Fluoro-functionalization mediated by the reactive chalcogen reagents

Article abstract of DOI:10.1016/S0022-328X(00)00325-9

Two types of fluoro-functionalizations mediated by reactive chalcogen reagents have been summarized. The first is a generation of benzeneselenenyl fluoride and its electrophilic reactions with alkenes, electron-deficient alkenes, isonitriles and α-diazoca

Full text of DOI:10.1016/S0022-328X(00)00325-9

www.elsevier.nl/locate/jorganchem
Journal of Organometallic Chemistry 611 (2000) 158–163
Review
Fluoro-functionalization mediated by the reactive chalcogen
reagents
Kenji Uneyama *
Department of Applied Chemistry, Faculty of Engineering, Okayama Uni6ersity, Okayama 700-8530, Japan
Received 29 February 2000; accepted 26 March 2000
Abstract
Two types of fluoro-functionalizations mediated by reactive chalcogen reagents have been summarized. The first is a generation
of benzeneselenenyl fluoride and its electrophilic reactions with alkenes, electron-deficient alkenes, isonitriles and a-diazocarbonyl
compounds. The second is a single electron transfer (SET) reaction of benzene chalcogenolates to perfluoroalkyl halides such as
trifluoromethyl bromide, dibromodifluoromethane, bromodifluoroacetates etc., where perfluorinated alkyl radicals generated in
the SET reaction undergo addition to alkenes and alkynes to give perfluoroalkyl-chalcogenated molecules. © 2000 Elsevier
Science S.A. All rights reserved.
Keywords: Fluoro-functionalization; Fluoro-selenenylation; Benzeneselenenyl fluoride; Single electron transfer; a,a-D-fluoro-g-lactam; Di-
fluoromethylene compound
ventional, organometal-mediated, electrochemical, pho-
tochemical methods etc. have been developed [2].
However, very few reactions mediated by chalcogen
reagents have been reported. An introduction of both
fluorine and chalcogen moieties into a molecule is
promising for the possible preparation of fluorinated
molecules by the versatile modification of the reactive
chalcogen moiety. The carbonꢀchalcogen bonds are
generally weak and can be cleaved easily and are thus
reactive. Chalcogen molecules are thermally, photo-
chemically and electrochemically susceptible so that
they can accept or donate electrons from or to reaction
partners, respectively, and thus they are readily reduced
or oxidized [3]. All of these unique properties make the
chalcogen functionality useful for the modification of
organic substrates. On this basis, it is reasonable to
choose chalcogen reagents as potential tools for fluoro-
functionalization of organic substrates. Here a short
account on chalcogeno-fluorination, in particular, se-
leno-fluorination leading to fluoro-functionalization of
organic substrates, is presented.
1. Introduction
Introduction of fluorine functionality into organic
molecules is one of the current important subjects for
many scientists, since organofluorine molecules have
been given much attention because of their unique
properties for medicinal and material sciences [1]. On
this basis, a number of fluorination reactions by con-
Scheme 1.
* Fax: +81-86-2518075.
E-mail address: uneyamak@cc.okayama-u.ac.jp (K. Uneyama).
0022-328X/00/$ - see front matter © 2000 Elsevier Science S.A. All rights reserved.
PII: S0022-328X(00)00325-9

