Perfluorinated markers for hypoxia detection: Synthesis of sulfur-containing precursors and [18F]-labelling

Article abstract of DOI:10.1016/j.bmc.2004.11.010

Synthetic pathways of two novel sulfurated precursors for [ ¹⁸F]-labelling by oxidative fluorodesulfurization reaction are described. A three-step sequence starting from N-phthalimido-β-alanine allows the preparation of a new trithioorthoester as valuable precursor of the synthesis of [¹⁸F]-3,3,3-trifluoropropylamine, a convenient radiolabelled intermediate for [¹⁸F]-EF3. A five-step sequence for the preparation of methyl 4-phthalimido-2,2-difluoropropanedithioate from ethyl 2,2-difluoropropanoate, via the key conversion step of α,α′- difluorothioamidate to the corresponding α,α′- difluorodithioester, and the first results of its use as precursor for oxidative fluorodesulfurization in [¹⁸F]-radiochemistry are also presented.

Full text of DOI:10.1016/j.bmc.2004.11.010

Bioorganic & Medicinal Chemistry 13 (2005) 1357–1367
Perfluorinated markers for hypoxia detection: synthesis of
sulfur-containing precursors and [18F]-labelling
Arnaud Cheguillaume,a Jacques Gillart,b Daniel Labar,b
c
Vincent Gregoire and Jacqueline Marchand-Brynaert
a,
*
´
a
´
´
ˆ
´
Unite de Chimie Organique et Medicinale, Batiment Lavoisier, place L. Pasteur nꢀ1, Universite catholique de Louvain,
B-1348 Louvain-la-Neuve, Belgium
b
´
ˆ
´
Unite de Tomographie Positrons, Batiment De Hemptinne, Chemin du cylcotron nꢀ2, Universite catholique de Louvain,
B-1348 Louvain-la-Neuve, Belgium
c
ˆ
´
Hopital Universitaire Saint-Luc, Laboratoire de Radiobiologie, avenue Hippocrate nꢀ10, Universite catholique de Louvain,
B-1200 Bruxelles, Belgium
Received 25 May 2004; accepted 5 November 2004
Available online 24 November 2004
Abstract—Synthetic pathways of two novel sulfurated precursors for [18F]-labelling by oxidative fluorodesulfurization reaction are
described. A three-step sequence starting from N-phthalimido-b-alanine allows the preparation of a new trithioorthoester as valu-
able precursor of the synthesis of [18F]-3,3,3-trifluoropropylamine, a convenient radiolabelled intermediate for [18F]-EF3. A five-step
sequence for the preparation of methyl 4-phthalimido-2,2-difluoropropanedithioate from ethyl 2,2-difluoropropanoate, via the key
conversion step of a,a0-difluorothioamidate to the corresponding a,a0-difluorodithioester, and the first results of its use as precursor
for oxidative fluorodesulfurization in [18F]-radiochemistry are also presented.
ꢁ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
NO2
NO2
X
X
H
N
OH
F
F
Hypoxia, that is, low tissue oxygen concentration, is a
typical feature in various pathological states such as
malignant tumour development, heart disease, stroke,
diabetes and wound healing. In solid tumours, experi-
mental and clinical evidences have shown that the hyp-
oxic fraction may influence the malignant phenotype,
the growth rate and the metastatic potential. Cellular
hypoxia is also known to reduce the sensitivity to radi-
ation therapy and to confer some resistance to chemo-
therapy.1 For these reasons, markers of hypoxia are
important prognostic tools in medicine. Nitroimidazole
derivatives constitute actually a major class of chemical
markers from which a few representatives (misonidazole
for instance; Scheme 1) have been radiolabelled with
[18F]-fluorine, thus making possible the in vivo detection
of hypoxia by a non-invasive imaging technique, namely
the positron emission tomography (PET).2–4 The most
N
N
N
N
X
O
F
Misonidazole (X=OMe)
[
EF3 (X=H)
EF5 (X=F)
18F]-Fluoromisonidazole
(X=18F)
Scheme 1. Hypoxia-binding chemical markers.
lipophilic nitroimidazole derivatives, such as EF3
[2-(2-nitroimidazol-1-yl)-N-(3,3,3)-trifluoropropyl)-acet-
amide] and EF5 [2-(2-nitroimidazol-1-yl)-N-(2,2,3,3,3)-
pentafluoropropyl)-acetamide] (Scheme 1), allowed bio-
distribution to all organs, including the brain.1,5 The
[18F]-fluorine radiolabelling of such hypoxia-detection
agents appears of great interest because the same mole-
cules could be measured both invasively and non-inva-
sively (the cold drug being the carrier of the
radioactive agent), in the same tumours.3,4
Keywords: Hypoxia detection; [18F]-labelling; Trithioorthoester; a,a0-
difluorodithioester.
The radiolabelling of perfluorinated motifs (CF3, C2F5)
is scarcely described in the literature. The methods
are based on isotopic exchange6,7 and nucleophilic
*
Corresponding author. Tel.: +32 10 472740; fax: +32 10 474168;
e-mail: marchand@chim.ucl.ac.be
0968-0896/$ - see front matter ꢁ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.11.010

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A. Cheguillaume et al. / Bioorg. Med. Chem. 13(2005) 1357–1367
X
X
X
X
X
X
FtN
SR
SR
FtN
SR
[F18]-H2N
CF3
SR
S
1a, X=H
b, X=F
2
3
Scheme 2. Sulfur-containing precursors of [18F]-labelled trifluoro- and pentafluoropropylamines.
substitution,8–11 from particular precursors, by using
[18F]–KF/[2,2,2]-kryptofix. Electrophilic fluorination
with [18F]–F2 has been mentioned in two cases: the
preparation of [18F]-EF512 from N-(2,3,3-trifluoroal-
lyl)-acetamide precursor, and the synthesis of [18F]-tri-
fluoromethyl ketones13 from the corresponding 2,2-
difluorosilylenol ethers.
2.1. Synthesis of trithioorthoesters
Only punctual examples of oxidative fluorodesulfuriza-
tion applied to trithioorthoester precursors are men-
tioned in the previous literature.24–26 We decided yet
to evaluate this synthetic route because, in the case of
success, this would be the shortest one towards 1a,b.
Recently, we considered the oxidative fluorodesulfuriza-
tion reaction14,15 as a useful strategy for [18F]-radiola-
belling of the CnF2n+1 motifs found in the hypoxia
markers EF3 and EF5. For that purpose, we developed
[18F]–HFÆpyridine16 as labelling reagent for the trans-
formation of dithioesters into [18F]–CF3 moieties, in
the presence of DBH (1,3-dibromo-5,5-dimethylhydan-
toin) as source of Br+ ion. The method was successfully
applied to the preparation of [18F]-EF3 (Scheme 1);17
the key intermediate was [18F]-3,3,3-trifluoropropyl-
amine 1a obtained by the radiolabelling of ethyl 3-
phthalimidopropanedithioate 3a (Scheme 2).18
The one-step transformation of an ester function into a
trithioorthoester function has been recently described by
using an excess of trimethylaluminium (10equiv) and a
large excess of alkane thiol (30equiv); the process was
developed in a-aminoacid and peptide series.27,28 Start-
ing from N-phthalimido-b-alanine (4a), we prepared
the corresponding acid chloride (5a) and then the t-butyl
ester 6a in 72% yield, which treatment with AlMe3/EtSH
gave the expected trithioethyl orthoester 7a in 52% yield
after several purifications by column chromatography
(Scheme 3). Indeed, the main side product was the cor-
responding dithioethyl keteneacetal resulting from EtSH
elimination (olefinic proton at d = 6.0ppm). The quater-
nary carbon of the orthoester function (7a) gave a typi-
cal line at d = 69.9ppm in 13C NMR.
