An efficient synthesis of ([18F]fluoropropyl)quinoline-5,8- diones by rapid radiofluorination-oxidative demethylation

Article abstract of DOI:10.1016/j.tet.2011.01.057

Since many molecules bearing quinoline-5,8-dione or fused 1,4-quinone moieties possess a wide spectrum of biological activities, efficient methods for incorporation of fluorine-18 (F-18) into quinoline-5,8-diones have received considerable attention in po

Full text of DOI:10.1016/j.tet.2011.01.057

Tetrahedron 67 (2011) 1763e1767
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
18
An efficient synthesis of ([ F]fluoropropyl)quinoline-5,8-diones by rapid
radiofluorinationeoxidative demethylation
Kalme Sachin , Hwan-Jeong Jeong , Seok Tae Lim , Myung-Hee Sohn , Dae Yoon Chi ,*,
a
a
a
a
b
a,
*
Dong Wook Kim
a
Department of Nuclear Medicine, Cyclotron Research Center, Research Institute of Clinical Medicine, Chonbuk National University Medical School, Jeonju,
Jeonbuk 561-712, Republic of Korea
Department of Chemistry, Sogang University, 1 Shinsudong, Mapogu, Seoul 121-742, Republic of Korea
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Since many molecules bearing quinoline-5,8-dione or fused 1,4-quinone moieties possess a wide spec-
trum of biological activities, efficient methods for incorporation of fluorine-18 (F-18) into quinoline-5,8-
diones have received considerable attention in positron emission tomography (PET) molecular imaging
studies. In this paper, we describe an efficient synthetic route for the regioselective preparation of
fluoropropyl-substituted quinoline-5,8-diones on the C3, C4, and C6 positions by tert-alcohol media
fluorination, followed by oxidative demethylation of the corresponding dimethoxy compound using
N-bromosuccinimide (NBS) in the presence of catalytic amounts of sulfuric acid. Moreover, F-18 labeled
Received 4 December 2010
Received in revised form 19 January 2011
Accepted 19 January 2011
Available online 25 January 2011
Keywords:
Quinoline-5,8-dione
Radiofluorination
Oxidative demethylation
Fluorine-18
Positron emission tomography (PET)
18
18
[
F]fluoropropylquinoline-5,8-diones [ F]21e23 were prepared from the corresponding mesylate pre-
18
cursors by a method of rapid and efficient one-pot, two-step reactions: radiofluorination using TBA [ F]F
generated under no-carrier-added (NCA) conditions; oxidative demethylation, resulting in a 45% radio-
chemical yield of [18F]21e23 (decay-corrected) with a total synthesis time (including HPLC purification)
of 75 min and high radiochemical purity (>99%), as well as high specific activity (w230 GBq/mmol).
Ó 2011 Elsevier Ltd. All rights reserved.
1
. Introduction
efficient protocols that can be performed on a trace level reaction
scale, considering the specific activity of the radionuclide, are re-
quired for effective radiotracer preparation.
4
It is well-known that low fluorinated compounds have played
a crucial role in the field of medicinal chemistry because of their
physiological properties. In particular, radiopharmaceuticals la-
A number of bioactive molecules bearing the quinoline-5,8-dione
and fused 1,4-quinone moieties are widespread in nature and have
received much interest given their wide spectra of biological activi-
1
beled with the short-lived positron-emitting radionuclide, in par-
5
ticular, fluorine-18 (t1/2¼110 min), are being increasingly used in
ties, such as antitumor and antibacterial. Thus, an efficient fluorine-
2
clinical diagnosis, as well as the molecular imaging field using
18 labeling protocol for quinoline-5,8-diones would afford
developmental opportunities of various new radiopharmaceuticals
for PET. However, it is hard to introduce fluorine-18 (F-18) at specific
sites of the quinoline-5,8-diones without their decomposition under
standard F-18 labeling reaction conditions since the quinone moiety
positron emission tomography (PET) as a noninvasive molecular
imaging protocol, which provides exciting opportunities to detect
diseases in humans and monitor biological processes in living
subjects.3 However, suitable chemical processes for the in-
troduction of fluorine-18 into organic molecules for preparation of
radiotracers are often limited by: harsh labeling reaction condi-
tions; the relative short half-life of fluorine-18; sensitive functional
groups or chemical structure of the radiotracer molecules that can
restrict the choice of potential synthetic pathways; synthesis of
a radiotracer, including purification, usually should be completed
within three half-lives of the radionuclide. Consequently, rapid and
6
is easily reduced and attacked by nucleophiles. Therefore, protection
of the quinone moiety is required for the labeling reaction to proceed.
It has been reported that oxidative demethylation of fused 1,4-
dimethoxybezenes to 1,4-quinones using N-bromosuccinimide (NBS)
2 4
in the presence of a catalytic amount of H SO can proceed nearly
7
quantitatively within 5 min at room temperature. Therefore, this
oxidation method allowed this lab to design an efficient retro-
synthetic route for the preparation of radiolabeled quinoline-5,8-
diones with F-18 from 5,8-dimethoxyquinoline mesylate precursors
18
via the [ F]radiofluorinationeoxidation reaction sequence as shown
in Fig. 1. Herein, we report the efficient syntheses of fluoropropyl- or
*
Corresponding authors. Tel.: þ82 63 250 2396; fax: þ82 63 255 1172; e-mail
addresses: dychi@sogang.ac.kr (D.Y. Chi), kimdw@chonbuk.ac.kr (D.W. Kim).
