Method for the silver salt promoted hydrolysis synthesis of 18o-labeled alpha, beta-unsaturated enoic acids from gem-difluoropropadienes

Abstract

Silver salt promoted hydrolytic synthesis of gem-difluoropropadienes 18 A method for labeling α,β-unsaturated olefins, which uses gem-difluoropropadienes as substrates and silver salts as promoters, H2 18 O simultaneously as hydrogen source and oxygen source, to synthesize (E)-α,β-unsaturated carboxylic acids with high stereoselectivity and high labeling rate under ligand-free and mild conditions. This method has the advantages of simple operation, wide substrate scope, good functional group compatibility, high labeling rate (up to 96%), and good stereoselectivity (up to 15:1 E / Z), and can be scaled up to a gram scale. The obtained products can be further converted into a variety of 18 O labeled molecules, and has broad application prospects in the fields of medicinal chemistry and isotope labeling. 18 O labeled molecules, and has broad application prospects in the fields of medicinal chemistry and isotope labeling.

Description

Technical Field

[0001] This invention relates to the field of organic synthetic chemistry. Specifically, it relates to a defluorination hydrolysis reaction of gem-difluoropropylene promoted by silver salt as a Lewis acid, resulting in the high-abundance synthesis of… 18 O-labeled α,β-unsaturated carboxylic acids, using H2 18 Using O as both a hydrogen and oxygen source, ligand-free materials were prepared to contain... 18 A method for synthesizing O-labeled α,β-unsaturated carboxylic acids. This invention belongs to the field of synthetic technology of pharmaceutical chemical intermediates and isotope-labeled compounds. Background Technology

[0002] Isotope labeling has become an indispensable analytical tool in modern chemistry, biology, and drug research. Among these techniques, oxygen-18(¹) 8 O)-labeled carboxylic acids are the preferred internal standard for quantification based on liquid chromatography-mass spectrometry (LC-MS), accurately determining endogenous metabolites, drug metabolites, and peptides / proteins. By reliably distinguishing between endogenous and exogenous substances, they significantly improve the accuracy of quantification in complex biological matrices. Currently,¹ 8 The widespread application of O-labeled molecules has encompassed clinical diagnostics, drug metabolism elucidation, and pharmacokinetic quantification (J. Anal. At. Spectrom. 2014, 29, 2251-2255; Angew. Chem. Int. Ed. 2024, 63, e202317711; J. Am. Chem. Soc. 2014, 136, 8714-8721).

[0003] Although¹ 8 O-labeled carboxylic acids and their derivatives have important applications in biomedicine, but the methods for synthesizing these molecules are still very limited. The most common method: in H2¹ 8 Heating an unlabeled carboxylic acid in O promotes oxygen exchange through acid or base exchange, thereby achieving¹ 8 The labeling of O (Tetrahedron Lett. 2010, 51, 6310-6312; Methods in Enzymology. 1990, 193, 338-348; Org. Lett. 2010, 12, 104-106); however, such reactions usually require high temperature, strong acid or strong base conditions, and generally take several days to complete, thus limiting the substrate scope. Furthermore, acid anhydrides, acyl chlorides, and esters react in H2 18 Hydrolysis in O can also yield 18O-labeled carboxylic acids (J. Labelled Compd. Radiopharm. 2014, 57, 481-508); however, these methods typically yield products labeled with only one oxygen atom. Nitriles can be hydrolyzed to obtain bis¹ 8 O-labeled carboxylic acids (J.Am. Chem. Soc. 2000, 122, 11602-11609); however, this hydrolysis process usually requires harsh conditions. In recent years, enzyme-catalyzed labeling strategies have been developed, such as using carboxylesterases or lipases to catalyze the reaction of carboxyl oxygen with H2. 18 Oxygen exchange via O2 can be carried out under mild pH conditions (Drug Metab. Pharmacokinet. 2019, 34, 308-316); however, enzyme-catalyzed methods suffer from limited substrate universality and difficulty in achieving complete dual labeling of the two oxygen atoms in the carboxyl group. Therefore, there is an urgent need to develop novel methods in the fields of organic synthesis and isotope labeling. 18 O-marking strategy to synthesize double 18 O-labeled carboxylic acids.

[0004] Gem-difluoroallenes (DFAs) are a unique class of fluorinated building blocks characterized by an allene skeleton linked to a gem-difluoromethylene group. Recently, these compounds have exhibited significant and unique reactivity in selective addition (Green Synth. Catal. 2020, 1, 134-142; Org. Lett. 2023, 25, 5957-5962; Org. Lett. 2025, 27, 8288-8292; ACS Catal. 2025, 15, 13747-13756), defluorination functionalization (Org. Lett. 2023, 25, 4546-4550), and cycloaddition transformations (Angew. Chem. Int. Ed. 2013, 125, 7951-7954). However, utilizing H2... 18 O directly α-adds, defluorinates, and hydrolyzes and oxidizes DFAs to synthesize compounds containing... 18 The strategy of O-labeling α,β-unsaturated carboxylic acids has not been reported to date. This strategy faces several major challenges, including: (1) the regioselectivity of nucleophilic attack by water; (2) the difficulty of breaking the high bond energy of the C–F bond to achieve defluorination; and (3) the pursuit of high abundance. 18 The O labeling rate, and both oxygen atoms are the labeled target products. Summary of the Invention

[0005] The present invention aims to address the lack of efficient and high-abundance methods for labeling carboxylic acid groups in the prior art, especially for the introduction of foreign oxygen atoms and the realization of high-abundance isotopic labeling of two oxygen atoms in carboxylic acids, and to solve the technical problems of long reaction time, narrow substrate range and harsh reaction conditions in existing methods.

