Dihydrobenzothiapyran-1, 1-dioxide compound as well as preparation method and application thereof

Abstract

The invention discloses a dihydrobenzothiapyran-1, 1-dioxide compound as well as a preparation method and application of the dihydrobenzothiapyran-1, 1-dioxide compound. The preparation method comprises the following steps: carrying out a catalytic reaction on a compound 1, a compound 2 and a photocatalyst in an N2 atmosphere irradiated by visible light, and then purifying a reaction product to obtain a compound 3, wherein the compound 1 has a structure as shown in formula 1, the compound 2 has a structure as shown in formula 2, and the compound 3 has a structure as shown in formula 3: # imgabs0 #

Description

Technical Field

[0001] This technical disclosure document relates to the field of chemical synthesis, particularly organic synthesis and medicinal chemistry, and specifically to a class of dihydrobenzothiopyran-1,1-dioxide compounds, their preparation methods, and uses. Background Art

[0002] Sulfur-containing heterocyclic scaffolds have become an important part of medicinal chemistry due to their diverse biological activities. Among them, dihydrobenzothiopyran-1,1-dioxide, as an important sulfur-containing heterocyclic compound, has received extensive attention due to its therapeutic potential. Compounds with this core structure have shown promising pharmacological characteristics, especially as regulators of key signaling pathways related to cancer, inflammation, and metabolic disorders.

[0003] Some studies have emphasized the relevance of similar heterocyclic frameworks in drug discovery. For example, the well-characterized Ro41-5253 (structural formula shown in Formula I) can act as a retinoic acid receptor (RAR) antagonist, selectively counteracting the effects of retinoic acid, and its therapeutic potential in breast cancer and other malignancies has been studied; the role of Ro41-5253 emphasizes the importance of targeting nuclear receptors to regulate cancer cell proliferation and apoptosis. In addition, the spirocholine derivative (structural formula shown in Formula II), which is considered an aldose reductase inhibitor, demonstrates the importance of a rigid sulfur-containing heterocycle in enzyme inhibition. It has also been found that 4H-benzothiopyran-4-one 1,1-dioxide (structural formula shown in Formula III) interacts with trypanothione reductase at key binding residues, leading to an increase in reactive oxygen species (ROS) levels and mitochondrial perturbation, ultimately resulting in parasite cell death.

[0004]

[0005] In terms of synthetic methods, the construction techniques of dihydrobenzothiopyran-1,1-dioxide and its derivatives have also undergone continuous development and optimization. As early as 1952, William Truce reported the Friedel-Crafts cyclization reaction of phenylalkylsulfonyl chloride, representing a classic and promising technique for constructing dihydrobenzothiopyran-1,1-dioxide ( Figure 1a). Subsequently, in 2003, Tartakovskii's strategy was to use 2,4,6-trinitrotoluene (TNT) as a building block, enabling access to thiochroman to form 1,1-dioxide frameworks through controlled reduction transformation. This approach exploited the reactive nitro group of TNT to promote multicomponent assembly reactions, providing a new route for the synthesis of structurally complex sulfur-containing heterocycles ( Figure 1 b). Another influential advance in 2019 involved multicomponent reductive cross-coupling of inorganic sulfur dioxide surrogates, which provided a simple and highly versatile platform for the construction of functionalized sulfones, which are key intermediates in the synthesis of dihydrobenzothiopyran-1,1-dioxide derivatives; the use of inexpensive sulfur dioxide sources in the reductive coupling framework enhanced the scalability and environmental friendliness of these synthetic routes ( Figure 1 c). Although significant progress has been made in the synthesis of dihydrobenzothiopyran-1,1-dioxide and its derivatives, there are still several defects and challenges. (1) Harsh reaction conditions and complex operation: Early Friedel-Crafts cyclization reactions usually require strong acid catalysts (such as AlCl), and the reaction temperature, time and reactant ratio need to be strictly controlled, which increases the difficulty of operation. (2) Environmental issues and safety: In 2003, TNT was used as a reaction substrate. Although it has good reactivity, TNT itself is a highly explosive substance. There are great safety hazards in its synthesis and storage, and it is not suitable as a raw material for large-scale production. (3) Cost and sustainability: In 2019, although the multi-component reductive cross-coupling of inorganic sulfur dioxide substitutes has great potential, it still relies on precious metal catalysts or expensive reagents, which increases costs. Although the use of cheap sulfur dioxide sources enhances scalability, the management and use of sulfur dioxide still need to pay attention to its corrosiveness and toxicity, which limits the speed of its large-scale promotion.

[0006] In summary, although the existing synthesis methods of dihydrobenzothiopyran-1,1-dioxide and its derivatives have made some progress, there are still challenges such as harsh reaction conditions, complex operations, environmental safety issues, and cost and sustainability. Therefore, it is urgent to develop a more efficient, environmentally friendly and low-cost synthesis method to meet the needs of drug research and industrial production. Summary of the invention

[0007] The object of the present invention is to address the deficiencies in the prior art and propose a new synthetic strategy that is more efficient, environmentally friendly, and cost-effective. This strategy uses commercially available sulfonyl chloride as a sulfonylation reagent and undergoes a photoredox-catalyzed sulfonylation cyclization reaction on 1-phenyl-2-(phenylsulfonyl)pent-4-en-1-one or its derivatives to easily obtain dihydrobenzothiopyran-1,1-dioxide compounds. This method is easy to operate, with readily available raw materials, effectively overcoming various limitations in the prior art. Moreover, the use of photoredox-catalysis technology makes the synthetic route more efficient and environmentally friendly. Through this research, the present invention can further expand the application scope of dihydrobenzothiopyran-1,1-dioxide compounds and contribute more candidate molecules for new drug research and development.

[0008] The present invention provides a dihydrobenzothiopyran-1,1-dioxide compound having the structures shown in Formula 3aa, Formula 3ba, Formula 3ca, Formula 3da, Formula 3ea, Formula 3fa, Formula 3ga, Formula 3ha, Formula 3ia, Formula 3ja, Formula 3ka, Formula 3la, Formula 3ma, Formula 3na, Formula 3oa, Formula 3ab, Formula 3bb, Formula 3cb, Formula 3db, Formula 3eb, Formula 3fb, Formula 3gb, Formula 3hb, Formula 3ib, Formula 3jb, or Formula 3kb:

[0009]

[0010]

[0011]

[0012] In the present invention, a compound having the structure shown in Formula X is directly abbreviated as compound X or X. For example, a compound having the structure shown in Formula 3aa is abbreviated as compound 3aa or 3aa.

[0013] The present invention also provides a method for preparing a dihydrobenzothiopyran-1,1-dioxide compound, comprising: subjecting compound 1, compound 2, and a photocatalyst to a catalytic reaction under visible light irradiation in an N2 atmosphere, and then purifying the reaction product to obtain compound 3;

[0014] wherein compound 1 has the structure shown in Formula 1, compound 2 has the structure shown in Formula 2, and compound 3 has the structure shown in Formula 3:

[0015]

[0016] When R1 is H, 2-substituted methoxy, 3-substituted methoxy, para-substituted bromine, para-substituted methyl, para-substituted methoxy, R2 is para-methyl, and R3 is methoxy;

[0017] When R1 is H, R2 is H, para-substituted tert-butyl, para-substituted fluorine, para-substituted chlorine, para-substituted bromine, 2-substituted methyl or 3-substituted methyl, and R3 is methoxy;

[0018] When R1 is para-substituted methoxy, R2 is para-substituted bromine or para-substituted methoxy, and R3 is methoxy;

[0019] When R1 is H, R2 is para-methyl, and R3 is 2-methyl, 2-bromo, 2-methoxy, 3-chloro, 3-methyl, 3-methoxy, H, para-methyl, para-tert-butyl, para-chlorine or para-bromine.

[0020] Furthermore, the raw materials for the catalytic reaction may further include at least one of an alkali, a solvent and an additive; the alkali is selected from at least one of potassium hydrogen phosphate, 2,6-dimethylpyridine, potassium bicarbonate, sodium tert-butoxide, potassium carbonate and sodium hydrogen phosphate, preferably potassium hydrogen phosphate; the solvent is selected from acetonitrile, dimethyl sulfoxide, acetone, 1,4-dioxane, chloroform, tetrahydrofuran and a co-solvent system of 1,4-dioxane / water, wherein the volume ratio of 1,4-dioxane to water in the co-solvent system of 1,4-dioxane / water is (10:1)-(1:1), and the solvent is preferably a co-solvent system with a volume ratio of 1,4-dioxane to water of 5:1; the additive is selected from at least one of sodium persulfate, potassium persulfate and ammonium persulfate, preferably sodium persulfate.

[0021] Furthermore, the photocatalyst is selected from at least one of tris(2-phenylpyridine)iridium, (4,4'-di-tert-butyl-2,2'-bipyridine)di[3,5-difluoro-2-[5-trifluoromethyl-2-pyridyl-KN)phenylKC]IRID, ruthenium(III) chloride hexahydrate and eosin Y, preferably tris(2-phenylpyridine)iridium.

[0022] Preferably, the molar ratio of Compound 1:Compound 2:tris(2-phenylpyridine)iridium:sodium persulfate:potassium hydrogen phosphate = 40:80:1:80:80.

[0023] The present invention also provides the use of the above-mentioned dihydrobenzothiopyran-1,1-dioxide compounds for preparing a drug for inhibiting Secreted Aspartic Protease (SAP). As an example, the above-mentioned dihydrobenzothiopyran-1,1-dioxide compounds can be used as the core structure of Sap2 inhibitors.

[0024] The present invention also provides the use of the above-mentioned dihydrobenzothiopyran-1,1-dioxide compounds for preparing a drug for anti-fungal infection. As an example, the fungus is Candida.

[0025] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0026] We developed an efficient route to a library of dihydrothiochroman-1,1-dioxides, a mild and easily accessible visible light-mediated sulfonylation / arylation of the C-C bond in 1-phenyl-2-(phenylsulfonyl)pent-4-en-1-one. Diversity in the reaction products can be achieved by varying the type of benzene ring in the two starting materials. Furthermore, the substituents attached to the scaffold can be easily extended to synthesize more biologically active cores, aiding future structure-activity relationship studies to discover potent and selective kinase inhibitors. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The invention is a relatively typical synthesis method of dihydrobenzothiopyran-1,1-dioxide and its derivatives in the prior art.

[0028] Figure 2 This is a schematic diagram of the reaction mechanism of dihydrothiobenzopyran-1,1-dioxide compounds according to an embodiment of the present invention. DETAILED DESCRIPTION

[0029] In conjunction with the following specific examples, the present invention is further described in detail, and the protection content of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, the changes and advantages that can be thought of by those skilled in the art are included in the present invention, and the attached claims are the scope of protection. The process, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the contents specifically mentioned below, are all common knowledge and common common sense in the art, and the present invention has no special restrictions. The data given in the following examples include specific operations and reaction conditions and products. The purity of the product is identified by nuclear magnetic resonance spectroscopy.

[0030] In the embodiment, the light source used in the photochemical experiment is a 5W blue LED light strip purchased from JD.com. Manufacturer: GreeThink, China; Model: 12v3528; Light source wavelength: λ=460-470nm; Irradiation container material: Schlenk reaction tube; Distance from light source to irradiation container: 6.0 cm (without using any filter).

