One-pot synthesis of [11C]ureas via triphenylphosphinimines

Article abstract of DOI:10.1002/jlcr.1052

A series of ¹¹C-labeled ureas was prepared using a rapid and efficient one-pot procedure. First, the intermediate [¹¹C] phenylisocyanate was formed with phenyltriphenylphosphinimine and [ ¹¹C]CO₂. A range of amines was then reacted with the [¹¹C]phenylisocyanate yielding the [¹¹C]urea derivatives in short synthesis times. This easy-to-handle method circumvents disadvantages of known procedures and generates the possibility to prepare other kinds of ¹¹C-labeled compounds using a variety of phenylphosphinimines in combination with different nucleophiles. The presented approach is an alternative to the use of established methods in ¹¹C-labeling chemistry. Copyright

Full text of DOI:10.1002/jlcr.1052

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2006; 49: 321–330.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.1052
Research Article
One-pot synthesis of [11C]ureas via
triphenylphosphinimines
Erica W. van Tilburg*, Albert D. Windhorst, Margreet van der Mey and
Jacobus D. M. Herscheid
Department of Nuclear Medicine & PET Research, VU University Medical Center,
De Boelelaan 1085c, 1081 HV Amsterdam, The Netherlands
Summary
A series of 11C-labeled ureas was prepared using a rapid and efficient one-pot
procedure. First, the intermediate [11C]phenylisocyanate was formed with phenyl-
triphenylphosphinimine and [11C]CO2. A range of amines was then reacted with the
[11C]phenylisocyanate yielding the [11C]urea derivatives in short synthesis times. This
easy-to-handle method circumvents disadvantages of known procedures and generates
the possibility to prepare other kinds of 11C-labeled compounds using a variety of
phenylphosphinimines in combination with different nucleophiles. The presented
approach is an alternative to the use of established methods in 11C-labeling
chemistry. Copyright # 2006 John Wiley & Sons, Ltd.
Key Words: [11C]CO2; [11C]isocyanates; phosphinimines; 11C-labeled ureas
Introduction
Positron emission tomography (PET) is a powerful technique for determining
noninvasively the in vivo biodistribution of compounds labeled with positron-
emitting radionuclides. The demand for new radiolabeling methods is growing
with the increasing use of PET throughout drug development processes and
medical imaging. The radioisotope 11C is very valuable for this purpose, since
it permits the radiosynthesis of the native compound. However, one has to
take into account that there is a relative limited number of labeled synthons
(e.g. [11C]CO2, [11C]CH4) or those rapidly prepared from them (e.g.
[11C]CH3I)1 as well as a desire to introduce the radioisotope as late as
possible during the synthesis, because of the half-life of 11C (20.3 min). Since
the molecular complexity and diversity of biologically active compounds have
*Correspondence to: E. W. van Tilburg, Netherlands Cancer Institute (NKI), Division of Cellular
Biochemistry, Chemical Biology (H3), Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
E-mail: e.v.tilburg@nki.nl
Copyright # 2006 John Wiley & Sons, Ltd.
Received 19 December 2005
Revised 2 January 2006
Accepted 2 January 2006

322
E. W. VAN TILBURG ET AL.
increased, there is a need for new and simple methodologies that give access to
11C-labeled pharmaceuticals in short synthesis times and in high yields.
Preferably, these general methodologies are suitable for automation.
A structural element that can often be found in biologically active
compounds is the urea group.2–5 So far, 11C labeling of ureas in the carbonyl
function has been performed mainly starting from [11C]phosgene. In this
paper, an efficient synthesis of [11C]ureas via triphenylphosphinimines and
[11C]CO2 is described. This procedure appeared to be simple and fast and is
therefore a powerful tool to circumvent the disadvantages of established
methods that use phosgene (COCl2) or its substitutes. The scope of this
reaction was demonstrated with a diversity of amines.
Results and discussion
The most common procedure for the synthesis of ureas, with the 11C label in
the carbonyl function, requires the preparation of the intermediate [11C]phos-
gene.6–10 However, [11C]phosgene is obtained via multistep syntheses in
low radiochemical yields and with relatively long reaction times (approx.
