New method of fluorination using potassium fluoride in ionic liquid: Significantly enhanced reactivity of fluoride and improved selectivity

Article abstract of DOI:10.1021/ja026242b

We have found the new nucleophilic fluorination reaction of some halo- and mesylalkanes to the corresponding fluoroalkanes with KF in the presence of [bmim][BF₄] under various reaction conditions. 2-(3-Methanesulfonyloxypropoxy)naphthalene (1) was used as a model compound to optimize this fluorination reaction. Whereas the fluorination of the mesylate 1 with KF in an organic solvent such as CH₃CN at 100 °C occurred hardly even after 24 h, the same reaction in ionic liquids, [bmim][BF₄], as a reaction solvent was completed within 1.5 h, affording the wanted product 2-(3-fluoropropoxy)naphthalene 2a (85%) together with the alkene byproduct 2c (10%). Very interestingly, however, the addition of water (5 equiv) completely eliminated the formation of the undesired alkene 2c and thus gave higher yield of 2a (92%, entry 2). The use of acetonitrile as a cosolvent did not affect the reactivity of the fluorination. The presence of a proper amount of cosolvent was rather desirable (94% yield of 2a). We performed fluorination reactions with other ionic liquids ([bmim][PF₆], [bmim][SbF₆], [bmim][OTf], and [bmim][N(Tf)₂], and two other cosolvents, to find the optimal ionic liquid and cosolvent. Nine different compounds were examined, including the 10 g-synthesis of 2-(fluoromethyl)naphthalene in 93% of isolated yield. Copyright

Full text of DOI:10.1021/ja026242b

Published on Web 08/10/2002
New Method of Fluorination Using Potassium Fluoride in Ionic Liquid:
Significantly Enhanced Reactivity of Fluoride and Improved Selectivity
,
†
Dong Wook Kim, Choong Eui Song,* and Dae Yoon Chi*
Department of Chemistry, Inha UniVersity, 253 Yonghyundong Namgu, Inchon 402-751, Korea, Life Sciences
DiVision, Korea Institute of Science and Technology, Cheongryang, Seoul, 130-650, Korea
Received March 20, 2002
Organic compounds with low fluorine content have received
1
much interest because of their physiological properties. Many
efforts have been made to increase the potency of biologically active
compounds by replacing hydrogen with a fluorine atom. The nucleo-
Figure 1. Ionic liquids.
philic displacement of various sulfonates and halides by fluoride
is the typical method for the introduction of a single fluorine atom
into aliphatic organic compounds. Alkali metal fluoride such as
Table 1. Fluorinations of Mesylate 1 with KF under Various
Reaction Conditionsa
2
potassium fluoride is the traditional reagent for this type of reaction.3
However, its limited solubility in organic solvent and low nucleo-
philicity require generally vigorous conditions. Thus, a number of
yield of product (%)b
4
[bmim][BF
4
]mL CH
3
CN
H
(µL)
2
O
raction
time (h)
metal fluoride reagents such as KF/18-crown-6, polymer supported
entry
(equiv)
(mL)
1
2a
2b
2c
5
6
fluoride, “spray-dried” KF, and calcium fluoride supported on
1
2
3
4
5
6
7
8
9
5
5
3.2
1.6
3
-
-
1.6
3.2
1.5 500
4
4.4
4.8
5
0
2
1.5
1.5
1.5
1.5
1.5
3
-
-
-
-
-
-
-
-
85
-
10
7
alkali metal fluoride have been reported to solve these problems.
90 (5 equiv)
92
93
94
88
92
91
89
-
-
1
8-Crown-6 derivatives have been largely used to enhance the
90
90
trace
-
6
-
-
4
solubility and nucleophilicity of KF in organic media. However,
these above-mentioned processes are generally less efficient than
those using tetraalkylammonium fluorides. Tetrabutylammonium
fluoride (TBAF) is the most popular reagent for the nucleophilic
-
1
90
90
90
90
0
-
-
0.57 (3)
0.19 (1)
0.1 (0.5)
-
trace
trace
8
-
6
-
12
24
24
trace 84
trace
-
8
fluorination. Despite its good solubility and reactivity, the fluorina-
10
5
5
86
53
trace
40
-
-
11
18-crown-6 (2)
0
-
tion using tetraalkylammonium fluorides has some drawbacks which
are that these reagents also cause the elimination of alkyl halides,
the formation of alkyl sulfonates to alkenes, and the hydroxylation
to alcohols because “naked” fluoride can act not only as a nucleo-
phile but also as a base.8 DeShong et al. recently developed the
fluorinating reagent, tetrabutylammonium triphenyldifluorosilicate
a
All reactions were carried out on a 1.0 mmol reaction scale of mesylate
using 5 mmol of KF at 100 °C. b Isolated yield.
