Solvent-free fluorination of organic compounds using N-F reagents

Article abstract of DOI:10.1016/j.tetlet.2007.02.077

Efficient fluorination of 1,3-dicarbonyl compounds, enol acetates of aromatic ketones, and activated aromatic compounds was achieved under solvent-free conditions using Selectfluor F-TEDA-BF₄ or Accufluor NFSi.

Full text of DOI:10.1016/j.tetlet.2007.02.077

Tetrahedron Letters 48 (2007) 2671–2673
Solvent-free fluorination of organic compounds using N–F reagents
a
a,b
Gaj Stavber, Marko Zupan and Stojan Stavber
b,
*
a
Faculty of Chemistry and Chemical Technology, University of Ljubljana, A sˇ ker cˇ eva 5, 1000 Ljubljana, Slovenia
b
Laboratory of Organic and Bioorganic Chemistry, Jo zˇ ef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia
Received 15 January 2007; revised 6 February 2007; accepted 15 February 2007
Available online 20 February 2007
Abstract—Efficient fluorination of 1,3-dicarbonyl compounds, enol acetates of aromatic ketones, and activated aromatic com-
TM
TM
4
pounds was achieved under solvent-free conditions using Selectfluor F–TEDA–BF or Accufluor NFSi.
Ó 2007 Elsevier Ltd. All rights reserved.
1
. Introduction
pounds could be performed in aqueous media using
1
3
F–TEDA–BF4, however, in the scope of green chemis-
1
4
Interest in fluorine-containing organic molecules has
been increasing since this element very often induces
beneficial changes in their specific physicochemical and
biological characteristics. The main problem in per-
forming selective and efficient fluorination of organic
compounds is connected with the low dissociation
energy of the fluorine–fluorine bond and the strength of
the fluorine–carbon bond. The solution to this problem
is focused on the development of special methodologies
for modulation of the extreme reactivity of molecular
try, the best solvent is regarded as ‘no solvent at all’.
Fluorofunctionalization of organic compounds under
these conditions is a rather unexplored area. Research
has been mainly focused on solvent-free nucleophilic
fluorination, such as nucleophilic aromatic substitution
1
,2
1
5
with KF in the presence of a phase transfer catalyst,
regioselective and stereoselective opening of epoxides
1
6
by NBu H F , or using electrochemical techniques
4
2 3
1
7
for fluorination of cyclic ethers and lactones. To our
knowledge it is still not clear whether solvent-free fluori-
nation using electrophilic fluorination reagents could be
efficiently and selectively performed, although Differ-
ding briefly noted fifteen years ago that neat anisole
(in 22-fold molar excess at 150 °C) and acetanilide (in
two-fold molar excess at 100 °C) were fluorinated using
3
fluorine (low temperature techniques and high dilution
with an inert gas, using strong acids as reaction media
4
5
6
or, more recently, micro-reactor technology ), or in the
design of F–L type reagents, where ‘L’ represents the
ligand part of the fluorinating reagent. This second
concept has resulted in the development of a variety of
fluorinating reagents known under the common name
1
8
NFSi. We now report our recent efforts in responding
to the challenging question of whether it is possible to
selectively and efficiently transform a C–H bond to a
C–F bond with electrophilic fluorinating reagents under
solvent-free conditions.
‘
electrophilic fluorinating reagents’, consisting of three
7
8
main classes: fluoroxy compounds, xenon fluorides,
9
–11
and N–F reagents.
In line with the concept and principles of green chemis-
In the case of solvent-free reactions the aggregate state
of the substrates and reagents plays an important role
in molecular migration and thus has a significant influ-
ence on the transformation. Improved contact between
the reagent and substrate can be established in the case
of liquid–liquid and liquid–solid systems. We decided to
start our investigation with liquid b-keto esters and
selected representatives of each class of N–F reagents,
all solids. In a typical experiment a mixture of 1 mmol
of b-keto ester 2 or 4 and 1.1 mmol of N–F reagent 1
was heated in a 15 ml reaction flask at 85 °C for 4 h
and the crude reaction mixture obtained analysed. As
1
2
try which emerged a decade ago, the suitability of safer
alternative reaction media in place of volatile or toxic
organic solvents is one of the major and still challenging
issues. Accepting this challenge in the field of organo-
fluorine chemistry, we have already shown that selective
and efficient fluorination of a variety of organic com-
TM
4
Keywords: Solvent-free; Fluorination; Selectfluor F–TEDA–BF ;
TM
Accufluor NFSi.