In continuation of our previous work, we report now the
preparation of novel sulfur-containing precursors (tri-
thioorthoester 2 and dithioester 3; Scheme 2) for the
oxidative fluorodesulfurization reaction with [18F]–
HFÆpyridine and DBH. The aim was to optimalize our
former synthesis of [18F]-EF319 and to propose an
alternative route towards [18F]-EF520 regarding the
electrophilic method of Koch and co-workers12 based
on [18F]–F2, a labelling reagent much less practical than
[18F]–HFÆpyridine.
Disappointingly, the same sequence of reactions per-
formed with N-phthalimido-a,a0-difluoro-b-alanine
(4b)29 did not furnish the desired product 7b; extensive
HF elimination and degradation occurred.
Having in hand the acid chloride 5b, we tested the pos-
sible direct formation of dithioester 3b (R= Et) by reac-
tion with the Davyꢁs reagent.30 We recovered the
thiolester 8b (44% isolated yield) and side products 8c
and 8d corresponding to the thionation of the phthal-
imide protecting group (monothionation 8c: C@S at
d = 196.6ppm and dithionation 8d: C@S at d =
197.3ppm), but no traces of the dithioester could be
identified.
2. Results and discussion
The hypoxia-markers EF3 and EF5 could be easily pre-
pared by coupling the tetrafluorophenyl ester of 2-(2-
nitroimidazol-1-yl) acetic acid21,22 with 3,3,3-trifluoro-
propylamine 1a17 and 2,2,3,3,3-pentafluoropropylamine
1b,23 respectively. We have previously shown that the
experimental conditions of this reaction (reaction time,
temperature, solvent, purification) are compatible with
the radiolabelling requirements when using [18F]-1a as
reagent.19 We have also established the advantages of
the phthalimido N-protective group: (i) this group is
stable under the drastic conditions of oxidative fluo-
rodesulfurization; (ii) this group is rapidly cleaved with
aqueous hydrazine at 85ꢀC; (iii) the resulting amine,
thus obtained ꢀacid freeꢁ, is readily purified by distilla-
tion from the aqueous mixture under an argon
stream.17 Accordingly, our synthetic targets are the N-
phthalimido-trithioorthoesters 2a,b and dithioester 3b
(Scheme 2).
2.2. Synthesis of dithioesters (Scheme 4)
We already prepared dithioester 16a, precursor of [18F]-
EF3, in six steps with an overall yield of 21% from N-
Boc-b-alanine.17,18 We thus applied the same synthetic
scheme for the preparation of dithioester 16b from ethyl
a,a0-difluoro-b-alanine (9b),29 with a minor modification
in the synthesis of the amide 11b. Indeed, due to the acti-
vating effect of the CF2 group, which increases the elec-
trophilic character of the carbonyl function, 11b could
be quantitatively obtained by simple aminolysis of the
ethyl ester 10b. In the non-fluorinated series, the corre-
sponding amide 11a resulted from the coupling of
N-Boc-b-alanine with ammonium bicarbonate in the

A. Cheguillaume et al. / Bioorg. Med. Chem. 13(2005) 1357–1367
1359
COCl
CO2H
CO2R
i
ii
FtN
FtN
FtN
X
X
X
X
X
X
4a, X=H
b, X=F
5a, 95%
b, 98%
6a, 76% (R=tBu)
b, 70% (R=iPr)
iv
iii
O
SEt
SEt
SEt
FtN
SEt
FtN
X
X
X
X
7a, 52%
b, 0%
8b, 44%
S
S
S
S
COSEt
COSEt
N
N
EtS
P
P
SEt
S
F
F
F
F
S
and
O
S
(Davy's reagent)
8c
8d
(side-products)
Scheme 3. Synthesis of trithioorthoester. Reagents and conditions: (i) (COCl)2, DMF catal., CHCl3; (ii) R–OH, CHCl3; (iii) AlMe3 (10equiv), EtSH
(30equiv), CH2Cl2, 0–20ꢀC; (iv) Davyꢁs reagent, THF, reflux, 18h; then toluene reflux, 18h.
presence of EEDQ (2-ethoxy-1-ethoxycarbonyl-1,2-dihy-
droquinoline) as activating agent.18 The next step was
the thionation of 11b with the Lawessonꢁs reagent31 to
furnish the thioamide 12b in moderate yield after
chromatography. Activation of the thioamide 12b by
transformation into the corresponding thioacyl-N-
phthalimide32 (13b) was less efficient compared to the
non-fluorinated analogue (13a). In this reaction with
phthaloyl dichloride, the thioamide function of 12b acts
as the nucleophilic partner, and thus the neighbouring
CF2 motif exercises a deactivating effect. Further treat-
ment of 13b with an excess of ethanethiol in the presence
of triethylamine gave the ethyl dithioester 14b in 70%
yield after chromatography. The following steps were,
as previously, the Boc deprotection with trifluoroacetic
acid and the two-step introduction of the phthalimido
protective group,33 transforming 15b into the target
16b, namely ethyl 3-phthalimido-2,2-difluoropropane
dithioate. Unfortunately, due to an arduous purifica-
tion, the yield of pure 16b was rather low (25%). As a
consequence, the overall yield of 16b from 9b is only
3%, for seven steps.
2.3. Synthetic improvement (Scheme 5)
Since the synthesis of 16b outlined in Scheme 4 was not
satisfactory, we examined a modified route based on
the thiolysis of thioamidium salt. This method was orig-
inally developed by Viehe and co-workers34,35 for the
preparation of methyl trifluorodithioacetate. N,N-di-
methylamide 17b was quantitatively formed by treatment
of ethyl ester 10b with dimethylamine in methanol. Thio-
nation with the Lawessonꢁs reagent31 gave thioamide
18b, which Boc protective group was cleaved with TFA
and replaced by the phthalimido group as previously
described. The resulting compound 20b was treated with
methyl triflate to furnish the reactive intermediate 21b
resulting from S-alkylation of the thioamide function.
The thioamidium salt was not isolated, but directly
reacted with H2S to give the dithioester 22b. The target
compound was contaminated with variable amounts of
thiolester 23b, depending on the presence of moisture in
the reaction medium. However, 22b could be separated
from 23b by column chromatography and the isolated
yields were around 60%. Compounds 17b to 23b (Scheme
5) were characterized by the usual spectroscopies (see
Experimental); 13C NMRchemical shifts of carbonyl
and thiocarbonyl carbons are presented in Table 1. Our
improved synthetic route allowed thus to obtain methyl
3-phthalimido-2,2-difluoropropanedithioate (22b) from
10b in five steps, with an overall yield of 18.5%.
