Deoxyradiofluorination Reaction from β-Hydroxy-α-aminoesters: an Entry to [18F]Fluoroaminoesters under Mild Conditions

Article abstract of DOI:10.1002/ejoc.201900300

We report the conversion of β-hydroxy-α-aminoesters derived from serine, α-methylserine or β-phenylserine to the corresponding [¹⁸F]fluorinated α or β-aminoesters by deoxyradiofluorination using [¹⁸F]fluoride. The method involved the

Full text of DOI:10.1002/ejoc.201900300

A Journal of
Accepted Article
Title: Deoxyradiofluorination Reaction from β-Hydroxy-α-aminoesters:
an Entry to [18F]Fluoroaminoesters under mild conditions
Authors: marine morlot, fabienne gourand, and Cécile Perrio
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900300
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10.1002/ejoc.201900300
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Deoxyradiofluorination Reaction from -Hydroxy--aminoesters:
an Entry to [18F]Fluoroaminoesters under mild conditions
Marine Morlot,[a] Fabienne Gourand,[a] and Cécile Perrio*[a]
Abstract: We report the conversion of β-hydroxy--aminoesters
derived from serine, -methylserine or -phenylserine to the
The deoxyfluorination reaction is a common method to
access to aliphatic fluorinated products (Scheme 1).[8,9]
Advantages are the use of readily accessible hydroxylated
starting materials and the large functional group compatibility. The
method has been successfully exploited for the synthesis of a
variety of fluoroaminoacids from hydroxyaminoesters.[9] DAST,
Deoxo-fluor, XtalFluor, Fluolead, DFI and PhenoFluor are popular
reagents to exchange hydroxyl groups for fluorine (Scheme 1).
They all usually exhibit high reactivity under mild reaction
conditions by converting the alcohol function into an activated
leaving group while providing the nucleophilic fluoride source for
fluorination. Unfortunately, these polyfluorinated reagents are not
suitable for fluorine-18 chemistry due to the inaccessibility of
isotopically pure 18F-radiolabelled variants.[10] Recently, PyFluor
has been reported as a new monofluorinated reagent efficient for
the deoxyfluorination of a broad range of alcohols.[11] Although
promising, [18F]PyFluor readily obtained from [18F]fluoride, was
found to be relatively weakly reactive in the radiosynthesis of a
[18F]fluoroglucose derivative, and optimization and scope studies
still are required.
In previous work, we developed the deoxyradiofluorination
of ethanolamines for the radiosynthesis of [18F]fluoroethylamines
using directly [18F]fluoride (Scheme 1).[12] The reaction involved a
three step procedure involving the activation of the aminoalcohol
precursor with triflic anhydride, then the in situ formation of an
aziridinium intermediate by anchimeric assistance of the tertiary
amine function, and finally the ring opening by [18F]fluoride. The
reaction was found to be efficient at room temperature, confirming
the strong electrophilic property of aziridinium. From
phenylalaninol substrates (R3 = Bn), the nucleophilic attack on the
aziridinum intermediate occurred preferentially at the quaternary
carbon leading to a moderate regioselectivity in favour of the
rearranged isomer. These results were in accordance with non-
radioactive reactions.
corresponding
[18F]fluorinated

or
-aminoesters
by
deoxyradiofluorination using [18F]fluoride. The method involved the
ring opening of an aziridinum intermediate formed in situ in the
presence of a base after activation of the alcohol function with triflic
anhydride. The overall process was carried out at room temperature.
Both the efficiency and the regioselectivity of the reaction were found
to be dependent on the starting substrates. [18F]Fluoroaminoesters
were obtained in radiochemical yields ranging from 10-75%. No
improvement was observed for reactions carried out under heating.
Introduction
Modification of organic molecules by introduction of fluorine is
known to provide compounds with unique biological properties
that could find utility in a variety of fields such as chemical biology,
pharmacology, drug discovery and medicinal chemistry for
therapeutic and diagnostic developments.[1] In particular, - and
-aminoacid derivatives bearing a fluorine atom at vicinal aliphatic
position have found widespread applications in peptide/protein
chemistry and protein recognition, and they represent an
important class of 1) enzyme inhibitors, 2) antitumor and
antibacterial agents, 3) probes for 19F NMR studies and 4)
radiotracers for Positron Emission Tomography after
radiolabelling with fluorine-18 such as [18F]NST732 and its
regioisomer for apoptosis imaging.[2] As a result, the development
of routes to [18F]fluoroaminoacids is demanding. The usual
approaches used nucleophilic [18F]fluoride anion in substitution of
halides[3] or sulfonates[4] and in ring opening of sulfamidates[5] or
aziridines[2k,6]. These reactions required heating conditions and
the preparation of precursors may involve a multi-step synthesis.
Recently, late-stage manganese salen and decatungstate-
catalyzed C-H radiofluorinations were reported but they were
restricted to benzylic or branched [18F]fluoroaminoacids.[7]
[a]
Normandie Univ, UNICAEN, CEA, CNRS, FRE2001-ISTCT, LDM-
TEP, Cyceron, Boulevard Henri Becquerel, 14000 Caen, France
E-mail: perrio@cyceron.fr
Homepage: http://www.istct.cyceron.fr/index.php/fr
Supporting information for this article is given via a link at the end of
the document.
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Scheme 1. Deoxy(radio)fluorination reactions
Aziridiniums have been largely proved to be key
Synthesis of β-hydroxy--aminoester precursors 1-8
intermediates
fluoroaminoacids by deoxyfluorination of
in
the
non-radioactive
synthesis
-hydroxy--
of
β-Hydroxy--aminoesters 1-8 derived from serine (R3 = H, R4 =
H), -methylserine (R3 = Me, R4 = H) or -phenylserine (R3 = H,
R4 = Ph) were chosen as precursors. Their synthesis is depicted
in Scheme 2. Methylester of serine compounds 9-11 were subject
to dibenzylation with benzylbromide (2 equiv) to give the N,N-
dibenzylamine derivatives 1, 4 and 7 in 83-52% yields.[13] N-
Monobenzylated analogues 12-14 were obtained in 60-33%
yields using equimolar amounts of benzyl bromide. Subsequent
alkylation with methyl iodide led to N-benzyl-N-methylamines 2, 5
and 8 (64-77% yields).[14] The synthesis of N-propargyl, N-
dimethoxybenzyl serine precursor 3 was carried out via the N-
dimethoxybenzyl-O-protected serine ester 15 prepared from
serine methylester 9 as previously reported by reductive
amination with dimethoxybenzadehyde then protection with
triisopropylsilyl (TIPS) group.[3d] Compound 15 was converted to
16 by N-alkylation with propargylbromide (90% yield).
Deprotection of 16 with TBAF yielded precursor 3 in 75% yield. N-
aminoesters with reagents such as DAST.[9] Substitution was a
major factor that determined the efficiency and the regioselectivity
of the ring opening. Fluoro--aminoesters were the sole
regioisomers obtained from -phenylserine substrates,[9f]
whereas fluoro--aminoesters were isolated as the major
products starting from serine or methylserine precursors.[9a-e] The
aim of this study was to develop a radioactive version of the
deoxyfluorination approach to easily access to 18F-
fluoroaminoacids.
We
thus
investigated
the
deoxyradiofluorination reaction of serine esters using [18F]fluoride
anion (Scheme 1). For this purpose, it was important to re-visit the
reaction under appropriate conditions. We first compared DAST
and TBAF in the non-radioactive reaction, then we studied the
deoxyradiofluorination and optimized the radiosynthesis
conditions. In all cases, we examined the influence of the
substituents of both the amine (R1, R2) and aziridinium ring (R3,
R4) on the regioselective formation of the corresponding - or -
aminoester products.
Methyl,N-dimethoxybenzyl--methylserine
6
was obtained
according to a two-step synthesis by reductive amination of -
methylserine methylester 10 with dimethoxybenzaldehyde
leading to 17 (64% yield), followed by N-methylation with methyl
iodide (72% yield).
Results and Discussion
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10.1002/ejoc.201900300
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Scheme 2. Syntheses of -hydroxy--aminoester precursors 1-8.
Deoxyfluorination of β-hydroxy--aminoesters 1-8 under
non-radioactive conditions
results were consistent with the fluorination of serine esters
reported in the literature.[9a-d,15] The nucleophilic attack took place
exclusively on the carbon of aziridinium bearing the electron-
withdrawing carboxylic function as this atom was the most
electropositive.[8i] The methyl in -position did not have any steric
or electronic effect on the overall transformation. Phenylserine
substrates 7-8 were less reactive than the serine and
methylserine analogues 1-2 and 4-5; the phenyl group in 
significantly inhibited the deoxyfluorination. Moreover, a mixture
of fluoro - and -aminoesters 24-25 and 32-33 was obtained
(entries 7-8). In these cases, the two carbons of aziridinium ring
were both ternary and competitive as electrophile sites. The
methylester and phenyl groups were not discriminant toward
fluoride. It is noteworthy that Davies et al described the
fluorination with XtalFluor-E and Et3N.3HF of the tert-butyl ester
analogue of substrate 7.[9f] They obtained the corresponding -
aminoester isomer in 94% yield, revealing a strong director and
activating effect of the tert-butyl ester function.