K. Uneyama / Journal of Organometallic Chemistry 611 (2000) 158–163
159
PhSe− adds to a carbonꢀcarbon double bond and the
subsequently generated perfluoroalkylated radical then
reacts with the benzeneselenolate anion to produce a
perfluoroalkyl-benzeneselenolated anion radical. Fi-
nally, the anion radical transfers one electron to per-
fluoroalkyl iodide to produce the perfluoroalkyl-
benzeneselenolated adduct 6 and propagate the radical
chain reaction. Some anions and radical anions have
already been demonstrated to mediate perfluoroalkyl-
iodination of alkenes [5].
Table 1
Yield of 8 in bromodifluoromethyl-selenenylation and the related
reaction of alkenes
This working hypothesis has been found to be effec-
tive to prepare perfluoroalkyl-benzeneselenolated com-
pounds 6 as shown in Scheme 1 [6,7]. Sodium
benzeneselenolate generated by reduction of diphenyl
diselenide with NaBH4 in dry ethanol was allowed to
react with perfluoroalkyl iodide at room temperature
for 2 h. Electron-rich terminal alkenes such as 1-alke-
nes, vinyl ether and vinyl thioether reacted smoothly,
affording the desired adducts in 59–86% yields for
Rf=C4F9, C6F13 and C8F17. Trifluoromethyl-iodina-
tion of vinyl isobutyl ether with CF3Br provided 6 in a
poor yield (38%). Internal alkenes such as cyclohexene
reacted unsatisfactorily, affording the desired product
in only 15% yield. The major product in this reaction of
cyclohexene was perfluoroalkyl phenyl selenide (60%).
The data suggest the perfluoroalkyl radical addition is
highly susceptible to steric hindrance.
Scheme 2.
Table 2
SET reaction between benzenechalcogenolate and perfluoroalkyl
halides
An electrochemical reduction is also useful for in situ
generation of an arene selenolate anion from diaryl
diselenide [8]. This method was used for the substituted
difluoromethyl-selenenylation of alkenes (Table 1).
Thus, reaction of ethyl bromodifluoroacetate with vinyl
isopropyl ether and subsequent oxidative deselenation
in aqueous medium provided 11, a useful functionalized
difluoromethylene ester (Scheme 2) [9].
M
RfꢀX
Solvent
Temperature
S
Se
Te
RfꢀI
RfꢀI (CF3ꢀBr)
RfꢀI (CF3ꢀBr)
Ether
DME
Ether–DME
Reflux
Room temperature
−100 to −80°C
2. Results and discussion
The reaction rate of the generation of perfluoroalkyl
radical by the SET reaction is highly dependent on the
electron-transfer ability of the chalcogen atom. As
shown in Table 2, the thiolate anion reacts so slowly
that refluxing in ether for several hours is needed for
the effective generation of perfluoroalkyl radical.
Meanwhile, selenolate reacts reasonably fast and the
desired reaction is complete within 2 h at room temper-
ature. Most interestingly the corresponding tellurolate
transfers one electron to perfluoroalkyl halides ex-
tremely fast. In fact it reacts with trifluoromethyl bro-
mide at −100°C and it efficiently promotes
trifluoromethyl-telluration of 1-octene (57%), allyl cya-
nide (44%), and ethylene (44%) [10].
The low reactivity of thiolates as compared with
selenolates is one of the disadvantages of per-
fluoroalkyl-sulfenylafion, which could be covered by
the cooperative use of a catalytic amount of the more
reactive selenolate. The idea is shown in Scheme 3. The
reaction is initiated by a SET reaction from the seleno-
late anion to form the perfluoroalkylated radical 15,
2.1. A single electron transfer (SET) from
chalcogenolate anions to perfluoroalkyl halides
Chalcogenolate anions are readily oxidized and their
oxidizability is in the order of RTe−\RSe−\RS−.
These facts suggest they are very strong nucleophiles
and are likely to react with alkyl halides and to donate
one electron to electron acceptors. Wakselman demon-
strated the reaction of the benzenethiolate anion with
perfluoroalkyl iodides leading to the formation of per-
fluoroalkyl phenyl sulfides is not a simple SN2 reaction,
but a radical chain reaction in which perfluoroalkyl
radicals 3 generated by SET reaction between ben-
zenethiolate anion 1 and perfluoroalkyl iodide 2 react
with a benzenethiolate anion [4]. The mechanism rea-
sonably suggests that the perfluoroalkyl radical and
benzeneselenenyl moiety can be incorporated into a
carbonꢀcarbon multiple bond via a possible radical
chain reaction (Scheme 1); the perfluoroalkyl radical
generated by the SET reaction between RfꢀI and