[0006] To solve the above-mentioned technical problems, the present invention adopts the following technical solution: A method for promoting the hydrolysis of gemdifluoropropylene to synthesize 18O-labeled α,β-unsaturated olefinic acid using silver salts includes the following steps: Under an inert gas atmosphere, silver salt additives are added to a reaction vessel, followed by the addition of gemdifluoropropylene substrate, DCM, and oxygen-18-labeled water (H2). 18 O), reacted under heating conditions with stirring, and then post-processed to obtain 18 O-labeled α,β-unsaturated carboxylic acid products. Chemical formula as follows: In the above formulas: R is substituted or unsubstituted C1–C 18 Alkyl, substituted or unsubstituted C3–C 18 Cycloalkyl, substituted or unsubstituted C2–C 18 alkenyl, substituted or unsubstituted C6–C 20 aryl, substituted or unsubstituted C3–C 20 Mixed aromatics; The substituents are independently selected from halogens, alkyl groups, alkoxy groups, haloalkyl groups, alkoxycarbonyl groups, cyano groups, nitro groups, aryl groups, or heteroaryl groups.

[0007] The silver salt is one or more of AgOTf, AgBF4, AgSbF6, AgPF6, or AgClO4.

[0008] The molar ratio of the silver salt to the gemdifluoropropylene substrate is 0.1:1–2:1.

[0009] The H2 18 The volume molar ratio of O to gem-difluoropropylene substrate is 0.05–1.5 mL / mmol.

[0010] The heating temperature is 30–50 °C.

[0011] The reaction time is 6–24 h.

[0012] The inert gas is argon or nitrogen.

[0013] The working principle of this invention: Through long-term and in-depth research, the applicant discovered that a gemini difluoroalkene substrate, when activated by silver salts, can react with H2. 18This method involves nucleophilic addition of O, protonation of silver ions, defluorination to generate an acyl fluoride intermediate, and hydrolysis to a carboxylic acid. It offers advantages such as requiring no additional ligands, broad substrate applicability, ease of operation, high reaction efficiency, and high stereoselectivity.

[0014] Compared with the prior art, the present invention has the following advantages: 1. High stereoselectivity: The method of this invention can synthesize (E)- with excellent E / Z selectivity (up to 15:1). 18 O-labeled α,β-unsaturated carboxylic acids solve the problem of poor stereoselectivity in existing methods.

[0015] 2. High labeling rate: The labeling rate of the method of the present invention can reach up to 96% and is stable, which is significantly better than the existing methods.

[0016] 3. Wide range of applicable substrates: The method of this invention is applicable to a variety of substituted gem-difluoropropene substrates, including aromatic substituted, heterocyclic substituted, aliphatic substituted, etc., and has good functional group compatibility.

[0017] 4. Simple operation: The method of this invention is carried out under conditions without ligands or additional catalysts, requiring only AgOTf as a promoter and H2. 18 O can be used as both a hydrogen and oxygen source, and the operation is simple and requires no special equipment.

[0018] 5. Scalability: The method of this invention can be scaled up to the gram level without significant decrease in yield and labeling rate, and has promising prospects for industrial application.

[0019] 6. High value of product derivatives: the obtained 18 O-labeled α,β-unsaturated carboxylic acids can be further converted into amides, thioesters, esters, redox-active esters, and heterocyclic skeletons, among other compounds. 18 O-labeled functional molecules with no significant loss in labeling rate have broad application prospects. Detailed Implementation

[0020] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated. Purification in the following embodiments is performed using conventional post-processing methods in the art.

