Preparation method of 2-oxo-4-phenyl oxazine sulfonyl fluoride

Abstract

The invention discloses a preparation method of 2-oxo-4-phenyl oxazine sulfonyl fluoride, and belongs to the field of organic chemical synthesis. According to the method, in a specific tetrahydrofuran solvent, a cinnamyl (fluorosulfonyl) carbamate compound is used as a substrate and reacts under the action of a catalyst and alkali, and the 2-oxo-4-phenyl oxazine sulfonyl fluoride compound is obtained through the reaction. According to the method, iodobenzene diacetic acid and potassium tert-butoxide which are low in price and easy to obtain are adopted as the catalyst and alkali respectively, the substrate applicability is wide, the raw materials are simple and easy to obtain, the economic cost is low, and the target product can be obtained with the good yield.

Description

Technical Field

[0001] The invention specifically relates to a method for preparing 2-oxo-4-phenyloxazinesulfonyl fluoride, and belongs to the field of organic chemical synthesis. Background Art

[0002] Virus outbreaks are a challenge to the global economic, medical, and public health infrastructure. Several well-known drugs have attracted attention as they are speculated to be useful in treating the novel coronavirus. Among the major drugs studied, the vast majority contain heterocyclic structures.

[0003] Heterocyclic chemistry is a core part of organic chemistry and biochemistry. These substances contain at least one carbon atom and one or more non-carbon elements such as nitrogen, oxygen or sulfur in the ring structure. It is the largest and most diverse family of organic compounds with important chemical, biomedical and industrial significance. Heterocyclic compounds include many biochemical substances that are essential to life. For example, many naturally occurring pigments, vitamins and antibiotics are heterocyclic compounds, and most hallucinogens are also heterocyclic compounds. Therefore, developing new methods for synthesizing heterocyclic compounds has always been an important challenge in the field of organic synthesis.

[0004] Sulfonyl fluorides are common building blocks in bioactive molecules and are also widely used synthetic intermediates in modern organic synthesis. Since Sharpless and his collaborators first proposed the concept of sulfur (VI) fluoride exchange (SuFEx) as a new generation of click chemistry in 2014, sulfonyl fluorides have received widespread attention and continued interest in synthetic chemistry and medicinal chemistry. In general, the strategies for constructing these frameworks focus on the fluorination and chlorination of the corresponding sulfonyl chlorides and SO 2 Insertion / fluorination method. Compared with these methods through SF bond formation, the use of FSO 2 It is a simple and effective method to directly carry out fluorination sulfonylation with reagents. It is worth noting that among the existing fluorination sulfonylation reagents, most of them are heterocyclic structures or contain heteroatoms, but their operation and synthesis process are cumbersome and highly toxic. At the same time, it is noted that in the process of reagent development by predecessors, reagents with a five-membered ring structure of succinamide are unstable, and FSI has broad prospects in the development of sulfonyl fluoride reagents. Therefore, based on the reference to the progress of related research, we are committed to exploring a synthetic strategy aimed at constructing compounds with a five-membered heterocyclic or six-membered heterocyclic structure containing a sulfonyl fluoride group. Summary of the invention

[0005] In order to solve the above problems, the present invention provides a new method for synthesizing 2-oxo-4-phenyloxazinesulfonyl fluoride, that is, a method for preparing a 2-oxo-4-phenyloxazinesulfonyl fluoride compound. Using cinnamyl (fluorosulfonyl) carbamate as a substrate, iodophenyl diacetic acid and potassium tert-butoxide as a catalyst and a base, the nucleophilic addition reaction of cinnamyl (fluorosulfonyl) carbamate is explored.

[0006] The invention selects cinnamyl (fluorosulfonyl) carbamate to react under the action of a catalyst and a base to synthesize a 2-oxo-4-phenyloxazinesulfonyl fluoride compound, thereby realizing the nucleophilic addition reaction of cinnamyl (fluorosulfonyl) carbamate.

[0007] The object of the present invention is to provide a method for preparing a 2-oxo-4-phenyloxazinesulfonyl fluoride compound, wherein the method comprises the following steps: in a solvent, a cinnamyl (fluorosulfonyl) carbamate compound represented by formula (1) is used as a substrate, and a reaction is carried out under the action of a catalyst and a base. After the reaction is completed, a 2-oxo-4-phenyloxazinesulfonyl fluoride compound represented by formula (2) is obtained;

[0008]

[0009] Wherein, R is selected from H, 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 iodophenyldiacetic 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, and specifically 8 hours.