[0031] In the Examples, NMR spectra were recorded on a Bruker Avance 500 spectrometer. 11H NMR chemical shifts are reported relative to TMS (δ = 0 ppm) or the internal solvent peak (CDCl3 δ = 7.26 ppm, CD3OD δ = 3.31 ppm or D2O δ = 4.79 ppm), and coupling constants are in hertz (Hz). The following abbreviations are used to denote spin multiplicities: s = singlet, d = doublet, t = triplet, dt = doublet of triplets, ddd = doublet of doublets of doublets, m = multiplet, and br = broad. 13 13C NMR chemical shifts are reported in ppm relative to the solvent peak (CDCl3 δ = 77.23 ppm, DMSO δ = 39.52 ppm, CD3OD δ = 49.00 ppm). Filtration was carried out on a silica bed (Screening Devices BV, 60 - 200 μm, ). Flash chromatography was performed on a Grace Reveleris Silica column (12 g) on Grace Reveleris X2, and a gradient of petroleum ether / ethyl acetate (0 - 100%) or dichloromethane / methanol (0 - 20%) was applied. Thin layer chromatography was carried out on Fluka pre-coated silica plates (0.20 mm thick, particle size 25 μm). Unless otherwise stated, reagents were obtained from commercial suppliers and used without any purification. Unless otherwise stated, the yields given refer to the isolated yields of chromatographically purified compounds.

[0032] Example 1

[0033] (1) Synthesis of Aromatic Sodium Sulfinate

[0034] The aromatic sodium sulfinate was prepared from its corresponding sulfonyl chloride, and its reaction general formula 1 is as follows::

[0035]

[0036] Compound 4 (5 mmol), sodium sulfite (10 mmol) and sodium bicarbonate (10 mmol) were dissolved in 10 mL of water and stirred at 70 - 80 °C for 5 h. After cooling to room temperature, the water was removed in vacuo, and the residue was extracted with ethanol and recrystallized to obtain compound 5 as a white solid in a yield of 60 - 70%.

[0037] (2) Synthesis of Compound 1

[0038] The reaction general formula 2 is as follows

[0039]

[0040] Compound 5 (3.6 mmol) and compound 6 (3.0 mmol) were dissolved in a co-solvent of 1,4-dioxane and water (20 mL, v / v = 1:1), and the mixture was stirred under reflux for 6 hours. After the reaction was completed, the reaction mixture was extracted with dichloromethane (3 × 20 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to obtain the crude β-ketosulfone (compound 7). The crude β-ketosulfone was recrystallized from petroleum ether / ethyl acetate in almost quantitative yield. Potassium carbonate (0.621 g, 4.5 mmol, 1.5 equiv) was added to a solution of β-ketosulfone (3.0 mmol, 1.0 equiv) in acetone (30 mL), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was added to allyl bromide (3.3 mmol) and stirred under reflux for 14 hours. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (30 mL × 3). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel (petroleum ether / ethyl acetate = 15:1) to obtain compound 1.

[0041] (3) Synthesis of compound 3

[0042] Reaction scheme 3 is as follows:

[0043]

[0044] In a 25 mL flask equipped with a magnetic stir bar, compound 1 (0.2 mmol), compound 2 (0.4 mmol, 2.0 equiv), and a photocatalyst (0.005 mmol) were added. The schlenk flask was evacuated at -78 °C and backfilled with nitrogen three times. The mixture was irradiated with a blue LED lamp (5 W) for 84 hours. The mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate system) to obtain compound 3.

[0045] When R1 is H, 2-substituted methoxy, 3-substituted methoxy, para-substituted bromo, para-substituted methyl, para-substituted methoxy, R2 is para-methyl, and R3 is methoxy;

[0046] When R1 is H, R2 is H, para-substituted tert-butyl, para-substituted fluoro, para-substituted chloro, para-substituted bromo, 2-substituted methyl, or 3-substituted methyl, and R3 is methoxy;

[0047] When R1 is para-substituted methoxy, R2 is para-substituted bromo or para-substituted methoxy, and R3 is methoxy;

[0048] When R1 is H, R2 is para-methyl, and R3 is 2-methyl, 2-bromo, 2-methoxy, 3-chloro, 3-methyl, 3-methoxy, H, para-methyl, para-tert-butyl, para-chloro, or para-bromo.

[0049] (3.1) Synthesis of Compound 3aa The reaction of 1-phenyl-2-(tosyl)pent-4-en-1-one (Compound 1a) and 4-methoxybenzenesulfonyl chloride (Compound 2a), and the optimal reaction conditions were determined by changing the photocatalyst, base, solvent, additive, and light source. The specific reaction formula A is as follows:

[0050]

[0051] First, under a N2 atmosphere irradiated with a blue LED lamp (5W), Compound 1a (0.2 mmol, 1.0 equivalent), Compound 2a (0.4 mmol, 2.0 equivalents), potassium hydrogen phosphate (0.4 mmol, 2.0 equivalents), and iridium tris(2-phenylpyridine) (0.005 mmol) were reacted at room temperature for 84 hours, and Compound 3aa was easily obtained with a yield of 36%.

[0052] Compound 1a (0.2 mmol, 1.0 equivalent) and Compound 2a (0.4 mmol, 2.0 equivalents) were used as model substrates. In the following experiments to determine the optimal reaction conditions, the following reaction conditions remained unchanged: under a N2 atmosphere irradiated with a blue LED lamp (5W), reacting at room temperature for 84 hours.

[0053] Using iridium tris(2-phenylpyridine) (0.005 mmol) as the photocatalyst and potassium hydrogen phosphate (0.4 mmol, 2.0 equivalents) as the base, various solvents used to study the optimal reaction conditions, including acetonitrile, dimethyl sulfoxide, acetone, 1,4-dioxane, chloroform, tetrahydrofuran, and the co-solvent system of 1,4-dioxane / water (volume ratio 10:1 - 1:1), could all improve the yield of Compound 3aa to a certain extent. Among them, the co-solvent system of 1,4-dioxane / water (5:1) was proven to be the most effective, producing Compound 3aa with a yield of 62%.

[0054] Using iridium tris(2-phenylpyridine) (0.005 mmol) as the photocatalyst, under the optimal solvent, the bases used to study the optimal reaction conditions included potassium hydrogen phosphate, 2,6-dimethylpyridine, potassium bicarbonate, sodium tert-butoxide, potassium carbonate, and sodium hydrogen phosphate. Among them, potassium hydrogen phosphate was the best choice with a yield of 62%.

[0055] Using potassium hydrogen phosphate (0.4 mmol, 2.0 equivalents) as the base, in the optimal solvent, other photocatalysts used to study the optimal reaction conditions included iridium tris(2-phenylpyridine), (4,4'-di-tert-butyl-2,2'-bipyridine)di[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl-KN)phenylKC]IRID, ruthenium(III) chloride tris(2,2'-bipyridine) hexahydrate, and eosin Y. Among them, iridium tris(2-phenylpyridine) was the best choice with a yield of 62%.

[0056] Using iridium tris(2-phenylpyridine) (0.005 mmol) as the photocatalyst and potassium hydrogen phosphate (0.4 mmol, 2.0 equivalents) as the base, in the optimal solvent, different additives used to study the optimal reaction conditions included sodium persulfate, potassium persulfate, and ammonium persulfate. Among them, sodium persulfate was the best choice.

[0057] By setting up three control groups of not adding a photocatalyst, conducting experiments in a dark environment, and conducting experiments with the system in contact with air, it was determined that a photocatalyst, visible light, and inert gas protection were essential conditions for this experiment.

[0058] In summary, through experiments, it was determined that the optimal reaction conditions were that compound 1a (1.0 equivalent), 4-methoxybenzenesulfonyl chloride (2.0 equivalents), iridium tris(2-phenylpyridine), sodium persulfate (2.0 equivalents), and potassium hydrogen phosphate (2.0 equivalents) reacted in a solvent system of 1,4-dioxane / water (5:1) under nitrogen atmosphere at room temperature irradiated with a blue LED lamp (5W) for 84 hours, with a yield of 75%. Among them, the molar ratio of compound 1a:compound 2a:iridium tris(2-phenylpyridine):sodium persulfate:potassium hydrogen phosphate = 40:80:1:80:80.

[0059] (3.2) Synthesis of compounds 3ba, etc. Under the optimal reaction conditions, by changing the substituents on the left benzene ring Ar1 of 1-phenyl-2-(phenylsulfonyl)pent-4-en-1-one, the corresponding compounds 3ba, 3ca, 3da, 3ea, and 3fa were obtained. The reaction general formula B is as follows:

[0060]

[0061] R1 were 2-substituted methoxy, 3-substituted methoxy, para-substituted bromo, para-substituted methyl, and para-substituted methoxy respectively. All substrates (compound 1) had good tolerance in this reaction, and the corresponding products (compound 3) were obtained with yields of 55 - 67%.

[0062] Under the optimal reaction conditions, the substituents on the right benzene ring Ar2 of 1-phenyl-2-(phenylsulfonyl)pent-4-en-1-one were changed. When R2 was H, para-substituted tert-butyl, para-substituted fluorine, para-substituted chlorine, para-substituted bromine, 2-substituted methyl, and 3-substituted methyl respectively, it was found that all the connected substituents were suitable for this reaction system and the compounds 3ga, 3ha, 3ia, 3ja, 3ka, 3la, and 3ma were successfully generated with a yield of 55 - 67%.

[0063] Under the optimal reaction conditions, the disubstituted 1-phenyl-2-(phenylsulfonyl)pent-4-en-1-one in benzene rings Ar1 and Ar2 could successfully provide the corresponding products in moderate yields, namely compound 3na and compound 3oa. Among them, the reaction substrate of compound 3na was para-substituted methoxy in benzene ring Ar1 and para-substituted bromine in benzene ring Ar2; the reaction substrate of compound 3oa was para-substituted methoxy in both benzene rings Ar1 and Ar2, with a yield of 55 - 67%.

[0064] However, when a methyl group was introduced at the α-position of the C-C double bond, it was incompatible with this reaction, and only trace amounts of products were observed. Similarly, in this reaction, attempts were also made to replace 1-phenyl-2-(phenylsulfonyl)pent-4-en-1-one with substrates containing other aromatic rings (such as thiophene), which were also incompatible with the standard reaction conditions.

[0065] This invention proposed a reasonable mechanism for this tandem reaction, assuming that the reaction occurred under an iridium catalyst, as Figure 2 shown. Under visible light irradiation, tris(2-phenylpyridine)iridium changed from the ground state to the excited state *Ir III , and then was oxidized by the arylsulfonyl chloride compound through a single electron transfer process to obtain sulfonyl A and form Ir IV . Subsequently, sulfonyl A was captured by the carbon-carbon double bond of substrate 1 to form a radical intermediate B, which underwent an intramolecular cyclization at the C-2 position of the indole moiety to obtain intermediate C. Then, intermediate C was further oxidized by the photocatalyst Ir IV to generate a cationic intermediate D, and the ground state photocatalyst was regenerated for the next catalytic cycle. Finally, intermediate D underwent deprotonation in the presence of a base to obtain the corresponding functionalized dihydrobenzothiopyran-1,1-dioxide compound 3.

[0066] (3.4) Synthesis of compounds 3ab, etc.

[0067] Under the optimal reaction conditions, the substituents on the arylsulfonyl chloride were changed to obtain the corresponding compound 3, and the reaction general formula C was as follows:

[0068]

[0069] R3 are respectively: 2-methyl substitution, 2-bromo substitution, 2-methoxy substitution, 3-chloro substitution, 3-methyl substitution, 3-methoxy substitution, H, p-methyl substitution, p-tert-butyl substitution, p-chloro substitution and p-bromo substitution. The corresponding compounds 3 are 3ab, 3bb, 3cb, 3db, 3eb, 3fb, 3gb, 3hb, 3ib, 3jb, 3kb respectively.