1
a
as CH CN at 100 °C occurred hardly even after 24 h (entry 10),
the same reaction in [bmim][BF ] as a reaction solvent was
3
4
(
TBAT), which is less basic than TBAF, free from anhydrous
completed within 2 h, affording the wanted product 2a (85%)
9
condition, yet, less nucleophilic. However, TBAT still requires
long reaction time due to its relative low reactivity. Moreover, it is
relative expensive and causes too much chemical waste considering
its large molecular weight as compared with that of KF.
together with the alkene byproduct 2c (10%) (entry 1). Very
interestingly, however, the addition of water (5 equiv) completely
eliminated the formation of the undesired alkene 2c and thus gave
higher yield of 2a (92%, entry 2). Moreover, entries 3 and 4 show
that the use of acetonitrile as a cosolvent does not affect the
reactivity of the fluorination. The presence of a proper amount of
Ionic liquids (see Figure 1) have recently been regarded as an
eco-friendly alternative to replace volatile organic solvents in current
chemical processing, due to their unique physical and chemical
properties.10 It has also been reported that ionic liquids containing
imidazolium cations can act as powerful media in some catalytic
organic reactions not only the for facilitation of catalyst recovery
and but also for the acceleration of reaction rate and improvment
of selectivity.11 In this report, we present a highly efficient method
for the synthesis of fluoroalkanes from alkyl mesylate or alkyl
halides by a nucleophilic substitution reaction using KF and ionic
14
cosolvent was rather desirable (94% yield of 2a in entry 4 ). When
an excess of water (10% of total reaction volume) was added, the
hydroxylation of the mesylate 1 to alcohol 2b (6%) took place,
although the fluoroalkane 2a was still a major product (88%) (entry
5). This result means that our fluorination method using [bmim]-
4
[BF ] does not require anhydrous conditions. In addition, as shown
in entries 6-9, the use of lesser amounts of [bmim][BF ] had little
4
influence on the reactivity of fluorination. It should be here noted
12
liquids such as [bmim][X]. In this method, ionic liquids play an
important role in significantly enhancing the reactivity of KF as
well as reducing formation of byproducts, for example, alkenes,
alcohols, or both.13
that the use of catalytic amounts (0.5 equiv) of [bmim][BF ] was
4
also enough to almost complete the reaction over 12 h. A
comparison of entries 9 and 11 demonstrates that when using only
catalytic amounts of the ionic liquid [bmim][BF ] fluorination
4
Table 1 illustrates the fluorination reaction of 2-(3-methane-
sulfonyloxypropoxy)naphthalene (1) with KF in the presence of
proceeded much faster than using 2 equiv of 18-crown-6.
To find the optimal ionic liquid and cosolvent, we next carried
out the fluorination of 1 under the same conditions as for entry 4
in Table 1, except for the use of the four other ionic liquids instead
[bmim][BF
4
] under various reaction conditions. Whereas the
fluorination of the mesylate 1 with KF in an organic solvent such
of [bmim][BF
In entries 1 and 2 (Table 2), using [bmim][PF
4
], and two other cosolvents instead of acetonitrile.
] and [bmim][SbF ],
*
To whom correspondence should be addressed. E-mail: dychi@inha.ac.kr.
Korea Institute of Science and Technology.
†
6
6
10278
9
J. AM. CHEM. SOC. 2002, 124, 10278-10279
10.1021/ja026242b CCC: $22.00 © 2002 American Chemical Society

C O MMU N I C A T I O N S
Table 2. Fluorinations of Mesylate 1 with KF in Various Ionic
Liquids and Cosolvents
in 54% yield with alkene in 39% yield. Interestingly, as shown in
entry 7 (Table 3), the reaction using an excess amount of water
(10% of total reaction volume, the conditions of entry 5 in Table
1) gave a significantly improved yield (75%) and reduced the
elimination product. This result suggests that the control of the
amount of water in the fluorination in the presence of ionic liquid
can suppress the elimination and provide a high yield of the desired
fluoroproduct. The fluorination of R-bromoacetophenone also
afforded R-fluoroacetophenone in good yield (entry 8). In the final
example, a 5,8-dimethoxy-4-fluoropropylquinoline16 was produced
in 95% isolated yield by the fluorination of the mesylate (entry 9).
