Samarium Diiodide-Mediated Cyclopropane Ring-Opening Deuteration Method and Its Application

Abstract

The present invention provides a samarium diiodide-mediated cyclopropane ring-opening and deuteration method and application, comprising the following steps: preparing a samarium diiodide solution; sequentially adding a nitrogen-containing alkaline compound and a deuterium source to the solution; subsequently adding an ester substrate, stirring the solution for reaction, and bubbling air to oxidize the excess samarium; sequentially adding dichloromethane and hydrochloric acid, diluting, separating the layers, and extracting the aqueous layer with an extractant; combining the remaining organic layers, drying, filtering, and then distilling under reduced pressure to purify the residue. This method utilizes inexpensive heavy water as a deuterium donor, combining SmI2-promoted cyclopropane ring-opening with the reduction of a carboxylic acid derivative to achieve deuteration reactions at multiple positions. Furthermore, the SmI2 / D2O system exhibits significantly broader substrate compatibility. By adjusting the reagent dosage to form different strategies for cyclopropane ring-opening and reductive deuteration, deuterium can be efficiently introduced into a variety of substrates, including ketones, esters, nitriles, acyl chlorides, acyl fluorides, and oximes.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular to a samarium diiodide-mediated cyclopropane ring-opening deuteration method and application. Background Art

[0002] Samarium diiodide (SmI2) is a versatile reagent exhibiting remarkable synthetic utility, finding widespread application in both classical reaction systems and the total synthesis of natural products. Its unexpected reactivity, coupled with remarkable chemoselectivity, has been systematically demonstrated in a wide range of transformations, making this lanthanide-based reagent a key tool in modern synthetic methodology. Over the past three decades, SmI2-mediated reductions of ketones (aldehydes), carboxylic acids, and carboxylic acid derivatives have been extensively studied. Furthermore, several comprehensive mechanistic elucidations of reduction reactions have been reported. The continued expansion of deuterium-labeled compounds in fields such as biomedicine, materials engineering, environmental monitoring, and food safety has driven the advancement of deuteration methodologies.

[0003] Samarium diiodide (SmI2) has been demonstrated to mediate carbon-carbon bond cleavage, particularly in regioselective cyclopropane ring-opening reactions of three- and four-membered carbocyclic rings. Early examples in the 1990s showed that SmI2 could mediate radical cyclopropane ring-opening reactions of cyclopropyl ketones and esters, using cyclohexane / pentane-fused cyclopropanes or cyclopropanes with electron-withdrawing groups to facilitate activation. However, a tandem reaction involving cyclopropane ring-opening and ester (or ketone) reduction remained uncharacterized until Procter et al. reported this process in 2014. In their mechanistic studies, they demonstrated that the cyclopropane ring-opening of a cyclopropane followed by the reduction of an ester or amide on the ring could be achieved sequentially using an SmI2 / amine / H2O system. It is worth noting that although there are some scattered examples of SmI2-mediated cyclopropane ring-opening deuterium labeling in previous mechanistic studies, these schemes rely on unconventional deuterium sources (such as tert-butoxide deuterium (t-BuOD), isopropoxide deuterium (i-PrOD)), and the number of deuterium labels is limited (1-2 deuterium atoms per molecule). Therefore, there is a need to develop practical methods and a more substrate-universal reaction system.

[0004] In view of this, the present invention is proposed. Summary of the Invention

[0005] The first objective of the present invention is to provide a samarium diiodide-mediated deuteration method for the ring-opening of cyclopropane. This method utilizes commercially available heavy water (D2O) as a deuterium donor, combining SmI2-promoted cyclopropane ring-opening with the reduction of carboxylic acid derivatives to achieve multiple deuteration reactions, making it more practical. In some cases, tandem reduction reactions of esters and carboxylic acids are also achieved. Secondly, the SmI2 / D2O system exhibits significantly broader substrate compatibility. By adjusting the reagent dosage to form different cyclopropane ring-opening and tandem reductive deuteration strategies, deuterium can be efficiently introduced into a variety of substrates, including ketones, esters, nitriles, acyl chlorides, acyl fluorides, and oximes.

[0006] The second object of the present invention is to provide an α,γ-bis-deuterated ester or α,α,β,δ-tetra-deuterated alcohol prepared by the above-mentioned samarium diiodide-mediated cyclopropane ring-opening deuteration method, wherein the deuterium labeling degree in the product synthesized regioselectively using this method is high.

[0007] The third object of the present invention is to provide the application of the above-mentioned samarium diiodide-mediated cyclopropane ring-opening deuteration method in the synthesis of deuterium-labeled compounds, especially in the cyclopropane reductive ring-opening deuteration reaction.

[0008] In order to achieve the above-mentioned purpose of the present invention, the following technical solutions are adopted:

[0009] The present invention provides a samarium diiodide-mediated cyclopropane ring-opening deuteration method, comprising the following steps:

[0010] Step 1: dissolving samarium diiodide in an organic solvent to prepare a samarium diiodide solution;

[0011] Step 2: adding a deuterium source and a nitrogen-containing alkaline compound to the samarium diiodide solution in sequence to obtain a mixed solution;

[0012] Step 3: Add the ester substrate to the mixture, stir to react, and then introduce air to oxidize excess samarium;

[0013] Step 4: Then add dichloromethane and hydrochloric acid in sequence, dilute, separate the layers, and extract the aqueous layer with the extract;

[0014] Step 5: The remaining organic layers are combined, dried, filtered, and then distilled under reduced pressure, and the residue is purified to obtain any one of α,γ-bis-deuterated ester or α,α,β,δ-tetra-deuterated alcohol.

[0015] Wherein, the purification system is a petroleum ether / ethyl acetate system.

[0016] This reaction pathway involves ring opening followed by reduction. By regulating the reaction system of samarium diiodide, organic solvent, and deuterium source, the tandem reaction of cyclopropane ring opening and ester / amide reduction was achieved for the first time. At the same time, it can effectively improve the deuterium labeling efficiency, achieving a deuterium labeling rate of >99%.

[0017] Preferably, as a further specific embodiment, the structural formula of the ester substrate is or Any of the following;

[0018] Wherein, R1 is any one of hydrogen, alkyl, amino or aromatic substituents;

[0019] R2 is any one or more of an aromatic substituent or a heterocyclic substituent.

