The Mannich reaction involves the condensation of an enolizable carbonyl compound, an aldehyde such as formaldehyde, and an amine to form a β-amino carbonyl compound known as a Mannich base. The reaction proceeds via the initial addition of the amine to the aldehyde to form an iminium ion intermediate, which then reacts with the enol form of the carbonyl compound to eliminate a proton and form the Mannich base product. While versatile building blocks in organic synthesis, the Mannich reaction has limitations in terms of substrate scope and control of regio- and stereoselectivity. Examples of applications include the synthesis of tropinone, a precursor of atropine, as well

1. Mannich reaction
Submitted by
Akshay
M.pharm(pharmaceutical chemistry)
1st sem

2. Contents
• Introduction
• Reaction
• Mechanism
• Limitations
• Applications
• References

3. Introduction
• The Mannich reaction is the amino alkylation reaction, involving the
condensation of an enolizable carbonyl compound with a non -
enolizable aldehyde (like formaldehyde) and ammonia, or a primary
or a secondary amine to furnish a β-amino carbonyl compound, also
known as Mannich base

4. • The condensation reaction of a CH-acidic compound—e.g. a
ketone 3—with formaldehyde 1 and ammonia 2 is called the
Mannich reaction;1–5 the reaction products 4 are called
Mannich bases. The latter are versatile building blocks in
organic synthesis, and of particular importance in natural
products synthesis.

5. Mechanism
• There have been extensive investigations on the reaction
mechanism.6,7 In most cases the reaction proceeds via initial
nucleophillic addition of ammonia 2 to formaldehyde 1 to give
adduct 5, which is converted into an iminium ion species 6
(note that a resonance structure—an aminocarbenium ion can
be formulated) through protonation and subsequent loss of
water. The iminium ion species 6 then reacts with the enol 7
of the CH-acidic substrate by overall loss of a proton:

7. Limitations
• Thus the range of application is limited (e.g. confined to
amino methylation)
• In many cases undesired side products are formed
• The ability to control regio- and stereoselectivity is
generally unsatisfactory

8. Applications
HN
N
H
O
O
HN
R1
R2
HCHO
HN
N
H
O
O
N
R1
R2
O
HCHO
Me2NH
HCl
O
N
F
F
F
O
HN
fluoxetin
O
(CH2O)n/AcOH
N
H
O
N HCLHCl
HO
O
N
Tramadol

9. • The synthesis of tropinone, a precursor of atropine and
related compounds, is a classical example. In 1917 Robinson
has prepared tropinone by a Mannich reaction of
succindialdehyde and methylamine with acetone; better yields
of tropinone were obtained when he used the calcium salt of
acetonedicarboxylic acid instead of acetone.
succindialdehyde
Methyl
amine
Acetone
Tropinone

10. References
• Name reactions 2nd edition By Thomas Laue and Andreas
Plagens