A process for the synthesis of linear carboxylic acids by hydrocarboxylation of olefins using formic acid as a carbonyl source

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing linear carboxylic acid by olefin hydrocarboxylation with formic acid as a carbonyl source. The method comprises the following steps: dispersing internal olefin, formic acid, a palladium catalyst, a diphosphine ligand 1.2-DTBPMB and an additive in an organic solvent in a protective atmosphere according to a molar ratio of 1:1-4:0.001-0.05:0.004-0.2:0-1.0, and reacting at 25-110 DEG C to obtain terminal alkyl carboxylic acid, and separating the target product alkyl carboxylic acid after the reaction is completed. The reaction successfully realizes the olefin hydrocarboxylation reaction with formic acid as a carbonyl source under the condition of no activator. Meanwhile, when acetic anhydride, formic acid phenyl ester and other additives are added to the reaction system, the reaction can also be successfully carried out. The amount of the palladium metal can be reduced to 0.1 mol%, the amount of the ligand can be reduced to 0.4 mol%, the reaction can be carried out in a common gas insertion ball test tube, and a high-pressure kettle is not needed. The reaction step is simple, the operation is simple, and the yield is high.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing linear carboxylic acid through olefin hydrocarboxylation with formic acid as a carbonyl source. BACKGROUND

[0002] Olefins, including terminal and internal olefins, are widely present in various natural products and drug structures. At the same time, carboxylic acid compounds are a very important class of synthetic intermediates and target products in organic synthesis, and their application in disciplines such as fine chemical industry and pharmaceutical chemistry is also extremely extensive. In addition, they play a huge role in industry as drugs, perfumes, synthetic building blocks, etc. By selecting specific catalysts and ligands, using internal olefins as raw materials, and synthesizing various carboxylic acid compounds through hydrocarboxylation under mild conditions, various possibilities are provided for natural product synthesis and drug modification.

[0003] In previous studies, the hydrocarboxylation of olefins mainly uses carbon monoxide as a carbonyl source, but carbon monoxide is toxic and flammable and explosive, and most reactions need to be carried out at high temperature and high pressure. Therefore, the development of olefin hydrocarboxylation reactions with non-CO as a carbonyl source has also been highly valued. The prior art has developed a series of olefin hydrocarboxylation reactions with formic acid as a carbonyl source, but they all need to add formic acid activators such as acetic anhydride or phenyl formate in the reaction system for the reaction to proceed, and only the hydrocarboxylation of terminal olefins can be solved. This system cannot proceed for the hydrocarboxylation of internal olefins. These all limit the application scenarios of such compounds in the pharmaceutical industry or industry. SUMMARY

[0004] To solve the above technical problems, the present application provides a method for preparing linear carboxylic acid through olefin hydrocarboxylation with formic acid as a carbonyl source, which does not involve carbon monoxide, does not need to add additives, and can successfully realize the hydrocarboxylation of olefins under mild conditions in the presence of equivalent formic acid by using only a catalyst, thereby efficiently and selectively preparing a series of alkyl carboxylic acid compounds.

[0005] The technical solution adopted by the present application is as follows:

[0006] A method for preparing linear carboxylic acid through olefin hydrocarboxylation with formic acid as a carbonyl source, comprising: dispersing internal olefin, formic acid, palladium catalyst, bisphosphine ligand 1.2-DTBPMB, and additive in an organic solvent in a molar ratio of 1:1-4:0.001-0.05:0.004-0.2:0-1.0 under a nitrogen protective atmosphere, then reacting at a certain temperature, and separating the target product after the reaction is completed to obtain linear carboxylic acid.

[0007] The reaction formula of the preparation method is as follows:

[0008]

[0009] Traditional activation of formic acid must be added acetic anhydride, phenyl formate, or DCC, etc. activator, then formic acid can occur with metal palladium palladium insertion reaction, so that the olefin hydrogen palladium reaction. But when using 1.2-DTBPMB as ligand, formic acid can occur with metal palladium palladium insertion reaction, without activator. The specific reaction mechanism is as follows:

[0010]

[0011] First, the palladium acetate and ligand combination Pd (0) L n ; then Pd (0) L n Oxidative addition reaction with formic acid, get H-Pd compound species M1. At the same time, formic acid decomposition into carbon monoxide under the action of palladium catalyst and ligand, M1 can be combined with the CO generated on-site, to generate reactive intermediate M2; intermediate M2 and olefin will occur hydrogen palladium (or migration hydrogen palladium) reaction, thus generating intermediate M3 (mainly); then, intermediate M3 occurs carbonyl migration insertion reaction to generate acyl palladium species M4, and then will occur reductive elimination reaction to generate intermediate M5, while generating Pd (0) L n Realize the cycle. Intermediate M5 under the action of palladium catalyst to generate CO and the final product 2, complete the reaction cycle.

[0012] Further: the structure of the olefin is

[0013]

[0014] R 1 Alkyl, 8-amino quinolinyl, phthalimide, acetoxy, cyano, sulfone, phosphorus ester, aryl, ester, Weinreb amide, cyclopentanone, cyclohexenyl or hydrogen atom;

[0015] R 2 Alkyl, 8-amino quinolinyl, phthalimide, acetoxy, cyano, sulfone, phosphorus ester, aryl, ester, Weinreb amide, cyclopentanone, cyclohexenyl or hydrogen atom;

[0016] R 3 Methyl or hydrogen atom.