[0020] Preferably, as a further specific embodiment, the structural formula of the ester substrate is 、 、 、 or Any of the following;

[0021] Wherein, R3 is any one or more of methyl, phenyl, alkoxy, benzyloxy, styryl, N-methylpyrrolyl, halogen atom or haloalkyl;

[0022] R4 is any one of hydrogen, alkyl, amino or aromatic substituents;

[0023] R5 is either hydrogen or alkoxy.

[0024] Preferably, as a further specific embodiment, the structural formula of the ester substrate is 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or Any one of .

[0025] In the synthetic route of the present invention, the system exhibits significantly broader substrate universality. By adjusting the dosage of reagents to form different cyclopropane ring-opening and tandem deuteration reduction strategies, deuterium can be efficiently introduced into a variety of substrates including ketones, esters, nitriles, acyl chlorides, acyl fluorides and oximes, breaking through the limitations of previous methods on substrate structure. At the same time, the reaction system has good compatibility with sensitive groups such as halogens or trifluoromethyl, and will not undergo dehalogenation or decomposition.

[0026] Preferably, as a further specific implementation manner, the deuterium source is heavy water.

[0027] By using cheap and readily available heavy water as a deuterium source, it can replace traditional expensive deuterated reagents (such as deuterium tert-butoxide and deuterium isopropoxide), significantly reducing costs, having practical applicability and easy operation.

[0028] Preferably, as a further specific embodiment, the organic solvent is any one or more of hexamethylphosphoric triamide, tetrahydrofuran or 1,4-dioxane;

[0029] Preferably, the organic solvent is tetrahydrofuran;

[0030] The nitrogen basic compound is any one or more of morpholine or triethylamine;

[0031] Preferably, the nitrogen basic compound is triethylamine.

[0032] In the present invention, tetrahydrofuran is preferably used as the organic solvent. Tetrahydrofuran has a greater polarity and better miscibility with heavy water, making the SmI2–Et3N–D2O complex more stable and facilitating subsequent reactions. Triethylamine can also stabilize the samarium-containing intermediates during the reaction, thereby regulating the reaction process.

[0033] Preferably, as a further specific embodiment, the molar ratio of samarium diiodide: nitrogen basic compound: deuterium source is (4:24:24)-(11:66:66);

[0034] Preferably, the molar ratio of samarium diiodide: nitrogen basic compound: deuterium source is 4:24:24.

[0035] Preferably, as a further specific embodiment, the molar ratio of samarium diiodide: triethylamine: heavy water is (4:24:24)-(11:66:66);

[0036] Preferably, the molar ratio of samarium diiodide:triethylamine:heavy water is 4:24:24.

[0037] In the present invention, the controllability of the reaction is achieved by regulating the amounts of samarium diiodide, nitrogen basic compound and deuterium source.

[0038] The present invention also provides α,γ-bis-deuterated esters, α,α,β,δ-tetradeuterated alcohols, α,γ-bis-deuterated amines, α,α-cyclopropane bis-deuterated amines or α,α-cyclopropane bis-deuterated alcohols prepared by the above-mentioned samarium diiodide-mediated cyclopropane reductive ring-opening site-selective deuteration method, specifically: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or Any one of .

[0039] The present invention also provides the application of the above-mentioned samarium diiodide-mediated cyclopropane reductive ring-opening site-selective deuteration method in the synthesis of deuterium-labeled compounds;

[0040] Preferably, the use of a reaction system consisting of samarium diiodide-nitrogen-containing basic compound-deuterium source in the synthesis of a deuterium-labeled compound;

[0041] Preferably, the use of a reaction system consisting of samarium diiodide-triethylamine-heavy water in the synthesis of deuterium-labeled compounds;

[0042] Preferably, the reaction for synthesizing the deuterium-labeled compound is a cyclopropane reduction ring-opening deuteration reaction;

[0043] Preferably, the reaction system consisting of samarium diiodide-triethylamine-heavy water is used in the deuteration reaction of cyclopropane reductive ring opening.

[0044] Compared with the prior art, the present invention has the following beneficial effects:

[0045] (1) For the first time, cheap and readily available heavy water was used as a deuterium source, replacing traditional expensive deuterated reagents, making the reaction more practical; at the same time, a deuterium labeling rate of >99% was achieved, far exceeding similar methods, providing an efficient approach for the preparation of isotope-labeled standards.

[0046] (2) By regulating the SmI2 / Et3N / D2O system, the tandem reaction of cyclopropane ring opening and ester / amide reduction was realized for the first time, making the reaction controllable, reducing the occurrence of side reactions, and significantly improving the purity of the product. In addition, the deuterated site was precisely controlled to synthesize α,γ-bis-deuterated esters and α,α,β,δ-tetra-deuterated alcohols, solving the problem of poor site selectivity in traditional methods.

[0047] (3) The substrates are diverse and can cover cyclopropanes with complex substituents such as carboxylates, amides, halogenated aromatics, and heterocycles (furan, indole), breaking through the limitations of previous methods on substrate structure; at the same time, it has good compatibility with sensitive groups and will not undergo dehalogenation or decomposition.

[0048] (4) The results can be directly applied to the fields of deuterated drug design, deuterium-labeled polymers, isotope tracing, etc. The established SmI2 / D2O system provides a universal template for other deuterated reactions (such as labeling of ketones and nitriles), promoting the overall development of isotope labeling technology. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 : is the product of Example 1 under reaction condition 1 1H spectrum;

[0050] Figure 2 : is the product of Example 1 under reaction condition 1 Carbon spectrum of

[0051] Figure 3 : is the product of Example 1 under reaction condition 1 Mass spectrum of

[0052] Figure 4 : generated in Example 26 1H spectrum;

[0053] Figure 5 : generated in Example 26 Carbon spectrum of

[0054] Figure 6 : generated in Example 26 Mass spectrum of

[0055] Figure 7 : generated in Example 29 1H spectrum;

[0056] Figure 8 : generated in Example 29 Carbon spectrum of

[0057] Figure 9: generated in Example 29 Mass spectrum of

[0058] Figure 10 : generated in Example 22 1H spectrum;

[0059] Figure 11 : generated in Example 22 Carbon spectrum of

[0060] Figure 12 : generated in Example 22 Mass spectrum of

[0061] Figure 13 : generated in Example 25 1H spectrum;

[0062] Figure 14 : generated in Example 25 Carbon spectrum of

[0063] Figure 15 : generated in Example 25 Mass spectrum of . DETAILED DESCRIPTION

[0064] The technical scheme of the present invention will be clearly and completely described below in conjunction with specific embodiments, but it will be understood by those skilled in the art that the following described embodiments are part of embodiments of the present invention, rather than all embodiments, and are only used to illustrate the present invention, and should not be considered as limiting the scope of the present invention. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work premise belong to the scope of protection of the present invention. Those who do not specify specific conditions in the embodiments are carried out according to normal conditions or the conditions recommended by the manufacturer. Those whose reagents or instruments are not specified by the manufacturer are conventional products that can be purchased commercially.

