Crown Ether Nucleophilic Catalysts (CENCs): Agents for Enhanced Silicon Radiofluorination

Article abstract of DOI:10.1021/acs.joc.6b02457

New bifunctional phase transfer agents were synthesized and investigated for their abilities to promote rapid fluorination at silicon. These agents, dubbed crown ether nucleophilic catalysts (CENCs), are 18-crown-6 derivatives containing a side-arm and a potentially nucleophilic hydroxyl group. These CENCs proved efficacious in the fluorination of hindered silicon substrates, with fluorination yields dependent on the length of linker connecting the metal chelating unit to the hydroxyl group. The efficacy of these CENCs was also demonstrated for rapid radiofluorination under mild conditions for eventual application in molecular imaging with positron emission tomography (PET). The hydrolysis-resistant aryl silicon fragment is promising as a convenient synthon for labeling potential PET radiotracers.

Full text of DOI:10.1021/acs.joc.6b02457

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Article
Crown Ether Nucleophilic Catalysts (CENCs):
Agents for Enhanced Silicon Radiofluorination
Susovan Jana, Mohammed H. Al-huniti, Bo Yeun Yang,
Shuiyu Lu, Victor W Pike, and Salvatore Donato Lepore
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02457 • Publication Date (Web): 07 Feb 2017
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The Journal of Organic Chemistry
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Crown Ether Nucleophilic Catalysts (CENCs): Agents for Enhanced
Silicon Radiofluorination
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Susovan Jana,†§ Mohammed H. Alꢀhuniti,†§ Bo Yeun Yang,‡ Shuiyu Lu,‡* Victor W. Pike,‡ and
Salvatore D. Lepore†*
†Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, FL 33431ꢀ0991
‡Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892ꢀ1003
KEYWORDS: phase transfer agent / fluorine-18 / silicon fluorination / PET / crown ether nucleophilic catalyst
ABSTRACT: New bifunctional phase transfer agents were synꢀ
thesized and investigated for their abilities to promote rapid
fluorination at silicon. These agents, dubbed crown ether nucleoꢀ
philic catalysts (CENCs), are 18ꢀcrownꢀ6 derivatives containing
a sideꢀarm and a potentially nucleophilic hydroxyl group. These
CENCs proved efficacious in the fluorination of hindered silicon
substrates, with fluorination yields dependent on the length of linker connecting the metal chelating unit to the hydroxyl group. The
efficacy of these CENCs was also demonstrated for rapid radiofluorination under mild conditions for eventual application in moꢀ
lecular imaging with positron emission tomography (PET). The hydrolysisꢀresistant aryl silicon fragment is promising as a convenꢀ
ient synthon for labeling potential PET radiotracers.
groups. This rate enhancement can be rationalized on the basis
of the entropic advantage afforded by localizing the fluoride
ion nucleophile near to the silicon center. However, this apꢀ
proach suffered problems with solubilizing the [18F]fluoride
ion due to the high lipophilicity of the silane part of the NALG
molecule leading to low overall yields (Strategy B).
INTRODUCTION
Organosilanes continue to elicit interest as acceptors of posiꢀ
tronꢀemitting fluoride ion ([18F]Fꢀ) for potential applications in
molecular imaging with positron emission tomography (PET).1
Low molecular weight 18Fꢀlabeled organosilanes are now apꢀ
pearing as PET radiotracers, including one example of a radioꢀ
tracer for imaging 5ꢀHT1A receptors in brain.2 Moreover, small
[18F]organofluorosilanes are finding use as synthons for labelꢀ
ing peptides and proteins.3 The silyl fluoride bond (Si−F) in
these tracers is often susceptible to hydrolysis in vivo. Incorꢀ
poration of bulky substituents on the silicon can remediate the
metabolic instability.4 Nonetheless, a sterically hindered siliꢀ
con center usually reacts slowly with [18F]fluoride ion. That is
because, in most cases, fluoride ion incorporation is achieved
with the help of a bulky ionophoric phase transfer agent (PTA;
e.g., 18ꢀcrownꢀ6 or kryptofix 2.2.2) to form a “naked” or minꢀ
imally hydrated 18FꢀꢀK+/PTA complex.5 Such complexes react
relatively slowly with sterically encumbered organosilanes,
partly due to a hindered approach of the large ionophore/metal
fluoride complex to the silicon center (Strategy A, Scheme 1).
This may sometimes become problematic for radiofluorination
considering the short halfꢀlife of 18F (t1/2 = 109.8 min).6
Scheme 1. Strategies for Silicon Radiofluorination
We have previously demonstrated that radiofluorination at
aliphatic carbon7 and silicon8 can be accomplished using metal
chelating leaving groups capable of facilitating nucleophilic
substitution reactions. We dubbed such groups as “nucleophile
assisting leaving groups” (NALGs), arguing that the observed
rate enhancements afforded by these nucleofuges are primarily
due to stabilizing interactions between substrates and metalꢀ
nucleophile pairs to lower transition state energies.9 These
reactions, especially with crown ether containing leaving
groups, were significantly faster than with traditional leaving
In seeking an improved approach to silicon radiofluorination,
we sought to exploit the ability of functionalized crown ethers
to sequester metal salts10 while maintaining the entropic adꢀ
vantage of intramolecular [18F]fluoride ion attack on silicon.