*
Corresponding author. Tel.: +386 1477 3660; fax: +386 1423 5400;
e-mail: stojan.stavber@ijs.si
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.077

2672
G. Stavber et al. / Tetrahedron Letters 48 (2007) 2671–2673
a
Table 1. Fluorination of b-ketoesters with N–F reagents 1 under
solvent-free conditions
O
O
O
O
1c,d
Me
Me
solvent-free
O
O
O
O
F
1
OEt
OEt
OEt
6
7
solvent-free
F
F-TEDA-BF
NFSi:
4
: 87%
78%
2
3
O
O
O
O
1
Me
Me
F
solvent-free
O
O
O
O
Ph
1c,d
Ph
OEt
H
F
4
5
solvent-free
b
9
Entry Substrate N–F (1)
Time (h) Yield (%)
8
NFSi: decomposition
F-TEDA-BF4 (dry): 27%
F-TEDA-BF4 (wet): 90%
1
2
3
4
a: NFTh
4
4
6
1
Trace
Trace
71 (76)
89 (82)
b: FB-P300
c: F–TEDA–BF
d: NFSi
2
4
4
OAc
O
1
c,d
F
5
6
7
8
a: NFTh
4
5
5
5
Trace
Trace
b: FB-P300
c: F–TEDA–BF
d: NFSi
solvent-free
c
4
82 (76)
c
87 (81)
10
11
NFSi:
F-TEDA-BF : 95%
92%
a
TM
11
Compounds 1a: Accufluor NFTh: 1-fluoro-4-hydroxy-1,4-diazo-
niabicyclo [2.2.2]octane bis(tetrafluoroborate); 1b: FB-B3009: N-
4
TM
OR
OR
fluoro-2,4,6-trimethylpyridinium tetrafluoroborate; 1c: Selectfluor
1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]-
octane bis(tetrafluoroborate); 1d: Accufluor NFSi: N-fluorobenzen-
1
1
F–TEDA–BF
4
:
F
1
d
TM
9
sulfonimide.
solvent-free
b
c
Values in brackets are yields of pure products isolated by column
; CH Cl –n-hexane = 1:9).
2 2 2
–10% of 2,2-difluoro-3-oxo-3-phenylpropionic acid ethyl ester was
tBu
tBu
chromatography (SiO
1
2a R=H
12b R= Et
13a 55%
13b 52%
8
1
9
also formed.
OMe
OMe
shown in the Table 1, both ethyl 2-oxocyclopentane-
carboxylate 2 and 3-oxo-3-phenylpropionic acid ethyl
ester 4 were efficiently transformed under solvent-free
conditions to their corresponding fluoro derivatives,
that is, ethyl 1-fluoro-2-oxocyclopentanecarboxylate 3
OMe
F
1
c,d
+
solvent-free
OMe
OMe
OMe
F
F
and 2-fluoro-3-oxo-3-phenylpropionic acid ethyl ester
TM
14
15
16
5
7
, using Selectfluor F–TEDA–BF 1c (entries 3 and
4
TM
) or Accufluor NFSi 1d (entries 4 and 8), while appli-
F-TEDA-BF : 78%
13%
15%
4
TM
cation of Accufluor NFTh 1a ( entries 1 and 5) or FP-
B300 1b (entries 2 and 6) were unsuccessful leading to
only trace amounts of the corresponding fluorinated
products 3 or 5 in these cases.
NFSi:
73%
F
OR
OR
1c,d
solvent-free
1
8
Encouraged by these results we further investigated the
possibility of fluorination of 1,3-diketones under solvent-
free conditions and chose derivatives structurally
similar to the mentioned targets: that is, 2-acetylcyclo-
hexanone 6, which is a liquid, and solid 2-methyl-1,3-
cyclohexadione 8. We established that 6 was readily con-
verted after 4 h to 2-fluoro-2-acetylcyclohexanone 7 in
1
7a R= Et
F-TEDA-BF : 61%
4
NFSi:
67%
17b R=i-Pr
F-TEDA-BF
NFSi:
4
: 52%
55%
Scheme 1.
