Dihydrobenzothiapyran compound as well as synthesis method and application thereof

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a dihydrobenzothiapyran compound as well as a synthesis method and application thereof. The structure of the dihydrobenzothiapyran compound is shown as a formula III or a formula IV. The invention also provides a synthesis method of the dihydrobenzothiapyran compound, which does not need a metal catalyst, is mild in reaction condition and wide in substrate applicability, and realizes controllable derivatization of the product.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a dihydrobenzothiam compound, its synthesis method, and its application. Background Technology

[0002] Benzothioheterocyclic compounds play a crucial role in organic synthesis as key intermediates, and are widely found in many functional materials, pharmaceuticals, and bioactive natural products. Therefore, the synthesis of benzothioheterocyclic compounds has always been a key research focus. Dihydrobenzothiarans are an important class of benzothioheterocyclic compounds, and are also recognized structural units in candidate drugs and bioactive compounds. For example, neomycin typically exhibits significant antibacterial activity; meticrane is a diuretic that inhibits the reabsorption of sodium and chloride ions in the distal convoluted tubule and is often used to treat essential hypertension; tetalol is an effective antagonist of β-adrenergic and serotonin receptors, possessing a unique renal vasodilatory effect. Since the benzothioheterocyclic functional groups embedded in these molecules significantly affect their biological properties, obtaining functionalized dihydrobenzothiarans is of significant practical importance for modern drug research and development.

[0003] Numerous synthetic strategies for dihydrobenzothiarans have been reported in the last decade or so. The earliest methods involved the Friedel-Crafts reaction of corresponding acyl chlorides or acids to synthesize thiobenzothiarans, followed by carbonyl reduction. Other methods included the formation of new CS bonds through coupling reactions catalyzed by transition metals Pd / Cu with additional sulfur sources; cyclization of dihydrobenzothiarans via a CH functional strategy using metal Pd; Ni-catalyzed intramolecular cyclization reactions; and Mo-mediated intramolecular dehydrogenation coupling reactions to construct CS bonds. Acid-catalyzed tandem hydrosulfidation / Friedel-Crafts reaction of 1,3-dienes is used to construct dihydrobenzothiarans. However, existing strategies for constructing dihydrobenzothiarans suffer from cumbersome synthetic steps, poor substrate adaptability, the use of expensive metal catalysts, and the potential for metal residues in the final product, limiting their application in the pharmaceutical field and causing environmental pollution. Therefore, developing a synthetic strategy with readily available starting materials, mild reaction conditions, and a green approach remains a significant challenge. Summary of the Invention

[0004] The present invention aims to solve the above-mentioned technical problems and provide a method for synthesizing dihydrobenzothiaran compounds that does not require metal catalysts, has mild reaction conditions, and has wide substrate applicability, and achieves controllable derivatization of the products.

[0005] The technical solution of this invention is as follows:

[0006] A dihydrobenzothiaran compound, with a structure as shown in Formula III or Formula IV:

[0007]

[0008] Among them, R 1 Selected from one of -H, -OCH3, -CH3, -F, -Cl, -Br; R 2 It is selected from one of -H, -F, -Br, -Cl, -CF3, -COOCH3, and -CH3.

[0009] The method for synthesizing dihydrobenzothiaran compounds according to the present invention includes the following steps: in a solvent environment, with the participation of an acid catalyst, an allene compound reacts with a thiophenol compound to generate dihydrobenzothiaran compounds.

[0010] Further, the acid catalyst is trifluoromethanesulfonic acid (TfOH) or trifluoroacetic acid (TFA), the solvent is dichloromethane (DCM), toluene, 1,4-dioxane, tetrahydrofuran (THF), acetonitrile or 1,2-dichloroethane, and the reaction conditions are at room temperature under argon protection.

[0011] Furthermore, the allene compound has the structure shown in Formula I:

[0012]

[0013] Among them, R 1 It is selected from one of -H, -OCH3, -CH3, -F, -Cl, and -Br.

[0014] Furthermore, the thiophenol compound has the structure shown in Formula II:

[0015]

[0016] Among them, R 2 It is selected from one of -H, -F, -Br, -Cl, -CF3, -COOCH3, and -CH3.

[0017] Preferably, the molar ratio of the allene compound to the thiophenol compound is 1:(1-1.2), the amount of the acid catalyst trifluoromethanesulfonic acid ranges from 10-46 mol%, and the reaction time is 7 hours.

[0018] The present invention also provides the application of the above-mentioned dihydrobenzothiaran compounds in the preparation of inhibitors for inhibiting the growth of Staphylococcus aureus.

[0019] Due to the adoption of the above technical solution, the beneficial effects of the present invention are as follows:

[0020] (1) This invention is the first to develop A novel acid-catalyzed hydrosulfonation / cascade Friedel-Crafts cyclization method for allenes eliminates the expensive metal catalysts and complex steps of traditional methods, achieving efficient and green synthesis of dihydrobenzothiaran compounds. The reaction proceeds at room temperature, without the need for high temperature or pressure, offering mild conditions and high atom utilization, aligning with the trend of green chemistry and providing a new approach for the sustainable synthesis of complex sulfur heterocyclic compounds.

[0021] (2) This invention exhibits excellent compatibility with both arylthiophenols and allene substrates. Thiophene substrates cover para, meta, and ortho substituents (including electron-donating groups such as -CH3 and electron-withdrawing groups such as -F / -Br / -CF3), while allene substrates cover unsubstituted, monosubstituted, and naphthyl-substituted structures, all capable of generating the target product in moderate to good yields (40%-78%). In particular, the activity of ortho-substituted thiophenols and naphthyl-substituted allenes overcomes the limitations of traditional methods, significantly expanding the substrate range.

[0022] (3) The reaction of this invention can be scaled up to the gram scale (yield up to 71%), demonstrating its industrial application potential. Furthermore, the target product can be further derivatized into sulfoxide or sulfone compounds (yield 78%-79%), which are of significant value in pharmaceuticals, materials, and other fields. Combined with a clear reaction mechanism study (protonation-hydrosulfidation-cyclization pathway), this invention not only provides an efficient synthetic platform but also lays the foundation for the structure-activity relationship in subsequent targeted functionalization modifications, possessing both practical and academic value. Attached Figure Description

[0023] Figure 1 The reaction formulas, target product structures, and corresponding yields are provided for the applicability studies of different thiophenol substrates;

[0024] Figure 2 The reaction formulas, target product structures, and corresponding yields are provided for the applicability studies of different allene substrates.

