A process for the preparation of 2-oxo-4-phenyl-oxazoline sulfonyl fluorides

Abstract

The application discloses a preparation method of 2-oxo-4-phenyl oxazine sulfonyl fluoride, and belongs to the field of organic chemical synthesis. The method is that a cinnamyl (fluorosulfonyl) carbamate compound is used as a substrate, and reacts under the action of a catalyst and a base in specific tetrahydrofuran solvent, and a 2-oxo-4-phenyl oxazine sulfonyl fluoride compound is obtained. The application uses cheap and easily obtained iodobenzene diacetic acid and potassium tert-butoxide as the catalyst and the base respectively, the substrate has wide applicability, the raw material is simple and easy to obtain, the economic cost is low, and the target product can be obtained in a good yield.

Description

Technical Field

[0001] This invention specifically relates to a method for preparing 2-oxo-4-phenyloxazine sulfonyl fluoride, belonging to the field of organic chemical synthesis. Background Technology

[0002] The viral outbreak poses a challenge to the global economy, healthcare, and public health infrastructure. Several well-known drugs have garnered significant attention due to speculation that they could be used to treat the novel coronavirus. The vast majority of the major drugs studied contain heterocyclic structures.

[0003] Heterocyclic chemistry is a core part of organic and biochemistry. These compounds contain at least one carbon atom and one or more non-carbon elements such as nitrogen, oxygen, or sulfur in their ring structure. They represent the largest and most diverse family of organic compounds, possessing significant chemical, biomedical, and industrial importance. Heterocyclic compounds include many biochemical substances essential to life; for example, many naturally occurring pigments, vitamins, and antibiotics are heterocyclic compounds, as are most hallucinogens. Therefore, developing new methods for synthesizing heterocyclic compounds remains a crucial challenge in the field of organic synthesis.

[0004] Sulfonyl fluorides are common structural units in bioactive molecules and widely used synthetic intermediates in modern organic synthesis. Since Sharpless and his collaborators first proposed the concept of sulfur (VI) fluoride exchange (SuFEx) in 2014 and presented it as a new generation of click chemistry, sulfonyl fluorides have received widespread attention and sustained interest from the synthetic chemistry and medicinal chemistry communities. Generally, strategies for constructing these frameworks mainly focus on fluorination-chloroexchange and SO2 insertion / fluorination from the corresponding sulfonyl chlorides. Compared with these methods formed via SF bonds, direct fluorosulfonation using FSO2-containing reagents is a simple and efficient approach. It is worth noting that most of the existing fluorosulfonation reagents are heterocyclic structures or contain heteroatoms; however, both their operation and synthesis processes suffer from problems such as cumbersome operation and high toxicity. Furthermore, it has been noted that reagents with succinamide five-membered ring structures are unstable in previous reagent development, and FSI shows great promise in the development of sulfonyl fluoride reagents. Therefore, based on relevant research progress, this study aims to explore a synthetic strategy to construct compounds with five-membered or six-membered heterocyclic structures containing sulfonyl fluoride groups. Summary of the Invention

[0005] To address the aforementioned problems, this invention provides a novel method for the synthesis of 2-oxo-4-phenyloxazine sulfonyl fluoride, specifically a method for preparing 2-oxo-4-phenyloxazine sulfonyl fluoride compounds. Using cinnamyl (fluorosulfonyl) carbamate as a substrate, and iodophenyldiacetic acid and potassium tert-butoxide as catalysts and bases, the nucleophilic addition reaction of cinnamyl (fluorosulfonyl) carbamate is explored.

[0006] This invention synthesizes 2-oxo-4-phenyloxazine sulfonyl fluoride compounds by reacting cinnamyl (fluorosulfonyl) carbamate with a catalyst and a base, thereby achieving the nucleophilic addition reaction of cinnamyl (fluorosulfonyl) carbamate.

[0007] The purpose of this invention is to provide a method for preparing a 2-oxo-4-phenyloxazine sulfonyl fluoride compound. The method involves using a cinnamyl (fluorosulfonyl) carbamate compound of formula (1) as a substrate in a solvent, reacting it under the action of a catalyst and a base. After the reaction is completed, the 2-oxo-4-phenyloxazine sulfonyl fluoride compound of formula (2) is obtained.

[0008]

[0009] Among them, R is selected from H and C. 1-4 Alkyl, halogen (F, Cl, Br, I), cyano, nitro, C 1-4 Alkoxy, acyl, amide, aryl.

[0010] In one embodiment of the present invention, the acyl group is -COR. a R a Selected from C 1-6 alkyl.

