CN112079678B - Method for constructing carboxylic acid or alcohol by olefin remote functionalization - Google Patents

Method for constructing carboxylic acid or alcohol by olefin remote functionalization Download PDF

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CN112079678B
CN112079678B CN202010982401.7A CN202010982401A CN112079678B CN 112079678 B CN112079678 B CN 112079678B CN 202010982401 A CN202010982401 A CN 202010982401A CN 112079678 B CN112079678 B CN 112079678B
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carboxylic acid
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余达刚
宋磊
付东民
陈亮
蒋元旭
叶剑衡
朱磊
蓝宇
付强
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Sichuan University
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    • C07C2601/14—The ring being saturated

Abstract

The invention discloses a method for constructing carboxylic acid or alcohol by olefin remote functionalization. The method comprises the following steps: (1) mixing an olefinic compound, a photocatalyst, a base, and a radical precursor; dissolving the obtained solid phase mixture in a nitrogen atmosphere, filling carbon dioxide after freezing and degassing, and then stirring for 2-10 min; or adding aldehyde or ketone into the obtained solid phase mixture, dissolving in a nitrogen atmosphere, freezing, degassing, filling nitrogen, and stirring for 2-10 min; (2) then, under the condition of room temperature, blue light is adopted for irradiation reaction for 2-30 h; after the reaction is finished, diluting with ethyl acetate, then quenching with hydrochloric acid, then extracting with ethyl acetate, and purifying after rotary evaporation and concentration to obtain the carboxylic acid or alcohol. The synthetic method of the invention has good reactivity for activated olefin and non-activated olefin substrates, and the yield of the target product is high.

Description

Method for constructing carboxylic acid or alcohol by olefin remote functionalization
Technical Field
The invention belongs to the technical field of compound synthesis, and particularly relates to a method for constructing carboxylic acid or alcohol through olefin remote functionalization.
Background
The bifunctional of olefins is an effective means of synthesizing complex compound molecules from simple substrates. The investigation of remote bifunctional reactions of non-activated olefins is a challenging but very attractive topic. Meanwhile, carbon dioxide is widely used in various chemical syntheses as an excellent carbon-carbon synthon which is wide in source, cheap, easy to obtain and reproducible. Due to the wide variety of olefins and the low price and easy availability, the realization of the carboxylation reaction of the olefins by using carbon dioxide is widely concerned by scientists. In addition, the reaction of carbonyl compounds such as aldehyde ketone and olefin to construct alcohol compounds is also an important synthetic reaction.
Visible light promoted difunctionalization of olefins has been previously reported, but visible light promoted difunctionalization of non-activated olefins has remained challenging, all using activated olefins as substrates. The alkene 1, 2-bifunctional carboxylation reaction promoted by carbon dioxide under visible light has been reported for many times, and can be used for a substrate with a double bond structure to construct a functionalized complex molecule. Scientists are increasingly interested in remote C-H functionalization and are trying to explore different strategies for the bi-functional migration of olefins to synthesize remotely functionalized products.
Disclosure of Invention
In view of the above-mentioned shortcomings in the prior art, the present invention provides a method for constructing carboxylic acid or alcohol by olefin remote functionalization, so as to provide an efficient and feasible strategy for the research blank of the reaction of synthesizing carboxylic acid and alcohol by olefin remote functionalization.
In order to achieve the purpose, the technical scheme adopted by the invention for solving the technical problems is as follows:
a method for the remote functionalization of an olefin to build a carboxylic acid or alcohol, comprising the steps of:
(1) adding stirrer, olefin compound and photocatalyst into a dry Schlenk tube, transferring the Schlenk tube into a glove box after mixing, adding alkali and free radical precursor, sealing the Schlenk tube, and pumping N2Twice, in a nitrogen atmosphere, adding a solvent, introducing carbon dioxide, and stirring for 2-10 min; or adding aldehyde or ketone into the obtained solid phase mixture, adding a solvent in a nitrogen atmosphere for dissolving, then introducing nitrogen after freezing and degassing, and stirring for 2-10 min;
wherein the addition amount of the photocatalyst is 0.01-20% of the molar equivalent of the olefin compound, the addition amount of the free radical precursor is 1-3 times of the molar equivalent of the olefin compound, and the addition amount of the base is 0.1-5 times of the molar equivalent of the olefin compound;
(2) and (2) carrying out an illumination reaction on the product obtained in the step (1) for 2-30 h at room temperature, diluting with ethyl acetate after the reaction is finished, then quenching with hydrochloric acid, extracting with ethyl acetate, carrying out rotary evaporation and concentration to obtain a crude product, and purifying the crude product.
Further, the pressure of the carbon dioxide charged in the step (1) is 0.5-30.0 times of atmospheric pressure, and the concentration of the solvent is 0.05-1.0M.
Further, olefinic compounds include amide substrates of different substituents, aromatic substrates of different substituents, and other non-activated olefins.
Further, the olefin compound has the structural formula:
Figure BDA0002688027760000021
wherein R is1Is phenyl, 4-methylphenyl, 4-methoxyphenyl,4-methoxycarbonylphenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, tert-butyl, cyclopropyl, thiophene, cyclohexyl, n-propyl, tert-butoxy, benzyloxy or ethoxy; r2Is phenyl, methyl, methoxy, phenoxy, carboxyl, methoxycarbonyl, diethylaminoacyl, fluorine, bromine, chlorine, trifluoromethyl, tert-butoxycarbonyl or 2-propynyloxy; r3、R4、R5Is methyl or hydrogen.
Further, amide substrates of different substituents include:
Figure BDA0002688027760000022
further, aromatic substrates of varying substituents include:
Figure BDA0002688027760000031
further, other non-activated olefins include:
Figure BDA0002688027760000032
further, the olefin compound is 6, 6-diphenyl-1-hexene, 1-allyl-2-ethylbenzene, N- (1- (4- (trifluoromethyl) phenyl) -5-pentenyl) benzamide or N- (1-phenyl) -5-pentenyl) benzamide.
Further, the photocatalyst is Ir (ppy)2(dtbbpy)(PF6)、Ir(ppy)2(bpy)(PF6) And 4 CzIPN.
Further, the radical precursor is at least one of sodium trifluoromethanesulfonate, diphenylphosphine oxide and N-benzyloxycarbonylproline.
Further, the base is cesium carbonate, potassium carbonate, cesium pivalate, cesium fluoride or cesium acetate.
Further, the light source in the step (2) is a blue LED lamp with the wavelength of 400-500 nm and the power of 3-60W.
Further, the solvent used in step (1) is N-methylpyrrolidone, N-dimethylaniline, N-dimethylformamide or N, N-dimethylacetamide.
Further, the purification is carried out by adopting a column chromatography method, wherein the eluent is petroleum ether/ethyl acetate/AcOH: 10/1/0.1% -2/1/0.1%.
The carboxylic acid constructed by the method has the structural formula:
Figure BDA0002688027760000041
wherein R is1Is phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-methoxycarbonylphenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, t-butyl, cyclopropyl, thiophene, cyclohexyl, n-propyl, t-butoxy, benzyloxy or ethoxy, etc.; r2Is phenyl, methyl, methoxy, phenoxy, carboxyl, methoxycarbonyl, diethylaminoacyl, fluorine, bromine, chlorine, trifluoromethyl, tert-butoxycarbonyl or 2-propynyloxy; r3、R4And R5Is methyl or hydrogen.
The reaction formula is as follows:
Figure BDA0002688027760000042
the structural formula of the alcohol obtained by the construction is as follows:
Figure BDA0002688027760000043
wherein R is1Is tert-butyloxycarbonyl, ethoxycarbonyl or hydrogen; r2Is phenyl, 4-fluorophenyl, 4-biphenyl, 4-phenoxyphenyl, 4-methoxycarbonylphenyl, 4-methylsulfonylphenyl or pyridine.
The reaction formula is as follows:
Figure BDA0002688027760000051
the reaction mechanism of the invention is as follows:
Figure BDA0002688027760000052
with IrIIIPhotosensitizers are exemplified. First, light-excited IrIIICatalyst formation [ IrIII]*Species, [ Ir ]III]*The species is quenched by sodium trifluoromethanesulphinate to form a trifluoromethyl radical and IrIIA species; the trifluoromethyl radical then performs a radical addition to the olefin to form the central carbon radical (I). The carbon radical then undergoes a remotely directed 1,5 hydrogen transfer, producing a more stable benzyl radical (II), which acts as the rate-determining step for the reaction. Benzylic radicals (II) by IrIISpecies reduction to generate alpha-aminobenzyl negative ions and IrIIIs oxidized to IrIIIBack into the catalytic cycle. The benzyl negative ions attack carbon dioxide to obtain alpha-amino acid; aldehydes or ketones can also be attacked to give the corresponding alcohol products.
The invention has the beneficial effects that:
1. the invention realizes the synthesis of carboxylic acid and alcohol by the remote functionalization reaction of common olefin through visible light catalysis. The process is preferably carried out with Ir (ppy)2(dtbbpy)(PF6) As a catalyst, cesium carbonate and potassium pivalate are used as alkali, N, N-dimethylacetamide is used as a solvent, carbon dioxide is used as an electrophilic reagent to realize the high-efficiency synthesis of carboxylic acid, and aldehyde ketone is used as an electrophilic reagent to realize the high-efficiency synthesis of alcohol. The method has the advantages of convenient operation, mild reaction conditions, wide substrate range, cheap and easily obtained raw materials and good industrial application prospect;
2. the synthesis method of the invention has good reactivity for activated olefin and non-activated olefin substrates and high yield of target products.
