Simple synthesis method and application of 1,5-alkenynyl compounds

Abstract

The application relates to the technical field of organic synthesis, in particular to a simple synthesis method of 1,5-alkenynyl compounds and application. The synthesis method is as follows: in an organic solvent, a protected alkyne halogenated alkyne shown in formula I, a diazonium compound shown in formula II and an allyl borate shown in formula III are reacted under the action of a palladium catalyst, an aromatic ring-containing phosphine ligand and an alkali under the protection of an inert gas at 50-100 DEG C for 10-48 h to prepare a 1,5-alkenynyl compound shown in formula IV; in formula I, R is a bulky silane protecting group, and X is a halogenated group; in formula II, Ar is any one of a benzene ring, a nitrogen-containing heterocycle, an oxygen-containing heterocycle and a sulfur-containing heterocycle or a polycyclic structure composed of at least two of the benzene ring, the nitrogen-containing heterocycle, the oxygen-containing heterocycle and the sulfur-containing heterocycle, and M is an ester group or an amide group. The simple synthesis method has good expandability, the product can be diversifiedly converted, and the simple synthesis method has great synthesis application value.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a simple method for synthesizing 1,5-enyne compounds and their applications. Background Technology

[0002] 1,5-Enyne compounds are important structural units for the synthesis of complex molecules. For example, metal-catalyzed 1,n-enyne cyclic isomerization is a direct method for constructing polycyclic structures. Meanwhile, all-carbon and quaternary carbon centers are widely present in natural products and bioactive molecules, and their synthetic methods have attracted considerable attention. Considering the importance of these two types of structures, developing methods capable of simultaneously constructing enyne skeletons and quaternary carbon centers is of significant importance, but challenges remain.

[0003] In existing technologies, the synthesis of 1,5-enyne compounds mainly employs palladium-catalyzed two-component coupling reactions of allyl alkyne esters and diazonium esters, or via rhodium / copper synergistic catalytic systems. Although significant progress has been made, these reactions rely on simple reaction systems, have stringent requirements regarding substrate structure (steric hindrance, electronic properties), and thus have limited applicability. Therefore, developing simpler catalytic systems and readily available raw materials to construct a widely applicable and convenient synthetic method for 1,5-enyne compounds remains a pressing technical challenge.

[0004] Therefore, this application is submitted. Summary of the Invention

[0005] In view of the background technology, the present invention provides a simple synthesis method and application of 1,5-enyne compounds, aiming to solve the problems of existing synthesis methods of 1,5-enyne compounds, such as single reaction system, narrow applicability and cumbersome operation.

[0006] Transition metal-catalyzed carbene coupling reactions have made great progress in the field of organic chemistry. The typical process is as follows: a diazo compound generates a carbene under the catalysis of a transition metal catalyst, then the carbene inserts into a CH or XH bond (where X is a heteroatom), and finally the two-component cross-coupling reaction is completed through β-H elimination or protonation.

[0007] In comparison, the three-component reaction is more attractive because it can simultaneously form two carbon-carbon bonds or carbon-heteroatom bonds at the carbene carbon center, thereby introducing two different functional groups in one step. Inspired by this, the inventors hypothesized that diazo compounds could be inserted into alkynyl-palladium(II) species generated by the oxidative addition of haloalkynes to palladium(O). Carbene migration insertion would form a propadienyl-palladium(II) intermediate, which would then undergo transmetallation with allyl borate esters, followed by reductive elimination to obtain 1,5-enyne compounds. However, the three-component reaction system may have more side reactions: (1) direct cross-coupling of the two components, such as the allylation of haloalkynes to generate 1,4-enyne compounds, or β-H elimination to generate 1,3-diene compounds; (2) the diazo compounds may undergo competitive hydroalkylation or hydroallylation to generate propynyl / allenyl esters or homoallyl esters, respectively. Therefore, matching appropriate reaction conditions, such as the specific selection of catalysts, ligands, and bases, as well as the setting of reaction temperature and reaction time, are crucial for obtaining the target product, 1,5-enyne compounds.