Deoxyfluorination of -hydroxy--aminoesters 1-8 was first
carried out using DAST as reference method. Reactions were
performed in THF at room temperature for 3 h. We also performed
the deoxyfluorination of 1-8 using fluoride anion according to the
protocol we previously developed for the deoxyfluorination of
ethanolamines.[12] -Hydroxy--aminoesters 1-8 were treated
with triflic anhydride in CH2Cl2 at room temperature for 1 h, then
with DIPEA for 1 min and finally with TBAF for 2 h. The results for
both DAST and TBAF methods are presented in Table 1.
Although no optimization was undertaken, the conversions
occured in moderate to high yields. Fluorinations were more
efficient with DAST than with TBAF as previously observed for the
deoxyfluorination of ethanolamines.[12] However, the differences
of yields remained relatively low except for reactions from
precursors 3 and 4 (entries 3-4). These results suggested that
the in situ generation of the intermediate aziridinium may be
easier with DAST than in TBAF method. The nature of the
nucleophilic fluoride in the two approaches may also have an
impact on the fluorination. Globally, no influence of N-substituents
could be concluded contrary to C-substitution. Serine and -
methylserine precursors 1-6 displayed a similar behaviour, and
led exclusively to fluoro--aminoesters 26-31 (entries 1-6). These
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Table 1. Deoxyfluorination of 1-8 using DAST or TBAF
Products
Yield (%)
+)
Ratio
Entry
Substrate
Method


:
DAST
TBAF
70
60
0:100
0:100
1
2
3
4
5
1
2
3
4
5
18
19
20
21
22
26
DAST
TBAF
68
50
0:100
0:100
27
28
29
30
DAST
TBAF
85
15
0:100
0:100
DAST
TBAF
98
50
0:100
0:100
DAST
TBAF
60
45
0:100
0:100
DAST
TBAF
56
30
0:100
0:100
6
7
8
6
7
8
23
24
25
31
32
33
DAST
TBAF
28
14
75:25
80:20
DAST
TBAF
37
21
50:50
55:45
Synthesis of -fluorinated -aminoesters 18-23
reductive amination from fluoroalanine derivatives in order to
prepare N-propargylfluoroalanine methyl ester 20. Fluorinated -
aminoesters 21-23 were obtained via the sulfamidate
intermediate 38 according to a multistep strategy reported by Yu
et al for the preparation of tert-butyl ester analogues.[5c]
Fluorination then deprotection of sulfamidate 38 led to
fluoroaminoester 39 which was involved in subsequent
transformations without isolation. N-Alkylation of 39 with
benzylbromide (2.5 equiv) afforded the monobenzyl derivative 40
in 48% yield (calculated from 38). A second alkylation with
benzylbromide or methyliodide gave the N-dialkylated
aminoesters 21 and 22 in poor yields (10 and 20% respectively).
Deoxyfluorination of serine and -methylserine precursors 1-6 did
not provide the fluorinated -aminoesters 18-23. However, these
compounds 18-23 were needed to confirm the identity and the
isomeric structure of the radiolabelled products by co-elution in
HPLC and we developed alternative syntheses (Scheme 3). The
reaction of -fluoroalanine methyl ester 34 with 2 equiv of
benzylbromide led to N,N-dibenzylfluoroalanine 18 (12% yield)
and N-monobenzylated analogue 35 (15% yield) that could be
separated. All attempts to alkylate 35 with methyl iodide failed and
N-methyl,N-benzylfluoroalanine 19 never could be obtained. We
also were unsuccessful in introducing dimethoxybenzyl group by
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Fluoroaminoester 39 was efficiently converted to 41 by reductive
amination with dimethoxybenzaldehyde. Methylation of 41 to
fluoroaminoester 23 occurred in high yield (72%). A similar
sulfamidate-based approach for the synthesis of -fluoroalanine
ester 20 failed. The overall syntheses displayed that the presence
of the -fluorine attenuated drastically the nucleophilicity of the
amine.[16] However the introduction of the electro-donor DMB
group on nitrogen allowed to restore its ability for nucleophilic
alkylation.
Scheme 3. Syntheses of the β-fluorinated α-aminoesters 18-23.
Deoxyradiofluorination
aminoester precursors 1-8
reactions
from
β-hydroxy--
solution was transferred onto dry [18F]KF/K222/K2CO3 complex
prepared according to the classic procedure. The mixture was
stirred for 30 min at room temperature and then analysed by
both radioTLC and HPLC by comparison with the non-
radioactive reference fluoro-  and -aminoester products 21
and 29. The radiofluorination of 4 led exclusively to the
[18F]fluoro--aminoester [18F]29 (entry 1). The regioselectivity
was identical to that observed in non-radioactive chemistry.
However, the radiofluorination was unreliable with an
incorporation mean about 51% (n = 7) and a deviation about ±
24%. In order to make the radiofluorination reproducible, we
The deoxyradiofluorination of -methylserine methylester 4 was
selected as the model reaction for the initial condition screening
(Table 2). We first applied the radiolabelling conditions
previously defined for the conversion of ethanolamines to
[18F]fluoroamines without any modifications.[12] Briefly, the
precursor 4 (33 mol; 10.5 mg) was stirred in the presence of
triflic anhydride in dichloromethane (300 L) for 1 h at room
temperature. DIPEA in acetonitrile (200 L) was added to the
crude mixture and allowed to react for 1 min. The resulting
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changed the volume of acetonitrile, the nature of [18F]fluoride
([18F]KF/K222/K2CO3 and [18F]TBAF obtained with TBAHCO3),
the amount of base (K2CO3 and TBAHCO3) as well as the
quantity of precursor 4. The treatment of precursor 4 with triflic
anhydride was not changed. The use of an increased volume of
acetonitrile (up to 1 mL) did not lead to improved and repeatable
radiochemical yields (entries 2-4). By increasing the amounts of
K2CO3 and K222, the radiochemical yields were constant
(deviation about 6% only) around 68% (entry 5). The
radiochemical yields then fell down drastically when the
precursor 4 was taken in low amount (6.6 mol; 2.1 mg) (entries
6-10). Finally, the replacement of [18F]KF/ K222/K2CO3 by
[18F]TBAF was detrimental (entries 11-12). This result was
different to the previously reported deoxyradiofluorination of -
aminoalcools; in the latter, the reaction was not sensitive to the
nature of [18F]fluoride anion.[12] We then selected the following
conditions, i.e. precursor 4 (16.5 µmol), triflic anhydride (37
µmol), dichloromethane (300 µL), DIPEA (40 µmol), acetonitrile
(700 µL) and [18F]KF prepared using K2CO3 (23 µmol) and K222
(28 µmol) (entry 8).
the only radiofluorinated products detected. These results were in
accordance with the non-radioactive chemistry. In the case of N-
dimethoxyphenyl serine and methylserine derivatives 3 and 6, the
formation of the expected [18F]fluoro--aminoesters [18F]28 and
[18F]31 was not observed, and the presence of the -isomers
[18F]20 and [18F]23 could not be confirmed (entries 3 and 6). For
reminder, the yields for the corresponding non-radioactive
reactions were low. The electron-donating effect of the DMB
group may decrease the electrophilicity of aziridinum and
consequently its reactivity toward fluoride. The radiofluorination of
the phenylalanine substrates 7-8 was carried out in radiochemical
yields that did not exceed 28% and led to mixture of the
[18F]fluoro-- and -aminoesters as for the non-radioactive
version (entries 7-8). However, the : ratios were not exactly in
the same range.
A
second set of assays were realized with the
radiofluorination step performed at 90 °C. Heating conditions did
not affect the regioselectivity of the reaction. The : ratios were
similar to those obtained at room temperature. At 90 °C, the
radiochemicals yields were not increased except for the N-
benzyl,N-methylmethylserine precursor
temperature did not significantly
deoxyradiofluorination.
5 (entry 5). Thus,
influence
the
Table 2. Optimization of the deoxyradiofluorination reaction.[a]
Table 3. Scope of the deoxyradiofluorniation reaction.[a]
Entry
4 [µmol]
Base [µmol]
ACN [mL]
RCC [%][b]
1
33
K2CO3/K222
K2CO3/K222
K2CO3/K222
K2CO3/K222
K2CO3/K222
K2CO3/K222
K2CO3/K222
K2CO3/K222
K2CO3/K222
K2CO3/K222
TBAHCO3
TBAHCO3
15/18
15/18
15/18
15/18
23/28
23/28
23/28
23/28
23/28
23/28
23
0.2
0.5
0.7
1.0
0.7
0.7
0.7
0.7
0.7
0.7
51±24 (n=6)
55±19 (n=3)
55±23 (n=9)
73±21 (n=3)
68±6 (n=4)
73±8 (n=3)
67±4 (n=3)
68±9 (n=3)
73±8 (n=3)
18±5 (n=2)
49±23 (n=4)
32±2 (n=2)
2
33
3
33
Product
T
RCC [%]
Ratio
Entry
Precursor
4
33


[°C]
+[b]
:[c]
5
33
20
90
45±2
55±7
0:100
0:100
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
[
[
[
[
[
[
[
[
18F]18
18F]19
18F]20
18F]21
18F]22
18F]23
18F]24
18F]25
[
[
[
[
[
[
[
[
18F]26
6
26.4
19.8
16.5
13.2
6.6
20
90
32±4
39±11
0:100
0:100
18F]27
18F]28
18F]29
18F]30
18F]31
18F]32
18F]33
7
8
[d]
[d]
20
90
-
-
[d]
[d]
-
-
9
20
90
67±3
68±9
0:100
0:100
10
11
12
16.5
16.5
0.7
20
90
33±7
57±7
0:100
0:100
[c]
23
-
[d]
[d]
20
90
-
-
[d]
[d]
[a] All radiofluorinations were carried out manually for 30 min at RT.
