A tridentate n-heterocyclic carbene ruthenium complex, its preparation method and application

Abstract

The application discloses a tridentate azacyclo-ruthenium complex and a preparation method and application thereof. The ruthenium complex can be used as a catalyst for an alkylation reaction, and under the joint action of an additive base, catalyzes a diphenyl methyl phosphine oxide compound and an alcohol compound to generate a diphenyl methyl phosphine oxide derivative. The ruthenium complex is stable to air and humidity, has good functional group compatibility for catalyzing the alpha-alkylation reaction of the diphenyl methyl phosphine oxide compound, can synthesize various diphenyl methyl phosphine oxide derivatives, has mild reaction conditions, short reaction time and good application prospect.

Description

Technical Field

[0001] This invention relates to a nitrogen heterocyclic carbene ligand, a class of tridentate nitrogen heterocyclic carbene-ruthenium complexes formed by the ligand and ruthenium, a method for preparing the complexes, and the application of the ruthenium complexes as catalysts for the efficient and selective catalytic reaction of methyl diphenylphosphine oxide with alcohols. It belongs to the field of transition metal complexes and catalysts. Background Technology

[0002] Phosphine oxides are an important class of organophosphorus compounds. Their stable phosphorus-oxygen double bonds (P=O) and good coordination ability make them widely used in medicinal chemistry, agrochemicals, luminescent materials, and catalysis. The main methods for preparing phosphine oxides include low-temperature lithium-halogen exchange, Suzuki coupling reactions, and Arbuzov reactions. However, these methods are often limited in practical applications, such as the presence of multiple reactive sites in the substrate, the tendency for raw materials to remain in the product, and the generation of stoichiometric inorganic waste. In 2021, Wang Zhongxia's team used a catalytic system composed of Ni(COD)₂ (10 mol%) and a nitrogen-containing heterocyclic carbene ligand at 140 °C... o The reaction of methyldiarylphosphine with alcohols was achieved under C conditions. C -Benzylation reaction (Org. Biomol. Chem., 2021, 19, 2233–2242). The following year, Darcel et al. discovered that Knölker-type iron complexes could also catalyze this type of reaction, but it required the addition of the additive Me3NO and a higher reaction temperature (J. Organomet. Chem. 2022, 979, 122510). Thus, these inexpensive metal catalytic systems often require more demanding reaction conditions, such as higher reaction temperatures and larger catalyst loadings, which limits the large-scale application of the reaction. Therefore, designing and synthesizing novel, highly efficient catalysts to achieve the coupling reaction of methyl diphenylphosphine oxide with benzyl alcohol under relatively mild conditions has significant research value and promising industrial application prospects. Summary of the Invention

[0003] To address the shortcomings of existing technologies, the first objective of this invention is to provide a tridentate nitrogen heterocyclic carbene ruthenium complex. This complex has a simple structure, low raw material cost, and can be used as a catalyst to catalyze the α-alkylation reaction of methyl diphenylphosphine oxide with alcohols. It has advantages such as good catalytic performance, wide substrate applicability, and mild reaction conditions, and has good prospects for industrial application.

[0004] The tridentate nitrogen heterocyclic carbene ruthenium complex of the present invention has the structural formula shown in Formula 1: In Formula 1, R is selected from hydrogen, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, or halogen. The alkyl group can be methyl, ethyl, propyl, butyl, pentyl, etc.; the alkoxy group can be methoxy, ethoxy, propoxy, butoxy, pentoxy, etc.; the haloalkyl group can be trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, trifluoropentyl, etc.; and the halogen can be fluorine, chlorine, bromine, or iodine.

[0005] Preferably, in Formula 1, R is hydrogen, methyl, methoxy, trifluoromethyl, or chlorine, more preferably methoxy.

[0006] Furthermore, when R is hydrogen, methoxy, or chlorine, these three ruthenium complexes have the structural formulas shown in formulas 1a, 1b, and 1c, respectively. Among them, the ruthenium complex with the chemical structure shown in formula 1b exhibits the best catalytic performance.

[0007] A second objective of this invention is to provide a method for preparing the aforementioned tridentate nitrogen-heterocyclic carbene ruthenium complex, which is formed by coordination of a tridentate nitrogen-heterocyclic carbene compound with RuHCl(CO)(PPh3)3. The structural formula of the tridentate nitrogen-heterocyclic carbene compound is shown in the following formula LH: .

[0008] In equation LH, the definition of R is the same as in equation 1 above.

[0009] Furthermore, when R is hydrogen, methoxy, or chlorine, the structural formula of the ligand is shown as L1H to L3H: Furthermore, the preparation method of the tridentate nitrogen-heterocyclic carbene ruthenium complex specifically includes the following steps: I. Preparation of the tridentate nitrogen heterocyclic carbene compound represented by formula LH (1) 2-bromoaniline and imidazole were coupled by Buchwald-Hartwig reaction in the presence of base, ligand and copper catalyst to obtain 2-(1H-imidazolyl-1-yl)aniline as shown in Formula A. (2) 2-bromophenylboronic acid and the substituted 2-bromopyridine shown in formula B were coupled by Suzuki-Miyaura reaction under the action of base and palladium catalyst to obtain the substituted 2-(2-bromophenyl)pyridine shown in formula C. (3) The 2-(1H-imidazolyl-1-yl)aniline shown in Formula A and the substituted 2-(2-bromophenyl)pyridine shown in Formula C were subjected to a Buchwald-Hartwig coupling reaction in the presence of a base, a ligand and a palladium catalyst to obtain the compound shown in Formula L. (4) The compound shown in formula L is subjected to an alkylation reaction with benzyl bromide to obtain the tridentate nitrogen heterocyclic carbene compound shown in formula LH; II. Preparation of the tridentate nitrogen heterocyclic carbene ruthenium complex shown in Formula 1 (5) The tridentate nitrogen heterocyclic carbene compound shown in formula LH is reacted with RuHCl(CO)(PPh3)3 to obtain the tridentate nitrogen heterocyclic carbene ruthenium complex shown in formula 1.