[0008] First, this invention proposes a simple synthetic method for 1,5-enyne compounds. In an organic solvent, alkynyl-protected haloynes of Formula I, diazo compounds of Formula II, and allyl borate esters of Formula III are reacted at 50-100°C for 10-48 h under an inert gas atmosphere with a palladium catalyst, an aromatic phosphine ligand, and a base to obtain 1,5-enyne compounds of Formula IV. The reaction equation is shown below: ; In Formula I: R is a sterically hindered silane protecting group, specifically selected from triisopropylsilane or tert-butyldimethylsilane, and X is selected from any one of Cl, Br, and I; In Formula II: Ar is any one of benzene ring, nitrogen-containing heterocycle, oxygen-containing heterocycle, sulfur-containing heterocycle, or a polycyclic structure composed of at least two of benzene ring, nitrogen-containing heterocycle, oxygen-containing heterocycle, and sulfur-containing heterocycle; M is an ester group or an amide group. The molar ratio of alkynyl-protected haloalkyn, diazo compound, allyl borate ester, and base is 1:(1-3):(1-10):(1-5). The molar percentages of palladium catalyst and aromatic ring-containing phosphine ligand are 5%-15% and 15%-25%, respectively, in units of the total molar amount of alkynyl-protected haloalkyn, diazo compound, allyl borate ester, and base.

[0009] Unlike conventional alkynes, this application introduces electrophilic haloalkynes as reactants in carbene chemistry for the first time. 1,5-Enyne compounds are generated by coupling readily available haloalkynes with diazo compounds and allyl borate esters, providing an efficient route for the synthesis of diverse 1,5-enyne compounds with all-carbon and quaternary carbon centers. Furthermore, scale-up experiments have verified that this simple synthetic method has good scalability. Additionally, R can be extended to non-silane protecting groups; allyl borate esters can be extended to cinnamyl borate esters, crotonyl borate esters, etc., to prepare other target products using the three-component system proposed in this invention.

[0010] Furthermore, the palladium catalyst is selected from any one of Pd(OAc)2, Pd(PPh3)4, Pd(dba)2, and PdCl2; Preferably, the aromatic phosphine ligand is selected from any one of triarylphosphine, 1,2-bis(diphenylphosphine)ethane (DPPE), 1,1'-bis(diphenylphosphine)ferrocene (DPPF), and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (XantPhos), wherein the general chemical formula of the triarylphosphine is PAr3, and Ar is selected from any one of 4-MeO-C6H4, 4-CF3-C6H4, and Ph; Preferably, taking into account both the reaction rate and the product yield, the reaction temperature is 70-80℃ and the reaction time is 16-24h.

[0011] Furthermore, the organic solvent is selected from any one of 1,2-dichloroethane (DCE), ethylene glycol dimethyl ether (DME), toluene, and 1,4-dioxane, with DCE being preferred; in addition, toluene-based solvents, ether solvents, n-hexane and n-hexane-based solvents can all be used as the organic solvent of the present invention.

[0012] Furthermore, the base is selected from any one of cesium neopentanoate, cesium acetate, cesium carbonate, and potassium carbonate.

[0013] .

[0014] Furthermore, the diazo compounds represented by Formula II include the compounds represented by Formulas II-1 to II-22 as shown above.

[0015] Furthermore, in 1,2-dichloroethane, TIPS-protected alkynyl bromide, methyl phenyl diazonate, and pinacol allyl borate were reacted at 80°C for 22 h under inert gas protection with the action of Pd(OAc)2, P(4-MeO-C6H4)3, and cesium neopentanoate to prepare the compound shown in formula V; ; The molar ratio of TIPS-protected alkynyl bromide, methyl phenyl diazonate, pinacol allyl borate, and cesium neopentanoate is 1:1.5:1.5:1.5, and the molar percentages of Pd(OAc)2 and P(4-MeO-C6H4)3 are 10% and 20%, respectively.

[0016] The NMR test results of the crude product showed that the crude NMR yield of the compound shown in Formula V was as high as 91%, and the separation yield of the purified product was as high as 87%. Such a high yield has a very positive effect on its transformation and application.

[0017] Taking this technical solution as an example, this invention hypothesizes that the reaction is initiated by palladium (0), followed by the transmetalation of the borate ester and subsequent carbene migration and insertion. The specific reaction mechanism is as follows: Figure 1 As shown: In the initial stage, the TIPS-protected alkynyl bromine undergoes oxidative addition with Pd(0) to form the alkynyl palladium(II) species Int-I, which is then denitrated to generate the propynyl palladium(II) species Int-II. At this point, there are two reaction pathways: one is that Int-II undergoes transmetalation with pinacol allyl borate in the presence of a base to form the palladium carbene species Int-III, which then undergoes migration insertion to generate propynyl palladium Int-IV or allenyl palladium Int-IV′; the other is that the palladium carbene species Int-II can first undergo migration insertion and then transmetalation to generate Int-IV / Int-IV′; finally, the target product is obtained through reductive elimination, while the palladium catalyst is regenerated.

[0018] Secondly, this invention proposes an application of the simple synthetic method for the above-mentioned 1,5-enyne compounds for the synthesis of ammonia glutathione.

