Polymer-supported pentaethylene glycol as a facile heterogeneous catalyst for nucleophilic fluorination

Article abstract of DOI:10.1021/ol101485n

Polymer-supported pentaethylene glycols (PSpentaEG) as promising catalysts for nucleophilic fluorination with alkali metal fluoride (MF) could significantly enhance the nucleophilicity of MF and provide simple purification and recycling in the reaction. F

Full text of DOI:10.1021/ol101485n

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3740-3743
Polymer-Supported Pentaethylene Glycol
as a Facile Heterogeneous Catalyst for
Nucleophilic Fluorination
Vinod H. Jadhav,† Seung Ho Jang,† Hwan-Jeong Jeong,† Seok Tae Lim,†
Myung-Hee Sohn,† Dae Yoon Chi,‡ and Dong Wook Kim*,†
Department of Nuclear Medicine, Cyclotron Research Center, Chonbuk National
UniVersity Medical School, Jeonju, Jeonbuk 561-712, Korea, and Department of
Chemistry, Sogang UniVersity, 1 Shinsudong, Mapogu, Seoul 121-742, Korea
kimdw@chonbuk.ac.kr
Received May 26, 2010
ABSTRACT
Polymer-supported pentaethylene glycols (PSpentaEG) as promising catalysts for nucleophilic fluorination with alkali metal fluoride (MF)
could significantly enhance the nucleophilicity of MF and provide simple purification and recycling in the reaction. Furthermore, by their
synergistic effect, the combination of PSpentaEG and a tert-alcohol media system showed tremendous efficiency in the fluorination of base-
sensitive substrates such as sec-alkyl halide.
Organic molecules with fluorine content have received much
attention in the field of life science, despite their rarity in
nature.1 Fluorine is often used as a substituent in pharma-
ceuticals and agrochemicals since it can often increase their
bioavailability, potency, and metabolic stability compared
to nonfluorinated analogues.2,3 Furthermore, radiopharma-
ceuticals labeled with fluorine-18 are also widely used as in
vivo probes for noninvasive imaging of biological processes
in living subjects using positron emission tomography
(PET).4 It is well-known that the most common method for
the introduction of fluorine into a specific aliphatic frame-
work is by the nucleophilic substitution of various sulfonates
and halides by fluoride in polar aprotic solvents employing
alkali metal fluorides (MF), which have traditionally been
used as a fluoride source; however, the low nucleophilicity
and solubility of MF in organic media make this reaction
require harsh conditions and restrict its wide applications.5
Thus, over the past several decades, a large number of phase-
transfer-type protocols, such as MF/crown ether complex-
ation,6 quaternary ammonium fluorides,7 and MF/ionic liquid
systems,8 have been developed to generate soluble and
reactive “naked” fluoride from MF.5-8 However, these
† Chonbuk National University Medical School.
‡ Sogang University.
(1) O’Hagan, D.; Schaffrath, C.; Cobb, S. L.; Hamilton, J. T. G.; Murphy,
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10.1021/ol101485n  2010 American Chemical Society
Published on Web 08/04/2010

