Reaction of silyl enol ethers with xenon difluoride in MeCN: Evidence for a nonclassical radical cation intermediate

Article abstract of DOI:10.1021/ol990231e

(matrix presented). The reactions of xenon difluoride in MeCN solution in Pyrex flasks with a series of TMS enol ethers have been investigated. The types of products formed are dependent on the structures of individual enol ethers, but under these conditions all products are consistent with a mechanism involving single electron transfer to un-ionized XeF₂ giving a radical cation and subsequent formation of an α-fluoroketone, together with some ketone formation. The results suggest that if the radical cation is particularly stable, fluorodesilylation leads to radical formation, and solvent-derived products are then observed. Using other solvents, such as CFCl₃ and C₆F₆, much more complex mixtures of products are obtained, and this is attributed to a different mode of reaction of xenon difluoride involving ionization to FXe⁺.

Full text of DOI:10.1021/ol990231e

ORGANIC
LETTERS
1999
Vol. 1, No. 10
1591-1594
Reaction of Silyl Enol Ethers with
Xenon Difluoride in MeCN: Evidence for
a Nonclassical Radical Cation
Intermediate
,†
Christopher A. Ramsden* and Rachel G. Smith
School of Chemistry and Physics, Keele UniVersity, Keele,
Staffordshire ST5 5BG, U.K.
cha33@cc.keele.ac.uk
Received August 13, 1999
ABSTRACT
The reactions of xenon difluoride in MeCN solution in Pyrex flasks with a series of TMS enol ethers have been investigated. The types of
products formed are dependent on the structures of individual enol ethers, but under these conditions all products are consistent with a
mechanism involving single electron transfer to un-ionized XeF2 giving a radical cation and subsequent formation of an r-fluoroketone,
together with some ketone formation. The results suggest that if the radical cation is particularly stable, fluorodesilylation leads to radical
formation, and solvent-derived products are then observed. Using other solvents, such as CFCl3 and C F6, much more complex mixtures of
6
products are obtained, and this is attributed to a different mode of reaction of xenon difluoride involving ionization to FXe+.
7
Using TMS derivatives that avoid the formation of HF, we
have reported evidence that uncatalyzed reactions of xenon
difluoride are dependent upon the nature of both the reaction
solvent and vessel.1 In glass flasks and solvents other than
MeCN, the reactive species appears to be FXe+,2 which is
isoelectronic with FI and which reacts as an electrophile.3,4
In nonvitreous flasks (e.g., FEP) or in glass flasks using
MeCN as solvent, the reactive species appears to be the un-
ionized XeF2 which reacts as a one-electron oxidizing agent.
We have also shown that under very specific reaction
conditions positron-emitting [18F]fluoride ion exchanges with
commercially available XeF2 to give MeCN solutions of
labeled [18F]xenon difluoride for use in positron emission
tomography (PET).5,6 A better understanding of the reaction
mechanisms of XeF2 will enhance its value as a selective
[18F] and [19F] fluorinating agent. To provide further evidence
for our mechanistic proposals1 and to further explore the one-
electron oxidation mode of reaction of XeF2 in MeCN/glass,
which is a particularly convenient reaction medium, we have
investigated the reactions of a selected series of TMS enol
ethers with XeF2 and now report the results and mechanistic
conclusions.
A limited number of reactions of TMS enol ethers with
XeF2 to form R-fluoroketones have previously been reported.
Four steroid ethers in CF2ClCFCl2/MeCN solutions at room
temperature without a catalyst gave good isolated yields of
the fluoroketones with R-stereoselectivity.8 These authors
concluded that radical involvement was unlikely and pro-
posed a mechanism in which un-ionized XeF2 reacted as a
† Tel: (01782) 583045. Fax: (01782) 712378.
(1) Ramsden, C. A.; Smith, R. G. J. Am. Chem. Soc. 1998, 120, 6842.
(2) Schrobilgen, G. J. In Synthetic Fluorine Chemistry; Olah, G. A.,
Chambers, R. D., Prakash, G. K. S., Eds.; John Wiley & Sons: New York,
1992; pp 1-30.
(3) Lothian, A. P.; Ramsden, C. A. Synlett 1993, 753.
(4) Nongkunsarn, P.; Ramsden, C. A. J. Chem. Soc., Perkin Trans. 1
1996, 121.
(5) Aigbirhio, F. I.; Pike, V. W.; Smith, R. G.; Ramsden, C. A. J. Nucl.
Med. 1998, 39, 231P.
(6) Constantinou, M.; Pike, V. W.; Aigbirhio, F. I.; Smith, R. G.;
Ramsden, C. A. J. Label Compd. Radiopharm. 1999, 42, S530.
(7) Tius, M. A. Tetrahedron 1995, 51, 6605.
(8) Tsushima, T.; Kawada, K.; Tsuji, T. Tetrahedron Lett. 1982, 23, 1165.
10.1021/ol990231e CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/06/1999

