CN109320468B

CN109320468B - Method for mild preparation of benzo [ a ] phenazine compound

Info

Publication number: CN109320468B
Application number: CN201811317457.XA
Authority: CN
Inventors: 刘晋彪; 叶秋香; 陈海清
Original assignee: Buddhist Tzu Chi General Hospital
Current assignee: Buddhist Tzu Chi General Hospital
Priority date: 2018-11-07
Filing date: 2018-11-07
Publication date: 2020-04-10
Anticipated expiration: 2038-11-07
Also published as: CN109320468A

Abstract

The invention discloses a method for preparing benzo [ a ] phenazine compounds in a mild way, which belongs to the technical field of organic chemistry. By the method, the benzo [ a ] phenazine compound is conveniently synthesized in one step by using low-toxicity and easily-obtained ceric ammonium nitrate as an accelerant. The method has the advantages of mild reaction conditions, wide substrate applicability, simple and convenient operation, low cost, no use of nitro compounds and heavy metals, high product purity, convenient separation and purification, and suitability for large-scale preparation.

Description

Method for mild preparation of benzo [ a ] phenazine compound

Technical Field

The invention belongs to the technical field of organic chemistry, and particularly relates to a method for mildly preparing benzo [ a ] phenazine compounds.

Background

Benzo [ a ] phenazines are widely found in nature and were originally used in dyes. In recent years, benzo [ a ] phenazine compounds are found to have excellent biological activity in the aspects of malaria resistance, hepatitis resistance, tumor resistance and the like. Besides the application in the aspect of biological medicine, benzo [ a ] phenazine compounds are also widely applied in the fields of color bodies, organic conductors, solar cell materials and the like. At present, the traditional methods for preparing benzo [ a ] phenazine compounds mainly comprise the following two methods: 1) 1, 2-naphthoquinone is prepared by naphthol oxidation, and then the naphthoquinone and o-phenylenediamine are subjected to ring closure to prepare the benzo [ a ] phenazine compound, so that the benzo [ a ] phenazine compound has the advantages of fewer side reactions, but the reaction needs to be carried out step by step, the yield is not high, and the operation is not simple; 2) the benzo [ a ] phenazine compound phenazine is prepared by taking o-nitrodiphenylamine as a raw material and then carrying out cyclization reaction under the promotion of zero-valent metal or low-valent metal oxide, but the method uses a large amount of dangerous aromatic compounds containing nitro groups, generates a large amount of waste materials containing heavy metals and pollutes the environment. Therefore, a general method for efficiently preparing the benzo [ a ] phenazine compound, which has mild reaction conditions, simple operation and environmental friendliness, is found, and has high theoretical and practical application values.

Disclosure of Invention

In order to overcome the defects in the prior art, the invention aims to provide a novel method for preparing a series of benzo [ a ] phenazine compounds mildly and efficiently by taking naphthol and o-phenylenediamine as raw materials under the promotion of ammonium ceric nitrate.

In order to achieve the purpose, the technical scheme of the invention is as follows:

a method for the mild preparation of benzo [ a ] phenazine compounds, the method comprising the steps of:

respectively adding naphthol, ammonium ceric nitrate and o-phenylenediamine into acetonitrile as solvent in air atmosphere, magnetically stirring at room temperature for 6-8 hr, monitoring by TLC until complete reaction, adding water for quenching, extracting with ethyl acetate, and extracting with anhydrous Na₂SO₄Drying, decompressing, spinning and drying the solvent, and separating by fast column chromatography to obtain the pure benzo [ a ] product]Phenazine compounds.

1.0 part by weight of naphthol and 1.0 part by weight of o-phenylenediamine are used as reaction substrates, 1.5 parts by weight of ammonium ceric nitrate is added as an accelerator, acetonitrile serving as a solvent is added, and the mixture is reacted for 6 to 8 hours at room temperature to obtain the benzo [ a ] phenazine compound.

The invention also has the following additional technical features:

further, the mass ratio of the naphthol, the ammonium ceric nitrate and the o-phenylenediamine is 1:1.5: 1.

Further, the benzo [ a ] phenazine compound series is prepared with higher yield.

Specifically, naphthol and o-phenylenediamine are used as raw materials, and are promoted by ceric ammonium nitrate to directly prepare a series of benzo [ a ] phenazine compounds by a one-step method.

Further, the naphthol substrate is 1-naphthol or 2-naphthol; the o-phenylenediamine substrate is o-phenylenediamine, 4, 5-difluoro o-phenylenediamine, 4, 5-dimethyl o-phenylenediamine and 4-methyl o-phenylenediamine.

Further, the reaction temperature is 10-30 ℃.

The reaction equation of the present invention is as follows:

wherein R is an electron donating group or an electron withdrawing group.

Preferably, the electron donating group is an alkyl group.