In summary, we have demonstrated facile nucleophilic fluorina-
tion of some halo- and mesylalkanes to the corresponding fluoro-
alkanes using KF in the presence of an ionic liquid and water. The
ionic liquid-water system could not only enhance the reactivity of
KF significantly but also reduce the formation of byproducts.
Further studies on the development of a more efficient protocol
a
yield of product (%)b
entry
ionic liquid
cosolvent
CH3CN
reaction time (h)
1
2a
2b
2c
1
2
3
4
5
[bmim][PF6]
2
-
-
-
90 trace
93
79 15
-
-
-
-
-
-
[bmim][SbF6] CH3CN
[bmim][OTf] CH3CN
[bmim][NTf2] CH3CN
2
-
4
5
61 35 trace
[bmim][BF4]
[bmim][BF4]
1,4-dioxane
t-BuOH
1.5
1.5
-
-
91
-
c
6
85 trace
a
All reactions were carried out under the same condition as entry 4 in
b
c
Table 1. Isolated yield. 7% of the tert-butoxylated compound was
detected by H NMR.
1
Table 3. Fluorinations of Various Alkyl Halides and Mesylates
a
Using KF in [bmim][BF4]
(lower reaction temperature, shorter reaction time, etc.) for nucleo-
philic fluorination using ionic liquids are in progress in our
18
laboratories. Applications of this fluorination method to F labeling
for diagnostic agents are also under investigations.
Acknowledgment. We thank the Korea Ministry of Science and
Technology Grant, Mid- and Long-term Nuclear R&D Program
(E-6-5) and National Research Laboratory Program.
Supporting Information Available: Experimental procedures and
1
13
H and C NMR spectra including characterization of all compounds
and ionic liquid information (PDF). This material is available free of
charge via a Internet at http://pubs.acs.org.
References
(
1) (a) Seebach, D. Angew. Chem., Int. Ed. Engl. 1990, 29, 1320. (b) Filler,
R. In Organofluorine Compounds in Medicinal Chemistry and Biomedical
Applications; Filler, R., Ed.; Studies in Organic Chemistry 48; Elsevier;
New York, 1993; pp 1-23.
(
2) For reviews on nucleophilic fluorination, see: (a) Gerstenberger, M. R.
C.; Haas, A. Angew. Chem., Int. Ed. Engl. 1981, 20, 647-667. (b)
Mascaretti, O. A. Aldrichimica Acta 1993, 26, 47-58.
a
Unless otherwise noted, all reactions were carried out under the same
(3) Forche, D. In Methoden der Organischen Chemie Houben-Weyl; Mueller,
E., Ed.; George Thieme Verlag: Stuttgart, 1962; Vol. 5/3.
(4) Liotta, C. L.; Harris, H. P. J. Am. Chem. Soc. 1974, 96, 2250-2252.
b
c
condition as entry 4 in Table 1. Isolated yield. Entry 5 was performed
in 10 g of reaction scale. The reaction was carried out under the condition
d
(
(
(
5) Colonna, S.; Re, A.; Gelbard, G.; Cesarotti, E. J. Chem. Soc., Perkin Trans.
of entry 5 in Table 1.
1
1979, 2248-2252.
6) Ishikawa, N.; Kitazume, T.; Yamazaki, T.; Mochida, Y.; Tatsumo, T.
Chem. Lett. 1981, 761-764.
we obtained results similar to those obtained with [bmim][BF
4
]
(Table 1, entry 4). However, the fluorination using [bmim][OTf]
7) (a) Clark, J. H.; Hyde, A. J.; Smith, D. K. J. Chem. Soc., Chem. Commun.
1986, 791-793. (b) Ichihara, J.; Matsuo, T.; Hanafusa, T.; Ando, T. J.
