Bis-tert-Alcohol-Functionalized Crown-6-Calix[4]arene: An Organic Promoter for Nucleophilic Fluorination

Article abstract of DOI:10.1002/chem.201504602

A bis-tert-alcohol-functionalized crown-6-calix[4]arene (BACCA) was designed and prepared as a multifunctional organic promoter for nucleophilic fluorinations with CsF. By formation of a CsF/BACCA complex, BACCA could release a significantly active and selective fluoride source for S_N2 fluorination reactions. The origin of the promoting effects of BACCA was studied by quantum chemical methods. The role of BACCA was revealed to be separation of the metal fluoride to a large distance (>8 ?), thereby producing an essentially "free" F^-. The synergistic actions of the crown-6-calix[4]arene subunit (whose O atoms coordinate the counter-cation Cs⁺) and the terminal tert-alcohol OH groups (forming controlled hydrogen bonds with F^-) of BACCA led to tremendous efficiency in S_N2 fluorination of base-sensitive substrates.

Full text of DOI:10.1002/chem.201504602

DOI: 10.1002/chem.201504602
Full Paper
&
Calixarenes |Hot Paper|
Bis-tert-Alcohol-Functionalized Crown-6-Calix[4]arene: An Organic
Promoter for Nucleophilic Fluorination
Vinod H. Jadhav,[a] Wonsil Choi,[a] Sung-Sik Lee,[b] Sungyul Lee,*[b] and Dong Wook Kim*[a]
Abstract: A bis-tert-alcohol-functionalized crown-6-calix[4]ar-
ene (BACCA) was designed and prepared as a multifunctional
organic promoter for nucleophilic fluorinations with CsF. By
formation of a CsF/BACCA complex, BACCA could release
a significantly active and selective fluoride source for SN2 flu-
orination reactions. The origin of the promoting effects of
BACCA was studied by quantum chemical methods. The role
of BACCA was revealed to be separation of the metal fluo-
ride to a large distance (>8 Š), thereby producing an essen-
tially “free” FÀ. The synergistic actions of the crown-6-cal-
ix[4]arene subunit (whose O atoms coordinate the counter-
cation Cs+) and the terminal tert-alcohol OH groups (form-
ing controlled hydrogen bonds with FÀ) of BACCA led to tre-
mendous efficiency in SN2 fluorination of base-sensitive sub-
strates.
Introduction
community as a result of the importance of these compounds
in the pharmaceutical sciences and in fluorine-18 labeling
chemistry for applications in positron emission tomography
(PET) molecular imaging studies.[6] Among the strategies for
their preparation, nucleophilic fluorination of various alkyl sul-
fonate or halide substrates by using alkali metal fluorides (MFs)
is a traditional approach because of the wide availability of
these substrates and easy access to MFs as fluoride sources.[7]
However, the strong Coulombic influence of the alkali metal
cation (M+) on fluoride makes MFs inactive toward nucleophil-
ic fluorination, and MFs are also insoluble in organic media.[7,8]
To solve these problems, crown ether derivatives have been
widely used as phase-transfer catalysts (PTCs) to enhance both
the reactivity and solubility of MFs by forming MF–crown ether
complexes (Figure 1A).[9] It is well known that selective solva-
tion of the alkali metal cation through crown ether complexa-
tion in polar aprotic solvents (e.g., CH3CN and DMF) generates
a highly reactive “naked” fluoride source for SN2 fluorination
reactions.[10] However, the “naked” fluoride can cause various
Calixarenes comprise an extensively studied class of macrocy-
clic compounds that are usually associated with host–guest
chemistry.[1] Several remarkable applications of calixarene deriv-
atives have been devised, including their uses as platforms for
shape-selective catalysts, efficient sensors, highly selective ex-
tractants, enzyme mimics, precursors of capsules, molecular
glue for multimetal assemblies, building blocks for nanoporous
materials, and sophisticated auxiliaries in separation science.[1,2]
Among various calixarene derivatives, calix[4]arene is the sim-
plest member of this family of compounds, which is easily ac-
cessible in large quantities as a very convenient building
block.[3] There have been many reports on the complexation
properties of calix[4]arene derivatives as potential ionophores
with metal cations or counter anions.[3,4] In particular, Sessler
et al. reported that a crown ether-strapped calix[4]arene-
capped calix[4]pyrrole showed good performance as an ion-
pair receptor for solvent-separated CsF ions by the binding of
cesium cation to the crown ether-strapped calix[4]arene subu-
nit together with complexation of fluoride anion within the
calix[4]pyrrole core.[5]
Over the last several decades, the synthesis of fluorinated
biomolecules has attracted much attention from the scientific
[a] Dr. V. H. Jadhav, W. Choi, Prof. Dr. D. W. Kim
Department of Chemistry, Inha University
100 Inha-ro, Nam-gu, Incheon 402-751 (Korea)
Fax: (+82)32-867-5604
E-mail: kimdw@inha.ac.kr
[b] S.-S. Lee, Prof. Dr. S. Lee
Department of Applied Chemistry, Kyung Hee University
Gyeonggi 446-701 (Korea)
E-mail: sylee@khu.ac.kr
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201504602.
