A method for synthesizing aromatic carbon-10 sulfur-containing compounds from isoprene

Abstract

This invention relates to a method for synthesizing aromatic carbon-10 sulfur-containing compounds from isoprene. Specifically, using disulfide, isoprene, and 2-methyl-1-buten-3-yne as raw materials, aromatic carbon-10 sulfur-containing compounds are constructed under cobalt catalyst and iodine tandem catalysis. This invention has the following advantages: the raw materials are simple and readily available, the synthesis is simple, it is environmentally friendly, the conditions are mild, and it has high atom economy. The compounds obtained from the bulk chemical isoprene have structures similar to natural terpenes and represent an important class of terpenes.

Description

Technical Field

[0001] This invention relates to a method for synthesizing aromatic carbon-10 sulfur-containing compounds from isoprene. Specifically, using isoprene, 2-methyl-1-buten-3-yne, and disulfide as raw materials, aromatic carbon-10 sulfur-containing compounds are constructed under cobalt catalyst and iodine tandem catalysis. This invention has the following advantages: simple and readily available raw materials, simple synthesis, environmentally friendly, mild conditions, and high atom economy. Background Technology

[0002] Terpenes are the largest class of natural products in nature, widely distributed in plants, animals, and microorganisms. Monoterpenes, in particular, possess physiological activities such as anti-inflammatory, analgesic, and antitumor effects. They are also important natural fragrances and indispensable raw materials for the cosmetics and food industries. In recent years, their use as raw materials has seen significant development in the fields of renewable energy development and the synthesis of steroidal drugs. The synthesis of terpenoid derivatives through biomimetic catalysis has become an effective strategy, providing a novel approach for the precise synthesis of terpenoids.

[0003] Conjugated dienes are a major industrial chemical, inexpensive, readily available, and produced in high annual quantities. Using them as C5 synthons to mimic biological processes for the construction of hemiterpenes or terpenoid derivatives holds significant research importance and promising prospects. In recent years, the synthesis of various types of terpenoid derivatives through metal-catalyzed coupling reactions of nucleophiles with isoprene has established a solid research foundation. Literature searches reveal that the research groups of Beller, Finn, Réau, Navarro, Carbó, and Chen Qing'an have conducted related studies on nucleophilic linear telomerization reactions based on isoprene. In contrast, reactions involving the cyclic telomerization of isoprene to construct aromatic monoterpene derivatives are rarely reported, and this reaction also faces challenges in terms of redox selectivity and regioselectivity. Therefore, developing an efficient and precise synthetic strategy is of great research significance.

[0004] The construction of aromatic carbon-10 sulfur-containing compounds from isoprene through biomimetic catalysis not only provides a way to precisely convert terpenoids but also builds a bridge for the synthesis of aromatic carbon-10 compounds from carbon-5 units.

[0005] Summary of the Invention

[0006] The purpose of this invention is to precisely construct aromatic carbon-10 sulfur-containing compounds by achieving an aromatization coupling reaction of isoprene, 2-methyl-1-buten-3-yne and disulfide in the tandem action of cobalt catalyst and iodine.

[0007] This invention is achieved through the following technical solution:

[0008] A method for synthesizing aromatic carbon-10 sulfur-containing compounds from isoprene

[0009] Using isoprene, 2-methyl-1-buten-3-yne, and disulfide as raw materials, a rapid telomerization and aromatization coupling reaction was achieved in excellent yield under cobalt catalyst and iodine tandem catalysis. The reaction formula is shown below:

[0010]

[0011] The specific operating steps are as follows:

[0012] Under an argon and / or nitrogen atmosphere, cobalt salt, phosphine ligand, additive, solvent A, and isoprene are added to a reactor. 2-Methyl-1-buten-3-yne is heated to 40-100℃ (preferably 60-80℃) and stirred for 2-12 hours (preferably 3-4 hours). The mixture is then cooled to room temperature, and an oxidant, iodine, disulfide, and solvent B are added. The mixture is reacted at 80-140℃ (preferably 100-120℃) for 10-24 hours (preferably 12-14 hours). The reaction system is monitored by TLC. After the reaction is complete, the solvent is evaporated, and the mobile phase for column chromatography is petroleum ether.

[0013] The reactant disulfide compound 1 (Formula 1) may have one or more substituents R, such as alkyl or phenyl groups.

[0014] The cobalt salt used is one or more of the following: cobalt dichloride, cobalt dibromide, cobalt diiodide, cobalt acetate, or cobalt di(acetylacetone); wherein the molar ratio of cobalt salt to disulfide is 0.01-0.20, preferably 0.08-0.10.

