Chiral 1,2-diamine-derived n,n,n-tridentate pincer ligands, methods of synthesis and applications thereof

Abstract

This invention discloses a chiral 1,2-diamine-derived N,N,N-tridentate pincer ligand, its synthesis method, and its applications. The structural formula of the ligand is as follows: Ar is a nitrogen donor, which is pyridine, benzimidazole, or quinoline; R is methyl, isopropyl, or tert-butyl. This ligand has a stable structure, is simple to synthesize, and is easy to prepare in large quantities. Under an inert atmosphere, the ligand of this invention coordinates with an iron salt in an organic solvent to obtain a ligand / iron catalyst, which catalyzes the Brown Hydroboration reaction of olefins with high conversion rate, good chemoselectivity, and broad substrate versatility.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a chiral 1,2-diamine-derived N,N,N-tridentate pincer ligand, its synthesis method, and its application. This invention utilizes the ligand / iron complex as a catalyst in the Brown Hydroboration reaction of olefins to synthesize organoboron compounds. Background Technology

[0002] C-bonds are an important structural unit in organic synthesis. Since the discovery of the Brown Hydroboration reaction in 1956 (J. Am. Chem. Soc. 1956, 78, 2582), they have become one of the most commonly used and classic reactions for constructing C-bonds due to their advantages such as wide substrate applicability, strong functional group tolerance, and high atom economy. They are frequently used in the construction of carbon-carbon and carbon-hetero-(oxygen, nitrogen, halogen) bonds and are widely applied in materials and synthetic chemistry. They are also important bioactive molecules and pharmaceutical intermediates.

[0003] The mechanism of transition metal-catalyzed olefin hydroboration is closely related to the metal catalyst and ligand. In the past few decades, noble metal catalysts such as rhodium, ruthenium, palladium, and iridium have dominated the hydroboration addition reactions of olefins, especially rhodium catalysts, which exhibit very high catalytic efficiency and regioselectivity and have been widely used in organic synthesis (Chem. Rev. 1991, 91, 1179. Adv. Synth. Catal. 2005, 347, 609). However, the scarcity, high cost, high toxicity, and cumbersome post-processing of these noble metals in the Earth's crust have limited their widespread application to some extent. With the pursuit of green chemistry and sustainable development, the abundant and inexpensive transition metals iron, cobalt, and nickel in the Earth's crust have attracted widespread attention from chemists. Therefore, designing and synthesizing ligands suitable for abundant metal catalysis is key to achieving efficient hydroboration reactions.

[0004] Chiral 1,2-diamine-derived diimine nitrogen-containing ligands possess advantages such as simple synthesis, insensitivity to air and water, and strong metal chelation. Previous research has yielded significant progress on C2-symmetric ligands derived from chiral 1,2-diamines, but reports on chiral imine ligands with C1-symmetric 1,2-chiral diamine skeletons are scarce. Compared to C2-symmetric ligands, C1-symmetric ligands have more modifiable sites, allowing for the modulation of electronic and steric effects, thus providing greater opportunities for chemoselectivity, regioselectivity, and stereoselectivity control. In practical applications, these ligands are widely used in the asymmetric hydrogenation of alkenes and imines, but their application in iron-catalyzed Brown Hydroboration is limited. This patent, based on this foundation, proposes a method for synthesizing chiral 1,2-diamine-derived N,N,N-tridentate pincer-shaped ligands and their application in Brown Hydroboration. Summary of the Invention

[0005] To address the problems existing in the prior art, this invention provides a method for synthesizing chiral 1,2-diamine-derived N,N,N-tridentate pincer ligands and their application in Brown Hydroboration reactions, namely, the Brown Hydroboration reaction of olefins co-catalyzed by the ligands and iron salts to synthesize organoboron compounds.

