阅读说明：本技术 一种制备杂环邻碘硫醚的方法 (Method for preparing heterocyclic o-iodosulfide ) 是由 张士磊 胡敏 胡延维 姜远锐 方春辉 祝文静 陈鑫 黄加文 于 2021-08-18 设计创作，主要内容包括：本发明公开了一种制备杂环邻碘硫醚的方法,以杂环硫酚与邻二碘苯为底物,在金属氢化物存在下、溶剂中反应,制备杂环邻碘硫醚。传统的无金属C-S偶联反应,需要预先制备碘鎓、硫鎓前体等活性物种,制备成本高、难度大。本发明在氢化钠作用下,邻二碘苯能够与硫酚反应合成杂环邻碘硫醚。邻二碘苯原料价廉易得、反应温和；同时,杂环邻碘硫醚可以进行下一步广泛转化,制备多样的1,2-二取代苯,为复杂的天然产物和药物分子合成提供了一条简捷途径。(The invention discloses a method for preparing heterocyclic o-iodosulfide, which takes heterocyclic thiophenol and o-diiodobenzene as substrates to react in a solvent in the presence of metal hydride to prepare the heterocyclic o-iodosulfide. The traditional metal-free C-S coupling reaction needs to prepare active species such as iodonium, sulfonium precursors and the like in advance, and has high preparation cost and great difficulty. Under the action of sodium hydride, o-diiodobenzene can react with thiophenol to synthesize heterocyclic o-iodosulfide. The o-diiodobenzene raw material is cheap and easy to obtain, and the reaction is mild; meanwhile, the heterocyclic o-iodosulfide can be widely converted in the next step to prepare various 1, 2-disubstituted benzenes, thereby providing a simple way for the synthesis of complex natural products and drug molecules.)

1. A method for preparing heterocyclic o-iodo thioether is characterized in that heterocyclic thiophenol and o-diiodobenzene are used as substrates and react in a solvent in the presence of metal hydride to prepare heterocyclic o-iodo thioether; the chemical structural formula of the heterocyclic thiophenol is RSH; the chemical structural formula of the o-diiodobenzene is as follows:

the chemical structural formula of the heterocyclic o-iodo thioether is as follows:

and R is heterocyclic or substituted heterocyclic.

2. The method for preparing heterocyclic iodonium sulfide as claimed in claim 1, wherein the substituent of the substituted heterocycle is one or more of halogen, alkyl, haloalkyl, cyano, nitro, alkoxy, phenyl, amino and amido.

3. The method for preparing heterocyclic iodonium sulfide as claimed in claim 1, wherein the heterocyclic thiophenol has one or more rings, and comprises at least one heterocyclic ring.

4. The method for preparing heterocyclic iodonium sulfide according to claim 1, wherein the heterocyclic ring or the substituted heterocyclic ring contains one or more of nitrogen, oxygen and sulfur.

5. The method for preparing heterocyclic ortho-iodo thioether according to claim 1, wherein the reaction is carried out in a solvent in the presence of a metal hydride, and the reaction is carried out at room temperature for 1 to 4 hours without using any other substance.

6. The method for preparing heterocyclic ortho-iodo thioether according to claim 1, wherein the metal hydride is one or more of sodium hydride, potassium hydride, calcium hydride and lithium hydride.

7. The method for preparing heterocyclic o-iodo thioether according to claim 1, wherein the metal hydride is used in an amount of 3 to 5 times the molar amount of the heterocyclic thiophenol; the dosage of the o-diiodobenzene is 1-3 times of the molar weight of the heterocyclic thiophenol.

8. The method for preparing heterocyclic iodonium sulfide as claimed in claim 1, wherein the solvent is one or more selected from dimethylacetamide, tetrahydrofuran, acetonitrile, ethylene glycol dimethyl ether and toluene.

9. The product of the process for preparing heterocyclic ortho-iodo thioether according to claim 1.

10. The application of metal hydride in the reaction of heterocyclic thiophenol and o-diiodobenzene to obtain heterocyclic o-iodosulfide.

Technical Field

The invention belongs to organic synthesis, and particularly relates to a method for preparing heterocyclic o-iodosulfide.

Background

Numerous scientists have made significant efforts to build aryl thioether compounds with considerable success. Traditionally, aryl sulfides have been obtained by cross-coupling reactions of pre-functionalized aromatics (such as aryl halides) with thiols or disulfides by metal catalysis (mainly palladium, copper, iron, nickel, cobalt, rhodium, etc.), which is a very efficient C — S building approach. However, compared with the mature metal-catalyzed cross-coupling reaction of C-O, C-N, etc., the metal coupling between C and S is not so smooth, and the organic sulfur reagent is easy to form excessive coordination with the metal catalyst due to the special electrical property of sulfur element, thereby causing the poisoning and deactivation of the metal catalyst. Therefore, most of the known metal-catalyzed C-S coupling methods require very severe reaction conditions, strong alkali (such as t-BuONa) or special air-sensitive, high-cost ligands and high temperature (80-140 ℃), and the like, and the methods are poor in practicability. Therefore, there is a need to find better alternatives for forming C — S bonds.

