Enolate Anions and Enamines

Organic Lecture Series

Chapter 19 1

Organic Lecture Series The Aldol Reaction

• The most important reaction of enolate anions is nucleophilic addition to the carbonyl group of another molecule of the same or different compound – although these reactions may be catalyzed by either acid or base, base catalysis is more common – The reaction results in a new C—C bond

1 Organic Lecture Series The Aldol Reaction The product of an aldol reaction is –a β-hydroxyaldehyde or a β-hydroxyketone

C H O+ R H(R') 3 OH H O + O + H3O HC C C C O R R H(R') OH- R R H(R') C OH- -hydroxycarbonyl -unsaturated carbonyl R H(R')

Frequently, there is a second, dehydration step

Organic Lecture Series The Aldol Reaction • The product of an aldol reaction is –a β-hydroxyaldehyde

O HO OH O NaOH β α CH3 -C-H + CH2 -C-H CH 3 -CH-CH2 -C-H Acetaldehyde Acetaldehyde 3-Hydroxybutanal (a β-hydroxyaldehyde; racemic) – or a β-hydroxyketone

OH O O H O Ba ( OH ) 2 β α CH3 -C-CH3 + CH2 -C-CH3 CH 3 -C-CH2 -C-CH3 CH 3 Acetone Acetone 4-Hydroxy-4-methyl-2-pentanone (a β-hydroxyketone) 4

2 Organic Lecture Series The Aldol Reaction • Base-catalyzed aldol reaction Step 1: formation of a resonance-stabilized enolate anion

- O O O - H- O + H- CH2 -C-H H- O- H + CH 2 -C-H CH 2 =C-H

pKa 20 pKa 15.7 An enolate anion (w e ak e r ac i d) (stronger acid) Step 2: carbonyl addition gives a TCAI

O O O - O CH3 -C-H + CH2 -C-H CH3 - CH- CH2 -C-H A tetrahedal carbonyl addition intermediate Step 3: proton transfer to O- completes the aldol reaction

Organic Lecture Series The Aldol Reaction-Acidic • Acid-catalyzed aldol reaction – Step 1: acid-catalyzed equilibration of keto and enol forms OOH HA CH3 -C-H CH2 =C-H – Step 2: proton transfer from HA to the carbonyl group of a second molecule of aldehyde or ketone

H O O

CH3 -C-H ++HA CH3 -C-H A

3 Organic Lecture Series The Aldol Reaction-acidic

– Step 3: attack of the enol of one molecule on the protonated carbonyl group of another molecule – Step 4: proton transfer to A- completes the reaction

H H O O OH O - + CH3 -C-H + CH 2 =C-H + :A CH3 -CH-CH2 -C-H H-A (race m i c)

(Steps 3 & 4 are combined here)

Organic Lecture Series The Aldol Products-H2O – aldol products are very easily dehydrated to α,β-unsaturated aldehydes or ketones

OHO warm in either O acid or base βα CH3 CHCH2 CH CH3 CH= CHCH+ H2 O An α,β-unsaturated aldehyde

– aldol reactions are reversible and often little aldol present at equilibrium

– Keq for dehydration is generally large – if reaction conditions bring about dehydration, good yields of product can be obtained 8

4 Organic Lecture Series Crossed Aldol Reaction

In a crossed aldol reaction, one kind of molecule provides the enolate anion and another kind provides the carbonyl group

O O O NaOH CH 3 CCH3 + HCH CH3 CCH2 CH2 OH 4-Hydroxy-2-butanone

Organic Lecture Series Crossed Aldol Reaction

Crossed aldol reactions are successful if: 1. one of the reactants has no α-hydrogen and, therefore, cannot form an enolate anion and 2. the other reactant has a more reactive carbonyl group, namely an aldehyde O CHO CH O HCH O CH O Formaldehyde Benzaldehyde Furfural 2,2-Dimethylpropanal

O O NaOH O CH 3 CCH3 + HCH CH3 CCH2 CH2 OH 4-Hydroxy-2-butanone 10

5 Polyalkylation of Enolates: Organic Lecture Series

Kinetic vs Thermodynamic EnoOrganiclates Lecture Series O-

CH3 Kinetic Enolate 1)"Less" Stable B: 2) Form with LDA O :B H H CH3

O-

CH3 Thermodynamic Enolate 1)"More" Stable 2) Form with OH- or OR- 3) Equilibrating conditions12

6 Organic Lecture Series Crossed Enolate Reactions using LDA

• With a strong enough base, enolate anion formation can be driven to completion. • The base most commonly used for this purpose is lithium diisopropylamide, LDA. • LDA is prepared by dissolving diisopropylamine in THF and treating the solution with butyllithium.

