A method for synthesizing a polysubstituted 1,3-butadiene compound

Abstract

The application discloses a kind of belonging to the field of organic synthesis, it is related to a kind of synthesis method of polysubstituted 1,3-butadiene compound.The polysubstituted 1,3-butadiene compound structural formula is as shown in formula I.The method involves decarboxylation hydrogen transfer under nitrogen protection, in the presence of tetra-triphenylphosphine palladium, phenol and R-BINAP, the GMDVs compound shown in formula (II).The method used in the application has the following advantages compared with traditional methods:1) high yield, good atom economy, excellent stereoselectivity;2) substrate has good universality, can be diversified synthesis to polysubstituted 1,3-butadiene compound;3) low catalyst consumption, raw material does not need complex pre-functionalization process, post-treatment is convenient and product is easy to separate and purify, easy to mass production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and mainly relates to a method for synthesizing polysubstituted 1,3-butadiene compounds. Background Technology

[0002] Polysubstituted 1,3-butadiene compounds are widely found in natural products and bioactive molecules closely related to human health, such as Vitamin A, JBIR-23 / 24, and Trichostatin A. Furthermore, polysubstituted 1,3-butadiene compounds are commonly used building blocks in the synthesis of adiponitrile, a key intermediate in waterproof coatings and nylon products. Some important chemical transformations, such as cycloaddition or polyfunctionalization processes, often choose 1,3-butadiene as a starting substrate.

[0003] Traditional methods for synthesizing polysubstituted 1,3-butadienes include elimination reactions and Wittig olefin synthesis. However, neither of these transformations effectively controls the Z / E configuration of the double bonds, requiring subsequent separation to obtain a single-selective product. In recent years, chemists have developed a series of stereoselective synthetic methods, including hydrocarbon activation, cross-coupling, and alkene-yyn metathesis reactions. However, these often require pre-functionalization of the starting materials and suffer from poor atom economy. Given the importance of polysubstituted 1,3-butadienes in chemical synthesis, biological research, and industrial applications, developing a highly efficient, stereoselective, and atom-economical strategy is crucial. Summary of the Invention

[0004] The purpose of this invention is to overcome the limitations of substrates and low atom economy in existing methods for synthesizing polysubstituted 1,3-butadiene compounds, and to provide an efficient and diversified method for synthesizing polysubstituted 1,3-butadiene compounds with readily available substrates and atom economy.

[0005] To achieve the above objectives, the present invention provides a method for preparing polysubstituted 1,3-butadiene compounds represented by formula (I), the method comprising: under nitrogen protection, in the presence of tetraphenylphosphine palladium, phenols and R-BINAP, performing decarboxylation hydrogen transfer of GMDVs compounds represented by formula (II).

[0006]

[0007] Among them, R 1 It is one of methyl, ethyl, and tert-butyl; R 2 It is one of methyl, benzyl, naphthyl, thiophene, and substituted or unsubstituted phenyl; the substituent is one of a halogen atom, methyl, methoxy, or phenyl, located at the 2, 3, or 4 positions of the benzene ring.

[0008] Preferably, the phenol is one of phenol, p-nitrophenol, p-methoxyphenol, p-methylphenol, and o-methylphenol.

[0009] Preferably, relative to 100 moles of the GMDVs compounds, the amount of tetraphenylphosphine palladium is 1-10 moles, the amount of phenol is 50-150 moles, and the amount of R-BINAP is 1-10 moles.

[0010] Preferably, the decarboxylation hydrogen transfer reaction of the GMDVs compounds is carried out at a temperature of 90-110°C with stirring for 12-24 hours.

[0011] Preferably, column chromatography is performed after the reaction using a mixed solvent of petroleum ether and ethyl acetate.

[0012] The method for preparing polysubstituted 1,3-butadiene compounds described in this invention has the following significant advantages compared with previous reports:

[0013] (1) High yield, good atom economy, and excellent stereoselectivity;

[0014] (2) The substrates have good versatility and can be used to synthesize a variety of polysubstituted 1,3-butadiene compounds.

