,1H),6.85(s,1H),6.07(dq,J＝17.3,10.2Hz,1H),5.60(dt,J＝17.2,2.8Hz,1H),5.51(d,J＝10.8Hz,1H),3.95(s,3H). 19 F NMR(376MHz,Chloroform-d)δ-96.7(dd,J＝9.8,2.6Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ164.43,147.55,147.05(t,J＝25.8Hz),132.51(t,J＝29.2Hz),120.70(t,J＝9.3Hz),117.85(t,J＝239.9Hz),113.08(t,J＝5.0Hz),107.71(t,J＝6.0Hz),53.69.MS(EI):m/z(％)185(M) + HRMS theoretical value C 9 H 9 ONF 2 185.0647; found 185.0650.
Figure BDA0003837221440000622
Compound (3 l) column chromatography (petroleum ether/ethyl acetate=10:1) gave 67mg of a colorless oil in 85% yield. The product (67 mg,85% yield) was purified with silica gel chromatography (petroleum ether/ethyl acetate=10:1) as a yellow oil. 1 H NMR(400MHz,Chloroform-d)δ8.21(d,J＝5.2Hz,1H),6.63–6.55(m,2H),6.09(dq,J＝17.2,10.1Hz,1H),5.61(dt,J＝17.2,2.6Hz,1H),5.49(d,J＝10.8Hz,1H),3.11(s,6H). 19 F NMR(376MHz,Chloroform-d)δ-96.9(dd,J＝9.8,3.0Hz,2F). 13 C NMR(101MHz,Chloroform-d)δ159.40,148.47,145.31(t,J＝28.0Hz),132.98(t,J＝20.9Hz),120.29(t,J＝9.3Hz),118.46(t,J＝240.0Hz),107.71(t,J＝25.0Hz),101.71(t,J＝6.3Hz),38.10.MS(EI):m/z(％)198(M) + HRMS theoretical value C 10 H 12 N 2 F 2 198.0963; found 198.0967.
Figure BDA0003837221440000631
Compound (3 m) column chromatography (petroleum ether/ethyl acetate=2:1) gave 52mg of a colorless oil in 73% yield. 1 H NMR(400MHz,Chloroform-d)δ8.99(s,1H),8.92(d,J＝4.8Hz,1H),7.63(d,J＝5.2Hz,1H),6.16(dq,J＝17.2,10.5Hz,1H),5.77(dt,J＝17.2,2.6Hz,1H),5.69(d,J＝11.2Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-96.3(dd,J＝10.5,3.0Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ154.29,153.58,146.89(t,J＝29.5Hz),130.41(t,J＝28.3Hz),122.89(t,J＝9.3Hz),120.05(t,J＝6.5Hz),116.74(t,J＝243.2Hz),114.55,107.02.MS(FI):m/z(％)180(M) + HRMS theoretical value C 9 H 6 N 2 F 2 180.0494; found 180.0497.
Figure BDA0003837221440000632
Compound (3 n) columnChromatography (petroleum ether/ethyl acetate=15:1) gave 84mg of a colorless oil in 91% yield. 1 H NMR(400MHz,Chloroform-d)δ8.96(s,2H),6.31(dq,J＝17.6,11.0Hz,2H),5.82(dt,J＝17.6,2.4Hz,2H),5.64(d,J＝11.2Hz,2H). 19 FNMR(376MHz,Chloroform-d)δ-98.9(dd,J＝11.3,2.3Hz,2F). 13 C NMR(101MHz,Chloroform-d)δ151.10(t,J＝31.6Hz),140.83(t,J＝4.8Hz),131.06(t,J＝27.0Hz),121.46(t,J＝9.5Hz),116.58(t,J＝241.4Hz).MS(ESI):m/z(％)233(M+H) + HRMS theoretical value C 10 H 9 N 2 F 2 233.0696; found 233.0699.
Figure BDA0003837221440000633
Compound (3 o). Column chromatography (petroleum ether/ethyl acetate=10:1) gave 60mg of a yellow oil in 75% yield. 1 H NMR(400MHz,Chloroform-d)δ8.61(s,2H),6.25–6.05(m,1H),5.76–5.55(m,2H),4.46(q,J＝7.1Hz,2H),1.44(t,J＝7.0Hz,3H). 19 FNMR(376MHz,Chloroform-d)δ-92.59(dd,J＝9.4,2.6Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ165.96,157.26(t,J＝5.2Hz),132.48(t,J＝29.5Hz),123.59(t,J＝29.5Hz),121.25(t,J＝9.2Hz),117.93(t,J＝238.5Hz),64.15,14.32.MS(FI):m/z(％)200([M] + ) HRMS theoretical value C 9 H 10 O 2 N 2 F 2 200.0756; found 200.0751.
