Synthesis, structure determination, and (radio-)fluorination of novel functionalized phosphanes suitable for the traceless Staudinger ligation

Article abstract of DOI:10.1016/j.tet.2011.04.091

An elegant and efficient synthesis approach for the preparation of novel benzoate and nicotinate containing phosphanes is presented. This reaction path has a broad substrate scope. Thus, various functionalized phosphanes were obtained in high yields using

Full text of DOI:10.1016/j.tet.2011.04.091

Tetrahedron 67 (2011) 4521e4529
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis, structure determination, and (radio-)fluorination of novel
functionalized phosphanes suitable for the traceless Staudinger ligation
,
a
b
b
a
Constantin Mamat a , Markus Franke , Tim Peppel , Martin Kockerling , Jorg Steinbach
*
€
€
a
€
Institut fur Radiopharmazie am Helmholtz-Zentrum Dresden-Rossendorf, Postfach 51 01 19, D-01314 Dresden, Germany
b
€
€
Institut fur Chemie der Universitat Rostock, Albert-Einstein-Strabe 3a, D-18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
An elegant and efficient synthesis approach for the preparation of novel benzoate and nicotinate con-
taining phosphanes is presented. This reaction path has a broad substrate scope. Thus, various func-
tionalized phosphanes were obtained in high yields using an esterification procedure under Steglich
conditions. A facile blocking of the phosphorus atom with BH3 was carried out. BH3 as easily insertable
and removable protecting group enables a further derivatization of the benzoate residue. The prepared
phosphane derivatives proved to be valuable labeling building blocks for the implementation of a bio-
orthogonal (radio-)fluorination strategy and were applied for labeling purposes using the traceless
Staudinger ligation. For this purpose, a selection of azide-functionalized small organic and bioactive
sample molecules was prepared. Furthermore, a mild and selective (radio-)fluorination of these de-
rivatives is demonstrated adopting this bioorthogonal ligation method.
Received 27 January 2011
Received in revised form 21 April 2011
Accepted 23 April 2011
Available online 6 May 2011
Keywords:
Staudinger ligation
Phosphane borane adduct
PeC cross-coupling
Radiofluorination
Bioorthogonal
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
To exploit the Staudinger ligation for labeling purposes easily
available fluorine-18 containing building blocks are required.
In recent years, both the traceless and the non-traceless Stau-
dinger ligation1 have become important coupling methods for the
bioorthogonal interconnection of bioactive molecules2 as well as in
material sciences.3 Additionally, this ligation was developed as an
important approach for the attachment of functional groups like
radioactive4 as well as non-radioactive labels5 to organic and bio-
active molecules. The chemoselective (radio-)labeling of bio-
macromolecules like peptides, proteins or antibodies still remains
a special challenge. Specific attention should be paid to the
implementation of fast and highly selective labeling reactions,
which tolerate other functional groups of the respective molecule.
Therefore, selective ligation reactions were evaluated. The traceless
Staudinger ligation is similar to the Cu(I) catalyzed Huisgen cyclo-
addition6 a powerful conjugation reaction. Beneficially, ligations
using the Staudinger approach proceed without the application of
cytotoxic Cu-salts in contrast to the Huisgen reaction. The bio-
orthogonal character7 of azides8 and phosphanes, which were used
as starting material for the Staudinger ligation as well as the mild
reaction conditions of this method remain the most important
advantages. Unpropitiously, primary amines, e.g., in peptides show
that unexpected side reactions with phosphanes used in Staudinger
ligations may occur.2b
Thus, we decided to evaluate various new benzoate and nic-
otinate functionalized phosphanes. The convenient access to
biologically active (radio-)fluorinated pyridine compounds was
previously shown9 and a wide variety of fluoropyridine contain-
ing compounds was applied as radiotracers.10 Furthermore, nic-
otinic acid as precursor for NADH, NADþ and other cofactors play
an essential metabolic role in living cells.11 In this case, direct
fluorination reactions of heteroaromatic systems were exempli-
fied due to the electron-deficient pyridine ring capable for
nucleophilic aromatic fluorinations.12 Herein, we have demon-
strated a facile and adequate access to novel functionalized
phosphane derivatives based on benzoate and nicotinate moieties
as versatile fluorine-18 labeling building blocks with the potential
for mild and bioorthogonal radiolabeling of diverse bioactive
small organic molecules as well as biomacromolecules with
fluorine-18 using the traceless Staudinger ligation. Advanta-
geously, this method provides access to compounds with a wide
variety of substitution patterns. Moreover, it was possible to
prepare phosphanes with a trimethylammonium-benzoate resi-
due using alkylating agents due to the protection of the central
phosphorus atom with BH3. The structures of all compounds were
confirmed by NMR and MS. Furthermore, crystals suitable for X-
ray structure determinations of key compounds were grown and
the structures were assigned.
* Corresponding author. Tel.: þ49 351 260 2805; fax: þ49 351 260 3232; e-mail
address: c.mamat@hzdr.de (C. Mamat).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.091

4522
C. Mamat et al. / Tetrahedron 67 (2011) 4521e4529
2. Results and discussion
Acylated phosphanes are of great interest as building blocks for
the Staudinger ligation, e.g., for the preparation of N-glycosides,13
the fluorescence labeling of cells,5b the interconnection of am-
ides,14 peptides, and proteines15 or the intramolecular ring closure
to form medium size lactames.16 Most of these derivatives were
prepared using carboxylic acid chlorides or anhydrides with
phosphanophenol 2b under basic conditions that led to the corre-
sponding esters.13 In the majority of cases, non-functionalized
carboxylic acid derivatives were used. Benzoate compounds were
rarely applied.17 Recently, we described a valuable synthesis path
using the Pd-catalyzed PeC cross-coupling strategy in which
diphenylphosphane was reacted with respective o-iodophenyl
esters.5a Unfortunately, the preparation of derivatives containing
a iodo- or nitrobenzoate function was not amenable using this
method. In contrast, the esterification under Steglich conditions
represented a valuable and adjuvant option consisting of the re-
action between phosphanophenol 2b and respective carboxylic
acids 1bei and led to the favored phosphanes in good to high yields.
Scope and limitations of this esterification procedure are shown in
Scheme 1 and Table 1. A broad incorporation of various radioactive
and non-radioactive labels is feasible using these benzoate-
functionalized phosphanes.
Fig. 1. Molecular structure and atom labeling scheme of 2-iodophenyl benzoate 3a.
Displacement ellipsoids are drawn at the 50% probability level.
O
O
OH
DCC, DMAP,
THF, 16 h
R3
OH
+
O
R3
R1
X
1a-i
R2
R1
X
R2
3a-n
Fig. 2. Molecular structure and atom labeling scheme of phosphane 3m. Displacement
ellipsoids are drawn at the 50% probability level.
2a,b
Scheme 1. Esterification of 1aei with 2a,b under Steglich conditions.
can be achieved on the one hand using electron withdrawing
groups like aldehydes, ester functions, nitriles or halogens attached
to the benzene residue and on the other hand by the introduction of
good leaving groups like I, NO2 or Me3Nþ. Benzoates functionalized
with a trimethylammonium group proved to be suitable precursors
and are widely used for radiofluorination purposes.19 Therefore,
compound 6 was synthesized using a three step procedure starting
from 3g. Alkylation reactions necessitate the blocking of the central
phosphorus atom to prevent the formation of phosphonium salts
with the alkylating agent. Thus, phosphane 3g was converted into
phosphane borane adduct 4 by direct transfer of BH3 from the
Table 1
Scope and limitations for the preparation of various 2-iodophenyl esters and
phosphanes
1
2
R1
R2
R3
X
Product
Yield [%]
a
b
c
d
e
f
b
c
d
e
f
a
a
a
a
a
a
b
b
b
b
b
b
b
b
NO2
NMe2
I
OH
Me
Br
NMe2
I
OH
Me
Br
H
H
H
H
H
H
H
H
H
H
H
H
Br
F
I
I
I
I
I
I
CH
CH
CH
CH
CH
N
CH
CH
CH
CH
N
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
83
42
74
39
40
58
75
76
73
98
87
21
76
36
5a
weaker THF$BH3 adduct at ꢀ78 ꢁC (Scheme 2).
PPh2
PPh2
PPh2
PPh2
PPh2
PPh2
PPh2
PPh2
O
O
THF-BH3, THF,
-78°C to rt, 16 h
O
O
.