[0019] The specific operation is as follows: using 1,2-dichloroethane as solvent, TIPS-protected alkynyl bromide, 4-nitrophenyl diazonium ester, and allyl borate ester react at 70°C for 24 h under inert gas protection with Pd(OAc)2, P(4-MeO-C6H4)3, and cesium neopentanoate to obtain intermediate 1; intermediate 1 undergoes a hydroboration-oxidation reaction to obtain intermediate 2; intermediate 2 is oxidized to intermediate 3 in DMF with pyridinium dichromate and 3Å molecular sieve; intermediate 3 reacts with ammonia in the presence of DMF catalyst, and then undergoes cyclization with potassium tert-butoxide to obtain intermediate 4; intermediate 4 undergoes a desilylation reaction to obtain ammonia luminate; the specific reaction flow is as follows: .

[0020] Thirdly, this invention proposes another application of the simple synthetic method for the above-mentioned 1,5-enyne compounds for the synthesis of anilidine.

[0021] The specific procedure is as follows: using 1,2-dichloroethane as solvent, TIPS-protected alkynyl bromide, phenyl diazoethyl acetate, and allyl borate ester reacted at 70°C for 24 h under inert gas protection with Pd(OAc)2, P(4-MeO-C6H4)3, and cesium neopentanoate to obtain intermediate 5; intermediate 5 was treated with TBAF to obtain intermediate 6; intermediate 6 was oxidized to intermediate 8 via a two-step oxidation method; intermediate 8 was subjected to a one-pot reductive acylation and deprotection reaction to obtain anilidin; the specific reaction flow is as follows: .

[0022] The total synthesis of the two drug molecules described above demonstrates that the simplified synthetic method for 1,5-enyne compounds proposed in this invention yields products that can be transformed in various ways, making it highly valuable for synthetic applications.

[0023] Compared with existing technologies, this invention achieves highly efficient conversion of 1,5-enyne compounds through a palladium-catalyzed three-component coupling reaction of haloalkynes, diazo compounds, and allyl borate esters, and also exhibits good scalability. This simple synthetic method provides a convenient route for synthesizing a series of 1,5-enyne compounds with all-carbon and quaternary carbon centers, possessing significant synthetic value and diverse conversion potential. Attached Figure Description

[0024] To more clearly illustrate the technical solutions in the embodiments of this application, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0025] Figure 1 This is the reaction mechanism of the present invention.

[0026] Figure 2 This is a schematic diagram of the relevant transformation study conducted in Example 18. Detailed Implementation

[0027] The technical solutions of the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of this application.

[0028] All reagents and solvents used in the following examples and comparative examples were commercially available and, unless otherwise stated, were generally used directly without further purification. Anhydrous solvents were treated according to standard methods. Reactions were carried out under nitrogen protection (if specified).

[0029] In the following examples and comparative examples, the aromatic cyclic phosphine ligands specifically involve PPh3, P(4-CF3-C6H4)3, P(4-MeO-C6H4)3, 1,2-bis(diphenylphosphine)ethane, 1,1'-bis(diphenylphosphine)ferrocene, and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene. For ease of description, they are referred to as L1, L2, L3, L4, L5, and L6 respectively; and "aromatic cyclic phosphine ligand" is abbreviated as "L", "palladium catalyst" is abbreviated as "Pd", and "base" is represented as "Base".

[0030] Thin-layer chromatography (TLC) was performed using a silica gel plate and a GF254 UV lamp for detection. Column chromatography was performed using 200-300 mesh silica gel. 1 H NMR (600MHz) and 13 ¹³C NMR (151 MHz) was performed in CDCl₃, and the chemical shift δ was expressed in ppm. High-resolution mass spectrometry (HRMS) was performed using the ESI method.

[0031] Example 1 0.1 mmol of TIPS-protected alkynyl bromide, 0.15 mmol of methyl phenyldiazoacetate, and 0.15 mmol of pinacol allyl borate were dissolved in Toluene and heated at 80 °C for 22 h under nitrogen protection in the presence of Pd(OAc)2, ligand L1, and 0.15 mmol of Cs2CO3 to obtain the product shown in Formula V. The reaction equation is as follows: ; The product was measured in units of the total molar amount of TIPS-protected alkynyl bromide, methyl phenyl diazonate, pinacol allyl borate, and Cs₂CO₃, with Pd(OAc)₂ comprising 10% molar percentage and ligand L1 comprising 20% ​​molar percentage. The crude NMR yield was 40% according to NMR analysis.

[0032] Example 2 Compared to Example 1, the palladium catalyst was changed from Pd(OAc)2 to an equal amount of Pd(PPh3)4, while all other aspects remained the same as in Example 1. The crude NMR yield of the product was 28% as determined by NMR analysis.