3. The synthesis method of the invention not only can use carbon dioxide as electrophilic reagents, but also can use other electrophilic reagents such as aldehyde, ketone, benzyl bromide and the like to show good reactivity, and the yield of the target product is higher.
Detailed Description
The following description of the embodiments of the present invention is provided to facilitate the understanding of the present invention by those skilled in the art, but it should be understood that the present invention is not limited to the scope of the embodiments, and it will be apparent to those skilled in the art that various changes may be made without departing from the spirit and scope of the invention as defined and defined in the appended claims, and all matters produced by the invention using the inventive concept are protected.
Example 1
A method for constructing carboxylic acid or alcohol by common olefin remote functionalization comprises the following specific processes:
to a dry 10mL Schlenk tube was added a stirrer, solid olefinic substrate (0.2mmol,1.0equiv), Ir (ppy)2(dtbbpy)PF6(2 mol%, 3.7mg), Schlenk tube was transferred to a glove box and Cs was added2CO3(0.26mmol,84.7mg,1.3equiv)、KOPiv(0.2mmol,28.0mg,1.0equiv)、CF3SO2Na (0.5mmol,78.0mg,2.5equiv), then the Schlenk tube was closed, and after removal from the glove box, the nitrogen in the reaction flask was replaced by N by suction through a dual-row gas directing system2Pumping and charging N2Either dry DMAc (2mL) or liquid olefin substrate was added twice under a nitrogen atmosphere. Freezing, degassing for three times, and introducing CO2. In CO2After stirring for two minutes under ambient atmosphere, the vessel was sealed under an atmosphere of carbon dioxide at one atmosphere. Irradiating the mixture for 24 hours at room temperature by using a 30W blue LED lamp, diluting the mixture by using 3mL of ethyl acetate after the reaction is finished, quenching the reaction by using 3mL of 2N hydrochloric acid, extracting the mixture for six times by using the ethyl acetate, and performing rotary evaporation and concentration to obtain a crude product; and (4) passing the obtained crude product through a silica gel column to obtain a target product. The eluent ratio is as follows: petroleum ether/ethyl acetate/AcOH 10/1/0.1% -2/1/0.1%
The results are as follows:
Figure BDA0002688027760000061
Figure BDA0002688027760000071
the experimental data show that the amide substrates modified by different substituents have better yield regardless of electron-withdrawing substituents or electron-donating substituents. A variety of functional groups or substituents are compatible in the reaction system, including: para-methyl, methoxy, methoxycarbonyl, trifluoromethyl, cyano, chloro-substituted phenyl. In addition, the system can be compatible with amides of other steric substituents: thiophene, tertiary butyl, cyclobutyl, cyclopropyl, n-propyl, tertiary butoxy, benzyloxy and ethoxy, etc., and the reaction effect is good.
The reactivity of aryl substrates modified with different substituents was further explored. Experiments have shown that a variety of benzylamides are compatible with the central aromatic component, including amide (1s), ester (1t,1aa), halide (1v,1ac-1af), alkyne (1z), carbonate (1ab), corresponding to moderate to good isolated yields (44-78%). The reaction is not influenced by the position of a substituent on a benzene ring, and both ortho-position (1af,1ag) and meta-position (1w-1ae) substitution can have better yield. Meanwhile, the substrate can be compatible with aromatic ring disubstituted (1af) or naphthalene ring (1ah), the olefin disubstituted substrate can also have good reactivity, and the 1ai can obtain the corresponding 2ai product with the separation yield of 59 percent. In addition, the reactivity of the 1aj substrate was also good, and the corresponding α, α -diphenylamino acid 2aj was obtained in an isolated yield of 59%.
Figure BDA0002688027760000081
Surprisingly, the tri-substituted non-activated alkene (1ak) migrates through 1,6 hydrogens to give the product 4, which is likely to be an alkane, the less sterically hindered the more readily the free radical attacks and the more stable the tertiary carbon radical.
Example 2
A method for constructing carboxylic acid by common olefin remote functionalization comprises the following specific processes:
a dry 10mL Schlenk tube was charged with a stirrer and the solid olefinic substrate (0.2mmol,1.0 e)quiv)、Ir(ppy)2(dtbbpy)PF6(2 mol%, 3.7mg), Schlenk tube was transferred to a glove box and Cs was added2CO3(0.26mmol,84.7mg,1.3equiv)、KOPiv(0.2mmol,28.0mg,1.0equiv)、CF3SO2Na (0.5mmol,78.0mg,2.5 equiv.) and then the Schlenk tube was closed and after removal from the glove box, the nitrogen in the reaction flask was replaced by N by suction through a dual-row gas-directing system2Pumping and charging N2Either dry DMAc (2mL) or liquid olefin substrate was added twice under a nitrogen atmosphere. Freezing, degassing for three times, and introducing CO2. In CO2After stirring for two minutes under ambient atmosphere, the vessel was sealed under an atmosphere of carbon dioxide at one atmosphere. Irradiating the mixture for 24 hours at room temperature by using a 30W blue LED lamp, diluting the mixture by using 3mL of ethyl acetate after the reaction is finished, quenching the reaction by using 3mL of 2N hydrochloric acid, extracting the mixture for six times by using the ethyl acetate, and performing rotary evaporation and concentration to obtain a crude product; and (4) passing the obtained crude product through a silica gel column to obtain a target product. The eluent ratio is as follows: petroleum ether/ethyl acetate/AcOH 10/1/0.1% -2/1/0.1%
The results are as follows:
Figure BDA0002688027760000091
as can be seen from the above, the non-activated olefin having a C-H bond at the benzylic position can also be reacted to give the corresponding target carboxylic acid.
Example 3
A method for constructing carboxylic acid by common olefin remote functionalization comprises the following specific processes:
for reaction A, a dry 10mL Schlenk tube was charged with stirrer, 1a (0.2mmol,63.9mg,1.0equiv), Ir (ppy)2(dtbbpy)PF6(4 mol%, 7.3mg), Schlenk tube was transferred to a glove box and Cs was added2CO3(0.26mmol,84.7mg,1.3equiv)、KOPiv(0.2mmol,28.0mg,1.0equiv)、CHF2SO2Na (0.5mmol,69.0mg,2.5equiv), then the Schlenk tube was closed, and after removal from the glove box, the nitrogen in the reaction flask was replaced by N by suction through a double-row gas directing system2Pumping and charging N2Two times, under nitrogen, anhydrous DMAc (2mL) was added. Freezing degassingFilling CO after three times2. In CO2After stirring for two minutes under ambient atmosphere, the vessel was sealed under an atmosphere of carbon dioxide at one atmosphere. Irradiating the mixture for 24 hours at room temperature by using a 30W blue LED lamp, diluting the mixture by using 3mL of ethyl acetate after the reaction is finished, quenching the reaction by using 3mL of 2N hydrochloric acid, extracting the mixture for six times by using the ethyl acetate, and performing rotary evaporation and concentration to obtain a crude product; and (4) passing the obtained crude product through a silica gel column to obtain a target product. The eluent ratio is as follows: petroleum ether/ethyl acetate/AcOH 10/1/0.1% -2/1/0.1%
For reaction B, a dry 10mL Schlenk tube was charged with stirrer, 1a (0.2mmol,63.9mg,1.0equiv), 4CzIPN (2 mol%, 3.2mg), the Schlenk tube was transferred to a glovebox and Cs was added2CO3(0.26mmol,84.7mg,1.3equiv)、KOPiv(0.2mmol,28.0mg,1.0equiv)、HP(O)Ph2(0.3mmol,60.4mg,1.5equiv), then the Schlenk tube was closed, taken out of the glove box, and the nitrogen in the reaction flask was replaced by N by suction through a double-row gas-directing system2Pumping and charging N2Two times, under nitrogen, anhydrous DMAc (2mL) was added. Freezing, degassing for three times, and introducing CO2. In CO2After stirring for two minutes under ambient atmosphere, the vessel was sealed under an atmosphere of carbon dioxide at one atmosphere. Irradiating the mixture for 24 hours at room temperature by using a 30W blue LED lamp, diluting the mixture by using 3mL of ethyl acetate after the reaction is finished, quenching the reaction by using 3mL of 2N hydrochloric acid, extracting the mixture for six times by using the ethyl acetate, and performing rotary evaporation and concentration to obtain a crude product; and (4) passing the obtained crude product through a silica gel column to obtain a target product.
The results are as follows:
Figure BDA0002688027760000101
from the above, it is known that the target carboxylic acid can be obtained by using sodium difluoromethylsulfinate as a radical donor or phosphorus diphenoxylate as a radical donor under the conditions of using 4CzIPN as a photocatalyst and DMSO as a solvent under the above strategy.
