A method for synthesizing arylsulfonyl derivatives

Abstract

The present invention relates to a method for synthesizing arylsulfonyl derivatives. The method uses aryldiphenylthiophene salt as an aryl source, bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct as a sulfonyl source, 10-phenyl-phenothiazine as a photocatalyst, an N-containing nucleophile as an amine source, and a fluorine-containing anion nucleophile as a F source, and prepares arylsulfonamide and arylsulfonyl fluoride under blue light catalysis. The synthetic method has wide adaptability and can be widely used to synthesize arylsulfonyl fluoride, primary arylsulfonamide, secondary arylsulfonamide and tertiary arylsulfonamide, which is of great significance.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis and relates to a method for synthesizing arylsulfonyl derivatives, and more specifically to a method for synthesizing arylsulfonyl fluoride and arylsulfonamide. Background Art

[0002] Sulfonamide and sulfonyl fluoride structures are among the most important structures in natural products, medicinal chemistry, and materials science, and have always been an important research direction in the field of organic synthesis. Since the introduction of prontosil as an antibacterial agent in 1932 (M. Wainwright, JE Kristiansen, On the 75th anniversary of prontosil. Dyes Pigm. 2011, 88, 231), cyclic amide structures have made up the largest proportion of sulfur-containing drugs. Among them, aryl sulfonamides are more valuable due to their unique physicochemical properties, such as chemical and metabolic stability, bioavailability, and high efficacy. The most notable molecular structures include Dabrafenib (TR Rheault..., ACS Med.Chem.Lett.2013,4,358-362.), Sulpiride(II)(SKVerma,R.Verma,F.Xue,PKThakur,YRGirish,KPRakesh,Bioorg.Chem.2 020,105,104400), belinosstat (III) (JAPlumb,PWFinn,RJWilliams,MJBandara,MRRomero,CJWatkins,NBLThangue,R.Brown,M ol. Cancer Ther. 2003, 2, 721-728), Fosamprenavir (IV) (I. Goldstein, T.F. Lue, H. Padma-Nathan, R.C. Rosen, W. D. Steers, P.A. Wicker, N. Engl. J. Med. 1998, 338, 1397-1404) and Sildenafil (V) (A. Kolaczek, I. Fusiarz, J. Lawecka, D. Branowska, CHEMIK 2014). The sulfonyl chloride structure has the effect of enhancing drug efficacy and good biological activity, and has always been one of the focuses in the field of drug synthesis.

[0003] In view of the important role of aryl sulfonamides, people have invested a lot of energy to develop an effective method for obtaining these frameworks. Common methods include the condensation of amines with aryl sulfonyl chlorides, however, this method is limited by the protection of sulfonyl chloride groups and the limited compatibility of functional groups. Obtained by the CN cross-coupling reaction of metal-catalyzed primary sulfonamides with aryl halides or boronic acids, primary sulfonamides are still mainly derived from sulfonyl chlorides (RTMcGuire, CMSimon, AA Yadav, MJFerguson, M.Stradiotto, Angew.Chem.Int.Ed.2020,59,8952-8956). Other substrates such as thiols, N-sulfonylbenzotriazoles, and sodium arylsulfinates have also been reported for the synthesis of sulfonamides (a) Z. Bao, J. Zou, C. Mou, Z. Jin, S.-C. Ren, Y. R. Chi, Org. Lett. 2022, 24, 8907; b) E. Qu, S. Li, J. Bai, Y. Zheng, W. Li, Org. Lett. 2022, 24, 58; c) X. Tang, L. Huang, C. Qi, X. Wu, W. Wu, H. Jiang, Chem. Commun. 2013, 49, 6102.). However, these methods also require the presynthesis of sulfonyl-containing substrates. Since then, a series of copper-catalyzed metal-catalyzed routes for the synthesis of aromatic cyclic amides have been established (a) Y. Chen, PRD Murray, A.T. Davies, M.C. Willis, J. Am. Chem. Soc. 2018, 140, 8781-8787; b) F. Zhang, D. Zheng, L. Lai, J. Cheng, J. Sun, J. Wu, Org. Lett. 2018, 20, 1167-1170; c) T.G. Luu, H. Kim, Adv. Synth. Catal. 2023, 365, 1671-1677). However, the use of primary aliphatic amines in these copper-catalyzed synthetic routes remains a challenge. This is because primary aliphatic amines have strong nucleophilicity. When they form intermediates with copper catalysts, they easily poison the copper catalyst and thus destroy the entire catalytic system, making the reaction difficult to occur. Fluorine-chlorine exchange reaction, fluorosulfonylation reaction of free radical substances, and oxidative fluorination of sulfur-containing substances are the main reactions for synthesizing sulfonyl fluorides. These reactions also have the problem of synthetic uneconomical due to the need to provide additional protection for the reaction reagent groups.

[0004] In view of this, it is of great significance to provide an efficient synthesis method of aryl cyclic acyl derivatives. Summary of the Invention

[0005] One aspect of the present invention is to provide a method for synthesizing arylsulfonyl derivatives, specifically a method for synthesizing arylsulfonyl fluoride and arylsulfonamide, comprising the following steps:

[0006] S1: placing the compound of formula (I), nucleophile TR, bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct (CAS No. 119752-83-9), and photocatalyst in a solvent;

[0007] S2: exposing the mixture formed in step S1 to blue light for a certain period of time to generate an arylsulfonyl fluoride compound or an arylsulfonamide compound as shown in formula (II), wherein Nu represents F or an amine substituent;

[0008] The specific method is as follows:

[0009]

[0010] The nucleophile TR is a fluorine-containing anion nucleophile or a nitrogen-containing nucleophile. When TR is a fluorine-containing anion nucleophile, the compound of formula (II) represents an arylsulfonyl fluoride compound in which Nu is F; when TR is a nitrogen-containing nucleophile, the compound of formula (II) represents an arylsulfonamide compound in which Nu is an amine substituent.