[0017] Further, the alkyl is methyl; and when R 1 8-amino quinolinyl, phthalimide, acetoxy, cyano, sulfone, phosphorus ester, aryl, Weinreb amide, cyclopentanone or cyclohexenyl, R 2 Methyl, ester or hydrogen atom; when R 2R is 8-aminoquinolyl, phthalimidyl, acetoxy, cyano, sulfone, phosphoester, aryl, Weinreb amide, cyclopentanonyl or cyclohexenyl when R is methyl, ester or hydrogen atom. 1 R is methyl, ester or hydrogen atom.

[0018] Further, the palladium catalyst is one or more of palladium acetate, tris(dibenzylideneacetone)dipalladium-chloroform adduct, palladium trifluoroacetate, palladium chloride, palladium iodide, palladium hydroxide and bis(acetylacetonate)palladium. Further preferably, the palladium catalyst is palladium acetate.

[0019] Further, the structure of the diphosphine ligand 1.2-DTBPMB is as follows:

[0020]

[0021] Further, the solvent is an organic solvent or water.

[0022] Further, the organic solvent is at least one of n-hexane, 1.2-dichloroethane, dichloromethane, acetonitrile, acetone, ethylene glycol dimethyl ether, tetrahydrofuran, 1.4-dioxane, ethyl acetate and DMF. Further preferably, the organic solvent is acetone or ethyl acetate.

[0023] Further, the reaction temperature is 20-110℃.

[0024] Further, the reaction pressure is normal pressure. The reaction does not require high pressure operation, and can be carried out in a pressure-resistant tube or a normal pressure tube with a deflated balloon.

[0025] Further, the additive is acetic anhydride or phenyl formate. In the present application, when acetic anhydride or phenyl formate and the like are added to the reaction system, the migratory hydrocarboxylation reaction of the olefin can still proceed smoothly.

[0026] The beneficial results of the present application are as follows: by using metal palladium salt and diphosphine ligand 1.2-DTBPMB as catalyst, the present application can react olefin with equivalent formic acid to obtain corresponding linear alkyl carboxylic acid and its derivatives under low temperature and non-high pressure mild conditions. The present application uses formic acid as the carbonyl source without adding formic acid activator, and the reaction can be carried out efficiently. The problem of selective migratory hydrocarboxylation of internal olefin is solved, and the reaction does not require additional formic acid activator. Under the mild reaction temperature of the present application, the use of formic acid as the carbonyl source avoids the use of carbon monoxide and the generation of toxic pollutants, and the synthesis method of the present application does not require the addition of additional formic acid activator, is simple and easy to operate, has high yield, and can greatly save energy and improve synthesis efficiency. DETAILED DESCRIPTION

[0027] In order to make the objectives, technical solutions and advantages of the present application clearer, the present application will be further described in details below with embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and not used to limit the protection scope of the present application.

[0028] Example 1

[0029] Synthesis of nonanoic acid (structure 2a)

[0030] Under argon protection, palladium acetate (0.0056g, 0.025mmol), bisphosphine ligand 1.2-DTBPMB (0.0197g, 0.050mmol), 0.1mL of acetone, olefin 1a (0.0561g, 0.5mmol) and formic acid (0.0460g, 1.0mmol) were added into a reactor in sequence and mixed well, after sealing, the mixed system in the reactor was heated to 70°C by heating plate for 12 hours, then the heating was stopped, and the reactor was naturally cooled to room temperature (25°C, same below), then column chromatography separation method (using petroleum ether to fill the column, and petroleum ether: ethyl acetate (volume ratio 5:1) as eluent) was used to separate the colorless oil, i.e. the target product (0.0673g, yield 85%, straight chain and branched chain ratio greater than 20:1). The reaction formula is as follows:

[0031]

[0032] The product structure confirmation results are as follows: 1 H NMR (400MHz, CDCI3) δ 11.5 (br s, 1H), 2.34 (t, J = 7.6 Hz, 2H), 1.69-1.57 (m, 2H), 1.36-1.22 (m, 10H), 0.87 (t, J = 6.8 Hz, 3H); 13 C NMR (100MHz, CDCI3) δ 180.9, 34.4, 32.0, 29.4, 29.32, 29.28, 24.9, 22.9, 14.3.

[0033] Example 2

[0034] Synthesis of nonanoic acid (structure 2a)

[0035] Under argon, palladium acetate (0.0056 g, 0.025 mmol), diphosphine ligand 1.2-DTBPMB (0.0197 g, 0.050 mmol), 0.1 mL of acetone, alkene 1a (0.0561 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) were added successively into a reactor and mixed well. After sealing, the mixture was heated to 70 °C for 12 hours. The heating was then stopped and the mixture was allowed to cool down to room temperature (25 °C). The product was isolated by column chromatography (petroleum ether was used to fill the column and petroleum ether: ethyl acetate (5:1, by volume) was used as the eluent) to give the target product as a colorless oil (0.0673 g, 85% yield, the ratio of straight chain to branched chain was greater than 20:1). The reaction scheme is as follows:

[0036]

[0037] The product structure confirmation results are shown in Example 1.

[0038] Example 3

[0039] Synthesis of nonanoic acid (structure 2a)

[0040] Under argon, palladium acetate (0.0056 g, 0.025 mmol), diphosphine ligand 1.2-DTBPMB (0.0197 g, 0.050 mmol), 0.1 mL of acetone, alkene 1a (0.0561 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) were added successively into a reactor and mixed well. After sealing, the mixture was heated to 70 °C for 12 hours. The heating was then stopped and the mixture was allowed to cool down to room temperature (25 °C). The product was isolated by column chromatography (petroleum ether was used to fill the column and petroleum ether: ethyl acetate (5:1, by volume) was used as the eluent) to give the target product as a colorless oil (0.0673 g, 85% yield, the ratio of straight chain to branched chain was greater than 20:1). The reaction scheme is as follows:

[0041]

[0042] The product structure confirmation results are shown in Example 1.