[0010] Furthermore, when R is hydrogen, methoxy, or chlorine, the reaction equation for the ruthenium complex is as follows: Furthermore, in step (1), the base is cesium carbonate, the copper catalyst is cuprous oxide, and the ligand is 8-hydroxyquinoline.

[0011] Furthermore, in step (1), the molar ratio of 2-bromoaniline, imidazole, base, ligand and copper catalyst is 1:1.4-1.6:2.0-2.2:0.2-0.3:0.05-0.06.

[0012] Furthermore, in step (1), the reaction temperature is 95-105 ℃, for example 95 ℃, 100 ℃, 105 ℃, and the reaction time is 72-73 h.

[0013] Furthermore, in step (1), the reaction is carried out in the presence of an organic solvent, such as anhydrous acetonitrile. The organic solvent serves only as a reaction medium, and its amount can be adjusted as needed.

[0014] Furthermore, in step (1), after the reaction is complete, the mixture is cooled to room temperature, and an equal volume of dichloromethane is added to dilute the reaction solution. The mixture is then filtered, and the filtrate is concentrated under reduced pressure to remove the solvent, yielding 2-(1H-imidazolyl-1-yl)aniline. Furthermore, the product can also be purified using neutral alumina column chromatography.

[0015] Furthermore, in step (2), the base is potassium carbonate and the palladium catalyst is tetra(triphenylphosphine)palladium.

[0016] Furthermore, in step (2), the molar ratio of 2-bromophenylboronic acid, the substituted 2-bromopyridine shown in formula B, the base and the palladium catalyst is 1:0.9-1.1:2.4-2.6:0.01-0.03.

[0017] Furthermore, in step (2), the reaction temperature is 95-105 ℃, for example 95 ℃, 100 ℃, 105 ℃, and the reaction time is 6-6.5 h.

[0018] Furthermore, in step (2), the reaction is carried out in the presence of an organic solvent, which is a mixture of DME (ethylene glycol dimethyl ether) and H2O, preferably in a volume ratio of 1:1. The organic solvent serves only as a reaction medium, and its amount can be adjusted as needed.

[0019] Furthermore, in step (3), the base is sodium tert-butoxide, the palladium catalyst is tris(dibenzylacetone)palladium, and the ligand is 1,1'-bis(diphenylphosphine)ferrocene.

[0020] Furthermore, in step (3), the molar ratio of 2-(1H-imidazolyl-1-yl)aniline shown in formula A, the substituted 2-(2-bromophenyl)pyridine shown in formula C, the base, the ligand and the palladium catalyst is 1:1.2-1.4:2.0-2.2:0.1-0.2:0.05-0.1.

[0021] Furthermore, in step (3), the reaction temperature is 105-115℃, for example 105℃, 110℃, 115℃, and the reaction time is 24-25h.

[0022] Furthermore, in step (3), the reaction is carried out in the presence of an organic solvent, such as toluene. The organic solvent serves only as a reaction medium, and its amount can be adjusted as needed.

[0023] Furthermore, in step (4), the molar ratio of the compound represented by formula L to benzyl bromide is 1:1.0-1.1.

[0024] Furthermore, in step (4), the reaction temperature is 105-115℃, for example 105℃, 110℃, 115℃, and the reaction time is 24-25h.

[0025] Furthermore, in step (4), the reaction is carried out in the presence of an organic solvent, such as toluene. The organic solvent serves only as a reaction medium, and its amount can be adjusted as needed.

[0026] Furthermore, in step (5), the molar ratio of the tridentate nitrogen heterocyclic carbene compound represented by formula LH to RuHCl(CO)(PPh3)3 is 1.0-1.1:1.

[0027] Furthermore, in step (5), the tridentate nitrogen heterocyclic carbene compound and RuHCl(CO)(PPh3)3 react in an organic solvent; the purpose of the organic solvent is to provide a reaction medium for the reaction, and any organic solvent that can dissolve the reactants is acceptable, such as tetrahydrofuran (THF), toluene, etc.

[0028] Furthermore, in step (5), the reaction between the tridentate nitrogen-heterocyclic carbene compound and RuHCl(CO)(PPh3)3 is carried out in the presence of a base to remove the HCl generated in the reaction. The base can be triethylamine, potassium tert-butoxide, etc. The molar ratio of the tridentate nitrogen-heterocyclic carbene compound to the base is 1:35-40.

[0029] Furthermore, in step (5), the reaction is carried out under reflux. The reaction time is generally 14-24h, for example 14h, 15h, 16h, 17h, 18h, 19h, 21h, 22h, 23h, 24h.

[0030] Furthermore, in steps (1)-(5), the reactions are all carried out under the protection of an inert gas, such as nitrogen or argon.

[0031] The ruthenium complexes of this invention are easy to synthesize, have a simple preparation method, and exhibit stable structures. The ruthenium complexes are solid powders that do not deteriorate upon prolonged exposure to air and are stable to air and humidity. Experimental verification shows that the ruthenium complexes of this invention can serve as catalysts for the α-alkylation reaction of diphenylmethylphosphine oxide compounds with alcohols. When these ruthenium complexes catalyze the α-alkylation reaction of diphenylmethylphosphine oxide compounds with alcohols to generate diphenylmethylphosphine oxide derivatives, the reaction conditions are mild, the product is singular, the substrate range is broad, and it exhibits excellent functional group compatibility. Furthermore, the product yield obtained through optimized reaction conditions is high, demonstrating excellent catalytic performance. Therefore, this invention also provides the application of such ruthenium complexes in catalyzing α-alkylation reactions, specifically: the ruthenium complexes act as catalysts for α-alkylation reactions; the α-alkylation reaction is a reaction between diphenylmethylphosphine oxide compounds and alcohols.