[0006] To achieve the above-mentioned technical objectives, the technical solution of the present invention is as follows: A chiral 1,2-diamine-derived N,N,N-tridentate pincer ligand has the following structure: ; Wherein, Ar is a nitrogen donor, which is pyridine, benzimidazole, or quinoline; R is methyl, isopropyl, or tert-butyl, as exemplified by the following compound: ; The method for synthesizing the chiral 1,2-diamine-derived N,N,N-tridentate pincer ligand comprises the following steps: Under anhydrous and oxygen-free inert gas protection, pyridine-2-carboxaldehyde, 1-methyl-2-carboxylbenzimidazole, or quinoline-2-carboxaldehyde were dissolved in an organic solvent, and chiral 1,2-diphenylethylenediamine was added. Finally, TsOH·H2O (p-toluenesulfonic acid monohydrate) was added as a dehydrating agent. The reaction was carried out at 25-160℃ for 1-12 hours. Heating was stopped, and the reaction system was cooled to room temperature. The mixture was then filtered under reduced pressure using a short silica gel column. The residue was used directly in the next step without further purification. Under nitrogen protection, 2-tert-butylbenzaldehyde and TsOH·H2O were added to the resulting solid. The reaction temperature was 50-150℃, and the reaction time was 2-12 hours. After the reaction was completed, the solvent was removed by reduced pressure filtration. The resulting solid was recrystallized to obtain N,N,N-tridentate pincer ligands. The chemical reaction equation for the synthesis of the ligands is as follows: ; Where R=Me, i-Pr, t-Bu The molar ratio of pyridine-2-carboxaldehyde or 1-methyl-2-carboxylbenzimidazole or quinoline-2-carboxaldehyde to chiral 1,2-diphenylethylenediamine is 1:1-4.

[0007] Wherein, the molar ratio of pyridine-2-carboxaldehyde or 1-methyl-2-carboxylbenzimidazole or quinoline-2-carboxaldehyde to the first added TsOH·H2O is 1:1-3, and the molar ratio of 2-tert-butylbenzaldehyde to the second added TsOH·H2O is 1:1-3.

[0008] The molar ratio of pyridine-2-carboxaldehyde or 1-methyl-2-carboxylbenzimidazole or quinoline-2-carboxaldehyde to 2-tert-butylbenzaldehyde is 1-3:1.

[0009] The organic solvent is toluene, xylene, mesitylene, dichloromethane, tetrahydrofuran, chloroform, pyridine, DMF, or DMSO.

[0010] The application of the chiral 1,2-diamine-derived N,N,N-tridentate pincer ligand in the iron-catalyzed Brown Hydroboration reaction of alkenes.

[0011] The application is as follows: Under inert gas protection, a chiral 1,2-diamine-derived N,N,N-tridentate pincer ligand reacts with an iron salt in an organic solvent to obtain a ligand / iron catalyst. The iron salt is FeCl2, FeBr2, or Fe(OTf)2, where OTf is trifluoromethanesulfonate. The organic solvent is dichloromethane, toluene, tetrahydrofuran, chloroform, pyridine, DMF, or DMSO. The molar ratio of the iron salt to the ligand is 1:1-3. The reaction temperature is 25-100 °C. The reaction time is 3-10 h.

[0012] Under inert gas protection, the ligand / iron catalyst is used to catalyze the Brown Hydroboration reaction of olefins; the specific description is as follows: olefins, HBpin and base are added sequentially to the solution of ligand / iron catalyst, monitored by TLC, and after the reaction is completed, quenched and separated by column chromatography to obtain the product.

[0013] The molar ratio of ligand / iron catalyst: olefin: HBpin is 1:20-30:30-40; the base agent is sodium triethylborohydride, sodium tert-butoxide, potassium tert-butoxide, ethyl magnesium bromide, or lithium methyl; the molar ratio of olefin: base agent is 1:1.4; the reaction temperature is 25-140 °C; the reaction time is 2-12 h; preferably, the molar ratio of ligand / iron catalyst: olefin: HBpin is 1:20:24; the reaction temperature is 25 °C; the reaction time is 5 h.

