Pd(0)-Catalyzed Carboiodination: Early Developments and Recent Advances - New Trends in Cross-Coupling: Theory and Applications - page 290

Pd 2 dba 3 (2.5 mol%), SPhos (7.5 mol%)
NaO t Bu (2.5 equiv),
PhMe, 80

PCy 2

R NH 2 (1.2 equiv)

MeO OMe

Br N

R

° C

Br

7.26

7.25

SPhos

Scheme 7.12 Synthesis of indoles via tandem inter- and intramolecular C-N

coupling.

intermolecular processes have been devised to achieve selective disubstitu-
tion in a one-pot protocol. 71 For example, Willis et al. developed a one-pot
method for the synthesis of indoles 7.26 via sequential inter- and intra-
molecular Buchwald-Hartwig aminations starting from arylalkenyl halides
7.25 (Scheme 7.12). 72 The amine coupling partner serves as both an external
and an internal nucleophile in this example. This particular strategy takes
advantage of the fact that intramolecular C-N coupling should occur faster
than the intermolecular process. Once the first amination has occurred at
either the aryl or vinyl bromide, the second amination is more likely to occur
intramolecularly rather than intermolecularly.

7.5.2 Tandem Cross-Couplings of gem-Dihaloolefins:
Synthesis of Benzo-Fused Heterocycles
The majority of the top-selling pharmaceuticals and bioactive natural
products contain at least one heterocyclic motif. 73 Fortunately, the advent of
modern metal-mediated cross-coupling technologies has provided a wealth
of synthetic tools to construct or derivatize heterocyclic cores. One meth-
odology utilizes 1,1- or gem-dihaloolefins, which are powerful building
blocks for the synthesis of highly substituted heterocycles and are readily
prepared via Ramirez olefination from the corresponding aldehyde pre-
cursors. 74 With a long-standing interest in domino chemistry and transition
metal-catalyzed heterocycle synthesis, Lautens and co-workers have utilized
the inherent reactivity of gem-dihaloolefins in tandem intra-/intermolecular
cross-couplings to access a variety of substituted indoles, benzofurans and
benzothiophenes. 75-81 The seminal report utilized the o-gem-dihalovinyla-
nilines 7.27 in a tandem Buchwald-Hartwig/Suzuki cross-coupling to fur-
nish 2-substituted indoles 7.31 in a single pot (Scheme 7.13). 75,76
Mechanistic studies suggest that intramolecular carbon-heteroatom coup-
ling precedes intermolecular cross-coupling, which implies selective oxida-
tive addition of Pd into the (Z)-halide of 7.27, as opposed to the more
accessible (E)-halide. 76 This tandem coupling strategy was later extended to
benzofurans and benzothiophenes. 77 Additionally, a variety of other
nucleophilic coupling partners could be used, such as terminal alkynes, 77
alkenes, 78 heteroatoms 79 and unactivated aryl groups, 80 using either Pd or