Catalyst system for aerobic dehydrogenation reaction of indoline derivatives containing hydrazine compounds

Abstract

The present invention relates to a catalyst system for an aerobic dehydrogenation reaction of an indoline derivative, specifically comprising a compound of [Chemical Formula 1]; a pyridine-based compound; and a copper halide, and is characterized by being carried out in a solvent under conditions in which oxygen (O2) is supplied. [Chemical Formula 1] Here, R1 is 4-NO2-PH and R2 is (C1 to C4)alkyl.

Description

Technology Field

[0001] The present invention relates to a catalyst system for an aerobic dehydrogenation reaction of an indoline derivative comprising a hydrazine compound, and more specifically, to a catalyst system for an aerobic dehydrogenation reaction of an indoline derivative comprising a compound of [Chemical Formula 1] below; a pyridine-based compound; and a copper halide, characterized by being carried out in a solvent under conditions in which oxygen (O2) is supplied:

[0002] [Chemical Formula 1]

[0003]

[0004] Here, R 1 is 4-NO2-PH, and R 2 is a (C1 to C4)alkyl. Background Technology

[0005] The dehydrogenation of saturated N-heterocycles into corresponding N-heteroaromatic compounds is a fundamental and fascinating transformation in synthesis, materials, and medicinal chemistry. Dehydrogenation of saturated N-heterocycles is typically performed using stoichiometric amounts of oxidizing agents, such as DDQ and metal oxides. However, these methods are less attractive due to the toxicity and waste disposal associated with the oxidizing agents. In recent years, acceptor-free dehydrogenation by transition metal catalysts has been regarded as a promising pathway for the synthesis of N-heteroaromatic compounds. This is because acceptor-free dehydrogenation does not require stoichiometric oxidizing agents and produces only molecular hydrogen as a byproduct.

[0006] Aerobic oxidative dehydrogenation offers another approach in terms of sustainability and eco-friendly chemistry because molecular oxygen is abundant and easily accessible, and water is produced as the sole byproduct. Various catalytic systems have been developed to facilitate the aerobic oxidative dehydrogenation of saturated N-heterocycles containing one or more free NH bonds.

[0007] However, aerobic dehydrogenation of N-substituted heterocycles such as tertiary indoline has been a difficult task. Recently, several successful cases have been reported. The Stahl group developed aerobic dehydrogenation of tertiary indoline using [Ru(phd)3](PF6)2 catalyst with indole, and Yang and colleagues reported that tertiary indoline underwent efficient Mn-catalyzed aerobic dehydrogenation in the presence of AcOH as a solvent.

[0008] Despite these advancements, there is still a need to develop more practical aerobic dehydrogenation methods for tertiary indoles, which are widely used in bioactive compounds and pharmaceuticals. Prior art literature

[0009] B. Li, AE Wendlandt and SS Stahl, Replacement of Stoichiometric DDQ with a Low Potential o-Quinone Catalyst Enabling Aerobic Dehydrogenation of Tertiary Indolines in Pharmaceutical Intermediates, Org. Lett., 2019, 21, 1176-1181.X. Niu and L. Yang, Manganese(III) Acetate Catalyzed Aerobic Dehydrogenation of Tertiary Indolines, Tetrahydroquinolines and an N-Unsubstituted Indoline, Adv. Synth. Catal., 2021, 363, 4209-4215. The problem to be solved

[0010] In this specification, Cu catalytic aerobic oxidative dehydrogenation of tertiary indoline is initiated using ethyl 2-(4-nitrophenyl)hydrazine-1-carboxylate (1) as a co-catalyst (Fig. 1).

[0011] The inventors have developed various aerobic oxidation transformations using azo compounds. Azo compounds can be utilized not only as reagents for heterocyclic synthesis but also as catalytic oxidizing agents for dehydrogenation. means of solving the problem

[0012] To achieve the above-mentioned technical problem, the present invention provides a catalyst system for an aerobic dehydrogenation reaction of an indoline derivative, comprising a compound of [Chemical Formula 1] below; a pyridine-based compound; and a copper halide, characterized by being performed in a solvent under conditions where oxygen (O2) is supplied:

[0013] [Chemical Formula 1]

[0014]

[0015] Here, R 1 is 4-NO2-PH, and R 2 is a (C1 to C4)alkyl.

[0016] The above indoline derivative is characterized by being substituted with an electron donating group.

[0017] Here, an electron donor group refers to a group that tends to donate electrons based on hydrogen within the molecule. For example, it may be one or more selected from the group comprising a hydroxyl group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 aryl group, or a halogen group, and preferably may be a substituent shown in [Table 2] of this specification.