+ - + [(CH3 ) 2 CH] 2 NH CH3 (CH2 ) 3Li [(CH3 ) 2 CH] 2 N Li + CH3 (CH2 ) 2CH3 Diisopropylamine Butyllithium Lithium diisopropylamde Butane (pKa 40 (stronger base) (weaker base) pKa 50 (stronger acid) (weaker acid)

Organic Lecture Series Crossed Enolate Reactions using LDA

• Using a molar equivalent of LDA converts an aldehyde, ketone, or ester completely to its corresponding enolate anion.

O OLi+ + CH3COC2H5 + [(CH3 ) 2 CH] 2 N Li CH2=COC2H5 + [(CH3 ) 2 CH] 2 NH Ethyl acetate Lithium Lithium enolate Diisopropylamine pKa 23 diisopropylamide (weaker base) pKa40 (stronger acid) (stronger base) (weaker acid)

7 Organic Lecture Series Crossed Enolate Reactions using LDA

• The crossed aldol reaction between acetone and an aldehyde can be carried out successfully by adding acetone to one equivalent of LDA to preform its enolate anion: O O O-Li+ OH O LDA 1.C6H5CH2CH C6H5 -78°C 2. H O Acetone Lithium 2 4-Hydroxy-5-phenyl-2-pentanone enolate (racemic) • which is then treated with the aldehyde.

Organic Lecture Series Crossed Enolate Reactions using LDA

• For ketones with two sets of nonequivalent α-hydrogens, is formation of the enolate anion regioselective? – The answer is that a high degree of regioselectivity exists and that it depends on experimental conditions.

8 Organic Lecture Series Crossed Enolate Reactions using LDA

– When 2-methylcyclohexanone is treated with a slight excess of LDA, the enolate is almost entirely the less substituted enolate anion.

slight excess of base O O-Li+ O-Li+ 0°C + [(CH ) CH] NH + LDA + 3 2 2

(racemic) 99% 1%

Organic Lecture Series Crossed Enolate Reactions using LDA

• When 2-methylcyclohexanone is treated with LDA under conditions in which the ketone is in slight excess, the product is richer in the more substituted enolate.

slight excess of the ketone O O-Li+ O-Li+ 0°C + [(CH ) CH] NH + LDA + 3 2 2

(racemic) 10% 90%

9 Organic Lecture Series Crossed Enolate Reactions using LDA

• The most important factor determining the composition of the enolate anion mixture is whether the reaction is under kinetic (rate) or thermodynamic (equilibrium) control. • Thermodynamic Control: Experimental conditions that permit establishment of equilibrium between two or more products of a reaction. The composition of the mixture is determined by the relative stabilities of the products.

Organic Lecture Series Crossed Enolate Reactions using LDA

– Equilibrium among enolate anions is established when the ketone is in slight excess, a condition under which it is possible for proton-transfer reactions to occur between an enolate anion and an α-hydrogen of an unreacted ketone. Thus, equilibrium is established between alternative enolate anions.

10 Organic Lecture Series Crossed Enolate Reactions using LDA

• Kinetic control: Experimental conditions under which the composition of the product mixture is determined by the relative rates of formation of each product. – In the case of enolate anion formation, kinetic control refers to the relative rate of removal of alternative α-hydrogens. – With the use of a bulky base, the less hindered hydrogen is removed more rapidly, and the major product is the less substituted enolate anion. – No equilibrium among alternative structures is set up.