[0011] In one embodiment of the present invention, the amide group is -NR. b COR c R b Selected from H, C 1-6 Alkyl, R c Selected from C 1-6 alkyl.

[0012] In one embodiment of the present invention, the aryl group includes a benzene ring or a naphthalene ring.

[0013] In one embodiment of the present invention, the catalyst is iodophenyl diacetic acid.

[0014] In one embodiment of the present invention, the base is potassium tert-butoxide.

[0015] In one embodiment of the present invention, the solvent is tetrahydrofuran.

[0016] In one embodiment of the present invention, the reaction temperature is 25°C-40°C.

[0017] In one embodiment of the present invention, the reaction time is 6-12 hours. Specifically, 8 hours is an option.

[0018] In one embodiment of the present invention, the molar ratio of the cinnamyl (fluorosulfonyl) carbamate compound to the catalyst is 1:(0.5-1.5). Specifically, 1:1 is optional.

[0019] In one embodiment of the present invention, the molar ratio of the cinnamyl (fluorosulfonyl) carbamate compound to the base is 1:(1.0 to 2.0). Specifically, 1:1 is optional.

[0020] In one embodiment of the invention, the reaction is carried out under an inert atmosphere, which includes nitrogen or argon.

[0021] In one embodiment of the present invention, the preparation method comprises the following steps:

[0022] Using cinnamyl (fluorosulfonyl) carbamate as a raw material, iodophenyl diacetic acid and potassium tert-butoxide were added, and the mixture was stirred and reacted at 25℃-40℃ for a period of time to obtain 2-oxo-4-phenyloxazine sulfonyl fluoride compound.

[0023] In one embodiment of the present invention, after the reaction is completed, pure 2-oxo-4-phenyloxazine sulfonyl fluoride is obtained by filtration, washing, vacuum distillation and column chromatography.

[0024] In one embodiment of the present invention, the separation method is a rapid column chromatography separation method to obtain the final product 2-oxo-4-phenyloxazine sulfonyl fluoride.

[0025] In one embodiment of the present invention, the method is preferably carried out as follows: cinnamyl (fluorosulfonyl) carbamate, iodophenyl diacetic acid, and potassium tert-butoxide are added to a reaction vessel containing tetrahydrofuran solvent in a molar ratio of 1:1:1, stirred at 25°C-80°C for 6-12 hours, and then separated and purified to obtain the target product.

[0026] Beneficial effects:

[0027] This invention provides a method for preparing a 2-oxo-4-phenyloxazine sulfonyl fluoride compound.

[0028] The method of this invention, using cinnamyl (fluorosulfonyl) carbamate as a substrate, can synthesize 2-oxo-4-phenyloxazine sulfonyl fluoride in one step under a nitrogen (N2) atmosphere with the aid of a catalyst and a base, yielding the target compound. The reaction mechanism of this invention is as follows: First, iodophenyldiacetic acid generates an iodide ion under the action of a base, which attacks the double bond to generate a carbocation at the α-position. Then, the lone pair electrons on the nitrogen atom attack the carbocation, thereby completing the cyclization reaction.

[0029] The method of this invention uses inexpensive and readily available iodophenyl diacetic acid and potassium tert-butoxide as catalysts and bases, respectively. It 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 a good yield in only 6-12 hours, which is faster and more efficient.

[0030] The present invention provides a method for synthesizing 2-oxo-4-phenyloxazine sulfonyl fluoride compounds from readily available cinnamyl (fluorosulfonyl) carbamate under relatively simple conditions. These fluorinated building block compounds have wide applications in the fields of medicine, pesticides, and click chemistry. Attached Figure Description

[0031] Figure 1 This is a synthesis route diagram for the method of the present invention. Detailed Implementation

[0032] The following are specific embodiments of the present invention.

[0033] The synthesis route diagram of this invention embodiment is as follows: Figure 1 As shown:

[0034] Using cinnamyl (fluorosulfonyl) carbamate as a raw material, iodophenyl diacetic acid as a catalyst, and potassium tert-butoxide as a base, the mixture is added to a reaction flask containing tetrahydrofuran. The reaction flask is then placed in an oil bath at 25°C-80°C and reacted for 6-12 hours. The reaction expression is as follows: Figure 1 .