Disclosure of Invention

The invention discloses a method for preparing heterocyclic o-iodosulfide, which is a novel method with easily obtained substrate, mild condition and high atom utilization rate, solves the problem that the coupling reaction without transition metal is difficult to be applied on a large scale, and is an important research direction in the field at present.

The invention adopts the following technical scheme:

a method for preparing heterocyclic o-iodosulfide takes heterocyclic thiophenol and o-diiodobenzene as substrates, and the heterocyclic o-iodosulfide is obtained by reaction in a solvent in the presence of metal hydride.

In the invention, the chemical structural formula of the heterocyclic thiophenol is RSH;

the chemical structural formula of the o-diiodobenzene is as follows:

the chemical structural formula of the heterocyclic o-iodo thioether is as follows:

the R is a heterocyclic ring or a substituted heterocyclic ring, and the heterocyclic ring or the substituted heterocyclic ring contains one or more of nitrogen, oxygen and sulfur; the substituent of the substituted heterocycle is halogen, alkyl, haloalkyl, cyano, nitro, alkoxy, phenyl, amino, acylamino and the like; furthermore, the heterocyclic thiophenol may have one or more rings in the structural formula, and at least includes one heterocyclic ring.

The reaction of the heterocyclic thiophenol and the o-diiodobenzene disclosed by the invention is carried out in a solvent in the presence of a metal hydride, and the reaction is carried out for 1-4 hours at room temperature without other substances, so that the product heterocyclic o-iodosulfide is obtained and is a single product.

In the present invention, the metal hydride is sodium hydride, potassium hydride, calcium hydride, lithium hydride, or the like; the dosage of the metal hydride is 3 to 5 times of the molar weight of the heterocyclic thiophenol, and preferably 4 times. Furthermore, the dosage of the o-diiodobenzene is 1-3 times of the molar weight of the heterocyclic thiophenol.

In the invention, the solvent is dimethylacetamide DMA, tetrahydrofuran THF and acetonitrile CH₃One or more of CN, ethylene glycol dimethyl ether DME and Toluene Toluene, preferably THF and DMA, and preferably the volume ratio of THF to DMA is (3-8) to 1.

The sodium hydride is very simple in form from the chemical structure, and the sodium hydride purchased in the market is very low in price and very convenient to use. Therefore, sodium hydride has been favored by chemists from a cost economy perspective. However, the application range of sodium hydride is very limited, and although sodium hydride is a species which stores a great amount of energy, the activity of sodium hydride is required to be well exerted so that sodium hydride becomes a reducing agent, and continuous research is still required. The NaH is used for synthesizing the heterocyclic o-iodosulfide product by using o-diiodobenzene, and has no need of transition metal and extra iodine source, thereby having practical value.

Drawings

FIG. 1 shows the NMR spectrum of Compound 3 ac.

Detailed Description

The invention takes heterocyclic thiophenol and o-diiodobenzene as substrates, can complete the reaction in the presence of metal hydride and solvent, obtains the product heterocyclic o-iodosulfide with high yield, does not need other substances, and solves the problems of the prior art that a metal catalyst, a format reagent and the like are needed.

The raw materials involved in the invention are all existing products, can be purchased in the market, and can also be prepared according to the existing method.

Nuclear magnetic spectrum¹H NMR was measured using Agilent 400 MHz and Bruker 400 MHz instruments,¹³c NMR was measured using a Bruker 400 MHz instrument and the sample solvent was CDCl₃Or deuterated DMSO with TMS internal standard in solvent. The LR-MS mass spectrometer was an ESI source. TLC monitoring uses a thin-layer silica gel plate produced by a tobacco yellow sea chemical plant, and the silica gel used for rapid column chromatography is 200-mesh and 300-mesh. The reagents are all commercially available analytically pure or chemically pure, have no special description and are used directly. The anhydrous solvent is either a redistilled solvent or a commercially available dry solvent (carbofuran).

