1 / 52

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.

oma
Download Presentation

21.7 The Acetoacetic Ester Synthesis

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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%)

More Related