Preparation method and application of enol compound

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method and application of an enol compound, and the preparation method is wide in applicability and can also be used for preparing other olefin compounds. The synthetic route provided by the invention has the characteristics of simple flow, simple and easily available raw materials, simple and convenient operation and the like; meanwhile, the catalyst is small in dosage, low in cost, easy to obtain and high in yield and has a good application prospect.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing enol compounds and their applications. Background Technology

[0002] Enols are primarily used in the biopharmaceutical field for drug molecule design and the synthesis of active intermediates. Their enol structure is a key group for regulating drug-target binding and enhancing biological activity, and they are widely used in the development of antitumor, antibacterial, and immunomodulatory drugs. Analysis of the structure of (E)-Suberenol reveals that it not only possesses a unique enol structure but can also be further modified to transform into other active natural products. Given that dimethylenols are an important class of potentially bioactive substances, research into their preparation methods is of great significance.

[0003] In 1990, Reisch's team reported the synthesis of Suberenol (Liebigs Ann. Chem. 1990, 9(12): 931-933.; https: / / doi.org / 10.1002 / jlac.1990199001171). Their synthetic route used the simple substrate 4-bromoresorcinol (1) as the starting material, and the relevant steps are as follows:

[0004] 4-Bromoresorcinol (1) first undergoes a condensation reaction with malic acid under the action of concentrated sulfuric acid to generate 6-bromo7-hydroxycoumarin (2); using potassium carbonate as an acid-binding agent, iodomethane is added to 6-bromo7-hydroxycoumarin (2) to carry out the reaction, completing the methylation of the phenolic hydroxyl group to obtain 6-bromo7-methoxycoumarin (3); with the aid of palladium-catalyzed Heck reaction, the C-C bond coupling between 6-bromo7-methoxycoumarin (3) and 2-methyl-3-buten-2-ol (4) is realized, and the synthesis of Suberenol is finally completed.

[0005] However, the above route has obvious shortcomings. The Heck coupling step requires the use of toxic tetrabutylammonium bromide (TBAB). Excessive TBAB not only wastes raw materials but also increases the difficulty of post-reaction processing and purification. At the same time, the phase transfer catalyst wastewater generated during the reaction makes this route difficult to apply to industrial production. The overall reaction process has a final yield of only 34.8%, which is low.

[0006]

[0007] In 1990, Furukawa's team at Meijo University in Japan, referencing Cairns' synthetic route (J. Am. Chem. Soc., 1986, (16): 1264-1266.; https: / / doi.org / 10.1039 / C39860001264), completed the total synthesis of (E)-Suberenol.

[0008] Its synthesis is carried out in two stages:

[0009] The first stage uses 7-methoxycoumarin (6) as the starting material to prepare natural compound (9): 7-methoxycoumarin (6) is cleaved to obtain coumarate (7); coumarate (7) is allylated with the corresponding isopentenyl bromide to generate compound (8); compound (8) is refluxed in N,N-diethylaniline for 2 hours and rearranged by Claisen to obtain compound (9).

[0010] The second stage involves the synthesis of the target product using compound (9): compound (9) was placed in pyridine and treated with a high-pressure mercury lamp for 30 minutes; the reaction system was filtered and dried, and methanol was added to dissolve the product; finally, triphenylphosphine was added and stirred at room temperature for 41 hours to obtain (E)-Suberenol (5).

[0011] This route has obvious shortcomings: the experimental steps are cumbersome, the starting materials are not universally applicable, and the reaction is slow with low yield.

[0012]

[0013] Existing technologies require stringent reaction conditions and involve highly reactive iodides that are difficult to prepare. Furthermore, traditional routes suffer from cumbersome steps, poor starting material versatility, long reaction times, inefficient atom economy, high preparation costs, and low overall yields. Research reports on the efficient synthesis of enols from simple starting materials under mild conditions remain scarce. Summary of the Invention

[0014] To address the shortcomings of existing technologies, this invention discloses a method for preparing enol compounds and its applications. This synthetic method is widely applicable and can also be used to prepare other olefin compounds. The synthetic route described in this patent features a simple process, readily available and simple raw materials, and easy operation; simultaneously, it requires a small amount of catalyst, is inexpensive and readily available, and the derivative yield is also good.

[0015] The technical solution of the present invention is as follows:

[0016] A method for preparing an enol compound includes the following steps:

[0017]

[0018] Compounds a and b undergo a coupling reaction in the presence of a catalyst, a ligand, a base, and a solvent to generate compound I.

[0019] Q is selected from benzene ring, naphthalene ring. The hydrogen atom at Q can optionally be substituted by one or more R atoms, wherein R is selected from hydrogen, methyl, methoxy, tert-butyl, n-pentyl, hydroxyl, amino, CF3CO-, halogen, methoxycarbonyl, nitro, formyl, acetyl, ethoxycarbonyl, TBSO-, etc.

[0020] In some implementations, the catalyst is selected from palladium acetate and the ligand is tri-tert-butylphosphine.

[0021] In some embodiments, the base is selected from triethylamine, tri-n-propylamine, tri-n-butylamine, diisopropylethylamine, or triethanolamine.

[0022] In some embodiments, the solvent is selected from toluene, tetrahydrofuran, 1,2-dichloroethane, or acetonitrile.

[0023] In some implementations, the reaction temperature is between 40°C and 145°C.

[0024] In some implementations, the feed ratio of compound a, compound b, catalyst, ligand and base is 4.5:1:0.08:0.2:1.5.

[0025] In some embodiments, the method for preparing enol compounds includes the following steps:

[0026] 1.0 eq. of compound b, 0.08 eq. of Pd(OAc)2, and 0.2 eq. of P(o-tol)3 were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times to replace the gas in the sealed tube with nitrogen. Then, CH3CN, 1.5 eq. of Et3N, and 4.5 eq. of compound a were added. The tube was sealed and placed in an oil bath at 115°C to start the reaction. During the reaction, TLC was used for monitoring, with PE:EA = 3:1 as the developing solvent. After the reaction was completed, the mixture was brought to room temperature and quenched with saturated NaHCO3 solution. After stirring, the mixture was filtered through a short silica gel column with EA, extracted with EA, washed with water, and washed with saturated NaCl aqueous solution. The organic phases were combined, dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was then loaded onto a silica gel column for chromatography (gradient eluent PE:EA = 3:1). After purification by silica gel column chromatography, compound I was obtained.

[0027] The beneficial effects of this invention: This patent provides an innovative technical solution for the synthesis of enol compounds.

[0028] In terms of synthetic route design, this route uses simple and easy-to-prepare brominated substrates as starting materials. Specifically, it utilizes compounds with different bromine substitutions to couple with 2-methyl-3-buten-2-ol via a Heck reaction under palladium catalysis, ultimately yielding enol compounds in medium to high yields. Among these, the synthesis of dimethylenol compounds in the reaction products enriches the preparation techniques for this type of substance.

[0029] This approach effectively addresses the shortcomings of existing technologies: on the one hand, it avoids the use of highly reactive iodides that are difficult to prepare, thus reducing the difficulty of obtaining raw materials; on the other hand, it overcomes the problems of environmental hazards, complex operation, and low yield in traditional methods, thus balancing environmental protection and practicality.

[0030] From the perspective of technological advantages and application prospects, this synthetic route uses readily available and simple raw materials, involves simple operation steps, and requires small amounts of catalyst that are low in cost and easy to obtain. Furthermore, the derivative yields are generally high. This not only provides a novel approach to the synthesis of enols but also offers practical support for the large-scale production and efficiency improvement of these products. In addition, the prepared dimethylenols possess potential physiological activities, laying the foundation for their subsequent applications in related fields. Detailed Implementation

[0031] The following embodiments are intended to enable those skilled in the art to more fully understand the present invention, but are not intended to limit the invention to the scope of the embodiments described.

[0032] Example

[0033]

[0034] Synthesis of (E)-2-methyl-4-(p-tolyl)but-3-en-2-ol 1-1: Substrate p-bromotoluene 1 (200 mg, 1.17 mmol, 1.0 eq.), Pd(OAc)2 (21 mg, 0.09 mmol, 0.08 eq.), and P(o-tol)3 (71.2 mg, 0.23 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (244 μL, 1.76 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (550 μL, 5.27 mmol, 4.5 eq.) were added. The tube was then sealed and placed in an oil bath at 115 °C to begin the reaction. During the reaction, TLC (developing solvent PE:EA = 3:1) was used for monitoring. After the reaction was completed, the reaction was removed from the oil bath, brought to room temperature, and quenched with 2-3 mL of saturated NaHCO3 solution. After stirring for 5 min, the mixture was filtered through a short silica gel column using EA and extracted with EA. The mixture was washed with water (2 × 10 mL) and the organic phase was washed with saturated NaCl aqueous solution (1 × 5 mL). The organic phases were combined and dried with anhydrous Na2SO4. After filtration, the crude product was concentrated under vacuum and loaded onto a silica gel column for chromatography (gradient eluent PE:EA = 3:1). After purification by silica gel column chromatography, a white solid (188 mg, 91.3%) was obtained.

