Process for the preparation of a gamma-oxo phenylpropylsulfonyl fluoride compound

Abstract

The application discloses a preparation method of a gamma-oxo benzene propyl sulfonamide fluoride compound and belongs to the field of chemical daily-use chemicals. In the method, aryl cyclopropanol is used as a substrate, and a reaction is caused under the action of a sulfur dioxide source and a fluorine source in a specific methanol solvent, so that the gamma-oxo benzene propyl sulfonamide fluoride compound is obtained. The method has wide substrate applicability, simple and easily-obtained raw materials, does not need to use a complex and expensive catalytic system, and has low economic cost. In addition, the method can realize the synthesis of a target product, and the target product can be obtained in a good yield only by reacting for 8-24 hours, so that the method is more rapid and efficient.

Description

Technical Field

[0001] This invention specifically relates to a method for preparing γ-oxophenylpropanesulfonyl fluoride compounds, belonging to the field of chemical and daily chemical products. Background Technology

[0002] In recent years, sulfonyl fluorides have attracted increasing attention from the academic community. Due to their favorable balance between reactivity and stability, sulfonyl fluorides have become an important framework in organic synthesis, pharmaceutical medicine, and materials science. Sulfonyl fluorides are also a key component of the next-generation "fluorine-sulfur exchange" concept proposed by Nobel laureate Sharpless. SuFEx click chemistry utilizes the strong nucleophilicity and electrophilicity between sulfur and fluorine to efficiently and selectively modify and functionalize organic molecules. Therefore, over the past decade, there has been an urgent need to study the synthesis and modification of sulfonyl fluorides, leading to the development of many complex synthetic methods. However, most new methods focus on the synthesis of aryl sulfonyl fluorides, while the synthesis of alkane sulfonyl fluorides is relatively less common. Furthermore, these synthetic reactions often employ expensive metal catalysis, photocatalysis, and electrocatalysis, as well as complex additive systems, or reagents with low boiling points and high toxicity such as ClSO₂F, ESF, and SO₂F.

[0003] The photocatalytic system reported in the prior art (Photocatalytic C–C Bond Cleavage and Fluorosulfonylation of Strained Cycloalkanols for Carbonyl-Containing Aliphatic SulfonylFluorides. Org. Lett. 2023, 25, 38, 7051-7056) has the following process:

[0004]

[0005] Although this method can achieve a target yield of about 80%, it requires the use of a complex and expensive photocatalytic system. Summary of the Invention

[0006] [Technical Issues]

[0007] This invention provides a photocatalytic system that does not require expensive additives and can still efficiently prepare arylcyclopropanol ring-opening fluorosulfonylation target compounds.

[0008] [Technical Solution]

[0009] This invention achieves the ring-opening fluorosulfonylation of arylcyclopropanol by selecting arylcyclopropanol to undergo ring-opening with the participation of [SO2], generating sulfinic acid anions in situ, and then oxidizing and combining the sulfinic acid anions with [F] to obtain the final product.

[0010] The purpose of this invention is to provide a method for preparing cyclopropanol fluorosulfonation. The method involves reacting arylcyclopropanol (1) as a substrate in a solvent under the action of a sulfur dioxide source and a fluorine source. After the reaction is completed, the oxophenylpropanesulfonyl fluoride compound (2) is obtained.

[0011]

[0012] Among them, R is selected from H and C. 1-6 Alkyl, halogen (F, Cl, Br, I), cyano, nitro, C 1-6 Alkoxy, acyl, amide, aryl.

[0013] In one embodiment of the present invention, the acyl group is -COR1, and R1 is selected from C 1-6 alkyl.

[0014] In one embodiment of the present invention, the amide group is -NR2COR3, and R2 is selected from H and C. 1-6 Alkyl group, R3 is selected from C 1-6 alkyl.

[0015] In one embodiment of the present invention, the aryl group includes a benzene ring or a naphthalene ring.

[0016] In one embodiment of the present invention, the solvent is methanol.

[0017] In one embodiment of the present invention, the sulfur dioxide source is K2S2O5.

[0018] In one embodiment of the present invention, the fluorine source is any one or more of Selectfluor, NFSI (N-fluorobisbenzenesulfonamide), and KHF2.

[0019] In one embodiment of the present invention, the molar ratio of the sulfur dioxide source to arylcyclopropanol is (1.5-3):1.

[0020] In one embodiment of the present invention, the molar ratio of the fluorine source to arylcyclopropanol is (1.5-3):1.

[0021] In one embodiment of the present invention, the molar ratio of the sulfur dioxide source to the fluorine source is 1:(0.5-2).

