Efficient synthesis of fluorobenzyloxoimidazolidinone derivatives: Precursors for the radiosynthesis of [18F]fluorophenylamino acids

Article abstract of DOI:10.1016/j.tet.2010.10.036

This paper describes an efficient synthesis of fluorobenzyloxoimidazolidinone derivatives. The title compounds 1a, 1b and 1c could be prepared with high diasteromeric purity (>99%) and overall yields of 19%, 48% and 41% in a ten or six-step synthetic proc

Full text of DOI:10.1016/j.tet.2010.10.036

Tetrahedron 66 (2010) 9996e10001
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient synthesis of fluorobenzyloxoimidazolidinone derivatives:
precursors for the radiosynthesis of [18F]fluorophenylamino acids
*
ꢀ
Johnny Castillo Melean, Johannes Ermert , Heinz H. Coenen
€
€
€
Forschungszentrum Julich GmbH, Institut fur Neurowissenschaften und Medizin, INM-5: Nuklearchemie, D-52425 Julich, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 August 2010
Received in revised form 13 October 2010
Accepted 14 October 2010
Available online 17 November 2010
This paper describes an efficient synthesis of fluorobenzyloxoimidazolidinone derivatives. The title
compounds 1a, 1b and 1c could be prepared with high diasteromeric purity (>99%) and overall yields of
19%, 48% and 41% in a ten or six-step synthetic procedure, respectively. These compounds are used as
precursors for isotopic 18F-labelling.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Amino acid
Oxoimidazolidinone
Fluorine-18
18[F]Fluorophenylamino acid
Radiopharmaceutical
1. Introduction
oxidation. Finally, an acid hydrolysis generated two hydroxyl groups
and unmasked the amino acid 6-[18F]fluoro-
-DOPA 4a (Scheme 1).
L
In nuclear medicine diagnosis 18F-labelled aromatic amino acids
are widely employed as radiopharmaceuticals for in vivo imaging
using Positron Emission Tomography (PET).1 The most represen-
When using (2S,5S)-tert-butyl-5-(5-acetyl-2-fluorobenzyl)-2-tert-
butyl-3-methyl-4-oxoimidazolidine-1-carboxylate 1b as precursor,
the BayereVilliger oxidation yielded 6-[18F]fluoro- -m-tyrosine 4b,7
L
tative of this class of compounds is 6-[18F]fluoro-
L
-DOPA, one of the
a radiopharmaceutical with similar pharmacological properties as
few established radiopharmaceuticals, which is used for the di-
agnosis of central motor disorders and also of brain and peripheral
endocrine tumours with PET.2
6-[18F]fluoro- -DOPA.8
L
In a second pathway the formyl group is removed by a reductive
decarbonylation reaction.9 This has been exemplified with the
Two general pathways have been developed for the radio-
fluorination of arene-derivatives of high electron density. Due to the
necessary generation of elemental [18F]fluorine, the currently used
methods for routine preparation of aromatic amino acids via elec-
trophilic labelling3 are limited to low amounts of activity at high
costs.4 Alternatively developed nucleophilic syntheses using the
advantage of large scale production of [18F]fluoride, however, result
either in insufficient enantiomeric purity or in a need of multi-step-
syntheses that are difficult to automate, due to their complexity.5
Recently, an isotopic exchange approach made the radiosynthesis
synthesis of 2-[18F]fluoro- -phenylalanine 4c from 1c.10 Similarly by
L
decarbonylation, 2-[18F]fluoro-
-tyrosine 4d, a radiotracer for the
L
quantitation of cerebral protein synthesis,11 becomes available also
from precursor 1a.12
Both three-step methods, using the conversion of the activating
carbonyl-group after isotopic 18F-exchange either by BaeyereVilliger
oxidationorbyreductivedecarbonylation, arenotonlymoreefficient
than known nucleophilic methods for the synthesis of [18F]fluoro-
phenylamino acids, but furthermore, they are capable of being
implemented in existing automated 18F-synthesizer modules offer-
ing a reliable large scale production method.
of 6-[18F]fluoro- -DOPA available in three-steps.6 In thisradiochemical
L
process the precursor (2S,5S)-tert-butyl 5-(4-benzyloxy-2-fluoro-for-
mylbenzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate
1a at first was radiofluorinated and subsequently the formyl
group was converted into the formate derivative by BaeyereVilliger
Isotopic substitution reactions for the synthesis of 18F-labelled
radiopharmaceuticals can only be used for non-toxic fluoro com-
pounds, which are applied as in vivo probes of non-saturable pro-
cesses, i.e., where a high specific activity [activity per unit mass] is
not needed. In isotopic exchange procedures the specific activity
obtained depends of course on both, the starting amount of the
fluoro compound and the quantity of [18F]fluoride used for label-
* Corresponding author. Tel.: þ49 2461613110; fax: þ49 2461612119; e-mail
ling. In the recently realised radiosynthesis of 6-[18F]fluoro-
L-DOPA,
address: j.ermert@fz-juelich.de (J. Ermert).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.036

ꢀ
J. Castillo Melean et al. / Tetrahedron 66 (2010) 9996e10001
9997
Scheme 2. Synthesis of 2-(benzyloxy)-5-bromo-4-fluorobenzaldehyde.
The first intention was to reduce the ester just to the corresponding
aldehyde, however, after several trials using 1 equiv of the reducing
agent at different temperatures the result was always a mixture of
1:1 of the starting material and the benzyl alcohol derivative 8.
Red-Al-pyrrolidine, which has been earlier successfully employed
in this kind of reduction,14 produced similar results. Reduction of
the ester to the alcohol using LiAlH4, on the other hand, generates
a mixture of the desired alcohol 8 plus the debrominated alcohol.
Oxidation of alcohol 8 with DesseMartin periodinane (DMP) in
dichloromethane at room temperature provides the aldehyde 9a in
a yield of 92%.15
Scheme 3 resumes the general synthetic pathway for 1a, 1b and
1c. In the first step the carbonyl function was protected as 1,3-
dithiolane derivative.16 The selection of the protecting group was
based on the bigger stability showed by the 1,3-dithiolane with
respect to the corresponding 1,3-dioxolane derivative. The latter
has shown moderate lability during the following synthetic steps.