[0065] Example 1

[0066] Reaction conditions 1:

[0067] Place a dry reaction flask equipped with a stir bar in a nitrogen positive pressure environment and perform a high vacuum evacuation / backfilling with nitrogen cycle three times to completely remove the air in the flask. Add a 0.10 M SmI2 solution (4.0 eq.) prepared in tetrahydrofuran (THF) to the reaction flask, followed by the addition of D2O (24 eq.) and Et3N (24 eq.) with vigorous stirring. The solution will then form the dark brown color characteristic of the SmI2–Et3N–D2O complex. Select the ester substrate (1.0 eq., dissolved in 1.0 mL of THF) was added to the above solution and the reaction was stirred. Excess Sm(II) was oxidized by bubbling air into the reaction mixture, followed by dilution with dichloromethane (30 mL) and 1 N hydrochloric acid (30 mL). After separation, the aqueous layer was extracted with dichloromethane (3 × 30 mL). The organic layers were combined, dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate system) to obtain the product. .

[0068]

[0069] Reaction conditions 2:

[0070] The specific operation steps and methods are the same as those in reaction condition 1, except that the equivalents of samarium diiodide, triethylamine, and heavy water are changed to SmI2 (8.0 eq.), D2O (48.0 eq.), and Et3N (48.0 eq.). The product is obtained. and .

[0071]

[0072] Methyl 4-Phenylbutanoate-2,4-d2 (2a), colorless oil, 52 mg; α-position deuterium content: 99%; γ-position deuterium content: 99%; yield: 82%. 1 H NMR (400 MHz, CDCl3) δ 7.33 – 7.24 (m, 2H), 7.20 (t, J = 7.4 Hz, 3H), 3.67 (s, 3H), 2.64 (t, J = 7.6 Hz, 1H), 2.37 – 2.27 (m,1H), 1.95 (t, J = 7.6 Hz, 2H); 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 173.9, 141.3,128.5, 128.4, 126.0, 51.5, 34.9, 34.7, 34.5, 33.3, 33.1, 32.9, 26.3; HRMS(ESI) m / z calcd for C 11 H 12 D2O2Na + [M+Na] + : 203.1012, found 203.1014.

[0073] 4-Phenylbutan-1,1,2,4-d4-1-ol (3a). 33 mg, colorless oil; α-deuterium content: 99%; γ-deuterium content: 99%; yield: 39%; 1 H NMR (400 MHz, CDCl3) δ 7.33 – 7.24 (m, 2H), 7.23 –7.15 (m, 3H), 2.71 – 2.59 (m, 1H), 1.69 (t, J = 7.8 Hz, 2H), 1.58 (t, J = 7.8Hz, 1H); 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 142.3, 128.4, 128.3, 125.7, 62.0,35.4, 35.2, 35.0, 31.8, 31.6, 31.5, 27.3; HRMS (ESI) m / z calcd for C 10 H 10 D4ONa + [M+Na] + : 177.1188, found 177.1193.

[0074] Example 2

[0075] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0076]

[0077] Methyl 4-(p-tolyl)Butanoate-2,4-d2 (2b). 35 mg, colorless oil; α-deuterium content: 99%; γ-deuterium content: 99%; yield: 67%; 1 H NMR (400 MHz, CDCl3) δ 7.10 (dd, J = 7.7,4.8 Hz, 4H), 3.67 (s, 3H), 2.60 (tt, J = 7.6, 1.9 Hz, 1H), 2.32 (s, 4H), 1.93(t, J = 7.5 Hz, 2H); 13 C{ 1H} NMR (101 MHz, CDCl3) δ 173.0, 137.2, 134.4,128.1, 128.0, 127.3, 127.3, 50.4, 33.4, 33.2, 33.0, 32.2, 32.0, 31.8, 25.4,20.0; HRMS (ESI) m / z calcd for C 12 H 14 D2O2Na + [M+Na] + : 217.1168, found 217,1176.

[0078] Example 3

[0079] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0080]

[0081] Methyl 4-(m-tolyl)Butanoate-2,4-d2 (2c). 43 mg, colorless oil; α-deuterium content: 99%; γ-deuterium content: 99%; yield: 53%; 1 H NMR (400 MHz, CDCl3) δ 7.25 – 7.11 (m, 1H),7.07 – 6.93 (m, 3H), 3.67 (s, 3H), 2.60 (t, J = 7.8 Hz, 1H), 2.34 (s, 4H),1.94 (t, J = 7.5 Hz, 2H); 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 174.0, 141.2, 137.9,129.3, 128.2, 126.7, 125.4, 77.2, 51.5, 34.8, 34.6, 34.4, 33.3, 33.1, 32.9,26.3, 21.4; HRMS (ESI) m / z calcd for C 12 H 14 D2O2Na + [M+Na] + : 217.1168, found217.1176.

[0082] Example 4

[0083] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0084]

[0085] Methyl 4-(3,4-Dimethylphenyl)butanoate-2,4-d2 (2d). 35 mg, colorless oil; α-deuterium content: 99%; γ-deuterium content: 99%; yield: 38%; 1 H NMR (400 MHz, CDCl3) δ 7.06 (d, J =7.6 Hz, 1H), 6.97 (s, 1H), 6.93 (d, J = 7.6 Hz, 1H), 3.68 (s, 3H), 2.57 (t, J= 7.7 Hz, 1H), 2.33 (q, J = 7.4 Hz, 1H), 2.24 (d, J = 4.6 Hz, 6H), 1.93 (t, J= 7.5 Hz, 2H); 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 174.0, 138.7, 136.4, 134.0,129.8, 129.7, 129.6, 125.8, 77.2, 51.4, 34.4, 34.2, 34.0, 33.3, 33.1, 32.9,26.4, 19.7, 19.3; HRMS (ESI) m / z calcd for C 13 H 16 D2O2Na + [M+Na] + : 231.1325,found 231.1331.

