A method for catalytic synthesis of N-substituted-3-methylindole compounds by using aza-cyclopaladium-oxazoline compound

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to a method for catalytically synthesizing N-substituted-3-methyl indole compounds by using aza carbene oxazoline ring palladium compound. The application aims to provide a new synthesis method for N-substituted-3-methyl indole compounds, specifically, a high-catalytic-activity aza carbene oxazoline ring palladium compound is used as a catalyst to catalyze a direct coupling cyclization reaction of o-dichlorobenzene or o-bromochlorobenzene compounds and allyl arylamine, so as to obtain N-substituted-3-methyl indole compounds. The catalyst used in the application has high catalytic activity, the reaction has good product and functional group compatibility, in addition, the catalyst itself is easy to synthesize, and aryl chlorides used in the synthesis route are cheap and easy to obtain. Therefore, the synthesis route provided in the application has great competitive advantages and industrial production utilization value.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a novel method for the efficient synthesis of N-substituted-3-methylindole compounds using a nitrogen-containing heterocyclic carbene oxazoline palladium compound as a catalyst. Background Technology

[0002] Indole, whose English name is derived from the first three letters of "indigo" and "oleum," is a chemical compound originally extracted from indigo oil dye. In chemistry, indole is an important skeletal structure widely found in drug molecules, natural product molecules, and other compounds, exhibiting excellent pharmacological activity in various therapeutic areas, including antihypertensive, antiproliferative, antiviral, antitumor, analgesic, anti-inflammatory, and antibacterial applications. In particular, when a methyl group is present at the 3-position of the indole molecule, the entire indole compound, namely 3-methylindole, exhibits higher biological activity and pharmacokinetic properties compared to the original molecule. For example, the drug molecule bazedoxifene is an excellent estrogen receptor modulator used clinically to prevent postmenstrual osteoporosis. Another example is drug molecule 3 (see specific implementation details), used to treat sodium channel-related diseases. Therefore, the effective construction of 3-methylindole derivatives has significant scientific and practical application value. The general formula of the N-substituted-3-methylindole compounds involved in this patent is shown in structural formula 1:

[0003]

[0004] Currently, the main methods for synthesizing 3-methylindole compounds are:

[0005] Route 1 is represented by the route published in the journal Advanced Synthetic Catalysis, Vol. 348, pp. 851-856, 2006: using 2-chloroacetophenone as a raw material, 1-chloro-2-(2-chloro-1-methylvinyl)benzene is first prepared and synthesized, and then reacted with aniline in the presence of a catalyst and phosphine ligand to obtain 1-phenyl-3-methylindole.

[0006]

[0007] Route 1

[0008] Route 2 is represented by a route published in *Angewandte Chemie*, Vol. 47, pp. 888-890, 2008: 1-bromo-2-iodobenzene reacts with allylamine in the presence of palladium and phosphine ligands at 140°C for 15 hours to yield 3-methylindole. The dppf value is 1,1′-bis(diphenylphosphine)ferrocene.

[0009]

[0010] Route 2

[0011] Route 3 is represented by the route in a paper published in European Chemistry, Vol. 19, 2013, pp. 12771-12777: using 2-isopropenylaniline and phenylboronic acid as starting materials, N-phenyl-2-(2-propenyl)aniline is obtained under the catalysis of copper acetate and myristic acid, and then 1-phenyl-3-methylindole is obtained by CH bond activation under the action of catalyst and ligand.

[0012]

[0013] Route 3

[0014] Route 4 is represented by the route in a paper published in European Chemistry, Vol. 22, 2016, pp. 12771-12777: using acrolein and N,N-diphenylhydrazine hydrochloride as starting materials, (1E)-2-propenyl-N,N-diphenylhydrazone is obtained through oxidative addition and reductive elimination, and then 1-phenyl-3-methylindole is obtained under reflux conditions of tert-butyl iodine and acetonitrile.

[0015]

[0016] Route 4

[0017] Route 5 is represented by a route published in Organic Letters, Vol. 22, pp. 7704-7708, 2020: using o-dichlorobenzene as the starting material, it reacts with allyl aniline to obtain 1-phenyl-3-methylindole under the catalysis of highly active bis(1,5-cyclooctadiene)nickel, wherein IPr·HCl is 1,3-bis(2,6-diisopropylphenyl)chloroimidazolide.