[0014] Compared with the prior art, the present invention has the following beneficial effects: This invention provides a chiral 1,2-diamine-derived N,N,N-tridentate pincer ligand. The ligand's spatial structure and reactivity are modulated by using nitrogen donors with different structures. This ligand is applied to iron-catalyzed Brown Hydroboration reactions, resulting in a highly reactive catalytic system with broad substrate versatility. The ligand of this invention has advantages such as readily available and simple raw materials, minimal synthetic steps, insensitivity to air and water, and strong metal chelation. Detailed Implementation

[0015] The technical solution of the present invention will be clearly and completely described below with reference to specific embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Example 1

[0016] This embodiment provides a method for synthesizing N,N,N-tridentate clamp ligand L1, the steps of which are as follows: ; Under anhydrous and oxygen-free conditions, pyridine-2-carboxaldehyde (1.07 g, 10.0 mmol) was dissolved in 25 mL of anhydrous toluene, and chiral 1,2-diphenylethylenediamine (2.33 g, 11.0 mmol) was added. Finally, p-toluenesulfonic acid monohydrate (2.85 g, 15.0 mmol) was added as a dehydrating agent, and the reaction was carried out at 110 °C for 6 hours. After heating was stopped and the reaction system was cooled to room temperature, it was filtered under reduced pressure using a short silica gel column. The residue was used directly in the next step without further purification. Under nitrogen protection, 2-tert-butylbenzaldehyde (1.62 g, 10.0 mmol) and p-toluenesulfonic acid monohydrate (2.85 g, 15.0 mmol) were added to the product. The reaction temperature was 110 °C, and the reaction time was 12 hours. After the reaction was completed, the mixture was cooled to room temperature, and the solvent was removed by filtration under reduced pressure. The crude product was recrystallized to give 2.8 g of white solid L1, with a yield of 63%.

[0017] MPa: 122-124 °C; 1 H NMR (400 MHz, CDCl3): δ 8.76 (s, 1H), 8.60 (d, J =2.0 Hz, 1H), 8.28 (s, 1H), 7.84-7.92 (m, 2H), 7.68 (d, J = 2.0 Hz, 1H), 7.39-7.32 (m, 12H), 7.20-7.13 (m, 2H), 4.80 (d, J = 2.4 Hz, 1H), 3.2 (d, J = 2.4Hz, 1H), 1.35 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 160.8, 159.7, 154.5, 153.7,149.1, 140.7, 136.1, 130.8, 130.6, 128.6, 127.7, 126.2, 125.9, 125.1, 120.0,71.1, 70.5, 54.5, 31.0. HRMS (ESI) calcd for C 31 H 32 N3 [M+H] + : 446.2591, found446.2595. Example 2

[0018] This embodiment provides a method for synthesizing N,N,N-tridentate clamp ligand L2, the steps of which are as follows: ; Under anhydrous and oxygen-free conditions, 1-methyl-2-formylbenzimidazole (1.60 g, 10.0 mmol) was dissolved in 25 mL of chloroform, and chiral 1,2-diphenylethylenediamine (8.44 g, 40.0 mmol) was added. Finally, p-toluenesulfonic acid monohydrate (1.90 g, 10.0 mmol) was added as a dehydrating agent, and the reaction was carried out at 25 °C for 12 hours. Heating was stopped, and the reaction system was cooled to room temperature. The mixture was then filtered under reduced pressure using a short silica gel column. The residue was used directly in the next step without further purification. Under nitrogen protection, 2-tert-butylbenzaldehyde (4.86 g, 30.0 mmol) and p-toluenesulfonic acid monohydrate (5.7 g, 30.0 mmol) were added to the product. The reaction temperature was 50 °C, and the reaction time was 12 hours. After the reaction was completed, the mixture was cooled to room temperature, and the solvent was removed by filtration under reduced pressure. The crude product was recrystallized to give 2.88 g of white foamy solid L2, with a yield of 58%.