PPh2 BH3
PPh2
Me2N
Me2N
g
h
i
F
H
H
N
N
N
3g
4
MeI, Et2O,
rt, 5 d
O
O
methanol
reflux, 2h
Accessorily, several functionalized 2-iodophenyl esters 3aef,
O
O
I
I
which were used as starting material for the alternative Pd-
catalyzed cross-coupling strategy, were prepared by the reaction
of 2-iodophenol (2a) with various benzoic acids 1aef using DCC/
DMAP in dry THF. The desired esters 3aef were obtained in yields
ranging from 39 to 83%.
.
BH3
PPh2
PPh2
Me3N
Me3N
5
6
Scheme 2. Preparation of trimethylammonium precursor 6.
Beside the benzoate derivatives 3aej, novel halo-nicotinate
compounds 3ken were synthesized (yield 21e98%). Substituted
pyridines served as important precursors for radiofluorination
purposes due to their electron-depleted aromatic system. It was
possible to obtain single crystals of the nitro compound 3a and
nicotinate 3m suitable for an X-ray structure determination.18 Figs.
1 and 2 depict the molecular structure of these two compounds.
The nucleophilic introduction of (radio-)fluorine into aromatic
compounds requires an electron-deficient aromatic system. This
The existence of the BH3 group in 4 and 5 was evidenced by 1H,
31P NMR as well as MS analyses. In addition, crystals suitable for an
X-ray structure determination of compound 4 were obtained from
a saturated ethyl acetate/petroleum ether solution. The corres-
ponding molecular structure is shown in Fig. 3.18 The three mo-
lecular structures, as derived from X-ray structure experiments, are
in complete accordance with those expected from the synthetic
procedures and spectroscopic properties.

C. Mamat et al. / Tetrahedron 67 (2011) 4521e4529
4523
O
O
I
3e
NBS, CCl4,
75°C, 16 h
O
NaI, acetone, rt, 16 h
O
Br
I
7
O
AgF,
acetonitrile,
dark, rt, 16 h
O
I
I
8
Fig. 3. Molecular structure and atom labeling scheme of compound 4. Displacement
ellipsoids are drawn at the 50% probability level.
O
AgF, acetonitrile,
dark, rt, 16 h
O
18/19F
I
10/[18F]10
AgOTs,
3. Radiolabeling
acetonitrile,
dark, rt, 16 h
[
18F]F-,
HPPh2, KOAc,
A multitude of biomacromolecules, such as proteins, peptides or
antibodies labeled with the positron emitting radionuclide fluorine-
18 function as radioactive probes to image physiological and path-
ological processes within humans. Usually, these compoundscannot
be labeled directly with 18F due to the required harsh reaction con-
ditions. Thus, various 18F-labeled prosthetic groups,19 such as N-
Pd(OAc)2
,
acetonitrile,
90 °C, 15 min
O
O
DMA, 70 °C
O
O
TsO
I
9
18F
PPh2
[6-(4-
[
18F]fluorobenzylidene)-aminooxyhexyl]-maleimide ([18F]
11/[18F]11
FBAM)20 or N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB)21 orig-
inally developed by Vaidyanathan and Zalutsky22a and modified by
Wester et al.22b were used. However, due to the wide variety of
functional groups in peptides and proteins a specific labeling strat-
egy for each of the above mentioned macromolecules has to be
developed. In this context, novel precursor molecules were created
consisting of activated benzoates 3a,h, 6 or nicotinates 3k,m, which
represent ideal substrates for a nucleophilic introduction of [18F]
fluoride (Scheme 3). Different classical as well as microwave con-
ditions were tested for the radiofluorination of these phosphanes,
but no radiolabeled product was found. Radio-HPLC and radio-TLC
evaluations pointed out that the precursor either led to de-
composition or the phosphorus atom of the precursor building block
core was oxidized during the labeling procedure.
Scheme 4. Functionalization, radiolabeling, and PeC cross-coupling to (radio-)fluori-
nated compounds 10/[18F]10 and 11.
A direct bromination of compound 3j using NBS in CCl4 was not
amenable. However, the reaction of iodophenyl benzoate 3e with
NBS proved to be successful and led to the desired bromomethyl
compound 7 in 81% yield. Subsequently, the iodinated compound 8
was prepared from 7 in 79% yield using a Finkelstein exchange with
NaI in acetone at room temperature. Afterward, 8 was successfully
reacted with AgOTs in anhydrous acetonitrile in the dark and
yielded 9 (89%), whereas reaction of 7 or 8 with AgF gave the de-
sired fluoro compound 10 in 41% (starting from 7) or 57% yield
(starting from 8), respectively. Besides, the fluoromethyl derivative
10 could be obtained in 46% yield when tosylate 9 was reacted with
CsF in t-BuOH (experimental procedure not shown).
Optimal reaction conditions for the preparation of [18F]10 were
evaluated using different leaving groups (Table 2) and various sol-
vents. In this context, precursor amounts as well as reaction times
were changed. All labeling reactions were carried out at 100 ꢁC.
The application of labeling conditions from entry 6 in Table 2
O
O
different
conditions
O
O
PPh2
PPh2
R
X
X
18F
X = CH, R = 4-I, 4-NO2, 4-Me3N+I-
X = CH or X = N
or
X = N, R = 2-Br, 4-Br
Scheme 3. Radiolabeling trials of various phosphane derivatives under different
conditions.
Table 2
RCY and scope of the labeling reaction
Leaving Precursor amount Solvent
Time
Yield [%]a
Group
[mg]
These results prompted us to develop a second, new approach
adopting 4-halomethyl-functionalized 2-iodophenyl benzoates.
The 4-fluoromethylbenzoate moiety was recently used as pros-
thetic group for labeling purposes.23 Thereby, it was found out that
bromide is rapidly displaced by fluoride at the benzylic position
instead of a direct substitution at the aromatic system. Moreover,
the resulting benzyl fluoride is relatively stable in aqueous medium
and benzyl halides are not subject to elimination, which has been
noted as side reaction with other methods of introducing fluorine-
18.23 Additionally, the use of precursors with leaving groups
like mesyl, tosyl or iodide were preferred for the introduction of
radiofluorine and the preparation of non-radioactive reference
compounds (Scheme 4).
1
2
3
4
5
6
7
8
9
Br
Br
Br
I
3.34
4.31b
3.34
2.33
5.21c
3.21
5.20
5.20
9.52
10.3
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
30 min
15 min
MWc
1
7
1
1
15 min
I
20 min 46
30 min 25
30 min 33
OTs
OTs
OTs
OTs
MWd
36
2
Acetonitrile/t-BuOH 1:4 15 min
Acetonitrile
10 OTs
15 min 66
a
Conversion determined via evaluation of radio-TLC.
AgNO3 (3.37 mg) was added.
AgOMs (5.12 mg) was added.
b
c
d
Microwave conditions: 5 min/50 W.

4524
C. Mamat et al. / Tetrahedron 67 (2011) 4521e4529
(Kryptofix K 2.2.2./K2CO3 in acetonitrile) delivered the highest
4-(fluoroethoxy)benzoate-functionalized phosphane 15 to yield
the respective Staudinger products 20 (95%), 21 (60%), 22 (66%), and
23 (50%). The ligation was performed in a mixture of acetonitrile/
water (v:v, 10:1) at 60 ꢁC for 2 h.
conversion of 66% (decay corrected, d.c.)24 (average of 5 runs) to
[
18F]10 when tosyloxymethyl compound 8 was used as precursor at
a synthesis time of 15 min.
Finally, the radiolabeled phosphane as well as the non-
radioactive reference compound should be prepared using the
Pd-catalyzed PeC cross-coupling. For this purpose, 2-iodophenyl
ester 10 was reacted with diphenylphosphane in dry DMA. The
desired fluoro-containing phosphane 11 was obtained in 30%
yield, whereas the synthesis of the radiofluorinated phosphane
Finally, the radiofluorinated phosphane [18F]15 was reacted
with benzyl azide (16) in a ‘one pot’ synthesis. Therefore, a so-
lution of 16 in 300 mL of an acetonitrile/water mixture (v:v, 10:1)
was added. After 15 min heating at 90 ꢁC, the ligation reaction
was complete and yielded [18F]20 (17%, d.c., after three steps
starting from [18F]fluoride).24 Fig. 4 shows the respective radio-
TLC chromatogram of [18F]20. Accessorily, Fig. 6 shows the
HPLC chromatogram with a mixture of non-radioactive starting
materials 3i and 16 as well as product 20 (UV-trace), whereas
Fig. 7 shows the appropriate radio-HPLC with radiofluorinated
[
18F]11 failed under the same conditions. An application of other
solvents, a variation of temperature as well as the base was not
successful. Based on these results, we developed another labeling
strategy.
