Are you still upset? The synthetic path of organic compounds is complex, time-consuming and laborious, and can also cause environmental pollution and waste! Try -cyclodextrin as a reaction catalyst, multi-component one-step reaction, a product, high yield, can be reused many times!
Today we'll look at the powerful catalytic role of cyclodextrin in the synthesis of pyranopyrimidine compounds.
What are pyrazole, pyran, and pyrimidines, and what do they do?
Pyriazole, pyran and pyrimidine are important compounds widely used in medicine, agriculture and materials science. Pyriazole has a variety of physiological functions, including analgesia, anti-inflammation, fever reduction, anti-arrhythmia, sedation, muscle relaxation, mental excitement, anti-spasm, monoamine oxidase inhibitor, anti-diabetes and anti-bacteria, etc. Similarly, the pyran nucleus is the basic structure of most glycosides (glucose, arabinose, etc.). Pyrimidine motifs have a wide range of biological activities and play a vital role in many drugs.
In addition, pyrrole pyranopyrimidine and its derivatives have A wide range of biological activities. For example, pyranopyrimidine A can be used as A mollusc insecticide, B is an inhibitor of Chk1, and C is an antimicrobial agent. Pyrazolopyrimidine nucleus is also present in the famous drug Sildenafil. Pyranopyrimidine unit in D can be used as an anti-diabetic drug, while pyranopyrimidine E is an anti-inflammatory drug.
Different organic compounds containing pyrazolpyrimidine ▲
Conventional synthetic methods are complex, time - consuming and easy to cause pollution and waste
The literature investigation shows that the synthesis path of pyrazole and pyripyrimidine is very complex and requires a lot of catalysts, such as DABCO, SDS, TiO2 nanowires, OMWC nanotubes, meglumine, Cu-IMS nanoparticles, ChCl: urea, oleic acid, MNS ionic liquid, PEG-400, magnetized water, cellulose based nanocomposites and SBA-PR-SO3H, etc. The existing synthetic route requires preparation of catalysts and special reaction conditions. The reaction time is long, and the synthesis process is complicated. Moreover, most organic solvents will be wasted in the synthesis process, which will pose a great threat to the environment.
Therefore, a green, efficient and economical synthesis method of pyrazole and pyranopyrimidine is urgently needed in production.
Highly effective catalyst for -cyclodextrin
Synthesis of pyrrole pyranopyrimidine using -cyclodextrin (-CD) is a greener and safer method. Because of its internal cavity and hydrophobicity, -CD is often used as a supramolecular catalyst to bind guest molecules, selectively catalyze various organic reactions by inclusion complexes, and thus obtain the corresponding bioactive heterocyclic compounds. With cyclodextrin as catalyst and water as solvent, organic synthesis products can be separated more easily.
The researchers found that pyrazole, pyran and pyrimidine could be synthesized in one step by using -cyclodextrin as a high efficiency catalyst in water, and through four components of aromatic aldehyde ethyl acetoacetate, hydrazine hydrate, benzaldehyde and barbiturate into pyrazole and pyripyrimidine by ultrasound. The reaction could be completed within 25 minutes, and the yield was as high as 84-91%.
Synthetic reaction formula
(1) EAA (2) hydrazine hydrate (3a) benzaldehyde (4) barbituric acid
The research process
● -cyclodextrin is the most efficient catalyst
The researchers first compared the catalytic effects of tauronic acid, CTAB, TBAB, -cyclodextrin and -cyclodextrin, and found that -cyclodextrin had the highest catalytic efficiency, while -cyclodextrin, also cyclodextrin, had a poor catalytic effect.
● The most efficient concentration of -cyclodextrin was selected
The researchers then compared the catalytic effects of 10, 20 and 25 moles of -CD and found that the catalytic effects were best at concentrations of 20.
● To find the most suitable reaction solvent and the best reaction temperature
Then, the researchers compared the reaction effects in polar aprotic solvents (DMF, THF, and CH3CN) and polar protic solvents (H2O and EtOH), and found that the reaction effects were best in polar protic solvents (H2O, EtOH: H2O (1:1).
In terms of the reaction temperature, the reaction product yield was not high at room temperature, and the reaction speed was the fastest and the reaction product yield was the highest when the temperature rose to 50 ℃.
● Examine the influence of functional groups
The compatibilities of various aromatic aldehydes with electron-absorbing or electron-giving substituents were also tested. Results show that the reaction can be carried out smoothly, and can tolerate a wide range of functional groups, such as chlorine, nitro bromine, fluorine, methyl phenyl, and hydroxyl, methoxy, electron-withdrawing substituent under the condition of high product yield, and slightly lower for electron substituent conditions, but are able to form a good or excellent yield of product.
● Verify the reuse of catalyst
The catalyst was reused to significantly reduce the production process and production cost. Finally, the researchers also studied the number of times the -cyclodextrin was reused. They found that bet-cyclodextrin could be reused for four cycles, maintaining a high yield of 91-84% in all. After 4 cycles, the reaction time increased and the product yield decreased.
Mechanism of -cyclodextrin catalysis
Finally, the possible mechanism of -cyclodextrin catalysis was proposed.
The first step in the reaction is the condensation of ethyl acetoacetate and hydrazine hydrate to form an intermediate which is in equilibrium with enolate A. The next intermediate is formed by the condensation of aryl aldehyde and barbituric acid to Aford B by Knoevenagel.
Aldehydes and barbituric acid may be in beta CD cavity forming non covalent reversible supramolecular complexes, and improve the local concentration of aldehydes and barbituric acid, aldehyde and barbituric acid dissolved in aqueous medium, it is easy to react with barbituric acid aldehyde, and generate benzalhydantoin pyrimidine B, this step acceleration can be attributed to the water condensation rate beta cyclodextrin truncated cone provides a unique hydrophobic cavity and outward hydrophilic hydroxyl groups.
Intermediates A and B undergo Michael addition in the cavity of -CD to form C. The adducts are unstable and are cycled internally by nucleophilic addition reaction of oxygen anions and carbonyl groups to produce intermediate D. Finally, intermediate D is dehydrated to produce pyrizole and pyripyrimidine products.
Mechanism of -CD catalyzing pyrazole and pyranopyrimidine ▲
The advantage of -cyclodextrin as catalyst
-cyclodextrin is an eco-friendly, reusable, inexpensive and biodegradable catalyst. Compared with other catalysts that condensed tricyclopyrazole and pyranopyrimidine derivatives, -cyclodextrin has the advantages of simple operation, short reaction time, high or even excellent yield, wide substrate range, and can also be used as a solvent to reduce organic solvent pollution, which is more green and environmental protection.
This issue Shared literature:
Akolkar, S.V., Kharat, N.D., Nagargoje, A.A. et al. Ultrasound Assisted beta - Cyclodextrin Catalyzed One - Pot Cascade short of Pyrazolopyranopyrimidines in Water (ultrasonic Assisted beta - Cyclodextrin pyrazole catalytic Water and step in the Cascade of pyran and thymine). The Catalysis Letters, 2020150450-460.