Organic Lecture Series Intramolecular Aldol Reactions intramolecular aldol reactions are most successful for formation of five- and six- membered rings consider 2,7-octadione, which has two α-carbons O O O α α 3 1 -H O KOH 2

O HO (formed) 2,7-Octanedione O O O α 1 -H O α3 KOH 2 OH O (n ot f o rm e d) 22

11 Organic Lecture Series Claisen Condensation

•Estersalso form enolate anions which participate in nucleophilic acyl substitution

the product of a Claisen condensation is a β-ketoester: O O β α CCCORC

A β-ketoester 23

Organic Lecture Series Claisen Condensation

– Claisen condensation of ethyl propanoate gives this β-ketoester

O O O O - + 1. EtO Na OEt + OEt OEt + Et OH 2. H2 O, HCl Ethyl Ethyl Ethyl 2-methyl-3- propanoate propanoate oxopentanoate (racemic)

Nota bene: the base should be the alkoxide of the ester group (This will overcome trans-esterification.)

12 Organic Lecture Series Claisen Condensation Step 1: formation of an enolate anion

O - O - O - Et O + H CH 2 -COEt Et OH+ CH 2 -COEt CH 2 =COEt

pKa = 22 pKa 15.9 Resonance-stabilized enolate anion (weaker acid) (stronger acid)

Step 2: attack of the enolate anion on a carbonyl carbon gives a TCAI

- O O O O CH3 -C-OEt + CH2 -COEt CH3 -C-CH2 -C-OEt OEt

A tetrahedral carbonyl 25 addition intermediate

Organic Lecture Series Claisen Condensation Step 3: collapse of the TCAI gives a β-ketoester and an alkoxide ion:

O O OO + CH3 -C-CH2 -C-OEt CH3 -C-CH2 -C-OEt Et O OEt

Step 4: an acid-base reaction drives the reaction to completion:

OO O O + Et O + CH3 - C-CH- C-OEt CH 3 -C- CH- C-OEt Et OH H pK 15.9 pKa 10.7 a (stronger acid) (weaker acid)26

13 Organic Lecture Series Crossed Claisen Condensations Crossed Claisen condensations between two different esters, each with α-hydrogens, give mixtures of products and are not useful – crossed Claisen condensations are useful, if there is an appreciable difference in reactivity between the two esters; when one of them has no α-hydrogens

O O O O O HCOEt EtOCOEt EtOC-COEt COEt

Eth yl Diethyl Diethyl ethanedioate Ethyl benzoate formate carbonate (Diethyl oxalate)

Organic Lecture Series Crossed Claisen Condensations

– the ester with no α-hydrogens is generally used in excess

OO O O - + 1. CH O Na + 3 Ph OCH3 Ph OCH3 OCH3 2. H2 O, HCl Methyl Methyl Methyl 2-methyl-3-oxo- benzoate propanoate 3-phenylpropanoate (racemic)

Only this enolate can be formed

14 Organic Lecture Series Dieckman Condensation

• An intramolecular Claisen condensation

O - + Et O 1. EtO Na OEt 2. H O, HCl O 2 Diethyl hexanedioate O O (Diethyl adipate) OEt + Et OH

Ethyl 2-oxocyclo- pentanecarboxylate

Organic Lecture Series Carbonyl Condensations in Biochemistry • Carbonyl condensations are among the most widely used reactions in the biological world for the formation of new carbon-carbon bonds in such biomolecules as: – fatty acids. – cholesterol, bile acids, and steroid hormones. – terpenes. • One source of carbon atoms for the synthesis of these biomolecules is acetyl coenzyme A (acetyl-CoA). Coenzyme A is a carrier of the

two-carbon acetyl group, CH3-CO-

15 Organic Lecture Series Cholesterol

H3 C H C 3 H

H H HO

More details in Chap. 26 31

Biosynthesis of Steroids Organic Lecture Series

The building block from which all carbon atoms of steroids are derived is the two carbon acetyl group of acetyl-CoA- Stage 1: synthesis of isopentenyl pyrophosphate from three molecules of acetyl-CoA Stage 2: synthesis of cholesterol Stage 3: conversion of cholesterol to other steroids

bile acids (e.g., cholic acid) sex hormones (e.g., testosterone and estrone) cholesterol mineralocorticoid hormones (e.g., aldosterone)

glucocorticoid hormones (e.g., cortisone) 32

16 Organic Lecture Series Acetyl-CoA in Biochemistry

– Claisen condensation of acetyl-CoA is catalyzed by the enzyme thiolase.