Figure 1. Concept of bis-tert-alcohol-functionalized crown-6-calix[4]arene
(BACCA) as a multifunctional organic promoter.
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side reactions, such as elimination and/or hydroxylation, in nu-
cleophilic fluorinations due to its strong basicity.[11]
Grignard reagent CH3MgBr successfully gave the BACCA in
85% yield. Finally, methylated BACCA was prepared by O-
methylation of the two terminal OH groups using methyl
iodide in order to investigate the role of the terminal tert-alco-
hol subunits of BACCA in SN2 fluorination reactions.
In recent advances, we found that bulky protic tert-alcohol
solvents such as tBuOH and tert-amyl alcohol—including oligo-
ethylene glycols—can increase the reactivity of MFs by form-
ing coordinated fluoride complexes (which we termed “flexi-
ble” fluoride) through controlled hydrogen bonding between
the tert-alcohol solvent and MF (Figure 1C).[12,13] Moreover, the
reduced basicity of this “flexible” fluoride allowed the SN2 fluo-
rination to proceed selectively while suppressing side reac-
tions.[12] Such controlled H-bonding is also known to play a cru-
cial role in an enzymatic nucleophilic fluorination system using
a fluorinase.[14] Thus, based on a combination of the two con-
cepts mentioned above—the crown ether-strapped calix[4]ar-
ene ion-pair receptor and tert-alcohol coordinated “flexible”
fluoride—we designed a bis-tert-alcohol-functionalized crown-
6-calix[4]arene (BACCA) as a new type of multifunctional or-
ganic promoter for highly efficient nucleophilic fluorination
with an alkali metal fluoride (Figure 1B). In these types of pro-
moter systems, it was expected that both the Lewis base and
Lewis acid parts would cooperate to produce the “flexible” and
active nucleophiles. The O atoms in the crown ether-strapped
calix[4]arene subunit of BACCA can bind to M+ (in particular,
Cs+),[5] whereas the tert-alcohol OH groups can act as anchors
for the nucleophile (in particular, FÀ)[12,13b] in a fluoride recogni-
tion site of initial interaction by hydrogen bonding to provide
rate enhancement. Herein, we describe the preparation of
BACCA and demonstrate its strong promoting effects for SN2
type fluorinations with high chemoselectivity. We also exam-
ined the origin of the rate acceleration by quantum chemical
methods, which showed that the crown ether and tert-alcohol
moieties in the promoter act on Cs+ and FÀ, respectively, to
separate CsF and thus produce an essentially “free” nucleo-
phile.
