Multifunctional Crown-5-calix[4]arene-based Phase-Transfer Catalysts for Aromatic 18F-Fluorination

Article abstract of DOI:10.1021/acs.orglett.0c03604

Methylated bis-triethylene glycolic crown-5-calix[4]arene (M-BTC5A) as a phase-transfer catalyst showed the best performance among other analogues and even conventional Kryptofix 222 in the nucleophilic aromatic 18F-fluorination of diaryliodonium tosylate precursors owing to (i) the efficient release of reactive "naked"[18F]fluoride, (ii) the high stabilization of the precursor in the reaction, and, presumably, (iii) the ease of access between the precursor and the K18F/M-BTC5A complex facilitated by π-πinteractions. [18F]Flumazenil was produced in high radiochemical yield using M-BTC5A.

Full text of DOI:10.1021/acs.orglett.0c03604

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Letter
Multifunctional Crown-5-calix[4]arene-based Phase-Transfer
18
Catalysts for Aromatic F‑Fluorination
Won Chang Lee, Seok Min Kang, Byung Chul Lee,* Sang Eun Kim,* and Dong Wook Kim*
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ABSTRACT: Methylated bis-triethylene glycolic crown-5-
calix[4]arene (M-BTC5A) as a phase-transfer catalyst showed
the best performance among other analogues and even conven-
tional Kryptofix 222 in the nucleophilic aromatic 18F-fluorination
of diaryliodonium tosylate precursors owing to (i) the efficient
release of reactive “naked” [18F]fluoride, (ii) the high stabilization
of the precursor in the reaction, and, presumably, (iii) the ease of
access between the precursor and the K18F/M-BTC5A complex
facilitated by π−π interactions. [18F]Flumazenil was produced in
high radiochemical yield using M-BTC5A.
strategy using novel PTCs and apply this strategy to the
practical synthesis of a known 18F-labeled radiotracer.
luorine-containing arenes are attractive for the develop-
Fment of new materials or technologies in diverse research
fields.1−4 The introduction of fluorine into bioactive molecules
enhances their potency and bioavailability by modulating
conformational and stereoelectronic properties such as the
polarity, lipophilicity, and pKa.5−7 The radioisotope fluorine-18
(18F) has also been extensively used to produce radiopharma-
ceuticals for positron emission tomography (PET).8,9 Because
of the relatively high in vivo stability of a CAr−F bond
compared with a C(sp3)−F bond, the introduction of 18F into
an aromatic ring of a radiopharmaceutical candidate increases
the metabolic stability of 18F in the parent molecule.10,11
Nucleophilic aromatic substitution (SNAr) with [18F]-
fluoride has been commonly used to generate 18F-labeled
radiotracers considering the operational simplicity, high molar
activity, and selectivity.12 The introduction of no-carrier-added
(n.c.a.) 18F into arenes via SNAr generally requires a polar
aprotic solvent and high temperature.13 Furthermore, the SNAr
18F-labeling reaction needs sufficient activation of the aromatic
ring from ortho or para electron-withdrawing groups.14 These
restrictions therefore limit the options for developing fluorine-
substituted arenes and radiotracers in which the late
introduction of [18F]fluoride is desired, prompting research
groups to explore new types of precursors and transition-metal
catalysts to attain a versatile SNAr 18F-labeling strategy.15−23
Indeed, such new approaches have led to the spectacular
growth of aromatic 18F-fluorination in recent years. Despite
these new strategies showing promising results, the archetypal
Kryptofix 222 (K222) is still used for numerous investigations as
a phase-transfer catalyst (PTC), which is one of the primary
components in aliphatic and aromatic 18F-labeling.8 Therefore,
we aimed to develop an effective aromatic 18F-fluorination
In our previous study, we reported that fluoride could be
effectively introduced into an aliphatic position using a bis-
triethylene glycolic crown-5-calix[4]arene (BTC5A). The
BTC5A consists of two polyethers to initially attract metal
fluorides and a crown-5-calix[4]arene subunit capable of
capturing an alkali metal cation, ultimately exhibiting excellent
PTC behavior toward nucleophilic fluorination.24
On the basis of the success of aliphatic fluorination using
BTC5A,24−29 we anticipate that the application of BTC5A to
aromatic 18F-fluorination will be promising; besides trapping
an alkali metal ion, it is expected that the crown-calix[4]arene
subunit containing four aromatic rings will also interact with
precursors via π−π interactions30,31 to further facilitate
approaching each other. Because of these π−π interactions,
we surmise that 18F will have more opportunities to participate
in aromatic 18F-fluorination with the help of BTC5A. To
elucidate the effect of the polyether moiety and the terminal
methyl group, methylated bis-triethylene glycolic crown-5-
calix[4]arene (M-BTC5A), which has polyether tails the same
length as BTC5A, and bis-methylated crown-5-calix[4]arene
(BMC5A) without polyether tails were also evaluated for
aromatic 18F-fluorination (Figure 1). Herein we investigated
various reaction conditions using K222 and three BTC5A-based
Received: October 29, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03604
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
half of that obtained with KF, even though fluoride from n-
Bu4NF was already in the reactive “naked” and “free” form
(Table 1, entry 10).