[0086] Example 5

[0087] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0088]

[0089] Methyl 4-([1,1'-Biphenyl]-4-yl)butanoate-2,4-d2 (2e). 37 mg, colorless oil; α-deuterium content: 99%; γ-deuterium content: 99%; yield: 48%; 1H NMR (400 MHz, CDCl3) δ 7.57 –7.44 (m, 4H), 7.38 (t, J = 7.5 Hz, 2H), 7.28 (t, J = 7.3 Hz, 1H), 7.21 (d, J= 8.2 Hz, 2H), 3.63 (s, 3H), 2.63 (t, J = 7.6 Hz, 1H), 2.31 (q, J = 7.3 Hz, 1H), 1.94 (t, J = 7.4 Hz, 2H); 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 173.9, 141.1,140.4, 138.9, 128.9, 128.7, 127.1, 127.0, 127.0, 77.2, 51.5, 34.5, 34.3,34.1, 33.2, 33.0, 32.8, 26.3; HRMS (ESI) m / z calcd for C 17 H 16 D2O2Na + [M+Na] + :279.1325, found 279.1334.

[0090] Example 6

[0091] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0092]

[0093] Methyl 4-(4-Methoxyphenyl)butanoate-2,4-d2 (2f). 24 mg, colorless oil; α-deuterium content: 99%; γ-deuterium content: 99%; yield: 48%; 1 H NMR (400 MHz, CDCl3) δ 7.09 (d, J =8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 3.78 (s, 3H), 3.66 (s, 3H), 2.57 (t, J= 7.4 Hz, 1H), 2.31 (q, J = 7.3 Hz, 1H), 1.91 (t, J = 7.4 Hz, 2H); 13 C{ 1H} NMR (101 MHz, CDCl3) δ 174.0, 157.8, 133.3, 129.3, 129.2, 113.7, 113.5, 77.2,55.2, 51.4, 33.9, 33.8, 33.6, 33.2, 33.0, 32.8, 26.5; HRMS (ESI) m / z calcdfor C 12 H 14 D2O3Na + [M+Na] + : 233.1117, found 233.1125.

[0094] Example 7

[0095] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0096]

[0097] Methyl 4-(4-(Benzyloxy)phenyl)butanoate-2,4-d2 (2g). 35 mg, colorless oil; α-deuterium content: 99%; γ-deuterium content: 99%; yield: 26%; 1 H-NMR (400MHz, CDCl3) δ 7.45 –7.37 (m, 4H), 7.32 (t, J = 7.1 Hz, 1H), 7.10 (d, J = 8.6 Hz, 2H), 6.93 – 6.89(m, 2H), 5.05 (s, 2H), 3.67 (s, 3H), 2.58 (t, J = 7.6 Hz, 1H), 2.34 – 2.28(m, 1H), 1.91 (t, J = 7.5 Hz, 2H); 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 174.0,157.1, 137.2, 133.7, 129.4, 128.5, 127.9, 127.5, 114.7, 77.2, 70.0, 51.5,34.0, 33.8, 33.6, 33.2, 33.0, 32.8, 26.5; HRMS (ESI) m / z calcd for C 18 H 18 D2O3Na + [M+Na] +:309.1430, found 309.1434.

[0098] Example 8

[0099] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0100]

[0101] Methyl 4-(2-Bromophenyl)butanoate-2,4-d2 (2h). 48 mg, colorless oil; α-deuterium content: 99%; γ-deuterium content: 99%; yield: 63%; 1 H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.0Hz, 1H), 7.24 – 7.15 (m, 2H), 7.11 – 6.96 (m, 1H), 3.67 (s, 3H), 2.82 – 2.70(m, 1H), 2.41 – 2.32 (m, 1H), 1.94 (t, J = 7.5 Hz, 2H); 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 173.8, 140.6, 132.8, 130.4, 128.3, 127.7, 127.4, 51.5, 35.1, 34.9,34.7, 33.2, 33.0, 32.8, 24.8; HRMS (ESI) m / z calcd for C 11 H 12 D2BrO2 + [M+H] + :259.0297, found 259.0300.

[0102] Example 9

[0103] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0104]

[0105] Methyl 4-(3-Bromophenyl)butanoate-2,4-d2 (2i). 40 mg, colorless oil; α-deuterium content: 99%; γ-deuterium content: 99%; yield: 35%; 1H NMR (400 MHz, DMSO-d6) δ 7.42 – 7.36(m, 2H), 7.27 – 7.16 (m, 3H), 3.57 (s, 3H), 2.56 (t, J = 7.7 Hz, 2H), 2.28(q, J = 7.5 Hz, 1H), 1.79 (t, J = 7.4 Hz, 2H); 13 C{ 1 H} NMR (101 MHz, CDCl3) δ173.8, 143.7, 131.6, 130.0, 129.2, 127.2, 122.5, 51.6, 34.6, 34.4, 34.2,33.1, 32.9, 32.7, 26.1; HRMS (ESI) m / z calcd for C 11 H 11 D2BrO2Na + [M+Na] + :281.0117, found 281.0127.

[0106] Example 10

[0107] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0108]

[0109] Methyl 4-(4-Bromophenyl)butanoate-2,4-d2 (2j). 21 mg, colorless oil; α-deuterium content: 99%; γ-deuterium content: 99%; yield: 41%; 1 H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.4Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 3.66 (s, 3H), 2.62 – 2.55 (m, 1H), 2.34 –2.24 (m, 1H), 1.91 (t, J = 7.5 Hz, 2H); 13 C{ 1H} NMR (101 MHz, CDCl3) δ 173.8,140.3, 131.4, 130.2, 119.7, 77.2, 51.5, 34.3, 34.1, 33.9, 33.1, 32.9, 32.7,26.1; HRMS (ESI) m / z calcd for C 11 H 12 D2BrO2 + [M+H] + : 259.0297, found 259.0304.

