阅读说明：本技术 一种α-硫氰酮类化合物的合成方法 (Synthetic method of alpha-thiocyananone compound ) 是由 周云兵 郭丽萍 李金承 刘妙昌 吴华悦 于 2021-11-03 设计创作，主要内容包括：本发明公开了一种无金属、无添加的催化反应条件下制备α-硫氰酮类化合物的新方法,利用含有α-H的酮类衍生物与单质硫以及TMSCN作为氰基源直接引入硫氰基,得到良好的产率,并且底物范围较宽广,该方法具有方便可行、易于操作、收率较高、绿色环保的优点。(The invention discloses a novel method for preparing alpha-thiocyanatone compounds under the condition of metal-free and additive-free catalytic reaction, which utilizes alpha-H-containing ketone derivatives, elemental sulfur and TMSCN as cyano-group sources to directly introduce thiocyano groups to obtain good yield, has wider substrate range, and has the advantages of convenience, feasibility, easy operation, higher yield and environmental protection.)

1. A synthetic method of alpha-thiocyananone compounds is characterized by comprising the following steps:

adding a ketone compound shown in a formula I, sulfur powder, TMSCN and an organic solvent into a reactor with magnetic stirring, then stirring the reaction mixture at 60-120 ℃ for reaction, and carrying out post-treatment after the reaction is completed to obtain an alpha-thiocyananone compound shown in a formula II; the reaction formula is as follows:

in the above reaction formula, R₁Is selected from C_1-20Alkyl radical, C_1-20Alkoxy, substituted or unsubstituted C_6-20Aryl, substituted or unsubstituted C_2-20Heteroaryl, substituted or unsubstituted C_3-20Cycloalkyl, substituted or unsubstituted C_2-20An alkenyl group;

R₂selected from hydrogen, halogen, C_1-20Alkyl, substituted or unsubstituted C_6-20Aryl, substituted or unsubstituted C_7-20Aralkyl group; alternatively, the first and second electrodes may be,

R₁and R₂To each other to form saturated or unsaturated C with or without hetero atoms_3-20A cyclic structure, the cyclic structure being optionally substituted with a substituent;

wherein the substituents in said "substituted" are selected from the group consisting of halogen, methyl, ethyl, t-butyl, methoxy, ethoxy, t-butoxy, -CN, -NO₂Phenyl, acetyl, acetoxy, 2,4, 4-trimethylcyclohexen-3-yl; and/or two adjacent substituents together form C_3-7Optionally substituted with one or more C_1-6Alkyl substitution.

2. The method of synthesis of claim 1, wherein R is₁Selected from substituted or unsubstituted C_6-12Aryl, substituted or unsubstituted C_2-12Heteroaryl, substituted or unsubstituted C_2-20An alkenyl group;

R₂selected from hydrogen, C_1-6Alkyl, substituted or unsubstituted C_6-20An aryl group; alternatively, the first and second electrodes may be,

R₁and R₂To each other to form saturated or unsaturated C with or without hetero atoms_6-12A cyclic structure.

3. The method of synthesis of claim 1, wherein R is₁Is selected fromWherein m is selected from 1,2,3,4 or 5; each R is_aIndependently of one another hydrogen, fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, nitro, cyano, acetyl, acetoxy;

R₂selected from hydrogen, methyl, ethyl, propyl, tert-butyl, phenyl; alternatively, the first and second electrodes may be,

R₁and R₂Are connected with each other in the following structure:

4. the method of claim 1, wherein the organic solvent is selected from the group consisting of DMSO.

5. The synthesis method of claim 1, wherein the molar ratio of the ketone compound represented by formula I to the sulfur powder to the TMSCN is (2-4): (5-9): (8-10).

6. The synthesis method according to claim 1, characterized in that the reaction temperature is 80-100 ℃; the reaction time is 5-20 h.

7. The synthesis method according to claim 6, characterized in that the reaction temperature is 80 ℃; the reaction time was 12 h.

