A method for the copper-catalyzed decarboxylative C-S coupling to form benzyl dithiocarbamates

Abstract

This invention discloses a copper-catalyzed decarboxylation C-S coupling method for the synthesis of benzyl dithiocarbamate, belonging to the field of dithiocarbamate organic compound synthesis technology. Using phenylacetic acid derivatives as substrates, sodium dialkyl dithiocarbamate as a sulfur source, monovalent copper salts as catalysts, 1,10-phenanthroline-5,6-dione as ligands, ammonium persulfate as an oxidant, and cesium carbonate as a base, the reaction is carried out in a 1,2-dichloroethane / water mixed solvent at 25-55℃ for 6-12 h. The target product is obtained by extraction, drying, and column chromatography purification. This method relies on the copper-catalyzed decarboxylation radical transformation pathway, selectively attacking the S-S bond of the disulfide substrate by generating alkyl radicals, efficiently constructing C-S chemical bonds, eliminating the need for pre-activation of carboxylic acids, and overcoming the shortcomings of traditional processes that are cumbersome and require activation reagents.

Description

Technical Field

[0001] This invention belongs to the field of synthesis technology of dithiocarbamate organic compounds, specifically relating to a method for copper-catalyzed decarboxylation and CS coupling to synthesize benzyl dithiocarbamate. Background Technology

[0002] Benzyl dithiocarbamates are an important class of sulfur-containing organic skeleton compounds, used as intermediates in organic synthesis, active pharmaceutical molecules, agrochemicals, and rubber vulcanization accelerators. These compounds effectively inhibit metalloenzyme activity, exhibiting various biological activities such as anticancer, antibacterial, and neuromodulatory effects, demonstrating significant application value. Therefore, developing efficient synthetic processes for preparing benzyl dithiocarbamates is of great practical importance. Existing processes for preparing benzyl dithiocarbamates mainly fall into three categories: the first category involves a one-pot reaction of carbon disulfide, amine compounds, and benzyl halides, benzyl alcohols, pseudohalides, methyl aromatics, aldehydes, and other benzyl precursors; the second category involves the reaction of thiuram disulfide or dithiocarbamates with benzyl halides, quaternary ammonium salts, benzyl alcohols, or borate esters; and the third category involves the nucleophilic addition of thiols to isothiocyanates and N,N-dimethylthiocarbamoyl chloride to obtain the target product. The aforementioned traditional processes have several drawbacks: the reactants contain toxic and harmful substances such as phosgene, carbon disulfide, and irritating odorous amines; the reaction conditions are stringent; the overall post-processing is complex; and the synthesis cost is relatively high. Carboxylic acid compounds are widely available, structurally diverse, and inexpensive, making them commonly used building blocks in organic synthesis and widely applied in the biopharmaceutical and fine chemical industries. Decarboxylation to construct CS bonds is currently the mainstream green synthetic approach for introducing sulfur-containing functional groups. Currently disclosed decarboxylation methods for synthesizing dithiocarbamates all require the pre-conversion of carboxylic acids into N-hydroxyphthalimide (NHPI) esters for substrate activation, resulting in numerous pretreatment steps and poor atom and step economy. Directly using unactivated carboxylic acids for decarboxylation CS coupling reactions could simplify the operation and shorten the synthetic route, but this conversion faces significant technical challenges. Aromatic acetic acid has a high oxidation potential, and conventional reaction systems require the addition of a large amount of strong oxidizing agent, which can easily lead to excessive oxidation of the substrate and the generation of byproducts such as aldehydes and ketones. At the same time, the alkyl radicals generated during the reaction are easily further oxidized to carbocations, which will compete with various nucleophiles in the system for side reactions, significantly reducing the yield of the target product. Summary of the Invention

[0003] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for copper-catalyzed decarboxylation and CS coupling to synthesize benzyl dithiocarbamate. This method has mild reaction conditions, simple operation, can be carried out at room temperature, has excellent functional group tolerance, and good yield, and can realize the late-stage functionalization modification of complex drug molecules.

