Quinuclidine and DABCO Enhance the Radiofluorination of 5-Substituted 2-Halopyridines

Article abstract of DOI:10.1002/ejoc.201700970

Positron emission tomography (PET) is an important molecular imaging technique for medical diagnosis, biomedical research and drug development. PET tracers for molecular imaging contain β⁺-emitting radionuclides, such as carbon-11 (t_1/2 = 20.4 min) or fluorine-18 (t_1/2 = 109.8 min). The [¹⁸F]2-fluoropyridyl moiety features in a few prominent PET radiotracers, not least because this moiety is usually resistant to unwanted radiodefluorination in vivo. Various methods have been developed for labeling these radiotracers from cyclotron-produced no-carrier-added [¹⁸F]fluoride ion, mainly based on substitution of a leaving group, such as halide (Cl or Br), or preferably a better leaving group, such as nitro or trimethylammonium. However, precursors with a good leaving group are sometimes more challenging or lengthy to prepare. Methods for enhancing the reactivity of more readily accessible 2-halopyridyl precursors are therefore desirable, especially for early radiotracer screening programs that may require the quick labeling of several homologous radiotracer candidates. In this work, we explored a wide range of additives for beneficial effect on nucleophilic substitution by [¹⁸F]fluoride ion in 5-substituted 2-halopyridines (halo = Cl or Br). The nucleophilic cyclic tertiary amines, quinuclidine and DABCO, proved effective for increasing yields to practically useful levels (> 15 %). Quinuclidine and DABCO likely promote radiofluorination through reversible formation of quaternary ammonium intermediates.

Full text of DOI:10.1002/ejoc.201700970

A Journal of
Accepted Article
Title: Quinuclidine and DABCO Enhance the Radiofluorinations of 5-
Substituted 2-Halo-pyridines
Authors: Gregory Naumiec, Lisheng Cai, Shuiyu Lu, and Victor W Pike
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10.1002/ejoc.201700970
European Journal of Organic Chemistry
Quinuclidine and DABCO Enhance the Radiofluorinations of 5-Substituted 2-
Halopyridines
Gregory R. Naumiec, Lisheng Cai, Shuiyu Lu, and Victor W. Pike*
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health,
Building 10, Rm B3C346, 10 Center Drive, Bethesda, MD 20892-1003, USA.

Fax: 301 480 5112; email: pikev@mail.nih.gov
1
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European Journal of Organic Chemistry
ABSTRACT. Positron emission tomography (PET) is an important molecular imaging technique
for medical diagnosis, biomedical research and drug development. PET tracers for molecular
imaging contain β+-emitting radionuclides, such as carbon-11 (t1/2 = 20.4 min) or fluorine-18 (t1/2
= 109.8 min). The [18F]2-fluoro-pyridyl moiety features in a few prominent PET radiotracers, not
least because this moiety is usually resistant to unwanted radiodefluorination in vivo. Various
methods have been developed for labeling these radiotracers from cyclotron-produced no-carrier-
added [18F]fluoride ion, mainly based on substitution of a leaving group, such as halide (Cl or Br),
or preferably a better leaving group, such as nitro or trimethylammonium. However, precursors
with a good leaving group are sometimes more challenging or lengthy to prepare. Methods for
enhancing the reactivity of more readily accessible 2-halopyridyl precursors are therefore
desirable, especially for early radiotracer screening programs that may require the quick labeling
of several homologous radiotracer candidates. In this work, we explored a wide range of additives
for beneficial effect on nucleophilic substitution by [18F]fluoride ion in 5-subsituted 2-
halopyridines (halo = Cl or Br). The nucleophilic cyclic tertiary amines, quinuclidine and
DABCO, proved effective for increasing yields to practically useful levels (> 15%). Quinuclidine
and DABCO likely promote radiofluorination through reversible formation of quaternary
ammonium intermediates.
Keywords: fluorine-18; radiofluorination; organocatalysis; 2-halopyridine; reactive
intermediates
2
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Introduction
Positron emission tomography (PET) is a molecular imaging modality that has increasing
importance for medical diagnosis, biomedical research[1,2] and drug development.[3,4] The scope
of PET for such applications very much depends on the development of radiotracers that are either
able to interact with a single specific protein to provide robust information on protein distribution,
protein function, or protein interaction with existing or experimental drugs, or that report on
metabolic or signal transduction processes, such as [18F]FDG for glycolysis and [18F]FDOPA for
the presynaptic dopaminergic system. Consequently, a demand for new radiotracers is ever
present. Successful PET radiotracers must satisfy a broad array of criteria with regard to
physicochemical, pharmacokinetic and pharmacological properties and therefore typically many
candidates must be screened to find a high performing radiotracer for a particular protein target.[5]
Usually PET radiotracers are labeled with a cyclotron-produced short-lived radionuclide,
such as carbon-11 (t1/2 = 20.4 min) or fluorine-18 (t1/2 = 109.8 min). 18F-Labeled radiotracers are
especially attractive because, unlike 11C-labeled radiotracers, they may be transported over
considerable distances to imaging sites that do not have a cyclotron. Moreover, fluorine-18 is
available as [18F]fluoride ion in high activity and in high (no-carrier-added; NCA) molar activity
18
18
(ratio of activity to mass) from the O(p,n)18F nuclear reaction on O-enriched water.[6] 18F-
Labeled tracers should be designed to resist extensive defluorination in vivo.[5] Otherwise the
generated [18F]fluoride ion binds avidly to bones, causing unnecessary radiation exposure of
healthy tissue as well as spillover effects.[5,7] A feature of the [18F]2-fluoro-pyridyl moiety is its
metabolic stability.[5,7] Therefore, there are notable examples of effective PET radiotracers that
contain this moiety. These include [18F]AZD4694 ([18F]1) for imaging Aβ-amyloid,[8] [18F]T807
([18F]2) for imaging neurofibrillary tangles,[9,10] [18F]NCFHEB ([18F]3) for imaging α4β2-nicotinic
3
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10.1002/ejoc.201700970
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acetylcholine receptors,[11,12] and [18F]fluoroisonicotinamide ([18F]4) for imaging melanoma[13]
(Figure 1).
Figure 1. Examples of PET radiotracers containing an [18F]2-fluoropyridyl moiety.
