Electrochemical Intramolecular Cross-dehydrogenative Coupling Of Tetrahydroisoquinoline Derivatives And C-P Bond Formation Of Aryl Bromides

This dissertation is divided into three chapters.The study offers an alternative to conventional methods and provides an efficient tool for the synthesis of tetrahydroisoquinoline derivatives and aryl phosphorus compounds under the condition of electrolysis.In the first chapter,the research progress of electrochemistry synthesis was summarized.The research background of tetrahydroisoquinoline derivatives and aryl phosphorus compounds was described.1,2,3,4-Tetrahydroisoquinoline represents an important group of natural products and exhibit a broad spectrum of biological activities,such as anti-tumor,anti-inflammatory and anti-platelet aggregation.Among all of substrates which can be used for C–N coupling reactions using cross-dehydrogenative coupling（CDC）,tetrahydroisoquinoline is the most interesting ones attributed to its prevalence and abundance in natural products.Direct formation of C–N bond by oxidative CDC reaction is an attractive research field in organic synthesis,since pre-functionalized precursors is not required in CDC methods,which are atom-economical and environmentally benign.Most of the intramolecular CDC reactions unavoidably have to use transition-metal catalysts（Cu,Mo,Au,and so on.）and/or stoichiometric non-metal oxidants（DDQ,TBHP,DEAD,and so on.）,which would produce undesired waste.Meanwhile,these reported procedures have the disadvantages of complicated procedure,harsh reaction condition,and non-environmental friendliness.As is known to all,electrochemical synthesis is sustainable and eco-friendly in comparison with the conventional redox processes,because electrons are employed as reagents without the existence of transition-metal catalysts or toxic oxidants.We designed a novel electrochemical intramolecular CDC reaction,with no chemical oxidant needed and mild reaction conditions,for the synthesis of tetrahydroisoquinoline derivatives.Aryl phosphorus compounds are widely applied to pharmaceuticals,biochemistry,organic synthesis and material science.Consequently,the development of efficient methodologies for the synthesis of aryl phosphorus compounds has been of great interest in organic synthesis.Inspired by the important work which we were doing to obtain phosphorylation from aryl bromides and dialkyl phosphites,and as part of our continuing interest for the synthesis of aryl phosphorus compounds,we envisioned that other phosphorus-based nucleophiles could participate in the same reaction effectively to produce the desired products.In the second chapter,the design of electrochemical intramolecular CDC of tetrahydroisoquinoline derivatives and C-P bond formation of aryl bromides was described.We first identified the optimal reaction conditions for the electrochemical intramolecularCDCreactionusing N-butyl-2-（3,4-dihydroisoquinolin-2（1H）-yl）benzamide as the model substrate to produce5-butyl-4b,5,12,13-tetrahydro-6H-isoquinolino[2,1-a]quinazolin-6-one through an intramolecular annulation,which involved 5mA constant-current electrolysis employing a graphite as rod anode（d=5mm）and Pt plate（0.5 cm×0.5cm）as cathode in an undivided cell containing n-Bu₄NBr（electrolyte）,ACN（solvent）,lutidine（base）,diethyl phosphite（additive）at room temperature for 8h.Underthesemildconditions,thedesiredproduct5-butyl-4b,5,12,13-tetrahydro-6H-isoquinolino[2,1-a]quinazolin-6-one was isolated in 68%yield.Having optimized the reaction conditions,we next examined the scope of the electrochemical intramolecular CDC reaction by testing a series of N-benzamide tetrahydroisoquinoline derivatives.To our satisfaction,various alkyl substituents,including n-butyl,cyclopropyl,and（un）substituted benzyl,underwent a smooth CDC reaction,furnishing the desired products in moderate yields.Moreover,a variety of functional groups,including alkoxy（OMe）,alkyl（Me）,halogen（F,Cl and Br）,cyano,and ester substituents in the phenyl ring,were well tolerated in the reaction system.On the basis of the observations above and a literature report,a possible mechanism for the electrochemical intramolecular CDC reaction was proposed.In addition,we examined the scope of phosphorus-based nucleophiles by using ethyl phenylphosphinate and diphenylphosphine oxide for the synthesis of aryl phosphorus compounds from aryl bromides.Ethyl phenylphosphinate and diphenylphosphine oxide participated in the reaction effectively to produce the desired products aryl phosphinates and arylphosphine oxides in moderate to high yields.It shows that ethyl phenylphosphinate and diphenylphosphine oxide have high coupling reactivity in the reaction system.The reaction mechanism was proposed.In the third chapter,we introduced the synthetic methods of precursor materials,the experimental procedures,the spectral data of precursor materials and products,as well as the NMR spectrum.