[0025] Figure 3 This provides reaction formulas, target product structures, and corresponding yields for gram-scale reaction and product derivatization studies.

[0026] Figure 4 The reaction formula, target product structure, and corresponding yield are provided for reaction mechanism studies.

[0027] Figure 5 This is a reaction mechanism diagram of the present invention;

[0028] Figure 6 The 1H NMR spectrum of compound 4 of this invention;

[0029] Figure 7The carbon NMR spectrum of compound 4 of this invention;

[0030] Figure 8 This is the NMR fluorine spectrum of compound 4 of the present invention. Detailed Implementation

[0031] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0032] Example

[0033] I. Optimization of Reaction Conditions

[0034] First, using allene 1 and thiophenol 2 as templates, the effect of different acids on the reaction was tested. The reaction was carried out at room temperature in dichloromethane for 7 hours. The results showed that when trifluoromethanesulfonic acid (TfOH) was used, the target product was obtained in 35% yield (Table 1, entries 1-3). Next, using trifluoromethanesulfonic acid as the optimal acid, different amounts of trifluoromethanesulfonic acid were investigated. Encouragingly, when the acid amount was 23% mol, the target product was obtained in 61% yield (Table 1, entries 4-7). Subsequently, different reaction times were investigated. Unfortunately, extending or decreasing the reaction time did not significantly promote the reaction (Table 1, entries 8-15). Finally, different solvents were also investigated. The results showed that when dichloromethane was used as the solvent, the target product, dihydrobenzothiamide compound 3, was obtained in 61% yield (Table 1, entries 16-21). The results are shown in Table 1, and the specific reaction formulas are as follows:

[0035]

[0036] Table 1 Optimization of Reaction Conditions

[0037]

[0038] Standard conditions: allene 1 (0.25 mmol), thiophenol 2 (0.3 mmol, 1.2 equivalents), acid (23 mol%), dichloromethane (1 mL), room temperature, 7 hours, argon atmosphere, separation yield.

[0039] II. Suitability Study of Different Thiophenol Substrates

[0040] Based on optimized reaction conditions, this study selected allene 1 and a series of thiophenol substrates for applicability studies, systematically investigating the effects of different substituent thiophenols on the trifluoromethanesulfonic acid (HOTf)-catalyzed hydrogen sulfide cascade / Friedel-Crafts cyclization reaction of allene. The reaction conditions were: allene 1 (0.25 mmol), thiophenol (0.25 mmol), trifluoromethanesulfonic acid (23 mol%), and dichloromethane (1 mL), reacted at room temperature for 7 hours under argon protection, and the target product was finally obtained by separation.

[0041] The results show that this catalytic system exhibits good versatility for arylthiophenol substrates:

[0042] 1. Para-substituent effect: When the para position of thiophenol is an electron-donating group (such as -CH3), the separation yield of the target dihydrobenzothiam compound 3 reaches 61%; while the thiophenol substrate substituted with electron-withdrawing groups (-F, -Br, -Cl, -CF3) can still maintain a medium-high yield of 45%-68%, indicating that the system has good compatibility with various para-substituents.

[0043] 2. Meta-substituent tolerance: Meta-substituted thiophenols (such as m-bromothiophenol) showed good compatibility in this system, with a separation yield of 40% for product 8, indicating that the steric hindrance effect of the meta-substituent did not significantly inhibit the cyclization process.

[0044] 3. Adaptability of ortho-substituents: Thiophenols with different ortho-substituents (-COOCH3, -CH3, -F, -Br, -Cl) can all participate in the reaction efficiently. The separation yield of target products 9-13 ranges from 59% to 78%, proving that the steric and electronic effects of ortho-substituents do not significantly affect the catalytic efficiency.

[0045] In summary, the trifluoromethanesulfonic acid-catalyzed allene hydrothiolation / cascade Friedel-Crafts cyclization reaction exhibits broad applicability to arylthiophenol substrates, efficiently constructing dihydrobenzothiaran compounds in moderate to good yields regardless of whether the substituents are located at the para, meta, or ortho positions. This reaction system demonstrates excellent compatibility with thiophenol substrates exhibiting different electronic and steric effects, providing an effective method for the synthesis of complex thioheterocyclic compounds.

[0046] For details on the reaction formula, target product structure, and corresponding yield, please refer to [link / reference]. Figure 1 .

[0047] III. Applicability Study of Different Allene Substrates

[0048] Under the same reaction conditions, this study further investigated the applicability of allene substrates. For the allene hydrosulfide / cascade Friedel-Crafts cyclization reaction system (reaction conditions: allene (0.25 mmol), thiophenol 2 (0.25 mmol), trifluoromethanesulfonic acid (23 mol%), dichloromethane (1 mL), reaction at room temperature for 7 hours under argon protection), allene substrates with para, meta, or ortho substituents could successfully participate in the cyclization reaction, generating the target products 14-28 in moderate to good yields (41%-77%).

[0049] The results show that the substituent position and electronic effects of the allene benzene ring have a significant impact on the reaction efficiency:

[0050] 1. Unsubstituted allenes: When the benzene ring is unsubstituted, the reaction proceeds smoothly, producing compound 14 in 48% yield.

[0051] 2. Para-substituted allenes: Allenes with electron-donating groups (-OCH3, -CH3) or electron-withdrawing groups (-F, -Br) at the para position can participate in the reaction efficiently, with the separation yields of products 15-18 ranging from 41% to 77%.

[0052] 3. Meta-substituted allenes: Allene substrates with different substituents at the meta position showed good adaptability, with the yields of products 19-22 ranging from 51% to 65%.

[0053] 4. Ortho-substituted allenes: Allenes with electron-donating groups (-OCH3, -CH3) or electron-withdrawing groups (-F, -Cl, -Br) at the ortho position can generate the target product 23-27 in moderate to good yields (47%-71%).

