Bis-triethylene Glycolic Crown-5-calix[4]arene: A Promoter of Nucleophilic Fluorination Using Potassium Fluoride

Article abstract of DOI:10.1021/acs.orglett.9b00649

We designed and synthesized a bis-triethylene glycolic crown-5-calix[4]arene (BTC5A) as a multifunctional promoter for nucleophilic fluorination using KF. The synergetic effect of the calix-crown moiety and ethylene glycols of BTC5A enabled KF to be easil

Full text of DOI:10.1021/acs.orglett.9b00649

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Bis-triethylene Glycolic Crown-5-calix[4]arene: A Promoter of
Nucleophilic Fluorination Using Potassium Fluoride
Seok Min Kang,† Chul Hee Kim,† Kyo Chul Lee,‡ and Dong Wook Kim*,†
†Department of Chemistry and Chemical Engineering, Inha University, 100 Inha-ro, Nam-gu, Incheon 402-751, Korea
‡Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul
139-706, Korea
S
* Supporting Information
ABSTRACT: We designed and synthesized a bis-triethylene glycolic crown-5-calix[4]arene
(BTC5A) as a multifunctional promoter for nucleophilic fluorination using KF. The synergetic
effect of the calix-crown moiety and ethylene glycols of BTC5A enabled KF to be easily
dissolved in organic solvents and activated the fluoride in even nonpolar aprotic media. To
validate its practicality, the SN2 fluorinations including 18F-fluorination of various substrates
were successfully conducted using KF(or [18F]F−) in the presence of BTC5A.
espite the low abundance of fluorine-containing organic
compounds in nature, they are of considerable interest in
terminal alcohols (“flexible” fluoride makes SN2 fluorination
proceed selectively and suppress side reactions due to its low
basicity and protic environment), and by selectively solvating
K+ with polyether, which can act as a Lewis base.1,9,10
However, the high boiling points of these oligo-ethylene
glycols restricts due to downstream separation issues.11
Calixarenes as macrocyclic oligomers have received a great
deal of interest in host−guest chemistry as enzyme mimics,
ion-pair receptors, extractants, catalyst platforms, and molec-
ular recognition agents.12,13 More recently, a bis-tert-alcohol-
functionalized crown-6-calix[4]arene (BACCA) was devised as
a PTC system for nucleophilic fluorination using CsF.14
BACCA could facilitate the reactivity of CsF by selective
binding of Cs+ toward its crown-6-calix[4]arene moiety as well
as the formation of “flexible” fluoride via the controlled
hydrogen bonding between the fluoride and its tert-alcohol
moiety with minimization of the β-elimination side reaction.
Several calixarenes derivatives have been designed to bind
specific alkali metals.14,15 For example, crown-6-calix[4]arene
and crown-5-calix[4]arene selectively bind Cs+ and K+,
respectively, due to their geometries and crown-calix cavity
sizes.15
D
the materials and pharmaceutical research areas, especially in
radiopharmaceutical science in the context of fluorine-18 (t1/2
= 110 min) use in positron emission tomography (PET).1,2
Nucleophilic fluorination using a fluoride source in polar
aprotic media (e.g., CH3CN, DMF) is commonly used to
prepare fluorinated organic molecules.3 The use of potassium
fluoride (KF) as a nucleophilic fluorine source is traditionally a
priority consideration for this type of reaction due to its
availability, low cost, and thermal stability.4 However, the high
lattice energy of KF results in low solubility and reactivity in
reaction media, which restricts its wider applications for
nucleophilic fluorination.4,5 To overcome these issues, crown
ether derivatives such as 18-crown-6 and Kryptofix 2.2.2
(K222) have been investigated as phase-transfer catalysts
(PTCs) to render KF soluble and facilitate its reactivity by
selective solvation of the K+ cation in organic solvents.6
Whereas 2D-structured 18-crown-6 inadequately activates KF,
strong coordination between the K+ cation and the 3D cavity
of K222 results in the release of reactive “naked” fluoride as a
strong nucleophile.1,6,7 However, this reactive fluoride can also
cause unexpected side reactions (e.g., β-elimination or
hydroxylation) due to its also high basicity.7 Furthermore,
the nitrogen of K222 may attack substrate electron-deficient