[0015] The phosphine ligand used is 1,2-bis(diphenylphosphine)ethane or 1,3-bis(diphenylphosphine)propane, and the molar ratio of the phosphine ligand to the disulfide is 0.01-0.20, preferably 0.08-0.10.

[0016] Solvent A used is one or more of the following: methanol, ethanol, isopropanol, tert-butanol, acetonitrile, toluene, n-hexane, cyclohexane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, dichloromethane, dichloroethane, 1,4-dioxane, ethyl acetate, N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide.

[0017] Solvent B used is one or more of the following: methanol, ethanol, isopropanol, tert-butanol, acetonitrile, toluene, n-hexane, cyclohexane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, dichloromethane, dichloroethane, 1,4-dioxane, ethyl acetate, N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide; preferably, tetrahydrofuran is used as the solvent.

[0018] Solvent A may be different from or the same as solvent B, preferably different from solvent B, and the volume ratio of solvent A to solvent B is 1:1-4; the concentration of disulfide in the solvent is in the range of 0.01-1.5 mol / L, preferably 0.05-1.0 mol / L.

[0019] The amount of isoprene and 2-methyl-1-buten-3-yne is 3-10 times the molar amount of disulfide, preferably 4-5 times; the reaction temperature is 80-140℃, preferably 100-120℃; the reaction time is 10-24h, preferably 12-14h.

[0020] Additive 1 is one or more of zinc powder, manganese powder or iron powder, and additive 2 is one or more of zinc iodide, zinc bromide, zinc chloride or indium chloride. The molar ratio of the additive to disulfide is 0.1-0.6, preferably 0.3-0.4.

[0021] The iodine source is one or more of iodine, hydroiodic acid, or N-iodosuccinimide, and the molar ratio of iodine to disulfide is 0.2-1.0, preferably 0.4-0.8.

[0022] The oxidant is one or more of potassium persulfate, sodium persulfate, peroxytert-butanol, dimethyl sulfoxide, or 2,5-di-tert-butyl-p-benzoquinone, and the molar ratio of the oxidant to the disulfide is 2-10, preferably 4-8.

[0023] The present invention has the following advantages:

[0024] The raw materials are simple and readily available, the synthesis is simple, the environment is friendly, the conditions are mild, and the atom economy is high. The compounds obtained from the bulk chemical isoprene are similar in structure to natural terpenes. These compounds are an important class of terpene derivatives and synthetic intermediates with a wide range of pharmacological activities, such as anti-inflammatory, antitumor, antibacterial and various biological enzyme inhibitors. They are common and advantageous skeletons in drug molecules. Detailed Implementation

[0025] The present invention will be described below with specific embodiments, but the scope of protection of the present invention is not limited to these examples.

[0026] Example

[0027] 1. Synthesis of aromatic carbon-10 sulfur-containing compounds from isoprene

[0028] Under a nitrogen atmosphere, in a 4.0 mL pressure-resistant tube (pressure-resistant reaction tube), cobalt bromide (10 mol% relative to diphenyl disulfide), 1,2-bis(diphenylphosphine)ethane (10 mol% relative to diphenyl disulfide, dppe), zinc powder additive (40 mol% relative to diphenyl disulfide), zinc iodide additive (40 mol% relative to diphenyl disulfide), 0.5 mL of 1,4-dioxane, isoprene (40 μL, 4 times the molar amount of diphenyl disulfide), and 2-methyl... -1-Buten-3-yne (36 μL, 4 times the molar amount of diphenyl disulfide) was added, and the mixture was heated to 60 °C and stirred for 3 h. Then, it was cooled to room temperature, and an oxidant (0.6 mmol, 6 times the molar amount of diphenyl disulfide), diphenyl disulfide (0.1 mmol), an iodine source (80 mol% of diphenyl disulfide), and tetrahydrofuran (0.5 mL) were added. The mixture was reacted at 100 °C for 12 h, and the reaction system was monitored by TLC. After the reaction was completed, trimethylbenzene was added as an internal standard, and the yield of the target product was determined by GC-FID.

