A method for synthesizing benzodithiepinone derivatives without metal catalysis

Abstract

This invention discloses a metal-free catalytic synthesis method for benzo[e][1,4]dithioheptan-5-one derivatives, belonging to the field of organic synthesis. The method uses benzo[e][1,4]dithioheptan-5-one compounds as raw materials, employing a dual-catalytic system composed of triethylenediamine and bis(diphenylphosphine)methane, and reacts under heating in a 1,4-dioxane solvent. After separation and purification, the target seven-membered thioheptan-5-one compounds are obtained. This method effectively solves the regioselective sulfidation problem of alkynes through the synergistic catalytic mechanism of organic amines and organic phosphines, achieving a highly precise cyclization reaction between benzo[e][1,4]dithioheptan-5-one compounds. The process features mild reaction conditions, requires no inert gas protection, is simple to operate, exhibits good functional group tolerance, and achieves 100% atom economy, providing an efficient and practical synthetic route for the construction of novel benzo[e][1,4]dithioheptan-5-one compounds.

Description

Technical Field

[0001] This invention belongs to the field of organic synthetic chemistry technology, specifically relating to a method for the metal-free catalytic synthesis of benzodithioheptanone derivatives. Background Technology

[0002] Among medium-ring compounds, sulfur-containing medium-ring drug molecules and active molecules have been widely used in the treatment of diseases related to antibacterial, anti-inflammatory, antidepressant, skin diseases, and cancer. Commercially available drug molecules, such as diltiazem, quetiapine, zaltopiprofen, and temopril, all contain a sulfur-containing medium-ring core skeleton. Given the important role of sulfur-containing medium-ring molecules in life sciences, pharmacy, and materials science, developing new synthetic methods for sulfur-containing medium-ring molecules and constructing novel sulfur-containing medium-ring molecules has significant theoretical and practical value. Compared to constructing five-membered and six-membered ring compounds, the synthesis of medium-ring compounds is more challenging due to unfavorable entropy effects and transring strain. Because sulfur atoms have large atomic radii and strong nucleophilicity, and are easily poisoned by metals, there are relatively few methods for synthesizing sulfur-containing medium-ring molecules, especially those containing two or more sulfur atoms. Currently, the construction of medium-ring molecules containing two sulfur atoms mainly relies on the nucleophilic cyclization reactions of dithiols or dihalogen compounds, which has significant substrate limitations. Therefore, there is an urgent need to develop novel and efficient synthetic methods to construct sulfur-containing medium-ring molecules, especially those containing multiple sulfur atoms. This would provide assistance for research on sulfur-containing medium-ring molecular skeletons in interdisciplinary fields such as supramolecular science, biomedicine, and materials science, and provide a richer pool of lead compounds for the selection of sulfur-containing drug molecules.

[0003] Currently, there are numerous reports on the cleavage of the SS bond in disulfide compounds, but most systems only utilize a portion of the sulfur-containing groups after cleavage, discarding the other part, resulting in low sulfur atom utilization. A synthetic strategy capable of efficiently converting both sulfur-containing units generated after SS bond cleavage and constructing compounds containing two sulfur atoms remains to be developed. Taking benzodisulfonic acid ketone as an example, its existing ring-opening reactions often have poor atom economy, and typically, after SS bond cleavage mediated by organophosphorus compounds, it only participates in the [5-1+n] cyclization reaction as a four-atom synthon, failing to achieve efficient utilization of all its atoms. To date, no all-atom-participating [5+n] cyclization reaction of benzodisulfonic acid ketone has been reported, and there are no literature records of constructing disulfide heterocyclic compounds using benzodisulfonic acid ketone as a five-atom synthon.

[0004] Therefore, developing a mild, efficient, and functionally tolerant synthetic method to directly construct disulfide or polysulfide-containing central ring molecules is of significant scientific importance and practical value. Such methods not only enrich the synthetic toolbox of sulfur chemistry but also meet the needs of late-stage functionalization modification of drug molecules and bioactive molecules, providing new molecular construction strategies for medicinal chemistry, materials science, and related industrial fields, and possessing broad academic prospects and practical application potential. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of the prior art and fill the gap in the synthesis of benzo[e][1,4]dithioneheptan-5-one. This method has mild reaction conditions, simple operation, no need for inert gas protection, good functional group tolerance, and high yield, and can realize the late-stage conversion of active molecules and drug molecules.