160
K. Uneyama / Journal of Organometallic Chemistry 611 (2000) 158–163
which then reacts with a large excess amount of thiolate
anion, generating the anion radical 16. The usual SET
reaction from 16 to 4 produces the sulfur product 13
and propagates the chain reaction. The yield of 13
(Rf=C4F9, C6F13 and C8F17, R=i-Bu) in the presence
of 10 mol% of the selenolate is in the range of 80–93%.
In particular, p-nitrobenzenethiolate does not react
with the vinyl ether, but it gives 45% of 13 in the
presence of a selenolate anion as catalyst [11]. The S,
O-acetals 13 can be transformed to perfluoroalkylated
aldehydes 14 by NBS oxidation in aqueous medium
(Scheme 3).
The SET reaction mediated by the selenolate anion is
applicable for the first synthesis of a,a-difluoro-g-lac-
tam (18) and a,a-difluoro-b-methylene-g-lactam (19) via
intramolecular cyclization as shown in Scheme 4. Note-
worthy is the fact that the yield of 18 is markedly
affected by the geometry of the N-allyl group. N-allyl
amide (17, R1=H, R2=H) provided no desired lactam
18, instead it gave a-benzeneselenenyl amide (17, a
replacement of Br with a PhSe group) in 45% yield.
Meanwhile, N,N-diallyl amide (17) (R1=allyl, R2=H)
gave 18 in 96% yield. Similarly, N,N-cinnamyl amide
(17) (R1=cinnamyl, R2=Ph) produced the target lac-
tam 18 in 72% yield. The syn-conformation of the
carbonꢀcarbon double bond to the initially formed
difluorinated carbon radical is essential for the effective
cyclization [12,13].
Introduction of perfluoroalkyl and aryltelluro groups
into alkynes was also achieved by the tellurolate medi-
ated reaction (Scheme 5). It is interesting that the
efficiency of the chalcogenation of alkynes is the order
of Te\Se\S. Thus, the telluro-compounds 25 for
1-hexyne were obtained in 81% for Rf=C4F9, 57% for
Rf=C8F17 and 50% for Rf=CF3, respectively [14].
2.2. Electrophilic fluoro-selenenylation with
benzeneselenenyl fluoride
Scheme 3.
Fluorinating reagents are divided into two categories,
that is, electrophilic fluorinating reagents such as Selec-
trofluor (F–TEDA–BF4), N-fluoropyridinium, N-
fluorosulfonamide, xenon difluoride, etc. and nucleo-
philic fluorinating reagents such as cesium fluoride,
potassium fluoride, tetraalkylammonium fluoride, hy-
drogen fluoride, iodo fluoride and so on. Benzenesele-
nenyl fluoride would be a promising reagent for
fluoro-selenenylating, but it has not yet been character-
ized although a great number of works on benzenesele-
nenyl chloride and bromide have been carried out [15].
Electrophilic reactivity of benzeneselenenyl reagents
(PhSeX) is undoubtedly dependent on the electronega-
tivity of X or the electron-withdrawing ability of sub-
stituent X. Therefore, benzeneselenenyl cyanide, triflate
and trifluoroacetate (X=CN, OTf and CF3CO2) are
strong electrophilic selenenylating reagents. On this ba-
sis, benzeneselenenyl fluoride must be one of the
strongest selenenylating reagents because of the strong
electronegativity of the fluorine atom. Recently, Nico-
laou and co-workers have demonstrated fluoro-sele-
nenylation of alkenes by the use of N-phenylseleno-
phthalimide, AgF–PhSeBr ultrasound system, AgF–
PliSeCl–MeCN systems [16]. However, these results do
not necessarily demonstrate the clearcut evidence of
benzeneselenenyl fluoride as a reactive intermediate.
Here a new method for generating a benzeneselenenyl
fluoride and its reaction with several substrates is de-
scribed (Scheme 6).
Scheme 4.
Scheme 5.
Scheme 6.

