No-carrier-added radioiodination of triolborates, water-soluble complexes of boronic acids

Article abstract of DOI:10.1002/jlcr.1831

A convenient and rapid synthesis of iodine-123 labeled aryl and heteroaryl iodides from water-soluble complexes of aryl- and heteroarylboronic acids has been developed. Copyright

Full text of DOI:10.1002/jlcr.1831

Research Article
Received 6 May 2010,
Revised 6 August 2010,
Accepted 11 August 2010
Published online 30 November 2010 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.1831
No-carrier-added radioiodination
of triolborates, water-soluble
complexes of boronic acids
Ã
Murthy R. Akula,a Min-Liang Yao,a and George W. Kabalkaa,b
A convenient and rapid synthesis of iodine-123 labeled aryl and heteroaryl iodides from water-soluble complexes of
aryl- and heteroarylboronic acids has been developed.
Keywords: triolborates; iodoarenes; arylboronic acids; Na123I; chloramine-T
while azeotropically removing water to obtain boronate esters
3. The crude esters were then treated with potassium hydroxide
to afford the cyclic triolborates 4.
The radioiodination of triolborates 4 with no-carrier-added,
iodine-123 labeled sodium iodide and chloramine-T in a
solvent mixture of THF:H2O (1:1) provided radioiodinated
arenes 5.
Introduction
Electrophilic halogenation is one of the widely used approaches
for preparing radiohalogenated tracers. The choice of a radio-
tracer precursor depends on a number of factors: ideally, it
should be non-toxic, environmentally friendly, efficiently under-
go halogenation, and be amenable to rapid isolation. Over the
years, we have investigated the use of organoborane reagents
as precursors to radiopharmaceuticals because boron is non-
toxic when compared with tin, mercury, and other metals.1 Our
recent efforts include the utilization of organoboronate esters2,3
and potassium organotrifluoroborates4–6 as starting materials in
the preparation of radiohalogenated aryl and vinyl compounds.
The recent development of novel cyclic triolborates7 prompted
us to investigate the use of these water-soluble and air-stable
crystalline solids as potential precursors in radioiodination
reactions. We wish to report the facile preparation of no-carrier-
added iodine-123 labeled aryl and heteroaryl iodides from
organotriolborates esters using the reaction of these water-
soluble complexes of arylboronic acids with Na123I in the presence
of a mild oxidant, chloramine-T. The water solubility of these
organoborate complexes is significant since the radiolabeled
product can be rapidly separated from excess starting material by
simply extracting the product into an organic solvent.
O
Na 123
I
-
123
Ar
B
I
Ar
O
Chloramine-T
THF:H2O
K+ O
4
5
A variety of iodine-123 labeled iodoarenes was prepared from
corresponding aryltriolborates. The results of these no-carrier-
added iodinations are summarized in Table 1. The new
chemistry is tolerant of a wide range of functional groups and
provides the radioiodinated products in good to excellent yields.
Substrates containing electron-donating groups undergo iodi-
nation rapidly at ambient temperature. Those containing
electron-withdrawing groups require longer reaction times
and higher temperatures. Ortho substituents do not sterically
influence the reaction, which takes place in very high yield
(entry 10). Heteroaryltriolborates also smoothly undergo radio-
iodination (entry 8).
OH
OH
OH
O
O
OH
O
-
Toluene
KOH/Toluene
-H2O
Ar
B
Ar B
+
Ar
B
O
K+ O
Reflux; -2H2O
OH OH
1
2
3
4
aDepartment of Radiology, The University of Tennessee, Knoxville, TN 37996-
1600, USA
Chemistry
bDepartment of Chemistry, The University of Tennessee, Knoxville, TN 37966-
1600, USA
Commercially available boronic acids 1 were conveniently
converted to the corresponding triolborates, 4, according to
the literature procedure.7 The aryl- or heteroarylboronic acids 1
and 1,1,1-tris(hydroxymethyl)ethane, 2, were refluxed in toluene
*Correspondence to: George W. Kabalka, Department of Chemistry and
Radiology, The University of Tennessee, Knoxville, TN, USA.
E-mail: kabalka@utk.edu
J. Label Compd. Radiopharm 2010, 54 132–134
Copyright r 2010 John Wiley & Sons, Ltd.