Example one

NaH (1.2 mmol, 4.0 equiv) was weighed into a reaction flask at room temperature, suspended in anhydrous THF (0.8 mL) with magnetic stirring, and during stirring heterocyclic thiophenol 1 (0.3 mmol, 1.0 equiv, dissolved in 0.2mL DMA) was added dropwise, after addition was completed, stirred at room temperature for 3min, then diiodobenzene 2a (0.6 mmol, 2.0 equiv, dissolved in 0.2mL THF) was added, stirring was continued at room temperature, and the reaction was monitored by TLC. After the reaction is finished, adding ice water and tetrahydrofuran for quenching reaction, extracting for 3 times by ethyl acetate, combining organic layers, washing by a saturated NaCl solution, drying by anhydrous sodium sulfate, filtering, spin-drying a solvent, adding silica gel powder for mixing samples, and performing rapid column chromatography separation to obtain a heterocyclic o-iodosulfide product 3, wherein the yield is calculated conventionally.

The yield below the product formula is the isolated yield, and the time noted is the time for TLC monitoring of the reaction to completion. FIG. 1 shows the NMR spectrum of product 3 ac.

The compound 1 is heterocyclic thiophenol, the structural formula of which can be determined according to the product, and the iodine-containing benzene ring in the product is replaced by H, for example, the structural formula of the heterocyclic thiophenol corresponding to the product 3ac is as follows:

the structural formula of the raw material heterocyclic thiophenol corresponding to the product 3ad is as follows:

the rest products, namely the raw material heterocyclic thiophenols, are the existing products according to the rule.

Product data characterization

¹H NMR (400 MHz, CDCl3) δ 8.45 (ddd, J = 4.8, 1.7, 0.7 Hz, 1H), 7.98 (dd, J = 7.9, 1.3 Hz, 1H), 7.67 (dd, J = 7.7, 1.6 Hz, 1H), 7.49 (td, J = 7.8, 1.9 Hz, 1H), 7.38 (td, J = 7.6, 1.3 Hz, 1H), 7.14 – 6.97 (m, 2H), 6.88 (d, J= 8.1 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 159.79, 150.00, 140.56, 136.99, 136.97, 135.82, 130.42, 129.39, 122.12, 120.44, 107.41。

¹H NMR (400 MHz, CDCl₃) δ 8.40 (d, J = 1.3 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.46 (dd, J = 8.5, 2.0 Hz, 1H), 7.40 (t, J= 7.5 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 157.96, 148.69, 140.72, 136.74, 136.45, 136.07, 130.79, 129.52, 128.86, 122.69, 107.68。

¹H NMR (400 MHz, CDCl₃) δ 8.62 (s, 1H), 8.49 (d, J = 1.2 Hz, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.69 (d, J = 7.5 Hz, 1H), 7.60 (dd, J = 8.5, 1.8 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 6.76 (d, J = 8.5 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 158.60, 150.85, 140.75, 139.49, 136.32, 136.17, 130.86, 129.54, 123.09, 117.14, 107.80。

¹H NMR (400 MHz, CDCl₃) δ 8.70 (d, J = 5.0 Hz, 1H), 8.02 (dd, J = 7.9, 1.2 Hz, 1H), 7.77 (dd, J = 7.7, 1.5 Hz, 1H), 7.43 (td, J = 7.6, 1.3 Hz, 1H), 7.29 (d, J = 5.0 Hz, 1H), 7.14 (td, J = 7.8, 1.6 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 173.25, 159.96, 156.22 (d, J = 37.4 Hz), 140.50, 136.87, 134.23, 131.32, 129.24, 120.2 (d, J = 276.7 Hz), 112.57, 108.77. ¹⁹F NMR (377 MHz, CDCl₃) δ -70.22。

¹H NMR (400 MHz, CDCl₃) δ 7.76 (dd, J = 7.8, 1.3 Hz, 1H), 7.58 (dd, J= 5.4, 1.2 Hz, 1H), 7.35 (dd, J = 3.6, 1.2 Hz, 1H), 7.22 – 7.13 (m, 2H), 6.83 (td, J = 7.7, 1.5 Hz, 1H), 6.75 (dd, J = 8.0, 1.5 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 143.96, 139.35, 137.46, 132.57, 130.50, 128.87, 128.50, 126.93, 126.52, 94.88。

¹H NMR (400 MHz, CDCl₃) δ 7.89 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.58 – 7.51 (m, 5H), 7.36 (t, J = 7.6 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 152.79, 140.65, 135.02, 133.97, 133.53, 132.93, 131.27, 130.54, 129.89, 129.83, 129.58, 124.41, 104.86。

¹H NMR (400 MHz, CDCl₃) δ 7.74 (d, J = 7.7 Hz, 1H), 7.21 (s, 1H), 7.17 – 7.09 (m, 2H), 6.82 (t, J = 7.4 Hz, 1H), 6.55 (d, J = 7.7 Hz, 1H), 3.62 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 140.63, 139.54, 137.81, 130.64, 129.00, 127.44, 127.21, 124.35, 95.65, 33.96。

