Study on the Novel Radical Relay Cyclization Based on Ortho-Alkynyl Arylcarbonitriles

Author:Zhu Xiao Tong

Supervisor:cai pei jun


Degree Year:2018





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 theα,β-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 byα,β-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.