[0035] 1 H NMR (400MHz, CDCl3) δ7.32–7.23(m,2H),7.10(d,J=7.9Hz,2H),6.53(d,J=16.1Hz,1H),6.29(d,J=16.1Hz,1H),2.32(s,3H),1.40(s,6H). 13 C NMR (100MHz, CDCl3) δ137.28,136.61,134.19,129.37,126.41,71.15,29.96,21.30.

[0036]

[0037] Synthesis of (E)-4-(4-(tert-butyl)phenyl)-2-methylbut-3-en-2-ol 1-2: The substrates 1-bromo-4-tert-butylbenzene 2 (300 mg, 1.41 mmol, 1.0 eq.), Pd(OAc)2 (25 mg, 0.11 mmol, 0.08 eq.), and P(o-tol)3 (86 mg, 0.28 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (240 μL, 2.12 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (663 μL, 6.35 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was then performed. Column chromatography (PE:EA = 10:1) was used to purify and separate a white crystalline solid (300 mg, 97.4%).

[0038] 1 H NMR (400MHz, CDCl3) δ7.32(d,J=1.3Hz,4H),6.56(d,J=16.1Hz,1H),6.32(d,J=16.1Hz,1H),1.41(s,6H),1.31(s,9H). 13 C NMR (100MHz, CDCl3) δ150.59,136.93,134.21,126.21,126.12,125.59,71.17,34.64,31.40,29.99.

[0039]

[0040] Synthesis of (E)-4-(3,5-di-tert-butylphenyl)-2-methylbut-3-en-2-ol 1-3: The substrates 1-bromo-3,5-di-tert-butylphenyl 3 (300 mg, 1.11 mmol, 1.0 eq.), Pd(OAc)2 (20 mg, 0.09 mmol, 0.08 eq.), and P(o-tol)3 (68 mg, 0.22 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (232 μL, 1.67 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (524 μL, 4.5 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was then performed. Purified by column chromatography (PE:EA = 20:1), a white needle-like solid (275 mg, 89.9%) was obtained.

[0041] 1H NMR (400MHz, CDCl3) δ7.32(t,J=1.8Hz,1H),7.24(d,J=1.9Hz,2H),6.61(d,J=16.1Hz,1H),6.36(d,J=16.1Hz,1H),1.44(s,6H),1.33(s,18H). 13 C NMR (100MHz, CDCl3) δ151.04,136.89,136.09,127.40,121.93,120.82,71.26,34.93,31.57,30.04.

[0042]

[0043] Synthesis of (E)-3-(3-hydroxy-3-methylbut-1-en-1-yl)phenol 1-4: Substrate 3-bromophenol 4 (300 mg, 1.73 mmol, 1.0 eq.), Pd(OAc)2 (31 mg, 0.14 mmol, 0.08 eq.), and P(o-tol)3 (106 mg, 0.35 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (362 μL, 2.6 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (816 μL, 7.8 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was then performed. The product was purified by column chromatography (PE:EA = 1:1) to obtain a white solid (276 mg, 89.3%).

[0044] 1 H NMR (400MHz, Acetone-d6) δ7.13 (t, J=7.8Hz, 1H), 6.93–6.87 (m, 2H), 6.72 (ddd, J= 8.1,2.5,1.0Hz,1H),6.55(d,J=16.1Hz,1H),6.39(d,J=16.0Hz,1H),1.36(s,6H). 13 C NMR (100MHz, Acetone-d6) δ206.65,158.33,139.75,139.19,130.26,126.38,118.54,114.94,113.68,70.68.

[0045]

[0046] Synthesis of (E)-4-(2-aminophenyl)-2-methylbut-3-en-2-ol 1-5: Substrate o-bromoaniline 5 (300 mg, 1.74 mmol, 1.0 eq.), Pd(OAc)2 (31 mg, 0.14 mmol, 0.08 eq.), and P(o-tol)3 (106 mg, 0.35 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (364 μL, 2.62 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (820 μL, 7.85 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was then performed. The product was purified by column chromatography (PE:EA = 1:1) to obtain a bright white solid (286 mg, 92.6%).

[0047] 1 H NMR (400MHz, CDCl3) δ7.28–7.20(m,1H),7.07(td,J=7.7,1.6Hz,1H),6.76(t d,J=7.5,1.1Hz,1H),6.70–6.60(m,2H),6.22(d,J=15.9Hz,1H),1.42(s,6H). 13 C NMR (100MHz, CDCl3) δ143.72,139.55,128.49,127.41,123.40,121.75,119.15,116.25,71.40,30.15.

[0048]

[0049] Synthesis of (E)-4-(2-methoxyphenyl)-2-methylbut-3-en-2-ol 1-6: The substrate 1-bromo-2-methoxyphenyl 6 (300 mg, 1.6 mmol, 1.0 eq.), Pd(OAc)2 (29 mg, 0.13 mmol, 0.08 eq.), and P(o-tol)3 (98 mg, 0.32 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (334 μL, 2.41 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (755 μL, 7.22 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was then performed. The product was purified by column chromatography (PE:EA = 6:1) to obtain a colorless oil (302 mg, 97.9%).

[0050] 1H NMR (400MHz, CDCl3) δ7.43 (dd, J=7.5, 1.7Hz, 1H), 7.21 (ddd, J=8.3, 7.4, 1.7 Hz,1H),6.96–6.82(m,3H),6.36(d,J=16.3Hz,1H),3.83(s,3H),1.43(s,6H). 13 C NMR (100MHz, CDCl3) δ156.75,138.19,128.56,126.72,125.95,121.09,120.71,110.88,71.37,55.48,29.94.

[0051]

[0052] Synthesis of (E)-4-(3,5-dimethoxyphenyl)-2-methylbut-3-en-2-ol 1-7: The substrate 1-bromo-3,5-dimethoxyphenyl 7 (300 mg, 1.38 mmol, 1.0 eq.), Pd(OAc)2 (25 mg, 0.11 mmol, 0.08 eq.), and P(o-tol)3 (84 mg, 0.28 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (288 μL, 2.07 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (650 μL, 6.22 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was then performed. Purified by column chromatography (PE:EA = 6:1), a colorless oily substance (300 mg, 97.7%) was obtained.

[0053] 1 H NMR (400MHz, CDCl3) δ6.57–6.47(m,3H),6.39–6.30(m,2H),3.79(s,6H),1.42(s,6H). 13 C NMR (100MHz, CDCl3) δ160.94,139.08,138.12,126.42,104.52,99.82,71.11,55.40,29.92.

[0054]

[0055] Synthesis of (E)-4-(2-methoxy-5-methylphenyl)-2-methylbut-3-en-2-ol 1-8: The substrate 2-bromo-4-methylanisole 8 (300 mg, 1.51 mmol, 1.0 eq.), Pd(OAc)2 (27 mg, 0.12 mmol, 0.08 eq.), and P(o-tol)3 (92 mg, 0.3 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (314 μL, 2.26 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (709 μL, 6.79 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was then performed. Purified by column chromatography (PE:EA = 13:1), a light yellow solid (294 mg, 95.5%) was obtained.

[0056] 1 H NMR (400MHz, Acetone-d6) δ7.30(d,J=2.2Hz,1H),7.00(dd,J=8.3,2.2Hz,1H),6.92(dt,J=16.3,1.8Hz,1H),6. 82(dd,J=8.3,1.1Hz,1H),6.40(dt,J=16.3,1.2Hz,1H),3.78(d,J=0.9Hz,3H),2.25(s,3H),1.37–1.35(m,6H). 13 C NMR (100MHz, Acetone-d6) δ206.28,155.52,139.39,130.05,129.30,127.49,126.67,120.85,111.68,70.71,55.74,20.54.

[0057]

[0058] Synthesis of (E)-2,2,2-trifluoro-1-(4-(3-hydroxy-3-methylbut-1-en-1-yl)phenyl)ethyl-1-one 1-9: The substrate 4-bromo-2,2,2-trifluoroacetophenone 9 (300 mg, 1.19 mmol, 1.0 eq.), Pd(OAc)2 (21 mg, 0.1 mmol, 0.08 eq.), and P(o-tol)3 (72 mg, 0.24 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (247 μL, 1.78 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (558 μL, 5.34 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was then performed. Purified by column chromatography (PE:EA = 3:1), a colorless oily substance (146 mg, 47.7%) was obtained.