[0006] The technical solution of the present invention is as follows:

[0007] A metal-free catalytic synthesis method for benzo[e][1,4]dithioheptan-5-one derivatives is described, using benzo[e][1,4]dithioheptan-5-one compounds (2) as reactants, in the presence of triethylenediamine and bis(diphenylphosphine)methane, with 1,4-dioxane as solvent, heated to 80°C and stirred for 10 hours. After the reaction is completed, the benzo[e][1,4]dithioheptan-5-one compounds (3) are obtained by separation and purification.

[0008] The molecular structures and reactions of the benzo[e][1,4]dithioheptan-5-one compounds are as follows:

[0009] ;

[0010] Furthermore, the organic amine is preferably triethylenediamine (DABCO), and the amount used is 20 mol% of the amount of benzodisulfonyl ketone (1), which has the best catalytic effect and can effectively promote the cyclization of alkynes.

[0011] Furthermore, the organophosphorus compound is bis(diphenylphosphine)methane (DPPM), and the molar ratio of benzodisulfonyl ketone to the organophosphorus compound is 1:1, which can significantly promote the cleavage of SS bonds and improve the reaction yield.

[0012] Furthermore, the molar ratio of the benzodisulfonyl ketone to the alkyne compound is 1:1.5 to ensure sufficient reaction of the raw materials and improve the yield of the target sulfur-containing heterocycle.

[0013] Furthermore, the separation and purification steps are as follows: after the reaction is completed, the mixture is cooled to room temperature, and the solvent is removed by rotary evaporation to obtain the crude product. The crude product is then separated by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to obtain a high-purity yellow solid target product.

[0014] Furthermore, the alkyne compound is 4-phenyl-3-butyn-2-one, thiophene-derived alkyne, furan-derived alkyne, menthol-derived alkyne, cyclododecyl-derived alkyne, geraniol-derived alkyne. This method can achieve post-functionalization modification of drug molecules and expand the diversity of drug molecule structures.

[0015] Beneficial effects

[0016] (1) Innovative synthetic route, filling a technological gap: This invention is the first to realize the cyclization reaction of benzodisulfonic acid ketones and alkynes under metal-free catalysis. In the synthesis of sulfur-containing medium-ring molecules, the construction of polysulfide medium-ring systems has always been extremely challenging. This invention provides a simple and green new synthetic route for the construction of seven-membered sulfur heterocycles, benzodisulfide heterocycles, and heptanones, filling a technological gap in this field.

[0017] (2) Overcoming reaction bottlenecks and achieving efficient conversion: In existing technologies, after the SS bond of benzodisulfonic acid ketone is broken, some sulfur atoms are usually lost, generating byproducts such as thiophosphine compounds. This invention overcomes the bottlenecks of existing technologies by utilizing the synergistic catalysis of organic amines and organic phosphines, enabling all atoms of benzodisulfonic acid ketone to participate in the cyclization reaction, with an atom utilization rate of up to 100%.

[0018] (3) The reaction conditions are mild and the operation is practical: the reaction does not require inert gas protection and can be completed in 10 hours at 80°C. Compared with the harsh conditions of high temperature, high pressure and strong oxidants in traditional methods, it significantly reduces energy consumption and production costs. The operation process is simple and the separation and purification adopts conventional silica gel column chromatography, which is suitable for large-scale preparation and industrial application.

[0019] (4) Excellent functional group compatibility, expanding application scenarios: The functional groups have good tolerance, breaking the defects of the limited substrate range of traditional methods; it supports the late functionalization modification of active molecule derivatives such as galactose, menthol, and geraniol, and can quickly construct drug lead compound analogs with diverse structures, shorten the drug development cycle, and provide efficient synthesis tools for pharmaceutical, agrochemical and other fields. Attached Figure Description

[0020] Figure 1 This is a single crystal diagram of the product;

[0021] Figure 2 The 1H NMR spectrum of the product in Example 1;

[0022] Figure 3 The carbon spectrum of the product in Example 1;

[0023] Figure 4 The 1H NMR spectrum of the product in Example 2;

[0024] Figure 5 The carbon spectrum of the product in Example 2;

[0025] Figure 6 The hydrogen NMR spectrum of the product in Example 3;

[0026] Figure 7 The carbon spectrum of the product in Example 3;

[0027] Figure 8 The 1H NMR spectrum of the product in Example 4;

[0028] Figure 9 The carbon spectrum of the product in Example 4; Detailed Implementation

[0029] To make the above-mentioned objectives, features, and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to examples. The following content is merely an example and illustration of the concept of the present invention. Those skilled in the art can make various modifications or additions to the described specific embodiments or use similar methods to replace them, as long as they do not deviate from the concept of the invention, they should all fall within the protection scope of the present invention.