Scheme 1. Radiosynthesis of aromatic amino acids labelled with [18F]fluoride.
for example, a maximum of 2.0 mg carrier is formed corresponding
to the amount of precursor 1a sufficient for an effective synthesis.6
This is considerably lower than that obtained by the state-of-the-
art electrophilic preparation where up to 15 mg of 6-fluoro-L-DOPA
are produced for human injection, which is tolerated by, for ex-
ample, the European Pharmacopoeia.13 Considering the much
higher starting activity of [18F]fluoride available for substitution
reactions under production conditions, a five times higher specific
activity can easily be achieved than by electrophilic labelling pro-
cedures. Because of the importance of this general 18F-labelling
procedure an efficient synthesis of the labelling precursors is
needed.
An earlier reported synthesis of 1a involved eleven reaction
steps in a total chemical yield of <1%. Here an optimized synthesis
of 1a is presented, where one reaction step is saved and the yield of
most others is considerably improved, leading to a total yield of
about 19%. Additionally, the preparation of the derivatives 1b and
1c is described.
2. Results and discussion
2-(Benzyloxy)-5-bromo-4-fluorobenzaldehyde 9a, 1-(3-bromo-
4-fluorophenyl)ethanone 9b and 3-bromo-4-fluorobenzaldehyde
9c were used as starting materials for precursors 1a, 1b and 1c,
respectively. The latter two are commercially available. The alde-
hyde 9a was prepared as shown in Scheme 2.
4-Fluoro-salicylic acid was brominated in basic alcoholic me-
dium using molecular bromine as brominating agent. The reaction
produced the desired 3-bromo-4-fluoro-salicylic acid 6 in a yield of
82%. Benzylation of 6 with benzyl bromide in basic media yielded
the compound 7 in 77%. The ester functionality of 7 was then re-
duced to the alcohol 8 with 92% yield using 2.1 equiv of DIBAL-H.
Scheme 3. General synthetic pathway to precursors 1a,b,c.

ꢀ
J. Castillo Melean et al. / Tetrahedron 66 (2010) 9996e10001
9998
The compounds 11 were achieved using the two-step one pot
transferred into the reaction flask, equipped with a septum,
through syringes. All the reaction mixtures were magnetically
stirred. Flash chromatography was performed following the pro-
cedure proposed by Still et al.22 on silica gel (Merck 60 mesh for
flash chromatography).
Dry solvents dichloromethane, tetrahydrofurane, dioxane and
methanol were purchased from Fluka, Germany. Diethylether, pe-
troleum ether, acetonitrile, ethyl acetate and ethanol were obtained
from Merck, Germany. All solvents were used without further
purification.
coupling reaction proposed by Krasovskiyet al.17 The first-step is the
bromo-magnesium exchange between 10 and a diisopropylmagne-
sium chloride lithium chloride complex followed by the coupling
with ethyl chloroformate. The use of ethyl chloroformate as elec-
trophile was preferred over DMF due to its higher electrophilic
character. This reaction represents a mild and regioselective alter-
native to the low yielding bromo-lithium exchange formylation
reaction using BuLi (20% in this case).18 Attempts to prepare the
benzyl alcohol 12 directly by means of coupling of organo-magne-
sium species with para-formaldehyde provided the desired com-
pound in poor yields of 10e20%.
1-(3-bromo-4-fluorophenyl)ethanone,
isopropylmagnesium
chloride, lithium chloride complex, lithium aluminium hydride,
diisobutylaluminium hydride, carbontetrabromide, triphenyl-
phosphine, diisopropylamine, butyllithium, [bis(trifluoroacetoxy)
iodo]benzene and DesseMartin periodinane were purchased from
Aldrich, Germany. Iodine, sodium acetate, benzyl bromide, etha-
nedithiol and ethyl chloroformate from Fluka, Germany and mo-
lecular bromine, (S)-Boc-BMI were acquired from Merck, Germany.
All the reagents were used without purification.
Reduction of 11 with LiAlH4 provided the benzyl alcohol 12 in
yields around 92% after 1 h at room temperature. The conversion of
the benzyl alcohol to the benzyl bromide was performed using the
Appel reaction with good yields.19 The stability of this group of
benzyl bromides has been a problematic issue. Immediate de-
composition is observed when solutions of the benzyl bromide in
dichloromethane or ethyl acetate are heated above room temper-
ature. In order to avoid this problem, the reaction solvent (CH2Cl2)
was partially evaporated under vacuo without application of ex-
ternal heating.
3.2. Compounds
Freshly prepared lithium diisopropylamide (LDA), product of
the reaction of diisopropylamine and BuLi at ꢀ78 ꢁC during
15 min, was used to generate the enolate derivative of the chiral
auxiliary (S)-(ꢀ)-1-BOC-2-tert-butyl-3-imidazolidinone (Seebach
reagent).20 Use of commercially available LDA leads to poor yields
(20e30%). On the other hand the synthesis of LDA at ꢀ78 ꢁC
provides better alkylation yields compared with LDA prepared at
3.2.1. 5-Bromo-4-fluoro-2-hydroxybenzoic
acid
(6). 4-Fluo-
rosalicilyc acid (1.00 g, 6.4 mmol) was dissolved in methanol
(10 mL). Sodium acetate (2.2 g, 26.88 mmol) was added and the
mixture was cooled to ꢀ78 ꢁC. Molecular bromine (0.33 mL,
6.4 mmol) dissolved in 10 mL of methanol was slowly added and
the mixture was allowed to warm to room temperature. After 5 h
the solvent was removed under vacuum and the remnants treated
with a solution of 10% HCl. The residue was filtered under vacuum,
washed with water and dissolved in EtOAc. After drying over
Na2SO4 the solvent was removed in vacuo to give 1.23 g (82%) of the
0
ꢁC. After optimization, the alkylated product 14 was obtained in
a range of 75e89% yield. Deprotection of the 1,3-dithiolane was
performed following the procedure described by Stork and Zhao
using [bis(trifluoroacetoxy)iodo]benzene regenerates the car-
bonyl functionality to afford the desired series of compounds 1
Table 1.21
desired product 6. Mp 205e207 ꢁC (lit. 203e205 ꢁ 23).