[0059] 1 H NMR (400MHz, CDCl3) δ8.07–7.96(m,2H),7.53(d,J=8.4Hz,2H),6.68(d,J=16.0Hz,1H),6.56(d,J=16.1Hz,1H),1.46(s,6H). 13 C NMR (100MHz, CDCl3) δ144.40,142.44,130.77,130.75,130.72,130.70,128.59,127.00,125.22,71.34,29.94.

[0060]

[0061] Synthesis of (E)-4-(4-chlorophenyl)-2-methylbut-3-en-2-ol 1-10: Substrate p-bromochloro-10 (300 mg, 1.57 mmol, 1.0 eq.), Pd(OAc)2 (28 mg, 0.13 mmol, 0.08 eq.), and P(o-tol)3 (95 mg, 0.31 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (327 μL, 2.35 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (737 μL, 7.05 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was then performed. The product was purified by column chromatography (PE:EA = 10:1) to obtain a white solid (298 mg, 96.8%).

[0062] 1H NMR (400MHz, CDCl3) δ7.27 (d, J = 2.9Hz, 4H), 6.51 (s, 1H), 6.33 (s, 1H), 1.41 (s, 6H). 13 C NMR (100MHz, CDCl3) δ138.22,135.51,133.00,128.75,127.68,125.27,71.11,29.93.

[0063]

[0064] Synthesis of (E)-4-(3-hydroxy-3-methylbut-1-en-1-yl)benzoate 1-11: The substrate methyl 4-bromobenzoate 11 (300 mg, 1.4 mmol, 1.0 eq.), Pd(OAc)2 (25 mg, 0.11 mmol, 0.08 eq.), and P(o-tol)3 (85 mg, 0.28 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (292 μL, 2.1 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (659 μL, 6.3 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was then performed. The mixture was purified by column chromatography (PE:EA = 3:1) to obtain a white solid (96 mg, 31.2%).

[0065] 1 H NMR (400MHz, CDCl3) δ7.97(d,J=8.4Hz,2H),7.41(d,J=8.4Hz,2H),6.60(s,1H),6.46(d,J=16.1Hz,1H),3.90(s,3H),1.44(s,6H). 13 C NMR (100MHz, CDCl3) δ167.39,141.98,140.65,130.32,129.14,126.69,125.92,71.48,52.51,30.22.

[0066]

[0067] Synthesis of (E)-2-methyl-4-(4-nitrophenyl)but-3-en-2-ol 1-12: The substrate 1-bromo-4-nitrobenzene 12 (300 mg, 1.49 mmol, 1.0 eq.), Pd(OAc)2 (27 mg, 0.12 mmol, 0.08 eq.), and P(o-tol)3 (90 mg, 0.3 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (310 μL, 2.23 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (699 μL, 6.68 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was then performed. The product was purified by column chromatography (PE:EA = 4:1) to obtain a white solid (289 mg, 93.9%).

[0068] 1 H NMR (400MHz, CDCl3) δ8.21–8.09(m,2H),7.54–7.45(m,2H),6.68(d,J=16.1Hz,1H),6.54(d,J=16.1Hz,1H),1.46(s,6H). 13 C NMR (100MHz, CDCl3) δ146.74,143.74,142.49,126.97,124.60,124.01,71.20,29.85.

[0069]

[0070] Synthesis of (E)-3-(3-hydroxy-3-methylbut-1-en-1-yl)benzaldehyde 1-13: The substrate 3-bromobenzaldehyde 13 (300 mg, 1.62 mmol, 1.0 eq.), Pd(OAc)2 (29 mg, 0.13 mmol, 0.08 eq.), and P(o-tol)3 (99 mg, 0.32 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (338 μL, 2.43 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (762 μL, 7.29 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was then performed. The product was purified by column chromatography (PE:EA = 4:1) to obtain a pale yellow oil (288 mg, 93.5%).

[0071] 1H NMR(400MHz, CDCl3)δ10.01(s,1H),7.89(t,J=1.8Hz,1H),7.73(d,J=7.6Hz,1H),7.65–7.60 (m,1H),7.48(t,J=7.6Hz,1H),6.66(d,J=16.1Hz,1H),6.47(d,J=16.1Hz,1H),1.45(s,6H). 13 C NMR (100MHz, CDCl3) δ192.57,139.61,138.12,136.73,132.54,129.35,128.83,127.28,125.14,71.15,29.99.

[0072]

[0073] Synthesis of (E)-2-(3-hydroxy-3-methylbut-1-en-1-yl)benzaldehyde 1-14: The substrate o-bromobenzaldehyde 14 (300 mg, 1.62 mmol, 1.0 eq.), Pd(OAc)2 (29 mg, 0.13 mmol, 0.08 eq.), and P(o-tol)3 (99 mg, 0.32 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (338 μL, 2.43 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (762 μL, 7.29 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was then performed. The product was purified by column chromatography (PE:EA = 4:1), yielding a pale yellow oil (269 mg, 87.3%).

[0074] 1 H NMR (400MHz, CDCl3) δ10.29(s,1H),7.82(dd,J=7.7,0.9Hz,1H),7.57–7.52(m,2H),7.46–7.39(m,2H),6.30(s,1H),1.47(s,6H). 13 C NMR (100MHz, CDCl3) δ192.69,143.48,140.19,133.90,133.06,131.53,127.84,127.66,122.89,71.40,29.94.

[0075]

[0076] Synthesis of (E)-4-(3-hydroxy-3-methylbut-1-en-1-yl)-1H-pyrrole-2-carboxaldehyde 1-15: The substrate 4-bromo-1H-pyrrole-2-carboxaldehyde 15 (300 mg, 1.72 mmol, 1.0 eq.), Pd(OAc)2 (31 mg, 0.14 mmol, 0.08 eq.), and P(o-tol)3 (105 mg, 0.35 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (359 μL, 2.59 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (811 μL, 7.76 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was then performed. Purified by column chromatography (PE:EA = 1:1), a light yellow oil (41 mg, 19.7%) was obtained.

[0077] 1 H NMR (400MHz, CDCl3) δ10.02(s,1H),9.47(d,J=1.1Hz,1H),7.07(dt,J=40.0,1.8Hz,2H),6.45(d,J=16.1Hz,1H),6.14(d,J=16.1Hz,1H),1.40(s,6H). 13 C NMR (100MHz, CDCl3) δ179.67,135.91,133.22,124.88,118.36,118.08,71.09,60.58,29.98.

[0078]

[0079] Synthesis of (E)-4-(1H-indol-4-yl)-2-methylbut-3-en-2-ol 1-16: The substrate 4-bromoindol 16 (300 mg, 1.53 mmol, 1.0 eq.), Pd(OAc)2 (27 mg, 0.12 mmol, 0.08 eq.), and P(o-tol)3 (93 mg, 0.31 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (319 μL, 2.3 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (720 μL, 6.89 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was performed. The product was purified by column chromatography (PE:EA = 4:1) to obtain a pale yellow oil (247 mg, 80.2%).

[0080] 1H NMR (400MHz, Acetone-d6) δ10.34(s,1H),7.38–7.32(m,2H),7.17(dt,J=7.3,0.8Hz,1H), 7.12–7.00(m,2H),6.74(ddd,J=3.1,2.0,1.0Hz,1H),6.60(d,J=16.1Hz,1H),1.44(s,6H). 13 C NMR (100MHz, Acetone-d6) δ139.62,137.53,130.15,127.20,125.58,125.06,122.15,117.44,111.02,100.92,70.81,30.55.

[0081]

[0082] Synthesis of (E)-2-methyl-4-(thiophen-3-yl)but-3-en-2-ol 1-17: The substrate 3-bromothiophene 17 (300 mg, 1.84 mmol, 1.0 eq.), Pd(OAc)2 (33 mg, 0.15 mmol, 0.08 eq.), and P(o-tol)3 (112 mg, 0.37 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (383 μL, 2.76 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (866 μL, 8.28 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was performed. The product was purified by column chromatography (PE:EA = 8:1), yielding a white needle-like solid (233 mg, 75.2%).

[0083] 1 H NMR (400MHz, CDCl3) δ7.30–7.11(m,3H),6.59(d,J=16.1Hz,1H),6.21(d,J=16.1Hz,1H),1.40(s,6H). 13 C NMR (100MHz, CDCl3) δ139.59,137.52,126.16,125.05,122.01,120.79,71.04,29.94.