O O thiolase SCoA + SCoA Clais en Acetyl-CoA Acetyl-CoA cond ensation O O SCoA + CoASH Acetoacetyl-CoA Coenzyme A

Organic Lecture Series Acetyl-CoA in Biochemistry

– This is followed by an aldol reaction with a second molecule of acetyl-CoA. Note that this reaction is stereoselective and gives only the S enantiomer.

O O O 3-hydroxy-3-methylglutaryl-CoA synthetase SCoA + SCoA Co AS H cond ensation at this carbonyl O OH O -O SCoA (S)-3-Hydroxy-3- methylglutaryl-CoA

17 Organic Lecture Series Acetyl-CoA in Biochemistry – Enzyme-catalyzed reduction by NADPH of the thioester group.

4 1 4 1 O OH O 3-hydroxy-3-methyl- O OH glutaryl-CoA reductase -O SCoA - 3 2 O 2 3 OH + (S)-3-Hydroxy-3- 2NADPH 2NADP (R)-Mevalonate methylglutaryl-CoA Phosphorylation by ATP followed by β-elimination. a phosphoric ester a pyrophosphoric ester 2- O OPO3 β-elimination 3- - 3- 3- + CO + PO OOPOP2 O6 2 O6 2 4 (R)-3-Phospho-5-pyrophospho- Isopentenyl mevalonate pyrophosphate 35

Biosynthesis of Cholesterol Organic Lecture Series O HO CH O 3 - CH3 -C-S-CoA O OH Acetyl Coenzyme A (R)-Mevalonate

3- OP2 O6 Isopentenyl pyrophosphate

C10terpenes (C10) Geranyl pyrophosphate

C15and C20 terpenes (C15) Farnesyl pyrophosphate

C30terpenes (C30) Squalene

Cholesterol 36

18 Organic Lecture Series Acetyl-CoA in Biochemistry – Enzyme-catalyzed reduction by NADPH of the thioester group.

4 1 4 1 O OH O 3-hydroxy-3-methyl- O OH glutaryl-CoA reductase -O SCoA - 3 2 O 2 3 OH + (S)-3-Hydroxy-3- 2NADPH 2NADP (R)-Mevalonate methylglutaryl-CoA

The “Statin” drugs inhibit HMGCoA Reductase and exert their action in this step

Organic Lecture Series

Atorvastatin Lipitor

Simvastatin Zocor Lovastatin Mevacor

Pravastatin Pravacol 38

19 Organic Lecture Series Enamines Enamines are formed by the reaction of a 2° amine with the carbonyl group of an aldehyde or ketone the 2° amines most commonly used to prepare enamines are pyrrolidine and morpholine:

N N H H Pyrrolidine M orpholine

Organic Lecture Series Preparation of Enamines

+ + O H H + N N N OH -H2 O H An enamine

O O O O + + H H + N N OH -H O N 2 H An enamine

Acid catalyst is usually TsOH; azeotropic removal of H2O. 40 See Chapter 16 for details

20 Organic Lecture Series Enamines-Alkylation The value of enamines is that the β-carbon is nucleophilic (same C that was α to carbonyl)

– enamines undergo SN2 reactions with methyl and 1° haloalkanes, α-haloketones, and α- haloesters

Enamines-Alkylation Organic Lecture Series treatment of the enamine with 1 eq of an alkylating agent gives an iminium halide:

O O

•• N N Br SN2 + Br

The morpholine 3-Bromopropene An iminium enamine of (Allyl bromide) bromide cyclohexan on e (racemic)

hydrolysis of the iminium halide (salt) gives the alkylated aldehyde or ketone:

O O O + N Br- + + - HCl/ H2O N Cl HH 2-Allylcyclo- Morpholinium hexanone chloride 42

21 Organic Lecture Series Enamines-Acylation enamines undergo acylation when treated with acid chlorides and acid anhydrides

N O + CH3 CCl Acetyl ch loride

+ OO - N O Cl + HCl + N Cl- H2 O HH An iminium 2-Acetylcyclo- chloride hexanone (racemic) (racemic) 43

Organic Lecture Series Synthetic Advantages of Enamines vs Enolates

1) Avoids proton transfer. 2) Regiochemistry of alkylation can be controlled. (For un-symmetric ketones) 3) Avoids polyalkylation. 4) Avoids O-alkylation.

