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A Su a y of U eful

Tapio Nevalainen

Drug synthesis II

2012

A Summary of Useful Reactions

Reactions of alkenes

Electrophilic Addition

H3C CH2 H C

Nu

ENuE

H3C CH2 H3C

Br

H

3 2 H3C

BrH

H3C CH2 H3C

OH

H+ H+H2O

Halogenation

3

Br-Br+

Br2Br

Br

2

Reactions of alkenes

Epoxidation and ring opening

Hydroxylation

Ozonolysis O R''

HR' O

R+

Reactions of alkenesHydroboration

Mechanism

Hydrogenation

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Formation of alkenes

Dissolving Metal Reduction

Wittig reaction

Formation of alkenes

LG

D

H3C

CH3

Ph

H

D

H3CCH3

Ph

E2

B:

H3C LG

H3C CH3

H2C

CH3

CH3

E1

B:

CH3

CH3

H

+

LG = Leaving group:CF3SO2O > Ts > CH3SO2O > H2O, I- > Br- > Cl-

-

ROH

R'SO2ClR

OS

O

O R'

R' = Me (mesylate)R' = CF3 (triftlate)R' = pCH3Ph (tosylate, Ts)

poor LG good LG

B:

H

OHO

R R'

OHO-

R R'

O

R R'- OH-

aldol -unsaturatedaldehyde or ketone= enone

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Alkynes

Aromatics

NO2

Br

Nucleophilic Substitution Reactions

LG

CH3H3CCH3

Nu

H3C

Nu:-

- LGprimary and secondaryalkyl halides and sulfonates

SN2LG 3LG

H3C LG

H3C CH3

H3C

H3C CH3

Nu

SN1

Nu:-

H3C

CH3

CH3+- LG

y

tertiary alkyl halidesand sulfonates

Alkyl halides and sulfonates are formed

ROH R'SO2Cl

RO

SO

O R'

SOCl2 or

PBr3R

X

yfrom the corresponding alcohols

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Chemistry of the Carbonyl GroupOxidation and reduction

Jones (CrO3 H2SO4 acetone)

PCD = Pyridiniumdichromate [C5H6N]2 [Cr2O7]

PCD

Nucleophilic Addition

R

OH

( 3, 2 4, )

PCC = Pyridiniumchlorochromate

NaBH4 or LiAlH4

R

OH

R'

NaBH4 or LiAlH4

PCC

PCD

CR OH

R'R''

CR

OH

R'

H

Overview of Organometallic Reactions 

via imine salt

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Chemistry of the Carbonyl Group

CR

OCR

O-

O CR

O

PhCR

OH

Ph

Ph

PhMgBr+MgBr

PhMgBr

OR'

R'PhR Ph Ph

CR

O

OH

PhMgBr

O R

α,β-Unsaturated Carbonyl Compounds

Chemistry of the Carbonyl Group

•• AcetalsAcetalsO

Lewis acidor H+

OHR''2Lewis acidor H+OHOH

•• CarboxylicCarboxylic AcidAcid DerivativesDerivatives

R

O

R'

H2O, Lewisacid or H+

H2O, Lewisacid or H+

R

O

OHR

O

R

O

R

O

OR

O

R

O

Cl

Most electrophilic Least electrophilic

O NR2R

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Chemistry of the Carbonyl Group

Enolate reactions

C

O

H

:R'C

C-

O

RR:B

X2R'

CC

H

RR

enolate

XR''

RC

R

O

CR''

O

2

R'C

C

O-

RR

Alkylation of Enolates

-Halogenation

R

NucleophilicNucleophilic conjugateconjugate additionaddition

AldolAldol reactionreaction

Carbonyl Condensation Reactions• The aldol reaction

– the carbon of one carbonyl component becomes bonded to thecarbonyl carbon of the other component.

‒ Under the basic reaction conditions, the aldol product loses H2O toform an ‐unsaturated carbonyl compound

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Carbonyl Condensation Reactions

•Crossed Aldol Reactions

– Crossed aldols are synthetically useful in two different situations:

1. When only one carbonyl component has  hydrogens—such cases e o y o e ca bo y co po e as y oge s suc casesoften lead to the formation of only one product.

