c-h. wong et. al. angew. chem., int. ed. engl., 2005, 44, 192-212

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Fluorination Reagents

Selectfluor: Mechanistic Insight and ApplicationsPaul T. Nyffeler, Sergio Gonzalez Durn, Michael D. Burkart, Stphane P. Vincent,

and Chi-Huey Wong*

AngewandteChemie

Keywords:

electrophilic addition · electrophilicsubstitution · fluorination ·fluorine · reactionmechanisms

C.-H. Wong et al.Reviews

192 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/anie.200400648 Angew. Chem. Int. Ed. 2005, 44, 192– 212


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1. IntroductionThe 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 fluori-

nating 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. Thefirst 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 fluo-

rides,[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 electro-

philic fluorine still remained.

Recently, a new class of electrophilic fluorinating reagents

with the general structure R2NF or R3N F began to gain

popularity. In comparison to the previous reagents, these

compounds were milder, safer, more stable, and less expen-

sive 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 goodactivity 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

[*] P. T. Nyffeler, Dr. S. G. Durn, Dr. M. D. Burkart, Dr. S. P. Vincent,Prof. C.-H. WongDepartment of Chemistry andThe Skaggs Institute for Chemical BiologyThe Scripps Research Institute10550 North Torrey Pines Road, BCC 357La Jolla, California 92037 (USA)Fax: ( 1)858-784-2409E-mail: [email protected]

T he replacement of hydrogen atoms with fluorine substituents inorganic 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 andexplosive 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 electro-

philic 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.

From the Contents

1. Introduction 193

2. Selectfluor: Properties and

Preparation 194

3. Electrophilic Fluorination withSelectfluor 196

4. Other Transformations with

Selectfluor 201

5. Enantioselective

Transformations 203

6. Mechanism of Fluorination

with Selectfluor: Electron

Transfer or S N2 Reaction? 204

7. Selected Applications of Fluorinated Compounds 208

8. Conclusion 211

Scheme 1. Electrophilic fluorinating reagents.

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

Electrophilic Fluorination Angewandte

Chemie

193 Angew. Chem. Int. Ed. 2005, 44, 192– 212 DOI: 10.1002/anie.200400648 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim


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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 ulti-

mately 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

lends itself to large-scale synthesis and

is commercially available. A number of

reagents, each with its advantages and

disadvantages, currently exist for the

electrophilic incorporation of fluorine

and have been the subject of several

reviews.[13–16] This Review focuses on the versatility of the

selectfluor reagent and its applications, and includes some

mechanistic insight into plausible reaction pathways.

2. Selectfluor: Properties and Preparation

Selectfluor,[15,17] an exceptionally stable, virtually non-

hydroscopic 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 transport-

ing 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

C for 7 days; during this time the temperature remained

constant within 5

C.[18] Selectfluor has been found to be

stable at temperatures up to 195

C, although the inventors

warn that bulk samples should only be heated above 80

C

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 isrelatively harmless. Toxicology studies revealed an oral LD50(dose needed to kill 50% of the subjects) of 640 mgkg1 for

male adult rats; skin exposure up to 2.0 gkg1 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.

Paul T. Nyffeler was born in Stromsburg,Nebraska in 1976. He received his BA in1999 from Carleton College, where he stud-ied the stereochemistry of enolate reactionsunder the tutelage of Prof. Jerry Mohrig. Hethen moved to The Scripps ResearchInstitute, where his ongoing research in thelaboratory of Chi-Huey Wong includes thediazotransfer reaction, regioselective azidereductions, fluorinated glycolipids, and the

study of dihydrogen trioxide.

Sergio G. Durn received his BS in chemistry from the University of Texas at Austin in1995. After a year at Hoechst-Celanese, hemoved to the University of Illinois atUrbana-Champaign, where he carried outresearch on the total synthesis of batzella-dine A with David Y. Gin. After completing his PhD he pursued postdoctoral studies atThe Scripps Research Institute with Chi-Huey Wong on new methods for the one-potsynthesis of complex oligosaccharides and the synthesis of fluorinated carbohydrates.He is currently at Kalypsys, Inc. in SanDiego.