20 min).6,8,10 Synthetic routes to isocyanates and ureas with phosgene
substitutes have also been described. Trichloromethyl chloroformate (diphos-
gene)11 was one of the first substitutes affording certain unlabeled isocyanates
in excellent yields. Carbon dioxide has also been used in methods that avoid
the preparation of phosgene, for example, [11C]urea has been prepared via
[11C]cyanamide12 starting from [11C]CO2. More general syntheses of ureas
have been done in three-step-reactions via dehydration of intermediary formed
carbamate salts starting from [11C]- or [14C]CO123,14 or via Mitsunobu
chemistry starting from [12C]CO2.15,16 More recently, [11C]CO has gained
more attention as a radioactive synthon.17,18 Its major drawbacks (low
reactivity and harsh reaction conditions) have been overcome by using
known palladium-catalyzed carbonylation reactions in combination with
[11C]CO,19,20 and selenium-mediated syntheses of 11C-carbamoyl com-
pounds.21 But still, it has been proven to be difficult to trap [11C]CO in a
reaction mixture using conventional methods, i.e. by leading the radioactive
precursor with a carrier gas into a solution.22 Because of the low solubility
of [11C]CO, it has been necessary to develop a specific gas handling system
for the preconcentration of [11C]CO2, the conversion to and recirculation of
[11C]CO.19,21
In this study, phosphinimines (iminophosphoranes)23 were used for the
synthesis of 11C-labeled ureas, to circumvent the mentioned disadvantages of
the described methods (i.e. the relatively large number of reaction steps, the
use of catalysts or reagents such as Pd, Se or Sn reagents, and specific
automation). The preparation of phosphinimines from either azides or
primary amines has been described,24–29 as well as their use in the
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ONE-POT SYNTHESIS OF [11C]UREAS
323
(inter- and intramolecular) synthesis of a variety of compounds.29 The reaction
of triphenylphosphinimines with carbon dioxide (Scheme 1), yielding
isocyanate derivatives under mild conditions,27,30 was particularly interesting.
Here, this concept could be implemented by using [11C]CO2 instead of CO2,
for the development of a new and simple alternative method for labeling
[11C]ureas. Furthermore, a large versatility can be created since the
phosphinimine of either the R–NH2 or the R0–NH2 can be prepared,
depending on the ease of its preparation.
Triphenylphosphinimines have been described to have great differences in
properties, from extremely hygroscopic and air sensitive to very stable
(resonance-stabilized) ones.24,26,28,30 Because of its stability26 and commer-
cially availability, phenyltriphenylphosphinimine (1, Scheme 2) was selected as
the model phosphinimine to investigate the radiochemical scope of this
method. The general idea was to react 1 with [11C]CO2 to obtain the
11C-labeled intermediate phenylisocyanate [11C]2, which in turn can react with
different amines (R0–NH2) to form the desired [11C]urea derivatives.
The formation of the [11C]phenylisocyanate ([11C]2) intermediate was
explored first. Compound [11C]2 was not isolated however, but with the aid
of benzylamine (R0=CH2C6H5, Scheme 2) the radiochemical yield of the
11C-labeled urea derivative was used as indication. [11C]CO2 was bubbled
through a solution of 1 (19.6 mmol) in benzene at 158C. This way, less than 5%
of the [11C]CO2 was trapped in the reaction vial. Tetrahydrofuran (THF) was
then tried as solvent, but still almost no [11C]CO2 was trapped at 158C. Using
THF in combination with a low trapping temperature of ꢀ608C solved this
problem (>80% of the [11C]CO2 in the vial). After trapping the [11C]CO2, the
mixture was heated for 6 min at 908C (formation of [11C]2), and finally
24,25,30
Scheme 1. Reaction of triphenylphosphinimines with CO2
Scheme 2. General scheme for the radiochemical synthesis of [11C]ureas starting
from [11C]CO2
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324
E. W. VAN TILBURG ET AL.
benzylamine was added (13 mmol) after which the solution was heated for
another 3 min at 358C. Urea [11C]4a was obtained in a 33% overall yield.
