Solid-phase nucleophilic fluorination

Article abstract of DOI:10.1080/00397911.2010.535950

This study demonstrates solid-phase nucleophilic fluorination. Polymer-bound 1-phenoxy-2-sulfonyloxyethane, as a model compound, is converted to a fluorinated compound in a short time. Furthermore, this method is applied to synthesize a precursor of 2-deoxy-2-fluoro-D-glucose by solid-phase synthesis using a microwave oven. Copyright Taylor & Francis Group, LLC.

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Solid-Phase Nucleophilic Fluorination
Yosuke Demizu a , Kaichi Sano a b , Naoki Terayama a , Wataru
Hakamata a , Yukiko Sato a , Hideshi Inoue b , Haruhiro Okuda a &
Masaaki Kurihara a
a Division of Organic Chemistry , National Institute of Health
Sciences , Tokyo , Japan
b Laboratory of Molecular Biochemistry, School of Life Sciences ,
Tokyo University of Pharmacy and Life Sciences , Tokyo , Japan
Accepted author version posted online: 17 Oct 2011.Published
online: 27 Feb 2012.
To cite this article: Yosuke Demizu , Kaichi Sano , Naoki Terayama , Wataru Hakamata , Yukiko Sato ,
Hideshi Inoue , Haruhiro Okuda & Masaaki Kurihara (2012) Solid-Phase Nucleophilic Fluorination,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 42:12, 1724-1730, DOI: 10.1080/00397911.2010.535950
To link to this article: http://dx.doi.org/10.1080/00397911.2010.535950
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Synthetic Communications1, 42: 1724–1730, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.535950
SOLID-PHASE NUCLEOPHILIC FLUORINATION
Yosuke Demizu,1 Kaichi Sano,1,2 Naoki Terayama,1
Wataru Hakamata,1 Yukiko Sato,1 Hideshi Inoue,2
Haruhiro Okuda,1 and Masaaki Kurihara1
1Division of Organic Chemistry, National Institute of Health Sciences,
Tokyo, Japan
2Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo
University of Pharmacy and Life Sciences, Tokyo, Japan
GRAPHICAL ABSTRACT
Abstract This study demonstrates solid-phase nucleophilic fluorination. Polymer-bound
1-phenoxy-2-sulfonyloxyethane, as a model compound, is converted to a fluorinated com-
pound in a short time. Furthermore, this method is applied to synthesize a precursor of
2-deoxy-2-fluoro-D-glucose by solid-phase synthesis using a microwave oven.
Keywords FDG; fluorination; microwave; solid-phase synthesis
INTRODUCTION
Organofluorine compounds are important building blocks in medicinal, phar-
maceutical, and agrochemical industries. In particular, 18F compounds are useful for
positron emission tomography (PET), which is an advanced biofunctional imaging
method for clinical diagnosis and uses very short half-life radioisotopes.[1]
2-Deoxy-2-fluoro-D-glucose ([18F]FDG) is the best clinically known and the most
successful commercial PET radiopharmaceutical developed so far.[2] Several drugs
Received August 31, 2010.
Address correspondence to Masaaki Kurihara, Division of Organic Chemistry, National Institute
of Health Sciences, 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan. E-mail: masaaki@nihs.go.jp
1724

SOLID-PHASE NUCLEOPHILIC FLUORINATION
1725
Figure 1. Examples of PET drugs.
have been developed for PET imaging of cancer cells and b-amyloid plaques in
Alzheimer’s disease. Some examples of labeled drugs for PET are shown in
Fig. 1.[3] The synthesis of labeled drugs for PET involves various difficult issues.
First, a very rapid process of synthesis and purification is required to allow for
the 110-min half-life of 18F. Second, synthesis must be performed using an auto-
mated device to avoid radiation exposure.
The recent solid-state synthesis of FDG by Brown et al.[4] prompted us to
describe a rapid solid-phase nucleophilic fluorination (Fig. 2).[5,6] Solid-phase syn-
thesis has various advantages: Unreacted compounds are bound to the resin and
only fluorinated compounds are released from the resin, purification is straightfor-
ward, and solid-phase reagents are handled and stored easily. Furthermore,
solid-phase synthesis is a suitable for an automated device.
Polymer-bound 1-phenoxy-2-sulfonyloxyethane 2, which contains part of the
structure of FET and BF-227, was synthesized as follows (Scheme 1): Polymer-
bound sulfonyl chloride (70–90 mesh, loading 2.5 mmol=g, 1% cross-linked with
divinylbenzene, 1) was packed in a MacroKan reactor and treated with Et3N and
2-phenoxyethanol in CH2Cl2 at room temperature for 4 days. The MacroKan
reactor was washed with MeOH and CH2Cl2 to afford compound 2.
Figure 2. Solid-phase fluorination.

