Hydroacylation of 4-[18F]fluorobenzaldehyde: A novel method for the preparation of 4′-[18F]phenylketones

Article abstract of DOI:10.1002/jlcr.623

To assess the potential of intermolecular hydroacylation reactions as a new fluorine-18 labeling method, model reactions of [¹⁸F]fluorobenzaldehyde with three different olefins (1-hexene (2a), allylbenzene (2b), and 3-phenoxypropene (2c)) in th

Full text of DOI:10.1002/jlcr.623

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2002; 45: 1045–1053.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.623
Research Article
18
Hydroacylation of 4-[ F]fluorobenzaldehyde:
a novel method for the preparation of
0
18
-[ F]phenylketones
4
1
1
Noor-Ul Hasan Khan , Byung Chul Lee , Sang-Yoon Lee ,
2
2
Yearn Seong Choe , Chul-Ho Jun and Dae Yoon Chi *
3
1,
1
Department of Chemistry, Inha University, 253 Yonghyundong Namgu, Inchon
4
2
02-751, South Korea
Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan
University School of Medicine, 50 Ilwon-dong Kangnam-ku, Seoul 135-710,
South Korea
3
Department of Chemistry, Yonsei University, Seoul 120-749, South Korea
Summary
To assess the potential of intermolecular hydroacylation reactions as a new
1
fluorine-18 labeling method, model reactions of [ F]fluorobenzaldehyde with
8
three different olefins (1-hexene (2a), allylbenzene (2b), and 3-phenoxypropene
(
2c)) in the presence of Wilkinson’s catalyst were performed. The procedure
1
8
gave high radiochemical yields (38–62%) of [ F]fluorophenylketones with
short reaction times (15 min). The intermolecular hydroacylation reaction
provides a new method for the preparation of fluorine-18 labeled com-
pounds. Copyright # 2002 John Wiley & Sons, Ltd.
1
8
Key Words: hydroacylation; p-[ F]fluorophenylalkyl ketone; F-18 labeling;
1
8
[
F]fluorobenzaldehyde; Wilkinson’s catalyst; Positron emission tomography
*Correspondence to: D. Y. Chi, Department of Chemistry, Inha University, 253 Yonghyundong
Namgu, Inchon 402-751, Korea. E-mail: dychi@inha.ac.kr
Contract/grant sponsor: Korea Science and Engineering Foundation; contract/grant number:
97-03-01-05-5-L
Copyright # 2002 John Wiley & Sons, Ltd.
Received 15 October 2001
Revised 1 December 2001
Accepted 31 May 2002

1
046
N-U. H. KHAN ET AL.
Introduction
Positron emission tomography (PET) is widely used as a basic tool for
1
the medical imaging of the human body. Fluorine-18 (t ¼ 110 min) is
1=2
a popular radionuclide for labeling biomolecules. Although fluorine-18
plays an important role in the field of biomedicinal chemistry, only few
chemical reactions are suitable for the introduction of fluorine-18 to
2
–5
biomolecules with high specific radioactivity.
An adequate method
for labeling of a molecule with fluorine-18 requires rapid, convenient
6
and efficient incorporation of the radionuclide into the molecule of
interest. Although fluorine-18 labeled aliphatic compounds can be easily
7
synthesized by nucleophilic substitution on sulfonate esters or by
8–11
halofluorination on olefins,
aromatic fluorides are more stable in vivo
than aliphatic fluorides. In general, aromatic fluorides do not easily
undergo metabolic defluorination in vivo, and therefore, it is desirable to
introduce the fluorine-18 to the aromatic ring. There are a number of
1
8
publications that describe these reactions, for example, the [ F]fluoride
ion displacement reaction of a leaving group on the aromatic ring with
an electron withdrawing group, such as a carbonyl group, ortho or para
to the leaving group. Another useful reaction is a fluoride ion
displacement of (4-formylphenyl)trimethylammonium triflate (4), pro-
1
8
12–14
18
viding 4-[ F]fluorobenzaldehyde (1).
This 4-[ F]fluorobenzalde-
hyde can be used directly in the reductive amination, or after further
1
modifications, such as reduction and iodonation to [ F]fluorobenzyl
8
15,16
iodide followed by N-alkylation.
Hydroacylation is a useful method for the synthesis of ketones from
aldehydes and olefins via C–H activation. Recently, Jun et al. developed
I
a general method for intermolecular hydroacylation using a Rh
7–19
1
complex and 2-amino-3-picoline as cocatalyst.
They observed a
remarkable enhancement of the reactivity when both benzoic acid and
aniline were used as additives. In the absence of both benzoic acid and
aniline in the reaction, the yield of intermolecular hydroacylation of
benzaldehyde and 1-hexene was less than 20% in 12 h, and the addition
of aniline alone increased the yield to 60% in 12 h. Moreover, the
presence of both additives increased the yield up to 98% within 1 h.
To assess the potential of intermolecular hydroacylation for the
1
8
fluorine-18 labeling, the radiochemical syntheses of [ F]fluorophenyl-
18
ketones from [ F]fluorobenzaldehyde and three different olefins
1-hexene (2a), allylbenzene (2b), and 3-phenoxypropene (2c)) were
(
evaluated.
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2002; 45: 1045–1053

