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σ
* (C
−
X)
PH
3
H
3
P
p
y
π
*
Pd
d
xy
(
HOMO
)
p
*
(
LUMO
)
d
xy
X
C
σ
(C
−
X)
Secondary orbital interaction
Pd
heterocycle
Figure 7.1 Key frontier molecular orbital interactions governing the interaction
energy.
Adapted from Ref. 68a. Copyright 2007 American Chemical Society.
Pd(PPh
3
)
4
,
i
Pr
2
NEt, LiCl
N
NH
2
N
NH
2
SnBu
3
S
S
Br
N
DMF, 120
°
C
Br
N
Br
7.23
7.24
74%
Scheme 7.11 Directing group ability overrides steric effects in Stille coupling of
unsymmetrical pyrazine 7.23.
surmised that the excellent E-selectivity observed for the Suzuki cross-
coupling was due to the steric effect exerted by the vicinal alkyl chain, hence
cross-coupling was observed at the less sterically hindered position.
In some cases, the directing ability of a neighboring functional group may
override any steric effects imparted by that substituent. For example, in a
study directed at synthesizing a library of chemi- or bioluminescent probes
based on the 2-aminopyrazine scaffold, Nakamura et al. found that the
amino group of 7.23 could direct oxidative addition into the ortho C3-Br
bond in preference to the less-hindered para C5-Br bond to afford 7.24 in
74% yield (Scheme 7.11).
69
The use of ortho-directing groups in transition
metal-catalyzed C-X or C-H functionalizations is common practice in syn-
thetic chemistry.
44,70
7.5.1.3 Tandem Intra- and Intermolecular Processes
The literature examples highlighted thus far have dealt only with systems
involving stepwise cross-couplings of polyhalogenated starting materials,
whereby the monofunctionalized intermediate is isolated before subjecting
it to the second set of cross-coupling conditions. Examples featuring one-
pot, domino cross-couplings of polyhalogenated substrates are less com-
mon, as issues of chemo- and site selectivity become more pronounced.
Nevertheless, through strategic starting material design, tandem intra- and
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