Reactions of Enolate Anions: Enolates + Electrophiles II 1

Condensations: Many Types, and (Other Reactions) Aldol, Claisen, Dieckmann, Acetoacetic / Malonic esters, etc. (Decarboxylation) (Acylation) (Michael Addition) (Lithium cuprates) 22

Condensation OH H C O C O A chemical definition: Addition with subsequent loss of H2O (eg. Dehydration of b-hydroxy carbonyl compounds) 12

Acylation of Ketones with Esters 3

Acylation of Ketones with Esters Esters that cannot form an enolate can be used to acylate ketone enolates. 6

Example O CH3CH2OCOCH2CH3 O + 1. NaH 2. H3O+ O COCH2CH3 (60%) 6

Example COCH2CH3 O CH3C O + 1. NaOCH2CH3 2. H3O+ O CCH2C O (62-71%) 6

Example CH3CH2CCH2CH2COCH2CH3 O 1. NaOCH3 2. H3O+ O CH3 (70-71%) 6

Ketone Synthesis via b-Keto Esters 3

Ketone Synthesis O RCH2CCHCOH R O RCH2CCH2R + CO2 b-Keto acids decarboxylate readily to give ketones. 6

Ketone Synthesis O RCH2CCHCOR' R O RCH2CCHCOH R H2O + R'OH b-Keto acids decarboxylate readily to give ketones . b-Keto acids are available by hydrolysis of b-keto esters. 6

Ketone Synthesis 2RCH2COR' O O RCH2CCHCOR' R 1. NaOR' + R'OH 2. H3O+ b-Keto acids decarboxylate readily to give ketones . b-Keto acids are available by hydrolysis of b-keto esters. b-Keto esters can be prepared by the Claisen condensation. 6

Example O 2 CH3CH2CH2CH2COCH2CH3 1. NaOCH2CH3 2. H3O+ O CH3CH2CH2CH2CCHCOCH2CH3 O CH2CH2CH3 (80%) 6

Example O CH3CH2CH2CH2CCHCOH CH2CH2CH3 1. KOH, H2O, 70-80°C 2. H3O+ O CH3CH2CH2CH2CCHCOCH2CH3 O CH2CH2CH3 6

Example O CH3CH2CH2CH2CCHCOH CH2CH2CH3 70-80°C O CH3CH2CH2CH2CCH2CH2CH2CH3 (81%) 6

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Decarboxylation of 3-Oxocarboxylic Acids

The Acetoacetic Ester Synthesis 3

Acetoacetic Ester O C H3C 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. 6

Deprotonation of Ethyl Acetoacetate OCH2CH3 H O H3C – + CH3CH2O Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide. pKa ~ 11 6

Deprotonation of Ethyl Acetoacetate OCH2CH3 H O H3C – + CH3CH2O Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide. pKa ~ 11 K ~ 105 C OCH2CH3 H O •• – H3C + CH3CH2OH pKa ~ 16 6

Alkylation of Ethyl Acetoacetate OCH2CH3 H O •• – H3C 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 X 6

Alkylation of Ethyl Acetoacetate OCH2CH3 H O •• – H3C 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 X C OCH2CH3 H O H3C R 6

Conversion to Ketone C OH H O H3C R Saponification and acidification convert the alkylated derivative to the corresponding b-keto acid. The b-keto acid then undergoes decarboxylation to form a ketone. 1. HO–, H2O 2. H+ C OCH2CH3 H O H3C R 6

Conversion to Ketone C OH H O H3C R Saponification and acidification convert the alkylated derivative to the corresponding b-keto acid. The b-keto acid then undergoes decarboxylation to form a ketone. O C + CO2 H3C CH2R 6

Example O CH3CCH2COCH2CH3 1. NaOCH2CH3 2. CH3CH2CH2CH2Br 6

Example O CH3CCH2COCH2CH3 1. NaOCH2CH3 2. CH3CH2CH2CH2Br O (70%) 6

Example O (60%) CH3CCH2CH2CH2CH2CH3 1. NaOH, H2O 2. H+ 3. heat, -CO2 O CH3CCHCOCH2CH3 CH2CH2CH2CH3 6

Example: Dialkylation CH3CCHCOCH2CH3 CH2CH CH2 6

Example: Dialkylation CH3CCHCOCH2CH3 CH2CH CH2 1. NaOCH2CH3 2. CH3CH2I O CH3CCCOCH2CH3 CH2CH CH2 CH3CH2 (75%) 6

Example: Dialkylation CH3CCH CH2CH CH2 O CH3CH2 Example: Dialkylation 1. NaOH, H2O 2. H+ 3. heat, -CO2 O CH3CCCOCH2CH3 CH2CH CH2 CH3CH2 6

Another Example O COCH2CH3 H b-Keto esters other than ethyl acetoacetate may be used. 6

Another Example O COCH2CH3 H 1. NaOCH2CH3 2. H2C CHCH2Br O COCH2CH3 (89%) 6

Another Example O O COCH2CH3 CH2CH CH2 6

Another Example O H (66%) CH2CH CH2 1. NaOH, H2O 2. H+ 3. heat, -CO2 O COCH2CH3 CH2CH CH2 6

The Malonic Ester Synthesis 3

Malonic Ester O C CH3CH2O OCH2CH3 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. 6

An Analogy O CH3CCH2COCH2CH3 O CH3CH2OCCH2COCH2CH3 O CH3CCH2R O HOCCH2R The same procedure by which ethyl acetoacetate is used to prepare ketones converts diethyl malonate to carboxylic acids. 6