[0004] The technical solution of the present invention is as follows: A method for synthesizing benzyl dithiocarbamate by copper-catalyzed decarboxylation and CS coupling includes the following steps: Using phenylacetic acid derivatives as the reaction substrate and sodium dialkyldithiocarbamate as the sulfur source, a reaction system consisting of monovalent copper salt, 1,10-phenanthroline-5,6-dione ligand (ligand L1), ammonium persulfate, and cesium carbonate was prepared. A mixed solvent of 1,2-dichloroethane and deionized water was used, and the reaction was stirred at 25-55 °C for 6-12 h. After the reaction was complete, dichloromethane was added for dilution, the organic phase was washed with deionized water, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the target product, benzyl dithiocarbamate.

[0005] The reaction structure of the phenylacetic acid derivative with the benzyl dithiocarbamate product is as follows: ; Furthermore, the phenylacetic acid derivative is selected from: p-chlorophenylacetic acid, p-cyanophenylacetic acid, isocolic acid, and biphenylacetic acid; the amount of the phenylacetic acid derivative is 0.20 mmol. Furthermore, the sulfur source is selected from: sodium dimethyl dithiocarbamate and sodium diethyl dithiocarbamate; Furthermore, the monovalent copper salt is selected from cuprous trifluoromethanesulfonate and cuprous chloride; the amount of the monovalent copper salt used is 10 mol%-12 mol%. Furthermore, the amount of the 1,10-phenanthroline-5,6-dione ligand used is 12 mol%-15 mol% Furthermore, based on the amount of phenylacetic acid derivatives as 1 equivalent (eq), the amount of ammonium persulfate is 1.5-2.0 eq, the amount of cesium carbonate is 1.5-2.0 eq, and the amount of sodium dialkyldithiocarbamate is 1.5 eq.

[0006] Furthermore, the volume ratio of 1,2-dichloroethane to deionized water is 1:1 to 3:1.

[0007] Beneficial effects (1) This invention is the first to use copper-catalyzed direct decarboxylation of unactivated phenylacetic acid derivatives to construct CS bonds without the need for preactivation of carboxylic acid, and prepares benzyl dithiocarbamate in one step, opening up a new synthetic route for this type of sulfur-containing compound.

[0008] (2) Traditional processes require the activation of carboxylic acids to NHPI esters, and are prone to over-oxidation and carbocation side reactions. This invention utilizes copper-ligand synergistic catalysis to regulate the free radical process, suppress side reactions, ensure sufficient substrate conversion, and achieve good product yield.

[0009] (3) It can be reacted at room temperature and normal pressure, with low requirements for anhydrous and oxygen-free environments; the reagents used are inexpensive and low in toxicity, avoiding highly toxic sulfur raw materials; the post-processing is simple, and it can be scaled up to the gram level, making it suitable for industrial applications.

[0010] (4) The system is compatible with functional groups such as ketones, ethers, cyano groups, and halogens, and has a wide range of substrate applications; it can complete the late-stage modification of drug molecules and is suitable for pharmaceuticals, rubber additives, fine chemicals and other fields. Attached Figure Description

[0011] Figure 1 This is a schematic diagram of the reaction principle; Figure 2 The 1H NMR spectrum of the product in Example 1; Figure 3 The carbon spectrum of the product in Example 1; Figure 4 The hydrogen NMR spectrum of the product in Example 2; Figure 5 The carbon spectrum of the product in Example 2; Figure 6 The hydrogen NMR spectrum of the product in Example 3; Figure 7 The carbon spectrum of the product in Example 3; Figure 8 The 1H NMR spectrum of the product in Example 4; Figure 9 The image shows the carbon spectrum of the product from Example 4. Detailed Implementation

[0012] To make the above-mentioned objectives, features, and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to examples. The following content is merely illustrative and explanatory of the concept of the present invention. Those skilled in the art can make various modifications or additions to the described specific embodiments or use similar methods to replace them, as long as they do not deviate from the concept of the invention, they should all fall within the protection scope of the present invention.