All compounds were characterized by the usual spec-
troscopies (see experimental). Typical 13C NMRfea-
tures are summarized in Table 1; the shielding effect of
the neighbouring CF2 motif can be pointed out (b series
of compounds).

1360
A. Cheguillaume et al. / Bioorg. Med. Chem. 13(2005) 1357–1367
X
X
X
X
X
X
i
ii
H3N
OEt
BocHN
OEt
BocHN
NH2
96%
84%
CF3CO2
O
O
O
9a, X=H
b, X=F
10b
11b
O
X
X
X
X
iii
iv
BocHN
NH2
BocHN
N
S
S
O
12a, 70% (ref. 18)
b, 51%
13a, 65% (ref. 18)
b, 45%
X
X
X
X
v
vi
BocHN
SEt
H3N
SEt
CF3CO2
S
S
14a, 75% (ref. 18)
b, 70%
15a, 95% (ref. 18)
b, 95%
O
N
O
F
F
vii, viii
16a, 90% (ref. 17)
b, 25%
SEt
S
Scheme 4. Synthesis of dithioester (first method). Reagents and conditions: (i) (Boc)2O, py, CH2Cl2; (ii) NH3, MeOH; (iii) Lawessonꢁs reagent;
(iv) phthaloyl dichloride, py; (v) EtSH, Et3N; (vi) TFA; (vii) 2-(methoxycarbonyl)benzoic acid, PyBOP; (viii) p-TsOH.
Table 1. 13C NMRchemical shifts (ppm) in CDCl
3
Compd
O@C–OEt
O@C–SRO
8; 23
@C–NR2
11; 17
—
S@C–NR2
12; 18
S@C–SR
10
14; 15; 16; 22
a
b
—
163.2
—
191.75 (R= Et),
192.33 (R= Me)
174.1 (R= H)
167.8a (R= H)
207.6 (R= H)
195.4 (R= H)
—
188.9 (R= Me)
235.6; 235.4; 233.0
222.5 (R= Me)
162.8 (R= Me)
a Solvent CD3OD.
2.4. [18F]-radiolabelling
We similarly conducted the [18F]-labelling of methyl
N-phthalimido-2,2-difluoro-propanedithioate
(Scheme 7).
(22b)
[18F]–HFÆpyridine was prepared from dry [18F]–KF and
HFÆpyridine, as previously described.17 By using the
radiolabelling process of 3a,17 that is, the preparation
of a [18F]-labelled intermediate 24 resulting from the sub-
stitution of one ethylthioxy group by [18F]-fluoride
under DBH activation followed by the substitution of
the remaining ethylthioxy groups by a large excess of
unlabelled fluoride (Scheme 6), we could obtain [18F]-
N-phthalimido-3,3,3-trifluoropropylamine (25a) from
the precursor trithioorthoester 7a.
We recovered [18F]-N-phthalimido-2,2,3,3-tetrafluoro-3-
methylthioxy-propylamine (26) as the main product and
variable amounts of the corresponding HF-elimination
product 27, depending on the reaction time in the excess
of HFÆpyridine used (analysis of the crude mixtures by
HPLC with double detection and mass spectrometry).
It appears thus that the creation of the CF3 motif next
to a pre-existing CF2 motif by S/F nucleophilic exchange
is rather difficult: the reaction stopped after the intro-
duction of two fluorine atoms.36 Even after addition of
a large excess of a silver or mercury salt and prolonged
reaction time (total reaction time: 40min), we found that
the reluctant methylthioxy group could not be satisfac-
torily substituted by HFÆpyridine. The expected [18F]-
The labelled compound was identified by HPLC (UV
and radiodetection) and mass spectrometry, by compar-
ison with an authentical sample. The reaction time was
less than 25min and the radiochemical yield was around
1.6% (decay corrected) (60.01mmol of precursor 7a).

A. Cheguillaume et al. / Bioorg. Med. Chem. 13(2005) 1357–1367
1361
F
F
F
F
i
ii
BocHN
OEt
BocHN
NMe2
66%
100%
O
O
10b
17b
F
F
F
F
iii
iv, v
52%
BocHN
NMe2
H3N
NMe2
95%
CF3CO2
S
S
18b
19b
F
F
F
F
vii
vi
FtN
SMe
Me
FtN
NMe2
>70%
N
S
Me
20b
21b (not isolated)
F
F
F
F
FtN
SMe
FtN
SMe
S
O
22b
23b
Scheme 5. Synthesis of dithioester (second method). Reagents and conditions: (i) HNMe2, MeOH, 1h, 0ꢀC; (ii) Lawessonꢁs reagent, toluene, 2h,
100ꢀC; (iii) TFA–CH2Cl2 (1:1), 1h, 0ꢀC; (iv) and (v): see Scheme 4; (vi) CF3SO3Me, CH2Cl2, 2h, rt; (vii) H2S, CH2Cl2, 0ꢀC, 1h.
Br
Et
+
SEt
18F
S
SEt
SEt
SEt
SEt
SEt
SEt
i
ii
FtN
FtN
FtN
7a
24
18F
F
F
iii, iv
FtN
[
18F]-25a
Scheme 6. [18F]-radiolabelling of trithioorthoester. Reagents and conditions: (i) DBH (2equiv); (ii) [18F]–HFÆpyridine (7equiv of fluoride), CH2Cl2,
20ꢀC, 10min; (iii) DBH (4equiv); (iv) HFÆpyridine (140equiv of fluoride), 20ꢀC, 10min.
N-phthalimido-2,2,3,3,3-pentafluoropropylamine (25b)
was identified only as traces in HPLC by comparison
with an authentical sample. Optimalization of the pro-
duction of [18F]-25b is still under investigation. An alter-
native strategy is currently examined, that is, the
radiolabelling of dithioketal or oxime derivatives of
the N-(phthalimido)methyl trifluoromethyl ketone pre-
cursor (CF2 labelling instead of CF3 labelling).
3. Conclusion
The [18F]-labelled precursors 25a and 25b of the hypoxia
markers [18F]-EF3 and [18F]-EF5 (see Schemes 1 and 2)
have been prepared from novel sulfur-containing com-
pounds, respectively N-phthalimido-3,3,3-(triethyl-
thioxy)propylamine (7a, see Scheme 6) and methyl
N-phthalimido-2,2-difluoropropanedithioate (22b, see

1362
A. Cheguillaume et al. / Bioorg. Med. Chem. 13(2005) 1357–1367
Br
S
Br
18F
SMe
S
S
i
ii
FtN
SMe
FtN
SMe
FtN
F
F
F
F
F
F
22b
Br
Br
18F
SMe
F
S
18F
SMe
v, iv
iii
iv
FtN
FtN
F
F
F
F
26
F
F
18F
SMe
18F
+
FtN
FtN
F
F
F
F
18F]-25b (traces)
27
[
Scheme 7. [18F]-radiolabelling of a,a0-difluorodithioester 22b. Reagents and conditions: (i) DBH (3equiv); (ii) [18F]–HFÆpyridine (7equiv of fluoride),
CH2Cl2, 20ꢀC, 15min; (iii) DBH (6equiv), (iv) HFÆpyridine (240equiv of fluoride), 20ꢀC, 15min; (v) HgCl2 (20equiv) or AgX.