two-electron oxidizing agent. Using the same conditions but
with a TBDMS enol ether, a monofluoro ketone peptide
isostere has been prepared in 71% yield.9 Fluorination of an
estrone derivative in CH2Cl2 gave a product with a much
lower yield (44%) but also with R-stereoselectivity.10 The
ethers of cycloalkanones are reported to give good yields of
fluoroketones in CH2Cl2 with a trace of pyridinium poly-
(hydrogen fluoride) catalyst.11 We have investigated the TMS
enol ethers shown in Table 1. These were selected to give a
previously reported1 the clean reaction of 1-((trimethylsilyl)-
oxy)cyclohexene 1b in MeCN solution, which clearly gives
results superior to those of other solvents (Table 1). Under
the same conditions the cyclopentene derivative 1a gave a
quantitative yield of 2-fluorocyclopentanone 3a. When the
4-tert-butylcyclohexene derivative 1c was investigated in
MeCN, the fluoroketone 3c was accompanied by ketone 4c
(20%). A similar yield of ketone was obtained when 1,1-
dimethyl-2-(trimethylsilyl)oxypropene 1d was used, and the
corresponding styrene derivative 1e gave acetophenone 4e
as the major product. We interpret all these results in terms
of the mechanism in Scheme 1. Initial SET, presumably via
Table 1. Reaction of TMS Enol Ethers with XeF2
Scheme 1
a short-lived electron donor-acceptor (EDA) complex, gives
radical cation 2 together with the radical anion XeF2•- . The
latter may act as fluorinating agent with formation of Xe0
and F- or may lose F- to give XeF•12 which delivers fluorine
to the radical cation. The liberated fluoride ion then acts as
desilylating agent. Alternatively, the radical cation may
undergo a 1,5-hydrogen transfer which leads to ketone 4 after
desilylation. Under these conditions there are no significant
amounts of HF in the reaction mixture and HF-mediated
ketone formation is unlikely. When reactions were carried
out in CD3CN solution, no deuterium was incorporated into
ketones 4, supporting the view that the ketones are formed
by an intramolecular mechanism (Scheme 1). This mecha-
nism is also consistent with the lack of stereoselectivity
observed for the t-Bu derivative 1c. The trans/cis product
ratio is presumably determined by the probabilities of the
XeF2 molecule (rXeF 2.0 Å; Xe atomic radius 2.2 Å)
approaching either face of the enol ether and not by the
energies of alternative transition states involving partially
formed C-F bonds.
It is not clear why acetophenone enol ether 1e gives the
ketone as major product, in contrast to aliphatic ether 1d.
We assume that the ratio of fluoroketone 3 to ketone 4 is
determined by factors which include the relative stability of
the radical cation and conformational flexibility. In this
context the behavior of the isomeric tetralone derivatives 1f
and 1g in MeCN is significant. Reaction of R-tetralone TMS
enol ether 1f gave an excellent yield of fluoroketone 3f and
only a small amount of R-tetralone 4f. In contrast â-tetralone
broad range of structural types, and we have observed
significant differences in their reactions. In general, MeCN
solution gives the best results and we propose that under
these condition they all react via an initial SET.
All reactions of the enol ethers 1 (Table 1) were carried
out under identical conditions using Pyrex flasks and a
reaction time of 1 h. Product composition was monitored
1
immediately after reaction by H and 19F NMR and GC-
MS, and major products were fully characterized. We have
(9) Garrett, G. S.; Emge, T. J.; Lee, S. C.; Fischer, E. M.; Dyehouse K.;
McIver, J. M. J. Org. Chem. 1991, 56, 4823.
(10) Patrick, T. B.; Mortezania, R. J. Org. Chem. 1988, 53, 5153.
(11) Cantrell, G. L.; Filler, R. J. Fluorine Chem. 1985, 27, 35.
(12) Eachus, R. S.; Symons, M. C. R. J. Chem. Soc. A 1971, 304.
Org. Lett., Vol. 1, No. 10, 1999
1592