[0033] Example 3 Compared to Example 1, the palladium catalyst was changed from Pd(OAc)2 to an equal amount of Pd(dba)2, while all other aspects remained the same as in Example 1. The crude NMR yield of the product was 25% as determined by NMR analysis.

[0034] Example 4 Compared to Example 1, the palladium catalyst was changed from Pd(OAc)2 to an equal amount of PdCl2, while all other aspects remained the same as in Example 1. The crude NMR yield of the product was 20% as determined by NMR analysis.

[0035] Example 5 Compared to Example 1, the ligand L1 was changed to an equal amount of L2, while all other aspects remained the same as in Example 1. The crude NMR yield of the product was 25% according to NMR analysis.

[0036] Example 6 Compared to Example 1, the ligand was changed from L1 to an equal amount of L3, while all other aspects remained the same as in Example 1. The crude NMR yield of the product was 50% as determined by NMR analysis.

[0037] Example 7 Compared to Example 1, the ligand was changed from L1 to an equal amount of L4, while all other aspects remained the same as in Example 1. The crude NMR yield of the product was 24% as determined by NMR analysis.

[0038] Example 8 Compared to Example 1, the ligand was changed from L1 to an equal amount of L5, while all other aspects remained the same as in Example 1. The crude NMR yield of the product was 21% as determined by NMR analysis.

[0039] Example 9 Compared to Example 1, the ligand was changed from L1 to an equal amount of L6, while all other aspects remained the same as in Example 1. The crude NMR yield of the product was 15% as determined by NMR analysis.

[0040] Example 10 Compared to Example 6, the organic solvent was changed from Toluene to an equal amount of Dioxane, while all other aspects remained the same as in Example 6. The crude NMR yield of the product was 42% according to NMR analysis.

[0041] Example 11 Compared to Example 6, the organic solvent was changed from Toluene to an equal amount of DME, while all other aspects remained the same as in Example 6. The crude NMR yield of the product was 43% as determined by NMR analysis.

[0042] Example 12 Compared to Example 6, the organic solvent was changed from Toluene to an equal amount of DCE, while all other aspects remained the same as in Example 6. The crude NMR yield of the product was 61% as determined by NMR analysis.

[0043] Example 13 Compared to Example 12, the reaction temperature was adjusted from 80°C to 70°C, while all other parameters remained the same as in Example 12. NMR analysis showed a crude NMR yield of 63% for the product.

[0044] Example 14 Compared to Example 13, the alkali was changed from Cs2CO3 to an equal amount of K2CO3, while all other aspects remained the same as in Example 13. The crude NMR yield of the product was 44% according to NMR analysis.

[0045] Example 15 Compared to Example 13, the base was changed from Cs₂CO₃ to an equal amount of CsOAc, while all other aspects remained the same as in Example 13. The crude NMR yield of the product was 79% as determined by NMR analysis.

[0046] Example 16 Compared to Example 13, the alkali was changed from Cs2CO3 to an equal amount of CsOPiv, and the reaction temperature was changed from 70°C to 80°C; all other aspects remained the same as in Example 13. Nuclear magnetic resonance (NMR) analysis showed a crude NMR yield of 91%, and after purification, the separation yield was 87%.

[0047] Example 17 Compared to Example 16, the amounts of TIPS-protected alkynyl bromide, methyl phenyldiazoacetate, and pinacol allyl borate were increased to four times, the reaction was carried out at 70°C for 18 hours, and the remaining conditions were the same as in Example 1. Nuclear magnetic resonance (NMR) analysis showed a crude NMR yield of 91%, and after purification, the separation yield was 87%.

[0048] Example 18 like Figure 2 As shown: Using the product obtained in Example 17 (the substance shown in Formula V) as raw material, product conversion studies were carried out. 1,4-enyne products containing phenylacetylene and indole structures were obtained by one-pot reaction of desilication and tandem Sonogashira coupling (as shown in Formula V-1 and Formula V-2, with yields of 96% and 82%, respectively).

[0049] Application 1: Hydrolyzing the substance shown in formula V in the presence of lithium hydroxide yields propynic acid as shown in formula V-3, with a yield of 81%.

[0050] Application 2: The substance shown in Formula V was treated with lithium aluminum hydride to obtain high propargyl alcohol as shown in Formula V-4, with a yield of 98%.

[0051] Application 3: The substance shown in Formula V was treated with a 9-BBN / hydrogen peroxide system and then subjected to a hydroboration / oxidation reaction to obtain the product shown in Formula V-5, with a yield of 42%.

[0052] Example 19 Compared to Example 17, methyl phenyldiazoacetate was adjusted to an equal amount of the starting material shown in Formula II-5, while all other aspects remained the same as in Example 17, yielding the product shown in Formula VI (yield 84%). The product shown in Formula VI was then subjected to Suzuki coupling with 2-furanboronic acid to obtain the furan-modified 1,5-enyne product shown in Formula VI-1 (yield 95%). .