[0070] In summary, preferably, the preparation process of compound 3 is as follows: In a 25 mL flask equipped with a magnetic stir bar, add compound 1 (0.2 mmol), compound 2 (0.4 mmol, 2.0 equivalents), potassium hydrogen phosphate (0.4 mmol, 2.0 equivalents), sodium persulfate (0.4 mmol, 2.0 equivalents), 1,4-dioxane / water = 5:1 (2 mL) and iridium tris(2-phenylpyridine) (0.005 mmol). The schlenk flask was evacuated at -78 °C and backfilled with nitrogen three times. The mixture was irradiated with a blue LED lamp (5 W) for 84 hours, and the reaction progress was monitored by thin layer chromatography. After determining the completion of the reaction, the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate system) to obtain compound 3.

[0071] General procedure for the gram-scale reaction of compound 3: In a 100 mL flask equipped with a magnetic stir bar, add compound 1 (4.5 mmol, 1.0 equivalent), 2 (9.0 mmol, 2.0 equivalents), potassium hydrogen phosphate (9.0 mmol, 2.0 equivalents), sodium persulfate (9.0 mmol, 2.0 equivalents), 1,4-dioxane / water = 5:1 (40 mL) and iridium tris(2-phenylpyridine) (148.5 mg). The flask was evacuated at -78 °C and backfilled with nitrogen three times. The mixture was irradiated with a blue LED lamp (5 W) for 86 hours, and the reaction progress was monitored by thin layer chromatography. After determining the completion of the reaction, the reaction mixture was quenched with 50 mL of water and extracted with ethyl acetate (50 mL × 4). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate system) to obtain the desired product.

[0072] SAP2 enzyme inhibition activity experiment

[0073] The compounds 3aa - 3oa, 3ab - 3kb synthesized in the examples were used as samples for the experiment.

[0074] (1) Prepare sodium citrate buffer: The concentration is 50 mM (containing 50 mM NaCl), and the pH is adjusted to 4.5;

[0075] (2) Preparation of protein substrate (customized by Gil Chemical Industry) and compound concentration gradient: Dissolve the protein substrate with DMSO (Sigma) to prepare a stock solution with a concentration of 18.75 μM for use; dissolve the positive drug PepA (Pepstatin A, Sigma) with DMSO (Sigma) at concentrations ranging from 10 μM to 0.001 nM; dissolve the compound to be tested with DMSO (Sigma) at concentrations ranging from 100 μM to 0.01 μM. Experimental unit: 200 μL per well, which contains 185 μL of buffer, 5 μL of enzyme, 5 μL of the compound solution to be tested, and 5 μL of the protein substrate solution, and double replicate wells are used for verification;

[0076] (3) Preparation of SAP2 enzyme (Zhongding Biologics): Dilute the original SAP2 enzyme 10 - 15 times with sodium citrate buffer and place it at room temperature for 2 h. Take the activated enzyme solution and dilute it in multiples. Determine the working concentration of the enzyme through the protein substrate hydrolysis experiment, that is, the concentration corresponding to a fluorescence change of 100 units / min, at which the curve of fluorescence intensity versus time is linear;

[0077] (4) Sample addition: Add 185 μL of sodium citrate buffer, 5 μL of SAP2 enzyme, and 5 μL of the compound solution to be tested into a black 96 - well plate (Corning, 3650) in sequence. The positive control is PepA (Sigma), and the blank control is DMSO (Sigma). Use a multi - functional microplate reader (Bioteck Synergy2) to fully oscillate the solution system and set the incubation temperature at 30 °C for 30 min;

[0078] (5) Detection after adding protein substrate: Add 5 μL of protein substrate to each well, oscillate and mix evenly. Starting from this point, read the fluorescence emission value of each well every 10 min, with the wavelength set at λex = 340 / 30 nm and λem = 485 / 20 nm;

[0079] (6) Data processing: According to the fluorescence increment per unit time, the inhibition rate % of the compound to be tested on the enzyme at the corresponding concentration can be calculated. Non - linearly fit the inhibition rate with log(c) to obtain the dose - effect relationship. Read the IC 50 . The fitting module is log(inhibitor) vs response ~ varible slop.

[0080] Table 1: Enzyme inhibition activity of dihydrobenzothiophene - 1,1 - dioxide compounds on Sap2

[0081]

[0082]

[0083] In vitro antifungal activity test experiment

[0084] The compounds 3aa - 3oa, 3ab - kb synthesized in the examples were used as samples for the experiment

[0085] Bacterial solution preparation: Activate Candida albicans in YPD liquid medium (Candida albicans SC5314, provided by the Pharmaceutical Research Center of the School of Pharmacy, Naval Medical University; cultivate at 35 °C for 16 h, count with a hemocytometer, and dilute the bacterial solution concentration to 1×10 3 CFU / mL with RPMI 1640 liquid medium;

[0086] (1) Preparation of the compound solution to be tested: Dissolve the compound to be tested with DMSO (Sigma) at a concentration of 3.2 mg / mL, and further dilute it to 320 μg / mL with RPMI 1640 medium;

[0087] (2) Sample addition and inoculation: Add samples to a 96 - well plate (Corning), with a sample addition unit of 200 μL: 180 μL of bacterial solution + 20 μL of drug solution, and the drug dilution concentration is 32 - 0.125 μg / mL. The blank control is RPMI 1640 (Sigma), and the positive control is Fluconazole (Sigma);

[0088] (3) Incubation: Place the plate in an incubator at 35 °C and incubate for 24 h;

[0089] (4) Detection: Use a multi - functional microplate reader to read the data of the 96 - well plate. The OD value of the positive control is 100%, and determine the MIC 80 : That is, the minimum inhibitory concentration corresponding to when the OD value drops by 80%.

[0090] Table 2: In vitro antifungal activity of the compounds (MIC 80 , μg·mL -1 ) a

[0091]

[0092]

[0093] a Abbreviations: C.alb. Candida albicans; C.par. Candida parapsilosis; C.gla

[0094] Candida glabrata; C.neo. Cryptococcus neoformans; T.rub. Trichophyton rubrum; M.

[0095] gyp Microsporum gypseum; FLZ: Fluconazole.

[0096] The above experimental results show that, compared with the positive control drug, some of the compounds described in the present invention have good anti-Candida activity, indicating that this type of compound can be used as the core structure of Sap2 inhibitors for the development of subsequent antifungal drugs.

[0097] The product structures obtained with different substituents and 1 H NMR, 13 C NMR and other spectral verification data are as follows:

[0098]

[0099] (((4-Methoxyphenyl)sulfonyl)methyl)-6-methyl-1,1-dioxidothiochroman-2-yl)(phenyl)methanone (3aa): Colorless solid (36.3 mg, 75% yield, dr = 2.0:1; 4.5 mmol scale, 1.546 g, 71% yield). 1 H NMR (500 MHz, CDCl3): δ H 8.10 - 8.06 (m, 2.0H), 7.91 - 7.86 (m, 2.0H), 7.81 (d, J = 8.0 Hz, 0.33H), 7.73 (d, J = 8.5 Hz, 0.67H), 7.67 - 7.64 (m, 1.0H), 7.55 - 7.50 (m, 2.0H), 7.38 - 7.34 (m, 0.33H), 7.24 (d, J = 8.5 Hz, 0.67H), 7.16 (s, 0.33H), 7.05 (d, J = 8.5 Hz, 1.33H), 7.00 (d, J = 8.5 Hz, 1.34H), 5.39 (dd, J = 9.5, 4.5 Hz, 0.67H), 5.25 (dd, J = 7.5, 7.0 Hz, 0.33H), 4.14 - 4.02 (m, 0.33H), 3.95 - 3.91 (m, 0.67H), 3.89 (s, 1.0H), 3.84 (s, 2.0H), 3.72 - 3.66 (m, 1.0H), 3.57 - 3.53 (m, 0.33H), 3.42 (dd, J = 14.5, 3.5 Hz, 0.67H), 3.12 - 3.06 (m, 0.67H), 2.97 - 2.94 (m, 0.66H), 2.90 - 2.86 (m, 0.67H), 2.41 (s, 1.0H), 2.38 (s, 2.0H);13 13C NMR(126MHz,CDCl3):δ c 13 13C NMR(126MHz,CDCl3)189.7,189.7,164.1,164.0,144.5,144.4,138.7,138.5,136.3,136.2,135.2,134.6,134.4,134.4,130.8,130.7,130.2,130.1,129.5,129.5,129.3,128.9,128.8,128.6,124.9,124.7,114.8,114.7,63.6,62.5,60.8,55.8,55.7,31.9,31.7,31.3,29.7,29.4,21.7,21.6;IR: HRMS(ESI-TOF)m / z:[M+H] + calcd for C 25 H 25 O6S2 + ,485.1087,Found 485.1074.

[0100]

[0101] (2-Methoxyphenyl)(4-(((4-methoxyphenyl)sulfonyl)methyl)-6-methyl-1,1-dioxidothiochroman-2-yl)methanon(3ba):Colorless solid(32.9 mg,64%yield,dr=2.0:1). 1 1H NMR(500MHz,CDCl3):δ H7.88 - 7.86 (m, 2.0H), 7.77 (d, J = 8.0Hz, 0.33H), 7.70 (d, J = 8.0Hz, 0.67H), 7.61 (dd, J = 8.0, 1.5Hz, 0.67H), 7.57 - 7.50 (m, 1.33H), 7.23 - 7.19 (m, 1.0H), 7.11 (s, 0.33H), 7.05 - 7.00 (m, 4.0H), 6.97 (s, 0.67H), 5.71 (dd, J = 8.3, 5.3Hz, 0.67H), 5.55 (dd, J = 9.5, 5.3Hz, 0.33H), 3.99 (s, 2.0H), 3.96 (s, 1.0H), 3.88 (s, 1.0H), 3.86 (s, 2.0H), 3.83 - 3.80 (m, 1.0H), 3.70 - 3.66 (m, 1.0H), 3.48 - 3.44 (m, 1.0H), 3.13 - 3.07 (m, 0.33H), 3.03 - 2.97 (m, 0.67H), 2.93 - 2.88 (m, 0.67H), 2.79 - 2.72 (m, 0.33H), 2.39 (s, 1.0H), 2.35 (s, 2.0H); 13 C NMR (126MHz, CDCl3): δ c 192.5, 192.2, 164.0, 164.0, 158.8, 158.8, 144.1, 144.0, 138.8, 138.6, 135.5, 135.1, 135.0, 134.8, 131.2, 131.1, 130.8, 130.6, 130.2, 129.8, 129.5, 129.4, 129.3, 129.1, 128.7, 128.2, 127.3, 127.2, 124.6, 124.4, 121.2, 121.1, 114.7, 114.7, 111.7, 111.7, 67.7, 66.4, 62.2, 61.4, 55.9, 55.8, 55.8, 55.7, 31.6, 31.4, 31.1, 29.8, 21.7, 21.6; IR: HRMS (ESI - TOF) m / z: [M + H] + calcd for C 26 H 27 O7S2 + , 515.1193, Found 515.1190.