8. The method of synthesis according to claim 1, wherein the reaction atmosphere is an air atmosphere.

9. The synthesis process according to claim 1, characterized in that the post-treatment operations are as follows: after the reaction is completed, water is added into the reaction system for quenching, then the reaction liquid is extracted by ethyl acetate, an organic phase is separated and concentrated, and the residue is purified by silica gel flash chromatography to obtain the alpha-thiocyananone compound shown in the formula II.

Technical Field

The application belongs to the technical field of organic synthesis, and particularly relates to a synthetic method of an alpha-thiocyananone compound.

Background

Alpha-thiocyanatone has extremely wide application in the fields of synthesis of a plurality of biological molecules, research of new materials, drug molecules and the like, and particularly in animal model systems, the compounds as a whole seem to play a role of a chemoprotectant to resist various chemical carcinogens. In addition, the alpha-thiocyananone derivatives have great application value, and the compounds can be used as a very useful intermediate in synthesis and can be used for synthesizing a series of sulfur trifluoromethyl, disulfide and drug molecules containing 2-aminothiazole skeletons. The synthesis and properties of such compounds have therefore been of increasing interest to organic synthetic chemists in the relevant field since the last century. After the intensive study of the efficient insertion of elemental sulfur, similar to the work of the previous work and the group of our subjects, the thiocyano group was directly introduced using a ketone derivative containing α -H, elemental sulfur and TMSCN as cyano sources, resulting in good yields and a wide substrate range. Finally, the method for synthesizing the alpha-thiocyanatone is convenient and feasible, easy to operate, high in yield and environment-friendly.

Disclosure of Invention

The invention aims to provide a novel method for preparing alpha-thiocyanatone compounds under the condition of metal-free and additive-free catalytic reaction, which utilizes alpha-H-containing ketone derivatives, elemental sulfur and TMSCN as cyano-group sources to directly introduce thiocyano groups to obtain good yield and wider substrate range.

The synthesis method of the alpha-thiocyananone compound provided by the invention comprises the following steps:

adding a ketone compound shown in a formula I, sulfur powder, TMSCN and an organic solvent into a reactor with magnetic stirring, then stirring the reaction mixture at 60-120 ℃ for reaction, and carrying out post-treatment after the reaction is completed to obtain an alpha-thiocyananone compound shown in a formula II; the reaction formula is as follows:

in the above reaction formula, R₁Is selected from C_1-20Alkyl radical, C_1-20Alkoxy, substituted or unsubstituted C_6-20Aryl, substituted or unsubstituted C_2-20Heteroaryl, substituted or unsubstituted C_3-20Cycloalkyl, substituted or unsubstituted C_2-20An alkenyl group;

R₂selected from hydrogen, halogen, C_1-20Alkyl, substituted or unsubstitutedC of (A)_6-20Aryl, substituted or unsubstituted C_7-20Aralkyl group; alternatively, the first and second electrodes may be,

R₁and R₂To each other to form saturated or unsaturated C with or without hetero atoms_3-20A cyclic structure, the cyclic structure being optionally substituted with a substituent.

In any of the sections herein, the substituents in said "substituted" are selected from the group consisting of halogen (including fluoro, chloro, bromo, iodo), methyl, ethyl, tert-butyl, methoxy, ethoxy, tert-butoxy, -CN, -NO₂Phenyl, acetyl, acetoxy, 2,4, 4-trimethylcyclohexen-3-yl; and/or two adjacent substituents together form C_3-7Optionally substituted with one or more C_1-6Alkyl substitution.

In any of the sections herein, the alkyl group having the indicated carbon atoms (including alkoxy, alkyl portion in aralkyl) may be selected from, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like. The aryl group having the indicated number of carbon atoms (including the aryl moiety in the aralkyl group) may be selected from, for example, phenyl, naphthyl, anthryl, phenanthryl, pyrenyl, and the like. The heteroaryl group having the indicated number of carbon atoms may be selected from, for example, thienyl, furyl, pyridyl, pyrazolyl, quinolyl, thiazolyl, oxazolyl and the like. Cycloalkyl groups having the indicated number of carbon atoms may be selected from, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and bridged cycloalkyl groups such as adamantyl and the like.