[0053] Example 20 Ammonia luminate was synthesized according to the following procedure: (1) 3.6 g of TIPS-protected alkynyl bromide, 5.6 mL of allyl borate ester, and 4.6 g of methyl-2-diazo-2-(4-nitrophenyl)acetic acid ester were reacted at 70 °C for 24 h to give 1.34 g of intermediate product 1 with a yield of 47%. It was a light yellow solid with structural characterization data: Rf=0.5 (hexane / EtOAc=40:1); mp 51-52 °C; 1 HNMR (600MHz, CDCl3) δ 8.24-8.18 (m, 2H), 7.79-7.73 (m, 2H), 5.70 (ddt, J=18.9, 9.4, 7.1 Hz, 1H), 5.08-5.02 (m, 2H), 3.71 (s, 3H), 3.05 (dd, J=13.8, 6.9 Hz, 1H), 2.78 (ddd, J=13.8, 7.4, 1.2 Hz, 1H), 1.11 (d, J =2.9Hz, 21H); 13 C NMR (151MHz, CDCl3) δ 170.98, 147.46, 146.11, 132.27, 128.11, 123.72, 119.75, 104.05, 90.02, 53.42, 53.37, 44.62, 18.75, 11.37; HRMS (ESI) calcd forC 23 H 34 NO4Si [M+H] + m / z 416.2252, found 416.2258.

[0054] (2) Under a nitrogen atmosphere, 2.73 g of intermediate product 1 was dissolved in 6 ml of THF and added to 9-BBN to form a 0.5 mol / L solution. The solution was heated to 80°C and stirred continuously for 3 h. After cooling to 0°C, 7.2 ml of H2O, 7.2 ml of 1.2 M NaOH solution and 2.6 mL of 30% H2O2 were added sequentially and stirred at room temperature for 12 h. The reaction solution was diluted with 20 ml of Et2O, the organic phase was washed with saturated NH4Cl solution and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane / EtOAc=3:1) to obtain 1.34 g of intermediate product 2, which was a light yellow liquid with a yield of 47%. The structural characterization data was: Rf=0.4 (hexane / EtOAc=3:1).

[0055] (3) Dissolve 1.34 g of intermediate product 2 in 10 ml of anhydrous DMF, add 5.8 g of pyridine dichromic acid (PDC) and 1.33 g of 3 Å molecular sieve, and stir at room temperature for 8 h. After the reaction is complete, filter with silica gel, elute three times with EtOAc, and wash twice with water. Combine the organic phases, adjust the pH value to <2 with 2.0 M HCl solution, wash with brine, dry with anhydrous Na2SO4, concentrate under reduced pressure, and purify by column chromatography (hexane / EtOAc=3:1) to obtain 1.1 g of intermediate product 3. Structural characterization data: Rf=0.3 (hexane / EtOAc=1:1).

[0056] (4) At 0°C, 448 mg of intermediate product 3 was dissolved in 5 ml of anhydrous THF, then 172 μL of oxalyl chloride was added, followed by 8 μL of DMF, and stirred at room temperature for 2 h; then 1.34 ml of 28% concentrated ammonia was added dropwise under ice bath, and stirred at room temperature for 5 h; the reaction solution was dissolved with EtOAc, washed with water and brine in sequence, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain crude product; the obtained crude product was dissolved in 5 ml of THF, 246 mg of KOtBu was added at 0°C, and stirred for 1 h; filtered, concentrated, and purified by column chromatography (hexane / EtOAc=5:1) to obtain 266 mg of intermediate product 4, which was a white solid with a yield of 64%, and structural characterization data: mp 149-151°C.

[0057] (5) Dissolve 266 mg of intermediate product 4 in 3 ml of THF, add 1 ml of 1.0 M TBAF in THF solution, and stir at room temperature for 2 h. After the reaction is complete, filter with silica gel, elute three times with EtOAc, remove solvent under reduced pressure to obtain crude product. Dissolve crude product in EtOAc, add Pd / C (10 mol%), and stir at room temperature for 4 h under hydrogen (1 atm). Filter the reaction solution, treat with silica gel to obtain 134 mg of the target product aminoluminate, which is a light yellow solid. The yield of this step is 90%. The structural characterization data are: Rf = 0.3 (hexane / EtOAc-2:1); mp 153-154°C.

[0058] Ammonia luminate was successfully obtained through the following five steps, with a total yield of 10%: .