[0054] 5. Allenes with naphthalene ring structure: Allene substrates with naphthalene ring structure also performed well in this system, yielding compound 28 in an excellent yield of 65%.

[0055] For the reaction formula, target product structure and corresponding yield, please refer to [link / reference]. Figure 2 .

[0056] IV. Gram-scale reaction and product derivatization studies

[0057] To verify the comprehensive applications of this transformation, gram-scale reaction studies were conducted. The results showed that the reaction can proceed on a gram scale, yielding compound 18 in 71% yield. Furthermore, sulfones or sulfoxides are an important class of organic synthons with wide applications in pharmaceuticals, plastics, and other fields. Therefore, the oxidation of dihydrobenzothianes to sulfones or sulfoxides is of significant importance. Compound 3 was oxidized to sulfoxide 29 under trifluoromethanesulfonic anhydride / hydrogen peroxide conditions, and to sulfone 30 under m-chloroperoxybenzoic acid (mCPBA) conditions.

[0058] For the reaction formula, target product structure and corresponding yield, please refer to [link / reference]. Figure 3 .

[0059] V. Reaction Mechanism Study

[0060] To further understand the hydrogenation reaction of allenes and the subsequent tandem cyclization transformation, a series of controlled experimental studies were conducted. Figure 4 ).like Figure 4 As shown in Figure a, compound 14 was obtained in 49% yield under standard conditions. Additionally, using the allene hydrosulfide product 2' as a substrate, compound 14 was obtained in 63% yield under standard conditions. Figure 4 b). Under standard conditions, compound 2” was found to be unable to cyclize to form dihydrobenzothiam compound 14 ( Figure 4 c). This result suggests that the cascaded cyclization process in the reaction may proceed via a Friedel-Crafts-type transformation. Meanwhile, when (4-methylthio)toluene 5' was used as a substrate in the reaction, the target product was not detected. Figure 4 d). These findings imply that in this reaction mechanism, The protonation of the allene is promoted, followed by a hydrosulfidation reaction, after which the proton may be transferred from the thiophenol to the TfO- anion.

[0061] The possible reaction mechanism is as follows: First, allene 1 gains a proton from trifluoromethanesulfonic acid to form intermediate A. Then, thiophenol attacks intermediate A, ultimately yielding intermediate B. Next, intermediate B is deprotonated to give compound 2'. Then, compound 2' again gains a proton from trifluoromethanesulfonic acid to form intermediate C. Subsequently, an intramolecular cyclization reaction occurs in the intermediate to give intermediate D, which is then deprotonated to give the target product 14 and trifluoromethanesulfonic acid, completing the catalytic cycle. Figure 5 ).

[0062] VI. Conclusion

[0063] In summary, this invention develops a method using A method for synthesizing dihydrobenzothiaran compounds via acid-catalyzed hydrosulfide cyclization of allenes offers advantages such as simple synthetic steps, mild reaction conditions, readily available starting materials, no metal catalysis, moderate to excellent yields of dihydrobenzothiaran compounds, and a broad substrate applicability. Therefore, this invention develops a novel, efficient, and environmentally friendly method for synthesizing dihydrobenzothiaran compounds, providing a significant supplement to the synthesis of dihydrobenzothiaran compounds.

[0064] VII. Synthesis method and product derivatization examples of dihydrobenzothiaran compounds of the present invention

[0065] 1. Instruments and Reagents

[0066] Nuclear magnetic resonance (NMR) spectroscopy was performed on a Bruker AV-400 or Bruker AV-600 instrument, using deuterated chloroform (CDCl3) and deuterated dimethyl sulfoxide (DMSO-d6) as solvents and tetramethylsilane (TMS) as an internal standard. Column chromatography was performed using silica gel (300–400 mesh), and all petroleum ether used in the column chromatography was redistilled under vacuum. All reaction reagents and solvents were commercially available anhydrous analytical grade reagents, purchased from Anengji, Bieder Pharmaceuticals, and Beijing Innocare Technology Co., Ltd., among others.

[0067] 2 Experimental Methods

[0068] 2.1 Synthesis of dihydrobenzothiam compounds 3-28

[0069] Under argon atmosphere, 0.25 mmol (1 equiv) of allene (Formula I) and 0.3 mmol (1.2 equiv) of thiophenol (Formula II) were weighed into a reaction tube, 1 mL of dichloromethane was added and mixed thoroughly, followed by the addition of trifluoromethanesulfonic acid (23% mol). The mixture was stirred at room temperature for 7 hours, and the reaction was monitored by TCL. After the reaction was completed, the reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate, V:V = 50:1 to 5:1) to obtain the target product, dihydrobenzothiaran compound.

[0070] The reaction process is shown in the following reaction equation:

[0071]

[0072] 2.2 Gram-scale synthesis of dihydrobenzothiaran compounds

[0073] Under argon atmosphere, thiophenol 2 (10.40 mmol, 1.2 equiv) was added to a 100 mL reaction flask, followed by the addition of allene 1 (8.67 mmol, 1 equiv) and HOTf (23% mol) in DCM (15 mL) under argon atmosphere. The reaction mixture was stirred at room temperature. When the reaction was complete (monitored by TLC), the solution was evaporated under vacuum. The crude product was directly purified by silica gel column chromatography, eluting with petroleum ether and ethyl acetate, to give 4-(4-chlorophenyl)-6-methylthiobenzodihydropyran compound 3 as a colorless liquid (1.70 g, 71%).

[0074] The reaction process is shown in the following reaction equation:

[0075]

[0076] 2.3 Synthesis of 4-(4-chlorophenyl)-6-methylthiosulfon-1-oxide 29

[0077] Compound 3 (82.44 mg, 0.3 mmol) was dissolved in ethanol (1.5 mL), hydrogen peroxide (30%, 60 μL, 0.6 mmol, 2 equiv), and trifluoromethanesulfonic anhydride (25 μL, 0.15 mmol, 0.5 equiv), and the mixture was stirred at room temperature. When the reaction was complete (monitored by TLC), the solution was evaporated under vacuum. The crude product was directly purified by silica gel column chromatography, eluting with petroleum ether and ethyl acetate, to give 4-(4-chlorophenyl)-6-methylthiosulfon-1-oxide 29 (67.60 mg, 78%), a colorless oily liquid.