[0029]

[0030] Table 1. Effects of ligands, oxidants, and iodine sources on the reaction

[0031]

[0032]

[0033] 2. Substrate type

[0034] Under a nitrogen atmosphere, in a 4.0 mL pressure-resistant tube (pressure-resistant reaction tube), cobalt bromide (10 mol% relative to diphenyl disulfide), phosphine ligand (10 mol% relative to diphenyl disulfide), zinc powder and zinc iodide additives (40 mol% relative to diphenyl disulfide), 0.5 mL of 1,4-dioxane, isoprene (40 μL, 4 times the molar amount of diphenyl disulfide), and 2-methyl-1-buten-3-yne (relative to...) were added sequentially. The mixture was heated to 60°C and stirred for 3 hours, then cooled to room temperature. 2,5-Di-tert-butyl-p-benzoquinone (6 times the molar amount of diphenyl disulfide, 0.6 mmol), diaryl disulfide (0.1 mmol), iodine (80 mol% of diphenyl disulfide), and tetrahydrofuran (0.5 mL) were added. The mixture was then reacted at 100°C for 12 hours. After the reaction was complete, the solvent was evaporated, and the mixture was separated by column chromatography using petroleum ether as the mobile phase.

[0035]

[0036]

[0037]

[0038] Example 1

[0039]

[0040] (E)-Phenyl(2-(p-tolyl)prop-1-en-1-yl)sulfane(4a)

[0041] Colorless oil, 37.9 mg, 79% yield, R f =0.5(PE).

[0042] 1 H NMR(400 MHz, Chloroform-d) δ 7.41 - 7.37(m, 2H), 7.33 - 7.28(m, 4H), 7.23 - 7.20(m, 1H), 7.16 - 7.11(m, 2H), 6.53(q, J=1.0 Hz, 1H), 2.34(s, 3H), 2.24(d, J=1.1 Hz, 3H).

[0043] 13 C NMR(100 MHz, Chloroform-d) δ 139.00, 137.70, 137.18, 136.73, 129.23, 129.17, 129.05, 126.44, 125.45, 120.27, 21.22, 17.92.

[0044] HRMS calculated for C 16 H 17 S[M + H] + 241.1045, found 241.1040.

[0045] Example 2

[0046]

[0047] (E)-p-Tolyl(2-(p-tolyl)prop-1-en-1-yl)sulfane(4b)

[0048] Yellow oil, 39.1 mg, 77% yield, R f =0.5(PE).

[0049] 11H NMR (400 MHz, Chloroform-d) δ 7.33 - 7.26 (m, 4H), 7.15 - 7.08 (m, 4H), 6.49 (q, J=1.2 Hz, 1H), 2.33 (s, 3H), 2.32 (s, 3H), 2.21 (d, J=1.1 Hz, 3H).

[0050] 13 13C NMR (100 MHz, Chloroform-d) δ 139.07, 136.98, 136.60, 136.45, 132.99, 129.95, 129.65, 129.19, 125.38, 121.40, 21.19, 21.15, 17.82.

[0051] HRMS calculated for C 17 H 19 S [M+H] + 255.1202, found 255.1194.

[0052] Example 3

[0053]

[0054] (E)-(4-Chlorophenyl)(2-(p-tolyl)prop-1-en-1-yl)sulfane (4c)

[0055] Yellow solid, 46.8 mg, 85% yield, M.P. 41 - 43℃, R f =0.5 (PE), 1 1H NMR (400 MHz, Chloroform-d) δ 7.32 - 7.23 (m, 6H), 7.13 (d, J=7.9 Hz, 2H), 6.44 (q, J=1.1 Hz, 1H), 2.34 (s, 3H), 2.22 (d, J=1.1 Hz, 3H).

[0056] 13 13C NMR (100 MHz, Chloroform-d) δ 138.89, 138.79, 137.41, 135.37, 132.34, 130.13, 129.26, 125.48, 119.38, 21.21, 17.96. (one sp 2 C-atom missing due tooverlap)

[0057] HRMS calculated for C16 H 16 ClS[M+H] + 275.0656, found 275.0648.

[0058] Example 4

[0059]

[0060] (E)-(4-Methoxyphenyl)(2-(p-tolyl)prop-1-en-1-yl)sulfane (4d)

[0061] Brown oil, 40.4 mg, 75% yield, R f =0.6 (PE / EA=10 / 1).

[0062] 1 H NMR (400 MHz, Chloroform-d) δ 7.38 - 7.34 (m, 2H), 7.29 - 7.25 (m, 2H), 7.10 (d, J=8.0 Hz, 2H), 6.87 - 6.83 (m, 2H), 6.44 (s, 1H), 3.77 (s, 3H), 2.31 (s, 3H), 2.20 (d, J=1.1 Hz, 3H).

[0063] 13 C NMR (100 MHz, Chloroform-d) δ 159.10, 139.00, 136.80, 135.11, 132.12, 129.15, 126.90, 125.27, 122.78, 114.85, 55.45, 21.15, 17.66.

[0064] HRMS calculated for C 17 H 19 OS[M+H] + 271.1151, found 271.1152.