C
3.2.2. Benzyl 2-(benzyloxy)-5-bromo-4-fluorobenzoate (7). K2CO3
(7.06 g, 51.08 mmol) and benzyl bromide (3.34 mL, 28.08 mmol)
were added to a solution of the acid 6 (3.00 g, 12.77 mmol) in ac-
etone (100 mL). The mixture was stirred under reflux. After 3 h the
reaction was cooled down to room temperature. Water was added
and the mixture extracted with CH2Cl2 (3ꢂ30 mL). The organic
fractions were combined and washed with brine. The organic layer
was separated, dried over Na2SO4 and the solvent removed under
vacuum. The crude product was purified by flash chromatography
(5% EtOAc/petroleum ether) to give 1.76 g of 7 (77%). Rf¼0.33 (5%
Table 1
Yields of the reaction steps to fluorobenzyloxoimidazolidinone derivatives 1a, 1b
and 1c (cf. Scheme 3)
Compound
a (%)
b (%)
c (%)
10
11
12
13
14
1
96
77
90
74
75
92
34a
95
81
91
84
89
91
48
97
81
91
74
84
93
41
EtOAc/petroleum ether); mp 77e78 ꢁC; 1H NMR (CDCl3)
d
8.07 (d,
J¼8.0 Hz, 1H), 7.41e7.29 (m, 10H), 6.79 (d, J¼10.4 Hz, 1H), 5.17 (s,
2H), 5.31(s, 2H); 13C NMR (CDCl3)
Overall yield
d
164.1, 161.9 (J¼253.4 Hz), 159.2
a
Including the synthesis of 9a the overall yield for 1a is 19%.
(J¼10.4 Hz), 136.6 (J¼2.5 Hz) 135.7, 135.4, 128.7, 128.6, 128.3, 128.24,
128.18, 127.1, 118.0 (J¼3.4 Hz), 102.8 (J¼26.2 Hz), 99.3 (J¼22.0 Hz),
71.2, 67.1; 19F NMR (CDCl3)
d
ꢀ97.7; HRMS C21H17BrFO3 m/z [MþH]þ
calculated 415.0345, found 415.0341.
In summary, the synthesis of (2S,5S)-tert-butyl 5-(4-(benzy-
loxy)-2-fluoro-5-formylbenzyl)-2-tert-butyl-3-methyl-4-oxoimi-
dazolidine-1-carboxylate 1a has been optimized. The 10 steps
procedure achieved the desired compound with an overall yield
of 19%. In addition, the derivatives 1b and 1c have been syn-
thesized in six steps with overall yields of 48% and 41%,
respectively.
3.2.3. (2-(Benzyloxy)-5-bromo-4-fluorophenyl)methanol (8). Ester 7
(3.06 g, 7.36 mmol) was dissolved in dry dichloromethane (50 mL)
and cooled to 0 ꢁC. 16.19 mL (1.0 M, 16.19 mmol) of a solution of
DIBAL was added dropwise. The reaction was stirred during 10 min
at 0 ꢁC and then was allowed to warm to room temperature. After
30 min the reaction mixture was quenched with water. The organic
layer was separated and the aqueous phase extracted with
dichloromethane, the organic fractions were combined and washed
with brine, separated and dried over Na2SO4. The solvent was re-
moved and the crude product purified by flash chromatography
(15% AcOEt/petroleum ether) yielded the product 8 in 90%. Rf¼0.60
(20% EtOAc/petroleum ether); mp 100e101 ꢁC; 1H NMR (CDCl3)
3. Experimental part
3.1. General techniques
All the reactions sensitive to moisture were carried out under
argon atmosphere and, prior to use, the reaction flasks were dried
over night in an oven at 95 ꢁC. All liquids sensitive to moisture were
d
7.47 (d, J¼7.8 Hz, 1H), 7.31e7.38 (m, 5H), 6.73 (d, J¼10.2 Hz, 1H),
5.09 (s, 2H), 4.65 (s, 2H), 2.08 (s, 1H); 13C NMR (CDCl3)
d
158.9

ꢀ
J. Castillo Melean et al. / Tetrahedron 66 (2010) 9996e10001
9999
(J¼245.7 Hz), 156.4 (J¼8.5 Hz), 135.6 (J¼2.5 Hz), 132.4, 128.8, 128.4,
2H); 13C NMR (CDCl3)
d
158.6 (J¼248.3 Hz), 138.1 (J¼3.4 Hz), 133.0,
127.3,127.1 (J¼4.2 Hz),101.3 (J¼27.0 Hz), 99.1 (J¼21.1 Hz), 70.7, 60.6;
128.6 (J¼7.6 Hz), 116.3 (J¼22.8 Hz), 108.9 (J¼22.0 Hz), 54.8, 40.3; 19F
19F NMR (CDCl3)
53.6H: 4.24.
d
ꢀ105.9; E.A. calculated C: 54.04, H: 3.89, found C:
NMR (CDCl3)
d
ꢀ108.4; HRMS C9H9BrFS2 m/z [MþH]þ calculated
278.9313, found 278.9133.
3.2.4. 2-(Benzyloxy)-5-bromo-4-fluorobenzaldehyde
(9a). DMP
3.2.8. Ethyl 4-(benzyloxy)-5-(1,3-dithiolan-2-yl)-2-fluorobenzoate
(1.50 g, 3.42 mmol) was added to a solution of the alcohol 8
(0.97 g, 3.13 mmol) in methylene chloride (20 mL) under stirring.
After 20 min the reaction mixture was diluted with 50 mL of ether
and poured into saturated aqueous NaHCO3 containing a seven-
fold excess of Na2S2O3. The mixture was stirred to dissolve the
solid, and the layers were separated. The organic layer was
washed with water, separated, dried over Na2SO4, filtrated and
the solvent evaporated in vacuo. The crude product was purified
by flash chromatography (5% EtOAc/petroleum ether) to give the
desired compound in 95% of yield. Rf¼0.45 (5% EtOAc/petroleum
(11a). Dioxane (0.3 mL) was added to a solution of iso-
propylmagnesium chloride lithium chloride complex in THF (1.3 M,
3.14 mL 4.08 mmol) and the mixture was cooled to 0 ꢁC. After 5 min
1.21 g (3.14 mmol) of compound 5 was added and the mixture
stirred during 1.0 h at 0 ꢁC. Then 0.61 mL (6.28 mmol) of ethyl
chloroformate was added and the mixture was allowed to reach
room temperature. The solution was stirred for 2 h and then
quenched with saturated aqueous NH4Cl solution (4 mL). The re-
action mixture was partitioned in H2O/ether (30:30) the organic
layer separated and the aqueous phase was extracted with ether
(2ꢂ20 mL), the organic fractions were combined dried over Na2SO4
and concentrated in vacuo. The crude residue was purified by flash
chromatography (10% AcOEt/petroleum ether) yielding compound
6 (77%). Rf¼0.39 (10% EtOAc/petroleum ether); mp 83e85 ꢁC; 1H
ether); mp 89e91 ꢁC; 1H NMR (CDCl3)
d
10.31 (s, 1H), 7.98 (d,
J¼8.2 Hz, 1H), 7.31e7.38 (m, 5H), 6.78 (d, J¼9.9 Hz, 1H), 5.10 (s,
2H); 13C NMR (CDCl3)
d
186.9, 163.3 (J¼255.9 Hz), 161.4
(J¼10.1 Hz), 134.8, 133.5 (J¼3.4 Hz), 128.9, 128.7, 127.4, 122.9
(J¼3.4 Hz), 102.4 (J¼26.2 Hz), 101.1 (J¼22.0 Hz), 71.2; 19F NMR
NMR (CDCl3)
d
8.29 (d, J¼8.4 Hz, 1H), 7.29e7.42 (m, 5H), 6.63 (d,
(CDCl3)
308.9926, found 308.9905.