[0078] The reaction process is shown in the following reaction equation:

[0079]

[0080] 2.4 Synthesis of 4-(4-chlorophenyl)-6-methylthiosulfon-1,1-dioxide 30

[0081] Compound 3 (54.96 mg, 0.2 mmol) and mCPBA (140.60 mg, 0.8 mmol, 4 equiv) were dissolved in dichloromethane (5 mL). The mixture was stirred at room temperature, and when the reaction was complete (monitored by TLC), the solution was evaporated under vacuum. The crude product was directly purified by silica gel column chromatography, eluting with petroleum ether and ethyl acetate, to give 4-(4-chlorophenyl)-6-methylthiosulfon-1,1-dioxide 30 (48.20 mg, 79%), a colorless oily liquid.

[0082] The reaction process is shown in the following reaction equation:

[0083]

[0084] VIII. The characterization data of the compounds involved in this embodiment are as follows:

[0085] 4-(4-Chlorophenyl)-6-methylthiochromane(3).Colorlessliquid(61%, 42mg). 1 H NMR (400MHz, CDCl3) δ7.25(d,J=8.0Hz,2H),7.06(d,J=8.0Hz,1H),7.00(d,J=8.0Hz,2H),6.93(d,J =8.0Hz,1H),6.69(s,1H),4.16(t,J=4.0Hz,1H),2.86-2.83(m,2H),2.31-2.23(m,2H),2.18(s,3H). 13 C NMR (101MHz, CDCl3) δ143.73,134.53,133.70,132.18,131.79,129.95,129.84,128.60,128.15,126.46,43.63,30.79,23.20,20.82.HRMS (ESI) m / z Calculated for C 16 H 16 ClS + [M+H] + :275.0661,found:275.0674.

[0086] 4-(4-Chlorophenyl)-6-fluorothiochromane(4).Colorlessliquid(65%, 45mg). 1 H NMR (400MHz, CDCl3) δ7.27-7.23(m,2H),7.11-7.07m,1H),7.00-6.96(m,2H),6.85-6.80(m,1H) ,6.57-6.54(m,1H),4.11(t,J=6.0Hz,1H),2.88-2.84(m,2H),2.31-2.20(m,2H),12.18(s,3H). 19 F NMR (376MHz, CDCl3) δ -118.85. 13C NMR(101MHz,CDCl3)δ160.01(d,J=242.0Hz),142.86,136.87(d,J=7.0Hz),132.57,129.86,128.81,128.44(d,J=4.0Hz),127.85(d,J=8.0Hz),117.53(d,J=22.0Hz),114.72(d,J=22.0Hz),44.03(d,J=1.0Hz),30.59,23.57. 19 F NMR(376MHz,CDCl3):δ=-118.85.HRMS(ESI)m / z Calculated for C 15 H 13 ClFS + [M+H] + :279.0411,found:279.0401.

[0087] 6-Chloro-4-(4-chlorophenyl)thiochromane(5).Colorlessliquid(68%,50mg). 1 H NMR(400MHz,CDCl3)δ7.44-7.40(m,2H),7.24-7.21(m,2H),7.15-7.12(m,2H),7.01-7.00(m,1H),4.29(t,J=6.0Hz,1H),3.03-3.00(m,2H),2.44-2.40(m,2H). 13 C NMR(101MHz,CDCl3)δ142.76,136.48,132.59,132.15,130.78,129.83,129.53,128.83,127.79,127.36,43.65,30.31,23.35.HRMS(ESI)m / z Calculated for C 15 H 13 Cl2S + [M+H] + :295.0115,found:295.0124.

[0088] 6-Bromo-4-(4-chlorophenyl)thiochromane(6).Colorlessliquid(64%,54mg). 1H NMR(400MHz,CDCl3)δ7.29-7.26(m,2H),7.23-7.21(m,1H),7.04(d,J=8.0Hz,1H),7.01-6.97(m,3H),4.15(t,J=4.0Hz,1H),2.88-2.84(m,2H),2.29-2.25(m,2H). 13 C NMR(101MHz,CDCl3)δ142.74,136.81,133.66,132.87,132.61,130.19,129.83,128.84,128.09,117.22,77.42,77.10,76.78,43.55,30.24,23.27.HRMS(ESI)m / zCalculated for C 15 H 12 BrSClNa + [M+Na] + :360.9429,found:360.9442. 4-(4-Chlorophenyl)-6-(trifluoromethyl)thiochromane(7).Colorless liquid(45%,37mg). 1 H NMR(400MHz,CDCl3)δ7.36-7.33(m,1H),7.30-7.26(m,3H),7.14(s,1H),7.00-7.69(m,2H),4.25(t,J=4.0Hz,1H),2.91-2.87(m,2H),2.35-2.28(m,2H). 19 F NMR(376MHz,CDC l3 )δ-62.28. 13 C NMR(101MHz,CDCl3)δ142.50,138.97,134.96,132.71,129.76,128.90,127.81(q,J=4.0Hz),126.88,126.40,126.07,123.72(q,J=3.6Hz),43.54,29.95,23.23. 19 F NMR(376MHz,CDCl3):δ=-62.28.HRMS(ESI)m / z Calculated for C 16 H 12 ClF3NaS + [M+Na] + :351.0198,found:351.0226.

[0089] 7-Bromo-4-(4-chlorophenyl)thiochromane(8).Colorlessliquid(40%,34mg). 1 H NMR(400MHz,CDCl3)δ7.33(d,J=4.0Hz,1H),7.28-7.27(m,1H),7.26-7.25(m,1H),7.06-7.04(m,1H),7.00-6.96(m,2H),6.72(d,J=8.0Hz,1H),4.14(t,J=6.0Hz,1H),2.88-2.84(m,2H),2.30-2.26(m,2H). 13 C NMR(101MHz,CDCl3)δ142.74,136.81,133.66,132.87,132.61,130.19,129.83,128.84,128.09,117.22,43.55,30.24,23.27.HRMS(ESI)m / z Calculated for C 15 H 12 BrClNaS + [M+Na] + :360.9429,found:360.9436.