Example 4
A method for constructing alcohol by common olefin remote functionalization comprises the following specific processes:
in a trunkA dry 10mL Schlenk tube was charged with a stirrer, followed by 1a (0.2mmol,63.9mg,1.0equiv), Ir (ppy)2(dtbbpy)PF6(2 mol%, 3.7mg), 17(0.3mmol,1.5equiv). The Schlenk tube was transferred to a glovebox and Cs was added2CO3(0.22mmol,71.7mg,1.1equiv)、CF3SO2Na (0.5mmol,78.0mg,2.5equiv). Then the Schlenk tube was closed and taken out of the glove box, and the nitrogen in the reaction flask was replaced by N by suction through a double-row gas-guiding system2Pumping and charging N2Two times, under nitrogen, anhydrous DMAc (2mL) was added. Freeze degassing three times. N at one atmosphere2Sealing under the atmosphere. Irradiating the mixture for 24 hours at room temperature by using a 30W blue LED lamp, diluting the mixture by using 3mL of ethyl acetate after the reaction is finished, quenching the reaction by using 3mL of 2N hydrochloric acid, extracting the mixture for six times by using the ethyl acetate, and performing rotary evaporation and concentration to obtain a crude product; and (4) passing the obtained crude product through a silica gel column to obtain a target product.
The results are as follows:
Figure BDA0002688027760000111
from the above, it can be seen that under this strategy, the synthesis of alcohols by remote functionalization of olefins can be achieved with aldehydes as electrophiles. The electrophiles substituted with various functional groups on the arylcarboxaldehyde are compatible. For example: fluorine (17a), phenoxy (17c), ester group (17d), sulfonyl (17e), pyridyl (17f), and the like. The reaction effect is good, and the separation yield is 55-68%.
Example 5
A method for constructing alcohol by common olefin remote functionalization comprises the following specific processes:
for reaction A, a dry 10mL Schlenk tube was charged with a stirrer followed by 1a (0.2mmol,63.9mg,1.0equiv), Ir (ppy)2(dtbbpy)PF6(2 mol%, 3.7mg), 21(0.6mmol,3 equiv). The Schlenk tube was transferred to a glovebox and Cs was added2CO3(0.3mmol,97.7mg,1.5equiv) and CF3SO2Na (0.5mmol,78.0mg,2.5 equiv.) then the Schlenk tube was closed, removed from the glove box, and the reaction flask was placed through a dual-row gas-directing systemThe nitrogen in the nitrogen is pumped and replaced to be N2Pumping and charging N2Two times, under nitrogen, anhydrous DMAc (2mL) was added. Freeze degassing three times. N at one atmosphere2Sealing under the atmosphere. Irradiating the mixture for 24 hours at room temperature by using a 30W blue LED lamp, diluting the mixture by using 3mL of ethyl acetate after the reaction is finished, quenching the reaction by using 3mL of 2N hydrochloric acid, extracting the mixture for six times by using the ethyl acetate, and performing rotary evaporation and concentration to obtain a crude product; and (4) passing the obtained crude product through a silica gel column to obtain a target product.
For reaction B, a dry 10mL Schlenk tube was charged with a stirrer followed by 1a (0.2mmol,63.9mg,1.0equiv), Ir (ppy)2(dtbbpy)PF6(2 mol%, 3.7 mg). The Schlenk tube was transferred to a glovebox and K was added2CO3(0.4mmol,55.3mg,2equiv) and CF3SO2Na (0.5mmol,78.0mg,2.5equiv). Then the Schlenk tube was closed and taken out of the glove box, and the nitrogen in the reaction flask was replaced by N by suction through a double-row gas-guiding system2Pumping and charging N2Twice, under a nitrogen atmosphere, anhydrous DMAc (2mL) and 19(0.6mmol,106.9mg,3equiv) were added. Freeze degassing three times. N at one atmosphere2Sealing under the atmosphere. Irradiating the mixture for 24 hours at room temperature by using a 30W blue LED lamp, diluting the mixture by using 3mL of ethyl acetate after the reaction is finished, quenching the reaction by using 3mL of 2N hydrochloric acid, extracting the mixture for six times by using the ethyl acetate, and performing rotary evaporation and concentration to obtain a crude product; and (4) passing the obtained crude product through a silica gel column to obtain a target product.
The results are as follows:
Figure BDA0002688027760000121
from the above, it is clear that aryl ketone esters can also react as electrophiles and that beta amino acids are obtained in moderate yields. The benzyl bromide substrate can also react, but the yield of the reaction is lower (37% -40%).
Example 6
The yield was compared by varying N- (2-allyl-4- (trifluoromethyl) phenyl) benzylamide (1a) and its reaction conditions.
Reaction conditions are as follows: solid olefinic substrate (0.2 mmol),1.0equiv)、Ir(ppy)2(dtbbpy)PF6(2mol％,3.7mg)，Cs2CO3(0.26mmol,84.7mg,1.3equiv), KOPiv (0.2mmol,28.0mg,1.0equiv) as base, CF3SO2Na (0.5mmol,78.0mg,2.5equiv) as a radical precursor, anhydrous DMAc (2mL) as a solvent,
Figure BDA0002688027760000122
TABLE 1 reaction conditions changes and yields
Figure BDA0002688027760000131
The yields in the above table are liquid phase yields and the isolated yields are in parentheses.
As can be seen from Table 1, the nuclear magnetic yield of the corresponding carboxylic acid under the reaction conditions of the invention is as high as 81%, and a series of control experiments show that the iridium catalyst and the light are indispensable, and the target product cannot be obtained if any one item is lacked. DMAc, Cs2CO3KOPiv has a significant effect of promoting the reaction. When other supporting photocatalysts or solvents were used, the yield dropped significantly and examination of the reaction time showed 24 hours as the optimum reaction time.
The parameters of the part of carboxylic acid synthesized by the invention are as follows:
example 7
2- (2- (4,4, 4-trifluorobutyl) -4- (trifluoromethyl) phenyl) -2-benzoylglycine:
Figure BDA0002688027760000132
the characteristics are as follows: a white solid;1H NMR(400MHz,DMSO-d6):δ9.15(d,J＝7.4Hz,1H),7.96–7.84(m,2H),7.71–7.60(m,3H),7.58–7.51(m,1H),7.47(dd,J＝8.2,6.7Hz,2H),5.94(d,J＝7.4Hz,1H),2.93(t,J＝8.0Hz,2H),2.42–2.23(m,2H),1.99–1.76(m,2H)；13C NMR(101MHz,DMSO-d6):δ172.04,166.69,141.69,140.91,133.95,132.05,129.42,129.11(q,J＝31.7Hz),128.68,128.10,127.96(q,J＝276.3Hz),126.64(q,J＝3.4Hz),124.62(q,J＝272.0Hz),123.76(q,J＝3.4Hz),53.13,32.82(q,J＝27.6Hz),31.22,23.47(q,J＝3.2Hz)；19F NMR(376MHz,DMSO-d6):δ-61.10,-64.75；HRMS(ESI-):calculated for C20H16F6NO3 -[M-H]-432.1040,found 432.1038.
example 8
2- (2- (4,4, 4-trifluorobutyl) -4- (trifluoromethyl) phenyl) -2- (4-methylben-zamido) acetic acid:
Figure BDA0002688027760000141
the characteristics are as follows: a white solid;1H NMR(400MHz,CD3OD):δ7.78–7.71(m,2H),7.63(d,J＝8.2Hz,1H),7.58(d,J＝1.9Hz,1H),7.54(dd,J＝8.1,2.0Hz,1H),7.26(d,J＝8.0Hz,2H),6.03(s,1H),3.15–2.87(m,2H),2.38(s,3H),2.32–2.16(m,2H),1.97(p,J＝8.0Hz,2H)；13C NMR(101MHz,CD3OD):δ171.88,168.41,142.36,141.25,139.70(q,J＝1.4Hz),130.54,130.10(q,J＝32.2Hz),128.72,128.20,127.25,127.24(q,J＝275.5Hz),126.17(q,J＝3.8Hz),124.06(q,J＝271.5Hz),123.20(q,J＝3.9Hz),52.81,32.70(q,J＝28.6Hz),31.16,23.11(q,J＝2.9Hz),20.04；19F NMR(376MHz,CD3OD):δ-64.17,-67.77；HRMS(ESI-):calculated for C20H18F6NO-[M-H,-CO2]-418.1247,found 418.1245.
example 9
2- (2- (4,4, 4-trifluorobutyl) -4- (trifluoromethyl) phenyl) -2- (4-methoxylcarbamido) acetic acid:
Figure BDA0002688027760000142
the characteristics are as follows: a white solid;1H NMR(400MHz,CD3OD):δ7.89–7.78(m,2H),7.64(d,J＝8.2Hz,1H),7.60–7.52(m,2H),7.03–6.91(m,2H),6.04(s,1H),3.83(s,3H),3.12–2.92(m,2H),2.36–2.17(m,2H),1.98(p,J＝8.0Hz,2H)；13C NMR(101MHz,CD3OD):δ172.01,168.03,162.84,141.32,139.82,130.15(q,J＝32.1Hz),129.17,128.24,127.30(q,J＝275.4Hz),126.20(q,J＝3.5Hz),125.49,124.12(q,J＝271.5Hz),123.22(q,J＝3.7Hz),113.35,54.52,52.88,32.74(q,J＝28.5Hz),31.18,23.15(q,J＝2.8Hz)；19F NMR(376MHz,CD3OD):δ-64.14,-67.76；HRMS(ESI-):calculated for C20H18F6NO2 -[M-H,-CO2]-418.1247,found 418.1245.