Reliable radiosyntheses of [18F]2-fluoropyridyl compounds from NCA [18F]fluoride ion
are based on aromatic nucleophilic substitution of good leaving groups.[14−27] The effectiveness of
the leaving group in radiofluorination follows the order: halide (Cl or Br) < nitro <
trimethylammonium.[19,27] Yields from 2-chloro or 2-bromo-pyridines are not however always
adequate for early candidate radiotracer evaluation experiments. Furthermore, the synthesis of
precursors with 2-trimethylammonium as a leaving group on a pyridyl ring, especially when
additional amino groups are present, can be challenging or lengthy. Although new methods have
been introduced recently for labeling pyridines in 2-position with fluorine-18 using precursors
such as diaryl sulfoxides[28] or diaryliodonium salts,[29] the preparation of these precursors usually
requires halopyridines as starting materials (Figure 2). Therefore, to enable the rapid screening of
homologous candidate PET radiotracers, methods for improving the radiosyntheses of [18F]2-
fluoropyridines directly from 2-halopyridyl precursors are desirable. Here we show that DABCO
4
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10.1002/ejoc.201700970
European Journal of Organic Chemistry
and quinuclidine activate substituted 2-halopyridines for nucleophilic substitution with
[18F]fluoride ion to improve significantly radiochemical yields of [18F]2-fluoropyridines.
Figure 2. Known methods for labeling pyridines in 2-position with [18F]fluoride ion.
Results and discussion
Syntheses of precursors and reference compounds. 6-(6-Chloropyridin-3-yl)naphthalen-2-
amine (5) and its 6-fluoro analog (6) were obtained in moderate yields by Suzuki coupling of the
respective 6-halopyridin-3-ylboronic acids with 6-bromonaphthalen-2-amine (Figure 3).
Treatment of amines 5 or 6 with Boc anhydride then gave the respective Boc-protected compounds
7 or 8 in high yields.
Figure 3. Syntheses of 6-(6-halopyridin-3-yl)naphthalene-2-amines and their N-Boc derivatives.
5
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Other halopyridyl precursors (halo = Cl or Br) or reference 2-fluoropyridyl compounds
were obtained commercially, or synthesized by well-known single-step general methods (Figure
4). Thus, 2-halo-5-alkoxy-pyridines were prepared through nucleophilic substitution in alkyl
iodides with 2-halo-5-hydroxypyridines under basic conditions. 2-Halo-5-aryloxy-pyridines were
prepared using copper salts as catalysts from iodoarenes. Suzuki coupling was used to prepare
several 2-halo-5-aryl-pyridines from halo-pyridines.
Figure 4. Methods used to prepare 5-substituted-2-halopyridines.
The quaternary salt 17 was prepared from commercially available 6-bromonaphthalen-2-
amine. First, the Boc-protected derivative (14) was prepared to facilitate the synthesis of the
boronic ester (15) through Pd-catalyzed borylation. Use of Pd(PPh3)4 plus KOAc in dioxane at 98
ºC for 72 h gave 15 as a clean product in high yield (81%). Pd(PPh3)4 was also effective for
coupling 15 with 3-bromopyridine oxide to give crude 16. Finally, immediate treatment of crude
16 with (CF3CO)2O in the presence of DABCO gave 17, which was then purified with HPLC.
6
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10.1002/ejoc.201700970
European Journal of Organic Chemistry
Figure 5. Synthesis of the quaternary ammonium salt, 17.
Exploration of additives to increase radiolabeling efficiency. As part of our ongoing
program to develop PET radiotracers for imaging neurofibrillary tangles,[30] we were initially
interested in the radiofluorination of tert-butyl (6-(6-chloropyridin-3-yl)naphthalen-2-
yl)carbamate (7) to produce [18F]6-(6-fluoropyridin-3-yl)naphthalen-2-amine ([18F]6) in two steps,
18
namely radiofluorination with F--K+-K 2.2.2 followed by removal of the Boc protecting group
(Table 1). This labeling strategy gave no [18F]6 in DMF at 120 °C (entry 1) or in DMSO at 200
°C (entry 2) and very low yield in DMSO at 220 °C (entry 3). Consequently, we considered
whether we might be able to promote the reaction with a suitable additive. We noted that DABCO
(1,4-diazabicyclo[2.2.2.]octane) has been reported to catalyze the substitution of chloro leaving
groups in heteroarenes by various non-halide nucleophiles as in, for example, the reaction of 2,6-
7
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dichloronicotinate with phenols,[31] and the reactions of 2-chloropyrimidines with hydroxide or
alkoxide ions.[32,33] A beneficial effect of DABCO on the preparation of 18F-labeled
trifluoroacetamides,[34] and the application of a DABCO-derived precursor for the preparation of
6-[18F]fluoronicotinaldehyde,[35] have also been reported. We therefore decided to explore
whether added DABCO might promote the radiofluorination of 7.
No [18F]6 was obtained when DABCO was used as additive in solvents of quite similar
polarity (Et value), but somewhat lower dielectric constant (), such as DMF, t-BuOH, or NMP
(Table 1, entries 4−6). DABCO altered the yield of [18F]6 in a concentration-dependent manner
for reactions performed in DMSO (entries 7−10). An increase of DABCO concentration from 34
to 140 mM for reactions at 200 °C increased the yield from 9 to 43% (entries 7 and 8). However,
further increases in DABCO concentration gave reduced yields (entries 9 and 10). The yield of
[18F]6 was optimal when DABCO was in 8-fold molar ratio to precursor 7. Dibasic DABCO gave
better yield enhancement to monobasic quinuclidine at a higher concentration in DMSO at 180 °C
for 30 min (entries 11 and 12). Because reactions were only successful in DMSO, this solvent was
used throughout further experiments.
Table 1. Effect of additives on the yields of the radiofluorination of 7 [2.82 µmol (1 mg), in 0.7 mL solvent ≡ 4 mM]
to give [18F]6.
Entry
Additive
Additive conc.
(mM)
Solvent
Temp.
(C)
Time
(min)
Yield of [18F]6
(%)
1
2
3
4
None
None
None
DMF
120
200
220
120
30
30
30
30
0
0
8
0
DMSO
DMSO
DMF
260
140
= DABCO
DABCO
5
t-BuOH
120
30
0
8
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6
7
8
9
10
11
12
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
260
34
NMP
200
200
200
200
200
180
180
15
15
15
15
15
30
30
0
9
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
140
260
2500
130
300
43
33
19
20
13
= quinuclidine
Tolerance of aryl amino groups. We noticed that the Boc protecting group was removed
during the two-step radiosynthesis of [18F]6 when the reaction temperature was above 150 °C. The
necessity for there to be a Boc protecting group in the precursor was therefore questionable.
Consequently, we wondered if quinuclidine or DABCO would enhance radiofluorination yields
even in the presence of a hydrogen bond donor such as a free aryl amino group. We tested the
radiofluorination of the corresponding unprotected precursor 5 in the presence of additive (Table
2). Under similar conditions of temperature and time, dibasic DABCO gave about the same yield
of [18F]6 as monobasic quinuclidine at a higher concentration (compare entries 2 and 1). The yield
increased with the concentration of DABCO and with reaction temperature (entries 2 to 4), to 30%
(entry 4) which was similar to that reached when precursor was Boc-protected (33%; Table 1,
entry 9). Therefore, the Boc protecting group was deemed unnecessary in further experiments.