Thus, preferably, R₁Selected from substituted or unsubstituted C_6-12Aryl, substituted or unsubstituted C_2-12Heteroaryl, substituted or unsubstituted C_2-20An alkenyl group;

R₂selected from hydrogen, C_1-6Alkyl, substituted or unsubstituted C_6-20An aryl group; alternatively, the first and second electrodes may be,

R₁and R₂To each other to form saturated or unsaturated C with or without hetero atoms_6-12A cyclic structure.

Further preferably, R₁Is selected fromWherein m is selected from 1,2,3,4 or 5; each R is_aIndependently of one another hydrogen, fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, nitro, cyano, acetyl, acetoxy;

R₂selected from hydrogen, methyl, ethyl, propyl, tert-butyl, phenyl; alternatively, the first and second electrodes may be,

R₁and R₂Are connected with each other in the following structure:

according to the aforementioned synthesis method of the present invention, the organic solvent is selected from DMSO.

According to the synthesis method, the feeding molar ratio of the ketone compound shown in the formula I, the sulfur powder and the TMSCN is (2-4): (5-9): (8-10).

According to the synthesis method, the reaction temperature is preferably 80-100 ℃; most preferably 80 ℃; the reaction time is 5-20h, preferably 12 h.

According to the synthesis method of the invention, the reaction atmosphere is air atmosphere.

According to the synthesis method of the invention, the post-treatment operation is as follows: after the reaction is completed, water is added into the reaction system for quenching, then the reaction liquid is extracted by ethyl acetate, an organic phase is separated and concentrated, and the residue is purified by silica gel flash chromatography to obtain the alpha-thiocyananone compound shown in the formula II.

The synthesis method of the invention has the following beneficial effects:

the invention reports the reaction of alpha-H-containing ketone compounds with elemental sulfur and trimethylsilyl cyanide (TMSCN) to construct alpha-thiocyanatone under the conditions of no metal and no addition. The new strategy has the advantages of no metal participation, no additive promotion, wide substrate range and good functional group compatibility, and provides an efficient and green synthesis approach for the preparation of various alpha-thiocyanatones in a highly concise manner.

Drawings

FIG. 1 is a nuclear magnetic hydrogen spectrum diagram of a target product prepared in example 5.

FIG. 2 NMR spectrum of target product prepared in example 5.

FIG. 3 nuclear magnetic hydrogen spectrum of the target product prepared in example 9.

FIG. 4 nuclear magnetic carbon spectrum of the target product prepared in example 9.

FIG. 5 nuclear magnetic fluorine spectrum of the target product prepared in example 9.

FIG. 6 nuclear magnetic hydrogen spectrum of the target product prepared in example 10.

FIG. 7 NMR spectrum of target product prepared in example 10.

FIG. 8 nuclear magnetic hydrogen spectrum of the target product prepared in example 11.

FIG. 9 nuclear magnetic carbon spectrum of the target product prepared in example 11.

FIG. 10 is a nuclear magnetic hydrogen spectrum of a target product prepared in example 12.

FIG. 11 NMR spectrum of target product prepared in example 12.

Detailed Description

The present invention will be described in further detail with reference to specific examples. In the following, unless otherwise specified, all methods used are conventional in the art, and all reagents used are commercially available and/or may be prepared by reference to known synthetic methods.