7
8% yield with 1.1 mmol of NFSi at 85 °C, while an even
more efficient transformation (87%) was obtained using
to 9 was established. 1-Indanone, as a monocarbonyl
substrate, could not be directly fluorinated under
solvent-free conditions, but after its transformation to
acetyl-3H-indene 10 an almost quantitative conversion
to 2-fluoro-1-indanone 11 was achieved with both the
N–F reagents employed.
F–TEDA–BF (Scheme 1). On the other hand, the treat-
ment of 8 with dry NFSi at 85 °C caused a vigorous and
uncontrollable reaction, resulting in decomposition of
4
the materials, while F–TEDA–BF under the same con-
4
ditions gave the expected 2-fluoro-2-methyl-cyclo-
hexadione 9, but in only 27% yield. The addition of a
drop of water (25–30 mg) to a mixture of F–TEDA–
In order to check the possibility of formation of a C–F
bond under solvent-free conditions in aromatic com-
pounds, we chose 4-tert-butyl-phenol 12a as a model
BF and 8 prior to heating considerably improved the
4
efficiency of the transformation and excellent conversion

G. Stavber et al. / Tetrahedron Letters 48 (2007) 2671–2673
2673
compound and established that by heating it at 85 °C for
hours with 1.1 mmol of NFSi, 2-fluoro-4-tert-butyl-
phenol 13a was formed in 55% of yield accompanied
J. C., Eds.; Georg Thieme: Stuttgart, New York, 1999;
Vol. E10a–c; (b) Chambers, R. D. Fluorine in Organic
Chemistry; Blackwell: Oxford, 2004.
. (a) Organofluorine Chemistry. Principles and Commercial
Applications; Banks, R. E., Smart, B. E., Tatlow, J. C.,
Eds.; Plenum Press: New York, London, 1996; (b)
Advances in Organic Synthesis Modern Organofluorine
Chemistry—Synthetic Aspects; Laali, K. K., Atta-
Ur-Rahman, Eds.; Bentham Science: Amsterdam, 2006;
Vol. 2.
4
2
with trace amounts of 4-fluorophenol and 2,6-difluoro-
4
1
-tert-butyl phenol. Similar results were observed when
-tert-butyl-4-ethoxybenzene 12b was treated under the
same reaction conditions to afford 1-tert-butyl-4-eth-
oxy-2-fluorobenzene 13b as the main product, accompa-
nied by a trace amount of 1-ethoxy-4-fluorobenzene.
The use of F–TEDA–BF in these two cases did not lead
3. Merrit, R. F.; Johnson, F. A. J. Org. Chem. 1966, 31,
4
to formation of any product. On the other hand, F–
1859–1863.
4
. (a) Purrington, S. T.; Kagen, B. S.; Patrick, T. B. Chem.
Rev. 1986, 86, 997–1018; (b) Rozen, S. Acc. Chem. Rev.
TEDA–BF was found to be efficient in the case of
4
1
,3-dimethoxybenzene 14 which was readily converted
1
988, 21, 307–312; (c) Chambers, R. D.; Parsons, M.;
into 4-fluoro-1,3-dimethoxybenzene 15 as the major
product, and 4,6-difluoro-1,3-dimethoxybenzene 16, as
the minor product, with a high overall yield. The same
mixture of products was also established when NFSi
was used under the same reaction conditions. Electro-
philic fluorination under solvent-free conditions was
also efficient in the case of 2-alkoxynaphthalene deriva-
tives. 2-Ethoxy-17a and 2-isopropyloxynaphthalene 17b
were converted with both N–F reagents at 85 °C into 1-
fluoro-alkoxynaphthalene derivatives 18 in reasonable
yield, while only trace amounts of 1,1-difluoro-2(1H)-
naphthalenone, the consequence of further fluorination,
were detected (Scheme 1).
Sandford, G.; Thomas, E.; Trmcic, J.; Moilliet, J. S.
Tetrahedron 2006, 62, 7162–7167, and references cited
therein.
