A method for the carbonylation preparation of α,β-unsaturated thioester compounds

Abstract

The present invention discloses a method for carbonylation to prepare α,β-unsaturated thioester compounds, which comprises the following steps: reacting tris(dibenzylideneacetone)dipalladium, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, potassium hydrogen phosphate, alkenyl trifluoromethanesulfonate and aryl thiophenol formate at 30 °C for 20 hours. After the reaction is complete, the α,β-unsaturated thioester compounds are obtained through post-treatment. The starting materials of this preparation method are cheap and easily available, the operation is simple, and the reaction efficiency is high. Using aryl thiophenol formate as both a carbonyl source and a sulfur source, a variety of α,β-unsaturated thioester compounds can be synthesized according to actual needs. The substrate functional group tolerance range is wide, which not only facilitates the operation but also broadens the practicability of this method.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a method for carbonylation to prepare α,β-unsaturated thioester compounds. Background Art

[0002] Thioester compounds, as a class of compounds with special structures, widely exist in natural products, biomolecules and drugs (J.Med.Chem.2014,57,2832-2842). Compared with acyl halides, thioester compounds are stable in air and easy to operate, and are often used as acyl donors to prepare various aldehydes, ketones, esters and other compounds. Among thioester compounds, α,β-unsaturated thioesters are a class of molecules with unique chemical properties and are often used as important reaction intermediates to prepare various complex molecules and natural products, showing very rich reaction activities (J.Am.Chem.Soc.2006,128,4546-4547). Therefore, the synthesis of α,β-unsaturated thioesters has always been the focus of attention of organic chemists. The traditional methods for synthesizing α,β-unsaturated thioesters mainly rely on condensation reactions, but such reactions usually have some disadvantages, such as high reaction temperature, narrow substrate scope, low atom economy, etc.

[0003] In recent years, transition metal-catalyzed thiocarbonylation reactions have received increasing attention due to their high efficiency and atom economy. In the 1990s, the Ogawa and Sonoda research groups developed a series of carbonylation reactions of transition metal-catalyzed organic sulfur compounds and terminal alkynes. In these reactions, thiocarbonylation products can be selectively synthesized by using a platinum catalyst. Subsequently, Xiao, Alper and others further extended the palladium-catalyzed thiocarbonylation reaction and developed various thiocarbonylation reactions of thiols with alkenes, vinyl cyclopropanes, 1,3-dienes and alkynes. Recently, our research group developed a regioselective thiocarbonylation reaction to selectively synthesize linear and branched α,β-unsaturated thioester compounds by ligand regulation (Angew.Chem.Int.Ed.2021,60,17178-17184). However, there are still some disadvantages in the application of CO gas and thiol compounds in the above thiocarbonylation reactions, such as 1) CO gas is highly toxic and difficult to control, and 2) thiols have an unpleasant smell and are toxic to the catalyst. Therefore, the development of carbonyl sources and sulfur sources in thiocarbonylation reactions is urgently needed.

[0004] Based on this, we have developed a palladium-catalyzed thiocarbonylation reaction for the synthesis of α,β-unsaturated thioester compounds. Using readily available alkenyl trifluoromethanesulfonates and aryl thiophenol formates as starting materials, a variety of α,β-unsaturated thioester compounds are synthesized. It is worth noting that this reaction uses aryl thiophenol formates as both the carbonyl source and the sulfur source, with palladium as the catalyst, opening up a new synthetic route for the carbonylation reaction to construct α,β-unsaturated thioester compounds. Summary of the Invention

[0005] The present invention provides a method for the carbonylation preparation of α,β-unsaturated thioester compounds. The reaction raw materials of this preparation method are cheap and readily available, the steps are simple, it can be compatible with a variety of functional groups, and the reaction applicability is good. Using palladium as the catalyst and aryl thiophenol formates as both the carbonyl source and the sulfur source, it provides a new direction for the synthesis of α,β-unsaturated thioester compounds.

[0006] A method for the carbonylation preparation of α,β-unsaturated thioester compounds, comprising the following steps: reacting a palladium catalyst, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, dipotassium hydrogen phosphate, alkenyl trifluoromethanesulfonate, and aryl thiophenol formate at 25-35 °C for 16-24 hours. After the reaction is complete, post-treatment is carried out to obtain the α,β-unsaturated thioester compound;

[0007] The alkenyl trifluoromethanesulfonate has a structure as shown in formula (II):

[0008]

[0009] The aryl thiophenol formate has a structure as shown in formula (III):

[0010]

[0011] The α,β-unsaturated thioester compound has a structure as shown in formula (I):

[0012]

[0013] In formulas (I)-(III), R is H or a C1-C4 alkyl group, and n is 1-3;

[0014] Ar is a substituted or unsubstituted aryl group.

[0015] The substituents on the aryl group are C1-C4 alkyl groups, methoxy groups, trifluoromethyl groups, or halogens.