The third and successful approach involved the indirect in-
corporation of radiofluorine into 4-hydroxybenzoate-functional-
ized phosphane 3i with [18F]fluoroethyl tosylate ([18F]12), which
served as alkylating agent. This building block is known to be an
excellent tool for the labeling of compounds bearing a hydroxyl or
an amine function25 and can be easily prepared from ethylene
ditosylate. Thus, a one pot procedure was developed for the
radiolabeling of 3i with [18F]12 followed by the Staudinger ligation
with several model compounds. (Scheme 5) For this purpose,
[ g-trace).
18F]20 (
Furthermore, it was possible to label the azide-functionalized
carbohydrate 17 successfully with fluorine-18 to yield [18F]21
(12%, d.c., after three steps starting from [18F]fluoride).24 For this
purpose, [18F]15 was prepared in dry acetonitrile and treated with
17 in an acetonitrile/water mixture (300 mL; v:v, 10:1) for 15 min
at 90 ꢁC. Verification of all resulting Staudinger products was
done using radio-HPLC as well as radio-TLC analyses.24 A radio-
TLC chromatogram of [18F]21 is shown in Fig. 5.
O
N3
N
16
H
18/19F
O
18
20/[ F]20
O
O
O
O
O
DAST, CH2Cl2,
-50 °C to rt, 24 h
O
O
O
O
O
O
O
O
O
O
17
N3
N
H
HO
I
F
I
18/19F
O
O
13
14
O
N3
21/[18F]21
O
HPPh2, KOAc,
DMA, Pd(OAc)2,
75 °C, 20 h
O
O
O
19F
O
O
O
O
O
O
18
NH
O
O
O
+
18/19F
PPh2
22
PPh2
O
O
O
O
HO
3i
15/[18F]15
O
O
O
O
O
O
18F
OTs
F]12
18
O
[
O
19F
O
N3
O
NH
O
19
23
O
Scheme 5. Radiofluorination using 2-[18F]fluoroethyl tosylate [18F]12 and subsequent traceless Staudinger ligation.
[
18F]12 was prepared and subsequently treated with 2e3 mg of 3i
dissolved in 300 mL of acetonitrile. The resulting mixture was
heated at 90 ꢁC for another 15 min to yield [18F]15.
4. Traceless Staudinger ligation
Non-radioactive reference compounds 15 and 20e23, which
were used for the identification of all radiolabeled derivatives, were
prepared starting from 2-iodophenyl ester 13. (Scheme 5) Thus, 13
was treated with DAST to obtain the fluorinated 2-iodophenyl ester
14. Subsequently, 14 was reacted with diphenylphosphane under
Pd-catalysis in a PeC cross-coupling reaction to yield the desired
non-radioactive phosphane 15 (60%).
To prove the applicability of the traceless Staudinger ligation for
labeling purposes with fluorine-18, various azides 16e19 were
synthesized. Subsequently, benzyl azide (16) and three different
carbohydrates 17, 18, and 19 with azide function were reacted with
Fig. 4. Radio-TLC chromatogram of Staudinger product [18F]20, Rf¼0.51 (petroleum
ether/ethyl acetate, 2:3).

C. Mamat et al. / Tetrahedron 67 (2011) 4521e4529
4525
prepared to prove the feasibility of the traceless Staudinger ligation
as radiolabeling procedure.
6. Experimental section
6.1. Reagents and techniques
All chemicals were purchased from SigmaeAldrich, abcr or
Acros and were used as received, dry solvents (THF, DMA, toluene,
and acetonitrile) were obtained from Fluka (anhydrous, over mo-
lecular sieves, 99.7%). Phosphanol 2b5a and compounds 4, 13,5a and
16e1926 were synthesized according to literature methods. The
reaction with BH3$THF, the Pd-catalyzed PeC cross-coupling and
the deprotection using MeOH/toluene were carried out using
Schlenk technique under an argon atmosphere. NMR spectra were
recorded on a Varian Inova-400 and chemical shifts of the 1H, 13C,
19F, and 31P spectra were reported in parts per million (ppm) using
the solvent shifts for 1H and 13C, CFCl3 for 19F and H3PO4 for 31P
spectra as internal standard. Mass spectrometric (MS) data was
obtained on a Quattro/LC mass spectrometer (MICROMASS) by
electron spray ionization or on a Bruker autoflex II TOF/TOF mass
spectrometer (Matrix:DHB, reflector mode). The melting points
were determined on a Galen III (Cambridge Instruments) melting
point apparatus (Leica, Vienna, Austria) and are uncorrected.
Fig. 5. Radio-TLC chromatogram of Staudinger product [18F]21, Rf¼0.44 (petroleum
ether/ethyl acetate, 1:1).
Crystallographic data were collected with a Bruker-Nonius Apex-X8
ꢀ
CCD-diffractometer with Mo K
a
radiation (
l
¼0.71073 A). The
structures were solved by direct methods using SHELXS-97 and
refined against F2 on all data by full-matrix least-squares with
SHELXL-97.27 All non-hydrogen atoms were refined anisotropically;
all hydrogen atoms bonded to carbon atoms were placed on geo-
metrically calculated positions and refined using a riding model.
The three hydrogen atoms of the BH3 group in 4 were refined iso-
tropically. Microanalyses were carried out with a Hekatech CHNS
elemental analyzer EuroEA 3000. Chromatographic separations
and TLC detections were carried out with Merck Silica Gel 60
Fig. 6. HPLC chromatogram (UV-trace) of starting materials 3i, 16, and non-radioactive
Staudinger product 20 (tR¼3.16 min).
(63e200
mm) and Merck Silica Gel 60 F254 sheets, respectively. TLCs
were visualized under UV light (
l
¼254 nm). All reactions con-
cerning the boraneephosphane-adduct formation were carried out
under an Argon atmosphere using Schlenk techniques. Analytical
HPLC was performed on a Hewlett Packard HP 1050 series HPLC
system, equipped with a reverse phase column (Supelco Discovery
C-18; 150ꢂ4.6 mm; 5
mm), a UV-diode array detector (230 nm) and
a scintillation radiodetector (Raytest, Gabi Star). The radioactive
compounds were identified with analytical radio-HPLC by com-
parison of the retention time of the reference compounds. Decay-
corrected RCYs were quantified by integration of radioactive
peaks on a radio-TLC using a radio-TLC scanner (Fuji, BAS2000).24
[
18F]Fluoride was produced utilizing the PET cyclotron Cyclone
18/9 (IBA, Belgium). [18O]H2O was irradiated with protons (18 MeV,
30
A) exploiting the 18O(p,n)18F nuclear reaction.
m
Fig. 7. Radio-HPLC chromatogram (
g
-trace) of Staudinger product [18F]20 (tR¼3.58 min).
6.2. General synthetic procedure for the preparation of 3aen
5. Conclusion
The respective benzoic acid 1aei (1.1 equiv) and o-iodophenol
(2a) or phosphanol 2b (1 equiv) with a catalytic amount of DMAP
were dissolved in dry THF and DCC (1.5e2 equiv) was added at
room temperature. The mixture was allowed to stir overnight at
60 ꢁC. Afterward, the precipitate was filtered off and the filtrate was
concentrated in vacuo. Purification was done via column chroma-
tography (silica gel, petroleum ether/EtOAc). The preparation and
analytical data of 3aed and 3g,h was previously published.5a
In conclusion, we demonstrated an easy and convenient syn-
thesis route for the preparation of benzoate and nicotinate func-
tionalized phosphanes with various functional groups. These
groups allow either the fast introduction of labels, such as fluorine-
18 or the alkylation of the benzoate residue when the phosphorus
atom is protected with BH3. Furthermore, we described a ‘one pot’
procedure for the successful introduction of radiofluorine into
a phosphane for a further application as radiolabeled building block
using the traceless Staudinger ligation. In this context, it was pos-
sible to label different model azides with fluorine-18. The re-
spective non-radioactive fluorinated reference compounds were
6.2.1. 2-Iodophenyl 4-methylbenzoate (3e). p-Tolylic acid (1e) (2 g,
14.7 mmol), o-iodophenol (2a) (3.55 g, 16.2 mmol), DCC (4.55 g,
22.0 mmol), and DMAP (100 mg) in dry THF (30 mL) yielded 3e
as colorless solid (2 g, 40%); mp¼61 ꢁC; Rf¼0.64 (petroleum

4526
C. Mamat et al. / Tetrahedron 67 (2011) 4521e4529
ether/EtOAc¼5:1); 1H NMR (400 MHz, C6D6):
d
1.97 (s, 3H, CH3),
1.93 mmol), DCC (722 mg, 3.50 mmol), and DMAP (30 mg) in dry
THF (15 mL) yielded 3l as colorless oil (150 mg, 21%); Rf¼0.56
3
3
6.44 (t, J3,4¼7.8 Hz, 1H, H-4), 6.87 (t, J5,6¼7.0 Hz, 1H, H-5), 6.91
3
3
(d, Jo,m¼8.5 Hz, 2H, Hmeta), 6.99 (d, J5,6¼7.0 Hz, 1H, H-6), 7.54 (d,
(petroleum ether/EtOAc¼3:1); 1H NMR (400 MHz, C6D6):
d 6.07
3J3,4¼7.8 Hz, 1H, H-3), 8.26 (d, Jo,m¼8.5 Hz, 2H, Hortho); 13C NMR
(dd, 3JH,F¼3.1 Hz, 3J4 ,5 ¼8.6 Hz,1H, H-5 ), 6.84 (t, J3,4¼7.0 Hz,1H, H-
3
3
0
0
0
(101 MHz, C6D6):
d 21.5 (CH3), 91.1 (C-2), 123.7 (C-6), 127.3 (Cipso),
4), 6.95e7.03 (m, 7H, H-3, Hmeta, Hpara), 7.07 (t, 3J5,6¼7.8 Hz, 1H, H-
3
127.5 (C-4), 129.4 (C-5), 129.6 (Cmeta), 130.9 (Cortho), 139.6 (C-3),
144.6 (Cpara), 152.1 (C-1), 164.2 (C]O); MS (ESIþ): m/z 339
(MþHþ); Anal. Calcd for: C14H11IO2 (338.1): C 49.73, H 3.28;
found: C 50.32, H 3.45.