In the present study, we used CsF as the alkali metal fluoride
source, considering the three-dimensional cavity generated by
the crown-6-calix[4]arene subunit on the upper rim of BACCA,
which is known to have a high affinity for Cs+. Initially, to in-
vestigate the promoter activity of BACCA, SN2 fluorination of
the model compound 2-(3-methanesulfonyloxypropoxy)naph-
thalene (3) was carried out by using 3 equivalents of CsF in the
presence of BACCA (1.0 equiv) at 1008C for 6 h in polar aprotic
CH3CN. The result of this reaction was compared with that of
the same reaction in the absence of any promoter or in the
presence of methylated BACCA, in which the two terminal tert-
alcohol groups were methylated to prevent H-bonding with
the fluoride of CsF (Figure 2). Fluorination in the absence of
Figure 2. Nucleophilic fluorination reaction using CsF with BACCA, methylat-
ed BACCA, or without any promoter. The quantity of product was deter-
1
mined by H NMR spectroscopy. R=naphthyl.
Results and Discussion
any promoter hardly proceeded, whereas the same reaction in
the presence of BACCA proceeded smoothly and was com-
plete within 6 h. This result showed that BACCA had very good
promoter activity for SN2 fluorination. To clarify the influence
of the two terminal tert-alcohols of BACCA, the same reaction
was performed in the presence of the dimethylated BACCA
promoter, which exhibited significantly lower promoter activity
in the SN2 fluorination reaction compared to BACCA. This
result suggests that controlled H-bonds between FÀ and
BACCA play a crucial role in enhancing the nucleophilicity of
CsF by producing the “flexible” fluoride effect,[12] as well as af-
fording fluoride recognition for the initial interaction in more
effectively forming the CsF–BACCA complex (Figure 1B).[13]
To determine the optimal reaction conditions and to further
study the properties of BACCA under various conditions, SN2
fluorination reactions were performed with various alkali metal
fluorides in the presence of BACCA (different molar ratios: 1.0,
0.5, or 0.25 equiv) in a range of solvent systems (Table 1). As
expected, fluorination in the presence of larger amounts of
BACCA proceeded faster while suppressing the competing b-
The BACCA promoter was prepared as shown in Scheme 1.
First, a crown-6-calix[4]arene (1) was prepared from the com-
mercially available calix[4]arene according to a previously re-
ported procedure.[4e] O-alkylation of the two remaining phenol-
ic OH groups of 1 using 1-bromo-2-butanone in the presence
of Cs2CO3 at reflux for 24 h then afforded the bis-keto inter-
mediate 2 in 72% yield. Subsequent reaction of 2 with
Scheme 1. Synthesis of bis-tert-alcohol-substituted crown-6-calix[4]arene. Re-
agents: a) BrCH2COCH2CH3, Cs2CO3, CH3CN, reflux, 24 h; b) CH3MgBr, THF,
08C to room temp, 3 h; c) CH3I, NaH, 608C, 24 h.
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Table 1. Fluorination of mesylate 3 with alkali metal fluoride (MF) in the
presence of BACCA.[a]
Entry BACCA [equiv] Solvent
MF
t [h]
Yield [%][b]
4b
4a
95 (91)[c] trace
90
87
1
2
3
4
5
6
7
8
1.0
0.5
0.25
1.0
1.0
1.0
1.0
1.0
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CsF
6
CsF 12
CsF 24
RbF 16
KF
NaF 24
7
9
88
10
trace
–
24
42[d]
[e]
–
t-amyl alcohol CsF
DMF CsF
1
96 (93)[c]
–
1.5 81
17
[a] Reaction conditions: Mesylate 3 (1.0 mmol), MF (3.0 equiv) in solvent
(4.0 mL) at 1008C; [b] yields determined by 1H NMR spectroscopy;
[c] yield of isolated product in parentheses; [d] 46% of starting material
remained; [e] no reaction. R=naphthyl.
Figure 3. Two views of the pre-reaction complex.
