C-H. Wong Et. Al. Angew. Chem., Int. Ed. Engl., 2005, 44, 192-212

Reviews
C.-H. Wong et al.
Fluorination Reagents
Selectfluor: Mechanistic Insight and Applications

Paul T. Nyffeler, Sergio Gonzalez Durn, Michael D. Burkart, Stphane P. Vincent,
and Chi-Huey Wong*
Keywords:
electrophilic addition electrophilic
substitution fluorination
fluorine reaction
mechanisms
Angewandte
Chemie
192
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200400648
Angew. Chem. Int. Ed. 2005, 44, 192 212
Angewandte
Electrophilic Fluorination
Chemie
The replacement of hydrogen atoms with fluorine substituents in
From the Contents
organic substrates is of great interest in synthetic chemistry because of

the strong electronegativity of fluorine and relatively small steric
footprint of fluorine atoms. Many sources of nucleophilic fluorine are
available for the derivatization of organic molecules under acidic,
basic, and neutral conditions. However, electrophilic fluorination has
historically required molecular fluorine, whose notorious toxicity and
explosive tendencies limit its application in research. The necessity for
an electrophilic fluorination reagent that is safe, stable, highly reactive,
and amenable to industrial production as an alternative to very
hazardous molecular fluorine was the inspiration for the discovery of
selectfluor. This reagent is not only one of the most reactive electrophilic fluorinating reagents available, but it is also safe, nontoxic, and
easy to handle. In this Review we document the many applications of
selectfluor and discuss possible mechanistic pathways for its reaction.
1. Introduction
The introduction of fluorine substituents into organic
molecules has a long history of development. In particular,
the development of (diethylamino)sulfur trifluoride
(DAST)[1] set the standard by which all nucleophilic fluorinating reagents are compared. Though many sources of
nucleophilic fluorine existed, fewer sources of electrophilic
fluorine were available. Initially, molecular fluorine was the
sole source for electrophilic fluorinations, but because of the
ease of FC formation and the extremely dangerous properties
of F2 (highly toxic, strong oxidant with little or no specificity,
potential runaway free-radical reactions), the development of
alternate sources of electrophilic fluorine was essential. The
first electrophilic fluorine reagent, fluoroxytrifluoromethane
(CF3OF), was reported by Barton et al.[2] The introduction of
other reagents followed, including perchloryl fluoride
(FClO3),[3, 4] xenon difluoride (XeF2),[5] nitrogen oxide fluorides,[6] and several other hypofluorides[7, 8] (Scheme 1).
Although these reagents served as a safer alternative to
fluorine gas and found widespread application in research and
industry, the need for a stable and nontoxic form of electrophilic fluorine still remained.
Recently, a new class of electrophilic fluorinating reagents
with the general structure R2NF or R3N+F began to gain
1. Introduction
193
2. Selectfluor: Properties and

Preparation
194
3. Electrophilic Fluorination with

Selectfluor
196
4. Other Transformations with

Selectfluor
201
5. Enantioselective
Transformations
203
6. Mechanism of Fluorination
with Selectfluor: Electron
Transfer or SN2 Reaction?
204
7. Selected Applications of
Fluorinated Compounds
208
8. Conclusion
211
popularity. In comparison to the previous reagents, these

compounds were milder, safer, more stable, and less expensive to produce. Furthermore, some of these compounds
proved to be as reactive as established reagents in some cases,
while also capable of a degree of selectivity that was
previously unattainable. Efforts by Umemoto et al. led to
the first isolatable N-fluoropyridinium salts, which had good
activity and were amenable to commercial production.[9] The
important role of the counteranion, which influences the
reactivity, selectivity, and stability of the reagent, was also
demonstrated.[10] DesMarteau and co-workers later reported
the discovery of N-fluorobis[(trifluoromethyl)sulfonyl]imide
(2), accessed by the reaction of bis[(trifluoromethyl)sulfonyl]imide with fluorine gas (Scheme 2).[11, 12] The synthesis of this
compound, which is still one of the most powerful sources of
Scheme 2. Synthesis of 2 by DesMarteau and co-workers.[11, 12]
Scheme 1. Electrophilic fluorinating reagents.

Angew. Chem. Int. Ed. 2005, 44, 192 212
[*] P. T. Nyffeler, Dr. S. G. Durn, Dr. M. D. Burkart, Dr. S. P. Vincent,

Prof. C.-H. Wong
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, BCC 357
La Jolla, California 92037 (USA)
Fax: (+ 1) 858-784-2409
E-mail: wong@scripps.edu
DOI: 10.1002/anie.200400648
193
Reviews
C.-H. Wong et al.
electrophilic fluorine, was a step forward in the identification

of a stable source of electrophilic fluorine with desirable
physical properties. One major drawback of 2 is that it is not
commercially available, so that the use of fluorine gas for its
preparation in the laboratory is ultimately required. More recently, the
development of the reagent selectfluor
(1, Figure 1) presented a major advance
for electrophilic fluorination, as it is a
reliable, mild, stable, and effective
source of electrophilic fluorine that
Figure 1. Selectfluor,
lends itself to large-scale synthesis and
1-chloromethyl-4-fluorodiazoniabicyis commercially available. A number of
clo[2.2.2]octane bis(- reagents, each with its advantages and
tetrafluoroborate).
disadvantages, currently exist for the
electrophilic incorporation of fluorine
and have been the subject of several
reviews.[1316] This Review focuses on the versatility of the
selectfluor reagent and its applications, and includes some
mechanistic insight into plausible reaction pathways.
Paul T. Nyffeler was born in Stromsburg,
Nebraska in 1976. He received his BA in
1999 from Carleton College, where he studied the stereochemistry of enolate reactions
under the tutelage of Prof. Jerry Mohrig. He
then moved to The Scripps Research
Institute, where his ongoing research in the
laboratory of Chi-Huey Wong includes the
diazotransfer reaction, regioselective azide
reductions, fluorinated glycolipids, and the
study of dihydrogen trioxide.
194
2. Selectfluor: Properties and Preparation

Selectfluor,[15, 17] an exceptionally stable, virtually nonhydroscopic crystalline solid, represents a significant
improvement on traditional electrophilic fluorinating agents,
which require special handling and tend to be synonymous
with danger. In an extreme experiment to demonstrate its
stability (and to satisfy the United States Department of
Transportation regarding the risks associated with transporting a potentially dangerous compound), a self-accelerating
decomposition temperature (SADT) test was performed, in
which a 55-gallon drum filled with selectfluor was heated to
56 8C for 7 days; during this time the temperature remained
constant within 5 8C.[18] Selectfluor has been found to be
stable at temperatures up to 195 8C, although the inventors
warn that bulk samples should only be heated above 80 8C
with caution.[15] Therefore, a significant advantage of the
selectfluor reagent remains its remarkable stability, as a result
of which it has become a commercially available, hazard-free
source of fluorine.
Compared to F2, which is extremely toxic, selectfluor is
relatively harmless. Toxicology studies revealed an oral LD50
(dose needed to kill 50 % of the subjects) of 640 mg kg1 for
male adult rats; skin exposure up to 2.0 g kg1 led to no
lethality in rats.[15, 18] Only mild eye and skin irritation was
observed in studies with rabbits and guinea pigs. Selectfluor
also failed to demonstrate any signs of mutagenic or
carcinogenic activity. Studies showed that the ecological and
environmental effects of selectfluor were also minor: Its
impact on algal growth, sewage-sludge respiration, and the
toxicity of several species were found to be within acceptable
levels.
Sergio G. Durn received his BS in chemistry

from the University of Texas at Austin in
1995. After a year at Hoechst-Celanese, he
moved to the University of Illinois at
Urbana-Champaign, where he carried out
research on the total synthesis of batzelladine A with David Y. Gin. After completing
his PhD he pursued postdoctoral studies at
The Scripps Research Institute with ChiHuey Wong on new methods for the one-pot
synthesis of complex oligosaccharides and
the synthesis of fluorinated carbohydrates.
He is currently at Kalypsys, Inc. in San
Diego.
Stphane Vincent received his PhD in bioorganic chemistry from the Universit Louis
Pasteur (Strasbourg, France) with Charles
Mioskowski. After postdoctoral studies first
at The Scripps Research Institute in the
research group of Chi-Huey Wong and then
in Strasbourg with Jean-Marie Lehn, he took
up a permanent position as a CNRS
researcher in 2001 in the laboratory of
Pierre Sinay (Ecole Normale Suprieure,
Paris). His research interests include the
glycosciences, biocatalysis, and mechanistic
enzymology.
Mike Burkart was born in Arlington, Texas in