Subsequently, a further simplification of the reaction conditions was
explored. The possibility of having benzylamine already present in the
reaction vial, together with 1, before the trapping of the [11C]CO2, was
investigated. This way, the formed isocyanate ([11C]2) could react immediately
with the amine, possibly speeding up the reaction (Table 1). The radioactivity
was now trapped quantitatively in the vial (>99%), using THF at ꢀ608C. An
explanation could be the formation of a complex between the [11C]CO2 and
the amine,16 or the increased basicity of the solution due to the amine. The
initial reaction temperature was chosen similar to that used earlier for the
formation of [11C]2 (908C, see Scheme 2), and these conditions gave the labeled
urea [11C]4a in a radiochemical yield of 44% (Table 1, entry 1).
With an elevated reaction temperature (1108C, Table 1, entry 2) it seemed
that more product was formed in the solution. However, part of the [11C]CO2
evaporated from the solution and this caused an overall (small) decrease in the
radiochemical yield. In fact, a reaction temperature of 608C gave a comparable
overall radiochemical yield of [11C]4a, since more [11C]CO2 stayed in solution
and was therefore available to react with 1 (entry 3). A reaction temperature of
only 218C decreased the radiochemical yield considerably (entry 4). Analyses
of all final reaction mixtures showed that the remainder of radioactivity was
mainly unreacted [11C]CO2, however, prolonged reaction times did not have a
beneficial effect on the overall yields. So, trapping the [11C]CO2 at ꢀ608C in a
reaction vial containing both 1 and the amine in THF, with a subsequent
reaction temperature of 608C (6 min), appeared to be the most optimal
conditions for the synthesis of [11C]4a.
To explore the scope of this concept, the following other amines (R0–NH2)
were selected: aniline (3b), n-propylamine (3c) and 5-methoxy-tryptamine (3d).
The latter amine was chosen with the view to prepare its biologically active
Table 1. Optimization of the one-pot reaction conditions
1) -60˚C, [11C]CO2
2) T ˚C
O
H2N
1
+
N
N
*
H
H
* = 11
C
3a
T (8C)
[
11C] 4a
Entrya
Time (min)
%b [11C]4a
1
2
3
4
90
110
60
6
6
6
6
44
43
45
21
21
a 19.6 mmol 1 and 73 mmol 3a were used, in 600 ml THF.
b Overall decay-corrected yield from [11C]CO2.
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ONE-POT SYNTHESIS OF [11C]UREAS
325
derivative in the future, since ureas containing a tryptamine moiety have been
shown to act as antagonists to the melatonin receptor.5 For identification
purposes of the radiolabeled compounds, the unlabeled reference compounds
were synthesized as well (4a-d, see Table 2 for corresponding labeled
compounds). The asymmetric unlabeled ureas were obtained in good overall
yields (70–90%) by reaction of phenylisocyanate with the corresponding
primary amines in ether (rt, 0.5–3 h), according to a known literature
procedure.5 The labeled compounds [11C]4b-d were synthesized under the same
reaction conditions that were used for preparing [11C]4a, without further
optimization (Table 2). The aliphatic amines 3c and 3d displayed a similar
behavior as our model amine 3a, and [11C]4c and [11C]4d were synthesized in
overall radiochemical yields of 49 and 45%, respectively. As expected, the
aromatic aniline 3b was less reactive under these conditions, giving [11C]4b in
a low yield of 8%.