[0059] Example 21 Anilidine was synthesized according to the following procedure: (1) Intermediate product 5 was prepared using the same procedure as in Example 17. It was an orange oily substance with a yield of 83% and structural characterization data of Rf=0.7 (petroleum ether / ethyl acetate=40:1). 1 HNMR (600MHz, CDCl3) δ 7.59 (d, J=7.8Hz, 2H), 7.33 (t, J=7.6Hz, 2H), 7.27 (d, J=7.2Hz, 1H), 5.75 (td, J=17.1, 7.0Hz, 1H), 5.04 (dd, J=24.0, 13.6Hz, 2H), 4.26-4.18 (m, 1H), 4.10-4.02 (m, 1H), 3.02 (dd, J=13.7, 7.1 Hz, 1H), 2.75 (dd, J=13.7, 7.1 Hz, 1H), 1.12 (s, 21H); 13 CNMR (151MHz, CDCl3) δ 171.44, 139.18, 133.48, 128.45, 127.55, 126.81, 118.68, 105.70, 88.09, 61.91, 53.35, 44.74, 18.79, 14.03, 11.44; HRMS (ESI) calculated value C 24 H 37 O2Si [M+H] + m / z 385.2557, measured value 385.2555.

[0060] (2) At room temperature, 1.6 g of intermediate product 5 was dissolved in 2 ml of THF and 6.45 mL of 1.0 M TBAF in THF solution was added. The mixture was stirred at room temperature for 3 h. After the reaction was completed, the mixture was filtered through thin-layer silica gel and eluted three times with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 886 mg of pale yellow liquid, which was intermediate product 6. The yield was 90%. The structural characterization data was: Rf = 0.6 (petroleum ether / ethyl acetate = 40:1). 1 H NMR (600MHz, CDCl3) δ7.62-7.54(m,2H),7.35 (t,J=7.6Hz,2H), 7.29(t,J=7.3Hz,1H), 5.77(ddt,J=17.2,10.2,7.1Hz,1H),5.13-5.04 (m, 2H), 4.21-4.16 (m, 2H), 3.03 (ddt, J=13.7, 7.2, 1.1Hz, 1H), 2.78 (ddt, J-13.8, 7.0, 1.2Hz, 1H), 2.64 (s, 1H), 1.20 (t, J=7.1Hz, 3H); 13 CNMR (151MHz, CDCl3) δ171.00, 138.59, 133.17, 128.61, 127.81, 126.64, 119.01, 82.48, 75.32, 62.24, 52.45, 44.23, 14.03; HRMS (ESI) calculated values ​​C 15 H 17 O2[M+H] + m / z 229.1223, measured value 229.1226.

[0061] (3) 457 mg of intermediate product 6 and 14.5 mg of RuCl3 were suspended in 10.5 ml of a mixed solvent of MeCN and deionized water with a volume ratio of 6:1. 107 mg of NaIO4 was added within 5 min, and the mixture was stirred continuously at room temperature for 6 h. After the reaction was completed, the mixture was filtered through diatomaceous earth, the filtrate was extracted with ethyl acetate, the organic layer was dried with Na2SO4 and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 242 mg of colorless liquid, which is intermediate product 7, with a yield of 50%. Its structural characterization data is: Rf = 0.4 (petroleum ether / ethyl acetate = 10:1). 1H NMR (600MHz, CDCl3) δ9.72 (s, 1H), 7.60-7.55 (m, 2H), 7.39 (t, J=7.7Hz, 2H), 7.33 (t, J=7.3Hz, 1H), 4.31-4.16 (m, 2H), 3.32 (dd, J=17.0, 1.7Hz, 1H), 2.99 (dd, J=17.0, 2.1Hz, 1H), 2.72 (s, 1H), 1.22 (t, J = 7.1Hz, 3H); 13 CNMR (151MHz, CDCl3) δ198.93, 170.17, 137.47, 128.96, 128.27, 126.22, 81.35, 76.14, 62.73, 52.58, 48.23, 13.82; HRMS (ESI) calculated value C 14 H 15 O3 [M+H] + m / z 231.1016, measured value 231.1019.

[0062] (4) 58.0 mg of intermediate product 7 was placed in a dried vial, and 7.3 mg of [CpRu(CH3CN)3]PF6, 12.6 mg of 5,5'-bis(trifluoromethyl)-2,2'-bipyridine and a magnetic particle were added. Under nitrogen protection, 1 ml of degassed water and N-methyl-2-pyrrolidone mixed solvent (volume ratio 1:4) was added. The mixture was stirred at 35 °C for 24 h. After the reaction was completed, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine in sequence, dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 35.2 mg of white solid, which is intermediate product 8. The yield of this step was 71%. Its structural characterization data: Rf=0.6 (petroleum ether / ethyl acetate=1:1).

