1, 1, 4-triaryl-1, 3-eneyne derivative and synthesis method thereof

Abstract

The invention discloses a 1, 1, 4-triaryl-1, 3-eneyne derivative and a synthesis method of the 1, 1, 4-triaryl-1, 3-eneyne derivative. According to the method, o-bromostilbene and propargyl alcohol are taken as initial raw materials, transition metal palladium salt is taken as a catalyst, a 1, 1, 4-triaryl-1, 3-eneyne skeleton is constructed in one step through 1, 4-palladium migration / beta-carbon fragmentation / reduction elimination under an alkaline condition, a series of 1, 1, 4-triaryl-1, 3-eneyne derivatives are generated, and the obtained 1, 3-eneyne derivatives contain conjugated olefin and alkyne units and have the advantages that the conjugated olefin and alkyne units have the structure represented by the formula (I); the block has rich reactivity and is an important synthetic block in organic synthesis. The method has the advantages of easily available raw materials, simple operation, mild synthesis reaction conditions, high reaction efficiency and diversity of functional groups.

Description

Technical Field

[0001] The present invention relates to a 1,1,4-triaryl-1,3-enyne derivative and a synthesis method thereof, belonging to the technical field of chemical organic synthesis. Background Art

[0002] 1,3-Enyne compounds contain conjugated olefin and alkyne units and have rich reactivity, being important synthetic building blocks in organic synthesis. Due to their own structural characteristics, they can not only undergo 1,2, 3,4 and 1,4 functionalization reactions on the double bond and triple bond respectively, showing unique advantages in the construction of carbon heterocyclic skeletons. 1,1,4-Triaryl-1,3-enynes are a representative class of 1,3-enyne organic molecules. Therefore, it is of great significance to develop a new method for the efficient synthesis of 1,1,4-triaryl-1,3-enynes under mild conditions.

[0003] So far, there are three reported synthetic strategies, namely the Sonogashira coupling of alkenyl bromide and alkyne (Tetrahedron Lett. 1975, 50, 4467), and the coupling of 1,3-butadiyne with organometallic reagents (Organometallics 2010, 29, 3012; Synlett 2014, 25, 527). However, these three methods have certain disadvantages. The former can only synthesize symmetric 1,3-enynes or a mixture of asymmetric 1,3-enynes, and it is difficult to synthesize stereospecific 1,3-enynes; the latter requires multiple steps, the synthetic steps are complex, sensitive functional groups cannot be compatible with acidic additives, and the scope of substrates is also very limited. Therefore, it is still very necessary to develop a method for the one-step catalytic and efficient synthesis of 1,1,4-triaryl-1,3-enynes. Summary of the Invention

[0004] The purpose of the present invention is to use easily prepared o-bromostilbene II and propargyl alcohol III with structural diversity and high reaction efficiency as raw materials, and through 1,4-palladium migration / β-carbon cleavage / reductive elimination, the construction of the 1,1,4-triaryl-1,3-enyne skeleton is achieved in one step, and by regulating the R 1 , R 2 , R 3 substituents, a series of 1,1,4-triaryl-1,3-enyne derivatives with rich reactivity and different structures are efficiently synthesized.

[0005] The present invention provides a 1,1,4-triaryl-1,3-enyne derivative, and its molecular structural formula I is as follows:

[0006]

[0007] R 1, R 2 , R 3 are each independently selected from hydrogen, methyl, ethyl, tert-butyl, phenyl, methoxy, phenoxy, benzyloxy, trifluoromethyl, trifluoromethoxy, fluorine, chlorine, cyano, methoxycarbonyl, and the number of substituents is 1-5.

[0008] The present invention provides a method for synthesizing the above-mentioned 1,1,4-triaryl-1,3-enyne derivative I. Using o-bromostilbene II as the starting material, a transition metal palladium salt as the catalyst, under alkaline conditions, reacting with propargyl alcohol III in a solvent, through a 1,4-palladium migration / β-carbon cleavage / reductive elimination process, constructing a 1,1,4-triaryl-1,3-enyne skeleton in one step to generate a series of 1,1,4-triaryl-1,3-enyne derivatives I;

[0009] The molecular structural formula of o-bromostilbene II is as follows:

[0010]

[0011] R 1 , R 2 are each independently selected from hydrogen, methyl, ethyl, tert-butyl, phenyl, methoxy, phenoxy, benzyloxy, trifluoromethyl, trifluoromethoxy, fluorine, chlorine, cyano, methoxycarbonyl, and the number of substituents is 1-5.