1972 and received his BA in chemistry from
Rice University. During his graduate studies
with Chi-Huey Wong at The Scripps
Research Institute, he explored the synthetic
chemistry of fluorinated carbohydrates and
their application as enzyme inhibitors. Following postdoctoral studies with Chris Walsh
at Harvard Medical School, he initiated his
own research group in 2002 at the University of California, San Diego. His current
research interests include natural product
biosynthesis and antibiotic design.
Chi-Huey Wong received his BS and MS

from the National Taiwan University, and
his PhD in chemistry from the Massachusetts Institute of Technology. After a year as
a postdoctoral fellow at Harvard University,
he moved to Texas A&M University in 1983.
He became Professor of Chemistry in 1989
at The Scripps Research Institute (Ernest W.
Hahn Chair). His research interests encompass organic and chemoenzymatic methods
in synthesis with a specific focus on the study
of carbohydrate-mediated biological
recognition.
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The preparation of selectfluor, which is produced in

multiton quantities per year, was designed to be simple,
flexible, and efficient.[18, 19] The most practical procedure for
the production of selectfluor involves the preparation of the
precursor 3 by initial alkylation of 1,4-diazabicyclo[2.2.2]octane (dabco, also known as triethylenediamine (TEDA)) with
the dichloromethane solvent (Scheme 3). After counterion
Scheme 3. Method for preparing 1.[18, 19]
compound. In earlier studies, no obvious effect of the

counterion on the reactivity had been observed, leading to
the commercialization of the tetrafluoroborate salt.[15] However, recent studies demonstrated that the use of the
trifluoromethanesulfonate (triflate) salt 4 g for the fluorination of glycals led to decreased side-product formation and
higher yields of the desired product than with 1.[20] This
outcome was rationalized by the greater solubility of the
triflate salt of selectfluor in the desired solvent (nitromethane) and the fact that no bisfluorinated by-products are
formed, a side reaction that occurs with 1.
The desired counteranion can be introduced by exploiting
the low solubility of metal halides in various solvents
(Scheme 4).[15, 17, 18] The procedure involves initial alkylation
with dichloromethane, which also serves as the solvent,
followed by the addition of lithium tetrafluoroborate, yielding
5 a upon filtration. A different counterion can be incorporated
during fluorination by using one of three methods. The first
method (Scheme 4, method A), primarily used for small-scale
exchange with sodium tetrafluoroborate and subsequent

precipitation of sodium chloride from the acetonitrile
solution, fluorination with F2 provides 1. Variations on this
scheme allow not only the synthesis of commercial selectfluor
on industrial scales, but also the preparation of a variety of
derivatives with different characteristics and reactivities.
The choice of the peripheral alkyl group on the dabco
moiety has the greatest impact upon the reactivity and cost of
production of the general class of F-TEDA-X reagents, which
includes 1.[15] Derivatives that have been made range from the
simple methyl derivative 4 a to the highly reactive 2,2,2trifluoroethyl derivative 4 j (Figure 2). The most powerful
Scheme 4. Methods for synthesizing F-TEDA-X derivatives.[15]
Figure 2. F-TEDA-X derivatives. Tf = trifluoromethanesulfonyl.
variant of the F-TEDA-X reagents is 4 j, which even

fluorinates benzene. In general, the more electron withdrawing the alkyl substituent is, the more electrophilic the fluorine
group will be. From an economic standpoint, the chloromethyl derivative 1 is an ideal reagent, as it has the secondhighest reactivity and can be synthesized conveniently. The
least reactive compounds are those with methyl, ethyl, or
octyl substituents. However, all F-TEDA-X derivatives are
reactive enough to fluorinate both pyridine and quinuclidine,
demonstrating their superior reactivity over N-fluoropyridinium and N-fluoroquinuclidinium reagents.
The counterion employed with selectfluor can have an
impact on both the reactivity and the cost of the final
Angew. Chem. Int. Ed. 2005, 44, 192 212
reactions, involves fluorination of 5 a at 35 8C in acetonitrile,

then addition of the desired counteranion in the form of the
lithium or sodium adduct, filtration, and evaporation. In the
second method (Scheme 4, method B), used for industrialscale production, fluorine is added to a solution of 5 a and the
appropriate lithium salt in acetonitrile. This process does not
require the separate addition of the salt after fluorination, but
does introduce the complication of precipitate formation
during the reaction. The third method involves the formation
of a Lewis acid (LA) adduct with 5 a prior to fluorination
(Scheme 4, method C). On small scales this method is ideal,
since no precipitate is formed, and therefore no filtration is
needed to provide the pure product. As F2 gas is used in all
methods, either at reduced pressures or diluted with an inert
gas such as N2, any attempts to produce these types of
reagents should be undertaken by trained people who are
fully aware of the dangers associated with molecular fluorine.
Fortunately, because of the efficiency and economic feasibility of this process, selectfluor is commercially available,
precluding the need for its preparation.
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C.-H. Wong et al.
3. Electrophilic Fluorination with Selectfluor

Since the publication of the original patent[19] that
described the discovery of selectfluor, the scope of its
application has become vast, thus demonstrating the necessity
for reagents with the electrophilic fluorination potential of
selectfluor. In fact, in a rather remarkable case, Chambers
et al. showed that selectfluor is capable of fluorinating
unfunctionalized hydrocarbons.[21] Taken together with the
examples to follow, there seems to be virtually no end to the
number of substrates amenable to transformation by selectfluor.
best reagent for converting 7 into 8 (Scheme 6).[26] In a further

investigation into the effects of fluorine substituents on the
behavior of bioactive compounds, Ge and Kirk reported the
synthesis of fluorinated derivatives of l-ascorbic acid
Scheme 6. Glucocorticoid fluorination.[26]
3.1. Solvent Requirements and Restrictions

As a dication, selectfluor is soluble in only a few polar
solvents, namely, acetonitrile, N,N-dimethylformamide
(DMF), and water.[15] Nitromethane may also be used, since
it is inert and sufficiently polar to dissolve the reagent.[20, 22]
Such a solvent is particularly effective when solvent participation, such as that by acetonitrile in glycosylations, is not
desired. The use of nitromethane may also be advantageous
when acidic conditions have to be avoided, as it precludes the
need for a base or proton sponge. Recently, the use of ionic
liquids, such as triflate, tetrafluoroborate, and phosphorous
hexafluoride salts of 1-ethyl-3-methylimidazolium or 1-butyl3-ethylimidazolium, for reactions with 1 has received attention.[23, 24] As reaction efficiencies are higher for many
substrates in these reusable and environmentally friendly
media, these studies have opened an interesting avenue for
further investigation.
(Scheme 7) and tetronic acid (Scheme 8).[27, 28] The tetronic

acid group is found in many important biologically active
compounds. By protecting the carbonyl group as a silyl enol
Scheme 7. Synthesis of a fluorinated derivative of l-ascorbic acid.[28]
3.2. a Fluorination of Carbonyl Functionalities

The incorporation of a fluorine substituent adjacent to a
carbonyl group is a common reaction motif. This transformation can be carried out by initial conversion of the
carbonyl functionality into an enol ester (e. g. 6 a) or a silyl
enol ether (e. g. 6 b) prior to reaction with selectfluor
(Scheme 5).[25] Fluorinated glucocorticoid derivatives are of
great interest in the field of medicinal chemistry, and
Herrinton and co-workers reported that selectfluor was the
Scheme 8. Synthesis of a fluorinated tetronic acid derivative.[27]
ether, Hoffman and Tao were able to synthesize fluorinated

peptide analogues with high diastereo- and enantioselectivity.[29] The incorporation of fluorine into b-diketones is readily
accomplished by the reaction of selectfluor with the corresponding enolate salts.[25, 30] This transformation is not limited
to enolates: The sodium salts of some phosphonates have also
been fluorinated in moderate yield. Alternatively, a,adifluoroketones can be formed regioselectively by the reaction of selectfluor with alkynes.[31]
3.3. a Fluorination and Oxidation of Thioethers

Scheme 5. a Fluorination of ketones via an enol ester or a silyl enol
ether.[25]
196
Reactions of thioether-containing compounds with selectfluor lead to interesting synthetic products. For example,
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thioethers with a protons can be converted into a-fluorosulfides in reasonable yields (Scheme 9).[25] This process occurs
by initial reaction of the sulfide with selectfluor in acetonitrile
Scheme 10. Direct conversion of thioglycosides into a-fluoro sugars.[32]
Glycosyl fluorides can be accessed directly from anomeric

hemiacetals in one step by using the reagent combination of
selectfluor and dimethylsulfide (Scheme 11). This reaction
[25]
Scheme 9. a Fluorination of thioethers.
at room temperature to form a fluorosulfonium salt (e. g. 9). It

was proposed that this intermediate undergoes a Pummererlike rearrangement upon treatment with a base, such as
triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),
providing the a-fluorosulfide product 10.
Selectfluor is also an excellent reagent for the conversion
of thioglycosides into the corresponding glycosyl sulfoxides
(Table 1).[20] These reactions are typically complete within
20 min at 0 8C in acetonitrile/water mixtures. Essentially
quantitative yields were observed for all substrates examined.
Table 1: Oxidation of thioglycosides to sulfoxides.[20]
Product[a]
Yield [%]
99
Product[a]
Yield [%]
99
99
99
99
99
99
99
95
99
[a] Bn = benzyl, Bz = benzoyl, Lev = levulinyl, Tol = tolyl, Troc = 2,2,2trichloroethoxycarbonyl.
3.4. Synthesis of Glycosyl Fluorides