K. Uneyama / Journal of Organometallic Chemistry 611 (2000) 158–163
161
l 7.62–7.75 ppm (m, 3H), which are downfield by
about 0.4 ppm from those of (PhSe)2 and are consider-
ably broadened within 15 min, revealing instability of
the active reagent [17]. The action of an excess amount
of xenon difluoride to diphenyl diselenide provides
PhSeF, and PhSeF5 which do not fluoro-selenate alke-
nes, but simply fluorinate them [18]. The addition of
alkenes makes the color of the dark brown solution
fade within several minutes, suggesting fluoro-seleneny-
lation to alkenes is extremely fast. The yields of adducts
are in the range of 43–82%, but those of methyl
acrylate and methyl methacrylate are very poor, 9 and
34%, respectively [17]. Prolonged reaction time was not
effective for improvement of the yield because of the
instability of the active reagent. To overcome this
difficulty several reaction conditions were examined in
detail and it was found that the higher concentration of
the reagent makes the lifetime of the reagent markedly
longer as shown in Fig. 1 (Scheme 7).
Fig. 1. Effect of the concentration of [PhSeF].
At the higher concentration, the yield of 30 for
methyl acrylate improved from 9 to 58%. The results
for other electron deficient alkenes are listed in Table 3
[19]. The longer lifetime may arise from the stabiliza-
tion of PhSeF by a possible intermolecular association
like a dimer or trimer of the reagent under the higher
concentration conditions. Calculation of heats of for-
mation of [PhSeF] as a monomer and its dimer by PM3
of MacSpartan Plus revealed that the dimer is more
stable by 18 kcal mol−1 than the monomer. The high
electrophilicity of [PhSeF] can be usable for the effec-
tive selenenylation of the strongly electron-deficient di-
fluoroacrylate 31 of which difluoromethylene carbon is
mostly attacked by nucleophiles (Scheme 8) [20].
The conventional oxidation of fluoro-selenenyl com-
pounds produced the corresponding allylic fluoride as
shown in the transformations of 33 to 35, via 34
(Scheme 9).
Scheme 7.
Table 3
Reaction of benzeneselenenyl fluoride with electron-deficient alkenes a
a Ratio of isomer (29:30).
Therefore, it is highly interesting to design a series of
reactions, namely generation of [PhSeF], fluoro-sele-
nenylation of alkenes and oxidative removal of seleno-
moiety, and recycling the selenenyl reagent usable for
one-pot preparation of allylic fluoride from alkenes.
This hypothetical reaction design was found to be
effective for the series of electrochemical oxidative
transformation as shown in Scheme 10. Diphenyl dise-
lenide is known to be electrochemically oxidized to
selenenyl reagent (PhSeX: X=OH, OW, OAc, NCMe)
in aqueous media, methanol, acetic acid and acetoni-
trile, respectively [21]. On this basis, benzeneselenenyl
fluoride would be the most probable initial product
produced by electrooxidation of diphenyl diselenide in
the Et3N·3HF–CH2Cl2 system. The selenenylating
reagent reacts with alkenes to form an adduct 37, which
is subsequently oxidized in situ to selenoxide 40. Syn-
elimination from selenoxide 40 would produce the de-
sired allylic fluoride 39 and regenerate active selenenic
Scheme 8.
Scheme 9.
Benzeneselenenyl fluoride is generated by the reaction
of diphenyl diselenide (1 mole eq) with xenon difluoride
(1 mole eq) at −20°C in methylene chloride. Gas
evolution was observed and the solution turned dark
brown. H-NMR of the solution in CDCl3 shows a new
set of phenyl protons at l 7.96–8.03 ppm (m, 2H) and
1

162
K. Uneyama / Journal of Organometallic Chemistry 611 (2000) 158–163
acid, which is converted to selenenyl fluoride in situ in
the presence of a large excess amount of amine complex
of HF and is used for further fluoro-selenenylation
(Scheme 10). The yields of 39 are in the range of
35–70% for internal aliphatic alkenes in the presence of
10 mol% of diphenyl diselenide [22].
It is reasonable to expect that benzeneselenenyl
fluoride should transfer both fluoro and selenenyl moi-
eties in a manner of 1,1-addition to the a-carbon atom
of carbene-like reactive species such as isonitriles and
a-diazocarbonyl compounds [23]. The selenium atom of
the reagents would attack electrophilically the filled
orbital of 41 and the fluorine atom would attack nucleo-
philically a vacant orbital as shown in Scheme 11. The
reaction of [PhSeF] with isonitriles went smoothly, but
the products were too unstable to be isolated.
The reaction of [PhSeF] with a-diazocarbonyl com-
pounds also went very smoothly and the reaction was
completed within 15 min at −20°C. Soon after addi-
tion of the diazocarbonyl compounds to the [PhSeF]
solution, nitrogen gas evolution was observed and the
dark orange color of the solution faded immediately.
a-Fluoro-a-selenenyl ketones and esters are stable
enough to be isolated by column chromatography. The
yields of the ketones and esters are 68–94% and 56–
74%, respectively [24]. The selenenyl moiety of 47 is
usable for carbonꢀcarbon formation and other func-
tionalization. Some oxidative and radical reactions are
shown in Scheme 12.
Acknowledgements
The authors are grateful to the Ministry of Educa-
tion, Culture, Sports and Science of Japan for the
financial support (Priority Area; Interelement Linkage
No. 11120233) and to the SC-NMR laboratory of
Okayama University for 19F-NMR analysis.
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Scheme 10.
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Scheme 12.

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