阅读说明：本技术 一种2-亚胺吲哚啉螺噻吩衍生物及其合成方法 (2-imine indoline spirothiophene derivative and synthetic method thereof ) 是由 余正坤 黄滋龙 于 2019-12-04 设计创作，主要内容包括：本发明公开了一种2-亚胺吲哚啉螺噻吩衍生物及其合成方法,以3-重氮2-亚胺吲哚、硫羰基氮硫缩烯酮为原料,以乙腈为溶剂,以醋酸铑催化剂,在空气中,经过一步反应得到2-亚胺吲哚啉螺噻吩衍生物。本发明的合成方法具有高原子经济、高选择性、高产率的优势,并且反应条件温和,操作简单安全。本发明2-亚胺吲哚啉螺噻吩衍生物具有一个季碳中心,可以作为重要的化工和医药中间体,在医药化工领域广泛应用,具有很大应用前景。(The invention discloses a 2-imine indoline spirothiophene derivative and a synthesis method thereof, wherein 3-diazo 2-imine indole and thiocarbonyl azothioketene are used as raw materials, acetonitrile is used as a solvent, a rhodium acetate catalyst is used, and the 2-imine indoline spirothiophene derivative is obtained through one-step reaction in the air. The synthesis method has the advantages of high atom economy, high selectivity and high yield, and is mild in reaction conditions, simple and safe in operation. The 2-imine indoline spirothiophene derivative has a quaternary carbon center, can be used as an important chemical and medical intermediate, is widely applied to the field of medical chemical industry, and has a great application prospect.)

1. A2-imine indoline spirothiophene derivative has a molecular structural formula shown as the following formula 1:

R¹the aryl group or substituted aryl group with 6-18 carbon atoms is selected, the substituted aryl group is selected from aryl group which is mono-substituted at ortho, meta or para positions, and the substituent is more than one of fluorine, chlorine, bromine, iodine, methyl, tertiary butyl, phenyl, methoxy, cyano, acetoxyl and the like;

R²one selected from methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl, allyl, benzyl, phenyl, acetyl and the like;

R³one or more than two of hydrogen, fluorine, chlorine, bromine, iodine, methyl, trifluoromethyl, tertiary butyl, phenyl, methoxy, cyano and acetoxy are respectively substituted in ortho, meta or para.

2. 2-iminoindolinylspirothiophene derivatives according to claim 1, wherein: the derivatives contain a chiral quaternary carbon center; is a heterocyclic spiro structure.

3. A method for synthesizing a 2-iminoindolinylspirothiophene derivative according to claim 1 or 2, wherein: the 2-imine indoline spirothiophene derivative is prepared by taking 3-diazo 2-imine indole formula 2 and thiocarbonyl nitrogen thioketal formula 3 as raw materials and performing one-step reaction under the conditions of an organic solvent and a rhodium catalyst, wherein the reaction formula is as follows:

in the reaction formula R¹、R²、R³The definition is the same as claim 1.

4. A method of synthesis according to claim 3, characterized in that:

the rhodium catalyst is selected from one or more of rhodium chloride, rhodium acetate, cyclopentenyl rhodium dichloride and monovalent and divalent copper; the molar ratio of the 3-diazo 2-imine indole formula 2 to the thiocarbonyl azothioketal formula 3 is 1:1-1: 4; the molar ratio of the 3-diazo 2-iminoindole formula 2 to the rhodium catalyst is 1:0.01-1: 0.5.

The organic solvent is selected from one or two of acetonitrile, benzene, toluene, benzotrifluoride, acetic acid or acetone.

The reaction atmosphere is one or more than two of air, oxygen, nitrogen or argon; the reaction temperature is 0-200 ℃.

5. The method of synthesis according to claim 4, wherein: the preferred molar ratio of 3-diazo 2-iminoindole to catalyst is 1: 0.06.

6. The method of synthesis according to claim 4, wherein: the reaction temperature was 25 ℃.

7. The method of synthesis according to claim 4, wherein: the organic solvent is acetonitrile.

Technical Field

The invention relates to a 2-imine indoline spirothiophene derivative and a synthesis method thereof, which take 3-diazo 2-imine indole and thiocarbonyl nitrogen thioketal as raw materials to obtain the 2-imine indoline spirothiophene derivative through one-step reaction.