Table 2. Tolerance for hydrogen-donor group in the radiofluorination of 5 [1.0 mg (3.93 µmol) in 0.7 mL solvent] to
give [18F]6.
Entry
Additive
Additive
conc.
(mM)
Temp.
Time
(min)
Yield of
[18F]6
(C)
(%)
14
15
1
2
Quinuclidine 200
DABCO 130
120
120
30
30
9
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3
4
DABCO
DABCO
160
250
150
200
30
15
28a
30
a In this example, we isolated 925 MBq of [18F]6 with a molar activity of 78 GBq/µmol.
The preceding labeling experiments were performed in septum-sealed glass reaction vials.
We have previously used a microfluidic apparatus (Nanotek; Advion) as a convenient platform for
rapidly investigating single-step radiofluorination reactions with tight control of reaction
temperature, time, and concentrations of reactants.[36] Further experiments were performed with
this apparatus. So as to attain 30 min reaction time, we used a “stopped flow” procedure to conduct
further investigations. In this apparatus, the single-step radiosynthesis of [18F]6 at 200 °C showed
optimal yield at 100 mM concentration of quinuclidine (Figure 6). This pattern of yields versus
additive concentration was similar to that from radiofluorinations of 7 in a conventional reaction
vial (Table 1).
18F
Cl
18F-
N
N
K+- K 2.2.2
quinuclidine
DMSO
200 oC, 30 min
microreactor
NH2
NH2
[18F]6
5
40
30
20
10
0
0
50
100
150
200
Quinuclidine (mM)
10
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Figure 6. The effect of quinuclidine concentration on yield of [18F]6 at a precursor concentration of 8.7 mM at 200
C in a Nanotek microfluidic apparatus.
The influences of added DABCO or quinuclidine at 100 mM concentration on yields of
[18F]6 from 5 at three temperatures were further evaluated in the microfluidic apparatus (Figure
7). We were further interested in whether yield enhancement was more strongly related to additive
basicity or nucleophilicity. Therefore, we examined other organic amines, namely triethylamine,
a strong base but a weaker nucleophile than either DABCO or quinuclidine, and also DBU, DMAP
and TMG, all weak nucleophiles but strong bases.[37] Generally, yields increased with
nucleophilicity rather than the basicity of the added amine. At 200 C, TEA slightly increased the
radiofluorination yield (8% to 17%). No enhancement of yield was observed when DBU, DMAP
or TMG was used. Thus, quinuclidine and DABCO were the most effective for promoting the
labeling reactions.
18F
Cl
18F-
N
N
K+- K 2.2.2
DMSO-0.1% H2O
additive
NH2
NH2
[18F]6
5
30 min
microreactor
40
30
20
10
0
Quinuclidine
DABCO
TEA
DMAP
DBU
No additive
TMG
100
150
200
Temperature (C)
Figure 7. The effects of various organic bases at 100 mM concentration on the yield of [18F]6 at a precursor
concentration of 8.7 mM at temperatures from 100 to 200 C. (TEA = triethylamine; DMAP = N,N-dimethylpyridin-
4-amine; DBU = 1,8-diazocyclo[5,4,0]undec-7-ene; TMG = 1,1,3,3-tetramethylguanidine).
11
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As a further test of the tolerability of free aryl amino groups in the quinuclidine- or
DABCO-promoted radiofluorinations of 2-chloro-heteroarenes, we performed similar experiments
on 2-chloroquinolin-6-amine (9) in the microfluidic apparatus. The pattern of results (Figure 8),
namely the beneficial effect of DABCO or quinuclidine at different temperatures, was like that
obtained in the radiofluorination of 5 (Figure 7). Yields of [18F]10 were greater when either
DABCO or quinuclidine was present and increased with temperature up to 200 °C, with the best
yield reaching 41%. Thus, the free aryl amino group was well-tolerated in this reaction.
NH2
NH2
18F-
K+- K 2.2.2
DMSO-0.1% H2O
additive
18F
N
Cl
N
18
9
10
[ F]
30 min
50
microreactor
40
30
20
10
0
Quinuclidine
DABCO
No additive
100
150
200
Temperature (oC)
Figure 8. The effects of DABCO or quinuclidine at 100 mM concentration on the yield of [18F]10 at a precursor
concentration of 8.7 mM and temperatures from 100 to 200 C.
Radiofluorinations of other 5-substituted 2-chloropyridines. We evaluated the effects
of the three nucleophilic organic bases, TEA, quinuclidine and DABCO, on the yields of reactions
of [18F]fluoride ion with two 5-substituted 2-chloro-pyridines, one with a 5-methyl substituent
(11a) and another with a 5-methoxy substituent (11b). All three bases enhanced the yields of
12
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European Journal of Organic Chemistry
[18F]12a from 11a at all three tested temperatures from 100 and 200 °C. Among the tested bases,
quinuclidine performed best, giving strong yield enhancement, i.e. to 18% at 150 °C and 52% at
200 °C (Figure 9). Much weaker yield increase was seen with quinuclidine and DABCO for the
radiofluorination of 11b to give [18F]12b (Figure 10). Yields were less than 10% even at 200 C,
showing that the 5-methoxy group was much more deactivating than the 5-methyl group.
Me
18F-
Me
K+- K 2.2.2
DMSO-0.1% H2O
additive
18F
N
Cl
N
18
11a
12a
[ F]
30 min
microreactor
60
Quinuclidine
DABCO
40
20
0
TEA
No additive
100
150
200
Temperature (C)
Figure 9. The effect of bases at 100 mM concentration on the yield of [18F]12a at a precursor (11a) concentration of
8.7 mM and temperatures from 100 to 200 C,
13
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OMe
OMe
18F-
Cl
N
K+- K 2.2.2
DMSO-0.1% H2O
additive
18F
N
18
12b
[ F]
11b
30 min
microreactor
10
Quinuclidine
8
6
4
2
0
DABCO
No additive
100
150
200
Temperature (C)
Figure 10. The effect of quinuclidine or DABCO at 100 mM concentration on the yield of [18F]12b at a precursor
(11b) concentration of 8.7 mM and temperatures from 100 to 200 C.