d
ꢀ93.6; HRMS C14H11BrFO2 m/z [MþH]þ calculated
J¼12.1 Hz, 1H), 5.13 (s, 2H), 4.35 (q, J¼7.1 Hz, 2H), 5.95 (s, 2H), 3.30
(m, 2H), 3.38 (m, 2H), 1.36 (s, J¼7.0 Hz, 3H); 13C NMR (CDCl3)
d 164.1
(J¼4.2 Hz), 162.7 (J¼260.9 Hz), 159.8 (J¼10.1 Hz), 135.4, 131.6
(J¼2.5 Hz), 128.7, 128.4, 127.3, 126.5 (J¼3.4 Hz), 110.7 (J¼9.3 Hz),
100.8 (J¼27.9 Hz), 70.9, 61.0, 48.4, 39.3, 14.3; 19F NMR (CDCl3)
3.2.5. 2-(2-(Benzyloxy)-5-bromo-4-fluorophenyl)-1,3-dithiolane
(10a). 1,3-Ethanedithiol (0.29 mL, 3.55 mmol) was added to a so-
lution of 9a (1.00 g, 3.23 mmol) and iodine (0.082 g, 0.32 mmol) in
dichloromethane (10 mL) and the mixture was stirred at room
temperature. After 1 h the reaction was quenched with NaS2O3
(0.1 M, 25 mL) and NaOH (10%, 25 mL). Then 25 mL of dichloro-
methane were added and the organic layer was separated, dried
over MgSO4 and filtrated. The solvent was removed in vacuo and
the crude product purified by flash chromatography (3% AcOEt/
petroleum ether) to give 1.21 g of 10a (97%). Rf¼0.49 (% EtOAc/pe-
d
ꢀ106.4; HRMS C19H20FO3S2 m/z [MþH]þ calculated 379.0838,
found 379.0830.
3.2.9. Ethyl 2-fluoro-5-(2-methyl-1,3-dithiolan-2-yl)benzoate (11b).
Compound 11b was prepared following the procedure described for
compound 11a. The crude residue was purified by flash chroma-
tography (10% AcOEt/petroleum ether) yielding compound 11a (81%)
as pale yellow oil. Rf¼0.57 (10% EtOAc/petroleum ether); 1H NMR
troleum ether); mp 117e118 ꢁC; 1H NMR (CDCl3)
d
7.82 (d, J¼8.0 Hz,
1H), 7.14e7.39 (m, 5H), 6.63 (d, J¼10.2 Hz, 1H), 5.03 (s, 2H), 5.90 (s,
1H), 3.25 (m, 2H), 3.32 (m, 2H); 13C NMR (CDCl3)
159.9
(CDCl3)
d
8.26 (dd, J¼6.8, 2.7 Hz,1H), 7.91 (ddd, J¼8.8, 4.5, 2.7 Hz,1H),
7.04 (dd, J¼8.8,10.0 Hz,1H), 4.38 (q, J¼7.2 Hz, 2H), 3.31e3.50 (m, 4H),
d
2.12 (s, 3H), 1.38 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3)
d 164.4
(J¼247.4 Hz), 156.8 (J¼8.9 Hz), 136.8, 133.3, 129.9, 129.4, 128.4, 129.2
(J¼3e9 Hz), 160.8 (J¼261.3 Hz), 142.1 (J¼3.8 Hz), 133.2 (J¼9.5 Hz),
130.3, 118.1 (J¼10.0 Hz), 116.5 (J¼22.5 Hz), 67.5, 61.4, 40.5, 33.5, 14.3;
(J¼3.2 Hz), 102.4 (J¼27.0 Hz), 100.3 (J¼21.1 Hz), 72.0, 49.4, 40.5; 19F
NMR (CDCl3)
384.9732, found 384.9726.
d
ꢀ105.9; HRMS C16H15BrFOS2 m/z [MþH]þ calculated
19F NMR (CDCl3)
d
ꢀ112.2; HRMS C13H16FO2S2 m/z [MþH]þ calcu-
lated 287.0576, found 287.0570.
3.2.6. 2-(3-Bromo-4-fluorophenyl)-2-methyl-1,3-dithiolane
(10b). 1,3-Ethanedithiol (0.435 mL, 5.07 mmol) was added to
3.2.10. Ethyl 5-(1,3-dithiolan-2-yl)-2-fluorobenzoate (11c). Comp-
ound 11c was prepared following the procedure described for
compound 11a. Yield 81%; Rf¼0.42 (10% EtOAc/petroleum ether);
a
solution of 1-(3-bromo-4-fluorophenyl)ethanone (1.00 g,
4.60 mmol) and iodine (0.117 g, 0.46 mmol) in dichloromethane
(10 mL) and the mixture was stirred under reflux. After 3.5 h the
reaction was cooled to room temperature and quenched with
NaS2O3 (0.1 M, 25 mL) and NaOH (10%, 25 mL). Then 25 mL of
dichloromethane were added and the organic layer was separated,
dried over MgSO4 and filtrated. The solvent was removed in vacuo
and the crude product purified by flash chromatography (3%
AcOEt/petroleum ether) to give 10b (95%) as pale yellow oil.