0
040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.057

1764
K. Sachin et al. / Tetrahedron 67 (2011) 1763e1767
ꢀ
O
O
OCH3
OCH3
in trimethylorthoformate, followed by thermolysis of 4 at 250 C in
diphenyl ether; treatment of quinolone 5 with triflic anhydride
4
6
7
3
10
18F
18F
afforded triflate 7. Stille reaction of 6e8 with allyltributyltin in the
presence of tetrakis (triphenylphosphine palladium(0)) and lithium
bromide provided the corresponding allyl-substituted quinoline
compounds at the C3, C4, and C6 positions (9e11, 90, 86, and 50%,
respectively).
The unlabeled fluoropropylquinoline-5,8-diones (21e23) and
the mesylate precursors for the F-labeled quinoline-5,8-dione
derivatives were synthesized as shown in Scheme 2. Hydro-
OMs
2
N
1
N
N
OCH
3
OCH
3
Fig. 1. Strategy for the preparation of radiolabeled quinoline-5,8-diones with fluorine-
8.
1
18
[18
F]fluoropropyl-substituted quinoline-5,8-diones on the C3, C4, and
11
boration of allyl compounds 9e11, followed by mesylation of al-
cohols 12e14, provided the corresponding mesylate precursors
5e17. The tert-alcohol media nucleophilic fluorination of these
C6 position using a one-pot, two-step radiofluorinationeoxidative
demethylation reaction sequence. This protocol afforded F-18 labeled
quinoline-5,8-diones in high radiochemical yield with short reaction
times.
12
1
precursors using tetrabutylammonium fluoride (TBAF) proceeded
selectively, affording the desired fluoropropylquinolines 18e20 in
very high yield. The oxidation reaction of fluoropropyl-5,8-dime-
thoxyquinolines 18e20 using NBS in the presence of catalytic
amounts of sulfuric acid could be completed within 5 min at room
temperature to give the fluoropropylquinoline-5,8-diones 21e23 in
high yield. This highly efficient oxidative demethylation method
allowed the dimethoxy group act as a good protecting group for the
synthesis of quinolinediones labeled by short half-life radioisotopes.
2
. Results and discussion
Scheme 1 illustrates the regioselective synthetic route for prep-
aration of allylquinoline derivatives 9e11 as key intermediates for
introduction of the fluoropropyl groupat the C3, C4, and C6 positions
of the quinoline-5,8-dione. 5,8-Dimethoxyquinoline (2) was pre-
pared from commercially available 2,5-dimethoxyaniline (1) by the
8
Skraup reaction. A bromine could be incorporatedat the C6 position
of quinoline compound 2 by brominationwith N-bromosuccinimide
OMe
OMe
OMe
OH
OMs
(
NBS), affording 6-bromo-5,8-dimethoxyquinoline (8) in 65% yield.
a
b
To introduce a bromine atom regioselectively at C3, oxidation of 2 to
the corresponding N-oxide compound 3 with 3-chloroperoxy-
benzoic acid (m-CPBA) was followed by C3 bromination using
phosphorus oxybromide to provide 3-bromo-5,8-dimethoxy-
quinoline (6). For placement of the trifluoromethanesufonyloxy
group at the C4 position using the Stille reaction, 5,8-dimethoxy-4-
9, 10 or 11
N
N
OMe 15: C3 (57%)
6: C4 (38%)
17: C6 (61%)
1
2: C3 (61%)
13: C4 (30%)
1
1
4: C6 (70%)
c
9
quinolone (5) was prepared by treatment of 1 with Meldrum’s acid
O
O
OMe
F
F
OMe
OMe
OMe
d
a
d
N
N
NH2
N
N
21: C3 (91%)
2: C4 (90%)
3: C6 (88%)
OMe 18: C3 (98%)
2
19: C4 (98%)
20: C6 (85%)
OMe
1
OMe
OMe O
3 (85%)
2
2 (23%)
Scheme 2. Synthesis of fluoropropylquinoline-5,8-diones. Reagents: (a) (i) 1.0 M BH
O, 4.0 N NaOH, H
TBAF, tert-amyl alcohol, 90 C, 1 h; (d) NBS, H
3
ꢀ
ꢀ
ꢀ
in THF, 0 C, 1 h; (ii) H
2
2
O
2
, 23 C, 3 h; (b) MsCl, TEA, 25 C, 1 h; (c)
f
b
e
ꢀ
ꢀ
2
O, H
2
SO
4
, THF, 25 C, 5 min.