[0012] The molecular structural formula of propargyl alcohol III is as follows:

[0013]

[0014] R 3 is selected from hydrogen, methyl, ethyl, tert-butyl, phenyl, methoxy, phenoxy, benzyloxy, trifluoromethyl, trifluoromethoxy, fluorine, chlorine, cyano, methoxycarbonyl, and the number of substituents is 1-5.

[0015] The synthesis route is shown in the following reaction formula:

[0016]

[0017] Among them: the transition metal palladium salt is selected from one or more of palladium chloride (PdCl 2 ), palladium bromide (PdBr 2 ), palladium acetate (Pd(OAc) 2 ), tetraphenylphosphine palladium (Pd(PPh 3 4 ), palladium trifluoroacetate, dichlorobis(triphenylphosphine)palladium, and the molar ratio of o-bromostilbene II to the catalyst is 1:0.01-1:0.5;

[0018] ​The molar ratio of o-bromostilbene II to propargyl alcohol III is 1:1 - 1:3;

[0019] The base is selected from one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium acetate, potassium acetate, cesium acetate, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide ( t BuOLi), and the molar ratio of o-bromostilbene II to the base is 1:0.1 - 1:5;

[0020] The reaction solvent is selected from one or more of N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), benzotrifluoride, acetonitrile, 1,2-dichloroethane, toluene (PhMe), 1,4-dioxane, tetrahydrofuran (THF), and the molar concentration of o-bromostilbene II in the reaction solvent is 0.05 - 1.0 M;

[0021] The reaction atmosphere is one or more of air, oxygen, nitrogen, argon; the reaction time is 0.1 - 48 hours; the reaction temperature is 0 - 130 °C.

[0022] Furthermore, in the above technical solution, the transition metal palladium salt is preferably PdCl 2 .

[0023] Furthermore, in the above technical solution, the base used in the reaction is preferably t BuOLi.

[0024] Furthermore, in the above technical solution, the reaction is preferably carried out in a nitrogen atmosphere.

[0025] Furthermore, in the above technical solution, the optimal reaction time for the reaction of o-bromostilbene II with propargyl alcohol III to form I is 1 - 4 hours.

[0026] Furthermore, in the above technical solution, the optimal reaction temperature is 40 - 80 °C.

[0027] Furthermore, in the above technical solution, the reaction is preferably carried out in the aprotic polar solvent dimethyl sulfoxide.

[0028] Furthermore, in the above technical solution, the preferred molar ratio of o-bromostilbene II to propargyl alcohol III is 1:2.0.

[0029] Furthermore, in the above technical solution, the preferred molar ratio of o-bromostilbene II to the catalyst (palladium salt) is 1:0.1.

[0030] Furthermore, in the above technical solution, the preferred molar ratio of o-bromostilbene II to the base is 1:1 - 1:4, and more preferably 1:2.0.

[0031] The present invention uses o-bromostilbene and propargyl alcohol as starting materials, a transition metal palladium salt as a catalyst, and under alkaline conditions, through a 1,4-palladium migration, β-carbon cleavage, and reductive elimination process, to generate 1,1,4-triaryl-1,3-enyne derivatives in one step. Compared with the reported methods for synthesizing 1,1,4-triaryl-1,3-enyne derivatives, the present invention only requires one-step reaction, the raw materials are easily available, the operation is simple, the reaction conditions are mild, the synthetic reaction efficiency is high, the yield is 31%-92%, preferably 50%-92%, and the product has good functional group diversity. The 1,1,4-triaryl-1,3-enyne synthesized by the present invention contains conjugated olefin and alkyne units, has rich reactivity, and is an important synthetic building block in organic synthesis. Due to its own structural characteristics, it can not only undergo 1,2, 3,4, and 1,4 functionalization reactions on the double bond and triple bond respectively, but also show its unique advantages in the construction of carbon heterocyclic skeletons.

[0032] The present invention has the following advantages:

[0033] 1) The synthons o-bromostilbene II and propargyl alcohol III have structural diversity and can be used to synthesize different types and structures of 1,1,4-triaryl-1,3-enyne derivatives I.