1726
Y. DEMIZU ET AL.
Scheme 1. Loading 2-phenoxyethanol on resin 1.
Compound 2 in a MacroKan reactor was treated with a fluorination reagent
under several conditions. The results are summarized in Table 1. The reaction was
stopped for 30 min, and after the usual workup, only the desired product 3[7] was
obtained in 17% yield (entry 1). The yield of 3 from NH4F was somewhat reduced
as compared with nBu4NF (entry 2). Although the use of KF gave 3 in a yield similar
to that of nBu4NF, it was required for the addition of cryptand (Kryptfix 222) to
dissolve in dimethylforamide (DMF) (entry 3). A higher temperature gave a better
yield (entries 4 and 5), and sufficient reaction time gave a good yield (entry 6).
Next, we attempted to synthesize the precursor 10 of FDG by solid-phase syn-
thesis. Mannose derivative 4[8] bound to polymer-bound sulfonyl chloride 1 did not
react with fluorination reagents under any conditions. Therefore, compound 9
was synthesized with a long linker as a new solid-bound mannose derivative
(Scheme 2). The synthesis of 9 from mannose derivative 4 was as follows: Compound
4 was treated with 4-nitrobenzenesulfonyl chloride to afford sulfonylated 5 followed
by reduction of the aromatic nitro group, and compound 6 was obtained. Linker was
introduced by coupling 6 with monomethyl adipate followed by alkaline hydrolysis,
and polymer-supported sugar 9 was finally obtained by the reaction of 8 with Nova-
Syn TG hydroxyl resin by the Mitsunobu reaction. The rapid solid-phase fluorina-
tion of 9 was performed with nBu4NF assisted with a microwave oven at 200 ꢀC
for 5 min, and a fluorinated product 10 was obtained with 6% yield (estimated based
on the amount of nBu4NF). The yield of solid-phase fluorination seemed to be some-
what low; however, this method gave only the desired product 10 without the need
Table 1. Solid-phase fluorination of model compound 2
Entry
Source of Fꢁ
Time (h)
Temp. (ꢀC)
Yield (%)a
1
2
3
4
5
6
nBu4NF
NH4F
0.5
0.5
0.5
0.5
0.5
6
100
100
100
50
17
12
KFb
18
nBu4NF
nBu4NF
nBu4NF
7
79
150
100
>99
aEstimated based on the amount of fluorination reagent using HPLC analysis.
bCryptand (Kryptfix 222) was added.

SOLID-PHASE NUCLEOPHILIC FLUORINATION
1727
Scheme 2. Solid-phase fluorination of FDG precursor.
for further purification[8] and was suitable for practical applications. Nucleophilic
fluorination of 2-sulfonlyoxy mannose derivative leads to an undesired product;
see Ref. 8. Treatment of 10 with acid gave FDG.[8]
The results show this is a practical method for solid-phase nucleophilic fluor-
ination. 1-Phenoxy-2-sulfonyloxyethane bound to a polymer was efficiently fluori-
nated to compound 3. The solid-phase fluorination of mannose derivative 9
afforded FDG precursor 10 with high purity without further purification. Develop-
ment of an automatic synthesis system for solid-phase fluorination and the use of an
[18F]-fluoride source are under way.
EXPERIMENTAL
Typical Procedure for Fluorination of Compound 2
Under an inert atmosphere, compound 2 (400 mg) was added to a solution of
nBu4NF (9.0 mg, 0.034 mmol) in DMF (20 mL) and then stirred for 30 min at 150 ꢀC.