In summary, [11C]ureas 4a-d were efficiently synthesized in an one-pot
procedure, with decay-corrected yields ranging from 8 to 49%. This fast,
simple and reproducible method includes leading the [11C]CO2 through a
solution of phenyltriphenylphosphinimine (1) and the amine of interest in
THF at ꢀ608C, and a subsequent reaction temperature of 608C for 6 min. In
theory, a large number of triphenylphosphinimines can be used to form
Table 2. Radiosynthesis of the 11C-labeled ureas
O
1) -60˚C, [11C]CO2
2) 60˚C, 6 min
R'
1
+
H2N
R'
N
N
*
H
H
* = 11
C
3a-d
[11C]4a-d
b
%
Amine
R0
mmola
Product
3a
73
[11C]4a
46 ꢁ 4
3b
66
[11C]4b
8 ꢁ 1
3c
3d
120
13
[11C]4c
[11C]4d
49 ꢁ 3
45 ꢁ 3
OMe
N
H
a 3a-d (all amines in excess compared to [11C]CO2)+1 (19.6 mmol) in 600 ml THF.
b Decay-corrected radiochemical yields from [11C]CO2 (n ¼ 3).
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326
E. W. VAN TILBURG ET AL.
intermediate [11C]isocyanates using [11C]CO2. In fact, by using azides for the
preparation of phosphinimines, a large variety of chemical structures can be
chosen for R (or R0, depending on the starting point of the synthesis route,
Scheme 1). Although not explored in this paper, it is obvious that other
variations on the presented method may be possible as well. For example, the
application of resin-bound triphenylphosphinimines,27 subjection of amines
on solid support31,32 to the intermediate [11C]isocyanate, as well as the use of a
wide range of other nucleophiles that can lead to compounds other than ureas
(i.e. thiols,33–35 alkynes,36,37 or alcohols/acids38–41). So, the present method
generates great possibilities for the preparation of a large number of different
11C-labeled compounds that can be prepared from [11C]isocyanates, obtained
from the reaction of triphenylphosphinimines with [11C]CO2.
Experimental
General methods
Unless otherwise stated, all chemical reagents were purchased from Aldrich.
Solvents were purified and dried by standard procedures before use. Thin-layer
chromatography (TLC) was carried out using aluminum sheets (20 ꢂ 20 cm)
with silica gel F254 from Merck. Spots were visualized under UV (254 nm).
1H- and 13C-NMR spectra were recorded on a Bruker AC-200 or a MSL 400
spectrometer. Chemical shifts (d) were determined relative to the solvent and
converted to the tetramethylsilane scale using d=2.52 ppm for DMSO-d6.
[11C]Carbon dioxide was produced by the 14N(p,a)11C nuclear reaction using
an IBA 18/9 cyclone (dimethylsulfoxide: DMSO; tetrahydrofuran: THF;
N,N-dimethylformamide: DMF).
Synthesis of the reference urea derivatives. General procedure
The appropriate amine (0.26 mmol) was dissolved in 400–600 ml ether.
Phenylisocyanate (0.32 mmol) was added and the solution was stirred for
0.5–3 h at room temperature. The formed white precipitate was filtered off,
washed with ether and dried. The products were analyzed by two different
HPLC systems: A: Kromasil 100 RP C18 column (250 ꢂ 4.6 mm; CH3CN/
H2O 40/60, 1 ml/min), and system B: RP-Select B C8, 5 mm column
(150 ꢂ 4.6 mm; MeOH/H2O 45/55, 1 ml/min); both systems with UV=221
and 254 nm.
1-benzyl-3-phenylurea (4a). Benzylamine (3a, 0.26 mmol, 29 ml) and phenyli-
socyanate (0.32 mmol, 35 ml) were used. Yield 48 mg (0.21 mmol, 82%).
1H NMR (200 MHz, DMSO-d6) d 8.58 (bs, 1H, CH2NH), 7.43–7.18 (m, 9H,
o- and m-arom, NH), 6.90 (t, 1H, J ¼ 7:20 Hz, p-benzyl), 6.63 (t, 1H,
J ¼ 6:80 Hz, p-phenyl), 4.30 (d, 2H, J ¼ 5:90 Hz, CH2) ppm,
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ONE-POT SYNTHESIS OF [11C]UREAS
327
13C NMR (50 MHz, DMSO-d6) d 157.8, 141.2, 138.6, 129.3, 128.4, 128.1,
126.8, 120.8, 117.4, 42.5 ppm. Analytically calculated for C14H14N2O: C,
74.31; H, 6.24; N, 12.38. Found: C, 74.25; H, 6.25; N, 12.31. M.p. 174–1768C.