[0043] Example 4

[0044] Synthesis of decanoic acid (structure 2d):

[0045] Under argon, palladium acetate (0.0056 g, 0.025 mmol), diphosphine ligand 1.2-DTBPMB (0.0197 g, 0.050 mmol), 0.1 mL of acetone, alkene 1d (0.0631 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) were sequentially added to a reactor and mixed well. After sealing, the mixture was heated to 70 °C for 12 h using a heating plate. After stopping the heating, the mixture was allowed to cool to room temperature (25 °C) naturally. The product was isolated by column chromatography (petroleum ether was used to fill the column, and petroleum ether: ethyl acetate (5:1, by volume) was used as the eluent) to give the target product (0.0676 g, 78% yield, the ratio of straight chain to branched chain was greater than 20:1) as a white solid. The reaction equation is as follows:

[0046]

[0047] The product structure confirmation results are as follows: 1 H NMR (400 MHz, CDC13) δ 10.51 (br s, 1H), 2.34 (t, J = 7.2 Hz, 2H), 1.68-1.57 (m, 2H), 1.36-1.21 (m, 12H), 0.88 (t, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 180.8, 34.4, 32.1, 29.6, 29.5, 29.3, 24.9, 22.9, 14.3.

[0048] Example 5

[0049] Synthesis of pentadecanoic acid (structure 2e):

[0050] Under argon, palladium acetate (0.0056 g, 0.025 mmol), diphosphine ligand 1.2-DTBPMB (0.0197 g, 0.050 mmol), 0.1 mL of acetone, alkene 1e (0.0982 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) were sequentially added to a reactor and mixed well. After sealing, the mixture was heated to 70 °C for 12 h using a heating plate. After stopping the heating, the mixture was allowed to cool to room temperature (25 °C) naturally. The product was isolated by column chromatography (petroleum ether was used to fill the column, and petroleum ether: ethyl acetate (5:1, by volume) was used as the eluent) to give the target product (0.0727 g, 60% yield, the ratio of straight chain to branched chain was greater than 20:1) as a white solid. The reaction equation is as follows:

[0051]

[0052] The product structure confirmation results are as follows: 1H NMR (400 MHz, CDC13) δ 11.30 (br s, 1H), 2.34 (t, J = 7.6 Hz, 2H), 1.69-1.57 (m, 2H), 1.36-1.21 (m, 22H), 0.88 (t, J = 6.4 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 180.8, 34.4, 32.2, 29.92, 29.90, 29.88, 29.83, 29.7, 29.6, 29.5, 29.3, 24.9, 22.9, 14.3.

[0053] Example 6

[0054] Synthesis of 5-cyanopentanoic acid (structure 2f):

[0055] Into a reactor, under argon protection, were sequentially added palladium acetate (0.0056 g, 0.025 mmol), diphosphine ligand 1.2-DTBPMB (0.0197 g, 0.050 mmol), 0.1 mL of acetone, olefin 1f (0.0406 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) and mixed well. After sealing, the reactor was heated to 70 °C for 24 hours. The heating was then stopped and the reactor was allowed to cool down to room temperature (25 °C). The product was isolated by column chromatography (column was packed with petroleum ether, eluent was petroleum ether: ethyl acetate = 1:1 by volume) to give the target product as a yellowish oil (0.0396 g, yield 62%, linear to branched ratio > 20:1). The reaction scheme was:

[0056]

[0057] The structure of the product was confirmed as follows: 1 H NMR (400 MHz, CDC13) δ 8.59 (br s, 1H), 2.41 (t, J = 6.8 Hz, 2H), 2.38 (t, J = 6.8 Hz, 2H), 1.83-1.68 (m, 4H); 13 C NMR (100 MHz, CDC13) δ 179.0, 119.4, 33.2, 24.8, 23.7, 17.1.

[0058] Example 7

[0059] Synthesis of hexanedioic acid (structure 2g):

[0060] Under argon protection, add palladium acetate (0.0056 g, 0.025 mmol), diphosphine ligand 1.2-DTBPMB (0.0197 g, 0.050 mmol), 0.1 mL of acetone, olefin 1g (0.0501 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) into a reactor in sequence and mix well, after sealing, heat the mixture in the reactor to 70 °C by heating plate and react for 12 hours, stop heating, and cool to room temperature (25 °C, same below) naturally, then filter to separate to obtain white solid, which is the target product (0.0723 g, yield 99%, linear and branched chain ratio is greater than 20:1). The reaction formula is:

[0061]

[0062] The product structure confirmation results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 11.99 (br s, 2H), 2.25-2.15 (m, 4H), 1.55-1.43 (m, 4H); 13 C NMR (100 MHz, DMSO-d6) δ 174.5, 33.5, 24.1.