[0090] Methyl 4-(4-chlorophenyl)thiochromane-8-carboxylate(9).Colorless liquid(60%,48mg). 1 H NMR(400MHz,CDCl3)δ7.92-7.90(m,1H),7.29-7.26(m,2H),7.08-7.06(m,1H),7.03-6.99(m,3H),4.31(t,J=6.0Hz,1H),3.95(s,1H),2.86-2.83(m,2H),2.35-2.30(m,2H). 13 C NMR(101MHz,CDCl3)δ167.15,143.64,138.30,136.28,135.57,132.41,130.63,129.90,128.72,126.99,123.03,52.21,44.47,29.58,23.67.HRMS(ESI)m / z Calculated for C 17 H 16ClO2S + [M+H] + :319.0560,found:319.0538.

[0091] 4-(4-Chlorophenyl)-8-methylthiochromane(10).Colorlessliquid(60%,41mg). 1 H NMR(400MHz,CDCl3)δ7.25(d,J=8.0Hz,2H),7.04-6.98(m,3H),6.88(t,J=8.0Hz,1H),6.75(d,J=4.0Hz,1H),4.24(t,J=4.0Hz,1H),2.93-2.82(m,2H),2.31-2.26(m,5H). 13 C NMR(101MHz,CDCl3)δ143.87,134.61,134.52,132.98,132.18,129.92,128.89,128.60,128.46,123.37,43.99,30.14,23.35,20.17.HRMS(ESI)m / zCalculated for C 16 H 16 ClS + [M+H] + :275.0661,found:275.0655.

[0092] 4-(4-Chlorophenyl)-8-fluorothiochromane(11).Colorlessliquid(78%,54mg). 1 H NMR(400MHz,CDCl3)δ7.28-7.25(m,2H),7.00–6.97(m,2H),6.93-6.88(m,2H),6.72-6.67(m,1H),4.24(t,J=6.0Hz,1H),2.93-2.81(m,2H),2.31-2.27(m,2H). 19 F NMR(376MHz,CDCl3)δ-113.42. 13C NMR(101MHz,CDCl3)δ158.47(d,J=241.0Hz),143.26,136.95(d,J=3.0Hz),132.47,129.84,128.74,126.64(d,J=3.0Hz),124.14(d,J=8.0Hz),121.99(d,J=17.0Hz),113.16(d,J=21.0Hz),43.15(d,J=3.0Hz),30.17,22.21(d,J=2.0Hz). 19 F NMR(376MHz,CDCl3):δ=-113.42.HRMS(ESI)m / z Calculated forC 15 H 13 ClFS + [M+H] + :279.0411,found:279.0410.

[0093] 8-Chloro-4-(4-chlorophenyl)thiochromane(12).Colorlessliquid(59%,43mg). 1 H NMR(400MHz,CDCl3)δ7.28-7.24(m,3H),6.99(d,J=8.0Hz,2H),6.91(t,J=6.0Hz,1H),6.82(d,J=8.0Hz,1H),4.26(t,J=6.0Hz,1H),2.96-2.84(m,2H),2.31-2.26(m,2H). 13 C NMR(101MHz,CDCl3)δ143.20,136.77,133.23,132.47,130.91,129.81,129.58,128.73,128.01,124.23,43.87,29.87,23.63.HRMS(ESI)m / z Calculatedfor C 15 H 13 Cl2S + [M+H] + :295.0115,found:295.0121.

[0094] 8-Bromo-4-(4-chlorophenyl)thiochromane(13).Colorlessliquid(62%,52mg). 1H NMR(400MHz,CDCl3)δ7.43(d,J=8.0Hz,1H),7.27(d,J=8.0Hz,2H),6.99(d,J=8.0Hz,2H),6.88-6.83(m,2H),4.25(t,J=4.0Hz,1H),2.96-2.85(m,2H),2.30-2.25(m,2H). 13 C NMR(101MHz,CDCl3)δ143.18,137.08,134.97,132.45,131.41,130.24,129.80,128.72,124.68,121.27,44.15,29.93,24.38.HRMS(ESI)m / z Calculatedfor C 15 H 12 BrClNaS + [M+Na] + :360.9429,found:360.9438.

[0095] 6-Methyl-4-phenylthiochromane(14).Colorless liquid(48%,29mg). 1 H NMR(400MHz,CDCl3)δ7.31(t,J=8.0Hz,2H),7.26-7.21(m,1H),7.10-7.08(m,3H),6.94(d,J=8.0Hz,1H),6.74(s,1H),4.21(t,J=4.0Hz,1H),2.95-2.82(m,2H),2.34-2.30(m,2H),2.19(s,3H),2.30-2.26(m,2H),2.16(s,3H). 13 C NMR(101MHz,CDCl3)δ145.31,135.07,133.58,131.94,129.88,128.64,128.47,127.96,126.38,126.34,44.20,30.88,23.32,20.84.HRMS(ESI)m / z Calculated for C 16 H 17 S + [M+H] + :241.1051,found:241.1034.

[0096] 6-Methyl-4-(p-tolyl)thiochromane(15).Colorless liquid(76%,48 mg). 1 H NMR(400MHz,CDCl3)δ7.10(d,J=8.0Hz,2H),7.06(d,J=8.0Hz,1H),6.96(d,J=8.0Hz,2H),6.92-6.91(m,1H),6.72(s,1H),4.15(t,J=4.0Hz,1H),2.94-2.87(m,1H),2.84-2.79(m,1H),2.32(s,3H),2.30-2.26(m,2H),2.16(s,3H). 13 C NMR(101MHz,CDCl3)δ141.36,134.92,134.25,132.55,130.93,128.78,128.15,127.50,126.88,125.29,42.76,29.88,22.29,20.07,19.83,0.09.HRMS(ESI)m / z Calculated for C 17 H 18 NaS + [M+Na] + :277.1027,found:277.1023.