[0022] In one embodiment of the invention, the reaction temperature is 20°C-80°C. Preferably, it is room temperature (20-30°C).

[0023] In one embodiment of the present invention, the reaction time is 8-24 hours.

[0024] In one embodiment of the invention, the reaction is carried out under an inert atmosphere, which includes nitrogen or argon.

[0025] In one embodiment of the present invention, the steps of a novel green and economical preparation method are as follows:

[0026] Using arylcyclopropanol, K2S2O5 and a fluorine source as raw materials, they are mixed in methanol and stirred at 25℃-80℃ for a period of time to obtain oxophenylpropanesulfonyl fluoride compounds.

[0027] In one embodiment of the present invention, after the reaction is completed, a pure oxophenylpropanesulfonyl fluoride compound is obtained by filtration, washing, vacuum distillation and column chromatography.

[0028] In one embodiment of the present invention, the separation method employs rapid column chromatography to obtain the final product, oxophenylpropanesulfonyl fluoride compound.

[0029] In one embodiment of the present invention, the method is preferably carried out as follows: arylcyclopropanol, K2S2O5, and NFSI are added to a reaction vessel containing methanol solvent in a molar ratio of 1:1.5:2, stirred at 25℃-80℃ for 8 hours, and then separated and purified to obtain the target product.

[0030] Beneficial effects:

[0031] This invention provides a method for preparing cyclopropanol fluorosulfonation.

[0032] The method of this invention, under a nitrogen (N2) atmosphere, using arylcyclopropanol compounds as substrates, K2S2O5 as a sulfur dioxide source, and NFSI as an fluorine source, can achieve ring-opening sulfonyl fluorination of arylcyclopropanol in one step to obtain the target compound. The reaction mechanism of this invention is as follows: This invention utilizes the ring-opening of arylcyclopropanol with the participation of [SO2] to generate sulfinic acid anions in situ. Subsequently, the sulfinic acid anions are oxidized and combined by [F] to obtain the final product, thus achieving the ring-opening fluorosulfonylation of arylcyclopropanol.

[0033] The method of this invention uses inexpensive and readily available K2S2O5 as the sulfur dioxide source and NFSI as the F source, which has wide substrate applicability, simple and readily available raw materials, and low economic cost. In addition, the method of this invention can achieve the synthesis of the target product with good yield in only 8-24 hours, which is faster and more efficient.

[0034] The synthesis method of this invention synthesizes oxophenylpropanesulfonyl fluoride compounds from readily available arylcyclopropanol under relatively simple conditions, achieving ring-opening fluorosulfonation of arylcyclopropanol and simultaneously converting it into fluorinated building block compounds with wide applications in the pharmaceutical, pesticide, and petrochemical fields. Attached Figure Description

[0035] Figure 1 This is a synthesis route diagram for the method of the present invention. Detailed Implementation

[0036] The following are specific embodiments of the present invention.

[0037] The synthesis route diagram of this invention embodiment is as follows: Figure 1 As shown:

[0038] Using arylcyclopropanol, K₂S₂O₅, and NFSI as raw materials, an oxophenylpropanesulfonyl fluoride compound was obtained after stirring at 25℃-80℃ for a period of time. The reaction formula is as follows: Figure 1 .

[0039] Example 1: Synthesis of 4-methoxy-γ-oxophenylpropanesulfonyl fluoride

[0040] Under nitrogen protection, K₂S₂O₅ (166.7 mg, 0.75 mmol, 1.5 equiv) and NFSI (315.3 mg, 1.0 mmol, 2.0 equiv) were added sequentially to a 20 mL dried Schlenk tube fitted with a magnetic stir bar. Then, 1-(4-methoxyphenyl)cyclopropanol (0.5 mmol, 1.0 equiv) was weighed, dissolved in 6 mL of ultra-dry methanol, and added to the reaction tube using a syringe. The reaction was carried out at 25 °C for 8 h. After the reaction was complete, the reaction solution was extracted with EA (3 × 10 mL) and saturated NaCl aqueous solution. The organic phase was dried over anhydrous MgSO₄ and filtered. The crude product was concentrated by rotary evaporation. The target analyte was purified by column chromatography to obtain 88.6 mg, with a yield of 72%.

[0041] 1 H NMR (400MHz, CDCl3) δ3.88-3.82(m,2H),6.97(d,J=8.9Hz,2H),3.89(s,3H),7.95(d,J=8.9Hz,2H),3.59-3.54(m,2H). 13 C NMR (101MHz, CDCl3) δ45.94 (d, J = 18.5Hz), 128.43 (s), 55.72 (s), 130.62 (s), 164.46 (s), 114.24 (s), 192.35 (s), 32.10 (s). 19F NMR (376MHz, CDCl3) δ53.96 (s).