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2
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4
CH2OH
CH2OMe
ꢀ
49
0*
18
4
5
This led us to propose a crown ether carrying a sideꢀarm (lariꢀ
1
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6
7
8
at) with a terminal nucleophile, i.e. a molecule which we term
a “crown ether nucleophilic catalyst” (CENC). Our hypothesis
was that a relatively unhindered nucleophile would quickly
react with the silicon center bringing with it the crown etherꢀ
complexed metal fluoride ion (Strategy C). The fluoride ion
might then be delivered intramolecularly to afford the desired
silyl fluoride. For this last step, we were inspired by reports
from Corriu and coworkers11 that demonstrated highly favoraꢀ
ble silicon substitution reactions with pentavalent silicon inꢀ
termediates analogous to those expected in our CENC apꢀ
proach. To our knowledge, there are no reports of CENCs for
silicon substitution reactions, although calix[4]areneꢀbased
ether catalysts were reported by the Mandolini group to aid the
formation of phosphodiesters.12 In addition, Bakó and
K 2.2.2
*Reaction time was 30 min.
We expect that one of the principal applications of a CENC
approach to fluorination could be to radiolabel peptides. To
this end, we prepared a small silylꢀcontaining fragment (11)
that can be easily appended to a peptide via an amide coupling
reaction (Scheme 2). Using this approach, we prepared comꢀ
pound 12 as a representative substrate.
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Scheme 2. Synthesis of Model Peptide Compound 12
coworkers utilized
a
glucopyranosideꢀbased hydroxylꢀ
containing crown ether to mediate Michael reactions13 and
Darzens condensations.10b,13d In our work, we aimed to demonꢀ
strate that CENCs, based on an 18ꢀcrownꢀ6 (18ꢀCꢀ6) scaffold,
enhance the fluorination of organosilanes with both KF and
cyclotronꢀproduced 18Fꢀfluoride ion under mild conditions.
RESULTS AND DISCUSSION
CENC design and fluorination with KF
In deciding on a nucleophilic unit for our CENC design, we
reasoned that silicon has a high bonding affinity for oxygen.
Thus, we began our studies with a commercially available 18ꢀ
crownꢀ6 lariat alcohol (4). In the presence of this simple
CENC, substrate 1 (synthesized from a corresponding silane)
was converted into silyl fluoride 2 at room temperature over
20 minutes in 49% yield based on KF as limiting reagent. A
lower conversion (30%) was observed with 18ꢀCꢀ6 (3); the
commonly used PTA, kryptofix 2.2.2 (K 2.2.2), led to an 18%
conversion under identical conditions (Scheme 2). It appears
that the hydroxyl group in 4 enhances the fluorination. In acꢀ
cord, when the terminal hydroxyl group was replaced with a
methoxy group, the resulting 5 proved ineffective in the fluorꢀ
ination of 1, even after 30 minutes (Table 1). Although it is
uncertain why 5 reacts much more slowly than 4 or even 18ꢀ
crownꢀ6 (3), these results support the notion that the oxygen of
the hydroxyl group in CENC 4 accelerates the fluorination
reaction by acting as a nucleophile and/or as a hydrogen bond
donor.
To explore the role of the length of the CENC sideꢀarm, we
prepared a series of derivatives of 18ꢀCꢀ6 (13−19) using our
previously reported procedure.14 In our initial series of experꢀ
iments, lariat alcohols containing hydrocarbon sideꢀarms varyꢀ
ing from one to four methylene units (4, 13–15) were used as
CENCs to fluorinate substrate 12. To represent more closely
the stoichiometry typically used in radiofluorination, substrate
was used in a twoꢀfold ratio to the preformed CENC/KF (1:1)
complex. In this series, the yields of silicon fluorination varied
as a function of hydrocarbon spacer chain length. For all reacꢀ
tion times examined in this hydrocarbon linker series, the opꢀ
timal length was three methylene units (as in 14), which gave
almost quantitative yield after 25 min (Fig. 1).
Table 1. Hydroxyl Group of CENC Improves Silicon
Fluorination of 1
Figure 1. Effect of Hydrocarbon Spacer of CENCs on Siliꢀ
con Fluorination Conversion
entry
1
PTA/CENC
3 (18ꢀCꢀ6)
R
H
conv to 2 (%)
30
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Table 3. Effect of Ethylene Glycol Sideꢀarms of CENCs on
Silicon Fluorination Conversion
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100
80
60
40
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0
25 min
20 min
15 min
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18
19
20
entry
CENC
16
17
18
19
n
1
2
3
ꢀ
ꢀ
ꢀ
conv to 20 (%)
10 min
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5
6
88
52
90
27
12
17
0
1
2
3
4
Carbons (n) in linker
3 (18ꢀCꢀ6)
K 2.2.2
Data are means +/- SD for 3 measurements.
