Method for preparing polyfluoroaryl sulfide

Abstract

The invention relates to a method for preparing polyfluoroaryl sulfide. The method comprises the step of reacting a compound as shown in a formula I with a compound as shown in a formula II to form a compound as shown in a formula III,

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis technology, specifically relating to a method for preparing polyfluoroaryl sulfides. Background Technology

[0002] Organosulfur compounds (polyfluoroaryl sulfides) are ubiquitous in naturally occurring compounds, agrochemicals, pharmaceuticals, and functional materials, playing a vital role in various chemical fields. They are typically synthesized from odorous, unstable thiols with various electrophilic reagents under transition metal catalysis. Thiosulfonates are a novel sulfur source and have been successfully applied to the synthesis of organosulfur compounds. For example, Ji Shunjun et al. reported a nickel-catalyzed cross-coupling reaction of alkyl bromides with thiosulfonates in 2018; Shao Xinxin et al. reported a nickel-catalyzed cross-coupling reaction of thiosulfonates with iodides under mild conditions in 2022. Direct coupling of easily prepared, stable, and safe thiosulfonates with zinc polyfluorobenzoate has not yet been developed. Summary of the Invention

[0003] This invention provides a method for preparing polyfluoroaryl sulfides, characterized in that the method includes the step of reacting a compound of formula I with a compound of formula II to form a compound of formula III.

[0004]

[0005] Ar is selected from C6 aryl or C6 aryl. 5-6 Mixed aromatics;

[0006] R 1 Selected from C 1-10 Alkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 5-10 heteroaryl or C 6-10 Aryl, the C 1-10 Alkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 5-10 heteroaryl or C 6-10 The aryl group is optionally surrounded by one or more elements selected from halogen, hydroxyl, cyano, nitro, amino, -COOCH3, -COOC2H5, C 1-6 Alkyl, C 1-6 Alkoxy, C 5-10 heteroaryl or C 6-10 Aryl groups are replaced;

[0007] R 2 Selected from nitro, C 1-3 Alkyl or C 1-3 Alkoxy, the C1-3 Alkyl or C 1-3 The alkoxy group may optionally be replaced by one or more halogens;

[0008] m and n are each independently selected from integers between 1 and 5.

[0009] In some embodiments, Ar is selected from C6 aryl, such as phenyl. Ar is selected from C... 5-6 Heteroaryl groups, such as pyridyl.

[0010] In some implementation schemes, R 1 Selected from C 1-10 Alkyl groups, such as C1 alkyl groups, C2 alkyl groups, C3 alkyl groups, C4 alkyl groups, C5 alkyl groups, C6 alkyl groups, C7 ... 2-3 Alkyl, C4 alkyl, C8 alkyl.

[0011] In some implementation schemes, R 1 Selected from phenyl, pyridyl, thiophenyl, furanyl, or naphthyl, optionally by one or more radicals selected from halogen, hydroxyl, cyano, nitro, amino, -COOCH3, -COOC2H5, C 1-6 Alkyl, C 1-6 Alkoxy, C 5-10 heteroaryl or C 6-10 Aryl groups are replaced.

[0012] In some implementation schemes, R 2 Selected from C 1-3 Alkyl groups, such as methyl or ethyl.

[0013] In some embodiments, the compound represented by Formula I is selected from...

[0014] In some embodiments, the compound of formula II is selected from...

[0015] In some embodiments, the molar ratio of the compound shown in Formula I to the compound shown in Formula II is 1 to 2:1, for example, 1:1 or 1.5:1.

[0016] In some embodiments, the reaction solvent for the compound of Formula I and the compound of Formula II is selected from dimethylformamide, dimethylacetamide, or N-methylpyrrolidone. In some embodiments, the reaction solvent for the compound of Formula I and the compound of Formula II is selected from dimethylacetamide.

[0017] In some embodiments, the compound of Formula I reacts with the compound of Formula II at a temperature of 50–130°C, for example, 60°C or 120°C.

[0018] On the other hand, the aforementioned preparation method includes the step of reacting the compound of formula A with zinc hydroxide to form the compound of formula I.

[0019] Where n and Ar are defined as described above.

[0020] The present invention also provides another method for preparing polyfluoroaryl sulfides, the method comprising the step of reacting the compound of formula A with the compound of formula II in the presence of zinc hydroxide to form the compound of formula III.

[0021]

[0022] Ar is selected from C6 aryl or C6 aryl. 5-6 Mixed aromatics;

[0023] R 1 Selected from C 1-10 Alkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 5-10 heteroaryl or C 6-10 Aryl, the C 1-10 Alkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 5-10 heteroaryl or C 6-10 The aryl group is optionally surrounded by one or more elements selected from halogen, hydroxyl, cyano, nitro, amino, -COOCH3, -COOC2H5, C 1-6 Alkyl, C 1-6 Alkoxy, C 5-10 heteroaryl or C 6-10 Aryl groups are replaced;

[0024] R 2 Selected from nitro, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group may optionally be replaced by one or more halogens;

[0025] m and n are each independently selected from integers between 1 and 5.

