Chiral Phosphoric Acid Catalyzed Asymmetric 1,4 And 1,8-Conjugate Addition Reactions Of Indolylmethanols

Chiral indole derivatives are the core structures of many natural products and drugs with biological activity.In organocatalytic reactions,indolylmethanols have been widely used to synthesize optically active indole derivatives,especially cycloaddition reactions and 1,4-or 1,6-conjugate addition reactions.In recent years,many research groups have reported asymmetric reactions involving 3-indolylmethanols and 2-indolylmethanols.However,other types of indolylmethanols,such as 6-indolylmethanols or7-indolylmethanols,have received less attention.In this context,it is highly desirable to develop new type of indolylmethanols and their involved reactions for synthesizing indole derivatives,especially in an enantioselective manner.On the basis of the previous work,our group actively explored the organically catalyzed asymmetric conjugated addition reactions of 6-indolylmethanols and 7-indolylmethanols with heteroatom-containing nucleophiles,and realized the construction of organic catalyzed remote stereoscopic control chiral centers of aza and thia tri-substituted carbon atoms.The first part of the work reported the asymmetric 1,8-conjugate addition reaction of6-indolylmethanols and benzotriazoles catalyzed by chiral phosphoric acid.Firstly,we screened the catalyst.After determining the best catalyst,we optimized a series of reaction parameters such as the type of solvent,the amount of solvent,the amount of catalyst,and the reaction time,and determined the best reaction conditions.Next,the suitability of the substrate was investigated.Under the optimal reaction conditions,the various substituted 6-indolylmethanols and benzotriazoles can be well compatible,and a series of nitrogen-containing hands are obtained.The yield of the obtained products was between 54-80%and ee value was between 76-92%.This strategy not only achieved the enantioselective N~2-selective alkylation of benzotriazoles,but also achieved the organocatalytic stereoselective 1,8-conjugate addition of nitrogen nucleophiles to6-methylene-6H-indoles.The second part of the work reported the asymmetric 1,8-conjugate addition reaction of 6-indolylmethanols and thiocarboxylic acids catalyzed by chiral phosphoric acid.Firstly,we screened the catalyst.After determining the best catalyst,we optimized a series of reaction parameters such as the type of solvent,reaction temperature,the amount of catalyst,and the reaction time,and determined the best reaction conditions.Next,the suitability of the substrate was investigated.Under the optimal reaction conditions,the various substituted 6-indolylmethanols and thiocarboxylic acids can be well compatible,and a series of sulfur-containing hands were obtained.The yield of the obtained products was between 70-78%and ee value was between 75-94%.Through this strategy,the organocatalytic enantioselective 1,8-conjugate addition of sulfur nucleophiles to6-methylene-6H-indoles were reported for the first time.The third part of the work reported the asymmetric 1,4-conjugate addition reaction of7-indolylmethanols and arylamines catalyzed by chiral phosphoric acid.Firstly,we screened the catalyst.After determining the best catalyst,we optimized a series of reaction parameters such as the type of solvent and its amount,the amount of catalyst,and the reaction time,and determined the best reaction conditions.Next,the suitability of the substrate was investigated.Under the optimal reaction conditions,the various substituted7-indolylmethanols and arylamines can be well compatible.The yield of the obtained products was between 66-96%and ee value was between 70-89%.Notably,the catalytic strategy not only achieves the organocatalytic asymmetric aza-Michael addition of arylamines but also enriches the chemistry of indolylmethanols,resulting in a series of chiral indole compounds with nitrogen-containing tertiary carbon stereocenters.In the fourth part,we took the reaction template product 1-3aa in the first part of this paper as an example to study the practical application of three instrumental analysis methods,nuclear magnetic resonance spectroscopy,mass spectrometry,and high performance liquid chromatography in the field of organic synthesis.