February 27, 2012 - IMM@BUCT

through his research dating back to the
mid-1990s that cleanly executed reductive
elimination of monofluorinated aryl groups
from palladium intermediates is difficult to
pull off. In reductive elimination, which is
the last step of a catalytic cross-coupling reaction,
the two molecular fragments bound
to the metal catalyst are released and join to
form the product.
Grushin found that standard approaches
to palladium-catalyzed cross-coupling using
tertiary phosphine ligands favor formation
of P–F bonds with the phosphine ligand on
the metal, rather than desired C–F bonds
with aryl substrates. His group overcame
the problem by using a bulkier ligand and
eventually reported a breakthrough in 2006:
the first aryl trifluoromethyl compounds
prepared by palladium-mediated crosscoupling.
The reaction showed that catalytic
aromatic fluorinations were at least possible.
IN 2009, fluorine newcomer Stephen L.
Buchwald ’s group at Massachusetts Institute
of Technology built on those and
other developments to design a palladiumcatalyzed
reaction to form C–F bonds on
prefunctionalized aryl rings. Buchwald’s
team used aryl triflates as the substrate and
CsF as a fluorine source to make various
monofluorinated aryl compounds ( Science,
DOI: 10.1126/science.1178239 ). In 2010,
Buchwald’s team followed up with similar
chemistry, using the ethyl analog of TMSCF 3
as a CF 3 source to achieve the first palladium-catalyzed
aryl trifluoromethylations
( Science, DOI: 10.1126/science.1190524 ).
Buchwald emphasizes that much credit
goes to Grushin for pointing the way. His
group’s success, Buchwald says, stems from
using one of its trademark bulky biaryl phosphine
ligands, named BrettPhos, to create
an aryl palladium fluoride complex.
BrettPhos appears to prevent formation
of P–F bonds and formation of a bridging
fluorine in palladium intermediates that can
block reductive elimination, he explains.
The catalytic process still needs to be optimized.
“There isn’t anything practical yet
in terms of getting to scalable processes,”
Buchwald says. The ligand is still too expensive,
he notes, and the substrate scope needs
to be expanded.
Even so, Buchwald is not sure metalcatalyzed
reactions for discovery chemistry
can compete with the new radical chemistry
from the groups of Baran and MacMillan.
Their systems are better geared toward discovery
research, Buchwald notes. “But everyone
is moving in the right direction,” he
says. “Hopefully we will be able to kick our
palladium fluorination work up a couple of
notches so that it will be user-friendly.”
“In terms of achieving metal-mediated
fluorine chemistry, we organic chemists are
Johnny-come-latelies,” Buchwald admits.
“But you see this type of discovery process
happen in so many fields.
“People are thinking about the same idea;
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then if you get a slightly different take on it,
the right student, and a little luck, you see
the first successful paper,” Buchwald continues.
“That’s why it’s important to have
a lot of groups from different backgrounds
working on topics such as catalytic fluorinations—inorganic
chemists, synthetic
organic chemists, fluorine chemists, and
hybrids of the three.” ◾
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WWW.CEN-ONLINE.ORG 17 FEBRUARY 27, 2012