Direct Arylation via C–H Activation - New Trends in Cross-Coupling: Theory and Applications - page 571

R 2

N

H

R 2

N

Y

R 3

X

X

R 3

Pd(OAc) 2 ,XPhos
K 2 CO 3 ,80-100°C

N

R 4

R 1

NN

DMF / t Bu OH ( 2: 1)

N

X=OTs,OMs

R 4

NN

R 5

R 5 H

Scheme 12.38 Arylations of heterocycles.

Br

N N

N N

PdCl(C 3 H 5 )(dppb)

+

H diethylcarbonate,

Cs 2 CO 3 ,130 ° C
17-72h

R

X

X
X=O,S,N

R

Scheme 12.39 Direct arylation of heterocycles in green media.

12.2.4 Direct C sp 3 -H Arylation
Despite the great advances in C-H activation, 4,10,68-71 C sp 3 -H bond functio-
nalization remains challenging, mainly due to some inherent limitations.
Direct arylation or functionalization of the C sp 2 -H bond is primarily facili-
tated by the interaction of stabilizing orbitals or specifically p-electrons with
the metal center that allows metal-substrate binding and C-H bond cleav-
age. Similarly the functionalization of benzylic or C sp 3 -H bonds in the a-
position to the heteroatom is facile because they are more acidic than alkyl
groups at distant positions. However, owing to the absence of these types of
orbitals or stabilizing effects in simple aliphatic systems, direct arylation of
C sp 3 -H bonds is dicult and remains underdeveloped. Also, competitive b-
hydride elimination gives rise to undesired side products and a decrease in
the catalytic eciency.
In 2005, Shabashov and Daugulis reported the use of a bidentate 8-
aminoquinoline as a directing group for Pd-catalyzed C sp 3 -H direct arylation
(Scheme 12.40). 72 They demonstrated that this directing group facilitates the
transformation by coordinating to the metal center in a bidentate fashion,
which provides stability to transient Pd IV species. Picolinic acid was also
used as the directing group for this transformation. This approach thus
offers an excellent method for the functionalization of various carboxylic
acids at the b-position by sequential amidation-C-H activation.
To probe the mechanism, they synthesized various palladacycle complexes
as possible reaction intermediates (Scheme 12.41). From the structure of
complex 1, it was evident that bi-coordination of the directing group is ne-
cessary to stabilize the metal complex. Reaction of 1 with bromine leads to a
stable Pd IV complex (2). Reaction of 1 with aryl iodide leads to arylation of