Conditions: Triflic anhydride in CH2Cl2 for 1 h then 1 min with DIPEA in ACN
then addition to dry [18F]-fluoride at RT. [b] Determined by radioTLC and
HPLC (± SEM). [c] In THF (0.7 mL).
-
-
20
90
17±4
14±3
60:40
62:38
The deoxyradiofluoration method was extended to β-
hydroxy-α-aminoesters 1-8 (Table 3). In the first set of
experiments, the radiofluorination step was conducted at room
temperature for 30 min. The highest radiochemical yields (32-
67%) were obtained starting from serine (entries 1-2) and
methylserine (entries 4-5) precursors 1-2 and 4-5 possessing a
dibenzylamine or a benzylmethylamine function. The [18F]fluoro-
-aminoester isomers [18F]26-[18F]27 and [18F]29-[18F]30 were
20
90
28±5
30±1
82:18
83:17
[a] Conditions: Triflic anhydride in CH2Cl2 for 1 h then 1 min with DIPEA in
ACN then addition to dry [18F]-fluoride at 20 or 90 °C for 30 min. [b] Determined
by radioTLC and HPLC (± SEM). [c] Determined by HPLC. [d] Not detected.
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shifts (δ) are quoted in parts per million (ppm). Coupling constants (J) are
given in Hz. Coupling patterns are abbreviated as follows: s (singlet), d
(doublet), m (mutiplet), dd (doublet of doublet). High resolution mass
spectra (HRMS) were recorded using a Waters Q-TOF micro spectrometer
by electrospray ionisation (ESI).
Methyl-2-(dibenzylamino)-3-hydroxypropanoate (1): To serine
methylester hydrochloride (500 mg, 3.2 mmol) and K2CO3 (1 g, 7.2 mmol)
in dry ACN (10 mL) was added benzylbromide (800 µL, 6.5 mmol) under
nitrogen atmosphere. After stirring at room temperature for 18 h then
filtration, the filtrate was concentrated under vacuum. Purification of the
residue by chromatography on silica gel (heptane/EtOAc, 85:15) gave
compound 1 as a colorless oil (800 mg, 83%). 1H NMR (400 MHz, CD3OD):
 = 7.38-7.22 (m, 10H), 3.93 (dd, J = 10.9, 7.8 Hz, 1H), 3.74 (dd, J = 10.9,
5.9 Hz, 1H), 3.87 and 3.59 (AB system, J = 13.7 Hz, 4H), 3.79 (s, 3H), 3.49
(dd, J = 7.8, 5.9 Hz, 1H) ppm. 13C NMR (100.6 MHz, CD3OD):  = 172.0,
139.4, 128.5, 127.9, 126.8, 62.8, 60.6, 54.9, 50.3 ppm. HRMS (ESI): calcd.
for C18H22NO3 [M+H]+ 300.1600; found 300.1603.
Figure 1. Radiofluorination of serine and methylserine esters 1-2 and 4-5.
Methyl-2-(benzylamino)-3-hydroxypropanoate
(12):
To
serine
methylester hydrochloride (200 mg, 1.3 mmol) and K2CO3 (360 mg, 2.6
mmol) in dry DMF (4 mL) under nitrogen atmosphere was added
benzylbromide (155 µL, 1.3 mmol). After stirring at 55 °C for 16 h then
dilution with ethyl acetate, the mixture was washed with water (10 mL) then
brine (10 mL). The organic phase was separated, dried over anhydrous
MgSO4, and concentrated under vacuum. The crude product was purified
on silica gel (pentane/EtOAc, 2:1) to give compound 12 as a pale yellow
oil (210 mg, 60%). 1H NMR (400 MHz, CDCl3):  = 7.20 (m, 5H), 3.81 and
3.70 (AB system, J = 12.9 Hz), 3.72 (dd, J = 10.9, 4.4 Hz, 1H), 3.66 (s,
Finally, we examined the influence of the reaction time
under both room temperature and heating conditions in the
radiofluorination of reactive serine and methylserine precursors 1-
2 and 4-5 (Figure 1). For all cases and whatever the reaction
temperature, the optimum radiochemical yields were reached
after 15 min and remained constant until 30 min. The results
obtained after 5 min reaction time were slightly below the optimum
3H), 3.58 (dd, J = 10.9, 6.0 Hz, 1H), 3.37 (dd, J = 6.0, 4.4 H, 1H) ppm. 13
C
NMR (100.6 MHz, CDCl3):  = 172.8, 138.3, 128.6, 128.5, 127.3, 62.1,
61.7, 52.4, 51.9 ppm. HRMS (ESI): calcd. for C11H16NO3 [M+H]+ 210.1130;
found 210.1132.
values, revealing
temperature.
a fast radiofluorination even at room
Methyl-2-(benzylmethylamino)-3-hydroxypropanoate
(2):
To
aminoester 12 (100 mg, 0.45 mmol) and K2CO3 (140 mg, 1.0 mmol) in dry
DMF (3 mL) under nitrogen atmosphere was added methyliodide (60 µL,
0.97 mmol). After stirring at room temperature for 3 h, then dilution with
ethyl acetate, the mixture was washed with water (10 mL) then brine (10
mL). The organic phase was separated, dried over anhydrous MgSO4, and
concentrated under vacuum. The crude product was purified on silica gel
(pentane/EtOAc, 8:2) to give the product 2 as a pale yellow oil (75 mg,
77%). 1H NMR (400 MHz, CDCl3):  = 7.24 (m, 5H), 3.83-3.66 (m, 7H),
3.51 (dd, J = 9.2, 6.1 Hz, 1H), 2.30 (s, 3H) ppm. 13C NMR (100.6 MHz,
CDCl3):  = 170.9, 138.0, 129.1, 128.6, 127.6, 65.7, 59.2, 58.8, 51.5, 37.4
ppm. HRMS (ESI): calcd. for C12H18NO3 [M+H]+ 224.1287; found
224.1291.
Conclusion
We developed the deoxyradiofluorination reaction using
[18F]fluoride anion for the radiosynthesis of [18F]fluoroaminoesters
from readily prepared stable hydroxyl precursors. The method
was efficient and rapid at room temperature from serine and -
methylserine esters bearing a benzylamine function. In addition,
the radiofluorination was totally regioselective with the exclusive
formation of the [18F]fluoro--aminoester products. -
Phenylserine derivatives were less reactive and gave access to a
mixture of [18F]fluorinated  and -aminoester isomers. Although
the efficiency of the radiofluorination was dependant on the
substrates structures, our results demonstrated the proof of
concept of this methodology. The very mild reaction conditions
made the approach useful and promising for the radiosynthesis of
temperature sensitive and enantiomerically pure aminoacid
radiopharmaceuticals. Such developments will be reported in due
course.
Methyl-2-((2,4-dimethoxybenzyl)(3-prop-2-yn-1-yl)amino)-3-
((triisopropylsilyl)oxy)propanoate (16): To aminoester 15 (1,6 g, 3,8
mmol)[3d] and cesium carbonate (500 mg, 7.4 mmol) in dry ACN (30 mL)
was added propargylbromide (700 µL, 3,9 mmol) under nitrogen
atmosphere. The reaction mixture was heated to 55 °C for 3 h. After
quenching with water (30 mL) then extraction with DCM (3 x 30 mL), the
combined organic phases were dried over MgSO4 and concentrated under
vacuum. Purification on silica gel (heptane/EtOAc, 94/6) gave compound
16 as a colorless oil (1.6 g, 90%). 1H NMR (400 MHz, CDCl3):  = 7.26 (s,
1H), 6.46-6.42 (m, 2H), 4.17-4.02 (m for ABC system, 2H), 3.90 and 3.76
(AB system, J = 13.9 Hz, 2H), 3.79 (s, 3H), 3.78 (s, 3H), 3.71 (s, 3H), 3.73-
3.66 (m, 1H), 3.50 (d, J = 1.6 Hz, 2H), 2.22 (t, J = 2.3 Hz, 1H), 1.07–1.00
(m, 21H) ppm. 13C NMR (100.6 MHz, CDCl3):  = 175.1, 160.1, 158.9,
131.2, 119.0, 103.9, 98.5, 80.5, 72.3, 65.9, 63.4, 55.4, 55.4, 51.2, 48.6,
40.5, 17.9, 11.9 ppm. HRMS (ESI): calcd. for C28H50NO5Si2 [M+H]+
536.3228; found 536.3238.
Methyl-2-((2,4-dimethoxybenzyl)(prop-2-yn-1-yl)amino)-3-hydroxy-
propanoate (3): To TIPS-protected aminoester 16 (1.6 mg, 3.5 mmol) in
dry THF (10 mL) was added tetrabutylammonium fluoride (1 M in THF, 12
mL). After stirring at room temperature for 16 h, the solvent was removed
under vaccum and the residue was purified on silica gel (heptane/EtOAc,
Experimental Section
Synthetic procedures
1
75/25) to give product 3 as a colorless oil (750 mg, 75%). H NMR (400
General Remarks: All commercially available reagents and solvents were
purchased from Sigma-Aldrich, Fluorochem or Apollo Scientific and used
without further purification. Thin-layer chromatographies (TLC) were run
on precoated aluminum plates of silica gel 60F254, and retention factors
(Rf) were established using a UV-lamp at 254 nm. Melting points were
determined with an Electrothermal IA900 instrument and are given in °C.
