Pd(0)-Catalyzed Carboiodination: Early Developments and Recent Advances - New Trends in Cross-Coupling: Theory and Applications - page 291

NH 2

Pd(OAc) 2 (1 mol%), SPhos (2 mol%)
K 3 PO 4 ⋅ H 2 O (5 equiv), PhB(OH) 2

Br

Ph

H

Br

PhMe, 90 ° C, 6 h

7.27

7.31

oxidative
addition

intermolecular
Suzuki reaction

PhB(OH) 2

intramolecular
C

oxidative
addition

Br

− N coupling

Br

[Pd]

[Pd]

H

H

Br Br

NH 2

7.28 7.29 7.30

Scheme 7.13 Synthesis of 2-substituted indoles via Pd-catalyzed tandem C-N/C-C

coupling of gem-dibromoolefins.

Cu catalysts. By modifying the backbone of the gem-dihaloolefins, azaindoles
and thienopyrroles could also be prepared. 81

7.5.3 Retention of Reactive Functionality: Synthesis
of Halogenated Heterocycles via Intramolecular
Cross-coupling of gem-Dihaloolefins
Halogenated heterocycles serve as particularly useful building blocks for
late-stage diversification and are present in bioactive natural products
themselves. 63b,82 While investigating the utility of gem-dihaloolefins, Lau-
tens and co-workers noted that in the absence of an external nucleophile,
entry to 2-bromoindoles 7.29 could not be achieved under the established
reaction conditions. 1 It was proposed that 2-bromoindole served as a cata-
lytic dead end via an irreversible oxidative addition process with Pd, forming
complex 7.30. If the product is more susceptible to oxidative addition than
the starting material, the Pd catalyst is rendered inactive after a single
turnover. Therefore, the external nucleophile in the tandem coupling is re-
quired to regenerate the active Pd(0) catalyst and prevent product inhibition.
The diculty in decoupling the intra- and intermolecular processes war-
ranted the development of a different catalytic system. In 2009, a mild and
site-selective approach to 2-bromobenzo-fused heterocycles from gem-
dihaloolefins via an intramolecular copper-catalyzed Ullmann-type coupling
was developed (Scheme 7.14). 83 Whereas palladium catalysis proved to be
ineffective towards this substrate class, the success of copper was thought to
originative from the precoordination of the heteroatom in the substrate to
the catalyst, which positions the (Z)-halide in close proximity for C-X
coupling. Cu(0) and Cu(II) precatalysts were also effective in the reaction.
Notably, this method allowed access to 2-halogenated benzo-fused hetero-
cycles that would be dicult to obtain via traditional protocols (i.e., aromatic