Monofluoroalkyl and (deuterated) monofluoromethyl substituted chiral allene compound as well as synthesis method and application thereof

Abstract

The invention discloses a chiral monofluoroalkyl or (deuterated) monofluoromethyl substituted chiral allene compound and an asymmetric catalytic synthesis method of the chiral monofluoroalkyl or (deuterated) monofluoromethyl substituted chiral allene compound. The compound has a structure as shown in the following formula (I) or (II), has important synthesis application value and potential biological activity, and can provide strong technical support for research and development of new fluorine-containing drugs. The synthesis method comprises the following steps: under the condition of a chiral catalyst, taking 1, 3-eneyne and fluorobisaryl sulfonylmethane as raw materials, and carrying out an asymmetric hydromonofluoroalkylation reaction or an asymmetric hydromonofluoroalkylation reaction / reductive desulfonylation cascade reaction, so as to obtain the 1, 3-eneyne-fluorobisaryl sulfonylmethane compound. And synthesizing the chiral monofluoroalkyl or (deuterated) monofluoromethyl substituted chiral allene compound with high stereoselectivity. The method has the advantages that raw materials are cheap and easy to obtain; reaction conditions are mild, and operation is simple; the method has the characteristics of abundant and diversified substrate structures, good to excellent yield, enantioselectivity and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis methods, and relates to a class of monofluoroalkyl and (deuterated) monofluoromethyl substituted chiral allene compounds and a synthesis method and application thereof. Background Art

[0002] Chiral allenes are a class of axial chiral compounds containing cumulative double bonds and have a wide range of applications in synthetic chemistry, medicinal chemistry, and materials science. [1] On the one hand, as core structural units, axially chiral allenes are widely present in active natural products and drug molecules. [2] As shown in Formula 1, some representative active natural products and bioactive molecules containing chiral allene structures are listed. Citroside A isolated from Cirsium setosum is a class of chiral allene compounds with anti-inflammatory activity. [3] ; Phomallenicacid C, a natural product containing an alkynyl allene structure [4] and Scorodonin [5] It has significant antibacterial activity; Panacene containing brominated allene [6] It can be used as a shark appetite suppressant; Laballenic acid is a natural product isolated from plant oils. [7] In addition, the introduction of allene structural fragments into biologically active compounds such as steroids, prostaglandins, and carbacycline can improve their metabolic stability and bioavailability. [8] For example, Enprostil, which contains allene units, has a stronger inhibitory effect on gastric acid secretion than natural prostaglandin E2. [9] .

[0003]

[0004] On the other hand, chiral allenes are a very important class of synthetic building blocks in organic synthesis. They can not only undergo a variety of transformations to synthesize high value-added chiral compounds,

[10] , and can also be used to construct a variety of important skeletons and functional molecules. For example, using chiral allene 162 as a key chiral intermediate, the synthesis of the proteasome inhibitor epoxomicin can be achieved (Formula 2)

[11] .

[0005]

[0006] Since enyne raw materials are cheap and readily available, and chiral allene compounds have important potential application value in the development of new drugs, it is of great significance to develop efficient synthesis of compounds with this type of structure. Summary of the invention

[0007] The purpose of the present invention is to provide a method for synthesizing chiral (deuterated) monofluoromethyl substituted allene compounds and chiral monofluoroalkyl substituted chiral allene compounds (including but not limited to monofluorobis(arylsulfonyl)methyl or diethyl fluoromalonate substituted allene compounds) with simple operation, high efficiency and high selectivity; this method has good universality of substrates, mild reaction conditions, and readily available raw materials and catalysts.

[0008] Another object of the present invention is to provide a series of chiral monofluoroalkyl substituted chiral allene compounds (including but not limited to chiral monofluorobis(arylsulfonyl)methyl and diethyl fluoromalonate substituted allene compounds) and (deuterated) monofluoromethyl substituted allene compounds with important synthetic value and potential biological activity, so as to provide effective technical support for the development of new drugs.

[0009] The specific technical solution for achieving the purpose of the present invention is:

[0010] The present invention provides a method for synthesizing a chiral monofluoroalkyl-substituted allenyl compound. In a solvent 1, 1,3-enyne and fluorobisarylsulfonyl methane or diethyl fluoromalonate undergo an asymmetric hydrogen monofluoroalkylation reaction under the action of a chiral catalyst, and a compound of formula (I) can be separated and purified. The method is shown in the following reaction formula (A):

[0011]

[0012] in,

[0013] R is selected from C1-C20 alkyl, C1-C20 alkenyl, phenyl, C1-C10 alkyl substituted aryl, halogen substituted aryl, C1-C10 alkoxy substituted aryl, heteroaryl; wherein the heteroaryl includes thiophene, benzofuran, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine, thiazole;

[0014] EWG is fluorobis(arylsulfonyl)methyl, diethyl fluoromalonate;

[0015] The chiral configuration of the chiral monofluoroalkyl substituted chiral allene compound may be (R) configuration or (S) configuration.

[0016] In the present invention, the chiral catalyst is a complex of a transition metal and a chiral ligand, and the transition metal part is selected from iron, copper, nickel, palladium, rhodium, cobalt, and iridium; preferably, the transition metal is Ni(COD) 2 、Ni(OAc) 2 , Pd 2 (dba) 3 、Pd(OAc) 2; The chiral ligand is selected from chiral bisoxazoline (pyridine) ligands, Salen ligands, Binap ligands, Josiphos ligands, PHOX ligands, QuinoxP ligands, Segphos ligands, and BIPHEP ligands; preferably, the chiral ligand is a chiral bisoxazoline ligand, Binap ligands, Josiphos ligands, PHOX ligands, and BIPHEP ligands.

[0017] In the present invention, the amount of the chiral catalyst is 0.1-50 mol % based on the amount of fluorobisarylsulfonylmethane or diethyl fluoromalonate; preferably, 5 mol %, 10 mol % or 20 mol %.

[0018] In the present invention, the solvent 1 is selected from one or more of toluene, dichloromethane, ethyl acetate, tetrahydrofuran, acetone, acetonitrile, ethanol, methanol, isopropanol, tert-butanol, trifluoroethanol, etc.; preferably, toluene, tetrahydrofuran, and ethanol.

[0019] In the present invention, the amount of the solvent 1 is 0.1 mL to 50 mL per mmol of fluorobisarylsulfonyl methane or diethyl fluoromalonate; preferably, 5 and 10 mL.

[0020] In the present invention, the molar ratio of the amount of 1,3-enyne to fluorobisarylsulfonylmethane or diethyl fluoromalonate is (1-10):1; preferably, it is 1.5 / 1 or 2 / 1.

[0021] In the present invention, the reaction temperature 1 is -10°C to 100°C, and the reaction time is 0.5-96 hours; preferably, the reaction temperature 1 is 0°C or 25°C, and the reaction time is 12 or 24 hours.

[0022] The present invention also provides chiral monofluoroalkyl-substituted allenyl compounds synthesized by the above method.

[0023] The present invention also provides a method for synthesizing a chiral (deuterated) monofluoromethyl substituted allene compound, wherein the compound represented by the formula (I) is used as a raw material, and a reduction desulfonylation tandem reaction is carried out in a solvent 2 under the action of a reducing agent to generate a chiral (deuterated) monofluoromethyl substituted allene compound represented by the formula (II). The method is shown in the following reaction formula (B):

[0024]

[0025] in,

[0026] R is selected from C1-C20 alkyl, C1-C20 alkenyl, phenyl, C1-C10 alkyl substituted aryl, halogen substituted aryl, C1-C10 alkoxy substituted aryl, heteroaryl, wherein the heteroaryl includes thiophene, furan, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine, thiazole; X = hydrogen, deuterium;

[0027] EWG is fluorobis(arylsulfonyl)methyl, diethyl fluoromalonate;

[0028] The chiral configuration of the chiral (deuterated) monofluoromethyl substituted allene compound can be (R) configuration or (S) configuration.

[0029] In the present invention, the reducing agent is a reducing metal, part of which is selected from iron, manganese, zinc, magnesium, and lithium; preferably, the metal reducing agent is iron, manganese, zinc, and magnesium.

[0030] In the present invention, the amount of the reducing agent used is 1 to 50 equivalents based on the amount of formula (I); preferably, it is 5 to 20 equivalents.

[0031] In the present invention, the solvent 2 is selected from one or more of ethanol, methanol, isopropanol, tert-butanol, trifluoroethanol, etc.; preferably, it is methanol or ethanol.

[0032] In the present invention, the amount of the solvent 2 is based on the amount of formula (I), and the amount used per millimole is 0.1 mL to 50 mL; preferably, 5 and 10 mL.

[0033] In the present invention, the reaction temperature 2 is 0°C to 100°C, and the reaction time is 1-7 days; preferably, the reaction temperature 2 is 25 or 50°C, and the reaction time is 12 or 24 hours.

[0034] The method for synthesizing the chiral (deuterated) monofluoromethyl substituted allene compound of the present invention specifically comprises the following steps:

[0035] A catalyst, 1,3-enyne, fluorobis(arylsulfonyl)methane or diethyl fluoromalonate are sequentially added to a reaction container, and then a solvent is added. The reaction is stirred until TLC shows that fluorobis(benzenesulfonyl)methane or diethyl fluoromalonate completely disappears or is almost unchanged, then the reaction is stopped, the solvent is removed by rotation, and the crude product is quickly concentrated through a short column; if column chromatography is directly used for separation and purification, a chiral monofluorobis(arylsulfonyl)methyl or diethyl fluoromalonate substituted allene compound of formula I can be obtained; if a solvent and a reducing agent are added to the crude product, the reaction is further continued until TLC shows that the intermediate I completely disappears or is almost unchanged, then the reaction is stopped, and the (deuterated) monofluoromethyl substituted allene compound of formula II can be separated by column chromatography; the enantioselectivity (ee value) of formulas I and II can be determined by high performance liquid chromatography HPLC.

[0036] The present invention also provides chiral (deuterated) monofluoromethyl substituted allene compounds synthesized by the above method.

[0037] In the present invention, the 1,3-enyne has a structure shown in the following formula (a):

[0038]

[0039] Wherein, R is selected from C1-C20 alkyl, C1-C20 alkenyl, phenyl, C1-C10 alkyl substituted aryl, halogen substituted aryl, C1-C10 alkoxy substituted aryl, heteroaryl; wherein the heteroaryl includes thiophene, furan, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine, thiazole;

[0040] Preferably, R is phenyl, naphthyl, thiophene, furan, p-methylphenyl, p-fluorophenyl, p-chlorophenyl, p-methoxyphenyl, n-pentyl, cyclohexyl, or phenethyl.

[0041] In the present invention, the fluorinated bisarylsulfonyl methane has a structure as shown in formula (b):

[0042]

[0043] Among them, R 1 is phenyl, C1-C20 alkyl-substituted aryl, halogen-substituted aryl, C1-C20 alkoxy-substituted aryl;

[0044] Preferably, it is phenyl, naphthyl, p-methylphenyl, p-fluorophenyl, p-chlorophenyl, p-methoxyphenyl. This type of fluorobisphenylsulfonyl methane can be conveniently synthesized according to the literature method [(a) U. Sankar, S. Mahalakshmi, KK Balasubramanian, Synlett 2013, 24, 1533; (b) M. Urban, M. Franc, M. Hofmanová, I. J. Org.Biomol.Chem.2017,15,9071]

[0045] In the present invention, the diethyl fluoromalonate has a structure as shown in formula (c):

[0046]

[0047] The present invention also provides a chiral monofluoroalkyl substituted chiral allene compound, the structure of which is shown in formula (I):

[0048]

[0049] in,

[0050] R is selected from C1-C20 alkyl, C1-C20 alkenyl, phenyl, C1-C10 alkyl substituted aryl, halogen substituted aryl, C1-C10 alkoxy substituted aryl, heteroaryl; wherein the heteroaryl includes thiophene, benzofuran, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine, thiazole;

[0051] EWG is fluorobis(arylsulfonyl)methyl, diethyl fluoromalonate;

[0052] The chiral configuration of the chiral monofluoroalkyl substituted chiral allene compound may be (R) configuration or (S) configuration.

[0053] The present invention also provides a chiral monofluorobis(arylsulfonyl)methyl substituted allene compound, the structural formula of which is shown in the following formula (I'):

[0054]

[0055] in,

[0056] R is selected from C1-C20 alkyl, C1-C20 alkenyl, phenyl, C1-C10 alkyl substituted aryl, halogen substituted aryl, C1-C10 alkoxy substituted aryl, heteroaryl; wherein the heteroaryl includes thiophene, furan, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine, thiazole;

[0057] R 1 It is phenyl, C1-C20 alkyl-substituted aryl, halogen-substituted aryl, C1-C20 alkoxy-substituted aryl; the chiral configuration of the allene can be (R) configuration or (S) configuration.