[0042] Example 2: Synthesis of 4-fluoro-γ-oxophenylpropanesulfonyl fluoride

[0043] Under nitrogen protection, K₂S₂O₅ (166.7 mg, 0.75 mmol, 1.5 equiv) and NFSI (315.3 mg, 1.0 mmol, 2.0 equiv) were added sequentially to a 20 mL dried Schlenk tube fitted with a magnetic magnet. Then, 1-(4-fluorophenyl)cyclopropanol (0.5 mmol, 1.0 equiv) was weighed, dissolved in 6 mL of ultra-dry methanol, and added to the reaction tube using a syringe. The reaction was carried out at 25 °C for 8 h. After the reaction was complete, the reaction solution was extracted with EA (3 × 10 mL) and saturated NaCl aqueous solution. The organic phase was dried over anhydrous MgSO₄ and filtered. The crude product was concentrated by rotary evaporation. The target analyte was purified by column chromatography to obtain 81.9 mg, with a yield of 70%.

[0044] 1 H NMR (400MHz, CDCl3) δ8.07-7.97(m,2H),7.24-7.13(m,2H),3.88(ddd,J=8.0,6.6,4.9Hz,2H),3.65-3.50(m,2H). 13 C NMR (101MHz, CDCl3) δ192.40 (s), 167.79 (s), 165.24 (s), 131.04 (d, J = 9.6Hz) ,116.36(d,J=22.2Hz),68.09(s),45.77(d,J=18.9Hz),32.49(s),25.74(s). 19 F NMR (376MHz, CDCl3) δ54.09 (s), 102.76 (s).

[0045] Example 3: Synthesis of 4-methyl-γ-oxophenylpropanesulfonyl fluoride

[0046] Under nitrogen protection, K₂S₂O₅ (166.7 mg, 0.75 mmol, 1.5 equiv) and NFSI (315.3 mg, 1.0 mmol, 2.0 equiv) were added sequentially to a 20 mL dried Schlenk tube fitted with a magnetic magnet. Then, 1-(4-methylphenyl)cyclopropanol (0.5 mmol, 1.0 equiv) was weighed, dissolved in 6 mL of ultra-dry methanol, and added to the reaction tube using a syringe. The reaction was carried out at 25 °C for 8 h. After the reaction was complete, the reaction solution was extracted with EA (3 × 10 mL) and saturated NaCl aqueous solution. The organic phase was dried over anhydrous MgSO₄ and filtered. The crude product was concentrated by rotary evaporation. The target analyte was purified by column chromatography to obtain 46 mg, with a yield of 40%.

[0047] 1 H NMR (400MHz, CDCl3) δ2.43 (s, 3H), 3.59 (t, J = 7.5Hz, 2H), 7.30 (d, J = 7.8Hz, 2H), 3.85 (t, J = 6.7Hz, 2H), 7.87 (d, J = 7.8Hz, 2H). 13 C NMR (101MHz, CDCl3) δ193.54(s), 145.43(s), 132.99(s), 129.76(s), 128.38(s), 45.90(d, J=18.7Hz), 32.39(s), 21.86(s). 19 F NMR (376MHz, CDCl3) δ54.00 (s).

[0048] Example 4 investigates the effect of sulfur source on the synthesis of γ-oxophenylpropanesulfonyl fluoride.

[0049] Referring to Example 1, the sulfur source was replaced with 1,4-diazabicyclo[2.2.2]octane-1,4-dionyl-1,4-disulfinic acid (DABSO), Na2S2O4, and TDO, respectively. In addition, an experiment was conducted without any sulfur source, with other conditions remaining unchanged, to prepare the corresponding γ-oxophenylpropanesulfonyl fluoride. The specific yield results are shown in Table 1.

[0050] Table 1. Effects of different sulfur sources on the synthesis of γ-oxophenylpropanesulfonyl fluoride

[0051]

[0052]

[0053] The results showed that the product yield was worse than that of Example 1 when no sulfur source was added or when DABSO, Na2S2O4, and TDO were used to replace K2S2O5 in Example 2 as the sulfur source, with the yield not exceeding 50%.

[0054] Example 5 investigates the effect of solvent selection on the synthesis of γ-oxophenylpropanesulfonyl fluoride.

[0055] Referring to Example 1, the solvent was replaced by 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane, acetonitrile, and tetrahydrofuran, respectively, while keeping other conditions unchanged, to prepare the corresponding γ-oxophenylpropanesulfonyl fluoride.