elimination compared to the same reaction using catalytic
amounts (0.5 and 0.25 equiv; Table 1, entries 1–3). Next, the ef-
ficiency of BACCA was examined with various alkali metal fluo-
rides, such as NaF, KF, and RbF (Table 1, entries 4–6); NaF was
inactive in the reaction despite the use of BACCA, whereas
BACCA did not show good efficiency with either KF or RbF
compared to CsF. Considering the three-dimensional cavity of
BACCA and the strong electrostatic interaction of small size
MFs, it may be difficult for such MFs to form a stable MF–
BACCA complex that would generate a reactive fluoride during
the reaction.[5] Furthermore, solvent effects with different types
of solvents, such as tert-amyl alcohol, DMF, and 1,4-dioxane,
were investigated in BACCA-promoted nucleophilic fluorina-
tion with CsF (Table 1, entries 7–9). In a bulky protic solvent,
tert-amyl alcohol, the fluorination had a significantly faster re-
action rate (within 1 h; entry 7), affording the desired fluorinat-
ed product 4a in excellent yield without the formation of by-
products (e.g. alkenes). It seems that a synergistic effect of the
tert-alcohol medium and BACCA promoter allowed the forma-
tion of a tetra-tert-alcohol-coordinated fluoride complex with
BACCA.[12,15] In a polar aprotic solvent, DMF (entry 8), even
though the fluorination reaction proceeded relatively quickly,
a large amount of alkene byproduct (17%) was formed. Pre-
sumably, BACCA acts solely as a phase-transfer catalyst by se-
lective solvation of the BACCA–Cs+ complex in DMF because
the O atom in DMF is a strong H-bond acceptor that competes
with fluoride for interaction with the bis-terminal tert-alcohol
subunit, thus preventing formation of the BACCA–FÀ complex.
To clarify the role of BACCA for promoting the SN2 fluorina-
tion presented in Figure 2 and Table 1, we examined the struc-
ion pair CsF was 2.347 Š,[20] which indicates that BACCA essen-
tially dissociates CsF. Figure 3 also shows that this very desira-
ble capability of BACCA was achieved by two cooperating ef-
fects: the oxygen atoms in the crown-6-calix[4]arene subunit
strongly coordinate to the counter cation Cs+, and the two ter-
minal tert-alcohols form hydrogen bonds with FÀ. Although
the presumed role of crown ethers for promoting SN2 reactions
by separating the metal cation from the nucleophile was con-
sidered dubious in recent investigations,[21] here the crown
ether clearly performs this important function with the help of
the OH groups. These two factors exert a strong synergistic in-
fluence to overcome the powerful Coulombic attraction be-
tween Cs+ and FÀ and to thereby separate the ions. The sub-
strate is situated in such a manner that the nucleophilic FÀ
may easily attack the close-lying electropositive carbon center
of the substrate by interactions of FÀ with the electropositive
carbon atom and the methyl hydrogen atoms. These intricate
interactions among Cs+, FÀ, BACCA, and the substrate function
to form a pre-reaction complex in a configuration that is ex-
tremely favorable for SN2 fluorination.
Our study further focused on the influence of BACCA on the
chemoselectivity of the SN2 fluorination reaction. For this pur-
pose, SN2 fluorinations were conducted with the base-sensitive
substrate 1-(2-methanesulfonylethyl)naphthalene (5) under
a range of conditions (Table 2). SN2 fluorinations of mesylate 5
using “naked” fluoride sources generated from conventional
PTC systems, such as tetrabutylammonium fluoride (TBAF) and
CsF/18-crown-6 complex in CH3CN, predominantly afforded
styrene 6b (88% and 81%, respectively; Table 2, entries 1 and
2), with the corresponding fluorinated product 6a formed in
only 12% and 19% yield, respectively. The use of CsF in the
absence of any PTC system in the same reaction gave a very
low reaction rate, as well as poor chemoselectivity (Table 2,
entry 3). Gratifyingly, the BACCA promoter not only increased
the nucleophilicity of CsF but also significantly enhanced the
chemoselectivity, even in a polar aprotic medium (CH3CN)
compared with conventional PTCs, and this fluorination reac-
ture of the calculated pre-reaction complex (B3LYP/6-31G**[16]
/
LANL2DZ(Cs)[17] SCRF=SMD method with the SMD tech-
nique[18] for the solvent continuum, as implemented in the
Gaussian 09 suite of programs[19]) for the reaction in CH3CN
(Figure 3). Bulky substrate 3 was modeled as C3H7ÀOMs, to