5), 7.22 (dd, J5,6¼7.8 Hz, 1H, H-6), 7.29e7.37 (m, 4H, Hortho), 7.79
4
4
(dd, 3J4 ,5 ¼8.6 Hz, J2 ,4 ¼2.3 Hz, 1H, H-4 ), 8.76 (d, J2 ,4 ¼2.3 Hz, H-
0
0
0
0
0
0
0
20); 13C NMR (101 MHz, C6D6):
d
¼109.2 (d, 2JC,F¼38.1, C-50), 123.0 (d,
3JC,P¼1.5 Hz, C-6), 123.9 (d, 4JC,F¼4.4 Hz, C-30), 128.9 (d, 3JC,P¼7.4 Hz,
2
Cmeta), 129.4 (Cpara), 130.1 (C-5), 131.4 (d, JC,P¼16.2 Hz, C-3), 134.1
3
2
6.2.2. 2-Iodophenyl 6-bromonicotinate (3f). 6-Bromonicotinic acid
(500 mg, 2.47 mmol), o-iodophenol (599 mg, 2.72 mmol), DCC
(1.02 g, 4.95 mmol), and DMAP (50 mg) in dry THF (30 mL) yielded
3f as colorless solid (584 mg, 58%); mp¼93 ꢁC; Rf¼0.49 (petroleum
(d, JC,P¼1.9 Hz, C-4), 134.4 (d, JC,P¼20.5 Hz, Cortho), 135.9 (d,
1JC,P¼10.8 Hz, Cipso), 142.7 (d, JC,F¼9.5 Hz, C-40), 151.1 (d,
3
3JC,F¼17.3 Hz, C-20), 153.0 (d, 2JC,P¼16.9 Hz, C-1), 162.0 (C]O), 166.3
(d, JC,F¼244.8 Hz, C-60); 19F NMR (376 MHz, C6D6):
d
ꢀ61.1; 31P
1
ether/EtOAc¼3:1); 1H NMR (400 MHz, C6D6):
d
6.43 (t, 3J3,4¼7.4 Hz,
NMR (162 MHz, C6D6):
d
ꢀ14.4; MS (ESIþ): m/z 424 (MþNaþ), 402
1H, H-4), 6.79e6.93 (m, 3H, H-3, H-5, H-6), 7.48 (d, 3J4 ,5 ¼8.6 Hz, H-
(MþHþ); Anal. Calcd for: C24H17FNO2P (401.4): C 71.82, H 4.27, N
0
0
3
50), 7.63 (d, J4 ,5 ¼8.6 Hz, H-4 ), 9.11 (s, 1H, H-2 ); 13C NMR
3.49; found: C 71.92, H 4.67, N 3.04.
0
0
0
0
(101 MHz, C6D6):
d
90.5 (C-2), 123.2 (C-6), 124.7 (C-30), 127.9 (C-50),
129.5 (C-5), 139.4 (C-40), 139.7 (C-3), 148.0 (C-60), 151.3 (C-1), 152.2
(C-20), 162.3 (C]O); MS (ESIþ): m/z 427 (MþNaþ); Anal. Calcd for:
C12H7BrINO2 (404.0): C 35.68, H 1.75, N 3.47; found: C 35.88, H 1.94,
N 3.41.
6.2.7. 2-(Diphenylphosphano)phenyl 2-bromonicotinate (3m). 2-
Bromonicotinic acid (279 mg, 1.38 mmol), phosphanol 2b (350 mg,
1.26 mmol), DCC (519 mg, 2.52 mmol), and DMAP (30 mg) in dry
THF (15 mL) yielded 3m as colorless solid (441 mg, 76%);
mp¼105 ꢁC; Rf¼0.69 (petroleum ether/EtOAc¼1:2); 1H NMR
3
3
0
0
0
0
0
6.2.3. 2-(Diphenylphosphano)phenyl 4-hydroxybenzoate (3i). 4-
Hydroxybenzoic acid (186 mg,1.35 mmol), phosphanol 2b (250 mg,
0.90 mmol), DCC (278 mg, 1.35 mmol), and DMAP (25 mg) in dry
THF (15 mL) yielded 3i as colorless solid (276 mg, 73%). Analytical
data are in accordance with the previously published.5a
(400 MHz, C6D6):
d
6.25 (dd, J4 ,5 ¼4.7 Hz, J5 ,6 ¼7.7 Hz, 1H, H-5 ),
3
6.83 (t, J4,5¼7.6 Hz, 1H, H-4), 6.99e7.02 (m, 7H, H-3, Hmeta, Hpara),
7.05 (t, 3J4,5¼7.6 Hz, 3J5,6¼8.0 Hz, 1H, H-5), 7.18 (dd, 3J5,6¼8.0 Hz, 1H,
3
0
0
H-6), 7.30e7.36 (m, 4H, Hortho), 7.65 (ddd, J5 ,6 ¼7.7 Hz,
4
3
4
0
0
0
0
0
0
0
J4 ,6 ¼2.0 Hz, 1H, H-6 ), 7.81 (d, J4 ,5 ¼4.7 Hz, J4 ,6 ¼2.0 Hz, 1H, H-
40); 13C NMR (101 MHz, C6D6):
d
121.8 (C-50), 123.1 (d, 3JC,P¼1.8 Hz,
3
6.2.4. 2-(Diphenylphosphano)phenyl 4-methylbenzoate (3j). p-Tol-
ylic acid (318 mg, 2.34 mmol), phosphanol 2b (591 mg, 2.12 mmol),
DCC (657 mg, 3.19 mmol), and DMAP (50 mg) in dry THF (15 mL)
yielded 3j as colorless solid (825 mg, 98%); mp¼144 ꢁC; Rf¼0.48
C-6), 126.8 (C-30), 129.0 (d, JC,P¼7.2 Hz, Cmeta), 129.3 (Cpara), 130.4
2
2
(C-5), 131.0 (d, JC,P¼16.0 Hz, C-3), 134.3 (d, JC,P¼20.5 Hz, Cortho),
134.4 (d, JC,P¼0.9 Hz, C-4), 136.1 (d, 1JC,P¼10.9 Hz, Cipso), 139.6 (C-
3
60), 141.7 (C-20), 152.0 (C-40), 153.5 (d, 2JC,P¼17.8 Hz, C-1), 162.6 (C]
(petroleum ether/EtOAc¼3:1); 1H NMR (400 MHz, C6D6):
d
1.91 (s,
O); 31P NMR (162 MHz, C6D6):
d
ꢀ15.5.; MS (ESIþ): m/z 485
3
3H, CH3), 6.80 (d, 3Jo,m¼8.6 Hz, 2H, Hmeta ), 6.84 (t, J3,4¼7.0 Hz, 1H,
(MþHþNaþ); Anal. Calcd for: C24H17BrNO2P (462.3): C 62.36, H
0
H-4), 6.98e7.08 (m, 8H, H-5, H-6, Hmeta
,
Hpara), 7.28 (dd,
3.71, N 3.03; found: C 62.81, H 4.07, N 2.93.