[0102]

[0103] (4-(((4-Methoxyphenyl)sulfonyl)methyl)-7-methyl-1,1-dioxidothiochroman-2-yl)(phenyl)methano ne(3ca): Colorless solid (26.6 mg, 55% yield, dr=2.0:1). 1 1H NMR (500 MHz, CDCl3): 1 1H NMR (500 MHz, CDCl3) δ H 8.07 - 8.00 (m, 2.0H), 7.83 - 7.78 (m, 2.0H), 7.66 (d, J=8.5 Hz, 0.33H), 7.60 - 7.57 (m, 1.67H), 7.49 - 7.44 (m, 2.0H), 7.33 - 7.29 (m, 0.33H), 7.27 - 7.22 (m, 1.0H), 7.09 (d, J=8.0 Hz, 0.67H), 6.97 (d, J=9.0 Hz, 0.67H), 6.92 (d, J=9.0 Hz, 1.33H), 5.31 (dd, J=10.0, 4.5 Hz, 0.67H), 5.19 (dd, J=8.7, 6.3 Hz, 0.33H), 3.97 - 3.82 (m, 1.0H), 3.82 (s, 1.0H), 3.77 (s, 2.0H), 3.62 - 3.57 (m, 1.0H), 3.46 - 3.41 (m, 0.33H), 3.33 (dd, J=14.5, 3.5 Hz, 0.67H), 3.05 - 2.99 (m, 0.67H), 2.95 - 2.87 (m, 0.66H), 2.83 - 2.79 (m, 0.67H), 2.33 (s, 1.0H), 2.30 (s, 2.0H); 13 13C NMR (126 MHz, CDCl3): δ c 189.6, 189.6, 164.1, 139.2, 138.0, 137.3, 136.3, 135.6, 134.4, 134.4, 134.2, 130.8, 130.2, 130.1, 129.6, 129.5, 128.9, 128.8, 128.1, 124.8, 124.6, 122.9, 114.8, 114.8, 62.7, 62.4, 60.9, 60.8, 55.7, 55.7, 31.8, 31.6, 31.1, 29.5, 21.0, 20.9; IR: HRMS (ESI - TOF) m / z: [M + H] + calcd for C 25 H25 O6S2 + ,485.1087,Found 485.1073.

[0104]

[0105] (4-Bromophenyl)(4-(((4-methoxyphenyl)sulfonyl)methyl)-6-methyl-1,1-dioxidothiochroman-2-yl)methanone(3da): Colorless solid(30.9 mg, 55% yield, dr=2.0:1). 1 1H NMR(500MHz, CDCl3): δ H 7.96 - 7.93(m, 2.0H), 7.91 - 7.89(m, 1.34H), 7.87(d, J=9.0Hz, 0.66H), 7.80(d, J=8.0Hz, 0.67H), 7.72(d, J=8.0Hz, 0.33H), 7.68 - 7.65(m, 2.0H), 7.27(m, 0.33H), 7.24(m, 0.67H), 7.16(s, 0.67H), 7.06 - 7.03(m, 1.67H), 7.00(d, J=9.0Hz, 0.66H), 5.33(dd, J=10.0, 4.5Hz, 0.33H), 5.19(dd, J=8.5, 6.5Hz,.0.67H), 3.97 - 3.91(m, 1.0H), 3.89(s, 2.0H), 3.85(s, 1.0H), 3.71 - 3.66(m, 1.0H), 3.54(dd, J=14.5, 8.0Hz, 0.67H), 3.40(dd, J=14.5, 3.5Hz, 0.33H), 3.10 - 3.04(m, 0.33H), 2.98 - 2.93(m, 1.34H), 2.91 - 2.86(m, 0.33H), 2.41(s, 2.0H), 2.38(s, 1.0H).; 13 13C NMR(126MHz, CDCl3): δ c188.8, 188.7, 164.1, 164.1, 144.7, 144.5, 138.6, 138.5, 135.1, 135.1, 135.0, 134.5, 132.2, 131.0, 130.9, 130.8, 130.7, 130.2, 130.1, 130.0, 129.6, 129.3, 128.9, 128.6, 124.9, 124.7, 114.8, 114.8, 63.8, 62.6, 62.4, 60.6, 55.8, 55.7, 32.0, 31.6, 31.3, 29.1, 21.7, 21.6.; IR: HRMS(ESI-TOF) m / z: [M+Na] + calcd for C 25 H 23 BrNaO6S2 + , 585.0012, Found 585.0022.

[0106]

[0107] (4-(((4-Methoxyphenyl)sulfonyl)methyl)-6-methyl-1,1-dioxidothiochroman-2-yl)(p-tolyl)methanone (3ea): Colorless solid (29.4 mg, 59% yield, dr = 2.3:1). 1 H NMR(500 MHz, CDCl3): δ H7.99 - 7.95 (m, 2.0H), 7.91 - 7.89 (m, 0.60H), 7.88 - 7.85 (m, 1.40H), 7.81 (d, J = 8.0Hz, 0.30H), 7.73 (d, J = 8.0Hz, 0.70H), 7.33 - 7.30 (m, 2.0H), 7.24 - 7.22 (m, 1.0H), 7.16 (s, 0.30H), 7.05 - 7.03 (m, 1.30H), 7.01 - 6.98 (m, 1.40H), 5.34 (dd, J = 9.5, 4.5Hz, 0.70H), 5.22 (t, J = 7.5Hz, 0.30H), 3.94 - 3.91 (m, 1.0H), 3.89 (s, 0.90H), 3.84 (s, 2.10H), 3.69 (dd, J = 14.5, 10.5Hz, 1.0H), 3.55 (dd, J = 14.5, 8.0Hz, 0.30H), 3.41 (dd, J = 14.5, 3.5Hz, 0.70H), 3.10 - 3.04 (m, 0.70H), 2.94 (t, J = 8.0Hz, 0.60H), 2.87 - 2.83 (m, 0.70H), 2.44 (s, 2.10H), 2.43 (s, 0.90H), 2.41 (s, 0.90H), 2.38 (s, 2.10H); 13 13C NMR (126MHz, CDCl3): δ c 189.1, 189.1, 164.1, 164.0, 145.7, 145.6, 144.5, 144.3, 138.7, 138.6, 135.3, 134.6, 133.9, 133.8, 130.8, 130.8, 130.2, 130.1, 129.7, 129.6, 129.5, 129.4, 129.3, 128.9, 128.6, 124.9, 124.7, 114.8, 114.7, 63.5, 62.5, 62.3, 60.9, 55.8, 55.7, 32.0, 31.7, 31.3, 29.4, 22.7, 21.8, 21.7, 21.6; IR: HRMS (ESI - TOF) m / z: [M + H] + calcd for C 26 H 27 O6S2 + , 499.1245, Found 499.1245.

[0108]

[0109] (3-Methoxyphenyl)(4-(((4-methoxyphenyl)sulfonyl)methyl)-6-methyl-1,1-dioxidothiochroman-2-yl)methanone (3fa): Colorless solid (33.9 mg, 66% yield, dr=2.3:1). 1 1H NMR (500 MHz, CDCl3): δ H 8.08 - 8.04 (m, 2.0H), 7.90 (d, J=8.7 Hz, 0.6H), 7.87 (d, J=8.7 Hz, 1.40H), 7.81 (d, J=8.0 Hz, 0.3H), 7.73 (d, J=8.0 Hz, 0.7H), 7.24 - 7.21 (m, 1.0H), 7.16 (s, 0.3H), 7.05 - 7.03 (m, 1.0H), 7.00 - 6.96 (m, 3.70H), 5.31 (dd, J=9.5, 4.5 Hz, 0.7H), 5.21 - 5.18 (m, 0.3H), 3.90 - 3.89 (m, 4.90H), 3.84 (s, 2.10H), 3.71 - 3.66 (m, 1.0H), 3.55 (dd, J=14.5, 8.0 Hz, 0.3H), 3.41 (dd, J=14.5, 3.5 Hz, 0.7H), 3.10 - 3.04 (m, 0.70H), 2.95 - 2.92 (m, 0.60H), 2.87 - 2.82 (m, 0.70H), 2.40 (s, 0.90H), 2.37 (s, 2.10H); 13 13C NMR (126 MHz, CDCl3): δ c 187.7, 187.6, 164.6, 164.6, 164.1, 164.0, 144.4, 144.3, 138.7, 138.6, 135.3, 134.7, 132.1, 132.0, 130.8, 130.7, 130.2, 130.1, 129.4, 129.4, 129.3, 129.3, 128.8, 128.6, 124.8, 124.7, 114.7, 114.7, 114.1, 63.2, 62.5, 62.1, 60.9, 55.8, 55.7, 55.6, 32.0, 31.7, 31.3, 29.3, 21.7, 21.6; IR: HRMS (ESI-TOF) m / z: [M+H] + calcd for C 26 H 27 O7S2 +,515.1193,Found 515.1190.

[0110]

[0111] (4-(((4-Methoxyphenyl)sulfonyl)methyl)-1,1-dioxidothiochroman-2-yl)(phenyl)methanone (3ga): Colorless solid (28.2 mg, 60% yield, dr=2.3:1). 1 H NMR (500 MHz, CDCl3): δ H 8.10 - 8.07 (m, 2.0H), 7.94 (dd, J=7.7, 0.75 Hz, 0.30H), 7.90 - 7.85 (m, 2.70H), 7.67 - 7.64 (m, 1.0H), 7.61 - 7.58 (m, 0.30H), 7.54 (t, J=7.5 Hz, 2.70H), 7.47 - 7.42 (m, 1.30H), 7.28 (d, J=7.5 Hz, 0.70H), 7.04 (d, J=8.7 Hz, 0.60H), 7.00 (d, J=8.7 Hz, 1.40H), 5.41 (dd, J=10.0, 5.0 Hz, 0.70H), 5.28 (dd, J=8.7, 6.7 Hz, 0.30H), 4.01 - 3.93 (m, 1.0H), 3.89 (s, 0.90H), 3.84 (s, 2.10H), 3.73 - 3.66 (m, 1.0H), 3.54 (dd, J=14.5, 8.0 Hz, 0.30H), 3.42 (dd, J=14.7, 3.7 Hz, 0.70H), 3.15 - 3.08 (m, 0.70H), 3.00 - 2.96 (m, 0.60H), 2.90 (dt, J=15.0, 4.5 Hz, 0.70H); 13 C NMR (126 MHz, CDCl3): δ c 189.5, 164.1, 164.1, 138.7, 138.6, 138.1, 137.6, 136.2, 136.1, 134.5, 134.4, 133.6, 133.4, 130.7, 130.6, 130.2, 130.1, 129.6, 129.5, 128.9, 128.9, 128.8, 128.2, 128.2, 124.8, 124.7, 114.8, 114.8, 63.5, 62.5, 62.4, 60.7, 55.8, 55.7, 32.0, 31.7, 31.3, 29.3.; IR: HRMS(ESI-TOF) m / z: [M+H] + Calculated for C 24 H 23 O6S2 + , 471.0931, Found 471.0952.