[0021] Example 1: Under argon protection, AgOTf (0.4 mmol, 2.0 equiv) was added to a 10 mL Schlenk tube, and the argon gas was purged three times. Then, gemdifluoropropylene substrate 1a (0.2 mmol, 1.0 equiv) and DCM (2 mL) were added, and finally H2 was added. 18 O (300 μL), seal the tube opening. Stir the reaction mixture at 50 °C for 12 hours. After the reaction is complete, concentrate the reaction solution and purify the crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to give a white solid product 3a, with a yield of 96%, a labeling rate of 93%, and an E / Z ratio of 13:1. 1 H NMR (400 MHz, chloroform-d) δ 11.00 – 8.20 (br,1H), 7.31 (t, J = 7.4 Hz, 2H), 7.25 – 7.17 (m, 3H), 7.13 (dt, J1= 16.0, J2=7.0 Hz, 1H), 5.86 (d, J = 15.6 Hz, 1H), 2.80 (t, J = 7.8 Hz, 2H), 2.61 – 2.53(m, 2H). 13 C NMR (101 MHz, chloroform-d) δ 172.05, 151.17, 140.70, 128.66,128.46,126.38, 121.35, 34.30, 34.12. HRMS (ESI) Calcd for C 11 H 11 18 O2 - ([MH) - ):179.0849, found: 179.0841. Example 2: Following the method of Example 1, substrate 1b was used instead of 1a, with other conditions remaining unchanged, to obtain yellow solid product 3b with a yield of 75%, a labeling rate of 91%, and an E / Z ratio of 9:1. 1H NMR (400 MHz, chloroform-d) δ 11.80 – 9.00 (br, 1H), 7.35 – 7.26 (m, 2H), 7.24 – 7.14 (m, 3H), 7.14 – 7.03 (m, 1H), 5.83 (d, J =15.6 Hz, 1H), 2.64 (t, J = 7.6 Hz, 2H), 2.31 – 2.23 (m, 2H), 1.73 – 1.62 (m, 2H), 1.58 – 1.48 (m, 2H). 13 C NMR (101 MHz, chloroform-d) δ 172.26, 152.20,142.27, 128.51, 128.46,125.92, 120.94, 35.78, 32.30, 31.04, 27.57. HRMS (ESI)Calcd for C 13 H 15 18 O2 - ([MH) - ): 207.1162, found: 207.1155. Example 3: Following the method of Example 1, substrate 1c was used instead of 1a, with other conditions remaining unchanged, to obtain white solid product 3c with a yield of 77%, a labeling rate of 93%, and an E / Z ratio of 12:1. 1 H NMR (400 MHz, chloroform-d) δ 12.80 – 9.60 (br,1H), 7.23 – 7.08(m, 5H), 5.90 (d, J = 15.6 Hz, 1H), 2.83 – 2.75 (m, 2H),2.59-2.47 (m, 2H), 2.33 (s, 3H). 13 C NMR (101 MHz, chloroform-d) δ 171.99,151.30, 138.90, 135.97, 130.49,128.78, 126.53, 126.27, 121.27, 32.94, 31.64,19.40. HRMS (ESI) Calcd for C 12 H 13 18 O2 - ([MH) -): 193.1006, found: 193.0998. Example 4: Following the method of Example 1, substrate 1d was used instead of 1a, with other conditions remaining unchanged, to obtain white solid product 3d with a yield of 84%, a labeling rate of 92%, and an E / Z ratio of 10:1. 1 H NMR (400 MHz, chloroform-d) δ 12.25 – 10.60 (br,1H), 7.25 – 7.17(m, 1H), 7.17 – 7.09 (m, 1H), 7.08 – 6.95 (m, 3H), 5.88 (d, J= 15.6 Hz, 1H), 2.81 – 2.72 (m, 2H), 2.62-2.52 (m, 2H), 2.36 (s, 3H). 13 C NMR(101 MHz, chloroform-d) δ 172.23, 151.31,140.66, 138.23, 129.25, 128.55,127.11, 125.44, 121.29, 34.22, 34.14, 21.52. HRMS (ESI) Calcd for C 12 H 13 18 O2 - ([MH) - ): 193.1006, found: 193.0997. Example 5: Following the method of Example 1, substrate 1e was used instead of 1a, with other conditions remaining unchanged, to obtain a white solid product 3e with a yield of 80%, a labeling rate of 90%, and an E / Z ratio of 15:1. 1 H NMR (400 MHz, Dimethyl Sulfoxide-d6) δ 13.70 – 9.90(br, 1H), 7.09 – 7.00 (m, 4H), 6.79 (dt, J1= 16.0, J2=6.8 Hz, 1H), 5.73 (d, J= 15.6 Hz, 1H), 2.65 (t, J = 7.6 Hz, 2H), 2.47 – 2.38 (m, 2H), 2.22 (s, 3H). 13C NMR (101 MHz, Dimethyl Sulfoxide-d6) δ 167.25, 148.25, 137.90, 135.03,129.05, 128.35, 122.44, 33.31, 33.20, 20.74.HRMS (ESI) Calcd for C 12 H 13 18 O2 - ([MH) - ): 193.1006, found: 193.0997. Example 6: Following the method of Example 1, substrate 1f was used instead of 1a, with other conditions remaining unchanged, to obtain a white solid product 3f with a yield of 66%, a labeling rate of 83%, and an E / Z ratio of 13:1. 1 H NMR (400 MHz, chloroform-d) δ 12.50 – 9.50 (br,1H), 7.34 (d, J = 8.4 Hz, 2H), 7.22 – 7.07 (m, 3H), 5.89 (d, J = 16.0 Hz,1H), 2.78 (t, J =7.6 Hz, 2H), 2.62-2.53 (m, 2H), 1.34 (s, 9H). 13 C NMR (101MHz, chloroform-d) δ 172.19, 151.43, 149.21, 137.64, 128.11,125.55, 121.27,34.53, 34.09, 33.75, 31.52. HRMS (ESI) Calcd for C 15 H 19 18 O2 - ([MH) - ): 235.1475, found: 235.1469. Example 7: Following the method of Example 1, 1g of substrate was used instead of 1a, with other conditions remaining unchanged, to obtain 3g of white solid product, yield 65%, labeling rate 96%, E / Z=7:1. 1H NMR (400 MHz, chloroform-d) δ 12.20 – 8.80 (br, 1H),7.17 – 7.02(m, 3H), 6.84 (d, J = 8.8 Hz, 2H), 5.84 (d, J = 15.6 Hz, 1H), 3.79(s, 3H), 2.74 (t, J = 7.6 Hz, 2H), 2.57-2.48 (m, 2H). 