Background

Sulfur is an important element in a variety of biological systems. Sulfur-containing organic compounds have been widely used in pharmaceutical chemistry and drug design due to their universal binding ability to proteins and other biomolecules. For example, over one fifth of the 200 most commonly used prescription drugs used in 2011 are sulfur-containing compounds. On the other hand, the spirooxindole scaffold belongs to a large family of biologically active natural and non-natural compounds, which exhibit significant biological activity. Sulfur-containing heterocyclic compounds of spiroheteroindoles with elemental sulfur have become very promising structural motifs in the medical and synthetic kingdoms.

Reference to the literature

[1]Fraústo da Silva,J.R.；Williams,R.J.P.The Biological Chemistry of the Elements；Oxford University Press:New York,2001.

[2]Sulphur-Containing Drugs and Related Organic Compounds；Damani,L.A.,Ed.；Wiley:New York,1989.

[3]Sobal,G.；Menzel,E.J.；Sinzinger,H.Biochem.Pharmacol.2001,61,373.

[4]Zhou,X.；Xiao,T.；Iwama,Y.；Qin,Y.Angew.Chem.,Int.Ed.2012,51,4909.

[5]Wang,S.；Jiang,Y.；Wu,S.；Dong,G.；Miao,Z.；Zhang,W.；Sheng,C.Org.Lett.2016,18,1028.

Disclosure of Invention

The invention aims to obtain a 2-imine indoline spirothiophene derivative through one-step reaction of 3-diazo 2-imine indole and thiocarbonyl azothioketal.

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

a2-imine indoline spirothiophene derivative has a molecular structural formula shown as the following formula 1:

R¹selecting aryl or substituted aryl with 6-18 carbon atoms, wherein the substituted aryl is aryl with different groups mono-substituted in ortho, meta or para positions respectively, and the substituent is one of fluorine, chlorine, bromine, iodine, methyl, tert-butyl, phenyl, methoxy, cyano, acetoxyl and the like;

R²one selected from methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl, allyl, benzyl, phenyl, acetyl and the like;

R³one or more selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, trifluoromethyl, tert-butyl, phenyl, methoxy, cyano, acetoxy and the like, each of which is ortho-, meta-or para-substituted.

The invention provides a synthesis method of 2-imine indoline spirothiophene derivatives, which takes a general formula 2 of 3-diazo 2-imine indole and a general formula 3 of thiocarbonyl nitrogen thioketal as raw materials, acetonitrile as a solvent and rhodium acetate as a catalyst to obtain the 2-imine indoline spirothiophene derivatives through one-step reaction in the air.

In the reaction formula R¹、R²、R³The definition is the same as above.

The catalyst is selected from one or more of rhodium chloride, rhodium acetate, cyclopentenyl rhodium dichloride and monovalent and divalent copper; the mol ratio of the 3-diazo 2-imine indole to the thiocarbonyl azothioketal is 1:1-1: 4; the mol ratio of the 3-diazo 2-imine indole to the catalyst is 1:0.01-1: 0.5.

The reaction solvent is one or two of acetonitrile, benzene, toluene, benzotrifluoride, acetic acid or acetone.

The reaction atmosphere is one or more than two of air, oxygen, nitrogen or argon; the reaction temperature is 0-200 ℃.

Further, in the technical scheme, the preferable molar ratio of the 3-diazo 2-imine indole to the catalyst is 1: 0.06.

Further, in the above technical scheme, the reaction temperature is 25 ℃.

Further, in the above technical scheme, the reaction solvent is acetonitrile.

Compared with the reported synthesis method of the indole spirothiophene, the synthesis method has the advantages of easily obtained raw materials, simple and convenient operation, mild synthesis reaction conditions, high efficiency and good diversity of functional groups of the product. The 2-imine indoline spirothiophene derivative has a quaternary carbon center, can be used as an important chemical and medical intermediate, is widely applied to the field of medical chemical industry, and has a great application prospect.

Furthermore, in the technical scheme, 3-diazo 2-imine indole and thiocarbonyl azathioenone are preferably used as raw materials; the reaction catalyst is rhodium acetate; a reaction solvent of acetonitrile; the mol ratio of the 3-diazo 2-imine indole to the thiocarbonyl azothioketal is 1: 1; the optimal reaction time is 1-24 hours; the optimum reaction temperature is 0-120 ℃.

Further, in the technical scheme, the obtained 2-imine indoline spirothiophene derivative contains a chiral quaternary carbon center and is a racemate; is a heterocyclic spiro structure.