Figure BDA0003837221440000641
Compound (3 p) column chromatography (petroleum ether/ethyl acetate=10:1) gave 81mg of yellow oil in 82% yield. 1 H NMR(400MHz,Chloroform-d)δ8.67(s,2H),7.45(t,J＝8.0Hz,2H),7.29(t,J＝7.4Hz,1H),7.24–7.17(m,2H),6.23–6.07(m,1H),5.71–5.59(m,2H). 19 F NMR(376MHz,Chloroform-d)δ-92.8(dd,J＝9.8,3.0Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ166.11,157.72(t,J＝5.2Hz),152.50,132.23(t,J＝29.4Hz),129.72,125.87,125.06(t,J＝5.2Hz),121.55,121.49(t,J＝8.3Hz),117.66(t,J＝239.0Hz).MS(FI):m/z(％)248(M + ) HRMS theoretical value C 13 H 10 ON 2 F 2 248.0756; found 248.0753.
Figure BDA0003837221440000642
Compound (3 q). Column chromatography (petroleum ether/ethyl acetate=20:1) gave 86mg of a yellow oil in 92% yield. The product (86 mg,92% yield) was purified with silica gel chromatography (petroleum ether/ethyl acetate=20:1) as a yellow oil. 1 H NMR(400MHz,Chloroform-d)δ8.92(s,2H),8.56–8.44(m,2H),7.61–7.43(m,3H),6.30–6.10(m,1H),5.74–5.59(m,2H). 19 F NMR(376MHz,Chloroform-d)δ-94.1(dd,J＝9.8,2.6Hz,2F). 13 C NMR(101MHz,Chloroform-d)δ165.87,154.84(t,J＝5.4Hz),136.66,132.39(t,J＝29.4Hz),131.43,128.69,128.54,127.36(t,J＝29.2Hz),121.51(t,J＝9.3Hz),117.88(t,J＝239.7Hz).MS(EI):m/z(％)232(M + ) HRMS theoretical value C 13 H 10 N 2 F 2 232.0807; found 232.0811.
Figure BDA0003837221440000651
Compound (3 r) column chromatography (petroleum ether/ethyl acetate=7:1) gave 84mg of a yellow oil in 87% yield. 1 H NMR(400MHz,Chloroform-d)δ8.40(s,2H),6.20–6.05(m,1H),5.61(dt,J＝17.2,2.8Hz,1H),5.54(d,J＝10.8Hz,1H),3.88–3.73(m,8H). 19 F NMR(376MHz,Chloroform-d)δ-91.8(dd,J＝9.4,2.6Hz,2F). 13 CNMR(126MHz,Chloroform-d)δ161.87,155.74(t,J＝5.2Hz),132.92(t,J＝30.3Hz),120.64(t,J＝9.0Hz),118.57(t,J＝237.3Hz),118.25(t,J＝29.4Hz),66.72,44.17.MS(FI):m/z(％)241(M + ) HRMS theoretical value C 11 H 13 ON 3 F 2 241.1021; found 241.1019.
Figure BDA0003837221440000652
Compound (3 s) column chromatography (petroleum ether/ethyl acetate=7:1) gave 47mg of a yellow oil in 63% yield. 1 H NMR(400MHz,Chloroform-d)δ9.94(s,1H),7.74–7.66(m,1H),7.35–7.30(m,1H),6.20(dq,J＝17.6,10.3Hz,1H),5.76(dt,J＝16.8,2.4Hz,1H),5.62(d,J＝10.8Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-85.2(d,J＝9.4Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ182.98,147.48(t,J＝32.9Hz),145.05(t,J＝1.3Hz),135.28,132.00(t,J＝32.9Hz),127.70(t,J＝5.0Hz),121.27(t,J＝8.8Hz),116.59(t,J＝239.3Hz).MS(FI):m/z(％)188(M + ) HRMS theoretical value C 8 H 6 OSF 2 188.0102; found 188.0105.
Figure BDA0003837221440000653
Compound (3 t). Column chromatography (petroleum ether/ethyl acetate=20:1) gave 76mg of a yellow oil in 82% yield. 1 H NMR(400MHz,Chloroform-d)δ7.78(s,1H),7.68(s,1H),6.24–6.07(m,1H),5.62(dt,J＝17.2,2.6Hz,1H),5.52(d,J＝10.8Hz,1H),4.35(q,J＝7.2Hz,2H),1.37(t,J＝7.0Hz,3H). 19 F NMR(376MHz,Chloroform-d)δ-89.3(dd,J＝10.0,2.8Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ161.52,138.33(t,J＝31.2Hz),135.50,132.75(t,J＝29.5Hz),130.84(t,J＝3.6Hz),130.40(t,J＝5.9Hz),120.44(t,J＝9.1Hz),116.72(t,J＝237.1Hz),61.50,14.23.MS(FI):m/z(％)232(M + ) HRMS theoretical value C 10 H 10 O 2 SF 2 232.0364; found 232.0366.