OMe
OMe
OMe
[18F]Fluoropropylquinoline-5,8-diones [18F]22e23 were gener-
ated by a one-pot, two-step procedure consisting of tert-alcohol
Br
Br
O
O
18
N
H
O
N
N
media [ F]fluorination and subsequent oxidative demethylation,
18
OMe
OMe
OMe
as shown in Scheme 3. The final labeled products [ F]22e23 were
O
prepared by radiofluorination of mesylate precursors 15e17 in tert-
4
(77%)
8 (65%)
6 (23%)
ꢀ
18
c
amyl alcohol at 100 C for 20 min with TBA [ F]F, generated under
no-carrier-added (NCA) conditions, followed by, without any pu-
rification procedures, direct oxidation of F-18 labeled dimethoxy
g
c
18
compounds [ F]18e20 with NBS in the presence of catalytic
amounts of sulfuric acid at room temperature for 5 min. During the
one-pot, two-step process, various reagents, chemicals, and tert-
amyl alcohol for the [ F]fluorination reaction did not inhibit oxi-
dation at all. The labeled products [ F]22e23 were isolated by
reversed-phase HPLC purification, each with high specific activities
OMe O
OMe OTf
OMe
h
c
18
18
N
N
N
H
OMe
OMe
OMe
5
(80%)
7 (52%)
9: C3 (90%)
0: C4 (86%)
1: C6 (50%)
(w230 GBq/mmol), as described in the experimental section. The
1
18
overall radiosyntheses of [ F]22e23 resulted in decay-corrected
radiochemical yields of approximately 45%, with a total synthesis
time (including HPLC purification) of 75 min from the end of
bombardment through the one-pot, two-step reaction. The radio-
1
Scheme 1. Synthesis of allyl-5,8-dimethoxylquinoline-5,8-diones as
termediate. Reagents: (a) acrolein, HBr, 60 C, 1 h; (b) NBS, CH Cl
2 2
LiBr, Pd(PPh
a
key in-
, 25 C, 12 h; (c) (i)
, THF, 30 C, 30 min; (ii) allyltributyltin, 85 C, 24 h; (d) m-CPBA, CH Cl
, chloroform, 60 C, 12 h; (f) (i) trimethylorthoformate, 90 C, 2 h;
ꢀ
ꢀ
ꢀ
ꢀ
3
)
3
2
2
,
18
ꢀ
ꢀ
ꢀ
chemical purities of [ F]22e23, which co-eluted on the analytical
6
(
5
C, 24 h; (e) POBr
3
ꢀ
ꢀ
HPLC with an authentic sample of the corresponding unlabeled
22e23, were >99%.
ii) 2,2-dimethyl-1,3-dioxane-4,6-dione, 90 C, 4 h; (g) phenyl ether, 250 C, 2 h; (h)
triflic anhydride, DMAP, 2,6-lutidine, CH
ꢀ
2
Cl
2
, 23 C, 12 h.

K. Sachin et al. / Tetrahedron 67 (2011) 1763e1767
1765
OMe
OMe
O
O
18F
flash column chromatography (hexane/EtOAc¼19:1) to give 3-allyl-
1
OMs
5
,8-dimethoxyquinoline (9) (215 mg, 90%) as a white solid; H NMR
600 MHz, CDCl
3.55 (d, J¼6.1 Hz, 2H), 3.92 (s, 3H), 4.00 (s, 3H),
.08e5.13 (m, 2H), 5.96e6.03 (m, 1H), 6.71 (d, J¼8.2 Hz, 1H), 6.85
a
(
3
) d
5
N
N
13
(
d, J¼8.2 Hz, 1H), 8.29 (s, 1H), 8.76 (s, 1H); C NMR (150 MHz,
CDCl 37.5, 55.8, 56.1, 103.8, 106.2, 117.0, 121.6, 129.7, 132.6, 133.2,
39.1, 148.5, 149.5, 150.1; FT-IR (KBr) 940, 982, 1463, 1478,
3
) d
1
1
1
8
8
8
15: C3
16: C4
17: C6
[
[
[
F]21: C3, RCY: 45%
1
1
F]22: C4, RCY: 45%
ꢂ1 þ
602 cm ; MS (EI) m/z 229 (M ), 214 (100); HRMS (EI) m/z cal-
F]23: C6, RCY: 46%
þ
2
culated for C14H15NO (M ) 229.1103, found 229.1100.
Scheme 3. Preparation of [18F]fluoropropylquinoline-5,8-diones by one-pot, two-step
reactions of radiofluorination and oxidative demethylation. Reagents: (a) (i) TBA [ F]F,
tert-amyl alcohol, 100 C, 20 min; (ii) NBS, H O, H SO , THF, 25 C, 5 min.
18
.2.1. 4-Allyl-5,8-dimethoxyquinoline (10). 1
4
H
NMR (600 MHz,
ꢀ
ꢀ
2 2 4
CDCl
3
)
d
3.60e3.61 (m, 2H), 3.87 (s, 3H), 4.06 (s, 3H), 5.12e5.16 (m,
2
H), 6.02e6.07 (m,1H), 6.72 (d, J¼8.2 Hz,1H), 6.85 (d, J¼8.2 Hz,1H),
3
. Conclusions
In summary, we have described an efficient synthetic route to
13
7
.48 (d, J¼4.1 Hz, 1H), 8.72 (d, J¼4.1 Hz, 1H); C NMR (150 MHz,
CDCl 19.0, 56.1, 56.2, 105.7, 106.7, 120.0, 120.3, 129.4, 132.4, 141.6,
45.3, 149.2, 149.9, 150.2; FT-IR (KBr) 966, 1476, 1515, 1589,
3
) d
1
regioselectively introduce a fluoropropyl group on the C3, C4, and
C6 positions of quinoline-5,8-diones. In this route, the synthetic
protocol of the protic media, fluorinationeoxidative demethylation,
described for preparation of the fluoroproylquinoline-5,8-diones, is
sufficiently rapid and efficient and appears suitable for the syn-
thesis of a variety of fused 1,4-quinone molecules labeled with the
short half-life (t1/2¼110 min) radionuclide fluoride-18 for PET mo-
lecular imaging study. Furthermore, using this efficient one-pot,
ꢂ1
þ
1617 cm ; MS (EI) m/z 229 (M ), 214 (100); HRMS (EI) m/z cal-
þ
culated for C14
H15NO
2
(M ) 229.1103, found 229.1107.