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Chemistry of the Carbonyl Group: Regioselective 

formation of enolates from ketones

• When an unsymmetrical carbonyl compound like 2-methylcyclohexanone is treated with base, two enolates are possible.

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• Path 1 occurs faster because it results in removal of the less hindered 2° H. Path2 results in formation of the more stable enolate. This enolate predominates atequilibrium.

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Carbonyl Condensation Reactions: Crossed Aldol Reactions

•2. When one carbonyl component has especially acidic  hydrogens, these hydrogens are more readily removed than the other H atoms. As a result, the ‐dicarbonyl compound always b h l f h ld lbecomes the enolate component of the aldol reaction.

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Carbonyl Condensation Reactions: Crossed Aldol Reactions

•Entacapone, a catechol‐O‐methyl transferase (COMT) inhibitor for th t t t f P ki ’ di i d b d ld lthe treatment of Parkinson’s disease, is prepared by crossed aldol reaction (Knoevenagel condensation).

CHO

HO

HO

NO2

+

CN

O

OHHO

HO

NO2

CN

O

NPiperidine,

CH3COOH,EtOH, 80 °C

cyanoaceticacid

HO

HO

NO2

CN

O

OH 1. SOCl2, 80°C

2. diethyl amine

entacapone

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entacapone

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Carbonyl Condensation Reactions: Intramolecular Aldol Reactions

•2,5‐hexadienone forms a five‐membered ring.

•Six‐membered rings can be formed from the intramolecular aldolreaction of 1 5 dicarbonyl compounds

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reaction of 1,5‐dicarbonyl compounds

Carbonyl Condensation Reactions: The Claisen Reaction

•A Claisen reaction is a nucleophilic substitution in which an enolate i th l hilis the nucleophile

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Carbonyl Condensation Reactions: The Crossed Claisen and 

Related Reactions

•A Claisen reaction between two different esters when only one has  hydrogens, one product is usually formed.

•A Claisen reaction between a ketone and an ester—the enolate is formed from the ketone and the ester has no hydrogens

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formed from the ketone and the ester has no  hydrogens

Carbonyl Condensation Reactions: The Crossed Claisen and 

Related Reactions

•‐Dicarbonyl compounds are also prepared by reacting an enolate with ethyl chloroformate or diethyl carbonate

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Chemistry of the Carbonyl Group: Regioselective formation of 

enolates from ketones

• A kinetic enolate is favored by a strong nonnucleophilic base like LDA,polar aprotic solvent and low temperature (‐78°C) .

• A thermodynamic enolate is favored by a strong base (NaOEt, t-BuOK) in a protic solvent (EtOH) and toom temperature (25°C).

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Carbonyl Condensation Reactions: The Crossed Claisen and 

Related Reactions

•An intramolecular Claisen reaction is called a Dieckmann reaction. Two types of diesters give good yields of cyclic products.

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Carbonyl Condensation Reactions: The Michael Reaction

•The Michael reaction involves the conjugate addition (1,4‐addition) of a enolate  to the ‐carbon of the ,‐unsaturated carbonyl compound.p

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Carbonyl Condensation Reactions: The Michael Reaction

•Michael reaction that was a key step in the synthesis of estrone, a female sex hormone

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Carbonyl Condensation Reactions: Nucleophilic Conjugate 

Addition Reactions

• -Unsaturated carbonyl compounds can potentially react with nucleophiles (amines thiols alcohols cyanide ions organocopper reagents R2CuLi and(amines, thiols, alcohols, cyanide ions , organocopper reagents R2CuLi, and enolates) at the end of the conjugated system:

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Carbonyl Condensation Reactions: The Robinson Annulation

• The Robinson annulation is a ring-forming reaction thatcombines a Michael reaction with an intramolecular aldolreaction.

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Chemistry of the Carbonyl Group: Regioselective formation of 

enolates from ketones

• An unsymmetrical ketone can be regioselectively alkylated to yieldj d tone major product.

• Treatment of 2‐methylcyclohexanone with LDA in THF solution at–78°C gives the less substituted kinetic enolate, which then reactswith CH3I to form A.

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Chemistry of the Carbonyl Group: Regioselective formation of 

enolates from ketones

•Treatment of 2‐methylcyclohexanone with NaOCH2CH3 in CH CH OH l ti t t t f thCH3CH2OH solution at room temperature forms the more substituted thermodynamic enolate, which then reacts with CH3I to form B.