Figure BDA0003837221440000661
Compound (3 u). Column chromatography (petroleum ether/ethyl acetate=20:1) gave 80mg of yellow oil in 95% yield. 1 H NMR(400MHz,Chloroform-d)δ8.00(s,1H),7.94(d,J＝8.4Hz,1H),7.53(d,J＝5.6Hz,1H),7.50–7.43(m,1H),7.39(d,J＝5.6Hz,1H),6.24(dq,J＝17.2,10.0Hz,1H),5.62(dt,J＝17.2,2.8Hz,1H),5.52(d,J＝10.8Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-92.2(dd,J＝9.4,2.6Hz). 13 C NMR(126MHz,Chloroform-d)δ141.10,139.20,133.90(t,J＝30.4Hz),132.49(t,J＝27.6Hz),127.71,124.05,122.58,121.40(t,J＝5.2Hz),120.79(t,J＝6.3Hz),119.86(t,J＝9.2Hz),119.63(t,J＝238.9Hz).MS(FI):m/z(％)210(M + ) HRMS theoretical value C 11 H 8 SF 2 210.0309; found 210.0312.
Figure BDA0003837221440000662
Compound (3 v). Column chromatography (petroleum ether/ethyl acetate=20:1) gave 100mg of yellow oil in 96% yield. 1 H NMR(400MHz,Chloroform-d)δ8.31(s,1H),8.23–8.17(m,1H),7.95–7.83(m,2H),7.59(d,J＝8.0Hz,1H),7.54–7.46(m,2H),6.28(dq,J＝17.2,9.9Hz,1H),5.66(dt,J＝17.2,2.8Hz,1H),5.56(d,J＝10.8Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-92.2(dd,J＝9.8,2.6Hz,2F). 13 CNMR(101MHz,Chloroform-d)δ141.07(t,J＝1.5Hz),139.78,135.41,135.04,133.89(t,J＝30.5Hz),132.66(t,J＝27.8Hz),127.19,124.62,123.86(t,J＝5.4Hz),122.85,122.81,121.77,120.04(t,J＝9.1Hz),119.61(t,J＝239.4Hz),118.68(t,J＝6.2Hz).MS(FI):m/z(％)260(M + ) HRMS: theoretical 260.0466; found 260.0467.
Figure BDA0003837221440000671
Compound (3 w). Column chromatography (petroleum ether/ethyl acetate=20:1) gave 68mg of a colorless oil in 88% yield. 1 H NMR(400MHz,Chloroform-d)δ7.77(t,J＝1.8Hz,1H),7.68(d,J＝7.6Hz,1H),7.53(d,J＝8.0Hz,1H),7.34(dt,J＝25.2,7.8Hz,2H),6.37–6.20(m,1H),5.75(dt,J＝17.2,2.6Hz,1H),5.59(d,J＝10.8Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-90.2(dt,J＝9.9,2.2Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ155.53,143.78(t,J＝8.1Hz),132.48(t,J＝29.3Hz),125.21,124.16(t,J＝2.0Hz),123.48,120.87(t,J＝8.7Hz),120.80,118.19(t,J＝32.1Hz),117.41(t,J＝233.6Hz),111.76.MS(FI):m/z(％)194(M + ) HRMS theoretical value C 11 H 8 OF 2 194.0538; found 194.0540.
Figure BDA0003837221440000672
Compound (3 x) column chromatography (petroleum ether/ethyl acetate=20:1) gave 68mg of a colorless oil in 88% yield. 1 H NMR(400MHz,Chloroform-d)δ7.78(s,1H),7.69(d,J＝2.4Hz,1H),7.55(d,J＝8.8Hz,1H),7.48–7.42(m,1H),6.82(d,J＝2.0Hz,1H),6.30–6.13(m,1H),5.59(dt,J＝17.6,2.8Hz,1H),5.50(d,J＝10.8Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-91.3(dd,J＝9.4,2.6Hz,2F). 13 C NMR(101MHz,Chloroform-d)δ155.45,146.08,134.12(t,J＝30.5Hz),131.09(t,J＝27.6Hz),127.30,121.96(t,J＝5.5Hz),119.68(t,J＝239.2Hz),119.66(t,J＝9.1Hz),118.84(t,J＝6.2Hz),111.38,106.83.MS(FI):m/z(％)194(M + ) HRMS theoretical value C 11 H 8 OF 2 194.0538; found 194.0536.
Figure BDA0003837221440000681
Compound (3 y). Column chromatography (petroleum ether/ethyl acetate=20:1) gave 95mg of a colorless oil in 98% yield. 1 H NMR(400MHz,Chloroform-d)δ8.13(s,1H),8.01–7.95(m,1H),7.66–7.57(m,3H),7.54–7.47(m,1H),7.41–7.35(m,1H),6.36–6.20(m,1H),5.64(dt,J＝17.2,2.8Hz,1H),5.55(d,J＝11.2Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-91.3(dd,J＝9.5,2.6Hz,2F). 13 C NMR(101MHz,Chloroform-d)δ156.75(t,J＝1.6Hz),156.70,134.03(t,J＝30.5Hz),131.00(t,J＝27.8Hz),127.73,124.76(t,J＝5.5Hz),124.27,123.70,123.07,120.81,119.92(t,J＝9.1Hz),119.62(t,J＝239.4Hz),118.25(t,J＝6.1Hz),111.83,111.61.MS(FI):m/z(％)244(M + ) HRMS theoretical value C 15 H 10 OF 2 244.0694; found 244.0693.