[0110] Example 11

[0111] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0112]

[0113] Methyl 4-(3-chlorophenyl)butanoate-2,4-d2 (2k). 37 mg, colorless oil; α-deuterium content: 99%; γ-deuterium content: 99%; yield: 52%; 1 H NMR (400 MHz, CDCl3) δ 7.25 – 7.13(m, 3H), 7.05 (dt, J = 7.2, 1.7 Hz, 1H), 3.67 (s, 3H), 2.64 – 2.57 (m, 1H),2.38 – 2.25 (m, 1H), 1.93 (t, J = 7.5 Hz, 2H); 13 C{ 1 H} NMR (101 MHz, CDCl3) δ173.7, 143.3, 134.1, 129.6, 128.5, 126.6, 126.2, 77.2, 51.5, 34.5, 34.3,34.1, 33.1, 32.9, 32.7, 26.0; HRMS (ESI) m / z calcd for C 11 H 11 D2ClO2Na + [M+Na] + :237.0622, found 237.0626.

[0114] Example 12

[0115] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0116]

[0117] Methyl 4-(4-Chlorophenyl)butanoate-2,4-d2 (2l). 49 mg, colorless oil; α-deuterium content: 99%; γ-deuterium content: 99%; yield: 69%; 1 H NMR (400 MHz, CDCl3) δ 7.24 (dd, J =8.5, 2.0 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 3.65 (s, 3H), 2.61 – 2.56 (m,1H), 2.33 – 2.26 (m, 1H), 1.91 (t, J = 7.4 Hz, 2H); 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 173.8, 139.7, 131.7, 129.8, 128.5, 51.5, 34.2, 34.0, 33.8, 33.1,32.9, 32.7, 26.2; HRMS (ESI) m / z calcd for C 11 H 12 D2ClO2 + [M+H] + : 215.0802, found215.0802.

[0118] Example 13

[0119] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0120]

[0121] Methyl 4-(2,4-Dichlorophenyl)butanoate-2,4-d2 (2m). 25 mg, colorless oil; α-deuterium content: 99%; γ-deuterium content: 99%; yield: 27%; 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J= 2.0 Hz, 1H), 7.22 – 7.11 (m, 2H), 3.67 (s, 3H), 2.71 (tt, J = 7.6, 1.8 Hz, 1H), 2.41 – 2.29 (m, 1H), 1.92 (t, J = 7.5 Hz, 2H); 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 173.6, 137.5, 134.6, 132.4, 131.2, 129.3, 127.0, 77.2, 51.6, 33.1,32.9, 32.7, 32.0, 31.8, 31.6, 24.5; HRMS (ESI) m / z calcd for C 11 H 11 D2Cl2O2 + [M+H] + : 249.0413, found 249.0416.

[0122] Example 14

[0123] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0124]

[0125] Methyl 4-(4-Fluorophenyl)butanoate-2,4-d2 (2n). 47 mg, colorless oil; α-deuterium content: 99%; γ-deuterium content: 99%; yield: 58%; 1 H NMR (400 MHz, CDCl3) δ 7.21 – 7.08(m, 2H), 7.02 – 6.91 (m, 2H), 3.66 (s, 3H), 2.64 – 2.57 (m, 1H), 2.34 – 2.27(m, 1H), 1.91 (t, J = 7.4 Hz, 2H); 13 C{ 1H} NMR (101 MHz, CDCl3) δ 173.9,162.5, 160.1, 136.9, 129.8, 129.7, 115.2, 115.0, 51.5, 34.0, 33.9, 33.7,33.2, 33.1, 32.9, 32.7, 26.4; HRMS (ESI) m / z calcd for C 11 H 12 D2FO2 + [M+H] + :199.1098, found 199.1096.

[0126] Example 15

[0127] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0128]

[0129] Ethyl 4-(3,4-Difluorophenyl)butanoate-2,4-d2 (2o). 95 mg, colorless oil; α-deuterium content: 99%; γ-deuterium content: 99%; yield: 75%; 1 H NMR (400 MHz, CDCl3) δ 7.10 – 6.93(m, 2H), 6.92 – 6.82 (m, 1H), 4.12 (q, J = 7.1 Hz, 2H), 2.59 (tt, J = 7.6,2.1 Hz, 1H), 2.34 – 2.26 (m, 1H), 1.90 (t, J = 7.2 Hz, 2H), 1.25 (t, J = 7.2Hz, 3H); 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 173.2, 151.4, 151.3, 150.1, 150.0,149.0, 148.8, 147.6, 147.5, 138.4, 138.3, 138.3, 124.2, 124.2, 124.1, 117.2,117.0, 116.9, 60.3, 34.0, 33.8, 33.7, 33.2, 33.0, 32.8, 26.2, 26.1, 14.2;HRMS (ESI) m / z calcd for C 12 H 12D2F2O2Na + [M+Na] + : 253.0980, found 253.0983.

[0130] Example 16

[0131] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0132]

[0133] Methyl 4-(4-(Trifluoromethyl)phenyl)butanoate-2,4-d2 (2p). 28 mg, colorless oil; α-deuterium content: 99%; γ-deuterium content: 99%; yield: 37%; 1 H NMR (400 MHz, CDCl3) δ 7.54(d, J = 7.5 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 3.67 (s, 3H), 2.72 – 2.66 (m,1H), 2.37 – 2.28 (m, 1H), 1.96 (t, J = 7.5 Hz, 2H); 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 173.7, 145.5, 128.8, 125.5, 125.3, 125.3, 77.2, 51.6, 34.7, 34.5,34.3, 33.1, 32.9, 32.7, 26.0; HRMS (ESI) m / z calcd for C 12 H 11 D2F3O2Na + [M+Na] + :271.0885, found 271.0886.

