Chemistry Reference
In-Depth Information
(11
:
25)
111
112
However, there are three main diculties with this as a general approach:
(1) the dearth of methods available for the synthesis of enantiomerically
pure alkyl halides; (2) the possibility of competing radical mechanisms for
oxidative addition that would be expected to occur with racemization; and
(3) the increased ease of b-hydride eliminations in secondary alkyl-metal
complexes relative to their primary congeners, which may lead to scrambling
of positional selectivity even after a successful oxidative addition event. As
shown in the examples below, the use of specific ligands can surmount
diculties with the b-hydride elimination reaction, but lack of S
N
2-type re-
activity and substrate limitations may be a more significant problem.
In fact, Fu and co-workers demonstrated that sterics have a strong effect
on the rate of oxidative addition of even primary alkyl halides to Pd
catalysts.
76
Systematically adding steric bulk to the g- and b-positions of a
primary alkyl bromide slows the rate of oxidative addition by factors of 5 and
20. respectively (Scheme 11.13), and the use of a secondary alkyl bromide
was found to completely shut down reactivity with Pd catalysts. This latter
fact seems to suggest that only activated secondary bromides are reasonable
partners, although it should be noted that a relatively bulky phosphine
ligand was employed in this study.
The first report of a stereospecific Suzuki-Miyaura reaction with
enantiomerically pure electrophiles involved the use of a-bromosulfoxides,
80
in which the bromide is activated by virtue of the adjacent sulfoxide in the
same manner as the benzyl substituent increases the reactivity of the
bromide in 111. As shown in eqn (11.26), the reaction of enantio- and dia-
stereo-defined bromide 113 with phenylboronic acid leads to the desired
product 114 with perfect inversion of stereochemistry. The authors proposed
that the inversion is related to the S
N
2 nature of the oxidative addition step
and that the remainder of the catalytic cycle proceeds with retention of
configuration.
80
The presence of tert-amyl alcohol was shown to be im-
portant to suppress b-hydride elimination as a non-oxidizable ligand for Pd.
R
THF, 0°C
L = P(
t
Bu)
2
Me
PdL
2
R-Br
+
L
Pd
L
Br
CH
3
CH
3
CH
3
Br
Br
H
3
C
H
3
C
Br
H
3
C
Br
H
3
C
R-Br
(k
rel
)
1.0
0.05
< 0.0001
0.2
Scheme 11.13 Relative rates for oxidative addition of various alkyl halides to Pd
0
.
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