MHz, CDCl3):  = 7.15 (d, J = 8.1 Hz, 1H), 6.54-6.38 (m, 2H), 4.05 and
3.60 (AB system, J = 13.1 Hz, 2H), 3.92-3.82 (m, 2H), 3.82 (s, 3H), 3.80
(s, 3H), 3.84-3.75 (m, 1H), 3.73 (s, 3H), 3-54-3.35 (m for ABC system, 2H),
2.23 (t, J = 2.4 Hz, 1H) ppm. 13C NMR (100.6 MHz, CDCl3):  = 171.4,
160.7, 158.8, 132.0, 118.1, 103.8, 98.9, 79.9, 72.8, 64.5, 59.0, 55.4, 55.3,
51.3, 48.1, 40.1 ppm. HRMS (ESI): calcd. for [M+H]+ C16H21NO5 308.1498;
found 308.1494.
Methyl-2-(dibenzylamino)-3-hydroxy-2-methylpropanoate (4): To a
mixture of -methylserine methyl ester 10[17] (500 mg, 3.76 mmol) and
K2CO3 (1 g, 7.25 mmol) in dry ACN (10 mL) was added benzylbromide (1
mL, 8.42 mmol) under nitrogen atmosphere. After stirring at 50 °C for 48 h
IR spectra were recorded on a FT-IR spectrometer and are given in cm−1
.
1H, 13C and 19F and 11B NMR spectra were recorded at 400 or 500 MHz
(1H), 101 or 126 MHz (13C), 376 or 471 MHz (19F). Samples were dissolved
in an appropriate deuterated solvent (CDCl3, MeOD or DMSO). Chemical
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900300
European Journal of Organic Chemistry
FULL PAPER
then filtration, the filtrate was concentrated under vacuum. Purification of
the residue on silica gel (heptane/EtOAc, 9:1) gave compound 4 as a
yellow solid (647 mg, 55%). Mp = 106 °C. 1H NMR (400 MHz, CD3OD): 
= 7.28-7.09 (m, 10H), 3.90 and 3.55 (AB system, J = 10.8 Hz, 2H), 3.81
(s, 4H), 3.68 (s, 3H), 1.48 (s, 3H) ppm. 13C NMR (100.6 MHz, CD3OD): 
= 174.6, 141.0, 128.2, 127.6, 126.3, 68.6, 66.4, 54.6, 50.6, 17.9 ppm.
HRMS (ESI): calcd. for C19H24NO3 [M+H]+ 314.1756; found 314.1760.
51.9 ppm. HRMS (ESI): calcd. for C17H20NO3 [M+H]+ 286.1443; found
286.1446.
Methyl-2-(dibenzylamino)-3-hydroxy-3-phenylpropanoate (7): To a
mixture of aminoester 11 (300 mg, 1.5 mmol) and K2CO3 (470 g, 3.4 mmol)
in dry DMF (10 mL) was added benzylbromide (360 µL, 3.0 mmol) under
nitrogen atmosphere. After stirring at 50 °C for 20 h, the reaction mixture
was quenched with water (20 mL) then extracted with CH2Cl2 (3 x 10 mL).
The combined organic layers were dried over MgSO4 then concentrated
under reduced pressure. Purification on silica gel (pentane/EtOAc, 97:3
then 80:20) gave compound 7 as a white solid (293 mg, 52%). Mp = 74
°C. 1H NMR (400 MHz, CDCl3):  7.21-7.16 (m, 15H), 4.86 (d, J = 10.0 Hz,
1H), 4.06 and 3.37 (AB system, J = 13.0 Hz, 4H), 3.55 (s, 3H), 3.34 (d, J
= 10.0 Hz, 1H) ppm. 13C NMR (100.6 MHz, CDCl3):  = 169.9, 140.4, 137.8,
129.3, 128.9, 128.7, 128.2, 127.7, 127.3, 69.5, 67.6, 54.8, 51.3 ppm.
HRMS (ESI): calcd. for C24H26NO3 [M+H]+ 376.1913; found 376.1913.
Methyl-2-(benzyl(methyl)amino)-3-hydroxy-3-phenylpropanoate (8):
To a mixture of aminoester 14 (108 mg, 0.38 mmol) and K2CO3 (110 mg,
0.81 mmol) in dry DMF (3 mL) was added methyliodide (50 µL, 0.81 mmol)
under nitrogen atmosphere. The reaction mixture was stirred at room
temperature for 4 h. After quenching with water (5 mL) then extraction with
CH2Cl2 (3 x 5 mL), the combined organic layers were dried over MgSO4
and concentrated under reduced pressure. Purification by chromatography
on silica gel (pentane/EtOAc, 97:3) gave compound 8 as a colorless oil (72
mg, 64%). 1H NMR (400 MHz, CDCl3):  = 7.34-7.29 (m, 10H), 4.89 (d, J
= 10.0 Hz, 1H), 3.91 and 3.64 (AB system, J = 13.0 Hz, 2H), 3.60 (s, 3H),
3.38-3.34 (m, 1H) 2.39 (s, 3H) ppm. 13C NMR (100.6 MHz, CDCl3):  =
169.4, 140.3, 137.8, 129.1, 128.6, 128.3, 128.0, 127.6, 127.3, 72.2, 69.6,
59.6, 51.1, 37.8 ppm. HRMS (ESI): calcd. for C18H22NO3 [M+H]+ 300.1600;
found 300.1601.
Methyl-2-(benzylamino)-3-hydroxy-2-methylpropanoate
(13):
To
aminoester 10[16] (330 mg, 2.5 mmol) in dry DMF (6 mL) was added under
nitrogen atmosphere at room temperature K2CO3 (640 mg, 4.6 mmol) then
benzylbromide (300 µL, 2.5 mmol). After stirring overnight at 50 °C then
quenching with water (20 mL), and extraction with CH2Cl2 (3 x 20 mL), the
combined organic layers were dried over MgSO4, filtered and concentrated
under vacuum. Purification on silica gel (heptane/EtOAc, 9:1 then 7:3)
1
gave compound 13 as a colorless oil (250 mg, 45%). H NMR (400 MHz,
CD3OD):  = 7.44-7.17 (m, 5H), 3.77 (s, 3H), 3.70 (s, 2H), 3.70 and 3.62
(AB system, J = 11.0 Hz, 2H), 1.43 (s, 3H) ppm. 13C NMR (100.6 MHz,
CD3OD):  = 175, 138, 128.9, 128.7, 127.9, 66.0, 64.4, 52.5, 48.1, 18.9
ppm. HRMS (ESI): calcd. for C12H18NO3 [M+H]+ 224.1287; found
224.1288.
Methyl-2-(benzyl(methyl)amino)-3-hydroxy-2-methylpropanoate (5):
To a mixture of aminoester 13 (220 mg, 1.0 mmol) and K2CO3 (280 mg,
2.0 mmol) in dry DMF (5 mL) was added methyliodide (125 µL, 2.0 mmol)
under nitrogen atmosphere. After stirring at room temperature for 3 h, the
mixture was quenched with water (20 mL). After extraction with CH2Cl2 (3
x 10 mL), the combined organic layers were concentrated under reduced
pressure. Purification by chromatography on silica gel (heptane/EtOAc,
75:25) gave compound 5 as a colorless oil (180 mg, 77%). 1H NMR (400
MHz, CD3OD):  = 7.26-7.19 (m, 5H), 3.78 and 3.67 (AB system, J = 11.2
Hz, 2H), 3.72 (s, 3H), 3.65 and 3.58 (AB system, J = 13.5 Hz, 2H), 2.20 (s,
3H), 1.43 (s, 3H) ppm. 13C NMR (100.6 MHz, CD3OD):  = 175.0, 138.0,
128.9, 128.7, 127.9, 66.0, 64.4, 52.5, 48.1, 18.9 ppm. HRMS (ESI): calcd.
for C13H20NO3 [M+H]+ 238.1443; found 238.1447.
General procedure for fluorination using DAST. To aminoacid alcohol
(0.6 mmol) in dry THF (4 mL) was added DAST (0.7 mmol) under nitrogen
atmosphere. The solution was stirred at room temperature for 3 h. After
quenching with water then extraction with CH2Cl2 (2 x 10 mL), the
combined organic layers were concentrated under reduced pressure and
the residue was purified by chromatography on silica gel.
Methyl-2-((2,4-dimethoxybenzyl)amino)-3-hydroxy-2-
methylpropanoate (17): To a mixture of aminoester 10 (500 mg, 3.8
mmol) and 2,4-dimethoxybenzaldehyde (650 mg, 3.9 mmol) in dry DMF
(10 mL) was added dry triethylamine (560 µL, 4.0 mmol) under nitrogen
atmosphere. After stirring at room temperature for
2
h, sodium
General procedure for fluorination using TBAF. To aminoacid alcohol
(0.6 mmol) in dry CH2Cl2 (4.5 mL) in a conic vial was added a solution of
trifluoromethanesulfonic anhydride (1 M in CH2Cl2, 0.66 mL) under
nitrogen atmosphere. After stirring at room temperature for 1 h, DIPEA
(125 µL, 0.72 mmol) then, 1 min later, a solution of TBAF (1 M in THF, 1.2
mL), were added. The reaction mixture was stirred for 2 h at room
temperature. After quenching with aqueous NaOH (15%, 5 mL) and
extraction with CH2Cl2 (2 x 10 mL), the combined organic layers were
concentrated under reduced pressure and the residue was purified by
chromatography on silica gel.
cyanoborohydride was added in one portion. The reaction mixture was
stirred at room temperature overnight then quenched with aqueous
NaHCO3 (20 mL). After extraction with CH2Cl2 (3 x 10 mL), the combined
organic layers were washed with water (20 mL), dried over MgSO4 and
concentrated under reduced pressure. Purification by chromatography on
silica gel (heptane/EtOAc, 40:60 then 20:80) gave compound 10 as a
yellow oil (685 mg, 64%). 1H NMR (400 MHz, CD3OD):  = 7.03 (d, J =
8.20 Hz, 1H), 6.41 (d, J = 2.2 Hz, 1H), 6.35 (dd, J = 2.3 Hz, 8.2 Hz, 1H),
3.72 (s, 3H), 3.66 (s, 3H), 3.55 (s, 3H), 3.54 and 3.47 (AB system, J = 12.0
Hz, 2H), 3.48 (s, 2H) 1.23 (s, 3H) ppm. 13C NMR (100.6 MHz, CDCl3):  =
175.0, 160.7, 158.8, 130.4, 119.4, 103.9, 97.9, 67.1, 67.0, 54.4, 54.3, 51.1,
42.2, 17.3 ppm. HRMS (ESI): calcd. for C14H22NO5 [M+H]+ 284.1498;
found 284.1489.