[0011] Wherein, in the compounds of formula (I) and formula (II), a is 0, 1, 2 or 3, and when a is 2 or 3, R1 is the same or different substituents; when a is 0, it indicates no substituents, and when a is 1, 2 or 3, it indicates that there are corresponding numbers of substituents distributed on the aromatic group;

[0012] T1 and T2 are the same or different substituents.

[0013] In certain embodiments, when TR is an ammonium salt, a metal azide salt or an organic azide reagent, the arylsulfonamide compound represented by formula (II) can be represented by the structure represented by the compound represented by formula (III); the structure of the compound represented by formula (III) is as follows: Wherein, R2 and R3 are H; the ammonium salt is selected from one or more of ammonium carbonate, ammonium chloride and ammonium nitrate. It should be understood that the ammonium salt contains NH4 + The salts of can be used in this reaction; the metal azide salt is selected from one or more of sodium azide, potassium azide and lithium azide. It should be understood that metal salts containing azide anions can be used in this reaction; the organic azide reagent is TMSN3.

[0014] In certain embodiments, when TR is a primary aromatic amine, the arylsulfonamide compound represented by formula (II) can be represented by the structure represented by the compound represented by formula (III); the structure of the compound represented by formula (III) is Wherein, R2 is H, R3 is -Ph-X, X is selected from one of alkyl, halogen, aryl, ester, nitrile and amine groups; the structural formula of the primary aromatic amine is X-PhNH2.

[0015] In certain embodiments, when TR is a primary fatty amine, the arylsulfonamide compound represented by formula (II) can be represented by the structure represented by the compound represented by formula (III); the structure of the compound represented by formula (III) is Wherein, R2 is H, R3 is selected from C 1-11 Alkyl, -C 1-4 One of alkylene-Y, benzyl, and phenethyl, wherein Y is selected from an alkoxy group or an ester group; preferably, the benzyl and phenethyl groups contain one or more of a halogen and an alkoxy group on the phenyl ring. As can be seen from the above technical content, the primary aliphatic amine refers to an amino group NH2 connected to an aliphatic carbon chain, which can be considered a primary aliphatic amine. The aliphatic carbon chain can contain non-carbon substituents, such as alkoxy groups and ester groups, or can be a pure carbon chain.

[0016] In certain embodiments, when TR is a secondary fatty amine, the arylsulfonamide compound represented by formula (II) can be represented by the structure represented by the compound of formula (III) or the compound of formula (IV); the compound of formula (III) is wherein R2 and R3 are the same or different and are independently selected from C 1-6 One of alkyl and benzyl. The compound of formula (IV) is Wherein, the B ring represents a four- to six-membered heterocyclic ring containing a N atom, and R4 is selected from one of H, an ester group and an aldehyde group; when the B ring is a six-membered heterocyclic ring, the heterocyclic ring also includes a N or O atom.

[0017] In certain embodiments, the R1 are the same or different and are independently selected from methyl, phenyl, biphenyl, methoxy, -C(O)OCH3, isopropyl, tert-butyl, phenoxy, -OTf, -F, -Cl, -Br, -CN, -C(O)Ph, p-chlorophenyl, T1 and T2 are the same or different and are independently selected from H, nitro, alkyl, alkoxy, and halogen.

[0018] In some embodiments, step S3 is further included: heating the reactant formed in step S2 for a certain time, with the temperature ranging from 30-80°C, preferably from 40-70°C, preferably at 60°C.

[0019] In certain embodiments, Q is selected from one of BF4, OTf, halogen and PF6, specifically, halogen includes F, Cl, Br and I.

[0020] In certain embodiments, the fluorine-containing anion nucleophile is NaF, LiF, KF, or KHF2. It is understood that any metal salt containing a fluorine anion can participate in the reaction to generate the corresponding sulfonyl fluoride.

[0021] In certain embodiments, the photocatalyst is Wherein, the substituents P1, P2 and P3 are the same or different and are independently selected from H, nitro, alkoxy and alkyl.

[0022] In certain embodiments, the synthesis method is performed in an air environment or an inert environment, wherein the inert gas is selected from one or more of nitrogen, argon and helium.

[0023] In certain embodiments, the solvent is selected from one or more of acetonitrile, DMSO, DMA, dichloromethane, and 1,2-dichloroethane.

[0024] In certain embodiments, step S2 is performed at 20-60°C, preferably 25°C.

[0025] The technical effects of the present invention are:

[0026] A brand-new synthetic route of aryl sulfonamide and aryl sulfonyl fluoride has been developed.This synthetic route is simple and easy, avoids using the acyl chloride (needing to implement group protection) that traditional amides synthetic route needs to use to reaction environment is extremely harsh.Secondly, the aryl sulfonamide synthetic route disclosed by the present invention does not contain metal catalyst, reduces cost on the one hand, eliminates the possibility of metal contamination of product on the other hand, improves the potentiality of this synthetic route in pharmaceutical synthesis application.In addition, the applicability of this synthetic route is very extensive, can be widely used in synthesizing sulfonyl fluoride, primary aryl sulfonamide, secondary aryl sulfonamide and tertiary aryl sulfonamide on the one hand, are extremely rare in sulfonamide synthetic route.On the other hand, overcome the technical challenge that primary aliphatic amine is difficult to use in the synthetic route of copper catalysis, can easily prepare the secondary sulfonamide comprising aliphatic amine group. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The synthetic route of the present invention is shown in FIG.

[0028] Figure 2 The yields of primary arylamines with different substituents in the synthesis route of arylsulfonamides are shown.

[0029] Figure 3 The yield of primary fatty amines with different substituents in the synthesis route of arylsulfonamides is shown.

[0030] Figure 4 The yield of secondary fatty amines with different substituents in the synthesis route of arylsulfonamides is shown.