13 C NMR (101 MHz,chloroform-d) δ 171.90, 158.17, 151.27, 132.77, 129.39,121.30, 114.07, 55.40,34.39, 33.44. HRMS (ESI) Calcd for C 12 H 13 O 18 O2 - ([MH) - ): 209.0955, found:209.0947. Example 8: Following the method of Example 1, substrate 1h was used instead of 1a, with other conditions remaining unchanged, to obtain a white solid product 3h with a yield of 65%, a labeling rate of 90%, and an E / Z ratio of 9:1. 1 H NMR (400 MHz, chloroform-d) δ 7.08 (dt, J1= 15.6, J2=6.8 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.69 – 6.65 (m, 1H), 6.65 – 6.60 (m,1H), 5.93 (s, 2H), 5.83 (d, J = 15.6 Hz, 1H) 2.71 (t, J = 7.4 Hz, 2H), 2.55–2.47 (m, 2H). 13 C NMR (101 MHz, chloroform-d) δ 171.78, 151.00,147.83, 146.06,134.49, 121.39, 121.29, 108.86, 108.40, 101.00, 34.37, 34.07.HRMS (ESI) Calcdfor C 12 H 11 O2 18 O2 - ([MH)- ): 223.0737, found: 223.0740. Example 9: Following the method of Example 1, substrate 1i was used instead of 1a, with other conditions remaining unchanged, to obtain white solid product 3i with a yield of 73%, a labeling rate of 82%, and an E / Z ratio of 12:1. 1 H NMR (400 MHz, Methanol-d4) δ 7.40 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 6.94 (dt, J1= 15.6, J2=7.0 Hz, 1H), 5.78 (d, J= 15.2 Hz, 1H), 2.74 (t, J = 7.6 Hz, 2H), 2.54 – 2.46 (m, 2H). 13 C NMR (101MHz, Methanol-d4) δ 169.91, 149.73, 141.45, 132.41, 131.42, 123.14, 120.69,34.61, 34.59. HRMS (ESI) Calcd for C 11 H 10 Br 18 O2 - ([MH) - ): 256.9955, found:256.9952 Example 10: Following the method of Example 1, substrate 1j was used instead of 1a, with other conditions remaining unchanged, to obtain white solid product 3j with a yield of 74%, a labeling rate of 91%, and an E / Z ratio of 8:1. 1 H NMR (400 MHz, chloroform-d) δ 12.40 – 9.30 (br, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.07 (dt, J1= 15.6, J2= 6.8 Hz, 1H), 6.93 (d, J =8.4 Hz, 2H), 5.83 (d, J = 15.6 Hz, 1H), 2.74 (t, J = 7.6 Hz, 2H), 2.58-2.49(m, 2H). 13C NMR (101 MHz, chloroform-d) δ 171.89, 150.56,140.26, 137.69,130.55, 121.63, 91.51, 33.84 – 33.71 (m, 2C). HRMS (ESI) Calcd for C 11 H 10 I 18 O2 - ([MH) - ): 304.9805, found: 304.9812. Example 11: Following the method of Example 1, substrate 1k was used instead of 1a, with other conditions remaining unchanged, to obtain white solid product 3j with a yield of 62%, a labeling rate of 93%, and an E / Z ratio of 10:1. 1 H NMR (400 MHz, chloroform-d) δ 11.60 – 9.20 (br,1H), 7.97 (d, J = 7.6 Hz, 2H), 7.25 (d, J =8.0 Hz, 2H), 7.13 – 7.02 (m, 1H),5.84 (d, J = 15.6 Hz, 1H), 3.91 (s, 3H), 2.85 (t, J = 7.8 Hz, 2H), 2.63-2.52(m, 2H). 13 C NMR (101 MHz, chloroform-d) δ171.72, 167.14, 150.32, 146.06,130.00, 128.49, 121.70, 52.16, 34.25, 33.56. HRMS (ESI) Calcd for C 13 H 14 O2 18 O2Na + ([M+Na)) + ): 261.0869, found: 261.0871. Example 12: Following the method of Example 1, substrate 1l was used instead of 1a, with other conditions remaining unchanged, to obtain white solid product 3l with a yield of 49%, a labeling rate of 89%, and an E / Z ratio of 8:1. 1H NMR (400 MHz, chloroform-d) δ 11.50 – 8.50 (br, 1H),7.56 (d, J = 8.0 Hz, 2H), 7.35 – 7.23 (m, 2H), 7.14 – 7.01(m, 1H), 5.85 (d, J= 16.0 Hz, 1H), 2.86 (t, J = 8.0 Hz, 2H), 2.63-2.53 (m, 2H). 13 C NMR (101 MHz, chloroform-d) δ 171.75, 150.27, 144.70, 128.85 (q, J = 10.8 Hz), 128.81,125.63 (q, J = 3.8 Hz), 121.78, 121.68 (q, J = 273.8 Hz), 34.10, 33.65. 19 F NMR(376 MHz, chloroform-d) δ -62.39. (s, 3F). HRMS (ESI) Calcd for C 12 H 10 F3 18 O2 - ([MH) - ): 247.0723, found: 247.0721. Example 13: Following the method of Example 1, substrate 1m was used instead of 1a, with other conditions remaining unchanged, to obtain a yellow solid product 3m with a yield of 40%, a labeling rate of 89%, and an E / Z ratio of 9:1. 1 H NMR (400 MHz, Methanol-d4) δ 7.65 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 6.94 (dt, J1= 15.6, J2=7.0 Hz, 1H), 5.80 (d, J= 15.6 Hz, 1H), 2.88 (t, J = 7.6 Hz, 2H), 2.60 – 2.52 (m, 2H). 13C NMR (101MHz, Methanol-d4) δ 169.95, 149.07, 148.40, 133.35, 130.66, 123.61, 119.85,110.98, 35.31, 34.18. HRMS (ESI) Calcdfor C 12 H 10 N 18 O2 - ([MH) - ): 204.0802, found:204.0795. Example 14: Following the method of Example 1, substrate 1n was used instead of 1a, with other conditions remaining unchanged, to obtain a yellow solid product 3n with a yield of 50%, a labeling rate of 72%, and an E / Z ratio of 9:1. 1 H NMR (400 MHz, chloroform-d) δ 12.80 – 8.80 (br, 1H),7.15 – 7.02(m, 1H), 5.82 (d, J = 15.6 Hz, 1H), 2.27-2.17 (m, 2H), 1.52 – 1.38(m, 2H), 1.37 – 1.16 (m, 16H), 0.93 – 0.82 (m, 3H). 13 C NMR (101 MHz, chloroform-d) δ 171.97, 152.64,120.67, 32.47, 32.05, 29.76, 29.70, 29.66,29.51, 29.47, 29.29, 28.02, 22.83, 14.25. HRMS (ESI) Calcd for C 14 H 25 18 O2 - ([MH) - ): 229.1945, found: 229.1941. Example 15: Following the method of Example 1, substrate 1o was used instead of 1a, with other conditions remaining unchanged, to obtain a yellow solid product 3o with a yield of 67%, a labeling rate of 70%, and an E / Z ratio of 8:1. 