MANNICH REACTION

ketone formaldehyde

O R C

excess

O
pH 6-8

+
CH3 H

+
H

Et2NH

..

C CH2 CH2 NEt2 R

O C -.. CH2 R
A variety of R groups may be used

+ Et C N H Et

Cl

iminium salt

Mannich Base Schiffs Base

Aldehydes other than formaldehyde may be used. The reaction works best with methyl ketones. Et2NH - HCl is generally used in excess, hence the chloride counter ion. Other secondary amines sometimes work in place of diethylamine.

Activated phenols will also give a reaction similar to the Mannich Condensation.

H O

H O
-

..
H

H H

+ Et

C N Et
Mannich Base

resonance structures

AROMATIC SUBSTITUTION
H O CH2 NEt2
+

H O CH2 NEt2 H

This is essentially an electrophilic aromatic substitution reaction a hydrogen on the ring is replaced by the Mannich Base which is an electrophile.

Phenols with activating substituents (methoxy, hydroxy, amino) can give this reaction.

Cl H N OH

O C H

+ Et2NH

Cl

N Et H N C + H

: O: _ ..

..
HNEt2

Et

Mannich Base

Cl

Cl

Et Et N CH2 OH N

Et Et N CH2 H N O

B:

H+

PICTET-SPENGLER REACTION
HO HO CH2 H CH2 NH2

+
H

C O

condensation occurs at biological pH values

HO HO

CH2

HO CH2 N
+

H H

H3O+/D

HO

N H

a tetrahydroisoquinoline ring if cyclization does not occur sponttaneously

Mannich Base

This is a general method for the synthesis of tetrahydroisoquinoline rings.

BISCHLER-NAPIERALSKI REACTION
amide
H3C O CH2 H3C O CH2 NH R O C O

H3PO4 or P2O5
R

via - H2O
Cl H3C O H3C O CH2 CH2 NH2 R N H OH

synthesis of the initial amide

Intermediate loses water

Synthesis of a dihydroisoquinoline An acid anhydride may be used instead of an acid chloride to synthesize the amide.

ester-amide (urethane) .. H3C O ..

CH2 H3C O CH2 NH EtO C O H+ N H

H3PO4 or P2O5
EtO O H

H+ ethyl chloroformate
H3C O N H O

synthesis of the initial urethane

EtO H3C O

Cl

CH2

CH2 NH2