1
8
HYDROACYLATION OF 4-[ F]FLUOROBENZALDEHYDE
1047
Results and discussion
Hydroacylation reactions of olefin 2 with 4-fluorobenzaldehyde
cold reactions)
(
Hydroacylation reaction of model olefins with 4-fluorobenzaldehyde
proceeded in moderate yield as summarized in Table 1 (Scheme 1).
At the tracer level, the solvent of choice for the preparation of
1
8
4
-[ F]fluorobenzaldehyde is dimethylsulfoxide (DMSO) as shown in
Scheme 2. If the hydroacylation reaction would go well in DMSO, we
1
8
would not have to change the solvent or to isolate 4-[ F]fluorobenzal-
dehyde in the next hydroacylation step. However, we have found that
the hydroacylation does not proceed in DMSO or acetonitrile, while
toluene is known as the best solvent for hydroacylation reaction. When
the hydroacylation reaction was carried out in one-tenth scale of the
reactions in Table 1 while the solvent volume was kept the same (entry
1
, Table 2), the yield dramatically dropped to 19%. Reoptimization of
Table 1. Hydroacylation reactions of olefin 2 with 4-fluorobenzaldehyde in
a
toluene or THF
b
Entry
Olefins
Solvent
Toluene
THF
Yield (%)
c
1
2
3
2a
2a
2b
68
50
d
c
70
Toluene
4
5
2b
2c
THF
Toluene
58
85
c
6
2c
THF
72
a
Reaction condition: To a stirred solution of 4-fluorobenzylaldehyde (54 ml, 500 mmol), 2-amino-3-
picoline (9.6 ml, 100 mmol), benzoic acid (3.8 mg, 30 mmol), aniline (27 ml, 300 mmol), and olefins
(
2500 mmol) in appropriate solvent (90 ml) was added Rh(PPh
3
)
3
Cl (9 mg, 10 mmol) as a catalyst and
the reaction mixture was heated at 1308C for 1 h.
O
H
O
R
Rh(PPh ) Cl
3
3
+
R
F
F
2
-amino-3-picoline
1
2a, R = n-butyl
benzoic acid
aniline
toluene (or THF)
3
2
2
b, R = CH Ph
2
c, R = CH OPh
2
1
30 °C
Scheme 1.
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2002; 45: 1045–1053