1H NMR (400 MHz, chloroform-d) δ 11.50 – 9.70 (br, 1H),7.10 (dt, J1= 15.6 Hz, J2=7.0 Hz, 1H), 5.82 (d, J = 15.6 Hz, 1H), 2.30-2.20(m, 2H), 1.82 – 1.69 (m, 3H), 1.63 – 1.56 (m, 2H), 1.54 – 1.43 (m, 4H), 1.15 –1.00 (m, 2H). 13 C NMR (101 MHz, chloroform-d) δ 172.37, 152.81, 120.61, 39.73,34.40,32.68, 31.73, 25.28. HRMS (ESI) Calcd for C 10 H 15 18 O2 - ([MH) - ): 171.1152, found: 171.1151. Example 16: Following the method of Example 1, substrate 1p was used instead of 1a, with other conditions remaining unchanged, to obtain a white solid product 3p with a yield of 45%, a labeling rate of 70%, and an E / Z ratio of 9:1. 1 H NMR (400 MHz, chloroform-d) δ 12.20 – 9.00 (br, 1H),7.09 (dt, J1= 15.6 Hz, J2=7.0 Hz, 1H), 5.82 (d, J = 15.6 Hz, 1H), 2.28 – 2.20(m, 2H), 1.77 – 1.59 (m, 5H), 1.39-1.30 (m, 2H), 1.26 – 1.14 (m, 4H), 0.95 –0.82 (m, 2H). 13 C NMR (101 MHz, chloroform-d) δ 172.27, 153.01, 120.54, 37.22,35.58, 33.27, 29.87, 26.71, 26.39. HRMS (ESI) Calcd for C 11 H 17 18 O2 - ([MH) -):185.1308, found: 185.1308. Example 17: Following the method of Example 1, substrate 1q was used instead of 1a, with other conditions remaining unchanged, to obtain a white solid product 3q with a yield of 70%, a labeling rate of 96%, and an E / Z ratio of 9:1. 1 H NMR (400 MHz, Methanol-d4) δ 6.88 (dd, J1= 15.6 Hz, J2=6.8 Hz, 1H), 5.77 (dd, J1= 15.6 Hz, J2=1.6 Hz, 1H), 3.65 (s, 3H), 2.37 –2.25 (m, 1H), 2.22 – 2.09 (m, 1H), 2.07 – 1.97 (m, 2H), 1.91 – 1.81 (m, 2H), 1.54 – 1.40 (m, 2H), 1.28 – 1.15 (m, 2H). 13 C NMR (101 MHz, Methanol-d4) δ177.90, 170.25, 155.12, 120.44, 52.10, 43.71, 40.82, 31.66, 29.36. HRMS (ESI)Calcd for C 11 H 15 O2 18 O2 - ([MH) - ): 215.1061, found: 215.1054. Example 18: Following the method of Example 1, substrate 1r was used instead of 1a, with other conditions remaining unchanged, to obtain a white solid product 3r with a yield of 49%, a labeling rate of 87%, and an E / Z ratio of 8:1. 1 H NMR (400 MHz, chloroform-d) δ 11.60 – 8.70 (br, 1H), 7.35 – 7.26 (m, 4H), 7.25 – 7.12 (m, 6H), 7.03 – 6.90 (m, 1H), 5.80 (d, J =15.6 Hz, 1H), 4.11 (t, J = 8.0 Hz, 1H), 2.99 (t, J = 7.6 Hz, 2H). 13C NMR (101MHz, chloroform-d)δ 171.53, 149.88, 143.62, 128.78, 127.88,126.73, 122.39,50.30, 38.51. HRMS (ESI) Calcd for C 17 H 15 18 O2 - ([MH) - ): 255.1162, found:255.1157. Example 19: Following the method of Example 1, substrate 1s was used instead of 1a, with other conditions remaining unchanged, to obtain a white solid product 3s with a yield of 47%, a labeling rate of 90%, and an E / Z ratio of 8:1. 1 H NMR (400 MHz, chloroform-d) δ 12.90 – 10.40 (br,1H), 7.89 (d, J = 8.4 Hz, 1H), 7.77 (d, J =7.6 Hz, 1H), 7.64 (d, J = 8.4 Hz,1H), 7.48 – 7.35 (m, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 6.8 Hz, 1H), 7.17 – 7.06 (m, 1H), 5.81 (d, J = 15.6 Hz, 1H), 3.15 (t, J =7.8 Hz, 2H),2.65-2.55 (m, 2H). 13 C NMR (101 MHz, chloroform-d) δ 172.13, 151.24, 136.71,134.06, 131.73, 129.07, 127.26, 126.19, 126.16, 125.75, 125.69, 123.48,121.38, 33.34, 31.43. HRMS (ESI) Calcdfor C 15 H 13 18 O2 - ([MH) - ): 229.1006, found:229.1003. Example 20: Following the method of Example 1, 1t of substrate was used instead of 1a, with other conditions remaining unchanged, to obtain 3t of white solid product, with a yield of 35%, a labeling rate of 79%, and an E / Z ratio of 8:1. 1 H NMR (400 MHz, Dimethyl Sulfoxide-d6) δ 13.00 – 11.40(br, 1H), 8.27 (d, J = 9.2 Hz,1H), 8.25 – 8.20 (m, 2H), 8.18 – 8.13 (m, 2H),8.10 – 8.07 (m, 2H), 8.02 (t, J = 7.6 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 6.92 (dt, J1= 15.6 Hz, J2=6.8 Hz, 1H), 5.83 (d, J = 15.6 Hz, 1H), 3.27 (t, J = 7.8Hz, 2H), 2.35-2.25 (m, 2H), 1.92 – 1.82(m, 2H). 13 C NMR (101 MHz, DimethylSulfoxide-d6) δ 167.22, 148.48, 136.35, 130.92, 130.44, 129.33, 128.10,127.46, 127.43, 127.26, 126.53, 126.14, 124.97, 124.94, 124.81, 124.27,124.19,123.37, 122.34, 32.12, 31.38, 29.81. HRMS (ESI) Calcd for C 22 H 17 18 O2 - ([MH) - ): 317.1319, found: 317.1319. Example 21: Under argon protection, AgOTf (14.0 mmol, 2.0 equiv) was added to a 200 mL Schlenk tube, and the argon gas was purged three times. Substrate 1a (7.0 mmol, 1.0 equiv) and H2 were then added. 18O (10.5 mL), seal the tube. Stir the reaction mixture at 50 °C for 12 hours. After the reaction is complete, the reaction solution is extracted with DCM (3 × 15 mL), the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to give 1.148 g of product 3a, yield 91%, labeling rate 96%, E / Z = 13:1.