Mike Burkart was born in Arlington, Texas in1972 and received his BA in chemistry fromRice University. During his graduate studieswith Chi-Huey Wong at The ScrippsResearch Institute, he explored the synthetic chemistry of fluorinated carbohydrates and their application as enzyme inhibitors. Fol-lowing postdoctoral studies with Chris Walshat Harvard Medical School, he initiated hisown research group in 2002 at the Univer-sity of California, San Diego. His currentresearch interests include natural productbiosynthesis and antibiotic design.

Stphane Vincent received his PhD in bio-organic chemistry from the Universit LouisPasteur (Strasbourg, France) with CharlesMioskowski. After postdoctoral studies firstat The Scripps Research Institute in theresearch group of Chi-Huey Wong and thenin Strasbourg with Jean-Marie Lehn, he took up a permanent position as a CNRS researcher in 2001 in the laboratory of Pierre Sinaÿ (Ecole Normale Suprieure,Paris). His research interests include theglycosciences, biocatalysis, and mechanistic enzymology.

Chi-Huey Wong received his BS and MS from the National Taiwan University, and his PhD in chemistry from the Massachu-setts Institute of Technology. After a year asa 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 encom-pass organic and chemoenzymatic methodsin synthesis with a specific focus on the studyof carbohydrate-mediated biological recognition.

Figure 1. Selectfluor,1-chloromethyl-4-flu-orodiazoniabicy-clo[2.2.2]octane bis(-tetrafluoroborate).


194 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org Angew. Chem. Int. Ed. 2005, 44, 192– 212

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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]oc-

tane (dabco, also known as triethylenediamine (TEDA)) with

the dichloromethane solvent (Scheme 3). After counterion

exchange with sodium tetrafluoroborate and subsequentprecipitation 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 2,2,2-

trifluoroethyl derivative 4 j (Figure 2). The most powerful

variant of the F-TEDA-X reagents is 4 j, which evenfluorinates benzene. In general, the more electron withdraw-

ing the alkyl substituent is, the more electrophilic the fluorine

group will be. From an economic standpoint, the chloro-

methyl derivative 1 is an ideal reagent, as it has the second-

highest 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 -fluoropyridin-

ium and N -fluoroquinuclidinium reagents.

The counterion employed with selectfluor can have an

impact on both the reactivity and the cost of the final

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] How-

ever, recent studies demonstrated that the use of the

trifluoromethanesulfonate (triflate) salt 4 g for the fluorina-

tion 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 (nitrometh-

ane) 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

reactions, involves fluorination of 5 a at35

C 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 industrial-

scale 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 formationduring 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 feasibil-

ity of this process, selectfluor is commercially available,

precluding the need for its preparation.

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

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

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


Chemie

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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 select-

fluor.

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 partic-ipation, 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-butyl-

3-ethylimidazolium, for reactions with 1 has received atten-

tion.[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.

3.2. a Fluorination of Carbonyl Functionalities

The incorporation of a fluorine substituent adjacent to a

carbonyl group is a common reaction motif. This trans-

formation 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

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 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

ether, Hoffman and Tao were able to synthesize fluorinated

peptide analogues with high diastereo- and enantioselectiv-

ity.[29]

The incorporation of fluorine into b-diketones is readilyaccomplished by the reaction of selectfluor with the corre-

sponding 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,a-

difluoroketones can be formed regioselectively by the reac-

tion of selectfluor with alkynes.[31]

3.3. a Fluorination and Oxidation of Thioethers

Reactions of thioether-containing compounds with select-

fluor lead to interesting synthetic products. For example,Scheme 5. a Fluorination of ketones via an enol ester or a silyl enolether.[25]

Scheme 6. Glucocorticoid fluorination.[26]

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

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





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thioethers with a protons can be converted into a-fluorosul-

fides in reasonable yields (Scheme 9).[25] This process occurs

by initial reaction of the sulfide with selectfluor in acetonitrile

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

was proposed that this intermediate undergoes a Pummerer-

like 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

C in acetonitrile/water mixtures. Essentiallyquantitative yields were observed for all substrates examined.

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]

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

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 highyields.[20,32] Its application in the glycosylation of 2-deoxy-

thioglycosides 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

C).[15]

Higher yields, up to 20% conversion, wereobserved 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]

Scheme 9. a Fluorination of thioethers.[25]

Table 1: Oxidation of thioglycosides to sulfoxides.[20]

Product[a] Yield [%] Product[a] Yield [%]

99 99

99 99

99 99

99 99

95 99

[a] Bn=

benzyl, Bz=

benzoyl, Lev=

levulinyl, Tol=

tolyl, Troc=

2,2,2-trichloroethoxycarbonyl.

