Method for synthesizing straight-chain carboxylic acid through olefin hydrocarboxylation with formic acid as carbonyl source

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing straight-chain carboxylic acid through 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 according to a molar ratio of 1: (1-4): (0.001-0.05): (0.004-0.2): (0-1.0) in a protective atmosphere, reacting at 25-110 DEG C to obtain terminal alkyl carboxylic acid, and separating out the target product alkyl carboxylic acid after the reaction is completed. The reaction successfully realizes olefin hydrocarboxylation reaction by taking formic acid as a carbonyl source under the condition of no activating agent. Meanwhile, when additives such as acetic anhydride and phenyl formate are added into the reaction system, the reaction can be successfully carried out. According to the method, the amount of metal palladium can be reduced to 0.1 mol%, the usage amount of the ligand can be reduced to 0.4 mol%, the reaction can be carried out in a common test tube in which a balloon is inserted, an autoclave is not needed, the reaction steps are simple and convenient, the operation is simple, and the yield is high.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing straight-chain carboxylic acid by hydrocarboxylation of olefins using formic acid as a carbonyl source. Background Art

[0002] Olefins, including terminal olefins 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 fine chemicals, medicinal chemistry and other disciplines is also extremely extensive. In addition, they play a huge role in industry as drugs, fragrances, synthetic building blocks, etc. By selecting specific catalysts and ligands, using internal olefins as raw materials, and synthesizing various carboxylic acid compounds through hydrocarboxylation reactions under mild conditions, it provides a huge variety of possibilities for natural product synthesis and drug modification.

[0003] In previous studies, the hydrocarboxylation reaction of olefins mainly uses carbon monoxide as the carbonyl source, but carbon monoxide is toxic, flammable and explosive, and most reactions need to be carried out under high temperature and high pressure. Therefore, the development of olefin hydrocarboxylation reactions with non-CO as the carbonyl source has also received great attention. The prior art has developed a series of olefin hydrocarboxylation reactions using formic acid as the carbonyl source, but they all require the addition of a formic acid activator, such as acetic anhydride or phenyl formate, to the reaction system for the reaction to proceed, and can only solve the problem of hydrocarboxylation of terminal olefins, and this type of system cannot be used for the hydrocarboxylation of internal olefins. These all limit the application scenarios of such compounds in the pharmaceutical industry or industry. Summary of the invention

[0004] In order to solve the above technical problems, the present invention provides a method that does not involve carbon monoxide, does not require the addition of additives, and can successfully achieve the hydrocarboxylation reaction of olefins under mild conditions in the presence of an equivalent amount of formic acid, thereby efficiently and selectively preparing a series of alkyl carboxylic acid compounds.

[0005] The technical solution adopted by the present invention is:

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

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

[0008]

[0009] Traditional formic acid activation requires the addition of acetic anhydride, phenyl formate, or DCC and other activators before formic acid can undergo palladium insertion reaction with metal palladium, thereby causing the hydrogen palladium reaction of olefins. However, when 1.2-DTBPMB is used as a ligand, formic acid can directly undergo palladium insertion reaction with metal palladium without the need for an activator. The specific reaction mechanism is as follows:

[0010]

[0011] First, palladium acetate combines with the ligand to form Pd(0)L n ; then Pd(0)L n It undergoes an oxidative addition reaction with formic acid to obtain H-Pd species M1. At the same time, formic acid decomposes into carbon monoxide under the action of palladium catalyst and ligand. M1 can combine with CO generated on site to generate reactive intermediate M2; intermediate M2 and olefin undergo hydrogen palladium (or transfer hydrogen palladium) reaction to generate intermediate M3 (main); then, intermediate M3 undergoes carbonyl migration insertion reaction to generate acyl palladium species M4, and then undergoes reduction elimination reaction to generate intermediate M5, and simultaneously generates Pd(0)L n The intermediate M5 generates CO and the final product 2 under the action of the palladium catalyst, completing the reaction cycle.

[0012] Further: the structural formula of the olefin is

[0013]

[0014] R 1 is an alkyl group, an 8-aminoquinolyl group, a phthalimide group, an acetoxy group, a cyano group, a sulfone group, a phosphoester group, an aryl group, an ester group, a Weinreb amide group, a cyclopentanone group, a cyclohexenyl group or a hydrogen atom;

[0015] R 2 is an alkyl group, an 8-aminoquinolyl group, a phthalimide group, an acetoxy group, a cyano group, a sulfone group, a phosphoester group, an aryl group, an ester group, a Weinreb amide group, a cyclopentanone group, a cyclohexenyl group or a hydrogen atom;

[0016] R 3 A methyl group or a hydrogen atom.