[0032] This invention also provides a method for the α-alkylation reaction of diphenylmethylphosphine oxide compounds with alcohol compounds to generate diphenylmethylphosphine oxide derivatives. This method includes the step of reacting the alcohol compound shown in Formula 2 and the diphenylmethylphosphine oxide compound shown in Formula 3 in the presence of a catalyst and a base to generate the diphenylmethylphosphine oxide derivative shown in Formula 4. The catalyst is the tridentate nitrogen-containing heterocyclic carbene ruthenium complex described above in this invention; the reaction formula is as follows: Furthermore, in Equation 2, R 1The substituents can be phenyl, substituted phenyl, naphthyl, substituted naphthyl, pyrene, substituted pyrene, furanyl, substituted furanyl, thiophene, substituted thiophene, benzothiophene, or substituted benzothiophene. The substituents on the benzene ring, naphthyl ring, pyrene ring, furan ring, thiophene ring, or benzothiophene ring can be methyl, isopropyl, tert-butyl, methoxy, tert-butoxy, halogen, trifluoromethoxy, etc., and their positions are arbitrary.

[0033] Furthermore, the alcohol compounds can be benzyl alcohol, p-methoxybenzyl alcohol, p-chlorobenzyl alcohol, 1-naphthyl alcohol, 2-furan alcohol, etc.

[0034] Furthermore, in Equation 3, R 2 It can be hydrogen, methyl, methoxy, or halogen.

[0035] Furthermore, in the above-mentioned synthesis method of diphenylmethylphosphine oxide derivatives, a base acts as both an additive and a catalyst to catalyze the dehydrogenation of the alcohol compound of formula 2 into the corresponding aldehyde or ketone intermediate. The base can be potassium tert-butoxide (KO). t Bu), lithium tert-butoxide (LiO) t Bu), potassium methoxide (KO t At least one of the following: Bu, potassium hydroxide (KOH), potassium carbonate (K2CO3), cesium carbonate (Cs2CO3).

[0036] Furthermore, the molar amount of the alcohol compound shown in Formula 2 is 100%-200% of the molar amount of the diphenylmethylphosphine oxide compound shown in Formula 3, for example, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, preferably 150%.

[0037] Furthermore, the molar amount of the catalyst is 0.3-1% of the molar amount of the diphenylmethylphosphine oxide compound shown in Formula 3, for example 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, preferably 0.5%.

[0038] Furthermore, the molar amount of the base is 50-75% of the molar amount of the diphenylmethylphosphine oxide compound shown in Formula 3, for example, 50%, 55%, 60%, 65%, 70%, 75%, preferably 50%.

[0039] Furthermore, in the above-mentioned synthesis method of diphenylmethylphosphine oxide derivatives, the reaction is carried out in an organic solvent. The role of the organic solvent is to provide a reaction environment for the chemical reaction. The reaction exhibits better reactivity in aromatic hydrocarbon organic solvents, such as toluene. The amount of solvent does not have a particularly large impact on the reaction; the organic solvent is added based on the actual solubility.

[0040] Furthermore, in the above-mentioned synthesis method of diphenylmethylphosphine oxide derivatives, the catalytic reaction temperature is relatively low, specifically 105-115°C, such as 105°C, 110°C, or 115°C, preferably 110°C. The reaction time is generally 12-14 hours, such as 12 hours, 13 hours, or 14 hours, preferably 14 hours.

[0041] Furthermore, the reaction is carried out under normal pressure and gas protection, and the protective gas can be an inert gas such as argon. The equipment requirements are low, the reaction operation is simple, and the reaction conditions are mild.

[0042] Compared with the prior art, the present invention has the following beneficial effects: 1. The ruthenium complex of the present invention has a simple structure, readily available raw materials, and is easy to prepare.

[0043] 2. The ruthenium complex of this invention can catalyze the α-alkylation reaction of diphenylmethylphosphine oxide compounds and alcohol compounds. It is a homogeneous ruthenium catalyst. The alcohol compounds are readily available and inexpensive, replacing the more expensive and easily oxidized aldehyde precursors, thus reducing costs and environmental pollution.

[0044] 3. The ruthenium complex of this invention is stable to air and humidity, exhibits good functional group compatibility and high selectivity in catalyzing the alkylation reaction of diphenylmethylphosphine oxide compounds with alcohols, and can catalyze the synthesis of a variety of diphenylmethylphosphine oxide derivatives. The reaction conditions are mild, the reaction time is short, and the cost is low, showing good development prospects.

[0045] 4. By optimizing the α-alkylation reaction conditions, the yield of the obtained diphenylmethylphosphine oxide derivatives can be improved. Attached Figure Description

[0046] Figure 1 The NMR spectrum is that of compound 1b obtained in Example 2.

[0047] Figure 2 The NMR spectrum is that of compound 4a obtained in Example 4. Detailed Implementation

[0048] The present invention will be further explained and illustrated below through specific embodiments. It should be understood that the following description is merely exemplary and does not limit its content.