Example O CH3CH2OCCH2COCH2CH3 1. NaOCH2CH3 2. H2C CHCH2CH2CH2Br CH2 (85%) 6

Example O HOCCH2CH2CH2CH2CH CH2 (75%) 1. NaOH, H2O 2. H+ 3. heat, -CO2 CH3CH2OCCHCOCH2CH3 6

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Dialkylation O CH3CH2OCCH2COCH2CH3 1. NaOCH2CH3 2. CH3Br CH3 O (79-83%) 6

Dialkylation O O CH3CH2OCCCOCH2CH3 CH3(CH2)8CH2 CH3 1. NaOCH2CH3 2. CH3(CH2)8CH2Br CH3 O CH3CH2OCCHCOCH2CH3 6

Dialkylation O O CH3CH2OCCCOCH2CH3 CH3(CH2)8CH2 CH3 1. NaOH, H2O 2. H+ 3. heat, -CO2 O CH3(CH2)8CH2CHCOH (61-74%) CH3 6

Another Example O CH3CH2OCCH2COCH2CH3 1. NaOCH2CH3 2. BrCH2CH2CH2Br O 6

Another Example This product is not isolated, but cyclizes in the presence of sodium ethoxide. CH2CH2CH2Br O CH3CH2OCCHCOCH2CH3 6

Another Example O CH3CH2OCCCOCH2CH3 H2C CH2 C H2 (60-65%) NaOCH2CH3 CH2CH2CH2Br O CH3CH2OCCHCOCH2CH3 6

Another Example O CH3CH2OCCCOCH2CH3 H2C CH2 C H2 1. NaOH, H2O 2. H+ 3. heat, -CO2 H2C CH2 C H2 C H CO2H (80%) 6

Barbiturates 3

Barbituric acid is made from diethyl malonate and urea H2C O COCH2CH3 C H2N O + 6

Barbituric acid is made from diethyl malonate and urea H2C O COCH2CH3 C H2N O + H2C O C N H 1. NaOCH2CH3 2. H+ (72-78%) 6

Barbituric acid is made from diethyl malonate and urea H2C O COCH2CH3 C H2N O + H O N 1. NaOCH2CH3 2. H+ O N O (72-78%) H 6

Substituted derivatives of barbituric acid are made from alkylated derivatives of diethyl malonate H2C O COCH2CH3 C O COCH2CH3 R R' 1. RX, NaOCH2CH3 2. R'X, NaOCH2CH3 6

Substituted derivatives of barbituric acid are made from alkylated derivatives of diethyl malonate COCH2CH3 R R' O N H R R' (H2N)2C O 6

5,5-Diethylbarbituric acid (barbital; Veronal) Examples O N H CH3CH2 5,5-Diethylbarbituric acid (barbital; Veronal) 6

5-Ethyl-5-(1-methylbutyl)barbituric acid (pentobarbital; Nembutal) Examples CH3CH2CH2CH H3C O H N O CH3CH2 N H O 5-Ethyl-5-(1-methylbutyl)barbituric acid (pentobarbital; Nembutal) 6

5-Allyl-5-(1-methylbutyl)barbituric acid (secobarbital; Seconal) Examples CH3CH2CH2CH H3C O H N O CHCH2 H2C N H O 5-Allyl-5-(1-methylbutyl)barbituric acid (secobarbital; Seconal) 6

Addition of Carbanions to a,b-Unsaturated Carbonyl Compounds: The Michael Reaction 1

Michael Addition Stabilized carbanions, such as those derived from b-diketones undergo conjugate addition to a,b-unsaturated ketones. 11

Example CH3 O O H2C CHCCH3 + KOH, methanol O CH3 CH2CH2CCH3 (85%) 20

The Stork Enamine Reaction Enamines are used in place of enolates in Michael reactions

Michael Addition The Michael reaction is a useful method for forming carbon-carbon bonds. It is also useful in that the product of the reaction can undergo an intramolecular aldol condensation to form a six-membered ring. One such application is called the Robinson annulation. 11

not isolated; dehydrates under reaction conditions Example O CH3 CH2CH2CCH3 OH O CH3 NaOH heat not isolated; dehydrates under reaction conditions 20

Example O CH3 CH2CH2CCH3 OH O CH3 NaOH heat O CH3 (85%) 20

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Michael Additions of Stabilized Anions 3

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Stabilized Anions The anions derived by deprotonation of b-keto esters and diethyl malonate are weak bases. Weak bases react with a,b-unsaturated carbonyl compounds by conjugate addition. C OCH2CH3 H O •• – H3C C OCH2CH3 H O CH3CH2O •• – 6

Example O CH3CH2OCCH2COCH2CH3 H2C CHCCH3 O + 6

Example O CH3CH2OCCH2COCH2CH3 H2C CHCCH3 O + KOH, ethanol CH2CH2CCH3 O (85%) 6

Example CH3CCH2CH2CH2COH O O (42%) 1. KOH, ethanol-water 2. H+ 3. heat CH2CH2CCH3 O CH3CH2OCCHCOCH2CH3 6

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Conjugate Addition of Organocopper Reagents to a,b-Unsaturated Carbonyl Compounds 1

Addition of Organocopper Reagents to a,b-Unsaturated Aldehydes and Ketones The main use of organocopper reagents is to form carbon-carbon bonds by conjugate addition to a,b-unsaturated ketones. 11

O CH3 Example + LiCu(CH3)2 1. diethyl ether 2. H2O O CH3 (98%) 21