sites to cause N-alkylation.8
In the present study, we designed and synthesized a
nucleophilic fluorination promoter called bis-triethylene
glycolic crown-5-calix[4]arene (BTC5A) for activation of KF
(Figure 1). BTC5A possesses multiple subunits that weaken
the strong ionic interaction of KF. We expected that oxygen
atoms present in the crown-calix moiety act as a Lewis base
Protic solvents, such as tertiary alcohols and oligo-ethylene
glycols, have recently been reported to be suitable for
chemoselective nucleophilic fluorination using alkali metal
fluorides.1,9,10 In particular, oligo-ethylene glycols appear to
provide a less basic but more reactive “flexible” fluoride from
KF by controlled hydrogen-bonding between fluoride and their
10
and coordinate with K+ and predicted two polyethers
Received: February 20, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00649
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Organic Letters
Letter
alkylation of the remaining two OH groups of 2 or 3 in the
presence of the corresponding ethylene glycol tosylate and
Cs2CO3 at 110 °C for 4 days gave BTC5A, methylated bis-
triethylene glycolic crown-5-calix[4]arene (M-BTC5A), bis-
hexaethylene glycolic crown-5-calix[4]arene (BHC5A), and
bis-triethylene glycolic crown-6-calix[4]arene (BTC6A). In
addition, bis-methylated crown-5-calix[4]arene (BMC5A) was
also prepared by O-methylation of the two phenolic OH
groups of 2 with methyl iodide to validate the PTC effect of
only 3D cavity of BMC5A toward KF in nucleophilic
fluorination.
To investigate the catalytic ability of a part of BTC5A, 2-(3-
methanesulfonyloxypropoxy)naphthalene (4) was subjected to
nucleophilic fluorination using 3 equiv of KF in the presence of
various promoters in acetonitrile (Table 1). SN2 fluorination
Figure 1. Bis-triethylene glycol-functionalized crown-5-calix[4]arene
(BTC5A) as a promoter of SN2 fluorination by KF.
Table 1. Nucleophilic Fluorination of Mesylate 4 in the
Presence of Various Promoters
containing oxygen atoms would attract K+ and facilitate its
approaching crown-calix cavities. In addition, we anticipated
terminal OH groups would hydrogen bond with fluoride to
make it “flexible” fluoride9 with enhanced fluorination
reactivity and selectivity. These cooperative activities were
found to enhance the reactivity of KF and provide excellent
fluorination efficiencies. In addition, rates of fluorination were
markedly enhanced in different solvents, even in toluene (a
nonpolar aprotic system), which is known to be unsuitable for
the SN2-type fluorination.
a
b
yield (%)
entry
promotor
time (h)
5
6
1
2
3
4
5
6
7
8
BMC5A
triethylene glycol (2 equiv)
BTC5A
BHC5A
BTC6A
M-BTC5A
18-crown-6
K222
12
12
6
6
24
9
93
22
7
c
97
97
97
93
91
88
3
3
2
6
9
BTC5A and its derivatives were synthesized as shown in
Scheme 1. Calix[4]arene (1), the catalyst platform, was
Scheme 1. Synthesis of Bis-oligothylene Glycolic Crown-
18
3
a
calix[4]arenes
11
a
All reactions were carried out on a 0.05 mmol reaction scale of
b
mesylate 4 with 3 equiv of KF in 0.2 mL of CH3CN. Yields were
c
determined by 1H NMR spectroscopy. 78% of starting material
remained. R = 2-naphthyl.
using BMC5A, which has only a crown-5-calix[4]arene cavity,
showed moderate fluorination activity and provided the
fluorinated product 5 in 93% yield with 7% of 6 as an alkene
byproduct (entry 1), whereas 2 equiv of triethylene glycol
barely promoted the same reaction (entry 2). Notably, when
two subunits (crown-5-calix[4]arene and triethylene glycols)
were combined to make BTC5A, fluorination activity was
obviously increased (entry 3). Furthermore, this result was
superior to that obtained when 18-crown-6 was used as a
conventional PTC in terms of reactivity and selectivity (entry
7). A comparison of entries 3 and 8 showed BTC5A provided
less alkene than K222 because the two terminal hydroxy
groups of BTC5A formed hydrogen bonding with fluoride to
a
Reagents: (a) TsO(CH2CH2O)3CH2CH2OTs, K2CO3, CH3CN,
generate reactive but less basic “flexible” fluoride.9
A
130 °C, 3 h, microwave; (b) CH3I, NaH, DMF, 30 °C, 3 h; (c)
TsO(CH2CH2O)nR, Cs2CO3, CH3CN, 100 °C, 4 days; (d)
TsO(CH2CH2O)4CH2CH2OTs, K2CO3, CH3CN, 100 °C, 4 days;
(e) TsO(CH2CH2O)3H, Cs2CO3, CH3CN, 100 °C, 4 days.