. (a) Chambers, R. D.; Skinner, C. J.; Thomson, J.;
Hutchinson, J. C. S. Chem. Commun. 1995, 17; (b)
Chambers, R. D.; Holling, D.; Sanford, G.; Batsanov,
A. S.; Howard, J. A. K. J. Fluorine Chem. 2004, 125, 661–
671, and references cited therein.
5
6
. (a) Chambers, R. D.; Spink, R. C. H. Chem. Commun. 1999,
8
83–884; (b) Chambers, R. D.; Fox, M. A.; Sanford, G. Lab
Chip 2005, 5, 1132–1139, and references cited therein.
. Rozen, S. Chem. Rev. 1996, 96, 1717–1736.
. (a) Zupan, M. In The Chemistry of Functional Groups,
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ster, 1995; pp 821–860; (b) Zajc, B. in Ref. 2b, 61–
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9. (a) Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev. 1996,
96, 1737–1755; (b) Taylor, D. S.; Kotoris, C. C.; Hum, G.
Tetrahedron 1999, 55, 12431–12477.
7
8
In conclusion direct selective fluorination under solvent-
free conditions was successfully achieved using electro-
philic fluorinating reagents from the N–F class. The best
results were obtained by heating the organic compound,
liquid or solid, with F–TEDA–BF or NFSi, at 80–
4
1
0. Umemoto, T. in Ref. 2b, pp 159–181 and references cited
therein.
1. (a) Singh, R. P.; Schreeve, J. M. Chem. Res. 2004, 37, 31–
9
0 °C. Solvent-free fluorination was efficiently and selec-
tively achieved on a variety of b-diketones, b-keto esters,
acetylated mono ketones, and various activated aro-
matic derivatives. Following our preliminary findings
it has thus been shown that transformation of a car-
bon–hydrogen bond into a carbon–fluorine bond could
also be selectively and efficiently achieved under solvent-
free conditions.
1
3
4; (b) Stavber, S.; Zupan, M. in Ref. 2b, pp 213–268 and
references cited therein.
1
2. Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and
Practice; Oxford University Press: New York, 1998.
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2004, 6, 4973–4976.
1
1
4. (a) Solvent-free Organic Synthesis; Tanaka, K., Ed.; Wiley:
Weinheim, 2003; (b) Tanaka, K.; Toda, F. Chem. Rev.
2
000, 100, 1025–1074; (c) Prakash, G. K. S.; Mathew, T.;
2. Typical experimental procedure for solvent-free
fluorination of organic compounds with N–F reagents
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cited therein; (d) Pravst, I.; Zupan, M.; Stavber, S. Green
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In the case of liquid substrates 1 mmol of target material
and 1.1 mmol of N–F reagent were homogenized in a
5 ml glass vessel using a glass stick and the mixture
1
heated at 85–90 °C for 1–8 h, while in the case of solid
target compounds the mixture of substrate and N–F re-
agent was triturated in a glass mortar for a minute, then
transferred to a glass vessel and heated. After routine
16. Barbier, P.; Mohr, P.; Muller, M.; Masciadri, R. J. Org.
Chem. 2002, 63, 6984–6989.
17. Hasegava, M.; Ishii, H.; Fuchigami, T. Tetrahedron Lett.
2
002, 43, 1503–1505.
9
a
20
18. Differding, E.; Ofner, H. Synlett 1991, 187–189.
work-up procedures for NFSi or F–TEDA–BF ,
4
1
9
19. The use of two molar excess of the N–F reagents 1c,d,
the crude reaction mixtures were analyzed by F and
1
3
1
contrary to the reaction in water, did not considerably
improve the formation of the 2,2-difluoro product, while
fluorination of mono fluoro compound 5 with an equi-
molar amount of the N–F reagent afforded no more than
H NMR spectroscopy using octafluoronaphthalene as
2
1
an internal standard. Pure products were isolated by
column chromatography.
1
5% of the difluoro product.
2
2
0. Zupan, M.; Iskra, J.; Stavber, S. Bull. Chem. Soc. Jpn.
1995, 68, 1655–1660.
1. A gram scale experiment was performed in the case of
fluorination of compound 8 with 1c and no uncontrollable
exotherm was observed.
References and notes
1
. (a) Organo-Fluorine Compounds Houben-Weyl Methods of
Organic Chemistry; Baasner, B., Hagemann, H., Tatlow,