[0084]

[0085] Synthesis of (E)-4-(benzofuran-5-yl)-2-methylbut-3-en-2-ol 1-18: Substrate 5-bromobenzofuran 18 (300 mg, 1.52 mmol, 1.0 eq.), Pd(OAc)2 (27 mg, 0.12 mmol, 0.08 eq.), and P(o-tol)3 (93 mg, 0.31 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (318 μL, 2.29 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (716 μL, 6.85 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was then performed. Purified by column chromatography (PE:EA = 10:1), a colorless oily substance (261 mg, 84.7%) was obtained.

[0086] 1 H NMR (400MHz, CDCl3) δ7.59 (dd, J=6.5, 2.0Hz, 2H), 7.43 (dt, J=8.6, 0.8Hz, 1H), 7.35 (dd, J=8. 6,1.8Hz,1H),6.73(dd,J=2.2,1.0Hz,1H),6.65(s,1H),6.33(d,J=16.0Hz,1H),1.44(s,6H). 13 C NMR (100MHz, CDCl3) δ154.64,145.56,136.56,132.09,127.86,126.60,122.96,119.20,111.50,106.75,71.21,30.05.

[0087]

[0088] Synthesis of (E)-2-methyl-4-(o-tolyl)but-3-en-2-ol 1-19: Substrate o-bromotoluene 19 (300 mg, 1.75 mmol, 1.0 eq.), Pd(OAc)2 (32 mg, 0.14 mmol, 0.08 eq.), and P(o-tol)3 (107 mg, 0.35 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (366 μL, 2.63 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (825 μL, 7.89 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was performed. The product was purified by column chromatography (PE:EA = 35:1) to obtain a yellow solid (239 mg, 77.3%).

[0089] 1 H NMR (400MHz, CDCl3) δ7.42(d,J=4.6Hz,1H),7.15(d,J=2.3Hz,3H),6.80(d,J=15.9Hz,1H),6.23(d,J=15.9Hz,1H),2.35(s,3H),1.44(s,6H). 13 C NMR (100MHz, CDCl3) δ139.13,136.13,135.63,130.38,127.45,126.20,125.67,124.17,71.39,30.10,19.98.

[0090]

[0091] Synthesis of (E)-2-methyl-4-(m-tolyl)but-3-en-2-ol 1-20: Substrate 3-bromotoluene 20 (300 mg, 1.75 mmol, 1.0 eq.), Pd(OAc)2 (32 mg, 0.14 mmol, 0.08 eq.), and P(o-tol)3 (107 mg, 0.35 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (366 μL, 2.63 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (825 μL, 7.89 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was then performed. The product was purified by column chromatography (PE:EA = 35:1) to obtain a yellow solid (291 mg, 94.2%).

[0092] 1 H NMR (400MHz, CDCl3) δ7.28–7.15(m,3H),7.05(dt,J=6.0,1.6Hz,1H),6.55(d,J=16.1Hz,1H),6.34(d,J=16.1Hz,1H),2.34(s,3H),1.42(s,6H). 13 C NMR (100MHz, CDCl3) δ138.21,137.40,136.91,128.58,128.32,127.19,126.46,71.19,29.96,21.51.

[0093]

[0094] Synthesis of (E)-4-(3,5-dimethylphenyl)-2-methylbut-3-en-2-ol 1-21: The substrate 3,5-dimethylbromobenzene 21 (300 mg, 1.62 mmol, 1.0 eq.), Pd(OAc)2 (29 mg, 0.13 mmol, 0.08 eq.), and P(o-tol)3 (99 mg, 0.32 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (338 μL, 2.43 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (762 μL, 7.3 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was then performed. The mixture was purified by column chromatography (PE:EA = 25:1) to obtain a yellow solid (280 mg, 91.0%).

[0095] 1 H NMR (400MHz, CDCl3) δ7.01(d,J=1.5Hz,2H),6.90–6.85(m,1H),6.52(d,J=16.1Hz,1H),6.33(d,J=16.0Hz,1H),2.34–2.28(m,6H),1.42(s,6H). 13 C NMR (100MHz, CDCl3) δ138.15,137.26,136.89,129.29,126.52,124.41,71.22,29.99,21.40.

[0096]

[0097] Synthesis of (E)-2-methyl-4-(pyridin-3-yl)but-3-en-2-ol 1-22: The substrate 3-bromopyridine 22 (300 mg, 1.9 mmol, 1.0 eq.), Pd(OAc)2 (37 mg, 0.15 mmol, 0.08 eq.), and P(o-tol)3 (116 mg, 0.38 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (396 μL, 2.85 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (893 μL, 8.55 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was then performed. The product was purified by column chromatography (PE:EA = 1:1) to obtain a colorless oil (300 mg, 96.8%).

[0098] 1H NMR (400MHz, Acetone-d6) δ8.69–8.57(m,1H),8.44(dd,J=4.8,1.6Hz,1H),7.85(dt,J=8. 0,2.0Hz,1H),7.32(dd,J=8.0,4.7Hz,1H),6.78–6.53(m,2H),1.39(dd,J=2.2,1.0Hz,6H). 13 C NMR (100MHz, Acetone-d6) δ148.84,148.76,142.00,133.95,133.39,124.33,122.77,70.45.

[0099]

[0100] Synthesis of (E)-1-(4-(3-hydroxy-3-methylbut-1-en-1-yl)phenyl)ethyl-1-one 1-23: The substrate 4-bromoacetophenone 23 (300 mg, 1.51 mmol, 1.0 eq.), Pd(OAc)2 (27 mg, 0.12 mmol, 0.08 eq.), and P(o-tol)3 (92 mg, 0.3 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (315 μL, 2.27 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (710 μL, 6.8 mmol, 4.5 eq.) were added. The synthesis procedure of compound 1-1 was then performed. Purified by column chromatography (PE:EA = 3:1), a white solid (94 mg, 30.7%) was obtained.

[0101] 1 H NMR (400MHz, CDCl3) δ7.90(d,J=8.4Hz,2H),7.45(d,J=8.4Hz,2H),6.64(d,J=16.1Hz,1H),6.48(d,J=16.1Hz,1H),2.59(s,3H),1.45(s,6H). 13 C NMR (100MHz, CDCl3) δ197.85,141.87,140.57,135.91,128.87,126.57,125.54,71.21,29.94,26.71.

[0102]

[0103] Synthesis of (E)-4-(3-hydroxy-3-methylbut-1-en-1-yl)benzaldehyde 1-24: The substrate p-bromobenzaldehyde 24 (300 mg, 1.62 mmol, 1.0 eq.), Pd(OAc)2 (29 mg, 0.13 mmol, 0.08 eq.), and P(o-tol)3 (99 mg, 0.32 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (338 μL, 2.43 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (762 μL, 7.29 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was then performed. The product was purified by column chromatography (PE:EA = 4:1) to obtain a yellow oil (296 mg, 91.0%).

[0104] 1 H NMR (400MHz, CDCl3) δ9.98 (s, 1H), 7.83 (d, J = 8.3Hz, 2H), 7.58–7.48 (m, 2H), 6.67 (d, J = 16.0Hz, 1H), 6.52 (d, J = 16.0Hz, 1H), 1.45 (s, 6H). 13 C NMR (100MHz, CDCl3) δ191.98,143.28,141.30,135.32,130.29,127.02,125.54,71.30,29.96.

[0105]

[0106] Synthesis of (E)-4-(2,6-dimethoxyphenyl)-2-methylbut-3-en-2-ol 1-25: The substrate 1-bromo-2,6-dimethoxyphenyl 25 (300 mg, 1.62 mmol, 1.0 eq.), Pd(OAc)2 (29 mg, 0.13 mmol, 0.08 eq.), and P(o-tol)3 (99 mg, 0.32 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (338 μL, 2.43 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (762 μL, 7.29 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was then performed. Purified by column chromatography (PE:EA = 6:1), a colorless oily substance (75 mg, 24.4%) was obtained.

[0107] 1H NMR (400MHz, CDCl3) δ7.14(t,J=8.4Hz,1H),6.94–6.76(m,2H),6.55(d,J=8.4Hz,2H),3.84(s,6H),1.43(s,6H). 13 C NMR (100MHz, CDCl3) δ158.52,158.49,141.44,127.98,116.60,104.00,103.97,55.80,30.00.

[0108]

[0109] Synthesis of (E)-1-(2-hydroxy-5-(3-hydroxy-3-methylbut-1-en-1-yl)phenyl)ethyl-1-one 1-26: The substrate 2-hydroxy-5-bromoacetophenone 26 (300 mg, 1.4 mmol, 1.0 eq.), Pd(OAc)2 (25 mg, 0.11 mmol, 0.08 eq.), and P(o-tol)3 (85 mg, 0.28 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (290 μL, 2.09 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (656 μL, 6.28 mmol, 4.5 eq.) were added. The synthesis procedure of compound 1-1 was then performed. Purified by column chromatography (PE:EA = 3:1), the product was a yellow oil (291 mg, 93.9%).

