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employed copper-free conditions to couple aryl bromides at high tempera-
ture. On the other hand, Sonogashira et al. found that the addition of copper
iodide was beneficial to promote the coupling of aryl iodides at room tem-
perature. Since then, these reactions have been the most commonly em-
ployed methodologies to create sp
2
-sp bonds.
4.3.3.1 The Beginning
The first investigations of the reaction were not highly successful using
NHCs:
19b,131
the reaction only worked using activated bromides and the
expected products were obtained in only moderate yields. One of the reasons
for this poor reactivity was attributed to the formation of a by-product re-
sulting from the dimerization of the terminal alkyne under the reaction
conditions.
97,132
The first highly successful reaction was demonstrated by Caddick et al. in
2001 using complex 62,
133
allowing the coupling between a vinyl iodide and
trimethylsilylacetylene in 85% yield (Scheme 4.38).
In 2002, Yang and Nolan were also interested in investigating the utility of
Pd-NHC systems in the reaction.
134
The reactivity of in situ-generated cata-
lysts constituted of Pd(OAc)
2
(3 mol%) and NHC
HCl (6 mol%) was in-
vestigated in the coupling between the deactivated bromoanisole and
1-phenyl-2-(trimethylsilyl)acetylene. In this case, the use of a protected
terminal alkyne was found to be necessary to avoid the dimerization of the
alkyne under the reaction conditions.
132
IMes
HCl outperformed the other
NHC ligands in the reaction. Cs
2
CO
3
appeared to be the base of choice to
promote the coupling, with DMAc as the optimum solvent. Notably, Et
3
N
was found to be completely ineffective in this case. Interestingly, the use of
copper salts could be avoided in some examples. Moreover, chlorobenzene
was also successfully used in the reaction (Scheme 4.39).
Soon after the aforementioned protocol was published, Batey et al. re-
ported on the use of a well-defined N-carbamoyl-substituted Pd-NHC com-
plex in the reaction (63, Scheme 4.40).
135
Using a 1 : 1 ratio between the Pd-
NHC complex and PPh
3
, the system allowed the coupling between a range of
activated and deactivated aryl iodides and bromides with terminal alkynes.
Cs
2
CO
3
was used as the base and DMF as the solvent, in the presence of a
NN
O
t Bu
t Bu
62
O
(1 mol%)
CuI (20 mol%)
Br
Br
O
Pd
+
SiMe
3
O
Pr
2
NEt, DMF
t Bu
t Bu
N
N
85%
I
SiMe
3
62
Scheme 4.38 First highly
successful
Sonogashira
reaction using Pd-NHC
complexes.
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