Method for preparing sulfinyl compound through palladium catalysis and application of sulfinyl compound

Abstract

The invention relates to a method for preparing a sulfinyl compound through palladium catalysis and application of the sulfinyl compound, in particular to a method for obtaining the sulfinyl compound through reaction of thioxanil and aryl thianthrene onium salt under the catalysis of metal palladium and RuPhos, the process conditions are simple, the yield is good, and the sulfinyl compound has wide functional group tolerance.

Description

Technical Field

[0001] The invention belongs to the field of chemical medicine and relates to a method for preparing a sulfinyl compound by using palladium catalysis and application thereof. Background Art

[0002] Sulfonitrile subunits have proven to be versatile building blocks in synthetic organic chemistry due to their easy accessibility, bench stability, and unique reactivity. Recent advances have demonstrated that sulfonitrile subunits can efficiently participate in a wide range of organic transformations, serving as attractive alternatives to potentially hazardous diazo compounds.

[0003] Generally, commonly used α-monosubstituted α-carbonylsulfinyls can be readily synthesized via acylation of trimethylsulfoxide halides with acid chlorides / anhydrides or amides under basic conditions. In contrast, the synthesis of disubstituted sulfosulfoxinium ylides is relatively challenging, especially the preparation of α-aryl α-carbonylsulfonyl ethers, which are important precursors to obtain a variety of synthetically useful α-aryl substituted carbonyl compounds.

[0004] The Burtoloso group reported the first arylation of β-ketosulfonyloxonium ylides in the presence of CsF by using 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (2-TMSC6H4OTf) as a benzylic acid precursor and arylating agent (Org. Lett. 2018, 20, 7206-7211).

[0005] and colleagues successfully achieved the coupling of α-ester sulfoxonium ylides with aromatic halides and pseudohalides under palladium catalysis (J.Org.Chem.2020,85,1126-1137.).

[0006] The Murphy / Burtoloso group described the catalytic coupling of diaryliodonium salts derived from Cu(I)-mesitylene with α-carbonylsulfonium ylides (Adv. Synth. Catal. 2024, 366, 396-401.).

[0007] The invention provides a method for obtaining a sulfinyl compound by reacting thioxylide with aryl fluorosulfate under the catalysis of metal palladium and RuPhos. Summary of the invention

[0008] On the one hand, the present invention provides a method for preparing a compound represented by formula C

[0009]

[0010] The method comprises the steps of: reacting a compound represented by formula A and a compound represented by formula B in the presence of Pd 2 (dba)3 and the step of reacting in the presence of RuPhos,

[0011]

[0012] Among them, R 1 is selected from -O-C6 aryl, aryl or 5-6 membered heteroaryl, wherein the -O-C6 aryl, C6 aryl or 5-6 membered heteroaryl is optionally substituted by one or more R 1a Replaced by R 1a are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, or two adjacent R 1a Forming a 5-6 membered heterocycloalkyl;

[0013] R 2 is selected from phenyl, wherein the phenyl is optionally selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, phenyl, -PhCOR 2a is substituted by one or more substituents;

[0014] R 2a Selected from C 1-3 Alkyl or C 1-3 Alkoxy.

[0015] In some embodiments, R 1 is selected from phenyl, the phenyl group is optionally substituted by halogen, C 1-6 The moiety is substituted with an alkyl group (eg, methyl or ethyl).

[0016] In some embodiments, R 1 is selected from 5-membered heteroaryl, such as thienyl.

[0017] In some embodiments, R 1 is selected from -O-C6 aryl, wherein the -O-C6 aryl is optionally substituted by one or more R 1a replaced.

[0018] In some embodiments, R 1a is selected from halogen (such as fluorine or chlorine), C 1-6 Alkyl (e.g. methyl, ethyl, tert-butyl), C 1-6 Alkoxy (eg, methoxy).

[0019] In some embodiments, two adjacent R 1a A 5-6 membered heterocycloalkyl group is formed.

[0020] In some embodiments, R 1 Selected from

[0021] In some embodiments, the compound represented by formula A is selected from:

[0022]

[0023] To ensure the smooth progress of the reaction, the method of the present invention uses Pd 2 (dba) 3 The amount of Pd is 5% to 15% of the molar amount of the compound shown in Formula A, including but not limited to 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or any value between two numbers. In some embodiments, in the method, Pd 2 (dba) 3 The amount used is 5% of the molar amount of the compound represented by formula B.

[0024] In some embodiments, the amount of RuPhos used in the reaction is 10% to 30% of the molar amount of the compound shown in Formula A, including but not limited to 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or any value between two numbers. In some embodiments, the amount of RuPhos used in the method is 20% of the molar amount of the compound shown in Formula A.

