Chemistry Reference
In-Depth Information
significantly accelerated (reaching equilibrium in hours) by using aniline as a nucleophilic
catalyst.
[
20
]
It remains to be verified if this catalyst is compatible with
in situ
DCC; however,
we can expect that future refinements of this finding will facilitate a greater use of the
hydrazone exchange reaction in DCC drug discovery applications.
7.5 Click Chemistry - an Overview
In the past few years, there has been a flurry of activity in the literature concerning the
1,3-dipolar cycloaddition reaction (1,3-DCR) of organic azides with terminal acetylenes
yielding 1,2,3-triazoles, i.e. the Huisgen reaction.
[
21
]
This renewed interest stems largely
from the optimization of this 1,3-DCR, independently by the groups of Meldal
[
22
]
and
Sharpless,
[
23
]
with respect to ease and efficiency of catalysis and regioselectivity to form
exclusively the 1,4-disubstituted 1,2,3-triazole (or
anti
-triazole) product (Scheme 7.2).
The reaction involves a stepwise Cu(I)-catalysed dipolar cycloaddition of a terminal acet-
ylene to an organic azide. The highly exothermic and kinetically controlled reaction is
conducted favourably in water at a physiologically relevant temperature and the react-
ants are bioorthogonal to biological systems. For these reasons, the reaction is now the
premier transformation of
in situ
Click chemistry reactions, wherein complementary frag-
ments bearing either azide or acetylene moieties are combined in the presence of a target
biomolecule.
[
24
]
R N
3
R
¢
ruthenium catalyst
or G
rignard reag
ent
R
¢
Cu(I)
N
N
+
N
N
N
N
R
1,5-disubstituted 1,2,3 triazole
R
R
¢
1,4-disubstituted 1,2,3 triazole
Δ
R
¢
R
¢
N
+
N
N
N
N
R
N
R
1,4-disubstituted 1,2,3 triazole
1,5-disubstituted 1,2,3 triazole
Scheme 7.2
Synthesis of 1,2,3-triazoles by the 1,3-dipolar cycloaddition reaction of organic
azides with terminal acetylenes.
The 1,5-disubstituted 1,2,3-triazole (
syn
-triazole) regioisomer may be regioselectively
synthesized by using magnesium acetylides
[
25
]
or the more recently discovered catalysis
by ruthenium complexes.
[
26
]
Almost equimolar
syn
- and
anti
-triazole mixtures are obtained
by heating neat mixtures of the corresponding azides and alkynes at elevated temperatures
(Scheme 7.2).
[
27
]