[0013] The preparation method of the present invention will be described below through specific embodiments.

[0014] Example 1 Synthesis of p-chlorobenzyl dimethyl dithiocarbamate: To a clean 4 mL reaction flask, p-chlorophenylacetic acid (0.20 mmol), cuprous trifluoromethanesulfonate (10 mol%), ligand L1 (15 mol%), ammonium persulfate (0.40 mmol, 2.0 eq), cesium carbonate (0.40 mmol, 2.0 eq), and sodium dimethyl dithiocarbamate (SDDC) (0.30 mmol, 1.5 eq) were added sequentially. DCE / H₂O (1:1 v / v, 2 mL total) was then added, and the mixture was stirred at 25 °C for 6 h. After the reaction was complete, the mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography to give a white solid product 1, with a yield of 58%.

[0015] according to Figure 2 The product's 1H NMR spectrum and Figure 3 The carbon spectrum of the product yields the following structural formula of the target product: ; 1 H NMR (300 MHz, Chloroform-d, 298 K, δ): 7.34 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 6.4 Hz, 2H), 4.53 (s, 2H), 3.57 (s, 3H), 3.36 (s, 3H) ppm. 13 C NMR (75 MHz, Chloroform-d, 298 K, δ): 196.4, 135.1, 133.3, 130.7,128.7, 45.6, 41.6, 41.5 ppm.

[0016] Example 2 To a clean 4 mL reaction flask, p-cyanophenylacetic acid (0.20 mmol), cuprous trifluoromethanesulfonate (10 mol%), ligand L1 (12 mol%), ammonium persulfate (0.30 mmol, 1.5 eq), cesium carbonate (0.40 mmol, 2.0 eq), and sodium dimethyl dithiocarbamate (0.30 mmol, 1.5 eq) were added sequentially. DCE / H₂O (1:1 v / v, 2 mL total) was then added, and the mixture was stirred at 25 °C for 12 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography to give a white solid product 2, with a yield of 41%.

[0017] according to Figure 4 The product's 1H NMR spectrum and Figure 5 The carbon spectrum of the product yields the following structural formula of the target product: ; 1 H NMR (300 MHz, Chloroform-d, 298 K, δ): 7.58 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 4.62 (s, 2H), 3.55 (s, 3H), 3.36 (s, 3H) ppm. 13 C NMR (75 MHz, Chloroform-d, 298 K, δ): 195.7, 142.8, 132.3, 130.0,118.8, 111.2, 45.8, 41.6, 41.5 ppm.

[0018] Example 3 To a clean 4 mL reaction flask, isoxepac (0.20 mmol), cuprous trifluoromethanesulfonate (12 mol%), ligand L1 (15 mol%), ammonium persulfate (0.40 mmol, 2.0 eq), cesium carbonate (0.30 mmol, 1.5 eq), and sodium dimethyl dithiocarbamate (0.30 mmol, 1.5 eq) were added sequentially. DCE / H₂O (1.5:0.5 v / v, 2 mL total) was then added. The mixture was stirred at 25 °C for 12 h, and the reaction was monitored by TLC. After the reaction was complete, the mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography to give the target product 3 as a white solid, with a yield of 45%.

[0019] according to Figure 6 The product's 1H NMR spectrum and Figure 7 The carbon spectrum of the product yields the following structural formula of the target product: ; 1H NMR (300 MHz, Chloroform-d, 298 K, δ): 8.21 (d, J = 2.6 Hz, 1H), 7.88 (dd, J = 7.6, 1.4 Hz, 1H), 7.59 - 7.51 (m, 2H), 7.46 (td, J = 7.5, 1.3Hz, 1H), 7.35 (d, J = 7.3 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 5.17 (s, 2H), 4.57 (s, 2H), 3.55 (s, 3H), 3.35 (s, 3H) ppm. 13 C NMR (75 MHz, Chloroform-d, 298 K, δ): 196.5, 190.8, 160.7, 140.5,136.5, 135.5, 132.8, 132.5, 130.3, 129.5, 129.3, 127.9, 125.2, 121.1, 73.7,45.5, 41.5 (2C) ppm. HRMS (ESI) m / z: [M+H] + Calcd for C 18 H 18 NO2S2 + 344.0774; Found 344.0809.

