Direct Arylation via C–H Activation - New Trends in Cross-Coupling: Theory and Applications - page 567

CONHAr CONHAr

CONHAr CONHAr

Pd(OAc) 2 (10 mol%)
PCy 3 t Bu-HBF 4 (10 mo l% )

Pd(OAc) 2 (10 mol%)
PCy 3 t Bu-HBF 4 (10 mol% )

H Ar

Ar

H

Cs 2 CO 3 (3 equiv), N 2 ,
toluene, 130 °C, 48h,
ArBr (1.5 equiv)

Cs 2 CO 3 (3 equiv), N 2 ,
toluene, 130 °C, 48h,
ArBr (1.5 equiv)

N

N

N

N

Scheme 12.28 Direct arylation reactions of pyridine derivatives with amide dir-
ecting groups.

p-tol O

H O p-tol O

Pd(OAc) 2 (10 mol%)
PCy 3 t Bu-HBF 4 (10 mol% )

+

NHX + NHX

p- TolBr NHX

Cs 2 CO 3 (3 equiv) , N 2 ,
Toluene, 130 °C, 48h,
ArBr (1.5 equiv)

N

N N

H p-tol

a b

F F

X:

Me Me

F F

F

a87%
b4%

a34%
b52%

a14%
b8%

Scheme 12.29 C3 arylation reactions of pyridine derivatives and effect of directing
group.

Ar O

H O

BF 4

Pd(OAc) 2 ,PR 3
Cs 2 CO 3 ,
toluene, 130 °C

NHPh R= P

NHPh + Ar Br

Me

N

N Me Me

Scheme 12.30 C4 arylation reactions of a nicotinic acid derivative.

center. Yu and co-workers approached this problem by introducing amide as
a directing group by which they achieved a complementary regioselectivity at
C3 and C4 positions of pyridine while previously reported C2 arylation used
N-oxides to determine the site of arylation (Schemes 12.28-12.30). 54-56
The C2 arylation in the pyridine ring is a challenging task owing to the
poor electron density on this carbon center and the counterproductive co-
ordination between the metal and nitrogen atom. One way to enforce se-
lectivity is to use N-oxides in place of pyridines or by protecting/blocking
other positions that are prone to arylation/activation (Scheme 12.31). 57-59 Yu
and co-workers described the selective C3 and C4 arylation of pyridines
using amide as a directing group. 56 However, direct C3 arylation of pyr-
idines 60 would be more interesting in terms of synthetic applicability if it
could be carried out without any directing group. In this context, Yu and co-
workers reported a directing group-free C3 arylation of unprotected pyr-
idines using a simple Pd(OAc) 2 /1,10-phenanthroline catalyst

system

(Scheme 12.31).
A plausible mechanism 60 is depicted in Figure 12.11. Phenanthroline is a
strongly coordinating ligand and therefore metal-pyridine-N coordination
can be destabilized. The dissociation rate increased the local concentration