[0065] Example 5

[0066]

[0067] (E)-4-((2-(p-Tolyl)prop-1-en-1-yl)thio)phenol (4e)

[0068] Brown oil, 38.8 mg, 76% yield, R f =0.4 (PE / EA=5 / 1).

[0069] 1 1H NMR (400 MHz, Chloroform-d) δ 7.32 - 7.28 (m, 2H), 7.28 - 7.25 (m, 2H), 7.11 (d, J = 7.9 Hz, 2H), 6.79 - 6.75 (m, 2H), 6.42 (s, 1H), 5.33 (s, 1H), 2.32 (s, 3H), 2.19 (d, J = 1.0 Hz, 3H).

[0070] 13 13C NMR (100 MHz, Chloroform-d) δ 155.01, 138.96, 136.90, 135.36, 132.30, 129.17, 127.06, 125.29, 122.56, 116.34, 21.15, 17.69.

[0071] HRMS calculated for C 16 H 17 OS [M + H] + 257.0995, found 257.0993.

[0072] Example 6

[0073]

[0074] (E)-(4-Bromophenyl)(2-(p-tolyl)prop-1-en-1-yl)sulfane (4i)

[0075] White solid, 49.7 mg, 78% yield, M.P. 64 - 66 °C, R f = 0.5 (PE).

[0076] 1 1H NMR (400 MHz, Chloroform-d) δ 7.43 - 7.38 (m, 2H), 7.33 - 7.28 (m, 2H), 7.25 - 7.20 (m, 2H), 7.17 - 7.11 (m, 2H), 6.44 (q, J = 1.1 Hz, 1H), 2.34 (s, 3H), 2.23 (q, J = 1.0 Hz, 3H).

[0077] 1313C NMR (100 MHz, Chloroform-d) δ 139.16, 138.78, 137.47, 136.09, 132.17, 130.33, 129.28, 125.50, 120.17, 119.12, 21.23, 17.99.

[0078] HRMS calculated for C 16 H 16 BrS [M+H] + 319.0151, found 319.0147.

[0079] Example 7

[0080]

[0081] (E)-(4-Fluorophenyl)(2-(p-tolyl)prop-1-en-1-yl)sulfane (4 g)

[0082] Colorless oil, 39.8 mg, 77% yield, R f = 0.5 (PE).

[0083] 1 1H NMR (400 MHz, Chloroform-d) δ 7.40 - 7.33 (m, 2H), 7.32 - 7.25 (m, 2H), 7.16 - 7.10 (m, 2H), 7.04 - 6.97 (m, 2H), 6.43 (q, J = 1.1 Hz, 1H), 2.33 (s, 3H), 2.22 (d, J = 1.1 Hz, 3H).

[0084] 13 13C NMR (100 MHz, Chloroform-d) δ 161.96 (d, J = 246.5 Hz), 138.85, 137.36, 137.20, 131.69 (d, J = 3.3 Hz), 131.46 (d, J = 8.0 Hz), 129.22, 125.40, 120.84, 116.26 (d, J = 22.0 Hz), 21.18, 17.83.

[0085] 19 19F NMR (376 MHz, Chloroform-d) δ -115.47.

[0086] HRMS calculated for C 16 H 16 FS [M+H] +259.0951, found 259.0946.

[0087] Product application examples:

[0088]

[0089] In a 4.0 mL pressure-resistant tube, 4a (0.2 mmol, 48.1 mg), DCM (1.5 mL), and m-chloroperoxybenzoic acid (m-CPBA, 0.22 mmol) were added sequentially under ice bath conditions. The mixture was stirred at 0 °C for 10 minutes. The reaction solution was then washed with aqueous sodium hydroxide solution, extracted with ethyl acetate, and the organic phase was evaporated to dryness. The product was then separated by column chromatography using petroleum ether / ethyl acetate (volume ratio 3:1) as the mobile phase to obtain the target product 5.

[0090] (E)-1-Methyl-4-(1-(phenylsulfinyl)prop-1-en-2-yl)benzene(5)

[0091] Colorless oil,45.6mg,89%yield,R f =0.4 (PE / EA = 3 / 1).

[0092] 1 H NMR (400MHz, Chloroform-d) δ7.68-7.62(m,2H),7.54-7.45(m,3H),7.37-7.31(m,2H),7.18-7.12(m,2H),6.52(s,1H),2.56(s,3H),2.35(s,3H).

[0093] 13 C NMR (100MHz, Chloroform-d) δ148.12,145.05,139.86,136.51,132.49,130.71,129.45,129.42,126.25,124.27,21.33,18.11.