To demonstrate whether 4 is affected by PTCs, the
instability of 4 was measured in the presence of either K222
or M-BTC5A (Table 2). DMSO was the desired solvent for
Table 2. Instability of 4 in the Presence of Different PTCs
a
with or without TEMPO
Figure 1. Structure and concept of BTC5A-based phase-transfer
catalysts for the aromatic 18F-fluorination of a diaryliodonium salt
precursor.
remaining % of 4 (with
ratio of 2/3 (with
TEMPO)
entry
PTC
TEMPO)
b
1
M-BTC5A
K222
BTC5A
M-BTC5A
51 1.1%
0.43
PTCs to validate the capability of each PTC as an organic
promoter to enhance the rate of fluorination.
The influence of different solvents, PTCs, and fluoride
sources was first explored to optimize the aromatic fluorination
of diaryliodonium tosylate 4 to produce 1 (Table 1). Aprotic
2
3
4
37 4.0% (69 4.0%)
66 2.0% (74 2.9%)
68 0.8% (78 0.9%)
0.64 (0.24)
0.35 (0.16)
0.30 (0.14)
a
All reactions were performed using 4 μmol of 4 with K2CO3 (0.8
equiv) and PTC (1.1 equiv) in DMSO (0.3 mL) at 120 °C for 15 min
(n = 3). DMF used instead of DMSO. Instability represents the
b
percentage of decomposed products (2 and 3) compared with the
concentration of 4 using HPLC. Results using 2,2,6,6-tetramethyl-1-
piperidinyloxyl (TEMPO, 1 mg, 6.4 μmol) are given in parentheses.
Table 1. Nucleophilic Aromatic Fluorination of
Diaryliodonium Tosylate 4 under Various Reaction
Conditions
a
the efficient fluorination of 4 to 1 with fewer decomposed
products (2 and 3) under basic conditions compared with
DMF (Table 2, entries 1 and 4 versus Table 1, entries 3 and
5). TEMPO is a well known radical scavenger that is a
common component in the 18F-fluorination reaction contain-
ing a diaryliodonium salt precursor because it can reduce the
generation of aromatic hydrocarbons via radical-induced
decomposition.32−35 Therefore, we added TEMPO to the
reaction medium in the presence of K222, showing that
TEMPO increased the stability of 4 to 69% (37% without
TEMPO). The addition of TEMPO to BTC5A and M-
BTC5A-treated groups improved the stability of 4 as well, but
to a lesser extent (Table 2, entries 3 and 4). In particular, M-
BTC5A not only gave the highest stability to 4 under SNAr but
also reduced the proportion of hydrogenated 2. Therefore, it is
reasonable to speculate that BTC5A-based PTCs could be
instrumental in the stabilization of precursor 4 without the aid
of TEMPO. It is beneficial to obtain a relatively low proportion
of hydrogenated products in the reaction mixture to facilitate
the isolation of pure 18F-labeled products.
From these results, we demonstrated that our protocol using
BTC5A-based PTCs is more effective than K222 in at least
three aspects. (i) BTC5A-based PTCs capture the alkali metal
cation to enhance the nucleophilicity of fluoride more than
with K222 (Table 1, entries 5, 7, and 8 versus Table 1, entry 6).
(ii) Related to the stability, the diaryliodonium tosylate
precursor 4 is more highly stabilized in the presence of the
BTC5A-based PTCs, and more opportunities to participate in
the reaction are available (Table 2, entries 3 and 4 versus Table
2, entry 2). Therefore, minimizing the decomposition of 4
using BTC5A-based PTCs significantly increases the yield of 1,
unlike with K222 (Table 1, entries 5−7). (iii) It is also
hypothesized that the ease of access between the precursor and
metal fluoride/BTC5A-based PTC complexes by π−π
interactions may increase the fluoride incorporation in 4 to
yield 1. In contrast, the metal fluoride/K222 complex, which
does not contain any aromatic rings, inherently lacks the ability
b
entry
PTC
MF
KF
KF
KF
KF
KF
KF
KF
KF
solvent
yield (%)
1
2
3
4
5
6
M-BTC5A
M-BTC5A
M-BTC5A
M-BTC5A
M-BTC5A
K222
BTC5A
BMC5A
M-BTC5A
M-BTC5A
NMP
DMA
DMF
CH3CN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
0
7.6 1.6
9.1 2.3
29.2 7.3
79.7 0.5
6.1 1.9
63.8 3.4
68.7 3.8
65.6 3.1
39.4 4.8
c
7
8
9
10
CsF
n-Bu4NF
a
All reactions were performed using KF (4 equiv), PTC (1.1 equiv),
and 4 (4 μmol) in solvent (0.3 mL) at 120 °C for 30 min. Yield
b
c
obtained from HPLC (n = 3). n = 5.