[0110] 1 H NMR (400MHz, CDCl3) δ12.25(s,1H),7.66(d,J=2.2Hz,1H),7.54(dd,J=8.7,2.3Hz,1H),6.93 (d,J=8.6Hz,1H),6.52(d,J=16.1Hz,1H),6.23(d,J=16.0Hz,1H),2.64(s,3H),1.43(s,6H). 13 C NMR (100MHz, CDCl3) δ204.69,161.85,136.45,134.06,128.91,128.21,125.07,119.53,118.81,71.14,30.06,26.83.

[0111]

[0112] Synthesis of (E)-2-(3-hydroxy-3-methylbut-1-en-1-yl)benzoate ethyl ester 1-27: The substrate ethyl 2-bromobenzoate 27 (300 mg, 1.31 mmol, 1.0 eq.), Pd(OAc)2 (24 mg, 0.11 mmol, 0.08 eq.), and P(o-tol)3 (80 mg, 0.28 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (273 μL, 1.97 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (616 μL, 5.9 mmol, 4.5 eq.) were added. The synthesis procedure of compound 1-1 was then performed. Purified by column chromatography (PE:EA = 5:1), the product was a yellow oil (285 mg, 92.8%).

[0113] 1 H NMR (400MHz, CDCl3) δ7.82 (dd, J=7.8, 1.3Hz, 1H), 7.47 (dd, J=8.2, 1.1Hz, 1H), 7.39 (td, J=7.6, 1.4Hz, 1 H),7.27–7.18(m,2H),6.17(d,J=16.0Hz,1H),4.30(q,J=7.2Hz,2H),1.38(s,6H),1.33(t,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3) δ167.64,140.36,139.09,132.06,130.44,128.83,127.53,127.02,125.52,71.07,61.14,29.66,14.35.

[0114]

[0115] Synthesis of (E)-3-(3-hydroxy-3-methylbut-1-en-1-yl)benzoate ethyl ester 1-28: Ethyl m-bromobenzoate 28 (300 mg, 1.31 mmol, 1.0 eq.), Pd(OAc)2 (24 mg, 0.11 mmol, 0.08 eq.), and P(o-tol)3 (80 mg, 0.28 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (273 μL, 1.97 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (616 μL, 5.9 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was then performed. The product was purified by column chromatography (PE:EA = 6:1) to obtain a yellow oil (286 mg, 93.2%).

[0116] 1 H NMR (400MHz, CDCl3) δ7.99(d,J=1.8Hz,1H),7.83(dt,J=7.7,1.4Hz,1H),7.47(dt,J=7.7,1.4Hz,1H),7.31(t,J=7. 7Hz,1H),6.56(d,J=16.1Hz,1H),6.37(d,J=16.1Hz,1H),4.31(q,J=7.1Hz,2H),1.37(s,6H),1.33(t,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3) δ166.73,138.85,137.34,130.89,130.86,128.71,128.49,127.45,125.59,71.21,61.20,30.00,14.47.

[0117]

[0118] Synthesis of (E)-4-(3-hydroxy-3-methylbut-1-en-1-yl)benzoate ethyl ester 1-29: ethyl 4-bromobenzoate 29 (300 mg, 1.31 mmol, 1.0 eq.), Pd(OAc)2 (24 mg, 0.11 mmol, 0.08 eq.), and P(o-tol)3 (80 mg, 0.28 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (273 μL, 1.97 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (616 μL, 5.9 mmol, 4.5 eq.) were added. The synthesis procedure of compound 1-1 was then performed. Purified by column chromatography (PE:EA = 6:1), the product was a yellow oil (300 mg, 97.7%).

[0119] 1 H NMR (400MHz, CDCl3) δ7.97–7.87(m,2H),7.43–7.33(m,2H),6.44(d,J=16.3Hz,1H),6.28(d,J=16 .4Hz,1H),4.30(q,J=7.1Hz,2H),3.34(q,J=7.0Hz,2H),1.36–1.30(m,9H),1.12(t,J=7.0Hz,3H). 13 C NMR (100MHz, CDCl3) δ166.58,141.50,138.81,130.01,129.31,127.82,126.33,75.02,61.06,58.26,26.52,16.25,14.48.

[0120]

[0121] Synthesis of (E)-4-(2,6-bis((tert-butyldimethylsilyl)oxy)-4-pentylphenyl)-2-methylbut-3-en-2-ol 1-30: Ethyl 4-bromobenzoate 30 (300 mg, 1.31 mmol, 1.0 eq.), Pd(OAc)2 (24 mg, 0.11 mmol, 0.08 eq.), and P(o-tol)3 (80 mg, 0.28 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (273 μL, 1.97 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (616 μL, 5.9 mmol, 4.5 eq.) were added. The synthesis procedure of compound 1-1 was then performed. Purified by column chromatography (PE:EA = 6:1), the product was a yellow oil (300 mg, 97.7%).

[0122] 1 H NMR (400MHz, CDCl3) δ6.84–6.63(m,2H),6.28(s,2H),2.45(t,J=7.5Hz,2H),1.55(p,J=7.5Hz,2H),1. 40(s,6H),1.29(dtd,J=16.8,8.9,7.9,5.0Hz,4H),1.00(s,18H),0.88(t,J=6.9Hz,3H),0.23(s,12H). 13 C NMR (100MHz, CDCl3) δ154.43,142.28,140.02,118.72,116.94,113.21,71.75,35.74,31.34,30.91,30.10,26.07,22.67,18.52,14.19,-3.76.

[0123]

[0124] Synthesis of (E)-3-(3-hydroxy-3-methylbut-1-en-1-yl)-7-methoxy-2H-chromen-2-one 1-31: The substrate 3-bromo-7-methoxycoumarin 31 (100 mg, 0.39 mmol, 1.0 eq.), Pd(OAc)2 (7 mg, 0.03 mmol, 0.08 eq.), and P(o-tol)3 (24 mg, 0.08 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (2 mL), Et3N (82 μL, 0.59 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (185 μL, 1.76 mmol, 4.5 eq.) were added. The tube was then sealed and placed in a 90°C oil bath to begin the reaction. During the reaction, TLC (developing solvent PE:EA = 2:1) was used for monitoring. After the reaction was completed, the reaction was removed from the oil bath, brought to room temperature, and quenched with 2-3 mL of saturated NaHCO3 solution. After stirring for 5 min, the mixture was filtered through a short silica gel column using EA and extracted with EA. The mixture was washed with water (2 × 10 mL) and the organic phase was washed with saturated NaCl aqueous solution (1 × 5 mL). The organic phases were combined, dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was then loaded onto a silica gel column using a dry method and subjected to silica gel column chromatography (gradient eluent PE:EA = 2:1) to separate a yellow solid (94 mg, 92.0%).

[0125] 1 H NMR (400MHz, CDCl3) δ7.60 (s, 1H), 7.35 (d, J = 8.6Hz, 1H), 6.86–6.74 (m, 3H), 6.62–6.53 (m, 1H), 3.86 (s, 3H), 1.43 (s, 6H). 13 C NMR (100MHz, CDCl3) δ162.51,160.81,154.75,141.77,138.09,128.70,121.18,120.54,113.28,112.98,100.45,71.42,55.91,30.02.

[0126]

[0127] Synthesis of (E)-6-(3-hydroxy-3-methylbut-1-en-1-yl)-7-methoxy-2H-chromen-2-one 1-32: The substrates 6-bromo-7-methoxycoumarin 32 (300 mg, 1.18 mmol, 1.0 eq.), Pd(OAc)2 (21 mg, 0.1 mmol, 0.08 eq.), and P(o-tol)3 (72 mg, 0.24 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (246 μL, 1.77 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (556 μL, 5.32 mmol, 4.5 eq.) were added. The synthesis of compound 1-31 was then performed. Purified by column chromatography (PE:EA = 6:1), a yellow solid (280 mg, 91.3%) was obtained.

[0128] 1 H NMR (400MHz, CDCl3) δ7.65(d,J=9.5Hz,1H),7.50(s,1H),6.86(d,J=16.2Hz,1H),6. 80(s,1H),6.37(d,J=16.2Hz,1H),6.28(d,J=9.5Hz,1H),3.92(s,3H),1.45(s,6H). 13 CNMR (100MHz, CDCl3) δ161.30,160.03,155.22,143.60,139.30,125.44,123.88,119.84,113.49,112.31,99.05,71.36,56.11,3 0.02.IR(KBr):3838.15,3732.92,3433.47,2932.10,2345.14,1728.08,1611.93,1356.06,1210.07,1020.71,830.13,675.92cm -1 HRMS(EI)calcd for C 15 H 16 O4[M+Na] + 283.0940, found 283.0941.