example 10
2- (2- (4,4, 4-trifluorobutyl) -4- (trifluoromethyl) phenyl) 2- (4- (methoxycarbonyl) benzamido) acetic acid:
Figure BDA0002688027760000151
the characteristics are as follows: a white solid;1H NMR(400MHz,CD3OD):δ8.11–8.04(m,2H),7.95–7.89(m,2H),7.64(d,J＝8.2Hz,1H),7.59(d,J＝1.9Hz,1H),7.55(dd,J＝8.2,1.9Hz,1H),6.05(s,1H),3.91(s,3H),3.11–2.94(m,2H),2.41–2.15(m,2H),1.97(p,J＝8.1Hz,2H)；13C NMR(101MHz,CD3OD):δ171.68,167.56,166.24,141.34,139.49,137.67,132.78,130.24(q,J＝32.3Hz),129.19,128.28,127.47,127.29(q,J＝275.4Hz),126.27(q,J＝3.9Hz),124.08(q,J＝271.4Hz),123.29(q,J＝3.7Hz),52.98,51.50,32.73(q,J＝28.6Hz),31.21,23.18(d,J＝3.2Hz)；19F NMR(376MHz,CD3OD):δ-64.17,-67.76；HRMS(ESI-):calculated for C21H18F6NO3 -[M-H,-CO2]-446.1196,found 446.1193.
example 11
2- (2- (4,4, 4-trifluorobutyl) -4- (trifluoromethyl) phenyl) -2- (4- (trifluoromethyl) benzamido) acetic acid:
Figure BDA0002688027760000152
the characteristics are as follows: a white solid;1H NMR(400MHz,CD3OD):δ8.01(d,J＝8.1Hz,2H),7.76(d,J＝8.2Hz,2H),7.67–7.51(m,3H),6.06(s,1H),3.13–2.93(m,2H),2.37–2.16(m,2H),2.07–1.89(m,2H)；13C NMR(101MHz,CD3OD):δ171.66,167.19,141.35,139.40,137.24,132.93(q,J＝32.4Hz),130.29(q,J＝32.3Hz),128.29,128.05,127.27(q,J＝275.4Hz),126.29(q,J＝3.5Hz),125.09(q,J＝3.9Hz),124.06(q,J＝271.4Hz),123.85(q,J＝271.7Hz),123.30(q,J＝3.7Hz),53.01,32.73(q,J＝28.6Hz),28.35,23.19(q,J＝2.8Hz)；19F NMR(376MHz,CD3OD):δ-64.20,-64.50,-67.79；HRMS(ESI-):calculated for C20H15F9NO-[M-H,-CO2]-456.1015,found 456.1011.
example 12
2- (2- (4,4, 4-trifluorobutyl) -4- (trifluoromethylphenyl) -2- (4-cyanobenzoylamino) acetic acid:
Figure BDA0002688027760000153
the characteristics are as follows: a white solid;1H NMR(400MHz,CD3OD):δ7.98(d,J＝8.1Hz,2H),7.82(d,J＝8.1Hz,2H),7.67–7.53(m,3H),6.04(s,1H),3.13–2.89(m,2H),2.38–2.16(m,2H),1.97(p,J＝8.1Hz,2H)；13C NMR(101MHz,CD3OD):δ166.84,141.39,139.38,137.76,132.09,130.31(q,J＝32.5Hz),128.66,128.29,128.17,127.29(q,J＝275.4Hz),126.31(q,J＝3.5Hz),124.07(q,J＝271.3Hz),123.31(q,J＝3.9Hz),117.61,114.93,53.08,32.72(q,J＝28.7Hz),31.19,23.18(q,J＝2.9Hz)；19F NMR(376MHz,CD3OD):δ-64.20,-67.77；HRMS(ESI-):calculated for C20H15F6N2O-[M-H,-CO2]-413.1094,found 413.1091.
example 13
2- (2- (4,4, 4-trifluorobutyl) -4- (trifluoromethyl) phenyl) -2- (4-chlorobenzoylamino) acetic acid:
Figure BDA0002688027760000161
the characteristics are as follows: a white solid;1H NMR(400MHz,CD3OD):δ7.87–7.80(m,2H),7.63(d,J＝8.1Hz,1H),7.58(d,J＝1.9Hz,1H),7.54(dd,J＝8.2,1.9Hz,1H),7.48–7.41(m,2H),6.04(s,1H),3.19–2.91(m,2H),2.45–2.16(m,2H),2.09–1.86(m,2H)；13C NMR(101MHz,CD3OD):δ171.73,167.33,141.28,139.47(q,J＝1.5Hz),137.67,132.07,130.19(q,J＝32.2Hz),128.94,128.29,127.23(q,J＝275.6Hz),127.20,126.22(q,J＝3.6Hz),124.03(q,J＝271.5Hz),123.24(q,J＝3.7Hz),52.90,32.69(q,J＝28.6Hz),31.17,23.14(q,J＝2.8Hz)；19F NMR(376MHz,CD3OD):δ-64.12,-67.71；HRMS(ESI-):calculated for C19H15ClF6NO-[M-H,-CO2]-422.0752,found 422.0757.
example 14
2- (2- (4,4, 4-trifluorobutyl) phenyl) -2- (thiophene-2-carboxamido) acetic acid:
Figure BDA0002688027760000162
the characteristics are as follows: a colorless oily liquid;1H NMR(400MHz,CD3OD):δ7.80(d,J＝3.8Hz,1H),7.63(dd,J＝5.3,1.8Hz,1H),7.48–7.39(m,1H),7.34–7.19(m,3H),7.14–7.03(m,1H),5.94(s,1H),3.01–2.77(m,2H),2.31–2.09(m,2H),1.98–1.83(m,2H)；13C NMR(101MHz,CD3OD):δ172.78,162.61,139.99,137.99,134.68,130.77,129.69,129.06,128.34,127.57,127.44,127.35(q,J＝275.7Hz),126.59,53.11,32.76(q,J＝28.6Hz),31.20,23.35(q,J＝3.0Hz)；19F NMR(376MHz,CD3OD):δ-67.83；HRMS(ESI-):calculated for C17H15F3NO3 -[M-H]-370.0730,found 370.0735.
example 15
2- (2- (4,4, 4-trifluorobutyl) -4- (trifluoromethyl) phenyl) -2-pivaloylamido acetic acid:
Figure BDA0002688027760000171
the characteristics are as follows: a white solid;1H NMR(400MHz,CD3OD):δ7.55(s,1H),7.52(d,J＝1.6Hz,2H),5.78(s,1H),3.04–2.90(m,2H),2.33–2.14(m,2H),2.01–1.87(m,2H),1.19(s,9H)；13C NMR(101MHz,CD3OD):δ179.34,171.93,141.26,139.91,130.05(q,J＝32.5Hz),127.82,127.32(q,J＝275.4Hz),126.13(q,J＝3.7Hz),124.11(q,J＝271.2Hz),123.17(q,J＝3.7Hz),52.49,38.19,32.75(q,J＝28.7Hz),31.13,26.19,23.04(q,J＝2.9Hz)；19F NMR(376MHz,CD3OD):δ-64.15,-67.69；HRMS(ESI-):calculated for C17H20F6NO-[M-H,-CO2]-368.1455,found 368.1454.
example 16
2- (2- (4,4, 4-trifluorobutyl) -4- (trifluoromethyl) phenyl) -2- (cyclohexylcarboxamido) acetic acid:
Figure BDA0002688027760000172
the characteristics are as follows: a white solid;1H NMR(400MHz,CD3OD):δ7.76–7.40(m,3H),5.79(s,1H),3.07–2.89(m,2H),2.41–2.16(m,3H),1.99–1.88(m,2H),1.88–1.62(m,5H),1.53–1.13(m,5H)；13C NMR(101MHz,CD3OD):δ177.40,171.87,141.11,139.84,130.13(q,J＝32.2Hz),127.96,127.29(q,J＝275.5Hz),126.25(q,J＝3.8Hz),124.08(q,J＝271.4Hz),123.26(q,J＝3.9Hz),52.10,44.34,32.72(q,J＝28.4Hz),31.17,29.12,29.10,25.46,25.32,25.29,23.14(q,J＝3.0Hz)；19F NMR(376MHz,CD3OD):δ-64.16,-67.74；HRMS(ESI-):calculated for C19H22F6NO-[M-H,-CO2]-394.1611,found 394,1611.
example 17
2- (2- (4,4, 4-trifluorobutyl) -4- (trifluoromethyl) phenyl) -2- (cyclopropylcarboxamido) acetic acid:
Figure BDA0002688027760000173
the characteristics are as follows: a white solid;1H NMR(400MHz,CD3OD):δ7.62–7.44(m,3H),5.82(s,1H),2.95(dt,J＝9.6,4.2Hz,2H),2.36–2.13(m,2H),1.99–1.83(m,2H),1.80–1.66(m,1H),0.95–0.67(m,4H)；13C NMR(101MHz,CD3OD):δ174.73,171.83,141.04,139.79,130.08(q,J＝32.7Hz),127.97,127.23(q,J＝275.5Hz),126.26(q,J＝3.6Hz),124.03(q,J＝271.4Hz),123.23(q,J＝3.7Hz),52.36,32.65(q,J＝28.5Hz),31.11,23.13(q,J＝2.9Hz),12.99,6.26,6.20；19F NMR(376MHz,CD3OD):δ-64.17,-67.79；HRMS(ESI-):calculated for C16H16F6NO-[M-H,-CO2]-352.1142,found 352.1144.