.2.2. 6-Allyl-5,8-dimethoxyquinoline (11). 1
4
H
NMR (600 MHz,
CDCl
3
)
d
3.60e3.61 (m, 2H), 3.87 (s, 3H), 4.06 (s, 3H), 5.12_5.16 (m,
2
8
H), 6.02e6.07 (m, 1H), 6.85 (s, 1H), 7.45 (dd, J¼13.0 , 4.1 Hz, 1H),
13
.37 (dd, J¼9.6 , 1.3 Hz, 1H), 8.89 (dd, J¼9.4 , 1.3 Hz, 1H); C NMR
3
(150 MHz, CDCl ) d 33.9, 55.9, 62.7, 109.2, 116.4, 121.6, 124.0, 128.6,
18
two-step protocol, synthesis of [ F]fluoropropylquinoline-5,8-
diones in high RCY within short reaction times proved possible.
130.7, 136.7, 139.8, 145.8, 148.8, 152.0; FT-IR (KBr) 920, 1503, 1504,
ꢂ1
þ
1593, 1618 cm ; MS (EI) m/z 229 (M ), 214 (100); HRMS (EI) m/z
þ
calculated for C14H15NO (M ) 229.1103, found 229.1104.
2
4
4
. Experimental section
4
.3. General procedure for the synthesis of 12e14
.1. General
To a solution of 9 (190 mg, 0.8 mmol) in dried THF (10 mL) at
ꢀ
Reagents and solvents are purchased from SigmaeAldrich and
0 C under nitrogen atmosphere was added 1.0 M bor-
anetetrahydrofuran complex (1.3 mL, 1.3 mmol). After 1 h, water
(1.0 mL) was added continuously to decompose the excess hydride.
To the reaction mixture was added 4.0 N NaOH (2.0 mL), followed
by addition of 28% hydrogen peroxide (3.0 mL) and stirred for
60 min. The crude product was extracted with EtOAc (2ꢁ5 mL) and
washed (H O, brine). The organic layer was dried over Na SO . After
used without further purification. Reaction progress was followed
by TLC on 0.25 mm silica gel glass plates containing F-254 indicator.
Visualization on TLC was monitored by UV light or radio-TLC scan-
ner. Flash chromatography was performed using a 230e400 mesh
1
silica gel (Merck KGaA). H NMR spectra were recorded on
a 600 MHz spectrometer. Chemical shifts were reported in
d units
2
2
4
(
ppm) relative to tetramethylsilane, and coupling constants were
removal of the solvent, silica gel flash column chromatography
(hexane/EtOAc¼1:5) gave 3-(3-hydroxypropyl)-5,8-dimethoxy-
13
reported in hertz. C NMR spectra were acquired at 125 MHz. Low-
and high-resolution electron impact (EI, 70 eV) spectra were
obtained. [18F]Fluoride ion was produced from a cyclotron (KIRAMS
1
quinoline (12) (125 mg, 61%) as a white solid; H NMR (600 MHz,
CDCl3)
d
1.89e1.93 (m, 2H), 2.84 (t, J¼7.8 Hz, 2H), 3.64 (t, J¼4.8 Hz,
1
8
18
1
1
3 MeV, South Korea) using the O(p,n) F nuclear reaction with
2H), 3.87 (s, 3H), 3.96 (s, 3H), 6.66 (d, J¼8.2 Hz, 1H), 6.78 (d,
18
13
9 MeV proton irradiation of an enriched [ O]H
2
O target. High-
J¼8.2 Hz, 1H), 8.27 (s, 1H), 8.74 (s, 1H); C NMR (150 MHz, CDCl )
3
performance liquid chromatography (HPLC) was performed with
a spectra system (Thermo Scientific, Waltham, MA, USA) using
d 29.5, 34.0, 55.8, 56.1, 61.9, 103.8, 106.0, 121.6, 129.7, 134.5, 139.0,
148.5, 149.5, 151.1; FT-IR (KBr) 920, 976, 1480, 1504, 1623,
ꢂ1
þ
a semipreparative column (C18 silica gel, 10
analytic column (C18 silica gel, 5
m, 4.6ꢁ250 mm). The flow was
mL/min, with a mobile phase of 10 mM aqueous phosphoric acid/
m
m, 10ꢁ250 mm) and
1624 cm ; MS (EI) m/z 247 (M ), 232 (100); HRMS (EI) m/z cal-
þ
m
culated for C14H17NO (M ) 247.1208, found 247.1207.
3
3
4.3.1. 4-(3-Hydroxypropyl)-5,8-dimethoxyquinoline (13). 1
(600 MHz, CDCl3)
1.84e1.88 (m, 2H), 3.26 (t, J¼7.6 Hz, 2H), 3.63 (t,
J¼6.2 Hz, 2H), 3.84 (s, 3H), 3.96 (s, 3H), 6.72 (d, J¼8.2 Hz, 1H), 6.86
H NMR
ethanol¼75:25 (v/v). The eluent was simultaneously monitored
with a UV detector (215 nm) and a NaI (Tl) radioactivity detector.