[0031] Figure 5 The yield of aryldiphenylthiophene salts with different substituents in the synthesis route of arylsulfonyl fluoride is shown. DETAILED DESCRIPTION

[0032] The present invention will be described in detail with reference to the following examples.

[0033] like Figure 1 As shown, the synthesis route of the present invention is to use aryl diphenylthiophene salt as the aryl source, bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct as the sulfur source, and nucleophilic reagent TR as the amino source or fluorine source to synthesize aryl sulfonamide or aryl sulfonyl fluoride. Figure 1 wherein Nu represents F or an amine substituent, and the nucleophile TR is a fluorine-containing anion nucleophile or a nitrogen-containing nucleophile.

[0034] The standard preparation procedure for aryl dibenzothiophene salts is as follows: To a solution of dibenzothiophene 5-oxide (DBTO, 0.150 g, 0.75 mmol, 1.5 equiv) and an aromatic hydrocarbon (0.50 mmol, 1.0 equiv) in dry MeCN (3 mL) was added dropwise trifluoroacetic anhydride (TFAA, 0.210 g, 1.0 mmol, 2.0 equiv) at -45°C, and the mixture was stirred at this temperature for 30 minutes. BF3.OEt2 (0.300 mL, 1.0 mmol, 2.0 equiv) was added at -45°C, and the reaction was stirred at -45°C for an additional 2 hours before being allowed to warm to room temperature and then stirred at room temperature for 4 hours. The mixture was concentrated, diluted with 15 mL of dichloromethane, and poured into water (30 mL). The organic layer was separated, and the aqueous solution was extracted twice with dichloromethane (15 mL x 2). The combined organic layers were washed with saturated aqueous NaHCO₃ (15 mL), then washed twice with saturated NaBF₄ solution (13 mL x 2), then dried over Na₂SO₄, filtered, and concentrated. The crude product was dissolved in 2 mL of dichloromethane and precipitated with ether. The suspension was decanted and the solid was dried to obtain the aryl dibenzothiophene salt. The yield was calculated.

[0035] Example 1

[0036] The preparation method of 4-isopropylbenzene-dibenzothiophene salt refers to the standard preparation process of aryl dibenzothiophene salts. The yield of the prepared product is 55%. The nuclear magnetic resonance detection data are: 1H NMR (600 MHz, CDCl3) δ8.19 (d, J=7.8 Hz, 2H), 8.07 (d, J=8.4 Hz, 2H), 7.84 (t, J=7.2 Hz, 2H), 7.61 (t, J=7.8 Hz, 2H), 7.54 (d, J=9.0 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 2.96-2.87 (m, 1H), 1.20 (d, J=6.6 Hz, 6H).

[0037] Example 2

[0038] The preparation method of 4-methoxybenzene-dibenzothiophene salt refers to the standard preparation process of aryl dibenzothiophene salts. The nuclear magnetic resonance detection data of the prepared product are: 1H NMR (600 MHz, CDCl3) δ8.16 (d, J=7.8 Hz, 2H), 8.07 (d, J=8.4 Hz, 2H), 7.84 (td, J=1.2, 7.8 Hz, 2H), 7.62 (t, J=7.8 Hz, 2H), 7.58 (d, J=9.0 Hz, 2H), 6.99 (d, J=9.6 Hz, 2H), 3.84 (s, 3H).

[0039] Example 3

[0040] The preparation method of 3-fluoro-4-methoxybenzene-dibenzothiophene salt refers to the standard preparation process of aryl dibenzothiophene salts. The nuclear magnetic resonance detection data of the prepared product are: 1H NMR (600 MHz, CDCl3) δ8.22-8.11 (m, 5H), 7.86 (t, J = 7.8 Hz, 2H), 7.66 (t, J = 7.8 Hz, 2H), 7.22 (t, J = 8.4 Hz, 1H), 6.67 (dd, J = 1.8, 9.6 Hz, 1H), 3.94 (s, 3H).

[0041] Example 4

[0042] The preparation method of 3-trifluoromethanesulfonic acid-4-methoxybenzene-dibenzothiophene salt refers to the standard preparation process of aryl dibenzothiophene salts. The nuclear magnetic resonance detection data of the prepared product are: 1H NMR (600 MHz, DMSO-d6) δ8.52 (d, J=7.2 Hz, 2H), 8.36 (d, J=7.2 Hz, 2H), 8.02 (s, 1H), 7.96 (td, J=1.2, 7.2 Hz, 2H), 7.80-7.73 (m, 2H), 7.46 (d, J=7.2 Hz, 2H), 3.93 (s, 3H).

[0043] Example 5

[0044] The preparation method of 3,4-dimethoxybenzene-dibenzothiophene salt refers to the standard preparation process of aryl dibenzothiophene salts. The nuclear magnetic resonance detection data of the prepared product are: 1H NMR (600 MHz, DMSO-d6) δ8.51 (d, J=7.2 Hz, 2H), 8.34 (d, J=7.8 Hz, 2H), 7.95 (t, J=7.8 Hz, 2H), 7.76 (t, J=7.8 Hz, 2H), 7.47 (d, J=2.4 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 6.86 (dd, J=2.4, 8.4 Hz, 1H), 3.77 (s, 3H), 3.76 (s, 3H).

[0045] Example 6

[0046] The preparation method of 2-methoxy-5-benzoylbenzene-dibenzothiophene salt refers to the standard preparation process of aryl dibenzothiophene salts. The nuclear magnetic resonance detection data of the prepared product are: 1H NMR (600 MHz, DMSO-d6) δ8.48 (d, J=7.8 Hz, 2H), 8.36 (d, J=7.8 Hz, 2H), 8.09 (dd, J=1.8, 8.4 Hz, 1H), 7.94 (td, J=1.2, 7.2 Hz, 2H), 7.77 (td, J=1.8, 7.8 Hz, 2H), 7.70-7.63 (m, 1H), 7.56 (t, J=7.8 Hz, 2H), 7.52 (t, J=7.8 Hz, 2H), 3.36 (s, 1H), 4.08 (s, 3H).