The inherent thiophilic properties of electrophilic fluorine
provide a useful avenue for accessing fluorinated compounds.
One possible route is the conversion of thioglycosides into the
corresponding
glycosyl
fluorides
with
selectfluor
(Scheme 10).[32] This method is an improvement on previous
methods with DAST, which was successfully used by Nicolaou
et al. to synthesize glycosyl fluoride donors.[33]
Angew. Chem. Int. Ed. 2005, 44, 192 212
Scheme 11. Proposed mechanism for the substitution of an anomeric

hydroxy group for a fluorine substituent in the presence of methyl
sulfide and 1.[20, 32]
demonstrates the potential of this combination as a safe

alternative to potentially explosive DAST for the conversion
of alcohols into fluorides.[20, 32] Selectfluor was also shown to
promote glycosylation with thioglycoside donors in high
yields.[20, 32] Its application in the glycosylation of 2-deoxythioglycosides is exceptional, as other methods of activation
fail as a result of the high reactivity of the glycosyl donors.[34]
3.5. Fluorination of Aromatic Compounds

Selectfluor has proven to be a competent reagent for the
fluorination of substituted aromatic systems. Banks et al.
reported that of all the F-TEDA series (Figure 2) only the
2,2,2-trifluoroethyl derivative 4 j fluorinates benzene, albeit in
very low yields when aqueous acetonitrile is used (3.5 % after
48 h at 80 8C).[15] Higher yields, up to 20 % conversion, were
observed when trifluoroacetic acid (10 % v/v) was added.
Many substituted aromatic compounds could readily be
fluorinated with selectfluor.[15] Electron-donating substituents
are known to increase the rate of formation and yield of the
fluorinated compounds. For example, when methoxybenzene
was exposed to 1, a 1:1 mixture of 2- and 4-fluoro(methoxy)benzene was obtained in high yield (72 % conversion).
Stavber et al. found that substituted phenols are fluorinated
by 1, in an efficient synthesis of 4-fluorocyclohexadienone
derivatives (Table 2).[35] Flanagan et al. employed 1 in the
synthesis of aromatic fluorescent dyes, which were used in
DNA-sequencing.[36]
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C.-H. Wong et al.
Table 2: Synthesis of 4-fluorocyclohexadienones from 4-substituted

phenol derivatives.[35]
Substrate
Product
atives of the cardiotonic oleandrigenin and the antibiotic

daunorubicin were accessed in good yields (Scheme 13). The
synthesis of fluorinated analogues of current pharmaceuticals
Yield [%][a]
R = Me: 60 (52)
R = iPr: 55 (44)
84 (77)
93 (82)
90 (79)
[a] Yield of the crude product by 19F NMR spectroscopy; the values in
brackets refer to the yield of the isolated product.
Scheme 13. 2-Fluoroglycosyl derivatives of oleandrigenin and daunomycinone.[20] Piv = pivaloyl.
3.6. Fluorination of Alkenes

The susceptibility of alkenes to functionalization with
electrophilic species provides a convenient handle for fluorination with selectfluor. Lal,[25] as well as Stavber et al.,[37]
demonstrated that 1,2-fluoroethers can be prepared from
alkenes by treatment with 1 in the presence of alcohols.
Stavber et al. studied the kinetics of this reaction[38] and
reported that the transformation was not limited to alcohols,
but that 1,2-fluoroamides could also be made efficiently with
various amines.[39] Castro et al. selectively introduced fluorine
into 3-[3-(piperidin-1-yl)propyl]indoles with 1 in excellent
yields. One fluorinated analogue had a higher oral absorption
than the corresponding nonfluorinated derivative.[40]
Alkenes contained within the enol ether moiety of glycals
are also susceptible to fluorination by 1. Selectfluor is capable
of converting glycals into the corresponding 2-deoxy-2fluoroglycosides in excellent yield (Scheme 12).[20, 22, 32, 41]
Many alcohols, including other protected sugars, can be
used as acceptors in this reaction. The fluorination and
subsequent glycosylation occur as a two-step one-pot reaction. By employing this methodology, 2-fluoroglycosyl deriv-
Scheme 12. Proposed mechanism for the fluorination and glycosylation

of glycals.[20, 22, 32, 41]
198
represents a potential avenue for the design of more potent

inhibitors.[20] This transformation is not limited to the use of
alcohols as acceptors; glycosyl azides, bromides, fluorides, and
acetamides can also be formed in high yields starting from
glycal precursors. Although pyranosyl glycals are generally
employed, furanosyl glycals can also be
used successfully. A potential application
of this strategy may be the derivatization
of 3-fluorosialic acid (11) starting from
glycal precursors. The resulting products
have been shown to be potent selective
inhibitors of the influenza virus. They bind to hemagglutinin
and neuraminidase, thus limiting the infectious ability of the
virus.[42, 43]
Detailed 19F NMR spectroscopic studies were undertaken
to gain insight into the stereoselectivity of anomer formation
and fluorination in glycals.[20] These studies demonstrated that
1 adds to the alkene functionality of the glycal in a syn
fashion, yielding an intermediate of the type 12 a, which then
slowly anomerizes to the more thermodynamically stable
intermediate 12 b (Scheme 14). Thus, a selectivity is observed
if the syn adduct has sufficient time to epimerize to the
thermodynamically more stable intermediate. Furthermore, it
was demonstrated that the steric demands of both the
nucleophile and the glycal also play an important role in the
anomeric selectivity, with increasing steric bulk favoring
a selectivity. Several factors were also shown to influence the
efficiency of the reaction. The use of nitromethane as the
solvent in lieu of acetonitrile and the replacement of
tetrafluoroborate as the counteranion with triflate led to
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Scheme 14. The conformation and configuration at the anomeric center of the intermediates determine the anomeric selectivity in reactions of
glycals.[20]
increased yields, decreased reaction times, and a dramatic

decrease in the formation of side products. The choice of
protecting groups on the glycal and the steric hindrance of the
alcohol acceptor had a significant influence on the selectivity
of the reaction.
3.7. Electrophilic Fluorination of Indoles

Indoles are convenient precursors in the synthesis of many
biologically active molecules, and their derivatives are also
useful probes for the study of enzymatic mechanisms and
metabolic pathways. Fluorinated analogues containing indole
moieties can be useful tools for the elucidation of various
biological processes. Indole derivatives can be fluorinated
efficiently by using selectfluor to provide various fluorooxindole derivatives (Scheme 15).[44] This method takes advan-
Table 3: Electrophilic fluorination of indoles.[44]
Yield [%]
(CH2)2CO2Me
(CH2)3CO2Me
(CH2)2CH(NHpNB)CO2Me[a]
(CH2)2NPhth[b]
(CH2)2NPhth[b]
H
H
H
H
OAc
82
77
92
82
82
[a] pNB = para-nitrobenzyl. [b] Phth = phthaloyl.
including gypsetin[45, 46] and brevianamide E.[47] The synthesis

of the fluorinated core of these biologically relevant molecules by using 1 is illustrated in Schemes 16 and 17).[48]
Scheme 15. Fluorination of an indole.[44]
tage of the nucleophilic character of the enamine functionality contained within the indole moiety. The choice of solvent
was crucial, as the products decomposed when only acetonitrile was used. Although mixtures of acetonitrile with either
methanol or trifluoroethanol were tolerated, the best results
were obtained with a 1:1 mixture of acetonitrile and water.
The generality of this method was further demonstrated by
the successful electrophilic fluorination of other indoles
(Table 3, entries 1 and 2), including biologically relevant
indoles, such as tryptophan (entry 3), tryptamine (entry 4),
and serotonin (entry 5) derivatives. In all cases, their conversion into the fluorooxindoles was efficient.
The functionalization of indoles with selectfluor was
further extended to the synthesis of some hexahydropyrazino[1,2-1,5]pyrrolo[2,3-b]indole-1,4-dione derivatives. This
indole moiety is present in a wide variety of natural products,
Angew. Chem. Int. Ed. 2005, 44, 192 212
Scheme 16. Fluorination of gypsetin derivatives.[52]
Scheme 17. Synthesis of the fluorinated core of brevianamide E.[48]
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3.9. Oxidative Phosphorylation: Synthesis of 2-Fluoro Sugar