[0035] The cinnamyl (fluorosulfonyl) carbamate involved in this invention is prepared by the following method:

[0036]

[0037] The standard conditions for the reaction were as follows: At 0°C under a nitrogen atmosphere, the cinnamyl alcohol (1.0 mmol, 1.0 equiv) obtained above was added to DCM (5.0 mL), stirred for 10 min, and cooled. Then, a mixture of FSI (fluorosulfonyl isocyanate) (1.2 mmol, 1.2 equiv) and DCM (5.0 mL) was slowly added dropwise using a syringe. After the addition was complete, stirring was continued at 0°C for 30 min. The reaction progress was monitored using a TCL. Once the cinnamyl alcohol had completely reacted, stirring was immediately stopped, and the solvent was removed by vacuum concentration at room temperature to obtain 233 mg of the corresponding product, with a yield of 86%. 1 H NMR (400MHz, CDCl3) δ4.97–4.86 (m, 2H), 6.26 (dt, J = 15.8, 6.7Hz, 1H), 6.73 (dd,J=15.9,1.5Hz,1H),7.37–7.26(m,3H),7.43–7.37(m,2H),8.28(s,1H).13 C NMR (101MHz, CDCl3) δ69.20 (s), 120.48 (s), 126.87 (s), 128.71 (s), 128.75 (s), 135.51 (s), 136.79 (s), 148.77 (d, J = 1.7Hz). 19 F NMR (376MHz, CDCl3) δ53.85 (s, 1F).

[0038] By replacing cinnamyl alcohol with substrates that have other substitutions on the benzene ring, various cinnamyl (fluorosulfonyl) carbamate compounds with expanded benzene ring substitutions are obtained.

[0039] Example 1: Synthesis of 2-oxo-4-phenyloxazine sulfonyl fluoride

[0040]

[0041] Cinnamyl (fluorosulfonyl) carbamate (260 mg, 1 mmol), iodophenyl diacetic acid (322 mg, 1.0 mmol), and potassium tert-butoxide (112 mg, 1.0 mmol) were added to a 25 ml reaction tube equipped with a rotor. After purging with nitrogen, the mixture was reacted thoroughly in 10 ml of tetrahydrofuran at 30 °C for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water and saturated sodium chloride solution, respectively. The mixture was concentrated under vacuum and dried over anhydrous magnesium sulfate. After further concentration, the target analyte was purified by column chromatography to obtain 141 mg of the target product, with a yield of 55%.

[0042] 1 H NMR (400MHz, CDCl3) δ4.33 (dd, J=9.1, 3.3Hz, 1H), 4.81 (t, J=9.3Hz, 1H), 5.83 (dd, J= 9.4, 3.2Hz, 1H), 7.51 (t, J = 7.7Hz, 2H), 7.66 (t, J = 7.4Hz, 1H), 7.83 (d, J = 7.6Hz, 2H). 19 FNMR (376MHz, CDCl3) δ56.82 (s 1F).

[0043] Example 2 investigates the effect of catalyst on the synthesis of 2-oxo-4-phenyloxazine sulfonyl fluoride.

[0044] Referring to Example 1, the catalyst was replaced by silver nitrate, palladium acetate, copper acetate, and platinum chloride, respectively. Additionally, an experiment was conducted without any catalyst, with other conditions remaining unchanged, to prepare the corresponding 2-oxo-4-phenyloxazine sulfonyl fluoride. Specific yield results are shown in Table 1.

[0045] Table 1 Effect of different catalysts on the synthesis of 2-oxo-4-phenyloxazine sulfonyl fluoride

[0046]

[0047]

[0048] The results showed that the product yield was worse than that of Example 1 when no catalyst was added or when silver nitrate, palladium acetate, copper acetate, or platinum chloride were used instead of iodophenyl diacetic acid as the catalyst, with a yield of no more than 30%.

[0049] Example 3 investigates the effect of solvent selection on the synthesis of 2-oxo-4-phenyloxazine sulfonyl fluoride.

[0050] Referring to Example 1, the solvent was replaced by acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, water, and NMP respectively, while other conditions remained unchanged, to prepare the corresponding 2-oxo-4-phenyloxazine sulfonyl fluoride.

[0051] The specific yield results are shown in Table 2.

[0052] Table 2 Effect of different solvents on the synthesis of 2-oxo-4-phenyloxazine sulfonyl fluoride

[0053] solvent Yield (%) DMSO 12 <![CDATA[CH3CN]]> 24 DMAc 0 DMF 15 NMP 0 <![CDATA[H2O]]> 0

[0054] The results showed that when acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, NMP, and water were used instead of tetrahydrofuran as solvent in Example 1, the yield of the obtained product was worse than that in Example 1, with a yield of no more than 25%.

[0055] Example 4 investigates the effect of reaction temperature on the synthesis of 2-oxo-4-phenyloxazine sulfonyl fluoride.