[0049] Example 1 Step 1: In a 100 mL round-bottom flask, add 2-bromoaniline (2.0 g, 11.6 mmol), imidazole (1.19 g, 17.4 mmol), cuprous oxide (83 mg, 0.58 mmol), 8-hydroxyquinoline (334 mg, 2.3 mmol), and cesium carbonate (7.58 g, 23.3 mmol) sequentially. Under nitrogen protection, add 15 mL of anhydrous acetonitrile. Place the round-bottom flask in an oil bath and inflate at 100 mL. o The reaction was heated and stirred at C for 72 h. After the reaction was completed, the mixture was cooled to room temperature, and 15 mL of dichloromethane was added to dilute the reaction solution. The solution was then filtered. The filtrate was concentrated under reduced pressure to remove the solvent, and purified by neutral alumina column chromatography (eluent: dichloromethane / methanol, 50:1, v / v) to obtain the target product 2-(1H-imidazolyl-1-yl)aniline (off-white solid, 1.53 g, 83%). 1 H NMR (400 MHz, CDCl3) d 7.63 (s, 1H), 7.24 – 7.20 (m, 2H), 7.12 – 7.09 (m, 2H), 6.84 – 6.79 (m, 2H), 3.72 (s, 2H). Step 2: Add 2-bromophenylboronic acid (1.00 g, 5.0 mmol), 2-bromopyridine (0.79 g, 5.0 mmol), tetrakis(triphenylphosphine)palladium (0.12 g, 0.1 mmol), and potassium carbonate (1.75 g, 12.6 mmol) to a 100 mL single-necked flask. Purge the flask three times with nitrogen. Under a nitrogen atmosphere, add 15 mL of a 1:1 mixture of ethylene glycol dimethyl ether and water. Heat to 100 °C and react for 6 h. After the reaction is complete, cool to room temperature, separate the phases, extract the aqueous phase with ethyl acetate (10 mL × 3), combine the organic phases, dry with anhydrous magnesium sulfate, and filter. The solvent was removed under vacuum, and the remaining yellow oily substance was separated and purified by neutral alumina column chromatography (eluent: petroleum ether: ethyl acetate = 10:1, volume ratio). After drying, a light yellow oily liquid was obtained, which was 2-(2-bromophenyl)pyridine (0.758 g, yield 65%). 1 H NMR (400 MHz, CDCl3) d 8.71 (d, J = 4.0 Hz, 1H, Py H ), 7.76 (t, J = 8.0 Hz, 1H, Ar H ), 7.67 (d, J = 8.0 Hz, 1H, Ar H),7.60 (d, J = 8.0 Hz, 1H, Ar H ), 7.53 (d, J = 7.6 Hz, 1H, Ar H ), 7.40 (t, J = 7.2 Hz, 1H, Py H ), 7.32 – 7.23 (m, 2H, Py H ). Step 3: In a 25 mL round-bottom flask, add sequentially the following compounds: 2-(1H-imidazolyl-1-yl)aniline (320 mg, 2.0 mmol) prepared in Step 1, 2-(2-bromophenyl)pyridine (565 mg, 2.4 mmol) prepared in Step 2, tris(dibenzylacetone)palladium (92 mg, 0.10 mmol), 1,1'-bis(diphenylphosphine)ferrocene (111 mg, 0.20 mmol), and sodium tert-butoxide (386 mg, 4.0 mmol). Under nitrogen protection, add 5 mL of toluene. Place the round-bottom flask in an oil bath at 110 °C. o The reaction was heated and stirred at C for 24 h. After the reaction was completed, the mixture was cooled to room temperature, and 15 mL of ethyl acetate was added to dilute the reaction solution. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The solution was then purified by neutral alumina column chromatography (eluent: petroleum ether / ethyl acetate, 20:1, v / v) to obtain the target product L1 (light yellow solid, 415 mg, yield 66%). 1 H NMR (400 MHz, CDCl3) d 10.59 (s, 1H), 8.28 (d, J = 4.0 Hz, 1H), 7.70 – 7.65 (m, 2H), 7.63 – 7.55 (m, 4H), 7.31 –7.25 (m, 3H), 7.19 (d, J = 8.8 Hz, 2H), 7.11 – 7.08 (m, 1H), 6.96 (t, J = 7.6 Hz, 1H), 6.89 (t, J = 7.6 Hz, 1H). 13 C NMR (101 MHz, CDCl3) d158.0, 147.4, 141.0,139.1, 137.8, 137.0, 129.8, 129.7, 129.4, 129.4, 127.6, 126.7, 125.9, 122.1,121.1, 120.7, 120.6, 120.0, 117.8, 116.4. MP: 98 - 101 o C. HR-MS (ESI-TOF):calcd for C 20 H 17 N4, [M+H] + 313.1448, found 313.1473. Step 4: Add L1 (325 mg, 1.0 mmol) and benzyl bromide (171 mg, 1.0 mmol) to a 100 mL Schlenk flask, purge three times with nitrogen, then add 5 mL of toluene and 110 mL of nitrate. o The reaction was heated and stirred at C for 24 h. After the reaction was complete, it was allowed to cool naturally to room temperature, and a large amount of brown precipitate was formed. The precipitate was filtered, washed once with 5 mL of n-hexane, and dried under vacuum to give L1H (a grayish-white solid, 414 mg, yield 86%). 1 H NMR (400 MHz, CDCl3) d 10.50 (s, 1H), 10.43 (s, 1H), 8.00 (d, J = 4.0 Hz, 1H), 7.78 (t, J = 7.2 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.63(d, J = 8.8 Hz, 2H), 7.59 – 7.56 (m, 3H), 7.46 – 7.40 (m, 3H), 7.37 – 7.34 (m,3H), 7.18 – 7.08 (m, 4H), 6.95 (t, J = 7.2 Hz, 1H), 5.89 (s, 2H). 13 C NMR (101MHz, CDCl3) d157.5, 146.9, 141.3, 137.8, 137.3, 137.2, 133.4, 131.7, 130.0,129.7, 129.4, 129.3, 127.1, 125.8, 124.5, 123.1, 122.5, 121.9, 121.5, 121.0,116.9, 53.4. MP: 187 - 190 o C. HR-MS (ESI-TOF): calcd for C 27 H 23 N4, [M-Br] + 403.1917, found 403.1925. Step 5: Add L1H (145 mg, 0.3 mmol) and RuHClCO(PPh3)3 (285 mg, 0.3 mmol) to a 100 mL Schlenk flask. After purging with nitrogen three times, add 7.5 mL of tetrahydrofuran and 1.5 mL of triethylamine. Heat to reflux and stir for 14 h. After the reaction is complete, allow to cool naturally to room temperature, add 10 mL of n-hexane, and a large amount of orange-yellow solid precipitates. Filter, and wash the filter cake once with 5 mL of n-hexane to obtain the crude product. The crude product is rapidly purified by neutral alumina column chromatography using tetrahydrofuran as the eluent. Collect the target fraction, concentrate, and obtain product 1a (orange-yellow solid, 186 mg, yield 71%). 1 H NMR (400 MHz, CDCl3) d 8.27 – 8.24 (m, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.60– 7.58 (m, 3H), 7.44 – 7.39 (m, 3H), 7.33 – 7.31 (m, 1H), 7.24 – 7.22 (m,3H), 7.11 – 7.09 (m, 7H), 7.00 – 6.91 (m, 10H), 6.77 – 6.70 (m, 2H), 6.64 –6.61 (m, 1H), 6.50 – 6.45 (m, 1H), 6.24 – 6.10 (m, 2H), 5.82 – 5.73 (m, 1H). 13 C NMR (101 MHz, CDCl3) d 199.8 (d, J = 8.1 Hz, Ru CO), 177.8, 136.9, 136.6,136.4, 133.8, 133.7, 133.2, 132.8, 132.2, 132.1, 132.0, 129.6, 129.5, 128.8,128.6, 128.5, 128.2, 128.1, 127.6, 127.5, 122.5, 122.4, 119.9, 119.1, 68.6ppm. 31 p NMR (202 MHz, CDCl3) d 29.33 (s, PPh3). IR ( n CO KBr pellet, cm -1 ): 1924(s). HR-MS (ESI-TOF): calcd for C 46 H 36 N4OPRu, [M-Br] + 793.1670, found 793.1688. Example 2 Step 1: Prepare 2-(1H-imidazol-1-yl)aniline, as in Example 1, Step 1.