[0134] Example 17

[0135] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0136]

[0137] Ethyl 4-Phenylbutanoate-2,4-d2 (2q). 30 mg, colorless oil; α-deuterium content: 99%; γ-deuterium content: 99%; yield: 44%; 1 H NMR (400 MHz, CDCl3) δ 7.25 – 7.17 (m, 2H), 7.17– 7.08 (m, 3H), 4.05 (q, J = 7.1 Hz, 2H), 2.62 – 2.52 (m, 1H), 2.27 – 2.19(m, 1H), 1.88 (t, J = 7.5 Hz, 2H), 1.18 (t, J = 7.1 Hz, 3H); 13 C{ 1 H} NMR (101MHz, CDCl3) δ 173.5, 141.4, 128.5, 128.3, 125.9, 77.2, 60.2, 34.9, 34.71,34.5, 33.5, 33.3, 33.1, 26.4, 26.4, 14.2; HRMS (ESI) m / z calcd for C 12 H 14 D2O2Na + [M+Na] + : 217.1168, found 217.1178.

[0138] Example 18

[0139] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0140]

[0141] tert-Butyl 4-Phenylbutanoate-2,4-d2 (2r). 96 mg, colorless oil; α-deuterium content: 99%; γ-deuterium content: 99%; yield: 90%; 1 H NMR (400 MHz, CDCl3) δ 7.33 – 7.24 (m, 3H),7.19 (d, J = 7.4 Hz, 3H), 2.63 (t, J = 7.1 Hz, 1H), 2.22 (t, J = 8.0 Hz, 1H), 1.90 (t, J = 7.5 Hz, 2H), 1.46 (s, 9H); 13 C{ 1H} NMR (101 MHz, CDCl3) δ 172.9,141.6, 128.5, 128.3, 125.9, 80.1, 34.9, 34.8, 34.7, 34.6, 34.5, 34.4, 28.1,26.6; HRMS (ESI) m / z calcd for C 14 H 18 D2O2Na + [M+Na] + : 245.1481, found 245.1487.

[0142] Example 19

[0143] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0144]

[0145] Phenyl 4-Phenylbutanoate-2,4-d2 & Phenyl (1R,2R)-2-Phenylcyclopropane-1-carboxylate (2s & 1s). 43 mg, colorless oil, mixed with inseparable phenyl 4-phenylbutanoate-2,4-d2 (2s) and phenyl (1R,2R)-2-phenylcyclopropane-1-carboxylate (1s), 2s:1s = 5:4 (n / n); Yield: 27% (2s); α-deuterium content (2s): 99%; γ-deuterium content (2s): 99%; 1 H NMR (400 MHz, CDCl3) δ 7.91 – 6.91 (m, 19H), 2.86 –2.69 (m, 2H), 2.68 – 2.54 (m, 1H), 2.23 – 2.16 (m, 1H), 2.11 (t, J = 7.5 Hz, 2H), 1.87 – 1.73 (m, 1H), 1.56 – 1.46 (m, 1H); 13 C{ 1H} NMR (101 MHz, CDCl3) δ170.9, 149.7, 149.6, 140.1, 138.6, 128.4, 127.5, 127.5, 127.4, 125.7, 125.2,125.0, 124.7, 120.5, 33.8, 33.6, 33.4, 32.5, 32.3, 32.1, 26.0, 25.4, 25.3,23.1, 16.7; HRMS (ESI) m / z calcd for C 16 H 14 D2O2Na + [M+Na] + : 265.1168, found265.1179.

[0146] Example 20

[0147] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0148]

[0149] Benzyl 4-Phenylbutanoate-2,4-d2 (2t). 952 mg, colorless oil; α-deuterium content: 99%; γ-deuterium content: 99%; yield: 83%; 1 H NMR (400MHz, CDCl3) δ 7.26 – 7.20 (m, 4H), 7.19 – 7.14 (m, 2H), 7.13 – 7.02 (m, 3H), 5.00 (s, 2H), 2.52 (t, J = 7.5 Hz,1H), 2.31 – 2.21 (m, 1H), 1.86 (t, J = 7.5 Hz, 2H); 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 173.3, 141.3, 136.0, 128.5, 128.5, 128.4, 128.2, 126.0, 66.1, 34.9,34.7, 34.5, 33.5, 33.3, 33.1, 26.3; HRMS (ESI) m / z calcd for C 17 H 16 D2O2Na + [M+Na] +: 279.1325, found 279.1331.

[0150] Example 21

[0151] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0152]

[0153] Methyl 4-(Naphthalen-2-yl)butanoate-2,4-d2 (2u). 15 mg, colorless oil; α-deuterium content: 99%; γ-deuterium content: 99%; yield: 22%; 1 H NMR (400 MHz, CDCl3) δ 7.85 – 7.74(m, 3H), 7.62 (s, 1H), 7.45 (pd, J = 6.8, 1.6 Hz, 2H), 7.34 (dd, J = 8.4, 1.8Hz, 1H), 3.67 (s, 3H), 2.85 – 2.77 (m, 1H), 2.42 – 2.31 (m, 1H), 2.05 (t, J =7.5 Hz, 2H); 13 C{ 1 H} NMR (101 MHz, DMSO-d6) δ 174.0, 138.8, 133.5, 132.0,128.0, 127.6, 127.4, 127.2, 126.6, 125.9, 125.2, 77.2, 51.5, 35.0, 34.8,34.6, 33.2, 33.0, 32.8, 26.2; HRMS (ESI) m / z calcd for C 15 H 14 D2O2Na + [M+Na] + :253.1168, found 253.1171.

[0154] Example 22

[0155] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0156]

[0157] Methyl 4-(6-Methoxynaphthalen-2-yl)butanoate-2,4-d2 (2v). 7 mg, colorless oil; α-deuterium content: 99%; γ-deuterium content: 99%; yield: 14%; 1 H NMR (400 MHz, CDCl3) δ 7.67(d, J = 8.4 Hz, 2H), 7.54 (s, 1H), 7.29 (dd, J = 8.4, 1.8 Hz, 2H), 7.12 (d, J= 8.7 Hz, 2H), 3.91 (s, 3H), 3.66 (s, 3H), 2.76 (t, J = 7.6 Hz, 1H), 2.44 –2.28 (m, 1H), 2.02 (t, J = 7.5 Hz, 2H); 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 174.0,157.2, 136.5, 133.1, 129.0, 128.9, 127.7, 126.8, 126.4, 118.7, 105.6, 55.3,51.5, 34.8, 34.7, 34.5, 33.2, 33.0, 32.9, 26.3; HRMS (ESI) m / z calcd forC 16 H 16 D2O3Na + [M+Na] + : 283.1274, found 283.1280.