Radioactivity was measured in a dose calibrator.
d
13
(
d, J¼8.2 Hz, 1H), 7.12 (d, J¼4.1 Hz, 1H), 8.68 (d, J¼4.1 Hz, 1H);
NMR (150 MHz, CDCl 33.3, 34.7, 55.8, 56.1, 62.5, 105.0, 106.7,
21.1, 123.1, 141.5, 149.0, 149.5, 149.9, 150.5; FT-IR (KBr) 971, 1403,
C
4
.2. General procedure for the synthesis of 9e11
3
) d
1
ꢂ1
þ
To a mixture of 6 (280 mg, 1.0 mmol) and lithium bromide
1468, 1521, 1610, 1617 cm ; MS (EI) m/z 247 (M ), 232 (100);
HRMS (EI) m/z calculated for C14
þ
(
755 mg, 8.7 mmol) in dried THF (10 mL) under nitrogen atmo-
H17NO
3
(M ) 247.1208, found
sphere was added tetrakis(triphenylphosphine)palladium (60 mg,
247.1211.
5
4
mol %). The mixture was stirred at room temperature. After
0 min, a colorless solution was generated that was added to
4.3.2. 6-(3-Hydroxypropyl)-5,8-dimethoxyquinoline (14). 1H NMR
(600 MHz, CDCl 1.92e1.97 (m, 2H), 2.92e2.97 (m, 2H),
allyltributyltin (0.65 mL, 2.1 mmol). This mixture was heated at
8
ture and diluted with EtOAc (10 mL), and the LiBrPd(II) complex
removed by filtration. The filtrate was washed with 10% NaOH
3
) d
ꢀ
0 C for 24 h. The reaction mixture was cooled to room tempera-
3.59e3.62 (m, 2H), 3.90 (s, 3H), 4.07 (s, 3H), 6.84 (s, 1H), 7.47 (dd,
J¼12.3 , 4.1 Hz, 1H), 8.35 (dd, J¼10.2, 2.0 Hz, 1H), 8.89 (dd, J¼10.2,
13
3
2.0 Hz, 1H); C NMR (150 MHz, CDCl ) d 25.9, 33.2, 56.1, 61.4,
aqueous (2ꢁ15 mL), and the organic layer dried over Na
2
SO
4
. After
62.7, 109.0, 121.7, 123.7, 130.3, 130.5, 139.7, 145.9, 148.8, 152.3; FT-IR
(KBr) 953, 1474, 1505, 1620, 1622 cm ; MS (EI) m/z 247 (M ), 232
ꢂ1
þ
the solvents were evaporated, the residue was purified by silica gel

1766
K. Sachin et al. / Tetrahedron 67 (2011) 1763e1767
þ
ꢂ1
þ
(
100); HRMS (EI) m/z calculated for C14
H17NO
3
(M ) 247.1208,
1616, 1621 cm ; MS (EI) m/z 249 (M ), 234 (100); HRMS (EI) m/z
þ
found 247.1207.
calculated for C14
H16NO
2
F (M ) 249.1165, found 249.1162.
4
.4. General procedure for the synthesis of 15e17
4.5.2. 6-(3-Fluoropropyl)-5,8-dimethoxyquinoline (20). 1
600 MHz, CDCl
H
NMR
(
3
)
d
2.06e2.15 (m, 2H), 2.95 (t, J¼7.9 Hz, 2H), 3.88 (s,
To a solution of 12 (100 mg, 0.40 mmol) and triethylamine
3H), 4.07 (s, 3H), 4.53 (dt, J¼47.4 , 5.8 Hz, 2H), 6.85 (s, 1H), 7.46 (dd,
(
0.12 mL, 0.80 mmol) in methylene chloride (10 mL) was added
J¼12.3 , 4.1 Hz, 1H), 8.36 (dd, J¼10.3 , 1.3 Hz, 1H), 8.89 (dd, J¼10.3,
ꢀ
13
methanesulfonyl chloride (0.05 mL, 0.60 mmol) at 0 C dropwise.
1.3 Hz, 1H); C NMR (150 MHz, CDCl
3
)
d
25.9 (d, J¼4.3 Hz), 31.4 (d,
After 1 h, the reaction mixture was quenched with H
mixture was extracted with CH Cl
(1ꢁ3 mL). The organic layer was
dried overNa SO . After removalof thesolvent, silicagelflash column
2
O. The reaction
J¼20.1 Hz), 56.1, 62.5, 83.4 (d, J¼165.1 Hz), 109.0, 121.7, 124.0, 129.9,
2
2
130.6, 139.8, 146.2, 148.8, 152.1; FT-IR (KBr) 910, 912, 1470, 1504,
ꢂ1
þ
2
4
1619, 1621 cm ; MS (EI) m/z 249 (M ), 234 (100); HRMS (EI) m/z
calculated for C14
þ
chromatography (hexane/EtOAc¼1:4) gave 3-(3-methansulfonylox-
H16NO
2
F (M ) 249.1165, found 249.1162.
