Pd(0)-Catalyzed Carboiodination: Early Developments and Recent Advances - New Trends in Cross-Coupling: Theory and Applications - page 293

7.5.4 Further Investigation into the Synthesis of Halogenated
Indoles: Importance of Reversible Oxidative Addition
As mentioned previously, the selectivity-determining step in most regiose-
lective cross-couplings of polyhalogenated substrates is believed to be oxi-
dative addition into the C-X bond, a generally irreversible step. This is
supported by computational studies, which reveal that oxidative addition of
palladium complexes containing simple phosphine ligands into aryl-halide
bonds is a highly exothermic process. 85 While stoichiometric studies by
Hartwig and co-workers demonstrated the feasibility of C-X reductive
elimination in the presence of P t Bu 3 , the implications and catalytic appli-
cations of this study were only realized recently by Buchwald and co-workers,
who published the first exchange reaction featuring carbon-halogen re-
ductive elimination from Pd(II) in 2009. 86 In this study, aryl triflates could be
converted into the corresponding aryl fluorides via a reductive elimination
process using CsF and a Pd catalyst (Scheme 7.16a). The authors observed
that the monoligated ArPd(II)F species could undergo reductive elimination
if t BuBrettPhos (a bulky, electron-rich monodentate phosphine ligand) was
employed. Following this seminal report, the same group reported the for-
mation of aryl and vinyl chlorides and bromides from the corresponding
triflates using similar conditions (Scheme 7.16b). 87 The proposed mech-
anism involves oxidative addition into the aryl-triflate bond followed by
ligand exchange/transmetallation with the desired halide and, finally, re-
ductive elimination to form the desired C-X bond. The use of t BuBrettPhos
as ligand is crucial, as it possesses the steric and electronic properties ideal
for carbon-halogen reductive elimination from the key ArPd(II)X complex.
Along the same theme of carbon-halogen reductive elimination, Lautens
and co-workers reported a Pd-catalyzed intramolecular C-N coupling of o-
gem-dibromoanilines providing access to 2-bromoindoles (Scheme 7.17). 1
While previous studies by the same group suggested the intermediacy of
2-bromoindole 7.29 in the Pd-catalyzed tandem C-N/C-C couplings of gem-
dihaloolefins, 75 attempts to isolate this intermediate in the absence of an
external nucleophile were unsuccessful (see Scheme 7.15). The catalytic dead
end was believed to be irreversible oxidative addition into the product C-Br

(a)

[(cinnamyl)PdCl 2 ] 2
t BuBrettPhos
PhMe, 110

OTf F

OMe

R

+ CsF R

° C

MeO P t Bu 2

i Pr i Pr

(b)

Pd 2 (dba) 3, t BuBrettPhos
KF
dioxane, 130

OTf X

i Pr
t BuBrettPhos

R + X R

° C

X = Br, Cl

Scheme 7.16 Pd-catalyzed conversion of aryl triflates to aryl halides.