solvents (except N-methyl-2-pyrrolidone (NMP)) generally
improved the yield of 1 using KF in the presence of M-BTC5A
(Table 1, entries 1−5). When DMF or CH3CN was used with
M-BTC5A, the aromatic fluorination of 4 resulted in
reasonable yields of 1, similar to our previous results.15,16
Notably, M-BTC5A resulted in the highest yield of 1 in
DMSO (Table 1, entry 5); the same conditions using the
conventional K222 instead of M-BTC5A resulted in a ∼13-fold
decreased yield (Table 1, entry 6). The other BTC5A-based
PTCs (BTC5A and BMC5A) also provided good yields of 1 in
DMSO (Table 1, entries 7 and 8), but they were not superior
to M-BTC5A. To explore fluoride sources in addition to KF,
CsF and n-Bu4NF were also investigated with 4 and M-
BTC5A. As expected, CsF, which is relatively inappropriate in
size for cation capture in the crown-calix subunit of M-BTC5A,
exhibited slightly reduced fluoride incorporation (Table 1,
entry 9). When using n-Bu4NF, the yield was approximately
B
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Letter
a
Scheme 1. Substrate Scope of 18F-Labeled Arenes
to introduce π−π interactions with the precursor (Table 1,
entry 6). Considering the size of the n-Bu4N+ cation, it is likely
that fluoride from n-Bu4NF may not form the F−/M-BTC5A
complex, and n-Bu4NF/M-BTC5A performed poorly com-
pared with KF/M-BTC5A, despite the use of highly reactive n-
Bu4NF (Table 1, entry 10). The comparison of entries 5 and 7
in Table 1 indicates that M-BTC5A is more efficient than
BTC5A. We propose the following plausible explanations: (i)
The terminal hydroxyl groups in BTC5A can interact with
fluoride by hydrogen bonding to generate “flexible” fluoride,36
which relatively reduces the reactivity of fluoride compared the
“naked” fluoride generated from M-BTC5A, and (ii) the
diaryliodonium tosylate precursor 4 is slightly more unstable in
the presence of BTC5A, containing more reactive terminal
hydroxyl groups than that of M-BTC5A (Table 2, entries 3 and
4). In addition, we conducted a kinetic study under optimized
conditions and identified that the micromole-scale SNAr
reactions were completed within 15−30 min (Figure 1S).
Table 3 summarizes the results of the aromatic 18F-
fluorination of 4 using different PTCs. We found that M-
a
Table 3. 18F-Fluorination with Different PTCs
a
All reactions were carried out on a 3 to 4 μmol scale of the precursor
with 18F (∼11 MBq), K2CO3 (0.8 equiv), and TEMPO (1 mg, 6.4
μmol) in the presence of M-BTC5A (0.55 equiv) in DMSO (0.3 mL)
at 120 °C for 15 min. Yields in parentheses were obtained using K222
(5.5 mg, 14.6 μmol) instead of M-BTC5A. Radiochemical yield was
measured by radio-TLC. In CH3CN. In DMF. Reported yield in
ref 16.
b
entry
PTC
K222
BTC5A
BTC5A
BMC5A
M-BTC5A
M-BTC5A
M-BTC5A
M-BTC5A
M-BTC5A
equiv of PTC
yield (%)
1
2
3
4
5
6
7
8
0.55
1.1
0.55
0.55
1.1
0.55
0.27
0.1
28.8 5.3
42.6 3.8
59.2 2.3
38.8 5.6
61.5 8.8
82.3 5.7
79.6 2.1
41.1 6.1
75.7 5.9
b
c
d
RCY compared with the conventional method. Furthermore,
whereas [18F]14−16 and [18F]18−21 were difficult to obtain
13,37−40
following the method using K222
,
they could be
c
9
0.55
synthesized in significantly or relatively high RCY from our
protocol using M-BTC5A. ([18F]14, [18F]15, and [18F]20
were also prepared in 14−59% RCY from oxidized
iodoarenes.41,42) These results indicate that our M-BTC5A-
catalyzed SNAr 18F-fluorination method is vital for the efficient
synthesis of a number of 18F-labeled radiopharmaceuticals. For
example, [18F]FMZ, a representative 18F-labeled radiopharma-
ceutical, was successfully prepared using our 18F-labeling
protocol with M-BTC5A from the corresponding diary-
liodonium salt in significantly high RCY (∼95%) compared
with the conventional labeling method employing K222
(∼55%).16 The molar activity (AM) of [18F]FMZ when
starting with 16.2 GBq of 18F was 316.7 GBq·μmol−1, which
is similar to the previously reported value, thus indicating that
aromatic 18F-fluorination with M-BTC5A does not adversely
affect the AM of [18F]FMZ.