[0019] MPa: 124-127 °C; 1 H NMR (400 MHz, CDCl3): δ 8.54 (s, 1H), 7.95 (s, 1H), 7.78-7.70 (m, 2H), 7.45-7.32 (m, 13H), 7.21-7.14 (m, 2H), 4.78 (d, J = 2.4Hz, 1H), 4.26 (s, 3H), 3.20 (d, J = 2.0 Hz, 1H), 1.37 (s, 9H). 13 C NMR (101MHz, CDCl3,): δ 163.7, 160.5, 153.9, 141.7, 140.7, 138.9, 134.2, 130.8,130.6, 128.8, 128.6, 125.9, 125.2, 123.0, 115.2, 110.2, 71.1, 70.5, 37.1,33.8, 31.3. HRMS (ESI) calcd for C 34 H 35 N4 [M+H] + : 499.2856, found 499.2853. Example 3

[0020] This embodiment provides a method for synthesizing the N,N,N-tridentate clamp ligand L3, the steps of which are as follows: ; Under anhydrous and oxygen-free conditions, quinoline-2-carboxaldehyde (1.57 g, 10.0 mmol) was dissolved in 25 mL of pyridine, and chiral 1,2-diphenylethylenediamine (2.12 g, 10.0 mmol) was added. Finally, p-toluenesulfonic acid monohydrate (5.7 g, 30.0 mmol) was added as a dehydrating agent, and the reaction was carried out at 160 °C for 1 hour. Heating was stopped, and the reaction system was cooled to room temperature. The mixture was then filtered under reduced pressure using a short silica gel column. The residue was used directly in the next step without further purification. Under nitrogen protection, 2-tert-butylbenzaldehyde (1.62 g, 10.0 mmol) and p-toluenesulfonic acid monohydrate (1.90 g, 10.0 mmol) were added to the product. The reaction temperature was 150 °C, and the reaction time was 2 hours. After the reaction was completed, the mixture was cooled to room temperature, and the solvent was removed by filtration under reduced pressure. The crude product was recrystallized to give 3.45 g of white foamy solid L3, with a yield of 70%.

[0021] MPa: 119-121 °C; 1 H NMR (400 MHz, CDCl3): δ 8.76 (s, 1H), 8.70 (d, J =3.6 Hz, 1H), 8.28 (s, 1H), 8.01-7.83 (m, 4H), 7.68 (d, J = 2.8 Hz, 1H), 7.53(t, J = 3.2 Hz, 1H), 7.46-7.32 (m, 11H), 7.20-7.13 (m, 2H), 4.81 (d, J = 2.4Hz, 1H), 3.16 (d, J = 2.0 Hz, 1H), 1.36 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ160.9, 155.4, 154.5, 153.8, 148.5, 140.9, 140.8, 136.5, 134.2, 130.8, 130.7,129.9, 128.8, 128.6, 127.6, 127.0, 125.8, 125.1, 119.6, 71.6, 71.5, 37.1,31.2. HRMS (ESI) calcd for C 35 H 34 N3 [M+H] + : 496.2747, found 496.2745. Example 4

[0022] This embodiment provides a method for synthesizing L3·FeCl2 catalyst, the steps of which are as follows: Under an inert gas atmosphere, L3 (2.47 g, 5.0 mmol) was dissolved in dichloromethane, followed by the slow addition of FeCl2 (0.63 g, 5.0 mmol), and the reaction was carried out at 25 °C for 10 hours. After the reaction was complete, the mixture was cooled to room temperature, the solvent was removed under reduced pressure, the residue was washed with diethyl ether, filtered, and dried under vacuum to give 2.33 g of the target product as a brown solid, with a yield of 75%.

[0023] Elemental analysis calcd for C 35 H 33 Cl2FeN3: C, 67.54; H, 5.34; N, 6.75; Found: C, 67.42; H, 5.20; N, 6.53. Example 5

[0024] This embodiment provides a method for synthesizing L3·FeBr2 catalyst, the steps of which are as follows: Under an inert gas atmosphere, L2 (4.95 g, 10.0 mmol) was dissolved in tetrahydrofuran, and FeBr2 (1.08 g, 5.0 mmol) was slowly added to the system. The reaction was carried out at 80 °C for 6 hours. After the reaction was complete, the mixture was cooled to room temperature, the solvent was removed under reduced pressure, the residue was washed with diethyl ether, filtered, and dried under vacuum to give 2.21 g of the target product as a brown solid, with a yield of 62%.