Figure BDA0003837221440000682
Compound (3 z). Column chromatography (petroleum ether/ethyl acetate=10:1) gave 105mg of a colorless oil in 90% yield. 1 H NMR(400MHz,Chloroform-d)δ8.62(d,J＝1.6Hz,1H),8.02(d,J＝1.6Hz,1H),7.71(d,J＝4.0Hz,1H),6.55(d,J＝4.0Hz,1H),6.21(dq,J＝17.6,9.5Hz,1H),5.61–5.45(m,2H),1.67(s,9H). 19 F NMR(376MHz,Chloroform-d)δ-91.7(dd,J＝9.4,3.0Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ148.73,147.66,142.84(t,J＝5.8Hz),133.52(t,J＝30.2Hz),127.92,126.92(t,J＝28.0Hz),126.61(t,J＝5.7Hz),122.26,120.52(t,J＝9.1Hz),119.11(t,J＝239.0Hz),104.56,84.55,28.02.MS(FI):m/z(％)244(M + ) HRMS theoretical value C 15 H 16 O 2 N 2 F 2 294.1174; found 294.1181.
Figure BDA0003837221440000683
Compound (3 aa) column chromatography (petroleum ether/ethyl acetate=20:1) gave 76mg of a colorless oil in 87% yield. 1 H NMR(400MHz,Chloroform-d)δ7.56(d,J＝8.4Hz,2H),7.45(d,J＝8.4Hz,2H),7.12(s,2H),6.37(s,2H),6.25–6.10(m,1H),5.61(dt,J＝17.6,2.4Hz,1H),5.52(d,J＝11.2Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-93.0(dd,J＝9.8,2.3Hz,2F). 13 C NMR(101MHz,Chloroform-d)δ141.85,133.57(t,J＝30.4Hz),133.32(t,J＝28.1Hz),127.03(t,J＝5.7Hz),120.03(t,J＝9.2Hz),120.01,119.17,119.07(t,J＝239.3Hz),111.01.MS(EI):m/z(％)219(M + ) HRMS theoretical value C 13 H 11 NF 2 219.0854; found 219.0856.
Figure BDA0003837221440000691
Compound (3 ab). Column chromatography (petroleum ether/ethyl acetate=20:1) gave 76mg of a colorless oil in 87% yield. 1 H NMR(400MHz,Chloroform-d)δ7.96(d,J＝2.4Hz,1H),7.80–7.72(m,3H),7.59(d,J＝8.8Hz,2H),6.49(t,J＝2.0Hz,1H),6.18(dq,J＝17.2,9.8Hz,1H),5.59(dt,J＝17.6,2.8Hz,1H),5.51(d,J＝11.2Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-93.0(d,J＝9.4Hz,2F). 13 C NMR(101MHz,Chloroform-d)δ141.55,141.20,134.09(t,J＝28.2Hz),133.52(t,J＝30.1Hz),126.90(t,J＝5.7Hz),126.73,120.13(t,J＝9.2Hz),119.04(t,J＝239.3Hz),118.76,108.09.MS(EI):m/z(％)220(M + ) HRMS theoretical value C 12 H 10 N 2 F 2 220.0807; found 220.0812.
Figure BDA0003837221440000692
Compound (3 ac). Column chromatography (petroleum ether/ethyl acetate=30:1) gave 120mg of a yellow oil in 94% yield. 1 H NMR(400MHz,Chloroform-d)δ8.18(d,J＝7.6Hz,2H),7.77(s,1H),7.73–7.61(m,3H),7.49–7.40(m,4H),7.37–7.30(m,2H),6.24(dq,J＝17.2,10.1Hz,1H),5.70(dt,J＝17.2,2.6Hz,1H),5.57(d,J＝10.8Hz,1H). 19 F NMR(376MHz,Chloroform-d)δ-93.7(dd,J＝9.8,2.6Hz,2F). 13 CNMR(101MHz,Chloroform-d)δ140.61,138.38(t,J＝28.2Hz),138.02,133.38(t,J＝29.9Hz),130.12,128.49,126.09,124.39(t,J＝5.7Hz),124.28(t,J＝5.8Hz),123.50,120.39,120.25(t,J＝9.2Hz),120.23,118.79(t,J＝240.1Hz),109.53.MS(FI):m/z(％)319(M + ) HRMS theoretical value C 21 H 15 NF 2 319.1167; found 319.1170.
