阅读说明：本技术 一种1,6-二氢哒嗪衍生物的合成方法 (Synthesis method of 1, 6-dihydropyridazine derivative ) 是由 邵银林 叶轩锃 刘千睿 黄奔凯 何腾航 刘杨丰 徐北航 孙佳妮 陈久喜 于 2021-01-08 设计创作，主要内容包括：本发明公开了一种1,6-二氢哒嗪衍生物的合成方法,其技术方案是通过单质碘催化β,γ-不饱和酰肼分子内加成环化从而实现结构多样化的1,6-二氢哒嗪衍生物合成。具体是在室温下,以分子碘为催化剂,DMSO为溶剂,以各种取代的β,γ-不饱和酰肼为原料,制备1,6-二氢哒嗪啉衍生物。本发明方法原料来源广泛或易于制备,操作简便、选择性可控,收率高,条件温和,普适性广。(The invention discloses a synthesis method of a 1, 6-dihydropyridazine derivative, which adopts the technical scheme that the synthesis of the 1, 6-dihydropyridazine derivative with diversified structures is realized by catalyzing beta, gamma-unsaturated hydrazide with elemental iodine to perform intramolecular addition cyclization. Specifically, at room temperature, molecular iodine is used as a catalyst, DMSO is used as a solvent, and various substituted beta, gamma-unsaturated hydrazides are used as raw materials to prepare the 1, 6-dihydropyridazoline derivative. The method has the advantages of wide raw material source or easy preparation, simple and convenient operation, controllable selectivity, high yield, mild conditions and wide universality.)

1. A method for synthesizing a 1, 6-dihydropyridazine derivative is characterized by comprising the following steps:

the method comprises the following steps of taking various substituted beta, gamma-unsaturated hydrazones of a compound shown as a formula (I) as a raw material, and carrying out intramolecular addition cyclization reaction under the catalysis of iodine in an air atmosphere to obtain a 1, 6-dihydropyridazine derivative (II), wherein the reaction formula is as follows:

in the above formula, R₁Is aryl, alkyl; r₂Is methyl, halogen, trifluoromethyl or methoxy.

2. The method for synthesizing a 1, 6-dihydropyridazine derivative according to claim 1, characterized in that: the reaction is carried out under solvent conditions.

3. The method for synthesizing a 1, 6-dihydropyridazine derivative according to claim 1, characterized in that: the solvent is dimethyl sulfoxide.

4. The method for synthesizing a 1, 6-dihydropyridazine derivative according to claim 1, characterized in that: the molar ratio of compound of formula (I)/iodine catalyst was 1.0/0.75.

5. The method for synthesizing a 1, 6-dihydropyridazine derivative according to claim 1, characterized in that: the reaction temperature is room temperature, and the reaction time is 30 min.

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing 1, 6-dihydropyridazine by C-H amination and intramolecular cyclization reaction of olefin, so as to realize structural diversification.

Background

The pyridazine compound is an important heterocyclic compound and is widely applied to the fields of medicine and agriculture due to various biological activities. Therefore, the development of new methods for synthesizing various and efficient pyridazine compounds has been an important issue in organic synthetic chemistry.

Conventionally, synthesis of pyridazine has been carried out by a method of synthesizing a starting material such as butenedial, formamidine acetate or pyridazine nucleus, or by a method of reacting maleic anhydride with hydrazine hydrate. The synthesis method comprises the following steps of taking butenediol as a raw material: is synthesized by butylene dialdehyde and hydrazine hydrate through Diels-Alder reaction. The method has few synthesis steps, but the reaction conditions are difficult to control, chain reaction is easy to occur, and the yield is low. The literature (J.org.chem.2013,78,7845-7858) reports a method of two-link design experiment, and in the first part, an ester group-containing pyridazine compound is synthesized as a model of an evaluation method. In the second part, various types of pyridazine derivatives with different substituents are synthesized by different cyclization methods using a modified procedure, resulting in several hitherto unknown bis-heterocyclic compounds. The method enriches the substrate library of the pyridazine derivative and makes great contribution to the future pharmacological research. However, the raw material synthesis steps are complicated and the conditions are harsh, for example, acetophenone derivatives need to be converted into the corresponding silylene ether by LiHMDS and trimethylsilylchloride at-78 ℃.

In addition, the literature (Nature Communications,2016,7: 11188-.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide a method for synthesizing a 1, 6-dihydropyridazine derivative, which takes beta, gamma-unsaturated hydrazone as a raw material and has the advantages of high selectivity and high yield.

In order to achieve the purpose, the technical scheme of the invention comprises the following steps:

the method comprises the following steps of taking various substituted beta, gamma-unsaturated hydrazones of a compound shown as a formula (I) as a raw material, and carrying out intramolecular addition cyclization reaction under the catalysis of iodine in an air atmosphere to obtain a 1, 6-dihydropyridazine derivative (II), wherein the reaction formula is as follows:

in the above formula, R₁Is aryl, alkyl; r₂Is methyl, halogen, trifluoromethyl or methoxy.