4
3J3,4¼7.8 Hz, JH,P¼4.7 Hz, 1H, H-3), 7.36e7.42 (m, 4H, Hortho), 8.01
(d, 3Jo,m¼8.6 Hz, 2H, Hortho ); 13C NMR (101 MHz, C6D6):
d
21.4 (CH3),
6.2.8. 2-(Diphenylphosphano)phenyl 2-fluoronicotinate (3n). 2-Flu-
oronicotinic acid (247 mg, 1.75 mmol), phosphanol 2b (536 mg,
1.93 mmol), DCC (722 mg, 3.50 mmol), and DMAP (30 mg) in dry
THF (15 mL) yielded 3n as colorless oil (280 mg, 36%); Rf¼0.20
0
3
0
0
123.3 (C-6), 127.4 (Cipso ), 128.8 (d, JC,P¼7.4 Hz, Cmeta), 129.1 (Cmeta ),
129.3 (C-5), 130.1 (Cortho ), 130.6 (Cpara), 131.4 (d, 2JC,P¼16.4 Hz, C-3),
0
2
1
134.0 (C-4), 134.5 (d, JC,P¼20.6 Hz, Cortho), 136.6 (d, JC,P¼11.8 Hz,
Cipso), 144.0 (Cpara ), 154.0 (d, JC,P¼17.6 Hz, C-1), 164.3 (C]O); 31P
(petroleum ether/EtOAc¼4:1); 1H NMR (400 MHz, C6D6):
d 6.25
2
0
3
3
5
¼ꢀ14.7; MS (ESIþ): m/z 397 (MþHþ); Anal.
(ddd, J4 ,5 ¼4.8 Hz, J5 ,6 ¼7.6 Hz, JH,F¼1.6 Hz, 1H, H-50), 6.84 (t,
0
0
0
0
NMR (162 MHz, C6D6):
d
Calcd for: C26H21O2P (396.4): C 77.78, H 5.34; found: C 77.74, H 5.47.
3J3,4¼7.5 Hz, 1H, H-4), 6.98e7.02 (m, 7H, H-3, Hmeta, Hpara), 7.05 (t,
3
3
3J4,5¼7.5 Hz, J5,6¼8.0 Hz, 1H, H-5), 7.18 (dd, J5,6¼8.0 Hz, 1H, H-6),
3
4
0
0
0
0
6.2.5. 2-(Diphenylphosphano)phenyl 6-bromonicotinate (3 k). 6-
Bromonicotinic acid (248 mg, 1.23 mmol), phosphanol 2b (310 mg,
1.11 mmol), DCC (460 mg, 2.23 mmol), and DMAP (30 mg) in dry
THF (15 mL) yielded 3k as colorless solid (446 mg, 87%);
7.31e7.37 (m, 4H, Hortho), 7.76 (ddd, J4 ,5 ¼4.8 Hz, J4 ,6 ¼2.0 Hz,
4
3
4
JH,F¼3.2 Hz, 1H, H-40), 7.89 (d, J5 ,6 ¼7.6 Hz, J4 ,6 ¼2.0 Hz,
0
0
0
0
4JH,F¼3.7 Hz, 1H, H-60); 13C NMR (101 MHz, C6D6):
d 113.1 (d,
2JC,F¼24.1, C-30), 121.0 (d, JC,F¼5.0 Hz, C-50), 123.2 (C-6), 128.9 (d,
3JC,P¼7.1 Hz, Cmeta), 129.2 (Cpara), 130.2 (C-5), 131.2 (d, 2JC,P¼16.5 Hz,
C-3), 133.9 (d, 1JC,P¼19.2 Hz, C-2), 134.3 (d, 3JC,P¼1.7 Hz, C-4), 134.4
4
mp¼105 ꢁC; Rf¼0.62 (petroleum ether/EtOAc¼3:1);0 1H NMR
3
0
0
(400 MHz, C6D6):
d
6.73 (d, J4 ,5 ¼8.7 Hz, 1H, H-5 ), 6.83 (t,
3J3,4¼7.7 Hz, 1H, H-4), 6.95e7.01 (m, 7H, H-3, Hmeta, Hpara), 7.05 (t,
(d, JC,P¼20.7 Hz, Cortho), 136.1 (d, JC,P¼11.1 Hz, Cipso), 143.6 (d,
2
1
3J5,6¼7.8 Hz, 1H, H-5), 7.19 (dd, 3J5,6¼7.8 Hz, 1H, H-6), 7.28e7.36 (m,
3JC,F¼15.8 Hz, C-40), 152.2 (d, JC,F¼15.9 Hz, C-60), 153.2 (d,
3
3
4
3
4H, Hortho), 7.48 (dd, J4 ,5 ¼8.7 Hz, J2 ,4 ¼2.4 Hz, 1H, H-4 ), 8.81 (d,
2JC,P¼17.7 Hz, C-1), 160.5 (d, JC,F¼8.7 Hz, C]O), 162.4 (d,
0
0
0
0
0
J2 ,4 ¼2.4 Hz, H-20); 13C NMR (101 MHz, C6D6):
d
3
122.9 (d,
1JC,F¼251.1 Hz, C-20); 19F NMR (376 MHz, C6D6):
d
ꢀ61.1; 31P NMR
4
0
0
3JC,P¼1.5 Hz, C-6), 124.8 (C-30), 127.9 (C-50), 129.0 (d, JC,P¼7.3 Hz,
(162 MHz, C6D6):
d
ꢀ14.7; MS (ESIþ): m/z 402 (MþHþ); Anal. Calcd
2
Cmeta), 129.4 (Cpara), 130.1 (C-5), 131.4 (d, JC,P¼16.2 Hz, C-3), 132.0
for: C24H17FNO2P (401.4): C 71.82, H 4.27, N 3.49; found: C 72.01, H
4.19, N 3.51.
1
3
(d, JC,P¼9.9 Hz, C-2), 134.1 (d, JC,P¼1.9 Hz, C-4), 134.4 (d,
2JC,P¼21.0 Hz, Cortho), 135.8 (d, 1JC,P¼10.9 Hz, Cipso), 139.2 (C-40), 147.6
(C-60), 152.0 (C-20), 153.0 (d, JC,P¼17.0 Hz, C-1), 162.4 (C]O); 31P
6.2.9. 4-(2-(Diphenylphosphano)phenoxy)carbonyl-N,N,N-trimethyl-
anilinium iodide borane adduct (5). Compound 4 (480 mg,
2
NMR (162 MHz, C6D6):
d
ꢀ14.5; MS (ESIþ): m/z 465 (MþHþ; 81Br),
463 (MþHþ; 79Br); Anal. Calcd for: C24H17BrNO2P (462.3): C 62.36,
1.09 mmol) was dissolved in methyl iodide (4 mL), and the mixture
was stirred for 7 days at room temperature. Afterward, the pre-
cipitate was filtered and washed with diethyl ether (3ꢂ10 mL) and
ethyl acetate (10 mL) to yield 5 as pale yellow solid (367 mg, 58%);
mp¼142 ꢁC (decomp.); 1H NMR (400 MHz, acetone-d6): 0.80e1.70
H 3.71, N 3.03; found: C 62.16H 3.91, N 2.94.
6.2.6. 2-(Diphenylphosphano)phenyl 6-fluoronicotinate (3l). 6-Flu-
oronicotinic acid (247 mg, 1.75 mmol), phosphanol 2b (536 mg,

C. Mamat et al. / Tetrahedron 67 (2011) 4521e4529
4527
(m, 3H, BH3), 4.03 (s, 9H, NMe3), 7.20e7.98 (m, 14H, AreH), 7.78 (d,
3Jo,m¼8.5 Hz, 2H, Hmeta), 8.23 (d, 3Jo,m¼8.5 Hz, 2H, Hortho); 31P NMR
127.7 (C-4), 128.4 (Cmeta), 129.4, 129.9 (CAr, OTs), 130.0 (Cipso), 130.9
(Cortho), 134.2 (Cq,OTs), 139.6 (C-3), 139.8 (Cq,OTs), 144.6 (Cpara), 151.9
(C-1), 163.6 (C]O); MS (ESIþ): m/z 509 (MþHþ); Anal. Calcd for:
C21H17IO5S (508.33): C 49.62, H 3.37, S 6.31; found: C 49.70, H 3.13, S
6.12.
