Biomedical Engineering Reference
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NH
Pd-catalysed
amination (
Pd
)
Thermal
amination (
T
)
H
N
N
N
N
or
Cl
2HCl
NH
N
NH
2
N
N
N
NH
2
10
11
A
Norastemizole
B
F
F
F
(
Pd
) Pd
2
(dba)
3
(1.25 mol%), BINAP (3.75 mol%)
t-
BuONa (4 equiv), PhMe, 85°C
A/B
35:1 (84%)
(
T
) Glycol, K
2
CO
3
, 140°C
A/B
1:6
Cl
Pd
2
(dba)
3
BINAP,
t-
BuONa
Toluene, 90°C
Cl
Me
O
O
Me
N
N
N
O
O
N
N
N
OH
N
N
Hydroxyitraconazole
SCHEME 3.7
Syntheses of norastemizole and hydroxyitraconazole by Senanayake and
coworkers.
Senanayake and coworkers reported the synthesis of norastemizole, a non-
sedating antihistaminic agent. Interestingly, a selective arylation occurred at
the primary amine center in the presence of a secondary amine in 84% yield (ratio
A
/
B
H
35:1) (Scheme 3.7) [22]. In contrast, when the reaction was performed
under thermal conditions and in the absence of palladium, the opposite selectivity
(
1:6) was observed. The same group also described the synthesis of a hydroxy
analogue of the potent antifungal and antiyeast itraconazole via a Pd-catalyzed
amination [23].
In 2000, Kamikawa and coworkers devised an efficient route to phenazines
A
/
B
.
Construction of the azine heterocycle relied on a selective inter- and intramolecular
arylation sequence (Scheme 3.8) [24].
16
/
17
Pd(OAc)
2
BINAP
Cs
2
CO
3
PhMe
100°C
99%
MeO
2
C
CO
2
Me
Br
H
N
H
2
N
2 steps
O
O
OMe
OMe
NO
2
NO
2
Ph
Ph
12
13
14
Pd(OAc)
2
BINAP
Cs
2
CO
3
PhMe
100°C
50%
MeO
2
C
CO
2
Me
CO
2
Me
H
N
N
N
O
O
O
OMe
OMe
N
N
H
2
N
Br
Ph
Ph
Ph
15
16
Ratio
16
/
17
3:1
Phenazines
17
SCHEME 3.8
Synthesis of phenazines by Kamikawa and coworkers.
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