Nucleotides
3.8. Synthesis of Vinyl and Alkyl Fluorides

Selectfluor is a versatile reagent for the synthesis of
alkenyl and alkyl fluorides. McCarthy and co-workers
reported the electrophilic fluorination of vinyl stannanes
with selectfluor.[49] Widdowson and co-workers applied this
strategy to steroid derivatives containing vinyl stannane
groups
to
prepare
fluorinated
steroid
products
(Scheme 18),[50] thus providing a potentially useful method
for the synthesis of 18F-labeled steroids for applications in
Scheme 18. Conversion of a vinyl stannane into a fluoride.[50]
positron emission tomography (PET). Greedy and Gouverneur showed that this transformation is not limited to tincontaining species, but that vinyl silanes are also suitable
substrates (Scheme 19).[51] The use of 1 equivalent of 1 leads
to fluoroalkene products. Interestingly, in the presence of an
excess of 1 in acetonitrile, solvent participation in the
formation of a,a-difluoro-substituted products was observed.
Furthermore, the addition of methanol or water to the
reaction mixture led to the incorporation of alcohol and ether
groups in the a,a-difluoro-substituted products.
Scheme 19. Conversion of vinyl silanes into fluoroalkanes or a,adifluoroethers.[51]
The substitution of the 2-hydroxy group of monosaccharides with fluorine provides useful analogues with which to
probe enzyme mechanisms. However, to be introduced into a
biological system, the corresponding nucleotide diphosphate
must be synthesized, which usually requires many tedious
steps involving selective protecting-group manipulations.
Recently, new methods for the synthesis of 2-fluoro sugar
diphosphates and nucleotide diphosphates with selectfluor
have simplified the preparation of these valuable substrates.
The direct oxidative fluorophosphorylation of glycals with
selectfluor provides protected 2-fluoroglycosyl phosphates in
a one-pot procedure.[20] The synthesis of a- and b-2-fluorofucosylguanine diphosphate (GDP-2F-Fuc; 13a and 13b,
respectively) is a demonstrative example of this general
strategy (Scheme 20). The electrophilic fluorination of 3,4-diO-benzoylfucal (14) with 4 g, followed by the addition of
dibenzyl phosphate, provided the protected 2-fluorofucosyl
phosphate 15 in 54 % yield and an a/b ratio of 2:3. After
chromatographic resolution, deprotection, and subsequent
coupling to GMP-morpholidate, both anomers of 13 were
obtained in moderate yield.[52]
N-Acetylneuraminic acid (NeuAc), also known as sialic
acid, is a structurally unique carbohydrate involved in many
recognition processes of cell surfaces, including viral infection, inflammation, and cell signaling.[42] Synthetic analogues
of this monosaccharide have been utilized to probe cellsurface recognition,[53] and could be useful in other areas of
research. As the synthesis of CMP-3F-NeuAc (16; CMP =
cytidine monophosphate) was hindered by the ester group
adjacent to the anomeric center, a three-step fluorophosphorylation was employed (Scheme 21).[42] The glycal derivative
17 of sialic acid was treated with 1 in the presence of water to
form the hemiacetal 18, which was phophitylated by using
standard phosphoramidite chemistry. Oxidation and palladium-catalyzed deallylation, deacetylation, and saponification then provided the desired product in good yield.
The use of selectfluor to prepare fluorinated monosaccharides is also amenable to the one-pot chemoenzymatic
synthesis of sugar nucleotide diphosphates (Scheme 22).[52]
The electrophilic fluorination of galactal with 1 was conducted in water to provide 2-fluorogalactose, which, after pH
Scheme 20. Synthesis of a-GDP-2F-Fuc (13a) and b-GDP-2F-Fuc (13b).[20, 52]
200
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Scheme 21. Synthesis of CMP-3F-sialic acid.[42]
Scheme 22. Chemoenzymatic synthesis of UDP-2F-Gal.[52]
adjustment, was phosphorylated by galactokinase. Adenosine

triphosphate (ATP), the phosphate source for this transformation, was generated economically in situ with an ATP
synthase and a stoichiometric amount of acetyl phosphate.
Upon completion of the reaction, the pH was again adjusted,
and galactose-1-phosphate uridyltransferase was added. The
desired product 19 is formed in good yield, and the procedure
can be carried out on a preparative scale.
4. Other Transformations with Selectfluor
properties of selectfluor for the synthesis of benzaldehyde

derivatives from benzylic alcohols in moderate yields.[54] The
authors postulated that the reaction most likely proceeds
through radical fluorination at the benzylic position initiated
by a single-electron transfer (SET), followed by the rapid loss
of HF to yield the aldehyde product. They also found that 1
could oxidize benzaldehyde derivatives to the corresponding
benzoic acids in good to excellent yields via a benzoyl fluoride
intermediate (Scheme 23). Furthermore, they demonstrated
that aldehydes can be converted into amides and esters in
good yields.
4.1. Oxidation of Benzylic Alcohols

4.2. Oxidation of Tertiary Carbon Centers
Alongside numerous examples of the use of selectfluor for
the electrophilic fluorination of organic molecules, reactions
with selectfluor that lead to nonfluorinated products have
also been discovered. Banks et al. capitalized on the oxidative
Angew. Chem. Int. Ed. 2005, 44, 192 212
In an interesting transformation of ()-menthol (20),

remote functionalization of alcohols in the presence of excess
selectfluor was demonstrated (Scheme 24).[55] The reaction
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C.-H. Wong et al.
Scheme 25. Allylstannation of aldehydes and imines.[56]
aldehyde for nucleophilic addition. However, one can also

imagine that the effective Lewis acid may be the tri-n-butyltin
cation, formed in conjunction with allyl fluoride from the
reaction between allyl(tri-n-butyl)tin and 1.
Scheme 23. Oxidative functionalization of p-chlorobenzaldehyde.[54]
4.4. Selectfluor-Mediated Functionalization of Aromatic Systems
Scheme 24. Remote functionalization of ()-menthol.[55]
proceeds through initial formation of a tertiary carbocation,

which subsequently reacts with the solvent (in this case
acetonitrile), and the resulting intermediate is trapped intramolecularly by the alcohol group through a Ritter-like
mechanism. The oxazinium salt 21 formed is then hydrolyzed
under basic conditions to provide the functionalized menthol
derivative 22. The presence of a tertiary carbon center b to
the alcohol group is a prerequisite for this reaction. This
method was found to be general, as a similar reaction occurs
in propionitrile and butyronitrile, albeit in lower yields. The
authors also proposed an SET mechanism to account for the
observed transformation.
202
Although selectfluor is most often used as an electrophilic

reagent for the introduction of fluorine substituents, it can
also mediate the electrophilic addition of other common
anions. The inherent electrophilic activity of 1 has been
exploited recently for the conversion of nucleophilic compounds into electrophilic reagents. It has been known for
some time that selectfluor decomposes in the presence of
iodide ions,[15] but when mixed with molecular iodine it forms
a potent iodonium source. Stavber et al. reported that
alkylated aromatic rings can be iodinated in excellent yield
in acetonitrile by using iodine and 1 (Table 4).[57] The reaction
Table 4: Iodination of aryl compounds with 1 and iodine.[57]
Substrate
Aryl/1/I2
Product
Yield [%]
1:0.75:0.75
95
4.3. Selectfluor-Mediated Allylstannation of Aldehydes and

Imines
1:0.6:0.6
93
A unique application of selectfluor as a promoter for the

allylstannation of aldehydes and imines was reported
recently.[56] Generally, strong Lewis acids, such as aluminum
trichloride and titanium tetrachloride, which require the
exclusion of moisture and strict maintenance of an inert
atmosphere, are employed in this reaction. With selectfluor
the desired homoallylic alcohols and amines are produced in
good yields with excellent tolerance of moisture and air
(Scheme 25). The reactions of aromatic and aliphatic aldehydes usually proceed to completion within hours when a
stoichiometric amount of 1 is used. With a catalytic amount of
1 (0.05 equiv) longer reaction times (24 h) are required and
yields are lower ( 60 % conversion). In the absence of
selectfluor no product formation was observed. Although the
mechanism for this transformation is not well understood, it
can be speculated that 1 may act as a Lewis acid to activate the
1:5:5
72
1:1.5:1.5
89
1:5:5
73
1:0.6:0.6
96
1:1.1:1.1
87
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is usually carried out with substoichiometric quantities of the

reagents, but when excess I2 and 1 were used, bis- and
trisiodinated products were formed. This transformation is
not limited to activated benzene derivatives, as aryl alkyl
ketones could be converted into aryl a-iodoketones in
excellent yields.[58] A solvent effect was noted in this reaction:
With methanol the a-iodoketones were formed, whereas the
use of acetonitrile led to aryl iodide species. A threecomponent mixture of the alkyl aryl ketone, iodine, and 1
was required for any reaction to occur. Selectfluor also proved
useful for the conversion of common anions into electrophilic
reagents. The reaction of 1 with the sodium or potassium salts
of Cl , Br , SCN , and NO2 converts the anions into the
corresponding electrophilic cations, which are capable of the
electrophilic functionalization of a variety of activated
benzene derivatives.[59] In general, the potassium salts are
more reactive than the sodium salts, and the reactivity
decreases in the order Cl+ > Br+ > SCN+ > NO2+. The reaction is substrate dependent and proceeds faster for some
nucleophiles in DMF and for others in acetonitrile. Acetate
and trifluoroacetate could be converted into the corresponding electrophilic species for a limited number of substrates,
but with other anions (CN , OCN , CH3O , CH3S) no
reaction occurred under any conditions investigated.
Table 6: Deprotection of p-methoxybenzylidene with 1.[62]

