21.8 Barbiturates Barbituric acid is made from diethyl

21.8 Barbiturates Barbituric acid is made from diethyl

21.8 Barbiturates Barbituric acid is made from diethyl malonate and urea O COCH2CH3 H2N + H2C COCH2CH3 O C H2N

O Barbituric acid is made from diethyl malonate and urea O COCH2CH3 COCH2CH3 C C O N H C

O H2N O N H2C H2N + H2C H C O O

(72-78%) 1. NaOCH2CH3 2. H+ Barbituric acid is made from diethyl malonate and urea O COCH2CH3 + H2C COCH2CH3 O N H

O H2N 1. NaOCH2CH3 2. H+ N O C O H O H2N (72-78%)

Substituted derivatives of barbituric acid are made from alkylated derivatives of diethyl malonate O COCH2CH3 H2C COCH2CH3 O O 1. RX, NaOCH2CH3 R 2. R'X, R' NaOCH2CH3 COCH2CH3 C COCH2CH3 O Substituted derivatives of barbituric acid are made

from alkylated derivatives of diethyl malonate O O R H N O R' O N H (H2N)2C O R R'

COCH2CH3 C COCH2CH3 O Examples O CH3CH2 H N O CH3CH2 O N H 5,5-Diethylbarbituric acid (barbital; Veronal)

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

O CH3CH2CH2CH H2C H N O CHCH2 O N H 5-Allyl-5-(1-methylbutyl)barbituric acid (secobarbital; Seconal) 21.9 Michael Additions of Stabilized Anions

Stabilized Anions O H3C C O C C OCH2CH3 H O CH3CH2O C

O C H C OCH2CH3 The anions derived by deprotonation of -keto esters and diethyl malonate are weak bases. Weak bases react with ,unsaturated carbonyl compounds by conjugate

addition. Example O O O CH3CH2OCCH2COCH2CH3 + H2C CHCCH3 Example O O O

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

CH3CCH2CH2CH2COH (42%) 1. KOH, ethanol-water 2. H+ 3. heat O O CH3CH2OCCHCOCH2CH3 CH2CH2CCH3 O 21.10 -Deprotonation of Carbonyl Compounds by Lithium Dialkylamides 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? Lithium diisopropylamide Li + CH3 H C CH3

N CH3 C H CH3 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. Lithium diisopropylamide (LDA) Lithium diisopropylamide converts simple esters to the corresponding enolate.

O CH3CH2CH2COCH3 + LiN[CH(CH3)2]2 pKa ~ 22 O CH3CH2CHCOCH3 + HN[CH(CH3)2]2 pKa ~ 36 + Li + Lithium diisopropylamide (LDA) Enolates generated from esters and LDA can be

alkylated. O CH3CH2CHCOCH3 CH2CH3 O CH3CH2CHCOCH3 CH3CH2I (92%) Aldol addition of ester enolates Ester enolates undergo aldol addition to aldehydes and ketones. O CH3COCH2CH3 1. LiNR2, THF 2. (CH3)2C 3. H3O+

O HO H3C O C CH2COCH2CH3 CH3 (90%) Ketone Enolates Lithium diisopropylamide converts ketones quantitatively to their enolates. O CH3CH2CC(CH3)3 1. LDA, THF O 2. CH3CH2CH 3. H3O+

O CH3CHCC(CH3)3 HOCHCH2CH3 (81%)

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