[0018]

[0019] Route 5

[0020] In summary, these reported synthetic routes all have certain drawbacks:

[0021] 1) The synthesis route is long and uses some dangerous chemicals (sodium hydride, acrolein), which poses serious production safety hazards and does not meet the requirements of green chemistry processes.

[0022] 2) The synthesis requires the use of metal catalysts that are unstable in air, such as bis(1,5-cyclooctadiene) nickel and phosphorus ligands, which increases the complexity of experimental operations and is not conducive to practical industrial applications; moreover, the amount used is relatively high, which increases the reaction cost.

[0023] 4) The reaction temperature is relatively high (for example, the reaction temperature of Route 2 is 140 degrees Celsius);

[0024] These drawbacks limit the industrial application of existing synthetic routes to some extent. Therefore, proposing a new, efficient synthetic route for N-substituted 3-methylindole compounds is both urgent and significant. Summary of the Invention

[0025] The purpose of this invention is to propose a new synthetic method for N-substituted-3-methylindole compounds, namely, using a highly catalytically active nitrogen-containing heterocyclic carbene oxazoline palladium compound as a catalyst to synthesize N-substituted-3-methylindole compounds from o-dichloroaryl compounds or o-bromochlorobenzene compounds.

[0026] The catalyst proposed in this invention is a highly catalytically active nitrogen-containing heterocyclic carbene oxazoline cyclic palladium compound with the chemical formula C. 52 H 55 BrN3OPd, its specific structural formula is shown below:

[0027]

[0028] The present invention proposes a novel synthetic route for N-substituted-3-methylindole compounds, the specific steps of which are as follows:

[0029] This invention proposes a novel synthetic method for N-substituted-3-methylindole compounds, the specific steps of which are as follows:

[0030] Under nitrogen atmosphere, sodium tert-butoxide (3.5 mmol), a nitrogen-containing carbene oxazoline palladium catalyst Cat.1 (0.5 mol%), 1,4-dioxane (3 mL), allyl aromatic amine (1.5 mmol), and o-dichlorobenzene or o-bromochlorobenzene compounds (1.0 mmol) were added sequentially to a 25 mL Schlenk reaction tube. The reaction tube was placed in an oil bath and heated to 100°C for 24 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the product was purified by column chromatography and dried under vacuum to obtain the target compound, an N-substituted-3-methylindole compound. The reaction formula for this synthetic method is as follows:

[0031]

[0032] The advantages of the novel synthetic method for N-substituted-3-methylindole compounds proposed in this invention are: chlorides are used as starting materials, which are inexpensive and readily available; the catalyst is stable to air and water, and the amount of catalyst used is low; the reaction process is simple to operate and has good safety and stability; the substrate functional groups have good compatibility and the product yield is high. Attached Figure Description

[0033] Figure 1The image shows the 1H NMR spectrum of 1-phenyl-3-methylindole prepared in Example 1.

[0034] Figure 2 The image shows the 1H NMR spectrum of 1-(4-methoxyphenyl)-3-methylindole prepared in Example 2.

[0035] Figure 3 The image shows the 1H NMR spectrum of 1-(3-fluorophenyl)-3-methyl-N-methylsulfonylindole-5-carboxamide (i.e., drug 3) prepared in Example 3. Detailed Implementation

[0036] The present invention will be further described in detail below through embodiments, but the present invention is not limited to the following embodiments.

[0037] Example 1: Preparation of 1-phenyl-3-methylindole, the reaction formula is as follows:

[0038]

[0039] Under nitrogen atmosphere, sodium tert-butoxide (3.5 mmol), a nitrogen-containing carbene oxazoline palladium catalyst Cat.1 (0.5 mol%), 1,4-dioxane (3 mL), N-allyl aniline (1.5 mmol), and o-dichlorobenzene (1.0 mmol) were added sequentially to a 25 mL Schlenk reaction tube. The reaction tube was placed in an oil bath and heated to 100°C for 24 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the product was separated by column chromatography and dried under vacuum to obtain a colorless oil, namely 1-phenyl-3-methylindole. Yield: 0.190 g, 92%.