1728
Y. DEMIZU ET AL.
The solution was poured into water and extracted with EtOAc. The combined
organic layer was dried over Na2SO4, and the solvent was removed under reduced
pressure to afford 3 (3.8 mg, 79% yield) without the need for further purification.
Methyl-3-O-benzyl-4,6-O-benzylidene-2-O-p-nitrobenzenesulfonyl-b-D-
mannopyranoside (5). p-Nitrobenzenesulfonyl chloride (0.47 g, 2.12 mmol) was
added to a solution of alcohol 4 (0.4 g, 1.06 mmol) in dry pyridine (10 ml), and stirred
at 80 ꢀC for 24 h. The reaction mixture was neutralized with 1 M aqueous HCl and
then extracted with EtOAc. The organic phase was washed with brine solution, dried
over Na2SO4, and concentrated in vacuo, and the resulting residue was purified by
column chromatography (SiO2, hex=EtOAc ¼ 2=1) to afford the sulfonate 5
(0.57 g, 96%).
1H NMR (400 MHz, CDC13) d 3.37 (dd, J ¼ 4.8, 10.0 Hz, 1H), 3.45 (s, 3H),
3.77 (dd, J ¼ 3.2, 9.6 Hz, 1H), 3.86 (d, J ¼ 10.4 Hz, 1H), 3.94 (m, 1H), 4.32 (dd,
J ¼ 4.8, 10.4 Hz, 1H), 4.51 (d, J ¼ 1.2 Hz, 1H), 4.69–4.77(m, 2H), 5.25 (dd, J ¼ 1.2,
3.2 Hz, 1H), 5.58 (s, 1H), 7.29–7.47 (m, 10H), 8.05–8.15 (m, 4H); ESI-MS: m=z:
580 [M þ Na]þ.
Methyl-3-O-benzyl-4,6-O-benzylidene-2-O-p-aminobenzenesulfonyl-b-
D-mannopyranoside (6). Encapsulated palladium on carbon (0.23 g, 3.9% load-
ing) was added to a solution of 5 (0.30 g, 0.54 mmol) in EtOH (30 ml) under an
atmosphere of hydrogen gas. The mixture was stirred for 2 h before filtering through
celite. The solvent was removed in vacuo, and the crude product was purified by col-
umn chromatography (SiO2, hex=EtOAc ¼ 2=3) to furnish the product 6 (0.28 g,
98%).
1H NMR (400 MHz, CDC13) d 3.34 (ddd, J ¼ 4.8, 10.0, 14.4 Hz, 1H), 3.46 (s
3H), 3.71 (dd, J ¼ 3.2, 10.0 Hz, 1H), 3.85 (d, J ¼ 10.0 Hz, 1H), 3.94 (dd, J ¼ 10.0,
14.4 Hz, 1H), 4.09 (s, 2H), 4.28 (dd, J ¼ 4.8, 10.0 Hz, 1H), 4.45 (d, J ¼ 0.8 Hz, 1H),
4.70–4.83 (m, 2H), 5.21 (dd, J ¼ 0.8, 3.2 Hz, 1H), 5.56 (s, 1H), 6.56–6.59 (m, 2H),
7.30–7.48 (m, 10H) 7.72–7.74 (m, 2H); ESI-MS: m=z: 550 [M þ Na]þ.
Methyl-3-O-benzyl-4,6-O-benzylidene-2-O-p-(6-methoxy-6-oxohexan-
amido)benzenesulfonyl-b-D-mannopyranoside (7). Methyl hydrogen adipate
(210 ml, 1.47 mmol), diethylphosphoryl cyanide (240 ml, 1.49 mmol), and Et3N
(415 ml, 2.97 mmol) were added to a solution of alcohol 6 (0.26 g, 0.49 mmol) in
dry CH2Cl2 (15 ml), and stirred at room temperature for 21 h before the addition
of saturated aqueous NaCl (10 mL) to quench. The reaction mixture was extracted
with EtOAc, the combined organic extract was washed with brine and dried over
Na2SO4, and the solvent was removed in vacuo. The residue was purified via column
chromatography (SiO2, hex=EtOAc ¼ 2=3) to afford the product 7 (0.21 g, 65%).
1H NMR (400 MHz, CDCl3) d 1.68–1.81 (m, 4H), 2.40 (m, 4H), 3.33 (ddd,
J ¼ 5.2, 9.6, 10.4 Hz, 1H), 3.43 (s, 3H), 3.70 (dd, J ¼ 3.6, 9.6 Hz, 1H), 3.69 (s, 3H)
3.84 (m, 1H), 3.94 (m, 1H), 4.28 (m, 1H), 4.45 (d, J ¼ 1.2 Hz, 1H), 4.70–4.80 (m,
2H), 5.21 (m, 1H), 5.56 (s, 1H), 7.28–7.92 (m, 15H); ESI-MS m=z 692 [M þ Na]þ.
Methyl-3-O-benzyl-4,6-O-benzylidene-2-O-p-(5-carboxypentanamido)-
benzenesulfonyl-b-D-mannopyranoside (8). Aqueous NaOH 1 M, (12 ml) was
added to a solution of 7 (0.43 g, 0.64 mmol) in MeOH and stirred at room tempera-
ture for 2 h. The mixture was neutralized with 1 M aqueous HCl (15 ml) and

