C–H FUNCTIONALIZATION: A NEW STRATEGY FOR THE SYNTHESIS OF BIOLOGICALLY ACTIVE NATURAL PRODUCTS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 2

contributions made in the field will be highlighted, an exhaustive list of syntheses
relying on this strategy will not be made. Instead, the examples described in the
following sections have been chosen to give the reader a broad perspective of the
different strategies of C-H bond functionalization that have been applied to natural
product synthesis.

1.2. PALLADIUM(0)-CATALYZED INTRAMOLECULAR
DIRECT ARYLATION

Direct arylation constitutes an important alternative to traditional cross-coupling
reactions for the formation of biaryl bonds [8], a prevalent motif in biologically active
and medicinally relevant molecules. In direct arylation reactions, one of the preacti-
vated coupling partners, often the organometallic component, is replaced by a simple
(hetero)arene C-H bond, streamlining the overall biaryl bond forming process
(Scheme 1.1a) [9]. Several transition metals have been used to harness this reactivity,
including ruthenium, rhodium, palladium, and copper to name a few. Pd(0)-based
catalyst systems have been extensively investigated in this area due to their functional
group tolerance. Moreover, they provide the ability to use commercially available (or
easilyprepared) aryl halides as the sole preactivatedcouplingpartner in theseprocesses.
The general catalytic cycle for this transformation consists of three steps
(Scheme 1.1b): (i) oxidative addition of the aryl (pseudo)halide to a Pd(0) catalyst
generates a Pd(II) intermediate, (ii) interaction of the Pd(II) species with the (hetero)
arene C-H bond leads to C-H bond cleavage and elimination of HX, and
(iii) reductive elimination produces the biaryl product while regenerating the
Pd(0) catalyst.
The selective functionalization of an sp 2 C-H bond in (hetero)arenes containing
several potential reaction sites poses a significant challenge to direct arylation
reactions. When the electronic and/or steric properties of the substrate do not lead
to regioselective C-H bond cleavage, strategies have been developed to overcome this
hurdle. The installation of a Lewis basic directing group on the unactivated coupling
partner, which acts as a ligand for the metal, can be used to guide site-specific arene
metalation [10]. On the other hand, intramolecular reactions also eliminate some of
the problems of regioselectivity. In these cases, C-H bond functionalization is
generally governed by the size of the metalacyclic intermediate formed during the
catalytic cycle.

(a) Pd(0)-catalyzed biaryl formation (b) Pd(0)-catalyzed direct arylation (simplified catalytic cycle)

MX

cat. Pd(0)

X M

+ Ar Ar'

Ar X

Traditional
cross-coupling

Pd(0)

R R'

reductive
elimination

oxidative
addition

X = I, Br, Cl, OTf ...
M = B, Sn, Zn ...

Ar Pd Ar' Ar Pd X

R R' C-H bond

cleaving event

cat. Pd(0)

X + H

Direct arylation

R R'

H X H X H Ar'

X = I, Br, Cl, OTf ...

SCHEME 1.1 Palladium(0)-catalyzed direct arylation.