Substrate
Product
Yield [%]
90
87
92
90
Table 7: Deprotection of 1,3-dithianes with 1.[62]

Substrate
Product
Yield [%]
95
85
95
85
4.5. Protecting-Group Removal

80
Selectfluor is a useful reagent for the removal of some

common protecting groups. The protection of alcohols as
their tetrahydropyranyl (THP) ethers was reported as early as
1934.[60, 61] This protecting group still sees widespread application as a result of its low cost, ease of introduction, and
stability. The addition of stoichiometric amounts of selectfluor leads to the selective, mild cleavage of THP ethers in
high yields (Table 5).[62] Under these mild conditions, alde-
Table 5: Deprotection of THP ethers with 1.[62]

Substrate
Product
Yield [%]
94
are commonly used as umpoled synthons and for the

protection of aldehydes and ketones.[63] However, one major
drawback to the use of dithiane groups is that mercury salts,
which are highly toxic and an environmental hazard, are
required for their removal. Selectfluor is capable of cleaving
1,3-dithianes in excellent yields in less than 5 min, with the
formation of innocuous by-products.[62] It has been proposed
that 1 acts as a Lewis acid in this process, but various other
reaction pathways are imaginable, including oxidation.
5. Enantioselective Transformations
92
95
89
hydes and olefins are tolerated. The protecting group pmethoxybenzylidene, commonly employed for the protection
of 1,3-diols, can also be removed easily in high yields with an
excess amount of 1 (Table 6).
The most useful deprotection by 1 is arguably the cleavage
of dithianes (Table 7). Dithianes have found wide application
in synthesis as a result of their stability and accessibility. They
Angew. Chem. Int. Ed. 2005, 44, 192 212
Selectfluor has been utilized, either directly or indirectly,

in many types of enantioselective reactions. Enders et al.
described the regio- and enantioselective electrophilic fluorination of enantiopure a-silylketones, but selectfluor found
limited success in this reaction.[64] Although indirect and
substrate-directed enantioselective reactions with selectfluor
can be useful, the enantioselective fluorination of nucleophilic substrates has been studied the most intensively.
The first report of an asymmetric a fluorination was by
Differding and Lang, who described the enantioselective
fluorination of an enolate with camphor-based N-fluoro
sultams.[65] These chiral electrophilic sources of fluorine
provided the anticipated a-fluorocarbonyl compounds upon
treatment with various metal enolates. Depending on the
substrate, enantioselectivities of up to 70 % ee were observed.
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C.-H. Wong et al.
Improved enantioselective fluorinations were observed

with a new class of charged [NF]+ reagents. Selectfluor was
used to prepare the N-fluoroammonium derivatives 23 ad of
cinchona alkaloids by transfer fluorination (Figure 3,
Scheme 26).[6668] The fluorinated reagents 23 ad were
Figure 3. N-Fluoroammonium derivatives of cinchona alkaloids for

enantioselective electrophilic fluorination.[6668]
Scheme 26. Synthesis of the fluorinated cinchona alkaloid F-CD-BF4.[66

68]
tested in the enantioselective fluorination of the sodium

enolate of 2-methyl-1-tetralone, providing the product in up
to 98 % yield and with up to 50 % ee (Table 8). Higher
enantioselectivities (up to 94 % ee) were later observed with
modified N-fluoro cinchona alkaloids.[69] In a similar manner,
enantioselective fluorinations with a reagent combination of a
cinchona alkaloid derivative and 1 were demonstrated
(Table 9).[70] This method bypasses the isolation of the Nfluoroammonium salt and therefore constitutes a one-pot
Table 8: Enantioselective fluorination with [NF]+ cinchona alkaloids
(see Figure 3).[6668]
204
[NF]+
ee [%]
Configuration
Yield [%]
23 a
23 b
23 c
23 d
50
40
27
20
S
R
R
S
98
70
87
98
Table 9: Enantioselective fluorination with a combination of DHQB and

1.[70]
ee [%]
Configuration
Yield [%]
Me
Et
Bn
Me
Et
Bn
1
1
1
2
2
2
53
73
91
40
67
71
R
R
R
R
R
S
93
100
86
94
71
95
procedure, in which a mixture of the cinchona alkaloid and 1

can be added to a variety of substrate types, including silyl
enol ethers. Both cyclic and acyclic carbonyl compounds were
fluorinated in good to excellent yields with selectivities
sometimes greater than 90 % ee by this method, which is
also useful for b-keto esters (up to 80 % ee) and acyclic bcyano esters (up to 87 % ee). Significant progress has been
made in the development of an enantioselective electrophilic
fluorination method. In most cases cinchona alkaloids and
selectfluor have been used in a transfer fluorination to access
the corresponding chiral electrophilic fluorination reagents.
This strategy has proved to be very practical, especially
because of the commercial availability of the cinchona
alkaloid derivatives.
A major breakthrough would be the development of
catalytically active enantioselective fluorination reagents. The
systematic investigation of the catalytic activity of various
transition-metal complexes in the electrophilic fluorination of
ketones led to the discovery that the taddol-modified
(taddol = a,a,a,a-tetraaryl-2,2-dimethyl-1,3-dioxolan-4,5-dimethanol) titanium complexes 24 a and 24 b are highly
efficient catalysts for the enantioselective fluorination of bketo esters (Scheme 27).[71] It was hypothesized that the
interaction of the ketoester with the Lewis acidic catalyst
induces enolization, and that the resulting enol is then
fluorinated enantioselectively with 1. This mechanistic rationalization is supported by previous reports of a rate enhancement in the fluorination of ketones with N-fluoropyridinium
salts in the presence of zinc(ii) chloride.[10] Further mechanistic details[72] were reported.
6. Mechanism of Fluorination with Selectfluor:

Electron Transfer or SN2 Reaction?
The mechanism of fluorination with NF reagents has
been a subject of debate since their introduction. There are
two possible mechanistic pathways: single-electron transfer
(SET) or nucleophilic SN2 substitution. As shown in
Scheme 28, both SET and SN2 pathways lead to the same
product, in this case a fluorinated carbocation. Banks and coworkers initially voiced support for a SET mechanism to
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Scheme 27. Catalytic enantioselective electrophilic fluorination with chiral titanium complexes.[71] DME = 1,2-dimethoxyethane.
Scheme 28. Single- and two-electron processes in the presence of 1

can result in identical products.
explain reactions with selectfluor,[54] but later spoke of a

substrate-dependent mechanistic continuum [SN2(F)$fully
developed SET process] [15] As discussed below, the
difference between the two mechanisms is probably smaller
than it appears, and the limits of current methods to study
extremely fast reactions inhibit the definitive elucidation of
the operative mechanism.
Supporters of the nucleophilic-substitution theory have
undertaken creative and elegant experiments to refute the
intermediacy of discrete radical species. Differding and coworkers were the first to use radical clocks to monitor the
Angew. Chem. Int. Ed. 2005, 44, 192 212
reaction for the presence of intermediate radicals.[73, 74] Their

