21 6 The Acetoacetic Ester Synthesis Acetoacetic Ester

Acetoacetic Ester H 3 C O O C C H C OCH 2 CH

Deprotonation of Ethyl Acetoacetate O H 3 C C O C C H H

Deprotonation of Ethyl Acetoacetate O H 3 C C OCH 2 CH 3 H

Alkylation of Ethyl Acetoacetate O H 3 C C O • • –C C

Conversion to Ketone O H 3 C C O C H H 3 C

Conversion to Ketone O H 3 C C H O C C OH R

Example O O CH 3 CCH 2 COCH 2 CH 3 1. Na. OCH

Example O CH 3 CCH 2 CH 2 CH 3 1. Na. OH, H

Example: Dialkylation O O CH 3 CCHCOCH 2 CH 3 CH 2 CH CH

Example: Dialkylation O CH 3 CCH CH 2 CH 3 CH 2 1. Na.

Another Example O O COCH 2 CH 3 H b-Keto esters other than ethyl

Another Example O O COCH 2 CH 3 H 1. Na. OCH 2 CH

Another Example O O COCH 2 CH 3 CH 2 CH CH 2

Another Example O H CH 2 CH O CH 2 (66%) 1. Na. OH,

Malonic Ester CH 3 CH 2 O O O C C H C OCH

An Analogy O O CH 3 CCH 2 COCH 2 CH 3 CH 2

Example O O CH 3 CH 2 OCCH 2 COCH 2 CH 3 1.

Example O HOCCH 2 CH 2 CH CH 2 (75%) 1. Na. OH, H

Dialkylation O O CH 3 CH 2 OCCH 2 COCH 2 CH 3 1.

Dialkylation O O CH 3 CH 2 OCCCOCH 2 CH 3(CH 2)8 CH 2

Another Example O O CH 3 CH 2 OCCH 2 COCH 2 CH 3

Another Example This product is not isolated, but cyclizes in the presence of sodium

Another Example O O CH 3 CH 2 OCCCOCH 2 CH 3 H 2

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21. 6 The Acetoacetic Ester Synthesis

Acetoacetic Ester H 3 C O O C C H C OCH 2 CH 3 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 H 3 C C O C C H H p. Ka ~ 11 OCH 2 CH 3 + CH 3 CH 2 O – Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide.

Deprotonation of Ethyl Acetoacetate O H 3 C C OCH 2 CH 3 H H p. Ka ~ 11 K ~ 105 O H 3 C C O • • –C H C + CH 3 CH 2 O – Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide. OCH 2 CH 3 + CH 3 CH 2 OH p. Ka ~ 16

Alkylation of Ethyl Acetoacetate O H 3 C C O • • –C C OCH 2 CH 3 H R X The anion of ethyl acetoacetate can be alkylated using an alkyl halide (SN 2: primary and secondary alkyl halides work best; tertiary alkyl halides undergo elimination).

Alkylation of Ethyl Acetoacetate O H 3 C C O • • –C C OCH 2 CH 3 H R H 3 C O O C C H C R X OCH 2 CH 3 The anion of ethyl acetoacetate can be alkylated using an alkyl halide (SN 2: primary and secondary alkyl halides work best; tertiary alkyl halides undergo elimination).

Conversion to Ketone O H 3 C C O C H H 3 C C R 1. HO–, H 2 O 2. H+ O O C C H OH C R OCH 2 CH 3 Saponification and acidification convert the alkylated derivative to the corresponding b-keto acid. The b-keto acid then undergoes decarboxylation to form a ketone.

Conversion to Ketone O H 3 C C H O C C OH R O H 3 C C CH 2 R + CO 2 Saponification and acidification convert the alkylated derivative to the corresponding b-keto acid. The b-keto acid then undergoes decarboxylation to form a ketone.