Scheme 7). The preparation of [18F]-25a works, while
the similar synthesis of [18F]-25b remains to be con-
firmed. This work represents the first example of the
[18F]-labelling of the CF3 motif by oxidative fluorodesul-
furization reaction of a trithioorthoester precursor, and
constitutes a significant improvement of the [18F]-EF3
preparation since the radiolabelling precursor is now di-
rectly available from t-butyl N-phthalimido-b-alaninate
6a (see Scheme 3).
tive elimination of HF occurred to furnish [18F]-27 as
the major product. Thus other routes towards [18F]-
25b have to be explored.
4. Experimental
Solvents were dried before use. Reagents (from Acros,
Fluka or Aldrich) were used as purchased. Melting
points (uncorrected) were recorded on an Electrother-
For the [18F]-labelling of the C2F5 motif of EF5, we se-
lected a a,a0-difluoro-dithioester precursor. This class of
compounds is scarcely described in the literature,37–40
comparatively to the simple dithioesters.41–43 The lack
of convenient methods of preparation, compatible with
N-functionalized aliphatic starting materials, led us to
propose the route outlined in Scheme 5, and applicable
to a,a0-difluoro-b-amino-esters, a class of compounds
now readily accessible.44,45 Our method relies upon: (i)
the transformation of the ester function into N,N-di-
methyl-thioamide; (ii) the S-alkylation with methyl tri-
flate followed by the in situ thiolysis.
mal apparatus. H (200MHz) and 13C (50MHz) NMR
1
spectra were recorded on Varian Gemini 200 spectro-
meter; 13C (125MHz) NMRspectra were recorded
on Bruker AM-500 apparatus and 19F (282MHz) on
Varian Gemini 300 spectrometer. Chemical shifts are
reported as d values (ppm) downfield from TMS. Mass
spectra were obtained on a Finnigan-MAT TSQ-70
instrument at 70eV. HRMS was recorded at the Univer-
sity of Mons, Belgium (Prof. R. Flammang). TLC were
carried out using silicagel 60 F254 (0.2mm, Merck) and
spots were visualized by UV. Silica gel 60, mesh size
0.04–0.063mm (Merck), was used for column
chromatography.
Having in hand the a,a0-difluoro-dithioester precursor
22b, we investigated the feasibility of the [18F]-labelling
of a C2F5 motif by S/F nucleophilic displacement acti-
vated with DBH as oxidant. We found that the tetraflu-
oro derivative [18F]-26 was readily and nearly
quantatively obtained; the radiolabelling of a tetrafluori-
nated motif has not been reported yet. However, the re-
quired [18F]-pentafluorinated compound 25b, resulting
from a forced substitution of the last alkylthio group
in the presence of a strong thiophilic Lewis acid, could
not be obtained at the preparative scale since competi-
4.1. 3-Phthalimido-propanoyl chloride (5a)
To a cold (0ꢀC) solution of N-phthalimido-b-Ala–OH
4a (2.5g, 11.41mmol) in ethanol-free chloroform
(12mL) and with a catalytic amount of DMF, was
added oxalyl chloride (2.9g, 2mL, 22.82mmol), drop-
wise and under vigorous stirring. After 10min at 0ꢀC,
and progressive return at room temperature, completion
of the reaction was observed with the end of CO2
release. Concentration of the solvent under reduced

A. Cheguillaume et al. / Bioorg. Med. Chem. 13(2005) 1357–1367
1363
pressure gave crude 5a as a yellow solid directly used in
the following step. Yield: 95% (2.58g); 1H NMR
(200MHz, CDCl3): d = 3.34 (t, 2H, J = 7Hz, CH2),
4.03 (t, 2H, J = 7Hz, CH2), 7.71–7.88 (m, 4H, C6H4).
2.18mol). After 15min of stirring, a solution of 6a
(2g, 7.27mmol) in chloroform (34mL) was added and
the cold bath was removed. After 24h stirring at room
temperature, the solution was poured in ice (140g) and
after the end of gas release, extracted with chloroform
(3 · 140mL). The organic phase was dried (MgSO4)
and concentrated to afford a pale yellow oil, which
was purified by flash chromatography on silica gel (ethyl
acetate/hexane: 2/98, (ethyl acetate/hexane: 20/80,
4.2. 3-Phthalimido-2,2-difluoropropanoyl chloride (5b)
To a cold (0ꢀC) solution of 3-phthalimido-2,2-difluoro-
propanoic acid 4b (0.30g, 1.18mmol) in ethanol-free
chloroform (10mL) and with a catalytic amount of
DMF, was added oxalyl chloride (0.3g, 0.21mL,
2.365mmol), dropwise and under vigorous stirring.
After 10min at 0ꢀC, and progressive return at room
temperature, completion of the reaction was observed
with the end of CO2 release. Concentration of the sol-
vent under reduced pressure gave crude 5b as a yellow
Rf = 0.67)) to afford 7a as a colourless oil. Yield:
1
52% (1.39g); H NMR(200MHz, CDCl ): d = 1.29 (t,
3
9H, J = 7.5Hz, CH3), 2.25 (m, 2H, CH2), 2.81 (q, 2H,
J = 7.5Hz, CH2), 4.11 (m, 2H, CH2), 7.70–7.87 (m,
4H, C6H4); 13C NMR(50MHz, CDCl 3): d = 13.82
(CH3), 24.65 (SCH2), 34.17 (CH2), 34.41 (CH2), 69.87
(C), 123.30, 132.38, 134.06 arom., 168.29 (N–C@O);
MS (ꢀc CI, CH4–NO2): m/z = 369.2 (Mꢀ1),
C17H23NO2S3.
solid directly used in the following step. Yield: 100%
1
(0.325g); H NMR(200MHz, CDCl ): d = 4.41 (t, 2H,
3
JHF = 7Hz, CH2), 7.78–7.96 (m, 4H, C6H4); 19F NMR
(282MHz, CDCl3/CFCl3): d = ꢀ104.96 (t, JF–H
=
4.6. Ethyl 3-phthalimido-2,2-difluoropropanethioate (8b)
12.7Hz, CH2CF2).
