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21.9 Michael Additions of Stabilized Anions

21.9 Michael Additions of Stabilized Anions. O. O. C. C. ••. H 3 C. C. OCH 2 CH 3. –. H. O. O. C. C. ••. C. OCH 2 CH 3. CH 3 CH 2 O. –. H. Stabilized Anions. The anions derived by deprotonation of  -keto esters and diethyl malonate are weak bases.

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21.9 Michael Additions of Stabilized Anions

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  1. 21.9Michael Additions of Stabilized Anions

  2. O O C C •• H3C C OCH2CH3 – H O O C C •• C OCH2CH3 CH3CH2O – H 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.

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

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

  5. 21.10Reactions of LDA-Generated Ester Enolates

  6. 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?

  7. 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.

  8. O CH3CH2CH2COCH3 O – + + + Li CH3CH2CHCOCH3 HN[CH(CH3)2]2 •• pKa ~ 36 Lithium diisopropylamide (LDA) • Lithium diisopropylamide converts simple esters to the corresponding enolate. + LiN[CH(CH3)2]2 pKa ~ 22

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

  10. 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%)

  11. 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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