A method for preparing α-carboline and its derivatives

Abstract

The present invention relates to the technical field of organic chemical synthesis, and particularly relates to a preparation method of α-carboline and its derivatives. Using a base as a promoter, under the condition of an organic solvent, an o-3-pyridyl-aniline compound reacts for 2-6 h under an inert gas condition at 80-110 °C; after the reaction is completed, water is added for quenching, and extraction is carried out with an organic solvent, followed by column chromatography separation (V 石油醚 : V 乙酸乙酯 = 10:1 to 1:10), to obtain an α-carboline derivative. The present invention uses a base as a promoter, and under an inert gas condition, an addition-elimination reaction occurs between an arylamine and the C2 position of a pyridine heterocycle in an organic solvent, and hydrogen is removed to obtain an α-carboline compound. This method has the following advantages: simple method, high atom economy, avoiding the use of expensive transition metals, mild reaction conditions, and producing environmentally friendly by-products.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic chemical synthesis and relates to a method for preparing α-carboline and its derivatives. Background Art

[0002] α-Carboline compounds are important structural units of many natural products and drugs (Zhang J. Y., Guo M.C., Org. Lett. 2019, 21, 1331-1336). Additionally, these compounds can be used to prepare ligands, artificial dyes, electronic materials, and optical materials (Hwang J., Lee C., Jeong J. E., ACS Appl. Mater. Interfaces. 2020, 12, 8485-8494). Therefore, many methods for synthesizing α-carboline compounds have been developed. Among these methods, the most classical ones are the modified Graber-Ullmann reaction (C. Schneider, D. Gueyrard, F. Popowycz, B. Joseph, P. G. Goekjian, Synlett. 2007, 14, 2237-2241) and the Diels-Alder reaction (A. Tahri, K. J. Buysens, E. V. V. D. Eycken, D. M. Vandenberghe, G. J. Hoornaert, Tetrahedron. 1998, 54, 3211-3226; P. Molina, M. Alajarin, A. Vidal, P. Sanchez-Andrada, J. Org. Chem. 1992, 57, 929-939), as well as transition-metal-catalyzed coupling. The disadvantages of these methods are that they require the pre-preparation of triazoles or the reservation of functional groups such as halogens. At the same time, the reaction routes are long, expensive transition metals are needed, and there is the residue of precious metals after the reaction, which is not conducive to atom economy. Therefore, exploring green and efficient synthesis methods is still urgently needed, and the metal-free catalytic CDC coupling amination reaction can well solve this problem. The CDC coupling amination reaction is the direct coupling of Ar-H / N-H bonds without the need for pre-functionalization. In the past few decades, the research on the direct Ar-H amination to construct N-aryl compounds has mainly focused on the catalysis of transition metals such as iridium, palladium, iron, copper, cobalt, silver, and manganese (Park Y, Kim Y, Chang S. Chem. Rev. 2017, 117, 9247-9301; Cho S H, Kim J Y, Kwak J, Chang S. Chem. Soc. Rev. 2011, 40, 5068; Yuan J, Liu C, Lei A. Chem. Commun. 2015, 51, 1394-1409; Kim H, Chang S. ACS Catal. 2016, 6, 2341-2351).This method involves the insertion of a transition metal into the Ar-H bond with the assistance of a directing group to form a stable cyclic metal complex intermediate, which then reacts with an organic amine to produce the target product containing a C-N bond.

