Biomedical Engineering Reference
In-Depth Information
1.4. PALLADIUM(0)-CATALYZED INTRAMOLECULAR
ARYLATION OF sp
3
C-H BONDS
While numerous methods have been developed and exploited for the functionaliza-
tion of sp
2
C-Hbonds, transformations at aliphatic C-Hbonds have been significantly
less investigated. The difficulty in functionalizing these positions has been attributed
to the lack of beneficial catalyst-substrate interactions through the
p
-system of the
latter [7,30]. Reactions at aliphatic positions are also inherently more challenging due
to the possibility of by-product formation via
b
-hydride elimination [31].
Pd(0)-catalyzed arylation of “unactivated” [32] sp
3
C-H bonds generally
involves intramolecular processes, not only to avoid problems of regioselectivity
(see Section 1.2) but also to promote interactions between the catalyst and the
C-H bond by limiting the degree of freedom in the system [1k,33]. Pioneering work
by Dyker demonstrated that oxidative addition of a Pd(0) catalyst into an aryl halide
bond, which lies in close proximity to the aliphatic position to be functionalized, could
be used as a tool to guide reactivity and selectivity (Scheme 1.7) [34]. Since then,
several intramolecular alkane arylation reactions proceeding through an ArPdX
intermediate have been reported [1k]. Significant advances were limited in this field
until the last decade, potentially due to the lack of knowledge related to the
mechanism of C-H bond cleavage in these reactions. However, recent computational
and experimental studies have shed light in this area and highlighted a potential
common mechanism for C-C bond formation at both aromatic and aliphatic
C-H bonds [35]. The proposed concerted metalation-deprotonation (CMD) pathway
for sp
3
C-H bond cleavage is similar to that proposed for Pd(0)-catalyzed direct
arylation reactions (Scheme 1.7; see also Section 1.2).
Recent efforts by Baudoin and coworkers have led to the development of a Pd
(0)-catalyzed synthesis of benzocyclobutenes (BCBs) via the functionalization of
methyl sp
3
C-H bonds [36]. Benzocyclobutenes are widely recognized as important
synthetic intermediates [37]. Their inherent ring strain allows them, for example, to
readily ring open, making them useful starting materials for the synthesis of more
complex structures. Baudoin and coworkers have capitalized on this reactivity
to synthesize (
), a tetrahydroprotoberberine alkaloid, using an
interesting sp
3
C-H activation/electrocyclization strategy to build its core
(Scheme 1.8) [38]. BCB
)-coralydine (
22
25
was isolated in 76% yield after treating aryl bromide
24
with Pd(OAc)
2
(10mol%), P(
t
-Bu)
3
HBF
4
(20mol%), and K
2
CO
3
(1.3 equiv) in
Pd(0)
H
reductive
elimination
oxidative
addition
X
H
Pd
Pd
X
CMD transition-state
‡
ligand
exchange
H
H
Pd
RCOO
Pd
RCOO
H
O
O
OO
proximity-
enabled metalation
R
R
Catalytic cycle for Pd(0)-catalyzed intramolecular arylation of sp
3
C-H
SCHEME 1.7
bonds.
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