[0025] In addition, the amount of RuPhos is Pd 2 (dba) 3 1-4 times of the molar amount, including but not limited to 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0 or any value between two numbers. In some embodiments, the amount of catalyst ligand used in the reaction is 4 times the molar amount of the catalyst.

[0026] On the other hand, the reaction described in the present invention also contains a base, such as cesium carbonate or potassium phosphate. In some embodiments, the amount of base used in the reaction is 1-3 times the molar amount of the compound shown in formula A, including but not limited to 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0 or any two numbers. In some embodiments, the amount of base used in the reaction is 2 times the molar amount of the compound shown in formula A.

[0027] Further, the reaction of the present invention is carried out in a solvent, and the solvent is selected from acetonitrile or tetrahydrofuran. In some embodiments, the reaction is carried out in acetonitrile.

[0028] On the other hand, the molar ratio of the compound represented by formula A to the compound represented by formula B in the method is 1:1 to 1:4 (including 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4 or any value therebetween). In some embodiments, the molar ratio of the compound represented by formula A to the compound represented by formula B in the method is 1:1 to 1:2. In some embodiments, the molar ratio of the compound represented by formula A to the compound represented by formula B in the method is 1:1.5.

[0029] In some embodiments, the reaction temperature may be 60-100°C (may be 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C or 100°C). In some embodiments, the reaction temperature is 60°C.

[0030] In some embodiments, R 2 is selected from phenyl, the phenyl group is optionally substituted by halogen, C 1-6 The moiety is substituted by an alkyl group (eg, methyl, ethyl or tert-butyl).

[0031] In some embodiments, R 2 is selected from phenyl, the phenyl group is optionally substituted by C 3-6 The radical is substituted by a cycloalkyl radical (such as cyclohexyl).

[0032] In some embodiments, R 2 is selected from phenyl, the phenyl group is optionally substituted by C 1-6 The group is substituted with an alkoxy group (methoxy or ethoxy).

[0033] In some embodiments, R 2 Selected from

[0034] In some embodiments, the compound represented by formula B is selected from

[0035] In some embodiments, the method for preparing the compound of formula C comprises reacting the compound of formula A and the compound of formula B in the presence of Pd 2 (dba) 3 The step of reacting in the presence of RuPhos and cesium carbonate,

[0036]

[0037] On the other hand, the method for preparing the compound represented by formula C further comprises the step of reacting aromatic hydrocarbon with thianthrene-5-oxide.

[0038] In some embodiments, the aromatic hydrocarbon and thianthrene-5-oxide ( The TTO reaction was carried out under trifluoroacetic anhydride / trifluoromethanesulfonic acid conditions.

[0039] In some embodiments, the aromatic hydrocarbon and thianthrene-5-oxide ( TTO) reaction under trifluoromethanesulfonic anhydride conditions.

[0040] Further, the method for preparing the compound represented by formula C comprises a) reacting an aromatic hydrocarbon with thianthrene-5-oxide, b) reacting the compound represented by formula A and the compound represented by formula B in the presence of Pd 2 (dba) 3 and reacted in the presence of RuPhos.

[0041] In some embodiments, in the method for preparing the compound represented by formula C, step a) and step b) are completed in one pot.

[0042] "One-pot process" refers to two or more steps of reaction without a separation / purification step, and the two or more steps of reaction are reacted continuously to obtain the target product.

[0043] The present invention also provides the use of the preparation method of the aforementioned sulfinyl compound such as the compound shown in formula C in the preparation of medicines, spices or pesticides.

[0044] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0045] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, and various branched isomers thereof. Alkyl can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any available point of attachment, and the substituent is preferably one or more of the following groups, such as halogen.

[0046] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings which share adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl.

[0047] Aryl may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy.

[0048] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 12 members, such as imidazolyl, furanyl, thienyl, pyrazolyl, pyrrolyl, pyridyl and the like.

[0049] Heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy.

[0050] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, such as halogen.

[0051] The term "cyano" refers to -CN.

[0052] The term "nitro" refers to -NO 2 .

[0053] The term "halogen" includes: fluorine, chlorine, bromine or iodine.

[0054] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0055] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

[0056] The reagents used in the present invention can be purchased from commercial sources.

[0057] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (Methanol-d4) as the solvent, and tetramethylsilane (TMS) as the internal standard. DETAILED DESCRIPTION

[0058] The present invention will be explained in detail below in conjunction with specific examples so that those skilled in the art can more fully understand that the specific examples of the present invention are only used to illustrate the technical solutions of the present invention and do not limit the present invention in any way.