comparison of entries 3 and 4 showed lengths of ethylene
glycol did not influence fluorination activity. Because BTC5A
has shorter ethylene glycol chains than BHC5A, and thus,
generates less chemical waste, we decided to use BTC5A for
further reaction studies. BTC6A, which has a larger cavity than
BTC5A, was also evaluated as a promoter for KF (entry 5), but
as was expected, the crown-6-calix[4]arene unit, which is
known to be suitable for Cs+, could did not efficiently
coordinate with K+ and fluorinations required considerably
longer. Finally, in order to confirm the hydrogen bonding
effect, which we consider enhances reactivity and selectivity,
we synthesized M-BTC5A in which terminal hydroxy groups
prepared as previously described.16 Crown-5-calix[4]arene
(2) and crown-6-calix[4]arene (3) were prepared in slightly
different manners. Compound 2 was prepared by the O-
alkylation of 1 at two of its four phenolic OH groups using
tetraethylene glycol ditosylate and K2CO3 in microwave
synthesizer for 3 h, whereas 3 was prepared by the O-
alkylation of calix[4]arene in the presence of pentaethylene
glycol ditosylate and K2CO3 at 100 °C for 4 days. Next, O-
B
DOI: 10.1021/acs.orglett.9b00649
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Organic Letters
Letter
were blocked by methyl groups (entry 6). As has been
previously reported,6 blocking H-bonding between BTC5A
and fluoride markedly reduced reactivity and selectivity.
We conducted a kinetic study to investigate the effects of
solvent and of the terminal OH groups of BTC5A on
fluorination (Figure 2) and compared reaction rates for
rapid in the presence of promoter. However, SN2 fluorination
of 4 in toluene proceeded more efficiently and faster than the
same reaction in CH3CN, which we suspect was caused by
hydrogen bonding between the terminal OH groups of BTC5A
and fluoride. We also performed the same reaction using M-
BTC5A. Surprisingly, the fluorination activity of M-BTC5A in
toluene (compared with CH3CN) was drastically lower than
that of BTC5A, indicating that hydrogen bonding between
promoter hydroxy groups and fluoride plays an important role
in the reaction. We consider that the terminal hydroxy groups
in BTC5A could produce “flexible” fluoride9 easily in toluene,
but that in CH3CN, the terminal hydroxy groups of BTC5A
are partially inhibited by dipole−dipole interactions with
CH3CN, and thus, hydrogen bonding between the terminal
hydroxy groups of BTC5A and fluoride did not efficiently
produce “flexible” fluoride. Accordingly, the reaction rate was
slower in CH3CN than in toluene and rates were no different
for BTC5A or M-BTC5A.
Inspired by the results of the kinetic study, we conducted
nucleophilic fluorination in a range of solvents and using
different alkali metals (Table 2). We confirmed toluene
produced better fluorination rates than CH3CN (Figure 2)
and screened diverse aliphatic and aromatic hydrocarbon
nonpolar aprotic solvents. Notably, all of these hydrocarbon
nonpolar aprotic solvents greatly improved fluorination rates
(3 h, 100%, entries 1−5). This result is contrary to the
expectation that a nonpolar aprotic solvent is undesirable for
nucleophilic displacement reactions. Next, the same reaction
using 0.5 equiv of BTC5A showed a similar reaction rate
(slightly slower, entry 6) to the reaction using 1.0 equiv of
BTC5A. However, using 0.25 equiv of BTC5A required a more
than 12 h reaction time (entry 7) to complete the fluorination.
We also investigated the fluorination efficiency of BTC5A in
the presence of NaF, RbF, and CsF (entries 8−10). NaF was
Figure 2. Catalytic activities of BTC5A and M-BTC5A on SN2
fluorination by KF in CH3CN or toluene reaction medium. Yields
were determined by H NMR spectroscopy. R = 2-naphthyl.
