Communication
Fluorine Transfer to Alkyl Radicals
Montserrat Rueda-Becerril,‡ Claire Chatalova Sazepin,‡ Joe C. T. Leung,‡ Tulin Okbinoglu,‡
Pierre Kennepohl,‡ Jean-Francois Paquin,§ and Glenn M. Sammis*,‡
̧
‡Chemistry Department, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada
§Canada Research Chair in Organic and Medicinal Chemistry, Dep
artement de chimie, 1045 avenue de la Medecine, Pavillon
ec G1V 0A6, Canada
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́
́ ́ ́
Alexandre-Vachon, Universite Laval, Quebec, Queb
S
* Supporting Information
fluorobenzenesulfonimide (NFSI),8 Selectfluor® reagent (Air
Products and Chemicals, Inc.),9,10 and N-fluoropyridinium salts
(NFPY).11,12
ABSTRACT: The development of new synthetic tech-
nologies for the selective fluorination of organic
compounds has increased with the escalating importance
of fluorine-containing pharmaceuticals. Traditional meth-
ods potentially applicable to drug synthesis rely on the use
of ionic forms of fluorine (F− or F+). Radical methods,
while potentially attractive as a complementary approach,
are hindered by a paucity of safe sources of atomic fluorine
(F•). A new approach to alkyl fluorination has been
developed that utilizes the reagent N-fluorobenzenesulfo-
nimide as a fluorine transfer agent to alkyl radicals. This
approach is successful for a broad range of alkyl radicals,
including primary, secondary, tertiary, benzylic, and
heteroatom-stabilized radicals. Furthermore, calculations
reveal that fluorine-containing ionic reagents are likely
candidates for further expansion of this approach to polar
reaction media. The use of these reagents in alkyl radical
fluorination has the potential to enable powerful new
transformations that otherwise would take multiple
synthetic steps.
It occurred to us that a technique for the fluorination of
carbon radicals, especially aliphatic ones, would be a powerful
tool that would nicely complement methodologies based on the
above reagents. Unfortunately, there are very few sources of
atomic fluorine (F•) that might be serviceable in such a
transformation. Molecular fluorine is a definite possibility,13 but
its notoriously uncontrollable reactivity and the hazards
associated with its use overshadow its application in preparative
operations.3 Similarly, fluoroxytrifluoromethane (trifluorometh-
yl hypofluorite) is a potential source of atomic fluorine, but it is
similar to molecular fluorine in its reactivity, along with the
associated hazards.14 At this time, the sole selective source of
fluorine atoms appears to be the expensive noble gas
compound, XeF2,15 although perfluoroalkanes may behave
similarly, at least toward aryl radicals.16,17
Literature data10 on Selectfluor imply that it, as well as its
congeners, may be suitable as radical transfer agents. Computa-
tional studies18 supported the foregoing surmise. Calculated
N−F homolytic bond dissociation energies (Table 1, DNF)
indicate that Selectfluor and NFSI share very similar homolytic
bond dissociation properties that are essentially independent of
the dielectric properties of the medium.
The greater electronegativity of the formally cationic
nitrogen in Selectfluor results in a more positively charged
(and thus electrophilic) fluorine atom (qF) than for NFSI.
While NFPY has a comparatively larger DNF, which is likely due
to poor delocalization of the unpaired electron in the resultant
nitrogen-centered radical, the N−F bond should be sufficiently
weak to react with most alkyl radicals. Thus, the use of these
reagents in alkyl radical fluorination has the potential to
revolutionize organic radical fluorination and enable powerful
new transformations that otherwise would take multiple
synthetic steps.19
he observation that fluorine incorporation into drugs
T
often leads to significantly improved medicinal properties
has revolutionized the development of pharmaceuticals.1−5
Indeed, there were no fluorinated medicaments on the market
in 1957, while today more than 20% of medicinal compounds
contain fluorine.6,7 As a consequence, synthetic technologies for
the selective fluorination of organic substrates are receiving
increasing attention.2,3 Virtually all contemporary fluorination
methods potentially applicable to drug synthesis rely on the use
of ionic forms of the halogen, i.e., on sources of F− or F+
(Figure 1). Notable among the latter are reagents such as N-
Experimental verification of our hypothesis focused on the
interaction of NFSI, which is soluble in organic media suitable
for conducting radical reactions, with lauroyl peroxide, a well-
known source of alkyl radicals.20,21 Heating a solution of lauroyl
peroxide and NFSI in benzene-d6 afforded 1-fluoroundecane
(2) in 20% yield (Scheme 1, eq 1). The majority of the
remaining mass balance was accounted for in the formation of
Received: December 14, 2011
Published: February 10, 2012
Figure 1. Synthetic approaches for the incorporation of fluorine.
© 2012 American Chemical Society
4026
dx.doi.org/10.1021/ja211679v | J. Am. Chem. Soc. 2012, 134, 4026−4029