Synthesis Of Nitrogen-containing Heterocycles And ?-amino Acids Using CO₂ As Carboxylative Reagent

Carbon dioxide is considered to be the chief culprits of the global warming problem.It is also a nontoxic,nonflammable,inexpensive and abundant C1 feedstock.Recently,the efficient chemical transformation of carbon dioxide into highly value-added fine chemicals is becoming one of the hottest topics in organic chemistry.However,the high thermodynamic and kinetic stabilities of carbon dioxide make its chemical transformation to be a challenging issue.Nitrogen-containing compounds play an important role in pharmacy and other fine chemical industry due to their good biological compatibility.Currently,over 95%commercial drug molecules contain the nitrogen atom.Thus the construction of new nitrogen-contained molecules is a vital subject in the pharmaceutical research area.This dissertation will focus on the development of new reaction system using carbon dioxide as a carboxylative reagent for the synthesis of nitrogen-containing heterocyclic or a-amino acids with pharmaceutical properties and biological activities,which mainly contains the following three aspects:?1?A CuI-catalyzed carboxylative cyclization of 2-alkynylaniline with CO₂ to produce 4-hydroxyquinolin-2?1H?-one derivatives was developed.This efficient reaction system showed the wide generality of substrates and gave moderate to good yield.In this reaction,one of the C=O bond of CO₂ was broken and rearranged into isocyanate and hydroxyl two moieties in the absence of reductive reagent.The possible reaction mechanism was proposed:firstly 2-alkynylaniline reacted with CO₂ to form carbamate.Then intermediates bearing isocyanate and enolate groups was formed via the C-O bond cleavaged and rearrangement,which went through intramolecular cyclization to produce the 4-hydroxyquinolin-2?1H?-one product.This catalyst system provides a more efficient and greener approach to synthesize 4-hydroxyquinolin-2?1H?-one derivatives.?2?An efficient transition-metal-free[3+2]cycloaddition of nitrile imine and carbon dioxide was enabled to synthsize 1,3,4-oxadiazole-2?3H?-one by the combination of CsF as a base and 18-crown-6 as a pivotal additive.This efficient reaction system showed the wide generality of substrates.The practical utility of this approach is highlighted by the convenient synthesis of a MAO B inhibitor and a commercial herbicide Oxadiazon.Based on in situ NMR and control experiments,it's speculated that the 18-crown-6 not only enhanced the formation of nitrile imine intermediate,but also increased the solubility of CsF,in which the released F-could activate CO₂ and accelerate the cycloaddition reaction.?3?A transition-metal-free,chemo-and regio-selective method for the synthesis of a-arylglycine derivatives from aromatic imines and carbon dioxide by an umpolung carboxylation reaction was developed.The key to the success of this transformation is the use of KOtBu as a base and 18-crown-6 as a pivotal additive.FT-IR,in situ NMR and DFT calculation showed that besides the enhancement of the solubility of KOtBu in THF,18-crown-6 also played a key role in suppressing the reverse protonation of the 2-azaallyl intermediate and the 1,3-proton-shift isomerization and by stabilizing the carboxylated intermediate.