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

Scheme 11. Proposed mechanism for the substitution of an anomerichydroxy group for a fluorine substituent in the presence of methylsulfide and 1.[20,32]


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3.6. Fluorination of Alkenes

The susceptibility of alkenes to functionalization with

electrophilic species provides a convenient handle for fluo-

rination 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-2-

fluoroglycosides 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 reac-

tion. By employing this methodology, 2-fluoroglycosyl deriv-

atives of the cardiotonic oleandrigenin and the antibiotic

daunorubicin were accessed in good yields (Scheme 13). The

synthesis of fluorinated analogues of current pharmaceuticals

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 generallyemployed, 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 synfashion, 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

Table 2: Synthesis of 4-fluorocyclohexadienones from 4-substitutedphenol derivatives.[35]

Substrate Product 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 inbrackets refer to the yield of the isolated product.

Scheme 12. Proposed mechanism for the fluorination and glycosylationof glycals.[20,22,32,41]

Scheme 13. 2-Fluoroglycosyl derivatives of oleandrigenin and daunomy-cinone.[20] Piv=pivaloyl.





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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 selectivityof 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 fluoroox-

indole derivatives (Scheme 15).

[44]

This method takes advan-

tage of the nucleophilic character of the enamine function-

ality contained within the indole moiety. The choice of solvent

was crucial, as the products decomposed when only acetoni-

trile was used. Although mixtures of acetonitrile with eithermethanol 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 con-

version into the fluorooxindoles was efficient.

The functionalization of indoles with selectfluor was

further extended to the synthesis of some hexahydropyra-

zino[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,

including gypsetin[45,46] and brevianamide E.[47] The synthesis

of the fluorinated core of these biologically relevant mole-

cules by using 1 is illustrated in Schemes 16 and 17).

[48]

Scheme 14. The conformation and configuration at the anomeric center of the intermediates determine the anomeric selectivity in reactions of glycals.[20]

Scheme 15. Fluorination of an indole.[44]

Table 3: Electrophilic fluorination of indoles. [44]

R R’ Yield [%]

(CH2)2CO2Me H 82(CH2)3CO2Me H 77(CH2)2CH(NHpNB)CO2Me

[a] H 92(CH2)2NPhth

[b] H 82(CH2)2NPhth

[b] OAc 82

[a] pNB=para-nitrobenzyl. [b] Phth=phthaloyl.

Scheme 16. Fluorination of gypsetin derivatives.[52]

Scheme 17. Synthesis of the fluorinated core of brevianamide E. [48]


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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

positron emission tomography (PET). Greedy and Gouver-

neur showed that this transformation is not limited to tin-containing 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.

3.9. Oxidative Phosphorylation: Synthesis of 2-Fluoro Sugar

Nucleotides

The substitution of the 2-hydroxy group of monosaccha-

rides 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-fluorofu-

cosylguanine diphosphate (GDP-2F-Fuc; 13a and 13b,

respectively) is a demonstrative example of this general

strategy (Scheme 20). The electrophilic fluorination of 3,4-di-

O-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. Afterchromatographic 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 infec-

tion, inflammation, and cell signaling.[42] Synthetic analogues

of this monosaccharide have been utilized to probe cell-

surface 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 fluorophosphor-

ylation was employed (Scheme 21).

[42]

The glycal derivative17 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 palla-

dium-catalyzed deallylation, deacetylation, and saponifica-

tion then provided the desired product in good yield.

The use of selectfluor to prepare fluorinated monosac-

charides is also amenable to the one-pot chemoenzymatic

synthesis of sugar nucleotide diphosphates (Scheme 22).[52]

The electrophilic fluorination of galactal with 1 was con-

ducted in water to provide 2-fluorogalactose, which, after pH

Scheme 18. Conversion of a vinyl stannane into a fluoride. [50]

Scheme 19. Conversion of vinyl silanes into fluoroalkanes or a,a-difluoroethers.[51]

Scheme 20. Synthesis of a-GDP-2F-Fuc (13a) and b-GDP-2F-Fuc (13b).[20,52]





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adjustment, was phosphorylated by galactokinase. Adenosine

triphosphate (ATP), the phosphate source for this trans-

formation, 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. Thedesired product 19 is formed in good yield, and the procedure

can be carried out on a preparative scale.