[0058] Preferably, R is C1-C10 alkyl, phenyl, C1-C10 alkyl-substituted phenyl, halogen-substituted phenyl, C1-C10 alkoxy-substituted phenyl, thiophene, furan, pyridine;

[0059] R 1 It is phenyl, C1-C10 alkyl-substituted phenyl, halogen-substituted phenyl, C1-C10 alkoxy-substituted phenyl.

[0060] More preferably, R is phenyl, naphthyl, thiophene, furan, p-methylphenyl, p-fluorophenyl, p-chlorophenyl, p-methoxyphenyl, n-pentyl, cyclohexyl, or phenethyl;

[0061] R 1 It is phenyl, naphthyl, p-methylphenyl, p-fluorophenyl, p-chlorophenyl and p-methoxyphenyl.

[0062] The present invention also provides a chiral (deuterated) monofluoromethyl substituted allene compound, the structural formula of which is shown in the following formula (II):

[0063]

[0064] in,

[0065] R is selected from C1-C20 alkyl, C1-C20 alkenyl, phenyl, C1-C10 alkyl substituted aryl, halogen substituted aryl, C1-C10 alkoxy substituted aryl, heteroaryl; wherein the heteroaryl includes thiophene, furan, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine, thiazole; X = hydrogen, deuterium.

[0066] The chiral configuration of the allene position may be (R) configuration or (S) configuration.

[0067] Preferably, R is C1-C10 alkyl, aryl, C1-C10 alkyl substituted aryl, halogen substituted aryl, C1-C10 alkoxy substituted aryl, thiophene, furan, pyridine;

[0068] More preferably, R is phenyl, naphthyl, thiophene, furan, p-methylphenyl, p-fluorophenyl, p-chlorophenyl, p-methoxyphenyl, n-pentyl, cyclohexyl, or phenethyl.

[0069] The present invention also provides a chiral diethyl fluoromalonate substituted allene compound, the structural formula of the compound is shown in the following formula (I"):

[0070]

[0071] in,

[0072] R is selected from C1-C20 alkyl, C1-C20 alkenyl, phenyl, C1-C10 alkyl substituted aryl, halogen substituted aryl, C1-C10 alkoxy substituted aryl, heteroaryl; wherein the heteroaryl includes thiophene, furan, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine, thiazole;

[0073] The chiral configuration of the chiral diethyl fluoromalonate-substituted allene compound can be (R) configuration or (S) configuration.

[0074] Preferably, R is C1-C10 alkyl, phenyl, C1-C10 alkyl-substituted phenyl, halogen-substituted phenyl, C1-C10 alkoxy-substituted phenyl, thiophene, furan, pyridine;

[0075] More preferably, R is phenyl, naphthyl, thiophene, furan, p-methylphenyl, p-fluorophenyl, p-chlorophenyl, p-methoxyphenyl, n-pentyl, cyclohexyl, or phenethyl.

[0076] The present invention also provides the use of the chiral monofluoroalkyl substituted chiral allene compound in the preparation of fluorinated allene alcohols, carboxylic acids, amides and allene substituted fluorinated oxygen heterocycles and anti-inflammatory drug naproxen fluorinated allene derivatives.

[0077] The chiral monofluoroalkyl substituted chiral allene compounds described in the present invention are an important class of multifunctional synthetic building blocks. As shown in Formula 3 below, the monofluoroalkyl allene products substituted with geminal diester groups can undergo diverse transformations, and the synthesized fluorinated allene alcohols and carboxylic acids can be further used for the later monofluoroalkylation modification of carboxylic acid drug molecules and amino acids.

[0078]

[0079] The beneficial effects of the present invention are as follows: a class of chiral monofluoroalkyl (methyl) substituted allenyl compounds and an asymmetric catalytic synthesis method thereof provided by the present invention have high practical value, and the method has the following remarkable characteristics: the raw materials are cheap and readily available; the reaction conditions are mild, and the operation is simple and convenient; the applicable range of the substrate is wide, and good yield and good to excellent enantioselectivity (up to 99% yield and 99% ee value) can be obtained; the chiral monofluorobis (arylsulfonyl) methyl, diethyl fluoromalonate and monofluoromethyl substituted allenyl compounds have important potential application value. DETAILED DESCRIPTION

[0080] The present invention is further described in detail in conjunction with the following examples, which show different aspects of the present invention, but the protection content of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, the changes and advantages that can be thought of by those skilled in the art are included in the present invention, and the attached claims are the scope of protection. The process, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the contents specifically mentioned below, are all common knowledge and common common sense in the art, and the present invention has no special restrictions. The data given in the following examples include the operation and reaction conditions and products of asymmetric synthesis. Enantioselectivity (ee value) is determined by HPLC.

[0081] Example 1 Synthesis of Chiral Monofluoroalkyl Substituted Allene Compound III-1

[0082]

[0083] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2(6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-1 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 104.7 mg of yellow oil III-1 was obtained with a yield of 94%. Chiral HPLC determined 92% ee (Chiralcel AD-H, i PrOH / hexane=20 / 80,1.0mL / min,254nm; t r (major) = 23.16min,t r (minor) = 25.49min); [α] D 20 =-67.9(c=0.1,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.94(d,J=8.0Hz,4H),7.74-7.66(m,2H),7.54(q,J=8.0Hz,4H),7.30-7.26(m,2H),7.23-7.18(m,3H),6 .16(dt,J=6.4,2.4Hz,1H),5.66(q,J=7.2Hz,1H),3.26(dd,J=8.0,2.8Hz,1H),3.21(dt,J=7.2,2.8Hz,1H); 13 C NMR (100 MHz, CDCl 3 ): δ207.7,135.3(d,J=1.9Hz),135.1,134.9,133.2,130.87,130.85,130.83,129.0(d,J=2.3 Hz), 128.6, 127.3, 127.1, 114.0 (d, J = 266.0Hz), 95.9, 85.4 (d, J = 8.1Hz), 30.8 (d, J = 18.9Hz); 19 F NMR (376 MHz, CDCl 3 ): δ-141.58(s,1F); IR(neat):1448,1348,1265,1151,1078,732,721,682,667,597cm-1 ; HRMS (ESI): calculated value C 23 H 19 FNaO 4 S 2 [M+Na] + :465.0606,Found:465.0599.

[0084] Example 2 Synthesis of Chiral Monofluoroalkyl Substituted Allene Compound III-2

[0085]

[0086] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (S)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-1 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 104.7 mg of yellow oil III-2 was obtained with a yield of 94%. Chiral HPLC determined 92% ee (Chiralcel AD-H, i PrOH / hexane=20 / 80,1.0mL / min,254nm; t r (major) = 23.16min,t r (minor) = 25.49min); [α] D 20 =-67.9(c=0.1,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.94(d,J=8.0Hz,4H),7.74-7.66(m,2H),7.54(q,J=8.0Hz,4H),7.30-7.26(m,2H),7.23-7.18(m,3H),6 .16(dt,J=6.4,2.4Hz,1H),5.66(q,J=7.2Hz,1H),3.26(dd,J=8.0,2.8Hz,1H),3.21(dt,J=7.2,2.8Hz,1H); 13 C NMR (100 MHz, CDCl3 ): δ207.7,135.3(d,J=1.9Hz),135.1,134.9,133.2,130.87,130.85,130.83,129.0(d,J=2.3 Hz), 128.6, 127.3, 127.1, 114.0 (d, J = 266.0Hz), 95.9, 85.4 (d, J = 8.1Hz), 30.8 (d, J = 18.9Hz); 19 F NMR (376 MHz, CDCl 3 ): δ-141.58(s,1F); IR(neat):1448,1348,1265,1151,1078,732,721,682,667,597cm -1 ; HRMS (ESI): calculated value C 23 H 19 FNaO 4 S 2 [M+Na] + :465.0606,Found:465.0599.

[0087] Example 3 Synthesis of Chiral Monofluoroalkyl Substituted Allene Compound III-3

[0088]

[0089] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-2 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 101.2 mg of yellow oil III-3 was obtained with a yield of 88%. Chiral HPLC determined 92% ee (Chiralcel AD-H, i PrOH / hexane=20 / 80,1.0mL / min,254nm; t r (major)=24.68min,t r (minor) = 28.19min); [α] D 20=1.2(c=0.3,CHCl 3 ); 1 H NMR (300 MHz, CDCl 3 ): δ7.94(dq,J=8.4,1.2Hz,4H),7.76-7.67(m,2H),7.59-7.51(m,4H),7.23-7.19(m,2H),7.01-6.94(m, 2H),6.14(dt,J=6.3,2.7Hz,1H),5.68(q,J=7.2Hz,1H),3.27-3.24(m,1H),3.20(dt,J=7.5,2.4Hz,1H); 13 C NMR (100 MHz, CDCl 3 ): δ207.6 (d, J = 2.4Hz), 162.0 (d, J = 245.1Hz), 135.3 (d, J = 1.4Hz), 135.0 (d, J = 18.1Hz), 130.87, 130.85, 129. 06,129.04,128.64,128.6,115.7,115.4,114.0(d,J=265.8Hz),95.0,85.7(d,J=8.1Hz),30.9(d,J=18.9Hz); 19 F NMR (376 MHz, CDCl 3 ): δ-114.67(s,1F),-141.45(s,1F); ； IR(neat):1730,1697,1599,1338,1155,1080,910,837,752,559cm -1 ; HRMS (ESI): calculated value C 23 H 18 F 2 NaO 4 S 2 [M+Na] + :483.0512, measured value:483.0505.

[0090] Example 4 Synthesis of Chiral Monofluoroalkyl Substituted Allene Compound III-4

[0091]

[0092] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2(6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-3 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 111.0 mg of yellow oil III-4 was obtained with a yield of 93%. Chiral HPLC determined 91% ee (Chiralcel AD-H, i PrOH / hexane=20 / 80,1.0mL / min,254nm; t r (major)=30.99min,t r (minor) = 33.83min); [α] D 20 =-67.2(c=0.03,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.93(d,J=8.4Hz,4H),7.75-7.68(m,2H),7.55(q,J=7.2Hz,4H),7.25-7.16(m,4H),6.13( dt,J=6.8,2.4Hz,1H),5.70(q,J=7.2Hz,1H),3.26-3.24(m,1H),3.21(dt,J=7.6,2.4Hz,1H); 13 C NMR (100 MHz, CDCl 3 ): δ207.8,135.3(d,J=1.7Hz),135.0,134.9,132.9,131.8,130.8,129.0(d,J=1.7Hz ), 128.7, 128.3, 114.0 (d, J = 266.0Hz), 95.0, 85.8 (d, J = 8.2Hz), 30.8 (d, J = 18.9Hz); 19 F NMR (376 MHz, CDCl 3 ): δ-141.24(s,1F); IR(neat):1583,1491,1448,1336,1151,1080,908,835,727,557cm -1 ; HRMS (ESI): calculated value C 23H 18 FClNaO 4 S 2 [M+Na] + :499.0216, measured value:499.0208.

[0093] Example 5 Synthesis of Chiral Monofluoroalkyl Substituted Allene Compound III-5

[0094]

[0095] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-4 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 118.3 mg of yellow oil III-5 was obtained with a yield of 91%. Chiral HPLC determined 86% ee (Chiralcel AS-H, i PrOH / hexane=30 / 70,1.0mL / min,254nm; t r (major)=55.55min,t r (minor) = 37.30min); [α] D 20 =-22.1(c=0.02,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.95(d,J=7.8Hz,4H),7.76-7.66(m,2H),7.58-7.51(m,4H),7.30(dt,J=7.2,1.5Hz,1H),7.24-7.18( m,3H),6.16(dt,J=6.3,2.7Hz,1H),5.66(q,J=7.5Hz,1H),3.26(dd,J=7.5,2.4Hz,1H),3.22-3.19(m,1H); 13 C NMR (100 MHz, CDCl 3): δ207.8,135.4(d,J=1.7Hz),135.1,134.9,132.3,131.7,130.9,129.1(d,J=1.5Hz ), 128.6, 121.0, 114.0 (d, J = 266.0Hz), 95.1, 85.9 (d, J = 8.1Hz), 30.8 (d, J = 19.0Hz); 19 FNMR (376MHz, CDCl 3 ): δ-141.37(s,1F); IR(neat):1489,1448,1348,1165,1080,752,721,684,561cm -1 ; HRMS (ESI): calculated value C 23 H 18 FBrNaO 4 S 2 [M+Na] + :542.9706, measured value:542.9706.