[0063] Example 8

[0064] Synthesis of 6-oxo-6-(quinolin-8-amino)hexanoic acid (structure 2h):

[0065] Under argon protection, add palladium acetate (0.0056 g, 0.025 mmol), diphosphine ligand 1.2-DTBPMB (0.0197 g, 0.050 mmol), 0.1 mL of acetone, olefin 1h (0.1131 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) into a reactor in sequence and mix well, after sealing, heat the mixture in the reactor to 70 °C by heating plate and react for 12 hours, stop heating, and cool to room temperature (25 °C, same below) naturally, then separate by column chromatography (use petroleum ether to fill the column, and petroleum ether: ethyl acetate volume ratio 2:1 to 1:1 as eluent) to obtain white solid, which is the target product (0.0854 g, yield 63%, linear and branched chain ratio is greater than 20:1). The reaction formula is:

[0066]

[0067] The product structure confirmation results are as follows: 1H NMR (400 MHz, CDC13) δ 9.81 (br s, 1H), 8.95 (br s, 1H), 8.77 (dd, J = 4.4, 1.6 Hz, 1H), 8.73 (dd, J = 7.2, 1.6 Hz, 1H), 8.12 (dd, J = 8.4, 1.6 Hz, 1H), 7.53-7.45 (m, 2H), 7.41 (dd, J = 8.0, 4.0 Hz, 1H), 2.67 (t, J = 7.6 Hz, 2H), 2.54 (t, J = 7.2 Hz, 2H), 2.19-2.09 (m, 2H); 13 C NMR (100 MHz, CDC13) δ 178.3, 171.4, 148.4, 138.4, 136.7, 134.3, 128.1, 127.5, 121.9, 121.7, 117.2, 36.8, 33.3, 20.7.

[0068] Example 9

[0069] Synthesis of 7-(1,3-dioxoisoindolin-2-yl)heptanoic acid (Structure 2i):

[0070] Under argon protection, into a reactor were added palladium acetate (0.0056 g, 0.025 mmol), diphosphine ligand 1.2-DTBPMB (0.0197 g, 0.050 mmol), 0.1 mL of acetone, olefin 1i (0.1146 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) in sequence and mixed well, after sealing, the mixed system in the reactor was heated to 70 °C by heating plate for 12 hours, then the heating was stopped, and the reactor was naturally cooled to room temperature (25 °C, same below), then column chromatography (column was filled with petroleum ether, eluent was petroleum ether: ethyl acetate = 2: 1 by volume) was used to separate the white solid, which was the target product (0.1303 g, yield 95%, straight chain and branched chain ratio was greater than 20: 1). The reaction formula was:

[0071]

[0072] The product structure confirmation results were as follows: 1 H NMR (400 MHz, CDC13) δ 10.74 (br s, 1H), 7.86-7.76 (m, 2H), 7.72-7.64 (m, 2H), 3.65 (t, J = 7.2 Hz, 2H), 2.32 (t, J = 7.2 Hz, 2H), 1.71-1.55 (m, 4H), 1.41-1.30 (m, 4H); 13C NMR (100 MHz, CDC13) δ 180.0, 168.6, 134.0, 132.2, 123.3, 38.0, 34.1, 28.7, 28.5, 26.6, 24.6.

[0073] Example 10

[0074] Synthesis of 10-acetyloxydecanoic acid (Formula 2j):

[0075] Into a reactor, under argon protection, were sequentially added palladium acetate (0.0056 g, 0.025 mmol), diphosphine ligand 1.2-DTBPMB (0.0197 g, 0.050 mmol), 0.1 mL of acetone, olefin 1j (0.0921 g, 0.5 mmol) and formic acid (0.0921 g, 2.0 mmol) and mixed well. After sealing, the reactor was heated to 90 °C for 12 hours. The heating was then stopped and the reactor was allowed to cool down to room temperature (25 °C). The product was isolated by column chromatography (petroleum ether was used to fill the column and petroleum ether: ethyl acetate (5:1 to 1:1) was used as eluent) to give the target product (0.0463 g, 40% yield, linear to branched ratio >20:1) as colorless oil. The reaction scheme was as follows:

[0076]

[0077] The product structure confirmation results were as follows: 1 H NMR (400 MHz, CDC13) δ 9.09 (br s, 1H), 4.04 (t, J = 6.8 Hz, 2H), 2.33 (t, J = 7.2 Hz, 2H), 2.04 (s, 3H), 1.66-1.55 (m, 4H), 1.38-1.23 (m, 10H); 13 CNMR (100 MHz, CDC13) δ 180.1, 171.6, 64.9, 34.2, 29.5, 29.34, 29.31, 29.2, 28.8, 26.1, 24.8, 21.2.

[0078] Example 11

[0079] Synthesis of 7-(phenylsulfonyl)heptanoic acid (Formula 2k):

[0080] Into a reactor, under argon protection, palladium acetate (0.0056 g, 0.025 mmol), diphosphine ligand 1.2-DTBPMB (0.0197 g, 0.050 mmol), 0.1 mL of acetone, olefin 1k (0.1122 g, 0.5 mmol) and formic acid (0.0921 g, 2.0 mmol) were added successively and mixed well. After sealing, the mixture was heated to 90 °C for 24 hours. After stopping heating, the mixture was allowed to cool down to room temperature (25 °C) naturally. The product was isolated by column chromatography (petroleum ether was used to fill the column, and petroleum ether: ethyl acetate (2:1 to 1:1) was used as eluent) to give the target product (0.1027 g, 76% yield, the ratio of straight chain to branched chain was more than 20:1) as white solid. The reaction equation is as follows:

[0081]

[0082] The structure confirmation results of the product are as follows: 1 H NMR (400 MHz, CDC13) δ 9.54 (br s, 1H), 7.89 (d, J = 7.6 Hz, 2H), 7.65 (t, J = 7.2 Hz, 1H), 7.56 (t, J = 7.6 Hz, 2H), 3.07 (t, J = 8.0 Hz, 2H), 2.30 (t, J = 7.2 Hz, 2H), 1.77-1.64 (m, 2H), 1.63-1.50 (m, 2H), 1.40-1.27 (m, 4H); 13 C NMR (100 MHz, CDC13) δ 179.7, 139.3, 133.9, 129.5, 128.2, 56.3, 33.9, 28.6, 28.1, 24.4, 22.6.