[0050] Step 2: Same as Step 2 in Example 1, except that 2-bromopyridine (0.79 g, 5.0 mmol) was replaced with 2-bromo-5-methoxypyridine (0.94 g, 5.0 mmol). The product 2-(5-methoxy-pyridin-2-yl)-aniline (yellow oily liquid, 0.906 g, 90% yield) was obtained.

[0051] Step 3: Same as Step 3 in Example 1, except that 2-(2-bromophenyl)pyridine is replaced with an equimolar amount of 2-(5-methoxy-pyridin-2-yl)-aniline to obtain product L2 (white solid, 0.484 g, yield 70%).

[0052] Step 4: Same as Step 4 in Example 1, except that L1 is replaced with an equimolar amount of L2 to obtain product L2H (grayish-white solid, 0.450 g, yield 88%). 1 H NMR (400 MHz, CDCl3) d10.40 (s, 1H), 10.18 (s, 1H),7.95 – 7.94 (m, 1H), 7.63 – 7.59 (m, 3H), 7.53 – 7.48 (m, 3H), 7.42 – 7.37(m, 3H), 7.32 – 7.29 (m, 4H), 7.11 – 7.09 (m, 2H), 7.03 (d, J = 8.0 Hz, 1H), 6.92 – 6.88 (m, 1H), 5.85 (s, 2H), 3.87 (s, 3H). 13 C NMR (101 MHz, CDCl3) d 154.3, 150.2, 141.0, 137.3, 134.4, 133.1, 131.7, 129.3, 129.2, 127.1, 126.4,124.6, 123.4, 123.4, 123.1, 123.0, 122.6, 122.4, 122.3, 120.8, 116.5, 56.1,53.5. MP: 198 - 201 o C. HR-MS (ESI-TOF): calcd for C 28 H 25 N4O, [M-Br] + 433.2023, found 433.2048. Step 5: Same as Step 4 in Example 1, except that L1H is replaced with an equimolar amount of L2H. The resulting product is 1b (orange-yellow solid, 216 mg, yield 80%), and the NMR spectrum of 1b is shown below. Figure 1 As shown. 1 H NMR (400 MHz, CDCl3) d 8.02 – 8.00 (m, 1H), 7.61 – 7.59 (m, 3H), 7.43 – 7.38 (m, 5H), 7.26 – 7.22 (m, 7H), 7.11 – 7.07 (m, 9H), 6.95 – 6.93 (m, 7H), 6.77 (s, 1H), 6.22 – 6.13 (m, 1H), 5.83 – 5.74 (m, 1H), 3.57 (s, 3H). 13 C NMR (101 MHz, CDCl3) d 203.9 (d, J = 8.1 Hz, RuC O), 177.8, 137.2, 136.6, 136.5, 133.8, 133.7, 133.3, 132.9, 132.2, 132.1,132.0, 129.6, 129.4, 128.8, 128.6, 128.5, 128.1, 127.6, 127.5, 122.4, 122.4,120.9, 119.1, 68.6, 55.9 ppm. 31 p NMR (202 MHz, CDCl3) d 29.26 (s, PPh3). IR ( n CO KBr pellet, cm -1 ): 1920 (s). HR-MS (ESI-TOF): calcd for C 47 H 38 N4O2PRu, [M-Br] + 823.1776, found 823.1781. Example 3 Step 1: Prepare 2-(1H-imidazol-1-yl)aniline, as in Example 1, Step 1.

[0053] Step 2: Same as Step 2 in Example 1, except that 2-bromopyridine (0.79 g, 5.0 mmol) was replaced with 2-bromo-5-chloropyridine (0.966 g, 5.0 mmol). The product 2-(5-chloropyridin-2-yl)-aniline (pale yellow solid, 0.775 g, yield 75%) was obtained.

[0054] Step 3: Same as Step 3 in Example 1, except that 2-(2-bromophenyl)pyridine was replaced with an equimolar amount of 2-(5-chloropyridin-2-yl)-aniline to obtain product L3 (white solid, 402 mg, yield 58%).

