CHAPTER 23 cormdicarbony Enolates and the Claisen etmont odum Condensation: ho:o absioe Synthesis of B-Dicarbonyl Compounds:Acyl Anion Equivalents P&R llde and the The first three st in the mecare reversible. otons flanked by two carbonyl groups are acidic. 3-p NCCH.CN 1
1 CHAPTER 23 Enolates and the Claisen Condensation: Synthesis of β-Dicarbonyl Compounds: Acyl Anion Equivalents β-Dicarbonyl Compounds: Claisen Condensations 23-1 Claisen condensations form β-dicarbonyl compounds. Ethyl acetate reacts with a stoichiometric amount of sodium ethoxide to give ethyl 3-oxobutanoate. The first three steps in the mechanism are reversible. Because ethoxide ion is consumed in Step 4, a stoichiometric amount of sodium ethoxide is required, rather than a catalytic amount to insure that some ethoxide is always available to catalyze Step 1. To prevent transesterification, both the alkoxide and the ester are usually derived from the same alcohol. Protons flanked by two carbonyl groups are acidic. The acidity of hydrogens flanked by two carbonyl groups is enhanced by resonance stabilization of the resulting anion. When only a single α-hydrogen is present, the Claisen condensation fails because the addition product lacks the additional acidic proton necessary to drive the equilibrium. The existence of the unfavorable equilibrium can be demonstrated by the reversal of a Claisen condensation (retro-Claisen condensation):
have two iffere gomcecolngersasencondenatonareautn eoac 8,y一 好 es undergo mixed claisen reactions. sare more aci nsations in syntheti tePpgaoaytepotnnes,p-ketogaehydsor 1.aasencndensatonsalnasfoml,3dlcarbon r the synth of 2-benzoylycohexanone onene8bea8asb传omweghgmgPeaiy aas8eo8 n this case,there are two possibilities: 2
2 Claisen condensations can have two different esters as reactants. Mixed Claisen condensations start with two different esters, are typically unselective and furnish product mixtures unless one of the esters has no α-hydrogens. Intramolecular Claisen condensations result in cyclic compounds. The Dieckmann condensation is an intramolecular version of the Claisen condensation which produces cyclic 3-keto esters. The method works best for the formation of five- and six-membered rings. Ketones undergo mixed Claisen reactions. Ketones are more acidic than esters and as a result are deprotonated and react before the ester has a chance to undergo self-condensation. The products may be β-diketones, β-ketoaldehydes or other β-dicarbonyl compounds. Retrosynthetic analysis clarifies the synthetic utility of the Claisen condensation. Three facts govern the use of Claisen condensations in synthetic design: 1. Claisen condensations always form 1,3-dicarbonyl compounds. 2. One of the reaction partners must be an ester. 3. The other reaction partner must contain at least two acidic hydrogens on an α-carbon. In addition, if a mixed condensation is being considered, one reaction partner should be incapable of self-reaction (no α- hydrogens). Consider the synthesis of 2-benzoylcyclohexanone: A Claisen condensation always forms a new bond connecting one of the carbonyl groups of the 1,3-dicarbonyl moiety to the carbon atom between them. Prior to bond formation, one of the carbonyls will be in the form of an ester. In this case, there are two possibilities: Both possibilities are feasible, however, the second possibility is preferred because it starts from two smaller fragments
23-2 B-Dicarbony Compounds as Synthetic thecrbnyl comounds undergosmreacts p-olcartbonyanionsarenueieophile alkoxid acids re dily undergo decarboxylation. vlic add products contain the alkyl group CHCH.CH CH f af 3-Ketaadids e。 3
3 β-Dicarbonyl Compounds as Synthetic Intermediates 23-2 β-Dicarbonyl anions are nucleophilic. The low pKa values of β-ketocarbonyl compounds allows alkoxide bases to remove a proton from the methylene carbon quantitatively, giving an enolate that may by alkylated. The remaining acidic hydrogen can then be removed by a stronger base allowing for doubly substituted products. Other β-dicarbonyl compounds undergo similar reactions. 3-Ketoacids readily undergo decarboxylation. 3-Ketoesters can be hydrolyzed to 3-ketoacids, which readily undergo decarboxylation under mild conditions. The ketone and carboxylic acid products contain the alkyl groups previously introduced. β-Keto acids are unusually prone to decarboxylation due to the formation of a cyclic six-atom transition state, which has aromatic character (3 electron pairs shift around the cyclic 6-atom transition state). Carboxylic acids lacking a β-carbonyl function do not decarboxylate, regardless of carbonyl groups elsewhere in the molecule. Decarboxylation only occurs readily from the neutral carboxylic acid. Acid must be added to protonate the carboxylate salt if the ester was hydrolyzed with base. The acetoacetic ester synthesis leads to methyl ketones. The acetoacetic ester synthesis is a strategy that combines alkylation followed by ester hydrolysis and finally decarboxlyation