1
048
N-U. H. KHAN ET AL.
O
O
H
H
DMSO
0 °C, 5 min
18F
nBu N18
F
+
4
9
N
+
−
OTf
[18F]1
4
Scheme 2.
Table 2. Optimization of reactions of olefin 2 with 4-fluorobenzaldehyde in
a
toluene or THF in diluted condition
b
Entry
Olefins
Solvent
Yield (%)
c
1
2a
2a
2a
2b
Toluene
Toluene
THF
19
40
27
53
2
3
4
d
Toluene
5
6
2b
2c
THF
Toluene
32
58
e
e
40
7
2c
THF
a
Reaction condition: To a stirred solution of 4-fluorobenzaldehyde (5.3 ml, 50 mmol), 2-amino-3-
picoline (2.9 ml, 30 mmol), benzoic acid (0.3 mg, 3 mmol), aniline (0.9 ml, 10 mmol), and olefins
3 3
(250 mmol) in appropriate solvent (200 ml) was added Rh(PPh ) Cl (3.4 mg, 4 mmol) as a catalyst and
the reaction mixture was heated at 1308C for 1 h.
HPLC yields.
b
c
This reaction was carried out in one-tenth scale of the reactions in Table 1 except solvent volume.
Care should be taken while using THF at high temperature.
Reaction was carried out for 45 min.
d
e
the hydroacylation reaction was thus made and smaller amounts of
-fluorobenzaldehyde (50 mmol) were sufficient to give the same yield of
the product as with the large amounts of the aldehyde (Table 2).
4
18
Hydroacylation reaction of 4-[ F]fluorobenzaldehyde with olefins 2
hot reactions)
(
1
In radiotracer experiments, the preparation of 4-[ F]fluorobenzalde-
8
1
hyde ([ F]1) was achieved by the nucleophilic aromatic substitution of
8
1
4-formylphenyl)-trimethylammonium triflate by [ F]fluoride ion in
8
(
DMSO at 908C within 5 min in an overall 90% yield as shown in
Scheme 2. [ F]1 was characterized by radio-TLC and separated by C-18
1
8
1
cartridge. The isolated [ F]1 was used for intermolecular hydroacyla-
4
18
tion of three different olefins using Wilkinson’s catalyst with other
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2002; 45: 1045–1053

1
8
HYDROACYLATION OF 4-[ F]FLUOROBENZALDEHYDE
1049
1
Table 3. Hydroacylation reaction of 4-[ F]fluorobenzaldehyde with olefins 2
8
a
b
Radiochemical field (%)
Toluene
c
c
Entry
Olefin
THF
d
1
2
3
2a
2b
2c
38 ꢀ 6.7 (3)
30 ꢀ 2.1 (3)
33 ꢀ 7.9 (3)
44 ꢀ 6.2 (3)
47 ꢀ 1.6 (3)
62 ꢀ 4.5 (3)
a
Typical hydroacylation reaction was carried out in
F]fluorobenzaldehyde (40–50 mCi), 2-amino-3-picoline (5 ml, 52 mmol), benzoic acid (1.5 mg,
2 mmol), aniline (1.5 ml, 19 mmol), olefine (165 mmol), toluene (or THF 100 ml) and Rh(PPh Cl
a
sealed vial.
A
solution of 4-
1
8
[
1
3 3
)
(2 mg, 2.3 mmol) was heated for 15 min at 1108C and then cooled. In the case of involving further
characterization, the product was purified by HPLC.
Average yield (%) measured by radio-TLC.
b
c
Volume of the solvent was 100 ml.
Number of reactions.
d
cocatalysts listed in Scheme 1. The progress of the reaction was
monitored by radio-TLC. Surprisingly, the acylation has been achieved
1
9
within 15 min only at 1108C, while Jun et al.
hydroacylation with benzaldehyde and 1-hexene in 45–60 min at
308C (Table 3). The radiochemical yield of the hydroacylated product
reported the
1
was not improved after 15 min, except the formation of some side
products.
1
Because [ F]1 is volatile and DMSO is not easily removed, a one-pot
8
1
8
synthesis was attempted in THF. The radiochemical yields of [ F]1
varied from 5 to 50%, and unknown compounds appeared during
hydroacylation in THF. Therefore, DMSO was used for preparation of
1
8
4
-[ F]fluorobenzaldehyde.
The maximum yield of hydroacylation was obtained in toluene rather
than in THF. The reason may be that THF is more polar solvent that
can make weak interaction with metal ion. The resulting competition
between olefin and THF seems to be responsible for the low yield. The
radiochemical yields of hydroacylations ranged from 30 to 62% (decay
corrected). The yield was the highest in the reaction of 3-phenoxypro-
18
pene and 1 or [ F]1. This may be due to electron donating property of
the phenoxide group that makes the reaction more feasible compared to
entries 1 and 2 (Table 3). Authenticity of the radiolabeled products,
3
a–c was confirmed by coinjection with the unlabeled authentic samples
by HPLC.
1
8
In conclusion, the efficient coupling of 4-[ F]fluorobenzaldehyde
with three alkenes was carried out in good radiochemical yield under
mild reaction conditions with a short reaction time. Intermolecular
hydroacylated products 3a–c were obtained with 10–15% isolated yield
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2002; 45: 1045–1053