[0016] The molar ratio of the palladium catalyst, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and dipotassium hydrogen phosphate is 0.05:0.05:1.5;

[0017] The substitution position on the aryl group of Ar can be ortho, meta or para.

[0018] The reaction formula is as follows:

[0019]

[0020] In the present invention, the optional post-treatment process includes: filtration, silica gel sample mixing, and finally purification by column chromatography to obtain the corresponding α,β-unsaturated thioester compound. Purification by column chromatography is a commonly used technical means in the art.

[0021] Preferably, the ring substituted by R is cyclohexenyl (n = 1), cycloheptenyl (n = 2) or cyclooctenyl (n = 3). At this time, the alkenyl trifluoromethanesulfonate is easily obtained, and the reaction yield is relatively high.

[0022] Preferably, R is H, methyl, ethyl, propyl or tert-butyl, n is 1-3; Ar is a substituted or unsubstituted phenyl or 2-naphthyl, and the substituents on the phenyl are methyl, methoxy, trifluoromethyl, F or Cl

[0023] The alkenyl trifluoromethanesulfonate and aryl thiophenol formate used to prepare the α,β-unsaturated thioester compound can be synthesized. The synthesis raw materials are relatively cheap and widely exist in nature. Preferably, in terms of molar amount, alkenyl trifluoromethanesulfonate: aryl thiophenol formate: palladium catalyst = 1:1.2-1.5:0.05-0.1; As a further preference, in terms of molar amount, alkenyl trifluoromethanesulfonate: aryl thiophenol formate: palladium catalyst = 1:1.5:0.05.

[0024] Preferably, the reaction time is 20 hours. Too long reaction time increases the reaction cost, while too short reaction time makes it difficult to ensure the completion of the reaction.

[0025] Preferably, the reaction is carried out in toluene. The amount of toluene used can dissolve the raw materials well. The amount of toluene used for 0.2 mmol of alkenyl trifluoromethanesulfonate is about 1-3 mL.

[0026] Preferably, the palladium catalyst is bis(dibenzylideneacetone)palladium(0). Among many palladium catalysts, bis(dibenzylideneacetone)palladium(0) is relatively cheap, and the reaction efficiency is relatively high when bis(dibenzylideneacetone)palladium(0) is used as the catalyst.

[0027] As a further preference, the α,β-unsaturated thioester compound is one of the compounds shown in formula (I-1)-formula (I-5):

[0028]

[0029] In the above preparation method, the tris(dibenzylideneacetone)dipalladium(0), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and potassium hydrogen phosphate are generally commercially available products and can be conveniently obtained from the market.

[0030] Compared with the prior art, the beneficial effects of the present invention are as follows: Using aryl thiolformate as the sulfur source, the preparation method is simple, easy to operate, the post-treatment is simple, the starting materials of the reaction are cheap and easily available, the tolerance range of substrate functional groups is wide, and the reaction efficiency is high. A variety of α,β-unsaturated thioester compounds can be synthesized according to actual needs, and the practicability is strong. Detailed implementation mode

[0031] The present invention will be further described below with reference to specific examples.

[0032] Examples 1 to 15

[0033] Add tris(dibenzylideneacetone)dipalladium(0), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, potassium hydrogen phosphate, alkenyl trifluoromethanesulfonate (II), and aryl thiolformate (III) into a 15 mL sealed tube according to the raw material ratio in Table 1, then add toluene (2 mL), mix and stir evenly, react according to the reaction conditions in Table 2. After the reaction is completed, filter, mix with silica gel, and purify by column chromatography to obtain the corresponding α,β-unsaturated thioester compound (I). The reaction process is shown in the following formula:

[0034]

[0035] Table 1 Raw material addition amounts of Examples 1 to 15

[0036]

[0037] Table 2

[0038]

[0039]

[0040] In Tables 1 and 2, T is the reaction temperature, t is the reaction time, Me is methyl, tBu is tert-butyl, OMe is methoxy, CF3 is trifluoromethyl, cyclohex is cyclohexenyl, and cyclooct is cyclooctenyl.

[0041] Structure confirmation data of the compounds prepared in Examples 1 to 5:

[0042] The nuclear magnetic resonance ( 1 HNMR and 13 C NMR) detection data of the α,β-unsaturated thioester compound (I-1) prepared in Example 1 are as follows:

[0043]

[0044] 1 H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H), 7.15–7.10 (m, 1H), 2.38 (s, 3H), 2.37–2.32 (m, 2H), 2.31–2.24 (m, 2H), 1.73–1.62 (m, 4H).

[0045] 13 C NMR (101 MHz, CDCl3) δ 191.2, 139.3, 139.1, 138.2, 135.0, 129.9, 124.4, 25.9, 24.2, 21.9, 21.5, 21.3.