[0056] The specific yield results are shown in Table 2.

[0057] Table 2 Effect of different solvents on the synthesis of γ-oxophenylpropanesulfonyl fluoride

[0058] solvent Yield (%) DCE 51 <![CDATA[MeOH:H2O=20:1]]> 15 DMSO 0 DMF 4 Dioxane 47 MeCN 32 MeOH 72

[0059] The results showed that replacing methanol in Example 2 with DCE, DMSO, DMF, Dioxane, MeCN, or THF as the solvent resulted in a lower product yield than in Example 1, with a yield of no more than 51%.

[0060] Example 6 investigates the effect of reaction temperature on the synthesis of γ-oxophenylpropanesulfonyl fluoride.

[0061] Referring to Example 1, the reaction temperature was changed from 25°C to 40°C, 60°C, and 80°C respectively, while other conditions remained unchanged, to obtain the corresponding γ-oxophenylpropanesulfonyl fluoride.

[0062] The specific yield results are shown in Table 3.

[0063] Table 3 Effect of different reaction temperatures on the synthesis of γ-oxophenylpropanesulfonyl fluoride

[0064] Temperature (°C) Yield (%) 25 72 40 37 60 16 80 0

[0065] The results showed that replacing 25°C in Example 1 with 40°C, 60°C, or 80°C resulted in a lower product yield than in Example 1, with a yield not exceeding 37%.

[0066] Application examples

[0067] Sulfonyl fluorides have become a prominent scaffold in organic synthesis, drug discovery, and materials science due to their favorable balance between reactivity and stability. In particular, sulfonyl fluorides are a major substrate for sulfur (VI) fluoride exchange (SuFEx), a novel and robust click reaction compatible with biological systems, initially introduced by Sharpless in 2014. Consequently, research on sulfonyl fluorides and related compounds has increased dramatically over the past decade. (From Photocatalytic CC BondCleavage and Fluorosulfonylation of Strained Cycloalkanols for Carbonyl-Containing Aliphatic SulfonylFluorides Org. Lett. 2023, 25, 7051-7056).

[0068] For example, a sulfonyl lactone can be synthesized from the resulting product. The sulfonyl lactone moiety is a class of hydroxysulfonyl lactones discovered by Erdmann in 1888. These heterocyclic compounds have important value in pharmaceuticals and materials, and are also widely used in various important research fields such as natural product synthesis, pharmaceutical chemicals as multifunctional building block materials, and electronic devices (according to patent document CN 108658959A).

[0069]

[0070] 4-Methoxy-γ-oxophenylpropanesulfonyl fluoride (69.3 mg, 0.20 mmol, 1.0 equivalence), Cs₂CO₃ (130.4 mg, 0.40 mmol, 2.0 equivalence), and then dried MeCN (2.0 mL) were added. The reaction mixture was stirred at room temperature for 12 hours to achieve complete conversion. The mixture was then concentrated under vacuum and subjected to rapid chromatography to give the sulfonyl lactone product (45.7 mg, 95% yield).

Claims

1. A method for preparing cyclopropanol fluorosulfonation, characterized in that, The method involves reacting arylcyclopropanol (as shown in formula (1)) as a substrate in a solvent under the action of a sulfur dioxide source and a fluorine source. After the reaction is completed, the oxophenylpropanesulfonyl fluoride compound (as shown in formula (2)) is obtained. Among them, R is selected from H and C. 1-6 Alkyl, halogen, cyano, nitro, C 1-6 Alkoxy, acyl, amide, aryl; The solvent is methanol, the sulfur dioxide source is K2S2O5, and the fluorine source is any one or more of Selectfluor, NFSI, and KHF2.

2. The method according to claim 1, characterized in that, The acyl group is -COR1, and R1 is selected from C 1-6 Alkyl group; amide group is -NR2COR3, R2 is selected from H, C 1-6 Alkyl group, R3 is selected from C 1-6 alkyl.

3. The method according to claim 1, characterized in that, The molar ratio of the sulfur dioxide source to arylcyclopropanol is (1.5–3):

1.

4. The method according to claim 1, characterized in that, The molar ratio of the fluorine source to arylcyclopropanol is (1.5–3):

1.

5. The method according to claim 1, characterized in that, The molar ratio of the sulfur dioxide source to the fluorine source is 1:(0.5-2).

6. The method according to claim 1, characterized in that, The reaction temperature is 20℃-80℃, and the time is 8-24h.

7. The method according to any one of claims 1-6, characterized in that, The reaction is carried out under an inert atmosphere, which includes nitrogen and argon.

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