[0017] Further, the alkyl group is methyl; and when R 1 When R is 8-aminoquinolyl, phthalimide, acetoxy, cyano, sulfone, phosphoester, aryl, Weinreb amide, cyclopentanone or cyclohexenyl, 2 is a methyl group, an ester group or a hydrogen atom; when R 2When R is 8-aminoquinolyl, phthalimide, acetoxy, cyano, sulfone, phosphoester, aryl, Weinreb amide, cyclopentanone or cyclohexenyl, 1 It is a methyl group, an ester group or a 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 di(acetylacetone)palladium. Further preferably, the palladium catalyst is palladium acetate.

[0019] Furthermore, the structural formula of the bisphosphine ligand 1.2-DTBPMB is:

[0020]

[0021] Furthermore, 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] Furthermore, the reaction temperature is 20-110°C.

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

[0025] Furthermore, the additive is acetic anhydride or phenyl formate. In the present invention, when additives such as acetic anhydride or phenyl formate are added to the reaction system, the migratory hydrogen carboxylation reaction of olefins can still proceed smoothly.

[0026] The beneficial results of the present invention are: the present invention uses metal palladium salt and bisphosphine ligand 1.2-DTBPMB as catalysts to react olefins with an equivalent amount of formic acid, and can react under mild conditions of low temperature and non-high pressure to obtain corresponding straight-chain alkyl carboxylic acids and their derivatives. This scheme uses formic acid as a carbonyl source, and does not need to add a formic acid activator, so that the reaction can be carried out efficiently. The problem of selective migration hydrogen carboxylation reaction of internal olefins is successfully solved, and the reaction does not require an additional formic acid activator. At the mild reaction temperature of this scheme, the use of formic acid as a carbonyl source avoids the use of carbon monoxide and the generation of toxic pollutants, and the synthesis method of this scheme does not need to add an additional formic acid activator, the steps are simple, easy to operate, and the yield is high, which can greatly save energy and improve synthesis efficiency. DETAILED DESCRIPTION

[0027] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the scope of protection of the present invention.

[0028] Example 1

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

[0030] 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 1a (0.0561 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) were added to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 70°C by a heating plate and reacted for 12 hours. The heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below). Then, a colorless oily substance was separated by column chromatography (with petroleum ether as the column, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 5:1), i.e., the target product (0.0673 g, yield 85%, and the ratio of straight chain to branched chain was greater than 20:1). The reaction formula is:

[0031]

[0032] The product structure confirmation results are as follows: 1 H NMR (400MHz, CDCl3) δ11.5 (br s, 1H), 2.34 (t, J = 7.6Hz, 2H), 1.69-1.57 (m, 2H), 1.36-1.22 (m, 10H), 0.87 (t, J = 6.8Hz, 3H); 13 C NMR (100MHz, CDCl3) δ180.9,34.4,32.0,29.4,29.32,29.28,24.9,22.9,14.3.

[0033] Example 2

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

[0035] Under argon 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 1b (0.0561 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) were added to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 70°C by a heating plate and reacted for 12 hours. The heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below). Then, a colorless oily substance was separated by column chromatography (with petroleum ether as the column, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 5:1), i.e., the target product (0.0673 g, yield 85%, and the ratio of straight chain to branched chain was greater than 20:1). The reaction formula is:

[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 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 1c (0.0561 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) were added to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 70°C by a heating plate and reacted for 12 hours. The heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below). Then, a colorless oily substance was separated by column chromatography (with petroleum ether as the column, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 5:1), i.e., the target product (0.0673 g, yield 85%, and the ratio of straight chain to branched chain was greater than 20:1). The reaction formula is:

[0041]

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

[0043] Example 4

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

[0045] 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 1d (0.0631 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) were added to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 70°C by a heating plate and reacted for 12 hours. The heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below). Then, a white solid was separated by column chromatography (with petroleum ether as the column, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 5:1), i.e., the target product (0.0676 g, a yield of 78%, and a ratio of straight chain to branched chain greater than 20:1). The reaction formula is:

[0046]

[0047] The product structure confirmation results are as follows: 1 H NMR (400MHz, CDCl3) δ10.51(br s,1H),2.34(t,J=7.2Hz,2H),1.68-1.57(m,2H),1.36-1.21(m,12H),0.88(t,J=6.8Hz,3H); 13 C NMR (100MHz, CDCl3) δ180.8,34.4,32.1,29.6,29.5,29.3,24.9,22.9,14.3.

