Chemistry Reference
In-Depth Information
NHMe
Ph
Ph
Cl
Cl
Cross metathesis
Reduction
Cl
Cl
CO
2
Me
95% ee
Cl
Cl
Sertraline (Zoloft)
Scheme 8B.92.
Using the Ir-catalyzed allylic alkylation for a synthesis of an antidepressant.
8B.8. COPPER - CATALYZED ENANTIOSELECTIVE
ALLYLIC ALKYLATIONS
Although the palladium-catalyzed allylic alkylation is by far the most popular version,
the poor regioselectivity observed with nonsymmetrical allylic substrates is a serious
limitation of this protocol. In this respect, the copper-catalyzed process is an interesting
alternative and caused a lot of research efforts during the last years. The attractiveness
of copper also arises from the fact that it tolerates a wide range of hard, nonstabilized
nucleophiles, such as organometallics. The developments in this important fi eld are
covered by various reviews on this topic [328a,330].
8B.8.1. Fundamentals of C u - Catalyzed Allylic Substitutions
If unsymmetric allylic substrates (R
1
R
2
) are used in allylic alkylations, in principle,
two different products can be expected, depending on the substitution mechanism. The
nucleophile can either attack directly at the leaving group (
Y
) in an S
N
2 - type reaction
(
≠
α
-product), or at the allylic position (
γ
-product) under migration of the double bond,
what is called an S
N
2
process (Scheme 8B.93). The regioselectivity is strongly infl uenced
by the reaction parameters (solvent, temperature) as well as by the substrate and the
organometallic source. In general, nucleophilic substitution of the leaving group (S
N
2
and S
N
2
′
′
) proceeds with clean inversion of the confi guration.
R
Y
R
RCu
S
N
2
γ
RCu
S
N
2'
α
α
γ
R
1
R
2
R
1
R
2
R
1
R
2
β
-Product
-Product
α
γ
Scheme 8B.93.
Regioselectivity in Cu - catalyzed allylations.
Corey and Boaz proposed a fi rst mechanistic rational based on frontier molecules
orbital considerations [331]. They proposed a simultaneous overlap of a full d-orbital of
the copper with both the π* orbital (LUMO) of the allylic double bond and the antibind-