We next sought to ascertain if this trend for CENC sideꢀarm
length extended to other substrates and conditions. To this
end, desilylation experiments were performed with tertꢀ
butyldiphenylsilyl (TPS) protected substrate 21 to form alcoꢀ
hol 22. In this series of experiments, preformed CENC/KF
complexes were used in a twoꢀfold molar ratio to substrate.
Again, CENC 14 (1ꢀhydroxypropyl sideꢀarm) proved most
effective (shortest time) in this desilylation reaction presumaꢀ
bly by more rapidly fluorinating the TPS group (Table 2).
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It was of interest to test the performance of 18 towards a pepꢀ
tidic substrate. Dipeptide 23 was prepared from aldehyde 10
under oxidative amidation conditions. Using CENC 18 with
23 the fluorosilyl dipeptidic product 24 was obtained in 90%
yield without epimerization in just 25 min at room temperature
(Scheme 3).
Scheme 3. Fluorination of Silicon on a Dipeptide Substrate
in the Presence of 18
Table 2. Effect of Hydrocarbon Spacer Length in CENCs
on the Rate of TPS Deprotection
time for complete conꢀ
entry
PTA/CENC
3 (18ꢀCꢀ6)
n
ꢀ
1
2
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4
version to 22 (h)
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38
31
24
15
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4
Radiofluorination reactions
13
14
15
A major drawback of our previously reported NALG approach
(Strategy B Scheme 1) was the poor ability of the NALG to
solubilize noꢀcarrierꢀadded (NCA) [18F]potassium fluoride into
an organic solvent for subsequent reaction. Therefore, it was
of primary interest to test the ability of CENCs to perform
such sequestration. Table 4 compares the abilities of CENCs 4
and 19 with those of 18ꢀCꢀ6 (3) and K 2.2.2 to sequester dried
NCA [18F]potassium fluoride into acetonitrile. CENC 19
showed excellent sequestration ability.
Other CENCs containing an alcoholic sideꢀarm were also preꢀ
pared and examined. The fluorination of 12 using CENCs
containing ethylene glycol sideꢀarms led to substantially enꢀ
hanced conversions in only 10 min (Table 3). These studies
revealed that CENCs with sideꢀarms of one (16) or three ethꢀ
ylene glycol units (18) performed virtually equally well. To
our surprise, a sideꢀarm comprised of two ethylene glycol
units (17) gave a much inferior result. Nevertheless, these
studies revealed substantial improvement over the perforꢀ
mance of traditional PTAs, such 18ꢀCꢀ6 and K 2.2.2.
Table 4. Sequestration efficiencies of NALG, PTA or
CENCs to sequester dry [18F]potassium fluoride into dry
acetonitrile for subsequent reaction
NALG/PTA/CENC
Sequestration
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(%)
<4ꢀ
21±28
70±6
93±3
91±2
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36±7
23±8
29±7
26±7
33±8
38±11
7±4
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NALGs
3 (18ꢀCꢀ6)
4
19
K 2.2.2
ꢀ From reference 8
19
3 + MeOH
3 + HO(CH2)2OH
K 2.2.2
12±3
38±5
9
ꢀMean ± SD, (n = 3)
We proceeded to compare the CENC 19 with K 2.2.2 and 18ꢀ
Cꢀ6 as a PTA for the radiofluorination of 12 (2 mg in 450 ꢀL
of MeCN). Control reactions using K2CO3 in the absence of a
PTA gave < 1% yield. Reactions using varying molecular ratiꢀ
os of K2CO3 to PTA afforded [18F]20 as the only product. Noꢀ
tably, yields of [18F]20 depended on the amount of
K2CO3/PTA (as K+−PTA complex in ꢀmol) (Fig. 2). A lower
amount of K+−PTA in the reaction (1.0 µmol) seemed benefiꢀ
cial, whereas excess base inhibited the reaction. CENC 19
performed slightly better than K 2.2.2 and much better than
18ꢀCꢀ6 as PTA.
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Use of CENCs with hydroxylꢀterminated sideꢀarms (4, 13−19)
clearly improved the yields for silicon radiofluorination over
use of the basal unit 18ꢀCꢀ6 (3). The top performer, 19 with
two –CH2OH sideꢀarm units, rivals the performance of K
2.2.2. By contrast, the simple addition of MeOH (2 eq) or ethꢀ
ylene glycol (1 eq) to 18ꢀCꢀ6 (3), to mimic the chemical comꢀ
position of 19, had detrimental or no effect respectively, on the
radiofluorination yield. CENCs containing a three methylene
unit spacer (14) or three ethylene glycol unit sideꢀarm (18) are
the best CENCs in their respective series. These radiochemisꢀ
try results parallel those from nonꢀradioactive materials conꢀ
ducted at much larger scale and stoichiometry.