[0048] Example 5

[0049] Synthesis of Pentadecanoic Acid (Structural Formula 2e):

[0050] 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 1e (0.0982 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) were added to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 70°C by a heating plate and reacted for 12 hours. The heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below). Then, a white solid was separated by column chromatography (with petroleum ether as the column, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 5:1), i.e., the target product (0.0727 g, a yield of 60%, and a ratio of straight chain to branched chain greater than 20:1). The reaction formula is:

[0051]

[0052] The product structure confirmation results are as follows: 1H NMR (400MHz, CDCl3) δ11.30(br s,1H),2.34(t,J=7.6Hz,2H),1.69-1.57(m,2H),1.36-1.21(m,22H),0.88(t,J=6.4Hz,3H); 13 C NMR (100MHz, CDCl3) δ180.8,34.4,32.2,29.92,29.90,29.88,29.83,29.7,29.6,29.5,29.3,24.9,22.9,14.3.

[0053] Example 6

[0054] Synthesis of 5-cyanovaleric acid (Structural Formula 2f):

[0055] 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 1f (0.0406 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) were added to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 70°C by a heating plate and reacted for 24 hours. The heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below). Then, a light yellow oily substance was separated by column chromatography (with petroleum ether as the column, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 1:1), i.e., the target product (0.0396 g, a yield of 62%, and a ratio of straight chain to branched chain greater than 20:1). The reaction formula is:

[0056]

[0057] The product structure confirmation results are as follows: 1 H NMR (400MHz, CDCl3) δ8.59 (br s, 1H), 2.41 (t, J = 6.8Hz, 2H), 2.38 (t, J = 6.8Hz, 2H), 1.83-1.68 (m, 4H); 13 C NMR (100MHz, CDCl3) δ179.0,119.4,33.2,24.8,23.7,17.1.

[0058] Example 7

[0059] Synthesis of adipic acid (structural formula 2g):

[0060] 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 1 g (0.0501 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) were added to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 70°C by a heating plate and reacted for 12 hours, then the heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below), and then filtered to separate the white solid, i.e., the target product (0.0723 g, yield 99%, the ratio of straight chain to branched chain greater than 20:1). The reaction formula is:

[0061]

[0062] The product structure confirmation results are as follows: 1 H NMR (400MHz, DMSO-d6) δ11.99(br s,2H),2.25-2.15(m,4H),1.55-1.43(m,4H); 13 C NMR (100MHz, DMSO-d6) δ174.5, 33.5, 24.1.

[0063] Example 8

[0064] Synthesis of 6-oxo-6-(quinoline-8-amino)hexanoic acid (structural formula 2h):

[0065] 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 1h (0.1131 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) were added to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 70°C by a heating plate and reacted for 12 hours. The heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below). Then, a white solid was separated by column chromatography (with petroleum ether as the column, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 2:1 to 1:1) to obtain the target product (0.0854 g, a yield of 63%, and a ratio of straight chain to branched chain greater than 20:1). The reaction formula is:

[0066]

[0067] The product structure confirmation results are as follows: 1H NMR(400MHz,CDCl3)δ9.81(br s,1H),8.95(br s,1H),8.77(dd,J=4.4,1.6Hz,1H),8.73(dd,J=7.2,1.6Hz,1H),8.12(dd,J=8.4,1.6Hz,1H),7.53-7.4 5(m,2H),7.41(dd,J=8.0,4.0Hz,1H),2.67(t,J=7.6Hz,2H),2.54(t,J=7.2Hz,2H),2.19-2.09(m,2H); 13 C NMR (100MHz, CDCl3) δ178.3,171.4,148.4,138.4,136.7,134.3,128.1,127.5,121.9,121.7,117.2,36.8,33.3,20.7.