experiment was based on the following logic: If the potassium
enolate 25 a were to react in an SET process, the resulting
radical 25 b would undergo cyclization to the radical 25 c
(Scheme 29). The recombination of 25 c and atomic fluorine
would produce some amount of 26 c and 26 d, thus proving the
existence of radicals in the reaction. Their results clearly
demonstrated that no products of cyclization were formed in
the reaction, providing support for the notion that electrophilic fluorination does not involve SET (Table 10).
However, other issues have to be taken into account. The
cyclization of a 5-hexenyl radical has been shown definitively
to occur at a rate of approximately 1 105 s1;[75] however,
according to Differding and Regg, 25 b is not a pure alkyl
radical, but is subject to the electronic effects of the adjacent
ester group. Furthermore, it was determined by laser flash
photolysis that the absolute rate constant for the reaction of
atomic fluorine (FC) with a solvent is between 109 and
1011 s1,[76] some four to six orders of magnitude faster than
the fastest possible closing of a 5-hexenyl radical. Since the
reactivity of FC was studied by the abstraction of a hydrogen
atom from the solvent and found to be diffusion controlled,[76]
the recombination of FC with any alkyl radical should proceed
at an equal or greater rate.
The arguments for an SET pathway for fluorination by N
F reagents are quite compelling, but they must be interpreted
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C.-H. Wong et al.
transition state for the SET reaction with organolithium

compounds occurs in such an early phase of the reaction that
FC reacts with the solvent preferentially, with no formation of
the desired product. Kochi and co-workers later suggested
that the stability of the organic radicals has a strong influence
upon whether fluorinated product is generated, or HF from
the reaction of FC with the solvent and numerous other organic
side products.[79] In the end, Umemoto may have been correct
in his interpretation of the data,[10] but until this question is
addressed further, caution should be employed when invoking this argument to support an SET mechanism with NF
reagents.
Much stronger evidence for the SET mechanism was
found first by Umemoto et al.[10] and later by Kochi and coworkers.[79, 80] Umemoto et al. commented on a color change
that occurred when 27 reacted with 2-napthol and a disappearance of the color as the reaction proceeded further.
They surmised that the color change was caused by the
formation of a p complex between the reagent and the
substrate (Scheme 30).[10] Later, Kochi and co-workers attrib-
Scheme 29. Experimental attempt to differentiate between SET (a) and

two-electron-transfer (b) reactions with 25 a.[73, 74]
Table 10: Yields of products (in %) from reactions of fluorinating

reagents with 25 a (see Scheme 29).[73, 74]
XF2
26 a
26 b
26 c
26 d
25 a
59
23
< 10
21
31
20
64
23
13
11
10
10
with caution. Umemoto et al. observed that the reaction of Nfluoropyridinium salts with Grignard reagents provided alkyl
fluorides, whereas their reaction with the related organolithium reagents did not.[10] They used this finding to justify
the notion that NF reagents react through SET, since
Grignard reagents were shown to react in such a manner.
However, work by Holm and Crossland showed that Grignard
reagents can react by an SN2 mechanism.[77] Thus, the degree
of SET versus SN2 character of reactions of Grignard reagents
depends on several factors. Furthermore, Yamataka et al.
reported that organolithium reagents react almost exclusively
by SET. They suggested that the rate-determining step is the
electron transfer, unlike for Grignard reagents, in which case
the recombination of the radicals is the rate-determining
step.[78] If both studies are taken together, one possible
interpretation of the finding of Umemoto et al. is that the
206
Scheme 30. Electrophilic fluorination via a charge-transfer (CT) complex as an intermediate.[10]
uted this color change to a charge-transfer complex, thus

relating the mechanism of electrophilic aromatic fluorination
with that of electrophilic aromatic nitration.[79, 80] The latter
was elegantly shown by Perrin to proceed by SET.[81] Singleelectron transfer from the substrate to 27 results in a complex
between FC and pyridine, which could be stabilized by the
donation of a p electron from pyridine to yield the chargetransfer complex 28. Kochi and co-workers also found
evidence for the participation of the charge-transfer complex
as a reaction intermediate by demonstrating that photoexcitation at the CT band led to a dramatic increase in the
rate of fluorination and the yield relative to the corresponding
thermochemical reaction (Scheme 31).[79]
Selectfluor and the other compounds of this general class
are the only electrophilic fluorination reagents for which no
clear evidence has been found for the intermediacy of radical
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Scheme 31. Comparison of photochemical and thermochemical

reaction products.[79]
intermediates. The DesMarteau reagent (2, Scheme 2) is

inhibited by p-dinitrobenzene,[12] an efficient electron-transfer quencher, and N-fluoropyridinium reagents display CT
bands indicative of SET, as described previously.[10] No
evidence for radical intermediates was identified in reactions
of 1 with 29 a (Scheme 32),[20] a derivative of a phenylcyclopropyl radical trap that was shown to undergo ring opening at
rates as high as 2 1011 s1.[82] Comparison of the fluorinating
reagents 4 g and 30, which is known to react by the SET
mechanism, led to inconclusive results, as 29 b was formed
from 29 a in virtually identical yield in the two reactions
(Table 11). Furthermore, the findings of Horner et al. indicate
that numerous other factors, such as solvent polarity and the
choice of nucleophile, may complicate the use of enol ether
Table 11: Yields of isolated products from reactions of electrophilic
fluorinating reagents with 29 a.[20]
Mechanism
29 b [%]
29 c [%]
???
45
not detected
SET
40
radical traps to detect radical intermediates.[83] However, the

fact that 2,2,6,6-tetramethylpiperidine N-oxide (TEMPO),
which is oxidized by a suitable oxidant (Cl2, Br2, XeF2, etc.) by
liberation of a single electron,[84] reacts rapidly with selectfluor[20] strongly suggests that selectfluor can participate in
SET reactions. Based on this evidence and on additional data
supporting SET with other NF reagents, it is probable that
SET also occurs with selectfluor, but that the radical
intermediates are strongly destabilized and therefore unlikely
to be detected. As 1, unlike 2 and 27, lacks a polarizable pelectron-donor center to stabilize FC, the unstabilized fluorine
radical would react immediately with the radical cation
formed from the substrate by SET. Thus, the use of radical
traps, such as the phenylcyclopropyl radical system,[82] would
be inappropriate, since they only measure rates below the
diffusion limit. This hypothesis was supported by molecular
dynamics calculations performed by Togni and co-workers on
a simplified system. Their results indicated that the lifetime of
the intermediate radicals is approximately 3 1015 s:[72]
roughly 1000 times shorter than the time required for
phenylcyclopropylmethyl radical to rearrange. If an SET
mechanism were operative in the case of selectfluor, then only
the first of two distinct reactions could be monitored: the SET
from the substrate to 1, and not the subsequent recombination
of the proximal radicals. As the reaction of FC with the solvent
occurs at the rate of diffusion (see above),[76] the reaction of FC
with an existing radical must also be at least as fast as
diffusion. Hence, the recombination of the carbon-centered
radical and FC would most likely occur faster than the
rearrangement of the solvent, making solvent interaction,
and therefore rates of diffusion, irrelevant. These arguments
suggest why selectfluor only displays net SN2 reactivity.
An explanation for the greater electrophilic reactivity of
selectfluor over other R3N+F reagents can most readily be
derived from the unique orbital configuration of dabco and
from an X-ray crystallographic analysis. Recently, electron
momentum spectroscopy[85] confirmed a long-standing theoretical prediction by Hoffmann et al.[86] that the lone pairs of
electrons on the two nitrogen atoms of dabco do not occupy
the expected orbitals according to classic valence bond
theory,[8789] but instead are delocalized throughout the
entire molecule. The discovery that the radical cation of
dabco was exceptionally stable[90] was directly attributed by
Scheme 32. Proposed mechanisms for the electrophilic fluorination of 29 a.[20]

Angew. Chem. Int. Ed. 2005, 44, 192 212
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C.-H. Wong et al.
Hoffmann et al. to a through-bond interaction in the molecule.[86] Theoretical calculations suggest that F+ is ten times
more unstable than atomic fluorine.[91] The structural changes
that occur upon the fluorination of 31 to give selectfluor (see
X-ray crystal structures)[92] suggest that the fluorine center has
more radical than fluoronium character, as the electron
density in the rest of the molecule decreases (Table 12).
Table 12: Structural comparison of the nonfluorinated cation 31 and 1.[92]
31
Structure
Bond lengths/
interatomic
distances []
N1N2
N2C1
C1Cl
Bond angles [8]
N1-C2-C3
N2-C3-C2
by radical recombination, the two reactions might occur in

such rapid succession that the intermediate is not detected.
William Jencks once wrote, An intermediate is, therefore,
defined as a species with a significant lifetime, longer than
that of a molecular vibration of ~ 1013 s, that has barriers for
its breakdown to both reactants and products.[93] When
reactions proceed at rates greater than 1011 s1, arguments for
or against an SET mechanism become pointless. In our view
selectfluor is capable of reacting through an SET mechanism,
as evident by its reaction with TEMPO, but in the case of
electrophilic fluorination the radicals, if formed at all, react
too quickly to be detected. Thus, based on our previous
work,[20] the only definitive answer is that if SET is occurring,
the radicals involved react faster than rates of diffusion, and
anything beyond that will probably remain unproven.
7. Selected Applications of Fluorinated Compounds