[0025] Elemental analysis calcd for C 35 H 33 Br2FeN3: C, 69.10; H, 4.68; N, 5.91; Found: C, 69.42; H, 4.40; N, 5.82. Example 6

[0026] This embodiment provides a method for synthesizing L3·Fe(OTf)2 catalyst, the steps of which are as follows: Under an inert gas atmosphere, L3 (7.42 g, 15.0 mmol) was dissolved in toluene, and Fe(OTf)2 (1.77 g, 5.0 mmol) was slowly added to the system. The reaction was carried out at 100 °C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, the solvent was removed under reduced pressure, the residue was washed with diethyl ether, filtered, and dried under vacuum to give 2.76 g of the target product as a brown solid, with a yield of 65%.

[0027] Elemental analysis calcd for C 37 H 33F6FeN3O6S2: C, 52.31; H, 3.92; N, 4.95; Found: C, 52.42; H, 3.48; N, 4.81.

[0028] Application of N,N,N-Tridentate Pincer Ligands / Iron in Catalytic Brown Hydroboration Coupling Reaction

[0029] Screening for optimal reaction conditions: Using 4-methoxystyrene and HBpin as templates, the ligands, iron salts, catalyst dosage, and bases were screened.

[0030]

[0031]

[0032] [a] Reaction conditions: 4-methoxystyrene (0.5 mmol), HBpin (0.6 mmol), Fe / L = 1:1, base (0.7 mmol), solvent (2.0 mL), reaction time 5 h, yield was the separation yield.

[0033] We first selected 4-methoxystyrene and HBpin as templates for the reaction, FeCl2 as the iron source, and 1.4 equivalents of sodium triethylborohydride as the base to screen the ligands. From Table 1, we can see that after 5 hours of reaction, the yield of ligand L3 was the highest at 92% (Examples 7-9). When FeBr2, Fe(OTf)2, etc., were used instead of FeCl2 (Examples 10-11), the yield decreased. Next, we screened the bases (Examples 12-15). When NaO was used instead... t Bu, KO t When using Bu, EtMgBr, and MeLi, the reaction yield could not be further increased. An investigation of commonly used solvents (Examples 16-20) revealed that tetrahydrofuran was the optimal solvent. Increasing the reaction temperature to 50 °C (Example 18) slightly reduced the yield to 90%. Finally, using tetrahydrofuran as the solvent, NaBHEt3 as the base, and at 25 °C, with the catalyst dosage reduced to 2.5 mol%, the catalyst still exhibited high catalytic activity.

[0034] Through screening of reaction conditions, we selected the optimal reaction conditions as follows: 25 °C, FeCl2 (2.5 mol%) / L3 (2.5 mol%) as catalyst, 1.4 equivalents of NaBHEt3 as base, and catalyzed Brown Hydroboration reaction in tetrahydrofuran solvent. We studied and explored alkenes with different structures and determined the universality of the reaction (Table 2).

[0035]

[0036] Table 2. Results of FeCl2 / L3 catalyzed Brown Hydroboration on different olefin substrates.

[0037]

[0038] Reaction conditions: olefin (0.5 mmol), HBpin (0.6 mmol), FeCl2 / L3 (2.5 mol%), NaBHEt3 (0.7 mmol), THF (2.0 mL), reaction time 5 h, yield was the isolated yield.

[0039] The reaction results (Table 2) show that the hydroboration of alkenes catalyzed by FeCl2 and N,N,N-tridentate pincer ligands exhibits high catalytic activity and a broad substrate applicability, with yields mostly exceeding 85%. Specifically, when aromatic alkenes are used as substrates, regardless of whether the 4-position contains an electron-donating group such as methyl (Example 24) or an electron-withdrawing group such as fluorine, chlorine, bromine, trifluoromethyl, or ester (Examples 25-29), the target product can be obtained in high yields (85-95%). To further verify the catalytic activity of this system, we tested the reaction of aliphatic alkene derivatives (Examples 34-36) with HBpin, and found that the N,N,N-tridentate pincer ligand also exhibits high catalytic activity for aliphatic alkene derivatives, yielding the target product in 92-94% yields.

[0040] Therefore, the above examples demonstrate that chiral 1,2-diamine-derived N,N,N-tridentate pincer ligands exhibit good activity and regioselectivity in catalyzing Brown Hydroboration reactions, and also demonstrate strong substrate versatility.