1H NMR (CDCl3)
d
7.67 (ddd, J¼8.4, 4.4, 2.6 Hz, 1H), 7.99 (dd, J¼6.8,
2.4 Hz, 1H), 7.04 (dd, J¼8.7, 10.2 Hz, 1H), 4.35 (q, J¼7.1 Hz, 2H), 5.59
(s, 1H), 3.47 (m, 2H), 3.34 (m, 2H), 2.12, 1.37 (t, J¼7.2 Hz, 3H); 13C
NMR (CDCl3)
d
164.0 (J¼4.2 Hz), 161.4 (J¼260.9 Hz), 136.5
(J¼3.4 Hz), 133.9 (J¼9.3 Hz), 131.5, 118.7 (J¼10.1 Hz), 117.2
(J¼22.8 Hz), 61.4, 55.0, 40.3, 14.2; 19F NMR (CDCl3)
ꢀ110.5; HRMS
d
C12H14FO2S2 m/z [MþH]þ calculated 273.0419, found 273.0414.
Rf¼0.35 (3% EtOAc/petroleum ether); 1H NMR (CDCl3)
d
7.94 (dd,
3.2.11. (4-(Benzyloxy)-5-(1,3-dithiolan-2-yl)-2-fluorophenyl)metha-
nol (12a). LiAlH4 1.21 mL in dry THF (2.0 M, 2.42 mmol) was
added dropwise to a solution of the ester 6 (0.81 g, 2.42 mmol)
dissolved in dry THF (25 mL). The reaction was stirred for 1 h at
room temperature. The mixture was quenched with water and
acidified with concentrated H2SO4 until the solid was dissolved.
The mixture was extracted with CH2Cl2, the organic phase sepa-
rated and dried over Na2SO4. The solvent was removed and the
crude purified by flash chromatography (25% AcOEt/petroleum
ether) yielded product 7 in 90%. Rf¼0.44 (30% EtOAc/petroleum
J¼6.4, 2.6 Hz,1H), 7.65 (ddd, J¼8.8, 4.5, 2.5 Hz,1H), 7.02 (t, J¼8.5 Hz,
1H), 3.29e3.49 (m, 4H), 2.09 (s, 3H); 13C NMR (CDCl3)
d 157.9
(J¼248.8 Hz), 143.8 (J¼3.3 Hz), 132.1, 127.7 (J¼7.6 Hz), 115.7
(J¼22.8 Hz), 108.3 (J¼24.7 Hz), 67.4, 40.5, 33.6; 19F NMR (CDCl3)
d
ꢀ110.1; HRMS C10H11BrFS2 m/z [MþH]þ calculated 292.9470,
found 292.9466.
3.2.7. 2-(3-Bromo-4-fluorophenyl)-1,3-dithiolane (10c). Compound
10c was prepared following the procedure described for compound
10a. Yield 97%; Rf¼0.51 (5% EtOAc/petroleum ether); mp 51e53 ꢁC;
ether); mp 114e117 ꢁC; 1H NMR (CDCl3)
d
7.73 (d, J¼8.6 Hz, 1H),
1H NMR (CDCl3)
d
7.71 (dd, J¼7.2, 2.2 Hz, 1H), 7.39 (ddd, J¼8.5, 4.5,
7.32e7.45 (m, 5H), 6.58 (d, J¼11.5 Hz, 1H), 5.06 (s, 2H), 4.63 (s,
2.3 Hz, 1H), 7.03 (t, J¼8.2 Hz, 1H), 5.53 (s, 1H), 3.47 (m, 2H), 3.34 (m,
2H), 6.00 (s, 1H) 3.28 (m, 2H), 3.37 (m, 2H); 13C NMR (CDCl3)

ꢀ
J. Castillo Melean et al. / Tetrahedron 66 (2010) 9996e10001
10000
d
160.6 (J¼247.4 Hz), 156.1 (J¼10.1 Hz), 136.0, 129.2 (J¼5.9 Hz),
125.1 (J¼14.9 Hz), 115.9 (J¼21.7 Hz), 55.3, 40.3, 25.5 (J¼4.4 Hz); 19
F
128.6, 128.1, 127.2, 125.8 (J¼3.4 Hz), 119.5 (J¼15.2 Hz), 100.1
NMR (CDCl3)
d
ꢀ117.7; HRMS C10H10FS2 [MþHeHBr]þ calculated
(J¼26.2 Hz), 70.6, 59.2 (J¼4.0 Hz), 48.6, 39.4; 19F NMR (CDCl3)
213.0208, found 213.0203.
d
ꢀ117.8; E.A. calculated C: 60.69, H: 5.09, S: 19.06, found C: 60.4,
H: 5.45, S: 21.1.
3.2.17. (2S,5S)-tert-Butyl
5-(4-(benzyloxy)-5-(1,3-dithiolan-2-yl)-
2-fluorobenzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carbox-
ylate (14a). A stirred solution of diisopropylamine (0.47 mL,
3.30 mmol) in dry THF (2 mL) was cooled down to ꢀ78 ꢁC, then BuLi
(2.5 M/hexane, 1.32 mL, 3.30 mmol) was added dropwise. The
resulting solution was stirred during 15 min. A solution of (S)-Boc-
BMI (0.71 g, 2.75 mmol) in dry THF (2 mL) was added slowly and
stirring was maintained for 40 min. The benzyl bromide 7 (1.10 g,
2.75 mmol) in THF (3 mL) was then added. The reaction mixture was
kept at room temperature and stirring was continued over 3 h. The
reactionwas quenched with saturated aqueous ammonium chloride
(10 mL), 30 mL of water were added and the reaction was extracted
with CH2Cl2 (3ꢂ25 mL). The organic layer was dried over sodium
sulfate and evaporated to give the crude product, which was purified
by flash chromatography (20% EtOAc/petroleum ether) (1.19 g, 75%,
pale yellow solid). Rf¼0.42 (25% EtOAc/petroleum ether); mp
3.2.12. (2-Fluoro-5-(2-methyl-1,3-dithiolan-2-yl)phenyl)methanol
(12b). Compound 12b was prepared following the procedure de-
scribed for compound 12a. Yield 91%; Rf¼0.52 (20% EtOAc/petro-
leum ether); 1H NMR (CDCl3)
d
7.79 (dd, J¼7.0, 2.5 Hz, 1H), 7.66
(ddd, J¼8.2, 4.9, 2.7 Hz, 1H), 6.95 (‘t’, J¼9.0 Hz, 1H), 4,73 (s, 2H),
3.32e3.44 (m, 4H), 2.12 (s, 3H); 13C NMR (CDCl3)
d
159.5
(J¼247.2 Hz), 142.0 (J¼3.8 Hz), 128.0 (J¼8.2 Hz), 127.9, 127.0
(J¼14.5 Hz), 114.7 (J¼21.5 Hz), 67.9, 59.5 (J¼3.9 Hz), 40.4, 33.9; 19F
NMR (CDCl3)
found C: 53.9, H: 5.84, S: 26.3.