[0047] The structures generated in Examples 1-6 are:

[0048]

[0049] The structures above demonstrate the reaction of various aromatic hydrocarbon substituents to form the corresponding aryl dibenzothiophene salts, demonstrating the robust synthesis of these salts. The processes for generating the corresponding dibenzothiophene salts from aromatic hydrocarbons with other aryl substituents are not detailed here.

[0050] In this invention, the standard synthesis route for arylsulfonamides is as follows: an aryl dibenzothiophene salt 1 (0.36 mmol, 1.2 equiv), a fluorine-containing nucleophile or a nitrogen-containing nucleophile (0.30 mmol, 1.0 equiv), and a photocatalyst 10-phenyl-phenothiazine (PTH) (4.1 mg, 0.0150 mmol, 5%) are added to a reaction vessel and purged with argon three times at room temperature (25°C). Acetonitrile (3.0 ml) and bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct (DABSO) (86.4 mg, 0.36 mmol, 1.2 equiv) are added to the mixture. The reaction is stirred at room temperature and irradiated with a blue LED (427 nm) for 21 h. The resulting mixture is poured into water (20 ml) and extracted with ethyl acetate (3 x 15 ml). The organic layer is washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated. The residue is then purified by column chromatography on silica gel to obtain an arylsulfonamide compound.

[0051] Through mechanism research, it was found that the principle of the synthesis route involved in the present invention is that when irradiated with blue light, the aryl dibenzothiophene salt undergoes a single electron transfer reaction under the action of a photocatalyst to generate a corresponding aryl radical, which then reacts with DABSO to generate an arylsulfonyl radical, which further reacts with 1,4-diazabicyclo[2.2.2]octane (the product of DABSO removing SO2) to generate an arylsulfonyl ammonium salt radical, which further reacts with the photocatalyst to generate an arylsulfonyl ammonium salt, which then generates a corresponding arylsulfonamide or arylsulfonyl fluoride product under the attack of a nucleophile.

[0052] Example 7

[0053] The corresponding arylsulfonamide was synthesized by reacting 2-methoxy-5-methylformate benzene-dibenzothiophene salt with p-acetylaniline. The specific synthesis route refers to the standard synthesis route of arylsulfonamides mentioned above. The yield of the product was 40%. The nuclear magnetic resonance data of the product were 1H NMR (600 MHz, CDCl3) δ8.59 (d, J=2.4 Hz, 1H), 8.19 (dd, J=2.4, 8.4 Hz, 1H), 7.81 (d, J=9.0 Hz, 2H), 7.41 (s, 1H), 7.15 (d, J=8.4 Hz, 2H), 7.03 (d, J=8.4 Hz, 1H), 4.07 (s, 3H), 3.91 (s, 3H), 2.50 (s, 3H).

[0054]

[0055] Examples 8-11

[0056] See Example 7, except that the temperature was set to 20°C (Example 8), 35°C (Example 9), 45°C (Example 10), and 60°C (Example 11), respectively. The product yields were 33% (Example 8), 38% (Example 9), 33% (Example 10), and 28% (Example 11), respectively.

[0057] Examples 12-15

[0058] See Example 7, except that, when the blue light irradiation time is 2 (Example 12), 5 (Example 13), 15 (Example 14) and 24 hours (Example 15), the yields of the products are 10% (Example 12), 18% (Example 13), 36% (Example 14) and 42% (Example 15), respectively.

[0059] Examples 16-24

[0060] See Example 7, except that the photocatalysts are replaced by

[0061] When the reaction mixture was stirred for 1 h, the yields of the products were 0 (Example 16), 0.3% (Example 17), 0.4% (Example 18), 0 (Example 19), 35% (Example 20), 31% (Example 21), 32% (Example 22), 35% (Example 23) and 28% (Example 24).

[0062] The data from Examples 16-24 indicate that the 10-phenyl-phenothiazine photocatalyst skeleton exhibits significant technical effectiveness in catalyzing this reaction. On the other hand, the presence of either pseudo-electron-donating or electron-withdrawing groups on the PTH photocatalyst skeleton can lead to a decrease in catalytic performance. Therefore, the increased steric hindrance caused by the presence of these substituents may be the cause of this decreased catalytic performance.

[0063] Examples 25-29

[0064] See Example 7, except that after the photocatalytic reaction, the blue light irradiation was stopped, and the reaction vessel was heated to 30° C. (Example 25), 40° C. (Example 26), 60° C. (Example 27), 70° C. (Example 28), and 80° C. (Example 29), respectively. The reaction time was 8 hours. The product yields were 45% (Example 25), 52% (Example 26), 72% (Example 27), 70% (Example 28), and 68% (Example 29). Examples 25-29 show that the yield is best when heated to 60° C.

[0065] Example 30

[0066] See Example 27, except that the reaction was conducted without blue light irradiation and the yield of the product was 0.

[0067] Example 31

[0068] See Example 27, the difference is that no photocatalyst PTH is added to the reaction and the yield of the product is 0.

[0069] Example 32

[0070] See Example 27, except that the reaction is carried out in an air environment and the yield of the product is 12%.

[0071] Examples 33-39

[0072] See Example 27, except that the reaction solvents were replaced with DMSO (Example 33), dichloromethane (Example 34), DMF (Example 35), DMA (Example 36), THF (Example 37), 1,2-dichloroethane (Example 38) and ethyl acetate (Example 39), and the yields of the products were 21% (Example 33), 23% (Example 34), 0 (Example 35), 12% (Example 36), 0 (Example 37), 20% (Example 38) and 0.5% (Example 39), respectively.