[0097] 4-(4-Methoxyphenyl)-6-methylthiochromane(16).Colorless liquid(41%,28mg). 1 H NMR(400MHz,CDCl3)δ7.07(d,J=8.0Hz,1H),7.01-6.99(m,2H),6.94-D6.92(m,1H),6.86-6.83(m,2H),6.74(s,1H),4.15(t,J=4.0Hz,1H),3.79(s,3H),2.95-2.81(m,2H),2.35-2.25(m,2H),2.319(s,3H). 13 C NMR(101MHz,CDCl3)δ158.12,137.43,135.45,133.55,131.88,129.78,129.54,127.88,126.31,113.85,55.31,43.36,30.92,23.32,20.85.HRMS(ESI)m / z Calculated for C 17 H19 OS + [M+H] + :271.1157,found:271.1148.

[0098] 4-(4-Fluorophenyl)-6-methylthiochromane(17).Colorless liquid(64%,41mg). 1 H NMR(400MHz,CDCl3)δ7.08-7.03(m,3H),7.02-7.00(m,1H),6.98(s,1H),6.96-6.93(m,1H),6.70(s,1H),4.18(t,J=6.0Hz,1H),2.88-2.85(m,2H),2.31-2.25(m,2H),2.19(s,3H). 19 F NMR(376MHz,CDCl3)δ-116.79. 13 C NMR(101MHz,CDCl3)δ161.52(d,J=243.0Hz),140.93(d,J=3.0Hz),134.91,133.70,131.82,130.02(d,J=7.0Hz),129.81,128.10,126.44,115.28(d,J=21.0Hz),43.48,30.91,23.23,20.85. 9 FNMR(376MHz,CDCl3):δ=-116.79.HRMS(ESI)m / z Calculated for C 16 H 15 FNaS + [M+Na] + :281.0776,found:281.0733.

[0099] 8-Bromo-4-(4-chlorophenyl)thiochromane(18).Colorlessliquid(77%,61mg). 1 H NMR(400MHz,CDCl3)δ7.42(d,J=8.0Hz,2H),7.07(d,J=8.0Hz,1H),6.97-6.93(m,3H),6.69(s,1H),4.15(t,J=4.0Hz,1H),2.86(t,J=6.0Hz,2H),2.32-2.24(m,2H),2.19(s,3H). 13C NMR(101MHz,CDCl3)δ144.28,134.43,133.74,131.81,131.57,130.37,129.83,128.18,126.47,120.29,43.70,30.74,23.20,20.84.HRMS(ESI)m / z Calculated for C 16 H 15 BrNaS + [M+Na] + :340.9976,found:340.9980.

[0100] 6-Methyl-4-(p-tolyl)thiochromane(19).Colorless liquid(65%,41mg). 1 H NMR(400MHz,CDCl3)δ7.21(t,J=6.0Hz,1H),7.11-7.05(m,2H),6.95(d,J=8.0Hz,2H),6.89(d,J=8.0Hz,1H),6.76(s,1H),4.18(t,J=6.0Hz,1H),2.98-2.91(m,1H),2.88-2.83(m,1H),2.35(s,3H),2.32-2.30(m,2H),2.20(s,3H). 13 C NMR(101MHz,CDCl3)δ145.33,138.03,135.16,133.52,131.96,129.81,129.27,128.32,127.89,127.15,126.30,125.80,44.14,30.91,23.37,21.57,20.84.HRMS(ESI)m / z Calculated forC 17 H 19 S + [M+H] + :255.1207,found:255.1226.

[0101] 4-(3-Methoxyphenyl)-6-methylthiochromane(20).Colorless liquid(55%,37mg). 1H NMR(400MHz,CDCl3)δ7.22(t,J=8.0Hz,1H),7.06(d,J=8.0Hz,1H),6.94-6.91(m,1H),6.78-6.74(m,2H),6.68-6.66(m,1H),6.65-6.64(m,1H),4.16(t,J=4.0Hz,1H),3.77(s,3H),2.96-2.82(m,2H),2.33-2.29(m,2H),2.18(s,3H). 13 CNMR(101MHz,CDCl3)δ159.73,146.97,134.98,133.58,131.92,129.83,129.42,128.00,126.36,121.14,114.77,111.40,55.24,44.27,30.82,23.45,20.85.HRMS(ESI)m / zCalculated for C 17 H 19 OS + [M+H] + :271.1157,found:271.1149.

[0102] 4-(3-Chlorophenyl)-6-methylthiochromane(21).Colorlessliquid(51%,35mg). 1 H NMR(400MHz,CDCl3)δ7.25-7.20(m,2H),7.09-7.06(m,2H),6.95(d,J=4.0Hz,2H),6.70(s,1H),4.16(t,J=6.0Hz,1H),2.88-2.84(m,2H),2.32-2.28(m,2H),2.19(s,3H). 13 C NMR(101MHz,CDCl3)δ147.36,134.38,134.23,133.75,131.85,129.88,129.72,128.67,128.24,126.91,126.65,126.52,44.01,30.79,23.25,20.83.HRMS(ESI)m / z Calculated for C 16 H 16 ClS[M+H] + :275.0661,found:275.0664.

[0103] 4-(3-Bromophenyl)-6-methylthiochromane(22).Colorlessliquid(59%,47mg). 1 H NMR(400MHz,CDCl3)δ7.35(d,J=8.0Hz,1H),7.26(s,1H),7.16(t,J=8.0Hz,1H),7.07(d,J=8.0Hz,1H),6.99-6.94(m,2H),6.70(s,1H),4.16(t,J=4.0Hz,1H),2.88-2.85(m,2H),2.33-2.28(m,2H),2.19(s,3H). 13 C NMR(101MHz,CDCl3)δ147.67,134.15,133.77,131.87,131.53,130.05,129.84,129.59,128.26,127.42,126.51,122.67,43.96,30.79,23.22,20.86.HRMS(ESI)m / z Calculated for C 16 H 15 BrNaS + [M+Na] + :340.9976,found:340.9988.