[0083] Example 12

[0084] Synthesis of 8-(diethoxyphosphoryl)octanoic acid (structure 2l):

[0085] Under argon, palladium acetate (0.0056 g, 0.025 mmol), bisphosphine ligand 1.2-DTBPMB (0.0197 g, 0.050 mmol), 0.1 mL of acetone, olefin 1l (0.1171 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) were added successively into a reactor and mixed well. The reactor was sealed and the mixture was heated to 70 °C for 12 hours. The heating was stopped and the reactor was allowed to cool down to room temperature (25 °C). The product was isolated by column chromatography (petroleum ether was used to fill the column and petroleum ether: ethyl acetate (1 : 1 to 1 :2) was used as eluent) to give the target product (0.0754 g, 54% yield, the ratio of straight chain to branched chain was more than 20: 1) as yellow oil. The reaction equation is:

[0086]

[0087] The product structure confirmation results are as follows: 1 H NMR (400 MHz, CDC13) δ 8.81 (br s, 1H), 4.14-4.00 (m, 4H), 2.28 (t, J = 7.6 Hz, 2H), 1.76-1.64 (m, 2H), 1.63-1.51 (m, 4H), 1.39-1.25 (m, 6H), 1.28 (t, J = 7.2 Hz, 6H); 13 C NMR (100 MHz, CDC13) δ 178.0, 61.9 (d, J = 6.5 Hz), 34.2, 30.5 (d, J = 16.9 Hz), 29.0, 28.9 (d, J = 0.4 Hz), 25.6 (d, J = 139.5 Hz), 24.9, 22.4 (d, J = 5.2 Hz), 16.6 (d, J = 5.9 Hz).

[0088] Example 13

[0089] Synthesis of 8-phenyloctanoic acid (structure 2m):

[0090] Under argon, palladium acetate (0.0056 g, 0.025 mmol), diphosphine ligand 1.2-DTBPMB (0.0197 g, 0.050 mmol), 0.1 mL of acetone, alkene 1m (0.0871 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) were sequentially added to a reactor and mixed well. After sealing, the mixture was heated to 70 °C for 12 h. After stopping heating, the mixture was allowed to cool to room temperature (25 °C) naturally. The product was isolated by column chromatography (petroleum ether was used to fill the column, and petroleum ether: ethyl acetate (5:1, by volume) was used as the eluent) to give the target product (0.0780 g, 71% yield, linear: branched ratio 6:1) as colorless oil. The reaction scheme is as follows:

[0091]

[0092] The structure of the product was confirmed as follows: 1 H NMR (400 MHz, CDC13) δ 11.17 (br s, 1H), 7.34-7.30 (m, 1H), 7.29-7.23 (m, 2H), 7.19-7.14 (m, 2H), 2.59 (t, J = 8.0 Hz, 2H), 2.32 (t, J = 7.6 Hz, 2H), 1.67-1.56 (m, 4H), 1.38-1.28 (m, 6H); 13 C NMR (100 MHz, CDC13) δ 180.8, 142.9, 128.6, 128.4, 125.8, 36.1, 34.3, 31.6, 29.29, 29.26, 29.2, 24.8.

[0093] Example 14

[0094] Synthesis of 5-ethoxy-5-oxopentanoic acid (structure 2n):

[0095] Under argon, palladium acetate (0.0056 g, 0.025 mmol), diphosphine ligand 1.2-DTBPMB (0.0197 g, 0.050 mmol), 0.1 mL of acetone, alkene 1n (0.0571 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) were sequentially added to a reactor and mixed well. After sealing, the mixture was heated to 70 °C for 12 h. After stopping heating, the mixture was allowed to cool to room temperature (25 °C) naturally. The product was isolated by column chromatography (petroleum ether was used to fill the column, and petroleum ether: ethyl acetate (2:1, by volume) was used as the eluent) to give the target product (0.0672 g, 84% yield, linear: branched ratio >20:1) as yellowish oil. The reaction scheme is as follows:

[0096]

[0097] The product structure confirmation results are as follows: 1 H NMR (400 MHz, CDC13) δ 10.61 (br s, 1H), 4.11 (q, J = 7.2 Hz, 2H), 2.43-2.34 (m, 4H), 1.97-1.88 (m, 2H), 1.23 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 179.3, 173.2, 60.7, 33.4, 33.2, 20.0, 14.3.

[0098] Example 15

[0099] Synthesis of 6-ethoxy-6-oxohexanoic acid (structure 2o):

[0100] Under argon protection, into a reactor were sequentially added palladium acetate (0.0056 g, 0.025 mmol), diphosphine ligand 1.2-DTBPMB (0.0197 g, 0.050 mmol), 0.1 mL of acetone, olefin 1o (0.0641 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) and mixed well, after sealing, the mixed system in the reactor was heated to 70 °C by heating plate for 12 hours, then the heating was stopped, and the natural cooling to room temperature (25 °C, same below) was carried out, and column chromatography (using petroleum ether to fill the column, and petroleum ether: ethyl acetate (volume ratio 2: 1) as eluent) was used to separate the yellow oily substance, i.e. the target product (0.0775 g, yield 89%, straight chain and branched chain ratio greater than 20: 1). The reaction formula was:

[0101]

[0102] The product structure confirmation results are as follows: 1 H NMR (400 MHz, CDC13) δ 9.96 (br s, 1H), 4.09 (q, J = 7.2 Hz, 2H), 2.38-2.24 (m, 4H), 1.71-1.58 (m, 4H), 1.21 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 179.6, 173.6, 60.6, 34.0, 33.8, 24.4, 24.2, 14.3.