example 18
2- (2- (4,4, 4-trifluorobutyl) -4- (trifluoromethyl) phenyl) -2-butyramidoacetic acid:
Figure BDA0002688027760000181
the characteristics are as follows: a white solid;1H NMR(400MHz,CD3OD):δ7.64–7.36(m,3H),5.82(s,1H),2.96(dd,J＝9.3,6.8Hz,2H),2.41–2.06(m,4H),2.00–1.88(m,2H),1.71–1.56(m,2H),0.92(t,J＝7.4Hz,3H)；13C NMR(101MHz,CD3OD):δ174.39,171.83,141.11,139.75,130.17(q,J＝32.5Hz),128.03,127.29(q,J＝275.5Hz),126.27(q,J＝3.7Hz),124.07(q,J＝271.2Hz),123.26(q,J＝3.8Hz),52.23,36.98,32.70(q,J＝28.7Hz),31.16,23.13(q,J＝2.9Hz),18.84,12.51；19F NMR(376MHz,CD3OD):δ-64.19,-67.78；HRMS(ESI-):calculated for C17H18F6NO3 -[M-H,]-398.1196,found 398.1194.
example 19
2- (4- (3- (4,4, 4-trifluorobutyl)) biphenyl) -2-benzamidoacetic acid:
Figure BDA0002688027760000182
the characteristics are as follows: a white solid;1H NMR(400MHz,CDCl3):δ7.78(d,J＝7.6Hz,2H),7.59–7.32(m,11H),7.17(d,J＝6.9Hz,1H),6.04(d,J＝6.9Hz,1H),3.08(dt,J＝15.1,7.8Hz,1H),2.96(dt,J＝14.7,7.9Hz,1H),2.19(tt,J＝16.2,8.3Hz,2H),2.03(dt,J＝8.7,5.6Hz,2H)；13C NMR(101MHz,CDCl3):δ174.89,167.23,142.03,140.29,140.24,133.34,133.08,132.18,128.92,128.87,128.70,127.71,127.22,127.17,127.13,127.13(q,J＝276.5Hz),126.08,52.59,33.41(q,J＝28.5Hz),31.78,23.35(q,J＝2.6Hz)；19F NMR(376MHz,CDCl3):δ-66.01；HRMS(ESI-):calculated for C25H21F3NO3 -[M-H]-440.1079,found 440.1477.
example 20
2- (2- (4,4, 4-trifluorobutyl) phenyl) -2-benzamidoacetic acid:
Figure BDA0002688027760000191
the characteristics are as follows: a white solid;1H NMR(400MHz,DMSO-d6):δ12.94(s,1H),9.00(d,J＝7.5Hz,1H),7.93–7.83(m,2H),7.58–7.50(m,1H),7.48–7.42(m,3H),7.33–7.20(m,3H),5.85(d,J＝7.5Hz,1H),2.89–2.74(m,2H),2.36–2.20(m,2H),1.90–1.75(m,2H)；13C NMR(101MHz,DMSO-d6):δ172.75,166.66,140.16,135.93,134.10,131.92,130.06,128.61,128.56,128.50,128.14,128.02(q,J＝276.5Hz),126.98,53.25,32.82(q,J＝27.5Hz),31.38,23.61(q,J＝3.1Hz)；19F NMR(376MHz,DMSO-d6):δ-64.71；HRMS(ESI-):calculated for C19H17F3NO3 -[M-H]-364.1166,found 364.1167.
example 21
2- (4-methyl-2- (4,4, 4-trifluorobutyl) phenyl) -2-benzamidoacetic acid:
Figure BDA0002688027760000192
the characteristics are as follows: a white solid;1H NMR(400MHz,CD3OD):δ7.86–7.78(m,2H),7.56–7.48(m,1H),7.46–7.40(m,2H),7.32(d,J＝7.8Hz,1H),7.12–7.04(m,2H),5.91(s,1H),3.01–2.71(m,2H),2.32(s,3H),2.27–2.13(m,2H),1.97–1.83(m,2H)；13C NMR(101MHz,CD3OD):δ172.94,168.56,139.71,138.20,133.67,131.43,130.27,128.05,127.38,127.34(q,J＝275.4Hz),127.26,127.19,127.15,52.92,32.74(q,J＝28.4Hz),31.23,23.38(q,J＝2.9Hz),19.74；19F NMR(376MHz,CD3OD):δ-67.78；HRMS(ESI-):calculated for C20H19F3NO3 -[M-H]-378.1323,found 378.1323.
example 22
2- (2- (4,4, 4-trifluorobutyl-4- (diethylaminoacyl)) phenyl) -2-benzamidoacetic acid:
Figure BDA0002688027760000193
the characteristics are as follows: a white solid;1H NMR(400MHz,CDCl3):δ7.82(d,J＝7.6Hz,2H),7.63(d,J＝5.9Hz,1H),7.51(t,J＝7.3Hz,1H),7.43(t,J＝7.5Hz,2H),7.22(d,J＝8.0Hz,1H),7.15–7.06(m,2H),5.75(d,J＝5.9Hz,1H),3.71–3.44(m,J＝6.9Hz,2H),3.23(q,J＝7.1Hz,2H),3.07(ddd,J＝15.3,9.3,6.4Hz,1H),2.95(ddd,J＝14.8,9.4,6.8Hz,1H),2.27–2.07(m,2H),2.06–1.92(m,2H),1.26(t,J＝7.1Hz,3H),1.10(t,J＝7.0Hz,3H)；13C NMR(101MHz,CDCl3):δ172.73,171.96,166.33,139.83,138.34,134.36,133.57,131.89,128.64,128.59,127.25(q,J＝276.6Hz),127.08,126.40,124.67,52.45,43.85,40.12,33.46(q,J＝28.5Hz),31.40,22.62(q,J＝2.5Hz),14.07,12.67；19F NMR(376MHz,CDCl3):δ-65.93；HRMS(ESI-):calculated for C20H19F3NO3 -[M-H]-463.1850,found 463.1855.
example 23
2- (4- (methoxycarbonyl) -2- (4,4, 4-trifluorobutyl) phenyl) -2-benzamidoacetic acid:
Figure BDA0002688027760000201
the characteristics are as follows: a white solid;1H NMR(400MHz,CD3OD):δ7.93(d,J＝1.8Hz,1H),7.88(dd,J＝8.1,1.9Hz,1H),7.86–7.81(m,2H),7.59–7.49(m,2H),7.48–7.40(m,2H),6.03(s,1H),3.89(s,3H),3.11–2.88(m,2H),2.36–2.14(m,2H),2.08–1.90(m,2H)；13C NMR(101MHz,CD3OD):δ171.98,168.53,166.74,140.52,140.46,133.57,131.59,130.53,129.96,128.16,127.73,127.51,127.34(q,J＝275.6Hz),127.23,53.04,51.32,32.76(q,J＝28.7Hz),31.18,23.15(q,J＝3.0Hz)；19F NMR(376MHz,CD3OD):δ-67.74；HRMS(ESI-):calculated for C20H19F3NO3 -[M-H,-CO2]-378.1323,found 378.1321.
example 24
3- (4,4, 4-trifluorobutyl) -4- (2-benzamidocarboxymethyl) benzoic acid
Figure BDA0002688027760000202
The characteristics are as follows: a white solid; [2.3equiv of Cs2CO3]1H NMR(400MHz,CD3OD):δ7.94(d,J＝1.8Hz,1H),7.90(dd,J＝8.1,1.8Hz,1H),7.87–7.82(m,2H),7.59–7.51(m,2H),7.45(dd,J＝8.3,6.8Hz,2H),6.04(s,1H),3.10–2.91(m,2H),2.35–2.15(m,2H),2.05–1.92(m,2H)；13C NMR(101MHz,CD3OD):δ172.07,168.58,168.00,140.37,140.17,133.59,131.58,130.77,130.59,128.15,127.77,127.65,127.34(q,J＝275.4Hz),127.25,53.06,32.77(q,J＝28.6Hz),31.20,23.16(q,J＝2.6Hz)；19F NMR(376MHz,CD3OD):δ-67.73；HRMS(ESI-):calculated for C19H17F3NO3 -[M-H,-CO2]-364.1166,found 364.1179.