d
ꢀ112.4; E.A. calculated C: 54.07, H: 5.36, S: 26.3,
3.2.13. (5-(1,3-Dithiolan-2-yl)-2-fluorophenyl)methanol
(12c). Compound 12c was prepared following the procedure de-
scribed for compound 12a. Yield 91%; Rf¼0.40 (20% EtOAc/petro-
leum ether); mp 60e61 ꢁC; 1H NMR (CDCl3)
d
7.37 (m, 1H), 7.53 (dd,
117e118 ꢁC; 1H NMR (CDCl3)
d
7.37 (d, J¼7.2 Hz, 1H), 7.32e7.45 (m,
J¼6.9, 1.9 Hz, 1H), 6.92 (‘t’, J¼9.0 Hz, 1H), 4.67 (s, 2H), 5.56 (s, 1H)
5H), 6.54 (d, J¼11.5 Hz, 1H), 4.95 (br, H), 5.03 (s, 2H), 4.30 (br, 1H),
3.44 (m, 2H), 3.30 (m, 2H); 13C NMR (CDCl3)
d
160.0 (J¼247.4 Hz),
5.99 (s, 1H), 3.29 (m, 2H), 3.41 (m, 2H), 2.89 (s, 3H), 1.34 (s, 9H), 3.18
136.2 (J¼3.4 Hz), 128.78 (J¼14.3 Hz), 128.76, 127.8 (J¼15.2 Hz), 115.2
(d, J¼15.8 Hz,1H), 3.60 (br,1H), 0.95 (s, 9H); 13C NMR (CDCl3)
d 171.5,
(J¼22.0 Hz), 59.2 (J¼4.2 Hz), 55.5, 40.2; 19F NMR (CDCl3)
d
ꢀ120.6;
160.9 (J¼246.6 Hz), 154.8 (J¼10.1 Hz), 152.8 (br), 136.3, 129.3
(J¼4.3 Hz), 128.6, 128.0, 127.2, 125.0 (br), 115.1 (J¼16.0 Hz), 100.0
(J¼27.0 Hz), 81.0, 80.9, 70.5, 58.9 (J¼4.0 Hz), 48.7, 40.9, 39.4, 39.4,
E.A. calculated C: 52.15, H: 4.81, S: 27.84, found C: 52.0, H: 4.95, S:
28.5.
39.2, 32.3, 28.0, 26.5, 26.6; 19F NMR (CDCl3)
d
ꢀ113.6; HRMS
3.2.14. 2-(2-(Benzyloxy)-5-(bromomethyl)-4-fluorophenyl)-1,3-di-
thiolane (13a). A magnetically stirred solution of the alcohol 12a
(1.25 g, 3.71 mmol) and 1.37 g (4.09 mmol) of carbontetrabromide
in 10 mL of dichloromethane was cooled to 0 ꢁC. A solution of tri-
phenylphosphine (1.46 g, 5.57 mmol) in 5 mL of dichloromethane
was added dropwise. After the addition the mixture was stirred for
further 5 min, whereupon the solvent was partially removed in
vacuo at room temperature. Ether (20 mL) was added and the
mixture filtered. The filter cake was washed with ether (2ꢂ20 mL).
The combined filtrates and washings were concentrated and the
residue purified via flash chromatography to give 1.10 g (74%) of the
bromide as a white solid. Rf¼0.46 (3% EtOAc/petroleum ether); mp
C30H40FN2O4S2 [MþH]þ calculated 575.2414, found 575.2413.
3.2.18. (2S,5S)-tert-Butyl 2-tert-butyl-5-(2-fluoro-5-(2-methyl-1,3-
dithiolan-2-yl)benzyl)-3-methyl-4-oxoimidazolidine-1-carboxylate
(14b). Compound 14b was prepared following the procedure de-
scribed for compound 14a. Yield 89%; Rf¼0.52 (25% EtOAc/petro-
leum ether); mp 103e105 ꢁC; 1H NMR (CDCl3)
4.9, 2.7 Hz, 1H), 7.37 (dd, J¼7.0, 2.3 Hz, 1H), 6.88 (‘t’, J¼9.4 Hz, 1H),
5.04 (br, 1H), 4.33 (br, 1H) 3.25e3.41 (m, 4H), 3.27 (br, 2H), 2.03
(s, 3H), 2.97 (s, 3H), 1.25 (s, 9H), 0.96 (s, 9H); 13C NMR (CDCl3)
d
7.51 (ddd, J¼8.6,
d
171.6, 154.9 (J¼248.6 Hz), 152.9 (br), 141.6 (br), 127.7 (br), 126.3
(J¼8.0 Hz), 123.0 (J¼15.1 Hz), 114.5 (J¼23.1 Hz), 81.0, 80.9, 68.6 (br),
114e115 ꢁC; 1H NMR (CDCl3)
d
7.74 (d, J¼8.7 Hz, 1H), 7.31e7.44 (m,
5H), 6.61 (d, J¼11.2 Hz, 1H), 5.09 (s, 2H), 4.48 (s, 2H), 5.97 (s, 1H)
3.40e3.27 (m, 4H); 13C NMR (CDCl3)
58.2 (br), 40.8, 40.0, 39.9 (br), 33.7 (br), 32.4, 27.9, 26.7 (br), 26.5;
19F NMR (CDCl3)
d
ꢀ118.5; HRMS C24H36FN2O3S2 m/z [MþH]þ cal-
d
160.7 (J¼250.9 Hz), 156.9
culated 483.2151, found 483.2148.