[0015] (3) The catalyst dosage is low, the raw materials do not require a complex prefunctionalization process, the post-processing is convenient, and the products are easy to separate and purify, making it easy to produce on a large scale. Attached Figure Description

[0016] Figure 1 The NMR spectrum of compound 2a prepared in Example 1;

[0017] Figure 2 The NMR spectrum of compound 2b prepared in Example 2;

[0018] Figure 3 The NMR spectrum of compound 2c prepared in Example 3;

[0019] Figure 4 The NMR spectrum of compound 2d prepared in Example 4;

[0020] Figure 5 The NMR spectrum of compound 2e prepared in Example 5;

[0021] Figure 6 The NMR spectrum of compound 2f prepared in Example 6;

[0022] Figure 7 The NMR spectrum of 2g of the compound prepared in Example 7;

[0023] Figure 8 The NMR spectrum of the compound prepared in Example 8 at 2h; Detailed Implementation

[0024] The method of the present invention is described in this article through specific embodiments, but the present invention is not limited thereto. Any modifications, equivalent substitutions and improvements made within the scope of the technical concept of the present invention should be included within the protection scope of the present invention.

[0025] The method for synthesizing polysubstituted 1,3-butadiene compounds according to the present invention includes: under nitrogen protection, in the presence of tetrakis(triphenylphosphine)palladium, phenols and R-BINAP, performing decarboxylation hydrogen transfer of GMDVs compounds.

[0026] In this invention, the structure of the GMDVs-type compounds is shown in formula (II).

[0027]

[0028] In equation (II), R 1 It is one of methyl, ethyl, and tert-butyl; R 2 It is one of methyl, benzyl, naphthyl, thiophene, and substituted or unsubstituted phenyl; the substituent is one of a halogen atom, methyl, methoxy, or phenyl, located at the 2, 3, or 4 positions of the benzene ring.

[0029] In the method described in this invention, relative to 100 moles of the GMDVs compound, the amount of tetraphenylphosphine palladium is 1-10 moles, more preferably 1-5 moles, and most preferably 5 moles; the amount of phenol is 50-150 moles, more preferably 50-100 moles, and most preferably 100 moles; and the amount of R-BINAP is 1-10 moles, more preferably 1-5 moles, and most preferably 5 moles.

[0030] In the method described in this invention, the phenol used is one of phenol, p-nitrophenol, p-methoxyphenol, p-methylphenol, and o-methylphenol.

[0031] In the method described in this invention, preferably, the decarboxylation hydrogen transfer reaction of the GMDVs compounds is carried out at a temperature of 90-110°C with stirring for 12-24 hours.

[0032] In the method described in this invention, in order to obtain a pure target product, the method preferably further includes: performing column chromatography with a mixed solution of petroleum ether and ethyl acetate after the reaction; in the mixed solvent of petroleum ether and ethyl acetate, the volume ratio of petroleum ether to ethyl acetate can be 30-80:1, preferably 40-60:1, and most preferably 50:1.

[0033] In one specific embodiment, the method for synthesizing polysubstituted 1,3-butadiene compounds includes:

[0034] (1) Under nitrogen protection, tetraphenylphosphine palladium was added to the reactor at a rate of 1-10 mol% of GMDVs;

[0035] (2) Under nitrogen protection, R-BINAP was added to the reactor of (1) at a rate of 1-10 mol% of GMDVs.

[0036] (3) Under nitrogen protection, phenols are added to the reactor of (1) at a rate of 50-150 mol% of GMDVs;

[0037] (4) Under nitrogen protection, GMDVs are added to the reactor in (1);

[0038] (5) Under nitrogen protection, the reaction solvent is added to the reactor of (1), wherein the solvent is one of diethyl ether, tetrahydrofuran, methyl tert-butyl ether, and 1,4-dioxane;

[0039] (6) Under nitrogen protection, the target product is purified after stirring the reaction at a temperature of 90-110°C for 12-24 hours.

[0040] The present invention will be further described in detail below through embodiments:

[0041] Example 1

[0042] The reaction equation is as follows:

[0043]

[0044] Under nitrogen protection, tetrakis(triphenylphosphine)palladium (2.5 mmol), R-BINAP (2.5 mmol), p-nitrophenol (50 mmol), and compound 1a (50 mmol) were added to a reactor, followed by the addition of 500 mL of diethyl ether. The reaction was stirred at 100 °C for 18 hours until completion. Column chromatography with a mixed solvent of petroleum ether and ethyl acetate (50:1 v / v) yielded pure 2a. The yield of 2a was 90%, with an E / Z ratio of 50:1.

