Photocatalytic Synthesis Of Phosphonate Derivatives Containing Tetrahydroindolizine

Objective:Tetrahydroindolizine skeleton is widely found in drug molecules and natural products,and phosphonic acid group can be used as the bioelectron isoarrangement of carboxyl group,sulfonyl amino group and other groups used for structural modification of drugs and active compounds.Therefore,it is of great significance to carry out research on the synthesis of phosphonate derivatives containing tetrahydroindolizine.Visible-mediated photocatalytic synthesis is characterized by mild reaction conditions and low environmental pollution,and has gradually become a research focus in recent years.The aim of this paper is to develop a method of photocatalytic synthesis of phosphonate derivatives containing tetrahydroindolizine with metal-free and mild conditions.The resulting products can be further converted into phosphonic acid and other derivatives,which provides a basis for structural modification and further activity screening of related drugs.Methods:Under the conditions of photocatalysts,oxidants,bases,solvents and additives,pyrrole/indole derivatives and phosphite esters were used as substrates to synthesize phosphonate derivatives containing tetrahydroindolizine in visible photocatalysis.According to the control variable method,the optimal conditions for the reaction are determined by optimizing types of photocatalysts,oxidants,bases,solvents,substrate and additives.Then,the mechanism of the reaction was explored and verified by free radical capture experiment and cyclic voltammetry.Subsequently,the gram-level reaction and product transformation of the obtained template products were carried out to explore its practicability and application value.Results:By optimizing the reaction conditions,the optimal reaction conditions are determined as follows:At the room temperature,Pyrrole/indole derivatives 1（0.2 mmol）,phosphite esters 2（0.4 mmol）,4DPAIPN（2 mol%）,DTBP（0.3 mmol）,Cs₂CO₃（0.4 mmol）,ultra dry CH₃CN（2 m L）and H₂O（10μL）reacted with 30 W blue LED for 12 h under the protection of argon.Finally,44 compounds were synthesized with yields ranging from 22%to 82%,and the amplification reaction also produced products with a moderate yield.Conclusion:In this paper,a method for the synthesis of phosphonate derivatives containing tetrahydroindolizine catalyzed by visible light has been developed with metal-free.Phosphonate derivatives containing tetrahydroindolizine can be obtained with good yield.At the same time,the reaction can be gram reaction,the product can also be converted into phosphonic acid derivatives through ester hydrolysis and sulfur exchange to obtain thioketone compounds,which can provide the basis for drug activity screening.The mechanism study indicated that the reaction may generate phosphorus radical by the oxygen radical produced by the radical precursor,and then generate cyclization with pyrrole/indole derivatives,and finally construct tetrahydroindolizine skeleton.