synthesis and catalytic functionalization of biologically active indoles

1 Palladium-catalyzed Coupling Reactions of Indoles 58
Table 9. Palladium-catalyzed N-arylation of indole, continued.
Entry Ar-Br R 1 R 2 NH Product Yield [%] Cond.
8 [a]
9 [c]
Br
Br
N
H
N
H
F
F
NH 2
NH 2
Br
Br
H 2N
H 2N
N
N
65 24 h,150 °C
0 24 h,180 °C
Reaction conditions: [a] Pd[P(o-tolyl)3]2Cl2, (+)-BINAP, Cs2CO3. [b] Pd[P(o-tolyl)3]2Cl2, PPh3, Cs2CO3.
[c] (+)-BINAP, Cs2CO3, without catalyst.
In contrast the reaction was completely unsuccessful at 130 °C after more than 24
h (Table 9, entry 6). The displacement of 3-fluoroaniline instead of 5-bromoindole
is not clear. Aryl fluorides have long been considered inert to palladium-catalyzed
coupling reactions. [131] Only aryl fluorides with strong electron-withdrawing
substituents give coupling reactions. [132] Just the high temperature can explain this
behavior. The attempts to couple these substrates without catalyst failed (Table 9,
entry 9). The pyridinylation of indole was also conducted in the same manner as
described above. In the reaction with 3-bromopyridine and indole the coupling
product resulted in a low yield (Table 9, entry 3). Nevertheless 2-bromopyridine
gave under the same conditions an excellent yield (Table 9, entry 4). In general,
this coupling reaction was found to be temperature dependent, higher temperature
increases the yield. By raising the temperature to 180 °C, the ratio of side products
was increased. However, this method allowed the synthesis of N-(3-aminophenyl)-
5-bromoindole.
Grossman et al. described a new protocol for palladium-catalyzed Buchwald-
Hartwig amination of aryl chlorides and -bromides with benzophenone imine as
ammonia surrogate. [133] Their suggested reaction conditions are mild and were
applied to numerous sensitive starting materials. Following Scheme 47 illustrates
one indole-containing example.