In all preceding experiments, the effect of quinuclidine on the yield of [18F]fluoropyridines
was usually as good as or better than that of DABCO. Therefore, quinuclidine was used as the
additive in subsequent experiments that were aimed at assessing the influence of substituents in
the 5-position of the pyridyl ring. Specifically, we compared the effect of quinuclidine at 100 mM
concentration on the radiofluorination yields of various 5-substituted 2-chloropyridines with and
without additive at temperatures of 100, 150 and 200 C (Figure 11). 2-Chloropyridine itself gave
no yield with or without additive. In the absence of additive (Figure 11A), yields were close to
zero at 100 °C for all tested substituents. Only 5-phenyl-2-chloropyridine gave a yield (54%)
above 20% at 150 °C. At 200 °C, precursors that had the 5-substituent bonded through aliphatic
carbon (R = Me: 24%) or aryl carbon (R = Ph: 80%, or 2-naphthyl: 54%) gave yields above 20%,
except for the precursor having a 9-anthracenyl substituent (8%). Precursors that have stronger
14
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10.1002/ejoc.201700970
European Journal of Organic Chemistry
electron-donating substituents, such as methoxy, gave lower yields. These yields decreased in
the order of the electron-donating ability of the substituent (OPh > OPn > OMe) and never exceed
20% at 200 C. In the presence of quinuclidine (Figure 11B), yields increased at all temperatures,
regardless of the nature of the substituent. For precursors bearing a 5-phenyl or 2-naphthyl
substituent, the yields at 200 °C with additive were lower than control (70% vs. 80%, 50% vs.
54%), but the yields at 100 °C with additives were higher than control (67% vs 54%, 56% vs.
14%). Precursors with a 5-methyl or 9-anthracenyl substituent gave yields above 18% at both 150
(18% and 26%) and 200 °C (52% and 24%). Precursors with a 5-methoxy substituent gave
enhanced yields (1% no additive vs. 7% with quinuclidine), but still below 20%, except that with
a 5-phenoxy substituent at 200 °C (21% increased from 5% at 150 C).
15
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10.1002/ejoc.201700970
European Journal of Organic Chemistry
R
R
18F-
K+-K 2.2.2
DMSO-0.1% H2O
With or without
quinuclidine
30 min
18F
N
Cl
N
18
18
12a
12h
[ F]
-[ F]
microreactor
R =
A. Without quinuclidine
80
60
40
20
0
Ph ([18F]12f)
2-Naphthyl ([18F]12g)
Me ([18F]12a)
OPh ([18F]12e)
9-Anthracenyl ([ 18F]12h)
OPn ([18F]12d)
OMe ([18F]12b)
H ([18F]12c)
0
10
0
15
0
20
Temperature (C)
B. With quinuclidine
80
60
40
20
0
Ph ([18F]12f)
2-Naphthyl ([18F]12g)
Me ([18F]12a)
OPh ([18F]12e)
9-Anthracenyl ([ 18F]12h)
OPn ([18F]12d)
OMe ([18F]12b)
H ([18F]12c)
0
10
0
15
0
20
Temperature (C)
Figure 11. The effect of quinuclidine on the yields of 5-substituted [18F]2-fluoropyridines from chloro precursors.
Data colored green, blue and red are for precursors having the 5-subsituent bonded to the 2-chloropyridyl ring through
aliphatic carbon, aryl carbon and oxygen, respectively.
Radiofluorinations of 5-substituted 2-bromopyridines. We also investigated the
influence of halide leaving group on radiofluorination yields. Various 5-substituted 2-bromo-
pyridines were evaluated with and without quinuclidine additive at temperatures of 100, 150 and
200 C (Figure 12). In the absence of quinuclidine (Figure 12A), no radioactive products were
16
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10.1002/ejoc.201700970
European Journal of Organic Chemistry
obtained at 100 °C. At 150 °C yields were slightly improved, but generally still low, except for
[18F]5(-(2-naphthyl))-2-fluoropyridine ([18F]12g; 34%) which was higher than that from the
corresponding chloro precursor (14%; Figure 11A). At 200 °C yields further improved. [18F]2-
Fluoropyridines bearing a 5-(O-2-naphthyl) ([18F]12i), 5-(2-naphthyl) ([18F]12g), 5-phenoxy
([18F]12e) or 5-methyl ([18F]12a) substituent gave yields of 58, 57, 44 and 19%, respectively.
[18F]2-Fluoropyridines bearing a 5-butoxy ([18F]12j) or 5-pentoxy ([18F]12d) substituent were
obtained in extremely low yields. Quinuclidine greatly improved the yields (Figure 12B) for O-
aryl and aryl substituents even at 100 and 150 C, with the optimal temperature at 150 C. O-alkyl
substituted precursors gave low yields.
17
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10.1002/ejoc.201700970
European Journal of Organic Chemistry
R
R
18F-
K+-K 2.2.2
DMSO-0.1% H2O
With or without
quinuclidine
30 min
Br
N
18F
N
18
18
12a,
12d,
[ F]
[ F]
[18F]12e, [18F]12g,
[18F]12i, [18F]12j
microreactor
A. Without quinuclidine
R =
80
60
40
20
0
O-2-Naphthyl ([18F]12i)
2-Naphthyl ([18F]12g)
OPh ([18F]12e)
Me ([18F]12a)
OBu ([18F]12j)
OPn ([18F]12d)
100
150
200
Temperature (C)
B. With quinuclidine
80
60
40
20
0
O-(2-Naphthyl) ([18F]12i)
OPh ([18F]12e)
2-Naphthyl ([18F]12g)
Me ([18F]12a)
OPn ([18F]12d)
OBu ([18F]12j)
100
150
200
Temperature (C)
Figure 12. The effect of quinuclidine on the yields of 5-substituted [18F]2-fluoro-pyridines from bromo-precursors.
Data colored green, blue and red are for precursors having the 5-subsituent bonded to the 2-bromopyridyl ring through
aliphatic carbon, aryl carbon and oxygen, respectively.
Mechanistic interpretation of quinuclidine- or DABCO-enhanced radiofluorinations
of halo-pyridines. In this study we observed that: 1) the highly nucleophilic tertiary amine bases
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quinuclidine and DABCO were the most effective for enhancing the radiofluorinations of 2-
halopyridines; 2) triethylamine, a tertiary amine base with weaker nucleophilicity, was less
effective; 3) weakly nucleophilic but very strong organic bases, such as DBU, were ineffective; 4)
bromide was a better leaving group than chloride in the presence or absence of quinuclidine; 5)
only a polar solvent with relatively high dielectric constant, such as DMSO, was suitable for the
reaction in the presence of tertiary amine additive; 6) the enhancement of yield by DABCO or
quinuclidine was concentration-dependent, first increasing with increasing concentration and then
declining with further increase; and 7) in the presence of DABCO or quinuclidine the
radiofluorination reactions tolerate free aryl amino groups in the precursor. These observations
lead us to suggest that the tertiary amines, DABCO or quinuclidine, form a more reactive
quaternary ammonium intermediate with a 2-halopyridine. A 2-fluoro substituent has been shown
to be an effective leaving group in SNAr reactions on pyridines.[38] Therefore, we also speculate
that the radiofluorinated product may form the same quaternary ammonium intermediate
reversibly. Such an intermediate must be formed in relatively low concentration, as we were
unable to observe formation in situ by either NMR or HPLC, when precursor and DABCO were
heated together in DMSO at temperatures up to 150 C. Finally, the tolerance of the reactions to
a free aryl amino group can perhaps be rationalized as being due to a strong charge interaction
between the free [18F]fluoride ion and the positively charged quaternary nitrogen at the expense of
any weak interaction of the [18F]fluoride ion with a free amino group.