ypropyl)-5,8-dimethoxyquinoline (15) (76 mg, 57%) as a white solid;
1
H NMR (600 MHz, CDCl
3
)
d
2.09e2.13 (m, 2H), 2.89 (t, J¼7.5 Hz, 2H),
4.6. General procedure for the synthesis of 21e23
2
.94 (s, 3H), 3.89 (s, 3H), 3.97 (s, 3H), 4.19 (t, J¼5.9 Hz, 2H), 6.69 (d,
13
J¼8.2 Hz,1H), 6.83 (d, J¼8.2 Hz,1H), 8.29 (s,1H), 8.74 (s,1H); C NMR
A solution of 18 (50 mg, 1.6 mmol) in THF (3.0 mL) was added to
a well-stirred mixture of NBS (285 mg,1.6 mmol) in a solution of THF
(
150 MHz, CDCl
3
)
d
29.2, 30.5, 37.5, 55.9, 56.1, 68.8,104.2,106.6,121.5,
ꢀ
129.5,133.0,138.9,148.4,149.3,150.5;FT-IR(KBr)932,979,1480,1543,
2
(5.0 mL), H O (1.0 mL), and sulfuric acid (0.01 mL) at 20 C. The
ꢂ1
þ
1607, 1623 cm ; MS (EI) m/z 325 (M ), 310 (100); HRMS (EI) m/z
mixture was stirred over 15 min and basified with aqueous NaHCO
The mixture was extracted with EtOAc (3ꢁ5 mL). The organic layer
was dried over Na SO . After removal of the solvent, silica gel flash
3
.
þ
calculated for C15
H19NO S (M ) 325.0984, found 325.0982.
5
2
4
4
.4.1. 4-(3-Methansulfonyloxypropyl)-5,8-dimethoxyquinoline
column chromatography (hexane/EtOAc¼1:4) gave 3-(3-fluoro-
1
3
(16). H NMR (600 MHz, CDCl ) d 2.04e2.08 (m, 2H), 2.94 (s, 3H),
propyl)quinoline-5,8-dione (21) (40 mg, 91%) as a tan solid; mp:
ꢀ
1
3
6
8
5
.30 (t, J¼7.5 Hz, 2H), 3.89 (s, 3H), 3.96 (s, 3H), 4.22 (t, J¼6.2 Hz, 2H),
163e165 C; H NMR (600 MHz, CDCl
3
) d 1.99e2.09 (m, 2H), 2.92 (t,
.74 (d, J¼8.2 Hz, 1H), 6.89 (d, J¼8.2 Hz, 1H), 7.13 (d, J¼10.6 Hz, 1H),
J¼7.5 Hz,2H), 4.44(dt, J¼46.7, 6.8 Hz,2H),7.19(s,1H), 7.51(s,1H), 8.17
1
3
13
.71 (d, J¼10.2 Hz, 1H); C NMR (150 MHz, CDCl
3
)
d
31.2, 33.3, 37.4,
(d, J¼2.1 Hz, 1H), 8.25 (d, J¼2.1 Hz, 1H); C NMR (150 MHz, CDCl
29.6 (d, J¼4.3 Hz), 31.3 (d, J¼20.1 Hz), 82.5 (d, J¼166.6 Hz), 128.9,
133.8, 138.0, 139.2, 142.2, 145.8, 155.2, 183.2, 184.9; FT-IR (KBr) 937,
3
)
5.7, 56.2, 69.7, 105.1, 107.0, 120.8, 123.8, 141.6, 147.86, 149.1, 149.9,
d
ꢂ1
150.3; FT-IR (KBr) 928, 980, 1502, 1504, 1594, 1620 cm ; MS (EI)
þ
ꢂ1
þ
m/z 325 (M ), 310 (100); HRMS (EI) m/z calculated for C15
H19NO
5
S
1590, 1687, 1716, 1782 cm ; MS (EI) m/z 219 (M ), 191 (100); HRMS
þ
þ
(
M ) 325.0984, found 325.0982.
(EI) m/z calculated for C12
H
10NO
2
F (M ) 219.0696, found 219.0692.
4
.4.2. 6-(3-Methansulfonyloxypropyl)-5,8-dimethoxyquinoline
4.6.1. 4-(3-Fluoropropyl)quinoline-5,8-dione (22). 1H NMR (600 MHz,
CDCl
1.99e2.09 (m, 2H), 3.25 (t, J¼7.5 Hz, 2H), 4.47 (dt, J¼47.4,
5.8 Hz, 2H), 7.10 (d, J¼10.2 Hz, 1H), 7.40 (d, J¼10.2 Hz, 1H), 7.46 (d,
1
(
17). H NMR (600 MHz, CDCl
J¼7.5 Hz, 2H), 3.02 (s, 3H), 3.87 (s, 3H), 4.07 (s, 3H), 4.29 (t, J¼6.2 Hz,
H), 6.85 (s, 1H), 7.46 (dd, J¼12.3 , 4.1 Hz, 1H), 8.35 (dd, J¼10.3,
3
)
d
2.15e2.19 (m, 2H), 2.95 (t,
3
) d
13
2
J¼4.8 Hz, 1H), 8.83 (d, J¼4.8 Hz, 1H); C NMR (100 MHz, CDCl
30.4 (d, J¼4.1 Hz), 30.6 (d, J¼20.0 Hz), 83.2 (d, J¼165.4 Hz), 127.0,
130.7, 138.7, 141.2, 149.4, 153.6, 154.1, 176.4, 183.9; FT-IR (KBr) 937,
3
)
13
1
d
.3 Hz, 1H), 8.90 (dd, J¼10.3 , 1.3 Hz, 1H); C NMR (150 MHz, CDCl
26.2, 30.1, 37.4, 56.2, 62.5, 69.5, 109.0, 121.7, 124.0, 129.2, 130.6,
39.8, 146.2, 148.9, 152.2; FT-IR (KBr) 928, 978, 1471, 1503, 1594,
3
)
d
ꢂ1
þ
1
1530, 1627, 1716, 1776 cm ; MS (EI) m/z 219 (M ), 198 (100); HRMS
ꢂ1
þ
þ
1620 cm ; MS (EI) m/z 325 (M ), 310 (100); HRMS (EI) m/z cal-
(EI) m/z calculated for C12
H
10NO
2
F (M ) 219.0696, found 219.0697;
þ
ꢀ
culated for C15
H19NO
5
S (M ) 325.0984, found 325.0980.