To a solution of 5b (0.238g, 0.87mmol) in THF (5mL)
was added Davyꢁs reagent (0.272g, 0.87mmol). The mix-
ture was heated to reflux during 18h. After cooling to
room temperature and concentration of the solvent under
reduced pressure, purification by flash chromatography
on silica gel (ether/petroleum ether: 3/17 (Rf = 0.11))
afforded 8b as an orange solid. Yield: 44% (0.114g);
mp = 121–122ꢀC; 1H NMR(200MHz, CDCl 3):
d = 1.31 (t, 3H, J = 7.3Hz, CH3), 3.00 (q, 2H,
J = 7.3Hz, CH2S), 4.31 (t, 2H, JHF = 13.6Hz, CH2CF2),
4.3. tert-Butyl 3-phthalimido-propanoate (6a)
To a crude solution of 5a (2.58g, 10.84mmol) in etha-
nol-free chloroform (12mL) was added a large excess
of tBuOH (3mL). After stirring for 24h and concentra-
tion of the solvent under reduced pressure, the residue
was purified by flash chromatography on silica gel (ethyl
acetate/hexane: 20/80 (Rf = 0.42)) to afford 6a as a white
solid. Overall yield for the two steps: 72% (2.26g);
mp = 112–113ꢀC; 1H NMR(200MHz, CDCl 3):
d = 1.41 (s, 9H, CH3), 2.65 (t, 2H, J = 7.3Hz, CH2),
3.96 (t, 2H, J = 7.3Hz, CH2), 7.70–7.88 (m, 4H,
7.78–7.95 (m, 4H, C6H4); 19F NMR(282MHz, CDCl /
3
CFCl3): d = ꢀ107.71 (t, JF–H = 13.8Hz, CH2CF2); 13C
NMR(125MHz, CDCl 3): d = 13.93 (CH3), 23.52
(CH2), 39.77 (t, JC–F = 32Hz, CH2CF2), 114.36 (t,
JC–F = 258Hz, CF2), 123.76, 131.74, 134.56 arom.,
167.07 (s, N–C@O), 191.75 (t, JC–F = 32Hz, C@O);
MS (+c APCI, CH4–NO2): m/z = 299.9 (M+1),
C13H11F2NO3S.
C6H4); 13C NMR(50MHz, CDCl ): d = 28.18 (CH3),
3
34.17 (CH2), 34.41 (CH2), 81.23 (C), 123.44, 132.33,
134.13 arom., 168.15 (N–C@O), 170.10 (C@O); MS
(+c CI, CH4–NO2): m/z = 276.1 (M+1), C15H17NO4.
4.4. iso-Propyl 3-phthalimido-2,2-difluoropropanoate (6b)
4.7. Ethyl 3-thiophthalimido-2,2-difluoropropanethioate
8c and ethyl 3-dithiophthalimido-2,2-difluoropropane-
thioate 8d
To a crude solution of 5b (0.1g, 0.39mmol) was added a
large excess of i-PrOH (3mL). After stirring for 24h and
concentration of the solvent under reduced pressure, the
residue was purified by flash chromatography on silica
gel (ethyl acetate/hexane: 20/80, (Rf = 0.75)) to afford
6b as a brown oil, which solidified slowly. Overall yield
for the two steps: 78% (0.09g); 1H NMR(200MHz,
CDCl3): d = 1.22 (d, 6H, J = 5.1Hz, CH3), 4.05
To a suspension of 8b (0.074g, 0.2.47mmol) in toluene
(10mL) was added Davyꢁs reagent (0.042g, 0.136mmol).
The mixture was heated to reflux over night. After cool-
ing to room temperature and concentration of the sol-
vent under reduced pressure, separation by flash
chromatography on silica gel (ether/petroleum ether:
3/17 (8c Rf = 0.58 and 8d Rf = 0.31)) afforded 8c as a pink
oil, which crystallizes slowly, and 8d as a red oil. Com-
pound 8c yield: 32% (0.025g); 8d yield: 63% (0.052g):
(sept, 1H, J = 5.1Hz, CH), 4.31 (t, 2H, JHF
=
13.6Hz, CH2), 7.74–7.94 (m, 4H, C6H4); 19F NMR
(282MHz, CDCl3/CFCl3): d = ꢀ109.83 (t, JFH
=
12.7Hz, CH2CF2); 13C NMR(50MHz, CDCl 3):
d = 21.60 (CH3), 40.30 (t, JC–F = 29.5Hz, CH2CF2),
72.22 (CH), 117.86 (t, JC–F = 254Hz, CF2), 123.90,
131.94, 134.58 arom., 162.27 (t, JC–F = 31Hz, C@O),
167.21 (s, N–C@O).
Compound 8c 1H NMR(200MHz, CDCl ): d = 1.31 (t,
3H, J = 7.4Hz, CH3), 3.00 (q, 2H, J = 7.4Hz, CH2S),
4.73 (t, 2H, JHF = 13.36Hz, CH2CF2), 7.72–8.06 (m,
3
2H, 1H, 1H, C6H4); 19F NMR(282MHz, CDCl
/
3
4.5. 3-Phthalimido-propyl trithioethyl orthoester (7a)
CFCl3): d = ꢀ106.02 (t, JF–H = 13.8Hz, CH2CF2); 13C
NMR(125MHz, CDCl 3): d = 14.00 (CH3), 23.68
(CH2), 42.26 (t, JC–F = 28.2Hz, CH2CF2), 114.61 (t,
JC–F = 258.4Hz, CF2), 123.38, 124.54, 126.95, 133.80,
134.65, 137.32 arom., 168.97 (s, N–C@O), 192.02 (t,
To a cold (0ꢀC) solution of AlMe3 (2.0M in heptane,
36.36mL, 72.72mmol) in ethanol-free chloroform
(140mL) was added dropwise EtSH (16.12mL,

1364
A. Cheguillaume et al. / Bioorg. Med. Chem. 13(2005) 1357–1367
JC–F = 31.9Hz, C@O), 196.64 (s, N–C=S); MS (+c
APCI, CH4–NO2): m/z = 315.9 (M+1), C13H11F2NO2S2.
residue was purified by flash chromatography on silica
gel (hexane/ethyl acetate: 80/20 (Rf = 0.18)) to afford
(12b) as a white solid. Yield: 69% (4.80g); mp = 131–
Compound 8d 1H NMR(200MHz, CDCl 3): d = 1.31 (t,
3H, J = 7.5Hz, CH3), 2.98 (q, 2H, J = 7.5Hz, CH2S),
5.19 (t, 2H, JHF = 13.3Hz, CH2CF2), 7.72–7.95 (m,
2H, 2H, C6H4); 19F NMR(282MHz, CDCl /CFCl3):
d = ꢀ103.85 (t, JF–H = 12.83Hz, CH2CF2); 133C NMR
(125MHz, CDCl3): d = 14.00 (CH3), 23.69 (CH2),
132ꢀC; H NMR(200MHz, CDCl ): d = 1.46 (s, 9H,
1
3
CH3), 3.97 (dt, 2H, JHF = 14Hz, JHH = 6.9Hz,
CH2CF2), 4.89 (s, 1H, NH), 7.63 (s, 2H, NH2);
19F NMR(282MHz, CDCl 3/CFCl3): d = ꢀ105.68 (t,
JF–H = 15Hz, CH2CF2); 13C NMR(50MHz, CDCl ):
3
d = 28.46 (CH3), 45.05 (t, JC–F = 25.6Hz, CH2CF2),
80.8 (C), 117.51 (t, JC–F = 254Hz, CF2), 155.74 (s, N–
C@O), 195.37 (t, JC–F = 26Hz, C=S); MS (+c CI,
CH4–NO2): m/z = 241.0 (M+1), C8H14F2N2O2S.