[0112]

[0113] (6-(tert-Butyl)-4-(((4-methoxyphenyl)sulfonyl)methyl)-1,1-dioxidothiochroman-2-yl)(phenyl)methanone (3ha): Colorless solid (30.0 mg, 57% yield, dr = 6.7:1), mp = 179.6 - 182.5 °C. 1 1H NMR (500 MHz, CDCl3): δ H 8.10 (d, J = 7.5 Hz, 1.74H), 8.07 (d, J = 7.5 Hz, 0.26H), 7.91 - 7.86 (m, 2.0H), 7.85 (d, J = 8.5 Hz, 0.13H), 7.77 (d, J = 8.5 Hz, 0.87H), 7.65 (t, J = 7.3 Hz, 1.0H), 7.53 (t, J = 8.0 Hz, 2.0H), 7.46 (dd, J = 8.3, 1.7 Hz, 1.0H), 7.40 (s, 0.13H), 7.21 (d, J = 1.5 Hz, 0.87H), 7.04 (d, J = 8.7 Hz, 0.26H), 7.00 (d, J = 8.7 Hz, 1.74H), 5.39 (dd, J = 10.5, 4.5 Hz, 0.87H), 5.23 (dd, J = 10.0, 5.0 Hz, 0.13H), 3.92 - 3.89 (m, 1.0H), 3.89 (s, 0.39H), 3.82 (s, 2.61H), 3.74 (dd, J = 14.5, 10.5 Hz, 0.87H), 3.66 (dd, J = 14.5, 3.5 Hz, 0.13H), 3.58 (dd, J = 15.0, 7.5 Hz, 0.13H), 3.41 (dd, J = 14.5, 3.5 Hz, 0.87H), 3.12 - 3.06 (m, 0.87H), 3.00 - 2.97 (m, 0.13H), 2.93 - 2.90 (m, 0.13H), 2.88 - 2.84 (m, 0.87H), 1.32 (s, 1.16H), 1.30 (s, 1.83H); 1313C NMR (126 MHz, CDCl3): δ c 189.5, 164.1, 157.4, 138.3, 136.4, 134.8, 134.4, 130.7, 130.2, 130.1, 129.6, 129.5, 128.8, 126.2, 125.6, 124.5, 124.4, 114.8, 114.8, 62.7, 60.5, 55.7, 35.2, 32.4, 31.0, 30.9, 29.4; IR: HRMS (ESI-TOF) m / z: [M+H] + calcd for C 28 H 31 O6S2 + , 527.1557, Found 527.1547.

[0114]

[0115] (6-Fluoro-4-(((4-methoxyphenyl)sulfonyl)methyl)-1,1-dioxidothiochroman-2-yl)(3-methoxyphenyl)methanone (3ia): Colorless solid (25.9 mg, 53% yield, dr = 2.3:1). 1 1H NMR (500 MHz, DMSO-d6): δ H8.18 (d, J = 7.5 Hz, 1.40H), 8.11 (d, J = 7.5 Hz, 0.60H), 7.91 - 7.87 (m, 3.0H), 7.77 - 7.73 (m, 1.0H), 7.62 - 7.58 (m, 2.0H), 7.47 (dd, J = 10.5 1.5 Hz, 0.30H), 7.42 - 7.39 (m, 0.70H), 7.38 - 7.34 (m, 1.0H), 7.14 (d, J = 8.5 Hz, 0.60H), 7.08 (d, J = 9.0 Hz, 1.40H), 6.17 (dd, J = 11.5, 3.0 Hz, 0.30H), 5.97 (dd, J = 11.5, 2.0 Hz, 0.70H), 4.32 (dd, J = 15.0, 9.5 Hz, 0.70H), 4.10 (dd, J = 15.0, 4.5 Hz, 0.30H), 3.94 - 3.90 (m, 0.30H), 3.85 (s, 0.9H), 3.81 (dd, J = 9.0, 4.0 Hz, 1.0H), 3.76 (s, 2.1H), 3.74 - 3.71 (m, 0.70H), 2.91 - 2.80 (m, 1.30H), 2.68 - 2.63 (m, 0.70H); 13 C NMR (126 MHz, DMSO-d6): δ c 190.1, 163.9, 163.8, 164.3 (d, J = 254.4 Hz), 164.2 (d, J = 252.1 Hz), 141.8, 141.7, 136.6, 136.4, 136.3, 135.7 (d, J = 2.8 Hz), 135.1, 135.0, 131.4, 131.3, 130.7, 130.4, 130.4, 130.1, 129.2, 129.1, 127.1, 127.0, 117.3 (d, J = 23.0 Hz), 116.8 (d, J = 23.0 Hz), 115.1, 115.0, 63.1, 60.3, 59.1, 58.1, 56.3, 56.2, 33.0, 32.5, 30.7, 27.6; 19 F NMR (470 MHz, DMSO-d6): δ F -102.5, -102.7, -103.0 (s) ppm; IR: HRMS (ESI-TOF) m / z: [M+H] + calcd for C 24 H 22 FO6S2 + , 489.0836, Found 489.0852.

[0116]

[0117] (6-Chloro-4-(((4-methoxyphenyl)sulfonyl)methyl)-1,1-dioxidothiochroman-2-yl)(phenyl)methano ne(3ja): Colorless solid (25.2 mg, 50% yield, dr=2.0:1). 1 H NMR(500MHz, DMSO-d6): δ H 8.18(d, J=7.5Hz, 1.34H), 8.10(d, J=7.5Hz, 0.66H), 7.88 - 7.86(m, 2.0H), 7.82 - 7.79(m, 1.0H), 7.77 - 7.72(m, 1.0H), 7.62 - 7.58(m, 3.0H), 7.57 - 7.53(m, 1.0H), 7.12(d, J=9.0Hz, 0.66H), 7.09(d, J=9.0Hz, 1.34H), 6.15(dd, J=11.0, 3.0Hz, 0.33H), 5.98(dd, J=11.5, 2.0Hz, 0.67H), 4.29(dd, J=14.5, 9.0Hz, 0.67H), 4.11(dd, J=15.0, 3.5Hz, 0.33H), 3.94(dd, J=14.5, 7.5Hz, 0.33H), 3.85(s, 1.0H), 3.83 - 3.80(m, 1.0H), 3.78(s, 2.0H), 3.75(dd, J=14.5, 4.0Hz, 0.67H), 2.97 - 2.89(m, 0.33H), 2.86 - 2.75(m, 1.0H), 2.69 - 2.63(m, 0.67H); 13 C NMR(126MHz, DMSO-d6): δ c 190.0, 189.5, 163.3, 163.3, 140.0, 139.9, 137.9, 137.7, 137.5, 137.5, 136.0, 135.9, 134.6, 134.5, 130.9, 130.9, 130.1, 129.9, 129.6, 128.8, 128.7, 128.6, 128.5, 114.6, 114.6, 62.6, 59.9, 58.5, 57.7, 55.8, 55.7, 32.4, 31.7, 30.0, 27.6; IR: HRMS(ESI-TOF) m / z: [M+Na] +Calculated for C 24 H 21 ClNaO6S2 + , 527.0360, Found 527.0359.

[0118]

[0119] (6-Bromo-4-(((4-methoxyphenyl)sulfonyl)methyl)-1,1-dioxidothiochroman-2-yl)(phenyl)methanone (3ka): Colorless solid (25.2 mg, 46% yield, dr=2.0:1). 1 1H NMR (500 MHz, CDCl3): δ H 8.08 - 8.05 (m, 2.0H), 7.91 - 7.86 (m, 2.0H), 7.78 (d, J=8.5 Hz, 0.67H), 7.71 (d, J=8.5 Hz, 0.33H), 7.70 - 7.65 (m, 1.0H), 7.61 - 7.58 (m, 1.0H), 7.57 - 7.53 (m, 2.0H), 7.50 (s, 0.67H), 7.41 (s, 0.33H), 7.06 (d, J=9.0 Hz, 1.34H), 7.02 (d, J=9.0 Hz, 0.67H), 5.42 (dd, J=9.0, 5.0 Hz, 0.33H), 5.28 (dd, J=9.5, 6.0 Hz, 0.67H), 4.01 - 3.93 (m, 1.0H), 3.90 (s, 2.0H), 3.86 (s, 1.0H), 3.68 - 3.63 (m, 1.0H), 3.53 (dd, J=14.5, 8.0 Hz, 0.67H), 3.43 (dd, J=14.5, 3.0 Hz, 0.33H), 3.14 - 3.08 (m, 0.33H), 3.03 - 2.98 (m, 0.67H), 2.96 - 2.90 (m, 1.0H); 13 13C NMR (126 MHz, CDCl3): δ c189.5,164.1,164.1,138.7,138.6,138.2,137.6,136.2,136.2,134.5,134.4,133.6,133.4,130.6,130.2,130.1,129.6,129.5,129.2,129.1,128.9,128.9,128.8,128.2,128.2,124.8,124.7,114.8,114.8,63.5,62.5,62.4,60.7,55.8,55.7,32.0,31.7,31.3,29.3.; IR: HRMS(ESI-TOF) m / z: [M+H] + calcd for C 24 H 22 BrO6S2 + ,549.0039, Found 549.0038.

[0120]

[0121] (4-(((4-Methoxyphenyl)sulfonyl)methyl)-8-methyl-1,1-dioxidothiochroman-2-yl)(phenyl)methanone (3la): Colorless solid (24.2 mg, 50% yield, dr=2.0:1). 1 H NMR(500 MHz, CDCl3): 1 H NMR(500 MHz, CDCl3) δ H8.15 (d, J = 7.5 Hz, 1.34H), 8.09 (d, J = 7.5 Hz, 0.66H), 7.90 - 7.85 (m, 2.0H), 7.66 (t, J = 7.5 Hz, 1.0H), 7.55 (t, J = 7.5 Hz, 2.0H), 7.35 (t, J = 7.5 Hz, 1.0H), 7.23 (d, J = 7.5 Hz, 0.33H), 7.19 (d, J = 7.5 Hz, 0.67H), 7.06 (d, J = 7.5 Hz, 1.0H), 7.00 - 6.98 (m, 2.0H), 5.42 - 5.38 (m, 1.0H), 3.90 - 3.83 (m, 1.0H), 3.84 (s, 1.0H), 3.81 (s, 2.0H), 3.72 - 3.67 (m, 0.33H), 3.66 - 3.61 (m, 0.67H), 3.41 (dd, J = 14.5, 3.5 Hz, 0.33H), 3.36 (dd, J = 15.0, 3.5 Hz, 0.67H), 3.11 - 3.05 (m, 1.0H), 2.90 - 2.86 (m, 0.33H), 2.85 - 2.80 (m, 0.67H), 2.64 (s, 2.0H), 2.38 (s, 1.0H); 13 13C NMR (126 MHz, CDCl3): δ c 189.7, 188.8, 164.1, 164.0, 138.6, 138.1, 138.1, 137.9, 137.1, 136.4, 136.2, 134.4, 132.6, 132.4, 131.8, 130.7, 130.5, 130.1, 130.1, 129.7, 129.5, 129.3, 128.8, 128.8, 126.9, 124.7, 114.8, 114.7, 63.5, 62.4, 60.7, 60.1, 55.7, 55.7, 33.2, 31.9, 29.3, 27.2, 21.6, 20.3.; IR: HRMS (ESI-TOF) m / z: [M+H] + calcd for C 25 H 25 O6S2 + , 485.1087, Found 485.1064.