1
050
N-U. H. KHAN ET AL.
(decay corrected from EOB) and the total time of synthesis was 60 min
from EOB. This reaction may be useful for the introduction of
1
8
[
F]fluorophenyl group to a variety of compounds.
Experimental
Materials and methods
All chemicals used were of reagent grade. Anhydrous solvents were
dried over a proper drying agent and used freshly distilled. The products
were separated by column chromatography using Merck silica gel (mesh
1
size 230–400 ASTM). H NMR spectra were obtained on Varian
1
3
Gemini-400 or 200 (Palo Alto, CA, USA) and C NMR spectra at 100
or 50 MHz. Chemical shifts were reported in parts per million (ppm, d
units). Chemical Ionization (CI) mass spectra were obtained on a
1
8
GC/MS QP5050A spectrometer (Shimadzu, Kyoto, Japan). [ F]Fluor-
18
ide ion was prepared form [ O]H O (Rotem Industries, Ltd., Israel) as
2
20
described previously in the PETtrace cyclotron (GEMS, Uppsala,
Sweden). High performance liquid chromatography (HPLC) was
carried out on a Thermo Separation Products System (Fremont, CA,
USA) with a semipreparative column (Alltech Econosil silica gel, 10 mm,
1
0 ꢁ 250 mm). The eluant was simultaneously monitored by a UV
detector (254 nm) and a NaI(Tl) radioactivity detector. Thin layer
chromatography (TLC) was performed on Merck F254 silica plates and
a Bioscan radio-TLC scanner (Washington DC, USA) was used for
radio-TLC.
1
-(4-Fluorophenyl)heptan-1-one (3a). A screw caped vial charged
with 4-fluorobenzaldehyde (54 ml, 0.5 mmol), 2-aminopicoline (10 ml,
0
1
.1 mmol), benzoic acid (3 mg, 0.03 mmol), aniline (27 ml, 0.3 mmol),
-hexene (210 ml, 2.5 mmol) and toluene/THF (90 ml) was stirred for a
few minutes. Rh(PPh ) Cl (9 mg, 0.01 mmol) was added into the
3
3
reaction mixture and the whole reaction mixture was heated with
stirring at 1308C for 1 h. After cooling the reaction mixture to room
temperature, the product 3a was isolated by flash column chromato-
graphy using hexane:ethyl acetate (4:1 mixture) as a white solid: m.p.
1
3
1
7
3.3–35.38C; H NMR (200 MHz, CDCl ) d 0.89 (t, J ¼ 6:2 Hz, 3 H),
3
.25–1.33 (m, 6 H), 1.60–1.80 (m, 2 H), 2.93 (t, J ¼ 7:4 Hz, 2 H),
.07–7.16 (m, 2 H), 7.94–8.01 (m, 2 H); C NMR (50 MHz, CDCl3)
1
3
d 198.9, 165.7 (d, J ¼ 252:6 Hz), 133.6, 130.6 (d, J ¼ 9:1 Hz), 115.6
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2002; 45: 1045–1053

