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The Synthesis And Transformation Of Oxygen-containing Six-membered Heterocycles

Posted on:2015-05-11Degree:DoctorType:Dissertation
Country:ChinaCandidate:M H LiFull Text:PDF
GTID:1221330428965961Subject:Materials Physics and Chemistry
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Oxygen-containing six-membered heterocycles have been widely found in natural products and pharmaceutically active compounds. They are important chemical raw materials and synthetic intermediates. The synthesis and transformation of these types of compounds are of great importance to the field of medicinal chemistry and natural products chemistry. This thesis focused on the development of efficient and green methods to synthesize oxygen-containing six-membered heterocycles and their downstream conversions.Firstly, various densely substituted4H-chromenes were synthesized on the basis of electrophilic addition of aldehyde. The thiol substituted4H-chromenes were synthesized through three-component reactions of salicylaldehydes, dimedone and thiophenols catalyzed by L-proline. The reaction commenced with the formation of an imine intermediate from salicylaldehyde and L-proline, which followed by a cascade nucleophilic addition and substitution to provide the desired product after an intramolecular dehydration. Many carbon-based nucleophiles such as enol, enamine and active C-H acids are all applicable in these three-component reactions, producing the corresponding4H-chromenes in good yields. Benzotriazole, which is a nitrogen-based nucleophile, could also be employed in this type of reaction, and intriguingly, the three-component adduct could react with some nucleophiles in the manner of reaction by using benzotriazole as leaving group, giving some functional4H-chromenes that could not be obtained directly by above mentioned three-component reaction. However, attempt to synthesize an indole-substituted4H-chromene with this catalytic system through three-component reaction of salicyaldehyde, dimedone and indole failed, which suffered from the side reaction between salicyaldehyde and dimedone. Fortunately when a combination of FeCl3and PPh3was used as catalyst, the main side product could react with indole to offer desired product by leaving dimedone. Therefore, the indole-substituted4H-chromene was synthesized successfully in the way of multicomponent reactions. During the reaction catalyzed by FeCl3and PPh3, PPh3was oxidized into P(O)Ph3. The generated P(O)Ph3acted as a hydrogen bond acceptor, which weaked the intramolecular hydrogen bond of the side-product of salicylaldehyde and dimedone, making the dimedone fragment flexible. This facilitated the coordination of dimedone fragment with FeCl3, rendering the substituted reaction proceed smoothly.Then, two kinds of substituted-3,4-dihydro-2H-pyrans were synthesized through inverse-electron-demand oxo-Diels-Alder reaction of a-methylene-1,3-dicarbonyl intermediate. Glycerol, the main by-product of biodiesel process, could promote efficiently a multicomponent reaction of dimedone, paraformaldehyde and styrene, offering an efficient way for the synthesis of2,5,6-substituted-3,4-dihydro-2H-pyran by tandem knoevenagel condensation and inverse-electron-demand oxo-Diels-Alder reaction. The wide liquid range, hydrogen bond-rich environment and unique solubility for polar organic compounds made glycerol to be a special solvent in this reaction. Besides Knoevenagel condensation, oxo-diene could also be synthesized by other methods. The three-component adduct of para-chlorobenzaldehyde, dimedone and thiophenol could be converted into a-benzylidene-1,3-dicarbonyl diene by leaving a thiophenol catalyzed by ZnCl2. The diene reacted with electron-rich alkene to furnish2,4,5,6-substituted-3,4-dihydro-2H-pyran in good diastereoselectivity in favor of the cis-product.Finally,2-ary-3,4-dihydro-2H-pyrans and2-alkoxyl-3,4-dihydro-2H-pyrans as raw materials were used in organic chemistry in the manner of electrophilic ring-opening reactions. Many1,3-dicarbonyl functionalized toluene derivatives were synthesized by the ring-opening reactions of2-ary-3,4-dihydro-2H-pyrans and nucleophiles, which involved a mechanism of forming and trapping of a benzyl carbocation. The reaction of a2-Ary-3,4-dihydro-2H-pyran and a indole catalyzed by MnCl2·4H2O opened an efficient way to synthesize1,3-dicarbonyl functionalized indole derivatives which could be used to synthesize an anti-Alzheimer’s disease active molecule promoted by Mn(OAc)3in a manner of radical ring closure. In the reaction of a2-ary-3,4-dihydro-2//-pyran and a thiophenol, MnBr2showed the highest catalytic activity. Benzenesulfinic acid, benzamide, allyltrimethylsilane,4-hydroxy-6-methyl-pyrone,2-naphthol, resorcinol and2-methylfuran could all be employed to react with a2-ary-3,4-dihydro-2H-pyran under acidic conditions. Many1,3-dicarbonyl functionalized symmetric methane derivatives were synthesized by ring-opening reactions of2-butoxy-3,4-dihydro-2H-pyrans with two molecules of nucleophiles, which were in fact nucleophilic substituted reactions of [O,O]-acetal. The electrophilic reactions of2-butoxy-3,4-dihydro-2H-pyran with indoles in the presence of MnCl2’4H2O performed also very well, providing the corresponding1,3-dicarbonyl functionalized diindolylmethane derivatives, which could be further converted to a pharmaceutical molecule possessing antiangiogenic activity. MnBr2could catalyze ring-opening reaction of2-butoxy-3,4-dihydro-2H-pyran and thiophenols, in which a linear [O,5]-acetal reaction intermediate was formed. The reaction of a molecular2-butoxy-3,4-dihydro-2H-pyran and a molecular thiophenol could be realized by using LiBr as catalyst and the product could further react with other nucleophile to synthesize1,3-dicarbonyl functionalized unsymmetric methane derivatives.
Keywords/Search Tags:4H-chromene, dihydropyran, multicomponent reaction, ring-opening reaction
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