Preparation method of gamma-oxobenzene propanesulfonyl fluoride compound

Abstract

The invention discloses a preparation method of a gamma-oxobenzene propanesulfonyl fluoride compound, and belongs to the field of chemical daily chemicals. According to the method, in a specific methanol solvent, aryl cyclopropanol is used as a substrate, and a reaction is carried out under the action of a sulfur dioxide source and a fluorine source, so that the gamma-oxobenzene propanesulfonyl fluoride compound is obtained. According to the method, the substrate is wide in applicability, raw materials are simple and easy to obtain, a complex and expensive catalytic system is not needed, and the economic cost is low; in addition, according to the method, synthesis of the target product can be achieved only through 8-24 hours of reaction, the target product can be obtained with the high yield, and rapidness and high efficiency are achieved.

Description

Technical Field

[0001] The invention specifically relates to a method for preparing a gamma-oxyphenylpropanesulfonyl fluoride compound, and belongs to the field of chemical daily chemicals. Background Art

[0002] In recent years, sulfonyl fluoride compounds have attracted more and more attention from the academic community. Sulfonyl fluoride compounds have become an important scaffold in the fields of organic synthesis, pharmaceutical medicine, and materials science due to their good balance between reactivity and stability. Sulfonyl fluoride compounds are also an important part of the new generation of "fluorine-sulfur exchange" concept proposed by Nobel Prize winner Sharpless. SuFEx click chemistry utilizes the strong nucleophilicity and electrophilicity between sulfur and fluorine, and can efficiently and selectively achieve the modification and functionalization of organic molecules. Therefore, in the past decade, there has been an urgent need to study the synthesis and modification components of sulfonyl fluoride, thereby developing many complex sulfonyl fluoride synthesis methods. However, most new methods focus on the synthesis of aryl sulfonyl fluoride compounds, while the synthesis of alkane sulfonyl fluoride compounds is relatively rare, and these synthetic reactions often use 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 Sulfonyl Fluorides. 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] The invention provides a photocatalytic system which does not require expensive additives and can still efficiently prepare the target product of the ring-opening fluorosulfonylation of aromatic cyclopropanol.

[0008]

Technical solution

[0009] The present invention selects an aromatic cyclopropanol to open the ring under the participation of [SO2], generates sulfinic acid anions in situ, and then the sulfinic acid anions are oxidized by [F] and combined to obtain the final product, thereby realizing the ring-opening fluorosulfonylation of the aromatic cyclopropanol.

[0010] The object of the present invention is to provide a preparation method of cyclopropanol fluorination sulfonylation, wherein the aryl cyclopropanol represented by formula (1) is used as a substrate in a solvent, and reacts under the action of a sulfur dioxide source and a fluorine source. After the reaction is completed, an oxyphenylpropanesulfonyl fluoride compound represented by formula (2) is obtained;

[0011]

[0012] Wherein, R is selected from H, 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, R1 is selected from C 1-6 alkyl.

[0014] In one embodiment of the present invention, the amide group is -NR2COR3, R2 is selected from H, C 1-6 Alkyl, 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 the aromatic cyclopropanol is (1.5-3):1.

[0020] In one embodiment of the present invention, the molar ratio of the fluorine source to the aryl cyclopropanol 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 present invention, the reaction temperature is 20° C.-80° C., preferably 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 present invention, the reaction is carried out under an inert atmosphere, which includes nitrogen and argon.

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

[0026] Aryl cyclopropanol, K2S2O5 and a fluorine source are used as raw materials, mixed in methanol, and stirred at 25°C-80°C for a period of time to obtain an oxyphenylpropanesulfonyl fluoride compound.

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

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

[0029] In one embodiment of the present invention, the method is preferably carried out in the following steps: adding aromatic cyclopropanol, K2S2O5, and NFSI in a molar ratio of 1:1.5:2 to a reaction vessel containing a methanol solvent, stirring at 25°C-80°C for 8 hours, separating and purifying to obtain the target product.