[0059] Example 1: Catalyst screening

[0060]

[0061] 2-(dimethyl(oxy)-λ 6 -sulfylidene) phenyl acetate (1a, 106 mg, 0.5 mmol, 1.0 equiv., prepared according to the method of Org. Lett. 2023, 25, 1214-1217), tolylthianthrenium salt (2a, 342 mg, 0.75 mmol, 1.5 equiv., prepared according to the method of Nature 2019, 567, 223-228.), catalyst (5 mol%), RuPhos (46.7 mg, 0.1 mmol), K 3 PO 4(211 mg, 1.0 mmol, 2.0 equiv.) was added to tetrahydrofuran, and the mixture was stirred and heated to react (60°C, 12 h). The reaction yield was estimated by NMR detection, or the yield was calculated by column chromatography purification. The specific data are shown in the following table:

[0062] Table 1

[0063]

[0064]

[0065] Note: [b] NMR detection to estimate the reaction yield; [c] Pd 2 (dba) 3 (5 mol%); [d] Cs 2 CO 3 Replace K 3 PO 4 ; [e] Isolation yield; [f] No base was used; [g] No RuPhos was used; [h] Reaction at room temperature; [i] Reaction at 40°C; [j] Compound 2a dosage 1.2 equiv.; [k] Pd 2 (dba) 3 (2.5 mol%) and RuPhos (10 mol%).

[0066] Example 2: Ligand Screening

[0067]

[0068]

[0069] 2-(dimethyl(oxy)-λ 6 -sulfylidene)acetate (1a, 106 mg, 0.5 mmol, 1.0 equiv.), tolylthianthrenium salt (2a, 342 mg, 0.75 mmol, 1.5 equiv.), Pd 2 (dba) 3 (22.9 mg, 5 mol%), ligand (20 mol%), K 3 PO 4 (211 mg, 1.0 mmol, 2.0 equiv.) was added to tetrahydrofuran, stirred and heated to react (60°C, 12 h), and the reaction yield was estimated by NMR detection. The specific data are as follows:

[0070]

[0071] Note: [b] Reaction yield was estimated by NMR detection.

[0072] Example 3: Base Screening

[0073]

[0074] 2-(dimethyl(oxy)-λ 6 -sulfylidene)acetate (1a, 106 mg, 0.5 mmol, 1.0 equiv.), tolylthianthrenium salt (2a, 342 mg, 0.75 mmol, 1.5 equiv.), Pd 2 (dba) 3 (22.9 mg, 5 mol%), RuPhos (46.7 mg, 0.1 mmol), and base (1.0 mmol, 2.0 equiv.) were added to tetrahydrofuran, and the mixture was stirred and heated to react (60°C, 12 h). The reaction yield was estimated by NMR detection. The specific data are shown in the following table:

[0075]

[0076] Note: [b] Reaction yield was estimated by NMR detection.

[0077] Example 4: Dissolution Screening

[0078]

[0079] 2-(dimethyl(oxy)-λ 6 -sulfylidene)acetate (1a, 106 mg, 0.5 mmol, 1.0 equiv.), tolylthianthrenium salt (2a, 342 mg, 0.75 mmol, 1.5 equiv.), Pd 2 (dba) 3 (22.9mg, 5mol%), RuPhos (46.7mg, 0.1mmol), Cs 2 CO 3 (325.8 mg, 1.0 mmol, 2.0 equiv.) was added to the solvent, stirred and heated to react (60°C, 12 h), and the reaction yield was estimated by NMR detection. The specific data are as follows:

[0080]

[0081] Note: [b] Reaction yield was estimated by NMR detection.

[0082] Example 5

[0083]

[0084] 2-(dimethyl(oxy)-λ 6-sulfylidene)acetate (1a, 636.8 mg, 3 mmol, 1.0 equiv.), tolylthianthrenium salt (2a, 2054.3 mg, 4.5 mmol, 1.5 equiv.), Pd 2 (dba) 3 (137.4mg, 5mol%), RuPhos (280.2mg, 0.6mmol), Cs 2 CO 3 (1954.9 mg, 6 mmol, 2.0 equiv.) was added to 12 ml of THF, stirred and heated to react (60°C, 12 h), quenched with ammonium chloride solution, extracted with ethyl acetate, washed with saturated brine, and then 2 SO 4 After drying, concentration and purification by column chromatography (MeOH / DCM), 694 mg of the target product was obtained with a yield of 77%.