[0103] Example 16

[0104] Synthesis of hexanedioic acid (structure 2g):

[0105] Under argon, palladium acetate (0.0056 g, 0.025 mmol), diphosphine ligand 1.2-DTBPMB (0.0197 g, 0.050 mmol), 0.1 mL of acetone, olefin 1p (0.0501 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) were sequentially added to a reactor and mixed well. After sealing, the mixture in the reactor was heated to 70 °C by a heating plate for 12 hours. After stopping heating, the reactor was naturally cooled to room temperature (25 °C, same below). The white solid was obtained by filtration, which was the target product (0.0578 g, yield 79%, linear to branched ratio > 20:1). The reaction equation is:

[0106]

[0107] The product structure confirmation results are shown in Example 7.

[0108] Example 17

[0109] Synthesis of 7-(methoxy(methyl)amino)-7-oxoheptanoic acid (structure 2q):

[0110] Under argon, palladium acetate (0.0056 g, 0.025 mmol), diphosphine ligand 1.2-DTBPMB (0.0197 g, 0.050 mmol), 0.1 mL of acetone, olefin 1q (0.0786 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) were sequentially added to a reactor and mixed well. After sealing, the mixture in the reactor was heated to 70 °C by a heating plate for 12 hours. After stopping heating, the reactor was naturally cooled to room temperature (25 °C, same below). The light yellow oil was obtained by column chromatography (column was filled with petroleum ether, eluent was petroleum ether: ethyl acetate in the volume ratio of 5:1 to 1:1), which was the target product (0.0715 g, yield 70%, linear to branched ratio > 20:1). The reaction equation is:

[0111]

[0112] The product structure confirmation results are as follows: 1 H NMR (400 MHz, CDCl3) δ 10.19 (br s, 1H), 3.64 (s, 3H), 3.14 (s, 3H), 2.39 (t, J = 6.8 Hz, 2H), 2.30 (t, J = 7.6 Hz, 2H), 1.68-1.55 (m, 4H), 1.41-1.29 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 179.0, 174.7, 61.3, 34.0, 32.3, 31.7, 28.9, 24.6, 24.3.

[0113] Example 18

[0114] Synthesis of 6-(2-methyl-5-oxochloro-l-en-l-yl)hexanoic acid (structure 2r):

[0115] Into a reactor, under argon protection, were sequentially added palladium acetate (0.0056 g, 0.025 mmol), diphosphine ligand 1.2-DTBPMB (0.0197 g, 0.050 mmol), 0.1 mL of acetone, olefin 1r (0.0821 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) and mixed well. After sealing, the reactor was heated to 70 °C for 12 hours. The heating was then stopped and the reactor was allowed to cool down to room temperature (25 °C). The product was isolated by column chromatography (petroleum ether was used to fill the column and petroleum ether: ethyl acetate (5: 1 to 2: 1) was used as eluent) to give the target product as a light yellow oil (0.0779 g, 74% yield, linear to branched ratio > 20: 1). The reaction scheme was as follows:

[0116]

[0117] The structure of the product was confirmed as follows: 1 H NMR (400 MHz, CDC13) δ 10.27 (br s, 1H), 2.51-2.43 (m, 2H), 2.37-2.32 (m, 2H), 2.30 (t, J = 7.2 Hz, 2H), 2.14 (t, J = 7.2 Hz, 2H), 2.02 (s, 3H), 1.66-1.54 (m, 2H), 1.41-1.23 (m, 4H); 13 C NMR (100 MHz, CDC13) δ 210.4, 179.6, 171.1, 140.5, 34.4, 34.1, 31.7, 29.1, 28.1, 24.6, 22.9, 17.4.

[0118] Example 19

[0119] Synthesis of 6-phenylheptanoic acid (structure 2s):

[0120] Under argon, a reactor was charged with palladium acetate (0.0056 g, 0.025 mmol), diphosphine ligand 1.2-DTBPMB (0.0197 g, 0.050 mmol), 0.1 mL of acetone, alkene 1s (0.0801 g, 0.5 mmol) and formic acid (0.0921 g, 2.0 mmol) and mixed well. The reactor was sealed and the contents were heated to 90 °C using a heating mantle. After 12 hours, the heating was stopped and the reactor was allowed to cool to room temperature (25 °C). The product was isolated by column chromatography (petroleum ether column, eluent petroleum ether: ethyl acetate 5:1 to 2:1) to give the target product as a colourless oil (0.0745 g, 72% yield, linear to branched ratio 10:1). The reaction scheme is:

[0121]

[0122] The product structure confirmation results are as follows: 1 H NMR (400 MHz, CDC13) δ 10.23 (br s, 1H), 7.31-7.23 (m, 2H), 7.20-7.13 (m, 3H), 2.72-2.60 (m, 1H), 2.28 (t, J = 7.6 Hz, 2H), 1.69-1.52 (m, 4H), 1.33-1.22 (m, 2H), 1.23 (d, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 180.5, 147.6, 128.5, 127.1, 126.1, 39.9, 38.1, 34.2, 27.3, 24.9, 22.5.