[0073] Examples 40-43

[0074] See Example 27, except that the heating time is controlled at 2 (Example 40), 4 (Example 41), 6 (Example 42) and 10 hours (Example 43), respectively, and the yields of the products are 45% (Example 40), 57% (Example 41), 64% (Example 42) and 73% (Example 43), respectively.

[0075] Examples 44-48

[0076] See Example 27, except that the structures of the aryl dibenzothiophene salts are replaced by

[0077]

[0078] The product yields were 64% (Example 44), 58% (Example 45), 55% (Example 46), 61% (Example 47), and 59% (Example 48). Examples 44-48 show that the presence of either electron-withdrawing or electron-donating substituents on the benzene ring of the dibenzothiophene structure is detrimental to the reaction, indicating that these substituents create steric hindrance that is detrimental to the reaction.

[0079] Example 49

[0080] See Example 27, the difference is that the aryl diphenylthiophene salt is replaced by a thiophene salt without a substituent on the aryl group, and the product is The yield is 61%. The nuclear magnetic resonance data are 1HNMR (600 MHz, CDCl3) δ7.91-7.86 (c, 3H), 7.84 (d, J = 8.4 Hz, 2H), 7.58-7.53 (m, 1H), 7.46 (t, J = 7.8 Hz, 2H), 7.19 (d, J = 9.0 Hz, 2H), 2.53 (s, 3H).

[0081] Example 50

[0082] See Example 27, the difference is that the aryl diphenylthiophene salt is replaced by a thiophene salt in which the para position of the aryl group is isopropyl, and the product is The yield was 53%. The nuclear magnetic resonance data were 1H NMR (600 MHz, CDCl3) δ7.84 (d, J = 9.0 Hz, 2H), 7.79 (d, J = 9.0 Hz, 2H), 7.69 (s, 1H), 7.30 (d, J = 7.8 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 2.99-2.87 (m, 1H), 2.53 (s, 3H), 1.22 (d, J = 7.2 Hz, 6H).

[0083] Example 51

[0084] See Example 27, the difference is that the aryl diphenylthiophene salt is replaced by a thiophene salt in which the para position of the aryl group is tert-butyl, and the product is The yield was 66%. The nuclear magnetic resonance data were 1H NMR (600 MHz, CDCl3) δ7.85 (d, J = 9.0 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.70 (s, 1H), 7.47 (d, J = 9.0 Hz, 2H), 7.19 (d, J = 9.0 Hz, 2H), 2.53 (s, 3H), 1.29 (s, 9H).

[0085] Example 52

[0086] See Example 27, except that the aryl diphenylthiophene salt is replaced with a thiophene salt having methyl groups at positions 2 and 4 of the aryl group, to obtain the product The yield was 52%. The nuclear magnetic resonance data were 1H NMR (600 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 9.0 Hz, 2H), 7.20-7.12 (c, 4H), 2.54 (s, 3H), 2.44 (s, 3H), 2.27 (s, 3H).

[0087] Example 53

[0088] See Example 27, the difference is that the aryl diphenylthiophene salt is replaced by a thiophene salt in which the aryl group is para-methoxy, and the product is The yield was 60%. The nuclear magnetic resonance data were 1H NMR (600 MHz, CDCl3) δ7.85 (d, J = 9.0 Hz, 2H), 7.78 (d, J = 9.0 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 6.97 (s, 1H), 6.92 (d, J = 9.0 Hz, 2H), 3.83 (s, 3H), 2.53 (s, 3H).

[0089] Example 54

[0090] See Example 27, the difference is that the aryl diphenylthiophene salt is replaced by a thiophene salt in which the para position of the aryl group is a phenyl group, and the product is The yield was 55%. The nuclear magnetic resonance data were 1H NMR (600 MHz, CDCl3) δ7.92 (d, J = 9.0 Hz, 2H), 7.86 (d, J = 9.0 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.60 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.45 (c, 2H), 7.40 (t, J = 7.2 Hz, 1H), 7.22 (d, J = 9.0 Hz, 2H), 2.53 (s, 3H).

[0091] Example 55

[0092] See Example 27, except that the aryl diphenylthiophene salt is replaced with a thiophene salt in which the 3-position of the aryl group is chlorine and the para-position is methoxy, and the product is The yield was 64%. The nuclear magnetic resonance data were 1H NMR (600 MHz, CDCl3) δ7.94-7.83 (c, 3H), 7.72 (dd, J = 2.4, 9.0 Hz, 1H), 7.39 (s, 1H), 7.17 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 1H), 3.92 (s, 3H), 2.54 (s, 3H).

[0093] Example 56

[0094] See Example 27, except that the aryl diphenylthiophene salt is replaced by a thiophene salt in which the 3-position of the aryl group is fluorine and the para-position is methoxy, and the product is The yield was 63%. The nuclear magnetic resonance data were 1H NMR (600 MHz, CDCl3) δ7.86 (d, J = 9.0 Hz, 2H), 7.64-7.60 (m, 1H), 7.56 (dd, J = 2.4, 10.2 Hz, 1H), 7.33 (s, 1H), 7.17 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 7.8 Hz, 1H), 3.91 (s, 3H), 2.54 (s, 3H).

[0095] Example 57

[0096] See Example 27, the difference is that the aryl diphenylthiophene salt is replaced by a thiophene salt with OTf at the 3-position of the aryl group and a methoxy group at the para position, and the product is The yield was 73%. The nuclear magnetic resonance data were 1HNMR (600 MHz, CDCl3) δ7.86 (d, J = 9.0 Hz, 2H), 7.82 (dd, J = 1.8, 8.4 Hz, 1H), 7.79 (s, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.18 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 9.0 Hz, 1H), 3.94 (s, 3H), 2.54 (s, 3H).