Examples 1-8 optimization of reaction conditions

Taking propiophenone as a template substrate, screening optimal reaction conditions (table 1), wherein the reaction formula is as follows:

the specific operation is as follows:

a10 mL pressure tube equipped with a stirring magneton was charged with propiophenone of formula Ia (0.2mmol), sulfur powder (0.6mmol), TMSCN (0.8mmol) and DMSO (1 mL). The reaction mixture was stirred at 80 ℃ for 12 hours. After the reaction2mL of water was added, the reaction solution was extracted 3 times with 20mL of ethyl acetate, the organic phase was separated, concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (200-500 mesh) to give the objective product of IIb.¹H NMR(400MHz,CDCl₃)δ7.98-7.96(m,2H),7.72-7.68(m,1H),7.59-7.55(m,1H),5.12(q,J＝7.1Hz,1H),1.89(d,J＝7.1Hz,3H)；¹³C NMR(126MHz,CDCl₃)δ194.8,134.6,133.2,129.2,128.9,111.4,49.9,19.8.。

Table 1:

examples	Temperature/. degree.C	Isolated yield/%)
			1	0	2
2	20	5
			3	40	20
4	60	62
			5	80	98
6	100	98
			7	120	50
8	140	30

The experimental results in table 1 show that the template reaction shows different reactivities at different temperatures, the yield of the template reaction is generally higher at 80 ℃, and especially in the case of dimethyl sulfoxide as a solvent, the target product is obtained with a yield of 98%. Finally, taking economic and efficient factors into consideration, DMSO is selected as a reaction solvent, and the reaction is carried out for 12 hours at 80 ℃ under the air condition, so as to serve as an optimal condition.

On the basis of optimizing the reaction conditions (example 5), we extended the substrate range for other α -H containing ketones. We found that the influence of electronic effect and steric effect is small, the yield is kept above 70%, and for the p-fluorophenone, the yield is as high as 90%. It is worth mentioning that non-aromatic boronic acids also have higher yields, the results are shown in table 2.

Table 2:

and (3) product structure characterization:

example 9:¹H NMR(400MHz,CDCl₃)δ8.02-7.98(m,2H),7.25-7.21(m,2H),5.06(q,J＝7.1Hz,1H),1.87(d,J＝7.1Hz,3H)；¹³C NMR(126MHz,CDCl₃)δ193.2,166.5(d,J＝257.9Hz),131.7(d,J＝9.7Hz),129.7(d,J＝2.9Hz),116.5(d,J＝22.2Hz),49.4,19.7；¹⁹F NMR(471MHz,CDCl₃)δ-101.8.。

example 10:¹H NMR(400MHz,CDCl₃)δ8.04-8.01(m,1H),7.62-7.58(m,1H),7.41-7.31(m,2H),4.61-4.55(m,1H),3.21-3.20(m,2H),2.90-2.84(m,1H),2.48-2.41(m,1H)；¹³C NMR(126MHz,CDCl₃)δ191.8,143.6,135.0,130.6,129.0,128.0,127.4,111.8,55.7,31.5,29.1.。

example 11:¹H NMR(500MHz,CDCl₃)δ7.63(s,1H),7.26(s,1H),4.76(s,2H),2.51(s,3H),1.90-1.86(m,1H),1.67-1.61(m,1H),1.44-1.41(m,1H),1.34(s,6H),1.28(s,3H),1.08(s,3H),1.01(d,J＝6.7Hz,3H)；¹³C NMR(126MHz,CDCl₃)δ192.67,152.63,143.05,137.01,131.42,130.93,128.48,112.35,45.22,43.27,38.19,34.34,34.13,32.50,31.95,28.23,24.65,21.74,16.72.。

example 12:

¹H NMR(500MHz,CDCl₃)δ6.85-6.79(m,1H),6.20-6.17(m,1H),5.55(s,1H),4.25(s,2H),2.34(d,J＝9.6Hz,1H),2.14-2.01(m,2H),1.57(s,3H),1.45-1.43(m,1H),1.26-1.24(m,1H),0.94(s,3H),0.87(s,3H)；¹³C NMR(126MHz,CDCl₃)δ190.1,152.8,131.0,128.1,123.6,111.6,54.7,42.8,32.8,31.0,28.0,26.7,23.0,22.7.。

the embodiments described above are only preferred embodiments of the invention and are not exhaustive of the possible implementations of the invention. Any obvious modifications to the above would be obvious to those of ordinary skill in the art, but would not bring the invention so modified beyond the spirit and scope of the present invention.