A method for synthesizing alpha-thiocyano sulfoxide sulfene compounds
By selectively using fluorine as an oxidant to react with α-carbonyl sulfoxide ylide compounds at room temperature, the problems of complex operation and high cost in the prior art are solved, and the effect of efficiently introducing thiocyanate groups onto sulfoxide ylide compounds is achieved, which is suitable for industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- CHANGZHOU PENGSENFU BIOTECHNOLOGY CO LTD
- Filing Date
- 2026-03-11
- Publication Date
- 2026-06-12
AI Technical Summary
In the existing technology, the synthesis methods of sulfoxide ylide compounds have problems such as complicated operation, high cost, need for precious metal electrodes and unsuitability for industrial production. In particular, the method of introducing active functional groups such as thiocyanate has problems of complicated operation and high cost.
Using selective fluorine as an oxidant, it reacts with α-carbonyl sulfoxide ylide compounds at room temperature, introducing a thiocyanate group at the α-position through a simple addition reaction. This avoids the use of noble metal electrodes and strong bases, and the reaction conditions are mild, the operation is simple, and it is suitable for industrial production.
This method enables the efficient and low-cost introduction of thiocyanate groups onto sulfoxide ylide compounds, achieving high reaction conversion rates, readily available products, suitability for industrial applications, and simplified operation procedures.
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Figure CN122187702A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical and chemical synthesis technology, specifically to a method for synthesizing α-thiocyanosulfoxide ylide compounds. Background Technology
[0002] As is well known, diazo compounds are classic carbene precursors, but their applications are limited in industry due to stability and safety constraints. In recent years, sulfoxide ylides, as stable and readily available carbene precursors, have been widely used in CH activation reactions, polar bond insertion, photoinduced radical reactions, and electrochemical reactions, successfully constructing a wide variety of bioactive molecules and drug molecules. During the formation of carbenes from sulfoxide ylides with metals, dimethyl sulfoxide is released, avoiding the generation of large amounts of gas, making it an ideal carbene precursor to replace diazo compounds. Therefore, sulfoxide ylides represent a novel and very important building block in organic synthesis.
[0003] Furthermore, the thiocyanate group is a very important functional group with wide applications in the biological and chemical fields. For example, the thiocyanate group has strong coordination ability, capable of coordinating with various metal ions, and can be used for rapid qualitative and quantitative detection of heavy metals through colorimetric reactions. Simultaneously, the thiocyanate group is a versatile reaction site for chemical transformations, readily undergoing addition, substitution, cyclization, hydrolysis, and other reactions, making it a highly functional organic synthon. In biology, compounds containing the thiocyanate group are common in drug molecules, exhibiting antibacterial, antiparasitic, and antitumor activities. For example, commercially available drugs such as erlotinib, propranolol, and erythromycin thiocyanate all contain the thiocyanate group.
[0004] Against this backdrop, if an efficient method can be developed to introduce the active functional group thiocyanate into the α-position of sulfoxide ylide, the preparation of functional molecules containing thiocyanate can be promoted.
[0005] Currently, sulfoxide ylides mainly include α-carbonyl ylides, trifluoromethylimine sulfoxide ylides, and α-alkenyl sulfoxide ylides. For example, α-carbonyl ylides are mainly synthesized in tetrahydrofuran via trimethyl iodide sulfoxide and the corresponding acyl chloride, requiring a large amount of strong base. Around these substrates, numerous CH activation / cyclization reactions have been developed, successfully constructing a variety of functional molecules (…). Org. Biomol. Chem . 2023, 21, 879). In addition, Cheng Guolin's research group successfully developed trifluoromethylimine sulfoxide ylide by replacing ordinary carboxylic acid acyl chloride with imine acyl chloride. Org. Lett. 2021, 23 Based on this, the sulfoxide ylide was used as a stable and readily available trifluoromethyl synthon to efficiently construct a series of fluorinated heterocyclic molecules (7407). Chem. Commun.(2023, 59, 318). For α-alkenyl sulfoxide ylides, the main synthetic method involves nucleophilic substitution of a haloalkene with trimethyl sulfoxide under strong base conditions. However, the variety of sulfoxide ylides is still very limited, especially in terms of efficient and low-cost modification to introduce active functional groups such as thiocyanate or halogens. In 2022, Qingdao University of Science and Technology reported the electrocatalytic introduction of a thiocyanate group at the α-position of sulfoxide ylides (using a platinum electrode). This method requires the use of precious metal electrodes, is complex to operate, and electrocatalysis is widely criticized in chemical production (poor stability; expensive, easily corroded, and clogged electrodes; poor performance under high current, numerous side reactions; requires a complete system). Summary of the Invention
[0006] The purpose of this invention is to address some shortcomings in the existing technology by proposing a method for synthesizing α-thiocyano sulfoxide ylide compounds. This method is safe and simple, operates under mild conditions, does not require strong bases, light, or complex devices such as electrodes, and has a high reaction conversion rate and low cost, which is beneficial for industrial production.