[0097] Example 58

[0098] See Example 27, the difference is that the aryl diphenylthiophene salt is replaced by a thiophene salt in which the para position of the aryl group is a phenoxy group, and the product is The yield was 70%. The nuclear magnetic resonance data were 1H NMR (600 MHz, CDCl3) δ7.86 (d, J = 9.0 Hz, 2H), 7.79 (d, J = 9.0 Hz, 2H), 7.39 (t, J = 1.8 Hz, 2H), 7.28 (s, 1H), 7.22 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 9.0 Hz, 2H), 7.03 (d, J = 7.8 Hz, 2H), 6.97 (d, J = 9.0 Hz, 2H), 2.54 (s, 3H).

[0099] Example 59

[0100] See Example 27, except that the aryl diphenylthiophene salt is replaced with a thiophene salt having methoxy groups at both the 3-position and the para-position of the aryl group, to obtain the product The yield was 64%. The nuclear magnetic resonance data were 1HNMR (600 MHz, CDCl3) δ7.85 (d, J=8.4 Hz, 2H), 7.48 (dd, J=2.4, 8.4 Hz, 1H), 7.41 (s, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.17 (d, J=9.0 Hz, 2H), 6.86 (d, J=9.0 Hz, 1H), 3.89 (s, 3H), 3.83 (s, 3H), 2.53 (s, 3H).

[0101] Example 60

[0102] See Example 27, except that the aryldiphenylthiophene salt is replaced by The product obtained is The yield was 54%. Nuclear magnetic resonance data were 1H NMR (600 MHz, CDCl3) δ7.86 (d, J = 9.0 Hz, 2H), 7.38 (d, J = 2.4 Hz, 1H), 7.33 (dd, J = 2.4, 9.0 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 6.98 (s, 1H), 6.89 (d, J = 8.4 Hz, 1H), 4.31-4.27 (m, 2H), 4.27-4.23 (m, 2H), 2.54 (s, 3H).

[0103] Example 61

[0104] See Example 27, except that the aryldiphenylthiophene salt is replaced by The product obtained is The yield was 61%. The nuclear magnetic resonance data were 1H NMR (600 MHz, CDCl3) δ8.31 (d, J = 2.4 Hz, 1H), 8.04 (dt, J = 2.4, 9.0 Hz, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.25 (s, 1H), 7.16 (d, J = 9.0 Hz, 2H), 7.00 (d, J = 8.4 Hz, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 2.53 (s, 3H).

[0105] Example 62

[0106] See Example 27, except that the aryldiphenylthiophene salt is replaced by The product obtained is The yield was 65%. The nuclear magnetic resonance data were 1H NMR (600 MHz, CDCl3) δ8.19 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 9.0 Hz, 2H), 8.04 (dd, J = 2.4, 9.0 Hz, 1H), 7.50 (s, 1H), 7.16 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 9.0 Hz, 1H), 4.07 (s, 3H), 2.51 (s, 3H).

[0107] Example 63

[0108] See Example 27, except that the aryldiphenylthiophene salt is replaced by The product obtained is The yield was 58%. The nuclear magnetic resonance data were 1H NMR (600 MHz, CDCl3) δ8.38 (d, J=2.4 Hz, 1H), 8.04 (dd, J=2.4, 9.0 Hz, 1H), 7.88 (s, 1H), 7.82 (d, J=9.0 Hz, 2H), 7.68 (d, J=7.2 Hz, 2H), 7.61 (t, J=7.8 Hz, 1H), 7.49 (t, J=7.8 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.4 Hz, 1H), 4.09 (s, 3H), 2.51 (s, 3H).

[0109] Example 64

[0110] See Example 27, except that the aryldiphenylthiophene salt is replaced by The product obtained is The yield was 47%. The nuclear magnetic resonance data were 1H NMR (600 MHz, CDCl3) δ7.91 (d, J = 8.4 Hz, 2H), 7.87 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 9.6 Hz, 2H), 7.50 (s, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 9.0 Hz, 2H), 7.16 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 12.0 Hz, 1H), 3.76 (q, J = 7.2 Hz, 1H), 3.70 (s, 3H), 2.54 (s, 3H), 1.53 (d, J = 7.2 Hz, 3H).

[0111] Example 65

[0112] See Example 27, except that the aryldiphenylthiophene salt is replaced by The product obtained is The yield was 53%. The nuclear magnetic resonance data were 1H NMR (600 MHz, CDCl3) δ 8.65 (d, J = 8.4 Hz, 1H), 8.46 (s, 1H), 8.44 (dd, J = 1.8, 4.8 Hz, 1H), 8.14 (d, J = 6.0 Hz, 1H), 8.01 (s, 1H), 7.88 (dd, J = 1.8, 9.0 Hz, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 1.8 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.37-7.32 (m, 1H), 7.24-7.18 (c, 4H), 2.52 (s, 3H).

[0113] Example 66

[0114] See Example 27, except that the aryldiphenylthiophene salt is replaced by The product obtained is The yield was 61%. The nuclear magnetic resonance data were 1H NMR (600 MHz, CDCl3) δ7.84-7.80 (c, 3H), 7.46 (s, 1H), 7.07 (d, J = 8.4 Hz, 2H), 6.59 (s, 1H), 3.93 (t, J = 6.0 Hz, 2H), 3.64 (s, 3H), 2.58 (s, 3H), 2.51 (s, 3H), 2.19 (s, 3H), 1.77-1.65 (m, 3H), 1.20 (s, 6H).

[0115] Examples 49-66 investigated the effectiveness of this synthetic route with various substituents on the aryl group of the aryldibenzothiophene salt. These examples demonstrate that the target product can be achieved with various substituents on the aryl group. Furthermore, Examples 63-66 further investigated the potential application of this synthetic route to large-scale pharmaceutical structures. These examples demonstrate that the target product can be effectively synthesized, further demonstrating the broad applicability of this synthetic route.