[0123] Example 20

[0124] Synthesis of 5-methoxy-4-methyl-5-oxopentanoic acid (structure 2t):

[0125] Under argon, a reactor was charged with palladium acetate (0.0056 g, 0.025 mmol), diphosphine ligand 1.2-DTBPMB (0.0197 g, 0.050 mmol), 0.1 mL of acetone, alkene 1t (0.0571 g, 0.5 mmol) and formic acid (0.0921 g, 2.0 mmol) and mixed well. The reactor was sealed and the contents were heated to 90 °C using a heating mantle. After 12 hours, the heating was stopped and the reactor was allowed to cool to room temperature (25 °C). The product was isolated by column chromatography (petroleum ether column, eluent petroleum ether: ethyl acetate 2:1) to give the target product as a yellowish oil (0.0632 g, 79% yield, linear to branched ratio 10:1). The reaction scheme is:

[0126]

[0127] The product structure confirmation results are as follows: 1 H NMR (400 MHz, CDC13) δ 8.47 (br s, 1H), 3.66 (s, 3H), 2.56-2.46 (m, 1H), 2.41-2.34 (m, 2H), 2.01-1.90 (m, 1H), 1.81-1.72 (m, 1H), 1.16 (d, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 179.3, 176.6, 51.9, 38.7, 31.8, 28.4, 17.2.

[0128] Example 21

[0129] Synthesis of adipic acid (structure 2g):

[0130] Under argon protection, the reactor was added with palladium acetate (0.0056 g, 0.025 mmol), diphosphine ligand 1.2-DTBPMB (0.0197 g, 0.050 mmol), 0.1 mL of acetone, olefin 1u (0.0167 g, 0.17 mmol), olefin 1g (0.0167 g, 0.17 mmol), olefin 1p (0.0167 g, 0.17 mmol) and formic acid (0.0460 g, 1.0 mmol) in sequence and mixed well, after sealing, the mixed system in the reactor was heated to 70°C by heating plate and reacted for 12 hours, then the heating was stopped, and the reactor was naturally cooled to room temperature (25°C, same below), then the white solid was separated by filtration, which was the target product (0.0618 g, yield 85%, linear and branched chain ratio greater than 20:1). The reaction formula is as follows:

[0131]

[0132] The product structure confirmation results are as shown in Example 7.

[0133] When acetic anhydride or phenyl formate is added to the reaction system, the reaction can also be carried out smoothly, and the reaction system with the addition of acetic anhydride or phenyl formate is further described in detail in combination with the examples. The specific examples described herein are only used to explain the present application and do not limit the protection scope of the present application.

[0134] For example, as shown below:

[0135] Example 22

[0136] Synthesis of nonanoic acid (structure 2a):

[0137] Under argon, palladium acetate (0.0056 g, 0.025 mmol), diphosphine ligand 1.2-DTBPMB (0.0197 g, 0.050 mmol), 0.1 mL of acetone, alkene 1a (0.0561 g, 0.5 mmol), formic acid (0.0460 g, 1.0 mmol) and acetic anhydride (0.0102 g, 0.1 mmol) were added successively into a reactor and mixed well. After sealing, the reactor was heated to 40 °C for 24 h. The heating was then stopped and the reactor was allowed to cool down to room temperature (25 °C). The product was isolated by column chromatography (petroleum ether was used to fill the column and petroleum ether: ethyl acetate (5:1, by volume) was used as the eluent) to give the target product (0.0727 g, 92% yield, the ratio of straight chain to branched chain >20:1) as a colorless oil. The reaction scheme is as follows:

[0138]

[0139] The product structure confirmation is shown in Example 1.

[0140] Example 23

[0141] Synthesis of 6-oxo-6-(quinolin-8-ylamino)hexanoic acid (structure 2h):

[0142] Under argon, palladium acetate (0.0056 g, 0.025 mmol), diphosphine ligand 1.2-DTBPMB (0.0197 g, 0.050 mmol), 0.1 mL of acetone, alkene 1a (0.0561 g, 0.5 mmol), formic acid (0.0460 g, 1.0 mmol) and acetic anhydride (0.0102 g, 0.1 mmol) were added successively into a reactor and mixed well. After sealing, the reactor was heated to 40 °C for 24 h. The heating was then stopped and the reactor was allowed to cool down to room temperature (25 °C). The product was isolated by column chromatography (petroleum ether was used to fill the column and petroleum ether: ethyl acetate (5:1, by volume) was used as the eluent) to give the target product (0.0727 g, 92% yield, the ratio of straight chain to branched chain >20:1) as a colorless oil. The reaction scheme is as follows:

[0143]

[0144] The product structure confirmation is shown in Example 1.

[0145] Example 23

[0146] Synthesis of 5-cyanopentanoic acid (structure 2f):

[0147] Under argon, palladium acetate (0.0056 g, 0.025 mmol), diphosphine ligand 1.2-DTBPMB (0.0197 g, 0.050 mmol), 0.1 mL of acetone, olefin 1f (0.0406 g, 0.5 mmol), formic acid (0.0460 g, 1.0 mmol) and acetic anhydride (0.0102 g, 0.1 mmol) were added successively into a reactor and mixed well. After sealing, the reactor was heated to 40 °C for 24 h. The heating was then stopped and the reactor was allowed to cool down to room temperature (25 °C). The product was isolated by column chromatography (petroleum ether was used to fill the column and petroleum ether: ethyl acetate (1 : 1) was used as eluent) to give the target product (0.0440 g, 69% yield, the ratio of linear to branched is more than 20: 1) as a yellow oil. The reaction scheme is as follows:

[0148]

[0149] The structure of the product was confirmed as shown in Example 6.