[0096] Example 6 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound III-6

[0097]

[0098] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-5 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 112.2 mg of yellow oil III-6 was obtained with a yield of 94%. Chiral HPLC determined 86% ee (Chiralcel AS-H, i PrOH / hexane=20 / 80,1.0mL / min,254nm; t r (major) = 46.15min, t r (minor) = 34.72min); [α] D 20 =-270.4(c=0.17,CHCl 3 );1 H NMR (400 MHz, CDCl 3 ): δ7.94(t,J=8.4Hz,4H),7.74-7.66(m,2H),7.54(dt,J=11.2,8.0Hz,4H),7.23-7.15(m,3H),7.11(dt,J=7.2,1.6H z,1H),6.11(dt,J=6.4,2.4Hz,1H),5.70(q,J=7.6Hz,1H),3.26(dd,J=7.6,2.4Hz,1H),3.22(dd,J=7.6,2.8Hz,1H); 13 C NMR (100 MHz, CDCl 3 ): δ207.9,135.3(d,J=3.5Hz),135.3,135.0,134.8,134.4,130.87,130.85,130.82,130.81,129.8,129. 1(d,J=1.3Hz),127.3,126.9,125.2,113.9(d,J=266.2Hz),95.0,86.0(d,J=8.2Hz),30.7(d,J=18.8Hz); 19 F NMR (376 MHz, CDCl 3 ): δ-141.58(s,1F); IR(neat):1508,1448,1346,1165,1080,912,729,684,563,557cm -1 ; HRMS (ESI): calculated value C 23 H 18 FClNaO 4 S 2 [M+Na] + :499.0216, measured value:499.0209.

[0099] Example 7 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound III-7

[0100]

[0101] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2(6.9 mg, 10 mol%), chiral ligand (S)-Tol-Binap (18.7 mg, 0.0275 mmol), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-6 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted, and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 108.7 mg of yellow oil III-7 was obtained with a yield of 90%. Chiral HPLC determined 94% ee (Chiralcel AD-H, i PrOH / hexane=15 / 85,1.0mL / min,254nm; t r (major)=21.01min,t r (minor) = 21.95min); [α] D 20 =-28.9(c=0.04,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.93(d,J=7.6Hz,4H),7.74-7.67(m,2H),7.53(q,J=8.4Hz,4H),7.39(dd,J=7.6,1.6Hz,1H),7.31(dd,J =7.6,1.6Hz,1H),7.19-7.10(m,2H),6.60(dt,J=6.4,2.4Hz,1H),5.72(q,J=7.2Hz,1H),3.32-3.15(m,2H); 13 CNMR (100MHz, CDCl 3 ): δ208.4,135.3,135.0,134.8,132.1,131.0,130.8,129.5,129.0(d,J=2.6Hz),128 .8,128.3,126.9,113.9(d,J=266.0Hz),92.3,85.7(d,J=8.4Hz),30.7(d,J=18.9Hz); 19 F NMR (376 MHz, CDCl 3 ): δ-141.26 (s, 1F); IR (neat): 1583,1477,1336,1151,908,750,727,682,557cm -1; HRMS (ESI): calculated value C 23 H 18 FClNaO 4 S 2 [M+Na] + :499.0217, measured value:499.0213.

[0102] Example 8 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound III-8

[0103]

[0104] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (R)-DTBM-Seghos (32.4 mg, 0.0275 mmol), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-7 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 122.6 mg of yellow oil III-8 was obtained with a yield of 94%. Chiral HPLC determined 91% ee (Chiralcel AD-H, i PrOH / hexane=20 / 80,1.0mL / min,254nm; t r (major) = 23.52min, t r (minor) = 28.47min); [α] D 20 =-18.3(c=0.05,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.92(d,J=5.6Hz,4H),7.74-7.67(m,2H),7.57-7.51(m,6H),7.35(d,J =8.0Hz,2H),6.21-6.20(m,1H),5.77(q,J=7.2Hz,1H),3.29-3.21(m,2H); 13 C NMR (100 MHz, CDCl 3): δ208.4,137.2(d,J=1.2Hz),135.4,135.3,135.0,134.8,130.8(q,J=1.5Hz),129.07,129.06,129.0(q,J=32.2Hz), 127.2, 125.5 (q, J = 3.9Hz), 124.1 (q, J = 270.3Hz), 113.9 (d, J = 266.1Hz), 95.1, 86.1 (d, J = 8.1Hz), 30.7 (d, J = 19.0Hz); 19 F NMR (376 MHz, CDCl 3 ): δ-62.42(s,3F),-141.24(s,1F); IR(neat):1749,1323,1269,1181,1064,1016,877,846cm -1 ; HRMS (ESI): calculated value C 24 H 18 F 4 NaO 4 S 2 [M+Na] + :523.0480, measured value:533.0469.

[0105] Example 9 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound III-9

[0106]

[0107] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (S, S)-Ph-Box (9.2 mg, 0.0275 mmol), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-8 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted and stopped the reaction. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 109.8 mg of orange oil III-9 was obtained with a yield of 94%. Chiral HPLC determined 90% ee (ChiralcelAD-H, i PrOH / hexane=50 / 50,0.8mL / min,254nm; t r (major) = 29.29min,t r(minor) = 33.24min); [α] D 20 =-131.1(c=0.3,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.97-7.88(m,4H),7.76-7.69(m,2H),7.58-7.52(m,6H),7.36(d,J=8.4H z,2H),6.21(dt,J=6.4,2.4Hz,1H),5.83(q,J=7.2Hz,1H),3.33-3.16(m,2H); 13 C NMR (100 MHz, CDCl 3 ): δ208.8,138.5,135.4(d,J=1.5Hz),134.9,134.7,132.3,130.8,129.1,127.6, 118.9, 113.8 (d, J = 266.1Hz), 110.4, 95.2, 86.5 (d, J = 8.1Hz), 30.6 (d, J = 19.0Hz); 19 F NMR (376 MHz, CDCl 3 ): δ-141.04(s,1F); IR(neat):1726,1448,1336,1163,1151,1080,910,752,727,682,557cm -1 ; HRMS (ESI): calculated value C 24 H 18 FWf 4 S 2 [M+Na] + :490.0559, measured value:490.0549.

[0108] Example 10 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound III-10

[0109]

[0110] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2(6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-9 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 62.7 mg of yellow solid product III-10 was obtained with a yield of 53%. Chiral HPLC determined 86% ee (Chiralcel AS-H, i PrOH / hexane=50 / 50,0.8mL / min,254nm; t r (major) = 38.77min,t r (minor) = 32.39min); [α] D 20 =3.3(c=0.1,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ9.97(s,1H),7.93(d,J=8.0Hz,4H),7.80(d,J=7.6Hz,2H),7.76-7.69(m,2H),7.56(q,J=7.6 Hz,4H),7.41(d,J=7.6Hz,2H),6.25(d,J=3.6Hz,1H),5.81(q,J=6.8Hz,1H),3.34-3.19(m,2H); 13 C NMR (100 MHz, CDCl 3 ): δ209.0,191.6,140.0,135.42,135.39,135.2,135.0,134.8,130.8,130.1,129.10 ,129.09,127.6,113.9(d,J=266.1Hz),95.5,86.2(d,J=8.1Hz),30.6(d,J=18.9Hz); 19 F NMR (376 MHz, CDCl 3 ): δ-141.29(s,1F); IR(neat):1693,1602,1448,1348,1165,1080,912,750,729,684cm -1 ; HRMS (ESI): calculated value C24 H 19 FNaO 5 S 2 [M+Na] + :493.0550, measured value:493.0556.

[0111] Example 11 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound III-11

[0112]

[0113] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-10 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 113.7 mg of yellow oil III-11 was obtained with a yield of 91%. Chiral HPLC determined 90% ee (Chiralcel AD-H, i PrOH / hexane=50 / 50,0.8mL / min,254nm; t r (major)=32.78min,t r (minor) = 27.09min); [α] D 20 =-31.2(c=0.02,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.96-7.92(m,6H),7.74-7.67(m,2H),7.54(q,J=8.4Hz,4H),7.29(d,J=8.0Hz,2H),6.22-6.19( m,1H),5.75(q,J=7.6Hz,1H),3.90(s,3H),3.28(dd,J=7.6,2.4Hz,1H),3.24(dd,J=8.0,2.0Hz,1H); 13 C NMR (100 MHz, CDCl 3): δ208.6,166.8,138.3,135.4(d,J=2.9Hz),135.0,134.8,130.84,130.82,130.80,129.9,129.0 6,129.04,128.7,126.9,113.9(d,J=266.1Hz),95.4,85.9(d,J=8.1Hz),52.0,30.6(d,J=19.0Hz); 19 F NMR (376 MHz, CDCl 3 ): δ-141.35 (s, 1F); IR (neat): 1716,1448,1348,1280,1153,1080,906,723,682,557,511cm -1 ; HRMS (ESI): calculated value C 25 H 21 FNaO 6 S 2 [M+Na] + :523.0661, measured value:523.0654.

[0114] Example 12 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound III-12

[0115]

[0116] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-11 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 102.6 mg of yellow oil III-12 was obtained with a yield of 90%. Chiral HPLC determined 86% ee (Chiralcel AS-H, i PrOH / hexane=30 / 70,1.0mL / min,254nm; t r (major) = 28.74min, t r (minor) = 24.65min); [α] D 20=-0.4(c=0.01,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.94(d,J=6.8Hz,4H),7.73-7.66(m,2H),7.56-7.51(m,4H),7.13-7.07(m,4H),6.13(dt,J=6. 4,2.8Hz,1H),5.63(q,J=7.2Hz,1H),3.24(dt,J=7.6,2.4Hz,1H),3.22-3.18(m,1H),2.32(s,3H); 13 C NMR (100 MHz, CDCl 3 ): δ207.5,137.1,135.3(d,J=1.8Hz),135.2,135.0,130.8,130.2,129.3,129.0(d,J=2 .3Hz), 127.0, 114.1 (d, J = 266.0Hz), 95.7, 85.2 (d, J = 8.1Hz), 30.9 (d, J = 18.9Hz), 21.2; 19 F NMR (376 MHz, CDCl 3 ): δ-141.57(s,1F); IR(neat):1734,1343,1238,1155,1043,756,684,592,559cm -1 ; HRMS (ESI): calculated value C 24 H 21 FNaO 4 S 2 [M+Na] + :475.0757, measured value:475.0763.

[0117] Example 13 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound III-13

[0118]

[0119] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2(6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-12 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 109.2 mg of yellow oily product III-13 was obtained with a yield of 91%. Chiral HPLC determined 90% ee (Chiralcel AD-H, i PrOH / hexane=30 / 70,1.0mL / min,254nm; t r (major) = 23.12min,t r (minor) = 26.74min); [α] D 20 =-4.4(c=0.2,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.96-7.93(m,4H),7.74-7.67(m,2H),7.57-7.52(m,4H),7.18-7.14(m,2H),6.84-6.81(m,2H),6.12( dt,J=6.4,2.4Hz,1H),5.62(q,J=7.2Hz,1H),3.79(s,3H),3.24(dt,J=7.2,2.4Hz,1H),3.21-3.18(m,1H); 13 C NMR (100 MHz, CDCl 3 ): δ207.3,159.0,135.3,135.2,135.0,130.9,129.03,129.01,128.2,125.4,11 4.13(d,J=266.0Hz),114.09,95.3,85.2(d,J=8.1Hz),55.3,31.1(d,J=18.7Hz); 19 F NMR (376 MHz, CDCl 3 ): δ-141.56 (s, 1F); IR (neat): 1732,1599,1512,1448,1249,1151,835,754,684,559cm -1; HRMS (ESI): calculated value C 24 H 21 FNaO 5 S 2 [M+Na] + :495.0706, measured value:495.0711.

