N
Li
Ph
Br
+
Pd(dba) 2 (4 mol %)
Pt-Bu 3 (8 mol %)
N
Ph
99%
toluene, DME
85 ºC
ð15Þ
N
H
H
O
TBSO
CO 2 Et
Pd(OAc) 2 (10 mol %)
Dpe-Phos (15 mol %)
90%
NH
H
H
O
TBSO
Cs 2 CO 3 toluene
100 ºC
I
CO 2 Et
ð16Þ
Barluenga and Willis have independently demonstrated that secondary amines can
be coupled with alkenyl bromides or triflates using a Pd/BINAP catalyst to generate
enamines [130–132]. Imines can also be accessed through the use of primary amines as
nucleophiles. Alkenyl chlorides or chlorodienes can be coupled with amines using
the Buchwald biaryl phosphines as ligands for palladium [133, 134]. As noted
above, these transformations have significant utility. For example, Pd-catalyzed
N-alkenylation reactions of t-butylcarbazide lead to selective reaction of the Boc
protected nitrogen atom (Eq. 17). The N
1
-Boc-N
1
-alkenylhydrazine products cannot
be prepared via condensation of t-butylcarbazide with aldehydes or ketones, as the
unsubstituted nitrogen is more nucleophilic. The observed regioselectivity in the Pdcatalyzed reactions is due to deprotonation of the NH-Boc group under the reaction
conditions, which affords the requisite intermediate palladium amido complex [135].
The related coupling of arylhydrazines with b-bromovinyl aldehydes has been
employed in the synthesis of pyrazoles ([136]; for analogous reactions of
2-bromobenzaldehyde derivatives, see [137]). The Buchwald ligands are also effective for coupling reactions of alkenyl tosylate substrates [138]. Verkade’s proazaphosphatane ligands have been used in Pd-catalyzed amination reactions with alkenyl
bromides and chlorides [139].
Br
H 2 N
H
N
Boc
+
Pd 2 (dba) 3 (2 mol %)
John-phos (8 mol %)
N
NH 2
Boc
62%
Cs 2 CO 3 , DMF
110 ºC
ð17Þ
A variety of nitrogen nucleophiles have been utilized in Pd-catalyzed
N-alkenylation reactions. For example, Bolm has employed N-alkenylation
reactions for the preparation of N-alkenyl sulfoximines (Eq. 18) [140], and
Yudin has applied this method to the synthesis of N-alkenyl aziridines (Eq. 19)
[141]. Analogous N-arylation reactions of sulfoximines and aziridines have also
been developed [142, 143]. Movassaghi has effected N-alkenylation reactions
between functionalized alkenyl triflates and several aromatic nitrogen heterocycles
including indoles and pyrroles (Eq. 20) [144]. The use of b-chloroacrolein
derivatives as substrates in N-alkenylation reactions has also been illustrated
[145, 146].
14
G.S. Lemen and J.P. Wolfe
Li
Ph
Br
+
Pd(dba) 2 (4 mol %)
Pt-Bu 3 (8 mol %)
N
Ph
99%
toluene, DME
85 ºC
ð15Þ
N
H
H
O
TBSO
CO 2 Et
Pd(OAc) 2 (10 mol %)
Dpe-Phos (15 mol %)
90%
NH
H
H
O
TBSO
Cs 2 CO 3 toluene
100 ºC
I
CO 2 Et
ð16Þ
Barluenga and Willis have independently demonstrated that secondary amines can
be coupled with alkenyl bromides or triflates using a Pd/BINAP catalyst to generate
enamines [130–132]. Imines can also be accessed through the use of primary amines as
nucleophiles. Alkenyl chlorides or chlorodienes can be coupled with amines using
the Buchwald biaryl phosphines as ligands for palladium [133, 134]. As noted
above, these transformations have significant utility. For example, Pd-catalyzed
N-alkenylation reactions of t-butylcarbazide lead to selective reaction of the Boc
protected nitrogen atom (Eq. 17). The N
1
-Boc-N
1
-alkenylhydrazine products cannot
be prepared via condensation of t-butylcarbazide with aldehydes or ketones, as the
unsubstituted nitrogen is more nucleophilic. The observed regioselectivity in the Pdcatalyzed reactions is due to deprotonation of the NH-Boc group under the reaction
conditions, which affords the requisite intermediate palladium amido complex [135].
The related coupling of arylhydrazines with b-bromovinyl aldehydes has been
employed in the synthesis of pyrazoles ([136]; for analogous reactions of
2-bromobenzaldehyde derivatives, see [137]). The Buchwald ligands are also effective for coupling reactions of alkenyl tosylate substrates [138]. Verkade’s proazaphosphatane ligands have been used in Pd-catalyzed amination reactions with alkenyl
bromides and chlorides [139].
Br
H 2 N
H
N
Boc
+
Pd 2 (dba) 3 (2 mol %)
John-phos (8 mol %)
N
NH 2
Boc
62%
Cs 2 CO 3 , DMF
110 ºC
ð17Þ
A variety of nitrogen nucleophiles have been utilized in Pd-catalyzed
N-alkenylation reactions. For example, Bolm has employed N-alkenylation
reactions for the preparation of N-alkenyl sulfoximines (Eq. 18) [140], and
Yudin has applied this method to the synthesis of N-alkenyl aziridines (Eq. 19)
[141]. Analogous N-arylation reactions of sulfoximines and aziridines have also
been developed [142, 143]. Movassaghi has effected N-alkenylation reactions
between functionalized alkenyl triflates and several aromatic nitrogen heterocycles
including indoles and pyrroles (Eq. 20) [144]. The use of b-chloroacrolein
derivatives as substrates in N-alkenylation reactions has also been illustrated
[145, 146].
14
G.S. Lemen and J.P. Wolfe