Example 25
2- (2- (4,4, 4-trifluorobutyl-4-fluoro) phenyl) -2-benzamidoacetic acid:
Figure BDA0002688027760000211
the characteristics are as follows: a white solid;1H NMR(400MHz,CD3OD):δ7.89–7.79(m,2H),7.59–7.39(m,4H),7.09–6.94(m,2H),5.93(s,1H),3.02–2.83(m,2H),2.34–2.14(m,2H),2.02–1.87(m,2H)；13C NMR(101MHz,CD3OD):δ172.54,168.58,162.57(d,J＝246.2Hz),142.86(d,J＝7.5Hz),133.64,131.54,131.10(d,J＝3.0Hz),129.54(d,J＝8.7Hz),128.13,127.32(q,J＝275.5Hz),127.23,115.95(d,J＝21.3Hz),113.29(d,J＝21.7Hz),52.65,32.72(q,J＝28.6Hz),31.22,23.07(q,J＝2.8Hz)；19F NMR(376MHz,CD3OD):δ-67.74,-115.61；HRMS(ESI-):calculated for C19H16F4NO3 -[M-H]-382.1072,found 382.1072.
example 26
2- (3- (4- (4,4, 4-trifluorobutyl) biphenyl) -2-benzamidoacetic acid:
Figure BDA0002688027760000212
the characteristics are as follows: a white solid;1H NMR(400MHz,CD3OD):δ7.88–7.81(m,2H),7.72(d,J＝2.0Hz,1H),7.64–7.49(m,4H),7.46–7.27(m,6H),6.03(s,1H),3.08–2.82(m,2H),2.35–2.13(m,2H),2.10–1.88(m,2H)；13C NMR(101MHz,CD3OD):δ168.74,140.38,139.77,138.96,135.49,133.76,131.48,130.21,128.47,128.11,127.40(q,J＝275.6Hz),127.28,127.03,126.70,126.48,126.14,53.34,32.80(q,J＝28.5Hz),30.99,23.31(q,J＝2.6Hz)；19F NMR(376MHz,CD3OD):δ-67.77；HRMS(ESI-):calculated for C25H21F3NO3 -[M-H]-440.1079,found 440.1476.
example 27
2- (2- (4,4, 4-trifluorobutyl-5-methoxy) phenyl) -2-benzamidoacetic acid:
Figure BDA0002688027760000213
the characteristics are as follows: a white solid;1H NMR(400MHz,DMSO-d6):δ12.97(s,1H),9.01(d,J＝7.6Hz,1H),7.94–7.81(m,2H),7.55–7.48(m,1H),7.43(t,J＝7.5Hz,2H),7.16(d,J＝8.4Hz,1H),7.02(d,J＝2.7Hz,1H),6.85(dd,J＝8.4,2.7Hz,1H),5.81(d,J＝7.6Hz,1H),3.71(s,3H),2.75(t,J＝7.9Hz,2H),2.34–2.13(m,2H),1.87–1.71(m,2H)；13C NMR(101MHz,DMSO-d6):δ172.66,166.63,158.13,137.03,134.09,131.91,131.11,128.03(q,J＝276.6Hz),128.59,128.11,114.15,113.77,55.50,53.15,32.68(q,J＝28.0,27.5Hz),30.66,23.71(q,J＝2.7Hz)；19F NMR(376MHz,DMSO-d6):δ-64.70；HRMS(ESI-):calculated for C20H19F3NO4 -[M-H]-394.1272,found 394.1270.
example 28
2- (2- (4,4, 4-trifluorobutyl) -5-phenoxyphenyl) -2-benzamidoacetic acid:
Figure BDA0002688027760000221
the characteristics are as follows: a colorless oily liquid;1H NMR(400MHz,CDCl3):7.73(d,J＝7.6Hz,2H),7.49(t,J＝7.4Hz,1H),7.39(t,J＝7.5Hz,2H),7.26(d,J＝7.3Hz,2H),7.15(d,J＝8.3Hz,2H),7.10–7.02(m,2H),6.95(d,J＝8.0Hz,2H),6.86(dd,J＝8.4,2.2Hz,1H),5.94(d,J＝6.6Hz,1H),2.93(ddt,J＝42.4,14.8,7.8Hz,2H),2.23-2.11(m,2H),1.97(p,J＝7.8Hz,2H)；13C NMR(101MHz,CDCl3):δ174.30,167.35,156.61,156.15,136.23,134.38,132.96,132.19,131.29,129.78,128.67,127.15(q,J＝276.4Hz),127.13,123.50,118.85,118.63,116.85,52.67,33.27(q,J＝28.5Hz),30.89,23.21(q,J＝2.6Hz)；19F NMR(376MHz,CDCl3):δ-66.00；HRMS(ESI-):calculated for C25H21F3NO4 -[M-H]-456.1428,found 456.1420.
example 29
2- (2- (4,4, 4-trifluorobutyl) -5- (2-alkynbutoxy) phenyl) -2-benzamidoacetic acid:
Figure BDA0002688027760000222
the characteristics are as follows: a white solid;1H NMR(400MHz,CD3OD):δ7.92–7.75(m,2H),7.55–7.49(m,1H),7.43(dd,J＝8.4,6.8Hz,2H),7.18(d,J＝8.5Hz,1H),7.07(d,J＝2.7Hz,1H),6.91(dd,J＝8.5,2.7Hz,1H),5.92(s,1H),4.63(q,J＝2.4Hz,2H),2.85(tt,J＝9.5,4.8Hz,2H),2.32–2.09(m,2H),1.91(p,J＝8.0Hz,2H),1.75(t,J＝2.4Hz,3H)；13C NMR(101MHz,CD3OD):δ172.37,168.33,156.41,135.59,133.43,132.07,131.25,130.35,127.86,127.16(q,J＝275.4Hz),126.99,114.55,113.65,82.74,73.45,55.48,52.98,32.46(q,J＝28.4Hz),30.29,23.16(q,J＝2.6Hz),1.42；19F NMR(376MHz,CD3OD):δ-67.72；HRMS(ESI-):calculated for C23H21F3NO4 -[M-H]-432.1428,found 432.1431.
example 30
2- (2- (4,4, 4-trifluorobutyl) -5- (benzoyloxy) phenyl) -2-benzoylamino acetic acid:
Figure BDA0002688027760000231
the characteristics are as follows: a colorless oily liquid;1H NMR(400MHz,CDCl3):δ8.19–8.08(m,2H),7.82–7.73(m,2H),7.65–7.58(m,1H),7.52–7.44(m,3H),7.39(dd,J＝8.2,6.8Hz,2H),7.28–7.20(m,3H),7.16(dd,J＝8.4,2.4Hz,1H),6.00(d,J＝6.8Hz,1H),3.14–2.84(m,2H),2.28–2.10(m,2H),2.00(p,J＝7.6,7.1Hz,2H)；13C NMR(101MHz,CDCl3):δ173.46,167.38,165.27,149.65,137.50,135.98,133.82,132.86,132.16,131.04,130.19,129.09,128.64,128.59,127.23,127.13(q,J＝276.6Hz),122.20,119.88,52.66,33.27(q,J＝28.6Hz),31.07,23.12(q,J＝2.6Hz)；19F NMR(376MHz,CDCl3):δ-65.99；HRMS(ESI-):calculated for C26H21F3NO5 -[M-H]-484.1377,found 484.1376.
example 31
2- (2- (4,4, 4-trifluorobutyl) -5- (tert-butoxycarbonyloxy) phenyl) -2-benzamidoacetic acid:
Figure BDA0002688027760000232
the characteristics are as follows: a colorless oily liquid;1H NMR(400MHz,CD3OD):δ7.91–7.80(m,2H),7.56–7.49(m,1H),7.44(dd,J＝8.3,6.8Hz,2H),7.31(d,J＝8.4Hz,1H),7.25(d,J＝2.5Hz,1H),7.10(dd,J＝8.4,2.5Hz,1H),5.98(s,1H),3.01–2.83(m,2H),2.35–2.14(m,2H),2.01–1.88(m,2H),1.51(s,9H)；13C NMR(101MHz,CD3OD):δ172.24,168.55,152.08,149.78,137.55,136.29,133.53,131.53,130.73,128.09,127.32(q,J＝275.6Hz),127.23,121.15,120.23,83.21,52.99,32.67(q,J＝28.5Hz),30.74,26.46,23.25(q,J＝2.9Hz)；19F NMR(376MHz,CD3OD):δ-67.63；HRMS(ESI-):calculated for C24H25F3NO6 -[M-H]-480.1639,found 480.1639.
example 32
2- (2- (4,4, 4-trifluorobutyl) -5-chlorophenyl) -2-benzoylglycine:
Figure BDA0002688027760000233
the characteristics are as follows: a white solid;1H NMR(400MHz,CD3OD):δ7.84(d,J＝7.6Hz,2H),7.62–7.37(m,4H),7.33–7.20(m,2H),5.97(s,1H),3.07–2.76(m,2H),2.39–2.09(m,2H),1.94(h,J＝9.0,8.0Hz,2H)；13C NMR(101MHz,CD3OD):δ172.04,168.51,138.62,137.19,133.46,132.09,131.55,131.18,128.15,128.09,127.42,127.29(q,J＝275.5Hz),127.23,52.81,32.67(q,J＝28.5Hz),30.71,23.15(q,J＝2.6Hz)；19F NMR(376MHz,CD3OD):δ-67.75；HRMS(ESI-):calculated for C19H16ClF3NO3 -[M-H]-398.0776,found 398.9778.
example 33
2- (2- (4,4, 4-trifluorobutyl) -5-bromophenyl) -2-benzamidoacetic acid:
Figure BDA0002688027760000241
the characteristics are as follows: a white solid;1H NMR(400MHz,CD3OD):δ7.89–7.79(m,2H),7.61(d,J＝2.2Hz,1H),7.56–7.50(m,1H),7.48–7.41(m,3H),7.20(d,J＝8.2Hz,1H),5.96(s,1H),3.01–2.76(m,2H),2.35–2.09(m,2H),2.02–1.85(m,2H)；13C NMR(101MHz,CD3OD):δ172.10,168.53,139.13,137.61,133.51,131.59,131.48,131.20,130.41,128.14,127.32(q,J＝275.5Hz),127.27,119.97,52.83,32.73(q,J＝28.5Hz),30.81,23.09(q,J＝2.9Hz)；19F NMR(376MHz,CD3OD):δ-67.77；HRMS(ESI-):calculated for C19H16BrF3NO3 -[M-H]-442.0271,found 442.0268.