(162 MHz, acetone-d6):
d
19.1 (m); MS (ESIþ): m/z 454 (MþꢀI), 440
(MþꢀIꢀBH3); MS (ESIꢀ): m/z 126 (Iꢀ); Anal. Calcd for: C28H30BINO2P
(581.23): C 57.86, H 5.20, N 2.41; found: C 57.88, H 5.51, N 2.44.
6.2.10. 4-(2-(Diphenylphosphano)phenoxy)carbonyl-N,N,N-trime-
thylanilinium iodide (6). Compound 5 (100 mg, 0.17 mmol) was
dissolved in methanol (5 mL) and was refluxed for 2 h. Afterward,
the solvent was removed and the residue was decanted with
diethyl ether (3ꢂ3 mL) to yield 6 as colorless syrup (86 mg, 88%);
1H NMR (400 MHz, acetone-d6): 4.04 (s, 9H, NMe3), 6.88e6.93 (m,
1H, AreH), 7.27e7.98 (m, 13H, AreH), 8.02 (d, 3J¼9.2 Hz, 2H, Hmeta),
8.39 (d, 3J¼9.2 Hz, 2H, Hortho); 13C NMR (101 MHz, acetone-d6):
6.2.14. 2-Iodophenyl 4-(fluoromethyl)benzoate (10). Compound 7
(300 mg, 0.72 mmol) and silver fluoride (228 mg, 1.80 mmol) were
dissolved in acetonitrile (8 mL) and the resulting mixture stirred at
room temperature in the dark overnight. Afterward, precipitate was
filtered and the solvent was removed in vacuo. After purification of
the crude product via column chromatography (silica gel, petro-
leum ether/EtOAc¼20:1) 10 was obtained as a colorless solid
(106 mg, 41%); mp¼72 ꢁC; Rf¼0.45 (petroleum ether/EtOAc¼6:1);
3
1H NMR (400 MHz, C6D6):
d
4.83 (d, 2H, 2JH,F¼47.2 Hz, CH2), 6.45 (t,
0
d
57.9 (NMe3), 122.4 (Cmeta ), 123.7 (d, JC,P¼1.6 Hz, C-6), 127.4 (C-4),
3
3
3
129.7 (d, JC,P¼7.4 Hz, Cmeta), 131.0 (C-5), 132.4 (Cortho ), 134.3 (d,
3J3,4¼6.9 Hz, 1H, H-4), 6.88 (t, J4,5¼6.9 Hz, J5,6¼7.9 Hz, 1H, H-5),
6.98 (d, 3J5,6¼7.9 Hz, 1H, H-6), 7.01 (d, 3Jo,m¼7.9 Hz, 2H, Hmeta), 7.53
(d, 3J3,4¼6.9 Hz, 1H, H-3), 8.23 (d, 3Jo,m¼7.9 Hz, 2H, Hortho); 13C NMR
0
2JC,P¼1.6 Hz, C-3), 134.7 (d, JC,P¼21.0 Hz, Cortho), 136.1 (d,
2
1
2
0
JC,P¼10.1 Hz, Cipso), 152.1 (Cpara ), 153.6 (d, JC,P¼17.4 Hz, C-1), 163.3
(C]O); 31P NMR (162 MHz, acetone-d6):
d
ꢀ15.2; MS (ESIþ): m/z
(101 MHz, C6D6):
d
83.3 (d, 1JC,F¼169.3 Hz, CH2), 90.9 (C-2),123.6 (C-
440 (MþꢀI); MS (ESIꢀ): m/z 126 (Iꢀ); Anal. Calcd for: C28H27INO2P
6), 126.9 (d, 3JC,F¼7.0 Hz, Cmeta), 127.7 (C-4), 129.5 (C-5), 129.7 (Cipso),
(567.40): C 59.27, H 4.80, N 2.47; found: C 59.06, H 4.81, N 2.21.
130.9 (Cortho), 139.6 (C-3), 142.6 (d, 2JC,F¼17.3 Hz, Cpara), 151.9 (C-1),
163.8 (C]O); 19F NMR (376 MHz, C6D6):
d
ꢀ214.2; MS (ESIþ): m/z
6.2.11. 2-Iodophenyl 4-(bromomethyl)benzoate (7). Compound 3e
(1.7 g, 5.03 mmol) and NBS (1.16 g, 6.54 mmol) were dissolved in
CCl4 (15 mL), benzoyl peroxide (100 mg) was added and the
resulting mixture stirred at 60 ꢁC overnight. Afterward, the solvent
was removed in vacuo. After purification of the crude product via
column chromatography (silica gel, petroleum ether/EtOAc¼20:1) 7
was obtained as a pale yellow solid (1.06 g, 81%); mp¼117 ꢁC;
Rf¼0.51 (petroleum ether/EtOAc¼6:1); 1H NMR (400 MHz, C6D6):
357 (MþHþ); Anal. Calcd for: C14H10FIO2 (356.1): C 47.22, H 2.83;
found C 47.55, H 2.96.
6.2.15. 2-(Diphenylphosphano)phenyl
(11). KOAc (38 mg, 0.39 mmol), HPPh2 (60
4-(fluoromethyl)-benzoate
L, 0.32 mmol) and
m
Pd(OAc)2 in catalytical amount were added to a solution of 2-
iodophenyl benzoate 10 (100 mg, 0.32 mmol) in dry DMA (2 mL)
under an argon atmosphere. The mixture was stirred at 90 ꢁC for
3 h. Afterward, water (15 mL) and CH2Cl2 (15 mL) were added, the
organic layer was separated, and the aqueous layer was extracted
with 3ꢂ10 mL CH2Cl2. The combined organic layers were dried over
Na2SO4, and the solvent was removed under reduced pressure.
Purification was done via column chromatography (silica gel, pe-
troleum ether/EtOAc¼6:1) to obtain 11 as a colorless solid (102 mg,
d
3.79 (s, 2H, CH2), 6.43 (t, 3J3,4¼7.0 Hz,1H, H-4), 6.86 (t, 3J5,6¼7.0 Hz,
1H, H-5), 6.93 (d, 3Jo,m¼8.1 Hz, 2H, Hmeta), 6.97 (d, 3J5,6¼7.0 Hz,1H, H-
6), 7.52 (d, 3J3,4¼7.0 Hz,1H, H-3), 8.14 (d, 3Jo,m¼8.1 Hz, 2H, Hortho); 13
C
NMR (101 MHz, C6D6): d 31.9 (CH2), 90.9 (C-2), 123.6 (C-6), 127.7 (C-
4), 129.4 (Cmeta), 130.0 (Cipso), 131.1 (Cortho), 139.6 (C-3), 143.8 (Cpara),
151.9 (C-1), 163.6 (C]O); MS (ESIþ): m/z 455 (MþKþ); Anal. Calcd
for: C14H10BrIO2 (417.0): C 40.32, H 2.42; found: C 40.30, H 2.76.
