Greener Approaches to Cross-Coupling - New Trends in Cross-Coupling: Theory and Applications - page 685

14.5.2 Direct Coupling by C-H Activation Under Green
Conditions
The direct arylation of arenes has been reviewed in Chapters 9 and 13. By
directly activating C-H bonds, halide and metal by-products can be avoided.
The current generation of direct C-H functionalization reactions often re-
quire stoichiometric oxidants or other additives that add to the waste output,
which may offset the advantage of using a C-H bond as the reaction site. The
use of water as a solvent in direct arylation reactions has attracted attention
recently. 206 Greaney and co-workers reported the first examples of direct
arylation using water as a solvent. 207 Aryl halides were coupled with thiazoles
using Pd(dppf)Cl 2 as the catalyst and Ag 2 CO 3 on water at 60 1C
(Scheme 14.71). The on-water reaction proceeded faster than reactions per-
formed under homogeneous conditions in acetonitrile. The authors noted
that reactions run either on water or neat had similar reaction rates, sug-
gesting the acceleration in water was really due to high local concentrations
of the water-insoluble substrates and catalyst. This methodology was ap-
plicable to other heterocyclic ring systems. 208 The proper choice of base
allowed for the selective 2- or 3-arylation of indole on water using Pd(OAc) 2 /
dppm (5 mol%) as the catalyst at 110 1C. 209 The 2-arylated product was
formed using potassium acetate, whereas lithium hydroxide preferentially
gave the 3-arylated product.
Palladium-catalyzed directed ortho-arylation of N-arylureas occurs eciently
in water at room temperature with Brij 35 (2 wt%) as surfactant
(Scheme 14.72). 210 The Brij surfactant gave superior results to PTS and other
nonionic surfactants. Addition of acetonitrile as a co-solvent shut down the
catalytic reaction. Water accelerated the coupling of aryl iodides with penta-
fluorobenzene catalyzed by Pd(OAc) 2 /MePhos [MePhos ¼ dicyclohexyl(2 0 ,6 0 -
dimethylbiphen-2-yl)phosphine] at room temperature (Scheme 14.73). 211 The
reaction required 16 h to reach completion in ethyl acetate or DMF. In con-
trast, the reaction gave higher yields after only 2 h in ethyl acetate-water
(2.5 : 1). Interestingly, increasing the water ratio lowered the reaction yield.

[Pd(DPPF)Cl 2 ]￿CHCl 3 (5 m ol%)
PPh 3 (10 m ol%)
Ag 2 CO 3 , H 2 O, 60 °C, 24 h

Ph

MeO

S

S S

Ph MeO

I

+

S

N

N

N

N

99%

Scheme 14.71

O O

MeO

HN NMe 2 Pd(OAc) 2 (10 m ol%)

AgOAc, HBF 4
Brij 35 (2 wt%), H 2 O
rt, 48 h

HN NMe 2

I

+

MeO

OMe OMe

76%

Scheme 14.72