Chemistry Reference
In-Depth Information
11.10.4 Pictet-Spengler
tetrahydroisoquinoline synthesis
reagent. The cyclizing agent P
2
O
5
also dehydrates the
intermediate hydroxyamine to a dihydroisoquinoline.
The isoquinoline is then obtained by heating over
a catalyst, effectively reversing a catalytic hydro-
genation reaction (see Section 9.4.3), facilitated by
the generation of aromaticity in the product. As
in the Skraup synthesis above, electron-withdrawing
substituents on the aromatic ring will deactivate
it towards electrophilic attack, whereas electron-
donating substituents will favour the reaction.
This approach to the isoquinoline ring, albeit a
reduced isoquinoline, is mechanistically similar to
the Bischler - Napieralski synthesis, in that it involves
electrophilic attack of an iminium cation on to an
aromatic ring. In this case, the imine intermediate
is formed by reacting a phenylethylamine with an
aldehyde.
loss of proton
restores aromaticity
formation of
iminium ion
reagents
HO
HO
HO
HO
HO
NH
2
CHO
CH
3
NH
NH
NH
NH
2
CHO
H
CH
3
CH
3
CH
3
electrophilic attack
facilitated by phenol
group in para position
CH
3
We have already met this reaction as an analogue
of the Mannich reaction (see Box 10.7), which we
then interpreted as nucleophilic attack of an electron-
rich phenolic ring on to an iminium cation. Is it
electrophilic or nucleophilic? It matters little; they
are the same, though the descriptor used depends
upon which species you consider the more important,
the nucleophilic phenol or the electrophilic iminium
cation. For effective cyclization, we need an electron-
donating substituent
para
to the point of ring closure,
since the Mannich-type electrophile is less reactive
than the phosphorus-linked intermediates in the Bis-
chler - Napieralski synthesis. It is also found that a
similar group in the
ortho
position does not work,
though we could still write an acceptable mecha-
nism. With a good electron-donating substituent like
hydroxyl, the whole process, imine formation and
cyclization, can occur under 'physiological' condi-
tions, pH 6 - 7 at room temperature. In nature, this
is precisely how tetrahydroisoquinoline alkaloids are
biosynthesized, though the reactions are enzyme con-
trolled.
11.10.5 Knorr pyrrole synthesis
This approach to the five-membered pyrrole ring
reacts
-ketoester. The
mechanism will probably involve imine formation
then cyclization via an aldol-type reaction using
the enamine nucleophile. Dehydration leads to the
pyrrole. Only the key parts of this sequence are shown
below.
an
α
-aminoketone
with
a
β
imine formation
imine-enamine
tautomerism
H
CO
2
Et
Me
O
CO
2
Et
Me
O
CO
2
Et
Me
O
aldol-type reaction with enamine
nucleophile
O
Me
EtO
2
C
NH
2
EtO
2
C
N
Me
EtO
2
C
H
Me
reagents
OH
Me
CO
2
Et
Me
CO
2
Et
CO
2
Et
Me
H
+
−
O
EtO
2
C
Me
−
H
2
O
EtO
2
C
Me
EtO
2
C
Me
H
N
NH
2
O
H