In conclusion, the 2-imine indoline spirothiophene derivative is obtained by one-step reaction in air by taking 3-diazo 2-imine indole and thiocarbonyl azothioketal as raw materials, acetonitrile as a solvent and rhodium acetate as a catalyst. The synthesis method has the advantages of high atom economy, high selectivity and high yield, and is mild in reaction conditions, simple and safe in operation.

Detailed Description

The invention synthesizes 2-imine indoline spirothiophene 1 from thiocarbonyl nitrogen sulfur epienone.

The following examples are provided to aid in the further understanding of the present invention, but the invention is not limited thereto.

The raw material preparation literature is as follows.

Reference to the literature

[1]F.Huang,Z.Q.Liu,Q.N.Wang,J.Lou,Z.K.Yu,Org.Lett.2017,19,3660.

[2]Guorong Sheng,Kai Huang,Shicong Ma,Jing Qian,Ping Lu,Yanguang Wang,Chem.Commun.2015,51,11056.

Example 1

The specific process is as follows: 2a (59.9mg,0.2mmol), 3a (65mg,0.2mmol) and rhodium acetate (3mg,0.012mmol) were weighed under nitrogen into a 25mL Schlenk reaction flask, 3mL of acetonitrile was added, and the reaction was stirred at room temperature for 12 hours. After completion of the reaction, volatile components were removed under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate; v/v. 4:1 as an eluent) to give the objective product 1a (84mg, yield 76%) as a white solid. The target product is confirmed by nuclear magnetic resonance spectrum and high resolution mass spectrum.

Compound characterization data

2-Iminoindolinylspirothiophene (1a) as a white solid,¹H NMR(400MHz,CDCl₃)δ7.64(t,J＝11.9Hz,2H),7.61–7.51(m,2H),7.31(d,J＝4.9Hz,3H),7.15(dd,J＝11.6,5.6Hz,2H),7.08–6.89(m,8H),6.77(dd,J＝21.5,13.4Hz,2H),4.68(d,J＝14.2Hz,1H),4.50(d,J＝14.0Hz,1H),3.16(s,3H),2.23(s,J＝12.9Hz,3H).¹³C NMR(101MHz,CDCl3)δ174.22,165.27,161.48,142.12,141.66,140.66,139.87,134.08,132.94,131.05,129.41,129.03,128.95,128.24,127.43,126.94,126.66,126.54,124.28,122.61,109.81,109.02,65.84,57.44,29.64,21.54.HRMS Calcd forC₃₂H₂₇N₃O₂S₂[M+H]+:550.1623；Found:550.1628.

example 2

The reaction procedure and operation were the same as in example 1, except that the solvent was acetone, as in example 1. The reaction was stopped and worked up to give the desired product 1a (36mg, yield 33%).

Example 3

The procedure was the same as in example 1, except that the temperature was 80 ℃ in example 1. The reaction was stopped and worked up to give the desired product 1a (62mg, 56% yield).

Example 4

The procedure is as in example 1, except that the amount of rhodium acetate used (0.02mmol,6mg) is changed from example 1. The reaction was stopped and worked up to give the desired product 1a (78mg, yield 71%).

Example 5

The procedure of the reaction was the same as in example 1, except that the reaction time was 6 hours, as in example 1. The reaction was terminated, and the reaction product was worked up to give the desired product 1a (61mg, yield 55%).

Example 6

The reaction procedure and operation were the same as in example 1, except that the solvent was methanol, as in example 1. The reaction was terminated, and the desired product 1a (50mg, yield 45%) was obtained by post-treatment.

Example 7

The reaction procedure was as in example 1, and the reaction was changed to 3b (68mg,0.2 mmol). The desired product 1b was obtained as a white solid (82.3mg, yield 73%). The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.

Example 8

The reaction procedure was as in example 1, and the reaction was changed to 3c (68mg,0.2 mmol). The desired product 1c was obtained as a white solid (84.5mg, yield 75%). The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.

Example 9

The reaction procedure was as in example 1, and the reaction was changed to 3d (68mg,0.2 mmol). The desired product, 1d, was obtained as a white solid (85.7mg, yield 76%). The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.

Example 10

The reaction procedure was as in example 1, and the reaction was changed to 3e (68mg,0.2 mmol). The desired product, 1e, was obtained as a white solid (86.8mg, 77% yield). The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.

Example 11

The reaction procedure was as in example 1, with the reactant being changed to 3f (68mg,0.2 mmol). The desired product, 1f, was obtained as a white solid (91.3mg, yield 81%). The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.