Figure BDA0003837221440000701
Compound (3 ad) column chromatography (petroleum ether/ethyl acetate=3:1) gives 76mg of a white solidThe yield was 91%. 1 H NMR(400MHz,Chloroform-d)δ7.98(d,J＝8.0Hz,1H),7.72–7.62(m,2H),6.15(dq,J＝17.2,10.3Hz,1H),5.62(dt,J＝17.6,2.8Hz,1H),5.56(d,J＝10.8Hz,1H),5.37(s,2H). 19 F NMR(376MHz,Chloroform-d)δ-94.2(dd,J＝9.8,2.6Hz,2F). 13 C NMR(126MHz,Chloroform-d)δ170.09,146.69,142.20(t,J＝27.8Hz),132.88(t,J＝29.5Hz),127.22,126.73(t,J＝5.4Hz),126.02,120.78(t,J＝9.3Hz),119.49(t,J＝6.0Hz),118.58(t,J＝240.5Hz),69.58.MS(FI):m/z(％)210(M + ) HRMS theoretical value C 11 H 8 O 2 F 2 210.0487; found 210.0485.
Figure BDA0003837221440000702
Compound (4 a) column chromatography (petroleum ether/ethyl acetate=3:1) gave 106mg of a yellow oil in 90% yield. The product (106 mg,90% yield) was purified with silica gel chromatography (petroleum ether/ethyl acetate=20:1) as a yellow oil. 1 H NMR(400MHz,Chloroform-d)δ7.94(s,1H),7.70(s,1H),7.63(d,J＝8.4Hz,2H),7.50–7.40(m,4H),7.36–7.29(m,4H),5.84(t,J＝1.8Hz,1H),5.66(s,1H). 19 FNMR(376MHz,Chloroform-d)δ-84.2(s,2F). 13 C NMR(126MHz,Chloroform-d)δ145.13(t,J＝25.9Hz),139.52,139.03(t,J＝3.8Hz),136.19,129.49,128.35,128.29,128.16,127.14,126.02(t,J＝5.1Hz),121.30(t,J＝32.8Hz),119.34,118.84(t,J＝7.8Hz),117.79(t,J＝238.0Hz).
Figure BDA0003837221440000711
Compound (4 b) column chromatography (petroleum ether/ethyl acetate=6:1) gave 126mg of yellow oil in 89% yield. 1 H NMR(400MHz,Chloroform-d)δ8.12(s,1H),8.00(d,J＝7.6Hz,1H),7.97(s,1H),7.69(s,1H),7.63(d,J＝7.6Hz,3H),7.43(dt,J＝16.1,7.7Hz,3H),7.32(t,J＝7.4Hz,1H),5.89(s,1H),5.71(s,1H),3.91(s,3H). 19 F NMR(376MHz,Chloroform-d)δ-84.34(s,2F). 13 C NMR(126MHz,Chloroform-d)δ166.68,144.43(t,J＝26.2Hz),139.47,138.96(t,J＝3.8Hz),136.46,132.49,130.33,129.50,129.45(t,J＝8.9Hz),128.41,127.22,126.00(t,J＝5.0Hz),120.92(t,J＝8.9Hz),119.96(t,J＝7.7Hz),119.39,117.73(t,J＝238.2Hz),52.23.
The above examples show that when R' is a substituent such as an aryl group, steric hindrance, charge properties of the substituent, etc. do not have a significant influence on the reaction, and similar effects can be achieved. The reaction has better substrate applicability, and further widens the subsequent application and industrialization.
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims (10)

1. The preparation method of the 3, 3-difluoroallyl compound shown in the formula F is characterized by comprising the following steps:
in an organic solvent, in the presence of alkali and a copper catalyst, carrying out the following reaction between a compound shown in a formula A and a compound shown in a formula B to obtain a 3, 3-gem-difluoroallyl compound shown in a formula F; the organic solvent is a mixture of one or more of halogenated aromatic hydrocarbon solvents, ether solvents and ester solvents and amide solvents;
Figure FDA0003837221430000011
Wherein R and R' are
Figure FDA0003837221430000012
R 'and R' are H, C 1 -C 20 Is or are R a Substitution ofC 1 -C 20 Alkyl, 5-7 membered heterocycloalkyl, or by one or more R b Substituted 5-7 membered heterocycloalkyl, C 1 -C 20 Is/are R c Substituted C 1 -C 20 alkyl-O-, C 6 -C 20 Is or are R d Substituted C 6 -C 20 Is aryl, 5-14 membered heteroaryl, substituted with one or more R e The heteroatoms in the substituted 5-14 membered heteroaryl, the 5-7 membered heterocycloalkyl, and the 5-14 membered heteroaryl are independently selected from one or more of N, O and S;
z is Si or Sn;
R 1 and R is 1’ H, C independently 1 -C 20 Is or are R a Substituted C 1 -C 20 Alkyl of (a);
alternatively, R 1 And R is 1’ Connected to and connected to
Figure FDA0003837221430000013
Together form: 5-7 membered heterocycloalkyl, or by one or more R b Substituted 5-7 membered heterocycloalkyl; wherein the heteroatom of the 5-7 membered heterocycloalkyl which is substituted or unsubstituted by a substituent is B and O;
R 2 、R 3 and R is 4 Independently is halogen, C 1 -C 20 Is or are R c Substituted C 1 -C 20 Alkyl, C of (2) 1 -C 20 Is/are R d Substituted C 1 -C 20 alkyl-O-, C 6 -C 20 Is or are R e Substituted C 6 -C 20 Aryl of (a);
alternatively, R 2 、R 3 And R is 4 Any 2 of which are linked together with the linked Z to form: 5-7 membered heterocycloalkyl, or by one or more R f Substituted 5-7 membered heterocycloalkyl; wherein the heteroatom of the 5-7 membered heterocycloalkyl group which is substituted or unsubstituted by a substituent is Si or Sn as shown;
R a 、R b 、R c 、R d 、R e and R is f Independently is halogen, C 1 -C 20 Alkyl, C of (2) 1 -C 20 alkyl-O-C (=o) -, C 1 -C 20 alkyl-O-or C 6 -C 20 When C is aryl 6 -C 20 Is singly linked or is connected with the 5-7 membered heterocyclic alkyl in a parallel ring.