1
BTC5A, M-BTC5A, or without either in two solvent systems,
that is, CH3CN (a polar aprotic solvent) and toluene (a
nonpolar aprotic solvent). Naturally, when an alkali metal salt
is used for a SN2 reaction polar aprotic solvents are more
suitable than nonpolar aprotic solvents, as in polar aprotic
solvents metal cations are selectively solvated by ion−dipole
interactions resulting in an increase in nucleophilicity, whereas
in nonpolar aprotic solvents the absence of a solvent dipole
moment means that alkali metal salts are barely solvated.3 As
we expected, in both cases, fluorination reactions were more
a
Table 2. Nucleophilic Fluorination in the Presence of BTC5A under Different Reaction Conditions
b
yield (%)
entry
solvent
toluene
benzene
xylene
cyclohexane
heptane
toluene
toluene
toluene
toluene
toluene
toluene
DMF
1,4-dioxane
tert-amyl alcohol
tert-amyl alcohol
tert-amyl alcohol
t-amyl alcohol
tert-amyl alcohol
BTC5A (equiv)
X
MF
time (h)
SM
5
c
1
2
3
4
5
6
7
8
9
10
1.0
1.0
1.0
1.0
1.0
0.5
0.25
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
-
OMs
OMs
OMs
OMs
OMs
OMs
OMs
OMs
OMs
OMs
OMs
OMs
OMs
OMs
OTs
I
KF
KF
KF
KF
KF
KF
KF
NaF
RbF
CsF
CsF
KF
KF
KF
KF
KF
KF
KF
2.5
3
3
3
3
100 (95 )
100
100
100
100
98
3
trace
4
100
6
12
24
12
1.5
3
96
94
100
trace
d
11
97
e
12
13
14
15
16
17
18
5
89
12
0.5
0.5
3
3
12
11
trace
trace
88
97
97
71
90
f
g
Br
OMs
96
4
a
b
Unless otherwise indicated, all reactions were carried out with SM (0.05 mmol) and MF (3.0 equiv) in 0.2 mL of solvent. Yields were determined
c
d
e
1
by H NMR spectroscopy. Yield of isolated product obtained using 1.0 mmol of 4. BMC5A was used instead of BTC5A. With 11% alcohol.
f
g
With 28% alkene. With 10% alkene. R = 2-naphthyl.
C
DOI: 10.1021/acs.orglett.9b00649
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Organic Letters
Letter
completely inactive. The reactions using RbF took a
considerable time (∼12 h) to convert 4 into 5 in 94% yield.
Unexpectedly, although Cs+ was not a suitable size for crown-
5-calix[4]arene cavity,15 the fluorination with CsF completed
only in 1.5 h, which has faster reaction rate compared to the
same reaction with KF and RbF (entries 1, 9, and 10). We offer
two reasons for these results: (i) CsF has a weaker lattice
energy than KF or RbF and (ii) the ethylene glycols play a
crucial role in the activation of CsF. To clarify these results, we
conducted fluorination with CsF in the presence of BMC5A
promoter without an ethylene glycol subunit in toluene, and as
was expected, the fluorination rate decreased noticeably (3 h,
3%, entry 11). Next, we investigated nucleophilic fluorination
with BTC5A in polar aprotic solvents. In DMF, it took 5 h to
complete the fluorination reaction, affording the fluoro product
5 in 89% yield with the 11% of alcohol byproduct (entry 12).
In 1,4-dioxane, the reaction proceeded poorly (12 h, 88%,
entry 13), presumably the two oxygen atoms of 1,4-dioxane
acted formed hydrogen bonds and inhibited the formation of
“flexible” fluoride by interacting with the terminal hydroxyls of
BTC5A. We also evaluated fluorination reactions using model
compounds with different leaving groups, such as halides and
sulfonates, in tert-amyl alcohol, which is known to be a suitable
solvent for this reaction (entries 14−17).9 For mesylate and
tosylate substrates, the reaction proceeded in excellent yields
(both 97%) and was completed within 30 min (entries 14 and
15) in tert-amyl alcohol. However, iodo and bromo substrates
were converted into the fluoro product 5 relatively slowly in
lower yields (71 and 90%, respectively) and produced alkene
byproducts (28 and 10%, entries 16 and 17, respectively). It is
notable that KF was almost inactive even in tert-alcohol
medium in the absence of BTC5A promoter (entry 18).
