Method for catalytically synthesizing dibenzo [b, d] azepine compound by using N-heterocyclic carbene oxazoline cyclic palladium compound

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a method for catalytically synthesizing a dibenzo [b, d] azepine compound by using an N-heterocyclic carbene oxazoline cyclic palladium compound. The invention aims to provide a novel synthesis method of a dibenzo [b, d] azepine compound, and particularly relates to a method for synthesizing the dibenzo [b, d] azepine compound by using a high-catalytic-activity N-heterocyclic carbene oxazoline cyclic palladium compound as a catalyst through a carbon-nitrogen / carbon-carbon bond cascade reaction. The 2, 2 '-dihalogenated biphenyl compound and an N-alkyl substituted allylamine compound are directly synthesized into the dibenzo [b, d] azepine compound in one step. The catalyst used in the invention has high catalytic activity, and the reaction has good compatibility of products and functional groups; the catalyst is easy to synthesize, and the raw materials of the 2, 2 '-dihalogenated biphenyl compound used in the synthesis route are cheap and easy to obtain.

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 dibenzo[b,d]azapyridine compounds using a nitrogen-heterocyclic carbene oxazoline cyclic palladium compound as a catalyst. Background Technology

[0002] Dibenzo[b,d]azapyridines are an important class of medium-sized nitrogen heterocyclic compounds. They are key structural units in many natural products and bioactive compounds, exhibiting good biological activities such as immunosuppression, potassium channel inhibition, anticancer properties, and action as serotonin receptors. Figure 1 For example, the seven-membered skeleton of erythritol B was isolated from cultured Erythrina flowers (Org. Lett. 2014, 16, 6400); compound LY- 411575 It is an effective γ-secretase inhibitor for the treatment of melanoma and Alzheimer's disease (Anticancer Res. 2013, 33, 1307); functionalized dibenzo[b,d]azazepines are also used clinically as 5-hydroxytryptamine (5-HT) receptor (Bioorg. Med. Chem. Lett. 2014, 24, 576) and potassium channel inhibitors (Bioorg. Med. Chem. Lett. 2009, 19, 2299) for the treatment of neurological and autoimmune diseases. Therefore, how to effectively construct dibenzo[b,d]azazepine compounds is of great significance for new drug development.

[0003]

[0004] Currently, the main methods for synthesizing dibenzo[b,d]azapyridine compounds are:

[0005] Route 1 is represented by a route published in the *Journal of Organic Chemistry*, Vol. 75, pp. 6445-6451, 2010: Using o-bromophenylboronic acid and o-iodoaniline as raw materials, 2′-bromo-2-aminobiphenyl (1) is first synthesized. Then, 1 undergoes a substitution reaction with an acyl chloride or carboxylic acid to obtain amide compound 2. Compound 2 undergoes methylation with iodomethane or benzylation with benzyl bromide to obtain o-phenylbenzoylenolide 3. Under the catalysis of palladium catalyst and phosphorus ligand, compound 3 undergoes an intramolecular tandem reaction to give a dibenzozazepine compound A, with a reaction yield of 8%-99%.

[0006]

[0007] Route 2 is represented by a paper published in *Angewandte Chemie*, Vol. 57, pp. 11040-11044, 2013: Under the catalysis of N,N-dimethylformamide (DMF), 2,2-diphenylpropionic acid reacts with oxaloyl chloride to generate 2,2-diphenylpropionyl chloride 4. Then, 4 undergoes a substitution reaction with o-bromoaniline to give amide compound 5. 5 undergoes methylation with iodomethane to give compound 6. Under the catalysis of tris(dibenzylacetone)dipalladium and a chiral phosphine ligand at 80°C, compound 6 undergoes an intramolecular tandem reaction to give a dibenzozazepine compound B, with a yield of 97%.

[0008]

[0009] Route 3 is represented by a route published in Angewandte Chemie, Vol. 14, 2015, pp. 15385-15389: 2-aminobiphenyl reacts with diphenylacetylene in an intermolecular tandem reaction under the catalysis of copper acetate and palladium acetate to give dibenzo[b,d]azapyridine compound C containing an imine, with a yield of 91%.