[0055] Step 4: Same as Step 4 in Example 1, except that L1 is replaced with an equimolar amount of L3 to obtain product L3H (grayish-white solid, 485 mg, yield 94%). 1 H NMR (400 MHz, CDCl3) d10.53 (s, 1H), 9.89 (s, 1H), 8.10– 8.07 (m, 1H), 7.74 – 7.63 (m, 4H), 7.56 – 7.49 (m, 4H), 7.45 – 7.41 (m,2H), 7.38 – 7.33 (m, 3H), 7.17 – 7.16 (m, 2H), 7.05 (d, J = 7.6 Hz, 1H), 6.92(t, J = 7.2 Hz, 1H), 5.84 (s, 2H). 13 C NMR (101 MHz, CDCl3) δ 156.2, 146.2,141.7, 137.6, 137.3, 136.8, 133.2, 131.8, 130.5, 130.1, 129.7, 129.5, 129.3,127.2, 124.2, 123.4, 123.2, 122.8, 122.2, 120.9, 116.6, 53.7. MP: 212 -215 o C. HR-MS (ESI-TOF): calcd for C 27 H 22 ClN4, [M-Br] + 437.1528, found 437.1536. Step 5: Add L3H (155 mg, 0.3 mmol) and RuHClCO(PPh3)3 (285 mg, 0.3 mmol) to a 100 mL Schlenk flask. After purging with nitrogen three times, add 7.5 mL of tetrahydrofuran and 1.5 mL of triethylamine. Heat to reflux and stir for 24 h. After the reaction is complete, allow to cool naturally to room temperature. Add 10 mL of n-hexane, and a large amount of orange-yellow solid precipitates. Filter, and wash the filter cake once with 5 mL of n-hexane to obtain the crude product. The crude product is rapidly purified by neutral alumina column chromatography using tetrahydrofuran as the eluent. Collect the target fraction, concentrate, and obtain product 1c (red solid, 122 mg, yield 45%). 1 H NMR (400 MHz, CDCl3) d 8.26 – 8.25 (m, 1H), 7.88 (d, J= 8.8 Hz, 1H), 7.69 –7.64 (m, 2H), 7.60 – 7.54 (m, 3H), 7.43 – 7.40 (m, 4H), 7.27 – 7.24 (m, 5H),7.13 – 7.12 (m, 9H), 7.02 – 7.00 (m, 3H), 6.80 – 6.70 (m, 3H), 6.54 – 6.50 (m, 1H), 6.27 – 6.21 (m, 1H), 6.10 – 6.05 (m, 1H), 5.77 – 5.70 (m, 1H). 13 C NMR (101 MHz, CDCl3) d 203.3 (d, J = 11.1 Hz, Ru C O), 179.1, 136.8, 136.8, 136.3,133.7, 133.6, 133.1, 132.9, 132.2, 132.1, 129.6, 129.6, 128.8, 128.6, 128.5,128.2, 128.2, 127.8, 127.7, 122.6, 122.5, 119.1, 117.8, 55.7 ppm. 31 P NMR (202MHz, CDCl3) d 29.36 (s, PPh3). IR ( n CO KBr pellet, cm -1 ): 1925 (s). HR-MS (ESI-TOF): calcd for C 46 H 35 ClN4OPRu, [M-Br] + 827.1281, found 827.1300. Example 4 Add benzyl alcohol 2a (81 mg, 0.75 mmol), methyl diphenylphosphine oxide 3a (108 mg, 0.5 mmol), potassium tert-butoxide (28 mg, 0.25 mmol), and ruthenium complex 1b (2.3 mg, 0.0025 mmol) sequentially to a 25 mL Schlenk tube. Under nitrogen protection, add 2.0 mL of toluene. Place in an oil bath at 110 °C. oThe reaction mixture was heated at C for 12 h. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was concentrated under reduced pressure. Then it was purified by neutral alumina column chromatography (eluent: petroleum ether / ethyl acetate, 10:1, v / v) to give a pale yellow solid 4a (141 mg, 92% yield).

[0056] The NMR spectrum of 4a is as follows Figure 2 As shown, the NMR data are: 1 H NMR (400 MHz, CDCl3) d 7.79 – 7.75 (m,4H), 7.55 – 7.46 (m, 6H), 7.28 – 7.25 (m, 2H), 7.20 – 7.16 (m, 3H), 2.96 –2.90 (m, 2H), 2.62 – 2.55 (m, 2H). 13 C NMR (101 MHz, CDCl3) d 141.3 (d, J = 15.1Hz), 132.8 (d, J = 97.9 Hz), 131.9 (d, J = 3.0 Hz), 130.9 (d, J = 10.1 Hz), 128.8 (d, J = 6.0 Hz), 128.7, 128.1, 126.4, 32.0 (d, J = 70.7 Hz), 27.6 (d, J = 3.0 Hz). 31 p NMR (162 MHz, CDCl3) d 31.50. Example 5 The reaction process and post-treatment were the same as in Example 4, except that benzyl alcohol 2a (81 mg, 0.75 mmol) was replaced with p-methoxybenzyl alcohol 2b (104 mg, 0.75 mmol), and finally a brown solid 4b (158 mg, 94% yield) was obtained.

[0057] 4b NMR data: 1 H NMR (400 MHz, CDCl3) d 7.78 – 7.74 (m, 4H), 7.52 – 7.46 (m, 6H), 7.07 (d,J = 8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 3.76 (s, 3H), 2.91 –2.85 (m, 2H), 2.58 – 2.52 (m, 2H). 13 C NMR (101 MHz, CDCl3) d 158.1, 133.3, 132.7(d, J = 93.9 Hz), 131.8 (d, J = 2.0 Hz), 130.8 (d, J = 10.1 Hz), 129.0, 128.8 (d, J =11.1 Hz), 114.0, 55.3, 32.1 (d, J = 70.7 Hz), 26.7 (d, J = 2.0 Hz). 31 P NMR (162MHz, CDCl3) d 31.58. Example 6 The reaction process and post-treatment were the same as in Example 4, except that benzyl alcohol 2a (81 mg, 0.75 mmol) was replaced with p-chlorobenzyl alcohol 2c (107 mg, 0.75 mmol), and finally a brown solid 4c (107 mg, yield 63%) was obtained.

[0058] 4c NMR data: 1 H NMR (400 MHz, CDCl3) d 7.78 – 7.73 (m, 4H), 7.53 – 7.46 (m, 6H), 7.21 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 2.96 – 2.87 (m, 2H), 2.58 – 2.51 (m, 2H). 13 C NMR (101 MHz, CDCl3) d 139.6 (d, J = 15.1 Hz), 133.6 (d, J =98.9 Hz), 132.0 (d, J = 3.0 Hz), 130.8 (d,J = 9.0 Hz), 129.5, 128.9, 128.8 (d, J =4.0 Hz), 128.1, 31.8 (d, J = 70.7 Hz), 27.1 (d, J = 2.0 Hz). 31 P NMR (162 MHz, CDCl3) d 31.29. Example 7 The reaction process and post-treatment were the same as in Example 4, except that benzyl alcohol 2a (81 mg, 0.75 mmol) was replaced with 1-naphthyl alcohol 2d (119 mg, 0.75 mmol), and finally a pale yellow solid 4d (160 mg, 90% yield) was obtained.