M. R. Akula et al.
Table 1. Synthesis of I-123 Labeled Aryl Iodides from Triolborates
Entry
1
Substrate
Product
Time (min)
20
Yield (%)
75a
O
123
-
I
B
O
K+
O
2
3
4
5
6
20
20
30
30
90
89a
85a
68b
64b
52b
O
123
-
I
OMe
Me
MeO
Me
B
O
K+
O
O
123
-
I
B
O
K+
O
O
123
-
I
CN
NC
B
O
K+
O
O
123
-
I
COOMe
NO2
MeOOC
O2N
B
O
K+
O
O
-
123
B
I
O
K+
O
7
8
20
20
80a
72a
O
123
-
I
Ph
Ph
B
O
K+
O
S
123
O
I
-
B
O
K+
S
O
9
20
20
86a
80a
O
-
123
I
B
O
K+
O
10
O
-
123
B
I
O
K+
O
aThe reaction was carried out at RT.
bThe reaction was carried out at 501C.
5000
4500
4000
3500
3000
2500
2000
1500
1000
500
Experimental
123
I
MeO
Preparation of potassium 4-methoxyphenyltriolborate
(representative procedure)
4-Methoxyphenylboronic acid (0.46 g, 3.0 mmol) and 1,1,1-tris
(hydroxymethyl)ethane (0.36 g, 3.0 mmol) were mixed in toluene
(6mL). Water was removed azeotropically over a 4 h period using
a Dean Stark trap. The solvent was then removed to obtain the
crude boronate ester. The crude boronate ester and KOH (0.16 g,
2.8 mmol) were suspended in toluene (5mL) and the mixture was
heated at reflux for 4 h while removing water using a Dean Stark
apparatus. The precipitated potassium triolborate was collected
by filtration, thoroughly washed with acetone (2Â 5 mL), and
dried under reduced pressure to afford potassium p-methox-
yphenyltriolborate as a white crystalline solid. Yield = 0.35g; 45%.
1H NMR (250MHz), DMSO-d6: d = 0.46 (s, 3H), 3.55 (s, 6H), 3.64
(s, 3H), 6.55 (d, 2H, J = 7.5 Hz) and 7.22 (d, 2H, J = 7.5 Hz). 13C NMR
(250MHz), DMSO-d6: d = 16.3, 54.4, 73.6, 111.2, 133.0, 156.6.
0
0
20
40
60
80
100
120
mm
Figure 1. Radio-TLC of 4-[123I]iodoanisole.
123I (37 MBq in 0.1% aqueous NaOH; MDS Nordion, Vancouver,
Canada) in a 1 mL Wheaton vial. To this stirred mixture was
added chloramine-T (58 mL of a 6.60 Â 10À3 solution in 50%
aqueous THF). The mixture was stirred at room temperature for
20 min, quenched with a drop of aqueous 10% sodium
thiosulfate, and the product was extracted into 300 mL of
EtOAc:hexane (1:1 by volume). The organic layer was separated,
Preparation of 4-[123I]Iodoanisole (representative iodination
procedure)
Potassium 4-methoxyphenyltriolborate (100 mL of a 3.62 Â 10À3
solution in 50% aqueous THF) was added to no-carrier-added Na
J. Label Compd. Radiopharm 2010, 54 132–134
Copyright r 2010 John Wiley & Sons, Ltd.
www.jlcr.org

M. R. Akula et al.
passed through a silica gel Sep-Pak cartridge, and the product Cole Foundation for support of this research. We also wish to
was isolated using hexane:ethyl acetate (9:1) as an eluant. The thank Frontier Scientific, Inc. for supplying many of the
radiochemical purity (99%) was determined by radio-TLC (Figure 1; boronated precursors.
Bioscan, Inc. Washington, D.C.) using an aluminum-backed silica
gel plate and hexane:EtOAc (9:1 by volume) as an eluent; RF =0.76.
The radiochemical yield was 0.89mCi (33MBq, 89%).
References
Conclusion
[1] G. Kabalka, R. Verma, Tetrahedron 1989, 45, 6601.
[2] G. Kabalka, M. Akula, J. Zhang, Nucl. Med. Biol. 2002, 29,
841–843.
[3] G. Kabalka, M. Akula, J. Zhang, Nucl. Med. Biol. 2003, 30,
369–372.
[4] G. Kabalka, A. Mereddy, J. Label. Compd. Radiopharm. 2005, 48,
359–362.
[5] G. Kabalka, A. Mereddy, J. Green, J. Label. Compd. Radiopharm.
2006, 49, 11–15.
In conclusion, a convenient method for efficiently preparing
radioiodinated aryl and heteroaryl iodides from potassium aryl-
and heteroaryltriolborates has been developed. The water
solubility of the triolborates contributes to the rapid isolation
and purification of the radiolabeled products.
Acknowledgement
[6] G. Kabalka, G. Tang, A. Mereddy, J. Label Compd. Radiopharm.
2007, 50, 446–447.
We wish to thank the US Department of Energy, the Molecular
Imaging and Translational Research Program, and the Robert H.
[7] Y. Yamamoto, M. Takizawa, X. Yu, N. Miyaura, Angew. Chem. 2008,
47, 928–931.
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Copyright r 2010 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2010, 54 132–134