[0150] Example 25

[0151] Synthesis of 6-ethoxy-6-oxohexanoic acid (structure 2o):

[0152] Under argon, palladium acetate (0.0056 g, 0.025 mmol), diphosphine ligand 1.2-DTBPMB (0.0197 g, 0.050 mmol), 0.1 mL of acetone, olefin 1o (0.0641 g, 0.5 mmol), formic acid (0.0460 g, 1.0 mmol) and acetic anhydride (0.0102 g, 0.1 mmol) were added successively into a reactor and mixed well. After sealing, the reactor was heated to 40 °C for 24 h. The heating was then stopped and the reactor was allowed to cool down to room temperature (25 °C). The product was isolated by column chromatography (petroleum ether was used to fill the column and petroleum ether: ethyl acetate (2: 1) was used as eluent) to give the target product (0.0775 g, 89% yield, the ratio of linear to branched is more than 20: 1) as a yellow oil. The reaction scheme is as follows:

[0153]

[0154] The structure of the product was confirmed as shown in Example 15.

[0155] Example 26

[0156] Synthesis of 7-(methoxy(methyl)amino)-7-oxoheptanoic acid (structure 2q):

[0157] Into a reactor, under argon protection, palladium acetate (0.0056 g, 0.025 mmol), bisphosphine ligand 1.2-DTBPMB (0.0197 g, 0.050 mmol), 0.1 mL of acetone, olefin 1q (0.0786 g, 0.5 mmol), formic acid (0.0460 g, 1.0 mmol) and acetic anhydride (0.0102 g, 0.1 mmol) were added successively and mixed well. After sealing, the reactor was heated to 40 °C by a heating plate and the mixture was allowed to react for 24 hours. After stopping heating, the reactor was allowed to cool to room temperature (25 °C) naturally. The product was isolated by column chromatography (column was packed with petroleum ether, eluent was petroleum ether: ethyl acetate with volume ratio of 5:1 to 1:1) to give the target product (0.0715 g, yield 70%, straight chain and branched chain ratio >20:1) as a yellowish oil. The reaction equation is as follows:

[0158]

[0159] The structure of the product was confirmed as shown in Example 17.

[0160] The above shows and describes the basic principles and main features of the present application and the advantages of the present application. It should be understood by those skilled in the art that the present application is not limited by the above examples, and the above examples and descriptions in the specification are only to illustrate the principles of the present application. Without departing from the spirit and scope of the present application, various changes and improvements can be made to the present application, and these changes and improvements all fall within the scope of the present application. The scope of protection of the present application is defined by the appended claims and their equivalents.

Claims

1. A process for the production of linear carboxylic acids by olefin hydrocarboxylation using formic acid as the source of carbonyl groups, characterized in that, comprises: Under the protection of nitrogen atmosphere, the olefin, formic acid, palladium catalyst, and 1.2-DTBPMB are dispersed in a solvent according to a molar ratio of 1:1-4:0.001-0.05:0.004-0.2, and then reacted at a certain temperature. After the reaction is completed, the target product is separated, and a linear carboxylic acid is obtained. The structural formula of the linear carboxylic acid is: ​ The structural formula of the olefin is: ; wherein: R1 is methyl, 8-aminoquinolinyl, phthalimidyl, acetoxy, cyano, aryl, Weinreb amide, cyclopentanonyl, cyclohexenyl, or a hydrogen atom; R2 is methyl, 8-aminoquinolinyl, phthalimidyl, acetoxy, cyano, aryl, Weinreb amide, cyclopentanonyl, cyclohexenyl, or a hydrogen atom; R3 is methyl or a hydrogen atom; when R1 is 8-aminoquinolinyl, phthalimidyl, acetoxy, cyano, aryl, Weinreb amide, cyclopentanonyl, or cyclohexenyl, R2 is methyl or a hydrogen atom; when R2 is 8-aminoquinolinyl, phthalimidyl, acetoxy, cyano, aryl, Weinreb amide, cyclopentanonyl, or cyclohexenyl, R1 is methyl or a hydrogen atom.

2. The process for the production of linear carboxylic acids by olefin hydrocarboxylation with formic acid as the source of carbonyl groups according to claim 1, characterized in that, The structural formula of the bisphosphine ligand 1.2-DTBPMB is: .

3. The process for preparing linear carboxylic acid by olefin hydrocarboxylation using formic acid as a carbonyl source according to claim 1, characterized by, The palladium catalyst is one or more of palladium acetate, tris(dibenzylideneacetone)dipalladium-chloroform adduct, palladium trifluoroacetate, palladium chloride, palladium iodide, palladium hydroxide, and bis(acetylacetonato)palladium.

4. The process for preparing linear carboxylic acid by olefin hydrocarboxylation using formic acid as a carbonyl source according to claim 1, characterized by, The solvent is an organic solvent or water.

5. The process for the production of linear carboxylic acids by olefin hydrocarboxylation with formic acid as the source of carbonyl groups according to claim 4, characterized in that, The organic solvent is at least one of n-hexane, 1.2-dichloroethane, dichloromethane, acetonitrile, acetone, ethylene glycol dimethyl ether, tetrahydrofuran, 1.4-dioxane, ethyl acetate, and DMF.

6. The process for preparing linear carboxylic acid by olefin hydrocarboxylation using formic acid as a carbonyl source according to claim 1, characterized by, The reaction temperature is 20-110°C.

7. The process for preparing linear carboxylic acid by olefin hydrocarboxylation using formic acid as a carbonyl source according to claim 1, characterized by, The reaction pressure is normal pressure.

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