Reactions of Enolate Anions: Enolates + Electrophiles II

1. Reactions of Enolate Anions: Enolates + Electrophiles II

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

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

4. Acylation of Ketones with Esters

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

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

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

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

9. Ketone Synthesis via b-Keto Esters

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

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

12. O O O 2RCH2COR' RCH2CCHCOR' R Ketone Synthesis 1. NaOR' • 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. + R'OH 2. H3O+

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

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

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

17. Decarboxylation of 3-Oxocarboxylic Acids

18. The Acetoacetic Ester Synthesis

19. 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.

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

21. 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

22. 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).

23. 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).

24. 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+

25. 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

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

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

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

29. O O CH3CCHCOCH2CH3 CH2 CH2CH Example: Dialkylation

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

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

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

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

34. O CH2 CH2CH Another Example O COCH2CH3

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

36. The Malonic Ester Synthesis

37. 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.

38. 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.

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

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

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

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

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

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

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

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

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

49. Barbiturates

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