Having investigated the effectiveness of BTC5A, we
explored substrate scope for the nucleophilic fluorinations of
various substrates using KF in different solvent systems. The
results are summarized in Scheme 2. Fluoroflumazenil (7) was
successfully prepared in the presence of BTC5A in CH3CN in
71% yield. A fluorinated estrone derivative 8 was synthesized in
97% yield from the corresponding mesylate, and 9 was
obtained in 98% yield using the same fluorination protocol. 2-
(Bromomethyl)naphthalene was successfully converted into 10
in 98% yield in CH3CN. 4-(3-Fluoropropoxy)benzophenone
(11) as photosensitizer was obtained from the corresponding
mesylate in 94% yield in toluene. The fluorination of 1-(3-
methanesulfonyloxypropoxy)pyrene in toluene provided 1-(3-
fluoropropoxy)pyrene (12) in 93% yield, and 2-(3-
fluoropropoxy)dibenzofuran (13) was also prepared in 90%
yield. We also fluorinated a coumarin mesylate and a
nitroimidazole mesylate in toluene and obtained 14 and 20
at good yields (97 and 96%, respectively). The fluorination of
1-(2-methanesulfonylethyl)naphthalene, which is known to be
base sensitive, proceeded to afford 15 in tert-amyl alcohol
solvent in a yield of 76%. Fluorination of secondary alkyl
mesylate (another base-sensitive substrate) in tert-amyl alcohol
produced the desired fluoro product 16 in a yield of 61%.
However, these base-sensitive compounds 15 and 16 could not
be obtained by the same reactions without BTC5A. For
application of click chemistry, a fluoro azide 17 and a fluoro-
alkyne 18 were synthesized from the corresponding mesylate
using the same method at yields of 95 and 98%, respectively. A
sec-fluoroproline derivative 19 was obtained in 47% yield using
this BTC5A-promoted fluorination reaction using KF.
Scheme 2. BTC5A-Promoted SN2 Fluorinations of the
Various Substrates in the Presence of KF
a
a
All reactions were carried out using 0.18 mmol of substrate, KF (3.0
equiv), and BTC5A (1 equiv) in 0.7 mL of solvent at 100 °C. Yields
b
of isolated products are indicated unless otherwise noted. Yields
c
were determined by 1H NMR spectroscopy. 10 was synthesized from
d
2-(bromomethyl)naphthalene. 19 was prepared from the corre-
sponding tosylate substrate.
In Scheme 3, we carried out 18F-fluorination of 4 using no-
carrier-added [18F]fluoride generated from cyclotron for PET
Scheme 3. 18F-Labeling Reaction with BTC5A
application of BTC5A. The desired 18F-labeled product [18F]5
was obtained at a radiochemical yield (RCY) of 90% after
reaction for only 20 min (radio TLC ratio 100%, total reaction
time 35 min). After the 18F-labeling reaction, BTC5A was
successfully removed by short column chromatography.
In summary, we designed and prepared BTC5A as a PTC
system and demonstrated its efficacy in nucleophilic
fluorination using KF. BTC5A in the presence of KF was
found to provide high fluorination rates. During reaction,
oxygen atoms in crown-5-calix[4]arene subunit appeared to act
as Lewis bases and coordinate K+ to allow the fluoride to be
“free” from K+ cation. Furthermore, bis-ethylene glycols
containing polyethers and terminal hydroxy groups seemed
to play important roles in two ways: (i) polyethers attracted
the K+ cation to BTC5A and facilitate K+ to crown-5-
calix[4]arene complexation and (ii) terminal hydroxy groups
formed the hydrogen bonding with fluoride to increase its
D
DOI: 10.1021/acs.orglett.9b00649
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Organic Letters
Letter
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Chi, D. Y.; Song, C. E. Angew. Chem., Int. Ed. 2009, 48, 7683−7688.
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reactivity and selectivity by forming “flexible” fluoride. In
particular, the nucleophilic fluorination with BTC5A in
nonpolar aprotic solvents (e.g., toluene, heptane, benzene)
proceeded faster than in CH3CN, which contradicted expect-
ations; that is, a nonpolar aprotic solvent is inadequate for SN2-
type nucleophilic displacement reactions. This result suggests
BTC5A may enable the use of nonpolar aprotic solvents for
SN2-type nucleophilic fluorination. We also observed good 18F-
labeling efficiency in the presence of BTC5A with [18F]-
fluoride.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00649.
■
S
Experimental procedures and characterization data for
all compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kimdw@inha.ac.kr.
ORCID
Dong Wook Kim: 0000-0002-6253-3393
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Basic Science Research
Program (Grant No. 2017R1A2A2A10001451), funded by the
Ministry of Science and ICT (MSIT), the MOTIE (Ministry
of Trade, Industry & Energy), and KSRC (Korea Semi-
conductor Research Consortium) support program (Grant No.
10080450), Korea.
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