Figure 2. Radiofluorination of 12 Using K 2.2.2, 18ꢀCꢀ6 or
19 as phase transfer agent
It was of interest to compare the performance of CENC 19
with that of 18ꢀCꢀ6 (3) for the radiofluorination of the silylꢀ
dipeptidic compound 23 under similar conditions (Table 6).
[18F]24 was the only product. Remarkably, the use of CENC
19 gave 6ꢀfold greater yield than the use of 18ꢀCꢀ6.
40
K+- 19
K+- K 2.2.2
30
K+-18-C-6
Table 6. Radiofluorination of Dipeptide 24
K2CO3 only
20
10
0
0
1
2
3
4
5
K+-PTA complex (ꢀmol)
entry
1
2
CENC
3 (18ꢀCꢀ6)
19
Yield of [18F]24 (%)
2±0.3
12±2
The radiofluorination of substrate 12 was screened with variꢀ
ous CENCs in optimal ratio to base. We selected the following
as standard conditions to evaluate all phase transfer agents in
radiofluorination: K2CO3/CENC (0.66/1.32 µmol), substrate (2
mg), solvent (MeCN, 450 ꢀL), reaction temperature (rt) and
reaction time (20 min). Some of these conditions were chosen
to closely resemble the conditions used for conversion measꢀ
urements earlier illustrated in Figure 1 and Table 3. [18F]20
was the only product (see Supplemental Fig. S1 for an examꢀ
ple of chromatogram). Yields are summarized in Table 5, and
are based on isolated product fraction from HPLC.
Mean± SD (n = 3)
Mechanistic considerations
Our studies on the mechanism of rate enhancement afforded
by our CENCs over 18ꢀCꢀ6 (3) are at an early stage. Our curꢀ
rent rationale is that the hydroxyl group of the lariat side arm
initially attacks the silicon center to give a pentacoordinate
intermediate such as A or B (Fig. 3). Studies by Corriu and
coworkers demonstrate that various silicon substitution reacꢀ
tions involving R3SiX were catalytically accelerated by Lewis
bases such as HMPA, carboxylates, and DMSO. These agents
led to the formation of a pentacoordinate silicon intermediate,
which proved to be reactive towards nucleophiles leading to a
hexacoordinate intermediate, which rapidly collapsed to give
substitution product.11 Others have shown that pentacoordinate
Table 5. Screening of CENCs or other PTA systems in Raꢀ
diofluorination of 12 to Afford [18F]20
entry
CENC/PTA
3 (18ꢀCꢀ6)
Yield of [18F]20ꢀ(%)
1
2
3
14±4
35±2
30±7
4
13
4
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sextet, sept = septet, m = multiplet; coupling constants in
silicon anions are exceptionally stabilized by an 18ꢀCꢀ6/K+
counter ion complex.15
Hertz (Hz). 13C{1H} NMR were measured on a 100 MHz
spectrometer. Chemical shifts are reported as δ (ppm) relative
to signal for TMS using solvent as an internal standard (CDCl3
at δ 77.0 or CD3CN at δ 1.39 and 118.69 ppm). Highꢀ
resolution mass spectra were recorded by an ESIꢀTOF MS
spectrometer (DART ion source). All reagents were obtained
commercially and were used without further purification. Solꢀ
vents were purchased in an anhydrous state, or purified and
dried as required.
1
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3
4
Figure 3. Possible Rationale for Enhanced Reactivity of
CENCs
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General procedure for synthesis of silane precursors:
A solution of bromophenyl/biphenyl substrate (1.0 eq.) in THF
(0.5 M) was chilled to −78 °C. nꢀBuLi (1.6 M in hexanes, 1.0
eq.) was added over 10 min. The mixture was stirred for 30
min at −78 °C, after which chlorodiisopropylsilane (1.0 eq.)
was slowly added via syringe. After 1 h, the iceꢀbath was reꢀ
moved and the solution was allowed to warm to rt with stirring
overnight. The reaction was quenched with saturated aq.
NH4Cl (5.0 mL) and extracted with ether (20 mL × 3). The
combined organic extracts were washed with brine, dried
(Na2SO4), filtered, and concentrated in vacuo to yield a lightꢀ
yellow oil which was purified by flash chromatography (1%
EtOAc/hexane), affording the product as a colorless oil.
Based on these precedents, it is possible that an initial hydroxꢀ
yl group attack is favorable due to a stabilizing interaction of
the nearby 18ꢀCꢀ6/K+ moiety with the silicon anion center
(Fig. 3). In this scenario, one might expect there to be an opꢀ
timal distance between the hydroxyl group and the crown
ether. With a hydrocarbon unit linking the hydroxyl group and
macrocyclic ether, the optimal distance appears to be three
methylene units. By contrast, an oligoether linker likely particꢀ
ipates in chelating interactions with the potassium cation perꢀ
haps affording additional stabilizing interactions. This may
explain the appreciable rate enhancement observed in the
fluorinations of agents 14 and 18 (Tables 2 and 3).