systems employing “naked” fluoride are generally strongly
basic, which restricts their synthetic utility because it
promotes various side reactions such as eliminations and
hydroxylations.9
The PSpentaEG were prepared by a simple one-step
reaction, as shown in Scheme 1. We prepared various
In a recent significant advance, it was reported that bulky
protic tert-alcohol solvents can be excellent media for the
fluorination of various sulfonate substrates with CsF through
the formation of “flexible” fluoride by controlled hydrogen
bonding between MF and these tert-alcohol media. However,
this tert-alcohol media protocol has these synthetic limita-
tions: (i) the tert-alcohol media fluorination of a substrate
with halide-leaving group showed poor performance because
of its requiring harsh conditions; (ii) tert-alcohol media could
not reduce enough the formation of side products in the
reaction of base-sensitive substrates using a “naked” fluoride
source such as tetrabutylammonium fluoride (TBAF), com-
pared with CsF; and (iii) tight-ion pair alkali metal fluo-
rides (e.g., KF, RbF) were observed to be inactive in the
reactions.10 More recently, it was reported that oligoethylene
glycols, such as triethylene or tetraethylene glycols, act as
highly efficient reaction solvents for nucleophilic fluorination
with KF.11 However, the high boiling point of these
oligoethylene glycols might cause purification problems or,
frequently, inconvenience in the chemical processes.12,13
The immobilization of a catalyst or reagent on various
polymeric supports is attracting considerable attention in
chemical processes, including the green chemistry field due
to its ease of recycling, easy handling, and the unique
microenvironment caused by the reactants within the poly-
meric support.12 Herein, we introduce polymer-supported
pentaethylene glycol (PSpentaEG) as a promising catalyst
for nucleophilic fluorination with MF. We found that this
PSpentaEG has the advantage of significantly enhancing the
nucleophilicity of the metal fluoride as well as the ease of
purification in the reaction. Moreover, the combination of
PSpentaEG catalyst and tert-alcohol media system showed
very good performance in the fluorination of base-sensitive
substrates.
Scheme 1. Preparation of Polymer-Supported Pentaethylene
Glycol- PSpentaEG and Methylated PSpentaEG
PSoligoEGs with different lengths of oligoEGs (EG )
ethylene glycol). The physical and chemical properties of
the PSoligoEGs depend on the length of oligoEGs. In this
report, the most efficient polymer-supported pentaethylene
glycol system is described. The treatment of Merrifield
resin14 (1% divinylbenzene, 3.7 mmol Cl/g) with pentaEG
in dried THF for 4 days afforded PSpentaEG (1.9 mmol of
pentaEG per gram of polymer-supported product obtained).
The PSpentaEG was characterized by 13C NMR (solid state)
spectroscopy and by elemental analysis.
Figure 1 illustrated the influence of the hydrogen bond
between the terminal hydroxyl group of PSpentaEG and
(6) Gokel, G. W. In Crown Ethers and Cryptands; Royal Society of
Chemistry: Cambridge, 1991.
(7) (a) Dehmlow, E. V.; Dehmlow, S. S. Phase Transfer Catalysis, 3rd
ed.; VCH Ltd.: New York, 1993. (b) Sun, H.; DiMagno, S. G. J. Am. Chem.
Soc. 2005, 127, 2050–2051.
Figure 1. (A) Nucleophilic fluorination using CsF with PSpentaEG,
PSpentaEGMe, or no catalyst. (B) Nucleophilic bromination using
CsBr with PSpentaEG or no catalyst. The quantity of starting
material remaining was determined by 1H NMR. R ) naphthyloxy.
(8) Kim, D. W.; Song, C. E.; Chi, D. Y. J. Am. Chem. Soc. 2002, 124,
10278–10279.
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S. J.; Kim, J. S.; Ryu, J.-S.; Moon, D. H.; Chi, D. Y. J. Am. Chem. Soc.
2006, 128, 16394–16397. (b) Kim, D. W.; Jeong, H.-J.; Lim, S. T.; Sohn,
M.-H.; Katzenellenbogen, J. A.; Chi, D. Y. J. Org. Chem. 2008, 73, 957–
962. (c) Kim, D. W.; Jeong, H.-J.; Lim, S. T.; Sohn, M.-H. Angew. Chem.,
Int. Ed. 2008, 47, 8404–8406. (d) Kim, D. W.; Jeong, H.-J.; Lim, S. T.;
Sohn, M.-H. Tetrahedron. Lett. 2010, 51, 432–434.
nucleophiles on the nucleophilic substitution reaction.
PSpentaEGMe, which is methylated at the terminal OH
group to prevent hydrogen bonding with the fluoride of
CsF, showed very low catalytic activity in nucleophilic
fluorination using CsF, and thus the fluorination reaction
with PSpentaEGMe proceeded very sluggishly compared
with the same reaction with PSpentaEG (Figure 1A).
Furthermore, comparison with parts A and B of Figure 1
shows that PSpentaEG has much higher activity in the
fluorination reaction with CsF, which can form a much
stronger hydrogen bond with PSpentaEG than CsBr than in
(11) Lee, J. W.; Yan, H.; Jang, H. B.; Kim, H. K.; Park, S.-W.; Lee, S.;
Chi, D. Y.; Song, C. E. Angew. Chem., Int. Ed. 2009, 48, 7683–7688.
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Org. Lett., Vol. 12, No. 17, 2010
3741

