Samarium diiodide-mediated cyclopropane ring-opening deuteration method and application

Abstract

The invention provides a samarium diiodide-mediated cyclopropane open-loop deuteration method and application. The method comprises the following steps: preparing a samarium diiodide solution; sequentially adding a nitrogen-containing alkaline compound and a deuterium source into the solution; then adding an ester substrate, stirring and reacting, and blowing air to oxidize excessive samarium; sequentially adding dichloromethane and hydrochloric acid, diluting, separating liquid, and extracting a water layer by using an extracting solution; and combining the residual organic layers, drying, filtering, carrying out reduced pressure distillation, and purifying the residues. According to the method, cheap heavy water is used as a deuterium donor, and SmI2-promoted cyclopropane ring opening and carboxylic acid derivative reduction are combined to realize deuteration reactions at multiple positions. Besides, the SmI2 / D2O system shows significantly wider substrate universality, and deuterium can be efficiently introduced into various substrates including ketone, ester, nitrile, acyl chloride, acyl fluoride, oxime and the like by adjusting the dosage of reagents to form different cyclopropane ring opening series reduction deuteration strategies.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and more particularly to a method for ring-opening deuteration of cyclopropanes mediated by samarium diiodide and its applications. Background Art

[0002] Samarium diiodide (SmI2), as a versatile reagent, has demonstrated remarkable synthetic utility and has been widely used in classical reaction systems as well as total syntheses of natural products. Its unexpected reaction characteristics, combined with significant chemoselectivity, have been systematically verified in various transformation reactions, making this lanthanide-based reagent a key tool in modern synthetic methodology. In the past three decades, the reduction reactions of ketones (aldehydes), carboxylic acids, and carboxylic acid derivatives mediated by SmI2 have been extensively studied. In addition, some comprehensive explanations of the reduction reaction mechanisms have also been reported. The expanding applications of deuterium-labeled compounds in fields such as biomedicine, materials engineering, environmental monitoring, and food safety have promoted the improvement of deuteration methodology.

[0003] Samarium diiodide (SmI2) has been demonstrated to be a mediator for carbon-carbon bond cleavage, especially in regioselective ring-opening reactions of three- and four-membered carbon rings. Early examples in the 1990s showed that SmI2 could mediate the radical ring-opening reactions of cyclopropyl ketones and esters, using cyclohexane / pentane-fused cyclopropanes or cyclopropanes with electron-withdrawing groups to facilitate activation. However, the tandem reaction involving ring-opening of cyclopropanes and reduction of esters (or ketones) has not been elucidated until Procter reported this process in 2014. In their mechanistic studies, it was found that the SmI2 / amine / H2O system could sequentially achieve ring-opening of cyclopropanes and reduction of esters or amides on the ring. It is worth noting that although there are some scattered examples of SmI2-mediated ring-opening deuterium labeling in previous mechanistic studies, these protocols rely on unconventional deuterium sources (such as tert-butanol-d (t-BuOD), isopropanol-d (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 an urgent need to develop a more substrate-general reaction system.

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

[0005] The first object of the present invention is to provide a samarium diiodide-mediated cyclopropane ring-opening deuteration method, which uses commercially available heavy water (D2O) as a deuterium donor, combines SmI2-promoted cyclopropane ring-opening and reduction of carboxylic acid derivatives to achieve multi-deuteration reaction, and is more practical; in some cases, a tandem reduction reaction of esters and carboxylic acids is also achieved. Secondly, the SmI2 / D2O system exhibits significantly broader substrate generality. By adjusting the dosage of reagents to form different strategies for cyclopropane ring-opening tandem reduction deuteration, deuterium can be efficiently introduced into various 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-bisdeuterated ester or α,α,β,δ-tetradeuterated alcohol prepared by the above samarium diiodide-mediated cyclopropane ring-opening deuteration method. The products synthesized regioselectively by this method have a relatively high degree of deuterium labeling.

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

[0008] To achieve the above objects of the present invention, the following technical solutions are specifically adopted:

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

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

[0011] Step 2: Sequentially add a deuterium source and a nitrogen-containing basic compound to the samarium diiodide solution to obtain a mixed solution;

[0012] Step 3: Add an ester substrate to the mixed solution, stir the reaction, and then blow air to oxidize the excess samarium;

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

[0014] Step 5: Combine the remaining organic layers, dry, filter, and then distill under reduced pressure. Purify the residue to obtain any one of α,γ-bisdeuterated esters or α,α,β,δ-tetradeuterated alcohols.