2. The method of preparation of claim 1, wherein the method of preparation satisfies one or more of the following conditions:
(1) The ester solvent is ethyl acetate; the halogenated aromatic solvent is chlorobenzene or fluorobenzene; the ether solvent is one or more of diethylene glycol dimethyl ether, dioxane and tetrahydrofuran; the amide solvent is one or more of dimethylacetamide, N-dimethylformamide, N-methylpyrrolidone and N, N-dimethylpropenyl urea; preferably a mixed solvent of tetrahydrofuran and dimethylacetamide;
(2) The volume ratio of the total volume of one or more of the halogenated aromatic solvents, ether solvents, and ester solvents to the amide solvents in the mixture is 100:1 to 1:100, e.g., 7.2:1, 3.2:1, 2.4:1, 2:1, 1.6:1, 1:1, 1:1.25, 1:2.5;
(3) The mass volume ratio of the compound shown in the formula A to the organic solvent is 0.01 mol/L-2 mol/L, for example 0.15 mol/L-1 mol/L;
(4) The mol ratio of the compound shown in the formula A to the compound shown in the formula B is 1:1.5 to 2:1; for example 1.5:1 to 2:1;
(5) The compound shown in the formula A is added in a solution form, for example, in a dimethylacetamide DMA solution, for example, 1.2M in DMA; alternatively, the compound shown in the formula A is added in a gas form; the gas pressure may be 1atm;
(6) The alkali is alcohol alkali metal alkali or alkali metal hydroxide; such as one or more of sodium hydroxide, potassium hydroxide, lithium t-butoxide, sodium t-butoxide, potassium t-butoxide, sodium methoxide, potassium methoxide, and lithium methoxide; and for example one or more of lithium t-butoxide, potassium methoxide and lithium methoxide;
(7) The molar ratio of the alkali to the compound shown as the formula A is 1.5:1 to 3:1; for example 2:1 to 2.5:1;
(8) The copper catalyst is a copper salt catalyst, such as halogenated cuprous, and also such as cuprous chloride;
(9) The molar ratio of the copper catalyst to the compound shown as the formula A is 0.00001:1 to 0.1:1; for example 0.00001:1, 0.0001:1, 0.0002:1, 0.001, 0.01:1, 0.05:1;
(10) The reaction is carried out under an inert atmosphere, which can be argon or nitrogen;
(11) The reaction is carried out in the presence of a ligand which may be selected from: 1, 3-bis (diphenylphosphine) propane, 1-bis (diphenylphosphine) ethane, 1-bis (diphenylphosphine) methane, bis (2-diphenylphosphine phenyl) ether, (R) - (+) -DM-SegPhos, bpy, 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene and
Figure FDA0003837221430000031
one or more of the following; preferably (R) - (+) -DM-SegPhos, 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene; the molar ratio of the ligand to the compound of formula a may be 1.5:1 to 3:1; for example 2:1 to 2.5:1;
(12) The temperature of the reaction is 10 to 80 ℃; for example 10 to 35 ℃;
(13) The raw materials in the reaction are the alkali, copper catalyst, compound shown in formula A, compound shown in formula B and the organic solvent;
(14) The reaction is as follows:
Figure FDA0003837221430000032
wherein R and R' are as defined in claim 1.