alonic ester synthesis furnishes carboxylic Ts2anY2heoaneco CH →CH./CH. CH 23-3 B-Dicarbonyl Anion Chemistry:Michael Additions he reaction is base-catah d and leads to 1,4 additions. thetnce Ca2aen6aenepmcaao6etablaedenoateon 合8ae62e5o8Ee5a CO.CHCH 4
4 Methyl ketones with either one or two substituent groups on C3 can be synthesized using this sequence. The malonic ester synthesis furnishes carboxylic acids. The malonic ester synthesis converts diethyl propanedioate into 2-alkylated and 2,2-dialkylated acetic acids. SN2 reaction limitations apply to the alkylation steps. •Tertiary haloalkanes exposed to β-dicarbonyl anions give mainly elimination products. •Alkanoyl halides, α-bromoesters, α-bromoketones and oxacyclopropanes can be successfully attacked by the anions. 23-3 β-Dicarbonyl Anion Chemistry: Michael Additions A Michael addition results from the reaction of a stabilized anion derived from a β-dicarbonyl compound with an α,β unsaturated carbonyl compound. The reaction is base-catalyzed and leads to 1,4 additions. The reaction works with α,β unsaturated ketones, aldehydes, nitriles and carboxylic acid derivatives, all of which are termed Michael acceptors. Stabilized anions undergo 1,4-additions rather than 1,2-additions. 1,2-Additions actually occur, but are reversible with relatively stable anionic nucleophiles because they lead to relatively highenergy alkoxides. Conjugate addition produces a resonance-stabilized enolate ion and is therefore thermodynamically favored. A Michael addition followed by an intramolecular aldol condensation represents a useful synthetic sequence. A diketone is formed as a reaction intermediate. Deprotonation of the α-methyl group in the side chain is followed by the aldol condensation
Cyclic thioacetals are masked alkanoyl(acyl)anion asobtaehooaaonaeeathamhhout 1知3 N-kkstclehetame Thiazolium aldehyde coupling catacthe nof .d.d.. *0 Tvethentath theyaredd nly theof molecules ea2heneenemtednkeoe 5
5 Alkanoyl (Acyl) Anion Equivalents: Preparation of α-Hydroxyketones 23-4 It would be desirable to create an alkanoyl anion which could be used to link two carbonyl functionalities together. To accomplish this type of C-C linkage, special nucleophiles called masked alkanoyl anions or alkanoyl anion equivalents can later be transformed into carbonyl groups. Cyclic thioacetals are masked alkanoyl (acyl) anion precursors. Cyclic thioacetals can be prepared by reacting dithiols with aldehydes and ketones. The hydrogens on the carbon positioned between the two sulfurs are acidic enough to be removed by suitably strong bases. The negative charge on the conjugate base is inductively stabilized by the polarizable sulfur atoms. The anion of 1,3-dithiacyclohexane, as well as its derivatives, are nucleophilic and will add to aldehydes and ketones, furnishing alcohols with an adjacent thioacetal group. Thiazolium salts catalyze aldehyde coupling. Thiazolium salts can be used to generate masked alkanoyl anions catalytically in the coupling of aldehydes. Thiazolium salts have the advantage that they are needed only in catalytic amounts. Their use is limited to the synthesis of molecules in which the two R groups are identical. The dithiacyclohexane method is more versatile and can be used to prepare a much wider range of substituted α-hydroxyketones
23 Important Concepts 23 Important Concepts 2 ehecoaoaot8weaaCao 5. 6
6 23 Important Concepts 1. Claisen Condensation – stoichiometric generation of a stable β-dicarbonyl anion in the presence of excess base 2. β-Dicarbonyl Compounds – hydrogens at the carbon between the carbonyl groups are acidic: • Electron-withdrawing power of two adjacent carbonyl groups • Resonance stabilization of the resulting anion 3. Mixed Claisen Condensations – between esters usually not selective, except with certain substrates (nonenolizable esters, intramolecular versions, ketones) 23 Important Concepts 4. 3-Ketoacids Are Unstable – they decarboxylate via a concerted mechanism through an aromatic transition state. • This, in conjunction with the nucleophilic reactivity of 3- ketoexter anions, allows the synthesis of substituted ketones and acids. 5. Alkanoyl (acyl) Anions – cannot be made by deprotonation of aldehydes. They have to be made as masked reactive intermediates or stoichiometric reagents by transformations of functional groups