[0045] 2a 1 The H NMR data are as follows: 1 H NMR (500MHz, CDCl3): δ7.52(s,1H),7.24(t,J=7.5Hz,1H),7.16(dd,J=16.6,7.9Hz,2H),7 .06(d,J=7.4Hz,1H),5.25(s,1H),5.19(s,1H),3.72(s,3H),2.17(s,3H),1.31(s,3H)ppm.

[0046] 2a 13 The C NMR data are as follows: 13 C NMR (125MHz, CDCl3): δ168.42,142.96,141.11,136.86,135.73,131.02,130.09,129.52,127.95,125.24,125.21,52.29,20.59,19.81ppm.

[0047] Example 2

[0048] The reaction equation is as follows:

[0049]

[0050] Under nitrogen protection, tetra(triphenylphosphine)palladium (2.5 mmol), R-BINAP (2.5 mmol), phenol (50 mmol), and compound 1b (50 mmol) were added to a reactor, followed by 500 mL of tetrahydrofuran. The reaction was carried out by stirring at 100 °C for 18 hours until completion. Column chromatography with a mixed solvent of petroleum ether and ethyl acetate (50:1 v / v) yielded pure 2b. The yield of 2b was 76%, with an E / Z ratio of 7:1.

[0051] 2b 1 The H NMR data are as follows: 1 H NMR (500MHz, CDCl3): δ7.49(s,1H),7.36(d,J=6.5Hz,0.28H),7.28(dd,J=20.0,11.7Hz,2H),7.19(s,1H),7.12(d,J=6.5Hz,0.28H),7.08(d,J=7.3 Hz,1H),6.53(s,0.14H),5.27(s,1H),5.23(s,1H),5.20(s,0.14H),5.17( s,0.14H),3.83(s,0.42H),3.74(s,3H),1.92(s,0.42H),1.40(s,3H)ppm.

[0052] 2b 13 The C NMR data are as follows: 13 C NMR (125MHz, CDCl3): δ167.95,143.54,140.50,137.81,133.61,130.36,130.12,128.94,128.33,127.82,125.73,52.37,21.30ppm.

[0053] Example 3

[0054] The reaction equation is as follows:

[0055]

[0056] Under nitrogen protection, tetrakis(triphenylphosphine)palladium (2.5 mmol), R-BINAP (2.5 mmol), p-methoxyphenol (50 mmol), and compound 1c (50 mmol) were added to a reactor, followed by 500 mL of 1,4-dioxane. The reaction was stirred at 100 °C for 18 hours until completion. Column chromatography with a 50:1 volume ratio of petroleum ether and ethyl acetate yielded pure 2c. The yield of 2c was 98%, with an E / Z ratio of 4:1.

[0057] 2c 1 The H NMR data are as follows: 1 H NMR (500MHz, CDCl3): δ7.46(s,1H),7.30(d,J=8.6Hz,0.46H),7.11(d,J=8.4Hz,2H),6.87(d,J=8.4Hz,2.46H),6.46(s,0.23H),5.2 5(s,1H),5.19(s,1H),5.15(s,0.23H),5.10(s,0.23H),3.82(s,3H),3.81(s,1.38H),3.74(s,3H),1.92(s,0.69H),1.41(s,3H)ppm.

[0058] 2c 13 The C NMR data are as follows: 13 C NMR (125MHz, CDCl3): δ167.78,158.14,141.68,140.14,130.48,130.30,130.20, 127.12,126.40,123.61,118.65,113.11,112.19,54.17,51.23,20.23,19.11ppm.

[0059] Example 4

[0060] The reaction equation is as follows:

[0061]

[0062] Under nitrogen protection, tetrakis(triphenylphosphine)palladium (2.5 mmol), R-BINAP (2.5 mmol), p-methylphenol (50 mmol), and compound 1d (50 mmol) were added to a reactor, followed by the addition of 500 mL of methyl tert-butyl ether. The reaction was stirred at 100 °C for 18 hours until completion. Column chromatography with a mixed solvent of petroleum ether and ethyl acetate (50:1 v / v) yielded pure 2d. The yield of 2d was 70%, with an E / Z ratio of 10:1.