Preferably, the electron withdrawing group is chlorine or fluorine.

The specific operation is as follows: air conditionerIn an atmosphere, 1.0 weight part of naphthol (1a), 1.5 weight parts of ammonium ceric nitrate and 1.0 weight part of o-phenylenediamine (2) were added to acetonitrile as a solvent, and the mixture was magnetically stirred at room temperature for 6 to 8 hours, followed by monitoring by TLC until the reaction was completed. After-treatment, the mixture was quenched with water, extracted with ethyl acetate and dried over anhydrous Na₂SO₄Drying, decompressing, spinning and drying the solvent, and separating by fast column chromatography to obtain the pure benzo [ a ] product]And (3) phenazine compounds.

In the invention, cerium ammonium nitrate is used for promoting naphthol and o-phenylenediamine to directly cyclize to prepare the benzo [ a ] phenazine compound. The reaction operation is simple and convenient, the complexity of step-by-step reaction and the use of toxic heavy metals are avoided, and the pollution to the environment is reduced.

The invention has the beneficial effects that:

1) the method for preparing the benzo [ a ] phenazine compound in a mild way avoids the use of explosive nitro compounds, and greatly improves the safety of the reaction process;

2) the method avoids the complexity of multi-step reaction, is simple and convenient to operate, has high yield, and is suitable for industrial production;

3) the raw materials are simple and easy to obtain, and the method is suitable for series of substituted benzo [ a ] phenazine compounds;

4) the method has the advantages of high reaction efficiency, mild conditions, wide substrate applicability, simple and convenient operation, low cost, few byproducts, high product purity, convenient separation and purification and suitability for large-scale preparation;

5) the product prepared by the method has a benzo [ a ] phenazine core skeleton, potential biological activity and excellent optical property, so that the obtained product has considerable application prospect.

Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.

Drawings

FIG. 1: hydrogen spectrum of compound 3 a.

FIG. 2: hydrogen spectrum of compound 3 b.

Detailed Description

Reference will now be made in detail to the embodiments of the present invention, wherein like or similar reference numerals refer to like or similar elements or elements having like or similar functions throughout. The embodiments described below with reference to the drawings are illustrative and intended to be illustrative of the invention and are not to be construed as limiting the invention. The present invention will be described in detail with reference to specific examples.

Example 1

In an air atmosphere, 1.0 part by weight of 2-naphthol (1a), 1.5 parts by weight of cerium ammonium nitrate, and 1.0 part by weight of o-phenylenediamine (2a) were added to 50 parts by weight of acetonitrile as a solvent, and the mixture was magnetically stirred at room temperature for 6.5 hours, followed by monitoring by TLC until the reaction was completed. After-treatment, the mixture was quenched with water, extracted with ethyl acetate and dried over anhydrous Na₂SO₄Drying, decompressing, spinning and drying the solvent, and separating by fast column chromatography to obtain the pure benzo [ a ] product]A phenazine compound (3 a). Isolation yield: 81 percent.

¹H NMR(400MHz,DMSO)δ9.22(d,J＝8.8Hz,1H),8.45(d,J＝1.8Hz,1H),8.41(dd,J＝6.8,3.2Hz,1H),8.37–8.31(m,1H),8.25(d,J＝9.4Hz,1H),8.06(ddd,J＝8.3,6.2,5.5Hz,5H).

Example 2

1.0 part by weight of 1-naphthol (1b), 1.5 parts by weight of cerium ammonium nitrate, and 1.0 part by weight of o-phenylenediamine (2a) were added to 50 parts by weight of acetonitrile as a solvent in an air atmosphere, and the mixture was magnetically stirred at room temperature for 6 hours, followed by monitoring by TLC until the reaction was completed. After-treatment, the mixture was quenched with water, extracted with ethyl acetate and dried over anhydrous Na₂SO₄Drying, decompressing, spinning and drying the solvent, and separating by fast column chromatography to obtain the pure benzo [ a ] product]A phenazine compound (3 a). Isolation yield: 72 percent.

Example 2 deals mainly with the substrate suitability of naphthols. The results of the examples show that 1-naphthol is also suitable for this reaction to give benzo [ a ] phenazine compounds (3 a).

Example 3

In an air atmosphere, 1.0 part by weight of 2-naphthol (1a), 1.5 parts by weight of cerium ammonium nitrate, and 1.0 part by weight of 4, 5-difluoroo-phenylenediamine (2b) were added to 50 parts by weight of acetonitrile as a solvent, and the mixture was magnetically stirred at room temperature for 7.2 hours, followed by monitoring by TLC until the reaction was completed. After-treatment, the mixture was quenched with water, extracted with ethyl acetate and dried over anhydrous Na₂SO₄Drying, decompressing, spinning and drying the solvent, and separating by flash column chromatography to obtain the pure product 9, 10-difluorobenzo [ a]And (3b) phenazine compounds. Isolation yield: 84 percent.

