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21.7 The Acetoacetic Ester Synthesis

21.7 The Acetoacetic Ester Synthesis. O. O. C. C. H 3 C. C. OCH 2 CH 3. H. H. Acetoacetic Ester. Acetoacetic ester is another name for ethyl acetoacetate . The "acetoacetic ester synthesis" uses acetoacetic ester as a reactant for the preparation of ketones. O. O. C. C. H 3 C.

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21.7 The Acetoacetic Ester Synthesis

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  1. 21.7The Acetoacetic Ester Synthesis

  2. O O C C H3C C OCH2CH3 H H Acetoacetic Ester • Acetoacetic ester is another name for ethylacetoacetate. • The "acetoacetic ester synthesis" uses acetoacetic ester as a reactant for the preparation of ketones.

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

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

  5. O O C C •• H3C C OCH2CH3 – H R X Alkylation of Ethyl Acetoacetate • 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).

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

  7. O O C C H3C C OH H R O O C C H3C C OCH2CH3 H R Conversion to Ketone • 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+

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

  9. O O CH3CCH2COCH2CH3 Example 1. NaOCH2CH3 2. CH3CH2CH2CH2Br

  10. O O CH3CCH2COCH2CH3 O O CH3CCHCOCH2CH3 CH2CH2CH2CH3 Example 1. NaOCH2CH3 2. CH3CH2CH2CH2Br (70%)

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

  12. O O CH3CCHCOCH2CH3 CH2 CH2CH Example: Dialkylation

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

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

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

  16. O O COCH2CH3 H CHCH2Br 2. H2C O O COCH2CH3 CH2 CH2CH Another Example 1. NaOCH2CH3 (89%)

  17. O CH2 CH2CH Another Example O COCH2CH3

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

  19. 21.8The Malonic Ester Synthesis

  20. O O C C C OCH2CH3 CH3CH2O H H Malonic Ester • Malonic ester is another name for diethylmalonate. • The "malonic ester synthesis" uses diethyl malonate as a reactant for the preparation of carboxylic acids.

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

  22. O O CH3CH2OCCH2COCH2CH3 H2C CHCH2CH2CH2Br O O CH3CH2OCCHCOCH2CH3 CH2 CH2CH2CH2CH Example 1. NaOCH2CH3 2. (85%)

  23. O HOCCH2CH2CH2CH2CH CH2 1. NaOH, H2O 2. H+ 3. heat, -CO2 O O CH3CH2OCCHCOCH2CH3 CH2 CH2CH2CH2CH Example (75%)

  24. O O CH3CH2OCCH2COCH2CH3 O O CH3CH2OCCHCOCH2CH3 CH3 Dialkylation 1. NaOCH2CH3 2. CH3Br (79-83%)

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

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

  27. O O CH3CH2OCCH2COCH2CH3 O O CH3CH2OCCHCOCH2CH3 CH2CH2CH2Br Another Example 1. NaOCH2CH3 2. BrCH2CH2CH2Br

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

  29. O O CH3CH2OCCCOCH2CH3 H2C CH2 CH2 O O CH3CH2OCCHCOCH2CH3 CH2CH2CH2Br Another Example (60-65%) NaOCH2CH3

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

  31. Barbiturates

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

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

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

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

  36. O O H COCH2CH3 N O (H2N)2C R R C O R' R' N COCH2CH3 H O O Substituted derivatives of barbituric acid are madefrom alkylated derivatives of diethyl malonate

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

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

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

  40. 21.9Michael Additions of Stabilized Anions

  41. O O C C •• H3C C OCH2CH3 – H O O C C •• C OCH2CH3 CH3CH2O – H 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.

  42. O O O H2C CHCCH3 CH3CH2OCCH2COCH2CH3 Example +

  43. O O O H2C CHCCH3 CH3CH2OCCH2COCH2CH3 O O CH3CH2OCCHCOCH2CH3 CH2CH2CCH3 O Example + KOH, ethanol (85%)

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

  45. 21.10 Reactions of LDA-Generated Ester EnolatesLithium diisopropylamide (LDA)

  46. 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?

  47. CH3 CH3 – + •• Li C N C H H •• CH3 CH3 Lithium diisopropylamide • 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.

  48. O CH3CH2CH2COCH3 O + Li CH3CH2CHCOCH3 Lithium diisopropylamide (LDA) • Lithium diisopropylamide converts simple esters to the corresponding enolate. + LiN[CH(CH3)2]2 pKa ~ 22 – + + HN[CH(CH3)2]2 •• pKa ~ 36

  49. O CH3CH2CHCOCH3 Lithium diisopropylamide (LDA) • Enolates generated from esters and LDA can be alkylated. O CH3CH2CHCOCH3 CH2CH3 CH3CH2I (92%) – ••

  50. O CH3COCH2CH3 2. (CH3)2C O O HO C CH2COCH2CH3 H3C CH3 Aldol addition of ester enolates • Ester enolates undergo aldol addition to aldehydes and ketones. 1. LiNR2, THF 3. H3O+ (90%)

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