mp: 180e182 C.
4
.5. General procedure for the synthesis of 18e20
4.6.2. 6-(3-Fluoropropyl)quinoline-5,8-dione (23). 1H NMR (600 MHz,
CDCl
1.90e1.98 (m, 2H), 2.96 (t, J¼7.5 Hz, 2H), 4.47 (dt, J¼47.4,
5.4 Hz, 2H), 7.19 (s, 1H), 7.64 (t, J¼12.4 Hz, 1H), 8.39 (t, J¼9.6 Hz, 1H),
3
) d
A mixture of 15 (40 mg, 0.12 mmol) and tetrabutylammonium
13
fluoride hydrate (TBAF) (64 mg, 0.24 mmol) was dissolved in tert-
amyl alcohol (3 mL) and heated at 80 C for 2 h. The residue was
8.98 (d, J¼4.8 Hz,1H); C NMR (150 MHz, CDCl
3
)
d
25.9 (d, J¼4.2 Hz),
ꢀ
28.8 (d, J¼21.4 Hz), 83.0 (d, J¼166.6 Hz), 109.0, 127.8, 129.3, 134.8,
extracted with EtOAc (3ꢁ5 mL), the organic layer dried over
135.7, 147.6, 154.7, 183.4, 184.6; FT-IR (KBr) 936, 1581, 1676, 1715,
ꢂ1
þ
Na
2
SO
4
, evaporated, and purified by silica gel flash column chro-
1780 cm ; MS (EI) m/z 219 (M ),198 (100); HRMS (EI) m/z calculated
þ
ꢀ
matography (60% hexane/EtOAc¼1:3) to give 3-(3-fluoropropyl)-
for C12H10NO F (M ) 219.0696, found 219.0697; mp: 156e158 C.
2
1
5
,8-dimethoxyquinoline (18) (30 mg, 98%) as a white solid; H NMR
(
600 MHz, CDCl
3
)
d
1.99e2.07 (m, 2H), 2.88 (t, J¼7.92 Hz, 2H), 3.88
4.7. General procedure for the labeling of [18F]21e23
(
1
(
s, 3H), 3.96 (s, 3H), 4.42 (dt, J¼47.4 , 5.8 Hz, 2H), 6.67 (d, J¼8.3 Hz,
1
3
[18F]Fluoride was produced in a cyclotron by the 18O(p,n)18F re-
H), 6.80 (d, J¼8.3 Hz, 1H), 8.29 (s, 1H) 8.74 (s, 1H); C NMR
18
150 MHz, CDCl
3
)
d
28.9 (d, J¼5.7 Hz), 31.9 (d, J¼20.1 Hz), 55.8, 56.1,
action. A volume of 100e200
was added to a vacutainer containing n-Bu
7.7 mol). The azeotropic distillations were conducted with 200
aliquots of CH
displacement reaction of 10 (2.5 mg, 7.7
tert-amyl alcohol (500
m
L of [ F]fluoride (370 MBq) in water
8
2.8 (d, J¼165.2 Hz), 103.9, 106.2, 121.5, 129.5, 133.5, 139.2, 148.4,
4
NHCO (40% aq, 3.7 L,
3
m
ꢂ1
149.6, 150.9; FT-IR (KBr) 914, 915, 1480, 1482, 1500, 1623 cm ; MS
m
mL
þ
ꢀ
18
(
EI) m/z 249 (M ), 234 (100); HRMS (EI) m/z calculated for
3
CN at 75 C under a stream of nitrogen. A [ F]fluoride
þ
18
C
14
H
16NO
2
F (M ) 249.1165, found 249.1162.