[0030] Beneficial effects:

[0031] The invention provides a preparation method of cyclopropanol by fluorosulfonylation.

[0032] The method of the present invention can realize the ring-opening sulfonyl fluorination of the aromatic cyclopropanol in one step to obtain the target compound in a nitrogen (N2) atmosphere with an aromatic cyclopropanol compound as a substrate, K2S2O5 as a sulfur dioxide source, and NFSI as a F source. The reaction mechanism of the present invention is as follows: the present invention selects an aromatic cyclopropanol to open the ring in the presence of [SO2], generates sulfinic acid anions in situ, and then the sulfinic acid anions are oxidized by [F] and combined to obtain the final product, thereby realizing the ring-opening sulfonyl fluorination of the aromatic cyclopropanol.

[0033] The method of the present invention uses cheap and readily available K2S2O5 as a sulfur dioxide source and NFSI as a F source, respectively. The substrate has wide applicability, the raw materials are simple and readily available, and the economic cost is low. In addition, the method of the present invention only requires 8-24 hours of reaction to achieve the synthesis of the target product, and the target product can be obtained in a good yield, which is faster and more efficient.

[0034] The synthesis method of the invention uses easily available aryl cyclopropanol to synthesize oxyphenylpropanesulfonyl fluoride compounds under relatively simple conditions, realizes the ring-opening fluorosulfonylation of aryl cyclopropanol and simultaneously converts it into a fluorine-containing building block compound which is widely used in the fields of medicine, pesticides and petrochemicals. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 The synthetic route diagram of the method of the present invention is shown in FIG. DETAILED DESCRIPTION

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

[0037] The synthetic route diagram of the embodiment of the present invention is as follows: Figure 1 As shown:

[0038] Using aromatic cyclopropanol, K2S2O5 and NFSI as raw materials, stirring and reacting at 25℃-80℃ for a period of time to obtain oxyphenylpropanesulfonyl fluoride compound. The reaction expression is: Figure 1 .

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

[0040] To a 20 mL dried Schlenk tube equipped with a magnet, K2S2O5 (166.7 mg, 0.75 mmol, 1.5 equiv) and NFSI (315.3 mg, 1.0 mmol, 2.0 equiv) were added in sequence under nitrogen protection. 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 with a syringe, and reacted at 25°C for 8 h. After the reaction was completed, 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, and concentrated by rotary evaporation to obtain a crude product. The target compound was separated and 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-oxybenzenepropanesulfonyl fluoride

[0043] To a 20 mL dried Schlenk tube equipped with a magnet, K2S2O5 (166.7 mg, 0.75 mmol, 1.5 equiv) and NFSI (315.3 mg, 1.0 mmol, 2.0 equiv) were added in sequence under nitrogen protection. 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 with a syringe, and reacted at 25°C for 8 h. After the reaction was completed, 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, and concentrated by rotary evaporation to obtain a crude product. The target compound was separated and 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-oxybenzenesulfonyl fluoride

[0046] To a 20 mL Schlenk tube dried and equipped with a magnet, K2S2O5 (166.7 mg, 0.75 mmol, 1.5 equiv) and NFSI (315.3 mg, 1.0 mmol, 2.0 equiv) were added in sequence under nitrogen protection. 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 with a syringe, and reacted at 25°C for 8 h. After the reaction was completed, 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, and concentrated by rotary evaporation to obtain a crude product. The target compound was separated and 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 Investigating the Effect of Sulfur Source on the Synthesis of γ-Oxyphenylpropanesulfonyl Fluoride

[0049] Referring to Example 1, the sulfur source was replaced with 1,4-diazabicyclo[2.2.2]octane-1,4-diamine-1,4-disulfinic acid (DABSO), Na2S2O4, and TDO, respectively. In addition, a group of experiments without any sulfur source was added, and other conditions remained unchanged to obtain the corresponding γ-oxyphenylpropanesulfonyl fluoride. The specific yield results are shown in Table 1.