the bromination with CsBr. These results suggest that it is
not only that the controlled hydrogen bonding of the terminal
hydroxyl group of PSpentaEG with the fluoride of MF may
allow its nucleophilicity to increase by a “flexible” fluoride
effect10 but also that the recognition of CsF by PSpentaEG
through the hydrogen bonding may also make the formation
of the CsF/ether complex more effective; this hydrogen
bonding may play an important role in the initial interaction
between PSpentaEG and CsF to form the complex.
performance in the reaction using KF (entry 9). To investigate
how many times PSpentaEG could be reused, we performed
the fluorination repeatedly under the conditions given in entry
2 in Table 1. PSpentaEG was observed to be able to indeed be
reused repeatedly without the loss of its catalytic activity; in
each cycle, the fluoro product 2 was obtained in high yield
(92-95%).
To investigate the influence of the synergistic effect
between PSpentaEG catalyst and tert-alcohol media on the
selectivity of the fluorination reactions, we conducted nu-
cleophilic fluorination on various base-sensitive substrates
with CsF in the presence of PSpentaEG in tert-amyl alcohol.
The results are summarized in Table 2, together with those
Table 1 presents the nucleophilic fluorination of 2-(3-
methanesulfonyloxypropyl)naphthalene (1), as a model com-
Table 1. Fluorination of Mesylate 1 with Alkali-Metal Fluorides
(MF) Using PSpentaEG or the Stated Alternative Reagentsa
Table 2. Selective Nucleophilic Fluorinations Using PSpentaEG
in tert-Alcohol Medium
PSpentaEG
(equivb)
yieldc
(%)
entry
MF time (h)
solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
tert-amyl alcohol
tert-amyl alcohol
tert-amyl alcohol
tert-amyl alcohol
1
2
3
4
5
6
7
8
9
2.0
1.0
0.5
CsF
CsF
CsF
CsF
2.5
2.5
4
93
95
92
10
88
97
94
24
29
4
18-crown-6d CsF
1.0
1.0
6
CsF
RbF
RbF
KF
1
3
3
24
1.0
a All reactions were carried out on a 1.0 mmol reaction scale of mesylate
1 using 3 mmol of CsF in 4.0 mL of solvent at 100 °C. b Equivalent amount
of the pentaethylene glycol portion, not PSpentaEG. c Yields were
determined by H NMR spectroscopy. d 2 equiv of 18-crown-6 was used.
1
pound, with various alkali-metal fluorides in the presence
of the PSpentaEG under various reaction conditions. Whereas
the fluorination reaction of mesylate 1 using 3 equiv of CsF
at 100 °C in a polar aprotic solvent such as acetonitrile barely
proceeded after 4 h (entry 4), the same reaction in the
presence of 2 or 1 equiv of PSpentaEG was complete within
2.5 h, providing the fluorinated product 2 in excellent yields
(93 and 95%, entries 1 and 2). Moreover, the fact that the use
of less than 1 equiv (0.5 equiv) of PSpentaEG also greatly
accelerated the reaction rate demonstrates that PSpentaEG is
likely to be a good catalyst for this reaction (entry 3). In addition,
the same fluorination using 18-crown-6 as a nonimmobilized
catalyst (entry 5), for which a hydrogen bonding effect with
CsF cannot be expected, proceeds much slower than that using
the same amount of PSpentaEG (entry 1). Bulky protic solvent
tert-amyl alcohol, which is known to be an excellent medium
for fluorination using CsF, also showed a greatly enhanced rate
of fluorination with PSpentaEG (entry 6). The combination
system of PSoligoEG and tert-amyl alcohol media could
enhance the nucleophilicity of RbF, which has stronger cou-
lombic influence than CsF, significantly with affording the
product in high yield (94%, entry 7), compared with a tert-
amyl alcohol media system in the absence of PSoligoEG (entry
8). However, this combination system still did not show good
a Method A: reactions were carried out on a 1.0 mmol scale of substrate
with 3.0 equiv of CsF and 1.0 equiv of PSpentaEG in 4.0 mL of tert-amyl
alcohol. Method B: with TBAF in CH3CN. Method C: with TBAF in tert-
amyl alcohol. Method D: with CsF in tert-amyl alcohol. Method E: with
5.0 equiv of KF in triethylene glycol. b Yields were determined by 1H NMR
spectroscopy. c 56% of starting material was remained. d With 18% alcohol
byproduct. e Reference 10b. f Reference 10d. g Reference 10a.
obtained in other systems reported previously. It is well-
known that the fluorination of secondary alkyl bromide to
3742
Org. Lett., Vol. 12, No. 17, 2010