example 34
2- (2- (4,4, 4-trifluorobutyl) -5- (trifluoromethyl) phenyl) -2-benzamidoacetic acid:
Figure BDA0002688027760000242
the characteristics are as follows: a white solid;1H NMR(400MHz,CD3OD):δ7.88–7.80(m,2H),7.78(d,J＝1.9Hz,1H),7.59(dd,J＝8.1,1.9Hz,1H),7.55–7.40(m,4H),6.07(s,1H),3.12–2.85(m,2H),2.40–2.13(m,2H),2.07–1.87(m,2H)；13C NMR(101MHz,CD3OD):δ172.01,168.62,144.54,136.57,133.54,131.60,130.36,128.80(q,J＝32.5Hz),128.15,127.30(q,J＝275.6Hz),127.26,124.79(q,J＝3.5Hz),124.43(q,J＝3.5Hz),124.18(q,J＝271.1Hz),52.90,32.77(q,J＝28.7Hz),31.18,23.01(q,J＝3.4Hz)；19F NMR(376MHz,CD3OD):δ-63.92,-67.76；HRMS(ESI-):calculated for C20H16F6NO3 -[M-H]-432.1040,found 432.1040.
example 35
2- (2-methyl-6- (4,4, 4-trifluorobutyl) -4-fluorophenyl) -2-benzamidoacetic acid:
Figure BDA0002688027760000243
the characteristics are as follows: a white solid;1H NMR(400MHz,CD3OD):δ7.81(d,J＝7.7Hz,2H),7.53(t,J＝7.3Hz,1H),7.48–7.38(m,2H),6.85(dq,J＝9.3,2.9Hz,2H),6.07(s,1H),3.05–2.91(m,1H),2.89–2.77(m,1H),2.46(s,3H),2.31–2.13(m,2H),1.96–1.77(m,2H)；13C NMR(101MHz,CD3OD):δ172.68,168.84,162.02(d,J＝245.0Hz),143.54(d,J＝7.9Hz),140.81(d,J＝8.3Hz),133.79,131.51,129.59(d,J＝3.0Hz),128.17,127.31(q,J＝275.4Hz),127.16,115.60(d,J＝21.1Hz),113.88(d,J＝21.1Hz),52.03,32.75(q,J＝28.5Hz),32.15,23.20(q,J＝2.9Hz),19.51；19F NMR(376MHz,CD3OD):δ-67.88,-116.96；HRMS(ESI-):calculated for C20H18F4NO3 -[M-H]-396.1228,found 396.1228.
example 36
2- (3-methyl-2- (4,4, 4-trifluorobutyl) phenyl) -2-benzamidoacetic acid:
Figure BDA0002688027760000251
the characteristics are as follows: a white solid;1H NMR(400MHz,CD3OD):δ7.89–7.78(m,2H),7.57–7.48(m,1H),7.43(dd,J＝8.5,6.9Hz,2H),7.29(dd,J＝7.4,1.8Hz,1H),7.21–7.08(m,2H),5.99(s,1H),2.92(t,J＝8.5Hz,2H),2.37(s,3H),2.35–2.21(m,2H),1.98–1.75(m,2H)；13C NMR(101MHz,CD3OD):δ173.00,168.63,138.52,136.78,134.95,133.73,131.47,130.39,128.10,127.37(q,J＝275.8Hz),127.24,126.31,125.31,53.49,33.11(q,J＝28.4Hz),27.77,22.11(q,J＝3.0Hz),18.72；19F NMR(376MHz,CD3OD):δ-67.64；HRMS(ESI-):calculated for C20H19F3NO3 -[M-H]-378.1323,found 378.1327.
example 37
2- (2- (3- (4,4, 4-trifluorobutyl) naphthalene)) -2-benzamidoacetic acid:
Figure BDA0002688027760000252
the characteristics are as follows: a white solid;1H NMR(400MHz,CD3OD):δ7.97(s,1H),7.90–7.79(m,4H),7.77(s,1H),7.56–7.40(m,5H),6.11(s,1H),3.08(t,J＝7.9Hz,2H),2.34–2.20(m,2H),2.12–1.97(m,2H)；13C NMR(101MHz,CD3OD):δ172.85,168.70,137.41,133.66,133.50,133.38,132.27,131.52,128.11,127.99,127.41(q,J＝275.5Hz),127.29,127.07,126.87,126.26,125.57,53.35,32.85(q,J＝28.5Hz),31.46,23.21(q,J＝3.0Hz)；19F NMR(376MHz,CD3OD):δ-67.65；HRMS(ESI-):calculated for C23H19F3NO3 -[M-H]-414.1323,found 414.1327.
example 38
2- (2- (2-methyl-4, 4, 4-trifluorobutyl) phenyl) -2-benzamidoacetic acid:
Figure BDA0002688027760000261
the characteristics are as follows: a colorless oily liquid;1H NMR(400MHz,CD3OD):δ7.88–7.78(m,4H),7.57–7.38(m,8H),7.35–7.18(m,6H),5.97(s,1H),5.96(s,1H),2.98-2.86(m,2H),2.82-2.71(m,2H),2.42–2.15(m,4H),2.14–1.95(m,2H),1.13–1.07(m,3H),1.06–1.02(m,3H)；13C NMR(101MHz,CD3OD):δ176.77,172.66,172.60,142.68,142.65,139.26,139.22,137.69,135.42,134.62,134.61,132.04,131.99,131.35(q,J＝276.5Hz),131.32(q,J＝276.7Hz),131.55,131.48,131.19,130.74,130.72,57.18,57.06,43.65,43.62,42.99(q,J＝27.1Hz),42.91(q,J＝27.2Hz),33.27(q,J＝4.2Hz),33.25(q,J＝4.0Hz),22.49,22.44；19F NMR(376MHz,CD3OD):δ-64.36,-64.45；HRMS(ESI-):calculated for C20H19F3NO3 -[M-H]-378.1323,found 378.1321.
example 39
2-phenyl-2- (2- (4,4, 4-trifluorobutyl) phenyl) acetic acid-2-benzamido:
Figure BDA0002688027760000262
the characteristics are as follows: a white solid;1H NMR(400MHz,CD3OD):δ7.88–7.80(m,2H),7.61–7.53(m,1H),7.53–7.44(m,4H),7.40–7.22(m,6H),7.19–7.09(m,1H),2.80–2.62(m,2H),2.00–1.81(m,2H),1.68–1.51(m,1H),1.42–1.30(m,1H)；13C NMR(101MHz,CD3OD):δ173.45,167.80,140.23,138.64,138.20,134.14,131.72,130.11,129.96,128.51,128.41,127.83,127.46,127.44,127.07(q,J＝275.9Hz),127.01,124.81,70.35,33.01(q,J＝28.4Hz),31.43,22.76(q,J＝2.9Hz)；19F NMR(376MHz,CD3OD):δ-67.75；HRMS(ESI-):calculated for C24H21F3NO-[M-H,-CO2]-396.1581,found 396.1583.
example 40
2- (2- (3-methyl-2- (trifluoromethyl) butyl) phenyl) -2-benzamidoacetic acid (4) and 2- (2- (4,4, 4-trifluoro-3, 3-dimethylbutyl) phenyl) -2-benzamido-acetic acid (2 ah):
Figure BDA0002688027760000263
the characteristics are as follows: a white solid;1H NMR(400MHz,CD3OD):δ7.85(dt,J＝7.0,1.4Hz,4H,4+2ah),7.59–7.53(m,2H,4+2ah),7.53–7.44(m,6H,4+2ah),7.36–7.23(m,6H,4+2ah),5.97(s,0.17H,2ah),5.96(d,J＝3.0Hz,2H,4),3.25(dd,J＝14.7,6.7Hz,1H,4),3.15(d,J＝7.2Hz,2H,4),3.07(dd,J＝14.7,7.8Hz,1H,4),2.97–2.84(m,2H,4+2ah),2.22–2.02(m,2H,4+2ah),1.91–1.81(m,0.38H,2ah),1.24(d,J＝16.6Hz,1H,2ah),1.15(ddd,J＝22.5,7.2,1.3Hz,6H,4),1.10–1.03(m,6H,4)；13C NMR(101MHz,CD3OD):δ173.82(2ah),172.46(4),168.60(4),168.59(4),140.83(2ah),137.66(4),137.58(4),135.62(4),135.58(4),134.58(2ah),133.73(4),131.52(4),131.50(4),131.01(4),130.98(4),129.74(2ah),128.79(q,J＝273.8Hz,4),128.76(q,J＝273.0Hz,4),128.45(2ah),128.15(4),128.12(4),127.98(4),127.36(4),127.27(4),127.23(4),127.10(4),127.07(4),126.49(2ah),53.20(2ah),53.00(4),52.96(4),48.65(q,J＝22.8Hz,4),48.63(q,J＝22.9Hz,4),37.49(2ah),28.47(q,J＝2.4Hz,4),28.25(q,J＝2.2Hz,4),26.90(2ah),26.63(4),26.55(4),19.56(2ah),19.39(d,J＝10.9Hz,2ah),19.02(4),18.84(4),17.98(4),17.55(4)；19F NMR(376MHz,CD3OD):δ-66.24(4),-66.45(4),-79.44(2ah)；HRMS(ESI-):calculated for C21H21F3NO3 -[M-H]-392.1479,found 392.1481.
