Coupling of Functionalized Grignard Reagents
A R T I C L E S
make this coupling methodology part of the standard repertoire
in synthetic chemistry.
Cu,8 Pd,16,17 Ni,9,19 Co,20-23 and particularly Fe12,13,15,31 are
active enough that the coupling can be carried out at mild
conditions (e.g., room temperature and below). Consequently,
a large number of alkyl halides containing reactive functional
groups such as keto, ester, amide, nitrile, alcohol, heterocycles,
etc. were selectively coupled to simple sp3 or sp2 Grignard
reagents. In terms of the electrophilic coupling partner, the scope
of these reactions is comparable to that of Negishi coupling,32
and in some cases approaches that of Suzuki-Miyaura
coupling.3,33 Nonetheless, the nucleophiles are limited to
conventional Grignard reagents. Parallel to this, the pioneer work
of Knochel and co-workers on the preparation of functional
Grignard reagents makes these nucleophiles readily available
for further reactions.26,34 Unfortunately, under most circum-
stances, these compounds cannot be directly used for cross-
coupling reactions because they are unstable under the condi-
tions required for such reactions (e.g., elevated temperature).
Only a few exceptions are known so far. Knochel et al. showed
that aryl Grignard reagents containing ester and nitrile groups
and pyridyl Grignard reagents could be coupled to alkenyl
halides, halopyridones, and lately aryl bromides.29,35,36 Buch-
wald et al. developed a Pd-catalyzed sp2-sp2 Kumada-Corriu-
Tamao coupling process that tolerates a wide range of functional
groups in either coupling partners using Knochel-type Grignard
reagents.28 Coupling of these reagents to alkyl halides, however,
has been scarce prior to the current study.
The Kumada-Corriu-Tamao coupling, in which an organic
electrophile is coupled to a Grignard nucleophile, was discovered
at the very early stage of modern cross-coupling chemistry.24
The high reactivity of Grignard reagents, however, results in
poor compatibility with functional groups. Subsequently, alter-
native coupling protocols employing less reactive organometallic
reagents such as Zn, B, Sn, and Si nucleophiles were
developed.1,25 Even so, Grignard reagents remain desirable
coupling partners because they are economical and easy to
synthesize, and many of them are commercially available.
Furthermore, many other organometallic coupling partners are
prepared from the corresponding Grignard reagents. Thus, the
Kumada-Corriu-Tamao coupling provides more direct access
to the same desired products.17,26-29 Improvements of functional
group tolerance in the Kumada-Corriu-Tamao coupling will
encourage the application of this atom-economic30 coupling
reaction in synthesis.
Several recent developments demonstrate that good functional
group compatibility can be achieved in the Kumada-Corriu-
Tamao coupling. A few catalytic systems based on Mn/Cu,6
(7) Giovannini, R.; Knochel, P. J. Am. Chem. Soc. 1998, 120, 11186–
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forming reactions.18,19,39 We found that 1 was an efficient
catalyst for the Kumada-Corriu-Tamao coupling of nonacti-
vated alkyl halides with alkyl Grignard reagents at low
temperatures (-20 to -35 °C) (Figure 1).19 The same protocol,
however, is inefficient for the coupling of alkyl halides with
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