[0003] Although the direct amination of Ar-H catalyzed by transition metals has been widely used, there are also a series of drawbacks. For example: 1) expensive ligands, catalysts, and additives are required; 2) relatively harsh conditions (high temperature or long reaction time) are needed; 3) heavy metal pollution is generated, especially when synthesizing compounds with high requirements for heavy metal content; 4) the removal of the directing group in the reaction substrate. Through literature research, we found that the research on the metal-free catalytic direct coupling reaction of Ar-H / N-H is less, and there is still great challenge and research value. Summary of the Invention

[0004] The object of the present invention is to provide a method for directly oxidative dehydrogenative coupling (CDC) to prepare α-carboline compounds under non-transition metal conditions. Using the nitrogen-containing aromatic ring in o-3-pyridyl-aniline compounds as the Ar-H source and aromatic amines such as aniline as the amine source, the direct arylamination reaction of the intramolecular nitrogen-containing aromatic ring is realized under the t-BuOK system. This method has the following advantages: simple method, high atom economy, avoiding the use of expensive transition metals, mild reaction conditions, and producing environmentally friendly by-products.

[0005] The preparation method of the α-carboline compound of the present invention uses a base as a promoter. Under the condition of an organic solvent, the o-3-pyridyl-aniline compound reacts for 2 - 6 h under an inert gas condition at 80 - 110 °C; after the reaction is completed, water is added to quench the reaction, and the organic solvent is extracted, and column chromatography separation (V 石油醚 :Vethyl 酸乙酯 = 10:1~1:10) is carried out to obtain α-carboline and its derivatives.

[0006] Furthermore, the o-3-pyridyl-aniline compound includes the compound represented by the general formula (1):

[0007]

[0008] Among them, X = C (carbon) or N (nitrogen); R 1 、R 2 、R 3 、R 4 、R 5 、R 6 are hydrogen, a C1 - C 40 aliphatic group, an aromatic group within C4 - C60, an alkoxy group, a trifluoromethoxy group, a trifluoromethyl group, a nitro group, a cyano group, an alkyl group, a hydroxyl group, a carboxyl group, an aldehyde group, a carbonyl group, an ester group, an amino group, a sulfo group, an amide, or a halogen.

[0009] Furthermore, the promoter base is one of the organic bases t-BuOK, t-BuONa or the inorganic bases KOH, NaOH, K2CO3, preferably t-BuOK, and the dosage of the promoter is 6 to 12 times the molar amount of the o-3-pyridyl-aniline compound.

[0010] Furthermore, the organic solvent can be toluene, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, benzene, 1,4-dioxane, ether, carbon tetrachloride, and the equivalent of the organic solvent is 40 to 100 equivalents of the o-3-pyridyl-aniline compound.

[0011] The synthesis general formula of the α-carboline and its derivatives of the present invention is:

[0012]

[0013] The present invention has the following advantages over the prior art:

[0014] 1. Under the promotion of the base as a promoter, the o-3-pyridyl-aniline compound reacts, and through the method of direct oxidative dehydrogenative coupling (CDC), the α-carboline compound can be efficiently obtained in one step. The raw materials and the promoter of this reaction are cheap and easily available, and the synthesis process is simple;

[0015] 2. The reaction conditions are mild, green, atom-economic, and the yield is excellent (up to 99%);

[0016] 3. The post-treatment is simple, and the use of expensive transition metals is avoided;

[0017] 4. The reaction can achieve gram-scale preparation. Specific embodiments

[0018] The present invention will be further described below through specific examples.

[0019] Example 1: Preparation of 2a - 2g.

[0020] Add the o-3-pyridyl-aniline compounds 1a - 1g (0.2 mmol) and t-BuOK (1.2 mmol) into a Schlenk tube, displace with inert gas three times, add toluene (1.0 ml) under an inert gas atmosphere, and react at 80 - 110 °C for 2 - 6 h. The reaction mixture is directly mixed with silica gel powder, and column chromatography (the eluent is V 石油醚 :V 乙酸乙酯 = 1:1) is used for separation to obtain the pure α-carboline 2a - 2g.