[0022] Example 22: Under argon protection, AgBF4 (0.4 mmol, 2.0 equiv) was added to a 10 mL Schlenk tube, and the argon gas was purged three times. Then, gemdifluoropropylene substrate 1a (0.2 mmol, 1.0 equiv) and DCM (2 mL) were added, and finally H2 was added. 18 O (300 μL), seal the tube opening. Stir the reaction mixture at 50 °C for 12 hours. After the reaction is complete, concentrate the reaction solution and purify the crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to give a white solid product 3a, with a yield of 87%, a labeling rate of 90%, and an E / Z ratio of 13:1.

[0023] Example 23: Under argon protection, AgSbF6 (0.4 mmol, 2.0 equiv) was added to a 10 mL Schlenk tube, and the argon gas was purged three times. Then, gemdifluoropropylene substrate 1a (0.2 mmol, 1.0 equiv) and DCM (2 mL) were added, and finally H2 was added. 18 O (300 μL), seal the tube opening. Stir the reaction mixture at 50 °C for 12 hours. After the reaction is complete, concentrate the reaction solution and purify the crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to give a white solid product 3a, yield 43%, labeling rate 91%, E / Z = 13:1.

[0024] Example 24: Under argon protection, AgPF6 (0.4 mmol, 2.0 equiv) was added to a 10 mL Schlenk tube, and the argon gas was purged three times. Then, gemdifluoropropylene substrate 1a (0.2 mmol, 1.0 equiv) and DCM (2 mL) were added, followed by the addition of H2. 18O (300 μL), seal the tube opening. Stir the reaction mixture at 50 °C for 12 hours. After the reaction is complete, concentrate the reaction solution and purify the crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to give a white solid product 3a, yield 32%, labeling rate 90%, E / Z = 13:1.

[0025] Example 25: Under argon protection, AgClO4 (0.4 mmol, 2.0 equiv) was added to a 10 mL Schlenk tube, and the argon gas was purged three times. Then, gemdifluoropropylene substrate 1a (0.2 mmol, 1.0 equiv) and DCM (2 mL) were added, and finally H2 was added. 18 O (300 μL), seal the tube opening. Stir the reaction mixture at 50 °C for 12 hours. After the reaction is complete, concentrate the reaction solution and purify the crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to give a white solid product 3a, yield 43%, labeling rate 91%, E / Z = 13:1.

[0026] Example 26: Under argon protection, AgOTf (0.2 mmol, 1.0 equiv) was added to a 10 mL Schlenk tube, and the argon gas was purged three times. Then, gemdifluoropropylene substrate 1a (0.2 mmol, 1.0 equiv) and DCM (2 mL) were added, and finally H2 was added. 18 O (300 μL), seal the tube opening. Stir the reaction mixture at 50 °C for 12 hours. After the reaction is complete, concentrate the reaction solution and purify the crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to give a white solid product 3a, yield 30%, labeling rate 88%, E / Z = 13:1.

[0027] Example 27: Under argon protection, AgOTf (0.4 mmol, 2.0 equiv) was added to a 10 mL Schlenk tube, and the argon gas was purged three times. Then, gemdifluoropropylene substrate 1a (0.2 mmol, 1.0 equiv) and DCM (2 mL) were added, and finally H2 was added. 18O (300 μL), seal the tube opening. Stir the reaction mixture at 50 °C for 24 hours. After the reaction is complete, concentrate the reaction solution and purify the crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to give a white solid product 3a, with a yield of 96%, a labeling rate of 93%, and an E / Z ratio of 13:1.

[0028] Example 28: Under argon protection, AgOTf (0.4 mmol, 2.0 equiv) was added to a 10 mL Schlenk tube, and the argon gas was purged three times. Then, gemdifluoropropylene substrate 1a (0.2 mmol, 1.0 equiv) and DCM (2 mL) were added, and finally H2 was added. 18 O (100 μL), seal the tube opening. Stir the reaction mixture at 50 °C for 12 hours. After the reaction is complete, concentrate the reaction solution and purify the crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to give a white solid product 3a, with a yield of 93%, a labeling rate of 88%, and an E / Z ratio of 13:1.

[0029] Example 29: Under argon protection, AgOTf (0.4 mmol, 2.0 equiv) was added to a 10 mL Schlenk tube, and the argon gas was purged three times. Then, gemdifluoropropylene substrate 1a (0.2 mmol, 1.0 equiv) and DCM (2 mL) were added, and finally H2 was added. 18 O (5.4 μL), seal the tube. Stir the reaction mixture at 50 °C for 12 hours. After the reaction is complete, concentrate the reaction solution and purify the crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to give a white solid product 3a, yield 93%, labeling rate 87%, E / Z = 13:1.

[0030] Example 30: Under argon protection, AgOTf (0.4 mmol, 2.0 equiv) was added to a 10 mL Schlenk tube, and the argon gas was purged three times. Then, gemdifluoropropylene substrate 1a (0.2 mmol, 1.0 equiv) and EtOAc (2 mL) were added, and finally H2 was added. 18O (300 μL), seal the tube opening. Stir the reaction mixture at 50 °C for 12 hours. After the reaction is complete, concentrate the reaction solution and purify the crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to give a white solid product 3a, yield 17%, labeling rate 97%, E / Z = 13:1.

[0031] Example 31: Under argon protection, AgOTf (0.4 mmol, 2.0 equiv) was added to a 10 mL Schlenk tube, and the argon gas was purged three times. Then, gemdifluoropropylene substrate 1a (0.2 mmol, 1.0 equiv) and THF (2 mL) were added, and finally H2 was added. 18 O (300 μL), seal the tube opening. Stir the reaction mixture at 50 °C for 12 hours. After the reaction is complete, concentrate the reaction solution and purify the crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to give a white solid product 3a, yield 44%, labeling rate 40%, E / Z = 13:1.

[0032] Example 32: Under argon protection, AgOTf (0.4 mmol, 2.0 equiv) was added to a 10 mL Schlenk tube, and the argon gas was purged three times. Then, gemdifluoropropylene substrate 1a (0.2 mmol, 1.0 equiv) and MeCN (2 mL) were added, and finally H2 was added. 18 O (300 μL), seal the tube opening. Stir the reaction mixture at 50 °C for 12 hours. After the reaction is complete, concentrate the reaction solution and purify the crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to give a white solid product 3a, yield 17%, labeling rate 44%, E / Z = 13:1.