simplify the computational effort. The most striking feature
was the extremely large distance (>8 Š) between the counter
cation Cs+ and the nucleophile FÀ. The Cs···F distance in the
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in triethylene glycol[13a] and polystyrene-supported pentaethy-
lene glycol-promoted fluorination with CsF in tert-alcohol[13b]
(Table 3, entries 5 and 6, respectively). The sec-alkyl fluoride
was also obtained from the corresponding sec-alkyl tosylate by
the BACCA-promoted fluorination reaction in tert-alcohol in ex-
cellent yield (90%; Table 3, entry 7). The fluorination of primary
iodo- and bromoalkanes in the presence of BACCA in tert-amyl
alcohol proceeded highly selectively, affording 6a in good
yields (83% and 91%; Table 3, entries 8 and 9, respectively). In-
terestingly, a primary bromoalkyl nitroimidazole was converted
into the corresponding fluorinated product in 85% yield with
an unexpectedly fast reaction rate (t=45 min; Table 3,
entry 10), compared with that of the bromoalkane (t=9 h;
entry 9) under the same fluorination conditions. Presumably,
strong H-bonding interactions between the CsF/BACCA com-
plex and the N and O atoms of the nitroimidazole substrate as
H-bond acceptors may facilitate their close proximity, thereby
increasing the reaction rate. 3-Fluoro-picoline-N-oxide was ob-
tained from 3-chloro-picoline-N-oxide in 78% yield by using
Table 2. Chemoselective fluorination of base-sensitive substrate 5 in the
presence of BACCA.[a]
Entry Fluoride source with or without promoter t [h]
Yield [%][b]
6a
6b
1
2
3
4
5
6
TBAF
CsF/18-crown-6
CsF
CsF/BACCA
CsF/methylated BACCA
CsF/BACCA in tert-amyl alcohol[d]
0.5
1
5
5
5
12
19
10[c]
81
9
92 (90)[e]
88
81
17
19
91
8
1
[a] Reaction conditions, unless otherwise indicated: 5 (1.0 mmol), fluoride
source (3.0 equiv) with or without promoter (1.0 equiv) in CH3CN (4.0 mL)
at 1008C; [b] yields determined by 1H NMR spectroscopy; [c] 73% of the
starting material remained; [d] reaction performed in 4.0 mL of tert-amyl
alcohol instead of CH3CN; [e] yield of isolated product in parentheses.
tion afforded product 6a in 81% yield along with only 19%
styrene 6b (Table 2, entry 4). Interestingly however, the
same reaction in the presence of methylated BACCA
showed quite poor chemoselectivity, providing predomi-
nantly the styrene byproduct 6b (91%) with only 9% of the
fluorinated product 6a (Table 2, entry 5), which suggests
that methylated BACCA has only a PTC-like property. This
result shows that the bis-tert-alcohol subunit of BACCA is
a very important site in the reaction process both for che-
moselectivity and for promoter activity. In particular, these
observations (entries 4 and 5) were highly consistent with
our hypothesis that the bis-tert-alcohol subunit of BACCA in-
teracts with FÀ to generate a less basic but active tert-alco-
hol-coordinated “flexible” fluoride and provide a “protic” en-
vironment[12] in the reaction medium by controlled H-bond-
ing, which is similar to the enzymatic fluorination system as-
sociated with fluorinase.[14] Next, we investigated the syner-
gistic effect between the BACCA promoter and tert-alcohol
medium in the fluorination of base-sensitive substrate 5
(Table 2, entry 6). Gratifyingly, as expected, this BACCA-pro-
moted fluorination reaction in tert-amyl alcohol provided
the best performance, with much higher selectivity and
a faster reaction rate, to afford 6a in 92% yield with only
8% styrene 6b.
We also examined the scope of this BACCA-promoted flu-
orination in tert-alcohol medium with a variety of substrates
(Table 3). Secondary alkyl bromides are known to be another
representative group of base-sensitive substrates for which
it is difficult to obtain secondary alkyl fluorides by nucleo-
philic fluorination with TBAF, even in protic tert-alcohol
media (Table 3, entries 3 and 4, respectively). Moreover, fluo-
rination in tert-alcohol by using CsF is also not efficient for
producing sec-alkyl fluorides, due to the extremely slow re-
action rate (Table 3, entry 2). Notably, the sec-alkyl fluoride
was readily produced by this BACCA-promoted fluorination
in tert-alcohol medium (Table 3, entry 1) compared with
other fluorination procedures developed to date, such as KF
Table 3. BACCA-promoted SN2 fluorination of various substrates with CsF in
tert-alcohol medium.