[0021] The synthesis route is as follows:

[0022]

[0023] Table 1 Synthesis Conditions and Products

[0024]

[0025] The structural formula and spectral analysis of the products are as follows:

[0026] The structural formula of 2a is: ;

[0027] 1 H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 8.45 (dd, J = 7.7, 1.7 Hz,1H), 8.40 (d, J = 4.8 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 8.1 Hz,1H), 7.43 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.21 - 7.14 (m, 2H). 1 H NMR (400 MHz,CDCl3) δ 10.70 (s, 1H), 8.54 (s, 1H), 8.37 (d, J = 7.7 Hz, 1H), 8.08 (d, J =7.8 Hz, 1H), 7.60 - 7.45 (m, 2H), 7.32 - 7.18 (m, 2H). 13 C NMR (100 MHz, DMSO-d6):δ 151.8, 146.0, 138.7, 128.3, 126.5, 121.0, 120.3, 119.3, 115.1, 114.9,111.1.

[0028] The structural formula of 2b is: ;

[0029] 1 H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 8.50 - 8.39 (m, 2H), 7.96(d, J = 7.8 Hz, 1H), 7.25 (d, J = 7.2 Hz, 1H), 7.18 (dd, J = 7.7, 4.9 Hz,1H), 7.12 (t, J = 7.5 Hz, 1H), 2.56 (s, 3H). 1313C NMR (100 MHz, DMSO-d6) δ 152.6, 146.3, 138.5, 128.8, 127.5, 121.1, 120.4, 119.9, 118.9, 116.0, 115.4, 17.5.

[0030] The structural formula of 2c is: ;

[0031] 1 1H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 8.43 (dd, J = 7.7, 1.6 Hz, 1H), 8.37 (dd, J = 4.8, 1.6 Hz, 1H), 7.94 (dd, J = 9.3, 2.6 Hz, 1H), 7.43 (dd, J = 8.8, 4.5 Hz, 1H), 7.23 (td, J = 9.2, 2.6 Hz, 1H), 7.12 (dd, J = 7.7, 4.8 Hz, 1H). 13 13C NMR (100 MHz, DMSO-d6) δ 158.3, 156.0, 153.0, 147.2, 135.6, 129.4, 121.2 (d, J = 10 Hz), 115.3, 114.8 (d, J = 25 Hz), 112.7 (d, J = 9 Hz), 107.3 (d, J = 24 Hz).

[0032] The structural formula of 2d is: ;

[0033] 1 1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 8.47 (dd, J = 7.7, 1.6 Hz, 1H), 8.39 (dd, J = 4.9, 1.6 Hz, 1H), 7.75 (d, J = 2.5 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.15 (dd, J = 7.7, 4.8 Hz, 1H), 7.09 (dd, J = 8.8, 2.6 Hz, 1H), 3.84 (s, 3H). 1313C NMR (100 MHz, DMSO-d6) δ 153.9, 152.7, 146.4, 133.8, 128.9, 121.2, 116.2, 115.7, 114.9, 112.4, 104.3, 56.

[0034] The structural formula of 2e is: ;

[0035] 1 1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 8.75 (d, J = 7.9 Hz, 1H), 8.27 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.55 (d, J = 3.6 Hz, 2H), 7.32 - 7.25 (m, 1H). 13 13C NMR (100 MHz, DMSO-d6) δ 151.4, 142.4 (m), 140.6, 130.2, 128.7, 124.2, 122.6, 120.7, 119.9, 118.9, 112.1, 111.7 (q, J = 3 Hz)

[0036] The structural formula of 2f is: ;

[0037] 1 1H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 9.42 (s, 1H), 8.91 (s, 1H), 8.21 (d, J = 7.8 Hz, 1H), 7.61 - 7.45 (m, 2H), 7.30 (t, J = 7.2 Hz, 1H). 13 13C NMR (100 MHz, DMSO-d6) δ 155.5 154.9, 149.0, 138.9, 128.1, 122.1, 121.4, 119.2, 114.3, 112.3.