[0034] 2) The synthon propargyl alcohol III can be prepared from alkyne and acetone in one step and is easy to synthesize.

[0035] 3) The synthesis reaction of 1,1,4-triaryl-1,3-enyne derivative I uses PdCl 2 as a catalyst.

[0036] 4) The synthesis reaction of 1,1,4-triaryl-1,3-enyne derivative I only needs to construct the 1,1,4-triaryl-1,3-enyne skeleton in one step, and the product yield is high, up to 92%.

[0037] 5) The synthesis reaction conditions of 1,1,4-triaryl-1,3-enyne derivative I are relatively mild, and the temperature range is 40-80 °C.

[0038] 6) The product of 1,1,4-triaryl-1,3-enyne derivative I has functional group diversity and has wide application.

[0039] In summary, the present invention utilizes the structural diversity and multi-reaction centers of o-bromostilbene II and propargyl alcohol III to efficiently synthesize different types and structures of 1,1,4-triaryl-1,3-enyne derivatives I. The raw materials are cheap and easily available, only one-step reaction is required, a series of 1,1,4-triaryl-1,3-enyne derivative structures can be obtained efficiently, the operation is simple, the conditions are mild, and the yield of the target product is high. Specific Embodiments

[0040] Under nitrogen, in a tetrahydrofuran solvent, o-bromobenzophenone A reacts with methyltriphenylphosphonium bromide B to form o-bromostilbene II. In formula A, R 1 and R 2 are defined the same as in formula II.

[0041]

[0042] The specific process is as follows: Add methyltriphenylphosphonium bromide B (10.0 mmol) and potassium tert-butoxide (16.5 mmol) into a reaction flask, add 10 mL of tetrahydrofuran under nitrogen, and slowly dropwise add a tetrahydrofuran solution (1 M) of o-bromobenzophenone A (2.0 mmol) at room temperature. Stir the reaction overnight at room temperature. Quench with saturated ammonium chloride solution, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, remove the volatile components under reduced pressure, and then separate by silica gel column chromatography (the eluent is petroleum ether (60 - 90 °C) / ethyl acetate, v / v = 50:1) to obtain the target product II. The target product is confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0043] The raw materials 2a, 2b, and 2c in the following examples were prepared by the following literature methods:

[0044] J. Lin, J. Ma, L. D. Wang, K. K. Wu, Y.-G. Zhou, and Z. K. Yu, Org. Chem. Front. 2023, 10, 5144 - 5150.

[0045] The raw materials 3a and 3b in the following examples were prepared by the following literature methods:

[0046] X. Chen, M. K. Li, Z. P. Liu, C. Yang, H. S. Xie, X. W. Hu, S.-J. Su, H. F. Jiang, and W. Zeng, Org. Lett. 2021, 23, 6724 - 6728.

[0047] The following examples help to further understand the present invention, but the content of the present invention is not limited thereto.

[0048] Example 1

[0049]

[0050] In a glove box, sequentially weigh PdCl 2 (0.03 mmol), t BuOLi (0.6 mmol), propargyl alcohol 3a (0.6 mmol), N 21-Bromo-2-(1-(4-fluorophenyl)vinyl)benzene 2a (0.3 mmol) was added, followed by 3 mL of dimethyl sulfoxide, and the mixture was reacted in an oil bath at 60 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature and then separated by silica gel column chromatography (the eluent was petroleum ether (60-90 °C) / dichloromethane, v / v = 10:1) to obtain the white solid target product 1a (77.0 mg, yield 86%). The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0051] Compound characterization data

[0052] (E)-1-(4-Fluorophenyl)-1,4-diphenyl-1-buten-3-yne (1a), white solid, M.P.: 94-95 °C. 1 HNMR(400MHz,CDCl 3 )δ7.67 - 7.57(m,2H),7.55 - 7.28(m,10H),7.08(t,J = 8.7Hz,2H),6.26(s,1H). 13 C{ 1 H}NMR(100MHz,CDCl 3 )δ163.0(d,J = 246.9Hz),151.6,139.1,137.6(d,J = 3.4Hz),131.5,130.2,129.8(d,J = 8.1Hz),128.43,128.37,128.2,128.0,123.7,115.4(d,J = 21.5Hz),107.1(d,J = 1.1Hz),93.8,and 89.2. 19 F{ 1 H}NMR(376MHz,CDCl 3 )δ - 113.34.HRMS Calcd for C 22 H 16 F[M + H] + :299.1231,found:299.1232.