Figure 13. Proposed pathway for the DABCO or quinuclidine mediated radiofluorinations of 2-halopyridines.
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To further probe our mechanistic interpretation, we made the quaternary ammonium salt,
17, and explored its reactivity towards [18F]fluoride ion. Radiofluorination of this salt in DMSO
and Boc-deprotection gave a high yield of [18F]6 without any additional additive (Table 3, entry
1), supporting the possible importance of such quaternary intermediates in the quinuclidine- or
DABCO-assisted radiofluorination reactions. Radiofluorination of 17 became possible in DMF
(entry 2) but not in less polar acetonitrile (entry 3).
Table 3. Conversion of the quaternary ammonium salt 17 into [18F]6.
Entry
Solvent Temp
Time
(min)
Yield of
[18F]6
(%)
(C)
1
2
3
DMSO
DMF
MeCN
120
120
110
10
10
20
36-58
25-45
0
Conclusions
Various tertiary amines were evaluated as additives to enhance the radiofluorination of 5-
substituted 2-halopyridines. DABCO and quinuclidine emerged as the most effective among those
tested. These additives either increased the radiolabeling yields to more useful levels or lowered
the temperatures needed for the radiolabeling reactions. Based on our observations, we suggest
that the tertiary amine-enhanced reactions occur through a reversibly formed quaternary
ammonium intermediate. A further useful feature of these reactions is their tolerance for free aryl
amino groups.
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Experimental
General
All solvents, bases, and reagents were purchased from Sigma-Aldrich (St. Louis, MO) or Combi-
Blocks (San Diego, CA) and were used without further purification. Non-substituted and
substituted 2-halopyridines (halo = F, Cl, or Br) were obtained commercially, except for those with
synthesis described below. All reactions were performed under inert atmosphere in oven-dried
glassware and monitored with TLC on silica layers (0.2 mm; Polygram® Sil G/UV254; Grace;
Deerfield, IL) visualized under UV light (254 nm). Column chromatography was performed with
a CombiFlash®Rf+ apparatus (Teledyne Isco; Lincoln, NE) on silica RediSep®Rf cartridges
(Teledyne Isco) with gradient elution (EtOAc/hexanes, 2: 98 v/v  EtOAc/hexanes, 10: 90 v/v).
13
1H- (400 MHz) and C- (100 MHz) NMR spectra were recorded in deuterated solvents on an
Avance 400 instrument (Bruker; Billerica, MA). Chemical shifts are given in parts per million
(ppm) (δ) downfield from the signal for tetramethylsilane. All new compounds were analyzed
with high resolution mass spectrometry (HRMS) at the Mass Spectrometry Laboratory, School of
Chemical Sciences, University of Illinois (Urbana-Champaign, IL) with a Micromass Q-T of
Ultima instrument for ESI (Waters Corp; Columbia, MD). Compound purities were determined
with HPLC on a LC-20AD instrument (Shimadzu; Columbia, MD) equipped with a diode array
detector (254 nm), and a Luna C18 column (5 µm; 100 Å; 4.6 × 250 mm; Phenomenex; Torrance,
CA) eluted with MeCN: H2O (9: 1 v/v) at 1 mL/min. The purity of all final compounds was ≥
95%.
Chemistry
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6-(6-Chloropyridin-3-yl)naphthalen-2-amine (5). 6-Bromonaphthalen-2-amine (1.1 g,
4.95 mmol), (6-chloropyridin-3-yl)boronic acid (1.0 g, 6.35 mmol), K2CO3 (1.2 g, 8.68 mmol),
and Pd(PPh3)4 (0.54 g, 0.467 mmol), were dissolved in DME-H2O (1: 1, v/v; 20 mL). The mixture
was subjected to microwave irradiation (90C20min150W250psi). HPLC analysis of an aliquot
showed 90% conversion. Another portion of Pd(PPh3)4 (0.15 g, 0.130 mmol) was added, and the
mixture was irradiated under the same conditions. HPLC analysis of an aliquot showed 95%
conversion. The mixture was partitioned between CHCl3 and H2O (100 mL each), and the aqueous
phase was extracted with CHCl3 (100 mL × 2). The combined organic phase was dried (MgSO4).
After filtration, the solvent was removed. The residue was washed with EtOAc and the solid was
1
dried under vacuum to give 5 (0.86 g; 67%). H-NMR in DMSO-d6: δ 8.80 (d, 4JHH = 2.5 Hz, 1H,
Ar-H), 8.21 (dd, 3JHH = 8.4 Hz, 4JHH = 2.6 Hz, 1H, Ar-H), 8.05 (s, 1H, Ar-H), 7.69−7.58 (m, 4H,
Ar-H), 6.98 (dd, 3JHH = 8.8 Hz, 4JHH = 2.2 Hz, 1H, Ar-H), 6.84 (d, 4JHH = 2.0 Hz, 1H, Ar-H), 5.56
(s, 2H, NH2). HRMS calculated for C15H12ClN2 [M + H]+: m/z = 255.0689, found 255.0690. Error
(ppm): 0.4.
6-(6-Fluoropyridin-3-yl)naphthalen-2-amine (6). 6-Bromonaphthalen-2-amine (100
mg, 0.450 mmol), (6-fluoropyridin-3-yl)boronic acid (98 mg, 0.695 mmol), K2CO3 (124 mg, 0.897
mmol), and Pd(PPh3)4 (31.2 mg, 0.0270 mmol) were dissolved in DME-H2O (1: 1, v/v; 10 mL).
The mixture was subjected to microwave irradiation (80C40min80W250psi). The mixture was
partitioned between CHCl3 and H2O (100 mL each), and the aqueous phase was extracted with
CHCl3 (100 mL × 2). The combined organic phase was dried (MgSO4). After filtration, the solvent
was removed. The residue was washed with EtOAc, and dried under vacuum to give 6 (91 mg;
1
85%). H-NMR in DMSO-d6: δ 8.59 (d, 4JHH = 2.5 Hz, 1H, Ar-H), 8.87 (dt, 3JHF = 3JHH = 8.3 Hz,
4JHH = 2.6 Hz, 1H, Ar-H), 8.01 (s, 1H, Ar-H), 7.67 (d, 3JHH = 8.8 Hz, 1H, Ar-H), 7.64 (ABd, 3JHH
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= 8.6 Hz, 4JHH = 1.8 Hz, 1H, Ar-H), 7.61 (AB, 3JHH = 8.6 Hz, 1H, Ar-H), 7.27 (dd, 3JHH = 8.5 Hz,
4JHH = 2.9 Hz, 1H, Ar-H), 6.98 (dd, 3JHH = 8.7 Hz, 4JHH = 2.2 Hz, 1H, Ar-H), 6.84 (d, 4JHH = 2.0
Hz, 1H, Ar-H), 5.53 (s, 2H, NH2). 13C{1H}-NMR in DMSO-d6: δ 162.3 (d, 1JCF = 233.9 Hz, 1C,
2-Py), 147.5, 145.0 (d, 3JCF = 14.8 Hz, 1C, 6-Py), 140.0 (d, 3JCF = 7.9 Hz, 1C, 4-Py), 134.7, 129.3,
2
128.2, 126.5, 126.2, 125.7, 124.8, 119.1, 109.7 (d, JCF = 37.6 Hz, 1C, 3-Py), 105.6. HRMS
calculated for C15H12FN2 [M + H]+: m/z = 239.0985, found 239.0984. Error (ppm): −0.4.