Methyl-3-(dibenzylamino)-2-fluoropropanoate (26): Compound 26 was
obtained from 1 (145 mg, 0.48 mmol) and DAST as a colorless oil (100
mg, 70%) after purification by chromatography on silica gel
(heptane/AcOEt, 95/5). Compound 26 was also obtained as a colorless oil
(95 mg, 60%) from 1 (160 mg, 0.55 mmol) and TBAF. 1H NMR (400 MHz,
CD3OD):  = 7.35-7.31 (m, 10H), 5.13-5.00 (m, 1H) 3.87-3.52 (m, 4H), 3.80
(s, 3H), 3.07-3.01 (m, 2H) ppm. 13C NMR (100.6 MHz, CD3OD):  = 171.0
(d, JCF = 21.9 Hz), 133.7, 130.1, 128.9, 128.7, 89.3 (d, JCF = 186.1 Hz),
58.1, 54.2 (d, JCF = 20.1 Hz), 53.4 (d, JCF = 22.8 Hz) ppm. 19F NMR (376.5
MHz, CD3OD) :  = -(190.4-190.6) (m) ppm. HRMS (ESI): calcd. for C17H19
FNO2 [M+H]+ 288.1400; found 2881403.
Methyl-3-(benzyl(methyl)amino)-2-fluoropropanoate (27): Compound
27 was obtained from 2 (85 mg, 0.38 mmol) and DAST as a colorless oil
(59 mg, 68%) after purification by chromatography on silica gel
(heptane/AcOEt, 95:5). Compound 27 was also obtained as a colorless oil
(42 mg, 50%) from 2 (85 mg, 0.38 mmol) and TBAF. 1H NMR (400 MHz,
CDCl3):  7.29-7.19 (m, 5H), 5.07 (ddd, J = 49.5, 6.3, 2.6 Hz, 1H), 3.74 (s,
3H), 3.66 and 3.50 (AB system, J = 13.2 Hz, 2H), 3.02-2,82 (m, 2H), 2.30
(s, 3H) ppm. 13C NMR (10006 MHz, CDCl3):  = 69.3 (d, JCF = 24 Hz),
138.2, 129.0, 128.3, 127.3, 89.1 (d, JCF = 185.6 Hz), 62.7 (d, JCF = 1.5 Hz),
57.9 (d, JCF = 19.9 Hz), 52.3, 43.0 (d, JCF = 2.1 Hz) ppm. 19F NMR (376.5
MHz, CDCl3) : = -(190.6-190.8) (m) ppm. HRMS (ESI): calcd. for C12H17
FNO2 [M+H]+ 226.1243; found 226.1248.
Methyl-2-((2,4-dimethoxybenzyl)(methyl)amino)-3-hydroxy-2-
methylpropanoate (6): To a mixture of 17 (400 mg, 1.4 mmol) and K2CO3
(400 mg, 2.9 mmol) in dry DMF (10 mL) was added methyliodide (180 µL,
2.9 mmol) under nitrogen atmosphere. The reaction mixture was stirred at
room temperature for 3 h, then quenched with water (20 mL). After
extraction with CH2Cl2 (3 x 10 mL), the combined organic layers were
concentrated under reduced pressure. Purification of the residue by
chromatography on silica gel (heptane/EtOAc, 2:8) gave compound 6 as a
1
yellow oil (300 mg, 72%). H NMR (400 MHz, CDCl3):  = 7.11 (d, J = 8
Hz, 1H), 6,44 (s, 1H) 6.44 (d, J = 8 Hz, 1H), 4.02 and 3.81 (AB system, J
= 11.6 Hz, 2H), 3.77 and 3.60 (AB system, J = 11.6 Hz, 2H), 3.82 (s, 3H),
3.79 (s, 3H), 3.76 (s, 3H), 2.27 (s, 3H), 1.50 (s, 3H) ppm. 13C NMR (100.6
MHz, CDCl3):  = 174.3, 160.4, 158.6, 131.9, 119,4, 103.9, 98.8, 64.3,
64.2, 55.4, 55.3, 51.50, 50.64, 34.9, 20.3 ppm. HRMS (ESI): calcd. for
C15H24NO5 [M+H]+ 298.1654; found 298.1651.
Methyl-2-(benzylamino)-3-hydroxy-3-phenylpropanoate (14): To
a
mixture of aminoester 11 (300 mg, 1.5 mmol) and K2CO3 (470 g, 3.4 mmol)
in dry DMF (10 mL) was added benzylbromide (180 µL, 2.5 mmol) under
nitrogen atmosphere. After stirring at 50 °C for 20 h, the reaction mixture
was quenched with water (20 mL) then extracted with CH2Cl2 (3 x 10 mL).
The combined organic layers were dried over MgSO4 then concentrated
under reduced pressure. Purification by chromatography on silica gel
(pentane/EtOAc, 97:3 then 80:20) gave compound 14 as a yellow oil (150
mg, 33%).1H NMR (400 MHz, CDCl3):  = 7.24-7.20 (m, 10H), 4.59 (d, J =
7.2 MHz, 1H), 3.68 and 3.58 (AB system, J = 13.0 Hz, 2H), 3.45 (s, 3H),
3.31 (d, J = 7.2 Hz, 1H) ppm. 13C NMR (100.6 MHz, CDCl3):  = 173.5,
140.2, 138.9, 129.0, 128.3, 128.2, 127.4, 126.4, 125.3, 74.3, 67.8, 52.5,
Methyl-3-((2,4-dimethoxybenzyl)(prop-2-yn-1-yl)amino)-2-
fluoropropanoate (28): Compound 28 was obtained from 3 (95 mg, 0.31
mmol) as a colorless oil (81 mg, 85%) after purification by chromatography
on silica gel (heptane/AcOEt, 82:18). Compound 28 was also obtained as
a colorless oil (32 mg, 15%) from 3 (160 mg, 0.55 mmol) after purification
by chromatography on silica gel (heptane/AcOEt, 80:20). 1H NMR (400
MHz, CDCl3):  = 7.27 (d, J = 8.7 Hz, 1H), 6.46-6.44 (m, 2H), 5.19 (ddd, J
= 49.3, 6.4, 2.7 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.76 (s, 3H), 3.70-3.68
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900300
European Journal of Organic Chemistry
FULL PAPER
(m, 2H), 3.51-3.37 (m for ABC system, 2H), 3.22-3.00 (m, 2H), 2.25 (t, J =
2.3 Hz, 1H) ppm. 13C NMR (100.6 MHz, CDCl3) : = 169.1 (d, JCF = 24.6
Hz), 160.3, 158.9, 131.3, 118.5, 103.9, 98.75, 89.4 (d, JCF = 185.6 Hz),
78.9, 73.1, 55.5, 55.4, 54.5 (d, JCF = 20.3 Hz), 52.3, 51.8, 42.9 ppm. 19F
NMR (376.5 MHz, CDCl3):  = -191.6 (td, J = 26.1, 49.3 Hz) ppm. HRMS
(ESI): calcd. for C16H21FNO4 [M+H]+ 310.1455; found 310.1453.
128.4, 128.3, 127.1, 126.7 (d, JCF = 6.4 Hz), 92.2 (d, JCF = 178.1 Hz), 70.1
(d, JCF = 24.5 Hz), 59.4, 51.3, 38.7 (d, JCF = 2.1 Hz) ppm. 19F NMR (376.5
MHz, CDCl3):  = -184.2 (dd, J = 47.4, 15.8 Hz) ppm. HRMS (ESI): calcd.
for C18H21FNO2 [M+H]+ 302.1556; found 302.1556.