[0053] Example 2

[0054]

[0055] In the glove box, PdCl 2 (0.03 mmol), t BuOLi(0.6 mmol), propargyl alcohol 3a(0.6 mmol), N 21-(1-phenylethenyl)-4-fluoro-2-bromobenzene 2b (0.3 mmol) was added, along with 3 mL of dimethyl sulfoxide, and the mixture was reacted in an oil bath at 60 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature and then separated by silica gel column chromatography (the eluent was petroleum ether (60 - 90 °C) / dichloromethane, v / v = 15:1) to obtain the white solid target product 1b (59.1 mg, yield 66%). The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0056] Compound characterization data

[0057] (Z)-1-(4-fluorophenyl)-1,4-diphenyl-1-buten-3-yne (1b), white solid, M.P.: 109 - 110 °C. 1 H NMR (400 MHz, CDCl 3 ) δ 7.60 - 7.51 (m, 2H), 7.39 - 7.27 (m, 10H), 7.17 - 7.08 (m, 2H), 6.25 (s, 1H). 13 C{ 1 H}NMR (100 MHz, CDCl 3 ) δ 162.7 (d, J = 246.2 Hz), 151.7, 141.4, 135.4 (d, J = 3.1 Hz), 132.2 (d, J = 8.1 Hz), 131.5, 128.6, 128.53, 128.46, 128.3, 128.1, 123.6, 114.9 (d, J = 21.5 Hz), 107.4, 94.0, and 89.1. 19 F{ 1 H}NMR (376 MHz, CDCl 3 ) δ -113.18. HRMS Calcd for C 21 H 16 F[M + H] + : 299.1231, found: 299.1234.

[0058] Example 3

[0059]

[0060] In the glove box, PdCl 2 (0.03 mmol), t BuOLi (0.6 mmol), propargyl alcohol 3b (0.6 mmol), N 21-(1-phenylethenyl)-2-bromobenzene 2c (0.3 mmol) was added thereto, and 3 mL of dimethyl sulfoxide was added. The mixture was placed in an oil bath at 60 °C and reacted for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, and then separated by silica gel column chromatography (the eluent was petroleum ether (60-90 °C) / dichloromethane, v / v = 10:1) to obtain the white solid target product 1c (82.1 mg, yield 75%). The target product was confirmed by nuclear magnetic resonance spectroscopy and high resolution mass spectrometry.

[0061] Compound characterization data

[0062] 1,1-Diphenyl-4-(4-trifluoromethoxyphenyl)-1-buten-3-yne (1c), white solid, M.P.: 68-69 °C. 1 H NMR (400 MHz, CDCl 3 ) δ 7.62-7.54 (m, 2H), 7.51-7.42 (m, 3H), 7.38 (s, 5H), 7.35-7.29 (m, 2H), 7.19-7.12 (m, 2H), 6.28 (s, 1H). 13 C{ 1 H}NMR (100 MHz, CDCl 3 ) δ 153.6, 148.8 (d, J = 1.6 Hz), 141.3, 139.3, 132.9, 130.3, 128.6, 128.5, 128.4, 128.2, 128.0, 122.6, 120.9, 120.5 (d, J = 256.1 Hz), 106.8, 92.24, and 90.20. 19 F{ 1 H}NMR (376 MHz, CDCl 3 ) δ -57.74. HRMS Calcd for C 23 H 16 F 3 O [M+H] + : 365.1148, found: 365.1152.

[0063] Example 4

[0064] The reaction procedure and operation were the same as those in Example 1. The difference from Example 1 was that the molar ratio of 2a to PdCl 2 was 1:0.05. The reaction was stopped, and the target product 1a (58 mg, yield 65%) was obtained after post-treatment.

[0065] Example 5

[0066] The reaction steps and operations are the same as those in Example 1. The difference from Example 1 is that DMSO is replaced by THF. The reaction is stopped, and after post-treatment, the target product 1a (54 mg, yield 60%) is obtained.

[0067] Example 6

[0068] The reaction steps and operations are the same as those in Example 1. The difference from Example 1 is that DMSO is replaced by PhMe. The reaction is stopped, and after post-treatment, the target product 1a (42 mg, yield 47%) is obtained.