[0046] 1H NMR and 1 1H NMR and 13 13C NMR) detection data of the α,β-unsaturated thioester compound (I-2) prepared in Example 2 are as follows:

[0047]

[0048] 1 H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 7.16–7.11 (m, 1H), 2.37–2.32 (m, 2H), 2.31–2.24 (m, 2H), 1.73–1.62 (m, 4H), 1.34 (s, 9H).

[0049] 13 C NMR (101 MHz, CDCl3) δ 191.2, 152.3, 139.1, 138.2, 134.7, 126.2, 124.4, 34.7, 31.2, 25.9, 24.1, 21.9, 21.5.

[0050] 1H NMR and 1 1H NMR and 13 13C NMR) detection data of the α,β-unsaturated thioester compound (I-3) prepared in Example 3 are as follows:

[0051]

[0052] 11H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.18–7.12 (m, 1H), 2.36–2.26 (m, 4H), 1.73–1.63 (m, 4H).

[0053] 13 13C NMR (101 MHz, CDCl3) δ 189.5, 140.3, 138.1, 135.2, 132.9, 131.0 (q, J = 32.7 Hz, 1C), 125.8 (q, J = 3.7 Hz, 1C), 123.9 (q, J = 272.1 Hz, 1C), 26.0, 24.2, 21.9, 21.5.

[0054] 1H NMR and 1 13C NMR) detection data of the α,β-unsaturated thioester compound (I-4) prepared in Example 4 are as follows: 13

[0055]

[0056] 1 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 7.8 Hz, 2H), 7.22 (d, J = 7.8 Hz, 2H), 7.11–7.07 (m, 1H), 2.55–2.46 (m, 1H), 2.38 (s, 3H), 2.38–2.21 (m, 2H), 1.93–1.77 (m, 2H), 1.76–1.64 (m, 1H), 1.32–1.21 (m, 1H), 1.01 (d, J = 6.6 Hz, 3H).

[0057] 13 13C NMR (101 MHz, CDCl3) δ 191.1, 139.3, 138.7, 137.9, 135.0, 129.9, 124.4, 34.3, 30.2, 27.7, 24.2, 21.4, 21.3.

[0058] 1H NMR and 1 13C NMR) detection data of the α,β-unsaturated thioester compound (I-5) prepared in Example 5 are as follows: 13

[0059]

[0060] 1 ​​1H NMR (400 MHz, CDCl3) δ 7.34–7.27 (m, 3H), 7.22 (d, J = 7.9 Hz, 2H), 2.57–2.51 (m, 2H), 2.41–2.34 (m, 5H), 1.84–1.75 (m, 2H), 1.62–1.52 (m, 4H).

[0061] 13 13C NMR (101 MHz, CDCl3) δ 192.1, 144.7, 143.9, 139.4, 135.1, 129.9, 125.0, 32.0, 29.1, 27.9, 26.2, 25.7, 21.4。

Claims

1. A method for the carbonylation preparation of α,β-unsaturated thioester compounds, characterized in that, It includes the following steps: reacting a palladium catalyst, a ligand, a base, an alkenyl trifluoromethanesulfonate and an aryl thiophenol formate at 25-35 °C for 16-24 hours, and after the reaction is complete, performing post-treatment to obtain the α,β-unsaturated thioester compound; The structure of the alkenyl trifluoromethanesulfonate is shown in formula (II): The structure of the aryl thiophenol formate is shown in formula (III): The structure of the α,β-unsaturated thioester compound is shown in formula (I): In formulas (I)-(III), R is H or a C1-C4 alkyl group, and n is 1-3; Ar is a substituted or unsubstituted aryl group; The substituent on the aryl group is a C1-C4 alkyl group, a methoxy group, a trifluoromethyl group or a halogen; The palladium catalyst is bis(dibenzylideneacetone)palladium(0).

2. The method for preparing α,β-unsaturated thioester compound by carbonylation according to claim 1, wherein R is H, methyl, ethyl, propyl or tert-butyl, n is 1-3; Ar is a substituted or unsubstituted phenyl group or a 2-naphthyl group, and the substituent on the phenyl group is methyl, methoxy, trifluoromethyl, F or Cl.

3. The method for preparing α,β-unsaturated thioester compounds by carbonylation according to claim 1, characterized in that In terms of molar amount, alkenyl trifluoromethanesulfonate: aryl thiophenol formate: palladium catalyst: ligand: base = 1:1.2-1.5:0.05-0.1:0.05-0.1:1.5-2.

4. The method for preparing an α,β-unsaturated thioester compound by carbonylation according to claim 1, wherein, Toluene is used as the solvent for the reaction.

5. The method for preparing an α,β-unsaturated thioester compound by carbonylation according to claim 1, wherein The ligand is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

6. The method for preparing an α,β-unsaturated thioester compound by carbonylation according to claim 1, wherein The base is dipotassium hydrogen phosphate.

7. The method for preparing an α,β-unsaturated thioester compound by carbonylation according to claim 1, wherein The α,β-unsaturated thioester compound is one of the compounds shown in formulas (I-1)-(I-5):

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