Chemistry Reference
In-Depth Information
the
Mannich reaction
proceeds via an intermediate iminium cation
and utilizes an enolate anion equivalent as the nucleophile
OH
O
H
3
C
H
+
H
+
HCHO
(CH
3
)
2
NH
+
NCH
2
CH
3
H
3
C
CH
3
H
3
C
aldehyde
O
H
3
C
amine
ketone
NCH
2
H
2
C
CH
3
O
OH
H
3
C
H
3
C
H
3
C
N
CH
3
N
CH
3
although it would be easier to use an
enolate anion as the nucleophile, the
reaction is conducted under mild acid
conditions, so the nucleophile cannot be
an anion and must therefore be the enol
CH
3
CH
3
N
,
N
-dimethyl-4-
aminobutan-2-one
general Mannich reaction:
amine
aldehyde (usually HCHO)
enolizable ketone
β
-aminoketone
This is a fairly general reaction, and requires an
amine plus an aldehyde (usually, but not necessarily,
formaldehyde) together with an enolizable ketone,
which
important in biochemical processes, especially in the
biosynthetic formation of alkaloids (see Box 10.7).
We shall also see several examples in heterocyclic
chemistry (see Chapter 11).
-aminoketone via an
iminium system. The Mannich reaction is surprisingly
together
generate
a
β
Box 10.6
Mannich reaction: the synthesis of tropine
The
Mannich reaction
was used for the first synthesis of
tropine
, the parent alcohol of the
tropane alkaloids
.
One of the natural tropane alkaloids used medicinally is hyoscyamine, sometimes in its racemic form atropine.
Hyoscyamine
is an anticholinergic, competing with acetylcholine for the muscarinic site of the parasympathetic
nervous system, and thus preventing the passage of nerve impulses.
CHO
H
3
C
N
H
+
Me
CH
3
NH
2
O
NCH
3
O
H
CH
2
OH
H
3
C
CHO
tropinone
O
succindialdehyde
acetone
O
NaBH
4
tropine
tropic acid
(-)-hyoscyamine
NCH
3
OH
tropine
The synthesis involved reaction of methylamine, succindialdehyde and acetone under mild acid conditions, and
although yields were poor, tropinone was formed. This could then be reduced with sodium borohydride to give
tropine.
