Study Of One-Pot Synthesis Of Picolinamides From Pyridine-N-Oxide And Copper-catalyzed Suzuki Coupling Reaction

Amides are important intermediates of various pharmaceutical molecules.Linkage of amides is critical not only in protein chemistry but also in general synthesis of polymers.There are many kinds of amides participating in important metabolic pathways,such as asparagine,glutamine,and nicotinamide.Asparagine and glutamine are significant compositions of proteins,while nicotinamide is an important component of coenzymes Ⅰand Ⅱ.Besides,it is also an essential component of vitamin B3,which can promote energy metabolism and growth.As an isomer of nicotinamide,picolinamide also has many biological activities,such as inhibiting activity of poly(ADP-ribose)synthetase,obliterating hydroxyl radical,inhibiting kidney injury induced by free Ferric nitrilotriacetate(Fe(Ⅲ)-NTA),analgesic and anti-inflammatory activities.Meanwhile,picolinamide is also an important metal ligand and building block in organic synthesis and precursor for biological active compounds.Picolinamide and its derivatives are used as ligands of organo-metallic catalyst in organic reactions.It has multiple coordination sites and modes around the metal center,and is often used as an N,O;N,N-bidentate ligand or an N,O,O;N,N,O-trid entate ligand to coordinate with two metal ions.Picolinamides can ligate with calixa rene and phenanthroline and the coordination complex is applied in disposal of nucl ear waste.Pyridinecarboxamides are used in crystal engineering as co-formers for th e synthesis of supramolecular compounds,especially pharmaceutical co-crystals.At present,general organic synthesis of picolinamide is dominated by metal-cat alyzed β-substituted pyridine reactions.Such as Pd catalyzed β-balogenated pyridine.Compared with β-substituted pyridine,pyridine N-oxides are low-cost,metal-free a nd environmentally friendly.In this research,an efficient one-pot synthesis of picolinamide from pyridine-N-oxide was developed for the first time.Under optimal conditions,the products were afforded in good yields(average yield>80%)To achieve the best combination of effects,different solvents,temperature,and cyano hydrolysis conditions were systematically tested and optimized.The optimum conditions were determined as follows:pyridine nitrogen oxides(lequiv)and trimethylsilyl cyanide(1.5equiv)as raw materials,1,4-dioxane as solvents,and dimethylcarbamoyl chloride(1.5equiv)as catalyst,react for 5h at 110℃;then add NaOH(2equiv)/H2O(0.5equiv)and 30%H2O2(0.2eqtriv),react for another 3h at 110℃.In total,we obtained 5 products.Attributed to the advantages of low cost,low toxicity and easy work-up,Suzuki coupling reaction has become one of the most important C-C bond forming methods since it was reported by Japanese chemists Suzuki and Miyaura.Suzuki coupling reaction is a metal-catalyzed C-C reaction in the presence of organic boron reagents.To date,the widely recognized reaction mechanism of Suzuki coupling reaction is a cycle with three catalytic reactions:1.oxidative addition of electrophilic reagents(generally refers to halogenated substrates);2.deboracic-acid,followed by transmetalation,then form the organic metal complex R-M-R’ by ligation with the intermediate in the first step;3.after a reductive elimination,the couplet aromatic compound R-R’ is generated from R-M-R’..The typical Pd-catalyzed Suzuki coupling reaction is limited in large-scale industrial application due to easy oxidation of some palladium reagents in air.What’s more,the catalyst is difficult to separate,the product is easily polluted,the recycling and repeating utilization is low and the reaction time is long.Therefore,scholars are searching for cheaper and more environmentally friendly metal catalysts to replace Pd in Suzuki coupling reaction,and adopting Ni and Cu as alternatives of Pd has been a focus in recent years.In 2004,we successfully achieved several coupling products with the laboratory-prepared(5-(benzyloxy)-2-methoxyphenyl)boronic acid as the boric acid substrate and Cul as catalyst under microwave conditions.However,no reaction proceeded when we use other boric acid substrates in the reaction.In addition,the reaction will happen without the presence of any ligands.Thus,we speculated that the self-prepared(5-(benzyloxy)-2-methoxyphenyl)boronic acid contain impurities that can coordinate with Cu,which result in catalyzing the reaction,and the existence of impurities is confirmed later.In this study,we conducted Cu-catalyzed Suzuki coupling reaction of(5-(benzyloxy)-2-methoxyphenyl)boronic acid and 5-Bromo-2-chloropyridine under microwave conditions.We discussed the influence of different solvents,bases,catalysts and microwave conditions and optimized each condition Eventually we determined the reaction conditions:bromine substrates(1 eq.),(5-(benzyloxy)-2-methoxyphenyl)boronic acid(1.2 eq.);base:K2CO3(leq.);solvent:DMF:H20=5:1;microwave condition:T=60℃ t=60s+60s:catalyst:Cul 5mol%.Besides,we obtained 15 compounds when we expanded the bromine substrates under the optimal reaction condition with the yield of 67%-91%,and the(5-(benzyloxy)-2-methoxyphenyl)boronic acid is used as ligand.In this project,we got 18 novel compounds in total We also proved that the impurity in the(5-(benzyloxy)-2-methoxyphenyl)boronic acid crude product is a good Cu ligand participate in Suzuki-Miyaura coupling reaction We roughly identified that the impurity is most likely a nitrogenous compound with molecular weight around 300.Unfortunately,it has no ultraviolet absorption,which makes it difficult to separate and purify.The structural identification will be completed in our further study.