Bài giảng Organic Chemistry - Chapter 23: Ester Enolates and the Claisen Condensation

Chapter 23: Ester Enolates and the Claisen CondensationRecall the aldol addition:Can we do this with ester enolates? The Claisen Condensation Driven by deprotonation of 3-oxoalkanoate (“β–ketoester”).Endothermic as written“Ketoester” versus two estersMechanism: Addition-EliminationHas to be the same or transesterification will occurAcidicClaisenProducts of Claisen condensation are alkyl 3-oxoalkanoates (IUPAC), common name β-keto-esters and, generally, β-dicarbonyl compounds The hydrogens between the two carbonyls are unusually acidic: Due to inductive effect of two carbonyls and resonance in the anion.Low pKas mean that alkoxide or hydroxide can make the enolates stoichiometrically!Acidity of Claisen product is essential to drive the reaction. Without the acidic H, reaction goes in the reverse!No go, starting on the left. Goes from right to left, when starting with the product (made by a different route, as will be seen later).Mechanism of reverse Claisen condensation:But: If one partner has no α-hydrogens (not enolizable), thenCrossed Claisen CondensationGives mixtures of products (as in the case of the crossed aldol addition).To minimize selfcondensationof ethyl propanoate, the benzoate ester is used in excess.Mixed Ketone Claisen CondensationKetones are more acidic than esters, function as enolate partners. Their competitive aldol additions are reversible, but Claisen is not.pKa = 19pKa = 25This is general for Intramolecular Claisen Condensation (Dieckmann Condensation)Ethyl 2-oxocyclohexanecarboxylateMixed Claisen-Dieckmann Condensation Walter Dieckmann1869-1925Use of β-Dicarbonyl Compounds acidicDerived enolates are relatively non-basic, but good nucleophiles: Particularly useful for oxoesters, because they can be decarbonylated:Alkylation:Note: Rsec!Recall: Can’t make disubstituted system by direct Claisen condensationEnolKetoDecarboxylation:Acetoacetic ester synthesis makes substituted methyl ketones. Advantage over direct ketone enolate alkylation: Much less basic enolate; avoids E2 for hindered R.Examples:Malonic ester synthesis makes substituted acetic acids.Michael Addition:Reaction of 3-oxo ester enolates with α,β– unsaturated carbonyls (1,4-addition)Recall: 1,4-Addition is the thermodynamic process, 1,2-addition does occur, but is reversible.Robinson Annulation70%Recall: Robinson annulation is a sequence of 1. Michael addition2. Intramolecular aldol condensationGoes via:Michael adductα-HydroxycarbonylsImportant function in nature and in drugs. How do we make it? Ideal retrosynthesis is:Problem: We cannot make acyl anions from aldehydes, because bases will either deprotonate alpha to make enolate or add to carbonyl function as nucleophiles.Therefore, we need to use masked acyl anions.Acyl anionStoichiometric reagents: 1,3-Dithia-cyclohexane (1,3-dithiane) anions Recall: Thioacetals are made from aldehydes and ketones with thiols-ZnCl2Dithiane is acidic because of the polarizability of sulfur, stabilizes adjacent charge.Very basic Synthetic ApplicationsReverse polarizationDeprotection1,2-Addition is faster (as for RLi)Other alkylating agents: Another aldehyde/ketone synthesisAgain: Limitation is E22. Catalytic version: Alkanal coupling using thiazolium ion catalystCrucial for catalysis is:Six electrons: CarbeneMinorNew bondMechanism of aldehyde coupling:Drawback of the catalytic version: Only symmetrical coupling.In nature: Thiamine (vitamin B1). Diet: Yeast, liver, cereal, rice.A = H, thiamineA = , thiamine pyrophosphate