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

[0016] This reaction pathway first opens the ring and then reduces, and by regulating the reaction system of samarium diiodide, organic solvent and deuterium source, for the first time, a tandem reaction of cyclopropane ring-opening and ester / amide reduction is achieved; at the same time, the deuterium labeling efficiency can be effectively improved, and a deuterium labeling rate of >99% can be achieved.

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

[0018] wherein, R1 is any one of hydrogen, alkyl, amino or aromatic substituent;

[0019] R2 is any one or more of aromatic substituents or heterocyclic substituents.

[0020] Preferably, as a further specific embodiment, the structural formula of the ester substrate is , , , or any one of;

[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 substituent;

[0023] R5 is any one of 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, this system exhibits significantly broader substrate generality. By adjusting the dosage of reagents to form different strategies for the tandem reductive deuteration of cyclopropane ring-opening, deuterium can be efficiently introduced into various substrates including ketones, esters, nitriles, acyl chlorides, acyl fluorides, and oximes, breaking through the limitations of previous methods on the substrate structure. At the same time, the reaction system has good compatibility with sensitive groups such as halogens or trifluoromethyl groups and will not undergo dehalogenation or decomposition.

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

[0027] Using inexpensive and readily available heavy water as the deuterium source to replace traditional expensive deuterated reagents (such as deuterated tert-butanol and deuterated isopropanol) significantly reduces costs, has practical applicability, and is easy to operate.

[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 nitrogenous basic compound is any one or more of morpholine or triethylamine;

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

[0032] In the present invention, tetrahydrofuran is preferably used as the organic solvent. Tetrahydrofuran has greater polarity and better miscibility with heavy water, making the SmI2–Et3N–D2O complex more stable and facilitating the subsequent reaction. 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: nitrogenous basic compound: deuterium source is (4:24:24) - (11:66:66);

[0034] Preferably, the molar ratio of samarium diiodide: nitrogenous 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 dosages of samarium diiodide: nitrogenous basic compound: deuterium source.

[0038] The present invention also provides α,γ-dideuterated esters, α,α,β,δ-tetradeuterated alcohols, α,γ-dideuterated amines, α,α-cyclopropane dideuterated amines or α,α-cyclopropane dideuterated alcohols prepared by the above-mentioned samarium diiodide-mediated regioselective deuteration method for the reduction of cyclopropanes to open rings, specifically: , , , , , , , , , , , , , , , , , , , , , , , , , , or any one of them.

[0039] The present invention also provides the application of the above-mentioned samarium diiodide-mediated regioselective deuteration method for the reduction of cyclopropanes to open rings in the reaction for the synthesis of deuterium-labeled compounds;

[0040] Preferably, the application of the reaction system composed of samarium diiodide - nitrogen-containing basic compound - deuterium source in the reaction for the synthesis of deuterium-labeled compounds;

[0041] Preferably, the application of the reaction system composed of samarium diiodide - triethylamine - heavy water in the reaction for the synthesis of deuterium-labeled compounds;

[0042] Preferably, the reaction for the synthesis of deuterium-labeled compounds is a regioselective deuteration reaction for the reduction of cyclopropanes to open rings;

[0043] Preferably, the application of the reaction system composed of samarium diiodide - triethylamine - heavy water in the regioselective deuteration reaction for the reduction of cyclopropanes to open rings.

[0044] Compared with the prior art, the beneficial effects of the present invention are as follows:

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

[0046] (2) The tandem reaction of cyclopropane ring opening and ester / amide reduction was realized for the first time by regulating the SmI2 / Et3N / D2O system, making the reaction controllable, reducing the occurrence of side reactions, and significantly improving the purity of the product. In addition, the deuteration sites were precisely controlled to synthesize α,γ-dideuterated esters and α,α,β,δ-tetradeuterated 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 carboxylic acid esters, amides, haloarenes, and heterocycles (furan, indole), breaking through the limitations of the substrate structure in previous methods. At the same time, it has good compatibility with sensitive groups and does not undergo dehalogenation or decomposition.