[0068] Example 9

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

[0070] 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 1i (0.1146 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) were added to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 70°C by a heating plate and reacted for 12 hours. The heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below). Then, a white solid was separated by column chromatography (with petroleum ether as the column, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 2:1), i.e., the target product (0.1303 g, yield 95%, and the ratio of straight chain to branched chain was greater than 20:1). The reaction formula is:

[0071]

[0072] The product structure confirmation results are as follows: 1 H NMR(400MHz,CDCl3)δ10.74(br s,1H),7.86-7.76(m,2H),7.72-7.64(m,2H),3.65(t,J=7.2Hz,2H),2.32(t,J=7.2Hz,2H),1.71-1.55(m,4H),1.41-1.30(m,4H); 13C NMR (100MHz, CDCl3) δ180.0,168.6,134.0,132.2,123.3,38.0,34.1,28.7,28.5,26.6,24.6.

[0073] Example 10

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

[0075] 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 1j (0.0921 g, 0.5 mmol) and formic acid (0.0921 g, 2.0 mmol) were added to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 90°C by a heating plate and reacted for 12 hours. The heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below). Then, a colorless oil was obtained by column chromatography (with petroleum ether as the column, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 5:1 to 1:1), i.e., the target product (0.0463 g, a yield of 40%, and a ratio of straight chain to branched chain greater than 20:1). The reaction formula is:

[0076]

[0077] The product structure confirmation results are as follows: 1 H NMR (400MHz, CDCl3) δ9.09 (br s, 1H), 4.04 (t, J = 6.8Hz, 2H), 2.33 (t, J = 7.2Hz, 2H), 2.04 (s, 3H), 1.66-1.55 (m, 4H), 1.38-1.23 (m, 10H); 13 CNMR (100MHz, CDCl3) δ180.1,171.6,64.9,34.2,29.5,29.34,29.31,29.2,28.8,26.1,24.8,21.2.

[0078] Embodiment 11

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

[0080] 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 1k (0.1122 g, 0.5 mmol) and formic acid (0.0921 g, 2.0 mmol) were added to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 90°C by a heating plate and reacted for 24 hours. The heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below). Then, a white solid was separated by column chromatography (with petroleum ether as the column, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 2:1 to 1:1) to obtain the target product (0.1027 g, a yield of 76%, and a ratio of straight chain to branched chain greater than 20:1). The reaction formula is:

[0081]

[0082] The product structure confirmation results are as follows: 1 H NMR (400MHz, CDCl3) δ9.54 (br s,1H),7.89(d,J=7.6Hz,2H),7.65(t,J=7.2Hz,1H),7.56(t,J=7.6Hz,2H),3.07(t,J=8. 0Hz,2H),2.30(t,J=7.2Hz,2H),1.77-1.64(m,2H),1.63-1.50(m,2H),1.40-1.27(m,4H); 13 C NMR (100MHz, CDCl3) δ179.7,139.3,133.9,129.5,128.2,56.3,33.9,28.6,28.1,24.4,22.6.

[0083] Example 12

[0084] Synthesis of 8-(diethoxyphosphoryl)octanoic acid (Structural Formula 21):

[0085] 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 1l (0.1171 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) were added to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 70°C by a heating plate and reacted for 12 hours. The heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below). Then, a yellow oily substance was separated by column chromatography (with petroleum ether as the column, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 1:1 to 1:2), i.e., the target product (0.0754 g, a yield of 54%, and a ratio of straight chain to branched chain greater than 20:1). The reaction formula is:

[0086]

[0087] The product structure confirmation results are as follows: 1 H NMR(400MHz, CDCl3)δ8.81(br s,1H),4.14-4.00(m,4H),2.28(t,J=7.6Hz,2H),1.76-1.64(m,2H),1.63-1.51(m,4H),1.39-1.25(m,6H),1.28(t,J=7.2Hz,6H); 13 C NMR (100MHz, CDCl3) δ178.0,61.9(d,J=6.5Hz),34.2,30.5(d,J=16.9Hz),29.0,28 .9(d,J=0.4Hz), 25.6(d,J=139.5Hz), 24.9, 22.4(d,J=5.2Hz), 16.6(d,J=5.9Hz).

[0088] Embodiment 13

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

[0090] 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 1m (0.0871 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) were added to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 70°C by a heating plate and reacted for 12 hours. The heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below). Then, a colorless oily substance was obtained by column chromatography (with petroleum ether as the column, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 5:1), i.e., the target product (0.0780 g, a yield of 71%, and a ratio of straight chain to branched chain of 6:1). The reaction formula is:

[0091]

[0092] The product structure confirmation results are as follows: 1 H NMR(400MHz,CDCl3)δ11.17(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 =8.0Hz,2H),2.32(t,J=7.6Hz,2H),1.67-1.56(m,4H),1.38-1.28(m,6H); 13 C NMR (100MHz, CDCl3) δ180.8,142.9,128.6,128.4,125.8,36.1,34.3,31.6,29.29,29.26,29.2,24.8.

