2/8/2023

Kwame Nkrumah University of

Science & Technology, Kumasi, Ghana

CHEM 353
Organic Synthesis and Spectroscopy

DR. CLEMENT OSEI AKOTO

Senior Research Scientist/Lecturer
Department of Chemistry, COS
1

Synthesis of Enamines:
Stork Enamine Reactions
O
OH
C R
C + HN R C C N
R
H R H

Aldehyde 2o Amine
R
or ketone
N R
C C + H2O

Enamine
2

2° amines most commonly used to prepare enamines

O

N N N
H H H
Pyrrolidine Piperidine Morpholine
● e.g.
O N
N
H
p-TsOH, H2O
3

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N R
(a) N-alkylated
(a) product
+X

(b) N heat
+R X

(b) N
R = H2C CH C-alkylated
R product
or Ph
+X
O
H2O
N + R
H 4

 Synthesis of b-diketones

O N O N O
N Cl
H R Cl R
p-TsOH
(enamine)

O O N O

R H2O R

 Synthesis of g-keto esters

O N OEt
Br
N
H O
p-TsOH
(enamine)

O N
OEt OEt
H2O
O O
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 Enamines can also be used in Michael additions

N EtOH N
+ CN
reflux CN

O
CN H2O

Summary of Enolate Chemistry

1. Formation of an Enolate
O O
+ :B
R R
H Resonance-
stabilized
enolate
O
H:B +
R
8

Racemization

R' O R' OH R' O

OH OH
R H
H Ph or H3O R Ph or H3O R Ph
Enol
(achiral)

Enantiomers

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Halogenation of Aldehydes & Ketones

O O
R' acid R'
R + X2 R
or base
H X
 Specific example: haloform reaction
O O
H OH X
Ph + 3 X2 Ph
H H2O X
H X
O
CHX3 +
Ph O 10

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Halogenation of Carboxylic Acids: The

HVZ Reaction

O
O 1. X2, P R
R OH
OH 2. H2O
X

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Direct Alkylation via Lithium Enolates

O O O
LDA, THF R'' X
R o R R
H(R') -78 C H(R') H(R')
(formation of the R''
kinetic enolate)

 Specific example:
O O Li O

LDA, THF CH3I

-78oC

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Direct Alkylation of Esters

O O
LDA
R R
OEt THF OEt

O R' Br

R
OEt

R'

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Acetoacetic Ester Synthesis

O O O O
1. NaOEt

OEt 2. RBr OEt

1. OH, heat R
O
2. H3O+
R
3. heat, ( CO2)

O O O O
1. tBuOK

OEt 2. R'Br OEt

R R'
R
O
1. OH, heat
R
2. H3O+
R' 3. heat, ( CO2)
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Malonic Ester Synthesis

O O O O
1. NaO Et

EtO OEt 2. RBr EtO OEt

1. O H , h eat R
O
2. H 3O +
R
HO 3 . h e a t, ( C O 2 )

O O O O
1 . tB u O K

EtO OEt 2 . R 'B r EtO OEt

R R'
R
O
1. O H , heat
R
HO 2 . H 3O +
R' 3 . h e a t, ( C O 2 )
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Stork Enamine Reaction

O NR' 2
R R + R'2 N H R

R
Enam ine
O
1. R'' Br
R R
2. heat
3. H 2 O
R''

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What to Know for Organic Synthesis

 molecular structure
 reaction mechanisms
 stereochemistry
 dependable reactions
 availability of compounds
 selectivity
 analytical methods
 lab technique
 process
 creativity
 economy 17

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Retrosynthetic Analysis – Planning the Synthesis

Example:
OH
MgBr
O
+
H

more accessible

H O

CH3MgBr +

18

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How to Plan a Grignard Synthesis

 Synthesis of

OH
Me
Me

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 Method 1
● Retrosynthetic analysis
OH
Me MgBr O
Me +
Me Me

disconnection

● Synthesis OH
MgBr O 1. Et2O Me
+ Me
+
Me Me 2. H3O
20

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 Method 2
● Retrosynthetic analysis
OH O
Me
Me Me
MeMgBr +

disconnection

● Synthesis
O OH

1. Et2O Me
Me Me
MeMgBr +
2. H3O+
21

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 Method 3
● Retrosynthetic analysis
OH disconnection O
Me
Me OEt
+ 2 MeMgBr

disconnection

● Synthesis
O OH

1. Et2O Me
OEt
Me
2. H3O+
+ 2 MeMgBr 22

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Restrictions on the Use of Grignard Reagents

 Grignard reagents are useful nucleophiles

but they are also very strong bases

 It is not possible to prepare a Grignard

reagent from a compound that contains any
hydrogen more acidic than the hydrogen
atoms of an alkane or alkene

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 A Grignard reagent cannot be prepared from a

compound containing an –OH group, an –NH–
group, an –SH group, a –CO2H group, or an –SO3H
group

 Since Grignard reagents are powerful nucleophiles,

we cannot prepare a Grignard reagent from any
organic halide that contains a carbonyl, epoxy, nitro,
or cyano (–CN) group

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 Grignard reagents cannot be prepared in the presence

of the following groups because they will react with
them:
OH, NH 2 , NHR, CO 2 H,

SO 3 H, SH, C C H,

O O O O

H, R, OR, NH 2 ,

NO 2 , C N, O

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Protecting Groups

OH
How?
I
HO HO

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 Retrosynthetic analysis
OH O
MgBr +
HO HO

disconnection
Br
HO

 However
Mg 
Br MgBr
HO Et2O H O


powerful
acidic proton
base
H
BrMg O 27

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 Need to “protect” the –OH group first

Br (protection) Br
HO "P"O

Mg, Et2O
O
OH
1.
MgBr
"P"O "P"O
2. H3O+
(no acidic OH group)
(deprotection)

OH

HO
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TBSCl
 Synthesis imidazole
Br DMF Br
HO (protection) TBSO
Me
TBSCl = tBu Si Cl Mg, Et2O
Me

Imidazole = N H MgBr
N TBSO
O
O
DMF = H Me
N 1.
Me
(a polar aprotic solvent) 2. H3O+
OH Bu4N F OH
THF
HO TBSO
(deprotection) 29

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