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

[0049] Figure 1 : 1H NMR spectrum of the product generated in Example 1 under Reaction Condition 1;

[0050] Figure 2 : 13C NMR spectrum of the product generated in Example 1 under Reaction Condition 1;

[0051] Figure 3 : Mass spectrum of the product generated in Example 1 under Reaction Condition 1;

[0052] Figure 4 : 1H NMR spectrum of the product generated in Example 26;

[0053] Figure 5 : 13C NMR spectrum of the product generated in Example 26;

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

[0055] Figure 7 : 1H NMR spectrum of the product generated in Example 29;

[0056] Figure 8 : 13C NMR spectrum of the product generated in Example 29;

[0057] Figure 9: Those generated in Example 29 mass spectrometry (MS) spectrum;

[0058] Figure 10 : Those generated in Example 22 1H nuclear magnetic resonance (1H NMR) spectrum;

[0059] Figure 11 : Those generated in Example 22 13C nuclear magnetic resonance (13C NMR) spectrum;

[0060] Figure 12 : Those generated in Example 22 mass spectrometry (MS) spectrum;

[0061] Figure 13 : Those generated in Example 25 1H nuclear magnetic resonance (1H NMR) spectrum;

[0062] Figure 14 : Those generated in Example 25 13C nuclear magnetic resonance (13C NMR) spectrum;

[0063] Figure 15 : Those generated in Example 25 mass spectrometry (MS) spectrum. Detailed Description of the Invention

[0064] The technical solutions of the present invention will be clearly and completely described below in conjunction with the specific embodiments. However, those skilled in the art will understand that the following described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments, and are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts fall within the scope of protection of the present invention. Those conditions not specified in the examples are carried out according to conventional conditions or conditions recommended by the manufacturer. Those reagents or instruments not specified by the manufacturer can be obtained as conventional products through commercial purchase.

[0065] Example 1

[0066] Reaction Condition 1:

[0067] Place a dried reaction flask equipped with a magnetic stir bar in a positive nitrogen pressure environment and perform three cycles of high vacuum evacuation / backfilling with nitrogen to completely remove the air inside the flask. Add a 0.10 M SmI2 solution (4.0 eq.) prepared in tetrahydrofuran (THF) to the reaction flask, and then sequentially add D2O (24 eq.) and Et3N (24 eq.) under vigorous stirring. At this time, a characteristic dark brown color of the SmI2–Et3N–D2O complex will form in the solution. Select the ester substrate (1.0 eq., in a solution of 1.0 mL of THF) was added to the above solution, and the mixture was stirred for reaction. The excess Sm(II) was oxidized by bubbling air into the reaction mixture. Subsequently, dichloromethane (30 mL) and 1 N hydrochloric acid (30 mL) were successively added to dilute the reaction solution. After liquid 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 condition 2:

[0070] The specific operation steps and methods were the same as those of Reaction condition 1, only changing the equivalents among samarium diiodide, triethylamine, and heavy water, specifically: SmI2 (8.0 eq.), D2O (48.0 eq.), and Et3N (48.0 eq.). At this time, the products and .

[0071]

[0072] Methyl 4-Phenylbutanoate-2,4-d2 (2a), colorless oil, 52 mg; deuterium content at the α position: 99%; deuterium content at the γ position: 99%; yield: 82%. 1 1H 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 13C{ 1 1H} 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 11 12 D2O2Na + [M+Na] + : 203.1012, found 203.1014.

[0073] 4-Phenylbutan-1,1,2,4-d4-1-ol (3a). 33 mg, colorless oil; deuterium content at α-position: 99%; deuterium content at γ-position: 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 = 7.8 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 / z calcd for C 10 H 10 D4ONa + [M+Na] + : 177.1188, found 177.1193.

[0074] Example 2

[0075] The specific implementation method is the same as that of Reaction Condition 1 in Example 1, and is selected as the ester substrate.

[0076]

[0077] Methyl 4-(p-tolyl)Butanoate-2,4-d2 (2b). 35 mg, colorless oil; deuterium content at α-position: 99%; deuterium content at γ-position: 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{ 11H 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 Reaction Condition 1 of Example 1, and is selected as the ester substrate.

[0080]

[0081] Methyl 4-(m-tolyl)Butanoate-2,4-d2 (2c). 43mg, colorless oil; Deuterium content at α position: 99%; Deuterium content at γ position: 99%; Yield: 53%; 1 1H 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 1H} 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, found 217.1176.

[0082] Example 4

[0083] The specific implementation method is the same as that of Reaction Condition 1 in Example 1, and is selected as the ester substrate.

[0084]

[0085] Methyl 4-(3,4-Dimethylphenyl)butanoate-2,4-d2 (2d). 35 mg, colorless oil; deuterium content at the α position: 99%; deuterium content at the γ position: 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 the same as that of Reaction Condition 1 in Example 1, and is selected as the ester substrate.