[1,1'ꢀBiphenyl]ꢀ4ꢀyldiisopropylsilane: Yield: 2.98 g (94%);
1H NMR (CDCl3): δ (ppm) 1.06 (d, J = 7.2 Hz, 6H), 1.13 (d, J
= 7.2 Hz, 6H), 1.24−1.34 (m, 2H), 4.02 (t, J = 3.2 Hz, 1H),
7.35−7.39 (m, 1H), 7.45−7.49 (m, 2H), 7.62−7.66 (m, 6H);
13C NMR (CDCl3): δ (ppm) 11.0(2C), 18.8(2C), 18.9(2C),
126.6(2C), 127.4(2C), 127.6, 129.0(2C), 133.1, 136.2(2C),
141.3, 141.9. ESIꢀHRMS: m/z [M+H] calcd for C18H24Si:
269.1726; found 269.1722.
CONCLUSION
We developed new 18ꢀCꢀ6ꢀbased CENCs giving high
[18F]potassium fluoride sequestration efficiency and rapid
fluorinations and radiofluorinations of organosilicon comꢀ
pounds under mild conditions. A key feature of these ionoꢀ
phoric agents is that they contain a sideꢀarm terminating in a
hydroxyl group, which may activate the silicon towards fluorꢀ
ination. Our studies of these CENCs demonstrate that the
length of the sideꢀarm correlates with the rate of silicon fluoriꢀ
nation. These observations are rationalized based on stabilizaꢀ
tion of a hypervalent silicon intermediate by an intramolecuꢀ
larly proximal potassium/18ꢀCꢀ6 complex.
Diisopropyl(4ꢀ(((tetrahydroꢀ2Hꢀpyranꢀ2ꢀyl)ꢀoxy)ꢀmethyl)ꢀ
1
phenyl)ꢀsilane (8): Yield: 1.88 g (92%); H NMR (CDCl3): δ
(ppm) 0.99 (d, J = 7.2 Hz, 6H), 1.06 (d, J = 7.2 Hz, 6H),
1.17−1.27 (m, 2H), 1.54−1.92 (m, 6H), 3.54−3.58 (m, 1H),
3.91−3.96 (m, 2H), 4.50 (d, J = 12.4 Hz, 1H), 4.74 (t, J = 4.0
Hz, 1H), 4.80 (d, J = 12.4 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H),
7.50 (d, J = 8.0 Hz, 2H); 13C NMR (CDCl3): δ (ppm)
10.9(2C), 18.7(2C), 18.9(2C), 19.6, 25.7, 30.8, 62.3, 69.1,
98.1, 127.2(2C), 133.4, 135.8(2C), 139.4. NMR data of this
b
material were consistent with reported values.4
EXPERIMENTAL SECTION
Procedure to synthesize 4ꢀ(diisopropylsilyl)ꢀbenzaldehyde
(9): To a solution THP ether 8 (1.0 eq.) in ethanol (13
mL/mmol) was added pꢀtoluenesulfonic acid monohydrate
(1.0 eq.) and the mixture was stirred for 2 h at rt. The mixture
was added to saturated aq. sodium bicarbonate and extracted
with CH2Cl2. The combined organic extracts were washed
with brine and dried (Na2SO4). After filtration and removal of
the solvent, the crude alcohol was used directly in the next
General Information: Reactions were performed in ovenꢀ
dried glassware with magnetic stirring under an argon atmosꢀ
phere (unless otherwise stated). Reaction products were puriꢀ
fied with flash chromatography on silica gel (40−63 ꢁm). Exꢀ
tracts were concentrated with a rotary evaporator (bath temꢀ
peratures up to 30 °C) at a pressure of either 15 mmHg (diaꢀ
phragm pump) or 0.1 mmHg (oil pump), as appropriate, and a
1
step. Yield: 1.36 g (100%); H NMR (CDCl3): δ (ppm) 0.99
high vacuum line at rt. Analytical thinꢀlayer chromatography
(d, J = 7.2 Hz, 6H), 1.06 (d, J = 7.2 Hz, 6H), 1.18−1.28 (m,
2H), 1.90 (brs, 1H), 3.95 (t, J = 3.2 Hz, 1H), 4.69 (s, 2H), 7.35
(d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H); 13C NMR
was performed on silica gel 60 Fꢀ254 plates (200 ꢁm). Plates
were visualized under UV light (254 or 365 nm), followed by
staining with vanillin, or potassium permanganate or silica/I2
and drying with a heat gun. 1H NMR spectra were acquired on
a 400 MHz spectrometer and are reported as δ in ppm relative
to TMS using solvent as an internal standard (CDCl3 at δ 7.26
or CD3CN at δ 1.94 ppm). Data are reported as br = broad, s =
singlet, d = doublet, t = triplet, q = quartet, p = pentet, sext =
(CDCl3):
δ (ppm) 10.9(2C), 18.7(2C), 18.9(2C), 65.6,
126.5(2C), 133.7, 135.9(2C), 141.9. NMR data of this material
were consistent with reported values.16
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A solution of alcohol (1.0 eq.) in dry CH2Cl2 (0.4 M) was addꢀ 172.6. ESIꢀHRMS: m/z [M+H] calcd for C14H22O3Si:
1
2
3
4
5
6
7
8
ed to a suspension of activated MnO2 (10 eq.) in dry CH2Cl2
(3.8 mL/mmol) at rt, and the mixture was stirred for 5 h. The
black residue was filtered on a pad of celite and washed thorꢀ
oughly with CH2Cl2. The collected organic layer was passed
through a silica gel bed. The filtrate was evaporated in vacuo
to give the aldehyde as a colorless oil. Yield: 1.08 g (80%); 1H
NMR (CDCl3): δ (ppm) 0.98 (d, J = 7.2 Hz, 6H), 1.07 (d, J =
7.2 Hz, 6H), 1.21−1.31 (m, 2H), 3.99 (t, J = 3.2 Hz, 1H), 7.69
267.1411; found 267.1407.