[0040] NMR analysis: 1 H NMR (CDCl3, 600MHz, 298K): δ=7.65 (d, J=7.7Hz, 1H), 7.58 (d, J=8.2Hz, 1H), 7.52-7.50 (m , 4H), 7.35-7.32 (m, 1H), 7.28-7.19 (m, 2H), 7.16 (d, J=1.0Hz, 1H), 2.41 (d, J=1.1Hz, 3H).

[0041] Example 2: Preparation of 1-(4-methoxyphenyl)-3-methylindole, the reaction formula is as follows:

[0042]

[0043] Under nitrogen atmosphere, sodium tert-butoxide (3.5 mmol), a nitrogen-containing carbene oxazoline palladium catalyst Cat.1 (2 mol%), 1,4-dioxane (3 mL), N-allyl-4-methoxyaniline (1.5 mmol), and o-dichlorobenzene (1.0 mmol) were added sequentially to a 25 mL Schlenk reaction tube. The reaction tube was placed in an oil bath and heated to 100 °C for 24 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the mixture was separated by column chromatography and dried under vacuum to obtain a white solid, namely 1-(4-methoxyphenyl)-3-methylindole. Yield: 0.214 g, 90%.

[0044] NMR analysis: 1 H NMR (CDCl3, 600MHz, 298K): δ=7.63 (d, J=7.5Hz, 1H), 7.45 (d, J=8.2Hz, 1H), 7.40-7.37 (m, 2H), 7 .22-7.15 (m, 2H), 7.08 (d, J=1.0Hz, 1H), 7.03-7.01 (m, 2H), 3.88 (s, 3H), 2.39 (d, J=1.1Hz, 3H).

[0045] Example 3: Preparation of 1-(3-fluorophenyl)-3-methyl-N-methylsulfonylindole-5-carboxamide (i.e., drug 3), the reaction formula is as follows:

[0046]

[0047] Under nitrogen atmosphere, sodium tert-butoxide (3.5 mmol), a nitrogen-containing carbene oxazoline palladium catalyst Cat.1 (2 mol%), 1,4-dioxane (3 mL), N-allyl-3-fluoroaniline (1.5 mmol), and 4-bromo-3-chloro-N-methylsulfonylbenzamide (1.0 mmol) were added sequentially to a 25 mL Schlenk reaction tube. The reaction tube was placed in an oil bath and heated to 100 °C for 24 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the mixture was separated by column chromatography and dried under vacuum to obtain a white solid, namely 1-(3-fluorophenyl)-3-methyl-N-methylsulfonylindole-5-carboxamide (i.e., drug 3). Yield: 0.229 g, 66%.

[0048] NMR analysis: 1H NMR(CDCl3,600MHz,298K):δ=8.97(s,1H),8.10(s,1H),7.67(d,J=8.3Hz,1H),7.61(dd,J=8.3Hz,J=1.3Hz,1H),7.51(q,J=7.5Hz,1H),7.30-7.28(m,2H),7.18-7.16(m,1H),7.11-7.08(m,1H),3.41(s,3H),2.39(s,3H)。

Claims

1. A method for the catalytic synthesis of N-substituted-3-methylindole compounds from nitrogen-containing heterocyclic carbene oxazoline cyclic palladium compounds, characterized in that... The steps are as follows: Under nitrogen atmosphere, nitrogen-containing heterocyclic carbene oxazoline palladium compounds catalyze the coupling ring-closure reaction of o-dichlorobenzene or o-bromochlorobenzene compounds with allyl aromatic amines to yield N-substituted-3-methylindole compounds. The amount of catalyst added ranges from 0.5 mol% to 2 mol%, and the reaction formula is as follows: X=Cl、R=H、R 1 =Ph X=Cl、R=H、R 1 =4-MeOPh X=Br、R=CONHSO2Me、R 1 =3-FPh Where tBuONa is sodium tert-butoxide, and Cat.1 in the reaction formula is a nitrogen-containing heterocyclic carbene oxazoline-cyclic palladium compound with the following structural formula:

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