Research And Application Of Electrochemical Synthesis Of Cyclohexadienones,γ-deuterated Pyridines And Monodeuterated Methylarenes

Cyclohexadienones,pyridines and methylarenes are common chemical structures in the pharmaceutical field and play important roles in new drug discovery and drug synthesis.Cyclohexadienones have a variety of biological activities,such as inhibiting interleukin,PTP1B and antimalarial,which can be used for the research and treatment of rheumatoid arthritis,diabetes and malaria.Pyridines can be used for the treatment of anti-tumor,Alzheimer’s disease and basal cell carcinoma by targeting inhibition of cellular-mesenchymal epithelial transition factor,inhibition ofβ-site amyloid precursor protein cleaving enzyme and selective inhibition of hedgehog pathway.Methylarenes can be used as cyclooxygenase-2 inhibitors,cytokine inhibitors and retinoic acid X receptor selective agonists to treat arthritis,pulmonary interstitial fibrosis,and cutaneous T-cell lymphoma.Currently,direct oxidation of phenolic compounds is a common chemical synthesis method for the construction of cyclohexadienones.Incorporation of deuterium atoms into drug candidates can alter their ADMET properties.The selective synthesis strategy ofγ-deuterated pyridines generally involves reductive deuteration of directing groups or functionalized substrates;the main method for the construction of monodeuterated methylarenes is the selective reductive deuteration of functionalized substrates.According to the literature review,the current synthetic methods have problems such as low synthesis efficiency,unsatisfactory site selectivity,and limited substrate scope,which limited their application in the field of medicinal chemistry.Organic electrochemical synthesis takes electrons as the medium and has the characteristics of atomic economy and step economy.It is a novel,efficient and sustainable synthesis technology to replace the traditional redox reaction.The electrochemical synthesis process can be converted under relatively mild conditions,avoiding the use of additional strong redox agents,and can tolerate a variety of sensitive functional groups.In addition,it can effectively control the reaction direction and rate by accurately adjusting the electrode potential,and has higher controllability,which has great application potential in the field of sustainable conversion synthesis.In summary,this paper intends to realize the efficient synthesis of cyclohexadienones,γ-deuterated pyridines and mono-deuterated methyl aromatics by developing organic electrochemical synthesis technology.This paper will focus on the following three aspects:Electrochemically mediated non-activated biphenyl dearomatization can rapidly and efficiently synthesize cyclohexadienones.We first investigated the electrochemical deuteration of 4-chlorobiphenyl（2-1a）as a model reaction.After initial optimization by screening the factors such as additives,solvents and electrode materials,the desired product 2-2a was isolated with 82%yield by constant-current electrolysis using a graphite anode and Ni foam cathode,in an undivided cell containing acetic acid,tetraethyl ammonium p-toluenesulfonate,water and methanol at room temperature for4 h,and the desired product was obtained with 82%yield.Having optimized the reaction conditions,we next examined the scope of the electrooxidation reaction by testing a series of biphenyls.A variety of functional groups,including halogen（Cl and Br）,ester（CO₂Me）,carboxylic acid（CO₂H）,carbonyl（CHO and COPh）,sulfonyl（SO₂Me）,cyano（CN）,alkyl（^tBu and Me）,and alkoxy（OMe）substituents in the phenyl ring,were tolerated in the reaction system.Moreover,it is important that a range of oxidation-sensitive functional groups,includingα-carbonyl alkyl,alcohol,and alkene were all well compatible with our electrochemical conditions.When comparing the reactivity of substrates substituted at different sites,it was found that the ortho-substituted biphenyl was less effective in comparison with the corresponding meta-and para-substituted analogs.These results indicated that the steric effect of substrate is important in this electrooxidative dearomatization reaction,and the large steric hindrance is not conducive to the dearomatization of electrocatalytic oxidation.Finally,it’s noteworthy that 1-butanol and isopropyl alcohol participated in the current reaction effectively to produce the desired product cyclohexadienones in moderate yields.To further demonstrate the synthetic utility of the methodology,the reaction of 1 mmol of2-1a could be easily performed to afford the corresponding product 2-2a in 78%yield.Furthermore,a notable benefit of the mild dearomatization procedure is its amenability to late-stage modification of drug molecules.The feasibility of this new electrochemical method by performing direct regioselective dearomatization of flurbiprofen methyl ester and fenbufen（NSAIDs）,which can provide a new useful strategy to prepare novel flurbiprofen and fenbufen analogues.These results demonstrated the synthetic practicality of this methodology.Based on the observations above and literature reports,a possible mechanism for the electrooxidation reaction was involved an EC process（electron transfer reaction-chemical