Chemistry Reference
In-Depth Information
Br
Potential Intermediate
Br
Br
NiL*
90%
ee
14%
ee
5%
ee
Scheme 11.16 Relationship between position of aromatic group and enantio-
selectivity of the cross-coupling reaction.
to differentiate between the two alkyl groups attached to the secondary halide,
thus ensuring the enantioselectivity of the C-C bond formation event.
Understanding these substrate-catalyst interactions allowed the authors to
expand the scope of highly selective halides from the original homobenzylic
systems to include acylated halohydrins
111
and arylated amines
112
for this
substrate-directed process. It should be noted, however, that the halides
employed are still unactivated by comparison with previous work.
Pushing the scope further, the enantioselective Suzuki-Miyaura reaction
of secondary halides has recently been applied to the g- and d-alkylation of
amides [eqn (11.39)].
109
Since there are a variety of methods for a and
b-functionalization of carbonyl compounds, this method provides a highly
useful new retrosynthetic approach to carbonyl synthesis. Remarkably,
g-chloroamides were shown to react not only with alkyl boranes, but also
with arylboranes and -boronic esters, giving modest enantioselectivity. Most
notably, a secondary organoborane (cyclopropyl-9-BBN) was also shown to
cross-couple successfully in high yield and enantioselectivity. Although the
cyclopropyl group is a privileged substrate, the enantioselective cross-
coupling of two secondary coupling partners is truly groundbreaking.
113
(11
:
39)
Recently, the scope of the effective directing groups has been expanded
even further to include carbamates and sulfamides.
114
This provides a syn-
thetically useful strategy for organic synthesis, as the carbamate acts as both
a protecting group and a directing group for the coupling reaction and can
be removed in high yield by hydrolysis. As observed previously, the distance
of the directing group to the halide has a significant effect on the observed
enantioselectivity. The replacement of the alkylborane with an aryl sub-
stituent resulted in the first example of arylation of an alkyl electrophile in
high yield and high enantioselectivity.
In another significant development, tertiary halides were also
shown to be competent partners for the Ni-catalyzed Suzuki-Miyaura
coupling [eqn (11.40)]. This concept was first demonstrated in the Miyaura
borylation of unactivated tertiary alkyl halides,
115
then subsequently in the
Suzuki-Miyaura reaction.
116
Specifically,
tertiary alkyl bromides were
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