(J¼9.8 Hz), 135.7, 130.5 (J¼4.9 Hz), 128.7, 128.3, 127.2, 126.5
(J¼3.5 Hz),116.6 (J¼14.9 Hz),100.3 (J¼25.6 Hz), 70.7, 48.5, 39.3, 29.3
3.2.19. (2S,5S)-tert-Butyl-5-(5-(1,3-dithiolan-2-yl)-2-fluorobenzyl)-
2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate
(14c). Compound 14c was prepared following the procedure de-
scribed for compound 14a. Yield 84%; Rf¼0.33 (25% EtOAc/petro-
(J¼3.6 Hz); 19F NMR (CDCl3)
d
ꢀ114.6; HRMS C17H17BrFOS2 [MþH]þ
calculated 298.9888, found 298.9708.
3.2.15. 2-(3-(Bromomethyl)-4-fluorophenyl)-2-methyl-1,3-dithiolane
(13b). Compound 13b was prepared following the procedure de-
scribed for compound 13a. Yield 84%; Rf¼0.51 (3% EtOAc/petroleum
leum ether); 1H NMR (CDCl3)
1H), 4.90 (br, 1H), 4.32 (br, 1H), 5.52 (s, 1H), 3.70 (br, 1H), 3.24
d
7.19e7.26 (m, 2H), 6.87 (‘t’, J¼9.3 Hz,
(d, J¼15.1 Hz, 1H), 3.46 (m, 2H), 3.30 (m, 2H), 2.88 (s, 3H), 1.33 (s,
ether); 1H NMR (CDCl3)
d
7.76 (dd, J¼7.1, 2.1 Hz, 1H), 7.66 (ddd,
9H), 0.93 (s, 9H); 13C NMR (CDCl3)
d
171.5, 160.7 (J¼247.4 Hz), 152.7
J¼8.0, 4.5, 2.5 Hz, 1H), 6.95 (‘t’, J¼7.5 Hz, 1H), 4,49 (s, 2H), 3.51e3.28
(br), 135.2 (br), 129.7, 127.5 (J¼8.7 Hz), 123.8 (J¼15.8 Hz), 115.0
(m, 4H), 2.01 (s, 3H); 13C NMR (CDCl3)
d
159.6 (J¼250.9 Hz), 142.4
(J¼23.4 Hz), 81.2, 81.0, 58.8, 55.9, 40.9, 40.0, 40.1, 32.2, 28.0, 27.0
(J¼3.4 Hz), 129.8 (J¼3.2 Hz), 128.3 (J¼8.2 Hz), 124.3 (J¼14.6 Hz),
(br), 26.5; 19F NMR (CDCl3)
d
ꢀ116.3; HRMS C23H34FN2O3S2 m/z
115.2 (J¼21.5 Hz), 67.7, 40.5, 33.7, 25.9 (J¼4.3 Hz); 19F NMR (CDCl3)
[MþH]þ calculated 469.1995, found 469.1994.
d
ꢀ119.5; MS C22H24BrF2S4 [2MþHeHBr]þ calculated 532.9912,
found 532.9908.
3.2.20. (2S,5S)-tert-Butyl 5-(4-(benzyloxy)-2-fluoro-5-formylbenzyl)-
2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate
(1a). [Bis
3.2.16. 2-(3-(Bromomethyl)-4-fluorophenyl)-1,3-dithiolane
(13c). Compound 13c was prepared following the procedure de-
scribed for compound 13a. Yield 74%; Rf¼0.49 (3% EtOAc/petroleum
(trifluoroacetoxy)iodo]benzene (1.37 g, 3.09 mmol) was added in
one portion to 1.19 g of 9 (2.06 mmol) dissolved in 10 mL of 9:1
MeOH/H2O. The reaction mixture was stirred at room temperature
during 5 min. The reaction was quenched with saturated aqueous
NaHCO3 (20 mL). The product was extracted with CH2Cl2 (3ꢂ25 mL).
The combined organic layers were washed with brine, dried over
Na2SO4, filtered and concentrated. Purification by flash
ether); mp 63e64 ꢁC; 1H NMR (CDCl3)
d
7.59 (dd, J¼7.1, 2.4 Hz, 1H),
7.50 (ddd, J¼8.4, 4.8, 2.3 Hz, 1H), 7.04 (‘t’, J¼9.0 Hz, 1H), 5.63 (s, 1H),
4.53 (s, 2H) 3.60e3.33 (m, 4H); 13C NMR (CDCl3)
160.2
(J¼249.7 Hz), 136.7 (J¼3.6 Hz), 130.8 (J¼3.5 Hz), 130.2 (J¼8.4 Hz),
d

ꢀ
J. Castillo Melean et al. / Tetrahedron 66 (2010) 9996e10001
10001
chromatography (30% EtOAc/petroleum ether) yields the desired
was supported by a Grant of the Technology Transfer Bureau of
€
aldehyde 10 in 92%. Rf¼0.42 (25% EtOAc/petroleum ether); mp
FZ-Julich.
90e92 ꢁC; 1H NMR (CDCl3)
d
10.36 (s, 1H), 7.51 (d, J¼8.8 Hz, 1H),
7.32e7.39 (m, 5H), 6.67 (d, J¼11.5 Hz, 1H), 4.88 (br, 1H), 5.10 (s, 2H),
Supplementary data
4.29 (br,1H), 2.98 (s, 3H), 3.28 (d, J¼14.9 Hz, 1H), 3.60 (br, 1H), 1.33 (s,
9H), 0.95 (s, 9H); 13C NMR (CDCl3)
d
187.9, 171.7, 165.8 (J¼256.7 Hz),
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.10.036.
160.9 (J¼11.0 Hz), 152.5 (br), 135.4, 130.1 (J¼8.4 Hz), 128.8, 128.4,
127.2, 121.4 (br), 117.0 (J¼18.1 Hz), 100.9 (J¼27.0 Hz), 81.2, 81.1, 70.7,
58.4 (br), 40.9, 32.1, 29.7, 27.9, 26.5; 19F NMR (CDCl3)
d-101.2; HRMS
References and notes
C28H36FN2O5 [MþH]þ calculated 499.2608, found 499.2602.
1. (a) Laverman, P.; Boerman, O. C.; Costens, F. H. M.; Oyen, W. J. G. Eur. J. Nucl.
Med. 2002, 29, 681; (b) Coenen, H. H. PET Studies on Amino Acid Metabolism
and Protein Synthesis. In; Mazoyer, B. M., Heiss, W. D., Comar, D., Eds.; Kluwer
Academic Publishers: Dordrecht, Boston, London, 2003; pp 109e129.