[0158] 4-(6-Methoxynaphthalen-2-yl)butan-1,1,2,4-d4-1-ol (3v). 33 mg as colorless oil; α-deuterium content: 99%; β-deuterium content: 99%; δ-deuterium content: 99%; yield: 46%; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.4 Hz, 2H), 7.50 (s, 1H), 7.30 – 7.23(m, 1H), 7.08 (d, J = 11.0 Hz, 2H), 5.25 (s, 5H), 3.87 (s, 3H), 3.74 (q, J =2.0 Hz, 1H), 2.71 (t, J = 7.9 Hz, 1H), 1.71 (t, J = 7.3 Hz, 2H), 1.54 (d, J =8.1 Hz, 1H); 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 157.0, 137.4, 132.9, 129.0, 128.8,127.7, 126.6, 126.2, 118.6, 105.6, 62.1, 55.2, 35.3, 35.1, 34.9, 31.8, 31.6,31.4, 27.2; HRMS (ESI) m / z calcd for C 15 H 14 D4O2Na + [M+Na] + : 257.1450, found257.1456.

[0159] Example 23

[0160] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0161]

[0162] Methyl 4-(Furan-2-yl)butanoate-2,4-d2 (2w). 19 mg, colorless oil; α-deuterium content: 99%; γ-deuterium content: 99%; yield: 27%; 1H NMR (400 MHz, DMSO-d6) δ 7.50 (dd, J =1.9, 0.9 Hz, 1H), 6.34 (dd, J = 3.2, 1.9 Hz, 1H), 6.09 (d, J = 3.2 Hz, 1H), 3.58 (s, 3H), 2.60 (q, J = 7.5 Hz, 1H), 2.32 (q, J = 7.4 Hz, 1H), 1.81 (t, J= 7.3 Hz, 2H); 13 C{ 1 H} NMR (101 MHz, DMSO-d6) δ 173.0, 154.8, 141.4, 110.3,105.4, 51.3, 32.4, 32.2, 32.0, 26.4, 26.2, 26.0, 22.9; HRMS (ESI) m / z calcdfor C9H 11 D2O3 + [M+H] + : 171.0985, found 171.0982.

[0163] Example 24

[0164] The specific implementation method is consistent with the reaction conditions 2 of Example 1, and the As ester substrate.

[0165]

[0166] Methyl 4-(1-Methyl-1H-indol-4-yl)butanoate-2,4-d2 (2x). 17 mg, colorless oil; α-deuterium content: 99%; γ-deuterium content: 99%; yield: 21%; 1 H NMR (400 MHz, CDCl3) δ 7.14 –7.04 (m, 2H), 6.95 (d, J = 3.1 Hz, 1H), 6.82 (d, J = 6.8 Hz, 1H), 6.43 (d, J= 3.1 Hz, 1H), 3.69 (s, 4H), 3.57 (s, 3H), 2.83 (t, J = 7.5 Hz, 1H), 2.26 (t,J = 7.4 Hz, 1H), 1.98 (t, J = 7.5 Hz, 2H); 13 C{ 1H} NMR (101 MHz, CDCl3) δ174.1, 136.6, 133.6, 128.3, 121.6, 118.8, 116.4, 107.3, 99.2, 77.2, 51.4,33.5, 33.3, 33.1, 32.9, 32.4, 32.2, 32.0, 25.5; HRMS (ESI) m / z calcd forC 14 H 15 D2NO2Na + [M+Na] + : 256.1277, found 256.1285.

[0167] Example 25

[0168] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0169]

[0170] Methyl (E)-4-(4-Styrylphenyl)butanoate-2,4-d2 (2y). 25 mg, colorless oil; α-deuterium content: 99%; γ-deuterium content: 99%; yield: 39%; 1 H NMR (400 MHz, CDCl3) δ 7.28 – 7.20(m, 2H), 7.20 – 7.11 (m, 3H), 7.11 – 7.02 (m, 4H), 3.62 (s, 3H), 2.83 (s,2H), 2.56 (t, J = 7.5 Hz, 1H), 2.33 – 2.22 (m, 1H), 1.89 (t, J = 7.5 Hz, 2H); 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 174.1, 141.1, 137.6, 135.3, 129.0, 128.8,128.6, 128.6, 128.5, 128.1, 127.6, 126.7, 126.6, 126.0, 51.7, 34.8, 34.6,34.4, 33.3, 33.2, 33.0, 26.4; HRMS (ESI) m / z calcd for C 19 H 18 D2O2Na + [M+Na]+ :305.1481, found 305.1488.

[0171] Methyl 4-(4-(2-Phenylethyl-1,2-d2)Phenyl)butanoate-2,4-d2 (2y'). 12 mg, colorless oil; α-position deuterium content: 99%; β-position deuterium content: 99%; δ-position deuterium content: 99%; yield: 15%; 1 HNMR (400 MHz, CDCl3) δ 7.28 – 7.20 (m, 2H), 7.20 – 7.11 (m, 3H), 7.11 – 7.02(m, 4H), 3.62 (s, 3H), 2.83 (s, 2H), 2.56 (t, J = 7.5 Hz, 1H), 2.33 – 2.22(m, 1H), 1.89 (t, J = 7.5 Hz, 2H); 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 174.0,141.8, 139.4, 138.8, 128.4, 128.3, 125.9, 51.5, 37.7, 37.5, 37.3, 37.3, 37.1,36.9, 34.5, 34.3, 34.1, 33.3, 33.1, 32.9, 26.4; HRMS (ESI) m / z calcd forC 19 H 18 D4O2Na + [M+Na] + : 309.1763, found 309.1773.

[0172] Example 26

[0173] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0174]

[0175] Diethyl 2-(2-Phenylethyl-2-d)malonate-d2 (2z). 30 mg, colorless oil; α-position deuterium content: 99%; γ-position deuterium content: 99%; yield: 30%; 1H NMR (400 MHz, CDCl3) δ 7.26 – 7.21 (m,2H), 7.19 – 7.11 (m, 3H), 4.15 (qd, J = 7.2, 1.2 Hz, 4H), 2.61 (t, J = 7.5Hz, 1H), 2.16 (d, J = 7.4 Hz, 2H), 1.22 (t, J = 7.2 Hz, 6H); 13 C{ 1 H} NMR (101MHz, CDCl3) δ 169.3, 140.6, 128.5, 128.4, 126.1, 61.3, 51.2, 50.7, 33.1,32.9, 32.7, 30.1, 14.0; HRMS (ESI) m / z calcd for C 15 H 18 D2O4Na + [M+Na] + :289.1379, found 289.1378.