2.559
1.491
1.760
2.477
1.525
1.715
108.61
108.65
107.79
110.59
Compensation occurs through a shortening of the CC bonds,

in agreement with the through-bond (not through-space)
interactions postulated by Hoffmann et al.,[86] and a simultaneous lengthening of the NCH2Cl bond and contraction of
the CH2Cl bond. The contraction of the CH2Cl bond is
suggestive of partial double-bond character between the
methylene and chlorine centers. Therefore, the resonance
structure 31 c, with fluorine as a radical, a double bond
between the methylene and chlorine groups, and dabco as a
radical cation, is perhaps a more realistic interpretation of the
molecular structure of selectfluor (Scheme 33). These results
The fluorination of molecules has many applications in

organic chemistry. For example, the high electronegativity of
fluorine can be used to modulate the electronic properties of a
molecule, and ultrasensitive 19F NMR spectroscopy is a useful
analytical technique for monitoring reactions and obtaining
molecular information (e. g. by Mosher ester analysis for the
determination of enantiomeric excess).[94, 95] However, the
applications of fluorinated molecules in biology are even
more intriguing. Perhaps the oldest examples of fluorinated
biologically relevant molecules are salts of fluoroacetate, the
active component of the poison derived from the South
African gifblaar plant (Dichapetalum cymosum).[96] Biochemically, fluoroacetate is converted into fluoroacetyl CoA,
which enters the tricarboxylic acid (TCA) cycle. Fluoroacetyl CoA condenses with oxaloacetate to form fluorocitrate
(an effective inhibitor of aconitase), which shuts down the
TCA cycle, resulting in convulsions, ventricular fibrillation,
and death.
7.1. Fluorinated Glucocorticoids
Scheme 33. Possible resonance structures for 1.
are consistent with the high reactivity of 1 and its ability to

react in an SET process, since the addition of a single electron
to this system would allow the formation of FC and restore the
electronic state of 31 to that prior to fluorination. Rearrangement of the bonds of 31 would follow, returning it to the more
stable configuration determined by crystallography and leaving unstabilized FC to react immediately with the newly
formed carbon radical.
Despite extensive research into the possible reaction
mechanisms of NF reagents, a definitive answer has not been
found and may remain undiscovered as a result of the
difficulty of assessing reactions in this timeframe. Even if a
reaction were known to proceed exclusively by SET followed
208
The first reported use of fluorination to enhance the

activity of a medicinally useful compound was by Fried and
Sabo in 1954.[97] A year earlier, they had described the
synthesis of derivatives of the glucocorticoid hydrocortisone
(33 a), a steroid hormone with anti-inflammatory and thymolytic activity. Substitution of the 9-aH atom of hydrocortisone
acetate for an iodine, bromine, or chlorine atom resulted in an
increase in activity relative to that of the natural compound
only in the case of the chlorine derivative 33 c.[98] The general
trend in this series suggested that the activity was inversely
proportional to the size of the halogen substituent, thus
prompting the synthesis of the fluorinated derivative.[97] As
can be seen in Table 13, 33 b is more than ten times as active as
naturally occurring hydrocortisone; more importantly, these
studies established fluorination as a promising method for
improving the activity of pharmacologically relevant compounds. Several examples of fluorinated glucocorticoids and
their corresponding activities can be found in Figure 4.[99] As
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Table 13: Activity of halogenated hydrocortisone derivatives.[97, 98]
Compound
Activity[a]
33 a
33 b
33 c
33 d
33 e
H
F
Cl
Br
I
1
10.7
4
0.28
0.1
[a] Assay of glycogen from rat liver.
rides and determinant structural motifs for specific biological

phenomena.
The inhibition of several glycotransferases by fluorinated
sugars has been investigated by our research group.[52, 101] Four
different fucosyltransferases were chosen for this inhibition
study (FucT-III, V, VI, and VII), as well as a-2,6-sialyltransferase and two galactosyltransferases (the configurationinverting bovine b-1,4-GalT and the configuration-retaining
a-1,3-GalT). For FucT, the fluorinated fucose analogues 13a,
13b, and 34 displayed Ki values that were similar to or less
than the KM value for GDP-Fuc (Table 14). Similar results
were obtained for the inhibition of sialyltransferase with 16
(Table 15). The Ki value for the inhibition of b-1,4-GalT by aTable 14: Inhibition of four human fucosyltransferases.[52, 101]
GDP-Fuc
FucT-III
FucT-V
FucT-VI
FucT-VII
KM [mm]
Ki [mm]
Ki [mm]
Ki [mm]
33.6
18.8
9
8
38 4
4 0.6
10 2.4
21 2
22 10
3.4 1
1 0.5
11 2
36 4
21
Table 15: Inhibition of a sialyl- and two galactosyltransferases.[52]

Glycosyltransferase
Inhibitor
a-2,6-SialylT (KM = 15 mm)
b-1,4-GalT (KM = 3 6 mm)

a-1,3-GalT (KM = 17 3 mm)
Figure 4. Biological activities of fluorocorticoids;[99] in each case the

anti-inflammatory activity in rats relative to hydrocortisone acetate is
given.
stated previously, Herrinton and co-workers determined that

1 is a highly efficient fluorinating reagent for the synthesis of
8.[26]
7.2. Fluorinated Glycosyltransferase Inhibitors

Carbohydrates with a fluorine atom adjacent to the
anomeric center demonstrate inhibitory activity towards
some glycosyltransferases and allow insight into enzyme
mechanisms.[100] Given the important role of oligosaccharides
in biological processes, the selective inhibition of certain
mammalian glycosyltransferases could be a potential strategy
against cancer proliferation, xenotransplant rejection, and
tissue inflammation. Fucose, sialic acid, and galactose moieties in particular are essential components of oligosacchaAngew. Chem. Int. Ed. 2005, 44, 192 212
Ki [mm]
5.7 2
2.0 0.3
245
UDP-2F-Gal (19) is approximately equal to the KM value for

the enzyme with the natural substrate, but for the inhibition of
a-1,3-GalT, the only configuration-retaining enzyme in the
study, a Ki value was observed that was 14-fold lower than the
KM value with the natural substrate.
Earlier mechanistic studies with FucT-V demonstrated a
secondary isotope effect with deuteriated GDP-[1-2H]-fucose
and competitive inhibition by 12b.[101] Similar inhibition
patterns were found for FucT-III, VI, and VII.[52] Given the
90 % homology between these enzymes, it was proposed that
they may share a considerable number mechanistic features,
including the formation of an oxycarbenium-like transition
state. These considerations also took into account the
inhibition of fucosyl transferases by 34. Evidence suggests
that the replacement of the hydroxy groups at the 6- or 2position, equidistant from the endocyclic oxygen atom, leads
to similar electronic effectsa potentially valuable result for
future inhibitor design. The good inhibition observed with the
anomerically nonnatural 13a indicates that the binding
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209
Reviews
C.-H. Wong et al.
domain of fucosyltransferases allows stereochemical flexibility.

Recent syntheses of potent inhibitors of a-2,6-sialyltransferase have elucidated important conformational parameters
of the transition-state structure, including sp2 character at the
anomeric position.[102106] However, a cationic transition state,
predicted based on the quaternary structure at the anomeric
carbon atom, has not yet been demonstrated. CMP-3F-sialic
acid (16) has been found to be a competitive inhibitor (Ki =
5.7 mm), thus supporting the involvement of an oxycarbenium
intermediate in the transition state.[42]
Interesting results were obtained with galactosyltransferases.[52] The configuration-inverting b-1,4-GalT was as susceptible to competitive inhibition by 19 as other inverting
glycosyltransferases (Figure 5), whereas the configuration-
(PET).[109] For some nuclei of small atomic mass, radioactive

decay occurs by the emission of a positron, which is a
positively charged particle with the mass of an electron.
Collision of a positron with an electron results in annihilation
and the release of a gamma-ray photon. The radiation can be
analyzed by a photomultiplier in similar way to the detection
of X-rays. A substance containing a b+ emitter can be
introduced into a living organism and then localized noninvasively by detecting the emitted gamma rays in a 3D image
of the organism.
Common positron-emitting nuclei include 11C, 15O, 13N,
and 18F (Table 16). 18F has a relatively long half-life of almost
Table 16: Physical properties of b+-emitting radionuclides.[109]
Radionuclide t1/2
[min]
b+
Maximum Maximum Maximum linear
decay specific
energy
range in H2O
[%]
activity[a]
[mm]
[MeV]
11
99
99
99.9
97
C
N
15
O
18
F
13
20.40
9.96
2.07
109.70
3.4 1011
6.9 1011
3.4 1012
6.3 1010
0.96
1.19
1.72
0.635
4.12
5.39
8.2
2.39
[a] Defined as the number of decay events per second per mole.
Figure 5. Putative transition state for configuration-inverting b-galactosyltransferase.[52]
retaining a-1,3-GalT was only weakly inhibited (Ki = 245 mm,