44.47 (t, JC–F = 27.3Hz, CH2CF2), 114.77 (t, JC–F
=
259.3Hz, CF2), 123.90, 133.70, 134.65, 134.96 arom.,
192.22 (t, JC–F = 31.9Hz, C@O), 197.35 (s, N–C=S);
MS (ꢀc APCI, CH4–NO2): m/z = 331.0 (Mꢀ1),
C13H11F2NOS3.
4.11. (N-tert-Butoxycarbonyl) 3-amino-2,2-difluoropro-
panethioacyl N-phthalimide (13b)
4.8. Ethyl (N-tert-butoxycarbonyl)-3-amino-2,2-difluoro-
propanoate (10b)
To a mixture of thioamide 12b (0.439g, 1.83mmol) and
pyridine (0.588mL, 0.578g, 7.32mmol) in dichlorome-
thane (15mL), cooled a 0ꢀC, was added dropwise (with-
in 4h and stirring under argon atmosphere) a solution of
phthaloyl dichloride (0.316mL, 0.446g, 2.196mmol) in
dichloromethane (15mL). After completion of the addi-
tion, the mixture was further stirred over night at 20ꢀC,
then poured into water (20mL) and extracted with ethyl
acetate (3 · 20mL). The organic phase was dried
(MgSO4), concentrated and purified by chromatography
on silica gel (hexane/ethyl acetate: 80/20 (Rf = 0.28)) to
afford 13b as a colourless oil, which crystallizes slowly.
Yield: 24% (0.165g); 1H NMR(200MHz, CDCl 3):
d = 1.45 (s, 9H, CH3), 3.97 (dt, 2H, JHF = 14Hz,
JHH = 6.9Hz, CH2CF2), 4.95 (s, 1H, NH), 7.74–7.91
(m, 4H, C6H4); 19F NMR(282MHz, CDCl 3/CFCl3):
d = ꢀ106.08 (t, JF–H = 12.7Hz, CH2CF2); 13C NMR
To a solution of 9b (4.18g, 15.68mmol) in dichlorome-
thane (10mL) and pyridine (5mL), cooled at 0ꢀC and
under stirring for 10min, was added dropwise a solution
of di-tert-butyl-dicarbonate (3.42g, 15.68mmol) in
dichloromethane (5mL). After the addition was com-
plete, the mixture was further stirred for 15h at 20ꢀC,
then poured into H2O (10mL) and extracted with
dichloromethane (2 · 15 mL). Drying (MgSO4) and
concentration of the solvent gave 10b as colourless oil.
Yield: 84% (3.31g); 1H NMR(200MHz, CDCl 3):
d = 1.36 (t, 3H, J = 7.1Hz, CH3), 1.44 (s, 9H, CH3),
3.76 (dt, 2H, JHF = 13.4Hz, JHH = 6.7Hz, CH2CF2),
4.33 (q, 2H, J = 7.16Hz, CH2O); 19F NMR(282MHz,
CDCl3/CFCl3): d = ꢀ111.66 (t, JF–H = 13Hz, CH2CF2);
13C NMR (50MHz, CDCl3): d = 13.91 (CH3), 28.29
(CH3), 43.71 (t, JC–F = 28.3Hz, CH2CF2), 63.26
(CH2O), 80.50 (C), 113.46 (t, JC–F = 251Hz, CF2),
155.50 (s, N–C@O), 163.19 (t, JC–F = 31.5Hz, C@O);
(125MHz, CDCl3): d = 28.36 (CH3), 44.78 (t, JC–F
=
28.3Hz, CH2CF2), 80.7 (C), 117.4 (t, JC–F = 253Hz,
CF2), 124.21, 131.58, 134.761, 155.85 (s, N–C@O),
195.17 (t, JC–F = 25.5Hz, C=S).
MS
(APCI,
CH4–NO2):
m/z = 254.2
(M+1),
C10H17F2NO4.
4.12. Ethyl 3-phthalimido-2,2-difluoropropane dithioate
(16b)
4.9. (N-tert-Butoxycarbonyl)-3-amino-2,2-difluoropro-
panamide (11b)
To a cold (0ꢀC) solution under argon atmosphere of 13b
(0.25g, 0.676mmol) in chloroform (3mL) were added
successively ethanethiol (0.25mL, 0.209g, 3.38mmol)
and dropwise triethylamine (0.094mL, 0.069g,
0.676mmol). The solution was allowed to reach room
temperature within 1h and left for another 1h at
20ꢀC. After addition of 4N NaOH (3mL), the mixture
was rapidly extracted with chloroform (3 · 3mL), dried
over MgSO4 and concentrated under vaccum. Purifica-
tion by flash chromatography on silica gel (hexane/ethyl
acetate: 70/30 (Rf = 0.39)) afforded 14b as a yellow solid.
Yield: 70% (0.134g). Compound 14b (0.134g,
0.47mmol) was dissolved under argon atmosphere in
cold (0ꢀC) trifluoroacetic acid (5mL) and left 1h under
stirring. Evaporation under vaccum to remove the ex-
cess of trifluoroacetic acid afforded pure 15b as a yellow
oil. Yield: 95% (0.133g). To a suspension of PyBOP
(0.255g, 0.49mmol) in THF (1mL) was added a solu-
tion of 2-(methoxycarbonyl)benzoic acid (0.095g,
0.49mmol) in THF (1mL) and pyridine (0.053mL,
0.052g, 0.66mmol). The mixture was stirred at room
temperature for 45min. Compound 15b (0.113g,
Compound 10b (7.58g, 29.94mmol) was added to a
solution of ammonia 7N in methanol (20mL) cooled
at 0ꢀC and the mixture was stirred for 2h at room
temperature. Concentration of the solvent under
reduced pressure gave 11b as a yellow solid. Yield:
98% (6.53g); mp = 124–125ꢀC; 1H NMR(200
MHz, CD3OD): d = 1.43 (s, 9H, CH3), 3.67 (t, 2H,
JHF = 19.9Hz, CH2CF2); 19F NMR(282MHz,
CD3OD): d = ꢀ111.47 (t, JF–H = 15Hz, CH2CF2); 13C
NMR(125MHz, CD OD): d = 28.63 (CH3), 43.84 (t,
3
JC–F = 27.5Hz, CH2CF2), 80.75 (C), 116.44 (t, JC–F
=
251.5Hz, CF2), 158.11 (s, N–C@O), 167.76 (t,
JC–F = 28.4Hz, C@O); MS (+c APCI, CH4–NO2):
m/z = 225.0 (M+1), C8H14F2N2O3.
