NH 2
+
N
H
Pd 2 (dba) 3 (1 mol %)
S-Phos (2 mol %)
K 3 PO 4 , toluene
90 °C
83%
Br
Br
B(OH) 2
OMe
OMe ð23Þ
Enamines generated by Pd-catalyzed coupling reactions have been employed in
several cascade processes. An interesting approach to the synthesis of indoles
involves a three-component coupling between an amine, an alkenyl halide, and a
1,2-dihalobenzene [160]. An initial N-alkenylation reaction provides an intermediate
imine, which undergoes a-arylation to yield an enamine. Intramolecular N-arylation
subsequently occurs to afford the indole product (Scheme 3). A related multicomponent reaction was reported for the generation of pyridines (Scheme 4) [161]. This
transformation proceeds via N-alkenylation of morpholine to generate an enamine,
which occurs simultaneously as desilylation and N-alkenylation of an N-silyl imine to
give a heterodiene. A [4þ2] cycloaddition followed by elimination then yields the
heterocyclic product. The Pd-catalyzed formation of enamines followed by reaction
with Michael acceptors to afford substituted malonate derivatives has also been
described [162].
3.3.2 Heteroaromatic Halides and Heteroaromatic Amines
A large number of interesting biologically active compounds and pharmaceutical
targets contain heteroaromatic groups. Thus, Pd-catalyzed N-arylation reactions
Ph
NH 2
Ph
Br
Br
Cl
BnO
+
+
Pd 2 (dba) 3 (4 mol %)
X-phos (8 mol %)
N
Ph
Ph
BnO
57%
Ph
N
Ph
Cl
BnO
Ph
NH
NaOt Bu, dioxane
100 ºC
Scheme 3 Multicomponent Synthesis of Indoles via Sequential Pd-Catalyzed C–C and C–N
Bond-Forming Reactions
Ph
Br
N
H
O
TMS N
PMP
Pd 2 (dba) 3 (1 mol %)
Dave-phos (4 mol %)
Yb(OTf) 3 (20 mol%)
+
N
Ph
Ph
PMP
55%
Ph
N
O
NaOt-Bu, toluene, 90 ºC
N
PMP
Ph
+
(2 equiv)
+
N
Ph
Ph
PMP
N
O
Scheme 4 Multicomponent Synthesis of Pyridines via Pd-Catalyzed N-alkenylation/Hetero
Diels-Alder Reactions
16
G.S. Lemen and J.P. Wolfe
+
N
H
Pd 2 (dba) 3 (1 mol %)
S-Phos (2 mol %)
K 3 PO 4 , toluene
90 °C
83%
Br
Br
B(OH) 2
OMe
OMe ð23Þ
Enamines generated by Pd-catalyzed coupling reactions have been employed in
several cascade processes. An interesting approach to the synthesis of indoles
involves a three-component coupling between an amine, an alkenyl halide, and a
1,2-dihalobenzene [160]. An initial N-alkenylation reaction provides an intermediate
imine, which undergoes a-arylation to yield an enamine. Intramolecular N-arylation
subsequently occurs to afford the indole product (Scheme 3). A related multicomponent reaction was reported for the generation of pyridines (Scheme 4) [161]. This
transformation proceeds via N-alkenylation of morpholine to generate an enamine,
which occurs simultaneously as desilylation and N-alkenylation of an N-silyl imine to
give a heterodiene. A [4þ2] cycloaddition followed by elimination then yields the
heterocyclic product. The Pd-catalyzed formation of enamines followed by reaction
with Michael acceptors to afford substituted malonate derivatives has also been
described [162].
3.3.2 Heteroaromatic Halides and Heteroaromatic Amines
A large number of interesting biologically active compounds and pharmaceutical
targets contain heteroaromatic groups. Thus, Pd-catalyzed N-arylation reactions
Ph
NH 2
Ph
Br
Br
Cl
BnO
+
+
Pd 2 (dba) 3 (4 mol %)
X-phos (8 mol %)
N
Ph
Ph
BnO
57%
Ph
N
Ph
Cl
BnO
Ph
NH
NaOt Bu, dioxane
100 ºC
Scheme 3 Multicomponent Synthesis of Indoles via Sequential Pd-Catalyzed C–C and C–N
Bond-Forming Reactions
Ph
Br
N
H
O
TMS N
PMP
Pd 2 (dba) 3 (1 mol %)
Dave-phos (4 mol %)
Yb(OTf) 3 (20 mol%)
+
N
Ph
Ph
PMP
55%
Ph
N
O
NaOt-Bu, toluene, 90 ºC
N
PMP
Ph
+
(2 equiv)
+
N
Ph
Ph
PMP
N
O
Scheme 4 Multicomponent Synthesis of Pyridines via Pd-Catalyzed N-alkenylation/Hetero
Diels-Alder Reactions
16
G.S. Lemen and J.P. Wolfe