2015-药物合成反应课件-第四章 缩合反应.ppt

第四章 缩合反应 Chapter 4-Condensation Reaction Section 1. α-Aldol、Haloalkylation、Aminoalkylation α-Hydroalkylating Reaction 1 . Aldol Condensation: Addition of the enol/enolate of a carbonyl compound (nucleophile) to an aldehyde or ketone (electrophile) self-condensation polycondensation dehydration followed by Michael addition Side Reactions: α-Aldol、Haloalkylation、Aminoalkylation Four types: （1）Self-condensation of aldehyde or ketone （2）Directed aldol condensation （3）Condensation of different aldehydes or ketones with formaldehyde （4）Condensation of aldehyde or ketone with arylaldehyde Development of methods for the formation and application of preformed enolates was a breakthrough in the aldol methodology. (1) Self-Condensation of Aldehyde or Ketone Mechanism: Base -catalyzed reaction mechanism Acid -catalyzed reaction mechanism 1）Base -Catalyzed Reaction Mechanism Example Example 2) Acid -Catalyzed Reaction Mechanism Catalysts：H2SO4 HCl TsOH Dowex-50 Aldol Condensation Intramolecular Intermolecular （2）Condensation between Different Aldehydes/Ketones Complicated products from cross-condensation, self-condensation Cross-Condensation Carbonyl with more substituents on α-Carbon works as Nu When aldehyde reacts with ketone, normally self condensation of aldhyde is the major side reaction；For acetone, cross-condensation easily happens Cross-Condensation Condensation with Formaldehyde Tollens Reaction Condensation with Formaldehyde Claisen-Schimidt Reaction Condensation with Aromatic aldehyde unstable Trans (major) Condensation with Aromatic aldehyde Condensation with Aromatic Aldehyde With single α-H, product is cleaner Robinson Annulation Robinson Annulation Directed Aldol Condensation Directed Aldol Condensation Mechanism Asymmetric Aldol Reaction Evans Aldol Asymmetric Aldol Reaction Evans Aldol-Mechanism Asymmetric Aldol Reaction Mukaiyama Aldol Asymmetric Aldol Reaction Mukaiyama Aldol-Mechanism Asymmetric Aldol Reaction Appli