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

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

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

[0021] In one embodiment of the present invention, the steps of the preparation method are as follows:

[0022] Cinnamyl (fluorosulfonyl) carbamate is used as a raw material, iodophenyl diacetic acid and potassium tert-butoxide are added, and the mixture is stirred and reacted at 25° C.-40° C. for a period of time to obtain a 2-oxo-4-phenyloxazinesulfonyl fluoride compound.

[0023] In one embodiment of the present invention, after the reaction is completed, pure 2-oxo-4-phenyloxazinesulfonyl fluoride is obtained by filtering, washing, distilling under reduced pressure and separating by 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-phenyloxazinesulfonyl 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 a tetrahydrofuran solvent in a molar ratio of 1:1:1, stirred at 25°C-80°C for 6-12 hours, separated and purified to obtain the target product.

[0026] Beneficial effects:

[0027] The invention provides a method for preparing a 2-oxo-4-phenyloxazinesulfonyl fluoride compound.

[0028] The method of the present invention is carried out in nitrogen (N 2) atmosphere, with cinnamyl (fluorosulfonyl) carbamate as substrate, under the action of catalyst and base, the synthesis of 2-oxo-4-phenyloxazinesulfonyl fluoride can be achieved in one step to obtain the target compound. The reaction mechanism of the present invention is as follows: first, iodophenyl diacetic acid generates iodine cations under the action of base to attack the double bond to generate carbon cations at the α position, and then the lone pair of electrons on the nitrogen atom attacks the carbon cation to complete the cyclization reaction.

[0029] The method of the invention uses cheap and readily available iodobenzenediacetic acid and potassium tert-butoxide as a catalyst and a base respectively, has wide substrate applicability, simple and readily available raw materials, and low economic cost; in addition, the method of the invention realizes the synthesis of the target product by only requiring a reaction of 6 to 12 hours, and can obtain the target product with a good yield, which is faster and more efficient.

[0030] The synthesis method of the invention uses cinnamyl (fluorosulfonyl) carbamate which is easily available to synthesize 2-oxo-4-phenyloxazinesulfonyl fluoride compounds under relatively simple conditions, and the fluorine-containing building block compounds are widely used in the fields of medicine, pesticides and click chemistry. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 The synthetic route diagram of the method of the present invention is shown in FIG. DETAILED DESCRIPTION

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

[0033] The synthetic route diagram of the embodiment of the present invention is as follows: Figure 1 As shown:

[0034] Cinnamyl (fluorosulfonyl) carbamate is used as raw material, iodophenyl diacetic acid is used as catalyst, and potassium tert-butoxide is used as base to add into a reaction bottle containing tetrahydrofuran, and then the reaction bottle is placed in an oil bath at 25°C-80°C for full reaction for 6-12 hours. The reaction expression is: Figure 1 .

[0035] The cinnamyl (fluorosulfonyl) carbamate of the present invention is prepared by the following method:

[0036]

[0037] The standard conditions of the reaction are: at 0°C, under nitrogen atmosphere, add the above-obtained cinnamyl alcohol (1.0 mmol, 1.0 equiv) to DCM (5.0 mL), stir for 10 min to cool, then slowly drop a mixture of FSI (fluorosulfonyl isocyanate) (1.2 mmol, 1.2 equiv) and (DCM, 5.0 mL) into the mixture using a syringe. After the addition is complete, continue to stir at 0°C for 30 min, monitor the reaction progress by TCL, and stop stirring immediately after the cinnamyl alcohol reacts completely, and concentrate in vacuo at room temperature to remove the solvent to obtain 233 mg of the corresponding product with a yield of 86%. 1 H NMR (400 MHz, CDCl 3 )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 (101 MHz, CDCl 3 )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 (376 MHz, CDCl 3 )δ53.85(s,1F).

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

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

[0040]

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

[0042] 1 H NMR (400 MHz, 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, CDCl 3 )δ56.82(s 1F).

[0043] Example 2 Investigating the effect of catalyst on the synthesis of 2-oxo-4-phenyloxazinesulfonyl fluoride

[0044] Referring to Example 1, the catalyst was replaced by silver nitrate, palladium acetate, copper acetate, and platinum chloride respectively from iodophenyl diacetic acid, and a group of experiments without any catalyst was added, and other conditions remained unchanged to obtain the corresponding 2-oxo-4-phenyloxazinesulfonyl fluoride. The specific yield results are shown in Table 1.