4. Other Transformations with Selectfluor

4.1. Oxidation of Benzylic Alcohols

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

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 1could 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.

4.2. Oxidation of Tertiary Carbon Centers

In an interesting transformation of ()-menthol (20),

remote functionalization of alcohols in the presence of excess

selectfluor was demonstrated (Scheme 24).[55] The reaction

Scheme 21. Synthesis of CMP-3F-sialic acid.[42]

Scheme 22. Chemoenzymatic synthesis of UDP-2F-Gal.[52]


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proceeds through initial formation of a tertiary carbocation,

which subsequently reacts with the solvent (in this case

acetonitrile), and the resulting intermediate is trapped intra-

molecularly 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. Thismethod 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.

4.3. Selectfluor-Mediated Allylstannation of Aldehydes and

Imines

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 theexclusion 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 alde-

hydes 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

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.

4.4. Selectfluor-Mediated Functionalization of Aromatic Systems

Although selectfluor is most often used as an electrophilic

reagent for the introduction of fluorine substituents, it canalso mediate the electrophilic addition of other common

anions. The inherent electrophilic activity of 1 has been

exploited recently for the conversion of nucleophilic com-

pounds 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

Scheme 23. Oxidative functionalization of p-chlorobenzaldehyde.[54]

Scheme 24. Remote functionalization of ()-menthol.[55]

Scheme 25. Allylstannation of aldehydes and imines.[56]

Table 4: Iodination of aryl compounds with 1 and iodine.[57]

Substrate Aryl/1/I2 Product Yield [%]

1:0.75:0.75 95

1:0.6:0.6 93

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 three-

component 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 reac-

tion is substrate dependent and proceeds faster for some

nucleophiles in DMF and for others in acetonitrile. Acetate

and trifluoroacetate could be converted into the correspond-ing electrophilic species for a limited number of substrates,

but with other anions (CN, OCN, CH3O , CH3S

) no

reaction occurred under any conditions investigated.

4.5. Protecting-Group Removal

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 appli-

cation as a result of its low cost, ease of introduction, and

stability. The addition of stoichiometric amounts of select-fluor leads to the selective, mild cleavage of THP ethers in

high yields (Table 5).[62] Under these mild conditions, alde-

hydes and olefins are tolerated. The protecting group p-

methoxybenzylidene, 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

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

Selectfluor has been utilized, either directly or indirectly,

in many types of enantioselective reactions. Enders et al.

described the regio- and enantioselective electrophilic fluo-rination 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 nucleo-

philic 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.

Table 5: Deprotection of THP ethers with 1.[62]

Substrate Product Yield [%]

94

92

95

89

Table 6: Deprotection of p-methoxybenzylidene with 1.[62]


90

87

92

90

Table 7: Deprotection of 1,3-dithianes with 1.[62]


95

85

95

85

80


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Improved enantioselective fluorinations were observed

with a new class of charged [NF] reagents. Selectfluor was

used to prepare the N -fluoroammonium derivatives 23 a–d of

cinchona alkaloids by transfer fluorination (Figure 3,

Scheme 26).[66–68] The fluorinated reagents 23 a–d were

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 N-

fluoroammonium salt and therefore constitutes a one-pot

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 selectivitiessometimes greater than 90% ee by this method, which is

also useful for b-keto esters (up to 80% ee) and acyclic b-

cyano 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 varioustransition-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-di-

methanol) titanium complexes 24 a and 24 b are highly

efficient catalysts for the enantioselective fluorination of b-

keto 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 ration-

alization is supported by previous reports of a rate enhance-

ment in the fluorination of ketones with N -fluoropyridinium

salts in the presence of zinc(ii) chloride.[10] Further mecha-

nistic details[72]

were reported.