[0038] The structural formula of 2g is: ;

[0039] 11H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 10.98 (s, 1H), 8.38 (d, J = 7.6 Hz, 1H), 8.27 (dd, J = 4.9, 1.5 Hz, 2H), 7.37 (s, 1H), 7.34 (p, J = 1.5Hz, 1H), 7.09 (ddd, J = 7.6, 4.9, 1.4 Hz, 1H), 6.55 - 6.49 (m, 1H). 13 13C NMR (100MHz, DMSO-d6) δ 153.3, 144.7, 137.0, 136.8, 127.2, 125.3, 123.6, 116.7, 116.3, 114.4, 112.0, 101.4, 92.0.

[0040] Example 2: Preparation of 2a on a gram scale

[0041] o - 3 - pyridyl aniline 1a (1.7 g, 10 mmol) and t - BuOK (11.4 g, 100 mmol) were added to a Schlenk tube, which was purged with an inert gas three times. Toluene (50 ml) was added under an inert gas atmosphere, and the reaction was carried out at 100 °C for 8 h. The reaction mixture was directly mixed with silica gel powder, and separated by column chromatography (eluent: V 石油醚 :V 乙酸乙酯 = 1 / 1) to obtain pure α - carboline 2a, 1.4 g of white solid, with a yield of 85%.

[0042] The synthetic route is as follows:

[0043]

[0044] Although the technical solutions of the present invention have been described in detail and listed, it should be understood that for those skilled in the art, making modifications to the above - mentioned embodiments or adopting equivalent alternative solutions are obvious to those skilled in the art. These modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection required by the present invention.

Claims

1. A α- method for preparing carbazole and its derivatives, characterized in that Using an alkali as a promoter, under the condition of an organic solvent, the raw material reacts for 2 - 6 h under an inert gas condition at 80 - 110 °C; after the reaction is completed, water is added for quenching, extraction is carried out with an organic solvent, and column chromatography separation is carried out to obtain α- carboline and its derivatives; The starting materials used are 2-(pyridin-3-yl)aniline, 2-methyl-6-(pyridin-3-yl)aniline, 4-fluoro-2-(pyridin-3-yl)aniline, 4-methoxy-2-(pyridin-3-yl)aniline, 2-(6-(trifluoromethyl)pyridin-3-yl)aniline, 5-(pyridin-3-yl)-1H-indol-6-amine or 2-(pyrimidin-5-yl)aniline; The α- carbazole and its derivatives are 9H-pyrido[2,3-b]indole, 8-methyl-9H-pyrido[2,3-b]indole, 6-fluoro-9H-pyrido[2,3-b]indole, 6-methoxy-9H-pyrido[2,3-b]indole, 2-(trifluoromethyl)-9H-pyrido[2,3-b]indole, 9H-pyrimido[4,5-b]indole or 1,9-dihydropyrido[2,3-b]pyrrolo[3,2-f]indole; The organic solvent is toluene, tetrahydrofuran, dimethyl sulfoxide, N,N -dimethylformamide, N,N -dimethylacetamide, benzene, 1,4-dioxane, diethyl ether or carbon tetrachloride, and the equivalent of the organic solvent is 40 to 100 equivalents of the raw material; The base is potassium tert-butoxide, and the equivalent amount of potassium tert-butoxide is 6 to 12 equivalents of the starting material.

2. A method for preparing a α- carboline and its derivatives, characterized in that: The method comprises the following steps: adding raw materials into a reaction vessel, then adding an alkali, replacing the inert gas in the reaction vessel three times, adding an organic solvent under the condition of the inert gas, stirring at 80-110 °C for 2-6 h, and obtaining α- carboline and its derivatives.

3. A method for preparing a α- carboline and its derivatives, characterized in that: The inert gas is argon or nitrogen.

4. A α- method for preparing carbazole and its derivatives, characterized in that: The column chromatography is a column chromatography technique using silica gel or neutral alumina as the stationary phase, and the eluent is a mixed eluent with a ratio of V 石油醚 :V 乙酸乙酯 = 10:1 to 1:10.

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