[0056] Referring to Example 1, the reaction temperature was replaced from 30°C to 55°C, 80°C, and 105°C respectively, while other conditions remained unchanged, to prepare the corresponding 2-oxo-4-phenyloxazine sulfonyl fluoride.

[0057] The specific yield results are shown in Table 3.

[0058] Table 3 Effect of different reaction temperatures on the synthesis of 2-oxo-4-phenyloxazine sulfonyl fluoride

[0059] Temperature (°C) Yield (%) 55 35 85 12 105 0

[0060] The results showed that replacing 30°C in Example 1 with 55°C, 80°C, and 105°C resulted in a lower product yield than in Example 1, with a yield not exceeding 35%.

[0061] Example 5 investigates the effect of different bases on the synthesis of 2-oxo-4-phenyloxazine sulfonyl fluoride.

[0062] Referring to Example 1, sodium bicarbonate, sodium hydride, lithium carbonate, and potassium carbonate were used instead of potassium tert-butoxide as the base in Example 1, while other conditions remained unchanged, to prepare the corresponding 2-oxo-4-phenyloxazine sulfonyl fluoride. Specific yield results are shown in Table 4.

[0063] Table 4. Effects of different bases on the synthesis of 2-oxo-4-phenyloxazine sulfonyl fluoride

[0064] alkali Yield (%) Sodium bicarbonate 22 Sodium hydride 0 lithium carbonate 25 Potassium carbonate 40

[0065] The results showed that replacing potassium tert-butoxide in Example 1 with sodium bicarbonate, sodium hydride, lithium carbonate, or potassium carbonate as the base resulted in a lower product yield than in Example 1, with a yield of no more than 40%.

[0066] Application example:

[0067] Using 2-oxo-4-phenyloxazine sulfonyl fluoride as a sulfonyl fluoride reagent to prepare alkenyl sulfonyl fluoride can be further applied to the later modification of natural products and peptides.

[0068]

[0069] Under a nitrogen atmosphere, tris(2-(4-n-hexylphenyl)quinoline)iridium(III) (0.05 mmol, 0.05 eq) and 2-oxo-4-phenyloxazine sulfonyl fluoride (1 mmol, 1.0 eq) were added to an oven-dried Schlenk tube, followed by anhydrous diethyl ether (5.0 mL), phenylacetylene (1 mmol, 1 eq), and 1,4-CHD (3 mmol, 3.0 eq). The reaction mixture was stirred for 24 hours at room temperature under blue LED (10 W, 400 nm) illumination. The desired pure product was obtained by column chromatography or preparative thin-layer chromatography on silica gel.

[0070] The resulting product is a class of alkenyl sulfonyl compounds used for the late modification of natural products and peptides. See the existing literature Radical Hydro-Fluorosulfonylation of Unactivated Alkenes and Alkynes. Angew. Chem. Int. Ed. 2022, 61, e20220768.

[0071]

[0072] Following the above process, if 2-oxo-4-phenyloxazine sulfonyl fluoride is replaced with an equimolar amount of cinnamyl (fluorosulfonyl) carbamate compound, the product is found to be complex and difficult to purify.

Claims

1. A method for preparing a 2-oxo-4-phenyloxazine sulfonyl fluoride compound, characterized in that, The method involves reacting the cinnamyl (fluorosulfonyl) carbamate compound shown in formula (1) in a solvent with a catalyst and a base. After the reaction is complete, the 2-oxo-4-phenyloxazine sulfonyl fluoride compound shown in formula (2) is obtained. Among them, R is selected from H and C. 1-4 Alkyl, halogen, cyano, nitro, C 1-4 Alkoxy, acyl, amide, aryl; The catalyst is iodophenyl diacetic acid; the base is potassium tert-butoxide; the solvent is tetrahydrofuran; and the reaction temperature is 25℃-40℃.

2. The method according to claim 1, characterized in that, Acyl group is -COR a R a Selected from C 1-6 Alkyl group; amide group is -NR b COR c R b Selected from H, C 1-6 Alkyl, R c Selected from C 1-6 Alkyl groups; aryl groups include benzene rings or naphthalene rings.

3. The method according to claim 1, characterized in that, The reaction takes 6-12 hours.

4. The method according to claim 1, characterized in that, The molar ratio of the cinnamyl (fluorosulfonyl) carbamate compound to the catalyst is 1:(0.5-1.5).

5. The method according to claim 1, characterized in that, The molar ratio of the cinnamyl (fluorosulfonyl) carbamate compound to the base is 1:(1.0 to 2.0).

6. The method according to claim 1, characterized in that, The reaction is carried out under an inert atmosphere, which includes nitrogen and argon.

Images