30%); mp¼164 ꢁC; Rf¼0.79 (petroleum ether/EtOAc¼1:1); 1H NMR
3
(400 MHz, C6D6):
d
4.77 (d, JH,F¼47.3 Hz, 2H, CH2F), 6.84 (t,
3
J3,4¼7.8 Hz, 1H, H-4), 6.89 (d, 3J¼8.0 Hz, 2H, Hmeta ), 6.99e7.04 (m,
8H, Hortho, Hmeta), 7.06 (t, 3J¼7.6 Hz, 1H, H-5), 7.26 (dd, 3J3,4¼7.8 Hz,
3JH,P¼4.1 Hz, 1H, H-3), 7.34e7.41 (m, 4H, Hpara), 7.99 (d, 3J¼8.0 Hz,
0
6.2.12. 2-Iodophenyl 4-(iodomethyl)benzoate (8). Compound
6
(816 mg, 1.92 mmol) was dissolved in acetone (5 mL), NaI (1.15 g,
7.67 mmol) was added and the mixture was allowed to stir at room
temperature overnight. Afterward, the mixture was filtered and the
solvent was removed. After purification of the crude product via
column chromatography (silica gel, petroleum ether/EtOAc¼20:1)
8 was obtained as a yellow solid (721 mg, 79%); mp¼86 ꢁC; Rf¼0.51
2H, Hortho ); 13C NMR (101 MHz, C6D6):
d
83.3 (d, JC,F¼169.8 Hz,
1
0
3
CH2), 123.2 (d, J¼1.7 Hz, C-6), 126.4 (C-4), 126.6 (d, JC,F¼6.6 Hz,
3
0
Cmeta ), 128.9 (d, JC,P¼7.2 Hz, Cmeta), 129.1 (Cpara), 130.2 (C-5), 130.7
(Cortho ),132.2 (d, JC,P¼9.9 Hz, C-2),134.1 (d, 2JC,P¼0.9 Hz, C-3),134.5
1
0
(petroleum ether/EtOAc¼6:1); 1H NMR (400 MHz, C6D6):
d
3.75 (s,
(d, JC,P¼20.7 Hz, Cortho), 136.4 (d, JC,P¼11.0 Hz, Cipso), 142.1 (d,
2 2
2
1
3
JC,F¼17.6 Hz, Cpara ), 153.8 (d, JC,P¼17.7 Hz, C-1), 163.9 (C]O); 19F
0
2H, CH2), 6.43 (t, J3,4¼7.8 Hz, 1H, H-4), 6.83e6.90 (m, 3H, H-5,
Hmeta), 6.97 (d, 3J5,6¼7.8 Hz, 1H, H-6), 7.52 (d, 3J3,4¼7.8 Hz, 1H, H-3),
NMR (376 MHz, C6D6):
d
d
ꢀ214.0; 31P NMR (162 MHz, C6D6):
3
8.09 (d, Jo,m¼7.8 Hz, 2H, Hortho); 13C NMR (101 MHz, C6D6):
d
3.4
ꢀ14.3; MS (ESIþ): m/z (%)¼415 (MþHþ); Anal. Calcd for:
(CH2), 90.9 (C-2), 123.6 (C-6), 127.6 (C-4), 129.1 (Cmeta), 129.4 (Cipso),
131.1 (Cortho), 139.6 (C-3), 145.6 (Cpara), 152.0 (C-1), 163.6 (C]O); MS
(ESIþ): m/z 465 (MþHþ); Anal. Calcd for: C14H10I2O2 (464.04): C
36.24, H 2.17; found: C 36.04, H 2.17.
C26H20FO2P (414.41): C 75.36, H 4.86; found: C 70.41, H 5.31.
6.2.16. 2-Iodophenyl 4-(2-fluoroethoxy)benzoate (14). Under an
Argon atmosphere compound 13 (208 mg, 0.54 mmol) was dis-
solved in dry dichloromethane (5 mL) and cooled to ꢀ78 ꢁC. Af-
6.2.13. 2-Iodophenyl 4-(tosyloxymethyl)benzoate (9). Compound 8
(700 mg, 1.51 mmol) and silver tosylate (447 mg, 1.96 mmol) were
dissolved in 10 mL acetonitrile and stirred at room temperature
overnight. Afterward, the solvent was removed and purification
was done via column chromatography (silica gel, petroleum ether/
EtOAc¼6:1) to obtain 9 as a colorless solid (683 mg, 89%);
mp¼91 ꢁC; Rf¼0.19 (petroleum ether/EtOAc¼6:1); 1H NMR
(400 MHz, C6D6): 1.83 (s, 2H, CH3), 4.74 (s, 2H, CH2), 6.44 (t,
3J3,4¼7.6 Hz, 1H, H-4), 6.68 (d, 3Jo,m¼8.0 Hz, 2H, OTsmeta), 6.83e6.97
terward,
diethylaminosulfurtrifluoride
(DAST)
(0.11 mL,
0.84 mmol) was added and the mixture was warmed slowly to
room temperature overnight. Saturated hydrogencarbonate solu-
tion (20 mL) was added, the mixture was extracted with dichloro-
methane (3ꢂ15 mL), the combined organic layers were dried over
Na2SO4, the solvent was removed, and the crude product was
purified via column chromatography (silica gel, petroleum ether/
EtOAc¼20:1) to obtain 14 as a colorless solid (114 mg, 55%);
Analytical data are in accordance to the previously published.5a
3
(m, 4H, H-5, H-6, Hmeta), 7.52 (d, J3,4¼8.0 Hz, 1H, H-3), 7.72 (d,
3Jo,m¼8.0 Hz, 2H, OTsortho), 8.11 (d, 3Jo,m¼8.5 Hz, 2H, Hortho); 13C NMR
6.2.17. 2-(Diphenylphosphano)phenyl 4-(2-fluoroethoxy)-benzoate
(15). Diphenylphosphane (188 mg, 1.01 mmol) and Pd(OAc)2 in
(101 MHz, C6D6):
d 21.2 (CH3),70.4 (CH2), 90.8 (C-2), 123.6 (C-6),

4528
C. Mamat et al. / Tetrahedron 67 (2011) 4521e4529
catalytical amount were added to a solution of 2-iodophenyl 4-(2-
fluoroethoxy)benzoate 14 (390 mg, 1.01 mmol) and KOAc (119 mg,
1.45 mmol) in 5 mL dry DMA at room temperature under an argon
atmosphere. The mixture was allowed to stir at 70 ꢁC overnight.
Afterward, water (10 mL) and CH3Cl (10 mL) were added, the or-
ganic layer was separated and the aqueous layer was extracted with
CH3Cl (3ꢂ10 mL). The combined organic layers were dried over
Na2SO4, and concentrated under reduced pressure. The crude
product was purified by column chromatography (petroleum ether/
EtOAc¼20:1/10:1) to obtain 15 as a colorless solid (270 mg, 60%).
Analytical data are in accordance to the previously published.5a
Cquart),114.4 (C-m),128.2 (C-i),129.2 (C-o),161.1 (C-p),166.7 (C]O);
19F NMR (376 MHz, C6D6):
d
ꢀ223.7; MS (ESIþ): m/z 448 (MþþNa),
426 (MþþH); Anal. Calcd for: C21H28FNO7 (425.45): C 59.28, H 6.63;
found: C 59.73, H 6.73.
6.2.21. 3-Deoxy-1,2:5,6-di-O-isopropylidene-3-(4-[2-fluoroethoxy]
benzamidyl)-a-D-allofuranose (23). Compounds 15 (122 mg,
0.27 mmol) and 19 (94 mg, 0.33 mmol) were dissolved in a 10:1
mixture of DMF/water (1 mL) and heated at 60 ꢁC for 2 h. After-
ward, the solvent was removed and the residue was purified via
column chromatography (petroleum ether/EtOAc¼1:2) to obtain
23 as a pale yellow syrup (58 mg, 50%); Rf¼0.32 (petroleum ether/
6.2.18. N-Benzyl-4-(2-fluoroethoxy)benzamide (20). Compounds 15
(155 mg, 0.35 mmol) and 16 (56 mg, 0.42 mmol) were dissolved in
a 10:1 mixture of DMF/water (3 mL) and heated at 60 ꢁC for 2 h.
Afterward, the solvent was removed and the residue was purified
via column chromatography (petroleum ether/EtOAc¼1:1) to ob-
tain 20 as a colorless solid (100 mg, 95%); mp¼215 ꢁC; Rf¼0.52
EtOAc¼1:2); 1H NMR (400 MHz, C6D6):
d 1.09 (s, 3H, CH3), 1.29 (s,
3H, CH3), 1.41 (s, 3H, CH3), 1.50 (s, 3H, CH3), 3.42 (dt, 3J¼3.9 Hz,
3JH,F¼28.0 Hz, 2H, CH2CH2F), 4.04e4.25 (m, 6H, H-3, H-5, H-6a, H-
6b, CH2CH2F), 4.39e4.46 (m, 2H, H-2, H-4), 5.52 (d, 3J¼3.2 Hz, 1H,
H-1), 6.48 (d, 3J¼8.6 Hz, 1H, NH), 6.58 (d, 3J¼8.6 Hz, 2H, H-m), 7.76
(d, 3J¼8.3 Hz, H-o); 13C NMR (101 MHz, C6D6):
d 25.5, 26.3, 26.7,
(petroleum ether/EtOAc¼1:2); 1H NMR (400 MHz, C6D6):
d
3.40 (dt,
26.8 (4ꢂ CH3), 54.3 (CH), 65.4 (CH), 67.1 (d, 2JC,F¼20.4 Hz, CH2CH2F),
3
2
1
2H, 3J¼3.7 Hz, JH,F¼27.1 Hz, CH2CH2F), 4.10 (dt, 2H, JH,F¼48.4 Hz,
76.4 (CH), 79.5 (CH), 79.7 (CH), 81.3 (d, JC,F¼172.0 Hz, CH2CH2F),
3J¼3.7 Hz, CH2CH2F), 4.48 (d, 2H, 3J¼3.7 Hz, CH2), 5.71 (br s, 1H,
104.8 (C-1), 109.7,112.4 (2ꢂ Cquart),114.6 (C-m),127.6 (C-i),129.3 (C-
3
NH), 6.60 (d, J3,4¼6.6 Hz, Hmeta), 6.90e7.20 (m, 5H, Bn), 7.57 (d,
o), 161.4 (C-p), 166.1 (C]O); 19F NMR (376 MHz, C6D6):
d
ꢀ223.8;
3J¼8.6 Hz, 2H, Hortho); 13C NMR (101 MHz, C6D6):
d
44.0 (CH2), 67.0
MS (ESIþ): m/z 448 (MþþNa), 426 (MþþH); Anal. Calcd for:
(d, 2JC,F¼20.6 Hz, CH2CH2F), 81.4 (d, 2JC,F¼170.6 Hz, CH2CH2F), 114.4
C21H28FNO7 (425.45): C 59.28, H 6.63; found: C 59.71, H 6.72.