[0104] 6-Methyl-4-(o-tolyl)thiochromane(23).Colorlessliquid(71%,45 mg). 1 H NMR(400MHz,CDCl3)δ7.21(d,J=8.0Hz,1H),7.15-7.07(m,3H),6.92(d,J=8.0Hz,1H),6.87-6.84(m,1H),6.65(s,1H),4.39(t,J=6.0Hz,1H),3.00-2.94(m,1H),2.91-2.85(m,1H),2.43(s,3H),2.34-2.19(m,2H),2.16(s,3H). 13C NMR(101MHz,CDCl3)δ143.41,135.88,135.19,133.71,131.64,130.56,130.02,129.69,127.78,126.39,126.33,126.08,40.61,29.78,28.94,23.80,20.85,19.55.HRMS(ESI)m / z Calculated forC 17 H 19 S + [M+H] + :255.1207,found:255.1183.

[0105] 4-(2-Methoxyphenyl)-6-methylthiochromane(24).Colorless liquid(65%,44mg). 1 H NMR(400MHz,CDCl3)δ7.23-7.19(m,1H),7.08(d,J=8.0Hz,1H),6.95-6.90(m,2H),6.70(s,1H),6.87-6.83(m,1H),6.75-6.73(m,2H),4.63(t,J=6.0Hz,1H),3.90(s,3H),2.92-2.85(m,1H),2.82-2.76(m,1H),2.43-2.35(m,1H),2.21-2.17(m,4H). 13 C NMR(101MHz,CDCl3)δ156.31,135.42,133.49,133.31,132.00,130.76,130.31,127.77,127.40,126.17,110.24,55.39,37.35,27.93,23.45,20.82.HRMS(ESI)m / zCalculated for C 17 H 18 NaOS + [M+Na] + :293.0976,found:293.0974.

[0106] 4-(2-Fluorophenyl)-6-methylthiochromane(25).Colorless liquid(56%,36mg). 1H NMR(400MHz,CDCl3)δ7.28-7.23(m,1H),7.07(d,J=8.0Hz,1H),6.95-6.86(m,3H),6.79-6.76(m,1H),6.71(s,1H),4.19(t,J=4.0Hz,1H),2.88-2.84(m,2H),2.33-2.28(m,2H),2.19(s,3H). 19 F NMR(376MHz,CDCl3)δ-119.04. 13 CNMR(101MHz,CDCl3)δ160.16(d,J=244.0Hz),134.01,133.76,131.86(d,J=14.0Hz),131.74,131.26(d,J=4.0Hz),130.21,128.17,128.06(d,J=8.0Hz),128.40,124.01(d,J=4.0Hz),115.33(d,J=22.0Hz),37.26(d,J=3.0Hz),28.75,23.41,20.84. 19 F NMR(376MHz,CDCl3):δ=-119.04.HRMS(ESI)m / z Calculated for C 16 H 16 FS + [M+H] + :259.0957,found:259.0939.

[0107] 4-(2-Chlorophenyl)-6-methylthiochromane(26).Colorlessliquid(47%,32mg). 1 H NMR(400MHz,CDCl3)δ7.41-7.38(m,1H),7.16-7.13(m,2H),7.08(d,J=8.0Hz,1H),6.95-6.93(m,1H),6.86-6.84(m,1H),6.70(s,1H),4.67(t,J=6.0Hz,1H),2.87-2.83(m,2H),2.45-2.38(m,1H),2.29-2.27(m,1H),2.18(s,3H). 13C NMR(101MHz,CDCl3)δ134.42,133.82,133.12,132.03,131.38,130.27,129.68,128.20,127.73,126.79,126.41,40.77,28.02,23.23,20.82.HRMS(ESI)m / z Calculated for C 16 H 16 ClS + [M+H] + :275.0661,found:275.0648.

[0108] 4-(2-Bromophenyl)-6-methylthiochromane(27).Colorlessliquid(49%,39mg). 1 H NMR(400MHz,CDCl3)δ7.59(d,J=8.0Hz,1H),7.18(t,J=8.0Hz,1H),7.09-7.05(m,2H),6.94(d,J=8.0Hz,1H),6.86(d,J=4.0Hz,1H),6.70(s,1H),6.65(t,J=6.0Hz,1H),2.86-2.84(m,2H),2.45-2.39(m,1H),2.30-2.21(m,2H),2.18(s,3H). 13 CNMR(101 MHz,CDCl3)δ144.04,134.47,133.82,133.02,132.08,131.47,130.19,128.21,128.04,127.43,126.39,123.85,43.26,29.79,28.15,23.13,20.82.HRMS(ESI)m / zCalculated for C 16 H 16 BrS + [M+H] + :319.0156,found:319.0145.

[0109] 6-Methyl-4-(naphthalen-2-yl)thiochromane(28).Colorless liquid(65%,47mg). 1H NMR(400 MHz,CDCl3)δ7.82-7.74(m,3H),7.44-7.43(m,3H),7.29-7.24(m,1H),7.11(d,J=8.0Hz,1H),6.95(d,J=8.0Hz,1H),6.74(s,1H),4.34(t,J=4.0Hz,1H),2.96-2.84(m,2H),2.44-2.33(m,2H),2.15(s,3H). 13 C NMR(101MHz,CDCl3)δ142.82,135.04,133.68,133.44,132.25,132.05,129.94,128.22,128.04,127.87,127.65,127.50,126.85,126.44,126.13,125.65,44.45,30.92,29.79,23.56,20.85.HRMS(ESI)m / z Calculated for C 20 H 18 NaS + [M+Na] + :313.1027,found:313.1016.

[0110] Cinnamyl(p-tolyl)sulfane(2').White solid(57%,2.266g). 1 H NMR(400MHz,CDCl3)δ7.29-7.25(m,6H),7.21-7.16(m,1H),7.06(d,J=8.0Hz,1H),6.36(d,J=16.0Hz,1H),6.25-6.17(m,1H),3.64-3.62(m,2H),2.28(s,3H). 13 C NMR(101MHz,CDCl3)δ 13 C NMR(101MHz,CDCl3)δ136.90,136.70,132.63,132.02,131.19,129.69,128.57,127.57,126.39,125.44,37.91,21.11.