[0116] Examples 67-78

[0117] See Example 27, the difference is that different primary arylamines are used to replace the acetanilide therein to obtain the corresponding arylsulfonamide product. The specific structure and yield are shown in Figure 2 Through these examples, it can be found that primary arylamines substituted with various substituents can be used as nitrogen sources to effectively synthesize the target arylsulfonamides.

[0118] Examples 79-94

[0119] See Example 27, the difference is that different primary fatty amines are used to replace the acetanilide to obtain the corresponding arylsulfonamide product. The specific structure and yield are shown in Figure 3 It was found that saturated linear primary aliphatic amines, primary aliphatic amines with alkoxy substituents on the carbon chain, primary aliphatic amines with aryl substituents on the carbon chain, and primary aliphatic amines containing 3-5 membered saturated carbocyclic rings can all react with aryldiphenylthiophene salts to produce the target arylsulfonamides. The direct use of these primary aliphatic amines in the synthesis of sulfonamides overcomes the synthetic limitations of the copper-catalyzed sulfonyl route, greatly improving and promoting the methodological research of sulfonamides, and is of great significance both academically and industrially.

[0120] Examples 95-106

[0121] See Example 27, except that different secondary amines are used to replace the acetanilide to obtain the corresponding arylsulfonamide product. The specific product structure and yield are shown in Figure 4 For the structure of secondary amine, those skilled in the art can Figure 3 The structure of the product is deduced from the above, that is, adding one H to the amine substituent in the generated sulfonamide is the secondary amine structure. Figure 3 The target product structures generated in the reaction are diverse, including saturated carbon linear substituents, six-membered carbon ring substituents, benzyl groups, and 4-6-membered heterocyclic amines formed with saturated carbon chains. The heterocyclic ring may further include a nitrogen or oxygen atom. Furthermore, various substituents, including ester and aldehyde groups, can be attached to the carbon atoms or heteroatoms of the heterocyclic ring, i.e., nitrogen or oxygen. This indicates that various types of secondary amines can participate in the synthesis route.

[0122] Example 107

[0123] See Example 27, except that the aryldiphenylthiophene salt is replaced by Replace the p-acetanilide with NaN3 to obtain the product: The yield was 51%. The nuclear magnetic resonance data were 1H NMR (600 MHz, CDCl3) δ7.85 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 4.94 (s, 2H), 3.02-2.91 (m, 1H), 1.27 (d, J = 7.2 Hz, 6H).

[0124] Examples 108-113

[0125] See Example 107, except that, NaN3 is replaced by KN3 (Example 108), LiN3 (Example 109), TMSN3 (Example 110), ammonium carbonate (Example 111), ammonium nitrate (Example 112) and ammonium chloride (Example 113), and the yields of the products are 50% (Example 108), 47% (Example 109), 52% (Example 110), 46% (Example 111), 42% (Example 112) and 45% (Example 113), respectively.

[0126] Example 114

[0127] See Example 27, except that the aryldiphenylthiophene salt is replaced by Replace the p-acetanilide with NaN3 to obtain the product: The yield was 60%. The nuclear magnetic resonance data were 1H NMR (600 MHz, CDCl3) δ 7.85 (d, J = 9.0 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 4.84 (s, 2H), 1.34 (s, 9H).

[0128] Example 115

[0129] See Example 27, except that the aryldiphenylthiophene salt is replaced by Replace the p-acetanilide with NaN3 to obtain the product: The yield was 62%. The nuclear magnetic resonance data were 1H NMR (600 MHz, DMSO-d6) δ 7.90 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 6.6 Hz, 2H), 7.51 (t, J = 7.8 Hz, 2H), 7.43 (t, J = 7.2 Hz, 1H), 7.40 (s, 2H).

[0130] Example 116

[0131] See Example 27, except that the aryldiphenylthiophene salt is replaced by Replace the p-acetanilide with NaN3 to obtain the product: The yield was 75%. The nuclear magnetic resonance data were 1HNMR (600 MHz, CDCl3) δ7.87 (d, J = 9.0 Hz, 1H), 7.40 (t, J = 7.8 Hz, 2H), 7.22 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 9.0 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 5.07 (s, 2H).

[0132] Example 117

[0133] See Example 27, except that the aryldiphenylthiophene salt is replaced by Replace the p-acetanilide with NaN3 to obtain the product: The yield was 62%. The nuclear magnetic resonance data were 1H NMR (600 MHz, DMSO-d6) δ 7.91 (d, J = 9.0 Hz, 2H), 7.78 (q, J = 8.4 Hz, 1H), 7.43 (s, 2H), 7.40-7.32 (c, 3H), 6.96 (d, J = 9.0 Hz, 1H).

[0134] Examples 107-117 demonstrate that the corresponding aryl dibenzothiophene salts generated in the present invention can be directly reacted with ammonium salts, metal azides, or organic azide reagents to produce primary aryl sulfonamides. Thus, the synthetic route disclosed herein can produce primary, secondary, and tertiary aryl sulfonamides, demonstrating the broad potential applications of the synthetic route disclosed herein.

[0135] In addition, experiments have shown that when a nucleophilic reagent containing a fluorine anion replaces the N source (i.e., various organic amines, ammonium salts, inorganic azides, and organic compounds) in the standard synthesis route of arylsulfonamides to react with aryl dibenzothiophene salts, the corresponding arylsulfonyl fluoride can be directly prepared.

[0136] Example 118

[0137] See Example 27, except that p-acetanilide was replaced with KHF2 to obtain the corresponding arylsulfonyl fluoride in 71% yield. Nuclear magnetic resonance data: 1H NMR (600 MHz, CDCl3) δ 8.62 (d, J = 2.4 Hz, 1H), 8.37 (dd, J = 2.4, 9.0 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 4.08 (s, 3H), 3.94 (s, 3H).