3. The preparation method according to claim 1 or 2, wherein the preparation method satisfies one or more of the following conditions:
(1)R”、R”’、R 1 、R 1’ 、R 2 、R 3 、R 4 、R a 、R b 、R c 、R d and R is f In (C) 1 -C 20 Alkyl, substituted C 1 -C 20 C in the alkyl group of (2) 1 -C 20 The alkyl groups of (a) are independently C 1 -C 10 Alkyl groups of (2), e.g. C 1 -C 6 Also for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
(2)R 2 、R 3 、R 4 、R a 、R b 、R c 、R d 、R e and R is f In (C) 1 -C 20 alkyl-O-, substituted C 1 -C 20 C in alkyl-O-of (C) 1 -C 20 The alkyl groups of (a) are independently C 1 -C 10 Alkyl groups of (2), e.g. C 1 -C 6 Also for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
(3)R 2 、R 3 、R 4 、R a 、R b 、R c 、R d 、R e and R is f Wherein the halogen is F, cl and Br;
(4)R”、R”’、R 2 、R 3 、R 4 、R a 、R b 、R c 、R d 、R e and R is f In (C) 6 -C 20 Aryl, substituted C 6 -C 20 C in aryl of (C) 6 -C 20 Is independently phenyl;
(5)R 1 and R is 1’ Connected to and connected to
Figure FDA0003837221430000041
Together form: 5-7 membered heterocycloalkyl, or by one or more R b In the substituted 5-7 membered heterocycloalkyl, the 5-7 membered heterocycloalkyl is +.>
Figure FDA0003837221430000042
Figure FDA0003837221430000043
4. A method of preparation as claimed in claim 3, wherein the method of preparation satisfies one or more of the following conditions:
(1)R b independently H, methyl, me-O-C (=o) -or phenyl;
(2)R 2 、R 3 and R is 4 Independently Cl, methyl, ethyl, phenyl, methyl-O-, n-butyl;
(3) R' is independently H, phenyl,
Figure FDA0003837221430000044
Figure FDA0003837221430000045
(4) R' "is independently H or
Figure FDA0003837221430000046
(5)R a Independently phenyl;
(6)R d h, cl, methoxy or-COOMe;
(7) R and R' are
Figure FDA0003837221430000051
Figure FDA0003837221430000052
5. The preparation method of claim 1, wherein the 3, 3-difluoroallyl compound of formula F has any one of the following structures:
Figure FDA0003837221430000053
6. a 3, 3-difluoroallyl compound of any one of the following structures:
Figure FDA0003837221430000054
Figure FDA0003837221430000061
7. an application of 3, 3-difluoroallyl compounds shown in a formula F, wherein the 3, 3-difluoroallyl compounds shown in the formula F are used as alpha, alpha-gem-difluoroallylation reagents,
Figure FDA0003837221430000062
/>
wherein R, R "and R'" are as defined in any one of claims 1 to 6.
8. The use according to claim 7, wherein,
the 3, 3-difluoroallyl compound shown in the formula F is
Figure FDA0003837221430000063
Wherein R is as defined in any one of claims 1 to 6;
and/or, the application is as follows: taking the 3, 3-difluoroallyl compound shown as a formula F as an alpha, alpha-gem difluoroallylation reagent, and carrying out suzuki coupling reaction on the reagent and halogenated aromatic hydrocarbon or halogenated heteroaromatic hydrocarbon compound to prepare alpha, alpha-gem difluoroallyl substituted aromatic hydrocarbon or heteroaromatic hydrocarbon compound;
for example, the application includes the steps of:
in an organic solvent, in the presence of a catalyst and alkali, carrying out a suzuki coupling reaction on a 3, 3-difluoroallyl compound shown as a formula F and halogenated aromatic hydrocarbon or halogenated heteroaromatic hydrocarbon compound to prepare the alpha, alpha-gem difluoroallyl substituted aromatic hydrocarbon or heteroaromatic hydrocarbon compound.
9. The application of claim 8, wherein the application satisfies one or more of the following conditions:
(1) The molar ratio of the 3, 3-difluoroallyl compound shown in the formula F to the halogenated aromatic hydrocarbon or heteroaromatic hydrocarbon compound is 1.5:1 to 1:1.5;
(2) The solvent is one or more of ether solvents, amide solvents, nitrile solvents, halogenated aromatic solvents and ester solvents; the ether solvent can be dioxane, tetrahydrofuran or ethylene glycol dimethyl ether; the amide solvent can be one or more of N, N-dimethylformamide and N, N-dimethylacetamide; the nitrile solvent can be acetonitrile; the halogenated aromatic solvent can be chlorobenzene; the ester solvent can be ethyl acetate;
(3) The mass volume ratio of the compound shown in the formula F to the organic solvent is 0.01 mol/L-2 mol/L; for example, 0.1mol/L to 0.375mol/L;
(4) The compound shown in the formula F is added in the form of a mixture with the solvent, and the concentration of the compound shown in the formula F in the mixture can be 3M;
