Study On The Novel Radical Relay Cyclization Based On Ortho-Alkynyl Arylcarbonitriles

1-Indenones widely exist in the structures of pharmaceuticals,pesticides,dyes,natural products,and other fine chemical intermediates.Especially in recent years,the synthesis of 1-indenones with anti-tumor and other biological activities has become a research hotspot.At present,the methods of synthesis 1-indenones still have some deficiencies such as high cost,complicated operation and environmental pollution.Therefore,it is a research and development trend to explore the green and efficient synthesis of bioactive indenone drug molecules.On the other hand,ortho-alkynyl arylcarbonitriles have two active sites of cyano and alkynyl groups,so their reactivity is higher.However,there are not many documents about the reactivity.In the dissertation,ortho-alkynyl arylcarbonitriles were used as the key synthons.Different functional groups were introduced into the structure and modified to obtain various1-indenones with potential bioactivity.All of the reactions were efficiently converted into cyclic compounds in a single step by easy-to-access open-chain compounds,effectively avoiding the interference and the separation of intermediates which complies with green and atomic economy synthetic strategies.The research mainly includes the following five parts:1.A detailed overview of the research status of various reactions involving ortho-alkynyl arylcarbonitriles at home and abroad was conducted,and the shortcomings of these reactions were described.At the same time,the advantages and disadvantages of synthetic 1-indenones at home and abroad were highlighted.Based on the research of the above-mentioned documents,we have elaborated on why we chosed the topic and the innovation of the dissertation.2.A new cyclization of in-situ generating phosphorus radicals with ortho-alkynyl arylcarbonitriles was developed under AgNO₃ mediating,and a series of3-phosphorylated 1-indenones were synthesized with excellent yields.The control experiments further confirmed that the reaction was a radical process.First,the phosphorus radicals with non-terminal alkynes conjugated together via the?,?-addition.Then the alkenyl radical relayed to the cyano group,thus resulting the exocyclic nitrogen radical by 5-exo-dig cyclization.The phosphorylation at 3-position of 1-indenone was finally achieved through hydrogen abstraction and hydrolysis,so the construction of new C-P,C-C,and C-O bonds was efficiently completed in one step.3.AgTFA and TBHP were used as the catalytic oxidation system.Under the action of sulfinate salt,the ortho-alkynyl arylcarbonitriles with cyclic ethers formed3-alkylated 1-indenones through radicals relay.According to experiments and researches,the possible mechanism was that the sulfinate salt firstly formed a sulfonyl radical which relayed to the sp³ carbon of cyclic ether,thereby triggering the cleavage of C?sp³?-H bond to generate alkyl radical.Followed by?,?-conjugated addition with ortho-alkynyl arylcarbonitriles,the target product was finally generated after5-exo-dig cyclization,H-abstraction and hydrolysis.4.A direct sulfonylation of ortho-arylalkynyl arylcarbonitrile was developed.A series of novel 3-sulfonyl-1-indenones were prepared by the synergistic catalysis of Cu?OTf?₂ and TBHP.The reaction could tolerate various functional groups such as halogens,alkyl,alkoxy,naphthalene and even cyclopropyl groups.The substrates have good applicability and excellent yields.Controlled experiments showed that the reaction was a radical process.The sulfonyl hydrazide in-situ generated sulfonyl radical under the oxidation of TBHP.At the same time,Cu?OTf?₂ acted as Lewis acid to coordinate with C-C triple bonds,and the sulfonyl radical was added to form alkenyl radical.The 5-exo-dig cyclization,H abstraction and hydrolysis were finally induced by the radical relay to achieve the sulfonylation of 1-indenones.5.A radical relay reaction of ortho-alkylalkynyl arylcarbonitriles with arylsulfonyl hydrazides was described.The reaction underwent 5-exo-dig cyclization and condensation which produced a series of novel functionalized 1-indenes in good yields,among which arylsulfonyl hydrazides were both a source of aryl and a donor of hydrazone.Controlled experiments demonstrated that the reaction process involved radical process.A possible mechanism was as follows:the aryl radical in-situ generated by the sulfonyl hydrazide initiated the reaction process,which combined with ortho-alkylalkynyl arylcarbonitriles to form 3-aryl-1-indenone,and then underwent Mannich condensation with another molecule of arylsulfonyl hydrazide.Thus,the sequence of functionalization was determined by two different functional groups.