Direct Arylation via C–H Activation - New Trends in Cross-Coupling: Theory and Applications - page 597

R 1 [Ir(cod)(py)PCy 3 ]PF 6 (5 mol%)

Ag 2 CO 3 (1.05 equiv)
m -xylene, 160 °C, 18 h

I

R 1

X

+

Ar

Ar

X

X= S, O, NR 2
R 1 ,R 2 =alkyl

31 examples
upto 87% yield

Scheme 12.89 Direct C-H arylation of heteroarenes at the 2-position.

Me

Me

S

Ar

N

O

I

Me

R

N

N

O O

H H

TAK-779

[Ir(cod)(py)PCy 3 ]PF 6 (5 mol%)
Ag 2 CO 3 (1.1 equiv)
1,4-dioxane, 165 °C, 12 h

S

Ar S

Ar +

I

7entries
upto 97% yield

OMe

1.4 equiv.

OMe

O

O

RNH 2

S

R

N

O

H

Scheme 12.90 Design of thiophene bioisosteric CCR5 receptor antagonists derived
from TAK-779.

2-position of various heterocycles with aryl iodides using Crabtree's catalyst,
[Ir(COD)(py)PCy 3 ]PF 6 (Scheme 12.89). 159 Highly substituted arenes could be
synthesized by twofold functionalization of the heteroarenes (C2 and C5).
Recently, thiophene-based TAK-779 analogs have been prepared using the
same strategy. 160 TAK-779 is a highly potent chemokine receptor 5 (CCR5) an-
tagonist with a potential application as an HIV entry inhibitor (Scheme 12.90).
When anisole was used instead of thiophene, low-yielding direct arylation
was found with an orttho:meta:para ratio of 37:17:46. This type of site se-
lectivity indicates an electrophilic metallation process. 159 Hence, first, oxi-
dative addition of aryl iodide leads to an Ir III complex and Ag 2 CO 3 serves to
abstract the iodide, to generate am Ir III -carbonate complex. The coordin-
ation of thiophene to electron-deficient Ir III was followed by electrophilic
concerted metallation-deprotonation (CMD) at the a-position of the thio-
phene ring. Finally, reductive elimination leads to the heterocyclic biaryl
product with regeneration of the Ir I species (Figure 12.24). 160,161
Following the directing group approach, an Ir/Pd co-catalyzed directed C-
H arylation with diaryliodonium regents was reported by Neufeldt and
Sanford (Scheme 12.91). 162

Pd-catalyzed directing group-assisted C-H