[0129]

[0130] Synthesis of (E)-8-(3-hydroxy-3-methylbut-1-en-1-yl)-7-methoxy-2H-chromen-2-one 1-33: The substrate 8-bromo-7-methoxy33 (300 mg, 1.18 mmol, 1.0 eq.), Pd(OAc)2 (21 mg, 0.1 mmol, 0.08 eq.), and P(o-tol)3 (72 mg, 0.24 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (246 μL, 1.77 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol a (556 μL, 5.32 mmol, 4.5 eq.) were added. The synthesis of compound 1-31 was then performed. Purified by column chromatography (PE:EA = 6:1), a yellow solid (285 mg, 92.7%) was obtained.

[0131] 1 H NMR (400MHz, CDCl3) δ7.63 (d, J = 9.5Hz, 1H), 7.34–7.24 (m, 1H), 7.06–6.95 ( m,2H),6.93–6.83(m,1H),6.26(d,J=9.4Hz,1H),3.95(s,3H),1.47(s,6H). 13 C NMR (100MHz, CDCl3) δ161.14,160.32,152.68,144.58,144.07,127.15,114.40,113.72,113.11,113.05,107.65,71.77,56.24,30.0 0.IR(KBr):3735.67,3466.37,2960.23,2347.90,1707.97,1598.36,1471.26,1252.81,1182.87,1087.44,823.12,703.70,562.82cm -1 HRMS(EI)calcdfor C 15 H 16 O4[M+Na] + 283.1038, found 283.1053

[0132]

[0133] Synthesis of (E)-3-(4-((E)-3-hydroxy-3-methylbut-1-en-1-yl)phenyl)methyl acrylate 1-34: The substrate methyl 4-bromocinnamate 34 (300 mg, 1.24 mmol, 1.0 eq.), Pd(OAc)2 (22 mg, 0.1 mmol, 0.08 eq.), and P(o-tol)3 (76 mg, 0.25 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (259 μL, 1.87 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol (585 μL, 5.6 mmol, 4.5 eq.) were added. The synthesis procedure of compound 1-1 was then performed. Purified by column chromatography (PE:EA = 3:1), a yellow solid was obtained (290 mg, 94.8%).

[0134] 1 H NMR (400MHz, CDCl3) δ7.60(d,J=16.0Hz,1H),7.41(d,J=8.2Hz,2H),7.32(d,J=8.3Hz ,2H),6.53(d,J=16.0Hz,1H),6.35(dd,J=16.1,1.2Hz,2H),3.74(s,3H),1.36(s,6H). 13 C NMR (100MHz, CDCl3) δ167.69,144.56,139.15,133.49,128.55,126.99,125.77,117.36,71.26,51.89,30.01,24.98.

[0135]

[0136] Synthesis of (E)-2-methyl-4-phenylbut-3-en-2-ol 1-35: The substrate bromobenzene 35 (300 mg, 1.91 mmol, 1.0 eq.), Pd(OAc)2 (34 mg, 0.15 mmol, 0.08 eq.), and P(o-tol)3 (116 mg, 0.38 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (363 μL, 2.87 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol (900 μL, 8.6 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was then performed. The product (236 mg, 76%) was obtained by column chromatography (PE:EA = 100:1, 50:1, 10:1).

[0137] 1 H NMR(400MHz, CDCl3)δ7.36–7.30(m,2H),7.26(t,J=7.6Hz,2H),7.22–7.12(m, 1H), 6.53 (d, J = 16.1Hz, 1H), 6.30 (d, J = 16.1Hz, 1H), 1.95 (s, 1H), 1.37 (s, 6H). 13 C NMR (100MHz, CDCl3) δ137.58,136.95,128.63,127.47,126.46,126.34,71.13,29.91.

[0138]

[0139] Synthesis of (E)-4-(2-fluorophenyl)-2-methylbut-3-en-2-ol 1-36: Substrate o-bromofluorobenzene 36 (300 mg, 1.71 mmol, 1.0 eq.), Pd(OAc)2 (31 mg, 0.14 mmol, 0.08 eq.), and P(o-tol)3 (103 mg, 0.34 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (325 μL, 2.57 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol (804 μL, 7.7 mmol, 4.5 eq.) were added. The synthesis procedure of compound 1-1 was then performed. Purified by column chromatography (PE:EA = 100:1, 50:1, 10:1), the product was separated (249 mg, 81%).

[0140] 1 H NMR (400MHz, CDCl3) δ7.44 (td, J=7.7, 1.8Hz, 1H), 7.18 (tdd, J=7.4, 5.2, 1.8Hz, 1H), 7.1 1–6.97(m,2H),6.75(d,J=16.3Hz,1H),6.44(d,J=16.3Hz,1H),2.12(s,1H),1.43(s,6H). 13 C NMR (100MHz, CDCl3) δ160.29 (d, J = 248.7Hz), 140.10 (d, J = 4.4Hz), 128.65 (d, J = 8.4Hz), 127.37 (d, J = 3.9H z), 124.71 (d, J = 12.2Hz), 124.10 (d, J = 3.6Hz), 118.84 (d, J = 3.7Hz), 115.71 (d, J = 22.1Hz), 71.25, 29.79.

[0141]

[0142] Synthesis of (E)-4-(4-fluorophenyl)-2-methylbut-3-en-2-ol 1-37: The substrate p-bromofluorobenzene 37 (300 mg, 1.71 mmol, 1.0 eq.), Pd(OAc)2 (31 mg, 0.14 mmol, 0.08 eq.), and P(o-tol)3 (103 mg, 0.34 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (325 μL, 2.57 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol (804 μL, 7.7 mmol, 4.5 eq.) were added. The synthesis procedure of compound 1-1 was then performed. Purification was performed by column chromatography (PE:EA = 100:1, 50:1, 10:1) to obtain the product (277 mg, 90%).

[0143] 1 H NMR (400MHz, CDCl3) δ7.38–7.26(m,2H),7.03–6.93(m,2H),6.53(d,J=16.1Hz,1H),6.25(d,J=16.1Hz,1H),2.46–2.26(m,1H),1.41(s,6H). 13 C NMR (100MHz, CDCl3) δ162.17 (d, J = 246.4Hz), 137.30 (d, J = 2.2Hz), 133.09 (d, J = 3.3Hz), 127.94, 127.86, 125.21, 115.55, 115.34, 71.07, 29.87.

[0144]

[0145] Synthesis of (E)-4-(3-hydroxy-3-methylbut-1-en-1-yl)benzonitrile 1-38: The substrate 4-bromobenzonitrile 38 (300 mg, 1.66 mmol, 1.0 eq.), Pd(OAc)2 (29 mg, 0.13 mmol, 0.08 eq.), and P(o-tol)3 (100 mg, 0.33 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (316 μL, 2.5 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol (780 μL, 7.47 mmol, 4.5 eq.) were added. The synthesis procedure of compound 1-1 was then performed. Purification was performed by column chromatography (PE:EA = 100:1, 50:1, 10:1) to obtain the product (305 mg, 98%).

[0146] 1 H NMR (400MHz, CDCl3) δ7.58–7.50(m,2H),7.46–7.37(m,2H),6.59(d,J=16.0Hz,1H),6.45(d,J=16.1Hz,1H),2.17–2.12(m,1H),1.41(s,6H). 13 C NMR (100MHz, CDCl3) δ141.69,141.56,132.38,126.91,124.88,119.07,110.35,71.09,29.84.

[0147]

[0148] Synthesis of (E)-2-methyl-4-(4-methylthiophene-3-yl)but-3-en-2-ol 1-39: Substrate 3-bromo-4-methylthiophene 39 (300 mg, 1.7 mmol, 1.0 eq.), Pd(OAc)2 (31 mg, 0.14 mmol, 0.08 eq.), and P(o-tol)3 (103 mg, 0.34 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (322 μL, 2.55 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol (800 μL, 7.65 mmol, 4.5 eq.) were added. The synthesis procedure of compound 1-1 was then performed. Purification was performed by column chromatography (PE:EA = 100:1, 50:1, 10:1) to obtain the product (241 mg, 78%).

[0149] 1H NMR (400MHz, CDCl3) δ7.21 (d, J=3.2Hz, 1H), 6.90 (dq, J=3.2, 1.1Hz, 1H), 6.53 (dd, J=16.0, 0.7Hz,1H),6.22(d,J=16.1Hz,1H),2.25(d,J=1.1Hz,3H),2.14–2.09(m,1H),1.42(s,6H). 13 C NMR (100MHz, CDCl3) δ138.51,138.41,136.38,121.59,120.38,119.46,71.13,29.94,15.10.