SOLID-PHASE NUCLEOPHILIC FLUORINATION
1729
extracted with EtOAc, the combined organic extracts were washed with brine and
dried over Na2SO4, and the solvent was removed in vacuo. The residue was purified
via column chromatography (SiO2, CH2Cl2=MeOH ¼ 10=1) to afford the product 8
(0.33 g, 78%).
1H NMR (400 MHz, CDC13) d 1.71–1.85 (m, 4H), 2.43 (m, 4H), 3.33 (ddd,
J ¼ 4.8, 9.6, 10.4 Hz, 1H), 3.43 (s, 3H), 3.71 (dd, J ¼ 3.2, 9.6 Hz, 1H), 3.84 (m, 1H),
3.94 (m, 1H), 4.28 (m, 1H), 4.45 (d, J ¼ 1.2 Hz, 1H), 4.70–4.80 (m, 2H), 5.21 (m, 1H),
5.56 (s, 1H), 7.28–7.91 (m, 15H), 9.02 (br s, 1H); ESI-MS m=z: 654 [M ꢁ H]-.
Coupling of Acid 8 to NovaSyn TG Hydroxy Resin
PPh3 (0.18 g, 0.7 mmol) and diethyl acetylenedicarboxylate (DEAD, 1.26 ml,
2.8 mmol) were added to a hydroxy resin (NovaSyn TG hydroxy resin, 200-400
mesh, loading 0.64 mmol=g, 1.09 g) and acid 8 in THF (10 ml). The reaction was
stirres gently under Ar gas at rt for 14 h. The resin was removed by filtration; washed
with THF (3 ꢂ 10 ml), DMF (3 ꢂ 10 ml), EtOH (3 ꢂ 10 ml), Et2O (3 ꢂ 10 ml); and
dried in vacuo at rt for 24 h.
Methyl-3-O-benzyl-4,6-O-benzylidene-2-fluoro-b-D-glucopyranoside (10).
Under an inert atmosphere, compound 9 (120 mg) and nBu4NF (42.7 mg,
0.167 mmol) in DMF (1 mL) were put into a 2-ml reaction tube sealed by the rubber
stopper, and then MW irradiation was carried out for 5 min at 200 ꢀC. The solution
was poured into water and extracted with EtOAc. The combined organic layer was
dried over Na2SO4, and the solvent was removed under reduced pressure to afford 10
(3.7 mg, 6% yield) without the need for further purification.
1H NMR (400 MHz, CDC13) d 3.59 (s, 3H), 3.49–3.94 (m, 4H), 4.34
(d, J ¼ 7.8 Hz, 1H), 4.38 (dd, J ¼ 4.6, 10.0 Hz, 1H), 4.49 (d, J ¼ 2.0 Hz, 1H), 4.86
(s, 2H), 5.56 (s, 1H), 7.27–7.55 (m, 10H); ESI-MS m=z: 375 [M þ H]-.
ACKNOWLEDGMENT
This work was supported in part by the Budget for Nuclear Research of the
Ministry of Education, Culture, Sports, Science, and Technology, based on screening
and counseling by the Atomic Energy Commission.
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