[0122]

[0123] (4-(((4-Methoxyphenyl)sulfonyl)methyl)-8-methyl-1,1-dioxidothiochroman-2-yl)(phenyl)methano ne(3ma): Colorless solid(24.2 mg, 50% yield, dr=2.0:1). 1 H NMR(500MHz, CDCl3): 1 H NMR(500MHz, CDCl3) δ H 8.15(d, J=7.5Hz, 1.34H), 8.09(d, J=7.5Hz, 0.66H), 7.90 - 7.85(m, 2.0H), 7.66(t, J=7.5Hz, 1.0H), 7.55(t, J=7.5Hz, 2.0H), 7.35(t, J=7.5Hz, 1.0H), 7.23(d, J=7.5Hz, 0.33H), 7.19(d, J=7.5Hz, 0.67H), 7.06(d, J=7.5Hz, 1.0H), 7.00 - 6.98(m, 2.0H), 5.42 - 5.38(m, 1.0H), 3.90 - 3.83(m, 1.0H), 3.84(s, 1.0H), 3.81(s, 2.0H), 3.72 - 3.67(m, 0.33H), 3.66 - 3.61(m, 0.67H), 3.41(dd, J=14.5, 3.5Hz, 0.33H), 3.36(dd, J=15.0, 3.5Hz, 0.67H), 3.11 - 3.05(m, 1.0H), 2.90 - 2.86(m, 0.33H), 2.85 - 2.80(m, 0.67H), 2.64(s, 2.0H), 2.38(s, 1.0H); 13 C NMR(126MHz, CDCl3): δ c 189.7, 188.8, 164.1, 164.0, 138.6, 138.1, 138.1, 137.9, 137.1, 136.4, 136.2, 134.4, 132.6, 132.4, 131.8, 130.7, 130.5, 130.1, 130.1, 129.7, 129.5, 129.3, 128.8, 128.8, 126.9, 124.7, 114.8, 114.7, 63.5, 62.4, 60.7, 60.1, 55.7, 55.7, 33.2, 31.9, 29.3, 27.2, 21.6, 20.3.; IR: HRMS(ESI - TOF) m / z: [M + H]+ Calculated for C 25 H 25 O6S2 + , 485.1087, Found 485.1064.

[0124]

[0125] (6-Bromo-4-(((4-methoxyphenyl)sulfonyl)methyl)-1,1-dioxidothiochroman-2-yl)(4-methoxyphenyl)methanone (3na): Colorless solid (24.3 mg, 42% yield, dr = 3.0:1). 1 1H NMR (500 MHz, CDCl3): δ H 8.06 - 8.03 (m, 2.0H), 7.89 (d, J = 8.7 Hz, 0.5H), 7.86 (d, J = 8.7 Hz, 1.5H), 7.78 (d, J = 8.3 Hz, 0.25H), 7.70 (d, J = 8.3 Hz, 0.75H), 7.59 (dd, J = 8.5, 1.0 Hz, 0.25H), 7.55 (dd, J = 8.5, 2.0 Hz, 0.75H), 7.50 (s, 0.25H), 7.39 (d, J = 1.5 Hz, 0.75H), 7.06 - 6.97 (m, 4.0H), 5.34 (dd, J = 9.3, 4.7 Hz, 0.75H), 5.22 (dd, J = 8.3, 5.7 Hz, 0.25H), 3.94 - 3.92 (m, 1.0H), 3.90 - 3.90 (m, 3.75H), 3.86 (s, 2.25H), 3.69 - 3.63 (m, 1.0H), 3.54 (dd, J = 14.5, 7.7 Hz, 0.25H), 3.43 (dd, J = 14.5, 4.0 Hz, 0.75H), 3.12 - 3.06 (m, 0.75H), 2.98 - 2.93 (m, 0.5H), 2.91 - 2.86 (m, 0.75H); 13 13C NMR (126 MHz, CDCl3): δ c187.4, 187.3, 164.8, 164.8, 164.2, 164.2, 140.7, 140.6, 136.9, 136.4, 132.1, 132.0, 131.9, 131.8, 131.5, 131.1, 130.5, 130.5, 130.2, 130.2, 129.2, 129.1, 128.4, 128.1, 126.5, 126.3, 114.9, 114.8, 114.2, 114.2, 63.2, 62.0, 61.9, 60.8, 55.8, 55.7, 55.7, 55.6, 31.8, 31.7, 31.2, 29.6; IR: HRMS(ESI-TOF) m / z: [M+H] + calcd for C 25 H 24 BrO7S2 + , 579.0141, Found 579.0161.

[0126]

[0127] (6-Methoxy-4-(((4-methoxyphenyl)sulfonyl)methyl)-1,1-dioxidothiochroman-2-yl)(4-methoxyphenyl)methanone (3oa): Colorless solid (24.4 mg, 46% yield, dr = 2.0:1). 1 H NMR(500 MHz, CDCl3): 1 H NMR(500 MHz, CDCl3) δ H8.07 - 8.05 (m, 2.0H), 7.90 - 7.85 (m, 2.33H), 7.78 (d, J = 9.0Hz, 0.67H), 7.04 (d, J = 8.5Hz, 0.67H), 7.01 - 6.97 (m, 3.33H), 6.94 - 6.90 (m, 1.33H), 6.74 (d, J = 2.0Hz, 0.67H), 5.29 (dd, J = 9.5, 5.0Hz, 0.67H), 5.20 (dd, J = 8.7, 6.3Hz, 0.33H), 3.94 - 3.90 (m, 1.0H), 3.90 - 3.89 (m, 3.90H), 3.87 (s, 0.90H), 3.85 - 3.84 (m, 4.20H), 3.74 - 3.66 (m, 1.0H), 3.56 (dd, J = 14.5, 7.5Hz, 0.33H), 3.42 (dd, J = 14.5, 3.5Hz, 0.67H), 3.11 - 3.05 (m, 0.67H), 2.94 - 2.89 (m, 0.66H), 2.85 - 2.80 (m, 0.67H); 13 13C NMR (126MHz, CDCl3): δ c 187.8, 187.7, 164.7, 164.6, 164.1, 164.1, 163.4, 163.1, 141.2, 141.1, 132.1, 132.0, 130.7, 130.7, 130.2, 130.1, 129.9, 129.9, 129.4, 129.4, 129.2, 127.1, 126.9, 114.8, 114.8, 114.2, 114.1, 113.7, 113.6, 113.3, 63.4, 62.3, 62.2, 61.0, 55.8, 55.7, 55.7, 55.6, 32.3, 31.9, 31.5, 29.7, 29.3, 29.2.; IR: HRMS (ESI - TOF) m / z: [M + H] + calcd for C 26 H 27 O8S2 + , 531.1142, Found 531.1160.

[0128]

[0129] (6-Methyl-1,1-dioxido-4-((o-tolylsulfonyl)methyl)thiochroman-2-yl)(phenyl)methanone(3ab): Colorless solid(24.8 mg, 53% yield, dr=2.0:1). 1 H NMR(500MHz, CDCl3): δ H 8.09(d, J=7.7Hz, 1.34H), 8.06(d, J=7.7Hz, 0.66H), 7.81 - 7.71(m, 3.0H), 7.64(t, J=7.5Hz, 1.0H), 7.54 - 7.47(m, 3.0H), 7.42(d, J=8.0Hz, 1.0H), 7.27 - 7.26(m, 0.33H), 7.22(d, J=8.0Hz, 0.67H), 7.15(s, 0.33H), 7.06(s, 0.67H), 5.41(dd, J=9.7, 4.7Hz, 0.67H), 5.27(t, J=7.5Hz, 0.33H), 3.98 - 3.92(m, 1.0H), 3.74 - 3.67(m, 1.0H), 3.59 - 3.55(m, 0.33H), 3.43(dd, J=14.5, 3.5Hz, 0.67H), 3.12 - 3.06(m, 0.67H), 2.98 - 2.95(m, 0.56H), 2.90 - 2.86(m, 0.67H), 2.45(s, 1.0H), 2.41(s, 2.0H), 2.40(s, 1.0H), 2.37(s, 2.0H); 13 C NMR(126MHz, CDCl3): δ c 189.6, 144.5, 144.3, 134.0, 139.1, 139.1, 138.5, 138.4, 136.2, 136.2, 135.2, 134.9, 134.9, 134.6, 134.4, 134.4, 129.7, 129.5, 129.5, 129.4, 129.3, 129.2, 128.9, 128.8, 128.6, 128.2, 128.1, 125.0, 124.9, 124.8, 124.6, 63.5, 62.4, 62.1, 60.4, 31.7, 31.7, 31.1, 29.4, 21.7, 21.5, 21.3, 21.3; IR: HRMS(ESI - TOF)m / z: [M + H] + calcd for C 25 H 25 O5S2+ ,469.1138,Found 469.1130.

[0130]

[0131] (4 - (((2 - Bromophenyl)sulfonyl)methyl)-6 - methyl - 1,1 - dioxidothiochroman - 2 - yl)(phenyl)methanone (3bb): Colorless solid (22.9 mg, 43% yield, dr = 2.0:1). 1 1H NMR (500 MHz, CDCl3): δ H 8.23 (dd, J = 7.5, 1.5 Hz, 0.33H), 8.19 (dd, J = 7.5, 1.5 Hz, 0.67H), 8.10 (d, J = 7.5 Hz, 1.33H), 8.07 (d, J = 7.5 Hz, 0.67H), 7.84 - 7.80 (m, 1.0H), 7.76 (d, J = 8.0 Hz, 0.67H), 7.71 (d, J = 8.0 Hz, 0.33H), 7.67 - 7.63 (m, 1.0H), 7.57 - 7.50 (m, 3.34H), 7.46 - 7.43 (m, 0.67H), 7.29 - 7.26 (m, 1.0H), 7.25 (s, 0.33H), 7.15 (s, 0.67H), 5.46 (dd, J = 10.0, 4.5 Hz, 0.67H), 5.25 (dd, J = 9.5, 5.5 Hz, 0.33H), 4.11 - 4.06 (m, 1.0H), 4.03 - 3.95 (m, 1.0H), 3.87 (dd, J = 14.5, 8.0 Hz, 0.33H), 3.78 (dd, J = 14.5, 3.0 Hz, 0.67H), 3.12 - 3.06 (m, 0.67H), 3.04 - 2.99 (m, 0.67H), 2.87 - 2.83 (m, 0.67H), 2.43 (s, 1.0H), 2.40 (s, 2.0H); 13 13C NMR (126 MHz, CDCl3): δ c189.5, 144.5, 144.4, 138.5, 138.4, 138.2, 138.1, 136.3, 136.2, 135.7, 135.6, 135.5, 135.2, 135.0, 134.4, 131.9, 131.8, 129.6, 129.5, 129.5, 129.3, 129.0, 128.8, 128.8, 128.6, 128.4, 128.3, 124.8, 124.7, 120.9, 120.7, 63.5, 62.2, 59.9, 57.9, 31.9, 31.6, 31.1, 29.1, 21.7, 21.6; IR: HRMS(ESI-TOF) m / z: [M+H] + calcd for C 24 H 22 BrO5S2 + , 533.0087, Found 533.0103.

