Biomedical Engineering Reference
In-Depth Information
macrocyclic core of cytotrienins A-D
, four powerful apoptosis-inducing
agents [52]. In the final steps of the synthesis of vasicoline, Ellman and coworkers
used a copper-catalyzed amide coupling/amide hydrolysis sequence to install the
amine function [53].
Another very elegant example of amide arylation was reported in 2007 on the
synthesis of the selective 5
57
-reductase inhibitor dutasteride (Avodar
), which is now
available for the treatment of prostate diseases [54]. The syntheses of linezolide,
toloxatone [55], and CJ-15161 [56] were accomplished via cross-coupling between
an oxazolidinone derivative and an aryl bromide in a more accessible, scalable, and
less expensive way compared to previously reported strategies.
a
3.3.5.3. Heterocycles Arylation One elegant example of a cross-coupling
reaction in which copper catalysis prevails over palladium was illustrated by Pu and
coworkers in their synthesis of a naphthalenoidH
3
antagonist (Scheme 3.25) [57]. In a
small-scale reaction, copper powder (2 equiv) in refluxing pyridine gave rise to the
desired cross-coupled compound between alcohol
58
and pyridazinone
59
with
moderate yield (
60%). Unfortunately, the same reaction was shown to be less
straightforward when multigram quantities of substrates were used. In this case, poor
reproducibility and low yields were observed. Switching to palladium catalysis gave
no better results. In spite of many combinations of catalytic systems investigated
(base, Pd source, ligand, solvent, temperature), only recovered startingmaterials were
isolated. Thus, the authors decided to reconsider novel, milder, and practical copper-
catalyzed reactions in the presence of ligands. In their case, CuCl (5 mol%) and
H
NH
Ar-X
N
Ar
X = I, Br, B(OH)
2
Br
N
CuCl,
L14
K
2
CO
3
DMF, 140°C
85%
N
HO
3 steps
N
58
N
Me
O
O
N
HN
N
HO
⋅
HBr
O
60
Naphthalenoid H
3
antagonist
59
CN
N
Cu(OAc)
2
, Py
CH
2
Cl
2
, rt
(93%)
NHMe
N
CuI,
L14
, K
2
CO
3
DMSO, 120°C
(75%)
CuI,
L11
, K
3
PO
4
dioxane, 90°C
(72%)
N
N
NH
N
N
H
Me
Me
H
N
N
N
Me
O
N
N
HO
2
C
NHMe
O
O
O
Me
CF
3
Me
AG3433
AMN107
(
±
)-Psychotrimine
SCHEME 3.25
Selected examples of Cu-mediated arylation of heterocycles.
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