21.6 The Acetoacetic Ester Synthesis Acetoacetic Ester O O C C H3C C OCH2CH3 H H Acetoacetic ester is another name for ethyl acetoacetate. The "acetoacetic ester synthesis" uses acetoacetic ester as a reactant for the preparation of ketones. Deprotonation of Ethyl Acetoacetate O O – C C + CH3CH2O H3C C OCH2CH3 H H Ethyl acetoacetate pKa ~ 11 can be converted readily to its anion with bases such as sodium ethoxide. Deprotonation of Ethyl Acetoacetate O O – C C + CH3CH2O H3C C OCH2CH3 H H Ethyl acetoacetate pKa ~ 11 can be converted readily to its anion K ~ 105 K ~ 10 with bases such as O O sodium ethoxide. C •• C + CH3CH2OH H3C –C OCH2CH3 3 2 H pKa ~ 16 Alkylation of Ethyl Acetoacetate O O The anion of ethyl C •• C acetoacetate can be H C C OCH CH 3 – C OCH2CH3 alkylated using an H alkyl halide (SN2: primary and R X secondary alkyl halides work best; tertiary alkyl halides undergo elimination). Alkylation of Ethyl Acetoacetate O O The anion of ethyl C •• C acetoacetate can be H C C OCH CH 3 – C OCH2CH3 alkylated using an H alkyl halide (SN2: primary and R X secondary alkyl O O halides work best; tertiary alkyl halides C C undergo elimination). H3C C OCH2CH3 H R Conversion to Ketone O O Saponification and C C acidification convert H3C C OH the alkylated H R derivative to the – 1. HO , H2O corresponding b-keto 2. H+ acid. O O The b-keto acid then undergoes C C decarboxylation to H C 3 C OCH2CH3 form a ketone. H R Conversion to Ketone O O Saponification and C C acidification convert H3C C OH the alkylated H R derivative to the corresponding b-keto acid. O The b-keto acid then undergoes decarboxylation to C + CO2 decarboxylation to H3C CH2R form a ketone. Example O O CH3CCH2COCH2CH3 1. NaOCH2CH3 2. CH3CH2CH2CH2Br Example O O CH3CCH2COCH2CH3 1. NaOCH2CH3 2. CH3CH2CH2CH2Br O O CH3CCHCOCH2CH3 CH2CH2CH2CH3 (70%) Example O (60%) CH3CCH2CH2CH2CH2CH3 (60%) 1. NaOH, H2O 2. H+ 3. heat, -CO2 O O CH3CCHCOCH2CH3 CH2CH2CH2CH3 Example: O O Dialkylation CH3CCHCOCH2CH3 CH2CH CH2 Example: O O Dialkylation CH3CCHCOCH2CH3 CH2CH CH2 1. NaOCH2CH3 2. CH3CH2I O O CH3CCCOCH2CH3 CH3CH2 CH2CH CH2 (75%) Example: O Dialkylation CH3CCH CH2CH CH2 CH3CH2 1. NaOH, H2O 2. H+ 3. heat, -CO2 O O CH3CCCOCH2CH3 CH3CH2 CH2CH CH2 Another O Example O COCH2CH3 H b-Keto esters other than ethyl acetoacetate may be used. Another O Example O COCH2CH3 H 1. NaOCH2CH3 2. H2C CHCH2Br O O COCH2CH3 (89%) CH2CH CH2 Another Example O O COCH2CH3 CH2CH CH2 Another Example O H CH2CH CH2 (66%) 1. NaOH, H2O 2. H+ 3. heat, -CO2 O O COCH2CH3 CH2CH CH2 21.7 The Malonic Ester Synthesis Malonic Ester O O C C CH3CH2O C OCH2CH3 H H Malonic ester is another name for diethyl malonate. The "malonic ester synthesis" uses diethyl malonate as a reactant for the preparation of carboxylic acids. An Analogy O O O O CH3CCH2COCH2CH3 CH3CH2OCCH2COCH2CH3 O O CH3CCH2R HOCCH2R The same procedure by which ethyl acetoacetate is used to prepare ketones converts diethyl malonate to carboxylic acids. Example O O CH3CH2OCCH2COCH2CH3 1. NaOCH2CH3 2. H2C CHCH2CH2CH2Br O O CH3CH2OCCHCOCH2CH3 CH2CH2CH2CH CH2 (85%) Example O HOCCH2CH2CH2CH2CH CH2 (75%) 1. NaOH, H2O 2. H+ 3. heat, -CO2 O O CH3CH2OCCHCOCH2CH3 CH2CH2CH2CH CH2 Dialkylation O O CH3CH2OCCH2COCH2CH3 1. NaOCH2CH3 2. CH3Br O O CH3CH2OCCHCOCH2CH3 (79-83%) CH3 Dialkylation O O CH3CH2OCCCOCH2CH3 CH3(CH2)8CH2 CH3 1. NaOCH2CH3 2. CH3(CH2)8CH2Br O O CH3CH2OCCHCOCH2CH3 CH3 Dialkylation O O CH3CH2OCCCOCH2CH3 CH3(CH2)8CH2 CH3 1. NaOH, H2O 2. H+ 3. heat, -CO2 O CH3(CH2)8CH2CHCOH (61-74%) CH3 Another Example O O CH3CH2OCCH2COCH2CH3 1. NaOCH2CH3 2. BrCH2CH2CH2Br O O CH3CH2OCCHCOCH2CH3 CH2CH2CH2Br Another Example This product is not isolated, but cyclizes in the presence of sodium ethoxide. O O CH3CH2OCCHCOCH2CH3 CH2CH2CH2Br O Another O Example CH3CH2OCCCOCH2CH3 H2C CH2 (60-65%) C H2 NaOCH2CH3 O O CH3CH2OCCHCOCH2CH3 CH2CH2CH2Br Another O O Example CH3CH2OCCCOCH2CH3 H2C CH2 C H2 1. NaOH, H2O 2. H+ 3. heat, -CO2 H CO2H C H2C CH2 (80%) C H2.