[0176] Example 27

[0177] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0178]

[0179] PFP is the abbreviation of pentafluorobenzene. Due to the strong electron-withdrawing effect of the five fluorine atoms on the benzene ring, the chemical reaction performance of this type of ester is abnormal. Under the current conditions, no ring opening of cyclopropane was observed.

[0180] It can be seen from the above examples that the nature of the connected group will affect whether the cyclopropane ring is opened.

[0181] (-)-trans-2-phenylcyclopropanemethanol-d2 (2aa'). 11 mg colorless oil; α-position deuterium content: 99%; yield: 32%; 1H NMR (400 MHz, CDCl3) δ 7.24 (t, J = 6.6 Hz, 2H),7.17 – 7.11 (m, 1H), 7.05 (d, J = 7.6 Hz, 2H), 1.80 (dt, J = 10.4, 5.0 Hz,1H), 1.42 (q, J = 6.2 Hz, 1H), 0.93 (dddt, J = 14.9, 10.6, 7.2, 3.5 Hz, 2H); 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 142.55, 128.48, 125.95, 125.78, 65.96, 31.57,30.32, 25.26, 21.36, 13.92, 1.16.

[0182] Example 28

[0183] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0184]

[0185] 4-Phenylbutan-1,1,2,4-d4-1-ol (3a). 33 mg colorless oil; α-deuterium content: 99%; β-deuterium content: 99%; δ-deuterium content: 99%; yield: 46%; 1 H NMR (400 MHz, CDCl3) δ 7.33 –7.24 (m, 2H), 7.23 – 7.15 (m, 3H), 2.71 – 2.59 (m, 1H), 1.69 (t, J = 7.8 Hz,2H), 1.58 (t, J = 7.8 Hz, 1H); 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 142.3, 128.4,128.3, 125.7, 62.0, 35.4, 35.2, 35.0, 31.8, 31.6, 31.5, 27.3; HRMS (ESI) m / zcalcd for C 10 H 10 D4ONa + [M+Na] + : 177.1188, found 177.1193.

[0186] Example 29

[0187] The specific implementation method is consistent with the reaction conditions 1 of Example 1, and the As ester substrate.

[0188]

[0189] (1R,2R)-2-Phenylcyclopropane-1-carboxamide & 4-Phenylbutanamide-2,4-d2 (1ac & 2ac). 31 mg, white solid, was unable to be separated mixture of (1R,2R)-2-phenylcyclopropane-1-carboxamide (1ac) and 4-phenylbutanamide-2,4-d2 (2ac), 1ac:2ac = 25:7 (n / n); Yield: 34% (2ac); Deuterium content at the α-position (2ac): 99%; Deuterium content at the γ-position (2ac): 99%; Deuterium content at the α-position: 99%; Deuterium content at the β-position: 99%; Deuterium content at the δ-position: 99%; 1 H NMR (400 MHz, CDCl3) δ 7.25 – 7.20 (m, 2H), 7.18 – 7.11 (m, 3H), 5.95 (s, 1H), 5.52 (s,1H), 2.61 (tt, J = 7.5, 2.1 Hz, 1H), 2.18 – 2.11 (m, 1H), 1.91 (t, J = 7.5Hz, 2H); 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 175.4, 174.6, 141.3, 140.5, 128.4,128.4, 126.3, 126.0, 125.9, 35.0, 34.9, 34.8, 34.6, 34.4, 26.7, 26.7, 25.8,25.5, 16.2; HRMS (ESI) m / z calcd for C 10 H 12 D2O + [M+H] + : 166.1195, found166.1201.

[0190] Example 30

[0191] Specific implementation method: Reaction condition 1 is consistent with that of Example 1, and different types of organic solvents, nitrogen-containing basic compounds, and different equivalents of organic solvents, nitrogen-containing basic compounds and deuterium sources are used, as shown in Table 1.

[0192] Table 1: Reaction results of different types of organic solvents, nitrogen-containing basic compounds, and different equivalents of organic solvents, nitrogen-containing basic compounds, and deuterium sources

[0193]

[0194] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A samarium diiodide-mediated cyclopropane ring-opening deuteration method, characterized in that: The steps include: Step 1: dissolving samarium diiodide in an organic solvent to prepare a samarium diiodide solution; Step 2: adding a deuterium source and a nitrogen-containing alkaline compound to the samarium diiodide solution in sequence to obtain a mixed solution; Step 3: Add the ester substrate to the mixture, stir to react, and then introduce air to oxidize excess samarium; Step 4: Then add dichloromethane and hydrochloric acid in sequence, dilute, separate the layers, and extract the aqueous layer with the extract; Step 5: The remaining organic layers are combined, dried, filtered, and then distilled under reduced pressure, and the residue is purified to obtain α,γ-bis-deuterated ester; Wherein, the ester substrate is The α,γ-bis-deuterated ester is The deuterium source is heavy water.

2. The samarium diiodide-mediated cyclopropane ring-opening deuteration method according to claim 1, characterized in that: The organic solvent is any one or more of hexamethylphosphoric triamide, tetrahydrofuran or 1,4-dioxane; The nitrogen basic compound is any one or more of morpholine and triethylamine.

3. The samarium diiodide-mediated cyclopropane ring-opening deuteration method according to claim 1, characterized in that: The molar ratio of the samarium diiodide: nitrogen basic compound: deuterium source is (4:24:24)-(11:66:66).

4. The samarium diiodide-mediated cyclopropane ring-opening deuteration method according to any one of claims 2 to 3, characterized in that: The molar ratio of samarium diiodide: triethylamine: heavy water is (4:24:24)-(11:66:66).

5. An α,γ-bis-deuterated ester prepared by the samarium diiodide-mediated cyclopropane ring-opening deuteration method according to claim 4, specifically:

6. Use of the samarium diiodide-mediated cyclopropane ring-opening deuteration method according to any one of claims 1 to 5 in a reaction for synthesizing a deuterium-labeled compound.

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