1. 21.8 Barbiturates

2. Barbituric acid is made from diethyl malonate and urea H2CH2CH2CH2CO COCH 2 CH 3 O + C H2NH2NH2NH2N O H2NH2NH2NH2N

3. H2CH2CH2CH2CO O + C H2NH2NH2NH2N O H2NH2NH2NH2N 1. NaOCH 2 CH 3 2. H + H2CH2CH2CH2COC C O C N O N H H (72-78%) Barbituric acid is made from diethyl malonate and urea

4. H2CH2CH2CH2CO COCH 2 CH 3 O + C H2NH2NH2NH2N O H2NH2NH2NH2N 1. NaOCH 2 CH 3 2. H + O O N O N H H (72-78%) Barbituric acid is made from diethyl malonate and urea

5. Substituted derivatives of barbituric acid are made from alkylated derivatives of diethyl malonate H2CH2CH2CH2CO COCH 2 CH 3 O 1. RX, NaOCH 2 CH 3 2. R'X, NaOCH 2 CH 3 CO COCH 2 CH 3 O R R'

6. Substituted derivatives of barbituric acid are made from alkylated derivatives of diethyl malonate OO N O N H H R R' CO COCH 2 CH 3 O R R' (H 2 N) 2 C O

7. ExamplesOO N O N H H CH 3 CH 2 5,5-Diethylbarbituric acid (barbital; Veronal)

8. Examples O O N O N H H CH 3 CH 2 5-Ethyl-5-(1-methylbutyl)barbituric acid (pentobarbital; Nembutal) CH 3 CH 2 CH 2 CH H3CH3CH3CH3C

9. Examples O O N O N H H 5-Allyl-5-(1-methylbutyl)barbituric acid (secobarbital; Seconal) CH 3 CH 2 CH 2 CH H3CH3CH3CH3C CHCH 2 H2CH2CH2CH2C

10. 21.9 Michael Additions of Stabilized Anions

11. Stabilized Anions The anions derived by deprotonation of  -keto esters and diethyl malonate are weak bases. Weak bases react with ,  - unsaturated carbonyl compounds by conjugate addition. C C C OCH 2 CH 3 HOO – H3CH3CH3CH3C C C C HOO CH 3 CH 2 O –

12. ExampleOO CH 3 CH 2 OCCH 2 COCH 2 CH 3 + H2CH2CH2CH2C CHCCH 3 O

13. Example KOH, ethanol OO CH 3 CH 2 OCCH 2 COCH 2 CH 3 (85%) + H2CH2CH2CH2C CHCCH 3 O CH 2 CH 2 CCH 3 OO CH 3 CH 2 OCCHCOCH 2 CH 3 O

14. Example 1. KOH, ethanol-water CH 2 CH 2 CCH 3 OO CH 3 CH 2 OCCHCOCH 2 CH 3 O 2. H + 3. heat CH 3 CCH 2 CH 2 CH 2 COH OO (42%)

15. 21.10  -Deprotonation of Carbonyl Compounds by Lithium Dialkylamides

16. 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?

17. Lithium diisopropylamide Lithium dialkylamides are strong bases (just as NaNH 2 is a very strong base). Lithium diisopropylamide is a strong base, but because it is sterically hindered, does not add to carbonyl groups. Li+ CNC HH CH 3 –

18. Lithium diisopropylamide (LDA) Lithium diisopropylamide converts simple esters to the corresponding enolate. CH 3 CH 2 CH 2 COCH 3 O+ pK a ~ 22 LiN[CH(CH 3 ) 2 ] 2 CH 3 CH 2 CHCOCH 3 O+ HN[CH(CH 3 ) 2 ] 2 – + Li+ pK a ~ 36

19. Lithium diisopropylamide (LDA) Enolates generated from esters and LDA can be alkylated. CH 3 CH 2 CHCOCH 3 O O – CH 3 CH 2 I CH 2 CH 3 (92%)

20. Aldol addition of ester enolates Ester enolates undergo aldol addition to aldehydes and ketones. CH 3 COCH 2 CH 3 O 1. LiNR 2, THF 2. (CH 3 ) 2 C O 3. H 3 O + C H3CH3CH3CH3C CH 3 HO CH 2 COCH 2 CH 3 O(90%)

21. Ketone Enolates Lithium diisopropylamide converts ketones quantitatively to their enolates. CH 3 CH 2 CC(CH 3 ) 3 O 1. LDA, THF 2. CH 3 CH 2 CH O 3. H 3 O + CH 3 CHCC(CH 3 ) 3 O HOCHCH 2 CH 3 (81%)