m
mol) with n-Bu
4
N [ F]F in
ꢀ
m
L) was carried out in a reaction vial at 100 C
4
(
3
.5.1. 4-(3-Fluoropropyl)-5,8-dimethoxyquinoline (19). 1
600 MHz, CDCl
1.95e2.03 (m, 2H), 3.30 (t, J¼7.5 Hz, 2H), 3.84 (s,
H), 3.96 (s, 3H), 4.43 (dt, J¼47.4 Hz, J¼5.8 Hz, 2H), 6.72 (d,
H
NMR
for 20 min. After cooling to room temperature, a solution of NBS
(5.6 mg, 30.7 mol) in THF (300 L), H O (100 L), and sulfuric acid
(50 L) was added to the reaction mixture directly, and stirred for
5 min at room temperature. After the reaction mixture was basified
with aqueous NaHCO , the solvent was removed with a gentle stream
3
)
d
m
m
2
m
m
J¼8.2 Hz, 1H), 6.87 (d, J¼8.2 Hz, 1H), 7.13 (d, J¼4.1 Hz, 1H) 8.70 (d,
13
J¼9.6 Hz, 1H); C NMR (150 MHz, CDCl
d, J¼18.7 Hz), 55.6, 56.2, 83.6 (d, J¼165.2 Hz), 104.9, 106.7, 121.0,
23.8, 141.8, 148.5, 150.0, 150.4; FT-IR (KBr) 904, 910, 1467, 1570,
3
)
d
32.5 (d, J¼4.3 Hz), 33.0
3
(
1
of nitrogen. The crude compound was injected onto a reversed-phase
HPLC column with 10 mM aqueous phosphoric acid (1 mL) and

K. Sachin et al. / Tetrahedron 67 (2011) 1763e1767
1767
purified. The desired compound [18F]21 was collected from the HPLC
18F-labeled derivatives [18F]21e23 are available free of charge via the
internet at http://www.elsevier.com. Supplementary data related to
this article can be found online at doi:10.1016/j.tet.2011.01.057.
(
t
R
¼12.33 min; C18 silica gel, 10 m, 4.6ꢁ250 mm; 10 mM aqueous
m
phosphoric acid/ethanol¼75:25 (v/v); 215 nm; 3 mL/min). For iden-
tification of the radioproduct, the collected HPLC fraction was co-
injected with the cold compound 21. The preparations of [1 F]22e23
were followed with the same procedure with the preparations of [ F]
2
8
18
References and notes
18
1. The total reaction time of [ F]21e23 was 75 min, and the overall
1. See: ChemBioChem 2004, 5, 557e726 Special Issue: Fluorine in the Life Sciences.
decay-corrected radiochemical yield was approximately 45%. Specific
activity was estimated bycomparing UV peakintensityof the purified
2
. (a) Gambhir, S. S. Nat. Rev. Cancer 2002, 2, 683e693; (b) Coenen, H. H.; Elsinga,
P. H.; Iwata, R.; Kilbourn, M. R.; Pillai, M. R. A.; Rajan, M. G. R.; Wagner, H. N., Jr.;
Zaknun, J. J. Nucl. Med. Biol. 2010, 37, 727e740.
1
8
[
F]-labeled compound with reference nonradioactive compounds
3. (a) Phelps, M. E. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 9226e9233; (b) Ametamey,
18
of known concentrations. The specific activities of [ F]21e23 (in the
S. M.; Honer, M.; Schubiger, P. A. Chem. Rev. 2008, 108, 1501e1516.
range of 220e250 GBq/
HPLC column.
mmol) were obtained after purification on the
4. (a) Saha, G. B. Fundamentals of Nuclear Pharmacy, 5th ed.; Springer: New York,
NY, 2003, pp 79e110; (b) Kim, D. W.; Jeong, H.-J.; Lim, S. T.; Sohn, M.-H. Nucl.
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Boger, D. L.; Yasuda, M.; Mitscher, L. A.; Drake, S. D.; Kitos, P. A.; Thompson, S. C.
J. Med. Chem. 1987, 30, 1918e1928; (c) Lazo, J. S.; Aslan, D. C.; Southwick, E. C.;
Cooley, K. A.; Ducruet, A. P.; Joo, B.; Vogt, A.; Wipf, P. J. Med. Chem. 2001, 44,
Acknowledgements
This work was supported by the Nuclear Research & De-
velopment Program of the Korea Science and Engineering Foun-
dation (KOSEF) grant funded by the Korean government (MEST)
4042e4049.
6. (a) Behforouz, M.; Haddad, J.; Cai, W.; Gu, Z. J. Org. Chem. 1998, 63, 343e346; (b)
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5390e5393; (c) Chio, H. Y.; Chi, D. Y. Tetrahedron 2004, 60, 4945e4951.
(
grant code: 2010-0017509), the Conversing Research Center Pro-
7. Kim, D. W.; Choi, H. Y.; Lee, K.-J.; Chi, D. Y. Org. Lett. 2001, 3, 445e447.
gram through the National Research Foundation of Korea (NRF)
funded by the MEST (grant code: 2010K001050), and research
funds of Chonbuk National University in 2010.
8. (a) Manske, R. H. Chem. Rev. 1942, 30, 113e144; (b) Matsumura, K. J. Am. Chem.
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Supplementary data
11. Brown, H. C.; Unni, M. K. J. Am. Chem. Soc. 1968, 90, 2902e2905.
12. (a) Kim, D. W.; Ahn, D.-S.; Oh, Y.-H.; Lee, S.; Kil, H. S.; Oh, S. J.; Lee, S. J.; Kim, J. S.;
Ryu, J. S.; Moon, D. H.; Chi, D. Y. J. Am. Chem. Soc. 2006, 128, 16394e16397; (b)
Kim, D. W.; Jeong, H.-J.; Lim, S. T.; Sohn, M.-H.; Katzenellenbogen, J. A.; Chi, D. Y.
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Detail procedures and characterization data including H and 13C
1
NMR spectra of all new compounds, and HPLC chromatograms of