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Common bases for preparing Common bases for preparing enolatesenolates

OH- CH3CH2O- (CH3)3O- Na+H-

N

H3C CH3

CH3

H3CLi

NH3C

H3CCH3

CH3

Li

Si

CH3 CH3

SiNH3C

H3CCH3

CH3

Li

lithium lithium lithium

HydroxidepKa (HB+) 15.7

EthoxidepKa (HB+) 16

t-ButoxidepKa (HB+) 18

Sodium hydridepKa (HB+) 35

lithiumdiisopropylamideLDApKa (HB+) 36

lithiumtetramethylpiperidineLTMPpKa (HB+) 37

lithiumhexamethyldisilazideLHMDSpKa (HB+) 30

SomeSome importantimportant pKapKa valuesvalues of of carbonylcarbonyl--containingcontainingmoleculesmolecules, nitro , nitro compoundscompounds and and nitrilesnitriles

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Enol equivalents : lithium enolates

•• In the presence of a very strong base such as lithium In the presence of a very strong base such as lithium diisopropyldiisopropyl amide (LDA), stable amide (LDA), stable enolatesenolates can be formedcan be formed

OOLiO OH

The lithium The lithium enolateenolate is stable at low temperature (is stable at low temperature (––78 78 °°C) but reactive enough to be useful.C) but reactive enough to be useful. Lithium Lithium enolatesenolates are the most commonly used stable are the most commonly used stable

enolateenolate equivalents in chemistryequivalents in chemistry

EE+E=alkyl halides,aldehydes, esters, etc.

ORAlkylation

Aldolreaction

R

RX

RCHO

Enol equivalents: silylsilyl enolenol ethersethers

SilylSilyl enolenol ethersethers are more stable, but less reactive, than lithium are more stable, but less reactive, than lithium enolatesenolates. .

They are made by treating an They are made by treating an enolateenolate with a silicon with a silicon electrophileelectrophile..

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Enol equivalents

•The problem of self‐condensation of carbonyl compounds can be avoided by using specific enol equivalents (lithium enolates, enamines, silyl enol ethers, aza‐enolates ).

• Use of enamines as enol equivalents (Stork enamine alkylation)

R1 OHR1 O

R1 O

R1 NR1 N

R1 NR3 R3

H2NR3H+

H+HNenol Li-enolate

enamineimine aza-enolate

BuLiorLDA

base

Li

R2 R2 R2

R2 R2 R2

Use of enamines as enol equivalents (Stork enamine alkylation)

Enol equivalents: aza‐enolates

•The aza‐enolates can be alkylated

•Mono‐protected dialdehydes can be made using aza‐enolates

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Reactions of Enolates—Malonic Ester Synthesis

•The malonic ester synthesis converts diethyl malonate to a carboxylic acid in three steps.

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Reactions of Enolates—Acetoacetic Ester Synthesis

•The acetoacetic ester synthesis is a stepwise method for converting th l t t t i t k t h i t lk lethyl acetoacetate into a ketone having one or two alkyl groups on the  carbon. Because the starting material is a ‐ketoester, the final product is a ketone, not a carboxylic acid

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Reactions of Enolates—Acetoacetic Ester Synthesis

•The steps in acetoacetic ester synthesis are exactly the same as those in the malonic ester synthesis.

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Nitriles and nitroalkanes are enolizable

•Nitriles and nitroalkanes can be alkylated and can undergo aldol‐like condensations

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Nitriles and nitroalkanes are enolizable

•Nitroalkanes are enolized to nitronates and react well with aldehydes and ketones.y

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The Mannich reaction

•Amino alkylation of an acidic proton with formaldehyde and amine. The product is known as a Mannich base 

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The Mannich reaction

• Electron-rich heterocycles such like indoles and pyrroles form Mannichbases

CH3+CH3H

•The Mannich products can be converted to enones (vinyl ketones) by alkylation with MeI and then treat the ammonium salt with base.

NH N

H

NCH3CH3

N+CH

- H+

Me2NH, CH2=O

NH

HOAc, H2O

The Mannich reaction

•In the original synthetic route of fluoxetine (4) starts with Mannichreaction of acetophenone (7) to yield the aminoketone 8.

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