reaction）.Electrochemically mediated pyridines C（sp²）-H hydrogen-deuterium exchange（HIE）can selectively synthesizeγ-deuterated pyridines.We first investigated the electrochemical deuteration of 2-phenylpyridine（3-1a）as a model reaction.After initial optimization by screening the factors such as electrode materials,deuterium source,and electrolyte,the desired deuterated product 3-2a was isolated in 97%yield with 95%deuterium incorporation by constant-current electrolysis using a graphite anode and zinc cathode,in an undivided cell containing deuterated water,tetrabutylammonium iodide,and N,N-dimethylformamide（DMF）at room temperature for 10.5 h.Having established the optimized conditions,we then evaluated the substrate scope of the electrochemical system by testing a variety of pyridines.A series of aryl groups,including or phenyl,furyl and dibenzo[b,d]thiophen-2-yl substituents at theα-position of pyridine,were tolerated,in the reaction system.It is worth mentioning that a range of acid/base-sensitive functional groups,including acetal,amide and ester were all well compatible with our electrochemical conditions.Moreover,various redox-sensitive functional groups,including benzyl,alcohol and amine were also tolerated in our mild electrochemical system.In addition,alkyl substituted pyridines could also be converted to the corresponding deuterated product with excellent deuterium incorporation.As expected,quinoline and acridine were smoothly converted into desired product in good yield with high deuterium incorporation.To further demonstrate the synthetic utility of the methodology,the scale up of this electrosynthesis was conducted As can be seen in paper,the reaction of 8 mmol of 3-1a,an important precursor for the synthesis of bioactive molecules such as vismodegib,could be easily performed using 0.55equivalent of electrolyte to afford the corresponding product 3-2a in 93%yield with 95%deuterium incorporation.To further illustrate the practical potentials of our deuteration method,we examined the feasibility of the late-stage modification of pharmaceutical molecules.It is important that a series of pyridines molecules were efficiently transformed into their deuterated forms,including natural products and active molecules such as CYP11B1 inhibitors and AWQ051.To reveal the reaction mechanism,we performed radical capture experiment.The deuterated product was not be obtained.It is speculated that free radicals may be involved in the reaction.Under N₂ and O₂atmosphere,product 3-2a was obtained with 95%and 45%deuterium incorporation respectively.Cyclic voltammetry（CV）experiments indicated that there is an interaction between O₂ and substrate 3-1a in the electrochemical system.Based on the above experimental results and previous reports,a possible mechanism for the electrochemically selective HIE carried out by the oxidation elimination of free radicals.Electrochemically mediated dehydroxydeuteratation of aryl methanols can selectively synthesize monodeuterated methylarenes.We first investigated the electrodehydration deuteration of aryl methanol（4-1a）as a model reaction.After initial optimization by screening deuterium sources,electrolytes and electrode materials,the desired deuterated product 4-2a was isolated in 91%yield with 97%deuterium incorporation by constant-current electrolysis using a graphite anode and graphite cathode,in an undivided cell containing deuterated water,tetrabutylammonium iodide,N,N-diisopropylethylamine（DIPEA）and DMF at room temperature for 2.5 h.Having established the optimized conditions,we then evaluated the substrate scope of the electrochemical system by testing a variety of aryl methanols.A series of aromatics,including polycyclic aromatic hydrocarbons,pyrazole amd indole were tolerated in the reaction system.It is worth mentioning that a range of functional groups,including ester（CO₂Me）,halogen（F）,amide（CONEt₂ and CONHEt）were all well compatible with our electrochemical conditions.Moreover,oxidation-sensitive functional groups,including morpholine,are also tolerated in our mild electrochemical systems.In addition,substrates containing N-H and amino acids could also be converted to the corresponding deuterated product with good deuterium incorporation.As expected,heterocyclic methanols such as pyridine,thiazole,furan,pyrimidine,thiazole,oxazole,imidazole,pyrrole were also smoothly converted into desired product in good yield with high deuterium incorporation.Based on the observations above and literature reports,a possible mechanism for the electroreduction deuteration was involved a carboanion process.In summary,in view of the importance of cyclohexadienones,γ-deuterated pyridines and monodeuterated methylarenes in the pharmaceutical field and the problems existing in the current synthesis methods.In this paper,electrochemical synthesis methods with high efficiency,high selectivity and wide applicability were developed,which provided new tools for the construction of C-O bond and C-D bond.These methods achieve the goal of synthesizing diverse cyclohexadienones,γ-deuterated pyridines and monodeuterated methylarenes,which are helpful to expand the library of drug-like diversity compounds and have potential application value in the field of medicine.