Methyl-3-(benzyl(methyl)amino)-2-fluoro-3-phenylpropanoate (33):
Compound 33 was obtained as a side product in the synthesis of 25 from
8 (68 mg, 0.23 mmol) and DAST, and isolated as a colorless oil (12 mg,
18%) after purification by chromatography on silica gel (heptane/AcOEt,
98:2). Compound 33 was also obtained as a side product in the synthesis
of 25 from 72 (62 mg, 0.20 mmol) and TBAF, and isolated as a colorless
oil (5 mg, 8%). 1H NMR (400 MHz, CDCl3):  7.35-7.12 (m, 15H), 5.38 (dd,
J = 49.3, 5.0 Hz, 1H), 3.99 (dd, J = 22.9, 5.0 Hz, 1H), 3.60 (s, 3H), 3.48
and 3.28 (AB system, J = 13.5 Hz, 2H), 2.09 (s, 3H) ppm. 13C NMR (100.6
MHz, CDCl3):  = 169.3 (d, JCF = 22.9 Hz), 138.8 (d, JCF = 4.2 Hz), 134.2,
129.4, 128.7, 128.3 (d, JCF = 3.5 Hz), 127.1, 89.0 (d, JCF = 191.4 Hz), 68.6
(d, JCF = 21.7 Hz), 59.3, 52.3, 38.6 ppm. 19F NMR (376.5 MHz, CDCl3): 
Methyl-3-(dibenzylamino)-2-fluoro-2-methylpropanoate
(29):
Compound 29 was obtained from 4 (73 mg, 0.23 mmol) and DAST as a
colorless oil (72 mg, 98%) after purification by chromatography on silica
gel (heptane/AcOEt, 95:5). Compound 29 was also obtained as a colorless
oil (48 mg, 50%) from 4 (95 mg, 0.31 mmol) and TBAF. 1H NMR (400 MHz,
CD3OD):  = 7.20-7.08 (m, 10H), 3.72 and 3.21 (AB system, J = 13.6 Hz,
4H), 3.48 (s, 3H), 2.92-2.63 (m, 2H), 1.28 (d, J = 21.3 Hz, 3H) ppm. 13C
NMR (100.6 MHz, CD3OD):  174.6 (d, J = 27.0 Hz), 139.0, 128.9, 127.8,
126.7, 97.2 (d, JCF = 183.1 Hz), 59.0, 58.7 (d, JCF = 22.4 Hz), 51.5, 21.0
(d, JCF = 24.4 Hz) ppm. 19F NMR (376.5 MHz, CD3OD):  = -155.6 (ddq, J
= 31.9, 21.3, 14.9 Hz) ppm. HRMS (ESI): calcd. for C19H23 FNO2 [M+H]+
316.1713; found 316.1719.
Methyl-3-(benzyl(methyl)amino)-2-fluoro-2-methylpropanoate (30):
Compound 30 was obtained from 5 (37 mg, 0.16 mmol) and DAST as a
colorless oil (23 mg, 60%) after purification by chromatography on silica
gel (heptane/AcOEt, 95:5). Compound 30 was also obtained as a colorless
oil (35 mg, 45%) from 5 (75 mg, 0.32 mmol) and TBAF. 1H NMR (400 MHz,
CDCl3):  = 7.29-7.20 (m, 5H), 3.75 (s, 3H), 3.68 and 3.53 (AB system, J
= 13.2 Hz, 2H), 3.01-2.70 (m, 2H), 2.25 (s, 3H), 1.52 (d, J = 21.2 Hz, 3H)
ppm. 13C NMR (100.6 MHz, CDCl3):  = 171.7 (d, JCF = 27 Hz), 129.1,
128.3, 127.4, 127.3, 96.8 (d, JCF = 187.0 Hz), 62.6 (d, JCF = 22.1 Hz), 52.5,
43.5, 29.7, 21.9 (d, JCF = 24.2 Hz) ppm. 19F NMR (376.5 MHz, CDCl3):  =
-(156.5-156.6) (m) ppm. HRMS (ESI): calcd. for C12H17 F NO2 [M+H]+
226.1243; found 226.1246.
Methyl-3-((2,4-dimethoxybenzyl)(prop-2-yn-1-yl)amino)-2-fluoro-2-
methylpropanoate (31): Compound 31 was obtained from 6 (83 mg, 0.28
mmol) and DAST as a colorless oil (47 mg, 56%) after purification by
chromatography on silica gel (heptane/AcOEt, 90:10). Compound 31 was
also obtained as a colorless oil (28 mg, 30%) from 6 (97 mg, 0.33 mmol)
and TBAF. 1H NMR (400 MHz, CD3OD):  = 7.04 (d, J = 8.4 Hz, 1H), 6.39-
6.35 (m, 2H), 3.67 (s, 3H), 3.66 (s, 3H), 3.60 (s, 3H), 3.47 and 3.39 (AB
system, J = 13.2 Hz, 2H), 2.95-2.57 (m, 2H), 2.16 (s, 3H), 1.35 (d, J = 20.8
Hz, 3H) ppm. 13C NMR (100.6 MHz, CD3OD):  = 172.1 (d, JCF = 27.2 Hz),
160.4, 158.8, 131.3, 118.2, 104.0, 97.7, 96.7 (d, JCF = 184.6 Hz), 62.4 (d,
JCF = 19.5 Hz), 55.9 (d, JCF = 2.2 Hz), 54.4, 54.4, 51.5, 42.7 (d, JCF = 3.9
Hz), 20.8 (d, JCF = 24.3 Hz) ppm. 19F NMR (376.5 MHz, CD3OD):  = -
(157.2 -157.3) (m) ppm. HRMS (ESI): calcd. for C15H22FNO4 [M+H]+
300.1611; found 300.1612.
=
-198 (dd, J = 49.3, 22.9 Hz) ppm. HRMS (ESI): calcd. for
C18H21FNO2 [M+H]+ 302.1556; found 302.1555.
Methyl-2-((tert-butoxycarbonyl)amino)-3-hydroxy-2-
methylpropanoate (36): To aminoester 9 (2.9 g, 22 mmol) in MeOH/TEA
(9/1) (60 mL) was added di-tert-butyl dicarbonate (8.6 g, 39 mmol). After
stirring at room temperature overnight, the reaction mixture was
concentrated under reduced pressure and purified on silica gel
(CH2Cl2/MeOH, 97/3) to give compound 36 as a white solid (3.8 g, 75%).
Mp = 115 °C. 1H NMR (400 MHz, CDCl3):  = 3.94 and 3.76 (AB system,
J = 10.8 Hz, 2H), 3.76 (s, 3H), 1.46 (s, 3H), 1.43 (s, 9H) ppm. 13C NMR
(100.6 MHz, CDCl3):  = 73.9, 155.4, 80.4, 67.0, 61.0, 52.7, 28.3, 20.8
ppm.
N-tert-Butoxycarbonyl-4-methyl-1,2,3-oxathiazolidine-4-carboxylic
acid methylester 2-oxide (37): To aminoester 36 (970 mg, 4.2 mmol) in
anhydrous acetonitrile (20 mL) at -40 °C was added dropwide thionyl
chloride (780 µL, 10.7 mmol) then dry pyridine (1.7 mL, 21 mmol). After
stirring at -40 °C for 30 min, then at room temperature for 30 min, the
reaction mixture was washed with water (10 mL), saturated sodium
bicarbonate (10 mL), then brine (10 mL). After drying over MgSO4, then
concentrating under reduced pressure, the crude product was purified on
silica gel (pentane/EtOAc, 85:15) to give compound 37 as pale yellow oil
1
(870 mg, 75%). H NMR (400 MHz, CDCl3):  = 5.16-4.40 (m, 2H), 3.80-
3.72 (m, 3H), 1.82-1.38 (m, 12H) ppm. 13C NMR (100.6 MHz, CDCl3):  =
84.5, 79.6, 65.9, 53.4, 28.1, 19.4 ppm. HRMS (ESI): calcd. for
C10H17NO6SNa [M+Na]+ 293.0807; found 293.0805.
N-tert-Butoxycarbonyl-4-methyl-1,2,3-oxathiazolidine-4-carboxylic
acid methylester 2,2-dioxide (38): To sulfamidite 37 (850 mg, 3.0 mmol)
in acetonitrile cooled at 0 °C(30 mL) was added a catalytic portion of RuCl3
(10 mg, 0.05 mmol) then sodium periodate (650 mg, 3.0 mmol). The
reaction mixture was treated with water (30 mL) and stirred at 0 °C for 15
min and then at room temperature overnight. After extraction with ether (2
x 30 mL), the combined organic layers were washed with saturated sodium
bicarbonate (40 mL) and brine (40 mL) and dried over MgSO4. The crude
mixture was purified on silica gel (pentane/EtOAc, 90:10) to give
compound 38 as white solid (775 mg, 86%). Mp = 72 °C. 1H NMR (400
MHz, CDCl3):  = 4.61 and 4.29 (AB system, J = 9.2 Hz, 2H), 3.83 (s, 3H),
1.79 (s, 3H), 1.54 (s, 9H) ppm. 13C NMR (100.6 MHz, CDCl3):  = 169.3,
147.9, 86.1, 72.8, 65.5, 53.7, 27.9, 20.6 ppm. HRMS (ESI): calcd. for
C10H17NO7SNa [M+Na]+ 318.0623; found 318.0627.
Methyl-2-(dibenzylamino)-3-fluoro-3-phenylpropanoate
(24):
Compound 24 was obtained from 7 (32 mg, 0.09 mmol) and DAST as a
colorless oil (6 mg, 20%) after purification by chromatography on silica gel
(heptane/AcOEt, 99:1). Compound 24 was also obtained as a colorless oil
(4 mg, 7%) from 7 (62 mg, 0.17 mmol) and TBAF. 1H NMR (400 MHz,
CDCl3):  = 7.33-7.16 (m, 15H), 5.96 (dd, J = 7.2, 47.2 Hz), 4.07 and 3.79
(AB system, J = 14.0 Hz, 4H), 3.92-3.84 (m, 1H), 3.67 (s, 3H) ppm. 13C
NMR (100.6 MHz, CDCl3):  = 169.3, 138.1, 135.9, 127.8, 127.4, 127.2,
127.2, 126.0, 125.2 (d, JCF = 7.3 Hz), 91.8 (d, JCF = 179.0 Hz), 64.5 (d, JCF
= 22.5 Hz), 54.3, 50.4 ppm. 19F NMR (376 MHz, CDCl3):  = -186.33 (dd,
J = 47.2, 19.4 Hz) ppm. HRMS (ESI): calcd. for C24H25FNO2 [M+H]+
378.1869; found 378.1872.