[0041] The foregoing has shown and described the basic principles and main features of the present invention, as well as its advantages. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the claimed invention.

Claims

1. A chiral 1,2-diamine-derived N,N,N-tridentate pincer ligand, characterized in that... The structure is as follows: Wherein, Ar is a nitrogen donor, which is pyridine, benzimidazole or quinoline; R is methyl, isopropyl or tert-butyl.

2. The method for synthesizing the chiral 1,2-diamine-derived N,N,N-tridentate pincer ligand as described in claim 1, characterized in that... The steps are as follows: Under anhydrous and oxygen-free inert gas protection, pyridine-2-carboxaldehyde, 1-methyl-2-carboxylbenzimidazole, or quinoline-2-carboxaldehyde were dissolved in an organic solvent, and chiral 1,2-diphenylethylenediamine was added. Finally, TsOH·H2O was added as a dehydrating agent, and the reaction was carried out at 25-160℃ for 1-12 hours. After heating was stopped and the reaction system was cooled to room temperature, it was filtered under reduced pressure using a short silica gel column. The residue was used directly in the next step without further purification. Under nitrogen protection, 2-tert-butylbenzaldehyde and TsOH·H2O were added to the obtained solid at a reaction temperature of 50-150℃ for 2-12 hours. After the reaction was completed, the solvent was removed by vacuum filtration, and the obtained solid was recrystallized to obtain N,N,N-tridentate pincer ligands.

3. The synthesis method according to claim 2, characterized in that: The molar ratio of pyridine-2-carboxaldehyde or 1-methyl-2-carboxylbenzimidazole or quinoline-2-carboxaldehyde to chiral 1,2-diphenylethylenediamine is 1:1-4.

4. The synthesis method according to claim 2, characterized in that: The molar ratio of pyridine-2-carboxaldehyde or 1-methyl-2-carboxylbenzimidazole or quinoline-2-carboxaldehyde to the first added TsOH·H2O is 1:1-3, and the molar ratio of 2-tert-butylbenzaldehyde to the second added TsOH·H2O is 1:1-3.

5. The synthesis method according to claim 2, characterized in that: The molar ratio of pyridine-2-carboxaldehyde or 1-methyl-2-carboxylbenzimidazole or quinoline-2-carboxaldehyde to 2-tert-butylbenzaldehyde is 1-3:

1.

6. The synthesis method according to claim 2, characterized in that: The organic solvent is toluene, xylene, mesitylene, dichloromethane, tetrahydrofuran, chloroform, pyridine, DMF, or DMSO.

7. The application of the chiral 1,2-diamine-derived N,N,N-tridentate pincer ligand as described in claim 1 in the iron-catalyzed Brown Hydroboration reaction of alkenes.

8. The application according to claim 7, characterized in that: Under inert gas protection, a chiral 1,2-diamine-derived N,N,N-tridentate pincer ligand reacts with an iron salt in an organic solvent to obtain a ligand / iron catalyst. The iron salt is FeCl2, FeBr2, or Fe(OTf)2, where OTf is trifluoromethanesulfonate. The organic solvent is dichloromethane, toluene, tetrahydrofuran, chloroform, pyridine, DMF, or DMSO. The molar ratio of the iron salt to the ligand is 1:1-3. The reaction temperature is 25-100 °C, and the reaction time is 3-10 h.

9. The application according to claim 8, characterized in that: Under inert gas protection, the ligand / iron catalyst is used to catalyze the Brown Hydroboration reaction of olefins; olefins, HBpin and base are added sequentially to the solution of the ligand / iron catalyst, and the reaction is monitored by TLC. After the reaction is completed, the product is obtained by quenching and column chromatography separation.

10. The application according to claim 9, characterized in that: The molar ratio of ligand / iron catalyst to olefin is 1:20-40; the alkaline agent is sodium triethylborohydride, sodium tert-butoxide, potassium tert-butoxide, magnesium ethyl bromide, or lithium methyl, and the molar ratio of olefin to alkaline agent is 1:1.4; the reaction temperature is 25-50 °C; and the reaction time is 5 h.

Images