[0018] The above pyridine compound is characterized as being one of 4-OMepy(4-methoxypyridine), DBU(1,8-Diazabicyclo[5.4.0]undec-7-ene), DMAP(4-dimethylaminopyridine), or pyridine.

[0019] The copper halide is characterized by being copper(I) chloride, copper(I) bromide, copper(II) chloride, copper(II) bromide, Cu(OAc)2, or a combination thereof.

[0020] The above solvent is characterized as being one of chloroform, dimethylformamide (DMF), acetonitrile (CH3CN), or dichloromethane (CH2Cl2).

[0021] The aerobic dehydrogenation reaction of the above indoline derivative is characterized by being carried out at a temperature of 15 to 60 degrees for 10 to 30 hours.

[0022] It is characterized in that the copper halide is CuCl, the pyridine compound is DMAP, and the solvent is acetonitrile (CH3CN).

[0023] The above catalyst system is characterized by generating indole through an aerobic dehydrogenation reaction.

[0024] The above indole is characterized by a production yield of 70%, 60%, or at least 50%.

[0025] According to another embodiment of the present invention, a method for preparing an alkyl 2-phenylazocarboxylate compound using an indoline derivative as a starting material is provided by using the catalyst system. Effects of the invention

[0026] The inventors developed a protocol for the Cu-catalyzed aerobic oxidative dehydrogenation of tertiary indoline using azo / hydrazide redox. Ethyl 2-(4-nitrophenyl)diazen-1-carboxylate (2) can promote the dehydrogenation of tertiary amines such as indoline and secondary amines. Various indolines were efficiently converted to their corresponding indoles, and reactivity did not decrease significantly upon scaling up. Interestingly, biologically active compounds were also produced using this method. A co-catalyzed mechanism was proposed consisting of the dehydrogenation of indoline by 2 and the regeneration of 2 by the Cu-catalyzed aerobic oxidation of the generated 1. Brief explanation of the drawing

[0027] Figure 1 shows the reaction scheme of the Cu-catalyzed aerobic oxidation dehydrogenation of tertiary indoline using ethyl 2-(4-nitrophenyl)hydrazine-1-carboxylate (1) as a co-catalyst. Figure 2 shows the reaction procedure for the dehydrogenation of tertiary indoline. Figure 3 shows the dehydrogenation reaction of tertiary indoline using stoichiometric amounts of azo compounds. Figure 4 shows a scale-up process for aerobic oxidative dehydrogenation of 4b. Figure 5 shows a method for synthesizing physiologically active substances through the development of an aerobic oxidative dehydrogenation method. Figure 6 shows the mechanism of aerobic oxidative dehydrogenation of the present invention. Specific details for implementing the invention

[0028] The present invention will be explained in more detail below through examples and experimental examples. However, these examples are intended only to aid in understanding the invention and do not limit the scope of the invention in any way.

[0030] <Experimental Method>

[0031] 1. Optimization of Aerobic Oxidative Dehydrogenation of Tertiary Indoline (Table 1)

[0032] A 10 mL flame-drying test tube equipped with a magnetic stirring rod was filled with catalyst (0.1 equivalent, 0.05 mmol), additive (0.2 equivalent, 0.10 mmol), and compound 1 (0.2 equivalent, 0.10 mmol), evacuated, and refilled with oxygen (this process was repeated 3 times). After adding 0.3 mL of solvent, 5-chloro-1-methylindoline 4a (0.5 mmol) and 0.7 mL of solvent were added sequentially. The reaction mixture was stirred at 40°C for 18 hours. The reaction mixture was quenched with a saturated aqueous NH4Cl solution, washed with water, and extracted with EtOAc. The combined organic layer was dried with MgSO4, filtered, and concentrated in a rotary evaporator. The residue was purified by silica gel column chromatography (EtOAc / Hx=1:10) to obtain the desired indole 5a.

[0034] 2. General Procedure for Cu-catalyzed Dehydrogenation of Tertiary Indoline

[0035] A 10 mL flame-drying test tube equipped with a magnetic stirring bar and filled with CuCl (0.1 equivalent, 0.05 mmol), DMAP (0.2 equivalent, 0.10 mmol), and Compound 1 (0.2 equivalent, 0.10 mmol) was evacuated and filled with oxygen (this process was repeated 3 times). After adding 0.3 mL of acetonitrile, indoline 4 (0.5 mmol) and 0.7 mL of acetonitrile were added sequentially. The reaction mixture was stirred at 40°C for 18 hours. The reaction mixture was quenched with a saturated aqueous NH4Cl solution, washed with water, and extracted with EtOAc. The combined organic layer was dried with MgSO4, filtered, and concentrated in a rotary evaporator. The residue was purified by silica gel column chromatography to obtain the desired indole 5.