Methyl-2-amino-3-fluoro-2-methylpropanoate
sulfamidate 38 (125 mg, 0.42 mmol) in anhydrous acetonitrile (4 mL) was
added tetrabutylammonium fluoride (1.1 mL of 1.0 solution in
(39):
To
cyclic
Methyl-3-(dibenzylamino)-2-fluoro-3-phenylpropanoate
(32):
M
Compound 32 has been obtained as a side product in the synthesis of 24
from 7 and DAST, and isolated after purification by chromatography on
silica gel (heptane/AcOEt, 99:1) as a colorless oil (2 mg, 8%). Compound
32 has also been obtained as a side product in the synthesis of 24 from 7
and TBAF, and isolated as a colorless oil (1 mg, 2%). 1H NMR (400 MHz,
CDCl3):  = 7.32-7.07 (m, 10H), 5.83 (dd, J = 48.5, 5.0 Hz, 1H), 3.97 (dd,
J = 22.8, 5.0 Hz, 1H), 3.63 (s, 3H), 3.52 and 3.35 (AB system, J = 13.2 Hz,
2H) ppm. 13C NMR (100.6 MHz, CDCl3):  = 169.6, 138.8, 135.7, 129.4,
128.7, 128.3, 127.3, 127.1, 126.7 (d, JCF = 6.2 Hz), 89.6 (d, JCF = 191.1
Hz), 67.8 (d, JCF = 22.8 Hz), 56.5, 51.3 ppm. 19F NMR (376.5 MHz, CDCl3):
 = -198.3 (dd, J = 48.5, 22.8 Hz) ppm. HRMS (ESI): calcd. for
C24H25FNO2 [M+H]+ 378.1869; found 378.1871.
Methyl-2-(benzyl(methyl)amino)-3-fluoro-3-phenylpropanoate (25):
Compound 25 was obtained from 8 (68 mg, 0.23 mmol) and DAST as a
colorless oil (13 mg, 19%) after purification by chromatography on silica
gel (heptane/AcOEt, 98:2). Compound 25 was also obtained as a colorless
oil (6 mg, 10%) from 8 (62 mg, 0.20 mmol) and TBAF. 1H NMR (400 MHz,
CDCl3):  = 7.40-7.24 (m, 10H) 5.90 (dd, J = 47.4, 8.0 Hz, 1H), 3.97 and
3.77 (AB system, J = 13.2 Hz, 2H), 3.79 (dd, J = 15.8, 8.0 Hz, 1H), 3.61
(s, 3H), 2.51 (s, 3H) ppm. 13C NMR (100.6 MHz, CDCl3):  = 169.7 (d, JCF
= 9.9 Hz), 138.9, 137.0 (d, JCF = 20.5 Hz), 129.9 (d, JCF = 2.2 Hz), 128.8,
tetrahydrofuran, 1.1 mmol). After stirring at room temperature overnight,
the reaction mixture was concentrated under reduced pressure. The
residue was treated with 3 N hydrochloric acid in water (8 mL) at 85 °C for
2 h. The reaction mixture was washed ether (3 x 10 mL) and then
concentrated under reduced pressure. The crude mixture was dissolved in
dry methanol (10 mL) at 0 °C, then thionyl chloride (200 µL, 2.7 mmol) was
added dropwise. After refluxing (55 °C) for 48 h, the residue was filtered
and the solvent was removed under vacuum to give a mixture of 39 and
TBAF as a yellow oil. 1H NMR (400 MHz, CH3OD):  = 5.06-4.73 (m, 2H),
3.92 (s, 3H), 1.59 (d, J = 2.0 Hz, 3H) ppm. 13C NMR (100.6 MHz, CH3OD):
 = 174.2, 84.2 (d, JCF = 178.9 Hz), 63.4 (d, JCF = 18.0 Hz), 53.1, 16.7 (d,
JCF = 5.6 Hz) ppm. 19F NMR (376.5 MHz, CH3OD):  = -(228.2-227.4) (m)
ppm. HRMS (ESI): calcd. for C5H11FNO2 [M+H]+ 136.0774; found
136.0773.
Methyl-2-(benzylamino)-3-fluoro-2-methylpropanoate (40): To
a
mixture of crude product 39 (0.35 mmol) and K2CO3 (115 mg, 0.84 mmol)
in anhydrous DMF (3 mL) was added benzylbromide (60 µL, 0.50 mmol)
under nitrogen atmosphere. After stirring at 50 °C for 64 h, the mixture was
diluted with dichloromethane (15 mL), washed with water (10 mL) then
brine (10 mL). After drying over MgSO4 then concentration under vacuum,
the crude product was purified by column chromatography
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900300
European Journal of Organic Chemistry
FULL PAPER
(pentane/EtOAc, 95/5) to give the product 40 as a colorless oil (38 mg,
(pentane/EtOAc, 99:1 then 95:5) gave compound 35 as a colorless oil (17
mg, 14%). 1H NMR (400 MHz, CDCl3):  = 7.27-7.15 (m, 5H), 4.64-4.44 (m
for ABC system, 2H), 3.85 and 3.67 (AB system, J = 13.1 Hz, 2H), 3.7 (s,
3H), 3.44 (td, J = 26.2, 4.2 Hz, 1H) ppm. 13C NMR (101 MHz, CDCl3):  =
172.2 (d, JCF = 5.3 Hz) 139.2, 128.5, 128.3, 127.3, 84.15 (d, JCF = 173.0
Hz), 60.4 (d, JCF = 20.3 Hz), 52.3, 52.0. 19F NMR (376 MHz, CDCl3):  = -
1
48% from compound 38). H NMR (400 MHz, CDCl3):  = 7.28-7.14 (m,
5H), 4.52-4.29 (m for ABC system, 2H), 3.68 (s, 3H), 3.61 (s, 2H), 1.29 (d,
J = 2.3 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3 ):  = 174.3, 140.0, 128.6,
128.5, 127.2, 87.1 (d, J = 176.5 Hz), 62.5 (d, J = 18.0 Hz), 52.3, 48.4, 19.0
(d, J = 6.0 Hz) ppm. 19F NMR (376.5 MHz, CDCl3):  = -225.0 (t, J = 47.2
Hz) ppm. HRMS (ESI): calcd. for C12H17FNO2 [M+H]+ 226.1243; found
226.1245.
228.1 (dt,
J = 46.9, 26.2 Hz) ppm. HRMS (ESI): calcd for
C11H15FNO2 [M+H]+ 212.1087; found 212.1088.
Methyl-2-(dibenzylamino)-3-fluoro-2-methylpropanoate (21): To
a
Methyl-2-(dibenzylamino)-3-fluoropropanoate (18): Compound 18 was
obtained as a side product in the synthesis of compound 35, and was
isolated as a colorless oil (7 mg, 8%) after purification on silica gel
(pentane/EtOAc, 99:1 then 95:5). 1H NMR (400 MHz, CDCl3):  = 7.41-
7.21 (m, 10H), 4.81-4.60 (m for ABC system, 2H), 3.90 and 3.75 (AB
system, J = 13.9 Hz, 4H), 3.81 (s, 3H), 3.76-3.68 (m, 1H) ppm. 13C NMR
mixture of 40 (90 mg, 0.40 mmol) and K2CO3 (120 mg, 0.90 mmol) in dry
DMF (3 mL) was added benzylbromide (60 µL, 0.50 mmol) under nitrogen
atmosphere. After stirring at 50 °C overnight, the reaction mixture was
quenched with water (5 mL). The aqueous layer was extracted with CH2Cl2
(3 x 5 mL) and the combined organic layers were dried over MgSO4 then
concentrated under reduced pressure. Purification on silica gel
(pentane/EtOAc, 98:2) gave compound 21 as a colorless oil (12 mg, 10%).
1H NMR (400 MHz, CDCl3):  = 7.36-7.12 (m, 10H), 4.68-4.40 (m for ABC
system, 2H), 3.85 (d, J = 4.1 Hz, 4H), 3.72 (s, 3H), 1.43 (d, J = 2.0 Hz, 3H)
ppm. 13C NMR (100.6 MHz, CDCl3):  = 173.3 (d, JCF = 4.4 Hz), 139.9,
128.6, 128.3, 126.7, 86.2 (d, JCF = 175.5 Hz), 67.1 (d, JCF = 18.5 Hz), 52.4,
48.4, 29.7, 19.7 (d, JCF = 5.2 Hz) ppm. 19F NMR (376.5 MHz, CDCl3):  =
-224.1 (t, J = 47.6 Hz) ppm. HRMS (ESI): calcd. for C19H23FNO2 [M+H]+
316.1713; found 316.1719.
(100.6 MHz, CDCl3):  = 165.2, 139.2, 128.7, 127.2, 126.9, 82.3 (d, JCF
=
172.2 Hz), 60.9 (d, JCF = 21.4 Hz), 57.9, 51.7 ppm. 19F NMR (376.5 MHz,
CDCl3) :  = -225.4 (dt, J = 46.9, 20.3 Hz) ppm. HRMS (ESI): calcd. for
C18H21FNO2 [M+H]+ 302.1556; found 302.1556.
