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21.8 Barbiturates

21.8 Barbiturates. O. COCH 2 CH 3. H 2 N. H 2 C. C. O. COCH 2 CH 3. H 2 N. O. Barbituric acid is made from diethyl malonate and urea. +. O. COCH 2 CH 3. H 2 N. H 2 C. C. O. COCH 2 CH 3. H 2 N. O. O. H. N. C. C. O. H 2 C. N. C. O. H.

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21.8 Barbiturates

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  1. 21.8Barbiturates

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

  3. 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%)

  4. 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

  5. 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

  6. 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

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

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

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

  10. 21.9Michael Additions of Stabilized Anions

  11. 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.

  12. O O O H2C CHCCH3 CH3CH2OCCH2COCH2CH3 Example +

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

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

  15. 21.10a-Deprotonation of Carbonyl Compoundsby 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. 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.

  18. 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

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

  20. 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%)

  21. O CH3CH2CC(CH3)3 O 2. CH3CH2CH O CH3CHCC(CH3)3 HOCHCH2CH3 Ketone Enolates • Lithium diisopropylamide converts ketones quantitatively to their enolates. 1. LDA, THF 3. H3O+ (81%)

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