[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows: A method for synthesizing α-thiocyano sulfoxide ylide compounds, comprising the following synthetic steps: In a reactor, compound 1, compound 2, an oxidant, and a suitable amount of solvent were added and reacted at room temperature for 10-20 minutes. After removing the solvent, the α-thiocyano sulfoxide ylide compounds were obtained by column chromatography purification. The reaction equation is as follows:
[0008] Compound 1 refers to a compound having the structure of formula (1): α-carbonyl sulfoxide ylide; Compound 2 refers to a compound having the structure of formula (2): thiocyanate; wherein R is phenyl, 4-methylphenyl, 4-bromophenyl; 1-naphthyl or tert-butyl; X is sodium, potassium, ammonium, iron, zinc or copper; and n is 1 or 2.
[0009]
[0010] Compound 1 refers to any one of benzoyl sulfoxide ylide, 4-methylbenzoyl sulfoxide ylide, 4-bromobenzoyl sulfoxide ylide, 1-naphthyl sulfoxide ylide, and trimethylacetyl.
[0011] Compound 2 refers to any one of sodium thiocyanate, potassium thiocyanate, ammonium thiocyanate, zinc thiocyanate, and copper thiocyanate.
[0012] Preferably, compound 2 is sodium thiocyanate.
[0013] Preferably, the molar ratio of compound 1 to compound 2 is 1:1-2. Here, the molar ratio is preferably 1:1.5.
[0014] Preferably, the solvent refers to acetonitrile, hexafluoroisopropanol, methanol, or ethanol. N , N -Dimethylformamide, N , N The solvent is any one of dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, and dioxane; the solvent-to-compound 1 ratio is 5-10 mL:1 mmol. Here, acetonitrile is preferred as the solvent; the solvent-to-compound 1 ratio is preferably 5 mL:1 mmol.
[0015] Preferably, the oxidant is any one of nitrobenzene, peroxytert-butanol, peroxybenzoic acid, and selective fluorine, and the molar ratio of the oxidant to compound 1 is 1:1-2. Here, the oxidant is preferably selective fluorine; the molar ratio of selective fluorine to compound 1 is preferably 1:1.5.
[0016] Preferably, the eluent used for purification by column chromatography or thin-layer chromatography is any one or a mixture of two of petroleum ether, dichloromethane, ethyl acetate, and diethyl ether; here, the eluent is preferably a mixture of ethyl acetate and petroleum ether (volume ratio of 1:2-5).
[0017] Preferably, the reactor refers to a Schlenk tube.
[0018] Compared with the prior art, the present invention has the following beneficial effects: 1. This invention reports for the first time the α-thiocyanation of sulfoxide ylides using selective fluorine as an oxidant. The selective fluorine used is characterized by high safety, low cost, mild reaction, good functional group compatibility, and ease of handling. This method avoids the use of traditional high-cost metal oxidants (highly corrosive, highly toxic, and highly polluting) and precious metals (high cost). Introducing a thiocyanate group into the sulfoxide ylide molecule can greatly promote its re-derivation, thereby easily constructing various functional molecules applicable to the synthesis of pesticide and pharmaceutical intermediates.
[0019] 2. The synthesis method proposed in this invention has the advantages of simple operation, high efficiency, mild conditions, and the reaction can be completed in less than 20 minutes at room temperature. The raw materials are readily available, the safety is high, and the cost is low, which is conducive to industrial production.
[0020] Of course, any product implementing this invention does not necessarily need to achieve all of the advantages described above at the same time. Attached Figure Description
[0021] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.
[0022] Figure 1 The hydrogen spectrum of product 3a obtained in Example 1 of this invention; Figure 2 The carbon spectrum of product 3a obtained in Example 1 of this invention; Figure 3 The hydrogen spectrum of product 3b obtained in Example 2 of this invention; Figure 4 The carbon spectrum of product 3b obtained in Example 2 of this invention; Figure 5 The hydrogen spectrum of product 3c obtained in Example 3 of this invention; Figure 6 The carbon spectrum of product 3c obtained in Example 3 of this invention; Figure 7 The hydrogen spectrum of the product obtained in Example 4 of this invention is shown in Figure 3. Figure 8 The carbon spectrum of the product obtained in Example 4 of this invention is shown in Figure 3. Figure 9 The hydrogen spectrum of product 3e obtained in Example 5 of this invention; Figure 10 This is the carbon spectrum of product 3e obtained in Example 5 of the present invention. Detailed Implementation
[0023] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0024] Example 1 The reaction equation is shown below.