System A: retention time of 16.7 min; system B: retention time of 13.6 min.
1,3-diphenylurea (4b). Aniline (3b, 0.26 mmol, 24 ml) and phenylisocyanate
(0.32 mmol, 35 ml) were used. Yield 38 mg (0.18 mmol, 70%). 1H NMR
(200 MHz, DMSO-d6) d 8.82–8.58 (bs, 2H, NH), 7.60–7.09 (m, 6H, phenyl),
7.09–6.81 (m, 4H, phenyl) ppm. 13C NMR (50 MHz, DMSO-d6) d 152.6,
140.2, 128.6, 121.6, 117.9 ppm. Analytically calculated for C13H12N2O: C,
73.57; H, 5.70; N, 13.20. Found: C, 73.29; H, 5.63; N, 13.03. M.p. 251–2538C.
System A: retention time of 21.0 min; system B: retention time of 13.9 min.
1-phenyl-3-propylurea (4c). n-Propylamine (3c, 0.26 mmol, 22 ml) and pheny-
lisocyanate (0.32 mmol, 35 ml) were used. Yield 42 mg (0.23 mmol, 90%).
1H NMR (200 MHz, DMSO-d6) d 8.41 (bs, 1H, NH), 7.51–6.78 (m, 5H,
phenyl), 6.19 (bs, 1H, NH), 3.19–2.92 (m, 2H, NHCH2), 1.62–1.30 (m, 2H,
CH2CH3), 1.06–0.72 (m, 3H, CH3) ppm. 13C NMR (50 MHz, DMSO-d6) d
151.3, 134.9, 128.3, 120.5, 117.2, 40.5, 22.6, 10.9 ppm. Analytically calculated
for C10H14N2O: C, 67.39; H, 7.92; N, 15.72. Found: C, 67.29; H, 7.83;
N, 15.58. M.p. 115–1178C. System A: retention time of 8.4 min; system B:
retention time of 6.9 min.
N-[2-(5-methoxy-1H-indol-3-yl)-ethyl]-benzamide (4d). 5-methoxy-tryptamine
(3d, 0.26 mmol, 50 mg) and phenylisocyanate (0.32 mmol, 35ml) were used.
Yield 60mg (0.19 mmol, 73%). 1H NMR (200MHz, DMSO-d6) d 10.69 (s, 1H,
NH), 8.50 (s, 1H, NH), 7.41–6.73 (8H, arom), 6.19–6.07 (m, 1H, phenyl), 3.74
(s, 3H, CH3), 3.48–3.30 (m, 2H, CH2NH), 2.82 (t, 2H, CH2CH2NH,
J ¼ 7:41 Hz) ppm. 13C NMR (50MHz, DMSO-d6) d 159.3, 153.3, 136.66,
132.4, 130.1, 128.7, 122.3, 120.6, 117.4, 111.4, 111.2, 101.9, 97.9, 55.5, 40.7,
24.6 ppm. Analytically calculated for C18H19N3O2: C, 69.88; H, 6.19; N, 13.58.
Found: C, 69.63; H, 6.00; N, 13.32. M.p. 80–828C. System A: retention time of
8.3 min; system B: retention time of 9.4 min.
Synthesis of 11C-labeled ureas. General procedure
The (dry) silicone septum sealed reaction vial was charged with phenyltriphe-
nylphosphinimine (1, 19.6 mmol, 7 mg) and the appropriate amine, dissolved in
600 ml of dry THF, cooled to ꢀ608C and purged with helium. The [11C]CO2
was transferred to the reaction vial via a helium carrier gas (10 ml/min). The
amount of [11C]CO2 trapped usually was >99% and varied in these
experiments between 5 and 7 GBq. After obtaining maximum radioactivity
in the vial, the carrier gas was switched off, needles were removed and the vial
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E. W. VAN TILBURG ET AL.
was heated at 608C for 6 min and then cooled to 218C. The product was
analyzed and identified by two different HPLC systems: A: Kromasil 100 RP
C18 column (250 ꢂ 4.6 mm; CH3CN/H2O 40/60, 1 ml/min), and system B:
RP-Select B C8, 5 mm column (150 ꢂ 4.6 mm; MeOH/H2O 45/55, 1 ml/min);
both systems with UV ¼ 221 and 254 nm and homemade radioactivity
detection (Na(I)). The radiochemical yields were determined based on the
HPLC chromatograms. In all cases, the retention time of the unreacted
[11C]CO2 was 6.2 min (A) or 4.5 min (B).