22 Organic Lecture Series Claisen condensations as routes to ketones

Reactions 1 & 2: Claisen condensation followed by acidification O - + O O 1. EtO Na OEt OEt + Et OH 2. H2 O, HCl Reactions 3 & 4: Saponification and acidification O O O O 3. NaOH, H O, heat OEt 2 OH + Et OH 4. H2 O, HCl Reaction 5: thermal decarboxylation O OO 5. heat OH + CO 2

This segment was added 45

Organic Lecture Series Claisen condensations as routes to ketones

The result of Claisen condensation, saponification, acidification, and decarboxylation is a ketone:

from the ester from the ester furnishing the furnishing the carbonyl group enolate anion O O several O steps + R- CH2 -C + CH2 -C-OR' R- CH2 -C-CH2 -R + 2HOR' CO2 OR' R

23 Organic Lecture Series Acetoacetic Ester Synthesis

The acetoacetic ester (AAE) synthesis is useful for the preparation of mono- and disubstituted acetones of the following types

O CH3 CCH2 R A monosubstituted O O acetone CH3 CCH2 COEt O Ethy l ace to ace tate (Acetoacetic ester) CH3 CCHR A disubstituted R' acetone

Organic Lecture Series Acetoacetic Ester Synthesis – consider the AAE synthesis of this target molecule, which is a monosubstituted acetone these three carbons the -R group of a monosubstituted are from ethyl O acetoacetate acetone

5-Hexen-2-one

24 Organic Lecture Series Acetoacetic Ester Synthesis – Step 1: formation of the enolate anion of AAE

O O + + Et O- Na + Na + Et OH COOEt COOEt Ethyl acetoacetate Sodium Sodium salt Eth ano l

pKa 10.7 ethoxide of ethyl pKa 15.9 (stronger acid) acetoacetate (weaker acid)

– Step 2: alkylation with allyl bromide O O Na+ SN2 + Br + NaBr COOEt COOEt 3-Bromopropene (racemic) (Allyl bromide) 49

Organic Lecture Series Acetoacetic Ester Synthesis

– Steps 3 & 4 saponification followed by acidification O O 3. NaOH, H2 O + Et OH 4. HCl, H O COOEt 2 COOH (racemic)

– Step 5: thermal decarboxylation OO heat + CO 2 COOH 5-Hexen-2-one (a monosubstituted acetone) 50

25 Organic Lecture Series Acetoacetic Ester Synthesis – to prepare a disubstituted acetone, treat the monoalkylated AAE with a second mole of base, etc O O Na+ + Et O- Na+ + Et OH COOEt COOEt (racemic) O Na+ O SN2 + - + CH3 I + Na I COOEt COOEt (racemic) O O 3. NaOH, H2 O +COEt OH + 2 COOEt 4. HCl, H2 O 5. heat (racemic) 3-Methyl-5-hexen-2-one (racemic) 51

Organic Lecture Series Acetoacetic Ester Synthesis The acetoacetic ester (AAE) synthesis is useful for the preparation of mono- and disubstituted acetones of the following types O CH3 CCH2 R A monosubstituted O O acetone CH3 CCH2 COEt O Ethy l ace to ace tate (Acetoacetic ester) CH3 CCHR A disubstituted R' acetone O These types of reactions involve CCH3 active (i.e. acidic) methylene units as the nucleophilic component. H2C

CO2Et 52

26 Organic Lecture Series Application: Synthesis of 4,4-Disubstituted Piperidines HO

2 "O" 3 O 6 4 N CH N CH 5 3 3 1 R HO "O"

53 Not exam material CH3

Organic Lecture Series Application: Synthesis of 4,4-Disubstituted Piperidines

Cl Ph NaH CH2 N CH3 NCH3 NC CN Cl 1) NaOH 2) HCl

Ph EtOH Ph NCH3 NCH cat H+ 3 EtO2C HOOC

Meperidine ® Demerol 54 Not exam material

27 Organic Lecture Series Malonic Ester Synthesis

– treat malonic ester with an alkali metal alkoxide

Na+ COOEt COOEt + Et O- Na+ + Et OH COOEt COOEt Diethyl malonate Sodium Sodium salt of Eth ano l

pKa 13.3 ethoxide diethyl malonate pKa 15.9 (stronger acid) (weaker acid) – alkylate with 1-bromo-3-methoxy propane

