Chemistry Reference
In-Depth Information
TBSO
TBSO
H
H
H
H
Pd(OAc)
2
DPEphos, K
2
CO
3
NH
N
CO
2
Et
Br
O
O
CO
2
Et
2.547
2.548
Scheme 2.161
NH
2
dppfPdCl
2
,
NaO
t
-Bu
N
N
N
Pd/C, MsOH,
EtOH
Br
H
NH
2
2.549
2.550
2.551
Scheme 2.162
Pd
2
(dba)
3
, BINAP,
NaO
t
-Bu, 18-Crown-6
I
N
Ph
Ph
+
HN
Ph
Ph
Br
Br
2
.
5
5
2
2
.
5
5
3
2
.
5
5
4
NH
2
H
3
O
+
Br
2.555
Scheme 2.163
and benzyl that can be easily cleaved after coupling.
196
The imine of benzophenone
2.553
has been found to
be useful despite the poor atom economy (Scheme 2.163). After coupling, the
N
-aryl imine
2.554
may be
converted to the aniline
2.555
by a number of methods including acidic hydrolysis, catalytic hydrogenation
or exchange with hydroxylamine.
197
Triflates can also be used as the substrate for this coupling reaction.
198
Benzophenone imine
2.553
has been used for the synthesis of a 5-HT
1F
receptor agonist
2.562
(Scheme 2.164)
to aminate chloropyridine
2.560
.
199
This synthesis included the use of an intramolecular Heck reaction
(Section 5.1.8) of iodopyridine
2.558
to form the furano ring.
Like the use of the imine as an ammonia surrogate, the hydrazone of benzophenone can be used as a
hydrazine surrogate (Scheme 2.165).
200
The coupling product
2.564
may be diverted directly into a Fischer
indole synthesis via hydrazone exchange with an added ketone. This pathway gives an indole
2.565
with a
free N-H. Alternatively, the available nitrogen atom may be alkylated or coupled a second time, and then
diverted into a Fisher indole synthesis. In this way, indoles with no nitrogen substituent, or an
N
-alkylated
indole
2.566
or an
N
-arylated indole
2.567
can be formed.
2.12.2 Palladium-Catalysed Synthesis of Ethers
Systems similar to those used for the formation of C-N bonds can also be applied to the formation of C-O
bonds.
201
The oxygen system is less reactive, with reductive elimination being slower, which explains why
alkoxide bases can be employed for C-N bond formation. Both alcohols
202
and phenols (Scheme 2.166)
203
can be the substrates. Intramolecular reactions (Scheme 2.167) are possible.
204