[0059] 4D NMR data: 1 H NMR (400 MHz, CDCl3) d 7.81 – 7.73 (m, 7H), 7.54 – 7.39 (m, 9H), 7.30 – 7.25 (m, 1H), 3.13 – 3.07 (m, 2H), 2.70 – 2.63 (m, 2H). 13 C NMR (101 MHz, CDCl3) d 137.3 (d, J = 15.1 Hz), 133.9, 132.8 (d, J = 97.9 Hz), 131.9 (d, J = 2.0 Hz), 131.3, 130.9 (d, J = 10.1 Hz), 128.9, 128.8 (d, J = 12.1 Hz), 127.3,126.2, 125.9, 125.7, 125.6, 123.3, 31.2 (d, J = 69.6 Hz), 24.8 (d, J = 3.0 Hz). 31 PNMR (162 MHz, CDCl3) d 31.79. Example 8 The reaction process and post-treatment were the same as in Example 4, except that benzyl alcohol 2a (81 mg, 0.75 mmol) was replaced with 2-furan alcohol 2e (74 mg, 0.75 mmol), and finally a brown solid 4e (74 mg, 50% yield) was obtained.

[0060] 4e NMR data: 1 H NMR (400 MHz, CDCl3) d 7.78 – 7.73 (m, 4H), 7.54 – 7.48 (m, 7H), 6.22 (s, 1H), 5.98 (s, 1H), 2.99 – 2.93 (m, 2H), 2.66 – 2.59 (m, 2H). 13 C NMR (101 MHz, CDCl3) d 154.2 (d, J = 16.1 Hz), 141.3, 132.5 (d, J = 98.9Hz), 131.9 (d, J = 2.0 Hz), 130.8 (d, J = 9.0 Hz), 128.8 (d, J = 12.1 Hz), 110.3,105.5, 28.4 (d, J = 71.7 Hz), 20.4 (d, J = 2.0 Hz). 31 p NMR (162 MHz, CDCl3) d 31.85. Example 9 The reaction process and post-treatment were the same as in Example 4, except that methyl diphenylphosphine oxide 3a (108 mg, 0.5 mmol) was replaced with di-p-tolylmethylphosphine oxide 3b (122 mg, 0.5 mmol), and finally a light yellow solid 4f (145 mg, yield 87%) was obtained.

[0061] 4e NMR data: 1 H NMR (400 MHz, CDCl3) d7.66 – 7.62 (m, 4H), 7.28 – 7.23(m, 6H), 7.18 – 7.13 (m, 3H), 2.94 – 2.88 (m, 2H), 2.57 – 2.50 (m, 2H), 2.38(s, 6H). 13 C NMR (101 MHz, CDCl3) d 142.2 (d, J = 2.0 Hz), 141.4 (d, J = 15.1 Hz), 130.9 (d, J = 9.0 Hz), 129.7 (d, J = 101.0 Hz), 129.5 (d, J = 12.1 Hz), 128.6,128.1, 126.3, 32.1 (d, J = 69.6 Hz), 27.7 (d, J = 3.0 Hz), 21.6. 31 P NMR (162 MHz, CDCl3) d 32.39. Example 10 The reaction process and post-treatment were the same as in Example 4, except that benzyl alcohol 2a (81 mg, 0.75 mmol) was replaced with p-methoxybenzyl alcohol 2b (104 mg, 0.75 mmol), and methyl diphenylphosphine oxide 3a (108 mg, 0.5 mmol) was replaced with di(4-methoxyphenyl)methylphosphine oxide 3c (138 mg, 0.5 mmol), finally yielding 4 g (174 mg, yield 88%) of brown solid.

[0062] 4g of NMR data: 1 H NMR (400 MHz, CDCl3) d 7.68 – 7.64 (m, 4H), 7.07 (d, J =8.4 Hz, 2H), 6.98 – 6.96 (m, 4H), 6.79 (d, J = 8.4 Hz, 2H), 3.82 (s, 6H), 3.75(s, 3H), 2.88 – 2.82 (m, 2H), 2.54 – 2.45 (m, 2H). 13 C NMR (101 MHz, CDCl3) d 162.3, 158.0, 132.6 (d, J = 10.1 Hz), 129.0, 124.7, 123.7, 114.3 (d, J = 13.1Hz), 114.0, 55.3, 55.2, 32.5 (d, J = 70.7 Hz), 26.8 (d, J = 3.0 Hz). 31 P NMR (162MHz, CDCl3) d 31.84. Example 11 Compound 4a was prepared according to the method described in Example 4 above, except that a different catalyst was used, as shown in Table 1 below. Table 1 Example 12 Compound 4a was prepared according to the method described in Example 4 above, except that the reaction conditions were different, as shown in Table 2 below: Table 2 Comparative Example 1 Compound 4a was prepared according to the method in Example 4 above, except that no catalyst was added, and the product yield was 0%.

[0063] Comparative Example 2 Compound 4a was prepared according to the method in Example 4 above, except that the catalyst used was replaced with an equimolar amount of RuHCl(CO)(PPh3)3, and the product yield was 0%.

[0064] Comparative Example 3 Compound 1c was prepared according to the method in Example 3 of CN118684621A.

[0065] Compound 4a was prepared according to the method described in Example 4 above, except that the catalyst used was replaced with an equimolar amount of compound 1c reported in CN118684621A. The results showed that the product yield was 62%.

Claims

1. A tridentate nitrogen-heterocyclic carbene ruthenium complex, characterized in that... It has the structural formula shown in Equation 1 below: In Formula 1, R is selected from hydrogen, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl or halogen; preferably, R is methoxy.