4.10. (N-tert-Butoxycarbonyl)-3-amino-2,2-difluoropro-
panethioamide (12b)
Compound 11b (6.52g, 29.12mmol) and Lawessonꢁs R e-
agent (7.06g, 12.47mmol) in THF (100mL) were stirred
at room temperature for 24h. After concentration, the

A. Cheguillaume et al. / Bioorg. Med. Chem. 13(2005) 1357–1367
1365
0.45mmol) in THF (1mL) was introduced in one por-
tion followed by slow addition of pyridine (0.106mL,
0.104g, 1.32mmol). After stirring at room temperature
for 6h, a catalytic amount of p-TsOH was added before
refluxing for 48h. After cooling at room temperature,
the solution was poured on aqueous 10% NaHCO3
(2mL) and extracted with ethyl acetate (3 · 5mL). The
organic layer was dried (MgSO4) and concentrated be-
fore purification by flash chromatography on silica gel
(ethyl acetate/hexane: 40/60 (Rf = 0.68)) to afford 16b
as an orange solid. Yield: 25% (0.033g); 1H NMR
(200MHz, CDCl3): d = 1.36 (t, 3H, J = 7.4Hz, CH3),
3.19 (t, 2H, J = 7.4Hz, CH2CF2), 4.57 (q, 2H,
J = 13.4Hz, CH2), 7.74–7.93 (m, 4Harom.); 19F NMR
atmosphere. Evaporation under vacuum to remove the
solvent and the excess of trifluoroacetic acid gave crude
19b as yellow oil, which crystallizes slowly. To a suspen-
sion of PyBOP (1.067g, 2.05mmol) in THF (10mL) was
added a solution of 2-(methoxycarbonyl)benzoic acid
(0.369g, 2.05mmol) in THF (10mL) and pyridine
(0.247mL, 0.243g, 3.08mmol). The mixture was stirred
at room temperature for 45min. Compound 19b
(0.526g, 1.86mmol) in THF (2mL) was introduced in
one portion followed by slow addition of pyridine
(0.748mL, 0.735g, 9.3mmol). After stirring at room
temperature for 4h, the mixture was poured into 10%
NaHCO3 solution (20 mL) and extracted with CH2Cl2
(3 · 20mL). The combined organic layers were dried
(MgSO4) and concentrated. The residue was dissolved
in anhydrous toluene (40mL) and a catalytic amount
of p-TsOH was added before refluxing for 48h. After
cooling at room temperature, the solution was poured
on aqueous 10% NaHCO3 (10mL) and extracted with
ethyl acetate (3 · 10mL). The organic layer was dried
(MgSO4) before purification by flash chromatography
on silica gel (hexane/ethyl acetate: 70/30 (Rf = 0.36)) to
afford 20b as a yellow solid. Yield: 52% (0.287g);
mp = 113–114ꢀC.
(282MHz, CDCl3/CFCl3): d = ꢀ104.43 (t, JF–H
=
12.7Hz, CH2CF2); MS (ꢀc CI, CH4–NO2): m/z =
314.0, C13H11F2NO2S2.
4.13. (N-tert-Butoxycarbonyl)-3-amino-2,2-difluoropro-
pane N,N-dimethylamide (17b)
Compound 10b (1.50g, 12.53mmol) was added to a
solution of dimethylamine 33% in ethanol (20mL)
cooled at 0ꢀC and the mixture was stirred for 1h at
room temperature. Concentration of the solvent under
1
reduced pressure gave 17b as an orange oil. Yield:
Compound 19b H NMR(200MHz, D O): d = 3.45 (s,
2
1
100% (1.5g); H NMR(200MHz, CDCl ): d = 1.43 (s,
3H, NCH3), 3.54 (s, 3H, NCH3), 4.06 (t, 2H,
3
9H, CH3), 2.99 (s, 3H, N–CH3), 3.18 (t, 3H,
JHF = 2.0Hz, N–CH3), 3.79 (dt, 2H, JHF = 13.5Hz,
JHF = 14.8Hz, CH2CF2); 19F NMR(282MHz, CDCl /
3
CFCl3): d = ꢀ76.07 (q, JF–H = 8.6Hz, CF3), 100.52 (t,
JHH = 6.7Hz, CH2CF2); 19F NMR(282MHz, CDCl /
JF–H = 15Hz, CH2CF2).
3
CFCl3): d = ꢀ106.40 (t, JF–H = 13Hz, CH2CF2); 13C
NMR(50MHz, CDCl 3): d = 28.29 (CH3), 35.58
(CH3), 43.76 (t, JC–F = 21Hz, CH2CF2), 79.84 (Cquater-
naire), 116.42 (t, JC–F = 257Hz, CF2), 155.81 (s, N–
C@O), 162.77 (t, JC–F = 28Hz, C@O); MS (+c CI,
CH4–NO2): m/z = 253.0 (M+1), C10H18F2N2O3.
1
Compound 20b H NMR(200MHz, CDCl ): d = 3.47
3
(s, 3H, N–CH3), 3.50 (t, 3H, JHF = 2.0Hz, N–CH3),
4.74 (t, 2H, JHF = 16.6Hz, CH2CF2), 7.73–7.94 (m,
4H, C6H4); 19F NMR(282MHz, CDCl 3/CFCl3):
d = ꢀ106.08 (t, JF–H = 15Hz, CH2CF2); 13C NMR
(50MHz, CDCl3): d = 43.12 (t, JC–F = 29Hz, CH2CF2),
45.89 (CH3), 45.95 (CH3), 116.61 (t, JC–F = 258Hz,
CF2), 123.74, 132.30, 134.35, 167.65 (s, N–C@O),
188.91 (t, JC–F = 24Hz, C=S); MS (APCI, CH4–NO2):
m/z = 299.0 (M+1), C13H12F2N2O2S.
4.14. (N-tert-Butoxycarbonyl)-3-amino-2,2-difluoropro-
pane N,N-dimethylthioamide (18b)
Compound 17b (1.54g, 6.24mmol) and Lawessonꢁs re-
agent (1.514g, 3.74mmol) in toluene (50mL) were stir-
red at reflux for 3h. After concentration, the residue
was purified by flash chromatography on silica gel (ethyl
acetate/hexane: 20/80 (Rf = 0.38)) to afford 18b as a yel-
low solid. Yield: 66% (1.092g); mp = 95–96ꢀC; 1H
4.16. Methyl 3-phthalimido-2,2-difluoropropanedithioate
(22b)
Freshly distillated methyl triflate (0.073mL, 0.109g,
0.664mmol) in dry and ethanol-free dichloromethane
(1mL) was added to a solution of 20b (0.180g,
0.604mmol) in dry and ethanol-free dichloromethane
(1mL) via a syringe and under argon. The mixture
was stirred at room temperature until reaction was com-
plete (2h) and ethanol-free dichloromethane (3.2mL)
was added to the solution. The solution of aminidium
salt 21b was cooled to 0ꢀC and a stream of H2S was
bubbled through the solution until an orange colour
appeared. The mixture was stirred for 25min at room
temperature and the solution was washed with HCl
(10%, 3mL), brine and water. The organic layer was
dried (MgSO4) and concentrated. Purification by flash
chromatography on silica gel (hexane/ethyl acetate:
80/20) allowed to separate 23b (Rf = 0.25) and 22b
(Rf = 0.31) isolated as an orange solid. Compound 22b
yield: 57% (0.114g); mp = 154–155ꢀC.