[0037] 3. Scale-up process of 5-methoxy-1-methyl-1H-indole

[0038] A 250 mL round-bottom flask equipped with a magnetic stirring bar and filled with CuCl (0.1 equivalent, 0.7 mmol), DMAP (0.2 equivalent, 1.4 mmol), and Compound 1 (0.2 equivalent, 1.4 mmol) was evacuated and refilled with oxygen (this process was repeated 3 times). After adding 4.0 mL of acetonitrile, 5-methoxy-1-methylindoline 4b (7.0 mmol) and 10 mL of acetonitrile were added sequentially. The reaction mixture was 40 The mixture was stirred for 18 hours. The reaction mixture was quenched with a saturated aqueous NH4Cl solution, washed with water, and extracted with EtOAc. The combined organic layer was dried with MgSO4, filtered, and concentrated in a rotary evaporator. The residue was purified by silica gel column chromatography (EtOAc / Hx=1:5) to obtain the desired indole 5b.

[0040] <Experimental Results>

[0041] Recently, the inventors of the present invention Mn(Pc) / 1 We reported the aerobic oxidative dehydrogenation of secondary amines such as tetrahydroquinoline using a catalytic system. In this system 1 It was converted to ethyl 2-(4-nitrophenyl)diazen-1-carboxylate (2) by Mn(Pc) and O2, and the resulting 2 It was reduced back to 1 by gaining two electrons and two protons from tetrahydroquinoline (one from the α position of nitrogen, the other from NH) (Fig. 2A).

[0042] This co-catalyst system promotes the aerobic oxidative dehydrogenation of tetrahydroquinoline to produce quinoline and water. 2 / 1Through continuous research on aerobic oxidative dehydrogenation using redox, the inventors became interested in more difficult substrates such as tertiary indolines. Based on the inventors' mechanical insights, it was hypothesized that in the absence of acidic NH protons, the proton at the C3 position of indoline could be removed by the generated hydrazide anion (3), which would facilitate the dehydrogenation of more difficult tertiary indolines to indole (Fig. 2B).

[0043] The inventors of the present invention [use] stoichiometric amounts 2 Dehydrogenation of 5-chloro-1-methylindoline (4) was performed using [the desired 5-chloro-1-methylindoline]. The desired 5-chloro-1-methylindoline (5) is a byproduct. 1 It was produced with a 90% yield using (Fig. 3).

[0044] Next, the amount of catalyst 1 The feasibility of aerobic oxidative dehydrogenation of tertiary indoline was investigated using (Table 1).

[0045] [Table 1]

[0046]

[0047] 2 / 1 Various catalysts capable of aerobically promoting redox cycles were selected (Items 1–4), and the CuCl / 4-(dimethylamino)pyridine (DMAP) system was found to be a potent co-catalyst (Item 4). Other additives, such as pyridine and 2,2'-bipyridine, exhibited poor reactivity (Items 5–6). Among the selected solvents, CH3CN was superior to other solvents (Items 7–9). Several control experiments were performed based on the optimized conditions. This reaction 1 If performed without 5a Only 9% was obtained (Item 10). This result is due to CuCl / DMAP / O2 4a It shows that the direct aerobic dehydrogenation of is slow.

[0049] In addition, it was found that the use of CuCl, DAMP, and O2 is essential for 1-catalytic dehydrogenation (Items 11-13). Various indolines were explored under optimized conditions to gain insight into the substrate range (Table 2).

[0050] [Table 2]

[0051]

[0052] Several 5-substituted indolines were examined (5a-5h). This dehydrogenation method was found to be effective for the synthesis of electron-rich indolines, but the dehydrogenation of electron-deficient indolines proceeded slowly.

[0053] To obtain synthetically reasonable yields (5f and 5g), the temperature and reaction time had to be increased slightly. However, the dehydrogenation of 5-nitroindoline (5h) was still problematic. The inferior reactivity of electron-deficient indoline is attributed to the slow nucleophilic addition of indoline to 2. The synthesis of 4-substituted indoline was also investigated (5i-5m). It is worth noting that the ester group is tolerant under optimal conditions (5l).