¹H NMR(400MHz,CDCl₃)δ9.31(d,J＝5.2Hz,1H),7.97(dt,J＝29.2,7.5Hz,5H),7.80(d,J＝4.0Hz,2H).

Example 3 mainly considers the compatibility of halogen atoms in this reaction. The results of examples show that o-phenylenediamine substituted with a fluorine atom can produce 9, 10-difluorobenzo [ a ] phenazine compounds (3 b).

Example 4

In an air atmosphere, 1.0 part by weight of 2-naphthol (1a), 1.5 parts by weight of cerium ammonium nitrate, and 1.0 part by weight of 4-nitrophthalenediamine (2c) were added to 50 parts by weight of acetonitrile as a solvent, and the mixture was magnetically stirred at room temperature for 6.8 hours, followed by monitoring by TLC until the reaction was completed. After-treatment, the mixture was quenched with water, extracted with ethyl acetate and dried over anhydrous Na₂SO₄Drying, decompressing, spinning and drying the solvent, and separating by flash column chromatography to obtain the pure product 9, 10-difluorobenzo [ a]A phenazine compound (3 c). Isolation yield: 75 percent.

¹H NMR(400MHz,CDCl₃)δ9.45–9.36(m,1H),9.19(d,J＝2.2Hz,1H),8.59(dd,J＝9.2,2.1Hz,1H),8.47(d,J＝9.2Hz,1H),8.08(d,J＝9.2Hz,1H),8.03–7.79(m,4H).

Example 4 primarily looks at the compatibility of electron withdrawing groups in this reaction. The results of the examples show that 4-nitrophthalenediamine can be suitably used in this reaction to give the product 3 c.

Example 5

In an air atmosphere, 1.0 part by weight of 2-naphthol (1a), 1.5 parts by weight of cerium ammonium nitrate, and 1.0 part by weight of 4, 5-dimethylphthaldiamine (2d) were added to 50 parts by weight of acetonitrile as a solvent, and the mixture was magnetically stirred at room temperature for 7.4 hours, followed by monitoring by TLC until the reaction was completed. After-treatment, the mixture was quenched with water, extracted with ethyl acetate and dried over anhydrous Na₂SO₄Drying, decompressing, spinning and drying the solvent, and separating by flash column chromatography to obtain the pure product 9, 10-dimethylbenzo [ a]And (3d) phenazine compounds. Isolation yield: 83 percent.

¹H NMR(400MHz,CDCl₃)δ9.40(d,J＝8.0Hz,1H),8.11(s,1H),8.02(s,1H),8.00-7.95(m,2H),7.92(d,J＝7.6Hz,1H),7.82-7.74(m,2H),2.59(s,3H),2.57(s,3H).

Example 5, which aims to illustrate the compatibility of the methyl group containing an electron-donating group in this reaction, shows that: the disubstituted methyl can be compatible in the reaction to obtain the 9, 10-dimethylbenzo [ a ] phenazine compound (3 d).

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples described in this specification can be combined and combined by those skilled in the art.

While embodiments of the invention have been shown and described, it will be understood by those of ordinary skill in the art that: various changes, modifications, substitutions and alterations can be made to the embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents.

Claims

1. A mild process for the preparation of benzo [ a ] phenazine compounds, said process comprising the steps of:

respectively adding naphthol, ammonium ceric nitrate and o-phenylenediamine into acetonitrile as solvent in air atmosphere, magnetically stirring at room temperature for 6-8 hr, monitoring by TLC until complete reaction, adding water for quenching, extracting with ethyl acetate, and extracting with anhydrous Na₂SO₄Drying, decompressing, spinning and drying the solvent, and separating by fast column chromatography to obtain the pure benzo [ a ] product]A phenazine compound;

the reaction equation of the present invention is as follows:

wherein R is an electron donating group or an electron withdrawing group, the electron donating group being an alkyl group; the electron-withdrawing group is chlorine or fluorine.

2. The mild method for preparing benzo [ a ] phenazine compound according to claim 1, wherein the mass ratio of naphthol, ammonium ceric nitrate and o-phenylenediamine is 1:1.5: 1.

3. The mild method for preparing benzo [ a ] phenazine compound according to claim 1, wherein the naphthol is 1-naphthol or 2-naphthol.

4. The mild process of claim 1 wherein the o-phenylenediamine is o-phenylenediamine, 4, 5-difluoroo-phenylenediamine, 4-nitrophthalenediamine or 4, 5-dimethylphthalenediamine.

5. The mild process for the preparation of benzo [ a ] phenazine compounds as claimed in claim 1, wherein the reaction temperature during the reaction is 10-30 ℃.