[0069] Example 7

[0070] The reaction steps and operations are the same as those in Example 1. The difference from Example 1 is that PdCl 2 is replaced by Pd(PPh 3 ) 4 . The reaction is stopped, and after post-treatment, the target product 1a (37 mg, yield 41%) is obtained.

[0071] Example 8

[0072] The reaction steps and operations are the same as those in Example 1. The difference from Example 1 is that PdCl 2 is replaced by Pd(OAc) 2 . The reaction is stopped, and after post-treatment, the target product 1a (28 mg, yield 31%) is obtained.

[0073] Example 9

[0074] The reaction steps and operations are the same as those in Example 1. The difference from Example 1 is that N 2 is replaced by O 2 . The reaction is stopped, and after post-treatment, the target product 1a (31 mg, yield 35%) is obtained.

[0075] Example 10

[0076] The reaction steps and operations are the same as those in Example 1. The difference from Example 1 is that N 2 is replaced by air. The reaction is stopped, and after post-treatment, the target product 1a (38 mg, yield 43%) is obtained.

[0077] Example 11

[0078] The reaction steps and operations are the same as those in Example 1. The difference from Example 1 is that 60 °C is changed to 40 °C. The reaction is stopped, and after post-treatment, the target product 1a (54 mg, yield 60%) is obtained.

[0079] The raw materials of the method of the present invention are easily available, the operation is simple, the synthesis reaction conditions are mild, the reaction efficiency is high, and its functional groups have diversity.

Claims

1. A 1,1,4-triaryl-1,3-enyne derivative, whose molecular structural formula Ⅰ is as follows: R 1 ,R 2 ,R 3 are each independently selected from hydrogen, methyl, ethyl, tert-butyl, phenyl, methoxy, phenoxy, benzyloxy, trifluoromethyl, trifluoromethoxy, fluorine, chlorine, cyano, methoxycarbonyl, and the number of substituents is 1 to 5.

2. The synthesis method of the 1,1,4-triaryl-1,3-enyne derivative according to claim 1, characterized in that: Using o-bromostilbene II as the starting material, a transition metal palladium salt as the catalyst, under alkaline conditions, reacting with propargyl alcohol III in a solvent to directly generate the 1,1,4-triaryl-1,3-enyne derivative I; The molecular structural formula of o-bromostilbene II is as follows: R 1 , R 2 is defined in the same way as in claim 1; The molecular structural formula of propargyl alcohol III is as follows: R 3 is defined in the same way as in claim 1; The synthesis route is shown in the following reaction formula:

3. According to the synthesis method described in claim 2, characterized in that: The transition metal palladium salt is selected from one or more of palladium chloride, palladium bromide, palladium acetate, tetraphenylphosphine palladium, palladium trifluoroacetate, and bis(triphenylphosphine) dichloropalladium. The molar ratio of o-bromostilbene II to the catalyst is 1:0.01 - 1:0.5; The molar ratio of o-bromostilbene II to propargyl alcohol III is 1:1 - 1:3; The base is selected from one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium acetate, potassium acetate, cesium acetate, potassium tert-butoxide, and lithium tert-butoxide. The molar ratio of o-bromostilbene II to the base is 1:0.1 - 1:5; The reaction solvent is selected from one or more mixtures of N,N-dimethylformamide, dimethyl sulfoxide, benzotrifluoride, acetonitrile, toluene, 1,4-dioxane, and tetrahydrofuran. The molar concentration of o-bromostilbene II in the reaction solvent is 0.05 - 1.0 M; The reaction atmosphere is one or more of air, oxygen, nitrogen, and argon; the reaction time is 0.1 - 48 hours; the reaction temperature is 0 - 130 °C.

4. According to the synthesis method described in claim 3, characterized in that: The molar ratio of o-bromostilbene II to the catalyst is 1:0.

1.

5. According to the synthesis method described in claim 3, characterized in that: The molar ratio of o-bromostilbene II to propargyl alcohol III is 1:2.

0.

6. According to the synthesis method described in claim 3, characterized in that: The molar ratio of o-bromostilbene II to the base is 1:1 - 1:

4.

7. According to the synthesis method described in claim 3, characterized in that: The reaction time is 1 - 4 hours.

8. According to the synthesis method described in claim 3, characterized in that: The reaction temperature is 40 - 80 °C.

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