tert-Butyl (6-(6-chloropyridin-3-yl)naphthalen-2-yl)carbamate (7). Compound 5 (1.0
g; 3.93 mmol) and Boc2O, (1.0 mL; d = 0.95 g/mL, 4.35 mmol) were dissolved in AcOH (3.0 mL).
The mixture was stirred overnight. The mixture was partitioned between EtOAc and H2O (100
mL each), and the aqueous phase was extracted with EtOAc (2 × 100 mL). The combined organic
phase was dried (MgSO4). After filtration, the solvent was removed. The residue was washed
with EtOAc, and the solid was dried under vacuum, to give 7 (1.27 g; 91%). 1H-NMR in DMSO-
d6: δ 9.66 (brs, 1H, NH), 8.87 (d, 4JHH = 2.1 Hz, 1H, Ar-H), 8.28 (dd, 3JHH = 8.6 Hz, 4JHH = 2.6 Hz,
1H, Ar-H), 8.22 (s, 1H, Ar-H), 8.16 (s, 1H, Ar-H), 7.91 (d, 3JHH = 8.6 Hz, 1H, Ar-H), 7.89 (d, 3JHH
3
3
= 8.7 Hz, 1H, Ar-H), 7.82 (dd, JHH = 8.5 Hz, 4JHH = 1.5 Hz, 1H, Ar-H), 7.63 (d, JHH = 8.3 Hz,
1H, Ar-H), 7.55 (dd, 3JHH = 8.9 Hz, 4JHH = 1.8 Hz, 1H, Ar-H), 1.52 (s, 9H, CH3). LC-MS, 355.0
([M+H]+, 100%), 357.1 ([M+H]+, 32%), 299.2 ([M-CH2=C(CH3)2+H]+, 26%), 301.2 ([M-
CH2=C(CH3)2+H]+, 9%), 255.3 ([M-CH2=C(CH3)2-CO2+H]+, 22%), 257.3 ([M-CH2=C(CH3)2-
CO2+H]+, 6%); HRMS calculated for C20H20ClN2O2 [M + H]+: m/z = 355.1213, found 355.1217.
Error (ppm): 1.1.
tert-Butyl (6-(6-fluoropyridin-3-yl)naphthalen-2-yl)carbamate (8). Compound 6 (1.0
g; 3.93 mmol) and Boc2O (1.0 mL; d = 0.95 g/mL, 4.35 mmol) were dissolved in AcOH (3.0 mL).
The mixture was stirred overnight. The mixture was partitioned between EtOAc and H2O (100
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mL each), and the aqueous phase extracted with EtOAc (2 × 100 mL). The combined organic
phase was dried (MgSO4). After filtration, the solvent was removed. The residue was washed
with EtOAc and dried under vacuum to give 8 (1.12 g; 78%). 1H-NMR in DMSO-d6: δ 9.67 (brs,
1H, NH), 8.67 (d, 4JHH = 2.1 Hz, 1H, Ar-H), 8.28 (dd, 3JHH = 8.2 Hz, 4JHH = 2.5 Hz, 1H, Ar-H),
8.18 (s, 1H, Ar-H), 8.16 (s, 1H, Ar-H), 7.89, 7.88 (AB, 3JHH = 8.5 Hz, 2H, Ar-H), 7.80 (dd, 3JHH
=
8.6 Hz, 4JHH = 1.7 Hz, 1H, Ar-H), 7.54 (dd, 3JHH = 8.8 Hz, 4JHH = 2.0 Hz, 1H, Ar-H), 7.31 (dd, 3JHH
= 8.5 Hz, 4JHH = 2.8 Hz, 1H, Ar-H), 1.52 (s, 9H, CH3). 13C{1H}-NMR in DMSO-d6: δ 162.6 (d,
3
3
1JCF = 234.3 Hz, 1C, 2-Py), 153.0, 145.5 (d, JCF = 15.0 Hz, 1C, 6-Py), 140.5 (d, JCF = 8.1 Hz,
1C, 4-Py), 137.9, 134.3, 133.2, 131.5, 129.4, 129.0, 128.2, 125.6, 125.3, 120.2, 113.2, 109.8 (d,
2JCF = 37.5 Hz, 1C, 3-Py), 79.6 (s, 1C, C-O), 28.3 (s, 3C, CH3). HRMS calculated for
C20H20FN2O2 [M + H]+: m/z = 339.1509, found 339.1506. Error (ppm): −0.9.
2-Chloro-5-(pentyloxy)pyridine (11d). 2-Chloro-5-hydroxypyridine (500 mg, 3.9
mmol), 1-iodopentane (852 mg, 4.3 mmol), and K2CO3 (539 mg, 3.9 mmol) were refluxed in
acetone (7 mL). After 16 h, the reaction mixture was cooled to rt, filtered, and the filtrate
concentrated. The crude residue was diluted in DCM, evaporated onto silica gel, and purified with
1
column chromatography to afford 11d (703 mg; 90%). H-NMR: δ 8.02–8.01 (m, 1H), 7.20–7.15
(m, 2H), 3.96 (t, J = 6.4 Hz, 2H), 1.78 (pentet, J = 6.4 Hz, 2H), 1.46–1.34 (m, 4H), 0.94 (t, J = 7.2
Hz, 3H); HRMS calculated for C10H14ClNO [M + H]+: m/z = 200.0837, found 200.0834. Error
(ppm): 1.35.
2-Chloro-5-phenoxypyridine (11e). A mixture of iodobenzene (204 mg, 1.0 mmol), 2-
chloro-5-hydroxypyridine (155 mg, 1.2 mmol), K2CO3 (166 mg, 1.2 mmol), and CuI (9.5 mg,
0.050 mmol) in DMF (1 mL) was stirred at rt for 30 min. The mixture was then transferred to a
hot oil bath (110 C). After 24 h, the reaction mixture was cooled to rt, diluted with EtOAc (3
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mL), and filtered over celite. The reaction mixture was then concentrated under reduced pressure,
diluted in DCM, evaporated onto silica gel, and purified with column chromatography to afford
1
11e (16 mg; 8%). H-NMR: δ 8.16 (t, J = 2.0 Hz, 1H), 7.40–7.36 (m, 2H), 7.27 (d, J = 2.0 Hz,
2H), 7.20–7.16 (m, 1H), 7.04–7.01 (m, 2H); HRMS calculated for C11H9ClNO [M + H]+: m/z =
206.0367, found 206.0363. Error (ppm): 2.39.