[0025] 10 mmol benzoyl sulfoxide ylide, 15 mmol sodium thiocyanate, and 15 mmol selective fluorine (CAS: 140681-55-6; Bid Pharmaceuticals) were added to a Schlenk tube. 50 mL of acetonitrile was added under a nitrogen atmosphere, and the reaction was carried out at room temperature for 15 minutes. After the reaction was complete, the crude product was obtained by vacuum distillation, and purified by column chromatography to obtain product 3a. The eluent used for column chromatography was a mixed solvent of ethyl acetate / petroleum ether = 1 / 5 (v / v), with a yield of 90%.
[0026] The proton and carbon spectra of the obtained product 3a are as follows: Figure 1 and Figure 2 As shown, the structural characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.77-7.69 (m, 2H), 7.53-7.44 (m, 3H), 3.65 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 189.45, 138.26, 131.04, 128.17, 127.93,114.23, 68.33, 42.49. HRMS (ESI): Calculated for C 11 H 12 NO2S2 [M+H] + : 254.0304; found: 254.0301. Based on the above experimental results, the structure of product 3a is shown in the following formula:
[0027] Example 2 The reaction equation is shown below.
[0028] 10 mmol of 4-methylbenzoyl sulfoxide ylide, 15 mmol of sodium thiocyanate, and 15 mmol of selective fluorine were added to a Schlenk tube. 50 mL of acetonitrile was added under a nitrogen atmosphere, and the reaction was carried out at room temperature for 15 minutes. After the reaction was complete, the crude product was obtained by vacuum distillation, which was then purified by column chromatography to obtain product 3b. The eluent used for column chromatography was a mixed solvent of ethyl acetate / petroleum ether = 1 / 5 (v / v), with a yield of 93%.
[0029] The proton and carbon spectra of the obtained product 3b are as follows: Figure 3 and Figure 4 As shown, the structural characterization data are as follows: 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 7.6 Hz, 2H), 7.27 (d, J = 7.6Hz, 2H), 3.64 (s, 6H), 2.42 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 189.32, 141.53, 135.42, 128.81, 128.11,114.25, 67.98, 42.62, 21.55. HRMS (ESI): Calculated for C 12 H 14 NO2S2 [M+H] + : 268.0460; found: 268.0456. Based on the above experimental results, the structure of product 3b is shown in the following formula: Example 3 The reaction equation is shown below.
[0030] 10 mmol of 4-bromobenzoyl sulfoxide ylide, 15 mmol of sodium thiocyanate, and 15 mmol of selective fluorine were added to a Schlenk tube. 50 mL of acetonitrile was added under a nitrogen atmosphere, and the reaction was carried out at room temperature for 15 minutes. After the reaction was complete, the crude product was obtained by vacuum distillation. The crude product was purified by column chromatography and thin-layer chromatography to obtain product 3c. The column chromatography eluent was a mixture of ethyl acetate and petroleum ether (v / v), with a yield of 86%.
[0031] The proton and carbon spectra of the obtained product 3C are as follows: Figure 5 and Figure 6 As shown, the structural characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.60 (s, 4H), 3.64 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 188.09, 137.08, 131.39, 129.57, 125.53,113.91, 68.69, 42.45. HRMS (ESI): Calculated for C 11 H 11BrNO2S2 [M+H] + : 331.9409; found: 331.9404. Based on the above experimental results, the structure of product 3c is shown in the following formula:
[0032] Example 4 The reaction equation is shown below.
[0033] 10 mmol of 1-naphthyl sulfoxide ylide, 15 mmol of sodium thiocyanate, and 15 mmol of selective fluorine were added to a Schlenk tube. 50 mL of acetonitrile was added under a nitrogen atmosphere, and the reaction was carried out at room temperature for 15 minutes. After the reaction, the crude product was obtained by vacuum distillation, and purified by column chromatography and thin-layer chromatography to obtain product 3d. The column chromatography eluent was a mixture of ethyl acetate and petroleum ether (v / v), with a yield of 95%.