[0093] Embodiment 14

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

[0095] 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 1n (0.0571 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) were added to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 70°C by a heating plate and reacted for 12 hours. The heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below). Then, a light yellow oily substance was separated by column chromatography (with petroleum ether as the column, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 2:1), i.e., the target product (0.0672 g, a yield of 84%, and a ratio of straight chain to branched chain greater than 20:1). The reaction formula is:

[0096]

[0097] The product structure confirmation results are as follows: 1 H NMR (400MHz, CDCl3) δ10.61 (br s, 1H), 4.11 (q, J = 7.2Hz, 2H), 2.43-2.34 (m, 4H), 1.97-1.88 (m, 2H), 1.23 (t, J = 7.2Hz, 3H); 13 C NMR (100MHz, CDCl3) δ179.3,173.2,60.7,33.4,33.2,20.0,14.3.

[0098] Embodiment 15

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

[0100] 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 1o (0.0641 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) were added to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 70°C by a heating plate and reacted for 12 hours. The heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below). Then, a yellow oily substance was separated by column chromatography (with petroleum ether as the column, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 2:1), i.e., the target product (0.0775 g, yield 89%, and the ratio of straight chain to branched chain was greater than 20:1). The reaction formula is:

[0101]

[0102] The product structure confirmation results are as follows: 1 H NMR (400MHz, CDCl3) δ9.96 (br s, 1H), 4.09 (q, J = 7.2Hz, 2H), 2.38-2.24 (m, 4H), 1.71-1.58 (m, 4H), 1.21 (t, J = 7.2Hz, 3H); 13 C NMR (100MHz, CDCl3) δ179.6,173.6,60.6,34.0,33.8,24.4,24.2,14.3.

[0103] Example 16

[0104] Synthesis of adipic acid (structural formula 2g):

[0105] 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 1p (0.0501 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) were added to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 70°C by a heating plate and reacted for 12 hours, then the heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below), and then filtered to separate the white solid, i.e., the target product (0.0578 g, yield 79%, the ratio of straight chain to branched chain greater than 20:1). The reaction formula is:

[0106]

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

[0108] Embodiment 17

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

[0110] 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) and formic acid (0.0460 g, 1.0 mmol) were added to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 70°C by a heating plate and reacted for 12 hours. The heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below). Then, a light yellow oily substance was separated by column chromatography (with petroleum ether as the column, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 5:1 to 1:1) to obtain the target product (0.0715 g, a yield of 70%, and a ratio of straight chain to branched chain greater than 20:1). The reaction formula is:

[0111]

[0112] The product structure confirmation results are as follows: 1 H NMR(400MHz, CDCl3)δ10.19(br s,1H),3.64(s,3H),3.14(s,3H),2.39(t,J=6.8Hz,2H),2.30(t,J=7.6Hz,2H),1.68-1.55(m,4H),1.41-1.29(m,2H); 13 C NMR (100MHz, CDCl3) δ179.0,174.7,61.3,34.0,32.3,31.7,28.9,24.6,24.3.

[0113] Embodiment 18

[0114] Synthesis of 6-(2-methyl-5-oxochloro-1-en-1-yl)hexanoic acid (Structural Formula 2r):

[0115] 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 1r (0.0821 g, 0.5 mmol) and formic acid (0.0460 g, 1.0 mmol) were added to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 70°C by a heating plate and reacted for 12 hours. The heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below). Then, a light yellow oily substance was separated by column chromatography (with petroleum ether as the column, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 5:1 to 2:1), i.e., the target product (0.0779 g, a yield of 74%, and a ratio of straight chain to branched chain greater than 20:1). The reaction formula is:

[0116]

[0117] The product structure confirmation results are as follows: 1 H NMR(400MHz, CDCl3)δ10.27(br s,1H),2.51-2.43(m,2H),2.37-2.32(m,2H),2.30(t,J=7.2Hz,2H),2.14(t,J=7.2Hz,2H),2.02(s,3H),1.66-1.54(m,2H),1.41-1.23(m,4H); 13 C NMR (100MHz, CDCl3) δ210.4,179.6,171.1,140.5,34.4,34.1,31.7,29.1,28.1,24.6,22.9,17.4.

[0118] Embodiment 19

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

[0120] 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 1s (0.0801 g, 0.5 mmol) and formic acid (0.0921 g, 2.0 mmol) were added to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 90°C by a heating plate and reacted for 12 hours. The heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below). Then, a colorless oily substance was separated by column chromatography (with petroleum ether as the column, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 5:1 to 2:1), i.e., the target product (0.0745 g, a yield of 72%, and a ratio of straight chain to branched chain of 10:1). The reaction formula is:

[0121]

[0122] The product structure confirmation results are as follows: 1 H NMR(400MHz,CDCl3)δ10.23(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 =7.6Hz,2H),1.69-1.52(m,4H),1.33-1.22(m,2H),1.23(d,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3) δ180.5,147.6,128.5,127.1,126.1,39.9,38.1,34.2,27.3,24.9,22.5.

[0123] Embodiment 20

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

[0125] 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 1t (0.0571 g, 0.5 mmol) and formic acid (0.0921 g, 2.0 mmol) were added to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 90°C by a heating plate and reacted for 12 hours. The heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below). Then, a light yellow oily substance was separated by column chromatography (with petroleum ether as the column, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 2:1), i.e., the target product (0.0632 g, yield 79%, ratio of straight chain to branched chain 10:1). The reaction formula is:

[0126]

[0127] The product structure confirmation results are as follows: 1 H NMR(400MHz,CDCl3)δ8.47(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=7.2Hz,3H); 13 C NMR (100MHz, CDCl3) δ179.3,176.6,51.9,38.7,31.8,28.4,17.2.

[0128] Embodiment 21

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

[0130] 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 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) were added to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 70°C by a heating plate and reacted for 12 hours, then the heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below), and then filtered to separate the white solid, i.e., the target product (0.0618 g, yield 85%, the ratio of straight chain to branched chain greater than 20:1). The reaction formula is:

[0131]

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

[0133] When acetic anhydride or phenyl formate is added to the reaction system, the reaction can also proceed smoothly. The following is a further detailed description of the reaction system in which acetic anhydride or phenyl formate is added in conjunction with the examples. The specific examples described herein are only used to explain the present invention and are not intended to limit the scope of protection of the present invention.

[0134] An example is shown below:

[0135] Embodiment 22

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

[0137] 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 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 to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 40°C by a heating plate and reacted for 24 hours. The heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below). Then, a colorless oily substance was separated by column chromatography (with petroleum ether as the column, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 5:1), i.e., the target product (0.0727 g, yield 92%, and the ratio of straight chain to branched chain was greater than 20:1). The reaction formula is:

[0138]

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

[0140] Embodiment 23

[0141] Synthesis of 6-oxo-6-(quinoline-8-amino)hexanoic acid (structural formula 2h):

[0142] Under argon protection, palladium acetate (0.0056g, 0.025mmol), bisphosphine ligand 1.2-DTBPMB (0.0197g, 0.050mmol), 0.1mL of acetone, olefin 1h (0.1131g, 0.5mmol), formic acid (0.0460g, 1.0mmol) and acetic anhydride (0.0102g, 0.1mmol) were added to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 40°C by a heating plate and reacted for 24 hours. The heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below). Then, a white solid was separated by column chromatography (with petroleum ether as the column, and the eluent was petroleum ether: ethyl acetate volume ratio of 2:1 to 1:1), i.e., the target product (0.0843g, yield 62%, the ratio of straight chain to branched chain greater than 20:1). The reaction formula is:

[0143]

[0144] The product structure is confirmed as shown in Example 8.

[0145] Embodiment 24

[0146] Synthesis of 5-cyanovaleric acid (Structural Formula 2f):

[0147] 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 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 to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 40°C by a heating plate and reacted for 24 hours. The heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below). Then, a light yellow oily substance was separated by column chromatography (with petroleum ether as the column, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 1:1), i.e., the target product (0.0440 g, a yield of 69%, and a ratio of straight chain to branched chain greater than 20:1). The reaction formula is:

[0148]

[0149] The product structure is confirmed as shown in Example 6.