2-Chloro-5-phenylpyridine (11f). A solution of 6-chloro-3-pyridylboronic acid (448 mg,
2.85 mmol) in EtOH (1.5 mL) was added to a mixture of Pd(PPh3)4 (150 mg, 0.13 mmol),
iodobenzene (526 mg, 2.58 mmol), aq. Na2CO3 (2 M; 2.85 mL), and toluene (5 mL). The reaction
mixture was heated to 80 C, stirred overnight, and cooled to rt. The reaction mixture was then
partitioned between EtOAc (20 mL) and H2O (10 mL), and the organic layer was collected, dried
(MgSO4), filtered, and evaporated to dryness under reduced pressure. The residue was diluted in
DCM, evaporated onto silica gel, and purified with column chromatography to afford 11f (180
mg; 37%). All characterization data agrees with the literature.[39]
2-Chloro-5-(naphthalen-2-yl)pyridine (11g). The reaction of 6-chloro-3-pyridylboronic
acid (448 mg, 2.85 mmol) with 2-iodonaphthalene (656 mg, 2.58 mmol) gave 11g (294 mg, 48%).
1H-NMR: δ 8.73 (dd, J = 2.4, 0.4 Hz, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.98–7.94 (m, 2H), 7.93–7.87
(m, 2H), 7.66 (dd, J = 8.4, 2.0 Hz, 1H), 7.57–7.51 (m, 2H), 7.44 (dd, J = 8.4, 0.4 Hz, 1H); HRMS
calculated for C15H10ClN [M + H]+: m/z = 240.0580, found 240.0582. Error (ppm): 0.8.
5-(Anthracen-9-yl)-2-chloropyridine (11h). The reaction of 6-chloro-3-pyridylboronic
acid (448 mg, 2.85 mmol) with 9-bromoanthracene (663 mg, 2.58 mmol) gave 11h (41 mg; 5%).
1H-NMR: δ 8.53 (s, 1H), 8.46 (dd, J = 2.4, 0.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.71 (dd, J = 8.0,
2.4 Hz, 1H), 7.57–7.54 (m, 3H), 7.49–7.45 (m, 2H), 7.41–7.37 (m, 2H); HRMS calculated for
C19H13ClN [M + H]+: m/z = 290.0731, found 290.0729. Error (ppm): 0.7.
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2-Bromo-5-butoxypyridine (13c). Application of the conditions used for the synthesis of
11d to 2-bromo-5-hydroxypyridine (679 mg, 3.9 mmol) and 1-iodobutane (791 mg, 4.3 mmol)
1
gave 13c (529 mg; 59%). H-NMR: δ 8.03 (d, J = 3.2 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.08 (dd,
J = 8.8, 3.2 Hz, 1H), 3.97 (t, J = 6.4 Hz, 2H), 1.76 (pentet, J = 6.4 Hz, 2H), 1.48 (sextet, J = 7.6
Hz, 2H), 0.99 (t, J = 7.2 Hz, 3H); HRMS calculated for C9H13BrNO [M + H]+: m/z = 230.0175,
found 230.0172. Error (ppm): 1.32.
2-Bromo-5-(pentyloxy)pyridine (13d). Application of the conditions used for the
synthesis of 11d to 2-bromo-5-hydroxypyridine (679 mg, 3.9 mmol) and 1-iodopentane (852 mg,
1
4.3 mmol) gave 13d (371 mg; 39%). H-NMR: δ 8.02 (d, J = 3.2 Hz, 1H), 7.32 (d, J = 8.8 Hz,
1H), 7.08 (dd, J = 8.8, 3.2 Hz, 1H), 3.95 (t, J = 6.8 Hz, 2H), 1.78 (pentet, J = 6.4 Hz, 2H), 1.45–
1.34 (m, 4H), 0.92 (t, J = 7.2 Hz, 3H); HRMS calculated for C10H15BrNO [M + H]+: m/z =
244.0332, found 244.0330. Error (ppm): 0.63.
2-Bromo-5-(naphthalen-2-yloxy)pyridine (13e). Application of the conditions used for
the synthesis of 13d to 2-iodonaphthalene (508 mg, 2.0 mmol), 2-bromo-5-hydroxypyridine (418
1
mg, 2.4 mmol), and CuI (20 mol%) gave 13e (26 mg; 5%). H-NMR: δ 8.39 (dd, J = 4.8, 1.6 Hz,
1H), 8.10–8.07 (m, 3H), 7.79–7.75 (m, 3H), 7.58–7.54 (m, 1H), 7.51–7.49 (m, 1H), 7.29–7.25 (m,
1H).
2-Bromo-5-phenoxypyridine (13f). Activated 4 Å molecular sieves (1.0 g), Cu(OAc)2
(363 mg, 2.0 mmol), and trimethylamine (1.0 g, 10 mmol) were added sequentially to a solution
of 2-bromo-5-hydroxypyridine (348 mg, 2.0 mmol), and phenylboronic acid (488 mg, 4.0 mmol)
in DMF (10 mL). The reaction mixture was cooled to 0 C (ice-bath) and stirred under air for 6 h.
The reaction mixture was filtered over celite, diluted in EtOAc (30 mL), and washed with HCl (1
M; 10 mL  2), water (10 mL), and brine (15 mL  2). The organic layer was then dried (MgSO4)
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and concentrated under reduced pressure. The crude residue was diluted in DCM, evaporated onto
silica gel, and purified with column chromatography to afford 13f (29 mg; 7%). All
characterization data agrees with the literature.[40]
2-Bromo-5-(naphthalen-2-yl)pyridine (13g). The reaction of 6-bromo-3-pyridylboronic
acid (575 mg, 2.85 mmol) and 2-iodonaphthalene (656 mg, 2.58 mmol) gave 13g (70 mg; 10%).
All characterization data agree with the literature.[41]
tert-Butyl (6-bromonaphthalen-2-yl)carbamate (14). 6-Bromonaphthalen-2-amine
(2.0 g, 9.01 mmol), (Boc)2O (2.7 mL, 11.8 mmol), and AcOH (10 mL) were mixed and stirred
for 6 d. The mixture was partitioned between EtOAc and saline. The combined EtOAc phase
was dried (MgSO4). After removing solvent, the solid was washed with hexane (10 mL× 3).
