Enolate Anions and Enamines Are Weak Nucleophiles, React Slowly with Α,Β-Unsaturated Carbonyl Compounds Give 1,4-Addition Products

Organic Lecture Series

EnolateEnolate AnionsAnions andand EnaminesEnamines

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

2 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 H O Ba ( OH ) O 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 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

6 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 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 Polyalkylation of Enolates: Organic Lecture Series

Kinetic vs Thermodynamic EnolOrganicates 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 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 O Li+ + 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)

14 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.

16 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%

18 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.

20 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 Organic Lecture Series Claisen Condensation

• Esters also form enolate anions which participate in nucleophilic acyl substitution

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

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.)

24 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 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 Et OC-COEt COEt

Eth yl Diethyl Diethyl ethanedioate Ethy l be n z oate 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

28 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 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

30 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. 31 See Chapter 16 for details

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

32 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 cyclohexanone (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 33

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) 34 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.

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, he a t OEt 2 OH + Et OH 4. H2 O, HCl Reaction 5: thermal decarboxylation O OO 5. heat OH + CO 2

This segment was added 36 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

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 Ethyl acetoacetate (Acetoacetic ester) CH3 CCHR A disubstituted R' acetone

38 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

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) 40 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) 41

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) 42 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 Ethyl acetoacetate (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 43

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"

44 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 45 Not exam material

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

46 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 + CO 2 COOH 5-Methoxypentanoic acid

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

48 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

49 CH3

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

50 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 51

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 + + 52 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 53

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 54 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

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

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

O O 2 . NaOEt , Et OH O (Aldol reaction) COOEt COOEt