[0150]

[0151] Synthesis of (E)-1-(3-(3-hydroxy-3-methylbut-1-en-1-yl)thiophen-2-yl)ethane-1-one 1-40: Substrate 1-(3-bromothiophen-2-yl)ethane-1-one 40 (300 mg, 1.47 mmol, 1.0 eq.), Pd(OAc)2 (27 mg, 0.12 mmol, 0.08 eq.), and P(o-tol)3 (88 mg, 0.29 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (280 μL, 2.21 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol (690 μL, 6.6 mmol, 4.5 eq.) were added. The synthesis procedure of compound 1-1 was then performed. Purified by column chromatography (PE:EA = 100:1, 50:1, 10:1), the product was separated (194 mg, 63%).

[0152] 1 H NMR (400MHz, CDCl3) δ7.39(d,J=2.3Hz,1H),7.37(s,1H),7.27(d,J=5.2Hz,1H),6.39(d,J=16.2Hz,1H),3.07(s,1H),2.50(s,3H),1.42(s,6H). 13 C NMR (100MHz, CDCl3) δ191.55,144.29,143.21,135.23,130.10,127.73,120.46,70.91,30.10,29.50.

[0153]

[0154] Synthesis of (E)-4-(benzo[b]thiophene-6-yl)-2-methylbut-3-en-2-ol 1-41: Substrate 6-bromobenzo[b]thiophene 41 (300 mg, 1.42 mmol, 1.0 eq.), Pd(OAc)2 (24.7 mg, 0.11 mmol, 0.08 eq.), and P(o-tol)3 (85 mg, 0.28 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (269 μL, 2.13 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol (669 μL, 6.4 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was then performed. Purified by column chromatography (PE:EA = 100:1, 50:1, 10:1), the product was separated (282 mg, 91%).

[0155] 1 H NMR(400MHz, CDCl3)δ7.90–7.82(m,1H),7.75(d,J=8.3Hz,1H),7.49–7.38(m,2H),7.30 (s,1H),6.69(d,J=16.1Hz,1H),6.43(d,J=16.0Hz,1H),2.05–1.94(m,1H),1.46(s,6H). 13 C NMR (100MHz, CDCl3) δ140.31, 138.98, 137.50, 133.39, 126.57, 126.34, 123.74, 122.73 (d, J = 3.4Hz), 120.59, 71.22, 29.96.

[0156]

[0157] Synthesis of (E)-4-(benzo[d][1,3]dioxolane-5-yl)-2-methylbut-3-en-2-ol 1-42: The substrate 5-bromobenzo[d][1,3]dioxolane 42 (300 mg, 1.5 mmol, 1.0 eq.), Pd(OAc)2 (27 mg, 0.12 mmol, 0.08 eq.), and P(o-tol)3 (91 mg, 0.3 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (285 μL, 2.25 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol (706 μL, 6.75 mmol, 4.5 eq.) were added. The synthesis of compound 1-1 was then performed. Purified by column chromatography (PE:EA = 100:1, 50:1, 10:1), the product was separated (260 mg, 84%).

[0158] 1 H NMR (400MHz, CDCl3) δ6.90(d,J=1.7Hz,1H),6.83–6.71(m,2H),6.47(d,J=16.1Hz,1H),6.17(d,J=16.0Hz,1H),5.92(s,2H),2.20(s,1H),1.39(s,6H). 13 C NMR (100MHz, CDCl3) δ147.98,147.01,135.83,131.39,125.97,121.05,108.30,105.69,101.04,71.02,29.90.

[0159]

[0160] Synthesis of (E)-2-methyl-4-(1-methyl-1H-indol-5-yl)but-3-en-2-ol 1-43: The substrate 5-bromo-1-methyl-1H-indol-43 (300 mg, 1.44 mmol, 1.0 eq.), Pd(OAc)2 (27 mg, 0.12 mmol, 0.08 eq.), and P(o-tol)3 (88 mg, 0.29 mmol, 0.2 eq.) were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times. After replacing the gas in the sealed tube with nitrogen, CH3CN (6 mL), Et3N (273 μL, 2.16 mmol, 1.5 eq.), and 2-methyl-3-buten-2-ol (677 μL, 6.48 mmol, 4.5 eq.) were added. The synthesis procedure of compound 1-1 was then performed. Purified by column chromatography (PE:EA = 100:1, 50:1, 10:1), the product was separated (180 mg, 58%).

[0161] 1 H NMR (400MHz, CDCl3) δ7.61(d,J=1.6Hz,1H),7.33(dd,J=8.5,1.6Hz,1H),7.25(d,J=8.6Hz,1H),7.01(d,J=3.1Hz,1H) ,6.69(d,J=16.1Hz,1H),6.45(dd,J=3.1,0.8Hz,1H),6.32(d,J=16.1Hz,1H),3.75(s,3H),1.77(s,1H),1.45(s,6H). 13 C NMR (100MHz, CDCl3) δ136.42,134.63,129.38,128.71,128.44,127.51,120.07,119.44,109.41,101.21,71.21,32.97,30.02.

[0162] The structures and yields of the compounds synthesized in this invention are as follows:

[0163]

[0164]

[0165] Comparative Example 1

[0166] Prior art document 1 (Heck reactions of aryl bromides with alk-1-en-3-olderivatives catalyzed by atetraphosphine / palladium complex) discloses the following palladium-catalyzed Heck reaction.

[0167]

[0168] Differences:

[0169] (1) The catalyst used in this application is different from that used in the comparative scheme. This application uses a palladium catalyst (such as Pd(OAc)2), while the comparative scheme uses a Tedicyp–palladium complex, such as [Pd(C3H5)Cl]2–Tedicyp.

[0170] (2) The strong acid and weak base salts used in this application and the comparative scheme are different. This application uses triethylamine, while the comparative scheme uses potassium carbonate.

[0171] (3) The solvent used in this application differs from that in the prior art; this application uses CH3CN, while the prior art uses DMF. (4) The temperatures used in this application and the prior art differ; this application uses 115℃, while the prior art uses 130℃. Detailed analysis of the differences between the patented application and prior art 1:

[0172] 1. Overall Yield and Economic Benefits: The comparative scheme uses the [Pd(C3H5)Cl]2–Tedicyp catalyst, which has the following disadvantages:

[0173] ①Reaction type limitations

[0174] Excessive specificity: This catalyst precursor is specifically designed for allylic substitution reactions. Its active center is the "π-allylpalladium" unit, which is highly suitable for reactions with nucleophiles. However, it is essentially ineffective or extremely inefficient for other very important palladium-catalyzed reactions, such as Suzuki coupling, Heck reaction, Negishi coupling, etc. This is because the catalytic cycle of these reactions begins with the oxidative addition of palladium(0) species to haloalkanes, while [Pd(η 3 Palladium in -C3H5)Cl]2 has a +2 valence, and its reduction to palladium(0) is not easy.

[0175] ②Stability and operation of catalyst precursors

[0176] Sensitive to air and humidity: [Pd(η 3 [C3H5)Cl]2 is quite sensitive to air and humidity, and needs to be stored and handled under the protection of an inert gas (such as argon or nitrogen). This increases the complexity and cost of experiments.

[0177] High ligand cost: The synthesis of chiral bisphosphine ligands such as Tedicyp is very difficult and extremely expensive, which greatly limits their application in large-scale industrial production.

[0178] Sensitive to substrate structure: The enantioselectivity and yield of this catalytic system are highly dependent on the structure of the allyl substrate. Subtle changes in the substitution mode of double bonds and the type of leaving group in the substrate can lead to significant fluctuations in the catalytic results (ee value and yield).

[0179] The palladium catalyst (Pd(OAc)2) used in this invention is highly versatile: it is commonly used in reactions such as Suzuki, Heck, Negishi, CH activation, and Wacker oxidation. It is also relatively stable, insensitive to air, and easy to weigh and handle; moreover, it is relatively inexpensive and is one of the most commonly used palladium sources in laboratories and industry.

[0180] 2. Process Safety Assessment: The reaction conditions of the two methods differ fundamentally in solvent selection and reaction temperature. This application uses acetonitrile (CH3CN) as the solvent, with the reaction temperature controlled at 115℃; the comparative method uses N,N-dimethylformamide (DMF) as the solvent, with a reaction temperature as high as 130℃. From a safety perspective, acetonitrile exhibits superior thermodynamic stability at the target reaction temperature and is less prone to decomposition; while DMF is easily decomposed at high temperatures and carries risks of liver damage, skin and respiratory irritation, as well as clear toxicity and potential carcinogenicity. Therefore, this application's method uses acetonitrile instead of DMF, which significantly improves process safety and reduces occupational health hazards and environmental risks.