Radiolabelling procedures
General remarks: No-carrier-added (NCA) [18F]-fluoride was produced via
the 18O[p,n]18F nuclear reaction by irradiating 18O-enriched water (97%,
Eurisotop; 1.8 mL) with a beam of protons (18 MeV; 20–25 μA for 60 min)
from a Cyclone 18/9 (IBA) cyclotron at the Cyceron PET Center.
Methyl-2-(benzyl(methyl)amino)-3-fluoro-2-methylpropanoate (22):
To a mixture of 40 (40 mg, 0.16 mmol) and K2CO3 (80 mg, 0.60 mmol) in
dry DMF (2.5 mL) was added methyliodide (20 µL, 0.32 mmol) under
nitrogen atmosphere. After stirring at room temperature for 3 h, the
reaction mixture was quenched with water (5 mL). The aqueous layer was
extracted with CH2Cl2 (3 x 5 mL). The combined organic layers were dried
over MgSO4 then concentrated under reduced pressure. Purification of the
residue on silica gel (pentane/EtOAc, 99:1) gave compound 22 as a yellow
oil (9 mg, 20%). 1H NMR (400 MHz, CDCl3):  = 7.35-7.22 (m, 5H), 4.79-
4.55 (m for ABC system, 2H), 3.79 (s, 3H), 3.64 (s, 2H), 2.24 (s, 3H), 1.50
[
18F]fluoride was delivered to a lead-shielded hot cell in 18O-enriched water
by nitrogen gas pressure. Analytical High Performance Liquid
Chromatography (HPLC) was carried out by a Waters e2695 (Separations
module) coupled with a Waters 2998 (Photodiode Array Detector) and a
MIP10 radioactive detector (Nardeux). Semi-preparative HPLC was
carried out by a Waters 515 HPLC pump coupled with a Waters 2487 UV
detector set up at λ = 254 nm and a MIP10 radioactive detector (Nardeux).
Measure of the radioactivity was carried out with a Capintec R15C. QMA
cartridges (QMA light, Waters, ABX) were obtained from ABX. Anhydrous
high grade solvents (ACN and CH2Cl2) purchased from Sigma-Aldrich
were used for all radioactive reactions.
(d, J = 2.3 Hz, 3H) ppm. 13C NMR (100.6 MHz, CDCl3):  = 173.0 (d, JCF
=
4.3 Hz), 140.0, 128.3, 128.2, 126.9, 85.8 (d, JCF = 165.8 Hz), 66.1 (d, JCF
= 18.0 Hz), 56.5 (d, JCF = 1.5 Hz), 51.8, 35.7, 18.6 (d, JCF = 5.2 Hz) ppm.
19F NMR (376.5 MHz, CDCl3):  = -225.1 (t, J = 47.1 Hz) ppm. HRMS (ESI):
calcd. for C13H19FNO2 [M+H]+ 240.1400; found 240.1399.
Typical procedure for the deoxyradiofluorination reaction: No-carrier-
added aqueous cyclotron produced [18F]fluoride (3-5 mCi; 111-185 MBq)
was trapped on a quaternary ammonium solid phase extraction cartridge
(QMA light, waters, ABX), then was eluted with a ACN/H2O (3/1, 500 µL)
solution containing K2CO3 (3.15 mg, 23 µmol) and K222 (10.2 mg, 28 µmol).
After three azeotropic evaporations with ACN (3 x 500 µL) at 110 °C under
a steam of nitrogen, dried [18F]KF/K222 complex was cooled to room
temperature. In parallel, triflic anhydride (1M solution in CH2Cl2, 37 µL, 37
µmol) was added to a solution of the hydroxyaminoester precursor (33
µmol) in CH2Cl2 (260 µL). After stirring for 1 h at room temperature, then
addition of DIPEA (6-7 L, 40 µmol) in ACN (200 µL) and stirring for 1 min,
the resulting solution was transferred into the vial containing the dried [18F]-
KF/K222 complex. The final reaction mixture was stirred at RT for 30 min.
Activities recovered at the end of the radiosynthesis were in the 1.8-3.2
mCi (66-118 MBq) range. Aliquots (20 µL) were taken off at 5, 10, 15 and
30 min, then diluted in MeOH (0.2 mL) and analyzed by radio-TLC and
radio-HPLC for the determination of the RCC and the isomeric ratio
respectively.
Methyl-2-((2,4-dimethoxybenzyl)amino)-3-fluoro-2-methylpropanoate
(41): To
a
mixture of 39 (220 mg, 1.6 mmol) and 2,4-
dimethoxybenzaldehyde (282 mg, 6.42 mmol) in dry methanol (5 mL),
anhydrous triethylamine (230 µL, 1.65 mmol) was added. After stirring at
room temperature for 30 min, sodium cyanoborohydride (225 mg, 3.5
mmol) was added in one portion. After stirring at room temperature
overnight, dichloromethane (10 mL) was added and the organic layer was
washed with sodium bicarbonate solution (3 x 10 mL). After drying over
MgSO4, then concentration under vacuum, purification on silica gel
(pentane/EtOAc, 9:1) gave product 41 as a pale yellow oil (260 mg, 60%).
1H NMR (400 MHz, CD3OD):  = 7.27 (d, J = 8.8 Hz, 1H), 6.54-6.52 (m,
2H), 4.57 (d, J = 47.0 Hz, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 3.80 (s, 3H), 3.92-
3.78 (m, 2H), 1.51 (d, J = 1.5 Hz, 3H) ppm. 13C NMR (100.6 MHz, CD3OD):
 = 174.3 (d, JCF = 2.5 Hz), 160.2, 158.5, 130.3, 120.4, 103.9, 98.5, 86.9
(d, JCF = 176 Hz), 61.9 (d, JCF = 19.5 Hz), 55.3, 55.2, 52.1, 42.7, 18.9 (d,
JCF = 4.7 Hz) ppm. 19F NMR (376.5 MHz, CD3OD):  = -225.69 (dt, J =
47.0, 1.5 Hz) ppm. HRMS (ESI): calcd. for C14H21FNO4 [M+H]+ 286.1376;
found 286.1375.
Methyl-2-((2,4-dimethoxybenzyl)(methyl)amino)-3-fluoro-2-
methylpropanoate (23): To a mixture of 41 (135 mg, 0.48 mmol) and
K2CO3 (145 mg, 1.1 mmol) in dry DMF (5 mL) was added methyliodide (65
µL, 1.1 mmol) under nitrogen atmosphere. After stirring at room
temperature for 2 h, the reaction mixture was quenched with water (10 mL)
then the aqueous layer was extracted with CH2Cl2 (3 x 5 mL). After drying
over MgSO4, then concentration under vacuum, purification of the residue
on silica gel (pentane/EtOAc, 97:3) gave compound 23 as a colorless oil
(105 mg, 72%). 1H NMR (400 MHz, CD3OD):  = 7.25 (d, J = 8.7 Hz, 1H),
6.47-6.44 (m, 2H), 4.85-4.50 (m for ABC system, 2H), 3.79 (s, 6H), 3.78
(s, 3H), 3.61 and 3.48 (AB system, J = 14.4 Hz, 2H), 2.28 (s, 3H), 1.49 (s,
3H) ppm. 13C NMR (100.6 MHz, CD3OD):  = 173.0, 160.0, 158.6, 130.6,
119.9, 103.9, 98.4, 85.9 (d, JCF = 175.2 Hz), 66.1 (d, JCF = 18.9 Hz), 55.4,
55.3, 51.7, 50.2, 35.8, 18.3 (d, JCF = 4.7 Hz) ppm. 19F NMR (376.5 MHz,
CD3OD):  = -226.3 (t, J = 47.1 Hz) ppm. HRMS (ESI): calcd. for
C15H22NO4FNa [M+Na]+ 322.1431; found 3221431.
Acknowledgements
This work was supported by Rꢀgion Normandie, CNRS, CEA,
Labex IRON (ANR-11-LABX-0018-01) and FR3038 INC3M. The
authors thank Dr. F. Sobrio and the cyclotron operators Mr. O.
Tirel and Mr. J. Delamare for [18F]fluoride production.
Keywords: Deoxyradiofluorination • Aziridinium • Aminoester •
Fluorine-18 • Radiochemistry
Methyl-2-(benzylamino)-3-fluoropropanoate (35): To a mixture of 34
(110 mg, 0.93 mmol) and K2CO3 (160 mg, 1.1 mmol) in dry acetonitrile (4
mL) was added benzylbromide (111 µL, 0.63 mmol) under nitrogen
atmosphere. After stirring at 50 °C overnight, the reaction mixture was
quenched with water (5 mL). The aqueous layer was extracted with CH2Cl2
(3 x 5 mL) and the combined organic layers were concentrated under
reduced pressure. Purification by chromatography on silica gel
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900300
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Radiofluorination
Marine Morlot, Fabienne Gourand and
Cécile Perrio*
Page No. – Page No.
Deoxyradiofluorination Reaction from
-Hydroxy--aminoesters: an Entry to
[18F]Fluoroaminoesters under mild
conditions
Deoxyradiofluorination of β-hydroxy--aminoesters was successfully achieved at
room temperature using [18F]fluoride anion. The reaction involved an aziridinium
intermediate and yielded the corresponding [18F]fluorinated  or -aminoesters in
good radiochemical yields. Regioselectivity was dependent on the nature of
substituents R1-R4.
This article is protected by copyright. All rights reserved.