Biomedical Engineering Reference
In-Depth Information
Substrate formation by Buchwald-Hartwig reaction
R
'
R
O
R
O
R
R
'
R
S
N
R
'
N
N
R
N
N
N
R
'
H
H
enamines
enamides
imines
sulfoximines
hydrazines
hydrazones
R
OR
NO
2
SiR
2
F
S
P(III) or (V)
enol ethers
vinyl silanes
vinyl nitro
vinyl fluorides
vinyl thioethers vinyl phosphorus-based
compounds
Representative examples of ligands
Me
Me
Me
P
t-
Bu
2
P
PPh
2
PPh
2
PCy
2
NMe
2
PCy
2
Fe
Me
P(
o-
Tol)
3
BINAP
2-Dicyclohexylphosphino-2'-
dimethylaminobiphenyl
Josiphos ligand CyPF
t-
Bu
SCHEME 3.3
3.2.4. Applications in the Synthesis of Complex
Bioactive Molecules
Soon after the seminal work by Buchwald and Hartwig, the first examples of synthetic
applications of these reactions have been employed in total synthesis to overcome
limitations of known amination processes such as nucleophilic aromatic substitution.
Selected examples are described next.
3.2.5. C-N Bond Formation
3.2.5.1. Vinyl Amination Andersen and coworkers reported the synthesis of the
antimitotic compound, desbromoceratamine A, in 2009 through a vinyl amidation/
heteroaryl amination sequence (Scheme 3.4) [19].
The main transformations in this sequence (see below) relied on an intramo-
lecular Cu(I)-catalyzed vinyl amidation reaction to form the azepine ring
(85%
yield) and an intermolecular Pd-catalyzed Buchwald-Hartwig amination reaction
between the chloroimidazole derivative
4
4
and the ammonia surrogate triphenylsily-
lamine. The free primary amine
5
was finally obtained after removal of the
triphenylsilyl group (69% yield).
3.2.5.2. Aryl Amination In 1998, Morita and coworkers used a Pd-catalyzed
intermolecular amination of tetrasubstituted benzene
6
with piperazine
7
for the
regioselective preparation of phenylpiperazine
in 94% yield (Scheme 3.5) [20]
The excellent yield was explained by the presence of the bulky benzyloxy group on the
benzene ring that disturbs the cross-coupling reaction between
8
7
and the neighboring
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