2. A method for preparing a tridentate nitrogen-heterocyclic carbene ruthenium complex, characterized in that... Includes the following steps: (1) 2-bromoaniline and imidazole were coupled by Buchwald-Hartwig reaction in the presence of base, ligand and copper catalyst to obtain 2-(1H-imidazolyl-1-yl)aniline as shown in Formula A. (2) 2-bromophenylboronic acid and the substituted 2-bromopyridine shown in formula B were subjected to a Suzuki-Miyaura coupling reaction in the presence of a base and a palladium catalyst to obtain the substituted 2-(2-bromophenyl)pyridine shown in formula C. (3) The 2-(1H-imidazolyl-1-yl)aniline shown in Formula A and the substituted 2-(2-bromophenyl)pyridine shown in Formula C were subjected to a Buchwald-Hartwig coupling reaction in the presence of a base, a ligand and a palladium catalyst to obtain the compound shown in Formula L. (4) The compound shown in formula L is subjected to an alkylation reaction with benzyl bromide to obtain the tridentate nitrogen heterocyclic carbene compound shown in formula LH; (5) The tridentate nitrogen heterocyclic carbene compound shown in formula LH is reacted with RuHCl(CO)(PPh3)3 to obtain the tridentate nitrogen heterocyclic carbene ruthenium complex shown in formula 1; In equations B, C, L, and LH, the definition of R is consistent with that in equation 1.

3. The preparation method according to claim 2, characterized in that: In step (1), the base is cesium carbonate, the copper catalyst is cuprous oxide, and the ligand is 8-hydroxyquinoline; Preferably, in step (1), the molar ratio of 2-bromoaniline, imidazole, base, ligand and copper catalyst is 1:1.4-1.6:2.0-2.2:0.2-0.3:0.05-0.06; Preferably, in step (2), the base is potassium carbonate and the palladium catalyst is tetrakis(triphenylphosphine)palladium; preferably, in step (2), the molar ratio of 2-bromophenylboronic acid, the substituted 2-bromopyridine of formula B, the base and the palladium catalyst is 1:0.9-1.1:2.4-2.6:0.01-0.03; Preferably, in step (3), the base is sodium tert-butoxide, the palladium catalyst is tris(dibenzylacetone)palladium, and the ligand is 1,1'-bis(diphenylphosphine)ferrocene; Preferably, in step (3), the molar ratio of 2-(1H-imidazolyl-1-yl)aniline represented by formula A, the substituted 2-(2-bromophenyl)pyridine represented by formula C, the base, the ligand, and the palladium catalyst is 1:1.2-1.4:2.0-2.2:0.1-0.2:0.05-0.1; Preferably, in step (4), the molar ratio of the compound represented by formula L to benzyl bromide is 1:1.0-1.1; Preferably, in step (5), the molar ratio of the tridentate nitrogen heterocyclic carbene compound represented by formula LH to RuHCl(CO)(PPh3)3 is 1.0-1.1:

1.

4. The preparation method according to claim 2, characterized in that: In step (1), the reaction temperature is 95-105℃ and the reaction time is 72-73h; Preferably, in step (2), the reaction temperature is 95-105℃ and the reaction time is 6-6.5h; Preferably, in step (3), the reaction temperature is 105-115℃ and the reaction time is 24-25h; Preferably, in step (4), the reaction temperature is 105-115℃ and the reaction time is 24-25h; Preferably, in step (5), the reaction is carried out under reflux and the reaction time is 14-24h.

5. The preparation method according to claim 2, characterized in that: In steps (1)-(5), each reaction is carried out in a solvent environment and under the protection of an inert gas, and the solvents used in each step are the same or different.

6. The preparation method according to claim 2, characterized in that: In step (5), the reaction between the tridentate nitrogen heterocyclic carbene compound and RuHCl(CO)(PPh3)3 is carried out in the presence of a base; preferably, the base is triethylamine or potassium tert-butoxide; preferably, the molar ratio of the tridentate nitrogen heterocyclic carbene compound to the base is 1:35-40.

7. The application of the tridentate nitrogen-heterocyclic carbene ruthenium complex according to claim 1 in catalytic α-alkylation reactions, characterized in that: The α-alkylation reaction is a reaction between diphenylmethylphosphine oxide compounds and alcohol compounds.

8. A method for preparing diphenylmethylphosphine oxide derivatives via α-alkylation reaction, characterized in that: The step involves reacting an alcohol compound of Formula 2 and a diphenylmethylphosphine oxide compound of Formula 3 in the presence of a catalyst and a base to generate a diphenylmethylphosphine oxide derivative of Formula 4, wherein the catalyst is the tridentate nitrogen heterocyclic carbene ruthenium complex of claim 1; the reaction formula is as follows: ； In Equation 2, R 1 It is phenyl, substituted phenyl, naphthyl, substituted naphthyl, pyrene, substituted pyrene, furanyl, substituted furanyl, thiophene, substituted thiophene, benzothiophene or substituted benzothiophene; In Equation 3, R 2 It can be hydrogen, methyl, methoxy, or halogen.

9. The method according to claim 8, characterized in that: The base is at least one selected from potassium tert-butoxide, lithium tert-butoxide, potassium methoxide, potassium hydroxide, potassium carbonate, and cesium carbonate; preferably, the alcohol compound is benzyl alcohol, p-methoxybenzyl alcohol, p-chlorobenzyl alcohol, 1-naphthyl alcohol, or 2-furan alcohol.

10. The method according to claim 8, characterized in that: The molar amount of the alcohol compounds shown in Formula 2 is 100%-200% of the molar amount of the diphenylmethylphosphine oxide compounds shown in Formula 3; Preferably, the molar amount of the catalyst is 0.3-1% of the molar amount of the diphenylmethylphosphine oxide compound shown in Formula 3; Preferably, the molar amount of the base is 50-75% of the molar amount of the diphenylmethylphosphine oxide compound shown in Formula 3; Preferably, the reaction temperature is 105-115°C and the reaction time is 12-14 hours; Preferably, the reaction is carried out under normal pressure and gas protection; Preferably, the reaction is carried out in an organic solvent.

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