EXAMPLE 41
2- (4- (trifluoromethyl) phenyl) -2-benzoylamino-8, 8, 8-trifluorooctanoic acid:
Figure BDA0002688027760000271
the characteristics are as follows: a colorless oily liquid;1H NMR(400MHz,CD3OD):δ7.87–7.80(m,2H),7.76(d,J＝8.3Hz,2H),7.65(d,J＝8.4Hz,2H),7.60–7.53(m,1H),7.52–7.45(m,2H),2.84(ddd,J＝13.1,11.7,4.5Hz,1H),2.62(ddd,J＝13.3,11.0,4.6Hz,1H),2.18–1.98(m,2H),1.64–1.42(m,4H),1.41–1.24(m,2H)；13C NMR(101MHz,CD3OD):δ173.25,167.19,144.69(q,J＝1.2Hz),134.05,131.69,129.20(q,J＝32.2Hz),128.40,127.37(q,J＝275.4Hz),126.77,126.70,124.77(q,J＝3.8Hz),124.20(q,J＝271.0Hz),65.40,32.80,32.77(q,J＝28.3Hz),28.08,23.60,21.36(q,J＝2.9Hz)；19F NMR(376MHz,CD3OD):δ-64.02,-67.94；HRMS(ESI-):C22H20F6NO3 -[M-H]-460.1353,found 460.1356.
example 42
2-phenyl-2-benzoyl-8, 8, 8-trifluoroacetic acid:
Figure BDA0002688027760000272
the characteristics are as follows: a white solid;1H NMR(400MHz,CD3OD):δ7.87–7.78(m,2H),7.56(ddt,J＝8.7,3.0,1.6Hz,3H),7.49(dd,J＝8.3,6.6Hz,2H),7.34(dd,J＝8.6,6.8Hz,2H),7.30–7.24(m,1H),2.85(ddd,J＝13.3,11.8,4.4Hz,1H),2.62(ddd,J＝13.4,11.2,4.6Hz,1H),2.17–1.98(m,2H),1.64–1.43(m,4H),1.42–1.22(m,2H)；13C NMR(101MHz,CD3OD):δ174.10,167.09,139.98,134.35,131.57,128.39,127.97,127.38(q,J＝275.4Hz),127.22,126.70,125.82,65.53,32.79(q,J＝28.3Hz),32.38,28.16,23.63,21.38(q,J＝3.0Hz)；19F NMR(376MHz,CD3OD):δ-67.93；HRMS(ESI-):C21H21F3NO3 -[M-H]-392.1479,found 392.1477.
example 43
2- (2- (4,4, 4-trifluorobutyl) phenyl) propionic acid:
Figure BDA0002688027760000281
the characteristics are as follows: a colorless oily liquid;1H NMR(400MHz,CDCl3):δ7.36–7.30(m,1H),7.25–7.19(m,2H),7.18–7.14(m,1H),3.96(q,J＝7.1Hz,1H),2.90–2.68(m,2H),2.22–2.07(m,2H),1.95–1.84(m,2H),1.49(d,J＝7.1Hz,3H)；13C NMR(101MHz,CDCl3):δ180.37,138.39,138.16,129.68,127.47,127.20,127.11(q,J＝276.4Hz),127.10,40.42,33.34(q,J＝28.5Hz),31.78,23.34(q,J＝2.5Hz),18.39；19F NMR(376MHz,CDCl3):δ-66.14；HRMS(ESI-):calculated for C13H14F3O2 -[M-H]-259.0951,found 259.0956.
example 44
2, 2-diphenyl-8, 8, 8-trifluorooctanoic acid:
Figure BDA0002688027760000282
the characteristics are as follows: a white solid;1H NMR(400MHz,CDCl3):δ7.38–7.19(m,10H),2.41–2.28(m,2H),2.03–1.88(m,2H),1.54–1.41(m,2H),1.37–1.28(m,2H),1.13–1.03(m,2H)；13C NMR(101MHz,CDCl3):δ179.97,142.38,128.98,127.98,127.18(q,J＝276.3Hz),127.04,60.18,37.70,33.61(q,J＝28.3Hz),29.08,24.84,21.61(q,J＝3.0Hz)；19F NMR(376MHz,CDCl3):δ-66.40；HRMS(ESI-):calculated for C20H20F3NO2 -[M-H]-349.1421,found 349.1417.
example 45
2- (2- (4, 4-difluorobutyl) -4- (trifluoromethyl) phenyl) -2-benzoylglycine:
Figure BDA0002688027760000283
traits: a white solid;1H NMR(400MHz,CD3OD):δ7.87–7.79(m,2H),7.62(d,J＝8.1Hz,1H),7.57(d,J＝1.9Hz,1H),7.56–7.51(m,2H),7.49–7.42(m,2H),6.04(s,1H),5.89(tt,J＝56.1,3.8Hz,1H),2.99(t,J＝7.7Hz,2H),2.04–1.81(m,4H)；13C NMR(101MHz,CD3OD):δ171.91,168.54,141.81,139.45(q,J＝1.3Hz),133.48,131.58,130.07(q,J＝32.1Hz),128.16,128.12,127.21,126.16(q,J＝3.8Hz),124.09(q,J＝271.4Hz),123.03(q,J＝3.8Hz),117.29(t,J＝237.7Hz),52.89,33.42(t,J＝21.0Hz),31.66,23.31(t,J＝5.6Hz)；19F NMR(376MHz,CD3OD):δ-64.17,-117.34；HRMS(ESI-):calculated for C19H17F5NO-[M-H,-CO2]-370.1236,found 370.1238.

Claims (6)

1. a method for constructing carboxylic acid or alcohol by olefin remote functionalization, which is characterized by comprising the following steps:
(1) mixing an olefin compound, a photocatalyst, a base and a free radical precursor; dissolving the obtained solid phase mixture in a nitrogen atmosphere, filling carbon dioxide after freezing and degassing, and then stirring for 2-10 min; or adding aldehyde or ketone into the obtained solid phase mixture, dissolving in a nitrogen atmosphere, freezing, degassing, filling nitrogen, and stirring for 2-10 min;
the addition amount of the photocatalyst is 0.01-20% of the molar equivalent of the olefin compound, the addition amount of the free radical precursor is 1-3 times of the molar equivalent of the olefin compound, and the addition amount of the base is 0.1-5 times of the molar equivalent of the olefin compound;
the olefin compound has the structural formula:
Figure 667700DEST_PATH_IMAGE001
、
Figure 731471DEST_PATH_IMAGE002
、
Figure 727108DEST_PATH_IMAGE003
or
Figure 458304DEST_PATH_IMAGE004
；
Wherein R is1Is phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-methoxycarbonylphenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, tert-butyl, cyclopropyl, thiophene, cyclohexyl, n-propyl, tert-butoxy, benzyloxy or ethoxy; r2Is phenyl, methyl, methoxy, phenoxy, carboxyl, methoxycarbonyl, diethylaminoacyl, fluorine, bromine, chlorine, trifluoromethyl, tert-butoxycarbonyl or 2-propynyloxy; r3、R4、R5Is methyl or hydrogen; r is CF3Or H;
the free radical precursor is sodium trifluoromethanesulfonate, phosphorus diphenoxylate andN-at least one benzyloxycarbonylproline;
the photocatalyst is Ir (ppy)2(dtbbpy)(PF6)、Ir(ppy)2(bpy)(PF6) And 4 CzIPN;
the base is cesium carbonate, potassium carbonate, cesium pivalate, cesium fluoride or cesium acetate;
(2) and (2) carrying out an illumination reaction on the product obtained in the step (1) for 2-30 h at room temperature, and purifying.
2. The method for constructing carboxylic acid or alcohol by olefin remote functionalization according to claim 1, wherein the pressure of the carbon dioxide charged in the step (1) is 0.5 to 30.0 times atmospheric pressure.
3. The method for the remote functionalization of an olefin to construct a carboxylic acid or alcohol according to claim 1, wherein the olefin compound is 6, 6-diphenyl-1-hexene or 1-allyl-2-ethylbenzene.
4. The method for constructing carboxylic acid or alcohol through olefin remote functionalization according to claim 1, wherein a light source of the illumination reaction in the step (2) is 3-60W, and a blue LED lamp with a wavelength of 400-500 nm.
5. The method of any one of claims 1 to 4, wherein the carboxylic acid has the formula:
Figure 248406DEST_PATH_IMAGE005
；
the reaction formula is as follows:
Figure 799473DEST_PATH_IMAGE006
wherein R is1Is phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-methoxycarbonylphenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, tert-butyl, cyclopropyl, thiophene, cyclohexyl, n-propyl, tert-butoxy, benzyloxy or ethoxy; r2Is phenyl, methyl, methoxy, phenoxy, carboxyl, methoxycarbonyl, diethylaminoacyl, fluorine, bromine, chlorine, trifluoromethyl, tert-butoxycarbonyl or 2-propynyloxy; r3、R4And R5Is methyl or hydrogen;
or the carboxylic acid has the formula:
Figure 598801DEST_PATH_IMAGE007
、
Figure 918924DEST_PATH_IMAGE008
、
Figure 145506DEST_PATH_IMAGE009
(ii) a R is CF3Or H.
6. The method according to any one of claims 1 to 4, wherein the alcohol has the formula:
Figure 449449DEST_PATH_IMAGE010
；
wherein R is1Is tert-butyloxycarbonyl, ethoxycarbonyl or hydrogen; r2Is phenyl, 4-fluorophenyl, 4-biphenyl, 4-phenoxyphenyl, 4-methoxycarbonylphenyl, 4-methylsulfonylphenyl or pyridine.
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