[0085] Example 6

[0086] Referring to the method of Example 5, 2-(dimethyl(oxy)-λ 6 Sulfinyl) phenyl acetate (1a, 0.5 mmol, 1.0 equiv.), compounds 2b-2j (0.75 mmol, prepared according to Nature 2019, 567, 223-228.), Pd 2 (dba) 3 (22.9mg, 5mol%), RuPhos (46.7mg, 0.1mmol), Cs 2 CO 3 (325.8 mg, 1.0 mmol, 2.0 equiv.) and THF. Heat and stir to react at 60°C. After TLC detection, the target product is purified by column chromatography. The yields are calculated respectively. The specific data are as follows:

[0087]

[0088]

[0089]

[0090]

[0091] Example 7

[0092] Referring to the method of Example 5, 2-(dimethyl(oxy)-λ 6Sulfinyl)acetic acid aryl ester (1b-2j, 0.5 mmol, prepared according to the method of Org. Lett. 2023, 25, 1214-1217), compound 2a (0.75 mmol), Pd 2 (dba) 3 (22.9mg, 5mol%), RuPhos (46.7mg, 0.1mmol), Cs 2 CO 3 (325.8 mg, 1.0 mmol, 2.0 equiv.) and THF. Heat and stir to react at 60°C. After TLC detection, the target product is purified by column chromatography. The yields are calculated respectively. The specific data are as follows:

[0093]

[0094]

[0095]

[0096]

[0097]

[0098] Example 8

[0099]

[0100] In a 100 ml reaction bottle, add toluene (10 mmol, 1.0 equiv.), thianthrene-5-oxide (2.32 g, 10 mmol) and 30 ml of dichloromethane, cool to -40 ° C, add trifluoromethanesulfonic anhydride (2 ml, 12 mmol) dropwise, stir to react for 30 min, warm to room temperature to react for 12 h, add sodium bicarbonate solution, extract with dichloromethane, wash, dry with sodium sulfate, concentrate, and crystallize from dichloromethane / ether to obtain the target product.

[0101] Example 9

[0102]

[0103] In a reaction flask, toluene (69.1 mg, 0.75 mmol), thianthrene-5-oxide (191.7 mg, 0.825 mmol) and 1 ml of dichloromethane were added, cooled to -40 ° C, trifluoroacetic anhydride (0.15 ml, 0.9 mmol) and trifluoromethanesulfonic anhydride (0.15 ml, 0.9 mmol) were added dropwise, stirred for 30 min, warmed to room temperature for 12 h, and compound 1a (106.1 mg, 0.5 mmol) and Pd were added. 2 (dba) 3(22.9mg, 0.025mmol), RuPhos (46.7mg, 0.1mmol), Cs 2 CO 3 (488.7 mg, 1.5 mmol) and 2 ml of tetrahydrofuran were heated at 60°C for 12 h, and ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and concentrated. The reaction yield was estimated to be 67% using NMR detection.

Claims

1. A method for preparing a compound represented by formula C, The method comprises the steps of reacting a compound represented by formula A and a compound represented by formula B in the presence of Pd2(dba)3 and RuPhos, in, R1 is selected from -O-C6 aryl, aryl or 5-6 membered heteroaryl, wherein the -O-C6 aryl, C6 aryl or 5-6 membered heteroaryl is optionally substituted by one or more R 1a Replaced by R 1a are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, or two adjacent R 1a Forming a 5-6 membered heterocycloalkyl; R2 is selected from phenyl, which is optionally selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, phenyl, -PhCOR 2a is substituted by one or more substituents; R 2a Selected from C 1-3 Alkyl or C 1-3 Alkoxy.

2. The method of claim 1, wherein the reaction solvent is selected from acetonitrile or tetrahydrofuran.

3. The method according to claim 1 or 2, wherein the amount of Pd2(dba)3 is 5% to 15% of the molar amount of the compound represented by formula A, preferably 5%.

4. The method according to any one of claims 1 to 3, wherein the reaction further comprises a base, preferably cesium carbonate or potassium phosphate; further, the base is used in an amount of 1 to 3 times, preferably 2 times, the molar amount of the compound shown in formula A.

5. The method according to any one of claims 1 to 4, wherein the amount of RuPhos used is 10% to 30% of the molar amount of the compound represented by formula A, preferably 20%.

6. The method according to any one of claims 1 to 5, wherein the compound represented by formula A is selected from:

7. The method according to any one of claims 1 to 6, wherein the compound represented by formula B is selected from 8. The method according to any one of claims 1 to 7, wherein the molar ratio of the compound represented by formula A to the compound represented by formula B is 1:1 to 1:4, preferably 1:1 to 1:2, for example 1:1.

5.

9. The method according to any one of claims 1 to 8, wherein the reaction temperature is 50 to 100°C, preferably 50 to 80°C, for example 60°C.

10. Use of the method according to any one of claims 1 to 9 in the preparation of medicines, spices or pesticides.

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