February 27, 2012 - IMM@BUCT

trifluoromethyltrimethylsilane (TMSCF 3 ).
In 1989, he and his colleagues showed it is
an ideal reagent for adding CF 3 to carbonyl
compounds. Now known as the Ruppert-
Prakash reagent, TMSCF 3 is the most
widely used source of CF 3 for trifluoromethylation
reactions.
Working with USC colleague and Nobel
Laureate George A. Olah, Prakash has made
dozens of fluorine chemistry discoveries
over the past 25 years. Just recently,
Prakash and his colleagues reported a
method to make a trifluoromethylated
version of the pesticide DDT, which
may be more potent than plain DDT and
biodegradable ( Org. Lett., DOI: 10.1021/
ol201669a ). They also developed
a Heck coupling
reaction for the synthesis
of trifluoromethylstyrenes
H 3 C
( Org. Lett., 10.1021/ol300076y ).
“This new trend is not a shift
where academics are suddenly spending
all their time on fluorine chemistry,” notes
fluorine newbie Phil
S. Baran of Scripps Research
Institute. “For
O
O
N
H
Cl
N
NH 2
H
N
N
O
CH 3 O
HN
Vandetanib (AstraZeneca’s Caprelsa)
N
H
Ezogabine (GlaxoSmithKline’s Potiga)
our group, it’s more of a hobby,
not a main thrust—we’re
dabbling in fluorine
chemistry.”
Baran explains
that during
consulting
trips to pharmaceutical
companies
he hears
about how
medicinal
F
O
HN
Vemurafenib (Genentech’s Zelboraf)
F
F
O
S
O
chemists sometimes struggle to add a CF 3 in
just the right place or put in a CF 2 H group.
“There is a fundamental desire for organic
chemists to understand chemical
reactivity with the potential for direct applications,”
Baran says. “These forays into
fluorine chemistry are a natural response of
the academic community to what discovery
chemists are saying is useful to them.”
Peter T. Cheng, a research scientist in
metabolic diseases discovery chemistry at
Bristol-Myers Squibb , says medicinal chemists
don’t normally talk with fluorine chemists,
although he and his colleagues do read
their research papers. On the other hand,
medicinal chemists do regularly interact
with frontline organic synthetic chemists.
“When we talk with academic chemists,
they very curiously ask about the synthetic
challenges we are facing,” Cheng says.
“They see problems out there that are of
importance to everyone that they think
they can solve.”
MEDICINAL CHEMISTS generally buy
prefluorinated starting materials and then
functionalize them further, Cheng notes.
But they would prefer to run a few synthetic
steps and then add fluorine later, he says.
“We are glad the organic
N
chemists are working on
fluorinations,” Cheng
N
F
Br
7 out of 35
new drugs approved in
2011 contain fluorine
O
O
F
H
F
Ioflupane (GE Healthcare’s DaTscan)
Roflumilast (Forest Pharmaceuticals’ Daliresp)
WWW.CEN-ONLINE.ORG 11 FEBRUARY 27, 2012
F
Cl
O
N
H
says. “Most fluorinations were previously
done on unadorned or simply functionalized
phenyl rings. But now direct fluorinations
are possible at C–H bonds of
complex functionalized phenyls and
heteroaromatics, which are the truly
useful building blocks for drugs. This new
trend will ultimately allow us to add fluorine
at will under mild conditions.”
Baran’s group now has two fluorine
chemistry papers to its credit, and more
are on the way. The first one, published
last year, reports the trifluoromethylation
of pyridines and other nitrogen-based
heteroaromatics using CF 3 radicals
( Proc. Natl. Acad. Sci. USA, DOI: 10.1073/
pnas.1109059108 ).
Fluorine chemists have been preparing
Cl
N
N
O
and using CF 3 radicals for decades, Baran
notes. One reaction involves CF 3 I gas,
which is inconvenient to handle and tends
to be too harsh for functionally complex
compounds, so medicinal chemists don’t
like using it, he says.
Baran’s team makes CF 3 radicals instead
by using tert -butyl hydroperoxide as an
oxidant to controllably decompose sodium
trifluoromethylsulfinate, NaSO 2 CF 3 . This
stable, inexpensive solid, known as Langlois
reagent for Bernard R. Langlois of Claude
Bernard University, in Lyon, France, has often
been used for fluorination reactions.
The second paper, published this year, reports
a similar process to add CF 2 H groups
to nitrogen heterocycles by generating
CF 2 H radicals from the reaction between
tert -butyl hydroperoxide and the new
reagent Zn(SO 2 CF 2 H) 2 ( J. Am. Chem.
OCH 3
F
123 I
F
S
N
NHH
N
N
N
NN OH OH
O
Ticagrelor (AstraZeneca’s Brilinta)
H
N
N N
Cl
Soc., DOI: 10.1021/ja211422g ). This
zinc reagent is already available
from Sigma-Aldrich.
O
N
Cl
Crizotinib (Pfizer’s Xalkori)
Generating a CF 2 H group
usually requires deoxyfluorinating
reagents. These
electrophilic reagents
F
NH 2
OH
typically store
fluorine
in an N–F bond and
convert carbonyl groups
into CF 2 H or CF 2 groups,
and alcohols into CH 2 F
groups. More than a halfdozen
such reagents
are commercially
available. But
they tend to be
harsh and nonselective
for discovery
chemistry
and thus
not practical
for
fluorinations at later stages of a multistep
synthesis. Adding a premade CF 2 H group
in the manner Baran’s team has done was
previously unheard of.
In a related development, last year David
W. C. MacMillan of Princeton University led
a team that made CF 3 radicals from a lightinduced
reaction involving a ruthenium