[0088]

[0089] Methyl 4-([1,1'-Biphenyl]-4-yl)butanoate-2,4-d2 (2e). 37 mg, colorless oil; deuterium content at the α position: 99%; deuterium content at the γ position: 99%; yield: 48%; 11H 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 1H} 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 1H 16 D2O2Na + [M+Na] + : 279.1325, found 279.1334.

[0090] Example 6

[0091] The specific implementation method is consistent with Reaction Condition 1 of Example 1, and is selected as the ester substrate.

[0092]

[0093] Methyl 4-(4-Methoxyphenyl)butanoate-2,4-d2 (2f). 24 mg, colorless oil; Deuterium content at the α position: 99%; Deuterium content at the γ position: 99%; Yield: 48%; 1 1H 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{ 11H 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 calcd for C 12 H 14 D2O3Na + [M+Na] + : 233.1117, found 233.1125.

[0094] Example 7

[0095] The specific implementation manner is consistent with Reaction Condition 1 of Example 1, and is selected as the ester substrate.

[0096]

[0097] Methyl 4-(4-(Benzyloxy)phenyl)butanoate-2,4-d2 (2g). 35 mg, colorless oil; Deuterium content at the α position: 99%; Deuterium content at the γ position: 99%; Yield: 26%; 1 1H-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 13C{ 1 1H} 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 the same as that of Reaction Condition 1 in Example 1, and is selected as the ester substrate.

[0100]

[0101] Methyl 4-(2-Bromophenyl)butanoate-2,4-d2 (2h). 48 mg, colorless oil; deuterium content at the α position: 99%; deuterium content at the γ position: 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 the same as that of Reaction Condition 1 in Example 1, and is selected as the ester substrate.

[0104]

[0105] Methyl 4-(3-Bromophenyl)butanoate-2,4-d2 (2i). 40 mg, colorless oil; deuterium content at the α position: 99%; deuterium content at the γ position: 99%; yield: 35%; 11H 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 1H} 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 1H 11 D2BrO2Na + [M+Na] + :281.0117, found 281.0127.

[0106] Example 10

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

[0108]

[0109] Methyl 4-(4-Bromophenyl)butanoate-2,4-d2 (2j). 21 mg, colorless oil; deuterium content at α position: 99%; deuterium content at γ position: 99%; yield: 41%; 1 1H 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{ 11H 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 condition 1 of Example 1, and is selected as the ester substrate.

[0112]

[0113] Methyl 4-(3-Chlorophenyl)butanoate-2,4-d2 (2k). 37 mg, colorless oil; deuterium content at the α position: 99%; deuterium content at the γ position: 99%; yield: 52%; 1 1H 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 1H} 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 is selected as the ester substrate.

[0116]

[0117] Methyl 4-(4-Chlorophenyl)butanoate-2,4-d2 (2l). 49 mg, colorless oil; deuterium content at the α position: 99%; deuterium content at the γ position: 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 is selected as the ester substrate.

[0120]

[0121] Methyl 4-(2,4-Dichlorophenyl)butanoate-2,4-d2 (2m). 25 mg, colorless oil; deuterium content at the α position: 99%; deuterium content at the γ position: 99%; yield: 27%; 11H 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 13C{ 1 1H} 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 1H 11 D2Cl2O2 + [M+H] + : 249.0413, found 249.0416.

[0122] Example 14

[0123] The specific implementation manner is the same as that of Reaction Condition 1 in Example 1, and is selected as the ester substrate.

[0124]

[0125] Methyl 4-(4-Fluorophenyl)butanoate-2,4-d2 (2n). 47 mg, colorless oil; Deuterium content at the α position: 99%; Deuterium content at the γ position: 99%; Yield: 58%; 1 1H 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 13C{ 11H 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 condition 1 of Example 1, and is selected as the ester substrate.

[0128]

[0129] Ethyl 4-(3,4-Difluorophenyl)butanoate-2,4-d2 (2o). 95 mg, colorless oil; deuterium content at the α position: 99%; deuterium content at the γ position: 99%; yield: 75%; 1 1H 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 = 7.2 Hz, 3H); 13 13C{ 1 1H} 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 the same as that of Reaction Condition 1 in Example 1, and is selected as the ester substrate.

[0132]

[0133] Methyl 4-(4-(Trifluoromethyl)phenyl)butanoate-2,4-d2 (2p). 28 mg, colorless oil; deuterium content at the α position: 99%; deuterium content at the γ position: 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 the same as that of Reaction Condition 1 in Example 1, and is selected as the ester substrate.