[0026] In some embodiments, the compound represented by Formula A is selected from...

[0027] In some embodiments, the molar ratio of the compound shown in Formula A to the compound described in Formula II is 1.5 to 3:1, for example 2:1.

[0028] In some embodiments, the method further includes the step of reacting the compound of Formula I with the compound of Formula II to form the compound of Formula III.

[0029]

[0030] In some embodiments, the compound of formula A is reacted with the compound of formula II in a one-pot reaction in the presence of zinc hydroxide to form the compound of formula III.

[0031] The preparation method of the present invention also includes one or more steps such as filtration, extraction, drying, concentration or purification (e.g., column chromatography).

[0032] "Optionally" means that the event or situation subsequently described may, but does not have to, occur; the description includes the possibility or possibility that the event or situation may or may not occur. For example, "optionally halogenated or cyano-substituted C..." 1-6 "Alkyl" means that halogens or cyano groups may or may not be present. This description includes cases where alkyl groups are substituted by halogens or cyano groups and cases where alkyl groups are not substituted by halogens or cyano groups.

[0033] "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 8 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and their various branched isomers. The alkyl group may be substituted or unsubstituted.

[0034] The term "cycloalkyl" or "alicyclic ring" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 6 carbon atoms, such as 4 or 5 carbons. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. Cycloalkyl groups can be substituted or unsubstituted.

[0035] The term "heterocycloalkyl" or "alicyclic heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 14 ring atoms, such as 4 or 5 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O). m Heteroatoms (where m is an integer from 0 to 2), excluding the ring moiety of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Non-limiting examples of "heterocyclic alkyl" include: Etc. Heterocyclic alkyl groups can be optionally substituted or unsubstituted.

[0036] The term "aryl" or "aromatic ring" refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group with a conjugated π-electron system, such as phenyl and naphthyl.

[0037] The term "heteroaryl" or "heteroary ring" refers to a heteroaryl system containing 1 to 4 heteroatoms and 5 to 10 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered, such as 7-membered, 8-membered, or 9-membered, and more preferably 5-membered or 6-membered.

[0038] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort.

[0039] The "substituents" of this invention include, but are not limited to, halogens (such as chlorine and fluorine), hydroxyl groups, cyano groups, nitro groups, amino groups, and C groups. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, or -OC 2-6 alkenyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, or -OC 2-6 Alkenyl groups are optionally replaced by one or more halogens, oxo groups, hydroxyl groups, cyano groups, nitro groups, amino groups, or C groups. 1-6 Alkyl or C 1-6 Alkyl-substituted.

[0040] The term "hydroxyl group" refers to the -OH group.

[0041] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0042] The term "cyano" refers to -CN.

[0043] The term "nitro" refers to -NO2.

[0044] The term "filtration" in this invention is merely a description of one method of separating solids and liquids, and does not refer to only one specific operation. In actual production, methods such as centrifugation or spin-filtering also fall into this category.

[0045] The values ​​used in this invention are instrument measurements and are subject to a certain degree of error. Generally, ±20% is within a reasonable error range. Of course, the context in which the value is used needs to be considered, and the values ​​can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0046] Compared with the prior art, the present invention has the following beneficial effects:

[0047] This invention provides a novel method for the direct cross-coupling of zinc polyfluorobenzoate and thiosulfonate. This reaction not only utilizes readily available and inexpensive zinc polyfluorobenzoate as the coupling substrate, but also uses thiosulfonate as a substitute for thiols, avoiding problems such as pungent reagent odor and instability during the process. Furthermore, thiosulfonate can be stored at room temperature, exhibiting excellent thermodynamic stability. Compared to thiols, they are more stable and easier to prepare. The preparation method of this invention features mild reaction conditions, simple post-processing, environmentally friendly procedures, low pollution, and high economic efficiency.

[0048] The structure of the compounds was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl₃), and deuterated methanol (Methanol-d4) as solvents, and tetramethylsilane (TMS) as the internal standard. Detailed Implementation

[0049] To make the above-mentioned objects, 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 the examples in the specification.

[0050] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0051] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single or selective embodiment that is mutually exclusive with other embodiments.

[0052] Unless otherwise specified, all raw materials used in the examples are commercially available.

[0053] The zinc polyfluorobenzoate (Formula I) used in this invention was synthesized with reference to the following literature:

[0054] [1]Wang, J.; Cui, Y.; Xie, S.; Zhang, J.-Q.; Hu, D.; Shuai, S.; Zhang, C.; Ren, H. Biaryls.Org.Lett.2024,26,137-141.