[0063] (5) 24.8 mg of intermediate product and 28 mg of 4-Boc-amino-phenylethylamine were dissolved in 1 ml of DCE, and 63.6 mg of NaBH(OAc)3 was added. The mixture was stirred at room temperature for 4 h (TLC monitoring). After the reaction was completed, the solvent was evaporated, and the residue was dissolved in 1 ml of DCM. Then 0.4 ml of CF3COOH was added, and the mixture was stirred for another 6 h. After the intermediate was consumed, the solution was adjusted to alkalinity with 1.0 M NaOH solution. The mixture was then extracted with ethyl acetate, the organic layer was dried and concentrated. The residue was purified by silica gel column chromatography to obtain 32.5 mg of white solid, which was the target product anilidine. The yield of this step was 92%. The structural characterization data were: Rf = 0.4 (petroleum ether / ethyl acetate = 1:1), mp 79-80℃.

[0064] Ammonia luminate was successfully obtained through the following five steps, with a total yield of 24%: .

[0065] Example 22 Compared with Example 16, the reaction temperature and time were adjusted to 65°C for 24 hours. The molar ratio of TIPS-protected alkynyl bromide, methyl phenyl diazonate, pinacol allyl borate, and cesium neopentanoate was 1:3:1:1:5. The molar percentages of Pd(OAc)2 and P(4-MeO-C6H4)3 were 5% and 25%, respectively. All other parameters remained the same as in Example 16.

[0066] Example 23 Compared with Example 16, the reaction temperature and time were adjusted to 100°C for 10 hours. The molar ratio of TIPS-protected alkynyl bromide, methyl phenyl diazonate, pinacol allyl borate, and cesium neopentanoate was 1:1:10:1:1. The molar percentages of Pd(OAc)2 and P(4-MeO-C6H4)3 were 15% and 15%, respectively. All other parameters remained the same as in Example 16.

[0067] The key technical parameters and corresponding crude NMR yields of each embodiment are shown in Table 1.

[0068] Table 1

[0069] As shown in Table 1, this invention successfully synthesized 1,5-enyne compounds through a palladium-catalyzed three-component coupling reaction of haloalkynes, diazo compounds, and allyl borate esters.

[0070] A comparison of the crude NMR yield results from Examples 1 to 4 shows that, under the same conditions, using Pd(OAc)2 as a palladium catalyst is more conducive to improving the yield.

[0071] A comparison of the crude NMR yield results from Examples 1 and 5-9 shows that, among the six ligands involved, the corresponding crude NMR yields are L3 > L1 > L2 > L4 > L5 > L6. This indicates that monodentate phosphine ligands are superior to bidentate phosphine ligands, and electron-rich monodentate phosphine ligands are superior to electron-deficient monodentate phosphine ligands.

[0072] A comparison of the crude NMR yields in Examples 6 and 10-12 shows that DCE is the most suitable among the four solvents used (Toluene, Dioxane, DME, and DCE), achieving a crude NMR yield as high as 61%, far superior to the other three solvents. Furthermore, a yield comparison between Examples 12 and 13 reveals that using DCE as the organic solvent and setting the reaction temperature to 70°C helps achieve a higher yield, indicating that lower temperatures are more conducive to the solvent effect compared to higher temperatures.

[0073] A comparison of the crude NMR yields of Examples 13-16 shows that Example 16, using CsOPiv as a base and setting the reaction temperature to 80°C, achieved a much higher yield than other bases, with a crude NMR yield as high as 91% and a purified yield as high as 87%. Example 16 is the optimal example of this application, and even after scaling up the reaction, it still has the same high yield as Example 16 (as shown in Example 17). In addition, the conversion studies of the product shown in Formula V in Example 18, the conversion studies of the product shown in Formula VI in Example 19, the total synthesis of ammonia glutathione in Example 20, and the total synthesis of anilidine in Example 21 demonstrate that the simple synthesis method for 1,5-enyne compounds proposed in this invention has great application value and practicality, and has good prospects for industrialization and large-scale production.

[0074] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make modifications, alterations, substitutions, and variations to the above embodiments within the scope of the present invention. Furthermore, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of the different embodiments or examples.