[0136]

[0137] Ethyl 4-Phenylbutanoate-2,4-d2 (2q). 30 mg, colorless oil; deuterium content at α position: 99%; deuterium content at γ position: 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 the same as that of Reaction Condition 1 in Example 1, and is selected as the ester substrate.

[0140]

[0141] tert-Butyl 4-Phenylbutanoate-2,4-d2 (2r). 96 mg, colorless oil; deuterium content at α position: 99%; deuterium content at γ position: 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{ 11H 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 the same as that of Reaction Condition 1 in Example 1, and is selected as the 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); Deuterium content at α position (2s): 99%; Deuterium content at γ position% (2s): 99%; 1 1H 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{ 11H NMR (101 MHz, CDCl3) δ 170.9, 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, found 265.1179.

[0146] Example 20

[0147] The specific implementation method is consistent with Reaction Condition 1 of Example 1, and is selected as the ester substrate.

[0148]

[0149] Benzyl 4-Phenylbutanoate-2,4-d2 (2t). 952 mg, colorless oil; deuterium content at α position: 99%; deuterium content at γ position: 99%; yield: 83%; 1 1H NMR (400 MHz, 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 1H} 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 Reaction Condition 1 of Example 1, and is selected as the ester substrate.

[0152]

[0153] Methyl 4-(Naphthalen-2-yl)butanoate-2,4-d2 (2u). 15 mg, colorless oil; deuterium content at the α position: 99%; deuterium content at the γ position: 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 Reaction Condition 1 of Example 1, and is selected as the ester substrate.

[0156]

[0157] Methyl 4-(6-Methoxynaphthalen-2-yl)butanoate-2,4-d2 (2v). 7 mg, colorless oil; deuterium content at α position: 99%; deuterium content at γ position: 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; deuterium content at α position: 99%; deuterium content at β position%: 99%; deuterium content at δ position%: 99%; yield: 46%; 11H 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, found 257.1456.

[0159] Example 23

[0160] The specific implementation manner is the same as that of Reaction Condition 1 in Example 1, and is selected as the ester substrate.

[0161]

[0162] Methyl 4-(Furan-2-yl)butanoate-2,4-d2 (2w). 19 mg, colorless oil; deuterium content at the α position: 99%; deuterium content at the γ position: 99%; yield: 27%; 11H 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 1H} 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 calcd for C9H 11 D2O3 + [M+H] + : 171.0985, found 171.0982.

[0163] Example 24

[0164] The specific implementation method is the same as that of Reaction Condition 2 in Example 1, and is selected as the ester substrate.

[0165]

[0166] Methyl 4-(1-Methyl-1H-indol-4-yl)butanoate-2,4-d2 (2x). 17 mg, colorless oil; deuterium content at α position: 99%; deuterium content at γ position: 99%; yield: 21%; 1 1H 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{ 11H NMR (101 MHz, CDCl3) δ 174.1, 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 for C 14 H 15 D2NO2Na + [M+Na] + : 256.1277, found 256.1285.

[0167] Example 25

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

[0169]

[0170] Methyl (E)-4-(4-Styrylphenyl)butanoate-2,4-d2 (2y). 25 mg, colorless oil; deuterium content at α position: 99%; deuterium content at γ position: 99%; yield: 39%; 1 1H 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 13C{ 1 1H} 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; Deuterium content at α position: 99%; Deuterium content at β position: 99%; Deuterium content at δ position: 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 the same as that of Reaction Condition 1 in Example 1, and is selected as the ester substrate.

[0174]

[0175] Diethyl 2-(2-Phenylethyl-2-d)malonate-d2 (2z). 30 mg, colorless oil; Deuterium content at α position: 99%; Deuterium content at γ position: 99%; Yield: 30%; 11H 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 = 7.5 Hz, 1H), 2.16 (d, J = 7.4 Hz, 2H), 1.22 (t, J = 7.2 Hz, 6H); 13 13C{ 1 1H} NMR (101 MHz, 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 13H 18 D2O4Na + [M+Na] + : 289.1379, found 289.1378.

[0176] Example 27

[0177] The specific implementation manner is consistent with Reaction Condition 1 of Example 1, and is selected as the 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 such esters is abnormal. Under the current conditions, ring-opening of the cyclopropane was not observed.

[0180] As can be seen from the above examples, the nature of the attached group will affect whether the cyclopropane undergoes ring-opening.