Entry Substrate
Method[a] t [h]
T
[oC]
Yield [%][b]
Product Alkene
1
A
B
C
D
E
12
12[d]
3
3
4
100 86
100 28
12
16
92
81
23
17
2[c]
3[c]
4[c]
5[c]
6[c]
100
8
100 19
100 59
100 80
F
3
7
A
3
100 90
8
8[d]
9[d]
A
A
5
8
100 83
100 91
17
9
10
A
45 min 90 85
7
11
A
5
1
100 78
80 96
–
12
13
A
A
–
–
5
5
100 97
100 93
14
A
–
[a] Method A: substrate (1.0 mmol), CsF (3.0 equiv), BACCA (1.0 equiv) in tert-
amyl alcohol (4.0 mL); method B: with CsF in tert-amyl alcohol; method C:
with TBAF in CH3CN; method D: with TBAF in tert-amyl alcohol; method E:
with KF (5.0 equiv) in triethylene glycol; method F: with CsF and polymer-
supported pentaethylene glycol (1.0 equiv) in tert-amyl alcohol; [b] yield of
isolated product; [c] reference [13b]; [d] yields determined by 1H NMR spec-
troscopy.
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Bis-tert-alcohol-functionalized crown-6-calix[4]arene (BACCA):
Under nitrogen, to a solution of compound 2 (850 mg, 1.10 mmol)
in anhydrous THF (25 mL) was added CH3MgBr in THF solution
(3m, 2.2 mL, 6.6 mmol) dropwise at 08C. The reaction mixture was
stirred for 3 h and then quenched by slow addition of 5% aqueous
HCl (20 mL). The organic layer was extracted with EtOAc (3”
30 mL), dried over sodium sulfate, and concentrated under re-
duced pressure on a rotary evaporator. Flash column chromatogra-
phy (EtOAc/hexane; 1:3) afforded BACCA (743 mg, 0.93 mmol,
this method (Table 3, entry 11) and the fluorination of a sugar
triflate proceeded at 808C within 1 h, to provide the corre-
sponding fluoro-sugar product in 96% yield (Table 3, entry 12).
A fluoropropyl ciprofloxacin,[22] which has antibacterial activity,
was produced in 97% yield by reaction with the corresponding
mesylate precursor (Table 3, entry 13). Finally, considering the
importance of azadibenzocyclooctyne (ADIBO) derivatives in
copper-free “click chemistry” for diverse applications of fluo-
rine-18 labeling chemistry,[23] a fluorinated ADIBO derivative
was prepared in 93% yield from the corresponding mesylate
precursor by using our fluorination protocol (Table 3, entry 14).
1
85%) as a white solid: M.p. 354–3588C; H NMR (400 MHz, CDCl3):
d=1.00 (t, J=7.6 Hz, 6H), 1.34 (s, 6H), 1.74 (q, J=7.6 Hz, 4H), 3.19
(d, J=14.0 Hz, 4H), 3.47–3.76 (m, 16H), 4.00 (t, J=6.8 Hz, 4H), 4.27
(t, J=6.4 Hz, 4H), 4.45 (d, J=13.2 Hz, 4H), 5.97 (d, J=7.6 Hz, 4H),
6.18 (t, J=7.6 Hz, 2H), 6.95 (t, J=7.6 Hz, 2H), 7.12 ppm (d, J=
7.6 Hz, 4H); 13C NMR (100 MHz, CDCl3): d=8.4, 23.5, 30.8, 31.9,
70.1, 70.2, 70.8, 71.0, 72.5, 82.5, 122.2, 122.8, 127.7, 129.4, 132.8,
132.9, 136.8, 136.9, 154.6, 158.0 ppm; HRMS (FAB TOF): m/z calcd
for C48H63O10 [M+H]+ 799.4421, found 799.4423.