(Cmeta), 127.5, 128.1, 128.8, 129.3 (CAr), 132.2, 139.6 (Cq), 161.2 (Cpara),
166.0 (C]O); 19F NMR (376 MHz, C6D6):
d
ꢀ123.8; MS (ESIþ): m/z
6.3. Radiochemistry
296 (MþþNa), 273 (MþþH); Anal. Calcd for: C16H16FNO2 (273.30): C
70.31, H 5.90, N 5.12; found: C 70.30, H 6.00.
An anion-exchanger cartridge (Waters, Sep-PakÒ Light AccellÔ
Plus QMA) was activated by rinsing with 10 mL of a 1 M NaHCO3
solution and 10 mL of deionized water. It was charged with [18F]
fluoride (500e800 MBq) and eluted with 1.5 mL of a solution of
Kryptofix 2.2.2. (10 mg/mL) and K2CO3 (13 mM) in 7 mL of aceto-
nitrile and 43 mL of water. The solvents were evaporated azeo-
tropically by subsequent addition of three 1 mL portions of dry
acetonitrile under a stream of nitrogen at 120 ꢁC.
6.2.19. 1-Deoxy-2,3:4,5-di-O-isopropylidene-1-(4-[2-fluoroethoxy]
benzamidyl)-a-D-fructopyranose (21). Compounds 15 (122 mg,
0.27 mmol) and 17 (94 mg, 0.33 mmol) were dissolved in a 10:1
mixture of DMF/water (1 mL) and heated at 60 ꢁC for 2 h. After-
ward, the solvent was removed and the residue was purified via
column chromatography (petroleum ether/EtOAc¼1:2) to obtain 21
as a pale yellow syrup (68 mg, 60%); Rf¼0.37 (petroleum ether/
EtOAc¼1:2); 1H NMR (400 MHz, C6D6):
d
1.09 (s, 3H, CH3), 1.21 (s,
6.3.1. N-Benzyl-4-(2-[18F]fluoroethoxy)benzamide ([18F]20). Ethylene
3H, CH3), 1.31 (s, 3H, CH3), 1.35 (s, 3H, CH3), 3.44 (dt, 3J¼3.9 Hz,
3JH,F¼28.1 Hz, 2H, CH2CH2F), 3.66e3.79 (m, 3H, H-5, H-6a, H-6b),
4.02e4.19 (m, 4H, CH2CH2F, H-1a, H-1b), 4.38 (dd, 3J¼7.8 Hz,
3J¼2.3 Hz, 1H, H-4), 4.43 (d, 3J¼2.3 Hz, 1H, H-3), 6.60e3.63 (m, 3H,
ditosylate (3e4 mg in 300
18F]fluoride containing vial and the mixture was heated at 90 ꢁC for
15 min. Subsequently, a solution of 3i (1e2 mg in 300 L of aceto-
nitrile) was added and the mixture was heated another 15 min at
90 ꢁC. In the final step, azide 16 (1e2 mg in 300
L of acetonitrile)
mL of acetonitrile) was added to the dry
[
m
H-m, NH), 7.78 (d, 3J¼7.8 Hz, H-o); 13C NMR (101 MHz, C6D6):
d
24.1,
m
2
25.0, 26.3 (CH3), 47.6 (C-1), 61.9 (C-6), 67.1 (d, JC,F¼20.6 Hz,
CH2CH2F), 70.9 (C-5), 71.0 (C-4), 72.4 (C-3), 81.5 (d, 1JC,F¼172.3 Hz,
CH2CH2F),103.6,108.3,109.0 (C-2, Cq),114.3 (C-m),129.6 (C-o),161.1
was added and the resulting solution was heated for 15 min at 90 ꢁC.
Samples for analytical radio-TLC/radio-HPLC were taken after cool-
ing to room temperature. Analytical radio-TLC: Rf¼0.51 (petroleum
ether/EtOAc¼2:3); analytical radio-HPLC: tR¼3.58 min (acetonitrile/
water¼60:40).
(C-p), 166.7 (C]O); 19F NMR (376 MHz, C6D6):
d
ꢀ223.8; MS
(MALDI-TOF): m/z 426 (MþþH), 425 (Mþ); Anal. Calcd for:
C21H28FNO7 (425.45): C 59.28, H 6.63; found: C 59.30, H 6.70.
6.3.2. 1-Deoxy-2,3:4,5-di-O-isopropylidene-1-(4-[2-[18F]fluo-
6.2.20. 6-Deoxy-1,2:3,4-di-O-isopropylidene-6-(4-[2-fluoroethoxy]
roethoxy]benzamidyl)-a-D
-fructopyranose ([18F]21). Ethylene dito-
benzamidyl)-
a
-D-galactofuranose (22). Compounds 15 (150 mg,
sylate (2e3 mg in 300 m
L of acetonitrile) was added to the dry [18F]
0.34 mmol) and 18 (116 mg, 0.41 mmol) were dissolved in a 10:1
mixture of DMF/water (1 mL) and heated at 60 ꢁC for 2 h. After-
ward, the solvent was removed and the residue was purified via
column chromatography (petroleum ether/EtOAc¼1:2) to obtain
22 as a colorless solid (95 mg, 66%); mp¼155 ꢁC; Rf¼0.33 (petro-
fluoride containing vial and the mixture was heated at 90 ꢁC for
15 min. Subsequently, a solution of 3i (1e2 mg in 300
nitrile) was added and the mixture was heated another 15 min at
90 ꢁC. In the final step, azide 17 (1e2 mg in 300
L of acetonitrile)
mL of aceto-
m
was added and the resulting solution was heated for 15 min at
90 ꢁC. Samples for analytical radio-TLC/radio-HPLC were taken after
cooling to room temperature. Analytical radio-TLC: Rf¼0.44 (pe-
troleum ether/EtOAc¼1:1); analytical radio-HPLC: tR¼3.11 min
(acetonitrile/water¼40:60).
leum ether/EtOAc¼1:2); 1H NMR (400 MHz, C6D6):
d 1.02 (s, 3H,
CH3), 1.13 (s, 3H, CH3), 1.42 (s, 3H, CH3), 1.48 (s, 3H, CH3), 3.41 (dt,
3
3J¼4.1 Hz, JH,F¼27.6 Hz, 2H, CH2CH2F), 3.52e3.59 (m, 1H, H-6a),
3
3
3.83 (dd, J4,5¼1.6 Hz, J3,4¼7.9 Hz, H-4), 4.01e4.18 (m, 4H, H-2, H-
3
6b, CH2CH2F), 4.26e4.36 (m, 1H, H-5), 4.43 (dd, J2,3¼2,3 Hz,
3J3,4¼7.9 Hz, 1H, H-3), 5.49 (d, 3J¼5.0 Hz, 1H, H-1), 6.29 (br s, 1H,
NH), 6.57 (d, 3J¼8.7 Hz, 2H, H-m), 7.67 (d, 3J¼8.7 Hz, H-o); 13C NMR
Acknowledgements
(101 MHz, C6D6):
d
24.3, 25.0, 26.2, 26.3 (4ꢂ CH3), 41.7 (C-6), 67.0
The Fonds der Chemischen Industrie (FCI) is gratefully ac-
knowledged for financial support. Waldemar Herzog is acknowl-
edged for his great experimental assistance.
2
(C-5), 67.0 (d, JC,F¼20.5 Hz, CH2CH2F), 71.2 (C-2), 71.4 (C-3), 72.0
(C-4), 81.4 (d, 1JC,F¼172.2 Hz, CH2CH2F), 96.9 (C-1), 108.8, 109.3 (2ꢂ

C. Mamat et al. / Tetrahedron 67 (2011) 4521e4529
14. Saxon, E.; Armstrong, J. I.; Bertozzi, C. R. Org. Lett. 2000, 2, 2141e2143.
4529
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