3.2.21. (2S,5S)-tert-Butyl-5-(5-acetyl-2-fluorobenzyl)-2-tert-butyl-
3-methyl-4-oxoimidazolidine-1-carboxylate (1b). Compound 1b
was prepared following the procedure described for compound
1a. Yield 91%; Rf¼0.29 (25% EtOAc/petroleum ether); mp
€
2. (a) Mohnike, K.; Blankenstein, O.; Minn, H.; Mohnike, W.; Fuchtner, F.; Oton-
koski, T. Horm. Res. 2008, 70, 65; (b) Jager, P. L.; Chirakal, R.; Marriott, C. J.;
Brouwers, A. H.; Koopmans, K. P.; Gulenchyn, K. Y. J. Nucl. Med. 2008, 49, 573.
76e78 ꢁC; 1H NMR (CDCl3)
d
7.76 (ddd, J¼8.4, 5.2, 2.4 Hz, 1H), 7.66
€
3. (a) de Vries, E. F. J.; Luurtsema, G.; Brussermann, M.; Elsinga, P. H.; Vaalburg, W.
(dd, J¼7.4, 2.3 Hz, 1H), 6.88 (‘t’, J¼8.7 Hz, 1H), 4.85 (br, 1H), 4.34
(br, 1H), 3.68 (br, 1H), 3.38 (d, J¼14 Hz, 1H), 2.94 (s, 3H), 2.52 (s,
Appl. Radiat. Isot. 1999, 51, 389; (b) Hess, E.; Sichler, S.; Kluge, A.; Coenen, H. H.
Appl. Radiat. Isot. 2002, 57, 185; (c) VanBrocklin, H. F.; Blagoev, M.; Hoepping, A.;
O’Neil, J. P.; Klose, M.; Schubiger, P. A.; Ametamey, S. Appl. Radiat. Isot. 2004, 61,
1289.
4. Hess, E.; Blessing, G.; Coenen, H. H.; Qaim, S. M. Appl. Radiat. Isot. 2000, 52, 1431.
5. Lemaire, C.; Gillet, S.; Guillouet, S. P.; Plenevaux, A.; Aerts, J.; Luxen, A. Eur. J.
Org. Chem. 2004, 2899.
6. Wagner, F. M.; Ermert, J.; Coenen, H. H. J. Nucl. Med. 2009, 50, 1724.
7. Castillo, J.; Ermert, J.; Coenen, H. H. Eur. J. Nucl. Med. 2009, 36, S221.
8. DeJesus, O.; Endres, C. J.; Shelton, S.; Nickles, J.; Holden, J. J. J. Nucl. Med. 1997,
38, 630.
9. Plenevaux, A.; Lemaire, C.; Palmer, A. J.; Damhaut, P.; Comar, D. Appl. Radiat.
Isot. 1992, 43, 1035.
3H), 1.33 (s, 9H), 0.96 (s, 9H); 13C NMR (CDCl3)
d 196.6, 171.6, 164.3
(J¼255.7 Hz), 152.7 (br), 130.9 (J¼5.4 Hz), 128.8 (J¼9.0 Hz), 124.3
(J¼14.4 Hz), 115.5, 113.0 (J¼3.0 Hz), 81.3, 81.1, 58.5, 40.9, 32.2, 27.9,
26.6, 26.5; 19F NMR (CDCl3)
d
ꢀ107.4; HRMS C22H32FN2O4 m/z
[MþH]þ calculated 469.1995, found 469.1994.
3.2.22. (2S,5S)-tert-Butyl-2-tert-butyl-5-(2-fluoro-5-formylbenzyl)-
3-methyl-4-oxoimidazolidine-1-carboxylate (1c). Compound 1c was
prepared following the procedure described for compound 1a.
Yield 93%; Rf¼0.34 (25% EtOAc/petroleum ether); mp 92e93 ꢁC; 1H
10. Castillo, J.; Ermert, J.; Wagner, F. M.; Coenen, H. H. J. Label. Compd. Radiopharm.
2009, 52, S163.
€
11. Coenen, H. H.; Kling, P.; Stocklin, G. J. Nucl. Med. 1989, 30, 1367.
NMR (CDCl3)
d
9.81 (s, H), 7.69 (m, 1H), 7.58 (dd, J¼7.0, 1.4 Hz, 1H),
12. Castillo, J.; Ermert, J.; Coenen, H.H. Org. Biomol. Chem. 2010, doi:10.1039/
C0OB00440E.
13. Fluorodopa (18F) (prepared by electrophilic substitution) injection European
Pharmacopoeia 2008, 6, 990.
14. Ahrendt, K.; Bergman, R.; Ellman, J. Org. Lett. 2003, 5, 1301.
15. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
16. Firouzabadi, H.; Iranpoor, N.; Hazarkhani, H. J. Org. Chem. 2001, 66, 7527.
17. Krasovskiy, A.; Straub, B.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 159.
18. For selected literature of the use bromo-lithium exchange reactions for the
synthesis of aromatics fluoro-amino acids see: (a) Ref. 6. (b) Monclus, M.;
Masson, C.; Luxen, A. J. Fluorine Chem. 1995, 70, 39.
7.10 (‘t’, J¼9.2 Hz, 1H), 4.84 (br, 1H), 4.33 (br, 1H), 3.65 (br, 1H), 3.41
(d, J¼15.2 Hz, 1H), 2.92 (s, 3H), 1.34 (s, 9H), 0.94 (s, 9H); 13C NMR
(CDCl3)
d
190.5, 171.4, 165.0 (J¼257.0 Hz), 152.5 (br), 132.5, 132.3
(J¼6.2 Hz), 130.2 (J¼10.0 Hz), 125.4 (J¼16.7 Hz), 116.2 (J¼24.4 Hz),
81.3, 81.1, 58.5, 40.9, 32.2, 28.0, 27.6 (br), 26.5; 19F NMR (CDCl3)
d
ꢀ104.3; HRMS C21H30FN2O4 m/z [MþH]þ calculated 393.2190,
found 393.2183.
19. Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801.
20. Fitzi, R.; Seebach, D. Tetrahedron 1988, 44, 5277.
Acknowledgements
21. Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 3, 287.
22. Still, W.; Kahn, M.; Mitra, A. J. J. Org. Chem. 1978, 43, 2923.
23. Shiraishi, M.; Hashiguchi, S.; Watanabe, T. Patent 5,270,308, 1993.
The authors want to thank Dr. S. Willbold, Dr. D. Hofmann and
Dr. M. Holschbach for recording the spectroscopic data. This work