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HYDROACYLATION OF 4-[ F]FLUOROBENZALDEHYDE
1051
(
d, J ¼ 21:6 Hz), 38.6, 31.7, 29.0, 24.4, 22.5, 14.0; MS(CI) m/z 209.2
+ +
M +1, 100), 138, 123, 113. HRMS (EI) m/z C H FO (M ) calcd:
(
13 17
2
08.1263; found: 208.1265.
-(4-Fluorophenyl)-4-phenylbutan-1-one (3b). The synthesis proce-
1
dure is same as for (3a) except allylbenzene (2.5 mmol, 330 ml): White
1
solid; m.p. 49.2–50.38C; H NMR (200 MHz, CDCl ) d 2.03–2.11
3
(
m, 2 H), 2.72 (t, J ¼ 7:3 Hz, 2 H), 2.95 (t, J ¼ 7:3 Hz, 2 H), 7.06–7.29
13
(
m, 7 H), 7.90–7.97 (m, 2 H); C NMR (100 MHz, CDCl ) d 198.5,
3
1
1
1
2
65.5 (d, J ¼ 253.0 Hz), 141.6, 133.4, 130.6 (d, J ¼ 9:1 Hz), 128.5, 128.4,
+
26.0, 115.6 (d, J ¼ 22:0 Hz), 37.5, 35.1, 25.6; MS(CI) m/z 243 (M +1,
00). HRMS (EI) m/z C H FO (M ) calcd: 242.1107; found:
+
16
15
42.1101.
-(4-Fluorophenyl)-4-phenoxybutan-1-one (3c). The synthesis proce-
1
dure is same as for (3a) except allyl phenyl ether (2.5 mmol, 342 ml) and
1
reaction was heated for 45 min: White solid; m.p. 59.4–61.28C; H NMR
(
(
(
(
200 MHz, CDCl ) d 2.16–2.30 (m, 2 H) 3.18 (t, J ¼ 7:1 Hz, 2 H), 4.07
t, J ¼ 5:8 Hz, 2 H), 6.87–7.31 (m, 7 H), 7.97–8.04 (m, 2 H); C NMR
3
1
3
100 MHz, CDCl ) d 198.0, 165.7 (d, J ¼ 253.2 Hz), 158.8, 133.4, 130.6
3
d, J ¼ 9:8 Hz), 129.5, 120.7, 115.7 (d, J ¼ 21:2 Hz), 114.4, 66.7, 34.9,
+
3.8; MS(CI) m/z 259 (M +1), 193, 165 (1 0 0), 95. HRMS (EI) m/z
2
+
C H FO (M ) calcd: 258.1056; found: 258.1059.
1
6
15
2
General procedure for hydroacylation reaction of olefins with
-fluorobenzaldehyde in diluted condition. To a stirred solution of
-fluorobenzaldehyde (5.3 ml, 50 mmol), 2-aminopicoline (2.9 ml,
0 mmol), benzoic acid (0.3 mg, 3 mmol), aniline (0.9 ml, 10 mmol) and
4
4
3
olefins (250 mmol), toluene/THF (200 ml), Rh(PPh ) Cl (3.4 mg, 4 mmol).
3
3
The whole reaction mixture was heated with stirring at 1308C for 45 min
to 1 h. After removal of solvent and addition of hexane, the catalyst was
removed by filtration. The product was analyzed by HPLC.
1
8
General procedure for hydroacylation reaction of 4-[ F]fluorobenzal-
18
18
dehyde with olefins. 4-[ F]Fluorobenzaldehyde ([ F]1) was obtained
from (4-formylphenyl)trimethylammonium triflate (4) and no-carrier-
1
8
ꢂ
o
18
added [ F]F in DMSO (90 C, 5 min). The [ F]fluoride ion was
resolubilized with THF (300 ml) and transferred to a glass vial
containing (4-formylphenyl)trimethylammonium triflate (4, 2 mg,
6
.4 mmol). The resolubilization procedure took 10–15 min with 85%
yield. [ F]1 was separated by C-18 cartridge in either toluene (or
2
1
18
THF). Typical hydroacylation reaction was carried out in a sealed vial.
18
A solution of 4-[ F]fluorobenzaldehyde (1.48–1.85 MBq), 2-aminopico-
line (5 ml, 52 mmol), benzoic acid (1.5 mg, 12 mmol), aniline (1.5 ml,
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2002; 45: 1045–1053

1
052
N-U. H. KHAN ET AL.
1
9 mmol) and olefins (165 mmol), toluene/THF (100 ml), Rh(PPh ) Cl
3
3
(2 mg, 2.3 mmol) was heated for 15 min at 1108C and cooled. Product
was checked by radio TLC and was purified using radio HPLC.
Purification of F-18 labeled products were carried out on a HPLC
column (Alltech Econosil silica gel, 10 m, 250 ꢁ 10 mm) eluted with a
8
0:20 hexane:CH Cl2 at a flow 4 ml/min. Authenticity of the
2
products were confirmed by coelution with unlabeled standards on
0
0
HPLC: 3a, R ¼ 12:3 min, k ¼ 1:73; 3b, R ¼ 20:2 min, k ¼ 3:51; 3c,
R ¼ 33:5 min, k ¼ 6:61.
t
t
t
0
Acknowledgements
We are grateful for the support of this work through grants from the
Korea Science and Engineering Foundation (No. 97-03-01-01-5-L) and
National Research Laboratory Program. N. H. Khan would like to
acknowledge the sanction of sabbatical leave from CSMCRI, Bhavna-
gar, Gujarat, India. Supported by Postdoctoral Fellowship from Inha
University.
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