[0055] [2]Takahashi, R.; Seo, T.; Kubota, K.; Ito, H. Palladium-Catalyzed Solid-State Polyfluoroarylation of Aryl Halides Using Mechanochemistry.ACSCatal.2021,11,14803-14810.

[0056] The thiosulfonate (Formula II) was synthesized with reference to the following literature:

[0057] [3]Fan, Q.; Zhao, Y.; Liang, J.; Zhang, Y.; Xu, Y.; Zhang, Q.; Zhu, H.; Jiang, M.; Shao, X. Nickel-Free Cross-Electrophile Coupling of Unactivated Alkyl Bromides with Thiosulfonates and Sulfinyl Sulfones.Org.Chem.Front.2024,11,2518-2527.

[0058] Example 1

[0059]

[0060] Under a nitrogen atmosphere, zinc pentafluorobenzoate (1a, 243.8 mg, 0.5 mmol, 1 equiv.) and phenyl thiosulfonate (2a, 125.2 mg, 0.5 mmol, 1 equiv.) were added to a sealed tube, followed by the addition of 3 mL of N,N-dimethylacetamide. The tube was then purged with nitrogen three times. The mixture was stirred at 60 °C for 12 hours. Extraction was then performed using ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and then removed by rotary evaporation. The crude product was purified by silica gel column chromatography under the following conditions: 200–300 mesh silica gel powder as the stationary phase and petroleum ether as the mobile phase. A final yield of 107.3 mg of the target product was obtained.

[0061] 1 H NMR (400MHz, CDCl3): δ7.37-7.34(m,2H),7.32-7.27(m,3H)ppm.

[0062] 13 C NMR (100MHz, CDCl3): δ147.7 (dm, J = 243.8Hz), 142.2 (dm, J = 256.5Hz), 138.0 (dm, J = 250.0Hz), 132.9, 130.6, 129.4, 128.0, 109.3-108.8 (m, 1C) ppm.

[0063] 19 F NMR (376MHz, CDCl3): δ-131.59--131.68(m,2F),-151.26--151.37(m,1F),-160.33--160.52(m,2F)ppm.HRMS(ESI,m / z):calcd for C 12 H6F5S[M+H] + 277.0105,found:277.0106.IR(KBr,neat):ν=3076,2965,1652,1557,1477,1111,975,864,737cm -1 .

[0064] Example 2

[0065]

[0066] Under a nitrogen atmosphere, zinc pentafluorobenzoate (1a, 243.8 mg, 0.5 mmol, 1 equiv.) and phenyl thiosulfonate (2a, 125.2 mg, 0.5 mmol, 1 equiv.) were added to a sealed tube, followed by the addition of 3 mL of solvent. The tube was then purged with nitrogen three times. The mixture was stirred at 60 °C for 12 hours. Extraction was then performed using ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and then removed by rotary evaporation. The crude product was purified by silica gel column chromatography under the following conditions: 200–300 mesh silica gel powder as the stationary phase and petroleum ether as the mobile phase. The yields were calculated, and the specific data are as follows:

[0067]

[0068] Example 3

[0069]

[0070] Under a nitrogen atmosphere, zinc pentafluorobenzoate (1a, 243.8 mg, 0.5 mmol, 1 equiv.) and 2b-2p (0.5 mmol, 1 equiv.) were added to a sealed tube, followed by the addition of 3 mL of N,N-dimethylacetamide. The tube was then purged with nitrogen three times. The mixture was stirred at 60 °C for 12 hours. Extraction was then performed using ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and then removed by rotary evaporation. The crude product was purified by silica gel column chromatography under the following conditions: 200–300 mesh silica gel powder as the stationary phase and petroleum ether as the mobile phase. The final target product was obtained. The yields were calculated, and the specific data are as follows:

[0071]

[0072] Example 4

[0073]

[0074] Under a nitrogen atmosphere, 1b-1c (0.5 mmol, 1 equiv.) and 2 (0.5 mmol, 1 equiv.) were added to the sealed tube, followed by the addition of 3 mL of N,N-dimethylacetamide. The tube was then purged with nitrogen three times. The mixture was stirred at 120°C for 12 hours. Extraction was then performed using ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and then removed by rotary evaporation. The crude product was purified by silica gel column chromatography under the following conditions: 200–300 mesh silica gel powder as the stationary phase and petroleum ether as the mobile phase. The final target product was obtained. The yields were calculated, and the specific data are as follows:

[0075]

[0076] Example 5

[0077]