[0030] The preparation method of the present invention will be described below through specific embodiments.

[0031] Example 1

[0032] Synthesis of menthol-derived benzodithionine heptanone

[0033] To a clean 10 mL reaction tube, benzodisulfonic acid 0.3 mmol, DABCO (0.06 mmol, 20 mol%), DPPM (0.45 mmol), and 2-butynediol menthyl ester (0.45 mmol) were added sequentially, followed by 1,4-dioxane (2 mL). The reaction mixture was heated to 80 °C and stirred for 10 hours, with the reaction progress monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation to obtain the crude product. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain the target product, a white solid, in 83% yield.

[0034] according to Figure 2 The product's 1H NMR spectrum and Figure 3 The carbon spectrum of the product yields the following structural formula of the target product:

[0035] ;

[0036] 1 H NMR (300 MHz, CDCl3) δ 8.48 (d, J = 8.1 Hz, 1H), 7.58 (ddd, J =8.0, 6.6, 1.5 Hz, 1H), 7.54 – 7.44 (m, 2H), 4.98 (td, J = 10.9, 4.3 Hz, 1H),2.44 (s, 3H), 2.28 (d, J = 12.0 Hz, 1H), 2.08 (dtt, J = 11.1, 6.9, 4.2 Hz,1H), 1.71 (d, J = 11.2 Hz, 2H), 1.63 – 1.52 (m, 1H), 1.51 – 1.40 (m, 1H),1.15 (q, J = 11.7 Hz, 2H), 0.95 (d, J = 6.5 Hz, 3H), 0.91 (d, J = 7.0 Hz, 3H), 0.87 (d, J = 6.9 Hz, 3H). 13 C NMR (75 MHz, CDCl3) δ 177.2, 165.9, 148.8,136.4, 131.7, 131.4, 130.5, 128.9, 127.8, 125.7, 46.8, 40.6, 34.2, 31.5,25.9, 23.1, 22.0, 21.1, 20.8, 15.9.

[0037] Example 2

[0038] Synthesis of galactose-derived benzodithionine:

[0039] To a clean 10 mL reaction tube, benzo[2]sulfonylphenol ketone (0.3 mmol), DABCO (0.06 mmol, 20 mol%), DPPM (0.45 mmol), and 2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxane)[4,5-b:4',5'-d]pyran-5-yl)methylbut-2-acetylacetate (0.45 mmol) were added sequentially, followed by 1,4-dioxane (2 mL). The reaction mixture was heated to 80 °C and stirred for 10 hours, with the reaction progress monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation to obtain the crude product. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain the target product, a white solid, in 77% yield.

[0040] according to Figure 4 The product's 1H NMR spectrum and Figure 5 The carbon spectrum of the product yields the following structural formula of the target product:

[0041] ;

[0042] 1 H NMR (300 MHz, CDCl3) δ 8.47 (d, J = 8.5 Hz, 1H), 7.58 (dd, J = 7.7,2.3 Hz, 1H), 7.55 – 7.47 (m, 2H), 5.54 (d, J = 5.0 Hz, 1H), 4.64 (dd, J =7.9, 2.4 Hz, 1H), 4.61 – 4.54 (m, 1H), 4.47 (dd, J = 11.5, 8.0 Hz, 1H), 4.35– 4.30 (m, 2H), 4.25 – 4.19 (m, 1H), 2.49 (s, 3H), 1.51 (s, 3H), 1.46 (s, 3H), 1.34 (s, 3H), 1.31 (s, 3H). 13 C NMR (75 MHz, CDCl3) δ 177.1, 165.9,150.5, 136.4, 131.8, 130.5, 128.9, 127.9, 125.7, 109.6, 108.8, 96.3, 71.0,70.7, 70.4, 65.9, 64.5, 26.0, 26.0, 24.9, 24.5, 21.5.

