t-BuO
O
OTf
MeO
OMe
+
N
H
Et
Et
O
Pd 2 (dba) 3 (7.5 mol %)
X-Phos (15 mol %)
N
Et
Et
O
t-BuO
O
MeO
OMe
95%
K 3 PO 4 , toluene
60 ºC
ð62Þ
N
Br
Me
O
CN
NH 2
F
+
Pd 2 (dba) 3 (3 mol %)
BINAP (4.5 mol %)
N
H
N
Me
O
CN
F
93%
Cs 2 CO 3 , toluene
80 ºC
ð63Þ
N
N
Br
O
O
MeO
MeO
MeO
NH 2
+
Pd(OAc) 2 (5 mol %)
BINAP (7.5 mol %)
N
N
N
H
O
O
MeO
MeO
MeO
Cs 2 CO 3 , toluene
105 ºC
62%
ð64Þ
In addition to the examples outlined above, Pd-catalyzed N-arylation reactions
have been employed in the synthesis of a number of natural products (Fig. 8), such
as the indole alkaloids anhydrolycorinone, hippadine (31), oxoassoanine, and
pratosine [329]. The N-arylation of 2-alkylpiperidines played a central role in the
synthesis of solenopsin A and dihydropinidine (32), with an N-phenyl moiety
serving as a nitrogen protecting group [330]. Other noteworthy work in this area
includes syntheses of hydroxyphenazine (33, a precursor to methanophenazine)
[331], nigellicene (34) [332], the core of nodulisporic acid A (35) [333], and
dapiramicin B (36) [334]. Additional representative applications of N-arylation
reactions towards the synthesis of pharmaceutical lead compounds, including
AMN107 (37, Ariad) [335], benzoxazine 38 (an intermediate in the preparation
of levofloxacin) [336], Lck inhibitor 39 (Amgen) [337], BMS-566419 (40, BristolMyers Squibb) [338], and KDR kinase inhibitor 41 (Merck) [339], are illustrated in
Fig. 9.
Palladium-Catalyzed sp
2 C–N Bond Forming Reactions. . .
29
O
OTf
MeO
OMe
+
N
H
Et
Et
O
Pd 2 (dba) 3 (7.5 mol %)
X-Phos (15 mol %)
N
Et
Et
O
t-BuO
O
MeO
OMe
95%
K 3 PO 4 , toluene
60 ºC
ð62Þ
N
Br
Me
O
CN
NH 2
F
+
Pd 2 (dba) 3 (3 mol %)
BINAP (4.5 mol %)
N
H
N
Me
O
CN
F
93%
Cs 2 CO 3 , toluene
80 ºC
ð63Þ
N
N
Br
O
O
MeO
MeO
MeO
NH 2
+
Pd(OAc) 2 (5 mol %)
BINAP (7.5 mol %)
N
N
N
H
O
O
MeO
MeO
MeO
Cs 2 CO 3 , toluene
105 ºC
62%
ð64Þ
In addition to the examples outlined above, Pd-catalyzed N-arylation reactions
have been employed in the synthesis of a number of natural products (Fig. 8), such
as the indole alkaloids anhydrolycorinone, hippadine (31), oxoassoanine, and
pratosine [329]. The N-arylation of 2-alkylpiperidines played a central role in the
synthesis of solenopsin A and dihydropinidine (32), with an N-phenyl moiety
serving as a nitrogen protecting group [330]. Other noteworthy work in this area
includes syntheses of hydroxyphenazine (33, a precursor to methanophenazine)
[331], nigellicene (34) [332], the core of nodulisporic acid A (35) [333], and
dapiramicin B (36) [334]. Additional representative applications of N-arylation
reactions towards the synthesis of pharmaceutical lead compounds, including
AMN107 (37, Ariad) [335], benzoxazine 38 (an intermediate in the preparation
of levofloxacin) [336], Lck inhibitor 39 (Amgen) [337], BMS-566419 (40, BristolMyers Squibb) [338], and KDR kinase inhibitor 41 (Merck) [339], are illustrated in
Fig. 9.
Palladium-Catalyzed sp
2 C–N Bond Forming Reactions. . .
29