[0078] Under a nitrogen atmosphere, 5a-5c and 2 (125.2 mg, 0.5 mmol, 1 equiv.) were added to a sealed tube, followed by the addition of 3 mL of N,N-dimethylacetamide. The tube was then purged with nitrogen three times. The mixture was stirred at 60 °C for 12 hours. Extraction was then performed using ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and then removed by rotary evaporation. The crude product was purified by silica gel column chromatography under the following conditions: 200–300 mesh silica gel powder as the stationary phase and petroleum ether as the mobile phase. The final target product was obtained. The yields were calculated, and the specific data are as follows:

[0079]

[0080] Example 6

[0081]

[0082] Under a nitrogen atmosphere, compound 8 (0.5 mmol, 1 equiv.) and phenyl thiosulfonate (2a, 125.2 mg, 0.5 mmol, 1 equiv.) were added to a sealed tube, followed by the addition of 3 mL of N,N-dimethylacetamide. The sealed tube was then purged with nitrogen three times. The mixture was stirred at 60 °C for 12 hours; HPLC analysis revealed only a small amount of the target analyte.

[0083] Example 7

[0084]

[0085] Under a nitrogen atmosphere, compound 8 (0.5 mmol, 1 equiv.) and phenyl thiosulfonate (2a, 125.2 mg, 0.5 mmol, 1 equiv.) were added to a sealed tube, followed by the addition of 3 mL of N,N-dimethylacetamide. The sealed tube was then purged with nitrogen three times. The mixture was stirred at 60 °C for 12 hours; HPLC analysis revealed only a small amount of the target analyte.

[0086] Example 8

[0087]

[0088] Under a nitrogen atmosphere, compound 8 (0.5 mmol, 1 equiv.) and phenyl thiosulfonate (2a, 125.2 mg, 0.5 mmol, 1 equiv.) were added to a sealed tube, followed by the addition of 3 mL of N,N-dimethylacetamide. The sealed tube was then purged with nitrogen three times. The mixture was stirred at 60 °C for 12 hours; HPLC analysis revealed only a small amount of the target analyte.

Claims

1. A method for preparing polyfluoroaryl sulfides, characterized in that, The method includes the step of reacting the compound of Formula I with the compound of Formula II to form the compound of Formula III. Ar is selected from C6 aryl or C6 aryl. 5-6 Mixed aromatics; R 1 Selected from C 1-10 Alkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 5-10 heteroaryl or C 6-10 Aryl, the C 1-10 Alkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 5-10 heteroaryl or C 6-10 The aryl group is optionally surrounded by one or more elements selected from halogen, hydroxyl, cyano, nitro, amino, -COOCH3, -COOC2H5, C 1-6 Alkyl, C 1-6 Alkoxy, C 5-10 heteroaryl or C 6-10 Aryl groups are replaced; R 2 Selected from nitro, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group may optionally be replaced by one or more halogens; m and n are each independently selected from integers between 1 and 5.

2. The method according to claim 1, characterized in that, The molar ratio of the compound shown in Formula I to the compound shown in Formula II is 1 to 2:1, for example, 1:

1.

3. The method according to claim 1 or 2, characterized in that, The reaction solvent for the compound of Formula I and the compound of Formula II is selected from dimethylformamide, dimethylacetamide or N-methylpyrrolidone, preferably dimethylacetamide.

4. The method according to any one of claims 1-3, characterized in that, The reaction temperature between the compound shown in Formula I and the compound shown in Formula II is 50–130 °C.

5. The method according to any one of claims 1-4, characterized in that, The compound shown in Formula I is selected from 6. The method according to any one of claims 1-5, characterized in that, The compound described in Formula II is selected from 7. The method according to claims 1-6, characterized in that, The method further includes the step of reacting the compound of formula A with zinc hydroxide to form the compound of formula I. Wherein n and Ar are defined as in claim 1.

8. A method for preparing polyfluoroaryl sulfides, characterized in that, The method includes the step of reacting the compound of formula A with the compound of formula II in the presence of zinc hydroxide to form the compound of formula III. Ar is selected from C6 aryl or C6 aryl. 5-6 Mixed aromatics; R 1 Selected from C 1-10 Alkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 5-10 heteroaryl or C 6-10 Aryl, the C 1-10 Alkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 5-10 heteroaryl or C 6-10 The aryl group is optionally surrounded by one or more elements selected from halogen, hydroxyl, cyano, nitro, amino, -COOCH3, -COOC2H5, C 1-6 Alkyl, C 1-6 Alkoxy, C 5-10 heteroaryl or C 6-10 Aryl groups are replaced; R 2 Selected from nitro, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group may optionally be replaced by one or more halogens; m and n are each independently selected from integers between 1 and 5.

9. The method according to claim 8, characterized in that... The molar ratio of the compound shown in Formula A to the compound described in Formula II is 1.5 to 3:1, preferably 2:

1.

10. The method according to claim 8 or 9, characterized in that, The method further includes the step of reacting the compound of Formula I with the compound of Formula II to form the compound of Formula III.

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