1-benzyl-3-phenyl-[11C]urea ([11C]4a). Benzylamine (3a, 8 ml, 73 mmol) was
used. System A: retention time of 16.7 min; system B: retention time of
13.6 min; both corresponding to 4a, thereby confirming its identity. The
overall decay-corrected radiochemical yield was 46 ꢁ 4% (n ¼ 3).
1,3-diphenyl-[11C]urea ([11C]4b). Aniline (3b, 6 ml, 66 mmol) was used.
System A: retention time of 21.0 min; system B: retention time of 13.9 min;
both corresponding to 4b, thereby confirming its identity. The overall decay-
corrected radiochemical yield was 8 ꢁ 1% (n ¼ 3).
1-phenyl-3-propyl-[11C]urea ([11C]4c). n-Propylamine (3c, 10 ml, 120 mmol)
was used. System A: retention time of 8.4 min; system B: retention time of
6.9 min; both corresponding to 4c, thereby confirming its identity. The overall
decay-corrected radiochemical yield was 49 ꢁ 3% (n ¼ 3).
N-[2-(5-methoxy-1H-indol-3-yl)-ethyl]-benz[11C]amide ([11C]4d). 5-Methoxy-
tryptamine (3d, 2.4mg, 13mmol) was used. System A: retention time of 8.3 min;
system B: retention time of 9.4 min; both corresponding to 4d, thereby confirming
its identity. The overall decay-corrected radiochemical yield was 45 ꢁ 3%
(n ¼ 3).
References
1. Langstrom B, Kihlberg T, Bergstrom M, Antoni G, Bjorkman M, Forngren BH,
¨ ¨ ¨
Forngren T, Hartvig P, Markides K, Yngve U, Ogren M. Acta Chem Scand 1999;
53: 651–669.
2. Abe Y, Kayakiri H, Satoh S, Inoue T, Sawada Y, Imai K, Inamura N, Asano M,
Hatori C, Katayama A, Oku T, Tanaka H. J Med Chem 1998; 41: 564–578.
3. Black SL, Jales AR, Brandt W, Lewis JW, Husbands SM. J Med Chem 2003; 46:
314–317.
4. Huang HC, Reitz DB, Chamberlain TS, Olins GM, Corpus VM, McMahon EG,
Palomo MA, Koepke JP, Smits GJ, McGraw DE, Blaine EH, Manning RE.
J Med Chem 1993; 36: 2172–2181.
5. Leclerc V, Fourmaintraux E, Depreux P, Lesieur D, Morgan P, Howell HE,
Renard P, Caignard D-H, Pfeiffer B, Delagrange P, Guardiola-Lemaıtre B,
Andrieux J. Bioorg Med Chem 1998; 6: 1875–1887.
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 321–330

ONE-POT SYNTHESIS OF [11C]UREAS
329
6. Crouzel C, Roeda D, Berridge M, Knipper R, Comar D. Int J Appl Radiat Isot
1983; 34: 1558–1559.
7. Crouzel C, Hinnen F, Maitre E. Appl Radiat Isot 1995; 46: 167–170.
8. Roeda D, Westera G. Int J Appl Radiat Isot 1981; 32: 931–932.
9. Babad H, Zeiler AG. Chem Rev 1973; 73: 75–91.
10. Landais P, Crouzel C. Appl Radiat Isot 1987; 38: 297–300.
11. Nowakowski J. J Prakt Chem 1992; 334: 187–189.
12. Kruijer PS, van Leuffen PJ, Herscheid JDM. Appl Radiat Isot 1996; 47: 611–616.
13. Dean DC, Wallace MA, Marks TM, Melillo DG. Tetrahedron Lett 1997; 38:
919–922.