It is further provided that the reaction is carried out under solvent conditions.

The further setting is that the solvent is dimethyl sulfoxide.

It is further provided that the molar ratio of compound of formula (I)/iodine catalyst is 1.0/0.75.

Further setting that the reaction temperature is room temperature and the reaction time is 30 min.

Through intensive research, the inventor discovers that the synthesis of the 1, 6-dihydropyridazine derivative with diversified structures is realized by catalyzing beta, gamma-unsaturated hydrazone intramolecular cyclization reaction under an iodine catalysis system, and the method has the advantages of high atom economy, high bonding efficiency and mild reaction conditions. Compared with the prior method, the method has the advantages that the reaction conditions and the substrate universality are obviously improved, which is difficult to realize by other methods. The invention has the following advantages and innovations:

(1) the reaction universality is good, the yield is high, most of the reaction yield is over 85 percent, and the atom economy is high;

(2) provides an important idea for constructing the nitrogen-containing heterocyclic compound;

(3) the reaction conditions are mild and no additive is needed.

(4) The method is also successfully applied to the synthesis of naphthalene ring derivatives.

(5) The iodine catalyst is simple, has moderate price and can be purchased commercially;

compared with the prior art, the invention has the following beneficial effects:

the 1, 6-dihydropyridazine derivative prepared by the method has high quality and high yield; the reaction universality is good, the reaction atom economy is high, and the post-treatment is convenient. The pyridazine compound is constructed by amination and cyclization of beta, gamma-unsaturated hydrazone carbon-hydrogen bonds under catalysis of molecular iodine, and important reference is provided for construction of the pyridazine compound and other heterocyclic compounds.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be further described in detail with reference to the following examples.

Example 1

Preparation of 3, 6-diphenyl-1-tolyl-1, 6-dihydropyridazine, structural formula:

under an air atmosphere, the starting material (Z) -N' - ((E) -1, 4-diphenylbut-3-en-1-ylene) -4-methylbenzyl phenylhydrazine (0.3mmol) and catalyst I were added₂(0.75eq) and dimethyl sulfoxide (2mL) were reacted at room temperature for 30min, and the isolation yield of the product was 86%.

¹H NMR(500MHz,CDCl₃)δ7.52-7.40(m,2H),7.42-7.40(m,5H),7.22-7.12(m,5H),7.0(d,J＝7.8Hz,2H),6.55(d,J＝10.0Hz,1H),6.36(dd,J₁＝6.2Hz,J₂＝9.7Hz,1H),5.99(d,J＝6.1Hz,1H),2.30(s,3H)；¹³C{¹H}NMR(125MHz,CDCl₃)δ146.2,143.3,138.6,135.8,135.2,132.5,129.7,128.9,128.8,128.7,128.1,127.9,115.3,56.0,21.6.。

Example 2

Preparation of 6-phenyl-3- (p-tolyl) -1-tosyl 1, 6-dihydropyridazine, structural formula:

under an air atmosphere, the starting material (Z) -4-methyl-N' - ((E) -4-phenyl-1- (p-tolyl) but-3-en-1-ylene) benzenesulfonylhydrazide (0.3mmol) and catalyst I were added₂(0.75eq) and dimethyl sulfoxide (2mL) were reacted at room temperature for 30min, and the isolated yield of the product was 91%.

¹H NMR(500MHz,DMSO)δ7.76(d,J＝8.2Hz,2H),7.43(d,J＝8.3Hz,2H),7.27-7.24(m,3H),7.22-7.14(m,6H),6.77(d,J＝10.0Hz,1H),6.57(dd,J₁＝6.3Hz,J₂＝10.1Hz,1H),6.01(d,J＝6.4Hz,1H),2.33(s,3H),2.29(s,3H)；δ；¹³C{¹H}NMR(125MHz,DMSO)δ146.7,143.6,139.6,138.8,135.4,133.3,131.7,129.4,129.1,128.6,128.5,127.4,127.1,125.3,114.8,54.9,21.0,20.9.。

Example 3

Preparation of 3- (4-methoxyphenyl) -6-phenyl-1-tolyl-1, 6-dihydropyridazine, structural formula:

under an air atmosphere, the starting material (Z) -4-methyl-N' - ((E) -4-phenyl-1- (p-methoxyphenyl) but-3-en-1-ylene) benzenesulfonyl hydrazide (0.3mmol) and catalyst I were added₂(0.75eq), dimethyl sulfoxide (2mL), at room temperature for 30min, with an isolated yield of 84%.