isomer 1g gave a poor yield of fluoroketone 3g, and
â-tetralone 4g was the major product. We interpret these
observations in terms of differences in the stabilities of the
intermediate radical cations 2f and 2g. In intermediate 2f
the aromatic ring is cross-conjugated with the enol radical
whereas in isomer 2g the radical is conjugated with the ring,
leading to greater stabilization and delocalization of spin
density. We assume that conjugated radical 2g does not react
so readily with the fluorinating agent, which diffuses away,
and intramolecular hydrogen transfer predominates. A similar
rationalization, supported by time-resolved spectroscopy, has
been proposed to account for differences in the thermal
reactions of tetralone enol ethers 1f and 1g with tetranitro-
methane.13 In this case the EDA complex of ether 1g appears
to be stable in solution and does not dissociate to the radical
cation.
of ketone 4h. The exo:endo ratio of R-fluoroketone, deter-
mined by 19F NMR,15 was in the range 0.5-0.8 (Table 1).
These ratios are in accord with the expected steric hindrance
to approach of the alternative faces. The results with the
corresponding norcamphor derivative 1i were unexpected.
Although the exo:endo ratio of R-fluoroketone isomers 3i
in various solvent systems is, as expected, significantly
greater (7.3-13.3) than that for camphor, the lowest yield
of fluoroketone was obtained using MeCN. Furthermore, in
this solvent ketone products 3i and 4i are accompanied by a
major solvent-derived product (ca. 25%) which after isolation
and purification was identified as amide 14 (mp 159-160
°C) (Scheme 3). This result parallels the behavior of
Scheme 3
A further feature of the reaction of â-tetralone derivative
1g, which is not observed for substrates 1a-f, is the high
yield of solvent-derived products in MeCN solution. In
particular, two products were identified by GC-MS as having
the oxazole structures 7 (16%) (M•+ m/z 185) and 8 (24%)
(M•+ m/z 183). The 1H NMR of the product mixture showed
two methyl singlets at δ 2.1and δ 2.2. When CD3CN was
the solvent, these singlets were absent and the molecular
weights increased by three mass units (M•+ m/z 188 and 186),
consistent with the incorporation of one molecule of nitrile
solvent. We propose that these solvent-derived products arise
because of the longer lifetime of resonance-stabilized ben-
zylic radical cation 5 which subsequently undergoes fluoro-
desilylation to give the highly reactive radical 6 (Scheme
2). Radical 6 immediately undergoes [3 + 2] cycloaddition
â-tetralone ether 1g, and we propose that this is a second
example in which the intermediate radical cation (i.e., 2i)
enjoys enhanced stability, in this case by adopting nonclas-
sical structure 9. Species 9 is isoconjugate with the meth-
ylenecyclopropene radical cation 10 which is aromatic.16
Scheme 2
Formation of amide 14 is accounted for by the mechanism
in Scheme 3, which parallels the â-tetralone mechanism
(Scheme 2). Dilution of the acetonitrile solvent with Freon
led to diminishing amounts of product 14 (Table 1), and use
of CD3CN gave a product incorporating CD3CN (M•+ m/z
170 and CD3CO+ m/z 46). We propose that radical 11 adds
to MeCN to give after fluorination either fluorooxazolidine
12 or acyclic fluoroimine 13. Upon workup and prior to
detection, product 12 or 13 is then rapidly hydrolyzed by
adventitious water to the observed amide 14. Some amide
formation has previously been reported to occur in the
photochemical fluorination of norbornene by XeF2.17 The
with MeCN and aromatizes (6 f 7). This mechanism of
oxazole formation has precedent in the reported one-electron
oxidation of enols in MeCN solution using CuII triflate.14
Further oxidation, possibly mediated by XeF2, leads to the
fully conjugated product 8 (Scheme 2).
When the TMS ether of camphor 1h was investigated,
fluoroketone 3h was accompanied by significant amounts
(15) Middleton, W. J.; Bingham, E. M. J. Am. Chem. Soc. 1980, 102,
4845. Rozen, S.; Menahem, Y. J. Fluorine Chem. 1980, 16, 19.
(16) Dewar, M. J. S.; Dougherty, R. C. The PMO Theory of Organic
Chemistry; Plenum Press: New York, 1975; p 499.
(13) Rathore, R.; Kochi, J. K. J. Org. Chem. 1996, 61, 627.
(14) Nagayoshi, K.; Sato, T. Chem. Lett. 1983, 1355.
(17) Hildreth, R. A.; Druelinger, M. L.; Shackelford, S. A. Tetrahedron
Lett. 1982, 23, 1059.
Org. Lett., Vol. 1, No. 10, 1999
1593

mechanistic details of these reactions of MeCN with radicals
requires further investigation.
f FXe•) or may initiate rearrangement reactions.3,4 All these
modes of reaction of FXe+ may account for the additional
products formed in Pyrex flasks and solvents other than
MeCN.
In conclusion, these results support the view that in
MeCN-glass XeF2 reacts via one-electron oxidation. The
stability of the radical cations formed from TMS enol ethers
determines the subsequent reaction pathway: stabilization
of radical cations leads to radical formation and addition to
MeCN in competition with R-fluorination. Results using the
TMS enol ether of norcamphor provide indirect evidence
that this radical cation is stabilized, possibly by formation
of nonclassical structure 9. With some exceptions, other
solvents give more complex mixtures and poorer yields of
R-fluoroketones. This can be ascribed to participation of the
ion FXe+, probably formed at the glass-solvent interface.1
The species FXe+ may act as a fluorinating agent via
electrophilic addition or via one-electron oxidation (FXe+
Acknowledgment. We thank the EPSRC for the award
of a project studentship (to R.G.S.), the EPSRC National
Mass Spectrometry Service Centre for high-resolution mass
spectra, and Mr. J. Clews for technical assistance.
Supporting Information Available: Experimental pro-
cedures, characterization for compound 14, and GC data for
reactions of 1b,c and 1f-i. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL990231E
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Org. Lett., Vol. 1, No. 10, 1999