General procedure for oxidative amidations: Aldehyde 10
(1.0 eq.), amine (1.5 eq.) and 2ꢀmethylbutꢀ2ꢀene (5.0 eq.) were
added to toluene (0.6 M) and allowed to stir for 5 min. NaClO2
(3.125 eq.) and NaH2PO4 (3.5 eq.) were then added to the mixꢀ
o
ture, which was then stirred at 40 C for 15–26 h. Reaction
progress was monitored with TLC. After the reaction was
complete, the mixture was diluted with anhydrous CH2Cl2 (5.0
mL), filtered and concentrated under reduced pressure. The
residue was purified with flash chromatography (5−10%
EtOAc/hexane) to afford the product as a gum.
(d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H), 10.02 (s, 1H); 13
C
9
NMR (CDCl3):
δ (ppm) 10.8(2C), 18.6(2C), 18.8(2C),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
128.7(2C), 136.2 (2C), 136.9, 143.4, 192.9. NMR data of this
material were consistent with reported values.16
NꢀBenzylꢀ4ꢀ(diisopropyl(methoxy)silyl)ꢀbenzamide
(12):
General procedure for the synthesis of silyl ethers: To a
suspension of trichloroisocyanuric acid (0.33 eq.) in CH2Cl2
(0.3 M) was added the previously synthesized silane (1.0 eq.)
1
Yield: 1.19 g (75%); H NMR (CDCl3): δ (ppm) 1.00 (d, J =
7.2 Hz, 6H), 1.06 (d, J = 7.2 Hz, 6H), 1.30 (sept, J = 7.2 Hz,
2H), 3.62 (s, 3H), 4.65 (d, J = 5.6 Hz, 2H), 6.57 (brs, 1H),
7.28−7.35 (m, 5H), 7.61 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0
Hz, 2H); 13C NMR (CDCl3): δ (ppm) 12.1(2C), 17.4(2C),
17.6(2C), 44.3, 52.3, 126.2(2C), 127.8, 128.1(2C), 129.0(2C),
135.0(2C), 135.2, 138.4, 139.1, 167.8. ESIꢀHRMS: m/z
[M+H] calcd for C21H29NO2Si: 356.2040; found 356.2038.
o
in CH2Cl2 (0.5 M) at 0 C under N2 atmosphere. The mixture
was stirred for 1 h at rt. Then the white solid was filtered off
through a short pad of celite. The filtrate was concentrated
under reduced pressure to give the chlorosilane, which is unꢀ
stable. Therefore, this product was used immediately in the
next step, as follows. A solution of the chlorosilane (1.1 eq.) in
o
CH2Cl2 (0.5 M) at 0 C under N2 atmosphere was added to a
Methyl
(4ꢀ(diisopropyl(methoxy)silyl)benzoyl)glycylꢀLꢀ
phenylalaninate (23): Yield: 0.18 g (65%); 1H NMR (CDCl3):
δ (ppm) 1.00 (d, J = 7.2 Hz, 6H), 1.06 (d, J = 7.2 Hz, 6H),
1.31 (sept, J = 8.0 Hz, 2H), 3.05−3.18 (m, 2H), 3.63 (s, 3H),
3.72 (s, 3H), 4.11 (s, 2H), 4.85−4.90 (m, 1H), 6.80 (d, J = 8.0
Hz, 1H), 7.07−7.17 (m, 5H), 7.62 (d, J = 8.0 Hz, 2H), 7.79 (d,
J = 8.0 Hz, 2H); 13C NMR (CDCl3): δ (ppm) 12.1(2C),
17.4(2C), 17.6(2C), 38.0, 43.7, 52.7, 53.5, 126.3(2C), 127.4,
128.9(2C), 129.4(2C), 134.2, 135.0(2C), 135.8, 139.6, 168.1,
168.9, 171.9. ESIꢀHRMS: m/z [M+H] calcd for C26H36N2O5Si:
485.2466; found 485.2464.
mixture of corresponding alcohol (1.0 eq.) and imidazole (1.2
eq.) in CH2Cl2 (0.3 M). The mixture was warmed to rt and
stirred for 4 h. After filtering off the white solid, the filtrate
was concentrated and purified with flash column chromatogꢀ
raphy (5% EtOAc/hexane) to give product as a colorless oil.