[0111] Cinnamyl(2,6-dimethylphenyl)sulfane(2”).Whitesolid(44%,1.86g). 1H NMR(400MHz,CDCl3)δ7.24-7.17(m,5H),7.08-7.06(m,2H),6.22-6.06(m,2H),3.41-3.39(m,2H),2.53(d,J=4.0Hz,6H). 13 C NMR(101MHz,CDCl3)δ143.41,136.94,132.83,131.85,128.48,128.39,128.07,127.38,126.19,125.43,38.12,22.19.

[0112] 4-(4-Chlorophenyl)-6-methylthiochromane 1,1-dioxide(29).Colorless oily liquid(78%,68mg). 1 H NMR(400MHz,CDCl3)δ7.65(d,J=8.0Hz,1H),7.32-7.30(m,2H),7.19-7.15(m,3H),6.76(s,1H),4.09-4.05(m,1H),3.27-3.21(m,1H),3.00-2.93(m,1H),2.83-2.73(m,1H),2.28-2.21(m,4H). 13 C NMR(101MHz,CDCl3)δ 13 C NMR(101MHz,CDCl3)δ143.38,142.69,138.22,135.70,132.87,131.72,131.53,130.26,129.07,128.59,44.87,44.66,22.81,21.51.HRMS(ESI)m / z Calculated forC 16 H 15 ClNaOS[M+Na] + :313.0430,found:313.0425.

[0113] 4-(4-Chlorophenyl)-6-methylthiochromane 1,1-dioxide(30).Colorless oily liquid(79%,48mg). 1H NMR (400MHz, CDCl3) δ7.17(d,J=8.0Hz,1H),7.21(d,J=8.0Hz,2H),7.17-7.15(m,1H),6.94(d,J=8.0Hz,1 H),6.65(s,1H),4.19-4.16(m,1H),3.30-3.16(m,2H),2.72-2.64(m,1H),2.51-2.43(m,1H),2.18(s,3H). 13 CNMR(101MHz, CDCl3)δ143.31,141.75,138.08,136.57,133.23,130.97,129.95,129.26,129.20,123.70,48.30,43.73,30.00,21.54.HRMS(ESI)m / z Calculatedfor C 16 H 15 ClNaO2S[M+Na] + :329.0379,found:329.0369.

[0114] The NMR spectra of compound 4 (H1N, C1N, and fluorine NMR) are as follows: Figures 6-8 As shown.

[0115] Example 2

[0116] To evaluate the bioactivity of the target compound, we used Staphylococcus aureus (ATCC 29213) for in vitro minimum inhibitory concentration (MIC) determination, with vancomycin (MIC = 2 μg / mL) as a positive control. The experiment employed the microbroth dilution method, and the results are shown in Table 2.

[0117] Table 2. MIC values ​​(μg / mL) of the compounds against Staphylococcus aureus.

[0118] compound Staphylococcus aureus compound Staphylococcus aureus 3 32 16 16 4 64 17 32 5 64 18 64 6 32 19 64 7 64 20 32 8 64 21 64 9 16 22 32 10 32 23 16 11 64 24 32 12 32 25 64 13 64 26 32 14 32 27 16 15 64 28 32 Vancomycin 2

[0119] Analysis of experimental results:

[0120] 1. Activity Trends: Some compounds (e.g., 9, 16, 23, 27) exhibited weak antibacterial activity with a MIC of 16 μg / mL; most compounds (e.g., 3, 6, 10, 12, 14, 20, 22, 24, 26, 28) had a MIC of 32 μg / mL; and the remaining compounds (e.g., 4, 5, 7, 8, 11, 13, 15, 18, 19, 21, 25) had a MIC of 64 μg / mL. This suggests that the activity of these compounds may be enhanced through structural optimization.

[0121] 2. All compounds showed significantly weaker activity than vancomycin (MIC = 2 μg / mL).

[0122] Conclusion: This series of dihydrobenzothiaran compounds (3-28) exhibited preliminary but limited antibacterial activity against Staphylococcus aureus (MIC = 16-64 μg / mL), and their activity was closely related to the electronic effects, positions, and conjugation system extension of the substituents. Although the activity was weak, the slight activity of some compounds provided a structure-activity relationship basis for subsequent targeted modification.

[0123] The above description is a detailed description of the preferred embodiments of the present invention. However, the embodiments are not intended to limit the scope of the patent application of the present invention. All equivalent changes or modifications made under the technical spirit of the present invention should fall within the patent scope covered by the present invention.

Claims

1. A dihydrobenzothiam compound, characterized in that, The structure is shown in Equation III or Equation IV: Among them, R 1 Selected from one of -H, -OCH3, -CH3, -F, -Cl, -Br; R 2 It is selected from one of -H, -F, -Br, -Cl, -CF3, -COOCH3, and -CH3.

2. The method for synthesizing dihydrobenzothiaran compounds as described in claim 1, characterized in that, The process includes the following steps: in a solvent environment, with the participation of an acid catalyst, allene compounds react with thiophenol compounds to generate dihydrobenzothiaran compounds.

3. The synthesis method as described in claim 2, characterized in that: The acid catalyst is trifluoromethanesulfonic acid or trifluoroacetic acid, the solvent is dichloromethane, toluene, 1,4-dioxane, tetrahydrofuran, acetonitrile or 1,2-dichloroethane, and the reaction conditions are at room temperature under argon protection.

4. The synthesis method according to claim 2, characterized in that: The allene compound has the structure shown in Formula I: Among them, R 1 It is selected from one of -H, -OCH3, -CH3, -F, -Cl, and -Br.

5. The synthesis method as described in claim 2, characterized in that: The thiophenol compound has the structure shown in Formula II: Among them, R 2 It is selected from one of -H, -F, -Br, -Cl, -CF3, -COOCH3, and -CH3.

6. The synthesis method according to claim 2, characterized in that: The molar ratio of the allene compound to the thiophenol compound is 1:(1-1.2), the amount of the acid catalyst trifluoromethanesulfonic acid ranges from 10-46 mol%, and the reaction time is 7 hours.

7. The use of the dihydrobenzothiaran compound of claim 1 in the preparation of an inhibitor for inhibiting the growth of Staphylococcus aureus.

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