[0120] Example 14 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound III-14

[0121]

[0122] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-13 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 81.9 mg of yellow oily product III-14 was obtained with a yield of 71%. Chiral HPLC determined 90% ee (Chiralcel AS-H, i PrOH / hexane=40 / 60,1.0mL / min,254nm; t r (major)=51.38min,t r (minor) = 37.21min); [α] D 20 =-50.2(c=0.04,CHCl 3 ); 1 H NMR (300 MHz, CDCl 3 ): δ7.92(d,J=7.5Hz,4H),7.74-7.65(m,2H),7.56-7.49(m,4H),7.27-7.19(m,4H),6.15(dt,J=6.6 ,2.4Hz,1H),5.65(q,J=7.5Hz,1H),4.62(s,2H),3.27-3.23(m,1H),3.22-3.17(m,1H),2.14(s,1H); 13 C NMR (100 MHz, CDCl 3): δ207.7,140.1,135.3(d,J=1.4Hz),134.9,134.7,132.3,130.7,129.0(d,J=2.0Hz),1 27.15, 127.09, 114.0 (d, J = 266.3Hz), 95.6, 85.3 (d, J = 8.1Hz), 64.6, 30.7 (d, J = 18.8Hz); 19 F NMR (376 MHz, CDCl 3 ): δ-141.36 (s, 1F); IR (neat): 1448,1348,1165,1155,1080,902,721,682,596,557cm -1 ; HRMS (ESI): calculated value C 24 H 21 FNaO 5 S 2 [M+Na] + :495.0712, measured value:495.0703.

[0123] Example 15 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound III-15

[0124]

[0125] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-14 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 111.6 mg of yellow oily product III-15 was obtained with a yield of 93%. Chiral HPLC determined 86% ee (Chiralcel AS-H, i PrOH / hexane=40 / 60,1.0mL / min,254nm; t r (major) = 33.16min,t r (minor) = 28.41min); [α] D 20 =-163.6(c=0.3,CHCl3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.95(t,J=6.8Hz,4H),7.78-7.68(m,4H),7.66-7.62(m,2H),7.56-7.48(m,4H ),7.46-7.40(m,3H),6.34-6.32(m,1H),5.74(q,J=7.2Hz,1H),3.31-3.25(m,2H); 13 C NMR (100 MHz, CDCl 3 ): δ208.3,135.3(d,J=3.3Hz),135.1,134.9,133.5,132.7,130.87,130.86,130.83,130.82,130.76,129.04,129.01,12 8.2, 127.7 (d, J = 4.4Hz), 126.2, 126.0, 125.8, 124.8, 114.0 (d, J = 265.9Hz), 96.2, 85.6 (d, J = 8.2Hz), 30.9 (d, J = 18.8Hz); 19 F NMR (376 MHz, CDCl 3 ): δ-141.39 (s, 1F); IR (neat): 1448,1336,1151,1078,906,821,723,682,599,557cm -1 ; HRMS (ESI): calculated value C 27 H 21 FNaO 4 S 2 [M+Na] + :515.0763, measured value:515.0751.

[0126] Example 16 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound III-16

[0127]

[0128] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2(6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-15 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 78.1 mg of yellow solid product III-16 was obtained with a yield of 69%. Chiral HPLC determined 98% ee (Chiralcel AD-H, i PrOH / hexane=30 / 70,1.0mL / min,254nm; t r (major) = 23.32min, t r (minor) = 25.26min); 1 HNMR (400MHz, CDCl 3 ): δ7.94-7.92(m,4H),7.74-7.67(m,2H),7.57-7.51(m,4H),7.24(dd,J=6.8,3.6Hz,1H),7.08(d,J=2.8H z,1H),7.04(dd,J=4.8,1.2Hz,1H),6.24(dt,J=6.8,2.4Hz,1H),5.61(q,J=7.2Hz,1H),3.28-3.13(m,2H); 13 C NMR (100 MHz, CDCl 3 ): δ208.1,135.31,135.29,135.1,134.9,134.3,130.84,130.82,130.81,129.0(d,J=2.5Hz ),126.5,125.9,121.6,114.0(d,J=266.1Hz),90.4,84.6(d,J=8.2Hz),31.0(d,J=18.8Hz); 19 F NMR (376 MHz, CDCl 3 ): δ-141.40 (s, 1F); IR (neat): 1448,1346,1313,1151,1080,908,750,682,559cm -1 ; HRMS (ESI): calculated value C 21 H 17 FNaO 4 S3 [M+Na] + :471.0712, measured value:471.0176.

[0129] Example 17 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound III-17

[0130]

[0131] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (S)-Difluorphos (18.8 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-16 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted, and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 76.5 mg of yellow oily product III-17 was obtained with a yield of 67%. HPLC analysis (Chiralcel AD-H, i PrOH / hexane=30 / 70,1.0mL / min,230nm; t r (major)=7.70min,t r (minor)=10.37min)gave the isomericcomposition of the product:76.5:23.5er.[α] D 20 =-86.9(c=0.2,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.94(d,J=8.4,4H),7.74-7.70(m,2H),7.56(t,J=7.2,4H),5.14-5.07(m,2H),3.21- 3.05(m,2H),1.94-1.85(m,2H),1.69-1.58(m,5H),1.29-1.06(m,3H),1.02-0.91(m,2H); 13 CNMR (100MHz, CDCl 3): δ205.6,135.4,135.2,135.1,130.9(d,J=1.4Hz),128.9(d,J=3.2Hz),114.3(d,J=266 .2Hz),98.4,81.9(d,J=7.9Hz),36.8,32.7(d,J=2.5Hz),31.3(d,J=18.7Hz),26.0,25.9; 19 F NMR (376 MHz, CDCl 3 ): δ-142.32(s,1F); IR(neat):1448,1346,1313,1153,1080,754,736,684,567cm -1 ;HRMS(ESI):Exact mass calcdfor C 23 H 26 FO 4 S 2 [M+H] + :449.1251,Found:449.1241.

[0132] Example 18 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound III-18

[0133]

[0134] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (S)-Difluorphos (18.8 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-17 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted, and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 38.8 mg of yellow oily product III-18 was obtained with a yield of 33%. HPLC analysis (Chiralcel AD-H, i PrOH / hexane=20 / 80,1.0mL / min,254nm; t r (major)=15.52min,t r(minor)=22.30min gave the isomericcomposition of the product:95:5er.[α] D 20 =-33.4(c=0.1,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.94-7.89(m,4H),7.73-7.68(m,2H),7.58-7.52(m,4H),7.30-7.26(m,2H),7.21-7. 14(m,3H),5.19-5.08(m,2H),3.21-2.95(m,2H),2.64(t,J=8.0,2H),2.29-2.23(m,2H); 13 C NMR (100 MHz, CDCl 3 ): δ206.7,141.4,135.3,135.2(d,J=1.7Hz),130.8,128.9(d,J=1.7Hz),128.4,128.3, 125.9, 114.3 (d, J = 266.1Hz), 91.7, 81.6 (d, J = 8.2Hz), 35.1, 31.0 (d, J = 18.5Hz), 29.7; 19 FNMR (376MHz, CDCl 3 ): δ-141.95 (s, 1F); IR (neat): 1450,1342,1157,1080,1026,995,871,732,678cm -1 ;HRMS(ESI):Exact mass calcd for C 25 H 24 FO 4 S 2 [M+H] + :471.1095,Found:471.1083.

[0135] Example 19 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound III-19

[0136]

[0137] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2(6.9 mg, 10 mol%), chiral ligand (S, S)-Benzp* (7.8 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-18 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted, and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 37.7 mg of yellow oily product III-19 was obtained with a yield of 43%. HPLC analysis (ChiralcelAD-H, i PrOH / hexane=20 / 80,1.0mL / min,254nm; t r (major)=16.14min,t r (minor)=13.55min gave the isomericcomposition of the product:91.5:8.5er.[α] D 20 =-120.2(c=0.1,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.94-7.88(m,4H),7.72-7.67(m,1H),7.66-7.62(m,1H),7.56-7.46(m,4H),7. 29-7.16(m,5H),5.90-5.87(m,1H),3.37-3.22(m,2H),1.79(dd,J=2.8,1.6Hz,3H); 13 C NMR (100 MHz, CDCl 3 ): δ206.2,135.3,135.2,135.12,135.11,134.2,131.0(d,J=1.4Hz),130.8(d,J=1.3Hz),128.9,128.5,127.1,127.0,115.3(d,J=269. 5Hz),94.8(d,J=3.3Hz),94.2,34.1(d,J=17.2Hz),19.6(d,J=2.0Hz); IR(neat):1450,1342,1265,1149,1080,825,732,686,624,601cm -1;HRMS(ESI):Exact mass calcd for C 24 H 22 FO 4 S 2 [M+H] + :457.0938,Found:457.0932.

[0138] Example 20 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound III-20

[0139]

[0140] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (S, S)-Benzp* (7.8 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-19 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted, and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 52.1 mg of yellow solid product III-20 was obtained with a yield of 44%. HPLC analysis (ChiralcelAD-H, i PrOH / hexane=20 / 80,1.0mL / min,254nm; t r (major)=17.57min,t r (minor)=15.76min gave the isomericcomposition of the product:94:6er.[α] D 20 =-89.9(c=0.1,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3): δ7.92-7.88(m,4H),7.72-7.63(m,2H),7.55-7.47(m,4H),7.21-7.18(m,2H),6.99-6.93(m,2H), 5.91-5.88(m,1H),3.30(t,J=2.0Hz,1H),3.25(dd,J=3.6,2.0Hz,1H),1.79(dd,J=2.8,1.6Hz,3H); 13 CNMR (100MHz, CDCl 3 ): δ206.0 (d, J = 2.5Hz), 161.9 (d, J = 244.6Hz), 135.23, 135.18, 135.14, 130.9 (d, J = 1.4Hz), 130.8 (d, J = 1.3Hz), 130.2 (d, J = 3.2Hz), 128.9 6,128.95,128.6(d,J=7.9Hz),115.4(d,J=21.5Hz),115.3(d,J=269.5Hz),95.1(d,J=3.0Hz),93.3,34.3(d,J=17.4Hz),19.6(d,J=2.2Hz); 19 F NMR (376 MHz, CDCl 3 ): δ-115.21(s,1F),-144.18(s,1F); IR(neat):1504,1450,1342,1157,1080,848,732,686,609,547,532cm -1 ;HRMS(ESI):Exact mass calcd forC 24 H 21 FO 4 S 2 [M+H] + :475.0849,Found:475.0838.

[0141] Example 21 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound III-21

[0142]

[0143] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2(6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-2 (0.25 mmol), II-1 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted, and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 102.7 mg of yellow solid product III-21 was obtained with a yield of 82%. HPLC analysis (ChiralcelAD-H, i PrOH / hexane=20 / 80,1.0mL / min,254nm; t r (major)=24.07min,t r (minor)=29.00min gave the isomericcomposition of the product:95.5;4.5er.[α] D 20 =-294.9 (c = 0.3, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.99-7.96(m,4H),7.32-7.18(m,9H),6.18(dt,J=6.8,2.8Hz,1H),5.69-5.63(m,1H),3.23(dd,J=7.6,2.4Hz,1H),3.19(dd,J=7.6,2.4Hz,1H); 13 C NMR (100 MHz, CDCl 3 ): δ207.8,168.3(d,J=2.0Hz),134.09-134.04(m),133.99-133.95(m),133.1,131.0(d,J=3.0Hz),128.7,127.5,1 27.1, 116.7 (d, J = 1.0Hz), 116.5 (d, J = 2.0Hz), 113.9 (d, J = 265.0Hz), 96.1, 85.2 (d, J = 9.0Hz), 31.0 (d, J = 19.0Hz); 19 F NMR (376 MHz, CDCl 3): δ-99.65(s,1F),-99.69(s,1F),-141.15(s,1F); IR(neat):1589,1491,1348,1242,1149,1080,906,837,729,650cm -1 ;HRMS(ESI):Exact mass calcd forC 23 H 17 F 3 NaO 4 S 2 [M+Na] + :501.0413,Found:501.0401.

[0144] Example 22 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound III-22

[0145]

[0146] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-3 (0.25 mmol), II-1 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted, and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 129.9 mg of yellow solid product III-22 was obtained with a yield of 92%. HPLC analysis (Chiralcel OD-H, i PrOH / hexane=10 / 90,1.0mL / min,254nm; t r (major) = 34.90min,t r (minor)=40.53min gave the isomericcomposition of the product:96:4er.[α] D 20 =-366.4(c=0.4,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3): δ8.42(d,J=9.6Hz,2H),7.84-7.79(m,7H),7.75(d,J=8.0Hz,1H),7.67-7.62(m,2H),7.57-7.53(m,2H),7.25-7.21(m,4H) ,7.20-7.17(m,1H),6.12(dt,J=6.4,2.4Hz,1H),5.82-5.76(m,1H),3.41(dd,J=7.6,2.4Hz,1H),3.37(dd,J=7.2,2.4Hz,1H); 13 C NMR (100 MHz, CDCl 3 ): δ207.7,135.8,133.4,133.34,133.27,131.9,131.8,131.71,131.68, 130.07,130.04,129.6,129.0,128.5,127.88,127.86,127.72,127.70,12 7.2,127.1,124.5,114.6(d,J=265.7Hz),95.9,85.6(d,J=8.4Hz),30.7( d,J=18.8Hz); IR(neat):1496,1334,1149,1072,856,817,740,686,640cm -1 ;HRMS(ESI):Exact mass calcd forC 31 H 23 FO 4 NaS 2 [M+Na] + :565.0914,Found:565.0902.

[0147] Example 23 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound III-23

[0148]

[0149] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2(6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-4 (0.25 mmol), II-1 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted, and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 100.1 mg of yellow oily product III-23 was obtained with a yield of 85%. HPLC analysis (ChiralcelAS-H, i PrOH / hexane=20 / 80,1.0mL / min,254nm; t r (major) = 25.44min, t r (minor)=31.64min gave the isomericcomposition of the product:96:4er.[α] D 20 =-130.3(c=0.3,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.983-7.80(m,4H),7.34-7.17(m,9H),6.15(dt,J=6.4,2.4Hz,1H),5.68-5.62(m,1 H),3.23(dd,J=7.6,2.4Hz,1H),3.19(dd,J=7.6,2.4Hz,1H),2.45(s,3H),2.40(s,3H); 13 C NMR (100 MHz, CDCl 3 ): δ207.6,146.7,133.3,132.1,131.9,130.9(dd,J=4.0,1.3Hz),129.6,128.5,127.2, 113.8 (d, J = 265.3Hz), 95.7, 85.6 (d, J = 8.0Hz), 30.9 (d, J = 19.1Hz), 21.8 (d, J = 3.6Hz); 19 F NMR (376 MHz, CDCl 3 ): δ-142.01 (s, 1F); IR (neat): 1450,1342,1265,1157,1080,732,686,648,594cm-1 ;HRMS(ESI):Exact mass calcd forC 25 H 24 FO 4 S 2 [M+H] + :471.1095,Found:471.1086.

[0150] Example 24 Synthesis of Chiral Monofluoroalkyl Substituted Allene Compound V-1

[0151]

[0152] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), IV (0.25 mmol), II-1 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted, and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1-15 / 1). 75.3 mg of yellow oil V-1 was obtained with a yield of 98%. HPLC analysis (Chiralcel OJ-H, i PrOH / hexane=2 / 98,1.0mL / min,254nm; t r (major) = 20.31min, t r (minor)=22.64min gave the isomericcomposition of the product:95.5:4.5er; [α] D 20 =-174.5(c=0.02,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3): δ7.31-7.26(m,4H),7.21-7.17(m,1H),6.19(dt,J=6.8,2.0Hz,1H),5.56-5.50(m,1H),4.32-4.20(m,4H ),3.03(dt,J=7.6,2.4Hz,1H),2.97(dt,J=7.6,2.0Hz,1H),1.30(t,J=7.2Hz,3H),1.26(t,J=7.2Hz,3H).; 13 C NMR (100 MHz, CDCl 3 ): δ207.4,165.7(d,J=4.8Hz),165.5(d,J=4.6Hz),133.6,128.5,127.1,126.9,95.3 ,93.9(d,J=198.7Hz),86.6(d,J=3.7Hz),62.7(d,J=4.5Hz),34.5,34.2,13.9,13.8; 19 F NMR (376 MHz, CDCl 3 ): δ-166.40 (s, 1F); IR (neat): 1749,1460,1369,1199,1084,1012,873,752,692,628cm -1 ;HRMS(ESI):Exact mass calcd for C 17 H 20 FO 4 [M+H] + :307.1340,Found:307.1337

[0153] Example 25 Synthesis of Chiral Monofluoroalkyl Substituted Allene Compound V-2

[0154]

[0155] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2(6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), IV (0.25 mmol), II-1 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1-15 / 1). 75.3 mg of yellow oil V-2 was obtained with a yield of 98%. Chiral HPLC determined 92% ee (ChiralcelAD-H, i PrOH / hexane=20 / 80,1.0mL / min,254nm; t r (major) = 23.16min,t r (minor) = 25.49min); [α] D 20 =-67.9(c=0.1,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.94(d,J=8.0Hz,4H),7.74-7.66(m,2H),7.54(q,J=8.0Hz,4H),7.30-7.26(m,2H),7.23-7.18(m,3H),6 .16(dt,J=6.4,2.4Hz,1H),5.66(q,J=7.2Hz,1H),3.26(dd,J=8.0,2.8Hz,1H),3.21(dt,J=7.2,2.8Hz,1H); 13 C NMR (100 MHz, CDCl 3 ): δ207.7,135.3(d,J=1.9Hz),135.1,134.9,133.2,130.87,130.85,130.83,129.0(d,J=2.3 Hz), 128.6, 127.3, 127.1, 114.0 (d, J = 266.0Hz), 95.9, 85.4 (d, J = 8.1Hz), 30.8 (d, J = 18.9Hz); 19 FNMR (376MHz, CDCl 3 ): δ-141.58(s,1F); IR(neat):1448,1348,1265,1151,1078,732,721,682,667,597cm-1 ; HRMS (ESI): calculated value C 23 H 19 FNaO 4 S 2 [M+Na] + :465.0606,Found:465.0599.

[0156] Example 26 Synthesis of Chiral Monofluoroalkyl Substituted Allene Compound V-3

[0157]

[0158] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), IV (0.25 mmol), II-2 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted, and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1-15 / 1). 76.4 mg of yellow oil V-3 was obtained with a yield of 94%. HPLC analysis (Chiralcel OD-H, i PrOH / hexane=20 / 80,1.0mL / min,254nm; t r (major) = 9.29min,t r (minor)=8.17min gave the isomeric composition of the product:96:4er.[α] D 20 =-102.5(c=0.2,CHCl 3 ); 1 HNMR (400MHz, CDCl 3 ): δ7.26-7.21(m,2H),7.01-6.96(m,2H),6.16(dt,J=6.4,2.4Hz,1H),5.56-5.50(m,1H),4.33- 4.19(m,4H),3.08-3.01(m,1H),3.00-2.91(m,1H),1.31(t,J=7.2Hz,3H),1.27(t,J=7.2Hz,3H);13 C NMR (100 MHz, CDCl 3 ): δ207.2(d,J=2.3Hz), 165.7(d,J=6.0Hz), 165.5(d,J=5.8Hz), 162.0(d,J=244.9Hz), 129.6(d,J=3.3Hz), 128.3(d,J= 7.9Hz), 115.5 (d, J = 21.5Hz), 94.4, 93.8 (d, J = 198.9Hz), 86.8 (d, J = 3.6Hz), 62.7, 62.7, 34.3 (d, J = 21.0Hz), 13.9, 13.8; 19 F NMR (376 MHz, CDCl 3 ): δ-115.02(s,1F),-166.41(s,1F); IR(neat):1747,1508,1300,1222,1157,1093,1012,839,698,536cm -1 ;HRMS(ESI):Exact mass calcd forC 17 H 18 F 2 NaO 4 [M+Na] + :347.1065,Found:347.1062.

[0159] Example 27 Synthesis of Chiral Monofluoroalkyl Substituted Allene Compound V-4

[0160]

[0161] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), IV (0.25 mmol), II-3 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted, and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 82.6 mg of yellow oil V-4 was obtained with a yield of 87%. HPLC analysis (Chiralcel OJ-H, iPrOH / hexane=2 / 98,1.0mL / min,254nm; t r (major) = 27.11min, t r (minor)=25.80min gave the isomericcomposition of the product:97.5:2.5er.[α] D 20 =-23.1(c=0.03,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.27-7.24(m,2H),7.21-7.18(m,2H),6.15(dt,J=6.4,2.4Hz,1H),5.57-5.52(m,1H),4.33- 4.23(m,4H),3.04-3.01(m,1H),2.99-2.95(m,1H),1.31(t,J=7.2Hz,3H),1.27(t,J=6.8Hz,3H); 13 C NMR (100 MHz, CDCl 3 ): δ207.4,165.7(d,J=5.5Hz),165.4(d,J=5.5Hz),132.7,132.2,128.7,128.1,94.5 ,93.8(d,J=199.0Hz),87.0(d,J=3.6Hz),62.8(d,J=3.3Hz),34.3,34.1,14.0,13.9; 19 F NMR (376 MHz, CDCl 3 ): δ-166.43 (s, 1F); IR (neat): 1593,1477,1336,1151,1078,908,790,752,682,555cm -1 ;HRMS(ESI):Exactmass calcd for C 17 H 18 FClNaO 4 [M+Na] + :363.0769,Found:363.0764.

[0162] Example 28 Synthesis of Chiral Monofluoroalkyl Substituted Allene Compound V-5

[0163]

[0164] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube.2 (6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), IV (0.25 mmol), II-4 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted, and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 87.3 mg of yellow oil V-5 was obtained with a yield of 91%. HPLC analysis (ChiralcelAD-H, i PrOH / hexane=5 / 95,0.8mL / min,254nm; t r (major)=11.06min,t r (minor)=10.07min gave the isomeric compositionofthe product:97:3er.[α] D 20 =-184.2(c=0.2,CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 ): δ7.42-7.40(m,2H),7.14(d,J=8.0Hz,2H),6.14-6.13(m,1H),5.55-5.52(m,1H),4.32-4.22(m,4 H),3.03-3.00(m,1H),2.99-2.96(m,1H),1.31(td,J=7.0,1.5Hz,3H),1.27(td,J=7.0,1.0Hz,3H); 13 C NMR (125 MHz, CDCl 3 ): δ207.5,165.7(d,J=6.8Hz),165.5(d,J=6.6Hz),132.7,131.7,128.4,120.8,94.6, 93.8(d,J=199.0Hz),87.1(d,J=3.7Hz),62.81,62.77,34.2(d,J=21.0Hz),14.0,13.9; 19 F NMR (376 MHz, CDCl 3): δ-166.43 (s, 1F); IR (neat): 1747,1489,1302,1242,1068,1008,856,833,501cm -1 ;HRMS(ESI):Exact mass calcd forC 17 H 18 BrFNaO 4 [M+Na] + :407.0264,Found:407.0271.

[0165] Example 29 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound V-6

[0166]

[0167] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), IV (0.25 mmol), II-5 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted, and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 84.6 mg of yellow oil V-6 was obtained with a yield of 97%. HPLC analysis (Chiralcel OJ-H, i PrOH / hexane=2 / 98,1.0mL / min,254nm; t r (major)=20.46min,t r (minor)=24.13min gave the isomericcomposition of the product:98:2er.[α] D 20 =-270.5(c=0.3,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3): δ7.26-7.24(m,1H),7.21(d,J=7.6Hz,1H),7.17-7.12(m,2H),6.14(dt,J=6.4,2.4Hz,1H),5.60-5.55(m,1H),4.36 -4.22(m,4H),3.04(dd,J=7.6,2.4Hz,1H),2.98(dd,J=7.6,2.4Hz,1H),1.31(t,J=7.2Hz,3H),1.28(t,J=7.2Hz,3H); 13 C NMR (100 MHz, CDCl 3 ): δ207.5,165.7(d,J=4.8Hz),165.4(d,J=4.6Hz),135.7,134.5,129.7,127.1,126.7,125.1 ,94.4,93.8(d,J=199.1Hz),87.2(d,J=3.8Hz),62.8(d,J=5.6Hz),34.3,34.1,13.93,13.88; 19 F NMR (376 MHz, CDCl 3 ): δ-166.37(s,1F); IR(neat):1749,1508,1307,1278,1259,1082,763,750cm -1 ;HRMS(ESI):Exact mass calcd for C 17 H 18 FClNaO 4 [M+Na] + :363.0769,Found:363.0772.

[0168] Example 30 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound V-7

[0169]

[0170] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2(6.9 mg, 10 mol%), chiral ligand (S)-Tol-Binap (18.7 mg, 0.0275 mmol), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), IV (0.25 mmol), II-6 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted, and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 86.0 mg of yellow oil V-7 was obtained with a yield of 95%. HPLC analysis (Chiralcel OJ-H, i PrOH / hexane=2 / 98,1.0mL / min,254nm; t r (major) = 27.11min, t r (minor)=25.80min gave the isomericcomposition of the product:97:3er.[α] D 20 =-23.1(c=0.06,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.43(d,J=8.0Hz,1H),7.32(d,J=8.0Hz,1H),7.20(t,J=7.2Hz,1H),7.12(t,J=7.6Hz,1H),6.66-6.64(m,1H),5.6 0-5.55(m,1H),4.33-4.19(m,4H),3.06-3.03(m,1H),3.00-2.97(m,1H),1.31(t,J=6.8Hz,3H),1.26(t,J=7.2Hz,3H); 13 C NMR (100 MHz, CDCl 3 ): δ208.1,165.7(d,J=6.2Hz),165.4(d,J=6.0Hz),132.0,131.4,129.5,128.5,128. 2,126.8,93.8(d,J=198.8Hz),91.7,86.8(d,J=3.6Hz),62.7,34.3,34.0,13.9,13.8; 19 FNMR (376MHz, CDCl 3): δ-166.31 (s, 1F); IR (neat): 1749,1477,1306,1288,1082,875,763,742,623cm -1 ;HRMS(ESI):Exact mass calcd for C 17 H 18 FClNaO 4 [M+Na] + :363.0769,Found:363.0769.

[0171] Example 31 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound V-8

[0172]

[0173] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (R)-DTBM-Seghos (32.4 mg, 0.0275 mmol), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), IV (0.25 mmol), II-7 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted, and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 89.6 mg of yellow oil V-8 was obtained with a yield of 96%. HPLC analysis (Chiralcel OJ-H, i PrOH / hexane=2 / 98,1.0mL / min,254nm; t r (major)=22.78min,t r (minor)=19.23min gave the isomericcomposition of the product:98:2er.[α] D 20 =-106.1(c=0.1,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3): δ7.54(d,J=8.0Hz,2H),7.37(d,J=8.4Hz,2H),6.24-6.21(m,1H),5.63-5.58(m,1H),4.33-4 .25(m,4H),3.07-3.03(m,1H),3.01-2.98(m,1H),1.31(t,J=6.8Hz,3H),1.27(t,J=7.2Hz,3H); 13 C NMR (100 MHz, CDCl 3 ): δ208.1,165.7(d,J=5.4Hz),165.4(d,J=5.4Hz),137.6(d,J=1.5Hz),129.0(q,J=32.1Hz),127.0,125.5(q,J=3.9 Hz), 124.1 (q, J = 270.2Hz), 94.5, 93.7 (d, J = 199.2Hz), 87.3 (d, J = 3.7Hz), 62.8 (d, J = 2.7Hz), 34.2, 34.0, 14.0, 13.9; 19 F NMR (376 MHz, CDCl 3 ): δ-62.53(s,3F),-166.39(s,1F); IR(neat):1749,1323,1244,1182,1064,1053,1016,877,846cm -1 ;HRMS(ESI):Exact mass calcdforC 18 H 18 F 4 NaO 4 [M+Na] + :397.1033,Found:397.1033.

[0174] Example 32 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound V-9

[0175]

[0176] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2(6.9 mg, 10 mol%), chiral ligand (S, S)-Ph-Box (9.2 mg, 0.0275 mmol), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), IV (0.25 mmol), II-8 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 74.2 mg of orange oil V-9 was obtained with a yield of 90%. Chiral HPLC determined 84% ee (Chiralcel OJ-H, i PrOH / hexane=10 / 90,1.0mL / min,254nm; t r (major)=55.60min,t r (minor) = 62.68min); [α] D 20 =-243.9(c=0.2,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.58(d,J=8.0Hz,2H),7.37(d,J=8.0Hz,2H),6.22-6.21(m,1H),5.63(q,J=7.2Hz,1H),4.34- 4.23(m,4H),3.12-3.03(m,1H),3.01-2.94(m,1H),1.32(d,J=7.2Hz,3H),1.28(d,J=7.2Hz,3H); 13 C NMR (100 MHz, CDCl 3 ): δ208.5,165.6(d,J=6.1Hz),165.3(d,J=6.2Hz),138.9,132.3,127.4,118.9,110.4,9 4.6,93.6(d,J=199.6Hz),87.7(d,J=3.4Hz),62.8(d,J=1.9Hz),34.0,33.8,14.0,13.9; 19 F NMR (376 MHz, CDCl 3 ): δ-166.30 (s, 1F); IR (neat): 2225,1747,1604,1304,1242,1201,1082,877,846,549cm -1 ; HRMS (ESI): calculated value C18 H 18 FWf 4 [M+Na] + :354.1112, measured value:354.1111.

[0177] Example 33 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound V-10

[0178]

[0179] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), IV (0.25 mmol), II-9 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted, and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 51.4 mg of yellow solid product V-10 was obtained with a yield of 62%. HPLC analysis (ChiralcelAD-H, i PrOH / hexane=10 / 90,1.0mL / min,254nm; t r (major)=14.01min,t r (minor)=13.09min gave the isomericcomposition of the product:96:4er.[α] D 20 =-5.0(c=0.01,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ9.97(s,1H),7.82(d,J=7.6Hz,2H),7.43(d,J=7.6Hz,2H),6.26(d,J=4.0Hz,1H),5.66- 5.60(m,1H),4.34-4.22(m,4H),3.08-3.05(m,1H),3.02-3.00(m,1H),1.34-1.26(m,6H),; 13 C NMR (100 MHz, CDCl 3): δ208.6, 191.6, 165.6 (d, J = 6.0Hz), 165.3 (d, J = 5.9Hz), 140.4, 135.1, 130.0, 127.3, 94. 9,93.7(d,J=199.1Hz),87.3(d,J=3.6Hz),62.84,62.81,33.9(d,J=21.1Hz),13.95,13.88; 19 F NMR (376 MHz, CDCl 3 ): δ-166.42 (s, 1F); IR (neat): 1747,1693,1602,1303,1209,1082,1012,854,837,790cm -1 ;HRMS(ESI):Exact mass calcd for C 18 H 19 FNaO 5 [M+Na] + :357.1109,Found:357.1100.

[0180] Example 34 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound V-11

[0181]

[0182] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), IV (0.25 mmol), II-10 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted, and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 85.5 mg of yellow oil V-11 was obtained with a yield of 94%. HPLC analysis (Chiralcel OJ-H, i PrOH / hexane=10 / 90,1.0mL / min,254nm; t r (major) = 44.21min, t r(minor)=39.83min gave the isomericcomposition of the product:96:4er.[α] D 20 =-49.0(c=0.06,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.97(d,J=8.4Hz,2H),7.33(d,J=8.4Hz,2H),6.23(dt,J=6.4,2.0Hz,1H),5.63-5.57(m,1H),4.33-4.2 2(m,4H),3.91(s,3H),3.07-3.04(m,1H),3.01-2.98(m,1H),1.31(t,J=7.2Hz,3H),1.27(t,J=7.2Hz,3H); 13 C NMR (100 MHz, CDCl 3 ): δ208.3,166.8,165.7(d,J=4.9Hz),165.4(d,J=4.8Hz),138.7,129.9,128.7,126.7,94.9,9 3.8(d,J=199.3Hz),87.1(d,J=3.7Hz),62.80,62.76,52.0,34.1(d,J=21.1Hz),13.95,13.89; 19 FNMR (376MHz, CDCl 3 ): δ-166.37(s,1F); IR(neat):2924,1751,1718,1608,1437,1278,1111,1018,738cm -1 ;HRMS(ESI):Exact mass calcd for C 19 H 21 FNaO 6 [M+Na] + :387.1214,Found:387.1209.

[0183] Example 35 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound V-12

[0184]

[0185] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2(6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), IV (0.25 mmol), II-11 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted, and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 73.6 mg of yellow oil V-12 was obtained with a yield of 90%. HPLC analysis (ChiralcelAD-H, i PrOH / hexane=5 / 95,1.0mL / min,254nm; t r (major)=7.38min,t r (minor)=6.66min gave the isomericcomposition of the product:96.5:3.5er.[α] D 20 =-20.6(c=0.03,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.16(d,J=8.0Hz,2H),7.10(d,J=8.0Hz,2H),6.16(dt,J=6.4,2.4Hz,1H),5.53-5.48(m,1H),4.34-4.19(m, 4H),3.02(dt,J=7.6,2.0Hz,1H),2.98-2.95(m,1H),2.32(s,3H),1.30(t,J=7.2Hz,3H),1.26(t,J=7.2Hz,3H); 13 C NMR (100 MHz, CDCl 3 ): δ207.2, 165.8 (d, J = 4.3Hz), 165.5 (d, J = 4.3Hz), 136.9, 130.6, 129.3, 126.8, 95.1, 94. 0(d,J=198.7Hz),86.4(d,J=3.7Hz),62.72,62.67,34.5(d,J=21.0Hz),21.1,14.0,13.9; 19 F NMR (376 MHz, CDCl 3): δ-166.48(s,1F); IR(neat):1749,1514,1369,1305,1201,1084,1012,856,732,702cm -1 ;HRMS(ESI):Exact mass calcd forC 18 H 21 FNaO 4 [M+Na] + :343.1316,Found:343.1312.

[0186] Example 36 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound V-13

[0187]

[0188] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), IV (0.25 mmol), II-12 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted, and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 71.4 mg of yellow oily product V-13 was obtained with a yield of 85%. HPLC analysis (ChiralcelAD-H, i PrOH / hexane=5 / 95,1.0mL / min,254nm; t r (major) = 12.37min,t r (minor)=11.41min gave the isomericcomposition of the product:96.5:3.5er.[α] D 20 =-56.6(c=0.2,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3): δ7.20(d,J=8.4Hz,2H),6.84(d,J=8.8Hz,2H),6.17-6.14(m,1H),5.52-5.47(m,1H),4.33-4.19 (m,4H),3.80(s,3H),3.02(dt,J=7.6,2.8Hz,1H),2.96(dt,J=7.6,2.8Hz,1H),1.33-1.26(m,3H); 13 C NMR (100 MHz, CDCl 3 ): δ207.0,165.9(d,J=5.2Hz),165.6(d,J=5.1Hz),158.9,128.1,125.9,114.1,94.8,94 .0(d,J=198.6Hz),86.5(d,J=3.7Hz),62.8,62.7,55.3,34.6(d,J=21.1Hz),14.0,13.9; 19 F NMR (376 MHz, CDCl 3 ): δ-166.49 (s, 1F); IR (neat): 2924,1749,1599,1512,1246,1026,854,825,607,597cm -1 ;HRMS(ESI):Exact mass calcd for C 18 H 21 FNaO 5 [M+Na] + :359.1265,Found:359.1261.

[0189] Example 37 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound V-14

[0190]

[0191] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2(6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), IV (0.25 mmol), II-13 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted, and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 69.9 mg of yellow oily product V-14 was obtained with a yield of 82%. HPLC analysis (Chiralcel OJ-H, i PrOH / hexane=20 / 80,1.0mL / min,254nm; t r (major)=22.40min,t r (minor)=25.80min gave the isomericcomposition of the product:97:3er.[α] D 20 =-22.2(c=0.02,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.30-7.25(m,4H),6.19(dt,J=6.4,2.4Hz,1H),5.56-5.50(m,1H),4.65(s,2H),4.32-4.21(m,4H),3.03( dt,J=7.6,2.4Hz,1H),2.97(dt,J=7.6,2.0Hz,1H),1.86(s,1H),1.31(t,J=7.2Hz,3H),1.27(t,J=7.2Hz,3H); 13 C NMR (100 MHz, CDCl 3 ): δ207.5,165.8(d,J=4.7Hz),165.5(d,J=4.6Hz),139.9,133.0,127.2,127.0,95.0,93. 9(d,J=198.9Hz),86.63(d,J=3.7Hz),65.0,62.7(d,J=4.2Hz),34.45,34.2,13.95,13.88; 19 F NMR (376 MHz, CDCl 3): δ-166.42 (s, 1F); IR (neat): 1747,1390,1303,1244,1084,1011,856,829,777,538cm -1 ;HRMS(ESI):Exact mass calcd forC 18 H 21 FNaO 5 [M+Na] + :359.1265,Found:359.1262.

[0192] Example 38 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound V-15

[0193]

[0194] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), IV (0.25 mmol), II-14 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted, and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 85.4 mg of yellow oily product V-15 was obtained with a yield of 96%. HPLC analysis (Chiralcel OJ-H, i PrOH / hexane=20 / 80,1.0mL / min,254nm; t r (major) = 30.94min,t r (minor)=40.29min gave the isomericcomposition of the product:95:5er.[α] D 20 =-89.5(c=0.07, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3): δ7.80-7.76(m,3H),7.65(s,1H),7.47-7.41(m,3H),6.37(d,J=3.6Hz,1H),5.64-5.59(m,1H),4.35- 4.20(m,4H),3.08(d,J=7.6Hz,1H),3.03(d,J=7.6Hz,1H),1.32(t,J=6.8Hz,3H),1.26(t,J=7.6Hz,3H); 13 C NMR (100 MHz, CDCl 3 ): δ207.9,165.8(d,J=5.1Hz),165.5(d,J=4.9Hz),133.5,132.7,131.1,128.2,127.6,126.2,125.8,1 25.7,124.7,95.7,93.9(d,J=198.7Hz),86.9(d,J=3.8Hz),62.7(d,J=3.3Hz),34.5,34.3,14.0,13.9; 19 FNMR (376MHz, CDCl 3 ): δ-166.35 (s, 1F); IR (neat): 1747,1303,1242,1201,1143,1128,1082,906,856,754,538cm -1 ;HRMS(ESI):Exact mass calcd for C 21 H 21 FNaO 4 [M+Na] + :379.1316,Found:379.1311.