14. Schirbel A, Holschbach MH, Coenen HH. J Label Compd Radiopharm 1999; 42:
537–551.
15. Horvath MJ, Saylik D, Elmes PS, Jackson WR, Lovel CG, Moody K.
Tetrahedron Lett 1999; 40: 363–366.
16. Saylik D, Horvath MJ, Elmes PS, Jackson WR, Lovel CG, Moody K. J Org
Chem 1999; 64: 3940–3946.
17. Doi H, Barletta J, Suzuki M, Noyori R, Watanabe Y, Langstrom B. Org Biomol
¨
Chem 2004; 2: 3063–3066.
18. Rahman O, Kihlberg T, Langstrom B. Org Biomol Chem 2004; 2: 1612–1616.
¨
19. Lidstrom P, Kihlberg T, Langstrom B. J Chem Soc Perkin Trans 1 1997; 18:
¨
2701–2706.
20. Rahman O, Kihlberg T, Langstrom B. J Org Chem 2003; 68: 3558–3562.
¨
21. Kihlberg T, Karimi F, Langstrom B. J Org Chem 2002; 67: 3687–3692.
¨
22. Brichard L, Del Fiore G, Lemaire C, Plenevaux A, Luxen A. J Label Compd
Radiopharm 2003; 46: S74.
23. Staudinger H, Meyer J. Helv Chim Act 1919; 2: 635–646.
24. Zimmer H, Jayawant M, Gutsch P. J Org Chem 1970; 35: 2826–2828.
25. Horner L, Oediger H. J Liebigs Ann Chem 1959; 627: 142–162.
26. Zimmer H, Singh G. J Org Chem 1964; 29: 1579–1581.
27. Molina P, Aller E, Lorenzo A, Lopez-Cremades P, Rioja I, Ubeda A,
Terencio MC, Alcaraz MJ. J Med Chem 2001; 44: 1011–1014.
28. Zimmer H, Singh G. J Org Chem 1963; 28: 483–486.
29. Molina P, Vilaplana MJ. Synthesis 1994; 12: 1197–1218.
30. Molina P, Alajarin M, Arques A. Synthesis 1982; 07: 596–597.
31. Park KH, Kurth MJ. Tetrahedron Lett 2000; 41: 7409–7413.
32. Boeijen A, Kruijtzer JAW, Liskamp RMJ. Bioorg Med Chem Lett 1998; 8:
2375–2380.
33. Beji M, Sbihi H, Baklouti A, Cambon A. J Fluor Chem 1999; 99: 17–24.
34. Cinque GM, Szajnman SH, Zhong L, Docampo R, Schvartzapel AJ, Rodriguez
JB, Gros EG. J Med Chem 1998; 41: 1540–1554.
35. Yamaguchi T, Harada N, Ozaki K, Hayashi M, Arakawa H, Hashiyama T.
Tetrahedron 1999; 55: 1005–1016.
36. D’hooge M, Van Brabandt W, De Kimpe N. J Org Chem 2004; 69: 2703–2710.
37. Lebreton S, Xie XS, Ferguson D, De Brabander JK. Tetrahedron 2004; 60:
9635–9647.
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 321–330

330
E. W. VAN TILBURG ET AL.
38. Barrett DG, Catalano JG, Deaton DN, Hassell AM, Long ST, Miller AB, Miller
LR, Shewchuk LM, Wells-Knecht KJ, Willard DH, Wright LL. Bioorg Med
Chem Lett 2004; 14: 4897–4902.
39. Galeazzi R, Martelli G, Mobbili G, Orena M, Rinaldi S. Org Lett 2004; 6:
2571–2574.
40. Murakami N, Kawanishi M, Itagaki S, Horii T, Kobayashi M. Bioorg Med Chem
Lett 2004; 14: 3513–3516.
41. Tiecco M, Testaferri L, Temperini A, Bagnoli L, Marini F, Santi C. Chem – Eur J
2004; 10: 1752–1764.
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 321–330