Chem. Soc., Chem. Commun. 1986, 793-794.
gave slightly lower yield (79%) (entry 3). 1,4-Dioxane could also
be used as a cosolvent in the fluorination reaction, while tert-butyl
alcohol was not a proper cosolvent because the tert-butoxylation of
(
8) (a) Cox, D. P.; Terpinsky, J.; Lawrynowicz, W. J. Org. Chem. 1984, 49,
3216-3219. (b) Chi, D. Y.; Kilbourn, M. R.; Katzenellenbogen, J. A.;
Welch, M. J. J. Org. Chem. 1987, 52, 658-664.
1
to 2-(3-tert-butoxypropoxy)naphthalene took place in 7% (entry 6).
(
9) Pilcher, A. S.; Ammon, H. L.; DeShong, P. J. Am. Chem. Soc. 1995,
117, 5166-5167.
Table 3 illustrates that the fluorination of primary, secondary,
(
10) For recent reviews on ionic liquids, see: (a) Sheldon, R. Chem. Commun.
and benzylic halides or mesylates using 5 equiv of KF in the
presence of [bmim][BF ] under the same conditions as for entry 4
2001, 2399-2407. (b) Wasserscheid, P.; Kein, W. Angew. Chem., Int. Ed.
4
2000, 39, 3772-3789. (c) Welton, T. Chem. ReV. 1999, 99, 2071-2083.
11) (a) Song, C. E.; Shim, W. H.; Roh, E. J.; Lee, S.-g.; Choi, J. H. Chem.
Commun. 2001, 1122-1123. (b) Song, C. E.; Shim, W. H.; Roh, E. J.;
Choi, J. H. Chem. Commun. 2000, 1695-1696. (c) Song, C. E.; Roh, E.
J. Chem. Commun. 2000, 837-838.
(
in Table 1 (with the exception of entry 7), provides corresponding
fluorocompounds in comparable or better yields than other methods
previously reported.4
,5,8,9
The fluorination of primary chloro-,
(
12) 1-n-Butyl-3-methylimidazolium cation [bmim] and its counteranions:
bromo-, and iodoalkane under these conditions provided 2a in good
yield (66, 83, and 76%, entries 1-3, respectively) with minimal
byproducts. The fluorination reaction of a secondary mesylate (entry
tetrafluoroborate [BF4], hexafluorophosphate [PF
6
], hexafluoroantimonate
[
SbF
used.
13) Dermeik, S.; Sasson, Y. J. Org. Chem. 1985, 50, 879-882.
6
], triflate [OTf], and bis(trifluoromethanesulfonyl)imide [NTf ] are
2
(
4) also proceeded smoothly, affording the corresponding fluoride
(14) Typical Procedure. KF (290 mg, 5 mmol) was added to the mixture of
-(3-methanesulfonyloxypropoxy)naphthalene (1, 280 mg, 1.0 mmol),
bmim][BF ] (1.6 mL), and H O (90 µL, 5 mmol) in acetonitrile (3.2
2
in 74% isolated yield, whereas secondary halides or mesylates
predominantly underwent the elimination under the other previously
reported conditions. A benzylic fluoride was produced in good yield
by the fluorination of the bromide (entry 5). It is difficult to
introduce the fluorine to haloethyl or alkanesulfonylethyl aromatic
[
4
2
mL). The mixture was stirred over 1.5 h at 100 °C. The reaction mixture
was extracted from the ionic liquid phase with ethyl ether (7 mL × 3).
The organic layer was dried over anhydrous sodium sulfate and evaporated
under reduced pressure. The residue was purified by flash column
chromatography (5% EtOAc/hexanes) to obtain 192 mg (94%) of 2-(3-
fluoropropoxy)naphthalene (2a).
compounds because the elimination of these to styrenes is the
dominant reaction.15 However, as shown in entry 6, the fluorination
of 2-(2-mesylethyl)naphthalene to 2-(2-fluoroethyl)naphthalene
proceeded predominantly and provided the corresponding fluoride
(15) Gerdes, J. M.; Keil, R. N.; Shulgin, A. T.; Mathis, C. A. J. Fluorine Chem.
1996, 78, 121-129.
(
16) Kim, D. W.; Choi, H. Y.; Lee, K.-J.; Chi, D. Y. Org. Lett. 2001, 3,
445-447.
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J. AM. CHEM. SOC.
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