synthesis and catalytic functionalization of biologically active indoles

1 Palladium-catalyzed Coupling Reactions of Indoles 12
Further work applying the same catalytic system to a wider array of heteroaryl
substrates was published one year later by the same workers. [37]
Buchwald and co-workers used the same reaction conditions for various indole
coupling products. Indole-derived boronic acids were investigated by several
groups, [38] but only a few protocols considered the cross coupling of heteroaryl
chlorides with these substrates. [31,34]
A wide variety of heterobiaryls in good to excellent yields were developed by the
authors (Table 3). Activated heteroaryl chlorides were successfully coupled with
indol-5-yl boronic acids by utilization of the palladium-catalyst system. N-Methyl-5indolyl
boronic acid 46 smoothly reacted with 3-chloro-2,5-dimethylpyrazine, 3chloropyridine
and 5-chloro-2-thiophenecarb-aldehyde in 90%, 77% and, 96%
yield, respectively (Table 3, entries 1-3) in the presence of Pd(OAc)2 (2 mol%, 0.25
mol% for entry 3) and ligand A (see Scheme 9). The reaction mixture was solved
in s-butanol and heated up to 100 °C for 10-18 h. Indol-5-yl boronic acid 13 was
converted with inactivated heteroaryl chlorides 47d-g (Table 3, entries 4-7) and led
to desired biaryls 48d-g in 71-91% yield. However, for reaction completion it was
necessary to increase the reaction temperature to 120 °C in the presence of 2
mol% Pd2(dba)3 and ligand B (see Scheme 9) in n-butanol. This method presented
an efficient Suzuki-Miyaura reaction of indole boronic acids with heteroaryl
chlorides.
Table 3. Suzuki-Miyaura reaction of indole boronic acids.
(HO) 2B
N
R1 13 R1 = H
46 R1 = Me
R 2 -Cl
R2 47a-g
= heteroaryl
Pd-catalyst/ligand A or B
K3PO4, nBuOH, 100 °C
R 2
48a-g
Entry Ar-Cl 47 Ligand Product 48 Yield[%]
1 a
Me
Cl
N
N
Me
A
MeN
Me
N
N
Me
N
R 1
90