(5) The catalyst is a Pd catalyst, for example selected from the group consisting of: pd (PPh) 3 ) 4 、PdCl 2 (dppf)、PdBr 2 、Pd(acac) 2 、PdCl 2 (PhCN) 2 、PdCl 2 (PPh 3 ) 2 、PdCl 2 (CH 3 CN) 2 、PdCl 2 (PCy 3 ) 2 、Pd(OAc) 2 、Pd(CF 3 COO) 2 、PdCl 2 、PdI 2 、PdCl 2 (dppb)、Pd 2 (dba) 3 、PdCl 2 (dppp)Pd(DPPF)Cl 2 、
Figure FDA0003837221430000071
Figure FDA0003837221430000072
Also e.g. PdBR 2 、PdCl 2 (PhCN) 2 、PdCl 2 (CH 3 CN) 2 ；
(6) The molar ratio of the catalyst to the 3, 3-difluoroallyl compound shown as the formula F is 0.0002:1 to 0.2:1; for example 0.01, 0.0375:1, 0.05:1, 0.001:1, 0.0002:1;
(7) The alkali is one or more of alkali metal fluoride, alkali metal hydroxide, alkali metal alkoxide, alkali metal carbonate and alkali metal phosphate; the alkali metal fluoride can be LiF, csF or KF; the alkali metal hydroxide can be NaOH, the alkali metal alkoxide can be Meona, meoli or t-Buona, and the alkali metal carbonate can be K 2 CO 3 、Cs 2 CO 3 The alkali metal phosphate can be K 3 PO 4 The method comprises the steps of carrying out a first treatment on the surface of the Preferably CsF;
(8) The molar ratio of the alkali to the 3, 3-difluoroallyl compound shown in the formula F is 1.5:1 to 3:1; for example 2.25:1;
(9) The reaction is carried out under an inert atmosphere, which can be argon or nitrogen;
(10) The suzuki coupling reaction is carried out in the presence of a ligand selected from the group consisting of: triphenylphosphine PPh 3 1, 2-bis (diphenylphosphine) benzene dppbz, 1' -bis (diphenylphosphine) ferrocene dppf, 1, 3-bis (diphenylphosphine) propane dppp, 1-bis (diphenylphosphine) ethane dppe, 1-bis (diphenylphosphine) methane dppm, bis (2-diphenylphosphine phenyl) ether DPEphos, (R) - (+) -DM-SegPhos, bpy and 4,5- Bis (diphenylphosphine) -9, 9-dimethylxanthenes Xantphos; for example PPh 3 ；
(11) The molar ratio of the ligand to the catalyst is from 1:1 to 5:1, for example from 2:1 to 3.7:1;
(12) The temperature of the reaction is from 10 to 100 ℃, for example from 60 to 80 ℃;
(13) The halogenated aromatic hydrocarbon compound and the alpha, alpha-gem difluoroallyl substituted aromatic hydrocarbon compound thereof are Ar-X and
Figure FDA0003837221430000081
wherein Ar is C substituted or unsubstituted by a substituent 6 -C 14 An aryl group; x is the halogen; the number of X may be 1 or more, for example 1, 2; the C is 6 -C 14 The aromatic ring may be a benzene ring or a naphthalene ring; the substituents may be: halogen, -CN, -NO 2 Methyl, trifluoromethyl, methyl-O-, bz, OBn, =s, =o, aldehyde, -NH 2 、-NMe 2 、-COOMe、-COOEt、-COOH、-OTBS、-Ts、/>
Figure FDA0003837221430000082
(14) The halogenated heteroarene compound and the alpha, alpha-gem difluoroallyl substituted heteroarene compound are hetAr-X
Figure FDA0003837221430000083
Or X-HetAr-X +.>
Figure FDA0003837221430000084
Wherein HetAr is a 5-14 membered heteroaryl substituted or unsubstituted with a substituent, X is said halogen; the number of X may be 1 or more, for example 1, 2; the hetero atom in HetAr is selected from one or more of N, O and S; such as furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolopyridyl, indazolyl, benzothiazolyl, dibenzothienyl, benzofuryl, pyrrolopyridinyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, and quinolyl An oxazolinyl group, a bipyridyl group, a benzothienyl group, a pyrazolyl group, a dibenzothienyl group, a benzofuranyl group, a benzothiazolinyl group, and a benzothiazolonyl group; the substituents may be: halogen, -CN, -NO 2 Methyl, trifluoromethyl, methyl-O-, ethyl-O-, phO-, boc-, bz, OBn, =s, =o, aldehyde, -NH 2 、-NMe 2 、-COOMe、-COOEt、-COOH、-OTBS、-Ts、/>
Figure FDA0003837221430000091
Figure FDA0003837221430000092
10. The use according to claim 8 or 9, wherein,
the halogenated aromatic hydrocarbon or heteroaromatic hydrocarbon compound and the corresponding alpha, alpha-geminal difluoroallyl substituted aromatic hydrocarbon or heteroaromatic hydrocarbon compound are any one group of the following:
Figure FDA0003837221430000093
/>
Figure FDA0003837221430000101
/>
Figure FDA0003837221430000111
/>
Figure FDA0003837221430000121
/>
Figure FDA0003837221430000131
/>
Figure FDA0003837221430000141
/>
CN202211091590.4A 2021-09-07 2022-09-07 3, 3-gem difluoro allyl compound, preparation method and application thereof Pending CN116102584A (en)

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