UNIVERSIDAD AUTNOMA DEL ESTADO DE

MXICO
FACULTAD DE QUMICA

ARYL RINGS GET A FLUORINE

FIX
By:

Guillermo Uriel Serrano Delgadillo

Rodrigo Ros Galvn
Oswaldo Gutirrez Pea

A mild and effective method for coupling trifluoromethyl groups

on to aryl rings has been developed by US chemists. With
increasing use of fluorine in drug molecules, the process should
be especially useful in medicinal chemistry and agrochemical
development.

Fluorination of organic molecules can have drastic effects on

their properties, changing their solubility and polarity, and in the
case of drug molecules, how well they are absorbed into the
body and how resistant they are to metabolism. However, as
Stephen Buchwald from the Massachusetts Institute of
Technology in Boston, explains, reliable methods to add fluorine particularly CF3 groups - to aromatic rings are lacking from the
synthetic chemist's toolkit

Buchwald's team has developed a catalytic system that can

substitute aryl chlorides for CF3 groups. The catalyst is based
around palladium and one of the group's trademark biaryl
phosphine ligands - BrettPhos - along with trifluoromethyl
triethylsilane (Et3Si-CF3) and potassium fluoride. Using aryl
chlorides rather than bromides, iodides or triflates drastically
expands the scope of the method, says Buchwald, because
there is a much wider range available.

A PALLADIUM CATALYSED PROCEDURE USES ONE OF THE

BUCHWALD GROUP'S LIGANDS, BRETTPHOS, TO ADD CF3
GROUPS TO ARYL RINGS

There are three key steps in a successful cross-coupling reaction:

oxidative addition of the metal into the C-Cl bond; transfer of the
other coupling partner (CF3 in this case) onto the complex; and
reductive elimination to bring the two partners together and
release the metal to catalyse another reaction.

Buchwald explains that although the reductive elimination step

was tricky, the biggest problem in this case was getting the
CF3 group to transfer

Melanie Sanford, a palladium catalysis expert from the University

of Michigan in Ann Arbor, US, praised the work, calling it 'a
spectacular advance' and reiterating its potential usefulness to
medicinal chemists. 'Buchwald's new ligands are really amazing,'
she adds, 'and they have allowed him to do reactions like this
that have been pursued unsuccessfully for over 20 years

While Buchwald is sure that the method as it stands will be useful

for drug discovery, he admits that it is still too expensive for
manufacturing molecules on a large scale. 'We want people to
be able to use the chemistry,' he adds, 'so we're working on
understanding the mechanism better and tweaking it to make it
more practical.'