NMR(200MHz, CDCl ): d = 1.45 (s, 9H, CH3), 3.46
3
(s, 3H, N–CH3), 3.52 (t, 3H, JHF = 2.0Hz, N–CH3),
4.07 (dt, 2H, JHF = 13.5Hz, JHH = 6.9Hz, CH2CF2);
19F NMR(282MHz, CDCl 3/CFCl3): d = ꢀ100.95 (t,
JF–H = 13Hz, CH2CF2); 13C NMR(50MHz, CDCl ):
3
d = 28.30 (CH3), 45.93 (CH3), 46.08 (t, JC–F = 30Hz,
CH2CF2), 79.92 (Cquaternaire), 117.86 (t, JC–F
=
257Hz, CF2), 155.87 (s, N–C@O), 188.68 (t, JC–F
24Hz, C=S); MS (+c CI, CH4–NO2): m/z = 268.7
=
(M+1), C10H18F2N2O2S.
4.15. 3-Phthalimido-2,2-difluoropropane N,N-dimeth-
ylthioamide (20b)
Compound 18b (1.092g, 4.075mmol) was dissolved in a
cold (0ꢀC) solution of trifluoroacetic acid (5mL) in
dichloromethane (5mL) and left 1h stirring under argon

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A. Cheguillaume et al. / Bioorg. Med. Chem. 13(2005) 1357–1367
1
Compound 22b H NMR(200MHz, CDCl ): d = 2.68
been identified by mass spectrometry (coupled to
HPLC): MS (+c CI, CH4–NO2): m/z = 280.0 (M+1),
C11H6F5NO2 and m/z = 288.0 (M+1), C12H8F3NO2S,
respectively.
3
(s, 3H, CH3), 4.48 (t, 2H, JHF = 13.8Hz, CH2CF2),
7.75–7.95 (m, 4H, C6H4); 19F NMR(282MHz, CDCl /
3
CFCl3): d = ꢀ95.95 (t, JF–H = 15Hz, CH2CF2); 13C
NMR(125MHz, CDCl 3): d = 19.53 (CH3), 42.64 (t,
JC–F = 28.5Hz, CH2CF2), 118.43 (t, JC–F = 253Hz,
CF2), 123.85, 131.85, 134.51 (arom.), 167.24 (s, N–
C@O), 222.47 (t, JC–F = 25.6Hz, C=S); MS (EI, CH4–
NO2): m/z = 300.9 (M+Æ); HRMS (M+1) m/z = calcd
for C12H9F2NO2S2 301.004279, found: 301.005433.
Acknowledgements
This work was generously supported by the Walloon
government (Belgium) with contract no 114656. The
authors thank FNRS and UCL for financial support.
Jacqueline Marchand-Brynaert is senior research associ-
ate of FNRS.
1
Compound 23b H NMR(500MHz, CDCl ): d = 2.42
3
(s, 3H, CH3), 4.32 (t, 2H, JHF = 13.5Hz, CH2CF2),
7.76–7.93 (m, 4H, C6H4); 19F NMR(282MHz, CDCl /
3
CFCl3): d = ꢀ107.85 (t, JF–H = 12.7Hz, CH2CF2); 13C
NMR(125MHz, CDCl 3): d = 11.66 (CH3), 40.15 (t,
JC–F = 28.2Hz, CH2CF2), 115.17 (t, JC–F = 259Hz,
CF2), 124.00, 131.86, 134.64 (arom.), 167.23 (s, N–
C@O), 192.33 (t, JC–F = 32.13Hz, C@O); MS (+c APCI,
CH4–NO2): m/z = 286.7 (M+1), C12H9F2NO3S.
References and notes
1. Evans, S. M.; Koch, C. J. Cancer Lett. 2003, 195, 1–16.
2. Ballinger, J. R. Sem. Nucl. Med. 2001, 31, 321–329.
3. Mahy, P.; DeBast, M.; Gallez, B.; Gueulette, J.; Koch, C.
´
J.; Scaillet, P.; Gregoire, V. Radiother. Oncol. 2003, 67, 53–
61, and references cited therein.
4.17. [18F]-N-(3,3,3-Trifluoropropyl)phthalimide (25a)
4. Ziemer, L. S.; Evans, S. M.; Kachur, A. V.; Shuman, A.
L.; Cardi, C. A.; Jenkins, W. T.; Karp, J. S.; Alavi, A.;
Dolbier, W. R., Jr.; Koch, C. J. Eur. J. Nucl. Med. Mol.
Imaging 2003, 30, 259–266.
Radiolabelling procedure: in polypropylene vessel dried
under argon containing DBH (0.030g, 0.11mmol) in sus-
pension in dichloromethane (300lL), [18F]–KF and
[18F]–(HF)nÆpyridinium (10lL, 7equiv of fluoride) (over-
all activity = 274mCi) was added 7a (0.018g, 0.05mmol)
in one portion and the mixture was stirred for 10min at
20ꢀC. Then DBH (0.060g, 0.22mmol) and ꢀcoldꢁ
(HF)nÆpyridinium (200lL, 140equiv of fluoride) were
introduced and the stirring was continued for additional
5min. The crude mixture was filtered on neutral alumina
and eluted with dichloromethane to give the crude prod-
uct. Analysis by HPLC using SiO2 column (rt = 19.8min;
hexane/ethyl acetate: 95/5) allowed to identify [18F]-25a
with 1.06% radiochemical yield (decay corrected)
(4.058mCi, radiochemical purity: 24%).
ˆ
5. Mahy, P.; DeBast, M.; Labar, D.; Leveque, P.; Marchand-
Brynaert, J.; Gregoire, V. Radiother. Oncol. 2002,
´
64(Suppl. 1), S189.
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F.; Nickles, R. J. Appl. Radiat. Isot. 1994, 45, 1093–1100.
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4.18. [18F]-N-(2,2,3,3-Tetrafluoro-3-methylthioxyprop-
yl)phthalimide (26)
Radiolabelling procedure:46 in polypropylene vessel
dried under argon containing DBH (0.041g, 0.15mmol)
in suspension in dichloromethane (300lL), [18F]–
KF and [18F]–(HF)nÆpyridinium (10lL, 7equiv of fluo-
ride) (overall activity = 904mCi) was added 22b
(0.015g, 0.05mmol) in one portion and the mixture
was stirred for 15min at 20ꢀC. Then DBH (0.081g,
0.30mmol) and ꢀcoldꢁ (HF)nÆpyridinium (400lL,
280equiv of fluoride) were introduced and the stirring
was continued for additional 15min. Then HgCl2
(0.27g, 1mmol) was introduced and the stirring was
continued for additional 10min. The crude mixture
was filtered on neutral alumina and eluted with dichlo-
romethane to give the crude product. Analysis by HPLC
using SiO2 column (rt = 7.5min; hexane/ethyl acetate:
85/15) allowed to identify [18F]-26, with 1.07% radio-
chemical yield (decay corrected) (MS (ꢀc CI, CH4–
NO2): m/z = 306.9 (Mꢀ1), C12H9F4NO2S, 5.148mCi,
radiochemical purity: 78%). Other compounds, [18F]-
25b (rt = 6.9min; hexane/ethyl acetate: 85/15) and
[18F]-27 (rt = 7.3min; hexane/ethyl acetate: 85/15) have
´
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