Conclusion
In conclusion, we have prepared BACCA as a new type of mul-
tifunctional organic promoter designed for SN2 fluorination
with CsF. In this reaction, BACCA showed a PTC effect by bind-
ing of Cs+ to its crown-6-calix[4]arene subunit, thus dissociat-
ing CsF in solution with the release of an essentially “free” fluo-
ride. Moreover, the bis-terminal tert-alcohol subunit of BACCA
played crucial roles in enhancing the nucleophilicity of CsF and
in reducing the formation of byproducts by generating tert-al-
cohol-coordinated “flexible” fluoride from controlled H-bond-
ing between the FÀ nucleophile and the tert-alcohol groups of
BACCA, as established in a quantum chemical study. In particu-
lar, the BACCA-promoted fluorination in tert-alcohol medium
exhibited tremendous efficiency in the SN2 fluorination of
base-sensitive substrates, allowing reactions to proceed with
much higher chemoselectivity and at a significantly faster rate
due to the synergistic effects of BACCA and the tert-alcohol
solvent. Our current work is focused on developing more effi-
cient calix[4]arene based multifunctional promoters through
structural modifications and also on PET applications of the
synthetic protocols for rapid 18F labeling of radiopharmaceuti-
cals.
Methylated BACCA: Under nitrogen, methyl iodide (1.78 g,
12.52 mmol) was added to a suspension of NaH (60% in mineral
oil, 336 mg, 8.4 mmol) and BACCA (500 mg, 0.63 mmol) in DMF
(15 mL), and stirred for 1 h at room temperature and then for 24 h
at 608C. After DMF was removed under reduced pressure, EtOAc
(15 mL) and water (35 mL) were added to the crude product. Then,
the aqueous layer was extracted with EtOAc (3”20 mL) and the
combined organic phases were dried over sodium sulfate and con-
centrated under reduced pressure. Flash column chromatography
EtOAc/hexane; 1:3) gave the methylated BACCA (462 mg,
1
0.56 mmol, 89%) as a slightly yellow oil. H NMR (400 MHz, CDCl3):
d=0.95 (t, J=8 Hz, 6H), 1.38 (s, 4H), 1.70–190 (m, 4H), 3.19 (d, J=
14 Hz, 2H), 3.23 (s, 6H), 3.59 (d, J=6.8 Hz, 2H), 3.61–3.85 (m, 10H),
3.96 (t, J=8 Hz, 4H), 4.24 (t, J=8 Hz, 2H), 4.40–4.52 (m, 4H), 5.96
(d, J=7.6 Hz, 4H), 6.08 (t, J=7.6 Hz, 2H), 6.96 (t, J=7.2 Hz, 2H),
7.12 ppm (d, J=7.2 Hz, 4H); 13C NMR (100 MHz, CDCl3): d=8.0,
20.8, 27.9, 31.1, 49.5, 49.5, 69.5, 70.9, 71.2, 71.4, 72.4, 76.9, 78.7,
122.2, 122.6, 127.7, 129.5, 132.9, 132.9, 132.9, 133.0, 137.0, 155.4,
158.3 ppm; HRMS (FAB TOF): m/z calcd for C15H28N2O6 [M]+
826.4656; found 826.4658.