The red hexane solution was decanted, and the white solid was dried in a vacuum-oven to give
14 (2.5 g; 86%). 1H-NMR in DMSO-d6: δ 9.65 (s, 1H, NH), 8.12 (s, 1H, Ar-H), 8.07 (d, 4JHH
=
1.8 Hz, 1H, Ar-H), 7.79 (d, 3JHH = 8.9 Hz, 1H, Ar-H), 7.75 (d, 3JHH = 8.8 Hz, 1H, Ar-H), 7.53 (d,
3JHH = 8.6 Hz, 3JHH = 1.6 Hz, 2H, Ar-H), 1.50 (s, 9H, CH3). HRMS calculated for
C15H16BrNO2Na [M + Na]+: m/z = 344.0262, found 344.0266. Error (ppm): 1.2.
tert-Butyl
(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-
yl)carbamate (15). Compound 14, 0.704 g (2.18 mmol), B2pin2, 0.872 g (3.43 mmol), Pd(PPh3)4,
0.101 g (0.0874 mmol), and KOAc, 2.34 g (23.8 mmol) were suspended in 1,4-dioxane (12 mL).
The mixture was heated at 98 C for 3 d. The mixture was partitioned between EtOAc and brine
(100 mL each), and the aqueous phase was extracted with EtOAc (100 mL× 2). The combined
organic phase was dried (MgSO4). After filtration, the solvent was removed. The resulting oily
product was dissolved in DCM (50 mL), and silica gel (20 mL) was added. After the solvent was
removed, the product was purified by Combi-Flash chromatography using EtOAc increased from
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0 to 100%, balanced by n-hexane. After the solvent was removed, the product was transferred into
1
a vial and dried by Centrifan to give 15 (0.65 g; 81%). H-NMR in CDCl3: δ 8.25 (s, 1H, NH),
7.96 (s, 1H, Ar-H), 7.77 (d, 3JHH = 8.4 Hz, 1H, Ar-H), 7.71 (d, 3JHH = 8.2 Hz, 1H, Ar-H), 7.30 (dd,
3JHH = 8.8 Hz, 4JHH = 2.1 Hz, 1H, Ar-H), 6.64 (s, 1H, Ar-H), 1.53 (s, 9H, CH3), 1.36 (s, 12H, CH3).
LC-MS, 531.4 (30%), 369.2 ([M + H]+, 50%), 287.2 (30%), 277.2 (80%), 255.2 (100%), 187.1
(25%); HRMS calculated for C21H28BNO4Na [M + Na]+: m/z = 391.2045, found 391.2050. Error
(ppm): 1.3.
3-(6-((t-Butoxycarbonyl)amino)naphthalen-2-yl)pyridine 1-oxide (16). The boronic
ester 15 (139.6 mg, 0.378 mmol), 3-bromopyridine 1-oxide (289.1 mg, 1.66 mmol), Pd(PPh3)4
(110.8 mg, 0.0959 mmol), K2CO3 (277.1 mg, 2.01 mmol) were suspended in DME-H2O (4: 1; 5.0
mL). The reaction was subjected to microwave irradiation (100C60min80W250psi). After the
reaction was complete, the mixture became homogeneous. This was then partitioned between
EtOAc and brine. The aqueous phase was extracted with EtOAc (100 mL× 2). The combined
organic phase was dried (MgSO4). After filtration, the solvent was removed. The residue was
purified on Combi-Flash with MeOH (0 to 20%) balanced with EtOAc to give 16 as a white
powder (183.1 mg), which was used without further purification.
1-(5-(6-((t-Butoxycarbonyl)amino)naphthalen-2-yl)pyridin-2-yl)-1,4-
diazabicyclo[2.2.2]octan-1-ium trifluoroacetate (17). The crude pyridine oxide 16 (183.1 mg;
0.544 mmol) was dissolved in DCM (10 mL), and DABCO (404.4 mg, 3.60 mmol) was added.
The mixture was stirred until it became homogeneous. (CF3CO)2O (0.40 mL, d = 1.49 g/mL, 2.84
mmol) was added dropwise. The solution changed from colorless to pale yellow. The solution
was stirred overnight. When all 16 had been consumed, as shown by HPLC, K2CO3 (1.1 g, 7.96
mmol) was added. The mixture was stirred for 0.5 h, and solid was filtered off. The solution was
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added to diethyl ether (250 mL) with stirring. A white precipitate formed. The suspension stood
overnight to form a clear solution with a transparent solid on the surface of the glassware. The
solid was dissolved in the minimal amount of DMF and purified with HPLC, to give 17 (45.6 mg;
1
15%) after removing solvent on a rotary evaporator with a bath at < 40 C. H-NMR in CD3OD:
δ 9.00 (d, 4JHH = 2.2 Hz, 1H, Ar-H), 8.46 (dd, 3JHH = 8.7 Hz, 4JHH = 2.4 Hz, 1H, Ar-H), 8.16 (s,
1H, Ar-H), 8.09 (s, 1H, Ar-H), 7.91 (d, 3JHH = 8.6 Hz, 1H, Ar-H), 7.91 (s, 1H, Ar-H), 7.89 (s, 1H,
Ar-H), 7.77 (dd, 3JHH = 8.5 Hz, 4JHH = 1.6 Hz, 1H, Ar-H), 7.55 (dd, 3JHH = 8.8 Hz, 4JHH = 2.0 Hz,
1H, Ar-H), 3.98 (t, 3JHH = 7.4 Hz, 6H, CH2), 3.40 (t, 3JHH = 7.4 Hz, 6H, CH2), 1.58 (s, 9H, CH3).
-
13C{1H}-NMR in CD3OD: δ 161.6 (CF3CO2 ), 156.0, 155.4, 148.5, 140.7, 140.0, 139.7, 135.8,
132.2, 131.4, 130.4, 129.8, 127.8, 126.1, 121.7, 116.9, 115.2, 81.4 (OC(CH3)3), 55.7 (NCH2), 46.7
(NCH2), 28.9 (CH3). HRMS calculated for C26H31N4O2 [ammonium cation]+: m/z = 431.2447,
found 431.2452. Error (ppm): 1.2.
Radiochemistry
General
All radiochemistry was performed in a lead-shielded hot-cell for personnel protection.
Radioactivity was measured with a calibrated Atomlab 300 ionization calibrator (Biodex Medical
Systems; Shirley, NY) and was corrected for background and decay. Radio-HPLC was performed
with a Model 166 UV absorbance detector (Beckman Coulter; CA) coupled with a PMT flow count
radioactivity detector (Bioscan, Washington DC). The radioactive compounds were eluted with a
gradient of a binary solvent mixture (H2O-MeCN) on a Luna C18 column (5 µm; 100 Å; 4.6 × 250
mm; Phenomenex; Torrance, CA). The mobile phase was initially composed of 35% MeCN,
which was linearly increased to 95% MeCN over 5 min, and then maintained at this composition
for the remainder of the run.
29
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