Direct Arylation via C–H Activation - New Trends in Cross-Coupling: Theory and Applications - page 564

12.2.3 Direct Arylation of Heterocycles
The first example of a direct heterocycle arylation appeared in 1989, when
Ohta and co-workers reported the C2 arylation of N-methylindole with a
pyrazine halide (Scheme 12.23). 37 Further studies demonstrated that various
p-electron-rich heterocycles can be arylated using similar reaction con-
ditions. 38-42 Mechanistically, it was generally accepted that in direct aryla-
tion reactions, p-electron-rich substrates can react via an electrophilic
palladation step and that the arylation is facilitated by the highly nucleo-
philic nature of these arenes. 43
Sames and co-workers reported a Pd-catalyzed direct C2 arylation of
N-substituted indoles with aryl iodides (Scheme 12.24). 43,44 They observed
that the selectivity can be altered from the C2 to the C3 position on
proper selection of the base and counter ion. Mechanistically, it was pro-
posed that the selectivity arises from the migration of Pd during the
metallation step. 43 Kinetic studies and isotope effects suggest an initial C3
arylation followed by deprotonation. On the other hand, the C2 regioisomer
is obtained if migration of the Pd center to C2 takes place prior to
deprotonation.
Using electrophilic arylating agents such as [Ar-I-Ar]BF 4 , Sanford and co-
workers reported a Pd-catalyzed C2 arylation of indoles in 2006
(Scheme 12.25). 45 The reaction was found to be highly C2 selective and C3
arylation was observed only when the C2 position was blocked.
A plausible mechanism involving a Pd II /Pd IV cycle was proposed. Previ-
ously, for arylation of indole, Pd II /Pd 0 was believed to be involved in the
turnover-limiting step along with a highly electron-rich phosphine ligand.
The rate of the electrophilic palladation step was proposed to increase if a

Et

Et

N

N

Pd(PPh 3 ) 4
KOAc, DMA, reflux, 12h

H

+ Cl

N
Me

N
Me

N

N

Et

Et

48%

Scheme 12.23 First example of direct heterocycle arylation.

I

Pd(OAc) 2 ,PPh 3
CsOAc, DMA, 125 °C, 24h

+

H

N
Me
88%

N
Me

I

MeMgCl
TMEDA
dioxane
65 °C, 0.5 h

N

CMe 2

Pd(OAc) 2 , PPh 3
CsOAc, DMA
125 °C, 24h

N
H

Cl

Mg

Me 2 C H

61 %

C3:C2 (14:1)

Scheme 12.24 Pd-catalyzed direct C2 arylation of an N-substituted indole with aryl
iodide.