[0063] 2D 1 The H NMR data are as follows: 1 H NMR (500MHz, CDCl3): δ7.56(d,J=7.5Hz,2H),7.50(d,J=8.1Hz,2.2H),7.44(s,1H),7.37(t,J=7.6Hz,2.5H),7.28(d,J=7.4Hz,1H),7.21 -7.18(m,2.2H),6.54(s,0.1H),5.21(s,1H),5.14(s,1.1H),5.09(s,0.1H),3.79(s,0.3H),3.69(s,3H),1.88(s,0.3H),1.37(s,3H)ppm.

[0064] 2D 13 The C NMR data are as follows: 13 C NMR (125MHz, CDCl3): δ168.53,143.01,140.98,140.69,140.42,135.00,1 31.51,130.51,128.76,127.36,127.06,126.37,125.00,52.32,21.33ppm.

[0065] Example 5

[0066] The reaction equation is as follows:

[0067]

[0068] Under nitrogen protection, tetrakis(triphenylphosphine)palladium (2.5 mmol), R-BINAP (2.5 mmol), o-methylphenol (50 mmol), and compound 1e (50 mmol) were added to a reactor, followed by the addition of 500 mL of diethyl ether. The reaction was stirred at 100 °C for 18 hours until completion. Column chromatography with a mixed solvent of petroleum ether and ethyl acetate (50:1 v / v) yielded pure 2e. The yield of 2e was 99%, with an E / Z ratio of 3:1.

[0069] 2e 1 The H NMR data are as follows: 1H NMR (500MHz, CDCl3): δ7.48(s,1H),7.29–7.27(m,1H),7.20-7.17(m,0.53 H),7.15(d,J=5.1Hz,0.23H),7.11(s,1H),6.98(d,J=4.7Hz,1H),6.94(d,J =5.1Hz,0.23H),6.57(s,0.33H),5.27(s,1H),5.22(s,1H),5.16(s,0.33H ),5.12(s,0.33H),3.84(s,1H),3.75(s,3H),1.91(s,1H),1.47(s,3H)ppm.

[0070] 2e 13 The C NMR data are as follows: 13 C NMR (125MHz, CDCl3): δ169.81,168.24,143.71,141.00,140.60,138.04,135.35,133.48,131.64,129.59,129.20,128.50,127.41, 127.17,126.69,126.52,126.24,125.13,124.92,124.74,124.46,122.57,121.87,120.09,117.01,52.28,52.13,20.58,20.05ppm.

[0071] Example 6

[0072] The reaction equation is as follows:

[0073]

[0074] Under nitrogen protection, tetrakis(triphenylphosphine)palladium (2.5 mmol), R-BINAP (2.5 mmol), p-nitrophenol (50 mmol), and compound 1f (50 mmol) were added to a reactor, followed by the addition of 500 mL of diethyl ether. The reaction was stirred at 100 °C for 18 hours until completion. Column chromatography with a 50:1 volume ratio of petroleum ether and ethyl acetate yielded pure 2f. The yield of 2f was 76%, with an E / Z ratio of 50:1.

[0075] 2f 1 The H NMR data are as follows: 1H NMR (500MHz, DMSO-d6): δ7.86(dd,J=12.3,5.1Hz,2H),7.76(s,1H),7.72(d,J=8.7Hz,1H),7.5 0-7.43(m,3H),7.30(d,J=6.9Hz,1H),5.31(s,1H),5.16(s,1H),3.66(s,3H),1.13(s,3H)ppm.

[0076] 2f 13 The C NMR data are as follows: 13 C NMR (125MHz, CDCl3): δ167.73,143.48,140.13,132.76,132.16,131.74,128.7 3,127.29,127.18,126.73,125.26,124.78,124.45,123.94,51.32,19.39ppm.

