Visible-Light/Enzyme-Catalyzed Synthesis And Derivatization Of Oxazine Derivatives

Energy conservation,green and sustainable development has become the theme with the development of the times.Sunlight is an abundant source of energy in nature,which is clean,green,sustainable and environmentally friendly.As a major component of sunlight,visible light has been successfully applied in the filed of synthetic chemistry.However,many organic molecules can not directly absorb light which limits the scope of application of visible-light catalysis.By using photocatalysts,the application of visible-light catalysis has been largely expanded.Presently,visible-light catalysis has become one of the hot spots of organic synthesis.New carbon-carbon and carbon-hetero bonds can be formed by a single electron transfer pathway through visible-light photoredox catalysis.Enzymes are green and efficient biocatalysts with many advantages such as mild reaction conditions,good stereoselectivity and environmental-friendliness.As a green catalytic method,enzymatic catalysis has been widely studied.Heterocyclic compounds occupy an important position in the field of organic chemistry.Oxazine derivatives have unique biological activity such as anti-tumor,anti-HIV,anti-malarial,anti-bacterial due to their special nitrogen and oxygen heterocyclic structure.At present,great progress has been made in the synthesis of oxazine derivatives,but most methods use toxic or dangerous reagents or require high temperature conditions.Therefore,the green synthe tic pathway of oxazine derivatives still faces enormous challenges.This thesis introduces the synthesis of 1,3-oxazine derivatives,the oxidative dehydrogenative coupling reaction of 1,4-oxazine derivatives by visible-light photoredox catalysis and the direct amination of sp2 C-H bonds catalyzed by laccase.In the second chapter of the thesis,enzyme and visible-light photoredox sequential catalysis in one pot for the synthesis of 1,3-oxazine derivatives from N-aryl glycinates and naphthols is described.Firstly,ethyl p-tolylglycinate and ?-naphthol were employed as the substrates for the model reaction.The type of photocatalysts,solvents,molar ratio of substrates,photocatalyst loading,enzyme loading,the wattages of the bulb and additional amounts of water were screened to obtain the optimal conditions for the reaction.Then,with the optimized reaction conditions in hand,the substrate scope of the reaction was explored and sixteen 1,3-oxazine derivatives were obtained with yields of up to 69%.Finally,a control experiment of formaldehyde,ethyl p-tolylglycinate and ?-naphthol(1:1:1)was made with yield of only 22%.Based on the control experiments and related literatures,we speculated that the reaction process involves sequential enzymatic hydrolysis,visible-light excited decarboxylation of ethyl N-aryl glycinates,oxidation of ?-amino radical,Mannich reaction,transimination and intramolecular cyclization.The research in this chapter provides a novel and simple alternative method for the synthesis of 1,3-oxazine derivatives.In the third chapter of the thesis,oxidative-cross dehydrogenative coulping reaction of 3,4-dihydro-1,4-benzoxazin-2-one by visible-light photoredox catalysis for the synthesis of 1,4-oxazine derivatives is described.Firstly,3,4-dihydro-1,4-benzoxazin-2-one and indole were employed as the substrates for the model reaction.The type of photocatalysts,solvents,molar ratio of substrates,photocatalyst loading and the wattages of the bulb were screened to obtain the optimal conditions for the reaction.Then,the substrate scope of the reaction was explored under the optimized reaction conditions,and twenty 1,4-oxazine derivatives were obtained with yields of up to 80%.Finally,a series of control experiments were performed to explore mechanism.We speculate that in the process of reaction ?-amino radical intermediates can be generated,which are subsequently oxidized by the oxygen in the air to give the iminium ion intermediates.The iminium ions directly reacts with various aromatic nucleophiles to provide the desired cross-coupling products 1,4-oxazine derivatives.The work of this chapter provides a sustainable and environmentally-friendly method for the synthesis of 1,4-oxazine derivatives.Biocatalysts are environmentally-friendly and green.Therefore,the development of biocatalytic conversion is of great significance for social and economic development.Laccase belongs to the blue multi-copper oxidase,which is stable and inexpensive and is one of the important biocatalysts.It is widely used in the fields of environment,industry,biology and chemistry.Laccase has a certain oxidizing ability,which can undergo a process of electron transfer with the substrate to oxidize the substrate.In the whole catalytic process of reaction,only oxygen is needed as an oxidant to facilitate different chemical reactions.Moreover,the entire catalytic process of reaction only generates water as a by-product.The C-H functionalization of aromatic ring is an important tool for the construction of drugs and natural products and is of great significance in the field of organic synthesis.However,the green method of the direct C-H functionalization of the aromatic ring is still a challenge.In the fourth chapter of the thesis,we preliminarily explored the application of laccase in the C-H amination of aromatic rings.