[0132]

[0133] (4-(((2-Methoxyphenyl)sulfonyl)methyl)-6-methyl-1,1-dioxidothiochroman-2-yl)(phenyl)methano ne(3cb): Colorless solid (21.8 mg, 45% yield, dr=2.3:1). 1 H NMR(500 MHz, CDCl3): δ H8.09 (dd, J = 8.3, 1.3 Hz, 1.40H), 8.06 (dd, J = 8.3, 1.3 Hz, 0.6H), 7.99 (dd, J = 7.7, 1.7 Hz, 0.3H), 7.96 (dd, J = 7.7, 1.7 Hz, 0.7H), 7.82 (d, J = 8.0 Hz, 0.3H), 7.74 (d, J = 8.0 Hz, 0.7H), 7.67 - 7.61 (m, 1.4H), 7.56 - 7.48 (m, 2.6H), 7.25 - 7.23 (m, 1.0H), 7.14 (d, J = 7.7 Hz, 0.3H), 7.11 (d, J = 7.7 Hz, 0.7H), 7.09 - 7.06 (m, 1.3H), 6.95 (d, J = 8.3 Hz, 0.7H), 5.42 (dd, J = 10.3, 4.7 Hz, 0.7H), 5.21 (dd, J = 10.3, 4.7 Hz, 0.3H), 4.03 - 3.98 (m, 1.9H), 3.96 (s, 2.10H), 3.92 - 3.84 (m, 1.3H), 3.76 (dd, J = 14.3, 3.7 Hz, 0.7H), 3.08 - 3.02 (m, 0.7H), 2.98 - 2.93 (m, 0.3H), 2.91 - 2.86 (m, 0.3H), 2.82 - 2.77 (m, 0.7H), 2.42 (s, 0.9H), 2.37 (s, 2.1H); 13 13C NMR (126 MHz, CDCl3): δ c 189.6, 189.5, 157.3, 157.1, 144.3, 144.1, 138.6, 138.5, 136.4, 136.2, 136.1, 136.0, 135.6, 134.9, 134.4, 134.3, 130.3, 130.2, 129.5, 129.5, 129.4, 129.0, 128.8, 128.8, 127.0, 124.7, 124.6, 121.1, 120.9, 112.5, 112.5, 63.5, 62.6, 60.8, 58.3, 56.5, 56.4, 32.0, 31.6, 31.3, 29.5, 21.7, 21.6; IR: HRMS (ESI - TOF) m / z: [M + H] + calcd for C 25 H 25 O6S2 + , 485.1087, Found 485.1085.

[0134]

[0135] (4-(((3-Chlorophenyl)sulfonyl)methyl)-6-methyl-1,1-dioxidothiochroman-2-yl)(phenyl)methanone (3db): Colorless solid (23.9 mg, 49% yield, dr=2.3:1). 1 1H NMR (500 MHz, CDCl3): δ H 8.09 (d, J=8.0 Hz, 1.4H), 8.07 (d, J=8.0 Hz, 0.6H), 7.94 (d, J=9.5 Hz, 1.0H), 7.86 - 7.80 (m, 1.4H), 7.72 (d, J=8.0 Hz, 0.6H), 7.64 (t, J=7.5 Hz, 1.4H), 7.59 (d, J=8.0 Hz, 0.6H), 7.54 - 7.48 (m, 3.0H), 7.26 (m, 0.3H), 7.23 (d, J=8.0 Hz, 0.7H), 7.16 (s, 0.3H), 7.09 (s, 0.7H), 5.46 (dd, J=9.5, 5.0 Hz, 0.7H), 5.28 (dd, J=8.7, 5.7 Hz, 0.3H), 4.00 - 3.97 (m, 1.0H), 3.77 - 3.71 (m, 1.0H), 3.64 (dd, J=14.5, 8.0 Hz, 0.3H), 3.48 (dd, J=14.0, 3.7 Hz, 0.7H), 3.15 - 3.09 (m, 0.7H), 3.03 - 2.95 (m, 0.6H), 2.92 - 2.87 (m, 0.7H), 2.42 (s, 0.9H), 2.39 (s, 2.1H); 13 13C NMR (126 MHz, CDCl3): δ c 189.7, 189.6, 144.7, 144.5, 141.1, 141.0, 138.3, 138.2, 136.2, 136.1, 135.8, 135.8, 134.5, 134.4, 134.4, 134.3, 134.2, 130.9, 130.8, 129.6, 129.6, 129.5, 129.3, 129.0, 128.8, 128.8, 128.8, 128.0, 127.9, 126.1, 126.0, 124.9, 124.7, 63.5, 62.5, 62.0, 60.4, 31.6, 31.6, 31.0, 29.7, 21.7, 21.6; IR: HRMS (ESI - TOF) m / z: [M + H] + calcd for C 24H 22 ClO5S2 + ,489.0592,Found 489.0611.

[0136]

[0137] (6-Methyl-1,1-dioxido-4-((m-tolylsulfonyl)methyl)thiochroman-2-yl)(phenyl)methanone(3eb):Colorless solid(24.3 mg,52%yield,dr=2.3:1). 1 1H NMR(500MHz,CDCl3):δ H 1 1H NMR(500MHz,CDCl3)8.10 - 8.06(m,2.0H),7.82(d,J = 8.0Hz,0.3H),7.78 - 7.72(m,2.7H),7.67 - 7.63(m,1.0H),7.53(t,J = 7.5Hz,2.0H),7.49 - 7.48(m,0.7H),7.44 - 7.41(m,1.3H),7.25(d,J = 8.0Hz,0.3H),7.23(d,J = 8.0Hz,0.7H),7.16(s,0.3H),7.07(s,0.7H),5.41(dd,J = 10.0,5.0Hz,0.7H),5.25(t,J = 8.0Hz,0.3H),3.98 - 3.93(m,1.0H),3.74 - 3.67(m,1.0H),3.58(dd,J = 14.5,8.0Hz,0.3H),3.43(dd,J = 14.5,4.0Hz,0.7H),3.13 - 3.07(m,0.7H),2.96(t,J = 7.5Hz,0.6H),2.91 - 2.86(m,0.7H),2.47(s,0.9H),2.43(s,2.1H),2.41(s,0.9H),2.38(s,2.1H); 13 13C NMR(126MHz,CDCl3):δ c189.6, 144.5, 144.3, 140.0, 139.1, 139.1, 138.5, 138.4, 136.3, 136.2, 135.2, 134.9, 134.9, 134.6, 134.4, 134.3, 129.7, 129.5, 129.5, 129.4, 129.3, 129.2, 128.9, 128.8, 128.6, 128.2, 128.1, 125.0, 124.9, 124.8, 124.6, 63.5, 62.4, 62.1, 60.4, 31.8, 31.7, 31.1, 29.4, 21.7, 21.5, 21.3, 21.3; IR: HRMS(ESI-TOF) m / z: [M+H] + calcd for C 25 H 25 O5S2 + , 469.1138, Found 469.1134.

[0138]

[0139] 4-(((3-Methoxyphenyl)sulfonyl)methyl)-6-methyl-1,1-dioxidothiochroman-2-yl)(phenyl)methanone (3fb): Colorless solid (22.8 mg, 47% yield, dr = 7.3:1), mp = 186.3 - 189.6 °C. 1 1H NMR (500 MHz, CDCl3): δ H8.09 (d, J = 7.5 Hz, 2.0H), 7.81 (d, J = 8.5 Hz, 0.12H), 7.73 (d, J = 8.0 Hz, 0.88H), 7.65 (t, J = 7.5 Hz, 1.0H), 7.53 (t, J = 8.0 Hz, 3.0H), 7.48 - 7.42 (m, 1.76H), 7.37 - 7.33 (m, 0.24H), 7.23 (d, J = 8.0 Hz, 1.0H), 7.19 (dd, J = 9.0, 2.5 Hz, 0.12H), 7.13 (dd, J = 8.5, 2.5 Hz, 0.88H), 7.06 (s, 1.0H), 5.40 (dd, J = 9.5, 5.0 Hz, 0.88H), 5.30 - 5.25 (m, 0.12H), 3.97 - 3.93 (m, 1.0H), 3.86 (s, 2.64H), 3.84 (s, 0.36H), 3.75 - 3.70 (m, 1.0H), 3.46 (dd, J = 14.5, 3.5 Hz, 0.88H), 3.42 (dd, J = 14.5, 3.5 Hz, 0.12H), 3.13 - 3.07 (m, 1.0H), 2.90 - 2.85 (m 1.0H), 2.39 (s, 0.36H), 2.38 (s, 2.64H); 13 13C NMR (126 MHz, CDCl3): δ c 189.7, 189.7, 164.1, 160.2, 144.4, 144.4, 140.4, 138.7, 138.6, 136.3, 134.6, 134.5, 134.4, 134.4, 130.7, 130.7, 130.2, 130.1, 129.6, 129.5, 129.5, 129.3, 129.3, 128.8, 127.9, 124.7, 124.7, 120.5, 119.9, 114.7, 112.3, 112.3, 62.5, 62.5, 60.8, 60.4, 55.8, 55.7, 31.9, 31.8, 29.5, 29.4, 21.6, 21.6; IR: HRMS (ESI - TOF) m / z: [M + H] + calcd for C 25 H 25 O6S2 + , 485.1087, Found 485.1097.

[0140]

[0141] (6-Methyl-1,1-dioxido-4-((phenylsulfonyl)methyl)thiochroman-2-yl)(phenyl)methanone(3gb): Colorless solid(25.0 mg, 55% yield, dr=2.3:1). 1 H NMR(500MHz, CDCl3): δ H 8.09(dd, J=8.0, 1.0Hz, 1.4H), 8.07(dd, J=8.0, 1.0Hz, 0.6H), 7.99 - 7.97(m, 0.6H), 7.96 - 7.94(m, 1.4H), 7.80(d, J=8.0Hz, 0.3H), 7.72(d, J=8.0Hz, 0.7H), 7.67 - 7.60(m, 2.0H), 7.58 - 7.49(m, 4.0H), 7.25 - 7.22(m, 1.0H), 7.15(s, 0.3H), 7.05(s, 0.7H), 5.43(dd, J=9.5, 4.5Hz, 0.7H), 5.26(t, J=7.5Hz, 0.3H), 3.99 - 3.93(m, 1.0H), 3.76 - 3.69(m, 1.0H), 3.60(dd, J=14.5, 8.0Hz, 0.3H), 3.46(dd, J=14.5, 3.5Hz, 0.7H), 3.13 - 3.07(m, 0.7H), 2.97 - 2.94(m, 0.6H), 2.91 - 2.86(m, 0.7H), 2.40(s, 0.9H), 2.37(s, 2.1H); 13 C NMR(126MHz, CDCl3): δ c 189.7, 189.6, 144.6, 144.4, 139.3, 139.3, 138.6, 138.4, 136.3, 136.2, 135.2, 134.5, 134.4, 134.4, 134.2, 134.1, 129.6, 129.6, 129.5, 129.3, 128.9, 128.8, 128.6, 127.9, 127.9, 124.9, 124.7, 63.5, 62.5, 62.2, 60.5, 31.7, 31.7, 31.1, 29.5, 21.7, 21.6; IR: HRMS(ESI - TOF)m / z: [M + H] + calcd for C 24 H 23 O5S2 +,455.0981,Found 455.0977.