[1,1'ꢀBiphenyl]ꢀ4ꢀyldiisopropyl(methoxy)ꢀsilane (1): Yield:
1
3.18 g (96%); H NMR (CDCl3): δ (ppm) 1.12 (d, J = 7.2 Hz,
6H), 1.17 (d, J = 7.2 Hz, 6H), 1.39 (sept, J = 7.2 Hz, 2H), 3.70
(s, 3H), 7.37−7.41 (m, 1H), 7.47−7.51 (m, 2H), 7.66−7.70 (m,
6H); 13C NMR (CDCl3): δ (ppm) 12.3(2C), 17.6(2C),
17.8(2C), 52.4, 126.6(2C), 127.4(2C), 127.7, 129.0(2C),
133.1, 135.4(2C), 141.3, 142.2. ESIꢀHRMS: m/z [M+H] calcd
for C19H26OSi: 299.1826; found 299.1821.
Procedure to synthesize 2ꢀmethoxymethylꢀ18ꢀCꢀ6 (5): 2ꢀ
hydroxymethylꢀ18ꢀCꢀ6 4 (1.0 eq.) was added to a suspension
of NaH (1.5 eq) in THF (0.1 M) and the mixture was stirred
for 2 h. Methyl iodide (2.0 eq.) was added, and the mixture
was stirred for 20 h and then refluxed for 10 h. The cooled
solution was then concentrated under reduced pressure and
purified with flash chromatography on neutral alumina using
EtOAc as eluent to afford product as a colorless oil. Yield:
0.23 g (59%); 1H NMR (CDCl3): δ (ppm) 3.31 (s, 3H),
3.52−3.69 (m, 24H), 3.81−3.85 (m, 1H); 13C NMR (CDCl3): δ
(ppm) 59.4, 68.4, 70.0, 70.03 (4C), 70.11 70.13, 70.4, 70.5,
71.6, 71.65, 77.6. Proton and carbon NMR data of this materiꢀ
al were consistent with reported values.17
4ꢀ(Diisopropyl(methoxy)ꢀsilyl)ꢀbenzaldehyde (10): Yield:
1
1.10 g (90%); H NMR (CDCl3): δ (ppm) 1.00 (d, J = 7.2 Hz,
6H), 1.07 (d, J = 7.2 Hz, 6H), 1.32 (sept, J = 7.2 Hz, 2H), 3.64
(s, 3H), 7.72 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 8.0 Hz, 2H),
10.03 (s, 1H); 13C NMR (CDCl3): δ (ppm) 12.1(2C), 17.4(2C),
17.5(2C), 52.4, 128.7(2C), 135.3(2C), 137.0, 143.3, 192.9.
ESIꢀHRMS: m/z [M+H] calcd for C14H22O2Si: 251.1467;
found 251.1464.
Procedure
to
synthesize
4ꢀ
(diisopropyl(methoxy)silyl)benzoic acid (11): The aldehyde
t
Procedure to synthesize 18ꢀCꢀ6ꢀmethyloxyꢀethoxyꢀethoxyꢀ
ethanol (18): The compound 18, a colorless oil, was prepared
using the standard reported procedure.14 Yield: 2.59 g (48%);
1H NMR (CDCl3): δ (ppm) 2.79 (brs, 1H), 3.55−3.82 (m,
37H); 13C NMR (CDCl3): δ (ppm) 61.7, 69.9, 70.3, 70.5,
70.58, 70.59, 70.61, 70.65, 70.67, 70.7, 70.75 (2C), 70.81,
70.82, 70.84, 71.3, 71.6, 72.5, 78.3. ESIꢀHRMS: m/z [M+H]
calcd for C19H38O10: 427.2543; found 427.2538.
10 (1.0 eq.) was dissolved in a mixture of BuOHꢀacetonitrile
(2:1, 0.03 M) and 2ꢀmethylꢀ1ꢀbutene (5.0 eq.) was added. The
o
mixture was cooled to 0 C. NaH2PO4 (3.5 eq.) and NaClO2
(3.125 eq.) were then added. The mixture was then slowly
warmed to rt over 5 h before it was quenched with saturated
Na2S2O3. After common workꢀup, the obtained product was
dissolved in dry CH2Cl2 (2 mL) and purified with flash chroꢀ
matography (5−20% EtOAc/hexane) to furnish product as a
1
colorless oil. Yield: 0.45 g (65%); H NMR (CDCl3): δ (ppm)
General procedure for fluorination: In an ovenꢀdried vial
purged with argon was added a CENC (0.10 mmol) and anhyꢀ
drous KF (0.10 mmol) in anhydrous MeCN (0.5 mL). After
the complexation reaction, the solvent was removed under
vacuum and the residue was kept under high vacuum overꢀ
1.02 (d, J = 7.2 Hz, 6H), 1.08 (d, J = 7.2 Hz, 6H), 1.33 (sept, J
= 7.2 Hz, 2H), 3.65 (s, 3H), 7.68 (d, J = 8.0 Hz, 2H), 8.11 (d, J
= 8.0 Hz, 2H); 13C NMR (CDCl3): δ (ppm) 12.1(2C),
17.4(2C), 17.6(2C), 129.1(2C), 130.5, 134.9(2C), 142.2,
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night followed by discharging under argon for 15 min. A soluꢀ
ACKNOWLEDGMENT
1
2
3
4
5
6
7
8
tion of silyl ether substrate (0.20 mmol) in anhydrous CD3CN
(0.1 M) was added to the CENC/KF complex. The mixture
This work was supported by grants from the National Instiꢀ
tutes Health (MH087932 and GM110651). BYY, SL, and
VWP were supported by the Intramural Research Program of
the National Institutes of Health (NIMH, ZIA MH002793).