[0033] Example 33: Under argon protection, AgOTf (0.4 mmol, 2.0 equiv) was added to a 10 mL Schlenk tube, and the argon gas was purged three times. Then, gemdifluoropropylene substrate 1a (0.2 mmol, 1.0 equiv) and DME (2 mL) were added, and finally H2 was added. 18O (300 μL), seal the tube opening. Stir the reaction mixture at 50 °C for 12 hours. After the reaction is complete, concentrate the reaction solution and purify the crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to give a white solid product 3a, yield 50%, labeling rate 71%, E / Z = 13:1.

[0034] Example 34: Under argon protection, AgOTf (0.4 mmol, 2.0 equiv) was added to a 10 mL Schlenk tube, and the argon gas was purged three times. Then, gemdifluoropropylene substrate 1a (0.2 mmol, 1.0 equiv) and DCM (2 mL) were added, and finally H2 was added. 18 O (300 μL), seal the tube opening. Stir the reaction mixture at 30 °C for 12 hours. After the reaction is complete, concentrate the reaction solution and purify the crude product by column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to give a white solid product 3a, yield 91%, labeling rate 91%, E / Z = 13:1.

[0035] Example 35: Under argon protection, 3a (0.2 mmol, 1.0 equiv), EDCI (0.3 mmol, 1.5 equiv), and DMAP (0.02 mmol, 10 mol%) were added to a 25 mL Schlenk tube, and the argon atmosphere was purged three times. Then, DCM (2 mL) and 2-phenylethylamine (0.22 mmol, 1.1 equiv) were added, and the tube was sealed. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 3:1) to give a white solid product 4, with a yield of 65% and a labeling efficiency of 95%. 1 H NMR (400 MHz, chloroform-d) δ 7.38 – 7.25 (m, 5H),7.25 – 7.16(m, 5H), 6.94 – 6.83 (m, 1H), 5.74 (d, J = 15.2 Hz, 1H), 5.57 (br,1H), 3.64-3.55 (m, 2H), 2.86 (t, J = 6.8 Hz, 2H), 2.77 (t, J =7.6 Hz, 2H), 2.55-2.46 (m, 2H). 13C NMR (101 MHz, Chloroform-d) δ 165.92, 143.58, 141.05,139.00, 128.84, 128.70, 128.50, 128.43, 126.57, 126.15, 124.20, 40.70, 35.73,34.65, 33.86. HRMS (ESI) Calcdfor C 19 H 21 N 18 ONa + ([M+Na)) + ): 304.1558, found:304.1555. Example 36: Add 3a (0.2 mmol, 1.0 equiv), EDCI (0.3 mmol, 1.5 equiv), and DMAP (0.02 mmol, 10 mol%) to a 25 mL Schlenk tube and place the mixture in an ice bath. Purge the reaction mixture three times with argon, then add DCM (2 mL) and stir in an ice bath for 15 minutes. Next, add 1-butanethiol (0.26 mmol, 1.3 equiv), continue stirring for 2 minutes, and then seal the reaction tube. Allow the resulting mixture to slowly rise to room temperature and stir overnight. Wash successively with saturated sodium bicarbonate solution and water, dry the organic layer with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by rapid column chromatography to give product 5, yield 71%, labeling efficiency 94%. 1 H NMR (400 MHz, chloroform-d) δ 7.33 – 7.27(m, 2H), 7.24 – 7.15 (m, 3H), 6.92 (dt, J1= 15.2 Hz, J2=6.8 Hz, 1H), 6.13 (dt,J1= 15.6 Hz, J2= 1.6 Hz, 1H), 2.94 (t, J = 7.4 Hz, 2H), 2.78 (t, J = 7.8 Hz,2H), 2.55 – 2.47 (m, 2H), 1.62 – 1.52(m, 2H), 1.46 – 1.35 (m, 2H), 0.92 (t, J= 7.2 Hz, 3H). 13C NMR (101 MHz, chloroform-d) δ 190.24, 144.00, 140.82,129.29, 128.65, 128.47, 126.35, 34.47, 34.04, 31.78,28.53, 22.13, 13.75. HRMS(ESI) Calcd for C 15 H 21 18 OS + ([M+H)) + ): 251.1350, found: 251.1345. Example 37: Add 3a (0.2 mmol, 1.0 equiv), DCC (0.22 mmol, 1.1 equiv), DMAP (0.02 mmol, 10 mol%), 2-hydroxy-1-phenylethyl ketone (0.2 mmol, 1.0 equiv), and dichloromethane (2 mL) to a 25 mL Schlenk tube, and seal the tube. Stir the reaction mixture at room temperature for 12 hours. Concentrate the mixture under vacuum, and purify the residue by silica gel column chromatography to give the corresponding compound 6 in 40% yield with 90% labeling. 1 H NMR (400 MHz, chloroform-d) δ 7.94 (d, J = 8.4 Hz, 2H), 7.65 – 7.58 (m, 1H), 7.49 (t, J =7.8 Hz, 2H), 7.31 (t, J = 7.2 Hz, 2H), 7.25 – 7.11 (m, 4H), 6.03 (d, J = 15.6Hz, 1H), 5.40 (s, 2H), 2.81 (t, J = 7.8 Hz, 2H), 2.63 – 2.53 (m, 2H). 13 C NMR(101 MHz, chloroform-d) δ 192.43, 165.86, 150.06, 140.83, 134.40,133.98,128.98, 128.63, 128.45, 127.92, 126.33, 120.84, 66.01, 34.32, 34.18. HRMS(ESI) Calcd for C 19 H 18 O2 18 ONa +([M+Na)) + ): 319.1191, found: 319.1187. Example 38: Following the method of Example 37, 2-hydroxy-1-phenylethyl ketone was replaced with the substrate 2-hydroxyisoindoline-1,3-dione, with other conditions remaining unchanged, to obtain a white solid product 7 with a yield of 78%, a labeling rate of 95%, and an E / Z ratio of 13:1. 1 H NMR (400 MHz, chloroform-d) δ 7.91 – 7.85 (m, 2H), 7.81 – 7.75(m, 2H), 7.40 – 7.27 (m, 3H),7.25 – 7.17 (m, 3H), 6.13 (dt, J1= 15.6 Hz, J2=1.6 Hz, 1H), 2.84 (t, J = 7.6Hz, 2H), 2.70 – 2.60(m, 2H). 13 C NMR (101 MHz, chloroform-d) δ 162.28, 162.10,154.71, 140.28, 134.81, 128.98, 128.68, 128.36, 126.45, 124.00, 116.10,34.58, 33.90. HRMS (ESI) Calcd for C 19 H 15 NO3 18 ONa + ([M+Na)) + ): 346.0936, found:346.0931. Example 39: At 0 °C, oxaloyl chloride (1.1 equiv) was added dropwise over 2 minutes to a solution of 3a (0.3 mmol, 1.0 equiv) and DMF (0.075 mmol, 0.25 equiv) in dichloromethane (1 mL). The mixture was stirred at 0 °C until no more bubbles were generated, yielding an α,β-unsaturated acyl chloride solution, which was used directly in the next step. The above acyl chloride solution was added dropwise to a mixture of aminoketone (0.3 mmol, 1.0 equiv) in dichloromethane (1 mL) and a saturated sodium carbonate aqueous solution (1 mL). The mixture was stirred at room temperature and monitored by TLC until the reaction was complete. The aqueous layer was separated and extracted with dichloromethane (4 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under vacuum, and the residue was purified by column chromatography to give the amide intermediate. The mixture of the amide intermediate obtained in the previous step (0.2 mmol, 1.0 equiv) and Ni(acac)2 (0.01 mmol, 5 mol%) in tetrahydrofuran (1.5 mL) was stirred at room temperature for 15 min. After cooling to 0 °C, Et2Zn (1 M in hexane, 0.4 mL, 0.4 mmol) was added rapidly in a single batch. The mixture was stirred at 0 °C for 1 h, then brought to room temperature and stirred continuously, monitored by TLC until the starting material was completely consumed. The resulting mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography to give a six-membered heterocyclic compound 8 in 70% yield with 94% labeling. 1 H NMR(400 MHz, chloroform-d) δ 7.46 (d, J = 7.2 Hz, 2H), 7.41 (t, J = 7.6 Hz, 2H),7.36 – 7.29 (m, 1H), 7.22 – 7.14 (m, 4H), 7.14 – 7.08(m, 1H), 7.02 (d, J =7.6 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 4.00 – 3.89 (m, 1H), 3.80 (s, 3H), 3.48 – 3.39 (m, 1H), 2.92 – 2.85 (m, 1H), 2.46 (t, J = 7.6 Hz, 2H), 2.43 –2.34(m, 1H), 2.29 – 2.14 (br, 1H), 2.13 – 1.96 (m, 2H), 1.92 – 1.78 (m, 1H), 1.60 – 1.48 (m, 1H), 1.48 – 1.38 (m, 1H). 13C NMR (101 MHz, chloroform-d) δ 172.33, 158.17, 145.98, 142.41,136.28, 128.73, 128.40, 128.19, 127.56, 127.42, 125.53, 124.69, 114.52,75.64, 55.57, 51.64, 47.76,37.13, 35.97, 31.55, 26.45. HRMS (ESI) Calcd forC 27 H 29 NO2 18 ONa + ([M+Na] + ): 440.2082, found: 440.2081。