¹H NMR(500MHz,DMSO)δ7.73-7.12(m,2H),7.44(d,J＝8.9Hz,2H),7.25-7.17(m,7H),7.01-6.99(m,2H),6.76(d,J＝9.9Hz,1H),6.58-6.54(m,1H),6.00(d,J＝6.2Hz,1H),3.79(s,3H),2.80(s,3H)；¹³C{¹H}NMR(125MHz,DMSO)δ160.7,146.6,143.5,138.8,135.5,133.3,129.1,128.6,128.5,127.4,127.2,127.0,126.9,114.8,114.2,55.3,54.9,21.0.。

Example 4

Preparation of 3- (4-chloro) -6-phenyl-1-tolyl-1, 6-dihydropyridazine, structural formula:

under an air atmosphere, the starting material (Z) -4-methyl-N' - ((E) -4-phenyl-1- (p-chlorophenyl) but-3-en-1-ylene) benzenesulfonylhydrazide (0.3mmol) and catalyst I were added₂(0.75eq), dimethyl sulfoxide (2mL), at room temperature for 30min, with 85% product isolation yield.

¹H NMR(500MHz,CDCl₃)7.7(d,J＝8.5Hz,2H),7.40-7.37(m,4H),7.23-7.22(m,1H),7.17-7.14(m,4H),7.00(d,J＝8.1Hz,2H),6.49(d,J＝10Hz,1H),6.35(dd,J₁＝6.2Hz,J₂＝9.9Hz,1H),5.99(d,J＝6.2Hz,1H),2.3(s,3H)；¹³C{¹H}NMR(125MHz,DMSO)δ145.1,143.3,138.4,135.7,135.6,133.6,132.7,128.8,128.7,128.0,127.8,126.9,114.8,56.0,21.2.。

Example 5

Preparation of 3- (naphthalen-2-yl) -6-phenyl-1-tolyl-1, 6-dihydropyridazine of the formula:

the starting material ((Z) -4-methyl-N' - ((E) -1- (naphthalen-2-yl) -4-phenylbut-3-en-1-ylene) phenylhydrazides (0.3mmol) and catalyst I were added to the flask under an air atmosphere₂(0.75eq) and dimethyl sulfoxide (2mL) were reacted at room temperature for 30min, and the isolated yield of the product was 88%.

¹H NMR(500MHz,CDCl₃)δ8.33(s,1H),8.00-7.92(m,4H),7.57-7.54(m,2H),7.50(d,J＝7.6Hz,2H),7.26-7.18(m,7H),6.99(d,J＝9.9Hz,1H),6.63(dd,J₁＝6.3Hz,J₂＝9.9Hz,1H),6.08(d,J＝6.2Hz,1H),2.27(s,3H)；13C{1H}NMR(125MHz,CDCl3)δ146.4,143.7,138.8,135.4,133.4,133.3,132.8,131.8,129.2,128.6,128.6,128.5,128.5,127.6,127.5,127.3,127.2,126.8,125.5,122.4,114.6,55.2,21.0.。

Example 6

Preparation of 3- (tert-butyl) -6-phenyl-1-tolyl-1, 6-dihydropyridazine, structural formula:

under an air atmosphere, the starting material (Z) -N' - ((E) -1- (4- (tert-butyl) phenyl) -4-phenylbut-3-en-1-ylene) -4-methylbenzyl phenylhydrazine (0.3mmol) and catalyst I were added₂(0.75eq) and dimethyl sulfoxide (2mL) were reacted at room temperature for 30min, and the isolation yield of the product was 82%.

¹H NMR(500MHz,CDCl₃)δ7.33(d,J＝8.0Hz,2H),7.23-7.13(m,5H),7.07(d,J＝7.4Hz,2H),6.4(dd,J₁＝6.3Hz,J₂＝9.9Hz,1H),6.31-6.29(m,1H),5.83(d,J＝6.0Hz,1H),2.27(s,3H),1.08(s,9H).¹³C{¹H}NMR(125MHz,CDCl₃)δ157.0,143.2,138.7,135.5,133.0,128.8,128.4,128.3,127.3,127.1,114.5,54.7,36.1,27.3,21.0.。

Example 7

The preparation of 3-phenyl-2-p-methyl benzenesulfonyl-1, 2,5,6,7, 8-hexahydro-o-dinitronaphthalene has the following structural formula:

under an air atmosphere, the starting material (E) -4-methyl-N' -2- (((E) -styryl) cyclohexylidene) benzenesulfonylhydrazide (0.3mmol) and catalyst I were added₂(0.75eq) and dimethyl sulfoxide (2mL) were reacted at room temperature for 30min, and the isolation yield of the product was 89%.

¹H NMR(500MHz,CDCl₃)δ7.83(brs,1H),7.29(d,J＝8.3Hz,2H),7.11-7.10(m,3H),7.01-6.98(m,2H),6.91(d,J＝8.1Hz,2H),5.95(s,1H),2.91-2.87(m,1H),2.65-2.52(m,3H),2.35(s,3H),1.96-1.94(m,1H),1.82-1.81(m,3H)；¹³C{¹H}NMR(125MHz,CDCl₃)δ144.2,133.9,132.1,131.8,131.6,129.2,128.0,127.9,127.2,125.8,116.8,107.8,23.6,23.11,23.0,21.8,21.6.。

The above disclosure is only for the purpose of illustrating the preferred embodiments of the present invention, and it is therefore to be understood that the invention is not limited by the scope of the appended claims.