Green chem.: efficient synthesis of [1,3] - oxazine-n-fused imidazole-2-thioketone by three component series reaction without catalyst

[1,3] - oxazine fused heterocycles widely exist in natural products and active molecules, some of which have certain antitumor and therapeutic effects on central nervous system disorders Therefore, chemists have done a lot of work and made a lot of progress in the synthesis of these compounds, such as silver catalyzed tandem cyclization between alkyne aldehydes and amino alcohols, acid promoted intramolecular tandem cyclization of α, β - unsaturated ketones, and visible light mediated oxidation cyclization of amino alcohols (scheme 1a-c) However, most of the synthesis has some limitations, such as the use of transition metals, the need for pre functionalization of substrates, harsh reaction conditions, long reaction time and so on Therefore, it is of great significance to develop a green and efficient method for the synthesis of [1,3] - oxazine fused heterocycles Recently, Professor Yu Yongping of Zhejiang University and assistant researcher Chen wenteng developed a green, efficient and rapid method to construct [1,3] - oxazine fused heterocyclic framework: scheme 1D of glyoxal hydrate, amino alcohol and KSCN The reaction has the characteristics of fast reaction rate (< 10 minutes), high bonding efficiency (three C-N bonds, one C-O bond and two rings are constructed in one step), and easy purification (gap Chemistry) The results were published in green chem (DOI: 10.1039/c8gc01766b) (source: Green chem.) firstly, the reaction conditions were screened with glyoxal monohydrate 1a (1.2 equivalent), 2-aminobenzyl alcohol 2A (1 equivalent) and KSCN (2 equivalent) The experimental results show that the reaction can be carried out efficiently with acetonitrile as solvent and 5 equivalent trifluoroacetic acid (TFA) in 95% yield When the amount of TFA was reduced or the reaction was carried out in other solvents such as dichloromethane and methanol, the yield of TFA decreased (source: Green chem.) then, the author investigated the application scope of the reaction substrate (Table 2) When R 1 is electron deficient or electron rich benzene ring, the reaction can be carried out, but when benzene ring is replaced by electron group, more excellent yield can be obtained When R 1 is naphthalene ring, heterocycle and alkyl with large steric resistance, the reaction can also be carried out In addition, the 3D structure of the target product was determined by X-ray single crystal diffraction analysis Aminobenzyl alcohol also has a very wide range of substrates, the electrical properties of substituents have no obvious effect on the reaction, most of which can be completed in 5-10 minutes Moreover, the pure target product can be obtained by simple filtration and washing (acetonitrile), without traditional purification steps such as column chromatography and recrystallization (source: Green chem.) the author found that the reaction can also be carried out efficiently in gram scale, and the target product 3U (Figure 2) can be obtained in a short time with 80% separation yield (source: Green chem.) further, the author found that amino alcohols substituted by different branched chains were also suitable for this reaction, and five, six and seven fused heterocycles (Table 3) were obtained by reacting with glyoxal monohydrate lacking or rich in electrons (source: Green chem.) in order to clarify the mechanism of the reaction, the author carried out some control experiments (scheme 2) 1A and 2A can be efficiently transformed into compound A in acetonitrile, and the final product 3A can be obtained by treating a with KSCN under standard conditions This suggests that a may be the intermediate of the reaction (source: Green chem.) according to this, the author proposed the possible reaction mechanism of this reaction, as shown in scheme 3: 1 Dehydration to obtain intermediate I, which reacts with amino alcohol 2 to obtain imine intermediate II; 2 Intramolecular cyclization to obtain intermediate III; KSCN protonation to obtain intermediate IV under acidic conditions, and then reacts with III to obtain intermediate V; V The final product 3 was obtained by intramolecular cyclization (source: Green chem.) conclusion: Professor Yu Yongping of Zhejiang University and assistant researcher Chen wenteng have developed a green and efficient three-component reaction method to synthesize [1,3] - oxazine fused heterocyclic skeleton The reaction involves series reaction steps of imine formation, intramolecular cyclization and [3 + 2] cycloaddition It has the characteristics of fast reaction speed, high bonding efficiency, simple purification and amplification.