the corresponding fluoride using TBAF as a “naked” fluoride
source is very difficult because of the competing elimination
to predominantly give the alkene byproduct, as shown in
entry 2 (method B; only 8% of the secondary fluoride product
was obtained). Despite the use of tert-amyl alcohol as a bulky
protic solvent to reduce the basicity of TBAF, the same
reaction also predominantly produced alkenes (81%), with
the desired sec-fluoroalkane product being formed in only
19% yield. Surprisingly, the combination of PSpentaEG
catalyst and tert-alcohol media system allowed the selectivity
of the fluorination to be enhanced dramatically, providing
the desired sec-fluoroalkane in excellent yield (80%, entry
1, method A) compared with the previous “naked” fluoride
systems. Moreover, a comparison of entries 1 and 4 (method
D) showed that the fluorination reaction using this combina-
tion system could proceed significantly fast as well as more
selectively compared with the tert-alcohol media fluorination
in the absence of PSpentaEG. Interestingly, this heteroge-
neous catalysis system which immobilized oligoethylene
glycols on polymeric supports showed much better perfor-
mance in this fluorination reaction than the nonimmobilized
triethylene glycol reaction medium system11 with KF as
shown in a comparison of entries 1 and 5 (method E). The
examples with other base-sensitive substrates such as 1-(2-
mesyloxyethy)naphthalene (entries 6-9) and primary ha-
loalkane substrates such as 2-(3-iodopropoxy)naphthalene
(entries 10-13) and 2-(3-bromopropoxy)naphthalene (entries
14 and 15) showed similar trends. A secondary alkyl fluoride
was produced by fluorination using this combination system
with the corresponding tosylate or mesylate substrate in
excellent yield (91 and 92%, entries 16 and 17, respectively).
In this reaction, we anticipated that this combination system
of PSpentaEG and tert-amyl alcohol media might generate
a polymer-supported activated “flexible” fluoride during the
reaction processing as depicted in Figure 2, and this polymer-
greatly suppress the competing elimination side reaction but
also accelerate the reaction rate. Entries 18-20 show the
fluorination of various substrates using PSpentaEG in
CH3CN. The fluorination reaction of R-bromoacetophenone
afforded R-fluoroacetophenone in good yield (entry 18). A
fluoroflumazenile, which can be a radiopharmaceutical for
PET,15 was synthesized in good yield through the fluorination
of the tosylate precursor (entry 19). In the final example, a
fluoroacetylene derivative, which is known to be useful in
the field of click chemistry,16 was produced in excellent yield
by the reaction with the corresponding tosylate (entry 20).
In summary, we report a polymer-supported pentaethylene
glycol as a highly effective catalyst for nucleophilic fluorina-
tion of various haloalkanes and sulfonyloxyalkanes to their
corresponding fluorinated products with alkali metal fluo-
rides. This PSpentaEG itself has many synthetic and practical
merits: it can significantly enhance the nucleophilicity of the
metal fluoride in the reaction and provide simple purification
of the product and ease of recycling, of which factors are
technically attractive for considering the use of this material
in industrial chemical processes. Furthermore, the combina-
tion of PSpentaEG and tert-alcohol media system showed
the tremendous efficiency in the fluorination of base-sensitive
substrates. In this method, this combination system could
make the fluorination reaction proceed much more selectively
at a remarkably fast rate by the synergistic effect of a
polymer-supported activated “flexible” fluoride and protic
atmosphere. In particular, this heterogeneous catalysis system
prepared by tethering pentaethylene glycol on the polymeric
support shows much higher efficiency in the fluorination than
the free triethylene glycol solvent system. Further studies
on the development of more efficient PSoligoEGs through
structural modifications and the application of these unusual
catalysts to the rapid 18F labeling for radiopharmaceuticals
with PET are currently underway.
Acknowledgment. This work was supported by Nuclear
Research & Development Program (grant code 2009-
0078422) and the Conversing Research Center Program
(grant code 2009-0081956) through the National Research
Foundation of Korea (NRF) grant funded by the Korean
government (MEST) and a grant from the 2010 Post-Doctoral
Fellowship Program, Chonbuk National University.
Supporting Information Available: Experimental pro-
cedures and characterization data of all compounds and
PSpentaEG. This material is available free of charge via the
Internet at http://pubs.acs.org.
Figure 2. Proposed polymer-supported “flexible” fluoride.
OL101485N
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