[0010]

[0011] Route 4 is represented by a route published in Organic Letters, Vol. 19, 2017, pp. 12771-12777: using N-p-toluenesulfonyl-2-aminobiphenyl and (E)-2,4-dienivalate ethyl ester as starting materials, a dibenzo[b,d]azapyridine compound D was obtained through a palladium-catalyzed [5+2] reaction with a yield of 82%.

[0012]

[0013] The synthetic routes reported above all have certain drawbacks:

[0014] 1) The synthesis route is long and uses some dangerous chemicals (sodium hydride, oxalyl chloride), which poses serious production safety hazards and does not meet the requirements of green chemistry processes.

[0015] 2) The synthesis requires the use of air-labile metal catalysts such as tris(dibenzylacetone)dipalladium and phosphorus ligands, which increases the complexity of experimental operations and is not conducive to practical industrial applications. At the same time, the amount of catalyst used is relatively high, which increases the reaction cost.

[0016] 3) The reaction temperature is relatively high (for example, the reaction temperature of routes three and four is 120 degrees Celsius);

[0017] These drawbacks limit the industrial application of existing synthetic routes to some extent. Therefore, proposing a new, efficient synthetic route for dibenzo[b,d]azapyridines is both urgent and significant. Summary of the Invention

[0018] The purpose of this invention is to propose a novel synthetic method for dibenzo[b,d]azapyridine compounds E, namely, using a highly catalytically active azapyridine carbene oxazoline palladium compound as a catalyst, and through an intermolecular carbon-nitrogen / carbon-carbon bond tandem reaction, directly synthesizing dibenzo[b,d]azapyridine compounds E in one step from 2,2′-dihalobiphenyl compounds and N-alkyl-substituted allylamine compounds.

[0019] The general structural formula of the dibenzo[b,d]azapyridine compound E involved in this patent is shown in structural formula 1:

[0020]

[0021] The catalyst used in the intermolecular tandem reaction proposed in this invention is a highly catalytically active nitrogen-heterocyclic carbene oxazoline cyclic palladium compound, abbreviated as Cat.1, with the chemical formula C. 49 H 54 BrN3OPd, its specific structural formula is shown below:

[0022]

[0023] This invention proposes a novel synthetic method for dibenzo[b,d]azapyridine compound E, the specific steps of which are as follows:

[0024] Under nitrogen atmosphere, potassium tert-butoxide (1.75 mmol), a 3 mol% (3 mol%), a 2,2′-dihalobiphenyl compound (0.5 mmol), tetrahydrofuran (1 mL), and an N-alkyl-substituted allylamine (1.25 mmol) were added sequentially to a 25 mL Schlenk reaction tube. The reaction tube was placed in an oil bath and heated to 90°C with stirring for 24 hours. After the reaction was completed, the solvent was removed under reduced pressure. The compound was purified by alkaline alumina column chromatography and dried under vacuum to obtain the target compound, dibenzo[b,d]azapyridine compound E. The reaction formula for this synthesis method is as follows:

[0025]

[0026] The advantages of the novel synthetic method for dibenzo[b,d]azapyridine compounds E proposed in this invention are: the raw materials are inexpensive and readily available; the catalyst is stable to air and water, and the amount of catalyst used is low; the synthetic steps are few and the reaction process is simple; the substrate functional groups have good compatibility and the product yield is high. Attached Figure Description

[0027] Figure 1 The image shows the 1H NMR spectrum of the 5,7-dimethyldibenzo[b,d]azapyridine prepared in Example 1.

[0028] Figure 2 The 1H NMR spectrum of the 7-methyl-5-n-octyldibenzo[b,d]azapyridine prepared in Example 2 is shown.

[0029] Figure 3 The image shows the 1H NMR spectrum of the 3,5,7,9-tetramethyldibenzo[b,d]azapyridine prepared in Example 3. Detailed Implementation

[0030] The present invention will be further described in detail below through embodiments, but the present invention is not limited to the following embodiments.