[0094] HRMS calculated for C 16 H 17 OS[M+H] + 257.0995, found 257.0998.

[0095] References: Guo, H., Ma, S. M. Highly Regio- and Stereoselective Palladium(0)-Catalyzed Addition of Organoboronic Acids with 1,2-Allenic Sulfones, Sulfoxides, or Alkyl- or Aryl-Substituted Allenes in the Presence of Acetic Acid: An Efficient Synthesis of E-Alkenes. Synth. 2007, 17, 2731-2745.

Claims

1. A method for synthesizing aromatic carbon-10 sulfur-containing compounds from isoprene, characterized in that: Isoprene, 2-methyl-1-buten-3-yne and disulfide undergo an aromatization coupling reaction in the presence of a cobalt catalyst and iodine in tandem, to synthesize an aromatic carbon-10 sulfur-containing compound.

2. The method according to claim 1, characterized in that: The specific operating steps are as follows: Under an argon and / or nitrogen atmosphere, cobalt salt, phosphine ligand, additive, solvent A, and isoprene are added to a reactor. 2-Methyl-1-buten-3-yne is heated to 40-100°C (preferably 60-80°C) and stirred for 2-12 hours (preferably 3-4 hours). Then, the mixture is cooled to room temperature, and an oxidant, iodine, disulfide, and solvent B are added. The mixture is then reacted at 80-140°C (preferably 100-120°C) for 10-24 hours (preferably 12-14 hours) to generate the target product.

3. The method according to claim 2, characterized in that: The reaction system was monitored by TLC. After the reaction was completed in 10-24 hours (preferably 12-14 hours), the solvent was evaporated and the mixture was separated by column chromatography. The mobile phase for column chromatography was petroleum ether.

4. The method according to any one of claims 1-3, characterized in that: The reaction formula is shown below: In the reactant disulfide compound 1 (Formula 1), the two substituents R can be C1-C30 alkyl or aryl, and the substituents on the carbon chain can be one or more of the following: fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, etc.

5. The method according to any one of claims 1-3, characterized in that: The cobalt salt used is one or more of the following: cobalt dichloride, cobalt dibromide, cobalt diiodide, cobalt acetate, or cobalt di(acetylacetone); The molar ratio of cobalt salt to disulfide is 0.01-0.20, with a preferred range of 0.08-0.

10.

6. The method according to any one of claims 1-3, characterized in that: The phosphine ligand used is 1,2-bis(diphenylphosphine)ethane or 1,3-bis(diphenylphosphine)propane, and the molar ratio of the phosphine ligand to the disulfide is 0.01-0.20, preferably 0.08-0.

10.

7. The method according to any one of claims 1-3, characterized in that: Solvent A used is one or more of the following: methanol, ethanol, isopropanol, tert-butanol, acetonitrile, toluene, n-hexane, cyclohexane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, dichloromethane, dichloroethane, 1,4-dioxane, ethyl acetate, N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. Solvent B used is one or more of the following: methanol, ethanol, isopropanol, tert-butanol, acetonitrile, toluene, n-hexane, cyclohexane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, dichloromethane, dichloroethane, 1,4-dioxane, ethyl acetate, N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide; the solvent is preferably tetrahydrofuran. Solvent A and solvent B may be different or the same, preferably solvent A and solvent B are different, and the volume ratio of solvent A to solvent B is 1:1-4; The concentration range of disulfide in the solvent is 0.01-1.5 mol / L, preferably 0.05-1.0 mol / L.

8. The method according to any one of claims 1-3, characterized in that: The amount of isoprene and 2-methyl-1-buten-3-yne is between 3 and 10 times the molar amount of disulfide, preferably between 4 and 5 times; Additive 1 is one or more of zinc powder, manganese powder or iron powder, and additive 2 is one or more of zinc iodide, zinc bromide, zinc chloride or indium chloride. The molar ratio of additive 1 and 2 to disulfide is 0.1-0.6, preferably 0.3-0.

4.

9. The method according to any one of claims 1-3, characterized in that: The iodine source is one or more of iodine, hydroiodic acid, or N-iodosuccinimide, and the molar ratio of iodine to disulfide is 0.2-1.0, preferably 0.4-0.

8.

10. The method according to any one of claims 1-3, characterized in that: The oxidant is one or more of potassium persulfate, sodium persulfate, peroxytert-butanol, dimethyl sulfoxide, or 2,5-di-tert-butyl-p-benzoquinone, and the molar ratio of the oxidant to the disulfide is 2-10, preferably 4-8.

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