[0142]

[0143] (6-Methyl-1,1-dioxido-4-(tosylmethyl)thiochroman-2-yl)(phenyl)methanone(3hb): Colorless solid (28.1 mg, 60% yield, dr=11.5:1), mp=187.4 - 190.2℃. 1 1H NMR (500 MHz, CDCl3): δ H 8.09 (d, J=8.0 Hz, 2.0H), 7.86 - 7.80 (m, 2.08H), 7.73 (d, J=8.0 Hz, 0.92H), 7.65 (t, J=7.0 Hz, 1.0H), 7.53 (t, J=7.5 Hz, 2.0H), 7.39 (d, J=8.0 Hz, 0.16H), 7.34 (d, J=8.0 Hz, 1.84H), 7.23 (d, J=8.0 Hz, 1.0H), 7.15 (s, 0.08H), 7.05 (s, 0.92H), 5.37 (dd, J=9.5, 4.5 Hz, 0.92H), 5.25 (t, J=7.5 Hz, 0.08H), 3.94 - 3.89 (m, 1.0H), 3.71 (dd, J=14.5, 10.5 Hz, 1.0H), 3.55 (dd, J=14.5, 8.0 Hz, 0.08H), 3.42 (dd, J=14.5, 3.5 Hz, 0.92H), 3.11 - 3.05 (m, 0.92H), 2.96 - 2.93 (m, 0.18H), 2.89 - 2.84 (m, 0.92H), 2.46 (s, 0.47H), 2.39 (s, 2.73H), 2.38 (s, 2.8H); 13 13C NMR (126 MHz, CDCl3): δ c 189.7, 189.6, 145.4, 145.3, 144.5, 144.4, 138.6, 138.4, 136.3, 136.3, 136.2, 136.2, 135.2, 134.6, 134.4, 134.4, 130.2, 129.5, 129.5, 129.3, 128.9, 128.8, 128.6, 128.0, 127.9, 124.8, 124.6, 63.5, 62.4, 62.2, 60.5, 31.9, 31.7, 31.2, 29.3, 21.7, 21.7, 21.6, 21.5.; IR: HRMS(ESI-TOF) m / z: [M+H] + calcd for C 25 H 25 O5S2 + , 469.1138, Found 469.1123.

[0144]

[0145] (4-(((4-(tert-Butyl)phenyl)sulfonyl)methyl)-6-methyl-1,1-dioxidothiochroman-2-yl)(phenyl)methanone (3ib): Colorless solid (29.1 mg, 57% yield, dr=2.3:1). 1 1H NMR (500 MHz, CDCl3): δ H 8.10 (d, J=8.0 Hz, 1.4H), 8.06 (d, J=8.0 Hz, 0.6H), 7.88 (d, J=8.5 Hz, 0.6H), 7.86 (d, J=8.5 Hz, 1.4H), 7.80 (d, J=8.0 Hz, 0.3H), 7.71 (d, J=8.0 Hz, 0.7H), 7.64 (t, J=7.0 Hz, 1.0H), 7.59 (d, J=8.5 Hz, 0.6H), 7.56 (d, J=8.5 Hz, 1.4H), 7.51 (dd, J=15.5, 7.0 Hz, 2.0H), 7.25 - 7.20 (m, 1.0H), 7.13 (s, 0.3H), 7.04 (s, 0.7H), 5.45 (dd, J=9.5, 4.5 Hz, 0.7H), 5.26 (t, J=7.5 Hz, 0.3H), 3.98 - 3.92 (m, 1.0H), 3.74 - 3.68 (m, 1.0H), 3.56 (dd, J=14.0, 8.0 Hz, 0.3H), 3.43 (dd, J=14.5, 3.5 Hz, 0.7H), 3.13 - 3.07 (m, 0.7H), 2.95 (t, J=7.5 Hz, 0.6H), 2.96 - 2.85 (m, 0.7H), 2.39 (s, 0.9H), 2.36 (s, 2.1H), 1.34 (s, 2.7H), 1.31 (s, 6.3H); 13 13C NMR (126 MHz, CDCl3): δ c189.7, 189.6, 158.2, 158.2, 144.4, 144.3, 138.7, 138.5, 136.4, 136.3, 136.3, 136.3, 135.3, 134.7, 134.4, 134.3, 129.5, 129.4, 129.3, 128.8, 128.6, 127.8, 127.7, 126.5, 124.8, 124.6, 63.6, 62.5, 62.2, 60.5, 35.3, 35.3, 31.8, 31.7, 31.2, 31.0, 31.0, 29.5, 21.7, 21.5; IR: HRMS(ESI-TOF) m / z: [M+H] + calcd for C 28 H 31 O5S2 + , 511.1607, Found 511.1616.

[0146]

[0147] (4-(((4-Chlorophenyl)sulfonyl)methyl)-6-methyl-1,1-dioxidothiochroman-2-yl)(phenyl)methanone (3jb): Colorless solid (26.8 mg, 55% yield, dr = 1.5:1). 1 H NMR(500 MHz, CDCl3): δ H8.10 - 8.06 (m, 2H), 7.91 (d, J = 8.5 Hz, 0.8H), 7.88 (d, J = 8.5 Hz, 1.2H), 7.81 (d, J = 8.0 Hz, 0.4H), 7.73 (d, J = 8.0 Hz, 0.6H), 7.67 - 7.63 (m, 1.0H), 7.57 - 7.50 (m, 4.0H), 7.26 (d, J = 6.5 Hz, 0.4H), 7.24 (d, J = 8.0 Hz, 0.6H), 7.15 (s, 0.4H), 7.06 (s, 0.6H), 5.44 (dd, J = 9.5, 5.0 Hz, 0.6H), 5.27 (dd, J = 8.5, 6.0 Hz, 0.4H), 4.00 - 3.94 (m, 1.0H), 3.76 - 3.68 (m, 1.0H), 3.63 (dd, J = 14.0, 7.5 Hz, 0.4H), 3.46 (dd, J = 14.5, 3.5 Hz, 0.6H), 3.14 - 3.08 (m, 0.6H), 3.02 - 2.93 (m, 0.8H), 2.93 - 2.87 (m, 0.6H), 2.41 (s, 1.2H), 2.38 (s, 1.8H).; 13 13C NMR (126 MHz, CDCl3): δ c 189.8, 189.7, 144.6, 144.5, 141.0, 141.0, 138.5, 138.3, 137.8, 137.8, 136.2, 136.2, 135.1, 134.5, 134.4, 134.4, 1299, 129.6, 129.5, 129.5, 129.4, 129.4, 129.3, 129.0, 128.9, 128.8, 128.7, 125.0, 124.8, 63.6, 62.6, 62.0, 60.6, 31.7, 31.6, 31.0, 29.7, 21.7, 21.6.; IR: HRMS (ESI - TOF) m / z: [M + H] + calcd for C 24 H 22 ClO5S2 + , 489.0592, Found 489.0571.

[0148]

[0149] 4-(((4-Bromophenyl)sulfonyl)methyl)-6-methyl-1,1-dioxidothiochroman-2-yl)(phenyl)methanone(3kb): Colorless solid(27.1 mg, 51% yield, dr=2.3:1). 1 1H NMR(500 MHz, CDCl3): δ H 8.10 - 8.06(m, 2.0H), 7.83 - 7.78(m, 2.0H), 7.73 - 7.68(m, 3.0H), 7.66 - 7.63(m, 1.0H), 7.53(t, J = 7.5 Hz, 2.0H), 7.25 - 7.22(m, 1.0H), 7.14(s, 0.3H), 7.05(s, 0.7H), 5.45(dd, J = 9.0, 4.5 Hz, 0.7H), 5.28(dd, J = 8.5, 6.0 Hz, 0.3H), 3.99 - 3.93(m, 1.0H), 3.76 - 3.68(m, 1.0H), 3.62(dd, J = 14.5, 8.0 Hz, 0.3H), 3.46(dd, J = 14.5, 4.0 Hz, 0.7H), 3.13 - 3.07(m, 0.7H), 3.02 - 2.94(m, 0.6H), 2.93 - 2.86(m, 0.7H), 2.41(s, 0.9H), 2.38(s, 2.1H); 13 13C NMR(126 MHz, CDCl3): δ c 189.8, 189.7, 144.6, 144.5, 138.4, 138.3, 136.2, 136.2, 135.1, 134.5, 134.4, 134.4, 133.0, 132.9, 129.7, 129.6, 129.6, 129.5, 129.5, 129.4, 129.3, 129.0, 128.9, 128.8, 128.7, 125.0, 124.8, 63.6, 62.6, 62.0, 60.5, 31.7, 31.6, 31.0, 29.7, 21.7, 21.6; IR: HRMS(ESI - TOF) m / z: [M + H] + calcd for C 24 H 22 BrO5S2 + , 533.0087, Found 533.0077.

Claims

1. A compound of dihydrobenzothiopyran-1,1-dioxide, characterized in that, Having the structure shown by Formula 3aa, Formula 3ba, Formula 3ca, Formula 3da, Formula 3ea, Formula 3fa, Formula 3ga, Formula 3ha, Formula 3ia, Formula 3ja, Formula 3ka, Formula 3la, Formula 3ma, Formula 3na, Formula 3oa, Formula 3ab, Formula 3bb, Formula 3cb, Formula 3db, Formula 3eb, Formula 3fb, Formula 3gb, Formula 3hb, Formula 3ib, Formula 3jb or Formula 3kb:

2. A method for preparing a dihydrobenzothiopyran-1,1-dioxide compound, characterized in that, Including: Compound 1, Compound 2 and a photocatalyst are subjected to a catalytic reaction under a nitrogen atmosphere irradiated with visible light, and then the reaction product is purified to obtain Compound 3; Wherein Compound 1 has the structure shown by Formula 1, Compound 2 has the structure shown by Formula 2, and Compound 3 has the structure shown by Formula 3: When R1 is H, 2-substituted methoxy, 3-substituted methoxy, para-substituted bromine, para-substituted methyl, para-substituted methoxy, R2 is para-methyl, and R3 is methoxy; When R1 is H, R2 is H, para-substituted tert-butyl, para-substituted fluorine, para-substituted chlorine, para-substituted bromine, 2-substituted methyl or 3-substituted methyl, and R3 is methoxy; When R1 is para-substituted methoxy, R2 is para-substituted bromine or para-substituted methoxy, and R3 is methoxy; When R1 is H, R2 is para-methyl, and R3 is 2-methyl, 2-bromine, 2-methoxy, 3-chlorine, 3-methyl, 3-methoxy, H, para-methyl, para-tert-butyl, para-chlorine or para-bromine.

3. The method according to claim 2, wherein At least one of an alkali, a solvent and an additive may be further included in the raw materials of the catalytic reaction; the alkali is selected from at least one of potassium hydrogen phosphate, 2,6-dimethylpyridine, potassium bicarbonate, sodium tert-butoxide, potassium carbonate and sodium hydrogen phosphate; the solvent is selected from acetonitrile, dimethyl sulfoxide, acetone, 1,4-dioxane, chloroform, tetrahydrofuran and a co-solvent system of 1,4-dioxane / water, wherein the volume ratio of 1,4-dioxane to water in the co-solvent system of 1,4-dioxane / water is (10:1)-(1:1); the additive is selected from at least one of sodium persulfate, potassium persulfate and ammonium persulfate.

4. The method according to claim 3, wherein The alkali is selected from potassium bicarbonate.

5. The method according to claim 3, characterized in that, The solvent is selected from a co-solvent system with a volume ratio of 1,4-dioxane to water of 5:

1.

6. The method according to claim 3, characterized in that The additive is selected from sodium persulfate.

7. The method according to claim 2, wherein The photocatalyst is selected from at least one of iridium tris(2-phenylpyridine), (4,4'-di-tert-butyl-2,2'-bipyridine)di[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl-KN)phenylKC]IRID, ruthenium(III) chloride tris(2,2'-bipyridyl) hexahydrate and eosin Y.

8. The method according to claim 3, wherein The alkali is selected from potassium hydrogen phosphate; the additive is selected from sodium persulfate; the photocatalyst is selected from iridium tris(2-phenylpyridine); the molar ratio of Compound 1:Compound 2:iridium tris(2-phenylpyridine):sodium persulfate:potassium hydrogen phosphate = 40:80:1:80:80; the solvent is selected from a co-solvent system with a volume ratio of 1,4-dioxane to water of 5:1.

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