[0054] Both 6-substituted indoline and 7-substituted indoline efficiently underwent the desired conversion (5n-5t). Dehydrogenation of 1,3-dimethylindoline and 1,2-dimethylindoline yielded the corresponding indole in 70% and 55% yields, respectively (5u and 5v).

[0055] Other N-substituted indolines also underwent efficient dehydrogenation (5w-5ab), but 1-(4-nitrophenyl)indoline was less reactive (5ac).

[0056] In the control experiment 1 It was shown that the use of is important for the dehydrogenation of N-arylated indoline, similar to the dehydrogenation of N-alkylated indoline. 1 Dehydrogenation of 4z and 4ac without 4z produced 5z and 5ac with yields of 24% and 6%, respectively.

[0057] When strong electron-withdrawing substituents such as ethoxycarbonyl or tosyl groups were introduced, dehydrogenation was completely inhibited (5ad and 5ae).

[0058] To demonstrate the synthetic utility of this method, gram-scale dehydrogenation of 4b was performed using optimized conditions (Fig. 4). The reaction proceeded smoothly without significant degradation of reactivity.

[0059] The developed dehydrogenation was evaluated in the preparation of two biologically active compounds (Fig. 5). The selective CDK4 / cyclin D1 inhibitor 5af, previously prepared by the dehydrogenation of 4af using stoichiometric amounts of MnO2, was readily obtained in 77% yield under slightly modified conditions (Fig. 5A). Additionally, the synthetic intermediate 5ag for norepinephrine and serotonin reuptake inhibitors was readily accessible through the developed protocol (Fig. 5B).

[0061] The mechanism for the developed aerobic oxidative dehydrogenation is proposed in Fig. 6. Initially, hydrazide 1 undergoes aerobic oxidation by a Cu catalyst to form azo compound 2. Conjugated addition of a tertiary indolin to the generated azo compound 2 forms intermediate A. Then, intramolecular removal of intermediate A generates iminium intermediate B and anion 3. Finally, deprotonation of B at the C3 position by anion 3 generates the desired indole product while simultaneously regenerating hydrazide 1 for the subsequent catalytic cycle.

[0063] In conclusion, the inventors developed a protocol for the Cu-catalyzed aerobic oxidative dehydrogenation of tertiary indolines using azo / hydrazide redox. Ethyl 2-(4-nitrophenyl)diazen-1-carboxylate (2) can promote the dehydrogenation of tertiary amines such as indolines and secondary amines. Various indolines were efficiently converted to their corresponding indoles, and reactivity did not decrease significantly upon scaling up. Interestingly, biologically active compounds were also produced using this method. A co-catalyzed mechanism was proposed consisting of the dehydrogenation of indolines by 2 and the regeneration of 2 by the Cu-catalyzed aerobic oxidation of the generated 1.

Claims

Claim 1 A catalyst system for the aerobic dehydrogenation reaction of a tertiary amine-type indoline derivative having a substituent on N of indoline, comprising the compound of [Chemical Formula 1] below; the pyridine-based compound DMAP (4-dimethylaminopyridine); and copper chloride (I), characterized by being carried out in an acetonitrile (CH3CN) solvent under conditions where oxygen (O2) is supplied: [Chemical Formula 1] Here, R 1 is 4-NO2-PH, and R 2 is a (C1 to C4)alkyl. Claim 2 A catalyst system for an aerobic dehydrogenation reaction of a tertiary amine-type indoline derivative having a substituent on N of indoline, characterized in that, in claim 1, the indoline derivative is substituted with an electron donating group. Claim 3 A catalyst system for the aerobic dehydrogenation reaction of a tertiary amine-type indoline derivative having a substituent on N of indoline, characterized in that, in claim 1, the aerobic dehydrogenation reaction of the indoline derivative is carried out at a temperature of 15 to 60 degrees for 10 to 30 hours. Claim 4 A catalyst system for the aerobic dehydrogenation reaction of an indolin derivative in the form of a tertiary amine having a substituent on N of indolin, characterized in that, in claim 1, the catalyst system produces an indole in the form of a tertiary amine having a substituent on N of indolin through an aerobic dehydrogenation reaction. Claim 5 A catalyst system for the aerobic dehydrogenation reaction of a tertiary amine-type indoline derivative having a substituent on N of indoline, characterized in that, in claim 4, the production yield of the indole is 50% or more. Claim 6 A method for preparing a tertiary amine-type indole compound having a substituent on indole N, using an indoline derivative as a starting material, by using a catalyst system according to any one of claims 1 to 5. Claim 7 delete Claim 8 delete Claim 9 delete Claim 10 delete

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