[0181] (-)-trans-2-phenylcyclopropanemethanol-d2 (2aa’). 11 mg colorless oil; deuterium content at the α position: 99%; yield: 32%; 11H 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 the same as that of Reaction Condition 1 in Example 1, and is selected as the ester substrate.

[0184]

[0185] 4-Phenylbutan-1,1,2,4-d4-1-ol (3a). 33 mg colorless oil; Deuterium content at α position: 99%; Deuterium content at β position: 99%; Deuterium content at δ position: 99%; Yield: 46%; 1 1H 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 / z calcd for C 10 H 10 D4ONa + [M+Na] + : 177.1188, found 177.1193.

[0186] Example 29

[0187] The specific implementation method is the same as that of Reaction Condition 1 in Example 1, and is selected as the ester substrate.

[0188]

[0189] (1R,2R)-2-Phenylcyclopropane-1-carboxamide & 4-Phenylbutanamide-2,4-d2 (1ac & 2ac). 31 mg, white solid, was a mixture of (1R,2R)-2-phenylcyclopropane-1-carboxamide (1ac) and 4-phenylbutanamide-2,4-d2 (2ac) that could not be separated, 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 = 7.5 Hz, 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, found 166.1201.

[0190] Example 30

[0191] The specific implementation manner is kept consistent with the reaction condition 1 of Example 1. Different types of organic solvents, nitrogen-containing basic compounds are used respectively, and different equivalents of organic solvents, nitrogen-containing basic compounds and deuterium sources are used. The specific details are 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 them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions 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, It includes the following steps: Step 1: Dissolve samarium diiodide in an organic solvent to prepare a samarium diiodide solution; Step 2: Sequentially add a deuterium source and a nitrogen-containing basic compound to the samarium diiodide solution to obtain a mixed solution; Step 3: Add an ester substrate to the mixed solution, stir and react, and then introduce air to oxidize the excessive samarium; Step 4: Subsequently, add dichloromethane and hydrochloric acid, dilute, separate the layers, and extract the aqueous layer with an extraction solution; Step 5: Combine the remaining organic layers, dry, filter, and then distill under reduced pressure. Purify the residue to obtain any one of α,γ-dideuterated esters or α,α,β,δ-tetradeuterated alcohols.

2. The samarium diiodide-mediated cyclopropane ring-opening deuteration method according to claim 1, wherein The structural formula of the ester substrate is or any one of them; Among them, R1 is any one of hydrogen, alkyl, amino, or aromatic substituents; R2 is any one or more of aromatic substituents or heterocyclic substituents.

3. The samarium diiodide-mediated cyclopropane ring-opening deuteration method according to claim 2, wherein The structural formula of the ester substrate is , , , or any one of them; Among them, R3 is any one or more of methyl, phenyl, alkoxy, benzyloxy, styryl, N-methylpyrrolyl, halogen atoms, or haloalkyls; R4 is any one of hydrogen, alkyl, amino, or aromatic substituents; R5 is any one of hydrogen or alkoxy.

4. The samarium diiodide-mediated cyclopropane ring-opening deuteration method according to claim 3, wherein The structural formula of the ester substrate is , , , , , , , , , , , , , , , , , , , , , , , , , , , or any one of them.

5. The samarium diiodide-mediated cyclopropane ring-opening deuteration method according to claim 1, wherein The deuterium source is heavy water.

6. The samarium diiodide-mediated cyclopropane ring-opening deuteration method according to claim 1, wherein The organic solvent is any one or more of hexamethylphosphoramide, tetrahydrofuran, or 1,4-dioxane; The nitrogen-containing basic compound is any one or more of morpholine or triethylamine.

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

8. The samarium diiodide-mediated cyclopropane ring-opening deuteration method according to any one of claims 5-7, characterized in that, The molar ratio of samarium diiodide:triethylamine:heavy water is (4:24:24)-(11:66:66).

9. An α,γ-dideuterated ester, α,α,β,δ-tetradeuterated alcohol, α,γ-dideuterated amine, α,α-cyclopropanedideuterated amine or α,α-cyclopropanedideuterated alcohol prepared by the samarium diiodide-mediated cyclopropane ring-opening deuteration method as claimed in claim 8, specifically: , , , , , , , , , , , , , , , , , , , , , , , , , , or any one of them.

10. Use of the method for samarium diiodide-mediated ring-opening deuteration of cyclopropane according to any one of claims 1-7 in the reaction for the synthesis of deuterium-labeled compounds.

Images