Example two

NaH (0.9 mmol, 3.0 equiv) was weighed into a reaction flask at room temperature, suspended in anhydrous THF (0.8 mL) under magnetic stirring, pyridylthiol 1a (0.3 mmol, 1.0 equiv, dissolved in 0.2mL DMA) was added dropwise during stirring, after the addition was completed, stirred at room temperature for 3min, diiodobenzene 2a (0.6 mmol, 2.0 equiv, dissolved in 0.2mL THF) was added, stirring was continued at room temperature, and the reaction was monitored by TLC. After the reaction is finished, adding ice water and tetrahydrofuran for quenching reaction, extracting for 3 times by ethyl acetate, combining organic layers, washing by a saturated NaCl solution, drying by anhydrous sodium sulfate, filtering, spin-drying a solvent, adding silica gel powder for mixing samples, and performing rapid column chromatography separation to obtain a heterocyclic o-iodo thioether product 3ac, wherein the yield is 65% by conventional calculation.

KH (4.0 equiv) is weighed in a reaction bottle at room temperature, the mixture is suspended in anhydrous THF (0.8 mL) and stirred by magnetic force, pyridylthiol 1a (0.3 mmol, 1.0 equiv, dissolved in 0.2mL DMA) is added dropwise in the stirring process, the mixture is stirred at room temperature for 3min after the addition is finished, then diiodobenzene 2a (0.6 mmol, 2.0 equiv, dissolved in 0.2mL THF) is added, the mixture is stirred at room temperature continuously, after the reaction is carried out for 24 h, ice water and tetrahydrofuran are added for quenching reaction, ethyl acetate is extracted for 3 times, organic layers are combined, the saturated NaCl solution is washed, anhydrous sodium sulfate is dried, the mixture is filtered, a solvent is dried by spinning, silica gel powder is added for sample stirring, and the heterocyclic o-iodosulfide product 3ac can not be obtained after the column chromatography is carried out quickly.

At room temperature, adding CaH₂(2.0 equiv) weighed into a reaction flask, suspended in anhydrous THF (0.8 mL) with magnetic stirring, pyridylthiol 1a (0.3 mmol, 1.0 equiv, in 0.2mL DMA) was added dropwise with stirring, after completion of addition, stirred at room temperature for 3min, and diiodobenzene 2a (0.6 mmol, 2.0 equiv, in 0.2mL THF) was addedStirring was continued at room temperature and the reaction was monitored by TLC. After the reaction is finished, adding ice water and tetrahydrofuran for quenching reaction, extracting for 3 times by ethyl acetate, combining organic layers, washing by a saturated NaCl solution, drying by anhydrous sodium sulfate, filtering, spin-drying a solvent, adding silica gel powder for mixing samples, and performing rapid column chromatography separation to obtain a heterocyclic o-iodo thioether product 3ac, wherein the yield is 19% by conventional calculation.

NaH (1.2 mmol, 4.0 equiv) was weighed into a reaction flask at room temperature, suspended in anhydrous THF (0.6 mL) and magnetically stirred, pyridylthiol 1a (0.3 mmol, 1.0 equiv, dissolved in 0.2mL DMA) was added dropwise during stirring, after completion of the addition, stirred at room temperature for 3min, diiodobenzene 2a (0.6 mmol, 2.0 equiv, dissolved in 0.2mL THF) was added, stirring was continued at room temperature, and the reaction was monitored by TLC. After the reaction is finished, adding ice water and tetrahydrofuran for quenching reaction, extracting for 3 times by ethyl acetate, combining organic layers, washing by a saturated NaCl solution, drying by anhydrous sodium sulfate, filtering, spin-drying a solvent, adding silica gel powder for mixing samples, and performing rapid column chromatography separation to obtain the heterocyclic o-iodo thioether product 3ac, wherein the yield is 71% by conventional calculation.

According to the invention, when the NaH equivalent is 4.0 equiv, heterocyclic thiophenol can well react with diiodobenzene, the yield is more than moderate, the product can be directly applied, the problem of large-scale application of transition-metal-free coupling is solved, and the practicability and the industrial application prospect of the reaction are shown; furthermore, the product ortho-iodine has great application value and can be further converted widely, for example, the ortho-iodine can be subjected to coupling reaction with phenylboronic acid, thiophenol, phenylacetylene and the like under the catalysis of Pd to prepare various 2-substituted thiophenols, and in addition, the ortho-iodine can be subjected to intramolecular cyclization reaction under the catalysis of metal. The invention utilizes the nucleophilic reaction of the o-diiodobenzene and the heterocyclic thiophenol under the action of NaH to generate the heterocyclic o-iodosulfide product, and the method completes the C-S bond coupling without the participation of transition metal, has simple and convenient operation, does not have the problems of metal reagent residue, pollution and the like, and has very important application prospect.