In conclusion, we demonstrated that BTC5A-based PTCs
(i.e., BTC5A, BMC5A, and M-BTC5A) could act as highly
efficient PTC systems for the nucleophilic aromatic 18F-
fluorination of various diaryliodonium tosylate precursors to
prepare the corresponding 18F-labeled arenes ([18F]1, [18F]14-
21, or [18F]FMZ). In this method, M-BTC5A performed
better in the 18F-labeling reaction than the conventional PTCs
studied owing to (i) the efficient capture of the alkali metal
cation to release the reactive “naked” [18F]fluoride, (ii) the
desirable high stability of diaryliodonium tosylates in the
presence of M-BTC5A, and (iii) the ease of access between the
a
All reactions were performed using 4 (4 μmol) and K2CO3 (0.8
equiv) in the presence of 1 mg of TEMPO in DMSO (0.3 mL) at 120
°C for 15 min. Radiochemical yield was obtained by radio-TLC
analysis (n = 3). TEMPO was not used.
b
c
BTC5A showed the best PTC activity to obtain 1 among the
PTCs studied, including conventional K222 (Table 3, entries
1−6). To optimize M-BTC5A for aromatic 18F-fluorination,
we performed radiolabeling reactions by changing the amount
of M-BTC5A and then determining the radiochemical yield
(RCY) of [18F]1 (Table 3, entries 5−8). The highest RCY of
[18F]1 was obtained with 0.55 equiv of M-BTC5A (∼82%;
Table 3, entry 6). Even when only 0.1 equiv of M-BTC5A was
used, the RCY was ∼41%. Interestingly, the use of M-BTC5A
in the absence of TEMPO resulted in only a slight reduction in
the RCY of [18F]1 (Table 3, entry 9), but it was considerably
sufficient for aromatic 18F-fluorination.
The optimized 18F-labeling conditions in the presence of M-
BTC5A were applied to various diaryliodonium tosylate
precursors (4−13) and compared with the conventional
labeling protocol using K222 (Scheme 1). The 18F-labeling
reaction proceeded in moderate to high RCY using diary-
liodonium tosylate with diverse electron densities and chemical
conformations. Our 18F-labeling protocol using M-BTC5A
produced some 18F-labeled products (e.g., [18F]17, [18F]19,
and [18F]Flumazenil ([18F]FMZ)) in up to three times higher
C
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precursor and the K18F/M-BTC5A complex probably facili-
tated by π−π interactions. It is notable that the PET
radiopharmaceutical [18F]FMZ was successfully prepared in
high RCY by the M-BTC5A-catalyzed nucleophilic aromatic
18F-fluorination protocol. These results suggest that this 18F-
labeling protocol using M-BTC5A has much potential in
radiopharmaceutical science.
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The Supporting Information is available free of charge at
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Experimental procedures and characterization data for
all compounds (PDF)
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Vaufrey, F.; Halldin, C.; McCarron, J. A.; Pike, V. W.; Dolle, F. Bioorg.
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Byung Chul Lee − Department of Nuclear Medicine, Seoul
National University Hospital, Seongnam 13620, Republic of
Korea; Center for Nanomolecular Imaging and Innovative
Drug Development, Advanced institutes of Convergence
Technology, Suwon 16229, Republic of Korea; orcid.org/
0000-0002-1425-5712; Email: leebc@snu.ac.kr
Sang Eun Kim − Department of Nuclear Medicine, Seoul
National University Hospital, Seongnam 13620, Republic of
Korea; Center for Nanomolecular Imaging and Innovative
Drug Development, Advanced institutes of Convergence
Technology, Suwon 16229, Republic of Korea; Department of
Molecular and Biophamaceutical Sciences, Graduate School
of Convergence Science and Technology, Seoul National
University, Seoul 08826, Republic of Korea; Email: kse@
snu.ac.kr
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Authors
Won Chang Lee − Department of Nuclear Medicine, Seoul
National University Hospital, Seongnam 13620, Republic of
Korea; Department of Transdisciplinary Studies, Graduate
School of Convergence Science and Technology, Seoul
National University, Seoul 08826, Republic of Korea
Seok Min Kang − Department of Chemistry and Chemical
Engineering, Inha University, Incheon 22212, Republic of
Korea.
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by a grant from the Korean Health
Technology R&D Project through the Korean Health Industry
Development Institute (KHIDI), funded by the Ministry of
Health & Welfare, Republic of Korea (no. HI16C0947).
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