[0020] Example 4 To a clean 4 mL reaction flask, add biphenylacetic acid (Isoxepac, 0.20 mmol), cuprous chloride (10 mol%), ligand L1 (15 mol%), ammonium persulfate (0.40 mmol, 2.0 eq), cesium carbonate (0.30 mmol, 1.5 eq), and sodium diethyldithiocarbamate (0.30 mmol, 1.5 eq), then add DCE (2 mL) and H₂O (10 μL). Stir the mixture at 55 °C for 6 h. After the reaction is complete, dilute with dichloromethane, wash with water, dry with anhydrous sodium sulfate, and evaporate the solvent to obtain the crude product. Purify the crude product by silica gel column chromatography to give the target product 4 as a white solid, with a yield of 42%.

[0021] according to Figure 8 The product's 1H NMR spectrum and Figure 9 The carbon spectrum of the product yields the following structural formula of the target product: ; 1H NMR (300 MHz, Chloroform-d, 298 K, δ): 7.62 - 7.53 (m, 4H), 7.51 -7.41 (m, 4H), 7.39 - 7.31 (m, 1H), 4.61 (s, 2H), 4.07 (q, J = 7.1 Hz, 2H),3.75 (q, J = 7.2 Hz, 2H), 1.30 (td, J = 7.2, 2.6 Hz, 6H) ppm. 13 C NMR (75 MHz, Chloroform-d, 298 K, δ): 195.3, 140.8, 140.5, 135.3,129.9, 128.9, 127.4 (2C), 127.1, 49.6, 46.9, 42.0, 12.6, 11.7 ppm.

Claims

1. A method for copper-catalyzed decarboxylation and CS coupling to synthesize benzyl dithiocarbamate, characterized in that, The preparation steps include the following: Using phenylacetic acid derivatives as the reaction substrate and sodium dialkyldithiocarbamate as the sulfur source, a reaction system consisting of monovalent copper salt, 1,10-phenanthroline-5,6-dione ligand, ammonium persulfate, and cesium carbonate was prepared. A mixed solvent of 1,2-dichloroethane and deionized water was used, and the reaction was stirred at 25-55 °C for 6-12 h. After the reaction was complete, dichloromethane was added for dilution, the organic phase was washed with deionized water, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the target product, benzyl dithiocarbamate. The phenylacetic acid derivative is one of p-chlorophenylacetic acid, p-cyanophenylacetic acid, isocolic acid, and biphenylacetic acid.

2. The method according to claim 1, characterized in that, The amount of the phenylacetic acid derivative used is 0.20 mmol.

3. The method according to claim 1, characterized in that, The sulfur source is selected from sodium dimethyl dithiocarbamate and sodium diethyl dithiocarbamate.

4. The method according to claim 1, characterized in that, The monovalent copper salt is selected from cuprous trifluoromethanesulfonate and cuprous chloride; the amount of the monovalent copper salt used is 10 mol%-12 mol.

5. The method according to claim 1, characterized in that, The amount of the 1,10-phenanthroline-5,6-dione ligand used is 12 mol%-15 mol%.

6. The method according to claim 1, characterized in that, Based on 1 eq of the amount of phenylacetic acid derivative, the amount of ammonium persulfate is 1.5-2.0 eq, the amount of cesium carbonate is 1.5-2.0 eq, and the amount of sodium dialkyl dithiocarbamate is 1.5 eq.

7. The method according to claim 1, characterized in that, The volume ratio of 1,2-dichloroethane to deionized water is 1:1 to 3:1.

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