[0043] Example 3

[0044] Synthesis of geraniol-derived benzodithionine:

[0045] To a clean 10 mL reaction tube, benzo[a]sulfonyl ketone (0.3 mmol), DABCO (0.06 mmol, 20 mol%), DPPM (0.45 mmol), and geraniol 2-butynediol (0.45 mmol) were added sequentially, followed by 1,4-dioxane (2 mL). The reaction mixture was heated to 80 °C and stirred for 10 hours, with the reaction progress monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation to obtain the crude product. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain the target product, a white solid, in 75% yield.

[0046] according to Figure 6 The product's 1H NMR spectrum and Figure 7 The carbon spectrum of the product yields the following structural formula of the target product:

[0047] ;

[0048] 1 H NMR (300 MHz, CDCl3) δ 8.48 (d, J = 8.0 Hz, 1H), 7.63 – 7.56 (m,1H), 7.55 – 7.48 (m, 2H), 5.47 (t, J = 6.7 Hz, 1H), 5.13 – 5.04 (m, 1H), 4.88(d, J = 7.2 Hz, 2H), 2.44 (s, 3H), 2.09 (d, J = 5.1 Hz, 4H), 1.76 (s, 3H), 1.67 (s, 3H), 1.59 (s, 3H). 13 C NMR (75 MHz, CDCl3) δ 177.2, 166.1, 149.8,143.3, 136.4, 131.8, 131.7, 130.8, 130.5, 128.9, 127.8, 125.7, 123.7, 117.7,62.7, 39.5, 26.3, 25.6, 21.2, 17.7, 16.6.

[0049] Example 4

[0050] Synthesis of thiophene-derived benzodithionine:

[0051] To a clean 10 mL reaction tube, benzodisulfonic acid ketone (0.3 mmol), DABCO (0.06 mmol, 20 mol%), DPPM (0.45 mmol), and 2-butynediol (2-thiophene methyl) ester (0.45 mmol) were added sequentially, followed by 1,4-dioxane (2 mL). The reaction mixture was heated to 80 °C and stirred for 10 hours, with the reaction progress monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation to obtain the crude product. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate) to obtain the target product, a white solid, in 90% yield.

[0052] according to Figure 8 The product's 1H NMR spectrum and Figure 9 The carbon spectrum of the product yields the following structural formula of the target product:

[0053] ;

[0054] 1 H NMR (300 MHz, CDCl3) δ 8.47 (d, J = 7.2 Hz, 1H), 7.54 (dd, J =17.8, 5.4 Hz, 3H), 7.43 (s, 1H), 6.44 (d, J = 43.9 Hz, 2H), 5.35 (s, 2H),2.37 (s, 3H). 13 C NMR (75 MHz, CDCl3) δ 177.1, 165.6, 150.5, 149.0, 143.4,136.3, 131.8, 130.5, 130.2, 129.0, 127.9, 125.7, 111.2, 110.7, 59.1, 21.1.

Claims

1. A method for the metal-free catalytic synthesis of benzodithionine derivatives, characterized in that, Using benzodisulfonyl ketone and alkyne compounds as reactants, and under the co-catalysis of organophosphorus and organic amine, 1,4-dioxane as solvent, the reaction was heated to 80°C and stirred for 10 hours. After the reaction was completed, the benzodisulfide heterocyclic heptaenolide compounds were obtained by separation and purification. The organophosphine is bis(diphenylphosphine)methane, and the molar ratio of benzo[2]sulfonylphenol ketone to bis(diphenylphosphine)methane is 1:

1. The organic amine is triethylenediamine, and the amount of triethylenediamine used is 20 mol% of the amount of benzodisulfonate. The molar ratio of the benzodisulfonyl ketone to the alkyne compound is 1:1.5; The alkyne compounds are 2-butynedic menthyl ester, 2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxacyclopentene)[4,5-b:4',5'-d]pyran-5-yl)methylbut-2-alkynate, 2-butynedic geraniol ester, and 2-butynedic acid (2-thiophene methyl) ester.

2. The method according to claim 1, characterized in that, The specific separation and purification steps are as follows: after the reaction is completed, the mixture is cooled to room temperature, and the solvent is removed by rotary evaporator to obtain the crude product. The crude product is then separated by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to obtain high-purity benzodithioheptanone compounds.

3. The method according to claim 1, characterized in that, The reaction does not require inert gas protection.

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