[0077] Example 7

[0078] The reaction equation is as follows:

[0079]

[0080] Under nitrogen protection, tetrakis(triphenylphosphine)palladium (2.5 mmol), R-BINAP (2.5 mmol), p-nitrophenol (50 mmol), and 1 g (50 mmol) of the compound were added to a reactor, followed by the addition of 500 mL of diethyl ether. The reaction was stirred at 100 °C for 18 hours until completion. Column chromatography with a mixed solvent of petroleum ether and ethyl acetate (50:1 v / v) yielded 2 g of pure compound. The yield of 2 g was 96%, with an E / Z ratio of 13:1.

[0081] 2g 1 The H NMR data are as follows: 1 C NMR (500MHz, CDCl3): δ7.34(s,1H),7.29-7.24(m,2.24H),7.16(dd,J=13.7,7.3Hz,3.16H),6.08(s,0.08H),5.19-5.16(m,1H),5.12(s, 1H),4.99(s,0.08H),4.95(s,0.08H),3.90(s,2H),3.80(s,0.16H),3.70-3.67(m,3H),3.63(s,0.24H),1.95(s,3H),1.83(s,0.24H)ppm.

[0082] 2g 13 The C NMR data are as follows:13 C NMR (125MHz, CDCl3): δ166.75,165.28,139.34,139.22,134.58,131.83,129.68,128.11,126.60 ,125.92,125.54,125.35,124.18,122.13,117.46,80.13,78.91,26.12,26.04,19.38,18.86ppm.

[0083] Example 8

[0084] The reaction equation is as follows:

[0085]

[0086] Under nitrogen protection, tetrakis(triphenylphosphine)palladium (2.5 mmol), R-BINAP (2.5 mmol), p-nitrophenol (50 mmol), and compound 1h (50 mmol) were added to a reactor, followed by the addition of 500 mL of diethyl ether. The reaction was carried out by stirring at 100 °C for 18 hours until completion. Column chromatography with a mixed solvent of petroleum ether and ethyl acetate (50:1 v / v) yielded pure 2h. The yield of 2h was 89%, with an E / Z ratio of 4:1.

[0087] 2 hours 1 The H NMR data are as follows: 1 H NMR (500MHz, CDCl3): δ7.40(d,J=7.6Hz,0.6H),7.36(s,1H),7.33(d,J=7.8Hz,0.8H),7.30(d,J=7.1Hz,3H),7.18(dd,J=7.3,1.4Hz,2H),6 .43(s,0.28H),5.21(s,1H),5.17(s,1H),5.15(s,0.28H),5.10(s,0.28H),2.00(s,0.84H),1.54(s,2.52H),1.46(s,9H),1.38(s,3H)ppm.

[0088] 2 hours 13 The C NMR data are as follows: 13 C NMR (125MHz, CDCl3): δ167.70,141.48,139.39,138.94,128.76,127.36,126.89,124.90,118.95,50.97,31.89,21.52ppm.

[0089] As can be seen from the above examples, the method for synthesizing polysubstituted 1,3-butadiene compounds according to the present invention can efficiently and stereoselectively obtain a variety of target products.

Claims

1. A method for synthesizing a polysubstituted 1,3-butadiene compound of Formula I, the method comprising: Under nitrogen protection, in tetraphenylphosphine palladium, phenols, R In the presence of BINAP and solvent, the decarboxylation hydrogen transfer of the GMDVs-type compounds shown in formula (II) is performed. ， Among them, R 1 It is one of methyl, ethyl, and tert-butyl; R 2 It is one of methyl, benzyl, naphthyl, thiophene, and substituted or unsubstituted phenyl groups, wherein the substituent is one of a halogen atom, methyl, methoxy, or phenyl, located at the 2, 3, or 4 positions of the benzene ring; the phenol is one of phenol, p-nitrophenol, p-methoxyphenol, p-methylphenol, and o-methylphenol.

2. The synthesis method according to claim 1, wherein, The amount of tetraphenylphosphine palladium used is 1-10 moles relative to 100 moles of the GMDVs compounds, and the amount of phenols is 50-150 moles. The dosage of R-BINAP is 1-10 moles.

3. The synthesis method according to claim 1, wherein, The decarboxylation hydrogen transfer reaction of the GMDVs compounds was carried out at a temperature of 90-110 °C with stirring for 12-24 hours.

4. The synthesis method according to claim 1, wherein, After the reaction, column chromatography was performed using a mixed solvent of petroleum ether and ethyl acetate.

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