Na+ COOEt S 2 N COOEt + - MeO Br + MeO+ Na Br COOEt COOEt

Organic Lecture Series Malonic Ester Synthesis – saponify and acidify

COOEt 3. NaOH, H2 O COOH MeO MeO + 2EtOH 4. HCl, H O COOEt 2 COOH

– decarboxylation

COOH heat COOH MeO MeO + CO2 COOH 5-Methoxypentanoic acid

28 Organic Lecture Series Addition to α,β-unsaturated Carbonyls When the carbonyl group is conjugated with an alkene, the two groups can act in tandem to expand synthetic utility. α,β-unsaturated carbonyl compounds can exhibit properties of both the carbonyl and alkene group:

1 3 1 3 1 3 O O O 4 4 4 2 2 2

CH3 CH3 CH3

Organic Lecture Series 1,2 Addition O O H :Nu Nu Nu CH3 CH3 3 1 O 4 δ + δ + 2

CH3 :Nu O O H

Nu CH3 Nu CH3 1,4 Addition Conjugate Addition Michael Addition Nu O

58 CH3

29 Organic Lecture Series Michael Reaction

• Michael reaction: the nucleophilic addition of an enolate anion to an α,β-unsaturated carbonyl compound (1,4 addition) –Example:

O - + O Et OOC Et O Na + EtOOC Et OH COOEt COOEt Diethyl 3-Buten-2-one propanedioate (Methyl vinyl (Diethyl malonate) ketone)

Organic Lecture Series Michael Acceptors & Nucleophiles

These Types of α,β-Unsaturated These Types of Compounds Compounds are Nucleophile Provide Effective Nucleophiles Acceptors in Michael Reactions for Michael Reactions O OO

CH2 = CHCH Aldehyde CH3 CCH2 CCH3 β-Diketone O OO β-Ketoester CH2 = CHCCH3 Ketone CH3 CCH2 COEt O O

CH2 = CHCOEt Ester CH3 CCH2 CN β-Ketonitrile O O O

CH2 = CHCNH2 Amide Et OCCH2 COEt β-Diester

CH2 =CHC N Nitrile En ami n e CH2 =CHNO2 Nitro compound N

CH3 C= CH2

NH3 , RNH2 , R2 NH Amine 60

30 Organic Lecture Series Michael Reaction

Example: O O O - + Et O Na + O COOEt Et OH Ethyl 3-oxobutanoate 2-Cyclohexenone COOEt (Ethyl acetoacetate) – the double bond of an α,β-unsaturated carbonyl compound is activated for nucleophilic attack:

O O O + + 61

Organic Lecture Series Michael Reaction

• Mechanism Step 1: proton transfer to the base

Nu-H++ :B- Nu:- H- B Base

Step 2: addition of Nu:- to the β carbon of the α,β-unsaturated carbonyl compound

O O O Nu + CCC NuC C C NuC C C

Resonance-stabilized enolate anion 62

31 Organic Lecture Series Michael Reaction Step 3: proton transfer to HB gives an enol

1 O O-H 432 NuC C C + H- B NuC C C + B

An enol (a product of 1,4-addition)

Step 4: tautomerism of the less stable enol form to the more stable keto form

O-H H O Nu C CCC Nu C C

Less stable enol form More stable keto form 63

Organic Lecture Series Michael Reaction

A final note about nucleophilic addition to α,β-unsaturated carbonyl compounds: resonance-stabilized enolate anions and enamines are weak nucleophiles, react slowly with α,β-unsaturated carbonyl compounds give 1,4-addition products

32 Organic Lecture Series Retrosynthesis of 2,6-Heptadione

these three carbons from this bond formed acetoacetic ester in a Michael reaction O O O O O O + COOEt COOH this carbon Ethyl Methyl vinyl lost by acetoacetate ketone decarboxylation

O MVK is the reagent to add a 2-oxobutyl side chain

H3C C C CH3 H2 65

Organic Lecture Series Michael-Aldol in Combination: The Robinson Ring Annulation

O O 1. NaOEt, EtOH H + COOEt (Michael reaction) 3-Buten-2-one Ethyl 2-oxocyclohex- (Methyl vinyl anecarboxylate ketone)

O O 2. NaOEt, EtOH O (Aldol reaction) COOEt COOEt