[0050] Table 1 Effect of different sulfur sources on the synthesis of γ-oxyphenylpropanesulfonyl fluoride

[0051]

[0052]

[0053] The results show that when no sulfur source is added and DABSO, Na2S2O4, or TDO is used to replace K2S2O5 in Example 2 as the sulfur source, the yield of the obtained product is worse than that of Example 1, and the yield does not exceed 50%.

[0054] Example 5 investigates the effect of solvent selection on the synthesis of γ-oxyphenylpropanesulfonyl 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 other conditions remained unchanged to obtain the corresponding γ-oxybenzenepropanesulfonyl fluoride.

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

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

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

[0059] The results showed that when DCE, DMSO, DMF, Dioxane, MeCN, THF were used as solvent instead of methanol in Example 2, the yield of the obtained product was lower than that in Example 1, and the yield did not exceed 51%.

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

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

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

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

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

[0065] The results showed that when 40°C, 60°C, and 80°C were used instead of 25°C in Example 1, the yield of the product obtained was worse than that in Example 1, and the yield did not exceed 37%.

[0066] Application Examples

[0067] Sulfonyl fluoride has become a prominent scaffold in organic synthesis, drug discovery, and materials science due to its good balance between reactivity and stability. In particular, sulfonyl fluoride is the main substrate for sulfur (VI) fluoride exchange (SuFEx), an emerging, powerful click reaction compatible with biological systems, originally introduced by Sharpless in 2014. As a result, research on sulfonyl fluoride and its related compounds has increased significantly in the past decade. (Quoted from the literature Photocatalytic CC Bond Cleavage and Fluorosulfonylation of Strained Cycloalkanols for Carbonyl-Containing Aliphatic Sulfonyl Fluorides Org. Lett. 2023, 25, 7051-7056).

[0068] For another example, a sultone can be synthesized from the obtained product. The sultone part is a class of hydroxy sultones discovered by Erdmann in 1888. This class of heterocyclic compounds has important value in medicine and materials, and is also widely used in various important research fields such as natural product synthesis, medicinal chemicals as multifunctional building block materials and electronic devices (according to patent document CN 108658959A).

[0069]

[0070] 4-Methoxy-γ-oxobenzenepropanesulfonyl fluoride (69.3 mg, 0.20 mmol, 1.0 eq), Cs2CO3 (130.4 mg, 0.40 mmol, 2.0 eq) and then dry MeCN (2.0 mL) were added. The reaction mixture was stirred at room temperature for 12 hours to achieve complete conversion. The mixture was concentrated in vacuo and flash chromatographed to give the sultone product (45.7 mg, 95% yield).

Claims

1. A method for preparing cyclopropanol by fluorosulfonylation, characterized in that: The method comprises the following steps: in a solvent, an aryl cyclopropanol represented by formula (1) is used as a substrate, and reacts under the action of a sulfur dioxide source and a fluorine source. After the reaction is completed, an oxyphenylpropanesulfonyl fluoride compound represented by formula (2) is obtained; Wherein, R is selected from H, C 1-6 Alkyl, halogen, cyano, nitro, C 1-6 Alkoxy, acyl, amide, aryl.

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

3. The method according to claim 1, characterized in that The solvent is methanol.

4. The method according to claim 1, characterized in that: The sulfur dioxide source is K2S2O5.

5. The method according to claim 1, characterized in that The fluorine source is any one or more of Selectfluor, NFSI, and KHF2.

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

1.

7. The method according to claim 1, characterized in that The molar ratio of the fluorine source to the aromatic cyclopropanol is (1.5-3):

1.

8. 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).

9. The method according to claim 1, characterized in that: The reaction temperature is 20°C-80°C and the reaction time is 8-24h.

10. The method according to any one of claims 1 to 9, characterized in that: The reaction is carried out under an inert atmosphere, which includes nitrogen and argon.

Images