The authors are grateful to the NIH Clinical PET Center for
the cyclotron production of fluorineꢀ18.
1
was directly transferred in a dry NMR tube and the H NMR
was acquired in 5 min intervals up to 25 min. The percent
conversions were then estimated based on comparisons of
1
integrations of the isopropyl group signals in the H NMR of
starting material versus product. Compounds 20 and 24 were
also characterized in solution by LC/MS because of their inꢀ
stabilities in the absence of solvent. (see SI for more details).
REFERENCES
9
(1) Wangler, C.; Kostikov, A.; Zhu, J.; Chin, J.; Wangler, B.;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure for radiofluorination: Noꢀcarrierꢀadded
(NCA) [18F]fluoride ion was obtained through the 18O(p,n)18F
nuclear reaction by irradiating [18O]water (95 atom %) for 90–
120 min with a proton beam (17 MeV; 20 ꢁA) generated with
a PETrace cyclotron (GE Medical Systems, Milwaukee, WI).
Cyclotronꢀproduced NCA [18F]fluoride ion (1.1−3.7 GBq) in
[18O]water (150−250 µL), and K2CO3/PTA stock solution
(0.66/1.32 ꢁmol; 15 µL) were loaded into a 5ꢀmL glass Vꢀvial.
MeCN (500 µL) was added and water/MeCN was azeotropiꢀ
cally removed at 110 oC under a stream of N2 gas (200
mL/min) and vacuum (< 20 mmHg). The azeotropic process
was repeated three more times to obtain dry [18F]fluoride ion
agent. The vial was cooled with several dryꢀice pellets over 4
min to rt. A solution of 12 or 23 (2.0 mg) was dissolved in
MeCN (450 µL) and transferred to the drying vial at rt. The
reaction mixture was allowed to stand at rt for 20 min before
dilution with water (1 mL) and injected onto a semiꢀ
preparative scale HPLC column (Luna C18, 10 ꢀm, 250 × 10
mm) for separation of products. The reaction mixture was
eluted at 6 mL/min, with a mixture of aq. ammonium formate
(A, 25 mM) and MeCN (B), with B initially 40% for 3 min,
and then increasing linearly to 90% over 2 min. The fractions
at tR = 14.7− 14.9 min ([18F]20) or 13.4−13.9 min ([18F]24)
were collected and measured for radioactivity. Identities of
[18F]20 and [18F]24 were verified by LCꢀMS analysis of assoꢀ
ciated carrier as m/z = 344.2 and 473.2 for [M++H], respecꢀ
tively.
Schirrmacher, R. Appl. Sci. 2012, 2, 277.
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Berends, L.; Wangler, C.; Zoller, T.; Hofner, G.; Wanner, K.
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For radiofluorination in the presence of added MeOH or ethꢀ
ylene glycol, the alcohol was added along with 12.
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ASSOCIATED CONTENT
1
Supporting Information. Copies of H and 13C NMR spectra of
all new compounds. NMRꢀbased percent conversion silicon fluorꢀ
ination data. HPLC chromatograms of [18F]20 and [18F]24. This
material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
†* Eꢀmail: slepore@fau.edu
‡* Eꢀmail: shuiyu.lu@mail.nih.gov
(5) Cai, L. S.; Lu, S. Y.; Pike, V. W. Eur. J. Org. Chem. 2008,
2853.
Author Contributions
§These authors contributed equally.
(6) For example, the radiofluorinations of some ethoxysilanes
were recently achieved with a solution of [18F]fluoride ionꢀ
quaternary ammonium salt in 2% acetic acidꢀDMSO at 90 °C
for 23 minutes: Balentova, E.; Collet, C.; LamandéꢀLangle, S.;
Notes
The authors declare no competing financial interest.
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Chrétien, F.; Thonon, D.; Aerts, J.; Lemaire, C.; Luxen, A.; Casnati, A.; Mandolini, L.; Salvio, R.; Sansone, F.; Ungaro, R.
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Fluorine Chem. 2014, 158, 4.
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