[0195] Example 39 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound V-16

[0196]

[0197] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2(6.9 mg, 10 mol%), chiral ligand (R)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), IV (0.25 mmol), II-15 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted, and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 42.6 mg of yellow solid product V-16 was obtained with a yield of 55%. HPLC analysis (Chiralcel OJ-H, i PrOH / hexane=10 / 90,1.0mL / min,254nm; t r (major)=21.00min,t r (minor)=28.48min gave the isomericcomposition of the product:95.5:4.5er.[α] D 20 =-49.7(c=0.2,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.27-7.25(m,1H),7.09(d,J=2.8Hz,1H),7.06(d,J=5.2Hz,1H),6.26(dt,J=6.4,2.4Hz,1H).5. 49-5.43(m,1H),4.33-4.22(m,4H),3.06-2.90(m,2H),1.31(t,J=7.2Hz,3H),1.27(t,J=7.2Hz,3H); 13 C NMR (100 MHz, CDCl 3 ): δ207.8,165.8(d,J=4.4Hz),165.5(d,J=4.2Hz),134.8,126.4,125.9,121.2,93.9 (d,J=198.8Hz),89.9,85.8(d,J=3.7Hz),62.8,62.7,34.5(d,J=21.1Hz),14.0,13.9; 19 F NMR (376 MHz, CDCl 3): δ-166.51(s,1F); IR(neat):1749,1369,1269,1244,1201,1149,1084,1012,856,788cm -1 ;HRMS(ESI):Exact mass calcd for C 15 H 17 FNaO 4 S[M+Na] + :335.0724,Found:335.0714.

[0198] Example 40 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound V-17

[0199]

[0200] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (S)-Difluorphos (18.8 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), IV (0.25 mmol), II-16 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted, and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 36.7 mg of yellow oily product V-17 was obtained with a yield of 47%. HPLC analysis (Chiralcel AS-3, i PrOH / hexane=0.5 / 99.5,1.0mL / min,230nm; t r (major)=6.37min,t r (minor)=6.85min gave the isomericcomposition of the product:87.5:12.5er.[α] D 20 =-40.3(c=0.1,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3):5.15-5.04(m,2H),4.35-4.23(m,4H),2.91-2.88(m,1H),2.85-2.82(m,1H),1.99-1.91(m,1H),1.7 5-1.68(m,4H),1.64-1.60(m,1H),1.31(td,J=6.8,1.6Hz,6H),1.29-1.13(m,3H),1.12-1.04(m,2H); 13 C NMR (100 MHz, CDCl 3 ): δ205.2, 165.9 (d, J = 3.7Hz), 165.7 (d, J = 3.7Hz), 96.7, 94.2 (d, J = 198.6Hz), 83.2 (d, J = 3.8Hz), 62 .6(d,J=2.9Hz),36.9,35.0(d,J=20.9Hz),32.8(d,J=4.2Hz),26.0(d,J=11.7Hz),13.9(d,J=4.0Hz); 19 F NMR (376 MHz, CDCl 3 ): δ-166.57(s,1F); IR(neat):1751,1450,1303,1242,1087,1049,748,493cm -1 ;HRMS(ESI):Exact mass calcd for C 17 H 26 FO 4 [M+H] + :313.1810,Found:313.1802.

[0201] Example 41 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound V-19

[0202]

[0203] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2(6.9 mg, 10 mol%), chiral ligand (S, S)-Benzp* (7.8 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), IV (0.25 mmol), II-18 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted, and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 20.8 mg of yellow oily product V-19 was obtained with a yield of 26%. HPLC analysis (Chiralcel OJ-H, i PrOH / hexane=2 / 98,1.0mL / min,254nm; t r (major)=16.74min,t r (minor)=22.59min gave the isomericcomposition of the product:97:3er.[α] D 20 =-55.4(c=0.05,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.30-7.23(m,4H),7.20-7.15(m,1H),6.09-6.06(m,1H),4.25-4.11(m,4H),3.08- 2.92(m,2H),1.87(dd,J=2.8,1.0Hz,3H),1.24(t,J=7.2Hz,3H),1.21(t,J=7.2Hz,3H); 13 C NMR (100 MHz, CDCl 3 ): δ204.2,165.9(d,J=3.0Hz),165.7(d,J=3.1Hz),134.6,128.5,126.94,126.89,96.5,9 4.7,94.4(d,J=200.4Hz),62.7,62.6,38.5(d,J=20.4Hz),19.8(d,J=1.5Hz),13.9,13.8; 19 F NMR (376 MHz, CDCl 3): δ-165.67(s,1F); IR(neat):1751,1450,1373,1303,1249,1165,1049,856,748,694cm -1 ;HRMS(ESI):Exact mass calcd forC 18 H 22 FO 4 [M+H] + :321.1497,Found:321.1492.

[0204] Example 42 Synthesis of Chiral Monofluoroalkyl Substituted Allenyl Compound V-20

[0205]

[0206] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (S, S)-Benzp* (7.8 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), IV (0.25 mmol), II-19 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw materials had basically reacted, and the reaction was stopped. The reaction solution was concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1-4 / 1). 38.1 mg of yellow oily product V-20 was obtained with a yield of 45%. HPLC analysis (ChiralcelAD-H, i PrOH / hexane=2 / 98,1.0mL / min,254nm; t r (major) = 9.70min,t r (minor)=8.10min gave the isomeric compositionofthe product:99:1er.[α] D 20 =-58.9(c=0.1,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3): δ7.24-7.18(m,2H),7.00-6.95(m,2H),6.07-6.03(m,1H),4.23-4.12(m,4H),3.02 -3.01(m,1H),2.96(d,J=2.4Hz,1H),1.86(dd,J=2.8,1.0Hz,3H),1.26-1.20(m,6H); 13 C NMR (100 MHz, CDCl 3 ): δ203.8(d,J=2.4Hz), 165.9(d,J=1.7Hz), 165.6(d,J=1.7Hz), 161.9(d,J=244.3Hz), 130.6(d,J=3.3Hz), 128.3(d, J=7.9Hz),115.4(d,J=21.6Hz),96.7,94.3(d,J=200.5Hz),93.8,62.7,62.6,38.48(d,J=20.4Hz),19.8,13.9,13.8; 19 F NMR (376 MHz, CDCl 3 ): δ-115.47(s,1F),-165.79(s,1F); IR(neat):1751,1512,1303,1257,1226,1157,1087,1049,848,732,702,570cm -1 ;HRMS(ESI):Exact mass calcd for C 18 H 21 FO 4 [M+H] + :339.1402,Found:339.1398.

[0207] Example 43 Synthesis of Chiral Monofluoromethyl Substituted Allenyl Compound VI-1

[0208]

[0209] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2(6.9 mg, 10 mol%), chiral ligand (S)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-1 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw material had basically reacted, and the reaction was stopped. The reaction solution was concentrated, the crude product was quickly passed through a short column, and then dried by rotation. Under a nitrogen atmosphere, methanol (2.5 mL) and active magnesium powder (120 mg, 5 mmol) were added to the crude product in sequence, and the reaction was carried out at 0°C for 12 hours. TLC detected that the raw material had basically reacted, and the reaction was stopped. Water (3 mL) was added to the reaction system, and dilute hydrochloric acid (3 mL, 2 M) was used to quench the reaction. The mixture was extracted with dichloromethane (2×15 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Column chromatography was performed using petroleum ether as eluent. 33.2 mg of colorless liquid product VI-1 was obtained with a yield of 82%. HPLC analysis (Chiralcel OD-H, i PrOH / hexane=0.1 / 99.9,1.0mL / min,254nm; t r (major) = 11.11min, t r (minor)=12.54min gave the isomeric composition of the product:95.5:4.5er.[α] D 20 =0.7(c=0.08,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.33-7.28(m,4H),7.23-7.17(m,1H),6.19(dt,J=6.4,2.8Hz,1H),5.62-5.56(m,1 H),4.61(t,J=6.0Hz,1H),4.50(t,J=6.0Hz,1H),2.59-2.53(m,1H),2.53-2.47(m,1H); 13 C NMR (100 MHz, CDCl 3 ): δ205.9,134.2,128.6,127.0,126.7,95.3,90.0(d,J=7.6Hz),82.8(d,J=166.7Hz),29.9(d,J=20.6Hz); 19 F NMR (376 MHz, CDCl3 ): δ-217.85(s,1F); IR(neat):1722,1452,1271,1176,1070,1028,1001,713,700cm -1 ;HRMS(ESI):Exact mass calcd for C 11 H 11 F[M] + :162.0839,Found:162.0841.

[0210] Example 44 Synthesis of Chiral Monofluoromethyl Substituted Allenyl Compound VI-2

[0211]

[0212] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (S)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-11 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw material had basically reacted, and the reaction was stopped. The reaction solution was concentrated, the crude product was quickly passed through a short column, and then dried by rotation. Under a nitrogen atmosphere, methanol (2.5 mL) and active magnesium powder (120 mg, 5 mmol) were added to the crude product in sequence, and the reaction was carried out at 0°C for 12 hours. TLC detected that the raw material had basically reacted, and the reaction was stopped. Water (3 mL) was added to the reaction system, and dilute hydrochloric acid (3 mL, 2 M) was used to quench the reaction. The mixture was extracted with dichloromethane (2×15 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Column chromatography was performed using petroleum ether as eluent. 29.9 mg of colorless liquid product VI-2 was obtained with a yield of 68%. HPLC analysis (Chiralcel OD-H, i PrOH / hexane=0.1 / 99.1,1.0mL / min,254nm; t r (major)=10.53min,t r (minor)=12.53min gave the isomeric composition of the product:93:7er.[α] D 20 =-22.4(c=0.07,CHCl 3 );1 H NMR (400 MHz, CDCl 3 ): δ7.18(d,J=8.0Hz,2H),7.11(d,J=8.0Hz,2H),6.17(dt,J=6.4,3.2Hz,1H),5.59-5.54(m,1H), 4.61(t,J=6.4Hz,1H),4.49(t,J=6.0Hz,1H),2.58-2.52(m,1H),2.52-2.46(m,1H),2.32(s,3H); 13 C NMR (100 MHz, CDCl 3 ): δ205.7,136.7,131.2,129.3,126.6,95.1,89.9(d,J=7.7Hz),82.9(d,J=166.6Hz),30.0(d,J=20.5Hz),21.2; 19 F NMR (376 MHz, CDCl 3 ): δ-217.80 (s, 1F); IR (neat): 1724,1670,1604,1512,1178,1111,1066,1037,910,879,844,732,505cm -1 ;HRMS(ESI):Exact mass calcd for C 12 H 13 F[M] + :176.0996,Found:176.0998.

[0213] Example 45 Synthesis of Chiral Monofluoromethyl Substituted Allenyl Compound VI-3

[0214]

[0215] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2(6.9 mg, 10 mol%), chiral ligand (S)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-12 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw material had basically reacted, and the reaction was stopped. The reaction solution was concentrated, the crude product was quickly passed through a short column, and then dried by rotation. Under a nitrogen atmosphere, methanol (2.5 mL) and active magnesium powder (120 mg, 5 mmol) were added to the crude product in sequence, and the reaction was tried at room temperature for 12 hours. TLC detected that the raw material had basically reacted, and the reaction was stopped. Water (3 mL) was added to the reaction system, and dilute hydrochloric acid (3 mL, 2 M) was used to quench the reaction. The mixture was extracted with dichloromethane (2×15 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Column chromatography was performed with an eluent of (petroleum ether / dichloromethane = 10:1). 40.2 mg of colorless liquid product VI-3 was obtained with a yield of 82%. HPLC analysis (Chiralcel OD-H, i PrOH / hexane=1 / 99,1.0mL / min,254nm; t r (major)=8.82min,t r (minor)=9.64min gave the isomeric compositionofthe product:95:5er.[α] D 20 =-7.4(c=0.1,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.23-7.20(m,2H),6.87-6.83(m,2H),6.16(dt,J=6.4,2.8Hz,1H),5.59-5.54(m,1H),4.6 1(t,J=6.0Hz,1H),4.49(t,J=6.4Hz,1H),3.80(s,3H),2.57-2.52(m,1H),2.51-2.46(m,1H); 13 CNMR (100MHz, CDCl 3 ): δ205.4,158.8,127.8,126.5,114.1,94.7,89.9(d,J=7.5Hz),82.9(d,J=166.6Hz),55.3,30.1(d,J=20.5Hz); 19F NMR (376 MHz, CDCl 3 ): δ-217.82(s,1F); IR(neat):1743,1600,1577,1512,1302,1249,1172,1161,1031,835cm -1 ;HRMS(ESI):Exactmass calcd forC 12 H 13 OF[M] + :192.0948,Found:192.0945.