Claims

1. A simple method for synthesizing 1,5-enyne compounds, characterized in that: In an organic solvent, alkynyl-protected haloalkynes of Formula I, diazo compounds of Formula II, and allyl borate esters of Formula III are reacted at 50-100°C for 10-48 h under an inert gas atmosphere with a palladium catalyst, an aromatic phosphine ligand, and a base to prepare 1,5-enyne compounds of Formula IV. The reaction equations are shown below: ； In Formula I: R is a sterically hindered silane protecting group, specifically selected from triisopropylsilane or tert-butyldimethylsilane, and X is selected from any one of Cl, Br, and I; In Formula II: Ar is any one of benzene ring, nitrogen-containing heterocycle, oxygen-containing heterocycle, sulfur-containing heterocycle, or a polycyclic structure composed of at least two of benzene ring, nitrogen-containing heterocycle, oxygen-containing heterocycle, and sulfur-containing heterocycle; M is an ester group or an amide group. The molar ratio of alkynyl-protected haloalkyn, diazo compound, allyl borate ester, and base is 1:(1-3):(1-10):(1-5). The molar percentages of palladium catalyst and aromatic ring-containing phosphine ligand are 5%-15% and 15%-25%, respectively, in units of the total molar amount of alkynyl-protected haloalkyn, diazo compound, allyl borate ester, and base.

2. The simplified method for synthesizing 1,5-enyne compounds according to claim 1, characterized in that: The palladium catalyst is selected from any one of Pd(OAc)2, Pd(PPh3)4, Pd(dba)2, and PdCl2; Preferably, the aromatic phosphine ligand is selected from any one of triarylphosphine, 1,2-bis(diphenylphosphine)ethane, 1,1'-bis(diphenylphosphine)ferrocene, and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, wherein the general chemical formula of the triarylphosphine is PAr3, and Ar is selected from any one of 4-MeO-C6H4, 4-CF3-C6H4, and Ph; Preferably, the reaction temperature is 70-80℃ and the reaction time is 16-24h.

3. The simplified method for synthesizing 1,5-enyne compounds according to claim 1, characterized in that: The organic solvent is selected from any one of 1,2-dichloroethane, ethylene glycol dimethyl ether, toluene, and 1,4-dioxane.

4. The simplified method for synthesizing 1,5-enyne compounds according to claim 1, characterized in that: The base is selected from any one of cesium neopentanoate, cesium acetate, cesium carbonate, and potassium carbonate.

5. The simplified method for synthesizing 1,5-enyne compounds according to claim 1, characterized in that: The diazo compounds represented by Formula II include the following compounds: 。 6. The simplified method for synthesizing 1,5-enyne compounds according to claim 1, characterized in that: In 1,2-dichloroethane, TIPS-protected alkynyl bromide, methyl phenyldiazoacetate, and pinacol allyl borate were reacted at 80°C for 22 h under inert gas protection with the action of Pd(OAc)2, P(4-MeO-C6H4)3, and cesium neopentanoate to prepare the compound shown in Formula V. ； The molar ratio of TIPS-protected alkynyl bromide, methyl phenyl diazonate, pinacol allyl borate, and cesium neopentanoate is 1:1.5:1.5:1.5, and the molar percentages of Pd(OAc)2 and P(4-MeO-C6H4)3 are 10% and 20%, respectively.

7. Application of a simple synthetic method for 1,5-enyne compounds as described in any one of claims 1-5, for the synthesis of ammonia luminate.

8. The application of the simplified synthetic method for 1,5-enyne compounds according to claim 7, characterized in that: Using 1,2-dichloroethane as solvent, TIPS-protected alkynyl bromide, 4-nitrophenyl diazonium ester, and allyl borate ester were reacted at 70°C for 24 h under inert gas protection with Pd(OAc)2, P(4-MeO-C6H4)3, and cesium neopentanoate to prepare intermediate 1. Intermediate 1 was subjected to a hydroboration-oxidation reaction to prepare intermediate 2. Intermediate 2 was oxidized to intermediate 3 in DMF with pyridinium dichromate and 3 Å molecular sieve. Intermediate 3 was reacted with ammonia in the presence of DMF catalyst, and then cyclized with potassium tert-butoxide to obtain intermediate 4. Intermediate 4 was subjected to a desilylation reaction to obtain ammonia luminate. The specific reaction process is as follows: 。 9. Application of a simplified synthetic method for a 1,5-enyne compound as described in claim 1, for the synthesis of anilidine.

10. The application of the simplified synthetic method for 1,5-enyne compounds according to claim 9, characterized in that: Using 1,2-dichloroethane as solvent, TIPS-protected alkynyl bromide, phenyl diazoethyl acetate, and allyl borate ester were reacted at 70°C for 24 h under inert gas protection with Pd(OAc)2, P(4-MeO-C6H4)3, and cesium neopentanoate to prepare intermediate 5. Intermediate 5 was then treated with TBAF to obtain intermediate 6. Intermediate 6 was oxidized to intermediate 8 via a two-step oxidation method. Intermediate 8 was then subjected to a one-pot reductive acylation and deprotection reaction to obtain anilidin. The specific reaction process is as follows: 。

Images