[0034] The 3d proton and carbon spectra of the obtained product are as follows: Figure 7 and Figure 8 As shown, the structural characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.00-7.86 (m, 3H), 7.65-7.51 (m, 4H), 3.75 (m, 6H). 13 C NMR (101 MHz, CDCl3) δ190.90, 136.99, 133.58, 129.89, 129.72,128.50, 126.90, 126.24, 124.87, 124.77, 124.65, 113.97, 70.47, 42.55. HRMS (ESI): Calculated for C 15 H 14 NO2S2 [M+H] + : 304.0460; found: 304.0455. Based on the above experimental results, the 3D structure of the product is shown in the following formula:
[0035] Example 5 The reaction equation is shown below.
[0036] 10 mmol of trimethylacetyl sulfoxide ylide, 15 mmol of sodium thiocyanate, and 15 mmol of selective fluorine were added to a Schlenk tube. 50 mL of acetonitrile was added under a nitrogen atmosphere, and the reaction was carried out at room temperature for 20 minutes. After the reaction, the crude product was obtained by vacuum distillation, and purified by column chromatography and thin-layer chromatography to obtain product 3d. The column chromatography eluent was a mixture of ethyl acetate and petroleum ether (1 / 3, v / v), with a yield of 73%.
[0037] The proton and carbon spectra of the obtained product 3e are as follows: Figure 9 and Figure 10 As shown, the structural characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 3.49 (s, 6H), 1.37 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 199.86, 114.42, 66.88, 43.81, 42.01, 27.14. HRMS (ESI): Calcd. for C9H 16 NO2S2 [M+H] + :234.0617; found: 234.0612. Based on the above experimental results, the structure of product 3e is shown in the following formula:
[0038] The above description is merely an example and illustration of the concept of the present invention. Those skilled in the art can make various modifications or additions to the specific embodiments described or use similar methods to replace them, as long as they do not deviate from the concept of the invention or exceed the scope defined in the claims, they should all fall within the protection scope of the present invention.
Claims
1. A method for synthesizing α-thiocyanosulfoxide ylide compounds, characterized in that, The synthesis includes the following steps: In a reactor, α-carbonyl sulfoxide ylide of compound 1, thiocyanate of compound 2, oxidant and solvent are added and reacted at room temperature for 10-20 minutes. After the reaction is completed, the crude product is obtained by vacuum distillation, and purified by column chromatography to obtain the thiocyano-substituted α-thiocyano sulfoxide ylide compound shown in Formula 3. The reaction equation is as follows: ； Wherein, R is phenyl, 4-methylphenyl, 4-bromophenyl, 1-naphthyl or tert-butyl; X is sodium, potassium, ammonium, zinc or copper; and n is 1 or 2.
2. The method for synthesizing an α-thiocyanosulfoxide ylide compound according to claim 1, characterized in that, Compound 1 refers to any one of benzoyl sulfoxide ylide, 4-methylbenzoyl sulfoxide ylide, 4-bromobenzoyl sulfoxide ylide, 1-naphthyl sulfoxide ylide, and trimethylacetyl.
3. The method for synthesizing an α-thiocyanosulfoxide ylide compound according to claim 1, characterized in that, Compound 2 refers to any one of sodium thiocyanate, potassium thiocyanate, ammonium thiocyanate, iron thiocyanate, zinc thiocyanate, and copper thiocyanate.
4. The method for synthesizing an α-thiocyanosulfoxide ylide compound according to claim 1, characterized in that, The molar ratio of compound 1 to compound 2 is 1:1-2.
5. The method for synthesizing an α-thiocyanosulfoxide ylide compound according to claim 1, characterized in that, The solvents mentioned refer to acetonitrile, hexafluoroisopropanol, methanol, and ethanol. N , N -Dimethylformamide, N , N - Any one of dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, and dioxane; the solvent to compound 1 ratio is 1-5 mL: 0.1 mmol.
6. The method for synthesizing an α-thiocyanosulfoxide ylide compound according to claim 1, characterized in that, The oxidant is any one of nitrobenzene, peroxytert-butanol, peroxybenzoic acid, and selective fluorine, and the molar ratio of the oxidant to compound 1 is 1:1-2.
7. The method for synthesizing an α-thiocyanosulfoxide ylide compound according to claim 1, characterized in that, The eluent used for column chromatography or thin-layer chromatography is any one or a mixture of two of petroleum ether, dichloromethane, ethyl acetate, and diethyl ether.
8. The method for synthesizing an α-thiocyanosulfoxide ylide compound according to claim 1, characterized in that, The reactor referred to is a Schlenk tube.