Claims

1. A silver salt for promoting the hydrolytic synthesis of gem-difluoropropylene 18 A method for labeling α,β-unsaturated enoic acids with O, characterized in that: To achieve the introduction of two external 18 The O-labeled hydrolysis reaction includes the following steps: under inert gas protection, silver salt and geminitrofluoropropylene substrate are added to the reaction vessel, followed by the addition of DCM and H2. 18 O, under heating conditions and with stirring, yields... 18 O-labeled α,β-unsaturated enoic acid; chemical formula as follows: In the above formulas: R is substituted or unsubstituted C1–C 18 Alkyl, substituted or unsubstituted C3–C 18 Cycloalkyl, substituted or unsubstituted C2–C 18 alkenyl, substituted or unsubstituted C6–C 20 aryl, substituted or unsubstituted C3–C 20 Mixed aromatics; The substituents are independently selected from halogens, alkyl groups, alkoxy groups, haloalkyl groups, alkoxycarbonyl groups, cyano groups, nitro groups, aryl groups, or heteroaryl groups.

2. The silver salt-promoted synthesis of gem-difluoropropylene according to claim 1 18 A method for labeling α,β-unsaturated enoic acids with O, characterized in that: The silver salt is one or more of AgOTf, AgBF4, AgSbF6, AgPF6, or AgClO4.

3. The silver salt-promoted synthesis of gem-difluoropropylene according to claim 1 18 A method for labeling α,β-unsaturated enoic acids with O, characterized in that: The molar ratio of the silver salt to the gemdifluoropropylene substrate is 0.1:1–2:

1.

4. The silver salt-promoted synthesis of gem-difluoropropylene according to claim 1 18 A method for labeling α,β-unsaturated enoic acids with O, characterized in that: The H2 18 The volume molar ratio of O to gem-difluoropropylene substrate is 0.05–1.5 mL / mmol.

5. The silver salt-promoted synthesis of gem-difluoropropylene according to claim 1 18 A method for labeling α,β-unsaturated enoic acids with O, characterized in that: The heating temperature is 30–50 °C.

6. The silver salt-promoted synthesis of gem-difluoropropylene according to claim 1 18 A method for labeling α,β-unsaturated enoic acids with O, characterized in that: The reaction time is 6–24 h.

7. The silver salt for promoting the hydrolysis synthesis of gem-difluoropropylene according to claim 1 18 A method for labeling α,β-unsaturated enoic acids with O, characterized in that: The inert gas is argon or nitrogen.

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