[0031] Example 1: Preparation of 5,7-dimethyldibenzo[b,d]azapyridine compounds, the reaction formula is as follows:

[0032]

[0033] Under nitrogen atmosphere, potassium tert-butoxide (1.75 mmol), a 3 mol% catalide catalyst (Carbene oxazoline cyclopalladium), 2,2′-dibromobiphenyl (0.5 mmol), tetrahydrofuran (1 mL), and N-methylallylamine (1.75 mmol) were added sequentially to a 25 mL Schlenk reaction tube. The reaction tube was placed in an oil bath and heated to 90°C with stirring for 24 hours. After the reaction was complete, the solvent was removed under reduced pressure. The mixture was purified by alkaline alumina column chromatography and dried under vacuum to give a white solid, namely 5,7-dimethyldibenzo[b,d]azapyridine. Yield: 0.095 g, 86%.

[0034] NMR analysis: 1 H NMR (600MHz, CDCl3): δ=7.37-7.36(m, 2H), 7.33-7.26(m, 4H), 7.10-7.08(m, 1H), 6.95 (d, J=8.1Hz, 1H), 5.90 (s, 1H), 2.92 (s, 3H), 2.04 (d, J=1.1Hz, 3H).

[0035] Example 2: Preparation of 7-methyl-5-n-octyldibenzo[b,d]azapyridine compounds, the reaction formula is as follows:

[0036]

[0037] Under nitrogen atmosphere, potassium tert-butoxide (1.75 mmol), a 3 mol% catalide catalyst (Carbene oxazoline cyclopalladium), 2,2′-dibromobiphenyl (0.5 mmol), tetrahydrofuran (1 mL), and N-n-octylallylamine (1.75 mmol) were added sequentially to a 25 mL Schlenk reaction tube. The reaction tube was placed in an oil bath and heated to 90°C with stirring for 24 hours. After the reaction was complete, the solvent was removed under reduced pressure. The product was purified by alkaline alumina column chromatography and dried under vacuum to obtain a colorless oil, namely 7-methyl-5-n-octyldibenzo[b,d]azapyridine. Yield: 0.116 g, 73%.

[0038] NMR analysis: 1 H NMR (600MHz, CDCl3): δ=7.39-7.35 (m, 2H), 7.32-7.25 (m, 4H), 7.07 (t, J=7.4Hz, 1H), 6.92 (d, J=8.0Hz, 1H), 5.88 (s, 1H), 3.21 (s, 1H), 3.08 (s, 1H), 2.04 (s, 3H), 1.53 (t, J = 7.3Hz, 2H), 1.27-1.18 (m, 10H), 0.86 (t, J = 7.1Hz, 3H).

[0039] Example 3: Preparation of 3,5,7,9-tetramethyldibenzo[b,d]azapyridine compounds, the reaction formula is as follows:

[0040]

[0041] Under nitrogen atmosphere, potassium tert-butoxide (1.75 mmol), a 3 mol% catalide carbene oxazoline palladium catalyst, 2,2′-dibromo-4,4′-dimethylbiphenyl (0.5 mmol), tetrahydrofuran (1 mL), and N-methylallylamine (1.75 mmol) were added sequentially to a 25 mL Schlenk reaction tube. The reaction tube was placed in an oil bath and heated to 90°C with stirring for 24 hours. After the reaction was complete, the solvent was removed under reduced pressure. The mixture was purified by alkaline alumina column chromatography and dried under vacuum to give a white solid, namely 3,5,7,9-tetramethyldibenzo[b,d]azapyridine. Yield: 0.080 g, 64%.

[0042] NMR analysis: 1H NMR(600MHz,CDCl3):δ=7.27(d,J=7.7Hz,1H),7.21(d,J=7.7Hz,1H),7.18(s,1H),7.11(d,J=7.9Hz,1H),6.91(d,J=7.7Hz,1H),6.76(s,1H),5.89(s,1H),2.91(s,3H),2.38(d,J=11.8Hz,6H),2.03(d,J=1.1Hz,3H)。

Claims

1. A method for the catalytic synthesis of dibenzo[b,d]azapyridine compounds from a nitrogen-heterocyclic carbene oxazolinocyclic palladium compound, characterized in that... The steps are as follows: Under nitrogen atmosphere, a nitrogen-containing carbene oxazoline palladium compound catalyzes a carbon-nitrogen / carbon-carbon tandem reaction between 2,2′-dihalobiphenyl compounds and N-substituted allylamines to yield dibenzo[b,d]azapyridine compounds. The catalyst dosage is 3 mol%. The reaction equation is as follows: Where tBuOK is potassium 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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