Typical procedure for BACCA-promoted fluorination in CH3CN
(Table 1, entry 1): CsF (456 mg, 3 mmol) was added to the mixture
of mesylate 3 (281 mg, 1.0 mmol) and BACCA (799 mg, 1.0 mmol)
and CH3CN (4 mL) in a reaction vial. The reaction mixture was
stirred for 6 h at 1008C. The reaction time was determined by
monitoring with TLC. The reaction mixture was filtered and the
solid was washed with diethyl ether (20 mL). The solvent was re-
moved from the filtrate under reduced pressure. Flash column
chromatography (10% EtOAc/hexanes) of the residue afforded 2-
Experimental Section
1,3-Alternate 25,27-Bis(propionylmethoxy)-26,28-calix[4]crown-6
(2): A solution of crown-6-calix[4]arene(1, 1.0 g, 1.59 mmol), 1-
bromo-2-butanone (961 mg, 6.37 mmol), and Cs2CO3 (1.04 g,
3.18 mmol) in CH3CN (35 mL) was heated at reflux for 24 h under
a nitrogen atmosphere. After the reaction mixture had cooled to
room temperature, the solvent was removed under reduced pres-
sure. To the resulting brownish solid, 5% aqueous HCl (35 mL) and
CH2Cl2 (25 mL) were added, and the organic layer was separated,
washed by water (35 mL), and dried over anhydrous sodium sul-
fate. After removal of the solvent, flash column chromatography
(EtOAc/hexane; 1:3) gave 2 (881 mg, 1.15 mmol, 72%) as a white
solid: M.p. 113–1178C; 1H NMR (400 MHz, CDCl3): d=1.13 (t, J=
7.2 Hz, 6H), 2.62 (q, J=7.2 Hz, 4H), 3.18 (d, J=13.6 Hz, 4H), 3.50–
3.75 (m, 12H), 4.01 (t, J=6.8 Hz, 4H), 4.27 (t, J=6.4 Hz, 4H), 4.36–
4.48 (m, 8H), 6.14 (d, J=7.2 Hz, 4H), 6.27 (t, J=7.2 Hz, 2H), 6.86 (t,
J=7.6 Hz, 2H), 7.02 ppm (d, J=7.6 Hz, 4H); 13C NMR (100 MHz,
CDCl3): d=7.4, 31.1, 32.7, 69.8, 70.8, 70.9, 71.0, 73.1, 78.9, 122.4,
123.0, 128.0, 129.2, 133.2, 136.3, 154.6, 157.9, 207.1 ppm; HRMS
(FAB TOF): m/z calcd for C46H55O10 [M+H]+ 767.3795; found
767.3798.
(3-fluoropropoxy)naphthalene (4a) as
a colorless oil (186 mg,
1
0.91 mmol, 91%). H NMR (400 MHz, CDCl3): d=2.14–2.39 (m, 2H),
4.24 (t, J=6.2 Hz, 2H), 4.72 (dt, J=46.8, 5.8 Hz, 2H), 7.16–7.22 (m,
2H), 7.34–7.53 (m, 2H), 7.76–7.83 ppm (m, 3H); 13C NMR (100 MHz,
CDCl3): d=30.4 (d, J=20.1 Hz), 63.6 (d, J=25.3 Hz), 80.8 (d, J=
163.9 Hz), 106.8, 118.8, 123.6, 126.4, 126.7, 127.6, 129.1, 129.4,
134.6, 156.7 ppm; MS (EI) m/z 204 (M+); HRMS (EI): m/z calcd for
C13H13FO [M]+ 204.0950; found 204.0932. Registry No. provided by
the author: 398–53–8.
Typical procedure for BACCA-promoted fluorination in tert-alco-
hol medium (Table 2, entry 6): CsF (456 mg, 3 mmol) was added
to the mixture of mesylate 5 (250 mg, 1.0 mmol), BACCA (799 mg,
1.0 mmol) and tert-amyl alcohol (4 mL) in a reaction vial. The reac-
tion mixture was stirred for 1 h at 1008C. The reaction time was
determined by monitoring with TLC. The reaction mixture was fil-
tered and the solid was washed with diethyl ether (20mL). The sol-
Chem. Eur. J. 2016, 22, 4515 – 4520
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Full Paper
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This work was supported by the Basic Science Research Pro-
gram (grant codes: NRF-2014R1A2A2A03007401 and NRF-2011-
0021836) and the Nuclear Research & Development Program
(grant
codes:
NRF-2015M2C2A1047692
and
2015M2A2A6A01045378) through the National Research Foun-
dation of Korea (NRF), funded by the Ministry of Science, ICT
and future Planning and KISTI (2015).
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Received: November 16, 2015
Published online on February 16, 2016
Chem. Eur. J. 2016, 22, 4515 – 4520
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim