Selective and effective fluorination of organic compounds in water using selectfluor F-TEDA-BF4

Article abstract of DOI:10.1021/ol047867c

(Chemical Equation Presented) Selective and effective fluorination of various types of organic compounds performed in water as the reaction medium using 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor F-TEDA-BF

Full text of DOI:10.1021/ol047867c

ORGANIC
LETTERS
2004
Vol. 6, No. 26
4973-4976
Selective and Effective Fluorination of
Organic Compounds in Water Using
Selectfluor F-TEDA-BF4
Gaj Stavber,† Marko Zupan,†,‡ Marjan Jereb,† and Stojan Stavber*,‡
Laboratory for Organic and Bioorganic Chemistry, “Jozef Stefan” Institute,
JamoVa 39, 1000 Ljubljana, SloVenia, and Department of Chemistry of the Faculty for
Chemistry and Chemical Technology, UniVersity of Ljubljana, AsˇkercˇeVa 5,
1000 Ljubljana, SloVenia
stojan.staVber@ijs.si
Received October 15, 2004
ABSTRACT
Selective and effective fluorination of various types of organic compounds performed in water as the reaction medium using 1-chloromethyl-
4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor F-TEDA-BF4) is reported. 2-Naphthole and 2-methoxynaphthalene
were thus transformed to 1,1-difluoro-2(1H)naphthalenone, estrone to 10â-fluoro-1,4-estradien-3,17-dione, phenyl-substituted alkenes to vicinal
fluorohydrins, and various ketones, 1,3-diketones, or -ketoesters to corresponding
â
r
-fluoro or -difluoro ketones.
r,r
The use of water as the medium for organic reactions was
rediscovered in the early 1980s,1 triggering a more wide-
spread interest in the field, which considering many scientific,
economic, and ecological challenges resulted in very intense
basic and applied research in the last two decades.2,3 As water
is the most benign and cheapest liquid in the world, in
addition to its essential role in life processes, the use of water
should be one of the priority issues in modern organic
chemistry and a basic challenge in view of the “green”
approach4 to organic compound transformations.
The versatile application of organofluorine compounds in
several branches of industry and medicine5 is generating a
permanent impetus to research their related chemistry.6
Developing new reagents and methods for site-selective
introduction of a fluorine atom into organic molecules under
mild reaction conditions has for a long time been one of the
main themes of these efforts. A very important breakthrough
was accomplished by the introduction and broad synthetic
† University of Ljubljana.
‡ “Jozef Stefan” Institute.
(1) (a) Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102, 7816-
7817. (b) Breslow, R.; Maitra, U.; Rideout, D. C. Tetrahedron Lett. 1983,
24, 1901-1904. (c) Breslow, R.; Maitra, U. Tetrahedron Lett. 1984, 25,
1239-1240. (d) Grieco, P. A.; Garner, P., He, Z. Tetrahedron Lett. 1983,
24, 1897-1890. (e) Grieco, P. A.; Yoshida, K.; Garner, P. J. Org. Chem.
1983, 48, 3137-3139.
(4) Lancaster, M. Green Chemistry; Royal Society of Chemistry:
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Wiley: New York, 1997. (b) Organic Synthesis in Water; Grieco, P. A.,
Ed.; Academic and Professional: London, 1998. (c) Adams, D. J.; Dyson,
P. J.; Tavener, S. J. Chemistry in AlternatiVe Reaction Media; Wiley: New
York, 2004.
(3) (a) Lubineau, A.; Auge´, J.; Queneau, Y. Synthesis 1994, 741-760.
(b) Yorimitsu, H.; Shinokubo, H.; Oshima, K. Synlett 2002, 674-686. (c)
Lindsto¨m, M. U. Chem. ReV. 2002, 2751-2772.
(5) (a) Chemistry of Organic Fluorine CompoundsII. A Critical ReView;
Hudlicky, M., Pavlath, A. E., Eds.; ACS Monograph 187; American
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(6) Methods in Organic Chemistry (Houben-Weyl): Organofluorine
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York, 1999; Vols. E10a and E10b.
10.1021/ol047867c CCC: $27.50
© 2004 American Chemical Society
Published on Web 12/01/2004

application of organic derivatives incorporating a reactive
N-F bond as mild fluorinating reagents.7 1-Chloromethyl-
4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluorobo-
rate) 1, scientifically introduced in the 1990s8 and soon after
commercialized as Selectfluor F-TEDA-BF4, became one of
the most important reagents for “electrophilic” fluorofunc-
tionalization of organic compounds,9 which in addition to
being today an ordinary benchtop material in research
laboratories is also multiton per year produced chemical for
several industrial applications.10
Scheme 1 a
Fluorination of organic compounds in pure water obviously
has not been an issue of much scientific interest so far.11
F-TEDA-BF4 should be a convenient reagent for water-
mediated transformations of organic compounds since it is
easily soluble (0.16 g/mL) and relatively stable in water,12
but only a few attempts to obtain potential advantage from
this fact have been reported so far.13 To try to remedy this
deficiency we now report a preliminary screening of
fluorination of a wide range of organic compounds with
F-TEDA-BF4 in water.
a Reaction conditions: (i) 1 mmol of substrate, 1.05 mmol of
F-TEDA-BF4 (1), 5 mL of H2O, 60 °C, 2-6 h.
The prejudices that ruled out the use of water as the
medium for organic reactions originated in several reasons,
where insolubility of the reactants and the incompatibility
of the intermediates with water were the main ones. To avoid
this disadvantage we started our screening with phenols,
which are at least slightly soluble in water. In a typical
experiment, we suspended 1 mmol of 2-naphthole (2a,
Scheme 1) in 5 mL of water, and after 5 min of vigorous
stirring at 60 °C, F-TEDA-BF4 was added. After a few
minutes, homogenization of reaction mixture took place
followed by continuing precipitation of yellow crystals
recognized as 1,1-difluoro-2(1H)-naphthalenone 3. Stirring
for 30 min at 60 °C and addition of 2.1 mmol of F-TEDA-
BF4 were sufficient for water-mediated transformation of 2a
to 3 isolated after purification by flash chromatography in
78% yield. The ether analogue of 2a, 2-methoxynaphthalene
(2b), was also transformed under the same reaction condi-
tions after 2 h into 3. Encouraged by this result, which from
the point of view of selectivity as well as of efficiency is
comparable with those obtained in analogous reactions of
2a in MeCN,14 we proceeded in our screening with the alkyl-
substituted phenol type of compounds known as precursors
for synthesis of 4-fluorocyclohexa-2,5-dienone derivatives.15
5,6,7,8-Tetrahydro-2-naphthole 4 was thus readily trans-
formed by F-TEDA-BF4 in aqueous medium to 4R-fluoro-
5,6,7,8-tetrahydro-(4RH)-naphthalen-2-one 5 and estrone 6
to 10âfluoro-1,4-estradien-3,17-dione (7, Scheme 1).
Phenyl-substituted alkenes have often been used as tools
for testing new reagents or methodologies for transformation
of alkenes under electrophilic reaction conditions. This was
also the case when fluorofunctionalizations of alkenes using
“electrophilic” fluorinating reagents was the object of
research.5-9 Alkenes are usually immiscible with water, so
that we were not really surprised when treatment of selected
alkenes 8 with F-TEDA-BF4 under the reaction conditions
used in the above-mentioned case of phenols did not give
such good results. More intense stirring of the reaction
mixture to disperse the drops of alkene in water as much as
possible helped in increasing the conversion of starting
material to products, but a considerable and satisfactory
improvement in the efficiency of the reaction was finally
achieved by using a surfactant compound that presumably
acted as an emulsifier of the alkene in water and promoted
its transformation with water-soluble F-TEDA-BF4 within a
reasonable reaction time. We used one of the most common
anionic types of surfactant, i.e., sodium lauryl ether sulfate,
commercially declared as C12-C14O(C2H4O)2SO3Na under
the trade name Genapol LRO, and found that a 0.05% water
solution of this material is optimal for regioselective and
almost quantitative transformation of phenyl-substituted
alkenes 8 to vicinal fluorohydrins 9 (Scheme 2) by F-TEDA-
BF4. Water is in this case the source of the external
nucleophile and the reaction medium, while the regiochem-
istry as well as efficiency of the addition process is the same
as that observed when acetonitrile was used as the solvent
and water or alcohols were added as nucleophiles.16
(7) (a) Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. ReV. 1996, 96, 1737-
1755. (b) Taylor, S. D.; Kotoris, C. C.; Hum, G. Tetrahedron 1999, 55,
12431-12477. (c) Furin G. G.; Fainzilberg, A. A. Russ. Chem. ReV. 1999,
68, 653-684.
(8) (a) Banks, R. E.; Mohialdin-Khaffaf, N. S.; Lal, G. S.; Sharif, I.;
Syvret, G. R. Chem. Commun. 1992, 595-596. (b) Lal, G. S. J. Org. Chem.
1993, 58, 2791-2796.
(9) (a) Banks, R. E. J. Fluorine Chem. 1998, 87, 1-17. (b) Singh, P.
R.; Shreeve, M. J. Acc. Chem. Res. 2004, 37, 31-44.
(10) Hart, J. J.; Syvret, G. R. J. Fluorine Chem. 1999, 100, 157-161.
(11) (a) Diksic, M.; Di Raddo, P. Tetrahedron Lett. 1984, 25, 4885-
4888. (b) Conte, L.; Gambaretto, G. P.; Napoli, M.; Fraccaro, C.; Legnaro,
E. J. Fluorine Chem. 1995, 70, 175-179.
(12) Zupan, M.; Papezˇ, M.; Stavber, S. J. Fluorine Chem. 1996, 78, 137-
140.
(13) (a) Lal, G. S.; Pastore, W.; Pesaresi, R. J. Org. Chem. 1995, 60,
7340-7342. (b) Petasis, A. N.; Yudin, K. A.; Zavialov. A. I.; Prakash, G.
K. S.; Olah, A. G. Synlett 1997, 606-608. (c) Banks, R. E.; Besheesh, M.
K.; Gorski, W. R.; Lawrence, J. N.; Taylor, J. A. J. Fluorine Chem. 1999,
96, 129-133.
(14) (a) Zupan, M.; Iskra, J.; Stavber, S. Bull. Chem. Soc. Jpn. 1995,
68, 1655-1660. (b) Stavber, S.; Zupan, M. Synlett 1996, 693-694.
(15) Stavber, S.; Jereb, M.; Zupan, M. Synlett 1999, 1375-1378.
Org. Lett., Vol. 6, No. 26, 2004
4974

Fluorofunctionalization of organic compounds bearing a
carbonyl group has been for a long time of special interest,5,6
since this reactive functional site is often present in bioactive
molecules or in potential building blocks for their synthesis,
while the carbon atom R to the carbonyl group seems to be
the most strategic one for fluorination.18 Direct R-fluorination
of ketones with F-TEDA-BF4 in water was found not to be
so efficient as in the case when MeCN or MeOH was used
as solvent,19 but by activation of the target molecule by
enolization to enolacetates almost quantitative formation of
the corresponding R-fluoro ketone could be achieved. Enol-
acetates of 1-indanone (13a, Scheme 4) or 1-tetralone 13b
were thus readily transformed to 2-fluoro-1-indanone 14a
or 2-fluoro-3,4-dihydronaphthalen-1(2H)-one 14b, respec-
tively.
Scheme 2 a
a Reaction conditions: (ii) 1 mmol of 8, 1.1 mmol of F-TEDA-
BF4, 5 mL of 0.05% water solution of surfactant sodium lauryl
ether sulfate (Genapol LRO), 60 °C, 6-24 h.
We further preliminarily checked the stereochemistry of
this fluorohydroxylation addition reaction and took (E)- and
(Z)-1,2-diphenylethene (10a and 10b, Scheme 3) as the tools
Scheme 4
Scheme 3 a
We further examined 1,3-diketones and â-ketoesters as
tools for water-mediated fluorofunctionalization with F-
TEDA-BF4 and established that both types of compounds
could also in this way be readily converted to R-fluoro
derivatives (Scheme 5). In the series of 1,3-diketones 1,3-
a
Scheme 5
a Reaction conditions: (ii) 1 mmol of 10, 1.1 mmol of F-TEDA-
BF4, 5 mL of 0.05% water solution of surfactant sodium lauryl
ether sulfate (Genapol LRO), 60 °C, 24 h.
often used for stereochemical evaluation of addition reactions
in the case of other fluorinating reagents.5-9 Both alkenes
were transformed with F-TEDA-BF4 in water to a mixture
of the diastereoisomers D,L-threo- (11) and D,L-erythro-1-
fluoro-2-hydroxy-1,2-diphenylethane (12). In the case of the
(E)-isomer 10a the formation of the erythro stereoisomer
12 was found to be predominant, while complete lack of
stereoselectivity of the addition process was observed when
the (Z)-isomer 10b was treated with F-TEDA-BF4 in water
solution of Genapol LRO (Scheme 3). These results are
similar to those observed when the same substrates were
treated in a MeCN solution of F-TEDA in the presence of
MeOH,17 indicating that the reaction mechanism is probably
alike.
(16) (a) Stavber, S.; Sotler, T.; Zupan, M. Tetrahedron Lett. 1994, 35,
1105-1108. (b) Stavber, S.; Zupan, M.; Poss, A. J.; Shia, G. A. Tetrahedron
Lett. 1995, 37, 6769-6772.
(17) Stavber, S.; Sotler-Pecan, T.; Zupan, M. Bull. Chem. Soc. Jpn. 1996,
69, 169-175.
a Reaction conditions: (ii) 1 mmol of 17, 19, or 21, 1.1 mmol
of F-TEDA-BF4, 5 mL of 0.05% water solution of surfactant sodium
lauryl ether sulfate (Genapol LRO), 60 °C, 2-4 h.
Org. Lett., Vol. 6, No. 26, 2004
4975

diphenyl-1,3-propandione 15a and 1,3-indandione 17 were
thus converted to R,R-difluoro derivatives 16a and 18 in high
yield with 2 equiv of F-TEDA-BF4 and 2-acetyl-1-tetralone
19 quantitatively to 2-acetyl-2-fluoro-3,4-dihydronaphtha-
lene-1(2H)-one 20 with 1 equiv of 1, while ethyl 3-oxo-3-
phenylpropanoate 15b was transformed to the 2,2-difluoro-
substituted product 16b with 2 mmols of F-TEDA-BF4 and
ethyl 2-oxocyclopentanecarboxylate 21 to its R-fluoro de-
rivative 22 with 1 equiv of the reagent. Unfortunately, in
the case of targets 15 and 17 the corresponding monofluoro-
substituted products could not be selectively obtained as
reported when MeCN was used as the reaction medium.20
On the basis of the above-mentioned results, we can in
conclusion claim that water could and should be used as a
reaction medium for fluorination of organic molecules with
Selectfluor F-TEDA-BF4. The selectivity and efficiency of
the reactions performed in water21 were found to be, at least
in the series of studied organic compounds and some rare
previous reports,13 comparable with those where other
organic solvents, mainly MeCN and MeOH, have been used.
The cost economy and environmental benefits so achieved
represent an important contribution to the green chemistry
approach to this field of organic chemistry.
Acknowledgment. We thank the Ministry of Education,
Science and Sport of the Republic of Slovenia for financial
support (contract P1-0134-0106-04).
Supporting Information Available: Yields and spectral
data of all product isolated. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL047867C
(21) Demineralized water solution of the surfactant Genapol LRO (5 mL,
0.05%) was poured over 1 mmol of target organic compound and the
suspension mixture magnetically stirred in a glass vessel for 10 minutes at
60 °C. Selectfluor F-TEDA-BF4 (1.05 or 2.1 mmol) was then added and
the reaction mixture stirred at 60 °C until the consumption of the reagent
was established by KI starch paper indication. Water (10 mL) was added
to the mixture, which after cooling to room temperature was extracted by
tert-butylmethyl ether (20 mL). The organic layer was washed with water
(20 mL) and dried (Na2SO4), and the solvent was evaporated. The crude
products were analyzed by 19F and 1H NMR, and pure material was obtained
by flash chromatography (SiO2) or TLC (SiO2) purification.
(18) Davis, F. A.; Kasu, P. V. N. Org. Prep. Proced. Int. 1999, 31, 125-
143.
(19) (a) Stavber, S.; Zupan, M. Tetrahedron Lett. 1996, 37, 3591-3594.
(b) Stavber, S.; Jereb, M.; Zupan, M. Synthesis 2002, 17, 2609-2615.
(20) Banks, E. R.; Lawrence, L. J.; Popplewell, A. L. Chem. Commun.
1994, 343-344.
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