6. Mechanism of Fluorination with Selectfluor:Electron Transfer or S N2 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 co-

workers initially voiced support for a SET mechanism to

Figure 3. N-Fluoroammonium derivatives of cinchona alkaloids forenantioselective electrophilic fluorination.[66–68]

Scheme 26. Synthesis of the fluorinated cinchona alkaloid F-CD-BF4.[66–

68]

Table 8: Enantioselective fluorination with [NF] cinchona alkaloids(see Figure 3).[66–68]

[NF] ee [%] Configuration Yield [%]

23 a 50 S 9823 b 40 R 7023 c 27 R 8723 d 20 S 98

Table 9: Enantioselective fluorination with a combination of DHQB and1.[70]

R n ee [%] Configuration Yield [%]

Me 1 53 R 93Et 1 73 R 100Bn 1 91 R 86Me 2 40 R 94Et 2 67 R 71Bn 2 71 S 95





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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 co-

workers were the first to use radical clocks to monitor the

reaction for the presence of intermediate radicals.

[73,74]

Theirexperiment was based on the following logic: If the potassium

enolate 25 a were to react in an SET process, the resulting

radical 25b 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 electro-

philic 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, 25b is not a pure alkylradical, 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

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 1can result in identical products.


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with caution. Umemoto et al. observed that the reaction of N -

fluoropyridinium salts with Grignard reagents provided alkyl

fluorides, whereas their reaction with the related organo-

lithium reagents did not.[10]

They used this finding to justifythe 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

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 invok-

ing 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 co-

workers.[79,80] Umemoto et al. commented on a color change

that occurred when 27 reacted with 2-napthol and a dis-

appearance 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-

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]

Single-electron 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 charge-

transfer complex 28. Kochi and co-workers also found

evidence for the participation of the charge-transfer complex

as a reaction intermediate by demonstrating that photo-

excitation 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

Scheme 29. Experimental attempt to differentiate between SET (a) andtwo-electron-transfer (b) reactions with 25 a.[73,74]

Table 10: Yields of products (in %) from reactions of fluorinatingreagents with 25 a (see Scheme 29).[73,74]

26 a 26 b 26 c 26 d 25 a

59 23 0 0


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intermediates. The DesMarteau reagent (2, Scheme 2) is

inhibited by p-dinitrobenzene,[12] an efficient electron-trans-

fer quencher, and N -fluoropyridinium reagents display CT

bands indicative of SET, as described previously.

[10]

Noevidence for radical intermediates was identified in reactions

of 1 with 29 a (Scheme 32),[20] a derivative of a phenylcyclo-

propyl 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 29a 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

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 select-

fluor[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 p-

electron-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 SETmechanism 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 bederived from the unique orbital configuration of dabco and

from an X-ray crystallographic analysis. Recently, electron

momentum spectroscopy[85] confirmed a long-standing theo-

retical 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,[87–89] 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 31. Comparison of photochemical and thermochemicalreaction products.[79]

Scheme 32. Proposed mechanisms for the electrophilic fluorination of 29 a.[20]

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 5


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Hoffmann et al. to a through-bond interaction in the mole-

cule.[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).

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 simulta-

neous 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 resonancestructure 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

are consistent with the high reactivity of 1 and its ability toreact 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. Rearrange-

ment of the bonds of 31 would follow, returning it to the more

stable configuration determined by crystallography and leav-

ing 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

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

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] Biochem-

ically, fluoroacetate is converted into fluoroacetyl CoA,

which enters the tricarboxylic acid (TCA) cycle. Fluoroace-

tyl 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

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 thymo-

lytic activity. Substitution of the 9-aH atom of hydrocortisoneacetate 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 com-

pounds. Several examples of fluorinated glucocorticoids and

their corresponding activities can be found in Figure 4.[99] As

Table 12: Structural comparison of the nonfluorinated cation 31 and 1.[92]

31 1

Structure

Bond lengths/interatomicdistances []N1N2 2.559 2.477N2C1 1.491 1.525C1Cl 1.760 1.715Bond angles [

]N1-C2-C3 108.61 107.79N2-C3-C2 108.65 110.59

Scheme 33. Possible resonance structures for 1.





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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 moi-

eties in particular are essential components of oligosaccha-

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-sialyltrans-

ferase and two galactosyltransferases (the configuration-

inverting bovine b-1,4-GalT and the configuration-retaining

a-1,3-GalT). For FucT, the fluorinated fucose analogues 13a,

13b, and 34 displayed K i values that were similar to or less

than the K M value for GDP-Fuc (Table 14). Similar results

were obtained for the inhibition of sialyltransferase with 16

(Table 15). The K i value for the inhibition of b-1,4-GalT by a-

UDP-2F-Gal (19) is approximately equal to the K M 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 K i value was observed that was 14-fold lower than the

K M value with the natural substrate.