KM = 17 mm). These results suggest that the mechanisms by
which these two galactosyltransferases catalyze the glycosylation may be strikingly different. This would be consistent
with the differences observed for the glycosidases as a
function of their inverting or retaining nature.[107] Since a
double displacement mechanism could rationally be invoked
for the retaining a-1,3-GalT, experiments were conducted to
determine whether 19 was a slow inactivator of this enzyme.
On the time scale of the experiments performed, no
inactivation was observed, demonstrating that the enzyme
does not form a covalent adduct with the fluorinated substrate
19. In the case of various retaining glycosidases, 2-fluoroglycosides had been shown to form covalent adducts, which is
evidence of the nucleophilic role of carboxylate groups
present in the vicinity of the anomeric center. Indeed, some
5-fluoroglycosides proved to be better, albeit very unstable,
inactivators than the corresponding derivatives fluorinated at
the 2-position.[108]
7.3. Electrophilic Fluorination for 18F Positron Emission

Tomography
The use of radioactive isotopes for chemotherapy and the
elucidation of reaction pathways is well established. Another
useful application for certain nuclei that decay through
positron (b+) emission is positron emission tomography
210
2 h, which makes it possible to carry out synthetic manipulations on substrates without significant loss of activity. The
other nuclei must be used immediately upon formation
(usually occurs in a cyclotron) because of their shorter halflives. 18F-labeled reagents can be delivered to nearby sites,
such as hospitals and universities, making research more
practical. Finally, the positrons emitted from 18F have much
lower kinetic energy than those from the other nuclei, which
translates to shorter distances between emission and annihilation, and thus to higher resolution.
Fluorination with 18F is limited by the small number of
labeled reagents that can be made. The bombardment of 18Olabeled water with high-energy protons results in the absorption of a proton by each 18O nucleus, followed by the emission
of a neutron, to provide nucleophilic 18F ions, which can be
separated by ion exchange. Alternatively, the absorption of a
high-energy deuteron by a 20Ne nucleus in a gas mixture of Ne
with 0.1 % F2, followed by the emission of an a particle, gives
18
F2 gas for electrophilic fluorination. Labeled molecular
fluorine has been used directly for electrophilic fluorinations,
but it has also been converted into other electrophilic
fluorinating reagents, such as acetyl [18F]fluoride
(AcO18F),[110, 111] [18F]fluoropyridones,[112, 113] [18F]fluoro-N-sulfonamides,[114] and labeled xenon difluoride (Xe18F2).[115, 116]
The use of 18F and other positron-emitting nuclei necessitates fast and simple chemistry, as well as safeguards against
the dangers of handling radioactive material. All manipulations for the synthesis of 18F-labeled compounds (including
purification) must be completed in approximately 12 h to
ensure sufficient active material for clinical use. The use of
automated synthesizers and robotics has shortened the length
of time needed to synthesize compounds and eliminates the
dangers associated with the handling of radioactive material.
Many different applications of 18F-labeled compounds in
PET have been described. The first 18F-labeled compound to
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Angew. Chem. Int. Ed. 2005, 44, 192 212
Angewandte
Chemie
be used in PET was [2-18F]fluoroglucose for monitoring

glucose metabolism in organs.[117119] This method is still the
most popular use of PET, with applications in oncology,
cardiology, and neurology. Dopamine metabolism can be
monitored by 18F-labeled l-DOPA, a technique that is useful
in neurological diseases, such as schizophrenia and Parkinsons disease (DOPA = 3-(3,4-dihydroxyphenyl)alanine).[120]
Steroids labeled with 18F have been used to image breast
and prostate tumors.[121]
The development of 18F-labeled selectfluor would revolutionalize electrophilic fluorination in much the same way as
the development of the unlabeled reagent, and would enable
the synthesis of labeled compounds with more complex
structures by existing methodologies. For example, the synthesis of the fluorinated daunorubicin analogue in Scheme 13
can be carried out quickly enough that 18F could be
introduced.[122] As the use of PET as a noninvasive imaging
technique becomes more widespread, there will be increased
demand for new methodology for the incorporation of 18F into
molecules of interest in a safe, efficient, and selective manner.
Because of its general applicability, high reactivity, and safety,
selectfluor is a reagent with great potential for the development of new fluorination methods.
8. Conclusion
Electrophilic fluorination is an extremely useful and
viable method for the incorporation of fluorine into organic
molecules and a natural complement to nucleophilic fluorination. Although initially molecular fluorine was the only
available reagent, the demand for a safe alternative has led to
a plethora of reagents that deliver fluorine effectively under
electrophilic conditions. Over the years the development of
safer and milder reagents ultimately led to the discovery of
selectfluor, which now represents the hallmark for stability,
reactivity, and mildness within the realm of electrophilic
fluorinations. Furthermore, the unique reactivity of selectfluor enables deeper insight into complex reactions and
demands new experiments and methods to probe the underlying mechanisms.
This work was supported by the NIH. P.T.N. acknowledges a
fellowship from the Skaggs Foundation.
Received: January 8, 2004
Published Online: December 1, 2004
Please note: Unfortunately the authors omitted to cite an important
review on fluorination with selectfluor in the version of their article
published online in Angewandte Chemie Early View.[123] The authors
apologize for this oversight.
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Selectfluor: Mechanistic Insight and Applications

2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Angew. Chem. Int. Ed. 2005, 44, 192 212

The replacement of hydrogen atoms with fluorine substituents in

From the Contents

organic substrates is of great interest in synthetic chemistry because of

2. Selectfluor: Properties and

3. Electrophilic Fluorination with

4. Other Transformations with

popularity. In comparison to the previous reagents, these

Scheme 2. Synthesis of 2 by DesMarteau and co-workers.[11, 12]

Scheme 1. Electrophilic fluorinating reagents.

[*] P. T. Nyffeler, Dr. S. G. Durn, Dr. M. D. Burkart, Dr. S. P. Vincent,

2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

C.-H. Wong et al.

electrophilic fluorine, was a step forward in the identification

2. Selectfluor: Properties and Preparation

Sergio G. Durn received his BS in chemistry

Mike Burkart was born in Arlington, Texas in

Chi-Huey Wong received his BS and MS

2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Angew. Chem. Int. Ed. 2005, 44, 192 212

The preparation of selectfluor, which is produced in

Scheme 3. Method for preparing 1.[18, 19]

compound. In earlier studies, no obvious effect of the

exchange with sodium tetrafluoroborate and subsequent

Scheme 4. Methods for synthesizing F-TEDA-X derivatives.[15]

Figure 2. F-TEDA-X derivatives. Tf = trifluoromethanesulfonyl.

variant of the F-TEDA-X reagents is 4 j, which even

reactions, involves fluorination of 5 a at 35 8C in acetonitrile,

2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

C.-H. Wong et al.

3. Electrophilic Fluorination with Selectfluor

best reagent for converting 7 into 8 (Scheme 6).[26] In a further

Scheme 6. Glucocorticoid fluorination.[26]

3.1. Solvent Requirements and Restrictions

(Scheme 7) and tetronic acid (Scheme 8).[27, 28] The tetronic

Scheme 7. Synthesis of a fluorinated derivative of l-ascorbic acid.[28]

3.2. a Fluorination of Carbonyl Functionalities

Scheme 8. Synthesis of a fluorinated tetronic acid derivative.[27]

ether, Hoffman and Tao were able to synthesize fluorinated

3.3. a Fluorination and Oxidation of Thioethers

2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Angew. Chem. Int. Ed. 2005, 44, 192 212

Scheme 10. Direct conversion of thioglycosides into a-fluoro sugars.[32]

Glycosyl fluorides can be accessed directly from anomeric

Scheme 9. a Fluorination of thioethers.

at room temperature to form a fluorosulfonium salt (e. g. 9). It

[a] Bn = benzyl, Bz = benzoyl, Lev = levulinyl, Tol = tolyl, Troc = 2,2,2trichloroethoxycarbonyl.

3.4. Synthesis of Glycosyl Fluorides

Scheme 11. Proposed mechanism for the substitution of an anomeric

demonstrates the potential of this combination as a safe

3.5. Fluorination of Aromatic Compounds

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C.-H. Wong et al.

Table 2: Synthesis of 4-fluorocyclohexadienones from 4-substituted

atives of the cardiotonic oleandrigenin and the antibiotic

3.6. Fluorination of Alkenes

Scheme 12. Proposed mechanism for the fluorination and glycosylation

2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

represents a potential avenue for the design of more potent