[0138]

[0139] Implementation of 119

[0140] See Example 118, except that KHF2 is replaced by KF to obtain the same product in a yield of 58%.

[0141] Example 120

[0142] See Example 118, except that KHF2 is replaced by NaF, and the same product is obtained in a yield of 55%.

[0143] Example 121

[0144] See Example 118, except that KHF2 is replaced by LiF to obtain the same product with a yield of 54%.

[0145] Examples 122-135

[0146] See Example 118, except that the substituents on the aryl dibenzothiophene salt are adjusted as shown below. The obtained product and yield are shown in Figure 5 .

[0147]

[0148] Depend on Figure 5 It can be seen that the above synthetic route can be used to synthesize arylsulfonyl fluorides with various substituents on the aryl group, which is of great significance in the field of sulfonyl fluoride synthesis.

Claims

1. A synthetic method for an arylsulfonyl derivative comprises the following steps: S1: placing the compound of formula (I), nucleophile TR, bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct, and photocatalyst in a solvent; S2: exposing the mixture formed in step S1 to blue light for a certain period of time to generate an arylsulfonyl fluoride compound or an arylsulfonamide compound as shown in formula (II), wherein Nu represents F or an amine substituent; ； The nucleophile TR is a fluorine-containing anion nucleophile or a nitrogen-containing nucleophile. When TR is a fluorine-containing anion nucleophile, the compound of formula (II) represents an arylsulfonyl fluoride compound in which Nu is F; when TR is a nitrogen-containing nucleophile, the compound of formula (II) represents an arylsulfonamide compound in which Nu is an amine substituent. in, In the compounds of formula (I) and formula (II), a is 0, 1, 2 or 3, and when a is 2 or 3, R1 is the same or different substituents; T1 and T2 are the same or different substituents; The nitrogen-containing nucleophile is selected from one of ammonium salts, metal azides, TMSN3, primary aromatic amines, primary fatty amines and secondary fatty amines; When the nitrogen-containing nucleophile is an ammonium salt, azide metal salt or TMSN3, the arylsulfonamide compound represented by formula (II) is represented by the structure of the compound represented by formula (III), R2 and R3 are H, and the compound represented by formula (III) is ； When the nitrogen-containing nucleophile is a primary aromatic amine, the arylsulfonamide compound represented by formula (II) is represented by the structure of the compound represented by formula (III), R2 is H, R3 is -Ph-X, X is selected from one of alkyl, halogen, aryl, ester, nitrile, and amine groups, and the compound of formula (III) is ; When the nitrogen-containing nucleophile is a primary fatty amine, the arylsulfonamide compound represented by formula (II) is represented by the structure of the compound represented by formula (III), R2 is H, and R3 is selected from C 1-11 Alkyl, -C 1-4 One of alkylene-Y, benzyl, phenethyl, wherein Y is selected from alkoxy or ester, and the compound of formula (III) is , and when R3 is benzyl or phenethyl, the benzyl ring in the benzyl and phenethyl groups further contains one or more of halogen and alkoxy groups; When the nitrogen-containing nucleophile is a secondary fatty amine, the arylsulfonamide compound represented by formula (II) is represented by the structure represented by the compound of formula (III) or the compound of formula (IV), in which R2 and R3 are the same or different and are independently selected from C 1-6 alkyl, benzyl; in the compound of formula (IV), ring B represents a four- to six-membered heterocyclic ring containing a N atom, and R4 is selected from one of H, an ester group and an aldehyde group; the compound of formula (III) is , the compound of formula (IV) is ; When TR is a fluorine-containing anion nucleophile, the fluorine-containing anion nucleophile is selected from one of LiF, NaF, KF and KHF2; The Q is selected from one of BF4, OTf, halogen and PF6; The solvent is selected from one of acetonitrile, DMSO, DMA, dichloromethane and 1,2-dichloroethane; The photocatalyst is , wherein the substituents P1, P2 and P3 are the same or different and are independently selected from H, nitro, alkoxy, and alkyl.

2. The synthesis method according to claim 1, wherein The ammonium salt is selected from one or more of ammonium carbonate, ammonium chloride and ammonium nitrate.

3. The synthesis method according to claim 1, wherein The metal azide salt is selected from one or more of sodium azide, potassium azide and lithium azide.

4. The synthesis method according to claim 1, wherein When the nitrogen-containing nucleophile is a secondary aliphatic amine, and when the B ring is a six-membered heterocyclic ring, the heterocyclic ring further includes an N or O atom.

5. The synthesis method according to claim 1, wherein The R1 are the same or different and are independently selected from methyl, phenyl, biphenyl, methoxy, -C(O)OCH3, isopropyl, tert-butyl, phenoxy, -OTf, -F, -Cl, -Br, -CN, -C(O)Ph, p-chlorophenyl, 、 and .

6. The synthesis method according to claim 1, wherein T1 and T2 are the same or different and are independently selected from H, nitro, alkyl, alkoxy, and halogen.

7. The synthesis method according to claim 1, wherein The method further comprises step S3: heating the reactant formed in step S2 for a certain period of time.

8. The synthesis method according to claim 7, wherein The step S3 is performed at 30-80°C.

9. The synthesis method according to claim 8, wherein The step S3 is performed at 40-70°C.

10. The synthesis method according to claim 9, wherein The step S3 is performed at 60°C.

11. The synthesis method according to claim 1, characterized in that: The synthesis method is carried out in an air environment or an inert gas environment, and the inert gas is selected from one or more of nitrogen, argon and helium.

12. The synthesis method according to claim 1, characterized in that: The step S2 is performed at 20-60°C.

13. The synthesis method according to claim 12, characterized in that: The step S2 is performed at 25°C.

14. The synthesis method according to claim 1, characterized in that: The wavelength of blue light is 380-500nm.

15. The synthesis method according to claim 14, characterized in that: The wavelength of blue light is 427nm.

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