1. 21.6 The Acetoacetic Ester Synthesis

2. 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. C C C OCH 2 CH 3 HHOO H3CH3CH3CH3C

3. Deprotonation of Ethyl Acetoacetate CH 3 CH 2 O C C C OCH 2 CH 3 HHOO H3CH3CH3CH3C + – pK a ~ 11 Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide.

4. Deprotonation of Ethyl Acetoacetate pK a ~ 16 CH 3 CH 2 O C C C OCH 2 CH 3 HHOO H3CH3CH3CH3C + C C C HOO – H3CH3CH3CH3C + CH 3 CH 2 OH – pK a ~ 11 Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide. K ~ 10 5

5. Alkylation of Ethyl Acetoacetate C C C OCH 2 CH 3 HOO – H3CH3CH3CH3C The anion of ethyl acetoacetate can be alkylated using an alkyl halide (S N 2: primary and secondary alkyl halides work best; tertiary alkyl halides undergo elimination). RX

6. Alkylation of Ethyl Acetoacetate C C C OCH 2 CH 3 HOO – H3CH3CH3CH3C The anion of ethyl acetoacetate can be alkylated using an alkyl halide (S N 2: primary and secondary alkyl halides work best; tertiary alkyl halides undergo elimination). RX C C C OCH 2 CH 3 HOO H3CH3CH3CH3C R

7. Conversion to Ketone Saponification and acidification convert the alkylated derivative to the corresponding  -keto acid. The  -keto acid then undergoes decarboxylation to form a ketone. C C C OCH 2 CH 3 HOO H3CH3CH3CH3C R C C C OH HOO H3CH3CH3CH3C R 1. HO –, H 2 O 2. H +

8. Conversion to Ketone Saponification and acidification convert the alkylated derivative to the corresponding  -keto acid. The  -keto acid then undergoes decarboxylation to form a ketone. C C C OH HOO H3CH3CH3CH3C R C CH 2 R CO 2 O H3CH3CH3CH3C +

9. Example 1. NaOCH 2 CH 3 2. CH 3 CH 2 CH 2 CH 2 Br OO CH 3 CCH 2 COCH 2 CH 3

10. Example (70%) 1. NaOCH 2 CH 3 2. CH 3 CH 2 CH 2 CH 2 Br OO CH 3 CCH 2 COCH 2 CH 3 OO CH 3 CCHCOCH 2 CH 3 CH 2 CH 2 CH 2 CH 3

11. Example (60%)O CH 3 CCH 2 CH 2 CH 2 CH 2 CH 3 1. NaOH, H 2 O 2. H + 3. heat, -CO 2 OO CH 3 CCHCOCH 2 CH 3 CH 2 CH 2 CH 2 CH 3

12. Example: Dialkylation OO CH 3 CCHCOCH 2 CH 3 CH 2 CH CH 2

13. Example: Dialkylation 1. NaOCH 2 CH 3 2. CH 3 CH 2 I OO CH 3 CCHCOCH 2 CH 3 CH 2 CH CH 2 O CH 3 CCCOCH 2 CH 3 CH 2 CH CH 2 O CH 3 CH 2 (75%)

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

15. Another Example OO H COCH 2 CH 3  -Keto esters other than ethyl acetoacetate may be used.

16. Another Example OO H COCH 2 CH 3 1. NaOCH 2 CH 3 2. H 2 C CHCH 2 Br OO CH 2 CH COCH 2 CH 3 CH 2 (89%)

17. Another Example OO COCH 2 CH 3 CH 2 CH CH 2

18. Another Example O HOO COCH 2 CH 3 CH 2 CH CH 2 1. NaOH, H 2 O 2. H + 3. heat, -CO 2 CH 2 CH CH 2 (66%)

19. 21.7 The Malonic Ester Synthesis

20. Malonic Ester Malonic ester is another name for diethyl malonate. The "malonic ester synthesis" uses diethyl malonate as a reactant for the preparation of carboxylic acids. C C C OCH 2 CH 3 HHOO CH 3 CH 2 O

21. An Analogy OO CH 3 CCH 2 COCH 2 CH 3 OO CH 3 CH 2 OCCH 2 COCH 2 CH 3 O CH 3 CCH 2 R O HOCCH 2 R The same procedure by which ethyl acetoacetate is used to prepare ketones converts diethyl malonate to carboxylic acids.

22. Example 1. NaOCH 2 CH 3 OO CH 3 CH 2 OCCH 2 COCH 2 CH 3 H2CH2CH2CH2C CHCH 2 CH 2 CH 2 Br 2. CH 2 CH 2 CH 2 CH 2 CH OO CH 3 CH 2 OCCHCOCH 2 CH 3 (85%)

23. Example (75%) 1. NaOH, H 2 O 2. H + 3. heat, -CO 2 CH 2 CH 2 CH 2 CH CH 2 OO CH 3 CH 2 OCCHCOCH 2 CH 3 O HOCCH 2 CH 2 CH 2 CH 2 CH CH 2

24. Dialkylation 1. NaOCH 2 CH 3 OO CH 3 CH 2 OCCH 2 COCH 2 CH 3 2. CH 3 Br CH 3 OO CH 3 CH 2 OCCHCOCH 2 CH 3 (79-83%)

25. Dialkylation 1. NaOCH 2 CH 3 O O CH 3 CH 2 OCCCOCH 2 CH 3 2. CH 3 (CH 2 ) 8 CH 2 Br CH 3 CH 3 (CH 2 ) 8 CH 2 CH 3 OO CH 3 CH 2 OCCHCOCH 2 CH 3

26. DialkylationO O CH 3 CH 2 OCCCOCH 2 CH 3 CH 3 O CH 3 (CH 2 ) 8 CH 2 CHCOH CH 3 CH 3 (CH 2 ) 8 CH 2 1. NaOH, H 2 O 2. H + 3. heat, -CO 2 (61-74%)

27. Another Example 1. NaOCH 2 CH 3 OO CH 3 CH 2 OCCH 2 COCH 2 CH 3 2. BrCH 2 CH 2 CH 2 Br CH 2 CH 2 CH 2 Br OO CH 3 CH 2 OCCHCOCH 2 CH 3

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

29. Another Example NaOCH 2 CH 3 CH 2 CH 2 CH 2 Br OO CH 3 CH 2 OCCHCOCH 2 CH 3 OO CH 3 CH 2 OCCCOCH 2 CH 3 H2CH2CH2CH2C CH 2 CH2CH2CH2CH2 (60-65%)

30. Another Example OO CH 3 CH 2 OCCCOCH 2 CH 3 H2CH2CH2CH2C CH 2 CH2CH2CH2CH2 1. NaOH, H 2 O 2. H + 3. heat, -CO 2 H2CH2CH2CH2C CH 2 CH2CH2CH2CH2 CH CO 2 H (80%)