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

[0046]

[0047]

[0048] The results showed that: without adding a catalyst and using silver nitrate, palladium acetate, copper acetate, platinum chloride to replace the iodophenyldiacetic acid in Example 1 as the catalyst, the yield of the obtained product was worse than that in Example 1, and the yield did not exceed 30%.

[0049] Example 3 Investigating the Effect of Solvent Selection on the Synthesis of 2-Oxo-4-phenyloxazinesulfonyl Fluoride

[0050] Referring to Example 1, the solvent was replaced from tetrahydrofuran with acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, water, and NMP, respectively, while other conditions remained unchanged, to obtain the corresponding 2-oxo-4-phenyloxazinesulfonyl 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-phenyloxazinesulfonyl fluoride

[0053] Solvents Yield (%) DMSO 12 <![CDATA[CH 3 CN]]> 24 DMAc 0 DMF 15 NMP 0 <![CDATA[H 2 The]]> 0

[0054] The results showed that when acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, NMP, and water were used as solvent instead of tetrahydrofuran in Example 1, the yield of the obtained product was worse than that in Example 1, and the yield did not exceed 25%.

[0055] Example 4 Investigating the effect of reaction temperature on the synthesis of 2-oxo-4-phenyloxazinesulfonyl fluoride

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

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

[0060] The results showed that when 55°C, 80°C, and 105°C were used instead of 30°C in Example 1, the yield of the product obtained was worse than that in Example 1, and the yield did not exceed 35%.

[0061] Example 5 Investigating the Effect of Different Bases on the Synthesis of 2-Oxo-4-phenyloxazinesulfonyl fluoride

[0062] Referring to Example 1, sodium bicarbonate, sodium hydride, lithium carbonate, and potassium carbonate were used to replace the potassium tert-butoxide in Example 1 as the base, and other conditions remained unchanged to obtain the corresponding 2-oxo-4-phenyloxazinesulfonyl fluoride. The specific yield results are shown in Table 4.

[0063] Table 4 Effect of different bases on the synthesis of 2-oxo-4-phenyloxazinesulfonyl fluoride

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

[0065] The results showed that when sodium bicarbonate, sodium hydride, lithium carbonate or potassium carbonate was used to replace potassium tert-butoxide in Example 1 as the base, the yield of the obtained product was lower than that in Example 1, and the yield did not exceed 40%.

[0066] Application examples:

[0067] 2-Oxo-4-phenyloxazinesulfonyl fluoride is used as a sulfonyl fluoride reagent to prepare alkenylsulfonyl fluoride, which can be further applied to the later modification of natural products and peptides.

[0068]

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

[0070] The obtained product is a class of olefin sulfonyl compounds used for the post-modification of natural products and peptides, which can be found in the existing literature Radical Hydro-Fluorosulfonylation of Unactivated Alkenes and Alkynes. Angew. Chem. Int. Ed. 2022, 61, e20220768.

[0071]

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

Claims

1. A method for preparing a 2-oxo-4-phenyloxazinesulfonyl fluoride compound, characterized in that: The method comprises the following steps: in a solvent, a cinnamyl (fluorosulfonyl) carbamate compound represented by formula (1) is used as a substrate, and reacts under the action of a catalyst and a base. After the reaction is completed, a 2-oxo-4-phenyloxazinesulfonyl fluoride compound represented by formula (2) is obtained; Wherein, R is selected from H, C 1-4 Alkyl, halogen, cyano, nitro, C 1-4 Alkoxy, acyl, amide, aryl.

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

3. The method according to claim 1, characterized in that The catalyst is iodophenyldiacetic acid.

4. The method according to claim 1, characterized in that: The base is potassium tert-butoxide.

5. The method according to claim 1, characterized in that The solvent is tetrahydrofuran.

6. The method according to claim 1, characterized in that The reaction temperature is 25°C-40°C and the reaction time is 6-12 hours.

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

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

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

10. The method according to any one of claims 1 to 9, characterized in that: The steps of the preparation method are as follows: Cinnamyl (fluorosulfonyl) carbamate is used as a raw material, iodobenzenediacetic acid and potassium tert-butoxide are added, and the mixture is stirred and reacted at 25° C.-40° C. for a period of time to obtain a 2-oxo-4-phenyloxazinesulfonyl fluoride compound.

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