Earlier mechanistic studies with FucT-V demonstrated a

secondary isotope effect with deuteriated GDP-[1-2

H]-fucoseand 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 2-

position, equidistant from the endocyclic oxygen atom, leads

to similar electronic effects—a potentially valuable result for

future inhibitor design. The good inhibition observed with the

anomerically nonnatural 13a indicates that the binding

Table 13: Activity of halogenated hydrocortisone derivatives.[97,98]

Compound X Activity[a]

33 a H 133 b F 10.733 c Cl 433 d Br 0.2833 e I 0.1

[a] Assay of glycogen from rat liver.

Figure 4. Biological activities of fluorocorticoids;[99] in each case theanti-inflammatory activity in rats relative to hydrocortisone acetate isgiven.

Table 14: Inhibition of four human fucosyltransferases.[52,101]

GDP-Fuc

K M [m m] K i [m m] K i [m m] K i [m m]

FucT-III 3 3.6 384 2210 –FucT-V 18.8 40.6 3.41 364FucT-VI 9 102.4 10.5 21FucT-VII 8 212 112 –

Table 15: Inhibition of a sialyl- and two galactosyltransferases.[52]

Glycosyltransferase Inhibitor K i [m m]

a-2,6-SialylT (K M=15 mm) 5.72

b-1,4-GalT (K M=36 mm) 2.00.3a-1,3-GalT (K M=173 mm) 245


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domain of fucosyltransferases allows stereochemical flexibil-

ity.

Recent syntheses of potent inhibitors of a-2,6-sialyltrans-

ferase have elucidated important conformational parameters

of the transition-state structure, including sp2 character at the

anomeric position.[102–106] 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 (K i=

5.7 m m), thus supporting the involvement of an oxycarbenium

intermediate in the transition state.[42]

Interesting results were obtained with galactosyltransfer-

ases.[52] The configuration-inverting b-1,4-GalT was as suscep-

tible to competitive inhibition by 19 as other inverting

glycosyltransferases (Figure 5), whereas the configuration-

retaining a-1,3-GalT was only weakly inhibited (K i=245 m m,

K M=17 m m). These results suggest that the mechanisms by

which these two galactosyltransferases catalyze the glycosy-lation 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-fluorogly-

cosides 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, some5-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

(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 non-

invasively 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

2 h, which makes it possible to carry out synthetic manipu-

lations 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 half-

lives. 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 annihi-

lation, and thus to higher resolution.Fluorination with 18F is limited by the small number of

labeled reagents that can be made. The bombardment of 18O-

labeled water with high-energy protons results in the absorp-

tion 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, gives18F2 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

(AcO18

F),[110,111]

[18

F]fluoropyridones,[112,113]

[18

F]fluoro-N -sul-fonamides,[114] and labeled xenon difluoride (Xe18F2).

[115,116]

The use of 18F and other positron-emitting nuclei neces-

sitates fast and simple chemistry, as well as safeguards against

the dangers of handling radioactive material. All manipula-

tions for the synthesis of 18F-labeled compounds (including

purification) must be completed in approximately 1–2 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

Figure 5. Putative transition state for configuration-inverting b-galacto-syltransferase.[52]

Table 16: Physical properties of b -emitting radionuclides.[109]

Radionuclide t1/2[min]

b

decay[%]

Maximumspecificactivity[a]

Maximumenergy

[MeV]

Maximum linearrange in H2O[mm]

11C 20.40 99 3.4 1011 0.96 4.1213N 9.96 99 6.9 1011 1.19 5.3915O 2.07 99.9 3.4 1012 1.72 8.218F 109.70 97 6.3 1010 0.635 2.39[a] Defined as the number of decay events per second per mole.





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be used in PET was [2-18F]fluoroglucose for monitoring

glucose metabolism in organs.[117–119] 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 Parkin-

sons 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 revolu-

tionalize 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 syn-

thesis 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 develop-

ment 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 fluori-

nation. 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 select-

fluor enables deeper insight into complex reactions and

demands new experiments and methods to probe the under-

lying 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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