[0216] Example 46 Synthesis of Chiral Deuterated Monofluoromethyl Substituted Allenyl Compound VII-1

[0217]

[0218] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (S)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-1 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw material had basically reacted, and the reaction was stopped. The reaction solution was concentrated, the crude product was quickly passed through a short column, and then dried by rotation. Under a nitrogen atmosphere, methanol (2.5 mL) and active magnesium powder (120 mg, 5 mmol) were added to the crude product in sequence, and the reaction was carried out at 0°C for 12 hours. TLC detected that the raw material had basically reacted, and the reaction was stopped. Water (3 mL) was added to the reaction system, and dilute hydrochloric acid (3 mL, 2 M) was used to quench the reaction. The mixture was extracted with dichloromethane (2×15 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Column chromatography was performed using petroleum ether as eluent. 33.2 mg of colorless liquid product VII-1 was obtained with a yield of 82%. HPLC analysis (Chiralcel OD-H, i PrOH / hexane=0.1 / 99.9,1.0mL / min,254nm; t r (major) = 11.11min, t r (minor)=12.54min gave the isomeric composition of the product:95.5:4.5er.[α] D 20=0.7(c=0.08,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.33-7.28(m,4H),7.23-7.17(m,1H),6.19(dt,J=6.4,2.8Hz,1H),5.62-5.56(m,1 H),4.61(t,J=6.0Hz,1H),4.50(t,J=6.0Hz,1H),2.59-2.53(m,1H),2.53-2.47(m,1H); 13 C NMR (100 MHz, CDCl 3 ): δ205.9,134.2,128.6,127.0,126.7,95.3,90.0(d,J=7.6Hz),82.8(d,J=166.7Hz),29.9(d,J=20.6Hz); 19 F NMR (376 MHz, CDCl 3 ): δ-217.85(s,1F); IR(neat):1722,1452,1271,1176,1070,1028,1001,713,700cm -1 ;HRMS(ESI):Exact mass calcd for C 11 H 11 F[M] + :162.0839,Found:162.0841.

[0219] Example 47 Synthesis of Chiral Deuterated Monofluoromethyl Substituted Allenyl Compound VII-2

[0220]

[0221] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2(6.9 mg, 10 mol%), chiral ligand (S)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-11 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw material had basically reacted, and the reaction was stopped. The reaction solution was concentrated, the crude product was quickly passed through a short column, and then dried by rotation. Under a nitrogen atmosphere, methanol (2.5 mL) and active magnesium powder (120 mg, 5 mmol) were added to the crude product in sequence, and the reaction was carried out at 0°C for 12 hours. TLC detected that the raw material had basically reacted, and the reaction was stopped. Water (3 mL) was added to the reaction system, and dilute hydrochloric acid (3 mL, 2 M) was used to quench the reaction. The mixture was extracted with dichloromethane (2×15 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Column chromatography was performed using petroleum ether as eluent. 32.9 mg of colorless liquid product VII-2 was obtained with a yield of 74%. HPLC analysis (Chiralcel OD-H, i PrOH / hexane=0.1 / 99.9,1.0mL / min,254nm; t r (major)=10.41min,t r (minor)=12.13min gave the isomeric composition of the product:93:7er.[α] D 20 =-54.8(c=0.08,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ7.18(d,J=8.0Hz,2H),7.11(d,J=8.0Hz,2H),6.17(dt,J=6.8,2.8Hz,1H),5.59- 5.54(m,1H),2.54(dd,J=7.2,2.8Hz,1H),2.48(dd,J=7.2,2.8Hz,1H),2.32(s,3H); 13 C NMR (100 MHz, CDCl 3 ): δ205.6,136.7,131.2,129.3,126.6,95.1,89.9(d,J=7.6Hz),83.2-82.8(m),81.6-81.1(m),29.8(d,J=20.5Hz),21.2; 19 F NMR (376 MHz, CDCl3 ): δ-219.01~-219.10(m,1F); IR(neat):1952,1512,1448,1149,1087,949,910,879,839,821,732,592,557cm -1 ;HRMS(ESI):Exactmass calcd for C 12 H 11 D 2 F[M] + :178.1124,Found:178.1121.

[0222] Example 48 Synthesis of Chiral Deuterated Monofluoromethyl Substituted Allenyl Compound VII-3

[0223]

[0224] In the glove box, Ni(COD) was added to a 10.0 mL sealed tube. 2 (6.9 mg, 10 mol%), chiral ligand (S)-MeO-BIPHEP (16.0 mg, 11 mol%), ethanol (0.5 mL). After the above mixture was stirred at room temperature for 15 minutes, DABCO (28.0 mg, 1.0 equiv), I-1 (0.25 mmol), II-12 (0.375 mmol, 1.5 equivs) and anhydrous ethanol (2.0 mL) were added in sequence, and then the reaction tube was removed from the glove box and reacted at room temperature for 3 days under nitrogen protection. TLC detected that the raw material had basically reacted, and the reaction was stopped. The reaction solution was concentrated, the crude product was quickly passed through a short column, and then dried by rotation. Under a nitrogen atmosphere, methanol (2.5 mL) and active magnesium powder (120 mg, 5 mmol) were added to the crude product in sequence, and the reaction was tried at room temperature for 12 hours. TLC detected that the raw material had basically reacted, and the reaction was stopped. Water (3 mL) was added to the reaction system, and dilute hydrochloric acid (3 mL, 2 M) was used to quench the reaction. The mixture was extracted with dichloromethane (2×15 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Column chromatography was performed with an eluent of (petroleum ether / dichloromethane = 10:1). 32.2 mg of colorless liquid product VII-3 was obtained with a yield of 67%. HPLC analysis (Chiralcel OD-H, i PrOH / hexane=2 / 98,1.0mL / min,254nm; t r (major)=6.48min,t r (minor)=6.87min gave the isomericcomposition of the product:95:5er; 1H NMR (500 MHz, CDCl 3 ): δ7.23-7.20(m,2H),6.86-6.84(m,2H),6.16(dt,J=6.5,3.0Hz,1H),5.58-5.5 4(m,1H),3.80(s,3H),2.53(dd,J=7.0,2.5Hz,1H),2.48(dd,J=7.0,2.5Hz,1H); 13 C NMR (125 MHz, CDCl 3 ): δ205.4,158.8,127.8126.5,114.1,94.7,89.9(d,J=7.7Hz),83.2-82.5(m),81.9-81.2(m),55.3,29.9(d,J=20.5Hz); 19 F NMR (376 MHz, CDCl 3 ): δ-219.05~-219.13(m,1F); IR(neat):1728,1604,1512,1465,1249,1165,1033,910,833,732,462cm -1 ;HRMS(ESI):Exact mass calcd forC 12 H 11 D 2 FO[M] + :194.1070,Found:194.1071.

[0225] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the essence of the content of the present invention are covered within the protection scope of the present invention.

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Claims

1. A chiral monofluoroalkyl substituted chiral allene compound, characterized in that: Its structure is shown in formula (I): in, R is selected from C1-C20 alkyl, C1-C20 alkenyl, phenyl, C1-C10 alkyl substituted aryl, halogen substituted aryl, C1-C10 alkoxy substituted aryl, heteroaryl; wherein the heteroaryl includes thiophene, benzofuran, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine, thiazole; EWG is fluorobis(arylsulfonyl)methyl, diethyl fluoromalonate; The chiral configuration of the chiral monofluoroalkyl substituted chiral allene compound may be (R) configuration or (S) configuration.

2. A chiral (deuterated) monofluoromethyl substituted allene compound, characterized in that: Its structure is shown in formula (II): in, R is selected from C1-C20 alkyl, C1-C20 alkenyl, phenyl, C1-C10 alkyl substituted aryl, halogen substituted aryl, C1-C10 alkoxy substituted aryl, heteroaryl, wherein the heteroaryl includes thiophene, furan, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine, thiazole; X = hydrogen, deuterium; The chiral configuration of the chiral (deuterated) monofluoromethyl substituted allene compound can be (R) configuration or (S) configuration.

3. A method for synthesizing a chiral monofluoroalkyl-substituted allene compound, characterized in that: In solvent 1, 1,3-enyne and fluorobisarylsulfonylmethane or diethyl fluoromalonate undergo asymmetric hydrogen monofluoroalkylation reaction under the action of a chiral catalyst, and the compound of formula (I) can be separated and purified. The method is shown in the following reaction formula (A): in, R is selected from C1-C20 alkyl, C1-C20 alkenyl, phenyl, C1-C10 alkyl substituted aryl, halogen substituted aryl, C1-C10 alkoxy substituted aryl, heteroaryl; wherein the heteroaryl includes thiophene, furan, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine, thiazole; EWG is fluorobis(arylsulfonyl)methyl, diethyl fluoromalonate; The chiral configuration of the chiral monofluoroalkyl substituted allene compound can be (R) configuration or (S) configuration.

4. The synthesis method according to claim 3, characterized in that The chiral catalyst is a complex of a transition metal and a chiral ligand, wherein the transition metal part is selected from iron, copper, nickel, palladium, rhodium, cobalt, and iridium; the chiral ligand is selected from chiral bisoxazoline (pyridine) ligands, Salen ligands, Binap ligands, Josiphos ligands, PHOX ligands, QuinoxP ligands, Segphos ligands, and BIPHEP ligands; the amount of the chiral catalyst used is 0.1-50 mol%, based on the amount of fluorobisbenzenesulfonyl methane or diethyl fluoromalonate.

5. The synthesis method according to claim 3, characterized in that The solvent 1 is selected from one or more of toluene, dichloromethane, ethyl acetate, tetrahydrofuran, acetone, acetonitrile, ethanol, methanol, isopropanol, tert-butanol, and trifluoroethanol; the amount of the solvent 1 is 0.1 mL to 50 mL per mmol of fluorobis(phenylsulfonyl)methane or diethyl fluoromalonate; The molar ratio of the conjugated 1,3-enyne to fluorobis(phenylsulfonyl)methane or diethyl fluoromalonate is (1-10):1; The reaction temperature 1 is -10°C to 100°C.

6. A method for synthesizing a chiral (deuterated) monofluoromethyl-substituted allene compound, characterized in that: The method comprises: using the compound represented by formula (I) in claim 3 as a raw material, in a solvent 2, a reduction desulfonylation tandem reaction is carried out under the action of a reducing agent to generate a chiral (deuterated) monofluoromethyl substituted allene compound represented by formula (II), and the method is shown in the following reaction formula (B): in, R is selected from C1-C20 alkyl, C1-C20 alkenyl, phenyl, C1-C10 alkyl substituted aryl, halogen substituted aryl, C1-C10 alkoxy substituted aryl, heteroaryl, wherein the heteroaryl includes thiophene, furan, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine, thiazole; X = hydrogen, deuterium; The chiral configuration of the chiral (deuterated) monofluoromethyl substituted allene compound can be (R) configuration or (S) configuration.

7. The synthesis method according to claim 6, characterized in that The reducing agent is a reducing metal, part of which is selected from iron, manganese, zinc, magnesium and lithium; the amount of the reducing agent used is 1 to 50 equivalents based on the amount of the compound of formula (I).

8. The synthesis method according to claim 6, characterized in that The solvent 2 is selected from one or more of ethanol, methanol, isopropanol, tert-butanol, and trifluoroethanol; the amount of the solvent 2 is based on the amount of the compound of formula (I), and the amount used per millimole is 0.1 mL to 50 mL.

9. The synthesis method according to claim 6, characterized in that The reaction temperature 2 is 0°C to 80°C; the reaction time is 1-7 days.

10. Use of the chiral monofluoroalkyl substituted chiral allene compound as claimed in claim 1 or the chiral (deuterated) monofluoromethyl substituted allene compound as claimed in claim 2 in the preparation of fluorinated allene alcohols, carboxylic acids, amides and allene substituted fluorinated oxygen heterocycles and the anti-inflammatory drug naproxen fluorinated allene derivatives.

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