[0181] 3. Comparison of Ease of Operation: This application employs a "one-pot" synthesis strategy, allowing the reaction to be initiated simply by adding the target catalyst. The process is concise, environmentally friendly, and economical, effectively reducing operational steps and intermediate processing. In contrast, the comparative scheme requires pre-preparation of the catalyst complex. While the amount of catalyst used is relatively smaller, it increases the operational and time costs associated with catalyst preparation, resulting in higher overall operational complexity. Overall, the patented solution's ease of operation better meets the high-efficiency requirements of industrial production.

[0182] 4. Reaction Controllability and Atom Economy: Reaction controllability is closely related to reagent solubility. The triethylamine used in this application has excellent organic solvent solubility, making it suitable for the reaction system of fine organic synthesis, effectively improving reaction selectivity and reducing by-product formation. In contrast, potassium carbonate used in the comparative application has low solubility in organic solvents, resulting in insufficient homogeneity of the reaction system, which not only reduces reaction selectivity but also leads to low atom utilization and poor atom economy. Therefore, the proposed method has a greater technical advantage in terms of reaction controllability and atom economy.

[0183] 5. Prospects for Industrial Production: The reagents involved in this application (acetonitrile, triethylamine, palladium catalyst, and tris(o-methylphenyl)phosphine) are all inexpensive and readily available, with a stable supply of raw materials. Combined with its core characteristics of simple operation, high selectivity, few byproducts, and excellent atom economy, this approach highly aligns with the actual needs of industrial production for "low cost, high efficiency, low pollution, and easy scale-up," providing a solid technical foundation for subsequent industrial scale-up and possessing broad prospects for industrial application.

[0184] Comparative Example 2

[0185] Prior art document 2 (PALLADIUM-CATALYZEDVINYLATION OF ORGANIC HALIDES) discloses the following reaction, a technique for constructing enol structures via the Heck reaction, using palladium chloride (PdCl2) as a catalyst precursor, triphenylphosphine (PPh3) as a ligand, hexamethylphosphoric triamine (HMPA) as a solvent, and sodium bicarbonate (NaHCO3) as a base in the catalytic system.

[0186]

[0187] Differences:

[0188] (1) The catalyst used in this application is different from that used in the comparative scheme. This application uses a palladium catalyst (such as Pd(OAc)2), while the comparative scheme uses PdCl2.

[0189] (2) The strong acid and weak base salts used in this application and the comparative scheme are different. This application uses triethylamine, while the comparative scheme uses sodium bicarbonate.

[0190] (3) The solvent used in this application is different from that used in the comparative scheme. This application uses CH3CN, while the comparative scheme uses HMPA.

[0191] Detailed analysis of the differences between the patented solution and comparative solution 2:

[0192] This application employs a novel catalytic system composed of palladium acetate (Pd(OAc)2), tris(o-methylphenyl)phosphine (P(o-tol)3), triethylamine (Et3N), and acetonitrile (CH3CN), enabling the efficient and high-yield construction of enol compounds. Compared with existing technologies, the technical solution of this application is not an obvious and simple replacement, but rather a fundamental and synergistic optimization and innovation of the entire reaction system, specifically reflected in the following aspects:

[0193] 1. Catalyst Precursor: The palladium acetate of this application is more readily reduced to a highly active zero-valent palladium species, thereby initiating the catalytic cycle. It contains no halide anions, avoiding unnecessary coordination interference, resulting in a "purer" catalytic active site and significantly improved reaction rate and efficiency. In contrast, palladium chloride (PdCl2) in the comparative scheme may be slower in reducing to the active zero-valent palladium species, and chloride ions may participate in coordination, interfering with the catalytic cycle.

[0194] 2. Ligand: This application innovatively introduces tris(o-methylphenyl)phosphine. The introduction of the ortho-methyl group produces significant electronic and steric hindrance effects. Compared with PPh3, P(o-tol)3 has stronger electron-donating ability and higher air stability, which can more effectively stabilize the palladium active intermediate in the catalytic cycle, inhibit palladium black precipitation, and reduce side reactions, thereby directly contributing to a significant increase in yield.

[0195] 3. Base: Triethylamine is far more basic than sodium bicarbonate, exhibiting superior solubility and neutralization efficiency in acetonitrile solvent. This allows it to more effectively promote the deprotonation step required for the reaction, ensuring a rapid and complete reaction, which is one of the key factors for achieving high conversion and high yield. When the amount of triethylamine is increased to 1.5 equivalents, a small amount of free triethylamine remains in the reaction system. This excess base neutralizes the slightly acidic environment created by triethylamine hydrobromide, mechanistically inhibiting the dehydration reaction and thus reducing the formation of diene products, maximizing the yield.

[0196] 4. Solvent: This is the most prominent environmental and safety innovation of this application. Acetonitrile is a common, low-toxicity, and easily recyclable organic solvent. The success of this application completely eliminates the use of highly toxic HMPA, greatly improving the safety of the production process, reducing environmental and health risks, and simplifying the post-processing procedures, making industrial-scale production possible.

[0197] 5. Overall Effect (Yield): The yield is significantly improved. The innovation of the four components is not a simple superposition, but rather constitutes a synergistic and novel highly efficient catalytic system. Experimental data show that under this system, the separation yield of the target product is significantly increased from 65% in the prior art to 78%, while 43 analogues were also synthesized efficiently, fully demonstrating the technical superiority of this application.

[0198] The innovation of this invention lies in:

[0199] 1. Systematic innovation: Synergistic and non-obvious comprehensive optimization of the four key components of the catalytic system.

[0200] 2. Safety and Environmental Protection Innovation: The use of low-toxicity acetonitrile successfully replaced the highly toxic HMPA, achieving a green process.

[0201] 3. Efficiency Innovation: By optimizing catalyst precursors and ligands, catalytic activity and reaction efficiency were significantly improved, resulting in significantly higher yields.

[0202] 4. Innovative application prospects: The method of this invention has mild conditions, is easy to operate, and has controllable costs, and has great potential for industrial application.

Claims

1. A method for preparing an enol compound, comprising the following steps: Compounds a and b undergo a coupling reaction in the presence of a catalyst, a ligand, a base, and a solvent to generate compound I. Q is selected from benzene ring, naphthalene ring. The hydrogen atom at Q can optionally be substituted with one or more R atoms, wherein R is selected from hydrogen, methyl, methoxy, tert-butyl, n-pentyl, hydroxyl, amino, CF3CO-, halogen, methoxycarbonyl, nitro, formyl, acetyl, ethoxycarbonyl, TBSO-, etc.

2. The preparation method according to claim 1, characterized in that, The catalyst was selected from palladium acetate, and the ligand was tritert-butylphosphine.

3. The preparation method according to claim 1, characterized in that, The base is selected from triethylamine, tri-n-propylamine, tri-n-butylamine, diisopropylethylamine, or triethanolamine.

4. The preparation method according to claim 1, characterized in that, The solvent is selected from toluene, tetrahydrofuran, 1,2-dichloroethane, or acetonitrile.

5. The preparation method according to claim 1, characterized in that, The reaction temperature is between 40℃ and 145℃.

6. The preparation method according to claim 1, characterized in that, The feed ratio of compound a, compound b, catalyst, ligand and base is 4.5:1:0.08:0.2:1.

5.

7. The preparation method according to claim 1, characterized in that, A method for preparing enol compounds includes the following steps: 1.0 eq. of compound b, 0.08 eq. of Pd(OAc)2, and 0.2 eq. of P(o-tol)3 were placed in a sealed tube, sealed with a rubber stopper, and the gas was evacuated three times to replace the gas in the sealed tube with nitrogen. Then, CH3CN, 1.5 eq. of Et3N, and 4.5 eq. of compound a were added. The tube was sealed and placed in an oil bath at 115°C to start the reaction. During the reaction, TLC was used for monitoring. The developing solvent was PE:EA = 3:

1. After the reaction was completed, the mixture was brought to room temperature and quenched with saturated NaHCO3 solution. After stirring, the mixture was filtered through a short silica gel column with EA and extracted with EA. The organic phase was washed with water and saturated NaCl aqueous solution. The organic phases were combined and dried with anhydrous Na2SO4. After filtration and vacuum concentration, the crude product was obtained. The crude product was loaded onto a dry silica gel column and purified by silica gel column chromatography (gradient eluent PE:EA = 3:1) to obtain compound I.

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