[4+1+1] Annulation Reaction Of Ammonium Ylides And The Mechanism Study

The benzofuran-fused nitrogen-containing heterocyclic system is one of the most fundamental structural motifs widely existing in natural products and bioactive compounds Their nitrogen and oxygen moieties are good H-bond acceptors to donors in physiologically functional enzymes,which make them potential pharmacologically active compounds Therefore,it is of great value to develop efficient synthetic pathways to construct this type of fused hererocyclic system,especially from easily available starting materials.Moreover,with the continuous development of the concept "fine chemistry",to discover larger in numbers of new reactions is no longer the pivotal goal in synthetic chemistry,but to dig further in depth of their mechanism.Thus,the use of quantitative computational calculations to decipher its mechanism has become a necessity along with the development of a new reaction.Acetylcholinesterase(AChE)inhibitor tacrine has severe hepatotoxicity,and it is particularly urgent to develop new low-toxic and highly effective AChE inhibitorN-ylides are a commonly recognized and important type of reagents in organic synthesis,providing a carbanion site for nucleophilic reactions.Over the past decades,a variety of[2+1],[3+1],[4+1]annulation reactions have been realized with ammonium centered N-ylides as the "1" carbon units.Extending the reaction type that N-ylides are not limited to one carbon unit to participate in the reaction is a major challenge.On this basis,we an unexpected[4+1+1]annulation reaction with this type of substrates was discovered,and thus expanded the utilization of N-ylide chemistryThis dissertation mainly focuses on two parts:one is the experimental exploration of the[4+1+1]annulation reaction;the other is the theoretical calculationsIn our work,it was found that 1-azadienes derived from benzofurans could react with S-ylides in a traditional[4+1]mode,while with in situ generated N-ylides,a distinct[4+1+1]reaction would occur.This is a previously unreported reaction mode of N-ylide chemistry,exhibiting good compatibility for different substrates with functional groups,including substrates with benzothiophene cores and bromoacetophenones.Moreover,a good yield was maintained when this reaction was amplified to a gram-scale,showing good potential for further synthesis.Besides,products from this[4+1+1]reaction could be derived to"drug-like" fused heterocycles with higher degrees of molecular complexity,via simple synthetic steps.In addition,an array of control experiments and mass spectrometry studies of the key proposed intermediates have been conducted,supporting that the enolates and ammonium ylides of a-bromo carbonyls,respectively,would be involved in the cascade reaction process.Using this readily available synthetic method,an array of fused heterocyclic compounds were constructed and screened for AChE inhibite activity which can reach up to 16%at 50 μmol/LPart Ⅱ:Theoretical calculations to interpret the mechanism of the[4+1+1]annulationUsing M06-2X theoretical method and 6-311++G(2d,p)/6-31G(d)basis set,the energy,charge distribution and orbital informations in[4+1]and[4+1+1]reaction systems were respectively calculated.Results have shown that,1)ammonium salt is easier to be formed than sulfur salt,because of higher negative charge density on N than on S;2)N-ylide exhibits better Michael addition activity because of its higher HOMO energy than S-ylide;3)the convetional[4+1]reaction was not observed,because its larger rotation energy and leaving reaction energy barriered the annulation step;4)in the[4+1+1]reaction mode,the introduction of the second ethyl bromoacetate would result from attack of N-ylide on the 3-membered system,while the energy barrier of the following annulation step was still huge On the other hand,the calculation figured out a more possible reaction mechanism:the Michael adduct undergoes intramolecular 1,5-hydrogen migration,regenerating N-ylide in situ,and the N-ylide attacks another free ethyl bromoacetate from the system.Sequentially,the α,β-unsaturated moiety generated via DABCO elimination is attacked by the N atom,leading to the final ring closure.The calculations also show that oxidative aromatization is less likely to occur spontaneously,but oxidized with external oxygenIn this dissertation,a new N-ylide-based reaction mode was discovered.The related theoretical calculations explained its internal mechanism and provided a reference for the subsequent development of nitrogen ylide chemistry.