21.7 The Acetoacetic Ester Synthesis Dr Wolf's CHM 201 & 202 21-1 Acetoacetic Ester Acetoacetic Ester O H3C O C C H C OCH2CH3 H Acetoacetic ester is another name for ethyl acetoacetate The "acetoacetic ester synthesis" uses acetoacetic ester as a reactant for the preparation of ketones Dr Wolf's CHM 201 & 202 21-2 Deprotonation of Ethyl Acetoacetate Deprotonation of Ethyl Acetoacetate O H3C O C C H C H pKa ~ 11 Dr Wolf's CHM 201 & 202 OCH2CH3 + – CH3CH2O Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide 21-3 Deprotonation of Ethyl Acetoacetate Deprotonation of Ethyl Acetoacetate O H3C O C C C H O H3C OCH2CH3 H pKa ~ 11 C + K ~ 105 O •• –C Dr Wolf's CHM 201 & 202 H C CH3CH2O – Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide OCH2CH3 + CH3CH2OH pKa ~ 16 21-4 Alkylation of Ethyl Acetoacetate Alkylation of Ethyl Acetoacetate O H3C C O •• –C C OCH2CH3 H R Dr Wolf's CHM 201 & 202 X The anion of ethyl acetoacetate can be alkylated using an alkyl halide (SN2: primary and secondary alkyl halides work best; tertiary alkyl halides undergo elimination) 21-5 Alkylation of Ethyl Acetoacetate Alkylation of Ethyl Acetoacetate O H3C C O •• –C C OCH2CH3 H R O H3C O C C X C H Dr Wolf's CHM 201 & 202 OCH2CH3 The anion of ethyl acetoacetate can be alkylated using an alkyl halide (SN2: primary and secondary alkyl halides work best; tertiary alkyl halides undergo elimination) R 21-6 Conversion to Ketone Conversion to Ketone O H3C C O C H C R HO–, H2O H+ O H3C OH O C C C H Dr Wolf's CHM 201 & 202 OCH2CH3 Saponification and acidification convert the alkylated derivative to the corresponding β-keto acid The β-keto acid then undergoes decarboxylation to form a ketone R 21-7 Conversion to Ketone Conversion to Ketone O H3C C O C H C OH R O H3C C CH2R Dr Wolf's CHM 201 & 202 + CO2 Saponification and acidification convert the alkylated derivative to the corresponding β-keto acid The β-keto acid then undergoes decarboxylation to form a ketone 21-8 Example Example O O CH3CCH2COCH2CH3 NaOCH2CH3 CH3CH2CH2CH2Br Dr Wolf's CHM 201 & 202 21-9 Example Example O O CH3CCH2COCH2CH3 NaOCH2CH3 CH3CH2CH2CH2Br O O CH3CCHCOCH2CH3 CH2CH2CH2CH3 Dr Wolf's CHM 201 & 202 (70%) 21-10 Examples Examples H3C O CH3CH2CH2CH H N O CH3CH2 O N H 5-Ethyl-5-(1-methylbutyl)barbituric acid (pentobarbital; Nembutal) Dr Wolf's CHM 201 & 202 21-38 Examples Examples H3C O CH3CH2CH2CH H2C H N O CHCH2 O N H 5-Allyl-5-(1-methylbutyl)barbituric acid (secobarbital; Seconal) Dr Wolf's CHM 201 & 202 21-39 21.9 Michael Additions of Stabilized Anions Dr Wolf's CHM 201 & 202 21-40 Stabilized Anions Stabilized Anions O H3C C O •• –C C OCH2CH3 H O CH3CH2O C O •• –C H Dr Wolf's CHM 201 & 202 C OCH2CH3 The anions derived by deprotonation of β-keto esters and diethyl malonate are weak bases Weak bases react with α,βunsaturated carbonyl compounds by conjugate addition 21-41 Example Example O O CH3CH2OCCH2COCH2CH3 + Dr Wolf's CHM 201 & 202 O H2C CHCCH3 21-42 Example Example O O O CH3CH2OCCH2COCH2CH3 + H2C CHCCH3 KOH, ethanol O O CH3CH2OCCHCOCH2CH3 (85%) CH2CH2CCH3 O Dr Wolf's CHM 201 & 202 21-43 Example Example O O CH3CCH2CH2CH2COH (42%) KOH, ethanol-water H+ heat O O CH3CH2OCCHCOCH2CH3 CH2CH2CCH3 O Dr Wolf's CHM 201 & 202 21-44 21.10 Reactions of LDA-Generated Ester Enolates Lithium diisopropylamide (LDA) Dr Wolf's CHM 201 & 202 21-45 Deprotonation of Simple Esters Deprotonation of Simple Esters Ethyl acetoacetate (pKa ~11) and diethyl malonate (pKa ~13) are completely deprotonated by alkoxide bases Simple esters (such as ethyl acetate) are not completely deprotonated, the enolate reacts with the original ester, and Claisen condensation occurs Are there bases strong enough to completely deprotonate simple esters, giving ester enolates quantitatively? Dr Wolf's CHM 201 & 202 21-46 Lithium diisopropylamide Lithium diisopropylamide Li + CH3 H C CH3 – •• N •• CH3 C H CH3 Lithium dialkylamides are strong bases (just as NaNH2 is a very strong base) Lithium diisopropylamide is a strong base, but because it is sterically hindered, does not add to carbonyl groups 21-47 Lithium diisopropylamide (LDA) Lithium diisopropylamide (LDA) Lithium diisopropylamide converts simple esters to the corresponding enolate O CH3CH2CH2COCH3 + LiN[CH(CH3)2]2 pKa ~ 22 O – CH3CH2CHCOCH3 + •• HN[CH(CH3)2]2 pKa ~ 36 + + Li 21-48 Lithium diisopropylamide (LDA) Lithium diisopropylamide (LDA) Enolates generated from esters and LDA can be alkylated O CH3CH2CHCOCH3 CH2CH3 O CH3CH2I (92%) – CH3CH2CHCOCH3 •• 21-49 Aldol addition of ester enolates Aldol addition of ester enolates Ester enolates undergo aldol addition to aldehydes and ketones O CH3COCH2CH3 LiNR2, THF (CH3)2C H3O+ O HO H3C O C CH2COCH2CH3 CH3 (90%) 21-50 Ketone Enolates Ketone Enolates Lithium diisopropylamide converts ketones quantitatively to their enolates O CH3CH2CC(CH3)3 LDA, THF O CH3CH2CH H3O+ O CH3CHCC(CH3)3 HOCHCH2CH3 (81%) 21-51 End of Chapter 21 End of Chapter 21 21-52 ...Acetoacetic Ester Acetoacetic Ester O H3C O C C H C OCH2CH3 H Acetoacetic ester is another name for ethyl acetoacetate The "acetoacetic ester synthesis" uses acetoacetic ester as a reactant... Alkylation of Ethyl Acetoacetate Alkylation of Ethyl Acetoacetate O H3C C O •• –C C OCH2CH3 H R Dr Wolf''s CHM 201 & 202 X The anion of ethyl acetoacetate can be alkylated using an alkyl halide... 201 & 202 OCH2CH3 The anion of ethyl acetoacetate can be alkylated using an alkyl halide (SN2: primary and secondary alkyl halides work best; tertiary alkyl halides undergo elimination) R 21-6 Conversion