Example O O CH 3 CCH 2 COCH 2 CH 3 1. Na. OCH 2 CH 3 2. CH 3 CH 2 CH 2 Br

Example O O CH 3 CCH 2 COCH 2 CH 3 1. Na. OCH 2 CH 3 2. CH 3 CH 2 CH 2 Br O O CH 3 CCHCOCH 2 CH 3 CH 2 CH 2 CH 3 (70%)

Example O CH 3 CCH 2 CH 2 CH 3 1. Na. OH, H 2 O 2. H+ 3. heat, -CO 2 O O CH 3 CCHCOCH 2 CH 3 CH 2 CH 2 CH 3 (60%)

Example: Dialkylation O O CH 3 CCHCOCH 2 CH 3 CH 2 CH CH 2

Example: Dialkylation O O CH 3 CCHCOCH 2 CH 3 CH 2 CH CH 2 1. Na. OCH 2 CH 3 2. CH 3 CH 2 I O O CH 3 CCCOCH 2 CH 3 CH 2 CH (75%) CH 2

Example: Dialkylation O CH 3 CCH CH 2 CH 3 CH 2 1. Na. OH, H 2 O 2. H+ 3. heat, -CO 2 O O CH 3 CCCOCH 2 CH 3 CH 2 CH CH 2

Another Example O O COCH 2 CH 3 H b-Keto esters other than ethyl acetoacetate may be used.

Another Example O O COCH 2 CH 3 H 1. Na. OCH 2 CH 3 2. H 2 C CHCH 2 Br O O COCH 2 CH 3 CH 2 CH CH 2 (89%)

Another Example O O COCH 2 CH 3 CH 2 CH CH 2

Another Example O H CH 2 CH O CH 2 (66%) 1. Na. OH, H 2 O 2. H+ 3. heat, -CO 2 O COCH 2 CH 3 CH 2 CH CH 2

21. 7 The Malonic Ester Synthesis

Malonic Ester CH 3 CH 2 O O O C C H C OCH 2 CH 3 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 CH 3 CCH 2 COCH 2 CH 3 CH 2 OCCH 2 COCH 2 CH 3 O O CH 3 CCH 2 R HOCCH 2 R The same procedure by which ethyl acetoacetate is used to prepare ketones converts diethyl malonate to carboxylic acids.

Example O O CH 3 CH 2 OCCH 2 COCH 2 CH 3 1. Na. OCH 2 CH 3 2. H 2 C O CHCH 2 CH 2 Br O CH 3 CH 2 OCCHCOCH 2 CH 3 CH 2 CH 2 CH (85%) CH 2

Example O HOCCH 2 CH 2 CH CH 2 (75%) 1. Na. OH, H 2 O 2. H+ 3. heat, -CO 2 O O CH 3 CH 2 OCCHCOCH 2 CH 3 CH 2 CH 2 CH CH 2

Dialkylation O O CH 3 CH 2 OCCH 2 COCH 2 CH 3 1. Na. OCH 2 CH 3 2. CH 3 Br O O CH 3 CH 2 OCCHCOCH 2 CH 3 (79 -83%)

Dialkylation O O CH 3 CH 2 OCCCOCH 2 CH 3(CH 2)8 CH 2 1. Na. OCH 2 CH 3 2. CH 3(CH 2)8 CH 2 Br O O CH 3 CH 2 OCCHCOCH 2 CH 3

Dialkylation O O CH 3 CH 2 OCCCOCH 2 CH 3(CH 2)8 CH 2 CH 3 1. Na. OH, H 2 O 2. H+ 3. heat, -CO 2 O CH 3(CH 2)8 CH 2 CHCOH CH 3 (61 -74%)

Another Example O O CH 3 CH 2 OCCH 2 COCH 2 CH 3 1. Na. OCH 2 CH 3 2. Br. CH 2 CH 2 Br O O CH 3 CH 2 OCCHCOCH 2 CH 3 CH 2 CH 2 Br

Another Example This product is not isolated, but cyclizes in the presence of sodium ethoxide. O O CH 3 CH 2 OCCHCOCH 2 CH 3 CH 2 CH 2 Br

Another Example O O CH 3 CH 2 OCCCOCH 2 CH 3 H 2 C CH 2 (60 -65%) C H 2 Na. OCH 2 CH 3 O O CH 3 CH 2 OCCHCOCH 2 CH 3 CH 2 CH 2 Br

Another Example O O CH 3 CH 2 OCCCOCH 2 CH 3 H 2 C CH 2 C H 2 H 1. Na. OH, H 2 O 2. H+ 3. heat, -CO 2 H C H 2 C CH 2 C H 2 (80%)