[0150] Embodiment 25

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

[0152] 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 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 to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 40°C by a heating plate and reacted for 24 hours. The heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below). Then, a yellow oily substance was separated by column chromatography (with petroleum ether as the column, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 2:1), i.e., the target product (0.0775 g, yield 89%, and the ratio of straight chain to branched chain was greater than 20:1). The reaction formula is:

[0153]

[0154] The product structure is confirmed as shown in Example 15.

[0155] Embodiment 26

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

[0157] 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 to the reactor in sequence and mixed thoroughly. After sealing, the mixed system in the reactor was heated to 40°C by a heating plate and reacted for 24 hours. The heating was stopped, and the mixture was naturally cooled to room temperature (25°C, the same below). Then, a light yellow oily substance was separated by column chromatography (with petroleum ether as the column, and the eluent was petroleum ether: ethyl acetate in a volume ratio of 5:1 to 1:1) to obtain the target product (0.0715 g, a yield of 70%, and a ratio of straight chain to branched chain greater than 20:1). The reaction formula is:

[0158]

[0159] The product structure is confirmed as shown in Example 17.

[0160] The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A method for preparing linear carboxylic acids by hydrocarboxylation of olefins using formic acid as a carbonyl source, characterized in that: include: Under nitrogen protective atmosphere, olefin, formic acid, palladium catalyst, diphosphine ligand 1.2-DTBPMB and additive are dispersed in a solvent according to a molar ratio of 1:1-4:0.001-0.05:0.004-0.2:0-1.0, and reacted at a certain temperature. After the reaction is completed, the target product is separated to obtain a straight-chain carboxylic acid.

2. The method for preparing linear carboxylic acid by hydrocarboxylation of olefins using formic acid as a carbonyl source according to claim 1, characterized in that: The structural formula of the olefin is: R 1 is an alkyl group, an 8-aminoquinolyl group, a phthalimide group, an acetoxy group, a cyano group, a sulfone group, a phosphoester group, an aryl group, an ester group, a Weinreb amide group, a cyclopentanone group, a cyclohexenyl group or a hydrogen atom; R 2 is an alkyl group, an 8-aminoquinolyl group, a phthalimide group, an acetoxy group, a cyano group, a sulfone group, a phosphoester group, an aryl group, an ester group, a Weinreb amide group, a cyclopentanone group, a cyclohexenyl group or a hydrogen atom; R 3 A methyl group or a hydrogen atom.

3. The method for preparing linear carboxylic acid by hydrocarboxylation of olefins using formic acid as a carbonyl source according to claim 2, characterized in that: The alkyl group is methyl; and when R 1 When R is 8-aminoquinolyl, phthalimide, acetoxy, cyano, sulfone, phosphoester, aryl Weinreb amide, cyclopentanone or cyclohexenyl, 2 is a methyl group, an ester group or a hydrogen atom; when R 2 When R is 8-aminoquinolyl, phthalimide, acetoxy, cyano, sulfone, phosphoester, aryl Weinreb amide, cyclopentanone or cyclohexenyl, 1 It is a methyl group, an ester group or a hydrogen atom.

4. The method for preparing linear carboxylic acid by hydrocarboxylation of olefins using formic acid as a carbonyl source according to claim 1, characterized in that: The structural formula of the diphosphine ligand 1.2-DTBPMB is:

5. The method for preparing linear carboxylic acid by hydrocarboxylation of olefins using formic acid as a carbonyl source according to claim 1, characterized in that: The palladium catalyst is one or more of palladium acetate, tris(dibenzylideneacetone)dipalladium-chloroform adduct, palladium trifluoroacetate, palladium chloride, palladium iodide, palladium hydroxide and di(acetylacetone)palladium.

6. The method for preparing linear carboxylic acid by hydrocarboxylation of olefins using formic acid as a carbonyl source according to claim 1, characterized in that: The solvent is an organic solvent or water.

7. The method for preparing linear carboxylic acid by hydrocarboxylation of olefins using formic acid as a carbonyl source according to claim 6, 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.

8. The method for preparing linear carboxylic acid by hydrocarboxylation of olefins using formic acid as a carbonyl source according to claim 1, characterized in that: The reaction temperature is 20-110°C.

9. The method for preparing linear carboxylic acid by hydrocarboxylation of olefins using formic acid as a carbonyl source according to claim 1, characterized in that: The reaction pressure is normal pressure.

10. The method for preparing linear carboxylic acid by hydrocarboxylation of olefins using formic acid as a carbonyl source according to claim 1, characterized in that: The additive is acetic anhydride or phenyl formate.

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